Activating Agents and Protecting Groups Handbook of Reagents For Organic Synthesis

Handbook of Reagents
for Organic Synthesis
Activating Agents and

Protecting Groups
Edited by
Anthony J. Pearson
Case Western Reserve
University
and
William R. Roush
University of Michigan
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Library of Congress Cataloguing-in-Publication Data
Handbook of reagents for organic synthensis.
p. cm
Includes bibliographical references.
Contents: [1] Reagents, auxiliaries, and catalysts for C-C bond
formation / edited by Robert M. Coates and Scott E. Denmark
[2] Oxidising and reducing agents / edited by Steven D. Burke and
Riek L. Danheiser [3] Acidic and bacic reagents / edited by
Hans J. Reich and James H. Rigby [4] Activating agents and
protecting groups / edited by Anthony J. Pearson and William R. Roush
ISBN 0-471-97924-4 (v. 1) ISBN 0-471-97926-0 (v. 2)
ISBN 0-471-97925-2 (v. 3) ISBN 0-471-97927-9 (v. 4)
1. Chemical tests and reagents. 2. Organic compounds-Synthesis.
QD77.H37 1999
547'.2 dc 21
98-53088
CIP
British Library Cataloguing in Publication Data
A catalogue record for this book is available from the British Library
ISBN 10: 0-471-97927-9 (H/B)
ISBN 13: 978-0-471-97927-2 (H/B)
Typeset by Thompson Press (India) Ltd., New Delhi
Printed and bound in Great Britain by Antony Rowe Ltd, Chippenham, Wiltshire.
This book is printed on acid-free paper responsibly manufactured from sustainable forestry
in which at least two trees are planted for each one used for paper production.
Editorial Board
Editor-in-Chief
Leo A. Paquette
The Ohio State University, Columbus, OH, USA
Editors
Scott E. Denmark
University of Illinois
at Urbana-Champaign, IL,
USA
Robert M. Coates
University of Illinois
at Urbana-Champaign, IL
USA
Rick L. Danheiser
Massachusetts Institute of
Technology, Cambridge, MA,
USA
David J. Hart
The Ohio State University
Columbus, OH, USA
Lanny S. Liebeskind
Emory University
Atlanta, GA, USA
Dennis C. Liotta
Emory University
Atlanta, CA, USA
Anthony J. Pearson
Case Western Reserve
University, Cleveland, OH, USA
Hans J. Reich
University of Wisconsin
at Madison, WI, USA
Steven D. Burke
University of Wisconsin
at Madison, WI, USA
James H. Rigby
Wayne State University
Detroit, MI, USA
William R. Roush
MI, USA
Assistant Editors
James P. Edwards
Ligand Pharmaceuticals
San Diego, CA, USA
Mark Volmer
Emory University
Atlanta, GA, USA
International Advisory Board

Leon A. Ghosez
Universit Catholique
de Louvain, Belgium
Jean-Marie Lehn
Universit Louis Pasteur
Strasbourg, France
Steven V. Ley
University of Cambridge
UK
Chun-Chen Liao
National Tsing Hua
University, Hsinchu, Taiwan
Lewis N. Mander
Australian National
University, Canberra
Australia
Giorgio Modena
Universit di Padua
Italy
Ryoji Noyori
Nagoya University, Japan
Pierre Potier
CNRS, Gif-sur-Yvette
France
Hishashi Yamomoto
Nagoya University, Japan
Gerald Pattenden
University of Nottingham
UK
Edward Piers
University of British
Columbia, Vancouver
Canada
W. Nico Speckamp
Universiteit van Amsterdam
The Netherlands
Ekkehard Winterfeldt
Universitt Hannover
Germany
Managing Editor
Colin J. Drayton
Woking, Surrey, UK
Preface
As stated in its Preface, the major motivation for our under
taking publication of the Encyclopedia of Reagents for
Organic Synthesis was "to incorporate into a single work
a genuinely authoritative and systematic description of the
utility of all reagents used in organic chemistry." By all
accounts, this reference compendium has succeeded admir
ably in attaining this objective. Experts from around the
globe contributed many relevant facts that define the var
ious uses characteristic of each reagent. The choice of a
masthead format for providing relevant information about
each entry, the highlighting of key transformations with
illustrative equations, and the incoroporation of detailed
indexes serve in tandem to facilitate the retrieval of desired
information.
Notwithstanding these accomplishments, the editors have
since recognized that the large size of this eight-volume
work and its cost of purchase have often served to deter
the placement of copies of the Encyclopedia in or near
laboratories where the need for this type of insight is most
critically needed. In an effort to meet this demand in a costeffective manner, the decision was made to cull from the
major work that information having the highest probability
for repeated consultation and to incorporate same into a set
of handbooks. The latter would also be purchasable on a
single unit basis.
The ultimate result of these deliberations is the publica
tion of the Handbook of Reagents for Organic Synthesis
consisting of the following four volumes:
Reagents, Auxiliaries and Catalysts for C-C Bond

Formation
Edited by Robert M. Coates and Scott E. Denmark
Oxidizing and Reducing Agents
Edited by Steven D. Burke and Rick L. Danheiser
Acidic and Basic Reagnets
Edited by Hans J. Reich and James H. Rigby
Activating and Protecting Groups
Edited by Anthony J. Pearson and William R. Roush
Each of the volumes contains a complete compilation of
those entries from the original Encyclopedia that bear on
the specific topic. Ample listings can be found to function
ally related reagents contained in the original work. For the
sake of current awareness, references to recent reviews and
monographs have been included, as have relevant new pro
cedures from Organic Syntheses.
The end product of this effort by eight of the original
editors of the Encyclopedia is an affordable, enlightening
set of books that should find their way into the laboratories
of all practicing synthetic chemists. Every attempt has been
made to be of the broadest synthetic relevance and our
expectation is that our colleagues will share this opinion.
Leo A. Paquette
Columbus, Ohio USA
Introduction
The combination of reagents included in this volume

reflects the fact that protecting groups and activation pro
cedures are often used in combination, one example being
in peptide synthesis, where an amino group of one amino
acid component must be blocked before its carboxylic acid
is activated for coupling with a second amino acid to form
the amide bond. There are many other instances in the
synthesis of natural and unnatural products, pharmaceuti
cals, oligosaccharides, and oligonucleotides, etc., where
similar tactics must be employed to prevent undesired acti
vation or reaction of functionality, such as hydroxyl, when
more than one such group is present, or to prevent reactive
functional groups from entering into unwanted reactions
with oxidizing agents, reducing agents, or organometallic
reagents commonly employed in organic synthesis. Accord
ingly, the most important reagents used to protect amines,
alcohols, carboxyl, carbonyl and other reactive functional
groups are included in this volume.
The selection of activating reagents includes both well
known and less traditional ones. Thus, typical peptide cou
pling reagents that activate carboxylic acids, such as dicyclohexylcarbodiimide, are listed in this volume, in addition
to reagents that are not immediately identified as activators.
One example of the latter is hexacarbonylchromium, which
may be used to activate aromatic substrates toward nucleophilic addition and substitution, via the formation of arenechromium tricarbonyl complexes. Another example is nonacarbonyldiiron, which can serve multiple purposes in acti
vating alkenes and dienes toward nucleophilic attack, or
allowing their conversion to cationic allyl- or dienyl- com
plexes, as well as protecting the same functionality from
reactions such as hydroboration, Diels-Alder cycloadditions,
etc. Transition metal systems that perform these types of
functions could have formed a separate volume if one
includes catalytic processes under the heading of activation.
To avoid a volume of unmanageable size, the choice of
these reagents has been limited to those that are used stoi-
chiometrically, and that are relatively familiar to the organic

chemistry community.
Some reagents, such as hexamethylphosphoric triamide
(HMPA)
and
N,N,N',N'-tetramethylethylenediamine
(TMEDA) that "activate" enolates and alkyllithium
reagents and increase their nucleophilicity, thereby facilitat
ing their reactions, are also included. A number of Lewis
acids appear in this volume, including the alkylaluminum
halides and the boron halides, as examples of reagents that
activate various functional groups by increasing their electrophilicity. The complete entries for all lewis acids and
nucleophilic catalysts (e.g. dimethylaminopyridine) also
appear in the volume on Acidic and Basic Reagents.
There are many reagents that may be considered as acti
vating in the broadest sense. The phosphorus halides, for
example, can be used to activate hydroxyl groups of alco
hols or carboxylic acids by converting them to halide leav
ing groups for nucleophilic substitution or elimination,
while the corresponding sulfonate esters activate alcohols
in the more traditional manner. Reagents such as N,N'thiocarbonyldiimidazole and phenyl chlorothionocarbonate,
which serve to activate alcohols for subsequent deoxygenation reactions with a trialkyltin hydride reagent, and (methoxycarbonylsulfamoyl)triethylammonium hydroxide, which
facilitates the dehydrative elimination of alcohols to
alkenes, also qualify as activating reagents in the broadest
sense and are included in the present volume. As many
examples of activating agents are included in this volume
as possible but, again, an effort has been made to produce a
work that is not too voluminous in scope.
Finally, there are many reagents that perform functions
other than those that are the immediate subject matter of
this volume. No attempt has been made to trim the original
entries that were prepared for the Encyclopedia of Reagents
for Organic Synthesis, since we recognize the value of hav
ing as much information as possible about each reagent,
thus allowing their optimal use in situations where side
xii
INTRODUCTION
reactions might be a problem when limited information is

at hand.
In preparing this volume we have been aware of the fact
that the original Encyclopedia entries were written several
years ago, and so may not be completely up to date with
regard to literature citations. This is inevitable in a work of
this kind, but we have tried to ameliorate the problem as
much as possible by including references to relevant arti
cles from Organic Syntheses Volumes 69-75 that either
deal with the preparation of a particular reagent or illustrate
its application, as well as recent (since 1993) review articles
and monographs that focus on various aspects of the subject
matter of this particular volume. For this purpose we have
included reviews that may not be directly connected with
any particular reagent, but that may be useful to the practi
cing organic chemist in seeking information concerning use
of the various technologies described in the present work.

Finally, we have also included expanded lists of "Related
Reagents" for each entry which will allow the reader to
locate additional information about additional related
reagents and methods in the original Encyclopedia.
Anthony J. Pearson
Department of Chemistry
Case Western Reserve University
Cleveland, Ohio
William R. Roush
Department of Chemistry
Ann Arbor, Michigan
ORGANIC SYNTHESES REFERENCES
Organic Syntheses References

I. Alcohol Activation (Substitution or
Elimination Reactions)
Behrens, C; Paquette, L. A. "N-Benzyl-2,3-azetidinedione"

OS, (1997), 75, 106.
Pansare, S. V.; Arnold, L. D.; Vederas, J. C. "Synthesis of N-tertButyloxycarbonyl-L-serine -Lactone and the p-Toluenesulfonic
Acid Salt of (5)-3-Amino-2-oxetanone" OS, (1991), 70, 10.
(80%)
(40%)
Stille, J. K.; Echavarren, A. ML; Williams, R. M.; Hendrix, J.

A. "4-Methoxy-4'-nitrobiphenyl" OS, (1992), 71, 97.
Dodge, J. A.; Nissen, J. S.; Presnell, M. "A Gen

eral Procedure for Mitsunobu Inversion of Sterically Hin
dered Alcohols: Inversion of Menthol. (15, 25, 5R)-5-Methyl2-(l-methylethyl)cyclohexyl 4-Nitrobenzoate" OS, (1995), 73,
110.
(91%)
II. Alcohol Functionalization or Protection:

(a)
(85.6%)
Acylation
Eberle, M.; Missbach, M.; Seebach, D. "Enantioselective Saponi

fication with Pig Liver Esterase (PLE): (15, 25, 3R)-3-Hydroxy2-nitrocyclohexyl Acetate" OS, (1990), 69, 19.
Thompson, A. S.; Hartner, F. W., Jr.; Grabowski, E. J. J. "Ethyl

(R)-2-Azidopropionate" OS, (1997), 75, 31.
(57%)
Sessler, J. L.; Mozaffari, A.; Johnson, M. R. "3,4-Diethylpyrrole

and 2,3,7,8,12,13,17,18-Octaethylporphyrin" OS, (1991), 70, 68.
Lynch, K. M.; Dialey, W. P. "3-Chloro-2-(chloromethyl)-lpropene"OS, (1997), 75, 89.

C(CH2OH)4
(96%)
+ Ac2O
(90%)
HOCH2C(CH2Cl)3 (57%)
Krakowiak, K. E.; Bradshaw, J. S. "4-Benzyl-10,19-diethyl4,10,19-triaza-1,7,1,16-tetraoxacycloheneicosane

(Triaza-21 Crown-7)" OS, (1991), 70, 129.
(73-77%)
Arnold, H.; Overman, L. E.; Sharp, M. J.; Witschel, M. C. "(E)1-Benzyl-3-(1 -iodoethylidene)piperidine: Nucleophile-Promoted
Alkyne-Iminium Ion Cyclizations" OS, (1991), 70, 111.
(93-100%)
Sun, R. C; Okabe, M. "(25, 45)-2,4,5-Trihydroxypentanoic

Acid 4,5-Acetonide Methyl Ester" OS, (1993), 72, 48.
(72-74%)
Deardorff, D. R.; Windham, C. Q.; Craney, C. L. "Enantio

selective Hyrolysis of cis-3,5-Diacetoxycyclopentene: (1R, 45)(+)-4-Hydroxy-2-Cyclopentenyl Acetate" OS, (1995), 73, 25.
(96-98%)
Avoid Skin Contact with All Reagents
Braun, M.; Graf, S.; Herzog, S. "(R)-(+)-2-Hydroxy-1,2,2Triphenylethyl Acetate" OS, (1993), 72, 32.
Overman, L. E.; Rishton, G. M. "3-(S)-[(fert-Butyldiphenylsilyl)oxy]-2-butanone" OS, (1992), 71, 56.

(99%)
(92%)
Furuta, K.; Gao, Q.-Z.; Yamamoto, H. "Chiral (Acycloxy)borane Complex-Catalyzed Asymmetric Diels-Alder Re
action: (1 R)-l,3,4-Trimethyl-3-cyclohexene-l-carboxaldehyde"
OS, (1993), 72, 86.
Wipf, P.; Xu, W. Allylic Alcohols by Alkene Transfer from

Zirconium to Zinc: l-[(tert-Butyldiphenylsilyl)oxy]-dec-3-en-5ol" OS, (1996), 74,205.
(96%)
(c)
Ether Formation
Bailey, W. F.; Carson, M. W.; Zarcone, L. M. J. "Selective Pro

tection of 1,3-Diols at the More Hindered Hydroxy Group: 3(Methoxymethoxy)-l-Butanol"OS, (1997), 75, 177.
(78-82%)
(b)
Silylation
(77-91%)
Tius, M. A.; Kannangara, G. S. K. "Benzoannelation of Ketones:

3,4-Cyclodedeceno-l-methylbenzene" OS, (1992), 71, 158.
Tamao, K.; Nakagawa, Y.; Ito, Y. "Regio- and Stereoselective

Intramolecular Hydrosilylation of -Hydroxy Enol Ethers: 2,3syn-2-Methoxymethoxy-l,3-nonanediol" OS, (1995), 73, 94.
(78%)
Paquette, L. A.; Earle, M. J.; Smith, G. F. "(4R)-(+)-tertButyldimethylsiloxy-2-cyclopenten-l-one" OS, (1995), 73, 36.
Danheiser, R. L.; Romines, K. R.; Koyama, H.; Gee, S. K.;

Johnson, C. R.; Medich, J. R. "A Hydroxymethyl Anion Equiv
alent: Tributyl[(methoxymethoxy)methyl]stannane" OS, (1992),
71, 133.
(64%)
Paquette, L. A.; Heidelbaugh, T. M. "(4S)-(-)-tert-Butyldimethylsiloxy-2-cyclopenten-l-one" OS, (1995), 73, 44.

(77-80%)
Mann, J.; Weymouth-Wilson, A. C. "Photoinduced-Addition of

Methanol to (5S)-(5-O-tert-Butyldimethylsiloxymethyl)furan2(5H)-one:
(4R, 5S)-4-Hydroxymethyl-(5-0-tert-Butyldimethylsiloxymethyl)furan-2(5H)-one" (OS, (1997), 75, 139.
Dondoni, A.; Merino, P. "Diastereoselective Homolo

gation of D-(R)-Glyceraldehyde Acetonide Using 2(Trimethylsilyl)thiazole:
2- O-Benzyl-3,4-isopropylidene-Derythrose" OS, (1993), 72, 21.
(96%)
Bhatia, A. V.; Chaudhary, S. K.; Hernandez, O. "4Dimethylamino-N-triphenylmethylpyridinium Chloride" OS,

(1997), 75, 184.
(96%)
(93%)
Lists of Abbreviations and Journal Codes on Endpapers
(d) Protection of Diols as Ketals

Ley, S. V.; Osborn, H. M. I.; Priepke, H. W. M.; Warriner,
S. L.; "(1'S, 2'S)-Methyl-3O,40-(l', 2'-dimethoxycyclohexane1', 2'-diyl)--D-mannopyranoside" OS, (1997), 75, 170.
Saito, S.; Komada, K.; Moriwake, T. "Diethyl (25, 3R)-2-(Ntert-Butoxycarbonyl)amino-3-hydroxysuccinate"

OS, (1995), 73,
184.
(86%)
(41-46%)
Schmid, C. R.; Bryant, J. D. "D-(R)-Glyceraldehyde Acetonide"OS, (1993), 72, 6.
Nikolic, N. A.; Beak, P. "(R)-(+)-2-(DiphenylhydroxymethyOpyrrolidine" OS, (1996), 74, 23.

(87%)
Chen, W.; Stephenson, E. K.; Cava, M. P.; Jackson, Y.

A. "2-Substituted Pyrroles from N-tert-Butyloxycarbonyl2-bromopyrrole: N-tert-Butoxy-2-trimethylsilylpyrrole" OS,
(1991), 70, 151.
(50-56%)
Sun, R. C ; Okabe, M. "(25, 4S)-2,4,5-Trihydroxypentanoic
Acid 4,5-Acetonide Methyl Ester" OS, (1993), 72, 48.
(90%)
(82-89%)
Iwao, M.; Kuraishi, T. "Synthesis of 7-Subtituted Indolines

via Directed Lithiation of l-(tert-Butoxycarbonyl)indoline: 7Indoline: 7-Indolinecarboxaldehyde" OS, (1995), 73, 85.
III. Amine Protection

Carrasco, M.; Jones, R. J.; Kamel, S.; Rapoport, H. Truong, T. "N(Benzyloxycarbonyl)-L-vinylglycine Methyl Ester" OS, (1991),
70, 29.
(98-99%)
Garner, P.; Park, J. M. "1,1-Dimethylethyl (S)- or (R)-4Formyl-2,2-dimethyl-3-oxazolidinecarboxylate: A Useful Serinal

Derivative" OS, (1991), 70, 18.
(98%)
Lakner, F. J.; Chu, K. S.; Negrete, G. R.; Konopelski, J. P.

"Synthesis of Enantiomerically Pure -Amino Acids from 2-tertButyl-l-carbomethoxy-2,3-dihydro-4(l H)-pyrimidinone: (R)-3Amino-3-(p-methoxyphenyl)propionic Acid" OS, (1995), 73,
201.
(72-79%)
(86%)
Lenz, G. R. Lessor, R. A. "Tetrahydro-3-benzazepin-2-ones:

Lead Tetraacetate Oxidation of Isoquinoline Enamides" OS,
(1991), 70, 139.
Hutchison, D. R.; Khau, V. V.; Martinelli, M. J.; Nayyar, N. K.;

Peterson, B. C ; Sullivan, K. A. "Synthesis of cis-4a(5),8a(R)Perhydro-6(2H)-isoquinolinones from Quinine: 4a(5),8a(R)-2Benzoyloctahydro-6(2H)-isoquinolinone" OS, (1997), 75, 223.
(96-98%)
(100%)
Krakowiak, K. E.; Bradshaw, J. S. "4-Benzyl-10,19-diethyl-4,10,19-triaza-1,7,13,16-tetraoxacycloheneicosane (Triaza21-Crown-7)" OS, (1991), 70, 129.
Nikolaides, N.; Schipor, I.; Ganem, B. "Conversion of Amines

to Phospho Esters: Decyl Diethyl Phosphate" OS, (1993), 72, 246.
CH3(CH2)9NH2 + (EtO)2POCl
CH3(CH2)9NH2PO(OEt)2
(95-99%)
(92-97%)
Carrasco, M.; Jones, R. J.; Kamel, S.; Rapoport, H. Truong,

T. "N-(Benzyloxycarbonyl)-L-vinylglycine Methyl Ester" OS,
(1991), 70, 29.
IV CarboxyI Activation:
Xavier, L. C ; Mohan, J. J.; Mathre, D. J.; Thompson, A. S.; Car
roll, J. D.; Corley, E. G.; Desmond, R. "(S)-Tetrahydro-l-methyl3,3-diphenyl-lH, 3H-pyrrolo-[l,2,-c][l,3,2]oxazaborole-Borane Complex" OS, (1996), 74, 50.
(80%)
Amat, M.; Hadida, S.; Sathyanarayana, S.; Bosch, J. "Regioselective Synthesis of 3-Substituted Indoles: 3-Ethylindole" OS,
(1996), 74, 248.
Barton, D. H. R.; MacKinnon, J.; Perchet, R. N.; Tse, C.-L.

"Efficient Synthesis of Bromides from Carboxylic Acids Con
taining a Sensitive Functional Group: Dec-9-enyl Bromide from
10-Undecenoic Acid" OS, (1997), 75, 124.
(95%)
Weinreb, S. M.; Chase, C. E.; Wipf, P.; Venkatraman, S. "2Trimethylsilylethanesulfonyl Chloride (SES-C1)" OS, (1997), 75,
161.
Hubschwerlen, C ; Specklin, J.-L. "(35, 4S)-3-Amino-l-(3,4dimethoxybenzyl)-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-azetidinone" OS, (1993), 72, 14.
(90%)
(68-77%)
Pikal, S.; Corey, E. J. "Enantioselective, Catalytic Diels-Alder

Reaction: (lS-endo)-3-(Bicyclo[2.2.1]hept-5-en-2-ylcarbonyl)2-oxazolidinone" OS, (1992), 71, 30.
(69%)
Schultz, A. G.; Alva. C. W. " Asymmetric Synthesis

of trans-2-Aminocyclohexanecarboxylic Acid Derivatives from
Pyrrolobenzodiazepine-5,11-diones" OS, (1995), 73, 174.
(61%)
Wang, X.; deSilva, S. O.; Reed, J. N.; Billadeau, R.; Griffen,

E. J.; Chan, A.; Snieckus, V. "7-Methoxyphthalide" OS, (1993),
72, 163.
(86-90%)
Meyers, A. I.; Flanagan, M. E. "2,2'~Dimethoxy-6-formylbiphenyl" OS, (1992), 71, 107.
(81-85%)

Gerlach, H.; Kappes, D.; Boeckman, R. K. Jr.; Maw, G. N.
"(-)-(1S, 4R)-Camphanoyl Chloride"OS, (1992), 71, 48.
VI. Carbonyl Activation or Functionalization:

Schmit, C; Falmagne, J. B.; Escudero, J.; Vanlierde, H.; Ghosez,
L. "A General Synthesis of Cyclobutanones from Olefins and Ter
tiary Amides: 3-Hexylcyclobutanone" OS, (1990), 69, 199.
(90%)
(91%)
(59%)
Rosini, G.; Confalonieri, G.; Marotta, E.; Rama, F.;

Righi, P. "Preparation of Bicyclo[3.2.0]hept-3-en-6-ones: 1,4Dimethylbicyclo[3.2.0]hept-3-en-6-one" OS, (1996), 74, 158.
Knapp, S.; Gibson, F. S. "Iodolactamization: 8-exo-Iodo-2azabicyclo[3.3.0]octan-3-one" OS, (1991), 70, 101.
(79%)
(76-81%)
V. Carbonyl Protection:
Ley, S. V.; Osborn, H. M. I.; Priepke, H. W. M.; Warriner,
S. L. "(l'S,2'S)-Methyl-O,4O-(l', 2'-dimethyoxycylohexane1', 2'-diyl)--D-mannopyranoside" OS, (1997), 75, 170.
Wender, P. A.; White, A. W.; MacDonald, F. E. "Spiroannelation via Organobis(cuprates): 9,9-Dimethylspiro[4.5]decan7-one"OS, (1991), 70, 204.
(93%)
(73%)
Polin, J.; Schottenberger, H. "Conversion of Methyl Ketones

into Terminal Acetylenes: Ethynylferrocene" OS, (1995), 73, 262.
Ni, Z.-J.; Luch, T.-Y. "Nickel-Catalyzed Silylolefination
of Allylic Dithioacetals: (E, E)-Trimethyl(4-phenyl-l,3butadienyl)silane" OS, (1991), 70, 240.
(85-93%)
(97%)
Yuan, T.-M.; Luh, T.-Y. "Nickel-Catalyzed, Geminal Dimethylation of Allylic Dithioacetals; (E)-l-Phenyl-3,3-dimethyl-lbutene" OS, (1996), 74, 187.
Myles, D. C; Bigham, M. H. "Preparation of (E, Z)-lMethoxy-2-methyl-3-(trimethylsiloxy)-1,3-pentadiene"

OS,
(1991), 70, 231.
(81-87%)
(56-61%)
Dahnke, K. R.; Paquette, L. A. "2-Methylene-l,3-dithiolane"

OS, (1992), 71, 175.
Umemoto, T.; Tomita, K.; Kawada, K. "7V-Fluoropyridinium

Triflate: An Electrophilic Fluorinating Agent" OS, (1990), 69,
129.
(54-59%)
(100%)
Reissig, H.-U.; Reichelt, I.; Kunz, T. "Methoxycarbonylmethylation of Aldehydes via Siloxycyclopropanes: Methyl 3,3Dimethyl-4-oxobutanoate" OS, (1992), 71, 189.
Lee, T. V.; Porter, J. R. "Spiroannelation of Enol Silanes: 2Oxo-5-methoxyspiro[5.4]decane" OS, (1993), 72, 189.
(67%)
Crabtree S. R.; Mander, L. N.; Sethi, S. P. "Synthesis of

-Keto Esters by C-Acylation of Preformed Enolates with
Methyl Cyanoformate: Preparation of Methyl (l,4,8a)-2oxodecahydro-1-naphthoate" OS, (1991), 70, 256.
(75%)
VIII. Sulfonylation Reagents:

Comins, D. L.; Dehghani, A.; Foti, C. J.; Joseph, S. P. "PyridineDerived Triflating Reagents: iV-(2-Pyridyl)triflimide and N-(5Chloro-2-pyridyl)triflimide" OS, (1996), 74,11.
X = H(81%)
X = CI (75%)
(81-84%)
VII. Lewis Acid Promoted Reactions

Overman, L. E.; Rishton, G. M. "Stereocontrolled Preparation of
3-Acyltetrahydrofurans from Acid-Promoted Rearrangements of
Allylic Ketals: (2S, 3S)-3-Acetyl-8-carboethoxy-2,3-dimethyl-loxa-8-azaspiro[4.5]decane" OS, (1992), 71, 63.
(90%)
Weinreb, S. M.; Chase, C. E.; Wipf, P.; Venkatraman, S. "2Trimethylsilylethanesulfonyl Chloride (SES-C1)" OS, (1997), 75,
161.
(68-77%)
Hazen, G. G.; Billinger, F. W.; Roberts, F. E.; Russ, W. K.;

Seman, J. J.; Staskiewicz, S. "4-Dodecylbenzenesulfonyl Azides"
OS, (1995), 73, 144.
Keck, G. E.; Krishnamurthy, D. "Catalytic Asymmertic Allylation Reactions: (S)-l-(Phenylmethoxy)-4-penten-2-ol" OS,

(1997), 75, 12.
Reid, J. R.; Dufresne, R. F.; Chapman, J. J. "Mesitylenesulfonylhydrazine, and (la, 2a, 6)-2,6-Dimethylcyclohexanecarbonitrile and (la, 2, 6)-2,6-Dimefhylcyclohexanecarbonitrile as a Racemic Mixture" OS, (1996), 74, 217.
(80-87%)
Jager, V.; Poggendorf, P. "Nitroacetaldehyde Diethyl Acetal"

OS, (1996), 74, 130.
(40-42%)
Naruta, Y.; Maruyama, K. "Ubiquinone-1" OS, (1992), 77, 125.
(90%)
(80%)
IX. Sulfoxide Activation

McCarthy, J. R.; Matthews, D. P.; Paolini, J. P. "Stereo
selective Synthesis of 2,2-Disubstituted 1-Fluoroalkenes: (E)[[Fluoro(2-phenylcyclohexylidene)methyl]sulfonyl] benzene and
(Z)-[2-(Fluoromethylene)cyclohexyl]benzene" OS, (1993), 72,
209.
Contents
Preface
ix
Introduction
xi
Organic Synthesis References
Recent Review Articles and Monographs
Acetic Anhydride
Acetyl Chloride (+ co-reactants)
Aluminum Chloride
Antimony(V) Fluoride
Azidotris(dimethylamino)phosphonium
Hexafluorophosphate
Azobisisobutyronitrile
Benzotriazoly-l-N-oxytris(dimethylamino)phosphonium
Hexafluorophosphate (BOP)
0-Benzotriazolyl-N, N, N', N'-tetramethyluronium
Hexafluorophosphate
Benzoyl Chloride
Benzyl Bromide
Benzyl Chloroformate
Benzyl Chloromethyl ether
Benzyl-2,2,2-trichloroacetimidate
2,4-Bis(4-methoxyphenyl-1,3,2,4-dithiadiphosphetane2,4-Disulfide
Bis(2-oxo-3-oxazolidinyl)phosphinic Chloride
Bis(tri-N-Butyltin) Oxide
Bis(trichloromethyl Carbonate)
Boron Tribromide
Boron Trichloride
Boron Trifluorideetherate
Bromodimethylborane
Bromotrimethylsilane
2-t-Butoxycarbonyloxyimino)-2-phenyl-acetonitrile
t-Butyl Chloroformate
t-Butyldimethylchlorosilane
t-Butyldimethylsilyl trifluoromethanesulfonate
t-Butyldiphenylchlorosilane
N, N'-Carbonyldiimidazole
Chloromethyl Methyl Ether
2-Chloro-1-methylpyridinium Iodide
Chlorotriethylsilane
9
16
26
29
34
35
37
40
42
45
46
50
51
53
57
59
61
62
66
68
77
79
81
83
84
89
91
93
96
99
100
Chlorotriemethylsilane
Copper(I) Trifluoromethanesulfonate
Diazomethane
Di-t-butyl Dicarbonate
Di-n-butyltin Oxide
1,3-Dicyclohexylcarbodiimide
Diethylaluminum chloride
N, N-Diethylaminosulfur Trifluoride (DAST)
Diethyl Azodicarboxylate
Diethyl Phosphorochloridate
3,4-Dihydro-2H-pyran
3,4-Dihydro-2H-pyrido[ 1,2-]pyrimidine-2-one
3,4-Dimethoxybenzyl bromide
2,2-Dimethoxypropane
Dimethylaluminum Chloride
4-Dimethylaminopyridine
Dimethylformamide diethyl acetal
2,2-Dimethyl-1,3-propanediol
Dimethyl Sulfate
Diphenylbis(1,1,1,3,3.3-hexafluoro-2-phenyl-2propoxy)-sulfirane
Diphenylphosphinic Chloride
Diphenyl phosphorazidate
2,2'-Dipyridyl disulfide
N,N'-Disuccinimidyl Carbonate
1,2-Ethanedithiol
2-Ethoxy-1-ethoxycarbonethoxydihydroquinoline
Ethylaluminum Dichloride
N-Ethylbenzisoxazolium Tetrafluoroborate
Ethyl Chloroformate
l-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide
Hydrochloride
Ethylene Glycol
N-Ethyl-5-phenylisoxazolium-3'-sulfonate
Ethyl Vinyl Ether
9-FluorenylmethylChloroformate
Hexacarbonyl Chromium
Hexamefhyldisilazane
Hexamethylphosphoric Triamide
Hexamethylphosphorous Triamide
Hydrazine
1 -Hydroxybenzotriazole
102
105
117
123
130
133
136
137
140
144
147
150
151
152
154
156
158
161
162
165
166
168
170
173
175
176
177
182
183
186
188
191
194
198
201
205
207
213
216
220
viii
CONTENTS
N-Hydroxypyridine-2-thione
N-Hydroxysuccinimide
Imidazole
Iodomethane
Iodonium Di-sym-collidine Perchlorate
Iodotrimethylsilane
Isobutene
Isobutyl Chloroformate
Isopropenyl Acetate
Lithium Bromide
Lithium Chloride
Lithium Iodide
Lithium Perchlorate
Magnesium Bromide
2-Mesitylenesulfonyl Chloride
Methanesulfonyl Chloride
p-Methoxybenzyl Chloride
(Methoxycarbonylsulfamoyl)triethylammonium
Hydroxide
Methoxyethoxymethyl Chloride
2-Methoxypropene
Methylaluminum Dichloride
Methyl Chloroformate
Methyl Cyanoformate
iV-Methyl-iV,iV'-dicyclohexylcarbodiimidium iodide
N-Methyl-N-nitroso-p-toluenesulfonamide, (Diazald)
Methyl fluorosulfonate & Methyl
Trifluoromethanesulfonate
Montmorillonite K-10
2-Morpholinoethyl Isocyanide
o-Nitrobenzyl Alcohol
o-Nitrophenol
p-Nitrophenol
Nonacarbonyldiiron
Octacarbonyl Dicobalt
Oxalyl Chloride
Pentacarbonyl Iron
Pentafluorophenol
Phenyl Chlorothionocarbonate
Phenyl N-Phenylphosphoramidochloridate
Phenyl Phosphorodi(1-imidazolate)
Phosgene
Phosphorus(III) Bromide
Phosphorus(V) Bromide
Phosphorus(III) Chloride
Phosphorus(V) Chloride
Phosphorus(III) Iodide
Phosphorus(V) Oxide
Phosphorus(V) Oxide Methanesulfonic Acid
222
225
227
228
232
234
240
243
244
247
248
249
251
253
255
257
260
263
265
267
269
270
273
276
277
278
282
285
287
289
290
292
298
307
311
318
322
324
327
328
330
332
333
335
338
341
343
Phosphorus Oxychloride
p-Picolyl chloride hydrochloride
1,3-Propanediol
1,3-Propanedithiol
Silver(I) Tetrafluoroborate
Tetra-n-butylammonium Fluoride
Tetrafluoroboric Acid
N,N,N' ,N'-Tetramethylethylenediamine
1, l'-Thiocarbonyldiimidazole
Thionyl Chloride
1,1'-Thionylimidazole
2-Thiopyridyl Chloroformate
Tin(IV) Chloride
Titanium(IV) Chloride
Titanium Tetraisoproxide
p-Toluenesulfonyl Chloride
1,2,4-Triazole
Trichloroacetonitrile
2,4,6-Trichlorobenzoyl Chloride
Triethylaluminum
Triethyl Orthoformate
Trifluoroacetic Anhydride
Trifluoromethanesulfonic Anhydride
Triisopropylsilyl Chloride
Trimethylacetyl Chloride
Trimethyloxonium Tetrafluoroborate
Trimethylsilyldiazomethane
-Trimethylsilylethanesulfonyl Chloride
2-(Trimethylsiyl)ethoanone
Trimethylsilyl Trifluoromethanesulfonate
Triphenylcarbenium Tetrafluoroborate
Triphenylphosphine-N-Bromosuccinimide
Triphenylphosphine-Carbon Tetrabromide
Triphenylphosphine-Carbon Tetrachloride
Triphenylphosphine Dibromide
Triphenylphosphine Dichloride
Triphenylphosphine-Diethyl Azodicarboxylate
Tris(dimethylamino)sulfonium
difluorotrimethylsilicate (TASF)
Zinc Bromide
Zinc Chloride
Zinc Iodide
Zinc Bis(p-toluenesulfonate)
346
350
350
351
355
358
361
364
368
370
373
375
377
383
389
394
399
400
402
404
406
409
410
416
418
419
422
425
427
432
436
438
440
442
445
450
454
List of Contributors
Reagent Formula Index
Subject Index
483
493
497
464
468
471
479
481
RECENT REVIEW ARTICLES AND MONOGRAPHS
Recent Review Articles and Monographs

General Carboxyl and Hydroxyl Activation
Chatgilialoglu, C ; Ferreri, C. Progress of the BartonMcCombie Methodology: From Tin Hydrides to Silanes. Res.
Chem. Intermed. 1993, 19, 755-775.
Norcross, R. D.; Paterson, I. Total Synthesis of Bioactive
Marine Macrolides. Chem. Rev. 1995, 95, 2041-2114.
Hughes, D. L. Progress in the Mitsunobu Reaction. A Review.
Org. Prep. Proc. Int., 1996, 28, 127-164.
Ryan, T. A. Phosgene and Related Compounds. Elsevier Sci
ence: New York, 1996.
Sherif, S. M.; Erian, A. W. The Chemistry of Trichloroacetonitrile, Heterocycles 1996, 43 (5), 1083-1118.
Cotarca, L.; Delogu, P.; Nardelli, A.; Sunjic, V. Bis(trichloromethyl) Carbonate in Organic Synthesis. Synthesis 1996,
553-576.
Dimon, C ; Hosztafi, S.; Makleit, S. Application of the Mit
sunobu Reaction in the Field of Alkaloids. J. Heterocyclic Chem.
1997, 34, 349-365.
Zard, S. Z. On the Trail of Xanthates: Some New Chemistry
from an Old Functional Group. Angew. Chem. Int. Ed. Engl. 1997,
36, 672-685.
Wisniewski, K.; Koldziejczyk, A. S.; Falkiewicz, B. Applica
tions of the Mitsunobu Reaction in Peptide Chemistry. J. Peptide
Sci. 1998, 4, 1-14.
Peptide Synthesis
Albericio, F.; Carpino, L. A. Coupling reagents and activation.
Method. Enzymol, 1997, 289, 104-126.
Albericio, F.; Lloyd-Williams, P.; Giralt, E. Convergent solidphase peptide synthesis. Method. Enzymol., 1997, 289, 313-336.
Bodanszky, M. Peptide Chemistry: A Practical Textbook, 2nd
ed. Springer-Verlag: Berlin, 1993.
Bodanszky, M. Principles of Peptide Synthesis, 2nd ed.
Springer-Verlag: Berlin, 1993.
Bodanszky, M.; Bodanszky, A. The Practice of Peptide Synthe
sis, 2nd ed. Springer-Verlag: Heidelberg, 1994.
Pennington, M. W.; Dunn, B. M.; Eds. Peptide Synthesis Pro
tocols (In: Methods Mol. Biol. 1994, 35) Humana Press: Totowa,
NJ 1994.
Mikhalkin, A. P. The Synthesis, Properties, and Applications
of N-Acyl--aminoacids. Russ. Chem. Rev. 1995, 64 (3), 259-75.
Wipf, P. Synthetic Studies of Biologically Active Marine Cyclopeptides. Chem. Rev. 1995, 95, 2115-2134.
Gutte, B., Ed. Peptides, Synthesis, Structures, and Applications.
Academic Press: San Diego, 1995.
Carpino, L. A; Beyermann, M.; Wenschuh, H.; Bienert, M. Pep
tide Synthesis via Amino Acid Halides. Acct. Chem. Res. 1996,
29, 268-274.
Deming, T.J. Polypeptide materials: New synthetic methods
and applications. Adv. Mater., 1997, 9, 299-311.
Stephanov, V. M. Proteinases as Catalysts in Peptide Synthesis.

PureAppl. Chem., 1996, 68 (6), 1335-1340.
Ichikawa, J. Fluorine as activator and controller in organic syn
thesis. J. Syn. Org. Chem. Jpn., 1996, 54, 654-664.
North, M. Amines and amides. Contemp. Org. Synth., 1996, 3,
323-343.
Humphrey, J. M.; Chamberlin, A. R. Chemical Synthesis of
Natural Product Peptides: Coupling Methods for the Incorporation
of Noncoded Amino Acids into Peptides. Chem. Rev. 1997, 97,
2243-2266.
Carbohydrate Activation/Glycosylation
Suzuki, K.; Nagasawa, T. Recent progress in O-glycoside syn
thesis - methodological aspects. J. Syn. Org. Chem. Jpn. 1992, 50,
378-390.
Toshima, K.; Tatsuta, K. Recent Progress in O-Glycosylation
Methods and Its Application to Natural Products Synthesis. Chem.
Rev.,1993,93, 1503-1531.
Schmidt, R. R; Kinzy, W. Anomeric-Oxygen Activation for
Glycoside Synthesis: The Trichloroacetimidate Method. Adv. Car
bohydrate Chem. Biochem. 1994, 50, 21-123.
Ogawa, T. Haworth Memorial Lecture: Experiments Directed
Towards Glycoconjugate Synthesis, CSR 1994, 23, 397-407
Wilson, L. J.; Hager, M. W.; El-Kattan, Y.A.; Liotta, D. C. Nitro
gen Glycosylation Reactions Involving Pyrimidine and Purine Nu
cleoside Bases with Furanoside Sugars. Synthesis-Stuttgart 1995,
1465-1479.
Boons, G.-J. Strategies in Oligosaccharide Synthesis. Tetra
hedron 1996, 52, 1095-1121.
Boons, G.-J. Recent Developments in Chemical Oligosaccha
ride Synthesis. Contemp. Org. Synth. 1996, 3, 173-200.
Danishefsky, S. J.; Bilodeau, M. T. Glycals in Organic Synthe
sis: The Evolution of Comprehensive Strategies for the Assembly
of Oligosaccharides and Glycoconjugates of Biological Conse
quence. Angew. Chem. Int. Ed. 1996, 35, 1380-1419.
Voelter, W.; Khan, K. M.; Shekhani, M. S. Anhydro Sugars,
Valuable Intermediates in Carbohydrate Syntheses. Pure Appl.
Chem. 1996, 68, 1347-1353.
Khan, S. H.; O'Neill, R. A., Eds. Modern Methods in Carbohy
drate Synthesis. Hardwood: Amsterdam, The Netherlands, 1996.
Whitfield, D. M.; Douglas, S. P. Glycosylation reactions:
Present status and future directions. Glycoconjugate J., 1996, 13,
5-17.
Garegg, P. J. Thioglycosides as Glycosyl Donors in Oligosac
charide Synthesis. Adv. Carbohydrate Chem. Biochem. 1997, 52,
179-205.
Hanessian, S. Preparative Carbohydrate Chemistry. Marcel
Dekker: New York, 1997.
Tsuda, Y. Regioselective manipulation of carbohydratehydroxyl groups (selective activation of a hydroxyl group by tin
compounds). J. Synth. Org. Chem. Jpn. 1997, 55, 907-919.
8 RECENT REVIEW ARTICLES AND MONOGRAPHS

Synthesis of Oligonucleotides
Beaucage, S. L.; Iyer, R. P. The Functionalization of Oligo
nucleotides via Phosphoramidite Derivatives. Tetrahedron, 1993,
49, 1925-1963.
Beaucage, S. L.; Iyer, R. P. The Synthesis of Modified Oligonu
cleotides by the Phosphoramidite Approach and Their Applica
tions. Tetrahedron. 1993, 49, 6123-6194.
Beaucage, S. L.; Iyer, R. P. The Synthesis of Specific Ri
bonucleotides and Unrelated Phosphorylated Biomolecules by the
Phosphoramidite Method. Tetrahedron. 1993,49, 10441-10488.
Lesnikowski, Z. J. Stereocontrolled Synthesis of P-Chiral
Analogs of Oligonucleotides. Bioorg. Chem. 1993, 21, 127-155.
Stec, W. J.; Wilk, A. Stereocontrolled Synthesis of
01igo(nucleoside phosphorothioate)s. Angew. Chem. Int. Ed.
Engl. 1994, 33, 709-722
Activation by Lewis Acids

Otera, J. Transesterification. Chem. Rev. 1993, 93, 1449-1470.
Oh, T.; Reilly. M. Reagent-Controlled Asymmetric Diels-Alder
Reactions. A Review. Org. Prep. Proced. Int., 1994, 26, 129-148.
Waldmann, H. Asymmetric Hetero Diels-Alder Reactions. Synthesis, 1994, 535-551.
Suzuki, K. Novel Lewis acid catalysis in organic synthesis. Pure
Appl. Chem. 1994, 66, 1557-1564.
Pons, J.-M.; Santelli, M.; Eds. Lewis acids and selectivity in
organic synthesis. CRC Press: Boca Raton, FL, 1996.
Hiroi, K. Transition metal or Lewis acid-catalyzed asymmetric
reactions with chiral organosulfur functionality. Rev. Heteroatom
Chem., 1996, 74,21-57.
Siling, M. I.; Laricheva, T. N. Titanium compounds as catalysts
for esterification and transesterification Reactions. Russ. Chem.
Rev. 1996, 65, 279-286.
Engberts, J. B. F. N.; Feringa, B. L.; Keller, E.; Otto, S. Lewisacid catalysis of carbon carbon bond forming reactions in water.
Recl. Trav. Chim. Pays-Bas 1996, 775, 457-464.
Holloway, C. E.; Melnik, M. Organoaluminium compounds:
classification and analysis of crystallographic and structural data.
J. Organomet. Chem. 1997, 543, 1-37.
Activation by Transition Metal Organometallic

Systems
Pearson, A. J.; Woodgate, P. D. Aromatic Compounds of the
Transition Elements. Second Supplement to the 2nd Edition of
Rodd's Chemistry of Carbon Compounds. Vol. IIIB/IIIC/IIID (par
tial): Aromatic Compounds. Sainsbury, M., Ed. Elsevier: Amster
dam, The Netherlands, 1995.
Donaldson, W. A. Preparation and Reactivity of Acyclic

(Pentadienyl)iron(l+) Cations: Applications to Organic Synthe
sis. Aldrichim. Acta 1997, 30, 17-24.
Gre, R.; Lellouche, J. P. Acyclic Diene Tricarbonyliron Com
plexes in Organic Synthesis. Advances in Metal-Organic Chem
istry. Vol. 4. Liebeskind, L. S., Ed. JAI: Greenwich, Connecticut,
1995.
Donohoe, T. J. Stoichiometric Applications of Organotransition Metal Complexes in Organic Synthesis. Contemp. Org. Synth.
1996, 3, 1-18.
Reviews of Protecting Group Chemistry

Green, T. W.; Wuts, P. G. M. Protective Groups in Organic
Chemistry, 2nd Ed; Wiley: New York, 1991.
Reidel, A.; Waldmann, H. Enzymatic Protecting Group Tech
niques in Bioorganic Synthesis. J. Praia. Chem. 1993, 335,
109-127.
Kocienski, P. J. Protecting Groups. Theime Verlag: Stuttgart,
1994.
Sonveaux, E. Protecting Groups in Oligonucleotide Synthesis.
in Methods in Molecular Biology, Vol. 26; Agrawal, S., Ed.; Hu
mana Press: Totowa, NJ, 1994, pp. 1-71.
Wong, C.-H.; Whitesides, G. M. Enzymes in Synthetic Organic
Chemistry. Pergamon: Oxford, 1994.
Waldmann, H.; Sebastian, D. Enzymatic Protecting Group
Techniques. Chem. Rev. 1994, 94, 911-937.
Jarowicki, K.; Kocienski, P. Protecting groups. Contemp. Org.
Synth. 1995, 2, 315-336; 1996, 3, 397-431; and 1997, 4, 454-492.
Donaldson, W. A. Transition Metal Alkene, Diene, and Dienyl
Complexes: Complexation of Dienes for Protection. in Compre
hensive Organometallic Chemistry II, Vol. 12. Hegedus, L. S., Ed.
Elsevier: New York, 1995, pp. 623-635.
Schelhaas, M.; Waldmann, H. Protecting Group Strategies
in Organic Synthesis. Angew. Chem., Int. Ed. Engl., 1996, 35,
2056-2083.
Nelson, T. D.; Crouch, R. D. Selective Deprotection of Silyl
Ethers. Synthesis, 1996, 1031-1069.
Ranu, B. C ; Bhar, S. Dealkylation of Ethers. A Review. Org.
Prep. Proced. Int. 1996, 28, 371-409.
Debenham, J. S.; Rodebaugh, R.; Fraser-Reid, B. Recent Ad
vances in TV-Protection for Amino Sugar Synthesis. Liebigs
Ann./Recueil 1997, 791-802.
El Gihani, M. T.; Heaney, H. The Use of Bis(trimethylsilyl)acetamide and Bis(trimethylsilyl)urea for Protection
and as Control Reagents in Synthesis. Synthesis, 1998, 357-375.
ACETIC ANHYDRIDE
eral, the addition of DMAP increases the rate of acylation by 104

(eq 2). 19
(2)
Acetic Anhydride 1
[108-24-7]
C4H6O3
(MW 102.09)
(useful for the acetylation of alcohols,2 amines, 3 and thiols,4 ox

idation of alcohols,5 dehydration,6 Pummerer7 reaction, Perkin8
reaction, Polonovski9 reaction, N-oxide reaction,10 Thiele 11 re
action, ether cleavage,12 enol acetate formation,13 gem-diacetate
formation14)
Physical Data: bp 138-140C; mp - 7 3 C ; d 1.082 g c m - 3 .
Solubility: sol most organic solvents. Reacts with water rapidly
and alcohol solvents slowly.
Form Supplied in: commercially available in 98% and 99+% pu
rities. Acetic anhydride-d6 is also commercially available.
Analysis of Reagent Purity: IR, NMR. 15
Preparative Methods: acetic anhydride is prepared industrially by
the acylation of Acetic Acid with Ketene.1b A laboratory prepa
ration of acetic anhydride involves the reaction of sodium ac
etate and Acetyl Chloride followed by fractional distillation.16
Purification: adequate purification is readily achieved by frac
tional distillation. Acetic acid, if present, can be removed
by refluxing with CaC 2 or with coarse magnesium filings at
80-90C for 5 days. Drying and acid removal can be achieved
by azeotropic distillation with toluene.17
Handling, Storage, and Precautions: acetic anhydride is corrosive
and a lachrymator and should be handled in a fume hood.
Acetylation. The most notable use of acetic anhydride is for

the acetylation reaction of alcohols,2 amines, 3 and thiols.4 Acids,
Lewis acids, and bases have been reported to catalyze the reac
tions.
Alcohols. The most common method for acetate introduction
is the reaction of an alcohol with acetic anhydride in the presence
of pyridine.2 Often, Pyridine is used as the solvent and reactions
proceed nearly quantitatively (eq 1).
ROH
ROAc
(1)
If the reaction is run at temperatures lower than 20C, primary

alcohols can be acetylated over secondary alcohols selectively.18
Under these conditions, tertiary alcohols are not acylated. Most
alcohols, including tertiary alcohols, can be acylated by the addi
tion of DMAP (4-Dimethylaminopyridine) and Acetyl Chloride
to the reaction containing acetic anhydride and pyridine. In gen
Recently, Vedejs found that a mixture of Tri-n-butylphosphine

and acetic anhydride acylates alcohols faster than acetic anhydride
with DMAP.20 However, the combination of acetic anhydride with
DMAP and Triethylamine proved superior. It is believed that the
Et 3 N prevents HOAc from destroying the DMAP catalyst.
Tertiary alcohols have been esterified in good yield using acetic
anhydride with calcium hydride or calcium carbide. 21 t-Butanol
can be esterified to t-butyl acetate in 80% yield under these con
ditions. High pressure (15 kbar) has been used to introduce the
acetate group using acetic anhydride in methylene chloride. 22
Yields range from 79-98%. Chemoselectivity is achieved using
acetic anhydride and Boron Trifluoride Etherate in THF at 0 C.
Under these conditions, primary or secondary alcohols are acety
lated in the presence of phenols. 23
-D-Glucose is peracetylated readily using acetic anhydride in
the presence of Zinc Chloride to give -D-glucopyranose pentaacetate in 63-72% yield (eq 3). 24
(3)
Under basic conditions, -D-glucose can be converted into D-glucopyranose pentaacetate in 56% yield (eq 4).
(4)
In the food and drug industry, high-purity acetic anhydride is

used in the manufacture of aspirin by the acetylation of salicylic
acid (eq 5). 25
(5)
Amines. The acetylation of amines has been known since 1853

when Gerhardt reported the acetylation of aniline.3 Acetamides
are typically prepared by the reaction of the amine with acetic
anhydride (eq 6).
(6)
10
ACETIC ANHYDRIDE
A unique method for selective acylation of secondary amines

in the presence of primary amines involves the use of 18-Crown6 with acetic anhydride and triethylamine.26 It is believed that
the 18-crown-6 complexes primary alkylammonium salts more
tightly than the secondary salts, allowing selective acetylation.
In some cases, tertiary amines undergo a displacement reaction
with acetic anhydride. A simple example involves the reaction of
benzyldimethylamine with acetic anhydride to give dimethylacetamide and benzylacetate (eq 7).27
(7)
Dimethyl Sulfoxide-Acetic Anhydride.5 The reaction proceeds

through an acyloxysulfonium salt as the oxidizing agent (eq 12).
(12)
The oxidations often proceed at room temperature, although

long reaction times (18-24 h) are sometimes required. A side
product is formation of the thiomethyl ethers obtained from the
Pummerer rearrangement.
If the alcohol is unhindered, a mixture of enol acetate (from
ketone) and acetate results (eq 13).32
Allylic tertiary amines can be displaced by the reaction of acetic

anhydride and sodium acetate.28 The allylic acetate is the major
product, as shown in eq 8.
(8)
Cyclic benzylic amines may undergo ring opening upon heating

with acetic anhydride (eq 9).29
40%
30%
The oxidation of carbohydrates can be achieved by this method,

as Hanessian showed (eq 14).33
(14)
(9)
-Amino acids react with acetic anhydride in the presence of

a base to give 2-acetamido ketones.30 This reaction is known
as the Dakin-West reaction (eq 10) and is believed to go
dirough a oxazolone mechanism. The amine base of choice is 4dimethylaminopyridine. Under these conditions, the reaction can
be carried out at room temperature in 30 min.
Aromatic -diketones can be prepared from the acyloin com

pounds; however, aliphatic diketones cannot be prepared by this
method.34 The reaction proceeds well in complex systems with
out epimerization of adjacent stereocenters, as in the yohimbine
example (eq 15).35 This method compares favorably with that of
Dimethyl SulfoxideDicyclohexylcarbodiimide.
(15)
(10)
Cyclic -amino acids rearrange to -methylene lactams upon

treatment with acetic anhydride, as shown in eq 11.31
(11)
Thiols. S-Acetyl derivatives can be prepared by the reaction

of acetic anhydride and a thiol in the presence of potassium
bicarbonate.4 Several disadvantages to the 5-acetyl group in pep
tide synthesis include -elimination upon base-catalyzed hydrol
ysis. Also, sulfur to nitrogen acyl migration may be problematic.
Oxidation. The oxidation of primary and secondary alcohols
to the corresponding carbonyl compounds can be achieved using
Dehydration. Many functionalities are readily dehydrated

upon reaction with acetic anhydride, the most notable of which is
the oxime.6 Also, dibasic acids give cyclic anhydrides or ketones,
depending on ring size.36
An aldoxime is readily converted to the nitrile as shown in
eq 16.37
(16)
When oximes of -tetralones are heated in acetic anhydride in

the presence of anhydrous Phosphoric Acid, aromatization occurs
as shown in eq 17.38
ACETIC ANHYDRIDE
(17)
Oximes of aliphatic ketones lead to enamides upon treatment

with acetic anhydride-pyridine, as shown in the steroid example
in eq 18.39
11
2-Phenylsulfonyl ketones rearrange in the presence of acetic

anhydride-sodium acetate in toluene at reflux to give S-aryl
thioesters (eq 23).42 Upon hydrolysis, an -hydroxy acid is ob
tained.
(23)
In the absence of sodium acetate, 2-phenylsulfonyl ketones give

the typical Pummerer product. Since -keto sulfoxides are avail
able by the reaction of esters with the dimsyl anion, this overall
process leads to one-carbon homologated -hydroxy acids from
esters (eq 24).42
(18)
(24)
Upon heating with acetic anhydride, dibasic carboxylic acids

lead to cyclic anhydrides of ring size 6 or smaller. Diacids longer
than glutaric acid lead to cyclic ketones (eq 19).36
Also, 2-phenylsulfonyl ketones can be converted to aphenylthio-,-unsaturated ketones via the Pummerer reaction
using acetic anhydride and a catalytic amount of Methanesulfonic Acid (eq 25).43
(25)
(19)
The Pummerer reaction has been used many times in hetero

cyclic synthesis as shown in eq 26.
N-Acylanthranilic acids also cyclize when heated with acetic
anhydride (eq 20). The reaction proceeds in 81% yield with slow
distillation of the acetic acid formed.40
(26)
(20)
Pummerer Reaction. In 1910, Pummerer7 reported that sul

foxides react with acetic anhydride to give 2-acetoxy sulfides
(eq 21). The sulfoxide must have one -hydrogen. Alternative
reaction conditions include using Trifluoroacetic Anhydride and
acetic anhydride.
(21)
-Hydroxy sulfoxides undergo the Pummerer reaction upon

addition of sodium acetate and acetic anhydride to give ,diacetoxy sulfides. These compounds are easily converted to ahydroxy aldehydes (eq 22).41
(22)
The Pummerer rearrangement of 4-phenylsulfinylbutyric acid

with acetic anhydride in the presence of p-Toluenesulfonic Acid
leads to butanolide formation (eq 27).44 Oxidation with mChloroperbenzoic Acid followed by thermolysis then leads to an
unsaturated compound.
(27)
An unusual Pummerer reaction takes place with penicillin sul

foxide, leading to a ring expansion product as shown in eq 28.45
(28)
This led to discovery of the conversion of penicillin V

and G to cephalexin,46 a broad spectrum orally active anti
biotic (eq 29).
12
ACETIC ANHYDRIDE
(29)
A Pummerer-type reaction was carried out on a dithiane pro

tecting group to liberate the corresponding ketone (eq 30).47 These
were the only reaction conditions which provided any of the de
sired ketone.
(35)
This reaction has been extended to a synthesis of 2acetoxybenzodiazepine via an TV-oxide rearrangement (eq 36).
(36)
An application of the Polonovski reaction forms carbonylenamines. N-Methylpiperidone is reacted with m-CPBA
followed by acetic anhydride and triethylamine to give the carbonyl enamine (eq 37).49
(30)
(37)
Perkin Reaction. The Perkin reaction,8 developed by Perkin in

1868, involves the condensation of an anhydride and an aldehyde
in the presence of a weak base to give an unsaturated acid (eq 31).
(31)
The reaction is often used for the preparation of cinnamic acids

in 74-77% yield (eq 32).
(32)
Aliphatic aldehydes give low or no yields of acid. Coumarin

can be prepared by a Perkin reaction of salicylaldehyde and acetic
anhydride in the presence of triethylamine (eq 33).
(33)
Polonovski Reaction. In the Polonovski reaction,9 tertiary

amine oxides react with acetic anhydride to give the acetamide
of the corresponding secondary amine (eq 34).
Reaction with N-Oxides. Pyridine 1-oxide reacts with acetic

anhydride to produce 2-acetoxypyridine, which can be hydrolyzed
to 2-pyridone (eq 38).10
(38)
Open chain N-oxides, in particular nitrones, rearrange to

amides (almost quantitatively) under acetic anhydride conditions
(eq 39).50
(39)
Heteroaromatic N-oxides with a side chain react with acetic

anhydride to give side-chain acyloxylation (eq 40).51
(40)
This reaction has been used in synthetic chemistry as the method

of choice to form heterocyclic carbinols or aldehydes.
(34)
In nonaromatic cases, the Polonovski reaction gives the Nacylated secondary amine as the major product and the deaminated
ketone as a minor product (eq 35).48
Thiele Reaction. The Thiele reaction converts 1,4benzoquinone to 1,2,4-triacetoxybenzene using acetic anhydride
and a catalytic amount of Sulfuric Acid.11 Zinc chloride has
been used without advantage. In this reaction, 1,4-addition to the
quinone is followed by enolization and acetylation to give the
substituted benzene (eq 41).
ACETIC ANHYDRIDE
(41)
13
Cyclic ethers are cleaved to-bromoacetatesusing Magnesium

Bromide and acetic anhydride in acetonitrile (eq 47).55
(47)
With unhindered quinones, BF3 etherate is a more satisfactory

catalyst but hindered quinones require the more active sulfuric acid
catalyst. 1,2-Naphthoquinones undergo the Thiele reaction with
acetic anhydride and sulfuric acid or boron trifluoride etherate
(eq 42).
The reaction occurs with inversion of configuration, as shown

in eq 48.
(48)
(42)
Ether Cleavage. Dialkyl ethers can be cleaved with acetic an

hydride in the presence of pyridine hydrochloride or anhydrous
Iron(III) Chloride. In both cases, acetate products are produced.
As shown in eq 43, the tricyclic ether is cleaved by acetic an
hydride and pyridine hydrochloride to give the diacetate in 93%
yield.12
(43)
Simple dialkyl ethers react with iron(III) chloride and acetic an

hydride to produce compounds where both R groups are converted
to acetates (eq 44).52
(44)
Cleavage of allylic ethers can occur using acetic anhydride in

the presence of iron(III) chloride (eq 45). The reaction takes place
without isomerization of a double bond, but optically active ethers
are cleaved with substantial racemization.53
Trimethylsilyl ethers are converted to acetates directly by the

action of acetic anhydride-pyridine in the presence of 48% HF or
boron trifluoride etherate (eq 49).56
(49)
Miscellaneous Reactions. Primary allylic alcohols can be pre

pared readily by the action of p-toluenesulfonic acid in acetic
anhydride-acetic acid on the corresponding tertiary vinyl carbinol,
followed by hydrolysis of the resulting acetate.57 The vinyl
carbinol is readily available from the reaction of a ketone with
a vinyl Grignard reagent. Overall yields of allylic alcohols are
very good (eq 50).
(50)
Enol lactonization occurs readily on an -keto acid using acetic

anhydride at elevated temperatures.58 The reaction shown in eq 51
proceeds in 89% yield. In general, acetic anhydride is superior to
acetyl chloride in this reaction.59
(51)
(45)
Cleavage of aliphatic ethers occurs with the reaction of acetic

anhydride, boron trifluoride etherate, and Lithium Bromide
(eq 46). The ethers are cleaved to the corresponding acetoxy
compounds contaminated with a small amount of unsaturated
product.54 In some cases, the lithium halide may not be neces
sary.
(46)
Aliphatic aldehydes are easily converted to the enol acetate us

ing acetic anhydride and potassium acetate (eq 52).13 This reaction
only works for aldehydes and is the principal reason for the failure
of aldehydes to succeed in the Perkin reaction. Triethylamine and
DMAP may also catalyze the reaction.
(52)
A cyclopropyl ketone is subject to homoconjugate addition

using acetic anhydride/boron trifluoride etherate. Upon acetate
addition, the enol is trapped as its enol acetate (eq 53).60
14
ACETIC ANHYDRIDE
(53)
When an aldehyde is treated with acetic anhydride/anhydrous

iron(III) chloride, geminal diacetates are formed in good to excel
lent yields. 14 Aliphatic and unsaturated aldehydes can be used in
this reaction as shown in eqs 54-56. Interestingly, if an -hydrogen
is present in an unsaturated aldehyde, elimination of the geminal
diacetate product gives a 1-acetoxybutadiene.
(60)
Twistane derivatives were obtained by the reaction of a decalindione with acetic anhydride, acetic acid, and boron trifluoride
etherate(eq 61). 65
(61)
(54)
A condensation/cyclization reaction between an alkynyl ke

tone and a carboxylic acid in the presence of acetic anhydride/triethylamine gives a butenolide (eq 62). 66
(55)
(56)
If an aldehyde is treated with acetic anhydride in the presence

of a catalytic amount of Cobalt(II) Chloride, a diketone is formed
(eq 57). 61
(62)
A few rearrangement reactions take place with acetic anhy

dride. A Claisen rearrangement is involved in the formation of the
aromatic acetate in eq 63. 67 The reaction proceeds in 44% yield
even after 21 h at 200 C.
(57)
(63)
However, if 1.5 equiv of cobalt(II) chloride is added, the gem

inal diacetate is formed (eq 58). 62
Complex rearrangements have occured using acetic anhydride

under basic conditions, as shown in eq 64. 68
(58)
(64)
Apparently, the reaction in eq 58 occurs only when the starting

material is polyaromatic or with compounds whose carbonyl IR
frequency is less than 1685 c m - 1 .
Acetic anhydride participates in several cyclization reactions.
For example, enamines undergo a ring closure when treated with
acetic anhydride (eq 59). 63
Aromatization occurs readily using acetic anhydride. Aromatization of -cyclohexanones occurs under acidic conditions to lead
to good yields of phenols (eq 65). 69 However, in totally unsubstituted ketones, aldol products are formed.
(59)
(65)
o-Diamine compounds also cyclize when treated with acetic

anhydride (eq 60). 64
Aromatization of 1,4- and 1,2-cyclohexanediones leads to

cresol products (eq 66) in over 90% yield.70
ACETIC ANHYDRIDE
15
14. Kochhar, K. S.; Bal, B. S.; Deshpande, R. P.; Rajadhyaksha, S. N.;

Pinnick, H. W. JOC 1983, 48, 1765.
(66)
Alkynes and allenes are formed by the acylation of nitrimines

using acetic anhydride/pyridine with DMAP as catalyst (eqs 67
and 68).71 Nitrimines are prepared by nitration of ketoximes with
nitrous acid.
(67)
15. For analysis by titration, see Ref. 1c. Spectra available from the Aldrich
Library.
16.
Vogel's Textbook of Practical Organic Chemistry, 4th ed.; Longman:

Harlow, 1978; p 499.
17.
Perrin, D. D.; Armarego, W. L. F.; Perrin, D. R. Purification of

Laboratory Chemicals, 2nd ed.; Pergamon: Oxford, 1985; p 77.
18.
Stork, G.; Takahashi, T.; Kawamoto, I.; Suzuki, T. JACS 1978, 100, 8272.
19. Holfe, G.; Steglich, W.; Vorbruggen, H. AG(E) 1978, 17, 569.
20.
Vedejs, E.; Diver, S. T. JACS 1993, 115, 3358.
21.
Oppenauer, R. V. M 1966, 97, 62.
22.
Dauben, W. G.; Bunce, R. A.; Gerdes, J. M.; Henegar, K. E.;

Cunningham, A. F., Jr.; Ottoboni, T. B. TL 1983, 24, 5709.
23.
Nagao, Y.; Fujita, E.; Kohno, T.; Yagi, M. CPB 1981, 29, 3202.
24.
Vogel's Textbook of Practical Organic Chemistry, 4th ed.; Longman:

Harlow, 1978; pp 454-455.
25.
See Ref. 1(b) and Candoros, F., Rom. Patent 85 726, 1984; CA 1985,
103, 104 715.
(68)
Lastly, acetic anhydride participates in the Friedel-Crafts

reaction.72 Polyphosphoric Acid is both reagent and solvent in
these reactions (eq 69).
(69)
Related Reagents. Acetyl Chloride; Acetyl Bromide; Isopropenyl Acetate; Vinyl Acetate; Acetyl Cyanide.
1. (a) Kim, D. H. JHC 1976,13, 179. (b) Cook, S. L. Chemical Industries

1993,49,145. (c) Joy, E. F.; Barnard, A. J., Jr. Encyclopedia ofIndustrial
Chemical Analysis; Interscience: New York, 1967; Vol. 4, p 102.
26.
Barrett, A. G. M.; Lana, J. C. A. CC 1978, 471.
27.
Tiffeneau, M.; Fuhrer, K. BSF 1914, 15, 162.
28.
Fujita, T.; Suga, K.; Watanabe, S. AJC 1974, 27, 531.
29.
Freter, K.; Zeile, K. CC 1967, 416.
30.
(a) Dakin, H. D.; West, R. JBC 1928, 78, 745, 757 (b) Allinger, N. L.;
Wang, G. L.; Dewhurst, B. B. JOC 1974, 39, 1730. (c) Buchanan, G. L.
CS 1988, 17, 91.
31.
(a) Ferles, M. CCC 1964, 29, 2323. (b) Rueppel, M. L.; Rapoport, H.
JACS 1972, 94, 3877.
32.
Glebova, Z. I.; Uzlova, L. A.; Zhdanov, Y. A. ZOB 1985, 55, 1435; CA

1986,704,69072.
33.
Hanessian, S.; Rancourt, G. CJC 1977, 55, 1111.
34.
Newman, M. S.; Davis, C. C. JOC 1967, 32, 66.
35.
(a) Albright, J. D.; Goldman, L. JACS 1965, 87, 4214. (b) JOC 1965, 30,
1107.
36.
(a) Blanc, H. G. CR 1907, 144, 1356. (b) Ruzicka, L.; Prelog, V.; Meister,
P. HCA 1945, 28, 1651.
37.
Beringer, F. M.; Ugelow, I. JACS 1953, 75, 2635, and references cited
therein.
(a) Weber, H.; Khorana, H. G. J. Mol. Biol. 1972, 72, 219 (b) Zhdanov,
R. I.; Zhenodarova, S. M. S 1975, 222.
38.
Newnan, M. S.; Hung, W. M. JOC 1973, 38, 4073.
39.
3.
Mariella, R. P.; Brown, K. H. JOC 1971, 36, 735 and references cited
therein.
Boar, R. B.; McGhie, J. F.; Robinson, M.; Barton, D. H. R.; Horwell, D.

C ; Stick, R. V. JCS(P1) 1975, 1237.
40.
Zentmyer, D. T.; Wagner, E. C. JOC 1949, 14, 967.
4.
Zervas, L.; Photaki, I.; Ghelis, N. JACS 1963, 85, 1337.
41.
Iruichijima, S.; Maniwa, K.; Tsuchihashi, G. JACS 1974, 96, 4280.
5.
Albright, J. D.; Goldman, L. JACS 1967, 89, 2416.
42.
Iriuchijima, S.; Maniwa, K.; Tsuchihashi, G. JACS 1975, 97, 596.
6.
(a) Buck, J. S.; Ide, W. S. OSC 1943, 2, 622. (b) White, D. M. JOC 1974,
39, 1951. (c) Nicolet, B. H.; Pelc, J. J. JACS 1922, 44, 1145. (d) Bell, M.
R.; Johnson, J. R.; Wildi, B. S.; Woodward, R. B. JACS 1958, SO, 1001.
43.
(a) Monteiro, H. J.; de Souza, J. P. TL 1975, 927. (b) Monteiro, H. J.;

Gemal, A. L. S 1975, 437.
44.
7.
(a) Pummerer, R. B 1910, 43, 1401. (b) Parham, W. E.; Edwards, L. D.

JOC 1968, 33, 4150. (c) Tanikaga, R.; Yabuki, Y.; Ono, N.; Kaji, A. TL
1976, 2257.
Watanabe, M.; Nakamori, S.; Hasegawa, H.; Shirai, K.; Kumamoto, T.

BCJ 1981, 54, 817.
45.
Morin, R. B.; Jackson, B. G.; Mueller, R. A.; Lavagnino, E. R.; Scanlon,

W. S.; Andrews, S. L. JACS 1963, 85, 1896.
8.
(a) Rosen, T. COS 1991, 2, 395. (b) Merchant, J. R.; Gupta, A. S. CI(L)
1978, 628.
46.
9.
Polonovski, M.; Polonovski, M. BSF 1927, 41, 1190.
Chauvette, R. R.; Pennington, P. A.; Ryan, C. W.; Cooper, R. D. G.; Jose,

F. L.; Wright, I. G.; Van Heyningen, E. M.; Huffman, G. W. JOC 1971,
36, 1259.
Smith, A. B., III; Dorsey, B. D.; Visnick, M.; Maeda, T.; Malamas,
M.S. JACS 1986, 70S, 3110.
(a) See Ref. 9. (b) Polonovski, M.; Polonovski, M. BSF 1926, 39, 147.
(c) Wenkert, E. E 1954, 10, 346. (d) Cave, A.; Kan-Fan, C ; Potier, P.;
LeMen, J . T 1967, 23, 4681.
2.
10.
Katada, M. J. Pharm. Soc. Jpn. 1947, 67, 51.
47.
11.
(a) Thiele, J. B 1898, 31, 1247. (b) Thiele, J.; Winter, E. LA 1899, 311,
341.
48.
12.
(a) Peet, N. P.; Cargill, R. L. JOC 1973, 38, 1215. (b) Goldsmith, D. J.;
Kennedy, E.; Campbell, R. G. JOC 1975, 40, 3571.
13.
(a) Bedoukin, P. Z. OSC 1955, 3, 127. (b) Cousineau, T. J.; Cook, S. L.;
Secrist, J. A., III SC 1979, 9, 157.
49.
Sttitz, P.; Stadler, P. A. TL 1973, 5095.
50.
Tamagaki, S.; Kozuka, S.; Oae, S. T 1970, 26, 1795.

16
ACETYL CHLORIDE
51.
(a) Kobayashi, G.; Furukawa, S, CPB 1953, 1, 347. (b) Boekelheide, V.;
Lim, W. J. JACS 1954, 76, 1286. (c) Bullit, O. H., Jr.; Maynard, J. T.
JACS 1954, 76, 1370. (d) Berson, J. A.; Cohen, T. JACS 1955, 77, 1281.
52.
53.
54.
Knoevenagel, E. LA 1914,402, 111.

Ganem, B.; Small, V. R Jr. JOC 1974, 39, 3728.
(a) Youssefyeh, R. D.; Mazur, Y. TL 1962, 1287. (b) Narayanan, C. R.;
Iyer, K. N. TL 1964, 759.
Goldsmith, D. J.; Kennedy, E.; Campbell, R. G. JOC 1975, 40, 3571.
(a) Voaden, D. J.; Waters, R. M. OPP 1976, 8, 227. (b) For conversion
of ROTBS to ROAc using Ac2O and FeCl3, see Ganem, B.; Small,
V. R. JOC 1974, 39, 3728.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
Babler, J. H.; Olsen, D. O. TL 1974, 351.

Eggette, T. A.; deBoer, J. J. J.; deKoning, H.; Huisman, H. O. SC 1978,
8, 353.
Rosenmund, K. W.; Herzberg, H.; Schutt CB 1954, 87, 1258.
(a) Rigby, J. H.; Senanayake, C. JACS 1987, 709, 3147. (b) Rigby, J. H.;
Senanayake, C. JOC 1988, 53, 440.
Ahmad, S.; Iqbal, J. CC 1987, 692.
Fry, A. J.; Rho, A. K.; Sherman, L. R.; Sherwin, C. S. JOC 1991, 56,
3283.
Friary, R. J., Sr.; Gilligan, J. M.; Szajewski, R. P.; Falci, K. J.; Franck,
R. W. JOC 1973, 38, 3487.
Meth-Cohn, O.; Suschitzky, H. In Advances in Heterocyclic Chemistry;
Katritzky, A. R.; Boulton, J., Eds.; Academic Press: New York, 1972;
Vol. 14, p 213.
Belanger, A.; Lambert, Y.; Deslongchamps, P. CJC 1969, 47, 795.
Rao, Y. S.; Filler, R. TL 1975, 1457.
(a) Rhoads, S. J.; Raulins, N. R. OR 1975, 22, 1. (b) Karanewsky, D. S.;
Kishi, Y.; JOC 1976, 41, 3026.
Gryer, R. I.; Brust, B.; Earley, J. V; Sternbach, L. H. JCS(C) 1967, 366.
Kablaoui, M. S. JOC 1974, 39, 2126.
Kablaoui, M. S. JOC 1974, 39, 3696.
Bchi, G.; West, H. JOC 1979, 44, 4116.
Edwards, J. D.; McGuire, S. E.; Hignite, C. JOC 1964, 29, 3028.
Regina Zibuck
Wayne State University, Detroit, MI, USA
Acetyl Chloride 1
[75-36-5]
C2H3ClO
(MW 78.50)
(useful for electrophilic acetylation of arenes,2 alkenes,2a,3

alkynes,4 saturated alkanes,3a,5 organometallics, and enolates (on
C or O);6 for cleavage of ethers;7 for esterification of sterically unhindered8 or acid-sensitive9 alcohols; for generation of
solutions of anhydrous hydrogen chloride in methanol;10 as a
dehydrating agent; as a solvent for organometallic reactions;11
for deoxygenation of sulfoxides;12 as a scavenger for chlorine13
and bromine;14 as a source of ketene; and for nucleophilic
acetylation15)
Physical Data: bp 51.8 C;la mp -112.9C;1a d 1.1051 g cm -3 ; 1a
refractive index 1.38976.1b IR (neat) v 1806.7 cm-1;16 1H
NMR (CDCl3) 2.66 ppm; 13C NMR (CDCl3) 33.69 ppm
(q) and 170.26 ppm (s); the bond angles (determined by elec
tron diffraction17) are 127.5 (O-C-C), 120.3 (O-C-Cl), and
112.2 (Cl-C-C).
Analysis of Reagent Purity: a GC assay for potency has been
described;18 to check qualitatively for the presence of HC1, a
common impurity, add a few drops of a solution of crystal violet
in chloroform;19 a green or yellow color indicates that HC1 is
present, while a purple color that persists for at least 10 min
indicates that HC1 is absent.1b
Preparative Methods: treatment of Acetic Acid or sodium ac
etate with the standard inorganic chlorodehydrating agents
(PCl3,lb,23 SO2Cl2,1a,24 or SOCl21b,25) generates mate
rial that may contain phosphorus- or sulfur-containing
impurities.lb,23a,26 Inorganic-free material can be prepared by
treatment of HOAc with Cl2CHCOCl (; 70%),27 PhCOCl (;
88%),28 PhCCl3 (cat. H2SO4, 90 C; 92.5%),29 or phosgene30
(optionally catalyzed by DMF,30e magnesium or other metal
salts,30a,b,d or activated carbon30b,c), or by addition of hy
drogen chloride to acetic anhydride (85-90C; 'practically
quantitative').1a,31
Purification: HCl-free material can be prepared either by dis
tillation from dimethylaniline11c,20 or by standard degassing
procedures.20c,21
Handling, Storage, and Precautions: acetyl chloride should be
handled only in a well-ventilated fume hood since it is volatile
and toxic via inhalation.22 It should be stored in a sealed con
tainer under an inert atmosphere. Spills should be cleaned up
by covering with aq sodium bicarbonate.1a
Friedel-Crafts Acetylation. Arenes undergo acetylation to

afford aryl methyl ketones on treatment with acetyl chloride
(AcCl) together with a Lewis acid, usually Aluminum Chloride3.
This reaction, known as the Friedel-Crafts acetylation, is valuable
as a preparative method because a single positional isomer is pro
duced from arenes that possess multiple unsubstituted electronrich positions in many instances.
For example, Friedel-Crafts acetylation of toluene
(AcCl/AlCl3, ethylene dichloride, rt) affords p-methylacetophenone predominantly (p:m:o =97.6:1.3:1.2; eq 1).32
(1)
Acetylation of chlorobenzene under the same condi

tions affords p-chloroacetophenone with even higher selec
tivity (p:m = 99.5:0.5).33 Acetylation of bromobenzene33 and
fluorobenzene33 afford the para isomers exclusively. The
para.meta34 and para:ortho32,34 selectivities exhibited by
AcCl/AlCl3 are greater than those exhibited by most other
Friedel-Crafts electrophiles.
Halogen substituents can be used to control regioselectivity. For
example, by introduction of bromine ortho to methyl, it is possible
to realize 'meta acetylation of toluene' (eq 2).35
ACETYL CHLORIDE
(2)
Regioselectivity is quite sensitive to reaction conditions (e.g.

solvent, order of addition of the reactants, concentration, and
temperature). For example, acetylation of naphthalene can be di
rected to produce either a 99:1 mixture of C-1:C-2 acetyl deriva
tives (by addition of a solution of arene and AcCl in CS 2 to
a slurry of AlCl 3 in CS 2 at 0C) or a 7:93 mixture (by addi
tion of the preformed ACCl/AlCl3 complex in dichloroethane to
a dilute solution of the arene in dichloroethane at rt). 36 Sim
ilarly, acetylation of 2-methoxynaphthalene can be directed to
produce either a 98:2 mixture of C-l:C-6 acetyl derivatives (us
ing the former conditions) or a 4:96 mixture (by addition of
the arene to a solution of the preformed AcCl/AlCl3 complex
in nitrobenzene).37 Also, acetylation of 1,2,3-mesitylene can be
directed to produce either a 100:0 mixture of C-4:C-5 isomers or
a 3:97 mixture.36c
Frequently, regioselectivity is compromised by side reactions
catalyzed by the HC1 byproduct. For example, acetylation of pxylene by treatment with AlCl3 followed by Ac 2 O (CS 2 , , 1
h) produces a 69:31 mixture of 2,5-dimethylacetophenone and
2,4-dimethylacetophenone, formation of the latter being indica
tive of competitive acid-catalyzed isomerization of p-xylene to
m-xylene.38 Also, although acetylation of anthracene affords 9acetylanthracene regioselectively, if the reaction mixture is al
lowed to stand for a prolonged time prior to work-up (rt, 20 h)
isomerization to a mixture of C-1, C-2, and C-9 acetyl derivatives
occurs.39
These side reactions can be minimized by proper choice of re
action conditions. Isomerization of the arene can be suppressed
by adding the arene to the preformed ACCl/AlCl3 complex. This
order of mixing is known as the Terrier modification' of the
Friedel-Crafts reaction.40 Acetylation of p-xylene using this order
of mixing affords 2,5-dimethylacetophenone exclusively.38 Iso
merization of the product aryl methyl ketone can be suppressed
by crystallizing the product out of the reaction mixture as it is
formed. For example, on acetylation of anthracene in benzene at
5-10C, 9-acetylanthracene crystallizes out of the reaction mix
ture (as its 1/1 AlCl 3 complex) in pure form.39 Higher yields of
purer products can also be obtained by substituting Zirconium(IV)
Chloride41 or Tin(IV) Chloride42 for A1C13.
AcCl is not well suited for industrial scale Friedel-Crafts acetylations because it is not commercially available in bulk (only by
the drum) and therefore must be prepared on site.1 The combi
nation of Acetic Anhydride and anhydrous Hydrogen Fluoride,
both of which are available by the tank car, is claimed to be more
practical.43 On laboratory scale, AcCl/AlCl3 is more attractive
than Ac 2 O/HF or Ac 2 O/AlCl 3 . Whereas one equivalent of AlCl 3
is sufficient to activate AcCl, 1.5-2 equiv AlCl 3 (relative to arene)
are required to activate Ac 2 O. 36a,37b,38,44 Thus, with Ac 2 O, greater
amounts of solvent are required and temperature control during
the quench is more difficult. Also, slightly lower isolated yields
have been reported with Ac 2 O than with AcCl in two cases. 36a,45
However, it should be noted that the two reagents generally afford
similar ratios of regioisomers. 36a,38,46
17
Acetylation of Alkenes. Alkenes, on treatment with

ACCl/AlCl3 under standard Friedel-Crafts conditions, are
transformed into mixtures of -chloroalkyl methyl ketones, allyl
methyl ketones, and vinyl methyl ketones, but the reaction is
not generally preparatively useful because both the products and
the starting alkenes are unstable under the hyperacidic reaction
conditions. Preparatively useful yields have been reported only
with electron poor alkenes such as ethylene (dichloroethane,
5-10C; >80% yield of 4-chloro-2-butanone)47 and Allyl Chlo
ride (CCl4, rt; 78% yield of 5-chloro-4-methoxy-2-pentanone
after methanolysis),48 which are relatively immune to the effects
of acid.
The acetylated products derived from higher alkenes are suscep
tible to protonation or solvolysis which produces carbenium ions
that undergo Wagner-Meerwein hydride migrations. 49 For exam
ple, on subjection of cyclohexene to standard Friedel-Crafts acety
lation conditions (ACCl/AlCl3, CS 2 18 C), products formed in
clude not only 2-chlorocyclohexyl methyl ketone (in 40% yield) 50
but also 4-chlorocyclohexyl methyl ketone. 2a,51 If benzene is
added to the crude acetylation mixture and the temperature is then
increased to 40-45C for 3 h, 4-phenylcyclohexyl methyl ketone
is formed in 45% yield (eq 3). 49a,b
(3)
Wagner-Meerwein rearrangement also occurs during acety

lation of methylcyclohexene, even though the rearrangement is
anti-Markovnikov (-tertiary -secondary; eq 4). 52 Acetyla
tion of ris-decalin53 (see 'Acetylation of Saturated Alkanes' sec
tion below) also produces a -tertiary carbenium ion that under
goes anti-Markovnikov rearrangement. The rearrangement is ter
minated by intramolecular O-alkylation of the acetyl group by the
--carbenium ion to form a cyclic enol ether in two cases. 49c,53
(4)
Higher alkenes themselves are also susceptible to protonation.

The resulting carbenium ions decompose by assorted pathways
including capture of chloride (with SnCl4 as the catalyst), 51 ' 54 ad
dition to another alkene to form dimer or polymer, 5b,55 proton loss
(resulting in exo/endo isomerization), or skeletal rearrangement.56
18
ACETYL CHLORIDE
Higher alkenes can be acetylated in synthetically useful yield

by treatment with AcCl together with various mild Lewis acids.
One that deserves prominent mention is Ethylaluminum Dichloride (CH2Cl2, rt), which is useful for acetylation of all classes of
alkenes (monosubstituted, 1,2-disubstituted, and trisubstituted).57
For example, cyclohexene is converted into an 82/18 mixture of 3acetylcyclohexene and 2-chlorocyclohexyl methyl ketone in 89%
combined yield.
The following Lewis acids are also claimed to be superior
to AlCl3: Zn(Cu)/CH2I2 (AcCl, CH2Cl2, ), by which cyclo
hexene is converted into acetylcyclohexene in 68% yield (af
ter treatment with KOH/MeOH);58 ZnCl2 (AcCl, Et2O/CH2Cl2,
-75 C -20C), by which 2-methyl-2-butene is converted into
a 15:85 mixture of 3,4-dimethyl-4-penten-2-one and 4-chloro3,4-dimethyl-2-pentanone in 'quantitative' combined yield;59 and
SnCl4, by which cyclohexene (AcCl, CS2, 5 C rt) is con
verted into acetylcyclohexene in 50% yield (after dehydrochlorination with PhNEt2 at 180C),60 methylcyclohexene (CS2, rt) is
converted into 1 -acetyl-2-methylcyclohexene in 48% yield (after
dehydrochlorination),52 and camphene is converted into an acety
lated derivative in 65% yield.49c
Conducting the acetylation in the presence of a nonnucleophilic base or polar solvent is reported to be advantageous.
For example, methylenecyclohexane can be converted into 1cyclohexenylacetone in 73% yield by treatment with AcSbCU in
the presence of Cy2NEt (CH2Cl2, -50C -25C, 1 h)61 and
cyclohexene can be converted into 3-acetylcyclohexene in 80%
yield by treatment with AcBF4 in MeNO2 at -25 C.62
Employment of Ac2O instead of AcCl is also advantageous
in some cases. For example, methylcyclohexene can be converted
into 3-acetyl-2-methylcyclohexene in 90% yield by treatment with
ZnCl2 (neat Ac2O, rt, 12 h).63
Finally, alkenes can be diacetylated to afford pyrylium salts
by treatment with excess AcCl/AlCl3,55b,56,64 albeit in low yield
(eq 5).64a
(5)
Acetylation of Alkynes. Under Friedel-Crafts conditions

(AcCl/AlCl3, CCU, 0-5 C), acetylene undergoes acetylation to
afford -chlorovinyl methyl ketone in 62% yield4 and under sim
ilar conditions (AcSbF6, MeNO2, 25 C) 5-decyne undergoes
acetylation to afford 6-acetyl-5-decanone in 73% yield.65
Acetylation of Saturated Alkanes. Saturated alkanes, on
treatment with a slight excess of AcCl/AlCl3 at elevated tem
perature, undergo dehydrogenation (by hydride abstraction fol
lowed by deprotonation) to alkenes, which undergo acetylation
to afford vinyl methyl ketones. The hydride-abstracting species
is believed to be either the acetyl cation66 or HAlCl4,67 with
most evidence favoring the former. Perhaps because the alkenes
are generated slowly and consumed rapidly, and therefore are
never present in high enough concentration to dimerize, yields
are typically higher than those of acetylation of the corresponding
alkenes.53b,68 A similar hypothesis has been offered to explain the
phenomenon that the yield from acetylation of tertiary alkyl chlo

rides is typically higher than the yield from acetylation of the cor
responding alkenes.55b,64a For example, methylcyclopentane on
treatment with AcCl/AlCl3 (CH2Cl2, ) undergoes acetylation to
afford l-acetyl-2-methylcyclopentene in an impressive 60% yield
(eq 6).53b,66a
(6)
If the reaction is carried out with excess alkane, a second hydride

transfer occurs, resulting in reduction of the enone to the corre
sponding saturated alkyl methyl ketone.69,70 For example, stir
ring ACCl/AlCl3 in excess cyclohexane (30-35 C, 2.5 h) affords
2-methyl-l-acetylcyclopentane in 50% yield (unpurified; based
on AcCl)55a,69,71 and stirring AcCl/AlBr3 in excess cyclopentane
(20 C, 1 h) affords cyclopentyl methyl ketone in 60% yield (based
on AcCl; eq 7).55c
(7)
If the reaction is carried out with a substoichiometric amount

of alkane, the product is either a 2:1 adduct (if cyclic)53b,66a or
pyrylium salt (if acyclic).66b,68b
Unbranched alkanes also undergo acetylation, but at higher tem
perature, so yields are generally lower. For example, acetylation
of cyclohexane by ACCl/AlCl3 requires refluxing in CHCl3 and
affords l-acetyl-2-methylcyclopentene in only 36% yield.55c,72
Despite the modest to low yields, acetylation of alkanes pro
vides a practical method for accessing simple methyl ketones be
cause all the input raw materials are cheap.
Coupling with Organometallic Reagents. Coupling of
organometallic reagents with AcCl is a valuable method for prepa
ration of methyl ketones. Generally a catalyst (either a Lewis acid
or transition metal salt) is required.
Due to the large number and varied characteristics of the
organometallics, comprehensive coverage of the subject would
require discussion of each organometallic reagent individually,
which is far beyond the scope of this article. Information pertain
ing to catalyst and condition selection should therefore be accessed
from the original literature; some seminal references are given in
Table 1.
C-Acetylation of Enolates and Enolate Equivalents. 3Diketones can be synthesized by treatment of metal enolates with
AcCl. O-Acetylation is often a significant side reaction, but the
amount can be minimized by choosing a counterion that is bonded
covalently to the enolate6 such as copper132 or zinc,133 and by
using AcCl rather than Ac2O.6a Proton transfer from the prod
uct -diketone to the starting enolate is another common side
reaction.134 Alternative procedures for effecting C-acetylation
ACETYL CHLORIDE
that avoid or minimize these side reactions include Lewis acidcatalyzed acetylation of the trimethylsilyl enol ether derivative
(AcCycat. ZnCl 2 , CH2C12 or CH2C12/Et2O, rt) 135 and addition of
ketene to the morpholine enamine (AcCl/Et3N, CHC13, rt). 136
Table 1
A)
or by HgBr2/Et3SiBr-catalyzed equilibration of the cis
isomer.137
Catalyst Selection Chart i,ii
Organometallic R = Alkyl Vinyl

RLi
R 2 Mg
RMgX
19
139
N73
iv
N74
iv
Aryl
Alkynyl Allyliii
N 81
N80,82
N80,83
Pd85
Pd87
Pd85
D89
N90
(8)
Fe75
Cu 76
Mn76b,77
D78
N79
RCuLRZnL
N 80
Pd
85,86
I83a
D89
N 84
N88
(9)
iv
The silyl ketene acetal strategy can also be used to effect -acetylation of ,-unsaturated esters (AcCl/cat. ZnBr 2 , CH 2 Cl 2 ,
rt) 140 and -ketoesters (AcCl, Et 2 O, - 7 8 C). 141
N91
RCdL
RHgL
RBL3RA1L2
93
Al
Pd96
N 98
N102
Cu103
R 4 Al -
N91c,92b,d,e
N91C,92
Fe104
Al
Al 93
94
Pd96,97
N99,100
Ti94v
Al 95
vi
N101
vi
N85,102b
Pd85
Pd85
Cu104
RTlL2
N105
RSiL3
Al106,107
N105
Al107,108,109
A l 1 0 7 , 1 1 0 A l l 0 7 , 1 1 1 , 1 1 2 viii
vii
113 i x
Ti114x
RGeL3
RSnL3
RBiL2
RTiL2
RZrL3
RVLz
RMnL
Al106b
Pd115
Al106b
Pd117
Pd118
N117c
Pd
Rh119x
N121,122iv
123
N124iv
N
125
Cu
127
N128
RRh
RNiL
Pd115,116
T i 1 2 0 iv
Cu
127
N128
N 126
Cu127
N 128
Cu 127
Cu127
N128
Enol Acetylation. Enol acetylation of ketones can be effected

by formation of a metal enolate in which the metal is relatively
dissociated6 (such as potassium142 or magnesium 143 ) followed by
quenching with AcCl. Alternatively, enol acetates can be synthe
sized directly from the ketones. For example, 3-keto- 4,6 -steroids
can be converted into 2,4,6 -trienol acetates by treatment with
AcCl/PhNMe 2 or into 3,5,7 -trienol acetates by treatment with
AcCl/Ac 2 O. 144
Acetyl Bromide (AcBr) is apparently superior to AcCl as
a catalyst for enol acetylation, based on a report that 17benzoyloxyestra-4,9(10)-dien-3-one is converted into estradiol 3acetate-17-benzoate in higher yield at much lower temperature
using AcBr rather than AcCl (87.5% yield with 1:2 AcBr:Ac 2 O,
CH 2 Cl 2 , rt, 1 h (eq 10) vs. 81.0% yield with 1:2 AcCl:Ac 2 O, ,
4.5 h). 145
N129
N130
N130,131
Codes (in headings): L = unspecified ligand and X = halogen; codes (in

entries): N = no catalyst required, Fe = FeIII salt, Cu = CuI salt, Mn = MnI
salt, D = dipolar aprotic additive, I = LiI, Pd = Pd0 or PdII salt, A1 = A1Cl 3 ,
Ti = TiCl 4 , and Rh = ClRh(PPh 3 )3. ii Coupling occurs at metal-bearing carbon
with retention of configuration to afford RCOMe unless otherwise indicated.
iii
Coupling occurs at 7-carbon unless otherwise indicated. iv Product is ter
tiary alcohol. v Coupling occurs with inversion of configuration. vi Coupling
occurs at -carbon. vii Coupling occurs at 8-carbon. viii Substrate is allenic
silane and product is furan. ix Substrate is propargylsilane. x Coupling occurs
at -carbon.
Analogously, esters can be C-acetylated by conversion into

the corresponding silyl ketene acetal followed by treatment with
AcCl. Depending on the coupling conditions (neat AcCl 137 or
AcCl/Et3N138), either the cis--siloxycrotonate ester or the cor
responding ,-isomer is produced (eqs 8 and 9). The third
possible isomer (trans--siloxycrotonate) is accessible either
by silylation of the acetoacetic ester (TMSC1, Et 3 N, THF,
(10)
-Keto esters can be converted into either trans or cis enol ac

etates. The trans isomer is accessible by treatment with AcCl/Et 3 N
(HMPA, rt) 146 or AcCl/DBU (MeCN, 5C rt; eq 11), 147
while the cis isomer is accessible by treatment with isopropenyl
acetate/HOTs.146 Each isomer couples with dialkylcuprates with
retention of configuration to afford stereoisomerically enriched
,-unsaturated esters. 146,148
(11)
Attempted enol acetylation of -keto esters by quenching the

sodium enolate 146,147 or magnesium chelate 149 with AcCl afforded
C-acetylated products.
Avoid Skin Contact with All
Reagents
20
ACETYL CHLORIDE
Adducts with Aldehydes and Ketones. AcCl combines with

aldehydes150 (cat. ZnCl 2 or AlCl 3 150f ) to afford -chloroalkyl ac
etates. The reaction is reversible,151 but at equilibrium the ratio
of adduct to aldehyde is usually quite high, and the reaction is
otherwise clean (92% yield for acetaldehyde,150e 97% yield for
benzaldehyde; eq 12 150f ).
(12)
AcCl also adds to ketones, 150e,151,152 but the adducts are much
less thermodynamically stable, so significant amounts of the start
ing materials are present at equilibrium. 151,152a,b The equilibrium
can be biased in favor of the adduct by employing high concentra
tion, low temperature, a nonpolar solvent, excess AcCl, or AcBr or
Acl instead of AcCl. 151,153 For example, the acetone/AcCl adduct
can be obtained in good yield (85%) by treatment of acetone with
excess (2 equiv) AcCl (cat. ZnCl 2 , CC14, - 1 5 0 C). 152c
Reduction of the aldehyde/AcBr adducts 151,154 with Zinc
or Samarium(II)
Iodide to -acetoxyalkylzinc154,155 and
156
samarium
compounds, respectively, completes an umpolung
of the reactivity of the aldehyde.
Cleavage of Ethers. THF can be opened by treatment with
AcCl in combination with either Sodium Iodide (MeCN, rt, 21 h;
91 % yield of 4-iodobutyl acetate) 157 or a Lewis acid such as ZnCl 2
(, 1.5 h; 76% yield of 4-chlorobutyl acetate), 158 SnCl 4 , 159 CoCl 2
(rt, MeCN; 90%), 160 ClPdCH 2 Ph(PPh 3 ) 2 /Bu 3 SnCl (63 C, 48 h;
95%), 161 Mo(CO) 6 (hexane, ; 78%), 162 KPtCl 3 (H 2 CCH 2 ), and
[ClRh(H 2 CCH 2 ) 2 ] 2 (rt; 75% and 83%, respectively).163 Acyclic
dialkyl ethers can also be cleaved efficiently and in many cases
regioselectively.159
Many of these methods are applicable to deprotection of ethertype protecting groups. For example, benzyl and allyl ethers can
be deprotected by treatment with AcCl/cat. CoCl 2 160 or AcCl/cat.
ClPdCH 2 Ph(PPh 3 ) 2 /cat. Bu 3 SnCl. 161 Dimethyl acetals can be
cleaved selectively to aldehydes in the presence of ethylene ac
etals (AcCl/cat. ZnCl 2 , Me 2 S/THF, 0 C), 164 or to -chloro ethers
(AcCl/cat. SOCl 2 , 55+C).165 Tetrahydropyranyl (THP) ethers 166
and t-butyl ethers 167 can be deprotected by stirring in 1:10
AcCLHOAc (40-50C).
Finally, t-alkyl esters can be cleaved to anhydrides and t-alkyl
chlorides by treatment with AcCl (MeNO 2 , 70 C). 168
Esterification. Although AcCl is intrinsically more reactive
than Ac 2 O, in combination with various acylation catalysts
the reverse reactivity order is exhibited. For example, Ac2O
4-Dimethylaminopyridine (DMAP) acetylates ethynylcyclohexanol three times faster than AcCl/DMAP (CDCl 3 , 27 C). 169 Also,
isopropanol does not react with AcCl/Bu 3 P (CD 3 CN, - 8 C; <5%
conversion after 30 min), but after addition of sodium acetate re
acts rapidly to form isopropyl acetate (complete in <10 min). 170 As
a general rule, therefore, Ac2O is preferable for acetylation of hin
dered alcohols while AcCl is preferable for selective monoacetylation of polyols. 171
Examples of selective acetylations involving AcCl include:
acetylation of primary alcohols in the presence of secondary alco
hols by AcCl/2,4,6-collidine or i-PrNEt2 (CH 2 C1 2 , -78C); 8 , 1 7 2
acetylation of primary alcohols in the presence of secondary

alcohols, 173 and secondary alcohols in the presence of tertiary
alcohols, 174 by AcCl/pyridine (CH 2 C1 2 , - 7 8 C); monoacetylation of a 2,4-dihydroxyglucopyranose by AcCl/pyridine/15 C
(Ac2O/pyridine/0 C is less selective);175 and acetylation of
steroidal 5-hydroxyls (not 50) by AcCl/PhNMe 2 (CHC13, ). 176
Although Ac 2 O/DMAP 177 and Ac 2 O/Bu 3 P 170 are the pre
ferred reagents for acetylation of most hindered alcohols, sat
isfactory results can be obtained with AcCl in combination
with PhNMe 2 (CHC13, ), 178 PhNEt 2 (CHC13, ), 179 AgCN
(benzene or HMPA, 80 C), 180 magnesium powder (Et 2 O, ;
45-55% yield of r-BuOAc), 181 and Na 2 CO 3 (cat. PhCH 2 NEt 3 Cl,
CH 2 C1 2 , ; 79% yield of t-BuOAc). 182 Use of the combination of
AcCl/DMAP is not recommended since unidentified byproducts
may be generated.169
Although acetylations with AcCl/pyridine produce an
acidic byproduct (pyridine hydrochloride), it is possi
ble to acetylate highly acid-sensitive alcohols such as
2-(tributylstannylmethyl)allyl alcohol (eq 13)9b and 2(trimefhylsilylmethyl)allyl alcohol9a with AcCl/pyridine in
>90% yield without competing protiodestannylation or protiodesilylation by selecting a solvent (CH 2 Cl 2 ,OC) in which the
pyridine hydrochloride is insoluble.
(13)
Alternatively, acid-sensitive alcohols may be acetylated by deprotonation with n-Butyllithium (THF, 78 C) 183 or Ethylmagnesium Bromide (Et 2 O, rt) 1 8 4 followed by quenching with AcCl.
Finally, by using a chiral tertiary amine as the base, it is
possible to effect enantioselective acetylations. For example,
racemic 1-phenethyl alcohol has been partially resolved by treat
ment with AcCl in combination with (S)-()-N,N-dimethyl-lphenethylamine (CH 2 Cl 2 , - 7 8 C rt; ee of acetate 52%, ee of
alcohol 59.5%). 185
Generation of Solutions of Anhydrous Hydrogen Chloride
in Methanol. Esterification of alcohols by AcCl proceeds in the
absence of HC1 scavengers. For example, on addition of AcCl
to methanol at rt, a solution of hydrogen chloride and methyl
acetate in methanol forms rapidly.10 This reaction provides a more
practical method for access to solutions of HC1 in methanol than
the apparently simpler method of bubbling anhydrous HC1 into
methanol because of the difficulty of controlling the amount of
anhydrous HC1 delivered. Solutions of anhydrous HC1 in acetic
acid can presumably be prepared analogously by addition of AcCl
and an equimolar amount of H2O to HOAc.
Primary,186 secondary,187 and tertiary alcohols 178a,188 also react
with AcCl, but the product is the alkyl chloride rather than the
ester in most cases. Thus as a preparative esterification method
this reaction has limited generality.
AcCl also reacts with anhydrous p-toluenesulfonic acid (3-4
equiv AcCl, ) to afford acetyl p-toluenesulfonate in 97.5% yield
along with anhydrous HC1.189 AcCl does not react with HOAc to
generate HC1 and Ac 2 O, at least in appreciable amounts. 31
Dehydrating Agent. AcCl reacts with H2O to afford HC1 and
HOAc rapidly and quantitatively31b and thereby qualifies as a
ACETYL CHLORIDE
strong dehydrating agent. Examples of reactions in which AcCl
functions as a dehydrating agent include: cyclization of dicarboxylic acids to cyclic anhydrides (neat AcCl, ); 190 cyclization
of keto acids to enol lactones (neat AcCl, A); 191 dehydration of
nitro compounds into nitrile oxides (by treatment with NaOMe
followed by AcCl); 192 and conversion of allylic hydroperoxides
into unsaturated ketones (AcCl/pyridine, CHCl 3 , rt). 193 The dehy
drating power of AcCl has been invoked as a possible explanation
for its effectiveness for activation of zinc dust.194
In Situ Generation of High-Valent Metal Chlorides. Many
high-valent metal chlorides are useful as reagents in organic syn
thesis but are difficult to handle due to their moisture sensitiv
ity. AcCl can be used to generate such reagents in situ from the
corresponding metal oxides 11 or acetates.195 Examples include: chlorination of ketones by treatment with AcCl/Manganese Diox
ide (HOAc, rt); 196cis-1,2-dichlorinationof alkenes by treatment
with AcCl/(Bu 4 N) 4 MO 8 O 26 (CH 2 Cl 2 , rt); 197 and dichlorination of
alkenes by treatment with AcCl/MnO 2 /MnCl 2 (DMF, rt). 198 At
tempts to dichlorinate alkenes by treatment with AcCl/MnO 2 in
THF, however, failed due to cleavage of THF to 4-chlorobutyl
acetate. 196,199 A milder reagent that can be used to activate MnO 2
for dichlorination of alkenes in THF is Chlorotrimethylsilane.199
Solvent for Organometallic Reactions. Because of its cheap
ness, volatility, and ability to form moisture-stable solutions of
metal chlorides, AcCl is useful as a solvent for reactions involv
ing hygroscopic metal salts.11 For example, AcCl has been used as
a co-solvent for 1,2-chloroacetoxylation of alkenes by Chromyl
Chloride (1:2 AcCl:CH 2 Cl 2 , - 7 8 C rt). 200
Reaction with Heteroatom Oxides. The key step in a method
for -acetoxylation of aldehydes involves rearrangement of an
AcCl-nitrone adduct (eq 14).201 Analogous methods for benzoylation and -pivaloylation are higher yielding.
(14)
80% from nitrone
-Nitrostyrenes cyclize to indolinones on treatment with AcCl

(FeCl3, CH 2 C1 2 , 0C; eq 15).202
(15)
A high-yielding method for deoxygenation of sulfoxides to sul

fides involves treatment with 1.1 equiv Tin(II) Chloride in the
presence of a catalytic amount (0.4 equiv) of AcCl (MeCN/DMF,
0 C rt). 12 The mildness of this method is demonstrated by its
usability for deoxygenation of a cephalosporin sulfoxide (eq 16).
Another method for deoxygenation of sulfoxides involves treat
ment with two equiv AcCl (CH 2 Cl 2 , rt); 203 the oxidized byproduct
is claimed to be gaseous chlorine. 203
21
(16)
Chlorine and Bromine Scavenger. AcCl (cat. H 2 SO 4 ,

40-70 C) scavenges Cl 2 efficiently (to afford chloroacetyl chlo
ride in 87.1% yield). 13 AcCl also scavenges Br2 efficiently at
35 C. 14
Source of Ketene. AcCl reacts with Triethylamine at low tem
perature (20 C) to afford acetyltriethylammonium chloride. 204
This salt functions as a source of ketene (or the functional equiv
alent). For example, it reacts with silyl ketene acetals (THF, rt)
to afford silyl enol ethers of acetoacetic esters (eq 9), 138 with
-alkoxycarbonylalkylidenetriphenylphosphoranes (CH 2 Cl 2 , rt)
to afford allenic esters, 205 with enamines (Et 2 O, 0 C) to afford
cyclobutanones,136a with certain acyl imines (Et 2 O, 0 C) to form
formal [4 + 2] ketene cycloadducts,206 and with certain nonenolizable imines (Et 2 O, rt) to afford formal [4 + 2] diketene cy
cloadducts in up to 55% yield.207 Also, on refluxing in Et2O
in the absence of a trapping agent, diketene is formed in 50%
yield.208
ACCl/AlCl3 decomposes to acetylacetone on heating (CHCl 3 ,
54-61 C, 6 h; 82.5% yield after aqueous work-up). 209 The mech
anism presumably involves ketene as an intermediate. However,
an attempt to trap the ketene was unsuccessful.210
N-Acetylation. Primary and secondary amines can be Nacetylated to form acetamides by treatment with AcCl under
Schotten-Baumann conditions (aq NaOH), 211 but hydrolysis of
AcCl is a significant competing side reaction.212 Use of Ac2O
(2.5 equiv; , 10-15 min) is therefore recommended. 211
Tertiary amines react with AcCl to afford acetylammonium
salts. Ordinarily, these salts fragment to ketene on warming
(see above). However, those that possess a labile alkyl group
fragment by loss of the alkyl group (von Braun cleavage). For
example, bis(dimethylamino)methane reacts with AcCl (Et 2 O,
rt) to afford chloromethyldimethylamine,213 a useful Mannich
reagent, and 1,3,5-trimethylhexahydro-i-triazine reacts with AcCl
(CHCl 3 , , 1 h) to afford chloromethylmethyl acetamide, 214 a use
ful amidomethylation reagent.215 Also, aziridines react with AcCl
(PhH, 0C) to afford chloroethylacetamides.216 Allylic amines
react with in situ-generated AcI (AcCl/Cul, THF, rt) to afford
acetamides.217
AcCl also activates pyridines toward nucleophilic addition.
For example, phenylmagnesium chloride adds to pyridine in the
presence of AcCl (cat. Cul, THF, - 2 0 C rt) to afford, af
ter catalytic hydrogenation, N-acetyl-4-phenylpiperidine in 65%
yield.218 Also, AcCl catalyzes the reaction between sodium iodide
22
ACETYL CHLORIDE
and 2-chloropyridine to afford 2-iodopyridine (MeCN, A, 24 h;

55%).219
N-Acetylation of enolizable imines to afford enamides can be
accomplished by treatment with AcCl/PhNEt2. For example, treat
ment of crotonaldehyde cyclohexylimine with AcCl followed by
PhNEt2 (toluene, rt) affords the enamide in 88% yield.220
Primary urethanes can be N-acetylated to afford imides by
treatment with AcCl (100C, 1 h).221 Alternatively, urethanes
can be converted into acetamides by treatment with AcBr
(120-130 C)221 or in situ-generated Acl222 (MeCN, 60 C).223
Finally, a convenient method for preparation of JVTrimethylsilylacetamide (MSA), a useful trimethylsilyl transfer
reagent, involves treatment of Hexamethyldisilazane with AcCl
(hexane, A; 88%).224
5-Acetylation. Both aliphatic and aromatic thiols can be 5acetylated by treatment with AcCl (cat. CoCl2, MeCN, rt).225
Nucleophilic Acetylation. AcCl together with Sml2 (MeCN,
rt) or SmCp2 delivers the acetyl anion synthon to ketones to afford
the corresponding acyloins (eq 17).l5
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(a) Milstein, D.; Stille, J. K. JACS 1978, 100, 3636. (b) Milstein, D.;
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19, 41.
118.
Logue, M. W.; Teng, K. JOC 1982, 47, 2549.
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122.
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Kasatkin, A. N.; Kulak, A. N.; Tolstikov, G. A. JOM 1988, 346, 23.
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Inaba, S.; Rieke, R. D. JOC 1985, 50, 1373.

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Lapkin, 1.1.; Saitkulova, E G. JOU 1971, 7, 2586.
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137.
138. Rathke, M. W.; Sullivan, D. F. TL 1973, 1297.

139. Chiba, T.; Ishizawa, T.; Sakaki, J.; Kaneko, C. CPB 1987, 35, 4672.
140. Fleming, I.; Goldhill, J.; Paterson, I. TL 1979, 3209.
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688.
142. Ladjama, D.; Riehl, J. J. S 1979, 504.
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148. Casey, C. P.; Marten, D. E; Boggs, R. A. TL 1973, 2071.
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151. Bigler, P.; Neuenschwander, M. HCA 1978, 61, 2165.
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154.
155.
156.
157.
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(a) Bigler, P.; Schonholzer, S.; Neuenschwander, M. HCA 1978, 61,

2059. (b) Bigler, P.; Neuenschwander, M. HCA 1978, 61, 2381.
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JOC 1989, 54, 5202.
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160. (a) Ahmad, S.; Iqbal, J. CL 1987, 953. (b) Iqbal, J.; Srivastava, R. R. T
1991,47,3155.
161. Pri-Bar, I.; Stille, J. K. JOC 1982, 47, 1215.
162. Alper, H.; Huang, C.-C. JOC 1973, 38, 64.
163. Fitch, J. W.; Payne, W. G.; Westmoreland, D. JOC 1983, 48, 751.
164. Chang, C ; Chu, K. C ; Yue, S. SC 1992, 22, 1217.
165. (a) Straus, F.; Heinze, H. LA 1932, 493, 191. (b) Quintard, J.-P;
Elissondo, B.; Pereyre, M. JOM 1981, 272, C31. (c) Quintard, J.-R;
Elissondo, B.; Pereyre, M. JOC 1983, 48, 1559.
166.
(a) Bakos, T.; Vincze, I. SC 1989, 79, 523. (b) Sabharwal, A.; Vig, R.;
Sharma, S.; Singh, J. IJC(B) 1990, 29, 890.
167.
(a) Pop, L.; Oprean, I.; Barabas, A.; Hodosan, F. JPR 1986, 328, 867.
(b) Oprean, I.; Ciupe, H.; Gansca, L.; Hodosan, F. JPR 1987, 329, 283.
ACETYL CHLORIDE
168. Dutka, F.; Marton, A. F. ZN(B) 1969, 24, 1664.
169. Hofle, G.; Steglich, W.; Vorbruggen, H. AG(E) 1978,17, 569.
170. (a) Vedejs, E.; Diver, S. T. JACS 1993, 115, 3358. (b) Vedejs, E.;
Bennett, N. S.; Conn, L. M.; Diver, S. T.; Gingras, M.; Lin, S.; Oliver,
P. A.; Peterson, M. J. JOC 1993, 58, 7286.
171. 1,2-Diols can be selectively monoacetylated by conversion into the
cyclic dibutylstannylidene derivative followed by treatment with AcCl:
(a) Anchisi, C ; Maccioni, A.; Maccioni, A. M.; Podda, G. G 1983, 113,
73. (b) Roelens, S. JCS(P2) 1988, 2105. (c) Anderson, W. K.; Coburn,
R. A.; Gopalsamy, A.; Howe, T. J. TL 1990, 31, 169. (d) Getman, D.
P.; DeCrescenzo, G. A.; Heintz, R. M. TL 1991, 32, 5691.
172. -Picoline might be unsuitable as a pyridine replacement because
it reacts with AcCl to form N-acetyl-4-(acetylmethylidene)-l,4dihydropyridine under standard acetylation conditions (CH2Cl2, rt,
8-16 h): Ippolito, R. M.; Vigmond, S. U.S. Patent 4681 944, 1987.
173. (a) Okamoto, K.; Kondo, T.; Goto, T. T 1987, 43, 5909. (b) McClure,
K. F.; Danishefsky, S. J. JACS 1993, 115, 6094.
174. (a) Braun, M.; Devant, R. TL 1984, 25, 5031. (b) Devant, R.; Mahler,
U.; Braun, M. CB 1988, 121, 397.
175. Capek, K.; Steffkova, J.; Jary, J. CCC 1966, 31, 1854.
176. Bladon, P.; Clayton, R. B.; Greenhalgh, C. W.; Henbest, H. B.; Jones,
E. R. H.; Lovell, B. J.; Silverstone, G.; Wood, G. W.; Woods, G. F. JCS
1952, 4883.
177. (a) Litvinenko, L. M.; Kirichenko, A. I. DOK 1967, 176, 763. (b)
Steglich, W.; Hofle, G. AG(E) 1969, 8, 981. (c) Hofle, G.; Steglich,
W. S 1972, 619. (d) Scriven, E. F. V. CSR 1983, 12, 129.
178. (a) Norris, J. F.; Rigby, G. W. JACS 1932, 54, 2088. (b) Plattner, Pl. A.;
Petrzilka, Th.; Lang, W. HCA 1944, 27, 513. (c) Hauser, C. R.; Hudson,
B. E.; Abramovitch, B.; Shivers, J. C. OSC 1955, 3, 142. (d) Ohloff, G.
HCA 1958, 41, 845.
179. (a) Plattner, Pl. A.; Furst, A.; Koller,F.;Lang, W. HCA 1948, 31, 1455.
(b) Williams, K. I. H.; Rosenfeld, R. S.; Smulowitz, M.; Pukushima,
D. K. Steroids 1963, 1, 377. (c) Kido, F.; Kitahara, H.; Yoshikoshi, A.
JOC 1986, 57, 1478.
180. (a) Takimoto, S.; Inanaga, J.; Katsuki, T.; Yamaguchi, M. BCJ 1976,
49, 2335. (b) Amouroux, R.; Chan, T. H. TL 1978, 4453.
181. Spassow, A. OSC 1955, 3, 144.
182. (a) Illi, V. O. TL 1979, 2431. (b) Szeja, W. S 1980, 402.
183. (a) Perriot, P.; Normant, J. F.; Villieras, J. CR(C) 1979, 289, 259. (b)
Trost, B. M.; Tour, J. M. JOC 1989, 54, 484. (c) Corey, E. J.; Su, W.
TL 1990, 31, 2089.
184. (a) Evans, D. D.; Evans, D. E.; Lewis, G. S.; Palmer, P. J.; Weyell, D.
J. JCS 1963, 3578. (b) Duboudin, J. G.; Ratier, M ; Trouve, B. JOM
1987, 331, 181.
185. Weidert, P. J.; Geyer, E.; Horner, L. LA 1989, 533.
186. (a) Heyse, M. Ger. Patent 524435, 1929. (b) Searles, S. Jr.; Pollart, K.
A.; Block, F. JACS 1957, 79, 952. (c) Sharma, K. K.; Torssell, K. B. G.
T 1984, 40, 1085.
187. Kotsuki, H.; Kataoka, M.; Nishizawa, H. TL 1993, 34, 4031.
188. Bryant, W. M. D.; Smith, D. M. JACS 1936, 58, 1014.
189. Karger, M. H.; Mazur, Y. JOC 1971, 36, 528.
190. (a) Lennon, J. J.; Perkin, W. H. Jr. JCS 1928, 1513. (b) Zilkha, A.;
Liwschitz, Y JCS 1957, 4397. (c) Bose, N. K.; Chaudhury, D. N. T
1964, 20, 49.
191. (a) Turner, R. B. JACS 1950, 72, 579. (b) Rosenmund, K. W.; Herzberg,
H.; Schutt, H. CB 1954, 87, 1258. (c) Vignau, M.; Bucourt, R.; Tessier,
J.; Costerousse, G.; Nedelec, L.; Gasc, J.-C; Joly, R.; Warnant, J.;
Goffinet, B. U.S. Patent 3 453 267, 1969.
192. (a) Harada, K.; Kaji, E.; Zen, S. CPB 1980, 28, 3296. (b) Fleming, I.;
Moses, R. C ; Tercel, M.; Ziv, J. JCS(P1) 1991, 617.
193. Farrissey, W. J. Jr. U.S. Patent 3 291 834, 1966.
194. Stirring zinc dust with AcCl and CuCl (Et2O, rt ) produces an
active zinc couple capable of reacting with methylene bromide to form
the Simmons-Smith reagent: Friedrich, E. C; Lewis, E. J. JOC 1990,
55,2491.
25
195.
Watt, G. W.; Gentile, P. S.; Helvenston, E. P. JACS 1955, 77, 2752.
196.
197.
198.
199.
200.
201.
202.
Bellesia, F.; Ghelfi, F.; Pagnoni, U. M.; Pinetti, A. JCR(S) 1990, 188.
Nugent, W. A. TL 1978, 3427.
Bellesia, F.; Ghelfi, P.; Pagnoni, U. M.; Pinetti, A. SC 1991, 21, 489.
Bellesia, F.; Ghelfi, F.; Pagnoni, U. M.; Pinetti, A. JCR(S) 1989, 108.
Backvall, J. E.; Young, M. W.; Sharpless, K. B. TL 1977, 3523.
Cummins, C. H.; Coates, R. M. JOC 1983, 48, 2070.
(a) Demerseman, P.; GuiUaumel, J.; Clavel, J.-M.; Royer, R. TL 1978,
2011. (b) Guillaumel, J.; Demerseman, P.; Clavel, J.-M.; Royer, R.;
Platzer, N.; Brevard, C. T 1980, 36, 2459.
203.
204.
Numata, T.; Oae, S. C1(L) 1973, 277.

(a) Adkins, H.; Thompson, Q. E. JACS 1949, 71, 2242. (b) Paukstelis,
J. V.; Kim, M. JOC 1974, 39, 1503.
(a) Lang, R. W.; Hansen, H.-J. HCA 1980, 63, 438. (b) Lang, R. W.;
Hansen, H.-J. OS 1984, 62, 202. (c) Abell, A. D.; Morris, K. B.; Litten,
J. C. JOC 1990, 55, 5217.
(a) Burger, K.; Huber, E.; Sewald, N.; Partscht, H. Chem.-Ztg. 1986,
110, 83. (b) Sewald, N.; Riede, J.; Bissinger, P.; Burger, K. JCS(P1)
1992, 267.
Maujean, A.; Chuche, J. TL 1976, 2905.
Sauer, J. C. JACS 1947, 69, 2444.
Hunt, C. F. U.S. Patent 2737 528, 1956.
Matoba, K.; Tachi, M.; Itooka, T.; Yamazaki, T. CPB 1986, 34, 2007.
Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell, A. R. Vogel's
Textbook of Practical Organic Chemistry, 5th ed.; Longman/Wiley:
New York, 1989; pp 916, 1273.
(a) Sonntag, N. O. V. CRV 1953, 52, 237. (b) To minimize the amount
of hydrolysis, the acetylation should be run at pH = (x + 13.25)/2, where
x is the pKa of the protonated amine: King, J. F.; Rathore, R.; Lam, J.
Y. L.; Guo, Z. R.; Klassen, D. P. JACS 1992, 114, 3028.
205.
206.
207.
208.
209.
210.
211.
212.
213.
214.
215.
(a) Bohme, H.; Hartke, K. CB 1960, 93, 1305. (b) Kinast, G.; Tietze,
L.-R AG(E) 1976, 15, 239.
Kritzler, H.; Wanger, K.; Holtschmidt, H. U.S. Patent 3 242 202, 1966.
(a) Ikeda, K.; Morimoto, T.; Sekiya, M. CPB 1980, 28, 1178. (b) Ikeda,
K.; Terao, Y.; Sekiya, M. CPB 1981, 29, 1156.
216.
217.
218.
219.
220.
Okada, I.; Takahama, T.; Sudo, R. BCJ 1970, 43, 2591.

Caubere, P.; Madelmont, J.-C. CR(C) 1972, 275, 1305.
Comins, D. L.; Abdullah, A. H. JOC 1982, 47, 4315.
Corcoran, R. C ; Bang, S. H. TL 1990, 31, 6757.
(a) Oppolzer, W.; Bieber, L.; Francotte, E. TL 1979, 981. (b) Ng, K. S.;
Laycock, D. E.; Alper, H. JOC 1981, 46, 2899.
221. Ben-Ishai, D.; Katchalski, E. JOC 1951, 16, 1025.
222. Hoffmann, H. M. R.; Haase, K. S 1981, 715.
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851.
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225. Ahmad, S.; Iqbal, J. TL 1986, 27, 3791.
Bruce A. Pearlman
The Upjohn Company, Kalamazoo, MI, USA
26
ALUMINUM CHLORIDE
(3)
Aluminum Chloride1
X = OSO2Me, OSO2Cl
[7446-70-0]
AlCl3
(MW 133.34)
(Lewis acid catalyst for Friedel-Crafts, Diels-Alder, [2 + 2] cycloadditions, ene reactions, rearrangements, and other reactions)
(4)
Physical Data: mp 190C (193-194C sealed tube); sublimes at

180C; d2.44 g c m - 3 .
Solubility: sol many organic solvents, e.g. benzene, nitroben
zene, carbon tetrachloride, chloroform, methylene chloride, nitromethane, and 1,2-dichloroethane; insol carbon disulfide.
Form Supplied in: colorless solid when pure, typically a gray
or yellow-green solid; also available as a 1.0 M nitrobenzene
solution.
Handling, Storage, and Precautions: fumes in air with a strong
odor of HC1. AlCl 3 reacts violently with H 2 O. All containers
should be kept tightly closed and protected from moisture. lc
Use in a fume hood.
12
Friedel-Crafts Chemistry. AlCl 3 has traditionally been

used in stoichiometric or catalytic3 amounts to mediate
Friedel-Crafts alkylations and acylations of aromatic systems
(eq 1).
(5)
(6)
Treatment of aryl azides with AlCl 3 has been reported to give

polycyclic aromatic compounds (eq 7), 11 or aziridines when the
reactions are run in the presence of alkenes (eq 8). 12
(7)
(1)
This is a result of the Lewis acidity of AlCl 3 which complexes

strongly with carbonyl groups. 4 Adaptations of these basic reac
tions have been reported.5 In chiral systems, inter- and intramolec
ular acylations have been achieved without the loss of optical ac
tivity (eq 2). 6
(2)
Friedel-Crafts chemistry at an asymmetric center generally pro

ceeds with racemization, but the use of mesylates or chlorosulfonates as leaving groups has resulted in alkylations with excellent
control of stereochemistry.7 The reactions proceed with inversion
of configuration (eq 3). Cyclopropane derivatives have been used
as three-carbon units in acylation reactions (eq 4). 8 In conjunc
tion with triethylsilane, a net alkylation is possible under acylation
conditions (eq 5). 9 These conditions are compatible with halogen
atoms present elsewhere in the molecule. Acylation reactions of
phenolic compounds with heteroaromatic systems have also been
accomplished (eq 6). 10
(8)
n = 1, 2
The scope of Friedel-Crafts chemistry has been expanded be

yond aromatic systems to nonaromatic systems, such as alkenes
and alkynes and the mechanistic details have been investigated.13
The Friedel-Crafts alkylation14 and acylation15 of alkenes pro
vide access to a variety of organic systems (eq 9). The acyla
tion of alkynes provides access to cyclopentenone derivatives
(eq 10).16 In addition, one can use this chemistry to access indenyl
systems 17 and vinyl chlorides. 18 Allylic sulfones can undergo al
lylation chemistry (eq 11). 19
(9)
(10)
ALUMINUM CHLORIDE
27
The Ferrario reaction generates phenoxathiins from diphenyl

ethers (eq 19).27 The rearrangement of acyloxy aromatic systems
is known as the Fries rearrangement (eq 20).28 Aryl aldehydes
are produced by the Gatterman aldehyde synthesis (eq 21).29 The
initial step of the Haworth phenanthrene synthesis makes use of a
Friedel-Crafts acylation.30 The acylation of phenolic compounds
is called the Houben-Hoesch reaction (eq 22).31 The Leuckart
amide synthesis generates aryl amides from isocyanates (eq 23).32
(11)
The use of silyl derivatives in Friedel-Crafts chemistry has not

only improved the regioselectivity but extended the scope of these
reactions. Substitution at the ipso position occurs with aryl silanes
(eq 12).20 The ability of silyl groups to stabilize -carbenium
ions -effect) affords acylated products with complete control of
regiochemistry (eq 13).21
(19)
(20)
(12)
(21)
(13)
The use of silylacetylenes gives ynones (eq 14),22 cyclopentenone derivatives (eq 15),23 and -amino acid derivatives
(eq 16).24
(22)
(14)
(23)
(15)
(16)
Propargylic silanes undergo acylation to generate allenyl

ketones (eq 17),25 while alkylsilanes afford cycloalkanones
(eq 18).26
Amides can also be obtained by AlCl3 catalyzed ester amine

exchange which proceeds primarily without racemization of chiral centers (eq 24).33 The reaction of phenols with -keto esters is
known as the Pechmann condensation (eq 25).34 Aryl amines are
used in the Riehm quinoline synthesis (eq 26).35 Aromatic sys
tems may be coupled via the Scholl reaction (eq 27)36 and indole
derivatives are prepared in the Stolle synthesis (eq 28).37 In the
Zincke-Suhl reaction, phenols are converted to dienones (eq 29).38
(24)
(17)
(25)
(18)
Several name reactions are promoted by A1C13. For example, the

Darzens-Nenitzescu reaction is simply the acylation of alkenes.
(26)
28
ALUMINUM CHLORIDE
(27)
(28)
(34)
Rearrangements. AlCl3 catalyzed rearrangement of hydro

carbon derivatives to adamantanes has been well documented
(eq 35).45 Other rearrangements have been used in triquinane syn
thesis (eq 36).46
(29)
Diels-Alder Reactions. There is some evidence that AlCl3

catalysis of Diels-Alder reactions changes the transition state
from a synchronous to an asynchronous one.39 This also enhances
asymmetric induction by increasing steric interactions at one end
of the dieneophile. There are many examples of AlCl3 promoted
Diels-Alder reactions (eq 30).40 Hetero-Diels-Alder reactions
can be used to generate oxygen (eq 31)41 and nitrogen (eq 32)42
containing heterocycles.
(35)
(36)
Miscellaneous Reactions. AlCl3 has been used to catalyze the

addition of allylsilanes to aldehydes and acid chlorides (eq 37).47
Cyclic ethers (pyrans and oxepins) have been prepared with hydroxyalkenes (eq 38).48 The course of reactions between aldehy
des and allylic Grignard reagents can be completely diverted to
-allylation by AlCl3 (eq 39).49 The normal course of the reaction
gives --allylation products.
(37)
(30)
(38)
(31)
(39)
AlCl3 can be used to remove t-butyl groups from aromatic
(eq 40),50 thereby using this group as a protecting ele
ment for a ring position. AlCl3 has also been used to remove
p-nitrobenzyl (PNB) and benzhydryl protecting groups (eq 41).51
The combination of AlCl3 and Ethanethiol has formed the ba
sis of a push-pull mechanism for the cleavage of many types of
bonds including C-X,52 C-NO2,53 C=C, 54 and C-O.55 Further
more, AlCl3 has been used to catalyze chlorination of aromatic
rings,56 open epoxides,57 and mediate addition of dichlorophosphoryl groups to alkanes.58
rings
(32)
AlCl3 can also be used to catalyze [2 + 2] cycloaddition reac

tions (eq 33)43 and ene reactions (eq 34).44
(33)
(40)
ANTIMONY(V) FLUORIDE
(41)
Related Reagents. Antimony(V) Fluoride; Boron Trifluoride

Etherate; Diethylaluminum Chloride; Dimethylaluminum Chlo
ride; Ethylaluminum Dichloride; Methylaluminum Dichloride;
Tin(IV) Chloride; Titanium(IV) Chloride; Triethylaluminum;
Trimethylaluminum.
1.
(a) Thomas, C. A. Anhydrous Aluminum Chloride in Organic Chemistry;

ACS Monograph Series; Reinholdt: New York, 1941. (b) Shine, H. J.
Aromatic Rearrangements; Elsevier: Amsterdam, 1967. (c) FF 1967, 7,
24. (d) Olah, G. A. Friedel-Crafts Chemistry; Wiley: New York, 1973.
(e) Roberts, R. M.; Khalaf, A. A. Friedel-Crafts Alkylation Chemistry;
Marcel Dekker: New York, 1984.
31.
Spoerri, P. E.; Dubois, A. S. OR 1949, 5, 387.
32.
Effenberger, F.; Gleiter, R. CB 1964, 97, All.
29
33.
Gless, R. D. SC 1986, 76, 633.
34.
Sethna, S.; Phadke, R. OR 1953, 7, 1.
35.
Elderfield, R. C.; McCarthy, J. R. JACS 1951, 73, 975.
36.
Clowes, G. A. JCS(P1) 1968, 2519.
37.
Sumpter, W. C. CR 1944, 34, 393.
38.
Newman, M. S.; Wood, L. L. JACS 1959, 81, 6450.
39.
Tolbert, L. M.; Ali, M. B. JACS 1984, 706, 3806.
40.
(a) Cohen, N.; Banner, B. L.; Eichel, W.F.SC 1978, 8, 427. (b) Fringuelli,
F.; Pizzo, F.; Taticchi, A.; Wenkert, E. SC 1979, 9, 391. (c) Ismail, Z.
M.; Hoffmann, H. M. R. JOC 1981, 46, 3549. (d) Vidari, G.; Ferrino,
S.; Grieco, P. A. JACS 1984, 706, 3539. (e) Angell, E. C ; Fringuelli, F.;
Guo, M.; Minuti, L.; Taticchi, A.; Wenkert, E. JOC 1988, 53, 4325.
41.
Ismail, Z. M.; Hoffmann, H. M. R. AG(E) 1982, 21, 859.
42.
LeCoz, L.; Wartski, L.; Seyden-Penne, J.; Chardin, P.; Nierlich, M. TL

1989, 30, 2795.
43.
Jung, M. E.; Haleweg, K. M. TL 1981, 22, 2735.
44.
(a) Snider, B. B.; Rodini, D. J.; Conn, R. S. E.; Sealfon, S. JACS 1979,
707, 5283. (b) Mehta, G.; Reddy, A. V. TL 1979, 2625. (c) Snider, B. B.
ACR 1980, 13, 426.
45.
(a) Bingham, R. C; Schleyer, P. R. Top. Curr. Chem. 1971, 18, 1. (b)

McKervey, M. A. CSR 1974, 3, 479. (c) McKervey, M. A. T 1980, 36,
971.
46.
Kakiuchi, K.; Ue, M.; Tsukahara, H.; Shimizu, T.; Miyao, T.; Tobe, Y.;
Odaira, Y.; Yasuda, M.; Shima, K. JACS 1989, 111, 3707.
47.
(a) Deleris, G.; Donogues, J.; Calas, R. TL 1976, 2449. (b) Pillot, J.-P;
Donogues, J.; Calas, R. TL 1976, 1871.
9. Jaxa-Chamiel, A.; Shah, V. P.; Kruse, L. I. JCS(P1) 1989, 1705.

10. (a) Pollak, A.; Stanovnik, B.; Tisler, M. JOC 1966, 31, 4297. (b) Coates,
W. J.; McKillop, A. JOC 1990, 55, 5418.
11. Takeuchi, H.; Maeda, M.; Mitani, M.; Koyama, K. CC 1985, 287.
48.
Coppi, L.; Ricci, A.; Taddai, M. JOC 1988, 55, 911.
49.
Yamamoto, Y.; Maruyama, K. JOC 1983, 48, 1564.
50.
Lewis, N.; Morgan, I. SC 1988, 18, 1783.
51.
Ohtani, M.; Watanabe, F.; Narisada, M. JOC 1984, 49, 5271.
12. Takeuchi, H.; Shiobara, Y.; Kawamoto, H.; Koyama, K. JCS(P1) 1990,
321.
13. (a) Puck, R.; Mayr, H.; Rubow, M.; Wilhelm, E. JACS 1986, 108, 7767.
(b) Brownstein, S.; Morrison, A.; Tan, L. K. JOC 1985, 50, 2796.
52.
Node, M.; Kawabata, T.; Ohta, K.; Fujimoto, M.; Fujita, E.; Fuji, K. JOC
1984,49,3641.
53.
Node, M.; Kawabata, T.; Ueda, M.; Fujimoto, M.; Fuji, K.; Fujita, E. TL
1982, 23, 4047.
14. Mayr, H.; Striepe, W. JOC 1983, 48, 1159.
54.
Fuji, K.; Kawabata, T.; Node, M.; Fujita, E. JOC 1984, 49, 3214.
15.
55.
Node, M.; Nishide, K.; Ochiai, M.; Fuji, K.; Fujita, E. JOC 1981, 46,
5163.
Watson, W. D. JOC 1985, 50, 2145.
2.
Gore, P. H. CR 1955, 55, 229.
3.
Pearson, D. E.; Buehler, C. A. S 1972, 533.
4.
(a) Tan, L. K.; Brownstein, S. JOC 1982, 47, 4737. (b) Tan, L. K.;
Brownstein, S. JOC 1983, 48, 3389.
5. Drago, R. S.; Getty, E. E. JACS 1988, 110, 3311.
6. McClure, D. E.; Arison, B. H.; Jones, J. H.; Baldwin, J. J. JOC 1981,
46, 2431.
7. Piccolo, O.; Spreafico, F.; Visentin, G.; Valoti, E. JOC 1985, 50, 3945.
8. Pinnick, H. W.; Brown, S. P.; McLean, E. A.; Zoller, L. W. JOC 1981,
46, 3758.
(a) Ansell, M. F.; Ducker, J. W. JCS 1960, 5219. (b) Cantrell, T. S. JOC
1967,32, 1669. (c)Groves, JK. CSR 1972, 1, 73. (d)House, H. O. Modern
Synthetic Reactions; Benjamin-Cummings: Menlo Park, CA, 1972; pp
786-816.
16.
(a) Martin, G. J.; Rabiller, C ; Mabon, G. TL 1970, 3131. (b) Rizzo, C.

J.; Dunlap, N. A.; Smith, A. B. JOC 1987, 52, 5280.
17. Maroni, R.; Melloni, G.; Modena, G. JCS(P1) 1974, 353.
18. Maroni, R.; Melloni, G.; Modena, G. JCS(P1) 1973, 2491.
19. Trost, B. M.; Ghadiri, M. R. JACS 1984, 706, 7260.
20.
21.
22.
23.
24.
(a) Eaborn, C. JCS 1956, 4858. (b) Habich, D.; Effenberger, F. S 1979,
841.
(a) Fleming, I.; Pearce, A. CC 1975, 633. (b) Fristad, W. E.; Dime, D.
S.; Bailey, T. R.; Paquette, L. A. TL 1979, 1999.
(a) Walton, D. R. M.; Waugh, F. JOM 1972, 37, 45. (b) Newman, H. JOC
1973, 38, 2254.
Karpf, M. TL 1982, 23, 4923.
Casara, P.; Metcalf, B. W. TL 1978, 1581.
25.
Flood, T.; Peterson, P. E. JOC 1980, 45, 5006.
26.
27.
Urabe, H.; Kuwajima, I. JOC 1984, 49, 1140.

Ferrario, E. BSF 1911, 9, 536.
28.
(a) Blatt, A. H. OR 1942, 7, 342. (b) Gammill, R. B. TL 1985, 26, 1385.
29.
Truce, W. E. OR 1957, 9, 37.
30.
Berliner, E. OR 1949, 5, 229.
56.
57.
Eisch, J. J.; Liu, Z.-R.; Ma, X.; Zheng, G.-X. JOC 1992, 57, 5140.
58.
Olah, G. A.; Farooq, O.; Wang, Q.; Wu, A.-H. JOC 1990, 55, 1224.
University
Paul Galatsis
of Guelph, Ontario,
Canada
Antimony(V) Fluoride 1
[7783-70-2]
F5Sb
(MW 216.74)
(one of the strongest Lewis acids,1 used as catalyst for

Friedel-Crafts reactions, isomerization, and other acid related
chemistry;1 an efficient acid system for preparation of carbocations and onium ions as well as their salts;1 afluorinatingagent,
and a strong oxidant)
30
Alternate Name: antimony pentafluoride.

Physical Data: bp 149.5 C.
Solubility: SbF 5 reacts with most organic solvents, forming solids
with ether, acetone, carbon disulfide, and petroleum ether. SbF5
is soluble in SO 2 and SO2C1F.
Form Supplied in: viscous liquid; commercially available.
Handling, Storage, and Precautions: SbF5 is extremely corrosive,
toxic, and moisture sensitive. It can be purified by distillation.
SbF 5 fumes when exposed to atmosphere. It should be stored
under anhydrous conditions in a Teflon bottle and handled using
proper gloves in a well ventilated hood.
Antimony pentafluoride is one of the strongest Lewis acids re
ported and is capable of forming stable conjugate superacid sys
tems with HF and FSO 3 H (see Hydrogen Fluoride-Antimony(V)
Fluoride and Fluorosulfuric Acid-Antimony(V) Fluoride).1 Its
complex with Trifluoromethanesulfonic Acid is, however, less
stable and cannot be stored for extended periods of time. Never
theless, CF 3 SO 3 H/SbF 5 is also auseful acid system when prepared
in situ.2 The most important properties of SbF5 include its high
acidity, strong oxidative ability, and great tendency to form stable
anions. 3 The chemistry of SbF5 is mainly characterized by these
properties. The major applications of SbF 5 in organic synthesis in
clude oxidation, fluorination, and as a catalyst for Friedel-Crafts
type reactions and other acid related chemistry, and as a medium
for preparation of carbocations and onium ions. 1
as acylating agents, diketones are obtained as the reaction products

(eq 2). The reaction of the anhydrides of dicarboxylic acids with
aromatic compounds does not stop at the keto acid stage, as is the
case when other Lewis acids are used. Using phosgene in place of
acid chlorides results in the formation of pentafluorobenzoic acid
in good yield.3
(2)
Perfluorobenzenium salt can be conveniently prepared from

the reaction of 1,4-perfluorocyclohexadiene with SbF 5 . 7 a - c In the
presence of SbF5, this salt is able to react with three equivalents
of pentafluorobenzene to yield perfluoro-1,3,5-triphenylbenzene
(eq 3). 7 a - c When 2,2'-di-H-octafluorobiphenyl is used as the sub
strate, perfluorotriphenylene is obtained in 50% yield (eq 4). Perfluoronaphthlenenium ion also reacts with polyfluorinated arenes
in a similar fashion. 7a-c The above reaction offers a facile ap
proach for the preparation of these perfluorinated polynuclear aro
matic compounds. Oxidation of perchlorobenzene with SbF5 in
the presence of pentafluorobenzene leads to the formation of cou
pling products.7d
(3)
Friedel-Crafts and Related Chemistry. The use of SbF 5 as

a Friedel-Crafts catalyst has significantly expanded the scope of
these reactions.3 This is made possible through the strong Lewis
acidity and oxidative ability of SbF 5 . Influenced by the strong
acidity, compounds of otherwise very weak nucleophilicity such
as perfluorocarbons can react readily with aromatics. Furthermore,
the strong oxidative ability of SbF5 enables unconventional sub
strates such as methane to be oxidized to form positively charged
species, which in turn can be applied as electrophilic reagents. On
the other hand, these factors also considerably restrict the use of
SbF5 in organic synthesis since the high reactivity makes it a less
selective Lewis acid for many reactions.
Alkylation of arenes proceeds readily under SbF5 catalysis. 3
In addition to alkyl halides, alkyl esters and haloesters have also
been applied to alkylate arenes under the reaction conditions.4
Perfluoro or perchlorofluoro compounds have been similarly used
as alkylating agents in the presence of SbF 5 . 5 For example, perfluorotoluene reacts with pentafluorobenzene to form perfluorodiphenylmethane in 68% yield after the reaction mixture is
quenched with HF. When H 2 O is used in the quenching step,
perfluorobenzophenone is obtained in 93% yield (eq l). 5 a
(1)
Acylation of pentafluorobenzene to form ketones either with

acid halides or with anhydrides has been achieved with an excess
of SbF5 . 6 In the case of dicarboxylic acid dichlorides or anhydrides
(4)
Friedel-Crafts sulfonylation of aromatics with alkane- and arenesulfonyl halides and anhydrides has been studied.8 Good yields
of sulfones are generally obtained (eq 5). In the case of pentafluorobenzenesulfonyl fluoride with pentafluorobenzene, decafluorodiphenyl sulfone is formed along with decafluorodiphenyl.8c A
convenient approach for synthesizing symmetrical aryl sulfones
is to react aromatics with Fluorosulfuric Acid in the presence of
SbF 5 (eq 6). 9 Certain phenylacetylenes react with SO2 and ben
zene in the presence of SbF5 to form benzothiophene S-oxides10
(eq 7). In some cases, 1,1-diphenylvinylsulfinic acids were also
obtained as side products of the reaction. Sulfinyl fluoride reacts
with arenes similarly under the catalysis of SbF 5 to give sulfoxides
(eq 8). 8c
(5)
X = Cl, F, RSO 3
(6)
31
In the presence of SbF5, alkyl chlorides are ionized to form car

bocations, which can be trapped with CO.15 Quenching the reac
tion intermediates with water or alcohols yields the corresponding
carboxylic acids or esters. For instance, halogenated trishomobarrelene reacts with CO in SbF5/SO2ClF to give, after treatment
with alcohol and water, a mixture of acid and ether (eq 13).15a
(7)
(13)
53%
(8)
Oxidation of elemental sulfur and selenium with SbF5 leads

to the formation of doubly charged polyatomic cations.11 These
cations are able to react with polyfluorinated arenes to form diaryl
sulfides or selenides (eq 9), 12a-c Under similar treatment, polyfluorodiaryl disulfides or diselenides also react with aromatics to
form diaryl sulfides and selenides, respectively (eq 10).12a,12b
24%
Studies have been carried out on the alky lation of alkenes in the
presence of SbF5, especially fluoroalkenes.16 For example, treat
ment of 1,1,1 -trifluoroethane with SbF5 in the presence of tetrafluoroethylene yields 90% of l,l,l,2,2,3,3-heptafluorobutane.16c
Perfluoroallyl or -benzoyl compounds with varying structures
have also been utilized as alkyating agents (eqs 14 and 15).16b,e-h
At elevated temperatures, intramolecular alkylation was ob
served in certain cases with perfluorodienes, forming perfluorocyclopentenes or perfiuorocyclobutenes (eq 16).17
(14)
(9)
X = F, CF 3
X = H, F, Br, SMe
(10)
(15)
X = F, Cl; Ar = polyfluoroaryl
In the presence of SbF5, inorganic halides such as NaCl and

NaBr can serve as electrophilic halogenating agents.5b,13 Even
deactivated arenes such as 5H-nonafluoroindan can be brominated
under the reaction conditions (eq 11 ).13b
33%
39%
(16)
(11)
Functionalization of alkanes has been achieved under SbF5

catalysis.3 Halogenation of alkanes is one of the widely studied
reactions in this field.14 A valuable synthetic procedure is the re
action of alkanes with methylene chloride (or bromide) in the
presence of SbF5 (eq 12).14d In these reactions, halonium ions are
initially formed, which in turn abstract hydride from hydrocar
bons. Quenching of the resulting carbocations with halides leads
to the desired haloalkanes.
Acylation of alkenes can also be similarly effected with

SbF5.18 Reaction of acetyl fluoride with trifluoroethylene pro
duces l,l,l,2-tetrafluorohexane-3,5-dione in 40% yield.18a When
antimony pentafluoride is used in excess (more than 6 molar equiv
alents), 1, 1, 1, 2-tetrafluorobutan-3-one is formed as a side product.
Benzoyl fluoride reacts with difluoroethylene to form the expected
ketone in 39% yield.18a ,-Unsaturated carboxylic acid fluorides
have also been used in reactions with perfluoroalkenes.18b In these
cases, a,-unsaturated ketones are obtained (eq 17). Enol acetates
of perfluoroisopropyl methyl ketone and perfiuoro-f-butyl methyl
ketone react with acetyl fluoride to provide the corresponding diketones (eq 18).18c
(12)
RH = secondary, tertiary alkanes
X = Cl, Br
(17)
32
(18)
32-35%
32-40%
Oxygenation of dienes with molecular oxygen to form

Diels-Alder-type adducts can be effected by Lewis acids and some
salts of stable carbenium ions.19 In the case of ergosteryl acetate,
SbF5 is by far the most active catalyst (eq 19).19a
When hexachlorobenzene is subjected to SbF5 treatment, 44%

of l,2-dichloro-3,3,4,4,5,5,6,6-octafluorocyclohex-1-ene is ob
tained as the major product of the reaction (eq 23).23 Using
SbCI5 as reaction solvent leads to better reaction control, result
ing in an increase in the product yield.23c In the case of polyfluoronaphthalenes, polyfluorinated tetralins are obtained.23d Treat
ment of hexafluoro-2-trichloromethyl-2-propanol with SbF5 gives
perfluoro-t-butyl alcohol in 92% yield (eq 24).24
(23)
(19)
(24)
Isomerization and Rearrangement. Isomerization of perfluoroalkenes can be realized with SbF5 catalysis.20 The terminal
carbon-carbon bonds of these alkenes are usually moved to the
2-position under the influence of this catalyst (eq 20). A further in
ward shift generally occurs only if H or CI atoms are present in the
4-position of the alkenes. As a rule, the isomerization leads to the
predominant formation of the trans isomers. Terminal fluorodienes also isomerize exothermally into dienes containing internal
double bonds in the presence of SbF5. With a catalytic amount
of SbF5, perfluoro-l,4-cyclohexadiene disproportionates to hexafluorobenzene and perfluorocyclohexene. The disproportionation proceeds intramolecularly in the case of perfluoro-1,4,5,8tetrahydronaphthalene. The starting material is completely con
verted to perfluorotetralin (eq 21).20f
(20)
Hydrolysis of CF3 groups to CO2H can be induced by SbF5.25a

In this reaction, the CF3-bearing compounds are first treated
with SbF5 and the resulting reaction mixtures are subsequently
quenched with water to form the desired products. For example,
perfluorotoluene was converted to pentafluorobenzoic acid in 86%
yield by this procedure. When perfluoroxylenes and perfluoromesitylene go through the same treatment, the corresponding di- or
triacids are obtained in high yields. It is also possible to partially
hydrolyze perfluoroxylenes and perfluoromesitylene through a
stepwise procedure and to isolate intermediate products. The hy
drolysis procedure is also applicable to other halogen-containing
compounds.25b
Under SbF5 catalysis, Trifluoromethanesulfonic Anhydride
is readily decomposed to trifluoromethyl triflate in high yield
(eq 25).26 This method is the most convenient procedure reported
for preparation of the triflate.
(CF3SO2)2O
CF3SO3CF3
(25)
(21)
Like most Lewis acids, SbF5 promotes the rearrangement of
epoxides to carbonyl compounds,21 and SbF5 is an efficient cat
alyst for this reaction. However, the migratory aptitude of sub
stitutent groups in the reaction under SbF5 catalysis is much less
selective compared to that promoted by weak Lewis acids such
as Methylaluminum Bis(4-bromo-2,6-di-t-butylphenoxide).21a
Nevertheless, SbF5 is well suited for the rearrangement of
perfluoroepoxides.21b-e Excellent yields of ketones are obtained
from the reaction. When diepoxides are used, diketones are ob
tained as the reaction products (eq 22).21c
CF3CO(CF2)2COCF3 (22)
Fluorination and Transformation of Fluorinated Com

pounds. SbF5 is a strong fluorinating agent. However, its use
is largely limited to the preparation of perfluoro- or polyfluoroorganic compounds.22 SbF5 has also been used for transformation
of perfluoro compounds.22
Preparation of Carbocations, Onium Ions, and Their

Salts. SbF5 is a preferred medium for the preparation of car
bocations and onium ions.1 In fact, the first observation of sta
ble carbocations was achieved in this medium.1,27 By dissolving
t-butylfluoridein an excess of SbF5, the t-butyl cation was ob
tained (eq 26). Subsequently, many alkyl cations have been ob
tained in SbF5 (either neat or diluted with SO2, SO2ClF, or SO2F2).
The 2-norbornyl cation, one of the most controversial ions in the
history of physical organic chemistry,28 was prepared from exo2-fluoronorbornane in SbF5/SO2 (or SO2C1F) solution (eq 27).1
Bridgehead cations such as 1-adamantyl, 1-trishomobarrelyl, and
1-trishomobullvalyl cations have also been similarly prepared
withtheuseofSbF 5 . 15a,29
(26)
(27)
Carbodications have also been studied.1 One convenient way

of preparing alkyl dications is to ionize dihalides with SbF5 in
Next Page
SO2CIF (eq 28). In these systems, separation of the two cation cen
ters by at least two methylene groups is necessary for the ions to be
observable.1 Aromatic dications are usually prepared by oxidiz
ing the corresponding aromatic compounds with SbF5 (eq 29).1,30
In the case of pagodane containing a planar cyclobutane ring,
oxidation leads to the formation of cyclobutane dication which
was characterized as a frozen two-electron Woodward-Hoffmann
transition state model (eq 30).31
33
Other Reactions. Reaction of ,-unsaturated carbonyl com

pounds with diazo compounds generally gives low yields of cyclopropyl compounds. The rapid formation of 1-pyrazolines and
their subsequent rearrangement products 2-pyrazolines is the rea
son for the inefficiency of cyclopropanation of these substrates.
However, in the presense of SbF5, the cyclopropanation of ,unsaturated carbonyl compounds with diazocarbonyl compounds
proceeds very well to produce the desired products in good yields
(eq 34).35
(34)
(28)
R = H, OMe; R1 = H, Me; R2 = Ph, OEt
(29)
(30)
SbF5 has also been found useful in the preparation of homoaromatic cations.1,32 For example, the simplest 2 monohomoaromatic cations, the homocyclopropenyl cations, can be prepared
from corresponding 3-halocyclobutenes in SbF5 (eq 31 ).32a
(3l)
Perfluorocarbocations are generally prepared with the aid of

SbF5.33 Perfluorobenzyl cations and perfluorinated ally] cations
are among the most well studied perfluorinated carbocations.
It was reported that in the perfluoroallyl cations containing a
pentafluorophenyl group at the 1- or 2-position, the phenyl groups
were partially removed from the plane of the allyl triad (eq 32).33b
(32)
Related Reagents. Fluorosulfuric Acid-Antimony(V) Flu

oride; Hydrogen Fluoride-Antimony(V) Fluoride; Methyl
Fluoride-Antimony(V) Fluoride.
1. Olah, G. A.; Prakash, G. K. S.; Sommer, J. Superacids; Wiley: New York,
1985.
2. For example, see (a) Ohwada, T.; Yamagata, N.; Shudo, K. JACS 1991,
113, 1364. (b) Farooq, O.; Famia, S. M. F.; Stephenson, M.; Olah, G. A.
JOC 1988, 53, 2840. (c) Carre, B.; Devynck, J. Anal. Chim. Acta. 1984,
759, 149. (d) Choukroun, H.; Germain, A.; Brunei, D.; Commeyras, A.
NJC 1983, 7, 83.
3.
4.
5.
Yakobson, G. G.; Furin, G. G. 5 1980, 345.

(a) Olah, G. A.; Nishimura, J. JACS 1974, 96, 2214. (b) Booth, B. L.;
Haszeldine, R. N.; Laali, K. JCS(P1) 1980, 2887.
(a) Pozdnyakovich, Y. V.; Shteingarts, V. D. JFC 1974, 4, 317. (b)
Brovko, V. V.; Sokolenko, V. A.; Yakobson, G. G. JOU 1974, 10, 300.
6. Furin, G. G.; Yakobson, G. G.; Izv. Sib. Otd. Akad. Nauk SSSR, Sen Khim.
Nauk 1974, 78 (CA 1974, 80, 120 457c.)
7. (a) Shteingarts, V. D. In Synthetic Fluorine Chemistry, Olah, G. A.;
Chambers, R. D.; Prakash, G. K. S., Eds.; Wiley: New York, 1992;
Chapter 12. (b) Pozdnyakovich, Y. V.; Shteingarts, V. D. JOU 1977,
13, 1772. (c) Pozdnyakovich, Y. V.; Chuikova, T. V.; Bardin, V. V.;
Shteingarts, V. D. JOU 1976, 12, 687. (d) Bardin, V. V.; Yakobson, G.
G. IZV 1976, 2350.
8. Olah, G. A.; Kobayashi, S.; Nishimura, J. JACS 1973, 95, 564. (b) Olah,
G. A.; Lin, H. C. S 1974, 342. (c) Furin, G. G.; Yakobson, G. G.; Izv.
Sib. Otd. Akad. Nauk SSSR, Ser. Khim. Nauk 1976, 120 (CA 1976, 85,
77 801z.)
9. Tanaka, ML; Souma, Y. JOC 1992, 57, 3738.
10. (a) Fan, R.-L.; Dickstein, J. I.; Miller, S. I. JOC 1982, 47, 2466. (b)
Miller, S. I.; Dickstein, J. I. ACR 1976, 9, 358.
11. Gillespie, R. J.; Peel, T. E. In Advances in Physical Organic Chemistry,
Gold, V., Ed.; Academic Press: London, 1971; Vol. 9, p 1.
Use of SbF5 as ionizing agent offers a convenient route to

acyclic and cyclic halonium ions from alkyl halides.1 Threemembered ring cyclic halonium ions are important intermedi
ates in the electrophilic halogenations of carbon-carbon double
bonds.1 More recently, a stable 1,4-bridged bicyclic bromonium
ion, 7-bromoniabicyclo[2.2. l]heptane, has been prepared through
the use of SbF5 involving an unprecedented transannular partici
pation in a six-membered ring (eq 33).34
12.
(a) Furin, G. G.; Terent'eva, T. V.; Yakobson, G. G. JOU 1973, 9, 2221.

(b) Yakobson, G. G.; Furrin, G. G.; Terent'eva, T. V. IZV 1972, 2128. (c)
Yakobson, G. G.; Furin, G. G.; Terent'eva, T. V. JOU 1974, 10, 802. (d)
Furin, G. G.; Schegoleva, L. N.; Yakobson, G. G. JOU 1975, 11, 1275.
13.
(a) Lukmanov, V. G.; Alekseeva, L. A.; Yagupol'skii, L. M. JOU 1977,

13, 1979. (b) Furin, G. G.; Malyuta, N. G.; Platonov, V. E.; Yakobson,
G. G. JOU 1974, 10, 832.
(33)
15.
14. (a) Olah, G. A.; Mo, Y. K. JACS 1972, 94, 6864. (b) Olah, G. A.; Renner,
R.; Schilling, P.; Mo, Y. K. JACS 1973, 95, 7686. (c) Halpern, Y Isr. J.
Chem. 1975, 13, 99. (d) Olah, G. A.; Wu, A.; Farooq, O. JOC 1989, 54,
1463.
(a) de Meijere, A.; Schallner, O. AG(E) 1973, 72, 399. (b) Farcasiu, D.
CC 1977, 394.
Previous Page
34
AZIDOTRIS(DIMETHYLAMINO)PHOSPHONIUMHEXAFLUOROPHOSPHATE
16. (a) Belen'kii, G. G.; Savicheva, G. I.; German, L. S. IZV 1978, 1433. (b)
Belen'kii, G. G.;3Lur'e,E. P.; German, L. S. IZV 1976, 2365. (c) Petrov,
V. A.; Belen'kii, G. G.; German, L. S. IZV 1980, 2117. (d) Karpov, V.
M ; Mezhenkova, T. V.; Platonov, V. E.; Yakobson, G. G. JOU 1984,
20, 1220. (e) Petrov, V. A.; Belen'kii, G. G.; German, L. S.; Kurbakova,
A. P.; Leites, L. A. IZV 1982, 170. (f) Karpov, V. M ; Mezhenkova, T.
V.; Platonov, V. E.; Yakobson, G. G. IZV 1985, 2315. (g) Petrov, V. A.;
Belen'kii, G. G.; German, L. S.; Mysov, E. I. IZV 1981, 2098. (h) Petrov,
V. A.; Belen'kii, G. G.; German, L. S. IZV 1981, 1920.
17. (a) Petrov, V. A.; Belen'kii, G. G.; German, L. S. IZV 1982, 2411. (b)
Petrov, V. A.; Belen'kii, G. G.; German, L. S. IZV 1989, 385. (c) Petrov,
V. A.; German, L. S.; Belen'kii, G. G. IZV 1989, 391.
18.
(a) Belen'kii, G. G.; German, L. S.; IZV 1974, 942. (b) Chepik, S. D.;
Belen'kii, G. G.; Cherstkov, V.F.;Sterlin, S. R.; German, L. S. IZV 1991,
513. (c) Knunyants, I. L.; Igumnov, S. M. IZV 1982, 204.
19.
(a) Barton, D. H. R.; Haynes, R. K.; Magnus, P. D.; Menzies, I. D. CC

1974, 511. (b) Barton, D. H. R.; Haynes, R. K.; Leclerc, G.; Magnus, P.
D.; Menzies, I. D. JCS(PI) 1975, 2055. (c) Haynes, R. K.AJC 1978, 31,
131.
20.
(a) Filyakova, T. I.; Belen'kii, G. G.; Lur'e, E. P.; Zapevalov, A. Y.;

Kolenko, I. P.; German, L. S. IZV 1979, 681. (b) Belen'kii, G. G.;
Savicheva, G. I.; Lur'e, E. P.; German, L. S. IZV 1978, 1640. (c)
Filyakova, T. I.; Zapevalov, A. Y. JOU 1991, 27, 1605. (d) Petrov, V.
A.; Belen'kii, G. G.; German, L. S. IZV 1989, 385. (e) Chepik, S. D.;
Petrov, V. A.; Galakhov, M. V.; Belen'kii, G. G.; Mysov, E. I.; German,
L. S. IZV 1990, 1844. (f) Avramenko, A. A.; Bardin, V. V.; Furin, G. G.;
Karelin, A. I.; Krasil'nikov, V. A.; Tushin, P. P. JOU 1988, 24, 1298.
21.
(a) Maruoka, K.; Ooi, T.; Yamamoto, H. T 1992, 48, 3303. (b) Zapevalov,
A. Y.; Filyakova, T. I.; Kolenko, I. P.; Kodess, M. I. JOU 1986, 22, 80. (c)
Filyakova, T. I.; Ilatovskii, R. E.; Zapevalov, A. Y. JOU 1991, 27, 1818.
(d) Filyakova, T. I.; Matochkina, E. G.; Peschanskii, N. V.; Kodess, M.
I.; Zapevalov, A. Y. JOU 1992, 28, 20. (e) Filyakova, T. I.; Matochkina,
E. G.; Peschanskii, N. V.; Kodess, M. I.; Zapevalov, A. Y JOU 1991, 27,
1423.
22.
23.
Yakobson, G. G.; Vlasov, V. M. S 1976, 652.

(a) Leffler, A. J. JOC 1959, 24, 1132. (b) McBee, E. T.; Wiseman, P.
A.; Bachman, G. B. Ind. Eng. Chem. 1947, 39, 415. (c) Christe, K. O.;
Pavlath, A. E. JCS 1963, 5549. (d) Pozdnyakovich, Y. V.; Shteingarts,
V. D. JOU 1978, 14, 2069.
Dear,R. E. A. S1970, 361.
(a) Karpov, V. M.; Panteleev, I. V.; Platonov, V. E. JOU 1991, 27, 1932.
(b) Karpov, V. M.; Platonov, V. E.; Yakoboson, G. G. IZV 1979, 2082.
24.
25.
26.
27.
Taylor, S. L.; Martin, J. C. JOC 1987, 52, 4147.

Olah, G. A.; Tolgyesi, W. S.; Kuhn, S. J.; Moffatt, M. E.; Bastien, I. J.;
Baker, E. B. JACS 1963, 85, 1328.
28.
For reviews, see (a) Olah, G. A.; Prakash, G. K. S.; Saunders, M. ACR
1983, 16, 440. (b) Brown, H. C. ACR 1983, 16, 432. (c) Walling, C. ACR
1983, 16, 448.
(a) Schleyer, P. v. R.; Fort, R. C. Jr.; Watts, W. E.; Comisarow, M. B.;

Olah, G. A. JACS 1964, 86, 4195. (b) Olah, G. A.; Prakash, G. K. S.;
Shih, J. G.; Krishnamurthy, V. V.; Mateescu, G. D.; Liang, G.; Sipos, G.;
Buss, V.; Gund, T. M.; Schleyer, P. v. R. JACS 1985, 107, 2764.
30. (a) Mills, N. S. JOC 1992, 57, 1899. (b) Krusic, P. J.; Wasserman, E.
JACS 1991, 113, 2322. (c) Mullen, K.; Meul, T.; Schade, P.; Schmickler,
H.; Vogel, E. JACS 1987, 109, 4992. (d) Lammertsma, K.; Olah, G. A.;
Berke, C. M.; Streitwieser, A. Jr. JACS 1979, 101, 6658. (e) Olah, G. A.;
Lang, G.; JACS 1977, 99, 6045.
34.
Prakash, G. K. S.; Aniszfeld, R.; Hashimoto, T.; Bausch, J. W.; Olah, G.

A./ACS 1989, 111, 8726.
35.
Doyle, M. P.; Buhro, W. E.; Dellaria, J. F. Jr. TL 1979, 4429.
George A. Olah, G. K. Surya Prakash, Qi Wang & Xing-ya Li

University of Southern California, Los Angeles, CA, USA
Hexafluorophosphate
[50281-51-1]
C 6 H 18 F 6 N 6 P 2
(MW 350.19)
(coupling reagent for amides and peptide synthesis via an acyl

azide;1 in the absence of a nucleophile undergoes a Curtius rear
rangement to give the corresponding isocyanate;1,2 by irradiation
gives the iminophosphonium salt;3,4 diazo transfer reagent5)
Physical Data: mp >250C; IR, v(N3) 2176 cm -1 .
Solubility: sol acetone, acetonitrile, DMF.
Form Supplied in: crystalline colorless solid; not available from
commercial sources.
Preparative Methods: Bromine (1 equiv) is added dropwise to
Hexamethylphosphorous Triamide (1 equiv) in dry diethyl
ether. After the addition is complete, Potassium Hexafluo
rophosphate (1 equiv), dissolved in H2O is added, and the solid
formed isfilteredand washed with H2O. After drying under vac
uum, the solid is dissolved in acetone and Sodium Azide (1.5
equiv) is added. The mixture is stirred overnight at 25 C, then
the sodium bromide formed and the excess of sodium azide is
filtered off and the solvent is removed under vacuum.
Purification: by crystallization in a mixture of acetone and diethyl
ether.
Handling, Storage, and Precautions: is very stable, not hygro
scopic, and can be stored indefinitely under vacuum. The related
bromine derivative is an exceptionally safe azide, that does not
detonate by shock, friction, rapid heating, or even flame.5 When
used in combination with carboxylic acids, the potential car
cinogenic Hexamethylphosphoric Triamide is a side-product
and the reagent must be handled with caution.6
29.
31.
Prakash, G. K. S.; Krishnamurthy, V. V.; Herges, R.; Bau, R.; Yuan, H.;
Olah, G. A.; Fessner, W-D.; Prinzbach, H. JACS 1988, 110, 7764.
32.
(a) Olah, G. A.; Staral, J. S.; Spear, R. J.; Liang, G. JACS 1975, 97, 5489.
(b) Olah, G. A.; Staral, J. S.; Paquette, L. A. JACS 1976, 98, 1267.
(a) Pozdnyakovich, Y. V.; Shteingarts, V. D. JFC 1974, 4, 283. (b)
Galakhov, M. V.; Petrov, V. A.; Chepik, S. D.; Belen'kii, G. G.;
Bakhmutov, V. I.; German, L. S. IZV 1989, 1773. (c) Petrov, V. A.;
Belen'kii, G. G.; German, L. S.IZV1984, 438.
33.
Coupling Reagent. Azidotris(dimethylamino)phosphonium

hexafluorophosphate has been used as a condensing reagent for
the preparation of peptides.1 Reaction of a-amino protected amino
acids or dipeptides with equimolar amounts of -carboxyl pro
tected amino acids or dipeptides and Triethylamine (2 equiv) in
DMF proceed cleanly overnight at 10 to 0 C, giving the corre
sponding peptides in good yields (81-97%) (eq 1). Neither acylation of the hydroxy group of serine nor dehydration of the side
chain of asparagine is reported during the coupling.1
RCO2H + R'NH2
RCONHR'
(1)
AZOBISISOBUTYRONITRILE
Racemization from azidotris(dimethylamino)phosphonium
hexafluorophosphate-mediated couplings is analyzed by differ
ent methods. While no racemization is detected by the Anderson7
and Weinstein8 methods, the Young9 method gave some degree
(3%) of racemization.
Although azidotris(dimethylamino)phosphonium hexafluorophosphate has not been used in solid-phase peptide synthesis,10
other commercial phosphonium salt derivatives such as
Benzotriazol-l-yloxytris(dimethylamino)phosphonium Hexafluorophosphate (BOP),11 benzotriazoI-I-yloxytris(pyrrolidino)phosphonium
hexafluorophosphate
(PyBOP),12 or
bromotris(pyrrolidino)phosphonium
hexafluorophosphate
(PyBroP)13 are commonly used in that strategy.
35
5. McGuiness, M.; Shechter, H. TL 1990, 31, 4987.

6. Zapp, J. A., Jr. Science 1975, 190, 422.
7. (a) Anderson, G. W.; Young, R. W. JACS 1952, 74, 5307. (b) Anderson,
G. W.; Zimmermann, J. E.; Callanan, F. M. JACS 1967, 89, 5012.
8. Weinstein, B.; Pritchard, A. E. JCS(C) 1972, 1015.
9. Williams, M. W.; Young, G. T. JCS(C) 1963, 881.
10. Fields, G. B.; Tian, Z.; Barany, G. In Synthetic Peptides: A User's Guide;
Grant, G. A., Ed.; Freeman: New York, 1992; p 77.
11. Castro, B.; Dormoy J. R.; Evin, G. TL 1975, 1219.
12. Coste, J.; Le-Nguyen, D.; Castro, B. TL 1990, 31, 205.
13. Frerot, E.; Coste, J.; Pantaloni, A.; Dufour, M. N.; Jouin, P. T 1991, 47,
259.
Fernando Albericio & Steven A. Kates

Millipore Corporation, Bedford, MA, USA
Isocyanate Formation. The coupling reaction described

above occurs via an acyl azide intermediate, which at 50 C suf
fers a Curtius rearrangement to give an isocyanate (eq 2),1 which
can further react with amines to give the corresponding ureas.
[78-67-1]
78%
Iminophosphonium Salt Formation. Irradiation of azidotris(dimethylamino)phosphonium hexafluorophosphate in acetonitrile at 254 nm using a Rayonnet photochemical reactor for
15 h at 25 C gives the iminophosphonium salt with release of ni
trogen (eq 3). This is the first example reported of a Curtius-type
rearrangement involving a charged atom.3,4
(3)
Diazo Transfer Reagent. The related compound azidotris(diefhylamino)phosphonium bromide has been used for the
preparation of diazo products.5 Active methylene compounds re
act with azidotris(diethylamino)phosphonium bromide in dry di
ethyl ether in the presence of only catalytic amounts of base, such
as Potassium t-Butoxide or other alkoxide, yielding the corre
sponding diazo products in good yields (70-78%) (eq 4).
C 8 H 12 N 4
(MW 164.21)
(reagent for initiation of radical reactions)

Alternate Name: AIBN.
Physical Data: mp 103-104 C.
Solubility: sol benzene, toluene.
Form Supplied in: commercially available as a white powder.
Preparative Method: prepared from the corresponding hydrazine
by oxidation with nitrous acid.1
Purification: recrystallized from ether.
Handling, Storage, and Precautions: avoid exposure of the
reagent to light and heat; store protected from light in a re
frigerator or freezer. AIBN is harmful; old or incorrectly stored
samples may also present an explosion risk.
Preparation. Azobisisobutyronitrile (AIBN) and analogs can

be prepared by a two-step procedure involving initial treatment
of a ketone with Hydrazine in the presence of Sodium Cyanide,
followed by oxidation of the so-formed hydrazine (eq l). 1,2
(1)
(4)
1. Castro, B.; Dormoy J. R. BSF(2) 1973, 12, 3359.

2.
Masson, M. A.; Dormoy J. R. J. Labelled Compd. Radiopharm. 1979,

16, 785.
3.
Majoral, J. P.; Bertrand, G.; Baceiredo, A.; Mulliez, M.; Schmutzler, R.

PS 1983, 18, 221.
Mulliez, M.; Majoral, J. P.; Bertrand, G. JCS(C) 1984, 284.
4.
Use in Radical Chemistry. AIBN is the initiator most com

monly employed in radical reactions, especially those using Trin-butylstannane. At temperatures above about 60 C, AIBN de
composes with evolution of nitrogen to generate isobutyronitrile
radicals, which are able to initiate radical chemistry, usually by
abstraction of a hydrogen atom from Bu3SnH or some other donor.
The useful working temperature range of AIBN is 60-120 C, with
the half-life at 80 C being 1 h. In many applications involving
36
AZOBISISOBUTYRONITRILE
C-C bond formation, the radical chemistry is designed to proceed

by a chain reaction, and so only small amounts (typically ca. 0.1
equiv) of the initiator is required. For best results, especially at
more elevated temperatures, AIBN is best added in portions or as
a solution by means of a syringe pump. Typical Bu3SnH-mediated
radical reactions, which involve the use of AIBN as initiator, in
clude cyclizations of alkyl and vinyl radicals (eqs 2 and 3).3,4
(7)
52%
major product
TMTHF = 2,2,5,5-tetramethyltetrahydrofuran
(2)
(8)
(9)
(3)
In eq 2, generation of an alkyl radical is achieved by attack of

a tributylstannyl radical on a Barton derivative, whereas in eq 3,
the vinyl radical required is generated by addition of the stannyl
radical to an alkyne. This type of cyclization has been extended to
many types of substrate, including those in which acarbonylgroup
acts as the acceptor (eq 4),5 and those in which additional types of
radical rearrangement or fragmentation occur (eq 5).5,6 The latter
sequence involves addition of the initially formed radical onto the
adjacent carbonyl group, followed by reopening of the so-formed
cyclopropanoxy radical in regioselective fashion.* The reaction
effects a one-carbon ring expansion in good chemical yield.
(4)
(10)
72%
For reactions which require temperatures above benzene re

flux, ACN, which decomposes markedly slower than AIBN, may
be a generally useful alternative to AIBN, although this possi
bility has not been examined in detail. At elevated temperatures,
other alternative initiators such as dialkyl peroxides and peresters
should also be considered, although the reactivity of the radicals
generated from these initiators is quite different to that of the
isobutyronitrile radicals generated from AIBN.
Related Reagents. l,l'-Azobis-l-cyclohexanenitrile (ACN).
(5)
AIBN can also be used in combination with many other types of

radical-generating systems other than those employing BusSnH.
Examples include cyclizations using Tris(trimethylsilyl)silane,7
Thiophenol,8 Diphenylphosphine,9 and carbonylation of radicals
using Ph3GeH and CO under pressure10 (eqs 6-9).
(6)
For certain types of radical reaction, AIBN may not always

give optimal results. Keck and Burnett found in their synthesis
of PGF2 that the introduction of the lower side chain, involv
ing radical addition onto a -stannyl enone, was inefficient when
AIBN was used as initiator at 65 C. By conducting the reaction in
refluxing toluene (110C), and replacing AIBN with the related
1,1'-Azobis-1-cyclohexanenitrile (ACN), a markedly better yield
of the desired adduct was obtained (eq 10).11
1. Thiele, J.; Heuser, K. LA 1896, 290, 1.

2. Overburger, C. G.; O'Shaughnessy, M. T.; Shalit, H. JACS 1949, 71,
2661.
3. RajanBabu, T. V. JACS 1987,109, 609.
4. Stork, G.; Mook, Jr., R. JACS 1987, 709, 2829.
5. Nishida, A.; Takahashi, H.; Takeda, H.; Takada, N.; Yonemitsu, O. JACS
1990, 112, 902.
6. Dowd, P.; Choi, S.-C. T 1989, 45, 77.
7.
Kopping, B.; Chatgilialoglu, C ; Zehnder, M.; Giese, B. JOC 1992, 57,

3994.
8. Broka, C. A.; Reichert, D. E. C. TL 1987, 28, 1503.
9. Brumwell, J. E.; Simpkins, N. S.; Terrett, N. K. TL 1993, 34, 1215.
10. Gupta, V.; Kahne, D. TL 1993, 34, 591.
11. Keck, G. E.; Burnett, D. A. JOC 1987, 52, 2958.
University
Nigel S. Simpkins
of Nottingham,
UK
BENZOTRIAZOL-1-YLOXYTRIS(DIMETHYLAMIN0)PH0SPHONIUMHEXAFLUOROPHOSPHATE
Benzotriazol-l-yloxytris(dimethylamino)phosphonium
Hexafluorophosphate1
[566002-33-6]
C 12 H 22 F 6 N 6 OP 2
37
agent) and the racemization suppressor (HOBt additive) in the

same compound, the BOP reagent has since then been widely de
veloped, mainly in peptide synthesis, as well as in other fields.
Mechanistic studies on the probable intermediates (acyloxyphosphonium salt, active ester, symmetrical anhydride, oxazolone,
eq 1) during the activation step of carboxylic acids with BOP
have been made. Early investigations indicating the intermediacy of a benzotriazolyl active ester, 1a,2b,3 as in activation with the
DCC/HOBt (see 1,3-Dicyclohexylcarbodiimide) reagent system,
were later questioned1c in the light of better results obtained with
BOP in a number of cases. After further studies, the direct for
mation of the acyloxyphosphonium salt, presumably through the
cyclic complex (eq 1), was postulated as likely.lc
(MW 442.29)
(peptide coupling agent providing high yield and low racemization levels;1 promotes peptide cyclization19 and other
lactamization,23 especially -lactam formation;24 used to effect
various amidification reactions 25-29 and selective esterification;31
reagent for nucleotidic coupling32)
Alternate Names: BOP; Castro's reagent.
Physical Data: mp 138 C (dec).
Solubility: insol H2O; sol THF, CH 2 Cl 2 , MeCN, acetone, DMF,
NMP, DMSO.
Form Supplied in: white solid; commercially available. Purity
97-98%.
Analysis of Reagent Purity: 'H NMR (acetone-d6): 3.0 (d, 18H,
J H - P = 10 HZ, NMe 2 ), 7.9 (m, 4H, arom.). 31 P NMR (CH 2 Cl 2 ):
+43.7 (s, P+), -144.2 (septet, P F 6 - ) . IR (KBr): 1010 (P-N),
840, 770, 560 (PF 6 - ).
Preparative Methods: BOP reagent was initially obtained2a
by
reaction
of
Hexamethylphosphorous
Triamide
(tris(dimethylamino)phosphine, TDAP) with CCl4 in the
presence of HOBt (1-Hydroxybenzotriazole) followed by
precipitation of the phosphonium salt by anion exchange with
aqueous KPF 6 solution. It was then prepared 2b,c by reaction
of cheaper (Me 2 N) 3 PO (HMPA) with COCl 2 (phosgene) to
generate the chlorophosphonium chloride intermediate, with
treatment of the latter with HOBt and base, and precipitation
as below. COCl 2 was further replaced by POCl 3 . 2d,e The crude
final product can, if necessary, be purified by recrystallization
from a mixture of acetone-ether or CH 2 Cl 2 (DCM)-ether.
Handling, Storage, and Precautions: irritant and harmful. Light
sensitive. Incompatibility: strong oxidizing agents. Avoid
breathing dust; avoid contact with eyes, skin, and clothing.
Keep container closed and store in the dark. Refrigerate. Al
though BOP is widely used, it is important to stress that the
carcinogenic HMPA is a side product and the reagent must be
handled with caution. All operations should be carried out in a
fume hood.
Peptide Coupling Reagent. First prepared with the aim to as

sociate both the coupling agent (phosphonium salt as dehydrating
(1)
Unoptimized initial work in peptide coupling with BOP had

already shown high yields and short reaction times, even with
bulky amino acids (eq 2) and little if no side reactions with some
sensitive amino acids bearing unprotected side chain functional
groups.2
Boc-Ile-OH + HC1, H-Ile-OMe
Boc-Ile-Ile-OMe (2)
Unlike DCC, BOP reacts exclusively with carboxylate salts,

with carboxylic acids remaining unchanged. The trifluoroacetate
anion is not activated by BOP; therefore the trifluoroacetylation
side reaction is never encountered.
In usual peptide synthesis (e.g. with the Boc/TFA deprotection strategy), a typical coupling step is conducted as follows:
BOP is added to the mixture of the Boc-amino acid (or peptide
acid segment) and the C-terminal-protected peptide salt (gener
ally the TFA salt). The solvent can be THF, DCM, MeCN, DMF,
or NMP, according to the solubility of the reaction partners, but
using as high a concentration as possible. No reaction occurs until
the tertiary base, N-methylmorpholine, Triethylamine, or prefer
ably Diisopropylethylamine (DIEA), is added. In every case the
reaction mixture has to be kept rather basic in order to ensure
a fast coupling. Three equiv of base are necessary to neutralize
the carboxylic acid, the amine salt, and the acidic HOBt. In such
conditions the coupling rate is so high that racemization is neg
ligible in urethane-protected amino acid coupling and fairly low,
albeit not negligible, in segment coupling (see eq 3). 4 The
38
BENZOTRIAZOL-1-YLOXYTRIS(DIMETHYLAMINO)PHOSPHONIUM HEXAFLUOROPHOSPHATE
excess of acid and BOP is typically 1.1 mol equiv in solution

synthesis.
Boc-His(Boc)-OH, DCHA + H-Leu-Ixu-Val-Tyr(Bn)-Ser(Bn)-OBn

Boc-His(Boc)-Leu-Leu-Val-Tyr(Bn)-Ser(Bn)-OBn (6)
Boc-Val-Val-OH + HCl, H-Leu-OMe

Boc-Val-Vai-Leu-OMe (3)
LDL/LLL% =17.2
Racemization in segment coupling has been studied with realis

tic models4a in solution; it appears to be very small when nonhindered amino acids (Ala, Leu, Lys . . . ) are activated, but coupling
of segments terminated with bulky residues (Val, Ile, T h r . . . ) are
to be avoided (eq 3). 4b
Segment condensation with BOP is generally peculiarly fast
compared with conventional use of the classical DCC/HOBt
method, as a few hours are enough to achieve coupling of equimolar quantities of both partners, provided the highest concentration
is used (eq 4). 5
(4)
It is very characteristic that this procedure allows the skipping

of a separate neutralization step, either in solution or in SPPS
(solid phase peptide synthesis) using the Boc/TFA strategy. This is
not only time-saving but also useful to minimize diketopiperazine
formation during the third step of a synthesis.
The coupling reaction of Boc-Ile-OH with H-His-Pro-OMe
TFA is generally a very low yield reaction as the neutralization
of the dipeptide salt is very readily followed by cyclization to
cyclo(His-Pro) (eq 5). Using the BOP procedure allows the ef
ficient 'in situ' trapping of the dipeptide amine by the acylating
reagent. This feature also makes strategies of segment coupling
at a proline residue possible, which are very often restricted by
the necessity of using prolyl t-butyl esters in order to avoid the
cyclization reaction.
Boc-Ile-His-Pro-OMe (5)
This specific ability of BOP for avoiding diketopiperazine for

mation is illustrated in liquid phase synthesis5a as well as in the
SPPS.
5c.d,6,7b
Another facility offered by BOP is the possibility to couple

DCHA salts, due to the high rate ratio of amino acid coupling
towards dicyclohexylamine (DCHA). This feature is especially
useful in SPPS where the small amount of dicyclohexylamide
formed is easily washed out. The main application of that proce
dure lies in the introduction of histidine as the cheap and easily
acessible Boc-His(Boc)-OH both in liquid (eq 6) 5a and solid7b-d
phase synthesis.
Many peptides have been synthesized in solution, 5a,b,8 stepwise

or by segment coupling, using BOP as coupling agent.
In solid phase synthesis, BOP exhibits some distinct advan
tages, including the suppression of a separate neutralization step
previously mentioned; indeed, after TFA treatment and washing,
it is convenient to introduce the next Boc-amino acid and BOP as
solids, with a minimal volume of solvent and, at last, DIEA. Cou
pling is generally completed after 15-30 min, with the pH main
tained at 8 with excess of acylating reagents (1.5-3M). Finally,
the water- and DCM-soluble byproducts, HMPA and HOBt, al
low very easy washing of the reaction product, in contrast to DCC
condensation where elimination of insoluble urea often remains a
problem.
The use of BOP in SPPS, initially limited,7 has since been
widely developed, with Boc/TFA, 9,10 Boc/HF, 11 and mainly
Fmoc/piperidine 12-15 deprotection systems. In most cases it com
pares favorably with other reagents such as DCC, DCC/HOBt,
and symmetrical anhydride. As already observed in the liquid
phase, some amino acids with side chain functional groups such
as Tyr, Thr, Ser (hydroxy group), 2a,9b or poorly soluble pGlu (lactam) 7d,9c can be used without protecting groups; other func
tional groups such as CONH2 (Asn) can lead in some cases
to partial dehydration (e.g. -cyanoalanine) 11,14b,c or cyclization
(succinimide) 9a,30 and need to be protected; such classical de
hydration reactions, not observed by others, 1a,2a,b are sometimes
dependent on reactions conditions (e.g. repeated coupling cycles)
and must be carefully examined.
Peptide Cyclization. Various results were provided 16-20 in
peptide chain cyclization with BOP, arising either from the reac
tion conditions or from the ring size, and from the linear precursor
conformation.
Better yields and purities are obtained16 with less powerful
coupling agents such as DPPA (Diphenyl Phosphorazidate) and
NDPP (norborn-5-ene-2,3-dicarboxamidodiphenyl phosphate) in
cyclization of tetra- and pentapeptide sequences, despite the
need for longer reaction times than with BOP or HBTU
(O-Benzotriazol-l-yl-N,N,N',N''-tetratnethyluronium
Hexafluorophosphate; 1,1,3,3-tetramethyluronium analog of BOP).
Comparable yields are given for Boc--D-Glu-Tyr-Nle-D-LysTrp-OMe cyclizations17 with BOP (NaHCO3, 4 h, 76%) and
MTPA (dimethylphosphinothioyl azide, NEt 3 , 36 h, 79%), albeit
in different reaction conditions; in this work the reported racem
ization associated with the use of BOP is not shown.
Cyclization,
leading
to
Gly/Lys-containing
peptide
macrocycles,18 has been investigated with a number of
coupling reagents. Among them DEPC (Diethyl Phosphorocyanidate), DPPA, and BOP are the most effective ones, giving
near-quantitative yields.
Macro ring closure of a partly proteinogenic sequence in the
synthesis19 of the cyclodepsipeptide Nordidemnin B was carried
out using BOP in heterogeneous conditions (eq 7).
BENZOTRIAZOL-1-YLOXYTRIS(DIMETHYLAMINO)PHOSPHONIUMHEXAFLUOROPHOSPHATE
39
(10)
P = Boc, Z; AA = Ala, Ile, Phe, Trp, Pro,

Ser, Met, Cys(SBn), Lys(eZ)
(7)
In SPPS, side chain to side chain cyclization by the BOP proce

dure not only proceeds more rapidly, but also gives a purer cyclic
product than the DCC/HOBt procedure.20
The use of BOP has been reported in the final cyclization of
cyclosporin,21b even if some racemization is observed. The very
difficult coupling of N-methyl amino acids is achieved in the same
work,21 as in the preceding syntheses.19 For the coupling of hin
dered N-methyl22a and ,-dialkyl22b amino acids, new reagents22
such as PyBroP, PyCloP, or PyClU seem to be more promising.
Besides the peptide field, cyclization leading to macrocyclic
polyether tetralactams (crown ethers) have been carried out with
BOP.23
-Lactam Cyclization. Cyclization of -amino acids to plactams is efficiently effected by treatment with BOP (eq 8).24a The
present method appears to be limited to the formation of -lactams
from N-unsubstituted -amino acids (R1 =R2 = R3 = R5 = H,
R4 = Me, yield 10%).
BOP in combination with Imidazole (ImH) as catalyst provides

a very mild system for selective esterification of polyhydroxy com
pounds such as carbohydrates; thus trehalose is converted into
mono-, di-, and tripalmitate mixtures, with the various quantities
of each of them depending on the solvent and acid/alcohol ratio.
Monoacylated compounds can be obtained selectively, albeit in
moderate yield (31%).31
Nucleotidic Coupling and Related Reactions. BOP has been
used as a condensing agent to promote internucleotidic bond for
mation in phosphotriester oligodeoxyribonucleotide synthesis.32
31
P NMR studies32a show that a benzotriazolyl phosphate deriva
tive is involved as an active ester intermediate, as with carboxylic
acids.3
The BOP procedure was applied to the preparation of undecanucleoside decaphosphate.32b The same type of activation with BOP
is carried out for introducing a phosphonamide bond in dipeptide models33 with good efficiency (>60%); coupling reactions
by activation of phosphinic acid derivatives34 with BOP give poor
yields.
(8)
1. (a) Le Nguyen, D.; Castro, B. Peptide Chemistry 1987; Protein Research
Foundation: Osaka, 1988; p 231. (b) Kiso, Y.; Kimura, T. Yuki Gosei
KagakuKyokaiShi 1990,48, 1032 (CA 1991,114, 164 722k). (c)Coste,
J.; Dufour, M. N.; Le Nguyen, D.; Castro, B. In Peptides, Chem. Struct.
Biol. ESCOM: Leiden, 1990; pp 885-888.
R1 = H, Me; R2 = H, OPh; R3 = H, Me, Ph;

R4 = H, Me, n-Pr; R5 = CH2Ph, c-C6H11, n-C8H17
In the cephem series, cyclization yields of 80% are obtained

with BOP, in DCM at rt, with retention of the initial chirality.24b
Amidation. A number of other various amidation reactions
have been conducted using BOP. Such preparations include N,0dimethyl hydroxamates of amino acids25a and peptides25b (precur
sors of chiral peptidyl aldehydes), heterocyclic amide fragments
in the synthesis of macrolide26 and porphyrin models,27 'dansylglycine anhydride' as a mixed sulfonic-carboxylic imide by
dehydration-cyclization of dansylglycine,28 and selective monoacylation of heterocyclic diamine in carbohydrate series (eq 9).29
(9)
Esterification. Treatment of N-protected amino acids with

phenol, NEt3, and BOP in the appropriate solvent (DCM, MeCN,
DMF) affords the corresponding phenyl esters in good yield
(eq 10).30
2.
(a) Castro, B.; Dormoy, J. R.; Evin, G.; Selve, C. TL 1975, 1219. (b)
Castro, B.; Dormoy, J. R.; Evin, G.; Selve, C. Peptides 1976; University
of Bruxelles: Brussels, 1976; p 79. (c) Castro, B.; Dormoy, J. R.;
Dourtoglou, B.; Evin, G.; Selve, C ; Ziegler, J. C. 5 1976, 751. (d)
Dormoy, J. R.; Castro, B. TL 1979, 3321. (e) Dormoy, J. R.; Castro,
B. T 1981, 37, 3699.
3.
Castro, B.; Dormoy, J. R.; Evin, G.; Selve, C.JCR(S) 1977, 182;JCR(M)
1977, 2118.
(a) Castro, B.; Dormoy, J. R.; Le Nguyen, D. TL 1978, 4419. (b) Castro,
B.; Dormoy, J. R.; Le Nguyen, D. Peptides 1978; Wroclaw University
Press, Poland, 1979; p 155. (c) Le Nguyen, D.; Dormoy, J. R.; Castro,
B.; Prevot, D. T 1981, 37, 4229.
4.
5.
(a) Le Nguyen, D.; Seyer, R.; Heitz, A.; Castro, B. JCS(P1) 1985, 1025.
(b)Fehrentz, J. A.; Seyer, R.; Heitz, A.; Fulcrand, P.; Castro, B.; Corvol, P.
Int. J. Pepl. ProteinRes. 1986, 28, 620. (c) Seyer, R.; Aumelas, A.; Tence,
M.; Marie, J.; Bonnafous, J. C ; Jard, S.; Castro, B. Int. J. Pept. Protein
Res. 1989, 34, 235. (d) Seyer, R.; Aumelas, A.; Marie, J.; Bonnafous, J.
C ; Jard, S.; Castro, B. HCA 1989, 72, 678.
6. Gairi, M.; Lloyd-Williams, P.; Albericio, F.; Giralt, E. T 1990, 31, 7363.
7. (a) Rivaille, P.; Gautron, J. P.; Castro, B.; Milhaud, G. T 1980, 36, 3413.
(b) Le Nguyen, D.; Heitz, A.; Castro, B. JCS(P1) 1987, 1915. (c) Ratman,
M.; Le Nguyen, D.; Rivier, J.; Sargent, P. B.; Lindstrom, J. B 1986, 25,
2633. (d) Seyer, R.; Aumelas, A.; Caraty, A.; Rivaille, P.; Castro, B. Int.
J. Pept. Protein Res. 1990, 35, 465. (e) Evin, G.; Galen, F. X.; Carlson, W.
D.; Handschumacher, M.; Novotny, J.; Bouhnik, J.; Menard, J.; Corvol,
P.; Haber, E. B 1988, 27, 156. (f) Bouhnik, J.; Galen, F. X.; Menard,
J.; Corvol, P.; Seyer, R.; Fehrentz, J. A.; Le Nguyen, D.; Fulcrand, P.;
Castro, B. JBC 1987, 262, 2913. (g) Fehrentz, J. A.; Heitz, A.; Seyer,
R.; Fulcrand, P.; Devilliers, R.; Castro, B.; Heitz, F.; Carelli, C. B 1988,
27, 4071. (h) Bonnafous, J. C ; Tence, M.; Seyer, R.; Marie, J.; Aumelas,
40
O-BENZOTRIAZOL-1-YL-N,N,N',N'-TETRAMETHYLURONIUMHEXAFLUOROPHOSPHATE
A.; Jard, S. BJ 1988, 251, 873. (i) Liu, C. F.; Fehrentz, J. A.; Heitz, A.;
Le Nguyen, D.; Castro, B.; Heitz, F.; Carelli, C ; Galen, F. X.; Corvol,
P.T1988, 44, 675.
8. (a)Eid,M.;Evin,G.;Castro,B.;Menard,J.;Corvol,P.BJ1981,i97,465.
(b) Cumin, F.; Evin, G.; Fehrentz, J. A.; Seyer, R.; Castro, B.; Menard,
J.; Corvol, P. JBC 1985, 260, 9154.
9.
(a) Fournier, A.; Wang, C. T.; Felix, A. M. Int. J. Pept. Protein Res. 1988,
31, 86. (b) Fournier, A.; Danho, W.; Felix, A. M. Int. J. Pept. Protein
Res. 1989, 33, 133. (c) Forest, M.; Fournier, A. Int. J. Pept. Protein Res.
1990, 35, 89.
10.
11.
12.
Jarrett, J. T.; Landsbury, Jr, P. T. TL 1990, 31, 4561.

Jezek, J.; Houghten, R. A. Peptides 1990; ESCOM: Leiden, 1991; p 74.
Rule, W. K.; Shen, J. H.; Tregear, G. W.; Wade, J. D. Peptides 1988; de
Gruyter. Berlin, 1989; p 238.
13. Hudson, D. JOC 1988, 53, 617.
14.
15.
16.
17.
(a) Frank, R. W.; Gausepohl, H. Modem Methods in Protein Chemistry;

de Gruyter; Berlin, 1988; Vol. 3. p 41. (b) Gausepohl, H.; Kraft, M.;
Frank, R. W. Int. J. Pept. Protein Res. 1989, 34, 287. (c) Gausepohl, H.;
Kraft, M.; Frank, R. W. Peptides 1988; de Gruyter: Berlin, 1989; p 241.
Waki, M.; Nakahara, T.; Ohno, M. Peptides Chemistry 1990; Protein
Research Foundation: Osaka, 1991; p 95.
Schmidt, R.; Neubert, K. Int. I. Pept. Protein Res. 1991, 37, 502.
Ueki, M.; Kato, T. see ref. 15, p 49.
18. Crusi, E.; Huerta, J. M.; Andreu, D.; Giralt, E. TL 1990, 31, 4191.
19. Jouin, P.; Poncet, J.; Dufour, M. N.; Pantaloni, A.; Castro, B. JOC 1989,
54, 617.
20. Felix, A. M.; Wang, C. T.; Heimer, E. P.; Fournier, A. Int. J. Pept. Protein
Res. 1988,31, 231.
21.
22.
(a) Wenger, R. M. HCA 1983, 66, 2672. (b) Wenger, R. M. HCA 1984,
67, 502.
(a) Coste, J.; Frerot, E.; Jouin, P.; Castro, B. TL 1991, 32, 1967. (b)
Frerot, E.; Coste, J.; Pantaloni, A.; Dufour, M. N.; Jouin, P. T 1991, 47,
259.
23.
Duriez, M. C ; Pigot, T.; Picard, C ; Cazaux, L.; Tisnes, P. 7" 1992, 48,
4347.
24.
(a) Kim, S.; Lee, T. A. Bull. Kor. Chem. Soc. 1988, 9, 189. (b) Roze,
J. C ; Pradere, J. P.; Duguay, G.; Guevel, A.; Quiniou, H.; Poignant, S.
CJC 1983, 61, 1169.
(a) Fehrentz, J. A.; Castro, B. S 1983, 676. (b) Fehrentz, J. A.; Heitz, A.;
Castro, B. Int. J. Pept. Protein Res. 1985, 26, 236.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
O-Benzotriazol-1-yl-N,N,N',N'-tetramethyluronium Hexafluorophosphate
Somers, P. K.; Wandless, T. J.; Schreiber, S. L. JACS 1991,113, 8045.

Selve, C ; Niedercorn, F.; Nacro, M.; Castro, B.; Gabriel, M. T 1981, 37,
1903.
Weinhold, E. G.; Knowles, J. R. JACS 1992, 114, 9270.
Chapleur, Y.; Castro, B. JCS(P1) 1980, 2683.
Castro, B.; Evin, G.; Selve, C ; Seyer, R. S 1977, 413.
[94790-37-1]
C 11 H 16 F 6 N 5 OP
(MW 379.29)
(coupling reagent for peptide synthesis1)

Alternate Name: HBTU.
Physical Data: mp 206-207 C (dec).
Solubility: sol DMF (0.5 mol L - 1 ). With the tetrafluoroborate
counterion the corresponding salt (TBTU) is slightly more sol
uble (0.6 mol L - 1 ).
Form Supplied in: white solid; widely available.
Purification: by crystallization in a mixture of MeCN and CH2Cl2.
Handling, Storage, and Precautions: very stable, not hygroscopic,
and can be stored indefinitely. Solutions in DMF (0.45 M) can
be stored in an inert atmosphere for weeks. Syntheses of pep
tides carried out with freshly prepared, 6 and 13 week stored
solutions show similar quality of the crude product.3 Violent
decomposition can occur when dried at elevated temperature.4
Both O-benzotriazol-l-yl-N,N,N',N'-tetramethyluroniurn hexa
fluorophosphate (HBTU) and tetrafluoroborate (TBTU) salts have
been used as condensing reagents for the preparation of peptides
in both solution and solid-phase strategies.1,4 In solution, reaction
of -amino protected amino acids or dipeptides with equimolar
amounts of -carboxyl protected amino acids or dipeptides and Diisopropylethylamine (DIEA) (2 equiv) in DMF proceeds cleanly
for 15 min at 0C, yielding the corresponding peptides in good
yields (80-96%) (eq 1).1,4
R1CO2H + R2NH2
R1CONHR2
(1)
HBTU activation has been adapted for automated stepwise

solid-phase peptide synthesis for both t-butoxycarbonyl (Boc)
and fluorenylmethoxycarbonyl (Fmoc) strategies.5 For the for
mer, a simple, effective protocol has been developed, which in
volves simultaneous in situ neutralization with coupling (extra
equivalents of base are required). This protocol is particularly
suitable for assembling complex peptides, arising from sequencedependent peptide chain aggregation. Since aggregation occurs
when protonated -ammonium peptide-resin intermediates are
Jean-Robert Dormoy & Bertrand Castro
neutralized, simultaneous neutralization and acylation can help
Sanofi Chimie, Gentilly, France
to overcome this phenomenon.6 For Fmoc chemistry, efficient
protocols are also available for both batch and continuous-flow
systems.3,7
Various protected peptide segments have been coupled on solidphase using a combination of TBTU, HOBt, and DIEA for the
syntheses of several small proteins. Coupling yields, using three-
Chapleur, Y.; Castro, B.; Toubiana, R. JCS(P1) 1980, 1940.

(a) Molko, D.; Guy, A.; Teoule, R.; Castro, B.; Dormoy, J. R. NJC 1982,
6,277. (b) Molko, D.; Guy, A.; Teoule, R. Nucleosides Nucleotides 1982,
/,65.
Dumy, P.; Escale, R.; Vidal, J. P.; Girard, J. P.; Parello, J. CR(C) 1991,
312, 235.
Elhaddadi, M.; Jacquier, R.; Petrus, C ; Petrus, F. PS 1991, 63, 255.
O-BENZOTRIAZOL-1-YL-N,N,N',N'-TETRAMETHYLUR0NIUMHEXAFLU0R0PH0SPHATE
fold excess of peptide segment and coupling times of ~ 12 h, are
greater than 95%.8
Racemization from uronium salt mediated couplings has been
determined by analysis of the epimeric products by HPLC using
different models. In all cases, racemization is similar or lower than
that obtained with carbodiimide and benzotriazole based phosphonium salt methods.1,2,4,9
In the absence of the carboxylic component, HBTU reacts
with amino groups leading to the formation of a Schiff base
(eq 2).10 Thus in syntheses conducted in solution, the excess
of both HBTU and amino component should be avoided. In
both solution and solid-phase strategies the sequence of reagent
addition is critical. HBTU should be delivered to the carboxylic
component for preactivation, prior to the addition of the amine.
The Schiff base formation can also occur during slow reactions,
such as the preparation of cyclic peptides, where both amino and
carboxylic components are in equimolar amounts and an excess
of the uronium salt can block the amino group.11 For the synthesis
of cyclic peptides the phosphonium derivatives Benzotriazol-1yloxytris(dimethylamino)phosphonium Hexafluorophosphate
(BOP)12 and benzotriazol-l-yloxytris(pyrrolidino)phosphonium
hexafluorophosphate (PyBOP),13 can be more useful.
(2)
Uronium salts have been used for cyclization of linear peptides

in both solution and solid-phase modes. Since this reaction is se
quence dependent, there are no general conditions. Thus cycliza
tion in solution with uronium salt methods give, for some peptides,
better results than the classical reagentDiphenylPhosphorazidate
(DPPA),14 but for another case the converse is true.15 Furthermore,
dehydration of C-terminal aspartylamide peptides during cycliza
tion with HBTU has been described. This side-reaction can be
prevented by the addition of one equivalent of HOBt.16 Although
good results have been obtained in the solid-phase,17 guanidino
formation side-reactions have also been reported.11
Recently, other uronium salts, such as O-(N-succinimidyl)N,N, N',N'-tetrametriyluronium tetrafluoroborate (TSTU),4,18
O-(N-5-norbornene-endo-2, 3-dicarboximidyl)-N, N, N', N'-tetramethyluronium tetrafluoroborate (TNTU),4,18 O-(2-oxo-1(2H)pyridyl)-N,N,N',N'-bis(pentamethylene)uroniurn tetrafluorobo
rate (TOPPipU),19 N-[(Dimethylamino)-lH-l,2,3-triazolo[4,5b]pyridin-l-ylmethylene]-N-methylmethanaminium Hexafluorophosphate N-Oxide (HATU),20 and O-(7-azabenzotriazol-lyl)-N,N,N',N'-bis(tetramethylene)uronium hexafluorophosphate
(HAPyU)21 have been described and are commerically available.
The uronium salts derived from 7-aza-l-hydroxybenzotriazole
(HATU and HAPyU) have been shown to be superior to
their benzotriazole analogs in terms of coupling efficiency,20'21
racemization,22 and cyclization,23 in both solution and solid-phase
strategies.
41
Finally, an X-ray structure determination of HBTU revealed that

the solid-state structure differs considerably from the formulation
commonly presented in the literature. The solid-state structure is
not the N,N,N',N'-tetramethyluronium salt but rather the guanidinium N-oxide (3).24
Related Reagents. N-[(Dimethylamino)-lH-l,2,3-tri azolo[4,5-b]pyridin-1 -ylmethylene]-N-methylmethanaminium Hex

afluorophosphate N-Oxide.
1. Dourtoglou, V; Ziegler, J. C ; Gross, B. TL 1978, 1269.

2. Dourtoglou, V.; Gross, B.; Lambropoulou, V.; Zioudrou, C. S 1984, 572.
3. Fields, C. G.; Lloyd, D. H.; Macdonald, R. L.; Otteson, K. M ; Noble,
R. L. Peptide Res. 1991, 4, 95.
4. Knorr, R.; Trzeciak, A.; Bannwarth, W.; Gillessen, D. TL 1989,30, 1927.
5. Fields, G. B.; Tian, Z.; Barany, G. In Synthetic Peptides: A User's Guide,
Grant, G. A. Ed.; Freeman: New York, 1992; pp 77-183.
6. (a) Schnoelzer, M.; Alewood, P; Jones, A.; Alewood, D.; Kent, S. B. H.
Int. J. Peptide Protein Res. 1992, 40, 180. (b) Reid, G. E.; Simpson, R. J.
Anal. Biochem. 1992, 200, 301. (c) Sueiras-Diaz, J.; Horton, J. TL 1992,
55,2721.
7. Poulat, F.; Guichard, G.; Goze, C ; Heitz, F.; Calas, B.; Berta, P. FEES
Lett. 1992, 309, 385.
8. Surovoy, A.; Metzger, J.; Jung, G. In Innovation and Perspectives in
Solid-Phase Synthesis: Peptides, Polypeptides and Oligonucleotides,
Epton, R. Ed.; Intercept: Andover, 1992, pp 467-473 (CA 1993, 118,
234476s).
9.
10.
11.
12.
13.
14.
15.
16.
17.
Benoiton, N. L.; Lee, Y. C ; Steinauer, R.; Chen, F. M. F. Int. J. Peptide

Protein Res. 1992, 40, 559.
Gausepohl, H.; Pieles, U.; Frank, R. W. In Proceedings of the Twelth
American Peptide Symposium; Smith, J. A.; Rivier, J. E. Eds.; ESCOM:
Leiden, 1992; pp 523-524. (CA 1992, 117, 171 98lj).
Story, S. G.; Aldrich, J. V. Int. J. Peptide Protein Res. 1994, 43, 292.
Castro, B.; Dormoy, J. R.; Evin, G. TL 1975, 1219.
Coste, J.; Le-Nguyen, D.; Castro, B. TL 1990, 31, 205.
(a) Hoffmann, E.; Beck-Sickinger, A. G.; Jung G. LA 1991, 585. (b)
Zimmer, S.; Hoffmann, E.; Jung, G.; Kessler, H. LA 1993, 497.
Schmidt, R.; Neubert, K. Int. J. Peptide Protein Res. 1991, 37, 502.
Rovero, P.; Pegoraro, S.; Bonelli, F.; Triolo, A. TL 1993, 34, 2199.
(a) Trzeciak, A.; Bannwarth, W. TL 1992, 33, 4557. (b) Neugebauer,
W.; Willick, G. In Proceedings of the Twenty-Second European Peptide
Symposium; Schneider, C. H.; Eberle, A. N. Eds.; ESCOM: Leiden, 1993;
pp 393-394.
18. Bannwarth, W.; Schmidt, D.; Stallard, R. L.; Hornung, C ; Knorr, R.;
Miiller, F. HCA 1988, 71, 2085.
19. Henklein, P.; Beyermann, M.; Bienert, M.; Knorr, R. In Proceedings of
the Twenty-First European Peptide Symposium; Giralt, E.; Andreu, D.
Eds.; ESCOM: Leiden, 1991; pp 67-68 (CA 1991 115, 232 811m).
20.
21.
22.
Carpino, L. A. JACS 1993, 115, 4397.

Carpino, L. A.; El-Faham, A.; Minor, C. A.; Albericio, F. JCS (P1) 1994,
201.
Carpino, L. A.; E.-Faham, A. JOC 1994, 59, 695.
42
BENZOYL CHLORIDE
23.
Ehrlich, A.; Rothemund, S.; Brudel, M.; Beyermann, M.; Carpino,

L. A.; Bienert, M. TL 1993,34, 4781.
24.
Abdelmoty, I.; Albericio, F.; Carpino, L.A.; Foxman, B. M.; Kates,

S. A. Lett. Peptide Sci. 1994, in press.
MeZnCl + PhCOCl
MeCOPh
(3)
no catalyst, 12 h: 10%
5% Pd(PPh3)4, 30 min: 80%
Fernando Albericio & Steven A. Kates

With the very reactive organomagnesium compounds, the acy
Millipore Corporation, Bedford, MA, USA lation takes place in the presence of Fe(acac)33d or MnCl23e (eqs 4
and 5). It is worthy of note that the 1,2-addition, which is rapid
under these reaction conditions (10-20 C), is completely avoided.
Benzoyl Chloride 1
PhCOCl + MeMgCl
MeCOPh
PhCOCl + BuMgCl
[98-88-4]
C7H5ClO
(MW 140.57)
(useful acylating agent; preparation of ketones from organometallic compounds;2'3 preparation of 1,3-dicarbonyl compounds
from enolates or enols;45 Friedel-Crafts acylation and related
reactions6 with aromatic and heterocyclic compounds,7 alkenes,8
alkynes,9 enoxysilanes,10 and silicon compounds;11 acylation of
enol ethers, ketene acetals,12 and enamines;13 protection of alco
hols as benzoates;14 protection of amines as benzamides15)
BuCOPh
(4)
(5)
Organocopper (60% of PhCOMe from MeCuPBu3)3f and

cuprate reagents (eq 6),3g which are now widely used, give only
moderate yields of phenyl ketones. Better yields are obtained at
low temperature by using a large excess of organocuprate3h or
heterocuprate (eq 7).3i
Me2CuLi + PhCOCl
MeCOPh
(6)
Physical Data: bp 197.2 C; mp - 1 C; d 1.21 g cm -3 .

Solubility: slowly decomposed by water and alcohols; sol most
t-BuCOPh (7)
t-Bu(PhS)CuLi + PhCOCl
organic solvents.
Form Supplied in: colorless liquid; penetrating odor; widely avail
able.
Organomanganese compounds afford excellent yields by the
Purification: the good commercial grade of benzoyl chloride can use of a stoichiometric amount of reagents under mild conditions
be purified by distillation. The technical material must be pu
(eq 8).3j
rified as follows: a 50% solution of PhCOCl in ether or cyclohexane is washed with cold 5% aqueous sodium bicarbonate;
after drying over CaCl2 the solvent is eliminated under vacuo
BuCOPh
BuMnCl + PhCOCl
(8)
and the PhCOCl is distilled.16
Handling, Storage, and Precautions: use in a fume hood; lachry
matory, irritating to skin, eyes and mucous membranes; toxic
Acylation of Enolates, Enols, and Related Reactions.4,5
by inhalation and ingestion.
According to the reaction conditions, PhCOCl reacts with ketone
enolates to lead to enol benzoates (O-acylation, kinetic product)
or -diketones (C-acylation, thermodynamic product) (eq 9).5a
Acylation of Organometallic Compounds.2,3 PhCOCl reacts
with various organometallic reagents to give the corresponding
phenyl ketones in variable yields. The first acylation reactions
were performed with organocadmium and organozinc compounds
(eqs 1 and 2).3a,b In THF, organozinc reagents give poor re
sults; however, the yields are clearly improved in the presence
of Tetrakis(triphenylphosphine)palladium(0) (eq 3).3c
MeCdCl + PhCOCl
MeCOPh
(1)
MeZnl + PhCOCl
MeCOPh
(2)
(9)
2 equiv of PhCOCl:
2 equiv of enolate:
41%
6%
9%
33%
PhCOCl very often gives a mixture of the O- and C-acylated

products. To prepare the enol ester (kinetic conditions) a more re
active acylating agent such as Acetyl Chloride is generally used.
Moreover, carboxylic acid anhydrides are generally preferred to
acyl halides. Accordingly, PhCOCl is preferred to prepare 1,3dicarbonyl compounds. Ketones (eq 10),5b esters (eq 11),5c and
more commonly -keto esters or related CH acidic compounds
BENZOYL CHLORIDE
5d-g
(eqs 1215)
can be C-acylated via the preformed enolate
(eq 11) or directly under basic conditions (eq 13).5e
PhCOCH2COPh
PhCOMe
Me2CHCO2-t-Bu
(10)
(11)
43
The electrophilic acylation of alkenes or alkynes is another ex

ample of Friedel-Crafts reactions and is carried out under similar
conditions.6,8,9 With PhCOCl, alkenes can lead to (3-chloro alkyl
ketones or, more frequently, to the corresponding ,-efhylenic
ketones (eq 19)8b according to the reaction conditions.6,8a Ph
COCl also adds to triple bonds to give a (3-chloro vinyl ketone9
(eq 20).9b
H2C=CH2 + PhCOCl
H2C=CHCOPh (19)
HCCH + PhCOCl
PhCOCH=CHCl (20)
55%
(12)
(13)
Under Friedel-Crafts conditions, PhCOCl reacts with various

silicon compounds. Thus -diketones are easily obtained from
enoxysilanes10a,b (eq 21).10c Conversely, vinyl-, aryl-, and allylsilanes lead to the corresponding vinyl, aryl, and allyl ketones in
good yields11a-c (eq 2211d and eq 2311e). Vinylsilanes can lead
to a mixture of (3-chloro alkyl ketones and conjugated enones; a
basic treatment is then necessary to obtain only the enone (eq 23).
(14)
(21)
(15)
PhCH=CHSiMe3
Friedel-Crafts Acylation and Related Reactions.67

Aromatic compounds (eqs 16 and 17)7a,b are acylated by PhCOCl in the presence of a Lewis acid such as AlCl3, TiCl4, BF3,
SnCl4, ZnCl2, or FeCl3, or of a strong acid such as polyphosphoric acid or CF3SO3H.6 Metallic Al or Fe and iodine (in situ
formation of a Lewis acid) can also act as a catalyst.6 Various
solvents that have been used to perform this reaction are CS2,
CH2Cl2, 1,2-dichloroethane, nitrobenzene, and nitromethane.6
PhCOCl is less reactive than aliphatic carboxylic acid chlorides
(with benzene in nitromethane the relative reaction rates are PhCOCl:MeCOCl = 6:100).7a As for all electrophilic substitutions,
the rate and the regioselectivity of the acylation closely depend on
the nature and on the position of the substituents on the aromatic
system6 (eqs 16 and 187c). The nature of the solvent can also exert
a strong influence.6
H2C=CHCH2SiMe3
PhCH=CHCOPh
(22)
H2C=CHCH2COPh (23)
Acylation of Enol Ethers, Ketene Acetals,12 and

Enamines.13 Enol ethers,12a ketene acetals (eq 24),12b and
enamines (eq 25)13g react with PhCOCl to provide the cor
responding -acylated products (eq 24).12b The acylation of
enamines has been extensively studied (eq 25); 13a-f the resulting
-acyl enamine is generally hydrolyzed to give (3-diketones
(eq 25).
(MeO)2C=CH2 + PhCOCl
(MeO)2C=CHCOPh (24)
(16)
(25)
(17)
(18)
Protection of Alcohols as Benzoates14 and of Amines as

Benzamides.15 PhCOCl easily reacts with alcohols to give the
corresponding benzoates in excellent yields.14a The acylation is
performed in the presence of an amine, very often pyridine or triethylamine. CH2Cl2 or a large excess of amine is generally used as
solvent (eq 26).14d The reaction has also been performed by phase
44
BENZOYL CHLORIDE
transfer catalysis (PhCOCl, benzene, Bu4NCl, 40% NaOH).14e

Alternatively, the alcohol can be converted to lithium alcoholate
(with BuLi), which readily reacts with PhCOCl to give quanti
tatively the corresponding benzoate (eq 27).14f Tributyltin ether
prepared by treatment of the alcohol with Bis(tri-n-butyltin) Ox
ide has also been used as intermediate.148 Benzoates are very often
prepared to protect alcohols14b,c because they are more stable than
acetates and their tendency to migrate to adjacent hydroxy1 groups
is lower.14h,i In most cases the benzoylation of polyhydroxylated
molecules is more selective than the acetylation.14h,i PhCOCl has
also been used to monoprotect diols,14f and to acylate a primary
alcohol in the presence of a secondary alcohol.14j Under similar
conditions (pyridine), phenols are converted to aryl benzoates.14a,k
HO(CH2)4OH
PhCO(CH2)4OH
PhCH2CH2NHCOPh
(a) Gilman, H.; Nelson, J. F. RTC 1936, 55, 518. (b) Blaise, E. E. BSF
1911, 9, I-XXVI. (c) Negishi, E.; Bagheri, V., Chatterjee, S.; Luo, F.;
Miller, J. A.; Stoll, A.T. TL 1983, 24, 5181. (d) Fiandanese, V.; Marchese,
G.; Martina, V.; Ronzini, L. TL 1984, 25, 4805. (e) Cahiez, G.; Laboue,
B. TL 1992, 33, 4439. (f) Whitesides, G. M.; Casey, C. P.; San Filippo
Jr, J.; Panek, E. J. Trans. N.Y. Acad. Sci. 1967, 29, 572. (g) Jallabert, C ;
Luong-Thi, N. T.; Riviere, H. BSF 1970, 797. (h) Posner, G. H.; Whitten,
C. E. TL 1970, 4647. (i) Posner, G. H.; Whitten, C. E. OSC 1988, 6, 248.
See also also Ref. 2e. (j) Cahiez, G.; Laboue, B. TL 1989, 30, 7369.
4. (a) House, H. O. Modern Synthetic Reactions, 2nd ed; Benjamin: Menlo
Park, CA, 1972, pp 734-786. (b) See Ref. 2a, p 490. (c) See Ref. 2g, pp
742 and 764-768. (d) Hauser, C. R.; Swamer, F. W.; Adams, J. T. OR
1954, 8, 59.
5. (a) Muir, W. M.; Ritchie, P. D.; Lyman, D. J. JOC 1966, 31, 3790. (b)
Vavon, G.; Conia, J. M. CR 1951, 233, 876. (c) Logue, M. W. JOC
1974, 39, 3455. (d) Lawesson, S. O.; Busch, T. ACS 1959, 13, 1717. (e)
Wright, P. E.; McEven, W. E. JACS, 1954, 76, 4540. (0 Korobitsyna, I.
K.; Severina, T. A.; Yur'ev, Yu. K. ZOB 1959, 29, 1960 (GA 1960, 54,
8772). (g) Gough, S. T. D.; Trippett, S. JCS 1962, 2333.
(26)
6.
(27)
7.
PhCOCl reacts also easily with primary or secondary amines

in the presence of a base, aqueous alkali (Schotten-Bauman pro
cedure), or tertiary amines (pyridine or Et3N), to afford the cor
responding amides (eq 28).15b This reaction is used to protect
amines.15c
PhCH2CH2NH2
3.
(28)
Miscellaneous Reactions. PhCOCN (see Acetyl Cyanide),

which is used as acylating agent (for instance, to protect
alcohols)17a can be prepared by reacting PhCOCl with Copper(I)
Cyanide (60-65%).17b,c Diazoalkanes are readily acylated by Ph
COCl to give diazo ketones.18a,b These compounds are interesting
as intermediates18c-e to prepare -halo ketones, a-hydroxy ke
tones or arylacetic acids (Arndt-Eistert reaction).18e PhCOCl has
also been used to prepare volatile acyl chlorides (C2 to C6) from
the corresponding carboxylic acids.19 On the other hand, it reacts
with sulfoxides to lead generally to the corresponding -chloro
sulfides (Pummerer rearrangement).20
8.
9.
10.
11.
12.
13.
14.
Related Reagents. Acetic Anhydride; Acetyl Chloride; Acetyl

Cyanide; Benzoic Anhydride; Benzoyl Trifluoromethanesulfonate; p-Nitrobenzoyl Chloride.
15.
1.
The Chemistry of Acyl Halides; Patai, S., Ed. Wiley: London, 1972. (b)
Sonntag, N. O. V. CRV 1953, 52, 237.
2. (a) March, J. Advanced Organic Chemistry, Reactions, Mechanisms and
Structures. 4th ed.; Wiley: New York, 1992; pp 487-488. (b) Sheverdina,
N. I.; Kocheskov, K. A. The Organic Compounds of Zinc and Cadmium;
North Holland: Amsterdam, 1967. (c) Shirley, D. A. OR 1954, 8, 28.
(d) Jorgenson, M. J. OR 1970, 18, 1. (e) Posner, G. H. OR 1975, 22,
253. (f) Wipf, P. S 1993, 537. (g) Larock, R. C. Comprehensive Organic
Transformations; VCH: New York, 1989; pp 686-692. (h) See also nButylmangenese Chloride.
(a) Olah, G. O. Friedel Crafts and Related Reactions; Wiley: New York,
1963-1965. Vol. 1-4. (b) See Ref. 4a, pp 786-816. (c) Gore, P. H. CRV
1955, 55, 229. (d) Gore, P. H. CI(L) 1974, 727. (e) Pearson, D. E.;
Buehler, C. A. 5 1972, 533. (f) See Ref. 2a, pp 539, 598 and 821. (g) See
Ref. 2g, pp 703 and 708.
(a) Gore, P. H.; Hoskins, J. A.; Thornburn, S. JCS(B) 1970, 1343. (b)
Minnis, W. OSC, 1943, 2, 520. (c) Orchin, M.; Reggel, L. JACS 1951,
73, 436.
(a) Groves, J. K. CSR 1972, 1, 73. (b) Matsumoto, T.; Hata, K. JACS
1957, 79, 5506.
(a) Pohland, A. E.; Benson, W. R. CRV 1966, 66, 161. (b) Kochetkov,
N. K.; Khorlin, A. Ya.; Karpeiskii, M. Ya. ZOB 1956, 26, 595 (CA 1956,
50, 13 799).
(a) Weber, W. P. Silicon Reagentsfor Organic Synthesis; Springer: Berlin,
1983; pp 214. (b) See Ref. 2g, p 753. (c) Fleming, I.; Iqbal, J.; Krebs, E.
P.T1983, 39, 841.
(a) See Ref. 10a, pp 86, 120, and 175. See Ref. 2g, pp 687 and 688. (c)
Fleming, I.; Dunogus, J.; Smithers, R. OR 1989, 37, 57. (d) Fleming,
I.; Pearce, A. JCS(P1) 1980, 2485. (e) Calas, R.; Dunogus, J.; Pillot, J.
P.; Biran, C ; Pisciotti, F.; Arreguy, B. JOM 1975, 85, 149.
(a) Andersson, C.; Hallberg, A. JOC 1988, 53, 4257. (b) McElvain, S.
M.; McKay, Jr., G. R. JACS 1956, 78, 6086.
(a) See Ref. 4a, pp 766-772. (b) See Ref. 2a, pp 601-603 (c) Enamines:
Synthesis, Structure and Reactions, 2nd ed; Cook, A. G., Ed.; Dekker:
New York, 1988. (d) Hiinig, S.; Hoch, H. Fortschr. Chem. Forsch. 1970,
14, 235. (e) Hickmott, P. W. CI(L) 1974, 731. (f) Hickmott, P. W. T 1984,
40, 2989; T 1982, 38, 1975 and 3363. (g) Campbell, R. D.; Harmer, W.
L. JOC 1963, 28, 379.
(a) See Ref. 2a, p 392. (b) Greene, T. W. Protective Groups in Organic
Synthesis; Wiley: New York, 1981; p 61. (c) Reese, C. B. Protective
Groups in Organic Chemistry; McOmie, J. F. W., Ed.; Plenum: London,
1973; p 111. (d) Seymour, F. R. Carbohydr. Res. 1974, 34, 65. (e) Szeja,
W. S 1979, 821. (f) Castellino, A. J.; Rapoport, H. JOC 1986, 51, 1006.
(g) Hanessian, S.; Roy, R. CJC 1985, 63, 163. (h) Haines, A. H. Adv.
Carbohydr. Chem. Biochem. 1976, 33, 11. (i) Kozikowski, A. P.; Xia, Y.;
Rusnak, J. M. CC 1988, 1301. (j) Schlessinger, R. H.; Lopes, A. JOC
1981, 46, 5252. (k) See Ref. 14b, p 103 and Ref. 14c, pp 171-177.
(a) See Ref. 2a, pp 417-418. (b) White, E. OSC, 1973, 5, 336. (c) See
Ref. 14b, pp 261-263 and Ref. 14c, pp 52-53.
16. See Ref. 17b, p 113, note 3.
17. (a) See Ref. 14b, p 61. (b) Oakwood, T. S.; Weisgerber, C. A. OSC 1955,
3, 112. (c) See Ref. 2a, p 495.
18. (a) Franzen, V. LA 1957, 602, 199. (b) Bestmann, H. J.; Kolm, H. CB
1963, 96, 1948. (c) Bridson, J. N.; Hooz, J. OSC, 1988, 6, 386. (d) Ried,
W.; Mengler, H. Fortschr. Chem. Forsch. 1965, 5, 1. (e) Fridman, A. L.;
Ismagilova, G. S.; Zalesov, V. S.; Novikov, S. S. RCR 1972, 41, 371. (f)
See Ref 2a, pp 1083-1085. (g) Meier, H.; Zeller, K.-P. AG(E) 1975, 14,
32.
BENZYL BROMIDE
19.
20.
(a) Finan, P. A.; Fothergill, G. A. JCS 1963, 2723. (b) Brown, H. C. JACS
1938, 60, 1325.
(a) See Ref 2a, p 1236. (b) Mikolajczyk, M.; Zatorski, A.; Grzejszczak,
S.; Costisella, B.; Midura, W. JOC 1978, 43, 2518. (c) De Lucchi, 0.;
Miotti, U.; Modena, G. OR 1991, 40, 157.
G. Cahiez
Universite Pierre et Marie Curie, Paris, France
Benzyl Bromide
[100-39-0]
C7H7Br
(MW 171.04)
(benzylating agent for a variety of heteroatomic functional groups

as well as carbon nucleophiles)
Physical Data: mp - 3 to - 1 C; bp 198-199 C; d 1.438 g c m - 3 .
Solubility: sol ethereal, chlorinated, and dipolar aprotic solvents.
Form Supplied in: 98-99% pure liquid.
Handling, Storage, and Precautions: the reagent is a potent
lachrymator and should be handled in a fume hood.
Benzylation of Heteroatomic Functional Groups. Benzylation of various heteroatomic functional groups is readily achieved
with this reagent under a variety of conditions and finds
widespread application in organic synthesis, primarily as a pro
tecting group. 1
Alcohols and phenols are benzylated upon treatment with ben
zyl bromide under basic conditions. For example, treatment of
alcohols with Sodium Hydride or Potassium Hydride in ethereal
solvent2 or DMF 3 generates alkoxides, which subsequently un
dergo Williamson reactions with benzyl bromide. Selective ben
zylation of a primary alcohol in the presence of a secondary alco
hol has been accomplished in DMF at low temperature.4
Benzylation of alcohols using Potassium Fluoride-Alumina
and benzyl bromide in acetonitrile at room temperature is
effective.5 Silver oxide in DMF is yet another base system.6 Of
particular interest in carbohydrate applications is the reaction of
benzyl bromide with carbohydrate derivatives which have been
pretreated with tin reagents. Thus it is possible to benzylate an
equatorial alcohol in the presence of an axial alcohol (eq 1 ) 7 and
also to selectively benzylate an anomeric hydroxy through Di-nbutyltin Oxide.8
45
Iodide, which generates the more reactive benzyl iodide in situ

(see Benzyl Iodide). Benzylation of phenols proceeds well un
der the conditions described for aliphatic alcohols. Owing to the
greater acidity of phenols it is possible to use weaker bases such
as Potassium Carbonate for these reactions.9
Benzyl bromide will readily alkylate amino groups. Reactions
are normally carried out in the presence of additional base and
dibenzylation of primary amines is usually predominant.10 Selec
tive quaternization of a less hindered tertiary amine in the pres
ence of a more hindered tertiary amine has been described.11
Amide and lactam nitrogens can be benzylated under ba
sic conditions,12 as can those of sulfonamides13 and nitrogen
heterocycles.14
Thiols,15 silyl thioethers,16 and thiosaccharins17 may be benzy
lated with benzyl bromide under basic conditions. Thus L-cysteine
is S-benzylated under basic conditions (eq 2). 18 Benzylation of
selenols is likewise possible.19 A synthesis of benzylic sulfones
is possible using Benzenesulfonyl Chloride and Sodium 0,0Diethyl Phosphorotelluroate with benzyl bromide. 20
(2)
Although the preparation of benzyl carboxylate esters from ben

zyl bromide and carboxylate anions is not the most common route
to these compounds, the reaction is possible when carried out in
DMF 20 or using zinc carboxylates.21
Nucleophilic attack on benzyl bromide by cyanide and azide an
ions is feasible with ion-exchange resins or with the corresponding
salts.22
Reactions with Active Methylene Compounds. Enolates of
ketones, 23 esters,24 enediolates,25 1,3-dicarbonyl compounds, 26
amides and lactams,27 as well as nitrile-stabilized carbanions, 28
can be alkylated with benzyl bromide. Cyclohexanone may
be benzylated in 92% ee using a chiral amide base. 29 Amide
bases as well as alkoxides have been employed in the case of
nitrile alkylations.28b Benzylation of metalloenamines may be
achieved30a and enantioselective reactions are possible using a
chiral imine (eq 3). 30b However, reactions between benzyl bro
mide and enamines proceed in low yield.31 The benzylation of
a ketone via its enol silyl ether, promoted by fluoride, has been
observed.32
(3)
79% ee
(1)
In some instances the sluggish reactivity of sterically hindered

alcohols toward benzyl bromide may be overcome through addi
tion of a catalytic iodide source such as Tetra-n-butylammonium
Reactions with Metals and Organometallics. Difficulties en

countered in the preparation of benzylic metal compounds with
active metals are due primarily to the tendency of these compounds
to undergo Wurtz coupling (self condensation). 33 Benzylmagnesium bromide may nevertheless be prepared from benzyl bromide
and used under standard34 or Barbier conditions.35 Benzyllithium
cannot be obtained practically from benzyl bromide. Benzylzinc
bromide and the cyanocuprate BnCu(CN)ZnBr have both been
46
BENZYL CHLOROFORMATE
prepared. The cuprate undergoes 1,2-additions with aldehydes and

ketones.36
The propensity of benzyl bromide to undergo coupling with
organometallic reagents may be used to advantage, as organolithiums,37
Grignard
reagents,38
organocuprates,39
40
41
organocadmiums,
organochromiums,
and organoiron
reagents42 are all known to give coupling products. An interesting
coupling of benzyl bromide with N-methylphthalimide under
dissolving metal conditions has been reported (eq 4).43
25.
Duhamel, L.; Poirier, J.-M. BSF(2) 1982, 297.
26.
(a) Berry, N. M.; Darey, M. C. P.; Harwood, L. M. 5 1986, 476. (b)

Bassetti, M.; Cerichelli, G.; Floris, B. G 1986, 116, 583. (c) Asaoka,
M.; Miyake, K.; Takei, H. CL 1975, 1149. (d) Ogura, K.; Yahata, N.;
Minoguchi, M.; Ohtsuki, K.; Takahashi, K.; lida, H. JOC 1986, 51, 508.
(a) Woodbury, R. P.; Rathke, M. W. JOC 1977, 42, 1688. (b) Klein, U.;
Sucrow, W. CB 1977, 110, 1611. (c) Meyers, A. I.; Harre, M.; Garland,
R. JACS 1984, 706, 1146.
27.
28.
29.
30.
(4)
31.
Related Reagents. Benzyl Chloride; Benzyl Iodide; Ben

zyl p-Toluenesulfonate; Benzyl 2,2,2-Trichloroacetimidate; Ben
zyl Trifluoromethanesulfonate; 3,4-Dimethoxybenzyl Bromide;
p-Methoxybenzyl Chloride; 4-Methoxybenzyl 2,2,2-Trichloro
acetimidate.
1. (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis,

2nd ed.; Wiley: New York, 1991. (b) Protective Groups in Organic
Chemistry; McOmie, J. F. W., Ed.; Plenum: New York, 1973.
2. Nicolaou, K. C ; Pavia, M. R.; Seitz, S. P. JACS 1981,103, 1224.
32.
33.
34.
35.
36.
37.
3.
Hanessian, S.; Liak, T. J.; Dixit, D. M. Carbohydr. Res. 1981, 88, C14.
38.
4.
Fukuzawa, A.; Sato, H.; Masamune, T. TL 1987, 28, 4303.
39.
5.
Ando, T.; Yamawaki, J.; Kawate, T.; Sumi, S.; Hanafusa, T. BCJ 1982,
55, 2504.
Kuhn, R.; Low, I.; Trischmann, H. CB 1957, 90, 203.
40.
41.
6.
7.
(a) Nashed, M. A.; Anderson, L. TL 1976, 3503. (b) Cruzado, C ;

Bernabe, M.; Martin-Lomas, M. JOC 1989, 54, 465.
8. Bliard, C.; Herczegh, P.; Olesker, A.; Lukacs, G. Carbohydr. Res. 1989,
8, 103.
9. Schmidhammer, H.; Brossi, A. JOC 1971, 93, 746.
42.
43.
(a) Arseniyadis, S.; Kyler, K. S.; Watt, D. S. OR 1984, 31, 1. (b) Cope,
A. C ; Holmes, H. L.; House, H. O. OR 1957, 9, 107.
Murakata, M.; Nakajima, M.; Koga, K. CC 1990, 1657.
(a) Stork, G.; Dowd, S. R. OSC 1988, 6, 526. (b) Saigo, K.; Kashahara,
A.; Ogawa, S.; Nohira, H. TL 1983, 24, 511.
(a) Enamines: Synthesis, Structure, and Reactions, 2nd ed.; Cook, A. G.,
Ed.; Dekker: New York, 1988. (b) Brannock, K. C ; Burpitt, R. D. JOC
1961, 26, 3576. (c) Opitz, G.; Hellmann, H.; Mildenberger, M.; Suhr, H.
LA 1961, 649, 36.
(a) Kuwajima, I.; Nakamura, E. JACS 1975, 97, 3257. (b) Binkley, E. S.;
Heathcock, C. H. JOC 1975, 40, 2156.
Wakefield, B. J. Organolithium Methods; Academic: New York, 1988.
(a) Kharasch, M. S.; Reinmuth, O. Grignard Reactions of Nonmetallic
Substances; Constable: London, 1954. (b) Reuvers, A. J. M.; van
Bekkum, H.; Wepster, B. M. T 1970, 26, 2683.
Blomberg, C ; Hartog, F. A. S 1977, 18.
Berk, S. C ; Knochel, P.; Yeh, M. C. P. JOC 1988, 53, 5789.
(a) Hirai, K.; Matsuda, H.; Kishida, Y. TL 1971, 4359. (b) Hirai, K.;
Kishida, Y. TL 1972, 2743. (c) Villieras, J.; Rambaud, M; Kirschleger,
B.; Tarhouni, R. BSF(2) 1985, 837.
Rahman, M. T.; Nahar, S. K. JOM 1987, 329, 133.
(a) Kobayashi, Y.; Yamamoto, K.; Kumadaki, I. TL 1979, 4071. (b)
Furber, M.; Taylor, R. J. K.; Burford, S. C. TL 1985, 26, 3285.
(a) Emptoz, G.; Huet, F. BSF(2) 1974, 1695.
Wellmann, J.; Steckhan, E. S 1978, 901.
(a) Sawa, Y.; Ryang, M.; Tsutsumi, S. JOC 1970, 35, 4183. (b) Cookson,
R. C ; Farquharson, G. TL 1979, 1255. (c) Sawa, Y.; Ryang, M.; Tsutsumi,
S.TL 1969, 5189.
Flynn, G. A. CC 1980, 862.
10.
(a) Yamazaki, N.; Kibayashi, C. JACS 1989, 111, 1396. (b) Gray, B. D.;
Jeffs, P. W. CC 1987, 1329.
11. (a) Chung, B.-H.; Zymalkowski, F. AP 1984, 317, 307. (b) Chung, B.-H.;
Zymalkowski, F. AP 1984, 317, 323.
12. (a) Landini, D.; Penso, M. SC 1988, 18, 791. (b) Staskun, B. JOC 1979,
44, 875. (c) Sato, R.; Senzaki, T.; Goto, T.; Saito, M. BCJ 1986, 59, 2950.
13.
14.
Sandoz Research
Institute,
William E. Bauta
East Hanover, NJ, USA
Benzyl Chloroformate1
Bergeron, R. J.; Hoffman, P. G. JOC 1979, 44, 1835.

Chivikas, C. J.; Hodges, J. C. JOC 1987, 52, 3591.
15.
Harpp, D. N.; Kobayashi, M. TL 1986, 27, 3975.
16.
17.
18.
19.
20.
Ando, W.; Furuhata, T.; Tsumaki, H.; Sekiguchi, A. SC 1982, 12, 627.
Yamada, H.; Kinoshita, K ; Inomata, K.; Kotake, H. BCJ 1983, 56, 949.
Dymicky, M.; Byler, D. M. OPP 1991, 23, 93.
Mitchell, R. H. CC 1974, 990.
Huang, X.; Pi, J.-H. SC 1990, 20, 2291.
21.
(a) Comber, M. F ; Sargent, M. V.; Skelton, B. W.; White, A. H. JCS(P1)

1989, 441. (b) Shono, T.; Ishige, O.; Uyama, H.; Kashimura, S. JOC
1986, 51, 546.
22.
(a) Gordon, M.; Griffin, C. E. C1(L) 1962, 1019. (b) Hassner, A.; Stern,
M. AG 1986, 98, 479. (c) Bram, G.; Loupy, A.; Pedoussaut, M. BSF(2)
1986, 124. (d) Ravindranath, B.; Srinivas, P. T 1984, 40, 1623.
23.
(a) Gall, M.; House, H. O. OSC 1988, 6, 121. (b) Sato, T.; Watanabe, T.;
Hayata, T.; Tsukui, T. CC 1989, 153.
24.
(a) Seebach, D.; Estermann, H. TL 1987, 28, 3103. (b) Lerner, L. M.

JOC 1976, 41, 2228.
[501-53-1]
C 8 H 7 ClO 2
(MW 170.60)
(protecting agent for many functional groups, especially for the

N-protection of amino acids;7 activates pyridine rings toward
nucleophilic attack;53 reagent for the preparation of other
benzyloxycarbonylating agents3)
Alternate Name: benzyloxycarbonyl chloride (CbzCl).
Physical Data: colorless oily liquid, bp 103 C/20 mmHg (with
slow decarboxylation to benzyl chloride at this temperature);
bp 85-87C/7 mmHg; mp 0C; d (20C) 1.195g cm"3; ng20D
1.5190.
Form Supplied in: widely available.
Preparative Methods: CbzCl can be readily prepared by the reac
tion of benzyl alcohol and phosgene, either in toluene solution4
or neat. 1b,5,6 Purification of such freshly prepared CbzCl is of
ten not necessary; indeed, ca. 25% residual toluene solvent does
not interfere with derivatization reactions.4
Purification: commercial CbzCl is typically better than 95% pure
and is often contaminated by benzyl chloride, benzyl alcohol,
toluene, and HC1. 2,3 On storage it can undergo a slow HC1catalyzed decomposition, even at low temperature. 1a,3 It has
been recommended 1b,2 that CbzCl which has been stored for
long periods be purified by flushing with a stream of dry air to
remove dissolved CO 2 and HC1 impurities. Filtration and stor
age over Na 2 SO 4 may be followed by distillation; it is important
that low temperatures (oil bath <85 C) 1b and high vacuum be
used to minimize thermal decomposition.3
Handling, Storage, and Precautions: CbzCl is highly toxic and is
a cancer suspect agent; it is a lachrymator with an acrid odor
and should be handled with caution in a fume hood.
Protection of Amines. The most widespread application of

CbzCl is in the protection of primary and secondary amines as
the corresponding benzyl carbamates. These reactions are usually
performed either under Schotten-Baumann conditions,7 by using
aq NaHCO 3 or aq Na 2 CO 3 as base in an organic solvent (eq 1),8
or in the presence of an organic base (typically Et 3 N) in CH 2 Cl 2 . 9
The isolation and/or crystallization of amines is often facilitated
by Cbz derivatization of the crude amine generated in another
reaction.10 A wide variety of primary and secondary aliphatic
amines, including aziridines,11 azetidines,12 and other sensitive7'9
and electron-deficient8c amines, can be selectively protected in
the presence of alcohol,81*13 phenol,14 and thiol15 functionality;
however, the selective protection of hindered secondary amines
over secondary alcohols has proved difficult.16
(1)
The N-protection of amino acids during peptide synthesis con

stitutes a major application of this methodology.1,8a References
to the N-protection of individual amino acids using CbzCl have
been tabulated. 1b,e Use of the N-Cbz protecting group generally
affords crystalline amino acid derivatives and suppresses racemization at the -stereocenter during peptide bond formation. The
N-Cbz group is stable to conditions used for the formation of
peptide bonds. Benzyl carbamates are highly complementary to tbutyl (i.e. Boc) carbamates in peptide synthesis (see t-ButylAzidoformate). Schotten-Baumann conditions are most commonly
employed for the preparation of N-Cbz amino acids (eq 2);1b,4
racemization at the a stereocenter is suppressed under these basic
conditions by the adjacent negatively charged carboxylate group.
The use of a lower reaction temperature (20 C) has been shown
in one case to afford a higher yield of pure N-Cbz derivative.17 One
disadvantage of the standard Schotten-Baumann protocol is the
need for either the simultaneous addition of CbzCl and aq NaOH,
or the sequential addition of small aliquots of these reagents,
throughout the course of the reaction. A modified procedure 1b
47
8d
using NaHCO 3 as the base avoids this inconvenience. A re

cent report indicates that N-Cbz derivatization of a range of amino acids can be conveniently achieved, albeit in only moderate
yield, by refluxing with CbzCl in ethyl acetate without added base;
interestingly, no racemization was observed.18
(2)
The selective protection of the -amine in ,-diamino acids

can be achieved by chelation of the -amino and -carboxylate
functionality by CuII ion (eq 3). 1b,f,18,19 The CuII chelate can be
cleaved by H 2 S, If by thioacetamide,19 or by use of a chelating
ion-exchange resin.17 Selective protection of the -amino group
in lysine, the imidazole ring nitrogen in histidine, and the -amino
function in serine, can all be accomplished in homogeneous aque
ous medium in the absence of added base using Cbz-imidazolium
chloride, a water-soluble benzyloxycarbonylating agent which is
prepared in situ from CbzCl and N-methylimidazole.20 Benzyl
succinimidyl carbonate, best prepared by reaction of the dicyclohexylammonium salt of N-hydroxysuccinimide with CbzCl, 21 is
also useful for the N-Cbz protection of -amino acids without the
need for added base.
(3)
The N-Cbz group is stable to a variety of weakly acidic and basic

conditions.22 Benzyl carbamates are most commonly cleaved to
the free amine by catalytic hydrogenolysis (H 2 /Pd-C) 23 although
a plethora of alternate reductive (e.g. transfer hydrogenolysis,24
Li/liq NH 3 25 ), strongly acidic (e.g. HBr/HOAc 26 ), and neutral con
ditions have been employed.1 The use of transfer hydrogenolysis
(cyclohexadiene, 10% Pd-C) allows for the clean deprotection
of N-Cbz pyrimidines without concomitant reduction of the 5,6double bond that is observed under standard catalytic hydrogenol
ysis conditions.27 The acid stability of the N-Cbz group can be ma
nipulated by the introduction of electron-withdrawing or electrondonating substituents onto the phenyl ring. Selective deprotection
of an N-Cbz group in the presence of an S-Cbz moiety can be
achieved using HBr/HOAc at rt. 28
Primary and secondary arylamines can also be Ncarbamoylated using CbzCl, typically in the presence of aq
Na 2 CO 3 (eq 4) 29 or pyridine.30 The protection of electrondeficient anilines can be accomplished using MgO in acetone. 31
Protection of a pyrrole nitrogen can be achieved by initial
deprotonation to the potassium salt.32
(4)
N-Benzyl carbamates prepared as outlined above can also serve

as useful intermediates in the overall N-methylation of secondary
48
amines, since LiA1H4 reduction of a benzyl carbamate affords the

corresponding tertiary N-methylamine (eq 5).33
alcohol-38,43 and phenol-derived44 benzyl carbonates are effi

ciently deprotected by catalytic hydrogenolysis; benzyl carbon
ates are more readily cleaved under these conditions than benzyl
ethers.38 Removal of the O-Cbz group can also be achieved by
electrolytic reduction.45
(5)
(8)
Other N-Protection Reactions. The protection of an amide

as its N-Cbz derivative can be achieved using CbzCl with
Et3N/DMAP,34 or by initial deprotonation of the amide using BuLi
or (Me3Si)2NLi.35 The N-protection of nucleosides is usually in
effective with CbzCl but can be selectively and efficiently accom
plished using N-Cbz imidazolium salts generated in situ from the
reaction of CbzCl with N-alkylimidazoles (eq 6).27,36
Protection of Thiols. The protection of thiols using CbzCl

can be achieved using Et3N as base.46 The use of aq NaHCO3
as base allows for the selective protection of the SH group
in cysteine (eq 9), while N,S-bisprotection is observed under
Schotten-Baumann conditions (eq 10).47 Selective protection
of the cysteine SH moiety can also be achieved using Cbzimidazolium chloride, a water-soluble benzyloxycarbonylating
agent prepared in situ from CbzCl and N-methylimidazole.20 Both
N- and S-Cbz groups are deprotected using refluxing CF3CO2H48
or by electrolytic reduction.45 The use of NaOMe/MeOH at rt for
5-10 min allows for the selective cleavage of S-Cbz over N-Cbz
groups.28
(6)
(9)
Protection of Alcohols and Phenols. Protection of alcohols

and phenols as the corresponding benzyl carbonates is typically
achieved using CbzCl in the presence of an organic base (e.g.
Et3N,37 pyridine38) in CH2Cl2 or ether at low temperature (-20 C
to rt). The selective protection of one secondary alcohol in the
presence of other secondary and tertiary alcohols has been accom
plished using DMAP at very low temperatures (40 to 20 C)
for 3 days (eq 7).39
(7)
(10)
Decarboxylative Esteriflcation of Carboxylic Acids. The

preparation of benzyl esters from sterically uncongested car
boxylic acids,49 including -keto acids37,50 and malonic acid half
esters,51 can be achieved using CbzCl in the presence of an or
ganic base (Et3N,37,50,51 pyridine,52 or Et3N/DMAP49 in CH2Cl2
or THF). The lack of reactivity of sterically crowded carboxylic
acids49 allows for the selective esteriflcation of the less crowded of
two acid moieties (eq 11).52 A major attraction of the benzyl ester
group is its susceptibility to cleavage to the free carboxylic acid
by catalytic hydrogenolysis1d,23 or transfer hydrogenolysis.1d
(11)
The use of NaH as base allows for the efficient protection of

even hindered electron-deficient alcohols (eq 8).40 A secondary
alcohol can be selectively protected over an indole nitrogen.41 1 O-Methylated 2-deoxyribose sugars can be protected at the 3- and
5-hydroxyl groups38 while the hemiacetal function is selectively
protected over secondary alcohols in 1 -unprotected sugars.42 Both
Activation of Pyridine Ring Towards Nucleophilic At

tack. Pyridine and various 4-substituted pyridines can be ac
tivated by CbzCl toward regioselective nucleophilic attack by
53
54
55
56
NaBH4 and by alkyl, aryl, and alkynyl Grignard reagents,

affording the corresponding 2-substituted 1,2-dihydropyridines
(eq 12). Treatment of a 3-substituted pyridine with CbzCl and
NaBH4 can afford a mixture of 1,2- and 1,4-reduction products;
however, reaction with CbzCl and Red-Al proceeds via regioselective 1,2-reduction at the less crowded -carbon (eq 13).57
(12)
9. Meyers, A. I.; Dupre, B. H 1987, 25, 113.

10. Bashyal, B. P.; Fleet, G. W. J.; Gough, M. J.; Smith, P. W. T 1987, 43,
3083.
11. Senter, P. D.; Pearce, W. E.; Greenfield, R. S. JOC 1990, 55, 2975.
12. Baldwin, J. E.; Adlington, R. M.; Jones, R. H.; Schofield, C. J.;
Zaracostas, C ; Greengrass, C. W. T 1986, 42, 4879.
13. Patel, A.; Poller, R. C. RTC 1988, 707, 182.
14. Van der Eycken, J.; et al. TL 1989, 30, 3873.
15. Atkinson, J. G.; Girard, Y.; Rokach, J.; Rooney, C. S. JMC 1979, 22, 99.
16. Iida, H.; Watanabe, Y.; Kibayashi, C. JACS 1985, 107, 5534.
17.
18.
19.
20.
(13)
Generation of Other Benzyloxycarbonylating Agents. A

variety of other benzyloxycarbonylating agents can be prepared
from CbzCl.3 For example, reaction of CbzCl with sodium
benzyl carbonate affords dibenzyl carbonate, a promising sta
ble crystalline alternative to CbzCl for achieving clean and ef
ficient TV-benzyloxycarbonylation.3 N-Cbz-imidazole, prepared
from CbzCl and imidazole, has proved a suitable reagent for the
selective protection of primary over secondary amines.58
Related Reagents. Allyl Chloroformate; 4-Bromobenzyl
Chloroformate; t-Butyl Chloroformate; Ethyl Chloroformate; 9Fluorenylmethyl Chloroformate; Isobutyl Chloroformate; Methyl
Chloroformate; 2,2,2-Tribromoethyl Chloroformate; 2,2,2Trichloroethyl Chloroformate; 2,2,2-Trichloro-t-butoxycarbonyl
Chloride; 2-(Trimethylsilyl)ethyl Chloroformate; Vinyl Chloro
formate.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
1.
2.
3.
4.
5.
6.
7.
8.
(a) Bodanszky, M. Peptide Chemistry A Practical Textbook; Springer:

Berlin, 1988. (b) Greenstein, J. P.; Winitz, M. Chemistry of the Amino
Acids; Wiley: New York, 1961; Vol. 2, pp 887-895. (c) Wunsch, E. MOC
1974, 15(1), 47-69. (d) Meienhofer, J. In Chemistry and Biochemistry of
the Amino Acids, Barrett, G. C., Ed.; Chapman & Hall: London, 1985;
pp 299-302. (e) Pettit, G. R. Synthetic Peptides; Van Nostrand Reinhold:
New York, 1970-71; Vols. 1,2, Academic: New York, 1975; Vol. 3. (f)
Bailey, P. D. An Introduction to Peptide Chemistry; Wiley: Chichester,
1990.
Perrin, D. D.; Armerago, W. L. F. Purification of Laboratory Chemicals,
3rd ed.; Pergamon: Oxford, 1988; p 97.
Wunsch, E.; Graf, W.; Keller, 0.; Keller, W.; Wersin, G. S 1986, 958.
Carter, H. E.; Frank, R. L.; Johnston, H. W. OSC 1955, 3, 167.
Katchalski, E. Methods Enzymol. 1957, 3, 541.
Farthing, A. C. JCS 1950, 3213.
Krow, G. R.; Cannon, K. C ; Carey, J. T.; Ma, H.; Raghavachari, R.;
Szczepanski, S. W. JOC 1988, 53, 2665.
(a) Bergmann, M.; Zervas, L. CB 1932, 65, 1192 (CA 1932, 26, 5072).
(b) Austin, G. N.; Baird, P. D.; Fleet, G. W. J.; Peach, J. M.; Smith, P.
W.; Watkin, D. J. T 1987, 43, 3095. (c) Takahashi, Y.; Yamashita, H.;
Kobayashi, S.; Ohno, M. CPB 1986, 34, 2732. (d) Akhtar, M.; Gani, D.
T 1987, 43, 5341.
49
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
Scott, J. W.; Parker, D.; Parrish, D. R. SC 1981, 11, 303.

Kruse, C. H.; Holden, K. G. JOC 1985, 50, 2792.
Payne, L. S.; Boger, J. SC 1985, 15, 1277.
Guibe-Jampel, E.; Bram, G.; Vilkas, M. BSF(2) 1973, 1021 (CA 1973,
79, 31 982g).
Paquet, A. CJC 1982, 60, 976.
(a) Boisonnas, R. A. Adv. Org. Chem. 1963, 3, 159. (b) Greene, T. W.;
Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley:
New York, 1991; pp 441-444.
Hartung, W. H.; Simonoff, R. OR 1953, 7, 263.
Jackson, A. E.; Johnstone, R. A. W. S 1976, 685.
Boutin, R. H.; Rapoport, R. H. JOC 1986, 57, 5320.
Ben-Ishai, D.; Berger, A. JOC 1952, 17, 1564.
Watkins, B. E.; Kiely, J. S.; Rapoport, H. JACS 1982, 104, 5702.
Sokolovsky, M.; Wilchek, M.; Patchornik, A. JACS 1964, 86, 1202.
Jones, G. B.; Moody, C. J. JCS(P1) 1989, 2455.
Torrini, I.; Zecchini, G. P.; Agrosi, F.; Paradisi, M. P. JHC 1986, 23,
1459.
Rewcastle, G. W.; Baguley, B. C ; Cain, B. F. JMC 1982, 25, 1231.
Drew, M. G. B.; George, A. V.; Isaacs, N. S.; Rzepa, H. S. JCS(P1) 1985,
1277.
Iida, H.; Yamazaki, N.; Kibayashi, C. JOC 1987, 52, 1956.
Fukuyama, T.; Nunes, J. J. JACS 1988, 110, 5196.
Nagasaka, T.; Koseki, Y.; Hamaguchi, F. TL 1989, 30, 1871.
Watkins, B. E.; Rapoport, H. JOC 1982, 47, 4471.
Arnoldi, A.; Merlini, L.; Scaglioni, L. JHC 1987, 24, 75.
Bobek, M.; Bloch, A.; Kuhar, S. TL 1973, 3493.
Baker, W. R.; Clark, J. D.; Stephens, R. L.; Kim, K. H. JOC 1988, 53,
2340.
Sutherland, J. K.; Watkins, W. J.; Bailey, J. P.; Chapman, A. K.; Davies,
G. M. CC 1989, 1386.
Kuehne, M. E.; Podhorez, D. E.; Mulamba, T.; Bornmann, W. G. JOC
1987, 52, 347.
Saito, H.; Nishimura, Y.; Kondo, S.; Umezawa, H. CL 1987, 799.
Daubert, B. F.; King, C. G. JACS 1939, 61, 3328.
Kuhn, M.; von Wartburg, A. HCA 1969, 52, 948.
Mairanovsky, V. G. AG(E) 1976, 15, 281.
Barton, D. H. R.; Manly, D. P.; Widdowson, D. A. JCS(P1) 1975, 1568.
Berger, A.; Noguchi, J.; Katchalski, E. JACS 1956, 78, 4483.
Zervas, L.; Photaki, I.; Ghelis, N. JACS 1963, 85, 1337.
(a) Kim, S.; Kim, Y. C ; Lee, J. I. TL 1983, 24, 3365. (b) Kim, S.; Lee,
J. I.; Kim, Y C. JOC 1985, 50, 560.
Domagala, J. M. TL 1980, 27, 4997.
Gutman, A. L.; Boltanski, A. TL 1985, 26, 1573.
Baldwin, J. E.; Otsuka, M.; Wallace, P. M. T 1986, 42, 3097.
Sundberg, R. J.; Amat, M.; Fernando, A. M. JOC 1987, 52, 3151.
(a) Comins, D. L.; Abdullah, A. H.; Smith, R. K. TL 1983, 24, 2711. (b)
Comins, D. L.; Brown, J. D. TL 1986, 27, 4549.
Kurita, J.; Iwata, K.; Tsuchiya, T. CPB 1987, 35, 3166.
Natsume, M.; Ogawa, M. H 1983, 20, 601.
50
BENZYL CHLOROMETHYL ETHER
57.
Natsume, M.; Utsonomiya, I.; Yamaguchi, K.; Sakai, S.-I. T 1985, 41,
2115.
58. Sharma, S. K.; Miller, M. J.; Payne, S. M. JMC 1989, 32, 357.
Paul Sampson
Kent State University, Kent, OH, USA
Benzyl Chloromethyl Ether 1
[3587-60-8]
C 8 H 9 ClO
(2)
Ethyl lactate can be protected as a BOM ether for subsequent

nucleophilic additions to the corresponding aldehyde with high
diastereoselectivity.12 A synthesis of zoapatanol used selective
protection of a diol (eq 3). 13 Primary alcohols can be protected
selectively in the presence of secondary hydroxy groups, 14 and
secondary hydronyls react more quickly than tertiary ones with
benzyl chloromethyl ether and base. 15 Removal of this protecting
group can be carried out by hydrogenolysis over Pd.
(MW 156.61)
(protecting group for alcohols2 and amines; 3 electrophile in

alkylation'of carbanions;4 and source of nucleophilic benzyloxymethyl anion 5 )
Physical Data: bp 53-56 C/1.5 mmHg; 96-99 C/11 mmHg; d
l . B g c m - 3 ; n 2 0 D1.5268-1.5279.
Solubility: sol THF, ether, dioxane, dichloromethane, chloroform,
benzene, toluene, DMF, DMSO, and acetonitrile.
Form Supplied in: liquid.
Analysis of Reagent Purity: NMR, GC.
Preparative Methods: benzyl alcohol plus aqueous formaldehyde
and hydrogen chloride g a s ; 1 6 7 reaction of benzyl methyl ether
with boron trichloride;8 cleavage of benzyloxymethyl methyl
sulfide with sulfuryl chloride.9
Purification: distillation.
Handling, Storage, and Precautions: stable indefinitely when kept
dry but destroyed by water and other nucleophilic reagents.
Alcohol Protecting Group. The foremost use for this reagent

is as a protecting group for the alcohol functional group. This can
be illustrated in a step utilized in the total synthesis of kijanolide
(eq 1 ). 10 An enantioselective synthesis of the taxol side chain used
the benzyloxymethyl (BOM) ether for protection of an alcohol
group (eq 2). 11
(3)
Amine Protecting Group. 2,3,5-Triiodoimidazole reacts with

Potassium Carbonate in DMF followed by benzyl chloromethyl
ether to give the 1-BOM derivative in 83% yield.3 A substituted
purine undergoes protection with benzyl chloromethyl ether and
Sodium Hydride (eq 4). 16 Imide nitrogens can be protected in the
presence of lactam nitrogens because of the difference in acidity.17
(4)
Alkylation of Carbanions. Methyl 2-phenylpropionate can

be deprotonated with LDA and alkylated on carbon with ben
zyl chloromethyl ether.4 Introduction of the BOM group in both
chiral amides (eq 5) 18 and dianions (eq 6) 19 gives good yields.
Removal of the benzyl group by hydrogenolysis completes the
hydroxymethylation process.
(5)
(6)
(1)
Benzyloxymethyl Anion. Both Grignard and organolithium

reagents of the benzyloxymethyl anion can be prepared. The Grig
nard reagent is formed by reaction with Magnesium. 20 Trapping
BENZYL 2,2,2-TRICHLOROACETIMIDATE
this species with Tri-n-butylchlorostannane and reaction of the
stannane with n-Butyllithium gives the organolithium.20 Addi
tion to electrophiles is predictable (eq 7).5 Removal of the benzyl
group via hydrogenolysis reveals that the ether anion is a masked
methanol dianion.
51
Benzyl 2,2,2-Trichloroacetimidate
[81927-55-1]
C 9 H 8 Cl 3 NO
(MW 252.53)
(7)
(reagent for protection of hydroxy groups as benzyl ethers under

mildly acidic conditions1)
Related Reagents. Benzyl Chloromethyl Sulfide; t-Butyl
Chloromethyl Ether; 2-Chloroethyl Chloromethyl Ether; Chloro
methyl Methyl Ether; Chloromethyl Methyl Sulfide; (p-Methoxybenzyloxy)methyl Chloride; 2-Methoxyethoxymethyl Chloride;
2-(Trimethylsilyl)ethoxymethyl Chloride.
1.
2.
3.
4.
5.
6.
7.
Connor, D. S.; Klein, G. W.; Taylor, G. N. OS 1972, 52, 16.

Stork, G.; Isobe, M. JACS 1975, 97, 6260.
Groziak, M. P.; Wei, L. JOC 1991, 56, 4296.
Miyamoto, K.; Tsuchiya, S.; Ohta, H. JACS 1992, 114, 6256.
Wipf, P.; Kim, Y. JOC 1993, 58, 1649.
Hill, A. J.; Keach, D. T. JACS 1926, 48, 257.
Paraformaldehyde can be used in place of formalin: Guedin-Vuong, D.;
Yoichi, N. BSF 1986, 245.
8. Goff, D. A.; Harris, R. N., III; Bottaro, J. C ; Bedford, C. D. JOC 1986,
57,4711.
9. Benneche, T.; Strande, P.; Undheim, K. S 1983, 762.
10. Roush, W. R.; Brown, B. B. JOC 1993, 58, 2162.

11. Denis, J. N.; Greene, A. E.; Serra, A. A.; Luche, M. J. JOC 1986, 51, 46.
12. Banfi, L.; Bernardi, A.; Colombo, L.; Gennari, C ; Scolastico, C. JOC
1984, 49, 3784.
13.
Nicolaou, K. C ; Claremon, D. A.; Barnette, W. E. JACS 1980, 102, 6611.
14. McCarthy, P. A. TL 1982, 4199.

15. Bender, S. L.; Widlanski, T.; Knowles, J. R.; B 1989, 28, 7560.
16. Shimada, J.; Suzuki, F. TL 1992, 33, 3151.
17. Yamagishi, M.; Yamada, Y.; Ozaki, K.; Asao, M.; Shimizu, R.; Suzuki,
M.; Matsumoto, M.; Matsuoka, Y.; Matsumoto, K. JMC 1992, 35, 2085.
18. Evans, D. A.; Urpi, F.; Somers, T. C ; Clark, J. S.; Bilodeau, M. T. JACS
1990,7/2,8215.
19. Fang, C ; Suganuma, K.; Suemune, H.; Sakai, K. JCS(P1), 1991, 1549.
20.
Still, W. C. JACS 1978, 100, 1481.
Harold W. Pinnick
Bucknell University, Lewisburg, PA, USA
Alternate Name: BTCA.

Physical Data: bp 106-114 C/0.5 mmHg; d 1.359 g c m - 3
Solubility: reactions are most often carried out in a mixture of
cyclohexane/dichloromethane;1 decomposition by rearrange
ment to TV-benzyl trichloroacetamide is accelerated in more
polar solvents.
Form Supplied in: colorless oil.
Purification: distillation under reduced pressure.
Handling, Storage, and Precautions: moisture sensitive.
Hydroxy Group Protection. The benzyl ether is one of the

most versatile and frequently used protecting groups in or
ganic synthesis.2 The most common way of introducing this
group is with a strong base and Benzyl Bromide using the clas
sical Williamson ether synthesis methodology. Recently, ben
zyl trichloroacetimidate3 has found widespread use to pro
tect hydroxy functionalities as their benzyl ethers under mildly
acidic conditions, 1,4,5a when the more conventional strong basemediated methods either failed or gave lower yields due to side
reactions and/or starting material decomposition.
The imidate can be prepared from the sodium alkoxide ion
of benzyl alcohol and trichloroacetonitrile according to proce
dures based on those developed by Cramer 3 in the late 1950s.
Substituted benzyl ethers have also been prepared this way,
for example using 4-methoxybenzyl trichloroacetimidate,5 3,4dimethoxybenzyl trichloroacetimidate,6 and 2,6-dichlorobenzyl
trichloroacetimidate,7 and the method has also been applied for
the synthesis of allyl lb and t-butyl ethers,8 as well as for 2phenylisopropyl esters9 for peptide synthesis. The benzyl and
4-methoxybenzyl 2,2,2-trichloroacetimidates are available com
mercially.
The reaction is performed in nonpolar media to prevent rear
rangement of the acetimidate to N-benzyl trichloroacetamide, and
as an added advantage the solid trichloroacetamide byproduct can
simply be removed by filtration. These constraints limit the sub
strate range to those molecules soluble in this type of solvent; for
example, a sugar triol which was insoluble in dichloromethane,
when reacted in DMSO yielded very little of the benzylated prod
uct desired.10 It was also noted that differential (primary versus
secondary) hydroxy protection in carbohydrates (eq 1) was poor,10
and the ratio of the 6-OBn to 4-OBn products was at best 2:1.
The reagent has been used widely in carbohydrate 1,10-14 chem
istry. The method was found to be useful in cases where Obenzoyl group migration had been observed under basic condi
tions (eq 2), 11 and has also been applied to inositol derivatives,15
when the same problem15a was encountered.
52
BENZYL 2,2,2-TRICHLOROACETIMIDATE
When JV-acetyl-protected sugar amines were under

investigation1,12 the N-acetyl group was observed to un
dergo transformation to the O-benzyl imidate in competition with
OH benzylation (eq 3). It appears for best yields at least 1 equiv
of reagent per OH and NAc group is needed, and subsequent
hydrolysis and reacetylation of the amine are necessary to
obtain are the originally desired material. Similar problems were
encountered with the morpholine derived lactams (eq 4),16a
where mixed products were obtained, but with -lactams16b
with N-amide protection (eq 5), O-benzylation with benzyl
trichloroacetimidate proceeded smoothly. BTCA has recently
been used to convert diketopiperazines into their bis-benzyl
imino ethers.17
(5)
44% after N-deprotection
Other classes of molecules which have been benzylated us

ing this reagent include hydroxy ketones,4 hydroxy halides4,7,18
and esters19-23 such as tartrates,19 hydroxy propionates or
butanoates,20 long alkyl chain hydroxy esters,21 and hydroxy
lactones.4 Under basic conditions problems such as enolization,
aldol reactions, elimination and epoxide formation can cause prob
lems and when 2-substituted esters, such as ethyl (S)-lactate,22
are required as homochiral starting materials, then protection us
ing this method circumvents the considerable risk of racemization
that accompanies the use of bases (eq 6).
(1)
(6)
[] D 2 0 -74.5 (c 2.94, CHCl3)
a:b = 2:1, 45-60% total
(2)
Under these benzylation reaction conditions, it has been

shown that the N-t-butoxycarbonyl (N-Boc) (eq 7) and N-(2trimethylsilyl)ethoxycarbonyl (N-TEOC) (eq 8) protected amino
acid derivatives are converted into their N-benzyloxycarbonyl (NZ) analogs.24 In most cases yields were moderate, but surpris
ingly the t-butyldimethylsilyloxy and t-butyl ester functions are
relatively unaffected by the acidic conditions.
(7)
(8)
(3)
2. nonaqueous work-up
(4)
a:b = 6:4, 80% total

The most frequently employed acid catalyst is TfOH (Trifluoromethanesulfonic Acid, or triflic acid), but others that have been
used include BF3OEt2,4,8 TMSOTf,4,16 p-TsOH,6 and TFA.23,16
Camphorsulfonic acid, pyridinium p-toluenesulfonate, and trityl
perchlorate have also been investigated in conjunction with the
more reactive 4-methoxybenzyl trichloroacetimidate.5a
Functional groups sometimes sensitive to acidic conditions such
as simple esters,1,19-23 lactones,4,5d acetals,1,5a,15 epoxides,53,13
2-methoxyethyloxymethyl (MEM) groups,6 t-butyldimethylsilyl
ethers,14,24-27 and orthoformates15b are generally unaffected by
the catalytic amounts of acid used, although some tertiary
alcohols4 and 1-trimethylsilylalkynes4 have been noted to give
poor yields.
Related Reagents. Benzyl Bromide; Benzyl Chloride; Benzyl
Iodide; Benzyl Trifiuoromethanesulfonate; 3,4-Dimethoxybenzyl
2,4-BIS(4-METHOXYPHENYL)-1,3,2,4-DITHIADIPHOSPHETANE 2,4-DISULFIDE
Bromide; p-Methoxybenzyl Chloride; 4-Methoxybenzyl 2,2,2Trichloroacetimidate.
1. (a) Wessel, H.-P.; Iversen, T.; Bundle, D. R. JCS(P1) 1985, 2247. (b)
Iversen, T.; Bundle, D. R. CC 1981, 1240.
2. Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis,
2nd ed.; Wiley: New York, 1991.
3. (a) Cramer, F.; Pawelzik, K.; Baldauf, H. J. CB 19S8, 91, 1049. (b)
Cramer, F.; Hennrich, N. CB 1961, 94, 976.
4.
5.
6.
7.
Eckenberg, P.; Groth, U.; Huhn, X; Richter, N.; Schmeck, C. T 1993,49,

1619.
(a) Nakajima, N.; Horita, K.; Abe, R.; Yonemitsu, O. TL 1988, 29, 4139.
(b) Takaku, H.; Ueda, S.; Ito, T. TL 1983, 24, 5363. (c) Romo, D.;
Johnson, D. D.; Plamondon, L.; Miwa, T.; Schreiber, S. L. JOC 1992,57,
5060. (d) Adams, E.; Hiegemann, M.; Duddeck, H.; Welzel, P. T 1990,
46, 5975.
Takaku, H.; Ito, T.; Imai, K. CL 1986, 1005.
Amouroux, R.; Gerin, B.; Chastrette, M. 7/1985, 41, 5321.
8.
Armstrong, A.; Brackenridge, I.; Jackson, R. F. W.; Kirk, J. M. TL 1988,

29, 2483.
9. Yue, C ; Thierry, J.; Potier, P. TL 1993, 34, 323.
10. Bovin, N. V.; Musina, L. Y.; Khorlin, A. Y. BAU 1986, 35, 614.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
Yasumori, T.; Sato, K.; Hashimoto, H.; Yoshimura, J. BCJ 1984, 57,
2538.
(a) Kusumoto, S.; Yamamoto, M.; Shiba, T. TL 1984, 25, 3727. (b) Imoto,
M.; Yoshimura, H.; Yamamoto, M; Shimamoto, T.; Kusumoto, S.; Shiba,
T. TL 1984, 25, 2667.
Schubert, J.; Schwesinger, R.; Knothe, L.; Prinzbach, H. LA 1986, 2009.
Takahashi, S.; Terayama, H.; Kuzuhara, H. TL 1992, 33, 7565.
(a) Ozaki, S.; Kondo, Y.; Nakahira, H.; Yamaoka, S.; Watanabe, Y. TL
1987, 28, 4691. (b) Baudin, G.; Glanzer, B. I.; Swaminathan, K. S.;
Vasella, A.; HCA 1988, 71, 1367. (c) Estevez, V. A.; Prestwich, G. D.
TL 1991, 32, 1623.
(a) Danklmaier, J.; Honig, H. LA 1989, 665. (b) Kawabata, T.; Kimura,
Y.; Ito, Y.; Terashima, S.; Sasaki, A.; Sunagawa, M. T 1988, 44, 2149.
Groth, U.; Schmeck, C ; Schollkopf, U. LA 1993, 321.
Voss, G.; Gerlach, H. HCA 1983, 66, 2294.
Hansson, T. G.; Kihlberg, J. O. JOC 1986, 51, 4490.
(a) White, J. D.; Kawasaki, M. JOC 1992, 57, 5292. (b) Keck, G. E.;
Murry, J. A. JOC 1991, 56, 6606.
(a) Imoto, M.; Yoshimura, H.; Yamamoto, M.; Shimamoto, T.;
Kusumoto, S.; Shiba, T. BCJ 1987, 60, 2197. (b) Widmer, U. S 1987,
568.
Ito, Y.; Kobayashi, Y.; Kawabata, T.; Takase, M.; Terashima, S. T 1989,
45, 5767.
Keck, G. E.; Andrus, M. B.; Romer, D. R.; JOC 1991, 56, 417.
Barrett, A. G. M.; Pilipauskas, D. JOC 1990, 55, 5170.
25. Hong, C. Y.; Kishi, Y.; JACS 1992, 114, 7001.

26. Lawrence, N. J.; Fleming, I. TL 1990, 31, 3645.
27. Danishefsky, S. J.; Deninno, S.; Lartey, P. JACS 1987, 109, 2082.
Andrew N. Boa & Paul R. Jenkins

Leicester University, UK
53
2,4-Bis(4-methoxyphenyl)-l,3,2,4dithiadiphosphetane 2,4-Disulfide1
[19172-47-5]
C14H14O2P2S4
(MW 404.45)
(reagent for the conversion of carbonyl into thiocarbonyl groups1)

Alternate Name: Lawesson's reagent.
Solubility: modestly sol boiling organic solvents such as toluene,
chlorobenzene, anisole, dimethoxyethane.
Form Supplied in: yellowish evil-smelling crystals; typical impu
rity is P4S10.
Analysis of Reagent Purity: FTIR spectrum.1c
Preparative Methods: reaction of P 4 S 10 with anisole in excess
refiuxing anisole.2
Purification: recrystallization from boiling toluene.
Handling, Storage, and Precautions: can be stored for months at
rt if moisture is excluded. Prolonged heating in solution causes
decomposition (polymerization). It is toxic and should be han
dled under a fume hood since hazardous H 2 S is easily liberated
with moisture.
Thionation of Carbonyl Compounds. Lawesson's reagent

(LR) is a most powerful reagent for the thionation of a wide
variety of carbonyl compounds. Ketones, enones, carboxylic es
ters, thiolocarboxylic esters, amides, and related substrates are
conveniently transformed into the corresponding thiocarbonyl
compounds. 1 In some cases, follow-up products are isolated since
certain thiones are labile under the reaction conditions. Com
pared with P 4 S 10 , from which it is easily prepared,2 LR exhibits
several advantages. Its reactivity is significantly higher and it
is sufficiently soluble in hot organic solvents, allowing homo
geneous reaction conditions to be applied. Therefore many car
bonyl compounds can be successfully thionated with LR but
not with P 4 S 10 , or at least thionated in higher yields. Several
reagents with structures similar to LR, which are even more
reactive or more selective than LR, have been developed and
are used in particularly difficult cases (see 2,4-Bis(methylthio)1,3,2,4-dithiadiphosphetane 2,4-Disulfide). The workup proce
dure depends on the reaction conditions applied, in particular on
the solvent, and the products formed. If DME is used, the reac
tion mixture can be poured into water and the product extracted
as usual. Low boiling hydrocarbons are best evaporated and the
residue, which contains the product together with 2,4,6-tris(4methoxyphenyl)cyclotriphosphoxane 2,4,6-trisulfide, is subjected
to column chromatography. High boiling solvents such as tetralin
or trichlorobenzene should be removed by flash chromatography
in order to avoid thermal decomposition of the labile thiones.
Thioketones. Thioketones of different types have been ob
tained from the corresponding ketones. Lawesson, who discovAvoid Skin Contact with All Reagents
54
2,4-BIS(4-METHOXYPHENYL)-1,3,2,4-DITHIADIPHOSPHETANE2,4-DISULFIDE
ered LR to be a powerful reagent for the conversion of C = 0

into C=S groups, described the preparation of diaryl thioketones.3
Substituents such as Me, Br, NO2, or NMe2 do not affect the good
yields of up to 98% (eq 1).
(5)
(1)
Recently, the diferrocenyl thioketones (1) and (2) were prepared

from the corresponding ketones.4 Alkyl aryl and dialkyl thioke
tones (3),3 (4),5 (5)6 are formed in good yields if enethiolization is
unfavored or impossible, whereas mainly enethiols are obtained
from cycloalkanones (eq 2).7
(6)
The thioanalogs of natural products such as the steroid (7)11 or

the colchicine alkaloid (8)12 have also been prepared by use of
LR.
(7) 96%
(2)
(8) 33%
Thio Analogs of Dicarbonyl Compounds. In general, the

most labile thiono analogs of -dicarbonyl compounds cannot
be prepared by any thionation procedure. However, thioacenaphthoquinone (9) as well as thioanthraquinone (10) were obtained
from the quinones and LR.13 Even -thioxo thioamides are avail
able (eq 7),14 whereas 2,2,5,5-tetramethyl-4-thioxo-3-hexanone,
which itself cannot be prepared from the corresponding diketone,
reacts with LR to yield 3,4-di-t-butyl-1,2-dithiete, the valence iso
mer of the open-chain dithione (eq 8).15
2-Cyclohexenones are thionated with LR (eq 3),7 but only the

vinylogous dithioester (6) is a stable compound. Acyclic enones
(chalcones) give on reaction with LR the enethione dimers (eq 4).8
(3)
(7)
(6)
(4)
(8)
Again, stable enethiones are formed if an electron donating substituent (e.g. NR2) is present in the -position (eq 5).9 Certain
isolable 2,5-cyclohexadienefhiones can be further transformed
into bicyclohexadienylidenes (eq 6).10
Thioketones with pronounced steric hindrance are obtained on

reaction of cyclobutane-l,3-diones with LR (eq 9).16
55
was achieved by using LR together with tetramethylthiourea in

xylene at 175C. 27
(9)
(14)
Diketones with remote C=O groups can be transformed by LR

into the mono- or dithiones.17
Thiono Esters and Lactones. Although thiono esters can be
conveniently prepared via imidates,18 the introduction of LR for
the thionation of esters 3 represents a great advance in synthetic
methodology since ordinary esters are used as educts and P 4 S 10
only reacts with esters if enforced reaction conditions are applied,
under which many thiono esters decompose. Facile conversion of
aliphatic and aromatic esters (eq 10), 319 a,p-unsaturated esters,20
and lactones 21 to the corresponding thiono derivatives is effected
in high yields (eqs 11 and 12). 22,23
Dithioesters and Related Compounds. Thioesters are trans

formed into the corresponding dithioesters on reaction with
LR. 3,20,28 Again the yields are nearly quantitative even if steric
hindrance can be expected (eq 15).3
(15)
(10)
(11)
The reaction is completed within 5-15 min if tetralin at

210 C is used as solvent.28 Also, dithio--lactones, 21,28 including
dithiophthalides29 and dithio--pyrones,30 are formed smoothly
whereas the hitherto unknown simple - or -dithiolactones can
not be prepared, neither with LR nor by any other method. Interest
ingly, dithiopilocarpine is formed as a mixture of diastereomers on
reaction of pilocarpine with LR (eq 16), i.e. both oxygen atoms of
(12) are replaced by sulfur.31 In an interesting sequence of thion
ation and rearrangement reactions, three different thiono analogs
of 1,8-naphthalic anhydride were prepared (eq 17).32
(12)
(16)
Thiono esters and lactones are important intermediates in mod

ern organic synthesis since they easily undergo useful follow-up
reactions. Ethers are formed on reduction with Raney Nickel24 or
Tri-n-butyltin Hydride (eq 13).25
(13)
(17)
Macrocyclic bis-thionolactones have been prepared with LR.

These were converted by reduction with Sodium Naphthalenide
into the radical anions, which gave bicyclic systems through
radical dimerization and subsequent methylation (eq 14).26 This
method was successfully applied by Nicolaou et al. 27 in the to
tal synthesis of hemibrevetoxin B. One of the crucial steps of the
synthesis was the preparation of the bis-thiono ester (11), which
Thioamides and Related Compounds. Thioamides are the

most stable thiocarbonyl compounds and have been prepared, for
a century, from amides and P 4 S 10 under rather drastic conditions.
However, even for this purpose LR has turned out to be a superior
56
reagent. High yields are obtained for all types of thioamides 1,33
and -lactams 1,33,34 including the elusive unsubstituted acrylothioamide (eq 18)35 and thioformamides or thioamides bearing
sensitive substituents such as NO 2 , Z-NH, 36 or OH (eq 19).33
(18)
(19)
-Lactams are also smoothly transformed34 (eq 20), 37 which

is important for the preparation of thio analogs of -lactam an
tibiotics or azetidines. Furthermore, endothio oligopeptides be
came conveniently available only after LR had been introduced as
reagent 1,38,39 (eq 21). 40
(20)
3.
Pedersen, B. S.; Scheibye, S.; Nilsson, N. H.; Lawesson, S.-O. BSB 1978,
87, 223.
4.
Sato, M.; Asai, M. JOM 1992, 430, 105.
5.
Klages, C.-R; Voss, J. CB 1980, 113, 2255.
6.
7.
Wenck, H.; de Meijere, A.; Gerson, F.; Gleiter, R. AG(E) 1986, 25, 335.
Scheibye, S.; Shabana, R.; Lawesson, S.-O.; R0mming, C. T 1982, 38,
993.
8.
Kametani, S.; Ohmura, H.; Tanaka, H.; Motoki, S. CL 1982, 793.
9.
(a) Walter, W.; Proll, T. 5 1979, 941. (b) Shabana, R.; Rasmussen, J. B.;
Olesen, S. O.; Lawesson, S.-O. T 1980, 36, 3047. (c) Rasmussen, J. B.;
Shabana, R.; Lawesson, S.-O. T 1982,38, 1705. (d) Pulst, M.; Greif, D.;
Kleinpeter, E. ZC 1988, 28, 345.
10.
Khn, R.; Otto, H.-H. AP 1989, 322, 375.
11.
Weiss, D.; Gaudig, U.; Beckert, R. S 1992, 751.
12.
Muzaffar, A.; Brossi, A. SC 1990, 20, 713.
13.
El-Kateb, A. A.; Hennawy, I. T.; Shabana, R.; Osman, F. H. PS 1984,

20, 329.
14.
Adiwidjaja, G.; Giinther, H.; Voss, J. LA 1983, 1116.
15.
Kopke, B.; Voss, J. JCR(S) 1982, 314.
16. Strehlow, T.; Voss, J.; Spohnholz, R.; Adiwidjaja, G. CB 1991, 124, 1397.
17. Ishii, A.; Nakayama, J.; Ding, M.; Kotaka, N.; Hoshino, M. JOC 1990,
55,2421.
18. Voss, J. COS 1991, 6, 435.
19. Jones, B. A.; Bradshaw, J. S. CRV 1984, 84, 17.
20.
(21)
Recently the cyclopeptide [D-cysteine]8cyclosporin has been

prepared from [D-serine]8cyclosporin via selective thionation with
LR at the 7-position followed by intramolecular sulfur transfer.41
Miscellaneous Reactions of LR. Under particular conditions,
certain carbonyl compounds and other substrates react with LR
to form thiophosphonates or heterocycles, which fact throws
some light on the mechanism of thionation reactions with LR. 1
Carbinols undergo nucleophilic substitution with LR to form the
corresponding thiols. 42 The redox properties of LR can be uti
lized to prepare dithiolactones from dialdehydes (eq 22), 43 oxo thioamides from nitro ketones (eq 23), 44 or sulfides from
sulfoxides.45
Pedersen, B. S.; Scheibye, S.; Clausen, K.; Lawesson, S.-O. BSB 1978,
87, 293.
21.
Scheibye, S.; Kristensen, J.; Lawesson, S.-O. T 1979, 35, 1339.
22.
Takano, S.; Tomita, S.; Takahashi, M.; Ogasawara, K. S 1987, 1116.
23.
Nicolaou, K. C ; McGarry, D. G.; Somers, P. K.; Kim, B. H.; Ogilvie, W.

W.; Yiannikouros, G.; Prasad, C. V. C ; Veale, C. A.; Hark, R. R. JACS
1990, 112, 6263.
24.
Baxter, S. L.; Bradshaw, J. S. JOC 1981, 46, 831.
25.
26.
Smith, C ; Tunstad, L. M.; Guttierrez, C. G. PS 1988, 37, 257.

Nicolaou, K. C ; Hwang, C.-K.; Marron, B. E.; DeFrees, S. A.;
Couladouros, E. A.; Abe, Y.; Carroll, P. J.; Snyder, J. P. JACS 1990,
112, 3040.
27.
Nicolaou, K. C ; Reddy, K. R.; Skokotas, G.; Sato, F.; Xiao, Xiao-Yi;

Hwang, C.-K. JACS 1993, 115, 3558.
28.
Ghattas, A.-B. A. G.; El-Khrisy, E.-E. A. M.; Lawesson, S.-O. Sulfur

Lett. 1982, 1, 69.
29.
Oparin, D. A.; Kuznetsova, A. S. Vestsi Akad. Navuk BSSR, Ser. Khim.

Navuk 1990, (6), 109 (CA 1991, 775, 29 039y).
Hoederath, W.; Hartke, K. AP 1984, 317, 938.
30.
31.
Shapiro, G.; Floersheim, P.; Boelsterli, J.; Amstutz, R.; Bolliger, G.;
Gammenthaler, H.; Gmelin, G.; Supavilai, P.; Walkinshaw, M. JMC
1992, 35, 15.
32.
Lakshmikantham, M. V; Chen, W.; Cava, M. P. JOC 1989, 54, 4746.
33.
Scheibye, S.; Pedersen, B. S.; Lawesson, S.-O. BSB 1978, 87, 229.
(22)
34.
(23)
Shabana, R.; Scheibye, S.; Clausen, K.; Olesen, S. O.; Lawesson, S.-O.
NJC 1980, 4, 47.
35. Khalid, M.; Vallee, Y.; Ripoll, J.-L. C1(L) 1988, 123.
36.
Kohrt, A.; Hartke, K. LA 1992, 595.
37.
Verkoyen, C ; Rademacher, P. CB 1985, 118, 653.
38.
Thorsen, M.; Yde, B.; Pedersen, U.; Clausen, K.; Lawesson, S.-O. T
1983, 39, 3429.
Sherman, D. B.; Spatola, A. F. JACS 1990, 112, 433.
1. (a) Cherkasov, R. A.; Kutyrev, G. A.; Pudovik, A. N. T 1985, 41, 2567.

(b) Cava, M. P.; Levinson, M. I. T 1985, 41, 5061. (c) Aldrich Library
of Infrared Spectra; Aldrich Chemical Co.: Milwaukee, 1985; Vol. 1 (2),
p 557B.
40.
2. Thomsen, I.; Clausen, K.; Scheibye, S.; Lawesson, S.-O. OS 1984, 62,
158.
41. Eberle, M. K.; Nuninger, F. JOC 1993, 58, 673.

42. Nishio, T. CC 1989, 205.
39.
Brown, D. W.; Campbell, M. M.; Chambers, M. S.; Walker, C. V. TL

1987, 28, 2171.
BIS(2-OXO-3-OXAZOLIDINYL)PHOSPHINIC CHLORIDE
43.
44.
45.
57
Nugara, P. N.; Huang, N.-Z.; Lakshmikantham, M. V.; Cava, M. P. HC

1991,32, 1559.
Harris, P. A.; Jackson, A.; Joule, J. A. Sulfur Lett. 1989, 10, 117.
Bartsch, H.; Erker, T. TL 1992, 33, 199.
Jiirgen Voss
Universitdt Hamburg, Germany
(1)
(2)
Bis(2-oxo-3-oxazolidinyl)phosphinic
Chloride 1
(3)
[68641-49-6]
C6H8C1N2O5P
(MW 254.57)
(reagent for activating carboxyl groups, 1 converting acids to

esters2 (including thioesters3 and phosphoesters4), amides5
(including peptides 6-8 and -lactams 9,10 ), and anhydrides;11
reagent for kinetic resolution of racemic carboxylic acids and
alcohols12)
Alternate Names: N,N-bis(2-oxo-3-oxazolidinyl)phosphordiamidic chloride; N,N-bis(2-oxo-3-oxazolidinyl)-phosphorodiamidic chloride; phosphoric acid bis(2-oxooxazolidide)chloride; BOP-C1; BOPDC1.
Physical Data: white powder, mp 195-198 C; hygroscopic.
Solubility: slightly sol CH 2 Cl 2 , MeCN, THF, DMF; dec H 2 O.
Form Supplied in: white to off-white powder, typically 97% pure.
Analysis of Reagent Purity: IR (KBr): 1775 (C=0), 765 (P-Cl)
cm-1.
Purification: the outcome of reactions can be greatly affected by
the purity of the reagent; commercial samples may require to
be washed with cold water and recrystallized from MeCN prior
to use. 13
Handling, Storage, and Precautions: store in a cool dry place
under nitrogen to preclude contact with moisture and oxygen.
Use only in a chemical fume hood. Wear suitable protective
clothing and eye/face protection. Causes burns and is harmful
if swallowed, inhaled, or absorbed through skin.
Carboxyl Group Activator. BOP-C11 is used for a direct,

one-pot conversion of carboxylic acids into esters (eq 1 ) 2 (in
cluding thioesters 3 and phosphoesters4), amides (eq 2), 5 and an
hydrides (eq 3). 11 Conditions for minimizing side reactions and
optimizing yields of both esters and amides are reported. 2,5 Ad
vantages offered over previously used reagents, such as N,N'Carbonyldiimidazole, carbodiimides, and unsymmetrical anhy
drides, include good yields (typically >80%), mild reaction con
ditions, and tolerance of both steric bulk and a wide range of
functional groups.
The mechanism of these reactions is assumed to involve dis

placement of chloride by the carboxylate anion to give a phosphorodiamidate (eq 4). Subsequent nucleophilic attack of an alcohol,
amine, or a carboxylate anion affords phosphorodiamidic acid and
esters, amides, and anhydrides, respectively (eq 5).
(4)
(5)
X = O, NH, OCO
For lactonization (eq 6), 14 including the synthesis of

macrolactones,15 BOP-C1 is a useful reagent.
(6)
Chemo- and regioselective acylation with BOP-C1 is illus

trated by the formation of 5'-benzoyldeoxyadenosine in good yield
(eq7). 16
58
BIS(2-OXO-3-OXAZOLIDINYL)PHOSPHINIC CHLORIDE
(7)
Cbz-Gly-D/L-Phe-L-Val-OMe
For the synthesis of oligonucleotides, BOP-C1 is an effective

coupling reagent, allowing phosphotriesters to be prepared in high
yields without detectable side reactions (eq 8).17
(8)
with HO-t-Bu
with imidazole
without HO-t-Bu
or imidazole
(12)
Yield (%) Epimerization (%)

88
0.0
96
0.8
78
5.6
Problems, notably racemization and poor yields due to oxazolone formation, are encountered when coupling N-acyl amino
acids with BOP-C1;6 1,3-Dicyclohexylcarbodiimide (DCC) is a
better reagent to use in such cases. Some limitations of BOP-C1
for peptide couplings have been discussed;7 it is not recommended
for -branched -amino acids (e.g. Boc-Val) or for couplings in
which the nucleophile is a primary amine.8
Kinetic Resolution. BOP-C1 is a condensation agent for the
kinetic resolution of racemic carboxylic acids and alcohols with
chiral alcohols (eq 13) and carboxylic acids, respectively.12
-Lactams may be prepared either by condensation of imines

with carboxylic acids (eq 9)9 or by cyclization of -amino acids
(ea 10).10
(13)
(9)
(10)
BOP-C1 has been used quite extensively for the synthesis of

peptides.6-8 It is particularly useful for coupling N-alkyl--amino
acids with minimal racemization (eq 11),18,19 although the qual
ity of BOP-C1 employed in these reactions can significantly affect
yields,13 and the analogous azide, BOP-N3, has been proposed
as an alternative reagent.20 Racemization can sometimes be sup
pressed by inclusion of additives such as 1-Hydroxybenzotriazole
(HOBt) or Imidazole (eq 12),21 although under certain conditions
HOBt can induce epimerization.22
(11)
1. (a) Diago-Meseguer, J.; Palomo-Coll, A. L. S 1980, 547. (b) FF 1982,

10, 41; 1984,11, 57; 1988, 13, 39.
2. Ballester-Rodes, M.; Palomo-Coll, A. L. SC 1984, 14, 515.
3. Arrieta, A.; Garcia, T.; Lago, J. ML; Palomo, C. SC 1983, 13, 471.
4. Katti, S. B.; Agarwal, K. TL 1986, 27, 5327.
5. Cabre, J.; Palomo, A. L. S 1984, 413.
6. Kolodziejczyk, A. M.; Wodecki, Z. J. Peptides, Proceedings of the
19th European Peptide Symposium, 1986; Theodoropoulos, D., Ed.; de
Gruyter: Berlin, 1987; p 115.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
Van der Auwera, C.; Anteunis, M. J. O. Int. J. Pept. Protein Res. 1987,
29, 574.
Colucci, W. J.; Tung, R. D.; Petri, J. A.; Rich, D. H. JOC 1990, 55, 2895.
Shridhar, D. R.; Ram, B.; Narayana, V. L. S 1982, 63.
Chung, B. Y.; Goh, W.; Nah, C. S. Bull. Korean Chem. Soc. 1991, 12,
457.
Cabre-Castellvi, J.; Palomo-Coll, A.; Palomo-Coll, A. L. S 1981, 616.
Mazon, A.; Najera, C ; Yus, M.; Heumann, A. TA 1992, 3, 1455.
Van der Auwera, C ; Anteunis, M. J. O. BSB 1986, 95, 203.
Cruickshank, K. A.; Reese, C.B.S 1983, 199.
Corey, E. J.; Hua, D. H.; Pan, B.-C; Seitz, S. P. JACS 1982, 104, 6818.
Liguori, A.; Perri, E.; Sindona, G.; Uccella, N. T 1988, 44, 229.
Katti, S. B.; Agarwal, K. L. TL 1985, 26, 2547.
Tung, R. D.; Dhaon, M. K.; Rich, D. H. JOC 1986, 51, 3350.
Tung, R. D.; Rich, D. H. JACS 1985, 107, 4342.
Katti, S. B.; Misra, P. K.; Haq, W.; Mathur, K. B. IJC(B) 1988, 27, 3.
BIS(TRI-n-BUTYLTIN) OXIDE
21.
22.
Van der Auwera, C ; Van Damme, S.; Anteunis, M. J. O. Int. J. Pept.

Protein Res. 1987, 29, 464.
Anteunis, M. J. O.; Sharma, N. K. BSB 1988, 97, 281.
David C. Rees & Niall M. Hamilton

Organon Laboratories Ltd, Newhouse, Lanarkshire, UK
59
in aqueous organic solvents. Oxidation of sulfenamides to sulfinamides can be achieved without formation of sulfonamides using
the reagent (eq 6). 4
PhCH2SCH2Ph
PhCH2SOCH2Ph
(5)
Bis(tri-n-butyltin) Oxide
(6)
[56-35-9]
C 24 H 54 OSn 2
(MW 596.20)
promotes the oxidation of secondary alcohols and sulfides with

Br 2 ; O- and N-activations; dehydrosulfurizations; hydrolysis
catalyst)
Physical Data: bp 180C/2 mmHg; d 1.170 g c m - 3 .
Solubility: sol ether and hexane.
Form Supplied in: colorless oil.
Handling, Storage, and Precautions: (Bu3Sn)2O should be stored
in the absence of moisture. Owing to the toxicity of organostannanes, this reagent should be handled in a well-ventilated fume
hood. Contact with the eyes and skin should be avoided.
Oxidations. Benzylic, allylic, and secondary alcohols are

oxidized to the corresponding carbonyl compounds by using
(Bu 3 Sn) 2 O-Bromine. 1 This procedure is quite useful for se
lective oxidation of secondary alcohols in the presence of pri
mary alcohols, which are inert under these conditions (eqs 1-3).2
(Bu3Sn)2O-N-Bromosuccinimide
can also be applied to the se
lective oxidation of secondary alcohols (eq 4). 3
(1)
(2)
(Bu 3 Sn) 2 O-Br 2 -Diphenyl Diselenide in refluxing CHCl 3

transforms alkenes into -seleno ketones (eq 7). 5
(7)
O- and N-activations. (Bu3Sn)2O has been used in the ac

tivation of hydroxy groups toward sulfamoylations, acylations,
carbamoylations, and alkylations because conversion of alcohols
to stannyl ethers enhances the oxygen nucleophilicity. Tributylstannyl ethers are easily prepared by heating the alcohol and
(Bu 3 Sn) 2 O, with azeotropic removal of water. Sulfamoylation of
alcohols can be achieved via tributyltin derivatives in high yields,
whereas direct sulfamoylation gives low yields (eq 8). 6 This acti
vation can be used for selective acylation of vicinal diols (eq 9). 7 In
carbohydrate chemistry this approach is extremely useful for the
regioselective acylation without the use of a blocking-deblocking
technique (eq 10).8 The order of the activation of hydroxy groups
on carbohydrates has been investigated, and is shown in par
tial structures (1), (2), and (3).9 Regioselective carbamoylation
can also be accomplished by changing experimental conditions
(eq 11).10 On the other hand, alkylations of the tin derivatives
are sluggish and less selective than acylations under similar con
ditions. Regioselective alkylation of sugar compounds, however,
can be carried out in high yield by conversion to a tributyltin ether
followed by addition of alkylating agent and quaternary ammo
nium halide catalysts (eq 12).11
(3)
(4)
(Bu 3 Sn) 2 O-Br 2 oxidizes sulfides to sulfoxides in CH 2 Cl 2 with

out further oxidation to sulfones, even in the presence of excess
reagent (eq 5). 4 This procedure is especially useful for sulfides
having long, hydrophobic alkyl chains, for which solubility prob
lems are often encountered in the Sodium Periodate oxidation
(8)
(9)
Next Page
60
BIS(TRI-n-BUTYLTIN) OXIDE
(15)
(10)
Hydrolysis. Esters are efficiently hydrolyzed with (Bu3Sn)2O

under mild conditions (eq 16).15
(16)
(11)
Transformation of primary alkyl bromides or iodides to the cor

responding primary alcohols is achieved in good yield by using
(Bu3Sn)2O-Silver(I) Nitrate (or Silver(I) p-Toluenesulfonate)
(eq 17),16 whereas this method is not applicable to secondary
halides due to elimination.
MeCO2(CH2)4I
(12)
MeCO2(CH2)4OH (17)
(Bu3Sn)2O is a useful starting material for the preparation of

tributyltin hydride, which is a convenient radical reducing reagent
in organic synthesis. Thus Tri-n-butyltin Hydride is easily pre
pared by using exchange reactions of (Bu3Sn)2O with polysiloxanes (eq 18).17
(18)
This O-activation is also effective for intramolecular alky lations

such as oxetane synthesis (eq 13).12 Similar N-activation has been
used in the synthesis of pyrimidine nucleosides (eq 14).13
Related Reagents. Tri-n-butyl(methoxy)stannane.
(13)
1. Saigo, K.; Morikawa, A.; Mukaiyama, T. CL 1975, 145.
(14)
2.
Ueno, Y.; Okawara, M. TL 1976, 4597.
3.
Hanessian, S.; Roy, R. CJC 1985, 63, 163.
4.
Ueno, Y.; Inoue, T.; Okawara, M. TL 1977, 2413.
5.
Kuwajima, I.; Shimizu, M. TL 1978, 1277.
6.
Jenkins, I. D.; Verheyden, J. P. H.; Moffatt, J. G. JACS 1971, 93,

4323.
7. (a) Ogawa, X; Matsui, M. T 1981, 37, 2363. (b) David, S.; Hanessian,
S. T 1985,41, 643.
Dehydrosulfurizations. The thiophilicity of tin compounds is

often utilized in functional group transformations. Thus conver
sion of aromatic and aliphatic thioamides to the corresponding
nitriles can be accomplished by using (Bu3Sn)2O in boiling ben
zene under azeotropic conditions (eq 15).14
8.
(a) Crowe, A. J.; Smith, P. J. JOM 1976, 110, C57. (b) Blunden, S. J.;
Smith, P. J.; Beynon, P. J.; Gillies, D. G. Carbohydr. Res. 1981, 88, 9.
(c) Ogawa, T.; Matsui, M. Carbohydr. Res. 1977, 56, Cl. (d) Hanessian,
S.; Roy, R. JACS 1979, 101, 5839. (e) Arnarp, J.; Loenngren, J. CC
1980, 1000. (f) Ogawa, T.; Nakabayashi, S.; Sasajima, K. Carbohydr.
Res. 1981, 96, 29.
9.
Tsuda, Y.; Haque, M. E.; Yoshimoto, K. CPB 1983, 31, 1612.
Previous Page
BIS(TRICHLOROMETHYL) CARBONATE
10.
11.
(a) Ishido,Y.;Hirao, I.; Sakairi, N.; Araki, Y H 1979,13, 181. (b) Hirao,
I.; Itoh, K.; Sakairi, N.; Araki, Y.; Ishido, Y. Carbohydr. Res. 1982, 109,
181.
(a) Alais, J.; Veyrires, A. JCS(P1) 1981, 377. (b) Veyrieres, A. JCS(P1)
1981, 1626.
12. Biggs, J. TL 1975, 4285.

13. Ogawa, T.; Matsui, M. JOM 1978, 145, C37.
14. Lim, M.-I.; Ren, W.-Y.; Klein, R. S. JOC 1982, 47, 4594.
15. Mata, E. G.; Mascaretti, O. A. TL 1988, 29, 6893.
16. Gingras, M.; Chan, T. H. TL 1989, 30, 279.
17. Hayashi, K.; lyoda, J.; Shiihara, I. JOM 1967, 10, 81.
61
good to excellent yields and often require only 1/3 equiv of triphos
gene.
(1)
(2)
Hiroshi Sano
Gunma University, Kiryu, Japan
(3)
Bis(trichloromethyl) Carbonate1
Chloroformylation. The use of triphosgene in the formation

of chloroformates with both hydroxy compounds (eq 4) and sub
stituted amines (eq 5) has been reported.1
(4)
[32315-10-9]
C3Cl6O3
(MW 296.73)
(5)
(a phosgene surrogate)
Alternate Name: triphosgene.
Physical Data: mp 81-83 C; bp 203-206 C.
Solubility: sol methanol, ethanol, benzene, diethyl ether, hexane,
THF, ethyl acetate; dec slowly in cold water.
Form Supplied in: white crystalline solid.
Handling, Storage, and Precautions: the reagent is somewhat
moisture sensitive, but scrupulously anhydrous conditions are
not necessary. Rapid handling of the reagent in open air, in the
absence of a glove bag or dry box, is usually satisfactory. This
reagent should only be handled in a fume hood.
Introduction. Phosgene gas is a versatile reagent for organic

synthesis, which has been used in carbonylation, chloroformylation, chlorination, and dehydration reactions, to name a few.1
However, because of the high toxicity of Phosgene, it has not
been used widely. Surrogates for phosgene have long been sought.
Trichloromethyl Chloroformate (diphosgene) was introduced
as one such phosgene substitute.2 To the extent that diphos
gene is a highly toxic, hygroscopic, and noxious liquid, it is
not a fully satisfactory phosgene substitute. On the other hand,
bis(trichloromethyl) carbonate (triphosgene; 1) is a crystalline
solid compound, is not very hygroscopic, and can substitute for
phosgene in a plethora of chemical reactions. Triphosgene has
been known since 1880,3 but its synthetic utility had not been
exploited until recently.
Carbonylation. The formation of oxazoles,4 quinazolinediones (eq l), 5 carbonates (eq 2), 6 urea analogs,7 and isocyanates
(eq 3) 1 have been reported with triphosgene. The reactions give
Dehydration.. Synthesis of isocyanides from formamides

(eq 6) is the only example of a dehydration reaction reported for
triphosgene to date.1
(6)
N-Carboxyamino Acid Anhydrides. Synthesis of Ncarboxyamino acid anhydrides (NCAs) is accomplished by

the reaction of the zwitterionic unprotected amino acid with
triphosgene at elevated temperatures (eq 7). 8 Wilder and
Mobashery reported a milder version of this reaction, utilizing
N-t-butoxycarbonyl--amino acids; in the presence of a stoichio
metric quantity of Triethylamine and 1/3 equiv of triphosgene
(eq 8) the reaction is believed to proceed via a chloroformic
N-t-butoxycarbonyl--amino acid anhydride intermediate to give
the corresponding NCA. 9 There are many synthetic routes to
NCAs; 10 however, the use of triphosgene in the preparation of
NCAs provides a facile, safe, mild, and practical entry to these
important molecules.
(7)
62
BORON TRIBROMIDE
(8)
(13)
Chlorination. Triphosgene has been used in the synthesis of

acyl chlorides (eq 9).1 Also, it has been shown to react with a
variety of aldehydes to give -chloro chloroformates (eq 10).11
Goren et al. have shown that triphosgene mediates chloride sub
(14)
stitution reactions on activated alcohols (eq 11);12 this reaction
involves the formation of an intermediary chloroformate species
en route to the chlorinated product. The generality of the reaction
Related Reagents. Phosgene; Trichloromethyl Chlorofor
was shown for benzylic (eq 12), allylic, and propargylic systems.
This reaction proceeds primarily via SN2, with some contribu
mate.
tion by SN 1 and/or SNi mechanisms.12 Chlorination with triphos
gene is considerably milder than the typical chlorination reac
tions with Thionyl Chloride, Phosphorus(III) Chloride, Phos1. Eckert, H.; Foster, B. AG(E) 1987, 26, 894.
phorus(V) Chloride, Oxalyl Chloride, and the like; for example,
2. Kurita, K.; Iwakura, Y. OSC 1988, 6, 715.
acid-labile functionalities, such as t-butyl carbamate (BOC), ben3. Councler, C. CB 1880,13, 1697.
zhydryl, and p-methoxybenzyl groups, can be tolerated in the
4.
Sicker, D. SC 1989, 875. Flouzat, C ; Blanchet, M.; Guillaumet, G. TL
triphosgene-mediated reactions, whereas they do not normally
1992, 33, 4571.
survive reactions with other chlorination reagents.
(9)
(10)
5.
Cortez, R.; Rivero, J. A.; Samanathan, R.; Aguire, G.; Ramirez, F. SC

1991, 21, 285.
6.
Laufer, D. A.; Doyle, K.; Zhang, X. OPP 1989, 21, 771.
7.
Zhao, X.; Chang, Y.-L.; Fowler, F. W. JACS 1990, 112, 6627. Cotarca,
L.; Bacaloglu, R.; Csunderlik, C ; Marcu, N.; Tarnaveanu, A. JPR 1987,
329, 1052.
8.
Daly, W. H.; Poch, D. TL 1988, 29, 5859.
9.
Kricheldorf, H. R. -Aminoacid-N-Carboxy-Anhydride and Related

Heterocycles; Springer: Berlin, 1987; pp 3-58. Blacklock, T. J.;
Hirschmann, R.; Veber, D. F. The Peptides; Academic: New York, 1987;
Vol. 9, pp 39-102.
11.
Coghlan, M. J.; Caley, B. A. TL 1989, 30, 2033.
12.
Goren, Z.; Heeg, M. J.; Mobashery, S. JOC 1991, 56, 7188.
13.
(a) Palomo, C.; Cossio, F. P.; Ontoria, J. M ; Odrizola, J. M. JOC 1991,

56, 5948. (b) Rivero, I. A.; Samanathan, R.; Hellberg, L. H. OPPI Briefs
1992, 24, 363.
(11)
(12)
Wilder, R.; Mobashery, S. JOC 1992, 57, 2755.
10.
14. Barton, D. H. R.; Garner, B. J.; Wightman, R. H. JCS 1964, 1855.
Juliatiek Roestamadji & Shahriar Mobashery

Oxidation. Palomo et al. have demonstrated that primary and
secondary alcohols are readily oxidized by triphosgene in the
presence of Dimethyl Sulfoxide (DMSO) in good to excellent
yields;13a the reaction is applicable to both activated (eq 13) and
unactivated alcohols (eq 14). This reaction is a variation of the
one reported by Barton with phosgene gas,14 and it is an excellent
alternative to Swern-type oxidations. Indeed, in some respects,
oxidation of alcohols by triphosgene is superior to the widely
used Swern oxidation. The triphosgene reaction tolerates acidlabile functionalities and is not as sensitive to residual moisture
as oxalyl chloride used in the Swern oxidation. An additional ad
vantage of the method of Palomo et al. is the ease of handling of
triphosgene, and the fact that the reaction is amenable to largescale synthesis. The breadth and scope of this reaction have been
investigated with a large variety of alcohol substrates.13b See also
Dimethyl Sulfoxide-Triphosgene.
Boron Tribromide 1
[10294-33-4]
BBr3
(MW 250.52)
(Lewis acid used for deprotection of OH and NH groups; cleaves

ethers or esters to alkyl bromides; bromoborates allene and
alkynes)
Physical Data: mp -45 C; bp 91.7C; d 2.650 g cm - 3 .
BORON TRIBROMIDE
63
Form Supplied in: colorless, fuming liquid; a 1.0 M solution in

generally cleaved at the Me-0 bond, as demonstrated in Corey's
prostaglandin synthesis (eq 5).10
dichloromethane and hexane; BBr3Me2S complex is available
as either a white solid or a 1.0 M solution in dichloromethane.
Purification: by distillation.
Handling, Storage, and Precautions: BBr3 is highly moisture sen
sitive and decomposes in air with evolution of HBr. Store under
a dry inert atmosphere and transfer by syringe or through a
Teflon tube. It reacts violently with protic solvents such as wa
ter and alcohols. Ether and THF are not appropriate solvents.
(4)
Removal of Protecting Groups. BBr3 is highly Lewis acidic.

It coordinates to ethereal oxygens and promotes C-O bond cleav
age to an alkyl bromide and an alkoxyborane that is hydrolyzed
to an alcohol during workup (eq l). 2
(1)
BBr3 has been widely used to cleave ethers because the reac
tion proceeds completely under mild conditions. In a special case,
BBr3 has been used to cleave acetals that cannot be deprotected
by usual acidic conditions.3 Because alkyl aryl ethers are cleaved
at the alkyl-oxygen bond to give ArOH and alkyl bromides, BBr3
has been most generally used for the demethylation of methyl
aryl ethers,2,4 for example as the final step of zearalenone synthe
sis (eq 2).5 Problems are sometimes encountered in attempts to
deprotect more than one nonadjacent methoxy group on one aro
matic ring, and when stable chelates are formed.6 The presence
of a carbonyl substituent facilitates the selective deprotection of
polymethoxyaryl compounds (eq 3).7
(5)
BBr3 has been also used for the deprotection of carbohydrate

derivatives11 and polyoxygenated intermediates in the synthesis
of deoxyvernolepin,12 vernolepin,13 and vernomenin.13 Although
one of the model compounds is deprotected cleanly (eq 6),14 appli
cation of BBr3 to more highly functionalized intermediates leads
to cleavage of undesired C-O bonds competitively (eq 7).12,13
(6)
(2)
(7)
(3)
The cleavage of mixed dialkyl ethers occurs at the more substi

tuted carbon-oxygen bond. Methyl ethers of secondary or tertiary
alcohols give methanol and secondary or tertiary alkyl bromides
selectively by the reaction with BBr3,8 although the addition of
Sodium Iodide and 15-Crown-5 ether can change this selectiv
ity (eq 4).9 In contrast, methyl ethers of primary alcohols are
For the complete cleavage, 1 mol of BBr3 is required for

each ether group and other Lewis-basic functional groups.
Sometimes it is difficult to find reaction conditions for
the selective cleavage of the desired C-O bond. Recently,
modified bromoboranes such as B-Bromocatecholborane,15
dialkylbromoboranes,16 Bromobis(isopropylthio)borane,17 and
9-Bromo-9-borabicyclo[3.3.1]nonane,18 have been introduced
to cleave C-O bonds more selectively under milder conditions.
BBr3SMe2 is also effective for ether cleavage and has the advan
tage of being more stable than BBr3. It can be stored for a long
time and handled easily. However, a two- to fourfold excess of
the reagent is necessary to complete the dealkylation of alkyl aryl
ether.19
64
BORON TRIBROMIDE
Amino acid protecting groups such as benzyloxycarbonyl and

t-butoxycarbonyl groups are cleaved by BBr3. However, the hy
drolysis of the ester function also occurs under the same reac
tion conditions.20 Debenzylation and debenzyloxymethylation of
uracils proceed successfully in aromatic solvents, but demethylation is more sluggish and less facile (eq 8).21
(8)
Substitution Reactions. BBr3 reacts with cyclic ethers to give

tris(-bromoalkoxy)boranes which provide -bromoalkanols or
-bromoalkanals when treated with MeOH or Pyridinium
Chlorochromate, respectively (eq 9).22 Unfortunately, unsymmetrically substituted ethers such as 2-methyltetrahydrofuran are
cleaved nonregioselectively. Generally, ester groups survive under
the reaction conditions for ether cleavage, but the ring opening of
lactones occurs under mild conditions to give -halocarboxylic
acids in good yields (eq 10).23
butylammonium Iodide is necessary for the reduction of sulfonic

acids and their derivatives.31
Transesterification of Esters or Conversion to Amides.
Transesterification reactions of carboxylic esters or conversion
into the amides is promoted by a stoichiometric amount of BBr3.32
Removal of Methyl Sulfide from Organoborane-Methyl
Sulfide Complexes. Methyl sulfide can be removed from
BrBR2SMe2 or Br2BRSMe2, which are prepared by the hydroboration reaction of alkenes or alkynes with BrBH2SMe2 or
Br2BHSMe2, by using BBr3.33 The resulting alkenyldibromoboranes are useful for the stereoselective synthesis of bromodienes
(eq 11).34
(11)
(9)
(10)
In the reaction with methoxybenzaldehyde, bromination of

the carbonyl group takes place more rapidly than demethylation; therefore benzal bromide formation is generally ob
served in the reaction with aromatic aldehydes.24 Cleavage of
t-butyldimethylsilyl ethers or t-butyldiphenylsilyl ethers occurs
at the C-O bond to give alkyl bromides.25 Alcohols can be con
verted to alkyl bromides by this method.
In a special case, BBr3 is used for the bromination
of hydrocarbons. Adamantane is brominated by a mixture
of Bromine, BBr3, and Aluminum Bromide to give 1,3dibromoadamantane selectively.26 Tetrachlorocyclopropene27
and hexachlorocyclopentadiene28 are substituted to the corre
sponding bromides by BBr3 and, in the latter case, addition of
AlBr3 and Br2 is effective to improve the result.29
Reduction of Sulfur Compounds. Alkyl and aryl sulfoxides
are reduced by BBr3 to the corresponding sulfides in good yields.30
Addition of Potassium Iodide and a catalytic amount of Tetra-nLists of Abbreviations and Journal Codes on Endpapers
Bromoboration Reactions. BBr3 does not add to isolated

double bonds, but reacts with allene spontaneously even
at low temperature to give (2-bromoallyl)dibromoborane,35
which provides stable (2-bromoallyl)diphenoxyborane by the
addition of anisole.36 The diphenoxyborane derivative reacts
with carbonyl compounds to give 2-bromohomoallylic alco
hols in high yields (eq 12). Bromoboration of 1-alkynes pro
vides (Z)-(2-bromo-l-alkenyl)dibromoboranes stereo- and regioselectively (eq 13),37 which are applied for the synthesis
of trisubstituted alkenes,38 ,-unsaturated esters,39 and 7,8unsaturated ketones,40 bromodienes,41 1,2-dihalo-l-alkenes,42 2bromoalkanals,43 and p-bromo-,-unsaturated amides.44
(12)
(13)
Chiral Bromoborane Reagents. Complexes made from

chiral
l-alkyl-2-(diphenylhydroxymethyl)pyrrolidines
and
BBr3 are effective catalysts for asymmetric Diels-Alder
reactions.45 Bromoboranes prepared from chiral 1,2-diphenyll,2-bis(arenesulfonamido)ethanes46,47 are used to prepare chiral
allylic boranes,47,48 allenylic borane,49 propargylic boranes,49
and enolates.46,47,50 The B-bromodiazaborolidinene (1), prepared
BORON TRIBROMIDE
from
l,2-diphenyl-l,2-bis(p-toluenesulfonamido)ethane,
is
particularly effective in these applications. The reagents prepared
from (1) are highly effective for the enantioselective synthesis
of homoallylic alcohols (eq 14),48 homopropargylic alcohols
(eq 15),49 propadienyl carbinols (eq 16),49 and aldol condensation
products (eq 17).46
(14)
(15)
15.
17.
18.
19.
(a) Boeckman, Jr., R. K.; Potenza, J. C. TL 1985, 26, 1411. (b) King, P.
E; Stroud, S. G. TL 1985, 26, 1415.
(a) Guindon, Y.; Morton, H. E.; Yoakim, C. TL 1983, 24, 3969. (b)
Gauthier, J. Y.; Guindon, Y. TL 1987, 28, 5985. (c) Guindon, Y.; Yoakim,
C ; Morton, H. E. TL 1983, 24, 2969. (d) Guindon, Y.; Yoakim, C ;
Morton, H. E. JOC 1984, 49, 3912.
Corey, E. J.; Hua, D. H.; Seitz, S. P. TL 1984, 25, 3.
Bhatt, M. V. JOM 1978, 156, 221.
Williard, P. G.; Fryhle, C. B. TL 1980, 21, 3731.
20.
21.
22.
23.
24.
Felix, A. M. JOC 1974, 39, 1427.

Kundu, N. G.; Hertzberg, R. P.; Hannon, S. J. TL 1980, 21, 1109.
Kulkarni, S. U.; Patil, V. D. H 1982, 18, 163.
Olah, G. A.; Karpeles, R.; Narang, S. C. S 1982, 963.
Lansinger, J. M.; Ronald, R. C. SC 1979, 9, 341.
25.
26.
Kim, S.; Park, J. H. JOC 1988, 53, 3111.

(a) Baughman, G. L. JOC 1964, 29, 238. (b) Talaty, E. R.; Cancienne,
A. E.; Dupuy, A. E. JCS(C) 1968, 1902.
Tobey, S. W.; West, R. JACS 1966, 88, 2481.
16.
27.
(16)
28.
29.
30.
31.
32.
33.
(17)
98% ee, 98% syn
Related Reagents. Boron Trichloride; Bromodimethylborane; Bromobis(isopropylthio)borane; 9-Bromo-9-borabicyclo[3.3.1]nonane; S-Bromocatecholborane; Thionyl Bromide;
Hydrogen Bromide.
1. Bhatt, M. V.; Kulkarni, S. U. S 1983, 249.

2. McOmie, J. F. W.; Watts, M. L.; West, D. E. T 1968, 24, 2289.
3. Meyers, A. I.; Nolen, R. L.; Collington, E. W.; Narwid, T. A.; Strickland,
R. C. JOC 1973, 38, 1974.
4. (a) Benton, F. L.; Dillon, T. E. JACS 1942, 64, 1128. (b) Manson, D. L.;
Musgrave, O. C. JCS 1963, 1011. (c) McOmie, J. F. W.; Watts, M. L.
CI(L) 1963, 1658. (d) Blatchly, J. M.; Gardner, D. V.; McOmie, J. F. W;
Watts, M. L. JCS(C) 1968, 1545.
5. (a) Vlattas, I.; Harrison, I. T.; Tokes, L.; Fried, J. H.; Cross, A. D. JOC
1968, 33, 4176. (b) Taub, D.; Girotra, N. N.; Hoffsommer, R. D.; Kuo,
C. H.; Slates, H. L.; Weber, S.; Wendler, N. L. T 1968, 24, 2443.
6.
7.
8.
9.
10.
11.
12.
13.
14.
(a) Stetter, H.; Wulff, C. CB 1960, 93, 1366. (b) Locksley, H. D.; Murray,
I. G. JCS(C) 1970, 392. (c) Bachelor, F. W.; Loman, A. A.; Snowdon, L.
R. CJC 1970, 48, 1554.
Schafer, W.; Franck, B. CB 1966, 99, 160.
Youssefyeh, R. D.; Mazur, Y. CI(L) 1963, 609.
Niwa, H.; Hida, T.; Yamada, K. TL 1981, 22, 4239.
Corey, E. J.; Weinshenker, N. M.; Schaaf, T. K.; Huber, W. JACS 1969,
91, 5675.
Bonner, T. G.; Bourne, E. J.; McNally, S. JCS 1960, 2929.
Grieco, P. A.; Noguez, J. A.; Masaki, Y. JOC 1977, 42, 495.
Grieco, P. A.; Nishizawa, M.; Burke, S. D.; Marinovic, N. JACS 1976,
98, 1612.
(a) Grieco, P. A.; Hiroi, K.; Reap, J. J.; Noguez, J. A. JOC 1975, 40,
1450. (b) Grieco, P. A.; Reap, J. J.; Noguez, J. A. SC 1975, 5, 155.
65
West, R.; Kwitowski, P. T. JACS 1968, 90, 4697.

Ungefug, G. A.; Roberts, C. W. JOC 1973, 38, 153.
Guindon, Y.; Atkinson, J. G.; Morton, H. E. JOC 1984, 49, 4538.
Olah, G. A.; Narang, S. C.; Field, L. D.; Karpeles, R. JOC 1981, 46,
2408.
Yazawa, H.; Tanaka, K.; Kariyone, K. TL 1974, 15, 3995.
(a) Brown, H. C.; Ravindran, N.; Kulkarni, S. U. JOC 1979, 44, 2417.
(b) Brown, H. C ; Ravindran, N.; Kulkarni, S. U. JOC 1980, 45, 384. (c)
Brown, H. C.; Campbell, Jr., J. B. JOC 1980, 45, 389.
34. Hyuga, S.; Takinami, S.; Hara, S.; Suzuki, A. TL 1986, 27, 977.
35. Joy, F.; Lappert, M. F.; Prokai, B. JOM 1966, 5, 506.
36. Hara, S.; Suzuki, A. TL 1991, 32, 6749.
37. (a) Lappert, M. F.; Prokai, B. JOM 1964, 1, 384. (b) Blackborow, J. R.
JOM 1977, 128, 161. (c) Suzuki, A.; Hara, S. Res. Trends Org. Chem.
1990, 77. (d) Suzuki, A. PAC 1986, 58, 629.
38. Satoh, Y.; Serizawa, H.; Miyaura, N.; Hara, S.; Suzuki, A. TL 1988, 29,
1811.
39. Yamashina, N.; Hyuga, S.; Hara, S.; Suzuki, A. TL 1989, 30, 6555.
40. (a) Hara, S.; Hyuga, S.; Aoyama, M.; Sato, M.; Suzuki, A. TL 1990, 31,
247. (b) Aoyama, M.; Hara, S.; Suzuki, A. SC 1992, 22, 2563.
41.
Hyuga, S.; Takinami, S.; Hara, S.; Suzuki, A. CL 1986, 459.
42.
43.
44.
Hara, S.; Kato, T.; Shimizu, H.; Suzuki, A. TL 1985, 26, 1065.
Satoh, Y.; Tayano, T.; Koshino, H.; Hara, S.; Suzuki, A. S 1985, 406.
Satoh, Y.; Serizawa, H.; Hara, S.; Suzuki, A. SC 1984, 14, 313.
45.
Kobayashi, S.; Murakami, M.; Harada, T.; Mukaiyama, T. CX 1991,

1341.
46. Corey, E. J.; Imwinkelried, R.; Pikul, S.; Xiang, Y. B. JACS 1989, 1,
5493.
47. Corey, E. J.; Kim, S. S. TL 1990, 31, 3715.
48. Corey, E. J.; Yu, C.-M.; Kim, S. S. JACS 1989, 111, 5495.
49. Corey, E. J.; Yu, C.-M.; Lee, D.-H. JACS 1990, 112, 878.
50. Corey, E. J.; Kim, S. S. JACS 1990, 112, 4976.
Akira Suzuki & Shoji Hara

Hokkaido University, Sapporo, Japan
66
BORON TRICHLORIDE
Boron Trichloride
[10294-34-5]
converted into glycosyl chlorides at 78 C without effecting ben

zyl and acetyl protecting groups.7
BCl3
(MW 117.17)
(Lewis acid capable of selective cleavage of ether and acetal

protecting groups; reagent for carbonyl condensations; precursor
of organoboron reagents)
Physical Data: bp 12.5 C; d 1.434 g cm-3 (0C).
Solubility: sol saturated and halogenated hydrocarbon and aro
matic solvents; solubility in diethyl ether is approximately 1.5
M at 0 C; stable for several weeks in ethyl ether at 0C, but
dec by water or alcohols.
Form Supplied in: colorless gas or fuming liquid in an am
poule; BCl3SMe2 complex (solid) and 1 M solutions in
dichloromethane, hexane, heptane, and p-xylene are available.
Handling, Storage, and Precautions: a poison by inhalation and an
irritant to skin, eyes, and mucous membranes. Reacts exothermically with water and moist air, forming toxic and corrosive
fumes. Violent reaction occurs with aniline or phosphine. All
operations should be carried out in a well-ventilated fume hood
without exposure to the atmosphere. The gas can be collected
and measured as a liquid by condensing in a cooled centrifuge
tube and then transferred to the reaction system by distillation
with a slow stream of nitrogen.
Cleavage of Ethers, Acetals, and Esters. Like many other

Lewis acids, BCl3 has been extensively used as a reagent for the
cleavage of a wide variety of ethers, acetals, and certain types of
esters.2 Ether cleavage procedures involve addition of BCl3, ei
ther neat or as a solution in CH2Cl2, to the substrate at 80 C.
The vessel is then stoppered and allowed to warm to rt. Whereas
the complexes of BCl3 with dimethyl ether and diethyl ether are
rather stable at rt, they decompose to form ROBCl2 or (RO)2BCl
with evolution of alkyl chloride upon heating to 56 C.1 Diaryl
ethers are unreactive. Mixed dialkyl ethers are cleaved to give
the alkyl chloride derived from C-O bond cleavage leading to
the more stable carbenium ion. The transition state is predomi
nantly SN1 in character, as evidenced by partial racemization of
chiral ethers1,2 and the rearrangement of allyl phenyl ethers to oallylphenols.3 BCl3 can be used for the deprotection of a variety of
methoxybenzenes including hindered polymethoxybenzenes and
peri-methoxynaphthalene.1,2,4 When methoxy groups are ortho
to a carbonyl group, the reaction is accelerated by the forma
tion of a chelate between boron and the carbonyl oxygen atom
(Scheme l). 4 a - c
The reagent is less reactive than Boron Tribromide for ether
cleavage; however, the type and extent of deetherification can
be more easily controlled by the ratio of substrate to BCl3 as
well as the reaction temperature and time. The transformation of
()--hydrastine (1) to ()-cordrastine II is efficiently achieved
by selective cleavage of the methylenedioxy group in prefer
ence to aromatic methoxy groups.5 The demethylation of (-)2-O-methyl-()-inositol in dichloromethane proceeds at 80 C
without cleavage of a tosyl ester group.6 Methyl glycosides are
R = MeH;
81%, rt, 5min
R = Me H;
90%, rt, 5 min
R = MeH;
78%, -80 C
(a) R = Me H, R' = Me;

80%, rt, 0.5 h
(b) R, R' = MeH;
97%, rt, 8 h
R, R' = -CH 2 -H;

81%, rt, 6 h
Scheme 1 Demethylation of aromatic ethers by BCl3 in CH2Cl2
One of the difficulties with the use of BCl3 arises from its ten
dency to fume profusely in air. The complex of BCl3 with dimethyl
sulfide is solid, stable in air, and handled easily. By using a twoto fourfold excess of the reagent in dichloroethane at 83 C, aro
matic methoxy and methylenedioxy groups can be cleaved in good
yields.8
Another application of BCl3 is for the cleavage of highly hin
dered esters under mild conditions. O-Methylpodocarpate (2) and
methyl adamantane-1-carboxylate are cleaved at 0 C.9 The highly
selective displacement of the acetoxy group in the presence of
other potentially basic groups in 2-cephem ester (3) provides the
corresponding allylic chloride. On the other hand, treatment of (3)
with an excess of BCl3 results in the cleavage of the acetoxy and
t-butyl ester groups.10
R = Me H; 90%
BCl3, CH2C12, 0 C
(1) R = t-Bu, X = OAc Cl; 64%

BCl3 (1 equiv), CH2C12, -5 C
(2) R = t-Bu H, X = OAc OH; 68%
BCl3 (3 equiv), CH2C12, rt
Tertiary phosphines are cleaved at the P-C bond to give

diphenylphosphine oxides. Workup with Hydrogen Peroxide pro
vides diphenylphosphinic acids (eq l). 11
(1)
BORON TRICHLORIDE
Condensation Reactions. Boron trichloride converts ketones
into (Z)-boron enolates at 95 C in the presence of Diisopropylethylamine. These enolates react with aldehydes with high syn
diastereoselectivity (eq 2). 12 A similar condensation of imines
with carbonyl compounds also provides crossed aldols in reason
able yields. 13 The reaction was extended to the asymmetric aldol
condensation of acetophenone imine and benzaldehyde by using
isobornylamine as a chiral auxiliary (48% ee). 14
(2)
(N-Alkylanilino)dichloroboranes (5), prepared in situ from

N-alkylanilines and boron trichloride, are versatile intermedi
ates for the synthesis of ortho-functionalized aniline derivatives
(eqs 3-5). 15 The regioselective ortho hydroxyalkylation can be
achieved with aromatic aldehydes.16
67
Aldehydes and ketones condense with ketene in the pres

ence of 1 equiv of boron trichloride to give ,-unsaturated
acyl chlorides.22 Aryl isocyanates are converted into allophanyl
chlorides, which are precursors for industrially important 1,3diazetidinediones (eq 7). 23
(7)
Synthesis of Organoboron Reagents. General method of syn

thesis of organoboranes consists of the transmetallation reaction of
organometallic compounds with BX3. 24 Boronic acid derivatives
[RB(OH)2] are most conveniently synthesized by the reaction of
B(OR) 3 with RLi or RMgX reagents, but boron trihalides are more
advantageous for transmetalation reactions with less nucleophilic
organometallic reagents based on Pb,25 Hg, 26 Sn, 27 and Zr 28 (eqs 8
and 9).
Pl4Sn + 2 BCl3
2 PhBCl2 + Ph2SnCl2
(8)
(9)
(3)
(4)
(5)
The reaction of (5) with alkyl and aryl nitriles and Aluminum
Chloride catalyst provides ortho-acyl anilines.16 When chloroacetonitrile is used, the products are ideal precursors for indole
synthesis.17 Use of isocyanides instead of nitriles provides orthoformyl TV-alkylanilines.18 Although these reactions with BCl 3 are
restricted to A'-alkylanilines, the use of Phenylboron Dichloride
allows the orffto-hydroxybenzylation of primary anilines.19
Analogously, boron trichloride induces ortho selective acylation of phenols at rt with nitriles, isocyanates, or acyl chlorides
(eq 6). 20 The efficiency and regioselectivity of these reactions are
best with BCl 3 among the representative metal halides that have
been examined. In both the aniline and phenol substitutions the
boron atom acts as a template to bring the reactants together, lead
ing to cyclic intermediates and exclusively products of ortho sub
stitution. A similar ortho selective condensation of aromatic azides
with BCl3 provides fused heterocycles containing nitrogen.21
(6)
Redistribution or exchange reactions of R3B with boron tri

halides in the presence of catalytic amounts of hydride provides
an efficient synthesis of RBX2 and R2BX.29 Another convenient
and general method for the preparation of organodichloroboranes
involves treatment of alkyl, 1-alkenyl, and aryl boronates with
BCl3 in the presence of Iron(III) Chloride (3 mol %). 3 0 Organo
dichloroboranes are valuable synthetic reagents because of their
high Lewis acidity, and their utility is well demonstrated in the syn
theses of piperidine and pyrrolidine derivatives by the intramolec
ular alkylation of azides (eq 10)31 or the synthesis of esters by
the reaction with Ethyl Diazoacetate.32 The various organoborane derivatives, R3B, R2BCI, and RBCl 2 , all react with organic
azides and diazoacetates. However, especially facile reactions are
achieved by using organodichloroboranes (RBCl 2 ).
(10)
Dichloroborane and monochloroborane etherates or their

methyl sulfide complexes have been prepared by the reaction
of borane and boron trichloride.33 However, hydroboration of
alkenes with these borane reagents is usually very slow due to
the slow dissociation of the complex. Dichloroborane prepared
in pentane from boron trichloride and trimethylsilane shows un
usually high reactivity with alkenes and alkynes; hydroboration is
instantaneous at - 7 8 C (eq 11).34
68
BORON TRIFLUORIDE ETHERATE
(11)
Direct boronation of benzene derivatives with BCl3 in the

presence of activated aluminum or AlCl3 provides arylboronic
acids after hydrolysis (eq 12).35 Chloroboration of acetylene with
boron trichloride produces dichloro(2-chloroethenyl)borane.36
Similar reaction with phenylacetylene provides (E)-2-chloro-2phenylethenylborane regio- and stereoselectively.37
(12)
The syntheses of thioaldehydes, thioketones, thiolactones, and

thiolactams from carbonyl compounds are readily achieved by
in situ preparation of B2S3 from bis(tricyclohexyltin) sulfide and
boron trichloride (eq 13).38 The high sulfurating ability of this
in situ prepared reagent can be attributed to its solubility in the
reaction medium.
3 (Cy3Sn)=S + 2 BCl3
B2S3
(13)
16.
Sugasawa, X; Xoyoda, X; Adachi, M.; Sasakura, K. JACS 1978, 100,

4842.
17.
Sugasawa, X; Adachi, M.; Sasakura, K.; Kitagawa, A. JOC 1979, 44,

578.
Sugasawa, X; Hamana, H.; Xoyoda, X; Adachi, M. S 1979, 99.
Toyoda, X; Sasakura, K.; Sugasawa, X TL 1980, 21, 173.
(a) Toyoda, X; Sasakura, K.; Sugasawa, T. JOC 1981, 46, 189. (b)
Piccolo, O.; Filippini, L.; Tinucci, L.; Valoti, E.; Citterio, A. T 1986,
42, 885.
(a) Zanirato, P. CC 1983, 1065. (b) Spagnolo, P.; Zanirato, P. JCS(P1)
1988, 2615.
Paetzold, P. I.; Kosma, S. CB 1970, 103, 2003.
Helfert, H.; Fahr, E. AG(E) 1970, P, 372.
(a) Nesmeyanov, A. N.; Kocheshkov, K. A. Methods of ElementoOrganic Chemistry; North-Holland: Amsterdam, 1967; Vol. 1, pp 20-96.
(b) Mikhailov, B. M.; Bubnov, Y. N. Organoboron Compounds in
Organic Synthesis; Harwood: Amsterdam, 1984.
Holliday, A. K.; Jessop, G. N. JCS(A) 1967, 889.
Gerrard, W.; Howarth, M.; Mooney, E. F.; Pratt, D. E. JCS 1963, 1582.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
94%, , 7 h
92%, , 3 h
unable to isolate
Related Reagents. Bis(tricyclohexyltin)

Sulfide-Boron
Trichloride; Catechylphosphorus Trichloride; Boron Tribromide;
Hydrogen Chloride.
34.
35.
36.
37.
38.
(a) Niedenzu, K.; Dawson, J. W. JACS 1960, 82, 4223. (b) Brinkman, F.
E.; Stone, F. G. A. C1(L) 1959, 254.
Cole, T. E.; Quintanilla, R.; Rodewald, S. OM 1991, 10, 3777.
Brown, H. C ; Levy, A. B. JOM 1972, 44, 233.
(a) Brindley, P. B.; Gerrard, W.; Lappert, M. F. JCS 1956, 824. (b) Brown,
H. C.; Salunkhe, A. M.; Argade, A. B. OM 1992, 11, 3094.
(a) Jego, J. M.; Carboni, B.; Vaultier, M.; Carrie', R. CC 1989, 142. (b)
Brown, H. C ; Salunkhe, A. M. TL 1993, 34, 1265.
Hooz, J.; Bridson, J. N.; Calzada, J. G.; Brown, H. C ; Midland, M. M.;
Levy, A. B. JOC 1973, 38, 2574.
(a) Brown, H. C. Organic Syntheses via Boranes; Wiley: New York,
1975; pp 45-47. (b) Brown, H. C ; Kulkarni, S. U. JOM 1982, 239, 23.
(c) Brown, H. C ; Ravindran, N. IC 1977, 16, 2938.
Soundararajan, R.; Matteson, D. S. JOC 1990, 55, 2274.
(a) Muetterties, E. L. JACS 1960, 82, 4163. (b) Lengyel, B.; Csakvari,
B. Z. Anorg. Allg. Chem. 1963, 322, 103.
Lappert, M. F.; Prokai, B. JOM 1964, 1, 384.
Blackborow, J. R. JCS(P2) 1973, 1989.
Steliou, K.; Mrani, M. JACS 1982, 104, 3104.
1. Gerrard, W.; Lappert, M. F. CRV 1958, 58, 1081.

2. (a) Bhatt, M. V.; Kulkami, S. U. S 1983, 249. (b) Greene, T. W. Protective
Groups in Organic Synthesis; Wiley: New York, 1981.
3.
(a) Gerrard, W.; Lappert, M. F.; Silver, H. B. Proc. Chem. Soc. 1957,
19. (b) Borgulya, J.; Madeja, R.; Fahrni, P.; Hansen, H.-J.; Schmid, Ft.;
Barner, R. HCA 1973, 56, 14.
4.
(a) Dean, R. B.; Goodchild, J.; Houghton, L. E.; Martin, J. A. TL 1966,

4153. (b) Arkley, V.; Attenburrow, J.; Gregory, G. I.; Walker, T. JCS
1962, 1260. (c) Barton, D. H. R.; Bould, L.; Clive, D. L. J.; Magnus, P.
D.; Hase, T. JCS(C) 1971, 2204. (d) Carvalho, C. F.; Seargent, M. V. CC
1984, 227.
5.
(a) Teitel, S.; O'Brien, J.; Brossi, A. JOC 1972, 37, 3368. (b) Teitel, S.;
O'Brien, J. P. JOC 1976, 41, 1657.
6.
Gero, S. D. TL 1966, 591.
7.
Perdomo, G. R.; Krepinsky, J. J. TL 1987, 28, 5595.
Norio Miyaura
Boron Trifluoride Etherate
(BF3OEt2)
[109-63-7]
(BF3MeOH)
[373-57-9]
C 4 H 10 BF 3 O
CH4BF3O
(MW 141.94)
(MW 99.85)
8. Williard, P. G.; Fryhle, C. B. TL 1980, 21, 3731.

9. Manchand, P. S. CC 1971, 667.
10.
Yazawa, H.; Nakamura, H.; Tanaka, K.; Kariyone, K. TL 1974, 3991.
11.
Hansen, K. C ; Solleder, G. B.; Holland, C. L. JOC 1974, 39, 267.
12. Chow, H-R; Seebach, D. HCA 1986, 69, 604.

13.
Sugasawa, T.; Toyoda, T. Sasakura, K. SC 1979, 9, 515.
14. Sugasawa, T.; Toyoda, X; TL 1979, 1423.

15.
Sugasawa, T. J. Synth. Org. Chem. Jpn. 1981, 39, 39.
(BF3OEt2: easy-to-handle and convenient source of BF3; Lewis

acid catalyst; promotes epoxide cleavage and rearrangement, con
trol of stereoselectivity; BF3MeOH: esterification of aliphatic
and aromatic acids; cleavage of trityl ethers)
Alternate Names: boron trifluoride diethyl etherate; boron triflu
oride ethyl etherate; boron trifluoride ethyl ether complex; trifluoroboron diethyl etherate.

-3
Physical Data: BF 3 OEt 2 : bp 126 C; d 1.15 g c m ; BF 3 MeOH:

bp 59C/4 mmHg; d 1.203 g cm-3 for 50 wt % BF 3 ,
0.868 g cm-3 for 12 wt % BF 3 .
Solubility: sol benzene, chloromethanes, dioxane, ether,
methanol, THF, toluene.
Form Supplied in: BF 3 OEt 2 : light yellow liquid, packaged un
der nitrogen or argon; BF 3 MeOH is available in solutions of
10-50% BF 3 in MeOH.
Preparative Methods: BF 3 OEt 2 is prepared by passing BF 3
through anhydrous ether;1a the BF 3 MeOH complex is formed
from BF 3 OET 2 and methanol.
Purification: oxidation in air darkens commercial boron trifluoride etherate; therefore the reagent should be redistilled prior to
use. An excess of the etherate in ether should be distilled in an
all-glass apparatus with calcium hydroxide to remove volatile
acids and to reduce bumping. 1b
Handling, Storage, and Precautions: keep away from moisture
and oxidants; avoid skin contact and work in a well-ventilated
fume hood.
Addition Reactions. BF 3 OEt 2 facilitates the addition of

moderately basic nucleophiles like alkyl-, alkenyl-, and aryllithium, imines, Grignard reagents, and enolates to a variety of
electrophiles.2
Organolithiums undergo addition reactions with 2isoxazolines to afford N-unsubstituted isoxazolidines, and
to the carbon-nitrogen double bond of oxime O-ethers to give
O-alkylhydroxylamines.3 Aliphatic esters react with lithium
acetylides in the presence of BF 3 OEt 2 in THF at 78 C to form
alkynyl ketones in 40-80% yields.4 Alkynylboranes, generated
in situ from lithium acetylides and BF 3 OEt 2 , were found to
react with oxiranes5 and oxetanes6 under mild conditions to
afford 0-hydroxyalkynes and -alkoxyalkynes, respectively.
(l-Alkenyl)dialkoxyboranes react stereoselectively with ,unsaturated ketones7 and esters8 in the presence of BF 3 OEt 2 to
give ,-unsaturated ketones and -acyl-7,8-unsaturated esters,
respectively.
The reaction of imines activated by BF 3 OEt 2 with 4(phenylsulfonyl)butanoic acid dianion leads to 2-piperidones in
high yields.9 (Perfluoroalkyl)lithiums, generated in situ, add to
imines in the presence of BF 3 OEt 2 to give perfluoroalkylated
amines. 10 Enolate esters add to 3-thiazolines under mild con
ditions to form thiazolidines if these imines are first activated
with BF 3 OEt 2 . 11 The carbon-nitrogen double bond of imines
can be alkylated with various organometallic reagents to pro
duce amines. 12 A solution of benzalaniline in acetone treated
with BF 3 OEt 2 results in the formation of -phenyl--anilinoethyl
methyl ketone. 13 Anilinobenzylphosphonates are synthesized in
one pot using aniline, benzaldehyde, dialkyl phosphite, and
BF 3 OEt 2 ; 14 the reagent accelerates imine generation and dialkyl
phosphite addition. Similarly, BF 3 OEt 2 activates the nitrile group
of cyanocuprates, thereby accelerating Michael reactions.15
The reagent activates iodobenzene for the allylation of aromatics, alcohols, and acids. 16 Allylstannanes are likewise activated
for the allylation of p-benzoquinones, e.g. in the formation of
coenzyme Q n using polyprenylalkylstannane.17
Nucleophilic silanes undergo stereospecific addition to electrophilic glycols activated by Lewis acids. The glycosidation
69
is highly stereoselective with respect to the glycosidic linkage

in some cases using BF 3 OEt 2 . Protected pyranosides undergo
stereospecific C-glycosidation with C-1-oxygenated allylsilanes
to form -glycosides.18,19 -Methoxyglycine esters react with al
lylsilanes and silyl enol ethers in the presence of BF 3 OEt 2 to
give racemic ,-unsaturated -amino acids and 7-oxo--amino
acids, respectively.20 -Glucopyranosides are synthesized from
an aglycon and 2,3,4,6-tetra-O-acetyl--D-glucopyranose.21 Al
cohols and silyl ethers also undergo stereoselective glycosylation
with protected glycosyl fluorides to form -glycosides.22
BF 3 OEt 2 reverses the usual anti selectivity observed in the
reaction of crotyl organometallic compounds (based on Cu, Cd,
Hg, Sn, Tl, Ti, Zr, and V, but not on Mg, Zn, or B) with alde
hydes (eq la) and imines (eq lb), so that homoallyl alcohols
and homoallylamines are formed, respectively. 23-28 The prod
ucts show mainly syn diastereoselectivity. BF 3 OEt 2 is the only
Lewis acid which produces hydroxy- rather than halotetrahydropyrans from the reaction of allylstannanes with pyranosides.29
The BF 3 OEt 2 mediated condensations of -oxygenated allylstan
nanes with aldehydes (eq 1c) and with 'activated' imines (eq 1d)
affords vicinal diol derivatives and 1,2-amino alcohols, respec
tively, with syn diastereoselectivity.30,31
The 'activated' imines are obtained from aromatic amines,
aliphatic aldehydes, and -ethoxycarbamates. The reaction of
aldehydes with -(alkoxy)--methylallylstannanes with aldehy
des in the presence of BF 3 OEt 2 gives almost exclusively syn-(E)isomers.31
(1)
(a) X = O, Y = Me
(b) X = NR2, Y = Me
(c) X = O, Y = OMe, OTBDMS
(d) X = NR2, Y = OMe, OTBDMS
or OCH2OMe
(a) X = OH, Y = Me
(b) X = NHR2, Y = Me
(c) X = OH, Y = OMe, OTBDMS
(d) X = NHR2, Y = OH or derivative
The reaction of -diketones with allyltrimethylstannane in

the presence of BF 3 OEt 2 yields a mixture of homoallylic al
cohols, with the less hindered carbonyl group being allylated
predominantly.32 The reaction between aldehydes and allylic
silanes with an asymmetric ethereal functionality produces synhomoallyl alcohols when Titanium(IV) Chloride is coordinated
with the allylic silane and anti isomers with BF 3 OEt 2 . 33
Chiral oxetanes can be synthesized by the BF 3 OEt 2 catalyzed
[2 + 2] cycloaddition reactions of 2,3-O-isopropylidenealdehydeD-aldose derivatives with allylsilanes, vinyl ethers, or vinyl
sulfides.34 The regiospecificity and stereoselectivity is greater
than in the photochemical reaction; trans-2-aikoxy- and trans2-phenylthiooxetanes are the resulting products.
2-Alkylthioethyl acetates can be formed from vinyl acetates by
the addition of thiols with BF 3 OEt 2 as the catalyst.35 The yield
is 79%, compared to 75% when BF 3 OEt 2 is used in conjunction
with Mercury(II) Sulfate or Mercury(II) Oxide.
-Alkoxycarbonylallylsilanes react with acetals in the presence
of BF 3 OEt 2 (eq 2). 36 The products can be converted into amethylene--butyrolactones by dealkylation with Iodotrimethylsilane.
(2)
70
The cuprate 1,4-conjugate addition step in the synthesis of (+)modhephene is difficult due to the neopentyl environment of C4 in the enone, but it can occur in the presence of BF3OEt2
(eq 3).37
(?)
(3)
The reagent is used as a Lewis acid catalyst for the intramolec

ular addition of diazo ketones to alkenes.38 The direct synthesis
of bicyclo[3.2.1]octenones from the appropriate diazo ketones us
ing BF3OEt2 (eq 4) is superior to the copper-catalyzed thermal
decomposition of the diazo ketone to a cyclopropyl ketone and
subsequent acid-catalyzed cleavage.38
(8)
(4)
BF3OEt2 reacts with fluorinated amines to form salts which

are analogous to Vilsmeier reagents, Arnold reagents, or
phosgene-immonium salts (eq 5).39 These salts are used to acylate electron-rich aromatic compounds, introducing a fluorinated
carbonyl group (eq 6).
(5)
R = Et; X = Cl, F, CF 3 (1)
(6)
Xenon(II) Fluoride and methanol react to form Methyl

Hypofluorite, which reacts as a positive oxygen electrophile in the presence of BF3 (etherate or methanol com
plex) to yield anti-Markovnikov fluoromethoxy products from
alkenes.40,41
Aldol Reactions. Although Titanium(IV) Chloride is a bet
ter Lewis acid in effecting aldol reactions of aldehydes, acetals,
and silyl enol ethers, BF3OEt2 is more effective for aldol reac
tions with anions generated from transition metal carbenes and
with tetrasubstituted enol ethers such as (Z)- and (E)-3-methyl2-(trimethylsilyloxy)-2-pentene.42,43 One exception involves the
preparation of substituted cyclopentanediones from acetals by the
aldol condensation of protected four-membered acyloin deriva
tives with BF3OEt2 rather than TiCl4 (eq 7).44 The latter cata
lyst causes some loss of the silyl protecting group. The pinacol
rearrangement is driven by the release of ring strain in the fourmembered ring and controlled by an acyl group adjacent to the
diol moiety.
The reagent is the best promoter of the aldol reaction of 2(trimethylsilyloxy)acrylate esters, prepared by the silylation of
pyruvate esters, to afford -alkoxy--keto esters (eq 8).4S These
esters occur in a variety of important natural products.
BF3OEt2 can improve or reverse the aldehyde diastereofacial

selectivity in the aldol reaction of silyl enol ethers with aldehy
des, forming the syn adducts. For example, the reaction of the silyl
enol ether of pinacolone with 2-phenylpropanal using BF3OEt2
gives enhanced levels of Felkin selectivity relative to the addition
of the corresponding lithium enolate.46,47 In the reaction of silyl
enol ethers with 3-formyl-2-isoxazolines, BF3OEt2 gives pre
dominantly anti aldol adducts, whereas other Lewis acids give syn
aldol adducts.48 The reagent can give high diastereofacial selec
tivity in the addition of silyl enol ethers or silyl ketones to chiral
aldehydes.49 In the addition of a nonstereogenic silylketene acetal
to chiral, racemic -thioaldehydes, BF3OEt2 leads exclusively to
the anti product.49
1,5-Dicarbonyl compounds are formed from the reaction of
silyl enol ethers with methyl vinyl ketones in the presence
of BF3OEt2 and an alcohol (eq 9).50 -Methoxy ketones are
formed from -diazo ketones with BF3OEt2 and methanol, or
directly from silyl enol ethers using iodobenzene/BF3OEt2 in
methanol.51
(9)
-Mercurio ketones condense with aldehydes in the presence of

BF3OEt2 with predominant erythro selectivity (eq 10).52 Enaminosilanes derived from acylic and cyclic ketones undergo syn
selective aldol condensations in the presence of BF3OEt2.53
(10)
erythro 90:10 threo

Cyclizations. Arylamines can undergo photocyclization in
the presence of BF3OEt2 to give tricyclic products, e.g. 9azaphenanthrene derivatives (eq 11).54
71
3,5-dioxoalkanoates are synthesized from tertiary amides or es

ters with the acetoacetate dianion in the presence of BF3OEt2
(eq 16).66
(15)
(11)
R = H, Me; R' = H, OMe; X = CH, N
Substituted phenethyl isocyanates undergo cyclization to lac

tams when treated with BF3OEt2.55 Vinyl ether epoxides
(eq 12),56 vinyl aldehydes,57 and epoxy -keto esters58 all un
dergo cyclization with BF3OEt2.
(12)
(16)
R = n-C9H19, ClCH2, Ph
Aldehydes and siloxydienes undergo cyclocondensation with

BF3OEt2 to form pyrones (eq 17).67 The stereoselectivity is in
fluenced by the solvent.
-Silyl divinyl ketones (Nazarov reagents) in the presence of

BF3OEt2 cyclize to give cyclopentenones, generally with reten
tion of the silyl group.59 BF3OEt2 is used for the key step in
the synthesis of the sesquiterpene trichodiene, which has adjacent
quaternary centers, by catalyzing the cyclization of the dienone
to the tricyclic ketone (eq 13).60 Trifluoroacetic acid and trifluoroacetic anhydride do not catalyze this cyclization.
(17)
solvent: CH2Cl2
PhMe
(13)
Costunolide, treated with BF3OEt2, produces the cyclocostunolide (2) and a C-4 oxygenated sesquiterpene lactone (3), 4ahydroxycyclocostunolide (eq 14).61
(14)
Other Condensation Reactions. BF3MeOH and BF3OEt2

with ethanol are widely used in the esterification of various kinds
of aliphatic, aromatic, and carboxylic acids;62 the reaction is mild,
and no rearrangement of double bonds occurs. This esterification
is used routinely for stable acids prior to GLC analysis. Hetero
cyclic carboxylic acids,63 unsaturated organic acids,64 biphenyl4,4'-dicarboxylic acid,65 4-aminobenzoic acid,63 and the very sen
sitive 1,4-dihydrobenzoic acid65 are esterified directly.
The dianion of acetoacetate undergoes Claisen condensations
with tetramethyldiamide derivatives of dicarboxylic acids to pro
duce polyketides in the presence of BF3OEt2 (eq 15).66 Similarly,
1:2.3
7:1
BF3OEt2 is effective in the direct amidation of carboxylic acids

to form carboxamides (eq 18).68 The reaction is accelerated by
bases and by azeotropic removal of water.
(18)
Carbamates of secondary alcohols can be prepared by a

condensation reaction with the isocyanate and BF3OEt2 or
Aluminum Chloride.69 These catalysts are superior to basic
catalysts such as pyridine and triefhylamine. Some phenylsulfonylureas have been prepared from phenylsulfonamides and
isocyanates using BF3OEt2 as a catalyst; for example, l-butyl-3(p-tolylsulfonyl)urea is prepared from p-toluenesulfonamide and
butyl isocyanate.70 BF3OEt2 is an excellent catalyst for the con
densation of amines to form azomethines (eq 19).71 The temper
atures required are much lower than with Zinc Chloride.
(19)
72
Acyltetrahydrofurans can be obtained by BF3OEt2 catalyzed

condensation of (Z)-4-hydroxy-l-alkenylcarbamates with aldehy
des, with high diastereo- and enantioselectivity.72 Pentasubstituted hydrofurans are obtained by the use of ketones.
Isobornyl ethers are obtained in high yields by the conden
sation of camphene with phenols at low temperatures using
BF3OEt2 as catalyst.73 Thus camphene and 2,4-dimethylphenol
react to give isobornyl 2,4-dimethylphenyl ether, which can un
dergo further rearrangement with BF3OEt2 to give 2,4-dimethyl6-isobornylphenol.73
The title reagent is also useful for the condensation of allylic
alcohols with enols. A classic example is the reaction of phytol in
dioxane with 2-methyl-1,4-naphthohydroquinone 1-monoacetate
to form the dihydro monoacetate of vitamin K1 (eq 20), which can
be easily oxidized to the quinone.74
(23)
The migration of the carbonyl during epoxide cleavage is used

to produce hydroxy lactones from epoxides of carboxylic acids
(eq 24).83 -Acyl-2-indanones,84 furans,85 and 2-oxazolines86
(eq 25) can also be synthesized by the cleavage and rearrange
ment of epoxides with BF3OEt2. The last reaction has been con
ducted with sulfuric acid and with tin chloride, but the yields were
lower. ,-Epoxy tin compounds react with BF3OEt2 to give the
corresponding cyclopropylcarbinyl alcohols (eq 26).87
(24)
R = H or COMe
(20)
BF3OEt2 promotes fast, mild, clean regioselective dehydra

tion of tertiary alcohols to the thermodynamically most stable
alkenes.75 11 -Hydroxysteroids are dehydrated by BF3OEt2 to
give 9(11)-enes(eq 21).76,77
(21)
Epoxide Cleavage and Rearrangements. The treatment of

epoxides with BF3OEt2 results in rearrangements to form alde
hydes and ketones (eq 22).78 The carbon a to the carbonyl group
of an epoxy ketone migrates to give the dicarbonyl product.79 The
acyl migration in acyclic ,-epoxy ketones proceeds through a
highly concerted process, with inversion of configuration at the
migration terminus.80 With 5-substituted 2,3-epoxycyclohexanes
the stereochemistry of the quaternary carbon center of the cyclopentanecarbaldehyde product is directed by the chirality of the
5-position.81 Diketones are formed if the -position of the ,epoxy ketone is unsubstituted. The 1,2-carbonyl migration of an
,-epoxy ketone, 2-cycloheptylidenecyclopentanone oxide, oc
curs with BF3OEt2 at 25 C to form the cyclic spiro-l,3-diketone
in 1 min (eq 23).82
(25)
(26)
Remotely unsaturated epoxy acids undergo fission rearrange

ment when treated with BF3OEt2. Hence, cis and trans ketocyclopropane esters are produced from the unsaturated epoxy ester
methyl vernolate (eq 27).88
(27)
Epoxy sulfones undergo rearrangement with BF3OEt2 to give

the corresponding aldehydes.89 -Epoxy sulfoxides, like other
negatively substituted epoxides, undergo rearrangement in which
the sulfinyl group migrates and not the hydrogen, alkyl, or aryl
groups (eq 28).89
(28)
R1 = Me, H; R2 = Me, Ph
,-Epoxy alcohols undergo cleavage and rearrangement with

BF3OEt2 to form -hydroxy ketones.90 The rearrangement is

stereospecific with respect to the epoxide and generally results
in anti migration. The rearrangement of epoxy alcohols with substituents leads to ,-disubstituted carbonyl compounds. 91
The BF 3 OEt 2 -induced opening of epoxides with alcohols is
regioselective, but the regioselectivity varies with the nature of
the substituents on the oxirane ring.92 If the substituent provides
charge stabilization (as with a phenyl ring), the internal position
is attacked exclusively. On the other hand, terminal ethers are
formed by the regioselective cleavage of the epoxide ring of glycidyl tosylate.92
A combination of cyanoborohydride and BF3OEt2 is used for
the regio- and stereoselective cleavage of most epoxides to the less
substituted alcohols resulting from anti ring opening.93 The reac
tion rate of organocopper and cuprate reagents with slightly reac
tive epoxides, e.g. cyclohexene oxide, is dramatically enhanced by
BF3OEt2.94 The Lewis acid and nucleophile work in a concerted
manner so that anti products are formed.
Azanaphthalene TV-oxides undergo photochemical deoxygenation reactions in benzene containing BF 3 OEt 2 , resulting in amines
in 70-80% yield;95 these amines are important in the synthesis of
heterocyclic compounds. Azidotrimethylsilane reacts with trans1,2-epoxyalkylsilanes in the presence of BF 3 OEt 2 to produce (Z)1-alkenyl azides.96 The cis-l,2-epoxyalkylsilanes undergo rapid
polymerization in the presence of Lewis acids.
Other Rearrangements. BF 3 OEt 2 is used for the regioselec
tive rearrangement of polyprenyl aryl ethers to yield polyprenyl
substituted phenols, e.g. coenzyme Q n .97 The reagent is used in the
Fries rearrangement; for example, 5-aeetyl-6-hydroxycoumaran is
obtained in 96% yield from 6-acetoxycoumaran using this reagent
(eq 29). 98
(29)
Formyl bicyclo[2.2.2]octane undergoes the retro-Claisen rear

rangement to a vinyl ether in the presence of BF 3 OEt 2 at 0C
(eq 30), rather than with HOAc at 110 C.99
(30)
BF3OEt2 is used for a stereospecific 1,3-alkyl migration

to form trans-2-alkyltetrahydrofuran-3-carbaldehydes from 4,5dihydrodioxepins (eq 31), which are obtained by the isomerization of 4,7-dihydro-1,3-dioxepins.100 Similarly, -alkyl-alkoxyaldehydes can be prepared from 1-alkenyl alkyl acetals by
a 1,3-migration using BF3OEt2 as catalyst.101 Syn products are
obtained from (E)-1-alkenyl alkyl acetals and anti products from
the (Z)-acetals.
(31)
The methyl substituent, and not the cyano group, of 4-methyl-4cyanocyclohexadienone migrates in the presence of BF3OEt2 to
give 3-methyl-4-cyanocyclohexadienone.102 BF3OEt2-promoted
73
regioselective rearrangements of polyprenyl aryl ethers pro

vide a convenient route for the preparation of polyprenylsubstituted hydroquinones (eq 32), which can be oxidized to
polyprenylquinones.103
(32)
The (E)-(Z) photoisomerization of ,-unsaturated esters, 104

cinnamic esters,105 butenoic esters, 106 and dienoic esters 106 is cat
alyzed by BF3OEt2 or Ethylaluminum Dichloride. The latter two
reactions also involve the photodeconjugation of ,-unsaturated
esters to ,-unsaturated esters. The BF 3 MeOH complex is used
for the isomerization of 1- and 2-butenes to form equal quantities
of cis- and trans-but-2-enes;107 the BF 3 OEt 2 -acetic acid complex
is not as effective.
The complex formed with BF3OEt2 and Epichlorohydrin in
DMF acts as a catalyst for the Beckmann rearrangement of
oximes. 108 Cyclohexanone, acetaldehyde, and syrc-benzaldehyde
oximes are converted into -caprolactam, a mixture of Nmethylformamide and acetamide, and 7V-phenylacetamide, re
spectively.
The addition of BF3OEt2 to an -phosphorylated imine results
in the 1,3-transfer of a diphenylphosphinoyl group, with resul
tant migration of the C-N=C triad.109 This method is less de
structive than the thermal rearrangement. The decomposition of
dimethyldioxirane in acetone to methyl acetate is accelerated with
BF3OEt2, but acetol is also formed.110 Propene oxide undergoes
polymerization with BF3OEt2 in most solvents, but isomerizes to
propionaldehyde and acetone in dioxane. 111
Hydrolysis. BF3OEt2 is used for stereospecific hydrolysis
of methyl ethers, e.g. in the synthesis of ()-aklavone. 112 The
reagent is also used for the mild hydrolysis of dimethylhydrazones. 113 The precipitate formed by the addition of BF3OEt2 to
a dimethylhydrazone in ether is readily hydrolyzed by water to
the ketone; the reaction is fast and does not affect enol acetate
functionality.
Cleavage of Ethers. In aprotic, anhydrous solvents,
BF 3 MeOH is useful for the cleavage of trityl ethers at rt. 114
Under these conditions, O- and JV-acyl groups, O-sulfonyl,
yV-alkoxycarbonyl, O-methyl, O-benzyl, and acetal groups are
not cleaved.
BF3OEt2 and iodide ion are extremely useful for the mild and
regioselective cleavage of aliphatic ethers and for the removal of
the acetal protecting group of carbonyl compounds. 115116 Aro
matic ethers are not cleaved, in contrast to other boron reagents.
BF3OEt2, in chloroform or dichloromethane, can be used for the
removal of the t-butyldimethylsilyl (TBDMS) protecting group
of hydroxyls, at 0-25 C in 85-90% yield.117 This is an alterna
tive to ether cleavage with Tetra-n-butylammonium Fluoride or
hydrolysis with aqueous Acetic Acid.
In the presence of BF3OEt2, dithio-substituted allylic anions
react exclusively at the -carbons of cyclic ethers, to give high
yields of the corresponding alcohol products (eq 33). 118 The dithiAvoid Skin Contact with All Reagents
74
ane moiety is readily hydrolyzed with Mercury(II) Chloride to

give the keto derivatives.
(33)
Inexpensive di-, tri-, and tetramethoxyanthraquinones can be

selectively dealkylated to hydroxymethoxyanthraquinones by the
formation of difluoroboron chelates with BF3OEt2 in benzene
and subsequent hydrolysis with methanol.119 These unsymmetrically functionalized anthraquinone derivatives are useful interme
diates for the synthesis of adriamycin, an antitumor agent. 2,4,6Trimethoxytoluene reacts with cinnamic acid and BF3OEt2, with
selective demethylation, to form a boron heterocycle which can
be hydrolyzed to the chalcone aurentiacin (eq 34).120
sodium acetate. Hence, 11-bromoketones are obtained in high

yields from methyl 3,7-diacetoxy-12-ketocholanate.126 Bromi
nation (at the 6-position) and dibromination (at the 6a- and 1 lapositions) of methyl 3a-acetoxy-7,12-dioxocholanate can occur,
depending on the concentration of bromine.127
A combination of BF3OEt2 and a halide ion (tetraethylammonium bromide or iodide in dichloromethane or chloroform, or
sodium bromide or iodide in acetonitrile) is useful for the conver
sion of allyl, benzyl, and tertiary alcohols to the corresponding
halides.128,129
Diels-Alder Reactions. BF3OEt2 is used to catalyze and re
verse the regiospecificity of some Diels-Alder reactions, e.g.
with peri-hydroxylated naphthoquinones,130 sulfur-containing
compounds,131 the reaction of 1-substituted trans-1,3-dienes with
2,6-dimethylbenzoquinones,132 and the reaction of 6-methoxy-lvinyl-3,4-dihydronaphthalene with p-quinones.133 BF3OEt2 has
a drastic effect on the regioselectivity of the Diels-Alder reaction
of quinoline- and isoquinoline-5,8-dione with piperylene, which
produces substituted azaanthraquinones.134 This Lewis acid is
the most effective catalyst for the Diels-Alder reaction of furan with methyl acrylate, giving high endo selectivity in the 7oxabicyclo[2.2.1]heptene product (eq 35).135
(35)
(34)
-Vinylidenecycloalkanones, obtained by the reaction of

Lithium Acetylide with epoxides and subsequent oxidation, un
dergo a Diels-Alder reaction at low temperature with BF3OEt2
to form spirocyclic dienones (eq 36).136
Reductions. In contrast to hydrosilylation reactions catalyzed
by metal chlorides, aldehydes and ketones are rapidly reduced at rt
by Triethylsilane and BF3OEt2, primarily to symmetrical ethers
and borate esters, respectively.121 Aryl ketones like acetophenone
and benzophenone are converted to ethylbenzene and diphenylmethane, respectively. Friedel-Crafts acylation-silane reduction
reactions can also occur in one step using these reagents; thus Benzoyl Chloride reacts with benzene, triethylsilane, and BF3OEt2
to give diphenylmethane in 30% yield.121
BF3OEt2 followed by Diisobutylaluminum Hydride is used
for the 1,2-reduction of --amino-a,-unsaturated esters to give
unsaturated amino alcohols, which are chiral building blocks for
a-amino acids.122 ,-Unsaturated nitroalkenes can be reduced
to hydroxylamines by Sodium Borohydride and BF3OEt2 in
THF;123,124 extended reaction times result in the reduction of the
hydroxylamines to alkylamines. Diphenylamine-borane is pre
pared from sodium borohydride, BF3OEt2, and diphenylamine
in THF at 0 C.125 This solid is more stable in air than BF3THF
and is almost as reactive in the reduction of aldehydes, ketones,
carboxylic acids, esters, and anhydrides, as well as in the hydroboration of alkenes.
Bromination. BF3OEt2 can catalyze the bromination of
steroids that cannot be brominated in the presence of HBr or
(36)
Other Reactions. The 17-hydroxy group of steroids can be

protected by forming the THP (O-tetrahydropyran-2-yl) deriva
tive with 2,3-dihydropyran, using BF3OEt2 as catalyst;137 the
yields are higher and the reaction times shorter than with ptoluenesulfonic acid monohydrate.
BF3OEt2 catalyzes the decomposition of ,-unsaturated diazomethyl ketones to cyclopentenone derivatives (eq 37).138,139
Similarly, ,-unsaturated diazo ketones are decomposed to ,unsaturated cyclohexenones, but in lower yields.140
(37)
BF3OEt2 is an effective reagent for debenzyloxycarbonylations of methionine-containing peptides.141 Substituted 6H-1,3thiazines can be prepared in high yields from BF3OEt2-catalyzed
reactions between ,-unsaturated aldehydes, ketones, or acetals

with thioamides, thioureas, and dithiocarbamates (eq 38).142
(38)
a-Alkoxy ketones can be prepared from a-diazo ketones

and primary, secondary, and tertiary alcohols using BF3OEt2
in ethanol.143 Nitrogen is released from a solution of aDiazoacetophenone and BF3OEt2 in ethanol to give aethoxyacetophenone.143
Anti-diols, can be formed from -hydroxy ketones using Tin(IV)
Chloride or BF3OEt2.144 The hydroxy ketones are silylated,
treated with the Lewis acid, and then desilylated with Hydrogen
Fluoride. Syn-diols are formed if Zinc Chloride is used as the
catalyst.
BF3OEt2 activates the formal substitution reaction of the hydroxyl group of -- or -lactols with some organometallic reagents
(M = Al, Zn, Sn), so that 2,5-disubstituted tetrahydrofurans or 2,6disubstituted tetrahydropyrans are formed.145
A new method of nitrile synthesis from aldehydes has been dis
covered using O-(2-aminobenzoyl)hydroxylamine and BF3OEt2,
achieving 78-94% yields (eq 39).146
(39)
Carbonyl compounds react predominantly at the a site of
dithiocinnamyllithium if BF3OEt2 is present, as the hardness of
the carbonyl compound is increased (eq 40).147 The products can
be hydrolyzed to -hydroxyenones.
2.
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(40)
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ditions ensure that the reaction will proceed even with alcohols
with acid-labile functionality.
Related Reagents. See entries for other Lewis acids,
e.g. Zinc Chloride, Aluminum Chloride, Titanium(IV) Chlo
ride; also see entries for Boron Trifluoride (and com
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Chenard, B. L.; Van Zyl, C. M.; Sanderson, D. R. TL 1986, 27, 2801.
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61. Jain, T. C ; McCloskey, J. E. TL 1971, 1415.
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Marshall, J. L.; Erikson, K. C ; Folsom, T. K. TL 1970, 4011.
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4767.
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Tani, J.; Oine, T.; Inoue, I. S 1975, 714.
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Ibuka, T.; Chu, G.-N.; Aoyagi, T.; Kitada, K.; Tsukida, T.; Yoneda, F.
CPB 1985, 33, 451.
Irie, H.; Nishimura, M.; Yoshida, M.; Ibuka, T. JCS(P1) 1989, 1209.
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Tomoda, S.; Matsumoto, Y.; Takeuchi, Y.; Nomura, Y. BCJ 1986, 59,
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97. Yoshizawa, T.; Toyofuku, H.; Tachibana, K.; Kuroda, T. CL 1982, 1131.
98. Davies, J. S. H.; McCrea, P. A.; Norris, W. L.; Ramage, G. R. JCS 1950,
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99. Boeckman, R. K. Jr.; Flann, C. J.; Poss, K. M. JACS 1985, 707, 4359.
100. Suzuki, H.; Yashima, H.; Hirose, T.; Takahashi, M., Moro-Oka, Y.;
Ikawa, T. TL 1980, 21, 4927.
101. Takahashi, M.; Suzuki, H.; Moro-Oka, Y.; Ikawa, T. TL 1982, 23, 4031.
102. Marx, J. N.; Zuerker, J.; Hahn, Y P. TL 1991, 32, 1921.
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Lewis, F. D.; Oxman, J. D. JACS 1981, 103, 7345.
Lewis, F. D.; Oxman, J. D.; Gibson, L. L.; Hampsch, H. L.; Quillen, S.
L. JACS 1986, 108, 3005.
Lewis, F. D.; Howard, D. K.; Barancyk, S. V.; Oxman, J. D. JACS 1986,
108, 3016.
Roberts, J. M.; Katovic, Z.; Eastham, A. M. J. Polym. Sci. Al 1970, 8,
3503.
Izumi.Y CL 1990, 2171.
Onys'ko, P. P.; Kim, T. V.; Kiseleva, E. I.; Sinitsa, A. D. TL 1992, 33,
691.
Singh, M.; Murray, R. W. JOC 1992, 57, 4263.
Sugiyama, S.; Ohigashi, S.; Sato, K.; Fukunaga, S.; Hayashi, H. BCJ
1989, 62, 3757.
Pearlman, B. A.; McNamara, J. M.; Hasan, I.; Hatakeyama, S.;
Sekizaki, H.; Kishi, Y JACS 1981, 103, 4248.
Gawley, R. E.; Termine, E. J. SC 1982, 12, 15.
Mandal, A. K.; Soni, N. R.; Ratnam, K. R. S 1985, 274.
Mandal, A. K.; Shrotri, P. Y.; Ghogare, A. D. S 1986, 221.
Pelter, A.; Ward, R. S.; Venkateswarlu, R.; Kamakshi, C. T 1992, 48,
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Kelly, D. R.; Roberts, S. M.; Newton, R. F. SC 1979, 9, 295.
Fang, J.-M.; Chen, M.-Y TL 1988, 29, 5939.
Preston, P. N.; Winwick, T.; Morley, J. O. JCS(P1) 1983, 1439.
Schiemenz, G. P.; Schmidt, U. LA 1982, 1509.
Doyle, M. P.; West, C. X; Donnelly, S. J.; McOsker, C. C. JOM 1976,
117, 129.
Moriwake, X; Hamano, S.; Miki, D.; Saito, S.; Torii, S. CL 1986, 815.
Varma, R. S.; Kabalka, G. W. OPP 1985, 17, 254.
Varma, R. S.; Kabalka, G. W. SC 1985, 15, 843.
Camacho, C ; Uribe, G.; Contreras, R. S 1982, 1027.
Yanuka, Y.; Halperin, G. JOC 1973, 38, 2587.
Takeda, K.; Komeno, X; Igarashi, K. CPB 1956, 4, 343.
Mandal, A. K.; Mahajan, S. W. TL 1985, 26, 3863.
Vankar, Y. D.; Rao, C. X TL 1985, 26, 2717.
Trost, B. M.; Ippen, J.; Vladuchick, W C. JACS 1977, 99, 8116.
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Kitchen, L. J. JACS 1948, 70, 3608.
Hirschmann, R.; Miller, R.; Wendler, N. L. JACS 1954, 76, 4592.
Posner, G. H.; Shulman-Roskes, E. M.; Oh, C. H.; Carry, J.-C; Green,
J. V.; Clark, A. B.; Dai, H.; Anjeh, T. E. N. TL 1991, 32, 6489.
76.
77.
Heymann, H.; Fieser, L. F. JACS 1952, 74, 5938.

Clinton, R. O.; Christiansen, R. G.; Neumann, H. C ; Laskowski, S. C.
JACS 1957, 79, 6475.
78.
House, H. O.; Wasson, R. L. JACS 1957, 79, 1488.
79.
80.
81.
Bird, C. W.; Yeong, Y. C ; Hudec, J. S 1974, 27.

Domagala, J. M.; Bach, R. D. JACS 1978, 100, 1605.
Obuchi, K.; Hayashibe, S.; Asaoka, M.; Takei, H. BCJ 1992, 65, 3206.
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83.
Bach, R. D.; Klix, R. C. JOC 1985, 50, 5438.

Hancock, W. S.; Mander, L. N.; Massy-Westropp, R. A. JOC 1973, 38,
4090.
84.
French, L. G.; Fenlon, E. E.; Charlton, T. P. TL 1991, 32, 851.
85.
Loubinoux, B.; Viriot-Villaume, M. L.; Chanot, J. J.; Caubere, P. TL

1975, 843.
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87.
Smith, J. R. L.; Norman, R. O. C ; Stillings, M. R. JCS(P1) 1975, 1200.

Sato, T.; Watanabe, M.; Murayama, E. SC 1987, 17, 781.
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Durst, T.; Tin, K.-C. TL 1970, 2369.

Maruoka, K.; Hasegawa, M.; Yamamoto, H.; Suzuki, K.; Shimazaki,
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Shimazaki, M.; Hara, H.; Suzuki, K.; Tsuchihashi, G. TL 1987, 28,

5891.
Liu, Y.; Chu, T.; Engel, R. SC 1992, 22, 2367.
136. Gras, J.-L.; Guerin, A. TL 1985, 26, 1781.

137. Alper, H.; Dinkes, L. S 1972,81.
138. Smith, A. B. III; Branca, S. J.; Toder, B. H. TL 1975, 4225.
139. Smith, A. B. III CC 1975, 274.
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103, 1996.
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94.
Alexakis, A.; Jachiet, D.; Normant, J. F. T 1986, 42, 5607.
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Stojanac, Z.; Dickinson, R. A.; Stojanac, N.; Woznow, R. J.; Valenta,
Z. CJC 1975, 53, 616.
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1979, 57, 3308.
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Hirakawa, K. JCS(P1) 1990, 3109.
Kotsuki, H.; Asao, K.; Ohnishi, H. BCJ 1984, 57, 3339.
BROMODIMETHYLBORANE
141.
142.
143.
144.
145.
146.
147.
148.
Okamoto, M.; Kimoto, S.; Oshima, T.; Kinomura, Y.; Kawasaki, K.;
Yajima, H. CPB 1967, 15, 1618.
Hoff, S.; Blok, A. P. RTC 1973, 92, 631.
Newman, M. S.; Beal, P. F. III JACS 1950, 72, 5161.
Anwar, S.; Davis, A. P. T 1988, 44, 3761.
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28, 6339.
Reddy, P. S. N.; Reddy, P. P. SC 1988,18, 2179.
Fang, J.-M.; Chen, M.-Y.; Yang, W.-J. TL 1988, 29, 5937.
Hiroi, K.; Kitayama, R.; Sato, S. S 1983, 1040.
substituent has a quantitative influence on the outcome of the re

action via steric effects and/or complexation to the reagent. It is of
interest to note that tetrahydrofurans can be cleaved in the presence
of acyclic ethers (eq 2).3
Veronica Cornel
Emory University, Atlanta, GA, USA
Bromodimethylborane1
[5158-50-9]
C2H6BBr2
(1)
R = Me
R = Bu
(MW 120.78)
(mild Lewis acid capable of selective cleavage of ethers2,3 and

acetals;4,5 deoxygenation of sulfoxides6)
-3
Physical Data: mp -129C; bp 31-32C; d 1.238gcm ; fp

-37C.
Solubility: sol dichloromethane, 1,2-dichloroethane, hexane.
Form Supplied in: colorless liquid.
Preparative Method: can be conveniently prepared by treating
Tetramethylstannane with Boron Tribromide.7
Handling, Storage, and Precautions: flammable liquid, moisture
sensitive; typically stored and dispensed as a 1.5-2 M solution
in dichloromethane or dichloroethane. Solutions of this sort are
stable for a period of months if stored at 15 C and properly
protected from moisture.
Cleavage of Ethers. Bromodimethylborane (Me2BBr) reacts

with primary, secondary, and aryl methyl ethers,2 in addition
to trityl,8 benzyl,2,8 and 4-methoxybenzyl9 ethers, to regener
ate the parent alcohol in good to excellent yield (e.g. eq 1).
The tertiary methyl ethers examined afforded the correspond
ing tertiary bromides.2 The reaction is typically carried out in
dichloromethane or 1,2-dichloroethane between 0 C and rt, in the
presence of 1.3-4 equiv of Me2BBr. The reaction is usually com
plete in a matter of hours. Triethylamine (0.1-0.15 equiv per equiv
of Me2BBr) is often added as an acid scavenger. 4-Methoxybenzyl
ethers are more reactive and are cleaved at 78 C, whereas aryl
methyl ethers require elevated temperatures to react. Other func
tional groups including acetates, benzoates, alcohols, ethyl esters,
and r-butyldiphenylsilyl ethers are recovered unchanged under the
standard reaction conditions.
Bromodimethylborane is also effective for the cleavage of
cyclic ethers.2,3 Epoxides react at 78C while the analogous
four- to seven-membered ring heterocycles react between 0 C and
rt. In contrast to other boron-containing Lewis acids, MeaBBr re
acts via a predominantly S N 2 mechanism. Tetrahydrofuran deriva
tives which are substituted at the 2-position give rise to primary
bromides as the major or exclusive products. The nature of the
77
93%
92%
(2)
It is also of considerable interest to note that no -elimination

of the hydroxy group was observed in the ring-opening of
2-(ethoxycarbonylmethyl)tetrahydrofurans (eq 3),3 whereas Cglycosides bearing more acidic protons on the aglycon react with
Me2BBr to generate acyclic alkenes (eq 4).10
(3)
(4)
Bromodimethylborane has also been used in conjunction with

Tetra-n-butylammonium Iodide to bring about the fragmentation
of iodomethyl ether derivatives (eq 5).11
(5)
Cleavage of Acetals.4,5 Cyclic and acyclic acetals react with

Me2BBr at 78 C to generate the parent aldehydes and ketones
in excellent yield (e.g. eq 6). Primary, secondary, and tertiary
(2-methoxyethoxy)methyl (MEM), methoxymethyl (MOM), and
(methylthio)methyl (MTM) ethers also react at 78 C to give,
after aqueous workup, the corresponding alcohol. It is interest
ing to note that even tertiary MEM ethers cleanly regenerate the
78
BROMODIMETHYLBORANE
parent alcohol without formation of the corresponding bromide

or elimination products (eq 7). Treatment of an acetonide with
Me2BBr gives the parent diol in high yield (eq 8).
ring-opened products (eq 11 ).13 This reaction has been extended

to glycosides which, although less reactive, behave in a similar
fashion.1415
(6)
R = n-C12H25
R = Me, -CH 2 CH 2 -
(11)
(7)
(8)
Tetrahydropyranyl (THP) and tetrahydrofuranyl (THF) ethers

are converted to the corresponding alcohols by Me2BBr at rt (eq 9),
although the acetals are cleaved at 78 C (see below).
Benzylidene acetals are recovered unchanged when treated with

Me2BBr under conditions which are used to cleave other acetals.16
It is, however, possible to cleave benzylidene acetals to gen
erate hydroxy-O.S-acetals in excellent yield, by treatment with
Me2BBr at -78 C followed by Thiophenol (eq 12).16 Sterically
encumbered bromoboranes optimize regioselective complexation
of boron to the least hindered oxygen atom and are, therefore,
the reagents of choice for this process (eq 12).l6 These experi
ments demonstrate that benzylidene acetals do indeed react with
Me2BBr at -78 C, like other acetals.
(9)
Bromodiphenylborane (Ph2BBr) and 9-Bromo-9-borabicyclo[3.3.1]nonane (Br-9-BBN) can often be used in place
of Me2BBr for the cleavage of acetals;4'5 however, the purifi
cation of products from reactions employing Me2BBr is facil
itated by the volatility of Me2B-containing byproducts, thus
making Me2BBr the reagent of choice in most instances.
Interconversion of Functional Groups. The reaction of
Me]BBr with MEM and MOM ethers is believed to proceed via
-bromo ether intermediates. It is possible to trap these interme
diates with nucleophiles such as thiols, alcohols, and cyanide. An
example of the utility of this sequence is the conversion of a readily
prepared MOM ether into an MTM ether (eq 10).12
(12)
MeoBBr
Ph2BBr
9-BrBBN
68%
96%
90%
17%
Treatment of glycoside benzylidene acetals with a variety of disubstituted bromoboranes, followed by Borane-Tetrahydrofuran,
generates 4-Obenzyl-6-hydroxypyranosides in excellent yield
(eq 13).16
(13)
(10)
While THP and THF ethers are converted to the corresponding

alcohols by Me2BBr at rt, the acetal is cleaved at - 7 8 C.13 The
initial products of the reaction are acyclic -bromo ethers. These
can be trapped with a variety of nucleophiles to generate stable
Acetals derived from Dimethyl L-Tartrate react with

Me]BBr to generate a-bromo ethers which react further
with cuprate reagents to give optically active secondary
alcohol derivatives (eq 14).17 The alcohols may be lib
erated by treatment with Samarium(II) Iodide or by a
straightforward sequence of reactions (mesylation and elim
ination to form an enol ether followed by exposure to
methoxide in refluxing methanol). Selectivity is enhanced by the
BROMOTRIMETHYLSILANE
use of Ph 2 BBr and by careful control of the reaction temperature
at each step.
(14)
Me2BBr, 80%
Ph2BBr, 62%
79
14. Guindon, Y.; Anderson, P. C. TL 1987, 28, 2485.

15. Hashimoto, H.; Kawanishi, M.; Yuasa, H. TL, 1991, 32, 7087.
16. Guindon, Y.; Girard, Y.; Berthiaume, S.; Gorys, V.; Lemieux, R.; Yoakim,
C. CJC 1990, 68, 897.
17. Guindon, Y.; Simoneau, B.; Yoakim, C.; Gorys, V.; Lemieux, R.; Ogilvie,
W. TL 1991, 32, 5453.
18. Kawate, T.; Nakagawa, M.; Ogata, K.; Hino, T. H 1992, 33, 801.
19. Mander, L. N.; Patrick, G. L. TL 1990, 31, 423.
Yvan Guindon & Paul C. Anderson

Bio-Mga/Boehringer Ingelheim Research, Laval, Quebec,
Canada
34:1
82:1
Miscellaneous Reactions. Bromodimethylborane can also be

used to convert dialkyl, aryl alkyl, and diaryl sulfoxides to the cor
responding sulfides (eq 15).6 Typically, the sulfoxides are treated
with 2.5 equiv of Me 2 BBr in dichloromethane at 23 C for 30
min and at 0C for 10 min. Bromine is produced in the reaction
and must be removed in order to avoid possible side reactions.
This is accomplished by saturating the solution with propene prior
to introducing the reagent or by adding cyclohexene. Phosphine
oxides and sulfones failed to react under the conditions used to
deoxygenate sulfoxides.
(15)
Bromodimethylborane has also been used as a catalyst for

the Pictet-Spengler reaction (eq 16)18 and to catalyze the 1,3transposition of an allylic lactone.19
(16)
Related Reagents. Boron Tribromide; Boron Trichlo

ride; Bromobis(isopropylthio)borane; 9-Bromo-9-borabicyclo[3.3.1]borane; B-Bromocatechalborane.
1. Guindon, Y.; Anderson, P. C ; Yoakim, C; Girard, Y.; Berthiaume, S.;

Morton, H. E. PAC 1988, 60, 1705.
2. Guindon, Y.; Yoakim, C ; Morton, H. E. TL 1983, 24, 2969.
3. Guindon, Y.; Therien, M.; Girard, Y.; Yoakim, C. JOC 1987, 52, 1680.
4. Guindon, Y.; Morton, H. E.; Yoakim, C. TL 1983, 24, 3969.
5. Guindon, Y.; Yoakim, C ; Morton, H. E. JOC 1984, 49, 3912.
6. Guindon, Y.; Atkinson, J. G.; Morton, H. E. JOC 1984, 49, 4538.
7. Noth, H.; Vahrenkamp, H. JOM 1968,11, 399.
8. Kodali, D. R.; Duclos Jr., R. I. Chem. Phys. Lipids 1992, 61, 169.
9. Hbert, N.; Beck, A.; Lennox, R. B.; Just, G. JOC 1992, 57, 1777.
10. Abel, S.; Linker, T.; Giese, B. SL 1991, 171.
11. Gauthier, J. Y.; Guindon, Y. TL 1987, 28, 5985.
12. Morton, H. E.; Guindon, Y. JOC 1985, 50, 5379.
13. Guindon, Y.; Bernstein, M. A.; Anderson, P. C. TL 1987, 28, 2225.
Bromotrimethylsilane1
[2857-97-8]
C 3 H 9 BrSi
(MW 153.09)
(mild and selective reagent for cleavage of lactones, epoxides,

acetals, phosphonate esters and certain ethers; effective reagent
for formation of silyl enol ethers; can function as brominating
agent)
Alternate Name: TMS-Br.
Physical Data: bp 79 C; d 1.188 g c m - 3 ; n20D 1.4240; fp 32 e C.
Solubility: sol CCl 4 , CHCl 3 , CH 2 Cl 2 , ClCH 2 CH 2 Cl, MeCN,
toluene, hexanes; reactive with THF (ethers), alcohols, and
somewhat reactive with EtOAc (esters).
Form Supplied in: colorless liquid, packaged in ampules.
Analysis of Reagent Purity: well characterized by 1H, 13 C, and
29
Si NMR spectroscopy.
Preparative Methods: although many methods are reported,1 only
a few are provided here: Chlorotrimethylsilane undergoes halo
gen exchange with either Magnesium Bromide2 in Et2O or
Sodium Bromide3 in MeCN, which allows in situ reagent for
mation (eq 1); alternatively, Hexamethyldisilane reacts with
Bromine in benzene solution or neat, to afford only TMS-Br
with no byproducts (eq 2). 4 TMS-Br may also be generated
by reaction of hexamethyldisiloxane and Aluminum Bromide
(eq 3).5 However, it should be noted that the reactivity of in
situ generated reagent appears to depend upon the method of
preparation.
(1)
Me3Si-SiMe3 + Br2
Me3SiOSiMe3 + AlBr3
Me3SiBr
Me3SiBr
(2)
(3)
Purification: by distillation.
Handling, Storage, and Precautions: extremely sensitive to light,
air, and moisture; fumes in air due to hydrolysis (HBr), and
becomes discolored upon prolonged storage (free Br 2 ).
Ester Cleavage.6 Although esters are readily cleaved with

Iodotrimethylsilane, reaction of esters with TMS-Br under simiAvoid Skin Contact with All Reagents
80
BROMOTRIMETHYLSILANE
lar conditions gives somewhat lower yields of silyl esters or acids

upon hydrolysis (eq 4). Lactones, however, react with TMS-Br at
100 C to afford -bromocarboxylic acids after hydrolysis of the
silyl ester (eq 5). 7
CH2Cl2, TMS-Br converted the acetonide to the anhydrouridine

within 1.5 h, but in MeCN the bromide is formed after 10 min.
(4)
(10)
(5)
Formation of Enol Ethers. 14 Bromotrimethylsilane with Triethylamine in DMF is an effective medium for production of
thermodynamic (Z) silyl enol ethers (eq 11).
Ether Cleavage. THF 8 reacts with TMS-Br, thereby rendering
ethereal solvents incompatible with the reagent. Smooth removal
of the methoxymethyl (MOM) protecting group can be accom
plished with TMS-Br at 0C (eq 6). 9 Whereas acetals, THP and
silyl ethers are slowly cleaved with TMS-Br, the reagent gener
ated in situ effects selective MOM ether cleavage in the presence
of an acetonide.10 The majority of published ether cleavages have
been accomplished with TMS-I, although limited data show that
the more vigorous conditions necessary for ethyl ether cleavage
also result in bromide formation.8
RO-CH2OMe
RO-H
(6)
Cleavage of Epoxides. Epoxide opening with TMS-Br occurs

to provide the primary alkyl bromide at 60 C (eq 7). 8
(11)
Formation of Alkyl Bromides. 6b Alcohols react with excess

TMS-Br (1.5-4 equiv) at 25-50 C to form the alkyl bromide and
hexamethyldisiloxane (eq 12). Benzylic and tertiary alcohols react
faster than secondary alcohols.
R-CH2OH
R-CH2Br
(12)
Reaction with Acid Chlorides. 15 Acid bromides may be pre

pared from acid chlorides by reaction with TMS-Br (eq 13).
(13)
(7)
Cleavage of Acetals. Acetals can be cleaved by analogy to

ethers, providing the parent carbonyl species. 3c,6b Glycosyl bro
mides have been prepared from the corresponding acetate by re
action with TMS-Br in CHCl 3 at rt (eq 8). 11 In conjunction with
CoBr2 and Tetra-n-butylammonium Bromide, TMS-Br converts
the glucopyranose to the -D-glucoside in the presence of an al
cohol (eq 9). 12
Cleavage of Phosphonate Esters. 16 Compared to the reactiv

ity of TMS-I with phosphonate and phosphate esters, TMS-Br
is more selective and will cleave phosphonate esters even in the
presence of carboxylic esters and carbamates. Benzyl ester pro
tecting groups on aryl phosphates are selectively removed with
TMS-Br.17 The reaction of phosphonate esters with TMS-Br pro
ceeds through a mechanism similar to ester cleavage, providing a
silyl ester which is subsequently hydrolyzed with MeOH or H2O
(eq 14).
(14)
(8)
Reaction with Amines. Amines react with TMS-Br to form

isolable adducts, which react readily with ketones to form enamines under mild conditions (eq 15).18
(9)
An interesting solvent effect was noted in the cleavage of the

acetonide moiety in some nucleoside derivatives (eq 10).13 In
(15)
2-(t-BUTOXYCARBONYLOXYIMINO)-2-PHENYLACETONITRILE
Conjugate Addition. ,-Unsaturated ketones undergo con
jugate addition with TMS-Br. Treatment of the intermediate
with p-Toluenesulfonic Acid and ethylene glycol provides (3bromoethyldioxolanes (eq 16).19
18.
Comi, R.; Franck, R. W.; Reitano, M.; Weinreb, S. M. TL 1973, 3107.
19.
Hsung, R. P. SC 1990, 20, 1175.
20.
Iwata, C ; Tanaka, A.; Mizuno, H.; Miyashita, K. H 1990, 31, 987.
21.
Seyferth, D.; Grim, S. O. JACS 1961, 83, 1610.
Michael J. Martinelli
Lilly Research Laboratories, Indianapolis, IN, USA
(16)
Bromolactonization. -Unsaturated carboxylic acids react

with TMS-Br in the presence of a tertiary amine in DMSO yield
ing bromolactones, resulting from cis addition across the double
bond (eq 17).20
81
2-(t-Butoxycarbonyloxyimino)-2phenylacetonitrile
(17)
[58632-95-4]
Ylide Formation. Methylenetriphenylphosphorane
reacts
with TMS-Br to provide the corresponding ylide (eq 18).21
(18)
Related Reagents. Bromodimethylborane; Chlorotrimethylsilane; Hydrogen Bromide; Iodotrimethylsilane.
1. Schmidt, A. H. Aldrichim. Acta 1981,14 (2), 31.

2. Krerke, U. CB 1962, 95, 174.
3. (a) Scheibye, S.; Thomsen, I.; Lawesson, S. O. BSB 1979, 88, 1043. (b)
Olah, G. A.; Gupta, B. G. B.; Malhotra, R.; Narang, S. C. JOC 1980,45,
1638. (c) Schmidt, A. H.; Russ, M. CB 1981,114, 1099.
4. Sakurai, H.; Sasaki, K.; Hosomi, A. TL 1980, 21, 2329.
5. (a) Voronkov, M. G.; Dolgov, B. N.; Dmitrieva, N. A. DOK 1952, 84,
959. (b) Gross, H.; Bock, C ; Costisella, B.; Gloede, J. JPR 1978, 320,
344.
6. (a) Ho, T. L.; Olah, G. A. S 1977, 417. (b) Jung, M. E.; Hatfield, G. L.
TL 1978, 4483.
7. Kricheldorf, H. R. AG(E) 1979, 18, 689.
8. Kricheldorf, H. R.; Mrber, G.; Regel, W. S 1981, 383.
9. Hanessian, S.; Delorme, D.; Dufresne, Y. TL 1984, 25, 2515.
10. Woodward, R. B.; Logusch, E.; Nambiar, K. P.; Sakan, K.; Ward, D.
E.; Au-Yeung, B.; Balaram, P.; Browne, L. J.; Card, P. J.; Chen, C.
H.; Chnevert, R. B.; Fliri, A.; Frobel, K.; Gais, H.-J.; Garratt, D.
G.; Hayakawa, K.; Heggie, W.; Hesson, D. P.; Hoppe, D.; Hoppe, I.;
Hyatt, J. A.; Ikeda, D.; Jacobi, P. A.; Kim, K. S.; Kobuke, Y.; Kojima,
K.; Krowicki, K.; Lee, V. J.; Leutert, T.; Malchenko, S.; Martens, J.;
Matthews, R. S.; Ong, B. S.; Press, J. B.; Rajan Babu, T. V.; Rousseau,
G.; Sauter, H. M.; Suzuki, M.; Tatsuta, K.; Tolbert, L. M.; Truesdale, E.
A.; Uchida, I.; Ueda, Y.; Uyehara, T.; Vasella, A. T.; Vladuchick, W. C ;
Wade, P. A.; Williams, R. M.; Wong, H. N.-C. JACS 1981, 103, 3213.
11.
12.
13.
14.
15.
16.
Gillard, J. W.; Israel, M. TL 1981, 22, 513.

Morishima, N.; Koto, S.; Kusuhara, C ; Zen, S. CL 1981, 427.
Logue, M. W. Carbohydr. Res. 1975, 40, C9.
Ahmad, S.; Khan, M. A.; Iqbal, J. SC 1988, 18, 1679.
Schmidt, A. H.; Russ, M.; Grosse, D. S 1981, 216.
(a) McKenna, C. E.; Schmidhauser, J. CC 1979, 739. (b) Breuer, E.;
Safadi, M.; Chorev, M.; Gibson, D. JOC 1990, 55, 6147.
17. Lazar, S.; Guillaumet, G. SC 1992, 22, 923.
C13H14N2O3
(MW 246.27)
(reagent for protection of amino acids as t-butyl carbamates 1-3

and for protection of alcohols as t-butyl carbonates4)
Alternate Name: Boc-ON.
Solubility: very sol ethyl acetate, ether, benzene, chloroform,
dioxane and acetone; sol methanol, 2-propanol, and t-butanol;
insol petroleum ether and water.
Form Supplied in: solid.
Handling, Storage, and Precautions: contact with the reagent may
cause irritation. The toxicological properties of the reagent have
not been thoroughly investigated. The reagent should be stored
in a brown bottle at 20 C to prolong shelf life. After several
weeks at rt the reagent undergoes gradual decomposition with
evolution of CO 2 .
Amine Protection. The reagent, informally referred to as BocON, has been widely employed for the protection of amines as
their t-butoxycarbonyl (Boc) derivatives. The original description
of Boc-ON reports its utility for the N-protection of -amino acids
(eq l), 1 and this use is still the major application.5
(1)
The reaction is generally carried out using 1.1 equiv of BocON and 1.5 equiv of Triethylamine in either 50% aqueous diox
ane or 50% aqueous acetone. Boc derivatives are obtained in high
yields after 4-5 h at 20 C or 1 h at 45 C. The oxime byproduct
(eq 1) can be easily and completely removed from the reaction
mixture by extraction with ether, ethyl acetate, or benzene. To se
cure high purity and high yield, distillation of the dioxane or ace
tone prior to extraction of the oxime byproduct is recommended,
though direct extraction may be feasible in most cases. Yields
82
2-(t-BUTOXYCARBONYLOXYIMINO)-2-PHENYLACETONITRILE
for various amino acids range from good to virtually quantitative

(Table 1).
Table 1 Examples of Boc-Amino Acids Prepared with Boc-ON2
Boc-amino
acid
Ala-OH
Asn-OH
Glu(OH)2
Gly-OH
Leu-OH0.5H2O
Met-OHDCHAa
Phe-OHDCHAa
Pro-OH
Trp-OH
a
Reaction
time (h)
Oxime
extraction solvent
Yield
4
20
3
2
3
3
5
1.5
3
Ether
EtOAc
EtOAc
EtOAc
Ether
EtOAc
Ether
Benzene
EtOAc
80
86
78
87
99
82
98
88
99
(%)
(5)
DCHA = dicyclohexylamine.
Boc-ON offers a distinct advantage over t-Boc azide which can

require reaction temperatures of 50-60 C. 6 In addition, t-Boc
azide is thermally unstable and decomposes with apparent det
onation at temperatures above 80 C. Boc-ON is comparable to
Di-t-butyl Dicarbonate in terms of reaction times, yields, conve
nience, availability, and work-up procedure.7
Boc-ON has also been employed for the protection of secondary
amines (eqs 2 and 3). 8,9
(6)
(2)
(7)
(3)
This selective protection has also been accomplished with

copper-chelated diamino acids (eq 8). 14
The reagent will selectively protect the amino group in the pres
ence of alcohols and phenols as well as carboxylic acids. Examples
include the Boc protection of a kanamycin A derivative (eq 4) 10
and of the glycopeptide antibiotic A41030A (eq 5). 11
(8)
(4)
In the case of diamino acids, such as ornithine or lysine, BocON has been used to effect selective protection of N w at pH 11
(eqs 6 and 7). 12,13
Alcohol Protection. Boc-ON has also been employed to pro

tect alcohols as their t-butyl carbonates. 4 1 5 1 6 For this application
the alcohol must first be deprotonated to its alkoxide conjugate
base (eqs 9 and 10).
(9)
t-BUTYL CHLOROFORMATE
(10)
Related Reagents. N-(t-Butoxycarbonyloxy)phthalimide; N(t-Butoxycarbonyloxy)succinimide; t-Butyl Azidoformate; tButyl Chloroformate; Di-t-butyl Dicarbonate.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
Itoh, M ; Hagiwara, D.; Kamiya, T. TL 1975, 49, 4393.

Itoh, M.; Hagiwara, D.; Kamiya, T. BCJ 1977, 50, 718.
Itoh, M.; Hagiwara, D.; Kamiya, T. OS 1980, 59, 95.
Barlett, P. A.; Meadows, J. D.; Ottow, E. JACS 1984, 106, 5304.
FF 1977, 6, 91.
OS 1977, 57, 122.
Persio, G.; Piani, S.; De Castiglione, R. Int. J. Peptide Protein Res. 1983,
21, 227.
Galardy, R. E. B 1987, 21,5777.
Vaurecka, M.; Hesse, M. HCA 1989, 72, 847.
Matsuda, K.; Yasuda, N.; Tsutsumi, H.; Takaya, T. J. Antibiot. 1985, 38,
1719.
Hunt, A. H.; Dorman, D. E.; Debono, M.; Molloy, R. M. JOC 1985, 50,
2031.
Heimer, E. P.; Wang, C.-T.; Lambros, T. J.; Felix, A. M. OPP 1983,15,
379.
Bigge, C. F.; Hays, S. J.; Novak, P. M.; Drummond, J. T.; Johnson, G.;
Bobovski, T. P. TL 1989, 30, 5193.
Rosowsky, A.; Freisham, J. H.; Moran, R. G.; Solan, V. C ; Bader, H.;
Wright, J. E.; Radike-Smith, M. JMC 1986, 29, 655.
Bartlett, P. A.; Meadows, J. D.; Brown, E. G.; Morimoto, A.; Jernstedt,
K.K. JOC 1982, 47, 4013.
Martin, S. F.; Zinke, P. W. JOC 1991, 56, 6600.
Michael S. Wolfe
National Institutes of Health, Bethesda, MD, USA
Jeffrey Aub
University of Kansas, Lawrence, KS, USA
[24608-52-4]
C 5 H 9 ClO 2
(MW 136.58)
(reagent for the protection of amino groups, including amino

acids2)
Alternate Name: Boc-Cl.
Physical Data: bp 3-4 C/0.9-1.7 mmHg. 1
Solubility: sol ether, toluene, and most organic aprotic solvents.
Form Supplied in: not commercially available; should be prepared
from t-butanol2 orpotassium t-butoxide1,3 and phosgene shortly
before use.
83
Handling, Storage, and Precautions: unstable at rt. t-Butyl chlo

roformate should be kept as a solution in anhydrous solvent
at low temperature (deep freezer) and for a period of time not
exceeding a few days. Decomposition leads to high pressure in
the storage vessel. May contain some residual phosgene. Reacts
with DMSO or DMF.
Protection of Amino Groups. t-Butyl chloroformate (BocCl), first prepared by Choppin and Rogers in 1948,1 has been used,
despite the reagent's instability, for the t-butyloxycarbonyl (Boc)
protection of amino compounds and especially of amino acids.
Boc protection has gained considerable importance because of
the resistance of the protecting group to strong base hydrolysis
and catalytic hydrogenation, as well as the ease of deprotection
under mildly acidic conditions. Boc protection has become a fun
damental tool of modern peptide synthesis and particularly of the
Merrifield strategy for solid-phase peptide synthesis. Most amino
acids have been protected with Boc-Cl using slightly modified
Schotten-Baumann conditions (eq 1). 2
(1)
Reaction of pyridine compounds with Boc-Cl and Sodium

Borohydride in methanol at 65 C afforded the corresponding
7V-r-butyloxycarbonyldihydropyridine derivatives in good yield
(eq 2). 4
(2)
The main drawback of the reagent remains its very low stability
and the difficulties encountered in its preparation. Various prepar
ative procedures are currently available in the literature.5 It is also
necessary to determine the reagent concentration in solution ac
curately, which can be done by reacting an aliquot with a selected
amino compound before use. These liabilities notwithstanding,
t-butyl chloroformate can be a cheap and valuable reagent for
Boc protection and in some cases it is the best reagent available.
This is, for instance, the case in the synthesis of Boc-protected Ncarboxy anhydrides, which are used as building blocks in peptide
synthesis (eq 3). 6 Di-t-butyl Dicarbonate required much longer re
action times in this case. These Boc-UNCAs (urethane-protected
N-carboxy anhydrides) are, in fact, best prepared from the re
action of Boc-Cl with Leuchs anhydride in the presence of Nmethylmorpholine or any nonnucleophilic organic base.
(3)
Preparation of Other Reagents for Boc Protection. Because

of its low stability, t-butyl chloroformate has mainly been used
84
t-BUTYLDIMETHYLCHLOROSILANE
as a source of various other reagents that are easier to handle

under ordinary conditions. t-ButylAzidoformate, the most widely
employed reagent before the discovery of Di-t-butylDicarbonate,
is conveniently obtained from Boc-Cl through the formation of tbutyl carbazate (eq 4). 7
3.
Howard, J. C. JOC 1981, 46, 1720.
4.
Dagnino, L.; Li-Kwong-Ken, M. C ; Wynn, H.; Wolowyk, M. W.;

Triggle, C. R.; Knaus, E. E. JMC 1987, 30, 640.
Ger. Patent 2 108 782 (CA 1967, 76, 24715).
Fuller, W. D.; Cohen, M. P.; Shabankareh, M.; Blair, R. B.; Goodman,
M.; Naider, F. JACS 1990,112, 7414.
Ovchinnikov, Y. A.; Kiryushkin, A. A.; Miroshnikov, A. I. E 1965, 21,
418.
Yajima, H.; Kawatani, H. CPB 1968,16, 183.
Rzeszotarska, B.; Wiejak, S.; Pawelczak, K. OPP 1973, 5, 71.
Olah, G. A.; Kuhn, S. J. JOC 1961, 26, 237.
Olah, G. A.; Kuhn, S. J. CB 1956, 89, 862.
5.
6.
7.
(4)
t-Butyl azidoformate is also obtained more directly from BocCl and hydrazoic acid (eq 5). 8
8.
9.
10.
11.
12.
13.
Schnabel, E.; Herzog, H.; Hoffmann, P.; Klauke, E.; Ugi, I. AG(E) 1968,
7, 380.
Jpn. Patent 04213 368 (CA 1993, 118, 14048).
(5)
Various active carbonates, which are primarily used for the

preparation of stable reagents for the introduction of the Boc pro
tection, have been prepared from Boc-Cl.9
Exchange reactions utilizing hydrogen fluoride10 and various
salts such as sodium 11 and silver fluoride do not lead to the more
stable t-butyl fluoroformate, which has to be prepared instead from
carbonyl chlorofluoride or fluorophosgene.12
G.Sennyey
SNPE, Vert-le-Petit, France
[18162-48-6]
t-Butyl Carbonates and Carbamates. Because Boc-Cl is po
tentially the cheapest reagent for the synthesis of t-butyl carbon
ates, e.g. (1) and (2), or carbamates, it has been claimed in numer
ous patents and may have growing utility in industrial processes,
such as for the production of carbonates as components in thermal
recording materials. 13
(1)
(2)
Related Reagents. Allyl Chloroformate; Benzyl Chloroformate; 4-Bromobenzyl Chloroformate; t-Butyl Azido
formate; 1-(t-Butoxycarbonyl)-1H-benzotriazole 3-7V-oxide;
1 -(t-Butoxycarbonyl)imidazole; 2-(t-Butoxycarbonyloxyimino)2-phenylacetonitrile;
N-(t-Butoxycarbonyloxy)phthalimide;
7V-(r-Butoxycarbonyloxy)succinimide; N-(t-Butoxycarbonyl)1,2,4-triazole; Di-t-butyl Dicarbonate; Ethyl Chloroformate; 9Fluorenylmethyl Chloroformate; Isobutyl Chloroformate; Methyl
Chloroformate; 2,2,2-Tribromoethyl Chloroformate; 2,2,2Trichloroethyl Chloroformate; 2,2,2-Trichloro-t-butoxycarbonyl
Chloride; 2-(Trimethylsilyl)ethyl Chloroformate; Vinyl Chloro
formate.
1. Choppin, A. R.; Rogers, J. W. JACS 1948, 70, 2967.

2. Sakakibara, S.; Shin, M.; Fujino, Y.; Shimonishi, Y.; Inouye, S.; Inukai,
N. BCS 1969, 42, 809.
C 6 H 1 5 ClSi
(MW 150.72)
(widely used reagent for the protection of alcohols, amines, carboxylic acids, ketones, amides, thiols, and phenols; 1 useful for
regioselective silyl enol ether formation2 and stereoselective silyl
keten acetal formation3)
Alternate Names: t-butyldimethylsilyl chloride; TBDMSCl; TBSCl.
Physical Data: mp 86-89 C; bp 125 C.
Solubility: very sol nearly all common organic solvents such as
THF, methylene chloride, and DMF.
Form Supplied in: moist white crystals, commonly available.
Handling, Storage, and Precautions: hygroscopic, store under
N 2 ; harmful if inhaled, swallowed, or absorbed through skin;
should be used and weighed out in a fume hood.
Protecting Group. The reactions of TBDMSCl closely paral

lel those of Chlorotrimethylsilane (TMSCl). However, TBDMS
ethers are about 104 more stable toward hydrolysis than the corre
sponding TMS ethers. 1,4 The hydrolytic stability of the TBDMS
group has made it very valuable for the isolation of many siliconcontaining molecules. Since its introduction in 1972, the TBDMS
protecting group has undoubtedly become the most widely used
silicon protecting group in organic chemistry.1 Alcohols are most
commonly protected as their TBDMS ethers by treatment of the
alcohol in DMF (2 mL g - 1 ) at rt with 2.5 equiv of Imidazole (Im)
and 1.2 equiv of TBDMSCl. Alcohol protection in the presence of
4-Dimethylaminopyridine (DMAP) allows a greater range of sol
vents to be used (protection of alcohols in solvents other than DMF
using TBDMSCl alone are sluggish) and distinguishes a kinetic
preference for protection of primary alcohols in the presence of
secondary alcohols.5 Table 1 outlines conditions for the selective
protection of primary and secondary alcohols using TBDMSCl
and DMAP as catalyst.
Table 1 Use of DMAP to Catalyze the Protection of Diols With
TBDMSCl
Amine(s)
Solvent
DMAP (0.04 equiv), Et3N (1.1 equiv)

Im (2.2 equiv)
Im (0.04 equiv), Et3N (1.1 equiv)
DMAP (0.04 equiv), Et3N (1.1 equiv)
CH2Cl2
DMF
DMF
DMF
Silyl stannanes have been prepared by trapping tin

anions with TBDMSCl or other silyl chlorides. Alkynes treated
with with silyl stannanes and catalytic Tetrakis(triphenylphosphine)palladium(0) give cis-silyl stannylalkenes in good
yields. 11
GC ratio of A:B:C
95:0:5
59:11:30
No reaction
0:0:96
Alcohol:
Table 2 6 compares the rate of hydrolysis of several bulky silicon

ethers with acid, base, and fluoride; TBDMS ethers are less resis
tant to hydrolysis than the corresponding TIPS (triisopropylsilyl)
and TBDPS (t-butyldiphenylsilyl) ethers.
Table 2 Comparison of TBDMS, TIPS, and TBDPS rates of hydrolysis
by F - , H + , and O H - (t 1/2 ).
R = n-Bua
85
R = Cya,b
ROSiR'3
H+
OH-
H+
OH-
F-
TBDMS
TIPS
TBDPS
<1 min
18 min
244 min
1h
14 h
<4h
<4 min
100 min
360 min
26 h
44h
14 h
76 min
137 h
H+ refers to 1% HCl in 95% EtOH at 22C; OH- refers to 5% NaOH in

95% EtOH at 90 C. b F- refers to 2 equiv of n-Bu4NF in THF at 22 C.
The TBDMS group is also suitable for the protection of amines,

including heterocycles, carboxylic acids, and phenols. Other more
reactive reagents are also available for introduction of the TB
DMS group including t-Butyldimethylsilyl Trifluoromethanesulfonate, MTBSA, and TBDMS-imidazole. 1,7
Anion Trap. TBDMSCl is useful as an anion trapping reagent.
For example, TBDMSCl was found to be an efficient trap of the
lithio -phenylthiocyclopropane anion.8 When dichlorothiophene
was treated with 2 equiv of n-Butyllithium followed by 2 equiv of
TBDMSCl the di-TBDMS-thiophene was isolated.9 The lithium
anions of primary (eq 1) and secondary (eq 2) nitriles were trapped
with TBDMSC1 to give C,iV-disilyl- and N-silylketenimines in
excellent yields.10
(1)
(2)
Silyl Ketene Acetals. The lithium enolates of esters may be

trapped with TBDMSCl to prepare the corresponding ketene silyl
acetals.3 The resulting TBDMS ketene acetals are more stable
than the corresponding TMS ketene acetals and have a greater
preference for O- vs. C-silylation products. When TMSCl was
used to trap the enolate of methyl acetate, a 65:35 ratio of Oto C-silated products was obtained. In addition, O-(TMS) silyl
ketene acetals are thermally and hydrolytically unstable. However,
similar treatment of lithium enolates with TBDMSCl provided
the corresponding O-(TBDMS) silyl ketene acetals exclusively
(eq 3). The O-TBDMS ketene acetals generally survive extraction
from cold aqueous acid. Lithium Diisopropylamide was found
to be satisfactory for the preparation of the ester enolates. The
lower reactivity of TBDMSC1 requires that the enol silation be
performed at 0 C with added HMPA.12
(3)
A detailed study of the formation of (E)- and (Z)-silyl ketene

acetals was recently published.3d It was found that the formation
of silyl enolates does not correspond to simple kinetic vs. thermo
dynamic formation of the enolates. Formation of the ester enolates
occurred under kinetic control and a kinetic resolution accounted
for selective formation of (E)- and (Z)-silyl ketene acetals. Table 3
summarizes some of these results.
Table 3 Effects of Reaction Conditions on (Z):(E) Ratio of TBDMS
Silyl Ketene Acetal Formation of Ethyl Propionate
Ester: base
ratio
Base
1:1
1.05:1
1.2:1
1:1
1:1
1.1:1
LDA
LDA
LDA
LDA
LHMDS
LHMDS
Solvent
THF
THF
THF
THF
THF
THF
Additive
45%
23%
23%
23%
23%
DMPU
HMPA
HMPA
HMPA
HMPA
(Z):(E) field
Silyl ketene (%)
acetal ratio
6:94
98:2
93:7
85:15
>91:9
>95:5
90
80
65
80
85
60
Claisen Rearrangement. The first silyl ketene acetal Claisen

rearrangement was introduced in 1972 using TMS ketene acetals.
Since then, the silyl Claisen rearrangement using TBDMS ketene
acetals has found widespread use in organic synthesis. 13,14 One
advantage of the silyl ketene acetal Claisen rearrangement is that
the ketene acetal geometry may be predictably controlled (see
above). Two components of the reaction contribute to stereocontrol: the geometry of the silyl ketene acetal and the contribution
of boat vs. chair transition state. A useful variant of the Claisen
86
rearrangement involves the use of an enantiomerically pure silyl secondary alcohol prepared by Brook rearrangement of a
TBDMS-protected primary alcohol. In this reaction the stereo
chemistry at the silicon-bearing center is transferred to the Claisen
product.15 The (E)-enolate was prepared by treatment of the ester
with Lithium Hexamethyldisilazide (eq 4); the (Z)-enolate was
prepared by treatment of the ester with LDA (eq 5).15b As ex
pected, the (Z)- and (E)-silyl ketene acetals gave the corresponding
syn and anti Claisen products in good selectivity. The vinylsilane
was hydrolyzed to the alkene using 50% HBF4 in acetonitrile at
55 C.
be protected under acidic conditions as their TBDMS ethers by

treatment with -silyl enol ethers in polar solvents.
(7)
(8)
(4)
Aldol Reaction. The catalyst system TBDMSCl/InCl3 selec

tively activates aldehydes over acetals for aldol reactions with TB
DMS enol ethers.24 Acetals and aldehydes are activated towards
aldol reactions using TMSCl/InCl3 or Et3SiCl/InCl3 as catalysts
(eq 9).
(5)
(9)
The silyl ketene acetals of methyl -(allyloxy)acetates were

found to undergo [3,3]-sigmatropic rearrangement, whereas
the corresponding lithium enolates undergo [2,3]-sigmatropic
rearrangement.16 An interesting ring contraction based on the
TBDMS silyl ketene acetal Claisen rearrangement has also been
reported.17
TBDMS Enol Ethers.18 Enolates trapped with TBDMSCl to
prepare the corresponding enol ethers are more stable than the
corresponding TMS enol ethers.19 The potassium enolate of 2methylcyclohexanone, prepared by addition of Potassium Hy
dride to a solution of the ketone and TBDMSCl in THF at -78 C
followed by warming to rt, gave the thermodynamic enol ether
in a 56:44 ratio. In the presence of HMPA, the ratio improves to
98:2 (eq 6). This method works especially well with ketones with
a propensity for self-condensation.20
(6)
Potassium enolates derived from acylfulvalenes were trapped

with TBDMSCl but not TMSCl or diphenylmethylsilyl chloride.21
Interestingly, TBDMSCl was found to be compatible with CpK
anion at 78 C. TBDMS enol ethers have also been used as acyl anion equivalents.22 The TBDMS-silyl enol ethers of diketones (eq 7) and -keto esters (eq 8) may be prepared by mixing
them with TBDMSCl in THF with imidazole.23 Alcohols may
TBDMSCl as Cl- Source. TBDMSCl was used as a source of

chloride ion in the Lewis acid-assisted opening of an epoxide.25
The epoxide was treated with TBDMSCl and Triethylamine fol
lowed by Titanium Tetraisopropoxide and additional TBDMSCl
to give the trans chloride as the major product in 67 % yield (eq 10).
(10)
TBDMSCI-Assisted Reactions. Nitro aldol (Henry) reactions

have been reported to be promoted by TBDMSC1.26 To a THF so
lution of Tetra-n-butylammonium Fluoride is added sequentially
equimolar amounts of the nitro compound, aldehyde, and Et3N,
followed by an excess of TBDMSC1 (eq 11). Substitution of TMSC1 for TBDMSC1 reduces the yield of nitro aldol product. The
authors speculate that TBDMSC1 is responsible for activation of
the aldehyde while n-Bu4NF activates the nitro compound. In a
related method, primary and secondary nitro alkanes were treated
with LDA in THF followed by addition of TBDMSC1 to give the
corresponding silyl nitronates. The silyl nitronates reacted with
87
a variety of aliphatic and aromatic aldehydes which gave vicinal

nitro TBDMS aldol products.27
(11)
(14)
Reaction with Nucleophiles. TBDMSCl is the reagent of

choice for the preparation of other TBDMS-containing reagents.
For example, t-Butyldimethylsilyl Cyanide may be prepared by
the reaction of TBDMSCl and Potassium Cyanide in acetonitrile containing a catalytic amount of Zinc Iodide.28 TBDMSCN
has also been prepared by treatment of TBDMSCl with KCN
and 18-Crown-6 in CH2Cl2 at reflux and by treatment of TBDMSCl with Lithium Cyanide prepared in situ.29 t-Butyldimethylsilyl
Trifluoromethanesulfonate is prepared by treatment of TBDMSCl with Trifluoromethanesulfonic Acid at 60 C.30 Other nu
cleophiles, such as thiolates, also react with TBDMSCl.31 tButyldimethylsilyl Iodide was prepared by treatment of TBDMSCl with Sodium Iodide in acetonitrile.32 In contrast to THF cleav
age reactions using TMSI, the more stable TBDMS-protected pri
mary alcohol may be isolated from the reaction in eq 12.
(12)
Mannich Reaction. The Mannich reaction of N-methyl-1,3oxazolidine with 2-methylfuran was shown to proceed smoothly
in the presence of TBDMSCl and catalytic 1,2,4-Triazole in 61%
yield. Interestingly, this reaction failed with TBDMSOTf due to
the destruction of 2-methylfuran. The reaction proceeds with de
creased yield (31 %) in the absence of triazole. These reaction con
ditions allowed for the isolation of the TBDMS-protected alcohol
(eq 13).33
(15)
(16)
-Silyl Aldehydes. Initial attempts to isolate TMS-silylalde

hydes were unsuccessful due to the lability of the TMS group.
However, the -silyl aldehyde was prepared from the cyclohexyl
imine of acetaldehyde by treatment with LDA followed by TBDMSCl (eq 17). Typical of TBDMSCl trapping reactions of imines
and hydrazones, C-silylation was observed. The imine was hydrolyzed with HOAc in CH2Cl2 which gave the -silyl aldehyde.
These compounds, after treatment with organometallic reagents
such as Ethylmagnesium Bromide or Ethyllithium, may be elim
inated in a Peterson-like manner to give either cis or trans alkenes
(eq 18).38
(17)
(13)
Acid Chlorides. TBDMS esters, when treated with DMF and

Oxalyl Chloride in methylene chloride at 0C, give the corre
sponding acid chlorides in excellent yields under neutral condi
tions (eq 14).34 Similarly, N-carboxyamino acid anhydrides were
prepared via the intermediacy of an acid chloride prepared from
a TBDMS ester (eq 15).35
Conjugate Additions. When a mixture of TBDMSCl and a
-aryl enone (2:1) was added to Bu2CuCNLi2 at - 7 8 C, the
TBDMS group added 1,4 to the enone to give -silyl carbonyl
compounds (eq 16).36 N-TBDMS silyliminocuprates also add to
,-unsaturated carbonyl compounds.37
(18)
-Silyl Ketones. When SAMP or RAMP hydrazones were

treated with LDA followed by TBDMSCl, the corresponding silyl hydrazones were isolated. Ozonolysis of the hydrazone gave
Next Page
88
the enantiomerically enriched -silyl ketones (eq 19).39 Yields

for the overall process are 52-79% for the preparation of -silyl
ketones and 22-42% for the preparation of -silyl aldehydes. TBDMSOTf may also be used for quench of the SAMP/RAMP hydrazone enolate.
(22)
(19)
Acyl Silanes. Although acyl trimethylsilanes are known, they

are usually unstable and lead to poor diastereoselectivity in aldol
reactions.40 TBDMS acyl silanes, however, were prepared in 50%
yield from 1 -methoxy-1-lithiopropene in the presence of TMEDA
at rt (eq 20). The lithium enolates of TBDMS acyl silanes were
treated with aldehydes to give the corresponding aldol products
in reasonable yields.
N-Formylation. When secondary amines were treated with

TBDMSCl, DMAP, and Et3N in DMF the corresponding N-formyl
derivatives were formed (eq 23).43 It was found that the reaction
proceeds through a Vilsmeier type reagent formed by the reaction
of TBDMSC1 and DMF. It is possible that other TBDMS alkylation reactions, such as protection of alcohols in DMF, may proceed
through a similar DMF-derived Vilsmeier reagent.
(23)
(20)
N-Silyl Imines. When aldehydes were treated first with

tris(trimethylstannyl)amine followed by TBDMSCl, the corre
sponding N-TBDMS imines were isolated in good yields.44 These
silyl imines reacted with ester enolates to give -lactams (eq 24).
TBDMS acyl enones were prepared by treatment of an

ethoxyethyl (EE)-protected alkoxyallene with n-BuLi at 85 C
followed by treatment of resulting anion with TBDMSCl (eq 21).
Acid hydrolysis of the OEE group led to the TBDMS acyl enones
in good yield.41
(24)
Related Reagents. t-Butyldimethylsilyl Cyanide; N-(tButyldimethylsilyl)-N-methyltrifluoroacetamide;

t-Butyldiphenylchlorosilane; Chlorotriphenylsilane; t-Butyldimethylsilyl
Trifluorosulfonate; Triethylchlorosilane; Trimethylchlorosilane;
Triisopropylsilyl Chloride.
(21)
1.
Modified Amine Base. The regioselectivity of ketone

deprotonation was improved by the use of lithium tbutyldimethylsilylamide as base.42 The base was prepared by de
protonation of isopropylamine with n-BuLi in THF (eq 22). The
resulting anion was quenched with TBDMSC1 to give the amine
in 70% yield after distillation. Deprotonation of various ketones
using this amide base was found to be equally or more selective
than LDA. For example, the TBDMS-modified base gave a 62:38
ratio of kinetic to thermodynamic enolate, whereas LDA gave a
34:66 ratio with phenyl acetone.
2.
3.
4.
5.
(a) Corey, E. J.; Venkateswarlu, A. JACS 1972, 94, 6190. (b) Lalonde, M.;
Chan, T. H. S 1985, 817. (c) Greene, T. W.; Wuts, P. G. M. Protective
Groups in Organic Synthesis; Wiley: New York, 1991. (d) Colvin, E.
Silicon in Organic Synthesis; Butterworths: London, 1981.
Stork, G.; Hudrlik, P. F. JACS 1968, 90, 4462.
(a) Rathke, M. W.; Sullivan, D. F. SC 1973, 3, 67. (b) Rathke, M. W.;
Sullivan, D. F. TL 1973, 1297. (c) An interesting application of TBS silyl
ketene acetals as homo-Reformatsky reagents may be found in: Oshino,
H.; Nakamura, E.; Kuwajima, I. JOC 1985, 50, 2802. (d) Ireland, R. E.;
Wipf, P.; Armstrong, J. D., III JOC 1991, 56, 650.
For general papers comparing the stability of silanes containing various
alkyl groups on Si see: (a) Sommer, L. H.; Tyler, L. J. JACS 1954, 76,
1030. (b) Ackerman, E. ACS 1956, 10, 298; ACS 1957,11, 373.
Hernandez, O.; Chaudhary, S. K. TL 1979, 99.
Previous Page
t-BUTYLDIMETHYLSILYLTRIFLUOROMETHANESULFONATE
6. Cunico, R. F.; Bedell, L. JOC 1980, 45, 4797.
7. Mawhinney, T. P.; Madson, M. A. JOC 1982,47, 3336.
8. Wells, G. J.; Yan, T.-H.; Paquette, L. A. JOC 1984, 49, 3604.
9. Okuda, Y.; Lakshmikantham, M. V.; Cava, M. P. JOC 1991, 56, 6024.
10. Watt, D. S. SC 1974, 4, 127.
11. Chenard, B. L.; Van Zyl, C. M. JOC 1986, 3561.
12. Ireland, R. E.; Mueller, R. H. JACS 1972, 94, 5897.
13. Ireland, R. E.; Mueller, R. H.; Willard, A. K. JACS 1976, 98, 2868.
14. For other examples see (a) Mohammed, A. Y.; Clive, D. L. J. CC 1986,
588. (b) Kita, Y.; Shibata, N.; Miki, T.; Takemura, Y.; Tamura, O. CC
1990, 727. (c) Metz, P.; Mues, C. SL 1990, 97.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
(a) Ireland, R. E.; Varney, M. D. JACS 1984, 106, 3668. (b) Ireland, R.
E.; Daub, J. P. JOC 1981, 46, 479.
Raucher, S.; Gustavson, L. M. TL 1986, 27, 1557.
(a) Abelman, M. M.; Funk, R. L.; Munger, J. D., Jr. JACS 1982, 104,
4030. (b) Funk, R. L.; Munger, J. D., Jr. JOC 1984, 49, 4320.
For a review see: Brownbridge, P. S 1983, 1; S 1983, 29.
(a) Ireland, R. E.; Courtney, L.; Fitzsimmons, B. J. JOC 1983, 48, 5186.
(b) Piers, E.; Burmeister, M. S.; Reissig, H.-U. CJC 1986, 64, 180.
(a) Orban, J.; Turner, J. V.; Twitchin, B. TL 1984, 25, 5099. (b) Orban,
J.; Turner, J. V. TL 1983, 24, 2697. (c) Ireland, R. E.; Thompson, W. J.;
Mandel, N. S.; Mandel, G. S. JOC 1979, 44, 3583.
McLoughlin, J. I.; Little, R. D. JOC 1988, 53, 3624.
Trimitsis, G.; Beers, S.; Ridella, J.; Carlon, M.; Cullin, D.; High, J.;
Brutts, D. CC 1984, 1088.
Veysoglu, T.; Mitscher, L. A. TL 1981, 22, 1299.
Mukaiyama, T.; Ohno, T.; Han, J. S.; Kobayashi, S. CL 1991, 949.
Hudlicky, T.; Luna, H.; Olivo, H. F.; Andersen, C ; Nugent, T.; Price, J.
D. JCS(P1) 1991, 2907.
Fernandez, R.; Gasch, C ; Gomez-Sanchez, A.; Vflchez, J. E. TL 1991,
32, 3225.
Colvin, E. W.; Beck, A. K.; Seebach, D. HCA 1981, 64, 2264.
Rawal, V. H.; Rao, J. A.; Cava, M. P. TL 1985, 26, 4275.
(a) Gassman, P. G.; Haberman, L. M. JOC 1986, 57, 5010. (b) Mai, K.;
Patil, G. JOC 1986, 51, 3545.
Corey, E. J.; Cho, H.; Rcker, C ; Hua, D. H. TL 1981, 22, 3455.
Aizpurua, J. M.; Paloma, C. TL 1985, 26, 475.
(a) Nystrom, J.-E.; McCanna, T. D.; Helquist, P.; Amouroux, R. S 1988,
56. (b) Detty, M. R.; Seidler, J. D. JOC 1981, 46, 1283.
Fairhurst, R. A.; Heaney, H.; Papageorgiou, G.; Wilkins, R. F.; Eyley, S.
C. TL 1989, 30, 1433.
Wissner, A.; Grudzinskas, C. V. JOC 1978, 43, 3972.
Mobashery, S.; Johnston, M. JOC 1985, 50, 2200.
Amberg, W.; Seebach, D. AG(E) 1988, 1718.
(a) Murakami, M.; Matsuura, T.; Ito, Y. TL 1988, 29, 355. (b) Ager, D.
J.; Fleming, I.; Patel, S. K. JCS(P1) 1981, 2520.
Hudrlik, P. F.; Kulkarni, A. K. JACS 1981, 103, 6251.
(a) Lohray, B. B.; Enders, D. HCA 1989, 72,980. (b) Enders, D.; Lohray,
B.B. AG(E) 1987,26,351.
Schinzer, D. S 1989, 179.
Reich, H. J.; Kelly, M. J.; Olsen, R. E.; Holtan, R. C. T 1983, 39, 949.
Prieto, J. A.; Suarez, J.; Larson, G. L. SC 1988, 18, 253.
Djuric, S. W. JOC 1984, 49, 1311.
Busato, S.; Cainelli, G.; Panunzio, M.; Bandini, E.; Martelli, G.; Spunta,
G. SL 1991, 243.
Bret E. Huff
89
t-Butyldimethylsilyl
Trifluoromethanesulfonate1
[69739-34-0]
C 7 H 15 F 3 O 3 SSi
(MW 264.33)
(highly reactive silylating agent and Lewis acid capable of convert

ing primary, secondary, and tertiary alcohols 1b to the correspond
ing TBDMS ethers, and converting ketones2 and lactones 2a,3 into
their enol silyl ethers; promoting conjugate addition of alkynylzinc
compounds4 and triphenylphosphine5 to ,-enones; activation of
chromones in [4 + 2] cycloaddition reactions;6 rearrangement of
allylic tributylstannyl silyl ethers;7 activation of pyridine rings
toward Grignard reagents8 and transalkylation of tertiary amine
N-oxides;9 and transformation of N-t-butoxycarbonyl groups into
N-alkoxycarbonyl groups 10 )
Alternate Name: TBDMS trifiate.
Physical Data: bp 60 C/7 mmHg; colorless oil, d 1.151 g c m - 3 .
Solubility: sol most organic solvents such as pentane, CH 2 Cl 2 ,
etc.
Analysis ofReagent Purity: 1 HNMR(CDCl 3 ) 1.00(s, 9H,t-Bu),
0.45 (s, 6H, Me).
Form Supplied in: liquid; widely available.
Preparative Method: 1b to 24 g (0.16 mol) of tButyldimethylchlorosilane at 23 C under argon is added 14
mL (0.16 mol) of Trifluoromethanesulfonic Acid dropwise.
The solution is heated at 60 C for 10 h, at which time no further
hydrogen chloride evolves (removed through a bubbler). The
resulting product is distilled under reduced pressure: 34 g
(80% yield) of TBDMS trifiate; bp 60C/7 mmHg.
Handling, Storage, and Precautions: the material should be stored
under argon at 0 C. The compound has an unpleasant odor and
reacts rapidly with water and other protic solvents.
Silylation of Alcohols.1 Primary, secondary, and tertiary al

cohols are silylated by reaction with TBDMS trifiate in ex
cellent yields. For instance, treatment of t-butanol with 1.5
equiv of TBDMS trifiate and 2 equiv of 2,6-Lutidine in
CH 2 Cl 2 at 25 C for 10 min gives a 90% yield of (t-butoxy)-tbutyldimethylsilane.1b The following alcohols are similarly sily
lated in excellent yields (70-90%): 2-phenyl-2-propanol, endonorborneol, cis-2,2,4,4-tetramefhylcyclobutane-l,3-diol, and 9O-methylmaytansinol (converted to the 3-TBDMS derivative)
(eq l). 1 b
(1)
Formation of Enol Silyl Ethers. 2,3 Various sterically hindered

ketones have been converted into enol silyl ethers by treatment
with 1-2 equiv of TBDMS trifiate and 1.5 equiv of Triethylamine
90
t-BUTYLDIMETHYLSILYL TRIFLUOROMETHANESULFONATE
in CH2Cl2 or 1,2-dichloroethane at rt. A representative example

is depicted in eq 2.2a
(2)
Reactions of chiral -keto sulfoxides with 1.1 equiv of Lithium

Diisopropylamide in THF at -78 C followed by 1.2 equiv of
TBDMS triflate at - 7 8 C produce the corresponding (Z)-enol
silyl ethers (eq 3).2b
(3)
Trimethylsilyl Trifluoromethanesulfonate can effectively replace

TBDMS triflate.
(7)
Phosphoniosilylation.5 Cyclic enones treated with TB

DMS triflate and Triphenylphosphine in THF at rt pro
vide the corresponding
1-(3-t-butyldimethylsilyloxy-2cycloalkenyl)triphenylphosphonium triflates (eq 8) which,
upon lithiation with n-Butyllithium followed by Wittig reaction
with aldehydes, afford various conjuated dienes.5
(8)
R1 = H, R2 = Me; R1 = R2 = Me; R1 = H, R2 = Ph
Lactones have also been transformed into silyl ketene acetals

upon treatment with TBDMS triflate and triethylamine in CH2Cl2
(eqs 4 and 5).2a,3 In the case of 8a-vinyl-2-oxooctahydro-2H-11,4benzoxazine, the resulting silyl ketene acetal undergoes Claisen
rearrangement to provide the octahydroquinoline (eq 6).3
Silylation of Chromones.6 The preparation of A-tbutyldimethylsilyloxy-1-benzopyrylium triflate is carried

out by heating chromone and TBDMS triflate at 80 C for
1 h (without solvent) under nitrogen (eq 9).6b The silylated
chromones undergo addition reaction with enol silyl ethers and
2,6-lutidine,6b and [4 + 2]-type cycloaddition reactions with
a,P-unsaturated ketones in the presence of TBDMS triflate and
2,6-lutidine. An example of the cycloaddition reaction is shown
in eq 10.6a
(9)
(4)
(5)
(10)
(6)
Rearrangement of Allylic Tributylstannyl Silyl Ethers.7 Silyloxy allylic stannanes are isomerized with TBDMS triflate
to (Z)-7-silyloxy allylic stannanes (eq 11).7 The resulting al
lylic stannanes undergo addition reactions with aldehydes in
the presence of Boron Trifluoride Etherate to provide the 3-(rbutyldimethylsilyloxy)-4-hydroxyalkenes.7a
Conjugate Addition of Alkynylzinc Bromides.4 Alkynylzinc

bromides undergo conjugate addition with ,-unsaturated ke
(11)
tones in the presence of TBDMS triflate in ether-THF at -40C
to give the corresponding 1,4-adducts (54-96% yields). A rep
resentative example is illustrated in eq 7.4 Other trialkylsilyl
Activation of Pyridine.8 N-(t-Butyldimethylsilyl)pyridimum
triflates such as Triisopropylsilyl Trifluoromethanesulfonate or triflate, prepared from pyridine and TBDMS triflate in CH2Cl2
t-BUTYLDIPHENYLCHLOROSILANE
at rt, undergoes addition reactions with alkyl and aryl Grignard
reagents to give 4-substituted pyridines after oxidation with oxy
gen (eq 12).8 Only about 1 % of the 2-substituted pyridines were
formed in the cases studied.
(12)
Transalkylation of Tertiary Amine N-Oxides.9 N-(tButyldimethylsilyloxy)-N-methylpiperidinium trifiate is quanti

tatively formed from the reaction of N-methylpiperidine N-oxide
(eq 13).9b The resulting amine salts derived from various
trialkylamine N-oxides undergo transalkylation by treatment
with Methyllithium in THF at 0 C followed by alkyl halides and
Tetra-n-butylammonium Fluoride in a sealed tube at 110C for
10 h, to afford trisubstituted amines (eq 14).9a
91
6.
(a) Lee, Y.; Iwasaki, H.; Yamamoto, Y.; Ohkata, K.; Akiba, K. H 1989,
29, 35. (b) Iwasaki, Ft.; Kume, T.; Yamamoto, Y.; Akiba, K. TL 1987,
28, 6355.
7. (a) Marshall, J. A.; Welmaker, G. S. JOC 1992, 57, 7158. (b) Marshall,
J. A.; Welmaker, G. S. TL 1991, 32, 2101. (c) Marshall, J. A.; Welmaker,
G. S. SL 1992, 537.
8. Akiba, K.; Iseki, Y.; Wata, M. TL 1982, 23, 3935.
9. (a) Tokitoh, N.; Okazaki, R. CL 1984, 1937. (b) Okazaki, R.; Tokitoh,
N. CC 1984, 192.
10. Sakaitani, M.; Ohfune, Y. TL 1985, 26, 5543.
Duy H. Hua & Jinshan Chen

Kansas State University, Manhattan, KS, USA
t-Butyldiphenylchlorosilane1
(13)
[58479-61-1]
C16H19ClSi
(MW 274.86)
(14)
Interconversion of N-Boc Group into N-Alkoxycarbonyl

Group. 10 Treatment of t-butyl alkylcarbamates with 1.5 equiv
of TBDMS trifiate and 2 equiv of 2,6-lutidine in CH 2 Cl 2 at rt for
about 15 min furnishes the corresponding TBDMS carbamates
(eq 15).10 Desilylation of these silyl carbamates with aqueous
fluoride ion gives excellent yields of the corresponding primary
amines. The silyl carbamates are also converted into other Nalkoxycarbonyl derivatives by treatment with TBAF and alkyl
halides in THF at 0C (82-88% yields).10
(15)
Related
Reagents. t-Butyldimethylchlorosilane; N-(tButyldimethylsilyl)-N-methyltrifluoroacetarnide;
t-Butyldimethylsilyl Perchlorate; Triethyl Trifluoromethanesulfonate;
TrimethylsilylTrifluoromethanesulfonate.
1.
(a) Stewart, R. R; Miller, L. L. JACS 1980, 702, 4999. (b) Corey, E. J.;
Cho, H.; Rucker, C ; Hua, D. H. TL 1981, 22, 3455. (c) For a review of
trialkylsilyl triflates: Emde, H.; Domsch, D.; Feger, H.; Frick, U.; Gotz,
A.; Hergott, H. H.; Hofmann, K.; Kober, W.; Krageloh, K.; Oesterle, X;
Steppan, W.; West, W.; Simchen, G. S 1982, 1.
2.
(a) Mander, L. N.; Sethi, S. P. TL 1984, 25, 5953. (b) Solladie, G.;
Mangein, N.; Morreno, I.; Almario, A.; Carreno, M. C ; Garcia-Ruano,
J. L.TL 1992, 35,4561.
3.
Angle, S. R.; Breitenbucker, J. G.; Arnaiz, D. O. JOC 1992, 57, 5947.
4.
Kim, S.; Lee, J. M. TL 1990, 31, 7627.
5.
Kozikowski, A. P.; Jung, S. H. JOC 1986, 57, 3400.
(reagent for the temporary protection of hydroxy groups as their

t-butyldiphenylsilyl ethers; selectivity can be obtained for pri
mary vs. secondary hydroxy groups; other protection (carbonyl,
amine, etc.) is also possible;2 deprotection is conveniently effected
with fluoride ion, strong acid, or base; the TBDPS ether group
is compatible with a large number of organic functional group
transformations, 1-3 in nucleoside chemistry,1 as well as in numer
ous examples in which polyfunctional molecules are chemically
manipulated4)
Alternate Name: TBDPS-C1.
Physical Data: colorless liquid, bp 93-95 C/0.015 mmHg; nD20
1.5680; d 1.057 g c m - 3 .
Solubility: miscible in most organic solvents.
Form Supplied in: colorless liquid 98%.
Preparative Method: a dry 1 L, three-necked round bottomed flask
is equipped with a magnetic stirring bar, a 500 mL equalizing
dropping funnel fitted with a rubber septum, a reflux condenser,
and nitrogen inlet tube. The flask is flushed with nitrogen, then
charged with 127 g (0.5 mol) of diphenyldichlorosilane in 300
mL of redistilled pentane. A solution of t-Butyllithium in pentane (500 mL, 0.55 mol), is transferred under nitrogen pres
sure to the dropping funnel using a stainless steel, double-tip
transfer needle. This solution is slowly added to the contents
of the flask and when the addition is complete, the mixture
is refluxed 30 h under nitrogen with stirring. The suspension
is allowed to cool to rt, the precipitated lithium chloride is
rapidly filtered through a pad of Celite, and the latter is washed
with 200 mL of pentane. The solvent is removed by evapora
tion, and the colorless residue is distilled through a short (10
cm), Vigreux column, to give 125-132 g of the colorless title
compound.
Handling, Storage, and Precautions: the reagent is stable when
protected from moisture and protic solvents. A standard M
solution of the reagent can be prepared in anhyd DMF and
92
t-BUTYLDIPHENYLCHLOROSILANE
kept at 0C under argon in an amber bottle. Use in a fume

hood.
Preparation of t-Butyldiphenylsilyl Ethers and Related
Transformations. A standard protocol1 involves the addition of
the reagent (1.1 equiv) to a solution of the alcohol (1 equiv) and
Imidazole (2 equiv) in DMF at 0 C or at room temperature. When
silylation is complete, the solution is diluted with water and ether
or dichloromethane and the organic layer is processed in the usual
way. In some instances the addition of 4-Dimethylaminopyridine
(DMAP) can enhance the reaction rate.5,6 Selective protection of
the primary hydroxy group in carbohydrate derivatives has been
achieved using this reagent and Poly(4-vinylpyridine) in CH2Cl2
or THF in the presence of Hexamethylphosphoric Triamide.7
Enol t-butyldiphenylsilyl ethers are easily formed by trapping of
enolates with the chloride.8 Amines can be selectively converted
into the corresponding primary t-butyldiphenylsilylamines essen
tially under the same conditions.9 t-Butyldiphenylsilyl cyanohydrins are prepared in the presence of Potassium Cyanide, Zinc
Iodide, and a carbonyl compound.10
Selectivity and Compatibility of O- and N-t-Butyldiphenyl
Silyl Derivatives. The O-t-butyldiphenylsilyl ether protective
group offers some unique advantages and synthetically useful
features compared to other existing counterparts.1,2 Silylation
of a primary hydroxy group takes place in preference to a sec
ondary, giving products that are often crystalline, and detectable
on TLC plates under UV light, because of the presence of a strong
chromophore. The TBDPS group is compatible with a variety of
conditions1 used in synthetic transformations such as hydrogenolysis (Pd(OH)2, C/H2, etc.), O-alkylation (NaH, DMF, halide),
de-O-acylation (NaOMe, NH4OH, K2CO3/MeOH), mild chem
ical reduction with hydride reagents, carbon-carbon bond for
mation with organometallic reagents, transition metal-mediated
reactions, Wittig reactions, etc. These reactions were tested dur
ing the total synthesis of thromboxane B211 for which the TBDPS
group was originally designed. Subsequently, numerous related
organic transformations have been carried out in the presence of
TBDPS ethers in the context of natural product synthesis3,4 and
functional group manipulations.2 It is distinctly more acid stable
than the O-trityl, O-THP, and OTBDMS groups, and is virtually
unaffected under conditions that cause complete cleavage of these
groups (50% HCO2H, 2-6 h; 50% aq TEA, 15 min; HBr/AcOH,
0C, few min; 80% aq acetic acid, few h).1 It is also compat
ible with conditions used for the acid-catalyzed formation and
hydrolysis of acetal groups and in the presence of some Lewis
acids (e.g. TMSBr,12 BCl3SMe2,13 Me2AlCl,8 etc.). The monoTBDPS derivative of a primary amine9 is stable to base, as well as
to alkylating and acylating reagents. Thus a secondary amine can
be acylated in the presence of a primary t-butyldiphenylsilylamino
group.
Deprotection.1,2 The O-TBDPS group can be cleaved under

the following conditions: Tetra-n-butylammonium Fluoride in
THF at rt; variations of F- -catalyzed reactions (e.g. F-/AcOH;
HF/pyridine;14 HF/MeCN,15 etc.); aqueous acids and bases1 (1 N
HC1, 5 N NaOH, aq methanolic NaOH or KOH); ion exchange
resins;7 Potassium Superoxide, Dimethyl Sulfoxide, 18-Crown6.16 Selective cleavage of a TBDPS ether in the presence of a
TBDMS ether in carbohydrate derivatives involves treatment with
Sodium Hydride/HMPAat 0 C.17 Although the O-TBDPS group
is stable to most hydride reagents, Lithium Aluminum Hydride
reduction of an amide group has resulted in the cleavage18 of an ad
jacent O-TBDPS ether, possibly via internal assistance. TBDPSamines are cleaved by 80% AcOH or by HF/pyridine.9
Related Reagents. t-Butyldimethylchlorosilane; t-Butyldimethylsilyl Trifluoromethanesulfonate; Chlorotriphenylsilane;
Triisopropylsilyl Chloride.
1. Hanessian, S.; Lavallee, P. CJC 1975, 53, 2975; Lavalle, P. Ph.D. Thesis,
Universit de Montral, 1977.
3. Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis; Wiley: New
York, 1989.
4. Hanessian, S. The Total Synthesis of Natural Products: The Chiron
Approach; Pergamon: Oxford, 1983.
5. Ireland, R. E.; Obrecht, D. M. HCA 1986, 69, 1273.
6. Chaudhary, S. K.; Hernandez, O. TL 1979, 99.
7. Cardillo, G.; Orena, M.; Sandri, S.; Tomasini, C. CI(L) 1983, 643.
8. Horiguchi, Y.; Suehiro, I.; Sasaki, A.; Kuwajima, I. TL 1992, 34, 6077.
9. Overman, L. E.; Okazaki, M. E.; Mishra, P. TL 1986, 27, 4391.
10. Duboudin, F.; Cazeau, P.; Moulines, F.; Laporte, O. S 1982, 212.
11. Hanessian, S.; Lavalle, P. CJC 1981, 59, 870.
12. Hanessian, S.; Delorme, D.; Dufresne, Y. TL 1984, 25, 2515.
13.
14.
15.
16.
17.
18.
Congreve, M. S.; Davison, E. C.;Fuhry, M. A.M.; Holmes, A. B.; Payne,

A. N.; Robinson, R. A.; Ward, S. E. SL 1993, 663.
Nicolaou, K. C ; Seitz, S. P.; Pavia, M. R.; Petasis, N. A. JOC 1979, 44,
4011.
Ogawa, Y; Nunomoto, M.; Shibasaki, M. JOC 1986, 51, 1625.
Torisawa, Y.; Shibasaki, M.; Ikegami, S. CPB 1983, 31, 2607.
Shekhani, M. S.; Khan, K. M.; Mahmood, K.; Shah, P. M.; Malik, S. TL
1990, 31, 1669.
Rajashekhar, B.; Kaiser, E. T. JOC 1985, 50, 5480.
University
of Montreal,
Stephen Hanessian
Quebec,
Canada
N,N'-CARBONYLDIIMIDAZOLE
93
catalytic amount of the alkoxide itself, allows rapid and complete

formation of the ester at room temperature.2 The base catalyst
must of course be added after formation of (2) from the acid is
complete, as indicated by cessation of evolution of carbon dioxide.
N,N' -Carbonyldiimidazole1
(1)
[530-62-1]
C7H6N4O
(MW 162.15)
(reagent for activation of carboxylic acids;1 synthesis of esters,2

amides, 3 peptides,4 aldehydes,5 ketones,6 -keto thioesters,7
tetronic acids; 8 ureas, 9 isocyanates,10 carbonates;9 halides
from alcohols; 11 glycosidation;12 dehydration 13-16 )
Solubility: no quantitative data available. Inert solvents such as
THF, benzene, CHCl 3 , DMF are commonly used for reactions.
Form Supplied in: commercially available white solid.
Analysis of Reagent Purity: purity can be determined by measur
ing the amount of CO 2 evolved on hydrolysis.
Preparative Methods: prepared by mixing phosgene with four
equivalents of imidazole in benzene/THF.17
Purification: may be purified by recrystallization from hot, anhy
drous THF with careful exclusion of moisture.17
Handling, Storage, and Precautions: moisture sensitive; reacts
readily with water with evolution of carbon dioxide. May be
kept for long periods either in a sealed tube or in a desiccator
over P 2 O 5 .
Activation of Carboxylic Acids: Synthesis of Acyl Imida

zoles. N,N'-Carbonyldiimidazole (1) converts carboxylic acids
into the corresponding acylimidazoles (2) (eq 1). 1 The method
can be applied to a wide range of aliphatic, aromatic, and hetero
cyclic carboxylic acids, including some examples (such as formic
acid and vitamin A acid) where acid chloride formation is diffi
cult. The reactivity of (2) is similar to that of acid chlorides, but
the former have the advantage that they are generally crystalline
and easily handled. Isolation of (2) is simple, but often unneces
sary; further reaction with nucleophiles is usually performed in
the same reaction vessel. Conversion of (2) into acid chlorides
(via reaction with HCl), 18 hydrazides,3 hydroxamic acids,3 and
peroxy esters 19 have all been described. Preparation of the more
important carboxylic acid derivatives is described below.
Esters from Carboxylic Acids. Reaction of equimolar
amounts of carboxylic acid, alcohol, and (1) in an inert sol
vent (e.g. THF, benzene, or chloroform) results in ester forma
tion (eq 2). Since alcoholysis of the intermediate acylimidazole is
relatively slow, the reaction mixture must be heated at 60-70 C
for some time. However, addition of a catalytic amount of a base
such as Sodium Amide to convert the alcohol to the alkoxide, or a
(2)
Esters of tertiary alcohols may not be prepared from car

boxylic acids containing acidic -protons using this modi
fied procedure, since deprotonation and subsequent conden
sation, competes. However, the use of stoichiometric 1,8Diazabicyclo[5.4.0]undec-7-ene as base has been shown to pro
vide good yields of t-butyl esters even for acids with acidic protons (eq 3). 20 This procedure was unsuccessful for pivalic acid
or for N-acyl--amino acids.
(3)
An alternative approach to increasing the rate of esterification is

to activate further the intermediate (2). N-Bromosuccinimide has
been used for this purpose,21 but unsaturation in the carboxylic
acid or alcohol is not tolerated. More generally useful is the addi
tion of an activated halide, usually Allyl Bromide, to a chloroform
solution of (1) and a carboxylic acid, resulting in formation of the
acylimidazolium salt (3) (eq 4).22 Addition of the alcohol and stir
ring for 1-10 h at room temperature or at reflux affords good yields
of ester in a one-pot procedure. These conditions work well for
the formation of methyl, ethyl, and t-butyl esters of aliphatic, aro
matic, and ,-unsaturated acids. Hindered esters such as t-butyl
pivalate can be prepared cleanly (90% yield). The only limita
tion is that substrates must not contain functionality that can be
alkylated by the excess of the reactive halide.
(4)
Since the purity of commercial (1) may be variable due to its wa

ter sensitivity, it is common to employ an excess in order to ensure
complete conversion of the carboxylic acid to the acylimidazole.
It has been suggested that alcohols react faster with residual (1)
than with the acylimidazole (2), thus reducing the yield of ester.
A procedure has been developed for removal of excess (1) before
addition of the alcohol.23
94
Macrolactonization has been accomplished using (1).24 Thiol

and selenol esters can also be prepared in one pot from carboxylic
acids using (1);25 reaction of the intermediate (2) with aromatic
thiols or selenols is complete within a few minutes in DMF, while
aliphatic thiols require a few hours. Formation of the phenylthiol
ester of N-Cbz-L-phenylalanine was accompanied by only slight
racemization. N,N'-Carbonyldi-sym-triazine can be used in place
of (1), with similar results.
Amides from Carboxylic Acids: Peptide Synthesis.
Analogous to ester formation, reaction of equimolar amounts of a
carboxylic acid and (1) in THF, DMF, or chloroform, followed by
addition of an amine, allows amide bond formation.3 The method
has been applied to peptide synthesis (eq 5).4 One equivalent of
(1) is added to a 1 M solution of an acylamino acid in THF, fol
lowed after 1 h by the desired amino acid or peptide ester. The
amino acid ester hydrochloride may be used directly instead of
the free amino acid ester. An aqueous solution of the amino acid
salt can even be used, but yields are lower.
(6)
C- Acylation of Active Methylene Compounds. Treatment of

an acylimidazole, derived from a carboxylic acid and (1), with the
magnesium salt of a malonic or methylmalonic half thiol ester re
sults in C-acylation under neutral conditions (eq 7).7 The presence
of secondary hydroxyl functionality in the carboxylic acid is tol
erated, but primary alcohols require protection. Magnesium salts
of malonic esters may be used equally effectively. Intramolecular
C-acylation of ketones has also been reported.33
(7)
(5)
As is the case in esterification reactions, the presence of unreacted (1) can cause problems since the amine reacts with this as
quickly as it does with the acylimidazole, forming urea byprod
ucts that can be difficult to separate. Use of exactly one equivalent
of (1) is difficult due to its moisture sensitivity, and also because
of the tendency of some peptides or amino acids to form hydrates.
Paul and Anderson solved this problem by use of an excess of
(1) to form the acylimidazole, then cooling to 5 C and adding a
small amount of water to destroy the unreacted (1) before addition
of the amine.26
For the sensitive coupling of Cbz-glycyl-L-phenylalanine and
ethyl glycinate (the Anderson test), Paul and Anderson reported
the level of racemization as 5% using THF as solvent at 10C,
but as <0.5% in DMF.4 Performing the same coupling reaction at
room temperature, Beyerman and van den Brink later claimed that
the degree of racemization in DMF was in fact as high as 17%,
and reported better results (no detectable racemization) using the
related reagent N,N'-carbonyl di-sym-triazine in place of (1).27 In
a comparative study of several reagents, Weygand and co-workers
also observed extensive racemization using (1).28 In the formation
of tyrosine esters, Paul reported that the mixed anhydride method
is to be preferred to use of (1), since O-acylation is a major side
reaction with the latter.29
Aldehydes and Ketones from Carboxylic Acids. Reduction
of the derived acylimidazole (2) with Lithium Aluminum Hy
dride achieves conversion of an aliphatic or aromatic carboxylic
acid to an aldehyde (eq 6).5 Diisobutylaluminum Hydride has also
been used, allowing preparation of -acylamino aldehydes from
N-protected amino acids.30 Similarly, reaction of (2) with Grignard reagents affords ketones,6 with little evidence for formation
of tertiary alcohol.
Reaction of acylimidazoles with the appropriate carbon nucleophile has also been used for the preparation of -nitro ketones31
and -keto sulfoxides.32
Tetronic Acids. A synthesis of tetronic acids reported by Smith

and co-workers relies on the reaction between (1) and the dianion
derived from an -hydroxy ketone (eq 8).8 The reaction proceeds
in moderate yield (31-57%).
(8)
Ureas and Carbonates. Reagent (1) may be used as a direct

replacement for the highly toxic Phosgene in reactions with alco
hols and amines. Reaction of (1) with two equivalents of a primary
aliphatic or aromatic amine at room temperature rapidly yields a
symmetrical urea (eq 9).9 If only one equivalent of a primary
amine is added to (1), then the imidazole-N-carboxamide (4) is
formed (eq 10). These compounds can dissociate into isocyanates
and imidazole, even at room temperature, and distillation from
the reaction mixture provides a useful synthesis of isocyanates
(eq 10).10 Secondary amines react only at one side of (1) at
room temperature, again giving the imidazole-N-carboxamide of
type (4).
(9)
(10)
Reaction of (1) with one equivalent of an alcohol provides the

imidazole-N-carboxylic ester (5) (eq 11).34Further treatment with
another alcohol or phenol yields an unsymmetrical carbonate;
alternatively, reaction with an amine affords a carbamate

(eq 12).34
95
decarboxylation, to give 2-aryl acetonitriles, upon reaction

with (1).16
(11)
(12)
(14)
Heating (1) with an excess of an alcohol or phenol gives the

symmetrical carbonate.9 This reaction can be accelerated dramati
cally by the presence of catalytic base (e.g. Sodium Ethoxide). Re
action under these conditions is so exothermic even at room tem
perature that only t-butanol stops at the imidazole-N-carboxylic
ester stage.
1,2-Diamines, 1,2-diols, or 1,2-amino alcohols react with (1)
to form cyclic ureas,35 carbonates,36 or oxazolidinones,35 respec
tively. In the case of cyclohexane-1,2-diols, the cis-diol reacts
much more rapidly than the trans, as would be expected.36 Thiazolidinones can also be prepared using (1).37
Halides from Alcohols. Treatment of an alcohol with (1) and
an excess (at least three equivalents) of an activated halide results
in its conversion to the corresponding halide (eq 13).11 Any halide
more reactive than the product halide may be used, but in prac
tice Allyl Bromide or Iodomethane give best results as they are
effective and readily removed after the reaction. Acetonitrile is
the best solvent and yields are generally high (>80%). Bromide or
iodide formation work well, but not chlorination. Optically active
alcohols are racemized.
(13)
Glycosidation. A mild glycosidation procedure involving (1)

has been reported by Ford and Ley.12 A carbohydrate derivative
in ether or dichloromethane reacts with (1) through the anomeric
C-l -hydroxyl to give the (1-imidazolylcarbonyl) glycoside (IMG)
(6) (eq 14). Isolation of (6) is not usually necessary; treatment with
one equivalent of an alcohol and two equivalents of Zinc Bromide
in ether at reflux gives the glycoside. Generally, higher : ratios
are obtained for more hindered alcohols and when ether is used
as solvent rather than the less polar dichloromethane. Along with
the fact that the : ratio is independent of the configuration of
(6), this suggests an Swl-type mechanism. In contrast, treatment
of (6) with Acetyl Chloride provides the anomeric chloride with
essentially exclusive inversion.
Dehydration. Reagent (1) has been used for the dehydration
of various substrates, including aldoximes (to give nitriles),13
-hydroxy amino acids,14 and -hydroxy sulfones.15 3-Aryl2-hydroxyiminopropionic acids undergo dehydration and
Related Reagents. N,N'-Carbonyldi-syn-triazine.
1. Staab, H. A. AG(E) 1962,1, 351.

2. Staab, H. A.; Mannschreck, A. CB 1962, 95,1284 (CA 1962,57,5846d).
3. Staab, H. A.; Lking, M ; Diirr, F. H. CB 1962, 95, 1275 (CA 1962, 57,
5908a).
4. Paul, R.; Anderson, G. W. JACS 1960, 82, 4596.
5. Staab, H. A.; Braunling, H. LA 1962, 654, 119 (CA 1962, 57, 5906c).
6. Staab, H. A.; Jost, E. LA 1962, 655, 90 (CA 1962, 57, 15 090g).
7. Brooks, D. W.; Lu, L. D.-L.; Masamune, S. AG(E) 1979, 18, 72.
8. Jerris, P. J.; Wovkulich, P. M.; Smith, A. B., III. TL 1979, 4517.
9. Staab, H. A. LA 1957, 609, 75 (CA 1958, 52, 7332e).
10. Staab, H. A.; Benz, W. LA 1961, 648, 72 (CA 1962, 57, 4649g).
11. Kamijo, T.; Harada, H.; Iizuka, K. CPB 1983, 31, 4189.
12. Ford, M. J.; Ley, S. V. SL 1990, 255.
13. Foley, H. G.; Dalton, D. R. CC 1973, 628.
14. Andruszkiewicz, R.; Czerwinski, A. S 1982, 968.
15. Kang, S.-K.; Park, Y.-W.; Kim, S.-G.; Jeon, J.-H. JCS(P1) 1992, 405.
16. Kitagawa, T.; Kawaguchi, M.; Inoue, S.; Katayama, S. CPB 1991, 39,
3030.
17. Staab, H. A.; Wendel, K. OS 1968, 48, 44.
18. Staab, H. A.; Datta, A. P. AG(E) 1964, 3, 132.
19. Hecht, R.; Ruchardt, C. CB 1963, 96, 1281 (CA 1963, 59, 1523h).
20. Ohta, S.; Shimabayashi, A.; Aono, M.; Okamoto, M. S 1982, 833.
21. Katsuki, T. BCJ 1976, 49, 2019.
22. Kamijo, T.; Harada, H.; Iizuka, K. CPB 1984, 32, 5044.
23. Morton, R. C ; Mangroo, D.; Gerber, G. E. CJC 1988, 66, 1701.
24. (a) White, J. D.; Lodwig, S. N.; Trammell, G. L.; Fleming, M. P. TL
1974, 3263. (b) Colvin, E. W.; Purcell, T. A.; Raphael, R. A. CC 1972,
1031.
25. Gais, H.-J. AG(E) 1977, 16, 244.
26. Paul, R.; Anderson, G. W. JOC 1962, 27, 2094.
27. Beyerman, H. C.; Van Den Brink, W. M. RTC 1961, 80, 1372.
28.
29.
30.
31.
32.
33.
34.
Weygand, F.; Prox, A.; Schmidhammer, L.; Konig, W. AG(E) 1963, 2,

183.
Paul, R. JOC 1963, 28, 236.
Khatri, H.; Stammer, C. H. CC 1979, 79.
Baker, D. C.; Putt, S. R. S 1978, 478.
Ibarra, C. A.; Rodriguez, R. C; Monreal, M. C. R; Navarro, F. J. G.;
Tesorero, J. M. JOC 1989, 54, 5620.
Garigipati, R. S.; Tschaen, D. M.; Weinreb, S. M. JACS 1985,107,7790.
Staab, H. A. LA 1957, 609, 83 (CA 1957, 52, 16341e).
96
CHLOROMETHYL METHYL ETHER
35. Wright, W.B., Jr. JHC 1965, 2,41.

36. Kutney, J. P.; Ratcliffe, A. H. SC 1975, 5, 47.
37. D'lschia, M.; Prota, G.; Rotteveel, R. C ; Westerhof, W. SC 1987, 17,
1577.
In the orthoester route when unsymmetrical diols are used, the

most hindered alcohol is protected, in contrast to the normal meth
ods which are expected to protect the least hindered alcohol. Diols
capable of forming a stannylene derivative are efficiently monoprotected (eq 3). 17
Alan Armstrong
University of Bath, UK
(3)
[107-30-2]
C 2 H 5 ClO
(MW 80.51)
(used for the protection of alcohols, phenols, acids, amines, -keto

esters and thiols. A one-carbon synthon for alkylation of aromatics
and active methylene derivatives)
Alternate Name: methoxymethyl chloride; MOMCl.
Physical Data: bp 55-57 C; d 1.060 g c m - 3 .
Solubility: sol nearly all organic solvents.
Form Supplied in: available as a technical grade liquid.
Preparative Methods: besides the original method2 which uses
HC1, formalin, and methanol, MOMCl can be prepared from
methoxyacetic acid3 or methylal (Dimethoxymethane).4
Handling, Storage, and Precautions: MOMCl is an OSHAregulated carcinogen and depending on the method of prepa
ration may contain bis(chloromethyl) ether, which is a more
potent carcinogen. This reagent should be handled in a fume
hood.
Protection of Alcohols. Treatment of an alcohol with MOMCl

and i-Pr2NEt (0 C, 1 h 25 C, 8 h, 86% yield) 5 is the most com
monly employed procedure for introduction of the MOM group.
Formation of the sodium alkoxide and reaction with MOMCl is
also very effective.6 This method is particularly useful for the
protection of the enol of -keto esters.7 Because of the car
cinogenicity of MOMCl, a number of methods for the intro
duction of the MOM group have been developed which do not
rely on the chloride. The methods are all based on the use of
CH 2 (OMe) 2 with various catalysts such as P 2 O 5 , 8 Me 3 SiI, 9 Nation
H,10 CH 2 =CHCH 2 SiMe 3 /TMSOTf/P 2 O 5 , 11 FeCl 3 , 12 Montmorillonite clay (H + ), 1 3 or TsOH/LiBr.14 In the last case, 1,3-diols give
methylene acetals. It is often difficult to achieve monoprotection
of 1,3-diols but some success has been recorded, as illustrated in
eqs 1-3. 15-17
(1)
(2)
Cleavage of MOM Ethers. Since the MOM group is an acetal,

it can be cleaved using acid hydrolysis. In general, aqueous acid
in an organic cosolvent has proven to be effective. 18-21 Use of the
weak acidPyridiniump-Toluenesulfonate inrefluxing t-BuOH or
2-butanone is particularly effective for cleavage of MOM ethers
of allylic alcohols. 22 MEM ethers are also cleaved under these
conditions. Eq 4 shows that a MOM group can be cleaved with
anhydrous Trifluoroacetic Acid in the presence of an acetonide
which is normally cleaved with aqueous acid.23
(4)
Catecholborane halides, particularly the bromide (BBromocatecholborane),

are effective reagents for the
cleavage of MOM ethers. The bromide cleaves the
following groups in the order: MOMOR MEMOR > tB o o C b z t-BuOR > BnOR > allylOR > t-BuO 2 CR secondary
alkylOR > BnO 2 CR > primary alkylOR alkylO 2 CR. The tbutyldimethylsilyl (TBDMS) group is stable to this reagent.
The chloride is less reactive and thus may be more useful for
achieving selectivity in multifunctional substrates. Yields are
generally >83%. 24 A variety of other boron based reagents
have been developed which are useful for MOM ether cleavage.
The use of Bromobis(isopropylthio)borane
(eq 5) 25 has the
advantage that 1,2- and 1,3-diols do not give formyl acetals as is
sometimes the case in cleaving MOM groups with neighboring
hydroxyl groups. 26 The reagent also cleaves MEM groups and
under basic conditions affords the i-PrSCH2OR derivatives. With
Bromodimethylborane, MEM and MTM ethers are also cleaved,
but esters are not affected.27
(5)
Bromotrimethylsilane, a reagent similar to but not as powerful

as lodotrimethylsilane, will cleave MOM ethers as well as ace
tonide, THP, trityl, and t-BuMe 2 Si groups, but the reagent will
not cleave esters, methyl and benzyl ethers, t-butyl-diphenylsilyl
ethers, and amides. One example is shown in eq 6.28
(6)
Boron Trifluoride Etherate in the presence of Thioanisole,29

Magnesium Bromide in the presence of butanethiol,30
Triphenylcarbenium
Tetrafluoroborate,31
and
Lithium
32
Tetrafluoroborate
are also useful for cleavage of the MOM
group. The action of lithium tetrafluoroborate is unique (eq 7)
and the mechanism for cleavage is not well understood.
(7)
Protection of Phenols. The reaction of MOMCl with a phe

nol under phase-transfer conditions works well to give pheno
lic MOM ethers 33 and will selectivity protect a phenol in the
presence of an alcohol.34 The more classical Williamson ether
synthesis35 also provides excellent results, but may require the
addition of a crown ether to enhance the nucleophilicity of the
phenolate anion.36 As in the case of alcohol protection, alter
natives using methylal have been developed for phenol protec
tion which do not rely on the carcinogenic MOMCl. 37 Phenolic
silyl ethers can be converted directly to MOM ethers by reaction
with TASF (Tris(dimethylamino)sulfonium
Difluorotrimethylsilicate) and MOMCl. 38
Cleavage of Phenolic MOM Ethers. Again, mild
acid 37 ' 39 is used for cleavage, but other alternatives such
as Sodium Iodide/acetone/cat. HCl/50C, 40 Diphosphorus
Tetraiodide/CH2Cl2/0 C rt,41 or TMSBr/CH 2 Cl 2 42 are also
effective.
Protection of Thiols. Lithium 43 and potassium44 thiolates re
act with MOMCl to form the thioethers. The use of MOMCl can
be avoided by the reaction of the zinc thiolate with methylal.45
Protection of Acids. The reaction of MOMCl with an acid
in the presence of a base affords the MOM ester. 46-48 As with
the thiols, the zinc carboxylate reacts with methylal to afford the
MOM ester.49 MOM esters are quite acid sensitive and are unstable
to silica gel chromatography.50 The MOM ester is easily cleaved
with acid, MgBr2,51 or Me 3 SiBr containing a trace of MeOH. 52
97
the amine or amide with MOMCl in the presence of a base

such as Diisopropylethylamine ,53 Sodium Hydride,54 LiH, Potassium t-Butoxide,55 or Sodium Hydroxide.56 These derivatives are
cleaved with Hydrogen Chloride/EtOH53 or Boron Tribromide .55
To hydrolyze scopolamine without formation of the rearranged
product (1) it was necessary to protect the amine nitrogen as the
methoxy-methochloride as illustrated in eq 8.57
(8)
Use in C-C Bond-Forming Reactions. Since MOMCl is an

excellent electrophile it readily reacts with enolates 58 and other
carbanions59 and thus serves as an easily handled one-carbon
synthon. Friedel-Crafts alkylation with MOMCl and a Lewis
acid such as Tin(IV) Chloride,60 Titanium(IV) Chloride61 Zinc
Chloride,62 and Aluminum Chloride63 or Acetic Acid64 is a com
mon method for introduction of a chloromethyl group onto an
aromatic nucleus (eqs 9 and 10).60,64 The reaction is quite general
and tolerates a broad range of functionality.
(9)
(10)
Alkenes react in a similar fashion giving methoxymethyl deriva

tives, but in this case the intermediate carbenium ion is trapped
with methoxide or another nucleophile such as a nitrile to afford
the methyl ether or amide in a Ritter-like reaction (eq 11). 65 In
similar fashion, silyl enol ethers give ketones (eq 12), 66,67 allylsilanes afford homologated alkenes (eq 13),68 and stannylalkynes
are converted to propargyl ethers.69
(11)
(12)
Protection of Amine Derivatives. Heterocyclic amines and

amides are protected as their MOM derivatives by reaction of
98
(13)
MOMCl can be converted to the Grignard reagent or the lithium

reagent and used to introduce one carbon by nucleophilic at
tack on ketones and esters. 70 These reagents are best prepared
in methylal. 71
Related Reagents. Benzyl Chloromethyl Ether; Benzyl
Chloromethyl Sulfide; t-Butyl Chloromethyl Ether; 2-Chloroethyl Chloromethyl Ether; Chloromethyl Methyl Sulfide;
Dimethoxymethane; (p-Methoxybenzyloxy)methyl Chloride; 2Methoxyethoxymethyl Chloride; 2-(Trimethylsilyl)ethoxymethyl
Chloride.
1. For a review on the use of this reagent in protective group chemistry, see:
Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis,
2. Marvel, C. S.; Porter, P. K., OSC 1941, 1, 377.
3. (a) Jones, M. S 1984, 727. (b) Stadlwieser, J. S 1985, 490.
4. Amato, J. S.; Karady, S.; Sletzinger, M.; Weinstock, L. M. S 1979, 970.
5. Stork, G.; Takahashi, T. JACS 1977, 99, 1275.
6. Kluge, A. F.; Untch, K. G.; Fried, J. H. JACS 1972, 94, 7827.
7. (a) Welch, S. C ; Hagan, C. P. SC 1973, 3, 29. (b) Roush, W. R.; Brown,
B. B. TL 1989, 30, 7309. (c) Coates, R. M.; Shaw, J. E. JOC 1970, 35,
2597,2601.
8. Fuji, K.; Nakano, S.; Fujita, E. S 1975, 276.
9. Olah, G. A.; Husain, A.; Narang, S. C. S 1983, 896.
10. Olah, G. A.; Husain, A.; Gupta, B. G. B.; Narang, S. C. S 1981, 471.
11. Nishino, S.; Ishido, Y. J. Carbohydr. Chem. 1986, 5, 313.
12. Patney, H. K.; SL 1992, 567.
13. Schaper, U. A. S 1981, 794.
14. Gras, J.-L.; Chang, Y.-Y. K. W.; Guerin, A. S 1985, 74.
15. Ihara, M.; Suzuki, M.; Fukumoto, K.; Kametani, T.; Kabuto, C. JACS
1988,110, 1963.
16. Takasu, M.; Naruse, Y.; Yamamoto, H. TL 1988, 29, 1947.
17. Nobuo, N.; Masaji, O. CL 1987, 141.
18. Auerbach, J.; Weinreb, S. M. CC 1974, 298.
19. Meyers, A. I.; Durandetta, J. L.; Munavu, R. JOC 1975, 40, 2025.
20. Bremmer, M. L.; Khatri, N. A.; Weinreb, S. M. JOC 1983, 48, 3661.
21. LaForge, F. B. JACS 1933, 55, 3040.
22. Monti, H.; Leandri, G.; Klos-Ringquet, M.; Corriol, C. SC 1983, 13,
1021.
23. Woodward, R. B. et al. JACS 1981, 103, 3210.
24. Boeckman, R. K., Jr.; Potenza, J. C. TL 1985, 26, 1411.
25. Corey, E. J.; Hua, D. H.; Seitz, S. P. TL 1984, 25, 3.
26. Barot, B. C.; Pinnick, H. W. JOC 1981, 46, 2981.
27. Guindon, Y.; Morton, H. E.; Yoakim, C. TL 1983, 24, 3969.
28. Hanessian, S.; Delorme, D.; Dufresne, Y. TL 1984, 25, 2515. For in situ
prepared TMSBr see: Woodward, R. B. et al. JACS 1981, 103, 3213 (note
2).
29. Kieczykowski, G. R.; Schlessinger, R. H. JACS 1978, 100, 1938.
30. Kim, S. SL 1991, 183.
31. Nakata, T.; Schmid, G.; Vranesic, B.; Okigawa, M.; Smith-Palmer, T.;
Kishi, Y. JACS 1978, 100, 2933.
32. Ireland, R. E.; Varney, M. D. JOC 1986, 51, 635.
33. van Heerden, F. R.; van Zyl, J. J.; Rall, G. J. H.; Brandt, E. V.; Roux, D.
G.TL 1978, 661.
34.
Kelly, T. R.; Jagoe, C. T.; Li, Q. JACS 1989, 111, 4522.
35.
36.
43.
44.
45.
Chiarello, J.; Joullie, M. M. T 1988, 44, 41.

Rall, G. J. H.; Oberholzer, M. E.; Ferreira, D.; Roux, D. G. TL 1976,
1033.
Yardley, J. P.; Fletcher, H., 3rd, S 1976, 244.
Noyori, R.; Nishida, I.; Sakata, J. TL 1981, 22, 3993.
Rahman, M. A. A.; Elliott, H. W.; Binks, R.; Kng, W.; Rapoport, H.
JMC 1966, 9, 1.
Williams, D. R.; Barner, B. A.; Nishitani, K.; Phillips, J. G. JACS 1982,
104, 4708.
Saimoto, H.; Kusano, Y.; Hiyama, T. TL 1986, 27, 1607.
Huffman, J. W.; Zheng, X.; Wu, M.-J.; Joyner, H. H.; Pennington, W. T.
JOC 1991, 56, 1481.
Brown, H. C ; Imai, T. JACS 1983, 105, 6285.
Fukuyama, T.; Nakatsuka, S.; Kishi, Y. TL 1976, 3393.
Dardoize, F.; Gaudemar, M.; Goasdoue, N. S 1977, 567.
46.
47.
48.
49.
Jansen, A. B. A.; Russell, T. J. JCS 1965, 2127.

Shono, T.; Ishige, O.; Uyama, H.; Kashimura, S. JOC 1986, 51, 546.
White, J. D.; Reddy, G.; Nagabhushana, S. G. O. JACS 1988, 110, 1624.
Dardoize, F.; Gaudemar, M.; Goasdoue, N. S 1977, 567.
50.
51.
Weinstock, L. M.; Karady, S.; Roberts, F. E.; Hoinowski, A. M.; Brenner,

G. S.; Lee, T. B. K.; Lumma, W. C.; Sletzinger, M. TL 1975, 3979.
Kim, S.; Park, Y. H.; Kee, I. S. TL 1991, 32, 3099.
52.
Masamune, S. Aldrichim. Acta 1978, 11, 23.
53.
54.
55.
56.
57.
58.
Ozaki, S.; Watanabe, Y.; Fujisawa, H.; Hoshiko, T. H 1984, 22, 527.
Moody C. J.; Ward, J. G. JCS(P1) 1984, 2895.
Kirby, G. W.; Robins, D. J.; Stark, W. M. CC 1983, 812.
Sundberg, R. J.; Russel, H. F. JOC 1973, 38, 3324.
Meinwald, J.; Chapman, O. L. JACS 1957, 79, 665.
(a) Vila, A. J.; Cravero, R. M.; Gonzalez-Sierra, M. TL, 1991, 32, 1929.
(b) Huet,F.;Pellet, M.; Conia, J. M. S 1979, 33. (c) Greene, A. E.; Coelho,
E; Depres, J.-P; Brocksom, T. J. JOC 1985, 50, 1973. (d) Kogen, H.;
Tomioka, K.; Hashimoto, S.-L; Koga, K. T 1981, 37, 3951.
59.
(a) Okazaki, R.; O-oka, M.; Akiyama, T.; Inamoto, N.; Niwa, J. JACS
1987, 109, 5413. (b) Alexakis, A.; Cahiez, G.; Normant, J. F. S 1979,
826. (c) Micetich, R. G.; Baker, V.; Spevak, P.; Hall, T. W.; Bains, B. K.
H 1985, 23,943. (d) Corriu, R. J. P.; Huynh, V. Moreau, J. J. E. TL 1984,
25, 1887.
60.
61.
62.
63.
64.
65.
Iyer, S.; Liebeskind, L. S. JACS 1987, 709, 2759.

Tashiro, M.; Yamato, T. S 1978, 435.
Steyn, P. S.; Holzapfel, C. W. T 1967, 23, 4449.
Cornforth, J.; Robertson, A. D. JCS(P1) 1987, 867.
Jaques, B.; Deeks, R. H. L.; Shah, P. K. J. CC 1969, 1283.
Wada Y.; Yamazaki, T.; Nishiura, K.; Tanimoto, S. Okano, M. BCJ 1978,
51, 1821.
66.
Fleming, I.; Lee, T. V. TL 1981, 22, 705.
67.
Shono, T.; Nishiguchi, I.; Komamura, T.; Sasaki, M. JACS 1979, 101,
984.
Uno, H. BCJ 1986, 59, 2471.
37.
38.
39.
40.
41.
42.
68.
69.
70.
71.
Zhai, D.; Zhai, W.; Williams, R. M. JACS 1988, 110, 2501.

Schollkopf, U. LA 1967, 704, 120.
(a) Runge, F. Taeger, E.; Fiedler, C ; Kahlert, E. JPR 1963, 19, 37. (b)
Schollkopf, U.; Kppers, H. TL 1964, 1503.
Peter G. M . Wuts
The Upjohn Co., Kalamazoo, Ml, USA
2-CHLORO-1-METHYLPYRIDINIUM IODIDE
2-Chloro-l-methylpyridinium Iodide
[14338-32-0]
C6H7ClIN
(MW 255.49)
99
entropically favored because of the close proximity of all reactants to a central pyridinium salt (4). Optimum conditions for the
process involve addition over 8 h of a solution of the hydroxy
acid (0.0125 M) and triethylamine (8 equiv) in dichloromethane
or acetonitrile to a solution of (1) (4 equiv; 0.04 M) in the same
solvent at reflux. After a further 30 min at reflux, evaporation of
the solvent and chromatography affords the lactone. Results of a
study of the formation of lactones of various ring sizes are shown
in Table 1. Good results are obtained for ring sizes 7 and > 12, but
attempts to form 8- or 9-membered lactones result in substantial
dimerization.
(activation of carboxylic acids;1 formation of esters2 and amides; 3

lactonization;4 ketene formation;5 -lactam synthesis;6,7 carbodiimide synthesis8)
Alternate Name: Mukaiyama's reagent.
Form Supplied in: commercially available yellow solid.
Preparative Method: by reaction between 2-chloropyridine and
Iodomethane in acetone at reflux.9
Purification: recrystallization from acetone.
Handling, Storage, and Precautions: hygroscopic.
Activation of Carboxylic Acids: Ester Formation. 2Chloro-1-methylpyridinium iodide (1) reacts with a mixture of a
carboxylic acid and an alcohol, in the presence of two equivalents
of base, to form an ester (eq 1).2 The pyridinium salt (2) is formed
rapidly by displacement of chloride from (1) by the carboxylate;
subsequent reaction with the alcohol results in formation of the
ester, along with 1-methyl-2-pyridone (3). A variety of solvents
may be employed, but yields are highest in dichloromethane or
pyridine. Tri-n-butylamine or Triethylamine are often used as
base. The co-product (3) is insoluble in dichloromethane and so
precipitates from this solvent. Good results are obtained even for
hindered carboxylic acids and alcohols.
(3)
Table 1 Lactone Formation by Cyclization of Hydroxy Acids with

Reagent (1)
Ring size
7
8
9
12
13
16
% Yield lactone
% Yield dimer
89
0
13
61
69
84
0
93
34
24
14
3
Cyclization of sensitive trans--hydroxy acids to give strained

trans-bicyclic -lactones of the type (5) is often problematic due
to dehydration of the tertiary alcohol. A study showed (1) to be the
reagent of choice for this transformation (eq 4). 10 Other reagents,
such as 1,3-DicyclohexylcarbodiimidelPyridine or 2,2' -Dipyridyl
Disulfide/Triphenylphosphine, give far lower yields.
(4)
(1)
Amide Synthesis. In a similar way, amides can be prepared

efficiently by treatment of an equimolar amount of a carboxylic
acid and an amine with (1) in the presence of base (eq 2). 3
Ketene Formation. There is evidence that the above esterification procedure may occur at least pation
of
the
ketene
fromthecarboxylicacid.5Ifacarboxylicacidcartlyvia formontains a suitably
placed alkene, the resulting ketene can undergo intramolecular
[2 + 2] cycloaddition (eq 5). 5 Benzene is the best solvent for this
reaction, giving yields comparable to those obtained by ketene
formation from the corresponding acid chloride.
(2)
Lactone Formation. The ester formation method has found

widespread use in the synthesis of lactones by cyclization of hy
droxy acids (eq 3). 4 The cyclization process is believed to be
-Lactam Synthesis. Dehydration of 0-amino acids to give

-lactams can be effected in high yield using (1) in CH 2 Cl 2 or
MeCN (eq 6). 6
-Lactams can also be prepared by the reaction of carboxylic
acids, activated by (1), with imines; best results are obtained with
Tripropylamine as base in CH 2 Cl 2 at reflux (eq 7). 7
100
CHLOROTRIETHYLSILANE
Solubility: readily sol most aprotic organic solvents, although

CH2Cl2 is most commonly used; reacts with H2O and other
protic solvents.
Form Supplied in: colorless liquid, or as a 1.0 M solution in THE
Handling, Storage, and Precautions: should be handled and stored
under an anhydrous, inert atmosphere.
(5)
(6)
General Considerations. The triethylsilyl moiety is often

used as a protecting group for alcohols because of its greater sta
bility towards hydrolysis than the smaller trimethylsilyl group.
Alcohols can normally be silylated with Et3SiCl using either Im
idazole in DMF or Triethylaminel4-Dimethylaminopyridine in
CH2Cl2 (eqs 1 and 2).1,2 For substrates which are more difficult
to derivatize, it may be advantageous to carry out the reaction in
neat Pyridine (eq 3)3 or to generate the alkoxide salt prior to the
addition of Et3SiCl (eq 4). 4-6
(7)
(1)
Carbodiimides from Thioureas. Conversion of N,N'disubstituted thioureas into carbodiimides can be effected by
treatment with (1) and 2 equiv of base (eq 8).8
(2)
(8)
1.
2.
Mukaiyama, T. AG(E) 1979,18, 707.

Mukaiyama, T.; Usui, M.; Shimada, E.; Saigo, K. CL 1975, 1045.
3.
Bald, E.; Saigo, K.; Mukaiyama, T. CL 1975, 1163.
4.
Mukaiyama, T.; Usui, M.; Saigo, K. CL 1976, 49.
5.
6.
7.
Funk, R. L.; Abelman, M. M.; Jellison, K. M. SL 1989, 36.

Huang, H.; Iwasawa, N.; Mukaiyama, T. CL 1984, 1465.
Georg, G. I.; Mashava, P. M.; Guan, X. TL 1991, 32, 581.
8.
Shibanuma, T.; Shiono, M.; Mukaiyama, T. CL 1977, 575.
9.
10.
Amin, S. G.; Glazer, R. D.; Manhas, M. S. S 1979, 210.

Strekowski, L.; Visnick, M ; Battiste, M. A. 5 1983, 493.
(3)
(4)
Alan Armstrong
[994-30-9]
C6H15ClSi
(MW 150.75)
(silylating agent, Lewis acid catalyst)

Alternate Name: triethylsilyl chloride.
Physical Data: bp 145-147 C; d 0.898 g cm -3 .
Silyl ethers have also been obtained by in situ trapping of an

intermediate alkoxide that results from a nucleophilic addition
onto an ester7 or epoxide8 (eqs 5 and 6).
Silyl enol ethers can be prepared from ketones by trapping
the kinetically formed lithium enolate with Et3SiCl (eqs 7 and
8), 910 or by the conjugate addition of a dialkylcuprate to an
,-unsaturated ketone with silylation of the enolate interme
diate (eq 9). 11-13 Surprisingly, the addition of Lithium Di-nbutylcuprate to an ,-unsaturated lactone in the presence of
Et3SiCl resulted in the 1,4-addition of the triethylsilyl moiety, ap
parently via the in situ formation of an intermediate silylcuprate
species (eq 10).14
CHLOROTRIETHYLSILANE
101
(5)
(15)
(6)
In a similar manner, aryl, vinyl-, and alkynylsilanes can be pre
pared by the reaction of the appropriate carbanion with Et 3 SiCl
(eqs 16-21). 20-25
(16)
(7)
(8)
(17)
(9)
(18)
(10)
(19)
Organolithium salts generally react with Et3SiCl to afford
organosilanes. Schlessinger used a deprotonation-silylation pro
cedure to introduce a triethylsilyl group at the -position of an
alkylimine (eq 11 ). 15 A variety of other stabilized carbanions have
been reported to react cleanly with Et 3 SiCl (eqs 12-15). 16-19
(20)
(21)
(11)
(12)
(13)
(14)
Related Reagents. t-Butyldimethylchlorosilane; t-Butyldimethylsilyl Trifiuoromethanesulfonate; Chlorotrimethylsilane;

Chlorotriphenylsilane; Triethylsilyl Trifiuoromethanesulfonate;
Trimethylsilyl Trifiuoromethanesulfonate.
1.
2.
3.
4.
5.
6.
Corey, E. J.; Link, J. 0. TL 1990, 31, 601.

Anderson, J. C ; Ley, S. V. TL 1990, 31, 431.
Hart, T. W.; Metcalfe, D. A.; Scheinmann, F. CC 1979, 156.
Hoffmann, R.; Bruckner, R. CB 1992, 125, 1471.
Smith, A. B., III; Richmond, R. E. JACS 1983, 105, 575.
Andrews, D. R.; Barton, D. H. R.; Hesse, R. H.; Pechet, M. M. JOC
1986, 51, 4819.
7. Cooke, M. P., Jr. JOC 1986, 51, 951.

8. Andrews, G. C; Crawford, T. C ; Contillo, L. G., Jr. TL 1981, 22, 3803.
9. (a) Sampson, P.; Hammond, G. B.; Wiemer, D. F. JOC 1986, 51, 4342.
(b) Sampson, P.; Wiemer, D. F. CC 1985, 1746.
102
10.
11.
CHLOROTRIMETHYLSILANE
(a) Danishefsky, S. J.; Uang, B. J.; Quallich, G. JACS 1985, 107, 1285.
(b) Danishefsky, S. J.; Harvey, D. F.; Quallich, G.; Uang, B. J. JOC 1984,
49, 392.
Horiguchi, Y.; Komatsu, M.; Kuwajima, I. TL 1989, 30, 7087.
12. Marino, J. P.; Emonds, M. V. M ; Stengel, P. J.; Oliveira, A. R. M.;

Simonelli, R; Ferreira, J. T. B. TL 1992, 33, 49.
13. (a) Ager, D. J.; Fleming, I.; Patel, S. K. JCS(P1) 1981, 2520; (b) Fleming,
I.; Newton, T. W. JCS(PI) 1984, 1805.
14. Amberg, W; Seebach, D. AG(E) 1988, 27, 1718.
15. Schlessinger, R. H.; Poss, M. A.; Richardson, S.; Lin, P. TL 1985, 26,
2391.
16. Szymonifka, M. J.; Heck, J. V. TL 1989, 30, 2873.
17.
(1)
(2)
Savignac, P.; Teulade, M.-P; Collignon, N. JOM 1987, 323, 135.
18. Oppolzer, W.; Snowden, R. L.; Simmons, D. P. HCA 1981, 64, 2002.
19. Seyferth, D.; Mammarella, R. E.; Klein, H. A. JOM 1980, 194, 1.
20. Block, E.; Eswarakrishnan, V.; Gernon, M.; Ofori-Okai, G.; Saha, C ;
Tang, K.; Zubieta, J. JACS 1989, 111, 658.
21. Lee, G. C. M.; Holmes, J. M.; Harcourt, D. A.; Garst, M. E. JOC 1992,
57,3126.
22. Soderquist, J. A.; Lee, S.-J. H. T 1988, 44, 4033.
23. Schinzer, D. S 1989, 179.
24.
25.
secondary, and tertiary alcohols can be silylated in this manner,

depending on the relative amounts of TMS and HMDS (eqs 4-6).23
(3)
(4)
Hiyama, T.; Nishide, K.; Obayashi, M. CL 1984, 1765.

Uchida, K.; Utimoto, K.; Nozaki, H. JOC 1976, 41, 2215.
Edward Turos
State University of New York at Buffalo, NY, USA
(5)
(6)
Chlorotrimethylsilane1,2
[75-77-4]
C3H9ClSi
(MW 108.64)
(protection of silyl ethers,3 transients,5-7 and silylalkynes;8

synthesis of silyl esters,4 silyl enol ethers,9,10 vinylsilanes,13
and silylvinylallenes;15 Boc deprotection;11 TMSI generation;12
epoxide cleavage;14 conjugate addition reactions catalyst16-18)
Alternate Names: trimethylsilyl chloride; TMSC1.
Physical Data: bp 57 C; d 0.856 g cm - 3 .
Solubility: sol THF, DMF, CH2Cl2, HMPA.
Form Supplied in: clear, colorless liquid; 98% purity; commer
cially available.
Analysis of Reagent Purity: bp, NMR.
Purification: distillation over calcium hydride with exclusion of
moisture.
Handling, Storage, and Precautions: moisture sensitive and cor
rosive; store under an inert atmosphere; use in a fume hood.
Protection of Alcohols as TMS Ethers. The most common

method of forming a silyl ether involves the use of TMSC1 and a
base (eqs 1-3).3,19-22 Mixtures of TMSC1 and Hexamethyldisilazane (HMDS) have also been used to form TMS ethers. Primary,
Trimethysilyl ethers can be easily removed under a variety of

conditions,19 including the use of Tetra-n-butylammonium Fluoride (TBAF) (eq 7),20 citric acid (eq 8),24 or Potassium Carbonate
in methanol (eq 9).25 Recently, resins (OH- and H + form) have
been used to remove phenolic or alcoholic TMS ethers selectively
(eq 10).26
(7)
(8)
(9)
(10)
103
Formation of Silyl Esters. TMS esters can be prepared in

good yields by reacting the carboxylic acid with TMSCl in 1,2dichloroethane (eq 14).4 This method of carboxyl group protec
tion has been used during hydroboration reactions. The organoborane can be transformed into a variety of different carboxylic acid
derivatives (eqs 15 and 16).7 TMS esters can also be reduced with
metal hydrides to form alcohols and aldehydes or hydrolyzed to
the starting acid, depending on the reducing agent and reaction
conditions.28
(14)
Transient Protection. Silyl ethers can be used for the tran

sient protection of alcohols (eq 11).27 In this example the hydroxyl groups were silylated to allow tritylation with concomitant
desilylation during aqueous workup. The ease of introduction and
removal of TMS groups make them well suited for temporary
protection.
(15)
(16)
(11)
Protection of Terminal Alkynes. Terminal alkynes can be

protected as TMS alkynes by reaction with n-Butyllithium in THF
followed by TMSCl (eq 17).8 A one-pot -elimination-silylation
process (eq 18) can also yield the protected alkyne.
Trimethylsilyl derivatives of amino acids and peptides have
been used to improve solubility, protect carboxyl groups, and
improve acylation reactions. TMSCl has been used to prepare
protected amino acids by forming the O,N-bis-trimethylsilylated
amino acid, formed in situ, followed by addition of the acylating
agent (eq 12).5 This is a general method which obviates the pro
duction of oligomers normally formed using Schotten-Baumann
conditions, and which can be applied to a variety of protecting
groups.5
(17)
(18)
Silyl Enol Ethers. TMS enol ethers of aldehydes and symmet

rical ketones are usually formed by reaction of the carbonyl com
pound with Triethylamine and TMSCl in DMF (eq 19), but other
bases have been used, including Sodium Hydride29 and Potassium
Hydride.30
(12)
Transient hydroxylamine oxygen protection has been success

fully used for the synthesis of N-hydroxamides.6 Hydroxylamines
can be silylated with TMSCl in pyridine to yield the N-substituted
O-TMS derivative. Acylation with a mixed anhydride of a pro
tected amino acid followed by workup affords the N-substituted
hydroxamide (eq 13).6
(13)
(19)
Under the conditions used for the generation of silyl enol ethers
of symmetrical ketones, unsymmetrical ketones give mixtures of
structurally isomeric enol ethers, with the predominant product
being the more substituted enol ether (eq 20).10 Highly hindered
bases, such as Lithium Diisopropylamide (LDA),31 favor for
mation of the kinetic, less substituted silyl enol ether, whereas
Bromomagnesium Diisopropylamide (BMDA)10 generates the
more substituted, thermodynamic silyl enol ether. A combination
of TMSCl/Sodium Iodide has also been used to form silyl enol
ethers of simple aldehydes and ketones32 as well as from ,unsaturated aldehydes and ketones.33 Additionally, treatment of
-halo ketones with Zinc, TMSCl, and TMEDA in ether provides
104
a regiospecific method for the preparation of the more substituted

enolether (eq 21).34
ion from a Shapiro reaction with TMSCl. Formation of either the

tosylhydrazone38 or benzenesulfonylhydrazone (eq 26)13,39 fol
lowed by reaction with n-butyllithium in TMEDA and TMSC1
gives the desired product.
(20)
(26)
Reagents
LDA, DME; TMSCl
NaH, DME; TMSCl
Et3N, TMSCl, DMF
KH, THF; TMSCl
TMSCl, Nal, MeCN, Et3N
BMDA, TMSCl, Et3N
Ratio (A):(B)
1:99
73:27
78:22
67:33
90:10
97:3
Epoxide Cleavage. Epoxides open by reaction with TMSCl in

the presence of Triphenylphosphine or tetra-n-butylammonium
chloride to afford O-protected vicinal chlorohydrins (eq 27).14
(21)
Mild Deprotection of Boc Protecting Group. The Boc pro

tecting group is used throughout peptide chemistry. Common
ways of removing it include the use of 50% Trifluoroacetic
Acid in CH2Cl2, Trimethylsilyl Perchlorate, or Iodotrimethylsilane (TMSI).19 A new method has been developed, using
TMSCl-phenol, which enables removal of the Boc group in less
than one hour (eq 22).11 The selectivity between Boc and benzyl
groups is high enough to allow for selective deprotection.
(27)
Formation of Silylvinylallenes. Enynes couple with TMSCl

in the presence of Li/ether or MglHexamethylphosphoric Triamide to afford silyl-substituted vinylallenes. The vinylallene can
be subsequently oxidized to give the silylated cyclopentanone
(eq 28).15
(22)
(28)
In Situ Generation of Iodotrimethylsilane. Of the published

methods used to form TMSI in situ, the most convenient involves
the use of TMSCl with Nal in acetonitrile.12 This method has been
used for a variety of synthetic transformations, including cleavage
of phosphonate esters (eq 23),35 conversion of vicinal diols to
alkenes (eq 24),36 and reductive removal of epoxides (eq 25).37
Conjugate Addition Reactions. In the presence of TMSCl,

cuprates undergo 1,2-addition to aldehydes and ketones to afford
silyl enol ethers (eq 29).16 In the case of a chiral aldehyde, ad
dition of TMSCl follows typical Cram diastereofacial selectivity
(eq 30).16,40
(23)
(29)
(30)
(24)
(25)
Conversion of Ketones to Vinylsilanes. Ketones can be trans

formed into vinylsilanes via intermediate trapping of the vinyl an
Conjugate addition of organocuprates to ,-unsaturated carbonyl compounds, including ketones, esters, and amides, are ac
celerated by addition of TMSCl to provide good yields of the
1,4-addition products (eq 31).17,41,42 The effect of additives such
as HMPA, DMAP, and TMEDA have also been examined.1843
The role of the TMSCl on 1,2- and 1,4-addition has been ex
plored by several groups, and a recent report has been published
by Lipshutz.40 His results appear to provide evidence that there is
COPPER(l)TRIFLUOROMETHANESULFONATE
an interaction between the cuprate and TMSCl which influences
the stereochemical outcome of these reactions.
(3D
The addition of TMSCl has made 1,4-conjugate addition reac

tions to a-(nitroalkyl)enones possible despite the presence of the
acidic -nitro protons (eq 32). 44 Copper-catalyzed conjugate ad
dition of Grignard reagents proceeds in high yield in the presence
of TMSC1 and HMPA (eq 33). 45 In some instances the reaction
gives dramatically improved ratios of 1,4-addition to 1,2-addition.
(32)
(33)
22.
Lissel, M.; Weiffen, J. SC 1981,11, 545.
23.
24.
Cossy, J.; Pale, P. TL 1987, 28, 6039.

Bundy, G. L.; Peterson, D. C. TL 1978, 41.
25.
Hurst, D. T.; Mclnnes, A. G. CJC 1965, 43, 2004.
26.
Kawazoe, Y.; Nomura, M.; Kondo, Y.; Kohda, K. TL 1987, 28, 4307.
27.
28.
Sekine, M.; Masuda, N.; Hata, T. T 1985, 41, 5445.

Larson, G. L.; Ortiz, M.; Rodrigues de Roca, M. SC 1981, 583.
29.
Stork, G.; Hudrlik, P. F. JACS 1968, 90, 4462.
30. Negishi, E.; Chatterjee, S. TL 1983, 24, 1341.

31.
Corey, E. J.; Gross, A. W. TL 1984, 25, 495.
32.
Cazeau, P.; Duboudin, F.; Moulines, F.; Babot, O.; Dunogues, J. T 1987,
43, 2075.
33.
34.
35.
Cazeau, P.; Duboudin, F.; Moulines, P.; Babot, O.; Dunogues, J. T 1987,
43, 2089.
Rubottom, G. M.; Mott, R. C.; Krueger, D. S. SC 1977, 7, 327.
Morita, T.; Okamoto, Y.; Sakurai, H. TL 1978, 28, 2523.
36.
37.
Barua, N. C.; Sharma, R. P. TL 1982, 23, 1365.

Caputo, R.; Mangoni, L.; Neri, O.; Palumbo, G. TL 1981, 22, 3551.
38.
Taylor, R. T.; Degenhardt, C. R.; Melega, W. P.; Paquette, L. A. TL 1977,

159.
Fristad, W. E.; Bailey, T. R.; Paquette, L. A. JOC 1980, 45, 3028.
39.
40.
41.
Related Reagents. N,O-Bis(trimethylsilyl)acetamide; N,N'Bis(trimethylsilyl)urea; Cyanotrimethylsilane; Hexamethyldisilazane; Hexamethyldisiloxane; Iodotrimethylsilane; N-(Trimethylsilyl)imidazole; Trimethylsilyl Trifluoromethanesulfonate.
1. Colvin, E. Silicon in Organic Synthesis; Butterworths: Boston, 1981.

2. Weber, W. P., Silicon Reagents for Organic Synthesis; Springer: New
York, 1983.
3. Langer, S. H.; Connell, S.; Wender, I. JOC 1958, 23, 50.
4. Hergott, H. H.; Simchen, G. S 1980, 626.
5. Bolin, D. R.; Sytwu, I.-I; Humiec, R; Meinenhofer, J. Int. J. Peptide
Protein Res. 1989, 33, 353.
6. Nakonieczna, L.; Chimiak, A. S 1987, 418.
7. Kabalka, G. W.; Bierer, D. E. SC 1989, 19, 2783.
8. Valenti, E.; Pericas, M. A.; Serratosa, F. JOC 1990, 55, 395.
9. House, H. O.; Czuba, L. J.; Gall, M.; Olmstead, H. D. JOC 1969, 34,
2324.
10. Krafft, M. E.; Holton, R. A. TL 1983, 24, 1345.
11. Kaiser, E.; Tarn, J. P.; Kubiak, T. M ; Merrifield, R. B. TL 1988, 29, 303.
12. Olah, G. A.; Narang, S. C ; Gupta, B. G. B.; Malhotra, R. JOC 1979, 44,
1247.
13. Paquette, L. A.; Fristad, W. E.; Dime, D. S.; Bailey, T. R. JOC 1980, 45,
3017.
14. Andrews, G. C.; Crawford, T. C.; Contillo, L. G. TL 1981, 22, 3803.
15. Dulcere, J.-P; Grimaldi, J.; Santelli, M. TL 1981, 22, 3179.
16. Matsuzawa, S.; Isaka, M.; Nakamura, E.; Kuwajima, I. TL 1989, 30,
1975.
17. Alexakis, A.; Berlan, J.; Besace, Y. TL 1986, 27, 1047.
18. Horiguchi, Y.; Matsuzawa, S.; Nakamura, E.; Kuwajima, I. TL 1986, 27,
4025.
19. Green, T. W.; Wuts, P. G. M., Protective Groups in Organic Synthesis;
Wiley: New York, 1991.
20. Allevi, P.; Anastasia, M.; Ciufereda, P. TL 1993, 34, 7313.
21. Olah, G. A.; Gupta, B. G. B.; Narang, S. C ; Malhotra, R. JOC 1979, 44,
4272.
105
42.
Lipschutz, B. H.; Dimock, S. H.; James, B. JACS 1993, 115, 9283.

Nakamura, E.; Matsuzawa, S.; Horiguchi, Y.; Kuwajima, I. TL 1986, 27,
4029.
Corey, E. J.; Boaz, N. W. TL 1985, 26, 6015.
43.
Johnson, C. R.; Marren, T. J. TL 1987, 28, 27.
44.
45.
Tamura, R.; Tamai, S.; Katayama, H.; Suzuki, H. TL 1989, 30, 3685.
Booker-Milburn, K. I.; Thompson, D. F. TL 1993, 34, 7291.
Ellen M. Leahy
Affymax Research Institute, Palo Alto, CA, USA
[42152-44-3]
(2:1 benzene complex)
[37234-97-2; 42152-46-5]
CCuF3O3S
(MW 212.62)
C 8 H 6 Cu 2 F 6 O 6 S 2
(MW 503.34)
(efficient catalyst for 2 + 2 photocycloadditions and other photoreactions of alkenes,1 and for alkene cyclopropanation and other
reactions of diazo compounds; also a selenophilic and thiophilic
Lewis acid that enhances the nucleofugacity of selenide and
sulfide leaving groups)
Alternate Name: copper(I) triflate.
Physical Data: moisture-sensitive white crystalline solid.
Solubility: sol MeCN, MeCO 2 H, 2-butanone, alkenes; slightly sol
benzene.
Form Supplied in: must be freshly prepared.
Preparative Methods: copper(I)
trifluoromethanesulfonate
(CuOTf) was first prepared as a solution in acetonitrile by
synproportionation of Copper(II) Trifluoromethanesulfonate
with copper(O).2 The CuI in these solutions is strongly
coordinated with acetonitrile, forming complexes analogous
to Tetrakis(acetonitrile)copper(I) Perchlorate.3 A white
106
crystalline solid benzene complex, (CuOTf)2C6H6, is pre

pared by the reaction of a suspension of Copper(I) Oxide in
benzene with TrifluoromethanesulfonicAnhydride.4Traces
of Trifluoromethanesulfonic Acid apparently catalyze the
reaction.5 CuOTf is generated in situ by the reduction of
Cu(OTf)2 with diazo compounds.6
Handling, Storage, and Precautions: moisture sensitive.
clobutene reacts with ethyl diazoacetate at 0 C to deliver a mixture

of exo- and endo-5-ethoxycarbonylbicyclo[2.1.0]pentanes (eq 5).7
(3)
(4)
Cyclopropanation with Diazo Compounds. Copper(I) triflate is a highly active catalyst for the cyclopropanation of alkenes
with diazo compounds.6 In contrast to other more extensively ligated copper catalysts, e.g. Copper(II) Acetylacetonate, that favor
cyclopropanation of the most highly substituted C=C bond, cyclopropanations catalyzed by CuOTf show a unique selectivity
for cyclopropanation of the least alkylated C=C bond in both intermolecular (eq 1) and intramolecular (eq 2) competitions. The
same selectivity is found with Cu(OTf)2 as nominal catalyst. This
is because Cu(OTf)2 is reduced by the diazo compound to CuOTf,
and CuOTf is the actual cyclopropanation catalyst in both cases.6
Selective cyclopropanation of the least substituted C=C bond is a
consequence of the alkene coordinating with the catalyst prior to
interaction with the diazo compound, and the increase in stability
of CuI-alkene complexes with decreasing alkyl substitution on
the C=C bond. For catalysts with more strongly ligated CuI, an
electrophilic carbene or carbenoid intermediate reacts with the free
alkene, and the preference for cyclopropanation of the more highly
substituted C=C bond arises from the enhancement of alkene nucleophilicity with increasing alkyl substitution (see Copper(II)
Trifluoromethanesulfonate).
(1)
CuXn
CuOTf
Cu(OTf)2
Cu(acac)2
Ratio
17% 0.25:1
21% 0.27:1
61% 1.78:1
67%
77%
35%
(5)
CuOTf is an outstandingly effective catalyst for the synthe

sis of cyclopropyl phosphonates by the reaction of Diethyl Diazomethylphosphonate with alkenes (eq 6).8 The resulting cyclopropylphosphonates are useful intermediates for the synthesis
of alkylidenecyclopropanes by Wadsworth-Emmons alkenation
with aromatic carbonyl compounds (eq 7).8
(6)
(7)
A complex of a chiral, nonracemic bis(oxazoline) with CuOTf

is a highly effective catalyst for asymmetric cyclopropanation of
alkenes.9 Copper(II) triflate complexes do not catalyze the re
action unless they are first converted to CuI by reduction with
a diazo compound or with phenylhydrazine. CuOTf complexes
are uniquely effective. Thus the observed enantioselectivity and
catalytic activity, if any, are much lower with other CuI or CuII
salts including halide, cyanide, acetate, and even perchlorate. Both
enantiomers of the bis(oxazoline) ligand are readily available.
Spectacularly high levels of asymmetric induction are achieved
with both mono- (eq 8) and 1,1-disubstituted alkenes (eq 9).
(2)
X = acetylacetonate
X = triflate
86%
33%
14%
66%
Cyclopropanecarboxylic esters are conveniently available,

even from volatile alkenes, because CuOTf promotes cyclopropanations in good yields at low temperatures. Thus trans
cis-2-butenes, boiling under reflux, react stereospecifically
with Ethyl Diazoacetate to produce the corresponding ethyl
2,3-dimethylcyclopropanecarboxylates (eqs 3 and 4),6 and cyLists of Abbreviations and Journal Codes on Endpapers
(8)
(9)
Asymmetric Aziridination. A chiral, nonracemic bis(oxazoline) complex of copper(I) triflate catalyzes asymmetric
aziridination of styrene in good yield (eq 10).9 However, enantioselectivity is not as high as the corresponding cyclopropanation
(eq 8).
107
(12)
(10)
(13)
Photocycloadditions. CuOTf is an exceptionally effective cat

alyst for 2 + 2 photocycloadditions of alkenes.1 Thus while
CuBr promotes photodimerization of norbornene in only 38%
yield,10 the same reaction affords dimer in 88% yield with CuOTf
as catalyst (eq 11). 11 A mechanistic study of this reaction revealed
that although both 1:1 and 2:1 alkene CuI complexes are in equi
librium with free alkene and both the 1:1 and 2:1 complexes ab
sorb UV light, only light absorbed by the 2:1 complex results
in photodimerization. In other words, photodimerization requires
precoordination of both C=C bonds with the CuI catalyst. Thus
the exceptional ability of CuOTf, with its weakly coordinating
triflate counter anion, to form -complexes with as many as four
C=C bonds 12 is of paramount importance for its effectiveness as
a photodimerization catalyst.
An isolable CuOTf complex of a highly strained alkene, transcycloheptene, is produced by UV irradiation of a hexane solu
tion of cis-cycloheptene in the presence of CuOTf (eq 14).14
Photocycloaddition of cycloheptene is also catalyzed by CuOTf.
Surprisingly, the major product is not a trans,antijrans dimer
analogous to that formed from cyclohexene (eq 12) but rather
a trans,anti,trans,anti,trans trimer (eq 15).15
The importance of precoordination is also evident in the CuOTfpromoted 2 + 2 photocycloaddition of enrfo-dicyclopentadiene.

This diene forms an isolable 2:1 complex with CuOTf involv
ing exomonodentate coordination with the 8,9-C=C bond of two
molecules of diene. Consequently, intermolecular 2 + 2 pho
tocycloaddition involving exo addition to the 8,9-C=C bond is
strongly favored over intramolecular reaction between the 8,9and 3,4-C=C bonds (eq 11).11 This contrasts with the intramolec
ular photocycloaddition that is promoted by high energy triplet
sensitizers.12
(15)
(14)
Dissolution of the trans-cycloheptene-CuOTf complex in cy

cloheptene and evaporation of the solvent delivers a tris alkene
complex of CuOTf containing one trans-cycloheptene and two ciscycloheptene ligands. Heating traras-cycloheptene-CuOTf in neat
cis-cycloheptene delivers the trans,anti,trans,antijrans
trimer
(eq 16). Experiments with cis-cycloheptene-d 4 show that the
cyclotrimerization involves only trans-cycloheptene molecules,
although the reaction is accelerated by the presence of ciscycloheptene.16 A likely explanation for these observations
is 'concerted "template" cyclotrimerization' of a tris-transcycloheptene-CuOTf complex formed by ligand redistribution
(eq 16).16
(11)
(16)
Especially interesting is the trans,anti,trans stereochemistry of

the major cyclobutane product generated in the photodimeriza
tion of cyclohexene (eq 12).13 It was noted that the formation of
this product may be the result of a preliminary CuOTf promoted
cis-trans photoisomerization that generates a trans-cyclohexene
intermediate (eq 13).13 Since one face of the trans C=C bond is
shielded by a polymethylene chain, the trans-cyclohexene is re
stricted to suprafacial additions. Although a highly strained transcyclohexene intermediate could be stabilized by coordination with
Cu I , such a complex has not been isolated.
The involvement of a transient photogenerated transcyclohexene-CuOTf intermediate was also adduced to explain
CuOTf catalysis of photoinduced 2 + 4 cycloaddition between
ris-cyclohexeneand 1,3-butadiene (eq 17).17 In contrast to thermal
108
Diels-Alder reactions, this reaction generates trans-2-octalin

rather than the cis cycloadduct expected for a 2s + 4 s cycloaddition. A mechanism was proposed that involves the 2 S + 4 S
cycloaddition of a rrans-cyclohexene with 1,3-butadiene in the
coordination sphere of CuI (eq 18).17
(21)
Yield (%)
Yield (%)
H
H
Me
Me
5
8
5
6
47
56
28
35
73
56
87
82
(17)
(22)
(18)
(23)
That CuOTf-catalyzed 2 + 2 photocycloadditions are not re

stricted to cyclic alkenes was first demonstrated in mixed cycloadditions involving allyl alcohol. To suppress homodimerization of
endo-dicyclopentadiene (i.e. eq 11) the diene to CuI ratio is main
tained at < 1:1 and allyl alcohol is used as solvent. Under these con
ditions, a high yield of mixed cycloadduct is generated (eq 19).18
(19)
That both C=C bonds participating in 2 + 2 photocycload

ditions can be acyclic is evident from the photobicyclization re
actions of simple diallyl ethers that deliver bicyclic tetrahydrofurans (eq 20).19,20 In conjunction with Ruthenium(VIII) Oxidecatalyzed oxidation by Sodium Periodate, these CuOTf-catalyzed
photobicyclizations provide a synthetic route to butyrolactones
from diallyl ethers (eq 20).20 The synthetic method is applicable
to the construction of multicyclic tetrahydrofurans and butyrolac
tones from diallyl ethers (eqs 21 and 22) as well as from homoallyl
vinyl ethers (eq 23).20
Yield (%)
Yield (%)
H
Me
H
5
5
6
92
50
48
78
71
85
3-Oxabicyclo[3.2.0]heptanes are also produced in the CuOTfcatalyzed photocycloadditions of allyl 2,4-hexadienyl ethers
(eq 24).21 The CuOTf-catalyzed photocycloadditions of bis-2,4hexadienyl ethers are more complex. Thus UV irradiation of
5,5'-oxybis[(E)-l,3-pentadiene] in THF for 120 h produces vinylcyclohexene and tricyclo[3.3.0.02,6]octane derivatives (eq 25).22
However, shorter irradiations reveal that these products arise
by secondary CuOTf-catalyzed rearrangements of 6,7-divinyl3-oxabicyclo[3.2.0]heptanes that are the primary photoproducts
(eq 26). UV irradiation of the divinylcyclobutane intermediates
in the presence of CuOTf promotes formal [1,3]- and [3,3]sigmatropic rearrangements to produce a vinylcyclohexene and
a 1,5-cyclooctadiene that is the immediate precursor of the
tricyclo[3.3.0.02,6]octane.
(24)
(20)
R1
R2
R3
Yield (%)
Yield (%)
H
Me
Me
Me
n-Bu
H
Me
Me
H
H
H
H
Me
H
Me
52
56
54
54
83
91
94
44
56
83
(25)
109
(30)
(26)
(31)
CuOTf-catalyzed photobicyclization of 1,6-heptadien-3-ols

produces bicyclo[3.2.0]heptan-2-ols (eq 27).23 In conjunction
with pyrolytic fragmentation of the derived ketones, these
CuOTf-catalyzed photobicyclizations provide a synthetic route
to 2-cyclopenten-l-ones from 1,6-heptadien-3-ols (eq 28).23
The derived ketones can also be converted into lactones by
Baeyer-Villiger oxidation and, in conjunction with pyrolytic frag
mentation, CuOTf-catalyzed photobicyclizations provide a syn
thetic route to enol lactones of glutaraldehydic acid from 1,6heptadien-3-ols (eq 28).23
(27)
R1
R2
R3
Yield (%)
Yield (%)
H
Me
H
H
Me
H
H
Me
H
Me
H
H
H
Me
H
86
81
91
84
83
78
67
92
92
93
(32)
-panasinsene, 14%
-panasinsene, 36%
(33)
In conjunction with carbocationic skeletal rearrange

ment, photobicyclization of l,6-heptadien-3-ols provides
a synthetic route to 7-hydroxynorbornanes (eq 34).26
Noteworthy is the stereoselective generation of exo-1,2polymethylenenorbornanes from either the exo or endo epimer of
2,3-polymethylenebicyclo[3.2.0]heptan-3-ol.
(28)
(34)
Copper(I) triflate-catalyzed photobicyclization of - and -(4pentenyl)allyl alcohols provides a synthetic route to various multicyclic carbon networks in excellent yields (eqs 29-31).24 The
reaction was exploited in a total synthesis of the panasinsene
sesquiterpenes (eq 32).25 It is especially noteworthy in this re
gard that attempted synthesis of a key tricyclic ketone interme
diate for the panasinsenes by the well-known photocycloaddition
of Isobutene to an enone failed to provide any of the requisite
cyclobutyl ketone (eq 33).25
(29)
Yield (%)
Yield (%)
5
6
7
8
70-75
51-84
73
74
64-85
76-77
73
66
N,N-Diallylamides are recovered unchanged when irradiated

in the presence of CuOTf.27 This is because the amide chromophore interferes with photoactivation of the CuI-alkene com
plex. Thus CuOTf-alkene complexes containing one, two, three,
or even four coordinated C=C bonds exhibit UV absorption at
235 5 nm (max 2950 450).12 The CuOTf complex of ethyl
N,N-diallylcarbamate exhibits max = 233.4 nm (max 2676) but
the free ligand is virtually transparent at this wavelength. Con
sequently, UV irradiation of ethyl N,N-diallylcarbamates in the
presence of CuOTf delivers bicyclic (eq 35) or tricyclic (eq 36)
110
pyrrolidines incorporating the 3-azabicyclo[3.2.0]heptane ring

system.27
(35)
R1
R2
R3
H
H
H
H
Me
H
H
H
Me
H
Me
H
OEt
OEt
OEt
233 nm
Yield (%)
192
231
15
0
0
74
60
76
(39)
(40)
(36)
Catalyzed Diels-Alder Reactions. The uncatalyzed ther

mal intramolecular Diels-Alder reaction of 5,5'-oxybis[(E)1,3-pentadiene] nonstereoselectively generates four isomeric 4vinylcyclohexenes (eq 37). The major product has a trans ring
fusion, in contrast to the single cis ring-fused isomer generated in
the copper(I) triflate-catalyzed photoreaction of the same tetraene
(eq 25). Copper(I) triflate also catalyzes a thermal Diels-Alder
reaction of 5,5'-oxybis[(E)-l,3-peritadiene] that proceeds under
milder conditions than the uncatalyzed reaction. The stereoselec
tivity is remarkably enhanced, generating mainly the major isomer
of the uncatalyzed thermal reaction and a single cis-fused isomer
(eq 37) that is different than the one favored in the photochemical
reaction (eq 25).
(37)
(a)
(b)
46%
76%
10%
<1%
21%
<1%
(41)
Biaryl is only a minor product from the reaction of methyl obromobenzoate with CuOTf (eq 42). The major product can result
from replacement of the halide by NH2, H, or OH, depending on
reaction conditions. In the presence of 5% aqueous NH3, methyl
anthranilate is the major product.30 More concentrated aqueous
NH3 (20%) favors the generation of methyl salicylate, and the
yield of this product is enhanced by the presence of a substantial
quantity of CuII ion.29 Reductive dehalogenation is favored by the
presence of ammonium ions, presumably owing to protonolysis
of an arylcopper(III) intermediate.29
3%
11%
Csp-H Bond Activation. Hydrogen-deuterium exchange be

tween terminal alkynes and CD3CO2D is catalyzed by CuOTf
(eq 38).28 Proton NMR studies revealed that CuOTf and alkynes
form -complexes that rapidly exchange coordinated with free
alkyne. A complex of CuOTf with 1,7-octadiene was isolated
(eq 39). The complex rapidly exchanges terminal alkynic hydro
gen with deuterium from CD3CO2D and undergoes a much slower
conversion to a copper alkynide (eq 39).28 Exchange of alkynic
hydrogen and deuterium is also catalyzed by CuOTf (eq 40).28
(38)
Activation of Aryl Halides. Ullmann coupling of obromonitrobenzene is accomplished under exceptionally mild
conditions and in homogeneous solution by reaction with cop
per(I) triflate in the presence of aqueous NH3 (eq 41).29 Yields
are enhanced by the presence of a small quantity of copper(II)
triflate. That the reaction is diverted to reductive dehalogenation
by Ammonium Tetrafluoroborate is presumptive evidence for an
organocopper intermediate that can be captured by protonation.
(42)
Activation of Vinyl Halides. Under the optimum conditions

for reductive coupling of o-bromonitrobenzene (eq 41), diethyl
111
iodofumarate gives very little coupling product; the overwhelm

ing product was diethyl fumarate generated by hydrodehalogenation (eq 43).29 Reductive coupling delivers trans,trans-1,2,3,4tetraethoxycarbonyl-l,3-butadiene in 95% yield (GLC, or 80% of
pure crystalline product) in 2 h if aqueous NH3 is replaced by anhy
drous NH3.29 Under the same conditions, diethyl iodomaleate un
(47)
dergoes 45% conversion in 20 h to deliver diethyl maleate, as well
as minor amounts of cis,cis- and trans,fran.s-tetraethoxycarbonyl1,3-butadiene (eq 44).29 The stereospecificity of the reductive dehalogenations in eqs 43 and 44 is presumptive evidence for the
A different synthesis generates 2-phenylthio-l,3-butadienes di
noninvolvement of radicals in these reactions.
rectly by elimination of two molecules of thiophenol from phenylthio thioacetals that are readily available from the corre
sponding ,-unsaturated ketones (eq 48).33
(48)
(43)
CuOTf-promoted elimination of thiophenol was ex

ploited in two syntheses of 1-phenylthio-1,3-butadiene,
one a C-C connective route from allyl bromide31 and
bis(phenylthio)methyllithium,34 and another from Crotonaldehyde (eq 49).33 A topologically analogous C-C connective
strategy provides 2-methoxy-l-phenylthio-1,3-butadiene from
acrolein (eq 50).5,33 That the phenylthio rather than the methoxy
substituent in 2-methoxy-1-phenylthio- 1,3-butadiene controls
the orientation of its Diels-Alder cycloadditions is noteworthy
(eq 50).
(44)
Elimination of Thiophenol from Thioacetals. Conversion of

thioacetals to vinyl sulfides is accomplished under exceptionally
mild conditions by treatment with (CuOTf)2C6H6 (eq 45).31 The
reaction involves an -phenylthio carbocation intermediate. Three
factors contribute to the effectiveness of this synthetic method:
the Lewis acidity of a copper(I) cation that is unencumbered by a
strongly coordinated counter anion, the solubility of the copper(I)
triflate-benzene complex, and the insolubility of CuSPh in the
reaction mixture. An analogous elimination reaction provides an
effective route to phenylthio eno) ethers from ketones (eq 46).31
(49)
(45)
(50)
(46)
This conversion of thioacetals into vinyl sulfides was applied to

a C-C connective synthesis of 2-phenylthio-l,3-butadienes from
aldehydes (eq 47).32 The key elimination step converts cyclobutanone thioacetal intermediates into 1-phenylthiocyclobutenes
that undergo electrocyclic ring opening to deliver dienes.
A synthesis of 4-alkyl-2-methoxy-l -phenylthio-1,3-butadienes

by a simple -elimination of thiophenol from a thioacetal is not
possible owing to skeletal rearrangement that is fostered by sta
bilization of a cyclopropylcarbinyl carbocation intermediate by
the alkyl substituent (eq 51).35 Interconversion of an initial phenylthio carbocation to a more stable -methoxy carbocation
112
intermediate leads to the generation of a 4-alkyl-l-methoxy-2phenylthio-1,3-butadiene instead.
(55)
(51)
Syntheses of l-phenylthio-l,3-butadienes from carboxylic es

ters (eq 52) and carboxylic acids (eq 53) are achieved by
CuOTf-promoted elimination of thiophenol from intermediate
thioacetals.36
Elimination of Benzylic Phenyl Thioethers. That C-S bond

activation by CuOTf is not limited to substrates that can generate
sulfur-stabilized carbocation intermediates is illustrated by a C-C
connective synthesis of trans-stilbene (eq 56).31 The elimination
of thiophenol under mild conditions is favored by benzylic sta
bilization of a carbocation intermediate or an E2 transition state
with substantial carbocationic character.
(56)
(52)
Hydrolysis of Vinylogous Thioacetals. Carbanions prepared

by lithiation of -phenylthioallyl phenyl thioethers can serve as
synthetic equivalents of -acyl vinyl anions.38 Umpolung of the
usual electrophilic reactivity of 2-cyclohexenone is achieved by a
sequence exploiting electrophilic capture of a lithiated vinylogous
thioacetal and subsequent CuOTf-assisted hydrolysis (eq 57).39
Otherwise unfunctionalized vinylogous thioacetals can be hydrolyzed to enones by Mercury(II) Chloride in wet acetonitrile.38
However, the keto-substituted derivative in eq 57 gave only a 25%
yield of enone by this method. A superior yield was obtained by
CuOTf-assisted hydrolysis.39
(53)
Heterocyclization of -Keto Dithioacetals. A C-C connec

tive synthesis of furans is completed by a CuOTf-promoted hete
rocyclization of -keto thioacetals (eq 54).31 Rather than simple
-elimination to generate a vinyl sulfide (eq 46), a presumed keto carbocation intermediate is captured intramolecularly by an
intimately juxtaposed carbonyl oxygen nucleophile.
(54)
Friedel-Crafts Alkylation of Arenes with Thioacetals.

(CuOTf)2C6H6 promotes -thioalkylation of anisole by a
dithioacetal under mild conditions (eq 55).37
Jsts of Abbreviations and Journal Codes on Endpapers
(57)
Grob Fragmentation of -[Bis(phenylthio)methyl]alkoxides. A method for achieving Grob-type fragmentation

of five- and six-membered rings depends upon the ability of
a thiophenyl group to both stabilize a carbanion and serve as
an anionic leaving group. For example, reaction of cyclohexene oxide with lithium bis(phenylthio)methide34 produces a
-[bis(phenylthio)methyl]alkanol that undergoes fragmentation
in excellent yield upon treatment with n-Butyllithium followed
by CuOTf (eq 58).40 Copper(I) trifluoroacetate is equally
effective but salts of other thiophilic metals, e.g. mercury
or silver, were ineffective. Treatment of the intermediate [bis(phenylthio)methyl]alkanol with CuOTf in the absence of
added strong base leads primarily to elimination of thiophenol
as expected (see eq 45). Fragmentation does not occur with only
113
one equivalent of CuOTf. This suggests a key intermediate with

at least one C u I ion to coordinate with the alkoxide and another
to activate the phenylthio leaving group (eq 58).
(60)
(61)
(58)
Ring-Expanding Rearrangements of
-[Bis(phenylthio)methyl]alkanols. A one-carbon ring-expanding synthesis
of -phenylsulfenyl ketones from homologous ketones depends
upon the ability of a thiophenyl group to both stabilize a carbanion
and serve as an anionic leaving group. For example, reaction
of cyclopentanone with lithium bis(phenylthio)methide34 pro
duces an -[bis(phenylthio)methyl]alkanol that rearranges to
a ring-expanded -phenylsulfenyl ketone in good yield upon
treatment with CuOTf in the presence of Diisopropylethylamine (eq 59). 41 Epoxy thioether intermediates are generated
from the -[bis(phenylthio)methyl]alkanols by intramolecular
nucleophilic displacement of thiophenoxide.
(62)
The -[bis(phenylthio)methyl]alkanol derived from cyclohexanone, upon treatment with CuOTf and EtN(i-Pr)2 in ben
zene, undergoes both ring-expanding rearrangement to de
liver -phenylsulfenylcycloheptanone as the major product, as
well as rearrangement involving 1,2-shift of a phenylsulfenyl
group to produce an -phenylsulfenylcyclohexanecarbaldehyde
(eq 63). 41 In contrast, neither ring expansion nor 1,2-shift
of a methylsulfenyl group occurs upon treatment of [tris(methylthio)methyl]cyclohexanol with n-butyllithium fol
lowed by (MeCN) 4 CuBF 4 . Rather, after aqueous workup, an hydroxy methylthio ester is obtained (eq 64). 43
(59)
(63)
An analogous synthesis of ,-bis(methylsulfenyl) ke

tones from homologous ketones by one-carbon ring ex
pansion depends on copper(I)-promoted rearrangement of
an -tris(methylthio)methyl alkoxide intermediate (eq 60).
Both
Tetrakis(acetonitrile)copper(I)
Perchlorate42
and
Tetrakis(acetonitrile)copper(I)
Tetraftuoroborate43
are ef
fective in promoting the rearrangement but (CuOTf) 2 C 6 H 6 ,
HgCl 2 , or Hg(TFA)2 are not. Apparently, the MeCN ligand is crucial. Furthermore, treatment of the intermediate
-[tris(methylthio)methyl] alcohol with CuOTf and EtN(i-Pr)2
in toluene followed by aqueous workup delivers an -hydroxy
methylthio ester (eq 61), 43 in contrast to the ring-expanding re
arrangement of the analogous a-[bis(phenylthio)methyl]alkanol
(eq 59). 41
The a-[bis(phenylthio)methyl]alkanol derived from cycloheptanone does not undergo ring expansion upon treatment with
CuOTf and EtN(i-Pr)2 in benzene. Instead, 1,3-eliminationofthiophenol delivers an epoxy thioether intermediate that undergoes a
rearrangement involving 1,2-shift of a phenylsulfenyl group to
produce an -phenylsulfenyl aldehyde (eq 62). 41
(64)
Chain-Extending Syntheses of -Phenylsulfenyl Ke

tones. A C-C connective, chain-extending synthesis of
-phenylsulfenyl ketones from aldehydes (eq 65) or acyclic
ketones (eq 66) 41 can be accomplished by a CuOTf-promoted
activation of the -[bis(phenylthio)methyl]alkanols generated
by addition of lithium bis(phenylthio)methide.34 Preferential
migration of hydride generates phenylsulfenylmethyl ketones
from aldehydes (eq 65). Regioselective insertion of a phenylsulfenylmethylene unit occurs owing to a preference for migration
of the more highly substituted alkyl group of dialkyl ketones
(eq 66).
114
(65)
copper(I) oxide that are not organic-soluble, all failed to pro

mote any acylation. The highly reactive CuOTf-benzene com
plex, in dramatic contrast, was found to readily promote the
acylations in benzene solution within minutes at room temper
ature. The presence of vinyl and keto groups is tolerated by
the reaction, and while the alkyl- and vinyl-substituted deriva
tives afford para substitution only, a 2:1 mixture of para and ortho substitution occurs with the methylseleno ester of levulinic
acid. Acylation of toluene is sluggish. Excellent yields of 2acylfurans, -thiophenes, and -pyrroles are generated by this new
variant of the Friedel-Crafts acylation reaction (eq 70). An in
tramolecular version of this reaction was shown to generate 1tetralone from the methylseleno ester of -phenylbutyric acid
(eq 71).37
(66)
Cyclopropanation of Enones. Conjugate addition of lithium

tris(phenylthio)methide44 to ,-unsaturated ketones produces
enolates that cyclize to bis(phenylthio)cyclopropyl ketones
at 78 C upon treatment with nearly one equivalent of
(CuOTf)2C6H6, i.e. 1.9 equivalents of CuI (eq 67).45 The mild
conditions that suffice to bring about nucleophilic displace
ment of thiophenoxide in the presence of CuOTf are espe
cially noteworthy. In view of the requirement for more than
one equivalent of CuI to achieve Grob-type fragmentation of
-[bis(phenylthio)methyl]alkoxides (see eq 58), it seems likely,
although as yet unproven, that one equivalent of CuI coordi
nates strongly with the enolate oxygen and that a second equiv
alent of CuI is required to activate the thiophenoxide leaving
group.
(68)
X = H, 78%; SPh, 83%
(69)
R = (CH2)5Me
R = CH2CH2CH=CH2
R = CH2CH2COMe
81%
63%
60%
(70)
(67)
Vinylcyclopropanation of Enones. Conjugate addition of

sulfur-stabilized allyl carbanions to ,-unsaturated ketones pro
duces enolates that cyclize to vinylcyclopropyl ketones upon treat
ment with nearly one equivalent of (CuOTf)2C6H6, i.e. 1.9 equiv
alents of CuI (eq 68).45
Friedel-Crafts Acylation with Thio- or Selenoesters.
Methylseleno esters are readily available in excellent yields by
the reaction of Dimethylaluminum Methylselenolate with Oalkyl esters.37 These selenoesters will acylate reactive arenes
(eq 69) and heterocyclic compounds (eq 70) when activated by
CuOTf, a selenophilic Lewis acid.37 Of the potential activating
metal salts tested, (CuOTf)2C6H6 is uniquely effective. Mercury(II) or copper(I) trifiuoroacetates that are partially organicsoluble, as well as the corresponding chlorides, silver nitrate, and
(71)
Notwithstanding a prior claim that methylthio esters re

act only sluggishly under these conditions,37 such a variant
proved effective for a short synthesis of the 4-demethoxy-11deoxyanthracycline skeleton (eq 72).46 This is especially sig
nificant because methylthio esters are available by an effi
cient C-C connective process involving C-acylation of ketone
lithium enolates with Carbon Oxysulfide (COS) followed by
S-methylation with Iodomethane.46 For the deoxyanthracycline
synthesis, the requisite enolate was generated by 1,4-addition
of a silyl-stabilized benzyllithium derivative to 2-cyclohexenone.
Treatment of the methylseleno ester with (CuOTf)2C6H6 in ben
zene, according to the method employed with analogous seleno
esters, 37 results in efficient cyclization to deliver a tetracyclic diketone in good yield.
115
3.
(a) Hathaway, B. J.; Holah, D. G.; Postlethwaite, J. D. JCS 1961,

3215. (b) Kubota, M.; Johnson, D. L. J. Inorg. Nucl. Chem. 1967,
29, 769.
4.
(a) Salomon, R. G.; Kochi, J. K. CC 1972, 559. (b) Salomon, R. G.;

Kochi, J. K. JACS 1973, 95, 1889. (c) Dines, M. B. Separ. Sci. 1973, 8,
661.
Cohen, X; Ruffner, R. J.; Shull, D. W.; Fogel, E. R.; Falck, J. R. OS
1980, 59, 202; OSC 1988, 6, 737.
5.
6.
Salomon, R. G.; Kochi, J. K. JACS 1973, 95, 3300.
7. Wiberg, K. B.; Kass, S. R.; Bishop, III, K. C. JACS 1985,107, 996.

8. Lewis, R. T.; Motherwell, W. B. TL 1988, 29, 5033.
9.
(a) Evans, D. A.; Woerpel, K. A.; Hinman, M. M.; Paul, M. M. JACS

1991, 113, 726. (b) Evans, D. A.; Woerpel, K. A.; Scott, M. J. AG(E)
1992, 31,430.
10. Trecker, D. J.; Foote, R. S. In Organic Photochemical Synthesis;

Srinivasan, R., Ed.; Wiley: New York, 1971; Vol. 1, p 81.
11. Salomon, R. G.; Kochi, J. K. JACS 1974, 96, 1137.
12.
13.
(72)
O-Acylation with Thioesters. Activation of a thioester with

(CuOTf) 2 C 6 H 6 was exploited as a key step in the synthesis of a
macrocyclic pyrrolizidine alkaloid ester (eq 73). 47 Since thioesters
are relatively unreactive acylating agents, a highly functionalized imidazolide containing acetate and t-butyl thioester groups
selectively acylated only the primary hydroxyl in the presence
of the secondary hydroxyl group in (+)-retronecine. Comple
tion of the synthesis required activation of the t-butylthio es
ter. Mercury(II) Trifluoroacetate, that had proven effective for
the synthesis of several natural products by lactonization,48,49
failed to promote any lactonization in the present case. 47 Simi
larly, Mercury(II) Chloride and Cadmium Chloride, that have
proven effective for promoting lactonizations,49 had no effect in
the present case. Even copper(I) trifluoroacetate failed to induce
the crucial lactonization. In contrast, CuOTf was uniquely effec
tive for inducing the requisite macrolactonization by activating the
thioester.
Salomon, R. G.; Kochi, J. K. JACS 1973, 95, 1889.

Salomon, R. G.; Foiling, K.; Streib, W. E.; Kochi, J. K. JACS 1974, 96,
1145.
14. Evers, J. T. M.; Mackor, A. RTC 1979, 98, 423.
15. Evers, J. T. M.; Mackor, A. TL 1980, 21, 415.
16. Spee, T.; Mackor, A. JACS 1981, 103, 6901.
17. Evers, J. T. M.; Mackor, A. TL 1978, 2317.
18. Salomon, R. G.; Sinha, A. TL 1978, 1367.
19.
Evers, J. T. M.; Mackor, A. TL 1978, 821.
20.
(a) Raychaudhuri, S. R.; Ghosh, S.; Salomon, R. G. JACS 1982, 104,

6841. (b) Ghosh, S.; Raychaudhuri, S. R.; Salomon, R. G. JOC 1987,
52, 83.
21.
Avasthi, K.; Raychaudhuri, S. R.; Salomon, R. G. JOC 1984, 49,

4322.
Hertel, R.; Mattay, J.; Runsink, J. JACS 1991, 113, 657.
(a) Salomon, R. G.; Coughlin, D. J.; Easier, E. M. JACS 1979, 101,3961.
(b) Salomon, R. G.; Ghosh, S. OS 1984, 62, 125; OSC 1990, 7, 177. (c)
Salomon, R. G.; Coughlin, D. J.; Ghosh, S.; Zagorski, M. G. JACS 1982,
104, 998.
Salomon, R. G.; Ghosh, S.; Zagorski, M. G.; Reitz, M. JOC 1982, 47,
829.
22.
23.
24.
25.
Avasthi, K.; Salomon, R. G. JOC 1986, 51, 2556.

Salomon, R. G.; Ghosh, S.; Raychaudhuri, S.; Miranti, T. S. TL 1984,
25,3167.
28. Hefner, J. G.; Zizelman, P. M.; Durfee, L. D.; Lewandos, G. S. JOM
1984, 260, 369.
29. (a) Cohen, T.; Cristea, I. JOC 1975, 40, 3649. (b) Cohen, T.; Cristea, I.
JACS 1976, 98, 748.
30. Cohen, T.; Tirpak, J. TL 1975, 143.
31.
32.
33.
(73)
McMurry, J. E.; Choy, W. TL 1980, 21, 2477.
26.
27.
Cohen, T.; Herman, G.; Falck, J. R.; Mura, Jr., A. J. JOC 1975, 40,
812.
Kwon, T. W.; Smith, M. B. SC 1992, 22, 2273.
Cohen, T.; Mura, A. J.; Shull, D. W.; Fogel, E. R.; Ruffner, R. J.; Falck,
J. R. JOC 1976, 41,3218.
34.
35.
36.
Corey, E. J.; Seebach, D. JOC 1966, 31, 4097.

Cohen, T.; Kosarych, Z. TL 1980, 21, 3955.
Cohen, T.; Gapinski, R. E.; Hutchins, R. R. JOC 1979, 44, 3599.
37.
(a) Kozikowski, A. P.; Ames, A. JACS 1980, 102, 860. (b) Kozikowski,
A. P.; Ames, A. T 1985, 41, 4821.
(a) Corey, E. J.; Noyori, R. TL 1970, 311. (b) Corey, E. J.; Erickson, B.
W.; Noyori, R. JACS 1971, 93, 1724.
38.
1.
(a) Salomon, R. G. Adv. Chem. Ser. 1978, 168, 174. (b) Salomon, R. G.
T 1983, 39, 485. (c) Salomon, R. G.; Kochi, J. K. TL 1973, 2529.
39.
Cohen, T.; Bennett, D. A.; Mura, A. J. JOC 1976, 41, 2506.
2.
Jenkins, C. L.; Kochi, J. K. JACS 1972, 94, 843.
40.
Semmelhack, M. F.; Tomesch, J. C. JOC 1977, 42, 2657.

Next Page
116
41.
42.
Cohen, T.; Kuhn, D.; Falck, J. R. JACS 1975, 97, 4749.

Knapp, S.; Trope, A. R; Ornaf, R. M. TL 1980, 21, 4301.
Knapp, S.; Trope, A. R; Theodore, M. S.; Hirata, N.; Barchi, J. J. JOC

1984, 49, 608.
44. Seebach, D. AG(E) 1967, 6, 442.
45. Cohen, T; Meyers, M. JOC 1988, 53, 457.
46. Vedejs, E.; Nader, B. JOC 1982, 47, 3193.
47.
48.
43.
49.
Huang, J.; Meinwald, J. JACS 1981, 103, 861.

(a) Masamune, S. Aldrichim. Acta 1978, 11, 23. (b) Masamune, S.;
Yamaraoto, H.; Kamata, S.; Fukuzawa, A. JACS 1975, 97, 3513.
Masamune, S.; Kamata, S.; Schilling, W. JACS 1975, 97, 3515.
Robert G. Salomon
Case Western Reserve University, Cleveland, OH, USA
Previous Page
DIAZOMETHANE
Diazomethane1
[334-88-3]
CH 2 N 2
(MW 42.04)
(methylating agent for various functional groups including carboxylic acids, alcohols, phenols, and amides; reagent for the syn
thesis of -diazo ketones from acid chlorides, and the cyclopropanation of alkenes1)
Physical Data: mp - 1 4 5 C; bp - 2 3 C.
Solubility: diazomethane is most often used as prepared in
ether, or in ether containing a small amount of ethanol. It is
less frequently prepared and used in other solvents such as
dichloromethane.
Analysis of Reagent Purity: diazomethane is titrated2 by adding a
known quantity of benzoic acid to an aliquot of the solution such
that the solution is colorless and excess benzoic acid remains.
Water is then added, and the amount of benzoic acid remaining
is back-titrated with NaOH solution. The difference between
the amount of acid added and the amount remaining reveals the
amount of active diazomethane present in the aliquot.
Preparative Methods: diazomethane is usually prepared by
the decomposition of various derivatives of N-methylN-nitrosoamines. Numerous methods of preparation have
been described,3 but the most common and most fre
quently employed are those which utilize N-Methyl-N-nitrosop-toluenesulfonamide
(Diazald; 1),4 1-Methyl-3-nitro-1nitrosoguanidine (MNNG, 2), 5 or N-methyl-N-nitrosourea
(3). 2
The various reagents each have their advantages and dis

advantages, as discussed below. The original procedure6 for
the synthesis of diazomethane involved the use of N-methyl-Nnitrosourea, and similar procedures are still in use today. An ad
vantage of using this reagent is that solutions of diazomethane
can be prepared without distillation,7 thus avoiding the most
dangerous operation in other preparations of diazomethane. For
small scale preparations (1 mmol or less) which do not contain
any alcohol, a kit is available utilizing MNNG which produces
distilled diazomethane in a closed environment. Furthermore,
MNNG is a stable compound and has a shelf life of many years.
For larger scale preparations, kits are available for the synthe
sis of up to 300 mmol of diazomethane using Diazald as the
precursor. The shelf life of Diazald (about 1-2 years), how
117
ever, is shorter than that of MNNG. Furthermore, the common

procedure using Diazald produces an ethereal solution of dia
zomethane which contains ethanol; however, it can be modified
to produce an alcohol-free solution. Typical preparations of dia
zomethane involve the slow addition of base to a heterogeneous
aqueous ether mixture containing the precursor. The precursor
reacts with the base to liberate diazomethane which partitions
into the ether layer and is concomitantly distilled with the ether
to provide an ethereal solution of diazomethane. Due to the
potentially explosive nature of diazomethane, the chemist is
advised to carefully follow the exact procedure given for a par
ticular preparation. Furthermore, since diazomethane has been
reported to explode upon contact with ground glass, apparatus
which do not contain ground glass should be used. All of the
kits previously mentioned avoid the use of ground glass.
Handling, Storage, and Precautions: diazomethane as well as the
precursors for its synthesis can present several safety hazards,
and must be used with great care. 8 The reagent itself is highly
toxic and irritating. It is a sensitizer, and long term exposure
can lead to symptoms similar to asthma. It can also detonate
unexpectedly, especially when in contact with rough surfaces,
or on crystallization. It is therefore essential that any glassware
used in handling diazomethane be fire polished and not contain
any scratches or ground glass joints. Furthermore, contact with
certain metal ions can also cause explosions. Therefore metal
salts such as calcium chloride, sodium sulfate, or magnesium
sulfate must not be used to dry solutions of the reagent. The rec
ommended drying agent is potassium hydroxide. Strong light
is also known to initiate detonation. The reagent is usually gen
erated immediately prior to use and is not stored for extended
periods of time. Of course, the reagent must be prepared and
used in a well-ventilated hood, preferably behind a blast shield.
The precursors used to generate diazomethane are irritants and
in some cases mutagens and suspected carcinogens, and care
should be exercised in their handling as well.
Methylation of Heteroatoms. The most widely used feature

of the chemistry of diazomethane is the methylation of carboxylic
acids. Carboxylic acids are good substrates for reaction with di
azomethane because the acid is capable of protonating the dia
zomethane on carbon to form a diazonium carboxylate. The carboxylate can then attack the diazonium salt in what is most likely
an S N 2 reaction to provide the ester. Species which are not acidic
enough to protonate diazomethane, such as alcohols, require an ad
ditional catalyst, such as Boron Trifluoride Etherate, to increase
their acidity and facilitate the reaction. The methylation reaction
proceeds under mild conditions and is highly reliable and very
selective for carboxylic acids. A typical procedure is to add a yel
low solution of diazomethane to the carboxylic acid in portions.
When the yellow color persists and no more gas is evolved, the
reaction is deemed complete. Excess reagent can be destroyed by
the addition of a few drops of acetic acid and the entire solution
concentrated to provide the methyl ester.
Esterification of Carboxylic Acids and Other Acidic Func

tional Groups. A variety of functional groups will tolerate the
esterification of acids with diazomethane. Thus ,-unsaturated
carboxylic acids and alcohols survive the reaction (eq 1), 9 as
118
DIAZOMETHANE
do ketones (eq 2),10 isolated alkenes (eq 3),11 and amines

(eq 4).12
lation with diazomethane to provide the methyl ester and aldehyde

(eq 10).18
(1)
(9)
(2)
(10)
(3)
(4)
Other acidic functional groups will also undergo reaction

with diazomethane. Thus phosphonic acids (eq 5)13 and phenols
(eq 6)14 are methylated in high yields, as are hydroxytropolones
(eq 7)15 and vinylogous carboxylic acids (eq 8).16 The origin of
the selectivity in eq 6 is due to the greater acidity of the A-ring
phenol.
Methylation of Alcohols and Other Less Acidic Functional

Groups. As previously mentioned, alcohols require the addition
of a catalyst in order to react with diazomethane. The most com
monly used is boron trifluoride etherate (eq 11 ),19 but Tetrafluoroboric Acid has been used as well (eq 12).20 Mineral acids are
not effective since they rapidly react with diazomethane to pro
vide the corresponding methyl halides. Acids as mild as silica gel
are also effective (eq 13).21 Monomethylation of 1,2-diols with
diazomethane has been reported using various Lewis acids as pro
moters, the most effective of which is Tin(II) Chloride (eq 14).22
(11)
(5)
(12)
(6)
(13)
(7)
(14)
(8)
Selective monomethylation of dicarboxylic acids has been re

ported using Alumina as an additive (eq 9).17 It is thought that
one of the two carboxylic acid groups is bound to the surface
of the alumina and is therefore not available for reaction. Car
boxylic acids that are engaged as lactols will also undergo methyLists of Abbreviations and Journal Codes on Endpapers
An interesting case of an alcohol reacting with diazomethane

at a rate competitive with a carboxylic acid has been reported
(eq 15).23 In this case, the tertiary structure of the molecule is
thought to place the alcohol and the carboxylic acid in proximity
to each other. Protonation of the diazomethane by the carboxylic
acid leads to a diazonium ion in proximity to the alcohol as well
as the carboxylate. These species then attack the diazonium ion at
competitive rates to provide the methyl ether and ester. No reaction
is observed upon treatment of the corresponding hydroxy ester
DIAZOMETHANE
with diazomethane, indicating that the acid is required to activate

the diazomethane.
119
(17)
(18)
(15)
(19)
Amides can also be methylated with diazomethane in the pres

ence of silica gel; however, the reaction requires a large excess of
diazomethane (25-60 equiv, eq 16).24 The reaction primarily pro
vides O-methylated material; however, in one case a mixture of Oand N-methylation was reported. Thioamides are also effectively
methylated with this procedure to provide S-methylated com
pounds. Finally, amines have been methylated with diazomethane
in the presence of BF3 etherate, fluoroboric acid,25 or copper(I)
salts;26 however, the yields are low to moderate, and the method
is not widely used.
(16)
The Arndt-Eistert Synthesis. Diazomethane is a useful

reagent for the one-carbon homologation of acid chlorides via a
sequence of reactions known as the Arndt-Eistert synthesis. The
first step of this sequence takes advantage of the nucleophilicity
of diazomethane in its addition to an active ester, typically an
acid chloride,27 to give an isolable -diazo ketone and HCl. The
HCl that is liberated from this step can react with diazomethane
to produce methyl chloride and nitrogen, and therefore at least
2 equiv of diazomethane are typically used. The -diazo ketone
is then induced to undergo loss of the diazo group and insertion
into the adjacent carbon-carbon bond of the ketone to provide a
ketene. The ketene is finally attacked by water or an alcohol (or
some other nucleophile) to provide the homologated carboxylic
acid or ester. This insertion step of the sequence is known as
the Wolff rearrangement28 and can be accomplished either ther
mally (eq 17)29 or, more commonly, by treatment with a metal
ion (usually silver salts, eq 18),30 or photochemically (eq 19).31
It has been suggested that the photochemical method is the most
efficient of the three.32 As eqs 18 and 19 illustrate, retention of
configuration is observed in the migrating group. The obvious lim
itations of this reaction are that there must not be functional groups
present in the molecule which will react with diazomethane more
rapidly than it will attack the acid chloride. Thus carboxylic acids
will be methylated under these conditions. Furthermore, electrondeficient alkenes will undergo [2,3] dipolar cycloaddition with di
azomethane more rapidly than addition to the acid chloride. Thus
when the Arndt-Eistert synthesis is attempted on ,-unsaturated
acid chlorides, cycloaddition to the alkene is observed in the prod
uct. In order to prevent this, the alkene must first be protected by
addition of HBr and then the reaction carried out in the normal
way (eq 20).33 Cycloaddition to isolated alkenes, however, is not
competitive with addition to acid chlorides.
(20)
Other Reactions of -Diazo Ketones Derived from Dia

zomethane. Depending on the conditions employed, the Wolff
rearrangement may proceed via a carbene or carbenoid interme
diate, or it may proceed by a concerted mechanism where the
insertion is concomitant with loss of N2 and no intermediate is
formed. In the case where a carbene or carbenoid is involved,
other reactions which are characteristic of these species can oc
cur, such as intramolecular cyclopropanation of alkenes. In fact,
the reaction conditions can be adjusted to favor cyclopropanation
or homologation depending on which is desired. Thus treatment
of the dienoic acid chloride shown in eq 21 with diazomethane
followed by decomposition of the -diazo ketone with silver benzoate in the presence of methanol and base provides the homolo
gated methyl ester. However, treatment of the same diazoketone
intermediate with CuII salts provides the cyclopropanation prod
ucts selectively.34 This trend is generally observed; that is, silver
salts as well as photochemical conditions (eqs 18 and 19) favor
the homologation pathway while copper or rhodium salts favor
cyclopropanation.35 Using copper salts to decompose the diazo
compounds, hindered alkenes as well as electron-rich aromatics
can be cyclopropanated as illustrated in eqs 22 and 23,36,37 re
spectively.
(21)
(22)
120
DIAZOMETHANE
(23)
In addition to these reactions, -diazo ketones will undergo

protonation on carbon in the presence of protic acids38 to pro
vide the corresponding -diazonium ketone. These species are
highly electrophilic and can undergo nucleophilic attack. Thus if
the proton source contains a nucleophile such as a halogen then
the corresponding -halo ketone is isolated (eq 24).39 However,
if the proton source does not contain a nucleophilic counterion
then the diazonium species may react with other nucleophiles that
are present in the molecule, such as alkenes (eq 25)40 or aromatic
rings (eq 26).41 Note the similarity between the transformations
in eqs 26 and 23 which occur using different catalysts and by dif
ferent pathways. Also, eq 26 illustrates the fact that other active
esters will undergo nucleophilic attack by diazomethane.
a bicyclo[2.1.0]pentanone derivative. This compound then under

goes a fragmentation to a ketene alkene before being trapped by
the solvent (eq 29). Inspection of the products reveals that they
are identical with those derived from the Claisen rearrangement
of the corresponding allylic alcohols, and as such this method can
be thought of as an alternative to the Claisen procedure. However,
the stereoselectivity of the alkene that is formed is not as high as
is typically observed in the Claisen rearrangement (eq 30), and in
some substrates the reaction proceeds with no selectivity (eq 31).
(28)
(24)
(29)
(25)
(26)
(30)
Lewis acids are also effective in activating -diazo ketones to

wards intramolecular nucleophilic attack by alkenes and arenes.42
The reaction has been used effectively for the synthesis of cyclopentenones (eq 27) starting with ,-unsaturated diazo ketones
derived from the corresponding acid chloride and diazomethane.
It has also been used to initiate polyalkene cyclizations (eq 28).
Typically, boron trifluoride etherate is used as the Lewis acid, and
electron-rich alkenes are most effective providing the best yields
of annulation products.
(31)
(27)
The Vinylogous Wolff Rearrangement. The vinylogous

Wolff rearrangement43 is a reaction that occurs when the
Arndt-Eistert synthesis is attempted on ,-unsaturated acid chlo
rides using copper catalysis. Rather than the usual homologation
products, the reaction proceeds to give what is formally the prod
uct of a [2,3]-sigmatropic shift, but is mechanistically not derived
by this pathway.44 The mechanism is thought to proceed by an ini
tial cyclopropanation of the alkene by the -diazo ketone to give
Insertions into Aldehyde C-H Bonds. The -diazo ketones

(and esters) derived from diazomethane and an acid chloride (or
chloroformate) will also insert into the C-H bond of aldehydes
to give 1,3-dicarbonyl derivatives.45 The reaction is catalyzed by
SnCh, but some simple Lewis acids, such as BF3 etherate, also
work. The reaction works well for aliphatic aldehydes, but gives
variable results with aromatic aldehydes, at times giving none of
the desired diketone (eq 32). Sterically hindered aldehydes will
also participate in this reaction, as illustrated in eq 33 with the reac
tion of ethyl -diazoacetate and pivaldehyde. In a related reaction,
-diazo phosphonates and sulfonates will react with aldehydes in
DIAZOMETHANE
the presence of SnCh to give the corresponding -keto phosphonates and sulfonates.46 This reaction is a practical alternative to
the Arbuzov reaction for the synthesis of these species.
121
51
the hydrocarbon (eq 36). Aldehydes will also react with dia
zomethane, but in this case homologation is not observed. Rather,
the corresponding methyl ketone derived from migration of the
hydrogen is produced (eq 37).
(32)
(35)
(33)
(36)
Additions to Ketones. The addition of diazomethane to

ketones 47 is also a preparatively useful method for one-carbon
homologation. This reaction is a one-step alternative to the
Tiffeneau-Demjanow rearrangement48 and proceeds by the mech
anism shown in eq 34. It can lead to either homologation or epoxidation depending on the substrate and reaction conditions. The
addition of Lewis acids, such as BF 3 etherate, or alcoholic cosolvents tend to favor formation of the homologation products over
epoxidation.
(34)
However, the reaction is limited by the poor regioselectivity

observed in the insertion when the groups R1 and R2 in the start
ing ketone are different alkyl groups. What selectivity is ob
served tends to favor migration of the less substituted carbon,49
a trend which is opposite to that typically observed in rearrange
ments of electron-deficient species such as in the Baeyer-Villiger
reaction. Furthermore, the product of the reaction is a ketone
and is therefore capable of undergoing further reaction with di
azomethane. Thus, ideally, the product ketone should be less
reactive than the starting ketone. Strained ketones tend to re
act more rapidly and are therefore good substrates for this re
action (eq 35). 50 This method has also found extensive use in
cyclopentane annulation reactions starting with an alkene. The
overall process begins with dichloroketene addition to the alkene
to produce an -dichlorocyclobutanone. These species are ideally
suited for reaction with diazomethane because the reactivity of
the starting ketone is enhanced due to the strain in the cyclobutanone as well as the -dichloro substitution. Furthermore, the
presence of the -dichloro substituents hinders migration of that
group and leads to almost exclusive migration of the methylene
group. Thus treatment with diazomethane and methanol leads to
a rapid evolution of nitrogen, and produces the corresponding dichlorocyclopentanone, which can be readily dehalogenated to
(37)
Cycloadditions with Diazomethane. Diazomethane will un

dergo [3 + 2] dipolar cycloadditions with alkenes and alkynes to
give pyrazolines and pyrazoles, respectively.52 The reaction pro
ceeds more rapidly with electron-deficient alkenes and strained
alkenes and is controlled by FMO considerations with the HOMO
of the diazomethane and the LUMO of the alkene serving as the
predominant interaction.53 In the case of additions to electrondeficient alkenes, the carbon atom of the diazomethane behaves
as the negatively charged end of the dipole, and therefore the
regiochemistry observed is as shown in eq 38. With conjugated
alkenes, such as styrene, the terminal carbon has the larger lobe in
the LUMO, and as such the reaction proceeds to give the product
shown in eq 39. Pyrazolines are most often used as precursors
to cyclopropanes by either thermal or photochemical extrusion of
N 2 . In both cases the reaction may proceed by a stepwise mecha
nism with loss of stereospecificity. As shown in eq 40, the thermal
reaction provides an almost random product distribution, while
the photochemical reaction provides variable results ranging from
20:1 to stereospecific extrusion of nitrogen.54
(38)
(39)
(40)
Cyclopropanes can also be directly synthesized from alkenes

and diazomethane, either photochemically or by using transiAvoid Skin Contact with All Reagents
122
DIAZOMETHANE
tion metal salts, usually Copper(II) Chloride or Palladium(II)

Acetate, as promoters. The metal-mediated reactions are more
commonly used than the photochemical ones, but they are not
as popular as the Simmons-Smith procedure. However, they do
occasionally offer advantages. Of the two processes, the Cucatalyzed reaction produces a more active reagent55 which will cyclopropanate a variety of alkenes, including enamines as shown in
eq 41. 56 These products can then be converted to -methyl ketones
by thermolysis. The cyclopropanation of the norbornenol deriva
tive shown in eq 42 was problematic using the Simmons-Smith
procedure and provided low yields, but occurred smoothly using
the CuCl2/diazomethane method.57
Additions to Electron-Deficient Species. Diazomethane will

also add to highly electrophilic species such as sulfenes or imminium salts to give the corresponding three-membered ring heterocycles. When the reaction is performed on sulfenes, the products
are episulfones which are intermediates in the Ramberg-Backlund
rearrangement, and are therefore precursors for the synthesis of
alkenes via chelotropic extrusion of SO2. The sulfenes are typi
cally prepared in situ by treatment of a sulfonyl chloride with a
mild base, such as Triethylamine (eq 47).62 Similarly, the addi
tion of diazomethane to imminium salts has been used to methylenate carbonyls.63 In this case, the intermediate aziridinium salt is
treated with a strong base, such as n-Butyllithium, in order to
induce elimination (eq 48).
(41)
(47)
(42)
(48)
The Pd(OAc)2-mediated reaction can be used to cyclopropanate

electron-deficient alkenes as well as terminal alkenes. Thus selec
tive reaction at a monosubstituted alkene in the presence of oth
ers is readily achieved using this method (eq 43).58 The example
shown in eq 44 is one in which the Simmons-Smith procedure
failed to provide any of the desired product, whereas the current
method provided a 92% yield of cyclopropane.59
(43)
(44)
Miscellaneous Reactions. Diazomethane has been shown to

react with vinylsilanes derived from ,-unsaturated esters to pro
vide the corresponding allylsilane by insertion of CH2 into the
C-Si bond (eq 49).64 The reaction has been shown to be stereospecific, with cw-vinylsilane providing cis-allylsilanes; however, the
mechanism of the reaction has not been defined. Diazomethane
has also been used in the preparation of trimethyloxonium salts.
Treatment of a solution of dimethyl ether and trinitrobenzenesulfonic acid with diazomethane provides trimethyloxonium trinitrobenzenesulfonate, which is more stable than the fluoroborate
salt.65
(49)
In the case of the photochemical reaction, irradiation of diazomethane in the presence of cis-2-butene provides cis-1,2dimethylcyclopropane with no detectable amount of the trans iso
mer (eq 45).60 This reaction is thought to proceed via a singlet
carbene. However, if the same reaction is carried out via a triplet
carbene, generated via triplet sensitization, then a 1.3:1 mixture
of trans to cis dimethylcyclopropane is observed (eq 46).61 The
yields in the photochemical reaction are typically lower than the
metal-mediated processes, and are usually accompanied by more
side products.
Related Reagents. 2-Diazopropane; 1-Diazo-2-propene;

Dimethyl Sulfate; Diphenyldiazomethane; Methyl Fluorosulfate;
Phenyldiazomethane; Trimethyloxonium Tetrafluoroborate;
Trimethyl Phosphate; Trimethylsilyldiazomethane.
1.
(a) Regitz, M.; Maas, G. Diazo Compounds, Properties and Synthesis;

Academic: Orlando, 1986. (b) Black, T. H. Aldrichim. acta 1983,16, 3.
(c) Pizey, J. S. Synthetic Reagents; Wiley: New York, 1974; Vol. 2, pp
65-142.
(45)
2.
3.
(46)
4.
Arndt, F. OSC 1943, 2, 165.

Moore, J. A.; Reed, D. E. OSC 1973, 5, 351. Redemann, C. E.; Rice, F. O.;
Roberts, R.; Ward, H. P. OSC 1955, 3, 244. McPhee, W. D.; Klingsberg,
E. OSC 1955, 3, 119.
De Boer, Th. J.; Backer, H. J. OSC 1963, 4, 250. Hudlicky, M. JOC
1980,45,5377. See also Aldrich Chemical Company Technical Bulletins
Number AL-121 and AL-131. Note that the preparation described in FF,
DI-t-BUTYL DICARBONATE
1967, 7, 191 is flawed and neglects to mention the addition of ethanol.
Failure to add ethanol can result in a buildup of diazomethane and a
subsequent explosion.
5. McKay, A. F. JACS 1948, 70,1914. See also Aldrich Chemical Company
Technical Bulletin Number AL-132.
6. von Pechman, A. CB 1894, 27, 1888.
7. Ref. 2, note 3.
8. For a description of the safety hazards associated with diazomethane,
see: Gutsche, C. D. OR 1954, 8, 391.
9. Fujisawa, T.; Sato, X; Itoh, T. CL 1982, 219.
10.
Nicolaou, K. C ; Paphatjis, D. P.; Claremon, D. A.; Dole, R. E. JACS

1981,103, 6967.
11. Fujisawa, T.; Sato, T.; Kawashima, M ; Naruse, K.; Tamai, K. TL 1982,
23, 3583.
12. Kozikowski, A. P.; Sugiyama, K.; Springer, J. P. JOC 1981,46, 2426.
13. De, B.; Corey, E. J. TL 1990, 31, 4831. Macomber, R. S. SC 1977, 7,
405.
14. Blade, R. J.; Hodge, P. CC 1979, 85.
15. Kawamata, A.; Fukuzawa, Y.; Fujise, Y.; Ito, S. TL 1982, 23, 1083.
16. Ray, J. A.; Harris, T. M. TL 1982, 23, 1971.
17. Ogawa, H.; Chihara, T.; Taya, K. JACS 1985, 707, 1365.
18. Frimer, A. A.; Gilinsky-Sharon, P.; Aljadef, G. TL 1982, 23, 1301.
19. Chavis, C ; Dumont, F.; Wightman, R. H.; Ziegler, J. C ; Imbach, J. L.
JOC 1982, 47, 202.
20. Neeman, M.; Johnson, W. S. OSC 1973, 5, 245.
21. Ohno, K.; Nishiyama, H.; Nagase, H. TL 1979, 20, 4405.
22. Robins, M. J.; Lee, A. S. K.; Norris, F. A. Carbohydr. Res. 1975, 41,
304.
23. Evans, D. S.; Bender, S. L.; Morris, J. JACS 1988, 110, 2506. For asimilar
example with the antibiotic lasalocid, see: Westly, J. W.; Oliveto, E. P.;
Berger, J.; Evans, R. H.; Glass, R.; Stempel, A.; Toome, V; Williams, T.
JMC 1973, 16, 397.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
Nishiyama, H.; Nagase, H.; Ohno, K. TL 1979, 20, 4671.

Muller, v. H.; Huber-Emden, H.; Rundel, W. LA 1959, 623, 34.
Seagusa, T.; Ito, Y.; Kobayashi, S.; Hirota, K.; Shimizu, T. TL 1966, 7,
6131.
In addition to acid chlorides, -diazo ketones can be synthesized from
carboxylic acid anhydrides; however, in this case one equivalent of
the carboxylic acid is converted to the corresponding methyl ester.
Furthermore, the anhydride can be formed in situ using DCC. See
Hodson, D.; Holt, G.; Wall, D. K. JCS(C) 1970, 971.
For a review of the Wolff rearrangement, see: Meier, H.; Zeller, K.-P.
AG(E) 1975, 14, 32.
Bergmann, E. D.; Hoffmann, E. JOC 1961, 26, 3555.
Clark, R. D. SC 1979, 9, 325.
Smith, A. B.; Dorsey, M.; Visnick, M.; Maeda, T.; Malamas, M. S. JACS
1986, 70S, 3110.
Smith, A. B.; Toder, B. H.; Branca, S. J.; Dieter, R. K. JACS 1981, 103,
1996.
Rosenquist, N. R.; Chapman, O. L. JOC 1976, 41, 3326.
Hudliky, T.; Sheth, J. P. TL 1979, 20, 2667.
For a review of intramolecular reactions of -diazo ketones, see: Burke,
S. D.; Grieco, P. A. OR 1979, 26, 361.
Murai, A.; Kato, K.; Masamune, T. TL 1982, 23, 2887.
Iwata, C ; Fusaka, T.; Fujiwara, T.; Tomita, K.; Yamada, M. CC 1981,
463.
For a review on the reactions of -diazo ketones with acid, see: Smith,
A. B.; Dieter, R. K. T 1981, 37, 2407.
Ackeral, J.; Franco, F.; Greenhouse, R.; Guzman, A.; Muchowski, J. M.
JHC 1980,17, 1081.
Ghatak, U. R.; Sanyal, B.; Satyanarayana, G.; Ghosh, S. JCS(P1) 1981,
1203.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
123
Blair, I. A.; Mander, L. N. AJC 1979, 32, 1055.

Smith, A. B.; Toder, B. H.; Branca, S. J.; Dieter, R. K. JACS 1981, 103,
1996. Smith, A. B.; Dieter, K. JACS 1981, 103, 2009. Smith, A. B.;
Dieter, K. JACS 1981, 103, 2017.
Smith, A. B.; Toder, B. H.; Branca, S. J. JACS 1984, 706, 3995.
Smith, A. B.; Toder, B. H.; Richmond, R. E.; Branca, S. J. JACS 1984,
106,4001.
Holmquist, C. R.; Roskamp, E. J. JOC 1989, 54, 3258. Padwa, A.;
Hornbuckle, S. F.; Zhang, Z. Z.; Zhi L. JOC 1990, 55, 5297.
Holmquist, C. R.; Roskamp, E. J. TL 1992, 33, 1131.
For a review of this reaction, see: Gutsche, C. D. OR 1954, 8, 364.
For a review, see: Smith, P. A. S.; Baer, D. R. OR 1960, 77, 157.
House, H. O.; Grubbs, E. J.; Gannon, W. F. JACS 1960, 82, 4099.
Majerski, Z.; Djigas, S.; Vinkovic, V. JOC 1979, 44, 4064.
Greene, A. E.; Depres, J-P. JACS 1979, 707, 4003.
For a review, see: Regitz, M.; Heydt, H. In 1,3-Dipolar Cycloadditions
Chemistry; Padwa, A.; Ed.; Wiley: New York, 1984; p 393.
For a discussion of the orbital interactions that control dipolar additions
of diazomethane, see: Fleming, I. Frontier Molecular Orbitals and
Organic Chemical Reactions; Wiley: New York, 1976; pp 148-161.
Van Auken, T. V.; Rienhart, K. L. JACS 1962, 84, 3736.
This is a very reactive reagent combination which will cyclopropanate
benzene and other aromatic compounds. See: Vogel, E.; Wiedeman, W.;
Kiefe, H.; Harrison, W. F. TL 1963, 4, 673. Muller, E.; Kessler, H.;
Kricke, H.; Suhr, H. TL 1963, 4, 1047.
Kuehne, M. E.; King, J. C. JOC 1973, 38, 304.
Pincock, R. E.; Wells, J. I. JOC 1964, 29, 965.
Suda,M. S 1981,714.
Raduchel, B.; Mende, U.; Cleve, G.; Hoyer, G. A.; Vorbruggen, H. TL
1975, 76, 633.
Doering, W. von E.; LaFlamme, P. JACS 1956, 78, 5447.
Duncan, F. J.; Cvetanovic, R. J. JACS 1962, 84, 3593.
Fischer, N.; Opitz, G. OSC 1973, J, 877.
Hata, Y.; Watanabe, M. JACS 1973, 95, 8450.
Cunico, R. F.; Lee, H. M.; Herbach, J. JOM 1973, 52, C7.
Helmkamp, G. K.; Pettit, D. J. OSC 1973, 5, 1099.
Tarek Sammakia
University of Colorado, Boulder, CO, USA
[24424-99-5]
C 10 H 18 O 5
(MW 218.25)
(efficient t-butoxycarbonylating agent for amines, 12 phenols,

and thiols; t-butoxycarbonylation of alcohols, amides, 3 lactams,
carbamates4 and NH-pyrroles5 occurs in the presence of 4dimethylaminopyridine)
Alternate Names: di-t-butyl pyrocarbonate; Boc anhydride;
Boc 2 O.
Physical Data: mp 22-24 C; bp 56-57 C/0.5 mm Hg; fp 37 C;
d 0.950 g c m - 3 ; n D 20 1.4103.
Solubility: insol cold H 2 O; sol most organic solvents such as decalin, toluene, CCl 4 , THF, dioxane, alcohols, acetone, MeCN,
DMF.
124
Form Supplied in: colorless liquid; widely available.

Analysis of Reagent Purity: IR 1810 and 1765 c m - 1 ; NMR 1.50
(CCU).
Preparative Method: prepared by the action of Phosgene on
potassium t-butyl carbonate, followed by conversion of the ob
tained di-t-butyl tricarbonate under the action of basic catalysts
such as 1,4-Diazabicyclo[2.2.2]octane.6
Handling, Storage, and Precautions: the liquid is flammable and
must be stored in a refrigerator in the absence of moisture. Do
not heat above 80 C.
t-Butoxycarbonylation of Amines. Owing to the instability of

the corresponding chloride (t-Butyl Chloroformate), the BoC2O
reagent is widely used for the introduction of the t-butoxycarbonyl
amino protecting group (Boc). This group is easily removed un
der moderately acidic conditions such as treatment with Trifluoroacetic Acid, or by thermolysis. The Boc-NHR group is not
hydrolyzed under basic conditions and is inert to many other
nucleophiles.1 Therefore the use of this amino protecting group
is not limited to amino acid and peptide synthesis; it has been ex
tended to the synthesis of amino sugars, alkaloids, etc. The great
importance of the t-butyl carbamate function in peptide synthesis
is not only due to the ease of its cleavage, but also to the fact
that the oxazolones formed from the activated N-alkoxycarbonyl
amino acids do not usually epimerize (racemize) during coupling
with amines.7
BoC2O reacts smoothly and rapidly with amino compounds in
organic solvents, or aqueous organic solvent mixtures, to form
pure derivatives in high yields, the only byproducts being the
innocuous and easily removable t-butanol and carbon dioxide
(eq 1). Innumerable examples are available. 8-11 Hydroxylamine
slightly accelerates the reaction through the in situ formation of
the Boc-ONH 2 intermediate.12 The reaction is also accelerated
by sonication of the amine salts. 13
cyclic amines provides amines which are substituted adjacent to

the nitrogen atom. 15
A suspension of 4-dimethylaminopyridinium fiuoroborate in
ethyl acetate reacts with Boc 2 O to give the corresponding 1t-butoxycarbonyl-4-dimethylaminopyridinium salt, which is an
efficient water-soluble agent for the t-butoxycarbonylation of
amines (eq 3). 24
(2)
(3)
Interesting chemo- and regioselective alkoxycarbonylation of

polyfunctional substrates, e.g. diamines, amino alcohols, and
amino acids, can be achieved under mild conditions. Treatment of
,-alkanediamines (6-10 molar excess) with the reagent in dioxane or acetone as solvent leads to the corresponding mono-Boc
diamines in 75-90% yields (eq 4). 25,26
(4)
(1)
14
15
16,17
Aliphatic,
alicyclic,
aromatic,
and heterocyclic
amines 1 8 , 9 have been t-butoxycarbonylated under a variety of
conditions. Anilines are sometimes heated at reflux in THF to ob
tain the corresponding Boc derivatives in good yields. However,
t-butoxycarbonylation also occurs at rt,17 and 4-aminobenzoic
acid reacts in DMF/aq NaOH at rt.20 The Boc-NHR substituent
is an ortto-directing group in heteroatom-facilitated lithiations
of aromatic and heterocyclic amines. 16,18,19,21 Reaction of the
resultant carbanions (eq 2), as well as that of the analogous
benzylic carbanions, with electrophiles is a powerful method for
the synthesis of substituted anilines and heterocycles. 16,22
Asymmetric deprotonation of Boc-pyrrolidine with sButyllithiuml()-Sparteine gives a chiral organolithium reagent,
which undergoes reaction with electrophiles to give enantiomerically enriched products. 23 The sequence of equatorial -lithiation
followed by an electrophilic substitution of a series of N-Boc
N-Boc-L-lysine has been selectively prepared from the copper

complex of lysine. 27 This complex, as well as that of N-BocL-ornithine, has been directly benzyloxycarbonylated to give the
corresponding -Cbz--Boc amino acids (eq 5). 28
(5)
In CH 2 Cl 2 at low temperature, selective t-butoxycarbonylation

of a -amino- in the presence of an -amino-ester function has
been recently realized (eq 6). 29
125
39
(6)
The substitution of a secondary amino group in the presence

of a primary amine has been performed by an indirect route: for
mation of the labile Schiff base of the primary amine and then
t-butoxycarbonylation of the secondary nitrogen (eq 7). 30 Selec
tive protection of polyamines may also be achieved by an indirect
route in the presence of DMAP (see below).
proteins. For the t-butoxycarbonylation of insulin, Boc 2 O is

much more reactive than the corresponding succinimidyl and pnitrophenyl esters.40 Bamberger ring-cleavage of the imidazole
nucleus slowly occurs in the presence of Potassium t-Butoxide.41
Selective N-protection of amino alcohols is also easily performed
(eqll).42
(10)
(11)
(7)
The Boc2O reagent has been widely used for the N-protection
of amino acids and peptides. When a carboxylic acid function is
present in the molecule, 1 equiv of base (NaOH, Et 3 N, Triton B)
is necessary (eq 8). 10,11,31
At pH 10.3, hydroxylamine itself gives the O-substituted

product,12 whereas treatment of N-alkylhydroxylamines in dioxane furnishes the N-Boc derivatives (eq 12).43 The O-Boc
hydroxylamine 12,44 as well as O-Boc oximes 45 are themselves
efficient t-butoxycarbonylating agents.
(8)
(12)
To avoid loss of the O-labeling, trialkylammonium salts of

amino acids have been t-butoxycarbonylated in dry methanol or
DMF. 32 N-t-butoxycarbonylation of an alkaline labile and hin
dered 2,2-dimethylthiazolidine-4-carboxylic acid has been per
formed in acetonitrile (eq 9). 33
Hydrazines and hydrazides are acylated by the reagent.46 The

mono-Boc derivatives of hydrazine or phenylhydrazine, obtained
in isopropanol, react further with Boc 2 O in benzene or dioxane
to give the (Boc-NR) 2 diacylated derivatives. Regioselective Nprotection of ethyl hydrazinoacetate is performed at 0 C and the
product used for the synthesis of hydrazino peptides (eq 13).47
(9)
(13)
In the presence of pyridine, a free carboxylic function reacts

with the reagent to give a mixed anhydride (see below). This re
action also occurs during the acylation of an amino acid salt with
Boc 2 O and is responsible for the formation of small amounts of
dipeptide byproducts by aminolysis of the mixed anhydride inter
mediate (eq 10).34
t-Butoxycarbonylation of phenolic amino acids in aqueous
Potassium Hydroxide gives the N,O-bis-Boc derivatives.35 Un
der phase-transfer conditions, selective N-t-butoxycarbonylation
of tyrosine ethyl ester has been observed (see below). The SH
group of cysteine,36 the imidazole of histidine,37 and even the
guanidine function of arginine38 have been acylated. Boc 2 O has
been used for the chemical modification of histidine residues of
Boc-amines can also be prepared directly from azides by hydrogenation in the presence of Boc 2 O (eq 14).48
(14)
The alkylation of Boc-amines, particularly that of the more

acidic Boc-anilines17 and the selective alkylation of N-Boc amino
126
acids, 49-51 has been done by using an alkylating agent and Sodium
Hydride or Silver(II) Oxide as a base. For the N-perbenzylation of
N-Boc peptides a P4-phosphazene base (see Phosphazene Base
P4-t-Bu) has been used at - 1 0 0 C. 52
Exchange
of
Amino-Protecting
Groups. N-Benzyloxycarbonyl (Cbz) and 9-fiuorenylmethyloxycarbonyl (Fmoc)
amino protecting groups are also widely used in peptide
synthesis.2 The choice of protecting groups, and hence of the
conditions for their cleavage (Cbz: hydrogenolysis or HBr/HOAc;
Fmoc: piperidine or F - ) 1 plays a key role in the planning of
a synthesis. For instance, orthogonal protection (Boc/Cbz or
Fmoc/Boc or Cbz) is of crucial importance in the case of
the trifunctional amino acids. For a given peptide segment,
chemoselective transformation of an amino protecting group into
another one under neutral conditions may be very useful for the
synthesis.
In the presence of a slight excess of Boc 2 O, conversion of a
benzyl carbamate into a t-butyl carbamate has been achieved by
catalytic hydrogenation,53 or by the use of cyclohexadiene as an
hydrogen donor (eq 15).54 The catalytic transfer hydrogenation
is the more selective: benzyl and BOM ethers are stable under
the reaction conditions. The Cbz Boc transformation can also
be performed using triethylsilane and a palladium catalyst.53 The
replacement of a Fmoc group by a Boc group has recently been
achieved by the in situ cleavage of the Fmoc group with Potassium
Fluoride in DMF (eq 15).55
philic amide and carbamate groups under anhydrous condi

tions. The reaction probably involves a 1-t-butoxycarbonyl4-dimethylaminopyridinium ion intermediate (eq 3). 24 This
enhanced reactivity has led to numerous interesting synthetic ap
plications. A wide range of amides, lactams, and urethanes have
been converted to the corresponding Boc derivatives using Boc2O
as reagent and DMAP as catalyst.
Secondary amides and lactams react with Boc2O in the pres
ence of both Triethylamine and DMAP in CH 2 Cl 2 to give stable
N-t-butoxycarbonylated products (eq 16).3 In the reaction of disubstituted pyrrolidones, the yields are much higher using THF as
solvent than with dichloromethane. 59
(16)
(15)
Ar = Ph
H2, 5% Pd/C, MeOH, rt, 5-40 h, 93-95%
1,4-cyclohexadiene, 10% Pd/C, EtOH, rt, 0.3-5 h, 86-96%
Et3SiH, Pd(OAc)2, Et3N, EtOH, rt, 15-30 h, 91-97%
KF, Et3N, DMF, rt, 5-10 h, 84-93%
t-Butoxycarbonylation of Phenols, Alcohols, Enols, and

Thiols. In alkaline media the nucleophilic phenolate
salts are easily t-butoxycarbonylated.35,56 Acylation of pdimethylsulfoniophenol gives a sulfonium salt which is a new
water-soluble t-butoxycarbonylating agent for amino acids. 57
Under anhydrous conditions, thiolate salts are also substituted
in good yields using the Boc 2 O reagent.56 Under phase-transfer
conditions, t-butoxycarbonylation of phenols as well as enols,
thiols, or alcohols can be realized. For phenols, enols, and thiols,
K 2 CO 3 (powder)/18-crown-6/THF are the best experimental
conditions. Biphasic conditions (Bu 4 NHSO 4 /CH 2 Cl 2 /aq. NaOH)
are also effective with sluggish alcoholic groups. 56 Using 1 equiv
of Boc 2 O, selective N-t-butoxycarbonylation of tyrosine ethyl
ester can be achieved. N,S-Bis(Boc)-cysteine ethyl ester has also
been prepared.56 The t-butoxycarbonylation of alcohols to give
alkyl t-butyl carbonates is efficiently catalyzed by DMAP. 58
t-Butoxycarbonylation of Amides, Lactams, and Carbamates. In the presence of 4-Dimethylaminopyridine, Boc2O is
a strong acylating agent able to react with the weakly nucleo
Exhaustive acylation of a series of secondary amides has also

been performed with Boc 2 O in dry acetonitrile at ambient tem
perature using DMAP as catalyst. The method has some steric
limitations. For instance, it is retarded in the case of the orthosubstituted benzamides. The reaction has been extended to the
acylation of carbamates and other amide type functions: sulfon
amides, sulfenamides, and phosphinamides. 60 -Lactams are also
N-protected in good yields (eq 17).61
(17)
Primary carboxamides react with 2 equiv of Boc 2 O and 1 equiv

of DMAP to give isolable N-acylimidodicarbonates which are acy
lating agents for amines (eq 18).62 Formamide itself furnishes the
unstable di-t-butyl N-formylimidodicarbonate (eq 19).63
(18)
(19)
Grieco has shown that the regioselective hydrolysis or
methanolysis of N-t-butoxycarbonyl derivatives of amides and lac
tams affords the corresponding carboxylic acids or methyl esters,
respectively (eq 16).3 1,1,3,3-Tetramethylguanidine efficiently
catalyzes the methanolic cleavage.64 Grieco's method has been
applied to a formal synthesis of gabaculine, in which Lithium
Hydroxide treatment induces both sulfoxide elimination and lac
tam cleavage (eq 20).65
127
has also been used in a palladium-catalyzed allylic amination.75

Labeled di-t-butyl imidodicarbonate leads to 13C and l 5 N glycine
derivatives.76 Alkylation with triflates prepared from -hydroxy
acid esters gives 15N-labeled chiral Boc-amino acids suitable for
the synthesis of labeled peptides.77
t-Butoxycarbonylation of benzyl or allyl N-Boc or N-Cbz amino
acid esters using Boc 2 O/DMAP gives N-bis(alkoxycarbonyl)
amino acid esters. Specific cleavage of the allyl protect
ing group with Chlorotris(triphenylphosphine)rhodium(I),
or
hydrogenolysis of the benzyl ester function, respectively,
gives N-benzyloxycarbonyl, N-t-butoxycarbonyl or N-di-tbutoxycarbonyl amino acids (eq 22). 78,79
(22)
(20)
Other regioselective attacks at the acyl function are known.

Aminolysis of substituted pyrrolidones gives the correspond
ing N-Boc -amino acid amides.59 The N-Boc five- to eightmembered lactams are cleaved with Grignard reagents at the
endocyclic carbonyl group to give -Boc-amino ketones, 66-68
which can be deprotected with TFA and cyclized with NaOH to
yield cyclic imines.67 Regioselective ring opening of the N-Bocpyroglutamate ethyl ester with the lithium enolates of carboxylic
esters, dithiane anion, alcohols, amines, and thiols occurs without
epimerization. 69-71 Selective cleavage of cyclic carbamates gives
TV-protected amino alcohols (eq 21). In this reaction, methyl es
ter substituents are not transformed into acids by using Cesium
Carbonate as a base. 72
where H2, Pd/C is used, R2 = Bn, Y = Boc

where (PPh3)3RhCl is used, R2 = allyl, Y = Cbz or Boc
The di-t-butoxycarbonyl amino acids have been applied to so

lution peptide synthesis using the 1,3-Dicyclohexylcarhodiimide
or p-nitrophenyl ester method in DMF for coupling. 79
Reaction of a bis(alkoxycarbonyl)amino acid pyridinium salt with cyanuric fluoride at 30 C gives a Nbis(alkoxycarbonyl)amino acid fluoride (eq 23). Owing to the
high electronegativity and small size of the fluorine atom, this
derivative is an efficient acylating agent for amines and pyrrole
anions.80 Use of the Vilsmeier reagent instead of cyanuric
fluoride leads to a chemically and optically pure N-Boc or N-Cbz
amino acid N-carboxy anhydride (Boc- or Cbz-NCA) without
the use of phosgene and the unstable t-butyl chlorocarbonate
(eq 23). 80 Peptide synthesis with these urethane protected amino
acid N-carboxy anhydrides (U-NCAs) is a very clean reaction
which liberates only CO 2 as a byproduct.81
(21)
(23)
The selective deacylation of N-Boc carboxamides has also

been achieved by aminolysis to give N-Boc amines. 2Diethylaminoethylamine in acetonitrile is particularly convenient,
but other conditions such as hydrazine in methanol can also be
used. 64,73 Aminolysis of di-t-butyl N-formylimidodicarbonate af
fords di-t-butyl imidodicarbonate, HN(Boc)2 (eq 19).63 This com
pound, as well as the unsymmetrical benzyl t-butyl imidocarbonate, has been used as a substitute for Phthalimide in the Gabriel
and Mitsunobu reactions to give primary amines. Compared to
the classical method, which requires the hydrazinolysis of the
phthaloyl protecting group, the main advantage of these novel
Gabriel reagents is the much milder and rather specific conditions
for the final deprotection step.74 The lithium salt of HN(Boc)2
R2 = Bn or t-Bu
Treatment
with
Boc 2 O/DMAP cat
allows
exhaustive
N-t-butoxycarbonylation
of some peptides. 82 The
tbutoxycarbonylation of the internal amide bonds favors the
cyclization of the peptides. 83 Interestingly, one Boc group can
be selectively removed from a bis(Boc)-amine 75,76 with a slight
excess of trifluoroacetic acid. Use of the Boc 2 O/DMAP cat /MeCN
conditions also allows selective protection of mixed
primary-secondary diamines. t-Butoxycarbonylation of a
128
N,N'-bis(benzyloxycarbonyl)diamine followed by hydrogenolysis of the Cbz groups furnishes the t-butoxycarbonylated

derivative of the primary amino function (eq 24).84 Analogous
strategies have been used for the selective indirect acylation of
polyamines such as spermidine.85,86
(24)
The t-butoxycarbonylation of the sodium salt of thiourea

does not require DMAP catalysis. The resulting N,N'-bis(tbutoxycarbonyl)thiourea reacts with amines to give bis(tbutoxycarbonyl)guanidines (eq 25).87
In the reaction with Boc2O/DMAP, N-Boc-tryptophan methyl

ester affords the N,Nin-di-Boc derivative in almost quantitative
yield. This product has been used in peptide synthesis. Moreover,
selective cleavage of the N-Boc group is possible in the presence
of the Nin-Boc function by using 2.7 N HCl in dioxane.94
Activation of the Carboxyl Group. Formation of Esters and
Anhydrides. In the presence of Pyridine in aprotic solvents, the
carboxyl function of a carboxylic acid or a N-Boc-amino acid is
activated with the Boc2O reagent. The resulting mixed anhydride
can react further with one molecule of the starting acid to give
a symmetrical anhydride. At an equimolar ratio of the acid and
the Boc2O reagent a mixture of the mixed and the symmetrical
anhydrides is formed. If 2 equiv of acid are used, the symmet
rical anhydride becomes the main reaction product. Addition of
certain nucleophilic agents to the Boc2O/carboxylic acid/pyridine
mixture leads to the acylation of the nucleophile (eq 28).58
(25)
Sequential diacylation of 1-guanidinylpyrazole gives the N,N'bis(Boc)-guanidinylpyrazole, which is also an efficient reagent for
the conversion of amines to protected monosubstituted guanidines
and therefore for the synthesis of arginine-containing peptides
from their ornithine counterparts (eq 26).88
(28)
From a preparative point of view, it is essential that Boc2O re

acts much more rapidly with the carboxylate function than with the
nucleophile. The reaction has been applied to the synthesis of aryl
and alkyl esters and anilides such as o-nitrophenyl, benzyl, or trifluoroethyl esters and p-nitroanilides of N-protected amino acids.
The formation of esters derived from secondary alcohols (benzhydryl, menthyl, or cholesteryl esters) is accelerated by addition
of DMAP. Depsipeptides are obtained in good yields. DMAP is a
necessary catalyst for the synthesis of t-butyl esters and the esterification of N-protected amino acids occurs without epimerization.58
(26)
N-t-Butoxycarbonylation of Pyrroles and Indoles. A se

ries of substituted pyrroles and indoles89-92 react smoothly with
Boc2O in the presence of catalytic amounts of DMAP in CH2Cl2
or acetonitrile to give the corresponding N-Boc pyrrole or indole
derivatives. The N-t-butoxycarbonylation allows direct lithiation
to the indole and pyrrole nitrogen at low temperature. Alterna
tively, lithium-halogen exchange of N-Boc-2-bromopyrroles gen
erates the N-protected 2-lithiopyrroles (eq 27).91 After reaction
with an electrophile, the Boc protecting group is easily removed
either by methoxide ion in methanol or by thermolysis.90,'93
t-Butoxycarbonylation of Carbanions. Preferential Ct-butoxycarbonylation of diethyl acetamidomalonate occurs

by treatment with Boc2O/DMAPcat in acetonitrile (eq 29).60
From the reaction of the potassium salt of diphenylphosphinyl isocyanide and Boc2O in CH2Cl2 at 70 C, the
corresponding Wittig-Horner reagent, t-butyl (diphenylphosphinyl)isocyanoacetate, is formed in near quantitative
yield.95 Similarly, treatment of -lithioalkylphosphonates
with Boc2O gives C-t-butoxycarbonylated enolates which
react with aldehydes to give substituted t-butyl acrylates.96
The lithium salt of the Schiff base derived from the
aminomethyldiphenylphosphine oxide reacts with Boc2O at low
temperature to give the imine of t-butyl -(diphenylphosphinoyl)glycinate.97
(29)
(27)
X = H, LiB = lithium tetramethylpiperidide

X = Br, LiB = BuLi
A = B = CO2Et
A = Ph2PO
A = (Et2O)2PO
A = Ph2PO
B = N=C
B = alkyl
B = N=CPh
R = NHAc
R=H
R=H
R=H
MeCN
CH2Cl2
THF
THF
rt
93%
-70 C 92%
-78 C quant.
-60 C 80%
t-Butoxycarbonylation of Imines. In previous examples, the

acylation occurred either at the amino function30 or at the carbanionic center97 and not at the imine function. However, the re
action of a nucleophilic imine possessing an electron-releasing
substituent (Ar = p-MeOCgHLt) with Boc2O in ethanol proceeds
through the intermediacy of an N-alkoxycarbonyl iminium ion to
give an -ethoxy carbamate (eq 30). As the trapping of the iminium
ion by the alcohol is a reversible process, the -ethoxy t-butyl car
bamate is a precursor of the electrophilic N-Boc iminium ion in
an intermolecular condensation with propargyltrimethylsilane.98
(30)
Related Reagents. t-Butyl Azidoformate; t-Butyl Chloroformate; l-N-(t-Butoxycarbonyl)-lH-benzotriazole 3-N-Oxide;

1 -(t-Butoxycarbonyl)imidazole; 2-(f-Butoxycarbonyloxyimino)2-phenylacetonitrile; N-(t-Butoxycarbonyloxy)phthalimide; N(t-Butoxycarbonyloxy)succinimide; 1 -t -Butoxycarbonyl-1,2,4triazole.
1. Greene, T. W.; Wuts, G. M. Protective Groups in Organic Synthesis 2nd

ed.; Wiley: New York, 1991; p 327.
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1984; p 99.
3.
4.
5.
6.
Flynn, D. L.; Zelle, R. E.; Grieco, P. A. JOC 1983, 48, 2424.

Gunnarsson, K.; Grehn, L.; Ragnarsson, U. AG(E) 1988, 27, 400.
Grehn, L.; Ragnarsson, U. AG(E) 1984, 23, 296.
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129
29.
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31.
Egbertson, M. S.; Homnick, C. F.; Hartman, G. D. SC 1993, 23, 703.

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34.
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Kemp, D. S.; Carey, R. I. JOC 1989, 54, 3640.
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35.
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38.
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Pozdnev, V. F. ZOB 1977, 48, 476 (CA 1978, 89, 24 739m).
Pozdnev, V. F. Bioorg. Khim. 1986, 12, 1013.
39.
Harris, R. B.; Wilson, I. B. JBC 1983, 258, 1357.
40. Losse, G.; Naumann, W.; Raddatz, H. ZC 1983, 23, 22.

41. Altman, Shoef, N.; Wilchek, M.; Warshawsky, A. CC 1985, 1133.
42. Lee, B. H.; Miller, M. J. JOC 1983, 38, 24.
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44.
45.
46.
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47. Lecoq, A.; Marraud, M.; Aubry, A. TL 1991, 32, 2765.

48. Saito, S.; Nakajima, H.; Inaba, M.; Moriwake, T. TL 1989, 30, 837.
49. Cheung, S. T.; Benoiton, N. L. CJC 1977, 55, 906.
50. Hansen, D. W.; Pilipauskas, D. JOC 1985, 50, 945.
51. Rich, D. H.; Dhaon, M. K.; Dunlap, B.; Miller, S. P. F. JMC 1986, 29,
978.
52.
53.
54.
Pietzonka, T.; Seebach, D. AG(E) 1992, 31, 1481.

Sakatani, M.; Hori, K.; Ohfune, Y. TL 1988, 29, 2983.
Bajwa, J. S. TL 1992, 33,2955.
55.
56.
Li, W.-R.; Jiang, J.; Joullie, M. M. TL 1993, 34, 1413.

Houlihan, F; Bouchard, F.; Frchet, J. M. F.; Wilson, C. G. CJC 1985,
63, 153.
Aruze, I.; Okai, H.; Kouge, K.; Yamamoto, Y.; Koizumi, T. Chem.
Express 1988, 3, 45.
Pozdnev, V. F. Int. J. Pept. Protein Res. 1992, 40, 407.
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Grehn, L.; Gunnarsson, K.; Ragnarsson, U. ACS 1986, B40, 745.
57.
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58.
59.
60.
10. Moroder, L.; Hallett, A.; Wiinsch, E.; Keller, O.; Wersin, G. Z. Physiol.
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12. Harris, R. B.; Wilson, I. B. TL 1983, 24, 231.
13. Einhom, J.; Einhorn, C.; Luche, J. L. SL 1991, 37.
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14. Guzman, A.; Quintero, C.; Muchowski, J. M. CJC 1991, 69, 2059.
15. Beak, P.; Lee, W. K. JOC 1993, 58, 1109.
16. Muchowski, J. M.; Venuti, M. C. JOC 1980, 45, 4798.
65. Hiemstra, H.; Klaver, W. J.; Speckamp, W. N. TL 1986, 27, 1411.

66. Ohta, T.; Hosoi, A.; Kimura, T.; Nozoe, S. CL 1987, 2091.
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17.
18.
19.
20.
21.
22.
Dalla Croce, P.; La Rosa, C.; Ritieni, A. JCR(S) 1988, 346.

Fishwick, C. W. G.; Storr, R. C ; Manley, P. W. CC 1984, 1304.
Fiakpui, C. Y.; Knaus, E. E. CJC 1987, 65, 1158.
Hofmann, K.; Finn, F.; Kiso, Y JACS 1978,100, 3585.
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Clark, R. D.; Muchowski, J. M.; Fisher, L. E.; Flippin, L. A.; Rebke,
D. B.; Souchet, M. S 1991, 871.
Kerrick, S. T.; Beak, P. JACS 1991, 113, 9708.
Guibe-Jampel E.; Wakselman, M. S 1977, 772.
68.
Shai, Y.; Kirk, K. L.; Channing, M. A.; Dunn, B. B.; Lesniak, M. A.;
Eastman, R. C ; Finn, R. D.; Roth, J.; Jakobsen, K. A. B 1989, 28,4801.
Krapcho, A. P.; Kuell, C. S. SC 1990, 20, 2559.
74. Ragnarsson, U.; Grehn, L. ACR 1991, 24, 285.

75. Connell, R. D.; Rein, T.; kermark, B.; Helquist, P. JOC 1988, 53, 3845.
76. Grehn, L.; Bondesson, U.; Pehk, T.; Ragnarsson, U. CC 1992, 1332.
77. Degerbeck, F.; Fransson, B.; Grehn, L.; Ragnarsson, U. JCS(P1) 1993,
11.
78. Gunnarsson, K.; Grehn, L.; Ragnarsson, U. AG(E) 1988, 27, 400.
23.
24.
25.
26.
27.
Scott, J. W.; Parker, D.; Parrish, D. R. SC 1981, 11, 303.
28.
Masukiewicz, E.; Rzeszotarska, B.; Szczerbaniewicz, J. OPP 1992, 24,

191.
62.
63.
64.
69.
70.
Baldwin, J. E.; Adlington, R. M.; Godfrey, C. R. A.; Gollins, D. W.;

Smith, M; L. Russel, A. SL 1993, 51.
Davidsen, S. K.; May, P. D.; Summers, J. B. JOC 1991, 56, 5482.
Grehn, L.; Ragnarsson, U. S 1987, 275.
Grehn, L.; Gunnarsson, K.; Ragnarsson, U. ACS 1987, B41, 18.
Klutchko, S.; Hamby, J. M.; Reilly, M.; Taylor, M. D.; Hodges, J. C. SC

1993,25,971.
Ohta, T.; Kimura, T.; Sato, N.; Nozoe, S. TL 1988, 29, 4303.
Ezquerra, J.; de Mendoza, J.; Pedregal, C ; Ramirez, C. TL 1992, 33,
5589.
71.
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T 1993,49,3801.
72. Ishizuka, T.; Kunieda, T. TL 1987, 28, 4185.
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130
DI-n-BUTYLTIN OXIDE
79.
80.
Gunnarsson, K.; Ragnarsson, U. ACS 1990, 44,944.

(a) Savrda, J.; Wakselman, M. CC 1992, 812. (b) Carpino, L. A.;
Mansour, E.-S. M. E.; El-Faham, A. JOC 1993, 58, 4162.
81. Fuller, W. D.; Cohen, M. P.; Shabankaresh, M.; Blair, R. K.; Goodman,
M.; Naider, F. R. JACS 1990, 112, 7414.
82. Grehn, L.; Ragnarsson, U. AG(E) 1985, 24, 400.
Cavelier-Frontin, F.; Achmad, S.; Verducci, J.; Ppe, G.; Jacquier, R. J.
Mol Struct. (Theochem) 1993, 105, 125.
84. Almeida, M. L. S.; Grehn, L.; Ragnarsson, U. CC 1987, 1250.
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nonreacting solvents. A reticulated network (1) consisting of fourmembered rings of alternating tin and oxygen has been suggested
as a possible structure for this compound. 10 The interaction of
diorganotin oxides with various biomolecules like amino acids,
peptides, carbohydrates, and nucleic acid components has been
reviewed9 and is beyond the scope of this article.
83.
R2SnX2
R2Sn(X)OSn(X)R2
R2(X)SnOSnR2(OH)
R2SnO (1)
86.
Arajo, M. J. S. M. P.; Ragnarsson, U.; Almeida, M. L. S.; Amaral Trigo,

M. J. S. A. JCR(S) 1992, 110.
87. Iwanowicz, E. J.; Poss, M. A.; Lin, J. SC 1993, 23, 1443.
88. Bernatowicz, M. S.; Wu, Y.; Matsueda, G. R. TL 1993, 34, 3389.
89. Grehn, L.; Ragnarsson, U. AG(E) 1984, 23, 296.
90. Rawal, V. H.; Cava, M. P. TL 1985, 26, 6141.
91. Chen, W.; Cava, M. P. TL 1987, 28, 6025.
92. Woolridge, E. M ; Rokita, S. E. TL 1989, 30, 6117.
93. Leroy, J.; Cantacuzene, D.; Wakselman, C. S 1982, 313.
94.
95.
96.
Franzn, H.; Grehn, L.; Ragnarsson, U. CC 1984, 1699.

Racho, J.; Schllkopf, U. LA 1981, 99.
Teulade, M. P.; Savignac, P.; About-Jaudet, E.; Colignon, N. SC 1989,
79,71.
97.
98.
van Es, J. J. G. S.; Jaarveld, K.; van der Gen, A. JOC 1990, 55, 4063.
Esch, P. M.; Hiemstra, H.; Speckamp, W. N. T 1992, 48, 3445.
Michel Wakselman
CNRS-CERCOA, Thiais, France
Di-n-butyltin Oxide1,2
[818-08-6]
C8H18OSn
(MW 248.92)
(converts diols to O-stannylene acetals2 which undergo regioselective acylation, alkylation, oxidation, and condensation
with activated carboxylic acid derivatives; activates ,-hydroxy
acids and ,-amino acids for lactone and lactam formation,
respectively;3 mediates epoxidation of allylic alcohols by t-butyl
hydroperoxide;4 catalyzes TMSN 3 addition to nitrile;5 useful
as a source of tin for Otera transesterification6 and 'organotin
phosphate condensate' 7 catalysts)
Alternate Name: DBTO.
Physical Data: mp >300 C.
Solubility: insol most organic solvents with which it does not
react. However solvents like toluene, benzene, and methanol
are routinely used for reactions of hydroxylic substrates.
Form Supplied in: white powder.
Handling, Storage, and Precautions: toxic and irritant;8'9 use in
a fume hood.
Introduction. Di-n-butyltin oxide, because of its biocidal and

antifouling properties, is one of the most widely used industrial
chemicals.9 It is the final product of hydrolysis of dialkyltin halides
(eq 1) and exists as an amorphous polymeric solid insoluble in
Formation and Reactions of Dibutylstannylenes. By far the

largest application of DBTO in organic chemistry is in the gener
ation and reactions of stannylenes from polyhydroxy compounds.
Dibutylstannylenes are prepared in nearly quantitative yields by
heating stoichiometric amounts of DBTO and the polyol in a sol
vent such as benzene or toluene with concomitant removal of
water (eq 2). 11 Compounds (2) 12 and (3) 13 are other prototypical
stannylenes that have been prepared by this method. Formation
and reactions of 1,6-stannylenes from monosaccharides have also
been reported recently.14 While the stannylene from ethylene gly
col (eq 2) is an infinite coordination chain polymer with hexacoordinated Sn,15 the stannylenes from cyclohexane-1,2-diols and the
methyl 4,6-O-benzylidene--D-glucopyranoside (3) 16 are dimeric
(e.g. 4).
(2)
Regioselective
Alkylation,
Acylation,
and
Sulfonylation. Synthetic applications of stannylenes have followed the
elegant studies of Moffatt17 and Ogawa, 18 who showed that
the inherent differences in the nucleophilicities of carbohydrate
hydroxys can be amplified by the formation of trialkyltin
ethers. Several selective acylations and alkylations could thus be
accomplished. Further it was noted that while acylation proceeds
DI-n-BUTYLTIN OXIDE
without any catalyst, alkylation is a sluggish reaction and needs
assistance from tetrabutylammonium halides (eq 3). 19
131
(7)
(also reactions with t-BuCOCl and TBDMS-Cl)
(3)
Reactions of stannylene (2) are typical and are shown in eq 4. 2
The structure of the dimeric complex (4) has been used to

explain the observed preferential reactivity of the C-2 hydroxy
groups.2 It is argued that the divalent oxygens that occupy the
axial position within the tin cordination sphere (i.e. this case, the
C-2 oxygens) are not only more nucleophilic, but also are more
accessible sterically. It is believed that the orientational prefer
ence of the hydroxy group is related to its acidity, and thus by
forming a Sn complex with the more acidic hydroxy group in the
axial position, its reactivity towards nucleophiles is enhanced. The
stannylene procedure can be used to reverse the stereochemistry
of the classical monoacylation regiochemistry observed in some
unsymmetrical diols.26
Regioselective Oxidation. Following the original discovery by
David and Thieffrey,27 several stannylenes have been oxidized by
bromine to acyloins (eq 8). Hanessian employed this reaction for
the synthesis of a densely functionalized intermediate which was
converted into (+)-spectinomycin.28 A detailed study of monooxidation of unprotected carbohydrates has also appeared.29 Stan
nylenes are oxidized the same way as diols, with Sodium Periodate and Lead(IV) Acetate.2
(4)
(8)
The stannylene (3) reacts with benzoyl chloride or tosyl chlo

ride to give the corresponding 2-0-derivative (eq 5). The alky
lation is less selective.20 Use of nonpolar solvents and tetrabuty
lammonium halide has been a significant improvement (eq 6) in
this alkylation procedure. 21 Several other examples of selective
acylation and alkylations are given by David and Hanessian.2
An intramolecular ether formation using DBTO has been used
for the synthesis of octosyl acid.22 Monoacylation of dimethyl
L-tartrate has been carried out using this procedure (eq 7). 23 Two
highly readable accounts of how the anomer composition and stoichiometry of reagents affect the regiochemistry of acylation24 and
tosylation25 have recently appeared.
Esterification Catalyst. In the presence of DBTO, alcohols

react with carboxylic acids to give esters30 and the reaction can be
extended to make lactones and lactams (eqs 9 and 10).3 It should be
noted that the stereochemistry of the alcohol center is unaffected.
A 'template-driven' extrusion process, in which an intermediate
where the hydroxy and the carboxyl groups are brought into close
proximity by tin oxide, has been proposed for this reaction.
(9)
(5)
(10)
(6)
Stannylenes derived from diols react with bifunctional

carboxylic acid derivatives to give macrocyclic polyolides of
various sizes. 31,32 This approach has been used for the synthe
sis of (+)-dicrotaline (eq 11).33
132
DI-n-BUTYLXIN OXIDE
Related Reagents. Bis(tri-n-butyltin) Oxide; 3-Chloro-lhydroxytetrabutyldistannoxane.

(11)
Dibutyltin oxide is the best source of tin for the Otera transesterification catalysts (eq 12),6 which have found wide use in organic
synthesis. DBTO has also been used as a catalyst for hydrolysis of
amides in very sensitive molecules, where other procedures have
failed.34
(12)
R = Bu, Y = NCS, X = OH
1.
Pereyre, M.; Quintard, J. P.; Rahm, A. Tin in Organic Synthesis;

Butterworth: London, 1987.
2.
3.
David, S.; Hanessian, S. T 1985, 41, 643.

Steliou, K.; Poupart, M. A. JACS 1983,105, 7130. See also: Steliou, K.;
Szczygielska-Nowosielska, A.; Favre, A.; Poupart, M. A.; Hanessian, S.
JACS 1980, 702, 7578.
4.
Kanemoto, S.; Nonaka, T.; Oshima, K.; Utimoto, K.; Nozaki, H. TL

1986, 27, 3387. For the possible structure of the reagent see: Davies, A.
G.; Grahan, I. F. CI(L) 1963, 1622.
5.
Wittenberger, S. J.; Donner, B. G. JOC 1993, 58, 4139.
6.
Otera, J.; Dan-oh, N.; Nozaki, H. JOC 1991, 56, 5307.
7. Otera, J.; Niibo, Y.; Nozaki, H. T 1991, 47, 7625.

8. Selwyn, M. J. In Chemistry of Tin; Harrison, P. G., Ed.; Chapman and
Hall: New York, 1989; p 359.
9.
Catalyst in Oxidation Reactions. DBTO has been used as a

catalyst in FeIII-mediated oxidation of thiols to disulfides, even
though Tri-n-butyl(methoxy)stannane seems to be better suited
for this purpose.35 Epoxidation of terminal alkenes in a two-phase
system (chloroform-water) containing H2O2/ammonium molybdate/DBTO has also been reported.36 A combination of DBTO
and t-Butyl Hydroperoxide oxidizes allylic alcohols with moder
ate regio- and stereoselectivity.4 Tri- and tetrasubstituted double
bonds are most easily oxidized and the selectivities are compa
rable to those of the corresponding Vanadyl Bis(acetylacetonate)
mediated reactions.
Miscelleneous Applications. The method of choice for the
regioselective opening of benzylic and tertiary epoxides with
alcohols (eq 13) appears to be a reaction mediated by 'organotin phosphate condensate (OPC)', which is readily prepared
from DBTO and tributyl phosphate.7 DBTO catalyzes rearrange
ment of 3-hydroxy-2-oxo carboxylic acid esters (eq 14), a re
action reminiscent of a similar one mediated by the enzyme
reductoisomerase.37 DBTO has been used as a catalyst for the
addition of Azidotrimethylsilane to nitriles5 for the production of
tetrazoles (eq 15).
(13)
(14)
(15)
10.
11.
Molloy, K. C. In The Chemistry of the Metal-Carbon Bond; Hartley, F.

R., Ed.; Wiley: Chichester, 1989; Vol. 5, p 465.
Davies, A. J.; Smith, P. J. In Comprehensive Organometallic Chemistry;
Wilkinson, G., Ed.; Pergamon: Oxford, 1982; Vol. 2, p 519.
12.
Considine, W. J. JOM 1966, J, 263. This compound wasfirstdescribed in

the patent literature: Ramsden, H. E.; Banks, C. K. U.S. Patent 2 789 994,
1957.
Wagner, D.; Verheyden, J. P. H.; Moffatt, J. G. JOC 1974, 39, 24.
13.
David, S.; Thieffry, A. CR(C) 1974, 279, 1045.
14.
15.
Kopper, S.; Brandenburg, A. LA 1992, 933.

Davies, A. G.; Price, A. J.; Dawes, H. M.; Hursthouse, M. B. JCS(D)
1986, 297. See also Ref. 10.
16.
David, S.; Pascard, C ; Cesario, M. NJC 1979, 3, 63.
17.
18.
Jenkins, I. D.; Verheyden, J. P. H.; Moffatt, J. G. JACS 1971, 93, 4323.

Ogawa, T.; Matsui, M. Carbohydr. Res. 1977, 56, C1. See also: Ogawa,
T.; Matsui, M. T1981, 37, 2363.
Veyrieres, A. JCS(P1) 1981, 1626. See also: David, S.; Thieffry, A.;
Veyrieres, A. JCS(P1) 1981, 1796.
19.
20.
Ogawa, T.; Kaburagi, T. Carbohydr. Res. 1982, 53, 1033. See also:
Nashed, M. A.; Anderson, L. TL 1976, 3503. For a recent reference
dealing with related chemistry in partially protected carbohydrates see:
Tsuda, Y.; Nishimura, M.; Kobayashi, X; Sato, Y.; Kanemitzu, K. CPB
1991, 39, 2883.
21.
22.
23.
David, S.; Thieffry, A.; Veyrieres, A. JCS(P1) 1981, 1796.

Danishefsky, S. J.; Hungate, R.; Schulte, G. JACS 1988, 110, 7434.
Nagashima, N.; Ohno, M. CL 1987,141. For an application in the inositol
area see: Yu, K.-L.; Fraser-Reid, B. TL 1988, 29, 979.
24.
25.
Helm, R. F.; Ralph, J.; Anderson, L. JOC 1991, 56, 7015.

Tsuda, Y.; Nishimura, M.; Kobayashi, T.; Sato, Y.; Kanemitzu, K. CPB
1991, 39, 2883.
26.
Ricci, A.; Roelens, S.; Vannuchi, A. CC 1985, 1457.
27.
David, S.; Thieffry, A. JCS(P1) 1979, 1568. For such oxidations on

unprotected carbohydrates see: Tsuda, Y.; Hanajima, M.; Matsuhira, N.;
Okuno, Y.; Kanemitzu, K. CPB 1989, 37, 2344.
28.
Hanessian, S.; Roy, R. JACS 1979, 101, 5839.
29.
Tsuda, Y.; Hanajima, M.; Matsuhira, N.; Okuno, Y.; Kanemitzu, K. CPB
1989, 37, 2344.
Habib, O. M. O.; Malek, J. CCC 1976, 41, 2724.
30.
31.
Shanzer, A. ACR 1983, 16, 60.
32.
Bredenkamp, M. W.; Flowers, H. M.; Holzapfel, C. W. CB 1992, 125,

1159.
Niwa, H.; Okamoto, O.; Ishiwata, H.; Kuroda, A.; Uosaki, Y.; Yamada,
K.BCJ 1988, 61,3017.
33.
1,3-DICYCLOHEXYLCARBODIIMIDE
34.
Chwang, T. L.; Nemec, J.; Welch, A. D. J. Carbohydr., Nucleosides

Nucleotides 1980, 7, 159.
35.
Tsuneo, S.; Otera, J.; Nozaki, H. TL 1990,31,3591.
36.
Kamiyama, T.; Inoue, M.; Kashiwagi, H.; Enomoto, S. BCJ 1990, 63,
1559. and references cited therein.
37.
Crout, D. H. G.; Rathone, D.L.CC 1987, 290.
T. V. (Babu) RajanBabu
1,3-Dicyclohexylcarbodiimide1
[538-75-0]
C13H22N2
(MW 206.33)
(powerful dehydrating agent commonly used for the preparation

of amides, 2 esters,3 and anhydrides;4 used with DMSO for the
mild oxidation of alcohols to ketones;5 used in the dehydrative
conversion of primary amides to nitriles,6 -hydroxy ketones
to ,-unsaturated ketones,7 and can effect the stereochemical
inversion of secondary alcohols8)
18
133
19
(HOAt), N-Hydroxysuccinimide (HOSu), and 3-hydroxy-3,4dihydro-1,2,3-benzotriazin-4-one20 can generally ameliorate both

problems. These additives are required for the coupling of sterically hindered components, or when the amine is weakly nucleophilic.
Another potential problem with DCC is that at the com
pletion of the reaction some DCU remains in solution with
the product, necessitating additional purification. Watersoluble carbodiimide derivatives such as
l-Cyclohexyl-3-(2morpholinoethyl)carbodiimide Metho-p-toluenesulfonate21 and
Hydrochlo
ride (EDO) 2 2 obviate this problem, as they are removed by a
simple extraction. Many newer coupling agents have been devel
oped for peptide synthesis and other acylation reactions. These
include
Hexafluorophosphate (BOP),23 0-Benzotriazol-l-yl-N,N,N',N'tetramethyluronium Hexafluorophosphate (HBTU),24 Bis(2oxo-3-oxazolidinyl)phosphinic
Chloride15
(BOP-Cl), and
(1H-1,2,3-benzotriazol-1 -yloxy)tris(pyrrolidino)phosphonium
hexafluorophosphate (PyBOP). 26 In addition to linear and
polymeric amides, lactams of various ring sizes have been
synthesized using these methods (eq 1). 27
(1)
R = (CH2)n, n = 0-6
Alternate Name: DCC.

Physical Data: mp 34-35 C; bp 122-124 C.
Solubility: highly sol dichloromethane, THF, acetonitrile, DMF.
Form Supplied in: opalescent solid; widely available.
Handling, Storage, and Precautions: is an acute skin irritant in
susceptible individuals. Because of its low melting point, it
is conveniently handled as a liquid by gentle warming of the
reagent container. It should be handled with gloves in a fume
hood, and stored under anhydrous conditions.
Amide Formation. Since the initial reports, 9,10 DCC has be

come the most common reagent in peptide synthesis 2,11,12 and
in other amide bond-forming reactions of primary and secondary
amines with carboxylic acids. The mechanism is considered to be
well understood. 2,5
Typically, DCC (1.1 equiv) is added to a concentrated solu
tion (0.1-1.0 M) of the carboxylic acid (1.0 equiv), amine (1.0
equiv), and catalyst (when used) in methylene chloride or acetoni
trile at 0 C. The hydrated DCC adduct, dicyclohexylurea (DCU),
quickly precipitates and the reaction is generally complete within
1 h at rt. The solvents THF and DMF can be used, but are re
ported to reduce reaction rates and encourage the formation of
the N-acylurea side product, as well as increasing racemization in
chiral carboxylic acids. 13-16 If the amine is initially present as the
salt (i.e. amine hydrochloride), it may be neutralized by adding
1 equiv of Diisopropylethylamine prior to adding DCC; how
ever, the addition of tertiary amines (particularly Triethylamine)
can facilitate N-acylurea formation and racemization.2 Racem
ization occurs via the formation of an oxazalone intermediate.2
The addition of coupling agents (acylation catalysts) such as
1-Hydroxybenzotriazole (HOBt),17 l-hydroxy-7-azabenzotriazole
Ester and Thioester Formation. These reactions occur

through the same O-acylurea or anhydride active intermediate as
in the amide coupling reactions, and the discussion of associated
problems applies here as well. In general, alkyl and (particularly)
aryl thiols can be efficiently coupled to carboxylic acids using
DCC. 28 Reactions of primary and secondary alcohols proceed
reliably, but require the presence of an acylation catalyst. This
is usually 4-Dimethylaminopyridine (DMAP), 29,30 (see also 1,3Dicyclohexylearbodiimide-4-Dimethylaminopyridine),
but oth
ers have been used including 4-pyrrolidinopyridine31 and pyridine
(solvent) with catalytic p-Toluenesulfonic Acid.32 The acylation
of more hindered alcohols often results in reduced yields; however,
even t-butanol can be acylated, providing a useful route to t-butyl
esters. 3,31 Various other carbodiimide derivatives have also been
used in the preparation of esters. 33,34 As with amides, which are
not limited to intermolecular reactions, a wide variety of lactones
can also be synthesized.35,36
Anhydride Formation. Among other anhydride-forming
reagents, including Acetic Anhydride, Trifluoroacetic Anhy
dride, and Phosphorus(V) Oxide, DCC is one of the simplest,
mildest, and most effective reagents for the preparation of sym
metrical anhydrides, 4,37 including formic anhydride,38 which is
useful in the preparation of formamides (eq 2).
Anhydride formation is associated with each of the reaction
types involving carboxylic acids. The anhydride is often the reac
tive species, to the extent that it competes with the O-acylurea or
covalent catalyst adduct (see discussion of amide bond formation
reactions).
134
Sulfinate and Phosphate Esters. Anhydrides of sulfuric and

sulfonic acids39,40 and phosphate monoesters can be prepared us
ing DCC. Further reaction with alcohols or phenols gives the corre
sponding sulfinates41 and phosphate diesters.42,43 Pyrophosphates
can be prepared from mono- and disubstituted phosphate esters.44
Reaction of activated sulfinates with amines gives the correspond
ing sulfinamides.45
oxides can be synthesized from the corresponding carboxylic acid

and peroxy acid.56
(6)
Aromatic and aliphatic alcohols and thiophenols can be coupled

to form ethers (eq 7)57,58 and thioethers (eq 8),59,60 respectively,
using DCC.
(7)
(2)
Oxidation of Alcohols to Aldehydes and Ketones: Moffatt

Oxidation. The oxidation of primary and secondary alcohols46
to aldehydes and ketones, respectively, can be carried out by re
action with DMSO activated by DCC (see Dimethyl SulfoxideDicyclohexylcarbodiimide).5,47,49 In comparison to the many
metal-mediated oxidative reactions, the Moffatt oxidation is car
ried out under very mild conditions, and has found widespread
use for reactions in the presence of sensitive functional groups
(eq 3).49 In addition, over-oxidation of aldehydes to form carboxylic acids is not observed. Under typical reaction condi
tions, a solution of the alcohol (1 equiv), DCC (3 equiv),
and a proton source (pyridinium trifiuoroacetate) (0.5 equiv)
is stirred in DMSO or DMSO/benzene overnight at rt. After
quenching the reaction with aqueous acetic acid and remov
ing DCU by filtration, the product can be isolated by extrac
tion. In modifications of this reaction,46 DCC can be replaced
by other DMSO-activating agents including acetic anhydride (see
Dimethyl Sulfoxide-Acetic Anhydride),50 trifluoroacetic anhy
dride (see Dimethyl Sulfoxide-Trifluoroacetic Anhydride),51 and
oxalyl chloride (seeDimethylSulfoxide-OxalylChloride).52,53
(8)
In cases where sensitivity of the compound precludes the for

mation of an acid chloride, -diazo ketones can be synthesized by
the DCC-mediated coupling of diazomethane to carboxylic acids
(eq 9).61,62
(9)
Dehydration to Alkenes, Epoxides, Nitriles, and Ketenes. (3Hydroxy ketones and -hydroxy esters can be dehydrated, using
DCC, to ,-unsaturated ketones (eq 10)7,63 and esters (eq 11),64
respectively. Cyclopropanes can be synthesized by the 'dehydra
tion' of --hydroxy ketones (eq 12).65
(10)
(11)
(3)
(12)
Dehydrative-Type Couplings. Because of the power of DCC

as a dehydrating agent, it has found many uses in a variety of other
dehydrative coupling reactions. These include the reaction of pri
mary amines with DCC and Carbon Dioxide or Carbon Disulfide
to form ureas (eq 4)54 or isothiocyanates (eq 5),55 respectively.
Other dehydration reactions include the conversion of primary

amides to nitriles,6 aldehydes to nitriles (via the hydroxylamine)
(eq 13),66,67 and carboxylic acids to ketenes (eq 14).68
(13)
(4)
(14)
(5)
Symmetrical peroxides can be synthesized from benzoic acid

derivatives and hydrogen peroxide (eq 6).56 Unsymmetrical per
Dehydroxylation of Alcohols. Alcohols and phenols can be

dehydroxylated to the corresponding alkane by hydrogenation of
the O-acylurea adduct formed from the reaction of the alcohol

with DCC (eq 15).69,70
(15)
Inversion of Secondary Alcohols. Secondary alcohols can be

stereochemically inverted by formylation (or esterification) with
DCC, followed by saponification (eq 16).8
(16)
Heterocyclization Reactions. DCC has frequently been used

both as a reagent and as a reactant in the synthesis of
heterocycles.1 For example, DCC-mediated cyclodesulfurative
annulation reactions71 have been used to synthesize guanosinetype nucleotide analogs (eq 17).72
(17)
1. (a) Mikolajczyk, M.; Kielbasinski, P. T 1981, 37, 233. (b) Williams, A.;
Ibrahim, I. T. CRV 1981, 81, 589. (c) Kurzer, F.; Douraghi-Zadeh, K.
CRV 1961, 67, 107.
2. Bodanszky, M. Peptide Chemistry: A Practical Textbook; Springer: New
York, 1988.
3. Neises, B.; Steglich, W. OS 1985, 63, 183.
4.
5.
6.
7.
8.
9.
Chen, F. M. F.; Kuroda, K.; Benoiton, N. L. S 1978, 928.

Moffatt, J. G. JOC 1971, 36, 1909.
Ressler, C.; Ratzkin, H. JOC 1961, 26, 3356.
Corey, E. J.; Andersen, N. H.; Carlson, R., M.; Paust, J.; Vedejs, E.;
Vlattas, I.; Winter, R. E. K. JACS 1968, 90, 3245.
Kaulen, J. AG(E) 1987, 26, 773.
Sheehan, J. C ; Hess, G. P. JACS 1955, 77, 1067.
10.
Khorana, H. G. CI(L) 1955, 1087.
11.
12.
Hudson, D.JOC 1988, 53, 617.

Wang, S. S.; Tam, J. P.; Wang, B. S. H.; Merrifield, R. B. Int. J. Pept.
Protein Res. 1981,19, 459.
Balcom, B. J.; Petersen, N. O. JOC 1989, 54, 1922.
13.
14. DeTar, D. F.; Silverstein, R. JACS 1966, 88, 1013.

15. DeTar, D. F.; Silverstein, R. JACS 1966, 88, 1020.
16. Mironova, D. F.; Dvorko, G. F.; Skuratovskaya, T. N. UKZ 1969, 35,
726.
17.
Konig, W.; Geiger, R. CB 1970, 103, 788.
18. Carpino, L. A. JACS 1993, 115, 4397.

19. Wiinsch, E.; Drees, F. CB 1966, 99, 110.
20. Konig, W.; Geiger, R. CB 1970, 103, 2034.
135
21.
Sheehan, J. C ; Hlavka, J. J. JOC 1956, 21, 439.
22.
Sheehan, J. C ; Cruickshank, P. A.; Boshart, G. L. JOC 1961, 26,

2525.
Castro, B.; Dormoy, J. R.; Evin, G.; Selve, C. TL 1975, 1219.
Knorr, R.; Trzeciak, A.; Bannwarth, W.; Gillessen, D. TL 1989, 30,
1927.
23.
24.
25.
26.
Cabre, J.; Palomo, A. L. S 1984, 413.

Frrot, E.; Coste, J.; Pantaloni, A.; Dufour, M.; Jouin, P. TL 1991, 47,
259.
27.
28.
Tanner, D.; Somfai, P. T 1988, 44, 613.

Grunwell, J. R.; Foerst, D. L. SC 1976, 6, 453.
29.
30.
Smith, R. J.; Capaldi, R. A.; Muchmore, D.; Dahlquist, F.B 1978, 17,
3719.
Neises, B.; Steglich, W. AG(E) 1978, 17, 522.
31.
32.
33.
34.
Hassner, A.; Alexanian, V. TL 1978, 4475.

Holmberg, K.; Hansen, B. ACS 1979, 33, 410.
Dhaon, M. K.; Olsen, R. K.; Ramasamy, K. JOC 1982, 47, 1962.
Ohta, S.; Shimabayashi, A.; Aono, M.; Okamoto, M. S 1982, 833.
35. Johnson, W. S.; Bauer, V. J.; Margrave, J. L.; Frisch, M. A.; Dreger, L.
H.; Hubbard, W. N. JACS 1961, 83, 606.
36. Woodward, R. B.; Bader, F. E.; Bickel, H.; Frey, A. J.; Kierstead, R. W.
T 1958,2, 1.
37. Rammler, D. H.; Khorana, H. G. JACS 1963, 85, 1997.
38. Chen, F. M. F.; Benoiton, N. L. S 1979, 709.
39. Samuel, D.; Silver, B. L. JACS 1963, 85, 1197.
40. Khorana, H. G. CJC 1953, 31, 585.
41. Mijaji, Y.; Minoto, H.; Kobayashi, M. BCJ 1971, 44, 862.
42. Kampe, W. CB 1965, 98, 1031.
43. Pal, B. C ; Schmidt, D. G.; Farrelly, J. G. Nucleic Acid Chem. 1978, 2,
963.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
Khorana, H. G.; Todd, A. R. JCS 1953, 2257.

Furukawa, M.; Okawara, T. S 1976, 339.
Tidwell, T. T. OR 1990, 39, Chapter 3.
Pfitzner, K. E.; Moffatt, J. G. JACS 1965, 87, 5661.
Moffatt, J. G. In Oxidation; R. L. Augustine and D. J. Trecker, Ed.;
Dekker: New York, 1971; Vol. 2, Chapter 1.
Albright, J. D.; Goldman, L. JOC 1965, 30, 1107.
Albright, J. D.; Goldman, L. JACS 1967, 89, 2416.
Huang, S. L.; Omura, K.; Swern, D. S 1978, 297.
Omura, K.; Swern, D. T 1978, 34, 1651.
Marx, M.; Tidwell, T. T. JOC 1984, 49, 788.
Ogura, H.; Takeda, K.; Tokue, R.; Kobayashi, T. S 1978, 394.
Jochims, J. C.; Seeliger, A. AG(E) 1967, 6, 174.
Greene, F. D.; Kazan, J. JOC 1963, 28, 2168.
Vowinkel, E. CB 1966, 99, 42.
Vowinkel, E. CB 1966, 99, 1499.
Vowinkel, E.; Wolff, C. CB 1974, 107, 496.
Vowinkel, E. S 1974, 430.
Penke, B.; Czombos, J.; Balspiri, L.; Petres, J.; Kovcs, K. HCA 1970,
53, 1057.
Hodson, D.; Holt, G.; Wall, D. K. JCS(C) 1970, 971.
63. Alexandre, C ; Rouessac, F. BSF(2) 1971, 1837.

64. Alexandre, C ; Rouessac, F. CR(C) 1972, 274, 1585.
65. Alexandre, C ; Rouessac, F. TL 1970, 1011.
66. Vowinkel, E.; Bartel, J. CB 1974, 707, 1221.
67. Vowinkel, E. AG(E) 1974, 13, 351.
68. Olah, G. A.; Wu, A.; Farooq, O. S 1989, 568.
69. Vowinkel, E.; Wolff, C. CB 1974, 707, 907.
70. Vowinkel, E.; Buthe, I. CB 1974, 107, 1353.
136
DIETHYLALUMINUM CHLORIDE
71. Mohsen, A.; Omar, M. E. M. E. O.; Habib, N. S.; Aboulwafa, O. M. S

1977,864.
72. Groziak, M. P.; Chern, J.; Townsend, L. B. JOC 1986, 51, 1065.
Catalysis of Ene Reactions. Et 2 AlCl has been used as a cat

alyst for ene reactions with ethyl propiolate as an enophile,7 for
intramolecular ene reactions of aldehydes,8 and for intramolecular
ene reactions with ,-unsaturated esters as enophiles (eq 3). 3e,9
Jeffrey S. Albert & Andrew D. Hamilton

University of Pittsburgh, PA, USA
(2)
Diethylaluminum Chloride
[96-10-6]
C4H10AlCl
(MW 120.56)
(strong Lewis acid that can also act as a proton scavenger; reacts
with HX to give ethane and EtAlClX)
Alternate Names: chlorodiethylaluminum; diethylchloroalane.
Physical Data: mp - 5 0 C; bp 125 C/50 mmHg; d 0.961 g c m - 3 .
Solubility: sol most organic solvents; stable in alkanes or arenes.
Form Supplied in: commercially available neat or as solutions in
hexane or toluene.
Analysis of Reagent Purity: solutions are reasonably stable but
may be titrated before use by one of the standard methods.1e
Handling, Storage, and Precautions: must be transferred under
inert gas (Ar or N 2 ) to exclude oxygen and water. Use in a fume
hood.
(3)
Catalysis of Claisen and Vinylcyclopropane Rearrange

ments. Et 2 AlCl has been used as a catalyst for Claisen re
arrangement of aryl allyl ethers. 10 The rearrangement of 2vinylcyclopropanecarboxylate esters to cyclopentenes is cat
alyzed by Et 2 AlCl (eq 4). 11
(4)
Introduction. The general properties of alkylaluminum

halides as Lewis acids are discussed in the entry for Ethylaluminum Dichloride. Dialkylaluminum halides are less acidic than
alkylaluminum dihalides. Et 2 AlCl is much cheaper than Dimethylaluminum Chloride and is used more frequently than Me 2 AlCl
since comparable results are usually obtained. In some cases, most
notably the ene reactions of carbonyl compounds, use of Me 2 AlCl
is preferable since its methyl groups are less nucleophilic than the
ethyl groups of Et 2 AlCl, which can act as a reducing agent.
Catalysis of Diels-Alder Reactions. Et 2 AlCl has been exten
sively used as a Lewis acid catalyst for Diels-Alder reactions. NAcyloxazolidinones can form both 1:1 (eq 1) and 1:2 complexes
with Et 2 AlCl (eq 2). 2 The 1:2 complex is ~100 times as reactive
as the 1:1 complex and gives greater endo selectivity and higher
de. Me 2 AlCl gives similar selectivity with fewer byproducts.
(1)
Et 2 AlCl has been extensively used as a Lewis acid catalyst for

intermolecular3 and intramolecular4 Diels-Alder reactions with
,-unsaturated ketones and esters as dienophiles. It also cat
alyzes inverse electron demand Diels-Alder reactions of alkenes
with quinone methides 5 and Diels-Alder reactions of aldehydes
as enophiles.6
Generation of Electrophilic Cations. Complexation of

Et 2 AlCl to ketones and aldehydes activates the carbonyl group
toward addition of a nucleophilic alkyl- or allylstannane or
allylsilane.12 Et 2 AlCl has been used to initiate Beckmann rear
rangements of oxime mesylates. The ring-expanded cation can
be trapped intermolecularly by enol ethers and cyanide and intramolecularly by alkenes (eq 5). 13
(5)
Formation and Reaction of Aluminum Enolates. Et2AlCl

has been used in modified Reformatsky reactions. Aldol adducts
are obtained in good yield by reaction of an -bromo ketone with
a ketone in the presence of Zinc and Et 2 AlCl in THF (eq 6). 14
Lithium enolates of esters do not react with epoxides. Reaction
of lithium enolates with Et 2 AlCl affords aluminum enolates that
react with epoxides at the less substituted carbon (eq 7). 15
(6)
N,N-DIETHYLAMINOSULFURTRIFLUORIDE
(7)
5.
6.
7.
8.
Formation
and
Reaction
of
Alkynylaluminum
Reagents. Lithium acetylides react with Et2AlCl to form
LiCl and diethylaluminum acetylides. The aluminum acetylides
are useful reagents for carrying out S N 2 reactions on epoxides
(eq 8)15c,16 and undergo conjugate addition to enones that can
adopt an S-cis conformation (eq 9).17
10.
(8)
12.
9.
11.
13.
(9)
14.
Reaction as a Nucleophile. Et2AlCl reacts analogously to

Ethylmagnesium Bromide and transfers an ethyl group to many
electrophiles. Since EtMgBr and Ethyllithium are readily avail
able, use of Et2AlCl to deliver an ethyl group is needed only when
the stereochemistry of addition is an important issue. High levels
of asymmetric induction are obtained in the conjugate addition
of Et2AlCl to unsaturated acyloxazolidinones with carbohydratederived chiral auxiliaries (eq 10).18 Et2AlCl opens epoxides to
chlorohydrins.19
15.
16.
17.
18.
(10)
19.
Related Reagents. Dimethylaluminum Chloride; Ethylaluminum Dichloride; Methylaluminum Dichloride; Triethylaluminum; Trimethylaluminum.
1. For reviews, see Ref. 1 in Ethylaluminum

2.
3.
4.
137
7791. (f) Funk, R. L.; Bolton, G. L. JACS 1986, 108,4655. (g) Taschner,
M. J.; Cyr, P. T. TL 1990, 31, 5297.
(a) Tietze, L. F.; Brand, S.; Pfeiffer, T.; Antel, J.; Harms, K.; Sheldrick,
G. M. JACS 1987, 109, 921. (b) Casiraghi, G.; Cornia, M.; Casnati, G.;
Fava, G. G.; Belicchi, M. F. CC 1986, 271.
Midland, M. M.; Afonso, M. M. JACS 1989, 111, 4368.
Dauben, W. G.; Brookhart, T. JACS 1981, 103, 237.
(a) Kamimura, A.; Yamamoto, A. CL 1990, 1991. (b) Andersen, N. H.;
Hadley, S. W.; Kelly, J. D.; Bacon, E. R. JOC 1985, 50, 4144.
(a) Oppolzer, W.; Robbiani, C ; Battig, K. T 984,40, 1391. (b) Oppolzer,
W.; Mirza, S. HCA 1984, 67, 730.
(a) Sonnenberg, F. M. JOC 1970, 35, 3166. (b) Bender, D. R.; Kanne,
D.; Frazier, J. D.; Rapoport, H. JOC 1983, 48, 2709. (c) Lutz, R. P. CR
1984, 84, 205.
(a) Corey, E. J.; Myers, A. G. JACS 1985, 107, 5574. (b) Davies, H. M.
L.; Hu, B. TL 1992, 33,453. (c) Davies, H. M. L.; Hu, B. JOC 1992, 57,
3186.
(a) McDonald, T. L.; Delahunty, C. M.; Mead, K.; O'Dell, D. E. TL 1989,
30, 1473. (b) Denmark, S. E.; Weber, E. J. JACS 1984, 106, 7970. (c)
Mooiweer, H. H.; Hiemstra, H.; Fortgens, H. P.; Speckamp, N. W. TL
1987, 28, 3285.
(a) Sakane, S.; Matsumura, Y.; Yamamura, Y.; Ishida, Y.; Maruoka,
K.; Yamamoto, H. JACS 1983, 105, 672. (b) Maruoka, K.; Miyazaki,
T.; Ando, M.; Matsumura, Y.; Sakane, S.; Hattori, K.; Yamamoto, H.
JACS 1983, 105, 2831. (c) Matsumura, Y.; Fujiwara, J.; Maruoka, K.;
Yamamoto, H. JACS 1983, 105, 6312.
(a) Maruoka, K.; Hashimoto, S.; Kitagawa, Y.; Yamamoto, H.; Nozaki,
H. JACS 1977, 99, 7705. (b) Maruoka, K.; Hashimoto, S.; Kitigawa,
Y; Yamamoto, H.; Nozaki, H. BCJ 1980, 53, 3301. (c) Stokker, G. E.;
Hoffmann, W. F.; Alberts, A. W.; Cragoe, E. J., Jr.; Deanna, A. A.;
Gilfillan, J. L.; Huff, J. W.; Novello, F. C ; Prugh, J. D.; Smith, R. L.;
Willard, A. K. JMC 1985, 28, 347. (d) Tsuboniwa, N.; Matsubara, S.;
Morizawa, Y.; Oshima, K.; Nozaki, H. TL 1984, 25, 2569. (e) Tsuji, J.;
Mandai, T. TL 1978, 1817.
(a) Nozaki, H.; Oshima, K.; Takai, K.; Ozawa, S. CL 1979, 379. (b)
Sturm, T.-J.; Marolewski, A. E.; Rezenka, D. S.; Taylor, S. K. JOC
1989, 54, 2039. (c) Danishefsky, S.; Kitahara, T.; Tsai, M.; Dynak, J.
JOC 1976, 41, 1669.
(a) Nicolaou, K. C ; Webber, S. E.; Ramphal, J.; Abe, Y. AG(E) 1987,
26, 1019. (b) Matthews, R. S.; Eickhoff, D. J. JOC 1985, 50, 3923. (c)
Ishiguro, M.; Ikeda, N.; Yamamoto, H. CL 1982, 1029.
Hooz, J.; Layton, R. B. JACS 1971, 93, 7320.
(a) Ruck, K.; Kunz, H. AG(E) 1991, 30, 694. (b) Ruck, K.; Kunz, H. SL
1992, 343. (c) Ruck, K.; Kunz, H. S 1993, 1018.
Gao, L.-X.; Saitoh, H.; Feng, F.; Murai, A. CL 1991, 1787.
Brandeis
University,
Barry B . Snider
Waltham, MA, USA
N, N-Diethylaminosulfur Trifluoride1
Dichloride.
Evans, D. A.; Chapman, K. T.; Bisaha, J. JACS 1988,110, 1238.

(a) Schlessinger, R. H.; Schultz, J. A. JOC 1983,48, 407. (b) Cohen, T.;
Kosarych, Z. JOC 1982,47,4005. (c) Hagiwara, H.; Okano, A.; Uda, H.
CC 1985, 1047. (d) Furuta, K.; Iwanaga, K.; Yamamoto, H. TL 1986, 27,
4507. (e) Oppolzer, W. AG(E) 1984,23, 876. (f) Reetz, M. T.; Kayser, F.;
Harms, K. TL 1992, 33, 3453. (g) Midland, M. M.; Koops, R. W. JOC
1992,57, 1158.
(a) Roush, W. R.; Gillis, H. R. JOC 1982, 47, 4825. (b) Reich, H. J.;
Eisenhart, E. K. JOC 1984, 49, 5282. (c) Shea, K. J.; Gilman, J. W. TL
1983, 24, 657. (d) Brown, P. A.; Jenkins, P. R. JCS(P1) 1986, 1303. (e)
Reich, H. J.; Eisenhart, E. K.; Olson, R. E.; Kelly, M. J. JACS 1986, 108,
[38078-09-0]
C4H10F3NS
(MW 161.18)
(mild reagent for converting primary, secondary, tertiary, allylic,

and benzylic alcohols to the corresponding fluorides,1 aldehy
des and ketones to difluorides,1a,15,19 carboxylic acids to acyl
fluorides,22 and sulfoxides to -fluoro sulfides23)
Alternate Name: DAST.
Physical Data: bp 30-32 C/3 mmHg; d 1.220g cm -3 .
138
N,N-DIETHYLAMINOSULFURTRIFLUORIDE
Solubility: sol ethereal, chlorinated, and hydrocarbon solvents;

reacts violently with water and rapidly with hydroxylic solvents.
Form Supplied in: amber yellow oil; widely available.
Purification: discolored (brown) samples give increasingly lower
yields of fluorinated products. Freshly distilled oil is satisfac
tory for use.
Handling, Storage, and Precautions: can be stored for extended
periods of time in the freezer under inert atmosphere. Use in a
fume hood.
Fluorodehydroxylation of Alcohols. DAST, like several other

variants of dialkylaminotrifluorosulfuranes, converts primary, sec
ondary, tertiary, allylic, and benzylic alcohols to monofluorides.1
The reaction conditions are mild (temperature as low as 78 to
0 C for reactive substrates), and a variety of functionalities such
as acetonides, isolated double/triple bonds, esters, ethers, amides,
and unactivated halides are tolerated (eqs l-3). 1 b , 8 - 1 0
optical purity) from (+)-5'-2-octanol.30 On the other hand, a mix

ture of products of inverted and retained stereochemistry are ob
tained in the reaction of DAST with some protected myoinositol
derivatives (eq 7). 11 Interestingly, in unprotected or minimally
protected sugars, 12a,b and inositols,12c,d where more than two hy
droxy groups are present, only one or two hydroxy groups react
regio- and stereoselectively (eq 8). 12d
(4)
(1)
(5)
(2)
(6)
(3)
The solvents usually employed are dichloromethane, chloro

form, carbon tetrachloride, fluorotrichloromethane, ether, THF,
benzene, and toluene. Generally, DAST is superior to classical
fluorinating agents such as Sulfur Tetrafluoride in that the latter
requires much higher temperatures (typically 100 C) and gives
undesired side products. With DAST, rearrangements are some
times observed, albeit to a lesser extent (eq 4). 1a,2,7 Thus elimination,1a ether formation,3 Friedel-Crafts alkylation,4 and
skeletal rearrangements involving norbornyl cations5 have been
reported. The DAST reaction with isobutyl alcohol yields a mix
ture of 49% isobutyl fluoride and 21% of t-butyl fluoride.1a Other
functionalities can interfere with the normal course of reaction.
A case in point is a pinacol rearrangement with concomitant ring
contraction (eq 5). 2a
S N 2' rearrangement may occur on reacting DAST with allylic
alcohols (eq 6). 6
Highly varied stereochemical outcomes have been obtained in
the reactions of DAST with secondary alcohols. Thus, although
products of partial or complete racemization through ionic or ionpair mechanisms1a have not been widely observed, the usual steric
course is complete inversion or complete retention at the reaction
center. An example is the formation of ()-2-fluorooctane (97.6%
(7)
(8)
Several synthetically useful transformations involving neigh

boring group participation exist.13 An example is the reaction of
DAST with N,N-dibenzyl-L-serine benzyl ester (eq 9). 13b
(9)
Geminal Difluorination of Aldehydes and Ketones. The carbonyl group of aldehydes and ketones can be converted to a
N,/V-DIETHYLAMINOSULFURTRIFLUORIDE
1a,8,14
1,1-difluoro group in moderate to high yields.

The reac
tion conditions are mild (rt to 80 C). The solvents generally
used are dichloromethane and chloroform. Functional groups
compatible with the fluorination of alcohols are also tolerated
in the 1,1-difluorination of aldehydes and ketones (see above).
An aldehyde carbonyl reacts much faster than a ketone carbonyl and selective difluorination of keto aldehydes at the alde
hyde carbonyl has been reported.14 The general order of reac
tivity is alcohols > aldehydes > ketones. A variety of aliphatic,15
aromatic,1a and heterocyclic16 aldehydes have been converted to
1,1-difluorinated compounds (eqs 10-12).14b,18,19
(10)
(11)
.(12)
139
has been accomplished in two steps using, respectively, cis- or

fraws-epoxides as starting materials (eq 16).22
(15)
(16)
Reaction with Organic Acids. Acyl fluorides can be prepared

by the reaction of DAST with carboxylic acids in good to excellent
yields.23 -Hydroxy acids give -fluoroacyl fluorides which hydrolyze on workup to form -fluoro acids.24 Sulfur tetrafluoride,
on the other hand, converts the carboxylic group into a trifluoromethyl group.21
Reaction with Halides and Sulfonates. Reactive halides such
as iodides, allylic, and benzylic halides, and chlorides of organic
acids (sulfinic, sulfonic, and phosphonic) react with DAST to form
the corresponding fluorides.1a
Reaction with Sulfoxides. DAST reacts with -hydrogen con
taining dialkyl and aralkyl sulfoxides to form -fluoroalkyl sul
fides in high yields (eq 17).25 This reaction can be extended to
less reactive sulfoxides by catalysis with certain Lewis acids, e.g.
Antimony(III) Chloride (eq 18)26 and Zinc Iodide.21
(17)
While the reactivity of ketones is similar to aldehydes in scope,

vinyl fluoride formation is a complication and sometimes DAST,
in conjunction with fuming Sulfuric Acid in glyme,17a,b or a mix
ture of Lithium Chloride and Copper(II)Chloride,17bis used for
the preparation of vinyl fluorides (eq 13).
(13)
-Diketones and -keto esters are oxidatively fluorinated with

DAST to furnish a,p-difluoro-,-unsaturated ketones and esters,
respectively (eq 14).20
(18)
Miscellaneous Reactions. Lactones containing -hydrogen or

fluorine do not react with DAST. However, -hydroxy lactones
undergo normal fluorodehydroxylation along with geminal di
fluorination at the lactone carbonyl.28 Glycosyl fluorides can be
obtained in high yield, and in a stereospecific manner, either
by reacting DAST with hemithioacetals in the presence of NBromosuccinimide or, more simply, hemiacetals.29b An interest
ing fluorination of a phenyl ring of N-benzylphenylhydroxylamine
has been reported (eq 19).30
(14)
(19)
Reaction with Epoxides. The reactivity of DAST with epox

ides varies with structure. Thus cyclopentene oxide and cyclohexene oxide give a mixture of 1,1-difluoro and bis(-fluoro) ethers
(eq 15).21 A stereospecific synthesis of meso- or ()-difluorides
An attempt to convert the C-7 hydroxy group of 7-epi-taxol to a

fluoride failed. Instead, a high yield of a cyclopropanated product
with A-ring contraction was obtained (eq 20). A cyclopropane
140
DIETHYL AZODICARBOXYLATE
intermediate corner-protonated at C-19 was postulated to explain

this anomalous transformation.31
27.
McCarthy, J. R.; Peet, N. P. JACS 1985, 107, 735.
28.
Albert, R.; Dax, K.; Katzenbeisser, U.; Sterk, H.; Stuetz, A. E. J.

Carbohydr. Chem. 1985, 4, 521.
29.
(a) Nicolaou, K. C ; Dolle, R. E.; Papahatjis, D. P.; Randall, J. L. JACS

1984, 106, 4189. (b) Posner, G. H.; Haines, S. R. TL 1985, 26, 5.
30.
Leroy, J.; Hebert, E.; Wakselman, C. JOC 1979, 44, 3406.
31.
Chen, S. H.; Huang, S.; Wei, J.; Farina, V. JOC 1993, 58, 4520.
Abdul H. Fauq
Mayo Foundation, Jacksonville, FL, USA
(20)
Diethyl Azodicarboxylate1
Related Reagents. Pyridinium
Sulfur Tetrafluoride.
Poly(hydrogen
fluoride);
1. (a) Middleton, W. J. JOC 1975,40, 574. (b) Hudlicky, M. OR 1988, 513.

2.
(a) Newman, M. S.; Khanna, V. K.; Kanakarajan, K. JACS 1979, 101,

6788. (b) Pankiewicz, K. W.; Krzeminski, J.; Ciszewski, L. A.; Ren, W.
Y.; Watanabe, K. A. JOC 1992, 57, 553.
3. Gai, S.; Hakomori, S.; Toyokuni, T. JOC 1992, 57, 3431.
4. Napolitano, E.; Fiaschi, R.; Hanson, R. CC 1989, 1330.
5. MacLeod, A. M.; Herbert, R.; Hoogsteen, K. CC 1990, 100.
6. (a) Blackburn, G. M.; Kent, D. E. CC 1981, 511. (b) Tellier, F.; Sauvetre,
R. TL 1992, 33, 3643. (c) Tellier, F.; Sauvtre, R. TL 1991, 32, 5963.
7. Uneme, H.; Okada, Y. BCJ 1992, 65, 2401.

8. Goswami, R.; Harsy, S. G.; Heiman, D. F.; Katzenellenbogen, J. A. JMC
1980, 23, 1002.
9. Rozen, S.; Faust, Y.; Ben-Yakov, H. TL 1979, 20, 1823.
10. Avent, A. G.; Bowler, A. N.; Doyle, P. M.; Marchand, C. M.; Young, D.
W. TL 1992, 33, 1509.
11. Moyer, J. D.; Reizes, O.; Malinowski, N.; Jiang, C ; Baker, D. C. ACS
Symp, Ser. 1988, 374, 43.
12. (a) Card, P. J.; Reddy, G. S. JOC 1983,48,4734. (b) Somawardhana, C.
W.; Brunngraber, E. G. Carbohydr. Res. 1981, 94, C14. (c) Kozikowski,
A. P.; Fauq, A. H.; Powis, G.; Melder, D. C. JACS 1990, 112, 4528. (d)
Kozikowski, A. P.; Fauq, A. H.; Rusnak, J. M. TL 1989, 30, 3365.
13. (a) Hasegawa, A.; Goto, M ; Kiso, M. J. Carbohydr. Chem. 1985, 4, 627.
(b) Somekh, L.; Shanzer, A. JACS 1982, 104, 5836. (c) Castillon, S.;
Dessinges, A.; Faghih, R.; Lukacs, G.; Olesker, A.; Thang, T. T. JOC
1985,50,4913.
14. (a) Biollaz, M ; Kalvoda, J. Swiss Patent 616433, 1980 (CA 1980, 93,
168491e). (b) Campbell, J. A. U.S. Patent 4416822, 1983.
15. Markovskij, L. N.; Pashinnik, V. E.; Kirsanov, A. V. S 1973, 787.
16. (a) Kotick, M. P.; Polazzi, J. O. JHC 1981, 18, 1029. (b) Boswell, G. A.,
Jr.; Brittelli, D. R. U.S. Patent 3 919204, 1975.
17. (a) Boswell, G. A., Jr. U.S. Patent 4212815, 1980 (CA 1980, 93,
239 789w). (b) Daub, W.; Zuckermann, R. N.; Johnson, W. S. JOC 1985,
50, 1599.
18. Boehm, M. F.; Prestwich, G. D. TL 1988, 29, 5217.
19. Ando, K.; Kondo, F.; Koike, F.; Takayama, H. CPB 1992, 40, 1662.
20. Asato, A. E.; Lieu, R. S. H. TL 1986, 27, 3337.
21. Hudlicky, M. JFC 1987, 36, 373.
22. Hamatani, T.; Matsubara, S.; Matsuda, H.; Schlosser, M. T 1988, 44,
2875.
23. Middleton, W.J. U.S. Patent 3 914 265, 1975.
24.
25.
26.
Cantrell, G. L.; Filler, R. JFC 1985, 27, 35.

Robins, M. J.; Wnuk, S. F. TL 1988, 29, 5729.
Wnuk, S. F.; Robins, M. J. JOC 1990, 55, 4757.
[1972-28-7]
(functional
C 6 H 10 N 2 O 4
group
oxidations;5 dealkylation
enophile; 24 dienophile33)
(MW 174.16)
of
amines; 16
Alternate Names: diethyl azidoformate; DEAD; DAD. 2

Physical Data: bp 108-110C/15 mmHg; bp211 C/760mmHg;
fp 110sp;C,d 1.11 g c m - 3 .
Solubility: sol CH 2 Cl 2 , Et 2 O, toluene.
Form Supplied in: orange liquid; 90% (technical grade) and 95%
purity are commonly available, as is a 40% solution in toluene.
Preparative Method: although widely available, diethyl azodi
carboxylate can be readily prepared from ethyl chloroformate
and hydrazine, followed by oxidation of the resulting diethyl
hydrazodicarboxylate.3
Purification: in most cases commercial samples are used without
purification. Distillation is possible, but not recommended.
Handling, Storage, and Precautions: flammable; may produce
toxic combustion byproducts. Heat and light sensitive; should
be stored in dark containers under refrigerated conditions.
These containers should also be vented periodically to reduce
pressure. DAD has been reported to occasionally decompose
violently when heated. 3a,4 Use in a fume hood.
Introduction. See Triphenylphosphine-Diethyl

Azodicarboxylate for reactions involving the use of the combination of
PPh 3 and DAD.
Functional Group Oxidations by Dehydrogenation. The
strong electron withdrawing character of diethyl azodicarboxy
late makes it suitable for certain types of oxidations. In general,
diethyl hydrazocarboxylate is formed as a product of any oxida
tion. Primary and secondary alcohols are oxidized to aldehydes
and ketones, respectively, although application of this method has
been limited.5 Thiols, similarly, are oxidized to disulfides. Unsymmetrical disulfides are also available by a variation of this
method.6 The oxidation of formamides to isocyanates has been
accomplished at high temperatures with DAD, although the yields
are frequently low and the method does not appear to be general.7
Arylhydroxylamines are readily converted into nitroso com
pounds with DAD at 0C (eq 1). 8 One example of the con
version of an N,N-dimethylhydrazone to a nitrile has been
reported.9 Sulfur-containing amino acids like methionine and Sethylcysteine can be oxidized to their sulfoxides in virtually quan
titative yields, although another reaction pathway occurs with
most other thioethers.10 Thioethers and ethers usually react with
DAD to yield -hydrazo derivatives by hydrogen abstraction.11
The initial ether/DAD adducts can be formed thermally at 100 C 12
or photochemically at much lower temperatures.13
141
(4)
(1)
The oxidation of propargylic hydrazine derivatives with DAD

to the corresponding propargylic diazenes (with subsequent spon
taneous loss of N 2 ) forms the basis of a powerful, yet mild, allene
synthesis (eq 2). 14
(5)
(2)
This methodology has been applied to the synthesis of the an

tibiotic fervenulin22 and 8-dimethylaminotheophylline.23 In gen
eral, high temperatures (>100C) are required to complete the
cyclization.
Dealkylation of Amines. Treatment of a secondary or ter

tiary amine with diethyl azodicarboxylate in nonpolar solvents
followed by acidic hydrolysis leads to the formation of monodealkylated amines. 15 The mechanism of this reaction is believed
to involve the formation of a triaza adduct (by Michael addition)
followed by a two-step ylide rearrangement yielding an alkylsubstituted hydrazocarboxylate.12a Research on unsymmetrically
substituted amines suggests that benzyl groups are more easily
removed than alkyl groups; methyl groups are the hardest to re
move except in cyclic amines like N-methylpiperidine (eq 3). 16
The N-dealkylation of imines has also been reported.17
Pericyclic Reactions. In general, -carboxyazo compounds

participate in a number of pericyclic processes as noted below.
Ene Reactions. Diethyl azodicarboxylate reacts with most
simple alkenes possessing an allyl hydrogen to yield the corre
sponding ene products, allylic hydrazocarboxylates.24 The uncatalyzed reaction takes place at moderate temperatures (80 C) and
bis-adducts can be formed if excess DAD is used.25 The use of
Tin(IV) Chloride catalyzes the reaction, allowing for rapid reac
tion at 60 C. 26 This reaction proceeds with a surprising degree
of selectivity for (E)-alkene geometry (eq 6). A particularly use
ful application of the ene reaction with DAD is in the synthesis
of allyl amines, which are readily available by reduction of the
initial adducts with Li/NH 3 . 27
(3)
Purine Synthesis. Aminopyrimidines and aminouracil deriva

tives can be converted into purines with diethyl azodicarboxylate
in a number of closely related synthetic methods. Treatment of
compound (1) with an aldehyde leads to the formation of imine
(2), which is converted to purine (3) with DAD (eq 4). 18 A number
of researchers have applied variations of this approach.19
Treatment of 6-aminouracils20 or 6-aminopyrimidines21 (unsubstituted at the 5-position) with DAD leads to the initial for
mation of hydrazino Michael adducts. Treatment of these adducts
with excess DAD leads to cyclization (eq 5).
(6)
Cycloheptatriene reacts with DAD to afford exclusively ene

products, 28 as do the enols of some triazene derivatives.29 Allenes
with alkyl substituents react with DAD to yield ene products in
most cases (eq 7). 30 Ene reactions with DAD have also been found
to be a useful way of cleaving allyl ethers. 31
142
(7)
Diels-Alder [4+2] Cycloadditions. Except as noted below,

diethyl azodicarboxylate reacts with conjugated dienes to yield
[4 + 2] cycloadducts.32 When the diene moiety is a vinyl aromatic,
cycloaddition with DAD is a powerful route for the preparation
of annulated tetrahydropyridazine derivatives.33 Thus the indole
derivative (4) reacts with DAD at rt to afford cycloadduct (5)
(eq 8). 34
Reactivities among cyclic dienes are equally complicated.

Cyclopentadiene gives exclusively [4 + 2] adducts. 47,48 1,3Cyclohexadiene, however, has been reported to give solely ene
products, 49 but careful reexamination of this reaction reveals that
5-15% yields of [4 + 2] cycloadducts can be obtained.50 The reac
tion can be optimized to yield exclusively cycloadducts by altering
experimental conditions. 43,51 In steroidal systems, dienes in inter
nal rings tend to undergo ene reactions, 52 while dienes located in
the terminal ring give mixtures where cycloadditions are the pre
dominant pathways (eq 10).53 In cholesterol derivatives, reduction
of the ene adducts with Li/EtNH 2 is a convenient way to isomerize the diene system (eq 11). 54 It has been reported that treatment
with DAD will aromatize certain cyclohexadiene systems. 44,55
(10)
(8)
The reaction of vinylfurans with DAD usually affords in

tractable mixtures; 33b,e however, furan itself undergoes cycloaddi
tion readily, provided suitable reaction conditions35 are employed
to avoid decomposition of the reactive products. 36 Oxazole deriva
tives readily participate in [4 + 2] cycloadditions with DAD. 37 An
asymmetric Diels-Alder reaction between DAD and pyridazin-3ones facilitated by Baker's Yeast has been reported with ee's in the
range of 9. l-62.7%. 38 The reactions of a number of acyclic heterodienes with DAD have also been reported recently, including
2-aza-l,3-dienes, 39 ,-unsaturated thioketones,40 and l-thia-3aza-1,3-dienes.41 The quinodimethane derivatives of a number of
heterocycles have been used in cycloadditions with DAD (eq 9). 42
(9)
Competition Between Ene and Diels-Alder Reactions. One

area of considerable research centers on the reactivity of diethyl
azodicarboxylate with conjugated dienes, systems in which two
pericyclic reaction pathways are possible: Diels-Alder and ene.
Although a number of researchers have investigated this area, no
clear explanation for the preference of one pathway over another
has emerged. 43 In most cases, one reaction course seems to be
strongly predominant. At this time, only generalizations are pos
sible.
Acyclic 1,3-dienes, for example, in which alkyl groups are
present at the terminus of the diene system, tend to give ene
products with DAD, while those with internal alkyl substituents
yield [4 + 2] adducts. 2,3-Dimethylbutadiene therefore reacts with
DAD to give the cycloadduct in 94% yield, while 2,5-dimethyl2,4-hexadiene gives only ene products. 44,55 In cases where mixed
substitution is present, predictive methods fail completely.46
(11)
Other Cycloadditions. Diethyl azodicarboxylate has seen lit

tle application to other types of pericyclic reactions. DAD
has been reported to undergo [2 + 2] 5 6 cycloadditions with
tetramethoxyallene.57 Two reports of [8 + 2] cycloadditions in
volving DAD have emerged recently, one involving 7-alkylidene1,3,5-cyclooctatrienes58 and the other 3-methoxy-3a-methyl3aH-indene. 59 Indolizine, which is known to undergo [8 + 2]
reactions with electron deficient alkenes, 60 reacts with DAD
exclusively in Michael fashion.61 A photochemically induced
1,3-dipolar cycloaddition involving DAD has been reported.62
Similar Reagents. In most of the reactions involving di
ethyl azodicarboxylate, two closely related compounds can be
employed instead. In many cases, 4-methyl-l,2,4-triazoline3,5-dione (MTAD) (6) and
4-Phenyl-l,2,4-triazoline-3,5-dione
(PTAD) (7) exhibit greater reactivity than DAD. 15,30a,37b,63
Next Page
1. Fahr, E.; Lind, H. AG(E) 1966, 5, 372.
2. The abbreviations DAD and DEAD have been frequently used to
represent diethyl acetylenedicarboxylate as well. To avoid confusion,
the abbreviation DAD will be used throughout to represent diethyl
azodicarboxylate.
3. (a) Kauer; J. C. OSC 1963, 4, 411. (b) Moriarty, R. M.; Prakash, I.;
Penmasta, R. SC 1987, 17, 409. (c) Rabjohn, N. OSC 1955, 3, 375.
(d) Kenner, G. W.; Stedman, R. J. JCS 1952, 2089. (e) Curtius, T.;
Heidenreich, K. B 1894, 27, 773. (f) Stoll, R.; Mampel, J.; Holzapfel,
J.; Leverkus, K. C. B 1912, 45, 273. (g) Picard, J. P., Boivin, J. L. CJC
1951, 29, 223.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
Fieser, L. F.; Fieser, M. F. FF 1967,1, 245.

(a) Yoneda, F.; Suzuki, K.; Nitta, Y. JACS 1966, 88, 2328. (b) Yoneda,
F.; Suzuki, K.; Nitta, Y. JOC 1967, 32, 727.
Mukaiyama, T.; Takahashi, K. TL 1968, 5907.
Fu, P. P.; Boyer, J. H. JCS(P1) 1974, 2246.
(a) Taylor, E. C ; Yoneda, F. CC 1967, 199. (b) Brill, E. E 1969, 25, 680.
Borras-Almenar, C ; Sepulveda-Arques, J.; Medio-Simon, M.; Pindur,
U. H 1990, 31, 1927.
Axen, R.; Chaykovsky, M.; Witkop, B. JOC 1967, 32, 4117.
Woodward, R. B.; Huesler, J.; Gosteli, J.; Naegeli, P.; Oppolzer, W.;
Ramage, R.; Ranganathan, S.; Vorbrugen, U. JACS 1966, 88, 852.
(a) Huisgen, R.; Jakob, F. LA 1954, 37, 590. (b) Diels, O.; Paquin, M. B
1913, 46, 2000.
Cookson, R. C.; Stevens, I. D. R.; Watts, C. T. CC 1965, 259.
Myers, A. G.; Finney, N. S.; Kuo, E. Y. TL 1989, 30, 5747.
Kenner, G. W.; Stedman, R. J. JCS 1952, 2089.
Smissman, E. E.; Makriyannis, A. JOC 1973, 38, 1652.
Doleschall, G.; Toth, G. T 1980, 36, 1649.
Nagamatsu, T.; Yamasaki, H. H 1992, 33, 775.
(a) Kaplita, P. V.; Abreu, M. E.; Connor, J. R.; Erickson, R. H.; Ferkany,
J. W.; Hicks, R. P.; Schenden, J. A.; Noronha-Blob, L.; Hanson, R. C.
Drug. Dev. Res. 1990, 20, 429. (b) Yoneda, F.; Higuchi, M. H 1976, 4,
1759.
Yoneda, F.; Matsumoto, S.; Higuchi, M. CC 1975, 146.
Taylor, E. C ; Sowinski, F. JOC 1974, 39, 907.
Taylor, E. C ; Sowinski, F. JACS 1968, 90, 1374.
Walsh, E. B.; Nai-Jue, Z.; Fang, G.; Wamhoff, H. TL 1988, 29, 4401.
For reviews of the ene reaction, see: (a) Hoffmann, H. M. R. AG(E) 1969,
8, 556. (b) Boyd, G. V. In The Chemistry of Double-Bonded Functional
Groups; Patai, S., Ed; Wiley: New York, 1989; Vol 2, Part 1, pp 477-526.
(c) Oppolzer, W.; Snieckus, V. AG(E) 1978, 17, 476. (d) Mikami, K.;
Shimizu, M. CR 1992, 92, 1021.
Thaler, W. A.; Franzus, B. JOC 1964, 29, 2226.
Brimble, M. A.; Heathcock, C. H. JOC 1993, 58, 5261.
Denmark, S. E.; Nicaise, O.; Edwards, J. P. JOC 1990, 55, 6219.
Cinnamon, J. M.; Weiss, K. JOC 1961, 26, 2644.
Bessiere-Chretien, Y.; Serne, H. JHC 1974, 11, 317.
(a) Lee, C. B.; Taylor, D. R. JCS(P1) 1977,1463. (b) Lee, C. B.;Newman,
J. J.; Taylor, D. R. JCS(P1) 1978, 1161.
Ho, T.-L.; Wong, C. M. SC 1974, 4, 109.
For pertinent reviews of the Diels-Alder reaction see: (a) Gillis, B. T.
In 1,4-Cycloaddition Reactions; Hamer, J., Ed.; Academic: New York,
1967; pp 143-177. (b) Needleman, S. B.; Changkuo, M. C. CR 1962,
62, 405. (c) Weinreb, S. M.; Staib, R. R. T 1982,36, 3087.
Cycloadducts with (a) l-phenyl-5-vinylpyrazole: Medio-Simn, M.;
Alvarez de Laviada, M. J.; Seqlveda-Arques, J. JCS(P1) 1990, 2749. (b)
2-(l-Trimethylsilyloxyvinyl)thiophene: Sasaki, T.; Ishibashi, Y.; Ohno,
M. H 1983, 20, 1933. (c) 3-Vinylcoumarins and chromenes: Minami, T.;
Matsumoto, Y.; Nakamura, S.; Koyanagi, S.; Yamaguchi, M. JOC 1992,
57, 167. (d) Cyanovinylthiophene: Abarca, B.; Ballesteros, R.; Soriano,
C. T 1987, 43, 991. (e) Vinylpyridines: Jones, G.; Rafferty, P.T.1979,
35, 2027. (f) Jones, G.; Rafferty, P. TL 1978, 2731.
143
34.
Pindur, U.; Kim, M.-H.; Rogge, M.; Massa, W.; Molinier, M. JOC 1992,
57, 910.
35. Yur'ev, Y. K.; Zefirov, N. S. JGU 1959, 29, 2916.
36. Barenger, P.; Levisalles, J. BSF(2) 1957, 704.
37. (a) Ibata, T.; Nakano, S.; Nakawa, H.; Toyoda, J.; Isogami, Y. BCJ 1986,
59, 433. (b) Shi, X.; Ibata, T.; Suga, H.; Matsumoto, K. BCJ 1992, 65,
3315. (c) Ibata, T.; Suga, H.; Isogami, Y.; Tamura, H.; Shi, X. BCJ 1992,
65, 2998.
38. Kakulapati, R. R.; Nanduri, B.; Yadavalli, V. D. N.; Trichinapally, N. S.
CL 1992, 2059.
39. Barluenga, J.; Gonzalez, F. J.; Fustero, S. TL 1990, 31, 397.
40. Motoki, S.; Matsuo, Y.; Terauchi, Y. BCJ 1990, 63, 284.
41. Barluenga, J.; Tomas, M.; Ballesteros, A.; Lopez, L. A. TL 1989, 30,
6923.
42. (a) N-BenzoyIindole-2,3-quinodimethane: Haber, M.; Pindur, U.T1991,
47, 1925. (b) 4,5-Dihydro-4,5-dimethylene-1-phenyl-1,2,3-triazole:
Mertzanos, G. E.; Stephanidou-Stephanatou, J.; Tsoleridis, C. A.;
Alexandrou, N. E. TL 1992, 33,4499. (c) 4,5-Dihydro-4,5-dimethylene3-phenylisoxazole: Mitkidou, S.; Stephanidou-Stephanatou, J. TL 1991,
32, 4603. (d) Benzotheite: Jacob, D.; Peter-Neidermann, H.; Meier, H.
TL 1986, 27, 5703.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
Jenner, G.; Salem, R. B. JCS(P2) 1990, 1961.

Gillis, B. T.; Beck, P. E. JOC 1962, 27, 1947.
Measurement of the rate of reaction with 2,3-dimethylbutadiene in many
solvents: Desimoni, G.; Faita, G.; Righetti, P. P.; Toma, L. T 1990, 46,
7951.
(a) Gillis, B. T.; Beck, P. E. JOC 1963, 28, 3177. (b) Jacobson, B. M.;
Feldstein, A. C.; Smallwood, J. I. JOC 1977, 42, 2849.
This reaction is one of the oldest examples of the Diels-Alder reaction:
Diels, O.; Blom, J. H.; Koll, W. LA 1925, 443, 242.
For representative applications of the [4 + 2] reaction of DAD and
cyclopentadiene: (a) Kam, S.-T; Portoghese, P. S.; Gerrard, J. M.;
Dunham, E. W. JMC 1979, 22, 1402. (b) Lyons, B. A.; Pfeifer, J.;
Peterson, T. H.; Carpenter, B. K. JACS 1993, 115, 2427. (c) Adam, W.;
Finzel, R. JACS 1992, 114, 4563. (d) Wyvratt, M. J.; Paquette, L. A. TL
1974, 2433.
Pirsh, J.; Jorgl, J. B 1935, 65, 1324.
(a) Franzus, B.; Surridge, J. H. JOC 1962, 27, 1951. (b) Franzus, B. JOC
1963, 28, 2954.
Askani, R. B 1965, 98, 2551.
van der Gen, A.; Lakeman, J.; Gras, M. A. M. P.; Huisman, H. O. T 1964,
20,2521.
Tomoeda, M ; Kikuchi, R.; Urata, M.; Futamura, T. CPB 1970, 18, 542.
Anastasia, M.; Fiecchi, A.; Galli, G. JOC 1981, 46, 3421.
(a) Mehta, G.; Kapoor, S. K. OPP 1972, 4, 257. (b) Medion-Simon, M.;
Pindur, U. HCA 1991, 74, 430.
Review: Muller, L. L.; Hamer, J. 1,2-Cycloadditions: The Formation of
Three- and Four-Membered Heterocycles; Wiley: New York, 1967.
Hoffmann, R. W. AG(E) 1972, 11, 324.
Ferber, P. H.; Gream, G. E.; Kirkbride, P. K. TL 1980, 21, 2447.
Gilchrist, T. L.; Rees, C. W.; Tuddenham, D. JSC(P1) 1981, 3214.
Galbraith, A.; Small, T.; Barnes, R. A.; Bockelheide, V. JACS 1961, 83,
453.
Masamura, M.; Yamashita, Y. H 1979, 72, 787.
Gilgren, P.; Heimgartner, H.; Schmid, H. HCA 1974, 57, 1382.
(a) Stickler, J. C ; Pirkle, W. H. JOC 1966, 31, 3444. (b) Cookson, R.
C ; Galani, S. S. H.; Stevens, I. D. R. TL 1962, 615. (c) McLellan, J. F.;
Mortier, R. M.; Orszulik, S. T.; Paton, R. M. C1(L) 1963, 94.
Abbott Laboratories,
Eric J. Stoner
North Chicago, 1L, USA
Previous Page
144
DIETHYL PHOSPHOROCHLORIDATE
of various substituted benzenes. 13 It has been noted that certain

heterocycles demonstrated alternative pathways, such as nucleophilic attack at carbon rather than phosphorus (eq 4). 14
(2)
[814-49-3]
(MW 172.55)
C 4 H 10 ClO 3 P
(highly electrophilic phosphorylating reagent easily installed

on anionic carbon,2 oxygen, 3 nitrogen,4 and sulfur;5 ketones
are converted to enol phosphates which can be reduced to
alkenes6 or alkanes,7 or coupled with organometallic reagents
to form substituted alkenes;8 enol phosphates can be tranformed into -keto phosphonates,9 useful for Horner-Emmons
homologation, or into terminal alkynes;10 used to convert carboxylic acids to other carboxylic derivatives11)
Alternate Name: diethyl chlorophosphate.
Physical Data: bp 60 C/2 mmHg; d 1.194 g c m - 3 .
Handling, Storage, and Precautions: highly toxic, corrosive. Use
in a fume hood.
Phosphorylation. Diethyl phosphorochloridate is highly elec

trophilic and can be cleanly reacted at an anionic center provided
that prior metalation is regio- and chemoselective. For example,
phenols, 12 thiophenols,5 and anilines4 can be phosphorylated un
der basic conditions (eq 1). The phosphorylated compound can
be isolated, or treated further with bases, resulting in orthometalation followed by a facile 1,3-phosphorus migration from the
heteroatom to carbon. If carbon phosphorylation is desired, sim
ply treating thiophenol with 2 equiv of n-Butyllithium followed
by diethyl phosphorochloridate gave a moderate yield (58%). 5
(1)
Step 1 (% yield (2))
Step 2 (% yield (3))
OH
LDA, THF
NaH, THF; (EtO)2P(O)Cl
(50-85%)
-78 C to rt (90%)
SH
NaH, THF, rt;
LDA, THF
(EtO)2P(O)Cl (63%)
-78 to OC(16%)
HNMe (EtO)2P(O)Cl, Et3N, THF (97%) LDA, THF
-78 to rt (63%)
Synthetic preparation of oligonucleotides in a cost-efficient

manner can be complicated by low chemoselectivity during phos
phorylation, suggesting the need for prior nitrogen protection. It
has been determined that despite the higher acidity of guanosine
and thymidine over a hydroxy, addition of 1 equiv of the phospho
rylating agent provided only the phosphates (eq 2). 3 Adenosine
and cytidine bases were compatible as well.
Phosphorylation of substituted 1,4-dihydropyridine dianions
occurred selectively (eq 3). 2b Other reports documented selective
phosphorylation at C-5 of thiophenes2a and the ortho position
R1
R2
Conditions
R1
R2
% Yield
TBS H
94
85
guanosine t-BuMgCl (2 equiv) TBS P(O)(OEt)2

THF.rt
(EtO)2P(O)Cl
TBS thymidine t-BuLi, (2 equiv)
P(O)(OEt)2 H
THF, -50 C
(EtO)2P(O)Cl
(3)
(4)
Trapping of ester, lactone, or ketone enolates results in rapid

O-phosphorylation, thus providing the enol phosphate (eq 5). 9
Further treatment with base resulted in facile rearrangement
to the (3-ketophosphonate (eq 5). 15 However, regioisomeric ketophosphonates can often be observed from a regiochemically
pure enol phosphate (eq 6). 9a Since the classical Arbuzov reaction
is limited to primary alkyl iodides (competing Perkov reaction is
known with secondary halides), an alternative method was sought.
Installation of an alkene blocking group sufficed (eq 7). 9a Dienol
phosphates have also been prepared and the authors note that
Lithium 2,2,6,6-Tetramethylpiperidide was the preferred base for
regiochemical control.16
(5)
145
Amines can be readily transformed to an alcohol surrogate

(eq 10)20 and phenols to anilines.21
(10)
(6)
(7)
-Ketophosphonates are valuable intermediates in the realm

of Horner-Emmons alkenation methodology. Acyclic variants
are difficult to obtain from enol phosphates due to compet
ing alkyne and allene formation. One solution utilized the dianion derived from -bromo ketones and trapping with diethyl
phosphorochloridate;17 however, only moderate yields of -keto
phosphonates were reported. The most efficient procedure utilizes
the anion derived from dialkyl methylphosphonate, addition to an
aldehyde, followed by oxidation (eq 8). 18
(8)
Deoxygenation of Phenols and Ketones. Excision of oxygen

from a molecule is often encountered in a synthetic sequence.
Phenols are readily deoxygenated by formation of the phosphate
followed by reduction under dissolving metal conditions.22 It has
been noted that the Birch conditions result in low yields, whereas
an alternative method utilizing activated Titanium metal is supe
rior (eq 11 ). 23 Under this protocol, enol phosphates are efficiently
reduced as well.6b Conversion of an enone to a regiochemically
defined alkene was accomplished via 1,4-reduction, enolate trap
ping, and reduction of the trapped enol phosphate (eq 12).6a Enol
phosphates can be fully reduced to alkanes by hydrogenation of
palladium catalysts7 or converted to vinyl iodides when treated
with Iodotrimethylsilane.24
(11)
(12)
Interconversion of Carboxylic Acid Derivatives. Diethyl

phosphorochloridate is useful for activation of carboxylic acids to
ward nucleophilic attack. Subsequent treatment of the phosphate
ester with thallium sulfides produced thiol esters.19 Variations11
on this theme included prior formation of a heterocyclic phosphonate followed by treatment with alcohols, amines, or thiols, thus
providing a racemization-free method to prepare esters, amides,
and thiol esters, respectively (eq 9). 11b
Synthesis of Alkenes and Alkynes. Enol phosphates are

smoothly transformed into substituted alkenes when treated with
organometallic reagents. If the enol phosphate was derived from
a -keto ester, cuprate reagents are generally reactive enough to
encourage conjugate addition-phosphate elimination (eq 13).25
In the event that this coupling fails, the combination of Pd
and Trimethylaluminum results in regio- and stereospecific
methylation.8b Substrates lacking an ester moiety on the enol
phosphate can be alkylated with Grignard reagents under nickel
catalysis (eq 14).8a
(9)
(13)
146
Related Reagents. Diethyl Phosphorobromidate;
Phosphorocyanidate.
Diethyl
(14)
One of the most useful applications of -keto phosphonates is

the Horner-Emmons alkenation procedure (eq 15).18 Variations of
this theme have employed -imino26 and -sulfonyl phosphates. 27
1. Koh, Y. J.; Oh, D. Y. SC 1993, 23, 1771.

2. (a) Graham, S. L.; Scholz, T. H. JOC 1991, 56, 4260. (b) Poindexter, G.
S.; Licause, J. R; Dolan, P. L.; Foley, M. A.; Combs, C. M. JOC 1993,
55,3811.
3.
4.
(a) Hayakawa, Y; Aso, Y. TL 1983, 24, 1165. (b) Uchiyama, M.; Aso,
Y; Noyori, R.; Hayakawa, Y JOC 1993, 58, 373.
Jardine, A. M.; Vather, S. M. JOC 1988, 53, 3983.
5.
Masson, S.; Saint-Clair, J.-E; Saquet, M. 5 1993, 485.
6.
(a) Grieco, P. A.; Nargund, R. P.; Parker, D. T. JACS 1989, 111, 6287.
(b) Welch, S. C ; Walters, M. E. JOC 1978, 43, 2715.
7. Jung, A.; Engel, R. JOC 1975, 40, 3652.
8. (a) Iwashima, M.; Nagaoka, H.; Kobayashi, K.; Yamada, Y. TL 1992, 33,
81. (b) Asao, K.; Iio, H.; Tokoroyama, T. S 1990, 382.
9. (a) Gloer, K. B.; Calogeropoulou, T.; Jackson, J. A.; Wiemer, D. F. JOC
1990, 55, 2842. (b) Jackson, J. A.; Hammond, G. B.; Wiemer, D. F. JOC
1989, 54, 4750.
(15)
10. Negishi, E.; King, A. O.; Tour, J. M. 0 5 1986, 64, 44.

11.
12.
10
Alkynes are available from methyl ketones by elimination

of the enol phosphate (eq 16).28 When the ketone contains branching, lithium tetramethylpiperidide has been recommended
to circumvent allene formation.
(a) Mikaye, M.; Kirisawa, M.; Tokutake, N. CL 1985, 123. (b) Kim, S.;
Chang, H.; Ko, Y. K. TL 1985, 26, 1341.
Casteel, D. A.; Peri, S. P. S 1991, 691.
13. Takenaka, H.; Hayase, Y. H 1989, 29, 1185.

14. Rani, B. R.; Bhalerao, U. T.; Rahman, M. F. SC 1990, 20, 3045.
15. Hammond, G. B.; Calogeropoulou, T.; Wiemer, D. F. TL 1986, 27,
4265.
16. Blotny, G.; Pollack, R. M. S 1988, 109.
17. Sampson, P.; Hammond, G. B.; Wiemer, D. F. JOC 1986, 51, 4342.
18. Nicolaou, K. C ; Pavia, M. R.; Seitz, S. P. JACS 1982, 104, 2027.
19. Masamune, S.; Kamata, S.; Diakur, J.; Sugihara, Y.; Bates, G. S. CJC
1975, 53, 3693.
(16)
20.
21.
22.
23.
Nikolaides, N.; Ganem, B. TL 1990, 31, 1113.

Rossi, R. A.; Bunnett, J. F. JOC 1972, 37, 3570.
Kenner, G. W.; Williams, N. J. JCS 1955, 522.
Welch, S. C ; Walters, M. E. JOC 1978, 43, 4797.
Miscellaneous. Allylic phosphates have found applications in

-allyl palladium chemistry. It has been demonstrated that al
lylic phosphates undergo oxidative addition more readily than
the corresponding acetate, such that chemoselectivity could be
achieved when these functionalities were present in the same
molecule (eq 17).29 Finally, -keto phosphonates were coupled
with epoxides to provide useful yields of spirocyclopropanes
(eq 18).30
24.
25.
26.
Lee, K.; Wiemer, D. F. TL 1993, 34, 2433.

Moorhoff, C. M ; Schneider, D. F. TL 1987, 28, 4721.
(a) Molin, H.; Pring, B. G. TL 1985, 26,677. (b) Meyers, A. I.; Shipman,
M. JOC 1991, 56, 7098. (c) Highet, R. J.; Jones, T. H. JOC 1992, 57,
4038.
27.
28.
Musicki, B.; Widlanski, T. S. TL 1991, 32, 1267.

Okuda, Y.; Morizawa, Y.; Oshima, K.; Nokaki, H. TL 1984, 25,
2483.
29.
Murahashi, S.-L; Taniguchi, Y.; Imada, Y.; Tanigawa, Y. JOC 1989, 54,
3292.
30.
Jacks, T. E.; Nibbe, H.; Wiemer, D. F. JOC 1993, 58, 4584.
Jonathan R. Young
University of Wisconsin, Madison, WI, USA
(17)
(18)
3,4-DIHYDRO-2H-PYRAN
[110-87-2]
C5H8O
(MW 84.12)
(widely used OH-protecting reagent;1 applicable to alkanols, phe

nols, thiols; stable at high pH; labile at low pH; generally resistant
to nucleophiles and organometallic reagents; resistant to hydride
reductions; labile under Lewis acidic conditions)
Physical Data: mp - 7 0 C; bp 86 C; fp - 1 5 C; d 0.922 g c m - 3 .
Solubility: sol water, ethanol.
Handling, Storage, and Precautions: it has been reported that
the tetrahydropyranyl (THP) ethers form sensitive organic per
oxides when in contact with peroxy reagents. Violent explo
sions have occurred during purification of these compounds.
Precautions normally sufficient in isolation of such products
have failed to destroy the sensitive components.2
Tetrahydropyranylation of Alcohols. Protection of alcohol

functionality as the THP ether is an often-utilized tool in organic
synthesis. It must be noted that the reaction of a chiral alcohol
with dihydropyran introduces an additional asymmetric center and
hence a diastereomeric mixture is obtained (eq 1). This can lead
to difficulties with purification, assignment of spectral features,
etc., but does not prevent successful implementation.3
(1)
A variety of reaction conditions for the synthesis of THP deriva

tives, the majority acidic, have been proposed in the literature
(eq 2). The techniques have been highly optimized and increas
ingly mild conditions have been developed. Mineral acids have
classically been used to effect the reaction.4 Products have been
obtained in 20-93% yields using these methods. However, the use
of mineral acids is clearly limiting with respect to substrates con
taining sensitive functionality. Nevertheless, many applications
in steroid5 and saccharide6 chemistry are possible using this tech
nology. Significantly, tetrahydropyranyl ethers are not known to
migrate in 1,2-diol systems.
147
lodotrimethylsilane (25 C, 30 min, 80-95%). Workup is par

ticularly convenient, consisting of evaporation of volatiles and
chromatography when required. Tertiary alcohols, however, yield
the corresponding iodide rather than the THP ether.9
Reaction using Boron Trifluoride Etherate (Et 2 O-petroleum
ether, 25 C, 47-76%) gives moderate yields with evaporation of
volatiles being the only workup required.10
Pyridinium p-Toluenesulfonate (25 C, 4 h, 94-100%) is a
mild and efficient catalyst, particularly applicable to the protec
tion of highly acid sensitive alcohols. Yields were markedly supe
rior to procedures employing BF 33-Et
Et 22O, p-TsOH, and Hydrogen
Chloride}11
Tetrahydropyranylation of tertiary alcohols, while more diffi
cult owing to the hindered nature of the substrates or competitive
elimination, can be carried out using dihydropyran and Triphenylphosphine Hydrobromide (25 C, 6-24 h, 80-96%). 12 The
method is applicable to even very sensitive substrates such as
mevalonolactone (eq 3).
(3)
Tetrahydropyranylation of alcohols can be carried out under

very mild conditions in the presence of bis(trimethylsilyl) sulfate
(0C, 1 h, 89-100%). No rearrangement is observed even with
tertiary allylic alcohols. 13
Protocols have been developed which utilize an insoluble solid
catalyst in combination with dihydropyran to effect the protec
tion of alcohols as their corresponding THP ethers. These pro
cedures are advantageous in that the catalyst may be recovered
by simple filtration and the products isolated by evaporation of
volatiles. In many cases the catalyst can be reused without regen
eration. Reaction of alcohols with dihydropyran in the presence
of Amberlyst H-15 (25 C, 1 h, 90-98%) yields THP derivatives.
Alternatively, a solution of dihydropyran and the alcohol may be
passed slowly through a column of silica overlaid with Amberlyst
H-15 to yield the THP ethers directly (73-97%). 14 The acidic
clay Montmorillonite K10 (25 C, 15-30 min, 63-95%) is sim
ilarly applicable.15 Reillex 425 resin (86 C, 1.5 h, 84-98%) 16
is applicable with the advantage that it does not promote the
sometimes troublesome polymerization of dihydropyran.17 Poly
meric derivatives of pyridinium p-toluenesulfonate are also ef
fective. Poly(4-vinylpyridinium p-toluenesulfonate) and poly(2vinylpyridinium p-toluenesulfonate) catalysts yield tetrahydropy
ranyl derivatives of primary, secondary, and tertiary alcohols
(24 C, 3-8 h, 72-95%). 18
(2)
The standard acid catalyst for effecting tetrahydropyranylation

of alcohols has becomep-Toluenesulfonic Acid. Reaction of even
tertiary alcohols with excess dihydropyran is usually complete in
0.5-1 h at rt, although sometimes reflux temperatures are required.
Yields range from 60 to 84% for tertiary alcohols.7 Catalysis by
p-TsOH can give very high yields, depending on conditions and
choice of solvent: p-TsOH (dioxane, 20 C, 5 min, 71-97%). 8
Tetrahydropyranylation of primary and secondary alcohols
can give high yields under mild and neutral conditions using
Cleavage of Tetrahydropyranyl Derivatives. Deprotection

of THP ethers has been carried out using Acetic Acid (H 2 O-THF
(3:3:2), 50 C, 5 h, 97%), 19 HOAc (H 2 O-THF (2:1:as re
quired), 47 C, 4 h, 82%), 20 HOAc (THF-H 2 O (4:2:1), 45 C,
3.5 h), 21 aqueous Oxalic Acid (MeOH, 50-90 C, 1-2 h), 22 pTsOH (MeOH, 25 C, 1 h, 94%), 23 pyridinium p-toluenesulfonate
(EtOH, 55 C, 3 h, 98-100%), 24 bis(trimethylsilyl) sulfate
(MeOH, 25 C, 10-90 min, 93-100%). 13 Cleavage with Am
berlyst H-15 (MeOH, 45 C, 0.5-2 h, 93-98%) 25 is advantageous
in that the acid catalyst can be recovered by filtration and no
aqueous workup is required. Organotin phosphate condensates are
148
effective in the selective cleavage of THP ethers (MeOH, reflux,

2 h, 80-90%) in the presence of MEM ethers, MOM ethers, and
1,3-dioxolanes.26 The catalyst is insoluble in the reaction medium
and can be reused repeatedly.
Selective cleavage of THP ethers in the presence of tbutyldimethylsilyl ethers can be accomplished by treatment with
mild Lewis acids: Dimethylaluminum Chloride (25 C to 25 C,
1 h, 98%) or Methylaluminum Dichloride ( - 2 5 C, 0.5 h,
90%). 27 Selective cleavage of THP ethers of primary, secondary,
and tertiary alcohols can be carried out in the presence of tbutyldimethylsilyl, acetyl, mesyl, and methoxymethyl ethers, in
the presence of thiostannane catalysts: Me 2 Sn(SMe) 2 -BF 3 Et 2 O
( - 2 0 C or 0C, 3-25 h, 80-97%). 28
Tetrahydropyranylation
of
Thiols. Tetrahydropyranyl
derivatives of thiols have been utilized for the masking of this
functional group (eq 4).
tetrahalides (0.14 h, 0C to 23 C, 81-96%). 38 Methyl esters

and r-butyldimethylsilyl ethers and alkenes are unreactive under
these reaction conditions. Direct conversion of alcohol tetrahy
dropyranyl ethers to bromides, chlorides, trifluoroacetates, methyl
ethers, or nitriles can be effected with Triphenylphosphine Dibromide (25 C, 30 min, 43-89%). 39 Tetrahydropyranyl ethers may be
converted to benzyl ethers, MEM ethers, benzoates, or tosylates
by reaction with the appropriate electrophile in the presence of
Bu 3 SnSMe-BF 3 EtO 2 (0C, 7-70 h, 75-78%). Oxidation of the
intermediate alkoxystannane with Pyridinium Chlorochromate
yields aldehydes (83%). 40
Ring Opening Reactions of Dihydropyran. Treatment of di
hydropyran with n-pentylsodium,41 or n-Butyllithium42 yields
trans-l-hydroxy-4-nonene (73%) (eq 6).
(6)
(4)
Cleavage of dihydropyran with HCl(aq) (30 min, 25 C) con

stitutes a convenient preparation of 5-hydroxypentanal (eq 7). 43
Thiols react with dihydropyran in the presence of BF 3 Et 2 O
(0C, 0.5 h, 25 C, 1 h) to yield (S)-2-tetrahydropyranyl
hemithioacetals in satisfactory yields. 29 In contrast to Otetrahydropyranyl ethers, an S-tetrahydropyranyl ether is sta
ble to 4 N HCl-MeOH. 30 Deprotection is conveniently accom
plished with Silver(I) Nitrate (0C, 10 min) 31 or Hydrogen
Bromide-Trifluoroacetic Acid (90 min) 32 in quantitative yields.
Oxidation to disulfides can be carried out with Iodine33 or
Thiocyanogen ,34
Tetrahydropyranylation of Amides. Aromatic amides, alkyl
amides, ureas, sulfonamides, and imides undergo reaction
with dihydropyran-Hydrogen Chloride (benzene, reflux, 2 h,
22-73%), yielding the expected adducts.35
Tetrahydropyranylation of Amines. Purines react with dihy
dropyran in the presence of a catalytic amount of p-TsOH to give
the 9-tetrahydro-2-pyranyl derivatives (50-87%) (eq 5). 36
(5)
(7)
Tetrahydropyranyl ethers are unstable to reduction with

Lithium Aluminium Hydride-Aluminium
Chloride (eq 8).
Cleavage occurs in the tetrahydropyranyl ring or exocyclicly.44
The reaction is seldom useful synthetically since the two modes
are competitive. In marked contrast, tetrahydropyranyl derivatives
of thiols are cleaved selectively at the ring carbon-oxygen bond,
giving hydroxyalkyl thioethers (58-82%) (eq 9). 45
(8)
(9)
Tetrahydropyranyl derivatives of amines are hydrogenolized by

LiAlH 4 in the absence of any Lewis acid (eq 10).46
(10)
Functional Group Manipulation of Tetrahydropyranyl

Derivatives. While tetrahydropyranyl derivatives are often uti
lized as masked equivalents of alcohols, etc., it is possible to per
form functional group manipulation on such species. In these cases
the tetrahydropyranyl derivatization serves to activate the alcohol
rather than protect it.
Conversion of alcohols to their corresponding alkyl halides can
be accomplished in two steps by conversion to the THP ethers fol
lowed by treatment with Triphenylphosphine-Carbon Tetrabromide (23 C, 24 h, 62-87%). 37 In the case of tertiary substrates,
15-25% elimination is observed. Similarly rapid conversion of
tetrahydropyranyl derivatives to their corresponding bromides or
iodides can be carried out with 1,2-bis(diphenylphosphino)ethane
Dihydropyran is a convenient starting material for the prepara

tion of (E)-4-hexen-l-ol, in three steps (eq 11).47
(11)
Anion Chemistry. Dihydropyran and derivatives can be quan

titatively deprotonated with t-Butyllithium ( - 7 8 C to 5 C, 0.5 h,
THF) (eq 12). The resulting anion reacts with electrophiles such as
ketones and alkyl halides in good yields. Cuprates derived from
this anion add smoothly in conjugate fashion to ,-enones in
excellent (91%) yields (eq 13).48
149
Chloride; (p-Methoxybenzyloxy)methyl Chloride; 2-Methoxyethoxymethyl Chloride; 2-Methoxypropene; 2-(Trimethylsilyl)ethoxymethyl Chloride.
(12)
1. Greene, T. W. Protective Groups in Organic Synthesis; Wiley: New York,
1981.
2.
(13)
3.
4.
5.
Electrophilic Addition to Dihydropyran. Electrophilic

addition of acetals and orthoesters to dihydropyran oc
curs in the presence of mild catalyst systems such as
Chlorotrimethylsilane-Tin(II)
Chloride (0C, 2 h, 55-84%)
(eq 14).49 The synthetic utility of the reaction is however limited
by the lack of stereocontrol.
(14)
Specific Applications. The THP protecting group has been

widely applied in the field of organic synthesis and no attempt
can be made to comprehensively review its use in these pages.
However, several specific applications may be of interest.
Introduction of the trans-CH=CHCH 2 OH moiety may be con
veniently accomplished using a mixed Gilman cuprate reagent
bearing a terminal THP-protected ether (eq 15).50 The transfor
mation is of considerable utility in several fields of synthesis,
including prostaglandin chemistry.
(15)
The tetrahydropyranyl derivative of propargyl alcohol,

tetrahydro-2-(2-propynyloxy)-2H-pyran, can be converted
to methyl 4-hydroxy-2-butynoate in four steps. 51 Diethyl
[(2-tetrahydropyranyloxy)methyl]phosphonate is a convenient
Wadsworth-Emmons reagent.52 Tetrahydropyranyl esters of
-bromo acids can be used in the Reformatsky reaction for the
preparation of -hydroxy acids. 53 Elimination of a tetrahydropyranyloxy moiety from butyne-1,4-diols with lithium hydride
constitutes an efficient method for the synthesis of allenic
alcohols.54
Related Reagents. Benzyl Chloromethyl Ether; 2-Chloroethyl Chloromethyl Ether; Chloromethyl Methyl Ether;
Dimethoxymethane; Ethyl Vinyl Ether; p-Methoxybenzyl
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
Meyers, A. I.; Schwartzman, S.; Olson, G. L.; Cheung, H.-C. TL 1976,

2417.
Corey, E. J.; Wollenberg, R. H.; Williams, D. R. TL 1977, 2243.
(a) Paul, R. BCF 1934, 1, 971. (b) Woods, G. F.; Kramer, D. N. JACS
1947,69,2246. (c) Parham, W. E.; Anderson, E. L. JACS 1948, 70,4187.
(d) Jones, R. G.; Mann, M. J. JACS 1953, 75, 4048.
(a) Loewenthal, H. J. E. T 1959, 6, 269. (b) Dauben, W. G.; Bradlow, H.
L. JACS 1952, 74, 559. (c) Ott, A. C ; Murray, M. F.; Pederson, R. L.
JACS 1952, 74, 1239.
(a) Straus, D. B.; Fresco, J. R. JACS 1965, 87, 1364. (b) Griffin, B. E.;
Jarman, M.; Reese, C. B. T 1968, 24, 639.
Robertson, D. N. JOC 1960, 25, 931.
van Boom, J. H.; Herschied, J. D. M.; Reese, C. B. S 1973, 169.
Olah, G. A.; Husain, A.; Singh, B. P. S 1985, 703.
Alper, H.; Dinkes, L. S 1972, 81.
Miyashita, N.; Yoshikoshi, A.; Grieco, P. A. JOC 1977, 42, 3772.
Bolitt, V; Mioskowski, C ; Shin, D.-S.; Falck, J. R. TL 1988, 4583.
Morizawa, Y.; Mori, I.; Hiyama, T.; Nozaki, H. S 1981, 899.
Bongini, A.; Cardillo, G.; Orena, M.; Sandri, S. S 1979, 618.
Hoyer, S.; Laszlo, P.; Orlovic, M.; Polla, E. S 1986, 655.
Johnston, R. D.; Marston, C. R.; Krieger, P. E.; Goe, G. L. S 1988, 393.
Olah, G. A.; Husain, A.; Singh, B. P. S 1983, 892.
Menger, F. M.; Chu, C. H. JOC 1981, 46, 5044.
Corey, E. J.; Nicolaou, K. C ; Melvin Jr., L. S. JACS 1975, 97, 654.
Corey, E. J.; Schaaf, T. K.; Huber, W., Koelliker, U.; Weinshenker, N.
M. JACS 1970, 92, 397.
Bernady, K. F.; Floyd, M. B.; Poletto, J. F.; Weiss, M. J. JOC 1979, 44,
1438.
Grant, H. N.; Prelog, V.; Sneeden; R. P. A. HCA 1963, 46, 415.
Corey, E. J.; Niwa, H.; Knolle, J. JACS 1978, 100, 1942.
Miyashita, N.; Yoshikoshi, A.; Grieco, P. A. JOC 1977, 42, 3772.
Bongini, A.; Cardillo, G.; Orena, M.; Sandri, S. S 1979, 618.
Otera, J.; Niibo, Y; Chikada, S.; Nozaki, H. S 1988, 328.
Ogawa, Y.; Shibasaki, M. TL 1984, 663.
Sato, T.; Otera, J.; Nozaki, H. JOC 1990, 55, 4770.
(a) Hiskey, R. G.; Tucker, W. P. JACS 1962, 84, 4789. (b) Holland, G.
F.; Cohen, L. A. JACS 1958, 80, 3765.
Griffin, B. E.; Jarman, M.; Reese, C. B. T 1968, 24, 639.
Holland, G. F.; Cohen, L. A. JACS 1958, 80, 3765.
Hammerstrom, K.; Lunkenheimer, W.; Zahn, H. Macromol. Chem.,
1970, 133, 41.
Holland, G. F.; Cohen, L. A. JACS 1958, 80, 3765.
Hiskey, R. G.; Tucker, W. P. JACS 1962, 84, 4794.
Speziale, A. J.; Ratts, K. W.; Marco, G. J. JOC 1961, 26, 4311.
Robins, R. K.; Godefroi, E. F.; Taylor, E. C ; Lewis, L. R.; Jackson, A.
JACS 1961, 83, 2514.
Wagner, A.; Heitz, M.-P; Mioskowski, C. TL 1989, 557.
Schmidt, S. P.; Brooks, D. W. TL 1987, 767.
Sonnet, P. E. SC 1976, 6, 21.
Sato, R.; Otera, J.; Nozaki, H. JOC 1990, 55, 4770.
Paul, R.; Tchelitcheff, S. BCF 1952, 808.
Pattison, F. L. M.; Dear, R. E. A. CJC 1963, 41, 2600.
(a) Woods, Jr., G. F. OSC 1955, 3, 470. (b) Paul, R. BCF 1934,1, 976.
150
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
3,4-DIHYDRO-2H-PYRIDO[1,2-a]PYRIMIDIN-2-ONE
Eliel, E. L.; Nowak, B. E.; Daignault, R. A.; Badding, V. G. JOC 1965,

50,2441.
Eliel, E. L.; Nowak, B. E.; Daignault, R. A. JOC 1965, 30, 2448.
Eliel, E. L.; Daignault, R. A. JOC 1965,30, 2450.
Paul, R.; Riob, O.; Maumy, M. OSC 1988, 6, 675.
Boeckman Jr., R. K.; Bruza, K. J. TL 1977, 4187.
Mukaiyama, T.; Wariishi, K.; Saito, Y.; Hayashi, M ; Kobayashi, S. CL
1988, 1101.
Corey, E. J.; Wollenberg, R. H. JOC 1975, 40, 2265.
Earl, R. A.; Townsend, L. B. OS 1981, 60, 81.
(a) Kluge, A. F. OS 1984, 64, 80. (b) Kluge, A. F.; Clousdale, I. S. JOC
1979, 44, 4847.
Bogavac, M.; Arsenijevic, L.; Arsenijevic, V. BCF 1980, 145.
(a) Cowie, J. S.; Landor, P. D.; Landor, S. R. CC 1969, 541. (b) Cowie,
J. S.; Landor, P. D.; Landor, S. R. JCS(P1) 1973, 720.
Paul Ch. Kierkus

BASF Corporation, Wyandotte, MI, USA
3,4-Dihydro-2H-pyrido[l,2-a]pyrimidin2-one
[5439-14-5]
C8H8N2O
Synthesis of Esters from Carboxylic Acids. 3 Esterification

(eq 1) proceeds by activation of the carboxyl component using a
2-halopyridinium salt (2; X = Cl, Y = I or X = F, Y = OTs) and (1)
(2.4 equiv) in the presence of an alcohol. The best solvents for this
process are CH 2 Cl 2 or MeCN, but a range of other solvents may
also be used.
(1)
Synthesis of Amides from Carboxylic Acids. 4 In the corre

sponding amidation process (eq 2) there is a requirement for the
addition of 1 equiv of a tertiary amine (Tri-n-butylamine) to en
sure efficient utilization of the amine component (R 2 R 3 NH). Once
again, carboxyl activation is achieved using a 2-halopyridinium
salt (2) but, unlike the esterification reaction, amidation is best
carried out as a two-step one-pot process.
(MW 148.16)
(synthesis of esters and amides from carboxylic acids; glycosylation)

Physical Data: mp 155-156 C; mp (HCl salt) 284-285.5 C
(dec); mp (HBr salt) 299-300 C (dec); mp (HI salt) 263-264 C
(dec).
Solubility: sol MeOH, EtOH, H 2 O.
Form Supplied in: both the free base and salts are obtained as
colorless solids.
Analysis of Reagent Purity: the reagent has a betaine-like structure
and behaves as a salt in terms of the reagent's solubility. The
literature reports various melting points for both the anhydrous
and hydrated forms of the reagent but the conditions used to
determine melting point have been shown to be critical and care
must be exercised if this property is to be used as a measure of
reagent purity.1
Preparative Methods: is prepared by reaction of 2-aminopyridine
with either Acrylic acid itself or an equivalent (2-bromo- or 2iodopropionic acid, Methyl Acrylate, ethyl 2-bromopropionate,
(i-Propiolactone).1,2
Purification: the free base and salts are readily recrystallized from
MeOH-EtzO. 1
Handling, Storage, and Precautions: the reagent may be dried
over P 2 O 5 in vacuo (135 C/17 mmHg).
Introduction. The principal synthetic application of 3,4dihydro-2H-pyrido[l,2-a]pyrimidin-2-one (1) is an acid scav

enger; it is an example of a 'proton sponge' (see 1,8Bis(dimethylamino)naphthalene).
The reagent has been used in
the esterification and amination of alkyl and aryl carboxylic acids

and also in glycosylation of 2-amino-2-deoxy sugars.
(2)
Yields for both the esterification (eq 1) and amidation (eq 2)

reactions are generally high, but the advantages associated with
use of (1) over other reagents for these types of transformation
have yet to be clearly defined.
Glycosylation.5 3, 4-Dihydro-2H-pyrido[l, 2-a]pyrimidin-2one has been used in conjunction with Silver(I) Trifluoromethanesulfonate as a reagent combination to mediate the
glycosylation of N-protected 2-amino-2-deoxy sugars using a
glycosyl bromide as the glycosyl donor (eq 3).
(3)
1. Hurd, C. D.; Hayao, S. JACS 1955, 77, 117.

2. (a) Magidson, O. Y.; Elina, A. S. JGU 1946, 16, 1933 (CA 1947, 41,
6219). (b) Adams, R.; Pachter, I. J. JACS 1952, 74, 4906, 5491. (c)
Krishnan, M.; PIA(A) 1955, 42, 289. (d) Baltrusis, R.; Maciulis, A.;
3,4-DIMETHOXYBENZYL BROMIDE
3.
4.
5.
Purenas, A. Lietuvos TSR Moksln Akad. Darbai. Ser. B 1962, 125 (CA
1963, 58, 6827a). (e) Biniecki, S.; Modrzejewska, W. Acta Pol. Pharm.
1984, 41, 607 (CA 1986,104, 50 843p).
Mukaiyama, T.; Toda, H.; Kobayashi, S. CL 1976, 13.
Mukaiyama, T.; Aikawa, Y.; Kobayashi, S. CL 1976, 57.
Ogawa, T.; Nakabayashi, S.; Sasajima, K. CR, 1981, 96, 29.
151
DDQ oxidation under anhydrous conditions, and further oxidized

to base cleavable benzoates.10 Simple benzyl ethers and many
other protecting and functional groups remain unaffected under
these conditions. 15
(1)
Timothy Gallagher
University of Bristol, UK
3,4-Dimethoxybenzyl Bromide
(2)
+ alcohol as major
product, 83% total
[21852-32-4]
C 9 H 11 BrO 2
(MW 231.09)
(reagent for introduction of 3,4-dimethoxybenzyl protecting

group, which can be cleaved selectively under conditions of
benzylic oxidation1)
Alternate Name: DMBBr.
Solubility: reactions are usually carried out in polar solvents such
as THF or DMF.
Preparative Methods: synthesized from commercially available
3,4-dimethoxybenzyl alcohol and PBr 3 2 or HBr.3
Purification: recrystallization from absolute ethanol.2
Handling, Storage, and Precautions: the reagent is quite unstable
and is best prepared fresh or stored at low temperature under
nitrogen. It is a lachrymator.
3,4-Dimethoxybenzyl Ethers (DMB Ethers). The benzyl

group is a frequently used protecting group 4 in organic synthesis
due to its acid and base stability, and its facile removal by catalytic
hydrogenation or with sodium in liquid ammonia. The group is
most commonly used to protect alcohol functions; however, it may
not be generally applied to substrates which have other functional
groups susceptible to the reductive conditions. To overcome this
problem and generally to extend the range of protecting groups
available, methoxy-substituted benzyl ethers have been prepared
(e.g. the 3,4-dimethoxy1 and 4-methoxybenzyl5 (PMB) ethers).
DMB ethers are made using the benzyl bromide (or chloride),
alcohol, and base, 1 or with base sensitive substrates using the
trichloroacetimidate6 (see Benzyl
2,2,2-Trichloroacetimidate).
PMB ethers can also made in similar fashion under either basic 5 or
acidic7 conditions. DMB ethers can be removed oxidatively using
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ) 1,5 or trityl
5b,c,6,7a
tetrafluoroborate,
and PMB ethers have also been cleaved
with a variety of other methods. 4,8 The products obtained are the
methoxy substituted benzaldehyde and the parent alcohol (eq 1),
although with an allylic alcohol there is a risk of over oxidation
to give the enone (eq 2). 9 Methoxybenzyl ethers with free a- or
-hydroxy groups can be converted to acid cleavable acetals with
Each substituted benzyl ether has a different oxidation poten

tial (1.45 V for the DMB-OR, and 1.78 V for the PMB-OR),
so each methoxy substitution pattern results in different rates
of ether cleavage. 1,11 This means that the DMB group can be
removed in the presence of a PMB ether with high selectivity
(eq 3). 1 It has also been shown that other methoxybenzyl ethers
react at widely differing rates. 11 For example, the reaction time
for the DMB ether was <20 min (86% yield of alcohol), and
the 2,6-dimethoxy isomer required 27.5 h (80% yield) (eq 4). 11
Other substitution patterns give reaction times between these two
extremes.
(3)
PMB and DMB ethers are less readily cleaved than sim
ple benzyl ethers using catalytic hydrogenation.12 W-4 Raney
Nickel gave the best selectivities (eq 5), but deprotection using
Sodium-Ammonia showed no discrimination at all.12
The versatility of a combination of the substituted and unsubstituted benzyl ethers as protecting groups has been shown in the
multi-step syntheses of 16-membered macrolides 13 and other nat
ural products. 1415 The DMB group alone has also been used as an
alcohol protecting group in molecules ranging from the relatively
simple 16 to complex oligoribonucleotides,6,7a and occasionally
for protection of nitrogen-containing groups. 8,17
152
2,2-DIMETHOXYPROPANE
Related Reagents. Benzyl Chloride; Benzyl 2,2,2Trichloroacetimidate; Benzyl Trifluoromethanesulfonate; pmethoxy benzyl bromide; p-methoxy 2,2,2-trichloroacetimidate.
2.
Lakhlifi, T.; Sedqui, A.; Laude, B.; Dinh An, N.; Vebrel, J. CJC 1991,
69, 1156.
the alkoxy or ketone groups in an acidic medium. Both symmetri

cal [R 1 R 2 C(OR 3 ) 2 ] and mixed [R 1 R 2 C(OR 3 )OR 4 ] acetals can be
obtained, depending upon the choice of conditions. 1
The three equilibria shown in eqs 1-3 are established when
2,2-dimethoxypropane, an alcohol, and a catalytic amount of acid
are mixed. Distillation of the methanol formed shifts the equilib
rium far in the direction of the new acetals. Methanol and 2,2dimethoxypropane form a binary azeotrope; however, this can be
broken by the addition of a hydrocarbon solvent such as hexane
or benzene.
3.
Coote, S. J.; Davies, S. G.; Middlemiss, D.; Naylor, A. JCS(P1) 1989,

2223.
(1)
4.

5.
(a) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. TL 1982, 23,885. (b) Takaku,
H.; Kamaike, K. CL 1982, 189. (c) Takaku, H.; Kamaike, K.; Tsuchiya,
H. JOC 1984, 49, 51.
6.
Takaku, H.; Ito, T.; Imai, K. CL 1986, 1005.
7.
(a) Takaku, H.; Ueda, S.; Ito, T. TL 1983, 24, 5363. (b) Nakajima, N.;
Horita, K.; Abe, R.; Yonemitsu, O. TL 1988, 29, 4139.
1. (a) Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.; Yonemitsu, O. T
1986, 42, 3021. (b) Oikawa, Y.; Tanaka, T.; Horita, K.; Yoshioka, T.;
Yonemitsu, O. TL 1984, 25, 5393.
8.
Begtrup, M. BSB 1988, 97, 573.
9.
Trost, B. M.; Chung, J. Y. L. JACS 1985, 107,4586.
(3)
10.
(a) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. TL 1982, 23,889. (b) Nozaki,
K.; Shirahama, H. CL 1988, 1847.
11.
Nakajima, N.; Abe, R.; Yonemitsu, O. CPB 1988, 36, 4244.
12.
Oikawa, Y.; Tanaka, T.; Horita, K.; Yonemitsu, O. TL 1984, 25, 5397.
13.
(a) Nakajima, N.; Hamada, T.; Tanaka, T.; Oikawa, Y.; Yonemitsu,
O. JACS 1986, 108, 4645. (b) Tanaka, T.; Oikawa, Y.; Hamada, T.;
Yonemitsu, O. TL 1986, 27, 3651.
14.
Masamune, S. PAC 1988, 60, 1587.
15.
Yadagiri, P.; Shin, D.-S.; Falck, J. R. TL 1988, 29, 5497.
16.
Lebeau, L.; Oudet, P.; Mioskowski, C. HCA 1991, 74, 1697.
17.
Grunder-Klotz, E.; Ehrhardt, J.-D. TL 1991, 32, 751.
Andrew N. Boa & Paul R. Jenkins

University of Leicester, UK
[77-76-9]
C 5 H 12 O 2
(MW 104.15)
(reagent used in the preparation of acetals, 1,2 acetonides,3 isopropylidene derivatives of sugars 4 - 6 and nucleosides,7 methyl
esters of amino acids, 8 and enol ethers; 9 undergoes the aldol
condensation with enol silyl ethers; 10 used in the preparation of
hypophosphite esters 11 and dimethylboronate esters 12 )
Physical Data: bp 83 C; d 0.847 g c m - 3 .
Handling, Storage, and Precautions: flammable liquid; irritant.
Formation of Acetals. The reagent can be used to prepare a va

riety of acetals via transacetalization. This involves interchanging
(2)
Methyl acetals of other ketones can be obtained by acidifying a

mixture of the ketone, methanol, and 2,2-dimethoxypropane and
removing the acetone formed by distillation. In this case, the func
tion of the 2,2-dimethoxypropane is to react with the water formed
to give methanol and acetone (eqs 4 and 5). This is evidenced by
the fact that the reaction is very slow in the absence of alcohol or
water, but fast when methanol is present. The rate of the reaction
is also directly related to the alcohol concentration.1
(4)
(5)
One undesirable side reaction is the formation of enol ethers via

the acid-catalyzed loss of one molecule of alcohol from the acetal.
This occurs even at relatively low temperatures (50 C). In order
to suppress this reaction, the procedure was modified to include a
neutralization with base prior to workup.
A recent example of the use of 2,2-dimethoxypropane in the
above capacity involves the reaction of an aldehyde or ketone
with o-Nitrobenzyl Alcohol to afford the bis-o-nitrobenzyl acetal
derivative.2 This protecting group has the advantage that it is photoremovable in high yield by irradiation at 350 nm.
Acetonide Formation. The reagent has been used to great ad
vantage as a protecting group for the labile dihydroxyacetone
side chain of the corticosteroids. Cyclic acetal formation between
the 17,21-diol grouping of the prednisolone side chain and 2,2dimethoxypropane in an acid-catalyzed exchange reaction gives
17,21-isopropylidenedioxypregnane in good yield (eq 6). 3
(6)
The base stability of the isopropylidenedioxy function makes

it useful for the preparation of C-21 modified cortical hormones
2,2-DIMETHOXYPROPANE
153
whose formation requires strongly basic conditions. The acetonide

is easily cleaved with aqueous acetic or formic acid in the presence
of heat.
Isopropylidene Derivatives of Sugars and Nucleosides. A
mixture of 2,2-dimethoxypropane, DMF, and a catalytic amount
of p-Toluenesulfonic Acid constitutes an efficient acetonating
agent capable of protecting vicinal, fraws-diequatorial hydroxy
groups and of forming N-acetyl-2,2-dimethyloxazolidines from
vicinal hydroxy and acetamido groups.4 Reaction of methyl -Dglucopyranoside under the above conditions gives recovered start
ing material, methyl 4,6-O-isopropylidene--D-glucoside, and a
trace amount of the diisopropylidene glucoside (eq 7). Similarly,
deoxyinosamine, upon treatment with the same reagent mixture,
affords as the major product the diisopropylidene derivative (eq 8).
(7)
(8)
A further improvement to the existing procedure involves the

substitution of Tin(II) Chloride for thep-toluenesulfonic acid and
1,2-dimethoxyethane for DMF.5a Studies involving D-mannitol
have shown that the tin(II) chloride does not act as a Lewis acid cat
alyst or as a source of HCl (by reaction with the hydroxy groups)
since the use of zinc chloride under identical conditions gives
no reaction. In this particular case, it was subsequently demon
strated that no catalyst is required and that isopropylidenation oc
curs under completely neutral conditions, presumably via acetal
exchange.515 Tin(II) chloride has been used to catalyze isopropy
lidene formation in other carbohydrate systems.6
The ability of 2,2-dimethoxypropane to act as a water scavenger
has resulted in its use (in conjunction with acetone and an acid
catalyst) in the protection of the 2',3'-hydroxy groups of purine
and pyrimidine nucleosides.7 Here again, the formation of acetone
and methanol serves to drive the equilibrium towards the product.
Esterification of Amino Acids. Methyl ester hydrochlo
rides of amino acids have been prepared in which 2,2dimethoxypropane has been used as the source of the methoxy
group, the reaction solvent, and the reagent for the removal of the
water formed by virtue of the hydrolysis of the acetal to methanol
and acetone.8a This procedure has also been used to prepare the
methyl esters of fatty acids. 8b
Enol Ethers. Treatment of testosterone acetate with 2,2dimethoxypropane/DMF/TsOH converts this material into the
enol ether (eq 9). 9 In this case, enol ether formation is attributed
to loss of water directly from the unsaturated hemiacetal.
(9)
Aldol Condensation with Enol Silyl Ethers. The first exam

ple of an aldol condensation between an unactivated enolate and an
electrophilically activated carbonyl substrate was accomplished
using enol silyl ethers and acetals or orthoesters in conjunction
with a catalytic amount of Trimethylsilyl Trifluoromethanesulfonate. The reaction proceeds very readily at 78 C and affords
the erythro-aidol product with high stereoselectivity.10 The use of
2,2-dimethoxypropane in this reaction affords -methoxy ketones
(eq 10).
Hypophosphite Esters. Methyl hypophosphite has been pre

pared by the reaction between Hypophosphorous Acid and
2,2-dimethoxypropane (eq 11).11 However, the product re
acts further with the acetone formed to give 1-hydroxy-1,1dimethylmethylphosphinate (eq 12).
(11)
(12)
Dimethyl Boronate Esters. Dimethyl esters of arylboronic

acids have been prepared by heating a mixture of the acid, 2,2dimethoxypropane, and Zinc Chloride (catalyst).12
Related Reagents. 2-Methoxypropene; Trimethyl orthoformate.
1. (a) Lorette, N. B.; Howard, W. L. JOC 1960, 25, 521, 525. (b) Brown,
B. R.; MacBride, J. A. H. JCS 1964, 3822.
2.
Gravel, D; Murray, S.; Ladouceur, G. CC 1985, 1828.
3.
(a) Tanabe, M.; Bigley, B. JACS 1961, 83, 756. (b) Robinson, C. H.;
Finckenor, L. E.; Tiberi, R.; Olivetto, E. P. JOC 1961, 26, 2863.
(a) de Belder, A. N. Adv. Carbohydr. Chem. Biochem 1965, 20, 219. (b)
de Belder, A. N., Adv. Carbohydr. Chem. Biochem. 1977, 34, 179. (c)
Evans, M. E.; Parrish, F. W.; Long, L. Carbohydr. Res 1967, 3, 453. (d)
Hasegawa, A.; Fletcher, H. G. Carbohydr. Res. 1973, 29, 209, 223. (e)
Hasegawa, A.; Nakajima, M. Carbohydr. Res. 1973, 29, 239.
4.
5.
(a) Chittenden, G. Carbohydr. Res. 1980, 84, 350. (b) Chittenden, G.

Carbohydr. Res. 1980, 87, 219.
154
DIMETHYLALUMIIMUM CHLORIDE
6.
(a) Vekemans, J. A. J. M.; deBruyn, R. G. M.; Caris, R. C. H. M.; Kokx,

A. J. P. M.; Konings, J. J. H. G.; Godefroi, E. F.; Chittenden, G. JOC
1987, 52, 1093. (b) Chittenden, G. RTC 1988, 107, 455.
7.
(a) Hampton, A. JACS 1961, 83, 3640. (b) Moffatt, J. G. JACS 1963, 85,
1118. (c) Hampton, A. JACS 1965, 87, 4654.
8.
(a) Rachele, J. R. JOC 1963, 28, 2898. (b) Radin, N. S.; Hajra, A. K.;
Akahori, Y. J. Lipid Res 1960, /, 250.
9.
Nussbaum, A. L.; Yuan, E.; Dincer, D.; Olivetto, E. P. JOC 1961, 26,
3925.
10.
Murata, S.; Suzuki, M.; Noyori, R. JACS 1980, 102, 3248.
11.
Fitch, S.J. JACS 1964, 86, 61.
12.
Matteson, D. S.; Kramer, E. JACS 1968, 90, 7261.
tions of ,-unsaturated N-acylsultams (eq 2) 6 and 1-mesityl2,2,2-trifluoroethyl acrylate (eq 3) 7 proceed in high yield with
excellent asymmetric induction. Methylaluminum sesquichloride,
prepared from Me 2 AlCl and Methylaluminum Dichloride, cat
alyzes an intramolecular Diels-Alder reaction with an aldehyde
as the dienophile to afford a dihydropyran.8
(1)
Joel Slade
Ciba-Geigy Corporation, Summit, NJ, USA
Dimethylaluminum Chloride 1
[1184-58-3]
C2H6AlCl
(MW 92.51)
(2)
with HX to give methane and MeAlClX)
Alternate Name: chlorodimethylaluminum.
Physical Data: mp - 2 1 C; bp 126-127 C; d 0.996 g c m - 3 .
Solubility: sol most orgatlanic solvents; stable in alkanes or
arenes.
hexane or toluene.
hood.

halides as Lewis acids are discussed in the entry for Ethylaluminum Dichloride. Dialkylaluminum halides are less acidic than
alkylaluminum dihalides. Me 2 AlCl is more expensive than Diethylaluminum Chloride, but the methyl group of Me 2 AlCl is
much less nucleophilic than the ethyl group of Et 2 AlCl. Much
higher yields will generally be obtained by use of Me 2 AlCl in
the ene reactions of carbonyl compounds. In other cases, such as
the Diels-Alder reactions of ,-unsaturated esters, comparable
yields will be obtained with either Lewis acid.
Catalysis of Diels-Alder Reactions. Me 2 AlCl has been
used as a Lewis acid catalyst for inter- and intramolecular
Diels-Alder reactions with a wide variety of dienophiles. High
diastereoselectivity is obtained from chiral ,-unsaturated Nacyloxazolidinones with more than 1 equiv of Me 2 AlCl. 2 Use
of Me2AlCl as a catalyst affords high yields in inter- and in
tramolecular Diels-Alder reactions of ,-unsaturated ketones
(eq 1 ) , 3 4 and intramolecular Diels-Alder reactions of ,unsaturated aldehydes. 4,5 MeaAlCl-catalyzed Diels-Alder reac
(3)
Catalysis of Ene Reactions. 9 A wide variety of Lewis acids

will catalyze the ene reactions of formaldehyde with electronrich
alkenes. Electron-deficient aldehydes, such as chloral and glyoxylate esters, also undergo ene reactions with a variety of Lewis acid
catalysts. Ene reactions of aliphatic and aromatic aldehydes with
alkenes that can form a tertiary cation, and of formaldehyde with
mono- and 1,2-disubstituted alkenes, are best carried out with 1
or more equiv of Me 2 AlCl. The alcohol-Me 2 AlCl complex pro
duced in the ene reaction decomposes rapidly to give methane
and a nonbasic aluminum alkoxide that does not react further
(eq 4). This prevents solvolysis of the alcohol-Lewis acid com
plex or protonation of double bonds. Good to excellent yields of
ene adducts are obtained from aliphatic and aromatic aldehydes
and 1,1 -di- and trisubstituted alkenes. Formaldehyde is more ver
satile and gives good yields of ene adducts with all classes of
alkenes. 10 When less than 1 equiv of Me 2 AlCl is used, -chloro
alcohols are formed, resulting from the stereospecifically cis addi
tion of the hydroxymethyl and chloride groups to the double bond
(eq 5). The chloro alcohols are converted to ene-type adducts in the
presence of excess Me 2 AlCl. Formaldehyde undergoes Me 2 AlClinduced reactions with terminal alkynes to give a 2:3 mixture of
the ene adduct allenic alcohol and the (Z)-3-chloro allylic alcohol
in 50-75% yield (eq 6). 11
DIMETHYLALUMINUM CHLORIDE
155
(11)
(4)
(5)
1 equiv
1.5 equiv
20%
73%
39%
2%
Type-II intramolecular ene reactions of aldehydes and ketones

proceed readily with Me 2 AlCl as the Lewis acid. 17-19 Unsatu
rated aldehydes and ketones can be generated in situ by Me 2 AlClcatalyzed reaction of Acrolein and Methyl Vinyl Ketone with
alkylidenecycloalkanes at low temperatures (eq 12).17 The mono
cyclic aldehyde reacts further under these conditions. The mono
cyclic ketone can be isolated at low temperature but undergoes
a second ene reaction at rt to give the bicyclic alcohol. -Keto
esters form tertiary alcohols in intramolecular ene reactions. The
products are stable because they are converted to the aluminum
alkoxide (eq 13).18 Intramolecular Me2AlCl-catalyzed ene reac
tions have been used for the preparation of the bicyclic mevinolin
ring system (eq 14).19
(6)
Me 2 AlCl catalyzes the ene reactions of a variety of aldehy

des with (Z)-3p-acetoxy-5,17(20)-pregnadiene at - 7 8 C. 12 The
stereoselectivity with aliphatic aldehydes is > 10:1 in favor of the
22-isomer, while aromatic aldehydes produce predominantly the
22-isomer (eq 7). Me 2 AlCl is also the Lewis acid of choice for
ene reactions of -halo aldehydes (eq 8). 13 Ene reactions of vinyl
sulfides to produce enol silyl ethers are also catalyzed by Me2AlCl
(eq 9). 14
(12)
49%, R = Me
63%, R = H
(13)
(7)
(14)
(8)
(9)
Type-I intramolecular ene reactions of aldehydes, such as citronellal, that contain electron-rich trisubstituted double bonds pro
ceed readily thermally or with a variety of Lewis acids. Intramolec
ular ene reactions with less nucleophilic 1,2-disubstituted double
bonds proceed efficiently with Me 2 AlCl as the Lewis acid catalyst
(eqs 10 and 11). 15,16
(10)
Generation of Electrophilic Cations. Me 2 AlCl in

dichloromethane cleaves THP ethers without deprotecting
t-butyldimethylsilyl ethers. 20 Azido enol silyl ethers undergo
Me2AlCl-catalyzed reactions with Allyltributylstannane and
enol ethers, giving conjugate addition-type products that are
isolated as the silyl enol ethers (eq 15).21 Me 2 AlCl will open
norbornane epoxide to the rearranged chlorohydrin.22
(15)
Formation and Reaction of Aluminum Enolates. Aluminum

enolates prepared from esters react with imines to give a lactam resulting from aldol-type addition followed by ring closure
(eq 16).23
156
4-DIMETHYLAMINOPYRIDINE
(16)
Formation
and
Reaction
of
Alkynylaluminum
Reagents. Lithium acetylides react with Me 2 AlCl to give
dimethylaluminum acetylides that react analogously to the more
commonly used diethylaluminum acetylides (see Diethylaluminum Ethoxyacetylide). Addition of the aluminum acetylide to
propiolactone results in an S N 2 reaction to give an alkynic acid
(eq 17).24
8. Trost, B. M.; Lautens, M.; Hung, M. H.; Carmichael, C. S. JACS 1984,

706,7641.
9.
(a) Snider, B. B. COS 1991, 5, 1. (b) Snider, B. B. COS 1991,2, 527. (c)
Mikami, K.; Shimizu, M. CRV 1992, 92, 1021.
10.
(a) Snider, B. B.; Rodini, D. J.; Kirk, T. C ; Cordova, R. JACS 1982, 104,
555. (b) Cartaya-Marin, C. P.; Jackson, A. C ; Snider, B. B. JOC 1984,
49,2443. (c) Tietze, L. F.; Beifuss, U.; Antel, J.; Sheldrick, G. M. AG(E)
1988, 27, 703. (d) Metzger, J. O.; Biermann, U. S 1992, 463.
11.
Rodini, D. J.; Snider, B. B. TL 1980, 21, 3857.
12.
(a) Mikami, K.; Loh, T.-P.; Nakai, T. TL 1988, 29, 6305. (b) Mikami,
K.; Loh, T.-P.; Nakai, T. CC 1988, 1430. (c) Houston, T. A.; Tanaka, Y.;
Koreda, M. JOC 1993, 58, 4287.
13.
Mikami, K.; Loh, T.-P; Nakai, T. CC 1991, 77.
14. Tanino, K.; Shoda, H.; Nakamura, T.; Kuwajima, I. TL 1992, 33, 1337.
(17)
Reaction as a Nucleophile. Me 2 AlCl will react analogously

to MeMgBr and transfer a methyl group to many nucleophiles.
Since Methylmagnesium Bromide and Methyllithium are read
ily available, use of Me 2 AlCl to deliver a methyl group is needed
only when the stereochemistry of addition is an important issue.
High levels of asymmetric induction are obtained in the conju
gate addition of Me 2 AlCl to unsaturated acyloxazolidinones with
carbohydrate-derived chiral auxiliaries (eq 18).25 Me 2 AlCl differs
from higher dialkylaluminum chlorides in that methyl addition is
a radical process that requires photochemical or radical initiation.
Me 2 AlCl will convert acid chlorides to methyl ketones.26
15.
Snider, B. B.; Karras, M.; Price, R. T.; Rodini, D. J. JOC 1982, 47,4538.
16.
(a) Smith, A. B., III; Fukui, M. JACS 1987, 109, 1269. (b) Smith, A. B.,
III; Fukui, M.; Vaccaro, H. A.; Empfield, J. R. JACS 1991, 113, 2071.
17.
(a) Snider, B. B.; Deutsch, E. A. JOC 1982, 47, 745. (b) Snider, B. B.;
Deutsch, E. A. JOC 1983, 48, 1822. (c) Snider, B. B.; Goldman, B. E. T
1986,42,2951.
18. Jackson, A. C ; Goldman, B. E.; Snider, B. B. JOC 1984, 49, 3988.

19.
20.
Ogawa, Y.; Shibasaki, M. TL 1984, 25, 663.
21.
Magnus, P.; Lacour, J. JACS 1992, 114, 3993.
22.
Murray, X F.; Varma, V.; Norton, J. R. JOC 1978, 43, 353.
23.
Wada, M.; Aiura, H.; Akiba, K.-Y. TL 1987, 28, 3377.
24.
Shinoda, M.; Iseki, K.; Oguri, X; Hayasi, Y.; Yamada, S.-I.; Shibasaki,
M. TL 1986, 27, 87.
25.
(a) Ruck, K.; Kunz, H. AG(E) 1991, 30, 694. (b) SL 1992, 343. (c) S
1993, 1018.
26.
Ishibashi, H.; Xakamuro, I.; Mizukami, Y.-I.; Irie, M.; Ikeda, M. SC 1989,
19, 443.
(18)
Related
Reagents. 1,8-Bis(dimethylamino)naphthalene;
Diethylaluminum Chloride; Dimethylaluminum Iodide; Ethylaluminum Dichloride; Methylaluminum Bis(2,6-di-t-butyl-4methylphenoxide); Methylaluminum
Bis(4-bromo-2,6-di-tbutylphenoxide); Methylaluminum Bis(2,6-di-t-butylphenoxide); Methylaluminum Dichloride; Trimethylsilyl Trifluoromethanesulfonate.
(a) Wovkulich, P. M.; Tang, P. C ; Chadha, N. K.; Batcho, A. D.; Barrish,

J. C ; Uskokovi, M. R. JACS 1989, 111, 2596. (b) Banish, J. C ;
Wovkulich, P. M.; Tang, P. C ; Batcho, A. D.; Uskokovi, M. R. TL 1990,
31, 2235. (c) Quinkert, G.; Schmalz, H.-G.; Walzer, E.; KowalczykPrzewloka, T.; Drner, G.; Bats, J. W. AG(E) 1987, 26, 61. (d) Quinkert,
G,; Schmalz, H.-G.; Walzer, E.; Gross, S.; Kowalczyk-Przewloka, T.;
Schierloh, C.; Durner, G.; Bats, J. W.; Kessler, H. LA 1988, 283. (e)
Cohen, X; Guo, B.-S. T 1986, 42, 2803.
Barry B. Snider
Brandeis University, Waltham, MA, USA
4-Dimethylaminopyridine1
1. For reviews, see Ref. 1 under Ethylaluminum Dichloride.

2.
3.
(a) Evans. D. A.; Chapman, K. T.; Bisaha, J. TL 1984, 25, 4071. (b)
Evans, D. A.; Chapman, K. T.; Bisaha, J. JACS 1984, 106, 4261. (c)
Evans, D. A.; Chapman, K. T.; Bisaha, J. JACS 1988, 110, 1238. (d)
Sugahara, T.; Iwata, X; Yamaoka, M ; Takano, S. TL 1989, 30, 1821. (e)
Hauser, F. M.; Tommasi, R. A. JOC 1991, 56, 5758.
4.
(a) Sakan, K.; Smith, D. A. TL 1984, 25, 2081. (b) Ireland, R. E.; Dow,
W. C ; Godfrey, J. D.; Thaisrivongs, S. JOC 1984, 49, 1001.
Marshall, J. A.; Shearer, B. G.; Crooks, S. L. JOC 1987, 52, 1236.
5.
Takeda, K.; Kobayashi, T.; Saito, K.; Yoshii, E. JOC 1988, 53, 1092.
6.
Oppolzer, W.; Dupuis, D.; Poli, G.; Raynham, T. M.; Bernardinelli, G.

TL 1988, 29, 5885.
7.
Corey, E. J.; Cheng, X.-M.; Cimprich, K. A. TL 1991, 32, 6839.
[1122-58-3]
C 7 H 10 N 2
(MW 122.19)
(catalyst for acylation of alcohols or amines, 1-11 especially for

acylations of tertiary or hindered alcohols or phenols 12 and for
macrolactonizations; 13-15 catalyst for direct esterification of carboxy lic acids and alcohols in the presence of dicyclohexylcarbodiimide (Steglich-Hassner esterification);5 catalyst for silylation or
tritylation of alcohols, 9,10 and for the Dakin-West reaction 20 )
4-DIMETHYLAMINOPYRIDINE
Alternate Name: DMAP.
Physical Data: colorless solid; mp 108-110 C; pKa 9.7.
Solubility: sol MeOH, CHCl 3 , CH 2 Cl 2 , acetone, THF, pyridine,
HOAc, EtOAc; partly sol cold hexane or water.
Form Supplied in: colorless solid; commercially available.
Preparative Methods: prepared by heating 4-pyridone with
HMPA at 220 C, or from a number of 4-substituted (Cl, OPh,
SO 3 H, OSiMe 3 ) pyridines by heating with DMA. 2 Prepared
commercially from the 4-pyridylpyridinium salt (obtained from
pyridine and SOCl 2 ) by heating with DMF at 155 C. 1 2
Purification: can be recrystallized from EtOAc.
Handling, Storage, and Precautions: skin irritant; corrosive, toxic
solid.
Acylation of Alcohols. Several 4-aminopyridines speed up esterification of hindered alcohols with acid anhydrides by as much
as 10000 fold; of these, DMAP is the most commonly used but
4-pyrrolidinopyridine (PPY) and 4-tetramethylguanidinopyridine
are somewhat more effective.11 DMAP is usually employed in
0.05-0.2 mol equiv amounts.
DMAP catalyzes the acetylation of hindered 11- or 12hydroxy steroids. The alkynic tertiary alcohol acetal in eq 1 is
acetylated at rt within 20 min in the presence of excess DMAP.3
(1)
Esterifications mediated by
2-Chloro-l-methylpyridinium
Iodide also benefit from the presence of DMAP.22
DMAP acts as an efficient acyl transfer agent, so that alcohols
resistant to acetylation by Acetic Anhydride-Pyridine usually re
act well in the presence of DMAP.4a Sterically hindered phenols
can be converted into salicylaldehydes via a benzofurandione pre
pared by DMAP catalysis (eq 2). 4b
157
13b
dihydroerythronolide.
Other macrolactonizations have been
achieved using 2,4,6-Trichlorobenzoyl Chloride and DMAP in
Triethylamine at rt14 or Di-2-pyridyl Carbonate (6 equiv) with 2
equiv of DMAP at 73 C. 15
Acylation of Amines. Acylation of amines is also faster in the
presence of DMAP,7 as is acylation of indoles,8a phosphorylation
of amines or hydrazines, 2,8 and conversion of carboxylic acids into
anilides by means of Phenyl Isocyanate.1 -Lactam formation
from -amino acids has been carried out with DCC-DMAP, but
epimerization occurs. 8b
(3)
Silylation, Tritylation, and Sulfinylation of Alcohols.

Tritylation, including selective tritylation of a primary alcohol in
the presence of a secondary one, 9 silylation of tertiary alcohols,
selective silylation to t-butyldimethylsilyl ethers,6 and sulfonylation or sulfinylation10 of alcohols proceed more readily in the pres
ence of DMAP. Silylation of -hydroxy ketones with Chlorodiisopropylsilane in the presence of DMAP followed by treatment
with a Lewis acid gives diols (eq 4). 16
(4)
Miscellaneous Reactions. Alcohols, including tertiary ones,

can be converted to their acetoacetates by reaction with Diketene
in the presence of DMAP at rt.17 Decarboxylation of -keto esters
has been carried out at pH 5-7 using 1 equiv of DMAP in refluxing
wet toluene (eq 5). 18
(5)
(2)
Direct Esterification of Alcohols and Carboxylic

Acids. Instead of using acid anhydrides for the esterifica
tion of alcohols, it is possible to carry out the reaction in
one pot at rt by employing a carboxylic acid, an alcohol,
1,3-Dicyclohexylcarbodiimide, and DMAP. 5,6 In this manner,
TV-protected amino acids and even hindered carboxylic acids
can be directly esterified at rt using DCC and DMAP or
4-pyrrolidinopyridine (eq 3). 5
DCC-DMAP has been used in the synthesis of depsipeptides.6b
Macrocyclic lactones have been prepared by cyclization of hy
droxy carboxylic acids with DCC-DMAP. The presence of
salts of DMAP, 13a such as its trifluoroacetate, is beneficial
in such cyclizations, as shown for the synthesis of a (95)-
Elimination of water from a t-alcohol in a -hydroxy alde

hyde was carried out using an excess of Methanesulfonyl
Chloride-DMAP-H2O at 25 C. 23
Glycosidic or allylic alcohols (even when s-) can be converted in
a 80-95% yield to alkyl chlorides by means of p-Toluenesulfonyl
Chloride-DMAP. Simply primary alcohols react slower and sec
ondary ones are converted to tosylates.24
Aldehydes and some ketones can be converted to enol acetates
by heating in the presence of TEA, Ac 2 O, and DMAP.2 DMAP
catalyzes condensation of malonic acid monoesters with unsatu
rated aldehydes at 60 C to afford dienoic esters (eq 6). 19
(6)
158
N,N-DIMETHYLFORMAMIDE DIETHYL ACETAL
The conversion of -amino acids into -amino ketones by

means of acid anhydrides (Dakin-West reaction) 20 also proceeds
faster in the presence of DMAP (eq 7).
19.
Rodriguez, J.; Waegell, B. S 1988, 534.
20.
(a) Buchanan, G. L. CSR 1988, 17, 91. (b) McMurry, J. JOC 1985, 50,
1112. (c) Hoefle, G., Steglich, W. CB 1971, 104, 1408.
21.
Buechi, G.; Wuest, H. JOC 1979, 44, 4116.
22.
Nicolaou, K. C.; Bunnage, M. E.; Koide, K. JACS 1994, 116, 8402.
23.
Furukawa, J.; Morisaki, N.; Kobayashi, H.; Iwasaki, S.; Nozoe, S.;
Okuda, S. CPB 1985, 33, 440.
24.
Hwang, C. K.; Li, W. S.; Nicolaou, K. C. TL 1984, 25, 2295.
(V)
Ketoximes can be converted to nitrimines which react with

Ac 2 O-DMAP to provide alkynes (eq 8). 21
Alfred Hassner
Bar-llan University, Ramat Gan, Israel
N,N-Dimethylformamide Diethyl Acetal
(8)
For the catalysis by DMAP of the t-butoxylcarbonylation of

alcohols, amides, carbamates, NH-pyrroles, etc., see Di-t-butyl
Dicarbonate.
Related Reagents. 1-Hydroxybenzotriazole;
succinimide; Imidazole; Pyridine.
N-Hydroxy-
(1;R1=Et, R2 = Me)
[1188-33-6]
(2; R1 = Me, R2 = Me)
[4637-24-5]
C 7 H 17 NO 2
(MW 147.25)
C 5 H 13 NO 2
(MW 119.19)
C 17 H 21 NO 2
(MW 271.39)
C 9 H 21 NO 2
(MW 175.31)
(3; R1 = PhCH2, R2 = Me)

[2016-04-8]
(4;R1=Et, R2 = Et)
1.
2.
3.
4.
Hoefle, G.; Steglich, W.; Vorbrueggen, H. AG(E) 1978,17, 569.

Scriven, E. F. V. CSR 1983,12, 129.
(a) Steglich, W.; Hoefle, G.AG(E) 1969, 8, 981. (b) Hoefle, G.; Steglich,
W.S 1972, 619.
(a) Salomon, R. G., Salomon, M. F.; Zagorski, M. G.; Reuter, J. M.;
Coughlin, D. J. JACS 1982, 104, 1008. (b) Zwanenburg, D. J.; Reynen,
W. A. P. S 1976, 624.
5.
(a) Neises, B.; Steglich, W. AG(E) 1978, 17, 522. (b) Hassner, A.;
Alexanian, V. TL 1978, 4475.
6. (a) Ziegler, F. E.; Berger, G. D. SC 1979, 539. (b) Gilon, C.; Klausner,
Y.; Hassner, A. TL 1979, 3811.
7.
Litvinenko, L. M., Kirichenko, A. C ; DOK 1967, 776, 97. (b)

Kirichenko, A. C.; Litvinenko, L. M ; Dotsenko, I. N.; Kotenko, N. G.;
Nikkel'sen, E.; Berestetskaya, V. D. DOK 1969, 244, 1125 (CA 1979,
90, 157 601).
8.
(a) Nickisch, K.; Klose, W.; Bohlmann, F. CB 1980, 113, 2036. (b)
Kametami, T.; Nagahara, T.; Suzuki, Y.; Yokohama, S.; Huang, S.-P;
Ihara.M. T1981, 37,715.
(a) Chaudhary, S. K.; Hernandez, O. TL 1979, 95, 99. (b) Hernandez,
O.; Chaudhary, S. K.; Cox, R. H.; Porter, J. TL 1981, 22, 1491.
9.
10.
11.
12.
Guibe-Jampel, E.; Wakselman, M.; Raulais, D. CC 1980, 993.

Hassner, A.; Krepski, L. R.; Alexanian, V. T 1978, 34, 2069.
Vorbrueggen, H. (Schering AG) Ger. Often. 2 517 774, 1976 (CA 1977,
56,55 293).
13.
(a) Boden, E. P.; Keck, G. E. JOC 1985, 50, 2394. (b) Stork, G.;
Rychnovsky, S. D. JACS 1987, 109, 1565.
14. Hikota, M.; Tone, H.; Horita, K.; Yonemitsu, O. JOC 1990, 55,7.
15. (a) Kim, S.; Lee, J. I.; Ko, Y. K. TL 1984, 25, 4943. (b) Denis, J.-N.;
Greene, A. E.; Guenard, D.; Gueritte-Voegelein, F.; Mangatal, L.; Potier,
P. JACS 1988, 110, 5917.
16. Anwar, S.; Davis, A. P. T 1988, 44, 3761.
17. Nudelman, A.; Kelner, R.; Broida, N.; Gottlieb, H. E. S 1989, 387.
18. Taber, D. F.; Amedio J. C , Jr.; Gulino, F. JOC 1989, 54, 3474.
[22630-13-3]
(mild and selective reagents for alkylation, formylation, and

aminomethylenation 1 )
Alternate Name: DMF diethyl acetal.
Physical Data: (1) bp 134-136 C/760 mmHg; pKb 6.2.5 (2)
bp 102-104 C/720 mmHg; pKb 6.25. 5 (3) bp 138-140 C/0.5
mmHg; pKb 6.2.5 (4) bp 57-58 C/20 mmHg; pKb 6.4.5
Solubility: sol a variety of inert solvents.
Form Supplied in: pure liquid.
Preparative Methods: (1) a solution of sodium alkoxide (1 mol)
and the secondary amine (1.1 mol) in 200-300 mL of the re
spective alcohol is refluxed as chloroform (39.5 g, 0.33 mol)
is added. The mixture is refluxed for 2 h and the filtrate ob
tained is distilled in vacuo. For example, N,N-diethylformamide
diethyl acetal is obtained in 32% yield.7 (2) A solution of
N,N-dialkyl(chloromethylene)ammonium chloride (Vilsmeier
reagent, 1 mol) in 640-500 mL of chloroform is stirred while
sodium alkoxide (2.1 mol) in 1 L of the respective alcohol is
added. After 1 h at 20 C the sodium chloride is separated and
the mixture is distilled in vacuo. For example, the yield of DMF
dimethyl acetal is 55%. 2
Handling, Storage, and Precautions: most of the known orthoamide derivatives are colorless, distillable liquids with an
amine-like smell. If moisture and presence of acids and high
temperature are avoided, most of the reagents can be stored
almost indefinitely. No significant toxicity has been reported.
Reactions and Synthetic Applications: General. The formamide acetals enter into two main categories of reactions,
159

namely alkylation and formylation, mostly via generation of azaoxo-stabilized carbenium ions (eq 1). 1 - 7 As alkylation reagents
they have been used in the synthesis of esters from acids, in the
synthesis of ethers and thioethers from phenols and aromatic and
heterocyclic thiols, and in the alkylation of CH-active methines.
As formylating agents, formamide acetals are useful in the synthe
sis of enamines from active methylene compounds and amidines
from amines and amides, as well as in the formation and modi
fication of many types of heterocyclic compounds. They can be
used for the dehydrative decarboxylation of -hydroxy carboxylic
acids to alkenes, and for the cyclization of trans vicinal diols to
epoxides. 1 From the numerous literature reports on applications
of these reagents, 1-7 some representative reactions are discussed
in the following sections.
DMF bis(4-dodecylbenzyl) acetal has also been used.

examples are given in Table 1.
1314
Some
(5)
(1)
Alkylation Reactions. DMF dialkyl acetals undergo a variety

of reactions with 1,2-diols.1 For example, the reaction of transcyclohexane-1,2-diol with DMF dimethyl acetal leads to the for
mation of cyclohexane epoxide (eq 2) 8 with inversion of config
uration. Similarly, meso-1,2-diphenyl-1,2-ethanediol gives transstilbene epoxide stereospecifically (eq 3). 8,9a This method has
also been applied in the synthesis of cholestane epoxide from vic
inal diols.8 If the intermediate 2-dimethylamino-1,3-dioxolane is
treated with Acetic Anhydride, reductive elimination to the alkene
occurs with retention of stereochemistry (eq 4). 9b
Table 1 Esterification of Amino Acid and Peptide Derivatives with

DMF Dibenzyl Acetal (3) and DMF Bis(4-dodecylbenzyl) Acetal (5)
Yield
RCO2Ha
(2)
(3)
Reaction conditions
(%)
13,14
97
C 6 H 6 ,80C, 1.5 h
(3)
90 14
C
H
,80C,
48
h
6 6
(3)
o
C 6 H 6 ,80 C, 2h
7813,14
(3)
C
H
,80C,
1h
7
313,14
6 6
(3)
CH 2 Cl 2 ,25C,48h
80 14
(3)
CH 2 Cl 2 ,25C, 90 h
80 14
(3)
CH 2 Cl 2 ,20C, 18 h
84 13
(5)
CH
Cl
,20C,50h
68 13
2
2
(5)
75 13
CH 2 Cl 2 , 20 C, 120 h
(5)
DOBC = 4-decyloxybenzyloxycarbonyl; Boc = t-butoxycarbonyl.
N-DOBC-L-Val
N-DOBC-L-Phe
N-DOBC-L-Try
N-DOBC-Gly-L-Leu
N-DOBC-Gly-L-Tyr
N-Boc-Gly-L-Phe
N-DOBC-L-Phe
N-DOBC-L-Try
N-DOBC-L-Phe-L-Ala
Acetal
DMF dineopentyl acetal has been used as a reagent for dehy

drative decarboxylation in order to avoid the possibility of com
peting O-alkylation of the carboxyl group. 15 This conversion of
-hydroxy carboxylic acids to alkenes by reaction with a DMF ac
etal involves an anti elimination, and it is thus complementary to
the syn elimination of these hydroxy acids via the -lactone. These
reactions have been used to obtain both (E)- and (Z)-1-alkoxy-1,3butadienes (eq 6). 15 For additional examples of alkenes obtained
from -hydroxy acids with DMF acetals, see Scheeren et al.7
(4)
DMF dimethyl acetal is an effective methylating reagent. For

example, heterocyclic thiols are transformed to S-methyl heterocycles in high yields (76-86%). 10 DMF dibenzyl acetal is an inter
esting reagent for selective protection of nucleosides. For exam
ple, uridine and guanosine are selectively blocked at the -CONH
function (eq 5). 11
In a very simple procedure, carboxylic acids can be esterified
under mild conditions with DMF dialkyl acetals. Some interesting
uses are the conversion of carboxylic acids to ethyl and benzyl
esters with DMF diethyl and dibenzyl acetals (yield 64-75%). 12
The dibenzyl acetal has been widely used as protecting group
reagent for the carboxyl end group in peptides. 13 In several cases,
(6)
Formylation Reactions. DMF dialkyl acetals exhibit reactiv

ity as a formyl cation synthon by introducing a C1 unit at many
nucleophilic centers (e.g. at N, S, O, or CH). For example, DMF
dimethyl acetal can be used instead of formic acid for conversion
160
of o-disubstituted aromatic systems into annulated heterocycles

(eq 7). 16
(7)
A nonacidic and regioselective route to Mannich bases from

ketones and esters involves reaction with DMF acetals at a high
temperature to form enamino ketones which are readily reduced
by Lithium Aluminium Hydride to the Mannich bases (eq 8). 17
A general indole synthesis involves reaction of an onitrotoluene derivative with DMF dimethyl acetal in refluxing
DMF (eq 12). 19,20 The initially formed o-nitroaryl-substituted (E)iV,/V-dimethylenamine is submitted to catalytic hydrogenation to
give the indole by spontaneous cyclization. According to a vari
ation of this methodology,20 2-arylindoles are readily available
by reaction of o-nitrotoluene with DMF diethyl acetal and ohalobenzoyl chloride. This reaction proceeds via benzoylation of
the respective enamine.
(12)
(8)
CH-acidic groups (including methyl) react with DMF acetals

via carbon-carbon bond formation and subsequent elimination
of the respective alkanols to form enamines (aminomethylenation). Thus 2,4,7-trimethyl-l,3-dithia-5,6-diazepine reacts with
DMF dialkyl acetals to give mono- or bis-aminomethylenated
products depending on the amount of reagent and the re
action conditions (eq 9). 18a The same reagents convert the
more nucleophilic 2,5-dimethyl-l,3,4-thiadiazolium salts to the
monoenamines (eq 10).18a Similarly, 1,2-dimethyl-3-cyano-5nitroindole condenses with DMF diethyl acetal to give the (E)indol-2-yl enamine (eq 1 l). 1 8 b
4-Dimethylamino-2-azabutadienes are readily accessible by

the reaction of azomethines (imines) with DMF diethyl ac
etal (eq 13).21 l-Dimethylamino-l,3-butadienes can be synthe
sized in the same manner.21 Reactions of 2-azavinamidinium
salts with DMF diethyl acetal give rise to 2-aza- and 2,4diazapentamethinium salts (eq 14).22
(13)
R1
R2
R3
CO2Me
CO2Me
CO2Me
H
H
H
Ph
p-ClC6H4
p-Tol
Yield (%)
83
70
82
(9)
(14)
(10)
R1
R2
Me
Me
Me
Bz
C8H17 Me
R3
Me
Me
Me
MeSO4
Br
I
Yield (%)
93
85
85
(11)
Miscellaneous Reactions. DMF acetals catalyze rearrange

ment reactions of allylic alcohols to ,-unsaturated amides. 23
This reaction, which involves a [2,3]-sigmatropic rearrangement,
occurs with complete transfer of chirality. Thus the reaction of the
(R,Z)-allylic alcohol (eq 15) with DMF dimethyl acetal gives the
enantiomerically pure (R,E)-,-unsaturated amide as the only
product. The (S,E)-isomer also rearranges mainly to the (R,E)amide, with only a trace of the (S,Z)-isomer. It has been suggested
that both rearrangements proceed via a five-membered cyclic tran
sition state with a carbene-like function.23
Enol acetates of oxo nucleosides are readily accessible by re
action of the nucleoside with DMF acetal and then with acetic an
hydride (eq 16).24 However, this method is limited to compounds
with an oxo group in the 4'-position and with a free CO-NH group
in the pyrimidine ring. This reaction is the first synthesis of oxo
nucleoside enol acetates by direct enolization. Previous methods
2,2-DIMETHYL-1,3-PROPANEDIOL
of enol formation fail with oxo nucleosides because of their insta
bility in alkaline media.
23.
24.
161
Yamamoto, H.; Kitatani, K.; Hiyama, T.; Nozaki, H. JACS 1977, 99,
5816.
Bessodes, M.; Ollapally, A.; Antonakis, K. CC 1979, 835.
Ulf Pindur
University of Mainz, Germany
(15)
2,2-Dimethyl-1,3-propanedioI
(16)
[126-30-7]
C 5 H 12 O 2
(MW 104.17)
(protecting group for aldehydes and ketones;9 a ligand used in

boron chemistry 12 )
Related
Reagents. t-Butoxybis(dimethylamino)methane;
N,N-Dimethylacetamide Dimethyl Acetal; Dimethylchloromethyleneammonium
Chloride;
N,N-Dimethylpropionamide Dimethyl Acetal; Triethyl Orthoformate; Tris(dimethylamino)methane; Tris(formylamino)methane.
1. Abdulla, R. F.; Brinkmeyer, R. S. T 1979, 35, 1675.

2. Eilingsfeld, H.; Seefelder, M.; Weidinger, H. CB 1963, 96, 2671.
3. DeWolfe, R. H. Carboxylic Ortho Acid Derivatives, Academic: New
York 1970.
4. Kantlehner, W. In The Chemistry of Acid Derivatives, Patai, S., Ed.;
Wiley: Chichester 1979, Part 1, Suppl. B, p 533.
5. Simchen, G. In Iminium Salts in Organic Chemistry; Bohme, H.; Viehe,
H. G., Eds.; Wiley: New York, 1979; p 393.
6. Pindur, U. In The Chemistry of Acid Derivatives, Patai, S. Ed.; Wiley:
Chichester, 1992; Vol. 2, Suppl. B, p 1005.
7. Scheeren, J. W.; Nivard, R. I. F. RTC 1969, 88, 289.
8. Neumann, H. C 1969, 23, 267.
9. (a) Harvey, R. G.; Goh, S. H.; Cortez, C. JACS 1975, 97, 3468. (b)
Eastwood, W.; Harrington, K. I.; Josan, J. S.; Pura, I. L. TL 1970, 5223.
10. Holy, A. TL 1972, 585.
11. Philips, K. D.; Horwitz, J. P. JOC 1975,40, 1856.
12. (a) Vorbruggen, H. AG(E) 1963, 2, 211. (b) Vorbriiggen, H. LA 1974,
821.
13. (a) Brechbhler, H.; Bchi, H.; Hatz, E.; Schreiber, J.; Eschenmoser, A.
AG(E) 1963, 2, 212; (b) Bchi, H.; Steen, K.; Eschenmoser, A. AG(E)
1964, 3, 62.
14. Brechbhler, H.; Bchi, H.; Hatz, E.; Schreiber, J., Eschenmoser, A.
HCA 1965, 48, 1746.
15. (a) Luengo, J. L.; Koreeda, M. TL 1984, 25, 4881. (b) Koreeda, M.;
Luengo, J. L. JOC 1984, 49, 2079.
16. Stanovnik, B.; Tisler, M. S 1974, 120.
17. Schuda, P. F.; Ebner, C. B.; Morgan, T. M. TL 1986, 27, 2567.
18. (a) Kantlehner, W.; Haug, E.; Hagen, H. LA 1982, 298. (b) Krichevski,
E. S.; Granik, V. G. KGS 1992, 502.
19. Batcho, A. D.; Leimgruber, W. U.S. Patent 3 976639, 1973; 3732 245,
1973.
20. Garcia, E. E.; Fryer, R. I. JHC 1974, 11, 219.
21. Gompper, R.; Heinemann, U. AG(E) 1981, 20, 296.
22. Gompper, R.; Heinemann, U. AG(E) 1981, 20, 297.
Physical Data: mp 123-127 C. 1

Solubility: sol H 2 O, chloroform, benzene; very sol ethyl alcohol,
diethyl ether.2
Form Supplied in: white crystals.
Handling, Storage, and Precautions: skin irritant; hygroscopic;
store in cool dry place.1
Cyclic Acetals. 2,2-Dimethyl-1,3-propanediol (1) has been

used effectively as a protecting group for ketones and aldehy
des. The formation of the cyclic acetal can be accomplished in
many ways. The most common is to reflux the ketone and diol
(1) with a catalytic amount of acid and force the reaction to
completion by removing H 2 O, usually with a Dean-Stark trap
(eq 1). 3 Other methods involve treating the ketone-diol mixture
with Chlorotrimethylsilane (eq 2) 4 or Boron Trifluoride Etherate
(eq 3). 5
(1)
(2)
(3)
162
DIMETHYL SULFATE
The advantages of diol (1) compared to other diols depend on

the compound being protected. In the formation of -halo acetals,
for example, reagent (1) was found to be more effective than Ethy
lene Glycol because of easier separation and a longer shelf life of
the product.6 Diol (1) was also considered to be superior to ethy
lene glycol when Grignard reagents were prepared from -halo
acetals (eq 4). 7
Related Reagents. 3-Bromo-l,2-propanediol; 2,3-Butanediol;

Ethylene
Glycol;
(2R,4R)-2,4-Pentanediol;
1,3Propanediol.
1. Sigma-Aldrich Library of Chemical Safety Data, 2nd ed.; Lenga, R. E.,

Ed.; Sigma-Aldrich: Milwaukee, WI, 1988; Vol. 1, p 1411B.
2.
(4)
3.
4.
5.
In comparing rates of acid hydrolysis of different cyclic acetals

formed from a variety of diols, the following order was discov
ered; 1,3-propanediol >>(1) > ethylene glycol > 2,2-diethyl-1,3propanediol > 2,2-diisopropyl-1,3-propanediol.8 This has been at
tributed to the gem-dialkyl effect which serves to stabilize the
cyclic acetal. Cleavage of the protecting group formed from diol
(1) is easily accomplished via acidic hydrolysis using acids such
as H 2 SO 4 , HCl, or TsOH.
Reagent (1) has been used in a variety of syntheses where its
merits have not been elucidated. The following reactions show
some of these transformations (eqs 5-7). 9-11
CRC Handbook of Data on Organic Compounds, 2nd ed.; Weast, R. C ;

Grasselli, J. G.; Eds.; CRC: Boca Raton, FL, 1989; Vol. 6, p 3645.
Williams, D. R.; McGill, J. M. JOC 1990, 55, 3457.
Honda, Y.; Ori, A.; Tsuchihashi, G.-I. CL 1987, 1259.
(a) Gopalakrishnan, G.; Jayaraman, S.; Rajagopalan, K.; Swaminathan,
S. S 1983, 797. (b) Brown, E.; Lebreton, J. TL 1986, 27, 2595.
6.
7.
8.
Burnell, D. J.; Wu, Y.-J. CJC 1989, 67, 816.

Stowell, J. C.; Keith, D. R.; King, B. T. OSC 1990, 7, 59.
(a) Newman, M. S.; Harper, R. J., Jr. JACS 1958, 80, 6350. (b) Smith,
S. W.; Newman, M. S. JACS 1968, 90, 1249. (c) Smith, S. W.; Newman,
M. S. JACS 1968, 90, 1253.
9. (a) Deslongchamps, P.; Cheriyan, U. O.; Lambert, Y.; Mercier, J.-C;
Ruest, L.; Russo, R.; Soucy, P. CJC 1978, 56, 1687. (b) Carceller, E.;
Moyano, A.; Serratosa, F.; Font-Altaba, M.; Solans, X. JCS(P1) 1986,
2055.
10. Annunziata, R.; Cinquini, M.; Cozzi, F.; Raimondi, L.; Restelli, A. HCA
1985,68, 1217.
11. Walkup, R. D.; Obeyesekere, N. U. S 1987, 607.
12. Narasaka, K.; Yamamoto, I. T 1992, 48, 5743.
13. Narasaka, K.; Shimada, S.; Osoda, K.; Iwasawa, N. S 1991, 1171.
Michael A. Walters & John J. Shay

Dartmouth College, Hanover, NH, USA
(5)
Dimethyl Sulfate1
(6)
[77-78-1]
(7)
C2H6O4S
(MW 126.13)
(effective methylating reagent1)

Physical Data: bp 188 C; mp - 3 2 C; d 1.333 g c m - 3 ; fp 83 C.
Form Supplied in: water-white liquid; widely available.
Handling, Storage, and Precautions: extremely toxic and carcino
genic; use in a fume hood with adequate protection.2
Use as a Boron Ligand. This diol has been used to com

plex boron.12 For example, diol (1) was employed to remove the
phenylboronic acid template from a Diels-Alder adduct under
neutral conditions (eq 8). 13
(8)
O-Alkylation. Dimethyl sulfate is a powerful alkylating agent

and has been used for the methylation of almost every imaginable
nucleophile over the years. 1 The variety of oxygen nucleophiles
include carboxylic acids, 3 alcohols,4 phenols, 5 lactams,6 oximes,7
pyridine N-oxides, 8 hydroxylamines, 9 hydroxamic acids, 10 and
hydroperoxides. 11
Carboxylic acids react with dimethyl sulfate in the presence
of Dicyclohexyl(ethyl)amine (DICE) to afford methyl esters
in high yield.3 The method is reported to be facile and par
ticularly useful when ester formation using Diazomethane or
DIMETHYL SULFATE
strongly acidic conditions is not possible. For example, -9,10,12trihydroxyoctadecanoic acid is readily converted to its methyl es
ter in 97% yield using this procedure (eq 1). Another example
of this type of esterification was demonstrated with the prepara
tion of bile acid methyl esters (eq 2). 12 These steroidal carboxylic
acids were methylated using Potassium Carbonate as a base in
refluxing acetone. Both of the aforementioned procedures avoid
significant side reactions such as dehydration or ether formation
resulting from competing alkylation of free hydroxy groups.
163
(4)
Several methods have been described for preparing aryl methyl

ethers from phenols using dimethyl sulfate. For example, defucogilvocarcin M was completed by methylating a sterically hin
dered C-12 hydroxyl group using dimethyl sulfate and potassium
carbonate (eq 5). 5 In addition, the synthesis of a carbazole al
kaloid was completed via the selective alkylation of a 5-indolyl
alcohol using dimethyl sulfate and Sodium Hydride to give 4deoxycarbazomycin B in 96% yield (eq 6). 15
(1)
(5)
(6)
(2)
Syntheses of aryl and alkyl methyl ethers using dimethyl sul

fate have also been reported. Simple alcohols and phenols may be
alkylated using dimethyl sulfate in slightly hydrated solid/liquid
heterogeneous media with 1,4-dioxane or triglyme/potassium hy
droxide and small amounts of water to give the corresponding
methyl ethers in excellent yield.4 For example, t-butyl alcohol
is converted to t-butyl methyl ether in nearly quantitative yield
(eq 3). The procedure calls for the use of only a stoichiometric
amount of dimethyl sulfate, which reduces problems associated
in the workup and the potential toxicity of remaining dimethyl sul
fate. In addition, methylation of alcohols using dimethyl sulfate
and Alumina as a solid adsorbent reaction medium affords ex
cellent yields of the corresponding alkyl alcohols. 13 Phenols and
carboxylic acids, however, gave lower yields of methylated prod
uct using this procedure. A second example involves the stereospecific formation of highly substituted tetrahydrofurans. Treat
ment of a 2,5-dihydroxy-4-phenyl sulfide with dimethyl sulfate in
dichloromethane at 0 C cleanly afforded the substituted tetrahydrofuran in excellent yield (eq 4). 14 It has been suggested that
the reaction proceeds via methylation of a free hydroxy group
followed by solvolysis of methanol assisted by the neighboring
thiophenyl group. Subsequent cyclization gave the tetrahydrofuran as a single stereoisomer.
(3)
The O-methylation of lactams to afford O-alkylimino ethers has

also been reported. For example, the large-scale preparation of Omethylcaprolactim proceeds in good yield using caprolactam and
1 equiv of dimethyl sulfate in benzene (eq 7). 6 The treatment of
caprolactam with excess dimethyl sulfate gives N-methyllactam
as the major product.
(7)
Other alkylation processes include the O-methylation of

oximes, N-oxides, hydroxylamines, and hydroxamic acids. The
preparation of oxime ethers using dimethyl sulfate has proven an
effective methodology for the construction of sidechains designed
for new cephalosporin antibiotics. Treatment of -oxime esters
with dimethyl sulfate afforded the -mefhoximino esters, which
were subsequently hydrolyzed to the acid and used as sidechains
via acylation chemistry (eq 8). 7
(8)
The methylation of pyridine, quinoline, and isoquinoline Noxides to afford N-methoxy salts has also been investigated.
For example, treatment of quinoline N-oxide with dimethyl
sulfate provides the N-methoxy methylsulfate salt in excellent
yield (eq 9). 8 The resulting salts were subsequently treated
164
DIMETHYL SULFATE
with cyanide ion to afford cyanopyridines in a mild overall

process.
nitro-N-methylaniline in one pot using phase-transfer conditions

(eq 13).17
(12)
(9)
A new route to 2-substituted indoles derived from 1methoxyindole was recently described. Dimethyl sulfate proved
to be the reagent of choice for the methylation of the unstable 1hydroxyindole to give 1-methoxyindole in 51 % yield (eq 10).9 The
resulting methoxyindole undergoes O-lithiation at the 2-position
using n-Butyllithium, and can be trapped with appropriate electrophiles. It should be noted that methylation of 1-hydroxyindole
using lodomethane afforded only very low yields of the desired
methoxyindole.
(13)
Tertiary alkyl and aromatic amines are also conveniently quaternized using dimethyl sulfate. For example, a series of thioquinanthrenediinium salts for use as potential antibiotics were prepared
via methylation of their quinoline precursors using dimethyl sul
fate (eq 14).19
(14)
(10)
Finally, a convenient synthesis of

N,0-Dimethylhydroxylamine, a reagent used to prepare aldehydes from
N-methoxy-N-rnethylamides, has been reported. It includes a key
dimethylation of an intermediate ethyl hydroxycarbamate using
dimethyl sulfate and sodium hydroxide (eq 11). 10
MeNHOMeHCl
(11)
S-Alkylation. The methylation of sulfur-containing com

pounds using dimethyl sulfate to afford sulfides and sulfonium
ions has also been explored. For example, trimethylsulfonium
methyl sulfate has been prepared on a large scale via methyla
tion of dimethyl sulfide.20 This salt has been subsequently used as
a precursor of Dimethylsulfonium Methylide, a popular reagent
for the preparation of epoxides from ketones (eq 15). O-Alkyl
S-methyl dithiocarbamates have also been prepared via conden
sation of an alkoxide with Carbon Disulfide, followed by methy
lation using dimethyl sulfate (eq 16).21 The resulting dithiocar
bamates can then be reduced via radical chemistry to afford the
alkane.
200 g
(15)
N-AIkylation. Dimethyl sulfate has also been a useful reagent

for the preparation of N-methyl alkyl- and aryl-substituted amines,
amides, and quaternary ammonium salts. Simple primary amines
can be selectively methylated to afford secondary amines by first
protecting the amine as a Schiff base or amidine ester,16 amide, 17
or carbamate, 18 followed by alkylation using dimethyl sulfate and
hydrolysis of the resulting amide or iminium ion. For example,
the methylation of amidines has been employed in a route to
N-alkyl amino acids. The amidine of phenylalanine methyl es
ter was prepared from the amino ester using dimethylformamide
dimethyl acetal (see N,N-Dimethylformamide Diethyl Acetal),
followed by methylation and hydrolysis to afford the correspond
ing N-methylphenylalanine in good yield without racemization
(eq 12).16 Certain substrates such as phenylglycine methyl es
ter required the use of Methyl Trifluoromethanesulfonate as
the alkylating agent and lower reaction temperatures to retain
optical purity throughout the process. The selective synthesis
of substituted N-monoalkylaromatic amines has also been re
ported. For example, 2-nitroacetanilide is cleanly converted to 2Lists of Abbreviations and Journal Codes on Endpapers
(16)
C-Alkylation. Several processes involving the formation of

C-C bonds via methylation of organometallics using dimethyl
DIPHENYLBIS(1,1,1,3,3,3-HEXAFLURO-2-PHENYL-2-PROPOXY)SULFURANE
sulfate have been reported. For example, a series of 2methylbutyrolactones and -valerolactones were prepared via
asymmetric alkylation using chiral oxazolines and Lithium Diisopropylamide followed by treatment with dimethyl sulfate
(eq 17).22 The resulting oxazoline was then hydrolyzed to afford
the optically active lactone. Aryllithium species also undergo rapid
alkylation using dimethyl sulfate as the electrophile. For exam
ple, 3,4-bis(tributylstannyl)furan undergoes a single tin-lithium
exchange and upon treatment with dimethyl sulfate and N,N'Dimethylpropyleneurea (DMPU) affords the monomethylated
product (eq 18).23 The resulting compounds were then subjected to
various palladium-mediated cross-coupling reactions to give 3,4disubstituted unsymmetrical furans. Dimethyl sulfate was found
to be superior to methyl iodide for this particular application.
165
16. O'Donnel, M. J.; Bruder, W. A.; Daugherty, B. W.; Liu, D.;

Wojcieehowski, K. TL 1984, 3651.
17.
Kalkote, U. R.; Choudhary, A. R.; Natu, A. A.; Lahoti, R. J.; Ayyangar,

N. R. SC 1991, 1889.
18. Clark-Lewis, J. W.; Thompson, M. J. JCS 1957, 442.

19. Maslankiewicz, A.; Zieba, A. H 1992, 33, 247.
20.
Kutsuma, T.; Nagayama, I.; Okazaki, T.; Sakamoto, T.; Akaboshhi, S. H

1977, 8, 397.
21.
Barton, D. H. R.; McCombie, S. W. JCS(P1) 1975, 1574.
22.
Meyers, A. I.; Yamamoto, Y.; Mihelich, E. D.; Bell, R. A. JOC 1980, 45,
2792.
23.
Yang, Y.; Wong, H. N. C. CC 1992, 1723.
Gregory Merriman
Hoechst-Roussel Pharmaceuticals, Somerville, NJ, USA
(17)
Diphenylbis(1,1,1,3,3,3-hexafluoro-2phenyl-2-propoxy)sulfurane1
(18)
Related Reagents. Diazomethane; Iodomethane; Methyl Trifluoromethanesulfonate; Trimethyloxonium Tetrafluoroborate;

Trimethyl Phosphate.
1. (a) Suter, C. M. The Organic Chemistry of Sulfur, Wiley: New York,

1944; pp 48-74. (b) Kaiser, E. T. The Organic Chemistry of Sulfur,
Plenum: New York, 1977; p 649. (c) Use as methylating agent: Fieser,
L.; Fieser, M. FF 1967, 1, 293 and further references cited therein.
2. (a) Material Safety Data Sheets (MSDS) on dimethyl sulfate are available
from various vendors. (b) Merck Index 11th ed.; 1989, p 3247. (c)
Review of carcinogenicity studies: IARC Monographs 1974, 4, 271. (d)
Mutagenicity studies: Hoffman, G. R. Mutat. Res. 1980, 75, 63.
3. Stodola, F. H. JOC 1964, 29, 2490.
4. Achet, D.; Rocrelle, D.; Murengezi, I.; Delmas, M.; Gaset, A. S 1986,
642.
5.
6.
7.
Hart, D. J.; Merriman, G. H. TL 1989, 30, 5093.

Benson, R. E.; Cairns, T. L. JACS 1948, 70, 2115.
Kukolja, S.; Draheim, S. E.; Pfeil, J. L.; Cooper, R. D. G.; Graves, B. J.;
Holmes, R. E.; Neel, D. A.; Huffman, G. W.; Webber, J. A.; Kinnick, M.
D.; Vasileff, R. T.; Foster, B. J. JMC 1985, 28, 1886.
8. Feely, W. E.; Beavers, E. M. JACS 1959, 81, 4004.

9. Kawasaki, T.; Kodama, A.; Nishida, T.; Shimizu, K.; Somei, M. H 1991,
32,221.
10. Goel, O. P.; Krolls, U. OPP 1987, 75.
11. Hock, H.; Lang, S.; Duyfjes, W. CB 1942, 75, 300.
12. Ballini, R.; Carotti, A. SC 1983, 1197.
13. Ogawa, H.; Ichimura, Y.; Chihara, T.; Shousuke, T.; Taya, K. BCJ 1986,
59,2481.
14. Williams, D. R.; Phillips, J. G.; Barner, B. A. JACS 1981, 103, 7398.
15. Knolker, H. J.; Bauermeister, M.; Blaser, D.; Boese, R.; Pannek, J. B.
AG 1989, 225.
[32133-82-7]
C30H20F12O2S
(MW 672.57)
(dehydration of alcohols;2 synthesis of epoxides and cyclic

ethers;3 cleavage of amides;5 oxidation of amines 6 )
Solubility: sol ether, benzene, acetone, alcohols.
Form Supplied in: white crystals.
Analysis of Reagent Purity: NMR, IR.
Preparative Method: by the reaction of the potassium salt of
1,1,1,3,3,3-hexafluoro-2-phenylisopropanol with diphenyl sul
fide in the presence of chlorine in ether at 78 C. 1a
Handling, Storage, and Precautions: avoid moisture; readily hy
drolyzed; stable at rt; decomposes slowly at rt in solution.
Dehydration of Alcohols. The title reagent (1) is useful for

the dehydration of alcohols. In general, tertiary alcohols are de
hydrated instantaneously at rt. Some secondary alcohols are de
hydrated. In cyclohexane rings, a frans-diaxial orientation of
the leaving groups significantly increases the rate of elimination
(eq 1). Primary alcohols do not yield products of dehydration un
less the -proton is sufficiently acidic. In most cases, the ether
[(CF 3 ) 2 PhCOR] is obtained.2
Epoxides. Vicinal diols, capable of attaining an antiperiplanar relationship, can be converted to epoxides (eq 2). The reaction
requires 1-2 equiv of (1) in chloroform, ether, or carbon tetrachlo
ride and takes place at rt. The reaction is postulated to take place
via ligand exchange with the sulfone followed by decomposition
166
DIPHENYLPHOSPHINIC CHLORIDE
to the epoxide, diphenyl sulfoxide, and 1,1,1,3,3,3-hexafluoro-2phenylisopropanol.
(4)
(1)
Oxidation of Amines. In a related reaction, (1) reacts with

primary amines (as well as amides and sulfonamides) to give sulfilimines (eq 5). Secondary amines are converted to imines on
reaction with (1) whereas benzylamine is converted to benzonitrile (89%) with 2 equiv of (1).6
(5)
1.
2.
3.
4.
(2)
5.
6.
Other cyclic ethers have been prepared, but yields are

highly dependent on product ring size. The following trans
formations are representative: 2,2-dimethyl-1,3-propanediol to
3,3-dimethyloxetane (86%), 1,4-butanediol to tetrahydrofuran
(72%), 1,5-pentanediol to tetrahydropyran (39%), and diethylene glycol to dioxane (40%). Longer chain diols yield ethers
[(CF3)2PhCO(CH2)n OCPh(CF3)2].3
Eschenmoser used this method to convert (5R,R)-5,6-dihydro,-carotene-5,6-diol to its epoxide (eq 3). This reagent is more
effective than other reagents due to the unique solubility profile
of the dihydrocarotenediol.4
(a) FF 1974, 4, 205. (b) FF 1975, 5, 270. (c) FF 1977, 6, 239. (d) FF
1980, 8, 208.
Martin, J. C ; Arhart, R. J. JACS 1971, 93, 4327.
Martin, J. C ; Franz, J. A.; Arhart, R. J. JACS 1974, 96, 4604.
Eschenmoser, W.; Engster, C. H. HCA 1978, 61, 822.
(a) Franz, J. A.; Martin, J. C. JACS 1973, 95, 2017. (b) Franz, J. A.;
Martin, J. C. JACS 1975, 97, 6137.
Franz, J. A.; Martin, J. C. JACS 1975, 97, 583.
Brian A. Roden
Abbott Laboratories, North Chicago, IL, USA
[1499-21-4]
C 1 2 H 1 0 ClOP
(MW 236.64)
(agent for acid activation,1 alkylphosphine oxide formation,2 and

amine protection3)
(3)
Cleavage of Amides. Secondary amides can be converted to

esters with (1). The rate is sensitive to steric constraints at the
nitrogen and the acyl carbon. In most cases the amine portion
is trapped as the sulfilimine and/or the imidate, which are easily
converted back to the amine (eq 4). The dual nature of this reaction
affords a mild conversion of amides to esters as well as a simple
method for deprotection of N-acylated amines.5
Alternate Name: chlorodiphenylphosphine oxide.

Physical Data: bp 222C/16 mmHg; d 1.240 g cm -3 .
Handling, Storage, and Precautions: handle only in a chemical
fume hood, wear chemical-resistant gloves and safety goggles.
do not breathe vapor, and avoid contact with eyes or skin. Store
in a 'flammable storage' cabinet under nitrogen. Contact with
water generates hydrogen chloride gas.
Acid Activation. Chlorodiphenylphosphine oxide has been

utilized for the activation of acids via in situ formation of the
diphenylphosphinic (DPP) mixed anhydrides. These anhydrides
are superior to carbon-based mixed anhydrides because they do not
suffer from disproportionation to symmetrical anhydrides.1 Also,
DIPHENYLPHOSPHINIC CHLORIDE
nucleophiles prefer to attack at carbon rather than phosphorus,
solving the regioselectivity problem associated with carbon-based
mixed anhydrides.4 Additionally, diphenylphosphinic mixed an
hydrides are more electrophilic. Finally, diphenylphosphinic
mixed anhydrides form rapidly allowing shorter activation times.
Diphenylphosphinic mixed anhydrides have been utilized to
form peptide bonds. 5 Peptides are easier to isolate by this method
than by employing 1,3-Dicyclohexylcarbodiimide. These anhy
drides are the method of choice for the formation of amides of
2-alkenoic acids (eq 1). 6 Carbodiimide and acyl carbonate meth
ods proved to be inferior. Primary amines result in better yields
than secondary amines. This activation protocol can be employed
to form thiol esters (eq 2). 7 -Amino acids are readily converted
to -lactams with chlorodiphenylphosphine oxide (eq 3). 8 Sec
ondary amines work best. This activation protocol has been uti
lized to convert acids to amines via a Curtius rearrangement.9 Phe
nols have been generated from diene acids, presumably via baseinduced elimination of diphenylphosphinic acid from the mixed
anhydrides to form ketenes which spontaneously cyclize.10 Acids
have been converted to ketones via activation followed by reaction
with organometallic reagents (eq 4). 11
(1)
167
Thiol Esters and Ketones. The Dpp mixed anhydrides re

act with thiols to yield thiol esters (eq 2) 7 and undergo carbonacylation reactions with both Grignard reagents and diethyl sodiomalonate in good yields (eq 6). 14
(5)
(6)
Protection of Amino Groups. In the presence of Nmethylmorpholine, Ph 2 POCl reacts with amino acid esters in
CH 2 Cl 2 at 0 C in 1.5-2 h to give N-diphenylphosphinyl (Dpp)
amino acid esters (65-80%), which are then hydrolyzed under
mild alkaline conditions to give N-Dpp amino acids (eq 7). 3,4
Since Ph2POCl hydrolyzes extremely quickly under aqueous
conditions, it is not possible to prepare N-Dpp amino acids
directly.
(2)
(7)
(3)
The Dpp derivatives are slightly more acid-labile than the

Boc derivatives and are cleaved by HOAc-HCOOH-H 2 O (7:1:2)
(24 h), 1 M HCl in H 2 O-dioxane (2:1) (3 h), TFA-CH 2 Cl 2 (1:1)
(40 min), and 95% TFA (10 min). Selective cleavage of the Dpp
group in the presence of a t-butyl ester and a phenyl ester is
possible.
Amination. P h 2 O C l reacts with Hydroxylamine to yield
O-(diphenylphosphinyl)hydroxylamine.15 This reagent aminates
stabilized carbanions and Grignard reagents in moderate yields
(eq 8). 16 Electrophilic N-amination of imide sodium salts is also
possible using this reagent (eq 9). 17
Phosphine Oxides. This reagent reacts with organometal

lic reagents to form phosphine oxides.2 Alkyl phosphonates
have been converted to diphenylvinylphosphine oxides via trap
ping of the a-lithioalkylphosphonate with diphenylchlorophosphine oxide, deprotonation, and reaction with aldehydes (eq 5). 12
Organometallic reagents have been converted to 1,3-dienes utiliz
ing Ph 2 P(O)Cl and carbonyl compounds). 13
(8)
168
DIPHENYL PHOSPHORAZIDATE
Diphenyl Phosphorazidate
(9)
Diphenylphosphinamide18 and
1-diphenylphosphinyl-2,2dimethylaziridine,19 which are derived from Ph 2 POCl, react with
Grignard reagents to give high yields of primary amines and
moderate yields of ,-dimethylarylalkylamines, respectively.
1. Jackson, A. G.; Kenner, G. W.; Moore, G. A.; Ramage, R.; Thorpe, W.

D. TL 1976, 3627.
2. Takaya, H.; Mashima, K.; Koyano, K.; Yagi, M.; Kumobayashi, H.;
Taketomi, T.; Akutagawa, S.; Noyori, R. JOC 1986, 51, 629.
3.
(a) Kenner, G. W.; Moore, G. A.; Ramage, R. TL 1976, 3623. (b)Ramage,

R.; Atrash, B.; Hopton, D.; Parrott, M. J. JCS(P1) 1985, 1217.
4.
Ramage, R.; Atrash, B.; Hopton, D.; Parrott, M. J. JCS(P1) 1985, 1617.
5.
Ramage, R.; Hopton, D.; Parrott, M. J.; Richardson, R. S.; Kenner, G.

W.; Moore, G. A. JCS(P1) 1985, 461.
6. Bernasconi, S.; Comini, A.; Corbella, A.; Gariboldi, P.; Sisti, M. S 1980,
385.
7. Horiki, K. SC 1977, 7, 251.
8. Kim, S.; Lee, P. H.; Lee, T. A. CC 1988, 1242.
9. (a) Armstrong, V. W.; Coulton, S.; Ramage, R. TL 1976, 4311. (b)
Ramage, R.; Armstrong, V. W.; Coulton, S. T 1981, 37, Supplement
No. 1, 157.
10. Clinch, K.; Marquez, C. J.; Parrott, M. J.; Ramage, R. T 1989, 45, 239.
11. Soai, K.; Ookawa, A. CC 1986, 412.
12. (a) Savignac, P.; Teulade, M.-P; Aboujaoude, E. E.; Collignon, N. SC
1987,17, 1559. (b) Aboujaoude, E. E.; Lietje, S.; Collignon, N. TL 1985,
26, 4435.
13. Davidson, A. H.; Warren, S. CC 1975, 148.
14. Kende, A. S.; Scholz, D.; Schneider, J. SC 1978, 59.
15. (a) Harger, M. J. P. CC 1979, 768. (b) Harger, M. J. P. JCS(P1) 1981,
3284.
16.
17.
(a) Colvin, E. W.; Kirby, G. W.; Wilson, A. C. TL 1982, 23, 3835. (b)
Boche, G.; Bernheim, M.; Schrott, W. TL 1982, 23, 5399.
Klotzer, W.; Stadlwieser, J.; Raneburger, J. OS 1985, 64, 96.
18. Zwierzak, A.; Slusarska, E. S 1979, 691.

19.
Buchowiecki, W; Grosman-Zjawiona, Z.; Zjawiony, J. TL 1985, 26,

1245.
David N. Deaton
Glaxo Research Institute, Research Triangle Park, NC, USA
Sunggak Kim
Korea Advanced Institute of Science and Technology,
Taejon, Korea
[26386-88-9]
C 12 H 10 N 3 O 3 P
(MW 275.22)
(peptide synthesis;1 synthesis of -aryl carboxylic acids; 4 syn

thesis of thiol esters; 7,8 stereospecific conversion of alcohols to
azides;9 ring contraction of cycloalkanones; 13 decarbonylation of
aldehydes 26 )
Alternate Names: DPPA; O,O-diphenylphosphoryl azide.
Physical Data: bp 157C/0.17 mmHg; d 1.277g c m - 3 ; fp
>110C.
Solubility: sol toluene, THF, DMF, t-butyl alcohol.
Form Supplied in: colorless liquid; commercially available in kilo
gram quantities.
Preparative Method: by the reaction of DiphenylPhosphorochloridate with a slight excess of Sodium Azide in acetone at rt
(85-90% yield). 1
Purification: vacuum distillation (bath temp <200C, dec
>200C)
Handling, Storage, and Precautions: handle and store under ni
trogen. Refrigerate. Decomposes at >200C and may produce
toxic fumes of phosphorus oxides and/or phosphine. Toxic, ir
ritant. Harmful if swallowed, inhaled, or absorbed through the
skin. Use in fume hood. Incompatible with oxidizing agents
and acids. Hazardous combustion or decomposition products
include carbon monoxide, carbon dioxide, and nitrogen oxides.
Prolonged contact with moisture may produce explosive hydro
gen azide (HN 3 ).
General. Diphenyl phosphorazidate is a readily available, nonexplosive, and relatively stable azide widely used as a reagent in
peptide synthesis, 1-3 and as a versatile reagent in a wide array of
organic transformations. DPPA has been successfully utilized in
the synthesis of -amino acids 4 and -aryl carboxylic acids; 5,6 di
rect preparation of thiol esters from carboxylic acids and thiols; 7,8
the stereospecific preparation of alkyl azides; 9 and the phospho
rylation of alcohols and amines. 10 The application of DPPA in a
modified Curtius 11 reaction permits a simple one-step conversion
of carboxylic acids to urethanes under mild reaction conditions.
DPPA acts as a nitrene source, 12 and can undergo 1,3-dipolar cycloaddition reactions. 5,13 The Curtius degradation14 of carboxylic
acids in the presence of t-butanol gives the Boc-protected amine
directly (eq 1).
(1)
DPPA has been utilized in the synthesis of 1,4-dinitrocubane by

Eaton and co-workers. 15 Refluxing cubane-1,4-dicarboxylic acid
with DPPA and Triethylamine in t-butanol forms the intermediate
DIPHENYL PHOSPHORAZIDATE
t-butyl carbamate in nearly quantitative yield. This method avoids

the formation of the explosive diacyl azide.
Peptide Synthesis. Urethanes are readily prepared by refluxing equimolar mixtures of DPPA, a carboxylic acid, an alcohol,
and triethylamine. The reaction involves transfer of the azide
group from DPPA to the carboxylic acid. The resulting acyl azide
subsequently undergoes a Curtius rearrangement. This reaction
has been successfully applied in the area of peptide synthesis.1
The coupling of acylamino acids or peptides with amino acid es
ters or peptide esters in the presence of base proceeds in high
yields without racemization, and is compatible with a variety of
functional groups. The reaction of malonic acid half-esters results
in the corresponding -amino acid derivatives4 (eq 2). It should be
noted that addition of the alcohol at the beginning of the reaction
results in esterification.
169
ing -triazolines, which are not isolated, undergo loss of nitro

gen to form ring-contracted products, which, on hydrolysis, yield
cycloalkanoic acids. In the case of six- to eight-membered cycloalkanones, overall yields as high as 75% have been reported
(eq 4).
(2)
(4)
-Aryl Carboxylic Acids. Alkyl aryl ketones are converted

into the corresponding -aryl alkanoic acids4 via a three-step
sequence. Yields of >90% are possible if the synthesis is car
ried out in a one-flask procedure. The sequence includes a 1,3dipolar cycloaddition of DPPA to the corresponding enamines
(eq 3). Although Thallium(III) Nitrate Trihydrate has also been
used in similar oxidative rearrangements,16 the DPPA method ex
hibits higher functional specificity, uses less toxic reagents, and
gives preparatively useful yields. Naproxen, a nonsterodial anti
inflammatory therapeutic, has been prepared by this route.6
Animation of Aromatic and Heteroaromatic Organometallics. Reaction of organic azides with Grignard and lithium
compounds gives 1,3-disubstituted triazenes,17 which are readily
converted to amines by reductive18,19 or hydrolytic20,21 workup.
These methods are limited to either the aromatic Grignard18,20 or
lithium21 compounds, and have not been very successful with
heteroaromatic organometallics. Aromatic and heteroaromatic
organometallics (Grignard and lithium compounds) are aminated
in good yields in a one-pot process by treatment with DPPA and
reduction of the resulting phosphoryltriazenes with Sodium Bis(2methoxyethoxy)aluminum Hydride (eq 5).22
(5)
(3)
Stereospecific Conversion of Alcohols to Azides. Reaction of

an alcohol with DPPA, Triphenylphosphine, and Diethyl Azodicarboxylate forms the corresponding azides in 60-90% yields.9
The stereospecific nature of this reaction permits the conver
sion of 5-sterols such as 3-cholestanol exclusively to the 3acholestanyl azide in 75% yield. This synthesis is clearly superior
to the alcohol tosylate azide route which is longer and also
prone to competing elimination reactions.
Metal-Catalyzed Decarbonylation of Primary Aldehy

des. The decarbonylation of primary aldehydes under catalytic
conditions is difficult, requiring high temperatures or involving
radical mechanisms;23 the rt decarbonylations24,25 using stoichio
metric Chlorotris(triphenylphosphine)rhodium(I) have had lim
ited practicality due to the high cost of the reagent. Recently,
a high-yielding, rt decarbonylation of primary aldehydes using
catalytic amounts (5 mol %) of Rh(PPh3)3Cl and stoichiometric
amounts of DPPA, with minimal formation of alkene byproducts,
has been developed26 (eq 6).
(6)
Ring Contraction Reactions. DPPA undergoes 1,3-dipolar

cycloadditions to the enamines of cyclic ketones.13 The result
170
2,2'-DIPYRIDYL DISULFIDE
Synthesis of Macrocyclic Lactams. Macrocyclic lactams are

conventionally prepared by the reaction of dicarboxylic acid chlo
rides with diamines, a method which is effective with simple acyl
chlorides. Activation of the carboxylic groups in order to over
come the drawbacks of high dilution and the low yields and pu
rity encountered with larger acyl chlorides has seen only limited
success.27 The superior activating ability of DPPA has recently
been demonstrated.28 The reactions of dicarboxylic acids and di
amines in the presence of DPPA form macrobicyclic lactams in
yields as high as 82%. By comparison, in a control experiment
using conventional high-dilution techniques, the corresponding
acyl chlorides cyclized with the diamine to form the lactam in
only 24% yield.
DPPA has been used for the direct C-acylation of
methyl isocyanoacetate with carboxylic acids to give 4methoxycarbonyloxazoles.29 L-Daunosamine, the glycone com
ponent of anticancer anthracycline antibiotics, has been synthe
sized from L-lactic acid in 9 steps with a 24% overall yield,30
where a key step in the sequence is the direct C-acylation of
methyl isocyanoacetate with the lithium salt of the lactate ester
using diphenyl phosphorazidate (eq 7).
23.
24.
25.
26.
27.
28.
29.
30.
Domazetis, G.; Tarpey, B.; Dolphin, D.; James, B. R. CC 1980, 939.

Tsuji, J.; Ohno, K. TL 1965, 3969.
Osborn, J. A.; Jardine, F. H.; Young, J. F.; Wilkinson, G. JCS(A) 1966,
1711.
O'Connor J. M.; Ma J. JOC 1992, 57, 5075.
Cazaux, L.; Duriez, M. C ; Picard, C ; Moieties, P. TL 1989, 30, 1369.
Qian, L.; Sun, Z.; Deffo, X; Mertes, K. B. TL 1990, 31, 6469.
Hamada, Y.; Shioiri, X TL 1982, 23, 235, 1226.
Hamada, Y.; Kawai, A.; Shioiri, X TL 1984, 25, 5409.
Albert V. Thomas
2,2'-Dipyridyl Disulfide1
[2127-03-9]
C 10 H 8 N 2 S 2
(MW 220.34)
(macrolactonization of -hydroxy acids,6 acylation of pyrroles,22

couplings at anomeric centers 27 )
(7)
Related Reagents. Diphenyl Phosphorochloridate.
1. Shioiri, T.; Ninomiya, K.; Yamada, S. JACS 1972, 94, 6203.

2.
Shioiri, T.; Yamada, S. CPB 1974, 22, 849.
3.
4.
5.
6.
7.
8.
9.
10.
11.
Yamada, S.; Ikota, N.; Shioiri, T.; Tachibana, S. JACS 1975, 97, 7174.
Yamada, S.; Ninomiya, K.; Shioiri, T. TL 1973, 2343.
Shioiri, T.; Kawai, N. JOC 1978, 43, 2936.
Riegel, J.; Madox, M. L.; Harrison, I. T. JMC 1974, 17, 377.
Yamada, S.; Yokoyama, Y.; Shioiri, T. JOC 1974, 39, 3302.
Yokoyama, Y.; Shioiri, T.; Yamada, S. CPB 1977, 25, 2423.
Lal, B.; Pramanik, B.; Manhas, M. S.; Bose, A. K. TL 1977, 1977.
Cremlyn, R. J. W. AJC 1973, 26, 1591.
(a) Ninomiya, K.; Shioiri, T.; Yamada, S. T 1974, 30, 2151. (b) Ninomiya,
K.; Shioiri, T.; Yamada, S. CPB 1974, 22, 1398.
12. Breslow, R.; Feiring, A.; Herman, F. JACS 1974, 96, 5937.
Alternate Names: 2,2'-dithiopyridine.

Solubility: benzene, THF, CH 2 Cl 2 , MeCN, DMF.
Form Supplied in: white (colorless) crystalline solid.
Preparative Methods: although 2,2'-dipyridyl disulfide is com
mercially available, it can be readily prepared from 2pyridinethione by oxidation with a number of reagents.2
Purification: recrystallization from hexane at 30 mL g-1
concentration.3
Handling, Storage, and Precautions: the solid is irritating to eyes,
mucus membranes, and respiratory tract, and physical contact
should be avoided. Combustion produces toxic byproducts in
cluding nitrogen oxides. Cold storage in air-tight containers is
recommended. Use in a fume hood.
17. Dimroth, R. CB 1903, 36, 909.

18. Smith, P. A. S.; Rowe, C. D.; Bruner, L. B. JOC 1969, 34, 3430.
19. Reed, J. N.; Snieckus, V. TL 1983, 24, 3795.
20. Trost, B. M.; Pearson, W. H. JACS 1981, 103, 2483.
Macrolactonization.4 When a carboxylic acid is treated with

2,2'-dipyridyl disulfide in the presence of Triphenylphosphine,
the corresponding 2-pyridinethiol ester is formed.5 Corey and
Nicolaou have developed an efficient method for the synthesis
of macrocyclic lactones based on these 2-pyridinethiol esters.6
When an -hydroxy thiolester is heated in refluxing xylene under
high dilution conditions (10 - 5 M, typically accomplished with
syringe pump techniques), macrolactonization occurs, liberating
triphenylphosphine oxide and pyridinethione. The reaction is quite
general and is believed to proceed by a 'double activation' mech
anism in which the basic 2-pyridinethiol ester simultaneously ac
tivates both the hydroxy and the carboxylic acid moieties with a
single proton transfer. It has been shown that the cyclization rate is
not affected by the presence of acids, bases, or any of the possible
reaction contaminants. 7
21.
22.
This method is mild, highly efficient for the preparation of

medium to large rings (7-16, 6 12-21 7 ), and has been applied to
13. Yamada, S.; Hamada, Y.; Ninomiya, K.; Shioiri, T. TL 1976, 4749.
14. Haefliger, W.; Kloppner, E. HCA 1982, 65, 1837.
15. Eaton, P. E.; Ravi Shanker, B. K. JOC 1984, 49, 185.
16. Taylor, E. C ; Chiang, C.-S.; McKillop, A.; White, J. F. JACS 1976, 98,
6750.
Hassner, A.; Munger, P.; Belinka, B. A. TL 1982, 23, 699.

Mori, S.; Aoyama, X; Shioiri, X TL 1984, 25, 429.
the synthesis of a number of important macrocyclic targets includ
ing monensin,8 brefeldin A (eq 1) and erythronolide B, 9 ()-11hydroxy-trans-8-dodecenoic acid lactone,10 ()-vermiculine, 11
enterobactin,12 and prostaglandins. 813
171
stoichiometric Copper(I) Iodide has been found to significantly

improve yields.24
(3)
(1)
In an effort to develop an even milder lactonization protocol,

other diaryl disulfides were explored, the most promising be
ing imidazole derivatives (1) and (2). 14 The formation of dilides
(dimers of macrocyclic lactones) is occasionally a problem, ne
cessitating the use of other cyclization methods. 4,15 A variation of
Corey's method using silver salts has been developed. 316
2-Pyridinethiol esters are readily reduced with Sodium Borohydride in the presence of isopropanol.25 Activation of 2pyridinethiol esters with Iodomethane allows for mild trapping
with alcohols or benzenethiol, yielding esters or thiolesters.26 In
these cases the use of iodomethane avoids the need for thiophilic
silver or mercury salts and allows for transthiolesterification.
Disaccharide Formation. Treatment of glycoside (3) with
2,2'-dipyridyl disulfide and Tri-n-butylphosphine in CH 2 Cl 2
rapidly yields thiopyridyl derivative (4) as a mixture of anomers.
Activation of (4) with iodomethane, followed by treatment with
glycoside acceptor (5), affords the disaccharide fragment of avermectin (6), 27 exclusively -linked in 78% yield (eq 4). 28 Although
other methods are available, this protocol offers advantages in
practicality and stereoselectivity.
(1) R = Me
(2) R = i-Pr
If an -aminopyridinethiol ester is used, macrolactamization

occurs. 17 A method for the synthesis of -lactams from -amino
acids has also been developed where the use of MeCN has been
found to be critical (eq 2). 18 The intermolecular version of this
reaction is a powerful peptide coupling method. 19,20
(2)
Related Reactions of 2-Pyridinethiol Esters. In the absence

of an internal nucleophile, the thiopyridyl esters generated by the
reaction of carboxylic acids with 2,2'-dipyridyl disulfide and triphenylphosphine exhibit other reactivities. Thiolesters are potent
acylating agents, reacting with Grignard reagents to yield ketones
instead of tertiary alcohols. 21,22 This activity has been exploited
for the synthesis of 2-acylpyrroles using pyrrylmagnesium salts as
the nucleophilic species. Nicolaou and co-workers have exploited
2-pyridinethiol esters in the synthesis of a number of complex
2-acylpyrroles (eq 3). 23 In certain troublesome cases, the use of
(4)
Carbon-carbon bonds can be similarly formed at the anomeric

center of carbohydrates. Oxonium ions, formed by the treatment of
1 -(2'-thiopyridyl)glycosides with Silver(I) Trifluoromethanesulfonate, can be trapped with silyl enol ethers, silyl ketene acetals,
and reactive aromatic compounds, where the stereoselectivity of
the addition is determined by solvent and nucleophile choice. 29
The intramolecular version of this process has also been exam
ined (eq 5). 30 Similarly, bicyclic piperazinediones are available
by the intramolecular trapping of iminium ions, generated from
the appropriate thiopyridyl derivatives withP h H g C l O 4(eq 6). 31
(5)
Next Page
172
(9)
(6)
Alkene Formation. The elimination of pyridinethione or 2pyridylsulfenic acid forms the basis of a number of alkene syn
theses. For example, treatment of dithioacetal anions with 2,2'dipyridyl disulfide affords the -thiopyridyl derivative, which un
dergoes elimination at below room temperature to give ketene
dithioacetals.32 Ester enolates have been similarly treated, al
though m-Chloroperbenzoic Acid is first used to generate the sul
foxide which reacts further to yield an ,-unsaturated ester.33
This methodology has been applied to the synthesis of methyl
dehydrojasmonate (7) (eq 7). 34
General Reactions of Diaryl Disulfides1. 2,2'-Dipyridyl

disulfide reacts with a variety of carbon nucleophiles, yielding the
corresponding thiopyridyl derivatives. These include phosphonate
stabilized anions, 39 bromouridine derivatives,40 indole anions, 41
and heterocyclic stabilized anions. 42
1. (a) Capozzi, G.; Modena, G. The Chemistry of the Thiol Group; Patai,
S.; Ed.; Wiley: New York, 1974; Part 2, pp 785-839. (b) Jocelyn, P. C.
The Chemistry of the SH Group; Academic: New York, 1972.
2.
(a) NaOH/KI3: Marckwald, W.; Klemm, W.; Trabert, H. CB 1900, 33,

1556. (b) Nickel peroxide: Nakagawa, K.; Shiba, S.; Horikawa, M.; Sato,
K.; Nakamura, H.; Harada, N.; Harada, F. SC 1980, 10, 305. (c) I 2 :
McAllan, D. T.; Cullum, T. V.; Dean, R. A.; Fidler, F. A. JACS 1951, 73,
3627. (d) Zn(BiO3)2: Firouzabadi, H.; Mohammadpour-Baltork, I. BCJ
1992, 65, 1131. (e) (NH 4 ) 2 Ce(NO 3 ) 6 (CAN): Dhar, D. N.; Bag, A. K.
IJC(B) 1984, 23B, 974. (f) Bromodimethylsulfonium bromide: Olah, G.
A.; Arvanaghi, M.; Vankar, Y. D. S 1979, 721. (g) NaBO3: McKillop, A.;
Koyuncu, D. TL 1990, 31, 5007. (h) Diethyl bromomalonate: Kato, E.;
Oya, M.; Iso, T.; Iwao, J.-I. CPB 1986, 34, 486. (i) FeCl3-Bu3SnOMe:
Sato, T.; Otera, J.; Nozaki, H. TL 1990, 31, 3591.
3.
4.
(7)
Thalmann, A.; Oertle, K.; Gerlach, H. OSC 1990, 7, 470.

Reviews: (a) Nicolaou, K. C. T 1977, 33, 683. (b) Back, T. G. T 1977,
33,3041. (c) Ogliaruso, M. A.; Wolfe, J. A. In Synthesis of Lactones and
Lactams; Patai, S.; Rappaport, Z.; Eds.; Wiley: New York, 1993.
5. Mukaiyama, T. SC 1972, 2, 243.
6. Corey, E. J.; Nicolaou, K. C. JACS 1974, 96, 5614.
7. Corey, E. J.; Brunelle, D. J.; Stork, P. J. TL 1976, 3405.
8. Corey, E. J.; Nicolaou, K. C.; Melvin, L. S. JACS 1975, 97, 653.

9. Corey, E. J.; Nicolaou, K. C.; Melvin, L. S. JACS 1975, 97, 654.
10. Corey, E. J.; Ulrich, P.; Fitzpatrick, J. M. JACS 1976, 98, 222.
11.
Other Reactions. Treatment of an active hydroxy compound

with 2,2'-dipyridyl disulfide and n-Bu 3 P yields the correspond
ing thiopyridyl derivative. This methodology has been applied
to the preparation of 5-arylthio-5'-deoxyribonucleosides (eq 8). 35
Monophosphate esters [ROP(O)(OH)2] will react similarly to
form the activated triphenylphosphonium adduct, which, in the
absence of an added external nucleophile, dimerizes yielding
a pyrophosphate.36 N-Methylimidazole has been found to cat
alyze this transformation. The addition of alcohols or amines,
however, traps the phosphoryloxyphosphonium salt as the mixed
diphosphate ester or mixed ester/amide, respectively (eq 9). 37
Chlorotrimethylsilane and (pyS)2 have also been reported to fa
cilitate the oxidation of phosphites to phosphates. 38
14.
Corey, E. J.; Brunelle, D. J. TL 1976, 3409.
15.
(a) Karim, M. R.; Sampson, P. JOC 1990, 55, 598. (b) Justus, K.; Steglich,
W. TL 1991, 32, 5781.
16. Gerlach, H.; Thalmann, A. HCA 1974, 57, 2661.
17.
Bai, D.; Shi,Y.TL 1992, 33, 943.
18.
(a) Ohno, M.; Kobayashi, S.; Iimori, T.; Wang. Y.-E; Izawa, T. JACS
1981, 103, 2405. (b) Ohno, M.; Kobayashi, S.; Iimori, T.; Wang. Y.-E;
Izawa, T. JACS 1981, 103, 2406.
19. Reviews: (a) Klausner, Y. S.; Bodanszky, M. S 1972, 453. (b)
Mukaiyama, T. AG(E) 1976,15, 94.
20.
21.
(a) Mukaiyama, T.; Matsueda, R.; Suzuki, M. TL 1970, 1901. (b)

Mukaiyama, T.; Matsueda, R.; Maruyama, H. BCJ 1970, 43, 1271.
(a) Araki, M.; Sakata, S.; Takei, H.; Mukaiyama, T. BCJ 1974, 47, 1777.
(b) Loader, C. E.; Anderson, H. J. CJC 1971, 49, 45.
22.
For other recent methods for the synthesis of 2-acylpyrroles, see: (a)
Review: Patterson, J. M. 5 1976, 281. (b) Kozikowski, A. P.; Ames, A.
JACS 1980, 102, 860. (c) Martinez, G. R.; Grieco, P. A.; Srinivasan, C.
V. JOC 1981, 46, 3760. (d) Edwards, M. P.; Ley, S. V.; Lister, S. G.;
Palmer, B. D. CC 1983, 630.
23.
24.
Nicolaou, K. C ; Claremon, D. A.; Papahatjis, D. P. TL 1981, 22, 4647.

Nakahara, Y.; Fujita, A.; Ogawa, T. ABC 1985, 49, 1491.
(8)
Corey, E. J.; Nicolaou, K. C.; Toru, T. JACS 1975, 97, 2287.
12. Corey, E. J.; Bhattacharyya, S. TL 1977, 3919.

13. Bundy, G. L.; Peterson, D. C.; Cornette, J. C ; Miller, W. L.; Spilman,
C. H.; Wilks, J. W. JMC 1983, 26, 1089.
Previous Page
N,N'-DISUCCINIMIDYL CARBONATE
25.
26.
Nicolaou, K. C ; Maligres, P.; Suzuki, T.; Wendeborn, S. V.; Dai, W.-M.;

Chadha, R. K. JACS 1992, 114, 8890.
Ravi, D.; Mereyala, H. B. TL 1989, 30, 6089.
Springer, J. P.; Arison, B. H.; Hirshfield, J. M.; Hoogsteen, K. JACS

1981, 103, 4221.
28. (a) Mereyala, H. B.; Kulkarni, V. R.; Ravi, D.; Sharma, G. V. M.; Rao, B.
V.; Reddy, G. B. T 1992,48,545. (b)Ravi, D.; Kulkarni, V. R.; Mereyala,
H. B. TL 1989, 30, 4287. (c) for mechanistic details see: Mereyala, H.
B.; Reddy, G. V. T 1991, 47,6435.
29. Williams, R. M.; Stewart, A. O. TL 1983, 24, 2715.
30. Craig, D.; Munasinghe, V. R. N. TL 1992, 33, 663.
31. Williams, R. M.; Dung, J.-S.; Josey, J.; Armstrong, R. W.; Meyers, H.
/ACS 1983, 705, 3214.
32. Nagao, Y.; Seno, K.; Fujita, E. TL 1979, 4403.
33. Nagao, Y.; Takao, S.; Miyasaka, T.; Fujita, E. CC 1981, 286.
34. Dubs, P.; Stiissi, R. HCA 1978, 61, 998.
35. (a) Nakagawa, I.; Hata. T. TL 1975, 1409. (b) Nakagawa, I.; Aki, K.;
Hata, T. JCS(P1) 1983, 1315.
36. Kanavorioti, A.; Lu, J.; Rosenbach, M. T.; Hurley, T. B. TL 1991, 32,
6065.
37. Mukaiyama, T.; Hashimoto, M. BCJ 1971, 44, 196.
173
Handling, Storage, and Precautions: moisture sensitive; stable

under refrigeration; irritant.
27.
38.
39.
40.
41.
42.
Hata, T.; Sekine, M. TL 1974, 3943.

Ebertino, F. H.; Degenhart, C. R.; Jamieson, L. A.; Burdsall, D. C. H
1990, 30, 855.
Hirota, K.; Tomishi, T.; Maki, Y. H 1987, 26, 3089.
Active Ester Preparation in Peptide Chemistry. Eq 2 shows

the method for activating acids for subsequent reaction with
amines, to give peptide bonds.1
(2)
Di(N-succinimidyl) Oxalate (DSO) has also been used as an

alternative to DSC in the preparation of esters.8
Carbamate Preparation. DSC reacts with primary and sec
ondary amines to give carbamates (eq 3), 4 in which the carbonyl
group is activated by the electron withdrawal of the succinimidyl
group. Further attack by the amino groups on the carbonyl of such
active carbamates gives ureas. Such carbamates produced by DSC
have been used in the preparation of chiral derivatizing agents for
amino compounds6 and in the preparation of nucleoside analogs. 7
Atkinson, J. G.; Hanel, P.; Girard, Y. S 1988, 480.

Mirazaei, Y. R.; Simpson, B. M.; Triggle, D. J.; Natale, N. R. JOC 1992,
57,6271.
(3)
Eric J. Stoner
-Eliminations. -Elimination of the hydroxy group of Nprotected -hydroxy--amino acids has been effected using DSC
and Triethylamine.2 Reaction of Z-threonine with equimolar
DSC/Et 3 N in acetonitrile gave exclusively the (Z)-isomer of ZDBut-OMe (eq 4). Similarly, use of a 1:2 molar ratio of DSC gave
the (Z)-isomer of Boc-DBut-OSuc, which on treatment with the
methyl ester of alanine gave Z-DBut-Ala-OMe (eq 5).
(4)
[74124-79-1]
C9H8N2O7
(MW 256.19)
(reagent for the preparation of (active) esters in peptide

chemistry;1 -eliminations2 and carbonyl insertions in hetero
cyclic and especially peptide chemistry;3 useful in preparation
of some carbamates, ureas, and nitrosoureas4)
Alternate Name: DSC.
Physical Data: mp 211-215 C (dec); prisms.5
Form Supplied in: white to off-white powder.
Preparative Methods: by treatment of N-Hydroxysuccinimide
(HOSu) with Trichloromethyl
Chloroformate
(TCF,
Cl 3 COCOCl) or using trimethylsilylated N-hydroxysuccinimide and phosgene, both giving DSC in good yield (eq 1 ).1
(5)
Carbonyl Insertions. DSC has been used as a replace

ment for Phosgene in the cyclization of N-aralkyl -amino
acids to N-carboxyanhydrides (eq 6). 9 This method releases Nhydroxysuccinimide as a byproduct, which is only weakly acidic
and so does not affect any acid sensitive groups, whereas phos
gene releases 2 equiv of hydrogen chloride. Unlike in ester for
mation using carboxylates, where the central carbonyl group of
DSC is released as CO 2 , with better nucleophiles, such as sec
ondary -amino functions, incorporation of the carbonyl group
occurs. This is assumed to be by N-substitution by R-CO-, fol
lowed by intramolecular anhydride formation by tertiary amine.
Similar carbonyl insertions by N,N'-Carbonyldiimidazole (CDI)
174
N,N'-DISUCCINIMIDYL CARBONATE
to give heterocycles10,11 leads to racemization. Use of DSC as a

carbonyl insertion reagent has led to its use in the preparation of
ureas and various heterocycles.3 Reaction with amines (to give
ureas), 1,2-diamines (to give cyclic ureas), 1,2-aminothiols (to
give cyclic thiocarbamates), and 1,2-hydroxyamines have all been
observed. One simple example is the action of DSC on cyclohexylamine to give dicyclohexylurea. A series of (thio)carbamates used
as muscle relaxants have also been prepared, e.g. chloroxazone
(5-chloro-2-hydroxybenzoxazole) (eq 7). 3-(Benzoxazolyl, benzimidazolyl)pyrazole derivatives have also been made using DSC
in MeCN.
(6)
(7)
Related Reagents. Di(N-succinimidyl) Oxalate.
1. Ogura, K ; Kobayashi, X; Shimizu, K.; Kawabe, K.; Takeda, K. TL 1979,

49, 4745. Ogura, H.; Takeda, K. NKK 1981, 5, 836.
2.
Ogura, H.; Sato, O.; Takeda, K. TL 1981, 22, 4817.
3.
4.
Takeda, K.; Ogura, H. SC 1982, 12, 213.

Takeda, K.; Akagi, Y.; Saika, A.; Tsukahara, X; Ogura, H. TL 1983, 24,
4569.
5.
Sigma-Aldrich Handbook of Chemical Safety Data, 2nd ed.; Lenga, R.

E., Ed.; Aldrich: Milwaukee, WI, 1987.
6.
Iwaki, K.; Yoshida, S.; Nimura, N.; Kinoshita, X; Takeda, K.; Ogura, H.
Chromatographia 1987, 23, 899.
7.
McCormick, J. E.; McElhinney, R. S.; McMurray, T. B. H.; Maxwell, R.

J. JCS(P1) 1991, 877.
8. Yamashina, X; Higuchi, K.; Hirata, H. YZ 1991, 40, 155.
9. Halstrom, J.; Kovcs, K. ACS(B) 1986, 462.
10. Wright, W. JHC 1965, 2,41.
11.
Kutney, J.; Ratcliffe, A. SC 1975, J, 47.
Edwin C. Davison
University of Cambridge, UK
1,2-ETHANEDITHIOL
Reduction. Raney Nickel desulfurization of 1,3-dithiolanes

effects overall reduction of C=O to CH 2 , as does SodiumAmmonia in THF (eqs 4 and 5). 7a,b Na/hydrazine is an alternative
reagent (eq 6). 10a Peptidic sulfoxides are reduced to thioethers
with (1) and an electrophilic catalyst.11a
1,2-Ethanedithiol1
[540-63-6]
175
C2H6S2
(4)
(MW 94.20)
(5)
(1,3-dithiolane formation; ether cleavage; reduction (carbonyl

to methylene; sulfoxide to thioether); gem-difluoride formation;
dithiolenium ion formation)
Physical Data: d 1.123 g c m - 3 (23.5 C); bp 146 C/760 mmHg;
63 C/46 mmHg.
Solubility: slightly sol water; miscible with many organic sol
vents.
Form Supplied in: widely available.
Handling, Storage, and Precautions: stench! Inhalation can cause
chest pain, headache, nausea, pulmonary edema; LD 50 (oral,
mouse) 342 mg k g - 1 ; see 1,3-Propanedithiol. Use in a fume
hood.
1,3-Dithiolane Formation. 1,2-Ethanedithiol (1) condenses

with aldehydes, ketones, and acetals to afford 1,3-dithiolanes,1,2
useful for carbonyl protection (eqs 1 and 2). 3a,b Stability, conden
sation selectivity, and conditions for carbonyl regeneration parallel
those discussed for 1,3-Propanedithiol.4 Esters and lactones can
be protected as ketene dithioacetals and/or dithioortholactones,
resistant to nucleophilic attack, using the bis(dimethylalanyl)
derivative of (1). 5
(1)
(6)
gem-Difluoride Formation. 1,3-Dithiolanes yield geminal difluorides on treatment with Pyridinium Poly(hydrogen Fluoride)
and a mild oxidant (eq 7). 8a,b 1,3-Dithianes react more slowly and
give lower yields.8a
(7)
Dithiolenium Ion Formation. Acid chlorides, anhydrides, es

ters, and orthoesters, upon treatment with (1) and a Lewis acid, can
produce electrophilic 1,3-dithiolenium cations which react with a
variety of carbon nucleophiles.9 Selective indole formylation in
the presence of a primary carboxamide could thus be achieved
(eq 8). 9a
(2)
Ether Cleavage. An acetonide can be cleaved in the presence

of a nearby t-butyldiphenylsilyl ether with (1).6a Under more vig
orous conditions, aliphatic methyl ethers are cleaved (eq 3). 6b
(8)
(3)
176
2-ETH0XY-1-ETHOXYCARBONYL-1,2-DIHYDROQUINOLINE
Miscellaneous. Racemic ketones have been resolved by con

densation with (R,R)- or (S,S)-2,3-butanedithiol, then reduced as
above to give resolved deoxy compounds (eq 6).10a,b Oxidation
of prochiral 1,3-dithiolanes under modified Katsuki-Sharpless
conditions yields monosulfoxides of high ee.10c In peptide
synthesis, (1) is frequently used as a cation scavenger dur
ing deprotection.11a,b Transition metal cations are strongly
chelated by (1), as exemplified by demetalation of CuII and NiII
metalloporphyrins.11c
Related
Reagents. Ethanethiol;
Propanedithiol.
Methanethiol;
1,3-
2-Ethoxy-1-ethoxycarbonyl-1,2dihydroquinoline
[16357-59-8]
C 14 H 17 NO 3
(MW 247.29)
(activating agent used in peptide synthesis)

2nd ed.; Wiley: New York, 1991; p 201. (b) Page, P. C. B.; van Niel, M.
B.; Prodger, J. C. T 1989, 45,7643; see pp 7647-7651.
2. 1,3-Dithiolanes are not generally useful as acyl anion equivalents: (a)
Oida, T.; Tanimoto, S.; Terao, H.; Okano, M. JCS(P1) 1986, 1715. (b)
An exception: Barton, D. H. R.; Bielska, M. T.; Cardoso, J. M.; Cussans,
N. J.; Ley, S. V. JCS(P1) 1981, 1840.
3. (a) Liu, H.-J.; Yeh, W.-L.; Chew, S. Y. TL 1993, 34, 4435. (b) Wolf, G.;
Seligman, A. M. JACS 1951, 75, 2082.
4.
(a) Sato, T.; Otera, J.; Nozaki, H. JOC 1993, 58, 4971. (b) Stahl, I.;
Schramm, B.; Manske, R.; Gosselck, J. LA 1982, 1158. (c) Nakata, T.;
Nagao, S.; Takao, S.; Tanaka, T.; Oishi, T. TL 1985, 26, 73. (d) Cardani,
S.; Bernardi, A.; Colombo, L.; Gennari, C.; Scolastico, C.; Venturing 1.
T 1988, 44, 5563. (e) Ni, Z.-J.; Luh, T.-Y. OS 1992, 70, 240. (f) Bellesia,
P.; Boni, M.; Ghelfi, F.; Pagnoni, U. M. 7/1993, 49, 199.
5.
6.
Corey, E. J.; Beames, D. J. JACS 1973, 95, 5829.

(a) Williams, D. R.; Sit, S.-Y JACS 1984, 106, 2949. (b) Vidari, G.;
Perrifio, S.; Grieco, P. A. JACS 1984, 106, 3539.
(a) Maurer, P. J.; Takahata, H.; Rapoport, H. JACS 1984, 106, 1095. (b)
Numazawa, M.; Mutsumi, A. Biochem. Biophys. Res. Commun. 1991,
177,401.
(a) Sondej, S. C ; Katzenellenbogen, J. A. JOC 1986, 51, 3508. (b) Jek,
J.; Timr, T.; Jaszberenyi, J. C. JOC 1991, 56, 6748.
7.
8.
9.
(a) Bene, J.; Semonsk, M. CCC 1982, 47, 1235. (b) Stahl, I. CB 1987,
120, 135. (c) Okuyama, X; Pujiwara, W.; Fueno, T. BCJ 1986, 59, 453.
(d) Houghton, R. P.; Dunlop, J. E. SC 1990, 20, 1.
Alternate Names: ethyl l,2-dihydro-2-efhoxy-l-quinolinecarboxylate; EEDQ.

Physical Data: mp 66-67 C; bp 125-128 C/0.1 mmHg.
Solubility: sol water, alcohol.
Form Supplied in: white powder; widely available and can be
easily prepared.1
Peptide Synthesis. In peptide synthesis, peptide bonds are cre

ated from the activated carboxylic group of aN-protected amino
acid that is reacted with the nucleophilic free amino group of an
other amino acid (eq 1).
(1)
Activation of the carboxylic acid can be performed according

to several strategies, leading mainly to two kinds of intermediates:
active esters and acid anhydrides, which can be either symmetrical
anhydrides or mixed anhydrides. EEDQ is a reagent used in pep
tide synthesis for the mixed carbonic anhydride strategy. It allows
a slow formation of unsymmetrical anhydrides under very mild
conditions (eq 2).2
10. (a) Corey, E. J.; Ohno, M.; Mitra, R. B.: Vatakencherry, P. A. JACS 1964,
86,478. (b) Buding, H.; Deppisch, B.; Musso, H.; Snatzke, G. CB 1985,
118, 4597. (c) Bortolini, O.; Di Furia, P.; Licini, G.; Modena, G.; Rossi,
M. TL 1986, 27, 6257.
11. (a) Futaki, S.; Taike, T.; Akita, T.; Kitagawa, K. CC 1990, 523. (b) Pields,
C. G.; Fields, G. B. TL 1993, 34, 6661. (c) Battersby, A. R.; Jones, K.;
Snow, R. J. AG(E) 1983, 22, 734.
Raymond E. Conrow
Alcon Laboratories, Fort Worth, TX, USA
(2)
Faster reaction of the mixed anhydride with nucleophilic species

reduces the extent of side reactions that occur with high concen
tration of the anhydride (eq 3).3
Boc-Cys(Bn)-Tyr(Bn)-Gln-Asn-Cys(Bn)-OBn (3)
The tendency for racemization is limited to a small extent. Nev

ertheless, wrong-side attack, leading to the formation of urethane,
is not suppressed (eq 4).4
ETHYLALUMINUM DICHLORIDE
177
Ethylaluminum Dichloride1
(4)
[563-43-9]
As best results had been obtained with mixed anhydrides of
Isobutyl Chloroformate, probably because the isobutyl group de
creases the amount of urethane products, IIDQ (1), an analog of
EEDQ, has been proposed for use in peptide synthesis.5,6
As another alternative, EEDQ has been linked to a polymeric

support, providing a supported coupling reagent in high yield
(eq 5). 7
(5)
Coupling reactions mediated by this reagent occur cleanly

in high yield and with a low degree of racemization, com
parable with that observed with EEDQ itself.8 Nevertheless,
the use of EEDQ in peptide synthesis is rather limited, other
coupling reagents being very much more popular. Examples
are: the carbodiimides, mainly 1,3-Dicyclohexylcarbodiimide
and diisopropylcarbodiimide; the family of BOP reagents
such as
Hexafluorophosphate; uroniums such as O-Benzotriazol-1-ylN,N,N',N'-tetramethyluronium Hexafluorophosphate (HBTU),
or urethane N-protected carbonic anhydrides (UNCA), and active
esters.
1. Fieser, M.; Fieser, L. F. FF 1969, 2, 191.
2. Belleau, B.; Malek, G JACS 1968, 90, 1651.
3. Miihlemann, M.; Titov, M., I.; Scweyzer, R.; Rudinger, J. HCA 1972,55,
2854.
4. Lombardino, J. G.; Anderson, S. L.; Norris, C. P. JHC 1978, 15, 655.
5. Kiso, Y.; Kai, Y.; Yajima, H. CPB 1973, 90, 1651.
6. Bodanszky, M.; Bodanszky, A. The Practice of Peptide Synthesis;
Springer: Berlin, 1984; p 148.
7. Brown, J.; Williams, R. E. CJC 1971, 49, 3765.
8. Lauren, D. R.; Williams, R. E. TL 1972, 2665.
Jean-Claude Gesquiere
Institut Pasteur, Lille, France
C2H5AlCl2
(MW 126.95)
with HX to give ethane and AlCl 2 X)
Alternate Name: dichloroethylaluminum.
Physical Data: mp 32 C; bp 115 C/50 mmHg; d 1.207 g c m - 3 .
hexane or toluene.
hood.
Alkylaluminum Halides. Since the early 1980s, alkylaluminum halides have come into widespread use as Lewis acid
catalysts. These strong Lewis acids offer many advantages over
traditional metal halide Lewis acids such as Boron Trifluoride,
Aluminum Chloride, Titanium(IV) Chloride, and Tin(lV) Chloride. Most importantly, the alkyl group on the aluminum will react
with protons to give an alkane and a new Lewis acid. Alkylalu
minum halides are therefore Brnsted bases, as well as Lewis
acids. The alkyl groups are also nucleophilic, and this is the major
disadvantage in the use of these compounds as Lewis acids.
Pure, anhydrous Lewis acids do not catalyze the polymeriza
tion of alkenes or the Friedel-Crafts alkylation of aromatics by
alkenes. Cocatalysts, such as water or a protic acid, react with the
Lewis acid to produce a very strong Brnsted acid that will protonate a double bond. Therefore, use of strictly anhydrous condi
tions should minimize side reactions in Lewis acid-catalyzed ene,
Diels-Alder, and [2 + 2] cycloaddition reactions. Unfortunately,
it is difficult to prepare anhydrous, proton-free AlCl 3 , BF 3 , etc.
Alkylaluminum halides are easily prepared and stored in anhy
drous form and, more importantly, scavenge any adventitious wa
ter, liberating an alkane and generating a new Lewis acid in the
process.
Using alkylaluminum halides, Lewis acid-catalyzed reactions
can now be carried out under aprotic conditions. This is of value
when side reactions can be caused by the presence of adventi
tious protons; it is of special value when acidic protons are pro
duced by the reaction. In these cases, use of the appropriate alkyl
aluminum halide in stoichiometric rather than catalytic amounts
gives high yields of products not formed at all with other Lewis
acids. The Me2AlCl-catalyzed ene reactions of aliphatic aldehy
des with alkenes, which give homoallylic alcohol-Me2AlCl com
plexes that react further to give methane and the stable methylaluminum alkoxides, is an example of this type of reaction (eq l). 1 h , 2
Loss of methane prevents the alcohol-Lewis acid complex from
solvolyzing or protonating double bonds.
The alkylaluminum halides cover a wide range of acidity.
Replacing chlorines with alkyl groups decreases Lewis acidity.
178
EtAlCl2 and Methylaluminum Dichloride are only slightly less

acidic than AlCl 3 . Diethylaluminum Chloride and Dimethylaluminum Chloride are substantially less acidic, and Trimethylaluminum, Me 2 AlOR, and MeAl(OR) 2 are even weaker Lewis acids.
Alkylaluminum halides with fractional ratios of alkyl to chloride
are also available. The sesquichlorides are commercially available.
Other reagents can be prepared by mixing two reagents in the de
sired proportion. If no reaction occurs with the alkylaluminum
halide, a stronger Lewis acid should be tried. If polymerization
or other side reactions compete, a weaker Lewis acid should be
used. The sequential ene and Prins reactions shown in eq 2 pro
ceed cleanly with Me 3 Al 2 Cl 3 . 3 Complex mixtures are obtained
with the stronger Lewis acid EtAlCl2 while the weaker Lewis
acid Me 2 AlCl reacts with Formaldehyde to give ethanol.
used unless the nucleophilicity of the alkyl group is a problem. Al

though the predominant use of alkylaluminum halides is as Lewis
acids, they are occasionally used for the transfer of an alkyl group
or hydride to an electrophilic center.
Eq 3 shows an unusual reaction in which the nature of the reac
tion depends on the amount, acidity, and alkyl group of the alkyla
luminum halide. 6 Use of 1 equiv of Me 2 AlCl leads to a concerted
ene reaction with the side chains cis. Use of 2 equiv of Me 2 AlCl
produces a more electrophilic aldehyde complex that cyclizes to
a zwitterion. Chloride transfer is the major process at 78 C; at
0 C, chloride transfer is reversible and a 1,5-proton transfer leads
to an ene-type adduct with the side chains trans. Use of 2 equiv
of MeAlCl 2 forms a cyclic zwitterion that undergoes two 1,2hydride shifts to form the ketone. A similar zwitterion forms with
EtAlCl 2 , but -hydride transfer leading to the saturated alcohol is
faster than 1,2-hydride shifts.
(1)
(3)
(2)
Use of more than one equivalent of Lewis acid will produce

complexes that are formally 1:2 substrate Lewis acid complexes,
but are more likely salts with a R 2 Al-substrate cation and an aluminate anion. 4-6 This substrate in this salt is much more electrophilic and reactive than that in simple Lewis acid complexes.
These reagents are easier to use than typical inorganic Lewis
acids. They are soluble in all organic solvents, including hexane
and toluene, in which they are commercially available as stan
dardized solutions. In general, alkane solvents are preferred since
toluene can undergo Friedel-Crafts reactions. On a laboratory
scale, these reagents are transferred by syringe like alkyllithiums
and, unlike anhydrous solid Lewis acids, they do not require a
glove bag or dry box for transfer.
While the Br0nsted basicity of the alkyl group is advantageous,
these alkyl groups are also nucleophilic. The addition of the alkyl
group from the aluminum in the Lewis acid-reagent complex to
the electrophilic center can be a serious side reaction. The ease of
alkyl donation is R 3 Al > R 2 AlCl > R 3 Al 2 Cl 3 > RAlCl 2 . When the
nucleophilicity of the alkyl group is a problem, a Lewis acid with
fewer alkyl groups should be examined. Addition of diethyl ether
or another Lewis base may moderate the reaction if its greater
acidity causes problems.
Ethylaluminum compounds are more nucleophilic than methy
laluminum compounds and can donate a hydrogen as well as an
ethyl group to the electrophilic center. Unfortunately, methylalu
minum compounds must be prepared from Chloromethane, while
ethylaluminum compounds can be prepared much more cheaply
from Ethylene. Therefore ethylaluminum compounds are usually
Catalysis of Diels-Alder Reactions. EtAlCl2 is a useful Lewis

acid catalyst for Diels-Alder reactions. It is reported to be more
efficacious for the Diels-Alder reaction of Acrolein and buta
diene than either AlCl 3 or Et 2 AlCl. 7 It is a useful catalyst for
intramolecular Diels-Alder reactions with ,-unsaturated esters
(eq 4) 8 and aldehydes 9 as dienophiles. It has also proven to be a
very efficient catalyst for the inter-10 and intramolecular11 asym
metric Diels-Alder reaction of chiral ,-unsaturated acyl sultams
(eq 5) and has been used to catalyze a wide variety of Diels-Alder
reactions. 12
(4)
(5)
Catalysis of Ene Reactions. Although AlCl 3 can be used as a

Lewis acid catalyst for ene reactions of ,-unsaturated esters,13a
better results are obtained more reproducibly with EtAlCl 2 . Ene
reactions of Methyl Propiolate proceed in good yield with 1,1-di, tri-, and tetrasubstituted alkenes (eq 6).14 A precursor to 1,25dihydroxycholesterol can be prepared by an ene reaction with
methyl propiolate. Three equiv of EtAlCl2 are needed since the
acetate esters are more basic than methyl propiolate (eq 7).15
Endo products are obtained stereospecifically with methyl haloacrylates (eq 8).14 EtAlCl2 has also been used to catalyze
intramolecular ene reactions (eq 9).16
(6)
179
(11)
Catalysis of Intramolecular Sakurai Reactions. EtAlCl2 has

been extensively used as a catalyst for intramolecular Sakurai ad
ditions. Enones (eqs 12 and 13)21'22 have been most extensively
explored. Different products are often obtained with fluoride or
Lewis acid catalysis. EtAlCl2 is the Lewis acid used most of
ten although TiCl4 and BF3 have also been used. EtAlCl2 also
catalyzes intramolecular Sakurai reactions with ketones23 and
other electrophiles.24 The cyclization of electrophilic centers onto
alkylstannanes25 and Prins-type additions to vinylsilanes26 are
also catalyzed by EtAlCl2.
(12)
(7)
(13)
(8)
(9)
EtAlCl2 is usually too strong a Lewis acid for ene reac

tions of carbonyl compounds.13b,c However, alkenes that con
tain basic sites that complex to the Lewis acid do not undergo
Me2AlCl-catalyzed ene reactions with formaldehyde. In these
cases, EtAlCl2 is the preferred catalyst.17,18 The dienyl acetate
shown in eq 10 reacts with excess Formaldehyde and EtAlCl2 to
provide the conjugated diene ene adduct that undergoes a quasiintramolecular Diels-Alder reaction to afford a pseudomonic acid
precursor. Me2AlCl catalyzes the ene reaction of aliphatic alde
hydes with 1,1-di-, tri-, and tetrasubstituted alkenes. Terminal
alkenes are less nucleophilic, so the only reaction is addition of a
methyl group to the aldehyde. EtAlCl2, a stronger Lewis acid with
a less nucleophilic alkyl group, catalyzes the reaction of aliphatic
aldehydes with terminal alkenes in CH2Cl2 at 0 C to give 50-60%
of the ene adduct.18 Use of EtAlCl2 as a catalyst affords the best
diastereoselectivity in the ene reaction of dibenzylleucinal with
Isobutene (eq 11).19 EtAlCl2 has also been used to catalyze in
tramolecular ene reactions of trifluoromethyl ketones.20
(10)
Catalysis of [2 + 2] Cycloadditions. EtAlCl2 catalyzes a wide

variety of [2 + 2] cycloadditions. These include the addition of
alkynes or allenes to alkenes to give cyclobutenes and alkylidenecyclobutanes (eq 14),27 the addition of electron-deficient
alkenes to allenyl sulfides (eq 15),28 the addition of propiolate
esters to monosubstituted and 1,2-disubstituted alkenes to form
cyclobutene carboxylates (eq 16),14b and the addition of allenic
esters to alkenes to form cyclobutanes.29
(14)
(15)
(16)
Generation of Electrophilic Cations. EtAlCl2 has proven to

be a useful Lewis acid for inducing a wide variety of electrophilic
reactions. It is particularly useful since an excess of the reagent can
be used so that all nucleophiles are complexed to acid. Under these
conditions, intermediates tend to collapse to give cyclobutanes
or undergo hydride shifts to give neutral species. Reaction of the
1:2 Crotonaldehyde-EtAlCl2 complex with 2-methyl-2-butene at
80 C affords a zwitterion that collapses to give mainly the cyclobutane. Closure of the zwitterion is reversible at 0C. Since
180
there are no nucleophiles in solution, two 1,2-hydride shifts take

place to give the enal (eq 17).5 Intramolecular versions of these re
actions are also quite facile (eqs 18 and 19).5'21 EtAlCl2 promotes
the ring enlargement of l-acylbicyclo[4.2.0]oct-3-enes (eq 20).30
EtAlCl2 reacts with aliphatic sulfones to generate an alu

minum sulfinate and a cation that can be reduced to a hy
drocarbon by EtAlCl2,37 trapped with a nucleophile such as
Allyltrimethylsilane,38 or undergo a pinacol-type rearrangement
(eq 24).39
(24)
(17)
Elimination Reactions. EtAlCl2 induces elimination of two

olecules of HBr from the dibromide to give the dihydropyridine
q 25).40 The usual base-catalyzed elimination is ineffective.
(25)
(18)
(19)
(20)
EtAlCl2 catalyzes the Friedel-Crafts acylation of alkenes with

acid chlorides,31 the formal [3 + 2] cycloaddition of alkenes with
cyclopropane-1,1-dicarboxylates (eq 21),32 the Friedel-Crafts
alkylation of anilines and indoles with -aminoacrylate esters,33
and the formation of allyl sulfoxides from sulfinyl chlorides and
alkenes.34 EtAlCh induces the Beckmann rearrangement of oxime
sulfonates. The cationic intermediates can be trapped with enol
silyl ethers (eq 22).35 EtAlCl2 is the preferred catalyst for addition
of the cation derived from an -chloro sulfide to an alkene to give
a cation which undergoes a Friedel-Crafts alkylation (eq 23).36
Nucleophilic Addition. EtAlCl2 has been used to activate con

jugated systems toward attack of an external nucleophile or to
transfer a hydride or ethyl group as a nucleophile. Addition of a
cuprate to the chiral amide in the presence of EtAlCl2 improves the
diastereoselectivity, affording a >93:7 mixture of stereoisomers
(eq 26).41 Reaction of butyrolactones with EtAlCl2 reduces the
lactone to a carboxylic acid by opening to the cation and hydride
delivery (eq 27).42 Sulfonimidyl chlorides react with EtAlCl2 at
78 C to provide S-ethyl sulfoximines in 65-95% overall yield
(eq 28).43
(26)
(21)
(27)
(22)
(23)
(28)
Modification of Carbanions. Trimefhylsilyl allylic carbanions react with aldehydes in the presence of EtAlCl2 exclusively
at the -position to give threo adducts (eq 29).44
(29)
Related Reagents. Aluminum Chloride; Boron Trifluoride

Etherate; Diethylaluminum Chloride; Diethylaluminum Iodide;
Dimethylaluminum Chloride; Dimethylaluminum Iodide; Ethylaluminum Dichloride; Methylaluminum Dichloride; Tin(IV)
Chloride; Titanium(IV) Chloride; Triethylaluminum; Trimethylaluminum.
1. (a) Mole, T.; Jeffery, E. A. Organoaluminum Compounds; Elsevier: New

York, 1972. (b) Bruno, G. The Use of Aluminum Alkyls in Organic
Synthesis; Ethyl Corporation: Baton Rouge, LA, 1970. (c) Bruno, G. The
Use of Aluminum Alkyls in Organic Synthesis, Supplement, 1969-1972;
Ethyl Corporation: Baton Rouge, LA, 1973. (d) Honeycutt, J. B. The Use
ofAluminum Alkyls in Organic Synthesis, Supplement, 1972-1978; Ethyl
Corporation: Baton Rouge, LA, 1981. (e) Aluminum Alkyls; Stauffer
Chemical Co.: Westport, CT, 1976. (f) Snider, B. B.; Rodini, D. J.; Karras,
M.; Kirk, T. C ; Deutsch, E. A.; Cordova, R.; Price, R. T.; T 1981, 37,
3927. (g) Yamamoto, H.; Nozaki, H. AG(E) 1978, 17, 169. (h) Snider,
B. B. In Selectivities in Lewis Acid Promoted Reactions; Schinzer, D.,
Ed.; Kluwer: Dordrecht, 1989; Chapter 8. (i) Maruoka, K.; Yamamoto,
H. AG(E) 1985, 24, 668; T 1988, 44, 5001.
(a) Snider, B. B.; Rodini, D. J.; Kirk, T. C ; Cordova, R. JACS 1982,104,
555. (b) Cartaya-Marin, C. P.; Jackson, A. C ; Snider, B. B. JOC 1984,
49, 2443.
3. Snider, B. B.; Jackson, A. C. JOC 1983, 48, 1471.
4. Evans, D. A.; Chapman, K. T.; Bisaha, J. JACS 1988, 110, 1238.
5. Snider, B. B.; Rodini, D. J.; van Straten, J. JACS 1980, 102, 5872.
6. Snider, B. B.; Karras, ML; Price, R. T.; Rodini, D. J. JOC 1982, 47,4538.
7. Miyajima, S.; Inukai, T. BCJ 1972, 45, 1553.
8. (a) Roush, W. R.; Ko, A. I.; Gillis, H. R. JOC 1980, 45,4264. (b) Roush,
W. R.; Gillis, H. R. JOC 1980, 45, 4267; JOC 1982, 47, 4825.
9. (a) Marshall, J. A.; Audia, J. E.; Grote, J. JOC 1984, 49, 5277. (b)
Marshall, J. A.; Grote, J.; Audia, J. E. JACS 1987, 109, 1186.
10. (a) Oppolzer, W.; Chapuis, C ; Bernardinelli, G. HCA 1984, 67, 1397.
(b) Smith, A. B., III; Hale, K. J.; Laasko, L. M.; Chen, K.; Riera, A. TL
1989, 30, 6963.
17.
(a) Snider, B. B.; Phillips, G. B. JACS 1982, 104, 1113. (b) Snider, B.
B.; Phillips, G. B.; Cordova, R. JOC 1983, 48, 3003.
18.
19.
Snider, B. B.; Phillips, G. B. JOC 1983, 48, 464.

Mikami, K.; Kaneko, M.; Loh, T.-P.; Tereda, M.; Nakai, T. TL 1990, 31,
3909.
20.
Abouadellah, A.; Aubert, C.; Bgu, J.-P.; Bonnet-Delpon, D.; Guilhem,

J. JCS(P1) 1991, 1397.
21.
(a) Majetich,G.;Behnke,M.; Hull, K.JOC1985, 50,3615. (b)Majetich,

G.; Hull, K.; Lowery, D.; Ringold, C ; Defauw, J. In Selectivities in
Lewis Acid Promoted Reactions; Schinzer, D., Ed.; Kluwer: Dordrecht,
1989; Chapter 9. (c) Majetich, G.; Khetani, V. TL 1990, 31, 2243. (d)
Majetich, G.; Hull, K.; Casares, A. M.; Khetani, V. JOC 1991, 56, 3958.
(e) Majetich, G.; Song, J.-S.; Ringold, C ; Nemeth, G. A.; Newton, M. G.
JOC 1991, 56, 3973. (f) Majetich, G.; Song, J.-S.; Leigh, A. J.; Condon,
S. M. JOC 1993, 58, 1030.
22.
(a) Schinzer, D.; Slyom, S.; Becker, M. TL 1985, 26, 1831. (b) Schinzer,
D. S 1988, 263.
(a) Trost, B. M.; Hiemstra, H. JACS 1982, 104, 886. (b) Trost, B. M.;
Coppola, B. P. JACS 1982, 104, 6879. (c) Trost, B. M.; Fray, M. J. TL
1984, 25, 4605.
23.
24.
Wada, M.; Shigehisa, T.; Akiba, K. TL 1985, 26, 5191. (b) Pirrung, M.
C ; Thomson, S. A. TL 1986, 27, 2703.
25. (a) McDonald, T. L.; Delahunty, C. M.; Mead, K.; O'Dell, D. E. TL 1989,
30, 1473. (b) Plamondon, L.; Wuest, J. D. JOC 1991, 56, 2066.
26.
27.
Casteiieda, A.; Kucera, D. J.; Overman, L. E. JOC 1989, 54, 5695.

(a) Lukas, J. H.: Kouwenhoven, A. P.; Baardman, F. AG(E) 1975, 14,
709. (b) Lukas, J. H.; Baardman, F.; Kouwenhoven, A. P. AG(E) 1976,
15, 369.
28.
29.
Hayashi, Y.; Niihata, S.; Narasaka, K. CL 1990, 2091.

(a) Snider, B. B.; Spindell, D. K. JOC 1980, 45, 5017. (b) Snider, B. B.;
Ron, E. JOC 1986, 51, 3643.
Fujiwara, T.; Tomaru, J.; Suda, A.; Takeda, T. TL 1992, 33, 2583.
Snider, B. B.; Jackson, A. C. JOC 1982, 47, 5393.
2.
11.
(a) Oppolzer, W.; Dupuis, D. TL 1985, 26,5437. (b) Oppolzer, W. AG(E)

1984, 23, 876.
12. (a) Poll, T.; Metter, J. O.; Helmchen, G. AG(E) 1985, 24, 112. (b)
Herndon, J. W. JOC 1986, 51, 2853. (c) Metral, J.-L.; Lauterwein, J.;
Vogel, P. HCA 1986, 69, 1287. (d) Waldmann, H.; Braun, M.; Drager,
M. AG(E) 1990, 29, 1468. (e) Kametani, T.; Takeda, H.; Suzuki, Y.;
Honda, T. SC 1985, 15, 499. (f) Vidari, G.; Ferrino, S.; Grieco, P. A.
JACS 1984, 106, 3539. (g) Funk, R. L.; ZeJler, W. E. JOC 1982, 47, 180.
(h) Fringuelli, F.; Pizzo, F.; Taticchi, A.; Wenkert, E. SC 1986, 16, 245.
13.
14.
(a) Snider, B. B. COS 1991, 5, 1. (b) Snider, B. B. COS 1991, 2,527. (c)
Mikami, K.; Shimizu, M. CRV 1992, 92, 1021.
(a) Snider, B. B.; Rodini, D. J.; Conn, R. S. E.; Sealfon, S. JACS 1979,
101, 5283. (b) Snider, B. B.; Roush, D. M.; Rodini, D. J.; Gonzalez, D.;
Spindell, D. JOC 1980, 45, 2773. (c) Snider, B. B.; Duncia, J. V. JACS
1980, 102, 5926. (d) Duncia, J. V.; Lansbury, P. X, Jr.; Miller, T.; Snider,
B. B. JACS 1982, 104, 1930. (e) Snider, B. B.; Phillips, G. B. JOC 1983,
48, 3685.
15.
(a) Batcho, A. D.; Berger, D. E.; Uskokovic, M. R.; Snider, B. B. JACS

1981, 103, 1293. (b) Dauben, W. G.; Brookhart, T. JACS 1981, 103,
237. (c) Batcho, A. D.; Berger, D. E.; Davoust, S. G.; Wovkulich, P. M.;
Uskokovic, M. R. HCA 1981, 64, 1682. (d) Wovkulich, P. M.; Batcho,
A. D.; Uskokovic, M. R. HCA 1984, 67, 612.
16.
Snider, B. B.; Phillips, G. B. JOC 1984, 49, 183.
181
30.
31.
32.
33.
34.
(a) Beal, R. B.; Dombroski, M. A.; Snider, B. B. JOC 1986, 51, 4391.
(b) Bambal, R.; Kemmit, R. D. W. CC 1988, 734.
Tarzia, G.; Balsamini, C ; Spadoni, G.; Duranti, E. 5 1988, 514.
Snider, B. B. JOC 1981, 46, 3155.
35.
Matsumura, Y.; Fujiwara, J.; Maruoka, K.; Yamamoto, H. JACS 1983,

105,6312.
36. (a) Ishibashi, H.; So, T. S.; Nakatani, H.; Minami, K.; Ikeda, M. CC
1988, 827. (b) Ishibashi, H.; Okoda, M.; Sato, K.; Ikeda, M.; Ishiyama,
K.; Tamura, Y. CPB 1985, 33, 90.
37. Trost, B. M.; Ghadiri, M. R. JACS 1984, 106, 7260.
38. Barton, D. H. R.; Boivin, J.; Sarma, J.; Da Silva, E.; Zard, S. Z. TL 1989,
30, 4237.
39. Trost, B. M.; Nielsen, J. B.; Hoogsteen, K. JACS 1992, 114, 5432.
40. (a) Raucher, S.; Lawrence, R. F. T 1983,39, 3731. (b) TL 1983, 24,2927.
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Yamamoto, Y.; Saito, Y.; Maruyama, K. CC 1982, 1326.
Brandeis
University,
Barry B . Snider
Waltham, MA, USA
182
N-ETHYLBENZISOXAZOLIUM TETRAFLUOROBORATE
N-Ethylbenzisoxazolium
Tetrafluoroborate
(2)
[4611-62-5]
C 9 H 10 BF 4 NO
(MW 234.99)
(peptide-coupling reagent;1 reacts with a wide range of nucleophiles to give o-hydroxy-N-ethylbenzamido derivatives2)
Physical Data: mp 109.5-110.2 C.
Solubility: sol acetonitrile; slightly sol dichloromethane; sol aqueous acid (unstable above pH 4).
Form Supplied in: crystalline solid; commercially available.
Preparative Methods: ethylation of benzisoxazole with purified
Triethyloxonium
Tetrafluoroborate.2
Handling, Storage, and Precautions: the salt is reported not to be
hygroscopic, although it etches glass on long exposure to moist
air; should be protected from light; reported to be an irritant.
Peptide Coupling. N-Ethylbenzisoxazolium tetrafluoroborate

(EBF) is used to couple amines and carboxylic acids in a two-stage
procedure. Firstly, EBF reacts with the carboxylic acid to form an
active phenolic ester. Secondly, the active ester reacts with the
amine to form the peptide linkage (eq 1). 3 The procedure for the
formation of the active ester employs a carefully buffered aqueous solution of the Cbz-protected aminoacid (or oligopeptide),
to which an equal volume of ethyl acetate or dichloromethane is
added, followed by 1.1 equiv of finely powdered EBF. The acylsalicylamide ester is isolated from the organic solvent and may
be recrystallized. This product is stable to storage. This procedure does not suffer when used with the sterically demanding
valine or proline residues. The active ester cleanly reacts with
peptide amines in dipolar aprotic solvents, yielding the amide and
N-ethylsalicylamide, which can be removed with alkali or carbon
tetrachloride. The second step is, however, very slow, taking ca.
48 h at room temperature (roughly 20 times slower than the rate of
p-nitrophenyl ester couplings 4 ), and suffers from unwanted sidereactions (Brenner rearrangements5) in the presence of strongly
basic amines such as triethylamine. More seriously, significant
amounts (up to 1-2%) of epimerization may occur.6
(3)
Peptide cyclotrimers have also been prepared in this manner.7,8

After deblocking at nitrogen, a highly dilute solution of the resulting free amine in dry pyridine was stirred for 65 h at room
temperature to give the cyclotrimer in an impressive 90% yield
(eq 4).
cyclo-(Gly-Cys(Bn)-Gly)3
(4)
Detailed mechanistic studies indicate that the N-ethylbenzisoxazolium cation readily undergoes base-catalyzed elimination to form a transitory N-ethylbenzoketoketenimine (eq 5).9
(5)
In the case of reactions with carboxylic acids (X = RCO2), the

initial addition product then rapidly rearranges to the active ester
(eq 6).
(6)
Several hydroxy-,10 nitro-, 3 and chloro-substituted11 Nethylbenzisoxazolium cations have been studied in attempts to
vary the reactivity of the intermediate active ester (see 2-Ethyl-7hydroxybenzisoxazolium
Tetrafluoroborate).
Reactions with Nucleophiles. The N-ethylbenzisoxazolium
cation reacts rapidly in aqueous solution with a range of nucleophiles, yielding o-hydroxy-N-ethylbenzimido
derivatives.
Hydrolysis proceeds smoothly in mild acid, but at pH above 7,
polymeric material is obtained (eq 7). 2
R-CONH-R'(1)
(7)
EBF has been used to prepare peptide cyclodimers in yields

which compare favorably with other procedures.1 For this method,
intermediate Cbz-protected acylsalicylamide esters were hydrogenolyzed to form the free amines which then yielded the
cyclodimers (eqs 2 and 3).
Treatment of EBF with aqueous solutions of simple nucleophiles ( H S - , F - , C N - ) or with methanolic methoxide gives high
yields of the benzimido derivatives (eq 8).
ETHYL CHLOROFORMATE
(8)
Reaction of EBF with cyanate, thiocyanate, and thiourea gen

erates initial adducts which can undergo internal rearrangements.
For example, the adduct of cyanate to EBF yields a cyclic urethane (eq 9); reaction with thiocyanate yields the analogous
thiourethane.2
(9)
1. Rajappa, S.; Akerkar, A. S. TL 1966, 25, 2893.

2. Kemp, D. S.; Woodward, R. B. T 1965, 21, 3019.
3. Kemp, D. S.; Wang, S.-W.; Mollan, R. C ; Hsia, S.-L.; Confalone, P. N.
T 1974, 30, 3677.
4. Kemp, D. S.; Wang, S.-W. JACS 1967, 89, 2745.
5. Kemp, D. S.; Duclos, J. M.; Bernstein, Z.; Welch, W. M. JOC 1971, 36,
157.
6. Kemp, D. S.; Wang, S.-W.; Busby, G., III; Hugel, G. JACS 1970, 92,
1043.
7. Kemp, D. S.; McNamara, P. TL 1981, 22, 4571.
8. Kemp, D. S.; McNamara, P. JOC 1985, 50, 5834.
9. Kemp, D. S. T 1967, 23, 2001.
10. Kemp, D. S.; Chien, S.-W. JACS 1967, 89, 2743.
11. Rajappa, S.; Akerkar, A. S. CC 1966, 826.
Ross R McGeary
183
Handling, Storage, and Precautions: slowly hydrolyzed by wa

ter to CO 2 and HCl; store at cool temperatures: pressure may
develop within bottle; thermal decomposition to CO 2 and EtCl
occurs; highly flammable (fp 2 C); toxic by inhalation and skin
absorption; lachrymatory, irritant; use in a fume hood.
Ethoxycarbonylation of Active Methylene Compounds.

Ethyl chloroformate3 reacts with a wide range of nucleophiles.
Enolates derived by deprotonation of aliphatic and aromatic car
boxylic acids bearing at least one -hydrogen with two equiva
lents of Lithium Diisopropylamide at low temperature in THF
are ethoxycarbonylated to give the monoesters of malonic acids
(eq 1).4 The yields are highest for alkyl carboxylic acids at
78 C. 5 Although higher yielding than with Diethyl Carbon
ate, treatment of the -lithiated esters with Carbon Dioxide fre
quently gives better yields of the malonates. 4,6 Mixed malonates,
especially those derived from bulky alkyl esters, can be similarly
prepared (eq 2). 5
(1)
(2)
-Lithionitriles are ethoxycarbonylated in good yield.7

Acetals 8 and 1,3-dithianes9 are effectively ethoxycarbonylated
(eq 3) if ethyl chloroformate is used as a cosolvent to prevent
side reactions. Ethoxycarbonylation of ketones is achieved when
enamines are treated with ethyl chloroformate, in some cases giv
ing comparable yields to those obtained using metal enolates.10
(3)
Ethyl Chloroformate1
[541-41-3]
C 3 H 5 ClO 2
Enantioselective ethoxycarbonylation has recently been

attempted11 via deprotonation of N-benzylidenebenzylamine with
two equivalents of a chiral lithium amide base and quenching with
ethyl chloroformate; levels of asymmetric induction were low but
higher than those obtained using other chloroformates (eq 4).
(MW 108.52)
(4)
(for ethoxycarbonylation of a wide variety of nucleophiles

including anions of carboxylic acids4 and esters,5 nitriles,7
difhianes,9 ketones, enamines,10 imines, 11 sulfones,12 cuprates,13
stannanes,14 Grignards, 15 alanes,18 furans,17 alkynes;19 acylation of alcohols, 20,22 carbonyls, 23,25 amines, and aziridines;27
cleavage of tertiary amines;32 formation of mixed anhydrides38)
Physical Data: mp - 8 1 C; bp 95 C; d 1.135 g c m - 3 .
Solubility: miscible with benzene, chloroform, diethyl ether,
ethanol; insol water.
Purification: the liquid is washed with water then distilled at at
mospheric pressure using an efficient fractionating column and
CaCl2 guard tube. 2
Ethoxycarbonylation of Vinyl Anions. ,-Unsaturated sul

fones are -ethoxycarbonylated (eq 5) on deprotonation with nButyllithium in THF at - 7 8 C and quenching with this reagent.12
(5)
Vinyl cuprates under Pd catalysis give ,-alkenic esters

(eq 6). 13 Aryl, vinyl, and heterocyclic stannanes14 react smoothly
184
ETHYL CHLOROFORMATE
0
under Pd catalysis at 100 C to give ethyl esters (eq 7) in good

yields if the catalyst and chloroformate are added to the reaction
mixture slowly. A wide variety of functionality on tin is toler
ated but allylstannanes are generally low yielding. Use of isobutyl
chloroformate improves the yields in these acylcarbonylations.
(O)
(7)
Ethyl esters are produced from Grignard reagents15 if the
organometallics are not present in excess. This is also the ba
sis of the 5-ethoxycarbonylation of 2,4-dimethylpyrrole.16 2Lithiofurans are ethoxycarbonylated in good yield (eq 8).17
(8)
Trans-,-unsaturated esters can be prepared by ethoxycarbonylation of vinylalanes derived from terminal alkynes bearing
primary, secondary, or tertiary alkyl substituents without the ne
cessity of forming an intermediate ate complex (eq 9).18 Cis-,unsaturated esters result from ethoxycarbonylation of lithiated
alkynes (eq 10)19 followed by reduction over Lindlar catalyst.
(9)
mon with other amine-derived bases such as LDA. Sodium and

potassium enolates are not useful, generally giving competitive Cacylation. This procedure avoids the use of classical methodology
relying on the use ofHg11salts.
(11)
Trans-l-(l,3-butadienyl) carbamates24 and carbonates25 are

useful dienes in Diels-Alder chemistry. The carbonates are pro
duced when Crotonaldehyde (and its congeners) are deprotonated
and treated at 78 C with ethyl chloroformate (eq 12). Use of
higher temperatures results in loss of some of the (Z) geome
try. Similar treatment of crotonaldehyde imines affords the carba
mates.
(12)
O-Ethylation occurs when the sodium enolates of -formyl and -lactones are refiuxed in THF with ethyl chloroformate.26
N-Ethoxycarbonylation forms the basis of a variety of
reactions of nitrogenous compounds. Aziridines form Nethoxycarbonylaziridines which are converted, on heating, to allylic amines (eq 13).27
(13)
Tertiary amines may be cleaved by ethyl chloroformate in cer

tain circumstances. N-Demethylation has been noted. For exam
ple, tropine acetate (eq 14) is readily converted to nortropine
hydrochloride28 on refluxing with ethyl chloroformate and sub
sequent acid-mediated hydrolysis of the intermediate urethane.
(14)
(10)
O-, N-, and S-Acylations. O-Ethoxycarbonylation is ob

served in some instances. Aliphatic alcohols, phenols,20 and
cyanohydrins21 react in the presence of tertiary amines to give
carbonates. Equatorial oriented steroid hydroxyls are selectively
acylated in the presence of axial hydroxyl groups.22 Enol carbon
ates (eq 11)23 are readily derived from ketones by formation of
the lithium enolate using Lithium 2,2,6,6-Tetramethylpiperidide
in THF/HMPA at -78 C followed by an ethyl chloroformate
quench at room temperature. The use of HMPA prevents competi
tive C-acylation. LiTMP is necessary to avoid side reactions com
Reductive C-N bond cleavage has been demonstrated in more

complex systems using ethyl chloroformate as a solvent.29 Chlorination of corticosteroid cyclic ethers has been observed.30 Tertiary
aliphatic and alicyclic amines can be dealkylated.31 Phenyl chlo
roformate, however, is usually regarded as the reagent of choice. In
summary, deamination, demethylation, debenzylation, and deallylation of tertiary amines can all occur on treatment with ethyl
chloroformate but the regioselectivities of these reactions are dif
ficult to predict.32
Imides (e.g. phthalimide) are ethoxycarbonylated if the potas
sium salt is treated with ethyl chloroformate at 5-10 C. At ele
vated temperatures (60-110 C) the lithium salts are N-ethylated
in high yield. N-Alkylation also occurs with other imide systems
ETHYL CHLOROFORMATE
185
33
such as barbiturates, hydantoins, and succinimides. Thiols give

the corresponding monothiocarbonates.34 Thioamides form ethyl
imidates35 and cyclic iminoethers36 are obtained from thiolactams
on mild warming with ethyl chloroformate. Sulfidc and sulfonic
acids yield their ethyl esters.37
Mixed Anhydrides. The preparation of mixed anhydrides
from ethyl chloroformate and carboxylic acids enables coupling of
peptides and amino acids.38 This coupling procedure has largely
been superseded by more effective methods relying on the use of
superior reagents; see 1,3-Dicyclohexylcarbodiimide (DCC) and
1-Hydroxybenzotriazole (HOBT).
Ethyl chloroformate enables the one-step cyclization of pep
tides (eq 15),39 yields generally being superior to those obtained
if Bis(2,4-dinitrophenyl) Carbonate is used. However, Isobutyl
Chloroformate/N-methylmorpholine is now the reagent of choice
for many solution-phase anhydride couplings.40
(17)
(Z)-Ethylenic mixed anhydrides are easily prepared with

out isomerization and react with vinyl cuprates (and other
organometallics) under Pd0 catalysis with >99% stereochemical
control to give unsymmetrical divinyl ketones (eq 18).13 Alterna
tive routes via (Z)-ethylenic acyl chlorides produce (E/Z) mixtures.
(18)
(15)
Miscellaneous. -Cyanoesters (eq 19)48 are produced from (3amido acids providing that the acid and amide functionality are
sufficiently close to enable formation of a cyclic intermediate.
N-Protected amino acids and peptides are rapidly converted to
the corresponding amino alcohols in high yields with complete
retention of optical purity via reduction of the mixed anhydride
by cold Sodium Borohydride in THF with dropwise addition of
methanol (eq 16).41 The disulfide bridges of cystine, the methyl
and benzyl esters of -carboxyl-protected glutamic and aspartic
acids of peptides, and N-Cbz andN-Bocprotection are compatible
with the methodology. The anhydrides derived from ethyl chlo
roformate are superior to isobutyl and benzyl carbonates both in
terms of yield and retention of optical purity.
(16)
Carboxylic acid triethylamine salts yield mixed anhydrides

which, when treated with ethoxymagnesiomalonic esters give the
benzoylated malonate.42 Alternatively, treatment of the mixed an
hydrides with sodium tetracarbonylferrate(II) produces the alde
hyde derived from the parent aliphatic or aromatic carboxylic acid
in good yield.43
Formation of mixed anhydrides also provides the basis for
the synthesis of acyl azides (eq 17)44 and hence amines via
the Curtius rearrangement. The azide ion is usually delivered
to the most electrophilic carbonyl,45 but steric considerations
may be important. The method is applicable even to strained
cyclopropyl- and cyclobutylcarboxylic acids.46 Diisopropylethylamine (Hunig's base) has been mooted as a superior base for the
formation of mixed anhydrides.47
(19)
Aromatics undergo Friedel-Crafts alkylation in the presence of

Aluminum Chloride, probably due to the formation of EtCl in
situ.49
Ethyl chloroformate has been used to moderate reactivity in
polymerizations. For example, PVC with good thermal stability
is prepared in the presence of this reagent.50
1. Matzner, M.; Kurkjy, R. P.; Cotter, R. J. CRV 1964, 64, 645.

2. Hamilton, C. S.; Sly, C. S. JACS 1925, 47, 435; Saunders, J. H.;
Slocombe, R. J.; Hardy, E. E. JACS 1951, 73, 3796.
3.
Cappelli, G. G 1920,50, 8 (CA 1921,15, 524).
4.
5.
6.
Krapcho, A. P.; Jahngen, E. G. E.; Kashdan, D. S. TL 1974, 15, 2721.

Brocksom, T. J.; Petragnani, N.; Rodrigues, R. JOC 1974, 39, 2114.
Reiffers, S.; Wynberg, S.; Strating, J. TL 1971, 12, 3001.
7.
Albarella, J. P. JOC 1977, 42, 2009.
8. Truce, W. E.; Roberts, F. E. JOC 1963, 28, 961.

9. Seebach, D.; Corey, E. J. JOC 1975, 40, 231; Corey, E. J.; Erickson, B.
W. JOC 1971, 36, 3553.
10. Stork, G.; Brizzdara, A.; Landesman, H.; Szmuszkovic, J.; Terrell, R.
JACS 1963, 85, 207.
11. Duhamel, L.; Duhamel, P.; Fouguay, S.; Eddine, J. J.; Peschard, O.;
Plaguevent, J.-C.; Ravard, A.; Soilard, R.; Valnol, J.-Y.; Vincens, H. T
1988, 44, 5495.
12.
13.
Alcaraz, C.; Carretero, J. C.; Dominguez, E. TL 1991, 32, 1385.

Jabri, N.; Alexakis, A.; Normant, J. F. T 1986, 42, 1369.
186
1-ETHYL-3-(3'-DIMETHYLAMINOPROPYL)CARBODIIMIDE HYDROCHLORIDE
14. Balas, L.; Jousseaume, B.; Shin, H.-A.; Verlhac, J.-B.; Wallian, F. OM
1991, 10, 366.
15. Gold, J. R.; Sommer, L. H.; Whitmore, F. C. JACS 1948, 70, 2874;
Warrener, R. N.; Cain, E. C. AJC 1971, 24, 785.
16. Fischer, H. OSC 1943, 2, 198.
17. Martin, S. F.; Zinke, P. W. JOC 1991, 56, 6600.
18.
19.
20.
21.
22.
Zweifel, G.; Lynd, R. A. S 1976, 625.

Taschner, M. J.; Rosen, T.; Heathcock, C. H. OSC 1990, 7, 226.
Claisen.L. CB 1894, 27, 3182.
Davis, O. C. M.JCS 1910, 97, 949.
Fieser, C. F.; Herz, J. E.; Klohs, M. W.; Romero, M. A.; Utne, T. JACS
1952, 74, 3309.
23. Olofson, R. A.; Cuomo, J.; Bauman, B. A. JOC 1978, 43, 2073.
24. Oppolzer, W.; Fostl, W. HCA 1975, 58, 587.
25. DeCusati, P. F.; Olofson, R. A. TL 1990, 31, 1405.
26.
27.
Murray, A. W.; Murray, N. D. SC 1986,16, 853.

Laurent, A.; Mison, P.; Nafti, A.; Cheikh, R. B.; Chaabouni, R. JCR(M)
1984,3164.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
Kraiss, G.; Nador, K. TL 1971, 12, 57.

Hanoaka, M.; Nagami, K.; Imanishi, T. H 1979, 12, 497.
Sugal, S.; Akaboshi, S.; Ikagami, S. CPB 1983, 31, 12.
Hobson, J. D.; McCluskey, J. G. JCS(C) 1967, 2015.
Kapnang, H.; Charles, G. TL 1983, 24, 3233.
Vida, J. A. TL 1972, 13, 3921.
Saloman, F. JPR 1873, 6, 433.
Snydam, F. H.; Greth, W. E.; Langerman, N. R. JOC 1969, 34, 292.
Mohacsi, E.; Gordon, E. M. SC 1984, 14, 1159.
Etienne, A.; Vincent, J.; Lonchambon, G. CR(C) 1970, 270, 841.
Greenstein, J. P.; Winitz, M. The Chemistry ofAmino Acids; Wiley: New
York, 1961; Vol. 2, pp 978-981. See also Vaughn, J. R., Jr. JACS 1951,
73, 3547; Boissonnas, R. A. HCA 1951, 34, 874; Wieland, T.; Bernhard,
H. LA 1951, 572, 190.
39.
40.
Wieland, T.; Faesal, J.; Faustich, H. LA 1968, 713, 201.

Kopple, K. D.; Renick, K. J. JOC 1958, 23, 1565; Merrifield, R. B.;
Mitchell, A. R.; Clarke, J. E. JOC 1974, 39, 660.
Kokotos, G. S 1990, 4, 299.
41.
42.
43.
Price, J. A.; Tarbell, D. S. OSC 1963, 4, 285.

Watanabe, Y.; Yamashita, M.; Mitsudo, T.; Igami, M.; Temi, K.;
Takegami, Y. TL 1975, 16, 1063; Watanabe, Y.; Yamashita, M.; Mitsudo,
T.; Igami, M.; Takegami, Y. BCJ 1975, 48, 2490.
44. Kaiser, C ; Weinstock, J. OS 1971, 51, 48.

45. Weinstock, J. JOC 1961, 26, 3511.
46. Finkelstein, J.; Chiang, E.; Vane, F. M.; Lee, J. JMC 1966, 9, 319.
47. Jessup, R. J.; Petty, C. B.; Roos, J.; Overman, L. E. OS 1979, 59, 1.
48. Sauers, C. K.; Cotter, R. J. JOC 1961, 26, 6.
49. Freidel, C ; Crafts, J. A. LA 1884, 1, 527; see also The Chemistry
of Functional GroupsThe Chemistry of Acyl Halides; S. Patai, Ed.;
Interscience: New York, 1972.
50.
l-Ethyl-.3-(3'-dimethylaminopropyl)
carbodiimide Hydrochloride1
[25952-53-8]
(base)
[1892-57-5]
(MeI)
[22572-40-3]
C 8 H 18 ClN 3
(MW 191.74)
(peptide coupling reagent;1b,2 amide formation;3 ester

formation;4 protein modification;5 mild oxidations of primary
alcohols6)
Alternate Name:
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide; water-soluble carbodiimide; EDC; EDCI.
Physical Data: free base is an oil, bp 47-48 C/0.27 mmHg; HC1
salt is a white powder, mp 111-113 C; Mel salt mp 97-99 C.
Solubility: sol H 2 O, CH 2 Cl 2 , DMF, THE
Form Supplied in: commercially available as HC1 salt and as methiodide salt that are white solids. Reagents are >98% pure;
main impurity is the urea that can form upon exposure to mois
ture.
Analysis of Reagent Purity: IR: 2150 c m - 1 (N=C=N stretch);
urea has C=O stretch near 1600-1700 c m - 1 .
Purification: recrystallization from CH 2 Cl 2 /ether.
Handling, Storage, and Precautions: EDC is moisture-sensitive;
store under N 2 in a cool dry place. It is incompatible with strong
oxidizers and strong acids. EDC is a skin irritant and a contact
allergen; therefore avoid exposure to skin and eyes.
Peptide Coupling Reagent. This carbodiimide (EDC) reacts

very similarly to 1,3-Dicyclohexylcarbodiimide
and other carbodiimides. The advantage EDC has over DCC is that the urea
produced is water soluble and, therefore, is easily extracted. Dicyclohexylurea is only sparingly soluble in many solvents and is
removed by filtration which may not be as effective as extrac
tion. A typical example of EDC for peptide coupling is shown in
(eq l). 2
CA 1984, 100, 175 541n.
Andrew N. Payne
(1)
The problems associated with carbodiimide couplings are

mainly from the O-acylisourea intermediate (1) having poor selecLists of Abbreviations and Journal Codes on Endpapers
1-ETHYL-3-(3'-DIMETHYLAMINOPROPYL)CARBODIIMIDE HYDROCHLORIDE
tivity for specific nucleophiles. This intermediate can rearrange to
an N-acylurea (2), resulting in contamination of the product and
low yields. Additionally it can rearrange to 5(4H)-oxazolones (3)
that tautomerize readily, resulting in racemization. Using low di
electric solvents like CH 2 Cl 2 or additives to trap (1) minimizes
these side reactions by favoring intermolecular nucleophilic at
tack on (1). 1b
187
Another method for formylation of amines is with p-nitrophenyl

formate, which usually gives products in high yield. However,
removing the last traces of the p-nitrophenol is difficult.12
(3)
Treating carbon dioxide and amines with EDC gives symmet

rical ureas (eq 4). 13 DCC with CO 2 at ambient pressure works
equally well.
R = carbodiimide chain; R1 = amino acid; R2 = amino acid side
chain; R3 = NH protecting group
(4)
When low dielectric constant solvents are used, the carboxylic

acid tends to dimerize, thus promoting symmetrical anhydride for
mation. This intermediate is stable enough to give good yields of
the desired product. High dielectric solvents such as DMF re
tard acylation of amino acids, and N-acylurea can be a major
byproduct. 1b Unfortunately, many starting materials require polar
solvents for dissolution.
Addition of trapping agents such as N-Hydroxysuccinimide7
and 1-Hydroxybenzotriazole (HOBt) 8 reduce the extent of many
side reactions, especially N-acylurea formation. Also, racemiza
tion is suppressed when these additives are present. The latter
reagent eliminates the intramolecular dehydration of co-amides of
asparagine and glutamine that occurs with carbodiimides (eq 2). 8,9
(2)
With EDC the addition of Copper(II) Chloride suppresses

racemization to <0.1% compared to 0.4% with HOBt under ideal
conditions.10 Combinations of HOBt and CuCl2 are also useful.10b
The suggested stoichiometry for the highest optical purity and
yield is 2 equiv of HOBt and 0.25-0.5 equiv of CuCl 2 in DMF.
A practical example of EDC's utility is the solution synthesis
of human epidermal growth factor, a 53-residue protein.11 This
included several couplings of fragments ranging from three to six
residues in length. All couplings were performed with EDC/HOBt
in DMF or NMP. At the completion of the synthesis, no racemized
material could be detected by HPLC.
Amide Formation. Formylated amino acids and peptides are
prepared in high yields by forming the acid anhydride (eq 3). 3
These products are pure without requiring chromatography or recrystallization.
EDC facilitates the synthesis of xanthine analogs by condensing

a diamine with water-soluble acids (eq 5). 14 The use of water as
the solvent precludes the use of DCC in this case.
(5)
Ester Formation. Esters of N-protected amino acids are pre

pared in high yield with EDC and 4-Dimethylaminopyridine
(eq 6). 4 DMAP causes extensive racemization if not used in a
catalytic amount.15 However, when esterifying the -carboxyl of
- and --benzyl esters of aspartyl and glutamyl derivatives, ex
tensive racemization was observed even with DMAP present in
catalytic amounts. It is postulated that the side-chain esters con
tribute in some fashion to the lability of the -H.
(6)
R1 = t-Bu, 76%; Me, 96%; CH2CCl3, 87%
Carbodiimides including EDC are also useful in preparing ac

tive esters such as the p-nitrophenyl, pentafluorophenyl, and Nhydroxysuccinimide esters. 1b Numerous additional methods have
been reported.16
Protein Modification. Carboxyl groups in proteins react with
EDC, resulting in an activated group that can be trapped with a
nucleophile such as glycine methyl ester.5 The nucleophile can
188
ETHYLENE GLYCOL
also be amino groups in the protein, causing cross-linking. Appli

cations for carboxylate modification include determining which
groups are buried versus exposed, and mechanistic studies for de
termining which carboxyl groups are essential for an enzyme's
activity.
EDC is used extensively in cross-linking proteins to solid sup
ports for affinity chromatography.17
diimidazole; 1 -Cyclohexyl-3-(2-morpholinoethyl)carbodiimide;
1,3-Dicyclohexylcarbodiimide;
Diphenyl Phosphorazidate;
Di-p-tolylcarbodiimide;
N-Ethyl-5-phenylisoxazolium-3'sulfonate; 1-Hydroxybenzotriazole; Isobutyl Chloroformate;
1,1'-Thionylimidazole.
1.
Oxidation of Primary Alcohols. One example of EDC sub

stituting for DCC in the Pfitzner-Moffatt oxidation is shown in
(eq 7).6 The use of DCC in this example resulted in a difficult
purification of the product and lower yields.
(7)
Miscellaneous Reactions. EDC is a useful water scavenger as

well. An example of this utility is given in (eq 8).18 The carbodiimide is required in this reaction, but DCC does not work well in
this transformation.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
(8)
12.
13.
14.
Another example of EDC having a marked improvement over

DCC is the formation of cyanoguanidines (eq 9).19 This was orig
inally attempted with DCC, which gives poor yields even after
extended reaction times. It is thought the positively charged ni
trogen in EDC facilitates the C-S bond cleavage and since DCC
lacks this atom the reaction goes slowly.
15.
(9)
Pyrroles are formed when acetylenes undergo cycloadditions

with N-acylamino acids in the presence of EDC.20 An Nalkenylmunchnone azomethine ylide is generated in situ and is
trapped by the dipolaraphile. Loss of CO2 yields the pyrrole
(eq 10).
16.
17.
18.
19.
20.
(a) Kurzer, F.; Douraghi-Zader, K. CRV 1967, 67, 107. (b) Rich, D. H.;
Singh, J. The Peptides: Analysis, Synthesis, Biology; Academic: New
York, 1979; Vol. 1, pp 241-261.
Sheehan, J. C ; Ledis, S. L. JACS 1973, 95, 875.
Chen, F. M. F.; Benoiton, N. L. S 1979, 709.
Carraway, K. L.; Koshland, Jr., D. E. Methods Enzymol. 1972, 25,
616.
Ramage, R.; MacLeod, A. M.; Rose, G. W. T 1991, 47, 5625.
Wuensch, E.; Drees, F. CB 1966, 99, 110.
Gish, D. T.; Katsoyannis, P. G.; Hess, G. P.; Stedman, R. J. JACS 1956,
78, 5954.
(a) Miyazawa, T.; Otomatsu, T.; Yamada, T.; Kuwata, S. TL 1984, 25,
771. (b) Miyazawa, T.; Otomatsu, T.; Fukui, Y.; Yamada, T.; Kuwata, S.
CC 1988, 419.
Hagiwara, D.; Neya, M.; Miyazaki, Y.; Hemmi, K.; Hashimoto, M. CC
1984, 1676.
Okawa, K.; Hase, S. BCJ 1963, 36, 754.
Ogura, H.; Takeda, K.; Tokue, R.; Kobayashi, T. S 1978, 394.
Shamim, M. T.; Ukena, D.; Padgett, W. L.; Daly, J. W. JMC 1989, 32,
1231.
Atherton, E.; Benoiton, N. L.; Brown, E.; Sheppard, R. C ; Williams, B.
J. CC 1981, 336.
Greene, T. W. Protective Groups in Organic Synthesis, Wiley: New York,
1981; pp 154-180.
Keeton, T. K.; Krutzsch, H.; Lovenberg, W. Science 1981, 211,
586.
Tarn, T. F.; Thomas, E.; Kruntz, A. TL 1987, 28, 1127.
Atwal, K. S.; Ahmed, S. Z.; O'Reilly, B. C. TL 1989, 30, 7313.
Anderson, W. A.; Heider, A. R. SC 1986, 357.
Marion Merrell Dow Research Institute,
University
Related
Reagents. Benzotriazol-l-yloxytris(dimethylamino)phosphonium Hexafluorophosphate; N,N' -CarbonylLists of Abbreviations and Journal Codes on Endpapers
Peter Szeto
of Bristol, UK
Ethylene Glycol1
[107-21-1]
(10)
Richard S. Pottorf
Cincinnati, OH, USA
C2H6O2
(MW 62.08)
(formation of acetals;1 stereoselective aldol reactions;2 solvent

for Diels-Alder reaction;3 solvent for Fischer indole reaction;4
preparation of tertiary alcohols from trialkylboranes5)
Alternate Name: ethane-1,2-diol.
Physical Data: bp 197 C; d 1.11 g cm -3 .
ETHYLENE GLYCOL
Solubility: completely sol H 2 O, low MW alcohols, acetone; insol
benzene, chlorinated hydrocarbons.
Handling, Storage, and Precautions: harmful or fatal if swal
lowed. Prolonged or repeated breathing of vapor harmful.
Causes eye irritation. May cause kidney and nervous system
damage. Causes birth defects in laboratory animals. Use in a
fume hood.
Acetal Formation.1 The dioxolane group is one of the most

widely used protecting groups for carbonyl compounds. Dioxolanes are generally stable to bases, Grignard reagents, alkyl
lithium reagents, metal hydrides, Na/NH 3 , Wittig reagents, hydrogenation conditions, oxidants, and bromination and esterification reagents.1 This wide range of stability has been espe
cially useful in steroid synthesis.6 The ease of formation of
dioxolanes roughly follows the order: aldehydes > acyclic ke
tones and cyclohexanones>cyclopentanones> ,-unsaturated
ketones > -mono- and disubstituted ketones aromatic ketones.
Ketones generally require stronger acids than aldehydes, such as
sulfuric, hydrochloric, or TsOH. 7 - 1 1 A typical protection proce
dure involves heating a benzene or toluene solution of the ketone
and p-Toluenesulfonic Acid (eq 1).9 Alternatively, a Lewis acid
catalyst, such as Boron Trifluoride Etherate12-14 may be used
(eqs 2 and 3). 13,14
(1)
189
(5)
Many procedures have also been developed for acid-sensitive

compounds. Use of either adipic 25 or Oxalic Acid16 gives good
yields of sensitive steroid 4-3-ethylene acetals. Selenium(IV)
Oxide has also been used effectively for steroid acetalization
(eq 6). 27
(6)
Pyridinium salts are mild catalysts for ethylene acetal

formation. 28-31 Pyridinium p-Toluenesulfonate (PPTS) cat
alyzes acetal formation with less than 4% epimerization, whereas
use of TsOH led to 34% epimerization (eq 7). 30
(7)
The use of a hindered pyridinium salt, such as 2,4,6Collidinium p-Toluenesulfonate (CTPS), allows acetalization of
,-unsaturated ketones in the presence of saturated carbonyl sys
tems (eq 8). 31
(2)
(8)
(3)
Water removal can be accomplished by using Dean-Stark

distillation,15 molecular sieves,16 CaSO 4 , 17 CuSO 4 , 18 or water
scavengers such as Triethyl Orthoformate19-21 or dialkyl sulfites
(eq4). 22
(4)
Compounds that are stable under strongly acidic conditions

can be derivatized using a mixture of ethylene glycol and HC1
(eq 5). 23,24
N,N-DimethylformamidelDimethyl Sulfate is another mild ac

etalization catalyst.32 Metal catalysts, such as Rh complexes 33 and
Palladium on Carbon1a have also been used effectively (eqs 9
and 10). Ion-exchange resins offer significant advantages for the
preparation of sensitive steroid acetals (eq 11).34 An especially
convenient method involves running a solution of the ketone and
ethylene glycol through a column of Amberlyst.35 Zeolites have
also been used to prepare acetals.36
(9)
190
ETHYLENE GLYCOL
(10)
pared from BCl3 and ethylene glycol, has been used for stereo
selective aldol reactions with aliphatic and aromatic aldehydes
(eq 16).2
(16)
(11)
Ketones that react slowly under normal acetalization conditions

can be converted into dioxolanes at high pressure (eq 12).37 A pro
cedure has also been developed for the dioxolanation of ketones
in the presence of aldehydes using a bis-silyl ether of ethylene
glycol (eq 13).38 The selective acetalization of aldehydes in the
presence of ketones has been accomplished using ethylene glycol
and alumina or silica gel.39
(12)
(13)
In addition to their use as protecting groups, dioxolanes have

been employed as intermediates. One example is a ring expansion
of cyclopentanones via Grob fragmentation of the acetal (eq 14).40
A novel synthesis of glycerol from formaldehyde and ethylene
glycol involves dioxolane intermediates.41
Solvent Effects.1d Ethylene glycol is an excellent solvent for

many reactions and its high boiling point (197.6 C) and low freez
ing point (13 C) permit a wide range of operating temperatures.
Both NaOH and KOH are very soluble in ethylene glycol. Exam
ples are the hydrolysis of t-butylurea,44 the dehydrochlorination of
monovinylacetylene,45 and the Wolff-Kishner deoxygenation.46
Dehydroxylations of (R,R)-tartrates with Samarium(II) Iodide
are best accomplished in ethylene glycol.47 The conversion of
alkyl bromides to alkyl fluorides has been carried out in ethylene
glycol.48 Removal of the acetonide group can be accelerated by
substituting ethylene glycol for H2O.49 The Fischer indole syn
thesis can be performed without the addition of an acid catalyst by
heating a phenylhydrazone in ethylene glycol.4,50 Ethylene gly
col has also been used as a substrate for the synthesis of indoles
and other heterocycles.51 The Ru complex catalyzed reaction of
substituted anilines and ethylene glycol offers an alternative route
to the indoles under milder conditions than conventional methods
(eq 17).51a,b
(17)
Ethylene glycol is superior to benzene, MeCN, DMSO, MeOH,

and H2O for the Diels-Alder reaction involving relatively hy
drophobic dienes and dienophiles. The increased reaction rate in
ethylene glycol is attributed to the improved aggregation of the
diene and dienophile (eq 18).3
(14)
(18)
Dioxolane formation is not limited to aldehydes and ketones.

Amide acetals have been prepared directly and by the alcohol
interchange method (eq 15).42
(15)
The interchange of carbonyl protecting groups can be quite

valuable in organic synthesis. For example, replacing a thioacetal with an acetal would allow a subsequent oxidation or hydrogenation which is not possible in the presence of a sensitive
sulfur-containing group. Reacting the thioacetal with MeOSO2F,
followed by treatment with ethylene glycol, achieves this transfor
mation under mild conditions.43 Ethylene Chloroboronate, pre
The synthesis of tertiary alcohols from trialkylboranes and CO

at 100-150 C has been improved in the presence of ethylene
glycol5,52-54 (eq 19).54a The purpose of the ethylene glycol is to
trap the intermediate boronic anhydride, which can form a poly
mer that is difficult to oxidize.
(19)
Related Reagents. 3-Bromo-l,2-propanediol; 2,3-Butanediol; 2,2-Dimethyl-l,3-propanediol; 2-Methoxy-1,3-dioxolane;
W-ETHYL-5-PHENYLISOXAZOLIUM-3'-SULFONATE
(2R,4R)-2,4-Pentanediol; 1,3-Propanediol; Triethyl Orthoformate.
40.
Sakai, K. CA 1992, 117, 130 946h.
41.
Sanderson, J. R.; Lin, J. J.; Duranleau, R. G.; Yeakey, E. L.; Marquis, E.

T. JOC 1988, 53, 2859.
Bredereck, H.; Sinchen, G; Rebstat, S.; Kantlehner, W.; Horn, P.; Wohl,
R.; Hoffman, H.; Grieshaber; P. CB 1968, 101, 41.
42.
1. (a) Meskens, A. J. S 1981, 501. (b) Greene, T. W. Protective Groups
in Organic Synthesis; Wiley: New York, 1981. (c) McOmie, J. F. W.
Protective Groups in Organic Chemistry; Plenum: New York, 1973. (d)
Fieser, L. F.; Fieser, M. FF 1967, 1, 375.
2.
3.
4.
5.
(a) Gennari, C.; Colombo, L.; Poli, G. TL 1984, 25, 2279. (b) Gennari,
C.; Cardani, S.; Colombo, L.; Scolastico, C. TL 1984, 25, 2283.
Dunams, T.; Hoekstra, W.; Pentaleri, M.; Liotta, D. TL 1988, 29, 3745.
Fitzpatrick, J. T.; Hiser, R. D. JOC 1957, 22, 1703.
Brown, H. C. ACR 1969, 2, 65.
(a) Loewenthal, H. J. E. T 1959, 6, 269. (b) Keana, J. F. W. Steroid

Reactions; Djerassi, C.,Ed.;Holden-Day: San Francisco, 1963; pp 1-87.
7. Salmi, E. J. CB 1938, 71, 1803.
8. Sulzbacher, M ; Bergmann, E.; Pariser, E. R. JACS 1948, 70, 2827.
9. Johnson, W. S.; Rogier, E. R.; Szmuszkovicz, J.; Hadler, H. I.; Ackerman,
J.; Bhattacharyya, B. K.; Bloom, B. M.; Stalmann, L.; Clement, R. A.;
Bannister, B.; Wynberg, H. JACS 1956, 78, 6289.
10. Campbell, J. A.; Babcock, J. C ; Hogg, J. A. JACS 1958, 80, 4717.
11. Daignault, R. A.; Eliel, E. L. OSC 1973, 5, 303.
43.
Corey, E. J.; Hase, T. TL 1975, 3267.
44.
45.
Pearson, D. E.; Baxter, J. F.; Carter, K. N. OSC 1955, 3, 154.

Hennion, G. F.; Price, C. C ; McKeon, T. F., Jr. OSC 1963, 4, 683.
46.
Georgiadis, M. P.; Tsekouras, A.; Kotretsou, S. I.; Haroutounian, S. A.;

Polissiou, M. G. S 1991, 929.
47.
48.
Kusuda, K.; Inanaga, J.; Yamaguchi, M. TL 1989, 30, 2945.

Vogel, A. I.; Leicester, J.; Macey, W. A. T. OSC 1963, 4, 525.
49.
Hampton, A.; Fratantoni, J. C.; Carroll, P. M.; Wang, S. JACS 1965, 87,
5481.
50.
51.
Borch, R. F.; Newell, R. G. JOC 1973, 38, 2729.

(a) Tsuji, Y.; Huh, K.-T.; Watanabe, Y. JOC 1987, 52, 1673. (b) Tsuji,
Y.; Huh, K.-T.; Watanabe, Y. TL 1986, 27, 377. (c) Kondo, T.; Kotachi,
S.; Watanabe, Y. CC 1992, 1318.
52.
(a) Hillman, M. E. D. JACS 1962, 84, 4715. (b) Hillman, M. E. D. JACS

1963, 85, 982.
(a) Puzitskii, K. V.; Pirozhkov, S. D.; Ryabova, K. G.; Pastukhova, I. V.;
Eidus, Ya. T. BAU 1972, 21, 1939. (b) Puzitskii, K. V.; Pirozhkov, S. D.;
Ryabova, K. G.; Pastukhova, I. V.; Eidus, Ya. T. BAU 1973, 22, 1760.
6.
12. Fieser, L. F.; Stevenson, R. JACS 1954, 76, 1728.

13. Engel, C. R.; Rakhit, S. CJC 1962, 40, 2153.
14. Swenton, J. S.; Blankenship, R. M.; Sanitra, R. JACS 1975, 97, 4941.
15. Sakane, K.; Otsuji, Y.; Imoto, E. BCJ 1974, 47, 2410.
16. Roelofsen, D. P.; van Bekkum, H. S 1979, 419.
17. Stenberg, V. I.; Kubik, D. A. JOC 1974, 39, 2815.
18. Hanzlik, R. P.; Leinwetter, M. JOC 1978, 43, 438.
19. Caserio, F. F., Jr.; Roberts, J. D. JACS 1958, 80, 5837.
20. (a) Marquet, A.; Dvolaitzky, M.; Kagan, H. B.; Mamlok, L.; Ouannes,
C; Jacques, J. BSF 1961, 1822. (b) Marquet, A.; Jacques, J. BSF 1962,
90.
21. Doyle, P.; Maclean, I. R.; Murray, R. D. H.; Parker, W.; Raphael, R. A.
JCS 1965, 1344.
22.
23.
24.
Hesse, G.; Frderreuther, M. CB 1960, 93, 1249.

Vogel, E.; Schinz, H. HCA 1950, 33, 116.
Howard, E. G.; Lindsey, R. V., Jr. JACS 1960, 82, 158.
25.
(a) Brown, J. J.; Lenhard, R. H.; Bernstein, S. E 1962, 18, 309. (b) Brown,
J. J.; Lenhard, R. H.; Bernstein, S. JACS 1964, 86, 2183.
Andersen, N. H.; Uh, H.-S. SC 1973, 3, 125.
Oliveto, E. P.; Smith, H. Q.; Gerald, C ; Weber, L.; Rausser, R.;
Hershberg, E. B. JACS 1955, 77, 2224.
26.
27.
28.
Rausser, R.; Lyncheski, A. M.; Harris, H.; Grocela, R.; Murrill, N.;
Bellamy, E.; Ferchinger, D.; Gebert, W.; Herzog, H. L.; Hershberg, E.
B.; Oliveto, E. P. JOC 1966, 31, 26.
29.
Bond, F. T.; Stemke, J. E.; Powell, D. W. SC 1975, 5, 427.
30.
Sterzycki, R. S 1979, 724.
31.
32.
33.
Nitz, T. J.; Paquette, L. A. TL 1984, 25, 3047.

Kantlehner, W.; Gutbrod, H.-D. LA 1979, 1362.
Ott, J.; Tombo, G. M. R.; Schmid, B.; Venanzi, L. M.; Wang, G.; Ward,
T. R. TL 1989, 30, 6151.
Jones, E. R. H.; Meakins, G. D.; Pragnell, J.; Mller, W. E.; Wilkins, A.
L. JCS(Pl) 1979, 2376.
Dann, A. E.; Davis, J. B.; Nagler, M. J. JCS(Pl) 1979, 158.
34.
35.
36.
37.
38.
39.
Corma, A.; Climent, M. J.; Hermenegildo, C ; Primo, J. CA 1990, 113,

61 675x.
Dauben, W. G.; Gerdes, J. M.; Look, G. C. JOC 1986, 51, 4964.
Kim, S.; Kim, Y. G.; Kim, D.-i. TL 1992, 33, 2565.
Kamitori, Y.; Hojo, M.; Masuda, R.; Yoshida, T. TL 1985, 26, 4767.
191
53.
54.
(a) Brown, H. C ; Rathke, M. W. JACS 1967, 89, 2737. (b) Negishi, E.;
Brown, H. C. OS 1983, 61, 103.
W. Christopher Hoffman
Union Carbide, South Charleston, WV, USA
iV-Ethyl-5-phenylisoxazolium-3'sulfonate1
[4156-16-5]
C 11 H 11 NO 4 S
(MW 253.30)
(coupling reagent for peptide synthesis;2 protein modification;3

reduction of carboxylic acids into alcohols4)
Alternate Names: Woodward's reagent K; NEPIS.
Physical Data: mp 206-208 C (dec); UV max () 283 nm
(22500) in 0.1 N HCl.
Solubility: insol MeCN, MeNO2, DMF, CH2C12; sol H2O.
Form Supplied in: crystalline, anhydrous zwitterion; widely avail
able as 95% pure that may contain some of the para sulfonate
derivative.
Analysis of Reagent Purity: material that is sufficiently pure has
mp 206-208 C.
Purification: dissolve in aqueous 1N HC1 and reprecipitate by the
slow addition of acetone. Afterfiltrationand drying the reagent
is a fluffy solid.
192
N-ETHYL-5-PHENYLISOXAZOLIUM-3'-SULFONATE
Handling, Storage, and Precautions: stable to light and tempera

ture and nonhygroscopic. No extra precautions need to be ob
served.
Peptide Coupling Reagent. Woodward's reagent K reacts

with an N-protected amino acid, under mild conditions, in the
presence of a tertiary amine to form an enol ester intermediate,
e.g. (1). This enol ester acylates an amino acid ester or peptide
to afford the elongated peptide derivative (eq 1). The isoxazolium
salt is not soluble in organic solvents, but as it reacts with a carboxyl group in the presence of a tertiary amine the reaction mixture
clears.
(1)
Examples of di- and tripeptide couplings abound with yields

typically >80%; minimal purification steps are required since the
byproducts are water soluble (eq 2). 2
(3)
Several studies7 on the extent of racemization with peptide cou

pling reagents have been published. This generally is a problem
when performing a fragment condensation, but normally not a
problem when the amino group is protected as a carbamate. For
best control of the extent of racemization, accurate measurement
of the tertiary amine is advised.7b The extent of racemization ob
served with reagent K is just a few percent for acylated amino
acids, 7c which is no worse than most coupling reagents except for
the azide coupling procedure. There are some disadvantages of
this reagent in peptide couplings. The most serious one is the lim
itation of solvents. Acetonitrile and nitromethane are the best for
high yield, high optical purity products. However, many peptides
are not readily soluble in these solvents. The next disadvantage is
that the enol ester intermediate can rearrange to the imide sideproduct (3) which is difficult to remove. 1 Another problem with
reagent K is its incompatibility with solid-phase peptide synthesis
because of its poor solubility in organic solvents and relatively
slow activation of carboxyl groups. 8
(2)
(3)
The recommended coupling procedure is to activate the carboxy 1 group in MeNCO2 or MeCN with vigorous stirring for 10
min at rt or 1 h at 0 C. Then the amino ester, dissolved in MeNO 2
or MeCN, is added and the coupling allowed to go at rt for several
hours.
Good yields are obtained in coupling asparagine and glutamine. With some coupling reagents the carboxamide of these
residues can undergo an intramolecular dehydration when the acarboxylate is activated to give a nitrile residue (2) in the peptide.5
However, this byproduct has not been observed with reagent K.
A good comparison of reagent K with other reagents is in

the synthesis of a protected derivative of oxytocin (eq 4). 9 This
product was further elaborated to give oxytocin. The results are
compared with those for 1,3-Dicyclohexylcarbodiimide and N,N'Carbonyldiimidazole in Table 1.
Cbz-Cys(Bn)-Tyr-Ile-Gln-Asn-Cys(Bn)-Pro-Leu-Gly-NH2 (4)
Table 1 Comparison of Coupling Agents for Protected Oxytocin

Coupling method
An additional advantage of reagent K is that when serine, thre

onine, etc., are activated their hydroxyl groups do not require
protection.6 For instance, the hydroxyproline tripeptide in eq 3
was obtained in good yield after crystallization.2
DCC
CDI
Reagent K
a
Yield (%)
80
70.5
85
Mp(C)
225-230
225-230
240-242
Biological activitya
81
50
134
Units mg-1 in avian depressor activity for deprotected and oxidized

nonapeptide.
N-ETHYL-5-PHENYLISOXAZOLIUM-3'-SULFONATE
193
10
An additional utility for reagent K is peptide cyclization. The

activation and cyclization steps are performed separately; there
fore each can be carried out under the appropriate dilution con
ditions. This is advantageous when the carboxyl group activates
slowly since it is in concentrated solution.
The isoxazolium salt has been used in the synthesis of other
difficult peptide structures. A peptidoglycan has been obtained in
good yield by this procedure (eq 5).11
(7)
(5)
Additionally, this reagent has been used repetitively in the syn

thesis of a steroid-peptide adduct with a free hydroxyl group
(eq 6).12 Deprotection and another coupling with Cbz-Arg(NGnitro) gave the dipeptide-steroid adduct in good yield. In both
couplings the steroid hydroxyl group was not acylated.
Another method15 to obtain alcohols is to reduce the mixed

carbonic acid anhydride prepared with Ethyl Chloroformate with
an excess of Sodium Borohydride. This method uses less costly
reagents; thus it is more useful for synthetic transformations.
Miscellaneous Reactions. Pantothenic acid has been coupled
to a long chain amine with reagent K (eq 8).16 This is another
example of the nonreactivity of hydroxyl groups with the enol
ester intermediate. Attempts to prepare this amide through the
mixed anhydride procedure give low yields.
(8)
(6)
Protein Modification. Since this reagent is water soluble and

is reactive under aqueous conditions below pH 4.75, it can specif
ically modify carboxyl groups in proteins.3,13 This has proven
useful in determining essential carboxyl groups in various en
zymes. The enol ester is stable enough to isolate the modified
protein and 'tag' with a nucleophile for eventual identification of
the modified amino acid. Other reagents such as the water-soluble
carbodiimides are also used extensively in these mechanistic stud
ies. However, an advantage with reagent K is that the enol ester
formed has a UV absorbance at 340 nm (E340 = 7000 M-1 cm -1 ); 14
thus the number of carboxyl groups modified can be quantified.
Reduction of Carboxylic Acids to Alcohols. The conversion
of carboxylic acids to alcohols occurs in a two-step process under
mild conditions using reagent K with yields for simple alcohols
ranging from 50-100%.4 The reduction of a dipeptide (eq 7) sug
gests a potential utility in modifying carboxyl groups in proteins.
Reagent K may have utility in sequencing peptides and pro

teins from the C-terminus (eq 9).17 The 2-thiohydantoin produced
is used to analyze a peptide sequence upon cleavage of the thiohydantoin from the peptide. This mild procedure gives good yields
with amino acids that have sensitive side chains such as serine and
lysine. The original Acetic Anhydride procedure18 for C-terminal
sequencing does not work well with these amino acids; therefore
this procedure is an improvement. Another activation reagent, hydroxysuccinimide esters of Fmoc-amino acids, fails to give the
thiohydantoin.17
(9)
R = variety of amino acid side chains
Related
Reagents. Benzotriazol-l-yloxytris(dimethylamino)phosphonium
Hexafluorophosphate;
1-Cyclohexyl3-(2-morpholinoethyl)carbodiimide;
1 -Ethyl-3-(3'-dimethylaminopropyl)carbodiimide Hydrochloride; Isobutyl Chlorofor
mate; p-Nitrophenol; Pentafluorophenol; 1,1'-Thionylimidazole.
1. Woodward, R. B.; Olofson, R. A.; Mayer, H. T 1969, 22(S8), 321.

2. Woodward, R. B.; Olofson, R. A. OS 1977, 56, 88.
194
ETHYL VINYL ETHER
3.
Bodlaender, P.; Feinstein, G.; Shaw, E. B 1969, 8, 4941.
4.
Hall, P. L.; Perfetti, R. B. JOC 1974, 39, 111.
5.
Gish, D. T.; Katsoyannis, P. G.; Hess, G. P.; Stedman, R. J. JACS 1956,

78, 5954.
6. Klausner, Y. S.; Bodanszky, M. S 1972, 453.
7. (a) Kemp, D. S. The Peptides: Analysis, Synthesis and Biology;
Academic: New York, 1979; Vol. 1, pp 315-383. (b) Woodward, R.
B.; Woodman, D. J. JOC 1969, 34, 2742. (c) Kemp, D. S.; Wang, S. W.;
Busby, G., III; Hugel, G. JACS 1970, 92, 1043.
8. Hudson, D. JOC 1988, 53, 617.
9.
Fosker, A. P.; Law, H. D. JCS 1965, 4922.
10. Blaha, K.; Rudinger, J. CCC 1965, 30, 3325.

11. Merser, C ; Sinay, P.; Adam, A. Biochem. Biophys. Res. Commun. 1975,
66, 1316.
12. (a) Pettit, G. R.; Gupta, A. K. D.; Smith, R. L. CJC 1966, 44, 2023. (b)
Pettit, G. R.; Smith, R. L.; Klinger, H. JOC 1967,10, 145.
13. Baker, A. J.; Weber, B. H. JBC 1974, 249, 5452.
14. Sinha, U.; Brewer, J. M. Anal. Biochem. 1985, 757, 327.
15. Ramsamy, K.; Olsen, R. K.; Emery, T. S 1982, 42.
16. Wagner, A. P.; Retey, J. Eur. J. Biochem. 1991, 795, 699.
17. Boyd, V. L.; Hawke, D. H.; Geiser, T. G. TL 1990, 31, 3849.
18. Cromwell, L. D.; Stark, G. R. B 1969, 8, 4735.
Richard S. Pottorf
Marion Merrell Dow Research Institute, Cincinnati, OH, USA
Ethyl Vinyl Ether 1
(R = Et)
[109-92-2]
(R = Me)
[107-25-5]
(R = n-Bu)
[111-34-2]
vinyl ethers are lachrymatory and irritate the respiratory system;

in particular, methyl vinyl ether can cause rapid suffocation if
inhaled. Use in a fume hood.
Protection of the Hydroxyl Group. 3 Acid-catalyzed reaction

of primary and secondary alcohols with ethyl vinyl ether gives the
-ethoxyethyl (EE) group. Acids commonly used in the forma
tion of the EE group include Trifluoroacetic Acid (eq 1),4 anhyd
Hydrogen Chloride (eq 2), 5 p-Toluenesulfonic Acid,6 and Pyridinium p-Toluenesulfonate (PPTS) (eq 3). 7 Whereas attempts
to form the methyl or benzyl ether of the hemiacetal (eq 3), and
reaction with DHP, result in decomposition, the hemiacetal is suc
cessfully converted into the EE group with ethyl vinyl ether in the
presence of PPTS (but not p-TsOH). 7 For extremely acid-sensitive
substrates, ethyl vinyl ether generated in situ from 1-chloroethyl
ethyl ether (MeCH(Cl)OEt) with PhNMe 2 in CH2C12 at 0 C gives
EE derivatives of primary, secondary, and some tertiary alcohols
in excellent yields (eq 4). 8 Selective protection of a primary alco
hol in the presence of a secondary alcohol with ethyl vinyl ether
may be achieved at low temperatures (eq 5). 9 The EE group is
more readily cleaved by acid hydrolysis than the THP ether, but is
more stable than the 1-methyl-1-methoxyethyl ether.3 In the case
of the nucleoside (eq 2), which is subsequently converted into a
nucleotide, the ethoxyethyl group is preferred to the THP group
because of its ease of removal (5% HOAc, 2 h, 20 C), with no
detectable isomerization of the 3'-5' nucleotide linkage.5 Other
methods of cleaving the EE group include 0.5N HC1 in THF at
0C, 6 and PPTS in n-PrOH, where cleavage is possible in the
presence of an acetonide group (eq 6). 10
(1)
C4H8O
(MW 72.12)
C3H6O
(MW 58.09)
C6H12O
(MW 100.18)
(protection of hydroxyl group; transvinylation, particularly

to prepare allyl vinyl ethers for use in the Claisen
rearrangement; condensation reactions; cycloaddition reactions)
Physical Data: R = Et, mp -115.8C, bp 35-36 C, d
0.7589gcm- 3 ; R = Me, mp - 1 2 3 C, bp 12C, d
0.7725 g cm-3 at 0C; R = n-Bu, mp - 9 2 C , bp 94C,
d 0.7888 g c m - 3 . 2
Solubility: sol all common organic solvents; slightly sol water.
Form Supplied in: ethyl vinyl ether and n-butyl vinyl ether are col
orless, extremely flammable liquids, while methyl vinyl ether is
a colorless, extremely flammable gas. Ethyl vinyl ether is sup
plied stabilized with triethanolamine and methyl vinyl ether is
supplied in stainless steel cylinders.
Purification: ethyl vinyl ether and n-butyl vinyl ether may be
distilled from K2CO3 or Na if purification of the commercial
materials is desirable.
Handling, Storage, and Precautions: all three compounds react
violently with halogens and with strong oxidizing agents, and
undergo rapid polymerization in the presence of acids. These
(2)
(3)
(4)
ETHYL VINYL ETHER
195
(10)
(5)
(11)
(6)
(12)
Augmenting its role as a protecting group, the EE group has

been used to direct ortho-lithiation in suitably substituted aromatic
ethers, yielding lithiated species that react rapidly with a variety
of electrophiles, such as Carbon Dioxide, to give the phthalide
(eq 7).11
(7)
Transvinylation. Acid-catalyzed transvinylation of allylic al

cohols with ethyl vinyl ether gives allyl vinyl ethers, Claisen
rearrangement12 of which affords 7,8-unsaturated aldehydes of
varying complexity (eqs 8-12). 13,14,16-18 Mercury(II) Acetate
(eq 8), 13 Phosphoric Acid (eq 9), 14 and p-TsOH 15 are frequently
used to catalyze the transvinylation reaction, and the allyl vinyl
ethers produced need not be isolated but may be subjected directly
to the Claisen rearrangement, typically at 145-200 C. Hg(OAc)2,
used in the transvinylation reaction, has been reported to effect the
rearrangement at lower temperatures (eq 10).16 Other examples il
lustrating the stereoselectivity of the reaction are given in eqs 11
and 12. 1 7 1 8
(8)
Condensation Reactions.
Acetal Condensations. The acid-catalyzed condensation of
ethyl vinyl ether with acetals derived from ,-unsaturated alde
hydes and ketones is an excellent method to lengthen a carbon
chain by two carbon atoms, particularly of polyenals. In an in
dustrial process for the manufacture of the C 16 aldehyde (eq 13),
the C 14 acetal is reacted with ethyl vinyl ether in the presence of
Zinc Chloride to give an alkoxy acetal, which, without isolation,
is then hydrolyzed with moist acetic acid.19 Longer conjugated
carotenals have been synthesized by this method,20 and montmorillonite K-10 clay (see Montmorillonite K10) has been reported
to be an excellent replacement for the Lewis acids normally used
in the condensation.21
(13)
Acyl Anion Equivalents.22 The -H of simple vinyl ethers

can be deprotonated with strong bases, such as t-Butyllithium,
to give highly reactive -alkoxyvinyllithium reagents (see also
1-Ethoxyvinyllithium and 1-Methoxyvinyllithium). These react
rapidly with various electrophiles, including aldehydes and ke
tones (eq 14),23 and can undergo conjugate addition to a,(3unsaturated carbonyl compounds via the corresponding cuprates
(eq 15).24
(14)
(9)
196
ETHYL VINYL ETHER

(15)
(20)
Cycloaddition Reactions.
(21)
Diels-Alder and Related Reactions. Owing to their electronrich nature, vinyl ethers participate in a number of inverse elec
tron demand Diels-Alder reactions.25 ,-Unsaturated aldehydes
and ketones react rapidly with vinyl ethers to give dihydropyrans (eq 16),26 with high endo selectivity (eq 17),27 the pro
portion of endo adduct being increased by conducting the reac
tion at low temperatures under pressure (eq 18).28 Lewis acids
can also catalyze these reactions and control the stereochem
istry of cycloaddition.251b,29 o-Quinone methides yield chromans
(eq 19),30 and imines give tetrahydroquinolines (eq 20).31 Vinyl
ethers react regio- and stereoselectively with isoquinolinium salts
giving cycloadducts, which on hydrolysis afford tetralins in ex
cellent yields (eq 21).32 The cycloaddition of vinyl ethers with
nitrones proceeds smoothly, giving, where relevant, isoxazolines
with extremely high diastereoselectivity (eq 22).33 Vinyl ethers
react with nitroalkenes to give nitronate esters in moderate yields
(eq 23),34 but excellent yields of cyclobutane derivatives are ob
tained with tetracyanoethylene (eq 24).35
(16)
R1 = H, Me, Ph; R2 = Et, Bu, Me
(17)
(23)
(24)
Photochemical. Vinyl ethers undergo the Paterno-Bchi reac

tion with simple aliphatic and aromatic carbonyl compounds to
give regioisomeric mixtures of alkoxyoxetanes, with a prepon
derance of the 3-alkoxy regioisomer (eq 25).36 Photoaddition of
vinyl ethers to enones produces alkoxycyclobutanes in excellent
yields, with the alkoxy group orientated predominantly away from
the carbonyl group (eq 26).36 Vinyl ethers also undergo photoad
dition to arenes, giving, with benzene, a mixture of ortho- and
meta-cycloadducts in low yields; only the exo isomer is produced
in the ortho-cycloaddition, whereas the meta-cycloaddition gives
a mixture of regio- and stereoisomers (eq 27).37
(25)
trans:cis= 12.5:1
(18)
90 C, 1 bar
0.5 C, 6 kbar
(22)
1.67:1
13.6:1
(26)
(27)
Related Reagents. 3,4-Dihydro-2H-pyran; 1,1-Dimethoxyethane; 1-Ethoxy-l-propene; 2-Methoxypropene; Vinyl Acetate.

(19)
1. Mundy, B. P.; Ellerd, M. G. Name Reactions and Reagents in Organic
Synthesis; Wiley: New York, 1988; p 354.
Next Page
ETHYL VINYL ETHER

2.
(a) CRC Handbook of Chemistry and Physics, 73rd ed.; CRC: Boca
Raton, FL, 1992; pp 3-241. (b) Dictionary of Organic Compounds,
5th ed.; Chapman & Hall: New York, 1982; Vol. 3, p 2571. (c) Sax's
Dangerous Properties of Industrial Materials, 8th ed.; Lewis, R. J., Ed.;
van Nostrand Rheinhold: New York 1992; Vol. 2, p 1668.
3.

2nd ed.; Wiley: New York, 1991; p 38.
4.
Manchand, P. S.; Schwartz, A.; Wolff, S.; Belica, P. S.; Madan, P.; Patel,
P.; Saposnik, S. J. H 1993, 35, 1351.
(a) Smrt, J.; Chladek, S. CCC 1966, 31, 2978. (CA 1966, 65, 10648c).
(b) Young, S. D.; Buse, C. T.; Heathcock, C. H. OSC 1990, 7, 381.
5.
6.
21.
22.
(a) Kraus, G. A.; Krolski, M. E. SC 1982, 521. (b) Baldwin, J. E.; Hfle,
G. A.; Lever, O. W. JACS 1974, 96, 7125.
24. Boeckman, R. K.; Bruza, K. J. JOC 1979, 44, 4781.
25. (a) Desimoni, G.; Tacconi, G. CRV 1975, 75, 651. (b) Boger, D. L. COS
1991, 5 451. (c) Carruthers, W. Cycloaddition Reactions in Organic
Synthesis; Pergamon: New York, 1990. (d) Boger, D. L.; Weinreb. S. M.
Hetero Diels-Alder Methodology in Organic Synthesis; Academic: San
Diego, 1987.
26.
Longley, R. I.; Emerson, W. J.; Blardinelli, A. J. OSC 1963, 4, 311.
27.
29.
(a) Apparao, S.; Maier, M. E.; Schmidt, R. R. S 1987, 900. (b) Schmidt,
R. R. ACR 1986, 19, 250.
Tietze, L. F.; Hbsch, T.; Voss, E.; Buback, M.; Tost, W. JACS 1988,
110, 4065.
Chapleur, Y.; Envrard, M.-N. CC 1987, 884.
30.
31.
32.
Inoue, X; Inoue, S.; Sato, K. CL 1989, 653.

Cabral, J.; Laszlo, P.; Montaufier, M. T. TL 1988, 29, 547.
Gupta, R. B.; Franck, R. W. JACS 1987, 109, 5393.
33.
(a) Advances in Cycloadditions; Curran, D. P., Ed.; Jai: Greenwich, CT,

1988; Vol. 1. (b) DeShong, P.; Leginus, J. M. JACS 1983, 105, 1686. (c)
Confalone, P. N.; Huie, E. M. OR 1988, 36, 1.
Backvall, J. E.; Karlsson, U.; Chinchilla, R. TL 1991, 32, 5607.
(a) Fatiadi, A. J. S 1987, 749. (b) Baldwin, J. E. COS 1991, 5, 63.
28.
10. Tius, M. A.; Fauq, A. H. JACS 1986, 108, 1035.

11. Napolitano, E.; Giannone, E.; Fiaschi.; Marsili, A. JOC 1983, 48, 3653.
12. (a) Rhoads, S. J.; Raulins, N. R. OR 1975, 22, 1. (b) Ziegler, F. E. CRV
1988, 88, 1423; (c) Wipf, P. COS 1991, 5, 827.
Dauben, G.; Dietsche, T. J. JOC 1972, 37, 1212.
Marbet, R.; Saucy, G. HCA 1967, 50, 2095.
Saucy, G.; Marbet, R. HCA 1967, 50, 1158.
Reed, S. F. JOC 1965, 30, 1663.
17.
18.
Grieco, P. A.; Takigawa, T.; Moore, D. R. JACS 1979, 101, 4380.

(a) Paquette, L. A.; Annis, G. D.; Schostarez, H. JACS 1981, 103, 6526.
(b) Paquette, L. A.; Annis, G. D.; Schostarez, H.; Blount, J. F. JOC 1981,
46, 3768.
19.
20.
Isler, O.; Lindlar, H.; Montavon, M.; Regg, R.; Zeller, P. HCA 1956,
39, 249.
(a) Isler, O.; Schudel, P. Adv. Org. Chem. Methods Results 1963, 4, 115.
(b) Effenberger, F. AG(E) 1969, 8, 295. (c) Carotenoids; Isler, O., Ed.;
Birkhauser: Basel, Switzerland, 1971. (d) Makin, S. M. PAC 1976, 47,
173.
Fishman, D.; Klug, J. T.; Shani, A. S 1981, 137.

Umpoled Synthons; Hase, T. A. Ed.; Wiley: New York, 1987.
23.
Meyers, A. I.; Comins, D. L.; Roland, D. M.; Henning, R.; Shimizu, K.

JACS 1979, 101, 7104.
7. Anderson, R. C ; Fraser-Reid, B. TL 1978, 3233.
8. Still, W. C. JACS 1978, 100, 1481.
9. Semmelhack, M. F.; Tomoda, S. JACS 1981, 103, 2427.
13.
14.
15.
16.
197
34.
35.
36.
37.
Synthetic Organic Photochemistry; Horspool, W. M., Ed.; Plenum: New

York, 1984.
Gilbert, A.; Taylor, G. N.; binSamsudi, M. W. JCS(Pl) 1980, 869.
Hoffmann-La
Percy S. Manchand
Roche, Nutley, NJ, USA
Previous Page
198
9-FLUORENYLMETHYL CHLOROFORMATE
FMOC protection of amino acids is accomplished with

Shotten-Bauman conditions (e.g. NaHCO3/dioxane/H2O
or NaHC03/DMF), or with anhydrous conditions (e.g.
pyridine/CH2Cl2) at room temperature or below (eq 1).3a,4
A typical synthetic protocol for solid-phase peptide synthesis
would involve coupling (eq 2), followed by deprotection with
20-30% Piperidine in DMF (eq 3), although other amines
(e.g. 2% DBU, 10% Et2NH, or 50% morpholine in DMF) have
been used. Many workers no longer use the chloroformate
ester FMOC-C1 (1), preferring the more shelf-stable carbonate
FMOC-OSu (2) [82911-69-1],5 or FMOC-pfp (3) [88744-04-1].
When used in the standard way,4 FMOC-C1 (1) has been shown
to promote the formation of 'FMOC-dipeptides' in 3-7% yield,
presumably via the mixed anhydride intermediate.5a
9-FIuorenylmethyl Chloroformate1
[28920-43-6]
C 15 H 11 ClO 2
(MW 258.71)
(2)
3
(base-labile protecting group for primary and secondary amines;

used in peptide synthesis;5 used for derivatization of amines and
amino acids prior to HPLC analysis and fluorescence detection13)
Alternate Names: 9-fluorenylmethoxycarbonyl chloride; FMOCCl.
Solubility: sol organics (CH2Cl2, THF, dioxane); reacts with al
cohols, amines, and water.
Form Supplied in: white crystalline solid; widely available.
Handling, Storage, and Precautions: FMOC-C1 is an acid chlo
ride, and should be protected from moisture and heat. The
reagent can evolve CO2 (pressure!) upon prolonged storage;
therefore bottles should be opened carefully. FMOC-C1 is harm
ful if swallowed, inhaled, or absorbed through skin, is corrosive,
and is a strong lachrymator. Inhalation may be fatal. Use in a
fume hood.
N-Terminus Blocking in Peptide Synthesis. Solid-phase

peptide synthesis based on base-labile FMOC protection1 is
rapidly augmenting and/or replacing older methods based on
Boc and Z (Cbz) protection. The major advantage offered by
the use of FMOC protection is that repetitive treatment with HF
or CF3CO2H is no longer required for the deprotection steps.
Most FMOC-protected amino acids are commercially available,
although the search for orthogonal side-chain functional group
protection continues.2 FMOC protection is currently the method
of choice for the synthesis of glycopeptides which carry acid-labile
O-glycosidic bonds (eq 1). 3,5b,7
(1)
(3)
Use of FMOC-OSu (2) provides N-protected amino acids

in comparable yields without the formation of the dipeptide
impurities.5 FMOC-pfp (3) has been used to prepare either
FMOC-protected amino acids, or the corresponding pfp esters
in one pot. Advantages of this reagent include supression of the
dipeptide byproducts, as well as the production of the activated
pfp esters using the same pentafluorophenol released during the
N-protection step (eq 4).6 This same N-protection/C-activation
procedure has been used to produce serine glycosides (eq 5),3b
and for the solid-phase synthesis of human intestinal mucin frag
ments (eq 6).7 The use of FMOC-N3 (4) is also claimed to reduce
dipeptide formation during the protection step,8 but the storage
or use of potentially explosive oxycarbonyl azides cannot be
recommended by this reviewer. Alternatively, the azide (4) may
be generated in situ from (1).4
(4)
(5)
(6)
Fluorenylmethyl esters have been used for C-terminus pro

tection in combination with FMOC N-terminus protection for
solution-phase coupling of protected amino acids and peptide frag
ments. This permits simultaneous deprotection of both termini
with Et 2 NH/DMF (eq 7). 9
199
protect the amino groups on various nucleoside bases (adeno

sine, cytosine, guanine, and their 2-deoxy derivatives) for
solid-phase oligonucleotide synthesis in a one-pot procedure. 10
Chlorotrimethyhilane in dry pyridine was used for transient pro
tection of the 2',3',5'- or 3',5'-hydroxyls, followed by the addition
of FMOC-C1, and hydrolytic workup of the TMS ethers to produce
crystalline FMOC-protected nucleosides and 2-deoxynucleosides
in good yield (eq 8). The FMOC group was removed from the
heterocyclic bases with excess Triethylamine in dry pyridine.
(8)
FMOC-C1 has been used for 3',5'-hydroxyl protection of

deoxyribose for the introduction of modified bases such as azacytidine using the classical Vorbrggen reaction.11 While the
carbonate protecting groups do not alter the stereoselectivity of
the N-glycoside formation, the FMOC groups can be removed
under much milder conditions (Et3 N/pyridine) than the typical
4-methylbenzoyl group (eq 9).
(9)
(7)
Perhaps the most impressive use of the FMOC group in the

synthesis of natural products is provided by the key tetrasaccharide intermediate to calicheamicin.12 The robust nature of this
particular FMOC group is amply demonstrated by the fact that
it survives 15 discrete reaction steps, including exposure to cat.
NaH/HOCH 2 CH 2 OH, Br 2 , EtN 3 , K-Selectride, i-Bu 2 AlH, and
NaSMe (eq 10). Clearly, the use of FMOC protection is not limited
to peptide synthesis.
Amine and Hydroxyl Protection for Nucleosides, Carbo

hydrates, and Natural Products. FMOC has been used to
FMOC Derivatization for Fluorescence Detection and

Analysis. Derivatization of amino acids and other primary and
secondary amines with (1) for HPLC analysis has been described.
The chief advantage of this methodology is the high sensitivity due
to the intense fluorescence of the fluorenyl moiety, but the FMOC
200
also reduces polarity for faster elution from the column. Amino
acids have been detected in concentrations as low as 26 femtomolar using a precolumn derivatization scheme.13 FMOC derivatization of lyso-gangliosides in a two-phase Et2O-H2O system fol
lowed by chromatographic purification with fluorescence detec
tion has also been reported.14 Optically active l-(9-fluorenyl)ethyl
chloroformate (FLEC) (5) is commercially available in both (+)
[707474-79-3] and () forms for the analysis of racemates.
(10)
1. For illustrative procedures using FMOC and other protection schemes,

see The Practice of Peptide Synthesis; Bodanszky, M.; Bodanszky, A.,
Eds.; Springer: Berlin, 1984.
2. (a) Histidine: Fischer, P. M. et al. Int. J. Pept. Protein Res. 1992, 40, 19.
(b) Glutamate: Handa, B. K.; Keech, E. Int. J. Pept. Protein Res. 1992,
40, 66.
3. (a) Polt, R.; Szabo, L.; Treiberg, J.; Li, Y.; Hruby, V. J. JACS 1992, 114,
10249. (b) Luning, B.; Norberg, T.; Tejbrant, J. CC 1989, 1267.
4. Carpino, L. A.; Han, G. Y. JOC 1972, 37, 3404.
5.
(a) Lapatsanis, L.; Milias, G.; Froussios, K.; Kolovos, M. S 1983, 671. (b)
Bardaji, E.; Torres, J. L.; Clapes, P.; Albericio, F.; Barany, G.; Rodriguez,
R. E.; Sacristin, M. P.; Valencio, G. JCS(Pl) 1991, 1755. For an alternate
synthesis of FMOC-OSu (2) from fluorenylmethyl alcohol and phosgene:
(c) Ten Kortenaar, P. B. W. et al. Int. J. Pept. Protein Res. 1986, 27, 398.
6.
7.
Schon, I.; Kisfalady, L. S 1986, 303.

(a) Jansson, A. M.; Meldal, M.; Bock, K. TL 1990, 31, 6991. (b) Bielfeldt,
T.; Peters, S.; Meldal, M.; Paulsen, H.; Bock, K. AG(E) 1992, 31, 857.
8.
Tessier, M. et al. Int. J. Pept. Protein Res. 1983, 22, 125.
9.
(a) Bednarek, M. A.; Bodanszky, M. Int. J. Pept. Protein Res. 1983, 21,
196. (b) Bodanszky, M. et al. Int. J. Pept. Protein Res. 1981, 17, 444.
10. Heikkila, J.; Chattopadhyaya, J. ACS 1983, B37, 263.
11. Ben-Hattar, J.; Jiricny, J. JOC 1986, 57, 3211.
12. Nicolaou, K. C.; Groneborg, R. D.; Miyazaki, T.; Stylianides, N.;
Schulze, T. J.; Stahl, W. JACS 1990, 112, 8193.
13. (a) Einarsson, S.;Folestad, S.; Josefsson, B. Anal. Chem. 1986,58, 1638.
(b) Einarsson, S. J. Chromatogr. 1985, 348, 213. (c) Veuthey, J.-L. J.
Chromatogr. 1990, 515, 385. (d) For a review: Betner, I.; Foeldi, P. In
Modern Methods in Protein Chemistry; Tschesche, H., Ed.; de Gruyter:
Berlin, 1988; Vol. 3, p 227.
14. Neuenhofer, S.; Schwarzmann, G.; Egge, H.; Sandhoff, K. B 1985, 24,
525.
Related Reagents. Allyl Chloroformate; Benzyl Chlorofor

mate; 4-Bromobenzyl Chloroformate; t-Butyl Chloroformate;
Ethyl Chloroformate; Isobutyl Chloroformate; Methyl Chloro
formate; 2,2,2-Tribromoethyl Chloroformate; 2,2,2-Trichloro-rbutoxycarbonyl Chloride; 2,2,2-Trichloroethyl Chloroformate; 2(Trimethylsilyl)ethyl Chloroformate; Vinyl Chloroformate.
University
of Arizona,
Robin L. Polt
Tucson, AZ, USA
HEXACARBONYLCHROMIUM
201
(arene)chromium complexes are superior catalysts for stereose

lective hydrogenation of alkynes to (Z)-alkenes, and in addition,
cisoid ,-unsaturated enones and imines can be reduced.8
(3)
Hexacarbonylchromium 1
(4)
[13007-92-6]
C6CrO6
(MW 220.06)
(catalyst for alkene isomerization, hydrogenation of 1,3conjugated dienes, oxidation of allylic and benzylic positions;
reagent for preparation of tricarbonyl(arene)chromium and Fis
cher carbene complexes)
Alternate Name: chromium hexacarbonyl.
Physical Data: sublimes at 50-80 C; mp 154-155 C (in sealed
tube); d 1.77 g c m - 3 .
Solubility: insol water, ethanol; slightly sol ether, CHCl 3 .
Form Supplied in: white solid; widely commercially available.
Handling, Storage, and Precautions: highly volatile and must be
stored and used in a well ventilated fume hood.
Oxidation. Treatment of alkenes with t-Butyl Hydroperoxide

in the presence of 0.5 equiv of Cr(CO) 6 or Cr(CO)x(MeCN)y.
species in refluxing MeCN results in the oxidation of allylic
methylene groups to give ,-unsaturated ketones selectively in
the presence of certain alcohols (eq 1).2 Benzylic positions are also
oxidized to phenyl ketone derivatives3 under the same conditions
(eq 2).
(5)
Chromium hexacarbonyl offers a highly regioselective method

for the isomerization of cisoid 1,3-dienes to transoid dienes
(eq 6). 9 (Naphthalene)chromium tricarbonyl catalyzes isomeriza
tion of silyloxymethylbutadiene derivatives to silyl dienol ethers
in quantitative yields via a U-shaped pentadienyl intermediate
(eq 7). 10
(6)
(1)
(7)
(2)
Hydrogenation and Isomerization of Dienes. The catalytic

behavior of (arene)Cr(CO)3 complexes has been exploited in the
homogeneous regioselective 1,4-hydrogenation of dienes to cisalkenes.4 Only 1,3-dienes that can easily achieve the less sta
ble s-cis configuration to undergo this catalytic hydrogenation
(eq 3). Similar catalytically active species Cr(CO) 3 H 2 (diene) (1)
can be generated photochemically from Cr(CO) 6 or from kinetically thermally labile -bonded ligated complexes (naphthalene,
anthracene, MeCN) in coordinating solvents (THF, acetone, dioxane) under milder conditions (eq 4). 5 This regioselective hydro
genation of dienes can be applied to the total synthesis of complex
natural products (eq 5) such as carbacyclin, cyanopcarbacyclin,
and deplanchein.6 1,4-Hydrosilylation of dienes is also achieved
to produce (Z)-allyltrimethylsilanes7 under these conditions. The
(Arene)Cr(CO)3 Complexes. Complexation of an arene ring

to the chromium tricarbonyl unit is easily accomplished by simple
heating with Cr(CO) 6 or by ligand transfer with Cr(CO) 3 L 3 . 1,11
The significant properties of (arene)chromium complexes in or
ganic synthesis are as follows: nucleophilic substitution to arene
ring; enhancement of acidity of aromatic hydrogen; enhancement
of acidity of benzylic hydrogen; enhancement of solvolysis at the
benzylic position; and steric hindrance of the Cr(CO) 3 group.
Nucleophilic Substitution.1 Some carbon nucleophiles add
to tricarbonyl(arene)chromium complexes to yield anionic 5cyclohexadienyl complexes (2) (eq 8), which give the substituted
arenes via decomplexation by oxidation with iodine. Protolysis of
the intermediate cyclohexadienylchromium complexes (2) gen
erate cyclohexadienes, and reaction with electrophiles generates
either the arene chromium complexes or produces the acylated
species.
202
irreversible conditions from dithiane carbanions produces trans

addition products (eq 13).17
(8)
(13)
t(Bu, Ph; R2 = Me, CH2Ph
With substituted aromatics, the following regioselectivity for

nucleophilic substitution is generally observed (eq 9); alkoxy substituents strongly direct to the meta position, and trimethylsilyl
groups ensure para substitution.12 Alkylation of the chromium
complexes of indoles and benzofurans takes place at the C-4 or C7 position, depending on the steric effect of the C-3 substituent.13
Intramolecular nucleophilic alkylation can also be achieved; the
products formed depend on chain length, reaction conditions,
and other substituents on the aromatic ring (eq 10).14 With an
(anisole)chromium complex, 3-substituted cyclohexenone deriva
tives can be obtained by the protolytic cleavage of the intermedi
ates (eq 11).17 A combination of the intramolecular alkylation with
protolysis gives an elegant synthesis of the spiro sesquiterpenoids
acorenone and acorenone B (eq 12).15,16
Lithiation. With anisole, fluorobenzene, and chlorobenzene

chromium complexes, lithiation always occurs at an ortho posi
tion of the substituents under mild conditions (eqs 14 and 15).18
Protected phenol or aniline chromium complexes with sterically
bulky substituents produce meta lithiation exculsively.19 The lithiated position of some (arene)chromium complexes (3) differs from
that of the corresponding chromium-free compounds (4).20
(9)
(14)
+
Y = H, OMe, F, Cl; E = CO2, MeX, TMSC1, aldehydes, ketones
(10)
(11)
(15)
(12)
Reaction with a range of electrophiles regenerates the

(arene)chromium complexes under reversible conditions, but electrophilic attack upon the cyclohexadienyl complex formed under
Activation of the Benzylic Position. Both chromium complexed carbanions and carbocations are stabilized at the benzylic
position.21 Dialkylation of alkyl halides at the benzylic position
occurs via stabilized carbanions under mild conditions (eq 16).22
Regio- and stereoselective products are obtained via the benzylic
carbanions, depending on the conformation of the tricarbonyl
group to the arene (eq 17).22 (Styrene)chromium complexes sta
bilize negative charges at the benzylic position by addition of
nucleophiles to the -position, giving bifunctionalization products

by trapping with electrophiles (eq 18).23
(16)
203
as o-substituted benzaldehyde and phenyl alkyl ketones with

electron-donating ortho substituents (OMe, Me, F), addition of
nucleophiles to the chromium complexed benzylic carbonyl group
proceeds stereoselectively, giving one diastereomeric complex
predominantly (eq 23).29 A Friedel-Crafts reaction produces pre
dominantly an exo-substituted complex (eq 24).30
(17)
(22)
X = OMe, NMe2
R = CMe2CN, C(CN)(Me)OR,
1,3-dithane, Bu
E = H+, Mel, RCOC1
(23)
(18)
Tricarbonylchromium stabilized benzylic carbocations

can be captured by a large variety of nucleophiles,24 such as
alcohols, amines, thiols, nitriles, trimethylsilyl enol ethers,
allylsilanes, electron-rich aromatics, dialkylzincs, and trialkylaluminums (eq 19). The relative stereochemistry formed
during these reactions via carbocations in acyclic systems
proceeds with net retention.21b,c,25 Friedel-Crafts acylation of
(styrene)chromium complexes has been explored via the benzylic
cations (eq 20).26 Tricarbonylchromium-stabilized oxonium ions
are also utilized for steroselective carbon-carbon bond forming
reactions (eq 21).27
(19)
(20)
(24)
A 1,2 or 1,3 unsymmetrically disubstituted arene is prochiral and therefore the corresponding chromium tricarbonyl com
pounds are chiral.31 (Substituted arene) complexes with amine,
carboxyl, and formyl groups at the ortho position are resolved
into optically active chromium complexes through correspond
ing diastereomeric adducts (eq 25).32 Biocatalysts also perform
the kinetic resolution of racemic chromium complexes (eq 26).33
The optically active chromium complexes can be prepared by diastereoselective ortho lithiation34 of the chiral benzaldehyde or
acetophenone acetal complexes, and diastereoselective chromium
complexation35 of the chiral ortho-substituted benzaldehyde aminals (eq 27). Catalytic asymmetric cross-coupling of meso (1,2haloarene)chromium complex produces chiral monosubstituted
complexes.36 The chiral (arene)chromium complexes can be used
as ligands in asymmetric reactions.37
(21)
racemic
X = OMe, SiMe3,
Me, halogen
Steric Effect of the Cr(CO)3 Group.1 A feature of (6arene)chromium complexes is the steric interference offered to
the approach of reagents, which occurs exclusively from the
era-face at the reactive center in cyclic chromium complexes
(eq 22).28 Even in the (acyclic arene)chromium complexes, such
(25)
204
16.
Semmelhack, M. F. Yamashita, A. JACS 1980, 102, 5924.
17.
(26)
(27)
(a) Kndig, E. P. PAC 1985, 57, 1855. (b) Kndig, E. P.; Thi, N. P. D.;
Paglia, P.; Simmons, D. P.; Spichiger, S.; Wenger, E. In Organometallics
in Organic Synthesis; de Meijere, A.; Tom Dieck, H., Eds; Springer:
Berlin, 1987; pp 265-276. (c) Kndig, E. P.; Desobry, V.; Simmons, D.
P. JACS 1983, 105, 6962. (d) Kndig, E. P.; Simmons, D. P. CC 1983,
1320.
18. (a) Semmelhack, M. F.; Bisaha, J.; Czarny, M. JACS 1979, 101, 768. (b)
Semmelhack, M. F ; Zask, A. JACS 1983, 105, 2034.
19. (a) Dickens, P. J.; Gilday, J. P.; Negri, J. T.; Widdowson, D. A. PAC 1990,
62, 575. (b) Masters, N. F ; Widdowson, D. A. CC 1983, 955. (c) Gilday,
J. P.; Widdowson, D. A. CC 1986, 1235. (d) Clough, J. M.; Mann, I. S.;
Widdowson, D. A. TL 1987, 28, 2645. (e) Fukui, M.; Ikeda, T.; Oishi,
T. TL 1982, 23, 1605. (f) Fukui, M.; Ikeda, T.; Oishi, T. CPB 1983, 31,
466.
20. (a) Uemura, M.; Nishikawa, N.; Hayashi, Y. TL 1980, 21, 2069. (b)
Uemura, M.; Take, K.; Isobe, K.; Minami, T.; Hayashi, Y. T 1985, 41,
5771.
21.
(a) Davies, S. G.; Coote, S. J.; Goodfellow, C. L. In Advances in

Metal-Organic Chemistry; Liebeskind, L. S., Ed.; JAI: London, 1991;
Vol. 2, pp 1-57. (b) Davies, S. G.; Donohoe, T. J. SL 1993, 323. (c)
Uemura, M. In Advances in Metal-Organic Chemistry; Liebeskind, L.
S., Ed.; JAI: London, 1991; Vol. 2, pp 195-245.
22.
(a) Jaouen, G.; Meyer, A.; Simmoneaux, G. CC 1975, 813. (b) Jaouen,
G.; Top, S.; Laconi, A.; Couturier, D.; Brocard, J. JACS 1984, 106, 2207.
(c) Caro, B.; Le Bihan, J.-Y.; Guillot, J.-P.; Top, S.; Jaouen, G. CC 1984,
602. (d) Brocard, J.; Laconi, A.; Couturier, D.; Top, S.; Jaouen, G. CC
1984, 475.
Related Reagents. (6-Benzene)tricarbonylchromium; Dodecacarbonyltriiron; Pentacarbonyliron.
1. (a) Collman, J. P.; Hegedus, L. S.; Norton, J. R.; Finke, R. G. Principles

and Applications of Organotransition Metal Chemistry; University
Science Books: Mill Valley, CA, 1987. (b) Jaouen, G. In Transition
Metal Organometallics in Organic Synthesis; Alper, H., Ed.; Academic:
New York, 1978; Vol. 2, pp 65-120. (c) Pearson, A. J. Metallo-organic
Chemistry; Wiley: Chichester, 1985. (d) Heck, R. F. Organotransition
Metal Chemistry; Academic: New York, 1974.
2.
(a) Pearson, A. J.; Chen, Y.-S.; Hus, S.-Y.; Ray, T. TL 1984, 25, 1235.
(b) Pearson, A. J.; Chen, Y.-S.; Han, G. R.; Hsu, S.-Y.; Ray, T. JCS(Pl)
1985, 267.
3.
Pearson, A. J.; Han, G. R. JOC 1985, 50, 2791.
4.
(a) Cais, M.; Frankel, E. N.; Rejoan, A. TL 1968, 1919. (b) Frankel, E.
N.; Selke, E.; Glass, C. A. JACS 1968, 90, 2446. (c) Frankel, E. N.; Selke,
E.; Glass, C. A. JOC 1969, 34, 3936.
5.
(a) Wrighton, M.; Schroeder, M. A. JACS 1973, 95, 5764. (b) Yagupsky,
G.; Cais, M. ICA 1975,12, L27.
6. (a) Shibasaki, M ; Sodeoka, M.; Ogawa, Y JOC 1984, 49, 4096. (b)
Shibasaki, M.; Sodeoka, M. TL 1985, 26, 3491. (c) Rosenmund, P.;
Casutt, M. TL 1983, 24, 1771.
7. Wrighton, M. S.; Schroeder, M. A. JACS 1974, 96, 6235.
8. Sodeoka, M ; Shibasaki, M. JOC 1985, 50, 1147.
9.
(a) Barton, D. H. R.; Davies, S. G.; Motherwell, W. B. S 1979, 265. (b)

Birch, A. J.; Cross, P. E.; Connor, D. T.; Rao, G. S. R. S. JCS(C) 1966,
54.
10.
(a) Sodeoka, M.; Yamada, H.; Shibasaki, M. JACS 1990, 112, 4906. (b)
Sodeoka, M.; Satoh, S.; Shibasaki, M. JACS 1988, 110, 4823.
(a) Mahaffy, C. A. L.; Pauson, P. L. Inorg. Synth. 1979, 19, 154. (b)
Seyferth, D.; Merola, J. S.; Eschbach, C. S. JACS 1978, 100, 4124. (c)
Trahanovsky, W. S.; Wells, D. K. JACS 1969, 91, 5870. (d) Kndig, E.
P.; Perret, C ; Spichiger, S.; Bernardinelli, G. JOM 1985, 286, 183.
11.
12.
(a) Semmelhack, M. F. PAC 1981, 53, 2379. (b) Semmelhack, M. F ;

Clark, G. R.; Garcia, J. L.; Harrison, J. J.; Thebtaranonth, Y.; Wulff, W.;
Yamashita, A. T 1981, 37, 3957.
13.
(a) Semmelhack, M. F.; Wulff, W.; Garcia J. L. JOM 1982, 240, C5. (b)
Boutonnet, J-C.; Levisalles, J.; Rose, E.; Precigoux, G.; Courseille, C ;
Platzer, N. JOM 1983, 255, 317.
14.
15.
Semmelhack, M. F ; Thebtaranonth, Y.; Keller, L. JACS 1977, 99, 959.

(a) Semmelhack, M. F.; Harrison, J. J.; Thebtaranonth,Y.JOC 1979, 44,
3275. (b) Boutonnet, J.-C.; Levisalles, J.; Normant, J.-M.; Rose, E. JOM
1983, 255, C21.
23.
(a) Semmelhack, M. F ; Seufert, W; Keller, L. JACS 1980, 102, 6584.

(b) Uemura, M.; Minami, T.; Hayashi, Y. CC 1984, 1193.
24. (a) Top, S.; Caro, B.; Jaouen, G. TL 1978, 787. (b) Top, S.; Jaouen, G.
JOC 1981, 46, 78. (c) Reetz, M. T.; Sauerwald, M. TL 1983, 24, 2837.
(d) Uemura, M.; Isobe, K.; Hayashi, Y. TL 1985, 26, 767.
25. (a) Uemura, M.; Kobayashi, T.; Isobe, K.; Minami, T.; Hayashi, Y. JOC
1986, 51, 2859. (b) Uemura, M.; Minami, T.; Hayashi, Y JACS 1987,
109, 5277. (c) Top, S.; Jaouen, G.; McGlinchey, M. J. CC 1980, 1110.
26. Senechal-Tocquer, M.-C.; Le Bihan, J.-Y.; Gentic, D.; Senechal, D.;
Caro, B. JOM 1988, 356, C5.
27. (a) Davies, S. G.; Newton, R. F ; Williams, J. M. J. TL 1989, 30, 2967.
(b) Normant, J. F.; Alexakis, A.; Ghribi, A.; Mangeney, P. T 1989, 45,
507.
28. (a) Meyer, A.; Jaouen, G. CC 1974, 787. (b) Jaouen, G.; Meyer, A. JACS
1975, 97, 4667. (c) des Abbayes, H.; Boudeville, M. A. TL 1976, 2137.
(d) des Abbayes, H.; Boudeville, M. A. JOC 1977, 42, 4104. (e) Jaouen,
G.; Meyer, A. TL 1976, 3547.
29.
(a) Besancon, J.; Tirouflet, J.; Card, A.; Dusausoy, Y. JOM 1973, 59, 267.
(b) Solladi-Cavallo, A.; Suffert, J. S 1985, 659. (c) Meyer, A.; Dabard,
R. JOM 1972, 36, C38.
30. (a) Uemura, M.; Isobe, K.; Take, K.; Hayashi, Y. JOC 1983, 48, 3855.
(b) Jaouen, G.; Dabard, R. BSF 1974, 1646.
31. Solladi-Cavallo, A. In Advances in Metal-Organic Chemistry;
Liebeskind, L. S., Ed.; JAI: London, 1989; Vol. 1, pp 99-133.
32. (a) Solladi-Cavallo, A.; Solladi, G.; Tsamo, E. Inorg. Synth. 1985,
23, 85. (b) Solladi-Cavallo, A.; Solladi, G.; Tsamo, E. JOC 1979, 44,
4189. (c) Davies, S. G.; Goodfellow, C. L. SL 1989, 59.
33.
(a) Top, S.; Jaouen, G.; Gillois, J.; Baldoli, C ; Maiorana, S. CC 1988,
1284. (b) Yamazaki, Y.; Hosono, K. TL 1989, 30, 5313. (c) Nakamura,
K.; Ishihara, K.; Ohno, A.; Uemura, M.; Nishimura, H.; Hayashi, Y. TL
1990,57,3603.
34.
(a) Kondo, Y.; Green, J. R.; Ho, J. JOC 1993, 58, 6182. (b) Aub, J.;
Heppert, J. A.; Milligan, M. L.; Smith, M. J.; Zenk, P. JOC 1992, 57,
3563.
Alexakis, A.; Mangeney, P.; Marek, I.; Rose-Munch, F.; Rose, E.; Semra,
A.; Robert, F. JACS 1992, 114, 8288.
Uemura, M.; Nishimura, H.; Hayashi, T. TL 1993, 34, 107.
35.
36.
HEXAMETHYLDISILAZANE
37.
(a) Uemura, M.; Miyake, R.; Nakayama, K.; Shiro, M ; Hyashi, Y. JOC
1993,58,1238. (b) Uemura, M.; Miyake, R.; Nishimura, H.; Matsumoto,
Y.; Hayashi, T. TA 1992, 3, 213. (c) Heaton, S. B.; Jones, G. B. TL 1992,
33, 1693.
Motokazu Uemura
Osaka City University, Japan
Hexamethyldisilazane
[999-97-3]
C 6 H 19 NSi 2
(MW 161.44)
(selective silylating reagent;1 animating reagent; nonnucleophilic

base2)
Alternate Name: HMDS.
Solubility: sol acetone, benzene, ethyl ether, heptane, perchloroethylene.
Form Supplied in: clear colorless liquid; widely available.
Purification: may contain trimethylsilanol or hexamethyldisiloxane; purified by distillation at ambient pressures.
Handling, Storage, and Precautions: may decompose on exposure
to moist air or water, otherwise stable under normal tempera
tures and pressures. Harmful if swallowed, inhaled, or absorbed
through skin. Fire hazard when exposed to heat, flames, or ox
idizers. Use in a fume hood.
Silylation. Alcohols,3 amines,3 and thiols4 can be trimethylsilylated by reaction with hexamethyldisilazane (HMDS). Ammo
nia is the only byproduct and is normally removed by distillation
over the course of the reaction. Hydrochloride salts, which are typ
ically encountered in silylation reactions employing chlorosilanes,
are avoided, thereby obviating the need to handle large amounts
of precipitates. Heating alcohols with hexamethyldisilazane to re
flux is often sufficient to transfer the trimethylsilyl group (eq 1).5
Completion of the reaction is indicated by either a change in the re
flux temperature (generally a rise) or by the cessation of ammonia
evolution.
205
the reaction is much faster in the presence of iodide, presumably

due to the in situ formation of a catalytic amount of the more
reactive Iodotrimethylsilane.
(2)
Hexamethyldisilazane is the reagent of choice for the direct

trimethylsilylation of amino acids, for which TMSC1 cannot be
used due to the amphoteric nature of the substrate.9 Silylation
of glutamic acid with excess hexamethyldisilazane and catalytic
TMSC1 in either refluxing xylene or acetonitrile followed by dilu
tion with alcohol (methanol or ethanol) yields the derived lactam
in good yield (eq 3).10
(3)
The efficiency of HMDS-mediated silylations can be markedly

improved by conducting reactions in polar aprotic solvents. For
example, treatment of methylene chloride solutions of primary al
cohols or carboxylic acids at ambient temperatures with HMDS
(0.5-1 equiv) in the presence of catalytic amounts of TMSC1 (0.1
equiv) gives the corresponding silyl ether and the trimethylsilyl
ester, respectively (eq 4).1 N-Silylation of secondary amines oc
curs in preference to primary alcohols when treated with 1 equiv
of HMDS and 0.1 equiv TMSC1 (eq 5). The silylation of secondary
amines cannot be effected in the absence of solvent.5 Secondary
and tertiary alcohols can also be silylated at ambient temperatures
in dichloromethane with HMDS and TMSC1 mixtures; however,
stoichiometric quantities of the silyl chloride are required. Catal
ysis by 4-Dimethylaminopyridine (DMAP) is necessary for the
preparation of tertiary silyl ethers.
(4)
(5)
(1)
Silylation with HMDS is most commonly carried out with

acid catalysis.5 The addition of substoichiometric amounts of
Chlorotrimethylsilane (TMSC1) to the reaction mixtures has been
found to be a convenient method for catalysis of the silylation
reaction.5,6 The catalytically active species is presumed to be
hydrogen chloride, which is liberated upon reaction of the
chlorosilane with the substrate. Alternatively, protic salts such
as ammonium sulfate can be employed as the catalyst.7 Addition
of catalytic Lithium Iodide in combination with TMSC1 leads
to even greater reaction rates.8 Anilines can be monosilylated by
heating with excess HMDS (3 equiv) and catalytic TMSC1 and
catalytic Lil (eq 2). Silylation occurs without added Lil; however,
DMF is a useful solvent for HMDS-induced silylation reactions,

and reaction rates 10-20 times greater than those carried out in
pyridine have been reported.11 DMSO is also an excellent solvent;
however, a cosolvent such as 1,4-dioxane is required to provide
miscibility with HMDS.12
Imidazole (ImH) catalyzes the silylation reaction of primary,
secondary, and tertiary alkanethiols with hexamethyldisilazane.12
The mechanism is proposed to involve the intermediacy
of N-(Trimethylsilyl)imidazole (ImTMS), since its prepa
ration from hexamethyldisilazane and imidazole to yield
l-(trimethylsilyl)imidazole is rapid.13 The imidazole-catalyzed
206
HEXAMETHYLDISILAZANE
reactions of hexamethyldisilazane, however, are more efficient

than the silylation reactions effected by ImTMS (eq 6 vs. eq 7) due
to reversibility of the latter. Imidazole also catalyzes the reaction
of HMDS with Hydrogen Sulfide, which provides a convenient
preparation of hexamethyldisilathiane, a reagent which has found
utility in sulfur transfer reactions.14
(6)
(7)
Titanium(IV) Chloride (eq 11).20 The reaction is successful for

sterically hindered ketones even though HMDS is a bulky amine
and a poor nucleophile. The use of ammonia is precluded in these
reactions since it forms an insoluble complex with TiCl4.
(11)
The reaction of phenols with diphenylseleninic anhydride

and hexamethyldisilazane gives the corresponding phenylselenoimines (eq 12).21 The products thus obtained can be converted
to the aminophenol or reductively acetylated using Zinc and Acetic
Anhydride. The use of ammonia or tris(trimethylsilyl)amine in
place of HMDS gives only trace amounts of the selenoimines.
Silyl Enol Ethers. Silylation of 1,3-dicarbonyl compounds can

be accomplished in excellent yield by heating enolizable 1,3dicarbonyl compounds with excess HMDS (3 equiv) and catalytic
imidazole (eq 8).15
(8)
In combination with TMSI, hexamethyldisilazane is useful

in the preparation of thermodynamically favored enol ethers
(eq 9).16 Reactions are carried out at rt or below and are complete
within 3 h.
(9)
(12)
Related Reagents. N,O-Bis(trimethylsilyl)acetamide; N,N'Bis(trimethylsilyl)urea; Chlorotrimethylsilane; Cyanotrimethylsilane; Hexamethyldisiloxane; Iodotrimethylsilane; N-(Trimethylsilyl)imidazole.
1.
2.
3.
4.
5.
6.
7.
8.
Related thermodynamic enolization control has been observed

using metallated hexamethyldisilazide to give the more substi
tuted bromomagnesium ketone enolates.17 Metallation reactions
of HMDS to yield Li, K, and Na derivatives are well known and the
resulting nonnucleophilic bases have found extensive applications
in organic synthesis (see Lithium Hexamethyldisilazide, Potassium Hexamethyldisilazide, Sodium Hexamethyldisilazide).2
Amination Reactions. Hexamethyldisilazane is a useful synthon for ammonia in amination reactions. Preparation of primary
amides by the reaction of acyl chlorides and gaseous Ammonia,
for example, is not an efficient process. Treatment of a variety of
acyl halides with HMDS in dichloromethane gives, after hydrol
ysis, the corresponding primary amide (eq 10).18 Omitting the
hydrolysis step allows isolation of the corresponding monosilyl
amide.19
(10)
Reductive aminations of ketones with HMDS to yield abranched primary amines can be effected in the presence of
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
Cossy, J.; Pale, P. TL 1987, 28, 6039.

Colvin, E. W. Silicon in Organic Synthesis, Butterworths: London, 1981.
Speier, J. L. JACS 1952, 74, 1003.
Bassindale, A. R.; Walton, D. R. M. JOM 1970, 25, 389.
Langer, S. H.; Connell, S.; Wender, I. JOC 1958, 23, 50.
Sweeley, C. C ; Bentley, R.; Makita, M.; Wells, W. W. JACS 1963, 85,
2497.
Speier, J. L.; Zimmerman, R.; Webster, J. JACS 1956, 78, 2278.
Smith, A. B., III; Visnick, M.; Haseltine, J. N.; Sprengeler, P. A. T 1986,
42, 2957.
Birkofer, L.; Ritter, A. AG(E) 1965, 4, 417.
Pellegata, R.; Pinza, M.; Pifferi, G. S 1978, 614.
Kawai, S.; Tamura, Z. CPB 1967, 15, 1493.
Glass, R. S. JOM 1973, 61, 83.
Birkofer, L.; Richter, P.; Ritter, A. CB 1960, 93, 2804.
Harpp, D. N.; Steliou, K. S 1976, 721.
Torkelson, S.; Ainsworth, C. 5 1976, 722.
(a) Hoeger, C. A.; Okamura, W. H. JACS 1985, 107, 268. (b) Miller, R.
D.; McKean, D. R. S 1979, 730.
Kraft, M. E.; Holton, R. A. TL 1983, 24, 1345.
Pellegata R.; Italia, A.; Villa, M. S 1985, 517.
Bowser, J. R.; Williams, P. J.; Kuvz, K. JOC 1983, 48, 4111.
Barney, C. L.; Huber, E. W.; McCarthy, J. R. TL 1990, 31, 5547.
Barton, D. H. R.; Brewster, A. G.; Ley, S. V.; Rosenfeld, M. N. CC 1977,
147.
Lilly Research Laboratories,
Benjamin A. Anderson
Indianapolis, IN, USA
HEXAMETHYLPHOSPHORIC TRIAMIDE
207
may exert its reactivity effects by a combination of one or more

of the following:
1. lowering the degree of aggregation16,17 or forming separated
ions, 18
2. increasing reactivity through cation coordination,17
3. activating the aggregate through insertion into the aggregate
site normally occupied by the anionic fragment,5,19
[680-31-9]
C 6 H 18 N 3 OP
(MW 179.24)
4. promoting triple ion (ate complex) formation.16a,20
(high Lewis basicity; dipolar aprotic solvent with superb ability

to form cation-ligand complexes; can enhance the rates of a wide
variety of main group organometallic reactions and influence
regio- or stereochemistry; additive in transition metal chemistry;
UV inhibitor in poly(vinyl chloride))
Alternate Names: HMPA; hexamethylphosphoramide; hexametapol; hempa; HMPT.
Physical Data: mp 7.2 C; bp 230-232 C/740 mmHg; d
1.025 g c m - 3 ; mild amine odor.
Solubility: sol water, polar and nonpolar solvents.
Form Supplied in: water-white liquid.
Drying: distilled from CaH 2 or BaO 1 at reduced pressure and
stored under N 2 over molecular sieves.
Handling, Storage, and Precautions: has low to moderate acute
toxicity in mammals.2a Inhalation exposure to HMPA has been
shown to induce nasal tumors in rats, 2b and has been classified
under 'Industrial Substances Suspect of Carcinogenic Potential
for Man'. 2c Adequate precautions must be taken to avoid all
forms of exposure to HMPA.
Introduction. Hexamethylphosphoric triamide has been used

extensively as an additive in organolithium chemistry.3 It is among
the strongest of electron pair donors and is superior to protic solvents in that it solvates the cation much better than the
anion.4 This coordinating ability gives HMPA its unusual chemi
cal properties. 5,6 For instance, HMPA dramatically enhances the
rates of a wide variety of organolithium reactions, as well as sig
nificantly influencing regio- or stereochemistry. The reactivity or
selectivity effects of HMPA are usually rationalized in terms of
changes in either aggregation state or ion pair structure.7 The
breaking up of aggregates to form reactive monomers or solventseparated ion pairs is often invoked.
(1)
HMPA can have large effects on equilibria. Phenyllithium reacts

with Diphenylmercury, Diphenyl Ditelluride, and iodobenzene
in THF to form ate complexes. In THF/HMPA the ate complex
formation constants are dramatically higher than in THF. 14,21
Enolate Formation. The formation of lithium enolates is one
instance where HMPA is sometimes needed.22 The difficult gen
eration of dimethyl tartrate acetonide enolate 23 and subsequent
benzylation (eq 2), as well as the double deprotonation of methyl
3-nitropropanoate,24 become possible (eq 3) with the addition of
HMPA (or N,N'-Dimethylpropyleneurea).25
Cosolvent (% vol) Yield (%)
_
HMPA(17)
DMPU (33)
_
Organolithium Reagent Solution Structure. The rate of metalation reactions with Lithium Diisopropylamide as base are sig
nificantly increased through the use of HMPA.8 Treatment of
LDA dimer with HMPA causes sequential solvation of the lithium
cation, but no significant deaggregation;8,9 nor does HMPA pro
mote the break up of tetrameric unhindered phenoxides 10,11 or
tetrameric MeLi. 12 A chiral bidentate lithium amide, 13 however,
was converted from a dimer to a monomer by HMPA, with an in
crease in reactivity and enantioselectivity in deprotonation (eq 1).
HMPA also converts Phenyllithium dimer into monomer. 1214
Other aggregated lithium reagents 12 in THF (MeSLi, LiCl) or
ether (Ph 2 PLi, PhSeLi) are first deaggregated to monomers, and
then solvent-separated ion pair species are formed.12,15 HMPA
HMPA(17)
DMPU (33)
(2)
<5
54
52
(3)
<5
50-85
50-85
Enolate Reactivity. Not only is HMPA necessary to the gen

eration of enolates, it is often needed in the electrophilic trapping
of enolates (eqs 46).26,31 Studies of the electrophilic trapping of
enolates have demonstrated that substantial increases in reaction
rates can be achieved through the use of a polar aprotic solvent
such as HMPA.4
(4)
208
(5)
acidic C-H acids, e.g. (l)-(6), can be successfully metalated

in the presence of HMPA.35 HMPA also aids in the formation
of dianions36 and increases the proton abstraction efficiency of
Sodium Hydride.37,38
(6)
The desired [2,3]-sigmatropic rearrangement of a bis-sulfur

cyano-stabilized lithium salt did not proceed (eq 7) without the ad
dition of 25% HMPA.27 Sometimes higher O/C-alkylation ratios
are obtained in THF-HMPA.28
(7)
Enolate Stereochemistry. Stereochemical control of an ester

enolate Claisen rearrangement was accomplished through stere
oselective enolate formation.29 The enolization of 3-pentanone
with LDA afforded predominantly the (E)-enolate in THF and
the (Z)-enolate in THF-HMPA, as shown by chlorotrialkylsilane
trapping experiments (eq 8). Similar stereoselectivity (Z:E = 94:6)
was obtained with the dipolar aprotic cosolvent DMPU.30
Carbanion Reactivity. An increase in reaction rate is observed

for the reaction of alkynyllithium reagents with alkyl halides3
and oxiranes39 (eq 10). The strongly coordinating HMPA proba
bly complexes the lithium cation, thereby increasing the negative
charge density on the carbon and creating a much more nucleophilic alkynyl anion. A similar effect is observed for (Trimethylstannylmethyl)lithium, which does not react with oxiranes in THF
but in THF-HMPA the reaction proceeds readily.40
(10)
(8)
In addition to altering the (E/Z) isomer ratio of enolates,17,32

HMPA has a noticeable effect on the metalation of imines and
their subsequent alkylation (eq 9).33 When the metalation (by sButyllithium) of an asymmetric imine is performed in THF, a
subsequent alkylation gives about a 1:1 mixture of regioisomers.
In the presence of HMPA, however, only the regioisomer due to
alkylation at the less-substituted site was observed. A synthetically
useful solvent effect for HMPA is also observed in the asymmet
ric synthesis of trimethylsilyl enol ethers by chiral lithium amide
bases.34 The asymmetric induction in THF can be greatly im
proved by simply adding HMPA as a cosolvent.
(9)
Carbanion Formation. Often substrates that cannot be metalated by LDA or n-Butyllithium in THF can be successfully deprotonated by adding HMPA as a cosolvent. Many other weakly
The decarboxylation41 of 4-t-butyl-l-phenyl-1-carboxycyclohexane with Methyllithium gave a mixture of axial and

equatorial products (eq 11), which was highly dependent on
the nature of the solvent at the time of aqueous workup. Axial
protonation was favored in ether-HMPA.
(11)
HMPA is also the only dipolar aprotic solvent to be used ex

tensively with organomagnesium compounds.42 Large effects are
observed when HMPA is used as either a solvent or a cosolvent. As
examples, HMPA accelerates addition of an allylic organomagne
sium compound to aryl-substituted alkenes,43 addition of Grignard
reagents to Carbon Monoxide,44 and addition of Propargylmagnesium Bromide to allylic halides to give allene products.45
Carbanion Regioselectivity (1,2- vs. 1,4-Addition). The regioselectivity of addition of certain organolithium reagents to a,(3unsaturated carbonyl compounds is affected by the addition of
HMPA. In the addition of 2-lithio-2-substituted-l,3-dithiane to
cyclohexenone, there was a complete reversal of regioselectivity
209
from 1,2-addition in THF to 1,4-addition with 2 equiv of HMPA

present (eq 12).46
(15)
Solvent
ether
THF
THF-5% HMPA
THF-20% HMPA
100
95
65
10
5
35
90
(12)
Additive
1,2-Addition
no HMPA
HMPA (2 equiv)
>99
5
1,4-Addition
<1
95
Lithium reagents that exhibit kinetic 1,4-addition in HMPA

are shown as (7)-(14).47 These include useful acyl anion
equivalents48 like phenylthio(trimethylsilyl)methyllithium (see
(Phenylthiomethyl)trimethylsilane).49
Ylide Reactivity. HMPA is used as a cosolvent in the Wittig re

action to increase reaction rate, yield, and stereoselectivity. HMPA
functions as a lithium cation-complexing agent and removes LiBr
salt from ether solution (LiBr/HMPA complexes form precipi
tates in ether).54 Such a 'salt-free' Wittig reaction mixture55 may
be responsible for the high level of cis-alkene observed in reac
tions of nonstabilized ylides with aldehydes in THF or ether with
added HMPA2556 (eq 16). Similarly, increased (Z) selectivity is
observed in the Wittig alkenation of 2-oxygenated ketones (eq 17)
to generate protected (Z)-trisubstituted allylic alcohols.55,57
(16)
46
44
39
HMPA (35)
DMPU (35)
(Z)
(E)
83
92
93
17
8
7
(17)
A carboxy anion equivalent was reported to undergo 1,2addition in the absence of HMPA;50 however, with 10 equiv of
HMPA present only 1,4-addition was observed (eq 13). The addi
tion of 1 equiv of HMPA promotes conjugate addition of alkyl and
phenylthioallyl anions to cyclopentanones (eq 14) through the position, whereas in THF alone, irreversible 1,2-addition occurs
with both - and -attack.51 The regioselectivities reported for
the addition to cyclic enones of ketene dithioacetal anions47a,52
or t-Butyllithium (eq 15)53 are also influenced by HMPA (and
counterion).
THF-HMPA
THF
(E):(Z) Yield (%) (E):(Z) Yield (%)
Me 2.6:1
Ph
5:1
TBS 7.6:1
Bz 1.1:1
50
77
61
55
8:1
10:1
26:1
36:1
76
84
90
86
With HMPA, Wittig reactions that give (E)-alkenes were also

observed (eq 18),58 as was the directed selectivity of a semistabilized arsonium ylide towards carbonyl compounds. The arsenic
ylide was generated from LDA in THF or THF/HMPA solution to
give exclusively epoxide (eq 19) or diene (eq 20), respectively.59
(13)
(18)
Ylide
(14)
Solvent
(E):(Z) Yield (%)
65:35
THF
Y=P
Y = P THF-HMPA 85:15
Y = As
THF
Y = As THF-HMPA 100:0
91
87
65
210
(19)
The conversion of cyclic alkenes to 1,3-cycloalkadienes can

be performed through a bromination/dehydrobromination proce
dure using LiCl/Lithium Carbonate/HMPA (eq 23). 70 The dehydrobromination of 2,3-dibromo-3-methyl-l-butanol to generate a
vinyl bromide has been accomplished through the use of 2.3 equiv
of LDA and 0.5 equiv of HMPA in THF at - 7 8 C. 71
(23)
(20)
Nucleophilic Cleavage of Esters and Ethers. The conver

sion of hindered methyl esters to carboxylic acids, and the
demethylation of methyl aryl ethers, can be effectively per
formed by using HMPA to increase the nucleophilicity of lithium
methanethiolate.60 HMPA (or N,N-Dimethylformamide) will also
facilitate the cleavage of methyl aryl ethers and their methylthio
analogs by sodium methaneselenolate (see Methaneselenol) to
give the phenol or thiophenol, respectively.60,61 Sodium efhanefhiolate (see Ethanethiol) in refluxing DMF or HMPA attacks alkyl
aryl selenides to give the corresponding diselenides. The most
reactive combination of solvent and halide salt for the decar
boxylation of -keto esters was found to be Lithium Chloride/HMPA, used as part of a stereoselective synthesis of 11deoxyprostaglandin E 1 . 62 In HMPA, the rate of ester cleavage
of 2-benzyl-2-methoxycarbonyl-l-cyclopentanone with Sodium
Cyanide is 30 times as fast as the more commonly used DMF. 62a
Anion Reactivity. HMPA is one of the most potent electron
pair donor solvents available for accelerating S N 2 reactions. 3,43a
The formation, for example, of an -silyl carbanion for use in a
Peterson alkenation reaction63 can be accomplished by the dis
placement of silicon using Sodium Methoxide64 or Potassium
t-Butoxide65 in HMPA (eq 21). The increased nucleophilicity of
halide ions in the presence of HMPA is seen by the increased
rate of silyl-protecting group removal with fluoride ion (Tetra-nbutylammonium Fluoride).66 The substitution of aryl chlorides
can be performed using sodium methoxide in HMPA67 to give
anisole derivatives, or by using sodium methanethiolate (MeSNa)
(see Methanethiol) in HMPA 61b,68 to generate either aryl methyl
sulfides or aryl thiols, depending on the reaction conditions. The
increased nucleophilicity of a magnesium alkoxide is demon
strated by the cyclization of a chloro alcohol to a 13-membered
cyclic ether (eq 22) upon treatment of the compound with Ethylmagnesium Bromide in refluxing THF/HMPA.69
(21)
(22)
Low-Valent Metal Coordination (Lanthanoids). HMPA is

used extensively as a solvent for dissolving-metal reductions.72
Used as a cosolvent (5-10%), it remarkably accelerates the oneelectron transfer reduction of organic halides by Samarium(II)
Iodide.73 The reductions work on a variety of primary, secondary,
or tertiary halides, including chlorides which could not be reduced
in pure THF (eq 24). The samarium Barbier reaction, which re
quires hours in refluxing THF, can be performed as a titration
in THF-HMPA at rt (eq 25). 74 The SmI2/THF/HMPA system
has recently been used in the deoxygenation of organoheteroatom
oxides,75 reductive dimerization of conjugated acid derivatives,76
and selective reduction of ,-unsaturated carbonyl compounds. 77
In addition, SmI 2 was used in a tandem radical cyclization,78 and
has been a useful reagent in Barbier-type reactions. 73b,79 The
dramatic acceleration of electron transfer is also observed for
Ytterbium(0).80
(24)
THF
Time
THF-HMPA
Yield Time Yield
6h
95% 5 min >95%
2 days 82% 10 min >95%
no reac tion
8h
>95%
(25)
Additive Time Yield

none
HMPA
4 h 82%
1 min 95%
Transition Metal Coordination. The ability of HMPA to

complex to metals and alter reactivity is also expressed in
palladium-catalyzed coupling reactions. For example, ethylbenzene can be formed from the Pd catalyzed cross-coupling of
Benzyl Bromide and Tetramethylstannane, with the formation
of almost no bibenzyl. 81 The reaction does not proceed in THF,
but requires a highly polar solvent like HMPA or 1-Methyl-2pyrrolidinone. Similarly, HMPA is necessary in the Pd-catalyzed
coupling of acid chlorides with organotin reagents to give ke
tones. In highly polar solvents like HMPA the transfer of a chiral
211
group from the tin occurs with preferential inversion of config

uration (eq 26).82 The relative rate of transfer of an alkynic or
vinyl group to acid chlorides82a or aryl iodides83 is also greatly
accelerated by HMPA. It can increase the rate of alkylation of TTallylpalladium chloride by ester enolates,84 and alter the chemoselectivity by leading to a cyclopropanation reaction instead of an
allylic alkylation.85
98
in ether or THF at very low temperature. Exchange, however,

is slowed in THF/HMPA or THF/12-crown-4, so that coupling is
easily observed. The effect of HMPA suggests that Li + is involved
in the exchange process.
(26)
(27)
Hydride Reductions. The reduction of organic compounds by

hydride can be influenced by the choice of cosolvent. Cyanoborohydrides (e.g. Sodium Cyanoborohydride) in HMPA provide a
mild, effective, and selective reagent system for the reductive
displacement of primary and secondary alkyl halides and sul
fonate esters in a wide variety of structural types.86 A Sodium
Borohydride/HMPA reagent system was used in the reduction
of N,N-disulfonamides87 and in the reduction of dibromides to
monobromides.37a Similarly, Tri-n-butylstannane/HMPA88 can
be utilized to chemoselectively reduce aldehydes with additional
alkene or halide functionality.89 Finally, the reduction of aldehy
des and ketones with hydrosilanes proceeds in the presence of
a catalytic amount of Bu4NF in HMPA.90 The reaction rate was
much lower in DMF than in HMPA, and the reaction yields de
creased considerably if less polar solvents like THF or CH2Cl2
were used.
Additive
none
HMPA
(12 equiv)
Proton, at C- Proton, at C-10

57
>95
43
<5
(28)
Oxidation. The oxidation of acid sensitive alcohols with

Chromium(VI) Oxide in HMPA is one example of the use
of HMPA in oxidation reactions.91 (CAUTION: Do not crush
CrO3 prior to reaction since violent decomposition can oc
cur. The use of DMPU has been reported to have a sim
ilar hazardous effect). Recently, a Bromine/NaHCO3/HMPA
system92 was used for the oxidative esterification of alcohols with
aldehydes, where the HMPA considerably accelerated the ox
idation by bromine and lowered the rate of unwanted haloHMPA Substitutes and Analogs. Researchers have searched
genation. Epoxidations of alkenes or allylic alcohols have been
for an alternative to HMPA. Such a solvent must be stable to
accomplished using MoO5. HMPA.pyridine (Oxodiperoxymolybpolar organometallic compounds and be comparable to HMPA in
denum(pyridine)(hexamethylphosphoric triamide); MoOPH).93
its many functions. Replacement solvents typically are useful in
some applications but have limited value in others. Examples of
Effect of HMPA on Protonation. The protonation of (9some useful alternatives are (15)-(19).30,42,99
anthryl)arylmethyllithium with various oxygen and carbon acids
in THF or in THF-HMPA had a significant effect on the product
ratio ofC-vs. C-10 protonation (eq 27).94 Another study95 found
that a nitronate protonation led to mainly one diastereomeric prod
uct in a THF solution containing HMPA or DMPU (eq 28). Panek
and Rodgers96 observed stereospecific protonation of 10-t-butyl9-methyl-9-lithio-9,10-dihydroanthracene: >99% cis protonation
was observed in THF or ether with greater than >99% trans pro
tonation observed in HMPA.
Inhibition by HMPA. Finally, it should be added that there
are a few cases where HMPA slows the rate of a reaction. Such
examples typically involved the inhibition of lithium catalysis by
strong coordination of HMPA to lithium.97 For instance, two-bond
13
C-13C NMR coupling in organocuprates is poorly observable
Chiral analogs of HMPA, (20)-(22), have been used as ligands

in transition metal complexes.93b,100
212
Seebach, D.; Siegel, H.; Gabriel, J.; Hssig, R. HCA 1980, 63, 2046.
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Related
Reagents. N,N-Dimethylformamide; N,N'Dimethylpropyleneurea;
Dimethyl
Sulfoxide;
Hexamethylphosphoric
Triamide-Thionyl
Chloride;
Lithium
Chloride-Hexamethylphosphoric
Triamide;
1-Methyl-2pyrrolidinone; Potassium t-Butoxide-Hexamethylphosphoric
Triamide; Potassium Hydride-Hexamethylphosphoric Tri
amide; Potassium Hydroxide-Hexamethylphosphoric Triamide;
N,N'-Tetramethylethylenediamine.
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(a) Evers, M.; Christiaens, L. TL 1983, 24, 377. Reich, H. J.; Cohen,
M. L. JOC 1979, 44, 3148. (b) Testaferri, L.; Tiecco, M.; Tingoli, M.;
Chianelli, D.; Montanucci, M. S 1983, 751.
Sakurai, H.; Nishiwaki, K.-i.; Kira, M. TL 1973, 4193.
65.
66.
67.
Bassindale, A. R.; Ellis, R. J.; Taylor, P. G. TL 1984, 25, 2705.

Falck, J. R.; Yadagiri, R JOC 1989, 54, 5851.
Shaw, J. E.; Kunerth, D. C ; Swanson, S. B. JOC 1976, 41, 732.
68.
Ashby, E. C ; Park, W. S.; Goel, A. B.; Su, W.-Y JOC 1985, 50, 5184.
69.
Marshall, J. A.; Lebreton, J.; DeHoff, B. S.; Jenson, T. M. JOC 1987,

52, 3883.
Normant, J. F.; Deshayes, H. BSF(2) 1967, 2455. Paquette, L. A.;
Meisinger, R. H.; Wingard, R. E., Jr. JACS 1973, 95, 2230. King, P.
F.; Paquette, L. A. S 1977, 279. Weisz, A.; Mandelbaum, A. JOC 1984,
49, 2648.
Roush, W R.; Brown, B. B. JACS 1993, 115, 2268.
Whitesides, G. M.; Ehmann, W. J. JOC 1970, 35, 3565 and references
cited therein.
71.
72.
73.
74.
99.
100.
Sowinski, A. F.; Whitesides, G. M. JOC 1979, 44, 2369.

(a) Wilson, S. R.; Price, M. F. SC 1982, 12, 657. (b) Bortolini, O.; Di
Furia, F.; Modena, G.; Schionato, A. J. Mol. Catal. 1986, 35, 47.
University
(a) Muller, P.; Siegfried, B. TL 1973, 3565. (b) Kondo, K.; Umemota,
T.; Takahatake, Y.; Tunemoto, D. TL 1977, 113.
Ager, D. J. OR 1990, 38, 1.
64.
70.
Fujita, M.; Hiyama, T. JOC 1988, 53, 5405.

Cardillo, G.; Orena, M.; Sandri, S. S 1976, 394.
Al Neirabeyeh, M.; Pujol, M. D. TL 1990, 31, 2273.
(a) Peyronel, J.-F.; Samuel, O.; Fiaud, J.-C. JOC 1987, 52, 5320 and
references cited therein. (b) Arcoria, A.; Ballistreri, F. P.; Tomaselli, G.
A.; Di Furia, F.; Modena, G. JOC 1986, 57, 2374.
94. Takagi, M.; Nojima, M.; Kusabayashi, S. JACS 1983, 105, 4676.
(a) Inanaga, J.; Ishikawa, M.; Yamaguchi, M. CL 1987, 1485. (b)

Otsubo, K.; Kawamura, K.; Iwanaga, J.; Yamaguchi, M. CL 1987, 1487.
Otsubo, K.; Inanaga, J.; Yamaguchi, M. TL 1986, 27, 5763.
Robert R. Dykstra
of Wisconsin, Madison, WI, USA
Hexamethylphosphorous Triamide1
[1608-26-0]
C 6 H 18 N 3 P
(MW 163.24)
(strong nucleophile;2 used to synthesize epoxides from

aldehydes 2,3 and arene oxides from aryldialdehydes; 4-7 replaces
Ph 3 P in the Wittig reaction;8 with CCl 4 , converts alcohols to
chlorides;9 with l2, converts disulfides to sulfides10 and deoxygenates sulfoxides and azoxyarenes;11 with dialkyl azodicarboxylate and alcohol, forms mixed carbonates;12 reduces ozonides 13 )
Alternate Name: tris(dimethylamino)phosphine.
Physical Data: mp 26 C; bp 162-164 C/760 mmHg, 50C/12
mmHg;n25D 1.4636; d 0.911 g c m - 3 .
214
Form Supplied in: commercially available; liquid, pure grade

>97% (GC).
Preparative Methods: reaction of Phosphorus(III) Chloride with
anhydrous dimethylamine; the same procedure can be used to
obtain higher alkyl homologs.14
Purification: distillation at reduced pressure; exposure of hot liq
uid to air should be avoided.
Handling, Storage, and Precautions: very sensitive to air; best
stored in nitrogen atmosphere; reacts with carbon dioxide; in
halation should be avoided. Use in a fume hood.
Synthesis of Epoxides. Reaction of (Me2N)3P with aromatic

aldehydes provides convenient direct synthetic access to symmet
rical and unsymmetrical epoxides in generally high yields. A typ
ical example is the reaction of o-chlorobenzaldehyde, which pro
vides the corresponding stilbene oxide as a mixture of the trans
and cis isomers (eq 1).2,3
(3)
(Me2N)3P reacts also with saturated and heterocyclic aldehy

des, but 1:1 adducts rather than epoxides are the predom
inant products. The reaction with Chloral takes a different
course2 and yields the dichlorovinyloxyphosphonium compound
Cl2C=CH-O-P(NMe2)3 Cl - .
The scope of the reaction is considerably extended by its ap
plicability to the synthesis of mixed epoxides.2 This is accom
plished by addition of (Me2N)3P to a mixture of aldehydes in
which the less reactive aldehyde predominates. For example, ad
dition of (Me2N)3P to a mixture of o-chlorobenzaldehyde and
2-furaldehyde yields the corresponding mixed epoxide (eq 4).
(4)
(1)
An advantage of the method is that it allows the synthesis of

epoxides unobtainable by the oxidation of alkene precursors with
peroxides or peracids due to the incompatibility of functional
groups with these reagents.
trans:cis = 1.38:1
The coproduct, Hexamethylphosphoric Triamide, is readily

separated by taking advantage of its water solubility. A competing
reaction pathway leads to formation of variable amounts of a 1:1
adduct in addition to the epoxide product (eq 2). Originally the
adduct was assigned the betaine structure (la). On the basis of
more detailed NMR analysis, this was subsequently revised to the
phosphonic diamide structure (lb). 15
(2)
The ratio of products depends upon the electronegativity of the

aldehyde and the mode of carrying out the reaction. Aromatic alde
hydes with electronegative substituents, especially in the ortho
position, undergo rapid exothermic reaction to yield epoxides ex
clusively. Conversely, aldehydes bearing electron-releasing sub
stituents react more slowly to afford mainly 1:1 adducts. Slow
addition of (Me2N)3P to the aldehyde tends to enhance the ratio
of the epoxide product. These observations are compatible with a
mechanism in which an initially formed 1:1 adduct reacts with a
second aldehyde molecule to form a 2:1 adduct which collapses
to yield the observed products (eq 3).
Synthesis of Arene Oxides. Reaction of (Me2N)3P

with aromatic dialdehydes provides arene oxides such as
benz[a]anthracene 5,6-oxide (2a) (eq 5). 4-7 These compounds,
also known as oxiranes, are relatively reactive, undergoing
thermal and acid-catalyzed rearrangement to phenols and facile
hydrolysis to dihydrodiols. Consequently, their preparation and
purification requires mild reagents and conditions. The impor
tance of this is underlined by successful synthesis of the reactive
arene oxide (2b) in 75% yield using appropriate care,7 despite
a previous report of failure of the method.4 While compound
(2b) is a relatively potent mutagen, it is rapidly detoxified by
mammalian cells.6 The principal limitation of the method is the
unavailability of the dialdehyde precursors, which are obtained
through oxidation of the parent hydrocarbons, e.g. by ozonolysis.
(5)
(2a) R = H
(2b) R = Me
Wittig and Horner-Wittig Reactions. (Me 2 N) 3 P may be
used in place of Triphenylphosphine in Wittig reactions with
aldehydes and ketones (eq 6). 8 It is advantageous because the wa
ter solubility of the byproduct, hexamethylphosphoric triamide,
renders it readily removable. This method has been used for the
preparation of unsaturated esters as well as alkenes (eq 7).
215
of configuration. Also, conversion of the salt prepared from reac

tion of (R)-()-2-octanol with (Me 2 N) 3 P/CCl 4 at low temperature
to the corresponding hexafluorophosphate salt, followed by reac
tion of this with potassium phenolate in DMF, gave optically pure
(S)(+)-2-phenoxyoctane in 93% yield (eq 11). 17
(10)
Me2CHCH=CHPh (6)
Nu = Cl, Br, I, N3, NH2, SCN, H
RCH=CHCO2Et (7)
The phosphonic diamide products (lb) obtained from the re

action of arylaldehydes having electron-donating groups with
(Me 2 N) 3 P can be deprotonated by n-Butyllithium in DME at
0 C. 15 These intermediates participate in Horner-Wittig-type re
actions with aromatic aldehydes to give enamines in good yield
(eq 8). In the examples studied the enamines have the (E) con
figuration. Mild acid hydrolysis of the reaction mixtures without
isolating the intermediate enamines provides the corresponding
deoxybenzoins. 15 The overall procedure represents an example of
reductive nucleophilic acylation of carbonyl compounds.
(11)
(Me 2 N) 3 P/CCl 4 may also be employed for the selective functionalization of primary long-chain diols. 17 Reactions of diols of
this type with (Me 2 N) 3 P and CCl 4 in THF followed by addition
of KPF 5 gives mono salts in high yield (eq 12).18 THF serves
to precipitate the mono salts as they are formed, thereby block
ing their conversion to bis salts. Reactions of the mono salts with
various nucleophiles provides the corresponding monosubstituted
primary alcohols.
(12)
(8)
Conversion of Alcohols to Alkyl Chlorides and Other

Derivatives. The reagent combination (Me 2 N) 3 P and CCl4 can
be used in place of Triphenylphosphine-Carbon Tetrachloride
for the conversion of alcohols to alkyl chlorides (eq 9). 9 An ad
vantage is the ease of removal of the water-soluble coproduct
(Me 2 N) 3 P=O. The mechanism entails initial rapid formation of a
quasiphosphonium ion, followed by reaction with an alcohol with
displacement of chloride, and nucleophilic attack by the chloride
ion on the carbon atom of the alcohol in a final rate-determining
step to yield an alkyl chloride.
Nu = I, N3, CN, SCN, MeO
Conversion of Disulfides to Sulfides. Alkyl, aralkyl, and

alicyclic disulfides undergo facile desulfurization to the cor
responding sulfides on treatment with (Me 2 N) 3 P or (Et 2 N) 3 P
(eq 13).10 For example, reaction of methyl phenyl disulfide with
(Et2N)3P in benzene at rt for 1 min furnishes methyl phenyl
sulfide in 86% yield. The desulfurization process is stereospecific, in that inversion of configuration occurs at one of the car
bon atoms a to the disulfide group. Thus desulfurization of cis3,6-dimethoxycarbonyl-l,2-dithiane affords a quantitative yield
of trans-2,5-dimethoxycarbonylthiolane (eq 14). It is worthy of
note that the rates of these reactions are markedly enhanced by
solvents of high polarity.
PhSSMe +
(R2N)3P
PhSMe + (R2N)3P=S
(13)
(9)
This reagent reacts more rapidly with primary than with sec
ondary alcohols. This property has been made use of to transform
the primary hydroxy groups of sugars to salts, which then may
be converted to halides (Cl, Br, I), azides, amines, thiols, thiocyanates, etc. by reaction with appropriate nucleophiles (eq 10).16
Arylalkyl ethers and thioethers may also be prepared by appropri
ate modification of this method.17 These reactions generally pro
ceed with high stereoselectivity. Thus reaction of chiral 2-octanol
with this reagent afforded 2-chlorooctane with complete inversion
(14)
Deoxygenation of Sulfoxides and Azoxyarenes. Sulfoxides

are deoxygenated to sulfides under mild conditions with (Me 2 N) 3 P
activated with Iodine in acetonitrile (eq 15).11 Equimolar ra
tios of the sulfoxide, (Me2N)3P, and I2 are generally employed.
216
HYDRAZINE
Yields are superior to those obtained with either (Me 2 N) 3 p/CCl 4

or Ph 3 P/I 2 . Reaction time is reduced by addition of Sodium Iodide.
Azoxyarenes, such as azoxybenzene, are converted to azoarenes
with this reagent combination under similar mild conditions
(eq 16).11
8.
Oediger, H.; Eiter, K. LA 1965, 682, 58.
9.
Downie, I. M.; Lee, J. B.; Matough, M. F. S. CC 1968, 1350.
10. Harpp, D. N.; Gleason, J. G. JACS 1971, 93, 2437.

11.
Olah, G. A.; Gupta, B. G. B.; Narang, S. C. JOC 1978, 43, 4503.
12. Grynkiewicz, G.; Jurczak, J.; Zamojski, A. T 1975, 31, 1411.

13.
Ph2S + (Me2N)3P=O
Ph2S=O + (Me2N)3P
(15)
Furlenmeier, A.; Frst, A.; Langemann, A.; Waldvogel, G.; Hocks, P.;
Kerb, U.; Wiechert, R. HCA 1967, 50, 2387.
14. Mark, V. OSC 1973, 5, 602.
(16)
15. Babudri, F.; Fiandanese, V.; Musio, R.; Naso, F.; Sciavovelli, O.;
Scilimati, A. S 1991, 225.
16. Castro, B.; Chapleur, Y.; Gross, B. BSF(2) 1973, 3034.
17. Downie, I. M.; Heaney, H.; Kemp, G. AG(E) 1975, 14, 370.
Preparation of Mixed Carbonates. The reaction of

(Me 2 N) 3 P with alcohols and dialkyl azodicarboxylates proceeds smoothly at rt to provide mixed dialkyl carbonate esters
in moderate to good yields (eq 17). 12 An advantage of the
method over the chloroformate method is the neutrality of
the conditions employed. It should be noted that the related
system Triphenylphosphine-Diethyl Azodicarboxylate converts
alcohols into amines.
18.
Boigegrain, R.; Castro, B.; Selve, C. TL 1975, 2529.
Ronald G. Harvey
University of Chicago, IL, USA
Hydrazine1
R1OH + R 2 O 2 C-N=N-CO 2 R 2
R 1 O-CO-OR 2 + HCO2R2 + N 2 (17)
Reduction of Ozonides. In the synthesis of ecdysone from

ergosterol, the ozonide product produced from (5) was reduced
with (Me 2 N) 3 P under mild conditions to the aldehyde (6) without
isomerization (eq 18). 13 The scope of this method has not been
investigated.
(N2H4)
[302-01-2]
(hydrate)
[10217-52-4]
(monohydrate)
[7803-57-8]
(monohydrochloride)
[2644-70-4]
(dihydrochloride)
[5341-61-7]
(sulfate)
[10034-93-2]
H4N2
(MW 32.06)
H5N2O
(MW 49.07)
ClH5N2
(MW 68.52)
C12H6N2
(MW 104.98)
H6N2O4S
(MW 130.15)
(reducing agent used in the conversion of carbonyls to

methylene compounds; 1 reduces alkenes,9 alkynes,9 and nitro groups; 14 converts ,-epoxy ketones to allylic alcohols;32
synthesis of hydrazides; 35 synthesis of dinitrogen containing
heterocycles 42-46 )
(18)
Related Reagents. Diphosphorus Tetraiodide; Tri-ra-butylphosphine; Triphenylphosphine; Raney Nickel.
1.
2.
3.
4.
5.
6.
Wurziger, H. Kontakte (Darmstadt) 1990, 13.

Mark, V. JACS 1963, 85, 1884.
Mark, V. OSC 1973, 5, 358.
Newman, M. S.; Blum, S. JACS 1964, 86, 5598.
Harvey, R. G. S 1986, 605.
Harvey, R. G. Polycyclic Aromatic Hydrocarbons: Chemistry and
Carcinogenesis; Cambridge University Press: Cambridge, 1991; Chapter
12.
7.
Harvey, R. G.; Goh, S. H.; Cortez, C. JACS 1975, 97, 3468.
Physical Data: mp 1.4C;bp 113.5 C; d 1.021 g c m - 3 .

Solubility: sol water, ethanol, methanol, propyl and isobutyl al
cohols.
Form Supplied in: anhydrate, colorless oil that fumes in air; hy
drate and monohydrate, colorless oils; monohydrochloride, di
hydrochloride, sulfate, white solids; all widely available.
Analysis of Reagent Purity: titration.1
Purification: anhydrous hydrazine can be prepared by treating
hydrazine hydrate with BaO, Ba(OH) 2 , CaO, NaOH, or Na.
Treatment with sodamide has been attempted but this yields
diimide, NaOH, and ammonia. An excess of sodamide led to
an explosion at 70 C. The hydrate can be treated with boric
acid to give the hydrazinium borate, which is dehydrated by
heating. Further heating gives diimide.1
Handling, Storage, and Precautions: caution must be taken to
avoid prolonged exposure to vapors as this can cause serious
damage to the eyes and lungs. In cases of skin contact, wash
HYDRAZINE
the affected area immediately as burns similar to alkali con
tact can occur. Standard protective clothing including an am
monia gas mask are recommended. The vapors of hydrazine
are flammable (ignition temperature 270 C in presence of air).
There have been reports of hydrazine, in contact with organic
material such as wool or rags, burning spontaneously. Metal ox
ides can also initiate combustion of hydrazine. Hydrazine and
its solutions should be stored in glass containers under nitrogen
for extended periods. There are no significant precautions for
reaction vessel type with hydrazine; however, there have been
reports that stainless steel vessels must be checked for signifi
cant oxide formation prior to use. Use in a fume hood.
Reductions. The use of hydrazine in the reduction of carbonyl compounds to their corresponding methylene groups via
the Wolff-Kishner reduction has been covered extensively in the
literature.1 The procedure involves the reaction of a carbonylcontaining compound with hydrazine at high temperatures in the
presence of a base (usually Sodium Hydroxide or Potassium Hy
droxide). The intermediate hydrazone is converted directly to the
fully reduced species. A modification of the original conditions
was used by Paquette in the synthesis of ()-isocomene (eq 1).2
(1)
Unfortunately, the original procedure suffers from the drawback

of high temperatures, which makes large-scale runs impractical.
The Huang-Minion modification3 of this procedure revolution
ized the reaction, making it usable on large scales. This proce
dure involves direct reduction of the carbonyl compound with
hydrazine hydrate in the presence of sodium or potassium hy
droxide in diethylene glycol. The procedure is widely applica
ble to a variety of acid-labile substrates but caution must be
taken where base-sensitive functionalities are present. This re
action has seen widespread use in the preparation of a variety of
compounds. Other modifications4 have allowed widespread ap
plication of this useful transformation. Barton and co-workers
further elaborated the Huang-Minion modifications by using an
hydrous hydrazine and Sodium metal to ensure totally anhydrous
conditions. This protocol allowed the reduction of sterically hin
dered ketones, such as in the deoxygenation of 11-keto steroids
(eq 2). 4a Cram utilized dry DMSO and Potassium t-Butoxide in
the reduction of hydrazones. This procedure is limited in that the
hydrazones must be prepared and isolated prior to reduction.4b
The Henbest modification4c involves the utilization of dry toluene
and potassium t-butoxide. The advantage of this procedure is the
low temperatures needed (110C) but it suffers from the draw
back that, again, preformed hydrazones must be used. Utilizing
modified Wolff-Kishner conditions, 2,4-dehydroadamantanone is
converted to 8,9-dehydroadamantane (eq 3). 5
Hindered aldehydes have been reduced using this procedure.6
This example is particularly noteworthy in that the aldehyde is
sterically hindered and resistant to other methods for conversion
to the methyl group.6a Note also that the acetal survives the ma
nipulation (eq 4). The reaction is equally useful in the reduction
of semicarbazones or azines.
217
(2)
(3)
(4)
In a similar reaction, hydrazine has been shown to desulfurize

thioacetals, cyclic and acyclic, to methylene groups (eq 5). The re
action is run in diethylene glycol in the presence of potassium hy
droxide, conditions similar to the Huang-Minion protocol. Yields
are generally good (60-95%). In situations where base sensitivity
is a concern, the potassium hydroxide may be omitted. Higher
temperatures are then required.7
(5)
Hydrazine, via in situ copper(II)-catalyzed conversion to Diimide, is a useful reagent in the reduction of carbon and nitrogen
multiple bonds. The reagent is more reactive to symmetrical rather
than polar multiple bonds (C=N, C=O, N=O, S=O, etc.) 8 and
reviews of diimide reductions are available.9 The generation of
diimide from hydrazine has been well documented and a wide va
riety of oxidizing agents can be employed: oxygen (air), 10 Hydro
gen Peroxide,10 Potassium Ferricyanide ,11 Mercury(II) Oxide,11
Sodium Periodate,12 and hypervalent Iodine13 have all been re
ported. The reductions are stereospecific, with addition occurring
cis on the less sterically hindered face of the substrate.
Other functional groups have been reduced using hydrazine. Nitroarenes are converted to anilines14 in the presence of a variety of
catalysts such as Raney Nickel,14a,15 platinum,14a ruthenium,14a
Palladium on Carbon,16 -iron(III) oxide,17 and iron(III) chlo
ride with activated carbon.18 Graphite/hydrazine reduces aliphatic
and aromatic nitro compounds in excellent yields. 19 Halonitrobenzenes generally give excellent yields of haloanilines. In exper
iments where palladium catalysts are used, significant dehalogenation occurs to an extent that this can be considered a general
dehalogenation method. 20 Oximes have also been reduced. 21
218
HYDRAZINE
Hydrazones. Reaction of hydrazine with aldehydes and ke

tones is not generally useful due to competing azine formation or
competing Wolff-Kishner reduction. Exceptions have been docu
mented. Recommended conditions for hydrazone preparation are
to reflux equimolar amounts of the carbonyl component and hy
drazine in n-butanol.22,23 A more useful method for simple hy
drazone synthesis involves reaction of the carbonyl compound
with dimethylhydrazine followed by an exchange reaction with
hydrazine.24 For substrates where an azine is formed, the hy
drazone can be prepared by refluxing the azine with anhydrous
hydrazine.25 gem-Dibromo compounds have been converted to
hydrazones by reaction with hydrazine (eq 6).26
(6)
compounds have given the expected products, and it therefore

appears this phenomenon is case-specific.33
(9)
Cyclic ,-epoxy ketones have been fragmented upon treatment

with hydrazine to give alkynic aldehydes.34
Hydrazides. Acyl halides,35 esters, and amides react with hy
drazine to form hydrazides which are themselves useful synthetic
intermediates. Treatment of the hydrazide with nitrous acid yields
the acyl azide which, upon heating, gives isocyanates (Curtius
rearrangement).36 Di- or trichlorides are obtained upon reaction
with Phosphorus(V) Chloride.37 Crotonate and other esters have
been cleaved with hydrazine to liberate the free alcohol (eq 10).38
Hydrazones are useful synthetic intermediates and have been

converted to vinyl iodides27 and vinyl selenides (eq 7) (see also
p-Toluenesulfonylhydrazide).28
(7)
R = I, PhSe; RX = I2, PhSeBr
base = pentaalkylguanidine, triethylamine
Diazomalonates have been prepared from dialkyl mesoxylates

via the Silver(I) Oxide-catalyzed decomposition of the inter
mediate hydrazones.29 Monohydrazones of 1,2-diketones yield
ketenes after mercury(II) oxide oxidation followed by heating.30
Dihydrazones of the same compounds give alkynes under similar
conditions.31
Wharton Reaction. ,-Epoxy ketones and aldehydes rear
range in the presence of hydrazine, via the epoxy hydrazone, to
give the corresponding allylic alcohols. This reaction has been suc
cessful in the steroid field but, due to low yields, has seen limited
use as a general synthetic tool. Some general reaction conditions
have been set. If the intermediate epoxy hydrazone is isolable,
treatment with a strong base (potassium t-butoxide or Potassium
Diisopropylamide) gives good yields, whereas Triethylamine can
be used with nonisolable epoxy hydrazones (eq 8).32
(8)
Some deviations from expected Wharton reaction products have

been reported in the literature. Investigators found that in some
specific cases, treatment of ,-epoxy ketones under Wharton
conditions gives cyclized allylic alcohols (eq 9). No mechanistic
interpretation of these observations has been offered. Related
(10)
Hydrazine deacylates amides (Gabriel amine synthesis) via the

Ing-Manske protocol.39 This procedure has its limitations, as
shown in the synthesis of penicillins and cephalosporins where
it was observed that hydrazine reacts with the azetidinone ring. In
this case, Sodium Sulfide was used.40
Heterocycle Synthesis. The reaction of hydrazine with ,unsaturated ketones yields pyrazoles.41,42 Although the products
can be isolated as such, they are useful intermediates in the synthe
sis of cyclopropanes upon pyrolysis of cyclopropyl acetates after
treatment with Lead(IV) Acetate (eq 11).
(11)
3,5-Diaminopyrazoles were prepared by the addition of

hydrazine (eq 12), in refluxing ethanol, to benzylmalononitriles (42-73%).43 Likewise, hydrazine reacted with 1,1diacetylcyclopropyl ketones to give p-ethyl-l,2-azole derivatives.
The reaction mixture must have a nucleophilic component (usually
the solvent, i.e. methanol) to facilitate the opening of the cyclo
propane ring. Without this, no identifiable products are obtained
(eq 13).44
(12)
Ar = Ph, 4-MeC6H4, 3-NO2C6H4
HYDRAZINE
4.
(a) Barton, D. H. R.; Ives, D. A. J.; Thomas, B. R. JCS 1955, 2056.

(b) Cram, D. J.; Sahyun, M. R. V.; Knox, G. R. JACS 1962, 90, 7287.
(c) Grundon, M. F.; Henbest, H. B.; Scott, M. D. JCS 1963, 1855. (d)
Moffett,R.B.;Hunter,J.H.JACS 1951, 73, 1973. (e)Nagata,W.;Itazaki,
H. CI(L)1964, 1194.
5.
6.
Murray, R. K., Jr.; Babiak, K. A. JOC 1973, 38, 2556.

(a) Zalkow, L. H.; Girotra, N. N. JOC 1964, 29, 1299. (b) Aquila, H.
Ann. Chim. 1968,721, 117.
(13)
R 1 ,R 2 = Me, Ph
X = Cl, Br, OMe, OEt, OPh, OAc, CN, etc.
In an attempt to reduce the nitro group of nitroimidazoles, an

unexpected triazole product was obtained in 66% yield. The sug
gested mechanism involves addition of the hydrazine to the ring,
followed by fragmentation and recombination to give the observed
product (eq 14).45
219
7.
vanTamelen, E. E.; Dewey, R. S.; Lease, M. F.; Pirkle, W. H. JACS 1961,

83, 4302.
8. Georgian, V.; Harrisson, R.; Gubisch, N. JACS 1959, 81, 5834.
9.
(a) Miller, C. E. J. Chem. Educ. 1965, 42, 254. (b) Hunig, S.; Muller, H.
R.; Thier, W. AG(E) 1965, 4, 271. (c) Hammersma, J. W.; Snyder, E. I.
JOC 1965, 30, 3985.
10. Buyle, R.; Van Overstraeten, A. Cl(L) 1964, 839.
11.
12:
13.
14.
(14)
Ohno, M.; Okamoto, M. TL 1964, 2423.

Hoffman, J. M., Jr.; Schlessinger, R. H. CC 1971, 1245.
Moriarty, R. M.; Vaid, R. K.; Duncan, M. P. SC 1987, 17, 703.
(a) Furst, A.; Berlo, R. C ; Hooton, S. CRV 1965, 65, 51. (b) Miyata, T.;
Ishino, Y.; Hirashima, T. S 1978, 834.
15. Ayynger, N. R.; Lugada, A. C ; Nikrad, P. V.; Sharma, V. K. S 1981, 640.
16.
(a) Pietra, S. AC(R) 1955, 45, 850. (b) Rondestvedt, C. S., Jr.; Johnson,
T. A. Chem. Eng. News 1977, 38. (c) Bavin, P. M. G. OS 1960, 40, 5.
17. Weiser, H. B.; Milligan, W. O.; Cook, E. L. Inorg. Synth. 1946, 215.
18.
19.
20.
21.
22.
Finally, hydrazine dihydrochloride reacted with 2alkoxynaphthaldehydes to give a product which resulted
from an intramolecular [3 + + 2] criss-cross cycloaddition
(42-87%) (eq 15).46
(15)
23.
24.
Hirashima, T.; Manabe, O. CL 1975, 259.

Han, B. H.; Shin, D. H.; Cho, S. Y. TL 1985, 26, 6233.
Mosby, W. L. CI(L) 1959, 1348.
Lloyd, D.; McDougall, R. H.; Wasson, F. I. JCS 1965, 822.
Schonberg, A.; Fateen, A. E. K.; Sammour, A. E. M. A. JACS 1957, 79,
6020.
Baltzly, R.; Mehta, N. B.; Russell, P. B.; Brooks, R. E.; Grivsky, E. M.;
Steinberg, A. M. JOC 1961, 26, 3669.
Newkome, G. R.; Fishel, D. L. JOC 1966, 31, 611.
25. Day, A. C; Whiting, M. C. OS 1970, 50, 3.

26. McBee, E. T.; Sienkowski, K. J. JOC 1973, 38, 1340.
27. Barton, D. H. R.; Basiardes, G.; Fourrey, J.-L. TL 1983, 24, 1605.
28. Barton, D. H. R.; Basiardes, G.; Fourrey, J.-L. TL 1984, 25, 1287.
29. Ciganek, E. JOC 1965, 30, 4366.
30. (a) Nenitzescu, C. D.; Solomonica, E. OSC 1943, 2, 496. (b) Smith, L.
I.; Hoehn, H. H. OSC 1955, 3, 356.
31. Cope, A. C; Smith, D. S.; Cotter, R. J. OSC 1963, 4, 377.
32.
33.
Dupuy, C ; Luche, J. L. T 1989, 45, 3437.

(a) Ohloff, G.; Unde, G. HCA 1970, 53, 531. (b) Schulte-Elte, K.
N.; Rautenstrauch, V.; Ohloff, G. HCA 1971, 54, 1805. (c) Stork, G.;
Williard, P. G. JACS 1977, 99, 7067.
34.
Peptide Synthesis. Treatment of acyl hydrazides with nitrous

acid leads to the formation of acid azides which react with amines
to form amides in good yield. This procedure has been used in
peptide synthesis, but is largely superseded by coupling reagents
such as 1,3-Dicyclohexylcarbodiimide.47
1.
(a) Todd, D. OR 1948, 4, 378. (b) Szmant, H. H. AG(E) 1968, 7, 120. (c)
Reusch, W. Reduction; Dekker: New York, 1968, pp 171-185. (d) Clark,
C. Hydrazine; Mathieson Chemical Corp.: Baltimore, MD, 1953.
2.
Paquette, L. A.; Han, Y. K. JOC 1979, 44, 4014.
3.
(a) Huang-Minion JACS 1946, 68, 2487; 1949, 71, 3301. (b) Durham,
L. J.; McLeod, D. J.; Cason, J. OSC 1963, 4, 510. (c) Hunig, S.; Lucke,
E.; Brenninger, W. OS 1963, 43, 34.
(a) Felix, D.; Wintner, C ; Eschenmoser, A. OS 1976, 55, 52. (b) Felix,
D.; Muller, R. K.; Joos, R.; Schreiber, J.; Eschenmoser, A. HCA 1972,
55, 1276.
35. ans Stoye, P. In The Chemistry of Amides (The Chemistry of Functional
Groups); Zabicky, J., Ed.; Interscience: New York, 1970; pp 515-600.
36. (a) The Chemistry of the Azido Group; Interscience: New York, 1971.
(b) Pfister, J. R.; Wymann, W. E. 5 1983, 38.
37. (a) Mikhailov, Matyushecheva, Derkach, Yagupol'skii ZOR 1970, 6,147.
(b) Mikhailov, Matyushecheva, Yagupol'skii ZOR 1973, 9, 1847.
38.
39.
40.
41.
42.
43.
Arentzen, R.; Reese, C. B. CC 1977, 270.

Ing, H. R.; Manske, R. H. F. JCS 1926, 2348.
Kukolja, S.; Lammert, S. R. JACS 1975, 97, 5582 and 5583.
Freeman, J. P. JOC 1964, 29, 1379.
Reimlinger, H.; Vandewalle, J. J. M. ANY 1968, 720, 117.
Vequero, J. J.; Fuentes, L.; Del Castillo, J. C ; Perez, M. L; Garcia, J. L.;
Soto, J. L. S 1987, 33.
220
1 -HYDROXYBENZOTRIAZOLE
44.
Kefirov, N. S.; Kozhushkov, S. I.; Kuzetsova, T.S.T 1986, 42, 709.
45.
Goldman, P.; Ramos, S. M.; Wuest, J. D. JOC 1984, 49, 932.
46.
Shimizu, T.; Hayashi, Y.; Miki, M.; Teramura, K. JOC 1987, 52, 2277.
47.
Bodanszky, M. The Principles of Peptide Synthesis; Springer: New York,

1984; p 16.
Brian A. Roden
1 -Hydroxybenzotriazole1
[2592-95-2]
(hydrate)
[123333-53-9]
C6H5N3O
contamination with dicyclohexylurea and the method is un

satisfactory for the coupling of TV-methylated amino acids. 3
The problem of purification can often be overcome by using
an alternative carbodiimide, e.g. ones that give water-soluble
byproducts can be used, such as EDCMel (see l-Ethyl-3-(3'dimethylaminopropyl)carbodiimide Hydrochloride).4 Polymerbound variants of HOBT have also been used to overcome purifi
cation problems, 5 since the urea byproduct can be removed from
the polymer-bound active ester intermediate (1) by washing with
chloroform-isopropyl alcohol mixtures. Once the urea has been
removed, the active ester can be reacted with the second peptide
fragment to give the product (eq 2), regenerating the polymerbound HOBT. While this method appears quite successful for the
preparation of small peptide fragments, it is clearly unsuitable for
the preparation of larger peptides by solid-phase synthesis.
(MW 135.14)
(peptide synthesis; nucleotide synthesis)

Alternate Names: HOBT; HOBt.
Physical Data: mp 155-160 C; exact melting point depends on
the amount of water of hydration present.
Form Supplied in: white solid usually containing 12-17% water
of hydration; widely available commercially.
Analysis of Reagent Purity: should be a white solid; if it becomes
discolored, it is advisable to purify.
Purification: recrystallize from either water or aqueous ethanol.
Handling, Storage, and Precautions: should be stored in the dark;
avoid contact with strong acids, oxidizing agents, and reducing
agents; heating above 180C causes rapid exothermic decom
position; toxicity not fully investigated so should be treated with
caution.
Peptide Coupling. 1-Hydroxybenzotriazole is most widely

used in reactions involving the coupling of amino acid units to
give peptides. 1 In this context it has been used mainly as an
'additive' to a coupling reaction, although there are also ex
amples of HOBT being incorporated into the coupling reagent
itself. The most common use of 1-hydroxybenzotriazole in pep
tide synthesis is in conjunction with a carbodiimide such as 1,3Dicyclohexylcarbodiimide (DCC). Although it is quite possible
to couple amino acids using DCC alone, it is found that the ad
dition of 1-hydroxybenzotriazole to the reaction system results in
improved reaction rates and suppressed epimerization of the chiral centres present in the peptide (eq 1). 2 This reaction appears to
proceed via DCC-mediated formation of a hydroxybenzotriazole
ester intermediate which then reacts with the amino function of a
second amino acid to give the coupled product.
This coupling protocol is not limited to the synthesis of
small peptides in solution, but can also be used in the
solid-phase preparation of larger peptides, and for the cou
pling of larger peptide fragments. It should be noted, how
ever, that there are some drawbacks to this method; most no
tably, it is sometimes difficult to purify the peptide due to
(1)
<0.1%DL
(1.8% DL in absence of HOBT)
(2)
Although the addition of HOBT to the carbodiimide-mediated

coupling of amino acids has been shown to suppress epimerization
of the chiral centres present, there are still a number of cases
where the level of epimerization is unsatisfactory. One method for
further suppressing epimerization is to add Copper(II) Chloride
to the reaction system.6 In this case it is important that the correct
stochiometry is determined, since the copper(II) chloride not only
suppresses epimerization, but it also slows down the reaction rate
and reduces the overall yield (eq 3).
The problem of epimerization during carbodiimide-mediated
coupling of amino acids can also be overcome by the use
of an alternative coupling agent. Once such system that
still employs HOBT as an additive involves the use of
bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl) and N-
1 -HYDROXYBENZOTRIAZOLE
methylmorpholine (NMM) (eq 4).
oxazolidinyljphosphinic Chloride.
See also
Bis(2-oxo-3-
221
As mentioned earlier, HOBT has also been incorporated into the

peptide coupling reagent itself and one example of such a reagent
is benzotriazol-l-yloxytris(dimethylamino)phosphonium chlo
ride (BOP).12 BOP is prepared by the reaction of HOBT with Hexamethylphosphorous Triamide in the presence of carbon tetra
chloride, and is very effective in the coupling of amino acids (eq 6).
See also
Hexafluorophosphate (also known as BOP).
(3)
HOBT
CuCl2
0 equiv
0 equiv
1 equiv
0 equiv
1 equiv 0.25 equiv
%DL % Yield
38
22
1.3
96
<0.1
79
(6)
(4)
HOBT has also been used as an additive in other reactions in

volving amino acid derivatives.8 It would appear that most reaction
systems that are capable of generating a hydroxybenzotriazole es
ter intermediate will give successful coupling. One such system
involves the use of amino acid derived trichlorophenyl esters.9
These can be readily reacted with a second amino acid unit in the
presence of HOBT to give the coupled product with little or no
racemization (eq 5). p-Nitrophenyl and pentachlorophenyl esters
can also be employed with similar success. This reaction again
is thought to proceed via the hydroxybenzotriazole ester inter
mediate and it has been shown that use of the potassium salt of
HOBT in conjunction with a crown ether can lead to substantial
rate increase,10 presumably by enhancing the rate of formation of
the active ester intermediate.
(5)
HOBT has also been used in conjunction with amino acid chlo
rides to facilitate peptide bond formation. This has proved of par
ticular use in the case of FMOC-protected amino acid chlorides in
solid-phase peptide synthesis where direct coupling is rather slow
and suffers from competing oxazolone formation.11
A second peptide coupling reagent that incorporates the HOBT

unit is 0-Benzotriazol-l-yl-N,N,N',N'-tetramethyluronium
Hexafluorophosphate (HBTU), 13 which can be prepared by the reac
tion of tetramethylurea with oxalyl chloride followed by treat
ment with HOBT and Potassium Hexafluorophosphate. HBTU
can then be used as a direct coupling agent as outlined in eq 7.
(7)
Nucleotide Synthesis. Phosphotriester derivatives of HOBT

have been employed in the synthesis of nucleotides.14 The phosphotriesters are readily formed by reaction of HOBT with the cor
responding aryl phosphorodichloridates in the presence of pyri
dine and can then be used to couple nucleosides as outlined in eq 8.
This reaction takes advantage of the fact that a differentially pro
tected nucleoside will react rapidly with the reagent, displacing
one molecule of HOBT to form an intermediate phosphotriester
(2), but at this stage reaction with a second nucleoside molecule
is extremely slow due to steric hindrance. Consequently the inter
mediate can then be reacted with a second nucleoside, the more re
active primary hydroxy displacing the second molecule of HOBT
and giving the coupled product. This method for coupling nucleo
sides has been applied to both solution and solid-phase synthesis
of a variety of RNA fragments.
Other Applications. HOBT has also been employed as a cat
alyst for the conversion of isoamides into maleimides (eq 9).
222
N-HYDROXYPYRIDINE-2-THIONE
9.
10. Horiki, K.; Murakami, A. H 1989, 28, 615.

11.
Carpino, L. A.; Chao, H. G.; Beyermann, M.; Bienert, M. JOC 1991, 56,
2635; Sivanandaiah, K. M.; Babu, V. V. S.; Renukeshwar, C. Int. J. Pept.
Protein Res. 1992, 39, 201.
12. Castro, B.; Dormoy, J. R.; Evin, G.; Selve, C. TL 1975, 1219.
13.
Dourtoglou, V.; Gross, B.; Lambropoulou, V.; Zioudrou, C. S 1984, 572.
14. van der Marel, G.; van Boeckel, C. A. A.; Wille, G.; van Boom, J. H.
TL 1981, 22, 3887; Marugg, J. E.; Tromp, M.; Jhurani, P.; Hoyng, C.
F.; van der Marel, G. A.; van Boom, J. H. T 1984, 40, 73; Gottikh, M.;
Ivanovskaya, M.; Shabarova, Z. Bioorg. Khim. 1988, 14, 500; Hirao, L;
Miura, K. CL 1989, 1799; Colonna, F. P.; Scremin, C. L.; Bonora, G. M.
TL 1991,32,3251.
Barry Lygo
Salford University, UK
Related
one.
(8)
(9)
[1121-30-8]
Reagents. 3-Hydroxy-l,2,3-benzotriazine-4(3#)-
1. For recent general reviews on peptide synthesis involving the use of

HOBT, see: Bodanszki, M. Int. J. Pept. Protein Res. 1985,25, 449; Kent,
S. B. H.; Annu. Rev. Biochem. 1988, 57, 957; Bodanszky, M. J. Protein
Chem. 1989, 8, 461; Fields, G. B.; Nobel, R. L. Int. J. Pept. Protein Res.
1990, 35, 161.
2.
Knig, W.; Geiger, R. CB 1970, 103, 788; Knig, W.; Geiger, R. CB

1970, 103, 2024; Knig, W.; Geiger, R. CB 1970, 103, 2034; Windridge,
G. C; Jorgensen, E. C. JACS 1971, 93, 6318; Nagaraj, R.; Balaram, P.
T 1981, 37, 2001; Benoiton, N. L.; Kuroda, K. Int. J. Pept. Protein Res.
1981, 17, 197; Chen, S. T.; Wu, S. H.; Wang, K. T. S 1989, 37; Dardoize,
F.; Goasdou, C.; Goasdou, N.; Laborit, H. M.; Topall, G. T 1989, 45,
7783; Bennoiton, N. L.; Lee, Y. C ; Steinaur, R.; Chen, F. M. F. Int. J.
Pept. Protein Res. 1992, 40, 559; Bennoiton, N. L.; Lee, Y. C ; Chen, F.
M. F. Int. J. Pept. Protein Res. 1993, 41, 587.
3.
4.
Coste, J.; Frrot, E.; Jouin, P.; Castro, B. TL 1991, 32, 1967.
Kimura, T.; Takai, M.; Masui, Y.; Morikawa, T.; Sakakibara, S.
Biopolymers 1981, 20, 1823; Hagiwara, D.; Neya, M.; Miyazaki, Y.;
Hemmi, K.; Hashimoto, M. CC 1984, 1676.
Berrada, A.; Cavelier, F.; Jacquier, R.; Verducci, J. BSF(1) 1989, 511;
Grigor'ev, E. I.; Zhil'tsov, O. S. JOU 1989,25,1774; Chen, S. T.; Chang,
C. H.; Wang, K. T. JCR(S) 1991, 206.
Miyazawa, T.; Otomatsu, T.; Fukui, Y.; Yamada, T.; Kuwata, S. CC 1988,
419; Miyazawa, T.; Otomatsu, T.; Fukui, Y.; Yamada, T.; Kuwata, S. Int.
J. Pept. Protein Res. 1992, 39, 237; Miyazawa, T.; Otomatsu, T.; Fukui,
Y.; Yamada, T.; Kuwata, S. Int. J. Pept. Protein Res. 1992, 39, 308.
5.
6.
7.
van der Auwera, C ; van Damme, S.; Anteunis, M. J. O. Int. J. Pept.

Protein Res. 1987, 29, 464.
8. Knorr, R.; Trzeciak, A.; Bannwarth, W.; Gillessen, D. TL 1989, 30,1927.
C5H5NOS
(MW 127.18)
(reaction with a carboxylic acid or acid chloride leads to the cor

responding O-acyl thiohydroxamate; treatment of these interme
diates with a radical source leads to alkyl or aryl radicals [R],
the fate of which depends on the precise reactions conditions1)
Alternate Name: l-hydroxy-2-(1H)-pyridinethione; the tau
tomeric 'N-oxide' form [1121-31-9], although the minor compo
nent, is often the source of alternate names for this compound,
which include 2-pyridinethiol 1-oxide, 2-mercaptopyridine TVoxide, 2-mercaptopyridine 1-oxide, and the abbreviated from
'pyrithione'.
Form Supplied in: both the pyridinethione and the correspond
ing sodium salt (sometimes as the hydrate) are commercially
available. A 40% aqueous solution of the sodium salt is also
available and cheaper (also referred to as sodium omadine). The
free thione can be obtained from this by acidification to neutral
ity using concentrated aq HC1, filtration of the crude product,
and crystallization from EtOH. Alternatively, evaporation of
the aqueous solution (<50 C) and crystallization of the residue
from ethanol provides the sodium salt, mp 285-290 C, after
slow crystallization from ethanol and drying at 50 C under
vacuum.3
Preparative Methods: prepared from 2-bromopyridine by oxida
tion to the TV-oxide using either Perbenzoic Acid or Peracetic
Acid, followed by displacement of bromide using either Sodium
Dithionite or Sodium Sulfide and Sodium Hydroxide} An al
ternative is to treat the TV-oxide with Thiourea and then hydrolyze the resulting thiouronium salt.
Handling, Storage, and Precautions: all operations in this area
should be carried out with due regard to both the thermal and
N-HYDR0XYPYRIDINE-2-THI0NE
photochemical sensitivity of the reagents and intermediate Oacyl thiohydroxamates.
223
and related radical reactions in general, consult Motherwell and

Crich.1
(4)
Preparation of O-Acyl Thiohydroxamates. There are three

commonly used options available for the preparation of O-acyl
thiohydroxamates, outlined in eq 1-;3. 1,4 Firstly, the carboxylic
acid can be activated by conversion into a mixed anhydride
from Isobutyl Chloroformate and then coupled directly with the
pyridinethione (1). Alternatively, O-acyl thiohydroxamates (2)
can be obtained using the DCC (1,3-Dicyclohexylcarbodiimide)
coupling method (eq 1). If acid chlorides are used, these are
best converted into the hydroxamates (2) by reaction with the
sodium salt (3) in the presence of 4-Dimethylaminopyridine
(eq 2). A further option is to activate the pyridinethione com
ponent by formation of the bicyclic system (4) from the parent
and Phosgene and then react this with the triethylammonium
salt of the carboxylic acid (eq 3). Compound (4) is commer
cially available as l-oxa-2-oxo-3-thiaindolizinium chloride (2oxo-[1.4.2]oxathiazolo[2,3-a]pyridinium chloride). 1,4b The latter
two methods appear to be the most favored; the sensitive esters are
used promptly with little purification, often just filtration through
a short silica column. 3
X = Bu3Sn, t-BuS, C11H23Me2CS
A wide variety of functionality can be incorporated into the sub

strate acids, such as in the decarboxylation of -amino acid deriva
tives which leads to amines (eq 5). 4d Application of this method
ology to the appropriate aspartate and glutamate derivatives pro
vides access to the useful radicals (5) which can be trapped in many
ways, such as by halides (overall, a Hunsdiecker reaction),4*1 as
can many other radical species obtained using this chemistry (see
below).
(5)
(1)
(2)
Alcohol Deoxygenation. A limitation of the useful

Barton-McCombie procedure for the deoxygenation of al
cohols is its application to tertiary alcohols because of difficulties
in preparing the required xanthate or other derivatives. A solution
to this is to first form a monoester with Oxalyl Chloride and
then react the remaining acyl chloride function with the sodium
salt (3) (eq 6). 6 In these reactions, although t-butanethiol is
suitable as the chain carrier, in some cases 3-ethyl-3-pentanethiol
gives superior yields (50-90%). The intermediate tertiary
radicals can be trapped by powerful Michael acceptors such as
1,2-dicyanoethylene.
(3)
(6)
Decarboxylation. Perhaps the best-known application of this

type of pyridinethione derivative in synthesis is in the over
all, radical-mediated decarboxylation of carboxylic acids, i.e.
R C O 2 H R H (eq 4). 1,4b The transformation is of a wide gen
erality and usually poceeds in good to excellent yields. The chain
carrier and hydrogen radical source is either Tri-n-butylstannane
or a tertiary thiol, most often t-butanethiol (but see Barton and
Crich 6 ), and the reactions are generally triggered thermally when
tin hydride is employed, or photolytically (tungsten lamp suf
fices) when a thiol is used.5 The latter method offers consid
erable advantages in terms of product purification; for details
of this aspect as well as sound advice on how to conduct these
Decarboxylative Rearrangement. When O-acyl thiohydrox

amates are simply heated or photolyzed alone, a decarboxylative
rearrangement occurs to give 71-92% yields of 2-thiopyridines
(eq 7). 4b,7 While the thermal process involves some contribution
from a cage recombination mechanism, the photolytic reaction is
a purely radical chain process.
(7)
Formation of Sulfides, Selenides, Tellurides, and Selenocyanates. When O-acyl thiohydroxamates are decomposed in the
presence of disulfides, diselenides or ditellurides, mixed sulfides,
Next Page
224
N-HYDROXYPYRIDINE-2-THIONE
selenides, or tellurides are formed, respectively (eq 8). 8 If the re

actions are triggered thermally, a large excess of the disulfide etc.
has to be used to avoid competition from decaboxylative rear
rangement (see above); however, light-induced reactions proceed
at lower temperatures and, in such cases, only a slight excess of the
trap is required. When the trapping agent is dicyanogen triselenide
then selenocyanates, RSeCN, are produced.
Decarboxylative Phosphorylation. In similar fashion to the

foregoing, radicals generated by decomposition of an O-acyl
thiohydroxamate can be trapped by tris(phenylthio)phosphine
(eq 11). 15 In some cases, the use of alternative thiohydroxamates
may be advantageous.
(11)
(8)
Decarboxylative Sulfonation. When a solution of an O-acyl

thiohydroxamate in CH 2 Cl 2 containing excess SO 2 is photolyzed
at 10 C, the initially formed radicals are intercepted by the latter
before decarboxylative rearrangement can take place. The result
ing radicals (RSO 2 ) then react with a second molecule of the
O-acyl thiohydroxamate to give an S-pyridyl alkylthiosulfonate
(38-91%) and the radical R (eq 9). 9 The products are useful as
precursors to unsymmetrical sulfones and sulfonamides, signifi
cantly by a nonoxidative procedure.
Michael Additions and Other Radical Reactions. As de

composition of O-acyl thiohydroxamates provides radicals, these
can subsequently participate in a variety of other reactions, the
most common of which are Michael additions to electrondeficient alkenes. The most commonly successful pathway (eq 12)
involves reaction of the intermediate carbon-centered radical ad
jacent to the electron-withdrawing group with a second molecule
of the thiohydroxamate, rather than hydrogen abstraction, to give
an -S-pyridyl derivative, 1,6,7b which can subsequently be manip
ulated in a variety of ways. 16 Other thiohydroxamates can lead to
higher yields; the mildness and potential of this methodology is
illustrated in eq 13. 17
(9)
(12)
The Hunsdiecker Reaction. The classical Hunsdiecker reac

tion is somewhat restricted due to the relatively harsh conditions
required. In the Barton version, alkyl radicals generated from Oacyl thiohydroxamates, under either thermal or photolytic condi
tions, are efficiently trapped either by Cl 3 C-X (X=C1 or Br; C l 3 O
is the chain carrier) or by Iodoform.1,4b,10 The method is appli
cable to sensitive substrates for which the classical methods are
unsuitable. 4d,11 thus allowing the preparation of a wide range of
alkyl chlorides, bromides, and iodides by the one-carbon degra
dation of a carboxylic acid. Similar reactions of aromatic acid
derivatives tend to require an additional radical initiator (e.g. Azobisisobutyronitrile), if high yields (55-85%) are to be obtained.12
Decarboxylative Hydroxylation. A close relative of the fore
going degradation, the transformation RCO 2 HROH can be car
ried out in two ways. Perhaps the most practical version con
sists of thermolysis or photolysis of an O-acyl thiohydroxamate,
typically in oxygen-saturated toluene, followed by reduction of
the initial hydroperoxide (eq 10). 4b,13 In similar fashion to de
carboxylative sulfonation (see above), the intermediate radicals
are trapped much faster (~10 4 ) by oxygen than by H-abstraction
from the thiol chain carrier. As an alternative, the initial hydroper
oxides can be O-tosylated in pyridine to give the corresponding
nor-aldehyde or ketone (53-62%). The alternative, mechanisti
cally more convoluted but still efficient and simple procedure
(82-93%), has tris(phenylthio)antimony, (PhS) 3 Sb, as the radi
cal trap in the presence of both oxygen and water (in practice, wet
air).14
(10)
(13)
Similar reactions, but using nitroalkenes as traps, lead to the cor

responding -pyridylfhio nitroalkanes, which are useful as precur
sors to the one-carbon homologated carboxylic acids, aldehydes,
or the related ketones, by starting with an -substituted nitroalkene
(eq 14). 7b,18
(14)
Radicals derived from decarboxylation of perfluorocarboxylic

acids will undergo addition to ethyl vinyl ether to provide the
expected homologs in ~ 6 0 % yields (eq 15).19
(15)
Protonated pyridines can also be used as acceptors of carbon

radicals generated from thiohydroxamates in general.20 A use
ful extension of the Michael addition reacations is to incorporate
an additional t-butylthio substituent into the acceptor component
(eq 16). 18b,21 Tandem reactions are also possible, as exemplified
by the conversion of a cyclopentenecarboxylic acid into a bicyclo[2.2.1]heptane (eq 17).22
Previous Page
N-HYDROXYSUCCINIMIDE
11.
(16)
225
See, for example: Fleet, G. W. J.; Son, J. C ; Peach, J. M.; Hamor, T. A. TL

1988, 29, 1449; Rosslein; L.; Tamm, C. HCA 1988, 77, 47; Kamiyama,
K.; Kobayashi, S.; Ohno, M. CL 1987, 29.
12. Vogel, E.; Schieb, T.; Schulz, W. H.; Schmidt, K.; Schmickler, H.; Lex,
J. AG(E) 1986, 25, 723; Barton, D. H. R.; Lacher, B.; Zard, S. Z. TL
1985, 26, 5939;.T1987, 43, 4321.
13. Barton, D. H. R.; Crich, D.; Motherwell, W. B. CC 1984, 242.
14. Barton, D. H. R.; Crich, D.; Motherwell, W. B. CC 1984, 242.
EWG = CO2Me, NO2
15. Barton, D. H. R.; Bridon, D.; Zard, S. Z. TL 1986, 27, 4309.

(17)
Carbon radicals obtained from thiohydroxamates can also be

trapped intramolecularly by unactivated alkene functions espe
cially in the 5-exo-trig mode, 7b,23 as can aminyl radicals gener
ated in the same way; better yields of cyclic products are obtained
in the presence of a weak acid which presumably protonates the
TV-centered radical prior to cyclization (eq 18).24
16.
See for example; Ahmad-Junan, S. A.; Walkington, A. J.; Whiting, D.

A. JCS(P1) 1992, 2313.
17. Barton, D. H. R.; Gateau-Olesker, A.; Gero, S. D.; Lacher, B.; Tachdjian,
C ; Zard, S. Z. CC 1987, 1790.
18.
(a) Barton, D. H. R.; Togo, H.; Zard, S. Z. TL 1985, 26, 6349; (b) T 1985,
41, 5507. (c) Barton, D. H. R.; Herve, Y.; Potier, P.; Thierry, J.T 1987,
43, 4297.
19.
20.
21.
22.
23.
24.
Barton, D. H. R.; Lacher, B.; Zard, S. Z. T 1986, 42, 2325.

Barton, D. H. R.; Garcia, B.; Togo, H.; Zard, S. Z. TL 1986, 27, 1327.
Barton, D. H. R.; Crich, D. JCS(P1) 1986, 1613.
Barton, D. H. R.; da Silva, E.; Zard, S. Z. CC 1988, 285.
See, for example: Green, S. P.; Whiting, D. A. CC 1992, 1754.
Newcomb, M.; Deeb, T. M.JACS 1987, 109, 3163.
(18)
Related Reagents. Mercury(II) Oxide-Bromine; Thallium(I)

Carbonate; Thallium(III) Acetate-Bromine.
1. For an excellent overview of this area, including examples, see

Motherwell, W. B.; Crich, D. Free Radical Chain Reactions in Organic
Synthesis, Academic: London, 1992.
2.
Shaw, E.; Bernstein, J.; Losee, K.; Lott, W. A. JACS 1950, 72, 4362.
3.
Barton, D. H. R.; Bridon, D.; Fernandez-Picot, I.; Zard, S. Z. T 1987,43

2733.
4.
(a) Barton, D. H. R.; Crich, D.; Motherwell, W. B. CC 1983, 939. (b)

Barton, D. H. R.; Crich, D.; Motherwell, W. B. T 1985, 41, 3901. (c)
Barton, D. H. R. Herve, Y.; Potier, P.; Thierry, J. CC 1984, 1298. (d)
Barton, D. H. R.; Herve, Y.; Potier, P.; Thierry, J. T 1988, 44, 5479.
5.
See, for example: Delia, E. W.; Tsanaktsidis, J. AJC 1986, 39, 2061;
Ihara, M.; Suzuki; M.; Fukumoto, K.; Kametani, T.; Kabuto, C. JACS
1988, 110, 1963; Crich, D.; Ritchie, T. J. CC 1988, 1461; Braeckman,
J. C ; Daloze, D.; Kaisin, M.; Moussiaux, B. T 1985, 41, 4603;
Campopiano, O.; Little, R. D.; Petersen, J. L. JACS 1985, 107, 3721;
Otterbach, A.; Musso, H. AG(E) 1987, 26, 554; Winkler, J. D.; Sridar,
V. JACS 1986, 108, 1708; Winkler, J. D.; Hey, J. P.; Willard, P. G. JACS,
1986, 70S, 6425; Winkler, J. D.; Henegar, K. F.; Williard, P. G. JACS
1987, 709, 2850.
6.
Barton, D. H. R.; Crich, D. JCS(P1) 1986, 1603.
7.
(a) Barton, D. H. R.; Crich, D.; Potier, P. TL 1985, 26, 5943. (b) Barton,
D. H. R.; Crich, D.; Kretzschmar, G. JCS(P1) 1986, 39.
8.
Barton, D. H. R.; Bridon, D.; Zard, S. Z. TL 1984, 25, 5777; H 1987,

25, 449; Barton, D. H. R.; Bridon, D.; Herve, Y.; Potier, P.; Thierry, J.;
Zard, S.Z.T 1986, 42,4983.
9.
Barton, D. H. R.; Lacher, B.; Misterkiewicz, B.; Zard, S. Z. T 1988, 44,

1153.
10.
Barton, D. H. R.; Crich, D.; Motherwell, W. B. TL 1983, 24, 4979.
David W. Knight
Nottingham University, UK
[6066-32-6]
C4H5NO3
(MW 115.10)
(activating agent for carboxylic acids in amide synthesis and

related coupling reactions; acyl transfer reagent)
Alternate Name: HOSu.
Physical Data: mp 96-98 C (99-100 C).
Solubility: sol H 2 O, DMF, alcohols, EtOAc; insol cold ether.
Form Supplied in: colorless crystalline solid, widely available.
Preparative Methods: by heating Succinic Anhydride with Hydroxylamine or, better, hydroxylamine hydrochloride followed
by crystallizations from ether, 1-butanol, and finally EtOAc.1
Purification: can be crystallized from 1-butanol, EtOAc, or
EtOH-EtOAc.
Peptide Bond Formation. The most important use of Nhydroxysuccinimide is in the formation of (isolable) activated
derivatives of TV-protected -amino acids, which subsequently
undergo generally smooth coupling reactions with amino esters.
Typically, 1,3-Dieyclohexylcarbodiimide (DCC) is used as the
initial coupling agent (the HOSu-DCC method) (eq 1 ) . 1 - 3 NHydroxyphthalimide can be employed in much the same way,
but a distinct advantage in the case of HOSu is its high water
solubility, which facilitates product purification.
226
N-HYDROXYSUCCINIMIDE
R1CO2H + H2NR2 +
R3NC
R1CONHR2 + R3NHCHO
(3)
(1)
In some cases, up to 3% racemization has been observed when

using the HOSu-DCC method, which renders it unsuitable for
some types of peptide synthesis. 4,5 Esters derived from HOSu
are relatively reactive, as shown by a kinetic study of their rates of
hydrolysis in aqueous buffers6 although, in some examples, endoJV-hydroxy-5-norbornene-2,3-dicarboximide has proven superior
to HOSu in peptide bond formation.7 Of course, the HOSu-DCC
method is not limited to peptide synthesis and is well suited to the
preparation of amides in general, both from ammonia and primary
amines (e.g. eq 2). 8
A rather unusual coupling reaction between HOSu and glyoxylic acid tosylhydrazone leads to succinimidyl diazoacetate
(eq 4); again, the leaving ability of the HOSu residue renders this a
useful compound for effecting the direct transfer of a diazoacetyl
function to amines, phenols, and peptides. 14
(4)
Modified Barton-McCombie intermediates are best prepared

from pentafluorophenyl chlorothionoformate and a catalytic quan
tity (15-20%) of HOSu in refluxing benzene rather than by using
4-Dimethylaminopyridine, the rather more conventional catalyst
of acyl group transfer (eq 5). 15
(5)
(2)
In order to avoid the need for DCC, a number of activated deriva

tives of N-hydroxysuccinimide itself have been developed which
react directly with, for example, an -amino acid to provide the
required activated a-amino acid esters. These include the com
mercially available carbonate (1), a stable crystalline solid ob
tained from HOSu and Trichloromethyl Chloroformate or from
O-trimethylsilyloxysuccinimide and Phosgene? and the related
phosphate (2) derived from HOSu and Diphenyl Phosphorochloridate under Schotten-Baumann conditions.10 Another alterna
tive (also commercially available) is the oxalate (3), formed from
HOSu and Oxalyl Chloride.11 In general, these intermediates react
rapidly with an N-protected -amino acid, usually in the presence
of a mild base such as pyridine, to provide excellent yields of the
required hydroxysuccinimide esters, generally with less racemiza
tion than is sometimes associated with the HOSu-DCC method. It
is also possible to carry out the entire process of peptide synthesis
in one pot using these reagents.
1. Anderson, G. W.; Zimmerman, J. E.; Callahan, F. M. JACS 1964, 86,

1839; Wegler, R.; Grewe, F.; Mehlhose, K. U.S. Patent 2816 111, 1957
(CA 1958, 52, 6405i).
2.
3.
For a review, see: Klausner, Y. S.; Bodansky, M. S 1972, 453.

For examples, see: Wunsch, E.; Drees, F. CB 1966, 99, 110; Manesis,
N. J.; Goodman, M. JOC 1987, 52, 5331; Mukaiyama, T.; Goto, K.;
Matsuda, R.; Ueki, M. TL 1970, 1901; Bosshard, H. R.; Schechter, I.;
Beger, A. HCA 1973, 56, 717.
4.
5.
Kemp, D. S.; Trangle, M.; Trangle, K. TL 1974, 2695.

For a review of side reactions in peptide synthesis, see: Martinez, J. 5
1981,333.
6. Cline, G. W.; Hanna, S. B. JOC 1988, 53, 3583.
7. Fujino, M.; Kobayashi, S.; Obayashi, M.; Fukuda, T.; Shinagawa, S.;
Nishimura, O. CPB 1974, 22, 1857.
8. Terao, S.; Shiraishi, M.; Kato, K.; Ohkawa, S.; Ashida, Y.; Maki, Y.
JCS(P1) 1982, 2909.
9.
Ogura, H.; Kobayashi, T.; Shimizu, K.; Kawabe, K.; Takeda, K. TL 1979,
4745.
10. Ogura, H.; Nagai, S.; Takeda, K. TL 1980, 21, 1467.
11. Takeda, K.; Sawada, I.; Suzuki, A.; Ogura, H. TL 1983, 24, 4451.
12.
A rather different approach to peptide bond formation and

amide synthesis in general is to treat a mixture of a carboxylic acid
and an amine with an isocyanide (2-Morpholinoethyl Isocyanide
is especially suitable), which effectively acts as a dehydrating
agent (eq 3). The procedure can result in extensive racemization
of both reactants and products which may be supressed by the
addition of HOSu; presumably an HOSu ester is the penultimate
intermediate.12 The addition of HOSu also decreases racemization
in polypeptide synthesis when 'Bates reagent' {[(Me 2 N) 3 P + ] 2 O
(BF 4 - ) 2 } is used as the coupling agent.13
Wackerle, L. S 1979, 197; Marquarding, D.; Aignar, H. Ger. Offen.

2942606, 1979 (CA 1981, 95, 62 73 1j).
13. Bates,A.J.;Galpin,I.J.;Hallett,A.;Hudson,D.;Kenner,G.W.;Ramage,
R.; Sheppard, R. C. HCA 1975, 58, 688.
14. Ouihia, A.; Rene, L.; Guilhem, J.; Pascard, C.; Badet, B. JOC 1993, 58,
1641.
15. Barton, D. H. R.; Jaszberenyi, J. Cs. TL 1989, 30, 2619. For an
application, see: Gervay, J.; Danishefsky, S. JOC 1991, 56, 548.
David W. Knight
IMIDAZOLE
useful astrans-silylatingagents. The HMDS-Im combination is

also useful for the silylation of thiols.9
(1)
Imidazole
[288-32-4]
227
C3H4N2
(MW 68.09)
Ester Hydrolysis. Inspired by evidence that the imidazole ring

of histidine residues present in various hydrolytic enzymes is
responsible for their proteolytic activities, imidazole itself has
been shown to be an excellent catalyst of ester hydrolysis (e.g.
eq 2).10 In intramolecular transesterifications and hydrolyses of
2-hydroxymethylbenzoic acid derivatives, the accelerating role of
imidazole is due to its ability to act as a proton transfer catalyst
rather than as a nucleophile.11
(nucleophilic catalyst for silylations and acylations; buffer; weak

base; iodination methods)
Alternate Names: Im; iminazole; 1,3-diazole; glyoxaline.
Physical Data: mp 90-91 C; bp 255 C, 138 C/12 mmHg.
Solubility: sol water, alcohols, ether, acetone, chloroform.
Form Supplied in: colorless crystalline solid; widely available.
Drying: 40 C in vacuo over P 2 O 5 .
Purification: can be crystallized from CgH6, CCl 4 , CH 2 C1 2 ,
EtOH, petroleum ether, acetone-petroleum ether, or water; can
also be purified by vacuum distillation, sublimation, or by zone
refining.
Introduction. Imidazole has a pKa of 7.1 and is thus a stronger

base than thiazole (pKa 2.5), oxazole (pKa 0.8), and pyridine (pKa
5.2). It is both a good acceptor and donor of hydrogen bonds. The
pKa for loss of the N-H is ~14.2, i.e. imidazole is a very weak
acid.
Silylations. Imidazole is a standard component in silylations
of alcohols as well as carboxylic acids, amines, and a variety of
other functions, typically in combination with a silyl chloride in
DMF (eq 1). 1 A very widely used procedure for alcohol protec
tion is by conversion into the corresponding t-butyldimethylsilyl
(TBDMS or TBS) ether using the method;2 in other solvents such
as pyridine or THF the reactions are much slower, probably be
cause the primary silylating reagent is t-BuMe 2 Si-Im. In this
and many other aspects, imidazole resembles another very use
ful transfer catalyst, 4-Dimethylaminopyridine (DMAP). Sim
ilarly, bulkier and hence more stable silyl groups, such as tbutyldiphenylsilyl (TBDPS) 3 and triisopropylsilyl (TIPS),4 can
be introduced. Times for completion of reaction at 20 C vary
(0.5-20 h); these silylating agents, originally developed for nu
cleoside protection,5 usually react faster with primary alcohols
and with certain secondary alcohols, thus allowing selective pro
tection of polyols to be achieved efficiently. (A faster alternative
involves the use of l,8-Diazabicyclo[5.4.0]undec-7-ene
(DBU)
in place of imidazole, in a variety of solvents such as CH 2 Cl 2 ,
C 6 H 6 , or MeCN, in combination with R 3 SiCl). 6 1,3-Diones can
be efficiently O-silylated using TBDMSCl-Im7 or Hexamethyldisilazane (HMDS) and imidazole; 8 other reagents are not as suit
able, even in cases where the enol content is high. The products are
(2)
Peptide Coupling. Peptide couplings involving p-nitrophenyl

and related esters (see p-Nitrophenol) are dramatically acceler
ated by the addition of imidazole.12 However, such reactions,
which probably proceed by way of an acylimidazole, can be prone
to racemization, in which case 1,2,4-Triazole can be a superior
activator.13 Imidazole also catalyzes peptide coupling using the
Triphenyl Phosphite method, with negligible racemization when
the reactions are carried out in dioxane or DMF, 14 and is use
ful for the activation of phosphomonoester groups in nucleotide
coupling, in combination with an arylsulfonyl chloride.15
Acylimidazoles and Nucleophiles. Acylimidazoles are read
ily prepared from the parent carboxylic acids by reaction of
the derived acid chloride with imidazole or directly using N,N'Carbonyldiimidazole. These intermediates react smoothly with
a variety of nucleophiles including Grignard reagents (eq 3), 16
Lithium Aluminum Hydride (eq 4), 16 and nitronates (eq 5). 17
At 20 C, aroylimidazoles can be reduced to the corresponding
aldehydes in the presence of an ester function.16
(3)
(4)
(5)
228
IODOMETHANE
The activation provided by an imidazole substituent is further

illustrated in a route to 1,3-oxathiole-2-thiones from sodium 1imidazolecarbodithioate, derived from the sodium salt of imida
zole and CS 2 (eq 6). 18
(6)
Other Uses. Imidazole is one of the best catalysts for the

preparation of acid chlorides from the corresponding carboxylic
acids and phosgene. 19 Aryl trifiates can be obtained from phenols,
or better phenolates, using Trifluoromethanesulfonic Anhydride
in combination with imidazole; N-trifiylimidazole is the reactive
species.20 Photochemical deconjugations of enones can be erratic
but are promoted by the presence of a weak base such as imidazole
or pyridine in polar solvents.21
Iodination of Alcohols. Imidazole, Triphenylphosphine, and
Iodine in hot toluene, 22 or preferably toluene-acetonitrile
mixtures, 23 is an excellent combination for the conversion of al
cohols into iodides, ROH RI. Secondary alcohols react with
inversion (but see below), although the method can be used for
the selective iodination of primary hydroxyls. Applications in the
area of natural product synthesis24 emphasize the mildness and
generality of the method as well as providing alternative recipes;
sometimes, 2,4,5-triiodoimidazole can be a superior reagent.22
Similarly, Ph 3 P-Cl 2 -Im can be used for the preparation of alkyl
chlorides, ROH RCl, and the addition of imidazole in the
Triphenylphosphine-Carbon Tetrachloride method for alcohol
chlorination has a beneficial effect.25
Diol Deoxygenation. The Ph 3 P-Im-I 2 combination can
also be used to convert vic-diols into the correspond
ing alkenes, although 2,4,5-triiodoimidazole is more effec
tive than imidazole itself.26 Alternative combinations are
Triphenylphosphine-Iodoform-Imidazole,
which can deoxygenate cis-diols but which is better suited to trans-isomers,27 and
Chlorodiphenylphosphine-I2-Im,
which can be used to deoxygenate vic-diols when both are secondary or when one is secondary
and one is primary.28
Epoxidation. t-Butyl Hydroperoxide in combination with
MoO 2 (acac) 2 can be used to oxidatively cleave alkenes, but will
epoxidize such functions in the presence of a metalloporphyrin or
a simple amine, the choice of which depends upon the substrate
structure. Imidazole is the most suitable for 1-phenylpropene,
Pyridine for stilbene, and N,N-dimethylethylenediamine for 1alkenes.29
1. Lalonde, M.; Chan, T. H. S 1985, 817. Greene, T. W.; Wilts, P. G. M.

Protecting Groups in Organic Synthesis, 2nd ed.; Wiley: New York,
1991. Kocieski, P. J. Protecting Groups; Thieme: Stuttgart, 1994.
2.
3.
4.
Corey, E. J.; Venkateswarlu, A. JACS 1972, 94, 6190.

Hanessian, S.; Lavallee, P. CJC 1975, 53, 2975.
Cunico, R. F.; Bedell, L. JOC 1980, 45, 4797.
5.
Ogilvie, K. K. CJC 1973, 57, 3799. Ogilvie, K. K.; Iwacha, D. J. TL

1973, 317. Ogilvie, K. K.; Sadana, K. L.; Thompson, E. A.; Quilliam,
M. A.; Westmore, J. B. TL 1974, 2861. Ogilvie, K. K.; Thompson, E.
A.; Quilliam, M. A.; Westmore, J. B. TL 1974, 2865.
6. Aizpurua, J. M.; Palomo, C. TL 1985, 26, 475.
7. Veysoglu, T.; Mitscher, L. A. TL 1981, 22, 1299, 1303.
8. Torkelson, S.; Ainsworth, C. S 1976, 722.
9. Glass, R. S. JOM 1973, 61, 83.
10. Bender, M. L.; Turnquest, B. W. JACS 1957, 79, 1652. Bruice, T. C ;
Schmir, G. L. JACS 1957, 79, 1663. Bender, M. L. CRV 1960, 60, 82.
Looker, J. H.; Holm, M. J.; Minor, J. L.; Kagal, S. A. JHC 1964, 1, 253.
11. Fife, T. H.; Benjamin, B. M. JACS 1973, 95, 2059. Kirby, A. J.; Lloyd,
G. J. JCS(P2) 1974, 637. Chiong, K. N. G.; Lewis, S. D.; Shafer, J. A.
JACS 1975, 97, 418. Pollack, R. M.; Dumsha, T. C. JACS 1975, 97, 377.
Belke, C. J.; Su, S. C. K.; Shafer, J. A. JACS 1971, 93, 4552.
12. Mazur, R. H. JOC 1963,28, 2498. Wieland, T.; Vogeler, K. AG(E) 1963,
2, 42; LA 1964, 680, 125. McGahren, W. J.; Goodman, M. T 1967, 23,
2017. Stewart, F. H. C. C1(L) 1967, 1960.
13. Beyerman, H. C ; van der Brink, W. M.; Weygand, F.; Prox, A.; Konig,
W.; Schmidhammer, L.; Nintz, E. RTC 1965, 84, 213.
14. Mitin, Y. V.; Glinskaya, O. V. TL 1969, 5267.
15. Berlin, Yu. A.; Chakhmakhcheva, O. G.; Efimov, V. A.; Kolosov, M. N.;
Korobko, V. G. TL 1973, 1353.
16. Staab, H. A.; Braunling, H. LA 1962, 654, 119. Staab, H. A.; Jost, E. LA
1962, 655, 90. Staab, H. A. AG(E) 1962, 1, 351.
17. Baker, D. C ; Putt, S. R. S 1978, 478.
18. Ishida, M.; Sugiura, K.; Takagi, K.;Hiraoka, H.; Kato, S. CL 1988, 1705.
19. Hauser, C. F.; Theiling, L. F. JOC 1974, 39, 1134.
20. Effenberger, F.; Mack, K. E. TL 1970, 3947.
21. Eng, S. L.; Ricard, R.; Wan, C. S. K.; Weedon, A. C. CC 1983, 236.
22. Garegg, P. J.; Samuelsson, B. CC 1979, 978; JCS(P1) 1980, 2866.
23. Garegg, P. J.; Johansson, R.; Ortega, C ; Samuelsson, B. JCS(P1) 1982,
681.
24. Corey, E. J.; Pyne, S. G.; Su, W. TL 1983, 24, 4883. Berlage, U.; Schmidt,
J.; Peters, U.; Welzel, P. TL 1987, 28, 3091. Corey, E. J.; Nagata, R. TL
1987, 28, 5391. Soll, R. M.; Seitz, S. P. TL 1987, 28, 5457.
25. Garegg, P. J.; Johansson, R.; Samuelsson, B. S 1984, 168.
26. Garegg, P. J.; Samuelsson, B. 5 1979, 469, 813.
27. Bessodes, M.; Abushanab, E.; Panzica, R. P. CC 1981, 26.
28. Liu, Z.; Classon, B.; Samuelsson, B. JOC 1990, 55, 4273.
29. Kato, J.; Ota, H.; Matsukawa, K.; Endo, T. TL 1988, 29, 2843.
David W. Knight
Iodomethane
[74-88-4]
CH 3 I
(MW 141.94)
(methylating agent for carbon, oxygen, nitrogen, sulfur, and trivalent phosphorus)
Alternate Name: methyl iodide.
Physical Data: bp 41-43 C; d 2.28 g c m - 3 .
Solubility: sol ether, alcohol, benzene, acetone; moderately sol
H 2 O.
Form Supplied in: colorless liquid; stabilized by addition of silver
wire or copper beads; widely available.
IODOMETHANE
Purification: percolate through silica gel or activated alumina then
distill; wash with dilute aqueous Na 2 S 2 O 3 , then wash with wa
ter, dilute aqueous Na 2 CO 3 , and water, dry with CaCl2 then
distill.
Handling, Storage, and Precautions: toxic, corrosive and a pos
sible carcinogen. Liquid should be stored in brown bottles to
prevent liberation of I2 upon exposure to light. Keep in a cool,
dark place. Use only in well ventilated areas.
C-Methylation. Methyl iodide is an 'active' alkylating agent

employed in the C-methylation of carbanions derived from ke
tones, esters, carboxylic acids, amides, nitriles, nitroalkanes,
sulfones, sulfoxides, imines, and hydrazones.1 The quantity of
methyl iodide utilized in methylations varies from a slight (1.1
equiv) to a large excess (used as solvent).
The monomethylation of carbanions derived from 1,3cyclohexanedione and acetylacetone has been described (eqs 1
and 2). 2 Selective monomethylation of -diketones is dependent
upon the base employed; variable amounts of O-methylation,
dimethylation, and carbon-carbon bond cleavage may occur. The
tetraethylammonium enolate of -diketones reportedly provides
higher yields of C-methylation without competing side reactions
(eq 3). 3 Dimethylation is sometimes a desired reaction pathway.
In this case, a large excess of both methyl iodide and base favors
the dimethylated product (eq 4). 4 Recently, the combination of a
potassium base and a catalytic amount of 18-Crown-6 (eq 5) has
been described to provide a higher yield of dimethylation. 5 *
229
lithium, may then be alkylated with methyl iodide (eq 6). Alterna
tively, quarternary ammonium enolates are produced by treatment
of the silyl enol ether with the corresponding fluoride salt. For ex
ample, monomethylation of a ketone is cleanly effected by treat
ment of an anhydrous mixture of the trimethylsilyl enol ether of the
ketone in methyl iodide with benzyltrimethylammonium fluoride
(eq 7). 9 Kinetic enolates produced from the conjugate addition of
an organocuprate to an unsaturated ketone or a dissolving metal
reduction of an enone may be methylated directly.7c However,
the choice of solvent is crucial for the success of these reactions.
Ether, the solvent typically used in organocopper conjugate ad
ditions, is a poor solvent for alkylation reactions.10 N,N,N',N'Tetramethylethylenediamine (TMEDA), Hexamethylphosphoric Triamide (HMPA) and liquid Ammonia have been used as
additives to increase the efficiency of alkylation. Alternatively, the
solvent used in the conjugate addition can be removed in vacuo
and replaced with a more effective medium for alkylation. For
example the rate of methylation of the enolate produced in the
conjugate addition of Lithium Dimethylcuprate to an enone is
approximately 105 times faster in DME than in ether (eq 8). 11
(6)
(1)
(7)
(2)
(3)
(8)
(4)
(5)
Methylation of kinetically derived enolates is most readily ac

complished via the corresponding silyl enol ether.7 Lithium eno
lates, generated by treatment of the silyl enol ether with Methyl-
The stereoselectivity of the methylation of ketone enolates

is determined by the structure of the substrate.12 Stereoselec
tive methylation of cyclic ketone enolates has been examined
in detail and current models reliably predict the stereochemi
cal outcome (eqs 9-11). 1 3 - 1 5 Diastereoselective methylation of
acyclic ketone and ester enolates has been accomplished em
ploying a variety of chiral auxiliaries (eq 12). 12,16 Efficient cat
alytic enantioselective methylation of 6,7-dichloro-5-methoxy-lindanone has been accomplished via a chiral phase-transfer cata
lyst (eq 13).17 An enantiomeric excess of 92% was observed when
employing Chloromethane as the methylating agent, whereas
230
IODOMETHANE
methyl iodide provided a product of only 36% enantiomeric

excess.
(9)
Phenolic hydroxyls are readily methylated by methyl iodide

under basic conditions. The most common conditions are methyl
iodide and potassium carbonate in acetone (eq 16).18a,21 The use of
Lithium Carbonate as the base allows for the selective protection
of phenols with a pKa < 8 (eq 17).18c The peri-hydroxy group of
an anthraquinone is methylated using methyl iodide and Silver(I)
Oxide in chloroform (eq 18).18a,22
(16)
(10)
(17)
(11)
(12)
(18)
Aliphatic alcohols are also methylated by methyl iodide under

basic conditions in dipolar aprotic solvents (eqs 19 and 20).23 Typ
ical conditions employ Sodium Hydride as a base, DMF as the
solvent and an excess of methyl iodide.24 Alternatively, dimethyl
sulfate or Methyl Trifluoromethanesulfonate may be used as the
methylating agent. Under acidic conditions, diazomethane will
also methylate aliphatic hydroxy groups. Finally, methylation of
a hydroxy group may be achieved under essentially neutral con
ditions using silver(l) oxide (eq 21).23,25
(13)
(19)
(20)
O-Methylation. Carboxylic acids can be converted to the cor

responding methyl ester by stirring a mixture of the carboxylic
acid in methanol with an excess of methyl iodide and Potassium
Carbonate.18 A recent report describes the esterification of car
boxylic acids using Cesium Fluoride and methyl iodide in DMF
(eq 14).19 Dimethyl Sulfate has also been advantageously utilized
to effect O-methylation of carboxylic acids as well as alcohols
(eq 15).18c,2 These methods often serve as useful alternatives to
Diazomethane for preparative scale esterification of carboxylic
acids.
(14)
(15)
(21)
S-Alkylation. Methyl iodide alkylates thioalkoxides and sul

fides to produce sulfides and sulfonium ions, respectively. For
example, thioalkoxides produced from thiocarbonyl compounds
are methylated with methyl iodide to generate the corresponding
methyl thioether (eq 22).26 Sulfonium halides, derived from the
reaction of methyl iodide with an alkyl sulfide, are sometimes
labile in solution and may undergo further reaction (eq 23).27,28
Dimethyl Sulfoxide when refluxed with an excess of methyl io
dide produces trimethyloxosulfonium iodide, which is collected
as a white solid and recrystallized from water. Similarly, methy
lation of Dimethyl Sulfide produces trimethylsulfonium iodide.29
Treatment of trimethyloxosulfonium and trimethylsulfonium salts
IODOMETHANE
with a base yields the corresponding ylides, which serve as useful
methylene transfer reagents. Silver(I) Perchlorate promotes the
methylation of less reactive sulfides (eq 24). 30
(22)
231
Secondary N-methylalkylamines can be prepared from primary

amines by a multi-step sequence involving first methylation of
the benzylidene of the primary amine followed by hydrolytic re
moval of the benzylidene group (eq 28). 34 An alternative to the
methylation procedure using methyl iodide is the employment
of Eschweiler-Clarke conditions.35 Exhaustive 7V-methylation of
amines results in the production of a quaternized amine. The use
of 2,6-Lutidine as base is beneficial to carry out quaternization of
amines due to the slow rate of methylation of 2,6-lutidine (eq 29). 36
Quaternized ammonium salts are employed in the Hofmann elimi
nation (eqs 30 and 31). 37,38 As in the case of alcohol methylation,
silver(I) salts may be used to facilitate the methylation process
(eq 32). 39 Finally, conditions for the methylation of indole have
been reported (eq 33). 40
(23)
(28)
(24)
(29)
Hydrolysis of sulfonium salts serves as a useful protocol for

removal of a protecting group or hydrolysis of a carboxylic acid
derivative. For example, thioamides are converted into the corre
sponding methyl esters by methylation with methanolic methyl
iodide followed by treatment with aqueous potassium carbonate
(eq 25). 31 Methyl thiomethyl ethers are readily hydrolyzed using
an excess of methyl iodide in aqueous acetone (eq 26). 32 Under
similar reaction conditions, thioacetals are hydrolyzed to the cor
responding carbonyl compounds (eq 27). 33
(30)
(31)
(32)
(25)
(26)
(27)
N-Methylation. The direct monomethylation of ammonia or

a primary amine with methyl iodide is usually not a feasible
method for the preparation of primary or secondary amines since
further methylation occurs. However, methylation of secondary
and tertiary amines leading to the production of tertiary amines
and quaternary ammonium salts, respectively, is a useful method.
(33)
P-Methylation. Phosphonium salts are prepared by the quat

ernization of phosphines with methyl iodide. 41 The displacement
reaction is usually conducted in polar solvents such as acetonitrile
or DMF. Dialkyl phosphonates are prepared from the reaction of
trialkyl phosphites with alkyl halides, commonly known as the Arbuzov reaction.42 For example, diisopropyl methylphosphonate is
prepared by heating a mixture of methyl iodide and Triisopropyl
Phosphite (eq 34). 43
(34)
1. (a) Stowell, J. C. Carbanions in Organic Synthesis; Wiley: New York,

1979. (b) Caine, D. COS 1991, 3, Chapter 1. (c) House, H. O. Modern
232
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
IODONIUM DI-sym-COLLIDINE PERCHLORATE

Synthetic Organic Reactions, 2nd ed.; Benjamin: Menlo Park, 1972;
Chapter 9.
Mekler, A. B.; Ramachandran, S.; Swaminathan, S.; Newman, M. S.
OSC 1973, 5, 742. (b) Johnson, A. W.; Markham, E.; Price, R. OSC
1973, 5, 785.
Shono, T.; Kashiura, S.; Sawamura, M.; Soejima, T. JOC 1988, 53, 907.
Nedelec, L.; Gasc, J. C ; Bucourt, R. T 1974, 30, 3263.
Prasad, G.; Hanna, P. E.; Noland, W. E.; Venkatraman, S. JOC 1991, 56,
7188.
Rubina, K.; Goldverg, Y.; Shymanska, M. SC 1989,19, 2489.
(a) Rasmussen, J. K. S 1979, 91. (b) Brownbridge, P. S 1983, 1. (c)
d'Angelo, J.T 1976,52,2979.
Stork, G.; Hudrlik, P. F. JACS 1968, 90, 4462, 4464.
(a) Kuwajima, I.; Nakamura, E. ACR 1985, 18, 181. (b) Kuwajima, I.;
Nakamura, E. JACS 1975, 97,3257. (c) Smith, A. B., III; Fukui, M. JACS
1987, 109, 1269.
Taylor, R. J. K. S 1985, 364.
Coates, R. M.; Sandfur, L. O. JOC 1974, 39, 275.
Evans, D. A. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic:
New York, 1984; Vol. 3, p 1.
Kuehne, M. E. JOC 1970, 35,171.
Bartlett, P. A.; Pizzo, C. F. JOC 1981, 46, 3896.
Ireland, R. E.; Evans, D. A.; Glover, D.; Rubottom, G. M.; Young, H.
JOC 1969, 34, 3717.
Evans, D. A.; Ennis, M. D.; Mathre, D. J. JACS 1982, 104, 1737.
(a) Dolling, U.-H.; Davis, P.; Grabowski, E. J. J. JACS 1984, 706, 446.
(b) Hughes, D. L.; Dolling, U.-H.; Ryan, K. M.; Schoenewaldt, E. F.;
Grabowski, E. J. J. JOC 1987, 52, 4745.
(a) FF 1967, 1, 682. (b) Haslam, E. In Protective Groups in Organic
Chemistry; McOmie, J. F. W., Ed.; Plenum: New York, 1973; Chapter 5.
(c) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis,
2nd ed.; Wiley: New York, 1991; Chapter 5.
Sato, T.; Otera, J.; Nozaki, H. JOC 1992, 57, 2166.
Chung, C. W.; De Bernardo, S.; Tengi, J. P.; Borgese, J.; Weigele, M.
JOC 1985, 50, 3462.
(a) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis,
2nd ed.; Wiley: New York, 1991; Chapter 3. (b) Wymann, W. E.; Davis,
R.; Patterson, Jr., J. W.; Pfister, J. R. SC 1988, 18, 1379.
Manning, W. B.; Kelly, T. R.; Muschik, G. M. TL 1980, 21, 2629.
2nd ed.; Wiley: New York, 1991; Chapter 2.
Fisher, M. J.; Myers, C. D.; Joglar, J.; Chen, S.-H.; Danishefsky, S. J.
JOC 1991, 56, 5826.
(a) Greene, A. E.; Le Drina, C ; Crabbe, P. JACS 1980, 102, 7583. (b)
Finch, N.; Fitt, J. J.; Hsu, I. H. S. JOC 1975, 40, 206. (c) Ichikawa, Y;
Tsuboi, K.; Naganawa, A.; Isobe, M. SL 1993, 907.
Nicolaou, K. C ; Hwang, C.-K.; Marron, B. E.; DeFrees, S. A.;
Coulandouros, E. A.; Abe, Y.; Carroll, P. J.; Snyder, J. P. JACS 1990,
112, 3040. (b) Nicoiaou, K. C ; McGarry, D. G.; Somers, P. K.; Kim,
B. H.; Ogilvie, W. W.; Yiannikouros, G.; Prasad, C. V. C ; Veale, C. A.;
Hark, R. R. JACS 1990, 112, 6263.
Barrett, G. C. In Comprehensive Organic Chemistry; Barton, D. H. R.,
Ed.; Pergamon: Oxford, 1979; Vol. 3, pp 105-120.
Helmkamp, G. K.; Pettitt, D. J. JOC 1960, 25, 1754.
(a) Corey, E. J.; Chaykovsky, M. JACS 1965, 87, 1353. (b) Kuhn, R.;
Trischmann, H. LA 1958, 611, 117. (c) Emeleus, H. J.; Heal, H. G. JCS
1946, 1126.
Hori, M.; Katakoka, T.; Shimizu, H.; Okitsu, M. TL 1980, 4287.
Tamaru, Y.; Harada, T.; Yoshida, Z.-I. JACS 1979, 101, 1316.
Pojer, P. M.; Angyal, S. J. TL 1976, 3067.
Fetizon, M.; Jurion, M. CC 1972, 382.
Wawzonek, S.; McKillip, W.; Peterson, C. J. OSC 1973, 5, 785.
March, J. Advanced Organic Chemistry, 3rd. ed.; Wiley: New York,
1985; p 799.
36.
Sommer, H. Z.; Jackson, L. L. JOC 1970, 35, 1558.
37.
Cope, A. C ; Trumbull, E. R. OR 1960, 11, 317.
38.
(a) Cope, A. C; Bach, R. D. OSC 1973, 5, 315. (b) Manitto, P.; Monti,
D.; Gramatica, P.; Sabbioni, E. CC 1973, 563.
39.
Horwell, D. C. T 1980, 36, 3123.
40.
Potts, K. T.; Saxton, J. E. OSC 1973, 5, 769.
41.
Smith, D. J. H. In Comprehensive Organic Chemistry; Barton, D. H. R.,

Ed.; Pergamon: Oxford, 1979; Vol. 2, p 1160.
42.
Arbuzov, B. A. PAC 1964, 9, 307.
43.
Gary A. Sulikowski & Michelle M. Sulikowski

Texas A&M University, College Station, TX, USA
[69417-67-0]
C16H22ClIN2O4
(MW 468.75)
(very reactive electrophile, superior source of I + , 1 useful in

the synthesis of cis--hydroxy amines, 2 activates glycosides for
glycosylation; 5,6 can be used for iodolactonization 1213 and vic
inal cis-diol 14 preparation)
Alternate Name: IDCP.
Solubility: sol chloroform; insol ether.
Form Supplied in: fine colorless crystalline powder.
Drying: see Bromonium Di-sym-collidine Perchlorate.
Handling, Storage, and Precautions: see Bromonium Di-symcollidine Perchlorate.
cis-Oxyamination. 2 IDCP (1) is useful in the synthesis of

cis-hydroxyamino sugars, e.g. methyl N-acetylristosaminide has
been obtained from an oxazoline which can be made by the re
action of a trichloromethyl imidate with IDCP. The imidate can
be prepared by reaction of the corresponding allylic alcohol with
Trichloroacetonitrile in presence of Sodium Hydride (eq 1).
(1)
IODONIUM DI-sym-COLLIDINE PERCHLORATE

3
The synthesis of methyl a,L-garosaminide, a key component

of aminocyclitol antibiotics, is complicated by the presence of
a cis-hydroxyamino group and by the tertiary character of the
hydroxy group. The problems have been resolved by use of the
allylic epoxide as starting material. This epoxide was converted in
three steps into an allylic amine. Treatment of iodonium salt gave
the iodooxazolidinone in 82% yield. The product was reduced and
the ethoxy ethyl group was removed and finally converted to the
desired product by hydrolysis (eq 2).
233
obtained in various proportions regardless of the nature of donors

or acceptors (primary or secondary hydroxyl groups). Glycosy
l a t e s of l,2:5,6-di-O-isopropylidene-a-D-galactopyranose and
methyl 2,3,4-tri-O-benzyl--D-glucopyranoside were investigated
with pent-4-enyl-2,3,4-tri-O-benzyl--D-glucopyranoside deriva
tives in which 6-OH was protected by a benzyl, a trityl, or a
TBDMS group in order to assess the effect of the bulk of the
6-substituents. The presence of a bulky 6-substituent (a) increases
significantly the proportion of the -product; (b) decreases the
yield when a secondary hydroxy group is glycosylated, but the ef
fect is less or opposite when a primary hydroxy group is involved;
(c) lowers the increase in yield of the -product when a primary
hydroxy group is glycosylated; (d) gives a much better yield of
the -anomer when there is a higher proportion of ether in the
solvent.
Chemospecific glycosidation of partially benzoylated thioglycosides ('disarmed' acceptors) with perbenzylated thioglycosides
('armed' donors) can be realized in the presence of the promotor
IDCP (eq 5).7
(2)
(5)
Similar methodology can convert an internal allylic amine into a

cis--hydroxyamine, as illustrated in a synthesis of holacosamin,
a component of some glycosteroids (eq 3).4
(3)
Reaction of IDCP with unsaturated alcohols and carboxylic

acids in dichloromethane at ambient temperature has afforded
three- to seven-membered ring iodoethers and four- to sevenmembered ring iodolactones, respectively, in moderate yields and
generally with high regioselectivity. The reaction has particular
utility for synthesis of 2-(l-iodoalkyl)oxiranes and -oxetanes.11
Glycosylation has also been achieved by electrophile-induced ac
tivation of anomeric O-glycosyl N-allyl carbamates (eq 6).8
-Linked Disaccharides5. The reagent functions as a superior

source of I + , probably because of the nonnucleophilic counterion.
Thus a pyranoid diene reacts with IDCP to give a planar ion to
which an alcohol adds in a 1,4-sense to give an -glycoside. Thus
tetraacetylfructose reacts to give an -disaccharide in 45% yield
(eq 4). The -isomer is not detected.
(6)
(4)
Examples are known where this reagent has activated pent-4enyl glycosides for glycosylation,6 but - and -glycosides were
Treatment of fully benzylated 1-methylene-D-glucose with

IDCP gives easy access to 1-iodoheptuloses or a 1-iodomethylene
derivative.9 The latter compound is, in turn, further amenable to
similar IDCP-mediated addition reaction. In the synthesis of ciclamycin O the required trisaccharide glycol was assembled by
substituent-directed iodinative coupling of glycals as shown in
(eq 7).10
234
IODOTRIMETHYLSILANE
Iodotrimethylsilane 1
[16029-98-4]
C 3 H 9 ISi
(MW200.11)
(a versatile reagent for the mild dealkylation of ethers, carboxylic

esters, lactones, carbamates, acetals, phosphonate and phosphate
esters; cleavage of epoxides, cyclopropyl ketones; conversion of
vinyl phosphates to vinyl iodides; neutral nucleophilic reagent
for halogen exchange reactions, carbonyl and conjugate addi
tion reactions; use as a trimethylsilylating agent for formation of
enol ethers, silyl imino esters, and N-silylenamines, alkyl, alkenyl
and alkynyl silanes; Lewis acid catalyst for acetal formation, aalkoxymethylation of ketones, for reactions of acetals with silyl
enol ethers and allylsilanes; reducing agent for epoxides, enediones, -ketols, sulfoxides, and sulfonyl halides; dehydrating
agent for oximes)
(7)
Iodolactonization of heptadienoic acid derivatives having

oxazolidin-2-ones or a sultam12 as chiral auxiliary gave the chiral
iodolactone with moderate to excellent enantioselectivity.13
Vicinal cis-Diols. 14 An allylic alcohol is converted into its pri
mary urethane derivative, which is then subjected to iodonium ion
induced cyclization to give a single iodocarbonate. The carbon
ate is then deiodinated reductively and hydrolyzed to afford the
vicinal diol.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
Lemieux, R. U.; Morgan, A. R. CJC 1965, 43, 2190.

Pauls, H. W.; Fraser-Reid, B. JOC 1983, 48, 1392.
Pauls, H. W.; Fraser-Reid, B. JACS 1980, 102, 3956.
George, M.; Fraser-Reid, B. TL 1981, 22, 4635.
Fraser-Reid, B.; Iley, D. E. CJC 1979, 57, 645.
Houdier, S.; Voltero, P. J. A. Carbohydr. Res. 1992, 232, 349.
(a) Veeneman, G. H.; Van Boom, J. H. TL 1990, 31, 275. (b) Veeneman
G. H.; Van Leeuwen, S. H.; Van Boom, J. H. TL 1990, 31, 1331.
Kuns, H.; Simmer, J. TL 1993, 34, 2907.
Noort, D.; Veeneman, G. H.; Boons, G. P. H.; Vander Marel, G. A.;
Mulder, G. J.; Van Boom, J. H. SL 1990, 205.
Susuki, K.; Sulikowski, G. A.; Friesen, R. W.; Danishefsky, S. J. JACS
1990, 112, 8895.
Evans, R. D.; Magee, J. W.; Schauble, J. H. S 1988, 862.
Oppolser, W.; Chapuis, C.; Bernardielli, G. HCA 1984, 67, 1397.
Yokomatsu, T.; Iwasawa, H.; Shibuya, S. CC 1992, 510.
Pauls, H. W.; Fraser-Reid, B. J. Carbohydr. Chem. 1985, 4, 1.
Tapan Ray
Sandoz Research Institute, East Hanover, NJ, USA
Alternate Names: TMS-I; TMSI; trimethylsilyl iodide.

Physical Data: bp 106-109C; d 1.406gcm - 3 ; n20D 1.4710; fp
-31C.
Solubility: sol CC14, CHC13, CH 2 C1 2 , C1CH2CH2C1, MeCN,
PhMe, hexanes; reactive with THF (ethers), alcohols, and
EtOAc (esters).
Form Supplied in: clear colorless liquid, packaged in ampules,
stabilized with copper; widely available.
Analysis of Reagent Purity: easily characterized by 1H, 13 C, or
29
Si NMR spectroscopy.
Preparative Methods: although more than 20 methods have been
reported1 for the preparation of TMS-I, only a few are summa
rized here. Chlorotrimethylsilane undergoes halogen exchange
with either Lithium Iodide2 in CHCl 3 or Sodium Iodide3 in
MeCN, which allows in situ reagent formation (eq 1). Alterna
tively, Hexamethyldisilane reacts with Iodine at 25-61 C to
afford TMS-I with no byproducts (eq 2). 4
(1)
(2)
Several other methods for in situ generation of the reagent have

been described. 5,6 It should be noted, however, that the reactivity
of in situ generated reagent appears to depend upon the method
of preparation.
Purification: by distillation from copper powder
Handling, Storage, and Precautions: extremely sensitive to light,
air, and moisture, it fumes in air due to hydrolysis (HI), and
becomes discolored upon prolonged storage due to generation
of I 2 . It is flammable and should be stored under N 2 with a
small piece of copper wire. It should be handled in a well ven
tilated fume hood and contact with eyes and skin should be
avoided.
IODOTRIMETHYLSILANE
Use as a Nucleophilic Reagent in Bond Cleavage Reactions.
Ether Cleavage.5,7 The first broad use of TMS-I was for
dealkylation reactions of a wide variety of compounds containing
oxygen-carbon bonds, as developed independently by the groups
of Jung and Olah. Simple ethers initially afford the trimethylsilyl
ether and the alkyl iodide, with further reaction giving the two
iodides (eq 3). 7,8 This process occurs under neutral conditions,
and is generally very efficient as long as precautions to avoid hy
drolysis by adventitious water are taken. Since the silyl ether can
be quantitatively hydrolyzed to the alcohol, this reagent permits
the use of simple ethers, e.g. methyl ethers, as protective groups
in synthesis. The rate of cleavage of alkyl groups is: tertiary
benzylic allylic methyl secondary > primary. Benzyl and
t-butyl ethers are cleaved nearly instantaneously at low tempera
ture with TMS-I. Cyclic ethers afford the iodo silyl ethers and then
the diiodide, e.g. THF gives 4-iodobutyl silyl ether and then 1,4diiodobutane in excellent yield. 7,8 Alcohols and silyl ethers are
rapidly converted into the iodides as well. 8a,9 Alkynic ethers pro
duce the trimethylsilylketene via dealkylative rearrangement.4b
Phenolic ethers afford the phenols after workup. 5,7,10 In general,
ethers are cleaved faster than esters. Selective cleavage of methyl
aryl ethers in the presence of other oxygenated functionality has
also been accomplished in quinoline.11 -Alkoxyl enones undergo
deoxygenation with excess TMS-I (2 equiv), with the first step be
ing conjugate addition of TMS-I.12
235
displacement of R by I . Upon prolonged exposure (75 C,

3 d) of simple esters to excess TMS-I (2.5 equiv), the corre
sponding acid iodides are formed. 14b,16 -Keto esters undergo
decarboalkoxylation when treated with TMS-I. 17 An interesting
rearrangement reaction provides -methylene lactones from 1(dimethylaminomethyl)cyclopropanecarboxylates (eq 6). 18
(5)
(6)
Lactone Cleavage.14,19 Analogous to esters, lactones are also

efficiently cleaved with TMS-I to provide -iodocarboxylic acids,
which may be further functionalized to afford bifunctional build
ing blocks for organic synthesis (eq 7). Diketene reacts with TMS-I
to provide a new reagent for acetoacylation.20
(7)
(3)
Cleavage of Epoxides. Reaction of epoxides with 1 equiv of

TMS-I gives the vicinal silyloxy iodide.8e With 2 equiv of TMS-I,
however, epoxides are deoxygenated to afford the corresponding
alkene (eq 4). 13a,b However, allylic alcohols are efficiently pre
pared by reaction of the intermediate iodosilane with base. 13c,d
Furthermore, acyclic 2-ene-1,4-diols react with TMS-I to undergo
dehydration, affording the corresponding diene. 13e
Cleavage of Carbamates.21 Since strongly acidic conditions

are typically required for the deprotection of carbamates, use of
TMS-I provides a very mild alternative. Benzyl and t-butyl car
bamates are readily cleaved at rt,22 whereas complete cleavage
of methyl or ethyl carbamates may require higher temperatures
(reflux). The intermediate silyl carbamate is decomposed by the
addition of methanol or water (eq 8). Since amides are stable to
TMS-I-promoted hydrolysis,7a this procedure can be used to deprotect carbamates of amino acids and peptides.21d
(8)
A recent example used TMS-I to deprotect three different pro

tecting groups (carbamate, ester, and orthoester) in the same
molecule in excellent yield (eq 9). 23
"(4)
(9)
Ester Dealkylation.14 Among the widest uses for TMS-I in

volves the mild cleavage of carboxylic esters under neutral con
ditions. The ester is treated with TMS-I to form an initial oxonium intermediate which suffers attack by iodide (eq 5). The
trimethylsilyl ester is cleaved with H2O during workup. Although
the reaction is general and efficient, it is possible to accom
plish selective cleavage according to the reactivity trend: ben
zyl, t-butyl > methyl, ethyl, i-propyl. Neutral transesterification is
also possible via the silyl ester intermediate.15 Aryl esters are
not cleaved by TMS-I, however, since the mechanism involves
Cleavage of Acetals.24 Acetals can be cleaved in analogy to

ethers, providing a newly functionalized product (eq 10), or simply
the parent ketone (eq 11). Glycals have also been converted to the
iodopyrans with TMS-I, 25 and glycosidation reactions have been
conducted with this reagent.26
(10)
236
JODOTRIMETHYLSILANE
(11)
Orthoesters are converted into esters with TMS-I. The dimethyl

acetal of formaldehyde, methylal, affords iodomethyl methyl ether
in good yield (eq 12)27a (in the presence of alcohols, MOM ethers
are formed).27b -Acyloxy ethers also furnish the iodo ethers,28
e.g. the protected -acetyl ribofuranoside gave the -iodide which
was used in the synthesis of various nucleosides in good yield
(eq 13).28b Aminals are similarly converted into immonium salts,
e.g. Eschenmoser's reagent, Dimethyl(methylene)ammonium
Iodide, in good yield.29
(12)
or Benzyl Bromide, and even with certain alkylfluorides,by using

TMS-I in the presence of (n-Bu)4NCl as catalyst (eq 17).
(17)
X = Br, Cl
Use of TMS-I in Nucleophilic Addition Reactions.

Carbonyl Addition Reactions.35 -Iodo trimethylsilyl ethers
are produced in the reaction of aldehydes and TMS-I (eq 18).
These compounds may react further to provide the diiodo deriva
tive or may be used in subsequent synthesis.
(18)
(13)
An example of a reaction of an iodohydrin silyl ether with a

cuprate reagent is summarized in eq 19.36 An interesting reaction
of TMS-I with phenylacetaldehydes gives a quantitative yield of
the oxygen-bridged dibenzocyclooctadiene, which was then con
verted in a few steps to the natural product isopavine (eq 20).35,37
Cleavage of Phosphonate and Phosphate Esters.30

Phosphonate and phosphate esters are cleaved even more readily
with TMS-I than carboxylic esters. The reaction of phospho
nate esters proceeds via the silyl ester, which is subsequently
hydrolyzed with MeOH or H2O (eq 14).
(19)
(14)
(20)
-Iodo ketones have been produced from reactions of TMS-I

Conversion of Vinyl Phosphates to Vinyl Iodides.31 Ketones
and ketones with -hydrogens.38 This reaction presumably in
can be converted to the corresponding vinyl phosphates which
volves a TMS-I catalyzed aldol reaction followed by 1,4-addition
react with TMS-I (3 equiv) at rt to afford vinyl iodides (eq 15).
of iodide.
(15)
Conjugate Addition Reactions.39 ,-Unsaturated ketones

undergo conjugate addition with TMS-I to afford the 3-iodo
adducts in high yield (eq 21). The reaction also works well with
the corresponding alkynic substrate.40
Cleavage of Cyclopropyl Ketones.32 Cyclopropyl ketones un

dergo ring opening with TMS-I, via the silyl enol ether (eq 16).
Cyclobutanones react analogously under these conditions.33
(21)
TMS-I has also been extensively utilized in conjunction with

organocopper reagents to effect highly stereoselective conjugate
additions of alkyl nucleophiles.41
(16)
Halogen Exchange Reactions.34 Halogen exchange can be ac

complished with reactive alkyl halides, such as Benzyl Chloride
Use of TMS-I as a Silylating Agent.

Formation of Silyl Enol Ethers.42 TMS-I in combination with
Triethylamine is a reactive silylating reagent for the formation
of silyl enol ethers from ketones (eq 22). TMS-I with Hexamethyldisilazane has also been used as an effective silylation agent,
IODOTRIMETHYLSILANE
affording the thermodynamic silyl enol ethers. For example, 2methylcyclohexanone gives a 90:10 mixture in favor of the tetrasubstituted enol ether product.42a The reaction of TMS-I with
1,3-diketones is a convenient route to 1,3-bis(trimethylsiloxy)1,3-dienes.42c
237
Use of TMS-I as a Lewis Acid.

Acetalization Catalyst.46 TMS-I used in conjunction with
(MeO)4Si is an effective catalyst for acetal formation (eq 28).
(28)
(22)
In an analogous process, TMS-I reacts with lactams in the pres

ence of Et 3 N to yield silyl imino ethers (eq 23). 43a
Catalyst for -Alkoxymethylation of Ketones. Silyl enol

ethers react with -chloro ethers in the presence of TMS-I to afford
-alkoxymethyl ketones (eq 29). 47
(29)
(23)
Halogenation of Lactams. 43b Selective and high yielding iodination and bromination of lactams occurs with Iodine or Bromine,
respectively, in the presence of TMS-I and a tertiary amine base
(eq 24). The proposed reaction mechanism involves intermediacy
of the silyl imino ether.
Catalyst for Reactions of Acetals with Silyl Enol Ethers

and Allylsilanes. TMS-I catalyzes the condensation of silyl enol
ethers with various acetals (eq 30) 48 and imines,49 and of allylsi
lanes with acetals.50
(30)
(24)
X = I, Br
Reaction with Carbanions.44 TMS-I has seen limited use in

the silylation of carbanions, with different regioselectivity com
pared to other silylating reagents in the example provided in eq 25.
Use of TMS-I as a Reducing Agent. TMS-I reduces enediones to 1,4-diketones,51 while both epoxides and 1,2-diols are
reduced to the alkenes. 13a,b,52 The Diels-Alder products of benzynes and furans are converted in high yield to the corresponding
naphthalene (or higher aromatic derivative) with TMS-I (eq 31 ). 53
(25)
(3D
Silylation of Alkynes and Alkenes.45 A Heck-type reaction

of TMS-I with alkenes in the presence of Pd0 and Et 3 N affords
alkenyltrimethylsilanes (eq 26).
(26)
Oxidative addition of TMS-I to alkynes can also be accom

plished with a three-component coupling reaction to provide the
enyne product (eq 27).
(27)
Styrenes and benzylic alcohols are reduced to the alkanes with

TMS-I (presumably via formation of HI). 54 Ketones produce the
symmetrical ethers when treated with trimethylsilane as a reducing
agent in the presence of catalytic TMS-I.55
Reduction of -Ketols.56,57 Carbonyl compounds containing
-hydroxy, -acetoxy, or -halo groups react with excess TMS-I
to give the parent ketone. -Hydroxy ketone reductions proceed
via the iodide, which is then reduced with iodide ion to form the
parent ketone (eq 32).
(32)
Sulfoxide Deoxygenation.58 The reduction of sulfoxides oc

curs under very mild conditions with TMS-I to afford the corre
sponding sulfide and iodine (eq 33). Addition of I2 to the reaction
238
IODOTRIMETHYLSILANE
mixture accelerates the second step. The deoxygenation occurs

faster in pyridine solution than the reactions with a methyl ester
or alcohol.59
discussed for the oximes (eq 38). Secondary nitro compounds af

ford the silyl oxime ethers, and tertiary nitro compounds afford the
corresponding iodide. Nitroalkenes, however, react with TMS-I at
0C to afford the ketone as the major product (eq 39).69
(33)
(38)
Pummerer reactions of sulfoxides can be accomplished in the

presence of TMS-I and an amine base, leading to vinyl sulfides.60
An efficient synthesis of dithioles was accomplished with TMS-I
and Hnig's base (Diisopropylethylamine) (eq 34).61
(34)
(39)
An interesting analogy to this dehydration process is found in

the reductive fragmentation of a bromoisoxazoline with TMS-I,
which yields the nitrile (eq 40).70
Reaction with Sulfonyl Halides.62 Arylsulfonyl halides un

dergo reductive dimerization to form the corresponding disulfides
(eq 35). Alkylsulfonyl halides, however, undergo this process un
der somewhat more vigorous conditions. Although sulfones gen
erally do not react with TMS-I, certain cyclic sulfones are cleaved
in a manner analogous to lactones.63
(40)
(35)
Other Reactions of TMS-I.

Reaction with Phosphine Oxides.64 Phosphine oxides react
with TMS-I to form stable adducts (eq 36). These O-silylated
products can undergo further thermolytic reactions such as alkyl
group cleavage.
Rearrangement Reactions. An interesting rearrangement oc

curs on treatment of a -alkoxy ketone with TMS-I which effects
dealkylation and retro-aldol reaction to give the eight-membered
diketone after reductive dehalogenation (eq 41).71 Tertiary allylie
silyl ethers a to epoxides undergo a stereocontrolled rearrange
ment to give the -hydroxy ketones on treatment with catalytic
TMS-I (eq 42).72
(36)
Chlorophosphines undergo halogen exchange reactions with

TMS-I.65
Reaction with Imines. Imines react with TMS-I to form Nsilylenamines, in a process analogous to the formation of silyl
enol ethers from ketones.66
(41)
67
Reaction with Oximes. Oximes are activated for dehydration

(aldoximes, with hexamethylsilazane) or Beckmann rearrange
ment (ketoximes) with TMS-I (eq 37).
(42)
(37)
Reactions with Nitro and Nitroso Compounds.68 Primary nitro derivatives react with TMS-I to form the oximino interme
diate via deoxygenation, which then undergoes dehydration as
Related Reagents. Bromotrimethylsilane; Chlorotrimethylsilane; Hydrogen Bromide; Hydrogen Iodide; Trimethylsilyl Trifluoromethanesulfonate.
1.
(a) Olah, G. A.; Prakash, G. K.; Krishnamurti, R. Adv. Silicon Chem.

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IODOTRIMETHYLSILANE
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A. N.; Russ, M.; Grosse, D. S 1981, 216.
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240
60.
61.
62.
63.
64.
65.
66.
67.
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69.
70.
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72.
ISOBUTENE
Miller, R. D.; McKean, D. R. TL 1983, 24, 2619.

Schaumann, E.; Winter-Extra, S.; Kummert, K.; Scheiblich, S. S 1990,
271.
Olah, G. A.; Narang, S. C ; Field, L. D.; Salem, G. F. JOC 1980, 45,
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ZOB 1979, 49, 1446.
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1991, 61, 1969.
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Heacock, D. J. JOC 1982, 47, 4820.
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Suzuki, K.; Miyazawa, M.; Tsuchihashi, G. TL 1987, 28, 3515.
Michael E. Jung
University of California, Los Angeles, CA, USA
(2)
(3)
Protection for the Hydroxy Group. In the presence of acid

catalysts, isobutene reacts to convert a variety of alcohols and
phenols to their corresponding t-butyl ethers. t-Butyl ethers are
stable to most reagents but are readily cleaved by strong acids.
Propargyl alcohols (eq 4), 6 steroidal alcohols (eq 5), 7 and phenols
(eq 6) 8 have been protected. The t-butyl group has also been used
to protect the hydroxy group of valinol (eq 7), 9 serine derivatives
(eq 8), 10 and tyrosine. 11
(4)
Isobutene
[115-11-7]
C4H8
(MW 56.12)
(carboxy and hydroxy protection; photochemical cycloaddition

with enones; ene reaction with enophiles; Friedel-Crafts and other
alkylations; reacts with carbenes; acid-catalyzed cycloadditions)
Alternate Name: isobutylene.
Physical Data: mp -140.4 C; bp - 6 . 9 C; vapor density 1.947.
Solubility: insol H 2 O; sol THF, pet ether, benzene.
Form Supplied in: gas (lecture bottle); widely available.
Handling, Storage, and Precautions: flammable gas; store and use
with adequate ventilation. Do not store with oxidizing materials
and compounds that add across double bonds.
Protection for the Carboxy Group. Isobutene has been

widely used in synthesis to convert carboxylic acids into corre
sponding r-butyl esters. 1,2 t-Butyl esters of aliphatic acids (eq 1), 3
aromatic carboxylic acids (eq 2), 4 and N-protected amino acids
(eq 3) 5 have been prepared. The hindered t-butyl esters are stable
to saponification but can be cleaved by acid-catalyzed hydrolysis,
with liberation of isobutene.
(1)
(5)
(6)
(7)
(8)
Photochemical Cycloadditions. Isobutene has been widely

used in intermolecular [2 + 2] photocycloaddition reactions with
enones. 11 The weakly polarized isobutene is often used to study
the regioselectivity of the photocycloaddition. Cyclohexenones
(eq 9), 12 cyclopentenones (eq 10),13 and functionalized enones
(eq 11) 14 undergo cycloaddition with isobutene. Paterno-Bchi
ISOBUTENE
241
photoadditions with isobutene have produced various oxetanes

(eq 12).15
(17)
(9)
(18)
(10)
(11)
Friedel-Crafts and Other Alkylation Reactions. A variety

of t-butyl-substituted aromatics have been prepared with isobutene
in the presence of acids (eqs 19-21).23-25 Due to steric factors,
the regiochemistry is enhanced. Isobutene can be alkylated by
benzylic and allylic halides in the presence of Zinc Chloride
(eqs 22-24).26,27
(19)
(12)
(20)
Ene Reactions. In the presence of Lewis acids, isobutene

adds to various enophiles to yield ene adducts.16 Enophiles such
as alkoxyaldehyde (eq 13),17 dialkyl aminoaldehyde (eq 14),18
haloaldehyde (eq 15),19 and vinyl sulfoxides (eq 16)20 have been
utilized. Chiral organoaluminum (eq 17)21 and organotitanium
reagents (eq 18)22 have been reported to give high levels of asym
metric induction in the ene reaction of isobutene with activated
aldehydes.
(21)
(22)
(13)
(23)
(24)
(14)
(15)
Carbene Chemistry. Isobutene reacts readily with carbenes and metallocarbenes to form substituted cyclopropanes
(eqs 25-27).28 Reaction of Ethyl Diazoacetate with isobutene in
the presence of a chiral copper catalyst affords the cyclopropane in
high optical purity (eq 28).29 Isobutene has also been used to form
titanocyclobutanes that are more stable forms of the Tebbe reagent
(see -Chlorobis(cyclopentadienyl)(dimethylaluminum)- methylenetitanium) (eq 29).30
(16)
(25)
242
ISOBUTENE
(26)
(34)
(27)
(35)
(28)
(29)
(36)
Other Acid-catalyzed Cycloadditions. Isobutene has been

used to form pyrylium salts (eqs 30 and 31 ),31 oxetanes by Boron
Trifluoride-catalyzed [2 + 2] cycloaddition (eq 32),32 and 3,4dihydropyrans by Diels-Alder reactions (eq 33).33
(37)
(38)
(30)
HO2CCH2SO3(39)
(31)
(32)
(33)
Miscellaneous Reactions. Isobutene, as the carbenium ion

source for Ritter reactions, produces N-t-butyl amides (eq 34).34
Isobutene undergoes highly regioselective cycloaddition with isocyanate to form azetidinones and with nitrones to yield isoxazolidines (eqs 35 and 36).35,36 Allyl thioethers are formed
by the electrophilic addition of Benzenesulfenyl Chloride
to isobutene (eq 37).37 Alkenylphosphonous dichlorides and
alkenylthionophosphonic dichlorides are also formed by addition
of PC15 and P2S5 (eqs 38 and 39).38
Related Reagents. t-Butyl 2,2,2-Trichloroacetimidate.
1. Fieser, L. F.; Fieser, M. FF 1967,7, 522.

2. Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis;
Wiley: New York, 1991; p 245.
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6.
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8.
9.
10.
11.
12.
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5570.
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14. Patjens, J.; Margaretha, P. HCA 1989, 72, 1817.
15. Arnold, D. R.; Hinman, R. L.; Glick, A. M. TL 1964, 1425. Jorgenson,
M. J. TL 1966, 5811. Kwiatkowski, G. T.; Selley, D. B. TL 1968, 3471.
16. Snider, B. B. ACR 1980,13, 426.
17. Mikami, K.; Loh, T.-R; Nakai, T. TA 1990, 1,13.
18. Mikami, K.; Kaneko, M.; Loh, T.-P.; Terada, M.; Nakai, T. TL 1990, 31,
3909.
ISOBUTYL CHLOROFORMATE
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
Mikami, K.; Loh, T.-P.; Nakai, T. CC 1991, 77.

Brichard, M.-H.; Janousek, Z.; Merenyi, R.; Viehe, H. G. TL 1992, 33,
2511.
Marouka, K.; Hoshimo, Y.; Shirasaka, T.; Yamamoto, H. TL 1988, 29,
3967.
Mikami, K.; Terada, M.; Nakai, T. JACS 1989, 111, 1940.
Chasar, D. W. JOC 1984, 49, 4302.
Loev, B.; Massengale, J. T. JOC 1957, 22, 988.
Caesar, P. D. JACS 1948, 70, 3623.
Olah, G. A.; Kuhn, S. J.; Barnes, D. G. JOC 1964, 29, 2685.
Mayr, H. AG(E) 1981, 20, 184. Mayr, H.; Striepe, W. JOC 1983, 48,
1159. Mayr, H.; Klein, G.; Kolberg, G. CB 1984, 117, 2555.
Casey, C. P.; Polichnowski, S. W. JACS 1977, 99, 6097. Casey, C. P.;
Miles, W. H.; Tukada, H. JACS 1985, 107, 2924. Curuco, R. F.; Chu, K.
S. SC 1987, 17, 271. Moss, R. A.; Zdrojewski, T.; Krogh-Jespersen, K.;
Wlostowski, M.; Matro, A. TL 1991, 32, 1925.
Evans, D. A.; Woerpel, K. A.; Hinman, M. M.; Faul, M. M. JACS 1991,
113, 726.
Dtz, K. H. AG(E) 1984, 23, 587.
Balaban, A. T.; Dinculescu, A. OPP 1982, 14,39. Praill,P. F. G.; Whitear,
A. L. JCS 1961, 3573. Anderson, A. G.; Stang, P. J. JOC 1976, 41, 3034.
Sugimura, H.; Osumi, K. TL 1989, 30, 1571.
Sera, A.; Ohara, M.; Yamada, H.; Egashira, E.; Ueda, N.; Setsune, J. CL
1990, 11, 2043.
Stephens, C. R.; Beereboom, J. J.; Rennhard, H. H.; Gordon, P. N.; Murai,
K.; Blackwood, R. K.; Schach von Wittenau, M. JACS 1963, 85, 2643.
Bishop, R. COS 1991, 6, 261.
Graf, R. OSC 1973, 5, 673. Arbuzov, B. A.; Zobova, N. N. S 1974, 461.
Prosyanik, A. V.; Mischenko, A. I.; Zaichenko, N. L.; Zorin, Y. Z. KGS
1979, 599 (CA 1979, 91, 175 249).
Giese, B.; Mazumdar, P. CB 1981, 114, 2859.
Walsh, E. N.; Beck, T. M.; Woodstock, W. H. JACS 1955, 77, 929.
243
in toluene or THF by addition of enough Triethylamine to form

the salt, and isobutyl chloroformate is added at 0C to produce
the mixed anhydride. A solution of an amino acid ester (or peptide
ester) to be N-acylated is added in an inert solvent and the mixture
is allowed to come to rt. Evolution of carbon dioxide begins im
mediately (eq 1). The isobutyl chloroformate is preferred to lower
esters for preparation of peptides of moderate or high molecular
weight;6,7 ethyl chloroformate is preferred for synthesis of dipeptides.
(1)
Boc-Gly-Gly-OEt and Boc-Gly-Gly-Gly-OEt have been suc

cessfully synthesized in reasonable yields (77% and 88%,
respectively) via mixed anhydride derivatives from isobutyl
chloroformate.8 Previously it was reported9 that considerable
quantities of diacylated side products are formed in mixed an
hydride syntheses with glycine when ethyl chloroformate is used.
5'-Hydroxy Function Blocking Agent for Deoxyribo
sides. The reagent has been used to block the 5'-hydroxy func
tion of deoxyribosides in oligonucleotide synthesis (eq 2). 4 The
reagent shows good selectivity for the 5'-hydroxy group, as is
evident in the high yield of (2). The blocking group is removed
smoothly by alkaline hydrolysis to give (4).
Michael T. Crimmins & Agnes S. Kim-Meade

University of North Carolina at Chapel Hill, NC, USA
[543-27-1]
C 5 H 9 ClO 2
(MW 136.59)
(used for making mixed anhydrides which serve as active interme

diates for peptide synthesis; 1-3 used to block the 5'-hydroxy func
tion of deoxyribosides in oligonucleotide synthesis;4 condensing
reagent5)
Physical Data: bp 128.8 C; d 1.04 g c m - 3 .
Solubility: miscible with benzene, chloroform, ether.
Form Supplied in: clear colorless liquid.
Handling, Storage, and Precautions: gradually decomposed by
water and alcohol; highly toxic; vapor irritates eyes and mucous
membranes; stable on storage. 6,7 Use in a fume hood.
Peptide Reagent. 13 Protected amino acids, such as the Nbenzyloxycarbonyl (Cbz) derivatives, are brought into solution
(2)
N-Protection.10 In the synthesis of enantiomerically pure sym

metric vicinal diamines involving chirality transfer from a sinAvoid Skin Contact with All Reagents
244
ISOPROPENYL ACETATE
gle chiral source,1,2-diphenylethane-1,2-diamine, hydrolysis of

the bisacetamides to the corresponding vicinal diamines was at
tempted using a number of amide hydrolysis procedures. However,
the various base- and acid-catalyzed procedures did not result in
a clean hydrolysis of the acetamide groups. This was achieved
by converting amines into biscarbamate derivatives, followed by
treatment with 30% HBr in acetic acid (eq 3).
toluenesulfonic acid. Isobutene was considered to be derived from

the t-butyl cation.
1. Boissonnas, R. A. HCA 1951, 34, 874; HCA 1952, 35, 2229 and 2237.
2. Vaughan, J. R. JACS 1951, 73,3547; JACS 1952, 74,676 and 6137; JACS
1953, 75, 5556; JACS 1954, 76, 2474.
3. Wieland, T.; Bernhard, H. LA 1951, 572, 190.
4.
5.
6.
7.
(3)
Cyclodehydration.5 In the synthesis of 1,4-dihydropyran[3,4fc]indolones, the reagent was used along with triethylamine for
cyclodehydration of hydroxymethylindoleacetic acid to produce
the lactone (eq 4).
(4)
Regioselective Arylation. 11 Arylation in the 4-position

in pyridines results from 1:1 adduct formation be
tween an aryltriisopropoxytitanium reagent and an Nisobutyloxycarbonylpyridinium salt, and after successive
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone
dehydrogenation
and cleavage of the 1-substituent (eq 5).
(5)
Isobutyl Sulfonate.12 With Silver(I) p-Toluenesulfonate,

alkyl chloroformate forms sulfonic carbonic anhydride which
when heated liberates carbon dioxide, producing alkyl sulfonate.
In order to find out the mechanism of the decomposition of
the mixed anhydride, reaction of isobutyl chloroformate and sil
ver p-toluenesulfonate was investigated. If the free alkyl cation,
i.e. isobutyl carbonium ion, is formed, the rearrangement to
s-butyl and t-butyl carbonium ion would be expected, finally
resulting in the formation of s-butyl p-toluenesulfonate. t-Butyl
p-toluenesulfonate is unstable and is not expected to survive un
der the reaction conditions. In fact, decomposition gave a mix
ture of isobutyl p-toluenesulfonate and s-butyl p-toluenesulfonate
in a 0.8:1 mol ratio, with a quantity of isobutene and free pLists of Abbreviations and Journal Codes on Endpapers
Ogilvie, K. K.; Letsinger, R. L. JOC 1967, 32, 2365.

Fray, E. B.; Moody, C. J.; Shah, P. T 1993, 49, 439.
Vaughan, J. R.; Osato, R. L. JACS 1952, 74, 676.
Anderson, G. W.; Zimmerman, J. E.; Callahan, F. M. JACS 1966, 88,
1336. ibid 1967, 59,5012.
8. Hoffmann, J. A.; Tilak, M. A. OPP 1975, 7, 215.
9. Kopple, K. D.; Renick, K. J. JOC 1974, 39, 660.
10. Nantz, M. H.; Lee, D. A.; Bender, D. M.; Roohi, A. H. JOC 1992, 57,
6653.
11. Gundersen, L.; Rise, F.; Undheim, K. T 1992, 48, 5647.
12. Yamamoto, A.; Kobayashi, M. BCJ 1966, 39, 1283.
Tapan Ray
Sandoz Pharmaceuticals, East Hanover, NJ, USA
Isopropenyl Acetate1
[108-22-5].
C5H8O2
(MW 100.13)
(conversion of carbonyl compounds to their enol acetates;5 acetylation of oxygen, 12 nitrogen,14 and carbon;12a acetone equivalent
in Lewis acid catalyzed aldol reactions; 15 conversion of malonic
acids to their isopropylidene derivatives17)
Physical Data: bp 97 C; 2 d 0.909 g c m - 3 ; fp 18 C.
Solubility: sol benzene, acetic acid.
Form Supplied in: 99 and 99+% pure liquid widely available.
Analysis of Reagent Purity: the acetone content may be deter
mined by addition of an excess of Hydroxylamine hydrochlo
ride to an ethanolic solution, followed by back titration against
sodium hydroxide. 3
Handling, Storage, and Precautions: flammable liquid; mild irri
tant; narcotic in high concentrations. LD50 orally in rats: 3.0 g
kg-1.4
Enol Acetylation. In the presence of catalytic acid, iso

propenyl acetate reacts with enolizable ketones to give the enol
acetate plus acetone. This reactivity has been exploited to ac
complish selective enolization of ketones, and to provide dienol
acetates for Diels-Alder reactions. Each of these reactions is de
scribed in more detail in the following sections.
Selective Generation of Kinetic and Thermodynamic Enol
Acetates. While the use of isopropenyl acetate with catalytic acid
is considered to provide conditions for the generation of kinetic
ISOPROPENYL ACETATE
enols, the ratio of kinetic to thermodynamic isomers obtained for a
given enolizable ketone appears to be highly dependent on the in
dividual system being studied. For example, in steroid chemistry,
isopropenyl acetate has been used to provide significant yields of
the kinetic 2-enol (2) over the thermodynamically favored A 3 enol (3) (eq 1).5 For comparison, the results of the corresponding
thermodynamically controlled enol acetylation reaction using per
chloric acid catalyst and Acetic Anhydride are also given.
(1)
(1a) R = OH
(2a) R = OAc (3a) R = OAc

isopropenyl acetate,
H2SO4, reflux 1 h
acetic anhydride,
HClO4, PhH, CCl4
(1b) R = H
isopropenyl acetate,
H2SO4, reflux 1 h
acetic anhydride,
HClO4, PhH, CCl4
47%
25%
(2b) R = H
(E)-(6b)
245
(3)
(Z):(E)=l:15
The use of isopropenyl acetate and catalytic acid for the for
mation of dienol acetates from ,-unsaturated aldehydes and ke
tones is known to favor the formation of the (E) isomer (10a)
(eq 4). 9 For the enolization of Crotonaldehyde (8) the reaction
gives 1-acetoxy-l-propene (10) as an 83:17 (E:Z) mixture. This
selectivity is credited to the intermediacy of cation (9) in this pro
cess. Cation (9b), which would lead to the (Z) isomer (10b), is
disfavored due to an unfavorable steric interaction between the
vinyl and acetoxy groups (eq 5).
(4)
53%
75%
(3b) R = H
(5)
29%
71%
6%
94%
As shown in eq 1, introduction of an 11 -hydroxy group causes

a 16-18% increase in the amount of the kinetic 2-enol acetate
(2) regardless of the reaction conditions. Additionally, enol acety
lation proceeds with concomitant acetylation of the 1 l -hydroxy
group under these same reaction conditions. While these condi
tions provide only a moderate predilection for formation of the
kinetic enol acetate in the cases presented above, other related
systems have shown excellent selectivity utilizing this method. 6,7
Selective Generation of (E)- or (Z)-Enol Acetates. The (E)and (Z)-enol acetates of -keto esters can be selectively generated
by careful choice of acetylation conditions.8 Under acidic condi
tions isopropenyl acetate gives, almost exclusively, the (Z) isomer
(6a) (eq 2). This selectivity is believed to arise because the re
active form of methyl acetoacetate under acidic conditions is the
internally hydrogen bound (Z)-enol (5) (eq 2). Alternatively, the
corresponding (E)-enol acetate (6b) may be selectively generated
under basic conditions utilizing Acetyl Chloride as the acetylating
agent (eq 3). The selectivity in this reaction is believed to be due to
the solvent-separated ion (7) generated in Hexamethylphosphoric
Triamide and Triethylamine. For the anion (7), the (E) conforma
tion places the negatively charged oxygen atoms at a maximum
separation.
(Z)-(6a)
(2)
(Z):(E)=18:1
Dienol Acetates for the Diels-Alder Reaction. Wolinsky and

Login10 found that the methodology described above allows for
the in situ generation of reactive dienes for use in Diels-Alder re
actions (eqs 6 and 7). The enol acetate of 2-methyl-2-butenone
(11) is generated by reaction with isopropenyl acetate and pToluenesulfonic Acid. In the presence of Dimethyl Acetylenedicarboxylate (DMAD), the resulting diene undergoes a cycloaddition reaction, giving, after loss of acetic acid, the phthalic acid
derivative (12) in 80% yield (eq 6). Similarly, crotonaldehyde (8)
is converted to 1-acetoxy-l-propene (10), as shown in eq 4. Diene
(10) is then trapped with chloromaleic anhydride (13). Loss of
acetic acid and HC1 gives phthalic anhydride (14) in 70% yield
(eq 7).
(6)
(7)
Acetylation of Other O, N, and C Centers. In addition to

the preparation of enol acetates from ketones, isopropenyl acetate
has also seen use in the acetylation of other O, N, and C centers.
Hydroxy acetylation was first noted11 as a simultaneous reaction
246
ISOPROPENYL ACETATE
occurring during the enol acetylation of steroids bearing unpro

tected hydroxy groups (eq 1). The reagent has since been used
more deliberately for the protection of alcohols.12 More recently
the reagent has been used in conjunction with enzymes to afford
chiral acylated material.13 Kaupp and Matthies14 were surprised to
observe N-acetylation of the benzothiazepine derivative (15) with
no formation of the isomer (17) (eq 8). Attempts by the authors
to generate the expected isomer (17) were unsuccessful.
(8)
Isopropenyl Acetate as a Source of Acetone. Under certain

reaction conditions, isopropenyl acetate reacts to deliver an equiv
alent of acetone for acetonide formation or for oxidative addition
to an enol. Under acidic conditions, isopropenyl acetate has been
used to generate isopropylidene derivatives of malonic acids.17
Isopropenyl acetate also undergoes an oxidative addition reaction
with ketones in the presence of Manganese(III) Acetate.18 An
acetone subunit is added to the -position of a ketone to give a
1,4-diketone.
Related Reagents. Acetic Anhydride; Acetyl Chloride; 2Methoxypropene; Vinyl Acetate.
1. Hagemeyer, H. J., Jr.; Hull, D. C. Ind. Eng. Chem. 1949, 41, 2920.
2. The Merck Index, 11th ed.; Budavari, S., Ed.; Merck: Rahway, NJ, 1989;
p 5092.
3. Jeffery, E. A.; Satchell, D. P. N. JCS 1962, 1876.
4.
5.
6.
The 5-position of some N-methylpyrrole derivatives (18) were

successfully acetylated using isopropenyl acetate in the presence
of catalytic acid under refluxing conditions (eq 9).12a
7.
Bold, G; Chao, S.; Bhide, R.; Wu, S.-H.; Patel, D. V.; Sih, C. J.; Chidester,
C.TL.1987,28, 1973.
8. Casey, C. P.; Marten, D. F. TL 1974, 925.
9.
(9)
(18a) R = CO2Et
(18b) R = H
Aldol Reactions. Isopropenyl acetate participates in some

aldol-type reactions. This enol ester, like enol ethers, can react
with various acetals (20) in the presence of a Lewis acid to afford
the aldol-type addition products (21 and 22) (eq 10).15 This same
reactivity is observed in the condensation of Succinic Anhydride
with isopropenyl acetate.16
(20a) R = Ph
(20b) R = i-Pr
(20c) R = CH=CHPh
(21a) 81%
(21b) 92%
(21c) 0%
(22a) 5%
(22b) 0%
(22c) 65%
(a) Gizur, T.; Harsanyi, K. SC 1990, 20, 2365. (b) Shiao, M.-J.; Lin, J.
L.; Kuo, Y.-H.; Shih, K.-S. TL 1986, 27, 4059. (c) Alarcon, P.; Pardo,
M.; Soto, J. L. JHC 1985, 273. (d) Pauluth, D.; Hoffmann, H. M. R. LA
1985, 403.
13. Asensio, G.; Andreu, C ; Marco, J. A. CB 1992, 2233.

14. Kaupp, G.; Matthies, D. CB 1987, 1741.
15. Mukaiyama, T.; Izawa, T.; Saigo, K. CL 1974, 323.
16. (a)Merenyi,F.;Nilsson,M. ACS 1963, 17,1801; 1964,78, 1368;Nilsson,
M. ACS 1964, 18, 441. (b) Merenyi, F.; Nilsson, M. OS 1972, 52, 1.
17.
18.
(10)
Fukuda, W.; Sato, H.; Kakiuchi, H. BCJ 1986, 59, 751.
10. Wolinsky, J; Login, R. B. JOC 1970, 35, 3205.

11. Villotti, R.; Ringold, H. J.; Djerassi, C. JACS 1960, 82, 5693. The
experimental data are cited by Djerassi, C. Steroid Reactions; HoldenDay; San Francisco, CA, 1963; p 41.
12.
(19a) 81%
(19b) 55%
Smyth, H. E, Jr.; Carpenter, C. P.; Weil, C. S. J. Ind. Hyg. Toxicol. 1949,

31, 60.
Liston, A. J.; Howarth, M. JOC 1967, 32, 1034.
Nemoto, H.; Kurobe, H.; Fukumoto, K.; Kametani, T. JOC 1986, 51,
5311.
(a) Davidson, D.; Bernhard, S. A. JACS 1948, 70, 3426. (b) Singh, R. K.;
Danishefsky, S. OS 1981, 60, 66. (c) Maier, G.; Wolf, B. S 1985, 871.
Dessau, R. M.; Heiba, E. I. JOC 1974, 39, 3457.
Michael A. Walters & Melissa D. Lee
LITHIUM BROMIDE
LiBr-mediated decomposition of dioxaphospholanes results in

the exclusive formation of the epoxide, whereas the thermal de
composition produces a mixture of products (eq 4). 8
(4)
Lithium Bromide1
[7550-35-8]
247
Protection of alcohols as their MOM ethers can be

achieved using a mixture of Dimethoxymethane, LiBr, and pToluenesulfonic Acid.9
BrLi
(MW 86.85)
(source of nucleophilic bromide;2 mild Lewis acid;1 salt effects

in organometallic reactions;1 epoxide opening1)
Physical Data: mp 550 C; bp 1265 C; d 3.464 g c m - 3 .
Solubility: 145 g/100 mL H2O (4 C); 254 g/100 mL H2O (90C);
73 g/100 mL EtOH (40 C); 8 g/100 mL MeOH; sol ether, gly
col, pentanol, acetone; slightly sol pyridine.
Form Supplied in: anhyd white solid, or as hydrate.
Purification: dry for 1 h at 120C/0.1 mmHg before use; or dry
by heating in vacuo at 70 C (oil bath) for 24 h, then store at
110 C until use.
Handling, Storage, and Precautions: for best results, dry before
use in anhyd reactions.
Alkyl and Alkenyl Bromides. LiBr has been extensively used

as a source of bromide in nucleophilic substitution and addi
tion reactions. Interconversion of halides2 and transformation of
alcohols to alkyl bromides via the corresponding sulfonate3 or
trifluoroacetate4 have been widely used in organic synthesis. Pri
mary and secondary alcohols have been directly converted to alkyl
bromides upon treatment with a mixture of Triphenylphosphine,
Diethyl Azodicarboxylate, and LiBr.5
(Z)-3-Bromopropenoates and -propenoic acids have been syn
thesized stereoselectively by the reaction of LiBr and propiolates
or propiolic acid (eq 1).6
(1)
Heterolytic Cleavage of C-X Bonds. In the presence of a

Lewis acid, LiBr acts as a nucleophile in the opening of 1,2oxiranes to produce bromohydrins (eq 2). 7 In the absence of an
external Lewis acid or nucleophile, epoxides generally give rise
to products resulting from ring-contraction reactions (eq 3).
Bifunctional Reagents. Activated -bromo ketones are

smoothly converted into the corresponding silyl enol ethers when
treated with a mixture of LiBr/R3,N/Chlorotrimethylsilane.10
Aldehydes are converted into the corresponding ,-unsaturated
esters using Triethyl Phosphonoacetate and Triethylamine in the
presence of LiBr (eq 5). 11,12 Similar conditions were extensively
used in the asymmetric cycloaddition and Michael addition reac
tions of N-lithiated azomethine ylides (eq 6). 13
(5)
MX = LiCl, 77%; LiBr, 93%; MgCl2, 15%; MgBr2, 71%
(6)
Additive for Organometallic Transformations. The addition

of LiBr and Lithium Iodide was shown to enhance the rate of
organozinc formation from primary alkyl chlorides, sulfonates,
and phosphonates, and Zinc dust.14 Beneficent effects of LiBr
addition have also been reported for the Heck-type coupling
reactions15 and for the nickel-catalyzed cross-couplings of alkenyl
and -metalated alkenyl sulfoximines with organozinc reagents.16
The addition of 2 equiv of LiBr significantly enhances the yield of
the conjugate addition products in reactions of certain organocopper reagents (eq 7). 17
(7)
LiBr (0 equiv), 61%
LiBr (2 equiv), 96%
Finally, concentrated solutions of LiBr are also known to alter

significantly the solubility and the reactivity of amino acids and
peptides in organic solvents.18
(2)
Related
Reagents. Tetra-n-butylammonium
Tetramethylammonium Bromide; Phosphorus(III)
Sodium Bromide; Triphenylphosphine Dibromide.
Bromide;
Bromide;
(3)
1. Loupy, A.; Tchoubar, B. Salt effects in Organic and Organometallic
Chemistry; VCH; Weinheim, 1992.
248
LITHIUM CHLORIDE
2.
Sasson, Y.; Weiss, M.; Loupy, A.; Bram, G.; Pardo, C. CC 1986, 1250.
3.
(a) Ingold, K. U.; Walton, J. C. JACS 1987, 109, 6937. (b) McMurry, J.
E.; Erion, M. D. JACS 198S, 707, 2712.
4.
Camps, F.; Gasol, V.; Guerrero, A. S 1987, 511.
5.
Manna, S.; Falck, J. R. Mioskowski, C. SC 1985, 15, 663.
6.
(a) Ma, S.; Lu, X. TL 1990, 31, 7653. (b) Ma, S.; Lu, X. CC 1990, 1643.
7.
(a) Bonini, C ; Giuliano, C.; Righi, G.; Rossi, L. SC 1992, 22, 1863. (b)
Shimizu, M.; Yoshida, A.; Fujisawa, T. SL 1992, 204. (c) Bajwa, J. S.;
Anderson, R. C. TL 1991, 32, 3021.
8.
(a) Murray, W. T.; Evans Jr., S. A. NJC 1989, 13, 329. (b) Murray, W.
X; Evans, S. A., Jr. JOC 1989, 54, 2440.
9.
Gras, J.-L.; Chang, Y.-Y. K. W.; Gurin, A. S 1985, 74.
10. Duhamel, L.; Tombret, F.; Poirier, J. M. OPP 1985, 17, 99.
11.
Rathke, M. W.; Nowak, M. JOC 1985, 50, 2624.
12.
13.
Seyden-Penne, J. BSF 1988, 238.

(a) Kanemasa, S.; Tatsukawa, A.; Wada, E. JOC 1991, 56, 2875. (b)
Kanemasa, S.; Uchida, O.; Wada, E. JOC 1990, 55, 4411. (c) Kanemasa,
S.; Yoshioka, M.; Tsuge, O. BCJ 1989, 62, 869. (d) Kanemasa, S.;
Yamamoto, H.; Wada, E.; Sakurai, T.; Urushido, K. BCJ 1990, 63, 2857.
(a) Cabri, W.; Candiani, I.; DeBernardinis, S.; Francalanci, F.; Penco,
S. JOC 1991, 56, 5796. (b) Karabelas, K.; Hallberg, A. JOC 1989, 54,
1773.
16. Erdelmeier, I.; Gais, H.-J. JACS 1989, 111, 1125.

17. Bertz, S. H.; Dabbagh, G. JOC 1984, 49, 1119.
18.
Seebach, D. Aldrichim. Acta 1992, 25, 59.
Andre B. Charette
Universite de Montreal, Quebec, Canada
Lithium Chloride
[7447-41-8]
CILi
(MW 42.39)
(source of Cl- as nucleophile and ligand; weak Lewis acid that

modifies the reactivity of enolates, lithium dialkylamides, and
other Lewis bases)
Physical Data: mp 605 C; bp 1325-1360 C; d 2.068 g c m - 3 .
Solubility: very sol H 2 O; sol methanol, ethanol, acetone, acetonitrile, THF, DMF, DMSO, HMPA.
Form Supplied in: white solid, widely available.
Drying: deliquescent; for most applications, drying at 150C
for 3 h is sufficient; for higher purity, recrystallization from
methanol, followed by drying at 140C/0.5 mmHg overnight,
is recommended.
Handling, Storage, and Precautions: of low toxicity; take directly
from the oven when dryness is required.
Source of Chloride Nucleophile. The solubility of LiCl in

many organic dipolar solvents renders it an effective source of
nucleophilic chloride anion. Lithium chloride converts alcohols
to alkyl chlorides 1 under Mitsunobu conditions,2 or by way of
the corresponding sulfonates3 or other leaving groups. 4 This salt
cleanly and regioselectively opens epoxides to chlorohydrins in
(1)
X = CO2R, COR, CN, SO2R; R3 = Me, Et
14. Jubert, C ; Knochel, P. JOC 1992, 57, 5425.

15.
the presence of acids and Lewis acids such as Acetic Acid,5 Amberlyst 15 resin,6 and Titanium(IV) Chloride.7 In the presence
of acetic acid, LiCl regio- and stereoselectively hydrochlorinates
2-propynoic acid and its derivatives to form the corresponding
derivatives of (Z)-3-chloropropenoic acid.8 Oxidative decarboxy
lation of carboxylic acids by Lead(IV) Acetate in the presence of
1 equiv of LiCl generates the corresponding chlorides. 9
In wet DMSO, LiCl dealkoxycarbonylates various activated es
ters (eq l). 1 0 , 1 1 If the reaction is performed in anhyd solvent the
reaction generates a carbanion intermediate, which can undergo
inter- or intramolecular alkylation or elimination. Other inorganic
salts (NaCN, NaCl, Lithium Iodide) and other dipolar aprotic sol
vents (HMPA, DMF) can also be employed. Under similar condi
tions, lithium chloride cleaves alkyl aryl ethers having electronwithdrawing substituents at the ortho or para positions.12
Source of Chloride Ligand. In palladium-catalyzed reactions,

LiCl is often the reagent of choice as a source of chloride ligand.
Lithium chloride is a necessary component in palladium-catalyzed
coupling and carbonylative coupling reactions of organostannanes and vinyl triflates.13,14 Lithium chloride has a dramatic
effect on the stereochemical course of palladium-catalyzed 1,4additions to 1,3-dienes.15 Treatment of 1,3-cyclohexadiene with
Palladium(II) Acetate and LiOAc and the oxidizing agents
1,4-Benzoquinone and Manganese Dioxide affords 1,4-transdiacetoxy-2-cyclohexene (eq 2). In the presence of a catalytic
quantity of LiCl, the cis isomer is formed (eq 3). If 2 equiv LiCl
are added, the cis-acetoxychloro compound forms (eq 4). These
methods are general for both cyclic and acyclic dienes, and have
recently been extended to the stereospecific formation of fused
heterocycles.16 Lithium chloride is also used in the preparation
of Dilithium Tetrachloropalladate(II)17 and zinc organocuprate
reagents. 18
(2)
(3)
(4)
Weak Lewis Acid. Lithium chloride is a weak Lewis acid

that forms mixed aggregates with lithium dialkylamides, eno
lates, alkoxides, peptides, and related 'hard' Lewis bases. 19 Thus
LiCl often has a dramatic effect on reactions involving these
species. In the deprotonation of 3-pentanone by Lithium 2,2,6,6-
LITHIUM IODIDE
Tetramethylpiperidide (LTMP), addition of 0.3 equiv LiCl in
creases the (E)/(Z) selectivity from 9:1 to 52:1 (eq 5). 20 Enhance
ment in the enantioselectivity of deprotonation of prochiral ke
tones by a chiral lithium amide has also been reported.21 Lithium
chloride stabilizes anions derived from -phosphonoacetates,
permitting amine and amidine bases to be used to perform
Horner-Wadsworth-Emmons reactions on base-sensitive aldehy
des under exceptionally mild conditions.22 Lithium chloride and
other lithium salts disrupt peptide aggregation and increase the
solubilities of peptides in THF and other ethereal solvents, often
by 100-fold or greater.23 These effects render LiCl a useful addi
tive in the chemical modification of peptides (e.g. by the formation
and alkylation of peptide enolates). 19,24 Lithium chloride has also
shown promise as an additive in solid-phase peptide synthesis, in
creasing resin swelling and improving the efficiencies of difficult
coupling steps.25
19.
Seebach, D. AG(E) 1988, 27, 1624.
20.
(a) Hall, P. L.; Gilchrist, J. H.; Collum, D. B. JACS 1991, 113, 9571. (b)
Hall, P. L.; Gilchrist, J. H.; Harrison, A. T.; Fuller, D. J.; Collum, D. B.
JACS 1991, 113, 9575.
Bunn, B. J.; Simpkins, N. S. JOC 1993, 58, 533.
21.
22.
(a) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.; Masamune,
S.; Roush, W. R.; Sakai, T. TL 1984, 25, 2183. (b)Rathke, M. W.; Nowak,
M. JOC 1985, 50, 2624.
23.
Seebach, D.; Thaler, A.; Beck, A. K. HCA 1989, 72, 857.
24.
Seebach, D.; Bossier, H.; Grundler, H.: Shoda, S.-i.; Wenger, R. HCA
1991, 74, 197.
(a) Thaler, A.; Seebach, D.; Cardinaux, F. HCA 1991, 74, 617. (b) Thaler,
A.; Seebach, D.; Cardinaux, F. HCA 1991, 74, 628.
25.
James S. Nowick
University of California, Irvine, CA, USA
Guido Lutterbach
Johannes Gutenberg University, Mainz, Germany
(5)
0.0 equiv LiCl
0.3 equiv LiCl
9:1
52:1
Related Reagents. Lithium

Chloride-Diisopropylethylamine; Lithium Chloride-Hexamethylphosphoric Triamide; Zinc
Chloride.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
249
Magid, R.M.T 1980, 36, 1901.

Manna, S.; Falck, J. R.; Mioskowski, C. SC 1985,15, 663.
(a) Owen, L. N.; Robins, P. A. JCS 1949, 320. (b) Owen, L. N.; Robins,
P. A. JCS 1949, 326. (c) Eglinton, G.; Whiting, M. C. JCS 1950, 3650.
(d) Collington, E. W.; Meyers, A. I. JOC 1971, 36, 3044. (e) Stork, G.;
Grieco, P. A.; Gregson, M. TL 1969, 18, 1393.
(a) Czernecki, S.; Georgoulis, C. BSF 1975, 405. (b) Camps, F.; Gasol,
V; Guerrero, A. S 1987, 511.
Bajwa, J. S.; Anderson, R. C. TL 1991, 32, 3021.
Bonini, C ; Giuliano, C ; Righi, G.; Rossi, L. SC 1992, 22, 1863.
Shimizu, M.; Yoshida, A.; Fujisawa, T. SL 1992, 204.
(a) Ma, S.; Lu, X. TL 1990, 31, 7653. (b) Ma, S.; Lu, X.; Li, Z. JOC
1992, 57, 709.
(a) Kochi, J. K. JACS 1965, 87, 2500. (b) Review: Sheldon, R. A., Kochi,
J. K. OR 1972, 19, 279.
Krapcho, A. P.; Weimaster, J. F.; Eldridge, J. M.; Jahngen, E. G. E., Jr.;
Lovey, A. J.; Stephens, W. P. JOC 1978, 43, 138.
Reviews: (a) Krapcho, A. P. S 1982, 805. (b) Krapcho, A. P. S 1982, 893.
Bernard, A. M.; Ghiani, M. R.; Piras, P. P.; Rivoldini, A. 5 1989, 287.
(a) Scott, W. J.; Crisp, G. T.; Stille, J. K. JACS 1984, 106, 4630. (b) Crisp,
G. T.; Scott, W. L.; Stille, J. K. JACS 1984, 706, 7500.
Reviews: (a) Stille, J. K. AG(E) 1986, 25, 508. (b) Scott, W. J.; McMurry,
J. E. ACR 1988, 21, 47.
(a) Bckvall, J. E.; Bystrom, S. E.; Nordberg, R. E. JOC 1984, 49, 4619.
(b) Bckvall, J. E.; Nystrm, J. E.; Nordberg, R. E. JACS 1985, 107,
3676.
(a) Bckvall, J. E.; Andersson, P. G. JACS 1992, 114, 6374. (b) Review:
Bckvall, J. E. PAC 1992, 64, 429.
Lipshutz, B. H.; Sengupta, S. OR 1992, 41, 135.
(a) Knochel, P.; Yeh, M. C. P.; Berk, S. C ; Talbert, J. JOC 1988, 53, 2390.
(b) Jubert, C ; Knochel, P. JOC 1992, 57, 5431. (c) Ibuka, T.; Yoshizawa,
H.; Habashita, H.; Fujii, N.; Chounan, Y.; Tanaka, M.; Yamamoto, Y. TL
1992, 33, 3783. (d) Yamamoto, Y.; Chounan, Y.; Tanaka, M.; Ibuka, T.
JOC 1992, 57, 1024. (e) Knochel, P.; Rozema, M. J.; Tucker, C. E.;
Retherford, C.; Furlong, M.; AchyuthaRao, S. PAC 1992, 64, 361.
Lithium Iodide1
[10377-51-2]
ILi
(MW 133.84)
(ester cleavage and decarboxylation;2 source of nucleophilic

iodide;3 mild Lewis acid;1 salt effects in organometallic
reactions;1 epoxide opening4)
Solubility: 165 g/100 mL H2O (20 C); 433 g/100 mL H2O
(80 C); 251 g/100 mL EtOH (20 C); 343 g/100 mL MeOH
(20 C); 43 g/100 mL acetone (18 C); very sol NH 4 OH.
Form Supplied in: anhydrous white solid or as the hydrate.
Preparative Methods: the anhydrous salt of high purity can be
prepared from lithium hydride and iodine in ether.5
Purification: crystallized from hot H 2 O (0.5 mL g - 1 ) by cooling
in CaCl2-ice or from acetone. Lil is dried for 2 h at 120 C (0.1
mmHg, P 2 O 5 ) before use.
Handling, Storage, and Precautions: for best results, Lil should
be dried prior to use in anhydrous reactions.
Heterolytic C-X Bond Cleaving Reactions. In the presence

of amine bases, Lil has been extensively used as a mild reagent
for the chemoselective cleavage of methyl esters (eq l). 6 De
carboxylation of methyl esters usually occurs when an electronwithdrawing group is present at the -position of the ester (eq 2). 7
Ester-type glycosyl linkages of acidic tri- and diterpenes can also
be selectively cleaved under these conditions.8 Aryl methyl ethers
can be demethylated to afford the corresponding phenols upon
heating with Lil and s-collidine.9
1,2-Oxiranes are readily opened by Lil and a Lewis acid to pro
duce iodohydrins (eq 3). 4 Conversely, l-oxaspiro[2.2]pentanes
and l-oxaspiro[3.2]hexanes give rise to bond migration
Next Page
250
LITHIUM IODIDE
products.10 -Vinyl--propiolactone is efficiently opened by Lil

to produce the corresponding substituted allyl iodide (eq 4).11
(1)
(2)
The addition of Lithium Bromide and Lil was shown to en

hance the rate of organozinc formation from primary alkyl chlo
rides, sulfonates, and phosphonates, and zinc dust.18 Beneficial
effects of Lil addition have also been reported for Heck-type
coupling reactions19 and in conjugate addition to chiral vinyl
sulfoximines.20
The (E)I(Z) alkenic ratio in Wittig-type alkenations was shown
to be dependent on the amount of Li salt present.21
Reduction of -Alkoxycarbonyl Derivatives. -Halo ke
tones are reduced to the corresponding ketones upon treatment
with a mixture of Lil and Boron Trifluoride Etherate.22
Related Reagents. Aluminum Iodide; Iodotrimethylsilane;
Lithium Chloride; Triphenylphosphine-Iodine.
(3)
1. Loupy, A.; Tchoubar, B. Salt Effects in Organic and Organometallic
Chemistry; VCH: Weinheim, 1992.
(4)
2.
3.
4.
Alkyl and Alkenyl Iodides. Lil has been used as a source of

iodide in nucleophilic substitution and addition reactions. Primary
alcohols have been directly converted to alkyl iodides upon treat
ment with a mixture of Triphenylphosphine, Diethyl Azodicarboxylate, and Lil.3 Tertiary alcohols can be converted into tertiary
alkyl iodides upon treatment with Hydrogen Iodide in the pres
ence of Lil.12
(Z)-3-Iodopropenoates and -propenoic acids have been synthe
sized stereoselectively by the reaction of Lil and propiolates or
propiolic acid.13
C-C Bond Forming Reactions. Lil was shown to efficiently
catalyze the Michael addition of -dicarbonyl compounds,14 and
the intramolecular allylsilane addition to imines to produce 4methylenepiperidine derivatives (eq 5).15
(5)
Lil as an Additive for Organometallic-Mediated

Transformations.16 The synlanti selectivity in the reduc
tion of -alkoxy ketones is markedly increased by the addition of
Lil (eq 6).17
(a) McMurry, J. OR 1976, 24, 187. (b) Krapcho, A. P. 5 1982, 805. (c)
Krapcho, A. P. S 1982, 893.
Manna, S.; Falck, J. R.; Mioskowski, C. SC 1985, 15, 663.
(a) Bonini, C ; Giuliano, C ; Righi, G.; Rossi, L. SC 1992, 22, 1863. (b)
Shimizu, M.; Yoshida, A.; Fujisawa, T. SL 1992, 204. (c) Bajwa, J. S.;
Anderson, R. C. TL 1991, 32, 3021.
5. Taylor, M. D.; Grant, L. R. JACS 1955, 77, 1507.

6. Magnus, P.; Gallagher, T. CC 1984, 389.
7. Johnson, F.; Paul, K. G.; Favara, D. JOC 1982, 47, 4254.
8. Ohtani, K.; Mizutani, K.; Kasai, R.; Tanaka, O. TL 1984, 25, 4537.
9.
(a) Kende, A. S.; Rizzi, J. P. JACS 1981, 103, 4247. (b) Harrison, I. T.
CC 1969, 616.
10. (a) Salaun, J.; Conia, J. M. CC 1971, 1579. (b) Aue, D. H.; Meshishnek,
M. J.; Shellhamer, D. F. TL 1973, 4799.
11.
12.
13.
Fujisawa, T.; Sato, T.; Takeuchi, M. CL 1982, 71.

Masada, H.; Murotani, Y. BCJ 1980, 53, 1181.
(a) Ma, S.; Lu, X. TL 1990, 31, 7653. (b) Ma, S.; Lu, X. CC 1990, 1643.
14. Antonioletti, R.; Bonadies, F ; Monteagudo, E. S.; Scettri, A. TL 1991,

32, 5373.
15. Bell, T. W.; Hu, L.-Y. TL 1988, 29, 4819.
16. For the effect of Lil on organocopper reagents see: Lipshutz, B. H.;
Kayser, F.; Siegmann, K. TL 1993, 34, 6693.
17. (a) Mori, Y.; Kuhara, M.; Takeuchi, A.; Suzuki, M. TL 1988, 29, 5419.
(b) Mori, Y; Takeuchi, A.; Kageyama, H.; Suzuki, M. TL 1988, 29,5423.
18. Jubert, C ; Knochel, P. JOC 1992, 57, 5425.
19. Cabri, W.; Candiani, I.; DeBernardinis, S.; Francalanci, F.; Penco, S.;
Santi, R. JOC 1991, 56, 5796.
20.
21.
(a) Pyne, S. G. JOC 1986, 51, 81. (b) Pyne, S. G. TL 1986, 27, 1691.
(a) Soderquist, J. A.; Anderson, C. L. TL 1988, 29, 2425. (b) Soderquist,
J. A.; Anderson, C. L. TL 1988, 29, 2777. (c) Buss, A. D.; Warren, S.;
Leake, J. S.; Whitham, G. H. JCS(P1) 1983, 2215. (d) Buss, A. D.;
Warren, S. JCS(P1) 1985, 2307.
22.
Townsend, J. M.; Spencer, T. A. TL 1971, 137.
Andr B. Charette
Universit de Montral, Qubec, Canada
(6)
with Lil
without Lil
syn:anti = 89:11
syn:anti = 79:21
Previous Page
LITHIUM PERCHLORATE
Lithium Perchlorate
[7791-03-9]
lyl vinyl ethers undergo [l,3]-sigmatropic rearrangements at rt

when submitted to 1.5-3.0 M LiClO 4 in Et2O (eq 5). 10
ClLiO 4
251
(MW 106.39)
(mild Lewis acid1 for cycloaddition reactions,2 conjugate

additions,3 ring opening of epoxides,4 and ring expansion of
cyclopropanes5)
Physical Data: mp 236 C; bp 430 C (dec); d 2.428 g c m - 3 .
Solubility: 60 g/100 mLH 2 O (25 C); 150 g/100 mLH 2 O(89C);
152 g/100 mL EtOH (25 C); 137 g/100 mL acetone (25 C);
182 g/100 mL MeOH (25 C); 114 g/100 mL ether.
Form Supplied in: white solid; widely available in anhydrous form
or as the trihydrate; it is usually used in solution in ether or
MeOH.
Purification: anhydrous lithium perchlorate is prepared by heating
the commercially available anhydrous material or its trihydrate
at 160 C for 48 h under high vacuum (P 2 O 5 trap).
Handling, Storage, and Precautions: the anhydrous material
should be used as prepared for best results. The decomposition
of lithium perchlorate starts at about 400 C and becomes rapid
at 430 C, yielding lithium chloride and oxygen. Perchlorates
are potentially explosive and should be handled with caution.
Lewis Acid Catalyst for Cycloaddition Reactions and Carbonyl Addition Reactions. This reagent, usually prepared as a
5.0 M solution in diethyl ether, produces a dramatic rate accel
eration of Diels-Alder reactions (eq 1). Evidence shows that this
rate acceleration, which was initially thought to be a result of high
internal solvent pressure, is due to the Lewis acid character of the
lithium ion.6
(2)
(3)
single diastereomer
(4)
(1)
5.0M LiClO4, Et2O, 5 h, it, 80% (endo:exo = 2.9:1)

benzene, 72 h, 60 C, 74% (endo:exo =1:11.5)
Under these conditions, reasonable levels of diastereoselectivity have been observed in the reaction between a chiral diene
and N-Phenylmaleimide (eq 2). 7 An interesting protecting group
dependence of diastereoselectivities has also been observed in
the hetero-Diels-Alder reaction of N-protected -amino aldehy
des with l-methoxy-3-t-butyldimethylsilyloxybutadiene to pro
duce dihydropyrones (eqs 3 and 4). 8
O-Silylated ketene acetals undergo 1,4-conjugate addition to
hindered a,p-unsaturated carbonyl systems 3 and quinones9 in the
presence of LiClO 4 .
[l,3]-Sigmatropic Rearrangements. In contrast to the [3,3]sigmatropic rearrangement observed under thermal conditions, al-
(5)
Epoxide Opening. LiClO 4 is an efficient promotor for the

regioselective nucleophilic opening of oxiranes with amines, 11
cyanide,12 azide,13 thiols,14 halides,15 and lithium acetylides. 16
The regioselective opening of oxiranes with lithium enolates de
rived from ketones has also been observed in the presence of
LiClO 4 (eq 6). 17
252
LITHIUM PERCHLORATE
(6)
without LiClO4, 30%
Ring Expansion. The condensation of aldehydes and ketones

with diphenylsulfonium cyclopropylide produces oxaspiropentanes which undergo ring expansion to produce cyclobutanones
upon treatment with lithium perchlorate. 18
Related Reagents. Diethylaluminum Chloride; Dimethylaluminum Chloride; Lithium Tetrafluoroborate; Magnesium
Bromide.
1. (a) Loupy, A.; Tchoubar, B. Salts Effects in Organic and Organometallic

Chemistry; VCH: Weinheim, 1992. (b) Grieco, P. A. Aldrichim. Acta
1991, 24, 59. (c) Waldmann, H. AG(E) 1991, 30, 1306.
2.
3.
(a) Grieco, P. A.; Nunes, J. J.; Gaul, M. D. JACS 1990, 112, 4595. (b)
Braun, R.; Sauer, J. CB 1986, 119, 1269.
Grieco, P. A.; Cooke, R. J.; Henry, K. J.; VanderRoest, J. M. TL 1991,
32, 4665.
4.
5.
Chini, M.; Crotti, P.; Flippin, L. A.; Macchia, F. JOC 1990, 55, 4265.
Rickborn, B.; Gerkin, R. M. JACS 1971, 93, 1693.
6.
(a) Forman, M. A.; Dailey, W. P. JACS 1991, 113, 2761. (b) Desimoni,
G.; Faita, G.; Righetti, P. P.; Tacconi, G. T 1991, 47, 8399.
Hatakeyama, S.; Sugawara, K.; Takano, S. CC 1992, 953.
Grieco, P. A.; Moher, E. D. TL 1993, 34, 5567.
Ipaktschi, J.; Heydari, A. AG(E) 1992, 31, 313.
7.
8.
9.
10.
11.
12.
13.
Grieco, P. A.; Clark, J. D.; Jagoe, C. T. JACS 1991, 113, 5488.

Chini, M.; Crotti, P.; Macchia, F. JOC 1991, 56, 5939.
Chini, M.; Crotti, P.; Favero, L.; Macchia, F. TL 1991, 32, 4775.
Chini, M.; Crotti, P.; Macchia, F. TL 1990, 31, 5641.
14. Chini, M.; Crotti, P.; Giovani, E.; Macchia, F.; Pineschi, M. SL 1992,
303.
15. (a) Chini, M.; Crotti, P.; Gardelli, C ; Macchia, F. T 1992, 48, 3805. (b)
Chini, M.; Crotti, P.; Flippin, L. A.; Macchia, F. JOC 1990, 55, 4265.
16. Chini, M.; Crotti, P.; Favero, L.; Macchia, F. TL 1991, 32, 6617.
17. Chini, M.; Crotti, P.; Favero, L.; Pineschi, M. TL 1991, 32, 7583.
18. Trost, B. M.; Bogdanowicz, M. J. JACS 1973, 95, 5321.
Universit de Montral,
Andr B . Charette
Qubec,
Canada
MAGNESIUM BROMIDE
253
Nucleophilic additions to ,-dialkoxy aldehydes via allyl

silanes (eq 3) 10 or silyl ketene acetals (Mukaiyama reaction)
(eq 4)11 exhibit similarly high selectivities. -Thio aldehydes also
react under MgBr2-catalyzed Mukaiyama conditions with effi
cient stereocontrol (eq 5). 1
Magnesium Bromide
(3)
syn:anti >98:2
(MgBr2)
[2923-28-6]
(MgBr2.6H2O)
[13446-53-2]
(MgBr2.OEt2)
[29858-07-9]
Br2Mg
(MW 184.11)
H 12 Br 2 MgO 6
(MW 292.23)
C 4 H 10 Br 2 MgO
(MW 258.25)
(4)
syn:anti >55:1
(Lewis acid capable of catalyzing selective nucleophilic

additions,1 cycloadditions,2 rearrangements,3 coupling
reactions;4 effective brominating agent5)
Physical Data: mp 165 C (dec) (etherate >300 C; fp 35 C).
Solubility: sol alcohol, H 2 O; etherate sol common organic sol
vents.
Form Supplied in: white solid, widely available; etherate gray
solid.
Preparative Method: the etherate is easily prepared from re
acting a slight excess of Magnesium turnings with 1,2Dibromoethane in anhydrous diethyl ether.13
Handling, Storage, and Precautions: etherate is flammable and
moisture sensitive; freshly prepared material is most reactive
and anhydrous. Irritant.
Nucleophilic Additions. MgBr2 has been shown to form dis

crete bidentate chelates with various species,6 particularly and/or ,-alkoxy carbonyl compounds,7 and thus functions
as a diastereofacial control element in many nucleophilic ad
dition reactions. In many cases, its inclusion completely re
verses the nonchelation-controlled stereochemistry observed with
nonchelating Lewis acids such as Boron Trifluoride Etherate.
Highest diastereoselectivity is observed with -substituted alde
hydes (eq 1 ). 8 High selectivities are observed for -alkoxy aldehy
des as well, including cases where three contiguous chiral centers
are defined during the reaction (eq 2). 9
(5)
syn:anti = 87:13
Rearrangements. The oxophilic nature of MgBr 2 renders it

effective in mediating many rearrangements wherein polarization
of a C-O bond initiates the process. A classic application involves
the conversion of an epoxide to an aldehyde (eq 6). 12
(6)
-Lactones, when treated with MgBr 2 , undergo ionization with

further rearrangement to afford either butyrolactones or (3,7unsaturated carboxylic acids (eq 7). 3 The reaction course is de
pendent upon whether the cation resulting from lactone ionization
can rearrange to a more or equivalently stable cation, in which case
ring expansion is observed. If the -lactone bears an -chloro substituent, ring expansion is accompanied by elimination of HC1 to
afford butenolides (eq 8). 13
(7)
(1)
MgBr2
BF3OEt2
syn:anti = 250:1
syn:anti = 39:61
(8)
(2)
81% diastereofacial selectivity
Cycloadditions. The MgBr2-mediated cyclocondensation of a

Danishefsky-type diene with chiral -alkoxy aldehydes affords a
254
MAGNESIUM BROMIDE
single diastereomer, which reflects a reacting conformer in which

the alkoxy group is syn to the carbonyl, which is then attacked from
its less-hindered face (eq 9). 2 The cycloaddition of ynamines with
cycloalkenones occurred selectively at the carbonyl, while in the
absence of MgBr2 reaction at the alkene C=C bonds was observed
(eq 10).14
(9)
only isomer detected
Epoxides are also converted regiospecifically to bromohydrins

byMgBr 2 . 1 9
Carbonyl Condensations. Bis- or tris-TMS ketenimines con
dense with ketones, mediated by MgBr 2 , to produce an inter
mediate that loses hexamethylsiloxane, affording 2-alkenenitriles
in high yield with high (E) selectivity (eq 16).20 MgBr 2 also
enables the use of very mild bases like Triethylamine in
Horner-Wadsworth-Emmons reactions, enabling the synthesis of
unsaturated esters from aldehydes or ketones without the need for
strongly basic conditions (eq 17).21
(16)
(10)
highly (E) selective
(17)
Organometallic Reactions. MgBr 2 often increases the yields

of Grignard reactions, as in the synthesis of cyclopropanols from
1,3-dichloroacetone (eq 11). 15 It also serves to form Grignard
reagents in situ via first lithiation followed by transmetalation with
MgBr 2 . This technique enables the formation of vinyl Grignards
from vinyl sulfones (eq 12),16 and of -silyl Grignard reagents
from allyl silanes (eq 13).17 In the latter case, the presence of
MgBr 2 provided regioselectivity at the -position; without it, sub
stitution at the 7-position was predominant.
1. Annunziata, R.; Cinquini, M.; Cozzi, F.; Cozzi, P. G.; Consoiandi, E.

JOC 1992, 57, 456.
2. Danishefsky, S.; Pearson, W. H.; Harvey, D. F.; Maring, C. J.; Springer,
J. P. JACS 1985, 107, 1256.
3.
(11)
4.
(12)
5.
6.
7.
8.
(13)
9.
10.
11.
(14)
Hannesian, S.; Kagotani, M.; Komaglou, K. H 1989, 28, 1115.

Keck, G. E.; Castellino, S. JACS 1986, 108, 3847.
Chen, X.; Hortelano, E. R.; Eliel, E. L.; Frye, S. V. JACS 1992, 114,
1778.
Keck, G. E.; Boden, E. P. TL 1984, 25, 265.
13.
Keck, G. E.; Abbott, D. E. TL 1984, 25, 1883.

Williams, D. R.; Klingler, F. D. TL 1987, 28, 869.
Bernardi, A.; Cardani, S.; Colombo, L.; Poli, G.; Schimperna, G.;
Scolastico, C. JOC 1987, 52, 888.
Serramedan, D.; Marc, F.; Pereyre, M.; Filliatre, C ; Chabardes, P.;
Delmond, B. TL 1992, 33, 4457.
Black, T. H.; McDermott, T. S.; Brown, G. A. TL 1991, 32, 6501.
14.
Ficini, J.; Krief, A.; Guingant, A.; Desmaele, D. TL 1981, 22, 725.
12.
Bromination. Magnesium bromide serves as a source of bro

mide ion, for displacement of sulfonate esters under mild condi
tions and in high yield. The reaction is known to proceed with
complete inversion at the reacting carbon center when backside
attack is possible (eq 14).5 Even bromination of highly congested
bridgehead positions is possible via triflate displacement, although
the reaction requires high temperatures, long reaction times, and
activation via ultrasound (eq 15).18
(a) Black, T. H.; Hall, J. A.; Sheu, R. G. JOC 1988, 53, 2371. (b) Black,
T. H.; Eisenbeis, S. A.; McDermott, T. S.; Maluleka, S. L. T 1990, 46,
2307.
Cai, D.; Still, W. C. JOC 1988, 53, 464.
15.
16.
17.
18.
Barluenga, J.; Florez, J.; Yus, M. S 1983, 647.

Eisch, J. J.; Galle, J. E. JOC 1979, 44, 3279.
Lau, P. W. K.; Chan, T. H. TL 1978, 2383.
Martinez, A. G.; Vilar, E. T.; Lopez, J. C ; Alonso, J. M ; Hanack, M.;
Subramanian, L. R. S 1991, 353.
19. Ueda, Y.; Maynard, S. C. TL 1988, 29, 5197.
20. Matsuda, I.; Okada, H.; Izumi, Y. BCJ 1983, 56, 528.
21. Rathke, M. W.; Nowak, M. JOC 1985, 50, 2624.
Eastern Illinois University,
(15)
T. Howard Black
Charleston, IL, USA
MESITYLENESULFONYL CHLORIDE
fonamide by treatment with n-Butyllithium and mesitylenesul

fonyl chloride, but the sulfonamide group was not subsequently
removed (eq 3). 8
Mesitylenesulfonyl Chloride
[773-64-8]
C 9 H 1 1 ClO 2 S
255
(MW 218.72)
(preparation of sulfonates;1 condensing agent in nucleotide

synthesis2)
Alternate Name: 2,4,6-trimethylbenzenesulfonyl chloride.
Solubility: sol organic solvents.
Form Supplied in: white crystalline solid; widely available.
Purification: can be recrystallized from hexane or pentane.
Handling, Storage, and Precautions: corrosive; moisture sensi
tive; handle and store under nitrogen.
Sulfonamide Formation. Reaction of mesitylenesulfonyl

chloride with amines in the presence of Pyridine or Triethylamine
yields the corresponding sulfonamides (eq 1 ), 3 which have been
used as intermediates in synthesis.
(1)
(3)
Sulfonate Formation. Treatment of alcohols with mesitylene

sulfonyl chloride yields the corresponding sulfonates. Mesitylene
sulfonyl chloride is particularly useful for the selective sulfonation
of polyhydroxylic systems such as carbohydrates (eq 4). 1,9 It is
more selective than p-Toluenesulfonyl Chloride, which has been
frequently used but gives mixtures of products. Unfortunately, the
mesitylenesulfonates are not as reactive as the corresponding tosylates. Numerous 1 '-derivatives of sucrose have been synthesized
via mesitylenesulfonyl derivatives.10
(4)
The mesityl group has been used as a protecting group for var
ious amines including amino acids (eq 2) 4 and peptides. 5-7
(2)
The mesitylsulfonyl-protected amino acids can be deblocked by

treatment with Hydrogen Bromide and Acetic Acid. The stability
of the sulfonamide towards both acidic and basic conditions makes
it a useful protecting group for peptide synthesis. The mesityle
nesulfonyl group has been used to protect the indole group of
tryptophan6 and the guanidine group of arginine.7 These mesityl
derivatives can be cleaved with Trifluoromethanesulfonic Acid
or Methanesulfonic Acid. Partial cleavage of the guanidinomesityl group occurs when treated with HBr/HOAc. The mesityle
nesulfonyl group has also been used as a blocking group for other
indoles. Boteju et al. reported the formation of the indole sul
The selectivity of sulfonation has also been applied to other

polyhydroxylic systems such as - and -cyclodextrins11,12 and
nucleotides.13 Monosulfonated products have been reported from
the treatment of diols with mesitylenesulfonyl chloride (eq 5). 14,15
(5)
Mesitylenesulfonyl derivatives which have specific bio

logical activities, such as 2,3-diaziridinyl-l,4-napthoquinone
sulfonates16 and l-arenesulfonyloxy-2-alkanones,17 have also
been prepared.
256
MESITYLENESULFONYL CHLORIDE
Nucleotide Synthesis. Mesitylenesulfonyl chloride has been

used as a condensing agent in the diester approach to nucleotide
synthesis (eq 6).2 However, it is not effective in the triester
approach due to extensive sulfonation of the 5'-hydroxy group.18
Other condensing agents include 1,3-Dicyclohexylcarbodiimide
(DCC), benzenesulfonyltriazole (BST), (l-mesitylyl-2-sulfonyl)3-nitro-l,2,4-triazole
(MSNT),
Mesitylsulfonyl-lH-1,2,4triazole (MST), p-nitrobenzenesulfonyltriazole (p-NBST),
p-toluenesulfonyltriazole (TST), and triisopropylbenzenesulfonyl chloride (TPS).
(8)
Sulfonylalkyne Synthesis. Sulfonylalkynes have been synthe

sized (eq 9) and subsequently reacted with N-(l-alkynyl)anilines
to give 2-anilino-5-sulfinylfurans.23
(9)
(6)
1. Guthrie, R. D.; Thang, S. AJC 1987, 40, 2133.
2. (a) Narang, S. A.; Khorana, H. G. JACS 1965, 87, 2981. (b) FF 1967, 1,
661.
3.
Condensation Reactions. Mesitylenesulfonyl chloride has

also been employed as a condensing agent for the preparation of
esters in the synthesis of nonactin (eq 7),19 N-methylmaysenine,20
and maysine.21
(a) Reetz, M. T.; Kukenhohner, T.; Weinig, P. TL 1986, 27, 5711. (b)
Pavlidis, V. H.; Chan, E. D.; Pennington, L.; McParland, M.; Whitehead,
M. SC 1988, 18, 1615. (c) Hoppe, I.; Hoffmann, H.; Gartner, I.; Krettek,
T.; Hoppe, D.S 1991, 1157. (d) Takahashi, H.; Takahashi, K.; Ohno, M.;
Yoshioka, M ; Kobayashi, S. T 1992, 48, 5691.
4.
5.
Roemmele, R. C ; Rapoport, H. JOC 1988, 2367.

(a) Corey, E. J.; Weigel, L. O.; Floyd, D.; Bock, M. G. JACS 1978, 100,
2916. (b)FF 1980, 8, 318.
6. Fuji, N.; Futaki, S.; Yasumura, K.; Yajima, H. CPB 1984, 2660.
7.
(a) Yajima, H.; Takeyama, M.; Kanaki, J.; Mitani, K. CC 1978, 482. (b)
Yajima, H.; Takeyama, M.; Kanaki, J.; Nishimura, O.; Fujino, M. CPB
1978, 26, 3752.
8. Boteju, L. W.; Wegner, K.; Hruby, V. J. TL 1992, 7291.
9.
(7)
Gilchrist, T. L.; Rees, C. W.; Stanton, E. CC 1971, 801.
10. Hough, L.; Phadnis, S. P.; Tarelli, E. Carbohydr. Res. 1975, 44, C12. (b)
Ball, D. H.; Bisett, F. H.; Chalk, R. C. Carbohydr. Res. 1977, 55, 149.
(c) Guthrie, R. D.; Jenkins, I. D.; Watters, J. J. AJC 1980, 33, 2487.
11.
Fujita, K.; Matsunaga, A.; Imoto, T. JACS 1984, 106, 5740.
12.
(a) Fujita, K.; Yamamura, H.; Imoto, T. JOC 1985, 50, 4393. (b) Fujita,
K.; Ishizu, T.; Minamiura, N.; Yamamoto, T. CL 1991, 1889. (c) Fujita,
K.; Ishizu, T.; Obe, K.; Minamiura, N.; Yamamoto, T. JOC 1992, 57,
5606.
13.
(a) Ueda, T.; Usui, H.; Shuto, S.; Inoue, H. CPB 1984, 32, 3410. (b)
Tanimura, H.; Sekine, ML; Hata, T. TL 1986, 27, 4047. (c) Xu, Y. Z.;
Zheng, Q.; Swann, P. F. TL 1991, 24, 2817. (d) Xu, Y. Z.; Zheng, Q.;
Swann, P. F. T 1992, 1729.
14. Nakata, T.; Fukui, M.; Ohtsuka, H.; Oishi, T. TL 1983, 24, 2661.
Sulfinate Ester Synthesis. Sulfinate esters of menthol can be

prepared via reaction of mesitylenesulfonyl chloride (as well as
other sulfonyl chlorides) with menthol using Trimethyl Phosphite
(eq 8).22 Sulfinate esters of menthol are used for the preparation of
optically active sulfoxides. See also 10-Camphorsulfonyl Chloride and p-Toluenesulfonyl Chloride.
15.
Rama Rao, A. V.; Gaitonde, A.; Prahlada Rao, S. IJC(B) 1992,

31B,641.
16.
Lin, T. S.; Xu, S. P.; Zhu, L. Y.; Cosby, L. A.; Sartorelli, A. C. JMC 1989,
32, 1467.
17.
Ogawa, K.; Terada, T.; Muranaka, Y.; Hamakawa, T.; Hashimoto, S.;
Fujii, S. CPB 1986, 34, 3252.
Katagiri, N.; Itakura, K.; Narang, S. A. JACS 1975, 97, 7332.
(a) Gerlach, H.; Oertle, K.; Thalmann, A.; Servi, S. HCA 1975, 58, 2036.
(b) FF 1977, 6, 625.
18.
19.
METHANESULFONYL CHLORIDE
20.
Corey, E. J.; Weigel, L. O.; Floyd, D.; Bock, M. G. JACS 1978, 100,
2916.
21.
Kitamura, M.; Isobe, M.; Ichikawa, Y.; Goto, T. JOC 1984, 49, 3517.
22.
23.
Sharpless, K. B.; Klunder, J. M. JOC 1987, 52, 2598.

Kosack, S.; Himbert, G. CB 1987, 120, 71.
CH 3 ClO 2 S
with phthalazine10 and addition of mesyl chloride to lactim ethers

(eq 1). 11
(1)
Valerie Vaillancourt & Michele M. Cudahy

The Upjohn Co., Kalamazoo, MI, USA
[124-63-0]
257
(MW 114.56)
Chlorination. Methanesulfonyl chloride can effect the direct

chlorination of various substrates. The most notable of these re
actions is the selective chlorination of the C-6 primary hydroxy
group of carbohydrates (eq 2). 12 Under these conditions, 2-furyl
alcohol (eq 3) 13 and guanine TV-oxide (eq 4) 14 can also be chlori
nated directly.
(2)
(synthesis of methanesulfonates;1 generation of sulfene)

Alternate Name: mesyl chloride.
Physical Data: bp 60C/21 mmHg; d 1.480 g c m - 3 .
Solubility: insol water; sol alcohol, ether.
Form Supplied in: liquid of 98% or 99+% purity.
Handling, Storage, and Precautions: highly toxic; corrosive;
lachrymator; moisture sensitive; store in a cool dry place.
(3)
(4)
Methanesulfonates. The most common use of methanesul

fonyl chloride is for the synthesis of sulfonate esters from alco
hols. This can be readily accomplished by treatment of an alcohol
with mesyl chloride in the presence of a base (usually Triethylamine or Pyridine).1 The methanesulfonates formed are func
tional equivalents of halides. As such they are frequently employed
as intermediates for reactions such as displacements, eliminations,
reductions,2 and rearrangements.3 Selective mesylation of a vici
nal diol is a common method of preparation of epoxides .4 Alkynyl
mesylates can be used for the synthesis of trimethylsilyl allenes.5
Oxime mesylates undergo a Beckmann rearrangement upon treat
ment with a Lewis acid.6 Aromatic mesylates have been used as
substrates for nucleophilic aromatic substitution.7 Mesylates are
more reactive than tosylates toward nucleophilic substitution, but
less reactive toward solvolysis.
Protection of Alcohols. In addition to being used as a halide
equivalent, methanesulfonates have also been used as protecting
groups for alcohols and phenols. The use of methanesulfonate as
a protecting group for alcohols is mainly limited to carbohydrate
synthesis due to the lability of the methanesulfonate group to
ward nucleophilic attack. The sulfonate ester is stable to acidic
conditions and can be cleaved by Sodium Amalgam.8
Protection of Amines. Amines also react with mesyl chloride
to form the corresponding sulfonamide. The sulfonamide group
is one of the most stable nitrogen-protecting groups, with good
stability to both acidic and basic conditions. The sulfonamide
can be cleaved back to the amine by Lithium Aluminium Hydride or dissolving metal reductions.9 In addition to treatment of
amines with mesyl chloride, other reports for the preparation of
sulfonamides include a Reissert-type reaction of mesyl chloride
Meyers developed a procedure for the direct conversion of allylic alcohols to allylic chlorides that is general for a variety of
terpenes (eq 5). 15 Primary alcohols give yields in the 85% range.
A single example of a secondary alcohol produced the chloride
in 50% yield. Certain allylic alcohols also undergo stereospecific
chlorination under the conditions normally employed for mesylate
formation (eq 6). 16
(5)
(6)
Under Lewis acid catalysis, mesyl chloride reacts with unactivated benzenes to produce the aromatic chloride and only trace
amounts of the corresponding sulfone (eq 7). 17 Mesylates have
also been used as intermediates for the transformation of alcohols
into halides.
(7)
258
Interconversion of Carboxylic Acid Derivatives.

Methanesulfonyl chloride is employed in the activation of
carboxylic acids for the preparation of anhydrides (eq 8),18
nitriles (eq 9),19 amides (eq 10), and esters (eq 11).20
(8)
(16)
The synthesis of -methylene lactones25 and ketones26 via the

elimination of a mesylate has also been reported (eqs 17 and 18).
In these cases, the pyridine or triethylamine is sufficiently basic to
induce elimination under standard mesylate forming conditions.
(9)
(17)
(10)
(18)
(11)
Eliminations. Alkene formation by elimination can also be

achieved with mesyl chloride. This is general for a variety of
substrates. Peterson reported the elimination of -hydroxy silanes
to give predominantly trans-alkenes upon treatment with mesyl
chloride (eq 12).21 In a similar manner, -hydroxyphenylselenates
can also be eliminated (eq 13).22
Heterocycles. Sulfene, generated by the treatment of methane

sulfonyl chloride with base, undergoes [2 + 2], [3 + 2], and [4 + 2]
cycloadditions to produce four-, five-, and six-membered het
erocycles, respectively. Alkynyl amines27 and enamines28 both
undergo [2 + 2] cycloadditions with sulfene to produce fourmembered cyclic sulfones (eqs 19 and 20).
(19)
(12)
(20)
(13)
Corey reported a mild elimination of iodohydrins by activation

with mesyl chloride (eq 14).23 The major advantage of this method
over traditional methods is that the use of a strong reducing agent
(Zinc or Tin(II) Chloride) is avoided.
Five-membered sultones can be formed by reaction of hydroxy ketones with sulfene (eq 21).29 Sulfene adds in a [4 + 2]
manner across azadienes (eq 22)30 and enones (eq 23).31
(21)
(14)
The direct elimination of tertiary alcohols by treatment with

mesyl chloride has also been reported.24 A variety of acid sensi
tive functional groups including silyl ethers and acetals are stable
to these reaction conditions (eq 15). Mixtures of cis and trans
and internal and terminal alkenes are formed in all cases where
possible (eq 16).
(15)
(22)
(23)
Addition Across Alkenes and Alkynes. In the presence of a

catalyst (usually Copper or ruthenium), methanesulfonyl chloride
adds across alkenes and alkynes to produce -chloro sulfones.32
The stereochemistry of the product of addition across phenylacetylene depends on the reaction conditions used. In the absence of an
added hydrochloride salt, the cis addition product predominates
(eq 24), whereas the trans product is favored when the salt is added
(eq 25).
259
36
these conditions, allylstannanes (eq 31) and cyclic vinyl sul

fides (eq 32)37 undergo addition to the iminium ion generated.
The allylstannane cyclizes with a high degree of endo selectivity.
(31)
(24)
(32)
(25)
TMS-substituted alkenes and alkynes are especially useful in

these reactions (eqs 26 and 27).33 Using this methodology, allylic
sulfones can be prepared (eq 28). Kamigata reported only minor
success in inducing chirality into this reaction by the use of opti
cally active ruthenium catalysts (eq 29).34
Lactone Inversion. Lansbury demonstrated the use of mesyl chloride for lactone inversion in his synthesis of aromatin
(eq 33).38 This method is superior to the classical methods since
the problems of racemization and relactonization are overcome.
(26)
(33)
(27)
(28)
Rearrangement of Thioacetals to Aldehydes. Sato et al. re

ported the rearrangement of -hydroxy thioacetals to -sulfenyl
aldehydes (eq 34).39 The thioacetals are prepared by the addi
tion of the anion of methoxy(phenylthio)methane to aldehydes
and ketones. This reaction is general for alkyl, allyl, and aromatic
carbonyl compounds.
(34)
(29)
Related Reagents. Methanesulfonyl

aminopyridine.
Synthesis of Vinyl and Allyl Sulfones. In addition to the meth
ods presented above, vinyl and allyl sulfones have been prepared
by the palladium-catalyzed cross coupling of vinyl- and allylstannanes with sulfonyl chlorides (eq 30).35
(30)
Acyliminium Cyclizations. Formation of acyliminium ions

by treatment of -hydroxy amides with methanesulfonyl chloride
is a mild way of effecting acyliminium ion cyclizations. Under
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Chloride-Dimethyl-
Furst, A.; Roller, F. HCA 1947, 30, 1454.

Baer, H. H.; Georges, F. F. Z. CJC 1977, 55, 1348.
Ritterskamp, P.; Demuth, M.; Schaffner, K. JOC 1984, 49, 1155.
Graber, R. P.; Meyers, M. B.; Landeryou, V. A. JOC 1962, 27, 2534.
Danheiser, R. L.; Carini, D. J.; Fink, D. M.; Basak, A. T 1983, 39, 935.
Maruoke, K.; Miyazaki, T.; Ando, M.; Matsumura, Y.; Sakane, S.;
Hattori, K.; Yamamoto, H. JACS 1983, 105, 2831.
Meltzer, R. I.; Lustgarten, D. M.; Fischman, A. JOC 1957, 22, 1577.
Webster, K. T.; Eby, R.; Schuerch, C. Carbohydr. Res. 1983, 123, 335.
Merlin, P.; Braekman, J. C.; Daloze, D. TL 1988, 29, 1691.
Takeuchi, I.; Hamada, Y.; Hatano, K.; Kurono, Y.; Yashiro, T. CPB 1990,
38, 1504.
260
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
p-METHOXYBENZYL CHLORIDE
Sheu, J.; Smith, M. B.; Oeschger, T. R.; Satchell, J. OPP 1992, 24, 147.
Evans, M. E.; Long, L., Jr.; Parrish, F. W. JOC 1968, 33, 1074.
Sanda, K.; Rigal, L.; Delmas, M.; Gaset, A. S 1992, 541.
Wolke, U.; Birdsall, N. J. M.; Brown, G. B. TL 1969, 785.
Collington, E. W.; Meyers, A. I. JOC 1971, 56, 3044.
Fujimoto, Y.; Shimizu, T.; Tatsuno, T. CPB 1976, 24, 365.
Hyatt, J. A.; White, A. W. S 1984, 214.
Nangia, A.; Chandrasekaran, S. JCR(S) 1984, 100.
Dunn, A. D.; Mills, M. J.; Henry, W. OPP 1982, 396.
Jaszay, Z. M.; Petnehazy, I.; Toke, L. S 1989, 745.
(a) Hudrlik, P. F.; Peterson, D. TL 1974, 1133. (b) Hudrlik, P. F.; Peterson,
D. JACS 1975, 97, 1464.
Paquette, L. A.; Yan, T.-H.; Wells, G. J. JOC 1984, 49, 3610.
Corey, E. J.; Grieco, P. A. TL 1972, 107.
Yadav, J. S.; Mysorekar, S. V. SC 1989,19, 1057.
Grieco, P. A.; Hiroi, K. CC 1972, 1317.
Kozikowski, A. P.; Stein, P. D. JACS 1982, 104, 4023.
Rosen, M. H. TL 1969, 647.
(a) Hasek, R. H.; Gott, P. G.; Meen, R. H.; Martin, J. C. JOC 1963, 28,
2496. (b) Ziegler, E.; Kappe, T. AG 1964, 76, 921.
(a) Patonay, T.; Batta, G.; Dinya, Z. JHC 1988, 25, 343. (b) Takada, D.;
Suemune, H.; Sakai, K. CPB 1990, 38, 234.
Mazumdar, S. N.; Sharma, M.; Mahajan, M. P. TL 1987, 28, 2641.
(a) Ziegler, E.; Kappe, T. AG 1964, 76, 921. (b) Menozzi, G.; Bargagna,
A.; Mosti, L.; Schenone, P. JHC 1987, 24, 633.
Amiel, Y. TL 1971, 661.
Pillot, J. P.; Dunogues, J.; Calas, R. S 1977, 469.
Kameyama, M.; Kamigata, N. BCJ 1989, 62, 648.
Labadie, S. S. JOC 1989, 54, 2496.
(a) Keck, G.; Enholm, E. J. TL 1985, 26, 3311. (b) Keck, G.; Cressman,
E. N. K.; Enholm, E. J. JOC 1989, 54, 4345.
Chamgerlin, A. R.; Nguyen, H. D.; Chung, J. Y. L. JOC 1984, 49, 1682.
Lansbury, P. T.; Vacca, J. P. T 1982, 38, 2797.
Sato, T.; Okazaki, H.; Otera, J.; Nozaki, H. JACS 1988, 110, 5209.
Valerie Vaillancourt & Michele M. Cudahy

Preparative Methods: to prepare the bromide, an ether solution of

the alcohol is stirred with concd HBr, the phases are separated,
and the organic phase is washed with saturated aq. NaBr, dried
over K 2 CO 3 , and concentrated.
Handling, Storage, and Precautions: the chloride is stored over
K2CO3 to stabilize it; the bromide is stored in the freezer to
prevent polymerization, which occurs within a few days at rt.2
Protection of Alcohols. The inherent stability of the MPM

ether, coupled with a large repertoire of methods for its re
moval under mild conditions that do not normally effect other
functional groups, makes it a particularly effective derivative
for the protection of alcohols. The most common method for
its introduction is by the Williamson ether synthesis. A num
ber of bases can be used to generate the alkoxide, but Sodium
Hydride3 in DMF (eq 1) or THF4 (eq 2) is the most common.
Other bases such as n-Butyllithium,5 Potassium Methylsulfinylmethylide (dimsylpotassium)6 (eq 3), and Sodium Hydroxide un
der phase-transfer conditions7 are also used. From these results,
it is clear that protection can be achieved without interference
from Payne rearrangement, and considerable selectivity can be ob
tained. In the ribose case, selectivity is probably achieved because
of the increased acidity of the 2'-hydroxy group. The additive
Tetra-n-butylammonium Iodide8 is used for in situ preparation
of the highly reactive p-methoxybenzyl iodide, thus improving
the protection of very hindered alcohols. Selective monoprotection of diols is readily occasioned with O-stannylene acetals.9
(1)
(2)
p-Methoxybenzyl Chloride1
(X = C1)
[824-98-6]
(X = Br)
[2746-25-0]
(3)
C8H9ClO
(MW 156.62)
C8H9BrO
(MW 201.07)
(protection of alcohols, 3 thiols,42 phenols, 29 amides, 55 amines,50

and carboxylic acids 31 )
Alternate Name: MPMC1.
Physical Data: X = Cl: bp 117-118 C/14 mmHg; d 1.155 g c m - 3 .
Solubility: sol all organic solvents.
Form Supplied in: the chloride is commercially available. The
bromide is not commercially available and is prepared imme
diately before use because of its instability.2
Cleavage of the MPM group is usually achieved oxidatively with

2,3-Dichloro-5,6-dicyano-l,4-benzoquinone.10-12
When DDQ is used, overoxidation of the alcohol occasionally
occurs, 13,14 but for the most part this is not a problem. In
general, selective cleavage of the MPM group is achieved
in molecules containing benzyl groups, but more forcing
conditions will result in benzyl cleavage.15Cerium(IV) Ammonium Nitrate,16 trityl tetrafluoroborate,17 photolysis, 18
electrolytic oxidation,19 Bromodimethylborane 20 Boron
Trichloride,21
lodotrimethylsilane,22
Tin(II)
Chloride/
Chlorotrimethylsilane/anisole23
hydrogenolysis,24
and
25
ozonolysis have also been used to cleave this derivative.

Selectivity for the 0-MPM is achieved over an amide MPM
derivative with DDQ. 26
In the presence of neighboring hydroxyl groups, the DDQ oxi
dation of MPM ethers leads to cyclic acetals, thus affording a level
of selectivity which may not be possible to achieve otherwise.27
In a synthesis of erythronolide (eq 4), the critical oxidative cyclization had to be performed with freshly recrystallized DDQ
supported on molecular sieves in order to prevent acid-catalyzed
isomerization of the acetal from its initial kinetic disposition to
the more thermodynamically favorable orientation.28
261
when treated with HF/anisole, form thiophenyl ethers that cannot

be deprotected; therefore the peptides should be subjected to a
reduction step prior to deprotection.49
(5)
(4)
Protection of Phenols. Protection of phenols is achieved us

ing p-methoxybenzyl chloride ( B u 4 N + I - , K 2 CO 3 ) in acetone,29
or the benzyl bromide (i-Pr2NEt) in CH 2 Cl 2 . 30 Deprotection is
occasioned with Trifluoroacetic Acid29 or 10-Camphorsulfonic
Acid/Me2C(OMe)2.30
Protection of Carboxylic Acids. p-Mefhoxybenzyl esters
have been prepared from the Ag1 salt of amino acids and
the benzyl halide (Et3N, CHCl 3 , 25 C, 24 h, 60% yield), 31
and from cephalosporin precursors and the benzyl alcohol
[Me 2 NCH(OCH 2 -t-Bu) 2 , CH 2 Cl 2 , 90% yield], 32 and from the
benzyl halide (NaHCO 3 , DMF). 33 They are also prepared
by activation of the acid with isopropenyl oxychloroformate
(MeOC 6 H 4 CH 2 OH, DMAP, 0C, CH 2 Cl 2 , 91%). 34 They are
cleaved by acidic hydrolysis (CF 3 CO 2 H/PhOMe, 25 C, 3 min,
98% yield;35 HCO 2 H, 22 C, 1 h, 81% yield),31 by heating
with phenol, 36 by treatment with AlCl 3 (anisole, CH 2 Cl 2 or
MeNO 2 , - 5 0 C; NaHCO 3 , - 5 0 C, 73-95% yield), 37 ' 38 or by
CF 3 CO 2 H/B(OTf) 3 . 39
Protection of Thiols. The protection of thiols as S-pmethoxybenzyl thioethers is occasioned with MPMC1 and a
base such as NH3, 40 KOH (MeOH), 41 and NaH (THF, 60 C,
1 h). 42 The reduction of disulfides with Lithium Aluminium
Hydride affords an intermediate thiolate that can be trapped
with MPMC1 to give the thioether.43 The cleavage of S-pmethoxybenzyl thioethers is effected with Hg(OAc) 2 /CF 3 CO 2 H
(0C, 10-30 min), Hg(OCOCF 3 ) 2 /aq AcOH (20 C, 2-3
h, followed by H 2 S or HSCH 2 CH 2 OH, 100% yield), 44,45
Hg(OCOCF 3 ) 2 /CF 3 CO 2 H/anisole, 46 CF3CO2H/reflux,40 anhy
drous HF/anisole (25 C, 1 h, quant),47 (4-BrC 6 H 4 ) 3 NH + SbCl6(75%), 48 HCO 2 H (5C, 30 min, 45%). 42 During the synthesis
of peptides which contain 4-methoxybenzyl-protected cysteine
residues, sulfoxide formation may occur (eq 5). These sulfoxides,
Protection of Amines. The use of the MPM group to protect

amines has not seen many applications, but a few examples are
available in the literature. The MPM group can be introduced on an
aromatic amine with MPMBr (DMF, KI, K 2 CO 3 , 92%), 50 or by
reductive amination (anisaldehyde, PhH, H 2 O; NaBH 4 , MeOH,
92%), 51 but for the most part the MPM group acts as a carrier for
the nitrogen to be introduced into a molecule. MPM amines can be
cleaved by hydrogenolysis,52 oxidation to the imine followed by
hydrolysis,53 or acylation with MeCHClOCOCl (CH 2 Cl 2 , - 7 C,
5 min; MeOH, reflux, 89%). 54
Protection of the Amide Nitrogen. Of the few methods for
protection of the amide NH, the MPM group has found success
where other methods have not been entirely successful.55 The
group can be introduced using methods similar to those used for
alcohols: MPMCl/NaH/DMF,56 MPMBr/NaH, 55 MPMC1 (DBU,
MeCN, 60 C, 5 h, 92%), 57 MPMCl/Ag 2 O. 58
The most common method for removal of the amide MPM
group is by oxidation with DDQ 59 or CAN. 60 With CAN, the
benzoyl imide is sometimes a byproduct of the reaction (eq 6), but
this is easily cleaved by hydrolysis.61 The amide MPM group is
also cleaved by solvolysis in TFA 51 or AlCl 3 /anisole. 62 Metalation
with t-Butyllithium followed by reaction with oxygen (62%) has
been used successfully (eq 7). 63
(6)
(7)
262
Protection of Phosphates. There is one example where the

MPM group is used for phosphate protection. It is cleaved with
48% aq HF/MeCN/H2O (eq 8).64
(8)
R =R =R =H
Related Reagents. Benzoyl

Trifluoromethanesulfonate;
Benzyl Bromide; Benzyl Chloride; Benzyl Iodide; Benzyl
2,2,2-Trichloroacetimidate; 3,4-Dimethoxybenzyl Bromide;
(p-Methoxybenzyloxy)methyl
Chloride; 4-Methoxybenzyl
2,2,2-Trichloroacetimidate.
20.
Hebert, N.; Beck, A.; Lennox, R. B.; Just, G. JOC 1992, 57,
1777.
21. Vanhessche, K.; Bello, C. G.; Vandewalle, M. SL 1991, 921.
22. Gordon, D. M.; Danishefsky, S. J. JACS 1992, 114, 695.
23. Akiyama, T.; Shima, H.; Ozaki, S. SL 1992, 415.
24. Hikota, M.; Tone, H.; Horita, K.; Yonemitsu, O. JOC 1990, 55, 7.
25. Hirama, M.; Shimizu, M. SC 1983, 13, 781.
26. Hamada, Y.; Tanada, Y.; Ykokawa, F.; Siori, T. TL 1991, 32,
5983.
27. Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. TL 1982, 23, 889.
28.
29.
30.
31.
Strmer, R.; Ritter, K.; Hoffmann, R. W. AG(E) 1993, 32, 101.

White, J. D.; Amedio, J. C., Jr. JOC 1989, 54, 736.
Nagaoka, H.; Schmid, G.; Iio, H.; Kishi, Y. TL 1981, 22, 899.
Stelakatos, G. C.; Argyropoulos, N. JCS(C) 1970, 964.
32.
Webber, J. A.; Van Heyningen, E. M.; Vasileff, R. T. JACS 1969, 91,

5674.
Baldwin, J. E.; Flinn, A. TL 1987, 28, 3605.
Jouin, P.; Castro, B.; Zeggaf, C.; Pantaloni, A.; Senet, J. P.; Lecolier, S.;
Sennyey, G. TL 1987, 28, 1661.
33.
34.
35.
36.
37.
38.
39.
40.
1. For a review of protective groups see: Greene, T. W.; Wuts, P. G. M.

Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York,
1991.
2. Ruder, S. M.; Ronald, R. C. TL 1987, 28, 135.
3. Takaku, H.; Kamaike, K.; Tsuchiya, H. JOC 1984, 49, 51.
4. Schreiber, S. L.; Smith, D. B. JOC 1989, 54, 9.
5. Hoshi, H.; Ohnuma, T.; Aburaki, S.; Konishi, M.; Oki, T. TL 1993, 34,
1047.
6. Nakajima, N.; Hamada, T.; Tanaka, T.; Oikawa, Y.; Yonemitsu, O. JACS
1986, 108, 4645.
7. Garegg, P. J.; Oscarson, S.; Ritzen, H. Carbohydr. Res. 1988, 181,
89.
8.
(a) Mootoo, D. R.; Fraser Reid, B. T 1990, 46, 185. (b) Trost, B.
M.; Hipskind, P. A.; Chung, J. Y. L.; Chan, C. AG(E) 1989, 28,
1502.
9. (a) Nagashima, N.; Ohno, M. CL 1987, 141. (b) Verduyn, R.; Elle, C. J.
J.; Dreef, C. E.; Van der Marel, G. A.; van Boom, J. H. RTC 1990, 109,
591. (c) Danishefsky, S.; Lee, J. Y. JACS 1989, 111, 4829.
10. (a) Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.; Yonemitsu, O. T
1986, 42, 3021. (b) Tanaka, T.; Oikawa, Y.; Hamada, T.; Yonemitsu, O.
TL 1986, 27, 3651.
11.
12.
13.
14.
15.
16.
17.
18.
19.
Oikawa, Y.; Tanaka, T.; Horita, K.; Yonemitsu, O. TL 1984, 25,

5397.
Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. TL 1982, 23, 885.
Nagaoka, H.; Baba, A.; Yamada, Y. TL 1991, 32, 6741.
Trost, B. M.; Chung, J. Y. L. JACS 1985, 707, 4586.
(a) Horita, K.; Nagato, S.; Oikawa, Y.; Yonemitsu, O. TL 1987, 28,3253.
(b) Ikemoto, N.; Schreiber, S. L. JACS 1992, 114, 2525.
(a) Classon, B.; Garegg, P. J.; Samuelsson, B. ACS(B) 1984, B38, 419.
(b) Johansson, R.; Samuelsson, B. JCS(P1) 1984, 2371.
Nakajima, N.; Abe, R.; Yonemitsu, O. CPB 1988, 36, 1988.
Pandey, G.; Krishna, A. SC 1988, 18, 2309.
(a) Schmidt, W.; Steckhan, E.AG(E) 1979, 18, 801. (b) Weinreb, S. M.;
Epling, G. A.; Comi, R.; Reitano, M. JOC 1975, 40, 1356.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
Stewart, F. H. C. AJC 1968, 21,2543.

Tanaka, H.; Taniguchi, M.; Kameyama, Y.; Torii, S.; Sasaoka, M.; Shiroi,
T.; Kikuchi, R.; Kawahara, I.; Shimabayashi, A.; Nagao, S. TL 1990, 31,
6661.
Ohtani, M.; Watanabe, F.; Narisada, M. JOC 1984, 49, 5271.
Tsuji, T.; Kataoka, T.; Yoshioka, M.; Sendo, Y.; Nishitani, Y.; Hirai, S.;
Maeda, T.; Nagata, W. TL 1979, 2793.
Young, S. D.; Tamburini, P. P. JACS 1989, 111, 1933.
Akabori, S.; Sakakibara, S.; Shimonishi, Y.; Nobuhara, Y. BCJ 1964, 37,
433.
Chambers, M. S.; Thomas, E. J. CC 1989, 23.
Taylor, A. W.; Dean, D. K. TL 1988, 29, 1845.
Baidoo, K. E.; Lever, S. Z. TL 1990, 31, 5701.
Nishimura, O.; Kitada, C.; Fujino, M. CPB 1978, 26, 1576.
Gordon, E. M.; Godfrey, J. D.; Delaney, N. G.; Asaad, M. M.; Von
Langen, D.; Cushman, D. W. JMC 1988, 31, 2199.
Holler, T. P.; Spaltenstein, A.; Turner, E.; Klevit, R. E.; Shapiro, B. M.;
Hopkins, P. B. JOC 1987, 52, 4420.
Sakakibara, S.; Shimonishi, Y. BCJ 1965, 38, 1412.
Platten, M.; Steckhan, E. LA 1984, 1563.
Funakoshi, S.; Fujii, N.; Akaji, K.; Irie, H.; Yajima, H. CPB 1979, 27,
2151.
Tamato, M.; Takeuchi, Y.; Ikeda, Y. H 1987, 26, 191.
Smith, A. B., III; Rano, T. A.; Chida, N.; Sulikowski, G. A. JOC 1990,
55, 1136.
Rowley, M. T 1992, 48, 3557.
Maruyama, K.; Kusukawa, T.; Higuchi, Y.; Nishinaga, A. CL 1991, 1093.
Yang, B. V.; O'Rourke, D.; Li, J. SL 1993, 195.
Smith, A. B., III; Leahy, J. W.; Noda, I.; Remiszewski, S. W.; Liverton,
N. J.; Zibuck, R. JACS 1992, 114, 2995.
Williams, R. M.; Maruyama, L. K. JOC 1987, 52, 4044.
Akiyama, T. BCJ 1990, 63, 3356.
Takahashi, Y.; Yamshita, H.; Kobayashi, S.; Ohno, M. CPB 1986, 34,
2732.
Smith, A. B., III; Rano, T. A.; Chida, N.; Sulikowski, G. A.; Wood, J. L.
JACS 1992, 114, 8008.
Williams, R. M.; Sabol, M. R.; Kim, H.-d.; Kwast, A. JACS 1991, 113,
6621.
Smith, A. B., III; Salvatore, B. A.; Hull, K. G.; Duan, J. J.-W. TL 1991,
32, 4859.
Akiyama, T.; Kumegawa, M.; Takesue, Y.; Nishimoto, H.; Ozaki, S. CL
1990, 339.
(METHOXYCARBONYLSULFAMOYL) TRIETHYLAMMONIUM HYDROXIDE

63.
64.
Smith, A. B., III; Noda, I.; Remiszewski, S. W.; Liverton, N. J.; Zibuck,
R. JOC 1990, 55, 3977.
263
(3)
Evans, D. A.; Gage, J. R.; Leighton, J. L. JACS 1992,114, 9434.
Peter G. M. Wuts
(Methoxycarbonylsulfamoyl)
triethylammonium Hydroxide1
[29684-56-8]
C8H18N2O4S
(MW 238.35)
(dehydration agent1)
Alternate Name: Burgess reagent.
Solubility: sol benzene, toluene, THF, triglyme, acetonitrile.
Form Supplied in: colorless solid.
Preparative Method: although the Burgess reagent is commer
cially available, it can be easily synthesized in two steps:1a
the reaction of anhydrous methanol with Chlorosulfonyl Isocyanate followed by the addition of Triethylamine affords the
reagent in good yield.
Handling, Storage, and Precautions: moisture sensitive; the use of
anhydrous solvent and atmosphere in reactions with this reagent
is recommended.
Formation of Carbamates. The reaction of primary al

cohols with the Burgess reagent (1) produces alkyl Nmethoxycarbonylsulfamate salts, which decompose on thermoly
sis via an S N 2 (or S N i) mechanism to give methyl urethanes (eqs 1
and 2). 1a,b The products are isolated in good yields. Hydrolysis
of the carbamate produces primary amines. Transformations of
alcohols to amines are often multistep syntheses; therefore this
reaction provides a distinct advantage over the existing method
ology for such substitution reactions.
(1)
(2)
It was noted that when this reaction was applied to allylic al

cohols, either elimination (see below) or an S N i ' rearrangement
ensued.1c The fate of this reaction can be determined by the ex
perimental conditions employed. Whereas the reaction in triglyme
gave good yields of dienes (eq 3), thermal decomposition of the
N-methoxycarbonylsulfamate intermediate at 80 C as a solid pro
vided >90% of the allylurethane product (eq 4).
(4)
Formation of Alkenes. The products of the reaction of the

Burgess reagent with secondary and tertiary alcohols decompose
smoothly at temperatures between 30 and 80 C in a variety of sol
vents to give alkenes.1 The stereochemical course of the reaction
was established to be stereospecific cis elimination. This reaction
minimizes the type of rearrangement products that are typical for
carbonium ion-mediated elimination reactions. For example, the
reaction of the Burgess reagent with 3,3-methyl-2-butanol gave
three products in the ratios given in eq 5. 1a The last two alkenes
were generated as a consequence of the Wagner-Meerwein rear
rangement, whereas the first product formed by direct -proton
removal. The choice of solvent did not affect the product ratios sig
nificantly. Usually, competition between the Wagner-Meerwein
rearrangement and -proton abstraction lies entirely in the direc
tion of the former, which is not seen when the Burgess reagent is
used.
(5)
The reaction of the Burgess reagent with 2-endomethylbicyclo[2.2.1]heptan-2-ol afforded a mixture of the
two cycloalkenes shown in eq 6.1a The ratio of the products
was unexpectedly 1:1, an observation which was attributed to
the steric effects of the endo C-5 hydrogen, whereby the rate of
proton abstraction at C-3 would be attenuated. No rearrangement
products were reported. The reaction in eq 7 proceeded to
give the sole product shown; no evidence for the formation
of 2-cyclopropylidenepropane was found on grounds that the
-cyclopropyl hydrogen is sterically encumbered and unavailable
for elimination.1a The reaction in eq 8 afforded a product mixture
favoring the (Z)-isomer.2 The selectivity is somewhat less in
the case of acid-catalyzed dehydration of the same compound.
It is noteworthy that similar CS2-mediated dehydrations in the
presence of base require pyrolysis at temperatures exceeding
200 C. 2 Some related applications for the Burgess reagent are
shown in eqs 9 and 10.3,4 Dehydration of eq 9 with Acetic
Anhydride in the presence of Pyridine at 70 C gave only 56%
of the desired product.
(6)
(7)
264
((METHOXYCARBONYLSULFAMOYL) TRIETHYLAMMONIUM HYDROXIDE
undergo dehydration in the presence of the Burgess reagent to give

isolable dienones, which are cyclized to give the corresponding
furanones in a separate acid-catalyzed step (eq 13).6
(13)
(8)
(9)
Formation of Vinyltributyltin Compounds and Tributyltin

Isocyanate. The use of the Burgess reagent in the facile formation
of vinyltributyltin compounds has been reported.7 This type of
molecule is otherwise typically synthesized under drastic flash
pyrolytic conditions. Reaction of the butyltin Grignard reagent
with ketones results in tertiary alcohols, which in the presence of
the Burgess reagent furnish the vinytributyltin products (eq 14).
(10)
The requirement for a cis elimination chemistry was discussed

earlier; however, there are a few exceptional reaction outcomes
reported in steroid chemistry.5 The results depicted in eqs 11 and
12 were unanticipated since the 11-hydroxyl and 9p-hydrogen
(eq 11) aretrans-diaxial,as are the 3-hydroxyl and 4-hydrogen
in eq 12. These results are rationalized by an intramolecular 1,2hydrogen transfer. For example, it was suggested for eq 11 that
a C-11 cation is formed first, which subsequently undergoes an
intramolecular hydrogen transfer from C-9 to C-11. The resultant
C-9 carbocation was postulated to be quenched by the loss of a
hydrogen from C-11 and the formation of the 9-double bond.5
(14)
It was discovered that a side reaction during the vinyltributyltin

formation, was the production of tributyltin isocyanate.8 The for
mation of tributyltin isocyanate could account for the major por
tion of the product mixture when cyclic ketones are used, an ob
servation which was attributed to the thermal instability of the
intermediary organotin alcohols. These reagents decompose at
elevated temperatures to the corresponding ketone and tributyltin
hydride, which react with (1) to give rise to the isocyanate (eq 15).
Correspondingly, it has been shown that tin hydride reduction of
(1) gives tributyltin isocyanate in quantitative yield (eq 16).
(15)
(16)
(11)
(12)
Formation of Dienones and Furanones. Furanones are

formed typically by treatment of -hydroxy enones with acid;
the reaction is presumed to proceed via an acid-labile dienone, al
though no direct evidence for the existence of such an intermediate
has been demonstrated. It has been shown that -hydroxy enones
Formation of Nitriles. Dehydration of the primary amide

function by the Burgess reagent takes place under mild condi
tions (eqs 17 and 18), and there is often no need for protection
of many functionalities in more complex molecules; the reagent
has been shown to tolerate alcohols, esters epoxides, ketones, car
bamates, and secondary amides.9 Excellent chemoselectivity is
observed in this reaction, which takes place at room temperature.
(17)
2-METHOXYETHOXYMETHYL CHLORIDE
(18)
Electrophilic Addition. The ethyl analog of (1), (ethoxycarbonylsulfamoyl)triethylammonium hydroxide (2), has also been
reported.10 Compound (2) has been shown to undergo elec
trophilic addition to alkenes in average to good yields (eqs 19
and 20).
(19)
(20)
Related
Chloride.
Reagents. Carbon
Disulfide;
p-Toluenesulfonyl
265
Handling, Storage, and Precautions: moisture sensitive; a lachrymator and possible carcinogen.
Protection of Alcohols. The 2-methoxyethylmethyl (MEM)

group was developed as a protective group that can be introduced
with the ease of the methoxymethyl (MOM) group but can be
cleaved under milder conditions, thus affording another level of se
lectivity in deprotection.2 The most common method for its intro
duction is occasioned with MEMC1 and Diisopropylethylamine
(CH 2 Cl 2 , 25 C, 3 h, quant.). Introduction of the MEM group
is also faster than the formation of the related MOM derivative,
which may be the result of anchimeric assistance. Alternatively
the salt, MEMNEt 3 + Cl- (MeCN, reflux, 30 min, >90% yield)
may be used for its introduction, but this procedure has not seen
extensive use. An alkoxide prepared from Sodium Hydride or
Potassium Hydride, when treated with MEMC1 (THF or DME,
0C, 10-60 min, >95% yield), affords the MEM ether. The re
action of tributyltin ethers in the presence of Cesium Fluoride,
DMF, and MEMCl has also been used to prepare MEM ethers,
but this method is primarily used as part of a scheme for the interconversion of protective groups.3 For example, the reaction of
THP ethers with Bu3SnSMe/BF3Et2O gives the corresponding
tin ethers. Since the MEM group is of low steric demand, little
selectivity is expected when protecting two similar alcohols, but
electronic effects can be used to advantage to achieve modest se
lectivity (eq 1).4
1. (a) Burgess, E. M.; Penton, H. R.; Taylor, E. A. JOC 1973, 38, 26. (b)
Burgess, E. M.; Penton, H. R.; Taylor, E. A.; Williams, W. M. OSC 1988,
6, 788. (c) Burgess, E. M.; Penton, H. R.; Taylor, E. A. JACS 1970, 92,
5224.
(1)
2.
McCague, R. JCS(P1) 1987, 1011.
3.
Stalder, H. HCA 1986, 69, 1887.
4.
Goldsmith, D. J.; Kezar, H. S. TL 1980, 21, 3543. Marino, J. P.; Ferro,

M. P. JOC 1981, 46, 1912. Crabbe, P.; Leon, C. JOC 1970, 35, 2594.
O'Grodnick, J. S.; Ebersole, R. C.; Wittstruck, T.; Caspi, E. JOC 1974,
39, 2124.
5.
6. Jacobson, R. M.; Lahm, G. P. JOC 1979, 44, 462.

7. Ratier, M.; Khatmi, D.; Duboudin, J. G.; Minh, D. T. SC 1989, 19, 285.
8. Ratier, M.; Khatmi, D.; Duboudin, J. G.; Minh, D. T. SC 1989, 19, 1929.
9.
Claremon, D. A.; Phillips, B. T. TL 1988, 29, 2155.
10. Atkins, G. M.; Burgess, E. M. JACS 1972, 94, 6135. Atkins, G. M.;
Burgess, E. M. JACS 1968, 90, 4744.
Pascale Taibi & Shahriar Mobashery

2-Methoxyethoxymethyl Chloride1
[3970-21-6]
C 4 H 9 ClO 2
(MW 124.58)
(protection of alcohols,2 phenols, 15 and carboxylic acids;20 functionalized one-carbon synthon23)

Alternate Name: MEMCl.
Physical Data: bp 50-52 C/13 mmHg; d 1.094 g c m - 3 .
The original method devised to effect deprotection is to

treat the MEM derivative with Zinc Bromide (CH 2 Cl 2 , 25 C,
2-10 h, 90% yield) 1 or Titanium(IV) Chloride (CH 2 Cl 2 , 0C,
20 min, 95% yield) 1 to form a chelate, which upon further
reaction reconstitutes the alcohol. Since then a number of
other cleavage methods have been developed which rely on
the fact that the MEM group can be viewed as an acetal or
ether. Reagents such as Bromodimethylborane (CH 2 Cl 2 , 78 C,
NaHCO 3 , H 2 O, 87-95% yield),5 Ph 2 BBr (CH 2 Cl 2 , - 7 8 C,
71% yield),6 (-SCH 2 CH 2 S-)BBr, 7 (i-PrS)2BBr (DMAP, K 2 CO 3 ,
H 2 O), 8 and 2-bromo-l,3,2-benzodioxaborole 9 cleave ethers like
BBr 3 . Me 2 BBr cleaves MTM and MOM ethers and acetals, but (iPrS)2BBr converts the MEM group to the i-PrSCH 2 - ether which
can be cleaved using the same conditions used to cleave the MTM
ether. The cyclic thio derivative appears to be sterically sensitive
(eq 2). It does not cleave benzyl, allyl, methyl, THP, TBDMS,
and TBDPS ethers, whereas the related oxygen analog (2-bromo1,3,2-benzodioxaborole) is a much more powerful reagent and
cleaves the following groups in the order: MOMOR MEMOR
> t-Boc > Cbz > t-BuOR > BnOR > allylOR > t-BuO2CR sec
ondary alkylOR > BnO 2 CR > primary alkylOR alkylO 2 CR. The
t-butyldimethylsilyl group is stable to this reagent.
Protic acids such as Pyridinium p-Toluenesulfonate (t-BuOH,
or 2-butanone, heat, 80-99% yield)10 and Teirafiuoroboric Acid
(CH 2 Cl 2 , 0C, 3 h, 50-60% yield) 11 can also be used to cleave
266
2-METHOXYETHOXYMETHYL CHLORIDE
the MEM ethers. The former also cleaves the MOM ether and
has the advantage that it cleanly cleaves allylic ethers which can
not be cleaved by Corey's original procedure. The MEM group
is reasonably stable to CF3CO2H/CH2Cl2 (1:1), which is used
to cleave Boc groups, and to 0.2 N HC1, but it is not stable to
2.0 N HCl or HBr-AcOH.12 Iodotrimethylsilane has long been
known as a powerful reagent for the cleavage of ethers, esters,
carbamates, etc., and thus it is no surprise that it will cleave the
MEM ether as well. It does tend to form iodides when cleaving
allylic and benzylic ethers, but this is somewhat suppressed when
the reagent is prepared in situ (Me3SiCl, NaI, MeCN, -20 C,
79%).13 In a synthesis of tirandamycin, deprotection of a MEM
ether was unsuccessful using conventional methods and an en
tirely new method was developed which oxidizes the methylene
(n-BuLi, THF; then Hg(OAc)2, H2O, THF, 81% yield) (eq 3).14
(2)
ester is effected with 3 M HC1 (THF, 40 C, 12 h) or with ZnBr221

or MgBr2.22
Miscellaneous Uses. Outside of the protective group arena,
MEMC1 has been used to alkylate enolates23 and aryllithium
reagents in the presence of Ph2TlBr.24 MEM ethers have also
proven to be a good one-carbon source for the preparation of
isochromans (eq 5)25 and other oxygen heterocycles (eq 6).26
(5)
(6)
Guaiacolmethyl chloride (GUMCl) (1) is a reagent similar to

MEMCl, but it produces derivatives that are somewhat more acid
sensitive. In fact the GUM group can be removed in the presence of
a MEM group. It is a more sterically demanding reagent, and thus
it is possible to introduce this group selectively onto a primary
alcohol in the presence of a secondary alcohol. Because of its
similarity to a p-methoxyphenyl group, it should be possible to
remove it oxidatively. Cleavage is effected with ZnBr2 in CH2Cl2
just as with the MEM group.27
(3)
Protection of Phenols. Methoxyethoxymethyl chloride can

also be used to protect phenols. The conditions for its intro
duction are similar to those used for alcohols (NaH, THF, 0C;
MeOCH2CH2OCH2Cl, 0C25C, 2 h, 75% yield).15,16 In
contrast to the alcohol derivatives, phenolic MEM ethers can
be cleaved with Trifluoroacetic Acid (CH2Cl2, 23 C, 1 h, 74%
yield).17 1MHCl(THF, 5 h, 60 C)18 and HBr/EtOH19 will also ef
fect cleavage. In general, the cleavage conditions used for alcohols
are also effective with the phenolic derivatives. During an exami
nation of the asymmetric reduction of an acetophenone derivative
with (+)-B-Chlorodiisopinocampheylborane, it was found that a
phenolic MEM ether was slowly cleaved (eq 4).16
(4)
Protection of Acids. Carboxylic acids are converted to MEM

esters using conditions similar to those used for alcohol protection
(MEMC1, i-Pr2EtN, CH2Cl2, 0C, 2 h).20 Deprotection of this
Related Reagents. Benzyl Chloromethyl Ether; Benzyl

Chloromethyl Sulfide; t-Butyl Chloromethyl Ether; 2-Chloroethyl
Chloromethyl Ether; Chloromethyl Methyl Ether; Chloromethyl
Methyl Sulfide; (p-Methoxybenzyloxy)methyl Chloride; 2(Trimethylsilyl)ethoxymethyl Chloride.

2. Corey, E. J.; Gras, J.-L.; Ulrich, P. TL 1976, 809.
3. Sato, T.; Otera, J.; Nozaki, H. JOC 1990, 55, 4770.
4. Posner, G. H.; Haces, A.; Harrison, W.; Kinter, C. M. JOC 1987, 52,
4836.
5. Quindon, Y.; Morton, H. E.; Yoakim, C. TL 1983, 24, 3969.
6. Shibasaki, M.; Ishida, Y.; Okabe, N. TL 1985, 26, 2217.
7. Williams, D. R.; Sakdarat, S. TL 1983, 24, 3965.
8. Corey, E. J.; Hua, D. H.; Seitz, S. P. TL 1984, 25, 3.
9. Boeckman, R. K., Jr.; Potenza, J. C. TL 1985, 26, 1411.
10. Monti, H.; Landri, G.; Klos-Ringuet, M.; Corriol, C. SC1983,13, 1021.
11. Ikota, N.; Ganem, B. CC 1978, 869.
12. Vadolas, D.; Germann, H. P.; Thakur, S.; Keller, W.; Heidemann, E. Int.
J. Pept. Protein Res. 1985, 25, 554.
13. Rigby, J. H.; Wilson, J. Z. TL 1984, 25, 1429.
14. Ireland, R. E.; Wuts, P. G. M.; Ernst, B. JACS 1981, 103, 3205.
15.
Corey, E. J.; Danheiser, R. L.; Chandrasekaran, S.; Siret, P.; Keck, G. E.;
Gras, J.-L. JACS 1978, 100, 8031.
2-METHOXYPROPENE
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
Everhart, E. T.; Graig, J. C. JCS(P1) 1991, 1701.

Mayrargue, J.; Essamkaoui, M.; Moskowitz, H. TL 1989, 30, 6867.
Brade, W.; Vasella, A. HCA 1989, 72, 1649.
Fujita, V.; Ishiguro, M.; Onishi, T.; Nishida, T. S 1981, 469.
Meyers, A. I.; Reider, P. J. JACS 1979, 101, 2501.
Posner, G. H.; Weitzberg, M.; Hemal, T. G.; Asiruatham, E.; Cun-Heng,
H. T 1986, 42, 2919.
Kim, S.; Park, Y. H.; Kee, I. S. TL 1991, 32, 3099.
Hlasta, D. J.; Casey, F. B.; Ferguson, E. W.; Gangell, S. J.; Heimann,
M. R.; Jaeger, E. P.; Kullnig, R. K.; Gordon, R. J. JMC 1991, 34, 1560.
Topgi, R. S. JOC 1989, 54, 6125. Laredo, G. C.; Maldonado, L. A. H
1987, 25, 179. Onaka, M.; Matsuoka, Y.; Mukaiyama, T. CL 1981, 531.
Marko, I. E.; Kantam, M. L. TL 1991, 32, 2255.
Mohler, D. L.; Thompson, D. W. TL 1987, 28, 2567.
Blumenkopf, T. A.; Look, G. C.; Overman, L. E. JACS 1990, 112, 4399.
Loubinoux, B.; Coudert, G.; Guillaumet, G. TL 1981, 22, 1973.
267
(1)
(2)
A useful entry into -keto allenes is provided by the reaction

of 2-MP with tertiary propargylic alcohols.4c Base-catalyzed re
arrangement of the allenes affords conjugated dienones (eq 3).
Peter G. M. Wuts
(3)
2-Methoxypropene1
86% trans
14% cis
[116-11-0]
C4H8O
(MW 72.12)
(electron-rich alkene used in the monoprotection of aliphatic,2

allylic,3 and propargylic4 alcohols, often followed by Claisen 3b-e
or other 2a,4c rearrangements; protection of peroxides,5
cyanohydrins,6 -hydroxy ketones, 2b and phenols;7 con
densation with amines; 8 protection of 1,2-9,10 and 1,3-diols,10,11
sometimes followed by Prins 9f,g rearrangements; protection
of l,2-dithiols 10a and -hydroxy carbamates;12 participant in
pericyclic reactions; 13 formation of 2-methoxyallyl halides14 and
substituted furans4b)
Alternate Names: 2-MP; isopropenyl methyl ether.
Physical Data: bp 34-36 C; n20D 1.3820; d 0.753 g c m - 3 ; flash
point - 2 9 C.
Form Supplied in: colorless liquid; commercially available.
Preparative Method: prepared in high yield from Succinic Anhy
dride, 2,2-Dimethoxypropane, benzoic acid, and Pyridine .15
Handling, Storage, and Precautions: flammable liquid; lightsensitive; should be refrigerated.
Monoprotection of Alcohols. 2-Methoxypropene is used as a

protective group for aliphatic, 2,11d allylic,3 and propargylic4 al
cohols, masking them as their mixed acetals (eq 1). Deprotection can be accomplished by stirring in MeOH over ion exchange
resin,4a by reaction in methanol with catalytic Acetyl Chloride,11d
by Potassium Carbonate in methanol,2c or by 20% Acetic Acid.3a
A general advantage of this acetal, which undergoes hydroly
sis at approximately 103 times the rate of THP, 2d,3a is that it
does not confer an additional diastereomeric center to the pro
tected substrate. Access to allyl vinyl ethers for subsequent Claisen
rearrangements 3b-e is illustrated in eq 2.
Stable allylic peroxyacetals have been prepared by reacting 2MP with hydroperoxides (eq 4). 5 Organomercury functionality is
tolerated in this reaction.5b Cyanohydrins,6 -hydroxy ketones, 2b
and phenols7 are similarly protected.
(4)
Condensation with Amines. Imine formation with loss of

methanol occurs under acidic conditions, as illustrated in eq 5. 8
(5)
Protection of 1,2- and 1,3-Diols and 1,3-Dithiols. When an

other hydroxy group is in close proximity to the initially pro
tected alcohol functionality, acetonide formation occurs. 9-11 The
kinetic product is preferentially formed. 10b,c,11c As anomeric hy
droxy groups do not usually 11 participate, this reagent provides
complementary selectivity to the more traditional acid/acetone
268
2-METHOXYPROPENE
acetonation protocol. Control of the amount of 2-MP can result in

varying degrees of protection (eq 6).10b
(9)
(10)
(6)
Acetonide formation using n-Butyltrichlorostannane with 2MP10a is quite general for 1,2- and 1,3-diols, as well as for 1,3dithiols. Monoacetonide formation occurs with 1,2,3- and 1,2,4triols. Yields of the acetonides (e.g. 1-5) show improvement over
conventional procedures.10a
Reaction with N-Halosuccinimides. 2-Methoxyallyl and

vinyl halides are formed by reaction of 2-MP with Nhalosuccinimides.14 Also, treatment of propargylic alcohols with
2-MP and N-Bromosuccinimide results in the formation of bromo
acetals, which are subsequently cyclized to furans in good yield
(eq11).4b
Protection of -Hydroxy Carbamates. Aminal formation

from -hydroxy carbamates also occurs using 2-MP, as illustrated
(11)
in eq 7.12
Related Reagents. Benzyl Isopropenyl Ether; 3,4-Dihydro2H-pyran; 2,2-Dimethoxypropane; Ethyl Vinyl Ether.
(7)
1. FF 1969, 2, 230; 1975, 5, 360; 1981, 9, 304; 1984, 11, 329; 1986, 12,
291.
Participation in Pericyclic Reactions. 2-MP is an active

participant in pericyclic reactions. A few examples include a
substitution-dependent ene reaction with an alkynyl Fischer carbene complex (eq 8),13c a [2 + 3] reaction with 2-amino-l,4naphthoquinone (eq 9),13f a solvent-dependent photochemical cycloaddition with o-naphthoquinones,13j and reaction with 2-nitro1,3-dienes to provide ,-unsaturated 1,4-diones (eq 10).13g
(8)
M = W, Cr R = TMS
R = Me
30%
<2%
<2%
63%
2.
(a) Kang, S. H.; Hwang, T. S.; Kim, W. J.; Lim, J. K. TL 1991, 32, 4015.
(b) Wilson, T. M.; Kocienski, P.; Jarowicki, K.; Isaac, K.; Faller, A.;
Campbell, S. F.; Bordner, J. T 1990, 46, 1757. (c) Tietze, L. F.; Lgers,
M. LA 1990, 261. (d) Reese, C. B.; Saffhill, R.; Sulston, J. E. JACS 1967,
89, 3366.
3.
(a) Kluge, A. F.; Untch, K. G.; Fried, J. H. JACS 1972, 94, 7827.
(b) Srikrishna, A.; Krishnan, K.; Vankateswarlu, S. CC 1993, 143. (c)
Srikrishna, A.; Krishnan, K. IJC(B) 1990, 29B, 879. (d) Gajewski, J. J.;
Gee, K. R.; Jurayj, J. JOC 1990, 55, 1813. (e) Saucy, G.; Marbet, R.
HCA 1967, 50, 2091.
4.
(a) Lampilas, M.; Lett, R. TL 1992, 33, 773. (b) Srikrishna, A.;
Sundarababu, G. T 1990,46, 7901. (c) Saucy, G.; Marbet, R. HCA 1967,
50, 1158.
5.
(a) Dussault, P.; Sahli, A.; Westermeyer, T. JOC 1993, 58, 5469. (b)
Bloodworm, A. J.; Cooksey, C. J.; Korkodilos, D. CC 1992, 926. (c)
Dussault, P.; Sahli, A. TL 1990, 31, 5117.
6.
Zanderbergen, P.; van den Nieuwendijk, A. M. C. H.; Brussee, J.; van

der Gen, A. T 1992, 48, 3977.
7.
Gibson, C. P.; Bern, D. S.; Falloon, S. B.; Hitchens, T. K.; Cortopassi, J.

E. OM 1992, 11, 1742.
8. Freeman, F.; Kim, D. S. H. L. JOC 1992, 57, 550.
METHYLALUMINUM DICHLORIDE
9.
(a) Kozikowski, A. P.; Ognyanov, V. I.; Fauq, A. H.; Nahorski, S. R.;

Wilcox, R.A. JACS 1993, 115,4429, (b) van der Klein, P. A. M.; Filemon,
W.; Boons, G. J. P. H.; Veeneman, G. H.; van derMarel, G. A.; van Boom,
J. H. T 1992, 48, 4649. (c) Barbat, J.; Gelas, J.; Horton, D. Carbohydr.
Res. 1991, 219, 115. (d) Shing, T. K. M.; Tang, Y. T 1991, 47, 4571. (e)
Fujisawa, T.; Takemura, I.; Ukaji, Y. TL 1990, 31, 5479. (f) Hopkins, M.
H.; Overman, L. E.; Rishton, G. M. JACS 1991, 113, 5354. (g) Brown,
M. J.; Harrison, T.; Herrington, P. M.; Hopkins, M. H.; Hutchinson, K.
D.; Mishra, P.; Overman, L. E. JACS 1991, 113, 5365.
10. (a) Carofiglio, T.; Marton, D.; Stivanello, D.; Tagliavini, G. Main Group
Chem. 1992, 15, 247. (b) Fanton, E.; Gelas, J.; Horton, D. JOC 1981,
46, 4057. (c) Gelas, J.; Horton, D. H 1981, 16, 1587.
11. (a) Guanti, G.; Banfi, L.; Narisano, E.; Thea, S. SL 1992, 311. (b)
Srikrishna, A.; Krishnan, K.; Yelamaggad, C. V. T 1992, 48, 9725. (c)
Jung, M. E.; Clevenger, G. L. TL 1991, 32, 6089. (d) Thom, M. A.;
Giudicelli, M. B.; Picq, D.; Anker, D. J. Carbohydr. Chem. 1991, 10,
923.
12.
13.
14.
15.
269
since EtAlCl2 is much cheaper and comparable results are usually

obtained. In some cases, use of MeAlCl 2 is preferable, since the
methyl group of MeAlCl2 is less nucleophilic than the ethyl group
of EtAlCl2 and EtAlCl2 can transfer a hydride.
Catalysis of Diels-Alder Reactions. MeAlCl 2 has been used
as a catalyst for Diels-Alder 2-4 and retro-Diels-Alder reactions. 5
MeAlCl2 is the catalyst of choice for intramolecular Diels-Alder
reactions of furans (eq 1) due to the ease of handling and reaction
workup.2
(1)
Melnick, M. J.; Bisaha, S. N.; Gammill, R. B. TL 1990, 31, 961.

(a) Deaton, M. V.; Ciufolini, M. A. TL 1993, 34, 2409. (b) Beak, P.;
Song, Z.; Resek, J. E. JOC 1992, 57, 944. (c) Faron, K. L.; Wulff, W.
D. JACS 1990,112,6419. (d) Kobayashi, K.; Suzuki, M.; Suginome, H.
JOC 1992, 57, 599. (e) Fannes, C.; Meerpoel, L.; Toppet, S.; Hoornaert,
G. S 1992, 705. (f) Kobayashi, K.; Takeuchi, H.; Seko, S.; Suginome, H.
HCA 1991, 74, 1091. (g) Bckvall, J.-E.; Karlsson, U.; Chinchilla, R. TL
1991, 32, 5607. (h) Coleman, R. S.; Grant, E. B. TL 1990, 31, 3677. (i)
Gupta, R. B.; Franck, R. W. SL 1990, 355. (j) Takuwa, A.; Sumikawa,
M. CL 1989, 9.
Catalysis of Ene Reactions. MeAlCl2 has been used as a

catalyst for ene reactions of trifluoroacetaldehyde6 and for in
tramolecular ene reactions of trifluoromethyl ketones (eq 2). 7 Use
of EtAlCl2 leads to the ene adduct in lower yield accompanied by
25% of the saturated analog resulting from hydride delivery to the
zwitterion.
(a) Jacobson, R. M.; Raths, R. A.; McDonald, J. H., III JOC 1977, 42,
2545. (b) Greenwood, G.; Hoffmann, H. M. R. JOC 1972, 37, 611.
Newman, M. S.; Vander Zwan, M. C. JOC 1973, 38, 2910.
(2)
K. Sinclair Whitaker
D. Todd Whitaker
Detroit County Day School, Beverly Hills, MI, USA
Generation of Electrophilic Cations. 1:2 Aldehyde- or

ketone-MeAlCl 2 complexes add intramolecularly to alkenes to
give zwitterions that undergo 1,2-hydride and alkyl shifts to re
generate a ketone (eqs 3 and 4). 8 - 1 1 EtAlCl2 can transfer a hydride
to the zwitterion to give the reduced product (eq 3). 8
Methylaluminum Dichloride1
(3)
[917-65-7]
CH 3 AlCl 2
(MW 112.92)
with HX to give methane and AlCl 2 X)
Alternate Name: dichloro(methyl)aluminum.
Physical Data: mp 72.7 C; bp 94-95 C/100 mmHg.
Form Supplied in: commercially available as solutions in hexane
or toluene.
may be titrated before use by one of the standard methods. 1b
hood.

halides as Lewis acids are discussed in the entry for Ethylaluminum Dichloride. MeAlCl 2 is used less frequently than EtAlCl2,
(4)
MeAlCl2 has been used as the catalyst for epoxide-initiated

cation-alkene cyclizations.12 A tertiary alcohol has been con
verted to a hydrazide by reaction with MeAlCl 2 in the pres
ence of MesitylenesulfonylhydrazideP -Trimethylsilyl enones
can be prepared by isomerization of l-(trimethylsilyl)-2-propynyl
trimethylsilyl ethers with MeAlCl 2 . 14
Nucleophilic Additions. MeAlCl 2 has occasionally been used
to introduce a methyl group. -Lactones react with MeAlCl 2
to give carboxylic acids with a methyl group at the 7position.15 The reagent prepared from MeAlCl 2 and Dichlorobis(cyclopentadienyl)titanium adds to trimethylsilylalkynes in
a syn fashion.16 Optimal stereoselectivity is obtained using
MeAlCl 2 to transfer a methyl group to a formyl amide (eq 5). 17
270
METHYL CHLOROFORMATE
(5)
Related Reagents. Diethylaluminum Chloride; Dimethylaluminum Chloride; Ethylaluminum Dichloride.
1. (a) For reviews, see ref. 1 in Ethylaluminum
Dichloride. (b)
to the eyes. It should be handled with caution in a fume hood

using protective gloves.
Functional Group Protection. The protection of alcohols 1

and phenols 2 as their methyl carbonates can be achieved using
methyl chloroformate under basic conditions (eq 1). Primary and
secondary alkylamines are readily protected as their methyl carba
mates using MCF, typically in the presence of Et 3 N, 3,4 Na 2 CO 3 , 5
K 2 CO 3 , 6 or NaHCO 3 . 7 Selective N-protection of amino alcohols
can be achieved under these conditions (eq 2). 5
Aluminum Alkyls; Stauffer Chemical Co.: Westport, CT, 1976.

2.
(a) Rogers, C.; Keay, B. A. TL 1991, 32, 6477. (b) Rogers, C.; Keay, B.
A. CJC 1992, 70, 2929.
3.
Boeckman, R. K., Jr.; Nelson, S. G.; Gaul, M. D. JACS 1992, 114, 2258.
4.
Trost, B. M.; Lautens, M.; Hung, M. H.; Carmichael, C. S. JACS 1984,

106, 7641.
5.
Grieco, P. A.; Abood, N. JOC 1989,54,6008.
6.
Ogawa, K.; Nagai, T.; Nonomura, M.; Takagi, T.; Koyama, M.; Ando,
A.; Miki, T.; Kumadaki, I. CPB 1991, 39, 1707.
Abouadellah, A.; Aubert, C.; Bgu, J.-R; Bonnet-Delpon, D.; Guilhem,
J. JCS(P1) 1991, 1397.
7.
8.
Snider, B. B.; Karras, M.; Price, R. T.; Rodini, D. J. JOC 1982, 47,4538.
9.
Snider, B. B.; Rodini, D. J.; van Straten, J. JACS 1980, 102, 5872.
10.
Snider, B. B.; Kirk, T. C. JACS 1983, 105, 2364.
11.
Snider, B. B.; Cartaya-Marin, C. P. JOC 1984, 49, 153.
(1)
(2)
12. Corey, E. J.; Sodeoka, M. TL 1991, 32, 7005.

13.
Wood, J. L.; Porco, J. A., Jr.; Taunton, J.; Lee, A. Y.; Clardy, J.; Schreiber,
S. L. JACS 1992, 114, 5898.
14.
Enda, J.; Kuwajima, I. CC 1984, 1589.
15.
Reinheckel, H.; Sonnek, G.; Falk, F. JPR 1974, 316, 215.
16.
Eisch, J. J.; Piotrowski, A. M.; Brownstein, S. K.; Gabe, E. J.; Lee, F. L.

JACS 1985, 107, 7219.
17. Fujii, H.; Taniguchi, M.; Oshima, K.; Utimoto, K. TL 1992, 33, 4579.
Methyl carbonates are more resistant to basic hydrolysis than

simple esters; however, both alcohol-1c and phenol-derived2
methyl carbonates can be selectively hydrolyzed under mildly ba
sic conditions in the presence of a methyl carbamate derivative,
allowing for the overall selective N-protection of amino alcohols
and amino phenols (eq 3).
Barry B. Snider
(3)
[79-22-1]
C 2 H 3 ClO 2
(MW 94.50)
(protecting agent for many functional groups; 1-16 activates Nheteroaromatic rings and carboxylic acids toward nucleophilic
attack; 17-26 methoxycarbonylating agent for organometallic
reagents and enolates 27-39 )
Alternate Name: MCF.
Physical Data: bp 70-72C; d (20 C) 1.223 g c m - 3 ; n20D 1.3870.
Solubility: slightly sol water with slow decomposition; miscible
with alcohols, benzene, chloroform, ether, etc.
Handling, Storage, and Precautions: flammable liquid; vesicant;
its vapors are highly toxic, lachrymatory, and strongly irritating
MCF is also useful for the N-protection of -amino

acids (Schotten-Baumann conditions), 8 primary arylamines
(using pyridine as base), 1b,9 amides (using Triethylamine/4Dimethylaminopyridine as base), 10 and pyrrole and indole ring
nitrogens (using NaH or KH as base). 11 N-Silylpyrroles can
be converted to the corresponding methyl carbamates under
milder conditions than are required for the direct N-protection
of pyrroles.12 ortho-Phenylenediamines are readily converted to
the corresponding benzimidazole-2-carbamates using MCF in
the presence of MeSCH(NH 2 )=NH. 13 The forcing conditions
that are often required for removal of a methyl carbamate pro
tecting group (e.g. Hydrazine, KOH, 14 or aq Ba(OH) 2 ) 15 have
limited the utility of this N-protecting group when compared
with other carbamates; although milder N-deprotection condi
tions have been reported (Iodotrimethylsilane, CHCl 3 ,50 C; then
MeOH), 16 this chemistry has not seen widespread use. Lithium
Aluminum Hydride reduction of methyl carbamates affords
the corresponding N-methylamines, 3,4 providing an attractive
method for the overall N-methylation of primary and secondary
amines (eq 4).
271
33
ums with MCF appears to be of little synthetic utility. The in

situ trapping of a simple phosphonium ylide with MCF followed
by deprotonation provides.a convenient synthetic approach to methoxycarbonylphosphonium ylides (eq 10).34
(4)
(8)
Activation of N-Heteroaromatic Rings Toward Nucleophilic

Attack. Pyridine, quinoline, and isoquinoline rings are acti
vated by MCF toward in situ nucleophilic attack, leading to the
formation of 1,2- and/or 1,4-dihydropyridines, -quinolines, or
-isoquinolines. The addition of alkyl Grignard reagents proceeds
with variable and often poor regioselectivity.17 However, alkenyland alkynyl-Grignard reagents (eq 5), 17b unhindered allylic18 and
allenylic19 stannanes, cyanide ion,20 and Sodium Borohydride
(in MeOH at - 7 0 C 21 ) all add with high 1,2-selectivity. Highly
1,4-selective addition reactions are observed using alkylcopper
reagents (eq 6), 17a,22 dialkylcuprates, 17b,23 silyl enol ethers,22 and
benzylic stannanes.24 The 1,4-addition of aryllithium reagents,25
and methylHthium and methylmagnesium bromide, 26 to chiral 3oxazolinylpyridines proceeds with high regio- and diastereofacial
selectivity (eq 7). Removal of the chiral auxiliary affords chiral
4-substituted dihydropyridines in high ee.
(5)
(6)
(9)
(10)
The C-methoxycarbonylation of lithium ester35 and amide 36

enolates can be effectively accomplished using MCF. Addition of
n-BuLi to a chiral 1-oxazolinylnaphthalene followed by trapping
the resulting azaenolate with MCF affords the C-acylation product
with high diastereoselectivity (eq 11).37 In contrast, reaction of
copper38 and potassium39 ketone enolates with MCF typically
results in O-acylation to afford the corresponding enol carbonates
(eq 12). The weak nucleophilicity of enol carbonates (they are
stable to peroxy acids and Ozone)38a makes them useful masked
enolate equivalents.
(11)
(7)
89:11 diastereoselectivity
(12)
Methoxycarbonylation of Organometallic Reagents and

Enolates. Deprotonation of terminal alkynes (typically using nBuLi, 27 LDA, 28 or EtMgBr 29 ), followed by trapping the resulting
alkynyllithium or -Grignard reagent with MCF, offers an excellent
route to methyl alkynoates (eq 8) (see 2,2,2-Trichloroethyl Chloroformate if subsequent cleavage to the carboxylic acid is desired).
A related approach to methyl alkynoates proceeds via homolo
gation of an aldehyde to the corresponding ,-dibromoalkene.
Dehydrobromination and halogen-metal exchange followed by
trapping the resultant alkynyllithium with MCF provides the
methyl alkynoate in high overall yield (eq 9). 30 Aryllithium31
and alkenylaluminium32 species are also effectively methoxycarbonylated by MCF, but the trapping of simple primary alkyllithi-
Activation of Carboxylic Acids as Mixed Anhy

drides. Activation of N-(alkoxycarbonyl)--amino acids as
mixed anhydrides using MCF/N-methylpiperidine in CH 2 Cl 2
minimizes urethane byproduct formation and racemization
during peptide bond formation.40 Reaction of these mixed
anhydrides with N,O-Dimethylhydroxylamine
followed by
LiAlH 4 reduction provides an attractive route to the corre
sponding N-(alkoxycarbonyl)--amino aldehydes (eq 13).41
Attempts to generate mixed anhydrides from N-acyl--amino
272
acids using MCF result in cyclization to the corresponding

5(4H)-oxazolones.42,43
(13)
10.
11.
12.
13.
14.
15.
16.
17.
-Diazo ketones may be conveniently prepared by reaction of

a mixed anhydride with Diazomethane; the mixed anhydrides are
typically prepared either by treatment of the parent carboxylic acid
with MCF/Triethylamine44 or by treatment of the corresponding
methyl ester with potassium silyloxide and then MCF.45 Attack by
amines46 or N-silylamines47 on such mixed anhydrides provides
a useful approach to amide synthesis (eq 14), while acyl azides
are prepared in excellent yield by reaction of the mixed anhydride
with Sodium Azide.48
(14)
While the mixed anhydrides derived from the reaction of

carboxylic acids with methyl chloroformate using Et3N as
base are relatively stable, the addition of catalytic amounts
of 4-Dimethylaminopyridine or N-methylmorpholine results in
facile conversion to the corresponding methyl esters under very
mild reaction conditions that are compatible with sensitive
functionality.49
Related Reagents. Allyl Chloroformate; Benzyl Chloroformate; 4-Bromobenzyl Chloroformate; t-Butyl Chloroacetate; Ethyl Chloroformate; 9-Fluorenylmethyl Chloroformate;
Isobutyl Chloroformate; 2,2,2-Tribromoethyl Chloroformate;
2,2,2-Trichloro-t-butoxycarbonyl Chloride; 2,2,2-Trichloroethyl
Chloroformate; 2-(Trimethylsilyl)ethyl Chloroformate; Vinyl
Chloroformate.
1. (a) Eren, D.; Keinan, E. JACS 1988, 110, 4356. (b) Trost, B. M.; Kuo,
G. H.; Benneche, T. JACS 1988, 110,621. (c) Fang, J.-M.; Cherng, Y.-J.
JCR(M) 1986, 1568.
2.
Schwartz, M. A.; Pham, P. T. K. JOC 1988, 53, 2318.
3.
Yamada, F.; Hasegawa, T.; Wakita, M.; Sugiyama, M.; Somei, M. H

1986,24, 1223.
4.
5.
Somei, M.; Yamada, F.; Makita, Y. H 1987, 26, 895.

Knapp, S.; Sebastian, M. J.; Ramanathan, H.; Bharadwaj, P.; Potenza, J.
A. T 1986,42, 3405.
6.
Corey, E. J. et al. TL 1978, 1051.
7.
Patjens, J.; Ghaffari-Tabrizi, R.; Margaretha, P. HCA 1986, 69, 905.
8. Itaya, T.; Mizutani, A.; Watanabe, N. CPB 1989, 37, 1221.

9.
Takai, H. et al. CPB 1985, 33, 1129.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
Kubo, A.; Saito, N.; Yamato, H.; Masubuchi, K.; Nakamura, M. JOC
1988, 53, 4295.
Somei, M.; Saida, Y.; Komura, N. CPB 1986, 34, 4116.
Keijsers, J.; Hams, B.; Kruse, C.; Scheeren, H. H 1989, 29, 79.
Akhtar, M. S.; Seth, M.; Bhaduri, A. P. IJC(B) 1986, 25B, 395.
Shono, T.; Matsumura, Y.; Uchida, K.; Tsubata, K.; Makino, A. JOC
1984, 49, 300.
Wovkulich, P. M.; Uskokovic, M. R. T 1985, 41, 3455.
(a) Jung, M. E.; Lyster, M. A. CC 1978, 315. (b) Wender, P. A.; Schaus,
J. M.; White, A. W. JACS 1980, 102, 6157.
(a) Gosmini, R.; Mangeney, P.; Alexakis, A.; Commercon, M.; Normant,
J. F. SL 1991, 111. (b) Yamaguchi, R.; Nakazono, Y.; Matsuki, T.; Hata,
E.-i.; Kawanisi, M. BCJ 1987, 60, 215.
Yamaguchi, R.; Moriyasu, M.; Yoshioka, M.; Kawanisi, M. JOC 1985,
50, 287; Yamaguchi, R.; Moriyasu, M.; Yoshioka, M.; Kawanisi, M. JOC
1988, 53, 3507.
Yamaguchi, R.; Moriyasu, M.; Takase, I.; Kawanisi, M.; Kozima, S. CL
1987, 1519.
Uff, B. C. et al. JCR(S) 1986, 206.
Fowler, F. W. JOC 1972, 37, 1321.
Akiba, K.; Ohtani, A.; Yamamoto, Y. JOC 1986, 51, 5328.
Piers, E.; Soucy, M. CJC 1974, 52, 3563.
Yamaguchi, R.; Moriyasu, M.; Kawanisi, M. TL 1986, 27, 211.
Meyers, A. I.; Oppenlaender, T. CC 1986, 920.
(a) Meyers, A. I.; Oppenlaender, T. JACS 1986, 108, 1989. (b) Meyers,
A. I.; Natale, N. R.; Wettlaufer, D. G. TL 1981, 22, 5123.
Mori, K.; Fujiwhara, M. T 1988, 44, 343.
Marshall, J. A.; Andrews, R. C.; Lebioda, L. JOC 1987, 52, 2378.
Earl, R. A.; Townsend, L. B. OS 1981, 60, 81.
Boeckman, R. K., Jr.; Perni, R. B. JOC 1986, 51, 5486.
Uemora, M.; Take, K.; Isobe, K.; Minami, T.; Hayashi, Y. T 1985, 41,
5771.
Zwiefel, G.; Lynd, R. A. S 1976, 625.
Rucker, C. JOM 1986, 310, 135.
Marshall, J. A.; DeHoff, B. S.; Cleary, D. G. JOC 1986, 57, 1735.
Hersloef, M.; Gronowitz, S. CS 1985, 25, 257.
Ackermann, J.; Matthes, M.; Tamm, C. HCA 1990, 73, 122.
Meyers, A. I.; Roth, G. P.; Hoyer, D.; Barner, B. A.; Laucher, D. JACS
1988, 110, 4611.
(a) Danishefsky, S.; Kahn, M.; Silvestri, M. TL 1982, 23, 703; however,
see also: (b) Trost, B. M.; Hiemstra, H. T 1986, 42, 3323.
Earley, W. G.; Jacobsen, E. J.; Meier, G. P.; Oh, T.; Overman, L. E. TL
1988,29,3781.
Chen, F. M. F.; Steinauer, R.; Benoiton, N. L. JOC 1983, 48, 2939.
Goel, O. P.; Krolls, U.; Stier, M.; Kesten, S. OS 1989, 67, 69.
Chen, F. M. F.; Benoiton, N. L. Int. J. Pept. Protein Res. 1988, 31, 396.
Chen, F. M. F.; Slebioda, M.; Benoiton, N. L. Int. J. Pept. Protein Res.
1988, 31, 339.
Padwa, A.; Fryxell, G. E.; Zhi, L. JACS 1990, 7/2, 3100.
Padwa, A.; Krumpe, K. E.; Kassir, J. M. JOC 1992, 57, 4940.
Rao, A. V. R.; Chavan, S. P.; Sivadasan, L. T 1986, 42, 5065.
Balogh, D. W.; Patterson, L. E.; Wheeler, W. J. SC 1988, 18, 307.
Tius, M. A.; Thurkauf, A. TL 1986, 27, 4541.
(a) Kim, S.; Kim, Y. C.; Lee, J. I. TL 1983, 24, 3365. (b) Burke, S. D.;
Pacofsky, G. J.; Piscopio, A. D. TL 1986, 27, 3345. (c) Davis, M.; Wu,
W.-Y. AJC 1987, 40, 223.
Paul Sampson
Kent State University, OH, USA
METHYL CYANOFORMATE
Methyl Cyanoformate1
273
(3)
(4)
( l ; R = Me)
[17640-15-2]
(2;R = Et)
[623-49-4]
(3;R = PhCH2)
[5532-86-5]
C3H3NO2
(MW 85.07)
C4H5NO2
(MW 99.10)
C9H7NO2
(MW 161.17)
(agent for the regioselective methoxycarbonylation of

carbanions; 1,2 reacts with organocadmium reagents to form
-keto esters; 3 may function as a dienophile,4 dipolarophile,5
or radical cyanating agent6)
Physical Data: (1) mp 26 C; bp 100-101 C; d 1.072 g c m - 3 . (2)
bp 115-116 C; d 1.003 g c m - 3 . (3) bp 66-67 C/0.6 mmHg; d
1.105 g c m - 3 .
Solubility: sol all common organic solvents; dec by H 2 O, alcohols,
amines.
Form Supplied in: colorless liquid; methyl cyanoformate, as well
as the ethyl and benzyl analogs, is available commercially.
Preparative Methods: small quantities of cyanoformate esters (up
to 30 g) may be conveniently prepared from alkyl chloroformates by procedures employing phase-transfer catalysis with
either 18-Crown-67 or Tetra-n-butylammonium Bromide,8 but
several workers have found the products to be unsatisfactory
when prepared on a larger scale.
Handling, Storage, and Precautions: store over 4A molecular
sieves; highly toxic; flammable; use in a fume hood.
Regioselective Methoxycarbonylation of Ketones. Methyl

cyanoformate gives generally excellent results in the regiocontrolled synthesis of -keto esters by the C-acylation of preformed
lithium enolates (eq 1) 1,2 and is normally superior to the more
traditional acylating agents such as acyl halides, anhydrides,9 and
CO 2 , 10 partly because these reagents afford variable amounts of
O-acylated products. 11 The enolates may be generated in a variety
of ways, including direct enolization of ketones with suitable bases
(eq 2), 2 liberation from silyl enol ethers and acetates (eq 3), 12 con
jugate additions of cuprates to ,-unsaturated ketones 13 (eq 4), 14
or by the reduction of enones by lithium in liquid ammonia
(eq 5). 1,12
R = TBDMSOCH2CH=CH
(5)
Lithium enolates derived from sterically unencumbered cyclohexanones undergo preferential axial acylation (eq 6), whereas
equatorial acylation is favored with 1(9)-2-octalones (eq 7), 12
even in the absence of an alkyl substituent at C-10.15
(6)
(7)
R=H
R = Me
53%
78%
14%
0%
For compounds in which the -carbon of the enolate is ster

ically hindered, treatment with methyl cyanoformate may result
in variable degrees of O-acylation, although this problem may be
ameliorated by the use of diethyl ether as the solvent. In several
cases a switch from predominantly O-acylation in THF to predom
inant C-acylation in diethyl ether has been observed (eqs 8-10). 12
(8)
(1)
(9)
(2)
MeLi, THF, -20 C

NCCO2Me, -78 to 0 C
78%
0%
BuLi, Et2O, -10 C

NCCO2Me, -78 to 0 C
9%
68%
274
METHYL CYANOFORMATE
(13)
(10)
solvent: THF
solvent: Et2O)
67%
0%
8%
71%
A comparative study of lithium, sodium, and potassium etiolates

indicated that the lithium derivatives reacted most satisfactorily.2
There may be substrates for which the thermodynamic enolates
are required, however, and the sodium and potassium enolates
may therefore be selected. Good results have been reported with
these intermediates (eqs 11 and 12), although the latter afford
significant amounts of O-acylated products.16,17 Quite apart from
the issue of regioselectivity, the cyanoformate based procedure
is exceptionally reliable and makes it possible to prepare -keto
esters from ketones under especially mild conditions. It is not only
the method of choice with sensitive substrates,16 but it will often
ensure superior results with more robust compounds as well.
(14)
(15)
(16)
(17)
(11)
LDA
NaHMDS
KHMDS
4:1:0
1:7:0
0:1:1.5
Higher Alkyl Cyanoformates. A range of other alkyl

cyanoformates has been successfully utilized for the acylation
of enolate anions, including ethyl,23 allyl,24 benzyl,25 and pmethoxybenzyl,26 but not t-butyl cyanoformate, which appears
to be insufficiently reactive. Enantiomerically enriched cyanofor
mates derived from (+)-menthol, ()-borneol, and the Oppolzer
alcohol were reported to furnish good chemical yields, but the
level of enantioselectivity was disappointingly low (eq 18).27
(12)
(18)
Methoxycarbonylation
of
Miscellaneous
Carbon
Acids. The title reagent has also been applied to the methoxycar
bonylation of esters (eq 13),18 lactones (eq 14),19 phosphonates
(eq 15),20 imines (eq 16),21 and the N-acylation of lactams
(eq 17).22
Additions to the Nitrile Group. Ethyl cyanoformate reacts

with organocadmium reagents to afford -keto esters (eq 19),3 and
with malonate esters, -keto esters, and other active methylene
METHYL CYANOFORMATE
28
compounds to give -aminoacrylates (eq 20). Both processes

require catalysis with Lewis acids, of which Zinc Chloride has
proven to be the most effective.
(19)
(20)
Cycloadditions. Methyl and ethyl cyanoformate have

been reported to undergo [4 + 2] cycloadditions, e.g. with
cyclopentadienones4 and 2-alkyl-l-ethoxybuta-l,3-dienes to
form pyridines (eq 21), 29 and with cyclobutadienes to form
Dewar pyridines (eq 22). 30 Ethyl cyanoformate is also an
effective dipolarophile, undergoing 1,3-dipolar addition to azides
(eq 23) 31 and cyclic carbonyl ylides (eq 24). 5
(21)
R = Me, Et, Pr, i-Pr, Bu, C5H11
(22)
(23)
R = H, 5-Me. 4-Cl, 5-Cl
(24)
Radical Cyanation. The peroxide-initiated radical cyanation

of cyclohexane and 2,3-dimethylbutane with methyl cyanofor
mate has been carried out in 72% and 77% yield, respectively.6
Related Reactions. -Keto ester formation from ketones
may be achieved directly with dialkyl carbonates32 and dialkyl
dicarbonates, 33 or indirectly with dialkyl oxalates,34 methyl mag
nesium carbonate,35 and ethyl diethoxyphosphinyl formate.36 Regiocontrol is problematical, however, and is more reliably effected
by trapping enolates with carbon dioxide,10 carbon disulfide,37 or
carbon oxysulfide38 followed by methylation. In the latter cases,
the dithio and thiol esters are converted into the parent carboxy
275
esters by mercury(II)-catalyzed hydrolysis. The chemistry of acyl

cyanides, but excluding cyanoformates, has been the subject of
several reviews.39
Related Reagents. Acetyl Cyanide; Carbon Dioxide; Car
bon Oxysulfide; N,N'-Carbonyldiimidazole; Diethyl Carbonate;
Methyl Chloroformate; Methyl Magnesium Carbonate.
1.
2.
3.
4.
Crabtree, S. R.; Mander, L. N.; Sethi, S. P. OS 1991, 70, 256.

Mander, L. N.; Sethi, S. P. TL 1983, 24, 5425.
Akiyama, Y.; Kawasaki, T.; Sakamoto, M. CL 1983, 1231.
Padwa, A.; Akiba, M.; Cohen, L. A.; Gingrich, H. L.; Kamigata, N. JACS
1982,104, 286.
5. Padwa, A.; Chinn, R. L.; Hornbuckle, S. F.; Zhang, Z. J. JOC 1991, 56,
3271.
6. Tanner, D. D.; Rahimi, P. M. JOC 1979, 44, 1674.
7.
Childs, M. E.; Weber, W. P. JOC 1976, 41, 3486.
8. Nii, Y.; Okano, K.; Kobayashi, S.; Ohno, M. TL 1979, 2517.

9. Caine, D. In Carbon-Carbon Bond Formation; Augustine, R. L., Ed.;
Dekker: New York, 1979; Vol. 1, pp 250-258.
10. (a) Stork, G.; Rosen, P.; Goldman, N.; Coombs, R. V.; Tsuji, J. JACS
1965, 87, 275. (b) Caine, D. OR 1976, 23, 1.
11. (a) House, H. O. Modern Synthetic Reactions; Benjamin: Menlo Park,
1972; pp 760-763. (b) Black, T. H. OPP 1989, 21, 179. (c) Seebach, D.;
Weller, T.; Protschuk, G.; Beck, A. K.; Hoekstra, M. S. HCA 1981, 64,
716. (d) cf. Ref. 5, p 258, footnote 69.
12. Crabtree, S. R.; Chu, W.-L. A.; Mander, L. N. SL 1990, 169.
13. (a) Ihara, M.; Suzuki, T.; Katogi, M.; Taniguchi, N.; Fukumoto, K.
JCS(P1) 1992, 865. (b) Haynes, R. K.; Katsifis, A. G. CC 1987,
340.
14. Hashimoto, S.; Kase, S.; Shinoda, T.; Ikegami, S. CL 1989, 1063.
15. cf. Mathews, R. S.; Girgenti, S. J.; Folkers, E. A. CC 1970, 708.
16. Ziegler, F. E.; Klein, S. I.; Pati, U. K.; Wang, T.-F. JACS 1985, 707,
2730.
17. Schuda, P. F.; Phillips, J. L.; Morgan T. M. JOC 1986, 51, 2742.
18. Ziegler, P. E.; Sobolov, S. B. JACS 1990, 112, 2749.
19. (a) Hanessian, S.; Faucher, A.-M. JOC 1991, 56, 2947. (b) Ziegler, F. E.;
Cain, W. T.; Kneisly, A.; Stirchak, E. P.; Wester, R. T. JACS 1988, 110,
5442. (c) Leonard, J.; Ouali, D.; Rahman, S. K. TL 1990, 31, 739.
20. McLure, C. K.; Jung, K.-Y. JOC 1991, 56, 2326.
21. Bennet, R. B.; Cha, J. K. TL 1990, 31, 5437.
22. (a) Melching, K. H.; Hiemstra, H.; Klaver, W. J.; Speckamp, W. N. TL
1986, 27, 4799. (b) Esch, P. M.; Hiemstra, H.; Klaver, W. J.; Speckamp,
W. N. H 1987, 26, 75. (c) Pirrung, F. O. H.; Rutjes, F. P. J. T.; Hiemstra,
H.; Speckamp, W. N. TL 1990, 31, 5365.
23. Mori, K.; Ikunaka, M. T 1987, 43, 45.
24. Barton, D. H. R.; Donnelly, D. M. X.; Finet, J. P.; Guiry, P. J.; Kielty, J.
M. TL 1990, 31, 6637.
25. Hashimoto, S.; Miyazaki, Y.; Shinoda, T.; Ikegami, S. CC 1990,
1100.
26. (a) Winkler, J. D.; Henegar, K. E.; Williard, P. G. JACS 1987, 109, 2850.
(b) Henegar, K. E.; Winkler, J. D. TL 1987, 28, 1051.
27. Kunisch, F.; Hobert, K.; Wetzel, P. TL 1985, 26, 5433.
28. Iimori, T.; Nii, Y.; Izawa T.; Kobayashi, S.; Ohno, M. TL 1979, 2525.
29. Potthoff, B.; Breitmaier, E. S 1986, 584.
30. (a) Krebs, A.; Franken, E.; Miiller, S. TL 1981, 22, 1675. (b) Fink, J.;
Regitz, M. BSF(2) 1985, 239.
31. Klaubert, D. H.; Bell, S. C.; Pattison, T. W. JHC 1985, 22, 333.
32. Deslongchamps, P.; Ruest, L. OS 1974, 54, 151.
33. Hellou, J.; Kingston, J. F.; Fallis, A. G. S 1984, 1014.
Next Page
276
N-METHYL-N,N'-DICYCLOHEXYLCARBODIIMIDIUM IODIDE
34.
35.
Snyder, H. R.; Brooks, L. A.; Shapiro, S. H. OSC 1943, 2, 531.

(a) Stiles, M. JACS 1959, 81, 2598. (b) Pelletier, S. W.; Chappell, R. L.;
Parthasarathy, P. C.; Lewin, N. JOC 1966, 1747.
36.
37.
38.
39.
Shahak, I. TL 1966, 2201.

Kende, A. S.; Becker, D. A. SC 1982,12, 829.
Vedejs, E.; Nader, B. JOC 1982, 47, 3193.
(a) Thesing, J.; Witzel, D.; Brehm, A. AE 1956, 68, 425. (b) Bayer,
O. MOC 1977, 7/2c, 2487. (c) Hunig, S.; Schaller, R. AG(E) 1982,
21, 36.
(1)
Lewis N. Mander
The Australian National University, Canberra, Australia
(2)
N-Methyl-N,N'-dicyclohexylcarbodiimidium Iodide
(3)
[36049-77-1]
C 1 4 H 2 5 IN 2
(MW 348.31)
(conversion of alcohols to iodides)

Physical Data: colorless hygroscopic crystals; mp 111-113 C.
Preparative Method: 1,3-Dicyclohexylcarbodiimide (42 g, 0.204
mol) was dissolved in a large excess of Iodomethane (90 mL,
1.45 mol) and stirred at 70 C for 3 days under a nitrogen at
mosphere. The excess MeI was removed by distillation under
reduced pressure and the residue was dissolved in dry toluene
(150 mL) at 40 C. The resulting crystalline mass was filtered
off under an inert atmosphere and the crystals were washed with
cold, dry toluene until colorless. The product was dried under
vacuum (0.1 mmHg) at rt to provide 35 g (75%) of colorless
crystals.
Handling, Storage, and Precautions: the compound should be
stored under an inert atmosphere at refrigerator temperatures,
where it is reputed to be stable for several months.
Conversion of Alcohols to Iodides. First reported in 1972, the

sole reported use of N-methyl-N,N'-dicyclohexylcarbodiimidium
idodide (1) is in the conversion of alcohols to iodides. The original
article1 contains the first description of the preparation in bulk of
a carbodiimidium salt and describes its use in the preparation of
some primary and secondary iodides. In three of the examples,
inversion of configuration was exclusive, (2) (4), hinting at a
mechanism such as that shown in eq 1. The reagent was said to
be good for the preparation of very hindered secondary iodides,
but the yields are generally low (eqs 2 and 3). The reagent is,
however, quite successful in preparing iodides from alcohols in
multifunctional compounds (6),2 (7), 3 and (8).4
1. R. Scheffold, R.; Saladin, E. AG(E) 1972, 11, 229.

2. Lischewski, M.; Adam, G. CA 1976, 85, 108 827u.
3.
4.
Gibson, A. R.; Vyas, D. M.; Szarek, W. A. CI(L) 1976, 67.

Scartazzini, R.; Bickel, H. CA 1974, 80, 95 974j.
Kim F. Albizati
University of California, San Diego, CA, USA
Previous Page
N-METHYL-N-NITROSO-p-TOLUENESULFONAMIDE
277
N-Methyl-N-nitroso-ptoluenesulfonamide
(1)
[80-11-5]
C8H10N2O3S
(MW 214.27)
(precursor of diazomethane1a)
Alternate Names: Diazald; p-tolylsulfonylmethylnitrosamide.
Solubility: sol petroleum ether, ether, benzene, alcohol, CHCl 3 ,
CCl 4 ; insol H 2 O.
Form Supplied in: pale yellow powder; commercially available.
Preparative Methods: prepared by the reaction of pToluenesulfonyl Chloride with methylamine, followed
by nitrosation with Sodium Nitrite in glacial acetic acid.1c
Purification: recrystallization is best achieved by dissolving the
reagent in hot ether (1 mL g - 1 ) , adding an equal volume of
petroleum ether (or pentane), and cooling in a refrigerator
overnight.1c
Handling, Storage, and Precautions: store in a brown bottle. Has a
shelf-life of at least 1 year at rt. For longer periods of storage, it is
recommended that the reagent be purified by recrystallization1c
and refrigerated. Toxic; severe skin irritant; handle only in a
fume hood.
General Discussion. Diazomethane

is a yellow gas
(bp - 2 3 C, mp - 1 4 5 C) with the dipole structure
C H 2 = N + = N - + C H 2 - N = N - - C H 2 - N = N + . This versa
tile compound behaves as a methylene precursor with release
of nitrogen and also functions as a 1,3-dipole in a variety of
reactions, as documented in several reviews.2 Diazomethane
itself is both highly toxic and unpredictably explosive, and has
been suggested to be a carcinogen.3 Great care must be taken
in handling this substance. However, these risks are minimal
when diazomethane is prepared and handled as a dilute solution
in an inert solvent such as ether using the proper equipment as
discussed below (for further discussion, see Diazomethane).
A large number of compounds which previously served as
diazomethane precursors can be represented by the formula
RN(NO)Me, where R can be sulfonyl, carbonyl, imidoyl, or
similar electron-withdrawing groups. Among these the reagent,
N-methyl-N-nitroso-p-toluenesulfonamide,
introduced by de
Boer and Backer in 1954,1a is the most common reagent
used for the preparation of diazomethane. However, in some
cases N-[N'-Methyl-N'-nitroso(aminomethyl)]benzamide
and
I-Methyl-3-nitro-l-nitrosoguanidine have advantages as diazo
methane precursors. In addition, N-mefhyl-N-nitroso-p-toluenesulfonamide does suffer from some drawbacks, including its
relatively short shelf life (1-2 years) and its mutagenic activity.4
Diazomethane is prepared as a dilute solution in ether by the de
composition (eq 1) of N-methyl-N-nitroso-p-toluenesulfonamide
catalyzed by alkali hydroxide.
This preparation and all reactions involving diazomethane

should be carried out in an efficient fume hood and behind a
sturdy safety shield. Rough surfaces and strong sunlight are known
to initiate detonation. Carefully fire-polished glassware for dia
zomethane preparation is commercially available.5 A typical ex
perimental procedure is as follows.1b A 125 mL, 3-neck flask is
charged with a solution of 6 g of potassium hydroxide in 10 mL of
water, 35 mL of 2-(2-ethoxyethoxy)ethanol (carbitol), and 10 mL
of ether, and is then fitted with an efficient condenser set down
ward for distillation. The condenser is connected to two receiving
flasks in series, both cooled in an ice-salt bath. The second receiver
contains 25 mL of ether and the inlet tube should dip below the sur
face of the solvent. The generating flask is heated in a water bath
at about 70 C, stirring is started (Teflon-coated magnetic stirring
bar), and a solution of 21.4 g (0.1 mol) of N-methyl-N'-nitroso-ptoluenesulfonamide in 125 mL of ether is added from the drop
ping funnel over about 20 min. The rate of addition should about
equal the rate of distillation. When the dropping funnel is empty,
50-100 mL of additional ether is added slowly. The distillation
is continued until the distilling ether is colorless. The combined
ethereal distillate contains 2.7-2.9 g (64-69%) of diazomethane.
The content of diazomethane in the codistilled ethereal solution
can be determined by titration; excess benzoic acid is added to
the solution (to react with diazomethane) and the excess acid is
titrated with a standard solution of NaOH. If moisture must be re
moved from the ethereal diazomethane solution, the drying agent
of choice is KOH pellets. It is recommended that diazomethane
solutions be used immediately and not stored, even at low
temperature.
An alternative popular procedure for the generation of small
quantities (1-50 mmol) of diazomethane from Diazald employs a
commercial 'mini-Diazald apparatus' with a dry-ice/acetone cold
finger in place of the water-jacketed condenser.5 The generation
of diazomethane is carried out by treatment of the Diazald with
KOH in aqueous ethanol.2g
Related
Reagents. Diazomethane;
l-Methyl-3-nitro-lnitrosoguanidine;
N-Mefhyl-N-nitrosoacetarnide
N-[N'Methyl-N'-nitroso(aminomethyl)]benzamide.
1. (a) de Boer, T. J; Backer, H. J. RTC 1954, 73, 229. (b) de Boer, T. J.;
Backer, H. J. OSC 1963, 4, 250. (c) de Boer, T. J.; Backer, H. J. OSC
1963, 4, 943.
2.
(a) Gutsche, C. D. OR 1954,8, 364. (b) Eistert, B.; Regitz, M.; Heck, G.;
Schwall, H. MOC 1968, 1014, 482. (c) Fieser L. F.; Fieser F. FF 1967,
7,191. (d) Pizey, J. S. Synthetic Reagents; Wiley: New York, 1974; Vol
2, Chapter 2, p 65. (e) Herrmann, W. A. AG(E) 1978, 17, 800. (f) Adam,
W.; De Lucchi, O. AG(E) 1980,19,762. (g) Black, T. H. Aldrichim. Acta
1983, 16, 3.
3.
Schoental, R. Nature (London) 1960, 188, 420.

278
METHYL FLUOROSULFONATE AND METHYL TRIFLUOROMETHANESULFONATE
4.
(a) Bignami, M.; Carere, A.; Conti, G; Conti, L.; Crebelli, R.; Frabrizi,
M. Mutat. Res. 1982, 97, 293. (b) Druckrey, H.; Preusmann, R. Nature
(London) 1962, 195, 1111.
5.
Aldrich Chemical Company, Inc.
Yoshiyasu Terao & Minoru Sekiya

University of Shizuoka, Japan
Methyl Fluorosulfonate and Methyl

(R = CF3)
[333-27-7]
(R=F)
[421-20-5]
C2H3F3O3S
(MW 164.12)
CH3FO3S
(MW 114.11)
(powerful methylating agents 1,2 )

Alternate Name: R = CF 3 , methyl triflate; R = F, Magic Methyl.
Physical Data: methyl triflate: bp 99 C, mp - 6 4 C, d
1.50 g c m - 3 . Methyl fluorosulfonate: bp 92C, mp - 9 2 . 5 C ,
d 1.45 g c m - 3 .
Solubility: both reagents are miscible with all organic solvents,
but react with many. They are only sl sol water, but hydrolyze
rapidly as they dissolve. Useful inert solvents are CH 2 Cl 2 , SO 2 ,
sulfolane, nitromethane, Me 2 SO 4 , and Me 3 PO 4 .
Form Supplied in: methyl triflate (MeOTf) is available as a color
less liquid. Methyl fluorosulfonate (MeOSO 2 F) was formerly
available as Magic Methyl but has been withdrawn (see be
low).
Analysis of Reagent Purity: MeOTf gives a singlet in 1H NMR
at 8 4.18, with 13C absorption at 8 61.60 and 119.32 (q), and a
19
F shift of 75.4 ppm. MeOSO 2 F absorbs at 4.19 in 1H NMR
(J H F 0.4 Hz or less), with 13C absorption at 8 62.45, and a 19 F
shift of - 3 1 . 2 ppm. 33 S and 17O NMR data have been reported
for both compounds. 9
Preparative Methods: both reagents are prepared 3,4 by distilling
an equimolar mixture of the corresponding acid with Dimethyl
Sulfate in an all-glass apparatus with a short Vigreux column.
They may be dried by standing over fused K 2 CO 3 and redis
tillation. Trifluoromethanesulfonic Acid and Fluorosulfutic
Acid are both available, and are comparably priced.
Handling, Storage, and Precautions: both reagents are extremely
hazardous. All possible precautions should be taken to avoid
inhalation or absorption through the skin. A fatality has
occurred with MeOSO 2 F through inhalation of the vapors
leading to pulmonary edema. 5 Dexamethasone isonicotinate
(Auxiloson spray) has been recommended as a first aid in
the treatment of such pulmonary irritation.5 The oral LD 50 of
MeOSO 2 F is 112 mg/kg in mice, and an LC 50 for 1 h expo
sure for rats between 5 and 6 ppm has been reported; severe
eye irritation was noted.6 It is very unlikely7 that MeOTf is
less dangerous, but no data on toxicity have been reported.
Both materials are extremely destructive to the tissue of the
mucous membranes and upper respiratory tract, eyes, and skin.

Inhalation may be fatal as a result of spasm, inflammation, and
edema of the larynx and bronchi, chemical pneumonitis, and
pulmonary edema. Use in a fume hood.
The reagents are stable in glass when dry, but storage of
MeOSO 2 F in bottles with ground glass joints should be avoided
as these slowly become fused. It is reported8 that MeOSO 2 F after
storage over CaH2 for two weeks contained 17% Me 2 SO 4 .
General Reactivity. MeOTf and MeOSO 2 F are two of the

most powerful reagents for methylation and are more reactive
by a factor of ~ 1 0 4 than Iodomethane and Me 2 SO 4 . 1,2 The
only reagents which are substantially more powerful are Methyl
Fluoride-Antimony(V) Fluoride and related reagents 10 and the
dimethylhalonium ions; these reagents pose more severe handling
problems. The reactivity of MeOTf and MeOSO 2 F is not effec
tively enhanced by addition of Lewis acids. Thus addition of Antimony(V) Chloride to MeOSO 2 F and Dimethyl Sulfone led to
complexation of the sulfone rather than methylation;11 it is also
reported that addition of SbCl5 leads to formation of MeCl. 12
The qualitative reactivity of some methylating agents toward
a range of functional groups is shown in tabular form (Table l). 1
Few quantitative data are available, but MeOTf and MeOSO 2 F are
only a little less reactive than the trimethyloxonium ion, with the
dimethoxycarbenium ion probably somewhat more reactive again.
Substitution rates with various nucleophiles are reported to be in
the order: Me 3 O + >MeOTf>MeOSO 2 F>MeOClO 3 , with rate
ratios of 109:23:8:6:1.0 for reaction with acetonitrile at 0 C. 13,14
Methyl perchlorate, an explosion hazard, therefore never offers a
practical advantage. Our experience is that the relative rates for
MeOTf and MeOSO 2 F rarely differ by more than a factor of 2-5.
It is noteworthy that neither MeOTf nor MeOSO 2 F shows any
reactivity on their own in Friedel-Crafts methylation reactions
even with highly reactive substrates (Me 3 O + ion is similar). Re
action has been observed in the presence of protic or Lewis acids. 15
Olah has recently suggested that this reactivity is associated
with generation of superelectrophiles by further protonation.16
MeOSO 2 F has been reported to react as a methylsulfonylating
agent towards phenol and anisole, 17 but this alternative reactivity
is usually not significant.
The alkylation reactions of MeOTf and MeOSO 2 F are discussed
according to the atom alkylated. To avoid unnecessary repeti
tion, reactions can be assumed to use MeOTf unless MeOSO 2 F is
specified. Historically, MeOSO 2 F was mainly used up until about
1980, but MeOTf has since become the reagent of choice. In the
great majority of cases these reagents can probably be used inter
changeably.
Alkylation at Nitrogen. Most amines react violently with
MeOTf or MeOSO 2 F, and only those with severe steric hin
drance or conjugated with strong electron-withdrawing groups
really require the use of these reagents. Of derivatives with sp 3 ni
trogen, Diisopropylamine, N',2,2,6,6-pentamethylpiperidine, and
l,8-Bis(dimethylamino)naphthalene
(Proton Sponge) can all
be quaternized by MeOSO 2 F, and N,N,2,6-tetramethylaniline
reacts on heating.1 However, it has been reported that iPr 3 N does not react with MeOSO 2 F. 19 2,6-Lutidine reacts
exothermically with MeOSO 2 F at room temperature, and 2,6-

Table 1 Reactivity
of Methylating Agents towards Functional Groups

Approx.
PK a 18
Me 3 N
Pyridine
Me 2 S
Me 2 SO
HCONMe 2
MeCN
Me2O
PhCHO
R 2 CO
Lactone
Ester
MeI
MeNO 2
Me 2 SO 2
279
9
5
1
0
0
-10
-5
-6
-6
-7
-7
?
-10
-10
MeI
Me 2 SO 4
+
+
+
+
+
+
+
+
MeOSO 2 F
(MeOTf)
++
++
++
+
+
+
+
+
(+)
(+)
Me 3 O +
HC(OMe) 2 +
Me 2 Cl +
++
++
++
+
+
+
++
++
++
+
+
+
+
+
++
++
++
++
++
+
+
+
+
+
+
+
+
+
(+)
+
+
(+)
Key: ++ methylation occurs and may be strongly exothermic; + methylation occurs; - little reaction; (+) equilibrium transfer reaction; - reaction is
complex.
dimethoxycarbonylpyridine can be quantitatively quaternized.1

A range of [n](2,6)-pyridinophanes have been methylated with
MeOSO 2 F, with n as small as 6 (eq 1). 20
(1)
2,6-Di-t-butylpyridine does not react at normal pressure, and

this or 2,6-di-t-butyl-4-mefhylpyridine (synthesis21), are often
used in applications which require base (see below). Note that
2,6-di-t-butylpyridine can be alkylated under high pressure with
MeOSO 2 F to give >90% of the methylation product when water
is carefully excluded.22
Simple imines, such as benzylideneaniline, react readily. The Nmethylation of imine and amidine derivatives of amino acid esters,
followed by hydrolysis, has been used as a method for the prepa
ration of N-alkylated amino acids with minimal racemization.23 A
convenient synthesis of N-methyl nitrones has been developed by
alkylation of OTMS oximes with MeOTf, followed by treatment
with fluoride ion.24
Besides the pyridine derivatives already mentioned, most hete
rocyclic nitrogens can be alkylated. Aspects of the quaternization of heteroaromatics have been recently reviewed.25 With
respect to the limits of reactivity, it is interesting that dimethylation of 2-phenyl-4,6-dimethylpyrimidine could only be achieved
with Trimethyloxonium Tetrafluoroborate; MeOSO 2 F only gave
monoalkylation.26 2-Benzoylbenzothiazole can be N-alkylated
with MeOSO 2 F (but not with MeI) and then acts as an active
acylating agent.27 Formation of an N-methylindole from an Nethoxycarbonylindole has been achieved with MeOSO 2 F. 28
A number of alkylation products from MeOTf and heterocycles have been advocated as useful intermediates.
Thus treatment of 2-substituted thiazoles with MeOTf
in acetonitrile, followed by reduction of the salt formed
with Sodium Borohydride/CuO
in CH 2 Cl 2 , leads to
aldehydes.29 l-(Benzenesulfonyl)-3-methylimidazolium
and
l-(p-toluenesulfonyl)-3-methylimidazolium triflates have been
proposed as efficient reagents for the preparation of aryl sul
fonamides and aryl sulfonates.30 MeOTf alkylates 2,5-oxazoles
to give salts which can be reduced by PhSiH 3 /CsF to give
4-oxazolines, and these provide a route to stabilized azomethine
ylides.31
A novel synthesis of 2-aryl-4-piperidones by Mannich cyclization of imino acetals, initiated by methylation of the imine,
has been described.32 MeOTf has been used in the generation
of a munchnone for cycloaddition.33 Finally, methylation of 1lithio-2-n-butyl-l,2-dihydropyridine with MeOTf gives 2-butyl5-methylpyridine in 42% yield.34
Nitriles, with sp hybridized nitrogen, are unreactive to MeI or
Me 2 SO 4 , but are readily methylated by MeOSO 2 F, 1 MeOTf,35 or
oxonium ions. Nitrilium salts have been shown to have a num
ber of useful applications. The reduction of nitrilium salts by
NaBH 4 in alcohols leads first to iminoethers and subsequently
to amines.36 Reduction of N-alkylnitrilium ions by organosilicon
hydrides gives n-alkylaldimines, and thus provides a route to alde
hydes from nitriles.37 Nitrilium triflate salts have been shown to
be useful reagents for the synthesis of ketones and ketenimines
by electrophilic substitution of reactive aromatics, and also pro
vide good routes to amidinium, imidate, and thioimidate salts. 35
Reaction with 2-amino alcohols gives oxazolidines.38 Synthesis
of either 5-substituted 1 -methyl- 1H-tetrazoles or 3,5-disubstituted
1,4-dimethyltriazolium salts from N-methylnitrilium triflate salts
can be controlled in reactions with (Me 2 N) 2 C=NH 2 + N 3 - . 3 9 Re
action of nitrilium ions with alkyl azides gives 1,2,3-trisubstituted
tetrazolium salts.40 These can be deprotonated to highly reactive
2-methy lenetetrazoles . 41
Amides are alkylated largely on oxygen, as expected (see be
low), although some N-alkylation can be seen by NMR. 1 NAlkylation is more apparent with carbamates (see the section on
ambident nucleophiles). N,N-Dimethylmethanesulfonarnides can
be N-alkylated (MeOSO 2 F) to provide salts which are effective
reagents for mesylation.42 N,N-Dimethylsulfamate esters react
280
with MeOSOaF to give trimethylammoniumsulfate esters, which

rapidly give methyl esters unless the O-group is aryl, showing that
Me 3 N + SO 3 - is a very powerful leaving group. 43 Me 3 N + SO 2 OPh
reacts with nucleophiles at either the sulfur or a methyl carbon
atom.44
Azo compounds, which do not react with methyl iodide, can be
N-methylated by MeOSO 2 F. 45
A steroidal oxaziridine was converted (MeOSO 2 F) to an oxaziridinium salt which showed oxidizing properties.46
Alkylation at Oxygen. Most neutral functionalities with lone
pairs on oxygen are not alkylated by MeI or Me 2 SO 4 but do re
act with MeOTf or MeOSO 2 F, although not all such reactions
are preparatively useful.1,2 Ethers react reversibly, and the ulti
mate product depends on the conditions. Thus good yields of the
oxonium ion can be obtained from reaction of THF with stoichio
metric amounts of MeOTf, but the use of catalytic amounts leads
to polymerization. Cationic ring opening polymerization, initi
ated by MeOTf and MeOSOaF among other reagents, has been
extensively investigated and recently reviewed.47
Reaction of MeOSOaF with 2-methoxyethyl carboxylates gives
2-alkyl-l,3-dioxolanium ions. 1 The reaction of these ions with
trialkylalkynylborate anions provides versatile and direct routes
to (Z)-,-unsaturated ketones (eq 2). Specifically protected 1,3diketones and other ketonic species can also be prepared from the
intermediates.48
(2)
Almost all carbonyl functions can be methylated. Enolizable aldehydes and ketones usually lead to complex mix
tures, probably because of deprotonation to enol ethers, fol
lowed by reaction of these with the electrophilic species in
the reaction mixture. Nonenolizable aldehydes and ketones
give methoxycarbenium ions cleanly, and the relative thermo
dynamic stabilities of these have been assessed via pairwise
equilibrations.49 Most esters only generate low equilibrium con
centrations of dialkoxycarbenium ions, but lactones are readily
alkylated.1
Amides, carbamates, and ureas are rapidly alkylated, usually on
carbonyl oxygen (see the section on ambident nucleophiles). Alky
lation of amides with MeOT5f in CH 2 Cl 2 followed by reduction
of the salts provides a route for the selective reduction of amides;
esters, nitriles, acetals, and double bonds are left unaffected by
this procedure. 50 Alkylation of isoindolin-1-ones and subsequent
deprotonation can provide routes to methoxyisoindoles.51
Alcohols can be converted to methyl ethers by the
use of MeOTf + 2,6-di-t-butylpyridine or 2,6-di-t-butyl-4methylpyridine. This procedure was initially developed in the
carbohydrate field.52 Me 3 PO 4 provides a good polar solvent for
this process. 53 A recent application, in the synthesis directed
at lonomycin, was to methylation of the complex alcohol (1)
without causing retro-aldol cleaveage.54
MeOTf has been reported to effect complete methylation of

inositol polyphosphates, P-OMe groups being formed as well. 55
MeOTf will effect O-alkylation at the anomeric center, but the
stereochemistry is affected by the presence of a crown ether.56
Reaction of Meisenheimer complexes with MeOSO 2 F can lead to
capture of the anion as a nitronate ester.57
Alkylation at Sulfur and Selenium. Dialkyl and most arylalkyl sulfides are readily converted into sulfonium salts.1 Cyclic
sulfides, especially dithiolanes, react somewhat faster.58 Reaction
of disulfides with MeOTf gives Me 2 SSMe+ OTf - ; this salt, with
Triphenylphosphine, reacts with alkenes in a stereo- and regioselective fashion and the products can be converted into vinylphosphonium salts.59 Thione groups are also alkylated even when
electronegative groups are present. Thus 4,5-bis(trifluoromethyl)1,3-dithiolane-2-thione was converted into a methylated salt.60
Sulfoxides are O-alkylated,1 and formation of various oxa- and
azasulfonium ions has been reported, up to and including triazasulfonium salts. 61 Alkylation of R 2 SO with MeOSO 2 F, fol
lowed by reduction with Sodium Cyanoborohydride, leads to
sulfides.62
Reaction of MeOTf with the product from P 2 S 5 /Na 2 CO 3
(Na 2 P 4 S 10 O) gave a useful electrophilic thionation reagent.63
MeOSOaF has been used in the conversion of thiols to reactive
sulfenating agents (eq 3). 64
(3)
Methylation of dithioacetals by MeOSO 2 F, followed by reac

tion with various nucleophiles, has been used for the removal of
this protecting group or its conversion into other protecting groups,
e.g. acetals (eq 4). 6 5 - 6 8
(4)
The reaction of the sulfonium intermediate with alcohols leads

to their protection as hemithioacetals.69 Treatment of thioglycosides with MeOTf gives an efficient glycosylating agent,70
and pyruvic acetal formation from a pyruvyl thioacetal has
been achieved in a reaction catalyzed by MeOTf (amongst other
electrophiles).71
Alkenes can be prepared by methylation of selenides by
MeOSO 2 F and treatment of the selenonium ions formed with
Potassium t-Butoxide. 72
Alkylation at Phosphorus. Phosphines and phosphites

undergo easy quaternization. Thus methylation of tris(2,6dimethylphenoxy)phosphine with MeOTf, followed by treatment
of the product with sodium 2,6-dimethylphenoxide, gave
methyltetrakis(2,6-dimethylphenoxy)phosphane.73
Methoxyphosphonium triflates are relatively stable intermediates in
Arbuzov reactions.74 Phosphine oxides and sulfides are alkylated.
S-Methylation of chiral phosphine sulfides, followed by treatment
with Hexamethylphosphorous Triamide, has been advocated as
a general synthesis of optically active phosphines.75
Ambident Nucleophiles. Amides and related functional
groups can be alkylated on oxygen or nitrogen and, as has been
noted already, alkylation on carbonyl oxygen normally predomi
nates. In the case of carbamates, O-alkylation by MeOSO2F can
be faster, but N-alkylation predominates at equilibrium.76 It has
been noted that methylation of secondary amides and thioamides
occurs at the protonless heteroatom in the major tautomer.77 The
ionic products of these reactions can be deprotonated to give syn
thetically useful products, e.g. imidates,78 but excess MeOSO2F
should be removed before treatment with base.77
Reaction of most enolates with MeOTf or MeOSO2F is al
ways likely to be kinetically controlled. There does not appear
to have been a definitive study, but O-alkylation is the normal
outcome. O-Alkylation of a bicyclodecatrienone by MeOSO2F is
enhanced by the use of polar solvents like HMPA.79 O- Alkylation
of enolates of appropriate cyclohexadienones by MeOTf has been
used to generate various 3aH-indenes.80 A ketene acetal is formed
by exclusive O-alkylation of the sodium enolate of isopropyl
bis(pentachlorophenyl)acetate by MeOTf.81
Alkylations at Carbon. In an important recent develop
ment, primary -alkylation of carbonyl compounds under nonbasic conditions has been achieved (eq 5) by alkylation of
silyl enol ethers with MeOTf and other primary alkyl tri
flates, catalyzed by Methylaluminum Bis(4-bromo-2,6-di-tbutylphenoxide) (MABR).82
(5)
Related Reagents. Dimethoxycarbenium Tetrafluoroborate;

Dimethyliodonium Hexafiuoroantimonate; Dimethyl Sulfate; OMethyldibenzofuranium Tetrafluoroborate; Methyl iodide; Trimethyloxonium Tetrafluoroborate.
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Roger W. Alder & Justin G. E. Phillips

Montmorillonite K10
[1318-93-0]
(catalyzes protection reactions of carbonyl and hydroxy

groups; promotes ene, 22 condensation,25 and alkene addition27
reactions)
Physical Data: the surface acidity of dry K10 corresponds to a
Hammett acidity function H0 = - 6 to - 8 . 1 3
Form Supplied in: yellowish-grey dusty powder. Formres with wa

ter a mud that is difficult to filter, more easily separated by centrifugation; with most organic solvents, forms a well-settling,
easy-to-filter suspension.6
Handling, Storage, and Precautions: avoid breathing dust; keep
in closed containers sheltered from exposure to volatile com
pounds and moisture.
General. Montmorillonite clays are layered silicates and are

among the numerous inorganic supports for reagents used in or
ganic synthesis. 1,2 The interlayer cations are exchangeable, thus
allowing alteration of the acidic nature of the material by simple
ion-exchange procedures. 3,4 Presently, in fine organic synthesis,
the most frequently used montmorillonite is K10, an acidic cata
lyst, manufactured by alteration of montmorillonite (by calcina
tion and washing with mineral acid; this is probably a proprietary
process).
The first part of this article specifically deals with representa
tive laboratory applications to fine chemistry of clearly identified,
unaltered K10, excluding its modified forms (cation-exchanged,
doped by salt deposition, pillared, etc.) and industrial uses in
bulk. This illustrative medley shows the prowess of K10 as a
strong Br0nsted acidic catalyst. The second part deals with cationexchanged (mainly Fe III ) montmorillonite. Clayfen and claycop,
versatile stoichiometric reagents obtained by metal nitrate depo
sition on K10, 5 are used in oxidation and nitration reactions. They
are treated under Iron(III) Nitrate-K10 Montmorillonite Clay
and Copper(II) Nitrate-K10 Bentonite Clay.
K10 is often confused, both in name and in use, with other
clay-based acidic catalysts (KSF, K10F, Girdler catalyst, 'acid
treated' or 'H + -exchanged' montmorillonite or clay, etc.) that can
be effectively interchanged for K10 in some applications. Between
the 1930s and the 1960s, such acid-treated montmorillonites were
common industrial catalysts, especially in petroleum processing,
but have now been superseded by zeolites.
Activation.6 K10 clay may be used crude, or after simple ther
mal activation. Its acidic properties are boosted by cation exchange
(i.e. by iron(III)7 or zinc(II)8) or by deposition of Lewis acids, such
as zinc(II) 9,10 or iron(III) 11 chloride (i.e. 'clayzic' and 'clayfec').
In addition, K10 is a support of choice for reacting salts, for exam
ple nitrates of thallium(III),12 iron(III) ('clayfen'), 5 or copper(II)
('claycop'). 5 Multifarious modifications (with a commensurate
number of brand names) result in a surprisingly wide range of ap
plications; coupled with the frequent imprecise identification of
the clay (K10 or one of its possible substitutes mentioned above),
they turn K10 into a Proteus impossible to grab and to trace ex
haustively in the literature.
Preparation of Acetals. Trimethyl orthoformate (see Triethyl
Orthoformate) impregnated on K10 affords easy preparation of
dimethyl acetals,14 complete within a few minutes at room tem
perature in inert solvents such as carbon tetrachloride or hexane
(eq 1). The recovered clay can be reused.
(1)
MONTMORILLONITE K10
283
Cyclic diacetals of glutaraldehyde are prepared in fair yields by

K10-promoted reaction of 2-ethoxy-2,3-dihydro-4H-pyran with
diols, under benzene azeotropic dehydration (eq 2). 15
(5)
(2)
Diastereoisomeric acetal formation catalyzed by K10 has been

applied to the resolution of racemic ketones, with diethyl (+)(R,R)-tartrate as an optically active vicinal diol.16
1,3-Dioxolanes are also prepared by K10-catalyzed reaction of
l-chloro-2,3-epoxypropane (Epichlorohydrin) with aldehydes or
ketones, in carbon tetrachloride at reflux (eq 3). 17 In the reaction
of acetone with the epichlorohydrin, the efficiency of catalysts
varies in the order: K10 (70%) > Tin(IV) Chloride (65%)>Boron
Trifluoride (60%) = Hydrochloric Acid (60%) > Phosphorus(V)
Oxide (57%).
50:50 mixture
44:49
of diastereoisomers 78%
(6)
Preparation of Monoethers of
3-Chloro-l,2-propanediol.
Alcohols react regioselectively with l-chloro-2,3-epoxypropane
to form l-alkoxy-2-hydroxy-3-chloropropanes. The K10catalyzed process is carried out in refluxing carbon tetrachloride
for 2.5 h (eq 7). 24 Yields are similar to those obtained by Sulfuric
Acid catalysis.
(3)
(7)
Preparation of Enamines. Ketones and amines form enamines in the presence of K10 at reflux in benzene or toluene, with
azeotropic elimination of water (eq 4). Typical reactions are over
within 3-4 h. With cyclohexanone, the efficiency depends on the
nature of the secondary amine: Pyrrolidine (75%) > Morpholine
(71%)>Piperidine (55%)>Dibutylamine (34%). 18 Acetophenone requires longer heating.19
(4)
The K10-catalyzed reaction of aniline with -keto esters gives

enamines chemoselectively, avoiding the competing formation of
anilide observed with other acidic catalysts. 20,21
Synthesis of -Lactones via the Ene Reaction. K10 catalyzes
the ene reaction of diethyl oxomalonate and methyl-substituted
alkenes at a rather low temperature for this reaction (80 C), fol
lowed by lactonization (eq 5). 22 When alkene isomerization pre
cedes the ene step, it results in a mixture of lactones. Using kaolinite instead of K10 stops the reaction at the ene intermediate, before
lactonization.
Synthesis of Enol Thioethers. Using a Dean-Stark water sep
arator, K10 catalyzes formation of alkyl- and arylthioalkenes from
cyclic ketones and thiols or thiophenols, in refluxing toluene
(eq 6). A similar catalysis is effected by KSF (in a faster reac
tion) and K10F. 23 The isomer distribution is under thermodynamic
control.
,-Umaturated Aldehydes via Condensation of Acetals with

Vinyl Ethers. K10-catalyzed reaction of diethyl acetals with
Ethyl Vinyl Ether leads to 1,1,3-trialkoxyalkanes. Hydrolysis
turns these into tran---unsaturated aldehydes. 25 The reaction
is performed close to ambient temperatures (eq 8). K10 is supe
rior to previously reported catalysts, such as Boron Trifluoride
or Iron(III) Chloride. The addition is almost instantaneous and
needs no solvent. Cyclohexanone diethyl acetal gives an analo
gous reaction.
(8)
Protective Tetrahydropyranylation of Alcohols and Phe

nols. With an excess of 3,4-Dihydro-2H-pyran, in the presence of
K10 at room temperature, alcohols are transformed quantitatively
into their tetrahydropyranyl derivatives. Run in dichloromethane
at room temperature, the reaction is complete within 5-30 min
(eq 9). The procedure is applicable to primary, secondary, tertiary,
and polyfunctional alcohols as well as to phenols. 26
(9)
284
MONTMORILLONITE K10
Markovnikov Addition of Hydrochloric Acid to Alkenes. 1 Chloro-1 -methylcyclohexane, the formal Markovnikov adduct of
hydrochloric acid and 1-methylcyclohexene, becomes largely pre
dominant when Sulfuryl Chloride is the chlorine source and K10
the solid acid.27 The reaction at 0C, in dry methylene chloride,
is complete within 2 h (eq 10).
(12)
(13)
(10)
1,1:1,2 = 91:9
(14)
Porphyrin Synthesis. Meso-tetraalkylporphyrins are formed

in good yields from condensation of aliphatic aldehy
des with pyrrole; thermally activated K10 catalyzes the
polymerization-cyclization to porphyrinogen, followed by pChloranil oxidation (eq 11). 28
The role of FeIII-impregnated montmorillonite, and other

cation-exchanged montmorillonites, in asymmetric Diels-Alder
reactions was found to be limited to the use of small chiral aux
iliaries; the results obtained from these reactions are similar to
those of homogeneous aluminum catalysts (eq 15). 33
(11)
Meso-tetraarylporphyrins, with four identical or with tuneable

ratios of different aryl substituents, are made by taking advantage
of modified K10 ('clayfen' or FeIII-exchanged) properties. 29,30
(15)
Iron(III)-Doped Montmorillonite.
General Considerations. The acid strength of some cationexchanged montmorillonites is between Methanesulfonic Acid
(a strong acid) and Trifluoromethanesulfonic Acid (a superacid)
and, in some instances, their catalytic activity is greater than that
of a superacid.31 Iron montmorillonite is prepared by mixing the
clay with various FeIII compounds in water.8,32 The resulting ma
terial is filtered and dehydrated to afford the active solid-acid cat
alyst. These solid-acid catalysts are relatively inexpensive and are
generally used in very small quantities to catalyze a wide variety
of reactions, including Friedel-Crafts alkylation and acylation,
Diels-Alder reactions, and aldol condensations. 1,5
Diels-Alder Reactions.33 Stereoselective Diels-Alder reac
tions involving an oxygen-containing dienophile are acceler
ated in the presence of FeIII-doped montmorillonite in organic
solvents (eq 12).34 Furans also undergo Diels-Alder reactions
with Acrolein and Methyl Vinyl Ketone in CH 2 Cl 2 to give
the corresponding cycloadducts in moderate yield (eq 13).35
The iron-doped clay also catalyzes the radical ion-initiated selfDiels-Alder cycloaddition of unactivated dienophiles such as 1,3cyclohexadiene and 2,4-dimethyl-l,3-pentadiene (eq 14).36
Friedel-Crafts
Acylation
and Alkylation.37,38 The
Friedel-Crafts acylation of aromatic substrates with vari
ous acyclic carboxylic acids in the presence of cation-exchanged
(H + , Al 3 + , Ni 2 + , Zr 2 + , Ce 3 + , Cu 2 + , La 3 + ) montmorillonites has
been reported.39 Curiously, the use of iron-doped montmoril
lonite was not included in the report; however, some catalysis is
expected. Under these conditions, the yield of the desired ketones
was found to be dependent on acid chain length and the nature of
the interlayer cation.
The direct arylation of a saturated hydrocarbon, namely
adamantane, in benzene using FeCl3-impregnated K10 was re
cently reported.11 Additionally, Friedel-Crafts chlorination of
adamantane in CCl4 using the same catalyst was also reported. The
alkylation of aromatic substrates with halides under clay catal
ysis gave much higher yields than conventional Friedel-Crafts
reactions employing Titanium(IV) Chloride or Aluminum Chloride as catalyst.8 Higher levels of dialkylation were observed in
some cases. The alkylation of aromatic compounds with alcohols
and alkenes was also found to be catalyzed with very low levels
of cation-exchanged montmorillonites, as compared to standard
Lewis acid catalysis; however, iron-doped clays performed poorly
compared to other metal-doped clays.
2-MORPHOLINOETHYL ISOCYANIDE
A Idol Condensations. Cation-exchanged montmorillonites ac
celerate the aldol condensation of silyl enol ethers with acetals and
aldehydes. 40 Similarly, the aldol reaction of silyl ketene acetals
with electrophiles is catalyzed by solid-acid catalysts. Neither re
port discussed the use of iron montmorillonite for these reactions;
however, some reactivity is anticipated.
Miscellaneous Reactions. The coupling of silyl ketene ac
etals (enolsilanes) with pyridine derivatives bearing an electronwithdrawing substituent, namely cyano, in the meta position is
catalyzed by iron montmorillonite and other similar solid-acid
catalysts (eq 16).41
(16)
25.
26.
Fishman, D.; Klug, J. T.; Shani, A. S 1981, 137.

Hoyer, S.; Laszlo, P.; Orlovic, M.; Polla, E. S 1986, 655.
27.
Delaude, L.; Laszlo, P. TL 1991, 32, 3705.
28.
29.
Onaka, M.; Shinoda, T.; Izumi, Y.; Nolen, R. CL 1993, 117.

Cornlis, A.; Laszlo, P.; Pennetreau, P. Clay Minerals 1983, 18,
437.
30.
Laszlo, P.; Luchetti, J. CL 1993, 449.
31.
32.
Kawai, M.; Onaka, M.; Isumi, Y. BCJ 1988, 61, 1237.

Tennakoon, D. T. B.; Thomas, J. M.; Tricker, M. J.; Williams, J. O.
JCS(D) 1974, 2207.
33.
Cativiela, C.; Figueras, F.; Fraile, J. M.; Garcia, J. I.; Mayoral, J. A. TA

1993, 4, 223 and references therein.
34. Laszlo, P.; Lucchetti, J. TL 1984, 25, 2147.
35. Laszlo, P.; Lucchetti, J. TL 1984, 25, 4387.
36.
37.
38.
Laszlo, P.; Lucchetti, J. TL 1984, 25, 1567.

Olah, G. A. Friedel-Crafts Chemistry; Wiley: New York, 1973.
Olah, G. A.; Reddy, V. P.; Prakash, G. K. S. In Kirk-Othmer Encyclopedia
of Chemical Technology, 4th ed.; Wiley: New York, 1994; Vol. 11,
p 1042.
39.
Chiche, B.; Finiels, A.; Gauthier, C.; Geneste, P.; Graille, J.; Piock, D.
J. Mol. Catal. 1987, 42, 229.
Onaka, M.; Ohno, R.; Kawai, M.; Isumi, Y. BCJ 1987, 60, 2689.
Onaka, M.; Ohno, R.; Izumi, Y. TL 1989, 30, 747.
R1 = Me, Et; R2 = H, Me; R3 = H, Me
The resulting N-silyldihydropyridines easily undergo desilylation by treatment with Cerium(IV) Ammonium Nitrate to afford
the desired dihydropyridine derivative. The reactivity was found
to be dependent on the montmorillonite counterion and to follow
the order: Fe 3 + > Co 2 + > Cu 2+ Zn 2 + > Al 3 + Ni 2 + Sn 4 + .
285
40.
41.
Andr Cornlis & Pierre Laszlo

Universit de Lige, Belgium
Mark W. Zettler
The Dow Chemical Company, Midland, MI, USA
1. Cornlis, A.; Laszlo, P. SL 1994, 155.

2. McKillop, A.; Young, D. W. S 1979, 401.
3. Theng, B. K. G. The Chemistry of Clay-Organic Reactions; Hilger:
London, 1974.
4. Thomas, J. M. In Intercalation Chemistry; Whittingham, M. S.;
Jacobson, J. A., Eds.; Academic: New York, 1982; p 55.
5. Cornlis, A.; Laszlo, P. S 1985, 909.
6.
7.
8.
9.
10.
11.
12.
13.
Cornells, A. In Preparative Chemistry Using Supported Reagents;

Laszlo, P., Ed.; Academic: New York, 1987; pp 99-111.
Cornells, A.; Gerstmans, A.; Laszlo, P.; Mathy, A.; Zieba, I. Catal. Lett.
1990, 6, 103.
Laszlo, P.; Mathy, A. HCA 1987, 70, 577.
Clark, J. A.; Kybett, A. B.; Macquarrie, D. J.; Barlow, S. J.; Landon, P.
CC 1989, 1353.
Cornlis, A.; Laszlo, P.; Wang, S. TL 1993, 34, 3849.
Chalais, S.; Cornlis, A.; Gerstmans, A.; Kolodziejski, W.; Laszlo, P.;
Mathy, A.; Mtra, P. HCA 1985, 68, 1196.
Taylor, E. C.; Chiang, C.-S.; McKiilop, A.; White, J. F. JACS 1976, 98,
6750.
Pennetreau, P. PhD Thesis, University of Liege (Belgium), 1986.
14. Taylor, E. C ; Chiang, C.-S. S 1977, 467.

15. Vu Moc Thuy; Maitte, P. BSF(2) 1979, 264.
16. Conan, J. Y.; Natat, A.; Guinot, F.; Lamaty, G. BSF(2) 1974,
1400.
17. Vu Moc Thuy; Petit, H.; Maitte, P. BSB 1980, 89, 759.
18. Hnig, S.; Benzing, E.; Lcke, E. CB 1957, 90, 2833.
19. Hnig, S.; Hbner, K.; Benzing, E. CB 1962, 95, 926.
20. Werner, W. T 1969, 25, 255.
21. Werner, W. T 1971, 27, 1755.
22.
23.
24.
Roudier, J.-F.; Foucaud, A. TL 1984, 25,4375.

Labiad, B.; Villemin, D. S 1989, 143.
Vu Moc Thuy; Petit, H.; Maitte, P. BSB 1982, 91, 261.
[78375-48-1]
C7H12N2O
(MW 140.21)
(coupling reagent for amino acids; amide synthesis)

Physical Data: bp 72-73C/0.7 mmHg; d 1.017g c m - 3 ; nD
1.469.
Solubility: usually used in CH 2 Cl 2 .
Form Supplied in: liquid, >98% pure.
Analysis of Reagent Purity: comparison wideth literature boil
ing point; also vmax (liquid film) at 2150 cm-1 is indicative of
isocyanide functionality.
Preparative Methods: by the reaction of 2-morpholinoethylamine
with Formic Acid in boiling toluene with a water separator, to
yield the formamide which is treated either with Phosgene and
Triethylamine in CH 2 Cl 2 or with Phosphorus Oxychloride and
Diisopropylamine.1,2 The use of diisopropylamine as base is fa
vored as yields are improved, typically to 68%. Trichloroacetic
Anhydride has also been used as an alternative for COCl 2 , giv
ing a yield of 74%. 3
286
2-MORPHOLINOETHYL ISOCYANIDE
Purification: when phosphorus oxychloride and diisopropylamine are employed, purification is not required.2
Introduction. The principal synthetic application of 2morpholinoethyl isocyanide is as a coupling reagent of amino
acids to yield peptides.2 It also reacts with aldehydes or ketones
to yield amides,4 with acids to yield imidazolinium salts,5 and has
been used as a ligand in spectroscopic studies to examine shielding
effects.6
Coupling of Amino Acids.2 The coupling reaction is
performed in CH2Cl2 with N-Hydroxysuccinimide or 1Hydroxybenzotriazole and 2-morpholinoethyl isocyanide (1) to
yield products in 61-95% yield (eq 1).
Cbz-Val-Gly-OMe
(3)
Use in Spectroscopic Studies.6 2-Morpholinoethyl iso

cyanide has been used to study the NMR 14N NMR signals of
molybdenum (95Mo) and tungsten (183W) carbonyl isocyanide
complexes M(CO)6-n(CNR)n (n = 0-6). When isocyanide is co
ordinated to the metal center, the 14N signal is deshielded but, with
further substitution, the N becomes more shielded again. With UV
and IR studies, substitution of CO by isocyanide shifts the absorp
tion toward longer wavelength so that the color of the complexes
changes from white to orange-red.
(1)
No racemization is observed, as determined by the coupling

reaction of CF3CO-Phe-OH with H-Phe-O-t-Bu in the presence
of HOSu.
Formation of Amides.4 The isocyanide moiety of 2morpholinoethyl isocyanide reacts with aldehydes and ketones
to form amides in good yields (eq 2).
1. Helmut, A.; Koch, G.; Marquarding, D. Chem. Pept. Proteins, Proc.

USSR-FRG Symp. 3rd; 1982; p 209.
2.
3.
4.
Obrecht, R.; Herrmann, R; Ugi, I. S 1985, 4, 400.

Eckert, H.; Forster, B. AG 1987, 99, 922.
Seebach, D.; Adam, G; Gees, T; Schiess, M; Wiegand, W. CB 1988,121,
507.
5.
Polyokov, A. I.; Baskakov, Y. A.; Artamonova, O. S.; Baranova, S. S.

KGS 1983, 6, 843.
Minelli, M; Masley, W. J. IC 1989, 28, 2954.
6.
(2)
University
Formation of Imidazolinium Salts by Cyclization.5 Treatment of the isocyanide with HZ (Z = Cl, TsO)
gives 40-60% of the spiroimidazolium salt which on addition
of excess HZ provides the imidazolinium salt in 70-95% yield
(eq 3).
Helen Osborn
of Bristol, UK
o-NITROBENZYL ALCOHOL
287
O 2 NC 6 H 4 CH(OH)CH 2 OH. The acetals are removed in excellent

yield by irradiation at 350 nm in benzene (eq 3). 1
(2)
(3)
[612-25-9]
C7H7NO3
(MW 153.15)
(photoremovable protective group for ketones and aldehydes,1

carboxylic acids,2 anhydrides,3 acid chlorides,4 and amines;5a re
action with isocyanates to generate protected amines; 5b,c,d pro
tection of amino acids; 2b,6 protection of the hydroxyl groups
of ribonucleotides, 7a,b,c dinucleotides,7d and furanoses;7e syn
thesis of a novel catalyst in the polymerization of epoxides;8
formation of leaving groups of enhanced ability;9 reaction with
formyl Meldrum's acid to afford the formylacetate;10 oxidation
to the corresponding aldehyde 11 or carboxylic acid 12 )
Alternate Name: o-NBA.
Physical Data: mp 70-72 C; bp 270 C. The thermal stability of
nitrobenzyl alcohols has been examined.17 Its conformation in
solution has been studied using 17O NMR 18a and 13C NMR 18b
analysis.
Form Supplied in: light tan powder.
Handling, Storage, and Precautions: light-sensitive. Harmful if
swallowed or inhaled.
Mechanism of Action. Under photolysis,19 acidic,20 and

electron bombardment 21 conditions, the transformation of onitrobenzyl alcohol or its derivatives involves an internal redox
reaction sequence followed by liberation of the deprotected alco
hol or amine (eq 1). Analogously, the photorearrangement of esters
of o-NBA, obtained through its reaction with acid chlorides 2a,4 or
anhydrides,3 also induces an internal redox reaction (eq 2).
(1)
R = H or protected functionality, X = O or N
Protection of Ketones and Aldehydes. o-NBA serves as a

photoremovable protective group for aldehydes and ketones. Bisacetals are prepared in a high-yield exchange reaction, except with
hindered ketones for which it is necessary to employ the diol o-
Ar = o-O2NC6H4
Generation of Carboxylic Acids. Photolabile phosphati

dylcholine (PLPC) has been synthesized by reaction of oNBA with dodecanedioyl dichloride followed by 1,3-Dicyclohexylcarbodiimide coupling. Subsequent photolysis of the result
ing 2-nitrobenzyl esters results in the instantaneous disintegration
of the PLPC liposomes, thus opening up the possibility of their
use as drug carriers in vivo.4 Irradiation of copolymers with onitrobenzyl ester side groups, synthesized from methacrylyl chlo
ride, generates free carboxylic acids, as illustrated in eq 4.2a The
positive photosensitive polyiimide biphenyl precursor pictured in
eq 5 has been made by treatment of biphenyltetracarboxylic acid
dianhydride (BPDA) with o-NBA.3
(4)
(5)
Protection of Amines. Reaction of o-NBA with Phosgene

yields the stable compound o-nitrobenzyloxycarbonyl chloride
(eq 6). 5a Subsequent reaction with 2-amino-2-deoxy-D-glucose
cleanly affords the protected amine. The yields of the free
amines obtained upon irradiation (eq 7) are lowered by side reac
tions with the o-nitrobenzaldehyde generated under the reaction
conditions. 2a,5a,b Yields are increased by the addition of poly
meric aldehydes or sulfuric acid to the reaction mixture during
irradiation,5a or by utilizing the related 2,6-dinitrobenzyl alco
hol in the first step. 5b Functional group tolerance for this entire
reaction sequence is impressively high.
288
o-NITROBENZYL ALCOHOL
(6)
Protection of Hydroxyl Groups. Photolabile 2'-O-(onitrobenzyl) derivatives of various ribonucleotides7a-c as well

as dinucleotides7d have been synthesized, and their subsequent
photodeprotections, which yield the corresponding alcohols,
examined (eq 11). Protection of the anomeric hydroxyl func
tionality of 2-deoxy-D-ribofuranose has been accomplished
using o-NBA (eq 12).7e This protective group is quite stable to
acidic conditions, and has proven invaluable in the synthesis of
abasic oligonucleotides. Similar conditions are employed in the
synthesis of bis(o-nitrobenzyl) ethers.25
(11)
(7)
Reaction with isocyanates also provides a route to carbamates,

which serve as masked amines5b,c (eq 8) or as diamines5*1 for
epoxy resin curing. Carbamates of o-NBA possess moderate an
titumor activity.22
(8)
B = purine or pyrimidine
(12)
Miscellaneous Reactions. o-Nitrobenzyl triphenylsilyl ether,

a latent photogenerated source of triphenylsilanol, has been syn
thesized from o-NBA (eq 13). This new catalyst, upon irradia
tion at 365 nm, serves as a coinitiator in the polymerization of
epoxides.8
(13)
Protection of Amino Acids. Photolabile N-protected amino

acids and peptides have also been synthesized via their
chloroformates.2b,6 Quantitative deprotection proceeds without
racemization23,24 when an excess of Sulfuric Acid or Semicarbazide hydrochloride is added to the reaction mixture (eq 9).
Conversely, treatment of serine with o-NBA in the presence of
catalyticp-Toluenesulfonic Acid provides the o-nitrobenzyl ester
of serine (eq 10).2b
Greatly enhanced leaving group ability has been realized by use

of o-NBA. Steroidal sulfonates synthesized from the sulfonylating
agent formed in eq 14 undergo bimolecular azide displacements
more efficiently than traditional sulfonates.9
(14)
(9)
(10)
o-Nitrobenzyl formylacetate has been made by the reaction of

formyl Meldrum's acid with o-NBA in dry toluene (eq 15).10
-Hydroxyimino phosphonates can serve as precursors to alkyl
metaphosphates when photolabile ester groups are incorporated
(eq 16).26
(15)
o-NITROPHENOL
Banerji, K. K. JCR(S) 1987, 176. (i) Sur, B.; Adak, M. M.; Pathak, T.;
Hazra, B.; Banerjee, A. S 1985, 652. (j) Rangadurai, A.; Thiagarajan,
V.; Venkatasubramanian, N. IJC(B) 1982, 21B, 42. (k) Fleet, G. W. J.;
Little, W. TL 1911, 3749. (1) Srinivasan, V. S.; Venkatasubramanian,
N. IJC 1975, 13, 526. (m) Syper, L. Rocz. Chem. 1973, 47, 43. (n)
Balasubramanian, T. R.; Venkatasubramanian, N. IJC 1970, 8, 305. (o)
Syper, L. TL 1967, 4193.
(16)
Oxidations and Reductions. Oxidation of o-nitrobenzyl

alcohol to its aldehyde has been accomplished using
bis(dihydrogentellurato)MIII where M = CuIII and A I I I , 1 1 a
chromium trioxide and alumina,11b biphasic nitric acid,11c
bromamine-B, 11d ethyl chlorocarbamate,11e potassium bromate in aqueous HCl,11f pyridinium fiuorochromate,11g
N-bromoacetamide, 11h thallium(III),11i ammonium molybdate
tetrahydrate in 6 M HCl, 11j l-chlorobenzotriazole,11k pyri
dine oxodiperoxychromium(VI),111 cobalt(III) hydroxide,11"1
cerium(IV) perchlorate,11n or silver(II) oxide in acidic media.11o
Oxidation to o-nitrobenzoic acid is possible using methyltrioctylammonium
tetrakis(oxodiperoxotungsto)phosphate,12a
electrogenerated superoxide,12b (NH 4 )VO 3 and dilute HClO 4 , 12c
or benzyltrimethylammonium tribromide.12d Biological oxida
tion of o-nitrotoluene to o-NBA by Pseudomonas sp. strain JS150
and Pseudomonasputida Fl has also been reported.13
Reduction of esters of o-nitrobenzyl alcohol to yield o-NBA
can be accomplished using sodium borohydride in aqueous
media.14 Reductions of o-nitrobenzaldehyde to o-NBA us
ing sodium borohydride under phase transfer conditions,150
dimethoxyborane-CoCl2, 15b
and
trimethoxysilane-lithium
methoxide 15c have been reported. Reduction of the nitro group of
o-NBA to the amine using catalytic hydrogenation with Pd0 and
polybenzimidazole resin in DMF is likewise known.16
289
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
(a) Venturello, C ; Gambaro, M. JOC 1991, 56, 5924. (b) Singh, M.;
Singh, K. N.; Dwivedi, S.; Misra, R. A. S 1991, 291. (c) Banerjee, A.;
Dutt, S.; Banerjee, G. C.; Hazra, B.; Datta, H.; Banerjee, S. IJC(B) 1990,
29B, 257. (d) Okamoto, T.; Uesugi, T.; Kakinami, T.; Utsunomiya, T.;
Kajigaeshi, S. BCJ 1989, 62, 3748.
Robertson, J. B.; Spain, J. C ; Haddock, J. D.; Gibson, D. T. Appl.
Environ. Microbiol. 1992, 58, 2643.
Bianco, A.; Passacantilli, P.; Righi, G. SC 1988, 18, 1765.
(a) Someswara Rao, C.; Deshmukh, A. A.; Patel, B. J. IJC(B) 1986,
25B, 626. (b) Nose, A.; Kudo, T. CPB 1989, 37, 808. (c) Hosomi, A.;
Hayashida, H.; Kohra, S.; Tominaga, Y. CC 1986, 1411.
Li, N.-H.; Frchet, J. M. J. CC 1985, 1100.
Cardillo, P.; Girelli, A. Chim. Ind. (Milan) 1986, 68, 68.
(a) Monti, D.; Orsini, F.; Ricca, G. S. Spectrosc. Lett. 1986, 19, 505. (b)
Abraham, R. J.; Bakke, J. M. T 1978, 34, 2947.
(a) Barltrop, J. A.; Bunce, N. J. JCS(C) 1968, 1467. (b) Wan, P.; Yates,
K. CJC 1986, 64, 2076.
Bakke, J. ACS(B) 1974, 28, 645.
McLuckey, S. A.; Glish, G. L. Org. Mass Spectrom. 1987, 22, 224.
Perlman, M. E.; Dunn, J. A.; Piscitelli, T. A.; Earle, J.; Rose, W. C.;
Wampler, G. L.; MacDiarmid, J. E.; Bardos, T. J. JMC 1991, 34, 1400.
Barltrop, J. A.; Plant, P. J.; Schofield, P. CC 1966, 822.
Manning, J. M.; Moore, S. JBC 1968, 243, 5591.
Smith, M. A.; Weinstein, B.; Greene, E D. JOC 1980, 45, 4597.
Breuer, E.; Mahajna, M. JOC 1991, 56, 4791.
Related Reagents. o-Nitrobenzyl Bromide.

D. Todd Whitaker
Detroit Country Day School, Beverly Hills, MI, USA
1. Gravel, D.; Murray, S.; Ladoucer, G. CC 1985, 1828.
2.
3.
(a) Barzynski, H.; Sanger, D. Angew. Makromol. Chem. 1981, 93, 131.
(b) Pirrung, M. C ; Nunn, D. S. BML 1992, 2, 1489.
Kubota, S.; Yamawaki, Y.; Moriwaki, T.; Eto, S. Polym. Eng. Sci. 1989,
29, 950.
4.
Kusumi, A.; Nakahama, S.; Yamaguchi, K. CL 1989, 433.
5.
(a) Amit, B.; Zehavi, U.; Patchornik, A. JOC 1974, 39, 192. (b)Cameron,
J.F.;Frichet, J. M. J. JACS 1991, 113, 4303. (c) Cummings, R. T.; Krafft,
G. A. TL 1988, 29, 65. (d) Nishikubo, X; Takehara, E.; Kameyama, A.
Polym. J. 1993,25,421.
6.
7.
Patchornik, A.; Amit, B.; Woodward, R. B. JACS 1970, 92, 6333.

(a) Ohtsuka, E.; Tanaka, T.; Tanaka, S.; Ikehara, M. JACS 1978, 100,
4580. (b) Ohtsuka, E.; Tanaka, S.; Ikehara, M. CPB 1977, 25, 949. (c)
Ohtsuka, E.; Tanaka, S.; Ikehara, M. 51977,453. (d) Ohtsuka, E.; Tanaka,
S.; Ikehara, M. Nucleic Acids Res. 1974, 1, 1351. (e) Poc'h, D.; Meyer,
A.; Imbach, J.-L.; Rayner, B. TL 1991, 32, 207.
Hayase, S.; Onishi, Y.; Suzuki, S.; Wada, M. Macromolecules 1985, 18,
1799.
8.
9.
10.
11.
Zehavi, U. JOC 1975, 40, 3870.

Sato, M.; Yoneda, N.; Katagiri, N.; Watanabe, H.; Kaneko, C. S 1986,
672.
(a) Gupta, K. K. S.; Nandy, B. K.; Gupta, S. S. JCS(P2) 1993, 767.
(b) Hirano, M.; Kuroda, H.; Morimoto, T. BCJ 1990, 63, 2433. (c)
Gasparrini, F.; Giovannoli, M.; Misiti, D.; Natile, G.; Palmieri, G. SC
1988, 18, 69. (d) Mathur, S.; Gupta, A.; Banerji, K. K. Oxid. Commun.
1988, 11, 137. (e) Jain, S. M.; Banerji, K. K. BCJ 1988, 61, 1767. (f)
Gupta, K. K. S.; Kumar, S. C.; Sen, P. K.; Banerjee, A. T 1988, 44, 2225.
(g) Banerji, K. K. JOC 1988, 53, 2154. (h) Agarwal, A.; Mathur, S.;
o-Nitrophenol
[88-75-5]
C6H5NO3
(MW 139.12)
(preparation of active esters for peptide synthesis1)

Physical Data: mp 45 C; bp 216 C; pKa 7.23 (at 25 C).
Solubility: sol ether, benzene; sparingly sol H 2 O.
Form Supplied in: yellow solid, commercially available.
Purification: crystallizes as yellow needles or prisms from ethanol
or ether.
Handling, Storage, and Precautions: moderately toxic by inhala
tion and skin absorption.
Preparation of Active Esters for Peptide Synthesis. Esters

of o-nitrophenol, prepared by the 1,3-Dicyclohexylcarbodiimide
290
NONACARBONYLDIIRON
coupling method, can be used in peptide synthesis (eq 1)1 in the

same way as are the corresponding p-nitrophenyl esters (see pNitrophenol). o-Nitrophenol is less reactive than p-nitrophenol in
the DCC coupling step; use of pyridine as solvent instead of ethyl
acetate increases the nucleophilicity of the hydroxyl group and
minimizes side reactions. In the aminolysis step, the o-nitrophenyl
esters are more reactive than thep-isomers, and the reaction rates
are less sensitive to changes in solvent or to steric hindrance. oNitrophenyl esters have been used in a stepwise synthesis of a
nonapeptide in which all synthetic operations are performed in
the same reaction vessel, without isolation of intermediates ('in
situ' peptide synthesis).1
mediated coupling between N-protected amino acids and pnitrophenol, are among the most useful activated esters for peptide
synthesis (eq 1). 1 They are readily purified by recrystallization, of
ten from alcoholic solvents with which they do not react. Aminol
ysis occurs at a reasonable rate, generally at room temperature
without a catalyst. The p-nitrophenol generated as a byproduct
in this step is easily removed. o-Nitrophenyl esters can be used
similarly (see o-Nitrophenol); a study of the rates of aminolysis
of Boc-L-leucine nitrophenyl esters showed the o-isomer to react
4-9 times faster than the p-isomer.2
(1)
(1)
1. Bodanszky, M.; Funk, K. W.; Fink, M. L. JOC 1973, 38, 3565;

Bodanszky, M.; Kondo, M.; Yang Lin, C ; Sigler, G. F. JOC 1974, 39,
AAA.
1. Bodanszky, M.; Du Vigneaud, V. JACS 1959, 81, 5688; Bodanszky, M.;

Meienhofer, J.; Du Vigneaud, V. JACS 1960, 82, 3195.
2.
Bodanszky, M.; Bath, R. J. CC 1969, 1259.
Alan Armstrong
Alan Armstrong
p-Nitrophenol
Nonacarbonyldiiron1
[100-02-7]
C6H5NO3
(MW 139.12)
[15321-51-4]
C 9 Fe 2 O 9
(MW 363.79)
(preparation of active esters for peptide synthesis1)
(precursor for iron carbonyl complexes, carbonylation, dehalogenation, deoxygenation, and reductionreactions)
Physical Data: mp 114 C; pKa 7.15 (at 25 C); dimorphous.

Solubility: moderately sol cold water; sol alcohol, chloroform,
ether.
Form Supplied in: generally obtained as a mixture of the two
crystalline forms.
Purification: recystallization from toluene gives the metastable aform if performed at >63 C; the -form is obtained as yellow
prisms at <63 C.
Handling, Storage, and Precautions: the -form is light stable,
whereas the yellow -form gradually turns red in light. Moder
ately toxic by inhalation and skin absorption.
Alternate Names: diiron enneacarbonyl; diiron nonacarbonyl; tri-carbonylhexacarbonyldiiron.

Physical Data: mp 100-120C (dec); d 2.08 g c m - 3 ; X-ray
diffraction study.3
Solubility: insol organic solvents.
Form Supplied in: orange flaky solid.
Preparative Method: formed by exposing Pentacarbonyliron to
light (eq 1). 1 The complex contains six terminal carbonyl groups
and three bridging carbonyl groups. 2
Preparation of Active Esters for Peptide Synthesis. pNitrophenyl esters, prepared by 1,3-Dicyclohexylcarbodiimide-
Handling, Storage, and Precautions: because of its much lower

solubility and volatility, Fe 2 (CO) 9 is less dangerous to handle
2 Fe(CO)5
Fe2(CO)9 + CO
(1)
NONACARBONYLDIIRON
than Fe(CO) 5 , though it should be remembered that Fe(CO) 5
is often formed in reactions using Fe 2 (CO) 9 ; when handling
Fe 2 (CO) 9 , avoid dust formed by this light flaky substance; use
in a fume hood; store in a freezer; when fully dried, commercial
samples can be pyrophoric.4
Diene Complexation.
Cyclohexadiene
Series. Tricarbonyliron complexes are
formed by reaction of Fe(CO) 4 with dienes. Fe 2 (CO) 9 is an
important starting material for this reaction because it offers
a convenient source of Fe(CO) 4 generated under much milder
conditions than from pentacarbonyliron (eq 2).
Fe2(CO)9
Fe(CO)4 + Fe(CO)5
(2)
Starting from a cisoid 1,3-diene, Fe 2 (CO) 9 can yield, un

der mild thermal conditions, tricarbonyl(4-1,3-diene)iron com
plexes. Cyclohexa-1,4-dienes (readily available from the Birch re
duction of substituted benzenes) often require prior conjugation,
but conjugated 1,3-dienes (both cyclic and acylic) can be con
verted into tricarbonyliron complexes directly. Some of the earliest
examples 5-9 of complexation of 1,3-dienes employed Fe 2 (CO) 9
(eq 3, dates shown in parentheses). (Alternative reagents in the
early days were Pentacarbonyliron or Dodecacarbonyltriiron.)
291
(4)
Good diastereoselectivity can also be a significant advantage.

The dioxygenation of arenes by Pseudomonas putida provides op
tically active cis-diol products.12 In the mild complexation con
ditions using Fe 2 (CO) 9 , the chirality of the diol is relayed to tri
carbonyliron complexes, providing enantiopure intermediates for
use in asymmetric synthesis.13
Cycloheptadiene Series. The treatment of (2) with Fe 2 (CO) 9
in acetone at 35 C gives a 1:4 mixture in favor of (4). Enriched
samples of (3) or (4) are accessible directly (eq 5), according to
the reaction conditions.14
(5)
Cycloheptatrienone (tropone) reacts efficiently in 60% yield

with Fe 2 (CO) 9 to give a complex (5) in which one double bond re
mains uncomplexed (eq 6).15 This double bond displays normal re
activity, while the remaining unsaturation is effectively protected.
Dinuclearbis-3-tricarbonyliron complexes can also be formed.16
(3)
(6)
More recently, the use of Fe 2 (CO) 9 has been increasingly val

ued because, under mild conditions, improved regio- and stereocontrol are possible, and sensitive functionality is less severely
affected by the complexation conditions. Regiocontrol is often a
problem in the complexation of 1,4-dienes by high-temperature di
rect reaction with Fe(CO) 5 . Preparation of the diene complex (1),
for example, can be improved by preconjugation of the 1,4-diene
with p-Toluenesulfonic Acid10 and by complexation of the re
sulting equilibrium concentration of the 1,3-diene with Fe 2 (CO) 9
under conditions in which the 1,4-isomer does not react (eq 4).
Bis-alkene complexes are formed when rearrangement to bring
the double bonds into conjugation is not possible. 11
Complexation of Natural Products. The Fe(CO) 3 moiety

can provide a method for diene protection. Steroid interconversions employed tricarbonyl(ergosteryl acetate)iron(O)17
and tricarbonyl(ergosteryl benzoate)iron(O).18 Thus treat
ment of ergosteryl acetate or benzoate with tricarbonyl(4methoxybenzylideneacetone)iron(O) (preformed by complex
ation using Fe 2 (CO) 9 , or with Fe 2 (CO) 9 in the presence of
4-methoxybenzylideneacetone19), gives the pure desired steroid
complex in good yield (60% and 80%, respectively). Nopadiene
has been complexed by reaction with Fe 2 (CO) 9 to form an
optically active metal complex.20
Exocyclic Diene Complexation. Formation of iron carbonyl
complexes of (6) illustrates the mild nature of the complexation
conditions (eq 7). 21
Reaction with Fe 2 (CO) 9 is exo face selective, giving a mix
ture of the corresponding mono complexes (7) (anti-exo) and (8)
(syn-exo). Further complexation of (8) with Fe 2 (CO) 9 occurs in
a nonstereoselective fashion to give mixtures of the diiron comAvoid Skin Contact with All Reagents
292
NONACARBONYLDIIRON
plexes (anti-exo, syn-endo), (anti-exo, syn-exo), and (anti-endo,

syn-exo).
On treatment of (9) with Fe2(CO)9, the endocyclic double bond
isfirstcoordinated to yield the exo-Fe(CO)4 complex (10), which
then further reacts with Fe2(CO)9 to afford the diiron complex as
a major product (eq 8).
1-Methoxybutadiene has been complexed photochemically

using Fe2(CO)9, instead of the more conventional thermal
conditions.27 Complexation of acyclic dienes with Fe2(CO)9 con
stituted the first step toward trimethylenemethane complexes.28
All details concerning the preparation and spectral properties
of tricarbonyl(butadiene)iron complexes are gathered in recent
29
reviews.29
Fe2(CO)9/Ultrasound Method of Complexation. The reac

tion of Fe2(CO)9 with sensitive dienes can be promoted by
ultrasound (eq 11). Syntheses of a variety of tricarbonyl(4diene)iron(O) complexes (16) use the convenient high-yielding
sonication method.30
(7)
(11)
R1 = OAc; R2, R3, R4 = H; 100%

(8)
Heating promotes deoxygenation to form the substituted

tricarbonyl(o-quinodimethide)iron complex (11). Oxidative re
moval of the Fe(CO)3 moiety in (11) affords the indanone deriva
tive (12) by CO insertion (eq 9).22
(9)
Complexes of 7-azanorbornadienes have been examined as

sources of nitrenes.23
Complexation of Acyclic Dienes. Complexation of trans-Amethyi-2,4-pentadienol (13) with Fe2(CO)9 gives the dienol com
plex (14) as a yellow oil. The product is valuable as a precursor
for the cation (15) by reaction with HPF6/Ac2O/Et2O (eq 10).24
Substituted dienes with the (Z) configuration at a methyl-bearing
terminus complex less efficiently.25
(10)
Fe(CO)3-diene aldehydes have been formed using Fe2(CO)9 in

work that culminated in an efficient asymmetric induction using
chiral allylborane reagents to give access to metal complexes in
high optical purity.26
Fe2(CO)9 Used with a Tertiary Amine. Aliphatic trialkylaminotetracarbonyliron(O) complexes result from direct reaction
between R3N and Fe2(CO)9.31 Fair to good yields of (17) can be
obtained (eq 12).
(12)
The complex (17) transfers Fe(CO)4 to dienes, monoenes (re

sulting in isomerization), and Fe(CO)5 (to form Fe2(CO)9 and
Fe3(CO)12). The R3N unit can also be replaced by other amines
and by phosphines. The amine/phosphine exchange was per
formed with Me3NFe(CO)4 at 60C in quantitative yield after
0.5 h. The amine/diene exchange reaction has been studied with
1,3-cyclohexadiene in hydrocarbon solution at 52C (eq 13).
(13)
Other Routes to4Complexes. Alternative access to Fe(CO)3

complexes are afforded by a variety of more unusual starting ma
terials: cyclopropenes, dibromides, dihydrothiophene dioxides,
alkynes/CO, allenes, and cyclohexadienones are all discussed be
low.
Enone Complexation. Various a,p-unsaturated ketones form
moderately stable tricarbonyliron complexes (18),32,37 and of
fer access to 1,4-diketones (19) by reaction with Grignard
reagents, organolithium reagents (eq 14), or organocuprates.33
Trimethylsilyloxybutadienes require phenyl substituents to form
stable complexes by reaction with Fe2(CO)9.34 Enone complexes
are also useful as transfer reagents to place Fe(CO)3 on diene
ligands.32,35 A related procedure employs complexes of ,unsaturated imines in the same way.36
NONACARBONYLDIIRON
293
Demetalation of ferralactone complexes with Cerium(IV) Am

monium Nitrate produces -lactones (at low temperature) and/or
-lactones (at high temperature, under a high pressure of carbon
monoxide).
(14)
Reagents for asymmetric transfer of Fe(CO)3 to dienes have

been obtained thermally from (+)-pulegone37,38 and ()-3|3acetyloxypregna-5,16-dien-20-one38 by reaction with Fe2(CO)9.
The chiral enone complexes are used without isolation to provide
a direct synthesis of optically active (diene)Fe(CO)3 complexes
in up to 40% ee.38,39
Formation of -Lactams. The synthesis and oxidative demetallation of ferralactam complexes affords a route to -lactams.42
The difficulty of preparation of the monoaziridines limits the scope
of direct ring opening, but ferralactam complexes are more read
ily obtained from ferralactones by reaction with an amine and a
mild Lewis acid catalyst.49 This methodology has been success
fully applied to the synthesis of (+)-thienamycin (28),50 via the
key intermediates (26) and (27).
Complexes from Alkenediols. 2-Butene-l,4-diols react with

Fe2(CO)9 in the presence of Lewis acids under ultrasound condi
tions to form 3-allyliron complexes.40
Ferralactone Complexes.
From Oxazines. The first ferralactone complex (21) was ob
tained during studies on -allyliron complexes by Heck, The same
compounds are also obtained by treatment of oxazines (20) with
Fe2(CO)9 (eq 15).41
(15)
Complexes from Electrophilic Cyclopropenes. Methyl- and

phenyl-substituted cyclopropenes have been shown to react with
iron carbonyls by ring opening and carbonylation to yield
tricarbonyl(3,1-allylcarbonyl)iron complexes (eq 17).51
FormationofB- and -Lactones from Vinyloxiranes. An ox
idative addition of vinyloxiranes (22) to iron(0) complexes pro
vides the most usual synthesis of ferralactone complexes (21)
(eq 16).42, 43
(16)
Efficient preparations are possible using Fe2(CO)9 according

to two different methods (in THF, or in lower polarity solvents
with ultrasound) to produce the ferralactone complexes in moder
ate to excellent yields.44 Removal of the metal to form -lactones
has been successfully applied to total syntheses of parasorbic acid
(23), the carpenter bee pheromone (24), and malyngolide (25).45
Epoxide-derived ferralactone complexes have provided key inter
mediates in syntheses of routiennocin,46 avermectin B1a,47 and
()-valilactone.48
(17)
Franck-Neumann, starting from the easily accessible elec

trophilic gem-dimethylcyclopropenes (29), could obtain the carbonyliron adducts (30) and (31) in excellent yields.52,53 The reac
tion of Fe2(CO)9 with the isomers of Feist's ester (32) leads first to
the formation of the corresponding tetracarbonyliron alkene com
plexes (33) (eq 18).54 Reaction of naphthalenocyclopropene with
Fe2(CO)9 has also been studied.55
(18)
The products from cyclopropene ring opening have the advan

tage of easy conversion into tricarbonyl(4-diene)iron complexes
(34), its regioisomer and (35), by thermal loss of carbon monoxide,
or photochemically without CO evolution (eqs 19 and 20).52,56
294
NONACARBONYLDIIRON
(19)
(20)
Opening of Cyclopropane Rings. Ring enlargement of com

pounds such as bicyclo[4.1.0]hept-2-ene (36) or its derivatives
(+)-2-carene (37) or (+)-3-carene (38) by carbonylation results
in the formation of bicycloheptenones or cycloheptadiene com
plexes, depending on the reaction conditions.57
(23)
Dehalogenation of , '-dihaloalkenes and Ketones. The

preparation (eq 24) of the iron carbonyl complex of trimethylenemethane (42) 62 and some Fe 2 (CO) 9 -mediated rearrangements of
dibromo ketones 63 constitute the pioneering work in this area.
Noyori has extended the dehalogenation reaction of -halo ke
tones to ,'-dibromo ketones and ,,','-tetrabromo ketones
which can be dehalogenated with Fe(CO)5 or Fe 2 (CO) 9 . 64
(24)
Under mild reaction conditions, (+)-2-carene affords the opti

cally active (1,3) complex (39) (eq 21).
(21)
Iron-stabilized oxallyl cations (generated in situ (eq 25) from

,'-dibromo ketones and Fe 2 (CO) 9 ) react with alkenes. Noyori
used this [3 + 2] cycloaddition reaction to produce cyclopentanone
or cyclopentanone derivatives, as illustrated by a single-step syn
thesis of ()--cuparenone (43) (eq 26). 65 The reaction of ,'dibromo ketones with enamines and Fe 2 (CO) 9 yields substituted
cyclopentenones in 50-100% yield (eq 27), as illustrated by the
reaction with the -morpholinostyrene (44). 66
[]D = +276
>95% ee
Metal and Lewis acid induced carbonylative ring enlarge

ment of chiral and prochiral cyclohexadienes can give access to
bicyclo[3.2.1]octanes.58
(25)
Dehalogenation Reactions.
Formation of Quinonedimethide Complexes. Formation of
a stable quinonedimethide complex (40) can be achieved by
dehalogenation.59 The product (40) decomposes to benzocyclobutene at 500 C (eq 22).
(26)
(22)
In the bis(bromomethyl)naphthalene
Fe(CO) 4 product has been reported.60
series, a
-bonded
(27)
Formation of Cyclobutadiene Complexes. Cyclobutadiene

can be prepared as the stable complex tricarbonyl(cyclobutadiene)iron(O) (41), by reaction of 3,4-dichlorocyclobutene with Fe 2 (CO) 9 (eq 23). 61
The reaction with dienes can be carried out either in ben

zene at 60-80 C using ,'-dibromo ketone, diene, and Fe 2 (CO) 9
NONACARBONYLDIIRON
295
(l:large excess: 1.2), in benzene at room temperature with irradi

ation (same ratio of reagents), or in benzene at 80-120 C using
the dibromide and tricarbonyl(4-diene)iron(0) complex (1:1.3).
Formation of (45) (eq 28) provides a typical example.67
(28)
Noyori et al. have reported a general synthesis of tropane al

kaloids from ,'-dibromo ketones.68 Reaction of tetrabromoacetone, N-methoxycarbonylpyrrole, and Fe2(CO)9 (3:1:1.5 mol ra
tio) in benzene (50 C, N2) produces two isomeric cycloadducts
in a 2:1 mixture, which can be used in the preparation of the alco
hol (46), a key intermediate in the synthesis of scopine and other
tropane alkaloids.69 A more recent example gives access to the
bicyclo[5.2.0]nonene skeleton.70
(30)
R = H, Me, OMe, NMe2
(31)
Reactions with Sulfur Compounds.

Desulfurization of Episulfides. The reaction of cyclohexene
episulfide with Fe3(CO)12, reported by King71 to produce cy
clohexene, has been improved:72 2-butene episulfides, e.g. (47)
(R1 = R2 = Me, R3 = R4 = H), yield alkenes by treatment with
Fe2(CO)9 in refluxing benzene (eq 29). The reaction occurs with
retention of the stereochemistry in yields superior to 80%.
Reactions with Alkynes. Fe2(CO)9 reacts with acetylene by

carbonylation/cyclotrimerization leading to the formation of tricarbonyl(tropone)iron(0) (51) (eq 32). (For comparison with di
rect complexation of tropone, see eq 6.) This complex is obtained
in low yield (28%) with Fe2(CO)9, but this represents a significant
improvement on results obtained with Fe(CO)5.79
(32)
(29)
Hexyne is carbonylated by Fe2(CO)9. An intermediate can be
isolated.80 Alkylthioalkynes are not desulfurized but form iron
complexes.81
Tetramethylallene episulfide, on the other hand, affords a thioallyl Fe(CO)3 complex.73
Reaction with Acid Chlorides. The reaction of an acid

chloride with one equivalent of Fe2(CO)9 affords symmetrical
Reaction with Thioketones. The reaction of thiobenzophenone ketones.82
derivatives (48) and similar compounds with Fe2(CO)9 has been
studied by Alper.74 It has been shown to result in the forma
Formation of 1,2,4-Triazines. 1,2,4-Triazines, e.g. (54), are
tion of ortho-metalated complexes (49) in reasonable to high
formed regioselectively (eq 33) by cocyclization of adiponitrile
yields (eq 30). Treatment of the complexes (49) with Mercury(II)
(52) and a nitrile (53) in the presence of Fe2(CO)9.83
Acetate effects ortho-mercuration.75 Thioketene complexes have
also been examined.76 Complexes of type (49) offer a new route
(33)
to lactones.74
Reaction with 2,5-Dihydrothiophene 1,1-Dioxide. 2,5Dihydrothiophene 1,1-dioxides are known to be converted
into 1,3-dienes after thermal displacement of sulfur dioxide.77
Reaction in situ with Fe2(CO)9 offers a general preparation
of highly functionalized tricarbonyl(4-buta-1,3-diene)iron(0)
complexes (50) (eq 31).78
Deprotection and Deoxygenation Reactions of Oximes and

Isobenzofurans. Oximes, oximic ethers, or oxime O-acetates
can be converted into the corresponding ketones by reac
tion with Fe2(CO)9 in methanol at 60 C.84 Deoxygenation
296
NONACARBONYLDIIRON
of 7-oxabicyclo[2.2.1]dienes with Fe2(CO)9 affords aromatic

products.85 This method is particularly recommended for deoxygenation of (55) in the formation of (56) (eq 34).86
(34)
10.
11.
Birch, A. J.; Dastur, K. P. JCS(P1) 1973, 1650.

Sakai, N.; Mashima, K.; Takaya, H.; Yamaguchi, R.; Kozima, S. JOM
1991,419, 181.
12. (a) Carless, H. A. J.; Billinge, J. R.; Oak, O. Z. TL 1989, 30, 3113.
(b) Hudlicky, T.; Luna, H.; Price, J. D.; Rulin, F. TL 1989, 30, 4053. (c)
Hudlicky, T.; Luna, H.; Barbieri, G.; Kwart, L. D. JACS 1988, 110, 4735.
(d) For examples of applications of an achiral arene-derived diol, see:
Ley, S. V.; Sternfeld, F.; Taylor, S. TL 1987, 28, 225. (e) Carless, H. A.
J.; Oak, O. Z. TL 1989, 30, 1719.
13.
Reaction with Electrophilic Allenes. Formation of

tricarbonyl(l,3-butadiene)iron(0) complexes from allenes
(e.g. 57) is possible via tricarbonyl(trimethylenemethane)iron(0)
intermediates (eq 35).87
14.
15.
16.
17.
18.
19.
(35)
20.
21.
22.
23.
24.
25.
Cyclohexadienone Reductions with Fe2(CO)9 and Wa

ter. Tricarbonyl(cyclohexadienol)iron(0) complexes are formed
by selective monohydrogenation of cyclohexadienones (58) by
reaction with Fe2(CO)9 and water, under unusually mild condi
tions (eq 36).88
(36)
(58) R = Me, Ph
26.
27.
28.
29.
30.
31.
32.
selectivity >90%
These reactions have been examined with a variety of

substrates.88,89 Regio- and stereoselectivity depends on the pH
of the reaction mixture.
(a) Braye, E. H.; Hbel, W. Inorg. Synth. 1966, 8, 178. (b) Speyer, E.;
Wolf, H. CB 1927, 60, 1424.
2. Griffith, W. P.; Wickham, A. J. JCS(A) 1969, 834.
3. Cotton, F. A. Prog. Inorg. Chem. 1976, 21, 1.
4. (a) Bretherick, L. Handbook of Reactive Chemical Hazards, 2nd ed.;
Butterworths: Woburn, MA, 1979; p 670 (b) Bretherick, L. Hazards in
the Chemical Laboratory, 3rd ed.; Royal Society of Chemistry: London,
1981; p421.
5. Musco, A.; Palumbo, R.; Paiaro, G. ICA 1971, 5, 157.
33.
34.
35.
1.
6.
7.
Banthorpe, D. V.; Fitton, H.; Lewis, J. JCS(P1) 1973, 2051.

Nametkine, N. S.; Tyurine, V. D.; Nekhaev, A. I.; Ivanov, V. I.;
Bayaouova, F. S. JOM 1976, 107, 377.
8. Pearson, A. J. JCS(P1) 1977, 2069.
9. Johnson, B. F. G.; Lewis, J.; Parker, D. G.; Postle, S. R. JCS(D) 1977,
794.
36.
37.
38.
39.
40.
41.
42.
43.
For examples, see: (a) Stephenson, G. R.; Alexander, R. P.; Morley, C;

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Pearson, A. J.; Burello, M. P. OM 1992, 11, 448.
Rosenblum, M.; Watkins, J. C. JACS 1990, 112, 6316.
Morita, N.; Kabuto, C ; Asao, T. BCJ 1989, 62, 1677.
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Barton, D. H. R.; Gunatilaka, A. A. L.; Nakanishi, T.; Patin, H.;
Widdowson, D. A.; Worth, B. R. JCS(P1) 1976, 821.
Howell, J. A. S.; Johnson, B. F. G.; Josty, P. L.; Lewis, J. JOM 1972, 39,
329.
Salzer, A.; Schmalle, H.; Stauber, R.; Streiff, S. JOM 1991, 408, 403.
Rubello, A.; Vogel, P.; Chapuis, G. HCA 1987, 70, 1638.
Bonfantini, E.; Metral, J.-L.; Vogel, P. HCA 1987, 70, 1791.
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Hwang, J.-J.; Sun, C.-H.; Ding, M.-F. OM 1993, 12, 3762.
Donaldson, W. A. JOM 1990, 395, 187.
Adams, C. M.; Cerioni, G.; Hafner, A.; Kalchhauser, H.; Von Philipsborn,
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Yeh, M-C. P.; Chu, C. H.; Sun, M. L.; Rang, K. P. J. Chin. Chem. Soc.
(Taipei) 1990, 37, 547.
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in Metal-Organic Chemistry; Liebeskind, L. S., Ed.; JAI: Greenwich,
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Ley, S. V; Low, C. M. R.; White, A. D. JOM 1986, 302, C13.
Birencwaig, F.; Shamai, H.; Shvo, Y. TL 1979, 2947.
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(c) Paquette, L. A.; Photis, J. M.; Ewing, G. D. JACS 1975, 97, 3538.
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39, 239. (b) Brookhart, M.; Nelson, G. O.; Scholes, G.; Watson, R. A.
CC 1976, 195. (c) Barton, D. H. R.; Gunatilaka, A. A. L.; Nakanishi, T.;
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Bates, R. W.; Dez-Martin, D.; Kerr, W. J.; Knight, J. G.; Ley, S. V;
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(a) Heck, R. F.; Boss, C. R. JACS 1964, 86, 2580. (b) Becker, Y.;
Eisenstadt, A.; Shvo, Y., T 1974, 30, 839. (c) Becker, Y.; Eisenstadt,
A.; Shvo, Y. T 1976, 32, 2123.
Aumann, R.; Frhlich, K.; Ring, H. AG(E) 1974, 13, 275.
(a) Annis, G. D.; Ley, S. V. CC 1977, 581. (b) Annis, G. D.; Ley, S. V.;
Self, C. R.; Sivaramakrishnan, R. JCS(P1) 1981, 270.
NONACARBONYLDIIRON
44.
45.
Horton, A. M.; Hollinshead, D. M.; Ley, S. V. T 1984, 40, 1737.

Horton, A. M.; Ley, S. V. JOM 1985, 285, C17.
46.
47.
Kotecha, N. R.; Ley, S. V.; Mantegani, S. SL 1992, 395.

Ley, S. V.; Armstrong, A.; Dez-Martn, D.; Ford, M. J.; Grice, P.; Knight,
J. G.; Klob, H. C ; Madin, A.; Marby, C. A.; Mukherjee, S.; Shaw, A.
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JCS(P1) 1991, 667.
48.
49.
Bates, R. W.; Fernndez-Moro, R.; Ley, S. V. T 1991, 47, 9929.

(a) Annis, G. D.; Hebblethwaite, E. M.; Ley, S. V. CC 1980, 297. (b)
Annis, G. D.; Hebblethwaite, E. M.; Hodgson, S. T.; Hollinshead, D.
M.; Ley, S. V. JCS(P1) 1983, 2851.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
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(a) Hodgson, S. T.; Hollinshead, D. M.; Ley, S. V. CC 1984, 494. (b)

Hodgson, S. T.; Hollinshead, D. M.; Ley, S. V. 71985, 41, 5871.
(a) Newton, M. G.; Pantaleo, N. S.; King, R. B.; Chu, C. K. CC 1979, 10.
(b) Binger, P.; Cetinkaya, B.; Kruger, C. JOM 1978, 159, 63. (c) Dettlaf,
G.; Behrens, U.; Weiss, E. CB 1978, 111, 3013.
Franck-Neumann, M. PAC 1983, 55, 1715.
Franck-Neumann, M.; Dietrich-Buchecker, C ; Khmiss, A. JOM 1991,
220, 187.
Whitesides, T. H.; Slaven, R. W. JOM 1974, 67, 99.
Mller, P.; Bernardinelli, G.; Jacquier, Y. HCA 1992, 75, 1995.
Franck-Neumann, M.; Dietrich-Buchecker, C ; Khe'miss, A. TL 1981,
22, 2307.
(a) Aumann, R. JOM 1973, 47, C29. (b) Aumann, R.; Knecht, J. CB
1976, 109, 174. (c) Wang, A. H.-J.; Paul, I. C.; Aumann, R. JOM 1974,
69, 301. (d) Eilbracht, P.; Winkels, I. CB 1991, 124, 191.
(a) Eilbracht, P.; Hittenger, C.; Kufferath, K. CB 1990, 123, 1071. (b)
Eilbracht, P.; Hittenger, C ; Kufferath, K.; Henkel, G. CB 1990, 123,
1079. (c) Eilbracht, P.; Hittinger, C ; Kufferath, K.; Schmitz, A.; Gilsing,
H. D. CB 1990, 123, 1089.
(a) Roth, W. R.; Meier, J. D. TL 1967, 2053. (b) Kerber, R. C; Ribakove,
E. C. OM 1991, 10, 2848.
Azad, S. M.; Azam, K. A.; Hasan, M. K.; Howlader, M. B. H.; Kabir, S.
E. J. Bangladesh Acad. Sci. 1990, 14, 149.
(a) Watts, L.; Fitzpatrick, J. D.; Pettit, R. JACS 1965, 87, 3253. (b) Watts,
L.; Fitzpatrick, J. D.; Pettit, R. JACS 1966, 88, 623. (c) Pettit, R. JOM
1975, 100, 205.
Emerson, G. F.; Ehrlich, K.; Giering, W. P.; Lauterbur, P. C. JACS 1966,
88, 3172.
(a) Noyori, R.; Hayakawa, Y.; Funakura, M.; Takaya, H.; Murai, S.;
Kobayashi, R.; Tsutsumi, S. JACS 1972, 94, 7202. (b) Noyori, R.;
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1978, 100, 1759.
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(a) Noyori, R.; Makino, S.; Takaya, H. JACS 1971, 93, 1272. (b) Noyori,
R.; Souchi, T.; Hayakawa, Y JOC 1975, 40, 2681. (c) Takaya, H.;
Makino, S.; Hayakawa, Y.; Noyori, R. JACS 1978, 100, 1765.
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68.
69.
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(a) Hayakawa, Y.; Baba, Y.; Makino, S.; Noyori, R. JACS 1978, 100,
1786. (b) Noyori, R.; Baba, Y.; Hayakawa, Y. JACS 1974, 96, 3336.
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Alper, H.; Root, W. G. TL 1974, 1611.
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L.J.; Tso, H.-H. JCS(P1) 1986, 1039. (c) Tso, H.-H.; Chou, T.; Hung,
S. C. CC 1987, 1552. (d) Chou, S.-S. P.; Liou, S.-Y; Tsai, C.-Y; Wang,
A.-J. JOC 1987, 52, 4468. (e) Chou, T.; Lee, S.-J.; Peng, M.-L.; Sun,
D.-J.; Chou, S.-S. P. JOC 1988, 53, 3027. (0 Tso, H.-H.; Chou, T.; Lai,
Y.-L. JOC 1989, 54, 4138.
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Eilbracht, P.; Jelitte, R. CB 1983, 116, 243.
Sylvie Samson & G. Richard Stephenson

University of East Anglia, Norwich, UK
O
298
OCTACARBONYLDICOBALT
Octacarbonyldicobalt
[10210-68-1]
C 8 Co 2 O 8
(MW 341.94)
(catalyst for carbonylation and related reactions; major source

of other synthetically useful organocobalt compounds)
Alternate Names: di--carbonylhexacarbonyldicobalt; cobalt carbonyl.
Physical Data: mp 51-52C (dec); subl 40C/vac.
Solubility: insol H 2 O; sol common org solvents.
Form Supplied in: dark orange crystals (commonly stabilized with
5-10% hexane).
Handling, Storage, and Precautions: toxic, moderately air sen
sitive, and unstable at ambient temperature, slowly releasing
carbon monoxide (residual finely divided metal may become
pyrophoric); may be stored for long periods at or below 0 C
in tightly closed vessels under inert gas (N2, Ar) or (best) CO;
brief handling (including weighing) in air causes no problems;
heating in inert solvents yields the less reactive Co 4 (CO) 12 ; use
in a fume hood.
Introduction. In the crystal, the molecule of this reagent con

sists of two cobalt atoms linked both directly and by two bridg
ing carbonyls and each carrying three terminal carbonyls (cf.
eq 33).1 In solution this form is in equilibrium with unbridged
(OC) 4 Co-Co(CO) 4 .
Halogen oxidation only leads to a halocarbonyl species in the
case of iodine; the unstable and incompletely characterized prod
uct, probably ICo(CO) 4 , has found little use. The anion Co(CO) 4 - ,
readily formed by reduction {Sodium Amalgam) or by disproportionation on reaction with bases, including not only pyridine
and other nitrogen bases but also such donor solvents as methanol
and acetonitrile, is treated separately. (See Sodium Tetracarbonylcobaltate.) However, reactions which utilize Co 2 (CO) 8 as starting
material are included here even if the reaction conditions imply
that this anion or its conjugate acid, HCo(CO) 4 (also formed from
Co 2 (CO) 8 + H 2 ), may be the 'active' intermediate. The chemistry
of the reagent has been reviewed.2,3
A valuable feature is the preference for straight chain over

branched chain products; since HCo(CO) 4 is an efficient alkene
isomerization catalyst, this is true even for internal alkenes. Much
research has been devoted to optimizing the product ratio for spe
cific uses, e.g. by adding phosphines or other catalyst modifiers.
While cobalt carbonyl (probably as HCo(CO) 4 ) is an effective cat
alyst for these and many related reactions and has found extensive
industrial use (albeit commonly generated in situ rather than intro
duced as such), it has largely been superseded by related rhodium
catalysts; the greater cost of the latter is offset by much higher
activity and hence efficient conversions using small catalyst con
centrations under much milder reaction conditions. Alkyl halides
and alcohols can replace alkenes in many such reaction.
RCH=CH2 + CO + H2
RCH2CH2CHO + RCH(Me)CHO
(1)
RCH2CH2CH2OH + RCH(Me)CH2OH
(2)
RCH=CH2 + CO + 2H 2
Whereas, in general, reduction of the formyl group (cf. eqs 1

and 2) requires a higher temperature than hydroformylation, re
duction of the C = C double bond can be a major side-reaction
of cobalt-catalyzed hydroformylation. Thus, in the reaction of
eugenol, which is accompanied by cyclization (eq 3), 40% of the
starting material is reduced to dihydroeugenol.9
(3)
The Co2(CO)8-catalyzed alkene hydrogenation can be useful,

as in the smooth reduction of alkylcinnamaldehydes (eq 4), 10 the
highly selective hydrogenation of methyl (E',E')-octadeca-9,11dienoate to methyl elaidate (eq 5), 11 and of a range of polycyclic
aromatics,12 e.g. naphthacene (eq 6).
(4)
e.g. R = t-Bu, 96%
(5)
Catalytic Uses.
Hydroformylation and Hydrogenation. Octacarbonyldicobalt
catalyzes a wide range of reactions of carbon monoxide (alone
or with hydrogen), 2 4 - 8 of which the best known is probably
the hydroformylation ('oxo reaction') of alkenes. Depending on
reaction conditions, notably CO:H 2 ratio and temperature, the
products are aldehydes (eq 1) or alcohols ('hydroalkylation')
(eq 2).
(6)
Dehydration or loss of alcohol accompanies hydroalkylation

(eq 2) when applied to allylic alcohols (giving tetrahydrofurans
rather than 1,4-diols) or to acrylic acids or esters, which give
butyrolactones (eq 7) in moderate to excellent yields. 13
(7)
In more or less related reactions, Co 2 (CO) 8 is a useful cata

lyst in carboxylation (viz. alkoxycarbonylation) and a wide range
of carbonylation reactions. Both catalysis of the water-gas shift
reaction14 and of Fischer-Tropsch processes15 have been demon
strated on solid supports and probably involve Co2(CO)8-derived
polynuclear carbonyls.16
299
rather poor yields quoted in these examples have been attributed to

extensive side-reactions, but specific cases giving excellent results
are also known, e.g. with a carbohydrate epoxide (eq 14).21
(12)
(13)
(14)
Carboxylation and Related Reactions. Although nickel, palla
dium, and other catalysts have been widely studied for carboxyla
tion reactions and are clearly preferable in the case of alkynes, octacarbonyldicobalt (especially in combination with Pyridine) is an
effective catalyst for the conversion of alkenes into acids and esters
(eq 8) and differs significantly in selectivity from the nickel-based
systems. Thus, whereas styrene gives predominantly the branched
esters with both types of catalyst, terminal n-alkenes give predom
inantly branched esters with nickel catalysts, but straight-chain
esters with Co 2 (CO) 8 , as in eq 9.4 The related hydrocyanation
reaction, on the other hand, gives branched-chain products and,
except with the most reactive alkenes, poor yields17 when using
Co 2 (CO) 8 and better nickel-based catalysts are available.
Carboxylations of halogen compounds include the technically

useful conversion of chloroacetate to malonate (eq 15),22 and sev
eral patent reports of quantitative conversion of Benzyl Chloride
to phenylacetic acid.23 The incorporation of two molecules of car
bon monoxide to give -keto-acids, as exemplified by the reaction
of benzyl chloride (eq 16), is remarkably solvent-dependent24 and
almost certainly involves reaction of the halide with Co(CO) 4 - .
(15)
RCH=CH2 + CO + R'OH
(16)
R' = H, Me, etc
RCH2CH2CO2R' + RCH(Me)CO2R'
(8)
A carboxylation which is followed by a Michael addition oc

curs with high overall efficiency when Acrylonitrile reacts in the
presence of an alcohol and pyridine (eq 17).25
C8H17CO2Me + Me(CH2)5CHMeCO2Me +
79%
14%
Me(CH2)4CHEtCO2Me + Me(CH2)3CHPrCO2Me (9)
4%
3%
The condensation of two alkene molecules with Carbon

Monoxide to yield ketones [e.g. ethylene 3-pentanone (95%)] 4
succeeds well only in special cases, e.g. with methyl acrylate
(eq 10).18
(10)
Octacarbonyldicobalt-catalyzed homologation of alcohols

(eq 11) is difficult to control and of little practical value, while
the related carboxylation of methanol to acetic acid requires such
extreme conditions that it cannot compete with the technically
important rhodium-catalyzed process.
(17)
Carbonylation. This term is used here to denote carbon

monoxide insertions (with or without cyclization) which do not
involve H 2 or ROH.
Unlike epoxides, oxetanes react with carbon monoxide in the
presence of Co 2 (CO) 8 by ring expansion to -butyrolactones,
rather than ring opening; thietanes (eq 18) as well as azetidines
(eqs 19 and 20) behave similarly. Mixtures of cobalt and ruthe
nium carbonyls (1:1) are reported to give better yields than either
catalyst separately.26 The examples shown illustrate the strong
dependence of regioselectivity on substitution pattern in the azetidine case. 27
(11)
(18)
Relatively mild conditions suffice for the regioselective car

bonylation (eq 12)19 and carboxylation of epoxides (eq 13).20 The
300
(19)
(20)
Co 2 (CO) 8 -catalyzed reactions of a variety of other nitrogen

compounds, e.g. azo compounds (eq 21), 28 imines (eq 22), 29 and
amides (eq 23), 30 involve CO insertion into N-N and N-H bonds
and cyclizations which probably proceed via cyclometalation.
carbonyl (eq 26) provides a valuable alternative to the

Strecker reaction as a route to N-acyl--amino acids. 8,34-36
Its convenience is enhanced by the possibility of generat
ing the aldehyde in situ by isomerization of an allylic al
cohol for which a cocatalyst [PdCl 2 (PPh 3 ) 2 , Carbonylhydridotris(triphenylphosphine)rhodium(I), or Nonacarbonyldiiron]
is advantageous,37 (e.g. eq 27), or by hydroformylation of an
alkene (e.g. by the reactions of eq 28 which can be combined
to give the N-acetylamino acid in 83% yield 8,38 ), or of an alcohol
(e.g. eq 29). In the last example 39 the product is isolated (as the
methyl ester after Diazomethane treatment) in 73% total yield as
a mixture of threo and erythro isomers.
(26)
(21)
(27)
(22)
(28)
(23)
The mechanism of the remarkable formation of furans31 from

3-diethylamino-l-propyne (or -butyne) (eq 24) (R = H or Me) is
unknown, but it must involve CO insertion into a C-N bond.
(24)
The carbonylation of Diphenyl Diselenide (eq 25) illustrates

the general behavior of diaryl diselenides and ditellurides,32 but
proceeds more smoothly than most other examples studied.
(29)
Other Octacarbonyldicobalt-Catalyzed Reactions. A retroDiels-Alder reaction catalyzed by Co 2 (CO) 8 was observed in

which a barrelene derivative loses a C 2 H 2 fragment (eq 30). 40
An analogous cleavage accompanies the cyclopentenone synthe
sis (see below) when norbornadiene reacts in certain solvents
with alkynehexacarbonyldicobalts, as shown by the formation of
dicarbonylcyclopentadienylcobalt,41 whereas a Diels-Alder addi
tion catalyzed by a cobalt carbonyl species is involved when the
same reaction is applied to cyclohexadiene.42
(25)
(30)
Reversibility of carbonylation processes is illustrated by decarbonylation of phthalic anhydride by Co 2 (CO) 8 under H 2 to

benzoic acid,33 and of Diphenylketene to tetraphenylethylene.34
Carbonylation of alkynes is discussed below in connection with
the stoichiometric reactions of alkyne-cobalt compounds.
Amidocarbonylation. The reaction of aldehydes with pri
mary amides and carbon monoxide in the presence of cobalt
Efficient and appreciably regioselective ring-opening addition

of Cyanotrimethylsilane to tetrahydrofurans is illustrated by the
example shown (eq 31). 43 The same reagent undergoes Co 2 (CO) 8
(or Dicarbonyl(cyclopentadienyl)cobalt(I)) catalyzed addition to
alkynes to give pyrrole derivatives (eq 32). 44
301
(34)
(31)
Greater synthetic interest attaches to the cycloaddition of

dienolates of (3-diketones or -keto esters, illustrated for the
cyclohexadiene complex (eq 35), which leads, after Tetra-nbutylammonium Fluoride treatment of an intermediate (not iso
lated), to dihydrofuran derivatives.
(32)
(35)
Octacarbonyldicobalt shares with many other metal carbonyls

and other organometallics the ability to catalyze the cyclotrimerization of alkynes 45 and related condensations, e.g. of two alkyne
and one nitrile molecule to give pyridines. Derived compounds
including Hg[Co(CO) 4 ] 2 , Co(CO) 3 NO (obtained from Co 2 (CO) 8
with NO or other nitrosating agents) and the alkyne complexes
(RC 2 R')Co 2 (CO) 6 (see below) all share this activity, but none of
these compare in efficiency with the preferred CpCoL2 catalysts.
The few examples of catalytic cyclopentenone formation from
alkyne, alkene, and CO are discussed below, as is the bifurylidenedione synthesis from alkyne and CO. It should also be noted
that Co 4 (CO) 12 , obtained by heating the dinuclear carbonyl, can
probably replace the latter in most of the above catalytic reactions,
but without obvious advantage.
Stoichiometric Reactions.
Reactions with Dienes. Conjugated dienes and norbornadiene
displace two terminal carbonyl groups from first one and then both
metal atoms of the octacarbonyl (eq 33). 46
Cyclopentadiene does not yield an isolable diene com

plex when reacting with Co 2 (CO) 8 , yielding instead Dicarbonyl(cyclopentadienyl)cobalt(I).
Reactions with Alkynes. In contrast to dienes (see above),
alkynes replace the two bridging carbonyls of Co 2 (CO) 8 produc
ing stable, readily isolated complexes in reactions which are nor
mally rapid at room temperature (eq 36). 49 The alkyne moiety lies
at right angles to the Co-Co bond, so that the alkyne carbons form
a tetrahedron with the two cobalt atoms. If the alkyne is terminal
(R2 = H), these products (hereafter drawn in the simplified form
of eq 37) react with acids (e.g. Sulfuric Acid in MeOH) to give
the trinuclear compounds RCH 2 C[Co 3 (CO) 9 ], 50 which also form
directly from the alkyne with Co 2 (CO) 8 at 85 C. 49b (For further
elaboration of such trinuclear complexes see Sodium Tetracarbonylcobaltate, from which a wider range of such compounds is
most conveniently prepared.)
(36)
(33)
Either of these products can be oxidized to [(diene)Co(CO) 3 ] +

salts,47 whose synthetic potential arises from their reactivity to
wards nucleophiles. 47b,48 Whether 1- or 2-substituted butadi
ene ligands react highly regioselectively at the 4-position (e.g.
eq 34), 47b or at both C-1 and C-4, depends both on the substituent and on the nucleophile, but attack at C-2 has only been
found in the reaction of the butadiene complex with Lithium
Diisopropylamide.48b
Reactions of the (RC 2 H)Co 2 (CO) 6 complexes with carbon

monoxide under pressure give lactone complexes 51a,b (reducible
to 7-butyrolactones51c) by insertion of two CO groups into
the Co-C bonds (eq 37); the further stepwise insertion of CO
and alkyne provides the mechanism for the efficient Co 2 (CO) 8 catalyzed synthesis of 2,2'-bifurylidene-5,5'-diones (eq 38). 52 Un
der relatively mild conditions and with a 1:1 ratio of C 2 H 2 :CO,
the extended bifurandiones of eq 39 also become significant
products. 53
(37)
302
(42)
(38)
(39)
The lactone complexes react with tertiary propynylamines at

room temperature in moderate to good yield to give unsaturated
aminolactones (eq 40), 54 while bifurandiones incorporating the
propynyl group and a solvent-derived hydrogen atom result when
quaternary propynylammonium salts are employed under similar
conditions (eq 41). 54
Intermediates of the reaction of eq 42 are not normally ob

served, but some examples of complexes formed from octacarbonyldicobalt and two alkyne moieties are known, e.g. from cyclooctyne, giving a product which promotes the cyclotrimerization of cyclooctyne (eq 43), 57 and also from MeN(CMe 2 C 2 H) 2 . 58
The product of the latter reaction has been treated with
phenylacetylene,58 forming an arene system (eq 44). Thus, both of
these examples show that this type of bis(alkyne)cobalt complex
can also be on the cyclotrimerization pathway.
(43)
(40)
(44)
(41)
Without CO pressure, the monoalkyne complexes react on

warming with an excess of alkyne to incorporate two more
molecules of the latter, giving 'flyover' complexes (eq 42).55
These cyclize on oxidation (by Br 2 ) or on heating (typi
cally to 150-170 C, but in refluxing toluene in the case of
the flyover complex from 3 moles of PhC2COMe 55b ), yield
ing benzene derivatives. This reaction sequence represents a
significantly different mechanism for alkyne cyclotrimerization under Co 2 (CO) 8 catalysis compared, for example, to the
dicarbonylcyclopentadienylcobalt-catalyzed process. The possi
bility of employing two different alkynes (eq 42) should permit
synthesis of a wider range of benzene derivatives and, indeed, the
use of alkynes with bulky R2 groups (e.g. R2 = t-Bu) provides a
route to benzene derivatives with two such groups in adjacent po
sitions (e.g. 1,2-di-r-butyl- and l,2,4,5-tetra-t-butylbenzenes from
the flyovers with R1 = H or t-Bu and R2 = t-Bu). 56 However, since
the initial complex, (R1 C 2 H)Co 2 (CO) 6 , also undergoes alkyne ex
change with the added alkyne, yields are severely limited and
product mixtures are inevitably formed.56
Alkyne Protection, Distortion, and Altered Substituent Re

activity. The hexacarbonyldicobalt moiety of the bridged alkyne
complexes (R 1 C 2 R 2 )Co 2 (CO) 6 can serve as a valuable protect
ing group which allows one to perform on other parts of the or
ganic ligand reactions which would not be possible with the free
alkyne. At the same time, complexation reduces the bond order
from triple to approximately that of a double bond, with corre
sponding change in bond angles. Hence substituents are in much
more favorable locations for many cyclization reactions. Some of
the most elegant synthetic applications use both of these features
in combination with the -cation stabilization discussed in the
next subsection.
The first demonstration of the stabilizing effect59 involved
Friedel-Crafts acetylation of the tolane complex to give regioselectively the 4-acetyl and 4,4'-diacetyl derivatives and the smooth
liberation of the free alkynes by cerium(IV) oxidation. Open-chain
enyne complexes (even with the double and triple bonds conju
gated) were shown60 to undergo smooth acid-catalyzed hydration
and hydroboration/Hydrogen Peroxide oxidation (e.g. eq 45), as
well as reduction of the double bond (by N 2 H 2 ) and again ox
idative decomplexation, while the 5,6-double bond of complexed
5-17-ethynylandrostene-3,17-diol was reduced by hydroboration followed by acetic acid treatment.60 The protective effect has
also been utilized to prevent alkyne-to-allene isomerization during
oxidation of an allylic alcohol function.61
303
(50)
(45)
The effect of distortion is clearly revealed in the macrocyclization of the but-2-yne-l,5-diol complex with diphenyldichlorosilane (eq 46),62 by elegant syntheses of cycloene-diynes related
to calicheamicin (e.g. eq 47),63 10- and 11-membered ring lac
tones (e.g. eq 48),64 but most strikingly in the construction of
the cyclooctadecanonayne system by oxidative coupling of 1,3,5hexatriyne, complexed to phosphine-substituted cobalt carbonyl
(eq 49).65
Cobalt-Complexed Propargyl Cations and Their Reactions. The stability and synthetic utility of hexacarbonyldicobalt
complexed cations was first reported in 1971.60,67 They are readily
formed by protonation of propargyl alcohol complexes or addition
of electrophiles (protons, or alkyl or acyl cations) to vinylacetylene
complexes. They can be isolated in pure form, usually by precipi
tation as hexafluorophosphates or tetrafluoroborates, but are more
commonly generated in situ and used directly. Most of the early
work is due to Nicholas, who has comprehensively reviewed the
work up to 1986.68 A detailed description of the procedure for
generating the 1 -methyl-2-propynyl complex and for its reaction
with trimethylsilyloxycyclohexene (eq 51) has been given.69
(46)
(51)
(47)
More recent studies of the utility of the complexed cations in

synthesis have paid particular attention to stereoselectivity in their
reaction with silyl enolates70 and enol borates,71 e.g. eq 52; in this
case the same products result, but with only 2.5:1 stereoselection when using the triethylsilyl enol ether and Boron Trifluoride
Etherate catalysis.
(48)
(52)
(49)
L2 = Ph2PCH2PPh2
Steric effects of the hexacarbonyldicobalt moiety may be

responsible for altered reactivity, notably enhanced stereoselec
tivity in reactions of adjacent substituents, e.g. formyl groups in
aldol condensations.66 Thus, condensation of trimethylsilylpropynal with the silyl enol ether of cyclopentanone gives a 90% yield
of the aldol product (eq 50) as a 40:60 erythro:threo mixture,
whereas reaction of the Co2(CO)6-complexed aldehyde followed
by cerium(IV) oxidation gives the same total yield, but in an 87:13
diastereomeric ratio.66a
Replacement of one carbonyl group by phosphine (thus creat

ing chirality at cobalt) has been shown to permit enantioselective
addition of nucleophiles to the cations.72 Regioselectivity of aro
matic substitution by the cations has been studied in resorcinol
derivatives73 and examples of aromatic substitution extended to
include indoles.74
An alternative approach to the antitumor active enediyne sys
tems (cf. eq 47) using 'Nicholas cations' has been extensively
studied75 and applied to the dynemycin core structure (eq 53).75c
Another example of the use of such cations in forming strained
rings is the preparation of a cobalt complex of a trithia-crown ether
(eq 54), which has been shown to complex Cu1 and Ag1.76
304
may be achieved with functional substituents, notably electrondonor groups in the homoallylic position, which favor formation
of the 5-substituted product.79 Thus, the example shown in eq 57
is the key step in a formal synthesis of PGA2;80 it also illustrates
the good yields obtainable by the simple thermal reaction in the
case of alkenes with donor substituents.
(53)
(57)
(54)
Cyclopentenone Synthesis. Synthesis of cyclopentenones

from alkynes + alkenes + CO has become a widely used pro
cess and is variously known as the Khand reaction or the
Pauson-Khand reaction. Although inter alia examples promoted
by Pentacarbonyliron, Hexacarbonylmolybdenum, tetracarbonylbis(cyclopentadienyl)ditungsten or -molybdenum, and carbene(pentacarbonyl)chromium have been described, octacarbonyldicobalt is the generally used reactant. The method has been
extensively reviewed.52"'77
The general reaction (eq 55) is most commonly conducted by
preparing the intermediate alkyne complex (R1C2R2)Co2(CO)6,
with or without isolation, before adding the alkene component,
but this is not necessary. Under a CO atmosphere, regeneration
of this complex from added free alkyne occurs and in at least one
case78 efficient catalytic synthesis has been achieved (eq 56). Un
der conditions of complete conversion of 1-heptyne, the product
was obtained in 47-49% yield and contained only 1-2% of the
regioisomer, 3-pentylcyclopent-2-en-1 -one.
(55)
Three more general techniques have greatly improved the ear

lier yields. Discussion of the solid-phase adsorption method is
included in more recent reviews.77a-d It probably remains the
method of choice in selected cases and sometimes has results
different from those of other methods. For example, the predomi
nant reduction to cyclopentanone in the intramolecular reaction of
N-acetyl-N-allylpropargylamine (eq 58)81 and the reductive ether
cleavage when related ethers react on alumina (eq 59),82 is avoided
on silica, in the presence of oxygen, with formation of the expected
bicyclic products.
(58)
(59)
This solid-phase technique has made possible efficient synthe

ses of bi- and polycyclic systems from precursors frequently gen
erated via Nicholas cations, (e.g. eq 60)83 and has been used for
intermolecular reactions with methylenecyclopropane (eq 61) and
methylenecyclobutane to give spirocyclic cyclopentenone deriva
tives. (1) is the major product when the alkyne is terminal (R2 = H),
but only (2) was isolated when EtC2Et or Me3 SiC2Me were used.84
(56)
Such high regioselectivity is typical of terminal alkynes, and

the less reactive internal alkynes show only slightly lower se
lectivity in forming the products with the bulkier group (R1) in
the 2-position. Only strong electronic effects may override this
sterically determined preference (e.g. see eq 63 below). Regiose
lectivity with respect to the alkene is much more variable. Simple
terminal alkenes show little or no selectivity when the alkyne is
also terminal, but significant preference for 5-substitution (R3 in
eq 55) when the alkyne is internal. More efficient regioselection
(60)
305
(61)
(64)
The more recent and now widely used improvement involves

the use of amine oxides, usually Trimethylamine N-Oxide85a or
N-Methylmorpholine N-Oxide.86 Alternatively, while requiring
slightly higher temperature and longer reaction time, DMSO (or
other sulfoxides) can give equally good yields. A range of other
polar solvents (e.g. MeOH, MeCN, HCO 2 Et) also exert a distinct,
but smaller, promoting effect.87
N-Methylmorpholine N-oxide, preferably as monohydrate,79b
as well as Me 3 NO not only induces cyclopentenone formation
under very mild conditions (0-20 C) and in frequently excellent
yields, but also removes some earlier limitations. The reductive
processes (eqs 58 and 59) do not occur when these promoters or
DMSO are used under oxygen. 85,87 Hence two efficient syntheses
of ()-kainic acid88 have employed cyclizations of allylpropargylamine derivatives as the key step; in one of these (eq 62), as
well as in a synthesis of the dendrobine skeleton,89 use of a chiral
precursor was shown to result in enantiospecific bicyclization.88a
(65)
Finally, reference is made to the remarkably facile cyclization

which alkynyl Fischer carbene complexes can undergo 95 under
conditions normally leading only to alkyne-cobalt complex for
mation (eq 66) (M = Cr or W.; R = Ph or Et).
(66)
Related Reagents. Dicarbonyl(cyclopentadienyl)cobalt(I);

Octacarbonyldicobalt-Diethyl(methyl)silane-Carbon Monoxide;
Sodium Tetracarbonylcobaltate.
(62)
Intramolecular cyclizations of enynes using catalytic amounts

of octacarbonyldicobalt (3 mol %) succeed in the presence of
biphenyl phosphite (10 mol %) under 3 atm of CO, typically in
DMF at 120C. 8 5 b
Whereas in earlier work the (uncatalyzed) reaction of alkenes
bearing electron-withdrawing groups with the alkynecobalt com
plexes gave conjugated dienes as the only or major products,77
intramolecular cyclizations involving such groups have now been
accomplished by both the solid-state method90 and using N-oxide
promotion. 91 Moreover, electron-deficient alkynes have been suc
cessfully employed in both inter- and intramolecular cases. The
use of ethyl 2-butynoate (eq 63) illustrates the preferred orienta
tion in this case. 92
(63)
Further examples of the efficiency of the N-oxide method are

the formation of bicyclic lactols (e.g. eq 64), utilized in a synthesis
of ()-loganin, 93 and the quantitative cyclization (eq 65) which
is the key step in a synthesis of decarboxydemethylquadrone.94
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81. Brown, S. W.; Pauson, P. L. JCS(P1) 1990, 1205.
82. Smit, W. A.; Simonyan, S. O.; Tarasov, V. A.; Mikaelian, G. S.; Gybin,
A. S.; Ibragimov, I.I.; Caple, R.; Froen, D.; Kreager, A. S 1989, 472.
83. Gybin, A. S.; Smit, V. A.; Veretenov, A. L. Simonyan, S. O.; Shashkov,
A. S.; Struchkov, Yu. T.; Kuz'mina, L. G.; Caple, R. IZV 1989, 2756;
BAU 1989, 2521.
84. Smit, W. A.; Kireev, S. L.; Nefedov, O. M.; Tarasov, V. A. TL 1989, 30,
4021.
85.
86.
87.
88.
89.
90.
91.
(a) Jeong, N.; Chung, Y. K.; Lee, B. Y.; Lee, S. H.; Yoo, S.-E. SL 1991,
204. (b) Jeong, N.; Hwang, S. H.; Lee,Y.;Chung, Y. K. JACS 1994, 116,
3159.
Shambayati, S.; Crowe, W. E.; Schreiber, S. L. TL 1990, 31, 5289.
Chung, Y. K.; Lee, B. Y.; Jeong, N.; Hudecek, M.; Pauson, P. L. OM
1993, 12, 220.
(a)Takano, S.; Inomata, K.; Ogasawara, K. CC 1992, 169. (b) Yoo, E.-e.;
Lee, S.-H.; Jeong, N.; Cho, I. TL 1993, 34, 3435.
Takano, S.; Inomata, K.; Ogasawara, K. CL 1992, 443.
(a) Veretenov, A.L.;Gybin,A.S.;Smit,V.A.IZV1990,1908;ftW1990,
1736. (b) Veretenov, A. L.; Smit, W. A.; Vorontsova, L. G.; Kurella, M.
G.; Caple, R.; Gybin, A. S. TL 1991, 32, 2109.
van der Waals, A.; Keese, R. CC 1992, 570.
Previous Page
OXALYL CHLORIDE
92.
(a) Krafft, M. E.; Romero, R. H.; Scott, I. L. JOC 1992, 57, 5277.
(b) Fonquerna, S.; Moyano, A.; Perics, M. A.; Riera, A. T 1995, 51,
4239.
93.
Jeong, N.; Lee, B. Y.; Lee, S. M.; Chung, Y. K.; Lee, S.-G. TL 1993,34,
4023.
94.
Forsyth, G. S.; Kerr, W. J.; Ladduwahetty, T. Personal communication.
95.
Camps, F.; Moret, J. M.; Ricart, S.; Vias, J. M. AG(E) 1991, 30,
1470.
307
15
prepared using these methods (eq 2). N-Carboxy-a-amino acid

anhydrides can also be made this way.16
(1)
Peter L. Pauson
University of Strathclyde, Glasgow, UK
Oxalyl Chloride
(2)
[79-37-8]
C 2 Cl 2 O 2
(MW 126.92)
(versatile agent for preparation of carboxylic acid chlorides;1

phosphonic acid dichlorides;2 alkyl chlorides;3 -chloro enones;4
acyl isocyanates5)
Physical Data: mp - 1 2 C; bp 63-64 C/763 mmHg; d
1.48 g c m - 3 ; n20D 1.4305.
Solubility: sol hexane, benzene, diethyl ether, halogenated sol
vents, e.g. dichloromethane and chloroform, acetonitrile.
Form Supplied in: colorless, fuming liquid; widely available; 2M
soln in dichloromethane.
Handling, Storage, and Precautions: liquid and solution are toxic,
corrosive, and severely irritating to the eyes, skin, and respi
ratory tract. Use in a fume hood and wear protective gloves,
goggles, and clothing. Bottles should be stored in a cool, dry
place and kept tightly sealed to preclude contact with moisture.
Decomposes violently with water, giving toxic fumes of CO,
CO 2 , HCl.
Preparation of Carboxylic Acid Chlorides (and Anhy

drides). Oxalyl chloride has found general application for the
preparation of carboxylic acid chlorides since the reagent was
introduced by Adams and Ulich.1 Acid chlorides produced
by this means have subsequently featured in the synthesis of
acyl azides,6 bromoalkenes,7 carboxamides,8 cinnolines,9 diazo
ketones, 10 (thio)esters,11 lactones,12 ketenes for cycloaddition
reactions, 13 intramolecular Friedel-Crafts acylation reactions,14
and the synthesis of pyridyl thioethers.11
Like Thionyl Chloride, oxalyl chloride gives gaseous byprod
ucts with acids and the chlorides can be readily isolated in a pure
form by evaporation of the solvent and any excess reagent, or used
in situ for further elaboration (eq 1).
Prior formation of an amine or alkali metal salt, with or
without pyridine, 1 has been used to advantage with substrates
that are sensitive to strong acids or are bases (see also Oxalyl
Chloride-Dimethylformamide for a procedure conducted under
neutral conditions using silyl esters). By adjusting the molar pro
portions of oxalyl chloride to substrate, anhydrides can also be
The use of nonpolar solvents such as hexane or toluene allows

for the removal of inorganic or amine salts which may otherwise
interfere with subsequent reactions.
Under the mild conditions employed (eqs 3 and 4), 17
racemization of stereogenic centers, skeletal rearrangement, or
byproduct formation, seen with other reagents such as thionyl
chloride/pyridine,18 are seldom observed.
(3)
(4)
Conversion of -bromoacrylic acid to the acid chloride us

ing thionyl chloride/DMF, Phosphorus(III) Chloride, or benzotrichloride/zinc chloride also resulted in bromine for chlorine
exchange. Use of oxalyl chloride with the preformed ammonium
salt provided a mild, general method to -bromoacryloyl chlo
rides (eq 5) 19 without halogen exchange or (EIZ) equilibration.
-Fluoro- and iodoacrylic acids have been cleanly converted to
the acid chlorides without prior salt formation.
(5)
As well as forming acid chlorides, -tertiary amino acids can

react with oxalyl chloride and undergo an oxidative decarboxy
lation to give iminium salts, or ring expansion, depending on the
substituents and their stereochemistry (eq 6). 20
Preparation of Phosphonic Acid Chlorides. Phosphonic acid
dichlorides have been obtained in high yield (determined by 31 P
308
OXALYL CHLORIDE
NMR) at low temperature from the corresponding acids using

oxalyl chloride and Pyridine (eq 7).2
Preparation of Chloroalkanes. Alcohols react with oxalyl

chloride to give oxalyl monoalkyl esters, which if heated in the
presence of pyridine give the alkyl chloride (eq 11).3
(6)
R1
R2
Me
H
H
H
t-Bu
CO2Me c-Hex
Me
Me
R3
Tertiary alcohols have been converted to tertiary chlorides in

a Barton-Hunsdiecker type radical process using hydroxamate
esters (eq 12).27
% Yield
(A) (B)
0
0
30
(11)
69
59
0
(7)
R = Et, PhCH2, CF2H, arabinomethyl, phthalidyl
(12)
Similarly, monoalkyl methylphosphonochloridates (eq 8)21

can be made from dialkyl esters; thionate acid chlorides could
not be made by this method. Thionyl chloride and PCl5 were
also used to make this type of compound (see also Oxalyl
Chloride-Dimethylformamide).
(8)
e.g. R = Me(CH 2 ) 16 CMe 2 -
Chlorination of Alkenes. A novel stereospecific dichlorination of electron rich alkenes has been reported using a manganese
reagent generated from Benzyltriethylammonium Chloride and
oxalyl chloride (eqs 13-17).28 No oxygenation byproducts are
observed.
R = Me, Et, Pr, i-Pr, Bu
Numerous other reagents such as PCl3, PCl5, POCl3, and

Ph3P/CCl4 are available for the preparation of acid chlorides and
anhydrides but may not be as convenient as the byproducts are not
so easily removed, or the reactions require more vigorous condi
tions.
Direct Introduction of the Chlorocarbonyl Group (Halocarbonylation). Alkanes or cycloalkanes react with oxalyl chloride
under radical conditions; typically, mixtures are produced.22 How
ever, bicyclo[2.2.1]heptane undergoes regio- and stereospecific
chlorocarbonylation, giving the ester on subsequent methanolysis
(eq 9).23
(13)
(14)
(15)
(9)
(16)
Certain alkenes such as 1-methylcyclohexene and styrene react

with oxalyl chloride, under ionic conditions without added cat
alyst, to give alkenoic acid chlorides in variable yields. Alkenes
such as octene and stilbene did not react under these conditions.24
Reactions of aromatic compounds with oxalyl chloride/Lewis
acid catalysts have been reviewed.25 Anthracene is unusual as it
undergoes substitution without added catalyst (eq 10).26
(10)
(17)
Reactions with Carbonyl Groups. Unsaturated 3-keto

steroids give the corresponding 3-chloro derivatives with ox
alyl chloride (eq 18).4 Prolonged heating can give rise to
OXALYL CHLORIDE
4
aromatization. Tropone gives the chlorotropylium chloride in

high yield.4 In a related reaction, 1,2-dithiol-3-ones and -3-thiones
give dithiolium salts when heated in toluene or chloroform with the
reagent.4 A range of -chloro enones has been prepared from diketones. Dimedone gives the -chloro enone in high yield (eq 19).29
Keto esters did not react to give -chloro esters.
309
Related Reagents. Dimethyl Sulfoxide-Oxalyl Chloride;

Oxalyl Chloride-Aluminum Chloride.
1. Adams, R; Ulich, L. H. JACS 1920, 42, 599.

2.
3.
Stowell, M. H. B.; Ueland, J. M.; McClard, R. W. TL 1990, 31, 3261.

Rhoads, S. J.; Michel, R. E. JACS 1963, 85, 585.
4.
(a) Moersch, G. W.; Neuklis, W. A.; Culbertson, T. P.; Morrow, D. F.;

Butler, M. E. JOC 1964, 29, 2495. (b) Haug, E.; Fohlisch, B. ZN(B)
1969, 24, 1353 (CA 1970, 72, 43 079m). (c) Bader, J. HCA 1968, 57,
1409. (d) Faust, J.; Mayer, R. LA 1965, 688, 150.
(a) Speziale, A. J.; Smith, L. R. JOC 1962, 27, 3742. (b) von Gizycki,
U. AG(E) 1971,10, 403.
' (18)
5.
6.
(19)
-Keto aldehydes give a single regio- and stereospecific isomer,

the chlorine being cis to the carbonyl group (eq 20).
(20)
(a) van Reijendam, J. W.; Baardman, F. S 1973, 413. (b) Lemmens, J.

M.; Blommerde, W. W. J. M.; Thijs, L.; Zwanenburg, B. JOC 1984, 49,
2231.
7. Paquette, L. A.; Dahnke, K.; Doyon, J.; He, W.; Wyant, K.; Friendrich,
D. JOC 1991, 56, 6199.
8. Keller-Schierlein, W.; Muller, A.; Hagmann, L.; Schneider, U.; Zhner,
H. HCA 1985, 68, 559.
9. Hutchings, M. G.; Devonald, D. P. TL 1989, 30, 3715.
10.
11.
(a) Wilds, A. L.; Shunk, C. H. JACS 1948, 70, 2427. (b) Hudlicky, T;
Kutchan, T. TL 1980, 21, 691. (c) Duddeck, H.; Ferguson, G.; Kaitner,
B.; Kennedy, M. JCS(P1) 1990, 1055.
(a) Szmuszkovicz, J. JOC 1964, 29, 843. (b) Hatanaka, M.; Yamamoto,
Y.; Nitta, H.; Ishimaru, T. TL 1981, 22, 3883. (c) Cochrane, E. J.; Lazer,
S. W.; Pinhey, J. T.; Whitby, J. D. TL 1989, 30, 7111.
12.
Certain triketones give 3-chlorides with excess oxalyl chloride,

in good yield (eq 21).30
(21)
Bacardit, R.; Cervell, J.; deMarch, P.; Marquet, J.; Moreno-Manas, M.;
Roca, J. L. JHC 1989, 26, 1205.
13. (a) Brady, W. T.; Giang, Y. F. JOC 1985, 50, 5177. (b) Snider, B. B.;
Allentoff, A. J. JOC 1991, 56, 321.
14. (a) Burke, S. D.; Murtiashaw, C. W.; Dike, M. S.; Smith-Strickland, S.
M.; Saunders, J. O. JOC 1981, 46, 2400. (b) Satake, K.; Imai, T.; Kimura,
M.; Morosawa, S. H 1981, 76, 1271.
15.
Preparation of Acyl Isocyanates and Aryl Isocyanates.

Certain primary carboxamides can be converted to acyl iso
cyanates in yields from 36-97% with the reagent (eq 22);5 Phos
gene gives nitriles under similar conditions. Oxalyl chloride has
found limited application for the preparation of triazine and
quinone isocyanates.5
(a) Wingfield, H. N.; Harlan, W. R.; Hanmer, H. R. JACS 1953, 75, 4364.
(b) Schrecker, A. W.; Maury, P. B. JACS 1954, 76, 5803.
16. Konopinska, D.; Siemion, I. Z. AG(E) 1967, 6, 248.
17. (a) Ihara, M.; Yasui, K.; Takahashi, M.; Taniguchi, N.; Fukumoto, K.
JCS(P1) 1990, 1469. (b) Nordlander, J. E.; Njoroge, F. G.; Payne, M. J.;
Warman, D. JOC 1985, 50, 3481.
18.
19.
20.
(22)
R = ClCH2, CCl3, PhCH2, 3,4-Cl2C6H3, Ph2CH
Miscellaneous Applications. Oxalyl chloride has been used

in the preparation of 2,3-furandiones from alkenyloxysilanes,31
o-aminophenols from N-aryl nitrones,32 dihydroquinolines
via a modified Bischler-Napieralski ring closure,33 2,3-furoquinoxalines from quinoxazolones,34 sterically hindered salicylaldehydes from phenoxyoxalyl chlorides,35 and in mild cleav
age of 7-carboxamido groups in cephalosporin natural products,
without cleavage of the lactam ring or disruption of optical
centers.36
21.
22.
23.
24.
25.
26.
27.
28.
(a) Simon, M. S.; Rogers, J. B.; Saenger, W.; Gououtas, J. Z. JACS 1967,
89, 5838. (b) Krubsack, A. J.; Higa, T. TL 1968, 5149.
(a) Stack, D. P.; Coates, R. M. S 1984, 434. (b) Gillet, J. P.; Sauvtre,
R.; Normant, J. F. S 1982, 297. (c) Wilson, R. M.; Commons, T. J. JOC
1975, 40, 2891.
(a) Wasserman, H. H.; Han, W. T.; Schaus, J. M.; Faller, J. W. TL 1984,
25,3111. (b) Clough, S. C.; Deyrup, J. A. JOC 1974, 39, 902. (c) Sardina,
F. J.; Howard, M. H.; Koskinen, A. M. P.; Rapoport, H. J. JOC 1989, 54,
4654.
Pelchowicz, Z. JCS 1961, 238.
(a) Kharasch, M. S.; Brown, H. C. JACS 1942, 64, 329. (b) Tabushi, I.;
Hamuro, J.; Oda, R. JOC 1968, 33, 2108.
Tabushi, I.; Okada, T.; Oda, R. TL 1969, 1605.
(a) Kharasch, M. S.; Kane, S. S.; Brown, H. C. JACS 1942, 64, 333.
(b) Bergmann, F.; Weizmann, M.; Dimant, E.; Patai, J; Szmuskowicz, J.
JACS 1948, 70, 1612.
Olah, G. A.; Olah, J. A. In The Friedel-Crafts Reaction; Olah, G. A.,
Ed.; Interscience: New York, 1964; Vol. 3, p. 1257.
Latham, H. G.; May, E. L.; Mosettig, E. JACS 1948, 70, 1079.
(a) Barton, D. H. R.; Crich, D. CC 1984, 774. (b) Crich, D.; Forth, S. M.
S 1987, 35.
Mark, I. E.; Richardson, P. R TL 1991, 32, 1831.
310
29.
OXALYL CHLORIDE
(a) Clark, R. D.; Heathcock, C. H. JOC 1976, 41, 636. (b) Pellicciari, R;
Fringuelli, F; Sisani, E.; Curini, M. JCS(P1) 1981, 2566. (c) Biichi, G.;
Carlson, J. A. JACS 1969, 91, 6470.
30.
Lakhvich, F. A.; Khlebnicova, T. S.; Ahren, A. A. S 1985, 784.
31.
32.
33.
Murai, S.; Hasegawa, K; Sonoda, N. AG(E) 1975, 14, 636.

Liotta, D.; Baker, A. D.; Goldman, N. L.; Engel, R. JOC 1974,39, 1975.
Larsen, R. D.; Reamer, R. A.; Corley, E. G.; Davis, P.; Grabowski, E. J.
J.; Reider, P. J.; Shinkai, I. JOC 1991, 56, 6034.
34.
Kollenz, G. LA 1972, 762, 13.
35.
Zwanenburg, D. J.; Reynen, W. A. P. S 1976, 624.
36.
Shiozaki, M; Ishida, N.; lino, K.; Hiraoka, T. TL 1977, 4059.
Roger Salmon
Zeneca Agrochemicals, Bracknell, UK
PENTACARBONYLIRON
Pentacarbonyliron1
[13463-40-6]
C5FeO5
(MW 195.90)
(diene complexation;4 carbonyl insertion;62-64 cycloaddition;

reduction96 and deoxygenation)
Physical Data: mp -20C; bp 103C; fp -15C; d
1.490gcm~3; n 1.5196; X-ray diffraction studies at -100C
confirm the trigonal bipyramidal structure of Fe(CO)5.2
Solubility: miscible with organic solvents.
Form Supplied in: straw-yellow liquid.
Handling, Storage, and Precautions: Fe(CO)5 is a volatile,
flammable, and highly toxic liquid,3 which does not react with
air at room temperature. It has a relatively high vapor pres
sure (21 mmHg at 20C). When Fe(CO)5 is exposed to light,
Fe2(CO)9 impurity slowly accumulates. The monomelic pentacarbonyl complex can be purified by trap-to-trap distillation
in a vacuum system, but for routine use this purification step is
usually omitted. Use in a fume hood.
Diene Complexation. Tricarbonyl(4-butadiene)iron(0), the

first iron-diene complex, was prepared as long ago as 1930 by
Reihlen and co-workers, by heating butadiene with Fe(CO)5.4
Subsequently, substituted derivatives were studied by Pettit's
group and by others.5 The first complex of a cyclic di
ene, tricarbonyl(4-cyclohexadiene)iron(0), became available in
1958.6 The real breakthrough for the development of synthetic
methods sprang from pioneering work with substituted complexes
in the cyclic (particularly cyclohexadiene) series in the 1960s and
1970s, by Birch,7-10 Lewis,11,12 and co-workers, then of the group
of Pearson,13 work which was initiated by the discovery by Fischer
and Fischer in 196014 of hydride abstraction from tricarbonyl(4cyclohexadiene)iron(0) to yield an 5 iron-complexed cyclohexadienyl cation.
A wide range of methods are now available for the prepara
tion of 4-diene tricarbonyliron complexes, but by far the most
common technique remains the direct complexation of free dienes. Fe(CO)5 is less reactive than Fe2(CO)g or Fe3(CO)12, but
under the right conditions it provides an inexpensive and effi
cient route to iron-alkene complexes, particularly from the 1,4cyclohexadienes.
1,4-Diene Complexation.
Thermal Complexation. Because 1,4-cyclohexadienes are
readily available from the metal-ammonia reduction (Birch reduc
tion) of the corresponding aromatic compounds,15 they have been
extensively studied as substrates for direct 1,4-diene complexa
311
tion, leading to isomerized 1,3-diene complexes. This method

ology suffers, however, from the disadvantage that products are
often obtained as mixtures of regioisomers. Fe(CO)5 provides a
simple, low-cost source of Fe(CO)4 for initial addition to the system of a double bond. By recycling the reagents and the uncomplexed ligand, preparations on a 50-60 g scale can be achieved
from a series of overnight thermal reactions. The procedure most
frequently used, that of Cais and Maoz,16 modified by Birch,8 in
volves heating a cyclohexadiene with pentacarbonyliron in boil
ing di-rc-butyl ether. In the extensive literature on the formation
of differently functionalized tricarbonyl(1,3-cyclohexadiene)iron
complexes from substituted 1,4-cyclohexadienes8-91,11,21,7,20 (in
cluding the tricarbonyliron complexes of a number of dihydroanisic esters,18 various cyclohexadiene esters,919 and 1methoxy-2,4-dimethyl-1,4-cyclohexadiene21), at present the most
useful and representative intermediates for synthetic applications
carry methoxy substituents on the diene ligand. For example, 2,5dihydroanisole (1) or 4-methyl-2,5-dihydroanisole (2) upon treat
ment with pentacarbonyliron at elevated temperature afford a mix
ture of the 1- and 2-OMe substituted complexes (3) and (5) or (4)
and (6) (eq 1). 7-9,11,12,22
(1)
(1)R = H
(2) R = Me
(3) R = H
(4) R = Me
(5) R = H
(6) R = Me
Although 1-methoxy-1,4-cyclohexadiene itself leads to a mix

ture of the 1 - and 2-OMe complexes, bicyclic compounds of sub
stitution type (7) do not give the 2-OMe regioisomer, affording
instead a mixture of complexes (8) and (9) in a 1:1 ratio (eq 2).22,23
In a more unusual case, an amide substituent was present on the
1,4-diene.24
(2)
More extensive rearrangement of the position of unsaturation

in ,-dienes also leads to4-dienecomplexes.25 In other cases
where rearrangement is blocked, homoconjugated dienes can form
stable bis(alkene) complexes by thermal reaction with Fe(CO)5.26
Isotetralene offers an unusual case where rearrangement to the
1,3-diene is possible, but a 1,4-diene complex is reported.27
Photolysis. Photolysis offers an alternative for the direct con
version of 1,4-dienes into 1,3-diene complexes. In eq 3 the
deuterium labeling reveals that isomerization during complex
ation of the 1,4-diene precursor proceeds by a 1,3-hydrogen
transfer.28
(3)
312
PENTACARBONYLIRON
The direct complexation of 1,4-dienes can form specific

stereoisomers. Initial -complexation occurs before the conju
gation step, and the hydrogen atom moves only on the face of the
ligand carrying the metal.29 Unfortunately, a mixture of regioisomers usually results, which may present separation problems.
Loss of OMe can also sometimes occur, particularly from some
l,3-dimethoxy-l,4-cyclohexadienes. In these cases, preconjugation of the diene is essential30 if a dimethoxydiene complex is
required. Mixtures of complexes obtained from 1,4-dienes may
also be equilibrated31 to thermodynamic ratios of isomeric com
plexes, which do not correspond to the equilibrium ratios of the
free dienes.32,33
1,3-Diene Complexation.
Thermal Complexation. Low yields and mixed products ren
der some nonconjugated dienes unattractive as precursors for 4complexes. For many synthetic applications, cleaner routes are
required to form a single defined compound in good yield. A good
approach employs a conjugation step prior to complexation.30 The
1-NR2 series can usually be conjugated thermally.33 Equilibration
of 1 -methoxy-1,4-cyclohexadiene with the 1,3-diene (ca. 75%) us
ing potassium in liquid ammonia as catalyst yields only the 1-OMe
substitution pattern on the conjugated isomer.34 Other conjugation
catalysts include bases,35 Wilkinson's catalyst,36 Cr derivatives,29
and charge-transfer complexation reagents such as dichloromaleic
anhydride.37 Frequently, only about 70-80% of the conjugated
isomer is present at equilibrium,38 but the complexation product,
if formed under mild conditions, corresponds to the conjugated
isomer present. This process of preconjugation followed by com
plexation, using the usual Fe(CO)5 thermal methodology, has led,
for example, to an important key intermediate in the synthesis39 of
limaspermine. The use of azadiene catalysts improves the thermal
complexation reaction.40
Complexation of dienes with several methyl,41 alkyl,42 or
methoxy43 groups is straightforward, but with bulky substituents, rearrangements can lead to the formation of mixtures of
products,44 and care is also needed in the presence of side-chain
leaving groups.45 Trialkylsilyl-substituted dienes complex well. In
the reactions of 2-(trimethylsilyl)-l,3-cyclohexadiene derivatives
with excess pentacarbonyliron in refluxing di-n-butyl ether,46 (10)
gave rise to an 8:2 mixture of (11) and its epimer (12), with coor
dination to Fe(CO)3 occurring preferentially on the less hindered
face of the 1,3-cyclohexadienyl ring (eq 4).
(4)
Photochemical Complexation. The studies of Birch et al. on the

thebaine modification using tricarbonyliron complexes47,48 exem
plify the possibility of complexation of 1,3-dienes by photolysis,
and illustrate the potential for iron complexes to ensure control of
skeletal rearrangement. Thus, via the initial step of complexation
of the methoxycyclohexadiene ring of thebaine (13), practically
quantitative access to northebaine (14) and 14-substituted theLists of Abbreviations and Journal Codes on Endpapers
bainone derivatives could be easily obtained with Fe(CO)5 under

UV irradiation (eq 5).47
(5)
Thermal and Photochemical Reactions in Other Ring Sizes.

Similar complexation reactions can be performed in seven- and
eight-membered rings,49 but with cyclopentadiene the reaction
takes a different course, producing a dimeric cyclopentadienyl
complex.50 Complexation of silyl-substituted cyclopentadienes
afforded dinuclear products.51 In more unsaturated systems, com
peting reduction processes are possible. Cycloheptatriene re
acts with pentacarbonyliron to give a mixture of tricarbonyliron
complexes of cycloheptatriene and 1,3-cycloheptadiene.52 Sub
stituted cycloheptatrienes53 and cycloheptadienes54 can also be
complexed. Thermal complexation of divinylpyrrolidines forms
exocyclic diene complexes by rearrangement of the location of
unsaturation.55
Complexation Using Fe(CO)5 and Me3NO. Reaction of a con
jugated diene with Fe(CO)5 in the presence of Trimethylamine
N-Oxide resulted in the formation of tricarbonyl(l,3-diene)iron
complexes. The use of amine oxides, preferably Me3NO, per
mits fast reactions even at low temperatures. Reduction of amine
oxides by Fe(CO)5 has been described by Alper et al.56 and, in
the case of trimethylamine N-oxide, the intermediate compound
trimethylaminotetracarbonyliron was isolated (eq 6).57,58
Fe(CO)5 + Me3NO
Me3NFe(CO)4 + CO2
(6)
The reverse reaction, namely the known disengagement of the

ligand from the (diene)Fe(CO)3 complex, presents no problem be
cause of the lower reaction temperature and the smaller molar ratio
of Me3NO:Fe(CO)5 employed in the complexation procedure.57
Trimethylaminotetracarbonyliron is attractive as a mild reagent
but further generalization is needed.
Acyclic Series. The first complex in the acyclic series was pre
pared from butadiene by the thermal method.4 Heating isoprene
and pentacarbonyliron at high temperature, however, is ineffi
cient due to competitive Diels-Alder dimerization. Despite the
formation of some bis(diene) iron carbonyl complexes on pro
longed irradiation, the photochemical method is superior in this
case. Complexation of acyclic dienes by Fe(CO)3 is limited to
those that can adopt a cisoid conformation, with the syn substitu
tion pattern normally preferred. 2,4-Hexadienoic acid, for exam
ple, can be conveniently complexed by a photolytic procedure.59
Trialkylsilyl-substituted dienes have also been complexed.60
Isomerization of Alkenes. In some cases the positional rear
rangement of alkenes affords useful products which are not 1,3diene complexes. The isomerization of allyl ethers in the presence
of Fe(CO)5 under UV irradiation has also been reported.61
PENTACARBONYLIRON
Ring-Opening Reactions with Carbonyl Insertion.

Cyclopropane rings. Synthesis of (diene)Fe(CO)3 complexes,
and of cyclohexenones, lactones, ketones, or sulfones, can fol
low from the opening of vinylcyclopropanes with Fe(CO)5 un
der either thermal or photochemical conditions. Reactions of the
vinylcyclopropane (15) with Fe(CO)5 under thermal conditions
resulted in ring opening with concomitant hydrogen shift to form
the dienecomplex (16) (eq 7).62,63,64
313
gives mixtures of diastereoisomers. Subsequent treatment of ferralactones with Cerium(IV) Ammonium Nitrate results predomi
nantly in the formation of -lactones, with a few exceptions where
-lactones are obtained.70
A thermal treatment of the ferralactone displaces one molecule
of CO. The ,-unsaturated epoxide (22) forms the lactone (23) af
ter irradiation in the presence of Fe(CO)5, but subsequent heating
leads to the formation of the (hydroxycyclohexadiene)Fe(CO)3
complex (24) (eq 10).67
(10)
(7)
The reaction of (16) under photochemical conditions led to (17)

by ring opening and carbonyl insertion. Conjugation may occur,
forming the cyclohexenone (18) (eq 7).65 The expansion of the
carbon skeleton of terpene hydrocarbons via carbonylation offers
an interesting means to prepare optically active strained ketones
(eq 8).66
UV irradiation of 9-oxabicyclo[6.1.0]nona-2,4,6-triene (25)

(the monoepoxide of cyclooctatetraene) in the presence of
Fe(CO)5 promotes an overall 1,2 to 1,4 skeletal rearrangement
via the lactone (26) and the Fe(CO)3 complex (27) to form
the Fe(CO)3-Fe(CO)4 complex (28). Subsequent decomposition
of the bis(iron) complex (28) gave the previously unknown 9oxabicyclo[4.2.1]nona-2,4,7-triene (29) (eq 11).71
(8)
(11)
Regiocontrol, however, is a limitation. In the reaction between

(+)-2-carene (19) and Fe(CO)5, five compounds are isolated. A
recent study67 improved the reaction with (+)-2-carene and ex
tended the method to (+)-3-carene.
Epoxide Rings. The synthesis of alcohols, -lactones, and bicyclic derivatives occurs via a ferralactone complex. Irradiation
of ,-unsaturated epoxides in the presence of Fe(CO)5 yields
ferralactone complexes by ring opening and CO insertion (eq 9).
For example, the vinyloxirane (20) gives the lactone (21).68
(9)
While the photochemical reaction69 proceeds stereospecifically, the thermal process between Fe(CO)5 and vinyl epoxides
Carbonylative Ring Expansion. When either - or -pinene

(30) or (31) is heated neat with an equimolar amount of Fe(CO)5
under an initial pressure of 30 psi CO at 160 C, two ketones
(32) and (33) are obtained, formed by insertion of CO into the
cyclobutane ring (eq 12).72 Both ketones are optically active.
Dehalogenation Reactions.
Coupling of gem-Dihalides. Pentacarbonyliron effects dehalogenative coupling of dichloro- or dibromodiphenylmethane
and benzylic gem-dihalides to form alkenic compounds in good
yields (eq 13).73
-Halo Ketones. Treatment of -halo ketones (34) with
Fe(CO)5 was found by Alper to result in formation of coupled
1,4-diketones (35) and reduced monoketones (36) (eq 14).74
314
PENTACARBONYLIRON
(18)
(12)
Dehydration and Dehydrosulfuration Reactions. Certain

amides and thioamides, on treatment with Fe(CO) 5 , yield ni
triles or imines depending on the degree of substitution present
(eq 19).80 Dithioesters, on the other hand, form trinuclear iron
carbonyl complexes. 81
(19)
(13)
(14)
Reaction with Oximes; Deprotection of Ketones. Re

generation of protected ketones from their oximes can be achieved
by refluxing the oxime in di-n-butyl ether with one equiv of
Fe(CO) 5 and a catalytic amount of a Lewis acid (eq 20). 82
,'-Dibromo Ketones and ,,',.'-Tetrabromo Ketones.

Although dehalogenation combined with carbon-carbon bond for
mation is more commonly performed with Nonacarbonyldiiron,
Fe(CO)5 may also be used. The use of a tribromo ketone, followed
by a separate reductive dehalogenation step, is illustrated for the
synthesis of carbocamphenilone (eq 15), a compound of interest
as a skewed glyoxal model. 75
(20)
(15)
Other Reactions Occurring with Carbonyl Insertion.
The reaction between the allylic bromide (37) and Fe(CO)5
constitutes an alternative method of preparation of tricarbonyl(1,3cyclohexadiene)iron (38) (eq 16).76 Allylic alcohols react in a sim
ilar way (eq 17) under neutral conditions,77 but in the presence of
acid (HBF 4 ), cationic 3 iron carbonyl complexes are produced.78
Carbonylation of Benzyl Halides. Benzyl halides can be con

verted into phenylacetic acids by reaction with Fe(CO)s . 83 Phasetransfer catalysis is useful in this reaction.84
(16)
Nucleophiles. Nucleophiles such as amines (eq 21) 86 and

organolithium reagents (eq 22) 87 are also found to react with
Fe(CO) 5 to give products of CO insertion. Cyclopentadienide,
on the other hand, undergoes an unusual tricarbonylation reac
tion to form a cyclopentadienyl complex with an iron-acyl bridge
connecting the metal and the cyclopentadienyl ring (eq 23). 88 The
product was isolated by protecting the two OH groups. An aryllithium reagent, in which the aromatic ring is bound to a tricarbonylchromium group, also follows a different reaction path, and
bimetallic tetracarbonyliron ferrate derivatives are isolated.89
(17)
Benzohydroxamoyl Chlorides. Benzohydroxamoyl chlorides

(39) are converted into nitriles (40) when refluxed with Fe(CO) 5
in THF (eq 18).79
Diazonium Salts. Carboxylic acids or ketones are obtained

from the reaction of diazonium salts with Fe(CO) 5 , depending
on the reaction conditions. 85
RNH2 + Fe(CO)5
RNHCHO
R2NH + Fe(CO)5
R2NCHO
(211
PENTACARBONYLIRON
315
(26)
(22)
(23)
(27)
An arylmethylmalonate derivative, with an ortho iodine substituent on the aromatic ring, undergoes a carbonylative cyclization by oxidative addition to the aryl iodide and reaction at the
nucleophilic center of the malonate group.90
Formylation and Acylation of Pyridine. Direct formylation
and acylation at the -position of pyridine is possible by reaction
with phenyllithium and then with Fe(CO)5. 2-Phenylpyridine is
also formed in these reactions.91
Formation ofN,N'-Disubstituted Ureas. The substituted ureas
are prepared in about 50-95% yield by reaction of aryl or alkyl
nitro compounds with the MgBr derivative of an amine in the
presence of Fe(CO)5 (eq 24).92
R'NHMgBr + R2NO2
R1NHCONHR2
Deoxygenation of Epoxides. Fe(CO)5 in N,N-dimethylacetamide or tetramethylurea deoxygenates epoxides (2 h,

145 C). The reaction is not stereospecific: trans-stilbene oxide is
converted into both trans- (56%) and cw-stilbene (22%).100 Epox
ides of 1 -alkenes are converted mainly into mixtures of internal
alkenes.
Stabilization of Reactive or Unstable Species. The complex
(42), formed from the reaction between the dibromoxylene (41)
and Fe2(CO)9 or Na2Fe(CO)4, reacts with Fe(CO)5 to yield the
mixture of stereoisomers (43) and the complex (44) (eq 28).101
With pentacarbonyliron, however, (41) is taken directly on to an
indanone by carbonylative cyclization (see above).102
(24)
Formation of Carboxylic Esters9395 and Ketones.94 Grignard

reagents can also be converted into esters and ketones by Fe(CO)5
(to supply CO). A cathodic ester synthesis from alcohols and
alkyl halides uses carbon monoxide (at 1 atm) and Fe(CO)5 as
a catalyst.95
(28)
Deoxygenation Reactions and Reductions.

Deoxygenation of N-0 Bonds. Deoxygenation of amine ox
ides has been discussed above (see eq 6); pyridine N-oxides pro
vide a further illustration (eq 25).96
(25)
A pentafulvalene has been trapped as a diiron complex us

ing Fe(CO)5.103 Thiophene dioxide has also been stabilized as
its tricarbonyliron complex.104 The irradiation of -pyrone (45)
in the presence of Fe(CO)5 gives cyclobutadiene stabilized by
complexation with the Fe(CO)3 moiety (46), together with the
(a-pyrone)Fe(CO)3 complex (47) (eq 29).105
(29)
Nitroso Compounds. Similar treatment of nitrosobenzene re
sulted in a 75% yield of azobenzene. Aromatic N-nitroso
amines have been converted into the secondary amines in
85-92% yields.97 Under photolytic conditions, azoxyarenes are
produced.98 The choice of solvent is important. Dialkylnitrosoamines afford ureas (eq 26).97
Aromatic Nitro Compounds. Indoles are formed99 by Fe(CO)5
catalyzed deoxygenation of o-nitrostyrenes with CO (eq 27).
Reactions with Alkynes.

Dimerization. Two alkynes can be combined to form a
cyclobutadiene ligand. The reaction has been reported for a
dialkylamino trimethylsilyl-substituted alkyne, and forms a diaminocyclobutadiene complex.10*
Avoid Skin Contact with All Reagent.
316
PENTACARBONYLIRON
Dimerization with Insertion of One Molecule of CO. A

number of tricarbonyliron complexes of substituted cyclopentadienones have been prepared from alkynes. The reaction was
first described by Jones et al.107 for Fe(CO)5 and Ph-CCH in
the presence of Ni(CO)4. A number of other alkynes (PhC2Me,
PhC2SiMe3, Me3SiC2R, BrC6H4C2H, CF3C2CF3, PhC2Ph and
a,co-diynes) give cyclopentadienone complexes (eq 30).108
(30)
Cyclization of an alkyne to an alkene with carbonyl insertion

(analogous to the Pauson-Khand reaction) has also been achieved
using pentacarbonyliron.109
(34)
Anionic Iron Carbonyl Reagents. The reagent [HFe(CO)4]can be generated in situ from pentacarbonyliron, allowing straight
forward, regiocontrolled, hydroxycarboxylation of acrylic acid by
Fe(CO)5, Ca(OH)2, and H2O/i-PrOH under 1 atm of CO.116
Formation of Iron Carbene Complexes. Fe(CO)5 is
the starting material for the preparation of the tetracarbonyl(ethoxyphenylmethylidene)iron(0) (50) (eq 35).117
(35)
Dimerization with Insertion of Two Molecules of CO. By ma

nipulating reaction conditions, formation of benzoquinones can be
achieved (eq 31).110
(31)
Iron carbene complexes react with alkynes under CO atmo

sphere to form (a-pyrone)Fe(CO)3 complexes.118
Modified Corey-Winter Alkene Synthesis. Daub et al.119
have obtained satisfactory yields by using Fe(CO)5 in an ironmediated version (eq 36) of the reaction of thionocarbonates with
Trimethyl Phosphite, which gives poor yields in the case of ther
mally labile alkenes.
Reaction with Allenes. A diallene, hexatetraene (eq 32), reacts

with Fe(CO)5 with insertion of carbon monoxide to form 2,5dimethylenecyclopent-3-enone.111 Allenyl ketones, on the other
hand, form dinuclear complexes.112
(36)
(32)
1.
Formation of Naphthoquinones via Iron Metallocycles. Benzocyclobutenedione (48) forms the iron complex (49)
by irradiation with Fe(CO)5.113 Complex (49) reacts with a wide
variety of alkynes to give naphthoquinones, in yields usually >70%
(eq 33).
(33)
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J.; Shively, Jr., R. J.; Dubbert, R. A. OM 1992, 11, 4096. (c) Knlker,
H.-J.; Heber, J.; Mahler, C. H. SL 1992, 1002.
109.
Pearson, A. J.; Dubbert, R. A. OM 1994, 13, 1656.
110.
Reppe, W.; Vetter, H. LA 1953, 582, 133.
111.
Eaton, B. E.; Rollman, B.; Kaduk, J. A. JACS 1992, 114, 6245.
112. Trifonov, L. S.; Orahovats, A. S.; Linden, A.; Heimgartner; H. HCA

1992,75, 1872.
113.
Liebeskind, L. S.; Baysdon, S. L.; South, M. S.; Blount, J. F. JOM 1980,

202, C73.
114.
Kettle, S. F. A.; Orgel, L. E. Proc. Chem. Soc. 1959, 307.
115.
Saegusa, T.; Ito, Y.; Shimizu, T. JOC 1970, 35, 3995.
116. Brunet, J.-J.; Niebecker, D.; Srivastava, R. S. TL 1993, 34, 2759.

117.
(a) Fischer, E. O.; Beck, H.-J.; Kreiter, C. G.; Lynch, J.; Mller, J.;
Winkler, E. CB 1972, 705, 162. (b) Fischer, E. O.; Kreissl, F. R.;
Winkler, E.; Kreiter, C. G. CB 1972, 105, 588. (c) Semmelhack, M.
F.; Tamura, R. JACS 1983, 705, 4099. (d) Chen, J.; Lei, G.; Yin, J.;
Huaxue Xuebao 1989, 47, 1105 (CA 1990, 113, 40941c). (e) Lotz, S.;
Dillen, J. L. M.,; Van Dyk, M. M. JOM 1989, 371, 371.
118. Semmelhack, M. F.; Tamura, R.; Schnatter, W.; Springer, J. JACS 1984,
106, 5363.
119.
Daub, J.; Trautz, V.; Erhardt, U. TL 1972, 4435.
with strong oxidizing agents, bases, acid chlorides, and anhy

drides. Keep away from heat and naked flames: combustible
solid/liquid. Store in a cool, dry place.
Use in Peptide Synthesis.

Solution Techniques. Simple alkyl esters of amino acids
(which may be protected) undergo aminolysis at a rate too slow
for peptide bond synthesis. Phenyl esters are more reactive and,
if electronegative substituents are present on the ring, may un
dergo aminolysis at rates similar to those of anhydrides. The
overriding requirements in peptide bond formation are efficiency
and freedom from side reactions. Esters of pentafluorophenol
have found wide application in the synthesis of peptides (cf.
Pentachlorophenol).1a-c Pentafluorophenol (1) serves as a cou
pling reagent, i.e. a compound added to a mixture of carboxyl and
amino components to promote condensation. However it is very
difficult to find efficient coupling reagents which do not give unde
sirable side reactions. Kinetic studies have shown the superiority
of pentafluorophenyl esters compared to other coupling reagents
with respect to speed of coupling (and thus lowering or elim
inating undesirable reactions, e.g. -hydrogen abstraction lead
ing to racemization). 2a,b Relative rates are OPFP OPCP > ONp,
corresponding to 111:3.4:1, where PFP = pentafluorophenyl;
PCP = pentachlorophenyl; Np = nitrophenyl.
Pentafluorophenyl esters have been used in both solution and
solid phase peptide syntheses, the difference being that solid
phase synthesis involves linking the peptide to a solid sup
port (see below), whilst solution techniques involve just one
phase. There are many examples of pentafluorophenyl esters be
ing used in peptide synthesis, 1a,3a-e e.g. the peptide sequence tBoc-Phe-Pro-Pro-Phe-Phe-Val-Pro-Pro-Ala-Phe-OMe 3 a and
the alkaloid peptide (2) 3b have been synthesized by these methods.
Sylvie Samson & G. Richard Stephenson

Pentafluorophenol
[771-61-9]
C 6 HF 5 O
(MW 184.07)
(preparation of pentafluorophenyl active esters for peptide

synthesis;1 formylating agent; preparation of aromatic fiuoro
derivatives)
Physical Data: white solid, mp 34-36 C; bp 143 C; fp >72 C;
nD 1.4263.
Solubility: sol most organic solvents, particularly aprotic ones.
Form Supplied in: available commercially.
Handling, Storage, and Precautions: toxic and irritant. Harmful if
swallowed, inhaled, or absorbed through the skin. Incompatible
More recently, the base labile 9-fluorenylmethoxycarbonyl

(Fmoc) group has become well established in peptide synthesis
for the protection of amino functionalities.4,5 The problem asso
ciated with this group is cleavage of the Fmoc group by the free
amino component to be acylated, which results in double acylations. The principal method of avoiding this now is to use the
Fmoc group in association with highly reactive pentafluorophenyl
esters to greatly increase the rate of coupling compared with
the undesirable reactions. Formation of these esters is shown in
eql.4
For example, this methodology was first used in the
synthesis of Fmoc-glycyl-L-tryptophyl-L-leucyl-L-aspartyl-Lphenylalaninamide (Fmoc-Gly-Trp-Leu-Asp-Phe-NH2) with
the isolation of all pentafluorophenyl ester intermediates in
PENTAFLUOROPHENOL
excellent yields (75-99%); the coupled amino acids were
subsequently prepared stepwise, again in very good yields, with
the minimum of undesirable side reactions.4
319
Table 1 gives some typical examples of the N-9Fluorenylmethoxycarbonyl (Fmoc) amino acids and their
pentafluorophenyl (PFP) esters which have been prepared by
these methods.4,67 The physical data are in agreement with
either preparative method, and with early preparations of these
compounds.4,5ab
Table 1 Examples of Fmoc-Protected Amino Acids and their
Pentafluorophenyl (PFP) Esters
Amino
acid
(1)
This method has since been modified and improved further by

utilizing 9-fluorenylmethyl pentafluorophenyl carbonate (eq 2).5a
(2)
There is a newer alternative method of synthesizing Fmocprotected pentafluorophenyl ester amino acids employing
pentafluorophenyl trifluoroacetate (3).5b
Gly
Ala
Leu
Val
Pro
Phe
Trp
Tyr
Ser
Ser (t-Bu)
Fmoc
derivative
mp(C)
Fmoc
derivative
yield (%)
171-172
141-142
151-152
143-144
114-115
181-182
163-165
98-107
90-94
84
93
83
90
82
86
89
70
78
Fmoc
amino
acid
PFP ester
mp(C)
Fmoc
amino
acid
PFP ester
yield (%)
Ref.
158-160
173-175
113-114
121-123
125-127
152-154
184-185
152-156
124-126
67-71
72
74
78
77
89
90
85
70
83
67
4,6
4,6
4,6
4,7
4,7
4,6
4,6
4
4,7
4,7
Solid Phase Peptide Synthesis (SPPS). Pentafluorophenyl es

ters have been used in both solution and solid phase peptide
synthesis. So far, only solution methods have been considered.
The principal of SPPS is incorporation of single amino acid
residues into peptide chains built on insoluble polymeric sup
ports. The famous Merrifield paper8 started the tradition of
SPPS using t-butoxycarbonyl (Boc) amino acids activated with
1,3-Dicyclohexylcarbodiimide, although this has now been su
perseded with the introduction of the Fmoc group in polystyreneand polyamide-based SPPS. The theory of SPPS will not be
discussed here. Needless to say, the use of pentafluorophenyl es
ters in SPPS was inevitable and was first reported by Atherton
in 1985.9 Fmoc-amino acid pentafluorophenyl active esters were
used in the polyamide solid phase series in polar DMF solutions
in the presence of 1-Hydroxybenzotriazole as a catalyst.
The preparation of the decapeptide H-Val-Gln-Ala-IleAsp-Tyr-Ile-Asn-Gly-OH (4) will be used as an example of
pentafluorophenyl esters in SPPS.910 This is a good example to
use since it contains normal, sterically hindered, and functionalized amino acids. All Fmoc-pentafluorophenyl esters were pre
pared by the method of Kisfaludy and Schon already described.4,5
Beaded polymethylacrylamide gel resin was used as the solid
phase with fivefold excesses of the pentafluorophenyl esters dis
solved in a minimum of DMF. The resin was first functionalized
with a reference norleucine residue and then with an acid-labile
linkage agent (5).
(5) R = 2,4,5-Cl3C6H2O
Esterification of the first residue, glycine, to the free OH used the

symmetrical mhydride/4-Dimethylaminopyridine procedure.11
The subsequent peptides were all coupled using standard techAvoid Skin Contact with All Reagents
320
PENTAFLUOROPHENOL
niques like those already described above and are fully docu
mented. Slightly varying conditions and catalysts were required
for some of the amino acids.10 After addition of the last amino
acid, thefinalFmoc group was cleaved and the complete decapeptide detached from the support resin using 95% aqueous Trifluoroacetic Acid. Side chain protecting groups were also cleaved
simultaneously. Crude peptide analysis was achieved by HPLC
and showed the samples obtained by this method to be extremely
pure.
More recently, SPPS has also been employed in glycopeptide
synthesis.12 There is an excellent review of active esters in SPPS,
including pentafluorophenyl esters.13
A New and Efficient Derivative of Pentafluorophenol.14 Pentafluorophenol has found many applications in both
solution and solid phase peptide syntheses. Diphenylphosphinic
mixed anhydrides are also well known in peptide chemistry.
A new and efficient reagent has been prepared from these
precursors: pentafluorophenyl diphenylphosphinate (FDPP; 6)
which can be used directly as a coupling reagent without side
reactions. FDPP is prepared from mixing equimolar amounts
of Diphenylphosphinic Chloride, pentafluorophenol (1), and
Imidazole in CH2Cl2 at room temperature (eq 3).14
As already mentioned, pentafluorophenyl derivatives are much

more reactive than pentachlorophenyl ones. The reason for this
is still not clear. Many calculations have been performed on the
net atomic energies of these esters and show that there is no sig
nificant difference between the environment of the electrophilic
center in OPFP esters compared to OPCP ones. Analysis of the
carbonyl stretching frequencies of these compounds is quite re
vealing (Table 2), i.e. there is no significant difference in the car
bonyl stretching frequencies of these functionalized esters. This,
plus additional evidence from MM calculations and NMR stud
ies, suggests that electronic factors do not play a significant role
in determining the reactivity of these esters.
Table 2
IR Stretching Frequencies of Carbonyl Groups in
Pentachlorophenyl (OPCP) and Pentafluorophenyl (OPFP) Active
Estersa
Amino acid
OPCP
OPFP
Z-Gly
Boc-Val
Boc-Phe
Boc-Tyr(r-Bu)
Z-Cys(Bn)
1794
1782
1784
1786
1784
1800
1788
1790
1794
1794
6
6
6
8
10
In CHCl3; in cm - 1 .
FDPP has been used in both solid and solution peptide syntheses
and analysis has shown it to have the lowest rate of racemization
of any of the common coupling reagents.14
There is however, an important steric effect, as would be ex

pected given the differing sizes of the halogens involved (van der
Waals atomic radii = 1.75 for Cl and 1.47for F). X -ray crystal
analysis is interesting in that it shows there is no intramolecular
interaction in OPFP esters and the structure is an extended con
formation. The main interaction is the strong dipole-dipole of a
negative fluorine to a positive carbon of another PFP ring in a
neighboring molecule. CO...NH interactions appear to be only
minor in comparison and the carbonyl group and PFP ring are
almost perpendicular. Studies have shown that the same confor
mation applies whether in solid or solution.
One of the explanations offered for the high reactivity of the
OPFP ester is neighboring group participation of an ortho fluorine
atom in accelerating the collapse of a tetrahedral intermediate tran
sition state, i.e. anchimeric acceleration. This would explain the
low solvent effect on aminolysis rates, the high second-order rate
constant, and unaffected third-order rate constant. Pentahalogen
esters fall midway between quinol-8-yl esters, where there is defi
nite participation, and nitrophenol esters where there is none (from
studies on the model system of phenyl acetates and piperidine).15
The PFP ester shows greater interaction than the PCP ester. There
are other possible explanations: this could still be explained in
steric terms, or by the high solvation of the leaving group (pentaflu
orophenol is much more soluble and reactive in aprotic solvents
than pentachlorophenol).
Comparison of Pentafluorophenyl Active Esters with Pentachlorophenyl Esters.15 It is interesting to compare these two
compounds with respect to active ester formation since they are
very closely related and both have been employed in both liquid
and solid phase peptide syntheses (see Pentachlorophenol). Pentachlorophenyl esters generally have higher melting points, which
can be of advantage if crystallization is difficult or a compound is
of low melting point, e.g. for serine and threonine the oily pentaflu
orophenyl esters are usually replaced by the pentachlorophenyl
esters.
Formylation Reactions.16 The problem with Acetic Formic

Anhydride, the most commonly used formylating agent, is un
desirable side reactions, particularly if there are acid sensitive
functionalities in the compound. One of the best alternatives is to
use pentafluorophenyl formate (7), an easily prepared and stable
compound which reacts with N-nucleophiles in minutes at room
temperature to yield the TV-formyl derivative (eq 5) (Table 3). Sig
nificantly, no reaction occurs with alcohols, thiols, or sterically
hindered amines.
(3)
FDPP may be kept refrigerated for several months and is used as

an efficient coupling reagent, by simply mixing the carbonyl and
amine components with a tertiary amine and FDPP in an organic
solvent, of which DMF was found to be the most efficient (eq 4).
(4)
PENTAFLUOROPHENOL
321
(5)
(?)
Table 3 Examples of N-Formylamines Prepared from Primary Amines

and Pentafluorophenyl Esters
Amine
Solvent
Yield (%)
mp (C)
Rf
Aniline
2-Aminobiphenyl
Benzylamine
H-Met-Leu-Phe-OMe
CHCl3
CHCl3
CHCl3
CHCl3
90
99
90
93
48
67-70
62-63
135-136
0.6a
0.6a
0.35a
0.4b
various amounts of the 2-, 2,6-, and 2,4,6substituted products depending on ratios
of (11):(1) and of KF and 18-crown-6
Chloroform-methanol (9:1). b Ethyl acetate.
Related Reagents. Pentachlorophenol.
Preparation of Aromatic Fluoro Derivatives. Reaction of

(1) with VF2, VF4, Vanadyl Trifluoride, or Xenon(II) Flu
oride in HF, CFCl3, or MeCN at -30 to 20 C yields mix
tures of perfluoro-2,5-cyclohexadien-l-one together with its
2- and 4-pentafluorophenoxy derivatives and/or perfluoro-6phenoxy-2,4-cyclohexadien-l-one, along with traces of perfluoro2-cyclohexen-l-one or perfluoro-p-benzoquinone. Using Antimony(V) Fluoride or NbF.4, however, only gives stable complexes
or pentafluorophenolates.17
Pentafluorophenol (1) reacts with Phosphorus(V) Chloride in
the presence of a base, triethy lamine or -collidine, to yield perfluoropentaphenoxyphosphorane (8) plus perfluorotriphenyl phos
phate (9) and perfluorodiphenyl ether (10) (eq 6).18
(C6F5O)5P + (C6F5O)3P=O + (C6F5)2O

(8)
(9)
1. For examples of early work on pentafluorophenyl esters in peptide

synthesis, see: (a) Kisfaludy, L.; Roberts, J. E.; Johnson, R. H.; Mayers,
G. L.; Kovacs, J. JOC 1970, 35, 3563 and references therein. (b)
Kisfaludy, L.; Schon, I.; Szirtes, T.; Nyki, O.; Low, M. TL 1974, 1785
and references therein. (c) Kovacs, J.; Kisfaludy, L.; Ceprini, M. Q. JACS
1967, 89, 183.
2.
(a) For a kinetic study of coupling rates and competing reactions,

see: Gross, E.; Meienhofer, J. In The Peptides-Analysis, Synthesis and
Biology, 2nd ed.; Academic: New York, 1980; p 519; (b) see also Ref.
3.
There are many examples of solution peptide synthesis utilizing

pentafluorophenyl esters. A few notable examples are cited here: (a)
Kisfaludy, L.; Schn, I.; Szirtes, T.; Nyeki, O.; Low, M. TL 1974, 1785.
(b) Schmidt, U.; Schanbacher, U. LA 1984, 6, 1205. See also Ref. 1(a).
(c) Schmidt, U.; Lieberknecht, A.; Griesser, H.; Haeusler, J. LA 1982,12,
2153. (d) Karel'skii, V. N.; Krysin, E. P.; Antonov, A. A.; Rostovskaya, G.
E. Khim. Prir. Soedin. 1982, 1, 96 (CA 1982, 97, 92 730s). (e) Polevaya,
L. K.; Vegners, R.; Ars, G.; Grinsteine, I.; Cipens, G. Latv. PSR Zinat.
Akad. Vestis, Khim. Ser. 1981, 4, 469 (CA 1982, 96, 7059s).
4.
Kisfaludy, L.; Schn, I. S 1983, 325.
5.
(a) Kisfaludy, L.; Schn, I. 5 1986, 303. (b) Green, M.; Berman, J. TL
1990, 31, 5851.
1(c).
(6)
(10)
This reaction has also been used to prepare pentafluorofhiophenol phosphorus derivatives. These compounds have been
utilized in 31P, 19F, and 1H variable temperature NMR studies
on intramolecular ligand rearrangement processes in phosphorus
compounds.18
The preparation and reactions of Polyfluoroaromatics, includ
ing pentafluorophenol derivatives, have been studied by various
Russian workers, who have also evaluated the pentafluorophenoxy
group as a leaving group (eq 7).19a
The main product of the reaction was the 4-substituted tetrafluoropyridine, although varying yields of the 2-, 2,6- and 2,4,6pentafluorophenoxypyridines were obtained depending on the ra
tios of (11):(1) and also on the levels of Potassium Fluoride,
18-Crown-6, the reaction temperature, and solvent. This reaction
has been studied in comparison with 4-NO2C6H4 (which is of
similar basicity) and in competition with F- anions.
More recently it has been shown that the substitution reaction
of pentafluoropyridine with (1) in the presence of Cesium Fluo
ride/graphite gave much better yields of (12), but still with traces
of the other products. The catalyst activity was found to increase
in the order: NaF < KF < RbF < CsF and was similar for the free
fluorides and their graphite-supported analogs.19b
6. Meienhofer, J.; Waki, M.; Heimer, E. P.; Lambros, T. J.; Makofske, R.

C ; Chang, C-D. Int. J. Pept. Protein Res. 1979, 13, 35.
7. Chang C-D.; Waki, M.; Ahmad, M.; Meienhofer, J.; Lundell, E. O.;
Haug, J. D. Int. J. Pept. Protein Res. 1980, 15, 59.
8. Merrineld, R. B. JACS 1963, 85, 2149.
9. Atherton, E.; Sheppard, R. C. CC 1985, 165.
10. Atherton, E.; Cameron, L. R.; Sheppard, R. C. T 1988, 44, 843.
11.
Atherton, E.; Logan, C. J.; Sheppard, R. C. JCS(P1) 1981, 538.
12. For the use of pentafluorophenyl esters in SPPS of glycopeptides, see:

Meldal, M.; Jensen, K. J. CC 1990, 483 and references therein.
13. For a review of active esters in SPPS, see: Bodanszky, M.; Bednarek, M.
A. J. Protein Chem. 1989, 8, 461.
14.
Chen, S.; Jiecheng, X. TL 1991, 32, 6711.
15.
Kisfaludy, L.; Low, M.; Argay, G.; Czugler, M.; Komives, T.; Sohar, P.;
Darvas, F. In Peptides (Proceedings 14th European Peptide Symposium);
Loffet, A., Ed.; Editions de l'Universite de Bruxelles: Bruxelles, 1976;
p 55 and references therein.
16.
Kisfaludy, L.; tvos, Jr., L. S 1987, 510.
17. Avramenko, A. A.; Bardin, V. V.; Karelin, A. L.; Krasil'nikov, V. A.;

Tushin, P. P.; Furin, G. G.; Yakobson, G. G. ZOR 1985, 21, 822 (CA
1985, 103, 141 551n).
18. Denny, D. B.; Denney, D. Z.; Liu L-T. PS 1982, 13, 1.
322
PHENYL CHLOROTHIONOCARBONATE
19. (a) Aksenov, V. V.; Vlasov, V. M.; Yakobson, G. G. JFC 1982, 20, 439.
(b) Aksenov, V. V.; Vlasov, V. M.; Danilkin, V. I.; Naumova, 0. Y.;
Rodionov, P. P.; Chertok, V. S.; Shnitko, G. N.; Yakobson, G. G. IZV
1984, 9, 2158 (CA 1985,102, 131 881k).
Keith Jones
King's College London, UK
(2)
[1005-56-7]
C7H5ClOS
(MW 172.64)
(forms thionocarbonate ester derivatives of alcohols which can

be deoxygenated with tin hydride reagents;1-5 converts ribonucleosides to 2'-deoxynucleosides;2 provides allylic thionocarbonates which undergo [3,3]-sigmatropic shifts;6-9 pro
vides precursors for radical bond-forming reactions;10,11
reagent for thioacylation12-16)
Physical Data: bp 81-83 C/6 mmHg; fp 81 C; d 1.248 g cm -3 .
Solubility: sol chloroform, THF.
Form Supplied in: colorless liquid.
Handling, Storage, and Precautions: corrosive; moisture sensi
tive; should be stored in airtight containers which exclude mois
ture; incompatible with alcohol solvents.
Deoxygenation of Secondary Alcohols. Reaction of sec

ondary alcohols with the reagent in the presence of Pyridine or
4-Dimethylaminopyridine (DMAP) provides thiocarbonate es
ter derivatives which can be reduced to alkanes using Tri-nbutylstannane (eq 1).1 The advantage of this method is the abil
ity to deoxygenate alcohols via radical intermediates and thereby
avoid problems associated with ionic reaction conditions (i.e. carbonium ion rearrangements, reduction of other functional groups).
This method is particularly useful for the conversion of ribonucleosides to 2'-deoxynucleosides. For example, adenosine can
be converted to 2'-deoxyadenosine in 78% overall yield by ini
tial protection of the 3'- and 5'-hydroxyl groups as a cyclic
disiloxane, thiocarbonylation, reductive cleavage, and then final
deprotection using a fluoride source (eq 2).2 Treatment of 11bromo-3'-phenoxyfhiocarbonyl nucleosides with tributyltin hy
dride affords 2',3'-didehydro-2',3'-dideoxy nucleosides via radi
cal -elimination.3
Synthetic intermediates can be selectively deoxygenated with
out reduction of other functional groups such as esters, ketones,
and oxime ethers (eq 3),4 as well as epoxides, acetate esters, and
alkenes.5
(3)
Sigmatropic Rearrangements of Allylic Thionocarbonates. The reaction of allyl alcohols with aryl chlorothionocarbonates affords S-allyl aryl thiocarbonates by [3,3]-sigmatropic
rearrangement via the intermediate thionocarbonate esters.6-9 For
example, treatment of 2-methyl-l-penten-3-ol with the reagent in
pyridine at 20 C affords phenyl 2-methyl-2-pentenyl thionocar
bonate in 67% yield (E:Z = 96.5:3.5)7 This type of rearrangement,
coupled with tin hydride mediated reduction of the phenyl thio
carbonate ester product, was used as a key step in the synthesis
of isocarbacyclin (eq 4).8 Rearrangement of cyclic thionocarbonates contained in eight-membered rings or smaller provides twoatom ring enlarged thiocarbonates having (Z) double bond geom
etry (eq 5).9 Depending on the system, the cyclic thiocarbonates
are obtained by either treatment of the diol monothionocarbonate
with base or by reaction of the diol with l,l'-thiocarbonyldi-2,2'pyridone. Cyclic thionocarbonates of ring size nine or larger afford
ring expanded products with exclusive (E) double bond geometry
in modest yields.
(4)
(1)
PHENYL CHLOROTHIONOCARBONATE
323
85% of 6-thionocarbonate. Further treatment with tributyltin hy

dride affords the corresponding deoxyglucose derivatives in high
yield.
(5)
Radical Coupling and Cyclization Reactions. Phenyl

thionocarbonate esters derived from alcohols serve as efficient
precursors for the generation of radical intermediates which can
be used for the formation of new carbon-carbon bonds. For exam
ple, a 4-thionocarbonate ester derived from L-lyxose undergoes a
stereoselective allylation upon photolysis in toluene in the pres
ence of 2.0 equiv ofAllyltributylstannane (eq 6).10 Photochemical
initiation is preferable to chemical initiation using Azobisisobutyronitrile which results in the formation of side products at the
expense of the desired product. The allylation product was used
further in a total synthesis of pseudomic acid C.
(6)
Oxime ethers derived from hydroxy aldehydes, upon conver

sion to their phenyl thionocarbonate esters, undergo radical cyclizations resulting in the formation of carbocycles.11 For exam
ple, an oxime ether obtained from D-glucose is converted into its
phenyl thionocarbonate ester at C-5 and, upon heating in ben
zene in the presence of tributyltin hydride, affords cyclopentanes
in 93% yield as a 62:38 mixture of two diastereomers (eq 7). In
general, only low to modest stereoselectivity between the newly
formed stereocenters is observed in a number of substrates exam
ined.
(8)
In a key step leading to a synthesis of saxitoxin, radical fragmen

tation of a pyrazolidine ring followed by intramolecular thioacyla
tion afforded the ring expanded tetrahydropyrimidine intermediate
(eq 9).13 The thionocarbamate activation of the pyrazolidine N-H
was found to be necessary to effect the desired transformation.
The intramolecular thioacylation of an ester enolate was
used for the synthesis of 2-alkylthiopenem carboxylic acid
derivatives.14 Sequential acylations have led to the synthesis
of zwitterionic pyrazole-5-thiones from acyclic precursors,15
whereas 2-ethoxyoxazolidines react with the reagent to afford the
products of N-acylation.16
(9)
Heating of 0-phenyl thionocarbonates of pyrrolidine and

piperidine-2-ethanols in acetonitrile gives a ring expanded azepine
or an octahydroazocine accompanied by the pyrrolidine and
piperidine O-phenyl ethers (eq 10).17 These products arise via the
internal expulsion of carbonyl sulfide, leading to formation of an
azetidinium intermediate followed by nucleophilic ring opening
with phenoxide ion.
(7)
(10)
Thioacylation Reagent. The regioselective thioacylation of

unprotected carbohydrates via the agency of Di-n-butyltin Ox
ide and the reagent has been investigated.12 Glycopyranosides
having a cis-diol arrangement, e.g. galactose, form cyclic thiocarbonates which can be either converted into dihydropyranosides using the Corey elimination procedure or deoxygenated to
a mixture of 3- and 4-deoxyglycopyranosides (eq 8). Methyl Dglucopyranoside is monothioacylated with the regioselectivity de
pendent upon the configuration at the anomeric carbon; the aepimer gives 83% of 2-thionocarbonate and the -epimer gives
n = 1,55%
n = 2, 16%
n= 1, 16%
n = 2, 60%
Related Reagents. Carbon Disulfide; N-Hydroxypyridine-2thione; l,l'-Thiocarbonyldiimidazole; p-Tolyl Chlorothionocarbonate; Phenyl Chlorothionocarbonate.
1. Barton, D. H. R.; Subramanian, R. JCS(P1) 1977, 1718.
2. Robins, M. J.; Wilson, J. S. JACS 1981, 103, 932; Robins, M. J.; Wilson,
J. S.; Hansske, F. JACS 1983, 705, 4059.
324
3.
4.
5.
6.
7.
8.
9.
10.
PHENYL N-PHENYLPHOSPHORAMIDOCHLORIDATE
Serafinowski, P. S 1990, 411.

Martin, S. P.; Dappen, M. S.; Dupre, B.; Murphy, C. J. JOC 1987, 52,
3706.
Schuda, P. F.; Potlock, S. J.; Wannemacher, R. W., Jr. J. Nat. Prod. 1984,
47,514.
Garmaise, D. L.; Uchiyama, A.; McKay, A. F. JOC 1962, 27, 4509.
Faulkner, D. J.; Petersen, M. R. JACS 1973, 95, 553.
Torisawa, Y.; Okabe, H.; Ikegami, S. CC 1984, 1602.
Harusawa, S.; Osaki, H.; Kurokawa, T.; Fujii, H.; Yoneda, R.; Kurihara,
T. CPB 1991, 39, 1659.
Keck, G. E.; Kachensky, D. F.; Enholm, E. J. JOC 1985, 50, 4317.
11. Bartlett, P. A.; McLaren, K. L.; Ting, P. C. JACS 1988, 770, 1633.
12. Haque, M. E.; Kikuchi, T.; Kanemitsu, K.; Tsuda, Y. CPB 1987, 35,
1016.
13. Jacobi, P. A.; Martinelli, M. J.; Polanc, S. JACS 1984, 706, 5594.
14. Leanza, W. J.; DiNinno,F.;Muthard, D. A.; Wilkering, R. R.; Wildonger,
K. J.; Ratcliffe, R. W.: Christensen, B. G. T 1983, 39, 2505.
15. Grohe, K.; Heitzer, H.; Wendisch, D. LA 1982, 1602.
16. Widera, R.; Muehlstaedt, M. JPR 1982, 324, 1005.
17.
membranes and upper respiratory tract), ingestion, or skin

absorption. Incompatible with strong oxidizing agents and
strong bases.
Phosphorylating
Agent. Phenyl
N-phenylphosphoramidochloridate (1) reacts readily at 0C in dry pyridine
with equimolar amounts of a corresponding alcohol or phenol to
give the O-alkyl-O-phenyl-ZV-phenylphosphoramides (eq 2).2
(2)
R = alkyl, aryl, e.g. t-BuCH2,
Sakanoue, S.; Harusawa, S.; Yamazaki, N.; Yoneda, R.; Kurihara, T. CPB
1990,58,2981.
The compound (3) is a useful intermediate for the synthesis of

Eric D. Edstrom
mixed
diesters of phosphoric acid (4). There are several methods
Utah State University, Logan, UT, USA
of cleaving the N-P bond, of which the method of Ikehara is the
most convenient.3 Reaction of (3) with a 40 molar excess of 3methylbutyl nitrite in acetic acid-pyridine (1:1 v/v) is successful in
removing the aniline protecting group from the phosphoryl moiety
in almost quantitative yields, giving the O-alkyl/aryl-O-phenyl
Phenyl N-Phenylphosphoramidohydrogen phosphate.
chloridate
Given the good yields and simplicity of the process,
this procedure has been used to prepare intermediates for
oligonucleotide synthesis, e.g. in the synthesis of 5'-0monomethoxytritylthymidine 3'-phenylphosphate (7) (eq 3).
Phosphorylation of 5'-O-monomethoxytritylthymidine (5) gave
the protected nucleoside phosphate (6) in 98% yield which, af
[51766-21-3]
(MW 267.66)
C 12 H 11 ClNO 2 P
ter removal of the aniline protecting group and workup, gave the
pyridinium salt in 85% yield.
(phosphorylating agent in oligonucleotide synthesis via the phosphotriester approach; for the conversion of acids to their sym
metrical anhydrides and for the coupling of acids and amines to
give amides; two important derivatives are also considered)
Physical Data: mp 132-134C.
Solubility: sol org solvents, e.g. acetone, dichloromethane.
Form Supplied in: white solid; widely available commer
cially.
Analysis of Reagent Purity: FT-IR;22 Rf (pure) = 0.63
(chloroform-acetone (5:1) on silica).
Drying: is moisture sensitive; dry in vacuo (10 - 2 mmHg) over
T = thymidinyl
MMTr = monomethoxytrityl
(3)
P 2 O 5 at rt.
Preparative Methods: obtainable from phenyl phosphorodichloridate (2) and aniline (eq 1). 1
(1)
Handling, Storage, and Precautions: irritant and moisture sen

sitive. May be harmful by inhalation (irritating to mucous
This chemistry has additionally been utilized in the prepa

ration of nucleoside phosphorothioates.4 Reaction of (6)
with NaH to remove the P-anilido group followed by CS2
gave the corresponding 5'-monomethoxytritylthymidine 3'-0phenylphosphorothioate (as a mixture of diastereomers, 8) which
was converted to the S-methyl ester (9) (eq 4). Owing to the chiral
PHENYL/V-PHENYLPHOSPHORAMIDOCHLORIDATE
nature of pentavalent phosphorus, the compound (9) could exist

as a mixture of diastereomers; however, the above reaction was
the first example of an asymmetric synthesis of a phosphorothioate. There are now more examples of stereospecific synthesis of
nucleoside derivatives utilizing this type of chemistry.5
325
ably powerful dehydrating agents that function in mild reaction

conditions. Organophosphorus compounds appear to be one such
group of compounds. Phenyl N-phenylphosphoramidochloridate
was found to be one of the most successful dehydrating agents.11
The proposed mechanism of polyanhydride formation is shown
in eq 6.
(4)
(6)
There are numerous reviews on phosphorylation meth

ods in biological molecules, some of which include aryl
phosphoramidochloridates.6
Formation of Carboxamides. There are many reagents for the

conversion of carboxylic acids to carboxamides.8,12-14 Activating
Activation of Carboxylic Acids.
agents such as DCC15 can lead to purification problems, whilst
involvement of the acid chloride can lead to racemization; there are
Formation of Symmetrical Anhydrides. Symmetrical car
also examples using phosphorus containing reagents, e.g. Diethyl
boxylic anhydrides are useful reagents for peptide or amide
Phosphorocyanidate,13,16 but again these reagents only react well
synthesis.7*8 Unfortunately, most methods require transformation
in certain systems. Other methods involve long reaction times,
of the acid first into the acid chloride or the use of condensation
high temperatures, or low yields.
agents, e.g. 1,3-Dicyclohexylcarbodiimide (DCC), which can lead
However, the use of phenyl N-phenylphosphoramidochloridate
to separation problems of the product anhydride from the hydrated
as a condensing agent for carboxylic acids and amines yields car
derivatives of the condensation reagents. The use of Thionyl Chlo- boxamides in a one-step method (eq 7).17 The amide (12) is pre
ridelPyridine to form the acid chloride is often complicated by
pared from the carboxylic acid, 2 equiv of triethylamine, 1 equiv of
racemization with amino acid derivatives.
amine, and 1 equiv of reagent (1) and isolated by filtration or evap
However, carboxylic acids are converted almost quantita
oration of solvent and washing with water. Once again, a mixed
tively to their corresponding symmetrical anhydride by treat
anhydride intermediate (13) is presumed, which results from nument with 1 equiv of Triethylamine or 1-Ethylpiperidine and 0.5 cleophilic attack by the carboxylate anion on the phosphorus atom
equiv of phenyl TV-phenylphosphoramidochloridate (or Diphenyl
with elimination of a chloride ion; a further nucleophilic attack by
Phosphorochloridate) in acetone or dichloromethane, with the the amine on the carbonyl group of (13) and breakdown of the com
product anhydride (10) being obtained by filtration or from
plex yields the amide (12) and phenyl N-phenylphosphoramidate
evaporation of the solvent after washing with water.9 The
(14) which can be recycled to (1) by reaction with phosphorus
resulting crude products are very nearly pure and the phenyl Npentachloride.
phenylphosphoramidochloridate can be regenerated as the aque
ous solutions yield the phosphoramidic acid on acidification,
which can be converted to (1) by reaction with Phosphorus(V)
Chloride. The proposed pathway for this is through the mixed an
hydride (11), which then reacts with a second molecule of acid.
The only limitation of this method is the reaction of some of the
anhydrides with water, e.g. as observed with trichloroacetic acid.
(7)
(5)
The Synthesis of Polyanhydrides by Dehydrative Coupling. The synthesis of polyanhydrides was first reported in
190910 and led on to a series of aliphatic polyanhydrides being
prepared in the 1930s, as potential materials for the textile in
dustry. One method for the formation of such polyanhydrides,
particularly where sensitive monomers are involved, is to find suit
A distinct order of reactivity is observed in these reactions with

(1): carboxylate anion>>aliphatic amines >> aromatic amines.
This has led to slight variations in the practical procedures
for preparing the amides but these are well documented in the
literature.17 The first route involves a one-step procedure; the sec
ond involves reaction of (1) with the carboxylate anion and sub
sequent treatment with the amine and is the preferred method
for converting alkanamines to the amides since the first one-step
method produces large amounts of phenyl phosphorodiamidates
as well as the amide, by nucleophilic attack of (1) by the amine.
The final method prevents the formation of phenyl phosphorodi
amidates as the carboxylic acidfirstreacts with 0.5 equiv of (1) to
326
PHENYL N-PHENYLPHOSPHORAMIDOCHLORIDATE
form its anhydride, which is then converted to the amide in almost

quantitative yield (this is largely utilizing the anhydride-formation
chemistry described above) (eq 8).
The reaction is believed not to work for (1) as it requires an ex

cess of triethylamine in the presence of a less nucleophilic imine,
which is unfavorable to a mixed anhydride intermediate. The pro
posed pathway for this reaction is shown in eq 11, and has been
performed on a wide variety of imines, proceeding in good yields
(44-78%).
(8)
(11)
Generally, phenyl N-phenylphosphoramidochloridate and other

very similar related organophosphorous reagents e.g. phospho
rus oxychloride, phenyl dichlorophosphate, diphenylchlorophosphate and N,N'-bis(2-oxo-3-oxazolinyl)phosphorodiamidic chlo
ride have been utilised in recent years not only to form
symmetrical carboxylic acid anhydrides but also in esterification and thiol esterification reactions; although phenyl Nphenylphosphoramidochloridate is not so efficient for the latter
two reactions compared to its analogs but is probably the best
choice for forming the anhydride.18
Two Important Derivatives of Phenyl N-Phenylphosphoramidochloridate.
Phenyl N-Phenylphosphoramidoazidate. This compound
(15) is a white solid, which is easily prepared from (1) (eq 9).19 It
is obtained in excellent yields and is unusual for an organophosphorus compound in that it shows little sensitivity to moisture at
room temperature for several months.
(9)
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
Cremlyn, R. W. J.; Kishore, D. N. JCS(P1) 1972, 585.

Zielinski, W. S.; Lesnikowski, Z. J. S 1976, 185.
Ikehara, M ; Uesugi, S.; Fukui, T. CPB 1967, 75, 440.
Zielinski, W. S.; Lesnikowski, Z. J.; Stec, W. J. CC 1976, 772.
Lesnikowski, Z. J.; Niewiarowski, W.; Zielinski, W. S.; Stec, W. J. T
1984, 40, 15.
Slotin, L. A. S 1977, 737 and references therein.
Chen, F. M. F.; Koroda, K.; Benoiton, N. L. S 1978, 928.
Jones, J. H. In The Peptides Gross, E.; Meienhofer, J., Eds.; Academic:
New York, 1979; p 65.
Mestres, R.; Palomo, C. S 1981, 219.
Bucher, J. E.; Slade, W. C. JACS 1909, 31, 1319.
Leong, K. W.; Simonte, V.; Langer, R. Macwmolecules 1987, 20, 705.
12.
It is an excellent reagent for the preparation of N,N'-diarylureas.

Reaction of a carboxylic acid, primary amine, and (15) in acetonitrile leads to the disubstituted urea (16) (eq 10). There is an
additional competing reaction to the formation of the diarylurea:
formation of phenyl N-phenylphosphorodiamidates, involving nucleophilic attack of the carboxylate ion and the alkylamine on the
phosphorus atom of phenyl N-phenylphosphoramidoazidate. This
work has been fully reviewed.20
(10)
Ogliaruso, M. A.; Wolfe, J. F. In The Chemistry of Acid Derivatives

Wiley: New York, 1979; Part 1, p 474.
13. Haslam, E., CI(L) 1979, 610.
14. Haslam, E. T 1980, 36, 2409.
15.
16.
17.
18.
19.
20.
21.
Mikolajczyk, M.; Kielbasinski, P. T 1981, 37, 233.

Shiori, T.; Yokoyama, Y.; Kasai, Y.; Yamada, S. T 1976, 32, 2213.
Mestres, R.; Palomo, C. S 1982, 288.
Arrieta, A.; Garcia, T.; Lago, J. M.; Palomo, C. SC 1983, 13, All.
Arrieta, A.; Palomo, C. TL 1981, 22, 1729.
Arrieta, A.; Palomo, C. BSF(2) 1982, 7.
Shridhar, D. R.; Bhagat, R.; Narayana, V. L.; Awasthi, A. K.; Reddy, G.
J. 5 1984, 846.
22.
Pouchert, C. I. Aldrich Library of FT-1R Spectra; Aldrich: Milwaukee,

WI, 1989; Vol. 1, p 556C.
Adrian P. Dobbs
Phenyl N-Methyl-N-phenylphosphoramidochloridate. Like
(1), phenyl N-methyl-N-phenylphosphoramidochloridate (17)
reacts under analogous conditions to give anhydrides and
carboxamides (see above). However, phenyl N-methyl-Nphenylphosphoramidochloridate undergoes one additional reac
tion which is not observed to any significant degree in (1). It is used
for the conversion of imines to -substituted -lactams (eq 11).21
PHENYL PH0SPH0R0DI(1 -IMIDAZOLATE)
327
ester of 2',3'-isopropylideneadenosine 5'-phosphate (2) has been

synthesized in 53.5% yield (eq 5).1
Phenyl Phosphorodi(l-imidazolate)
(5)
[15706-68-0]
C 12 H 11 N 4 O 2 P
(MW 274.24)
(used in phosphorylation,1 as a peptide coupling reagent,1

and in the dehydration of aldoximes to nitriles2)
Alternate Name: phenyl diimidazol-1-ylphosphinate.
Physical Data: an exceedingly hygroscopic white solid, mp 96-97
C2 (mp 90-92 C also reported1).
Solubility: sol acetonitrile, dioxane, THF; relatively insol ben
zene, ether.
Form Supplied in: not commercially available.
Preparative Methods: this reagent was first prepared in 81% yield
by reaction of 4 equiv of imidazole with 1 equiv of phenyl
phosphorodichloridate in benzene at 60 C.4 The use of 2 equiv
of imidazole and 2 equiv of triethylamine as base has been
reported to give a yield of 98% of (1) (eq 1).2
Peptide Synthesis. Reagent (1) has been used as a coupling

reagent in the synthesis of benzyloxycarbonylalanylalanine (3).1
Initial treatment of benzyloxycarbonylalanine with (1) in acetoni
trile at 45 C for 12 h followed by reaction with an excess of an
aqueous solution (pH 8-9) of alanine gave the protected dipeptide
in 85% yield (eq 6). No reference to the stereochemistry of the
starting materials or product was made.
(6)
Acylimidazolides have been isolated from the reaction of (1)

with carboxylic acids1 and may be involved in the above reaction.
(1)
Purification: recrystallization from benzene, filtration under a

water-free atmosphere, and drying under vacuum.
Handling, Storage, and Precautions: owing to its hygroscopic
nature, exclusion of moisture in handling and use is essential;
should be stored in a sealed tube at 20 C.3
Phosphorylation. The title reagent (1) reacts with amines, al

cohols, and water to give amides and esters of phenyl phosphate
(eqs 2-4).1 The monoimidazole derivatives are formed rapidly
with a much slower reaction to give the disubstitution products.1
(2)
Dehydration of Aldoximes to Nitriles. Reagent (1) has been

shown to be excellent for the dehydration of aldoximes of both
aromatic and aliphatic aldehydes.2 This is accomplished by react
ing the aldoxime with (1) in dioxane at 20 C for 20 h (eq 7).2
(7)
R = pentyl, hexyl, cyclohexyl, undecyl, cinnamyl, 4-methoxyphenyl,
4-chlorophenyl, 2,4-dichlorophenyl, 4-nitrophenyl, 2-pyridyl
Reagent (1) is superior in terms of yield to a variety of phosphorochloridates, including Phosphorus Oxychloride. For example,
in the case of 2-pyridyl aldoxime, with (1) a yield of 52% was ob
tained, whereas with phosphorus oxychloride the yield was 33%
and with phenyl phosphorodichloridate the yield was 47%.2 The
reaction is thought to proceed via an intermediate formed by Ophosphorylation of the aldoxime.2 The use of spin-labeled ver
sions of (1) has been explored, in which the phenyl is replaced
with the 2,2,6,6-tetramethylpiperidyl N-oxide group.3,5
(3)
(4)
This behavior can be used to synthesize mixed diphosphates by

treatment with a small excess of alcohol followed by hydrolysis
of the monoimidazole derivative. In this manner the monophenyl
1.
2.
3.
4.
5.
Cramer, F.; Schaller, H. CB 1961, 94, 1634.

Konieczny, M.; Sosnovsky, G. ZN(B) 1978, 33b, 1033.
Konieczny, M.; Sosnovsky, G. S 1976, 537.
Cramer, F.; Schaller, H.; Staab, H. A. CB 1961, 94, 1612.
Konieczny, M.; Sosnovsky, G. ZN(B) 1977, 32b, 1179.
Keith Jones
328
PHOSGENE
Phosgene
[75-44-5]
Dimethyl Sulfoxide and elimination by base (eq 3),12b a mecha

nism closely related to that of the Swern and Moffatt oxidations.13
CC120
(MW 98.91)
(chlorinating agent;2 carbonylating agent; dehydrating agent;1

with DMF forms a chloromethyleniminium salt, used in formylation reactions3)
Alternate Name: carbonyl chloride.
Physical Data: mp - 118 C; bp 8.3 C; d 1.381 g cm - 3 .
Solubility: slightly sol H2O (dec); sol toluene, chloroform.
Form Supplied in: liquefied gas in cylinders; solution in toluene.
Purification: chlorine is an impurity which can be detected by
bubbling through mercury (gives discoloration) and removed
by bubbling through two wash bottles containing cottonseed
oil.
Handling, Storage, and Precautions: highly toxic gas; avoid con
tact or inhalation; there may be a delay of several hours be
fore symptoms of exposure develop (pulmonary edema); keep
container tightly closed and well-ventilated; excess phosgene
should be vented into a water-fed scrubbing tower. Use in a
fume hood.
(3)
There are many examples of further displacement of the chloroformate in an intramolecular or intermolecular sense by suit
ably disposed second nucleophiles (e.g. hydroxy, amino, thio,
or acid groups), resulting in carbonates (eq 4),14 ureas (eq 5),15
carbamates,1116 dithiocarbonates (eq 6),17 etc.
(4)
Reactions with Carboxylic Acids, Alcohols, and

Amines. Phosgene reacts with carboxylic acids to give an
hydrides, with liberation of carbon dioxide.4 This has been
used to activate acids to attack from nucleophiles, e.g. in
esterification,5 lactonization,6 and thiolation.7 For example,
acids can be protected as 3-butenyl esters using phosgene and
Pyridine,5 followed by addition of 3-buten-1-ol (eq 1).
(5)
(1)
(6)
The ester is removed under mild conditions by ozonolysis
and -elimination of the resulting aldehyde. In contrast, reac
tion with acids in the presence of a variety of catalysts (in
cluding Imidazole, l,8-Diazabicyclo[5.4.0]undec-7-ene, and 1,3Dicyclohexylcarbodiimide) cleanly affords the corresponding
acid chloride.2 N,N-Dimethylformamide has also been used as
The reaction of phosgene with primary amines initially forms
a catalyst (eq 2).8
chloroformamides which on heating above 50 C eliminate HC1 to
give isocyanates. This useful reaction constitutes a general method
for isocyanate synthesis (eq 7).18
(2)
RNH2 + COCl2
Phosgene reacts with alcohols to give chloroformates,9,1b and

with secondary amines to give chloroformamides10 (it reacts
preferentially with the latter).11 The formation of a chloroformate is the first step in the Barton oxidation of primary alco
hols to aldehydes,12 which is followed by complex formation with
RNHCOCl
RN=C=O
(V)
With tertiary amines, phosgene-amine complexes can be

formed.1a Warming results in decomposition to an N,Ndialkylchloroformamide by elimination of alkyl chloride.19 This
has been utilized for the mild and high yielding deprotection of
TV-methyl amines (eq 8).20 a-Chloroethyl chloroformate, prepared
PHOSGENE
329
from phosgene and Acetaldehyde, has also been used for this
purpose.21
(13)
Secondary thioureas can be dehydrated to carbodiimides

(eq 14).27
(8)
Reactions with Amides and Thioamides. The action of phos

gene on amides (and thioamides) initially gives dehydration to a
chloromethyleneiminium chloride (eq 9). Primary amides react
further, losing HC1 to form nitriles in the presence of a base such as
pyridine22 (this can also be accomplished by the Vilsmeier-Haack
reagent generated using phosgene - see below). Secondary formamides are converted to isocyanides in the presence of Triethylamine or pyridine (eq 10).23 Af-Formyl enamines also form iso
cyanides (eq 11);24 1,4-Diazabicyclo[2.2.2]octane is claimed to
be a more efficient base due to the avoidance of azeotrope forma
tion with the low boiling vinyl isocyanide products. Other sec
ondary amides lose HC1 to give imidoyl chlorides, which can
undergo further reaction, e.g. to form pyrroles (eq 12)25 and oxazolones (eq 13).26
(9)
(14)
Tertiary amides give stable chloromethyleneiminium chlorides.

A particularly important example is the complex formed between
phosgene and DMF (known as the Vilsmeier-Haack reagent),
which is a versatile formylating agent.3 An identical or equivalent
species can be generated with Oxalyl Chloride, Thionyl Chloride,
or Phosphorus Oxychloride, and these are perhaps preferred in
view of phosgene's toxicity. However, the Vilsmeier reagent gen
erated from phosgene is claimed to be a more efficient reagent for
the dehydration of primary amides to nitriles.28
Tertiary amides (and thioamides)29 with an -proton react in
stead to give chloro enamines.30 These can undergo nucleophilic
substitution (eq 15).30,31 Chloro enamines are also intermediates in
synthetically useful dehydrogenation reactions, using Pyridine NOxide or DMSO as oxidant (eq 16).32 Tertiary ureas and thioureas
form related adducts which have been utilized in the synthe
sis of hindered guanidine bases by further reaction with amines
(eq 17).33
(10)
(11)
(15)
R1 = R2 = (CH2)2O(CH2)2
(12)
(16)
330
PHOSPHORUS(III) BROMIDE
(17)
20.
Banholzer, R.; Heusner, A.; Schulz, W. LA 1975, 2227.
21.
(a) Olofson, R. A.; Martz, J. T.; Senet, J-P; Piteau, M.; Malfroot, T. JOC
1984, 49, 2081. (b) Olofson, R. A.; Abbott, D. E. JOC 1984, 49, 2795.
Ficken, G. E.; France, H.; Linstead, R. P. JCS 1954, 3731.
22.
23.
Phosgene Equivalents. In recent years, Bis(trichloromethyl)

Carbonate (triphosgene) has been introduced as a crystalline
phosgene source;34 similarly, Trichloromethyl Chloroformate
(diphosgene) has been used as a liquid equivalent35 (bp 128 C,
d15 1.65 g mL -1 ). They have the advantages of much easier ma
nipulation (particularly for small-scale work), safer transport and
storage, and they are less susceptible to hydrolysis. Triphosgene
has so far been shown to perform several reactions undergone
by phosgene itself, e.g. carbonylation36 and Barton oxidation.37
Diphosgene generates phosgene slowly at elevated temperatures,
or rapidly in the presence of a charcoal catalyst;38 it is also
effective in several of the reactions of phosgene, including Ncarboxyanhydride formation38 and the conversion of amino al
cohols to oxazolidinones,39 where it has been recommended for
large-scale use.
Related Reagents. Dimethyl Sulfoxide-Phosgene.
1. (a) Babad, H.; Zeiler, A. G. CRV 1973, 73, 75. (b) Fieser, L. F.; Fieser,
M. FF 1967, 1, 856; 1969, 2, 328; 1972, 3, 225; 1974, 4, 157; 1975, 5,
532; 1979, 7, 289; 1990, 15, 265.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
Hauser, C. F.; Theiling, L. E JOC 1974, 39, 1134.

Marson, C. M. T 1992, 48, 3659.
Rinderknecht, H.; Guterstein, M. OSC 1973, 5, 822.
Barrett, A. G. M.; Lebold, S. A.; Zhang, X. TL 1989, 30, 7317.
Wehrmeister, H. L.; Robertson, D. E. JOC 1968, 33, 4173.
Bates, G. S.; Diakur, J; Masumune, S. TL 1976, 4423.
Ulrich, H.; Richter, R. JOC 1973, 38, 2557.
(a) Matzner, M.; Kurkjy, R. P.; Cottner, R. J. CRV 1964, 64, 645. (b)
Kevill, D. N. In The Chemistry of Acyl Halides; Patai, S, Ed.; Wiley:
New York, 1972; p 381. (c) Samsel, E. G.; Norton, J. R. JACS 1984, 706,
5505.
(a) Marley, H.; Wright, S. H. B.; Preston, P. N. JCS(P1) 1989, 1727. (b)
Goerdeler, J.; Bartsch, H-J. CB 1985, 118, 2294.
Hall, H. K., Jr; El-Shekeil, A. JOC 1980, 45, 5325.
(a) Barton, D.H.R.; Garner, B. J.; Wightman, R. H. JCS(P1) 1964, 1855.
(b) Epstein, W. W.; Sweat, F. W. CR 1967, 67, 247. (c) Finch, N.; Fitt, J.
J.; Hsu, I. H. S. JOC 1975, 40, 206.
Mancuso, A. J.; Swern, D. S 1981, 165.
(a) Ona, H.; Uyeo, S. TL 1984, 25, 2237. (b) Krespan, C. G.; Smart, B.
E. JOC 1986, 51, 320. (c) Das, J.; Vu, T.; Harris, D. N.; Ogletree, M. L.
JMC 1988, 31, 930. (d) Nishiyama, T.; Yamaguchi, H.; Yamada,F.JHC
1990, 27, 143.
(a) Confalone, P. N.; Lollar, E. D.; Pizzolato, G. JACS 1978, 100, 6291.
(b) Henning, R.; Lattrell, R.; Garhards, H. J.; Leven, M. JMC 1987, 30,
814. (c) Cram, D. J.; Dicker, I. B.; Lauer, M.; Knobler, C. B.; Trueblood,
K.N. JACS 1984, 706,7150.
16.
(a) Gelb. M. H.; Abeles, R. H. JMC 1986, J, 585. (b) Uff, B. C.; Joshi,
B. L.; Popp, F. D. JSC(P1) 1986, 2295.
17. Rasheed, K.; Warkentin, J. D. JHC 1981, 18, 1581.
18. (a) Richter, R.; Ulrich, H. In The Chemistry of Cyanates and their
Derivatives; Patai, S., Ed.; Wiley: New York, 1977; Part 2, p 619. (b)
Butler, D. E.; Alexander, S. M. JHC 1982, 19, 1173. (c) Weisenfeld, R.
B.JOC 1986, 57, 2434.
19. Cooley, J. H.; Evain, E. J. S 1989, 1.
24.
25.
26.
Bentley, P. H.; Clayton, J. P.; Boles, M. O.; Girven, R. J. JCS(P1) 1979,

2455.
Barton, D. H. R.; Bowles, T.; Husinec, S.; Forbes, J. E.; Llobera, A.;
Porter, A. E. A.; Zard, S. Z. TL 1988, 29, 3343.
Engel, N.; Steglich, W. AG(E) 1978,17,676.
Miyoshi, M. BCJ 1913, 46, 212.
27.
Groziak, M. P.; Townsend, L. B. JOC 1986, 57, 1277.
28.
Bargar, T.; Riley, C. M. SC 1980, 10, 479.
29.
30.
Dietliker, K.; Heimgartner, H. HCA 1983, 66, 262.

(a) Henriet, M.; Houtekie, M.; Techy, B.; Touillaux, R.; Ghosez, L. TL
1980, 27, 223. (b) Bernard, C.; Ghosez, L. CC 1980, 940.
31.
32.
Toye, J.; Ghosez, L. JACS 1975, 97, 2276.

Da Costa, R.; Gillard, M.; Falmagne, J. B.; Ghosez, L. JACS 1979, 707,
4381.
33. Barton, D. H. R.; Elliott, I. D.; Gero, S. D. JCS(P1) 1982, 2085.
34. Eckert, H.; Forster, B. AG(E) 1987, 26, 894.
35.
36.
37.
38.
39.
Kurita, K.; Iwakura, Y. OSC 1988, 6, 715.

Burk, R. M.; Roof, M. B. TL 1993, 34, 395.
Palomo, C.; Cossio,F.P.; Ontario, J. M.; Odriozola, J. M. JOC 1991, 56,
5948.
Katakai, R.; Iizuka, Y. JOC 1985, 50, 715.
Pridgen, L. N.; Prol, J.; Alexander, B.; Gillyard, L. JOC 1989, 54, 3231.
Peter Hamley
Fisons Pharmaceuticals, Loughborough, UK
[7789-60-8]
Br 3 P
(MW 270.67)
(brominating agent for conversion of alcohols to bromides)

Alternate Name: phosphorus tribromide.
Physical Data: mp 41.5C; bp 168-170C/725 mmHg; d
2.85 g cm - 3 .
Solubility: sol acetone, CH2Cl2, CS2.
Form Supplied in: widely available as liquid and 1.0 M solution
in CH2Cl2.
Preparative Method: from Bromine and red phosphorus.1
Purification: generally used without purification; can be distilled
under N2 at atmospheric pressure.
Handling, Storage, and Precautions: corrosive. The colorless,
fuming liquid has a very penetrating odor. It has a vapor pres
sure of 10 mmHg at 48 C. The reagent is stable if kept dry, but
reacts violently with water. It is extremely destructive to tissue
of mucous membranes, upper respiratory tract, eyes, and skin.
This reagent should only be used in a fume hood.
Conversion of Alcohols to Bromides. The conversion of al

cohols (ROH) into bromides (RBr) using PBr3 is very general.
Reaction conditions for this transformation are quite varied. Each
PHOSPHORUS(III) BROMIDE
of the bromine atoms in the reagent is available for reaction with
an alcohol. The reagent can be used to prepare chiral bromides
from chiral alcohols (eq 1).2 It is generally important to carry out
the conversion under 'relatively mild' conditions (between 4C
and rt). Addition of HBr at the end of workup increases both the
optical purity and the isolated yield. An example is provided by
eq 2. A polyhydroxylic compound has been converted to a polybrominated product (eq 3).3
331
tion of stereochemistry due to -bond participation, in contrast to

a similar system without the -system (eq 9).12
(8)
(9)
(1)
(2)
The reagent will convert an alcohol to a bromide in the presence

of an ether (eq 10).13 Acetals are also stable to the bromination
procedure,14 although an interesting reaction of a cyclopropanone
acetal has been reported (eq 11).15
(3)
(10)
Bromination of Allylic Alcohols. The reaction of an allylic

alcohol with PBr3 in ether at 0C leads to both stereoselective
and regioselective replacement of the hydroxy group by bromine.4
Examples of this transformation are given in eqs 4 and 5.5,6 The
latter example shows that the reaction can be run in the presence
of significant unsaturation. There are many examples of similar
reactions.7
(4)
(11)
Use for Alkene Preparation. Replacement of two alcohol

groups by bromine, followed by zinc dehalogenation, provides an
interesting alkene synthesis methodology (eq 12).16 The prepara
tion of 1,3,5-hexatriene is readily accomplished via a PBr3 step
(eq 13).17 In the presence of DMF, PBr3 has been used to eliminate
a hindered diallylic tertiary alcohol (eq 14).18 See also Phosphorus(III) Bromide-Copper(I) Bromide-Zinc.
(12)
(5)
Silverstein8 followed an older procedure9 that results in rear

rangement of a secondary allylic alcohol to a terminal bromide
(eq 6). In a similar fashion, the conversion of propargylic alcohols
to allenyl bromides has been noted (eq 7).10
(13)
(6)
(14)
(7)
Remote -bond participation provides important stereochemi

cal control in the reaction. Heathcock (eq 8)11 has reported reten
Other Reactions. A simple one-step preparation of 2-bromo2,3-dihydro-l,3,4,2-oxadiazaphospholes has been reported

332
PHOSPHORUS(V) BROMIDE
(eq 15).19 An interesting preparation of 1,5-dibromopentane from

piperidine is available (eq 16).20
(15)
[7789-69-7]
(16)
Related Reagents. A number of related reagents have

been used for the conversion of alcohols to bromides.
Other reagents for this purpose covered in this encyclo
pedia include l,2-Bis(diphenylphosphino)ethane Tetrabromide, Bromine-Triphenyl Phosphite, Hydrogen Bromide,
Triphenylphosphine-Carbon Tetrabromide, and Triphenylphosphine Dibromide.
1. (a) Gay, J. F.; Marxson, R. N. Inorg. Synth 1946, 2, 147. (b) Noller, C.
R.; Dinsmore, R. OSC 1943, 2, 358.
2. Hutchins,R.O.;Masilamani,D.;Maryanoff,C. A. JOC 1976, 41, 1071.
3. Schurink, H. B. OSC 1943, 2, 476.
4. Corey, E. J.; Kirst, H. A.; Katzenellenbogen, J. A. JACS 1970, 92, 6314.
5.
6.
7.
8.
Miyaura, N.; Ishikawa, M.; Suzuki, A. TL 1992, 33, 2571.

Effenberger, F.; Kesraarszky, T. CB 1992, 125, 2103.
See, for example: (a) Marshall, J. A.; Faubl, H.; Warne, T. M., Jr. CC
1967, 753. (b) Piers, E.; Britton, R. W.; deWaal, W. TL 1969, 1251. (c)
Mori, K. T 1974, 30, 3807. (d) Bestmann, H. J.; Stransky, W.; Vostrowsky,
O. CB 1976, 109, 1942. (e) Mori, K.; Tominaga, M.; Matsui, M. T 1975,
31, 1846. (f) Gonzales, A. G.; Martin, J. D.; Melian, M. A. TL 1976,
2279.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
Silverstein, R. M.; Rodin, J. O.; Burkholder, W. E.; Gorman, J. E. Science

1967, 157, 85.
Celmer, W. D.; Solomons, I. A. JACS 1953, 75, 3430.
Leznoff, C. C ; Sondheimer, F. JACS 1968, 90, 731.
Heathcock, C. H.; Kelly, T. R. T 1968, 24, 1801.
Mathur, R. K.; Rao, A. S. T 1967, 23, 1259.
Smith, L. H. OSC 1955, 3, 793.
Corey, E. J.; Cane, D. E.; Libit, L. JACS 1971, 93, 7016.
Miller, S. A.; Gadwood, R. C. 0 5 1989, 67, 210.
Tanaka, S.; Yasuda, A.; Yamamoto, H.; Nozaki, H. JACS 1975, 97, 3252.
Hwa, J. C. H.; Sims, H. OS 1961, 41, 49.
Nampalli, S.; Bhide, R. S.; Nakai, H. SC 1992, 22, 1165.
19.
20.
Kimura, H.; Konno, H.; Takahashi, N. BCJ 1993, 66, 327.

von Braun, J. OSC 1941, 1, 428.
Br 5 P
(MW 430.47)
(bromination agent for conversion of alcohols to bromides)

Alternate Name: phosphorus pentabromide.
Physical Data: mp 179-181 C; The Merck Index (11th ed.) re
ports dec above 100 C.
Solubility: sol CS2, CCl4.
Form Supplied in: yellow solid; commercially available.
Preparative Method: from Bromine and Phosphorus(III)
Bromide,1 with which it is in equilibrium.
Handling, Storage, and Precautions: corrosive and highly toxic;
stable if kept dry, but reacts violently with water; store under
N2 at rt; use in a fume hood.
Conversion of Alcohols to Bromides. The conversion of
alcohols (ROH) into bromides (RBr) using PBr5 would ap
pear to be quite general for alcohols; however, the literature
does not report many examples of this reaction. Eliel2 reported
that PBr5 is better able to convert 4-t-butylcyclohexanol to 4-tbutylbromocyclohexane than Phosphorus(III) Bromide (eq 1).
(1)
In the steroid series, D-ring enlargement accompanies reaction

of a secondary alcohol with PBr5 (eq 2).3 It should be noted
that reaction of Phosphorus(V) Chloride with this same sub
strate gave direct replacement of the OH with Cl with inversion
of configuration.4 Rearrangement and addition of bromine across
a double bond has been noted in the reaction with a propargyl
alcohol derivative (eq 3).5
(2)
Bradford P. Mundy
Colby College, Waterville, ME, USA
(3)
PHOSPHORUS(III) CHLORIDE
Cleavage of Ethers. PBr5 has been used to cleave diisopropyl

ether to isopropyl bromide.5
Reaction with Ketones. A regioselective dibromination of a
diketone has been reported (eq 4).6
(4)
Related Reagents. Many related reagents are available for the

conversion of alcohols to bromides (see Phosphorus(III) Bro
mide and related reagents cited therein).
1.
(a) Gay, J. F.; Marxson, R. N. Inorg. Synth. 1946, 2, 147. (b) Noller, C.
R.; Dinsmore, R. OSC 1943, 2, 358. (c) Mellor, J. W. Comprehensive
Treatise on Inorganic and Theoretical Chemistry; Longmans: London,
1936; Vol. 8, pp 1034-1036 provides an old, but interesting, account of
early work with the reagent. (d) Kaslow, C. E.; Marsh, M. M. JOC 1947,
12, 456.
2.
Eliel, E. L.; Haber, R. G. JOC 1959, 24, 143.
3.
Li, R. T.; Sato, Y. JOC 1968, 33, 3632.
4.
Adam, G.; Schreiber, K. 71966, 22, 3581.
5.
Verny, M.; Vessiere, R. BSF 1968, 2585.
6.
Kutyrev, A. A.; Biryukov, V. V.; Litvinov, I. A.; Katayeva, O. N.; Musin,

R. Z.; Enikeyev, K. M.; Naumov, V. A.; Ilyasov, A. V.; Moskva, V. V. T
1990, 46, 4333.
333
and death. Contact with water will be violent and result in suf
ficient gas evolution to rupture closed or inadequately vented
containers. Acids produced by contact with water can evolve
hydrogen on contact with metals. This reagent must be used in
a fume hood.
Chlorinations. Alcohols, aldehydes, ketones, and carboxylic acids have been chlorinated with PCl3. The alter
native phosphorochloridites, SOCl2, HC1, PCl5, Ph3PCl2,
Ph3P-hexachloroacetone, Ph3P-CCl4, and NCS-SEt2,1,2 have
been used to convert alcohols to chlorides. Aldehydes and
ketones are converted to phosphites by PCl3. Conversion of
a carboxylic acid to the acid chloride has been accomplished
using PCl3, PCl5, POCl3, and SOCl2. In some cases, these
reactions tend to be sluggish and substrate, solvent, and
temperature dependent. Modified phosphorus halides, i.e.
2,2,2-trichloro-l,3,2-benzodioxaphospholes or Ph3PCl2, are
superior phosphorus reagents for acid chloride formation.1
Carboxylic acids are -brominated with a combination of PCl3
and Br2.3 Imidoyl halides, generated from amides, thioamides,
or hydroxamic acid derivatives with PCl3, are valuable synthetic
intermediates and provide access to a wide range of heterocycles,
e.g. quinazolinones and oxadiazoles.4
Preparation of Phosphites. Alcohols, diols, and phenols are
readily converted to phosphites. Analogous reactions are seen with
thiols1 and amines.5 Diaryl phenols react to form medium-sized
heterocyclic ring systems (eq 1).6
Bradford P. Mundy
(1)
Phosphorus(III) Chloride1
[7719-12-2]
Cl3P
(MW 137.32)
(reactive chlorinating agent;1,2 strong oxo, aza, thio, and

dienophilicity; reactive with organometallics and metal salts;
phosphorus source for metal ion ligand synthesis28)
Dihydroxyarenes yield dioxaphospholes with PCl3.7 A spe

cial subclass of phosphite reactions are phosphitylations.
Dichlorophosphite derived from PCl3 and an alcohol, epoxide,
or P(OMe)3 are common phosphitylation reagents. Replacement
of the alcohol by an amine leads to dialkylaminodichlorophosphites and subsequent phosphoramidation of the substrate.8 Di
rect phosphitylation with PCl3 is useful with sterically hindered
axial hydroxy functions which fail to phosphorylate with other
reagents (eq 2).9
Alternate Name: phosphorus trichloride.

Physical Data: mp -112C; bp 76 C; d 1.586 g cm - 3 .
Solubility: sol benzene, CHCl3, CH2Cl2 ether, CS2; dec in water
or alcohols.
Form Supplied in: water-white liquid; widely available.
Purification: generally used as received without further purifica
tion. To purify, heat under reflux to expel dissolved hydrogen
R1 = 4-MeOC6H4CO, R2 = 1-menthol
chloride, then distill at atmospheric pressure under N2. Further
purification is possible by vacuum fractionation several times
through a 45 C trap into a 78 C receiver.
Oxidations. Oxidation
of
PC13
with
Handling, Storage, and Precautions: the liquid is highly toxic by
11
12
diazomethane/chlorine,
or
oxygen/ethylene,
ingestion and slightly toxic by single dermal applications. In
POCl3 or, in the latter two cases, phosphate esters.
halation can cause delayed, massive, acute pulmonary edema
(2)
ozone,10
produces
Next Page
334
PHOSPHORUS(III) CHLORIDE
Deoxygenations. Sulfoxides,13 amine N-oxides,14 and hy

droxy amides15 are readily reduced with PCl3 to the correspond
ing sulfides, amines, and amides. Alternative sulfoxide reducing
agents include AcCl, RCOC1, I-, Sn2+, Fe 2+ , SiHCl3, Si2H2Cl2,
LiAlH4, NaBH4/CoCl2, BHC12 (aliphatic aryl), Rh/H2, Pd/C/H2,
Fe(CO)5, TiCl3, TMSI, TMSBr, I2, and PhSiMe3. The presence
of active hydrogens will complicate attempts to reduce amine TVoxides. Amine TV-oxides can also be reduced using H2SO3, Raney
Ni, Pd/C/H2, and R3P (R = alkyl or aryl).
Amines. Reaction of PCl3 with quaternary ammonium salts
yields phosphaindolizines and thiazolodiazaphospholes.16 Imines
produce phosphonates17 whereas hydrazones are converted to
pyrazoles, indoles, and nitriles.18 Nitrones undergo rearrange
ment to secondary or tertiary amides19 and primary alkylnitro
compounds are reduced to nitriles (eq 3).20 Diazonium salts are
transformed to phosphonic acids.21
(3)
silane;
Lithium Aluminium Hydride; Pentacarbonyliron; Phosphorus(V) Chloride; Phosphorus Oxychloride;
Sodium Borohydride; Thionyl Chloride; Titanium(III)
Chloride; Trichlorosilane; Triphenylphosphine Dichloride;
Triphenylphosphine-Hexachloroacetone.
1. (a) Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon:

Oxford, 1991. (b) Comprehensive Organic Chemistry; Barton, D.;
Ollis, W. D., Eds.; Pergamon: Oxford, 1979. (c) The Chemistry of
Organophosphorous Compounds; Hartley, F. R., Ed.; Wiley: New York,
1990. (d) Encyclopedia of Chemical Technology, 3rd ed.; Grayson, M.,
Ed.; Wiley: New York, 1982; Vol. 17. (e) Perrin, D. D.; Armarego,
W. L. F.; Perrin, D. R. Purification of Laboratory Chemicals, 2nd ed.;
Pergamon: Oxford, 1980.
2.
(a) Boughdady, N. M.; Chynoweth, K. R.; Hewitt, D. G. AJC 1987, 40,

767. (b) Sanda, K.; Rigal, L.; Gaset, A. CR 1989,187, 15. (c) Newkome,
G. R.; Theriot, K. J.; Majestic, V. K.; Spruell, P. A.; Baker, G. R. JOC
1990, 55, 2838. (d) Gazizov, M. B.; Khairullin, R. A.; Moskva, V. V.;
Savel' eva, E. I.; Ostanina, L. P.; Nikolaeva, V. G. ZOB 1990, 60, 1766.
3.
Clarke, H. T.; Taylor, E. R. OSC 1941, 1, 115.
4.
The Chemistry of Amidines and Imidates; Patai, S.; Rappoport, Z., Eds.;
Wiley: New York, 1991.
(a) Skolimowski, J. J.; Quin, L. D.; Hughes, A. N. JOC 1989, 54, 3493. (b)
Cabral, J.; Laszlo, P.; Montaufier, M.-T.; Randriamahefa, S. L. TL 1990,
31, 1705. (c) Bansal, R. K.; Mahnot, R.; Sharma, D. C ; Karaghiosoff,
K. S 1992, 267.
5.
Reaction with Organometallic Compounds. Organomagnesium (eq 4),22,23 lithium,24 and other main group metals25
readily undergo ligand transfer with PCl3 to form mono-, di-, or
trialkyl(aryl) phosphines. A subclass of reactions include Aluminum Chloride-assisted transformations to form phosphetanes
(eq 5).26
(4)
(5)
cisltrans = 77%
Enols and Ketene Silyl Acetals. Reaction of a silyl enol ether

with PCl3/Zinc Chloride leads to the formation of dichlorophosphine addition products (see also Phosphorus(III) ChlorideZinc(II) Chloride). Ketene silyl acetals react directly with PCl3
under very mild conditions to form similar addition products
(eq 6).27
(6)
Ligands. Synthesis of some phosphorus-containing ligand

molecules have utilized PCl3 as a key reagent for introduction
of the phosphorus atom.28
Related Reagents. Acetyl Chloride; Bromotrimethylsilane; N-Chlorosuccinimide-Dimethyl Sulfide; Dichloroborane
Diethyl Etherate; Hydrogen Chloride; Iodine; IodotrimethylLists of Abbreviations and Journal Codes on Endpapers
6.
(a) Nachev, I. A. PS 1988, 37, 149. (b) Mukmeneva, N. A.; Kadyrova,

V. K.; Zharkova, V. M.; Cherkasova O. A.; Voskresenskaya, O. V. ZOB
1986, 56, 2267.
7.
8.
Pastor, S. D.; Spivack, J. D. JHC 1991, 28, 1561.

Yamana, K.; Nishijima, Y.; Oka, A.; Nakano, H.; Sangen, O.; Ozaki, H.;
Shimidzu, T. T 1989, 45,4135.
9. Watanabe, Y.; Ogasawara, T.; Shiotani, N.; Ozaki, S. TL 1987, 28, 2607.
10. Caminade, A. M.; El Khatib, F.; Baceiredo, A.; Koenig, M. PS 1987, 29,
365.
11.
12.
Calvo, K. C. J. Labelled Compd. Radiopharm. 1989, 27, 395.

Stringer, O. D.; Charig, A. J. Labelled Compd. Radiopharm. 1989, 27,
647.
13. The Chemistry of Sulphones and Sulphoxides; Patai, S.; Rappoport, Z.;
Stirling, C , Eds.; Wiley: New York, 1988.
14. Begtrup, M.; Jonsson, G. ACS(B) 1987, B41, 724.
15. Goerlitzer, K.; Heinrici, C. AP 1988, 321, All.
16.
(a) Bansal, R. K.; Mahnot, R.; Sharma, D. C ; Karaghiosoff, K. S 1992,

267. (b) Bansal, R. K.; Kabra, V.; Gupta, N.; Karaghiosoff, K. IJC(B)
1992, 31B, 254.
17. Lukanov, L. K.; Venkov, A. P. S 1992, 263.

18. (a) Bartoli, G.; Bosco, M.; Dalpozzo, R.; Marcantoni, E. TL 1990,
31, 6935. (b) Baccolini, G.; Evangelisti, D.; Rizzoli, C ; Sgarabotto,
P. JCS(P1) 1992, 1729.
19. Brever, E.; Aurich, H. G.; Nielson, A. Nitrones, Nitronates, and
Nitroxides; Wiley: New York: 1989.
20. Koll, P.; Kopf, J.; Wess, D.; Brandenburg, H. LA 1988, 685.
21. Klumpp, E.; Eifert, G.; Boros, P.; Szulagyi, J.; Tamas, J.; Czira, G. CB
1989, 722,2021.
22. Voskvil, W.; Arens, 3. F. OSC 1973, 5, 211.
23. Denmark, S. E.; Dorow, R. L. JOC 1989, 54, 5.
24. Kuhn, N.; Kuhn, A.; Schulten, M. JOM 1991, 402, C41.
25. Douglas, T.; Theopold, K. H. AG(E) 1989, 28, 1367.
26. (a) Lochschmidt, S.; Mathey, F.; Schmidpeter, A. TL 1986, 27, 2635. (b)
Yao, E.; Szewczyk, J.; Quin, L. D. S 1987, 265.
27. Pellon, P.; Hamelin, J. TL 1986, 27, 5611.
Previous Page
PHOSPHORUS(V) CHLORIDE
28.
(a) Cunningham, A. E, Jr.; Kndig, E. P. JOC 1988, 53, 1823. (b)

Meyer, T. G.; Jones, P. G.; Schmutzler, R. ZN(B) 1992, 47, 517. (c)
Comprehensive Coordination Chemistry; Wilkinson, G., Ed.; Pergamon:
Oxford, 1987.
335
In select cases, secondary alcohols undergo chlorination with

inversion of configuration upon reaction with PCl 5 (eq 2). 11
(2)
Kenneth P. Moder
Eli Lilly and Company, Lafayette, IN, USA
Phosphorus(V) Chloride 1
[10026-13-8]
C15P
(MW 208.22)
(chlorination of alcohols,2 carboxylic acids, 3 amides,4 aldehy

des, ketones, and enols; Bischler-Napieralski synthesis of 3,4dihydroisoquinolines;5 Beckmann rearrangement of oximes6)
Alternate Name: phosphorus pentachloride.
Physical Data: mp 179-181 C (sublimes); d 1.6gcm - 3 .
Solubility: sol CS 2 , CCl 4 . Typical solvents for reactions which
use PCl 5 are CCl 4 , CHCl 3 , CH2Cl2, hexane, decane, benzene,
toluene, and diethyl ether.
Form Supplied in: white to pale yellow solid; widely available. In
the solid state, PCl 5 exists in the ionic form, [PCl 4 ] + [PCl 6 ] - .
Purification: by vacuum sublimation.7
Handling, Storage, and Precautions: reacts with moisture to lib
erate hydrochloric acid and phosphoric acids. It is extremely
corrosive to the skin, eyes, and mucous membranes. It should
be stored in a dry area in containers impervious to moisture and
resistant to corrosion. Laboratory quantities may be stored in
polyethylene bags placed within glass containers. This reagent
should be used in a fume hood.
Chlorides from Alcohols and Phenols. Alcohols are con

verted to alkyl chlorides with the formation of 1 equiv of HC1
and POCl 3 by the action of PCl 5 . 2 The stability of the substrate
and product to acidic reaction conditions and the ease by which
the product can be separated from the reaction byproducts greatly
influences the suitability of PCl5 for this functional group trans
formation. Depending upon the structure of the alcohol, dehy
dration to form an alkene8 or rearrangement9 may be significant
competing processes. The conversion of the 3-hydroxymethyl
cephalosporin to the 3-chloromethyl derivative10 shown in eq 1
illustrates the use of PCl5 for the chlorination of a primary al
cohol with a substrate of considerable functional complexity and
lability.
(1)
R = CO(CH2)3CH(NHCOPh)CO2CHPh2
Tertiary alcohols are converted to tertiary chlorides under mild

conditions with retention of configuration, presumably through an
SN 1, tight ion-pair mechanism (eq 3). 12 The reactions are com
plete within minutes of mixing the tertiary alcohol with PCl 5
in CHCl 3 or ether at 0 C in the presence of calcium carbon
ate. Chlorination of l,l,l-trifluoro-2-(trifluoromethyl)-3-butyn2-ol with PCl5 leads to l-chloro-3,3-bis(trifluoromethyl)allene
(eq 4). 13 This tertiary alcohol is unreactive towards SOCl 2 , POCl 3 ,
PCl 3 , coned. HC1, and POCh/pyridine. Phenols substituted with
strong electron-withdrawing groups can be converted to aryl chlo
rides with PCl 5 . 14
(3)
(4)
A polymer-supported form of PCl5 has been developed by slur

rying PCl5 with Amberlite IRA 93 resin in CCl 4 . 15 The resulting
resin is effective for the chlorination of primary and secondary
alcohols in yields of 70-98%. Some elimination products are ob
served with secondary alcohols. The reaction may be conducted
in hydrocarbon, ether, or halogenated hydrocarbon solvents. The
phosphorus byproducts are retained on the resin and separated
from the product by filtration. Regeneration of the resin is possible
by washing with aqueous acid and base. Acid-sensitive substrates
are susceptible to degradation.
Carboxylic Acid Chlorides from Acids. PCl 5 may be em
ployed for the conversion of carboxylic acids to their acid
chlorides.16 Typically, the acid is combined with PCl 5 either neat17
or in solvents such as ether18 or benzene. 19 The use of PCl 5
is most convenient when the product can be isolated by direct
crystallization20 or distillation21 from the crude reaction mixture.
In some cases, aqueous workups may be employed to remove
acidic byproducts without significant hydrolysis.22 Because of
the difficulties associated with separating the acid chloride from
the byproduct POCl 3 , the use of PCl 5 for this functional group
transformation has largely been supplanted by SOCl 2 , COCl 2 , or
(COCl) 2 , 23 particularly in conjunction with catalytic amounts of
DMF. 24 The polymer-supported form of PCl 5 , 15 described above
for the chlorination of alcohols, also converts carboxylic acids to
the corresponding acid chlorides in 48-91% yields.
Nitriles from Amides. Primary amides are dehydrated to af
ford nitriles upon heating with PCl 5 . 4 a - e Due to the severity of the
reaction conditions, substrates of limited functional complexity
are tolerated. The reactions are generally conducted either neat25
or with POCl 3 26 as a solvent. This method is useful for products
336
which can be isolated by distillation from the crude reaction mix

ture. Secondary amides, most notably N-alkylbenzamides, when
subjected to PCl5 may undergo the von Braun degradation to pro
duce a benzonitrile and an alkyl chloride.27
Chloromethyleneiminium Chlorides and Imidoyl Chlorides
from Amides, Oximes, Hydroxamic Acids, and Ureas. Tertiary
amides react with PCl5 to afford chloromethyleneiminium
chlorides,4d,g-i whereas secondary amides afford imidoyl
chlorides.4d-f,j In each case, POCl3 and HC1 are generated as re
action byproducts. The amide chlorides and imidoyl chlorides are
frequently used as intermediates for subsequent chemical trans
formation and are not isolated. When desired, isolation has been
accomplished by either distillation or crystallization. In choosing
PCl5 as a reagent for this transformation, consideration must be
given to the acid lability and reactivity of the substrate. Depend
ing upon the substrate and reaction conditions, the formation of
imidoyl chlorides by the action of PCl5 may be accompanied by
further reaction to produce a nitrile and alkyl chloride via the von
Braun degradation.27 -Chlorination can be a problem if excess
PCl5 is used, and self-condensation can occur at elevated tempera
tures if an -CH is present in the imidoyl chloride.46 The presence
of a strong electron-withdrawing group to the amide carbonyl
can influence the course of the chlorination of an amide with PCl5,
as seen by the formation of the diazadiphosphetidine (eq 5) when
N-methyltrifluoroacetamide is reacted with PCl5.28
(5)
A highly practical example of the reaction of PCl5 with a tertiary

amide is the synthesis of Dimethylchloromethyleneammonium
Chloride, the Vilsmeier reagent. This salt is obtained in 88% yield
by the careful addition of PCl5 to N,N-Dimethylformamide while
allowing the reaction to exotherm to 100 C followed by cooling
to 0 C, filtration, and washing.29 The Vilsmeier reagent is useful
for the chlorination of alcohols and acids.
PCl5 has found considerable application for the removal of
amide side chains30 in the industrial scale manufacture of semisyn
thetic cephalosporins31 and penicillins.32 The intermediate imi
doyl chlorides, produced by the action of PCl5 on a secondary
amide, are converted to imino ethers upon the introduction of an
alcohol to the reaction mixture. The imino ethers undergo further
reaction to afford the deprotected C(7)-amino cephalosporin or
C(6)-amino penicillin.33
Iminium and imidoyl chlorides have a prominent position as
intermediates for the synthesis of heterocyclic compounds. In this
regard, PCl5 has found extensive application. Imidoyl chlorides
derived from the treatment of N-(2-phenylethyl)carboxamides
with PCl5 can undergo Bischler-Napieralski cyclization5 to form
3,4-dihydroisoquinolines (eq 6).34 In addition to PCl5, this cy
clization has been effected with P2O5, POCl3, POCl3 in refluxing
xylene or decalin, P2O5 in pyridine, and polyphosphoric acid.
N,N'-Disubstituted oxamides (eq 7)35 and the imines or hydrazones of -acylamino ketones (eq 8)36 react with PCl5 to form
imidoyl chlorides which undergo subsequent intramolecular cy
clization to produce imidazoles.
(6)
(7)
(8)
The reaction of oximes with PCl5 can lead to imidoyl chlorides

via Beckmann rearrangement.6 The reaction is frequently con
ducted in ether at or below ambient temperature. Aromatic, hy
drocarbon, and halogenated hydrocarbon solvents are also used.
The oxime of 4-phenyl-3-methyl-3-buten-2-one undergoes Beck
mann rearrangement within 5 to 15 min upon treatment with PCl5
in decalin at 0C to give an imidoyl chloride.37 Subsequent treat
ment with P2O5 at reflux affords 1,3-dimethylisoquinoline (eq 9).
2-(Oximino)indan-l-ones afford 1,3-dichloroisoquinolines when
subjected to 1 equiv of PCl5 in POCl3 followed by treatment with
anhydrous HCl and then a second equiv of PCl5 (eq 10).38 Treat
ment of an oxime which contains an -alkoxy, -alkylthio, or alkylamino group with PCl5 can lead to 'second-order' Beckmann
rearrangement,39 as exemplified in eq 11.40
(9)
(10)
(11)
The reaction of alkylbenzohydroxamates with PCl5 in ether

offers a general preparative method for the synthesis of Oalkylbenzohydroximoyl chlorides.41 Ketenimines42 can be de
rived by the treatment of secondary amides bearing a sin
gle -CH with PCl5 followed by dehydrohalogenation with
triethylamine.43 Alkoxycarbonylimidoyl chlorides are obtained
by the reaction of the esters of N-acylcarbamic acids with PCl5.44
N,N-Dialkylureas in which the alkyl groups are primary react with
PCl5 to form l,3-diaza-2-Pv-phosphetidinones, whereas chloroformamidinium chlorides are produced when the alkyl groups
45
are secondary. N-Alkyl-N-nitrosamides undergo rearrangement

to the corresponding N-alkyloxamides via an intermediate Nnitrosochloroiminium chloride upon reaction with PCl5.46
gem-Dichlorides from Ketones, Aldehydes, and Esters.
Ketones and aldehydes may be converted into gem-dichlorides
by the action of PCl5.47 Formate esters48 and esters with strong
electron-withdrawing groups to the carbonyl47 react with PCl5 to
give the corresponding gem-dichlorides. Conversions have been
effected either neat,49 or with PCl3,50 POCl3,51 or halogenated
hydrocarbons52 as solvents. The reaction rate and product dis
tribution are influenced by the solvent employed.52a,b Polar sol
vents, such as nitromethane and acetonitrile, greatly retard the re
action. The presence of an -CH group can lead to the formation
of vinyl chlorides as frequent by products.52a,53 Perhaloacetones
are resistant to chlorination with PCl5 under the typical conditions
employed for this conversion; however, the gem-dichlorides can
be obtained in modest yields upon heating at 275-300 C in an
autoclave.54
Vinyl Chlorides from Enols. PCl5 reacts with the enolic form of enolizable cyclic55 and acyclic56 carbonyls to
form vinyl chlorides. A side-reaction encountered with es
ters has been formation of the acid chloride, in which case
reesterification during the reaction workup affords improved
yields (eq 12).55 Hydroxypyridines,57 hydroxyquinolines,58 and
hydroxyisoquinolines38 are converted to chloropyridines, chloroquinolines, and chloroisoquinolines by the action of PCl5.
(12)
methods for the chlorination of alcohols; however, synthesis of

the alkyl salicylate is required.
Related
Reagents. Dimethylchloromethyleneammonium
Chloride; Oxalyl Chloride; Phosphorus(III) Chloride; Phosphorus(V) Oxide; Phosphorus Oxychloride; Thionyl Chloride;
Triphenylphosphine-Carbon Tetrachloride; Triphenylphosphine
Dichloride.
1. (a) The Chemistry of the Hydroxyl Group; Patai, S., Ed.; Interscience:
New York, 1971; Part 1. (b) The Chemistry of Acyl Halides; Patai, S.,
Ed.; Interscience: New York, 1972. (c) The Chemistry of the Cyano
Group; Rappoport, Z., Ed.; Interscience: New York, 1970. (d) The
Chemistry of Amides; Zabicky, Z., Ed.; Interscience: New York, 1970.
(e) The Chemistry of the Carbon-Nitrogen Double Bond; Patai, S., Ed.;
Interscience: New York, 1970.
2.
(a) Brown, G. W. In The Chemistry of the Hydroxyl Group; Patai, S. Ed.;

Interscience: New York, 1971; Part 1, pp 603-612. (b) COS 1991, 6, 204.
3. (a) Comprehensive Organic Chemistry; Barton, D. H. R.; Ollis, W. D.,
Eds.; Pergamon: Oxford, 1979; Vol. 2, pp 633-634. (b) COS 1991, 6,
301. (c) Ansell, M. F. In The Chemistry of Acyl Halides; Patai, S., Ed.;
Interscience: New York, 1972; pp 40-44. (d) Buehler, C. A.; Pearson, D.
E. Survey of Organic Syntheses; Wiley: New York, 1970; pp 859-873.
4. (a) Mowry, D. T. CRV 1948, 42, 189. (b) Friedrich, K.; Wallenfels, K. In
The Chemistry of the Cyano Group; Rappoport, Z., Ed.; Interscience:
New York, 1970; pp 96-103. (c) Bieron, J. F.; Dinan, F. J. In The
Chemistry of Amides; Zabicky, Z., Ed.; Interscience: New York, 1970;
pp 274-279. (d) Challis, B. C.; Challis, J. A. In The Chemistry of
Amides; Zabicky, Z., Ed.; Interscience: New York, 1970; pp 801-814.
(e) Sustman, R.; Korth, H.-G. MOC 1985, E5, 628. (f) Bonnett, R. In
The Chemistry of the Carbon-Nitrogen Double Bond; Patai, S., Ed.;
Interscience: New York, 1970; pp 601-606. (g) COS 1991, 6, 495. (h)
Eilingsfeld, H.; Seefelder, M.; Weidinger, H. AG 1960, 72, 836. (i)
Kantlehner, W. Adv. Org. Chem. 1979, 9, 65. (j) COS 1991, 6, 524.
5.
Other Applications. Alkanes,59 arylalkanes,59a heteroaromatics,60 and alkenes59,61 have been chlorinated with PCl5
to afford chloro alkanes, chloro aromatics and vic-dichlorides.
The use of PCl5 as a catalyst for the chlorination of alkanes,
cycloalkanes, and arylalkanes has been reported.62 Secondary
nitriles are -chlorinated when subjected to PCl5 either neat63
or in an inert solvent such as CCl4 or CHCl3.64 Anhydrides
are converted to diacid chlorides by the action of PCl5.65
Sulfonyl and sulfamoyl chlorides may be prepared by heating
the corresponding acid66 or acid salt67 either neat or in an inert
solvent with PCl5. PCl5 has been used to deoxygenate TV-oxides,68
hydroxylamines,69 and sulfoxides.70 Hydroxylamines in which
the -carbon is tertiary can undergo the Stieglitz rearrangement
to afford imines when treated with PCl5.71 Highly fluorinated
carbinols bearing an -CH, which prove resistant to the action
of SOCl2, SO2Cl2, HCl, and ZnCl2, are converted to alkenes by
the action of PCl5.72 Cyclic acetals of -keto acids, when reacted
with PCl5 in CH2Cl2, afford esters of halohydrins.73 Glyoxal
bis-acetals are converted to l,2-dichloro-l,2-dialkoxyethanes by
the action of PCl5.74 This has been developed into a procedure for
the synthesis of alkynic diethers.75 Imines have been converted
into amides upon heating with PCl5, either neat or in a solvent
such as xylene, followed by treatment with water.76 A method
has been developed for the synthesis of alkyl chlorides by the
reaction of PCl5 with the alkyl salicylates.77 The yields are
higher in several cases for this procedure when compared to other
337
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
(a) Gensler, W. J. In Heterocyclic Compounds; Elderfield, R. C , Ed.;

Wiley: New York, 1952; p 344. (b) Comprehensive Organic Chemistry;
Barton, D. H. R.; Ollis, W. D., Eds.; Pergamon: Oxford, 1979; Vol. 4, p
207. (c) Whaley, W. M.; Govindachari, T. R. OR 1951, 6, 74. (d) Fodor,
G.; Nagubandi, S. 7/1980, 36, 1279.
(a) Donaruma, L. G.; Heldt, W. Z. OR 1960, 11, 1. (b) Beckwith, A.
L. J. In The Chemistry of Amides; Zabicky, J., Ed.; Interscience: New
York, 1970; pp 131-137. (c) March, J. Advanced Organic Chemistry:
Reactions, Mechanisms, and Structures, 3rd ed.; Wiley: New York, 1985;
pp 987-989.
Suter, R. W.; Knachel, H. C ; Petro, V. P.; Howatson, J. H.; Shore, S. G.
JACS 1973, 95, 1474.
Shoppee, C. W.; Lack, R. E.; Sharma, S. C ; Smith, L. R. JCS(C) 1967,
1155.
(a) Carman, R. M.; Shaw, I. M. AJC 1980, 33, 1631. (b) Fry, J. L.; West,
J. W. 70C 1981, 4(5, 2177.
Yamanaka, H.; Chiba, T.; Kawabata, K.; Takasugi, H.; Masugi, T.;
Takaya, T. J. Antibiot. 1985, 38, 1738.
Shoppee, C. W.; Coll, J. C. JCS(C) 1970, 1124.
Carman, R. M.; Shaw, I. M. AJC 1976, 29, 133.
(a) Abele, H.; Haas, A.; Lieb, M. CB 1986, 119, 3502. (b) Simmons, H.
E.; Wiley, D. W. JACS 1960, 82, 2288.
Comprehensive Organic Chemistry; Barton, D. H. R.; Ollis, W. D., Eds.;
Pergamon: Oxford, 1979; Vol. 1, p 736.
Cainelli, G.; Contento, M.; Manescalchi, F.; Plessi, L.; Panunzio, M. S
1983, 306.
(a) Comprehensive Organic Chemistry; Barton, D. H. R.; Ollis, W. D.,
Eds.; Pergamon: Oxford, 1979; Vol. 2, pp 633-634. (b) COS 1991, 6,
301. (c) Ansell, M. F. In The Chemistry of Acyl Halides; Patai, S., Ed.;
Interscience: New York, 1972; pp 40-44. (d) Buehler, C. A.; Pearson, D.
E. Survey of Organic Syntheses; Wiley: New York, 1970; pp 859-873.
338
PHOSPHORUS(III) IODIDE
17. Adams, R.; Jenkins, R. L. OSC 1941, 1, 394.

18. Ireland, R. E.; Chaykovsky, M. OS 1961, 41, 5.
19. Sherk K. W.; Augur, M. V.; Softer, M. D. JACS 1945, 67, 2239.
20. Braun, C. E.; Cook, C. D. OS 1961, 41, 79.
21. Feuer, H.; Pier, S. M. OSC 1963, 4, 554.
22. Ansell, M. F. In The Chemistry of Acyl Halides; Patai, S., Ed.;
Interscience: New York, 1972; p 41.
23. Buehler, C. A.; Pearson, D. E. Survey of Organic Syntheses; Wiley: New
York, 1970; pp 860-861.
24. COS 1991, 6, 302.
25. Corson, B. B.; Scott, R. W.; Vose, C. E. OSC 1943, 2, 379.
26. Taylor, E. C , Jr.; Crovetti, A. J. OSC 1963, 4, 166.
27. (a) Bieron, J. F.; Dinan, F. J. In The Chemistry of Amides; Zabicky, Z.,
Ed.; Interscience: New York, 1970; p 277. (b) Challis, B. C; Challis,
J. A. In The Chemistry of Amides; Zabicky, Z., Ed.; Interscience: New
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28.
29.
30.
Norris, W. P.; Jonassen, H. B. JOC 1962, 27, 1449.

Hepburn, D. R.; Hudson, H. R. C1(L) 1974, 664.
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Penicillins: Chemistry and Biology; Flynn, E. H., Ed.; Academic: New
York, 1972; pp 39-70.
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32.
33.
Fechtig, B.; Peter, H.; Bickel, H.; Vischer, E. HCA 1968, 51, 1108.
Weissenburger, H. W. O.; van der Hoeven, M. G. RTC 1970, 89, 1081.
Hatfield, L. D.; Lunn, W. H. W.; Jackson, B. G.; Peters, L. R.; Blaszczak,
L. C ; Fisher, J. W.; Gardner, J. P.; Dunigan, J. M. In Recent Advances
in the Chemistry of -Lactam Antibiotics; Gregory, G. I., Ed.; Royal
Society of Chemistry: London, 1980; pp 109-124.
(a) Lindenmann, A. HCA 1949, 32, 69. (b) Pfister, J. R. H 1986, 24, 2099.
(c) Badia, D.; Carrillo, L.; Dominguez, E.; Cameno, A. G.; deMarigorta,
E. M.; Vicento, T. JHC 1990, 27, 1287. (d) Fodor, G.; Gal, J.; Phillips,
B. A. AG(E) 1972, 77, 919.
Godefroi, E. F.; van der Eycken, C. A. M.; Janssen, P. A. J. JOC 1967,
32, 1259.
Engel, N.; Steglich, W. LA 1978, 1916.
Zielinski, W. S 1980, 70.
Simchen, G.; Krmer, W. CB 1969, 702, 3666.
Comprehensive Organic Chemistry; Barton, D. H. R.; Ollis, W. D., Eds.;
Ohno, M.; Naruse, N.; Torimitsu, S.; Teresawa, I. JACS 1966, 88, 3168.
(a) Johnson, J. E.; Nalley, E. A.; Weidig, C. JACS 1973, 95, 2051. (b)
Johnson, J. E.; Springfield, JR.; Hwang, J. S.; Hayes, L. J.; Cunningham,
W. C.; McClaugherty, D. L. JOC 1971, 36, 284. (c) Taylor, E. C ; Kienzle,
F. JOC 1971, 36, 233.
Krow, G. R. AG(E) 1971, 10, 435.
Stevens, C. L.; French, J. C. JACS 1954, 76, 4398.
Neidlein, R.; Bottler, R. TL 1966, 1069.
Ulrich, H.; Sayigh, A. A. R. AG(E) 1966, 5, 704.
Murakami, M.; Akagi, K.; Takahashi, K. JACS 1961, 83, 2002.
March, J. Advanced Organic Chemistry: Reactions, Mechanisms, and
Structures, 3rd ed.; Wiley: New York, 1985; pp 807-809.
(a) Gross, H.; Rieche, A.; Hft, E.; Beyer, E. OSC 1973, 5, 365. (b)
Rieche, A.; Gross, H.; Hft, E. CB 1960, 93, 88.
Buck, J. S.; Zimmerman, F. J. OSC 1943, 2, 549.
(a) Rieke, R. D.; Bales, S. E. OSC 1988, 6, 845. (b) Wiberg, K. B.; Lowry,
B. R.; Colby, T. H. JACS 1961, 83, 3998.
Looker, J. J. JOC 1966, 31, 3599.
(a) Newman, M. S.; Fraenkel, G.; Kirn, W. N. JOC 1963, 28, 1851. (b)
Newman, M. S.; Kaugars, G. JOC 1966, 31, 1379. (c) Schoberth, W.;
Hanack, M. S 1972, 703.
(a) Paukstelis, J. V.; Macharia, B. W. JOC 1973, 38, 646. (b) Bryson, T.
A.; Dolak, T. M. OSC 1988, 6, 505.
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35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54. Farah, B. S.; Gilbert, E. E. JOC 1965, 30, 1241.

55. Harding, K. E.; Tseng, C. JOC 1978, 43, 3974.
56. Friedrich, K.; Thieme, H. K. 5 1973, 111.
57. Berrie, A. H.; Newbold, G. X; Spring, F. S. JCS 1952, 2042.
58. Beisler, J. A. JMC 1971, 14, 1116.
59. (a) Wyman, D. P.; Wang, J. Y. C ; Freeman, W. R. JOC 1963, 28, 3173.
(b) Fell, B.; Kung, L.-H. CB 1965, 98, 2871.
60. (a) Chambers, R. D.; MacBride, J. A. H.; Musgrave, W. K. R. Cl(L)
1966, 1721. (b) Comprehensive Organic Chemistry; Barton, D. H. R.;
Ollis, W. D., Eds.; Pergamon: Oxford, 1979; Vol. 1, p 523.
61. (a) Speigler, L.; Tinker, J. M. JACS 1939, 61, 940. (b) Uemura, S.;
Okazaki, H.; Onoe, A.; Okano, M. BCJ 1978, 51, 3568.
62. (a) Messina, G.; Moretti, M. D.; Ficcadenti, P.; Cancellieri, G. JOC 1979,
44, 2270. (b) Olah, G. A.; Schilling, P.; Renner, R.; Kerekes, I. JOC 1974,
39, 3472.
63. Stevens, C. L.; Coffield, T. H. JACS 1951, 73, 103.
64. (a) Bellu, D.; von Bredow, K.; Sauter, H.; Weis, C. D. HCA 1973, 56,
3004. (b) Bellu, D.; Sauter, H.; Weis, C. D. OSC 1988, 6, 427.
65. Ott, E. OSC 1943, 2, 528.
66. (a) Bartlett, P. D.; Knox, L. H. OSC 1973, 5, 196. (b) Kloek, J. A.;
Leschinsky, K. L. JOC 1976, 41, 4028.
67. (a) Goldberg, A. A. JCS 1945, 464. (b) Adams, R.; Marvel, C. S. OSC
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1980, 67.
71. Comprehensive Organic Chemistry; Barton, D. H. R.; Ollis, W. D., Eds.;
72. Kaufman, M. H.; Braun, J. D. JOC 1966, 31, 3090.
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John E. Burks, Jr.
[13455-01-1]
I3P
(MW 411.67)
(conversion of alcohols to iodides; deoxygenation of epox

ides to alkenes; reduction of sulfoxides, selenoxides, selenones,
ozonides, and -halo ketones; elimination of -hydroxy sulfides,
dithioacetals, and orthothioesters or their selenium counterparts to
form alkenes; conversidion of aldoximes and nitro compounds to
nitriles; cleavage of dimethyl acetals; water-soluble phosphorus
byproducts are usually formed)
Alternate Name: phosphorus triiodide.
Physical Data: mp 61 C.
Solubility: very sol CS2; reacts with protic solvents.

Form Supplied in: red solid; widely available commercially.
Handling, Storage, and Precautions: commercial samples are
generally suitable for use without purification; store under an
inert atmosphere.
Conversion of Alcohols to Iodides. PI3 is a classic reagent

for the conversion of iodides to alcohols. For example, cetyl alco
hol is converted to 1-iodohexadecane in 85% yield by treatment
with PI3 (neat).1 More recently, Krief and co-workers2 found that
a cyclopropyl carbinol (eq 1) is cleanly converted to the iodide
with ring opening upon treatment with PI3 (Et3N, CH2Cl2, 0 C,
0.5 h, 73%). Diphosphorus Tetraiodide, a commercially available
phosphorus halide which is in equilibrium with PI3 in solution, is
a more commonly employed reagent for the conversion of alco
hols to iodides and effects many of the same transformations as
PI3.3 See also Triphenylphosphine-Iodine for the conversion of
alcohols to iodides.
(1)
Deoxygenations and Reductions. PI3 has found use as a deoxygenating and reducing agent. Epoxides are stereospecifically
deoxygenated to the corresponding alkenes in good yield and
with retention of configuration. For example, the cis- and transepoxides shown in eq 2 are converted (CS2, 20 C, 6-8 h) to
cis- andtrans-9-octadecenein 83 and 90% yields, respectively.4
Diphosphorus tetraiodide (P2I4) and Iodotrimethylsilane (TMSI)
give similar results. A number of other methods for epoxide deoxygenation have been developed.5
(2)
(a) R1, R3 = (CH2)7Me; R2 = H; 83%
(b) R1 = H; R2, R3 = (CH2)7Me; 90%
A variety of methods for the reduction of sulfoxides to sulfides

are available.6 PI3 rapidly reduces aryl alkyl and dialkyl sulfox
ides and selenoxides, usually at 78 C (eq 3).7 For example,
treatment of ethyl phenyl sulfoxide with 1 equiv of PI3 (CH2Cl2,
- 7 8 C, 15 min) affords ethyl phenyl sulfide in 91% yield. Others
have successfully employed this procedure.8'9 Dialkyl sulfoxides
generally react in somewhat lower yield. A phenyl vinyl sulfoxide
(eq 3, entry c) requires ambient temperatures to react. Selenoxides
behave similarly, and P2I4 can usually be used in place of PI3.10
Treatment of decyl phenyl selenone with PI3 (CH2Cl2, 0C, 30
min) affords a mixture of the reduced product, decyl phenyl selenide (69%), and the substitution product, n-decyl iodide.11
PI3 can be used for the efficient reduction of an ozonide, as
illustrated by the formation of the cyclopropanecarbaldehyde in
eq 4.12, 13 An advantage over the traditional Triphenylphosphine
reduction is the formation of water-soluble phosphorus byproducts
from PI3. It should be noted, however, that PI3 is reported to react
with certain aldehydes.14
339
(3)
(a)
(b)
(c)
(d)
(e)
X = S; R1 = Ph; R2 = Et; 91%

X = S;R 1 ,R 2 = Pr;71%
X = S; R1 = Ph; R2 = CH=CHC5H11; 75%
X = Se; R1 = Ph; R2 = C 10 H 21 ; 93%
X = Se; R1 = Me; R2 = CH(Me)C6H13; 87%
(4)
PI3 is reported to dehalogenate -bromo and -iodo ketones.15

For example, as shown in eq 5, 1-iodo-2-dodecanone is reduced
to 2-dodecanone by PI3 in CH2Cl2 (25 C, l h, 89%). 1-Bromo-2octanone affords 2-octanone in 75% yield (25 C, 4.5 h). This PI3
reduction can be coupled with the regioselective opening of termi
nal epoxides by TMSI and alcohol oxidation for a three-step trans
formation of a terminal epoxide to a methyl ketone.15,16 P2I4,15.
triphenylphosphine,17 1,3-Dimethyl-2-phenylbenzimidazoline,18
PhSiH3/Mo0,19 Samarium(II) Iodide,20 Zinc-Acetic Acid,21
Iron-Graphite,22 Tri-n-butylstannane23 Sodium O,O-Diethyl
Phosphorotelluroate,24 lithium 2-thiophenetellurolates,25 and a
wide variety of other reagents26,27 can also be used for the reduc
tion of -halo carbonyl compounds.
(5)
R1 = C10H21, R2 = H, X = I; 89%
R1 = C6H13, R2 = H, X = Br, 75%
R1, R2 = C8H17, X = I;97%
Elimination Reactions. PI3 or P2I4 effects the stereospecific anti-elimination of -hydroxy sulfides to alkenes.28 For
example (eq 6), treatment of the anti--hydroxy sulfide with
PI3 (CH2Cl2-Et3N, 50 C, 1.5 h) affords (E)-9-octadecene (93%
yield). Treatment of the syn-isomer affords (Z)-9-octadecene
(93% yield, Z:E = 94:6). Trisubstituted, but apparently not tetrasubstituted, alkenes can also be formed from the appropriately
substituted -hydroxy sulfides using these reagents. Similarly,
-hydroxy selenides undergo elimination to the correspond
ing alkenes. With these latter substrates, certain tetrasubstituted
alkenes are accessible.29 Methanesulfonyl Chloride/Et3N30 and
N-ethyl-2-fluoropyridinium tetrafluoroborate/lithium iodide31 are
alternative reagents.
(6)
anti; R1 = C8H17, R2 = H
syn; R1 = H, R2 = C8H17
(E) isomer, 93%

(Z) isomer, 90%
Vinyl sulfides and ketene dithioacetals32 are available via treat

ment of (3-hydroxy thioacetals and -hydroxy orthothioesters with
PI3 or P2I4.33 For example (eq 7), treatment of the -hydroxy orthothioester (entry a) with PI3 (CH2Cl2-Et3N, 0 C, 0.5 h) affords
the thioketene acetal (1) in 69% yield. With certain substitution
340
patterns the rearranged product (2) competes (e.g. entry b) or is

the predominant product (e.g. entry c). The rearrangement is less
of a problem with the corresponding -hydroxy orthoselenoester
(i.e. entry c vs. entry d). Thionyl Chloride is also a useful reagent
in some cases.
workup) affords the ketone in 85% yield. Alternative non

aqueous acetal cleavage reagents include P2I4,43 TMSI,44,45
Diiodosilane46 TiCl4/Lithium Iodide,47 Bromodimethylborane or bromodiphenylborane,48 and Samarium(III)
Chloride/Chlorotrimethylsilane.49
(7)
(a) R1 = c-C3H5, R2 = Me, X = S

(b)R 1 = C 5 H 11 ,R 2 = H, X = S
(c) R1 = Ph, R2 = H, X = S
(d) R1 = Ph, R2 = H, X = Se
(a) R1 = C9H19, R2 = Me, 85%

(b)R 1 = C 8 H 17 ,R 2 = H, 57%
(1):(2) = 69: 0
(1):(2) = 63:13
(1):(2)= 7:68
(1):(2) = 86: 0
Vinyl sulfides and ketene thioacetals32 are also available via

treatment of thioacetals and orthothioesters with PI3 or P2I4 (eqs 8
and 9).34 The corresponding seleno analogs are similarly available.
For example (eq 8), treatment of the trimethyl orthoselenoester
with PI3 (CH2Cl2-Et3N, 20 C, 1 h) affords the ketene selenoacetal in 90% yield. Tin(IV) Chloride or Titanium(IV) Chloride
in combination with Diisopropylamine is also effective for the
transformation of orthothioesters and orthoselenoesters to ketene
acetal derivatives.35 Copper(I) Trifluoromethanesulfonate,36
Mercury(II) Trifluoroacetate/Lithium Carbonate,31 and Benzenesulfenyl Chloride38 are useful reagents for the conversion
of dithioacetals to vinyl sulfides.
(8)
(9)
7
(12)
10
In the presence of Triethylamine, PI3 or P2I4 effects the con

version of aldehyde oximes or primary nitro compounds to nitriles.
For example, treatment of the aldoxime derived from phenylacetaldehyde with 1 equiv of PI3 (CH2Cl2-Et3N, 25 C, 15 min)
affords benzyl cyanide in 83% yield (eq 10). Similarly, treatment
of l-nitrodecane with 2 equiv of PI3 (CH2Cl2-Et3N, 25 C, 15
min) affords l-cyanononane (82%) (eq 11). Other reagents for
the direct conversion of primary nitro compounds to nitriles in
clude Sn(SPh)4/Ph3P/DEAD,39 TMSI,40 Sulfur Dioxide/Et3N,41
and Phosphorus(III) Chloride.42
(10)
R = PhCH2, 83%
R = C10H21, 85%
PI3 is a useful Hydrogen Iodide precursor in the silica- and

alumina-mediated additions of HI to alkenes.50,51 PI3 has also
found use as a source of electrophilic phosphorus in the synthesis
of novel organophosphorus compounds (e.g. (CF3)3P52) and novel
phosphorus-containing organometallic compounds.53
Related Reagents. Diphosphorus Tetraiodide; Iodotrimethylsilane; Triphenylhosphine-Iodine.
1. Hartman, W. W.; Byers, J. R.; Dickey, J. B. OS 1943, 2, 322.

2. Halazy, S.; Dumont, W.; Krief, A. TL 1981, 22, 4737.
3. Lauwers, M.; Regnier, B.; Van Eenoo, M.; Denis, J. N.; Krief, A. TL
1979, 1801.
4. Denis, J. N.; Magnane, R.; Eenoo, M. v.; Krief, A. NJC 1979, 3, 705.
5. Wong, H. N. C ; Fok, C. C. M.; Wong, T. H 1987, 26, 1345.
6. Madesclaire, M. T 1988, 44, 6537.
7. Denis, J. N.; Krief, A. CC 1980, 544.
8. Lown, J. W.; Koganty, R. R.; Joshua, A. V. JOC 1982, 47, 2027.
9. Binns, M. R.; Haynes, R. K. JOC 1981, 46, 3790.
10. Denis, J. N.; Krief, A. TL 1979, 3995.
11.
12.
13.
14.
15.
16.
17.
Krief, A.; Dumont, W.; Denis, J. N. CC 1985, 571.

Denis, J. N.; Krief, A. CC 1983, 229.
Halazy, S.; Krief, A. TL 1981, 22, 4341.
Michie, J. K.; Miller, J. A.; Nunn, M. J.; Stewart, D. JCS(P1) 1981, 1744.
Denis, J. N.; Krief, A. TL 1981, 22, 1431.
Borowitz, I. J.; Grossman, L. I. TL 1962, 471.
18.
19.
20.
21.
22.
Chikashita, H.; Ide, H.; Itoh, K. JOC 1986, 51, 5400.

Perez, D.; Greenspoon, N.; Keinan, E. JOC 1987, 52, 5570.
Molander, G. A.; Hahn, G. JOC 1986, 51, 1135.
Zimmerman, H. E.; Mais, A. JACS 1959, 81, 3644.
Savoia, D.; Tagliavini, E.; Trombini, C ; Umani-Ronchi, A. JOC 1982,
47, 876.
23. Bak, D. A.; Brady, W. T. JOC 1979, 44, 107.
24. Clive, D. L. J.; Beaulieu, P. L. JOC 1982, 47, 1124.
25. Engman, L.; Cava, M. P. JOC 1982, 47, 3946.
26.
(11)
R = C9H19, 82%
Miscellaneous Transformations. PI3 has been used for the

cleavage of dimethyl acetals under nonaqueous conditions.43
For example (eq 12), treatment of the dimethyl acetal de
rived from 2-decanone with PI3 (CH2Cl2, 20 C, 15 min; aq
DeKimpe, N.; Nagy, M.; Boeykens, M.; Schueren, D. v. d. JOC 1992,

57, 5761.
27. DeKimpe, N.; Verhe, R. In The Chemistry of -Haloketones, Haloaldehydes and -Haloimines; Patai, S.; Rappoprt, Z. Eds.: Wiley:
Chichester, 1988.
28. Denis, J. N.; Dumont, W.; Krief, A. TL 1979, 4111.
29. Halazy, S.; Krief, A. CC 1979, 1136.
30. Reich, H. J.; Chow, F. CC 1975, 790.
31. Mukaiyama, T.; Imaoka, M. CL 1978, 413.
32. Kolb,M. 51990, 171.
PHOSPHORUS(V) OXIDE
33.
34.
35.
36.
Denis, J. N.; Desauvage, S.; Hevesi, L.; Krief, A. TL 1981, 22, 4009.
Nsunda, K. M.; Hevesi, L. CC 1985, 1000.
Cohen, T.; Herman, G.; Falck, J. R.; Mura, A. J. JOC 1975, 40, 812.
37.
38.
Trost, B. M.; Lovoie, A. C. JACS 1983,105, 5075.

Bartels, B.; Hunter, R.; Simon, C. D.; Tomlinson, G. D. TL 1987, 28,
2985.
39.
40.
41.
42.
Urpi, F.; Vilarrasa, J. TL 1990,31, 7497.

Olah, G.; Narang, S. C ; Field, L. D.; Fung, A. P. JOC 1983, 48, 2766.
Olah, G. A.; Vankar, Y. D.; Gupta, B. G. B. S 1979, 36.
Werli, P. A.; Schaer, B. JOC 1977, 42, 3956.
43.
Denis, J. N.; Krief, A. AG 1980, 92, 1039.
44.
45.
Jung, M. E.; Andrus, W. A.; Orenstein, P. L. TL 1977, 4175.

Olah, G. A.; Husain, A.; Singh, B. P.; Mehrotra, A. K. JOC 1983, 48,
3667.
Keinan, E.; Perez, D.; Sahai, M.; Shvily, R. JOC 1990, 55, 2927.
46.
47.
48.
49.
50.
51.
52.
53.
Balme, G.; Gore, J. JOC 1983, 48, 3336.

Guindon, Y.; Yoakim, C ; Morton, H. E. JOC 1984, 49, 3912.
Ukaji, Y.; Koumoto, N.; Fujisawa, T. CL 1989, 1623.
Kropp, P. J.; Daus, K. A.; Tubergen, M. W.; Kepler, K. D.; Wilson, V. P.;
Craig, S. L.; Baillargeon, M. M ; Breton, G. W. JACS 1993, 115, 3071.
Kropp, P. J.; Daus, K. A.; Crawford, S. D.; Tubergen, M. W.; Kepler, K.
D.; Craig, S. L.; Wilson, V. P. JACS 1990, 112, 7433.
Krause, L. J.; Morrison, J. A. JACS 1981, 103, 2995.
Binger, P.; Wettling, T.; Schneider, R.; Zurmuehlen, F.; Bergstraesser,
U.; Hoffmann, J.; Maas, G.; Regitz, M. AG 1991, 103, 208.
University
James M. Takacs
of Nebraska-Lincoln,
NE, USA
341
3,4
leads to good yields of the nitrile (eq 1). In many cases the
reaction is carried out in the absence of solvents, although suit
ably high-boiling solvents can be used. These conditions are not
compatible with many common functional groups, and this trans
formation can be achieved by other reagents,5 including Thionyl
Chloride and Phosphorus Oxychloride.
(1)
Amides can be made by treatment of silyl esters with P2O5,
followed by treatment with Hexamethyldisilazane.6 Some Nsubstituted amides afford ketene imines upon treatment with P2O5
(eq 2).7
(2)
Formation of Anhydrides. Dehydration of carboxylic acids

with P2O5 is an effective method for the preparation of car
boxylic anhydrides (eq 3). Acids have been converted to anhy
drides with silica gel-supported P2O5, marketed as 'Sicapent' by
Merck.8 Similar results are obtained by heating a suspension of
a carboxylic acid with a powdered mixture of P2O5, CuSO4, and
Na2SO4 in a primary alcohol. This gives the ester in 60-80%
yields.9
Phosphorus(V) Oxide
(3)
(P2O5)
[1314-56-3]
O5P2
(MW 141.94)
O10P4
(MW 283.88)
(P4O10)
[16752-60-6]
(dehydrating agent for acids and amides;1 cyclization catalyst)

Alternate Names: phosphorus pentoxide; phosphoric anhydride.
Physical Data: mp 569 C; sublimes at 250 C under vacuum.
Solubility: sol H2SO4, MeSO3H.
Form Supplied in: white powder; commercially available from
many sources.
Preparative Method: prepared by combustion of phosphorus in
dry air.
Purification: generally used without further purification; can be
sublimed under vacuum.
Handling, Storage, and Precautions: corrosive! Reacts violently
with water, releasing H3PO4 and heat.
Dehydration of Amides to Nitriles. Dehydration of amides
with P2O5 is one of many methods for the synthesis of nitriles.2
Distillation of an unsubstituted amide from an excess of P2O5
Cyclization Catalyst. A 10% by weight (approximately satu

rated) solution of P2O5 in Methanesulfonic Acid (Eaton's reagent)
has been used as an effective replacement for Polyphosphoric Acid
(PPA) as an acid cyclization catalyst. Advantages to this reagent
include the ease of stirring MeSO3H solutions relative to PPA and
the greater solubility of many organic compounds in MeSC3H
relative to PPA. Yields are comparable to or better than those ob
tained with PPA in Beckmann rearrangements (eq 4).10 The com
bination of P2O5 and methanesulfonic acid is an efficient catalyst
for acid/alkene cycloadditions (eq 5).11 See also Phosphorus(V)
Oxide-Methanesulfonic Acid.
(4)
(5)
342
PHOSPHORUS(V) OXIDE
This mixture is a particularly useful catalyst in the synthesis

of 2-substituted indole derivatives via the Fischer indole reac
tion of unsymmetrical ketones (eq 6).12 Other catalysts (PPA,
H2SO4/MeOH, PPSE, Amberlyst 15) give lower regioselectivity. Decomposition of the starting material can be minimized by
dilution of the P2O5/MeSO3H mixture with CH2Cl2. Treatment of
(1) with P2O5 at high temperature results in cyclization to produce
7-deazahypoxanthines (eq 7).13
(eq 11).20 Lower temperatures lead to oxazoles, which can be

converted to the isoquinolines by heating to 196 C.
(11)
(6)
Trimethylsilyl Polyphosphate. Heating a mixture of P2O5

with Hexamethyldisiloxane results in the formation of
Trimethylsilyl Polyphosphate (PPSE), an organic soluble, aprotic
alternative to PPE or PPA.21 This reagent has proven useful for
Beckmann rearrangements (eq 12),21-23 and for generation and
cyclization of nitrilium ions.24
contains 2%
3-substituted
(7)
(12)
Condensing Agent. Heating a mixture of P2O5, a primary

or secondary amine (often using the amine as solvent), and a
heterocyclic ketone or alcohol is a general route to substituted
adenines (eq 8),14,15 purines,16,17 and pyrimidines.18 Cyclization
and ketone/amine condensations can often be combined in the onepot transformations of 4,5-disubstituted imidazoles to substituted
adenines (eqs 9 and 10).19
Formamidines. Condensation of formanilides with secondary

amines in the presence of P2O5 produces formamidines in good
yield (eq 13).25 The reaction is compatible with electron-rich and
electron-deficient arenes, but is limited to secondary amines.
(13)
(8)
(9)
(10)
Related Reagents. Dimethyl Sulfoxide-Phosphorus Pentoxide; Phosphorus(V) Oxide-Methanesulfonic Acid; Phosphorus(V) Oxide-Phosphoric Acid.
1. FF 1967,1,871.
2.
Mowry, D. T. CR 1948, 42, 189.
3.
Reisner, D. B.; Hornung, E. C. OSC 1963, 4, 144.
4.
Rickborn, B.; Jensen, F. R. JOC 1962, 27, 4608.
5.
Larock, R. C. Comprehensive Organic Transformations; VCH: New

York, 1989; pp 991-992.
6.
Rao, C. S., Rambabu, M.; Srinirasan, P. S. IJC(B) 1987, 26B, 407.
7.
Stevens, C. L.; Singhal, G. H. JOC 1964, 29, 34.
8.
Burton, S. G.; Kaye, P. T. SC 1989, 19, 3331.
9.
Banerjee, A.; Sengupta, S.; Adak, M. M.; Banerjee, G. C. JOC 1983,48,

3106.
10. Jeffs, P. W.; Molina, G.; Cortese, N. A.; Hauck, P. R.; Wolfram, J. JOC
1982, 47, 3876.
11.
Eaton, P. E.; Carlson, G. R.; Lee, J. T. JOC 1973, 38, 4071.
12. Zhao, D.; Hughes, D. L.; Bender, D. R.; DeMarco, A. M.; Reider, P. J.
JOC 1991, 56, 3001.
13.
Cyclodehydrations. The Pictet-Gams modification of the

Bischler-Napieralski reaction is an important method for the
preparation of isoquinolines.19 This reaction relies on the dehy
dration of molecules such as (2) with P2O5 at high temperature
Girgis, N. S.; J0rgensen, A.; Pedersen, E. B. S 1985, 101.
14. Girgis, N. S.; Pedersen, E. B. S 1982, 480.

15.
Nielsen, F. E.; Pedersen, E. B. T 1982, 38, 1435.
16. El-Bayouki, K. A. M.; Nielsen, F. E.; Pedersen, E. B. S 1985, 104.

17. Nielsen, F. E.; Nielsen, K. E.; Pedersen, E. B. CS 1984, 24, 208.
PHOSPHORUS(V) OXIDE-METHANESULFONIC ACID

18. Hilmy, K. M. H.; Mogensen, J.; Jorgensen, A.; Pedersen, E. B. H 1990,
31, 367.
19.
Kametani, T.; Fukumoto, K. In Isoquinolines; Grethe, G., Ed.; Wiley:

New York, 1981; Vol. 31, Part 1, pp 142-160.
20.
Fitton, A. O.; Frost, J. R.; Zakaria, M. M.; Andrew, G. CC 1973, 889.
21.
Imamoto, T.; Yokoyama, H.; Yokoyama, M. TL 1981, 22, 1803.
22.
Donaruma, L. G.; Heldt, W. Z. OR 1960, 11, 1.
23.
Gawley, R. E. OR 1988, 35, 1.
24.
Gawley, R. E.; Chemburkar, S. R. H 1989, 29, 1283.
25.
Hansen, B. W.; Pedersen, E. B. ACS 1980, 5, 369.
Mark S. Meier
University of Kentucky, Lexington, KY, USA
Phosphorus(V) Oxide-Methanesulfonic
Acid1
[39394-84-8]
(P 2 O 5 )
[1314-56-3]
(MeSO 3 H)
[75-75]-2
CH 4 O 8 P 2 S
(MW 238.06)
O5P2
(MW 141.94)
CH4O3S
(MW 96.12)
(acidic dehydrating agent used in cycloalkenone synthesis,1

Friedel-Crafts reactions,1 the Fischer indole synthesis,2 the Beckmann rearrangement,1 and other dehydrations; an alternative
to polyphosphoric acid1)
Alternate Name: Eaton's reagent.
Physical Data: 7.5 wt% solution: bp 122C/1 mmHg; d
1.500 g c m - 3 .
Solubility: sol ether, alcohol, MeCN, CH 2 Cl 2 ; insol toluene,
hexane. 2,3
Form Supplied in: 7.5 wt% solution is commercially available.
Preparative Method: prepared1 by adding Phosphorus(V) Oxide
(P2O5, 36 g) in one portion to Methanesulfonic Acid (360 g)
and stirring at rt 3 until the P 2 O 5 dissolves.4 Although Eaton
recommends the use of freshly distilled methanesulfonic acid
to allow for a clean workup and good yields,1 others report
using the acid as purchased. 5,6
Handling, Storage, and Precautions: Eaton's reagent is toxic and
corrosive. Direct contact with this reagent should be avoided.
The solution begins to yellow upon standing for long periods
of time; however, this does not appear to affect the viability of
the reagent.1 Use in a fume hood.
Reagent Description. The reagent was conceived as an alter

native to the widely used, but often inconvenient, Polyphosphoric
Acid (PPA) (see also Polyphosphate Ester, PPE). 1 Eaton's reagent
successfully addresses the drawbacks of PPA's physical proper
ties. It is much less viscous, and is, therefore, easier to stir. Organic
compounds are generally soluble in Eaton's reagent, and the hydrolytic workup is less tedious. 1 Reactions are run at ambient or
slightly elevated temperatures. Standard aqueous workup is easy
343
and clean. Eaton recommends quenching the reaction with wa

ter; quenching in ice may cause methanesulfonic anhydride to
precipitate and be extracted into the organic layer; quenching in
aqueous base may cause extensive foaming.1 In addition to its
ease of handling, yields obtained with Eaton's reagent compare
favorably with those obtained with PPA.7 Few modifications of
Eaton's original procedure have appeared. A 1:5 by weight ra
tio has been reported to be as effective as a 1:10 ratio. 8 It has
been noted that, to avoid polymer formation, only the minimum
amount of reagent needed to effect condensation should be used.9
The nature of the reagent has not been rigorously determined. It
appears that the reactive or catalytic species may vary by reac
tion. In certain acid-catalyzed reactions, P 2 O 5 has been found to
be superfluous.10
Cycloalkenones. P 2 O 5 /MeSO 3 H is used as a reagent in sev
eral reactions leading to cycloalkenones. First described in
Eaton's original paper, the lactone-to-cyclopentenone rearrange
ment (eq l) 1 has since found wide use. 11
(1)
In a related reaction, readily available nitroalkanoic acids cyclize to form cyclopentenones (eq 2). 12 As illustrated in eq 3, 1 3 a
vinylcyclobutanones undergo acyl migration to produce either cy
clopentenones or cyclohexenones.13
(2)
(3)
R=H
R = Me
65%
13%
0%
51%
Vinylcyclopentenones have undergone the Nazarov cyclization

in good yield in the presence of Eaton's reagent (eq 4). 14 How
ever, other reagents may be more generally useful, since there are
reports of Eaton's reagent not providing optimal results in this
reaction.15
(4)
Friedel-Crafts Acylations of Aromatic Rings. Eaton's

reagent has been used widely and very effectively16a to catalyze
Friedel-Crafts acylations.16 One of the few potential drawbacks
is the deprotection of an aryl ether. The examples shown below
compare the utility of Eaton's reagent vs. PPA with regard to this
deprotection problem. In eq 5, although the cyclization proceeds
with an undesired protecting group exchange, the cyclization fails
344

17
in PPA. Deprotection of an aryl methyl ether is avoided by us

ing Eaton's reagent in place of PPA in one case (eq 6),18 but not
in another.19 Intramolecular Friedel-Crafts acylations have been
observed to occur without the addition of P2O5.10 A compara
tive study found this observation to be generally applicable to
intramolecular acylations, but not intermolecular acylations.10b,20
Fischer Indole Synthesis. The use of Eaton's reagent as the

acid catalyst in the Fischer indole reaction results in unprece
dented regiocontrol favoring 2-substituted indoles (eq 10).2 In
cases where the harshness of the reagent results in low yields of
indoles, dilution of the reaction mixture in sulfolane or CH2Cl2
attenuates the problem. Mechanistic studies indicate that the cat
alytic species, in this reaction, is MeSO3H. The role of P2O5 is
to act as a drying agent. Further experiments indicate that for the
Friedel-Crafts acylation this is not the case; a mixed anhydride is
the catalytic species.2
(5)
(10)
AcOH
PPA
Eaton's reagent
100: 1
50:50
78:22
95%
(6)
Eaton's reagent
PPA
Heterocycle Preparation. Various heterocycles have been

prepared through P2O5/MeSO3H-mediated cyclizations. Conden
sation, and subsequent dehydration, of aminothiophenol and the
appropriate acid provides benzothiazoles (eq 11).25
R = Me, 70%
R = H, 28%
Friedel-Crafts Alkylations. P2O5/MeSO3H compares fa

vorably with other reagents in the Friedel-Crafts alkylation
reaction.21 Mechanistic aspects of this reaction have been
discussed.21b Eq 7 shows an alkene-initiated alkylation that pro
vides (+)-O-methylpodocarpate selectively.22
(11)
Oxadiazoles can be prepared from diacylhydrazines (eq 12).26

Furans are formed from the cyclodehydration of a phenolic ketone
(eq 13).27
(12)
(7)
Dehydration. Alcohols have been dehydrated to alkenes with

Eaton's reagent (eq 8).23 In a formal dehydration, a cyclopentenone has been transformed into a diene (eq 9).24
(8)
(13)
Butenolides have been prepared by cyclization of keto esters

(eq 14)28 or by elimination of H2O from a preformed hydroxy
butenolide (eq 15).29
(14)
(9)
Lists ofAbbreviations and Journal Codes on Endpapers

7.
(15)
Yields in the synthesis of thiadiazolo[3,2-a]pyrimidin-5-ones
have been greatly improved by using Eaton's reagent in the place
of PPA(eq 16).8b
(16)
P2O5, MeSO3H; 1:5
PPA
87%
18%
345
Examples of exceptions: (a) PPA is superior to either Eaton's reagent

or H 2 SO 4 in a Friedel-Crafts acylation: Hormi, O. E. O.; Moisio, M.
R.; Sund, B. C. JOC 1987, 52, 5272. (b) PPA is superior to Eaton's
reagent, BF 3 OEt 2 , HCO2H, ZnCl2, CF3CO2H, p-TsOH, and H 2 SO 4 in
a Friedel-Crafts alkylation: Maskill, H. JCS(Pl) 1987, 1739. (c) PPA
is superior to Eaton's reagent or CF3CO2H/(CF3CO)2O/BF3OEt2 in a
Friedel-Crafts acylation: Hands, D.; Marley, H.; Skittrall, S. J.; Wright,
S. H. B.; Verhoeven, T. R. JHC 1986, 23, 1333. (d) PPA is superior
to Eaton's reagent in a Friedel-Crafts acylation: Bosch, J.; Rubiralta,
M.; Domingo, A.; Bolos, J.; Linares, A.; Minguillon, C ; Amat, M.;
Bonjoch, J. JOC 1985, 50, 1516. (e) PPA is superior to Eaton's reagent
or PPE in a Friedel-Crafts acylation: Jilek, J.; Holubek, J.; Svatek, E.;
Schlanger, J.; Pomykacek, J.; Protiva, M. CCC 1985, 50, 519. (f) In
a Friedel-Crafts acylation, where PPA or Eaton's reagent fails to give
satisfactory results, the corresponding acid chloride is cyclized using
AlCl3: Barco, A.; Benetti, S.; Pollini, G. P. OPP 1976, 8,7.
8.
Eaton's reagent is superior to PPA in the addition of an amide

across a double bond (eq 17).30 In another synthesis of lac
tams, 3-alkenamides reacted stereoselectively with benzaldehyde
to provide lactams containing three contiguous stereogenic cen
ters (eq 18).31
(17)
(a) Eaton, P. E.; Mueller, R. H.; Carlson, G. R.; Cullison, D. A.; Cooper,
G. F.; Chou, T.-C.; Krebs, E.-P. JACS 1977, 99, 2751. (b) Tsuji.-T;
Takenaka, K. BCJ 1982, 55, 637.
9. Parish, W. W.; Stott, P. E.; McCausland, C. W.; Bradshaw, J. S. JOC
1978, 43, 4577.
10. (a) Leon, A.; Daub, G.; Silverman, I. R. JOC 1984, 49, 4544. (b)
Premasagar, V.; Palaniswamy, V. A.; Eisenbraun, E. J. JOC 1981, 46,
2974.
11.
(18)
(a) Jacobson, R. M.; Lahm, G. P.; Clader, J. W. JOC 1980, 45, 395. (b)
Inouye, Y.; Fukaya, C ; Kakisawa, H. BCJ 1981, 54, 1117. (c) Murthy,
Y. V. S.; Pillai, C. N. T 1992, 48, 5331. (d) Eaton, P. E.; Srikrishna,
A.; Uggeri, F. JOC 1984, 49, 1728. (e) Pohmakotr, M.; Reutrakul, V.;
Phongpradit, T; Chansri, A. CL 1982, 687. (f) Baldwin, J. E.; Beckwith,
P. L. M. CC 1983, 279. (g) Mundy, B. P.; Wilkening, D.; Lipkowitz, K.
B. JOC 1985, 50, 5727. (h) Mehta, G.; Karra, S. R. TL 1991, 32, 3215.
(i) Ho, T.-L.; Yeh, W.-L; Yule, J.; Liu, H.-J. CJC 1992, 70, 1375.
12.
13.
Beckmann Rearrangement. Eaton's disclosure of P2O5/

MeSO3H as an alternative to PPA compared the two reagents'
ability to effect the Beckmann rearrangement.1 Eaton's reagent
has been reported to be superior to other reagents at induc
ing stereospecific rearrangement of the (E)- and (Z)-oximes of
phenylacetone.4 However, this is not a general finding. Rearrange
ment of the oxime in eq 19 does not provide the product expected
from an anti-migration process.32
Ho, T.-L. CC 1980, 1149.

(a) Matz, J. R.; Cohen, T. TL 1981, 22, 2459. (b) For a related ring
expansion of 1-alkenylcyclopropanols to cyclopentenones, see: Barnier,
J.-P.; Karkour, B.; Salaun, J. CC 1985, 1270.
14. Paquette, L. A.; Stevens, K. E. CJC 1984, 62, 2415.
15. (a) This paper reports obtaining Nazarov cyclization products in 8-10%
yield with either Eaton's reagent or FeCl3. A silicon assisted Nazarov
was also explored: Cheney, D. L.; Paquette, L. A. JOC 1989, 54, 3334. (b)
PPA is superior to Eaton's reagent or methanesulfonic acid in effecting
cyclization of 1,1'-dicyclopentenyl ketone: Eaton, P. E.; Giordano, C ;
Schloemer, G.; Vogel, U. JOC 1976, 41, 2238. (c) Many other reagents
including HCO2H/H3PO4, HCl, H 2 SO 4 , SnCl4, and TsOH have been
used in this type of Nazarov cyclization. For a review of the Nazarov
cyclization, see: Santelli-Rouvier, C ; Santelli, M. S 1983, 429.
16.
(19)
1. Eaton, P. E.; Carlson, G. R.; Lee, J. T. JOC 1973, 38, 4071.

2.
This paper reports that in the preparation of 2-substituted indoles Eaton's

reagent is superior to PPA, H 2 SO 4 , and PPSE: Zhao, D.; Hughes, D. L.;
Bender, D. R.; DeMarco, A. M.; Reider, P. J. JOC 1991, 56, 3001.
3.
These authors report the presence of a finely-divided solid after stirring

for 6 h. It was removed by filtration under nitrogen.
4.
Alternatively, the solution may be heated during dissolution of the P 2 O 5 .

See: Stradling, S. S.; Hornick, D.; Lee, J.; Riley, J. J. Chem. Educ. 1983,
60, 502.
5.
Akhtar, S. R.; Crivello, J. V.; Lee, J. L. JOC 1990, 55, 4222.
6.
Corey, E. J.; Boger, D. L. TL 1978, 5.
Examples: (a) McGarry, L. W.; Detty, M. R. JOC 1990, 55, 4349. (b)
Grunewald, G. L.; Sall, D. J.; Monn, J. A. JMC 1988, 31, 433. (c) Russell,
R. K.; Rampulla, R. A.; van Nievelt, C. E.; Klaubert, D. H. JHC 1990, 27,
1761. (d) Ye, Q.; Grunewald, G. L. JMC 1989, 32, 478. (e) Kelly, T. R.;
Ghoshal, M. JACS 1985, 107, 3879. (f) Eck, G.; Julia, M.; Pfeiffer, B.;
Rolando, C. TL 1985, 26, 4723. (g) Kitazawa, S.; Kimura, K.; Yano, H.;
Shono, T. JACS 1984, 706, 6978. (h) Stott, P. E.; Bradshaw, J. S.; Parish,
W. W.; Copper, J. W. JOC 1980, 45, 4716. (i) Cushman, M.; Abbaspour,
A.; Gupta, Y. P. JACS 1983, 705, 2873. (j) Acton, D.; Hill, G.; Tait, B.
S. JMC 1983, 26, 1131. (k) Miller, S. J.; Proctor, G. R.; Scopes, D. I. C.
JCS(P1) 1982, 2927.
17. Cushman, M.; Mohan, P. JMC 1985, 28, 1031.

18. Inouye, Y.; Uchida, Y; Kakisawa, H. BCJ 1977, 50, 961.
19. Falling, S. N.; Rapoport, H. JOC 1980, 45, 1260.
20. For an example of an intermolecular acylation of cyclohexenone, see:
Cargill, R. L.; Jackson, T. E. JOC 1973, 38, 2125.
21. (a) Fox, J. L.; Chen, C. H.; Stenberg, J. F. OPP 1985, 17, 169. (b) Davis,
B. R.; Hinds, M. G.; Johnson, S. J. AJC 1985, 38, 1815.
22. Hao, X.-J.; Node, M.; Fuji, K. JCS(P1) 1992, 1505.
23. Ziegler, F. E.; Fang, J.-M.; Tam, C. C. JACS 1982, 704, 7174.
346
PHOSPHORUS OXYCHLORIDE
24.
Scott, L. T.; Minton, M. A.; Kirms, M. A. JACS 1980, 102, 6311.
25.
Boger, D. L. JOC 1978, 43, 2296.
26.
Rigo, B.; Couturier, D. JHC 1986, 23, 253.
27.
Cambie, R. C ; Howe, T. A.; Pausler, M. G.; Rutledge, P. S.; Woodgate,

P. D. AJC 1987, 40, 1063.
28.
Schultz, A. G.; Yee, Y. K. JOC 1976, 41, 561.
Formylation of Aromatic Rings.2,5,6,8,11 The Vilsmeier

reagent attacks electron-rich aromatic systems to form arylmethyleneiminium ions which liberate a formylated aromatic
compound upon hydrolysis (eq 2). Thio- and selenoaldehydes
can be prepared by hydrolysis in the presence of Sodium Hydro
gen Sulfide611 or Sodium Hydrogen Selenide.13 A wide range
of aromatic systems611 can be formylated in this fashion, includ
ing benzene derivatives, polyaromatic hydrocarbons (eq 3), and
azulene.11 Substitution occurs at relatively electron-rich positions.
29.
Schultz, A. G.; Godfrey, J. D. JACS 1980, 102, 2414.
30.
Tilley, J. W.; Clader, J. W.; Wirkus, M.; Blount, J. F. JOC 1985, 50, 2220.
31.
Marson, C. M ; Grabowska, U.; Walsgrove, T.; Eggleston, D. S.; Baures,

P. W. JOC 1991, 56, 2603.
32.
Jeffs, P. W.; Molina, G.; Cortese, N. A.; Hauck, P. R.; Wolfram, J. JOC
1982, 47, 3876.
(2)
Lisa A. Dixon
Research
Institute,
Raritan, NJ, USA
(3)
The R. W. Johnson Pharmaceutical
[10025-87-3]
Cl3OP
(MW 153.32)
(formylation of aromatic rings1,2 (Vilsmeier-Haack reaction);

phosphorylating agent;3 dehydrating agent for amides; halogenation of alcohols, phenols, and heterocycles)
Formylation of Heterocycles.6,11,14 Many heterocycles are

readily formylated by POCl3/DMF, including pyrroles, thiophenes, furans, indoles, quinolines, pteridines, and purines.6 Re
action at the 2- and 5-positions of pyrroles, furans, and thiophenes
is preferred, and indoles undergo attack at the 3-position (eq 4).6
(4)
Alternate Name: phosphoryl chloride.

Physical Data: mp 1 C; bp 106C; d 1.675 g cm - 3 ; n 1.461.
Solubility: sol THF, MeCN, CH2Cl2, many other solvents.
Formylation of Alkenes.10,11 Both activated and unactivated
Form Supplied in: colorless, fuming liquid; commercially avail alkenes undergo electrophilic attack by (2).5 Reaction at terminal
able.
positions is preferred.6 Styrene derivatives give cinnamaldehydes;
Purification: by distillation in vacuo.4
enamines6 and aryl polyenes15,16 react at terminal positions (eq 5).
Handling, Storage, and Precautions: toxic and corrosive; reacts
vigorously with alcohols and water, liberating HC1, phosphoric
acid, and heat. Protect from water. Use in a fume hood.
(5)
Chloromethyleneiminium Ions.5-8 Phosphorus oxychloride

(1) is a strong Lewis acid that is widely used in synthe
sis. Of particular importance are reactions of (1) with substi
tuted amides, most often N,N-Dimethylformamide or dimethylacetamide (DMA). These reactions lead to the formation of
chloromethyleneiminium salts (2) (eq 1). These salts (Vilsmeier
reagents, see Dimethylchloromethyleneammonium Chloride)
are highly versatile intermediates6 and are involved in numer
ous important reactions, including the Vilsmeier-Haack2,6 and
Bischler-Napieralski9 reactions. Formation of (2) can be achieved
using Thionyl Chloride or Phosgene, although there have
been reports of differences in reactivity between POCl3/DMF,
SOCl2/DMF, and COCl2/DMF systems.7,10,11
(1)
Bischler-Napieralski Reaction. A widely used method for

cyclization of N--phenylethyl amides to form dihydroisoquinolines and isoquinolines (eq 6) 17-19 is the Bischler-Napieralski
reaction.9 A nitrilium ion intermediate has been implicated in this
reaction.20,21
(6)
Fragmentation of the nitrilium ion interferes with the

cyclization20,21 of 1,2-diphenylethane derivatives, leading to for
mation of stilbenes rather than cyclization products. This prob
lem has been overcome by using Oxalyl Chloride instead of (1).22
Fragmentation (von Braun reaction or retro-Ritter reaction) occurs
20
whenever a highly stable cation can be formed, such as benzyl

or t-butyl (eq 7).21,23,24
347
idines, diazepines, quinolines, quinolizines, and vinylogous

sulfonamides.30
(12)
(7)
Treatment of tertiary amides with POCl3/DMF (2) results in for

mation of -dimethylamino ,-unsaturated amides. The highly
electrophilic iminium ion (3) is formed in this reaction, and in the
presence of an alkene this undergoes cyclization (eq 8).14,25
The Vilsmeier reagent (2) reacts with Grignard reagents as well

as with alkylzinc and alkylaluminum reagents to form tertiary
amines.31 It also reacts with heteroatom nucleophiles, includ
ing thiols,32 alcohols, and amines,8 as well as with nucleophilic
amines containing other functional groups.5,33,34 Aromatic alco
hols react with POCl3/DMF to form aryl formates in 50-80%
yield,35 but aliphatic alcohols are more efficiently formylated with
Benzoyl Chloride/DMF.36 Homoallylic alcohols such as (4) pro
duce biphenyls in 30-98% yield16 through initial dehydration6
(eq 13) followed by electrophilic attack on the resulting aryl diene.
(13)
(8)
Excess POCl3 and DMF can lead to formylation of the initial

heterocycle (eq 9). A series of -substituted acrylonitriles has
been prepared by dehydration of ,-unsaturated amides (eq 10).
POCl3/DMF and SOCl2/DMF give comparable results.26
(9)
Halogenation of Alcohols. The combination of POCl3 and

DMF can be used to halogenate primary, secondary, and tertiary
aliphatic alcohols (eq 14),37 whereas the reaction of primary al
cohols and POCl3 without DMF or DMA will generally lead to
the formation of trialkyl phosphates.
(14)
A comparison of POCl3 with SO2Cl2, PCl3, MsCl, and SOCl2

indicated that optimum conditions for the conversion of (5) to (6)
(eq 15) are 1.1 equiv POCl3 in DMF at 0 C.38
(10)
(15)
Chloroaldehydes from Carbonyl Compounds.7 The enol

tautomers of ketones react with POCl3/DMF to form chloroacrolein derivatives (eq 11). The regiochemistry is deter
mined both by the stability of the enol as well as by steric factors.
Nonsymmetrical ketones often give a mixture of regioisomers,
and most ketones produce a mixture of (E) and (Z) isomers of the
product.27 Aldehydes will undergo this type of reaction, although
there are relatively few reports.
Halogenation of Heterocycles. Phosphorus oxychloride is

widely used in the chlorination of heterocycles. In general, hete
rocyclic ketones (eq 16) or alcohols (eq 17) react readily with (1),
including pteridines,39 purines,40,41 and others.
(16)
(11)
(Z):(E) = 5:1
Reaction of POCl3/DMF with carboxylic acids results in

vinamidinium ions (eq 12).28,29 These ions react with a va
riety of nucleophiles to produce pyrazoles, oxazoles, pyrim-
(17)
In the chlorination of the isoxazole (7), it was noted that freshly

distilled POCl3 is ineffective but that an older sample leads to
348
the formation of the chloride (8). Further investigation showed

that a mixture of POCl3, acid (H3PO4), and an additional chloride
source (pyridinium chloride) leads to reliable conversion of (7) to
(8) (eq 18).42
of amines. Again, like the reaction of POCl3 with diols, diamines

react with POCl3 to form diazaphospholidines (eq 21).52
(20)
(18)
Phosphorylation.3,43 Phosphorus oxychloride reacts with al

cohols, amines, and thiols, resulting in phosphorylation of these
functional groups. Trimethyl phosphate is a particularly effec
tive solvent,44 and tertiary amine bases are generally used as well.
Treatment of primary alcohols with POCl3 results in the formation
of phosphonyl dichloride intermediates which, in the presence of
excess alcohol, convert to symmetrical trialkyl phosphates.10 It is
generally possible to isolate aryl phosphorodichloridates when a
two-fold excess of (1) is used and AlCl3, KCl, or pyridine is used
as a catalyst.45,46 Secondary and tertiary alcohols tend to form
alkyl chlorides and phosphoric acid.
Phosphorus oxychloride is very useful in the preparation of
nucleoside 5'-phosphates (eq 19) given appropriate mixtures of
POCl3, pyridine, and water.44,47 The primary hydroxy (5') is
sufficiently reactive for there to be minimal formation of cyclic
phosphates at the 2,3-positions of nucleosides. The intermedi
ate phosphorodichloridate can be converted to the corresponding
triphosphate by treatment with inorganic phosphate in a conve
nient one-pot fashion.
(21)
Carboxylic anhydrides can be prepared by treatment of carboxylic acids with POCl3,32 allowing the formation of both
esters32 and amides, although other methods are more common.53
Dichloroacetyl chloride produces dichloroketene when treated
with POCl3 and Zinc/Copper Couple.54
Dehydration of Amides. Unsubstituted amides undergo de
hydration upon treatment with POCl3. This reaction can also be
performed with P2O5, SOCl2, or other reagents, and in a study
of racemization at the -position it was determined that dehydra
tion with POCl3 leads to more (albeit little) epimerization than
dehydration with P2O5 or SOCl2 (eq 22).55
(22)
(19)
Under anhydrous conditions, POCl3 can be used to produce

cyclic dialkyl phosphonyl chlorides from diols, and these can be
hydrolyzed with water to the cyclic phosphates or with an alcohol
to trialkyl phosphates. Treatment of forskolin (9) with POCl3 leads
to the formation of the cyclic phosphoryl chloride (10) in 55%
yield as a mixture of two stereoisomers at phosphorus (eq 20).48 A
comparison of several phosphorylating agents showed that POCl3,
(MeOC6H4)2POCl, and 2-chloro-2-oxo-1,3,2-dioxaphospholane
all give the analogous products in virtually identical yield.48
Similar results can be obtained with primary amines,49 al
though it is possible to obtain diamidophosphorochloridates by
reaction of POCl3 with substoichiometric amounts of amine.50
Phosphorus oxychloride reacts more readily with primary amines
than with primary alcohols, so that it is possible to prepare
phosphoramides.51 Alkoxides, however, react more rapidly than
amines so it is possible to phosphorylate hydroxyls in the presence
Dehydration of alkyl and aryl N-formyl compounds with POCl3

is one of the more general routes to alkyl and aryl isocyanides
(eq 23). 56-59 A base, typically an amine base or Potassium tButoxide, is also required. The method is simple and effective,
although less useful for small, volatile isocyanides than other
techniques.60 The Bischler-Napieralski reaction can occur pref
erentially to isocyanide formation.17
(23)
Dehydration of Alcohols. The combination of POCl3 and

Pyridine is an effective dehydrating agent for alcohols (eq 24)61
and cyanohydrins.62 The stereochemistry of elimination is anti,
although the regioselectivity is often not high, particularly for ter
tiary alcohols.63
(24)
The combination of phosphorus oxychloride and Tin(II) Chloride reduces halohydrins to alkenes (eq 25). The elimination pro
ceeds in an anti fashion.64
26.
27.
28.
29.
(25)
86% from the epoxide precursor
Beckmann Rearrangement. Treatment of ketoximes with

POCl3 induces Beckmann rearrangement to form amides
(eq 26).65 Numerous other Lewis acids can be used for this
transformation.66,67
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
(26)
42.
43.
Related Reagents. Bis(trichloromethyl) Carbonate; Phosphorus(V) Oxide; Phosphorus Oxychloride-Zinc(II) Chloride;

Thionyl Chloride; p-Tolyl Vinyl Sulfoxide; Trichloromethyl
Chloroformate.
1.
2.
3.
4.
FF 1967, 1, 876.
Seshadri, S. J. Sci. 1nd. Res. 1973, 32, 128.
Hayakawa, H. COS 1991, 6, 601.
Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory Chemicals,
3rd ed.; Pergamon: Oxford, 1988.
5. Meth-Cohn, O.; Stanforth, S. P. COS 1991, 2, 777.
6. Jutz, C. In Iminium Salts in Organic Chemistry; Bhme, H.; Viehe, H.
G.; Eds.; Wiley: New York, 1976; Vol. 9, pp 225-342.
7. Marson, C. M. T 1992, 48, 3659.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
Kantlenher, W. COS 1991, 6, 485.

Hilger, C. S.; Fugmann, B.; Steglich, W. TL 1985, 26, 5975.
Burn, D. CI(L) 1973, 870.
Khimii, U. RCR 1960, 29, 599.
Lin, Y.; Lang, S. A. JOC 1980, 45, 4857.
Reid, D. H.; Webster, R. G.; McKenzie, S. JCS(P1) 1979, 2334.
Meth-Cohn, O. H 1993, 35, 539.
Jutz, C ; Heinicke, R. CB 1969, 103, 623.
Suresh Chandler Rao, M. S. C ; Krishna Rao, G. S. K. S 1987, 231.
Badia, D.; Carrillo, L.; Dominguez, E.; Cameno, A. G.; Martinez de
Marigorta, E.; Vincente, T. JHC 1990, 27, 1287.
Kametani, T.; Fukumoto, K. In Isoquinolines; G. Grethe, Ed.; Wiley:
New York, 1981; Vol. 31, Part 1, pp 142-160.
Knabe, J.; Krause, W.; Powilleit, H.; Sierocks, K. Pharmazie 1970, 25,
313.
Fodor, G.; Gal, J.; Phillips, B. A. AG(E) 1972, 11, 919.
Fodor, G.; Nagubandi, S. T 1980, 36, 1279.
Larsen, R. D.; Reamer, R. A.; Corley, E. G.; Davis, P.; Grabowski, E. J.
J.; Reider, P. J.; Shinkai, I. JOC 1991, 56, 6034.
23.
Ketcha, D. M.; Gribble, G. W. JOC 1985, 50, 5451.
24.
25.
Perni, R. B.; Gribble, G. W. OPP 1983, 75, 297.

Meth-Cohn, O.; Tarnowski, B. Adv. Heterocycl. Chem. 1982, 31, 207.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
349
Bargar, T. M.; Riley, C. M. SC 1980, 10, 479.

Schellhorn, H.; Hauptmann, S.; Frischleder, H. ZC 1973, 13, 97.
Gupton, J. T.; Riesinger, S. W.; Shah, A. S.; Bevirt, K. M. JOC 1991,
56, 976.
Gupton, J. T.; Gall, J. E.; Riesinger, S. W; Smith, S. Q.; Bevirt, K. M.;
Sikorski, J. A.; Dahl, M. L.; Arnold, Z. JHC 1991, 28, 1281.
McNab, H.; Lloyd, D. AG(E) 1976, 15, 459.
Mesnard, D.; Miginiac, L. JOM 1989, 373, 1.
Arrieta, A.; Garcia, T.; Lago, J. M.; Palomo, C. SC 1983, 13, 471.
Harris, L. N. S 1981, 907.
Zelenin, K. N.; Khrustalev, V. A.; Sergutina, V. P. CA 1980, 93, 70910.
Morimura, S.; Horiuchi, H.; Muruyama, K. BCJ 1977, 50, 2189.
Barluenga, J.; Campos, P. J.; Gonzalez-Nunez, E.; Asensio, G. S 1985,
426.
Yoshihara, M.; Eda, T.; Sakaki, K.; Maeshima, T. S 1980, 746.
Sanda, K.; Rigal, L.; Delmas, M.; Gaset, A. S 1992, 6, 541.
Albert, A.; Clark, J. JCS 1964, 1666.
Golovchinskaya, E. S. RCR 1974, 43, 1089.
Robins, R. K.; Revankar, G. R.; O'Brien, D. E.; Springer, R. H.;
Novinson, T.; Albert, A.; Senga, K.; Miller, J. P.; Streeter, D. G. JHC
1985,22,601.
Andersen, K.; Begtrup, M. ACS 1992, 46, 1130.
Edmunson, R. S. In Comprehensive Organic Chemistry; Barton, D. H.
R.; Ollis, W. D., Eds.; Pergamon: Oxford, 1979; Vol. 2, pp 1262-1263.
Yoshikawa, M.; Kato, T.; Takenishi, T. BCJ 1969, 42, 3505.
Owen, G. R.; Rees, C. B.; Ransom, C. J.; van Boom, J. H.; Herscheid,
J. D. H. S 1974, 704.
Taguchi, Y.; Mushika, Y. TL 1975, 1913.
Sowa, T.; Ouchi, S. BCJ 1975, 2084.
Lal, B.; Gangopadhyay, A. K. JCS(P1) 1992, 15, 1993.
Edmunson, R. S. In Comprehensive Organic Chemistry; Barton, D. H.
R.; Ollis, W. D., Eds.; Pergamon: Oxford, 1979; Vol. 2, pp 1262-1265.
Ireland, R. E.; O'Neil, T. H.; Tolman, G. L. OS 1983, 61, 116.
Crans, D. C.; Whitesides, G. M. JACS 1985, 107, 7008.
Alexakis, A.; Mutti, S.; Mangeney, P. JOC 1992, 57, 1224.
Mulzer, J. COS 1991, 6, 323.
Hassner, A.; Dillon, J. S 1979, 689.
Rickborn, B.; Jensen, F. R. JOC 1962, 27, 4608.
Sandler, S. R.; Karo, W. In Organic Functional Group Preparations, 2nd
ed.; Academic: San Diego, 1989; Vol. 3, pp 207-238.
Ugi, I.; Meyr, R.; Lipinski, M.; Bodesheim, F.; Rosendahl, F. OSC 1973,
5, 300.
van Leusen, D.; van Leusen, A. M. RTC 1992, 47, 1249.
van Leusen, A. M.; Boerma, G. J. M.; Helmholdt, R. B.; Siderius, H.;
Strating, J. TL 1972, 2367.
Hfle, G.; Lange, B. OS 1983, 61, 14.
Mehta, G.; Murthy, A. N.; Reddy, D. S.; Reddy, A. V JACS 1986, 108,
3443.
Oda, M.; Yamauro, A.; Watabe, T. CL 1979, 1427.
Giner, J.-L.; Margot, C ; Djerassi, C. JOC 1989, 54, 369.
Cornforth, J. W.; Cornforth, R. H.; Mathew, K. K. JCS 1959, 2539.
Fujita, S.; Kotauna, K.; Inagaki, Y. S 1982, 68.
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Donaruma, L. G.; Heldt, W. Z. OR 1960, 11, 1.
University
Mark S. Meier
of Kentucky, Lexington, KY, USA
Virginia Commonwealth
Suzanne M. Ruder
University, Richmond, VA, USA
350
1,3-PROPANEDIOL
4-Picolyl Chloride Hydrochloride
[1822-51-1]
C 6 H 7 Cl 2 N
(MW 164.04)
(protection of alcohols,1,2 phenols,3 thiols,3,4 and carboxylic

acids5)
Alternate Name: 4-(chloromethyl)pyridine hydrochloride.
Solubility: sol H2O, EtOH; insol CH2Cl2, acetone.
Form Supplied in: white or off-white crystalline solid; available
from several commercial sources.
Handling, Storage, and Precautions: the free base is reported to
be unstable,1 and should be generated shortly before use.
Protection Reagent. Alcohols (eq 1)1,2 (including hydroxycontaining amino acid derivatives),2 phenols,3 carboxylic acids
(eq 2),5 and thiols (eq 3)3,4 have all been alkylated by this reagent
(1). Esters (2) are also available from the respective acids by
1,3-Dicyclohexylcarbodiimide coupling with 4-pyridylmethanol
in CH2Cl25 in comparable yield.
tion at a mercury cathode. The protected alcohols,1,2 phenols,3

and thiols3,4 are similarly deprotectable by electrolysis.
The use of 2-1 and 3-picolyl2 ethers in such cases has also been
investigated, and an N-protecting group, (4-picolyloxy)carbonyl,6
has also been described. The increased polarity of these picolylcontaining materials, relative to the more typical benzylic pro
tecting groups, can appreciably assist in their purification.2 Nev
ertheless, these protecting groups remain outside the mainstream
of peptide chemistry, probably due to the greater familiarity and
availability of, for example, the benzyl- or t-butyl-based groups,
and the fact that the Na/NH3 or electrolytic deprotection of the
4-picolyl group is likely to be incompatible with these. In this
regard, the use of 2-(2'- or 4'-pyridyl)ethyl protecting groups7
('Pyoc' carbamates,7a 'Pet' esters,7b,7c), likely to impart similar
polarity, but deprotectable cleanly in the presence of these other
common functionalities, appears distinctly advantageous.
1. Wieditz, S.; Schfer, H. J. ACS 1983, B37, 475.

2.
Rizo, J.; Albericio, F.; Romero, G.; Garcia-Echeverria, C ; Claret, J.;

Muller, C.; Giralt, E.; Pedroso, E. JOC 1988, 53, 5386.
3.
Gosden, A.; Stevenson, D.; Young, G. T. CC 1972, 1123.
4.
Gosden, A.; Macrae, R.; Young, G. T. JCR(S) 1977, 22.
5.
Camble, R.; Garner, R.; Young, G. T. JCS(C) 1969, 1911.
6.
Veber, D. F.; Paleveda, W. J.; Lee, Y. C.; Hirschmann, R. JOC 1977, 42,
3286.
7.
(a) Kunz, H.; Barthels, R. AG(E) 1983, 22, 783. (b) Katritzky, A. R.;
Khan, G. R.; Schwarz, O. A. TL 1984, 25, 1223. (c) Kessler, H.; Becker,
G.; Kogler, H.; Wolff, M. TL 1984, 25, 3971.
(1)
Peter Ham
SmithKline Beecham Pharmaceuticals, Harlow, UK
(2)
1,3-Propanediol1
[504-63-2]
(3)
Dihydric alcohols such as (3) are preferentially alkylated on

the primary OH, but (4) yields a mixture of dialkylated and both
monoalkylated products.1
The protected materials have been of particular value in pep

tide chemistry. Cleavage5 of esters (2) takes place not only under
the more obvious aqueous alkali or catalytic hydrogenation con
ditions, but also with Sodium-Ammonia or by electrolytic reduc
C3H8O2
(MW 76.10)
(preparation of acetals,2,3 quinolines,4 indoles,5 boron esters;6

traps Wacker aldehyde intermediates;7 reaction solvent for
Wolff-Kishner reduction8)
Alternate Name: trimethylene glycol.
Physical Data: liquid, bp 214C; mp -27C; d 1.053g cm -3 .
Solubility: sol H2O, alcohol; v sol ether; sol (hot) benzene.
Form Supplied in: >97% purity, depending on supplier.
Purification: dried with K2CO3 and distilled under reduced pres
sure.
Reactions with Carbonyls. The chemistry of 1,3-propanediol
(1) is dominated by acetal2,3,9,10 formation.11 Its ketone ac
etals show differential hydrolytic stability: cyclopentanone ac
etals hydrolyze faster than cyclohexanone acetals, and both hydrolyze faster than ethylene glycol-derived acetals (Table 1).3a
The ketone-acetal equilibrium lies far to the left.3 Its aldehyde
1,3-PROPANEDIOL
acetals, however, show the opposite behavior and are hydrolytically more stable than ethylene glycol acetals.3b,12 Polyketones3
and 1,4-diones13 may be selectively protected by judicious choice
of substituted 1,3-propanediols. For protection of steroidal ke
tones, (1) is preferred over ethylene glycol, which is susceptible
to attack by alkyllithium reagents.10
351
(1) gives 2-imino-1,3-oxazine (5) (CuCl, 95%) which is converted

into urea derivatives in high yields.27
Table 1 Relative Hydrolysis Rates of 5-Androstane Acetals

Glycol
Ethylene glycol
1,3-Propanediol
3-Acetal
17-Acetal
1.0
14.5
1.64
40.5
In an alternative route to the Skraup synthesis, quinolines are

prepared from (1) and primary anilines (eq 3). Choice of stoichiometry, solvent, and ligand greatly affect yield.4
(3)
n = 0, 1
Conversion to Reactive Intermediates. Acrolein condenses

with (1) to give 2-(2-bromoethyl)-1,3-dioxane,2 which finds use as
a three-carbon homologating agent (eq 1)14 and in the preparation
of -keto aldehydes.15 Use of (1) is essential as the correspond
ing ethylene glycol dioxolane is thermally unstable2 and gives
Grignard reagents that tend to autodestruct.15,16 Hydrolysis of the
product acetals requires special conditions.14,15
Regioselective synthesis of indoles is accomplished by in situ

trapping of Wacker aldehydes with (1) (eq 4). o-Vinylacetanilides
give indoles directly under similar reaction conditions.5 Isocoumarins and 1-isoquinolinones are also prepared by this
chemistry.28 Electron-deficient alkenes give acetals with (1) un
der Wacker conditions (see Palladium(II) Chloride-Copper(I)
Chloride).7
(1)
Diol (1) is used to prepare cyclopropenone acetal (2).17,18 Its

highly nucleophilic double bond forms addition products with
alcohols and amines17 and cycloaddition products with dienes
to give norcarenes,17 ketones to give furanones and oxetanes,17
aldehydes to give butenolide, furan, and -keto ester deriva
tives (eq 2),18 electrophilic alkenes to give cyclopropanes19 and
functionalized cyclopentenones,20 and an -pyrone to give a
cycloheptatrienone.21
(4)
Miscellaneous Transformations. 1,3-Propanediol can be

converted to 3-chloro-l- (60%),29 3-iodo-l- (68%),30 and
3-bromo-l-propanol (90%)31 or to 1,3-dibromopropane
(85-95%).32 With imidoyl chlorides, 3-chloropropyl benzoates
are produced.33 The title reagent has good solvent properties
and finds use in the Wolff-Kishner reduction.8 Cyclohexenones
and (1) give hydroxypropyl phenols under oxidative conditions
(eq 5).34
(2)
(5)
Formation of Boron Esters. Esterification of boronic acid

derivatives occurs readily with (1), and has been used in many
hydroboration reaction sequences.6,22 The six-membered ring
boronates are more stable than the corresponding five-membered
ring or acyclic products made from 1,2-diols or alcohols. The title
reagent has been used to regenerate carbohydrates from boronate
derivatives.23
Related
Reagents. 3-Bromo-l,2-propanediol;
2,3Butanediol; 2,2-Dimethyl-l,3-propanediol; Ethylene Glycol;
2-Methoxy-l,3-dioxolane; ( 2 R , 4R)-2,4-Pentanediol; Triethyl
Orthoformate.
Heterocycle Synthesis. Alkyl (3)24 and alkoxy (4)25 1,3,2dioxophosphorinane 2-oxides are prepared in good yields by basecatalyzed condensation of (1) with the appropriate phosphonous
dichloride. Iminosulfinyl dichlorides react similarly.26 With DCC,
1. (a) Cameron, D. C ; Tong, I. T.; Skraly, F. A. Prepr.-Am. Chem. Soc., Div.

Pet. Chem., 1993, 38, 294. (b) Avots, A.; Glemite, G.; Dzenitis, J. Latv.
PSR Zinat. Akad. Vestis, Kim. Ser. 1986, 398 (CA 1987, 706, 17 529d).
2.
Stowell, J. C ; Keith, D. R.; King, B. T. OS 1984, 62, 140.

352
1,3-PROPANEDITHIOL
3.
(a) Smith, S. W.; Newman, M. S. JACS 1968, 90, 1249. (b) Newman, M.
S., Harper, R. J. JACS 1958, 80, 6350. (c) Smith, S. W.; Newman, M. S.
JACS 1968, 90, 1253.
4. Tsuji, Y.; Huh, K.-T.; Watanabe, Y. JOC 1987, 52, 1673.
5. Kasahara, A.; Izumi, T.; Murakami, S.; Miyamoto, K.; Hino, T. JHC
1989, 26, 1405.
6. Brown, H. C ; Bhat, N. G.; Somayaji, V. OM 1983, 2, 1311.
7. (a) Hosokawa, T.; Ataka, Y.; Murahashi, S.-I. BCJ 1990, 63, 166. (b)
Hosokawa, T.; Ohta, T.; Kanayama, S.; Murahashi, S.-I. JOC 1987, 52,
1758.
8. Campbell, T. W.; Ginsig, R.; Schmid, H. HCA 1953, 36, 1489.
9.
10.
11.
12.
13.
14.
15.
Marton, D.; Slaviero, P.; Tagliavini, G. G 1989, 119, 359.

Dann, A. E.; Davis, J. B.; Nagler, M. J. JCS(P1) 1979, 158.
Sandler, S. R.; Karo, W. Organic Functional Group Preparations 2nd
ed.; Academic: New York, 1989; Vol. 3, p 1.
Stowell, J. C. JOC 1976, 41, 560.
Cole, J. E.; Johnson, W. S.; Robins, R. A.; Walker, J. JCS 1962,
244.
Stowell, J. C.; Keith, D. R. S 1979, 132.
Stowell, J. C. JOC 1976, 41, 560.
16. Ponaras, A. A. TL 1976, 36, 3105.

17. (a) Butler, G. B.; Herring, K. H.; Lewis, P. L.; Sharpe, V. V; Veazey, R.
L. JOC 1977, 42, 679. (b) Albert, R. M.; Butler, G. B. JOC 1977, 42,
674.
18. Boger, D. L.; Brotherton, C. E.; Georg, G. I. OS 1986, 65, 32.
19. Boger, D. L.; Brotherton, C. E. TL 1984, 25, 5611.
20. Boger, D. L.; Brotherton, C. E. JACS 1984, 106, 805.
21. Boger, D. L.; Brotherton, C. E. JOC 1985, 50, 3425.
22. For alkenyl borinate transformations, see: (a) Brown, H. C ; Bhat, N. G.
TL 1988, 29, 21. (b) Brown, H. C ; Imai, T.; Bhat, N. G. JOC 1986, 51,
5277. (c) Srebnik, M.; Bhat, N. G.; Brown, H. C. TL 1988, 29, 2635. (d)
Brown, H. C ; Bhat, N. G.; Iyer, R. R. TL 1991, 32, 3655. For asymmetric
hydroboration of prochiral alkenes, see: Brown, H. C ; Imai, T.; Desai,
M. C ; Singaram, B. JACS 1985, 107, 4980.
23.
24.
Ferrier, R. J.; Prasad, D.; Rudowski, A.; Sangster, I. JCS 1964,

3330.
Yuan, C ; Li, S.; Cheng, Z. S 1988, 186.
25. Boisdon, M.-T.; Munoz, A.; Vives, J.-P. CR(C) 1961, 253, 1570.
26. Picard, C ; Cazaux, L.; Tisnes, P. PS 1981, 10, 35.
27. Vowinkel, E.; Gleichenhagen, P. TL 1974, 2, 143.
28. Izumi, T.; Nishimoto, Y.; Kohei, K.; Kasahara, A. JHC 1990, 27, 1419.
29. Marvel, C. S.; Calvery, H. O. OSC 1941, 1, 533.
30. Buijs, W.; van Elburg, P.; van der Gen, A. SC 1983, 13, 387.
31. Kang, S.-K.; Kim, W.-S.; Moon, B.-H. S 1985, 1161.
32. Kamm, O.; Marvel, C. S. OSC 1941, 1, 25.
33. Back, T. G.; Barton, D. H. R.; Rao, B. L. JCS(P1) 1977, 1715.
34. Horiuchi, C. A.; Fukunishi, H.; Kajita, M.; Yamaguchi, A.; Kiyomiya,
H.; Kiji, S. CL 1991, 1921.
Union Carbide Corporation,
1,3-Propanedithiol1
[109-80-8]
C3H8S2
(MW 108.25)
(1,3-dithiane formation; reduction (carbonyl to methylene, azide

to primary amine, peptidic disulfide to dithiol, demercuration);
ketene dithioacetal formation)
Physical Data: d20 1.077g cm - 3 ; bp 170C/760 mmHg,
92-98 C/56 mmHg.
Solubility: slightly sol water; miscible with many organic sol
vents.
Handling, Storage, and Precautions: stench! Use in a fume hood.
Can undergo air oxidation to form disulfides. The cyclic disul
fide forms a polymeric precipitate in methanol.17a Extraction
into aqueous NaOH serves to separate thiols from nonacidic
impurities.1f For toxicity data, see 1,2-Ethanedithiol.
1,3-Dithiane Formation. 1,3-Propanedithiol (1) condenses

under protic or Lewis acid catalysis with aldehydes and ketones
to afford 1,3-dithianes (eqs 1-4).2-5 Useful for carbonyl protec
tion, the 1,3-dithianyl group is compatible with aqueous acid,
strong bases, anionic (eq 3)4 and Pd-catalyzed (eq 5)6a C-C bondforming reactions, catalytic hydrogenation in the presence of the
Crabtree catalyst,6b and many other synthetic processes.7 Often,
(1) shows useful selectivity in reactions with dicarbonyl com
pounds (eq 3; structures 2-5).4,8 In contrast to acetalization with
diols,9a (1) reacts selectively with ,-alkenyl ketones in the pres
ence of moderately hindered saturated ketones;1c double bond
migration is not observed;1a conjugate addition can compete if
sterically favored.9b In ,-alkynyl ketones (not aldehydes),10a
conjugate addition prevails (eq 6).10b
(1)
(2)
Kenneth C. Caster
South Charleston, WV, USA
(3)
(4)
1,3-PROPANEDITHIOL
353
(8)
(5)
(9)
R = SiPh2-t-Bu
(2) [(1), BF3OEt2, 55-65%]
(3) [(1), TeCl4, 68%]

(10)
(11)
(4) [(1), BF3OEt2, >98%]
(5) [bis-TMS-(1), ZnI2, 88%]
(12)
(6)
Acetals, enol ethers, and oxazolidines also give dithianes with

(1) (eqs 7-12). 11a-f, 12 This reaction can be useful for opening
resistant cyclic structures;13a,c Titanium(IV) Chloride is an es
pecially effective catalyst in such cases.13b Reaction of (1) with
dihalomethanes,14a,b or with carboxylic acids in the presence of
Tin(II) Chloride,14c also yields 1,3-dithianes.
(7)
1,3-Dithianes derived from aldehydes are important synthetic

intermediates because they undergo deprotonation to 2-lithio- 1,3dithianes which function as carbonyl anion equivalents (umpolung reagents).1b-e The vinylogous process (eq 4)5 is a subject of
current study.15
Regeneration of the carbonyl group can entail a trial-and-error
process with the many procedures available.1a-e HgII salts and
N-halo amides remain the most frequently employed reagents.
Aqueous Iodomethane is a mild alternative.8c Epimerization at an
stereocenter does not normally attend the formation or removal
of the dithianyl group (eqs 8, 9, 12, 13).
Reduction. Raney Nickel treatment of thioacetals is a standard
method for carbonyl-to-methylene reduction.1b In the presence of
Triethylamine, (1) reduces azides to primary amines (eq 14).16a,b
Under the acidic conditions employed for thioacetal formation,
this reduction does not occur (eq 8).11b,16c Reduction of peptidic
disulfides to dithiols can be conveniently accomplished with (1).17
354
1,3-PROPANEDITHIOL
Treatment with (1) effected demercuration to an ester diastereoselectively (eq 15).18
3.
Jacobi, P. A.; Brownstein, A.; Martinelli, M.; Grozinger, K. JACS 1981,

103, 239.
4. (a) Stahl, I.; Manske, R.; Gosselck, J. CB 1980, 113, 800. (b) Stahl, I.;
Gosselck,J. 51980, 561.
5. Fang, J.-M.; Liao, L.-F.; Hong, B.-C. JOC 1986, 51, 2828.
6. (a) Schmidt, U.; Meyer, R.; Leitenberger, V.; Griesser, H.; Lieberknecht,
A. S 1992, 1025. (b) Schreiber, S. L.; Sommer, T. J. TL 1983, 24, 4781.
7. (a) Chakraborty, T. K.; Reddy, G. V. JOC 1992, 57, 5462. (b) Jones, T.
K.; Mills, S. G.; Reamer, R. A.; Askin, D.; Desmond, R.; Volante, R. P.;
Shinkai, I. JACS 1989, 111, 1157. (c) Chen, S. H.; Horvath, R. F.; Joglar,
J.; Fisher, M. J.; Danishefsky, S. J. JOC 1991, 56, 5834. (d) Rosen, T.;
Taschner, M. J.; Thomas, J. A.; Heathcock, C. H. JOC 1985, 50, 1190.
(e) Golec, J. M. C ; Hedgecock, C. J. R.; Kennewell, P. D. TL 1992, 33,
547.
8.
(13)
(a) Xu, X.-X.; Zhu, J.; Huang, D.-Z.; Zhou, W.-S. T 1986, 42, 819. (b)
Tani, H.; Masumoto, K.; Inamasu, T.; Suzuki, H. TL 1991, 32, 2039. (c)
Myers, A. G.; Condroski, K. R. JACS 1995, 117, 3057. (d) Corey, E. J.;
Tius, M. A.; Das, J. JACS 1980, 702, 1742.
9.
(14)
(15)
Ketene Dithioacetal Formation. These versatile interme

diates1c arise from 1,3-dithiane anions by elimination (eq 8)11b, 19
or vinylogous alkylation (eq 4),5 and by condensation of carboxylic acid derivatives with (1) (eq 13).20a Ketene dithioacetals
derived from lactones can cyclize to give dithio orthoesters, which
can be selectively deprotected (eq 16).20b
(16)
Related Reagents. 1,2-Ethanedithiol; Ethanethiol; Methanethiol.
(a) Reference 1 (a), p. 188. (b) Hoppmann, A.; Weyerstahl, P.; Zummack,
W. LA 1977, 1547.
10. (a) Johnson, W. S.; Frei, B.; Gopalan, A. S. JOC 1981, 46, 1512. (b)
Ranu, B. C ; Bhar, S.; Chakraborti, R. JOC 1992, 57, 7349.
11. (a) Tanino, H.; Nakata, T.; Kaneko, T.; Kishi, Y. JACS 1977, 99, 2818.
(b) Moss, W. O.; Bradbury, R. H.; Hales, N. J.; Gallagher, T. JCS(P1)
1992, 1901. (c) Myles, D. C ; Danishefsky, S. J.; Schulte, G. JOC 1990,
55, 1636. (d) Nakata, T.; Nagao, S.; Oishi, T. TL 1985, 26, 75. (e) Corey,
E. J.; Kang, M.-c; Desai, M. C ; Ghosh, A. K.; Houpis, I. N. JACS 1988,
110, 649. (f) Hoppe, I.; Hoppe, D.; Herbst-Irmer, R.; Egert, E. TL 1990,
31, 6859.
12. (a) Sato, T.; Otera, J.; Nozaki, H. JOC 1993, 58, 4971. (b) Sanchez, I.
H.; Lpez, F. J.; Soria, J. J.; Larraza, M. I.; Flores, H. J. JACS 1983, 705,
7640. (c) Burford, C ; Cooke, F.; Roy, G.; Magnus, P. T 1983, 39, 867.
13. (a) Alonso, R. A.; Vite, G. D.; McDevitt, R. E.; Fraser-Reid, B. JOC
1992, 57, 573. (b) Page, P. C. B.; Roberts, R. A.; Paquette, L. A. TL
1983, 24, 3555. (c) Corey, E. J.; Reichard, G. A. TL 1993, 34, 6973.
14.
15. (a) Moss, W. O.; Jones, A. C.; Wisedale, R.; Mahon, M. F.; Molloy, K.
C ; Bradbury, R. H.; Hales, N. J.; Gallagher, T. JCS(P1) 1992, 2615. (b)
Kksal, Y.; Raddatz, P.; Winterfeldt, E. LA 1984, 450.
16. (a) Goldstein, S. W.; McDermott, R. E.; Makowski, M. R.; Eller, C. TL
1991, 32, 5493. (b) Lim, M.-I.; Marquez, V. E. TL 1983, 24, 5559. (c)
Durette, P. L. Carbohydr. Res. 1982, 700, C27.
17. (a) Ranganathan, S.; Jayaraman, N. CC 1991, 934. (b) Lees, W. J.;
Whitesides, G. M. JOC 1993, 58, 642.
18. Gouzoules, F. H.; Whitney, R. A. JOC 1986, 57, 2024.
19. (a) Muzard, M.; Portella, C. JOC 1993, 58, 29. (b) Barton, D. H.
R.; Gateau-Olesker, A.; Anaya-Mateos, J.; Cleophax, J.; Gero, S. D.;
Chiaroni, A.; Riche, C. JCS(P1) 1990, 3211.
20.

2nd ed.; Wiley: New York, 1991, p 201. (b) Grbel, B.-T.; Seebach, D.
S 1977, 357. (c) Page, P. C. B.; van Niel, M. B.; Prodger, J. C. T 1989,
45, 7643. (d) Kolb, M. S 1990, 171. (e) Ogura, K. COS 1991, 7, Chapter
2.3; Krief, A. COS 1991, 3, Chapter 1.3. (f) Perrin, D. D.; Armarego,
W. L. F.; Perrin, D. R. Purification of Laboratory Chemicals, 2nd ed.;
Pergamon: Oxford, 1980.
2.
Ohmori, K.; Suzuki, T.; Miyazawa, K.; Nishiyama, S.; Yamamura, S. TL

1993,34,4981.
(a) Page, P. C. B.; Klair, S. S.; Brown, M. P.; Smith, C. S.; Maginn, S.
J.; Mulley, S. T 1992, 48, 5933. (b) Lissel, M. LA 1982, 1589. (c) Kim,
S.; Kim, S. S.; Lim, S. T.; Shim, S. C. JOC 1987, 52, 2114.
(a) Corey, E. J.; Pan, B.-C.; Hua, D. H.; Deardorff, D. R. JACS 1982,
704, 6816. (b) Dziadulewicz, E.; Giles, M.; Moss, W. O.; Gallagher, T.;
Harman, M.; Hursthouse, M. B. JCS(P1) 1989, 1793.
Alcon Laboratories,
Raymond E. Conrow
Fort Worth, TX, USA
SILVER(I) TETRAFLUOROBORATE
(3)
[14104-20-2]
AgBF4
355
(MW 194.68)
(mild Lewis acid with a high affinity for organic halides)

Physical Data: mp 200C (dec).
Solubility: sol benzene, toluene, nitromethane, diethyl ether, wa
ter.
Form Supplied in: white solid; widely available.
Analysis of Reagent Purity: contents of Ag can be assayed con
veniently by volumetric titration of AgI.
Preparative Method: can be prepared by reacting Silver(I) Fluo
ride with Boron Trifluoride in nitromethane.1
Handling, Storage, and Precautions: should be protected from
light and moisture; very hygroscopic.
Introduction. This reagent has replaced Silver(I) Perchlorate

to a large extent because of the sensitivity of perchlorates.
Intramolecular substitutions mediated by Ag+ do not seem to

require activated halides.8 For example, -chloro amides react
with AgBF4, giving products from intramolecular attack of the
amide oxygen. Depending on the structure of the amide, imino
lactones,9 imino lactonium salts,10 or lactone hydrazones (eq 4)11
are obtained as products. Fluorination of -bromo ketones using
AgBF4 has also been reported.12
(4)
Nucleophilic Aromatic Substitution. In one case, it has been

reported that AgBF4 promotes the nucleophilic substitution of an
aromatic chloride (eq 5).13 This is not due to activation of the
halide, but apparently to suppression of halide-promoted decomplexation of the arene-manganese derivative.
Activation of Acyl Chlorides. In several cases, AgBF4 has

been used to increase the reactivity of acyl chlorides towards
nucleophiles.2 For example, N-acylammonium salts were pre
pared for the first time by the reaction of a tertiary amine and
an acyl chloride in the presence of AgBF4 (eq 1 ).3
(1)
Nucleophilic Substitution on Alkyl Halides by Heteroatoms. A number of more or less activated alkyl halides, such as
benzyl halides4 and allyl halides,5 undergo substitution reactions
mediated by AgBF4 in the presence of a heteroatom nucleophile.
For example, treatment of pentamethylcyclopentadienyl bromide
with AgBF4 in the presence of a nucleophile gives the correspond
ing substituted product (eq 2). Thiols, amines, and alcohols have
been used as nucleophiles.6
(5)
Carbon-Carbon Bond Formation via Cationic Interme

diates. In analogy with the heteroatom substitutions described
above, certain aliphatic halides undergo substitution reactions
with carbon nucleophiles promoted by AgBF4. For example, Eschenmoser and co-workers used AgBF4 in order to transform chloro nitrones into 1,3-dipoles which react with ordinary alkenes
in a cycloaddition manner (eq 6).14
(2)
(6)
Adenine analogs are prepared stereoselectively from cyclopentene derivatives using a two-step procedure (eq 3). The reaction
probably involves a seleniranium salt as an intermediate.7
Livinghouse and co-workers have shown that acy lnitrilium ions,

prepared from isocyanides and an acid chloride followed by treatAvoid Skin Contact with All Reagents
356
ment with AgBF4, are useful intermediates in the synthesis of

nitrogen-containing heterocycles (eq 7).15
Trifluoromethanesulfonate)35 or to dihydrofurans,36 the

Claisen rearrangement of aryl allenylmethyl ethers,37 and the
rearrangement of silyloxycyclopropanes (eq 12, also effected by
Copper(II) Tetrafluoroborate).38
(7)
(12)
In certain cases, allylsilanes16 and trimethylsilyl enol ethers17

react with alky 1 halides with the formation of a new carbon-carbon
bond. -Bromo imidates18 (eq 8) and -chloro imines19 have been
reported to undergo electrophilic aromatic substitution on rela
tively electron-rich aromatics in the presence of AgBF4.
(8)
Synthesis via Iminium Ions. -Cyano amines react with

AgBF4 with the formation of an intermediate iminium ion.20 This
has been used synthetically as a method for removal of the cyano
group either by a consecutive reduction21,22 to the amine (eq 9) or
by elimination to the imine23 or enamine.24
Activation of Thiol Esters. Pyridyl thiol esters are converted

into esters on treatment with AgBF4 and an alcohol.39 Acylation
of alkynylsilanes can also be carried out using thiol esters in the
presence of AgBF4.40
Alkylation of Thioethers. Thioethers can be methylated
by Iodomethane in the presence of AgBF4.41 Benzylation of
thioethers in the presence of AgBF4 has also been reported.42
Electrophilic Aromatic Substitution. Electrophilic nitration
using a combination of NO2Cl and AgBF4 has been reported.43
Conversion of arylsilanes into iodides and bromides has been
achieved using a combination of the halogen and AgBF4 (eq 13).44
(13)
(9)
Rearrangements. A number of strained alkyl and/or re

active halides, such as cyclopropyl25 and bicyclic26,27 chlo
rides, rearrange on treatment with AgBF4. For example,
-bromotetrahydropyrans rearrange to tetrahydrofurans stereoselectively on treatment with AgBF4 (eq 10).28 Other examples in
clude the rearrangement of -haloalkyl aryl ketones into arylacetic
acid derivatives,29 and the rearrangement of -haloalkylsilanes
upon treatment with AgBF4.30
(10)
Catalysis of Cycloadditions. Addition of catalytic amounts of

AgBF4 greatly increases the selectivity of [2 + 4] cycloadditions
of benzyne.45
Related Reagents. Dimethyl Sulfoxide-Silver Tetrafluoroborate.
1. Olah, G. A.; Quinn, H. W. J. Inorg. Nucl. Chem. 1960,14, 295.

2. Schegolev, A. A.; Smit, W. A.; Roitburd, G. V.; Kucherov, V. F. TL 1974,
3373.
3. King, J. A., Jr.; Bryant, G. L., Jr. JOC 1992, 57, 5136.
4. Zimmerman, H. E.; Paskovich, D. H. JACS 1964, 86, 2149.
5. Bloodworth, A. J.; Tallant, N. A. CC 1992, 428.
6. Jutzi, P.; Mix, A. CB 1992,125, 951.
7. Wolff-Kugel, D.; Halazy, S. TL 1991, 32, 6341.
In the presence of strained hydrocarbons, AgBF4 functions as

a mild Lewis acid and causes rearrangements.31-33 For example,
the tricyclic hydrocarbon (1) rearranges upon treatment with a
catalytic amount of AgBF4 to the less strained hydrocarbon (2)
(eq 11).34
(11)
Numerous examples include the rearrangement of

propargyl esters into allenyl esters (see also Silver(I)
8.
9.
Lucchini, V.; Modena, G.; Pasquato, L. CC 1992, 293.

Peter, H.; Brugger, M ; Schreiber, J.; Eschenmoser, A. HCA 1963, 46,
577.
10. Nader, R. B.; Kaloustain, M. K. TL 1979, 1477.

11. Enders, D.; Brauer-Scheib, S.; Fey, P. S 1985, 393.
12. Fry, A. J.; Migron, Y. TL 1979, 3357.
13. Pearson, A. J.; Shin, H. T 1992, 48, 7527.
14. Kempe, H. M.; Das Gupta, T. K.; Blatt, K.; Gygax, P.; Felix, D.;
Eschenmoser, A. HCA 1972, 55, 2187.
15. Lee, C. H.; Westling, M.; Livinghouse, T.; Williams, A. C. JACS 1992,
114, 4089; Luedtke, G.; Westling, M.; Livinghouse, T. T 1992, 48, 2209.
16. Nishiyama, H.; Naritomi, T.; Sakuta, T.; Itoh, K. JOC 1983, 48, 1557.
17. Padwa, A.; Ishida, M. TL 1991, 41, 5673; Padwa, A.; Austin, D. J.; Ishida,
M.; Muller, C. M.; Murphree, S. S.; Yeske, P. E. JOC 1992, 57, 1161.
357
18.
19.
20.
Shatzmiller, S.; Bercovici, S. LA 1992, 997.

Kuehne, M.; Matson, P. A.; Bornmann, W. G. JOC 1991, 56, 513.
Grierson, D. S.; Bettiol, J. L.; Buck, I.; Husson, H. P. JOC 1992, 57,
6414.
34.
35.
Paquette, L. A.; Leichter, L. M. JACS 1972, 94, 3653.

Koch-Pomeranz, U.; Hansen, H. J.; Schmid, H. HCA 1973, 56, 2981.
36.
21.
22.
Bettiol, J. L.; Buck, I.; Husson, H. P.; Grierson, D. S. TL 1991, 32, 5413.
Theodorakis, E.; Royer, J.; Husson, H. P. SC 1991, 521.
37.
Shigemans, Y.; Yasui, M.; Ohrai, S.; Sasaki, M.; Sashiwa, H.; Saimoto,
H. JOC 1991, 56, 910.
Dikshit, D. K.; Singh, S.; Panday, S. K. JCR(S) 1991, 298.
23.
24.
Belattar, A.; Saxton, J. E. JCS(P1) 1992, 1583.

Agami, C.; Couty, F.; Lin, J. H 1993, 36, 25.
25.
26.
27.
Birch, A. J.; Keeton, R. JCS(C) 1968, 109.

Yamada, Y.; Kimura, M.; Nagaoka, H.; Ohnishi, K. TL 1977, 2379.
Kraus, G. A.; Zheng, D. SL 1993, 71.
28.
29.
30.
Ting, P. C.; Bartlett, P. A. JACS 1984, 106, 2668.

Giordano, C.; Castaldi, G.; Casagrande,F.;Belli, A. JCS(P1) 1982, 2575.
Eaborn, C.; Lickiss, P. D.; Najim, S. T.; Stanczyk, W. A. JCS(P2) 1993,
59; Eaborn, C.; Lickiss, P. D.; Najim, S. T. JCS(P2) 1993, 391.
31. Paquette, L. A. S 1975, 349.
32. Paquette, L. A. JACS 1970, 92, 5765.
33. Fitjer, L.; Justus, K.; Puder, P.; Dittmer, M.; Hassler, C.; Noltemeyer, M.
AG(E) 1991, 30, 436.
38.
Ruy, I.; Ando, M.; Ogawa, A.; Murai, S.; Sonoda, N. JACS 1983, 105,
7192.
39.
40.
41.
Gerlach, H.; Thalmann, A. HCA 1974, 57, 2661.

Kawanami, Y.; Katsuki, T.; Yamaguchi, M. TL 1983, 24, 5131.
Ishibashi, H.; Tabata, T.; Kobayashi, T.; Takamuro, I.; Ikeda, M. CPB
1991, 39, 2878.
Beerli, R.; Borschberg, H. J. HCA 1991, 74, 110.
42.
43.
44.
45.
Olah, G. A.; Pavlth, A.; Kuhn, S. CI(L) 1957, 50; Kuhn, S. J.; Olah, G.
A. JACS 1961, 83, 4564.
Furukawa, N.; Hoshiai, H.; Shibutani, T.; Higaki, M.; Iwasaki, F.;
Fujihara, H. H 1992, 34, 1085.
Crews, P.; Beard, J. JOC 1973, 38, 529.
Lars-G. Wistrand
Nycomed Innovation, Malm, Sweden
358
TETRA-n-BUTYLAMMONIUM FLUORIDE
are used as substrates for this reaction, (E/Z) mixtures of 2cyanocyclopropanecarboxylates are obtained by an intramolec
ular cyclization (eq 6).
(2)
Tetra-n-butylammonium Fluoride 1
(TBAF)
[429-41-4]
(TBAF-3H2O)
[87749-50-6]
C 16 H 36 FN
(MW 261.53)
C 16 H 42 FNO 3
(MW 315.59)
(3)
(TBAFXH2O)
[22206-57-1]
(4)
(can be used for most fluoride-assisted reactions; deprotection of

silyl groups;1e desilylation;2,3 fluorination;4 used as a base5,6)
Alternate Name: TBAF.
Physical Data: TBAFXH 2 O: mp 62-63 C.
Solubility: sol H2O, THF, MeCN.
Form Supplied in: trihydrate, 1.0 M solution in THF, and 75
wt % solution in water.
Preparative Method: aqueous Hydrofluoric Acid is passed
through an Amberlite IRA 410 OH column, followed by an
aqueous solution of Tetra-n-butylammonium Bromide. After
the resin is washed with water, the combined water fractions
are repeatedly evaporated until no water is present. Tetrabutylammonium fluoride is collected as an oil in quantitative yield.
Handling, Storage, and Precautions: use in a fume hood.
Deprotection of Silyl Groups. Tetrabutylammonium fluoride

has been used widely as a reagent for the efficient cleavage of
various silyl protecting groups such as O-silyls of nucleosides,7,8
pyrophosphate,9 N-silyls,10,11 CO2 -silyl, and S-silyl derivatives.1e
These reactions are often carried out under very mild condi
tions in excellent yields. Thus it has been used in the synthe
sis of base-sensitive chlorohydrins (eq 1)12 and -lactams.10,13
2-(Trimethylsilyl)ethoxymethyl groups can also be effectively re
moved from various substrates (eq 2). 14-18 Silyl ethers can be
converted to esters in one pot when they are treated with TBAF,
followed by exposure to acyl chlorides19,20 or anhydride21 in the
presence of base (eq 3). Treatment of triisopropylsilyl enol ethers
with Iodosylbenzene/Azidotrimethylsilane, followed by desilyla
tion and elimination with TBAF, gives good yields of the ,unsaturated ketones (eq 4).22,23
(5)
(6)
11-Membered pyrrolizidine dilactones have been synthesized

by treating a trimethylsilylethyl ester with TBAF in MeCN to form
an anion, which then undergoes cyclization by displacement of the
mesylate.
Desilylation Reagent. Cleavage of carbon-silicon bonds with
fluoride has been studied very extensively. TBAF is a very power
ful reagent for desilylation of a wide range of silicon-containing
compounds, such as vinylsilanes,2,25,26 alkynylsilanes,23,27
arylsilanes,28,29 acylsilanes,30 -silyl sulfones,31-33 and other
silane derivatives.3,34-37 It appears that cleavage of sp-C-Si bonds
is more facile than that of sp2-C-Si and sp3-C-Si bonds and that
substituted groups, such as phenyl and alkoxyl, can often facili
tate cleavage. A dimethylphenylsilyl group can be removed from
a vinyl carbon by TBAF with retention of the alkene stereochem
istry (eq 7).2 This method has been applied to the synthesis of
terminal conjugated trienes (eqs 8 and 9).38 The five-membered
siloxanes can be desilylated with 3 equiv of TBAF in DMF and
this protodesilylation is very sensitive to subtle structure changes
(eq 10).39
(7)
(1)
Cyclobutanone alkyl silyl acetals, obtained from [2 + 2] cycloadditions, can be deprotected with 1 equiv of TBAF in
THF to give the open-chain cyano esters in excellent yields
(eq 5).24 When 4-chloro-2-cyanocyclobutane alkyl silyl acetals
(8)
359
forms thioaldehydes, which have been trapped by cycloaddition

with cyclopentadiene (eq 16).65
(15)
(9)
(10)
(16)
The anions, generated in situ by desilylation of

silylacetylenes,40,41 allylsilanes,42-44 propargylsilanes,45 silyloxetanones,46 bis(trimethylsilylmethyl) sulfides,47 and other
silane derivatives,48-51 can undergo nucleophilic addition to ke
tones and aldehydes (eq 11).52 N-(C,C-bis(trimethylsilyl)methyl)
amido derivatives can add to aldehydes followed by Pe
terson alkenation to form acyl enamines.48,53 Treatment of
2-trimethylsilyl-l,3-dithianes can generate dithianyl anions,
which are capable of carbocyclization via direct addition to
carbonyl or Michael addition (eq 12). The fluoride-catalyzed
Michael additions are more general than Lewis acid-catalyzed
reactions and proceed well even for those compounds with
enolizable protons and/or severe steric hindrance (eq 13).54,55
(11)
(12)
exo:endo = 1:7
Use as a Base. TBAF has been widely used for a variety

of base-catalyzed reactions such as alkylation,66 elimination,67
halogenation,68 Michael addition,69-71 aldol condensation, and in
tramolecular cyclizations.5,72-74 It is especially useful when other
inorganic bases face solubility problems in organic solvents. The
reactions are usually carried out below 100 C due to the low ther
mal stability of TBAF.1e
TBAF is very useful for alkylation of nucleic acid derivatives.
Methylation75 or benzylation66 of uracil gives almost quantitative
yields of alkylated product when using alkyl bromides, dialkyl sul
fates (eq 17), trialkyl phosphates, or alkyl chlorides with TBAF.
Alkylation of the thiol anions generated from deprotection by 1,2dibromoethane produces interesting tetrachalcogenofulvalenes.14
Under phase-transfer conditions, selective mono- and dialkylations of malononitrile have been achieved by using neat TBAF
with Potassium Carbonate or Potassium t-Butoxide and control
ling the amount of alkyl bromides or iodides used (eqs 18 and
19).76
(13)
(17)
Direct fluoride-induced trifluoromethylation of -keto esters

(eq 14),56 ketones,57 aldehydes,58,59 and sulfoxides59 have beenreported using Trifluoromethyltrimethylsilane with TBAF in THE
(18)
(14)
(19)
Desilylation of some compounds can generate very reac

tive species such as benzynes,60 pyridynes,61 xylylenes,62,63
and benzofuran-2,3-xylylenes.64 1,4-Elimination of o-(trimethylsilylalkyl)benzyltrirnethylammonium halides with
TBAF in acetonitrile generates o-xylylenes, which undergo
intermolecular and intramolecular cycloadditions (eq 15).62-64
Treatment of -silyl disulfides with Cesium Fluoride or TBAF
Enol silyl ethers react with aldehydes with a catalytic amount

of TBAF to give the aldol silyl ethers in good yields. These
reactions generally proceed under very mild conditions and
within shorter periods of time than conventional strong acidic
or basic conditions. The products from 4-t-butyl-1-methyl2-(trimethylsilyloxy)cyclohexene and benzaldehyde show very
Next Page
360
good axial selectivity and a little anti-syn selectivity (eq 20).77

The aldol condensation of ketones and aldehydes can be achieved
in one pot when ethyl (trimethylsilyl)acetate is used as a silylation
agent with TBAF (eq 21).
2.
3.
4.
(20)
5.
6.
7.
8.
9.
(21)
Pless, J. JOC 1974, 39, 2644.

Seebach, D.; Beck, A. K.; Mukhopadhyay, X; Thomas, E. HCA 1982,
65, 1101.
Krawczyk, S. H.; Townsend, L. B. TL 1991, 32, 5693.
Meier, C ; Tam, H.-D. SL 1991, 227.
Valentijn, A. R. P. M.; van der Marel, G. A.; Cohen, L. H.; van Boom, J.
SL 1991, 663.
10. Hanessian, S.; Sumi, K.; Vanasse, B. SL 1992, 33.

11. Kita, Y.; Shibata, N.; Tamura, O.; Miki, T. CPB 1991, 39, 2225.
12.
Silyl nitronates undergo aldol condensation with aldehydes in

the presence of a catalytic amount of anhydrous TBAF to form
highly diastereoselective erythro products, which can be elabo
rated to give synthetically useful 1,2-amino alcohols (eq 22).6,78
A one-pot procedure has been developed for direct aldol conden
sation of nitroalkanes with aldehydes by using TBAF trihydrate
with Triethylamine andt-Butyldimethylchlorosilane.79 It appears
that silyl nitronates are not reactive intermediates in this case, and
the reactions proceed by a different mechanism.
1991. (f) Sharma, R. K.; Fry, J. L. JOC 1983, 48, 2112. (g) Cox, D. P.;
Terpinski, J.; Lawrynowicz, W. JOC 1984, 49, 3216.
Oda, H.; Sato, M.; Morizawa, Y.; Oshima, K.; Nozaki, H. T 1985, 41,
3257.
Dhar, R. K.; Clawson, D. K.; Fronczek, F. R.; Rabideau, P. W. JOC 1992,
57, 2917.
Gerdes, J. M.; Bishop, J. E.; Mathis, C. A. JFC 1991, 51, 149.
13.
Solladi-Cavallo, A.; Quazzotti, S.; Fischer, J.; DeCian, A. JOC 1992,

57, 174.
Konosu, T.; Oida, S. CPB 1991, 39, 2212.
14. Zambounis, J. S.; Mayer, C. W. TL 1991, 32, 2737.

15. Kita, H.; Tohma, H.; Inagaki, M.; Hatanaka, K. H 1992, 33, 503.
16. Stephenson, G. R.; Owen, D. A.; Finch, H.; Swanson, S. TL 1991, 32,
1291.
17. Fugina, N.; Holzer, W.; Wasicky, M. H 1992, 34, 303.
18. Shakya, S.; Durst, T. H 1992, 34, 67.
19. Beaucage, S. L.; Ogilvie, K. K. TL 1977, 1691.
20. Ma, C ; Miller, M. J. TL 1991, 32, 2577.
21. Mandai, T.; Murakami, T.; Kawada, M.; Tsuji, J. TL 1991, 32, 3399.
22. Magnus, P.; Evans, A.; Lacour, J. TL 1992, 33, 2933.
23. Ihara, M.; Suzuki, S.; Taniguchi, N.; Fukumoto, K.; Kabuto, C. CC 1991,
1168.
24. Rousseau, G.; Quendo, A. T 1992, 48, 6361.
25. Fleming, I.; Newton, T. W.; Sabin, V.; Zammattio, F. T 1992, 48, 7793.
(22)
Miscellaneous. Fluoride ion from anhydrous TBAF undergoes

nucleophilic displacement of tosylates,4,80 halides,80 and aryl nitro
compounds81 to give fluorinated products. When used with NBromosuccinimide, bromofluorination products are obtained.82
Several important peptide-protecting groups such as 9fluorenylmethyloxycarbonyl,83 benzyl,84 4-nitrobenzyl,85 2,2,2trichloroethyl,85 and acetonyl (eq 23)86 can be removed by TBAF
under mild conditions.
(23)
Related Reagents. Cesium Fluoride; Lithium Fluoride; Potas

sium Fluoride; Tetra-n-butylammonium Fluoride (Supported);
Tris(dimethylamino)sulfonium Difluorotrimethylsilicate.
1. (a) Corey, E. J.; Snider, B. B. JACS 1972, 94, 2549. (b) Hudlicky, M.
Chemistry of Organic Fluorine Compounds, 2nd ed.; Horwood: New
York, 1992. (c) Umemoto, T. Yuki Gosei Kagaku Kyokaishi 1992, 50,
338. (d) Clark, J. H. CRV 1980, 80, 429. (e) Greene, T. W.; Wuts, P. G.
M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York,
26. Ito, T.; Okamoto, S.; Sato, F. TL 1990, 31, 6399.

27. Lopp, M.; Kanger, T.; Mraus, A.; Pehk, T.; Lille, . TA 1991, 2, 943.
28. Yu, S.; Keay, B. A. JCS(P1) 1991, 2600.
29. Mukai, C ; Kim, I. J.; Hanaoka, M. TA 1992, 3, 1007.
30. Degl'Innocenti, A.; Stucchi, E.; Capperucci, A.; Mordini, A.; Reginato,
G.; Ricci, A. SL 1992, 329.
31. Kocienski, P. J. TL 1979, 2649.
32. Kocienski, P. J. JOC 1980, 45, 2037.
33. Hsiao, C. N.; Hannick, S. M. TL 1990, 31, 6609.
34. Bonini, B. F.; Masiero, S.; Mazzanti, G.; Zani, P. TL 1991, 32, 2971.
35. Nativi, C.; Palio, G.; Taddei, M. TL 1991, 32, 1583.
36. Okamoto, S.; Yoshino, T.; Tsujiyama, H.; Sato, F. TL 1991, 32, 5793.
37. Kobayashi, Y.; Ito, T.; Yamakawa, I.; Urabe, H.; Sato, F. SL 1991, 813.
38. Kishi, N.; Maeda, T.; Mikami, K.; Nakai, T. T 1992, 48, 4087.
39. Hale, M. R.; Hoveyda, A. H. JOC 1992, 57, 1643.
40. Nakamura, E.; Kuwajima, I. AG(E) 1976, 15, 498.
41. Mohr, P. TL 1991, 32, 2223.
42. Furuta, K.; Mouri, M.; Yamamoto, H. SL 1991, 561.
43. Hosomi, A.; Shirahata, A.; Sakurai, H. TL 1978, 3043.
44. Nakamura, H.; Oya, T.; Murai, A. BCJ 1992, 65, 929.
45.
46.
47.
48.
49.
Pornet, J. TL 1981, 22, 455.

Mead, K. T.; Park, M. JOC 1992, 57, 2511.
Hosomi, A.; Ogata, K.; Ohkuma, M.; Hojo, M. SL 1991, 557.
Lasarte, J.; Palomo, C.; Picard, J. P.; Dunogues, J.; Aizpurua, J. M. CC
1989, 72.
Watanabe, Y.; Takeda, X; Anbo, K.; Ueno, Y.; Xoru, T. CL 1992, 159.
Previous Page
TETRAFLUOROBORIC ACID
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
Paquette, L. A.; Blankenship, C ; Wells, G. J. JACS 1984, 106, 6442.

Seitz, D. E.; Milius, R. A.; Quick, J. TL 1982, 23, 1439.
Grotjahn, D. B.; Andersen, N. H. CC 1981, 306.
Palomo, C.; Aizpurua, J. M.; Legido, M.; Picard, J. P.; Dunogues, J.;
Constantieux, T. TL 1992, 33, 3903.
Majetich, G.; Casares, A.; Chapman, D.; Behnke, M. JOC 1986, 51,
1745.
Majetich, G.; Desmond, R. W.; Soria, J. J. JOC 1986, 57, 1753.
Ramaiah, P.; Prakash, G. K. S. SL 1991, 643.
Coombs, M. M.; Zepik, H. H. CC 1992, 1376.
Bansal, R. C ; Dean, B.; Hakomori, S.; Toyokuni, T. CC 1991, 796.
Patel, N. R.; Kirchmeier, R. L. IC 1992, 31, 2537.
Himeshima, Y.; Sonoda, T.; Kobayashi, H. CL 1983, 1211.
Tsukazaki, M.; Snieckus, V. 77 1992, 33, 533.
Ito, Y.; Nakatsuka, M.; Saegusa, T. JACS 1980, 702, 863.
Ito, Y.; Miyata, S.; Nakatsuka, M.; Saegusa, T. JOC 1981, 46, 1043.
Bedford, S. B.; Begley, M. J.; Cornwall, P.; Knight, D. W. SL 1991, 627.
Krafft, G. A.; Meinke, P. T. TL 1985, 26, 1947.
Botta, M.; Summa, V.; Saladino, R.; Nicoletti, R. SC 1991, 27, 2181.
Ben Ayed, T.; Amri, H.; El Gaied, M. M. T 1991, 47, 9621.
Sasson, Y.; Webster, O. W. CC 1992, 1200.
Kuwajima, I.; Murofushi, T.; Nakamura, E. S 1976, 602.
Yamamoto, Y.; Okano, H.; Yamada, J. TL 1991, 32, 4749.
Arya, P.; Wayner, D. D. M. TL 1991, 32, 6265.
Taguchi, T.; Suda, Y.; Hamochi, M.; Fujino, Y.; Iitaka,Y.CL 1991, 1425.
Ley, S. V.; Smith, S. C ; Woodward, P. R. T 1992, 48, 1145, 3203.
White, J. D.; Ohira, S. JOC 1986, 51, 5492.
Ogilvie, K. K.; Beaucage, S. L.; Gillen, M. F. TL 1978, 1663.
Dez-Barra, E.; De La Hoz, A.; Moreno, A.; Snchez-Verd, P. JCS(P1)
1991, 2589.
Nakamura, E.; Shimizu, M.; Kuwajima, I.; Sakata, J.; Yokoyama, K.;
Noyori, R. JOC 1983, 48, 932.
Colvin, E. W.; Seebach, D. CC 1978, 689.
Fernndez, R.; Gasch, C ; Gmez-Snchez, A.; Vlchez, J. E. TL 1991,
32, 3225.
Cox, D. P.; Terpinski, J.; Lawrynowicz, W. JOC 1984, 49, 3216.
Clark, J. H.; Smith, D. K. TL 1985, 26, 2233.
Maeda, M.; Abe, M.; Kojima, M. JFC 1987, 34, 337.
Ueki, M.; Amemiya, M. TL 1987, 28, 6617.
Ueki, M.; Aoki, H.; Katoh, T. TL 1993, 34, 2783.
Namikoshi, M.; Kundu, B.; Rinehart, K. L. JOC 1991, 56, 5464.
Kundu, B. TL 1992, 33,3193.
Du Pont Merck Pharmaceutical
Company,
Hui-Yin Li
Wilmington,
DE, USA
[16872-11-0]
(HBF4OMe2)
[67969-83-9]
(HBF4OEt2)
[67969-82-8]
BF4H
(MW 87.82)
C 2 H 7 BF 4 O
(MW 133.90)
C 4 H 11 BF 4 O
(MW 161.96)
(strong acid with pKa = 0.441 and a noncoordinating

counterion2)
361
Solubility: sol H2O, alcohols and ethers.

Form Supplied in: 48% aq solution; diethyl ether complex;
dimethyl ether complex.
Purification: commercial 50% solutions can be concentrated by
evaporation at 50-60 C/5 mmHg to give a residue of 11 N total
acidity. Water can also be removed by slow addition to ice-cold
acetic anhydride (dangerously exothermic reaction: caution is
advised!).3
Handling, Storage, and Precautions: storage in glass containers is
not recommended, although dilute solutions can be used in glass
containers over short periods. Poisonous: causes burns to eyes,
skin, and mucous membranes and may be fatal if ingested. Use
in a fume hood with safety goggles and chemically resistant
gloves and clothing. Incompatible with cyanides and strong
bases: decomposes to form HF.
General Considerations. Tetrafluoroboric acid is a useful

strong Br0nsted acid with a nonnucleophilic counterion. Its solu
bility in polar organic solvents makes it a useful strong acid under
nonaqueous conditions.
Preparation of Arenediazonium Tetrafluoroborates.
Arenediazonium salts can be precipitated as their tetrafluoroborate salts by addition of a cold solution of HBF4 to a solution of the
initial arenediazonium chloride. 4-Methoxybenzenediazonium
tetrafluoroborate is thus obtained in 94-98% yield. The arylamine can be diazotized with Sodium Nitrite in the presence of
HBF4, and the diazonium fluoroborate then precipitates directly.
3-Nitroaniline, when treated in this manner, provides a 90-97%
yield of 3-nitrobenzenediazonium tetrafluoroborate (eq 1).4
Diazotizations of arylamines and heteroarylamines in organic
solvents can be conveniently conducted using HBF4OEt2 and
alkyl nitrites.5
(1)
Protecting-Group Manipulations. A preparation of monoesters of glutamic and aspartic acids using HBF4OEt2 as a
catalyst has been developed. The diesters are generally side prod
ucts when other acids are used, but HBF4OEt2 appears to suppress
the diesterification. Thus L-glutamic acid -benzyl ester was ob
tained in 94% yield by treatment of the carboxylic acid in BnOH
with the HBF4OEt2 catalyst and a drying agent.6
When di-t-butyl carbonate is treated with DMAPHBF4,
water-soluble Boc-pyridinium tetrafluoroborate is formed.36 This
reagent installs the Boc protecting group onto amino acids in aque
ous NaOH. Thus L-proline is converted to its N-Boc derivative in
nearly quantitative yield in 10 min.
Carbohydrate protection and deprotection reactions are
amenable to HBF4 catalysis; aqueous HBF4 and HBF4OEt2 are
complementary in these applications. Transacetalization with benzaldehyde dimethyl acetal and ethereal HBF4 gives a monobenzylidene product without disturbing the isopropylidene and trityl
groups of the substrate (eq 2). Aqueous HBF4 is useful in selective
deprotection reactions, cleaving a trityl group in the presence of
other acid-sensitive functionality (eq 3).7
362
(2)
(3)
Recently developed in solid-phase peptide synthesis is the use

of HBF4/thioanisole/m-cresol as a general deprotection reagent.
Most commonly used groups are cleaved from termini or side
chain functionality under mild conditions (1 M HBF4, 4 C, 30-60
min) in very high yields. Human glucagon (a 29 residue peptide)
has been synthesized as a demonstration of the effectiveness of
the method,8 which has been successful in both solid-phase and
solution-phase syntheses.9
General Acid Catalysis. HBF4 is a versatile acid catalyst
which is applicable to many typical acid-catalyzed reactions.
Some adducts obtained upon reaction of cyclopropyl phenyl sul
fide anion with carbonyl compounds can be rearranged to cyclobutanones under the catalytic influence of HBF4 (eq 4), although
different acids have been required for other substrates.10 Acidcatalyzed rearrangement of 2-cyclopropylphenyl phenyl ether or
sulfide with HBF4 has been reported (eq 5).11
Other catalytic applications of HBF4 include alkene

isomerizations,14 alkylation of alcohols with diazoalkanes,15
preparations of substituted pyridines,16 hydrolysis of hydroxyketene or -(methylthio)ketene thioacetals to a,punsaturated thioesters,17 and terpene formation from isoprenic
precursors.18
Preparation of Annulated Triazolones. Cyclization of the
isocyanate in eq 8 in the presence of HBF4 affords an oxotriazolium tetrafiuoroborate, which then rearranges to form
a 1,5-heteroannulated 1,2-dihydro-2-phenyl-3H-1,2,4-triazol-3one (eq 8).19
(8)
Carbenium Tetrafiuoroborate Preparation. 4,6,8-Trimethylazulene is converted by ethereal HBF4 into 4,6,8trimethylazulenium tetrafiuoroborate.20 A convenient preparation
of tropylium tetrafiuoroborate employs HBF4 to precipitate the
product from a solution of the double salt [C7H7]PCl6[C7H7]Cl
in ethanol (eq 9). An indefinitely stable, nonhygroscopic, and
nonexplosive white solid is obtained, a distinct advantage of a
fluoroborate salt.21
(4)
(9)
(5)
Z =S,O
Acid-catalyzed oxidation of epoxides with HBF4OMe2/
DMSO results in the formation of -hydroxy ketones (eq 6).12 This
procedure in an acidic medium complements the -hydroxylation
of ketone enolates under strongly basic conditions.
(6)
The formyl cation equivalent 1,3-benzodithiolylium tetrafiu

oroborate can be made in 94% yield by treatment of a
dithioorthoformate with HB 4 /Ac 2 O (eq 10).22 2-Deuterio-1,3benzothiolylium tetrafiuoroborate prepared by this method has
been used to produce 1-deuterioaldehydes by homologation.23 An
analogous preparation of a similar formyl cation equivalent, 1,3dithiolan-2-ylium tetrafiuoroborate, employs HBF4OEt2 (eq 11)
to provide the intermediate salt. Subsequent reaction with a silyl
enol ether forms a masked 2-formylcyclohexanone in high yield
(eq 11).
(10)
An intramolecular alkylation of a diazomethyl ketone was

achieved with catalysis by HBF4, providing an angularly fused
cyclopentanone hydrofluorene (eq 7).13
(7)
(11)
Ethynylfluorenylium dyes can be obtained by treatment of ap
propriate tertiary alcohols with HBF4 (eq 12).24
363
regard to their selectivity as alkylating agents. N-Acetyl-3,4dimethoxyphenethylamine undergoes selective aromatic substitu
tion, whereas the unprotected amine undergoes N,N-dialkylation
but not aromatic substitution (eq 15).34
(12)
(14)
In addition to the aforementioned carbenium ions and diazonium ions, numerous other organic cations can be obtained as
their fiuoroborate salts by treatment of appropriate precursors with
HBF4.25
Dimerization of Carbodiimides. Treatment of alkyl carbodiimides with anhydrous HBF4OEt2 in CH2Cl2 results in rapid
dimerization to tetrafluoroborate salts in 95% yield (eq 13). Basification converts the salts to diazetidines.26 In the same work, aryl
carbodiimides undergo a similar reaction, but substituted quinazolines are obtained.
(15)
(13)
Mercury(II) Oxide/Tetrafluoroboric Acid. Yellow Mercury(II) Oxide is added to 48% aqueous HBF4 to yield, upon
solvent removal, HgO2HBF4 as a hygroscopic white solid.27
This reagent is useful in applications involving mercuration of
alkenes, including diamination of alkenes and preparation of
trans-cinnamyl ethers from allylbenzene.28 Alkylations of carboxylic acids29 and alcohols30 with alkyl halides are also facil
itated by HgO2HBF4. Mercury(II) oxide and HBF4 in alcohol
effected mild solvolysis of 2-hydroxytrithioorthoesters to yield
-hydroxycarboxylic esters in high yield.31 See also Mercury(II)
Oxide-Tetrafiuoroboric Acid.
Preparation of a Useful Hypervalent Iodine Reagent. When
treated with HBF4OMe2 at low temperatures, Iodosylbenzene
reacts with silyl enol ethers to form a hypervalent iodine adduct
capable of useful carbon-carbon bond formation reactions with
alkenes (eq 14).32
Synthesis of Cationic Organometallic Complexes. TetrafluoroUbrate is frequently encountered as the counterion in
cationic organometallic compounds; its lack of nucleophilic re
activity makes HBF4 and its etherates ideal reagents for delivery
of protons without side reactions. The poorly coordinating conju
gate base of HBF4 allows substrates greater opportunity to bind
to metals in organometallic reactions requiring the presence of
acids.33
Propargylium complexes of cobalt, obtained by treatment of
propargylic alcohols with HBF4OEt2, have been studied with
Oxidation. In a reaction proposed as a model for substrate

reactions at metal-sulfur centers of enzymes, HBF4 apparently
functions as an oxidizing agent in a two-electron oxidation of a
ruthenium benzenedithiolate complex (eq 16).35
(16)
1. (a) Sudakova, T. N.; Krasnoshchekov, V. V. Zh. Neorg. Khim. 1978, 23,

1506. (b) Acidity relative to other strong acids: Bessiere, J. BSF 1969,
9, 3356.
2.
Ellis, R.; Henderson, R. A.; Hills, A.; Hughes, D. L. JOM 1987, 333,
C6.
3.
(a) Lichtenberg, D. W.; Wojcicki, A. JOM 1975, 94, 311. (b) Wudl, F.;
Kaplan, M. L. Inorg. Synth. 1979, 19, 27.
4.
Roe, A. OR 1949, 5, 193. See also: (a) Starkey, E. B. OSC 1943, 2, 225.
(b) Curtin, D. Y.; Ursprung, J. A. JOC 1956, 21, 1221. (c) Schiemann,
G.; Winkelmuller, W. OSC 1943, 2, 299.
5.
(a) Cohen, T.; Dietz, A. G., Jr.; Miser, J. R. JOC 1977, 42, 2053. (b)
Allmann, R.; Debaerdemaeker, T.; Grehn, W. CB 1974, 107, 1555.
6.
Albert, R.; Danklmaier, J.; Honig, H.; Kandolf, H. S 1987, 635.
7.
Albert, R.; Dax, K.; Pleschko, R.; Stutz, A. E. Carbohydr. Res. 1985,
137, 282.
364
N,N,N', N'-TETRAMETHYLETHYLENEDIAMINE
8.
Akaji, K.; Yoshida, M.; Tatsumi, T.; Kimura, T.; Fujiwara, Y.; Kiso, Y.
CC 1990, 288.
Kiso, Y.; Yoshida, M.; Tatsumi, T.; Kimura, T.; Fujiwara, Y.; Akaji, K.
CPB 1989, 37, 3432.
Trost, B. M.; Keeley, D. E.; Arndt, H. C ; Bogdanowicz, M. J. JACS
1977, 99, 3088.
Shabarov, Y. S.; Pisanova, E. V.; Saginova, L. G. ZOR 1980, 16, 418 (CA
1981,94,3819a).
Tsuji, T. BCJ 1989, 62, 645.
Ray, C ; Saha, B.; Ghatak, U. R. SC 1991, 21, 1223.
Powell, J. W.; Whiting, M. C. Proc. Chem. Soc. 1960, 412.
(a) Neeman, M.; Johnson, W. S. OS 1961, 41, 9. (b) Bruckner, R.;
Peiseler, B. TL 1988, 29, 5233.
(a) Schulz, W.; Pracejus, H.; Oehme, G. J. Mol. Catal. 1991, 66, 29. (b)
Kanemasa, S.; Asai, Y.; Tanaka, J. BCJ 1991, 64, 375.
Dieter, R. K.; Lin, Y. J.; Dieter, J. W. JOC 1984, 49, 3183.
Babin, D.; Fourneron, J.-D.; Julia, M. BSF(2) 1980, 588.
Gstasch, H.; Seil, P. S 1990, 1048.
(a) Hafner, K.; Pelster, H.; Schneider, J. LA 1961, 650, 62. (b) Hafner,
K.; Pelster, H.; Patzelt, H. LA 1961, 650, 80.
Conrow, K. OS 1963, 43, 101.
Nakayama, J.; Fujiwara, K.; Hoshino, M. CL 1975, 1099.
Nakayama, J. BCJ 1982, 55, 2289.
Nakatsuji, S.; Nakazumi, H.; Fukuma, H.; Yahiro, T.; Nakashima, K.;
Iyoda, M.; Akiyama, S. JCS(P1) 1991, 1881.
A few examples: (a) oxotriazolium: Gstasch, H.; Seil, P. 5 1990, 1048.
(b) pyridinium: Paley, M. S.; Meehan, E. J.; Smith, C. D.; Rosenberger,
F. E.; Howard, S. C ; Harris, J. M. JOC 1989, 54, 3432. (c) pyridinium:
Guibe-Jampel, E.; Wakselman, M. S 1977, 772. (d) tetrameric dication
from 2-aminobenzaldehyde: Skuratowicz, J. S.; Madden, I. L.; Busch,
D. H. IC 1977, 16, 1721. (e) tetrathiafulvenium: Wudl, F. JACS 1975, 97,
1962. Wudl, F.; Kaplan, M. L. Inorg. Synth. 1979, 19, 27. (f) sulfonium:
LaRochelle, R. W.; Trost, B. M. JACS 1971, 93, 6077. (g) diazetidinium:
Hartke, K.; Rossbach, F. AG(E) 1968, 7, 72.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26. Hartke, K.; Rossbach, F. AG(E) 1968, 7, 72.

27. Barluenga, J.; Alonso-Cires, L.; Asensio, G. S 1979, 962.
28. Barluenga, J.; Alonso-Cires, L.; Asensio, G. TL 1981, 22, 2239.
29. Barluenga, J.; Alonso-Cires, L.; Campos, P. J.; Asenio, G. S 1983, 649.
30. Barluenga, J.; Alonso-Cires, L.; Campos, P. J.; Asensio, G. T 1984, 40,
2563.
31. Scholz, D. SC 1982, 12, 527.
32. Zhdankin, V. V.; Tykwinski, R.; Caple, R.; Berglund, B.; Koz'min, A.
S.; Zefirov, N. S. TL 1988, 29, 3703.
33. Ellis, R.; Henderson, R. A.; Hills, A.; Hughes, D. L. JOM 1987, 333, C6.
Some other recent examples of the use of HBF4OEt2 in synthesis and/or
reactions of organometallics: (a) Field, J. S.; Haines, R. J.; Stewart, M.
W.; Sundermeyer, J.; Woollam, S. F. JCS(D) 1993, 947. (b) Dawson, D.
M.; Henderson, R. A.; Hills, A.; Hughes, D. L. JCS(D) 1992, 973. (c)
Lemos, M. A. N. D. A.; Pombeiro, A. J. L.; Hughes, D. L.; Richards,
R. L. JOM 1992, 434, C6. (d) Arliguie, T.; Chaudret, B.; Jalon, F. A.;
Otero, A.; Lopez, J. A.; Lahoz, F. J. OM 1991, 10, 1888. (e) Bassner, S.
L.; Sheridan, J. B.; Kelley, C ; Geoffrey, G. L. OM 1989, 8, 2121. For
use of HBF 4 OMe 2 : (a) Schrock, R. R.; Liu, A. H.; O'Regan, M. B.;
Finch, W. C ; Payack, J. F. IC 1988, 27, 3574. (b) Blagg, J.; Davies, S.
G.; Goodfellow, C. L.; Sutton, K. H. JCS(P1) 1987, 1805.
Gruselle, M.; Philomin, V.; Chaminant, F.; Jaouen, G.; Nicholas, K. M.
JOM 1990, 399, 317.
35. Sellmann, D.; Binker, G.; Knoch, F. ZN(B) 1987, 42, 1298.
36. Guibe-Jampel, E.; Wakselman, M. S 1977, 772.
N, N, N', N'-Tetramethylethylenediamine1
[110-18-9]
C 6 H 16 N 2
(MW 116.24)
(bidentate tertiary amine Lewis base with good solvating proper

ties; used as an additive to stabilize and activate organometallic
reagents and inorganic salts; enhances the rate of metalation of a
variety of aromatic and unsaturated systems as well as influenc
ing the regiochemical outcome of these reactions; effective as a
neutral amine in base catalyzed reactions)
Alternate Name: TMEDA.
Solubility: very sol water, most organic solvents.
Form Supplied in: colorless liquid, typically of 99% purity as
obtained commercially.
Drying: for uses in conjunction with organometallic reagents,
moisture exclusion is necessary. Removal of water is best
achieved by refluxing over lithium aluminum hydride or cal
cium hydride for 2 h under nitrogen and distilling immediately
prior to use.
Handling, Storage, and Precautions: TMEDA should be used di
rectly after distilling. However, it may be stored under nitrogen
and transferred by using a syringe and septum cap as required.
For most applications the amine is removed during aqueous
workup simply by washing with water owing to its high water
solubility. Use in a fume hood.
Lithiation of Difficult Substrates. TMEDA, through an erst
while perception of enhanced chelating ability,1b but more likely
through presentation of a more labile environment, activates
organolithium reagents.1j n-Butyllithium forms hexamers in hexane but in the presence of TMEDA exists as a solvated tetramer.2
Thus the use of the n-butyllithium/TMEDA complex in hexane3
effects the dilithiation of Furan and thiophene,4 and lithiation of
benzene,5 in high yields. The allylic deprotonation of unactivated
alkenes is normally difficult to achieve with BuLi alone. However,
in the presence of TMEDA, propene is monolithiated or dilithiated in the allylic position,6 and limonene is selectively lithiated
at C-10.7 The resulting allylic carbanion and electrophiles such as
Paraformaldehyde give functionalized products (eq 1).8
(1)
34.
However, when vinylic metalation is desired, competing al

lylic
deprotonation may occur. In general, thermodynamic acid
Gregory K. Friestad & Bruce P. Branchaud
ity
and
the kinetic preference for vinylic deprotonation of cyclic
University of Oregon, Eugene, OR, USA
alkenes decrease with increasing ring size.1h The stable alkanesoluble reagent n-Butyllithium-Potassium t-Butoxide-TMEDA
in hexane9 metalates Ethylene with potassium10 and effects selec-
N,N,N',N'-TETRAMETHYLETHYLENEDIAMINE
11
365
12
tive vinylic deprotonation of cyclopentene (eq 2), cyclobutene,

norbomene, and norbornadiene.10
(2)
(6)
N-Alkyl- andN-arylpyrrolesare readily -lithiated.1c For exam

ple, N-methylpyrrole is deprotonated with Ethyllithium/TMEDA
and the lithiated product has been treated with Carbon Dioxide to
give the corresponding carboxylic acid in 70% yield (eq 3).13
(3)
Numerous examples exist in which TMEDA not only facilitates

the lithiation of aromatic and heteroaromatic substrates but also
controls the regioselectivity of lithiation.1c While tertiary benzamides are susceptible to nucleophilic attack by n-butyllithium
to give aryl butyl ketones, the use of s-Butyllithium/TMEDA in
THF at 78 C provides the synthetically useful ortho metalated
tertiary benzamide which may be treated with a large variety of
electrophiles (eq 4).1d,14 Even with compounds having a second
more acidic site the above conditions allow ortho lithiation to take
place under kinetic control. Thus a p-toluamide is ortho lithiated
with s-butyllithium/TMEDA in THF at -78 C, but when Lithium
Diisopropylamide is used as the base in THF at 0 C the thermodynamically favored benzyllithium species is obtained (eq 5).15 The
very marked influence of TMEDA on the lithiation of naphthyl
methyl ether in hydrocarbon solvents is dramatically illustrated in
the example in eq 6.16
(4)
EX = D2O, Mel, DMF, CO2, (CO2Et)2, ArCHO, I2, TMSCl,

B(OMe)3/H2O2, PhNCO, Ph2CO
(5)
R = Bu, hexane/TMEDA
R = t-Bu, cyclohexane
>99.3:<0.3 60%
1:99 35%
The use of the s-butyllithium/TMEDA system in THF at -78 C

is widely employed for the lithiation of amide and thioamide
derivatives adjacent to nitrogen.1f The resulting lithiated species
undergo reaction with a variety of electrophiles such as aldehydes
and ketones17a and dihalides (eq 7).17b
(7)
Ligand for Crystallographic Studies. TMEDA markedly fa

cilitates the isolation of otherwise inaccessible crystalline organolithium reagents suitable for structural determination by X-ray
crystallographic means.18 In most cases, bidentate binding of the
TMEDA ligand to the lithium ion is observed.
Control of Regioselectivity and Stereoselectivity. The recog
nition by Ireland and co-workers19 that Hexamethylphosphoric
Triamide has a profound effect on the stereochemistry of lithium
enolates has led to the examination of the effects of other addi
tives, as the ability to control enolate stereochemistry is of ut
most importance for the stereochemical outcome of aldol reac
tions. Kinetic deprotonation of 3-pentanone with Lithium 2,2,6,6Tetramethylpiperidide at 0 C in THF containing varying amounts
of HMPA or TMEDA was found to give predominantly the (Z)enolate at a base:ketone:additive ratio of ca. 1:1:1, whereas with a
base:ketone:additive ratio 1:0.25:1, formation of the (E)-enolate
was favored (Table 1).20 This remarkable result contrasts with
those cases where HMPA:base ratios were varied towards larger
amounts of HMPA, which favored formation of the (Z)-enolate.21
However, TMEDA unlike HMPA, does not cause flow over
from a carbonyl to conjugate addition manifold for many lithiated
systems. For example, lithiated allylic sulfides undergo conjugate
(or ' 1,4') addition to cyclopent-2-enone in the presence of HMPA
(see Allyl Phenyl Sulfide), but in the presence of TMEDA, car
bonyl addition only is observed.22 The perception that TMEDA
is unable to form solvent-separated ion pairs required for conju
gate addition in this case now requires reevaluation.1j,23 In the
reaction of lithio -trimethylsilylmethyl phenyl sulfide with cyclohexenone, HMPA promotes predominant conjugate addition,
whereas TMEDA has little effect on the normal carbonyl addition
pathway taken in THF alone (eq 8).24
366
Table 1 Deprotonation of 3-Pentanone with LiTMP (1.0 mmol) in THF at 0 C in the Presence of TMEDA or HMPA19
3-Pentanone
(mmol)
0.9
0.45
0.25
0.9
0.45
0.25
TMEDA (mmol)
HMPA (mmol)
(E)-Enolate
(Z)-Enolate
Total % yield of silyl

enol ether derivatives
1.0
1.0
1.0
_
-
1.0
1.0
1.0
17
91
95
8
65
66
83
9
5
92
35
34
70
90
70
89
75
80
(8)
Likewise, TMEDA in THF has little effect on the stereo

chemical outcome of the Horner-Wittig reaction of lithiated
ethyldiphenylphosphine oxide with benzaldehyde in THF at low
temperature compared to the reaction in THF alone: a very slight
enhancement in favor of the erythro (anti) hydroxy phosphine ox
ide intermediate (erythro:threo from 85:15 to 88:12), thus leading
to slightly enhanced (Z)-alkene formation, is observed. By con
trast, a reaction in ether alone provides less of the erythro prod
uct (erytho:threo 60:40). 25 These examples serve to emphasize
current thought that TMEDA is not a 'good' chelating agent for
lithium in relation to THF itself.1j It is noteworthy that the substi
tution of methyl in TMEDA by chiral binaphthylmethyl ligands
generates a reagent which efficiently catalyzes asymmetric addi
tion of butyllithium to benzaldehyde in ether at low temperature
(eq 9). 26
Stabilization and Activation of Organometallic Reagents.

The development and use of organocopper reagents as nucleophiles in the conjugate addition to enones is an important area
of organic synthesis. It has been found that the reactivity of aryland alkylcopper reagents is dramatically improved through the
use of Chlorotrimethylsilane and TMEDA. 29 The TMEDA not
only stabilizes and solubilizes the organocopper reagent but also
facilitates the trapping of the resulting enolates, thereby affording
silyl enol ethers in excellent yields.29a Such a role is also played
by HMPA30 and 4-Dimethylaminopyridine 30b However, the low
toxicity and cost of TMEDA makes it an attractive alternative.
Conjugate addition of Lithium Di-n-butylcuprate to methyl 2butynoate in diethyl ether provides a 74:26 mixture of (E)- and
(Z)-alkylated enoates, whereas in the presence of TMEDA this
ratio increases to 97:3. Stereoselectivity of the conjugate addition
of the copper reagent derived from butylmagnesium bromide and
Copper(I) Iodide to ethyl pentynoate in diethyl ether is also en
hanced when TMEDA or pyrrolidone are used as additives, to give
the (E)- and (Z)-enoates in a ratio of 99:1. In contrast, the use of
HMPA affords a selectivity of only 78:22 for the (E)-isomer.31
The preparation of a trifluoromethylvinyl anion equivalent has
been described in which the vinyl bromide is converted into the
zinc reagent with Zinc/Silver Couple in the presence of TMEDA.
The conversion proceeds very cleanly to afford a thermally stable
vinylzinc bromide-TMEDA complex which can undergo reac
tions with electrophiles. TMEDA is essential for the conversion
(eq 10).32
(10)
(9)
Butylmagnesium bromide in THF in the presence of excess

TMEDA undergoes addition to a chiral crotonamide derivative to
give the conjugate adduct in modest diastereomeric excess (67%)
compared with 16% in the absence of TMEDA. 27 On the other
hand, diastereoselection in the alkylation of enolates of chiral diamides derived from piperazines in THF containing TMEDA was
minimal, with better results being provided by HMPA.28
The intramolecular insertion of unactivated alkenes into

carbon-lithium bonds to give cycloalkylmethyllithium com
pounds provides a high-yielding alternative to analogous radical
cyclizations. 1g,33 In many cases the addition of Lewis bases such
as TMEDA increases the rate of cyclization 1g,33 and dramatically
improves those cyclizations which are otherwise sluggish at room
temperature (eq 11). 34
Open chain allylic alcohols add organolithium reagents in the
presence of TMEDA. The reactions are regio- and stereoselective;
the suggestion is made that the TMEDA complexes the alkoxide
lithium counterion, allowing the alkoxide to orientate the incom
ing organolithium reagent and stabilize the resulting intermediate
(eq 12).35
367
42
(eq 14). In this case the relative mildness of the reaction condi
tions prevents subsequent elimination of t-butoxide from occur
ring to give the unwanted enone.
(11)
TMEDA (2 equiv)
no TMEDA
68%
6%
31%
93%
(12)
(13)
threo:erytho = >50:1
TMEDA 98:2
i-Pr2NEt 94:6
Inorganic Complexes useful in Organometallic Reactions

and Organic Synthesis. The complexing properties of TMEDA
have made it possible to prepare and handle salts which are other
wise air and moisture sensitive. Thus Zinc Chloride in the pres
ence of one equivalent of TMEDA forms a crystalline air sta
ble solid, ZnCl2TMEDA,36 which with three equivalents of an
alkyllithium reagent is converted into trialkylzinclithium. Like
wise, Cul and TMEDA react to form the CuITMEDA complex,29
a stable solid which is used for the preparation of stabilized
organocopper reagents. The rate of CuI-catalyzed oxidative cou
pling of terminal alkynes in the presence of oxygen to form
diynes is considerably increased by using TMEDA as a solubilizing agent for Copper(I) Chloride.37 Magnesium hydride,
rapidly acquiring widespread recognition as a versatile reduc
ing agent (see Magnesium Hydride-Copper(I) Iodide), is pre
pared from phenylsilane and Dibutylmagnesium in the presence
of TMEDA to give a very active THF-soluble complex free
of halide or impurities derived from the usual reducing agents
such as Lithium Aluminum Hydride.38 TMEDA (see also 1,4Diazabicyclo[2.2.2]octane) forms insoluble adducts with boranes
and alanes. In particular, the formation of air-stable adducts with
monoalkyl boranes is of synthetic usefulness. The free monoalkyl
borane may be regenerated by treating the adduct with Boron
Trifluoride Etherate in THF and filtering off the newly formed
TMEDA2BF3 precipitate.1e
Base Catalyzed Reactions. TMEDA can be monoprotonated
(pKa 8.97) and diprotonated (pKa 5.85).39 Titanium enolate forma
tion from ketones and acid derivatives has been achieved by using
Titanium(IV) Chloride and tertiary amines including TMEDA in
dichloromethane at 0 C.40 The reactive species, which is likely
to be a complex with the tertiary amine, undergoes aldol reaction
with aldehydes to form syn adducts with high stereoselectivity
(eq 13).
In the case of TMEDA, stereoselection in favor of the syn
product (98:2) is enhanced over that achieved with Diisopropylethylamine (94:6).40 Along with bases such as Triethylamine and ethylisopropylamine, TMEDA facilitates the prepa
ration of cyanohydrin trimethylsilyl ethers from aldehydes and
Cyanotrimethylsilane .41 It has been suggested that coordination
by nitrogen induces formation of an active hypervalent cyanation intermediate from cyanotrimethylsilane. The conjugate addi
tion of thiols to enones has been successfully catalyzed by using
TMEDA in methanol at room temperature, as exemplified by the
reaction of 10-mercaptoisoborneol and 4-t-butoxycyclopentenone
(14)
Related Reagents. Hexamethylphosphoric Triamide; N,N,

N',N'',N''-Pentamethyldiethylenetriamine; Potassium Hydrides-Butyllithium-N,N,N',N'-Tetramethylethylenediamine;
()Sparteine.
1. (a) Agami, C. BSF(2) 1970, 1619. (b) Wakefield, B. J. The Chemistry

of Organolithium Compounds; Pergamon: Oxford, 1974. (c) Gschwend,
H. W.; Rodriguez, H. R. OR 1979, 26, 1. (d) Beak, P.; Snieckus, V.
ACR 1982, 15, 306. (e) Singaram, B.; Pai, G. G. H 1982, 18, 387. (f)
Beak, P.; Zajdel, W. J.; Reitz, D. B. CRV 1984, 84, 471. (g) Klumpp,
G. W. RTC 1986, 105, 1. (h) Brandsma, L.; Verkruijsse, H. Preparative
Polar Organometallic Chemistry 1; Springer: Berlin, 1987. (i) Advances
in Carbanion Chemistry; Snieckus, V., Ed.; JAI: Greenwich, CT, 1992;
Vol. 1. (j) For a review and critical analysis of TMEDA complexation to
lithium, see: Collum, D. B. ACR 1992, 25, 448.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
Lewis, H. L.; Brown, T. L. JACS 1970, 92, 4664.

Peterson, D. J. JOC 1967, 32, 1717.
Chadwick, D. J.; Willbe, C. JCS(P1) 1977, 887.
Eberhardt, G. G.; Butte, W. A. JOC 1964, 29, 2928. Rausch, M. D.;
Ciappenelli, D. J. JOM 1967, 10, 127.
Klein, J.; Medlik-Balan, A. CC 1975, 877.
Crawford, R. J.; Erman, W. F.; Broaddus, C. D. JACS 1972, 94, 4298.
Crawford, R. J. JOC 1972, 37, 3543.
Schade, C.; Bauer, W.; Schleyer, P. v. R. JOM 1985, 295, C25.
Brandsma, L.; Verkruijsse, H. D.; Schade, C.; Schleyer, P. v. R. CC 1986,
260.
Broaddus, C. D.; Muck, D. L. JACS 1967, 89, 6533.
Sthle, M.; Lehmann, R.; Kramar, J.; Schlosser, M. C 1985, 39, 229.
Gjs, N.; Gronowitz, S. ACS 1971, 25, 2596.
Beak, P.; Brown, R. A. JOC 1977, 42, 1823.
Beak, P.; Brown, R. A. JOC 1982, 47, 34.
Shirley, D. A.; Cheng, C. F. JOM 1969, 20, 251.
(a) Reitz, D. B.; Beak, P.; Tse, A. JOC 1981, 46, 4316. Beak, P.; Zajdel,
W. J. JACS 1984, 106, 1010. (b) Lubosch, W.; Seebach, D. HCA 1980,
63, 102.
368
18.
1,1'-THIOCARBONYLDIIMIDAZOLE
Seebach, D. AG(E) 1988, 27, 1624. Boche, G. AG(E) 1989, 28, 277;
Zarges, W.; Marsch, M.; Harms, K.; Koch, W.; Frenking, G.; Boche, G.
CB 1991, 124, 543.
Ireland, R. E.; Mueller, R. H.; Willard, A. K. JACS 1976, PS, 2868.
Fataftah, Z. A.; Kopka, I. E.; Rathke, M. W. JACS 1980,102, 3959.
Romesberg, F. E.; Gilchrist, J. H.; Harrison, A. T.; Fuller, D. J.; Collum,
D. B. JACS 1991, 113, 5751.
Binns, M. R.; Haynes, R. K.; Houston, T. L.; Jackson, W. R. TL 1980,
21, 573.
Cohen, T.; Abraham, W. D.; Myers, M. JACS 1987, 709, 7923. Binns,
M. R.; Haynes, R. K.; Katsifis, A. G.; Schober, P. A.; Vonwiller, S. C.
JOC 1989, 54, 1960.
Ager, D. J.; East, M. B. JOC 1986, 51, 3983.
19.
20.
21.
22.
23.
24.
25.
Buss, A. D.; Warren, S. TL 1983, 24, 3931.
26.
Mazaleyrat, J.-P.; Cram, D. J. JACS 1981, 103, 4585; Maigrot, N.;

Mazaleyrat, J.-P. CC 1985, 508.
Soai, K.; Machida, H.; Yokota, N. JCS(P1) 1987, 1909.
Soai, K.; Hayashi, H.; Shinozaki, A.; Umebayashi, H.; Yamada, Y. BCJ
1987, 60, 3450.
(a) Johnson, C. R.; Marren, T. J. TL 1987, 28, 27. (b) Van Heerden, P.
S.; Bezuidenhoudt, B. C. B.; Steenkamp, J. A.; Ferreira, D. TL 1992, 33,
2383 and cited references.
(a) Horiguchi, Y.; Matsuzawa, S.; Nakamura, E.; Kuwajima, I. TL 1986,
27, 4025. (b). Nakamura, E.; Matsuzawa, S.; Horiguchi, Y.; Kuwajima,
I. TL 1986, 27, 4029.
27.
28.
29.
30.
31.
Anderson, R. J.; Corbin, V. L.; Cotterrell, G.; Cox, G. R.; Henrick, C.

A.; Schaub, F.; Siddall, J. B. JACS 1975, 97, 1197.
32.
33.
Jiang, B.; Xu, Y. JOC 1991, 56, 7336.

Bailey, W. F.; Khanolkar, A. D.; Gavaskar, K.; Ovaska, T. V.; Rossi, K.;
Thiel, Y.; Wiberg, K. B. JACS 1991, 113, 5720.
Bailey, W. F.; Nurmi, T. T.; Patricia, J. T.; Wang, W. JACS 1987, 109,
2442.
Felkin, H.; Swierczewski, G.; Tambut, A. TL 1969, 707.
Watson, R. A.; Kjonaas, R. A. TL 1986, 27, 1437. Isobe, M.; Kondo, S.;
Nagasawa, N.; Goto, T. CL 1977, 679.
Hay, A. S. JOC 1962, 27, 3320. Jones, G. E.; Kendrick, D. A.; Holmes,
A. B. OS 1987, 65, 52.
Michalczyk, M. J. OM 1992, 11, 2307.
Spialter, L.; Moshier, R. W. JACS 1957, 79, 5955.
Evans, D. A.; Rieger, D. L.; Bilodeau, M. X; Urpi, F. JACS 1991, 113,
1047.
Kobayashi, S.; Tsuchiya, Y.; Mukaiyama, T. CL 1991, 537.
Eschler, B. M.; Haynes, R. K.; Ironside, M. D.; Kremmydas, S.; Ridley,
D. D.; Hambley, T. W. JOC 1991, 56, 4760.
34.
35.
36.
37.
38.
39.
40.
41.
42.
Hong Kong University
Richard K. Haynes
of Science and Technology, Hong Kong
The University
1,1'-Thiocarbonyldiimidazole1
[6160-65-2]
C7H6N4S
(MW 178.24)
(conversion of vicinal diols to alkenes;1 deoxygenation of

alcohols;13 thiocarbonyl transfer agent29)
Alternate Name: TCDI.
Physical Data: mp 101-103C.
Solubility: sol many organic solvents including THF, CH2Cl2,
toluene.
Form Supplied in: yellow solid; 90% pure or >97% pure.
Preparative Methods: prepared by the reaction of Thiophosgene
with 2 equiv of Imidazole.
Purification: can be recrystallized from THF to give yellow crys
tals; can also be sublimed.
Handling, Storage, and Precautions: very hygroscopic; should be
reacted and stored in a dry atmosphere.
Alkene Synthesis. The Corey-Winter alkene synthesis is an

effective method for the deoxygenation of vicinal diols.1,2 The
method involves formation of a 1,3-dioxolane-2-thione [cyclic
thionocarbonate (or thiocarbonate)] by treatment of a vicinal diol
with TCDI. Decomposition of the thionocarbonate, usually with a
phosphorus compound, affords the alkene (eq 1 ).3 The breakdown
of the thionocarbonate occurs in a stereospecific sense; details of
investigations into the mechanism have been summarized.1
(1)
Simone C. Vonwiller
of Sydney, NSW, Australia
The conditions required for the introduction of the thio

carbonyl group vary greatly, depending on the structure
of the diol.1,4 The thionocarbonate may also be pre
pared without TCDI. The reaction of vicinal diols with
thiophosgene/DMAP/CH2Cl2/0 C,5 with base/CS2/MeI/heat,1 or
with 1,1'-thiocarbonyl-2,2'-pyridone/toluene/110C6 also pro
vides thionocarbonates. Along with phosphines and phosphites,
other reagents can decompose the thionocarbonates, but not al
ways in a stereospecific manner. The Corey-Hopkins reagent 1,3dimethyl-2-phenyl-1,3,2-diazaphospholidine,5 along with Raney
1,1'-THI0CARB0NYLDIIMIDAZ0LE
369
Nickef and Bis(1,5-cyclooctadiene)nickel(0), affords products

of stereospecific cis-elimination, while the alkyl iodide/Zinc
combination9 and Pentacarbonyliron10 yield products of nonstereospecific elimination or unknown stereochemistry.
The Corey-Winter synthesis has proved useful for the genera
tion of a large number of structurally interesting alkenes,1 includ
ing some unstable alkenes that must be captured in situ (eq 2).4
(2)
The method has found its niche in the chemistry of sugars.

Their polyhydroxylated nature make them excellent substrates
provided the by-standing hydroxyls are protected (eq 3).11 The
2'- and 3'-oxygens of nucleosides are readily are removed under
the Corey-Winter conditions.12
(5)
The mechanism of the radical attack at the thiocarbonyl group

and the ensuing breakdown has been outlined elsewhere.13,14
Some groups have studied the comparative chemistries of the
possible thiocarbonyl derivatives, with no particularly obvious
trends arising.13,16,17 There are numerous reports of the deoxy
genation of carbohydrates13,16,18 and related polyhydroxylated
species.14,17,19,20 In one instance of amino glycoside deoxygena
tion, the C(3')-OH group can be selectively functionalized with
TCDI, while the C(5)-OH group is unaffected and the radical
reduction proceeds without protection of the C(5)-OH group
(eq 6).20
(3)
(6)
Radical Chemistry. Treatment of secondary alcohols with 1

equiv of TCDI affords an imidazole-1-thiocarbonyl derivative
(imidazolide), which can be reduced to a CH2 unit under Tri-nbutylstannane (TBTH) radical chain reaction conditions.13,14 The
deoxygenation of secondary alcohols by way of an imidazolide
or other thiocarbonyl derivative is called the Barton-McCombie
reaction (eq 4).6,14 Since imidazolide formation (TCDI, reflux,
65 C) and the subsequent radical chemistry are done under neu
tral or near-neutral conditions, the overall reduction is tolerant of
the presence of many sorts of functional groups. Furthermore, the
low solvation requirements of radical species permits deoxygena
tion in sterically congested environments (eq 5).15
Reduction of tertiary alcohols is not recommended due to the

instability of the tertiary imidazolide, although, as an alternative,
a thioformaldehyde version has been developed.21 Imidazolides
from primary alcohols do not respond well to the same conditions
as the secondary systems, but performing the radical chemistry at
130-150 C can lead to deoxygenation.22 As an alternative to the
high-temperature radical chemistry, the imidazolide can be con
verted by methanolysis to a thiocarbonate which can be reduced
at room temperature (Et3B, TBTH, benzene).23 Tin hydride treat
ment of thionocarbonates derived from primary/secondary diols
affords, after base exposure, the product of selective reduction of
the secondary site, leaving the primary hydroxyl (eq 7).14,24 The
approach has also been successfully applied to 1,3-diols.24,25
(7)
(4)
Since the reduction method proceeds via radical chemistry, the

intermediate radicals are prone to bimolecular chemistry and unimolecular reactions such as rearrangements or -scission, if suitAvoid Skin Contact with All Reagents
370
THIONYL CHLORIDE
able functionality is proximal.14 Indeed, the imidazolides have

been employed as radical precursors when rearrangement is the
desired result.14
Thiocarbonyl Transfer. While virtually all uses of TCDI in
volve a thiocarbonyl transfer reaction, this section covers those
uses of the thiocarbonyl transfer that do not lead to radical chem
istry or alkene syntheses. TCDI has been used for the simple place
ment of a thiocarbonyl group between two nucleophilic atoms of
one26 or two molecules.27 An alcohol which has been converted to
an imidazolide is a reactive functionality for coupling reactions,28
for sigmatropic rearrangements,29 and for elimination (eq 8).30
The TCDI alternative 1,1'-thiocarbonyl-2,2'-pyridone6 seems to
be an excellent thiocarbonyl transfer agent.
(8)
Related Reagents. Carbon Disulfide; N,N-Dimethylformamide Diethyl Acetal; N-Hydroxypyridine-2-thione; Phenyl

Chlorothionocarbonate; Triethyl Orthoformate.
1. Block, E. OR 1984, 30, 457.

2. Corey, E. J.; and Winter, R. A. E. JACS 1963, 85, 2677.
3.
Koreeda, M.; Koizumi, N.; Teicher, B. A. CC 1976, 1035.
4.
Greenhouse, R.; Borden, W. T.; Ravindranathan, T.; Hirotsu, K.; Clardy,

J. JACS 1977, 99, 6955.
Corey, E. J.; Hopkins, P. B. TL 1982, 23, 1979.
5.
6. Kim, S.; Yi, K. Y. JOC 1986, 51, 2613.

7. Ireland, R. E.; Anderson, R. C ; Badoud, R.; Fitzsimmons, B. J.;
McGarvey, G. J.; Thaisrivongs, S.; Wilcox, C. S. JACS 1983, 105, 1988.
8.
9.
Semmelhack, M. F.; Stauffer, R. D. TL 1973, 2667.

Vedejs, E.; Wu, E. S. C. JOC 1974, 39, 3641.
10. Daub, J.; Trautz, V.; Erhardt, U. TL 1972, 4435.

11. (a) Akiyama, T.; Shima, H.; Ozaki, S. TL 1991, 32, 5593. (b) Horton,
D.; Turner, W. N. TL 1964, 2531.
12. Manchand, P. S.; Belica, P. S.; Holman, M. J.; Huang, T.-N.; Maehr, H.;
Tam, S. Y.-K.; Yang, R. T. JOC 1992, 57, 3473.
13. Barton, D. H. R.; McCombie, S. W. JCS(P1) 1975, 1574.
14. (a) McCombie, S. W. COS 1991, 8, 811. (b) Hartwig, W. T 1983, 39,
2609. (c) Crich, D.; Quintero, L. CRV 1989, 89, 1413.
15. Corey, E. J.; Ghosh, A. K. TL 1988, 29, 3205.
16. Rasmussen, J. R.; Slinger, C. J.; Kordish, R. J.; Newman-Evans, D. D.
JOC 1981, 46, 4843.
24.
Barton, D. H. R.; Subramanian, R. JCS(P1) 1977, 1718.
25.
(a) Mubarak, A. M.; Brown, D. M. TL 1981, 22, 683. (b) Suzuki, M.;
Yanagisawa, A.; Noyori, R. TL 1984, 25, 1383.
26.
Chiang, L.-Y., Shu, P.; Holt, D.; Cowan, D. JOC 1983, 48, 4713.
27.
Sugimoto, H.; Makino, L; Hirai, K. JOC 1988, 53, 2263.
28.
Ley, S. V.; Armstrong, A.; Diez-Martin, D.; Ford, M. J.; Grice, P.; Knight,
J. G.; Kolb, H. C ; Madin, A.; Marby, C. A.; Mukherjee, S.; Shaw, A.
N.; Slawin, A. M. Z.; Vile, S.; White, A. D.; Williams, D. J.; Woods, M.
JCS(P1) 1991, 667.
29.
Nicolaou, K. C ; Groneberg, R. D.; Miyazaki, T.; Stylianides, N. A.;

Schulze, T. J.; Stahl, W. JACS 1990, 772, 8193.
30.
Ge, Y.; Isoe, S. CL 1992, 139.
Adrian L. Schwan
University of Guelph, Ontario, Canada
Thionyl Chloride 1
[7719-09-7]
(MW 118.97)
Cl2OS
(chlorination of alcohols,2 carboxylic acids,3 and sulfonic acids;4

dehydration of amides;5 formation of imidoyl chlorides,6 sulfurcontaining heterocycles,7 and the Vilsmeier reagent)
Physical Data: 8 bp 76C; d 1.631 g cm - 3 .
Solubility: sol ethers, hydrocarbons, halogenated hydrocarbons;
reacts with water, protic solvents, DMF, DMSO.
Form Supplied in: colorless to yellow liquid.
Purification: impurities cause formation of yellow or red colors.
Iron contamination can cause a black color. Fractional distilla
tion, either directly9 or from triphenyl phosphite10 or quinoline
and linseed oil,11 has been recommended.
Handling, Storage, and Precautions: very corrosive and reac
tive; the vapor and liquid are irritating to the eyes, mucous
membranes, and skin. Protective gloves should be worn when
handling to avoid skin contact. Thionyl chloride should be
stored in glass containers at ambient temperature and pro
tected from moisture. It reacts with water to liberate the toxic
gases HCl and SO2. Since most reactions using SOCl2 evolve
these gases, they should be performed only in well-ventilated
hoods. Above 140C, SOCl2 decomposes to Cl2, SO2, and
S2Cl2. Iron and/or zinc contamination may cause catastrophic
decomposition.12
17. Robins, M. J.; Wilson, J. S.; Hansske, F. JACS 1983, 705, 4059.
18. Lin, T.-H.; Kov, P.; Glaudemans, C. P. J. Carbohydr. Res. 1989, 188,
228.
19. Piccirilli, J. A.; Krauch, T.; MacPherson, L. J.; Benner, S. A. HCA 1991,
74, 397.
20.
21.
22.
23.
Carney, R. E.; McAlpine, J. B.; Jackson, M.; Stanaszek, R. S.; Washburn,

W. H.; Cirovic, M.; Mueller, S. L. J. Antibiot. 1978, 31, 441.
Barton, D. H. R.; Hartwig, W.; Hay Motherwell, R. S.; Motherwell, W.
B.; Stange, A. TL 1982, 23, 2019.
Barton, D. H. R.; Motherwell, W. B.; Stange, A. S 1981, 743.
Chu, C. K.; Ullas, G. V.; Jeong, L. S.; Ahn, S. K.; Doboszewski, B.; Lin,
Z. X.; Beach, J. W.; Schinazi, R. F. JMC 1990, 33, 1553.
Chlorides from Alcohols. Thionyl chloride reacts with pri

mary, secondary, and tertiary alcohols to form chlorosulfite esters
(eq 1) which can be isolated.13 The fate of these esters depends
on the reaction conditions, especially the stoichiometry, solvent,
and base. If 2 equiv of alcohol and pyridine are used relative to
thionyl chloride, dialkyl sulfites may be isolated (eq 2).14
ROH + SOCl2
ROSOCl
+ HCl
(1)
(2)
THIONYL CHLORIDE
When thionyl chloride is in excess, or when alkyl chlorosulfites

are treated with thionyl chloride,15 alkyl chlorides are produced
and the byproducts are HC1 and SO2. The mechanism of this re
action may be S N 1, S N 2, SNi, or SN2' (with allylic or propargylic
alcohols). In the absence of base the SNi mechanism operates; re
tention of configuration is observed in the alkyl chloride (eq 3).16
Considerable ionic character may be involved in this process and
small amounts of elimination or rearrangement are common as
side reactions.17
371
such as succinic acid proceeds completely to the diacid chloride

rather than stopping at the anhydride.31 The preparation of aro
matic acid chlorides also commonly uses pyridine as a catalyst
(eq 6).32 Trichloroacetic acid, which is unreactive toward thionyl
chloride alone, is chlorinated by the use of pyridine catalyst.33
(5)
(3)
(6)
Thus, simple heating of the alcohol with thionyl chloride alone

is often the preferred method for retaining the configuration of the
alcohol in the chloride. Alternatively, use of amine bases, most
commonly Pyridine,18 results in a shift in the mechanism to S N 2
(eq 4) and consequently overall inversion. Excess pyridine may
cause dehydrochlorination or alkylation of the base. If inversion
of the substrate is desired or the stereochemical outcome need
not be controlled, the use of pyridine or other amine base is rec
ommended since the resulting high chloride concentrations min
imize rearrangements and eliminations.19,17a Alternatively, catal
ysis of the chlorination by Hexamethylphosphoric Triamide re
sults in inversion.20 With allylic substrates, rearranged products
generally predominate, especially in nonpolar solvents.21 Use of
Tri-n-butylamine as the base can result in unrearranged allylic
products.22
(4)
Representative procedures are available for the chlorina

tion of tetrahydrofurfuryl alcohol,23 benzoin,24 and ethyl
mandelate.25 The use of thionyl chloride for this transforma
tion usually gives less rearrangement and elimination than conc
HCl, PCl3, or PCl5. For compounds which are acid-sensitive,
Triphenylphosphine-Carbon Tetrachloride may be used.
Carboxylic Acid Chlorides from Acids. Thionyl chloride has
been the most widely used reagent for the preparation of acid chlo
rides. Carboxylic anhydrides also react with SOCl2, giving 2 equiv
of the acid chloride.26 The procedure normally involves heating
the carboxylic acid with a slight to large excess of SOCl2 in an
inert solvent or with SOCl2 itself as the solvent. Operation at the
boiling point of the solvent speeds removal of the byproducts,
HC1 and SO2. The ease of removal of the byproducts is the chief
advantage of SOCl2 over PCl5 and PCl3. This simple procedure
gives good yields of the acid chlorides of butyric,27 cinnamic,28
and adipic acid.29 The reactions are first order in each reactant and
electron-withdrawing groups on the acid decrease the rate.30 Sev
eral agents have been developed for the catalysis of this reaction.
Pyridine was historically the most common; its presumed mode of
action is to ensure the presence of soluble chloride (as Pyridinium
Chloride) which reacts with the intermediate as shown in eq 5.
Catalytic pyridine ensures that the chlorination of certain diacids
N,N-Dimethylformamide is a particularly effective catalyst for

the formation of acid chlorides with SOCl2 and is now com
monly the catalyst of choice.34 The chloromethyleneiminium
chloride intermediate is the active chlorinating species (see
Dimethylchloromethyleneammonium Chloride).
Esters of amino acids may be produced directly from the amino
acid, alcohol, and thionyl chloride. One procedure involves the
sequential addition of thionyl chloride and then the acid to chilled
methanol.35 Alternatively, benzyl esters have been prepared by
the slow addition of SOCl2 to a suspension of the amino acid in
benzyl alcohol at 5 C.36
For the formation of acid chlorides, the competing reactions of
concern are -oxidation and acid-catalyzed degradation. The use
of solid Sodium Carbonate in the reaction mixture can minimize
the latter for some compounds.37 As shown in eq 7, even simple
carboxylic acids with enolizable hydrogens to the carboxylic
functionality are subject to oxidation under standard chlorinating
conditions.38 Since the unoxidized acid chloride is the precursor
to the sulfenyl chloride, careful attention to stoichiometry and
reaction time can effectively minimize this problem.
(7)
Sulfonyl and Sulfinyl Chlorides from Sulfonic and Sulflnic

Acids. Alkyl or arylsulfonyl chlorides are prepared by heating
the acid with thionyl chloride; DMF catalyzes this reaction. (+)Camphorsulfonyl chloride is produced in 99% yield without a
catalyst.39 Use of the salts of sulflnic acids minimizes their oxida
tion; p-toluenesulfinyl chloride is produced in about 70% yield
from sodium p-toluenesulfinate dihydrate with excess thionyl
chloride.40 Phosphorus(V) Chloride is more commonly used for
this transformation.
Nitriles and Isocyanides via Amide Dehydration. Thionyl
chloride dehydrates primary amides to form nitriles (eq 8); for
example, 2-ethylhexanonitrile is produced in about 90% yield by
heating with SOCl2 in benzene.41 Substituted benzonitriles are
readily produced from benzamides.42 These reactions may also
be catalyzed by DMF.43 N-Alkylformamides may be dehydrated
to isocyanides.44
372
THIONYL CHLORIDE
RCONH2 + SOCl2
RCN + SO2 + 2 HCl
(8)
Reactions with Secondary Amides. Treatment of N-alkyl or

N-aryl secondary amides with thionyl chloride in an inert solvent
such as methylene chloride results in the formation of imidoyl
chlorides (eq 9).45 Upon heating, the imidoyl chlorides from Nalkylamides undergo scission to generate nitriles and alkyl chlo
rides via the von Braun degradation (eq 10).46
(9)
(10)
Reactions with Aldehydes and Ketones. Aromatic or ,unsaturated aldehydes or their bisulfite addition compounds are
converted to gem-dichlorides by treatment with SOCl2, either neat
or in an inert solvent such as nitromethane (eq 11).47 This process
is readily catalyzed by HMPA.48 Thionyl chloride may be pre
ferred over the more commonly used PCl5 if removal of byprod
ucts is problematic with the latter reagent.
(11)
Carbonyl compounds or nitriles49 with -hydrogens may be

oxidized at this position by thionyl chloride. This reaction appears
more often as a troublesome side reaction than a useful synthetic
procedure. Nitriles with one -hydrogen produce -cyanosulfinyl
chlorides (eq 12) while those with two -hydrogens give moderate
yields of -chloro--cyanosulfinyl chlorides.50
methyl and carboxylic acid groups, both oxidation of the methyl

group and cyclization to a -thiolactone can occur.55 In conjunc
tion with radical initiators, SOCl2 can chlorinate alkanes.56 Aryl
methyl ethers can be oxidized on the aromatic ring to give arylsulfenyl chlorides which may undergo further reactions.57 This
latter process, which presumably occurs via electrophilic aromatic
substitution, is another potential serious side reaction for active
substrates.
Rearrangement Reactions. Thionyl chloride can act as the
dehydrating agent in the Beckman58 and Lossen rearrangements59
and promotes the Pummerer rearrangement.60
Synthesis of Heterocyclic Compounds. Thionyl chloride and
pyridine at elevated temperatures convert diarylalkenes, styrenes,
and cinnamic acids to benzo[b]thiophenes61 and adipic acid to 2,5bis(chlorocarbonyl)thiophene.62 Additional heterocycles which
have been prepared include thiazolo[3,2-a]indol-3(2H)-ones,63
oxazolo[5,4-d]pyrimidines,64 and 1,2,3-thiadiazoles.65 Treatment
of 1,2-diamino aromatic compounds with thionyl chloride gives
good yields of fused 1,2,5-thiadiazoles.66
Other Applications. Thionyl chloride has been used to con
vert epoxides to vicinal dichlorides67 and for the preparation of dialkyl sulfides from Grignard reagents.68 Phenols react with SOCl2
to produce aryl chlorosulfites and diaryl sulfites69 or nuclear sub
stitution products. As shown in eq 14, Aluminum Chloride catal
ysis yields symmetric sulfoxides, while in the absence of Lewis
acids, aromatic thiosulfonates are the principal products.70 Pri
mary amines, especially aromatic ones, react with SOCl2 to pro
duce N-sulfinylamines, which are potent enophiles and useful pre
cursors to some heterocyclic compounds.71
(12)
(14)
Oxidation of Activated C-H Bonds. As shown in eq 13, ex

tensive oxidation adjacent to carbonyl groups is possible with
SOCl2 under relatively mild conditions.51 The process often stops
after formation of the -chlorosulfenyl chloride. Remarkably,
these may be easily hydrolyzed back to the carbonyl compounds
from which they were derived.52 Alternatively, they may be treated
with a secondary amine such as morpholine followed by hydroly
sis to yield the -dicarbonyl compound. Similar oxidation of acid
derivatives during acid chloride formation is possible (see above).
Related
Reagents. Dimethylchloromethyleneammonium
Chloride; Hexamethylphosphoric Triamide-Thionyl Chloride;
Hydrogen Chloride; Oxalyl Chloride; Phosgene; Phosphorus(III)
Chloride; Phosphorus(V) Chloride; Phosphorus(V) Oxide; Phos
phorus Oxychloride; Triphenylphosphine-Carbon Tetrachloride;
Triphenylphosphine Dichloride.
(13)
Methyl groups attached to benzenoid rings may be oxidized by

SOCl2 without added catalysts. The range of reactivity is large and
not well understood; the products may be monochlorinated or fur
ther oxidation to the trichloromethyl aromatic system is possible.53
2-Methylpyrroles are similarly oxidized.54 In systems with vicinal
1. (a) Pizey, J. S. Synthetic Reagents; Wiley: 1974; Vol. 1, pp 321-357. (b)

Davis, M.; Skuta, H.; Krubsack, A. J. Mech. React. Sulfur Compd. 1970,
5,1.
2.
Brown, G. W. In The Chemistry of the Hydroxyl Group; Patai, S., Ed.;

Interscience; London, 1971; Part 1, pp 593-622.
3.
Ansell, M. F. In The Chemistry of Acyl Halides; Patai, S., Ed.;

Interscience: London, 1972; pp 35-68.
1-1'THIONYLIMIDAZOLE
4.
5.
Hoyle, J. In The Chemistry of Sulfonic Acids, Esters, and Their

Derivatives; Patai, S.; Rappoport, H., Eds.; Wiley: New York, 1991;
pp 379-386.
Mowry, D. T. CRV 1948, 42, 257.
6.
Ulrich, H. Chemistry of Imidoyl Halides; Plenum: New York, 1968; pp

13-54.
7.
Davis, M. Adv. Heterocycl. Chem. 1982, 30, 62.
8.
9.
10.
Weil, E. D. In Kirk-Othmer Encyclopedia of Chemical Technology, 3rd

Ed.; Wiley: New York, 1978; Vol. 22, pp 127-131.
Bell, K. H. AJC 1985, 38, 1209.
11.
12.
Martin, E. L.; Fieser, L. F. OSC 1943, 2, 569.

Spitulnik, M. J. Chem. Eng. News 1977, (Aug 1), 31.
13. Gerrard, W. JCS 1940, 218.

14. Suter, C. M.; Gerhart, H. L. OSC 1943, 2, 112.
15. Frazer, M. J.; Gerrard, W.; Machell, G.; Shepherd, B. D. CI(L) 1954,
931.
16. Lewis, E. S.; Boozer, C. E. JACS 1952, 74, 308.
(a) Hudson, H. R.; de Spinoza, G. R. JCS(P1) 1976, 104. (b) Lee, C. C ;
Finlayson, A. J. CJC 1961, 39, 260.
18. Ward, A. M. OSC 1943, 2, 159.
48. Khurana, J. M.; Mehta, S. IJC(B) 1988, 27, 1128.

49. Martinetz, D. ZC 1980, 20, 332.
50. Ohoka, M.; Kojitani, T.; Yanagida, S.; Okahara, M.; Komori, S. JOC
1975, 40, 3540.
51. (a) Oka, K.; Hara, S. TL 1976, 2783. (b) Oka, K. S 1981, 661.
52. Oka, K.; Hara, S. TL 1977, 695.
53. Davis, M.; Scanlon, D. B. AJC 1977, 30, 433.
54. Brown, D.; Griffiths, D. SC 1983, 13, 913.
55. Walser, A.; Flynn, T. JHC 1978, 15, 687.
56. Krasniewski, J. M., Jr.; Mosher, M. W. JOC 1974, 39, 1303.
57. Bell, K. H.; McCaffery, L. F. AJC 1992, 45, 1213.
58. Donaruma, L. G.; Heldt, W. Z. OR 1960, 11, 1.
59. Yale, H. L. CRV 1943, 33, 242.
60. (a) Russell, G. A.;Mikol, G. J. In Mechanisms of Molecular Migrations;
Thyagarajan, B. S., Ed.; Interscience: New York, 1968; Vol. 1, pp
157-207. (b) Durst, T. Adv. Org. Chem. 1969, 6, 356.
61.
17.
19.
20.
21.
Stille, J. K.; Sonnenberg, F. M. JACS 1966, 88, 4915.

Normant, J. F.; Deshayes, H. BSF 1972, 2854.
Caserio, F. F.; Dennis, G. E.; DeWolfe, R. H.; Young, W. G. JACS 1955,
77,4182.
22.
Young, W. G.; Caserio, F. F., Jr.; Brandon, D. D., Jr.; JACS 1960, 82,
6163.
Brooks, L. A.; Snyder, H. R. OSC 1955, 3, 698.
Ward, A. M. OSC 1943, 2, 159.
Eliel, E. L.; Fisk, M. T.; Prosser, T. OSC 1963, 4, 169.
Kyrides, L. P. JACS 1937, 59, 206.
Helferich, B.; Schaefer, W. OSC 1932, 1, 147.
Womack, E. B.; McWhirter, J. OSC 1955, 3, 714.
Fuson, R. C.; Walker, J. T. OSC 1943, 2, 169.
Beg, M. A.; Singh, H. N. Z. Phys. Chem. 1968, 237, 128; 1964, 227,
272.
Cason, J.; Reist, E. J. JOC 1958, 23, 1492.
Sandler, S. R.; Karo, W. Organic Functional Group Preparations, 2nd
ed.; Academic: Orlando, 1983; Vol. 1, p 157.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
Gerrard, W.; Thrush, A. M. JCS 1953, 2117.

Bosshard, H. H.; Mory, R.; Schmid, M.; Zollinger, H. HCA 1959, 42,
1653.
Uhle, F. C.; Harris, L. S. JACS 1956, 78, 381.
Patel, R. P.; Price, S. JOC 1965, 30, 3575.
Coleman, G. H.; Nichols, G.; McCloskey, C. M.; Anspon, H. D. OSC
1955,5,712.
Krubsack, A. J.; Higa, T. TL 1968, 5149.
39.
40.
41.
42.
43.
44.
Sutherland, H.; Shriner, R. L. JACS 1936, 58, 62.

Kurzer, F. OSC 1963, 4, 937.
Krynitsky, J. A.; Carhart, H. W. OSC 1963, 4, 436.
Goldstein, H.; Voegeli, R. HCA 1943, 26, 1125.
Thurman, J. C. CI(L) 1964, 752.
(a) Tennant, G. In Comprehensive Organic Chemistry; Barton, D. H. R.;
Ollis, W. D., Eds.; Pergamon: Oxford, 1979; Vol. 2, p 569. (b) Niznik,
G. E.; Morrison, W. H., III; Walborsky, H. M. OS 1971, 51, 31.
45.
von Braun, J.; Pinkernelle, W. CB 1934, 67, 1218.
46.
(a) Challis, B. C ; Challis, J. A. The Chemistry of Amides; Zabicky, J.,

Ed.; Interscience; New York, 1970; pp 809-810. (b) Vaughn, W. R.;
Carlson, R. D. JACS 1962, 84, 769.
47.
Newman, M. S.; Sujeeth, P. K. JOC 1978, 43, 4367.
373
(a) Blatt, H.; Brophy, J. J.; Colman, L. J.; Tairych, W. J. AJC 1976,
29, 883. (b) Campaigne, E. In Comprehensive Heterocyclic Chemistry;
Katritzky, A. R.; Rees, C. W., Eds.; Pergamon: Oxford, 1984; Vol. 4, p
870, 889.
62.
Nakagawa, S.; Okumura, J.; Sakai, F.; Hoshi, H.; Naito, T. TL 1970,
3719.
63. Showalter, H. D. H.; Shipchandler, M. T.; Mitscher, L. A.; Hagaman, E.
W. JOC 1979, 44, 3994.
64. Senga, K.; Sato, J.; Nishigaki, S. H 1977, 6, 689.
65. Meier, H.; Trickes, G.; Laping, E.; Merkle, U. CB 1980, 113, 183.
66. (a) Komin, A. P.; Carmack, M. JHC 1975, 12, 829. (b) Hartman, G. D.;
Biffar, S. E.; Weinstock, L. M.; Tull, R. JOC 1978, 43, 960.
67. Campbell, J. R.; Jones, J. K. N.; Wolfe, S. CJC 1966, 44, 2339.
68. Drabowicz, J.; Kielbasinski, P.; Mikolajczyk, M. In The Chemistry of
Sulphones and Sulphoxides; Patai, S.; Rappoport, Z.; Stirling, C. J. M.,
Eds.; Wiley: New York, 1988; Chapter 8, p 257.
69.
70.
71.
Gerrard, W. JCS 1940, 218.

(a) Takimoto, H. H.; Denault, G. C. JOC 1964, 29, 759. (b) Oae, S.;
Zalut, C. JACS 1960, 82, 5359.
Kresze, G.; Wucherpfennig, W. AG(E) 1967, 6, 149.
David D. Wirth
Eli Lilly & Co., Lafayette, IN, USA
1,1'-Thionylimidazole1
[3005-50-3]
C 6 H 6 N 4 OS
(MW 182.23)
(forms N-acylimidazolides1 used to synthesize amides, peptides,2

esters,3 and ketones;4 synthesis of symmetrical sulfoxides,5 inor
ganic esters,6 and N-alkylimidazoles7)
Alternate Names: N,N'-thionylimitedazole; N,N'-thionyldiimidazole; TDI.
Solubility: sol THF, CH2Cl2, toluene.
Form Supplied in: not commercially available; usually used in
THF solution.
374
1-1'THIONYLIMIDAZOLE
Analysis of Reagent Purity: usual preparations are used immedi

ately without analysis.
Preparative Method: the reagent is prepared by reacting Thionyl
Chloride with 4 equiv of Imidazole in anhydrous THF at 0 C.
The precipitated imidazole hydrochloride is filtered and the so
lution is pure enough to use.8
(3)
Purification: filter to remove imidazole hydrochloride. Analyti
cally pure samples have been prepared by reaction of thionyl
chloride and N-(Trimethylsilyl)imidazole .9
Handling, Storage, and Precautions: extremely hygroscopic; re
Ketones. N-Acylimidazolides react with Grignard reagents to
acts exothermically with water and alcohols. Store as a solution
give ketones in good yields.4 A comparison of N-acylimidazolides
in THF or CH2Cl2 under dry N2.8b Use in a fume hood.
and mixed acid anhydrides in Grignard reactions indicates that the
imidazolides result in higher yields (eq 4).10 There are many pro
cedures for reacting Grignard reagents with 'activated' carboxylic
N-Acylimidazolides. N,N'-Thionylimidazole reacts with
acids to give ketones. Other reagents used with varying degrees
carboxylic acids to form N-acylimidazolides (eq 1) that readily
of success are acid chlorides (e.g. Ethyl Chloroformate), nitriles,
acylate amines, amino acids, or alcohols.1 The products are
and 2-pyridylthiol esters (e.g. 2-Thiopyridyl Chloroformate).11
readily purified since the byproducts, imidazole and SO2, are
easily removed. N,N'-Carbonyldiimidazole (CDI) is another
useful reagent for formation of N-acylimidazolides. TDI is used
(4)
less frequently for formation of N-acylimidazolides because of its
high reactivity; also, CDI is commercially available and easier to
handle. Most reported transformations from N-acylimidazolides
R
Anhydride Imidazolide
involve CDI; however, TDI should give similar results.
Et
Pr
C6H13
Ph
(1)
Peptide Coupling Reagent. N-Acylimidazolides are useful

acylating intermediates in peptide synthesis (eq 2).2 These are
direct couplings where the amine and acid components are premixed in solution. There are only a few examples of peptides being
synthesized with this reagent. Therefore it is not known what lim
itations exist, such as extent of racemization, ease of handling,
etc. Comparisons with many of the well-known peptide coupling
reagents (e.g. 1,3-Dicyclohexylcarbodiimide) have not been pub
lished. CDI is used more frequently if the imidazolide intermediate
is desired because of its ease of handling.
57
57
62
0
68
74
74
79
Symmetrical Sulfoxides. Thionylimidazole reacts directly

with Grignard reagents resulting in symmetrical sulfoxides in rea
sonable yields (eq 5).5 This method offers an easy workup and
purification since the main byproduct is imidazole.
(5)
Inorganic Ester Formation. Phenols and alcohols react

exothermically with TDI to give sulfonic acid diesters in high
yield (eq 6).6
(6)
(2)
Ester Formation. N-acylimidazolides react with alcohols very

fast in the presence of catalytic amounts of the alkoxide (eq 3).3
With this method the methyl ester of vitamin A has been obtained
in 91% yield.3
N-Alkylimidazoles. Thionylimidazole has found great utility

in the synthesis of N-alkylimidazoles.7 Tertiary alcohols react with
TDI to form monosulfonic ester imidazolides that rearrange to
transfer the imidazole to the tertiary carbon (eq 7).12 The products
are also obtained by treatment of the trityl chloride with imidazole;
however, comparison of the two procedures is not possible as
yields were not reported.12
2-THIOPYRIDYL CHLOROFORMATE
(7)
375
12. Buechel, K. H.; Draber, W.; Regal, E.; Plempel, M. AF 1972, 22, 1260
(CA 1972, 77, 152 067e).
13. Ogata, M.; Matsumoto, H.; Kida, S.; Shimizu, S. TL 1979,
5011.
Richard S. Pottorf
R = H, Me, NH2; R1 = H, Me, di-Me; R2 = H, Cl, Ph
This imidazole transfer reaction occurs readily with ohydroxybenzyl alcohols, giving the imidazole from a primary or
secondary alcohol (eq 8). 7 It is thought that the o-hydroxy group
contributes to the facile transfer of the imidazole. Similarly, oamines promote the transfer of the imidazole. Carbonyl diimidazole also works in this imidazole transfer reaction, but it usually
gives lower yields of the desired product.7
2-Thiopyridyl Chloroformate1
[73371-99-0]
(8)
This imidazole transfer reaction works with ketones as well;

however, in this case two products, the mono- and diimidazoles,
are obtained (eq 9). 13 Increasing the temperature does not change
the product ratio or yield. Some examples contain hydrogenbonding groups on the ring, but this does not modify the product
ratio or yield either. CDI gives similar results in most cases. This
imidazole transfer reaction does not work with aldehydes under
these conditions.13
(9)
37%
12%
1. Staab, H. A. AG(E) 1962, 1, 351.

2. Wieland, T.; Vogeler, K. AG 1961, 73, 435.
3. Staab, H. A.; Rohr, W.; Mannschreck, A. AG 1961, 73, 143 (CA 1961,
55, 14437h).
4. Staab, H. A.; Jost, E. LA 1962, 655, 90 (CA 1962, 57, 15 090g).
5. Bast, S.; Andersen, K. K. JOC 1968, 33, 846.
6. Staab, H. A.; Wendel, K. LA 1966, 694, 86 (CA 1966, 65,
12195c).
7. Ogata, M.; Matsumoto, H.; Kida, S.; Shimizu, S. CI(L) 1980, 85.
8. (a) Staab, H. A.; Wendel, K. AG 1961, 73, 26 (CA 1961, 55, 12 389e).
(b)FF 1967,1, 1163.
9. Birkofer, L.; Gilgenberg, W.; Ritter, A. AG 1961, 73, 143.
10. Bram, G.; Vilkas, M. BSF(2) 1964, 945.
11. (a) Shirley, D. A. OR 1954, 8, 28. (b) Posner, G.; Witten, C. E. TL
1970, 4647. (c) Mukaiyama, T.; Araki, M.; Takei, H.; JACS 1973, 95,
4763.
C 6 H 4 ClNOS
(MW 173.63)
(convenient preparation of 2-pyridylthiol esters;2 subsequent

transformation into lactones,3 peptides,4 and ketones 5 )
Physical Data: 1H NMR (CDCl3) 8.64 m (1H), 7.75 m (2H),
7.38 m ( l H ) .
Solubility: sol CH 2 Cl 2 , ether.
Form Supplied in: colorless oil; main impurity is bis(thiopyridyl)
carbonate; not commercially available.
Analysis of Reagent Purity: IR(CH 2 Cl 2 ) 1765 c m - 1 (C=O);main
impurity: IR (CH 2 Cl 2 ) 1715 c m - 1 (C=O).
Preparative Method: Phosgene (5 equiv) in toluene and CH 2 Cl 2
is cooled to 0C. Dropwise addition (5 min) of a CH 2 Cl 2 so
lution of Triethylamine (slight excess) and 2-Pyridinethiol is
followed by stirring for 10 min. After removal of excess phos
gene and CH 2 Cl 2 in vacuo, hexane is added and the resulting
precipitate is filtered. After concentration of the combined fil
trates, the colorless oil (96%) is dissolved in CH 2 Cl 2 and stored
at - 2 5 C.
Handling, Storage, and Precautions: very unstable to water and
silica gel; however, it can be handled in air. It is stable for one
month if stored at 25 C. Since phosgene is used in preparing
this reagent, preparation should be in a working fume hood and
extreme caution is required.
Preparation of 2-Pyridylthiol Esters. 2-Pyridylthiol esters

are formed by treating a carboxylic acid with 2-thiopyridyl chlo
roformate under extremely mild conditions (eq 1). 2 The Et 3 NHCl
is removed by filtration or by washing with cold aqueous acid and
base. After thorough drying, the thiol esters are generally pure
enough to use in many synthetic applications.
+ CO2 + Et3NHCl
(1)
376
2-THIOPYRIDYL CHLOROFORMATE
There are several other reagents for preparing 2-pyridylthiol es

ters. 1,3-Dicyclohexylcarbodiimide4 generally gives lower yields
of the thiol ester and removal of the dicyclohexylurea can be diffi
cult. Treating an acid chloride with thallium(I) 2-pyridinethiolate6
has been used, but thallium salts are toxic. The method used most
frequently before the introduction of 2-thiopyridyl chloroformate
involves reacting a carboxylic acid with Triphenylphosphine and
2,2'-Dipyridyl Disulfide.1 This procedure suffers from the neces
sity of removing 2-pyridinethiol and triphenylphosphine oxide by
chromatography, which precludes preparing large batches of the
thiol esters since there can be a loss of product by reaction with the
silica gel. 2-Thiopyridyl chloroformate provides access to many
reported synthetic transformations. In some of these reports, the
thiol ester has been prepared by other methods. However, use of
2-thiopyridyl chloroformate should make these transformations
even more accessible.
Lactone Formation. There are several examples of the syn
thesis of lactones with 2-pyridylthiol esters.3 Since this is a facile
reaction, reasonable yields of complex macrocycles are obtained
(eq 2).8 The pyridine nitrogen may provide anchimeric assistance
for the approaching nucleophile, thus facilitating the acylation.3
p-Nitrophenol, and N-Hydroxysuccinimide. However, these do

not work as well with the hindered amino acids shown in eq 4.
Additionally, there are many direct coupling procedures; therefore
the 2-pyridylthiol esters have not been used frequently.
(4)
Ketones. Reaction of 2-pyridylthiol esters with Grignard

reagents occurs rapidly to give ketones in almost quantitative
yields (eq 5).5 In all studies, less than 1% of the tertiary alcohol is
observed. This procedure works reasonably well with a suitably
protected amino acid to give the ketone (eq 6).11 Phthaloyl protec
tion of the amine is required since esters with amide NH groups
decompose when treated with Grignard reagents.11
(2)
(5)
Ester Formation. 2-Pyridylthiol esters acylate lysophosphatidylcholines rapidly when catalyzed by silver ion, giving
mixed-chain phosphatidylcholines in high yields and isomeric
purity (eq 3).9 The main advantages of this procedure over the
usual 4-Dimethylaminopyridine catalyzed acylation with acid
anhydrides10 are that less acylating reagent is required to give
high yields and rearrangement of the fatty acids is minimized.
The main disadvantage is the sensitivity of the 2-pyridylthiol es
ter to water.
(6)
1:1 ratio of diastereomers
(3)
R1 = Me(CH2)14
R2 = Me(CH2)14
1.5% isomeric purity
Peptide Coupling. These thiol esters have been used in the

synthesis of several dipeptides. Many of the examples involve
highly sterically hindered amino acids and result in very good
yields and high optical purity (eq 4).4 There are many useful
active esters for peptide coupling, such as Pentafluorophenol,
Preparation of thiol esters of highly elaborated phosphoranes with thiopyridyl chloroformate has been reported. Treat
ment of the thiol ester with an aryl Grignard reagent gives the
corresponding ketone without epimerization of the chiral cen
ters (eq 7).12 There are many procedures for reacting Grignard
reagents with 'activated' carboxylic acids to give ketones. Other
reagents used with varying degrees of success include acid chlo
rides, nitriles, acid anhydrides, and N-acylimidazolides (e.g. N,N'Carbonyldiimidazole, 1,1'-Thionylimidazole).13 Many of these
give higher yields of the tertiary alcohol. However, treating acid
chlorides with Grignard reagents at 78 C gives better results,14
so this may be an alternative to the thiol esters.
TIN(IV) CHLORIDE
377
Handling, Storage, and Precautions: hygroscopic; should be

stored in a glove box or over P 2 O 5 to minimize exposure to
moisture. Containers should be flushed with N 2 or Ar and tightly
sealed. Perform all manipulations under N 2 or Ar. Solvating
with H 2 O liberates much heat. Use in a fume hood.
(7)
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
Haslam, E. T 1980, 36, 2409.

Corey, E. J.; Clark, D. A. TL 1979, 31, 2875.
Corey, E. J.; Nicolaou, K. C. JACS 1974, 96, 5614.
Lloyd, K.; Young, G. T. JCS(C) 1971, 2890.
Mukaiyama, T.; Araki, M.; Takei, H. JACS 1973, 95, 4763.
Masamune, S.; Kamata, S.; Diakur, J.; Sugihara, Y.; Bates, G. S. CJC
1975, 53, 3693.
Mukaiyama, T.; Matsueda, R.; Suzuki, M. TL 1970, 1901.
Le Drian, C.; Greene, A. E. JACS 1982, 104, 5473.
Nicholas, A. W.; Khouri, L. G.; Ellington, J. C , Jr.; Porter, N. A. Lipids
1983, 18, 434.
Gupta, C. M.; Radhakrishran, R.; Khorana, H. G. PNA 1971, 74, 4315.
Almquist, R. G.; Chao, W.-R.; Ellis, M. E.; Johnson, H. L. JMC 1980,
23, 1392.
Guthikonda, R. N.; Cama, L. D.; Quesada, M.; Woods, M. F.; Salzmann,
T. N.; Christensen, B. G. JMC 1987, 30, 871.
(a) Shirley, D. A. OR 1954, 8, 28. (b) Posner, G.; Witten, C. E. TL 1970,
4647. (c) Staab, H. A.; Jost, E. LA 1962, 655, 90.
Sato, F.; Inoue, M.; Oguro, K.; Sato, M. TL 1979, 4303.
Marion Merrell Dow Research Institute,
Richard S. Pottorf
Cincinnati, OH, USA
Tin(IV) Chloride
[7646-78-8]
Introduction. SnCl4 is used extensively in organic synthesis

as a Lewis acid for enhancing a variety of reactions. SnCl 4 is
classified as a strong Lewis acid according to HSAB theory, and
therefore interacts preferentially with hard oxygen and nitrogen
bases. Six-coordinate 1:2 species and 1:1 chelates are the most sta
ble coordination complexes, although 1:1 five-coordinate species
are also possible.1 SnCl4 can be used in stoichiometric amounts,
in which case it is considered a 'promoter', or in substoichiometric amounts as a catalyst, depending upon the nature of the
reaction. SnCl4 is an attractive alternative to boron, aluminum,
and titanium Lewis acids because it is monomeric, highly soluble
in organic solvents, and relatively easy to handle. SnCl4 and TiCl4
are among the most common Lewis acids employed in 'chelation
control' strategies for asymmetric induction. However, SnCl4 is
not often the Lewis acid of choice for optimum selectivities and
yields.
SnCl4 is also the principal source for alkyltin chlorides,
R n SnCl 4 - n . 2 Allyltrialkyltin reagents react with SnCl4 to produce
allyltrichlorotin species through an S E 2 ' pathway (eq 1). 3 Silyl
enol ethers react with SnCl4 to give -trichlorotin ketones (eq 2). 4
Transmetalation or metathesis reactions of this type are compet
ing pathways to nucleophilic addition reactions where SnCl4 is
present as an external Lewis acid. As a consequence, four impor
tant experimental variables must be considered when using SnCl4
as a promoter: (1) the stoichiometry between the substrate and
the Lewis acid; (2) the reaction temperature; (3) the nature of
the Lewis base site(s) in the substrate; and (4) the order of addi
tion. These variables influence the reaction pathway and product
distribution.5
(1)
(2)
Cl 4 Sn
(MW 260.51)
(strong Lewis acid used to promote nucleophilic additions, pericyclic reactions, and cationic rearrangements; chlorination
reagent)
Alternate Name: stannic chloride.
Physical Data: colorless liquid; mp 33 C; bp 114.1C; d
2.226 g c m - 3 .
Solubility: reacts violently with water; sol cold H 2 O; dec hot H 2 O;
sol alcohol, Et 2 O, CCI 4 , benzene, toluene, acetone.
Form Supplied in: colorless liquid; 1 M soln in CH 2 Cl 2 or heptane;
widely available.
Purification: reflux with mercury or P 2 O 5 for several hours, then
distill under reduced nitrogen pressure into receiver with P 2 O 5 .
Redistill. Typical impurities: hydrates.
Nucleophilic Additions to Aldehydes. SnCl4 is effective in

promoting the addition of nucleophiles to simple aldehydes.
Among the most synthetically useful additions are allylstannane
and -silane additions. The product distribution in the stannane re
actions can be influenced by the order of addition, stoichiometry,
and reaction temperature. The anti geometry of the tin-aldehyde
complex is favored due to steric interactions. Furthermore, the sixcoordinate 2:1 complex is most likely the reactive intermediate in
these systems. The use of crotylstannanes provides evidence for
competing transmetalation reaction pathways (eq 3). 6 Superior
selectivities are provided by Titanium(IV) Chloride.
The presence of additional Lewis base sites within the molecule
can result in the formation of chelates with SnCl4 or TiCl 4 , which
can lead to 1,2- or 1,3-asymmetric induction with the appropriate
substitution at the C-2 or C-3 centers. NMR studies have pro
vided a basis for explaining the levels of diastereofacial selectiv
ity observed in nucleophilic additions to Lewis acid chelates of
378
TIN(IV) CHLORIDE
-alkoxy aldehydes with substitution at the C-2 or C-3 positions.7

These studies reveal thatS n C l 4chelates are dynamically unsta
ble when substrates are sterically crowded at the alkoxy center,
thus enhancing the formation of 2:1 complexes and/or competing
metathesis pathways. Furthermore, for -siloxy aldehydes, the 2:1
SnCl4 complex is formed preferentially over the corresponding
chelate.8
normal addition
inverse addition
normal addition
inverse addition
1.3 equiv SnCl4

1.3 equiv SnCl4
1.05 equiv TiCl4
2.1 equiv TiCl4
22.8
21.8
90.5
4.4
(3)
26.0
74.9
7.0
90.8
36.4
1.2
2.1
gives ,-dehydro--amino acid derivatives (eq 5).15 SnCl4 is

the Lewis acid of choice for the condensation of aroyl chlorides
with sodium isocyanate, affording aroyl isocyanates in 70-85%
yields.16 Nonaromatic acyl chlorides react under more variable
reaction conditions.
(5)
Hydrochlorination of Allenic Ketones. SnCl4 is also a source

for generating chloride anions which form new carbon-chlorine
bonds. This occurs through a ligand exchange pathway which
has been exploited in the formation of -chloro enones from
conjugated allenic ketones (eq 6).17 Yields range from 36-82%
with complete selectivity for the trans geometry. A variety of
substituents (R1, R2) can be tolerated including aryl, rings, and
alkoxymethyl groups (R1).
14.8
2.2
0.5
4.9
(6)
Mukaiyama Aldol Additions. Lewis acid-promoted addi

tions of a chiral aldehyde to a silyl enol ether or silyl ketene
acetal (the Mukaiyama9 aldol addition) occurs with good diastereofacial selectivity.10 The reaction has been investigated with
nonheterosubstituted aldehydes, - and -alkoxy aldehydes,11
- and -amino aldehydes,12 and thio-substituted aldehydes.13
High diastereoselectivity is observed in the SnCl4- or TiCl4promoted aldol addition of silyl enol ethers to - and -alkoxy
aldehydes. Prior chelation of the aldehyde before addition of
the enol silane is important because certain enol silanes interact
with SnCl4 to produce -trichlorostannyl ketones, which provide
lower selectivity.14 Simple diastereoselectivity is independent of
the geometry of the enol silane, and the reaction does not pro
ceed through prior Si-Ti or Si-Sn exchange. Good anti selectivities (up to 98:2) are obtained in the SnCl4-promoted reactions
of chiral -thio-substituted aldehydes only with -phenylthiosubstituted aldehydes (eq 4). Stereorandom results are obtained
with SnCl4 when other alkylthio-substituted aldehydes, such as
-isopropylthio-substituted aldehydes, are used. Boron Trifluoride Etherate catalysis gives better anti selectivities than SnCl4
for aldehydes with smaller alkylthio substituents. Excellent syn
selectivities are obtained for -thio-substituted aldehydes with
TiCl4.
Glycosylations. The reaction of glycofuranosides having

a free hydroxyl group at C-2 with functionalized organosilanes, in the presence of SnCl4, provides C-glycosyl com
pounds in high stereoselectivity (eq 7).18 Organosilanes such
as 4-(chlorodimethylsilyl)toluene, chlorodimefhylvinylsilane, Allyltrimethylsilane, and allylchlorodimethylsilane are effective
reagents. The presence of a leaving group on the silane is
essential for good selectivity since the reaction proceeds intramolecularly through a 2-O-organosilyl glycoside. The avail
ability of furanosides in the ribo, xylo, and arabino series make
this reaction valuable for the stereoselective synthesis of Cfuranosides. Regioselective glycosylation of nitrogen-containing
heterocycles is also effectively promoted by SnCl4, and has
been used in the synthesis of pentostatin-like nucleosides, such
as (1).19
(7)
(4)
R = H: pentostatin
R = OH: coformycin
Additions to Nitriles. SnCl4-promoted addition of malonates

and bromomalonates to simple nitriles (not electron deficient)
TIN(IV) CHLORIDE
Selective De-O-benzylation. Regioselective de-O-benzylation of polyols and perbenzylated sugars is achieved with organotin reagents or other Lewis acids.20,21 The equatorial O-benzyl
group of 1,6-anhydro-2,3,4-tri-O-benzyl--D-mannopyranose is
selectively cleaved by SnCl4 or TiCl4 (eq 8).2 The equato
rial O-benzyl group is also selectively cleaved when one of
the axial O-benzyl groups is replaced by an O-methyl group.
The 2-O-benzyl group of l,2,3-tris(benzyloxy)propane is selec
tively cleaved (eq 9), but no debenzylation is observed with 1,2bis(benzyloxy)ethane.
379
Rearrangements of acetals require substitution at the internal

alkene carbon.
(12)
(13)
(8)
SnCl4
TiCl4
92%
77%
5%
19%
(9)
Rearrangement of Allylic Acetals. Lewis acid-promoted

(SnCl4 or Diethylaluminum Chloride) rearrangements of allylic
acetals provide substituted tetrahydrofurans.22 Upon addition of
Lewis acid, (2) rearranges to the all-cis furan (3) (eq 10). No
racemization is observed with optically active allylic acetals; how
ever, addition of KOH completely epimerizes the furan-carbonyl
bond, as does quenching at room temperature. Acetals success
fully undergo similar rearrangement provided the alkene is sub
stituted. Completely substituted tetrahydrofurans are synthesized
stereoselectively (>97% ee) by the rearrangement of disubstituted ally] acetals (eq 11). This reaction is related to the acidcatalyzed rearrangements of 5-methyl-5-vinyloxazoIidines to 3acetylpyrrolidines, which involves an aza-Cope rearrangement
and Mannich cyclization.23
-t-Alkylations. SnCl4-promoted -t-alkylations of alkenyl

-dicarbonyl compounds is a particularly useful cyclization
reaction.25 Cyclization occurs through initial formation of a stannyl enol ether, followed by protonation of the alkene to form a carbocation which undergoes subsequent closure (eq 14). The anal
ogous -s-alkylation reactions are best catalyzed by other Lewis
acids.
(14)
This reaction is useful for cyclizations involving 6-endotrigonal (eq 14) and 'allowed' 7-endo trigonal processes (eq 15),
but not for those involving 5-endo trigonal processes (eq 16).
These observations are consistent with the Baldwin rules.
(10)
(15)
(11)
R1 = Me, R2 = H; 90%
R1 = H, R2 = Me; 73%
The rearrangement is also useful for furan annulations, through

enlargement of the starting carbocycle.24 Thus addition of SnCl4
to either diastereomer of the allylic acetal (4) produces the cisfused cycloheptatetrahydrofuran (5) in 48-76% yield (eq 12). Ac
etals derived from trans-diote rearrange to the same cw-fused bicyclics in higher yield. The stereochemistry of a terminal alkene is
transmitted to the C-3 carbon of the bicyclic products (eq 13).
(16)
Reactions involving 4- and 6-exo trigonal cyclizations result in

poor yields or undesired products, while those involving 5-exo
trigonal cyclizations produce higher yields (eq 17). This synthetic
380
TIN(IV) CHLORIDE
strategy can also be used to form bicyclic and spiro compounds

(eqs 18 and 19).
(22)
(17)
(18)
SnCl4-induced cyclizations between alkenes and enol acetates

result in cycloalkanes or bicycloalkanes in high yield (eq 23). It is
interesting to note that the TMSOTf-catalyzed reaction can yield
fused products rather than bicyclo products. Alkenic carboxylic
esters, allylic alcohols, sulfones, and sulfonate esters are also cy
clized in the presence of SnCl4; however, alkenic oxiranes often
cyclize in poor yield.26a
(19)
(23)
Alkene Cyclizations. Cationic cyclizations of polyenes, con

taining initiating groups such as cyclic acetals, are promoted by
SnCl4 and have been utilized in the synthesis of cis- and transdecalins, cis- andtrans-octalins,and tri- and tetracyclic terpenoids
and steroids.26 In most instances, all-trans-alkenes yield products
with trans,anti,trans stereochemistry (eq 20), while cis-alkenes
lead to syn stereochemistry at the newly formed ring junctions.
The stereoselectivity of polyene cyclizations are often greatly di
minished when the terminating alkene is a vinyl group rather than
an isopropenyl group. Acyclic compounds which contain termi
nal acyclic acetals and alkenes or vinylsilanes can be cyclized in
a similar fashion to yield eight- and nine-membered cyclic ethers
(eq 21).27
SnCl4 is also effective in the opening of cyclopropane rings to

produce cationic intermediates useful in cyclization reactions. For
example, the cyclization of aryl cyclopropyl ketones to form aryl
tetralones, precursors of aryl lignan lactones and aryl naphthalene
lignans, is mediated by SnCl4 (eq 24).29 The reaction is success
ful in nitromethane, but not in benzene or methylene chloride.
Analogous cyclizations with epoxides result in very low yields
(2-5%).
(24)
(20)
Polymerization. Cationic polymerizations are catalyzed by

SnCl4 and other Lewis acids (eq 25). Propagation is based upon the
formation of a cationic species upon complexation with SnCl4.30
Radical pathways are also possible for polymer propagation.31
(21)
R1 = H, TMS; R2 = (CH2)2OMe
The analogous cyclization of chiral imines occurs in high yields

(75-85%) with good asymmetric induction (36-65% ee).28 For
example, the cyclization of aldimine (6), derived from methyl citronellal, using SnCl4 affords only the trans-substituted aminocyclohexane (7) in high yield (eq 22). Exo products are formed exclu
sively or preferentially over the thermodynamically favored endo
products.
(25)
Diels-Alder Reactions. Diels-Alder reactions are enhanced

through the complexation of dienophiles or dienes by Lewis
acids.32 Furthermore, Lewis acids have been successfully em
ployed in asymmetric Diels-Alder additions.33 Although SnCl4
is a useful Lewis acid in Diels-Alder reactions, in most in
stances titanium or aluminum Lewis acids provide higher
yields and/or selectivities. The stereoselectivity in Lewis acidpromoted Diels-Alder reactions between chiral ,-unsaturated
N-acyloxazolidinones shows unexpected selectivities as a function
TIN(IV) CHLORIDE
34
of the Lewis acid (eq 26). Optimum selectivity is expected for

chelated intermediates, yet both SnCl4 and TiCl4 perform poorly
relative to Et2AlCl (1.4 equiv). The formation of the SnCl4-Nacyloxazolidinone chelate has been confirmed by solution NMR
studies.35 These data suggest that other factors such as the steric
bulk associated with complexes may contribute to stereoselectiv
ity.
381
ratio with a yield of 83% when SnCl4 is used in acetonitrile. TiCl4

provides slightly higher selectivities (1:8) but lower yield (70%)
(eq 28).
(26)
(28)
SnCl4
TiCl4
Lewis acid
1.1 equiv SnCl4
1.1 equiv TiCl4
1.4 equiv Et2AlCl
conv %
endo:exo
70
100
100
14.9
9.9
50.0
1:5
1:8
endo I:endo II
3.1
2.7
17
In Lewis acid-promoted Diels-Alder reactions of cyclopentadiene with the acrylate of (S)-ethyl lactate, good diastereofacial and endolexo selectivity are obtained with SnCl4 (84:16;
endolexo= 18:1) and TiCl4 (85:15; endolexo= 16:1).36 It is inter
esting to note that boron, aluminum, and zirconium Lewis acids
give the opposite diastereofacial selectivity (33:67 to 48:52). Com
peting polymerization of the diene is observed in methylene chlo
ride, particularly with TiCl4, but not in solvent mixtures containing
n-hexane.
Cycloalkenones generally perform poorly as dienophiles in
Diels-Alder reactions but their reactivity can be enhanced by
Lewis acids.37 SnCl4 is effective in promoting the Diels-Alder
reaction between simple 1,3-butadienes, such as isoprene and
piperylene, and cyclopentenone esters. For example, the SnCl4promoted cycloaddition between (8) and isoprene is completely
regioselective, providing the substituted indene in 86% yield
(eq 27).38 However, cycloaddition does not occur in the pres
ence of SnCl4 when the diene contains an oxygen-bearing substituent such as an alkoxy or siloxy group. In these cases, as is
generally true for the Diels-Alder reactions of cycloalkenones,
other Lewis acids are more effective. For example, SnCl4promotion of the cycloaddition between (8) and 3-methyl-2-(tbutyldimethylsiloxy)butadiene yields 37% of the desired prod
uct, while Zinc Chloride provides a 90% yield. When furan or
2-methyl-1-alkylsiloxybutadiene are utilized as dienes, only de
composition of the starting material is observed with SnCl4.
When the dienophile N--methylbenzylmaleimide (9) is re

acted with 2-t-butyl-1,3-butadiene in the presence of Lewis acids,
cycloadducts (10) and (11) are formed (eq 29).40 While SnCl4 pro
vides (10) and (11) in a 5:1 ratio, TiCl4 and EtAlCl2 both provide
a 15:1 ratio. Polymerization of the diene competes with adduct
formation under all conditions.
(29)
[4 + 3] Cycloadditions. Oxyallyl cations,41 which react as C3

rather than C2 components in cyclization reactions, are gener
ated by the addition of SnCl4 to substrates which contain silyl
enol ethers which are conjugated with a carbonyl moiety. Thus 2(trimethylsiloxy)propenal undergoes cyclization with cyclopentadiene or furan (eq 30).42 Substituted 1,1-dimethoxyacetones
also form these intermediates and undergo subsequent cyclizations (eq 31).43 This method complements the usual synthesis of
oxyallyl cations involving reductive elimination of halogens from
halogenated ketones or electronically equivalent structures.44
(27)
(30)
The Lewis acid-promoted Diels-Alder reaction has been

employed in the assembly of steroid skeletons.39 The cy
cloaddition reaction between a substituted bicyclic diene and
2,6-dimethylbenzoquinone produces two stereoisomers in a 1:5
(31)
382
TIN(IV) CHLORIDE
[3 + 2] Cycloadditions. Lewis acid-mediated [3 + 2] cycloadditions of oxazoles and aldehydes or diethyl ketomalonate have
been observed using organoaluminum and SnIV Lewis acids.45
The reactions are highly regioselective, with stereoselectivity ex
tremely dependent upon Lewis acid (eq 32). For example, the
(BINOL)AlMe-promoted reaction between benzaldehyde and the
oxazole (12) provides the oxazoline with a cis/trans ratio of
98:2. The selectivity is reversed with SnCl4 which provides a
cis/trans ratio of 15:85.trans-5-Substituted4-alkoxycarbonyl-2oxazolines are synthesized under thermodynamic conditions in
the aldol reaction of isocyanoacetates with aldehydes.46
(32)
[2 + 2] Cycloadditions. The regioselectivity in the cycloaddition reactions of 2-alkoxy-5-allyl-l,4-benzoquinones with

styrenes is controlled by the choice of TiIV or SnCl4 Lewis acids
(eq 33).47 The use of an excess of TiCl4 or mixtures of TiCl4 and
Ti(O-i-Pr)4 produces cyclobutane (13) as the major or exclusive
product, while SnCl4 promotion with one equivalent of Lewis acid
results in the formation of (14) only. These reactions represent a
classic example of the mechanistic variability often associated
with seemingly modest changes in Lewis acid.
Related Reagents. Tin(IV) Chloride-Zinc Chloride.
1. (a) Shambayati, S.; Crowe, W. E.; Schreiber, S. L. AG(E) 1990, 29,

256. (b) Reetz, M. T. In Selectivities in Lewis Acid Promoted Reactions;
Schinzer, D., Ed.; Kluwer: Dordrecht, 1989; pp 107-125. (c) Denmark,
S. E.; Almstead, N. G. JACS 1993, 7/5, 3133.
2. Davies, G. A.; Smith, P. J. In Comprehensive Organometallic Chemistry;
Wilkinson, G.; Stone, F. G. A.; Abel, E. W., Eds.; Pergamon: New York,
1982; Vol. 2, p 519.
3. Naruta, Y.; Nishigaichi, Y.; Maruyama, K. T 1989, 45, 1067.
4. (a) Nakamura, E.; Kuwajima, I. CL 1983, 59. (b) Yamaguchi, M.;
Hayashi, A,; Hirama, M. JACS 1993, 115, 3362. (c) Yamaguchi, M.;
Hayashi, A.; Hirama, M. CL 1992, 2479.
5. (a) Keck, G. E.; Castellino, S.; Andrus, M. B. In Selectivities in Lewis
Acid Promoted Reactions; Schinzer, D., Ed.; Kluwer: Dordrecht, 1989;
pp 73-105. (b) Keck, G. E.; Andrus, M. B.; Castellino, S. JACS 1989,
111, 8136. (c) Denmark, S. E.; Wilson, T.; Wilson, T. M. JACS 1988,
110, 984. (d) Boaretto, A.; Marton, D.; Tagliavini, G.; Ganis, P. JOM
1987, 321, 199. (e) Yamamoto, T.; Maeda, N.; Maruyama, K. CC 1983,
742. (f) Quintard, J. P.; Elissondo, B.; Pereyre, M. JOC 1983, 48, 1559.
6.
Keck, G. E.; Abbott, D. E.; Boden, E. P.; Enholm, E. J. TL 1984, 25,

3927.
7.
(a) Keck, G. E.; Castellino, S. JACS 1986, 108, 3847. (b) Keck, G. E.;
Castellino, S.; Wiley, M. R. JOC 1986, 51, 5478.
8. Keck, G. E.; Castellino, S. TL 1987, 28, 281.
9. Mukaiyama, T.; Banno, K.; Narasaka, K. JACS 1974, 96, 7503.

10. Review of Mukaiyama aldol reaction: Gennan, C. COS 1991, Vol. 2.
11. Reetz, M. T.; Kesseler, K.; Jung, A. T 1984, 40, 4327.
12.
13.
(a) Reetz, M. T. AG(E) 1984, 23, 556. (b) ref 11.

(a) Annunziata, R.; Cinquini, M.; Cozzi, F.; Cozzi, P. G.; Consolandi, E.
JOC 1992, 57, 456. (b) Annunziata, R.; Cinquini, M.; Cozzi, F.; Cozzi,
P. G. TL 1990, 31, 6733.
14. Nakamura, E.; Kawajima, I. TL 1983, 24, 3343.
(33)
X = H, 3,4-(OMe)2, 3,4-(-OCH2O-);
R = Me, R = Bn
15. Scavo, F.; Helquist, P. TL 1985, 26, 2603.

16. Deng, M. Z.; Caubere, P.; Senet, J. P.; Lecolier, S. T 1988, 44, 6079.
17. Gras, J. L.; Galledou, B. S. BSF(2) 1982, 89.
18. Martin, O. R.; Rao, S. P.; Kurz, K. G.; El-Shenawy, H. A. JACS 1988,
770, 8698.
19. Showalter, H. D. H.; Putt, S. R. TL 1981, 22, 3155.
20. Wagner, D.; Verheyden, J. P. H.; Moffat, J. G. JOC 1974, 39, 24.
21.
22.
23.
Ene Reactions. The Lewis acid-catalyzed ene reaction is syn

thetically useful methodology for forming new carbon-carbon
bonds.48 Ene reactions utilizing reactive enophiles such as
formaldehyde and chloral can be promoted by SnCl4. SnCl4 also
enhances intramolecular ene reactions, such as the cyclization
of (15) which produces the -hydroxy -lactone in 85% yield
(eq 34).49 The ene cyclization of citronellal to give isopulegol has
also been reported.50 Proton scavenging aluminum Lewis acids
such as RAICI2 are most often used in ene reactions to eliminate
proton-induced side reactions.
(34)
24.
25.
26.
27.
(a) Overman, L. E.; Blumenkopf, T. A.; Castaneda, A.; Thompson, A. S.

JACS 1986, 108, 3516. (b) Overman, L. E.; Castaneda, A.; Blumenkopf,
T. A. JACS 1986, 108, 1303.
28. ]Demailly, G.; Solladie, G. JOC 1981, 46, 3102.
29. Murphy, W. S.; Waltanansin, S. JCS(P1) 1982, 1029.
30.
Hori, H.; Nishida, Y.; Ohrui, H.; Meguro, H. JOC 1989, 54, 1346.
Hopkins, M. H.; Overman, L. E. JACS 1987, 109, 4748.
Overman, L. E.; Kakimoto, M. E.; Okazaki, M. E.; Meier, G. P. JACS
1983, 705, 6622.
Herrington, P. M.; Hopkins, M. H.; Mishra, P.; Brown, M. J.; Overman,
L. E. JOC 1987, 52, 3711.
Review of -alkylations to carbonyl compounds: Reetz, M. T. AG(E)
1982, 27, 96.
(a) Review of asymmetric alkene cyclization: Bartlett, P. A. Asymmetric
Synthesis; Morrison, J. D., Ed.; Academic: New York, 1984; Vol. 3, Part
B, pp 341-409. (b) Review of thermal cycloadditions: Fallis, A. G.; Lu,
Y.-F. Advances in Cycloaddition; Curran, D. P., Ed.; JAI: Greenwich,
CT, 1993; Vol. 3, pp 1-66.
(a) Kamigaito, M.; Madea, Y.; Sawamota, M.; Higashimura, T.

Macromolecules 1993, 26, 1643. (b) Takahashi, X; Yokozawa, T.; Endo,
T. Makromol. Chem. 1991, 192, 1207. (c) Ran, R. C ; Mao, G. P.
TITANIUM(IV) CHLORIDE
J. Macromol. Sci. Chem. 1990, A27, 125. (d) Kurita, K.; Inoue, S.;
Yamamura, K.; Yoshino, H.; Ishii, S.; Nishimura, S. I. Macromolecules
1992, 25, 3791. (e) Yokozawa, T.; Hayashi, R.; Endo, T. Macromolecules
1993,26,3313.
31.
(a) Tanaka, H.; Kato, H.; Sakai, I.; Sato, T.; Ota, T. Makwmol. Chem.
Rapid Commun. 1987, 8, 223. (b) Yuan, Y.; Song, H.; Xu, G. Polym. Int.
1993, 31, 397.
32.
33.
Birney, D. M.; Houk, K. N. JACS 1990, 112, 4127.

For leading references on asymmetric Diels-Alder reactions, see: (a)
Paquette, L. A. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic:
New York, 1984; Vol. 3, pp 455-483. (b) Oppolzer, W. AG(E) 1984, 23,
876. (c) Carruthers, W. Cycloaddition Reactions in Organic Synthesis;
Pergamon: New York, 1990; pp 61-72.
Evans, D. A.; Chapman, K. T.; Bisaha, J. JACS 1988, 110, 1238.
34.
35.
36.
37.
Castellino, S. JOC 1990, 55, 5197.

Poll, T.; Helmchen, G.; Bauer, B. TL 1984, 25, 2191.
(a) Fringuelli, F.; Pizzo,F.;Taticchi, A.; Wenkert, E. JOC 1983, 48, 2802.
(b) Fringuelli, F.; Pizzo, F.; Taticchi, A.; Halls, T. D. J.; Wenkert, E. JOC
1982, 47, 5056.
38. Liu, H. J.; Ulibarri, G.; Browne, E. N. C. CJC 1992, 70, 1545.
39. Arseniyadis, A.; Rodriguez, R.; Spanevello, J. C; Thompson, A.; Guittet,
E.; Ourisson, G. T 1992, 48, 1255.
40.
41.
Baldwin, S. W.; Greenspan, P.; Alaimo, C ; McPhail, A. T. TL 1991, 42,

5877.
For a recent review of oxyallyl cations, see: Mann, J. T 1986, 42, 4611.
42. Masatomi, O.; Kohki, M.; Tatsuya, H.; Shoji, E. JOC 1990, 55, 6086.
43. Murray, D. H.; Albizati, K. F. TL 1990, 31, 4109.
44. Hoffman, H. M. R. AG(E) 1973, 12, 819; 1984, 23, 1.
45. Suga, H.; Shi, X.; Fujieda, H.; Ibata, T. TL 1991, 32, 6911.
46. For examples of enantioselective synthesis of trans-4-alkoxy-2oxazolines, see: Ito. Y; Sawamura, M.; Shirakawa, E.; Hayashizaki, K.;
Hayashi, T. TL 1988, 29, 235; T 1988, 44, 5253.
47. Engler, T. A.; Wei, D.; Latavic, M. A. TL 1993, 34, 1429.
48. Reviews of ene reactions: (a) Hoffman, H. M. R. AG(E) 1969, 8, 556. (b)
Oppolzer, W.; Sniekus, V. AG(E) 1978, 17, 476. (c) Snyder, B. B. ACR
1980, 13, 426.
49. Lindner, D. L.; Doherty, J. B.; Shoham, G.; Woodward, R. B. TL 1982,
25,5111.
50. Nakatani, Y.; Kawashima, K. S 1978, 147.
Rhne-Poulenc
Ag. Co., Research
Stephen Castellino
Triangle Park, NC, USA
David E. Volk
North Dakota State University, Fargo, ND, USA
383
Solubility: sol THF, toluene, CH 2 Cl 2 .

Form Supplied in: neat as colorless liquid; solution in CH 2 Cl 2 ;
solution in toluene; TiCl 4 2THF [31011-57-1].
Preparative Methods: see Perrin et al. 1
Purification: reflux with mercury or a small amount of pure cop
per turnings and distill under N 2 in an all-glass system. Organic
material can be removed by adding aluminum chloride hexahydrate as a slurry with an equal amount of water (ca. 2% weight
of the amount of TiCl 4 ), refluxing the mixture for 2-6 h while
bubbling in Cl 2 which is subsequently removed by a stream
of dry air, before the TiCl4 is distilled, refluxed with copper,
and distilled again. Volatile impurities can be removed using a
technique of freezing, pumping, and melting.2
Handling, Storage, and Precautions: moisture sensitive; reacts
violently, almost explosively, with water; highly flammable;
toxic if inhaled or swallowed; causes burns on contact with
skin; use in a fume hood.
General Discussion. TiCl4 is a strong Lewis acid and is used

as such in organic reactions. It has high affinity for oxygenated
organic molecules and possesses a powerful, dehydrating ability.
Low-valent titanium, from the reduction of TiCl4 by metal or metal
hydrides, is used for reductive coupling reactions and for reduction
of functional groups.
Carbon-carbon bond formation by reductive coupling of ke
tones by low-valent titanium leads to vicinal diols and alkenes,
as does coupling using low-valent reagents from Titanium(III)
Chloride. Reviews are available on the preparation and reac
tions of low-valent titanium. 3-6 The reagent from Titanium(IV)
Chloride-Zinc in THF or dioxane in the presence of pyridine
transforms ketones into tetrasubstituted alkenes. Unsymmetrical ketones yield (E)/(Z)-isomer mixtures (eq 1). Strongly hin
dered ketones react slowly and may preferentially be reduced
to alcohols.7 Reductive coupling of diketo sulfides yields 2,5dihydrothiophenes (eq 2). 8 The macrocyclic porphycene has been
obtained, albeit in low yield, by McMurry coupling of diformylbipyrrole (eq 3). 9 Aldimines are reductively coupled in a reaction
analogous to the reaction of carbonyl compounds. The product is
a 1:1 mixture of meso- and ()-isomers (eq 4). 10
(1)
(2)
[7550-45-0]
Cl4Ti
(MW 189.68)
(Lewis acid catalyst;52 affects stereochemical course in

cycloaddition 38,39 and aldol reactions; 4-17 electrophilic
substitutions;55 powerful dehydrating agent; when reduced
to low-valent state, effects C-C bond formation by reductive
coupling; 7-9 reduction of functional groups 81 )
Physical Data: mp - 2 4 C , bp 136.4C, d 1.726gcm - 3 .
(3)
(4)
Methylenation of aldehydes and ketones results from reac

tions with the complex from TiCl 4 -Zn and Diiodomethane or
384
Dibromomethane (eq 5). The reagent can be used for methylenation of enolizable oxo compounds.6 Recommended modifi
cations to the reagent have been reported.11 In keto aldehydes,
selective methenylation of the keto group results when the alde
hyde is precomplexed with Titanium Tetrakis(diethylamide).
Chemoselective methenylation of the aldehyde function is pos
sible by direct use of CH2I2/Zn/Titanium Tetraisopropoxide
(eq 6).12 Cyclopropanation to gem-dihalocyclopropanes uses
Lithium Aluminum Hydride-Titanium(IV) Chloride. The exclu
sion of a strong base, as frequently used in alternative procedures,
is an advantage (eq 7).13 Allylation of imines has been effected by
low-valent titanium species generated from TiCl4 and Aluminum
foil (eq 8).14
Titanium enolates are generally prepared by transmetalation of

alkali-metal enolates but may also arise as structural parts of inter
mediates in TiCl4-promoted reactions. This is illustrated in a stere
oselective alkylation using an oxazolidinone as a chiral auxiliary
(eq 11). The enolate, or its ate complex, may be the intermediate
in the reaction.17
(11)
(5)
R 1 ,R 2 = H, aryl, alkyl
(6)
The stereoselectivity in TiCl4-promoted reaction of silyl ketene

acetals with aldehydes may be improved by addition of Triphenylphosphine (eq 12).18 Enol ethers, as well as enol acetates, can
be the nucleophile (eqs 13 and 14).19 2-Acetoxyfuran, in analogy
to vinyl acetates, reacts with aldehydes to furnish 4-substituted
butenolides under the influence of TiCl4 (eq 15).20
(7)
(12)
anti:syn = 10.5:1
no PPh3, 4:1
(8)
(13)
TiCl4 is a powerful activator of carbonyl groups and promotes

nucleophilic attack by a silyl enol ether. The product is a titanium
salt of an aldol which, on hydrolysis, yields a -hydroxy ketone.
(14)
TiCl4 is generally the best catalyst for this reaction. The tem
perature range for reactions with ketones is normally 0-20 C;
aldehydes react even at 78 C, which allows for chemoselectivity (eq 9).15 In a- or -alkoxy aldehydes, the aldol reaction
(15)
can proceed with high 1,2- or 1,3-asymmetric induction. With the
nonchelating Lewis acid Boron Trifluoride Etherate, the diastereoselectivity may be opposite to that obtained for the chelating
Silyl enol ethers react with acetals at 78 C to form -alkoxy
TiCl4 or Tin(IV) Chloride (eq 10).16
ketones.21 In intramolecular reactions, six-, seven-, and eightmembered rings are formed.22 With 1,3-dioxolanes (acetals), 1-2
equiv of TiCl4 leads to pyranone formation (eq 16), whereas no
(9)
cyclization products are obtained with SnCl4 or ZnCl2.23
(16)
(10)
Alkynyltributyltin compounds react with steroidal aldehydes.

In the presence of TiCl4 the reaction gives 9:1 diastereoselectivity (eq 17). Reactions of alkynylmetals with chiral aldehydes
24
generally show only slight diastereoselectivity. With silyloxyacetylenes and aldehydes, ,-unsaturated carboxylic acid esters
are formed with high (E) selectivity (eq 18).25
385
results from the reaction of propargylsilanes with acetals. The

products are -allenyl ethers (eq 24).35
(17)
(23)
(18)
Allylsilanes are regiospecific in their Lewis acid-catalyzed re

actions, the electrophile bonding to the terminus of the allyl
unit remote from the silyl group (eq 19).26,27 Allylstannanes are
less reliable in this respect.26,28 The example in eq 19 illustrates
regioselectivity.29 On extended conjugation the reaction takes
place at the terminus of the extended system (eq 20).30
(24)
Homoallylamines are formed in TiCl4- or BF3OEt2-mediated

reactions between allylstannanes and aldimines. Crotyltributyltin
gives mainly syn--methyl homoallylamines under optimal con
ditions (eq 25).36
(25)
(19)
(20)
Intramolecular reactions work well, both for allylstannanes and

allylsilanes. An epoxide can be the electrophile. Opening of the
epoxide with allylic attack gives the cyclic product (eq 21). TiCl4
is superior to Ti(O-i-Pr)4, SnCl4, and Aluminum Chloride, the
other Lewis acids tested in the cyclization reaction. The reaction
is stereospecific.31
(21)
Stereochemical aspects in these TiCl4-promoted reactions have

been covered in reviews.26,27 Acetals are very good electrophiles
for allylsilanes, and may be better than the parent oxo compounds
because the products are less prone to further reaction; intramolec
ular reactions are facile.26,32 In the unsymmetrical acetal in eq 22,
the methoxyethoxy group departs selectively because of chelation
to the Lewis acid.33
(22)
The TiCl4-mediated addition of allenylsilanes to aldehydes and

ketones provides a general, regiocontrolled route to a wide va
riety of substituted homopropargylic alcohols. With acetals, cor
responding ethers are formed (eq 23).34 Allenylation of acetals
Diastereoselective Mannich reactions may result with TiCl4 as

adjuvant (eq 26); transmetalation of the initial lithium alkoxide
adduct and displacement by a lithium enolate gives a diastereos
electivity of 78%.37
(26)
Lewis acid catalysis increases the reactivity of dienophiles

in Diels-Alder reactions by complexing to basic sites on the
dienophile. In aldehydes, complexation takes place via the lone
pair on the carbonyl oxygen. The stereochemistry is strongly in
fluenced by the Lewis acids.38 Under chelating conditions, when
-alkoxy aldehydes are used, the prevalent products from TiCl4
catalysis have cis configuration (eqs 27 and 28). Stereochemical
aspects of pericyclic pathways or passage through aldol type in
termediates have been summarized and discussed.38,39
(27)
(28)
Ketene silyl acetals can be dimerized to succinates on treatment

with TiCl4 in CH2Cl2 (eq 29). No reaction occurs with TiCl3, nor
386
are other metal salts efficient.40 -Amino esters are formed in the
presence of Schiff bases (eq 30).41
(35)
(29)
(30)
Cycloaddition of alkenes to quinones is effected by TiIV deriva

tives. The composition of the TiIV adjuvant largely controls the
type of cycloadduct. TiCl4 favors [3 + 2] cycloaddition; [2 + 2] cy
cloaddition requires a mixed TiCU-Ti(O-i-Pr)4 catalyst (eq 31 ).42
(36)
Conjugate propynylation of enones results from TiCl4mediated addition of allenylstannanes. Other Lewis acids are in
effective in this reaction (eq 37).48
(37)
(31)
The TiCl4-promoted Michael reaction proceeds under very

mild conditions (78 C); this suppresses side-reactions and 1,5dicarbonyl compounds are formed in good yields.3 For TiCl4sensitive compounds, a mixture of TiCl4 and Ti(O-i-Pr)4 is
used. From silyl enol ethers and ,-unsaturated ketones, 1,5dicarbonyl compounds are formed (eq 32).3 The reaction also
proceeds for ,-unsaturated acetals.43 Silylketene acetals react
with ,-unsaturated ketones or their acetals to form 8-oxo esters
(eq 33).44
(32)
The 3,4-dichloro derivative of squaric acid, on TiCl4-catalysis,

reacts with silyl enol ethers or allylsilanes to form 1,2- or 1,4adducts depending on the substitution. The 3,4-diethoxy deriva
tive, however, adds silyl enol ethers in a 1,4-fashion; the adduct
subsequently eliminates the ethoxy group (eq 38).49
(38)
The Knoevenagel reaction with TiCl4 and a tertiary base (eq 39)
is recommended over methods which rely on strongly basic
conditions.50 The TiCl4-procedure at low temperature is suitable
for base-sensitive substrates.51
(39)
(33)
Conjugate addition of allylsilanes to enones results in regiospecific introduction of the allyl group (eq 34).45 The reaction can be
intramolecular (eq 35).46 TiCl4 or SnCl4 activates nitro alkenes for
Michael addition with silyl enol ethers or ketene silyl acetals. The
silyl nitronate product is hydrolyzed to a 1,4-diketone or -keto
ester (eq 36).47
(34)
TiCl4, as a Lewis acid, is used as a catalyst in Friedel-Crafts

reactions. AlCl3, SnCl4, and BF3OEt2 are more commonly used
Friedel-Crafts catalysts for reactions with arenes.52 Use of TiCl4
as catalyst in the preparation of aromatic aldehydes is shown in
eq 40.53
The formylation reaction can be used to prepare (E)-,unsaturated aldehydes from vinylsilanes by ipso substitution
(eq 41).54 Regioselectivity in alkylation reactions may de
pend on the Lewis catalyst. In a fluorene, regioselective 1,8chloromefhylation results with TiCl4 (eq 42).55 TiCl4 activates
387
nitroalkenes for electrophilic substitution into arenes. The inter

mediate is hydrolyzed to the oxoalkylated product (eq 43).56
(46)
(40)
In analogy to the acylation reactions, vinylsilanes can be alky

lated by ipso substitution. In the example in eq 47, the MEM group
is activated as leaving group by metal complexation61 The silyl
group in allylsilanes directs the incoming electrophile to the allylic -carbon (eq 48). TiCl4 is one of several Lewis acids used for
catalysis in acylations.58 The same reaction is seen in allylsilanes
with extended conjugation.62 eq 49 shows the TiCl4-catalyzed
alkylation of an allylsilane.63
(47)
(41)
(48)
(49)
(42)
TiCl4 is a useful catalyst for the Fries rearrangement of phenol

esters to o- or p-hydroxy ketones (eq 50). TiCl4 is a cleaner cata
lyst than the more frequently used AlCl3, which may cause alkyl
migrations.64
(50)
(43)
TiCl4 is generally a good catalyst for Friedel-Crafts acylation

of activated alkenes. In the acylation of pyrrolidine-2,4-diones,
particularly with unsaturated acyl substrates, TiCl4 is superior to
SnCl4 and BF3OEt2 (eq 44).57
(44)
The ready ipso substitution of a silyl group favors substitution

rather than addition of electrophiles in alkenylsilanes.58 Direct
acylation of isobutene is not satisfactory, but the acylation is suc
cessful on silyl derivatives (eq 45).59 Intramolecular acylation of
alkenylsilanes leads to cyclic products. Even (E)-silylalkenes have
been cyclized to enones (eq 46).60
(45)
TiCl4 is both a strong Lewis acid and a powerful dehydrating

agent, and hence useful as a water scavenger in the synthesis of
enamines. It is particularly useful for the preparation of enamines
of acyclic ketones. It is recommended that TiCl4 is complexed
with the amine before addition of the ketone.65 Highly sterically
hindered enamines are available by this method (eq 51).66 Primary
amines generally react very slowly with aromatic ketones to form
imines. TiCl4 is a good catalyst (eq 52).67
(51)
(52)
TiCl4 with a tertiary base provides mild conditions for dehydra

tion of both aldoximes and primary acid amides to form nitriles.68
Vinyl sulfides are formed from oxo compounds using TiCl4 and a
Next Page
388
tertiary amine.3 TiCl4 activates carbon-carbon double bonds for

thiol addition (eq 53).3
(53)
TiCl4 mediates thioacetalization of aldehydes and ketones with

alkanethiols or alkanedithiols in yields >90%. The reaction is
satisfactory also for readily enolizable oxo compounds.69 Lactols, which are generally more stable than acyclic analogs,
are amenable to dithiol cleavage (eq 54).70
from TiCl4-NaBH4 (1:2) in DME has been described.78 Carboxylic acids can be reduced to primary alcohols by TiCl4-NaBH4
(ratio 1:3). For reduction of amides and lactams the optimum mo
lar ratio is 1:2.79
Several low-valent metal species have been found active in
reductive elimination of vicinal dibromides to the correspond
ing alkenes. In most cases, e.g. with TiCl4-LAH and TiCl4-Zn,
the reactions proceed through predominant anti elimination to
yield alkenes with high isomeric purity.80 The low-valent tita
nium reagent obtained from TiCl4-LAH (ca. 2:1) will saturate the
double bond of enedicarboxylates in the presence of triethylamine
(eq 58).81
(54)
(58)
-Hydroxy amides are formed in a reaction involving an isocyanide, TiCl4, and an aldehyde or a ketone (eq 55).71 Vinyl chlo
rides undergo ready hydrolysis on combined use of TiCl4 and
MeOH-H2O (eq 56).72 TiCl4-mediated hydrolysis of vinyl sul
fides is a good preparative route to ketones.3'73
(55)
Related
Reagents. Dibromomethane-Zinc-Titanium(IV)
Chloride;
Diiodomethane-Zinc-Titanium(IV)
Chloride;
(4R, 5R)-2,2-Dimethyl-4, 5-bis(hydroxydiphenylmethyl)-1,3-dioxolane-Titanium(IV) Chloride; Lithium Aluminum HydrideTitanium(IV) Chloride; Titanium(IV) Chloride-Diazabicyclo[5.4.0]undec-7-ene; Titanium(IV) Chloride-2,2,6,6-Tetramethylpiperidine; Titanium(IV) Chloride-Triethylaluminum; Titanium(IV) Chloride-Zinc.
1. Perrin, D. D.; Armarego, W. L. F.; Perrin, D. R. Purification of

Laboratory Chemicals, 2nd ed.; Pergamon: Oxford, 1980; p 542.
2. Gmelin Handbuch der Anorganischen Chemie; Verlag Chemie:
Weinheim, 1951; Titan, p 92, 299.
3. Mukaiyama, T. AG(E) 1977, 16, 817.
4. Betschart, C.; Seebach, D. C 1989, 43, 39.
5. Pons, J.-M.; Santelli, M. T 1988, 44, 4295.
6.
7.
8.
(56)
Low-valent titanium can be used to reduce sulfides and

haloarenes to the corresponding hydrocarbons (eq 57).3,74 Lowvalent titanium, prepared from TiCl4 and Magnesium Amalgam,
will reduce nitroarenes to amines in THF/t-BuOH at 0 C with
out affecting halo, cyano, and ester groups.75 SnCl2.2H2O is an
alternative reagent for nitro group reduction.76
9.
10.
11.
12.
13.
14.
15.
16.
17. Evans, D. A.; Urp, E; Somers, T. C ; Clark, J. S.; Bilodeau, M. T. JACS

1990, 112, 8215.
(57)
18.
19.
Deoxygenation of sulfoxides is a rapid reaction using [TiCl2]

formed in situ by reduction of TiCl4 with Zn dust in CH2Cl2 or
Et2O at it, with yields in the range 85-90%.77 For deoxygenation
of N-oxides of pyridine-based heterocycles, a reagent prepared
20.
21.
22.
23.
24.
Reetz, M. T. Organotitanium Reagents in Organic Synthesis; Springer:

Berlin, 1986; p 223.
Lenoir, D. S 1977, 553.
(a) Nakayama, J.; Machida, H.; Hoshino, M. TL 1985, 26, 1981. (b)
Nakayama, J.; Machida, H.; Satio, R.; Hoshino, M. TL 1985, 26, 1983.
Vogel, E.; Kcher, M.; Schmickler, H.; Lex, J. AG(E) 1986, 25, 257.
Betschart, C.; Schmidt, B.; Seebach, D. HCA 1988, 71, 1999.
(a) Lombardo, L. TL 1982, 23, 4293. (b) Lombardo, L. OS 1987, 65, 81.
Hibino, J.; Okazoe, T.; Takai, K.; Nozaki, H. TL 1985, 26, 5579.
Mukaiyama, T.; Shiono, M.; Watanabe, K.; Onaka, M. CL 1975, 711.
Tanaka, H.; Inoue, K.; Pokorski, U.; Taniguchi, M.; Torii, S. TL 1990,
31, 3023.
Mukaiyama, T.; Narasaka, K.; Banno, K. JACS 1974, 96, 7503.
(a) Reetz, M. T. AG(E) 1984, 23, 556. (b) Reetz, M. T.; Kesseler, K. CC
1984, 1079.
Palazzi, C.; Colombo, L.; Gennari, C. TL 1986, 27, 1735.

(a) Kitazawa, E.; Imamura, T.; Saigo, K.; Mukaiyama, T. CL 1975, 569.
(b) Mukaiyama, T.; Izawa, T.; Saigo, K. CL 1974, 323.
Shono, T.; Matsumura, Y.; Yamane, S. TL 1981, 22, 3269.
Mukaiyama, T.; Banno, K. CL 1976, 279.
Mukaiyama, T. OR 1982, 28, 203.
Cockerill, G. S.; Kocienski, P. CC 1983, 705.
Yamamoto, Y.; Nishii, S.; Maruyama, K. CC 1986, 102.
Previous Page
TITANIUM TETRAISOPROPOXIDE
25.
Kowalski, C. J.; Sakdarat, S. JOC 1990, 55, 1977.
26.
27.
28.
Fleming, I. COS 1991, 2, 563.

Fleming, I.; Dunogus, J.; Smithers, R. H. OR 1989, 37, 57.
Yamamoto, Y. ACR 1987, 20, 243.
29.
Hosomi, A.; Shirahata, A.; Sakurai, H. TL 1978, 3043.
30.
31.
Seyferth, D.; Pornet, J.; Weinstein, R. M. OM 1982, 1, 1651.

(a) Molander, G. A.; Shubert, D. C. JACS 1987,109, 576. (b) Molander,
G. A.; Andrews, S. W. JOC 1989, 54, 3114.
Mukaiyama, T.; Murakami, M. S 1987, 1043.
32.
33. Nishiyama, H.; Itoh, K. JOC 1982, 47, 2496.

34. (a) Danheiser, R. L.; Carini, D. J.; Kwasigroch, C. A. JOC 1986, 51,
3870. (b) Danheiser, R. L.; Carini, D. J. JOC 1980, 45, 3925.
35.
Pornet, J.; Miginiac, L.; Jaworski, K.; Randrianoelina, B. OM 1985, 4,

333.
36. Keck, G. E.; Enholm, E. J. JOC 1985, 50, 146.
37. Seebach, D.; Betschart, C.; Schiess, M. HCA 1984, 67, 1593.
38. Bednarski, M. D.; Lyssikatos, J. P. COS 1991, 2, 661.
39. Danishefsky, S. J.; Pearson, W. H.; Harvey, D. F. JACS 1984, 106, 2456.
40. Inaba, S.; Ojima, I. TL 1977, 2009.
41. Ojima, I.; Inaba, S.; Yoshida, K. TL 1977, 3643.
42. Engler, T. A.; Combrink, K. D.; Ray, J. E. JACS 1988, 110, 7931.
43. Narasaka, K.; Soai, K.; Aikawa, Y; Mukaiyama, T. BCJ 1976, 49, 779.
44. Saigo, K.; Osaki, M.; Mukaiyama, T. CL 1976, 163.
45. Hosomi, A.; Sakurai, H. JACS 1977, 99, 1673.
46. Majetich, G.; Hull, K.; Defauw, J.; Shawe, T. TL 1985, 26, 2755.
47. Miyashita, M.; Yanami, T.; Kumazawa, T.; Yoshikoshi, A. JACS 1984,
106, 2149.
48. Haruta, J.; Nishi, K.; Matsuda, S.; Tamura, Y; Kita, Y. CC 1989, 1065.
49. Ohno, M.; Yamamoto, Y; Shirasaki, Y; Eguchi, S. JCS(P1) 1993, 263.
50. (a) Lehnert, W. S 1974, 667. (b) Campaigne, E.; Beckman, J. C. 5 1978,
385.
51. Courtheyn, D.; Verhe, R.; De Kimpe, N.; De Buyck, L.; Schamp, N. JOC
1981, 46, 3226.
52. (a) Olah, G. A.; Krishnamurti, R.; Prakash, G. K. S. COS 1991, 3, 293.
(b) Heaney, H. COS 1991, 2, 733.
53. (a) Rieche, A.; Gross, H.; Hft, E. OS 1967, 47, 1. (b) Rieche, A.; Gross,
H.; Hft, E.; Beyer, E. OS 1967, 47, 47.
54.
(a) Yamamoto, K.; Nunokawa, O.; Tsuji, J. S 1977, 721. (b) Yamamoto,
K.; Yoshitake, J.; Qui, N. T., Tsuji, J. CL 1978, 859.
55. Tsuge, A.; Yamasaki, T.; Moriguchi, T.; Matsuda, T.; Nagano, Y.; Nago,
H.; Mataka, S.; Kajigaeshi, S.; Tashiro, M. S 1993, 205.
56. Lee, K.; Oh, D. Y TL 1988, 29, 2977.
57. Jones, R. C. R; Sumaria, S. TL 1978, 3173.
58.
59.
60.
61.
62.
63.
64.
65.
Eyley, S. COS 1991, 2, 707.

Pillot, J.-P.; Bennetau, B.; Dunogues, J.; Calas, R. TL 1980, 21, 4717.
(a) Burke, S. D.; Murtiashaw, C. W.; Dike, M. S.; Strickland, S. M. S.;
Saunders, J. O. JOC 1981, 46, 2400. (b) Nakamura, E.; Fukuzaki, K.;
Kuwajima, I. CC 1983, 499.
Overman, L. E.; Castaeda, A.; Blumenkopf, T. A. JACS 1986, 108,
1303.
Hosomi, A.; Saito, M.; Sakurai, H. TL 1979, 429.
(a) Albaugh-Robertson, P.; Katzenellenbogen, J. A. TL 1982, 23, 723.
(b) Morizawa, Y.; Kanemoto, S.; Oshima, K.; Nozaki, H. TL 1982, 23,
2953.
Martin, R.; Demerseman, P. S 1992, 738.
Carlson, R.; Nilsson, .; Strmqvist, M. ACS 1983, B37,7.
66.
(a) White, W. A.; Weingarten, H. JOC 1967, 32, 213. (b) White, W. A.;
Chupp, J. P.; Weingarten, H. JOC 1967, 32, 3246.
67.
68.
Moretti, I.; Torre, G. S 1970, 141.

(a) Lehnert, W. TL 1971, 559. (b) Lehnert, W. TL 1971, 1501.
389
69. Kumar, V.; Dev, S. TL 1983, 24, 1289.

70. Bulman-Page, P. C.; Roberts, R. A.; Paquette, L. A. TL 1983, 24, 3555.
71. Schiess, M.; Seebach, D. HCA 1983, 66, 1618.
72. (a) Mukaiyama, T.; Imamoto, T.; Kobayashi, S. CL 1973, 261. (b)
Mukaiyama, T.; Imamoto, X; Kobayashi, S. CL 1973, 715.
73. Seebach, D.; Neumann, H. CB 1974, 107, 847.
74. Mukaiyama, T.; Hayashi, M.; Narasaka, K. CL 1973, 291.
75. George, J.; Chandrasekaran, S. SC 1983, 13, 495.
76. (a) Ballamy, F. D.; Ou, K. TL 1984, 25, 839. (b) Varma, R. S.; Kabalka,
G. W. CL 1985, 243.
77. Drabowicz, J.; Mikolajczyk, M. S 1978, 138.
78. Kano, S.; Tanaka, Y; Hibino, S. H 1980, 14, 39.
79. Kano, S.; Tanaka, Y; Sugino, E.; Hibino, S. S 1980, 695.
80. Imamato, T. COS 1991, 1, 231.
81. Hung, C. W.; Wong, H. N. C. TL 1987, 28, 2393.
Norwegian
Lise-Lotte Gundersen
College of Pharmacy, Oslo, Norway
Frode Rise & Kjell Undheim
University of Oslo, Norway
Titanium Tetraisopropoxide1
[546-68-9]
C 12 H 28 O 4 Ti
(MW 284.28)
(mild Lewis acid used as a catalyst in transesterification reactions,

nucleophilic cleavages of 2,3-epoxy alcohols and isomerization
reactions; additive in the Sharpless epoxidation reaction and in
various reactions involving nucleophilic additions to carbonyl and
,-unsaturated carbonyl compounds)
Physical Data: mp 18-20C; bp 218C/10 mmHg; d
0.955 g cm-3.
Solubility: sol a wide range of solvents including ethers,
organohalides, alcohols, benzene.
Form Supplied in: low-melting solid; widely available.
Handling, Storage, and Precautions: flammable and moisture
sensitive; acts as an irritant.
Transesterification and Lactamization Reactions. 2-5 Ti(Oi-Pr)4, as well as other titanium(IV) alkoxides, has been recom
mended as an exceptionally mild and efficient transesterification
catalyst which can be used with many acid-sensitive substrates
(eq 1). 2,3 Thus the acetonide as well as C = 0 , OH, OTBDMS,
and lactam functional groups (eq 2) are unaffected by these con
ditions, although acetates are hydrolyzed to the parent alcohol.
The alcohol solvent employed in such processes need not be an
hydrous, nor need it be identical with the OR group in the titanate,
because exchange of these moieties is generally slow compared
to the transesterification reaction.
(1)
390
(2)
N-Protected esters of dipeptides can be transesterified using

Ti(O-i-Pr)4 in the presence of 4 molecular sieves and this procedure provides a good way of converting methyl esters into their
benzyl counterparts. Such reactions (eq 3) proceed without racemization in 70-85% yield.4 In a related process,5 (3-, 7-, and 8-amino
acids undergo lactamization on treatment with Ti(O-i-Pr)4 in refluxing 1,2-dichloroethane (eq 4).
(3)
The C-3:C-2 selectivity is, in the cases shown above, greater

than 100:1, although lower selectivities (e.g. 20:1) are observed
with other nucleophiles such as Et2NH and PhSH. It should be
noted that glycidic acids and amides react preferentially with dialkylamines at C-2, but one equivalent or greater of Ti(O-i-Pr)4
ensures reaction occurs with high selectivity at C-3. Combining
this type of protocol with the Sharpless asymmetric epoxidation
reaction has permitted the development of stereoselective syntheses (eqs 7 and 8)6,7 of all four stereoisomers of the unusual
N-terminal amino acid of amastatin, a tripeptide competitive inhibitor of aminopeptidases.8
(4)
R, R1 = H, Me
n = 1-3
Nucleophilic Cleavage of 2,3-Epoxy Alcohols and Related

Compounds.6-10 Titanium alkoxides are weak Lewis acids
which generally have no effect on simple epoxides. However, reaction of 2,3-epoxy alcohols (available, for example, from the
Sharpless-type epoxidation of allylic alcohols) with nucleophiles
in the presence of Ti(O-i-Pr)4 results in highly regioselective ringcleavage reactions involving preferential nucleophilic attack at C3 (eq 5).6 In the absence of the titanium alkoxide, no reaction is
observed under otherwise identical conditions, except in the case
of PhSNa.
(5)
R = Me(CH2)2; YH = CH2=CHCH2OH
R = Me(CH2)2; YH = Et2NH
R = Me(CH2)2; YH = PhCO2H
R = Me(CH2)2; YH = TsOH (with 2,6-lutidine)
R = Me(CH2)2; YH = PhSH
R = Me(CH2)6; YH = AcSH
R = Me(CH2)6; Y- = NO3-
90%;C-3:C-2
90%;C-3:C-2
74%;C-3:C-2
64%;C-3:C-2
95%;C-3:C-2
91%;C-3:C-2
86%;C-3:C-2
>
=
>
>
=
>
>
100:1
20:1
100:1
100:1
6.4:1
100:1
100:1
These types of conversion can be extended7 to 2,3-epoxy carboxylic acids (glycidic acids) and the related amides. The former compounds are readily available through Ruthenium(VIII)
Oxide-mediated oxidation of the appropriate 2,3-epoxy alcohols
(eq 6).
(7)
The reaction of both open-chain and cyclic 2,3-epoxy alcohols

with molecular Bromine or Iodine in the presence of Ti(O-i-Pr)4
at 0 C leads to the regioselective formation of halo diols (eq 9).9a
Interestingly, if these reactions are conducted at 25 C a 1:1 mixture of the C-2 and C-3 cleavage products is obtained, and the same
outcome is observed, even at 0C, when the acetate derivative of
the 2,3-epoxy alcohol is involved as substrate. Dialkylamine hydrochlorides can be used as sources of halide nucleophiles in these
types of epoxide ring-cleavage reactions.9b
2,3-Epithio alcohols have been obtained by reacting 2,3-epoxy
alcohols with Thiourea at room temperature or 0C in the presence of Ti(O-i-Pr)4 and using THF as solvent (eq 10).10 The
reactions proceed with high regio- and stereoselectivity, transsubstituted 2,3-epoxy alcohols giving onlytrans-2,3-epithioalcohols with complete inversion of configuration at both stereogenic
centers. However, when cis-2,3-epoxyalcohols are used as starting materials the yields of epithio alcohols were low and thiodiols
were also formed. Epithiocinnamyl alcohols could also be prepared from the corresponding epoxycinnamyl alcohols at 0C.
However, these products were found to decompose to cinnamyl

alcohol and sulfur on standing. Without Ti(O-i-Pr)4, thiourea was
insoluble in THF and the reaction did not proceed. One equivalent
of Ti(O-i-Pr)4 was required to achieve complete reaction, and THF
was the best solvent (no reaction was observed in ether, CH2Cl2,
or benzene under similar conditions).
391
Under similar conditions, the pendant double bond attached to

a 2,3-epoxy alcohol acts as an internal nucleophile attacking at
C-3, resulting, after proton loss, in a mixture of cyclized products
(eq 12).12 The cyclopropane-containing products are believed to
arise via a retro-homo Prins reaction. Pendant triple bonds can also
participate in related cyclization reactions and cyclic allenes result
(eq 13).12 The observation that the threo isomer of the substrate
shown in eq 12 is stable to Ti(O-i-Pr)4 has led to the suggestion that
an intramolecular metal alkoxide is the active catalyst in successful
cyclization reactions.
(12)
(8)
(13)
Ti(O-i-Pr)4 has also played a key role in the synthesis of taxanes

(eq 14).12b,c
(9)
87% (X = I); C-3:C-2 = 7:1

78% (X = Br);C-3:C-2 = 15:l
(14)
(10)
Isomerization Reactions.11-14 The reaction of certain 2,3epoxy alcohols with Ti(O-i-Pr)4 can result in isomerization. For
example (eq 11), reaction of the illustrated substrate in CH2Cl2 results in rearrangement to the isomeric enediol, and this conversion
represents a key step in a synthesis of the marine natural product
pleraplysillin.11
Allylic hydroperoxides, which are readily obtained by reaction of the corresponding alkene with Singlet Oxygen, have been
shown to isomerize to the corresponding 2,3-epoxy alcohol when
treated with catalytic amounts of Ti(O-i-Pr)4 (eq 15).13 The title
reagent is the one of choice when converting di-, tri-, and tetrasubstituted alkenes (both cyclic and acyclic) into the corresponding
2,3-epoxy alcohols by this protocol. The reactions are generally
highly stereoselective and deoxygenation of the allylic hydroperoxide (to give the corresponding allylic alcohol) is not normally
a process which competes significantly with the isomerization reaction.
(15)
(11)
cis:trans = 98:2
This type of chemistry has been extended to the preparation of

epoxy diols from chiral allylic alcohols (eq 16).13,14 The methodology is impressive in that three successive chiral centers are constructed with predictable configuration. Furthermore, the rapid
392
rate of the isomerization process is remarkable, given that a,(3unsaturated diols are generally poor substrates for titanium metalmediated epoxidations. This rate enhancement is attributed to the
tridentate nature of the intermediate hydroperoxides.
(18)
(16)
80% of a 86:14 mixture
Asymmetric Epoxidation Reactions.15 While Ti(O-i-Pr)4

clearly has the capacity to bring about the nucleophilic ringcleavage of 2,3-epoxy alcohols (see above), it remains the pre
ferred species for the preparation of the titanium tartrate com
plex central to the Sharpless asymmetric epoxidation process (see,
for example, eq 7). Since t-butoxide-mediated ring-opening of 2substituted 2,3-epoxy alcohols (a subclass of epoxy alcohols par
ticularly sensitive to nucleophilic ring-cleavage) is much slower
than by isopropoxide, the use of Ti(O-t-Bu)4 is sometimes rec
ommended in place of Ti(O-i-Pr)4. However, with the reduced
amount of catalyst that is now needed for all asymmetric epoxi
dations, this precaution appears unnecessary in most instances.
Nucleophilic Additions to Carbonyl Compounds.16-28 A
wide range of organometallic compounds react with Ti(O-i-Pr)4 to
produce organotitanium/titanium-'ate' species which may exhibit
reactivities that differ significantly from those of their precursor.1
Thus Ti(O-i-Pr)4 forms '-ate' complexes with, amongst others,
Grignard reagents and the resulting species show useful selectivities in their reaction with carbonyl compounds. For example, the
complex with allylmagnesium chloride is highly selective in its
reaction with aldehydes in the presence of ketones, or ketones in
the presence of esters (eq 17).16 Interestingly, the corresponding
amino titanium- 'ate' complexes react selectively with ketones in
the presence of aldehydes.
(17)
Reaction of certain sulfur-substituted allylic anions with Ti(O-iPr)4 produces a 3-(alkylthio)allyltitanium reagent that condenses,
through its -terminus, with aldehydes to give anti--hydroxy
sulfides in a highly stereo- and regioselective manner (eq 18).
These latter compounds can be transformed, stereoselectively, into
trans-vinyloxiranes or 1,3-dienes.17
The titanium species derived from sequential treatment of aalkoxy-substituted allylsilanes with s-Butyllithium then Ti(O-iPr)4 engages in a Peterson alkenation reaction with aldehydes to
give, via electrophilic attack at the -terminus of the allyl anion,
2-oxygenated 1,3-butadienes which can be hydrolyzed to the cor
responding vinyl ketone (eq 19).18a
(19)
The titanium-'ate' complexes of -methoxy allylic phosphine

oxides, generated in situ by reaction of the corresponding lithium
anion and Ti(O-i-Pr)4, condense with aldehydes exclusively at
the -position to produce homoallylic alcohols in a diastereoselective fashion.18b The overall result is the three-carbon homolo
gation of the original aldehyde, and this protocol has been used
in a synthesis of (-)-aplysin-20 from nerolidol.19 The titanium'ate' complex produced by reaction of the chiral lithium anion of
an (E)-crotyl carbamate with Ti(O-i-Pr)4 affords -condensation
products (homoaldols) on reaction with aldehydes.18c,d Allyl an
ions produced by the reductive metalation of allyl phenyl sul
fides condense with ,-unsaturated aldehydes in a 1,2-manner at
the more substituted () allyl terminus in the presence of Ti(O-iPr)4.20 1,2-Addition of dialkylzincs to a,p-unsaturated aldehydes
can be achieved with useful levels of enantiocontrol when the
reaction is conducted using a chiral titanium(IV) catalyst in the
presence of Ti(O-i-Pr)4 (eq 20).21 Higher ee values are observed
when an -substituent (e.g. bromine) is attached to the substrate
aldehyde, but a-substituentcis-relatedto the carbonyl group has
the opposite effect.
(20)
R = Et, 68%; 93% ee
R = C 5 H 11 ,75%;85% ee
R = (CH2)5OPiv,
90%; 92% ee
Highly enantioselective trimethylsilylcyanation of various alde

hydes can be achieved by using Cyanotrimethylsilane in the pres
ence of a modified Sharpless catalyst consisting of Ti(O-i-Pr)4
22
and chiral diisopropyl tartrate. Best results are obtained using

dichloromethane as solvent and isopropanol as additive and run
ning the reaction at 0 C. The same type of catalyst system also ef
fects the asymmetric ring-opening of symmetrical cycloalkene ox
ides with Azidotrimethylsilane.trans-2-Azidocycloalkanolsare
obtained in up to 63% optical yield.22 The titanium amide com
plexes derived from the reaction of lithium dialkylamides with
Ti(O-i-Pr)4 condense with alkyl and aryl aldehydes and the re
sulting aminal derivatives undergo C-O bond displacement by
benzylmagnesium chloride, thereby generating -substituted phenethylamines (eq 21).23
(21)
R1 = alkyl; R2 = alkyl, aryl
The aldol-type condensation of aldehydes and ketones with

ketenimines24 and ketones25 can be catalyzed by titanium alkoxides and, in appropriate cases, useful levels of stereocontrol can
be achieved (eq 22).
reaction is presumed to generate C-allylated -dicarbonyl com

pounds as the primary products of reaction, but these compounds
suffer deacylation in the presence of Ti(O-i-Pr)4.
(24)
1. (a) Shiihara, I.; Schwartz, W. T., Jr.; Post, H. W. CRV 1961, 61, 1. (b)
Reetz, M. T. Top. Curr. Chem. 1982,106, 3. (c) Seebach, D.; Weidmann,
B; Widler, L. Mod. Synth. Methods 1983, 3, 217. (d) Reetz, M. T.
Organotitanium Reagents in Organic Synthesis; Springer: Berlin, 1986.
(e) Hoppe, D.; Kramer, T.; Schwark, J.-R.; Zschage, O. PAC 1990, 62,
1999.
2.
3.
4.
5.
6.
(22)
7.
8.
E:Z=8:92
A variety of useful reducing agents have been generated by

combining hydrides with Ti(O-i-Pr)4.26-28 For example, the com
bination of 5 mol % Ti(O-i-Pr)4 with 2.5-3.0 equiv of Triethoxysilane cleanly hydrosilylates esters to silyl ethers at 40-55 C, and
these latter compounds can be converted into the corresponding
primary alcohols via aqueous alkaline hydrolysis (eq 23).26 The
actual reducing agent is presumed to be a titanium hydride species
which is produced by a -bond metathesis process involving Ti(Oi-Pr)4 and the silane. The procedure has considerable merit in that
no added solvent is required and the active reagent can be gener
ated and used in air. Halides, epoxides, alcohols, and an alkyne all
survive the reduction process. Lithium Borohydride reduction of
2,3-epoxy alcohols yields 1,2-diols highly regioselectively when
used in the presence of Ti(O-i-Pr)4,27 while the combination of
the reagent with Sodium Cyanoborohydride is reported28 to of
fer superior results in reductive amination processes with difficult
carbonyls and those sensitive to acidic conditions.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
(23)
Miscellaneous Applications.2
The chemoselective oxida
tion of alcohols and diols using Ti(O-i-Pr)4/t-Butyl Hydroperox
ide has been reported.29 The title reagent has also been employed
as a catalyst in Diels-Alder reactions30 and as an additive in the
palladium-catalyzed reaction of aryl-substituted allylic alcohols
with zinc enolates of -dicarbonyl compounds (eq 24).31 The latter
393
(a) Imwinkelried, R.; Schiess, M.; Seebach, D. OS 1987, 65, 230. (b)
Seebach, D.; Hungerbhler, E.; Schnurrenberger, P.; Weidmann, B.;
Zuger, M. S 1982, 138.
(a) Schnurrenberger, P.; Zger, M. F.; Seebach, D. HCA 1982, 65, 1197.
(b) Frzou, J. P.; Julia, M.; Liu, L. W.; Pancrazi, A. SL 1991, 618.
Rehwinkel, H.; Steglich, W. S 1982, 826.
Mader, M.; Helquist, P. TL 1988, 29, 3049.
(a) Caron, M.; Sharpless, K. B. JOC 1985, 50, 1557. (b) Aldrichim. Acta
1985, 18, 53.
Chong, J. M ; Sharpless, K. B. JOC 1985, 50, 1560.
Tobe, H.; Morishima, H.; Aoyagi, T.; Umezawa, H.; Ishiki, K.;
Nakamura, K.; Yoshioka, T.; Shimauchi, Y.; Inui, T. ABC 1982, 46,
1865.
(a) Alvarez, E.; Nuez, T.; Martin, V. S. JOC 1990, 55, 3429. (b) Gao,
L.; Murai, A. CL 1989, 357.
Gao, Y.; Sharpless, K. B. JOC 1988, 53, 4114.
Masaki, Y.; Hashimoto, K.; Serizawa, Y.; Kaji, K. BCJ 1984, 57, 3476.
(a) Morgans, D. J., Jr.; Sharpless, K. B.; Traynor, S. G. JACS 1981, 103,
462. (b) Holton, R. A.; Juo, R. R.; Kim, H. B.; Williams, A. D.; Harusawa,
S.; Lowenthal, R. E.; Yogai, S. JACS 1988, 110, 6558. (c) Wender, P. A.;
Mucciaro, T. P. JACS 1992, 114, 5878.
(a) Mihelich, E. D. US Patent 4 345 984 (CA 1983, 98, 125 739c). (b)
Adam, W.; Braun, M.; Griesbeck, A.; Lucchini, V.; Staab, E.; Will,
B. JACS 1989, 111, 203. (c) Adam, W.; Nestler, B. JACS 1993, 115,
7226.
Adam, W.; Nestler, B. AG(E) 1993, 32, 733.
Johnson, R. A.; Sharpless, K. B. COS 1991, 7, 389.
Reetz, M. T.; Wenderoth, B. TL 1982, 23, 5259.
Furuta, K.; Ikeda, Y.; Meguriya, N.; Ikeda, N.; Yamamoto, H. BCJ 1984,
57, 2781.
(a) Murai, A.; Abiko, A.; Shimada, N.; Masamune, T. TL 1984, 25, 4951.
(b) Birse, E. F.; McKenzie, A.; Murray, A. W. JCS(P1) 1988, 1039. (c)
Frzou, J. P.; Julia, M.; Khourzom, R.; Pancrazi, A.; Robert, P. SL 1991,
611. (d) Hoppe, D.; Zschage, O. AG(E) 1989, 28, 69.
19. Murai, A.; Abiko, A.; Masamune, T. TL 1984, 25, 4955.

20. Cohen, T.; Guo, B.-S. T 1986, 42, 2803.
21. Rozema, M. J.; Eisenberg, C.; Ltjens, H.; Ostwald, R.; Belyk, K.;
Knochel, P. TL 1993, 34, 3115.
22. (a) Hayashi, M.; Matsuda, T.; Oguni, N. JCS(P1) 1992, 3135. (b)
Hayashi, M.; Kohmura, K.; Oguni, N. SL 1991, 774.
23. Takahashi, H.; Tsubuki, T.; Higashiyama, K. S 1988, 238.
24. Okada, H.; Matsuda, I.; Izumi, Y. CL 1983, 97.
25. Vuitel, L.; Jacot-Guillarmod, A. HCA 1974, 57, 1703.
394
p-TOLUENESULFONYL CHLORIDE
26.
Berk, S. C.; Buchwald, S. L. JOC 1992, 57, 3751.
27.
Dai, L.; Lou, B.; Zhang, Y.; Guo, G. TL 1986, 27, 4343.
28.
Mattson, R. J.; Pham, K. M.; Leuck, D. J.; Cowen, K. A. JOC 1990,55,
Handling, Storage, and Precautions: freshly purified tosyl chlo

ride should be used for best results. Tosyl chloride is a moisturesensitive, corrosive lachrymator.
2552.
29.
Yamawaki, K.; Ishii, Y.; Ogawa, M. Chem. Express 1986,1, 95.
30.
McFarlane, A. K.; Thomas, G.; Whiting, A. TL 1993, 34, 2379.
31.
Itoh, K.; Hamaguchi, N.; Miura, M.; Nomura, M. JCS(P1) 1992,

2833.
Martin G. Banwell
University of Melbourne, Parkville, Victoria, Australia
General Discussion. The tosylation of alcohols is one of the

most prevalent reactions in organic chemistry.1 Optimized con
ditions for this reaction include the use of a 1:1.5:2 ratio of alcohol/tosyl chloride/pyridine in chloroform (eq 1). 2a This proce
dure avoids formation of unwanted pyridinium salts inherent to
reactions where higher relative quantities of pyridine have been
employed. 2b
(1)
p-Toluenesulfonyl Chloride1
[98-59-9]
C 7 H 7 ClO 2 S
(MW 190.66)
(sulfonyl transfer reagent; O-sulfonylation of alcohols2 for con

version to chlorides 3 or intermolecular4 and intramolecular5
displacements, vicinal diols for epoxidation,6 1,3-diols for
oxetane (formation,7 carboxylic acids for esterification8 or
decarboxylation,9 oximes for Beckmann rearrangements10 or
fragmentations11 and Neber rearrangements,12 hydroxamic acids
for Lossen rearrangements, 13 nitrones for rearrangements,14 con
version of N-cyclopropylhydroxylamines to -lactams;15 Nsulfonylation of aliphatic amines 16 for subsequent deamination17
or displacement,18 aromatic amines for protection;19 Csulfonylation of alkenes20 and silylalkynes;21 dehydration of
ureas, 22 formamides,23 and amides 24 )
Good yields (81-88%) for tosylation have also been observed

under biphasic conditions where Benzyltriethylammonium Chlo
ride is employed as a phase-transfer catalyst between benzene and
aqueous sodium hydroxide solution.2c
It has long been known that it is possible to selectively tosylate
primary over secondary alcohols (eq 2). 2d
(2)
Alternate Names: tosyl chloride.

Physical Data: mp 67-69 C; bp 146 C/15 mmHg.
Solubility: insol H 2 O; freely sol ethanol, benzene, chloroform,
ether.
Form Supplied in: white solid, widely available.
Purification: upon prolonged standing the material develops im
purities of p-toluenesulfonic acid and HCl. Tosyl chloride is
purified by dissolving 10 g in a minimum volume of CHCl 3
(ca. 25 mL), filtering, and diluting with five volumes (ca. 125
mL) of petroleum ether (bp 30-60 C) to precipitate impurities
(mostly tosic acid, mp 101-104C). The solution is filtered,
clarified with charcoal, and concentrated to ca. 40 mL by evap
oration. Further evaporation to a very small volume gives 7 g
of pure white crystals (mp 67.5-68.5C). 25
Tosyl chloride may also be recrystallized from petroleum ether,
from benzene, or from toluene/petroleum ether (bp 40-60C)
in the cold. Tosyl chloride in diethyl ether can be washed with
aqueous 10% NaOH until colorless, then dried with Na 2 SO 4 and
crystallized by cooling in powdered dry ice. It can also be puri
fied by dissolving in benzene, washing with aqueous 5% NaOH,
drying with K 2 CO 3 or MgSO 4 , and distilling under reduced
pressure.26
It is also possible to regioselectively mono-O-tosylate var

ious nonprotected hydroxyl functionalities, as illustrated in
Scheme 1.2e This method employs a preliminary activation of a
glycopyranoside with Di-n-butyltin Oxide and usually requires
the use of a basic catalyst such as 4-Dimethylaminopyridine
(DMAP) in conjunction with tosyl chloride. Regioselectivity dif
fers markedly from acylation reactions and is thought to be a func
tion of changes in the kinetics of the reactions with the various tin
intermediates which are in equilibrium.
Regioselective mono- and ditosylation of aldonolactones has
also been reported.2f A few of these products are shown in
Scheme 2. In no instances was the -hydroxy function tosylated.
The regioselective tosylation of various cyclodextrins has been
reported. The two major products resulting from the tosyla
tion of -cyclodextrin are heptakis(6-O-(p-tosyl))-p-cyclodextrin
(1) and heptakis(6-O-(p-tosyl))-2-O-(p-tosyl))-p-cyclodextrin
(2). 2g,h Yamamura has also prepared hexakis(6-O-(p-tosyl))-cyclodextrins2i as well as polytosylated -cyclodextrins.2j
395
tive groups and with no rearrangement of the allylic substrate

(eq 4).21
(4)
Studies on reactions of various types of alcohols with the related

tosyl chloride/dimefhylaminopyridine (TsCl/DMAP) system have
led to the following conclusions: allylic, propargylic, and glyco
sidc hydroxyls quickly react to form the corresponding chlorides,
2,3-epoxy and selected primary alcohols yield chlorides but at a
slower rate, and reactions of aliphatic secondary alcohols stop at
the tosylate stage. Example reactions are illustrated in eqs 5-10.3a
R1 = R 2 = H
R1 = Ts, R 2 = H (0%)
R 1 = H, R 2 = Ts (92%)
R= H
R = Ts (sole product)
(5)
R= H
R = Ts (99%)
(6)
Scheme 1
(7)
Scheme 2
(8)
(9)
By proper choice of base it is possible to selectively O-tosylate

in the presence of a free amine or N-tosylate in the presence of
a free hydroxyl, with yields in excess of 94% (eq 3). The prob
able explanation for selective O-tosylation in the presence of the
stronger base is formation of an adequate amount of phenoxide to
allow the anion to act as the nucleophile.2k
(10)
(3)
Tosyl chloride has been used in the preparation of allylic

chlorides from their respective alcohols, leaving in place sensi
Attempted tosylation of 3-methoxy-21-hydroxy-5-pregnan20-one afforded its -chloro derivative.3b This reinforces the rule
Avoid Skin Contact with All
Reagents
396
that as hybridization a to the alcohol increases in s character,

displacement of the intermediate tosylate is facilitated (eq 11).
excess of tosyl chloride. This fast reaction, illustrated in eq 16,

can be used to prepare enantiopure epoxides in good to excellent
yields.6b
(11)
(16)
The -chlorination of sulfoxides can also be achieved using

tosyl chloride and pyridine, albeit in poor yield (32%), as shown
in eq 12.3c
(12)
Phase-transfer catalysis has also been successfully employed

to achieve epoxidation. A variety of cyclictrans-substituteddiols
in dichloromethane were treated with a 50% aqueous solution of
sodium hydroxide in the presence of the phase-transfer catalyst
benzyltriethylammonium bromide. Consistently good yields were
achieved for these as well as glycosidic and acyclic substrates
(eq 17).6c
Alcohols treated with tosyl chloride are transformed into their

corresponding sulfonate esters without manipulation of existing
(17)
stereochemistry in the substrate. The p-toluenesulfonyloxy moi
ety subsequently serves as a good leaving group in intermolecular nucleophilic substitution or elimination reactions.4 Treatment
of multifunctional alcohols with tosyl chloride can result in the
A one-pot conversion of a variety of 1,3-diols to oxetanes has
formation of intermediate O-sulfonylated species, which can un
also been reported.7 The procedure entailed alcohol deprotonation
dergo intramolecular displacement of the tosylate group. For ex
with one equivalent of n-Butyllithium followed by treatment with
ample, treatment oftrans-2-hydroxycyclohexaneacetamidewith
tosyl chloride and then a second equivalent of base (eq 18).
tosyl chloride in pyridine is the key step in the conversion of the
lactone of trans-2-hydroxycyclohexaneacetic acid to its cis isomer
(eq 13).5a
(18)
(13)
Alcohols treated with tosyl chloride can also serve as alkylating

agents for thioamides to make thiazolines (eq 14).5b
(14)
Several useful one-pot procedures employing the reaction of

tosyl chloride with vicinal diols have been used to form epox
ides. Treatment of variously substituted diols with 1 equiv of tosyl
chloride and sodium hydroxide in monoglyme provides access to
a variety of 1-alkynyloxiranes (R1 and/or R3 being terminal or
substituted alkynes) in moderate to good yield (eq 15).6a
(15)
Another method entails treatment of the diol in THF with 2.2

equiv of Sodium Hydride followed by reaction with a slight molar
When a solution of a carboxylic acid and an alcohol in pyridine

is treated with tosyl chloride, an ester is formed rapidly in excel
lent yield. This procedure is useful especially in the esterification
of tertiary alcohols. The combination of a carboxylic acid and to
syl chloride serves as a convenient method of in situ preparation
of symmetrical acid anhydrides for further formation of esters and
amides (eq 19). The novelty of this protocol is that the acid can be
recycled through the anhydride stage in the presence of the alco
hol, thereby resulting in complete conversion to the ester (eq 20).8a
Reactivity is determined by the strength of the acid: strong acids
facilitate the esterifications.8b
(19)
(20)
Similarly, a two-step procedure employing treatment of a mix

ture of tosic acid and various amino acids with alcoholic tosyl
chloride results in the isolation of the esters of the amino acids
as their p-toluenesulfonate salts in excellent yield. The tosic acid
used in the esterification is added to make the amino acids more
soluble and to prevent N-tosylation (eq 21).8c
a. ethyl alcohol
b. benzyl alcohol
397
amino acids: Gly, Leu, Tyr, Trp

TsOHH2NCHR'CO2R
a. 90-97%
b. 81-85%
(21)
A novel formal decarboxylation of the amino acid -anilino,-diphenylacetic acid has been observed upon treatment with
tosyl chloride in pyridine.9 It has been proposed that a mixed anhy
dride of p-toluenesulfonic acid has undergone an elimination via
N-deprotonation and synchronous extrusion of carbon monoxide
in this reaction. Interestingly, no N-tosylation occurs (eq 22).
(22)
(26)
2:1:1 inseperable mixture,
Rearrangements of hydroxamic acids using sulfonyl chlorides

have been accomplished, albeit without reported yields, the net
result being a unique variation of the Lossen rearrangement
(eq 27). 13
(27)
Spontaneous Beckmann rearrangement has been observed upon

O-tosylation of oximes. Lactams can therefore be conveniently
prepared from cyclic oximes, as shown in eq 23. 10a The rear
rangement has long been known to proceed with retention of con
figuration of the migrating group. 10b,c This is complementary to
the reaction of oximes with Sulfuric Acid (eq 24). 10b
As an alternative to the Beckmann rearrangement, ketonic nitrones can be treated with tosyl chloride in pyridine in the presence
of water, as illustrated in eq 28. 14
(28)
(23)
(24)
A Beckmann fragmentation of oximes using tosyl chloride in

a basic ethanol-water system has also been observed.11 Forma
tion of the cyclic product shown in eq 25 was consistent with
a base-induced opening of an intermediate lactone followed by
rearrangement and incipient extrusion of benzoic acid.
Rearrangement reactions which utilize tosyl chloride seem to

progress in a two-step process: the displacement of chlorine from
the sulfonyl halide resulting in the formation of an oxygen-sulfur
bond, followed by the migration, elimination, or intramolecu
lar displacement of the sulfonylate anion.8a When the series of
carbinolamines depicted in eq 29 were treated with tosyl chloride,
they decomposed into the corresponding electron-deficient nitro
gen species, which subsequently triggered ring enlargement to the
p-lactams in moderate yields.15
(29)
R = various alkyl groups

(25)
Oximes which are treated with tosyl chloride can also be used
as substrates in the Neber rearrangement to -amino ketones.12a
The mixture shown in eq 26 was further subjected to reductive
amination to yield 14% of the CNS-active cis-N,N-dimethylated
a-amino alcohol. 12b
N-Tosylation is a facile procedure. For inexpensive amines a

useful procedure entails treating 2 equiv of the amine with to
syl chloride. This is the first step in the convenient preparation
of Diazald (N-Methyl-N-nitroso-p-toluenesulfonamide),
a Diazomethane precursor (eq 30). 16a
(30)
398
Protection of 3-amino-3-pyrazoline sulfate, a key intermediate

in the preparation of 3(5)-aminopyrazole, was achieved in the pres
ence of an excess of sodium bicarbonate in good yields (eq 3 l). 16b
tube or bomb (eq 36).20c Cycloheptatriene, 1,4-norbornadiene, and

phenylacetylene are a few examples of a variety of compounds
which are reactive substrates in this protocol.
(36)
(31)
Sodium Carbonate can also be used as the base in the tosylation

of amines, as shown in the reaction of anthranilic acid with tosyl
chloride. There was no competing nucleophilic attack at sulfur by
the resonance-stabilized carboxylate group (eq 32).16c
Radical addition of tosyl chloride to norbornene and aldrin with

out skeletal rearrangement can be achieved using Dibenzoyl Per
oxide as an initiator (eq 37).20a,d Reaction with 1,4-norbornadiene
gives rise to a rearranged addition product.
(37)
(32)
Primary, benzyl, and unhindered secondary amines can be ditosylated and deaminated in good to excellent yields, using Sodium
Borohydride as the nucleophile, to afford the corresponding alkanes; only highly congested substrates experience competing attack
at nitrogen.17 Similarly, primary aliphatic amines, when ditosylated and treated with iodide ion in DMF at 90-120 C yielded, as
their major products, the corresponding alkyl iodides, with some
competition arising from elimination reactions (eqs 33 and 34).18
(33)
(34)
Tosyl chloride has been used in the protection of the imidazole

residue of N-acylhistidine peptides19a,b and the guanidino residue
of arginine peptides.19c The resulting nitrogen-protecting group is
stable to most conditions but is easily removable in anhydrous
hydrogen fluoride at 0 C.
The tosylation of carbon can be accomplished using electron
transfer conditions. Treatment of styrene20a and analogs20b with
Copper(II) Chloride and tosyl chloride or Benzenesulfonyl Chlo
ride results in a formal replacement of the vinyl proton by the
sulfonyl moiety (eq 35). The intermediacy of a trans--chloro
sulfone has been demonstrated by 1H NMR. Treatment with base
induced the elimination of HCl. A variety of other sulfonyl trans
fer reagents can be employed in the synthesis of isolated chloro sulfones, with good results (60-97% yield) for a variety
of alkenes (ethylene, 1-butene, 2-butene, 1-octene, acrylonitrile,
methyl acrylate, and 1,3-butadiene).20a
Treatment of bis(trimethylsilyl)acetylene with tosyl chloride

and a slight excess of anydrous Aluminum Chloride affords ptolyl (trimethylsilyl)ethynyl sulfone, a precursor to the reactive
Michael acceptor ethynyl p-tolyl sulfone (eq 38).21
(38)
The dehydration of ureas employing tosyl chloride provides

access to substituted carbodiimides, as depicted in eq 39. The urea
made from treatment of ethyl isocyanate with N,N-dimethyl-l,3propanediamine was treated in situ with 1.1 equiv of tosyl chloride
and a large excess of Triethylamine to afford the corresponding
carbodiimide in high yield.22a,b
(39)
Various ureas upon treatment with tosyl or benzenesulfonyl

chloride in the presence of a phase transfer catalyst, benzyltriethylammonium chloride, results in moderate to excellent yields
of carbodiimides (eq 40).22c The polymeric carbodiimide in eq 41
offers the advantages of cleaner workup and recyclability if used
to prepare aldehydes under Moffatt oxidation conditions.22d
(40)
(35)
(41)
Although it was found that tosyl chloride does not react with
3-sulfolene at temperatures below 110C, upon further warming
to 140 C addition to the diene afforded l-chloro-4-tosyl-2-butene
in a convenient procedure that did not require the use of a sealed
styrene-divinylbenzene copolymer
1,2,4-TRIAZOLE
Isocyanides can be made from treatment of formamides with
tosyl chloride in pyridine, as illustrated in eq 42. 2 3 a , b Similarly,
nitriles can be synthesized in moderate to good yields by dehydration of primary amides using tosyl chloride in pyridine 23a,b or
quinoline (eq 43). 23c
(42)
(43)
19.
(a) Sakakibari, S.; Fujii, T. BCJ 1969, 42, 1466. (b) Fujii, T.; Sakakibari,
S. BCJ 1974, 47, 3146. (c) Mazur, R. H.; Plume, G. E 1968, 24, 661.
20. (a) Asscher, M.; Vofsi, D. JCS 1964, 4962. (b) Truce, W. E.; Goralski,
C. T. JOC 1970, 35, 4220. (c) Truce, W. E.; Goralski, C. T.; Christensen,
L. W.; Bavry, R. H. JOC 1970, 35, 4217. (d) Cristol, S. J.; Reeder, J. A.
JOC 1961, 26, 2182.
21. Waykole, L.; Paquette, L. A. OS 1989, 67, 149.
22. (a) Sheehan, J. C.; Cruickshank, P. A. OSC 1973, 5, 555. (b) Sheehan, J.
C ; Cruickshank, P. A.; Boshart, G. L. JOC 1961, 26, 2525. (c) Jszay,
Z, M.; Petnehzy, I.; Tke, L.; Szajni, B. S 1987, 520. (d) Weinshenker,
N. M.; Shen, C. M.; Wong, J. Y. OSC 1988, 6, 951.
23.
24.
1. FF 1967, 7, 1179; FF 1972, 3, 292; FF 1974, 4, 510; FF 1975, 5, 676;
FF 1977, 6, 598; FF 1980, 8, 489; FF 1981, 9, 472; FF 1984, 11, 536;
FF 1988, 13,311.
2. (a) Kabalka, G. W.; Varma, M.; Varma, R. S. JOC 1986, 51, 2386. (b)
Marvel, C. S.; Sekera, V. C. OSC 1955, 3, 366. (c) Szeja, W. S 1979, 822.
(d) Johnson, W. S.; Collins, J. C., Jr.; Pappo, R.; Rubin, M. B.; Kropp, P.
J.; Johns, W. F.; Pike, J. E.; Bartmann, W. JACS 1963, 85,1409. (e) Tsuda,
Y.; Nishimura, M.; Kobayashi, T.; Sato, Y.; Kanemitsu, K. CPB 1991, 39,
2883. (f) Lundt, I.; Madsen, R. S 1992,1129. (g) Yamamura, H.; Fujita, K.
CPB 1991, 39, 2505. (h) Ashton, P. R.; Ellwood, P.; Staton, I.; Stoddart,
J. F. JOC 1991, 56, 7274. (i) Fujita, K. E.; Ohta, K.; Masunari, K.; Obe,
K.; Yamamura, H. TL 1992, 33, 5519. (j) Yamamura, H.; Kawase, Y.;
Kawai, M.; Butsugan, Y. BCJ 1993, 66, 585. (k) Kurita, K. CI(L) 1974,
345. (1) Stork, G.; Grieco, P. A.; Gregson, M. OSC 1988, 6, 638.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
(a) Hwang, C. K.; Li, W. S.; Nicolaou, K. C. TL 1984, 25, 2295. (b)
Revelli, G. A.; Gros, E. G. SC 1993, 23, 1111. (c) Hojo, M.; Yoshita,
Z.-i. JACS 1968, 90, 4496.
(a) For a general discussion of S N 2 displacement reactions see: Carey, F.
A.; Sundberg, R. J. Advanced Organic Chemistry Part A: Structure and
Mechanisms, 3rd ed.; Plenum: New York, 1990; pp 261-264. (b) For a
general discussion of leaving group effects see: ibid., pp 290-293.
(a) Brewster, J. H.; Kucera, C. H. JACS 1955, 77, 4564. (b) Eberle, M.
K.; Nuninger, F. JOC 1993, 58, 673.
(a) Holand, S.; Epsztein, R. S 1977, 706. (b) Murthy, V. S.; Gaitonde, A.
S.; Rao, S. P. SC 1993, 285. (c) Sjeja, W. S 1985, 983.
Picard, P.; Leclercq, D.; Bats, J.-P.; Moulines, J. S 1981, 550.
(a) Brewster, J. H.; Ciotti, C. J., Jr. JACS 1955, 77, 6214. (b) Hennion, G.
F.; Barrett, S. O. JACS 1957, 79, 2146. (c) Arai, I.; Muramatsu, I. JOC
1983, 48, 121.
Sheehan, J. C.; Frankenfeld, J. W. JOC 1962, 27, 628.
(a) Oxley, P.; Short, W.F. JCS 1948, 1514. (b) Hill, R. K.; Chortyk, O. T.
JACS 1962, 84, 1064. (c) Wheland, G. W. Advanced Organic Chemistry,
3rd ed., Wiley: New York, 1960; pp 597-610.
Mataka, S.; Suzuki, H.; Sawada, T.; Tashiro, M. BCJ 1993, 66, 1301.
(a) O'Brien, C. CRV 1964, 64, 81. (b) Wnsch, B.; Zott, M.; Hfner, G.
LA 1992, 1225.
Hurd, C. D.; Bauer, L. JACS 1954, 76, 2791.
(a) Barton, D. H. R.; Day, M. J.; Hesse, R. H.; Pechet, M. M. JCS(P1)
1975, 1764. (b) Barton, D. H. R.; Day, M. J.; Hesse, R. H.; Pechet, M.
M. CC 1971, 945.
Wasserman, H. H.; Glazer, E. A.; Hearn, M. J. TL 1973, 4855.
(a) De Boer, T. J.; Backer, H. J. OSC 1963, 4, 943. (b) Dorn, H.; Zubek,
A. OSC 1973, 5, 39. (c) Scheifele, H. J., Jr.; De Tar, D. F. OSC 1963, 4,
35.
Hutchins, R. O.; Cistone, F.; Goldsmith, B; Heuman, P. JOC 1975, 40,
2018.
DeChristopher, P. J.; Adamek, J. P.; Lyon, G. D.; Galante, J. J.; Haffner,
H. E.; Boggio, R. J.; Baumgarten, R. J. JACS 1969, 91, 2384.
399
25.
26.
(a) Stephens, C. R.; Bianco, E. J.; Pilgrim, F. J. JACS 1955, 77, 1701.
(b) Stephens, C. R.; Conover, L. H.; Pasternack, R.; Hochstein, F. A.;
Moreland, W. T.; Regna, P. P.; Pilgrim, F. J.; Pilgrim, F. J.; Brunings, K.
J.; Woodward, R. B. JACS 1954, 76, 3568.
(a) Hertler, W. R.; Corey, E. J. JOC 1958, 23, 1221. (b) Corey, E. J.;
Hertler, W. R. JACS 1959, 81, 5209. (c) Schuster, R. E.; Scott, J. E.;
Casanova, J., Jr. OSC 1973, 5, 772.
Pelletier, S. W. CI(L) 1953, 1034.
Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory Chemicals,
3rd ed.; Pergamon: Oxford, 1988; p 291.
D. Todd Whitaker, K. Sinclair Whitaker & Carl R. Johnson
1,2,4-Triazole
[288-88-0]
C2H3N3
(MW 69.08)
(transacylating agent used for ester and amide synthesis, especially in peptide synthesis; cyclization reactions; oligonucleotide
synthesis)
Physical Data: mp 120-121 C; bp 260 C (dec above 187C);
fp 140C.
Solubility: sol water, alcohol.
Form Supplied in: white powder.
Acylating Reagent. The great ability of triazole to accept and

transfer acyl groups has made it a catalyst for the synthesis of
esters and amides. In particular, triazole has been used in peptide
synthesis, for the formation of peptide links as well as for the
introduction of amino-protecting groups. It acts as a bifunctional
catalyst, accelerating the aminolysis of p-nitrophenyl esters 1 and
p-thiocresyl esters.2 The catalytic effect is both by a general base
mechanism (eq 1) and a specific mechanism (eq 2).
(1)
400
TRICHLOROACETONITRILE
(2)
(2)
(1)
It has been used to introduce the Boc group onto an amino

acid from t-butyl carbonates (eq 3), and it allows the coupling
of an N-protected amino acid with a fully unprotected amino
acid (eq 4). Interestingly, racemization is not observed during coupling of amino acids in the presence of 1,2,4-triazole.1
Nevertheless, its coupling efficiency depends on the reaction
medium and in solvents like DMF, which increase the rate of
aminolysis, its usefulness is limited. 1,2,4-Triazole is now seldom used in peptide synthesis, whereas other catalytic additives
like 1-Hydroxybenzotriazole are widely used as activated esters as well as in conjunction with coupling reagents like 1,3Dicyclohexylcarbodiimide.
1. Beyerman, H. C.; Massen van den Brink, W.; Weygand, F.; Prox, A.;
Konig, W.; Scmidhammer, L.; Nintz, E. RTC 1965, 54, 213.
2.
Wieland, T.; Kahle, W. LA 1966, 691, 212.
3.
Rentzea, C. N. AG(E) 1981, 20, 885.
4.
Reese, C. B.; Titmas, R. C.; Yau, L. TL 1978, 2727.
5.
Blankemeyer-Menge, B.; Nintz, M.; Frank, R. TL 1990, 31, 1701.
Jean-Claude Gesquire
(3)
[545-06-2]
C 2 Cl 3 N
(MW 144.38)
(makes trichloroacetimidates from alcohols; trichloroacetimidates

are used to introduce nitrogen into molecules via rearrangements1c
and cyclizations; trichloroacetimidates are useful alkylating
agentsld,e)
(4)
Catalysis of Ring Formation. 1,2,4-Triazole can induce the

formation of isoxazole rings from conjugated ketones and hydroxylamine (eq 5).3
(5)
Oligonucleotide Synthesis. Sulfonyl derivatives of 1,2,4triazole, e.g. (1), are used as efficient coupling reagents in oligonucleotide synthesis by the phosphotriester method.4 A nitro derivative (2) allows esterification of amino acids onto hydroxymethyl
polymers.5
Physical Data: mp -42C; bp 83-84C; d 1.440 g cm - 3 .

Solubility: sol most organic solvents.
Form Supplied in: neat colorless liquid.
Analysis of Reagent Purity: 1HNMR, l3CNMR.
Handling, Storage, and Precautions: toxic lachrymator; use only
in a fume hood. Reagent can be absorbed through the skin.
Always wear gloves when handling this reagent.
Preparation of Trichloroacetimidates. The imidates derived

from the addition of alcohols to trichloroacetonitrile have become
important and versatile intermediates in synthetic chemistry.1
Consequently the principal synthetic use of trichloroacetonitrile
has been in the formation of these useful trichloroacetimidate intermediates. The imidates are most often prepared by simple addition of a sodium or potassium alkoxide to the electron-deficient
trichloroacetonitrile (eq 1). lc,d,2 In certain cases, slight modifications of the above procedure are utilized.2d,3 The product imidates
are isolable and, despite their propensity to rearrange,2b,e,4 can in
some instances be purified by distillation2a,d,e or chromatography. Typically the addition reaction is sufficiently clean to use the
imidates without further purification.2f
(1)
401
TRICHLOROACETONITRILE
Rearrangement of Trichloroacetimidates. The thermal re

arrangement of imidates has been known for many years.2b,4 In
1974, Overman2c described a useful conversion of allylic alco
hols to allylic amines utilizing a [3,3]-sigmatropic rearrangement
of allylic trichloroacetimidates (eq 2). lc,2e In addition to simple
thermolysis it was found that the rearrangement could be cat
alyzed at room temperature with either HgII or PdII salts.1c,5 As
with many sigmatropic rearrangements, the reaction is stereos
elective and produces double bonds of defined stereochemistry
while efficiently transferring chirality.1c,5,6
2f,l0a,b,d
2f
10e
transferred include benzyl,

allyl, propargyl,
and
t-butyl.10c This methodology has been used to protect alcohols.
The use of glycosyl trichloroacetimidates has found widespread
use in the synthesis of oligosaccharides and glycoconjugates
(eq 7). ld,e,11 This is a particularly powerful method for controlling
stereochemistry at the anomeric position.
(6)
R = ArCH2, CH2=CHCH2, MeCCCH2, t-Bu
(7)
(2)
A comparison of reaction conditions5b,c,d has shown that pal

ladium catalysis is particularly effective in achieving complete
chiral transfer (eq 3).5b Propargylic imidates also rearrange when
heated in refluxing xylene.10,7 The initially formed allene under
goes a series of tautomerizations so that amino 1,3-dienes are the
ultimate products (eq 4). lc These dienes have found use in the
Diels-Alder reaction.1c
1. (a) Sandler, S. R.; Karo, W. Organic Functional Group Preparations;

Academic: New York, 1972; Vol. 3, Chapter 8. (b) Patai, S. The Chemistry
of Anticlines and Imidates; Wiley: New York, 1975. (c) Overman, L. E.
ACR 1980, 13, 218. (d) Schmidt, R. R. AG(E) 1986, 25, 212. (e) Schmidt,
R. R. PAC 1989, 61, 1257.
2.
3.
4.
(3)
5.
6.
(4)
7.
8.
Electrophilie Cyclization of Trichloroacetimidates. Tri

chloroacetimidates derived from allylic8a,c-f and homoallylic8b,c
alcohols undergo electrocyclic ring closure when treated with a
source of I + (eq 5).8c Cyclization can also be triggered via the
Lewis acid-mediated opening of epoxides.9 In at least one case
the imidate proved more reactive than related reactions using
carbamates.9c These are useful methods for the stereoselective
introduction of nitrogen into cyclic and acyclic systems.
9.
10.
(5)
11.
Alkylation using Trichloroacetimidates. Under mildly

acidic conditions, alkyl trichloroacetimidates act as reason
able alkylating agents2f,10 toward heteroatom nucleophiles,
most notably alcohols (eq 6). Alkyl groups which have been
(a) Cramer, F.; Pawelzik, K.; Baldauf, H. J. CB 1958, 91, 1049. (b)
Cramer, F.; Hennrich, N. CB 1961, 94, 976. (c) Overman, L. E. JACS
1974, 96, 597. (d) Overman, L. E. JACS 1976, 98, 2901. (e) Clizbe, L.
A.; Overman, L. E. OS 1978, 58, 4. (f) Wessel, H.-P.; Iverson, T.; Bundle,
D. R. JCS(P1) 1985, 2247.
(a) Hauser, F. M.; Ellenberger, S. R.; Glusker, J. P.; Smart, C. J.; Carrell,
H. L. JOC 1986, 57, 50. (b) Oehler, E.; Kotzinger, S. S 1993, 497.
(a) Mumm, O.; Mller, F. CB 1937,70, 2214. (b) McCarty, C. G.; Garner,
L. A. In The Chemistry of Amidines; Patai, S., Ed.; Wiley: New York,
1975; Chapter 4.
(a) Overman, L. E. AG(E) 1984, 23, 579. (b) Metz, P.; Mues, C.; Schoop,
A. T 1992, 48, 1071. (c) Mehmandoust, M.; Petit, Y.; Larcheveque, M.
TL 1992, 33, 4313. (d) Doherty, A. M.; Kornberg, B. E.; Reily, M. D.
JOC 1993, 55, 795.
(a) Yamamoto, Y.; Shimoda, H.; Oda, J.; Inouye, Y. BCJ 1976, 49, 3247.
(b) Isobe, M.; Fukuda, Y.; Nishikawa, T.; Chabert, P.; Kawai, T.; Goto,
T. TL 1990, 31, 3327.
Overman, L. E.; Clizbe, L. A. JACS 1976, 98, 2352.
(a) Cardillo, G.; Orena, M ; Porzi, G.; Sandri, S. JCS(C) 1982, 1308.
(b) Cardillo, G.; Orena, M.; Porzi, G.; Sandri, S. JCS(C) 1982, 1308.
(c) Fraser-Reid, B.; Pauls, H. W. JOC 1983, 48, 1392. (d) Bongini, A.;
Cardillo, G.; Orena, M ; Sandri, S.; Tomasini, C. JOC 1986, 51, 4905.
(e) Cardillo, G.; Orena, M.; Sandri, S.; Tomasini, C. T 1986, 42, 917. (f)
Sammes, P. G.; Thetford, D. JCS(P1) 1988, 111.
(a) Jacobsen, S. ACS 1988, B42, 605. (b) Schuerrle, K.; Beier, B.;
Piepersberg, W. JCS(P1) 1991, 2407. (c) Hart, T. W.; Vacher, B. TL
1992, 33, 3009.
(a) Amouroux, R.; Gerin, B.; Chastrette, M. T 1985, 41, 5321. (b)
Widmer, U. S 1987, 568 (c) Armstrong, A.; Brackenridge, I.; Jackson,
R. F. W.; Kirk, J. M. TL 1988, 29, 2483. (d) Audia, J. E.; Boisvert, L.;
Patten, A. D.; Villalobos, A.; Danishefsky, S. J. JOC 1989, 54, 3738, (e)
Wei, S. Y.; Tomooka, K.; Nakai, T. T 1993, 49, 1025. (f) Bourgeois, M.
J.; Montaudon, E.; Maillard, B. T 1993, 49, 2477.
(a) Nicolaou, K. C.; Daines, R. A.; Ogawa, Y.; Chakraborty, T. K. JACS
1988, 110, 4696. (b) Barrett, A. G. M.; Pilipauskas, D. JOC 1991, 56,
2787.
Patrick G. McDougal
Reed College, Portland, OR, USA
402
2,4,6-TRICHLOROBENZOYL CHLORIDE
carboxylate anion (6) a good leaving group, enhancing the rate of
reaction.
[4136-95-2]
C 7 H 2 Cl 4 O
(MW 243.89)
(strong acylating agent; used with DMAP in the formation

of esters,1 thioesters,2 amides,3 and, particularly, small- and
medium-ring lactones1,4)
Physical Data: bp 107-108 cC/6mmHg; d 1.561 g cm -3 .
Form Supplied in: liquid; commercially available.
Purification: redistill under reduced pressure.5
Preparative Methods: first prepared by Yamaguchi from 2,4,6trichloroaniline,7 but Seebach has reported a simpler synthesis
from 1,3,5-trichlorobenzene (1) (eq 1).8
Lactone Formation. Although many methods exist for lactonizing ,-hydroxy acids,10 2,4,6-trichlorobenzoyl chloride re
mains one of the most powerful and has been widely used in
the synthesis of naturally occurring macrolides.11 Yamaguchi first
showed how 9-, 12-, and 13-membered lactones could be synthe
sized using high dilution techniques (Table 1)1 and went on to
demonstrate the potential of his reagents by using them to syn
thesize methynolide and ()-brefeldin A (7) (eq 3), 12- and 13membered lactones, respectively.712
Table 1 Synthesis of Lactones1
Ring size of
lactone formed
9
1013
12
13
DMAP
(equiv)
Time of
addition (h)
3
6
6
6
8
20
5
1.5
Yield of
monomer
Yield of
dimer
(%)
(%)
36
33
48
67
23
0
20
10
(1)
Handling, Storage, and Precautions: irritant and moisture sensi

tive. Incompatible with strong bases (see Aldrich safety index
for Benzoyl Chloride).6
Carboxylic Acid Derivatives. 2,4,6-Trichlorobenzoyl chlo
ride was designed to react rapidly with carboxylic acids to form
mixed anhydrides (2),9 which would then quickly react with alco
hols, amines, and thiols to give esters (3), amides (4), and thioesters
(5) in high yields (eq 2).
(3)
Other groups have also used the Yamaguchi lactonization pro

cedure to synthesize natural products, most notably Seebach in the
synthesis of (+)-myscovirescine M2, a 27-membered lactone, in
which the seco acid was converted to the lactone in 83% yield.14
Symmetrical diolides (8) have been prepared from unprotected
seco acids in fair yields (eq 4)15 when other lactonization pro
cedures failed.9 Unsymmetrical diolides require protected seco
acids.16
(2)
+ RCO2R1 or RCONR2R3 or RCOSR4

(3) 95-100% (4) ~90% (5) 80-90%
The trichloro-substituted phenyl ring serves two purposes: to

prevent any side reaction occurring, due to attack of the alcohol
at the carbonyl adjacent to the aromatic ring, and to make the
(4)
More recently, treatment of 3-hydroxybutanoic acid (9) under

the Yamaguchi lactonization conditions of high dilution gave, in
2,4,6-TRICHLOROBENZOYL CHLORIDE
403
equal proportions, macropentolides, macrohexolides, and macroheptolides in good yields (eq 5).17
(5)
(8)
n = 5,6, 7
ratio 1:1:1
The Shanzer lactonization method produces a lower over

all yield of macrolides, but an increased ratio of the higher
homologs.18
Effect on Stereochemistry. The Yamaguchi esterification is
also often used in preference to other methods because of its lack
of racemization of stereogenic centers. Kunz used it to esterify an
N-Boc protected aspartate (10)19 when other methods have been
known to racemize the chiral center (eq 6).20
Limitations of the Yamaguchi Lactonization Conditions.

The tendency of the Yamaguchi lactonization conditions to form
diolides from some seco acids, as shown by Seebach,15 can also
pose a problem. Steglich has shown that some ,-hydroxy acids
(13) tend to dimerize under the Yamaguchi lactonization condi
tions. However, by using a modified Mitsunobu lactonization, the
monolide was obtained in 59% yield (eq 9). All other lactoniza
tion procedures also gave varying amounts of diolide, including
the standard Mitsunobu lactonization procedure.23
(6)
(9)
The Yamaguchi lactonization also leaves intact any stereochem

istry at the carbon bearing the hydroxyl group. This is in contrast
to the Mitsunobu lactonization, which inverts that stereochemistry
(eq 7).21
+ Tetrolide, 0%
(7)
Furthermore, when no base is present during esterification, dou

ble bonds are also little affected, as Greene showed when convert
ing a variety of alcohols to angelate esters (12) in quantitative
yield; standard esterification procedures gave a mixture of ange
late and tiglate esters (eq 8).22
Related Reagents. 2-Chloro-1-methylpyridinium Iodide;

1,3-Dicyclohexylcarbodiimide; 2-Thiopyridyl Chloroformate;
Trimethylacetyl Chloride.
1. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. BCJ 1979,
52, 1989.
2. (a)FF 1984, 11,552. (b) Kawanami, Y.; Dainobu, Y.; Inanga, J.; Katsuki,
T.; Yamaguchi, M. BCJ 1981, 54, 943.
3. Tanaka, T.; Sato, T.; Imura, T. Jpn. Patent 0499 757 [92 99757] (CA
1992, 117, 111 155h)
4. FF 1981, 9, 478.
5. Harwood, L. M.; Moody, C. J. Experimental Organic Chemistry;
Blackwell: Oxford, 1989; p 147.
6. Sigma-Aldrich Library of Chemical Safety Data, 2nd ed.; Lenga, R. E.,
Ed.; Sigma-Aldrich: Milwaukee, 1987; Vol. 2, p371B.
7. Inanaga, J.; Katsuki, T.; Takimoto, S.; Ouchida, S.; Inoue, K.; Nakano,
A.; Okukado, N.; Yamaguchi, M. CL 1979, 1021.
8. Sutter, M. A.; Seebach, D. LA 1983, 939.
9. Albertson, N. F. OR 1962, 12, 157.
10. (a) Corey, E. J.; Nicolaou, K. C. JACS 1974, 96, 5614. (b) Corey, E.
J.; Brunelle, D. J. TL 1976, 3409. (c) Mukiyama, T.; Usui, M.; Saigo,
K. CL 1976, 49. (d) Boden, E. P.; Keck, G. E. JOC 1985, 50, 2394. (e)
Mitsunobu, O. S 1981, 1.
11. See, for example: (a) Seebach, D.; Brndli, U.; Mller, H.-M.; Dobler,
M.; Egli, M.; Przybylski, M.; Schneider, K. HCA 1989, 72, 1704. (b)
Mulzer, J.; Mareski, P. A.; Buschmann, J.; Luger, P. S 1992, 215.
404
TRIETHYLALUMINUM
12. Honda, M.; Hirata, K.; Sueoka, H.; Katsuki, T.; Yamaguchi, M. TL 1981,
22, 2679.
13.
Inanaga, J.; Kawanami, Y.; Yamaguchi, M. BCJ 1986, 59, 1521.
14.
Seebach, D.; Maestro, M. A.; Sefkow, M.; Neidlein, A.; Sternfeld, F.;
Adam, G.; Sommerfeld, T. HCA 1991, 74, 2112.
15.
Seebach, D.; Chow, H.-R; Jackson, R. F. W.; Sutter, M. A.; Thaisrivongs,

S.; Zimmerman, J. LA 1986, 1281 and references cited therein.
16.
Schregenberger, C.; Seebach, D. LA 1986, 2081.
17.
(a) Seebach, D.; Brndli, U.; Schnurrenberger, P. HCA 1988, 71, 155. (b)
For a review of poly(hydroxyalkanates), see: Mller, H.-M.; Seebach, D.
AG(E) 1993, 32, 477.
18.
Seebach, D.; Brndli, U.; Mller, H.-M.; Dobler, M.; Egli, M.;
Przybylski, M.; Schneider, K. HCA 1989, 72, 1704.
can be effected with Et3 Al. -Lactols react with Et 3 Al in the pres
ence of Boron Trifluoride Etherate to deliver 2,5-disubstituted
tetrahydrofurans stereoselectively (eq 3). 5
(1)
(2)
19. Waldmann, H.; Kunz, H. JOC 1988, 53, 4172.

20.
21.
Tsutsui, H.; Mitsunobu, O. TL 1984, 25, 2163.
22. Hartmann, B.; Kanazawa, A. M.; Deprs, J.-P.; Greene, A. E. TL 1991,

32, 5077.
23.
(3)
Justus, K.; Steglich, W. TL 1991, 32, 5781.
Richard A. Ewin
Triethylaluminum1
trans:cis = 13:1
Conjugate addition of Et 3 Al to 2-nitrofurans provides, after

hydrolysis, dihydro-2(3H)-furanones (eq 4). 6 Regioselective ad
dition of Et 3 Al to unsymmetrical l,l'-azodicarbonyl compounds
has been reported.7
(4)
[97-93-8]
C 6 H 15 Al
(MW 114.19)
2-5
(Lewis acid and source of nucleophilic ethyl groups;

couples with alkenyl halides in the presence of a transition metal
catalyst; 8-11 selective hydrocyanation agent in combination with
HCN 12 )
Physical Data: mp - 5 8 C ; bp 62C 0.8 mmHg; d 0.835 g c m - 3
(25 C).
Solubility: freely miscible with saturated and aromatic hydrocarbons; reacts violently with H 2 O and protic solvents.
Form Supplied in: as a neat liquid in a stainless container or as a
solution in hydrocarbon solvents (hexane, heptane, toluene).
Analysis of Reagent Purity: brochures from manufacturers, describe an apparatus and method for assay.
Handling, Storage, and Precautions: indefinitely stable under an
inert atmosphere. The neat liquid or dense solutions are highly
pyrophoric. Solutions more dilute than a certain concentration
are not pyrophoric and are safer to handle. The nonpyrophoric
limits are 13 wt % in isopentane, 12 wt % in hexane, and 12
wt % in heptane, respectively. Use of halogenated hydrocarbons as solvents should be avoided because of possible explosive reactions sometimes observed for mixtures of CCl 4 and
organoaluminums.
Ethylation. Et 3 Al, like other organoaluminums, can act as a

Lewis acid to activate Lewis basic functionalities and also as a captor of electrophilic species by ethylation, as illustrated in eq 1. 2
Substitution reactions of glycosyl fluorides (eq 2) 3 and bromides 4
Cross coupling of Et 3 Al with aryl phosphates 8 or alkynyl

bromides 9 proceeds with a Ni catalyst to provide alkylated arenes
or alkynes (eqs 5 and 6). While Pd or Cu complexes are used as the
catalyst for the coupling of Et 3 Al with carboxylic acid chlorides
or thioesters (eq 7), 10 Iron(III) Chloride is used for reactions of
propargyl acetates to give substituted allenes (eq 8). 11
(5)
(6)
(7)
(8)
Lewis Acid. Et3Al-Hydrogen Cyanide and Diethylaluminum

Cyanide are two optional reagents for conjugate hydrocyana
tion of ,-unsaturated ketones. 12,13 The results from these two
TRIETHYLALUMINUM
reagents often differ. Due to a rather slow reaction rate between

Et3Al and HCN, the former reagent contains a proton source
(HCN) which can quench aluminum enolate intermediates. An
impressive example is shown in eq 9. Preformed Et2AlCN gives
cis-isomer, whereas HCN-Et3Al leads tofrans-isomer.14A vari
ant involves trapping of the enolates as TMS ethers by use of
Cyanotrimethylsilane-Et3Al (eq 10).14
405
Rearrangements. Allyl vinyl ethers undergo [3,3]sigmatropic rearrangements promoted by Et3Al, which also
effects subsequent ethylation of the resulting aldehydes (eq 13).
Use of Triisobutylaluminum leads to primary alcohols by
-hydride reduction.17
(13)
Alkylative Beckmann rearrangements of oxime sulfonates are

promoted by trialkylaluminums. The rearrangements give the
imines, which are reduced with Diisobutylaluminum Hydride to
the corresponding amines (eq 14).18 Related alkylative Beckmann
fragmentations have also been reported.19
(14)
(9)
Et2AlCN, Ph, 99%

Et3Al-HCN, THF, 89%
15:1
1:5
(10)
Et3Al promotes stereospecific pinacol-type rearrangements

of chiral -methanesulfonyloxy alcohols. Aryl20a or alkenyl
groups20b cleanly take part in the 1,2-migration to provide a range
of -chiral ketones (eq 15). The 1,2-migration of alkyl groups is
effected by the more Lewis acidic Diethylaluminum Chloride.20c
The reagent combination of DIBAL and Et3Al effects the reduc
tive 1,2-rearrangement of -mesyloxy ketones (eq 16).20d,e
(15)
The HCN-Et3Al system has been used to cleave oxiranes in

steroids15a or carbohydrates (eq 11) to give -cyano alcohols.15b
(16)
(11)
The ate complex, formed on metalation of allyl i-propyl ether

with s-Butyllithium followed by addition of Et3Al, reacts with
carbonyl compounds at the -position in syn-selective manner
(eq 12).16
Cyclopropanation. The reagent combination of Diiodomethane and Et3Al (or other organoaluminums) leads to
cyclopropanation of alkenes (eq 17).21
(17)
Related
minum.
(12)
syn:anti = 92:8
none, 95%
28:72
Et3Al, 81% >99:<1
Reagents. Titanium(IV)
Chloride-Triethylalu-
1. (a) Mole, T.; Jeffery, E. A. Organoaluminum Compounds; Elsevier:

Amsterdam, 1972. (b) Reinheckel, H.; Haage, K.; Jahnke, D. Organomet.
Chem. Rev. A 1969, 4, 47. (c) Lehmkuhl, H.; Ziegler, K.; Gellert, H. G.
MOC 1970, 8/4. (d) Negishi, E. JOM Libr. 1976, 1, 93. (e) Yamamoto,
H.; Nozaki, H. AG(E) 1985, 17, 169. (f) Negishi, E. Organometallics
in Organic Synthesis; Wiley: New York, 1980; Vol. 1, pp 286-393, (g)
406
TRIETHYL ORTHOFORMATE
Eisch, J. J. In Comprehensive Organometallic Chemistry, Wilkinson,

G.; Stone, F. G. A.; Abel, E. W., Eds.; Pergamon: Oxford, 1982; Vol.
1, pp 555-682. (h) Zietz, J. R. Jr.; Robinson, G. C ; Lindsay, K. L. In
Comprehensive Organometallic Chemistry, Wilkinson, G.; Stone, F. G.
A.; Abel, E. W., Eds.; Pergamon: Oxford, 1982; Vol. 7, pp 365-464.
(i) Maruoka, K.; Yamamoto, H. AG(E) 1985, 24, 668. (j) Maruoka, K.
Yamamoto, H. T 1988, 44, 5001.
2.
3.
4.
5.
6.
7.
8.
9.
Hashimoto, S.; Kitagawa, Y.; Iemura, S.; Yamamoto, H.; Nozaki, H. TL

1976,2615.
(a) Posner, G. H.; Haines, S. R. TL 1985, 26, 1823. (b) Nicolaou, K. C.;
Dolle, R. E.; Chucholowski, A.; Randall, J. L. CC 1984, 1153.
Tolstikov, G. A.; Prokhorova, N. A.; Spivak, A. Yu.; Khalilov, L. M.;
Sultanmuratova, V. R. ZOK 1991, 27, 2101.
Tomooka, K.; Matsuzawa, K.; Suzuki, K.; Tsuchihashi, G. TL 1987, 28,
6339.
Pecunioso, A.; Menicagli, R. JCR(S) 1988, 228.
Yamamoto, Y.; Yumoto, M.; Yamada, J. TL 1991, 32, 3079.
Hayashi, T.; Katsuro, Y.; Okamoto, Y.; Kumada, M. TL 1981, 22, 4449.
Giacomelli, G.; Lardicci, L. TL 1978, 2831.
10.
(a) Takai, K.; Oshima, K.; Nozaki, H. BCJ 1981, 54, 1281. (b)
Wakamatsu, K.; Okuda, Y.; Oshima, K.; Nozaki, H. BCJ 1985, 58, 2425.
11. Tolstikov, G. A.; Romanova, T. Yu.; Kuchin, A. V. JOM 1985, 285, 71.
12. (a)Nagata, W.; Yoshioka, M. OS 1972, 52, 100. (b)Nagata, W.; Yoshioka,
M. OR 1977, 25, 255.
13. Ireland, R. E.; Dawson, M. I.; Welch, S. C.; Hagenbach, A.; Bordner, J.;
Trus, B. JACS 1973, 95, 7829.
14. (a) Utimoto, K.; Obayashi, M.; Shishiyama, Y.; Inoue, M.; Nozaki, H.
TL 1980, 21, 3389. (b) Utimoto, K.; Wakabayashi, Y.; Horiie, T.; Inoue,
M.; Shishiyama, Y.; Obayashi, M.; Nozaki, H. T 1983, 39, 967.
15.
(a) Nagata, W.; Yoshioka, M.; Okumura, T. TL 1966, 847. (b) Davidson,
B. E.; Guthrie, R. D.; McPhail, A. T. CC 1968, 1273.
(a) Yamamoto, Y.; Yatagai, H.; Maruyama, K. JOC 1980, 45, 195. (b)
Yamamoto, Y.; Yatagai, H.; Saito, Y.; Maruyama, K. JOC 1984, 49,1096.
(c) Yamamoto, Y.; Saito, Y.; Maruyama, K. JOM 1985, 292, 311.
17. (a) Takai, K.; Mori, I.; Oshima, K.; Nozaki, H. TL 1981, 22, 3985. (b)
Takai, K.; Mori, I.; Oshima, K.; Nozaki, H. BCJ 1984, 57, 446.
Triethyl Orthoformate1
(1;R = Et)
[122-51-0]
(2;R = Me)
[149-73-5]
C 7 H 16 O 3
(MW 148.23)
C 4 H 10 O 3
(MW 106.14)
(precursor for higher analogs by reaction with alcohols,1c including cyclic orthoesters from polyols;2 for deoxygenation of 1,2diols, affording alkenes;3 acetalization of carbonyl compounds;4
a dehydrating agent5 for enol ether formation;6 esterification
of acids;7 formylation of active methylene compounds,8 heteroatom nucleophiles9 and organometallic reagents;10 formylation of electron-rich species; dialkoxycarbenium ion precursor;11
solvent for thallium trinitrate reactions12)
Alternate Name: triethoxymethane.
Physical Data: (1) bp 146C; d = 0.891 gcm - 3 ; (2) bp 102C;
d= 0.970 g cm - 3 .
Form Supplied in: clear liquid; widely available.
Purification: distillation.
Handling, Storage, and Precautions: highly moisture sensitive;
flammable; irritant with high volatility. Use in a fume hood.
16.
18.
(a) Hattori, K.; Matsumura, Y.; Miyazaki, T.; Maruoka, K.; Yamamoto,
H. JACS 1981, 103, 7368. (b) Sakane, S.; Matsumura, Y.; Yamamura,
Y.; Ishida, Y.; Maruoka, K.; Yamamoto, H. JACS 1983, 105, 672. (c)
Maruoka, K.; Miyazaki, T.; Ando, M.; Matsumura, Y.; Sakane, S.;
Hattori, K.; Yamamoto, H. JACS 1983, 705, 2831.
19.
Fujioka, H.; Yamanaka, T.; Takuma, K.; Miyazaki, M.; Kita, Y. CC 1991,
533.
(a) Suzuki, K.; Katayama, E.; Tsuchihashi, G. TL 1983, 24, 4997. (b)
Suzuki, K.; Katayama, E.; Tsuchihashi, G. TL 1984, 25,1817. (c) Suzuki,
K.; Tomooka, K.; Tsuchihashi, G. TL 1984, 25, 4253. (d) Suzuki, K.;
Tomooka, K.; Katayama, E.; Matsumoto, T.; Tsuchihashi, G. JACS 1986,
108, 5221. (e) Suzuki, K.; Katayama, E.; Matsumoto, T.; Tsuchihashi,
G. TL 1984, 25, 3715.
20.
21.
(a) Maruoka, K.; Fukutani, Y.; Yamamoto, H. JOC 1985, 50, 4412. (b)
Maruoka, K.; Sakane, S.; Yamamoto, H. OS 1988, 67, 176.
Keisuke Suzuki & Tetsuya Nagasawa

Keio University, Yokohama, Japan
Introduction. The orthoformates are a remarkably useful

group of reagents. They are shelf-stable, yet highly reactive. As
alkylating agents, they readily transfer the associated alkyl group,
a large variety of which are easily available. As formylation
reagents, they are reactive under both acidic and basic conditions.
The choice of ester is often arbitrary in this context.
Transesterification.
Higher Orthoformates. While there are many ways to obtain
esters of orthoformic acid,lc an easy method takes advantage of the
rapid equilibrium among orthoesters (eq 1). By starting with the
lowest analog, trimethyl orthoformate, essentially complete conversion to the higher esters is possible by carrying out the reaction
at such a temperature as to distill away the evolving methanol. It is
important that reactions be carried out under anhydrous conditions
to avoid formation of the formate through hydrolysis.
HC(OR)3 + 3 R'OH
HC(OR')3 + 3 ROH
(1)
Cyclic Orthoformates.2 When the above strategy is applied to

polyols, cyclic orthoformates can be isolated. Most common are
the cyclization of 1,3-diols (eq 2)2,13 and 1,2-diols,14 as well as the
formation of caged structures from the use of polyols (eq 3).15,16
Those orthoformates obtained from 1,2-diols (eq 4)3 can undergo cycloelimination upon pyrolysis to afford alkenes in high
yield.17 There are a variety of methods for carrying out this overall
18
process, but the orthoester route is competitive if the alkene is

thermally stable.
407
Esterification. In a related process, orthoformates are good

esterification agents; they operate on carboxylic acids (eq 8),7
sulfonic acids,30 and carboxyboranes,31 often without the need
for acid catalysis.
(2)
(8)
(3)
Formylation. The orthoformate carbon is highly reactive in a

number of bond-forming reactions. It is capable of reaction un
der both electrophilic and nucleophilic conditions and serves as a
formylation reagent.
(4)
Acetals and Enol Ethers. The conversion of the orthoformate

to formate is energetically favored. As a result, the acetalization
of ketones by orthoformate is a highly favored process and allows
the formation of acetals under exceedingly mild conditions. A
wide variety of ketones can be converted into dimethyl acetals by
the action of trimethyl orthoformate and p-Toluenesulfonic Acid.
The methyl formate thus evolved is distilled away.4
The process is general and allows isolation of quite sensitive
acetals (eq 5).19 The technique accommodates protection of ,unsaturated carbonyl compounds.20,21,22 While some form of acid
catalysis is usually needed, there is greatflexibilityin the choice
of acid, including Amberlyst 1523 and, in particular, Montmorillonite K10.24 Cyclic acetals are also accessible (eq 6).25
Active Methylene Compounds. Triethyl orthoformate can

formylate diethyl malonate under slightly acidic conditions.8 With
less activated compounds it can be induced to undergo a Mannich
reaction,32 and can also formylate a cyclohexanone enolate anion
(eq 9).33
(9)
This reaction is noteworthy in its propensity for C-alkylation

and the fact that the protected acetal raises the pKa of the product
relative to the unprotected -dicarbonyl compound.
Heteroatom Nucleophiles. The formylation of anilines is well
known34 and provides entry to a large array of functional groups.35
Of greater interest is the ability of the product to be trapped in a
subsequent reaction to afford heterocycles (eq 10).9,36-38 Ortho
formates also react readily with phosphorus nucleophiles.39
(5)
(6)
Upon distillation of some acetals,26 or upon attempted acetal

ization of highly conjugated species,26,27 the enol ether can also be
observed. The choice of acid often determines whether the acetal
or the enol ether is isolated.
Orthoformates are also useful in promoting the formation of
other acetals5 by functioning as dehydrating agents. This function
is useful for -lactone formation as well (eq 7).28,29
(7)
(10)
Organometallic Reactions. In addition to the enolate reac

tions described above, orthoformates can also carry out the formal
formylation of Grignard reagents.10
Electrophilic Formylation. It has been shown that the dialkoxycarbenium ion can be readily formed by acid treatment
of orthoformates. While the reactive ion can be isolated and used
directly,11 the typical practice is to generate it in situ.
While not as universal as the Gatterman-Koch reaction, the
cation works well for the formylation of activated aromatic comAvoid Skin Contact with All Reagents
408
pounds (eq 11).40,41 Of greater synthetic utility is the effective

formylation of alkynes (eq 12)42 and alkenes (see below).
1. (a) DeWolfe, R. H. Carboxylic Ortho Acid Derivatives; Academic: New

York, 1970. (b) Ghosh, S.; Ghatak, U. R. Proc. Ind. Acad. Sci. 1988,700,
235. (c) DeWolfe, R. H. S 1974, 153.
2.
3.
(11)
Denmark, S. E.; Almstead, N. G. JOC 1991, 56, 6458.

Camps, P.; Cardellach, J.; Font, J.; Ortuno, R. M.; Ponsati, O. T 1982,
38, 2395.
4. Napolitano, E.; Fiaschi, R.; Mastrorilli, E. 5 1986, 122.

5. Marquet, A.; Dvolaitzky, M ; Kagan, H. B.; Mamlok, L.; Ouannes, C.;
Jacques, J. BSF 1961, 1822.
6. Wohl, R. A. S 1974, 38.
7. Cohen, H.; Mier, J. D. Cl(L) 1965, 349.
8. Parham, W. E.; Reed, L. J. OSC 1955, 3, 395.
(12)
Reactions of silyl enol ethers with dialkoxycarbenium ions re

sult in -formyl ketones (eq 13),43 much like those achieved above
through the use of enolate anions. With a dienol silane (eq 14),
regioselective -formylation is achieved.44 In extended alkenic
systems, cationic cyclization (eq 15) can be realized.45
(13)
(14)
(15)
Solvent for Thallium Trinitrate Oxidations. While Thallium(IH) Nitrate oxidations of aromatic ketones and chalcones
often gives rise to mixtures of products, the use of trimethyl orthoformate as solvent gives substantially cleaner reactions and
higher yields (eq 16).12
(16)
Related Reagents. Diethyl Phenyl Orthoformate; Dimethoxycarbenium Tetrafluoroborate; Dimethylchloromethyleneammonium Chloride;

N,N-Dimefhylformamide;
N,N-Dimefhylformamide Diethyl Acetal; Methyl Formate.
9.
10.
11.
12.
Harden, M. R.; Jarvest, R. L.; Parratt, M. J. JCS(P1) 1992, 2259.

Bachman, G. B. OSC 1943, 2, 323.
Pindur, U.; Flo, C. SC 1989,19, 2307.
Taylor, E. C.; Robey, R. L.; Liu, K.-T.; Favre, B.; Bozimo, H. T.; Conley,
R. A.; Chiang, C.-S.; McKillop, A.; Ford, M. E. JACS 1976, 98, 3037.
13. Gardi, R.; Vitali, R.; Ercoli, A. TL 1961, 448.
14. Takasu, M.; Naruse, Y.; Yamamoto, H. TL 1988, 29, 1947.
15. Stetter, H.; Steinacker, K. H. CB 1953, 86, 790.
16. Yu, K.-L.; Fraser-Reid, B. TL 1988, 29, 979.
17. Burgstahler, A. W.; Boger, D. L.; Naik, N. C. T 1976, 32, 309.
18. Block, E. OR 1984, 30, 457.
19. Frickel, F. S 1974, 507.
20.
Taylor, E. C.; Conley, R. A.; Johnson, D. K.; McKillop, A. JOC 1977,

42, 4167.
21.
van Allen, J. A. OSC 1963, 4, 21.
22. Wengel, J.; Lau, J.; Pedersen, E. B.; Nielson, C. M. JOC 1991, 56, 3591.
23. Patwardhan, S. A.; Dev, S. S 1974, 348.
24. Taylor, E. C.; Chiang, C.-S. S 1917, 467.
25. Rychnovsky, S. D.; Griesgraber, G. CC 1993, 291.
26. Meek, E. G.; Turnbull, J. H.; Wilson, W. JCS 1953, 811.
27. van Hulle, F.; Sipido, V.; Vandewalle, M. TL 1973, 2213.
28. Rogic, M. M.; van Peppe, J. F.; Klein, K. P.; Demmin, T. R. JOC 1974,
39, 3424.
29. Blume, R. C. TL 1969, 1047.
30. Padmapriya, A. A.; Just, G.; Lewis, N. G. SC 1985, 75, 1057.
31. Mittakanti, M.; Feakes, D. A.; Morse, K. W. 5 1992, 380.
32. El Cherif, S.; Rene, L. S 1988, 138.
33. Suzuki, S.; Yanagisawa, A.; Noyori, R. TL 1982, 23, 3595.
34. Roberts, R. M.; Vogt, P. J. JACS 1956, 78, 4778.
35. Crochet, R. A.; Blanton, C. D., Jr. S 1974, 55.
36. Jenkins, G. L.; Knevel, A. M.; Davis, C. S. JOC 1961, 26, 274.
37. Patridge, M. W.; Slorach, S. A.; Vipond, H. J. JCS 1964, 3670.
38.
39.
40.
Lee, K.-J.; Kim, S. H.; Kim, S.; Cho, Y. R. S 1992, 929.

Bailie, A. C.; Cornell, C. L.; Wright, B. J.; Wright, K. TL 1992, 33, 5133.
Treibs, W. TL 1967, 4707.
41.
42.
43.
44.
45.
Gross, H.; Rieche, A.; Matthey, G. CB 1963, 96, 308.

Howk, B. W.; Sauer, J. C. OSC 1963, 4, 801.
Mukaiyama, T.; Iwakiri, H. CL 1985, 1363.
Pirrung, M. C.; Thomson, S. A. TL 1986, 27, 2703.
Perron-Sierra, F.; Promo, M. A.; Martin, V. A.; Albizati, K. F. JOC 1991,
56, 6188.
Richard T. Taylor
Miami University, Oxford, OH, USA
TRIFLUOROACETIC ANHYDRIDE
409
Primary alkanols and 2-alkenols are converted into the corre

sponding halides in high yield by a one-pot, two-step reaction
via transformation into intermediate trifluoroacetates, followed
by nucleophilic substitution with lithium halides (eq 5). 9
Trifluoroacetic Anhydride1
(5)
[407-25-0]
C4F6O3
(MW 210.04)
Sulfoxides are reduced to sulfides under mild conditions with
Trifluoroacetic Anhydride-Sodium Iodide (eq 6). 10
(activating agent; oxidation)

Alternate Name: TFAA.
Physical Data: mp - 6 5 C; bp 39-40 C; d 1.487 g c m - 3 .
Solubility: sol C 6 H 6 , CH 2 Cl 2 , Et 2 O, DMF, THF, MeCN.
Analysis of Reagent Purity: by standard analytical techniques.
Preparative Methods: by distilling Trifluoroacetic Acid from
Phosphorus(V) Oxide.1
Handling, Storage, and Precautions: corrosive and moisture sen
sitive; toxic by inhalation; should be freshly distilled prior to
reaction. Use in a fume hood.
Activated Esters. Mixed anhydrides may be prepared by re

action of carboxylic acids with trifluoroacetic anhydride.2 The
method has been used widely as a means of activating carboxyl
groups to nucleophilic attack. The method has also been highly
useful in Friedel-Crafts acylation of arenes (eqs 1 and 2). 3,4 Sul
fonic acids are also activated to nucleophilic attack; substituted
sulfones result. Intramolecular Friedel-Crafts reactions are also
facilitated, but only for formation of six-membered rings.5
(6)
Primary amides are converted under mild conditions to the cor

responding nitriles using TFAA in pyridine (eq 7). 11 Similarly,
aldoximes are converted to nitriles by TFAA in pyridine (eq 8). 12
(7)
(8)
TFAA in triethylamine can be used for the dehydration of aldols

to enones where other methods are less successful (eq 9). 13 When
Acetic Anhydride is employed instead of TFAA, the reaction pro
ceeds slowly.
(9)
(1)
(2)
The Pummerer rearrangement of sulfoxides to -acyloxy sul

fides, induced by TFAA, has been used as a means of converting
sulfoxides to aldehydes (eq 10).14
(10)
Anhydrides of diacids are prepared in (about) 90% yield by

reaction with TFAA in ether.6 The method involves formation of
the monotrifluoroacetyl mixed anhydride, which may be converted
to the cyclic anhydride by heating under vacuum (eq 3). 7
(3)
An inversion of alkene geometry is made possible by the re

action of their derived epoxides with lithium halides and TFAA
(eq 4); 8 the products of this reaction are the corresponding halohydrin trifluoroacetates, which undergo a syn elimination upon
reaction with Lithium Iodide.
(4)
e.g. R = C7H15, PhCH2OCH2
Methyl aryl sulfides are converted in a mild, one-pot, threestep procedure via Pummerer rearrangement of the corresponding
sulfoxides, and without purification of intermediates, to provide
arylthiols in excellent yields (eq 11).15
(11)
Oxidation. Trifiuoroacetoxydimethylsulfonium
trifiuoroacetate is prepared in situ from Dimethyl Sulfoxide and TFAA
below -50C and reacts rapidly with alcohols in the presence
410
TRIFLUOROMETHANESULFONIC ANHYDRIDE
of Triethylamine to give the corresponding carbonyl compounds

(eq 12).16
(12)
TFAA/DMSO also efficiently converts vicinal diols to the

corresponding -dicarbonyl compounds or derivatives thereof
(eq 13).17 Unlike the Swern oxidant (Dimethyl Sulfoxide-Oxalyl
Chloride), this reagent mixture gives good yields for halogenated
substrates. The preparation of previously inaccessible compounds
(such as -homo-ortho-benzoquinones) is thus facilitated.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
(13)
Undesired electrophilic chlorination as a side-reaction in Swern

oxidations is avoided by use of TFAA in place of oxalyl chloride. 18
See also Dimethyl Sulfoxide-Trifluoroacetic Anhydride.
Miscellaneous. Enamines of -amino acids react rapidly with
TFAA to give pyrrole derivatives (eq 14).19
19.
20.
21.
22.
23.
24.
Bourne, E. J.; Stacey, M.; Tatlow, J. C.; Tedder, J. M. JCS 1951, 718.
Galli, C. S 1979, 703.
Ferrier, R. J.; Tedder, J. M. JCS 1957, 1435.
Duckworth, A. C. JOC 1962, 27, 3146.
Moore, J. A.; Kelly, J. E. Org. Prep. Proc. Int. 1974, 6, 255.
Sonnet, P. E. JOC 1980, 45, 154.
Camps, F.; Gasol, V.; Guerrero, A. S 1987, 511.
Drabowitz, J.; Oae, S. S 1977, 404.
Campagna, F.; Carotti, A.; Casini, G. TL 1977, 1813.
Carotti, A.; Canpagna, F. S 1979, 56.
Narasaka, K. OS 1987, 65, 12.
Sugiharo, H.; Tanikoga, R.; Kaji, A. S 1978, 881.
Young, R. N.; Gauthier, J. Y.; Coombs, W. TL 1984, 25, 1753.
Omuro, K.; Sharma, A. K.; Swern, D. JOC 1976, 41, 957.
Amon, C. M.; Banwell, N. G.; Gravatt, G. L. JOC 1987, 52, 4851.
Smith, A. B.; Leenay, T. L.; Liu, H. J.; Nelson, L. A. K.; Ball, R. G. TL
1988, 29, 49.
Gupta, S. K. S 1975, 726.
Ahond, A.; Cav, A.; Kan-Fan, C ; Potier, P. BCF 1970, 2707.
Nordlander, J. E.; Catalare, D. B.; Eberlein, T. H.; Farkas, L. V.; Howe,
R. S.; Stevens, R. M ; Tripoulas, N. A. TL 1978, 19, 4987.
Dampawan, P.; Zajac, W. W. S 1983, 545.
Suri, S. C.; Chapman, R. D. S 1988, 743.
van der Eijk, J. M.; Nolte, R. J. M.; Zwikker, J. W. JOC 1980, 45, 547.
Joseph Sweeney & Gemma Perkins

(14)
The reaction of TFAA with triethylamine N-oxide

leads to formation of the trifluoroacetate salt of N,Ndimethylformaldimmonium ion. This ion is a superior reagent in
the Mannich reaction.20
TFAA is used to prepare trifluoroacetamides from amines; these
amides may be used in Gabriel-type reactions. The use of TFAA
delivers an amide of enhanced acidity and which is easily hydrolyzed in situ, thereby allowing a one-pot alkylation process
(eq 15).21
(15)
Reaction of TFAA with ammonium nitrate provides an in situ

source of trifluoroacetyl nitrate, which has been used for the ni
tration of enol acetates22 and as an N-nitrating agent.23
TFAA efficiently cleaves N-tosyl protecting groups from histidine (eq 16).24
(16)
Related
Chloride.
Reagents. Acetic
Anhydride;
Trifluoroacetyl
1. Tedder, J. M. CR 1955, 55, 787.

2. Emmons, W. D.; McCallum, K. S.; Ferris, A. F. JACS 1953, 75, 6047.
Trifluoromethanesulfonic Anhydride 1
[358-23-6]
C2F6O5S2
(MW 282.16)
(preparation of trifiates;1 mild dehydrating reagent; promoter for

coupling reactions in carbohydrates2)
Alternate Name: triflic anhydride.
Physical Data: bp 81-83 C/745 mmHg; d 1.677 g c m - 3 ; nD20
1.3210.
Solubility: sol dichloromethane; insol hydrocarbons.
Form Supplied in: colorless liquid in ampules. Once opened it
should be immediately used.
Analysis of Reagent Purity: IR, NMR.
Preparative Methods: by distillation of Trifluoromethanesulfonic Acid with an excess of Phosphorus(V) Oxide.1
Purification: by redistillation with a small amount of P 2 O 5 . It is
advisable to freshly distill the reagent from a small quantity of
P 2 O 5 before use.
Handling, Storage, and Precautions: the pure reagent is a colorless liquid that does not fume in air and is stable for a long
period. It is not soluble in water and hydrolyzes only very slowly
to trifiic acid over several days at room temperature. Preferably
stored under N 2 in a stoppered flask.
Reaction with Alcohols and Phenols. The reaction of alcohols and phenols with trifiic anhydride (Tf2O) at ~ 0 C in the
presence of a base (usually Pyridine) in an inert solvent (usually

dichloromethane) for 2-24 h affords the corresponding reactive
trifluoromethanesulfonate esters (triflates).1 When triflic anhydride and pyridine are combined, the pyridinium salt forms immediately and normally precipitates out from the reaction mixture.
Nevertheless, the salt is an effective esterifying agent, reacting
with the added alcohol to give triflates in high yields (eq 1).3
411
Alkyl triflates are known to be powerful reagents for the alkylation of aromatic compounds.lb,l4 However, the reaction of alkyl
triflates with heterocycles affords N-alkylation products.15
In an improved modification of the Ritter reaction, primary and
secondary alcohols react with Tf2O in CH2Cl2 in the presence of
a 2:1 excess of nitriles to give the corresponding amides in good
yields (eq 4).16
(1)
R = alkyl, aryl
Pyridine can become involved in nucleophilic substitution

when very reactive triflates are being synthesized.2,3 One approach to minimize this disadvantage is to replace it with sterically hindered bases, such as 2,6-di-t-butyl-4-methylpyridine,3'4
2,4,6-trisubstituted pyrimidines,5 or nonnucleophilic aliphatic
amines (usually N,N-diisobutyl-2,4-dimethyl-3-pentylamine). No
salt formation appears to take place under these conditions. The
triflic anhydride seems to be the direct triflating agent and the
base only neutralizes the triflic acid formed. Numerous alkyl triflates have been prepared in the literaturelb by the above method.
Some recent examples of triflates prepared from alcohols are illustrated in eqs 2 and 3. 6 7 As an exception, 2,6-dinitrobenzyl alcohol
does not react with Tf2O although similar sulfonyl esters could be
prepared.8
(4)
Aryl triflates are prepared from phenols at 0C using pyridine as

solvent.lb Sometimes it is useful to conduct the reaction in CH2Cl2
at -77 C, as in the preparation of 3,5-di-t-butyl-4-hydroxyphenyl
triflate (eq 5).17 Aryl triflates are synthetically transformed into
several products of interest and applications in organic chemistry,
by cross-coupling reactions with organometallics (eqs 5 and 6).18
(5)
(2)
(6)
(3)
Alkyl triflates have come to be recognized as useful intermediates for the functionalization of organic substrates by nucleophilic substitution, e.g. in carbohydrate chemistry.9 Triflate is
the best leaving group knownlb next to the nonaflate and hence
a large number of triflates, obtained in good yields by reaction
of the corresponding alcohols (or alkoxides) with Tf2O, have
been used to generate unstable or destabilized carbocations under
solvolytic conditions.1b Some new typical examples are shown in
(1)-(4).10-13
Reaction of Tf2O with Amines. The reaction of 1 equiv of

Tf2O in CH2Cl2 and Et3N with amines (or their salts) affords
trifluoromethanesulfonamides (triflamides) in good yields.19,20 If
2 equiv of Tf2O are used, triflimides are formed. The triflamides
are soluble in alkali and readily alkylated to triflimides (eq 7).19,20
(7)
R1 = R2 = alkyl
(1)
(3)
(2)
(4)
Triflamides can be deprotected reductively (SodiumAmmonia) to yield the corresponding amines.21 This protocol
has been employed in the facile two-step synthesis of aza
macrocycles starting from trifluoromethanesulfonyl derivatives
of linear tetramines (eq 8).22
Several triflamides (5-8)23 and O-triflylammonium salts24 have
been used for the formation of vinyl triflates from regiospecifically
412
generated metalloenolates or for preparing triflates

alcohols.
from
The reaction of ketones with Tf2O is governed by

Markovnikov's rule and results in the formation of the more substituted triflate as the major product. When the reaction of ketones 27
and a-halo ketones 29 with Tf2O is carried out in the presence of
a nitrile, the intermediate trifloxy cation (eq 9) can be trapped,
forming pyrimidines in good yields (eq 11).
(8)
(11)
X = Cl, Br, I
R1 = R2 = alkyl, aryl
The reaction of Tf2O with strained bicyclic ketones such as 2norbornanone and nopinone takes place with Wagner-Meerwein
rearrangement of the corresponding triflyloxy cations, forming bridgehead triflates in good yields (eq 12).30 These triflates are key compounds in the preparation of other bridgehead
derivatives by substitution31 and of substituted cyclopentanes by
fragmentation.32
(12)
Reaction of Tf2O with Carbonyl Compounds. The reaction
of Tf2O with carbonyl compounds consists of the electrophilic
attack of the anhydride on the carboxylic oxygen, resulting in
the formation of triflyloxycarbenium ions as intermediates (eq 9).
According to the nature of the carbonyl compound, the triflyloxycarbenium cations can eliminate a proton giving a vinyl triflate,
undergo a rearrangement, or be trapped by the gegenion yielding
gem-bistriflates (eq 9).
In the reaction of Tf2O with norcaranones and spiro[2.5]octan-4-one, the cyclopropane ring undergoes fragmentation to
give vinyl triflates (eqs 13 and 14). 33
(13)
(9)
(14)
In the case of acyclic and monocyclic ketones, the reaction with
Tf2O affords vinyl triflates in good yields. Several methods exist
to realize this reaction. lb,25 For example, the reaction is carried
out at room temperature in CH 2 Cl 2 (or pentane) in the presence
of 2,4-di-t-butyl-4-methylpyridine (DTBMP) (eq 10).4
(10)
Other bases such as pyridine, lb lutidine, lb Et 3 N, l b polymerbound 2,6-di-t-butyl-4-methylpyridine,26. and 2,4,6-trialkylsubstituted pyrimidines27 were also used. The commercially
available N,N-diisobuty]-2,4-dimethyl-3-pentylamine is a very
convenient base to prepare the vinyl triflates.28 In the case of nonfunctionalized ketones, anhydrous Na 2 CO 3 has been proved to be
very successful. lb,25
However, a cyclopropane ring is formed in the reaction of 5methylnorborn-5-en-2-one with Tf2O under the same conditions
(eq 15).34
(15)
When the ketone can accomplish neither the stereoelectronic

conditions for the elimination of TfOH nor for a rearrangement,
the reaction of ketones with Tf2O results in the formation of a

gem-bistriflate (eqs 16 and 17).35
413
nish the corresponding vinyl triflates or dienyl triflates (eq 22).45

These triflates are transferred into monoketones, monoalcohols,
alkanes, and unsaturated ketones by means of various reducing
reagents.45
(16)
(21)
(17)
Sensitive ketones such as 3-pentyn-2-one also afford the corre

sponding vinyl triflate on treatment with Tf2O in the presence of
a base (eq 18).36
(22)
(18)
Substituted cyclopropenones and tropones react with Tf2O with

the formation of the corresponding dication ether salts (eq 19).37
The reaction of 3-methylcyclopentane-l,2-dione with

Tf2O/Et3N affords the vinyl triflate in 53% yield (eq 23).46 The
reaction takes place probably through the enol form. The product
was coupled with alkenylzinc compounds in the presence of a
palladium catalyst.46
(19)
(23)
Treatment of trifluoroacetyl ylides with Tf2O results in the for

mation of gem-bistriflates (eq 20).38
(20)
Reaction of Tf2O with Aldehydes. The reaction of aliphatic

aldehydes with Tf2O in the presence of 2,6-di-t-butyl-4methylpyridine (DTBMP) in refluxing CH2Cl2 or ClCH2CH2Cl
for 2 h affords the corresponding vinyl triflates as a mixture of (Z)and (E)-isomers.4,39 When the reaction is carried out at 0 C, gembistriflates are formed as products (eq 21).40 The gem-bistriflates
result due to the trapping of the intermediate triflyloxycarbenium
ion by the triflate anion. Primary vinyl triflates have been used
extensively in the generation of alkylidene carbenes,41 and gembistriflates are interesting precursors for gem-dihaloalkanes42,43
and (E)-iodoalkenes.44
Reaction with Dicarbonyl Compounds. 1,3-Diketones can
be reacted with an equimolar amount of Tf2O or in excess to fur
The reaction of -keto esters47 with Tf2O in the presence of a

base results in the formation of 2-carboxyvinyl triflates (eq 24).
These substrates undergo nucleophilic substitution of the TfOgroup (eq 24)47 and also coupling reactions.48
1. TFA, anisole
2. phenoxyacetic anhydride,
i-Pr2NEt
3. HSCH2CH2NHCO2PNB
(24)
PNB = p-nitrobenzyl carbamate
414
Reaction with Carboxylic Acids and Esters. The reaction of

carboxylic acids and esters with Tf2O takes place according to the
scheme shown in eq 25. 49
R = alkyl, aryl; R = alkyl, H
convenient variation of the Vilsmeier-Haack reaction (eq 30). 53
(30)
R 1 -CO 2 Tf + TfOR2(H) (25)
The trifluoromethanesulfonic carboxylic anhydrides are highly

effective acylation agents, which react without catalysts even with
deactivated aromatics to yield aryl ketones (eq 26). 50
The reaction of N-methylpyridone and substituted urea systems

with Tf2O gives heteroatom-stabilized dicarbonium salts (eqs 31
and 32). 37,54
(26)
(31)
Alkyl arylacetates react with Tf2O to give a cation which in the

presence of a nitrile affords isoquinoline derivatives via cyclization of the intermediate nitrilium cation (eq 27). 50
(32)
Secondary amides can be converted to tetrazoles with Tf2O in

the presence of Sodium Azide (eq 33). 55
(33)
(27)
R1 = alkyl, Ph; R2 = alkyl, (CH2)2OAc, (CH2)2OTBDMS
R1 = H, 6-Me, 7-Cl, 5-NO 2 , 6,7-(OMe)2; R2 = Et, Me
Reaction of Tf2O with Amides. The reaction of a 2-oxo-l,2dihydroquinoline with Tf2O in the presence of pyridine affords
the corresponding 2-quinoline triflate (eq 28). 51
Other Applications. Activated arenes can be converted to ary

triflones by Friedel-Crafts reaction with Tf2O using Aluminun
Chloride as catalyst (eq 34). 56
(34)
(28)
The reaction of tertiary amides with Tf2O gives a mixture of

O-sulfonylated (major) and N-sulfonylated (minor) products. In
the presence of collidine and an alkene, [2 + 2] cycloadducts are
formed which hydrolyze to give cyclobutanones (eq 29). 52
The reaction of Tf2O with Ph 3 PO in CH 2 Cl 2 at 0C affords

triphenylphosphine ditriflate, which can be used as an oxygen
activator, and then to a diphosphonium salt (eq 35). 57
Ph3P-O-PPh3
2OTf-
(35)
The less stable dimethyl sulfide ditriflate, obtained from Tf2O

and DMSO, has been used to oxidize alcohols (eq 36). 58
(29)
Treatment of DMF with Tf2O results in the formation of an

imminium triflate, which formylates less active aromatics. It is a
(36)
Next Page
Tetrahydropyran is not a suitable solvent in reactions involving Tf2O because it is cleaved, affording 1,5-bistrifloxypentane
(eq 37).59
(37)
Diols react with Tf2O to yield the corresponding ditriflates;

however, the reaction of l,1,2,2-tetraphenyl-1,2-ethanediol with
Tf2O takes place with rearrangement (eq 38).59
415
(43)
Reaction of enaminones with Tf2O in a 1:1 molarratio affords 3trifioxypropeniminium triflates by O-sulfonylation. From a cyclic
enaminone, by using a 2:1 molar ratio, the corresponding bis(3amino-2-propenylio) bistriflate is obtained (eq 44).66
(44)
(38)
Vinylene 1,2-bistriflates are formed by the reaction of azobenzils with Tf2O (eq 39).60
(39)
The reaction of enolates, prepared from silyl enol ethers and

Methyllithium, with Tf2O affords vinyl triflates (eq 40).61
(40)
The combination of equimolecular quantities of Iodosylbenzene and Tf2O generates PhI(OTf)2, a compound also formed
by treatment of Zefiro's reagent with Tf2O. As shown in eq 41,
this compound can be used to prepare para-disubstituted benzene
derivatives in good yields.62
(41)
Tf2O is a suitable promoter for the stereoselective glucosidation

of glycosyl acceptors using sulfoxides as donors.63
The reaction of Tf2O with a catalytic amount of Antimony(V)
Fluoride at 25 C produces trifluoromethyl triflate in 94% yield
(eq 42).64
(42)
Useful application of Tf2O as dehydrating reagent is accounted

by the synthesis of isocyanides from formamides and vinylformamides (eq 43).65
Related Reagents. Methanesulfonyl Chloride; Mesitylenesulfonyl Chloride;N-Phenyltrifluoromethanesulfonimide;

pToluenesulfonyl Chloride; Trifiuoromethanesulfonyl Chloride.
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Gramstad, T.; Husebye, S.; Saebo, J. TL 1983, 24, 3919.

Thomas, E. W. S 1993, 767.
56.
57.
Hendrickson, J. B.; Bair, K. W. JOC 1977, 42, 3875.

Hendrickson, J. B.; Schwartzman, S. M. TL 1975, 277.
58.
59.
60.
61.
Hendrickson, J. B.; Schwartzman, S. M. TL 1975, 273.

Lindner, E.; v. Au, G.; Eberle, H.-J. CB 1981, 114, 810.
Maas, G.; Lorenz, W. JOC 1984, 49, 2273.
(a) Stang, P. J.; Magnum, M. G.; Fox, D. P.; Haak, P. JACS 1974, 96,
4562. (b) Hanack, M.; Mrkl, R.; Garca Martnez, A. CB 1982, 775,
772.
62.
(a) Kitamura, T.; Furuki, R.; Nagata, K.; Taniguchi, H.; Stang, P. J. JOC
1992, 57, 6810. (b) Stang, P. J.; Zhdankin, V. V.; Tykwinski, R.; Zefirov,
N.TL1992, 33, 1419.
63.
64.
Raghavan, S.; Kahne, D. JACS 1993, 775, 1580.

Taylor, S. L.; Martin, J. C. JOC 1987, 52, 4147.
65.
66.
Baldwin, J. E.; O'Neil, I. A. SL 1990, 603.

Singer, B.; Maas, G. CB 1987, 720, 485.
Antonio Garca Martnez, Lakshminarayanapuram R.

Subramanian & Michael Hanack
Universitt Tbingen, Germany
[131154-24-0]
C9H21ClSi
(MW 192.84)
(hydroxy protecting group;1,2 formation of triisopropylsilyl ynol

ethers;3 TV-protection of pyrroles;4,5 prevents chelation with Grignard reagents6)
Alternate Names: TIPSC1; chlorotriisopropylsilane.
Physical Data: bp 198 C/739 mmHg; d 0.901 g mL -3 .
Solubility: sol THF, DMF, CH2Cl2.
Form Supplied in: clear, colorless liquid; commercially available
(99% purity).
Analysis of Reagent Purity: bp; NMR.
Purification: distillation under reduced pressure.
Handling, Storage, and Precautions: moisture sensitive; therefore
should be stored under an inert atmosphere; corrosive; use in a
fume hood.
Hydroxy Protecting Group. Several hindered triorganosilyl

protecting groups have been developed to mask the hydroxy
functionality. Although the t-butyldiphenylsilyl (TBDPS) and tbutyldimethylsilyl (TBDMS) groups are the most widely used, the
triisopropylsilyl group (TIPS) has several properties which make
it particularly attractive for use in a multi-step synthesis.1,2
Introduction of the TIPS group is most frequently accomplished using TIPSC1 and Imidazole in DMF,1 although
several other methods exist, including using TIPSC1 and 4Dimethylaminopyridine in CH2Cl2. It is possible to silylate
hydroxy groups selectively in different steric environments. For
TRIISOPROPYLSILYL CHLORIDE
example, primary alcohols can be silylated in the presence of sec
ondary alcohols (eq 1)7 and less hindered secondary alcohols can
be protected in the presence of more hindered ones (eq 2).8
(1)
(2)
A comparison of the stability of different trialkylsilyl groups has

shown that TIPS ethers are more stable than TBDMS ethers but
less stable than TBDPS ethers toward acid hydrolysis.2 The rate
difference is large enough that a TBDMS group can be removed
in the presence of a TIPS group (eq 3).7 Under basic hydrolysis,
TIPS ethers are more stable than TBDMS or TBDPS ethers.2 The
cleavage of TIPS ethers can also be accomplished by using Tetran-butylammonium Fluoride (TBAF) in THF at rt.1 This is most
convenient if only one silyl protecting group is present or if all of
those present can be removed in one synthetic step.
417
can be trapped by electrophiles to provide the silylated 3substituted pyrrole (eq 7).5 As expected, the silyl group can be
removed with TBAF to furnish the 3-substituted pyrrole. It should
also be mentioned that the TV-TIPS group also enhances the stabil
ity of some pyrroles. For example, 3-bromopyrrole is very unsta
ble, but the N-silylated derivative is stable for an indefinite period
of time.5
(6)
(7)
Prevention of Chelation in Grignard Reactions. The bulky

TIPS protecting group has proven extremely effective in prevent
ing competing chelation of - and -oxygen functionalities dur
ing Grignard reactions (eq 8).6 It was determined that this effect
is steric and not electronic since TMS and TBDMS ethers did not
affect selectivity.
(3)
An additional feature of TIPS ethers is that they are volatile

enough to make them amenable to GC and MS analysis. In fact,
MS fragmentation patterns have been used to discern the structures
of isomeric nucleosides.9
Formation of Silyl Ynol Ethers. Esters can also be trans
formed into triisopropylsilyl ynol ethers.3 The ester is first con
verted to the ynolate anion, followed by treatment with TIPSC1 to
furnish the TIPS ynol ether (eq 4). This method has even proven
successful with lactones as starting materials (eq 5).
(4)
(5)
N-Protection of Pyrroles. Pyrroles typically undergo electrophilic substitution at the -(2)-position, but when protected
as N-triisopropylsilylpyrroles, substitution occurs exclusively at
the -(3)-position (eq 6).4 It has been shown that 3-bromol-(triisopropylsilyl)pyrrole undergoes rapid halogen-metal ex
change with n-Butyllithium to generate the 3-lithiopyrrole, which
(8)
Related
Reagents. t-Butyldimethylchlorosilane; tButyldimethylsilyl
Trifluoromethanesulfonate;
3t-Butyldiphenylchlorosilane; Chlorotriphenylsilane; Triisopropylsilyl
Trifluoromethanesulfonate.
1. Green, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis,

2nd ed.; Wiley: New York, 1991; p 74.
2. Cunico, R. F.; Bedell, L. JOC 1980, 45, 4797.
3. Kowalski, C. J.; Lal, G. S.; Haque, M. S. JACS 1986, 108, 7127.
4. Muchowski, J. M.; Solas, D. R. TL 1983, 24, 3455.
5. Kozikowski, A. P.; Cheng, X.-M. JOC 1984, 49, 3239.
6. Frye, S. V.; Eliel, E. L. TL 1986, 27, 3223.
7. Ogilvie, K. K.; Thompson, E. A.; Quilliam, M. A.; Westmore, J. B. TL
1974, 2865.
8. Ogilvie, K. K.; Sadana, K. L.; Thompson, E. A.; Quilliam, M. A.;
Westmore, J. B. TL 1974, 2861.
9. Ogilvie, K. K.; Beaucage, S. L.; Entwistle, D. W.; Thompson, E.
A.; Quilliam, M. A.; Westmore, J. B. J. Carbohydr., Nucleosides,
Nucleotides 1976, 197.
Ellen M . Leahy
418
TRIMETHYLACETYL CHLORIDE
trimethylacetyl derivative (4), which was then treated with a Grig

nard reagent. Acid workup gave the -keto aldehyde (5) (eq 4).8
[3282-30-2]
C 5 H 9 ClO
(MW 120.59)
(ether cleavage;1 synthesis of ketonesfromcarboxylic acids;2 pep

tide synthesis;3 selective protection of polyols4)
(4)
Alternate Names: pivaloyl chloride; 2,2-dimethylpropanoyl chlo

ride.
Physical Data: bp 105-106C; d 0.979 g cm -3 .
Peptide Synthesis. Trimethylacetyl chloride has been used to
synthesize
peptidic bonds by the mixed anhydride method (eq 5).
Handling, Storage, and Precautions: flammable; can cause severe
burns and is irritating to the eyes and respiratory system; toxic
by contact with the skin, by inhalation, and if swallowed. It
(5)
should be used in a fume hood. During use, avoid sources of
ignition and any contact. Avoid exposure to moisture.5
A comparison of a range of carboxylic acid chlorides showed
trimethylacetyl chloride to be one of the most effective for pep
Ether Cleavage. Ethers can be cleaved by the action of
tide synthesis, though slightly inferior to diethylacetyl chloride.3
trimethylacetyl chloride (t-BuCOCl) and Sodium Iodide to give
The extent of racemization that occurred using various acyl chlo
the corresponding trimethylacetate and alkyl iodide.1 The reaction
rides has been studied and trimethylacetyl chloride was shown to
is regioselective, the cleavage occurring at the less substituted give only a very small amount of racemization.9 Trimethylacetyl
1,6
carbon-oxygen bond. Other acyl chlorides can be used, but the
chloride has been used in the synthesis of adrenocorticotrophic
reaction is more regioselective with trimethylacetyl chloride.1 The
hormone.10,11
1
reaction is particularly useful for cleaving methyl ethers (eq 1).
Selective Protection of Polyols. The protection (as the
trimethylacetate) of a primary alcohol in the presence of two sec
(1)
ondary alcohols has been achieved in high yield using 1 equiv of
trimethylacetyl chloride (eq 6).4
Ketone Synthesis. Carboxylic acids can be converted to ke
tones by first forming the mixed anhydride with trimethylacetyl
chloride and then treating it with a Grignard reagent (eq 2).2 In ad
dition to trimethylacetyl chloride, ortho-substituted benzoyl chlo
rides such as o-anisoyl chloride can be used to form the mixed
anhydride. Yields were found to be slightly higher than when
trimethylacetyl chloride was used.2
(6)
The selective protection of a less hindered primary alcohol in

the presence of another more hindered one has also been achieved
(eq7).12
(7)
(2)
The carboxylic acid (1) has been converted to the ketone (2) via
the mixed anhydride with trimethylacetyl chloride (eq 3).7
Sucrose has been selectively protected using trimethylacetyl

chloride. By varying the conditions a variety of penta-, hexa-, and
heptatrimethylacetates was obtained.13
Related Reagents. Acetic Anhydride; Isobutyl Chloroformate; 2,4,6-Trichlorobenzoyl Chloride.
(3)
A -keto aldehyde synthesis has been developed using simi

lar methodology. The ethoxy lactam (3) was converted to its NLists of Abbreviations and Journal Codes on Endpapers
1. Oku, A.; Harada, T.; Kita, K. TL 1982, 23, 681.

2. Araki, M.; Mukaiyama, T. CL 1974, 663.
3. Vaughan, J. R.; Osato, R. L. JACS 1951, 73, 5553.
TRIMETHYLOXONIUMTETRAFLUOROBORATE
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
Nicolaou, K. C.; Webber, S. E. S 1986, 453.

For further information, see: The Sigma-Aldrich Library of Chemical
Safety Data, 2nd ed.; Leng, R. E., Ed.; Sigma-Aldrich: Milwaukee, 1987;
Vol. 2, p 3479.
Rodriguez, J.; Dulcere, J.-P.; Bertrand, M. TL 1984, 25, 527.
Bakuzis, P.; Bakuzis, M. L. F. JOC 1977, 42, 2362.
Savoia, D.; Concialini, V.; Roffia, S.; Tarsi, L. JOC 1991, 56, 1822.
Taschner, E.; Smulkowski, M.; Lubiewska-Nakonieczna, L. LA 1970,
739, 228.
Schwyzer, R.; Sieber, P. Nature 1963,199, 172.
Schwyzer, R.; Sieber, P. HCA 1965, 49, 134.
Schuda, P. F.; Heimann, M. R. TL 1983, 24, 4267.
Hough, L.; Chowdhary, M. S.; Richardson, A. C. CC 1978, 664.
13
14
419
13g
sulfides, thioamides, thiophenes, and sulfonium ylides.14

As should be expected for strongly electrophilic agents,lc the
hard oxonium salt yields considerable amounts of products de
rived from methylation at the site of the highest electron den
sity (HSAB principle) when it reacts with ambident nucleophiles.
O-Methylation of sulfoxides,15 N-methylation of sulfoximides,16
sulfinyl amines,17 sulfodiimides, and nitrites10 and S-methylation
of thioamides14b have been observed. The very reactive cationic
intermediates (e.g. carboxonium, carbosulfonium, or nitrilium
ions) as primary products in those reactions are versatile inter
mediates for synthetic transformations. Ketones can be converted
into a-acetoxy ketones via N-methylation of the oxime acetates
(eq 1)18 and thioamides to amides (eq 2).14a,b
Christopher J. Urch
Zeneca Agrochemicals,
Bracknell, UK
TrimethyloxoniumTetrafluoroborate1
[420-37-1]
C3H9BF4O
(MW 147.93)
(1)
(methylating agent; activates C-X multiple bonds; esterifies

polyfunctional carboxylic acids;3 catalyst for polymerization of
cyclic sulfides and ethers; Beckmann rearrangement of oximes4)
Physical Data: mp 179.6-180.0C (sealed tube, with dec).
Solubility: sol nitrobenzene, nitromethane, CHCl3, acetone (hot),
SO2 (liq); slightly sol CH2Cl2; insol common organic solvents.
Form Supplied in: white crystalline solid; commercially available;
is contaminated by ethyldimethyloxonium tetrafluoroborate.
Analysis of Reagent Purity: 1H NMR (CD2Cl2/SO2) 4.68 (s,
CH3); l3C NMR (CD2Cl2/SO2) 78.8 (CH3).
Purification: highly pure oxonium salt is obtained from
dimethoxycarbenium tetrafluoroborate and dimethyl ether.5
The resulting solid is vacuum dried at 50C/1 mmHg for 30
min.
Handling, Storage, and Precautions: when prepared according to
Curphey,6 the oxonium salt is stable, nonhygroscopic, and may
be readily handled in the air for short periods of time. The dry
oxonium salt should be stored under argon at -15 C or as a
suspension in CH2Cl2 at -20C forprolonged periods. Batches
stored in this manner for over a year have been successfully
used for alkylations. Highly pure samples5 showed no change
in spectral data after this time. Reactions of the reagent should
be performed under an argon or a nitrogen atmosphere; dry
solvents are also necessary. Because of its caustic nature and
potent properties as an alkylating agent, direct contact with the
skin must be avoided.
Functional Group Methylations. The powerful alkylating

property of trimethyloxonium tetrafluoroborate allows methylation of sensitive or weakly nucleophilic functional groups. Smooth
alkylation of a variety of anions or uncharged molecules has
been reported. Examples include carboxylic acids,7 ketones,2,8
lactones,4,9 nitrites,4,10 O-acetals,4 S-acetals,11 sulfoxides,12
(2)
The reactions of thioacetals with Me3O+ BF4- constitute a

high-yielding method for deprotection of thioacetals to give ke
tones (eq 3). lla,19
(3)
The reagent has been employed as a quatemizing agent for a va

riety of N-heterocycles.20 Regioselective N-methylation has been
observed (eq 4).20c Thiazoles are exclusively N-methylated,20a,b
whereas tetrazoles yield regioisomeric products.20d,h The dication of squaric acid bis(amidine) is prepared by regioselective
N-methylation (eq 5).21
(4)
420
(9)
(5)
1,3-Benzothiazolines react preferentially at nitrogen,22

whereas heterocycles containing dipolar carbonyl groups usually
yield products resulting from O-methylation.2,23 Furthermore,
Me 3 O + BF 4 - is the reagent of choice for the synthesis of higher
alkylated products which are otherwise not obtainable. Examples
are the preparation of vinylidene disulfonium salts (eq 6), 13c
dionium salts of N,S-13b and S,S-acetals, 11a-c,24 or 1,4-dithianium
ditetrafluoroborates (eq 7), 19 and a heterocyclophane-type
tetrasulfonium salt (eq 8). The latter introduces a hydrophobic
cavity into the aqueous phase, thus serving as an inclusion
catalyst.25
(6)
(7)
mixture of two stereoisomers
(8)
Trialkyloxonium salts such as Me 3 O + BF 4 - are excellent

reagents for the generation of cyclopropenylium cations by Omethylation of suitable cyclopropenones (eq 9). 26
The reaction of trialkyloxonium salts with carboxylic acids is

a mild, general esterification procedure that does not require the
use of more hazardous reagents such as Hexamethylphosphoric Triamide-Thionyl Chloride, lodomethane, Dimethyl Sulfate,
3-Methyl-l-p-tolyltriazene, or Diazomethane. The reaction pro
ceeds smoothly with sterically hindered acids, as well as with
acids containing various functional groups such as amides or ni
trites (eq 10). 3,7
(10)
One of the major advantages of the use of oxonium salts is

that alkylations can be effected under reaction conditions that
are generally much milder than those necessary with conven
tional alkyl halides and sulfonates. Me 3 O + BF 4 - has been used
as a suspension in CH 2 Cl 2 or dichloroethane, or as a solution in
nitromethane or liquid SO 2 . Alkylations in water27 and trifluoroacetic acid28 have been described, and direct fusion has been
used in cases where other conditions failed.29 An S N 2 mecha
nism must be assumed in the reaction of the reagent with nucleophiles. The rates of the complete hydrolysis decrease in the
sequence Me 3 O + >>Et 3 O + >Pr 3 O + > c-C 5 H 10 OEt. 30 Compar
ative studies on the alkylating ability of common methylating
agents 31 show that Me 3 O + ions are more reactive than the trifluoromethanesulfonate ester (factor 5 to 12), following the or
der Me 3 O + > MeOSO 2 CF 3 > MeOSO 2 F > MeOClO 3 . In terms of
availability, stability, and freedom from hazards, however, oxo
nium salts often appear the reagents of choice (including compar
isons with other powerful alkylating agents such as dialkoxycarbenium ions, 32 dialkylhalonium ions, 33 and haloalkanes in the pres
ence of silver salts 34 ). While the carcinogenic properties of other
potent alkylating agents are well documented,35 any such dan
gers associated with trialkyloxonium salts are presumably mini
mized by the fact that these compounds are water-soluble, non
volatile, crystalline solids which are rapidly solvolyzed in aqueous
solution. lb,36 Although Triethyloxonium Tetrafluoroborate is the
cheaper and much more used oxonium salt in synthetic chemistry,
Me3O+BF4effects alkylations which the triethyl analog does
not. 11,37
Use in Transition Metal Chemistry. Me3O+BF4- has been
successfully used in the generation of transition metal carbene
complexes by direct methylation of lithium acylcarbonylmetalates
(eq 11). 38 Oxidative addition processes by which metal-carbon bonds are formed have also been observed.39 Me3O+BF4- also
serves as a halide acceptor in the reaction with square planar plat
inum(II) complexes.40
(11)
+
Catalytic Properties. Me3O BF4 has been used as a catalyst

for the polymerization of cyclic sulfides and in the polymerization
of THF to macrocyclic ethers.4 A valuable modern application is
the catalytic Beckmann rearrangement of oximes in homogeneous
liquid phase,41 the active species being a formamidinium salt.
421
Modena, G.; Pasquato, L. CC 1992, 293. (f) Solladi, G.; Maugein, N.;
Morreno, I.; Almario, A.; Carreno Carmen, M.; Garcia-Ruano, J. L. TL
1992,55,4561.
13.
(a) Shanklin, J. R.; Johnson, C. R.; Ollinger, J.; Coates, R. M. JACS

1973, 95, 3429. (b) Boehme, H.; Daehler, G.; Krack, W. LA 1973,
1686. (c) Braun, H.; Amann, A. AG 1975, 87, 773. (d) Minato, H.;
Miura, T.; Kobayashi, M. CL 1975, 1055. (e) Watanabe, Y.; Shiono,
M.; Mukaiyama, T. CL 1975, 871. (f) Boehme, H.; Krack, W. LA 1977,
51. (g) Hoffmann, R. W.; Ladner, W. CB 1983, 116, 1631. (h) Furuta,
K.; Ikeda, Y.; Meguriya, N.; Ikeda, N.; Yamamoto, H. BCJ 1984, 57,
2781. (i) Bodwell, J. R.; Patwardhan, B. H.; Dittmer, D. C. JOC 1984,
49, 4192.
14.
(a) Mukherjee, R. JCS(D) 1971, 1113. (b) Mukherjee, R. IJC(B) 1977,

15B, 502. (c) Kosbahn, W.; Schaefer, H. AG 1977, 89, 826. (d) Casadei,
M. A.; Di Rienzo, B.; Moracci, F. M. SC 1983, 13, 753.
Other Reactions. The reaction of -alkenyl--butyrolactones

with allylsilanes in the presence of Me3O+BF4- as the lactoneactivating agent is reported to proceed with high regio- and stereo
selectivity to afford methyl (E)-4,8-alkadienoates in high yields
(eq 12).42
15.
(a) Hayashi, Y.; Nozaki, H. BCJ 1972, 45, 198. (b) Johnson, C. R.;
Rogers, P. E. JOC 1973, 38, 1798.
16. Johnson, C. R. ACR 1973, 6, 341.
(12)
Me3O+BF4- has also been used as a methylating agent of the

lithium enolate of a -keto sulfoxide, leading to a mixture of iso
meric dienol ethers, which are of potential interest as substrates
for asymmetric Diels-Alder cycloadditions (eq 13).43
(13)
(EZ):(EE) = 84:16
Related Reagents. Diazomethane; Dimethyl Sulfate; Iodomethane; Methyl Flurosulfonate; Methyl Trifiuoromethanesulfonate; Triethyloxonium Tetrafluoroborate; Trimethyl Phosphate.
1. (a) Meerwein, H. MOC 1965, 6/3, 335. (b) Perst, H. Oxonium Ions in
Organic Chemistry; Verlag Chemie: Weinheim, 1971. (c) Granik, V. G.;
Pyatin, B. M.; Glushkov, R. G. RCR 1971, 40, 747. (d) Perst, H. In
Carbonium Ions; Olah, G. A.; Schleyer, P. v. R., Eds.; Wiley: New York,
1976; Vol. 5, pp 1961-2047.
2.
3.
4.
5.
6.
7.
8.
9.
Meerwein, H.; Hinz, G.; Hofmann, P.; Kroning, E.; Pfeil, E. JPR 1937,
147, 257.
(a) Raber, D. J.; Gariano, P. TL 1971, 4741. (b) Raber, D. J.; Gariano, P.,
Jr.; Brod, A. O.; Gariano, A. L.; Guida, W. C. OSC 1988, 6, 576.
Meerwein, H.; Borner, P.; Fuchs, O.; Sasse, H. J.; Schrodt, H.; Spille, J.
CB 1956, 89, 2060.
17.
(a) Kresze, G.; Rssert, M. AG 1978, 90, 61. (b) Kresze, G.; Rssert, M.
LA 1981, 58.
18. House, H. O.; Richey, F. A., Jr. JOC 1969, 34, 1430.
19. Gundermann, K. D.; Hoenig, W.; Berrada, M.; Giesecke, H.; Paul, H. G.
LA 1974, 809.
20. (a) Altman, L. J.; Richheimer, S. L. TL 1971, 4709. (b) Meyers, A. I.;
Munavu, R.; Durandetta, J. TL 1972, 3929. (c) Heine, H. W.; Newton,
T. A.; Blosick, G. J.; Irving, K. C ; Meyer, C ; Corcoran G. B., III JOC
1973, 38, 651. (d) Quast, H.; Bieber, L. CB 1981, 114, 3253. (e) Hnig,
S.; Prockschy, F. CB 1984, 117, 2099. (f) Meyers, A. I.; Hoyer, D. TL
1984, 25, 3667. (g) Reichardt, C.; Kaufmann, N. CB 1985, 118, 3424.
(h) Quast, H.; Bieber, L.; Meichsner, G. LA 1987, 469. (i) Hanquet, G.;
Lusinchi, X.; Milliet, P. TL 1987, 28, 6061.
21.
Hnig, S.; Ptter, H. CB 1977, 110, 2532.
22.
Akiba, K.; Ohara, Y.; Inamoto, N. BCJ 1982, 55, 2976.
23.
Kosbahn, W.; Schfer, H. AG 1977, 89, 826.
24.
Iwamura, H.; Fukunaga, M. CL 1974, 1211.
25.
Tabushi, I.; Sasaki, H.; Kuroda, Y. JACS 1976, 98, 5727.
26.
27.
Dehmlow, E. V. AG 1974, 86, 203.

Aumann, R.; Fischer, E. O. CB 1968, 101, 954.
28.
Hesse, G.; Broil, H.; Rupp, W. LA 1966, 697, 22.
29.
Rapko, J. N.; Feistel, G. 1C 1970, 9, 1401.
30. Meerwein, H.; Battenberg, E.; Gold, H.; Pfeil, E.; Willfang, G. JPR 1939,
154, 83.
31.
(a) Lewis, E. S.; Vanderpool, S. JACS 1977, 99, 1946. (b) Kevill, D. N.;
Lin, G. M. L. TL 1978, 949.
32.
Kabuss, S. AG(E) 1966, 5, 675.
33.
Olah, G. A.; DeMember, J. R. JACS 1970, 92, 2562.
Earle, M. J.; Fairhurst, R. A.; Giles, R. G.; Heaney, H. SL 1991, 728.

Curphey, T. J. OSC 1988, 6, 1019.
Raber, D. J.; Gariano P., Jr.; Brod, A. O.; Gariano, A.; Guida, W. C.;
Guida, A. R.; Herbst, M. D. JOC 1979, 44, 1149.
Mock, W. L.; Hartmann, M. E. JOC 1977, 42, 466.
34.
(a) Meerwein, H.; Hederich, V.; Wunderlich, K. AP 1958, 297, 541. (b)
Boulton, A. J.; Gray, A. C. G.; Katritzky, A. R. JCS(B) 1967, 911. (c)
Acheson, R. M.; Harrison, D. R. JCS(C) 1970, 1764.
35.
(a) Pirkle, W. H.; Dines, M. JHC 1969, 6, 313. (b) Deslongchamps, P.;
Chenevert, R.; Taillefer, R. J.; Moreau, C.; Saunders, J. K. CJC 1975,
53, 1601. (c) Kaloustian, M. K.; Khouri, F. TL 1981, 22, 413.
36.
(a) Poirier, L. A.; Stoner, G. D.; Shimkin, M. B. Cancer Res. 1975, 35,
1411. (b) McCann, J.; Choi, E.; Yamasaki, E.; Ames, B. N. PNA 1975,
72,5135.
Diem, M. J.; Burow, D. F.; Fry, J. L. JOC 1977, 42, 1801.
10. Eyley, S. C.; Giles, R. G.; Heaney, H. TL 1985, 26, 4649.

11. (a) Stahl, I.; Hetschko, M.; Gosselck, J. TL 1971, 4077. (b) Bhme, H.;
Krack, W. LA 1972, 758, 143. (c) Wolfe, S.; Chamberlain, P.; Garrard,
T. F. CJC 1976, 54, 2847.
12. (a) La Rochelle, R. W.; Trost, B. M. JACS 1971, 93, 6077. (b) Tsumori,
K.; Minato, H.; Kobayashi, M. BCJ 1973, 46, 3503. (c) Andersen, K.
K.; Caret, R. L.; Karup-Nielsen, I. JACS 1974, 96, 8026. (d) Andersen,
K. K.; Caret, R. L.; Ladd, D. L. JOC 1976, 41, 3096. (e) Lucchini, V.;
37.
Baldwin, J. E.; Hackler, R. E.; Kelly, D. P. JACS 1968, 90, 4758.
38.
(a) Fischer, E. O. AG 1974, 86, 651. (b) Fischer, E. O.; Fischer, H. CB

1974, 107, 657. (c) Rausch, M. D.; Moser, G. A.; Meade, C. F. JOM
1973,5/, 1.
39.
(a) Strope, D.; Shriver, D. F. JACS 1973, 95, 8197. (b) Olgemller, B.;
Bauer, H.; Lbermann, H.; Nagel, U.; Beck, W. CB 1982, 115, 2271.
40. Treichel, P. M.; Wagner, K. P.; Knebel, W. J. ICA 1972, 674.

41.
Izumi. Y. CL 1990, 2171.
42.
Fujisawa, T.; Kawashima, M.; Ando, S. TL 1984, 25, 3213.

422
43.
TRIMETHYLSILYLDIAZOMETHANE
Solladi, G.; Maugein, N.; Moreno, I.; Alraario, A.; Carreno, M. C.;
Garcia-Ruano, J. L. TL 1992, 33, 4561.
Ingfried Stahl
Universitt Kassel, Germany
for regioselective methylene insertion (eq 5). Homologation of

aliphatic and alicyclic aldehydes with TMSCHN2 in the pres
ence of Magnesium Bromide smoothly gives methyl ketones after
acidic hydrolysis of the initially formed -keto silanes (eq 7).6
(4)
Trimethylsilyldiazomethane1
(5)
[18107-18-1]
C 4 H 10 N 2 Si
(MW 114.25)
(one-carbon homologation reagent; stable, safe substitute for diazomethane; [C-N-N] 1,3-dipole for the preparation of azoles1)
Physical Data: bp 96 C/775 mmHg;nD201.4362.2
Solubility: sol most organic solvents; insol H2O.
Form Supplied in: commercially available as 2 M and 10 w/w%
solutions in hexane, and 10 w/w% solution in CH2Cl2.
Analysis ofReagent Purity: concentration in hexane is determined
by 1HNMR.3
Preparative Method: prepared by the diazo-transfer reaction
of Trimethylsilylmethylmagnesium Chloride with Diphenyl
Phosphorazidate (DPPA) (eq 1).3
Handling, Storage, and Precautions: should be protected from

light.
One-Carbon Homologation. Along with its lithium salt,

which is easily prepared by lithiation of trimethylsilyl
diazomethane (TMSCHN2) with n-Butyllithium, TMSCHN2
behaves in a similar way to Diazomethane as a one-carbon ho
mologation reagent. TMSCHN2 is acylated with aromatic acid
chlorides in the presence of Triethylamine to give -trimethylsilyl
diazo ketones. In the acylation with aliphatic acid chlorides, the
use of 2 equiv of TMSCHN2 without triethylamine is recom
mended. The crude diazo ketones undergo thermal Wolff rear
rangement to give the homologated carboxylic acid derivatives
(eqs 2 and 3).4
(6)
(7)
O-Methylation of carboxylic acids, phenols, enols, and alco

hols can be accomplished with TMSCHN2 under different re
action conditions. TMSCHN2 instantaneously reacts with car
boxylic acids in benzene in the presence of methanol at room tem
perature to give methyl esters in nearly quantitative yields (eq 8).7
This method is useful for quantitative gas chromatographic anal
ysis of fatty acids. Similarly, O-methylation of phenols and enols
with TMSCHN2 can be accomplished, but requires the use of Diisopropylethylamine (eqs 9 and 10).8 Although methanol is rec
ommended in these O-methylation reactions, methanol is not the
methylating agent. Various alcohols also undergo O-methylation
with TMSCHN2 in the presence of 42% aq. Tetrafluoroboric Acid,
smoothly giving methyl ethers (eq 11).9
(8)
(9)
(10)
(2)
(11)
(3)
Various ketones react with TMSCHN2 in the presence of Boron

Trifluoride Etherate to give the chain or ring homologated ketones
(eqs 4-6).5 The bulky trimethylsilyl group of TMSCHN2 allows
Alkylation of the lithium salt of TMSCHN2 (TMSC(Li)N2)

gives -trimethylsilyl diazoalkanes which are useful for the
preparation of vinylsilanes and acylsilanes. Decomposition of trimethylsilyl diazoalkanes in the presence of a catalytic amount
of Copper(I) Chloride gives mainly (E)-vinylsilanes (eq 12),10
while replacement of CuCl with rhodium(II) pivalate affords (Z)vinylsilanes as the major products (eq 12).11 Oxidation of atrimethylsilyl diazoalkanes with m-Chloroperbenzoic Acid in a
two-phase system of benzene and phosphate buffer (pH 7.6) af
fords acylsilanes (-keto silanes) (eq 12).12
423
tion of [C-N-N] azoles. The reaction mode is similar to that

of diazomethane but not in the same fashion. TMSC(Li)N2 (2
equiv) reacts with carboxylic esters to give 2-substituted 5trimethylsilyltetrazoles (eq 19).18 Treatment of thiono and dithio
esters with TMSC(Li)N2 followed by direct workup with aqueous
methanol gives 5-substituted 1,2,3-thiadiazoles (eq 20).19 While
reaction of di-f-butyl thioketone with TMSCHN2 produces the
episulfide with evolution of nitrogen (eq 21),20 its reaction with
TMSC(Li)N2 leads to removal of one t-butyl group to give the
l,2,3-thiadiazole(eq 21).20
(12)
(19)
(E)--Trimethylsilylstyrenes are formed by reaction of alkanesulfonyl chlorides with TMSCHN2 in the presence of triethylamine (eq 13).13 TMSC(Li)N2 reacts with carbonyl compounds
to give -diazo--hydroxy silanes which readily decompose to
give ,-epoxy silanes (eq 14).14 However, benzophenone gives
diphenylacetylene under similar reaction conditions (eq 15).15
(13)
(20)
X = OMe or SMe
X = OMe, 79%; SMe, 84%
(21)
(14)
(15)
Silylcyclopropanes are formed by reaction of alkenes with

TMSCHN2 in the presence of either Palladium(II) Chloride or
CuCl depending upon the substrate (eqs 16 and 17).16 Silylcyclopropanones are also formed by reaction with trialkylsilyl and
germyl ketenes (eq 18).17
(16)
(17)
TMSCHN2 reacts with activated nitriles only, such as

cyanogen halides, to give 1,2,3-triazoles.21 In contrast with this,
TMSC(Li)N2 smoothly reacts with various nitriles including aro
matic, heteroaromatic, and aliphatic nitriles, giving 4-substituted
5-trimethylsilyl-1,2,3-triazoles (eq 22).22 However, reaction of
,-unsaturated nitriles with TMSC(Li)N2 in Et2O affords 3(or
5)-trimethylsilylpyrazoles, in which the nitrile group acts as a
leaving group (eq 23).23 Although ,-unsaturated nitriles bear
ing bulky substituents at the - and/or -positions of the nitrile
group undergo reaction with TMSC(Li)N2 to give pyrazoles, sig
nificant amounts of 1,2,3-triazoles are also formed. Changing the
reaction solvent from Et2O to THF allows for predominant forma
tion of pyrazoles (eq 24).23 Complete exclusion of the formation of
1,2,3-triazoles can be achieved when the nitrile group is replaced
by a phenylsulfonyl species.24 Thus reaction of a,p-unsaturated
sulfones with TMSC(Li)N2 affords pyrazoles in excellent yields
(eq 25). The geometry of the double bond of ,-unsaturated sul
fones is not critical in the reaction. When both a cyano and a
sulfonyl group are present as a leaving group, elimination of the
sulfonyl group occurs preferentially (eq 26).24 The trimethylsilyl
group attached to the heteroaromatic products is easily removed
with 10% aq. KOH in EtOH or HCl-KF.
(18)
(22)
[C-N-N] Azole Synthon. TMSCHN2, mainly as its lithium

salt, TMSC(Li)N2, behaves like a 1,3-dipole for the prepara
424
(30)
(23)
(24)
Pyrazoles are formed by reaction of TMSCHN2 or

TMSC(Li)N2 with some alkynes (eqs 31 and 32)24,30 and quinones
(eq 33).31 Some miscellaneous examples of the reactivity of
TMSCHN2 or its lithium salt are shown in eqs 34-36.20,31,32
(31)
(25)
(32)
(26)
(33)
Various 1,2,3-triazoles can be prepared by reaction of

TMSC(Li)N2 with various heterocumulenes. Reaction of isocyanates with TMSC(Li)N2 gives 5-hydroxy-1,2,3-triazoles
(eq 27).25 It has been clearly demonstrated that the reaction proceeds by a stepwise process and not by a concerted
1,3-dipolar cycloaddition mechanism. Isothiocyanates also react with TMSC(Li)N2 in THF to give lithium 1,2,3-triazole-5thiolates which are treated in situ with alkyl halides to furnish
1 -substituted 4-trimethylsilyl-5-alkylthio-1,2,3-triazoles in excellent yields (eq 28).26 However, changing the reaction solvent from
THF to Et2O causes a dramatic solvent effect. Thus treatment of
isothiocyanates with TMSC(Li)N2 in Et2O affords 2-amino-1,3,4thiadiazoles in good yields (eq 28).27 Reaction of ketenimines
with TMSC(Li)N2 smoothly proceeds to give 1,5-disubstituted
4-trimethylsilyl- 1,2,3-triazoles in high yields (eq 29).28 Ketenimines bearing an electron-withdrawing group at one position of
the carbon-carbon double bond react with TMSC(Li)N2 to give
4-aminopyrazoles as the major products (eq 30).29
(27)
(28)
(29)
(34)
(35)
(36)
Related Reagents. Diazomethane.
1.
(a) Shioiri, T.; Aoyama, T. J. Synth. Org. Chem. Jpn 1986, 44, 149 (CA
1986, 104, 168 525q). (b) Aoyama, T. YZ 1991, 111, 570 (CA 1992,
116, 58 332q). (c) Anderson, R.; Anderson, S. B. In Advances in Silicon
Chemistry; Larson, G. L., Ed.; JAI: Greenwich, CT, 1991; Vol. 1, pp
303-325. (d) Shioiri, T.; Aoyama, T. In Advances in the Use of Synthons
in Organic Chemistry; Dondoni, A., Ed.; JAI: London, 1993; Vol. 1, pp
51-101.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
Seyferth, D.; Menzel, H.; Dow, A. W.; Flood, T. C. JOM 1972, 44, 279.
Shioiri, T.; Aoyama, T.; Mori, S. OS 1990, 68, 1.
Aoyama, T.; Shioiri, T. CPB 1981, 29, 3249.
Hashimoto, N.; Aoyama, T.; Shioiri, T. CPB 1982, 30, 119.
Aoyama, T.; Shioiri, T. S 1988, 228.
Hashimoto, N.; Aoyama, T.; Shioiri, T. CPB 1981, 29, 1475.
Aoyama, T.; Terasawa, S.; Sudo, K.; Shioiri, T. CPB 1984, 32, 3759.
Aoyama, T.; Shioiri, T. TL 1990, 31, 5507.
Aoyama, T.; Shioiri, T TL 1988, 29, 6295.
Aoyama, T.; Shioiri, T CPB 1989, 37, 2261.
-TRIMETHYLSILYLETHANESULFONYL CHLORIDE
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
Aoyama, T.; Shioiri, T. TL 1986, 27, 2005.

Aoyama, T.; Toyama, S.; Tamaki, N.; Shioiri, T. CPB 1983, 31, 2957.
Schllkopf, U.; Scholz, H.-U. S 1976, 271.
Colvin, E. W.; Hamill, B. J. JCS(P1) 1977, 869.
Aoyama, T.; Iwamoto, Y.; Nishigaki, S.; Shioiri, T. CPB 1989, 37, 253.
Zaitseva, G. S.; Lutsenko, I. F.; Kisin, A. V.; Baukov, Y. I.; Lorberth, J.
JOM 1988, 345, 253.
Aoyama, T.; Shioiri, T. CPB 1982, 30, 3450.
Aoyama, T.; Iwamoto, Y.; Shioiri, T. H 1986, 24, 589.
Shioiri, T.; Iwamoto, Y.; Aoyama, T. H 1987, 26, 1467.
Crossman, J. M.; Haszeldine, R. N.; Tipping, A. E. JCS(D) 1973, 483.
Aoyama, T.; Sudo, K.; Shioiri, T. CPB 1982, 30, 3849.
Aoyama, T.; Inoue, S.; Shioiri, T. TL 1984, 25, 433.
Asaki, T.; Aoyama, T.; Shioiri, T. H 1988, 27, 343.
Aoyama, T.; Kabeya, M.; Fukushima, A.; Shioiri, T. H 1985, 23, 2363.
Aoyama, T.; Kabeya, M.; Shioiri, T. H 1985, 23, 2371.
Aoyama, T.; Kabeya, M.; Fukushima, A.; Shioiri, T. H 1985, 23, 2367.
Aoyama, T.; Katsuta, S.; Shioiri, T. H 1989, 28, 133.
Aoyama, T.; Nakano, T.; Marumo, K.; Uno, Y.; Shioiri, T. S 1991, 1163.
Chan, K. S.; Wulff, W. D. JACS 1986, 108, 5229.
Aoyama, T.; Nakano, T.; Nishigaki, S.; Shioiri, T. H 1990, 30, 375.
Rosch, W.; Hees, U.; Regitz, M. CB 1987, 720, 1645.
425
(2)
(3)
Handling, Storage, and Precautions: stable liquid that can be

stored at room temperature for weeks. Prone to hydrolysis.
Protection of Amines. Sulfonamides are among the most

stable of amine protecting groups and it is this stability that
detracts from their utility, since harsh reaction conditions are
often needed for their removal. The advantage of using the
-trimethylsilylethanesulfonyl (SES) protecting group is that the
sulfonamide (5) can be easily cleaved to regenerate the parent
amine (eq 4)1 in good yields with either Cesium Fluoride (2-3
equiv) in DMF at 95 C for 9-40 h, or Tetra-n-butylammonium
Fluoride trihydrate (3 equiv) in refluxing MeCN. The main dis
advantage of the latter procedure is an occasional difficulty in
separating tetrabutylammonium salts from some amines.
Takayuki Shioiri & Toyohiko Aoyama

Nagoya City University, Japan
TMSF + H2C=CH2 + SO2 + RR'NH
[97203-62-8]
C5H13ClO2SSi
(MW 200.79)
(protection of primary and secondary amines as their sulfon

amides, which are cleaved by fluoride ion1)
Alternate Name: SESC1.
Physical Data: bp 60 C/0.1 mmHg; yellow oil.
Solubility: sol most common organic solvents.
Preparative Methods: can be most conveniently synthesized from
commercially available Vinyltrimethylsilane (1) (eq 1).1 Rad
ical addition of sodium bisulfite to the vinyl group catalyzed
by t-butyl perbenzoate yields the sulfonate salt (2) which can
be directly converted to SESC1 (3) with Phosphorus(V) Chlo
ride. The chloride (3) can then be purified by distillation. The
intermediate sulfonate salt (2) is commercially available. The
chloride (3) can also be prepared in 62% yield from the salt
(2) using Sulfuryl Chloride and Triphenylphosphine (eq 2).2
A less convenient procedure to synthesize SESCl (3) using trimethylsilylethylmagnesium chloride (4) and sulfuryl chlo
ride has also been developed (eq 3).1
(1)
(4)
The sulfonamides can be prepared from a wide variety of pri

mary and secondary amines using sulfonyl chloride (3) in DMF
containing Triethylamine. For aromatic and heterocyclic amines,
Sodium Hydride is the preferred base. The sulfonamides are gen
erally quite stable and are untouched by refluxing TFA, 6 M HCl
in refluxing THF, 1 M TBAF in refluxing THF, LiBF4 in refluxing
MeCN, BF3 .OEt2, and 40% HF in ethanol. Table 1 lists a few
examples of various amines and their protection as SES sulfon
amides and cleavage with CsF in DMF at 95 C.1
Table 1 Synthesis and Cleavage of SES Sulfonamides with CsF, DMF,
95C
Amine
% Yield sulfonamide % Yield of cleavage (time
92
82 (29 h)
92
86(16 h)
83
93 (40 h)
93
91 (9 h)
88
89 (24 h)
426
-TRIMETHYLSILYLETHANESULFONYL CHLORIDE
SESCI in Synthesis.3 The SES group has been used success

fully in the synthesis of glycosides (eq 5).4 Reaction of (6) with
SES-sulfonamide and Iodonium Di-sym-collidine Perchlorate
provides the iodo sulfonamide (7) in 82% yield. Treatment of
(7) with (benzyloxy)tributylstannane in the presence of Silver(I)
Trifluoromethanesulfonate provides the -benzyl glycoside (8).
Fluoride treatment of (8) removes both the silyl ether and the SES
group, giving the amino alcohol (9).
(7)
(8)
(5)
The smooth removal of the SES protecting group from pyrrole

and pyrrole-containing peptides demonstrates the synthetic poten
tial of this protecting group in heterocyclic chemistry (eq 6).5 The
SES group of (10) is removed with TBAF.3H2O in DMF at room
temperature to yield (11). Other protecting groups (i.e. mesylate,
triflate) cannot be removed without destruction of the substrates.
(9)
In a total synthesis of the antitumor antibiotic (-)-bactobolin

(18), the choice of protecting group on the nitrogen was crucial
(eq 10).6 Unlike other protecting groups, the SES group is com
patible with a wide variety of transformations and reagents, and
is easily removed at the end of the synthesis.
(6)
(10)
The N-SES group can be incorporated by treating an aldehyde

with N-sulfinyl--trimethylsilylethanesulfonamide (SESNSO)
(13), which can be made by treating the sulfonamide (12)
with Thionyl Chloride and a catalytic amount of N,Ndichloro-p-toluenesulfonamide (eq 7) (see also N-Sulfinyl-ptoluenesulfonamide).6 The N-sulfonyl imine can be used in situ
in a number of reactions. For example, the N-sulfonyl imine from
aldehyde (14) reacts with 2,3-dimethylbutadiene (eq 8)7 to give
the Diels-Alder adduct (15). Treatment of (15) with fluoride ion
affords the bicyclic lactam (16). Also, the N-sulfonyl imine de
rived from isobutyraldehyde and (13) reacts with Vinylmagnesium Bromide to provide the allylic SES-sulfonamide (17) in 65%
yield (eq 9).8
Related Reagents. Benzenesulfonyl Chloride; 4-Bromobenzenesulfonyl Chloride; Mesitylenesulfonyl Chloride;

Methanesulfonyl Chloride; p-Toluenesulfonyl Chloride; Trifluoromethanesulfonic Anhydride.
1. Weinreb, S. M.; Demko, D. M.; Lessen, T. A. TL 1986, 27, 2099.

2.
Huang, J.; Widlanski, T. S. TL 1992, 33, 2657.
2-(TRIMETHYLSILYL)ETHAN0L
3.
For the use of SESC1 in the synthesis of (-butyl [[2-(trimefhylsilyl)ethyl]sulfonyl]carbamate, a useful reagent in Mitsunobu reactions,
see N-(t-Butoxycarbonyl)-p-toluenesulfonamide,
Steven M. Weinreb & Janet L. Ralbovsky

The Pennsylvania State University, University Park, PA, USA
A variety of methods are available for the protection of carboxylic acids as 2-(trimethylsilyl)ethyl esters.9 2(Trimethylsilyl)ethyl esters are stable to conditions used in
peptide synthesis. Deprotection of the ester is readily accomplished by treatment with Tetra-n-butylammonium Fluoride
(TBAF).9 Hemisuccinates have been prepared indirectly under
nonacidic conditions by monoprotection of succinic anhydride as
2-(trimethylsilyl)ethyl esters followed by esterification (eq 4) and
then selective deprotection of the resultant diester (eq 5). 10
(4)
2-(Trimethylsilyl)ethanol
C 5 Hi 4 OSi
Handling, Storage, and Precautions: corrosive; irritant.
Campbell, J.
A.; Hart, D. J. JOC 1993, 58, 2900.

4. Danishefsky, S. J.; Koseki, K.; Griffith, D. A.; Gervay, J.; Peterson, J.
M.; McDonald, F. E.; Oriyama, T. JACS 1992, 114, 8331.
5. Miller, A. D.; Leeper, F. J.; Battersby, A. R. JCS(P1) 1989, 1943.
6. Garigipati, R. S.; Tschaen, D. M.; Weinreb, S. M. JACS 1990, 112, 3475.
7. Sisko, J.; Weinreb, S. M. TL 1989, 30, 3037.
8. Sisko, J.; Weinreb, S. M. JOC 1990, 55, 393.
[2916-68-9]
427
(MW 118.28)
(protecting reagent for carboxyl, phosphoryl, hydroxyl, and amino

groups)
Physical Data: bp 50-52 C/10 mmHg, 71-73 C/35 mmHg; d
0.825 g c m - 3 .
Form Supplied in: colorless liquid; 99% purity; widely available.
Preparative Methods: three methods of preparation have
been reported: (a) from the treatment of ethyl bromoacetate with Zinc followed by the reaction with
Chlorotrimethylsilane1 and subsequent reduction of the resultant Ethyl Trimethylsilylacetate with Lithium Aluminum
Hydride2,3 or Borane-Tetrahydrofuran4 (eq 1); (b) from the
hydroboration/oxidation5,6 or oxymercuration/demercuration7
of Vinyltrimethylsilane (eq 2); and (c) most conveniently, by the reaction of the Grignard reagent formed
from (Chloromethyl)trimethylsilane with Paraformaldehyde
(eq 3).8
(5)
Transesterification of methyl esters to 2-(trimefhylsilyl)ethyl

esters under mild and neutral conditions takes place in the
presence of Titanium Tetraisopropoxide (eqs 6-8). 11 Deprotection of the 2-(trimethylsilyl)ethyl ester in the presence of
an O-TBDMS protected secondary hydroxyl group has been
achieved (eq 9). l l b An alternative method for the transesterification uses l,8-Diazabicyclo[5.4.0]undec-7-ene/Lithium
Bromide
and 2-(trimethylsilyl)ethanol.12
(6)
(7)
(8)
(1)
(2)
(9)
(3)
Protection of hydroxyl groups as 2-(trimethylsilyl)ethyl

ethers 13a and 2-(trimethylsilyl)ethyl carbonates 13b (eq 10) has
been utilized as illustrated below. The 2-(trimethylsilyl)ethyl carAvoid Skin Contact with All Reagents
428
2-(TRIMETHYLSILYL)ETHANOL
bonate group can be cleaved under mild conditions using TBAF

in dry THF (eq11).13b
(10)
R = primary, secondary
(14)
(11)
Methods for the protection of pyranosides and furanosides as

2-(trimethylsilyl)ethyl glycosides (eq 12) and deprotection using
dry Lithium Tetrafluoroborate in MeCN have been developed
(eq 13).14
(15)
(12)
G = OH, halogen; n = 0, 1
(16)
(13)
R = Bn
2-(Trimethylsilyl)ethanol has been used as a protecting

group in phosphate monoester synthesis and involves the use
of 2-(trimethylsilyl)ethyl dichlorophosphite (eq 14).15 Bis[2(trimethylsilyl)ethyl] N,N-diisopropylphosphoramidite has been
prepared from dichloro(diisopropylamino)phosphine and 2(trimethylsilyl)ethanol and used as a phosphitylating agent in the
synthesis of phosphotyrosine containing peptides (eq 15).16
2-(Trimethylsilyl)ethoxycarbonyl (Teoc) groups have been
used to protect amine functionalities (eq 16).17 Using a mixture
of tetra-n-butylammonium chloride and KF.2H2O deprotects the
Teoc group.18 N-Debenzylation and concurrent protection as NTeoc results when tertiary N-benzylamines are treated with 2(Trimethylsilyl)ethyl Chloroformate.19
A new method for the synthesis of imidazolones involves

the replacement of the C-2 nitro group of N-protected dinitroimidazoles by nucleophilic addition of the sodium salt of 2(trimethylsilyl)ethanol (eq 17).20
(17)
Reaction of 2-(trimethylsilyl)ethyl benzenesulfenate with

halides in the presence of TBAF yields phenyl sulfoxides
(eq 18).21 2-(Trimethylsi]yl)ethyl benzenesulfenate is prepared by
2-(TRIMETHYLSILYL)ETHOXYMETHYL CHLORIDE
the reaction of Benzenesulfenyl Chloride and the lithium salt of
2-(trimethylsilyl)ethanol.
(18)
Related Reagents. 2-(Trimethylsilyl)ethoxycarbonylimidazole;

2-(Trimethylsilyl)ethoxymethyl Chloride; 2-(Trimethylsilyl)ethyl Chloroformate.
1. Fessenden, R. J.; Fessenden, J. S. JOC 1967, 32, 3535.

2. Gerlach, H. HCA 1977, 60, 3039.
3. Jansson, K.; Ahlfors, S.; Frejd, T.; Kihlberg, J.; Magnusson, G.; Dahmen,
J.; Noori, G.; Stenvall, K. JOC 1988, 53, 5629.
4. Rosowsky, A.; Wright, J. E. JOC 1983, 48, 1539.
5. Soderquist, J. A.; Hassner, A. JOM 1978, 156, C12.
6. Soderquist, J. A.; Brown, H. C. JOC 1980, 45, 3571.
7. Soderquist, J. A.; Thompson, K. L. JOM 1978, 159, 237.
8. Mancini, M. L.; Honek, J. F. TL 1982, 23, 3249.
9.
From acids: (a) Sieber, P. HCA 1977, 60, 2711. (b) Brook, M. A.; Chan,
T. H. S 1983, 201. (c) White, J. D.; Jayasinghe, L. R. TL 1988, 29, 2139.
From an acid chloride: see Ref. 2. From an anhydride: Vedejs, E.; Larsen,
S. D. JACS 1984, 106, 3030. For cleavage: see Ref. 9a, and Forsch, R.
A.; Rosowsky, A. JOC 1984, 49, 1305.
10.
11.
Pouzar, V.; Drasar, P.; Cerny, I.; Havel, M. SC 1984, 14, 501.
(a) Seebach, D.; Hungerbhler, E.; Naef, R.; Schnurrenberger, P.;
Weidmann, B.; Zger, M. S 1982, 138. (b) Frzou, J. P.; Julia, M.;
Liu, L. W.; Pancrazi, A. SL 1991, 618.
12.
13.
Seebach, D.; Thaler, A.; Blaser, D.; Ko, S. Y. HCA 1991, 74, 1102.
(a) Burke, S. D.; Pacofsky, G. J.; Piscopio, A. D. TL 1986, 27, 3345. (b)
Gioeli, C.; Balgobin, N.; Josephson, S.; Chattopadhyaya, J. B. TL 1981,
22, 969.
Lipshutz, B. H.; Pegram, J. J.; Morey, M. C. TL 1981, 22, 4603; also see
Ref. 3.
Sawabe, A.; Filla, S. A.; Masamune, S. TL 1992, 33, 7685.
Chao, H.-G.; Bernatowicz, M. S.; Klimas, C. E.; Matsueda, G. R. TL
1993, 34, 3371.
(a) Shute, R. E.; Rich, D. H. S 1987, 346. (b) Ref. 4. (c) Carpino, L. A.;
Tsao, J.-H. CC 1978, 358.
Carpino, L. A.; Sau, A. C. CC 1979, 514.
Campbell, A. L.; Pilipauskas, D. R.; Khanna, I. K.; Rhodes, R. A. TL
1987, 28, 2331.
Marlin, J. E.; Killpack, M. O. H 1992, 34, 1385.
Oida, T.; Ohnishi, A.; Shimamaki, T.; Hayashi, Y.; Tanimoto, S. BCJ
1991, 64, 702.
14.
15.
16.
17.
18.
19.
20.
21.
429
2-(TrimethylsiIyl)ethoxymethyl Chloride 1
[76513-69-4]
C6H15ClOSi
(MW 166.75)
(protection of alcohols, 1,2 secondary aryl amines, 3 and imidazole, indole, and pyrrole nitrogens; 4-6 electrophilic formaldehyde
equivalent;7 acyl anion equivalent8)
Alternate Name: SEM-C1.
Physical Data: bp 57-59 C/8 mmHg; d 0.942 g c m - 3 .
Solubility: sol most organic solvents (pentane, CH 2 Cl 2 , Et 2 O,
THF, DMF, DMPU, HMPA).
Form Supplied in: liquid; commercially available 90-95% pure;
HC1 is typical impurity.
Analysis of Reagent Purity: GC.
Preparative Methods: several syntheses have been reported. 2,9-12
Handling, Storage, and Precautions: water sensitive; corrosive;
should be stored in a glass container under an inert atmosphere;
a lachrymator; flammable (fp 46 C).
Reagent for the Protection of Alcohols. Lipshutz and coworkers introduced the use of SEM-C1 for the protection of primary, secondary, and tertiary alcohols (eq 1).2 SEM-C1 is now
widely employed in organic synthesis for the protection of hydroxyl functionalities (eqs 2 and 3). 13,14
(1)
(2)
Jayachandra P. Reddy
Indiana University, Bloomington, IN, USA
(3)
430
The resulting SEM ethers are stable under a variety of conditions. Most SEM ethers are cleaved with a fluoride anion source
(eqs 4 and 5), 2,15-17 although this fragmentation is generally
much less facile than fluoride-induced cleavage of silyloxy bonds.
Therefore the selective deprotection of other silyl ethers in the
presence of SEM ethers is possible (eq 6).15 Vigorous conditions
with anhydrous fluoride ion are required for the cleavage of some
tertiary SEM ethers (eq 7).18,19
sium Bromide (eq 8).21 SEM, MOM, and MEM phenolic protective groups are removed with Diphosphorus Tetraiodide (eq 9).22
(8)
(9)
(4)
SEM-Cl has also proven useful in carbohydrate synthesis where

the resulting SEM ethers can be cleaved under less acidic conditions than those required for the cleavage of MOM and MEM
ethers (eq 10).23
(10)
(5)
Reagent for the Protection of Acids. Carboxylic acids can

be protected as SEM esters (eq 11).24,25 Cleavage of the SEM
esters occurs with refluxing methanol24 or magnesium bromide
(eq 12).25,26
(6)
(11)
(12)
R = SEM
R=H
(7)
The stability of SEM ethers has necessitated the development of

a variety of other deprotection methods. SEM protective groups
are stable to the acidic conditions used to hydrolyze THP, TBDMS, and MOM ethers (AcOH, H2O, THF, 45 C),2 but can be
removed under strongly acidic conditions with Trifluoroacetic
Acid.20 SEM, MTM, and MOM ethers are selectively cleaved in
the presence of MEM, TBDMS, and benzyl ethers with MagneLists of Abbreviations and Journal Codes on Endpapers
Reagent for the Protection of Secondary Amines. SEM-C1

can be used to protect secondary aromatic amines (eq 13),3 and
is an ideal reagent for the protection of imidazoles, indoles, and
pyrroles (eqs 14-16).4-6,27 Many functional groups are compatible with the introduction and cleavage of SEM amines, and the
SEM substituent is unusually stable to further functionalization of
the molecule.4-6,27 Recently, a one-pot method for protection and
alkylation of imidazoles employing n-Butyllithium and SEM-C1
has been developed (eq 17).28-30
431
(18)
(13)
(19)
(14)
Related Reagents. BenzylChloromethyl Ether; t-Butyl

Chloromethyl Ether; 2-(Chloroethyl) chloromethyl Ether;
Chloromethyl Methyl Ether; Chloromethyl Methyl Sulfide; (pMethoxybenzyloxy)methyl Chloride; 2-Methoxyethoxymethyl
Chloride; 2-(Trimethylsilyl)ethanol.
(15)

2.
(16)
Lipshutz, B. H.; Pegram, J. J. TL 1980, 21, 3343.
3.
Zeng, Z.; Zimmerman, S. C. TL 1988, 29, 5123.
4.
Whitten, J. P.; Matthews, D. P.; McCarthy, J. R. JOC 1986, 51, 1891.
5.
Ley, S. V.; Smith, S. C ; Woodward, P. R. T 1992, 48, 1145.
6. Muchowski, J. M.; Solas, D. R. JOC 1984, 49, 203.

7. Baldwin, J. E.; Lee, V.; Schofield, C. J. SL 1992, 249.
8.
Schnauer, K.; Zbiral, E. TL 1983, 24, 573.
9.
Sonderquist, J. A.; Hassner, A. JOM 1978, 156, C12.
10.
(17)
Sonderquist, J. A.; Thompson, K. L. JOM 1978, 159, 237.
11.
Gerlach, H. HCA 1977, 60, 3039.
12.
Fessenden, R. J.; Fessenden, J. S. JOC 1967, 32, 3535.
13.
Kotecha, N. R.; Ley, S. V.; Mantegani, S. SL 1992, 395.
14. Lipshutz, B. H.; Moretti, R.; Crow, R. TL 1989, 30, 15.
One-Carbon Homologations. SEM-Cl has functioned as an

alternative to the use of Formaldehyde (eq 18).7 The enolate of the
lactone (1) undergoes C-alkylation with SEM-C1, and the resulting
SEM substituent can be subsequently treated with trifluoroacetic
acid to afford the alcohol (2).
SEM-Cl has been transformed to a formaldehyde carbanion
equivalent.8 SEM-Cl is converted to the ylide upon treatment with
Triphenylphosphine and Sodium Hydride. This ylide reacts with
a variety of aldehydes and ketones affording enol ethers (eq 19).8
Hydrolysis with 5% aqueous HF gives the corresponding aldehyde.
15. Williams, D. R.; Jass, P. A.; Tse, H.-L. A.; Gaston, R. D. JACS 1990,
112, 4552.
16.
Shull, B. K.; Koreeda, M. JOC 1990, 55, 99.
17. Ireland, R. E.; Varney, M. D. JOC 1986, 51, 635.

18. Kan, T.; Hashimoto, M.; Yanagiya, M.; Shirahama, H. TL 1988, 29, 5417.
19. Lipshutz, B. H.; Miller, T. A. TL 1989, 30, 7149.
20.
Schlessinger, R. H.; Poss, M. A.; Richardson, S. JACS 1986, 108, 3112.
21.
Kim, S.; Kee, I. S.; Park, Y. H.; Park, J. H. SL 1991, 183.
22.
Saimoto, H.; Kusano, Y.; Hiyama, T. TL 1986, 27, 1607.
23.
Pinto, B. M.; Buiting, M. M. W.; Reimer, K. B. JOC 1990, 55, 2177.
24.
Logusch, E. W. TL 1984, 25, 4195.

432
TRIMETHYLSILYLTRIFLUOROMETHANESULFONATE
25.
26.
27.
28.
29.
Kim, S; Park, Y. H.; Kee, I. S. TL 1991, 32, 3099.

Salomon, C. J.; Mata, E. G.; Mascaretti, O. A. T 1993, 49, 3691.
Lipshutz, B. H.; Vaccaro, W.; Huff, B. TL 1986, 27, 4095.
Lipshutz, B. H.; Huff, B.; Hagen, W. TL 1988, 29, 3411.
Demuth, T. P., Jr.; Lever, D. C.; Gorgos, L. M.; Hogan, C. M.; Chu, J.
JOC 1992, 57, 2963.
30. For a similar method with pyrroles, see Ref. 13.
over O-silylation. The exact ratio of products obtained depends on

the ester structure7 (eq 5).8 Nitriles undergo C-silylation; primary
nitriles may undergo C,C-disilylation.9
(5)
Jill Earley
TMS enol ethers may be prepared by rearrangement of ketosilanes in the presence of catalytic TMSOTf (eq 6).10,11
Trimethylsilyl Trifluoromethanesulfonate1
(6)
[88248-68-4; 27607-77-8]
C 4 H 9 F 3 O 3 SSi
(MW 222.29)
Enhanced regioselectivity is obtained when trimethylsilyl enol

ethers are prepared by treatment of -trimethylsilyl ketones with
catalytic TMSOTf (eq 7).12
Alternate Name: TMSOTf.

Physical Data: bp 45-47 C/17 mmHg, 39-40 C/12mmHg; d
1.225 g cm - 3 .
(7)
Solubility: sol aliphatic and aromatic hydrocarbons, haloalkanes,
ethers.
The reaction of imines with TMSOTf in the presence of Et3N
Preparative Methods: may be prepared by a variety of methods.2
13
Handling, Storage, and Precautions: flammable; corrosive; very gives N-silylenamines.
Ethers do not react, but epoxides are cleaved to give silyl
hygroscopic.
ethers of allylic alcohols in the presence of TMSOTf and 1,8Diazabicyclo[5.4.0]undec-7-ene; The regiochemistry of the re
action is dependent on the structure of the epoxide (eq 8).14
Silylation. TMSOTf is widely used in the conversion of car9
bonyl compounds to their enol ethers. The conversion is some 10
faster with TMSOTf/Triethylamine than with Chlorotrimethylsilane (eqs 1-3).3-5
(8)
(1)
(2)
Indoles and pyrroles undergo efficient C-silylation with TM

SOTf (eq 9).15
(9)
(3)
Dicarbonyl compounds are converted to the corresponding bisenol ethers; this method is an improvement over the previous twostep method (eq 4).6
t-Butyl esters are dealkylatively silylated to give TMS esters by

TMSOTf; benzyl esters are inert under the same conditions.16
Imines formed from unsaturated amines and -carbonyl esters
undergo ene reactions in the presence of TMSOTf to form cyclic
amino acids.17
(4)
In general, TMSOTf has a tendency to C-silylation which is seen

most clearly in the reaction of esters, where C-silylation dominates
Carbonyl Activation. 1,3-Dioxolanation of conjugated

enals is facilitated by TMSOTf in the presence of 1,2bis(trimethylsilyloxy)ethane. In particular, highly selective
protection of sterically differentiated ketones is possible
18
(eq 10). Selective protection of ketones in the presence of enals

is also facilitated (eq 11).19
433
in the presence of the silyl triflate. The activation of acetals was

first reported by Noyori and has since been widely employed
(eq 14).22,23
(10)
(14)
In an extension to this work, TMSOTf catalyzes the first step of a

[3 + 2] annulation sequence which allows facile synthesis of fused
cyclopentanes possessing bridgehead hydroxy groups (eq 15).24
(11)
1:27
(15)
The similar reaction of 2-alkyl-l,3-disilyloxypropanes with

chiral ketones is highly selective and has been used to prepare
spiroacetal starting materials for an asymmetric synthesis of tocopherol subunits (eq 12).20
The use of TMSOTf in aldol reactions of silyl enol ethers and

ketene acetals with aldehydes is ubiquitous. Many refinements of
the basic reaction have appeared. An example is shown in eq 16.25
(16)
(12)
The preparation of spiro-fused dioxolanes (useful as chiral glycolic enolate equivalents) also employs TMSOTf (eq 13).21
The use of TMSOTf in the reaction of silyl ketene acetals with

imines offers an improvement over other methods (such as TiIV- or
ZnII-mediated processes) in that truly catalytic amounts of activa
tor may be used (eq 17);26 this reaction may be used as the crucial
step in a general synthesis of 3-(l'-hydroxyethyl)-2-azetidinones
(eq 18).27
(17)
(13)
~ 1:1 mixture
TMSOTf mediates a stereoselective aldol-type condensation

of silyl enol ethers and acetals (or orthoesters). The nonbasic
reaction conditions are extremely mild. TMSOTf catalyzes many
aldol-type reactions; in particular, the reaction of relatively
nonnucleophilic enol derivatives with carbonyl compounds is facile
(18)
434
Stereoselective cyclization of ,-unsaturated enamide esters is

induced by TMSOTf and has been used as a route to quinolizidines
and indolizidines (eq 19).28
Miscellaneous. Methyl glucopyranosides and glycopyranosyl

chlorides undergo allylation with allylsilanes under TMSOTf
catalysis to give predominantly -allylated carbohydrate analogs
(eq 24).33
(24)
:=10:l
(19)
Glycosidation is a reaction of massive importance and

widespread employment. TMSOTf activates many selective gly
cosidation reactions (eq 25).34
The formation of nitrones by reaction of aldehydes and ketones
with N-Methyl-N,O-bis(trimethylsilyl)hydroxylamine is acceler
ated when TMSOTf is used as a catalyst; the acceleration is par
ticularly pronounced when the carbonyl group is under a strong
electronic influence (eq 20).29
(20)
(25)
-Stannylcyclohexanones undergo a stereoselective ring con

traction when treated with TMSOTf at low temperature. When
other Lewis acids were employed, a mixture of ring-contracted
and protiodestannylated products was obtained (eq 21).30
TMSOTf activation for coupling of 1-O-acylated glycosyl

donors has been employed in a synthesis of avermectin disaccharides (eq 26).35
(21)
The often difficult conjugate addition of alkynyl organometallic

reagents to enones is greatly facilitated by TMSOTf. In particular,
alkynyl zinc reagents (normally unreactive with a,(3-unsaturated
carbonyl compounds) add in good yield (eq 22).31 The proportion
of 1,4-addition depends on the substitution pattern of the substrate.
(22)
The 1,4-addition of phosphines to enones in the presence of

TMSOTf gives -phosphonium silyl enol ethers, which may be
deprotonated and alkylated in situ (eq 23).32
(23)
(26)
Similar activation is efficient in couplings with

trichloroimidates36 and O-silylated sugars.37,38
2-Substituted 3-piperidines may be prepared by the reaction
of 4-hydroxy-1,2,3,4-tetrahydropyridines with a variety of carbon
and heteronucleophiles in the presence of TMSOTf (eqs 27 and
28).39
(27)
TRIMETHYL SILYLTRIFLUOROMETHANESULFONATE
(28)
Iodolactamization is facilitated by the sequential reaction of

unsaturated amides with TMSOTf and Iodine (eq 29).40
(29)
By use of a silicon-directed Beckmann fragmentation, cyclic

(E)--trimethylsilylketoxime acetates are cleaved in high yield in
the presence of catalytic TMSOTf to give the corresponding un
saturated nitriles. Regio- and stereocontrol are complete (eq 30).41
(30)
A general route to enol ethers is provided by the reaction of

acetals with TMSOTf in the presence of a hindered base (eq 31 ).42
The method is efficient for dioxolanes and noncyclic acetals.
(31)
-Halo sulfoxides are converted to -halovinyl sulfides by re

action with excess TMSOTf (eq 32),43 while -cyano- and alkoxycarbonyl sulfoxides undergo a similar reaction (eq 33).44
TMSOTf is reported as much superior to Iodotrimethylsilane in
these reactions.
(32)
(33)
Related Reagents. t-Butyldimethylsilyl Trifluoromethanesulfonate; Chlorotrimethylsilane; Iodotrimethylsilane; Triethylsilyl Trifluoromethanesulfonate.
2.
3.
4.
5.
435
Simchen, G.; Kober, W. S 1976, 259.

Hergott, H. H.; Simchen, G. LA 1980, 1718.
Simchen, G.; Kober, W. S 1976, 259.
Emde, H.; Gtz, A.; Hofmann, K.; Simchen, G. LA 1981, 1643.
6.
7.
8.
9.
10.
11.
Krgeloh, K.; Simchen, G. S 1981, 30.

Emde, H.; Simchen, G. LA 1983, 816.
Emde, H.; Simchen, G. S 1977, 636.
Emde, H.; Simchen, G. S 1977, 867.
Yamamoto, Y.; Ohdoi, K.; Nakatani, M.; Akiba, K. CL 1984, 1967.
Emde, H.; Gtz, A.; Hofmann, K.; Simchen, G. LA 1981, 1643.
12.
13.
14.
15.
16.
17.
18.
19.
20.
Matsuda, I.; Sato, S.; Hattori, M.; Izumi, Y. TL 1985, 26, 3215.
Ahlbrecht, H.; Dber, E. O. S 1980, 630.
Frick, U.; Simchen, G. S 1984, 929.
Borgulya, J.; Bernauer, K. S 1980, 545.
Tietze, L. F.; Bratz, M. S 1989, 439.
Hwu, J. R.; Wetzel, J. M. JOC 1985, 50, 3946.
Hwu, J. R.; Robl, J. A. JOC 1987, 52, 188.
Harada, T.; Hayashiya, T.; Wada, I.; Iwa-ake, N.; Oku, A. JACS 1987,
109, 527.
Pearson, W. H.; Cheng, M-C. JACS 1986, 51, 3746.
Murata, S.; Suzuki, M.; Noyori, R. T 1988, 44, 4259.
Lee, T. V.; Richardson, K. A. TL 1985, 26, 3629.
Mukaiyama, T.; Uchiro, H.; Kobayashi, S. CL 1990, 1147.
Guanti, G.; Narisano, E.; Banfi, L. TL 1987, 28, 4331.
Guanti, G.; Narisano, E.; Banfi, L. TL 1987, 28, 4335.
Ihara, M.; Tsuruta, M.; Fukumoto, K.; Kametani, T. CC 1985, 1159.
Robl, J. A.; Hwu, J. R. JOC 1985, 50, 5913.
Sato, T.; Watanabe, T.; Hayata, T.; Tsukui, T. CC 1989, 153.
Kim, S.; Lee, J. M. TL 1990, 31, 7627.
Kim, S.; Lee, P. H. TL 1988, 29, 5413.
Hosomi, A.; Sakata, Y.; Sakurai, H. TL 1984, 25, 2383.
Yamada, H.; Nishizawa, M T 1992, 3021.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35. Rainer, H.; Scharf, H.-D.; Runsink, J. LA 1992, 103.

36. Schmidt, R. R. AG(E) 1986, 25, 212.
37. Tietze, L.-F.; Fischer, R.; Guder, H.-J. TL 1982, 23, 4661.
38. Mukaiyama, T.; Matsubara, K. CL 1992, 1041.
39. Kozikowski, A. P.; Park, P. JOC 1984, 49, 1674.
40. Knapp, S.; Rodriques, K. E. TL 1985, 26, 1803.
41. Nishiyama, H.; Sakuta, K.; Osaka, N.; Itoh, K. TL 1983, 24, 4021.
42. Gassman, P. G.; Burns, S. J. JOC 1988, 53, 5574.
43. Miller, R. D.; Hssig, R., SC 1984, 14, 1285.
44. Miller, R. D.; Hssig, R., TL 1985, 26, 2395.
Joseph Sweeney & Gemma Perkins

1. Reviews: (a) Emde, H.; Domsch, D.; Feger, H.; Frick, U.; Gtz, H. H.;
Hofmann, K.; Kober, W.; Krgeloh, K.; Oesterle, T.; Steppan, W.; West,
W.; Simchen, G. S 1982, 1. (b) Noyori, R.; Murata, S.; Suzuki, M. T
1981, 37, 3899. (c) Stang, P. J.; White, M. R. Aldrichim. Acta 1983, 16,
15. Preparation: (d) Olah, G. H.; Husain, A.; Gupta, B. G. B.; Salem,
G. F.; Narang, S. C. JOC 1981, 46, 5212. (e) Morita, T.; Okamoto, Y.;
Sakurai, H. S 1981, 745. (f) Demuth, M.; Mikhail, G. S 1982, 827. (g)
Ballester, M.; Palomo, A. L. S 1983, 571. (h) Demuth, M.; Mikhail, G.
T 1983, 39, 991. (i) Aizpurua, J. M.; Palomo, C. S 1985, 206.
436
TRIPHENYLCARBENIUMTETRAFLUOROBORATE
TriphenylcarbeniumTetrafluoroborate
[341-02-6]
Ci 9 H 15 BF 4
(MW 330.15)
(easily prepared1 hydride abstractor used for conversion of dihydroaromatics to aromatics,2-4 and the preparation of aro
matic and benzylic cations;5-8 oxidative hydrolysis of ketals9
and thioketals;10 conversion of acetonides to -hydroxy ketones;9
oxidation of acetals11 and thioacetals;12 selective oxidation of
alcohols and ethers to ketones;9,13-15 oxidation of silyl enol
ethers to enones;16 hydrolysis of TBS and MTM ethers;17
oxidation of amines and amides to iminium salts;18-20 oxi
dation of organometallics to give alkenes;21-23 sensitizer for
photooxidation using molecular oxygen;24 Lewis acid cata
lyst for various reactions;25 polymerization catalyst;26 other
reactions27-30)
Alternate Name: trityl fiuoroborate.
Physical Data: mp ~200C (dec).
Solubility: sol most standard organic solvents; reacts with some
nucleophilic solvents.
Form Supplied in: yellow solid; commercially available.
Preparative Methods: the most convenient procedure involves
the reaction of Ph3CCl with Silver(I) Tetrafluoroborate in
ethanol.lb The most economical route employs the reaction
of Ph3CCl with the anhydrous Tetrafluoroboric Acid-Et2O
complex,1c or Ph3COH with HBF4 in acetic anhydride.1d
Purification: recrystallization of commercial samples from a min
imal amount of dry MeCN provides material of improved purity,
but the recovery is poor.la
Handling, Storage, and Precautions: moisture-sensitive and cor
rosive. Recrystallized reagent can be stored at rt for several
months in a desiccator without significant decomposition. This
compound is much less light-sensitive than other trityl salts
such as the perchlorate.1a
Preparation of Aromatic Compounds via Dehydrogenation. Dihydroaromatic compounds are easily converted
into the corresponding aromatic compound by treatment
with triphenylcarbenium tetrafluoroborate followed by base.2
Certain ,-disubstituted dihydroaromatics are converted
to the 1,4-dialkylaromatic compounds with rearrangement
(eq 1).3 Nonbenzenoid aromatic systems, e.g. benzazulene4a
or dibenzosesquifulvalene,4b are readily prepared from their
dihydro counterparts. Aromatic cations are also easily prepared
by hydride abstraction, for example, tropylium ion (e.g. in the
synthesis of heptalene (eq 2)),5 cyclopropenyl cation,6 and
others, including heterocyclic systems.7 Some benzylic cations,
especially ferrocenyl cations,8 can also be formed by either
hydride abstraction or trityl addition.
Oxidation by Hydride Abstraction. In the early 1970s, Bar
ton developed a method for the oxidative hydrolysis of ketals to
ketones, e.g. in the tetracycline series (eq 3).9 The same condi
tions can also be used to hydrolyze thioketals.10 Acetonides of
1,2-diols are oxidized to the -hydroxy ketones in good yield

by this reagent (eq 4).9 The hydrogen of acetals is easily ab
stracted (eq 5), providing a method for the conversion of benzylidene units in sugars to the hydroxy benzoates.11 The hydro
gen of dithioacetals is also abstracted to give the salts.12 Since
benzylic hydrogens are readily abstracted, this is also a method
for deprotection of benzyl ethers.9,13 Trimethylsilyl, t-butyl, and
trityl ethers of simple alcohols are oxidized to the corresponding
ketones and aldehydes in good yield. Primary-secondary diols are
selectively oxidized at the secondary center to give hydroxy ke
tones by this method (eq 6).14 2,2-Disubstituted 1,4-diols are ox
idized only at the 4-position to give the corresponding lactones.15
Trimethylsilyl enol ethers are oxidized to ,-unsaturated ke
tones, thereby providing a method for ketone to enone conversion
(eq 7).16 t-Butyldimethylsilyl (TBDMS) ethers are not oxidized
but rather hydrolyzed to the alcohols, as are methylthiomethyl
(MTM) ethers.17 Benzylic amines and amides can be oxidized to
the iminium salts,18 allylic amines and enamines afford eniminium
salts,19 and orthoamides give triaminocarbocations.20
(1)
(2)
(3)
(4)
(5)
(6)
(7)
Generation of Alkenes from Organometallics. Various metalloalkanes can be oxidized by trityl fiuoroborate to the cor
responding alkenes.21-23 The highest yields are obtained for the
TRIPHENYLCARBENIUMTETRAFLUOROBORATE
437
-iron derivatives (eq 8), which are easily prepared from the cor
responding halides or tosylates.21 Grignard reagents and organolithiums also undergo this reaction (eq 9),22 as do Group 14
organometallics (silanes, stannanes, etc.).23
(13)
(8)
(9)
Sensitizer of Photooxygenation. Barton showed that oxygen,

in the presence of trityl fluoroborate and ordinary light, adds to
cisoid dienes at -78C in very high yields.24 For example, the
peroxide of ergosterol acetate is formed in quantitative yields un
der these conditions (eq 10),24a,b which have been used also for
photocycloreversions of cyclobutanes.24c
Polymerization Catalyst. Several types of polymerization26

have been promoted by trityl fluoroborate, including reactions
of orthocarbonates26a and orthoesters,26b-d vinyl ethers,26e-g
epoxides,26h,i and lactones.26j,k
Other Reactions. Trityl fluoroborate has been used often to
prepare cationic organometallic complexes, as in the conversion
of dienyl complexes of iron, ruthenium, and osmium into their
cationic derivatives.27 It alkylates pyridines on the nitrogen atom
in a preparation of dihydropyridines28a and acts as a tritylating
agent.28b It has also been used in attempts to form silyl cations
and silylfluoridesfrom silanes.29 Finally, it has been reported to
be a useful desiccant.30
1.
(10)
Lewis Acid Catalysis. Tritylfluoroborateis a good Lewis acid

for various transformations,25 e.g. the Mukaiyama-type aldol re
action using a dithioacetal and silyl enol ether (eq 11 ).25a It has
also been used as the catalyst for the formation of glycosides from
alcohols and sugar dimethylthiophosphinates (eq 12)25b and for
the formation of disaccharides from a protected -cyanoacetal of
glucose and a 6-O-trityl hexose.25c Michael additions of various
silyl nucleophiles to conjugated dithiolenium cations also pro
ceed well (eq 13).25d,e Finally, the [4 + 2] cycloaddition of cyclic
dienes and oxygenated allyl cations has been effected with trityl
fluoroborate.25f
(11)
(a) Dauben, H. J., Jr.; Honnen, L. R.; Harmon, K. M. JOC 1960, 25,
1442. (b) Fukui, K.; Ohkubo, K.; Yamabe, T. BCJ 1969, 42, 312. (c)
Olah, G. A.; Svoboda, J. J.; Olah, J. A. S 1972, 544. (d) Pearson, A. J.
Iron Compounds in Organic Synthesis, Academic Press, 1994, p. 155.
2.
(a) Mller, P. HCA 1973, 56, 1243. (b) Giese, G.; Heesing, A. CB 1990,
123, 2373.
3. (a) Karger, M. H.; Mazur, Y. JOC 1971, 36, 540. (b) Acheson, R. M.;
Flowerday, R. F. JCS(P1) 1975, 2065.
4. (a) O'Leary, M. A.; Richardson, G. W.; Wege, D. T 1981, 37, 813. (b)
Prinzbach, H.; Seip, D.; Knothe, L.; Faisst, W. LA 1966, 698, 34.
5. (a) Dauben, H. J., Jr.; Gadecki, F. A.; Harmon, K. M.; Pearson, D. L.
JACS 1957, 79, 4557. (b) Dauben, H. J., Jr.; Bertelli, D. J. JACS 1961, 83,
4657, 4659. (c) Peter-Katalinic, J.; Zsindely, J.; Schmid, H. HCA 1973,
56, 2796. (d) Vogel, E.; Ippen, J. AG(E) 1974, 13, 734. (e) Beeby, J.;
Garratt, P. J. JOC 1973, 38, 3051. (f) Murata, I.; Yamamoto, K.; Kayane,
Y. AG(E) 1974, 13, 807, 808. (g) Kuroda, S.; Asao, T. TL 1977, 285. (h)
Komatsu, K.; Takeuchi, K.; Arima, M.; Waki, Y; Shirai, S.; Okamoto,
K. BCJ 1982, 55, 3257. (i) Mller, J.; Mertschenk, B. CB 1972, 105,
3346. (j) Schweikert, O.; Netscher, T.; Knothe, L.; Prinzbach, H. CB
1984, 117, 2045. (k) Bindl, J.; Seitz, P.; Seitz, U.; Salbeck, E.; Salbeck,
J.; Daub, J. CB 1987, 120, 1747.
6.
(a) Zimmerman, H. E.; Aasen, S. M. JOC 1978, 43, 1493. (b) Komatsu,
K.; Tomioka, I.; Okamoto, K. BCJ 1979, 52, 856.
7. (a) Yamamura, K.; Miyake, H.; Murata, I. JOC 1986, 57, 251. (b)
Matsumoto, S.; Masuda, H.; Iwata, K.; Mitsunobu, O. TL 1973, 1733.
(c) Yano, S.; Nishino, K.; Nakasuji, K.; Murata, I. CL 1978, 723. (d)
Kedik, L. M.; Freger, A. A.; Viktorova, E. A. KGS 1976, 12, 328 (Chem.
Heterocycl. Compd. (Engl. Transl.) 1976, 12, 279). (e) Reichardt, C ;
Schafer, G.; Milart, P. CCC 1990, 55, 97.
8.
(a) Muller, P. HCA 1973, 56, 500. (b) Boev, V. I.; Dombrovskii, A. V.
ZOB 1987, 57, 938, 633. (c) Klimova, E. I.; Pushin, A. N.; Sazonova, V.
A. ZOB 1987, 57, 2336. (d) Abram, T. S.; Watts, W. E. JCS(P1) 1975,
113; JOM 1975, 87, C39. (e) Barua, P.; Barua, N. C.; Sharma, R. P. TL
1983, 24, 5801. (f) Akgun, E.; Tunali, M. AP 1988, 321, 921.
9.
(12)
(a) Barton, D. H. R.; Magnus, P. D.; Smith, G.; Strecker, G.; Zurr, D.
JCS(P1) 1972, 542. (b) Barton, D. H. R.; Magnus, P. D.; Smith, G.; Zurr,
D. CC 1971, 861.
10. Ohshima, M.; Murakami, M.; Mukaiyama, T. CL 1986, 1593.
438
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
TRIPHENYLPHOSPHINE-N-BROMOSUCCINIMIDE
(a) Hanessian, S.; Staub, A. P. A. TL 1973, 3551. (b) Jacobsen, S.;

Pedersen, C. ACS 1974, 28B, 1024, 866. (c) Wessel, H.-P.; Bundle, D.
R.JCS(P1)19S5,225\.
(a) Nakayama, J.; Fujiwara, K.; Hoshino, M. CL 1975, 1099; BCJ 1976,
49, 3567. (b) Nakayama, J.; Imura, M ; Hoshino, M. BCJ 1980, 53,
1661. (c) Nakayama, J. BCJ 1982, 55, 2289. (d) Bock, H.; Brhler, G.;
Henkel, U.; Schlecker, R.; Seebach, D. CB 1980, 113, 289. (e) Neidlein,
R.; Droste-Tran-Viet, D.; Gieren, A.; Kokkinidis, M.; Wilckens, R.;
Geserich, H.-P.; Ruppel, W. HCA 1984, 67, 574. (f) However, azide
abstraction is seen with azidodithioacetals: Nakayama, J.; Fujiwara, K.;
Hoshino, M. JOC 1980, 45, 2024.
(a) Barton, D. H. R.; Magnus, P. D.; Streckert, G.; Zurr, D. CC 1971,
1109. (b) Doyle, M. P.; Siegfried, B. JACS 1976, 98, 163. (c) Hoye, T.
R.; Kurth, M. J. JACS 1979, 101, 5065. (d) For simple ethers, see: Deno,
N. C ; Potter, N. H. JACS 1967, 89, 3550.
(a) Jung, M. E. JOC 1976, 41, 1479. (b) Jung, M. E.; Speltz, L. M. JACS
1976, 98, 7882. (c) Jung, M. E.; Brown, R. W. TL 1978, 2771.
Doyle, M. P.; Dow, R. L.; Bagheri, V.; Patrie, W. J. JOC 1983, 48, 476;
TL 1980, 21, 2795.
(a) Jung, M. E.; Pan, Y.-G.; Rathke, M. W.; Sullivan, D. F.; Woodbury,
R. P. JOC 1977, 42, 3961. (b) Reetz, M. T.; Stephan, W. LA 1980, 533.
(a) Metcalf, B. W.; Burkhardt, J. P.; Jund, K. TL 1980, 21, 35. (b)
Chowdhury, P. K.; Sharma, R. P.; Baruah, J. N. TL 1983, 24, 4485. (c)
Niwa, H.; Miyachi, Y. BCJ 1991, 64, 716.
(a) Damico, R.; Broaddus, C. D. JOC 1966, 31, 1607. (b) Barton, D.
H. R.; Bracho, R. D.; Gunatilaka, A. A. L.; Widdowson, D. A. JCS(P1)
1975, 579. (c) Wanner, K. T.; Praschak, I.; Nagel, U. AP 1990, 322, 335;
H 1989, 29, 29.
Reetz, M. T.; Stephan, W; Maier, W. F. SC 1980, 10, 867.
Erhardt, J. M.; Grover, E. R.; Wuest, J. D. JACS 1980, 702, 6365.
(a) Laycock, D. E.; Hartgerink, J.; Baird, M. C. JOC 1980, 45, 291. (b)
Laycock, D. E.; Baird, M. C. TL 1978, 3307. (c) Slack, D.; Baird, M. C.
CC 1974, 701. (d) Bly, R. S.; Bly, R. K.; Hossain, M. M.; Silverman, G.
S.; Wallace, E. T 1986, 42, 1093. (e) Bly, R. S.; Silverman, G. S.; Bly,
R. K. OM 1985, 4, 374.
Reetz, M. T.; Schinzer, D. AG(E) 1977, 16, 44.
(a) Traylor, T. G.; Berwin, H. J.; Jerkunica, J.; Hall, M. L. PAC 1972,
30, 597. (b) Jerkunica, J. M.; Traylor, T. G. JACS 1971, 93, 6278. (c)
Washburne, S. S.; Szendroi, R. JOC 1981, 46, 691. (d) Washburne, S. S.;
Simolike, J. B. JOM 1974, 81, 41. (e) However, organostannanes lacking
a (-hydrogen afford alkyltriphenylmethanes in good yield. Kashin, A.
N.; Bumagin, N. A.; Beletskaya, I. P.; Reutov, O. A. JOM 1979, 171,
321.
(a) Barton, D. H. R.; Haynes, R. K.; Leclerc, G.; Magnus, P. D.; Menzies,
I. D. JCS(P1) 1975, 2055. (b) Barton, D. H. R.; Leclerc, G.; Magnus, P.
D.; Menzies, I. D. CC 1972, 447. (c) Okada, K.; Hisamitsu, K.; Mukai,
T. TL 1981, 22, 1251. (d) Futamura, S.; Kamiya, Y. CL 1989, 1703.
(a) Ohshima, M.; Murakami, M.; Mukaiyama, T. CL 1985, 1871. (b)
Inazu, T.; Yamanoi, T. Jpn. Patent 02 240 093, 02 255 693 (CA 1991, 114,
143 907j, 143 908k); Jpn. Patent 01 233 295 (CA 1990, 112, 198 972r).
(c) Bochkov, A. F.; Kochetkov, N. K. Carbohydr. Res. 1975, 39, 355; for
polymerizations of carbohydrate cyclic orthoesters, see; Bochkov, A. F.;
Chernetskii, V. N.; Kochetkov, N. K. Carbohydr. Res. 1975, 43, 35; BAU
1975, 24, 396. (d) Hashimoto, Y.; Mukaiyama, T. CL 1986, 1623, 755.
(e) Hashimoto, Y.; Sugumi, H.; Okauchi, T.; Mukaiyama, T. CL 1987,
1691. (f) Murray, D. H.; Albizati, K. F. TL 1990, 31, 4109.
(a) Endo, T.; Sato, H.; Takata, T. Macromolecules 1987, 20, 1416. (b)
Uno, H.; Endo, T.; Okawara, M. J. Polym. Sci., Polym. Chem. Ed. 1985,
23, 63. (c) Nishida, H.; Ogata, T. Jpn. Patent 62 295 920 (CA 1988, 109,
57 030h). (d) See also Ref. 25c. (e) Kunitake, T. J. Macromol. Sci., Chem.
1975, 49, 797. (f) Kunitake, T.; Takarabe, K.; Tsugawa, S. Polym. J. 1976,
8, 363. (g) Spange, S.; Dreier, R.; Opitz, G.; Heublein, G. Acta Polym.
1989, 40, 55. (h) Mijangos, F.; Len, L. M. J. Polym. Sci., Polym. Lett. Ed.
1983, 21, 885; Eur. Polym. J. 1983, 19, 29. (i) Bruzga, P.; Grazulevicius,
J.; Kavaliunas, R.; Kublickas, R. Polym. Bull. (Berlin) 1991, 26, 193. (j)
Khomyakov, A. K.; Gorelikov, A. T.; Shapet'ko, N. N.; Lyudvig, E. B.
Vysokomol. Soedin., Ser. A 1976, 18, 1699, 1053; DOK 1975, 222, 1111.
27.
(a) For a review, see any basic organometallic text, e.g. Coates, G.
E.; Green, M. L. H.; Wade, K. Organometallic Compounds; Methuen;
London, 1968; Vol. 2, pp 136ff. (b) Birch, A. J.; Cross, P. E.; Lewis, J.;
White, D. A. CI(L) 1964, 838. (c) Cotton, F. A.; Deeming, A. J.; Josty,
P. L.; Ullah, S. S.; Domingos, A. J. P.; Johnson, B. F. G.; Lewis, J. JACS
1971, 93, 4624.
28.
29.
(a) Lyle, R. E.; Boyce, C. B. JOC 1974, 39, 3708. (b) Hanessian, S.;
Staub, A. P. A. TL 1973, 3555.
(a) Sommer, L. H.; Bauman, D. L. JACS 1969, 91, 7076. (b) Bulkowski,
J. E.; Stacy, R.; Van Dyke, C. H. JOM 1975, 87, 137. (c) Chojnowski,
J.; Fortuniak, W.; Stanczyk, W. JACS 1987, 109, 7776.
30.
Burfield, D. R.; Lee, K.-H.; Smithers, R. H. JOC 1977, 42, 3060.
University
of California,
Michael E. Jung
Los Angeles, CA, USA
Triphenylphosphine-NBromosuccinimide1
(Ph3P)
[603-35-0]
(NBS)
[128-08-5]
(NCS)
[128-09-6]
(NIS)
[516-12-1]
C 18 H 15 P
(MW 262.30)
C 4 H 4 BrNO 2
(MW 177.99)
C 4 H 4 ClNO 2
(MW 133.54)
C4H4INO2
(MW 224.99)
(conversion of primary alcohols to alkyl halides)

Physical Data: See Triphenylphosphine, N-Bromosuccinimide,
N-Chlorosuccinimide, and N-Iodosuccinimide.
Preparative Methods: the mixed reagent is prepared in situ as
needed by combining triphenylphosphine, the alcohol, and
N-halosuccinimide in a suitable solvent (usually DMF) and
heating.
Handling, Storage, and Precautions: precautions in handling
should be made as described for the individual reagents. This
mixed reagent is not appropriate for storage. Recrystallization
of the triphenylphosphine and N-halosuccinimide is necessary
to achieve the most efficient halogenation reaction. In addition,
the use of anhydrous solvent is important for the success of the
reaction.
Introduction. The combination of triphenylphosphine and Nhalosuccinimide was applied by Hanessian2 to the preparation
of primary halides from carbohydrate precursors. This method is
related to a number of other methods for hydroxyl substitution via
oxyphosphonium salts as described in a comprehensive review.1
Conversion of Alcohols to Alkyl Halides. The typical
procedure2 as applied to the preparation of methyl 5-deoxy-5-
TRIPHENYLPHOSPHINE-N-BROMOSUCCINIMIDE
iodo-2,3-O-isopropylidene--D-ribofuranose (eq 1) involves the

addition of 2 equiv of N-iodosuccinimide followed by 2 equiv
of triphenylphosphine to a cooled solution of the alcohol in anhy
drous DMF and heating the mixture to 50 C for 20 min. Methyl al
cohol is added to destroy excess reagent, followed by n-butanol to
aid in the removal of DMF under reduced pressure. After concen
tration, the product is purified from the byproducts (succinimide
and triphenylphosphine oxide) by addition of ether and aqueous
extraction followed by column chromatography. Isolated yields
of 70-85% are regularly obtained using this procedure for the
preparation of chlorides, bromides, and iodides. In addition, the
reaction conditions allow the preparation of primary halides in the
presence of many functional groups used in carbohydrate chem
istry, including the ester, amide, lactone, benzylidene acetal, and
acetonide groups (eq 2). In fact, moderate yields (49-82%) of a
number of primary halides are obtained using this procedure on
sugars containing one or more free secondary hydroxyl groups
(eq 3). 2-4
(1)
439
(5)
(6)
The standard procedure has often been found to be un

satisfactory for substrates which are prone to acid-catalyzed
rearrangements (including migration of acetonide protecting
groups) and cleavage and is also not suitable for substrates
containing labile protecting groups such as THP ethers.1011
In some cases this problem has been circumvented by the
addition of various bases such as BaCO3 (eq 7),12 Pyridine,
and Imidazole. A recent study has achieved the preparation of
3-bromo-3-deoxy-1,2:5,6-di-O-isopropylidene-a-D-allofuranose
by addition of 2 equiv of N-halosuccinimide to a refluxing
solution of the secondary alcohol and 2 equiv each of PPh3
and imidazole in toluene or chlorobenzene (eq 8). Previous
applications of PPh3 and N-halosuccinimide alone afforded
only the primary halide products resulting from acetonide
migration. The use of pyridine and imidazole have also been
found to play an essential role in the conversion of carbohydrates
to halides using the reagents Triphenylphosphine-Iodine
and Triphenylphosphine-Carbon Tetrachloride, respec
tively.13
(2)
(7)
(3)
(8)
Other examples of the use of this method include the prepara

tion of tetrahydrofurfuryl bromide,5 3-cholestanyl bromide (us
ing THF as solvent, 85% yield),6 and intermediates toward the
syntheses of alkaloids (eqs 4 and 5).7 The reaction of the reagent
with DMF alone generates the formamidinium salt which can ul
timately result in the isolation of the formate ester derivative of
the alcohol substrate (eq 6). 18 It is therefore important that the Nhalosuccinimide is added last for the preparation of alkyl halides.
Other solvents used for this reaction include CH2Cl2 (which can
facilitate the workup of the reaction products) and HMPA.9
Related Reagents. Triphenylphosphine-/V-Chlorosuccinimide; Triphenylphosphine-N-iodosuccinimide.
1. Castro, B.R. OR 1983, 29, 1.

2.
(a) Ponpipom, M. M.; Hanessian, S. Carbohydr. Res. 1971,18, 342. (b)

Hanessian, S.; Ponpipom, M. M.; Lavallee, P. Carbohydr. Res. 1972, 24,
45.
3.
(a) Nakane, M.; Hutchinson, C. R.; Gollman, H. TL 1980, 21, 1213. (b)
Aspinall, G. O.; Carpenter, R. C ; Khondo, L. Carbohydr. Res. 1987,
165, 281.
Hasegawa, A.; Morita, M.; Ishida, H.; Kiso, M. J. Carbohydr. Chem.
1989, 8, 579.
(4)
4.
440
5.
6.
7.
8.
9.
10.
11.
12.
13.
TRIPHENYLPHOSPHINE-CARBONTETRABROMIDE
Schweizer, E. E.; Creasy, W. S.; Light, K. K.; Shaffer, E. T. JOC 1969,
34, 212.
Bose, A. K.; Lal, B. TL 1973, 3937.
(a) Birkinshaw, T. N.; Holmes, A. B. TL 1987, 28, 813. (b) Comins, D.
L.; Myoung, Y. C. JOC 1990, 55, 292.
Hodosi, G.; Podnyi, B.; Kuszmann, J. Carbohydr. Res. 1992, 230, 327.
Baker, C. W.; Whistler, R. L. Carbohydr. Res. 1975, 45, 237.
Yunker, M. B.; Tam, S. Y.K.; Hicks, D. R.; Fraser-Reid, B. CJC 1976,
54, 2411.
Gensler, W. J.; Marshall, J. P.; Langone, J. J.; Chen, J. C. JOC 1977, 42,
118.
Jger, V.; Hfele, B. S 1987,801.
(a) Garegg, P. J.; Johansson, R.; Samuelsson, B. S 1984, 168. (b) Whistler,
R. L.; Anisuzzaman, A. K. M. Methods Carbohydr. Chem. 1980, 8, 221.
Scott C. Virgil
Massachusetts Institute of Technology, Cambridge, MA, USA
Triphenylphosphine-Carbon
Tetrabromide1
(Ph3p)
[603-35-0]
(CBr4)
[558-13-4]
The geometry about the double bond of an allylic alcohol is

usually not compromised (eq 2).3 Allylic rearrangement is also
not commonly observed. Although ketones are known to react
with this reagent combination, the reaction of an allylic alcohol
has been selectively achieved in the presence of a ketone (eq 3).4
(2)
(3)
Regioselective bromination of primary alcohols in the presence

of secondary alcohols is possible. These reactions are usually per
formed in pyridine as solvent. The reaction of the methyl glucopyranoside (eq 4) results in the selective formation of the primary
bromide in 98% yield.5 An investigation of this reaction with a
chiral deuterated neopentyl alcohol yielded a partially racemized
bromide.6
C18H15P
(MW 262.30)
CBr4
(MW 331.61)
(4)
(reagent combination for the conversion of alcohols to bromides,

aldehydes and ketones to dibromoalkenes, and terminal alkynes
to 1-bromoalkynes; carboxyl activation)
Silyl ether protected alcohols (eq 5) have been converted di

rectly into the corresponding bromides with Ph3P and CBr4. The
Physical Data: Ph3P: mp 79-81C; bp 377 C; d 1.0749 g cm .
reaction works best if 1.5 equiv of acetone are added.7 TetrahyCBr4: mp 90-91 C; bp 190C; d 3.273 g cm-3.
dropyranyl ether protected alcohols have also been directly trans
Solubility: sol MeCN, CH2C12, pyridine, DMF.
formed into the bromides using this reagent combination. The
Preparative Method: the reactive species is generated in situ by
reaction has been reported to proceed with inversion of config
reaction of Ph3P with CBr4.
uration (eq 6).8 If unsaturation is appropriately placed within a
Handling, Storage, and Precautions:Ph3Pis an irritant; CBr4 is tetrahydropyranyl (eq 7) or a methoxymethyl (eq 8) protected
toxic and a cancer suspect agent. All solvents used must be
alcohol, cyclization occurs to afford tetrahydropyrans.9 The con
carefully dried because the intermediates are all susceptible to
version of an alcohol to the bromide without complications with
hydrolysis. This reagent should be used in a fume hood.
a methoxymethyl protected alcohol in the molecule is possible
(eq 9).10
-3
Conversion of Alcohols to Alkyl Bromides. The reaction of

alcohols with Triphenylphosphine and Carbon Tetrabromide re
sults in the formation of alkyl bromides. The conditions are suffi
ciently mild to allow for the efficient conversion of alcohols into
the corresponding bromides. The uridine derivative (eq 1) is trans
formed into its bromide with Ph3P and CBr4.2
(5)
(6)
(1)
(7)
Next Page
TRIPHENYLPHOSPHINE-CARBONTETRABROMIDE
(8)
441
of the aldehyde derived from (S)-ethyl lactate under the reaction

conditions (eq 15).15
(14)
(15)
(9)
Amides from Carboxylic Acids. N-Methoxy-N-methyl

amides can be prepared from carboxylic acids and the amine
hydrochlorides. In the case of an -phenyl carboxylic acid
(eq 10), the amide is formed in 71% yield and no racemization is
detected.11
-Bromo Enones from 1,3-Diketones. The reaction of Ph3P

and CBr4 with a 1,3-diketone efficiently converts it to the -bromo
enone (eq 16).16
(16)
(10)
Dibromoalkenes
from
Aldehydes
and
Ke
tones. Benzaldehyde is transformed into the dibromoalkene
in 84% yield when treated with Ph3P and CBr4 (eq 11).12 An
alternative procedure for the conversion of an aldehyde to the
dibromoalkene uses Zinc dust in place of an excess of the phosphine. This allows the amount of Ph3P and CBr4 to be reduced
to 2 equiv each as opposed to 4 equiv. This procedure gives
comparable results to the original procedure. The dibromoalkenes
can be reacted with n-Butyllithium to form the intermediate
lithium acetylide. The acetylides can then be reacted with
electrophiles such as H2O (eq 12) and CO2 (eq 13). This offers a
convenient method for the formyl to ethynyl conversion.13
(11)
(12)
1-Bromoalkynes from Terminal Alkynes. Terminal alkynes

on reaction with Ph3P and CBr4 afford 1-bromoalkynes in high
yield (eq 17).17
(17)
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
Castro, B. R. OR 1983, 29, 1.

Verheyden, J. P. H.; Moffatt, J. G. JOC 1972, 37, 2289.
Axelrod, E. H.; Milne, G. M.; van Tamelen, E. E. JACS 1970, 92, 2139.
Kang, S. H.; Hong, C. Y. TL 1987, 28, 675.
Kashem, A.; Anisuzzaman, M.; Whistler, R. L. CR 1978, 61, 511.
Weiss, R. G.; Snyder, E. I. JOC 1971, 36, 403.
Mattes, H.; Benezra, C. TL 1987, 28, 1697.
Wagner, A.; Heitz, M.-P.; Mioskowski, C. TL 1989, 30, 557.
Wagner, A.; Heitz, M.-P; Mioskowski, C. TL 1989, 30, 1971.
Clinch, K.; Vasella, A.; Schauer, R. TL 1987, 28, 6425.
Einhorn, J.; Einhorn, C ; Luche, J.-L. SC 1990, 20, 1105.
12.
13.
14.
15.
16.
17.
Ramirez, E; Desai, N. B.; McKelvie, N. JACS 1962, 84, 1745.

Corey, E. J.; Fuchs, P. L. TL 1972, 3769.
Posner, G. H.; Loomis, G. L.; Sawaya, H. S. TL 1975, 1373.
Mahler, H.; Braun, M. TL 1987, 28, 5145.
Gruber, L.; Tmskzi, I.; Radics, L. S 1975, 708.
Wagner, A.; Heitz, M.-P.; Mioskowski, C. TL 1990, 31, 3141.
(13)
Michael J. Taschner
The University of Akron, OH, USA
Ketones are converted to dibromomethylene derivatives. These
intermediates can be transformed to isopropylidene compounds
by reaction with Lithium Dimethylcuprate and Iodomethane
(eq 14).14 No racemization was reported for the chain extension
Previous Page
442
TRIPHENYLPHOSPHINE-CARBON TETRACHLORIDE
chemical integrity of the double bond also remains intact under
these conditions.8
Triphenylphosphine-Carbon
Tetrachloride1
(Ph3P)
[605-35-0]
(CCl4)
[56-23-5]
(2)
C 18 H 15 P
(MW 262.30)
CCl4
(MW 153.81)
(3)
(reagent combination for the conversion of a number of functional

groups into their corresponding chlorides and for dehydrations)
(4)
-3
Physical Data: Ph3P: mp 79-81 C; bp 377 C; d 1.0749 g cm .

CC14: mp - 2 3 C; bp 77 C; d 1.594 g cm - 3 .
Solubility: sol CC14, MeCN, CH2C12, 1,2-dichloroethane.
Preparative Method: reactive intermediates are generated in situ
by reaction of Ph3P and CC14.
Handling, Storage, and Precautions: Ph3P is an irritant; CCl4 is
toxic and a cancer suspect agent; use in a fume hood. Solvents
must be carefully dried because the intermediates are all sus
ceptible to hydrolysis.
(5)
(6)
Combination of Triphenylphosphine and Carbon Tetrachloride. This reagent combination is capable of performing a
range of chlorinations and dehydrations. The reactions are typi
cally run using the so-called two-component or three-component
systems. Carbon tetrachloride can function as both the reagent and
solvent. However, the rates of the reactions are highly solventdependent, with MeCN providing the fastest rates.1
Conversion of Alcohols to Alkyl Chlorides. The reaction of
alcohols with Triphenylphosphine and carbon tetrachloride re
sults in the formation of alkyl chlorides.2 The mild, neutral condi
tions allow for the efficient conversion of even sensitive alcohols
into the corresponding chlorides (eqs 1 and 2).3,4 The reaction
typically proceeds with inversion of configuration.5 In eq 3, it is
interesting to note that the reaction not only proceeds with inver
sion of configuration but also no acyloxy migration is observed.6
If the conversion of the alcohol to the chloride is attempted

in refluxing MeCN, dehydration to form the alkene occurs (eqs 7
and 8).9 Occasionally the separation of the product from the triph
enylphosphine oxide produced in the reaction can be problematic.
This can be overcome by using a polymer-supported phosphine.10
Simple filtration and evaporation of the solvent are all that is re
quired under these conditions. Not only is the workup facilitated,
but the rate of the reaction is also increased by employing the
supported reagent.10c
(7)
(8)
(1)
The conversion of an allylic alcohol to an allylic chloride occurs

with no or minimal allylic rearrangement (eqs 4 and 5).7 For the
synthesis of low boiling allylic alcohols, it is advantageous to
substitute hexachloroacetone (HCA) for CC14 (eq 6). The stereo
Conversion of Acids to Acid Chlorides. The reaction of carboxylic acids with triphenylphosphine-CCLt reportedly produces
acid chlorides in good yield under mild conditions (eq 9).11 These
conditions will allow acid sensitive functional groups to survive.
Phosphoric mono- and diesters are successfully converted into the
phosphoric monoester dichlorides and diester chlorides, respec
tively. The reaction of the diethyl ester does not produce the acid
chloride. Instead, the anhydride is formed. Phosphinic acid chlo
rides can also be prepared from the corresponding phosphinic acid
under these conditions (eq 10).12
(9)
443
(16)
(10)
(17)
Epoxides to cis- 1,2-Dichloroalkanes. Epoxides are con

verted into cis-l,2-dichlorides by the action of triphenylphosphine in refiuxing CCl 4 . 13 Cyclohexene oxide forms cis-1,2dichlorocyclohexane (eq 11) contaminated by a trace of the transisomer. Cyclopentene oxide gives only the cis-isomer.
(11)
Dehydrations. Diols may be cyclodehydrated to the corre

sponding cyclic ethers. The reaction is most effective for 1,4-diols
(eq 12). Dehydration of 1,3- and 1,5-diols is not as successful,
except in the case of the configurationally constrained 1,5-diol
shown in eq 13. 14 The reaction of trans-1,2-cyclohexanediol with
the reagent affords trans-2-chlorocyclohexanol with none of the
cis-isomer or the trans-dichloride being detected. If the reaction
is performed in the presence of K 2 CO 3 as an HC1 scavenger, the
epoxide is formed (eq 14).14 The yields are not as good with sub
stituted acyclic diols. 15
(18)
Substituted hydroxamic acids successfully cyclize to form (3lactams as long as Et 3 N is present (eq 19). In the absence of the
base, complex mixtures are formed.19 Unsubstituted amides can
be converted into nitriles via dehydration (eq 20). 20 This is the
reagent of choice for the transformation of the amide to the nitrile
in eq 21. 2 1
(19)
(20)
(12)
(21)
(13)
(14)
Dehydration of N- substituted -amino alcohols with

triphenylphosphine-CCl 4 and Triethylamine produces aziridines
in good yield (eq 15).16 This reaction has been success
fully employed in the preparation of stable arene imines
(eq 16).17 Azetidines can be obtained from the correspond
ing 3-aminoalkanols (eq 17).18 Additionally, reaction of
2-(3-hydroxypropyl)piperidine under these conditions yields
octahydroindolizine (eq 18).
(15)
Nitriles can also be obtained from aldoximes using this reagent

(eq 22). 22 Ketoximes produce imidoyl chlorides via a Beckmann
rearrangement under these conditions (eq 23). 23 Imidoyl chlorides
are also available by the reaction of monosubstituted amides with
Ph 3 P-CCl 4 in acetonitrile (eq 24). 24
(22)
(23)
(24)
444
N,N,N'-Trisubstituted ureas afford chloroformamidine deriva

tives (eq 25),25 while N,N'-disubstituted ureas and thioureas pro
duce carbodiimides (eq 26).26 When carbamoyl chlorides are
treated with the reagent in MeCN, they are converted into isocyanates (eq 27).27 Dehydration of N-substituted formamides pro
vides access to isocyanides (eq 28).28
to form 2-oxazolines (eq 31), 2-oxazines, 2-thiazolines, or

2-imidazolines.33 The reaction requires the use of 3 equiv of the
Ph3P-CCl4 reagent. The reaction is reported to fail if a commer
cial sample of the polymer-supported phosphine is used instead
of triphenylphosphine.
(31)
(25)
(26)
1,1-Dichloroalkenes and Vinyl Chlorides. The reaction of

aldehydes produces a mixture of the 1,1-dichloroalkene and the
dichloromethylene derivatives. These are the result of reaction of
the in situ generated Dichloromethylenetriphenylphosphorane
and Triphenylphosphine Dichloride, respectively. Benzaldehyde
(eq 32) produces a 1:1 mixture of the dichloroalkene and benzal
chloride in 72% yield.34
(27)
(32)
(28)
Amide Formation. The synthesis of an amide can be accom

plished by initial reaction of an acid with Ph3P-CCl4 and then re
action of the intermediate with 2 equiv of the appropriate amine. A
tertiary amine, such as Diisopropylethylamine, can be employed
as the HC1 scavenger in cases where one would not want to waste
any of a potentially valuable amine.29 This method has been used
in the construction of an amide in the synthesis of the skeleton of
the lycorine alkaloids (eq 29).30
Ketones can also be used in this transformation, but sometimes

enolizable ketones lead to the formation of the vinyl chloride
derived from the enol. This is usually more of a problem for
six-membered ring ketones than forfive-memberedring ketones.
Cyclopentanone yields predominantly the 1,1-dichloroalkene
(eq 33), while cyclohexanone provides mainly the vinyl chloride
(eq 34) 35
(33)
(34)
(29)
The method is effective for peptide coupling in that the yields

are typically good; however, the reaction is often accompanied
by racemization of the product.31 The racemization problem
can be suppressed, but this involves a change in the phosphine
employed32 or slightly modified reaction conditions. These mod
ified conditions have been used successfully in the construction
of a hexapeptide without racemization (eq 30).33
Cbz-Leu-Ala-Val-Phe-Gly-Pro-OBn (30)
If amino alcohols, amino thiols, or diamines are used, the in

termediate amides cyclodehydrate under the reaction conditions
1. (a) Appel, R. AG(E) 1975, 14, 801. (b) Appel, R.; Halstenberg, M.
Organophosphorus Reagents in Organic Synthesis; Cadogan, J. I. G.,
Ed.; Academic: New York, 1979; pp 387-431.
2.
3.
(a) Lee, J. B.; Nolan, T. J. CJC 1966, 44, 1331. (b) Lee, J. B.; Downie,
I. W. T 1967, 23, 359.
Verheyden, J. P. H.; Moffat, J. G. JOC 1972, 37, 2289.
4.
5.
Calzada, J. G.; Hooz, J. OS 1974, 54, 63.

Weiss, R. G.; Snyder, E. I. JOC 1970, 35, 1627.
6.
7.
8.
Aneja, R.; Davies, A. P.; Knaggs, J. A. CC 1973, 110.

Snyder, E. I. JOC 1972, 37, 1466.
Majid, R. M.; Fruchey, O. S.; Johnson, W. L. TL 1977, 2999.
9. Appel, R.; Wihler, H.-D. CB 1976, 109, 3446.

10. (a) Harrison, C. R.; Hodge, P. CC 1975, 622. (b) Regen, S. L.; Lee, D.
P. JOC 1975, 40, 1669. (c) Harrison, C. R.; Hodge, P. CC 1978, 813.
11.
12.
Lee, J. B. JACS 1966, 88, 3440.

Appel, R.; Einig, H. Z. Anorg. Allg. Chem. 1975, 414, 236.
TRIPHENYLPHOSPHINE DIBROMIDE
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
Isaacs, N. S.; Kirkpatrick, D. TL 1972, 3869.

Barry, C. N.; Evans, S. A. JOC 1981, 46, 3361.
Barry, C. N.; Evans, S. A. TL 1983, 24, 661.
Appel, R.; Kleinstuck, R. CB 1974, 107, 5.
Ittah, Y.; Shahak, I.; Blum, J. JOC 1978, 43, 397.
Stoilova, V; Trifonov, L. S.; Orahovats, A. S. S 1979, 105.
Miller, M. J.; Mattingly, P. G.; Morrison, M. A.; Kerwin, J. F. JACS 1980,
102, 7026.
(a) Yamato, E.; Sugasawa, S. TL 1970, 4383. (b) Appel, R.; Kleinstck,
R.; Ziehn, K.-D. CB 1971, 104, 1030.
Juanin, R.; Arnold, W. HCA 1973, 56, 2569.
Appel, R.; Kohnke, J. CB 1971, 104, 2023.
Appel, R.; Warning, K. CB 1975, 108, 1437.
Appel, R.; Warning, K.; Ziehn, K.-D. CB 1973, 106, 3450.
(a) Appel, R.; Warning, K.; Ziehn, K.-D. CB 1974, 107, 698. (b) Appel,
R.; Warning, K.; Ziehn, K.-D. CB 1973, 706, 2093.
Appel, R.; Warning, K.; Ziehn, K.-D.; Gilak, A. CB 1974, 107, 2671.
Appel, R.; Kleinstck, R.; Ziehn, K.-D. AG(E) 1971, 10, 132.
Barstow, L. E.; Hruby, V. J. JOC 1971, 36, 1305.
Stork, G.; Morgans, D. J. JACS 1979, 101, 7110.
Wieland, X; Seeliger, A. CB 1971, 104, 3992.
Takeuchi, Y.; Yamada, S. CPB 1974, 22, 832.
Appel, R.; Bumer, G.; Strver, W. CB 1975, 108, 2680.
Rabinowitz, R.; Marcus, R. JACS 1962, 84, 1312.
Isaacs, N.; Kirkpatrick, D. CC 1972, 443.
Michael J. Taschner
Triphenylphosphine Dibromide1
[1034-39-5]
C 15 H 18 Br 2 P
(MW 389.10)
(bromination of alcohols, 3,4 phenols, 22 and enols; 3 cleavage

of ethers 23,32,33 and acetals25 to alkyl bromides; cyclization
of amino alcohols 34,35 to cyclic amines; conversion of carbneoxylic acid derivatives into acyl bromides; 36,37 bromination39
or dehydration38 of carboxamide groups)
Alternate Names: bromotriphenylphosphonium bromide; dibromotriphenylphosphorane.
Physical Data: adduct:2 colorless crystalline solid; mp 235 C
(dec). Ph 3 P: mp 80.5 C; bp 377 C (in inert gas); d425
1.194gcm - 3 ; nD80 1.6358. Br 2 : mp - 7 . 2 C ; bp 59.5C; d425
3.12gcm - 3 .
Solubility: adduct: sol CH 2 C1 2 , MeCN, PhCN, DMF; less sol
PhH, PhCl. Ph 3 P: sol ether, PhH, CHC13, AcOH; less sol al
cohol; pract. insol. H 2 O. Br 2 : sol H2O (3.58 g/100 mL); very
sol. alcohol, ether, CHC13, CC14, CS 2 .
Form Supplied in: adduct: hygroscopic solid; commercially avail
able; purity 95-96%. Both parent compounds, Ph 3 P and Br2,
are widely available. Ph 3 P: odorless platelets or prisms; purity
99%; typical impurity Ph 3 PO 1%. Br 2 : dark reddish liquid,
volatile, with suffocating odor; vaporizes rapidly at rt; purity
>99.5%.
445
31
Analysis of Reagent Purity: adduct: P NMR (CH2C12) +49 ppm

(ionic form);2 Raman (solid phase) 239 c m - 1 (P-Br). Typical
impurities, Ph 3 P and Ph 3 PO: 31 P NMR (various solvents) 5
to 8 ppm and +25 to +29 ppm, respectively.
Preparative Methods: several preparations are described, 2,23b,32b
but in most cases the hygroscopic reagent is prepared just before
use by addition of Bromine to Triphenylphosphine in a dry
solvent with cooling.
Handling, Storage, and Precautions: adduct: corrosive; very hy
groscopic; moisture sensitive; incompatible with strong oxi
dizing agents and strong bases; may decompose on exposure to
moist air or water; do not get in eyes, on skin, or on clothing;
keep containers tightly closed and store in a cool dry place;
these reagents should be handled in a fume hood.
Introduction. The Ph 3 PBr 2 adduct was first used in synthesis

in 19593 for the preparation of alkyl and acyl bromides from alco
hols and carboxylic acids, and for the dehydration of amides and
oximes to nitriles. Since then it has been widely employed as a
versatile reagent for a number of synthetic reactions.
Conversion of Alcohols into Alkyl Bromides. It has been
established that Ph 3 PX 2 reagents present considerable advan
tages over phosphorus halides (i.e. PX 3 , PX 5 ) for which only
two replaceable groups would be 'necessary and desirable'. 4a The
mechanism 4b of the reaction of Ph 3 PBr 2 with an alcohol involves
initial rapid formation of an alkyloxyphosphonium bromide, 4,5,7a
which then collapses slowly to the phosphine oxide and an alkyl
bromide (eq 1). S N 2 substitution and high yields are generally
observed with primary and secondary alcohols. 3,4a This reagent
shows little tendency to induce either carbonium ion rearrange
ment in the carbon skeleton or elimination reactions; this is illus
trated by the preparation of neopentyl bromide from neopentyl
alcohol (eq 2) 4a and in the steroid field,6 in which cholesterol
and 3-cholestanol give respectively 3-bromocholest-5-ene and
3-bromocholestane in yields of about 80%. Inversion of con
figuration is found in the S N 2 reactions of (+)-endo-norbornanol
(eq 3) 7a,8 and 7-norbomanol. However, a similar reaction with
()-endo-norbornanol leads mainly to racemic bromide via a
nonclassical norbornyl cation intermediate.7b Likewise, little rear
rangement is observed in the bromination of 3-methyl-2-butanol
(eq 4). 9 Greater amounts of rearranged product are formed in
the same reaction with Ph 3 PCNBr (3%), Bromine-Triphenyl
Phosphite (55.6%), or Triphenylphosphine-Carbon Tetrabromide (6-10%).
(1)
(2)
(3)
446
(4)
Ph3PBr2 can be used with sensitive substrates which in

corporate cyclopropyl rings (e.g. cyclopropyl carbinol11,12) or
unsaturation10,13 (e.g. cinnamyl alcohol and alkynediols) with lit
tle if any side reactions. Cyclopropyl carbinols are transformed
into bromides in good yield without ring opening or ring expan
sion, with the formation of only trace amounts of homoallylic
bromides; no bromocyclobutane derivatives are detected (eq 5).
Ph3PBr2 also proves superior to Phosphorus(III) Bromide for the
bromination of alkynediols to dibromoalkynes (eq 6).13
been employed in these bromination reactions, depending on sub

strate solubility. Both O- and C-formylations are encountered in
some cases when DMF is the solvent. Ph3PBr2 and both Ph3PX2
analogs (X = Cl, I) can react with DMF according to the sequence
in eq 9.20 The intermediate alkoxyimonium bromide (3) affords
either the expected bromide by heating, or the formyl ester by
hydrolytic workup with secondary20 or tertiary16 alcohols (e.g.
eq 10). Vilsmeier-type formylation reactions on nucleophilic car
bon atoms can also take place, as developed early38a and then
encountered later as a side reaction in the steroid field.21 Such
O-formylation of secondary alcohols is interestingly used in the
differentiation of diols, leading to a new synthesis of bromo for
mates (eq 10).20b Under mild conditions, primary alcohols still
afford bromides whereas secondary ones are converted almost
exclusively to the corresponding formate esters.
(5)
R = H, Me, Et, Pr, Bu, i-Pr, t-Bu
(9)
R = H , M e ; n = 1,2
Br-CR 2 -(OC) n -CR 2 -Br
(6)
Ph3PBr2 provides comparable yields to Ph3P/CBr4 in the

bromination of diethyl 1-hydroxyalkylphosphonates.14 A num
ber of other primary,15 secondary,11-14 and even tertiary al
cohols are brominated with Ph3PBr2, but with preponderant
elimination4a,6,16 in the latter case. A polymer-supported Ph3PBr2
reagent17 has been successfully applied to alcohol bromination in
refluxing CHC13; product isolation is facilited by the ready sep
aration of supported from the nonsupported species. However,
note that a polymer-supported Ph3P/CBr4 reagent leads to better
bromination results than the Ph3PBr2 system in a number of cases.
Similar mono- and dibrominations have also been achieved
in the carbohydrate field (eq 7).18 Configurational inversion at
chiral centers is observed throughout.Ph 3 PBr 2 /Imidazole(ImH)
or Ph3P/2,4,5-tribromoimidazole/ImH combinations in reflux
ing PhMe or in PhMe-pyridine mixtures are preferred in some
cases. In the nucleoside field,19 double activation is achieved with
Ph3PBr2 in pyridine, leading both to bromination of the 5'-position
of the sugar moiety and to substitution on the C-6 position of the
adenine part (eq 8).19b
(10)
x = 1, 2; R1 H; R2, R3 = H, Me, (CHx)n
Synthesis of Aryl Bromides from Phenols. Already devel

oped in the pioneering work,4a the preparation of aryl bromides
from phenols with Ph3PBr2 was later extended to a number of
substrates (eq 11).22
(11)
(7)
X, Y = C, N; R2 = H; R3 = H, Cl, NO2, MeO;
R1 + R2 = Ph; 2,3-pyridyl; R2 + R3 = Ph, 3,4-phenol
(8)
A variety of solvents such as CCl4, PhH, triglyme, CHCl3,

PhMe, pyridine, NMP, MeCN, DMF, and mixtures of these have
Alkyl Bromides from Ethers and Acetals. Ph3PBr2 cleaves

dialkyl ethers to give the two alkyl bromides under essentially
neutral conditions.23 This reaction offers obvious advantages as
it avoids both the strongly acidic and basic media which are usu
ally employed for ether cleavage. Brominations are generally con
ducted at reflux in high boiling solvents such as PhCl, PhCN,
DMF, or NMP. Primary and secondary alkyl groups provide good
yields of bromides without rearrangement in PhCl or PhCN, at
23a,b
23c
60 to 120C,
as illustrated in eq 12. Phenyl alkyl ethers
initially afford aryloxyphosphonium bromides which collapse to
bromobenzene only by heating at higher temperature (>230C
as seen before). Alkyl t-butyl ethers are cleaved more easily in
DMF 23b or in MeCN, 24 usually between 60 and 110 C; the t-butyl
group is converted into isobutene in this process. In a related re
action, endoxides are transformed into arenes28 by Ph 3 PBr 2 treat
ment in PhCl. Aromatization takes place via HBr elimination from
the initially formed dibromide.
447
(eq 15). Ethynyltriphenylphosphonium bromides are similarly

obtained30c starting from (benzoylmethylene)- and (carbamoylmethylene)triphenylphosphoranes.
(15)
(12)
Direct conversion of tetrahydropyranyl (THP) 25 and tetrahydrofuranyl ethers 26 (THF) to bromides can be achieved by Ph 3 PBr 2
treatment under milder conditions (eq 13).25a THP and THF ethers
afford good yields of acyclic, saturated, and unsaturated,25c pri
mary, secondary, and even tertiary alkyl bromides; under the same
conditions, cyclohexyl THF ethers provide mainly cyclohexene
derivatives. In view of the fact that the preceding reaction of THP
ethers can be stopped (at low temperature) at the stage of either
the alkoxyphosphonium (see eq 1) or the pentacovalent ROPPh3Br
intermediate, hydrolysis of the reaction mixture at 50 C, leads
to the corresponding alcohols in good yield (74-97%) (eq 14).29
The method is efficient for the deprotection of secondary and ter
tiary THP ethers, as well as for acyclic acetal ether, dialkyl acetals,
and O-glucosides. Acetal functions can be removed with retention
of stereochemistry, as illustrated in the conversion of ()-menthol
THP ether into ()-menthol with full recovery of the optical activ
ity. This procedure is not applicable to primary THP ethers, where
the corresponding bromides are formed under these conditions.
(13)
(14)
Reaction of hindered trialkylsilyl ethers with Ph 3 PBr 2 in

CH 2 Cl 2 at rt affords primary and secondary alkyl bromides in
excellent yield (70-94%); the reaction is valuable in the -lactam
field.27a The reaction rate is increased by addition of a cat
alytic amount of Zinc Bromide. Silylated enol ethers, such as
trimethylsilyl(l-phenylvinyloxy)silane, provide vinyl bromides
such as -bromostyrene with Ph 3 PBr 2 in refluxing CCl 4 . 27b
-Alkynyl Ketones and -Bromo--Vinyl Ketones from Diketones. The previously described bromination of alcohols can
be applied to the enol form of -diketones. The first attempts
in this field were conducted with the Ph3PBr2/Triethylamine
system on dibenzoylmethane, leading to phenylethynyl phenyl
ketone.30a Elimination at the oxyphosphonium stage or HBr elim
ination from the initially generated vinyl bromide is probably
involved in this reaction. Analogously, reaction of unsymmetrical -diketones30b with excess Ph 3 PBr 2 /Et 3 N proceeds with the
formation of 3:1 mixtures of a,p-ynones in good overall yield
Similar treatment of unconjugated -diketones31 in PhH or

MeCN as solvent leads to -bromo-,-unsaturated ketones with
superior results relative to the same transformation with PBr 3
as the brominating agent (eq 16).31c The reaction of acyclic
2,4-pentanedione with Ph 3 PBr 2 /Et 3 N in PhH-MeCN 31c or in
CH 2 Cl 2 , 31d but in the absence of Et 3 N, appears not to be to
tally stereoselective, since a mixture of the geometrically iso
meric bromo enones is produced, with 88% (E/Z 87/13) and
85% (E/Z93/7) yields, respectively.
(16)
R1 = H, Me, allyl, 2-cyanoethyl

n = 0, 1; R2 = H, Me; R3 = H, Me
Epoxide Opening to Vicinal Dibromides or Bromohydrins. Epoxide ring opening with Ph 3 PBr 2 32a takes place in
MeCN or PhH at 20-50 C, affording vicinal dibromides
(32-74%); cis-trans isomer mixtures are obtained in the case of
cycloalkene epoxides. This reaction involves initial cleavage of the
epoxide C-O bond at the most substituted epoxide carbon; bromoalkoxyphosphonium salts are thus formed, and these undergo
subsequent substitution to give dibromides and Ph 3 PO. In fur
ther studies, 32b reaction of cis-epoxides in PhH produced erythrodibromides exclusively (eq 17); trans-epoxides exhibit less speci
ficity, leading to a mixture of threo- and erjtfftro-dibromides. Use
of a more polar solvent such as CH 2 Cl 2 or MeCN, instead of
PhH, with cis-epoxides provides erythro-threo mixtures (60-40
to 50-50). By reacting epoxides first with HC1 and then with
Ph 3 PBr 2 , it is possible to obtain vicinal bromochlorides stereospecifically that are also products of two S N 2 displacements.
(17)
R1 = nonyl; R2 = Bu
The reaction can also be carried out so as to give bromohydrins.

In the steroid field33a with conformationally rigid epoxides, oxirane cleavage appears to be quite stereoselective and leads only to
the bromohydrin resulting from the usual anti opening of the ring
in high yield (90-97%). Less hindered and rigid substrates afford
448
regioisomeric mixtures of cyclictrans-bromohydrins.Equivalent

results33b are obtained, in the steroid series, by use of polymeric
Ph3PBr2 for the transformation of epoxides to bromohydrins under
mild nonacidic conditions; oxirane ring opening remains regioand stereoselective.
Ph3PBr2 presumably forms an oxonium salt, which then under

goes cleavage through reaction with bromide ion. Prolonged heat
ing (80-110 C) of lactones with Ph3PBr2 gives the expected acyl
alkyl dibromides, but in low yield (<50%) due to a concomitant
degradation.37d
Cyclization of - and -Amino Alcohols to Aziridines

and Azetidines. -Amino alcohols undergo cyclization
upon Ph3PBr2/Et3N treatment,34 providing the corresponding
aziridines along with substituted piperazines as dimeric byprod
ucts (eq 18). Walden inversion is observed in the ring closure
of both threo- and erythro-ephedrine and this supports the
postulated 1,2-trans-elimination. Application of this procedure
to the synthesis of 1-monosubstituted aziridines is unsuccessful,
giving only the piperazine byproduct. N-Aryl -amino alcohols
are cyclized to azetidines by Ph3PBr2/Et3N in MeCN (eq 19).35a
Under these conditions, some starting material is recovered
unchanged along with mixed tetrahydroquinolines as side
products and the expected N-arylazetidine. Comparable results
are obtained (45-65%)35b with some other TV-protecting groups.
Dehydration of Ureas and Amides to Carbodiimides, Ni

trites, Isocyanides, and Ketenimines. Dehydration of N,N'disubstituted ureas by heating with Ph3PBr2/Et3N in PhH or PhCl
at 70-80 C affords carbodiimides38a in good yields. Subsequent
improvements38d involving milder conditions provides access to
certain unstable derivatives from N,N'-disubstituted ureas; this
procedure compares favorably with previous ones and with an
other related approach using the Triphenylphosphine-Carbon
Tetrachloride reagent system (eq 21). Reaction of N,N'dialkylidene ureas with Ph3PBr2 in PhH leads to -haloalkyl
carbodiimides.38e
(18)
R1N=C=NR2
PhH or PhCl, reflux

CH2C12, 0 C
Ph3P/CCl4, Et3N,
CH2C12, rt
R1 = Me, Et, Bu, Cy, Ph
(21)
57-75%
70-90%
30-40%
R2 = Et, C1CH2CH2, BrCH2CH2, Bu, Hex, Cy, Ph
R1 = Bu, t-Bu, cyclohexyl, benzyl; R2 = Me, Ph
(19)
R1 = Me, Ph; R2 = H, Me; R3 = H, Me, Ph
Acyl Bromides from Carboxylic Acids, Anhydrides, and

Esters. Carboxylic acid bromides are prepared by reaction of
Ph3PBr2 with various carboxylic acids and anhydrides in boiling
PhCl.36a Milder conditions and better yields were later obtained
in a comparative study36b by using CH2Cl2 at rt (eq 20). Further
improvements are observed through the use of the correspond
ing trimethylsilyl esters; acyl bromides are thus obtained under
mild and neutral conditions, allowing reactions with sensitive acid
substrates without side reactions (eq 20). This transformation is
also applicable to generate the acyl bromides of more hindered
trialkylsilyl esters such as the TBDMS, TIPS, and TBDPS carboxylates; in CH2Cl2, the reaction rate increases in the presence
of a catalytic amount of ZnBr2.27a
By the same Ph3PBr2/Et3N procedure carried out in refluxing PhH, disubstituted cyanamides such as Me2NCN are ob
tained from the N,N-disubstituted urea Me2NCONH2 (67%);
similarly, isocyanides result from monosubstituted formamides
(56-73%),38a,40b and nitriles from primary amides and oximes
(58-68%).3 Via the same route, ketenimines (R1R2C=C=NR3)
are prepared38a,40b in CH2Cl2 at reflux by dehydration of sec
ondary amides having a C-H bond adjacent to the carbonyl func
tion (45-93%). Application of this procedure to sulfimides gives
highly reactive ketenimines, which are used for further reac
tions without isolation; [2 + 2] cycloaddition of such species with
Schiff bases provides, in good yield, N-(tosyl)azetidin-2-imines
related to -lactam derivatives (eq 22).38b The diphosphorylated
ketenimine [(EtO)2(O)P]2C=C=NPh is obtained analogously in
87% yield with Ph3PBr2/Et3N from the ,-diphosphorylated
acetanilide.38c
(22)
(20)
Z = H; PhCl, reflux
Z = H; CH2C12, rt
Z = TMS; CH2C12, rt
R = Ph, 2-ClC6H4, 4-ClC6H4, Et, PhCH2CH2,
MeCH=CH
50-80%
64-90%
70-90%
PhCH=CH, PhCH(CO2Z),
Direct reaction of less reactive alkyl esters and lactones37 with

Ph3PBr2 affords both acyl and alkyl bromides. This reaction is
achieved at MeCN reflux37a-c for -halogenated esters such as
CF3CO2R, but only at higher temperatures and with longer reac
tion times for unhalogenated ones. The reaction of an ester with
Imidoyl Bromides from Secondary Amides. In the case

of the secondary diarylamide benzanilide, reaction with
Ph3PBr2/Et3N in refluxing PhH provides N-phenylbenzimidoyl
bromide in 65% yield, whereas a 70% yield is attained
with the Ph3P/CBr4 reagent system.39 The closely related Nmethylbenzamide affords a dimeric compound40b with Ph3PBr2
in boiling CH2Cl2 by intermolecular N-imidoylation (see below
for a similar intramolecular process) between generated imidoyl
bromide or oxyphosphonium species and the starting carboxam-
ide. Cyclodehydration of secondary carboxylic diamides with

Ph3PBr2/Et3N affords intramolecular O-imidoylation products
with a benzoxadiazepine structure.40 Without Et3N, intramolecu
lar N-imidoylation products with an -imino lactam structure are
obtained; O-imidoylated products rearrange to TV-analogs under
acidic conditions.
Iminophosphoranes from Amines, Hydrazines, and
Related Derivatives. Compounds containing a P=N bond,
such as iminophosphoranes, are widely used as synthetic
intermediates, especially in the heterocyclic field. Aromatic
primary amines are generally transformed into iminotriphenylphosphoranes, and aliphatic amines into aminophosphonium
bromides with Ph3PBr2/Et3N in PhH, PhCl, CC14, or CH2C12
as solvent;41a,b more basic conditions are usually required to
convert an alkylaminophosphonium salt into the corresponding
iminophosphorane.41b As protected primary amines, these
phosphinimines (iminophosphoranes) can then be subjected to
monoalkylation, the Ph3P protecting group being cleaved in a
subsequent step to provide secondary amines (eq 23). 41a-c
(23)
Some aliphatic and aromatic phosphinimines (prepared as

above) undergo a Wittig-like condensation with CO2 or CS2, giv
ing rise to isocyanates and isothiocyanates, respectively (eq 23).41d
Dehydration reactions promoted by Ph3PBr2/Et3N are used for
intramolecular cyclizations involving an imide carbonyl group
and an aromatic amine;42 an aza-Wittig reaction of a phosphinimide intermediate is assumed to occur. Iminophosphoranes de
rived from hydrazines43a and acylhydrazines43b,c are also used as
intermediates in heterocyclic synthesis. Reactions of metalated
amines RNHMgX with Ph3PBr2 in PhH-ether can also provide
+
aminophosphonium salts Ph3 PNHR Br- in fair to good yields
43d
(33-74%).
the appropriate salt XM in DMF (X = N3, NCO, CN; M = K,

Na,).49 Treatment of Ph3PBr2 with Iodotrimethylsilane in CH2C12
at 0C yields Ph3PI2 (86%).50 Reaction of Ph3PBr2/Et3N with
EtO2CCH2CH=CHCO2Et in PhH leads to the corresponding
alkylidenephosphonium ylide in 80% yield.51 Beckmann re
arrangement of cycloalkanone oximes into lactams (74-81%
yields) is effected by Ph3PBr2 in dry PhH at 50-60 C.52 The
Ph3PBr2-Et3N reagent system compares favorably with a number
of other related phosphorus reagents for the rearrangement of Nallylamides into nitriles under mild conditions via 3-aza-Claisen
reaction.53
1. Castro, B. R. OR 1983, 29, 1.

2. Physical studies on the Ph3P-dihalide adducts indicates that the extent
of ionic (and covalent) behavior is a function of solvent polarity; see
especially: Bricklebank, N.; Godfrey, S. M.; Mackie, A. G.; McAuliffe,
C. A.; Pritchard, R. G. CC 1992, 355, and references cited therein.
3. Horner, L.; Oediger, H.; Hoffmann, H. LA 1959, 626, 26.
4. (a) Wiley, G. A.; Hershkowitz, R. L.; Rein, B. M.; Chung, B. C. JACS
1964, 86, 964. (b) Wiley, G. A.; Rein, B. M.; Hershkowitz, R. L. TL
1964, 2509.
5. Kaplan, L. JOC 1966, 31, 3454.
6. (a) Levy, D.; Stevenson, R. TL 1965, 341. (b) Levy, D.; Stevenson, R.
JOC 1965, 30, 3469.
7. (a) Schaefer, J. P.; Weinberg, D. S. JOC 1965, 30, 2635. (b) Schaefer, J.
P.; Weinberg, D. S. JOC 1965, 30, 2639.
8. Brett, D.; Downie, I. M.; Lee, J. B.; Matough, M. F. S. CI(L) 1969, 1017.
9. Arain, R. A.; Hargreaves, M. K. JCS(C) 1970, 67.
10. (a) Schaefer, J. P.; Higgins, J. G.; Shenov, P. K. OS 1968, 48, 51. (b)
Sandri, J.; Viala, J. SC 1992, 22, 2945.
11. Hrubiec, R. T.; Smith, M. B. JOC 1984, 49, 431.
12. Hanack, M.; Auchter, G. JACS 1985, 707, 5238.
13. Machinek, R.; Lttke, W. S 1975, 255.
14. Gajda, T. PS 1990, 53, 327.
15. (a) Piper, J. R.; Rose, L. M.; Johnston, T. P.; Grenan, M. M. JMC 1979, 22,
631. (b) Zakharkin, L. I.; Kovredov, A. I.; Kazantsev, A. V.; Meiramov,
M. G. JGU 1981, 51, 289. (c) Janda, K. D.; Weinhouse, M. I.; Danon, T.;
Pacelli, K. A.; Schloeder, D. M. JACS 1991, 113, 5427. (d) Skvarchenko,
V. R.; Lapteva, V. L.; Gorbunova, M. A. JOU 1990, 26, 2244.
16. Caubere, P.; Mourad, M. S. T 1974, 30, 3439.
17. Hodge, P.; Khoshdel, E. JCS(P1) 1984, 195.
18.
Other Applications. Reaction of Ph3PBr2 with benzoins in

MeCN at rt provides diaryl -diketones in excellent yields
(75-98%).44 Ph3PBr2 is used as a precursor in the synthesis of
dialkoxytriphenylphosphoranes such as (CF3CH2O)2PPh345 and
(t-BuCH2O)2PPh3,46 which are used as alkylating or acylating
and cyclodehydration agents, respectively. Direct synthesis of (3lactams by [2 + 2] cycloaddition between carboxylic acids and
imides, thus avoiding the use of acid halides, is achieved with
Ph3PBr2 (40-55%).47 Ph3PBr2, as a dehydrating agent, effects
esterification reactions with tertiary alcohols,48a such as t-BuOH
in PhH-HMPA, and with aromatic or aryl allylic acids and primary
or secondary aliphatic alcohols in petroleum ether (27-85%).48b
Preparation of Bromotrimethylsilane in quantitative yield oc
curs by deoxygenation of (Me3Si)2O with Ph3PBr2 (in 1,2dichlorobenzene at reflux) in the presence of a catalytic amount
of Zn; a one-pot preparation of pseudohalogenosilanes, in ex
cellent yield (80-95%), can follow by subsequent addition of
449
19.
20.
21.
22.
23.
24.
25.
26.
(a) Garegg, P. J. PAC 1984, 56, 845. (b) Classon, B.; Garegg, P. J.;
Samuelsson, B. CJC 1981, 59, 339.
(a) Haga, K.; Yoshikawa, M.; Kato, T. BCJ 1970, 43, 3922. (b) Bridges,
A. J. Nucleosides Nucleotides 1988, 7, 375.
(a) Herr, M. E.; Johnson, R. A. JOC 1972, 37, 310. (b) Boeckman, R.
K., Jr.; Ganem, B. TL 1974, 913.
Dahl, T.; Stevenson, R.; Bhacca, N. S. JOC 1971, 36, 3243.
(a) Schaefer, J. P.; Higgins, J. JOC 1967, 32, 1607. (b) Schaefer, J. P.;
Higgins, J.; Shenoy, P. K. OS 1969, 49, 6. (c) Porzi, G.; Concilio, C.
JOM 1977, 128, 95.
(a) Anderson, A. G., Jr.; Freenor, F. J. JACS 1964, 86, 5037. (b) Anderson,
A. G., Jr.; Freenor, F. J. JOC 1972, 37, 626. (c) Kato, M.; Nomura, S.;
Kobayashi, H.; Miwa, T. CL 1986, 281.
Marchand, A. P.; Weimar, W. R., Jr. CI(L) 1969, 200.
(a) Schwartz, M.; Oliver, J. E.; Sonnet, P. E. JOC 1975, 40, 2410. (b)
Sonnet, P. E. SC 1976, 6, 21. (c) Buser, H. R.; Guerin, P. M.; Toth, M.;
Szcs, G.; Schmid, A.; Francke, W.; Arn, H. TL 1985, 26, 403.
Kruse, C. G.; Jonkers, F. L.; Dert, V.; van der Gen, A. RTC 1979, 98,
371.
450
27.
28.
TRIPHENYLPHOSPHINE DICHLORIDE
(a) Aizpurua, J. M.; Cosso, F. P.; Palomo, C. JOC 1986, 51, 4941. (b)
Lazukina, L. A.; Kolodyazhnyi, 0. I.; Pesotskaya, G. V.; Kukhar, V. P.
JGU 1976, 46, 1931.
De Wit, J.; Wynberg, H. RTC 1973, 92, 281.
29. Wagner, A.; Heitz, M.-P.; Mioskowski, C. CC 1989, 1619.

30. (a) Hoffmann, H.; Diehr, H. J. TL 1962, 583. (b) Chechulin, P. I.;
Filyakova, V. I.; Pashkevich, K. I. BAU 1989, 189. (c) Bestmann, H.
J.; Kisielowski, L. CB 1983,116, 1320.
31.
(a) Carnduff, J.; Miller, J. A.; Stockdale, B. R.; Larkin, J.; Nonhebet, D.
C ; Wood, H. C. S. JCS(P1) 1972, 692. (b) Piers, E.; Nagakura, I. SC
1975, 5, 193. (c) Piers, E.; Grierson, J. R.; Lau, C. K.; Nagakura, I. CJC
1982, 60, 210. (d) Buono, G. S 1981, 872.
32.
(a) Thakore, A. N.; Pope, P.; Oehlschlager, A. C. T 1971, 27, 2617. (b)
Sonnet, P. E.; Oliver, J. E. JOC 1976, 41, 3279.
33. (a) Palumbo, G.; Ferreri, C ; Caputo, R. TL 1983, 24, 1307. (b) Caputo,
R.; Ferreri, C ; Noviello, S.; Palumbo, G. 5 1986, 499.
34. Okada, I.; Ichimura, K.; Sudo, R. BCJ 1970, 43, 1185.
35. (a) Gogte, V. N.; Kulkarni, S. B.; Tilak, B. D. TL 1973, 1867. (b) Freeman,
J. P.; Mondron, P. J. S 1974, 894.
36. (a) Bestmann, H.-J.; Mott, L. LA 1966, 693, 132. (b) Aizpurua, J. M.;
Palomo, C. S 1982, 684.
37. (a) Burton, D. J.; Koppes, W. M. CC 1973, 425. (b) Burton, D. J.; Koppes,
W. M. JOC 1975, 40, 3026. (c) Anderson, A. G. Jr.; Kono, D. H. TL
1973, 5121. (d) Smissman, E. E.; Alkaysi, H. N.; Creese, M. W. JOC
1915, 40, 1640.
38.
(a) Bestmann, H. J.; Lienert, J.; Mott, L. LA 1968, 718, 24. (b) Van
Camp, A.; Goossens, D.; Moya-Portuguez, M.; Marchand-Brynaert, J.;
Ghosez, L. TL 1980, 21, 3081. (c) Bestmann, H. J.; Lehnen, H. TL 1991,
32, 4279. (d) Palomo, C ; Mestres, R. S 1981, 373. (e) Fetyukhin, V. N.;
Vovk, M. V.; Samarai, L. I. JOU 1981, 17, 1263.
39.
40.

(a) Mazurkiewicz, R. M 1988, 119, 1279. (b) Mazurkiewicz, R. Acta
Chim. Hung. 1990, 127, 439 (CA 1990, 114, 206 693).
(a) Horner, L.; Oediger, H. LA 1959, 627, 142. (b) Zimmer, H.; Jayawant,
M.; Gutsch, P. JOC 1970, 35, 2826. (c) Briggs, E. M.; Brown, G. W.;
Jiricny, J.; Meidine, M. F. S 1980, 295. (d) Molina, P.; Alajarin, M.;
Arques, A. S 1982, 596.
41.
Triphenylphosphine Dichloride1
42.
(a) Al-Khathlan, H.; Zimmer, H. JHC 1988, 25, 1047. (b) Al-Khathlan,
H. Z.; Al-Lohedan, H. A. PS 1991, 61, 367.
43.
(a) Cullen, E. R.; Guziec, F. S., Jr.; Hollander, M. I.; Murphy, C. J. TL

1981, 22, 4563. (b) Molina, P.; Alajarin, M.; Saez, J. R. S 1984, 983. (c)
Froyen, P. PS 1991, 57, 11. (d) Zbiral E.; Berner-Fenz, L. M 1967, 98,
666.
44.
Ho, T.-L. S 1972, 697.
45.
Kubota, T.; Miyashita, S.; Kitazume, T.; Ishikawa, N. JOC 1980, 45,
5052.
46.
47.
48.
Kelly, J. W.; Evans, S. A., Jr. JOC 1986, 51, 5490.

Cosso, F. P.; Ganboa, I.; Palomo, C. TL 1985, 26, 3041.
(a) Haynes, R. K.; Katsifis, A.; Vonwiller, S. C. AJC 1984, 37, 1571. (b)
Lajis, N. Penanika 1985, 8, 67 (CA 1986, 105, 6277d).
49. Aizpurua, J. M.; Palomo, C. NJC 1984, 8, 51.
50. Romanenko, V. D.; Tovstenko, V. I.; Markovski, L. N. S 1980, 823.
51. Labuschagne, A. J. H.; Schneider, D. F. TL 1982, 23, 4135.
52. Sakai, I.; Kawabe, N.; Ohno, M. BCJ 1979, 52, 3381.
53. Walters, M. A.; Hoem, A. B.; Arcand, H. R.; Hegeman, A. D.;
McDonough, C. S. TL 1993, 34, 1453.
[2526-64-9]
C 18 H 15 Cl 2 P
(MW 333.20)
(conversion of alcohols,6-10 phenols,13 and enols15 into alkyl

chlorides; synthesis of vic-dichlorides16 or chlorohydrins17 from
epoxides; conversion of carboxylic acids11 and derivatives20 into
acyl chlorides; chlorination23,24 or dehydration11 of the CONH
group; production of iminophosphoranes from amines and related
compounds27-29)
Alternate Names: dichlorotriphenylphosphorane; triphenyldichlorophosphorane; chlorotriphenylphosphonium chloride.
Physical Data: adduct:2 white crystalline solid; mp 85-100 C;4
fp 20 C. Ph3P: mp 80.5 C; bp 377 C (in inert gas); d254
1.194gmL-3;n80D1.6358. Cl2: mp -101 C; bp -34.6C; d0
3.214gL -1 .
Solubility: adduct: slightly sol ether, THF, PhMe; sol CC14,
CH2C12, DMF, MeCN, pyridine; insol petroleum ether. Ph3P:
sol ether, PhH, CHC13, AcOH; less sol alcohol; pract insol H2O.
Cl2: sol CCl4, alcohol.
Form Supplied in: very hygroscopic solid; commercially avail
able; purity ~80%; the remainder is 1,2-dichloroethane. The
precursors Ph3P and Cl2 are both widely available. Ph3P: odor
less platelets or prisms; purity ~99%; typical impurity is Ph3PO
~ 1 % . Cl2: greenish-yellow gas, with suffocating odor; purity
99.3%; typical impurities are Br2, C2C16, C6C16, and H2O.
Analysis of Reagent Purity: adduct:2,331P NMR (various solvents
and solid state) +47 to +66 (ionic form), 6.5 to +8 (covalent
form); Raman (solid state) v(P-Cl) 593 cm -1 (ionic form), 274
cm -1 (covalent form). Typical impurities, Ph3P and Ph3PO:31P
NMR (various solvents) 5 to 9 and +25 to +42, respectively.
Preparative Methods: various preparations have been described;5
the adduct is usually prepared just before use by addition of a
stoichiometric amount of Chlorine to Triphenylphosphine in
a dry solvent.2
Handling, Storage, and Precautions: adduct: exceedingly sensi
tive to moisture; incompatible with strong oxidizing agents and
strong bases; may decompose on exposure to moist air or wa
ter; do not get in eyes, on skin, or on clothing; keep containers
closed and store in a cool dry place; these reagents should be
handled in a fume hood.
Alkyl Chlorides from Alcohols and Ethers. The reaction of

Ph3PCl2 with alcohols provides an excellent synthetic method for
the preparation of alkyl chlorides.6 Mechanistic studies6c suggest
the rapid initial formation of an alkyloxyphosphonium intermedi
ate which then undergoes slow conversion into Ph3PO and alkyl
chloride (eq l). 6b,c It is assumed that chlorination takes place by
an S N 2 reaction in most cases; thus, inversion of configuration is
observed in the transformation of ()-menthol to (+)-neomenthyl
6a
6b,7
6
SANOFI Chimie, Gentilly, France chloride (eq 2). As illustrated in eq 1, primary, secondary,
6b
and even tertiary alcohols are chlorinated with Ph3PCl2, al
though reactions of tertiary alcohols are often accompanied by
elimination (10%).
(1)
R = Bu, neopentyl, Cy, t-Bu; DMF, reflux
(2)
451
system as the electrophilic chlorine source. With this reagent,

in MeCN at rt, aromatic hydrocarbons bearing electron-donating
substituents, such as 2,4,6-tri-t-butylbenzene and mesitylene, af
ford 1 -monochloroarenes, while anisole gives a mixture of 2- and
4-chloro derivatives, in moderate to good yields (44-86%).14a
Similar aromatic para chlorination has also been observed by
heating anisole with Ph3pCl PC1 5 - , albeit in low yield (33%).14b
(6)
'Ph3PCl2', generated in situ from Ph3P and Hexachloroacetone (HCA) has proven to be a very efficient reagent for the regioand stereoselective chlorination of allylic alcohols (eq 3),8 and for
the regioselective conversion of sterically hindered cyclopropylcarbiny1 alcohols into cyclopropyIcarbinyl chlorides (eq 4).9 Chlo
rination of allylic alcohols occurs in less than 20 min, with total
preservation of the double bond geometry and with >99% inver
sion of configuration for optically active alcohols. Primary and
secondary alcohols give predominantly the unrearranged chlo
rides, while tertiary alcohols provide mostly rearranged prod
ucts, with elimination to dienes becoming an important side reac
tion with more highly substituted systems. Similarly, cyclopropylcarbinyl alcohols yield the corresponding chlorides with no trace
of homoallylic chlorides or cyclobutane derivatives.
(3)
R 1 ,R 2 , R3, R4 = H, Me
R1 = H, NO2, Me; R2 = H; R3 = H, Me, NO2, Ph

R1 + R2, R2 + R3 = Ph
Vinyl Chlorides, Alkynyl Ketones, and -Chloro-a-vinyl

Ketones from Ketones and -Diketones. 1-Chlorocyclohexene
(45%) and ,-dichlorotoluene (59%) are produced by
the reaction of cyclohexanone and benzaldehyde with
Ph3PCl2/Triethylamine and Ph3PCl2 alone, respectively, in
refluxing PhH.6a In MeCN as solvent, polymer-supported
Ph3PCl2 converts acetophenone into -chlorostyrene (75%).11
In a similar fashion, unsymmetrical fluorinated -diketones
give 3:1 mixtures of a,p-ynones (eq 7) in good overall yields
(slightly lower than those obtained with Triphenylphosphine
Dibromide)15a -Chloro-,-unsaturated ketones are prepared
in high yield from cyclic 3-diketones (eq 8).15b,c
:= 100:0 to 82:18
(7)
(4)
R = H, Me, Et, Pr, Bu, i-Pr, t-Bu

(8)
In the carbohydrate field, primary and secondary alco

hols are chlorinated in excellent yield (80-95%) with the
Ph3PCl2/ImH (Imidazole) reagent system in PhMe, MeCN, or
a MeCN/pyridine mixture at rt to reflux temperature.10 Polymersupported Ph3PCl2,11 prepared by the Ph3PO/COCl2 (Phosgene)
procedure,5b has been used to transform PhCH2OH to PhCH2Cl
(88%) in MeCN as a solvent; the simple workup consists of filtra
tion of polymeric phosphine oxide and solvent removal. Several
examples have been reported of the direct conversion of ethers
into chlorides, as in eq 5.7 Enol ethers such as acetophenone
trimethylsilyl ether give -chlorostyrene (30%) by Ph3PCl2 treat
ment at CC14 reflux.12
(5)
R1, R2, R3 = H,Me; n = 0, 1
Epoxide Cleavage to Vicinal Dichlorides and Chlorohydrins. Early reports of work in this area described the ring open
ing of ethylene oxide with Ph3PCl2 in CCl4 at rt, leading to
l,2-dichloroethane.16a Subsequently,16b,c excellent yields were
reported in the reaction of Ph3PCl2 with aliphatic epoxides to pro
duce the corresponding vicinal dichlorides. The ring opening takes
place stereospecifically with both cis and trans epoxides in PhH
or CH2C12 at reflux, in each case providing the dichloride derived
from SN2 displacement on each C-O bond (eq 9).16c Alkoxyphosphonium chloride intermediates have even been isolated and char
acterized in a study involving ethylene oxide derivatives.16d
(9)
Aryl Chlorides from Phenols and Arenes. Heating phenols

with Ph3PCl2 at 120-140C leads to the corresponding aryl chlo
rides in good yield (eq 6).13 A related chlorination reaction em
ploys the Ph3PCl2/BSPO (Bis(trimethylsilyl) Peroxide) reagent
The reaction of epoxides with Ph3PCl2 in anhydrous CH2C12 at

rt17a results in chlorohydrins in generally high yields (90-96%).
452
With conformationally rigid epoxides the oxirane ring cleavage

appears to be quite stereoselective, leading only to the prod
ucts resulting from the usual anti opening of the ring. Less hin
dered and rigid cyclic substrates provide regioisomeric mixtures of
cyclictrans-chlorohydrins.The reaction of the polymer-supported
Ph3PCl2 reagent proceeds in a similar fashion with even higher
yields and easier workup; simple filtration and evaporation pro
vides the product (eq 10).17b
(10)
chloroformamidines,5a,24 respectively, by reaction with Ph3PCl2

(eqs 14 and 15). Unsupported or polymer-supported reagent has
been used, with or without Et3N, in a variety of solvents. Under
very similar conditions, with Ph3PCl2 in CH2C12 at reflux, the pri
mary amide PhCONH2 is dehydrated to the nitrile PhCN (78%),11
while aryl-substituted arylhydroxamic acids are dehydrated to the
corresponding aryl isocyanates.25 In the latter case, dehydration
occurs via Lossen-type rearrangement of a phosphorane interme
diate. In a related reaction, chlorination-dehydrochlorination of
7V-acylated hydrazines with the Ph3PCl2/Et3N system is a smooth
one-pot procedure to generate nitrilimines.26 Thus, by such treat
ment, PhCONHNHPh affords [PhC=N-N-Ph] in situ; this reacts
with alkenic or alkynic dipolarophiles to give pyrazolines and
pyrazoles.
Acid Chlorides from Acids and Esters. Mono- and dicarboxylic acids give acyl chlorides on reaction with Ph3PCl26a
or polymer-supported Ph3PCl211 in PhH, CH2C12, or MeCN
(eq 11).11 On similar Ph3PC12 treatment in PhH at -10 C tort,sul
famic acid (H2NSO3H) is transformed into Ph3P=NSO2Cl in 95%
yield.18 Analogously, Ph3PCl2, generated in situ from Ph3P and
(EtO)2P(=O)SCl, reacts with Et3N and (EtO)2P(O)SH at - 7 8 C
to provide the corresponding acid chloride (EtO)2P(S)Cl.19
(11)
R = PhCH2, 4-MeC6H4 (n = 1); 1,4-C6H4, 1,3-C6H4 (n = 2)
Direct cleavage of esters or lactones20 to both acid and alkyl

chlorides is achieved with Ph3PCl2; halogenated esters (RCO2Me;
R = CF3, CC13, CH2C1) are readily cleaved in refluxing MeCN,
while esters of nonhalogenated acids and lactones (eq 12) require
higher temperatures or/and the use of additives such as Boron Trifluoride. Cleavage is considerably retarded by steric hindrance in
the alkoxy fragment. A mechanism involving initial nucleophilic
cleavage of the O-alky) bond with Cl- is proposed for halogenated
esters, whereas an initial electrophilic attack by Ph3P+Cl on the
carbonyl oxygen is assumed for the cleavage of nonhalogenated
esters.
(14)
(15)
R1 = Et, Pr, Ph; R2 = Et, Bu, Ph; R3 = Me, Et, Bu
Iminophosphoranes from Amines, Hydrazines, and Related

Derivatives. Iminophosphoranes (or phosphinimines) are com
monly used as intermediates, especially in heterocyclic synthesis.
Phosphinimines can be obtained via phosphorylation of primary
amines with Ph3PCl2 alone,27 or in the presence of Et3N,28 if
necessary, to ensure the last dehydrochlorination step. In the hete
rocyclic -enamino ester field, iminophosphoranes are submitted
to vinylogous alkylation28a or cycloaddition (eq 16)28a,b with ring
enlargement. The =PPh3 moiety, which serves as a temporary
amino protecting group, is then cleaved hydrolytically. Reaction
of phosphinimines with aryl isocyanates affords carbodiimides,28c
whereas iminophosphoranes of acyl hydrazines undergo dimerization to tetrazines.28d Other phosphinimines and phosphonium salts
have been prepared from phosphorylation of amino derivatives,
such as hydrazines,29a urethanes,29b and N-silylated imines,29c
with Ph3PCl2.
(12)
Similar transformations of esters to acid chlorides have also

been achieved in the phosphonate diester field21 and in the con
version of trialkyl phosphites into dialkyl chlorophosphites.22
Ph3PCl2 acts as a mild reagent for the replacement of a single
ester linkage by a chloride in phosphonate diesters (eq 13).
(16)
(13)
R = Me, Pr, allyl, MeOCO, i-PrOCO, PhOCO
Chlorination and Dehydration of Substituted Carboxamide

Groups. Secondary amides and N,N,N'-trisubstituted ureas pos
sessing an N-H bond are converted to imidoyl chlorides11'23 and
Other Applications. Ph3PCl2 is a good condensation reagent

for the synthesis of ketones (48-90%) from carboxylic acids and
Grignard reagents. The versatility of the method is illustrated by
the chemoselective reaction of carboxylic acids possessing such
functional groups as halogen, cyano, and carbonyl (eq 17).30
7.
(17)
8.
Beckmann rearrangement of benzophenone oxime to

PhC(Cl)=NPh (82%) is promoted by Ph3PCl2/Et3N in
CH2Cl2 at rt.31a Cyclopentanone and cyclohexanone oxime
are converted to -valero- and -caprolactam (76 and 86%)
with Ph3PCl2 in PhH at 50-60 C.31b The action of heat
(120-130 C) on a mixture of Ph3PCl2 with the highly fluorinated propanol (CF3)2C(OH)CH2SO2CF3 leads to elimination
of the CF3SO2 group and formation of the vinylic chloride
(CF3)2C=CHC1.32 Ph3PCl2 reacts with Pb(SCN)2 to form
Ph3 p-N=C=S SCN - , another reagent of the pseudohalophosphonium type, which is used for converting hydroxy groups
into thiocyanate and isothiocyanate functions.33 Ylides such
as triphenylphosphonio(vinylsulfonylphenylsulfonylmethanide),
CH2=CHSO2 C-(PPh3)SO2Ph, can be prepared by reaction
of Ph3PCl2 with the very activated methylene derivative
CH2=CHSO2CH2SO2Ph.34 Heating Ph3PCl2 with (Me3Si)2S
at 60-70 C leads to the formation of Ph3PS (85%) after
distillation of the Me3SiCl byproduct.35 Ph3PCl2 is reduced to
Ph3P with formation of alkyl or aryl chlorides by reaction with
organometallic reagents (Mg, Li).36
1. Castro, B. R. OR 1983, 29, 1.

2. The Ph3PCl2 adduct can be prepared by different routes; the most
common involves the reaction of Ph3P and Cl 2 , both being generally
used in solution, in order to ensure a correct 1/1 stoichiometry. As
illustrated by physical studies,3 the resultant product is often a mixture
of several compounds depending on starting materials (Ph3P, Ph3PO,
Cl 2 , COCl2, CCl3CCl3, CCl3COCCl3), on their stoichiometries, and on
the polarity of the solvent used for the preparation. 31 P NMR studies
under various conditions, and solid state Raman measurements, lead to
different values for ionic P IV and molecular P v species or to average
values corresponding to equilibrated mixtures of the both structures
according to the polarity of the solvent.
3.
4.
5.
6.
(a) Al-Juboori, M. A. H. A.; Gates, P. N.; Muir, A. S. CC 1991, 1270.

(b) Dillon, K. B.; Lynch, R. J.; Reeve, R. N.; Waddington, T. C. JCS(D)
1976, 1243, and literature cited therein.
Another preparation from Ph3P and CCl3CCl3 in MeCN provides
material of higher mp: 207-210 C (from MeCN-petroleum ether); see
Appel, R.; Schler, H. CB 1977, 110, 2382.
Apart from the classical Ph 3 P + Cl2 method, the following routes have
been reported: (a) Ph3P + COCl2: Appel, R.; Ziehn, K. D.; Warning,
K. CB 1973, 106, 2093, and literature cited therein, (b) Ph3PO + COCl2:
Masaki, M.; Kakeya, N.AG(E) 1977, 16, 552, and literature cited therein.
(c) Ph3P + CCl4 in the presence of RNHCOC1; Appel, R.; Warning, K.;
Ziehn, K. D.; Gilak, A. CB 1974, 107, 2671. (d) With Ph3P + CC14 alone,
a mixture of equal amounts of Ph3PCl2 and Ph 3 P=CCl 2 is obtained:
Rabinowitz, R.; Marcus, R. JACS 1962, 84, 1312; Appel, R.; Knoll, F.;
Michel, W.; Morbach, W.; Wihler, H.-D.; Veltmann, H. CB 1976, 109,
58. (e) Ph 3 P + CCl3CCl3, e.g. Ref. 4 and: Appel, R.; Halstenberg, M. In
Organophosphorus Reagent in Organic Synthesis, Cadogan, J. I. G., Ed.;
Academic: New York, 1979; Chapter 9 and literature cited therein, (f)
Ph3P + CCl3COCCl3 for in situ preparation of Ph3PCl2: see Ref. 8 and
9. (g) Ph3PO or Ph3P + PCl5: Dillon, K. B.; Reeve, R. N.; Waddington,
T. C. J. Inorg. Nucl. Chem. 1976, 38, 1439, and literature cited therein.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
453
Skvarchenko, V. R.; Lapteva, V. L.; Gorbunova, M. A. JOU 1990, 26,

2244.
(a) Magid, R. M.; Fruchey, O. S.; Johnson, W. L. TL 1977, 2999. (b)
Magid, R. M.; Fruchey, O. S.; Johnson, W. L.; Allen, T. G. JOC 1979,
44, 359.
(a) Hrubiec, R. T.; Smith, M. B. SC 1983, 13, 593. (b) Hrubiec, R. T.;
Smith, M. B. JOC 1984, 49, 431.
(a) Garegg, P. J.; Johansson, R.; Samuelsson, B. S 1984, 168. (b) Garegg,
P. J. PAC 1984, 56, 845.
Relies, H. M.; Schluenz, R. W. JACS 1974, 96, 6469.
Lazukina, L. A.; Kolodyazhnyi, O. I.; Pesotskaya, G. V.; Kukhar', V. P.
JGU 1916, 46, 1931.
Hoffmann, H.; Horner, L.; Wippel, H. G.; Michael, D. CB 1962, 95, 523.
(a) Shibata, K.; Itoh, Y.; Tokitoh, N.; Okazaki, R.; Inamoto, N. BCJ 1991,
64, 3749. (b) Timokhin, B. V.; Dudnikova, V. N.; Kron, V. A.; Glukhikh,
V. I. JOU 1979,15,337.
(a) Chechulin, P. I.; Filyakova, V. I.; Pashkevich, K. I. BAU 1989, 38,
189. (b) Piers, E.; Nagakura, I. SC 1975, 5, 193. (c) Piers, E.; Grierson,
J. R.; Lau, C. K.; Nagakura, I. CJC 1982, 60, 210.
(a) Gloede, J.; Keitel, I.; Gross, H. JPR 1976, 318, 607. (b) Sonnet, P.
E.; Oliver, J. E. JOC 1976, 41, 3279. (c) Oliver, J. E.; Sonnet, P. E. OS
1978, 58, 64. (d) Appel, R.; Glsel, V. I. ZN(B) 1981, 36, 447.
(a) Palumbo, G.; Ferreri, C ; Caputo, R. TL 1983, 24, 1307. (b) Caputo,
R.; Ferreri, C; Noviello, S.; Palumbo, G. S 1986, 499.
Arrington, D. E.; Norman, A. D. Inorg. Synth. 1992, 29, 27.
Krawczyk, E.; Mikolajczak, J.; Skowroska, A.; Michalski, J. JOC 1992,
57, 4963.
(a)Burton, D. J.; Koppes, W. M. CC 1973, 425. (b)Burton, D. J.; Koppes,
W. M. JOC 1975, 40, 3026.
Ylagan, L.; Benjamin, A.; Gupta, A.; Engel, R. SC 1988, 18, 285.
Gazizov, M. B.; Zakharov, V. M.; Khairullin, R. A.; Moskva, V. V. JGU
1986,56, 1471.
von Hinrichs, E.; Ugi, I. JCR(S) 1978, 338; JCR(M) 1978, 3973.
Wamhoff, H.; Zahran, M. S 1987, 876.
(a) Roesky, H. W.; Giere, H. H. CB 1969, 102, 2330. (b) Gotsmann, G.;
Schwarzmann, M. LA 1969, 729, 106.
(a) Wamhoff, H.; Haffmanns, G.; Schmidt, H. CB 1983, 116, 1691.
(b) Wamhoff, H.; Hendrikx, G. CB 1985, 118, 863. (c) Wamhoff, H.;
Haffmanns, G. CB 1984, 117, 585. (d) Farkas, L.; Keuler, J.; Wamhoff,
H. CB 1980, 113, 2566.
(a) Zhmurova, I. N.; Yurchenko, V. G.; Pinchuk, A. M. JGU 1983, 53,
1360. (b) Shevchenko, V. I.; Shtepanek, A. S.; Kirsanov, A. V. JGU 1962,
32, 2557. (c) Lazukina, L. A.; Kristhal', V. S.; Sinitsa, A. D.; Kukhar',
V. P. JGU 1980, 50, 1761.
Fujisawa, T.; Iida, S.; Uehara, H.; Sato, T. CL 1983, 1267.
(a) Appel, R.; Warning, K. CB 1975, 108, 1437. (b) Sakai, I.; Kawabe,
N.; Ohno, M. BCJ 1979, 52, 3381.
Samusenko, Y. V.; Aleksandrov, A. M.; Yagupol'skii, L. M. JOU 1975,
11, 622.
Burski, J.; Kieszkowski, J.; Michalski, J.; Pakulski, M.; Skowroska, A.
CC 1978, 940.
Diefenbach, H.; Ringsdorf, H.; Wilhelms, R. E. CB 1970, 103, 183.
Markovskii, L. N.; Dubinina, T. N.; Levchenko, E. S.; Kukhar', V. P.;
Kirsanov, A. V. JOU 1972, 8, 1869.
(a) Denney, D. B.; Gross, F. J. JOC 1967, 32, 3710. (b) Dmitriev, V. I.;
Timokhin, B. V.; Kalabina, A. V. JGU 1979, 49, 1936.

SANOFI Chimie, Gentilly, France
(a) Horner, L.; Oediger, H.; Hoffmann, H. LA 1959, 626, 26. (b) Wiley,
G. A.; Hershkowitz, R. L.; Rein, B. M.; Chung, B. C. JACS 1964, 86,
964. (c) Wiley, G. A.; Rein, B. M.; Hershkowitz, R. L. TL 1964, 2509.
454
TRIPHENYLPHOSPHINE-DIETHYLAZODICARBOXYLATE
Triphenylphosphine-Diethyl
Azodicarboxylate1
(Ph3p)
[603-35-0]
(DEAD)
[1972-28-7]
C 18 H 15 P
(MW 262.30)
C 6 H 10 N 2 O 4
(MW 174.18)
(reagent in the Mitsunobu reaction, which is a versatile, mild de

hydration reaction, widely used for the synthesis of esters and
ethers, for the formation of C-N, C-S, and C-halogen bonds, and
for inverting the configuration of a stereogenic carbon containing
an OH group1)
Physical Data: see Triphenylphosphine and Diethyl Azodicar
boxylate.
Handling, Storage, and Precautions: all reagents and solvents
must be anhydrous. In general, the Mitsunobu betaine (1) is
generated in situ from the phosphine and the azodicarboxylate;
however, in some cases it is essential to preform the betaine.
The betaine is an unstable, colorless, crystalline solid, rapidly
hydrolyzed on contact with moisture. It can be crystallized from
dry THF or CHCl3/hexane.
The Mitsunobu Reaction. A mixture of triphenylphosphine

(TPP) and diethyl azodicarboxylate (DEAD) is generally used;
however, diisopropyl azodicarboxylate (DIAD) is cheaper and
works just as well. The overall reaction enables the replacement
of the hydroxy 1 group of an alcohol by a nucleophile X (eq 1).
generally be less than 13. LiX or ZnX2 sometimes give better

results than HX.lc THF is the most commonly used solvent,
but other solvents such as dichloromethane, chloroform, ben
zene, toluene, ethyl acetate, DMF, and HMPA can also be used.
The reaction is faster in nonpolar solvents; for example, forma
tion of ethyl benzoate is about 30 times faster in CHCl3 than in
MeCN.5a A problem commonly encountered with the Mitsunobu
reaction is the separation of the product from triphenylphosphine
oxide. This can be overcome by the use of a phosphine con
taining a basic group such as diphenyl(2-pyridyl)phosphine6 or
(4-dimethylaminophenyl)diphenylphosphine,7 where an aqueous
acid wash removes the corresponding phosphine oxide, or by
using a polymer-bound phosphine.8 Similarly, dimethyl azodi
carboxylate (the corresponding hydrazine is water soluble)9 and
a polymer-supported azodicarboxylate10 can be used to facili
tate product isolation. The reaction is best explained by assum
ing successive formation of the betaine (1), the protonated Nphosphonium salt (2), and the alkoxyphosphonium salt (3), which
collapses in S N 2 fashion (eq 2).
(2)
Without acidic components, 7V-alkylhydrazinedicarboxylates

(4) can be formed.5b,11 NMR studies of the reaction of alcohols
with DEAD and TPP in the absence of acidic components have
revealed that the key intermediate is the pentavalent dialkoxyphosphorane (5).1c,5 In the presence of an acidic component, phosphorane intermediates are present in equilibrium with the oxyphosphonium salt (3).3
(1)
The phosphine accepts the oxygen (to give triphenylphosphine

oxide) while the azodicarboxylate accepts the two hydrogens (to
give the corresponding hydrazine derivative). The reaction occurs
under mild (0-25 C), essentially neutral conditions, can be car
ried out in the presence of a wide range of functional groups, and
usually gives good yields (60-90%). In general, the reaction pro
ceeds well with primary and secondary alcohols, and inversion of
configuration is observed.1 Retention of configuration may result
from neighboring group participation,2 or a change in mecha
nism if the alcohol is very hindered.3a Racemization may result
if the C-O bond is prone to SN 1 cleavage.4 Examples of H-X in
the reaction (eq 1) include carboxylic acids, thioacids, phenols,
thiols, imides, sulfonamides, hydrazoic acid, heterocyclic com
pounds, hydrogen halides, phosphate diesters, phosphinic acids,
and certain active methylene compounds. The pKa of H-X should
The combination of DEAD and TPP has been utilized most of

ten as the condensation reaction system, but dimethyl, diisopropyl,
and di-t-butyl azodicarboxylates (6) can also be used instead of
DEAD; the azodicarboxamide (7) has been used as well.112 Triph
enylphosphine can be substituted by a variety of trivalent phos
phorus compounds, including substituted triarylphosphines and
trialky lphosphines.1c
Order of Addition of the Reagents. The order of addition can
be crucial. The most commonly used procedure is to dissolve the
alcohol (ROH), the acid (HX), and triphenylphosphine in THF,
cool to 0 C, add the DEAD (or DIAD) slowly with stirring, and
then stir at room temperature for several hours. If this procedure
fails to give the desired product, the betaine (TPP-DEAD adduct)
should be preformed (addition of DEAD to TPP in THF at 0 C)
13
before addition of a mixture of the ROH and the HX, or ad

dition of ROH followed by slow addition of HX or HX and a
buffering salt (strong acids),14'15 or addition of HX followed by
ROH (weak acids).16 The advantage of preforming the betaine is
that X~ is not generated in the presence of a powerful oxidant (the
azodicarboxylate). Preformation of the betaine should minimize
radical-induced side-reactions (radicals are produced when TPP
and DEAD are mixed17).
455
of increased yield and ease of purification and removal of the

carboxyl group from the resulting esters.
(5)
R = Me, 65%; OMe, 66%; H, 74%; NC, 80%; O2N, 85%

R = Me: DMAD
R = Et: DEAD
R = i-Pr: DIAD
R = t-Bu: DBAD
X = CH2: ADDP
X = O, NMe
Ester Formation. A variety of alcohols react at room temper

ature with carboxylic acids in the presence of DEAD and TPP
to produce the corresponding esters.1 When polyols are used,
the reaction generally takes place at the less hindered hydroxyl
group, as exemplified in the reaction of 1,3-butanediol (eq 3). 1819
When 1,2-propanediol or styrene glycol is used, however, the more
sterically encumbered C-2 benzoate is predominantly obtained
with complete inversion of the stereochemistry.19 This result has
been explained by the formation of a dioxaphospholane (8) as
the key intermediate (eq 4).3b,19,20a with acyclic 1,4-diols such as
isomaltitol,20b five-membered cyclic ether formation takes place
in preference to esterification.
(6)
(3)
(7)
(4)
Thymidine (9) reacts with aromatic carboxylic acids to give 5'O-aroylthymidines (10) (eq 5). The yield of esters increases with
the acidity of the carboxylic acid, indicating the importance of the
protonated N-phosphonium salt (2).21'22
The reaction of chiral secondary carbinols with carboxylic
acids, DEAD, and TPP gives the corresponding esters with
inverted configuration. Removal of the carboxyl group af
fords the enantiomer of the parent alcohol (eqs 6-9). 23-27
For the purpose of inverting the stereochemistry of a sec
ondary carbinol center, 3,5-dinitrobenzoic acid,28 p-nitrobenzoic
acid,22b and chloroacetic acid29 have been recommended, because
(8)
456
the nearly exclusive production of (14a,b) (73%; a/b= 10:1) via

(12).37d
(9)
(11)
With some exceptions, a primary hydroxyl group is generally

more reactive than a secondary one.22a,30 Steric congestion and
electronic effects sometimes retard the reaction and/or result in
the formation of a complex mixture.31
The solvent also plays an important role in the success of
the reaction. In general, reaction in benzene or toluene gives
higher yields of inverted products.1,22b,32 Although pyridine is
not suitable in the preparation of nucleotides,33a pyridine can be
used for the synthesis of sucrose epoxide,33b and a mixture of
dioxane-pyridine (9:1) can be utilized in the preparation of sugar
carboxylates.22a Mixed solvent systems may be necessary when
the acid and alcohol components have widely differing solubili
ties. Thus a mixture of HMPA and dichloromethane works well
in the synthesis of lipophilic carbohydrate esters such as cord
factor.33c
Allylic and benzylic cyanohydrins react with carboxylic acids,
DEAD, and TPP to give inverted esters with 92-99% ee, while ex
tensive racemization takes place with benzaldehyde cyanohydrins
containing strongly electron-donating substituents (eq 10). Satu
rated aliphatic cyanohydrins afford esters in which the original
configuration is retained.34
(12)
(13)
(10)
R = H, 76% (96% ee)

R = MeO, 80% (6% ee)
Propargylic alcohols react with carboxylic acids, DEAD, and

TPP to give the corresponding inverted esters without formation
of allenic alcohols.35 Similarly, in allylic alcohols where no bias
exists against the normal S N 2 process, clean regiospecific inver
sion is invariably observed or implied.1,36 In specific cases where
the S N 2 pathway is hindered for some reason, such as eclipsing
of substituents, allylic rearrangement can occur (eqs 11-13).1,37
When compound (11) reacts with benzoic acid, DEAD, and TPP,
(13) and(14a,b) (a/b = 4:l) are obtained in a ratio of 1:1. Similar
treatment of (11) in the presence of PdCb (0.1 equiv) results in
(14a) X = BzO, Y = H
(14b) X = H, Y = BzO
Reaction with Thiocarboxylic Acids, Phosphoric Acids, Sul

fonic Acids, and their Derivatives.1 Thiocarboxylic acids,3813
dithiocarboxylic acids,39 and dimethyldithiocarbamic acid zinc
salt,40 as well as various phosphorus oxyacids41 and phospho
rus thioacids,42 can also be utilized. ,-Mercapto alcohols form
cyclic thioethers whereas thiols react with both DEAD and
TPP-DEAD to form disulfides.43a 2-Mercaptoazoles also react
with alcohols in the presence of DEAD and TPP.43b Although
arenesulfonic acids do not enter into the reaction, a combination
of DEAD-TPP with methyl p-toluenesulfonate as a nucleophile
carrier gives the corresponding alkyl sulfonates (eq 14).44 Alterna-
tively, Zincp-Toluenesulfonate reacts with a variety of secondary

alcohols to produce the desired tosylates with clean inversion and
in good yields, with some exceptions (eq 15).45
457
(18) with DEAD (5.0 equiv) and TPP (5.0 equiv) at 25 C for 18 h
gives (19) and (20) in 2% and 40% yields, respectively (eq 17).47
(14)
(17)
(15)
Reaction with Hydroxy Acids. A study of reactions of threo3-hydroxycarboxylic acids (15) with DEAD and TPP revealed
that both hydroxyl group activation (HGA) and carboxyl group
activation processes (CGA) are involved. With small R1 and R2,
the zwitterion (16) is more stable than (17), so that HGA is ex
clusively observed, resulting in the formation of alkenes. On the
other hand, the CGA process via (17) is progressively preferred
as the size of R1 and R2 increases (eq 16).46a,b When the reaction
is carried out in acetonitrile, CGA predominates.46c
The reaction of the seco acid (21) of colletodiol with DEAD

and TPP gives the lactone (22) in 45% yield after recrystallization
(eq 18),48a while the seco acid (23), which has a closely related
structure to (21), affords the corresponding lactone (24) in only
4% yield (eq 19).48b,49
(18)
(16)
(19)
Hydroxy acids HO-(CH2)n-CO2H with n3 react with

DEAD and TPP to afford the corresponding lactones.1 This proce
dure can be utilized in the preparation of macrolide antibiotics and
related compounds. Macrolactonization by the use of DEAD-TPP
depends on the reaction conditions and the structure of the seco
acids. Thus dropwise addition of the hydroxy acid (18) over a pe
riod of 10 h to a mixture of DEAD (7.7 equiv) and TPP (7.5 equiv)
affords the lactone (19) in 59% yield as well as the unwanted dilactide (20) in a yield of <1%. On the other hand, the reaction of
Reaction with Phenols and Other Oxygen Nucleophiles. When alcohols react with phenols, DEAD, and TPP, the
corresponding aryl alkyl ethers are produced. A tertiary amine
may facilitate the reaction.50a In general, the reaction proceeds
with clean inversion of chiral secondary carbinol centers (eq 2;
AH = a phenol).50b Depending on the structure of the substrate, allylic rearrangement51'52 and neighboring group participation can
458
TRIPHENYLPHOSPHINE-DIETHYL AZODICARBOXYLATE
be observed.2,53 Phenols having a hydroxyalkyl chain in a suit

able position for cyclization afford the corresponding cyclic aryl
ether.54 Silanols react with phenols and with alcohols in the pres
ence of DEAD and TPP to afford the corresponding silyl ethers.55
Oximes56 and N-hydroxy imides57 can also be utilized as acidic
components.
Reaction with Di- and Polyols. Although intermolecular de
hydration between two molecules of alcohols to afford acyclic
ethers usually does not occur with the DEAD-TPP system,
intramolecular cyclization of diols to produce three to sevenmembered ethers is a common and high yielding reaction.
Contrary to an early report,58a 1,3-propanediol does not form
oxetane.5b Oxetanes can be formed, however, using the trimethyl
phosphite modification of the Mitsunobu reaction.1c The reaction
of (S)-l,2-propanediol and (R)-1,4-pentanediol with DEAD and
TPP affords the corresponding cyclic ethers with 80-87% reten
tion of stereochemistry at the chiral carbon, while (S)-phenyl1,2-ethanediol affords racemic styrene oxide. In contrast to the
reaction of the same 1,2-diols with benzoic acid (eq 4), oxyphosphonium salts (25a) and (25b) have been postulated as key inter
mediates in the present reaction (eq 20).58b,e
phthalimide.22a If the reaction site is hindered and an S N 1 pro

cess favored, some stereochemical scrambling is observed. For
example, the reaction of (27) with phthalimide in the presence of
DEAD and TPP results in complete epimerization, giving (28a)
and (28b) in a ratio of 1:1 (eq 23).62 Neighboring group partici
pation is also possible in some cases.63
(22)
(20)
(23)
The reaction of cyclic trans-1,2-diols with DEAD and TPP gen

erally gives the corresponding oxiranes via phosphoranes.1,33b,59
Cyclic cis-1,2-diols also react with DEAD/TPP to afford primar
ily phosphoranes (26) which decompose intofinalproduct(s) such
as oxiranes (with retention of configuration) (eq 21)60 and dehy
drated alcohols and/or ketones (eq 22).61
Alcohols having an acidic hydrogen atom adjacent to the hydroxyl group may undergo dehydration rather than substitution.1
Thus the reaction of diethyl maleate (29) with phthalimide,
DEAD, and TPP gives diethyl fumarate without any detectable
formation of the substituted product.64a With Hydrazoic Acid,
however, (29) gives the expected azido succinate (30) in 74%
yield (eq 24).44a Dehydration is regioselective in some cases.64b,c
(24)
(21)
Carbon-Nitrogen Bond Formation. Phthalimide reacts

with alcohols, DEAD, and TPP to give the corresponding
N-alkylphthalimides with inversion of configuration (eq 2;
HA = phthalimide).1 Nitrophthalimide is more reactive than
Since azides are very useful in organic synthesis (especially for

the introduction of primary amino groups and the construction of
heterocyclic systems), the direct conversion of alcohols into azides
has been extensively studied (eq 2; HA = HN3).1,65 Diphenyl
Phosphorazidate66 and the zinc azide/bis-pyridine complex67 can
be used instead of HN3. Treatment of alcohols with hydrazoic acid,

DIAD, and excess TPP in THF, followed by addition of water or
aqueous acid, affords amines in moderate to good yields (eq 25).68
(25)
Acyclic amides and imides with pKa < 13 can be expected to

function as acidic components in the present reaction system. Thus
the reaction of N-benzyloxycarbonylbenzamide with ethyl (S)
()-lactate gives the inverted N-alkylated product (31a) and the
O-alkylated product (31b) in 19% and 48% yields, respectively
(eq 26).69 This result suggests that the alkoxyphosphonium salt
(3) is a hard alkylating reagent.
(26)
In the alkylation of imidodicarbonates and tosylcarbamates, the yield of alkylated product increases as the acid
ity of the NH acids increases. Thus imidodicarbonates and
tosylcarbamates with pKa < 13 give the corresponding Nalkylated products in 83-93% yields, while lower yields
are obtained with less acidic substrates.70a The combina
tion of 1,1'-(Azodicarbonyl)dipiperidine (ADDP) with Tri-nbutylphosphine appears to be superior to that of DEAD with TPP
in the alkylation of amides.12 In the presence of DEAD and TPP,
dibenzyl imidodicarbonate does not react with alcohols, but it
does react with -hydroxy stannanes to give the corresponding
N-alkylated products (eq 27).71
459
(28)
Intramolecular dehydration of 3-hydroxy carboxamides affords

the corresponding -lactams. Side reactions include elimination
and formation of aziridines and oxazolidines (eq 29).72,73 The
efficiency of -lactam formation is dependent on substrate substituents (including protecting groups for the side-chain amino
group) as well as on the choice of azodicarboxylate and PIII
compound.1c,74-76 For example, the dipeptide (33) reacts with
DEAD and TPP to give a 2:1 mixture of the -lactams (34a) and
(34b). Control of the labile C-5 stereocenter can be achieved by use
of Triethyl Phosphite instead of TPP; (34a) and (34b) are obtained
in a >50:1 ratio (eq 30).75 3-Hydroxy O-alkylhydroxamates can
also be converted into the corresponding -lactams (eq 31).1c,77
(29)
(30)
(31)
(27)
The O-acylhydroxamate (32a) (pKa 6-7) reacts with benzyl

alcohol, DEAD, and TPP to give N- and O-alkylated products,
while the less acidic O-alkylhydroxamate (32b) (pKa 9-10) gives
only the N-alkyl product (eq 28).72a
Purines and pyrimidines react with various alcohols in the pres

ence of DEAD and TPP (eq 32).78 The alcohol (35) gives a carAvoid Skin Contact with All Reagents
460
bocyclic nucleoside (36) in 65% yield along with a small amount

(9%) of the 7-substituted purine derivative (eq 33). 79-81
(36)
(37a) R = H
(37b) R = Me
(32)
X=Y=H
X = H, Y = CI
X = Y = Cl
70%
67%
69%
9%
23%
26%
21%
9%
(38a) R = H, 63%
(38b) R = Me, 55%
In the absence of an acidic component, -(N-carbonylamino)

alcohols afford aziridines or oxazolines, depending on the struc
ture of the substrate. Contrary to the case of (37), the Nbenzyloxycarbonylamino alcohol (39), with no acidic hydrogen
present at the position adjacent to the hydroxyl group, affords the
aziridine (40) in 85% yield (eq 37),86'87 while the N-acylamino
alcohols (41) give the oxazolines (42) in 31-68% yields (eq 38).88
(37)
(33)
(38)
Protection of the amino group by an electron-withdrawing

group is not necessarily required for the cyclization. Amino al
cohols of general structure HO-(C)n-NHR react with DEAD
Reaction with Amino Alcohols and Related Com
and TPP to form the corresponding cyclic amines. Thus 2pounds. Both secondary and tertiary carbamates bearing a vic
aminoethanols give aziridines in 18-90% yields.89 The reaction
inal hydroxyl group react with carboxylic acids in the pres
of the tetrailuoroborate salt of 3-(benzylamino)-l-propanol with
ence of DEAD and TPP to afford the corresponding esters
DEAD and TPP gives the corresponding azetidine in 50% yield
with inversion of configuration (eq 34).82 Reaction of N-t(eq 39).90 Five- and six-membered cyclic amines are also pre
butoxycarbonylserine with methanol, DEAD, and TPP gives the
pared by the reaction of amino alcohols with DEAD and TPP
corresponding methyl ester in >98% yield (eq 35).83 Without
91
methanol, N-benzyloxycarbonyl- or N-f-butoxycarbonylserine re (eqs 40 and 4l). Although azepines are not formed from straightchain amino alcohols, compound (43) gives the azepines (45a) and
acts with the preformed adduct of DEAD and TPP to afford the
(45b) by S N 2' substitution of the intermediate phosphorane (44)
-lactone (eq 35).84 The TV-protected serine methyl ester (37a) and
(eq 42).92
threonine methyl ester (37b) react with DEAD and TPP to give
the dehydrated products (38a) and (38b) (eq 36).85
(39)
(34)
(40)
(41)
461
(44)
(42)
O-Glycosidation with Phenols. Monosaccharides possessing

a free anomeric hydroxyl group react with phenol, DEAD, and
trivalent phosphorus compounds to give phenyl glycosides. The
yield is higher with trialkylphosphines (Bu3P, Pr3P).93 Cou
pling of phenols and 2--(phenylthio)- or 2--(phenylseleno)-D-pyranoses by the use of DEAD and TPP gives aryl 2-deoxy--Dglycosides in 70-85% yields with high stereoselectivity (inversion
of anomeric center) (eq 43).94 Intramolecular phenolic glycosidation is also possible.95
(45)
(46)
(43)
selectivity = 87:13 to 95:5
R1 = H, R2 = BnO or R1 = BnO, R2 = H
X = PhS or PhSe; ArOH = 2-naphthol, phenol, or 2-cresol
O-Glycosidation with Carboxylic Acids. Reaction of car

bohydrates having a free anomeric hydroxyl group with car
boxylic acids gives the corresponding glycosyl esters (eq 44).96
Intramolecular glycosidation of (46) can be accomplished by the
use of the preformed BU3P-DEAD betaine at low temperature
(eq 45).97
Glycosidation with Nitrogen Nucleophiles and N-Hydroxy
Compounds. Reaction of an anomeric hydroxyl group with ni
trogen nucleophiles and with N-hydroxy heterocycles affords the
corresponding glycosides.1,98,99 The -lactol (48) (: = ca. 8:1)
reacts with N-hydroxyphthalimide, DIAD, and TPP to give the
-glycoside (49) (eq 46).100
Carbon-Carbon Bond Formation. Direct coupling of an al

cohol with a carbon acid by the use of DEAD/TPP has been limited
to only a few examples because of the lack of carbon acids with
pKa < 13. If enolizable carbonyl compounds are used, alkylation
generally takes place on oxygen.69"101 Thus the reaction of 1,3cyclohexanedione with isopropanol, DEAD, and TPP affords ex
clusively the O-alkylated product (eq 47).101a Cyanoacetate reacts
at the carbon atom, while diethyl malonate is unreactive.101a How
ever, the reaction of diethyl malonate with alcohols in the presence
of ADDP and Bu3P affords C-alkylated products in 3-56% yields
(eq 48).12 Ethyl nitroacetate and nitromalonate oxidize the alco
hol via an aci-nitro ester (eq 49).102 o-Nitroarylacetonitriles of
general formula (50) undergo alkylation on carbon (eq 50).16,103
(47)
462
(48)
(eq 55).5a TPP-DIAD reacts with KHF2 or HF-pyridine to form

difluorotriphenylphosphorane (eq 56).106
(55)
(56)
(49)
(50)
-Nitro alcohols react with DEAD and TPP to afford nitrocyclopropanes in good to excellent yields (eq 5 l). 104a On the
other hand, nitro alcohols bearing electron-withdrawing or un
saturated substituents at the -carbon experience exclusive intraand intermolecular O-alkylation and furnish good to excellent
yields of alkyl nitronates (eq 52). In contrast, 1-phenylsulfonyll-nitro-3-propanol affords the corresponding cyclopropane.104b
Bis-sulfones readily undergo alkylation by alcohols.104c Novel
intramolecular S N 2 and S N 2' type arylation occurs with certain
aromatic and allylic alcohols (eqs 53 and 54).105
(51)
(52)
1. (a) Mitsunobu, O. S 1981, 1. (b) Castro, B. R. OR 1983, 29, 1. (c)

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6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
(53)
21.
22.
23.
24.
(54)
25.
Miscellaneous Reactions. Dialkyl phosphonates react with al

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27.
28.
Camp, D.; Jenkins, I. D. AJC 1988, 41, 1835.

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100. Nicolaou, K. C.; Groneberg, R. D. JACS 1990, 112, 4085.

101.
(a) Kurihara, T.; Sugizaki, M.; Kime, I.; Wada, M.; Mitsunobu, O. BCJ
1981, 54, 2107. (b) Bajwa, J. S.; Anderson, R. C. TL 1990, 31, 6973.
(c) Nakayama, E.; Watanabe, K.; Miyauchi, M.; Fujimoto, K.; Ide, J.
J. Antibiot. 1990, 43, 1122. (d) Czernecki, S.; Valry, J.-M. S 1991,
239.
102.
Mitsunobu, O.; Yoshida, N. TL 1981, 22, 2295.
103.
Macor, J. E.; Wehner, J. M. TL 1991, 32, 7195.
104.
(a) Yu, J.; Falck, J. R.; Mioskowski, C. JOC 1992, 57, 3757. (b) Falck,
J. R.; Yu, J. TL 1992, 33, 6723. (c) Yu, J.; Cho, H.-S.; Falck, J. R. JOC
1993, 58, 5892.
105.
(a) Magnus, P.; Gallagher, T.; Schulz, J.; Or, Y.-S.; Ananthanarayan, T.
P. JACS 1987, 109, 2706. (b) Boger, D. L.; Wysocki, R. J., Jr; Ishizaki,
T. JACS 1990, 112, 5230. (c) Magnus, P.; Mugrage, B.; DeLuca, M. R.;
Cain, G. A. JACS 1990, 112, 5220.
106.
Harvey, P.; Jenkins, I. D. TL 1994, 35, 9775.
Ian D. Jenkins
Griffith University, Brisbane, Australia
Oyo Mitsunobu
Aoyama Gakuin University, Tokyo, Japan
Tris(dimethylamino)sulfonium
Difluorotrimethylsilicate1
(R = Me)
[59218-87-0]
(R = Et)
[59201-86-4]
C 9 H 2 7 F 2 N 3 SSi
(MW 275.55)
C 15 H 39 F 2 N 3 SSi
(MW 359.73)
(anhydrous fluoride ion source; synthesis of C-F compounds

by nucleophilic displacement of sulfonates;3 promoter for electrophilic reactions of silyl enolates of ketones and esters; 4-6
source of sulfonium cation capable of stabilizing or imparting
high nucleophilic reactivity to other anions; 46,8a,10a activator of
vinylsilanes in Pd-catalyzed cross-coupling reactions;7 also used
for generation8 and reactions 10 of a- and -halo carbanions;
hydrosilylation11 and cyanomethylation14 of ketones)
Alternate Name: TASK
Physical Data: R = Me, mp 98-101 C; R = Et, mp 90-95 C.
Solubility: R = Me, sol MeCN, pyridine, benzonitrile; partially sol
THF. R = Et, sol THF, MeCN. Both react slowly with MeCN.
Form Supplied in: R = Me, white crystalline solid, ~ 9 0 % pure;
major impurity is tris(dimethylamino)sulfonium bifluoride
[(Me 2 N) 3 S+ H F 2 - ] .
Analysis of Reagent Purity: mp; 19 F NMR (at 200 MHz, CFC13
standard) TASMe 3 SiF 2 (CD 3 CN) - 6 0 . 3 ; TASHF 2 -145.8
(d, JHF = 120Hz).
Preparative Methods: the methyl derivative is prepared by the
reaction of dimethylaminotrimethylsilane and Sulfur Tetrafluoride at 70 C to rt in ether; the precipitated solid is fil
tered off.1a The ethyl derivative is best prepared by the re
action of N,N-Diethylaminosulfur Trifluoride (DAST) and
diethylaminotrimethylsilane. 1b,11b
Handling, Storage, and Precautions: because of the extreme hy
groscopic nature of this compound, it is best handled in a dry
box or a polyethylene glove bag filled with high purity nitrogen.
Use in a fume hood.
Introduction. The acronym TASF has been used to refer to

both (Me 2 N) 3 S+F 2 Me 3 Si- and (Et 2 N) 3 S+F 2 Me 3 Si - . To elim
inate confusion, the sulfonium salt containing dimethylamino
groups is referred to as TASF(Me), and the sulfonium salt contain
ing diethylamino groups is referred to as TASF(Et). Reactions of
both reagents are similar. Since both of these salts can be prepared
in a rigorously anhydrous state, they have an advantage over qua
ternary ammonium fluorides which usually contain some water.
TASF(Me) has a slight advantage over TASF(Et) in that it is highly
crystalline and easier to prepare in a high state of purity, whereas
TASF(Et) has an advantage over TASF(Me) in that it has greater
solubility in organic solvents. The tris(dialkylamino)sulfonium
cation is often referred to by the acronym TAS.
TASF is a source of organic soluble fluoride ion2 with a bulky
noncoordinating counter ion (eq 1).9
TAS + Me 3 SiF 2 -
Me3SiF + TAS+ + F-
465
Conjugated esters undergo sequential additions to form poly

mers (group transfer polymerization).5b The molecular weight and
the end group functionality of the polymer can be controlled by this
method. Mechanistic studies indicate an associative intramolec
ular silicon transfer process via (2), with concomitant C-C bond
formation during the polymer growth (eq 6).
(1)
(5)
Fluoride Ion Source in Nucleophilic Displace

ments. TASF(Me) can be used to prepare fluorides from
halides1b and sulfonates3 under relatively mild conditions (eq 2).
(2)
Generation of Enolates and Enolate Surrogates from Enol

Silanes. Enol silanes react with TASF(Et) to give highly reac
tive 'naked enolates' which have been characterized by NMR
and electrochemical measurements.4 These enolates, generated in
situ, can be regioselectively alkylated without complications from
polyalkylation or rearrangements of the alkylating agent (eq 3).
(6)
Si* = SiR3F
poly = polymer chain
(3)
In the presence of excess Fluorotrimethylsilane, TASF(Et) cat

alyzes aldol reactions of silyl enol ethers and aldehydes.4 The
stereochemical course of the reaction (syn selectivity, independent
of the enol geometry, (Z)- or (E)-(1), eq 4), has been interpreted
as arising from an extended transition state in which steric and
charge repulsions are minimized.
Silyl enol ethers and ketene silyl acetals add to aromatic nitro
compounds in the presence of TASF(Me) to give intermediate dihydro aromatic nitronates which can be oxidized with Bromine or
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone to give -nitroaryl
carbonyl compounds;6a the latter are precursors for indoles and
oxindoles.6b The reaction is widely applicable to alkyl-, halo-,
and alkoxy-substituted aromatic nitro compounds, including het
erocyclic and polynuclear derivatives (eq 7).
(4)
(7)
Very potent carbon nucleophiles formally equivalent to ester

enolates are generated by the interaction of TASF(Me) with un
hindered trialkylsilyl ketene acetals. In contrast to lithium eno
lates, these TAS enolates add 1,4 (nonstereoselectively) to ,unsaturated ketones. These adducts can be alkylated in situ to
form two new C-C bonds in one pot, or they can be hydrolyzed
to give 1,5-dicarbonyl compounds (eq 5).5a
Cross-Coupling Reactions. TASF(Et) activates vinyl-,

alkynyl-, and allylsilanes in the Pd-mediated cross-coupling
with vinyl and aryl iodides and bromides.7 As illustrated in
466
eqs 8-10, the reaction is stereospecific and chemoselective. This

cross-coupling protocol is remarkably tolerant towards a variety
of other functional groups such as carbonyl, amino, hydroxy, and
nitro. Vinylsilanes can be synthesized from Hexamethyldisilane
and vinyl iodides in the presence of TASF(Et) (eq 10) via cleavage
of a Si-Si bond.7a Aryl iodides can also be synthesized by this
method. TASF is superior to Tetra-n-butylammonium Fluoride
for these reactions. In the absence of a vinylsilane reagent, one of
the methyl groups from the difiuorotrimethylsilicate is substituted
for the halide(eq 11).7d
Other Applications. TASF(Et) catalyzes the addition of

Dimethyl(phenyl)silane to -alkoxy, -acyl or -amido ketones to
give the corresponding anti aldols (eq 14).11 This complements
the acid-catalyzed reduction which gives the syn isomer.
(14)
(8)
Dimethyl(phenyl)silane will reduce aldehydes and ketones to

hydroxyl compounds under very mild conditions in the presence
of a catalytic amount of TASF(Et).11c
Aryl or vinyl anions can be generated by the reaction of the
corresponding vinyl iodide with Bu3Sn anion, which in turn is
produced from TASF(Et) and Bu3SnSiMe3. With an appropri
ately placed carbonyl group, an intramolecular cyclization ensues
(eq 15).12
(9)
(15)
(10)
(11)
Generation and Reactions of Unusual Carbanions. Both

- and -halo carbanions are generally labile species and their
generation and reactions require extremely low temperatures.
TASF(Me) has been used to prepare several stable and isolable
perfluorinated carbanions (eq 12)8a or alkoxides.8b As compared
to the corresponding metal salts, the TAS+ counterion has little
coordination to the fluorines of the anion,9 and this presumably
slows the decomposition of the TAS salts to carbenoids or alkenes.
Addition of a- and -halo carbanions to carbonyl compounds may
be achieved by the in situ generation of these species by the re
action of TASF(Et) with the corresponding silylated derivatives
(eq 13).10
A useful variation of the Peterson alkenation relies on the gener

ation of -silyl carbanions from geminal disilyl compounds con
taining an additional stabilizing group (CO2R, SPh, SO2Ph, OMe,
CN, Ph) at the -carbon.13 A related reaction is the cyanomethylation of ketones and aldehydes with Trimethylsilylacetonitrile
in the presence of TASF(Me).14 TASF(Me) was found to be the
best fluoride ion source for the synthesis of aryl trifluoromethyl
sulfones from the corresponding sulfonyl fluorides and Trifluoromethyltrimethylsilane or Me3SnCF3 (eq 16).15
(16)
The carbanions formed by scission of a C-Si bond with TASF

can also be oxygenated. Benzylic trimethylsilyl groups can be
converted to hydroxyl groups in 20-95% yield by reaction with
TASF(Me) in the presence of oxygen and Trimethyl Phosphite
(eq 17).16 No other source of fluoride ion was found that could
replace TASF.
(12)
(17)
(13)
Related Reagents. Cesium Fluoride; Potassium Fluoride;

Tetra-n-butylammonium Fluoride.
Next Page
1.
2.
3.
4.
5.
6.
7.
8.
9.
(a) Middleton, W. J. OS 1985, 64, 221. (b) Middleton, W. J. U.S. Patent

3 940402, 1976 (CA 1976, 85, 6388j). See also Ref. 11(b).
For a review of applications of fluoride ion in organic synthesis, see:
Clark, J. H. CRV 1980, 80, 429.
(a) Card, P. J.; Hitz, W. D. JACS 1984, 106, 5348. (b) Doboszewski, B.;
Hay, G. W.; Szarek, W. A. CJC 1987, 65, 412.
10.
(a) Noyori, R.; Nishida, I.; Sakata, J. JACS 1983, 705, 1598. (b) Noyori,
R.; Nishida, I.; Sakata, J. TL 1981, 22, 3993.
(a) RajanBabu, T. V. JOC 1984, 49, 2083. (b) Webster, O. W.; Hertler,
W. R.; Sogah, D. Y.; Famham, W. B.; RajanBabu, T. V. JACS 1983, 705,
5706.
(a) RajanBabu, T. V.; Reddy, G. S.; Fukunaga, T. JACS 1985, 707, 5473.
(b) RajanBabu, T. V.; Chenard, B. L.; Petti, M. A. JOC 1986, 57, 1704.
(a) Hatanaka, Y.; Hiyarna, T. TL 1987, 28, 4715. (b) Hatanaka, Y.;
Hiyama, T. JOC 1988, 53, 918. (c) Hatanaka, Y.; Fukushima, S.; Hiyama,
T. H 1990, 30, 303. (d) Hatanaka, Y.; Hiyama, T. TL 1988, 29, 97.
13.
(a) Smart, B. E.; Middleton, W. J.; Farnham, W. B. JACS 1986, 108,

4905. (b) Farnham, W. B.; Smart, B. E.; Middleton, W. J.; Calabrese, J.
C ; Dixon, D. A. JACS 1985, 707, 4565.
For a discussion of structural aspects of TAS salts, see: (a) Farnham,
W. B.; Dixon, D. A.; Middleton, W. J.; Calabrese, J. C ; Harlow, R. L.;
Whitney, J.F.;Jones, G. A.; Guggenberger, L. J. JACS 1987, 109, 476. (b)
Dixon, D. A.; Farnham, W. B.; Heilemann, W.; Mews, R.; Noltemeyer,
M. HC 1993, 4, 287.
467
(a) Fujita, M.; Hiyama, T. JACS 1985, 707, 4085. (b) Hiyama, T.;
Obayashi, M.; Sawahata, M. TL 1983, 24, 4113. See also: de Jesus,
M. A.; Prieto, J. A.; del Valle, L.; Larson, G. L. SC 1987, 77, 1047.
11. (a) Fujita, M.; Hiyama, T. JOC 1988, 53, 5405. (b) Fujita, M.; Hiyama,
T. OS 1990, 69, 44. (c) Fujita, M; Hiyama, T. TL 1987, 28, 2263.
12. Mori, M.; Isono, N.; Kaneta, N.; Shibasaki, M. JOC 1993, 58, 2972.
Palomo, C; Aizpurua, J. M.; Garcia, J. M.; Ganboa, I.; Cossio, F. P.;
Lecea, B.; Lpez, C. JOC 1990, 55, 2498. Also see: Padwa, A.; Chen.
Y.-Y; Dent, W.; Nimmesgern, H. JOC 1985, 50, 4006.
14. Palomo, C ; Aizpurua, J. M.; Lopez, M. C ; Lecea, B. JCS(P1) 1989,

1692.
15.
Kolomeitsev, A. A.; Movchun, V. N.; Kondratenko, N. V.; Yagupolski,

Yu. L. S 1990, 1151.
16. Vedejs, E.; Pribish, J. R. JOC 1988, 53, 1593.
William J. Middleton & Victor J. Tortorelli
Ursinus College, Collegeville, PA, USA
Previous Page
468
ZINC BROMIDE
Organozinc intermediates formed via transmetalation using
ZnBr 2 have been used to effect carbozincation of alkenes and
alkynes through metallo-ene and metallo-Claisen reactions. Both
intermolecular and intramolecular variants of these reactions have
been described, often proceeding with high levels of stereoselec
tivity and affording organometallic products that may be used in
subsequent transformations (eqs 5 and 6), 10 including alkenation
(eq 6). 10b,c Bimetallic zinc-zirconium reagents have also been
developed that offer a method for the alkenation of carbonyl com
pounds (eq 7). 11
Zinc Bromide1
[7699-45-8]
Br2Zn
(MW 225.19)
(used in the preparation of organozinc reagents via

transmetalation;1 a mild Lewis acid useful for promoting
addition2 and substitution reactions3)
Physical Data: mp 394 C; bp 697C (dec); d 4.201 g c m - 3 .
Solubility: sol Et 2 O, H2O (1 g/25 mL), 90% EtOH (1 g/0.5 mL).
Form Supplied in: granular white powder; principal impurity is
H 2 O.
Analysis of Reagent Purity: melting point.
Purification: heat to 300 C under vacuum (2 1 0 - 2 mmHg) for
1 h, then sublime.
Handling, Storage, and Precautions: very hygroscopic; store un
der anhydrous conditions. Irritant.
Organozinc Reagents. The transmetalation of organomagnesium, organolithium, and organocopper reagents by anhydrous
ZnBr 2 in ethereal solvents offers a convenient method of preparing
organozinc bromides and diorganozinc reagents.1a Alternatively,
anhydrous ZnBr2 may be reduced by potassium metal to result in
highly activated Zn 0 , which is useful for the preparation of zinc
reagents through oxidative addition to organic halides.4 Alkyl,
allylic, and propargylic zinc reagents derived by these methods
have shown considerable value in their stereoselective and regioselective addition reactions with aldehydes, ketones, imines, and
iminium salts. 1a,5 Zinc enolates used in the Reformatsky reac
tion may also be prepared through transmetalation using ZnBr 2 . 1b
Organozinc species are especially useful in palladium- and nickelcatalyzed coupling reactions of sp2 carbon centers. In this fashion,
sp 2 -sp 3 (eq 1)6 and sp 2 -sp 2 (eqs 2 and 3) 7,8 carbon-carbon bonds
are formed selectively in high yields. The enantioselective cross
coupling of secondary Grignard reagents with vinyl bromide is
strongly affected by the presence of ZnBr 2 , which accelerates the
reaction and inverts its enantioselectivity (eq 4). 9
(3)
(4)
without ZnBr2
with ZnBr2
R1 = Me, R2 = H; >95% (52% ee)

R1 = H, R2 = Me; >95% (49% ee)
(5)
(1)
(6)
(2)
ZINC BROMIDE
469
(7)
(12)
ZnBr2, THF, 20 C, 6 h
CsF, CH2C12. 20 C, 14 h
Concerted Ring-Forming Reactions. The mild Lewis acid

character of ZnBr2 sometime imparts a catalytic effect on ther
mally allowed pericyclic reactions. The rate and stereoselectivity
of cycloaddition reactions (eq 8),12 including dipolar cycloadditions (eq 9),13 are significantly improved by the presence of this
zinc salt.
(8)
no catalyst, 5 h
with ZnBr2, 3 h
100:0
5:95
Activation of C-X Bonds. Even more important than car

bonyl activation, ZnBr2 promotes substitution reactions with suit
ably active organic halides with a variety of nucleophiles. Alkylation of silyl enol ethers and silyl ketene acetals using benzyl
and allyl halides proceeds smoothly (eq 13).3 Especially use
ful electrophiles are -thio halides which afford products that
may be desulfurized or oxidatively eliminated to result in a,(3unsaturated ketones, esters, and lactones (eq 14).18 Other elec
trophiles that have been used with these alkenic nucleophiles
include Chloromethyl Methyl Ether, HC(OMe)3, and Acetyl
Chloride.3,19
70%, 78% endo

80%, 95% endo
(13)
(9)
Some intramolecular ene reactions benefit from ZnBr2 catalysis

to afford the cyclic products under milder conditions, in higher
yields and selectivities (eqs 10 and 11).14,15 Generally, the use of
ZnBr2 is preferred over Zinc Chloride or Zinc Iodide in this type
of reaction.15
(10)
180 C, o-dichlorobenzene
ZnBr2, CH2C12, 25 C
66% (83% de)

79% (95% de)
(11)
(14)
Enol ethers and allylic silanes and stannanes will engage

cyclic -seleno sulfoxides,20 -acetoxy lactams,21 and acyl gly
cosides (eq 15)22 in the presence of ZnBr2 catalysis. Along these
lines, it has been found that ZnBr2 is superior to Boron Trifluoride Etherate in promoting glycoside bond formation using
trichloroimidate-activated glycosides (eq 16).23 Imidazole carba
mates are also effective activating groups for ZnBr2-mediated
glycosylation (eq 17).24
(R1 = CN, R2 = H):(R1 = H, R2 = CN) = 88:12

(15)
Activation of C=X Bonds. Lewis acid activation of carbonyl

compounds by ZnBr2 promotes the addition of allylsilanes and
silyl ketene acetals.16 Addition to imines has also been reported.17
In general, other Lewis acids have been found to be more useful,
though in some instances ZnBr2 has proven to be advantageous
(eq 12).2
Cyclic acetals also undergo highly selective, Lewis aciddependent ring opening substitution with Cyanotrimethylsilane
(eq 18).25
470
ZINC BROMIDE
Reduction. Complexation with ZnBr2 has been shown to

markedly improve stereoselectivity in the reduction of certain
heteroatom-substituted ketones (eqs 19 and 20).26,27 Furthermore,
the anti selectivity observed in BF3 OEt2-mediated intramolecular
hydrosilylation of ketones is reversed when ZnBr2 is used instead
(eq 21).28
(21)
Deprotection. ZnBr2 is a very mild reagent for several deprotection protocols, including the detritylation of nucleotides29
and deoxynucleotides,30 N-deacylation of N,O-peracylated
nucleotides,31 and the selective removal of Boc groups from sec
ondary amines in the presence of Boc-protected primary amines.32
Perhaps the most widespread use of ZnBr2 for deprotection is in
the mild removal of MEM ethers to afford free alcohols (eq 22).33
(16)
(22)
Miscellaneous. An important method for the synthesis of

stereodefined trisubstituted double bonds involves the treatment
of cyclopropyl bromides with ZnBr2. The (E) isomer is obtained
almost exclusively by this method (eq 23).34
(23)
(17)
The rearrangement of a variety of terpene oxides has been ex
amined (eq 24).35 While ZnBr2 is generally a satisfactory catalyst
for this purpose, other Lewis acids, including ZnCl236 and Mag
nesium Bromide,37 are advantageous in some instances.
(24)
(18)
(19)
In the presence of ZnBr2/48% Hydrobromic Acid, suitably

functionalized cyclopropanes undergo ring expansion to afford
cyclobutane (eq 25)38 and -methylene butyrolactone products
(eq 26).39 One-carbon ring expansion has been reported when
certain trimethylsilyl dimethyl acetals are exposed to ZnBr2 with
warming (eq 27).40
(25)
(20)
(26)
ZINC CHLORIDE
(27)
26.
27.
28.
29.
Related Reagents. Magnesium Bromide; Zinc Chloride; Zinc

Iodide.
1.
2.
3.
4.
5.
6.
(a) Knochel, P. COS 1991, 1, Chapter 1.7. (b) Rathke, M. W.; Weipert,
P. COS 1991, 2, Chapter 1.8.
For an example: Bellassoued, M.; Ennigrou, R.; Gaudemar, M. JOM
1988, 338, 149.
For examples: (a) Reetz, M. T.; Maier, W. F. AG(E) 1978, 17, 48. (b)
Reetz, M. T.; Chatziiosifidis, I.; Lowe, W. F.; Maier, W. F. TL 1979,
1427. (c) Paterson, I. TL 1979, 1519.
Riecke, R. D.; Uhm, S. J.; Hudnall, P. M. CC 1973, 269.
For representative examples of allylic and propargylic zinc reagents: (a)
Yamamoto, Y.; Nishii, S.; Maruyama, K.; Komatsu, T.; Ito, W. JACS
1986, 108, 7778. (b) Yamamoto, Y.; Ito, W. T 1988, 44, 5414. (c)
Yamamoto, Y.; Ito, W.; Maruyama, K. CC 1985, 1131. (d) Yamanoto,
Y.; Komatsu, T.; Maruyama, K. CC 1985, 814. (e) Fronza, G.; Fuganti,
C.; Grasselli, P.; Pedrocchi-Fantoni, G.; Zirotti, C. TL 1982, 23, 4143.
(f) Fujisawa, T.; Kojima, E.; Itoh, T.; Sato, T. TL 1985, 26, 6089. (g)
Pornet, I.; Miginiac, L. BSF 1975, 841. (h) Yamamoto, Y.; Komatsu,
T.; Maruyama, K. JOM 1985, 285, 31. (i) Bouchoule, C.; Miginiac, P.
CR(C) 1968, 266, 1614. (j) Miginiac, L.; Mauz, B. BSF 1968, 3832.
(k) Arous-Chtara, R.; Gaudemar, M.; Moreau, J.-L. CR(C) 1976, 282,
687. (1) Moreau, J.-L.; Gaudemar, M. BSF 1971, 3071. (m) Miginiac, L.;
Mauz, B. BSF 1968, 2544.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
Bartnik, R.; Lesniak, S.; Laurent, A. TL 1981, 22, 4811.

Barros, D.; Carreo, M. C ; Ruano, I. L. G.; Maestro, M. C. TL 1992,
33, 2733.
Anwar, S.; Davis, A. P. T 1988, 44, 3761.
Waldemeier, F.; De Bernardini, S.; Leach, C. A.; Tamm, C. HCA 1982,
65, 2472.
(a) Kohli, V.; Blocker, H.; Kster, H. TL 1980, 21, 2683. (b) Matteuci,
M. D.; Caruthers, M. H. TL 1980, 21, 3243.
Kierzek, R.; Ito, H.; Bhatt, R.; Itakura, K. TL 1981, 22, 3761.
Nigam, S. C ; Mann, A.; Taddei.M.; Wermuth, C.-G. SC 1989, 79, 3139.
Corey, E. J.; Gras, J.-L.; Ulrich, P. TL 1976, 809.
Johnson, W. S.; Li, T.; Faulkner, D. J.; Campbell, S. F. JACS 1968, 90,
6225. See also: (a) Brady, S. F.; Ilton, M. A.; Johnson, W. S. JACS 1968,
90, 2882. (b) Nakamura, H.; Yamamoto, H.; Nozaki, H. TL 1973, 111.
Lewis, J. B.; Hendrick, G. W. JOC 1965, 30, 4271. See also: (a) Settine,
R. L.; Parks, G. L.; Hunter, G. L. K. JOC 1964, 29, 616. (b) BessiereChrieu, Y; Bras, J. P. CR(C) 1970, 271, 200. (c) Clark, Jr., B.C.; Chafin,
T. C ; Lee, P. L.; Hunter, G. L. K. JOC 1978, 43, 519. (d) Watanabe, H.;
Katsuhara, J.; Yamamoto, N. BCJ 1971, 44, 1328.
Kaminski, J.; Schwegler, M. A.; Hoefnagel, A. J.; van Bekkum, H. RTC
1992, 111, 432.
Serramedan, D.; Marc, F.; Pereyre, M.; Filliatre, C ; Chabardes, P.;
Delmond, B. TL 1992, 33, 4457.
Kwan, T. W.; Smith, M. B. SC 1992, 22, 2273.
Hudrlik, P. F.; Rudnick, L. R.; Korzeniowski, S. H. JACS 1973, 95, 6848.
(a) Tanino, K.; Katoh, T.; Kuwajima, I. TL 1988, 29, 1815. (b) Tanino,
K.; Katoh, T; Kuwajima, I. TL 1988, 29, 1819. See also: Tanino, K.;
Sato, K.; Kuwajima, I. TL 1989, 30, 6551.
Glenn J. McGarvey
University of Virginia, Charlottesville, VA, USA
Negishi, E.; King, A. O.; Okudado, N. JOC 1977, 42, 1821.
Sengupta, S.; Snieckus, V. JOC 1990, 55, 5680. See also: Gilchrist, T.
L.; Summersell, R. I. TL 1987, 28, 1469.
8. (a) Jabri, N.; Alexakis, A.; Normant, I. F. BSF(2) 1983, 321. (b) Jabri,N.;
Alexakis, A.; Normant, I. F. TL 1982, 23, 1589. (c) Jabri, N.; Alexakis,
A.; Normant, I. F. TL 1981, 22, 959. (d) Jabri, N.; Alexakis, A.; Normant,
I. F. 7X 1981, 22, 3851.
471
7.
9.
19.
20.
21.
22.
Cross, G.; Vriesema, B. K.; Boven, G.; Kellogg, R. M.; van Bolhuis, F.
JOM 1989, 370, 357.
(a) Courtemanche, G.; Normant, J.-F. TL 1991, 32, 5317. (b) Marek,
I.; Normant, J.-F. TL 1991, 32, 5973. (c) Marek, I.; Lefrancois, J.-M;
Normant, J.-F. SL 1992, 633.
Tucker, C. E.; Knochel, P. JACS 1991, 113, 9888.
Narayana Murthy, Y. V. S.; Pillai, C. N. SC 1991, 21, 783. See also:
Lopez, R.; Carretero, J. C. TA 1991, 2, 93.
Kanemasa, S.; Tsuruoka, T.; Wada, E. TL 1993, 34, 87.
Tietze, L. F.; Biefuss, U.; Ruther, M. JOC 1989, 54, 3120. See also:
(a) Tietze, L. F.; Ruther, M. CB 1990, 123, 1387. (b) Nakatani, Y.;
Kawashima, K. 5 1978, 147.
Hiroi, K.; Umemura, M. TL 1992, 33, 3343.
(a) Mikami, K.; Kawamoto, K.; Loh, T.-P.; Nakai, T. CC 1990, 1161. (b)
Bellassoued, M.; Gaudemar, M. TL 1988, 29, 4551.
Gaudemar, M.; Bellassoued, M. TL 1990, 31, 349.
Khan, H. A.; Paterson, I. TL 1982, 23, 5083. See also: (a) Paterson, I.
T 1988, 44, 4207. (b) Khan, H. A.; Paterson, I. TL 1982, 23, 4811. (c)
Paterson, I.; Fleming, I. TL 1979, 20, 993, 995, 2179.
Fleming, I.; Goldhill, J.; Paterson, I. TL 1979, 3209.
Ren, P.; Ribezzo, M. JACS 1991, 113, 7803.
Ohta, T.; Shiokawa, S.; Iwashita, E.; Nozoe, S. H 1992, 34, 895.
Kozikowski, A. P.; Sorgi, K. L. TL 1982, 23, 2281.
23.
Urban, F. J.; Moore, B. S.; Breitenbach, R. TL 1990, 31, 4421.
24.
25.
Ford, M. I.; Ley, S. V. SL 1990, 255.

Corcoran, R.C. TL 1990, 31, 2101.
10.
11.
12.
13.
14.
15.
16.
17.
18.
Zinc Chloride1
[7646-85-7]
Cl2Zn
(MW 136.29)

cycloaddition,2 substitution,3 and addition reactions,4 including
electrophilic aromatic additions;5 has found use in selective
reductions 6 )
Solubility: sol H2O (432 g/100 g at 25 C), EtOH (1 g/1.3 mL),
glycerol (1 g/2 mL).
Form Supplied in: white, odorless, very deliquescent granules;
principal impurities are H 2 O and zinc oxychloride.
Analysis of Reagent Purity: melting point.
Purification: reflux (50 g) in dioxane (400 mL) in the presence
of Zn dust, then filter hot and allow to cool to precipitate pu
rified ZnCl 2 . Also, anhydrous material may be sublimed under
a stream of dry HC1, followed by heating to 400 C in a stream
of dry N 2 .
Handling, Storage, and Precautions: very hygroscopic; store un
der anhydrous conditions; moderately irritating to skin and mu
cous membranes.
Organozinc Reagents. The transmetalation of organomagnesium, organolithium, and organocopper reagents is an important
472
ZINC CHLORIDE
and versatile method of preparing useful zinc reagents.1a Alter

natively, ZnCl2 may be employed for direct insertion of Zn0 into
carbon-halogen bonds using Mg/ultrasound7 or prior reduction
with K0.8 The addition of the resultingallyliecand propargylic or
allenic zinc reagents to carbonyl compounds, imines, and iminium
salts represents an important method of selective carbon-carbon
bond formation.9,11 These reactions are generally guided by chela
tion and the Zimmerman-Traxler transition state10 to control
the relative stereochemistry about the new carbon-carbon bond
(eq 1),12 as well as with respect to preexisting stereocenters
(eq 2).13 Anions derived from propargylic deprotonation add to
carbonyl compounds with a high degree of regiochemical integrity
in the presence of ZnCl2, i.e. allenic organozinc intermediates
cleanly afford the propargylic product (eq 3).11b
the presence of ZnCl2. This effect has been noted in other metalmediated carbon bond formations,25 though the role of this ZnCl2
catalysis is not understood at present.
(5)
(6)
(1)
Lewis acid
none
0.5 equiv ZnCl2
63% 53:47
68% 89:11
(7)
(2)
(8)
(3)
(9)
Alkylzinc reagents, often in the presence of copper salts, effec
tively participate in conjugate addition reactions14 and clean S N 2'
reactions (eq 4).15
(4)
Organozinc reagents are superior species for palladium- and

nickel-catalyzed coupling reactions.16 This offers an exceptional
method for the selective formation of sp2-sp3 (eq 5),17 sp2-sp2
(eqs 6 and 7), 1819 and sp2-sp (eq 8)20 carbon-carbon bonds. In
addition, the palladium-catalyzed coupling reactions of sp and sp2
halides with vinylalanes (eq 9),21 vinylcuprates,22 vinylzirconium
(eq 10)23 and acyliron species24 often proceed more effectively in
(10)
Organozinc reagents have been successfully exploited in asym

metric carbon bond formation.26 Chiral glyoxylate esters engage
organozinc species derived from Grignard reagents in selective
addition reactions to afford enantiomerically enriched -hydroxy
acids (eq 11).27 Enantioselective addition reactions of Grignard
reagents have been achieved by sequential addition of ZnCl2 and
a chiral catalyst to afford secondary alcohols (eq 12).28
(11)
ZINC CHLORIDE
(12)
Zinc Enolates. Zinc enolates can be prepared by deprotonation

of carbonyl compounds using standard bases, followed by transmetalation with ZnCl 2 1b These enolates offer important oppor
tunities for stereoselective aldol condensations, including higher
yields and stereochemical selection for threo crossed-aldol prod
ucts (eq 13).29 Both of these consequences are the result of the
reversible formation of a six-membered zinc chelate intermediate
(1) which favors the anti disposition of its substituents. Though
their use has been mostly replaced by kinetically controlled al
dol methodology, zinc enolates sometimes present advantages in
specific cases.30 For example, chelated zinc enolates derived from
a-amino acids have been shown to be of value in the stereoselec
tive synthesis of -lactams (eq 14).31 Controlled monoalkylation
of unsymmetrical ketones has been accomplished via treatment
of zinc enolates with -chlorothio ethers (eq 15),32 and mild allylation of -dicarbonyl compounds may be realized through ex
posure of the corresponding zinc enolate to an allyl alcohol in the
presence of a palladium catalyst (eq 16).33
473
(15)
(16)
Homoenolates. Readily available mixed Me3Si/alkyl acetals

are converted into zinc homoenolates in high yield through expo
sure to ZnCl2 in Et2O (eq 17).34 These mildly reactive species,
which tolerate asymmetry to the carbonyl, are useful for a va
riety of bond-forming reactions. In the presence of Me3Si activa
tion they undergo addition to aldehydes and, when admixed with
CuBr.DMS (see Copper(I) Bromide), can be allylated or conjugatively introduced to ,-unsaturated ketones (eq 18).35 Copper
salts are not required for conjugate addition to propargylic esters
(eq 19).36 These zinc species also participate in useful palladiumcatalyzed bond-forming processes (eq 20).37
(13)
additive
none, -72 C
ZnCl2, DME, 14 C
(17)
52:48
83:17
(18)
(19)
(14)
474
ZINC CHLORIDE
Magnesium Bromide, and Tin(IV) Chloride, to name a few.4 In

some instances, excellent levels of stereocontrol have been ob
served (eq 28).43 Analogous additions to imines have been noted
as well.4e-g,44 Some conjugate addition reactions may also benefit
from ZnCl2 catalysis (eq 29).45
(20)
Cycloaddition Reactions. Catalysis by ZnCl2 is often a pow

erful influence on cycloaddition reactions.2 In addition to im
proving the rate of Diels-Alder reactions, enhanced control over
regioselectivity (eq 21)2c and stereochemistry (eq 22)2e may be
observed. An exceedingly important application of ZnCl2 cataly
sis is found in the reaction of electron-rich dienes with carbonyl
compounds.2a,b Intensive mechanistic studies on these reactions
has uncovered two mechanistic pathways that afford stereochemically contrasting products, depending upon which Lewis acid is
employed (eq 23).38 It was concluded that cycloaddition reactions
catalyzed by ZnCl2 proceed via a classical [4 + 2] concerted pro
cess, whereas Lewis acids such as Boron Trifluoride Etherate
and Titanium(IV) Chloride afford products through sequential
aldol/cyclization processes. Examples abound wherein advantage
has been taken of the predictable Cram-Felkin selectivity of this
ZnCl2 catalysis to exploit asymmetric variants of this reaction to
synthesize a variety of natural products (eq 24).39 The selective
cycloaddition of electron-rich dienes with imines has also been
catalyzed by ZnCl2 (eq 25).40
(23)
BF3OEt2, CH2C12, -78 C

ZnCl2, THF, 25 C
21%
91%
69%
2%
(24)
(21)
(22)
Activation of C=X Bonds. The mild Lewis acid character of

ZnCl2 is frequently exploited to promote the addition of vari
ous nucleophiles to carbon-heteroatom double bonds.4 The wellestablished Knoevenagel condensation and related reactions have
been effectively catalyzed by ZnCl2 (eq 26).41 The addition of
enol ethers and ketene acetals to aldehydes and ketones has been
noted (eq 27),42 though ZnCl2 has been used less widely in these
aldol-type condensations than other Lewis acids, including TiCl4,
(25)
(26)
ZINC CHLORIDE
475
(33)
(27)
(28)
(34)
(29)
(35)
A, PhMe, 24 h
1 equiv ZnCl2, CH2C12, 0 C, 2 d
50%
98%
The formation of cyanohydrins using Cyanotrimethylsilane

and Isoselenocyanatotrimethylsilane has been effectively cat
alyzed by ZnCl2 (eq 30),46 as has Strecker amino acid synthesis
via the treatment of imines with Me3SiCN/ZnCl2.47 The com
bination of carbonyl compounds with Acetyl Chloride or Acetyl
Bromide may be promoted by ZnCl2 to afford protected vicinal
halohydrins (eq 31).48
In a similar fashion, acetals (eq 36)54 and orthoesters (eq 37)55

may be used as electrophiles in substitution reactions with
electron-rich alkenic nucleophiles. The combination of ZnCl2
with co-catalysts has sometimes proven advantageous in these
reactions (eq 38).56
(30)
(36)
(31)
(37)
It is noteworthy that the treatment of carbonyl compounds

with Chlorotrimethylsilane/ZnCl2 results in a useful synthesis of
Me3Si enol ethers which, in turn, may be useful for other carbon
bond-forming processes (eq 32).49
(32)
(38)
Activation of C-X Bonds. The activation of C-X single bonds

toward nucleophilic substitution is also mediated by the Lewis
acidic character of ZnCl2.3 Benzylic (eq 33),50 allylic (eq 34),3d,51
propargylic,52 and tertiary halides (eq 35)53 undergo substitution
with mild carbon and heteroatom3e nucleophiles.
The regioselective ring opening reactions of epoxides

(eq 39),57,58 oxetanes,58 and tetrahydrofurans (eq 40)59 has been
promoted by ZnCl2 to afford adducts with suitable nucleophiles.
476
ZINC CHLORIDE
(39)
(40)
Activation by ZnCl2 of allylic (eq 41 )60 and propargylic chlo

rides (eq 42),61 as well as -chloroenamines (eq 43),62 in the pres
ence of simple alkenes has been shown to yield four-membered
andfive-memberedcycloadducts.
(41)
(42)
related reagent, ZnCRASi, which includes Me3SiCl in the mix

ture, selectively reduces ketones in high yield, though the levels
of selectivity do not compete with other selective reagents.69
The reduction of ketones and aldehydes by silicon and tin
hydrides in the presence of ZnCl2 has been documented.70 In
the presence of Pd0 catalysts and ZnCl2, these hydrides selec
tively reduce ,-unsaturated aldehydes and ketones to the cor
responding saturated products (eq 44).71 The presence of ZnCl2
has been shown to modify the reactivity of several common re
ducing agents. For example, the mixture of Sodium Cyanoborohydride and ZnCl2 selectively reduces tertiary, allylic, and benzylic halides (eq 45),72 Sodium Borohydride, in the presence of
ZnCl2 and PhNMe2 will reduce aryl esters to primary alcohols,73
and Lithium Aluminum Hydride with ZnCl2/CuCl2 desulfurizes
dithianes (eq 46).74
(44)
(45)
(46)
Stereoselectivity is also modified by the presence of ZnCl2

(eq 47).75 Enantioselective reduction of aryl ketones has been ob
served with Diisobutylaluminum Hydride (DIBAL) modified by
ZnCl2 and chiral diamine ligands (eq 48).76
(47)
(43)
Chlorination of alcohols by Thionyl Chloride,63 the preparation

of acyl chlorides from lactones and anhydrides,64 and the bromination and iodination of aromatic rings by Benzyltrimethylammonium Tribromide and Benzyltrimethylammonium Dichloroiodate, respectively,65 are all effectively catalyzed by the presence
of ZnCl2. In addition, ZnCl2 acts as a source of chloride for the
halogenation of primary, secondary, and allylic alcohols using
Triphenylphosphine-DiethylAzodicarboxylate.66
Reduction. The very useful reducing agent Zinc Borohydride
is prepared by exposure of NaBH4 to ZnCl2 in ether solvents.67
Its use in selective reductions is described elsewhere.6a A com
plex reducing agent resulting from the mixture of NaH/t-pentylOH/ZnC^, given the acronym ZnCRA (Zinc Complex Reducing
Agents), is found to open epoxides in a highly regioselective fash
ion, favoring hydride delivery at the least hindered position.68 A
(48)
Protection/Deprotection. The acetylation of carbohy

drates and other alcohols has been realized using Acetic
Anhydride/ZnCl2 (eq 49).77 It is found that ZnCl2 imparts selec
tivity to both acetylation78 and acetonide formation79 of polyols,
which is useful in the synthetic manipulation of carbohydrates.
Synthetically useful selective deprotection of acetates (eq 50)80
ZINC CHLORIDE
477
81
and dimethyl acetals (eq 51 ) has been reported to be mediated

by ZnCl2.
(49)
(56)
(50)
ZnCl2, EtOH
SnCl2
(57)
R 1 = H , R2 = Ac, 100%
R1 =Ac, R2 = H, 100%
(58)
(51)
Acylation. Unsaturated esters are obtained through acylation

of alkenes by anhydrides using activation by ZnCl2 (eq 52).82 The
mixture of RCOCl/ZnCl2 is effective in the acylation of silyl enol
ethers to afford -dicarbonyl products (eq 53).83 Friedel-Crafts
acylation is catalyzed by ZnCl2, using anhydrides or acyl halides
as the electrophiles (eqs 54 and 55).84,85
(52)
Related Reagents. Aluminum Chloride; DiphenylsilaneTetrakis(triphenylphosphine)palladium(0)-Zinc Chloride; Phosphorus(III) Chloride-Zinc(II) Chloride; Phosphorus Oxychloride-Zinc(II) Chloride; Tin(IV) Chloride; Tin(IV) Chloride-Zinc
Chloride; Titanium(IV) Chloride; Zinc Bromide.
1. (a) Knochel, P. COS 1991, 1, Chapter 1.7. (b) Rathke, M. W.; Weipert,
P. COS 1991, 2, Chapter 1.8.
2. For examples: (a) Danishefsky, S.; DeNinno, M. P. AG(E) 1987, 26, 15.
(b) Danishefsky, S. Aldrichim. Acta 1986, 19, 59. (c) Chou, S.-S.; Sun,
D.-J. CC 1988, 1176. (d) Liu, H.-J.; Ulibarri, G.; Browne, E. N. C. CJC
1992, 70, 1545. (e) Liu, H.-J.; Han, Y. TL 1993, 34, 423.
3.
For examples: (a) Zhai, D.; Zhai, W.; Williams, R. M. JACS 1988, 110,
2501. (b) Williams, R. M.; Sinclair, P. J.; Zhai, D.; Chen, D. JACS 1988,
110, 1547. (c) Paterson, I.; Fleming, I. TL 1979, 20, 993, 995, 2175.
(d) Godschalz, J. P.; Stille, J. K. TL 1983, 24, 1905. (e) Miller, J. A. TL
1975, 2050. (f) Shikhmamedbekova, A. Z.; Sultanov, R. A. JGU 1970,
40, 72. (g) Ishibashi, H.; Nakatani, H.; Umei, Y.; Yamamoto, W.; Ikeda,
M. JCS(P1) 1987, 589. (h) Mori, I.; Bartlett, P. A.; Heathcock, C. H.
JACS 19S7, 109, 7199.
4.
For examples: (a) Eliel, E. L.; Hutchins, Sr., R. O.; Knoeber, M. OS

1970, 50, 38. (b) Angle, S. R.; Turnbull, K. D. JACS 1989, 111, 1136. (c)
Takai, K.; Heathcock, C. H. JOC 1985, 50, 3247. (d) Chiba, T.; Nakai,
T. CL 1987, 2187. (e) Taguchi, T.; Kitagawa, O.; Suda, Y.; Ohkawa, W.;
Hashimoto, A.; Iitaka, Y.; Kobayashi, Y. TL 1988, 29, 5291. (f) Kunz,
H.; Pfrengle, W. AG(E) 1989, 28, 1067. (g) Kunz, H.; Pfrengle, W. JOC
1989,54,4261.
5.
For examples: (a) Gulati, K. C ; Seth, S. R.; Venkataraman, K. OSC 1943,

2, 522. (b) Bhmer, V.; Deveaux, J. OPP 1972, 4, 283. (c) Chapman, N.
B.; Clarke, K.; Hughes, H. JCS 1965, 1424.
For examples: (a) Oishi, T.; Nakata, T. ACR 1983, 24, 2653. (b) Fort,
Y.; Feghouli, A.; Vanderesse, R.; Caubre, P. JOC 1990, 55, 5911. (c)
Solladi, G.; Demailly, G.; Greek, C. OS 1977, 56, 8.
Boerma, J. In Comprehensive Organometallic Chemistry; Wilkinson, G.,
Ed.; Pergamon: Oxford, 1982, 2, Chapter 16.
Rieke, R. D.; Uhm, S. J. S 1975, 452.
Allylic organozinc chlorides: (a) Masuyama, Y.; Kinugawa, N.; Kurusu,
Y. JOC 1987, 52, 3702. (b) Tamao, K.; Nakajo, E.; Ito, Y. JOC 1987,
52, 957. (c) Pettier, C ; Luche, J.-L. JOC 1985, 50, 910. (d) Tamao, K.;
Nakajo, E.; Ito, Y. T 1988, 44, 3997. (e) Jacobson, R. N.; Clader, J. W. TL
1980,21,1205.(f)Hua,D.H.;Chon-Yu-King,R.;McKie,J.A.;Myer,L.
JACS 1987, 109, 5026. (g) Courtois, G.; Harama, M.; Miginiac, P. JOM
1981, 218, 275. (h) Evans, D. A.; Sjogren, E. B. TL 1986, 27, 4961. (i)
(53)
(54)
(55)
6.
7.
Aromatic Substitution. Several important classes of aromatic

substitutions are mediated by ZnCl2, including the Hoesch reac
tion (eq 56)86 and the Fischer indole synthesis (eq 57).87 Haloalkylation of aromatic rings using Formaldehyde or Chloromethyl
Methyl Ether is readily accomplished through the agency of ZnCl2
and warming (eq 58).88
8.
9.
478
ZINC CHLORIDE
Fujisawa, T.; Kofima, E.; Itoh, T.; Sato, T. TL 1985, 26, 6089. (j) Fang,
J.-M.; Hong, B.-C. JOC 1987, 52, 3162. (k) Auvray, P.; Knochel, P.;
Normant, J.-F. TL 1986, 27, 5091. For general reviews on the reactions
of allylic organometallic reagents, see ref. 10.
10.
37.
(a) Tamaru, Y.; Ochiai, H.; Nakamura, T.; Yoshida, Z. TL 1986, 27, 955.
(b) Tamaru, Y.; Ochiai, H.; Nakamura, T.; Tsubaki, K.; Yoshida, Z.-i. TL
1985, 26, 5559.
38.
(a) Danishefsky, S. J.; Kerwin, Jr., J. F.; Kobayashi, S. JACS 1982, 104,
358. (b) Danishefsky, S. J.; Larson, E. R.; Askin, D. JACS 1982, 104,
6437. (c) Larson, E. R.; Danishefsky, S. J. JACS 1982, 104, 6458. (d)
Danishefsky, S. J.; Maring, C. J. JACS 1985, 107, 1269. (e) Danishefsky,
S. J.; Larson, E. R.; Askin, D.; Kato, N. JACS 1985, 107, 1246. (f)
Danishefsky, S. J.; Kato, N.; Askin, D.; Kerwin, Jr., J. F. JACS 1982,
104, 360. (g) Midland, M. M.; Graham, R. S. JACS 1984, 106, 4294. (h)
Garner, P. TL 1984, 25, 5855.
39.
40.
41.
42.
Danishefsky, S. J.; Hungate, R. JACS 1986, 108, 2486.

Waldmann, H.; Braun, M. JOC 1992, 57, 4444.
Rao, P. S.; Venkataratnam, R. V. TL 1991, 32, 5821. See also Ref. 4a.
Hofstraat, R. G.; Lange, J.; Scheeren, H. W.; Nivard, R. J. F. JCS(P1)
1988,2315.
van der Werf, A. W.; Kellogg, R. M.; van Bolhuis, F. CC 1991, 682.
Beslin, P.; Marion, P. TL 1992, 33, 5339.
Page, P. C. B.; Harkin, S. A.; Marchington, A. P. SC 1989, 19, 1655. See
also: Yamauchi, M.; Shirota, M.; Watanabe, T. H 1990, 31, 1699.
Sukata, K. JOC 1989, 54, 2015. See also: (a) Deuchert, K.; Hertenstein,
W.; Wehner, G. CB 1979, 112, 2045. (b) Ruano, J. L. G.; Castro, A. M.
M.; Rodriguez, J. H. TL 1991, 32, 3195.
Kunz, H.; Sager, W.; Pfrengle, W.; Schanzenback, D. TL 1988, 29,
4397.
(a) Neuenschwander, M.; Bigler, P.; Christen, K.; Iseli, R.; Kyburz,
R.; Mhle, H. HCA 1978, 61, 2047. (b) Bigler, P.; Schonholzer,
S.; Neuenschwander, M. HCA 1978, 61, 2059. (c) Bigler, P.;
Neuenschwander, M. HCA 1978, 61, 2165.
Danishefsky, S. J.; Kitahara, T. JACS 1974, 96, 7807.
Buml, E.; Tschemschlok, K.; Pock, R.; Mayr, H. TL 1988, 29, 6925.
See also: (a) Clark, J. H.; Kybett, A. P.; Macquarrie, D. C ; Barlow, S.
J.; Landon, P. CC 1989, 1353. (b) Reetz, M. T; Sauerwald, M. TL 1983,
24, 2837.
(a) Yamamoto, Y. ACR 1987, 20, 243. (b) Hofmann, R. W. AG(E) 1982,
21, 555. (c) Yamamoto, Y.; Maruyama, K. H 1982, 18, 357. (d) Courtois,
G.; Miginiac, L. JOM 1974, 69, 1.
11.
(a) Zweifel, G.; Hahn, G. JOC 1984, 49, 4565. (b) Evans, D. A.; Nelson,
J. V. JACS 1980, 102, 774.
12. Verlhac, J.-B.; Pereyre, M. JOM 1990, 391, 283.
13. (a) Fuganti, C ; Grasselli, P.; Pedrocchi-Fantoni, G. JOC 1983, 48,
909. (b) Fronza, G.; Fuganti, C ; Grasselli, P.; Pedrocchi-Fantoni, G.
J. Carbohydr. Chem. 1983, 2, 225.
14. Watson, R. A.; Kjonaas, R. A. TL 1986, 27, 1437.
15. Yamamoto, Y.; Chounan, Y.; Tanaka, M.; Ibuka, T. JOC 1992, 57, 1024.
See also: Arai, M.; Kawasuji, T.; Nakamura, E. CL 1993, 357.
16. For examples: (a) Negishi, E.; Takahashi, T.; King, A. O. OS 1988,
66, 67. (b) Murahashi, S.-I.; Yamamura, M.; Yanagisawa, K.; Mita, N.;
Kondo, K.; Negishi, E. JOC 1983, 48, 1560. (c) Tius, M. A.; Trehan,
S. JOC 1986, 51, 765. (d) Rossi, R.; Carpita, A.; Cossi, P. T 1992,
48, 8801. (e) Shiragami, H.; Kawamoto, T.; Imi, K.; Matsubara, S.;
Utimoto, K.; Nozaki, H. T 1988, 44, 4009. (f) Matsushita, H.; Negishi,
E. JACS 1981, 103, 2882. (g) Pelter, A.; Rowlands, M.; Jenkins, I. H. TL
1987, 28, 5213. (h) Andreini, B. P.; Carpita, A.; Rossi, R. TL 1988, 29,
2239. (i) Negishi, E.; Okukado, N.; Lovich, S. F.; Luo, T.-T. JOC 1984,
49, 2629.
17. Tamao, K.; Ishida, M.; Kumada, M. JOC 1983, 48, 2120.
18. Russell, C. E.; Hegedus, L. S. JACS 1983, 105, 943.
43.
44.
45.
46.
47.
48.
19. Takahashi, K.; Ogiyama, M. CC 1990, 1196.

20.
(a) King, A. O.; Okukado, N.; Negishi, E. CC 1977, 683. (b) King, A.
O.; Negishi, E.; Villiani, Jr., F. J.; Silveira, A. JOC 1978, 43, 358.
21.
Negishi, E.; Takahashi, T.; Baba, S. OS 1988, 66, 60. See also: Zweifel,
G.; Miller, J. A. OR 1984, 32, 375.
22.
(a) Jabri, N.; Alexakis, A.; Normant, J.-F. BSF(2) 1983, 321, 332.
(b) Jabri, N.; Alexakis, A.; Normant, J.-F. TL 1981, 22, 959, 3851.
(c) Nunomoto, S.; Kawakami, Y.; Yamashita, Y. JOC 1983, 48,
1912.
23.
24.
25.
26.
27.
28.
29.
30.
Negishi, E.; Okukado, N.; King, A. O.; Van Horn, D. E.; Spiegel, B.
I. JACS 1978, 100, 2254. See also: Van Horn, D. E.; Valente, L. F.;
Idacavage, M. J.; Negishi, E. JOM 1978, 156, C20.
Koga, T; Makinouchi, S.; Okukado, N. CL 1988, 1141.
(a) Godschalx, J.; Stille, J. K. TL 1980, 21, 2599. (b) Erdelmeier, I.; Gais,
H.-J. JACS 1989, 111, 1125. (c) Cahiez, G.; Chavant, P.-Y. TL 1989, 30,
7373.
For examples: (a) Jansen, J. F. G. A.; Feringa, B. L. JOC 1990, 55, 4168.
(b) Soai, K.; Kawase, Y.; Oshio, A. JCS(P1) 1991, 1613.
Boireau, G.; Deberly, A.; Abeuhaim, D. T 1989, 45, 5837. See also:
Fujisawa, T.; Ukaji, Y.; Funabora, M.; Yamashita, M.; Sato, T. BCJ 1990,
63, 1894.
Seebach, D.; Behrendt, L.; Felix, D. AG(E) 1991, 30, 1008.
House, H. O.; Crumrine, D. S.; Teranishi, A. Y.; Olmstead, H. D. JACS
1973,95,3310.
For a general review on stereoselective aldol condensations, see: Evans,
D. A.; Nelson, J. V; Taber, T. R. Top. Stereochem. 1982, 13, 1.
31.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
van der Steen, F. H.; Jastrzebski, J. T. B. H.; van Koten, G. TL 1988, 29,
765, 2467. See also: van der Steen, F. H.; Boersma, J.; Spek, A. L.; van
Koten, G. OM 1991, 10, 2467.
32. Groth, U.; Huhn, T; Richter, N. LA 1993, 49.
63.
33.
Itoh, K.; Hamaguchi, N.; Miura, M.; Nomura, M. JCS(P1) 1992, 2833.
65.
34. Nakamura, E.; Sekiya, K.; Kuwajima, I. TL 1987, 28, 337.

35. Nakamura, E.; Aoki, S.; Sekiya, K.; Oshino, H.; Kuwajima, I. JACS
1987, 109, 8056.
36. Crimmins, M. T.; Nantermet, P. G. JOC 1990, 55, 4235.
66.
67.
64.
Other examples: (a) Koschinsky, R.; Khli, T.-P; Mayr, H. TL 1988, 29,
5641. (b) Alonso, F.; Yus, M. T 1991, 47, 9119.
Mayr, H.; Klein, H. JOC 1981, 46, 4097.
Reetz, M. T.; Schwellus, K. TL 1978, 1455.
Isler, O.; Schudel, P. Adv. Org. Chem. 1963, 4, 128. See also: Oriyama,
T; Iwanami, K.; Miyauchi, Y.; Koga, G. BCJ 1990, 3716.
Parham, W. E.; Reed, L. J. OSC 1955, 3, 395. See also: (a) Grgoire,
de Bellemont, E. BSF 1901, 25, 18. (b) Hatanaka, K.; Tanimoto, S.;
Sugimoto, T.; Okano, M. TL 1981, 22, 3243.
Hayashi, M.; Inubushi, A.; Mukaiyama, T. BCJ 1988, 61, 4037.
Halcomb, R. L.; Danishefsky, S. J. JACS 1989, 111, 6661.
Scheeren, H. W.; Dahman, F. J. M.; Bakker, C. G. TL 1979, 2925. See
also: (a) Sukata, K. BCJ 1990, 63, 825. (b) Hug, E.; Mellor, M.; Scovell,
E. G.; Sutherland, J. K. CC 1978, 526.
Grummett, O.; Stearns, J. A.; Arters, A. A. OSC 1955, 3, 833.
Klein, H.; Mayr, H. AG(E) 1981, 20, 1027.
Mayr, H.; Seitz, B.; Halberstat-Kausch, I.-K. JOC 1981, 46, 1041.
Hoornaert, C ; Hesbain-Frisque, A. M.; Ghosez, L.AG(E) 1975, 14, 569.
See also: Sidani, A.; Marchand-Brynaert, J.; Ghosez, L. AG(E) 1974, 13,
267.
Squires, T. G.; Schmidt, W. W.; McCandlish, Jr., C. S. JOC 1975, 40,
134.
(a) Goel, O. P.; Seamans, R. E. S 1973, 538. (b) Kyrides, L. P. OSC 1943,
2, 528.
(a) Kajigaeshi, S.; Kakinami, T.; Moriwaki, M.; Tanaka, T.; Fujisaki,
S.; Okamoto, T. BCJ 1989, 62, 439. (b) Kajigaeshi, S.; Kakinami, T.;
Watanabe, F.; Odanoto, T. BCJ 1989, 62, 1349.
Ho, P.-T.; Davies, N. JOC 1984, 49, 3027.
Gensler, W. J.; Johnson, F.; Sloan, A. D. B. JACS 1960, 82, 6074.
ZINC IODIDE
68.
69.
70.
71.
72.
Fort, Y.; Vanderesse, R.; Caubre, P. TL 1985, 26, 3111.

See Ref. 6b and Caubre, P.; Vanderesse, R.; Fort, Y. ACS 1991, 45, 742.
(a) Anwar, S.; Davies, A. P. T 1988, 44, 3761. (b) Laurent, A. J.; Lesniak,
S.TL 1992,33, 3311.
Keinan, E.; Greenspoon, N. JACS 1986, 108, 7314.
Kim, S.; Kim, Y. J.; Ahn, K. H. TL 1983, 24, 3369.
73.
Yamakawa, T.; Masaki, M.; Nohira, H. BCJ 1991, 64, 2730.
74.
(a) Mukaiyama, T. IJS(B) 1972, 7, 173. (b) Sttz, P.; Stadler, P. A. OS

1977, 56, 8.
75.
Solladi, G.; Demailly, G.; Greck, C. TL 1985, 26, 435. See also:
Hanamoto, X; Fuchikama, T. JOC 1990, 55, 4969 and Ref. 6c.
Falorni, M.; Giacomelli, G.; Lardicci, L. G 1990, 120, 765.
76.
77.
Braun, C. E.; Cook, C. D. OS 1961, 41, 79.
78.
79.
80.
81.
82.
Hanessian, S.; Kagotani, M. Carbohydr. Res. 1990, 202, 67.

Angyal, S. J.; Gilham, P. T.; Macdonald, C. G. JCS 1957, 1417.
Griffen, R. J.; Lowe, P. R. JSC(P1) 1992, 1811.
Chang, C ; Chu, K. C ; Yue, S. SC 1992, 22, 1217.
Groves, J. K.; Jones, N. JCS(C) 1968, 2898. See also: (a) Marshall, J.
A.; Andersen, N. H.; Schlicher, J. W. JOC 1979, 35, 858. (b) Groves, J.
K.; Jones, N. JCS(C) 1969, 2350. (c) House, H. O.; Gilmore, W. F. JACS
1961, 83, 3980.
Tirpak, R. E.; Rathke, M. W. JOC 1982, 47, 5099. See also: Reetz, M.
T.; Kyung, S.-H. TL 1985, 26, 6333.
84. Cooper, S. R. OSC 1955, 3, 761. See also: Baddeley, G.; Williamson, R.
JCS 1956, 4647. See also: Zani, C. L.; de Oliveira, A. B.; Snieckus, V.
TL 1987, 28, 6561.
85. Dike, S. Y.: Merchant, J. R.; Sapre, N. Y. T 1991, 47, 4775. See also: (a)
Shah, V. R.; Bose, J. L.; Shah, R. C. JOC 1960, 25, 677. (b) Dallacker,
F.; Kratzer, P.; Lipp, M. LA 1961, 643, 97.
479
Handling, Storage, and Precautions: very hygroscopic and light

sensitive; store under anhydrous conditions in the absence of
light.
Organozinc Reagents. Organozinc reagents may be prepared

through transmetalation of organolithium, organomagnesium, and
organocopper species with ZnI 2 , although Zinc Chloride and Zinc
Bromide are used far more frequently.1a It is more usually the case
that organozinc iodides are prepared by zinc insertion into alkyl
iodides using Zinc/Copper Couple.1a These zinc reagents pos
sess reactivity analogous to the other organozinc halides, finding
particular use in palladium-catalyzed coupling reactions (eq 1 ).4
An alternative method for the preparation of the Simmons-Smith
reagent (Iodomethylzinc Iodide) involving the treatment of Diazomethane with ZnI 2 has been reported (eq 2). 5
83.
86.
87.
88.
Ref. 5a and Ruske, W. In Friedel-Crafts and Related Reactions; Olah,

G. A., Ed.; Interscience: New York, 1964, Vol. 3, p 383.
Ref. 5c and (a) Shriner, R. L.; Ashley, W. C; Welch, E. OSC 1955, 3,
725. (b) Prochazki, M. P.; Cartson, R. ACS 1989, 43, 651.
Ref. 5b and Olah, G. A.; Tolgyesi, W. S. In Friedel-Crafis and Related
Reactions; Olah, G. A., Ed.; Interscience: New York, 1964, Vol. 2, p 659.
(1)
(2)
Cycloaddition Reactions. The catalytic effect of ZnI 2 on the

Diels-Alder reaction has been noted (eq 3), 6 but its use in such
cycloaddition reactions is rare compared with ZnCl2 and ZnBr 2 .
Glenn J. McGarvey
(3)
Zinc Iodide1
[10139-47-6]
I2Zn
(MW 319.19)

addition2 and substitution reactions3)
Physical Data: mp 446 C; bp 625 C (dec); d 4.740 g c m - 3 .
Solubility: sol H 2 O (1 g/0.3 mL), glycerol (1 g/2 mL); freely sol
EtOH, Et 2 O.
Form Supplied in: white, odorless, granular solid; principal im
purities are H 2 O and iodine.
Analysis of Reagent Purity: mp.
Purification: heat to 300 C under vacuum for 1 h, then
sublime.
Activation of C=X Bonds. Catalysis of aldol condensation

reactions using silyl ketene acetals and ZnI 2 has been the subject
of several studies.7 It is observed that ZnI 2 favors the activation
of functionalized carbonyl compounds via -chelates to impart
useful stereoselectivity (eq 4). 7a In analogous fashion, diastereoselective additions to imines and nitrones have been reported
which offer useful access to -lactams (eq 5). 8 ,-Unsaturated
esters are subject to conjugate addition reactions by silyl ketene
acetals, also through the agency of ZnI 2 activation (eq 6). 9
(4)
480
ZINC IODIDE
(5)
(11)
(6)
An important role for ZnI2 has been found in the catalysis of

R3SiCN addition to ketones and aldehydes to afford silyl protected
cyanohydrins.10 This is a very general reaction that is effective
even with very hindered carbonyl compounds (eq 7).11 Diastereoselective cyanohydrin formation has been reported when these
reaction conditions are applied to asymmetric carbonyl substrates
(eq 8).2a
(7)
(12)
(R1 = Me, R2 = H):(R1 = H, R2 = Me) = 3:1
Substitution reactions of orthoesters3b and acetals,3c including

anomeric bond formation in carbohydrates (eq 13),16 have been
catalyzed by ZnI2.
(13)
(8)
Activation of C-X Bonds. The Lewis acidity of ZnI2 may

be exploited to activate various carbon-heteroatom bonds to nucleophilic substitution. Treatment of epoxides and oxetanes with
Cyanotrimethylsilane/ZnI2 results in selective C-N bond forma
tion with ring opening (eq 9).12 Similarly, C-S and C-Se bonds
may be formed by treating cyclic ethers with ZnI2 and RSSiMe3
and RSeSiMe3, respectively (eq 10).13
(9)
Reduction. Allyl and aryl ketones, aldehydes, and alco

hols are reduced to the corresponding hydrocarbon by Sodium
Cyanoborohydride/Znl2 (eq 14).17 This is a reasonably reactive
reducing mixture which will also attack nitro and ester groups.
(14)
Deprotection. Methyl and benzyl ethers may be cleaved by the

combination of (Phenylthio)trimethylsilane/ZnI2 (eq 15).18 Sim
ilar cleavage of alkyl and benzyl ethers takes place using Acetic
Anhydride/ZnI2 to afford the corresponding acetate (eq 16).19
(10)
(15)
Treatment of 4-acetoxy- and 4-sulfoxyazetidin-2-ones with

ZnI2 results in the formation of the corresponding imine or
iminium species which subsequently suffers silyl-mediated addi
tion. These reactions result in the formation of trans substitution
(eqs 11 and 12).14,15
(16)
ZINC p-TOLUENESULFONATE
481
Related Reagents. Zinc Bromide; Zinc Chloride.
Zinc p-Toluenesulfonate
1. (a) Knochel, P. COS 1991, 1, Chapter 1.7. (b) Rathke, M. W.; Weipert,
P. COS 1991, 2, Chapter 1.8.
2. For examples: (a) Effenberger, T.; Hopf, M.; Ziegler, T.; Hudelmayer, J.
CB 1991, 124, 1651. (b) Klimba, P. G.; Singleton, D. A. JOC 1992, 57,
1733. (c) Colvin, E. W.; McGarry, D. G. CC 1985, 539.
3.
For examples: (a) Paquette, L. A.; Lagerwall, D. R.; King, J. L.;

Niwayama, S.; Skerlj, R. TL 1991, 32, 5259. (b) Howk, B. W.; Sauer, J.
C. OSC 1963, 4, 801. (c) Kubota, T.; Iijima, M.; Tanaka, T. TL 1992,33,
1351.
4.
(a) Sakamoto, T.; Nishimura, S.; Kondo, Y.; Yamanaka, H. S 1988, 485.
(b) See also: Yamanaka, H.; An-naka, M.; Kondo, Y.; Sakamoto, T. CPB
1985, 38, 4309.
5.
(a) Wittig, G.; Schwarzenback, K. LA 1961, 650, 1. (b) Wittig, G.;

Wingher, F. LA 1962, 656, 18.
Brion, F. TL 1982, 23, 5239.
(a) Kita, Y; Yasuda, H.; Tamura, O.; Itoh, F.; Yuan Ke, Y.; Tamura, Y. TL
1985, 26, 5777. (b) Kita, Y.; Tamura, O.; Itoh, F.; Yasuda, H.; Kishino,
H.; Yuan Ke, Y.; Tamura, Y. JOC 1988, 53, 554. (c) Annunziata, R.;
Cinquini, M ; Cozzi, P. G.; Consolandi, E. JOC 1992, 57, 456.
6.
7.
[13438-45-4]
(.6H2O)
[60553-56-2]
(.xH2O; 'hydrate')
[123334-05-4]
C 14 H 14 O 6 S 2 Zn
(MW 407.81)
(agent for tosylation1 under mild Mitsunobu conditions, usually

with inversion)
Alternate Name: zinc tosylate.
Solubility: insol H2O, benzene.
Form Supplied in: white solid; the 'hydrate' is commercially avail
able.
Preparative Method: anhydrous material1 is prepared when the
precipitate formed from mixture of p-Toluenesulfonic Acid and
Zinc Chloride in water is filtered off and dried in vacuo at rt
for 1 h. Purification is not usually required.
Handling, Storage, and Precautions: no unusual precautions are
noted, but storage in a well stoppered container is advisable.
8.
(a) Colvin, E. W.; McGarry, D.; Nugent, M. J. T 1988, 44, 4157, and
reference 2c. See also: (b) Kita, Y.; Itoh, F.; Tamura, O.; Yuan Ke, Y.;
Tamura, Y. TL 1987, 28, 1431. (c) Reider, P. J.; Grabowski, E. J. J. TL
1982, 23, 2293. (d) Chiba, T.; Nakai, T. CL 1987, 2187. (e) Chiba, T.;
Nagatsuma, ML; Nakai, T. CL 1985, 1343.
9.
10.
Quendo, A.; Rousseau, G. TL 1988, 29, 6443.

(a) Rassmussen, J. K.; Heihmann, S. M. S 1978, 219. (b) Gassman,
P.; Talley, J. J. TL 1978, 3773. (c) Foley, L. H. SC 1984, 14, 1291. (d)
Higuchi, K.; Onaka, M.; Izumi,Y.CC 1991, 1035. (e) Quast, H.; Carlson,
J.; Klaubert, C. A.; Peters, E.-M.; Peters, K.; von Schnering, H. G. LA
1992, 759. (f) Batra, M. S.; Brunet, E. TL 1993, 34, 711.
11.
12.
Tosylate Formation with Inversion of Configuration. Alkyl

tosylates can be formed directly from secondary alcohol function
ality with retention of carbon stereochemistry by treatment with pToluenesulfonyl Chloride and Pyridine. However, conversion of
an alcohol to the corresponding tosylate of opposite stereochem
istry typically requires a minimum of three steps. For example,
inversion of the stereocenter with benzoic acid under Mitsunobu
reaction conditions, hydrolysis of the resulting ester, and finally
conventional tosylation of the alcohol, provides an attractive route
for this transformation.2 A similar route, the inversion of a sec
(a) Hanessian, S.; Guidon, Y. Carbohydr. Res. 1980, 86, C3. (b) Chu,
ondary alcohol directly with p-TsOH, Diethyl Azodicarboxylate
S.-H. L.; Anderson, L. Carbohydr. Res. 1976, 50, 227.
(DEAD),
and Triphenylphosphine, does not produce the desired
Lau, C. K.; Dufresne, C ; Blanger, P. C; Pitr, S.; Scheigetz, J. JOC
tosylate product.1
1986, 51, 3038.
Hanessian, S.; Guidon, Y. TL 1980, 21, 2305.
Modification of this procedure, through the use of bis(ptoluenesulfonato)zinc ((p-TsO)2Zn) with Mitsunobu conditions,
Benedetti, M. O. V.; Monteagudo, E. S.; Burton, G. JCS(S) 1990, 248.
allows this transformation to proceed in a single step.1 Although
somewhat slower than the analogous inversion with benzoic acid,
Glenn J. McGarvey
treatment
of secondary alcohols with (p-TsO)2Zn, DEAD, and
Ph3P gives the desired tosylate product in high yield. This re
action is effective for tosylate formation from either acyclic or
cyclic secondary alcohols with clean inversion of stereochemistry
(eq 1). As expected, this reaction is very sensitive to the steric
hindrance at the reacting sp3 center; moderately hindered alco
hols, e.g. (1), require longer reaction times and greater quantities
of DEAD and Ph3P to undergo the transformation in high yield
(eq 2). Similarly, the use of p-TsOLi is effective for this trans
formation, but yields are slightly lower than those obtained with
(p-TsO)2Zn.
Golinski, M.; Brock, C. P.; Watt, D. S. JOC 1993, 58, 159.

(a) Gassman, P. G.; Gremban, R. S. TL 1984, 25, 3259. (b) See also:
Gassman, P. G.; Haberman, L. M. TL 1985, 26, 4971.
13. (a) Miyoshi, N.; Hatayama, Y.; Ryu, I.; Kambe, N.; Murai, T.; Murai, S.;
Sonoda S 1988, 175. (b) See also: Guidon, Y.; Young, R. N.; Frenette,
R. SC 1981,11,391.
14. (a) Kita, Y.; Shibata, N.; Yoshida, N.; Tohjo, T. TL 1991, 32, 2375. (b)
See also: Kita, Y.; Shibata, N.; Miki, T.; Takemura, Y.; Tamura, O. CC
1990, 727.
15. Fuentes, L. M.; Shinkai, I.; Salzmann, T. N. JACS 1986, 108, 4675.
16.
17.
18.
19.
482
ZINC p-TOLUENESULFONATE
(1)
It was suggested that this anomaly could be explained by the intermediacy of a cyclopropylmethyl/homoallylic species, trapped
by addition of tosylate ion. Indeed, the more vigorous Mitsunobu
reaction 2 of (3a) with benzoic acid leads to a mixture of four
products, confirming involvement of this type of homoallylic re
arrangement.
Although anomalous, it is conceivable that this Mitsunobu pro
cedure could be of use in effecting tosylation with retention in less
common systems in which neighboring group effects, for exam
ple, override the normal stereochemical outcome.
(2)
Tosylation with Retention of Stereochemistry1. Although

dihydrocholesterol (2) undergoes clean tosylation with inversion
in 88% yield using the procedure described above, cholesterol
(3a) itself gives an 85% yield of the 3-tosylate (3b).
1. Galynker, I.; Still, W. C. TL 1982, 23, 4461.

2. (a) Mitsunobu, O.; Eguchi, M. BCJ 1971, 44, 3427. (b) Mitsunobu, O. S
1981, 1.
3. Keinan, E.; Sinha, S. C; Sinha-Bagchi, A. JOC 1992, 57, 3631.
4. Ager, D. J.; East, M.B.T 1992, 48, 2803.
Peter Ham
John R. Stille
Michigan State University, East Lansing, Ml, USA
List of Contributors
Fernando Albericio
Jeffrey S. Albert
Kim F. Albizati
Roger W. Aider
Benjamin A. Anderson
Paul C. Anderson
Toyohiko Aoyama
Alan Armstrong
Jeffrey Aub
Martin G. Banwell
William E. Bauta
T. Howard Black
Andrew N. Boa
Bruce P. Branchaud
John E. Burks, Jr.

O-Benzotriazol-1-y1-N,N,N',N'-tetramethyluroniumHexafluorophosphate
Azidotris(dimethylamino)phosphonium Hexafluorophosphate
40
34

133
University of California, San Diego, CA, USA

276
Methyl fluorosulfonate and Methyl Trifluoromethanesulfonate
278

205
Bio-Mga/Boehringer Ingelheim Research, Laval, Quebec, Canada

Bromodimethylborane
77

422
N,N'-Carbonyldiimidazole
o-Nitrophenol
p-Nitrophenol
93
289
290
99
University of Kansas, Lawrence, KS, USA

2-(t-Butoxycarbonyloxyimino)-2-phenylacetonitrile
81
University of Melbourne, Parkville, Victoria, Australia

Titanium Tetraisopropoxide
389
Sandoz Research Institute, East Hanover, NJ, USA

Benzyl Bromide
45
Eastern Illinois University, Charleston, IL, USA

Magnesium Bromide
253
51
151

361

335
484
LIST OF CONTRIBUTORS
G. Cahiez
Stephen Castellino
Kenneth C. Caster
Bertrand Castro
Andre B. Charette
Jinshan Chen
Raymond E. Conrow
Andre Cornlis
Veronica Cornel
Michael T. Crimmins
Michele M. Cudahy
Edwin C. Davison
David N. Deaton
Lisa A. Dixon
Adrian P. Dobbs
Jean-Robert Dormoy
Robert R. Dykstra
Jill Earley
Universit Pierre et Marie Curie, Paris, France

Benzoyl Chloride
42
Rhone-Poulenc Ag. Co., Research Triangle Park, NC, USA

Tin(IV) Chloride
377
Union Carbide Corporation, South Charleston, WV, USA

1,3-Propanediol
350

Benzotriazol-1-yloxytris(dimethylamino)phosphonium Hexafluorophosphate
445
450
37
Universit de Montral, Qubec, Canada

Lithium Bromide
Lithium Iodide
Lithium Perchlorate
247
249
251

t-Butyldimethylsilyl Trifluoromethanesulfonate
89
Alcon Laboratories, Fort Worth, TX, USA

1,2-Ethanedithiol
1,3-Propanedithiol
175
352

Montmorillonite K10
282
Emory University, Atlanta, GA, USA

68

Isobutene
240

255
257
173
Glaxo Research Institute, Research Triangle Park, NC, USA

166
The R. W. Johnson Pharmaceutical Research Institute, Raritan, NJ, USA

Phosphorus(V) Oxide-Methanesulfonic Acid
343

324

Benzotriazol-1-yloxytris(dimethylamino)phosphonium Hexafluorophosphate
445
450
37

207

2-(Trimethylsilyl)ethoxymethyl Chloride
429
Eric D. Edstrom
Richard A. Ewin
Abdul H. Fauq
Gregory K. Friestad
Paul Galatsis
Timothy Gallagher
Yvan Guindon
Lise-Lotte Gundersen
Andrew D. Hamilton
Niall M. Hamilton
Peter Hamley
Peter Ham
Michael Hanack
Stephen Hanessian
Shoji Hara
Ronald G. Harvey
Alfred Hassner
Richard K. Haynes
W. Christopher Hoffman
485
Utah State University, Logan, UT, USA

322

402
Mayo Foundation, Jacksonville, FL, USA

N,N-Diethylaminosulfur Trifluoride
137

361

Aluminum Chloride
26
3,4-Dihydro-2H-pyrido[l,2-a]pyrimidin-2-one
150

1,2,4-Triazole
399

2-Ethoxy-1 -ethoxycarbonyl-1,2-dihydroquinoline
176
Bio-Mga/Boehringer Ingelheim Research, Laval, Quebec, Canada

Bromodimethylborane
77
Norwegian College of Pharmacy, Oslo, Norway

383

1,3-Dkyclohexylcarbodiimide
133

57
Fisons Pharmaceuticals, Loughborough, UK

Phosgene
328

350
481

410
University of Montreal, Quebec, Canada

91

Boron Tribromide
62
University of Chicago, IL, USA

213
Bar-Ran University, Ramat Gan, Israel

156
Hong Kong University of Science and Technology, Hong Kong

N, N, N', N'-Tetramethylethylenediamine
364
Union Carbide, South Charleston, WV, USA

Ethylene Glycol
188
486
Duy H. Hua
Bret E. Huff
Ian D. Jenkins
Paul R. Jenkins
Paul R.Jenkins
Carl R. Johnson
Keith Jones
Michael E. Jung
Steven A. Kates
Paul Ch. Kierkus
Agnes S. Kim-Meade
Sunggak Kim
David W. Knight
Pierre Laszlo
Ellen M. Leahy
Melissa D. Lee
Hui-Yin Li
Xing-ya Li
Guido Lutterbach

89

84
Griffith University, Brisbane, Australia

454
51
University of Leicester, UK
151

394

Pentafluorophenol
318
327
University of California, Los Angeles, CA, USA

Iodotrimethylsilane
234
436

O-Benzotriazol-l-yl-N,N,N',N'-tetramethyluroniumHexafluorophosphate
40
34
BASF Corporation, Wyandotte, MI, USA

147

Isobutene
240
Korea Advanced Institute of Science and Technology, Taejon, Korea

166
Imidazole
222
225
227

Montmorillonite K10
282

Chlorotrimethylsilane
102
416

Isopropenyl Acetate
244
Du Pont Merck Pharmaceutical Company, Wilmington, DE, USA

358

Johannes Gutenberg University, Mainz, Germany
Lithium Chloride
29
248
Barry Lygo
Percy S. Manchand
Lewis N. Mander
Antonio Garcia Martinez
Patrick G. McDougal
Glenn J. McGarvey
Ross P. McGeary
Mark S. Meier
Gregory Merriman
William J. Middleton
Oyo Mitsunobu
Norio Miyaura
Shahriar Mobashery
Kenneth P. Moder
Bradford P. Mundy
Tetsuya Nagasawa
James S. Nowick
George A. Olah
487
Salford University, UK
1-Hydroxybenzotriazole
220
Hoffmann-La Roche, Nutley, NJ, USA

Ethyl Vinyl Ether
194
The Australian National University, Canberra, Australia

Methyl Cyanoformate
273

Iodotrimethylsilane
79
234
Universitdt Tubingen, Germany

410
Reed College, Portland, OR, USA

400

Zinc Bromide
Zinc Chloride
Zinc Iodide
468
471
479
182
University of Kentucky, Lexington, KY, USA

Phosphorus(V) Oxide
346
341
Hoechst-Roussel Pharmaceuticals, Somerville, NJ, USA

Dimethyl Sulfate
162

Tris(dimethylamino)sulfoniurn Difiuorotrimethylsilicate
464
Aoyama Gakuin University, Tokyo, Japan

454

Boron Trichloride
66

(Methoxycarbonylsulfamoyl)triethylammonium Hydroxide
Bis(trichloromethyl) Carbonate
263
61

333

330
332

Triethylaluminum
404
University of California, Irvine, CA, USA

Lithium Chloride
248

29
488
Helen Osborn
Peter L. Pauson
Andrew N. Payne
Bruce A. Pearlman
Gemma Perkins
Justin G. E. Phillips
Ulf Pindur
Harold W. Pinnick
Robin L. Polt
Richard S. Pottorf
G. K. Surya Prakash
Janet L. Ralbovsky
Tapan Ray
Jayachandra P. Reddy
David C. Rees
Frode Rise
Brian A. Roden
Juliatiek Roestamadji
285
University of Strathclyde, Glasgow, UK

298
Ethyl Chloroformate
183
The Upjohn Company, Kalamazoo, Ml, USA

Acetyl Chloride
16
409
432
278
University of Mainz, Germany

158
Bucknell University, Lewisburg, PA, USA

Benzyl Chloromethyl Ether
50
University of Arizona, Tucson, AZ, USA

9-Fluorenylmethyl Chloroformate
198

191
373
375

29

Di-n-butyltin Oxide
Tris(dimethylamino)sulfonium Difluorotrimethylsilicate
130
464

425
Sandoz Pharmaceuticals, East Hanover, NJ, USA

243
232

2-(Trimefhylsilyl)ethanol
427

57

383
Abbott Laboratories, North Chicago, 1L, USA

Diphenylbis(1,1,1,3,3,3-hexafluoro-2-phenyl-2-propoxy)sulfurane
Hydrazine
165
216
Wayne State University, Detroit, Ml, USA

61
Suzanne M. Ruder
Roger Salmon
Robert G. Salomon
Tarek Sammakia
Paul Sampson
Sylvie Samson
Hiroshl Sano
Adrian L. Schwan
Minoru Sekiya
G. Sennyey
John J. Shay
Takayuki Shioiri
Nigel S. Simpkins
Joel Slade
Barry B. Snider
Ingfried Stahl
G. Richard Stephenson
John R. Stille
Eric J. Stoner
489
Virginia Commonwealth University, Richmond, VA, USA

346

Oxalyl Chloride
307
Case Western Reserve University, Cleveland, OH, USA

Copper(1)Trifluoromethanesulfonate
105
University of Colorado, Boulder, CO, USA

Diazomethane
117
Kent State University, Kent, OH, USA

46
270

Nonacarbonyldiiron
Pentacarbonyliron
290
311
Gunma University, Kiryu, Japan

59

1,1'-Thiocarbonyldiimidazole
368

N-Methyl-N-nitroso-p-toluenesulfonamide
277
SNPE, Vert-le-Petit, France

83

161

422
University of Nottingham, UK
35
Ciba-Geigy Corporation, Summit, NJ, USA

152

136
154
177
269
Universitt Kassel, Germany

Trimethyloxonium Tetrafiuoroborate
419

Nonacarbonyldiiron
Pentacarbonyliron
290
311
Michigan State University, East Lansing, MI, USA

481

2,2'-Dipyridyl Disulfide
170
140
490
Lakshminarayanapuram R.
Subramanian

410
Gary A. Sulikowski

Iodomethane
228

Iodomethane
228
Michelle M. Sulikowski
Akira Suzuki
Keisuke Suzuki
Joseph Sweeney
Peter Szeto
Pascale Taibi
James M. Takacs
Michael J. Taschner
Richard T. Taylor
Yoshiyasu Terao
Albert V. Thomas
Victor J. Tortorelli
Edward Turos
Motokazu Uemura
Kjell Undheim
Christopher J. Urch
Valerie Vaillancourt
Scott C. Virgil

Boron Tribromide
62

Triethylaluminum
404
409
432
l-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide Hydrochloride
186
Wayne State University, Detroit, Ml, USA

263
University of Nebraska-Lincoln, NE, USA

338

440
442
Miami University, Oxford, OH, USA

406

277

168

464
State University of New York at Buffalo, NY, USA

100
Osaka City University, Japan

Hexacarbonylchromium
201

383

418

255
257
Massachusetts Institute of Technology, Cambridge, MA, USA

438
David E. Volk
Simone C. Vonwiller
Jrgen Voss
Michel Wakselman
Michael A. Walters
Qi Wang
Steven M. Weinreb
D. Todd Whitaker
David D. Wirth
Lars-G. Wistrand
Michael S. Wolfe
Peter G. M. Wilts
Jonathan R. Young
Mark W. Zettler
Regina Zibuck
491
North Dakota State University, Fargo, ND, USA

Tin(IV) Chloride
377
The University of Sydney, NSW, Australia

N, N, N', N'-Tetramethylethylenediamine
364
Universitt Hamburg, Germany

2,4-Bis(4-methoxyphenyl)-l,3,2,4-dithiadiphosphetane 2,4-Disulfide
53
CNRS-CERCOA, Thiais, France

123

2,2-Dimethyl-l,3-propanediol
Isopropenyl Acetate
161
244

Detroit Country Day School, Beverly Hills, Ml, USA
2-Methoxypropene
29
425
287
267
394

2-Methoxypropene
287
394
267
Eli Lilly & Co., Lafayette, IN, USA

Thionyl Chloride
370
Nycomed Innovation, Malm, Sweden

355
National Institutes of Health, Bethesda, MD, USA

81

2-Methoxyethoxymethyl Chloride
260
265
96

144
The Dow Chemical Company, Midland, MI, USA

Montmorillonite K10
282

Acetic Anhydride
Index
Links
492
Reagent Formula Index

AgBF4
AlCl3
Aluminum Chloride
BBr3
Boron Tribromide
BCl3
Boron Trichloride
BF4H
BrLi
Lithium Bromide
Br2Mg
Magnesium Bromide
Br2Zn
Zinc Bromide
Br3P
Br5P
C2Cl2O2
Oxalyl Chloride
C2Cl3N
C3Cl6O3
C2F6O5S2
C2H3ClO
Acetyl Chloride
C2H3ClO2
C2H3F3O3S
C2H3N3
1,2,4-Triazole
C2H5AlCl2
C2H5ClO
C2H6AlCl
C2H6BBr2
Bromodimethylborane
C2H6O2
Ethylene Glycol
C2H6O4S
355
26
62
66
361
247
253
468
330
332
307
400
61
410
16
270
278
399
177
96
154
77
188
Index
Links
Dimethyl Sulfate
C2H6S2
1,2-Ethanedithiol
C2H7BF4O
C3H3NO2
Methyl Cyanoformate
C3H4N2
Imidazole
C3H5ClO2
Ethyl Chloroformate
C3H6O
Ethyl Vinyl Ether
C3H8O2
1,3-Propanediol
C3H8S2
1,3-Propanedithiol
C3H9BF4O
C3H9BrSi
C3H9ClSi
C3H9ISi
Iodotrimethylsilane
C4F6O3
C4H10AlCl
C4H10BF3O
C4H10Br2MgO
Magnesium Bromide
C4H10ClO3P
C4H10F3NS
N, N-Diethylaminosulfur Trifluoride
C4H10N2Si
C4H10O3
C4H11BF4O
C4H4BrNO2
C4H4ClNO2
C4H4INO2
493
162
175
361
273
227
183
194
350
352
419
79
102
234
409
136
68
253
144
137
422
406
361
438
438
Index
Links
C4H5NO2
Methyl Cyanoformate
C4H5NO3
C4H6O3
Acetic Anhydride
C4H8
Isobutene
C4H8O
2-Methoxypropene
Ethyl Vinyl Ether
C4H9ClO2
C4H9F3O3SSi
C5FeO5
Pentacarbonyliron
C5H5NOS
C5H8O
C5H8O2
Isopropenyl Acetate
C5H9ClO
C5H9ClO2
C5H12O2
C5H13ClO2SSi
C5H13NO2
C5H14OSi
C6CrO6
C6H4ClNOS
C6HF5O
Pentafiuorophenol
C6H5N3O
C6H5NO3
o-Nitrophenol
494
438
273
225
9
240
267
194
265
432
311
222
147
244
418
83
243
152
161
425
158
427
201
375
318
220
289
Index
Links
p-Nitrophenol
C6H6N4OS
l,l'-Thionylimidazole
C6H7Cl2N
C6H7C1IN
C6H8ClN2O5P
C6H10N2O4
C6H12O
Ethyl Vinyl Ether
C6H15Al
Triethylaluminum
C6H15ClOSi
C6H15ClSi
C6H16N2
N,N,N',N'-Tetramethylethylenediamine
C6H18F6N6P2
C6H18N3OP
C6H18N3P
C6H19NSi2
C7H2Cl4O
C7H5ClO
Benzoyl Chloride
C7H5ClOS
C7H6N4O
N,N'-Carbonyldiimidazole
C7H6N4S
C7H7Br
Benzyl Bromide
C7H7ClO2S
C7H7NO3
C7H10N2
495
290
373
350
99
57
140
454
194
404
429
84
100
364
34
207
213
205
402
42
322
93
368
45
394
287
Index
Links
C7H12N2O
C7H15F3O3SSi
C7H16O3
C7H17NO2
C8Co2O8
C8H6Cu2F6O6S2
C8H7ClO2
C8H8N2O
3,4-Dihydro-2H-pyrido[1,2-a]pyrimidin-2-one
C8H9BrO
C8H9ClO
C8H10N2O3S
C8H12N4
C8HI8ClN3
1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide Hydrochloride
C8H18N2O4S
(Methoxycarbonylsulfamoyl)triethylarnmoniurn Hydroxide
C8H18OSn
Di-n-butyltin Oxide
C9Fe2O9
Nonacarbonyldiiron
C9H7NO2
Methyl Cyanoformate
C9H8Cl3NO
C9H8N2O7
C9H10BF4NO
C9H11BrO2
C9H11ClO2S
C9H21ClSi
496
156
285
89
406
158
298
105
46
150
260
260
50
277
35
186
263
130
290
273
51
173
182
151
255
416
Index
Links
C9H21NO2
C9H27F2N3SSi
C10H8N2S2
C10H18O5
C11H11NO4S
N-Ethy]-5-phenylisoxazolium-3'-sulfonate
C11H16F6N5OP
O-Benzotriazol-1-yl-N,N,N',N'-tetramethyluronium Hexafluorophosphate
C12H10ClOP
C12H10N3O3P
C12H11ClNO2P
C12H11N4O2P
C12H22F6N6OP2
Benzotriazol-l-yloxytris(dimethylamino)phosphoniurn
Hexafluorophosphate
C12H28O4Ti
C13H14N2O3
2-(r-Butoxycarbonyloxyimino)-2-phenylacetonitrile
C13H22N2
C14H14O2P2S4
2,4-Bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4Disulfide
C14H14O6S2Zn
C14H17NO3
2-Ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline
C14H25IN2
C15H11ClO2
C15H18Br2P
C15H39F2N3SSi
C16H19ClSi
C16H22ClIN2O4
497
158
464
170
123
191
40
166
168
324
327
37
389
81
133
53
481
176
276
198
445
464
91
232
Index
Links
C16H36FN
Cl6H42FNO3
C17H21NO2
Cl8H15Cl2P
C18H15P
Triphenylphosphine-yV-Bromosuccinimide
C19H15BF4
C24H54OSn2
C30H20F12O2S
Diphenylbis(1,1,1,3,3,3-hexafluoro-2-phenyl-2propoxy)sulfurane
CBr4
CCl2O
Phosgene
CCl4
CCuF3O3S
CH2N2
Diazomethane
CH3AlCl2
CH3ClO2S
CH3FO3S
CH3I
Iodomethane
CH4BF3O
CH4O3S
CH4O8P2S
Cl2H6N2
Hydrazine
Cl2OS
Thionyl Chloride
498
358
358
158
450
440
442
454
438
436
59
165
440
328
442
105
117
269
257
278
228
68
343
343
216
370
Index
Links
Cl2Zn
Zinc Chloride
Cl3OP
Cl3P
Cl4Sn
Tin(IV) Chloride
Cl4Ti
Cl5P
ClH5N2
Hydrazine
CILi
Lithium Chloride
ClLiO4
Lithium Perchlorate
F5Sb
H12Br2MgO6
Magnesium Bromide
H4N2
Hydrazine
H5N2O
Hydrazine
H6N2O4S
Hydrazine
ILi
Lithium Iodide
I2Zn
Zinc Iodide
I3P
O5P2
Phosphorus(V) Oxide
O10P4
Phosphorus(V) Oxide
499
471
346
333
377
383
335
216
248
251
29
253
216
216
216
249
479
338
341
343
341
Index
Links
500
Subject Index
Acetaldehyde
Acetic Acid
Acetic Anhydride
acetylation
dehydration
oxidation
reaction with N-oxides
related reagents
Acetic Anhydride
Acetic Anhydride-Pyridine
Acetic Formic Anhydride
Acetyl Bromide
Acetyl Chloride
C-acetylation
N-acetylation
S-acetylation
acetylation of alkenes
acetylation of alkynes
acetylation of saturated alkanes
adducts with aldehydes and ketones
cleavage of ethers
coupling with organometallic reagents
dehydrating agent
enol acetylation
esterification
in situ generation of high-valent metal chlorides
nucleophilic acetylation
reaction with heteroatom oxides
related reagents
solvent for organometallic reactions
source of ketene
Acetyl Cyanide
Acetyl Fluoride
Acrolein
Acrylic acid
Acyl Imidazoles
Acyl Silanes
O-Acyl Thiohydroxamates
Acylimidazoles
N-Acylimidazolides
Alcohol Activation
Alcohol Functionalization or Protection
Alkenyl Bromide
Alkyl Bromide
73
10
193
409
17
206
410
22
245
418
44
246
477
9
245
15
19
15-25 42
246
334
22
44
469
15
44
155
178
80
328
255
9-16
9-10
10
10
12
15
133
263
480
157
320
475
95
475
18
21
22
17
17
18
20
20
18
20-1
19
20
21
22
21
22
21
21
275
22
284
150
93
88
223
227
374
1
1-3
247
247
Index
Alkylaluminum halides
N-Alkylimidazoles
-Alkynyl ketones
Alkynylzinc Bromide
Allyl Bromide
Allyl Chloride
Allyl Chloroformate
Allylic Tributylstannyl Silyl Ethers
rearrangement of
Allyltrimethylsilane
Allytributylstannane
Alumina
Aluminum
Aluminum Bromide
Aluminum Chloride
Diels-Alder reactions
Friedel-Crafts reaction
rearrangements
related reagents
Aluminum Chloride
Links
501
93
49
84
200
180
118
64
16
177
67
181
Aluminum enolates
Aluminum Iodide
Amine Protection
Ammonia
Ammonium Tetrafluoroborate
Antimony(III) Chloride
fluorination and transformation of fluorinated compounds
isomerization
preparation of carbocations
onium ions and their salts
rearrangement
related reagents
(Arene)Cr(CO)3 complexes
Arenediazonium Tetrafluoroborates
Arndt-Eistert synthesis
-Aryl carboxylic acids
Aryl halides
Azidotrimethylsilane
Hexafluorophosphate
coupling reagent
diazo transfer reagent
iminophosphonium salt formation
isocyanate formation
71
185
398
75
284
414
136
29-34 278
358
177
374
447
90
95
17
272
90
378
155
163
384
79
26-9
28
26
28
29
97
372
477
155
250
3-4
229
110
139
321
32
30
32
32
32
33
201
361
119
169
110
393
34-5
34-5
35
35
35
Index
Links
l,l'-Azobis-l-cyclohexanenitrile (ACN)
related reagents
Azobisisobutyronitrile (AIBN)
preparation
use in radical chemistry
l,l'-(Azodicarbonyl)dipiperidine
Baker's Yeast
Beckmann rearrangement
Benzenesulfenyl Chloride
Benzenesulfonyl Chloride
(6-Benzene)tricarbonylchromium
Benzohydroxamoyl Chloride
Benzoic Anhydride
Benzonitriles
1,4-Benzoquinone
O-BenzotriazoI-l-yl-N,N,N',N'tetramethyluronium Hexafluorophosphate
related reagents
O-Benzotriazol-l-yl-N,N,N',N'-tetramethyluronium
Hexafluorophosphate
Hexafluorophosphate
amidation
-lactam cyclization
esterification
nucleotide coupling
peptide cyclization
related reactions
Benzotriazol-1-yloxytris(pyrrolidino)phosphonium
Hexafluorophosphate
Benzoyl Chloride
acylation of enol ethers, ketene acetals, and enamines
acylation of enolates, enols, and related reactions
acylation of organometallic compounds
Friedel-Crafts acylation and related reactions
protection of alcohols as benzoates and of amines as
benzamides
related reagents
Benzoyl Trifluoromethanesulfonate
Benzyl Bromide
benzylation of heteroatomic functional groups
reactions with active methylene compounds
reactions with metals and organometallics
related reagents
Benzyl Bromide
Benzyl Chloride
52
502
345
242
45
349
340
398
36
36
35-6
35
35
459
142
405
429
426
204
314
44
316
248
40-2
41
38
133
177
35
177
37-41 133
188
193
39
39
39
39
38
39
42-6
74
44
52
210
152 236
46-50 84
236
262
200
221
41
347
43
42-3
42
43
43-4
44
262
45-6
45
45
45-6
46
262
299
272
Index
Links
503
activation of pyridine ring towards nucleophilic attack

decarboxylative esterification of carboxylic acids
generation of other benzyloxycarbonylating agents
N-protection reactions
protection of alcohols and phenols
protection of amines
protection of thiols
related reagents
alcohol protecting group
alkylation of carbanions
amine protecting group
benzyloxymethyl anion
related reagents
Benzyl Chloromethyl Sulfide
Benzyl halides
Benzyl Iodide
Benzyl Isopropenyl Ether
Benzyl p-Toluenesulfonate
hydroxy group protection
related reagents
Benzyl Trifluoromethanesulfonate
Benzyltriethylammonium Chloride
Benzyltrimethylammonium Dichloroiodate
Benzyltrimethylammonium Tribromide
Bischler-Napieralski reaction
Bis(1,5-cyclooctadiene)nickel(0)
1,8-Bis(dimethylamino)naphthalene
Bis(2,4-dinitrophenyl) Carbonate
1,2-Bis(diphenylphosphino)ethane Tetrabromide
2,4-Bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane
2,4-Disulfide
dithioesters and related compounds
lactones
thio analogs of dicarbonyl compounds
thioamides and related compounds
thioketones
thionation of carbonyl compounds
thiono esters
carboxyl group activator
kinetic resolution
dehydrosulfurizations
hydrolysis
45
50-1
98
266
51
98
46
52
46
46
152
52
308
156
57-9
48
48
49
48
48
47
48
49
149
431
50
50
50
50
51
266
314
262
268
46
51-3
51
52-3
262
152
394
476
476
346
369
278
185
332
53-7
55
55
54-5
55-6
53-4
53
55
133
57
58
59-61
60
60
Index
Links
504
N-activations
O-activations
oxidations
related reagents
carbonylation
N-carboxyamino acid anhydrides
chlorination
chloroformylation
dehydration
oxidation
related reagents
Bis(tricyclohexyltin) Sulfide-Boron Trichloride
Bis(trimethylsilyl) Peroxide
N,O-Bis(trimethylsilyl)acetamide
N,N'-Bis(trimethylsilyl)urea
Borane-Tetrahydrofuran
Boron Tribromide
bromoboration reactions
chiral bromoborane reagents
reduction of sulfur compounds
related reagents
removal of protecting groups
substitution reactions
Boron Trichloride
cleavage of ethers, acetals , and esters
condensation reactions
related reagents
synthesis of organoboron reagents
Boron Trifluoride
addition reactions
aldol reactions
bromination
cleavage of ethers
cyclizations
epoxide cleavage
hydrolysis
rearrangements
Boron Trifluoride Etherate (cont.)
reductions
related reagents
61-2
62-6
75
9
117
330
105
105
78
68
79
65-8
79
177
283
29
147
90
161
59-60
59-60
59
60
132
349
61
61
62
61
61
62
62
68
451
206
206
427
77
97
64
64
64
65
63
64
260
66
67
68
67
452
68-77
69
70
74
73
71
71
74
72-3
73
72-3
74
75
97
181
Index
Links
Bromine
scavenger
Bromine-Triphenyl Phosphite
4-Bromobenzenesulfonyl Chloride
4-Bromobenzyl Chloroformate
Bromobis(isopropylthio)borane
9-Bromo-9-borabicyclo[3.3.1]borane
9-Bromo-9-borabicyclo[3.3.1]nonane
B-Bromocatecholborane
Bromodimethylborane
cleavage of acetals
cleavage of ethers
interconversion of functional groups
related reagents
Bromomagnesium Diisopropylamide
3-Bromo-l,2-propanediol
N-Bromosuccinimide
bromolactonization
cleavage of acetals
cleavage of epoxides
cleavage of esters
cleavage of ethers
cleavage of phosphonate esters
conjugate addition
formation of alkyl bromides
formation of enol ethers
formation of ylides
reaction with acid chlorides
reaction with amines
related reagents
-Bromo--vinyl ketones
Burgess reagent
2,3-Butanediol
t-Butoxybis(dimethylamino)methane
l-(t-Butoxycarbonyl)-lH-benotriazole 3-N-oxide
l-(t-Butoxycarbonyl)imidazole
alcohol protection
amine protection
related reagents
505
250
378
253
384
34
211
59
330
303
404
470
64
332
445
332
49
63
84
65
200
79
63
65
63
65
77-9
260
65
79
81
265
59
162
93
190
139
96
238
334
162
190
84
84
81-4
367
422
474
79
390
465
21
445
426
272
96
79
78
96
96
340
77-8
77
78
79
103
351
360
79-81
81
80
80
79-80
80
80
81
80
80
81
80
80
81
449
447
263
351
161
129
129
129
82
81
83
Index
Links
506
N-(t-Butoxycarbonyloxy)phfhalimide
N-(t-Butoxycarbonyloxy)succinimide
N-(t-Butoxycarbonyl)-1,2,4-triazole
t-Butyl Azidoformate
t-Butyl Carbamates
t-Butyl Carbonates
t-Butyl Chloroacetate
protection of amino groups
related reagents
t-Butyl Chloromethyl Ether
t-Butyl Hydroperoxide
t-Butyl 2,2,2-Trichloroacetimidate
83
83
83
49
51
132
acid chlorides
aldol reaction
anion trap
Claisen rearrangement
conjugate additions
N-formylation
Mannich reaction
modified amine base
protecting group
reaction with nucleophiles
related reagents
silyl ketene acetals
TBDMS enol ethers
TBDMSC1 as Cl- source
TBDMSCl-assisted reactions
t-Butyldimethylsilyl Cyanide
Butyldimethylsilyl Iodide
t-Butyldimethylsilyl Perchlorate
activation
chromones
conjugate addition of alkynylzinc aromides
formation of enol silyl ethers
interconversion of N-boc group into N-alkoxycarbonyl group
phosphoniosilylation
pyridine
rearrangement of allylic tributylstannyl silyl ethers
related reagents
silylation
silylation of alcohols
transalkylation of tertiary amine N-oxides
84
84
84
84
98
201
83
129
266
228
84-9
101
91
360
87
129
129
129
129
84
84
272
83-4
83
84
124
200
431
393
242
92
417
87
86
85
85-6
87
88
87
88
84
87
88
85
86
86
86-7
88
87
91
89-91
90
90
90
89-90
91
90
90
90
91
90
89
91
Index
Links
507
85
101
87
417
88
88
91-2
t-Butyldimethylsilyl Trifluorosulfonate
N-(t-Butyldimethylsilyl)-N-methyltrifluoroacetamide
deprotection
preparation of t-butyldiphenylsilyl ethers and related
transformations
related reagents
selectivity and compatibility of O- and N-t-butyldiphenyl silyl
derivatives
t-Butyldiphenylsilyl Ethers
n-Butyllithium
51
85
144
255
417
s-Butyllithium
208
t-Butyllithium
148
n-Butyllithium-Boron Trifluoride Etherate
n-Butyllithium-Potassium f-Butoxide
Butyllithium/(-)-Sparteine
n-Butyltrichlorostannane
Cadmium Chloride
10-Camphorsulfonic Acid
Carbenium Tetrafluoroborate
Carbodiimides
Carbohydrate Activation/Glycosylation
Carbon Dioxide
90
164
260
422
365
195
Carbon Disulfide
134
183
275
164
323
208
57
188
275
93-6
192
374
Carbon Monoxide
Carbon Oxysulfide
Carbon Tetrabromide
Carbonates
Carbonyl Activation or Functionalization
Carbonyl compounds, thionation of
Carbonyl Protection
N,N'-Carbonyldiiniidazole
activation of carboxylic acids

C-acylation of active methylene compounds
aldehydes and ketones from carboxylic acids
amides from carboxylic acids
carbonates
dehydration
esters from carboxylic acids
92
435
88
91
417
92
92
92
103
183
364
430
392
209
100
134
92
92
112
215
396
441
405
261
75
364
124
268
115
261
362-3
316
7
195
365
265
370
299
275
440
94
5-6
53
5
173
227
376
93
94
94
94
94
95
93
Index
Links
508
glycosidation
halides from alcohols
peptide synthesis
related reagents
synthesis of acyl imidazoles
tetronic acids
ureas
N,N'-Carbonyldi-sym-triazine
Carbonylhydridotris(triphenylphosphine)rhodium(I)
iV-Carboxyamino Acid Anhydrides
Carboxyl Activation
Carboxylic acids
activation
aldehydes from
amides from
esterification
esters from
ketones from
Carboxylic Esters
Catechylphosphorus Trichloride
Cerium(III) Acetate-Boron Trifluoride Etherate
Cerium(IV) Ammonium Nitrate
Cesium Carbonate
Cesium Fluoride
4-5
93
p-Chloranil
Chloride-Dimethylaminopyridine
Chlorine
(+)-B-Chlorodiisopinocampheylborane
Chlorodiphenylphosphine
2-Chloroethyl Chloromethyl Ether
285
230
360
265
425
21
51
3-Chloro-1-hydroxytetrabutyldistannoxane
Chloromethane
cleavage of MOM ethers
cleavage of phenolic MOM ethers
protection of acids
protection of alcohols
protection of amine derivatives
protection of phenols
related reagents
use in C-C bond-forming reactions
Chloromethyl Methyl Sulfide
260
98
266
178
51
51
431
98
149
469
266
95
95
94
95
93
94
94
94
95
300
61
7
99
94
94
117-18
93
94
315
68
75
313
127
359
466
284
259
450
266
228
149
431
132
229
96-8
96
97
97
96
97
97
97
97
97
266
477
431
Index
Links
Chloromethyleneiminium Chlorides
Chloromefhyleneiminium Ions
2-Chloro-1-methylpyridinium Iodide
amide synthesis
carbodiimides from thioureas
ester formation
ketene formation
-lactam synthesis
lactone formation
(Chloromethyl)trimethylsilane
Chloroperbenzoic Acid
m-Chloroperbenzoic Acid
3-Chloro-l,2-propanediol
N-Chlorosuccinimide-Dimethyl Sulfide
related reagents
conjugate addition reactions

conversion of ketones to vinylsilanes
epoxide cleavage
formation of silyl esters
in situ generation of iodotrimethylsilane
mild deprotection of Boc protecting group
protection of alcohols as TMS ethers
protection of terminal alkynes
related reagents
transient protection
Chlorotrimethylsilane-Tin(II) Chloride
Chlorotriphenylsilane
Chlorotris(triphenylphosphine)rhodium(I)
Chromium(VI) Oxide
Chromones
Chromyl Chloride
Claisen rearrangement
Cobalt(II) Chloride
2,4,6-Collidinium p-Toluenesulfonate
Copper(II) Acetylacetonate
Copper(I) Chloride
Copper(II) Chloride
Copper(I) Cyanide
Copper(I) Iodide
Copper(II) Nitrate-K10 Bentonite Clay
509
99-100 157
21
92
199
247
79
101-5
205
260
432
81
161
206
366
435
88
101
127
122
367
139
220
336
346
403
99
99
100
99
99
99
99
427
11
422
283
334
100-2
101
84
172
238
427
475
104-5
104
104
103
104
104
102
103
105
103
149
417
169
211
90
21
136
14
189
106
422
187
398
44
366
282
Index
Links
510
Copper(I) Oxide
Copper(II) Tetrafluoroborate
O-acylation with thioesters
asymmetric aziridination
catalyzed Diels-Alder reactions
chain-extending syntheses of -phenylsulfenyl ketones
Cs p-H bond activation
cyclopropanation of enones
cyclopropanation with diazo compounds
elimination of benzylic phenyl thioethers
elimination of thiophenol from thioacetals
Friedel-Crafts acylation with thio- or sele-noesters
Grob fragmentation of -[Bis(phenylthio)methyl]-alkoxides
heterocyclization of--keto dithioacetals
hydrolysis of vinylogous thioacetals
photocycloadditions
ring-expanding rearrangements of
-[Bis(phenylthio)methyl]alkanols
vinylcyclopropanation of enones
Copper(II) Trifluoromethanesulfonate
Corey-Hopkins reagent
Corey-Winter alkene synthesis
Crotonaldehyde
111
15-Crown-5
18-Crown-6
Cyanotrimethylsilane
l-Cyclohexyl-3-(2-morpholinoethyl)carbodiimide
l-Cyclohexyl-3-(2-morpholinoethyl)carbodiimide
Metho-p-toluenesulfonate
Dakin-West reaction
Darzens-Nenitzescu reaction
Diaryl Disulfides
l,4-Diazabicyclo[2.2.2]octane
l,8-Diazabicyclo[5.4.0]undec-7-ene
Diazoacetophenone
Diazomethane
additions to electron-deficient species

additions to ketones
Arndt-Eistert synthesis
cycloadditions with diazomethane
-diazo ketones
105
206
405
106
356
105-16
115
106
110
113-14
110
114
106
112
111
114
112-13
112
112
107-10
179
184
10
229
300
470
87
273
367
475
188
10
93
227
124
328
272
420
162
277
421
165
300
422
117-23
113
114
340
105
368
316
245
63
92
321
392
480
193
133
158
27
172
329
432
75
230
397
479
122
121
119
121
119-20
Index
Links
esterification of carboxylic acids and other acidic functional

groups
insertions into aldehyde C-H bonds
methylation of alcohols and other less acidic functional groups
methylation of heteroatoms
related reagents
vinylogous Wolff rearrangement
Diazonium salts
2-Diazopropane
l-Diazo-2-propene
Dibenzoyl Peroxide
1,2-Dibromoethane
Dibromomethane
Dibromomethane-Zinc-Titanium(IV) Chloride
activation of the carboxyl group
t-Butoxycarbonylation of amides
lactams, and carbamates
t-butoxycarbonylation of amines
t-butoxycarbonylation of carbanions
t-butoxycarbonylation of imines
t-butoxycarbonylation of phenols
alcohols, enols and thiols
N-t-butoxycarbonylation of pyrroles and indoles
exchange of amino-protecting groups
formation of esters and anhydrides
Dibutylamine
Dibutylmagnesium
2,6-Di-t-butylpyridine
Dibutylstannylenes, formation and reactions
Di-n-butyltin Oxide
45
catalyst in oxidation reactions
esterification catalyst
regioselective alkylation
acylation and sulfonylation
regioselective oxidation
related reagents
Dicarbonyl compounds
thio analogs of
Dicarbonyl(cyclopentadienyl)cobalt(I)
1,1-Dichloroalkenes
Dichloro-bis(cyclopentadienyl)titanium
Dichloroborane Diethyl Etherate
2,3-Dichloro-5,6-dicyano-l,4-benzoquinone
151
Dichloromethylenetriphenylphosphorane
37
157
188
511
117-18
120-1
118-19
117
122
120
314
122
122
398
253
383
388
123-30
128
82-4
126-8
124-6
128
129
130-3 323
126
128
126
128
283
367
279
130
394
132
131-2
130-1
131
132
300
301
244
260
99
167
192
127
177
219
54-5
305
444
269
334
465
444
133-35
186
220
Index
Links
512
223
319
amide formation
anhydride formation
dehydration to alkenes
epoxides, nitriles and ketenes
dehydrative-type couplings
dehydroxylation of alcohols
ester formation
heterocyclization reactions
inversion of secondary alcohols
oxidation of alcohols to aldehydes and ketones
phosphate esters
sulfinate esters
thioester formation
Dicyclohexylcarbodiimide-4-Dimethylaminopyridine
Dicyclohexyl(ethyl)amine
Dienol Acetates
competition between ene and Diels-Alder reactions
dealkylation of amines
Diels-Alder [4+2] Cycloadditions
ene reactions
functional group oxidations by dehydrogenation
pericyclic reactions
purine synthesis
related reagents
Diethyl Carbonate
Diethyl Diazomethylphosphonate
Diethyl Phenyl Orthoformate
Diethyl Phosphorobromidate
deoxygenation of phenols and ketones
interconversion of carboxylic acid derivatives
phosphorylation
related reagents
synthesis of alkenes and alkynes
Diethyl Phosphorocyanidate
29
181
catalysis of Claisen rearrangement
catalysis of Diels-Alder reactions
catalysis of ene reactions
225
325
376
276
328
400
28
74
142
154
245
251
380-1
110
178
284
385
140-3 169
250
183
38
136-7 154
252
270
146
156
379
287
350
403
133
133
134
134
134-5
133
135
135
134
134
134
133
133
162
136
196
300
479
245
481
142
141
142
141
140
141
141
142
275
106
408
146
144-6
145
145
144
146
145
325
178
405
136
136
136
Index
Links
catalysis of vinylcyclopropane rearrangement

formation and reaction of alkynylaluminum reagents
formation and reaction of aluminum enolates
generation of electrophilic cations
reaction as nucleophile
related reagents
Diethylaluminum Cyanide
Diethylaluminum Iodide
N,N-Diethylaminosulfur Trifluoride
fluorodehydroxylation of alcohols
geminal difluorination of aldehydes and ketones
N,N-Diethylaminosulfur Trifluoride (cont.)
reaction with epoxides
reaction with halides and sulfonates
reaction with organic acids
reaction with sulfoxides
related reagents
anion chemistry
cleavage of tetrahydropyranyl derivatives
electrophilic addition to dehydropyran
functional group manipulation of tetrahydropyranyl
derivatives
related reagents
ring opening reactions of dihydropyran
tetrahydropyranylation of alcohols
tetrahydropyranylation of amides
tetrahydropyranylation of amines
tetrahydropyranylation of thiols
3,4-Dihydro-2H-pyrido[1,2-a]pyrimidin-2-one
glycosylation
synthesis of amides from carboxylic acids
synthesis of esters from carboxylic acids
Diimide
Diiodomethane
Diiodomethane-Zinc-Titanium(IV) Chloride
Diiodosilane
Diisobutylaluminum Hydride
Diisopropylamide
Diisopropylamine
Diisopropylethylamine
a-Diketones
Dilithium Tetrachloropalladate(II)
related reagents
3,4-Dimethoxybenzyl Ethers
513
136
137
136
136
137
137
405
181
464
138
138
137-40
148-9 196
74
94
37
185
40
238
46
52-3
268
139
139
139
139
140
147-50
283
147-8
149
148
149
148
147
148
148
148
150-2
150
150
150
217
383
405
388
340
405
476
301
278
285
97
133
265
367
422
444
447
248
151-2 262
152
151
Index
Links
514
Dimethoxycarbenium Tetrafluoroborate
1,1-Dimethoxyethane
Dimethoxymethane
acetonide formation
aldol condensation with enol silyl ethers
esterification of amino acids
isopropylidene derivatives of sugars and nucleosides
related reagents
Dimethyl Acetylenedicarboxylate
Dimethyl Boronate Esters
Dimethyl Sulfate
122
C-alkylation
N-alkylation
O-alkylation
S-alkylation
related reagents
Dimethyl Sulfide
Dimethyl Sulfone
Dimethyl Sulfoxide
62
Dimethyl Sulfoxide-Acetic Anhydride

Dimethyl Sulfoxide-Dicyclohexylcarbodiimide
Dimethyl Sulfoxide-Oxalyl Chloride
Dimethyl Sulfoxide-Phosgene
Dimethyl Sulfoxide-Phosphorus Pentoxide
Dimethyl Sulfoxide-Silver Tetrafluoroborate
Dimethyl Tartrate
N,N-Dimethylacetamide Dimethyl Acetal
281
29
154-6 178

formation and reaction of alkynylaluminum reagents
formation and reaction of aluminum enolates
reaction as a nucleophile
related reagents
Dimethylaluminum Iodide
acylation of alcohols
acylation of amines
direct esterification of alcohols and carboxylic acids
9
126
205
272
408
196
98
149
247
152-4 267
268
152-3
153
153
153
153
245
153
162-5 230
278
281
420
421
164
164
162
164
165
230
278
92
212 230
328
409
10
10
309
410
330
342
356
78
161
136
137
148
181
252
270
154
154
156
155
155
156
156
156
181
20
84
92
133
156-8 187
223
226
227
320
322
366
376
394
416
157
157
157
Index
Links
515
related reagents
silylation, tritylation, and sulfinylation of alcohols
N-(Dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1ylmethylene]-Af-methylmethanaminium
Hexafluorophosphate N-Oxide
(4R,5R)-2,2-Dimethyl-4,5-bis(hydroxydiphenylmethyl)-1,3dioxolane-Titanium(IV) Chloride
Dimethylchloromethyleneammonium Chloride
N,N-Dimethylformamide
alkylation reactions
formylation reactions
related reagents
N,N-Dimethylformamide/Dimefhyl Sulfate
N,O-Dimethylhydroxylamine
Dimethyliodonium Hexafluoroantimonate
Dimethyl(methylene)ammonium Iodide
l,3-Dimethyl-2-phenylbenzimidazoline
Dimethyl(phenyl)silane
2,2-Dimethyl-l,3-propanediol
cyclic acetals
related reagents
use as boron ligand
N,N-Dimethylpropionarmde Dimethyl Acetal
N,N'-Dimethylpropyleneurea
Dimethylsulfonium Methylide
Diols, protection as ketals
Diphenyl Diselenide
Diphenyl Ditelluride
41
amination of aromatic and
heteroaromatic organometallics
metal-catalyzed decarbonylation of primary aldehydes
peptide synthesis
related reagents
ring contraction reactions
stereospecific conversion of alcohols to azides
synthesis of macrocyclic lactams
Diphenyl Phosphorochloridate
158
157
41
388
337
408
210
212
336
346
408
158-61
408
159
159
161
189
164
271
281
236
339
466
161-2 190-1 351
161
162
162
161
165 207 212
164
3
300
207
168-70
422
458
Diphenylbis(1,1,1,3,3,3-hexafluoro-2-phenyl-2-propoxy)sulfurane
cleavage of amides
dehydration of alcohols
epoxides
oxidation of amines
161
168
336
372
328
371
370
170
226
169
169
169
170
169
169
170
188
325
165-6
166
165
165-6
166
Index
Links
Diphenyldiazomethane
Diphenylketene
Diphenylmercury
Diphenylphosphine
acid activation
amination
phosphine oxides
protection of amino groups
Diphenylsilane-tetrakis(triphenylphosphine)palladium(O)-Zinc
Chloride
Diphosphorus Tetraiodide
97
Di-2-pyridyl Carbonate
alkene formation
disaccharide formation
macrolactonization
related reactions of 2-pyridinethiol esters
2,2'-Dipyridyl Disulfide/Triphenylphosphine
active ester preparation in peptide chemistry
carbamate preparation
carbonyl insertions
a-eliminations
related reagents
Di(N-succinimidyl) Oxalate
1,3-Dithiane formation
Dithioesters and related compounds
1,3-Dithiolane
Di-p-tolylcarbodiimide
Dodecacarbonyltriiron
Eaton's reagent
Epichlorohydrin
1,2-Ethanedithiol
gem-difluoride formation
dithiolenium ion formation
ether cleavage
reduction
related reagents
Ethanethiol
Ether Formation
2-Ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, peptide
synthesis
1-Ethoxy-l-propene
Ethyl Chloroformate
O-acylations
N-acylations
516
122
300
207
36
320
166
167-8
167
167
166-8
216
340
170-3
173
73
175-6
28
49
193
176
84
200
477
430
157
376
172
171
170
171
99
173-4
173
173
173
173
174
174
352
55
175
188
204
344
283
354
175
175
175
175
176
354
2
176-7
196
183-6
272
184
184
Index
Links
S-acylations
ethoxycarbonylation of active methylene compounds
ethoxycarbonylation of vinyl anions
mixed anhydrides
Ethyl Diazoacetate
Ethyl Trimethylsilylacetate
Ethyl Vinyl Ether
acetal condensations
acyl anion equivalents
cycloaddition reactions
photochemical
protection of hydroxyl group
related reagents
transvinylation
18
29
154
156
catalysis of [2 + 2] cycloadditions
catalysis of intramolecular Sakurai reactions
elimination reactions
modification of carbanions
nucleophilic addition
related reagents
peptide coupling
reactions with nucleophiles
Hydrochloride
amide formation
ester formation
oxidation of primary alcohols
peptide coupling reagent
protein modification
related reagents
1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide Hydrochloride
Ethylene
Ethylene Chloroboronate
Ethylene Glycol
162
acetal formation
related reagents
solvent effects
Ethyllithium
Ethylmagnesium Bromide
517
184
183
183-4
185
67
106
241
427
149
194-7 268
195
195
195
196
196
196
194-5
196
195
73
136
137
177-81
270
179
178
178-9
179
180
179
180
180
181
182-3
182
182
133
178
188-91
87
87
137
137
186-8
187
187
188
186-7
187-8
188
193
364
190
351
189
190
190
365
210
191-4
Index
Links
518

protein modification
reduction of carboxylic acids to alcohols
related reagents
1-Ethylpiperidine
Ferrario reaction
Fischer Indole synthesis
49
84
amine and hydroxyl protection for nucleosides
carbohydrates, and natural products
FMOC derivatization for fluorescence detection and analysis
related reagents
N-terminus blocking in peptide synthesis
Fluorosulfuric Acid
Fluorosulfuric Acid-Antimony(V) Fluoride
Fluorotrimethylsilane
Formaldehyde
198-200
154
Formic Acid
Friedel-Crafts acetylation
Friedel-Crafts acylation
43
114
343
Friedel-Crafts alkylation
15
26
178
Furan
Grignard reagents
activation of benzylic position
hydrogenation and isomerization of dienes
lithiation
nucleophilic substitution
oxidation
related reagents
steric effect of Cr(CO)3 group
Hexacarbonylmolybdenum
Hexachloroacetone
Hexamethyldisilane
amination reactions
related reagents
silylation
Hexamethyldisiloxane
229
245
22
227
105
92
365
192
193
193
193
188
325
27
344
272
199
199-200
200
198-9
30
278
33
465
178
179
431
477
285
16
180
284
387 409
344
29
30
241 409
364
417
473
201-5
202-3
201
202
201-2
201
204
203
304
451
79
466
205-6
206
206
205
102 105
236
341
206 342
104
207-14
367
371
Index
Links
519
anion reactivity
carbanion formation
carbanion reactivity
carbanion regioselectivity
effect on protonation
enolate formation
enolate reactivity
enolate stereochemistry
hydride reductions
inhibition by
low-valent metal coordination
nucleophilic cleavage of esters and ethers
organolithium reagent solution structure
oxidation
related reagents
substitutes and analogs
transition metal coordination
ylide reactivity
Hexamethylphosphoric Triamide-Thionyl Chloride
212
34
conversion of alcohols to alkyl chlorides and other derivatives

conversion of disulfides to sulfides
deoxygenation of sulfoxides and azoxyarenes
preparation of mixed carbonates
reduction of ozonides
related reagents
synthesis of arene oxides
synthesis of epoxides
Horner-Wittig reactions
Hunsdiecker reaction
Hydrazides
Hydrazine
35
heterocycle synthesis
peptide synthesis
reductions
Hydrazoic Acid
Hydrazones
Hydrobromic Acid
Hydrochloric Acid
Hydroformylation
Hydrogen Bromide
65
Hydrogen Bromide-Trifluoroacetic Acid
Hydrogen Chloride
Hydrogen Cyanide
Hydrogen Fluoride
20
68
194
372
37
221
216
81
255
97
334
17
210
208
208
208
211
207
207
208
211
211
210
210
207
211
212
211
210-11
209
420
213-16
281
215
215
215-16
216
216
216
214
214
215
224
218
270
218
219
217
458
218
470
283
298
238
332
148
147
372
405
75
Index
Links
520
Hydrogen Fluoride-Antimony(V) Fluoride

Hydrogen Iodide
Hydrogen Peroxide
Hydrogen Sulfide
Hydrogenation
3-Hydroxy-1,2,3-benzotriazine-4(3H)-one
nucleotide synthesis
peptide coupling
related reagents
Hydroxyl Activation
Hydroxylamine
alcohol deoxygenation
decarboxylation
decarboxylative hydroxylation
decarboxylative phosphorylation
decarboxylative rearrangement
decarboxylative sulfonation
formation of sulfides
selenides, tellurides, and selenocyanates
related reagents
peptide bond formation
Hypophosphite esters
Hypophosphorous Acid
Imidazole
diol deoxygenation
epoxidation
ester hydrolysis
iodination of alcohols
peptide coupling
silylations
Imidoyl Chlorides
Iodine
Iodomethane
124
238
250
66
37
187
133
188
319
167
225
323
133
187
158
286
39
158
320
439
84
205
328
446
148
228
390
99
171
95
164
33
340
217
206
298
222
220-2
221
220
222
158
286
400
7
244
222-5
223
223
224
224
223
224
223
225
370
225-6
225-6
173
376
153
153
92
227-8
416
451
228
228
227
228
227
227
336
334
435
115
228-32
Index
Links
521
276
420
S-alkylation
C-methylation
N-methylation
O-methylation
P-methylation
Iodomethylzinc Iodide
cis-oxyamination
'-linked disaccharides
vicinalcis-diols
Iodosylbenzene
Iodotrimethylsilane
206
acetalization catalyst
Iodotrimethylsilane (cont.)
carbonyl addition reactions
catalyst for a-alkoxymethylation of ketones
catalyst for reactions of acetals with silyl enol ethers and
allylsilanes
cleavage of acetals
cleavage of carbamates
cleavage of cyclopropyl ketones
cleavage of epoxides
cleavage of phosphonate and phosphate esters
conjugate addition reactions
conversion of vinyl phosphates to vinyl iodides
ester dealkylation
ether cleavage
halogen exchange reactions
halogenation of lacltams
lactone cleavage
Lewis acid
nucleophilic addition reactions
nucleophilic reagent in bond cleavage reactions
reaction with carbanions
reaction with imines
reaction with nitro and nitroso compounds
reaction with oximes
reaction with phosphine oxides
reaction with sulfonyl halides
rearrangement reactions
reducing agent
278
421
353
441
230-1
229
231
230
231
480
165
232-4 426
232-3
233-4
234
358
363
69
79
81
96
104
105
145
147
205
234-40
250
260
266
270
334
340
435
237
236
237
237
235
235
236
235
236
236
236
235
235
236
237
235
237
236
235
237
238
238
238
238
238
238
237
Index
Links
reduction of '-ketols
related reagents
silylating agent
silylation of alkynes and alkenes
sulfoxide deoxygenation
Iron Carbene
Iron Carbonyl
Iron(III) Chloride
Iron(III)-doped montmorillonite
Iron-Graphite
Iron(III) Nitrate-K10 Montmorillonite Clay
Isobutene
acid-catalyzed cycloadditions
alkylation reactions
carbene chemistry
ene reactions
photochemical cycloadditions
protection for carboxy group
protection for hydroxy group
related reagents
cyclodehydration
5'-hydroxy function blocking agent for deoxyribosides
N-protection
regioselective arylation
Isobutyl Sulfonate
Isopropenyl Acetate
acetylation of other O, N and C centers
aldol reactions
as source of acetone
enol acetylation
related reagents
selective generation of (E)- or (Z)-enol acetates
selective generation of kinetic and thermodynamic enol
acetates
Isoselenocyanatotrimethylsilane
Ketals, protection of diols as
Khand reaction
Knoevenagel reaction
Lawesson's reagent
Lead(IV) Acetate
Lewis Acids
activation by
promoted reactions
522
13
67
179
188
49
185
84
188
200
243-4 272
15
29
251
131
237
405
237
238
236-7
237
237
316
316
404
284
339
282
240-3
242
241
241
241
240-1
240
240
242
177
193
223
418
244
243
243-4
244
244
244-6
245
246
246
244
246
245
244-5
475
3
304
386
53
248
248
437
8
6
Index
Links
523
Lithium Acetylide
Lithium Aluminum Hydride
334
Lithium Aluminum Hydride-Aluminum Chloride
Lithium Aluminum Hydride-Boron Trifluoride Etherate
Lithium Aluminum Hydride-Titanium(IV) Chloride
Lithium Borohydride
Lithium Bromide
additive for organometallic transformations
bifunctional reagents
heterolytic cleavage of C-X bonds
related reagents
Lithium Carbonate
Lithium Chloride
related reagents
source of chloride ligand
source of chloride nucleophile
Lithium Chloride-Diisopropylethylamine
Lithium Chloride-Hexamethylphosphoric Triamide
Lithium Di-n-butylcuprate
Lithium Diisopropylamide
Lithium Dimethylcuprate
Lithium Fluoride
Lithium Hexamethyldisilazide
Lithium Hydroxide
Lithium Iodide
92
227
367
94
261
427
384
13
247-8 250
139
90
183
205
additive for organometallic-mediated transformations

alkyl and alkenyl iodides
C-C bond forming reactions
heterolytic C-X bond cleaving reactions
reduction of '-alkoxycarbonyl derivatives
related reagents
Lithium Perchlorate
epoxide opening
Lewis acid catalyst for cycloaddition reactions and carbonyl
addition reactions
related reagents
ring expansion
[l,3]-sigmatropic rearrangements
Lithium Tetrafluoroborate
Lithium 2,2,6,6-Tetramethylpiperidide
144
2,6-Lutidine
Magnesium
Magnesium Amalgam
247
97
184
210
210
212
100
103
207
229
248
340
252
248
231
74
160
270
476
148
75
388
393
427
247
247
247
247
230
248-50
249
248
248
249
249
366
165
365
441
360
86
127
249-50
409
250
250
250
249-50
250
250
251-2
251 -2
251
252
252
251
428
365
278
253
388
Index
Links
Magnesium Bromide
bromination
carbonyl condensations
cycloadditions
Magnesium Bromide (cont.)
nucleophilic additions
organometallic reactions
rearrangements
Manganese(III) Acetate
Manganese Dioxide
Markovnikov addition
Mercury(II) Acetate
Mercury(II) Chloride
Mercury(II) Oxide
Mercury(II) Oxide-Bromine
Mercury(II) Sulfate
Mercury(II) Trifluoroacetate
Mercury(II) Trifiuoroacetate/Lithium Carbonate
nucleotide synthesis
sulfinate ester synthesis
sulfonamide formation
sulfonate formation
sulfonylalkyne synthesis
Mesitylenesulfonylhydrazide
Methanesulfonates
Methanesulfonic Acid
524
13
79
252-4 422
470
21
69
255-7 415
11
339
acyliminium cyclizations
addition across alkenes and alkynes
chlorination
eliminations
heterocycles
interconversion of carboxylic acid derivatives
lactone inversion
rearrangement of thioacetals to aldehydes
related reagents
synthesis of vinyl and allyl sulfones
Methanesulfonyl Chloride Chloride-Dimethyl aminopyridine
Methanethiol
Methanol
73
217
255
341
157
415
176
97
430
475
254
254
253-4
253
254
253
246
248
284
195
115
363
225
69
115
340
426
256
256
256
255
255
256
269
257
284
343
257-60
426
259
259
257
258
258
258
259
257
257
259
259
259
259
354
20
Index
p-Methoxybenzyl Bromide
protection of amide nitrogen
protection of carboxylic acids
protection of phosphates
related reagents
(p-Methoxybenzyloxy)methyl Chloride
Links
525
46
53
149
51
262
46
98
266
53
4-Methoxybenzyl-2,2,2-trichloroacetimidate
electrophilic addition
formation of alkenes
formation of carbamates
formation of dienones and furanones
formation of nitriles
formation of vinyltributyltin compounds and tributyltin
isocyanate
related reagents
2-Methoxy-l,3-dioxolane
51
98
149
protection of acids
related reagents
2-Methoxypropene
condensation with amines
monoprotection of alcohols
pericyclic reactions
protection of 1,2 and 1,3-diols and 1,3-dithiols
protection of -hydroxy carbamates
reaction with N-halosuccinimides
related reagents
2-Methoxypropene
149
153
p-Methoxy-2,2,2-trichloroacetimidate
Methyl Acrylate
activation of carboxylic acids as mixed anhydrides
activation of N-heteroaromatic rings toward nucleophilic
attack
functional group protection
methoxycarbonylation of organometallic reagents and enolates
related reagents
49
84
Methyl Cyanoformate
152
260-3
260-1
261
261
261
261
262
261
262
149
431
262
263-5
265
263-4
263
264
264-5
264
265
191 351
265-7 431
266
265
266
266
267-9
267
267
268
267-8
268
268
268
196
246
152
150
270-2
271 -2
200
271
270-1
271
272
275
273-6
Index
Links
526
addtions to nitrile group

cycloadditions
higher alkyl cyanoformates
methoxycarbonylation of miscellaneous carbon acids
radical cyanation
regioselective methoxycarbonylation of ketones
related reactions
related reagents
Methyl Fluoride-Antimony(V) Fluoride
Methyl Fluorosulfate
Methyl Fluorosulfonate
alkylation at nitrogen
alkylation at oxygen
alkylation at phosphorus
alkylation at sulfur and selenium
alkylations at carbon
ambident nucleophiles
general reactivity
related reagents
Methyl Formate
Methyl Hypofluorite
Methyl iodide
Methyl Magnesium Carbonate
Methyl Propiolate
Methyl Sulfide
Methyl Trifluoromethanesulfonate
alkylation at carbon
alkylation at nitrogen
alkylation at oxygen
alkylation at phosphorus
alkylation at sulfur and selenium
ambident nucleophiles
Methyl Trifluoromethanesulfonate (cont.)
general reactivity
related reagents
Methyl Trifluoromethanesulfonate
Methyl Vinyl Ketone
Methylaluminum Bis(4-bromo-2,6-di-t-butylphenoxide)
Methylaluminum Bis(2,6-di-t-butyl-4-methylphenoxide
Methylaluminum Bis(2,6-di-t-butylphenoxide
catalyst for Diels-Alder and retro-Diels-Alder reactions
nucleophilic additions
related reagents
33
278-82
154
165
230
155
32
29
156
137
178
274
275
274
274
275
273-4
275
275
278
122
421
278
280
281
280
281
281
278
281
408
70
281
275
179
64
278-82
281
278
280
281
280
281
278
281
421
284
156
156
156
269-70
269
269
269
269-70
270
148
181
Index
Links
N-Methyl-N, O-bis(trimethylsilyl)hydroxylamine
Methylcopper-Boron Trifluoride Etherate
O-Methyldibenzofuranium Tetrafluoroborate
conversion of alcohols to iodides
Methylene compounds
Methylenetriphenylphosphorane
Methyllithium
N-Methylmorpholine N-Oxide
l-Methyl-3-nitro-l-nitrosoguanidine
N-Methyl-N-nitrosoacetamide
N-[N'-Methyl-N'-nitroso(aminomethy)benzamide
related reagents
l-Methyl-2-pyrrolidinone
3-Methyl-1-p-tolyltriazene
4-Methyl-l,2,4-triazoline-3,5-dione
Michael additions
Mitsunobu reaction
Montmorillonite K10
activation
aldol condensations
preparation of acetals
preparation of enamines
preparation of monoethers of 3-chloro-l,2-propanediol
protective tetrahydropyranylation of alcohols and phenols
synthesis of enol thioethers
synthesis of gamma-lactones via ene reaction
',a-unsaturated aldehydes via condensation of acetals with
vinyl ethers
Montmorillonite K10
Morpholine
coupling of amino acids
formation of amides
formation of imidazolinium salts by cyclization
use in spectroscopic studies
Mukaiyama Aldol additions
Nitro compounds
p-Nitrobenzoyl Chloride
generation of carboxylic acids
mechanism of action
oxidations
protection of amino acids
527
94
91
117
117
210
147
238
152
434
75
281
276
276
407
81
229
305
277
277
277
277-8
277
397
212
420
142
224
454
282-5
282
285
282
283
283
283
283
283
283
407
283
285-6
286
286
286
286
226
378
315
44
287-9
287
287
289
287
288
Index
Links
protection of hydroxyl groups

protection of ketones and aldehydes
reductions
related reagents
o-Nitrobenzyl Bromide
o-Nitrophenol
preparation of active esters for peptide synthesis
p-Nitrophenol
preparation of active esters for peptide synthesis
Nitroso compounds
Nonacarbonyldiiron
complexation of acyclic dienes
complexation of natural products
complexes from alkenediols
complexes from electrophilic cyclopropenes
cycloheptadiene series
cyclohexadiene series
cyclohexadienone reductions with Fe2(CO)9 and water
dehalogenation of ',''-dihaloalkenes and ketones
dehalogenation reactions
deprotection and deoxygenation reactions of oximes and
isobenzofurans
desulfurization of episulfides
diene complexation
enone complexation
exocyclic diene complexation
Fe2(CO)9 used with tertiary amine
Fe2(CO)9/ultrasound method of complexation
ferralactone complexes from oxazines
formation of 1,2,4-triazines
formation of a-lactones
formation of '-lactams
formation of cyclobutadiene complexes
opening of cyclopropane rings
reaction with acid chlorides
reaction with alkynes
reaction with 2,5-dihydrothiophene 1,1-dioxide
reaction with electrophilic allenes
reaction with sulfur compounds
reaction with thioketones
alkyne protection, distortion
and altered substituent reactivity
amidocarbonylation
carbonylation
carboxylation and related reactions
catalytic uses
cobalt-complexed propargyl cations and their reactions
528
193
288
287
289
289
289
289-90
289
290
376
290
238
315
290-7 300
292
291
293
293-4
291
291
296
294-5
294
295-6
295
291-2
292-4
291-2
292
292
293
295
293
293
294
294
295
295
295
296
295
295
298
302-4
300
299-300
299
298-301
303
Index
Links
cyclopentenone synthesis
reactions with alkynes
reactions with dienes
related reagents
stoichiometric reactions
Octacarbonyldicobalt-Diethyl(methyl)silane-Carbon Monoxide
Oligonucleotides, synthesis
Organoborane-methyl Sulfide complexes
Oxalic Acid
Oxalyl Chloride
226
529
147
62
87
307-10
337 346
chlorination of alkenes
direct introduction of chlorocarbonyl group
(halocarbonylation)
preparation of acyl isocyanates and aryl isocyanates
preparation of carboxylic acid chlorides (and anhydrides)
preparation of chloroalkanes
preparation of phosphonic acid chlorides
reactions with carbonyl groups
related reagents
Oxalyl Chloride-Aluminum Chloride
Oxodiperoxymolybdenum(pyridine)(hexamethylphosphoric
triamide)
Ozone
Palladium on Carbon
Palladium(II) Acetate
Palladium(II) Chloride
Paraformaldehyde
Pauson-Khand reaction
Pentacarbonyliron
204
311-16
acyclic series
carbonylation of benzyl halides
carbonylative ring expansion
complexation using Fe(CO)5 and Me3NO
coupling of gem-dihalides
cyclopropane rings
dehalogenation reactions
dehydration and dehydrosulfuration reactions
deoxygenation of epoxides
deoxygenation of N-O bonds
deoxygenation reactions and reductions
deprotection of ketones
, '-dibromo ketones
diene complexation
1,3-diene complexation
1,4-diene complexation
304
301
301
305
301
305
8
64
189
223
329
372
308
308
309
307
308
307-8
308-9
309
309
189
122
364
290
334
211
271
217
248
423
427
304
304
369
312
314
313
312
313
313
313
314
315
315
315
314
314
311
312
311-12
Index
Links
epoxide rings
formation of naphthoquinones via iron metallocycles
-halo ketones
isomerization of alkenes
nucleophiles
reaction with allenes
reaction with oximes
reactions with alkynes
ring-opening reactions with carbonyl insertion
stabilization of reactive or unstable species
, , ', '-tetrabromo ketones
Pentachlorophenol
Pentafluorophenol
193
formylation reactions
preparation of aromatic fluoro derivatives
related reagents
solid phase peptide synthesis (SPPS)
use in peptide synthesis
N,N,N',N',N'-Pentamethyldiethylenetriamine
(2R,4R)-2,4-Pentanediol
Peptide Synthesis
Peptide synthesis
Peracetic Acid
Perbenzoic Acid
Perkin reaction
cyclization reactions
deoxygenation of secondary alcohols
radical coupling
related reagents
sigmatropic rearrangements of allylic thionocarbonates
thiocyclation reagent
Phenyl N-Methyl-N-phenylphosphoramidochloridate
Phenyl N-Phenylphosphoramidoazidate
formation of carboxamides
formation of symmetrical anhydrides
phosphorylating agent
Phenyl Phosphorodi(1-imidazolate)
dehydration of aldoximes to nitriles
peptide synthesis
phosphorylation
Phenylboron Dichloride
Phenyldiazomethane
Phenyllithium
N-Phenylmaleimide
530
318-22
162
190
322-4
323
313
316
313-14
312
314-15
316
314
315-16
313
315
314
321
376
320-1
321
321
319
318-21
367
351
7
94
222
222
12
370
323
322
323
323
322
323
370
326
326
324
325
325
325
324-5
327
327
327
327
67
122
207
251
Index
Links
531
(Phenylthio)trimethylsilane
4-Phenyl-1,2,4-triazoline-3,5-dione
N-Phenyltrifluoromethanesulfonimide
Phosgene
equivalents
reactions with amides and thioamides
reactions with carboxylic acids
alcohols, and amines
related reagents
Phosphine oxides
Phosphonate esters
Phosphonic Acid Dichlorides
Phosphoric Acid
bromination of allylic alcohols
conversion of alcohols to bromides
related reagents
use for alkene preparation
cleavage of ethers
conversion of alcohols to bromides
reaction with ketones
related reagents
chlorinations
deoxygenations
enols
ketene silyl acetals
oxidations
preparation of phosphites
reaction with organometallic compounds
related reagents
carboxylic acid chlorides from acids

chlorides from alcohols and phenols
gem-dichlorides from ketones
aldehydes, and esters
nitriles from amides
related reagents
Phosphorus(III) Chloride-Zinc(II) Chloride
conversion of alcohols to iodides
61
124
285
346
62
223
287
372
10
247
330-2
62
214
337
307
340
62
325
371
218
332
372
480
142
415
94
226
328-30
451
330
329
328
330
238
80
307-8
195
346
331
330
332
331
332-3
333
332
333
333
333-5
372
333
334
334
334
333
333
334
334
321
334-8
425
335
335
337
335-6
337
477
338-41
339
Index
Links
deoxygenations
elimination reactions
reductions
related reagents
Phosphorus(V) Oxide
532
133
349
condensing agent
cyclization catalyst
cyclodehydrations
formamidines
formation of anhydrides
related reagents
Beckmann rearrangement
cycloalkenones
dehydration
Friedel-Crafts acylations of aromatic rings
Friedel-Crafts alkylations
heterocycle preparation
Phosphorus(V) Oxide-Phosphoric Acid
chloroaldehydes from carbonyl compounds

dehydration of alcohols
dehydration of amides
formylation of alkenes
formylation of aromatic rings
formylation of heterocycles
halogenation of alcohols
halogenation of heterocycles
phosphorylation
related reagents
Phosphorus Oxychloride-Zinc(II) Chloride
Phthalimide
protection reagent
Piperidine
Polonovski reaction
Polyphosphoric Acid
Poly(4-vinylpyridine)
Porphyrin synthesis
Potassium t-Butoxide
Potassium t-Butoxide-Hexamethylphosphoric Triamide
Potassium Carbonate
Potassium Cyanide
283
372
337
409
342
285
327
334
337
346-9
349
127
198
35
15
341
97
217
125
280
45
102
230
87
339
339-40
339
340
341-3
410
342
341
342
342
341
342
343-6
345
343
344
343
344
344
342
329
341
372
347
348-9
348
346
346
346
347
347-8
348
349
477
458
350
350
283
12
343
92
284
210
359
212
163
359
92
Index
Links
Potassium Diisopropylamide
Potassium Ferricyanide
Potassium Fluoride
Potassium Fluoride-Alumina
Potassium Hexafluorophosphate
Potassium Hydride
Potassium Hydride-s-Butyllithium-N,N,N',N'Tetramethylethylenediamine
Potassium Hydride-Hexamethylphosphoric Triamide
Potassium Hydroxide
Potassium Hydroxide-Hexamethylphosphoric Triamide
Potassium Iodide
Potassium Methylsulfinylmethylide
Potassium Superoxide
1,3-Propanediol
conversion to reactive intermediates
formation of boron esters
heterocycle synthesis
reactions with carbonyls
related reagents
1,3-Propanedithiol
ketene dithioacetal formation
reduction
related reagents
Propargylmagnesium Bromide
-Propiolactone
Protecting Group Chemistry
Protection of Diols as Ketals
Pummerer reactions
Pummerer rearrangement
Pyridine
533
126
45
9
158
299
325
Pyridine N-Oxide
Pyridinium Chlorochromate
Pyridinium Poly(hydrogen Fluoride)
Pyridinium p-Toluenesulfonate
321
360
86
34
103
162
190
175
176
90
228
308
328
411
11
10
99
263
315
348
439
64
96
147
194
Pyrroles
Pyrrolidine
Raney Nickel
55
151
217
Ruthenium(VIII) Oxide
Sakurai reactions
Samarium(III) Chloride/Chlorotrimethylsilane
Samarium(II) Iodide
175
353
108
20
78
210
218
217
466
45
221
265
367
212
125
212
64
260
92
350-2
351
351
351
350
351
352-4
354
353
354
208
150
8
3
238
409
128
267
322
371
481
329
148
140
189
265
417
283
216
368-9
390
179
340
339
Index
Links
Schotten-Baumann conditions
Selenium(IV) Oxide
Semicarbazide
Silver(I) Nitrate
Silver(I) Oxide
Silver(I) Percholorate
activation of acyl chlorides
activation of thiol esters
alkylation of thioethers
carbon-carbon bond formation via cationic
intermediates
catalysis of cycloadditions
electrophilic aromatic substitution
nucleophilic aromatic substitution
nucleophilic substitution on alkyl halides by
heteroatoms
rearrangements
related reagents
synthesis via iminium ions
Silver(I) p-Toluenesulfonate
Silver(I) Trifluoromethanesulfonate
a-Silyl aldehydes
Silyl enol ethers
Silyl esters
N-Silyl imines
Silyl ketene acetals
-Silyl ketones
Silyl ynol ethers
Silylation
Simmons-Smith reagent
Singlet Oxygen
Sodium
Sodium Amide
Sodium-Ammonia
Sodium Azide
Sodium Bis(2-methoxyethoxy)aluminum Hydride
Sodium Borohydride
Sodium Bromide
Sodium Carbonate
Sodium Cyanide
Sodium Cyanoborohydride
Sodium O,O-Diethyl Phosphorotelluroate
Sodium Dithionite
Sodium Hydride
534
218
355-7
21
189
288
148
230
231
436
355
356
356
355-6
356
356
355
150
103
206
236
151
175
34
350
168
74
193
334
171
211
398
79
371
35
476
45
393
45
97
50
103
355
356
356
356
129
171
87
237
103
88
85
87-8
417
2
479
391
217
93
411
272
169
185
279
476
247
398
210
480
339
222
92
163
Index
Links
535
Sodium Hydrogen Selenide

Sodium Hydrogen Sulfide
Sodium Hydroxide
Sodium Iodide
Sodium Methoxide
Sodium Naphthalenide
Sodium Nitrite
Sodium Periodate
Sodium Sulfide
Sodium Tetracarbonylcobaltate
(-)-Sparteine
Succinic Anhydride
N-Sulfinyl-p-toluenesulfonamide
Sulfonyl halides
Sulfonylation Reagents
Sulfoxide Activation
Sulfur compounds
Sulfur Dioxide
Sulfur Tetrafluoride
Sulfuric Acid
dimerization of carbodiimides
general acid catalysis
oxidation
preparation of annulated triazolones
preparation of hypervalent iodine reagent
protecting-group manipulations
synthesis of cationic organometallic complexes
Tetrakis(acetonitrile)copper(I) Perchlorate
Tetrakis(acetonitrile)copper(I) Tetrafiuoroborate
Tetrakis(triphenylphosphine)palladium(0)
230
265
425
97
20
222
63
97
108
131
218
225
12
288
Sulfuryl Chloride
Tetra-n-butylammonium Bromide
deprotection of silyl groups

desilylation reagent
related reagents
use as base
Tetra-n-butylammonium Iodide
208
260
340
140
139
301
284
247
86
102
73
92
358-61
425
427
45
64
118
77
265
422
106
42
232
396
431
346
346
260
87
103
210
55
361
217
222
305
367
267
426
238
6
6
64
464
283
397
425
273
91
210
417
466
358
358
360
359
260
361-4
436
363
362
363
362
363
361-2
363
113
113
85
Index
Links
Tetramethylammonium Bromide
N,N,N',N'-Tetramethylethylenediamine
212
base catalyzed reactions
control of regioselectivity and stereoselectivity
inorganic complexes useful in organometallic reactions and
organic synthesis
ligand for crystallographic studies
lithiation of difficult substrates
related reagents
stabilization and activation of organometallic reagents
1,1,3,3-Tetramethylguanidine
Tetramethylstannane
Tetronic acids
Thallium(III) Acetate-Bromine
Thallium(I) Carbonate
Thallium(III) Nitrate
Thiele reaction
Thio analogs of dicarbonyl compounds
Thioacetals
Thioamides and related compounds
Thioanisole
alkene synthesis
radical chemistry
related reagents
thiocarbonyl transfer
Thiocyanogen
Thioketones
Thiol esters and ketones
Thiols
Thiono esters
Thionyl Bromide
Thionyl Chloride
carboxylic acid chlorides from acids
chlorides from alcohols
nitriles and isocyanides via amide dehydration
oxidation of activated C-H bonds
reactions with aldehydes and ketones
reactions with secondary amides
rearrangement reactions
related reagents
sulfonyl and sulfinyl chlorides from sulfonic and sulfinic acids
synthesis of heterocyclic compounds
Thionyl Chloride
62
329
340
349
188
193
536
229
247
364-8
367
365-6
367
365
364
367
366
127
77
210
94
225
225
408
12
54-5
111 112
55-6
97
323
368-70
368
369-70
370
370
148
53-4
167
10
55
65
370-3
371
370-1
371-2
372
372
372
372
372
371
372
307
325
334
337
341
346
426
476
373-4 376
Index
Links
ester formation
inorganic ester formation
ketones
symmetrical sulfoxides
Thiophenol
ester formation
ketones
lactone formation
peptide coupling
preparation of 2-pyridylthiol esters
Thioureas
Tin(II) Chloride
Tin(IV) Chloride
537
374
374
374
36
100
21
17
97
181
377-82
222
118
260
29
141
283
475
additions to nitriles
alkene cyclizations
-t-alkylations
[2+2] cycloadditions
Tin(IV) Chloride (cont.)
ene reactions
glycosylations
hydrochlorination of allenic ketones
nucleophilic additions to aldehydes
polymerization
rearrangement of allylic acetals
related reagents
selective De-O-benzylation
Tin(IV) Chloride-Zinc Chloride
Titanium
Titanium(III) Chloride
related reagents
Titanium(IV) Chloride-Diazabicyclo-[5.4.0]undec-7-ene
Titanium(IV) Chloride-2,2,6,6-Tetramethylpiperidine
382
29
97
206
340
334
69
177
265
353
377
474
374
374
111
375-7
376
376
376
376
375-6
403
390
153
353
75
177
340
384
477
378
380
379
382
382
381
382
378
378
377
380
379
382
379
477
145
383
75
181
284
367
383-9
477
388
388
388
Index
Links
538
Titanium(IV) Chloride-Triethylaluminum
Titanium(IV) Chloride-Zinc
388
383
86
389-93
asymmetric epoxidation reactions

isomerization reactions
lactamization
nucleophilic additions to carbonyl compounds
nucleophilic cleavage of 2,3-epoxy alcohols and related
compounds
transesterification
Titanium Tetrakis(diethylamide)
p-Toluenesulfonic Acid
11
147
245
157
415
p-Tolyl Chlorothionocarbonate
p-Tolyl Vinyl Sulfoxide
Transition Metal Organometallic Systems
1,2,4-Triazole
acylating reagent
catalysis of ring formation
oligonucleotide synthesis
2,2,2-Tribromoefhyl Chloroformate
Tri-n-butylamine
Tri-n-butylchlorostannane
Tri-n-butyl(methoxy)stannane
Tri-n-butylphosphine
Tri-n-butylstannane
Tri-w-butyltin Hydride
Trichloroacetic Anhydride
Trichloroacetimidates
alkylation using trichloroacetimidates
electrophilic cyclization of trichloroacetimidates
preparation of trichloroacetimidates
rearrangement of trichloroacetimidates
carboxylic acid derivatives
effect on stereochemistry
lactone formation
limitations of Yamaguchi lactonization conditions
related reagents
2,2,2-Trichloro-t-butoxycarbonyl Chloride
49
84
9
35
157
49
84
405
388
384
427
392
391
389-90
392
390-1
389-90
384
81
133
153 194
247 288
291 481
255
265
277
394-9
426
481
323
349
8
227 399-400
399
400
400
200
272
99
371
51
60
132
216
459
223 322
339
369
55
285
400-1
232
400-1
401
401
400
401
402-4 418
402
403
402
403
403
200 272
Index
Links
539
2,2,2-Trichloroethyl Chloroformate
Trichloromethyl Chloroformate
173
Trichlorosilane
Triethoxysilane
acetals
cyclic orfhoformates
electrophilic formylation
enol ethers
esterification
formylation
heteroatom nucleophiles
higher orfhoformates
organometallic reactions
related reagents
transesterification
Triethyl Phosphite
Triethyl Phosphonoacetate
Triethyl Trifluoromethanesulfonate
Triethylaluminum
cyclopropanation
ethylation
rearrangements
related reagents
Triethylamine
Triethylchlorosilane
Triethyloxonium Tetrafluoroborate
Triethylsilane
Triethylsilyl Trifluoromethanesulfonate
Trifluoroacetic Acid
activated esters
oxidation
related reagents
Trifluoroacetic Anhydride-Sodium Iodide
Trifluoroacetyl Chloride
49
61
226
161
351
29
137
9
61
86
133
199
245
325
367
21
77
99
157
218
247
329
398
425
182
96
11
104
266
133
200
62
330
272
84
349
334
393
406-8
407
189
191
370
406-7
407
407
407
407
407
406
407
408
406
459
247
91
181
404-6
405
404
405
405
34
37
80
81
103
126
168
173
236
243
272
285
353
360
410
422
432
443
88
420
421
74
101 435
194
261
409
430
409-410
409
409-10
410
409
410
426
Index
Links
Trifluoromethanesulfonic Acid
reaction with alcohols and phenols
reaction with aldehydes
reaction with amides
reaction with amines
reaction with carbonyl compounds
reaction with carboxylic acids and esters
reaction with dicarbonyl compounds
related reagents
Trifluoromefhanesulfonyl Chloride
Trifluoromethyltrimethylsilane
Triisobutylaluminum
Triisopropyl Phosphite
formation of silyl ynol ethers
hydroxy protecting group
prevention of chelation in Grignard reactions
N-protection of pyrroles
related reagents
Triisopropylsilyl Trifluoromethanesulfonate
Trimethyl Arthoformate
Trimethyl Phosphate
Trimethyl Phosphite
ether cleavage
ketone synthesis
peptide synthesis
related reagents
selective protection of polyols
Trimethylaluminum
Trimethylamine N-Oxide
Trimethylchlorosilane
catalytic properties
functional group methylations
related reagents
use in transition metal chemistry
Trimethylsilyl Perchlorate
Trimethylsilyl Polyphosphate
540
52
106
87
255
284
32
106
410-11
359
88
92
90
122
256
165
316
403
29
137
178
122
281
165
90
105
91
156
89
278
410
410-16
228
426
413
414
411
412-13
414
413
415
415
466
405
231
416-17
417
416
417
417
417
417
153
421
466
418-19
418
418
418
418
418
145
181
305
88
279
419-22
421
419-20
421
420
104
342
101
238
432-5
Index
Links
carbonyl activation
related reagents
silylation
N-Trimethylsilylacetamide
Trimethylsilylacetonitrile
[C-N-N] azole synthon
one-carbon homologation
related reagents
synthesis
related reagents
2-(Trimethylsilyl)ethoxycarbonylimidazole
one-carbon homologations
protection of acids
protection of secondary amines
related reagents
2-(Trimethylsilyl)ethyl Chloroformate
N-(Trimethylsilyl)imidazole
Trimethylsilylmethylmagnesium Chloride
Triphenyl Phosphite
generation of alkenes from organometallics
Lewis acid catalysis
oxidation by hydride abstraction
polymerization catalyst
preparation of aromatic compounds via dehydrogenation
sensitizer of photooxygenation
Triphenylphosphine
90
215
339
431
440
conversion of alcohols to alkyl halides
related reagents
148
amides from carboxylic acids
a-bromo enones from 1,3-diketones
1-bromoalkynes from terminal alkynes
conversion of alcohols to alkyl bromides
dibromoalkenes from aldehydes and ketones
541
51
266
49
272
105
97
104
216
376
445
332
432-5
435
432
22
466
122
422-5
423-4
422
425-7
425
426
426
427-9
429
431
429
98
149
429-32
431
430
429-30
430
431
84
200
428
429
205
206
422
227
250
436-8
436-7
437
436
437
436
437
169
170
228
247
384
425
450
481
438-40
438-9
439
440-1 445
441
441
441
440
441
Index
Links
542
228
372
amide formation
combination of triphenylphosphine and carbon tetrachloride
conversion of acids to acid chlorides
conversion of alcohols to alkyl chlorides
conversion of epoxides to cis-l,2-dichloroalkanes
dehydrations
Triphenylphosphine-N-Chlorosuccinimide
148
247
conversion of alcohols into alkyl bromides
cyclization of a- and g-amino alcohols to aziridines and
azetidines
dehydration of ureas and amides to carbodiimides, nitriles,
isocyanides and ketenimines
epoxide opening to vicinal dibromides or
bromohydrins
preparation of acyl bromides from carboxylic acids, anhydrides
and esters
preparation of imidoyl bromides from secondary amides
preparation of iminophosphoranes from amines, hydrazines
and related derivatives
synthesis of alkyl bromides from ethers and acetals
synthesis of aryl bromides from phenols
334
chlorination of substituted carboxamide groups
dehydration of substituted carboxamide groups
epoxide cleavage to vicinal dichlorides and chlorohydrins
preparation of acid chlorides from acids and esters
preparation of alkyl chlorides from alcohols and ethers
preparation of aryl chlorides from phenols and arenes
preparation of iminophosphoranes from amines, hydrazines
and related derivatives
preparation of vinyl chlorides, alkynyl ketones and
a-chloro-a-vinyl ketones from ketones and a-diketones
140
carbon-carbon bond formation
carbon-nitrogen bond formation
ester formation
O-glycosidation with carboxylic acids
glycosidation with nitrogen nucleophiles and N-hydroxy
compounds
O-glycosidation with phenols
order of addition of reagents
reaction with amino alcohols and related compounds
reaction with di- and polyols
reaction with hydroxy acids
337
439
332
371
442-5
444
442
442
442
443
443
439
445-51
445-6
448
448
447
448
448-9
337
444
449
446-7
446
372
450-3
452
452
451-2
452
450-1
451
452-3
454-64
451
476
461-2
458
455-6
461
461
461
454-5
460
458
457
Index
Links
reaction with phenols and other oxygen nucleophiles

reaction with thiocarboxylic acids, phosphoric acids, sulfonic
acids and their derivatives
Triphenylphosphine-Hexachloroacetone
Triphenylphosphine Hydrobromide
Triphenylphosphine-Iodine
Triphenylphosphine-Iodoform-Imidazole
Triphenylphosphine-N-Iodosuccinimide
Tripropylamine
Tris(dimethylamino)methane
cross-coupling reactions
fluoride ion source in nucleophilic displacements
generation and reactions of unusual carbanions
generation of enolates and enolate surrogates from enol silanes
related reagents
Tris(formylamino)methane
Tris(trimethylsilyl)silane
Ureas
Vanadyl Trifluoride
Vilsmeier reagent
Vilsmeier-Haack reagent
Vinyl Acetate
Vinyl Chlorides
Vinyl Chloroformate
49
Vinyl Halides
Vinylmagnesium Bromide
Vinylogous Wolff rearrangement
Vinyltrimethylsilane
Wagner-Meerwein hydride migrations
Wagner-Meerwein rearrangement
Wharton reaction
Wittig reaction
Wolff-Kishner reduction
Xenon(II) Fluoride
Yamaguchi lactonization
Ytterbium(0)
Zinc
Zinc-Acetic Acid
Zinc Borohydride
Zinc Bromide
activation of C-X bonds
activation of C=X bonds
concerted ring-forming reactions
deprotection
organozinc reagents
543
457-8
250
340
97
360
94
15
84
196
337
200
425
218
70
103
369
206
427
95
265
468-71
456-7
334
147
439
228
439
100
161
464-7
465-6
465
466
465
466
161
36
315
321
336
329
246
444
272
110-11
426
120
427
17
17
218
215
351
321
403
210
247
441
339
476
447
479
469
469
469
470
468
Index
Links
reduction
Zinc Chloride

acylation
aromatic substitution
homoenolates
organozinc reagents
protection/deprotection
reduction
related reagents
zinc enolates
Zinc Complex Reducing Agents
Zinc/Copper Couple
Zinc Iodide
deprotection
organozinc reagents
reduction
Zinc/Silver Couple
tosylate formation with inversion of configuration
tosylation with retention of stereochemistry
Zincke-Suhl reaction
Zirconium(IV) Chloride
544
9
195
71
249
367
20
87
470
75
97
275
334
381
469
471-9 481
475
474
477
477
474
473
472
477
476
477
473
476
348
479
92
139
469
479-81
480
479-80
479
480
479
480
366
456
481-2
481
482
27
17

Activating Agents and Protecting Groups Handbook of Reagents For Organic Synthesis

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Activating Agents and Protecting Groups Handbook of Reagents For Organic Synthesis

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Handbook of Reagents

for Organic Synthesis

Activating Agents and

JOHN WILEY & SONS

Copyright 1999 John Wiley & Sons Ltd,

(+44) 1243 779777

Email (for orders and customer service enquiries): [email protected]

Other Wiley Editorial Offices

International Advisory Board

Reagents, Auxiliaries and Catalysts for C-C Bond

The combination of reagents included in this volume

chiometrically, and that are relatively familiar to the organic

reactions might be a problem when limited information is

of the various technologies described in the present work.

ORGANIC SYNTHESES REFERENCES

Organic Syntheses References

Behrens, C; Paquette, L. A. "N-Benzyl-2,3-azetidinedione"

Stille, J. K.; Echavarren, A. ML; Williams, R. M.; Hendrix, J.

Dodge, J. A.; Nissen, J. S.; Presnell, M. "A Gen

II. Alcohol Functionalization or Protection:

Eberle, M.; Missbach, M.; Seebach, D. "Enantioselective Saponi

Thompson, A. S.; Hartner, F. W., Jr.; Grabowski, E. J. J. "Ethyl

Sessler, J. L.; Mozaffari, A.; Johnson, M. R. "3,4-Diethylpyrrole

Lynch, K. M.; Dialey, W. P. "3-Chloro-2-(chloromethyl)-lpropene"OS, (1997), 75, 89.

Krakowiak, K. E.; Bradshaw, J. S. "4-Benzyl-10,19-diethyl4,10,19-triaza-1,7,1,16-tetraoxacycloheneicosane

Sun, R. C; Okabe, M. "(25, 45)-2,4,5-Trihydroxypentanoic

Deardorff, D. R.; Windham, C. Q.; Craney, C. L. "Enantio

Avoid Skin Contact with All Reagents

ORGANIC SYNTHESES REFERENCES

Overman, L. E.; Rishton, G. M. "3-(S)-[(fert-Butyldiphenylsilyl)oxy]-2-butanone" OS, (1992), 71, 56.

Wipf, P.; Xu, W. Allylic Alcohols by Alkene Transfer from

Bailey, W. F.; Carson, M. W.; Zarcone, L. M. J. "Selective Pro

Tius, M. A.; Kannangara, G. S. K. "Benzoannelation of Ketones:

Tamao, K.; Nakagawa, Y.; Ito, Y. "Regio- and Stereoselective

Danheiser, R. L.; Romines, K. R.; Koyama, H.; Gee, S. K.;

Paquette, L. A.; Heidelbaugh, T. M. "(4S)-(-)-tert-Butyldimethylsiloxy-2-cyclopenten-l-one" OS, (1995), 73, 44.

Mann, J.; Weymouth-Wilson, A. C. "Photoinduced-Addition of

Dondoni, A.; Merino, P. "Diastereoselective Homolo

Bhatia, A. V.; Chaudhary, S. K.; Hernandez, O. "4Dimethylamino-N-triphenylmethylpyridinium Chloride" OS,

Lists of Abbreviations and Journal Codes on Endpapers

ORGANIC SYNTHESES REFERENCES

(d) Protection of Diols as Ketals

Saito, S.; Komada, K.; Moriwake, T. "Diethyl (25, 3R)-2-(Ntert-Butoxycarbonyl)amino-3-hydroxysuccinate"

Schmid, C. R.; Bryant, J. D. "D-(R)-Glyceraldehyde Acetonide"OS, (1993), 72, 6.

Nikolic, N. A.; Beak, P. "(R)-(+)-2-(DiphenylhydroxymethyOpyrrolidine" OS, (1996), 74, 23.

Chen, W.; Stephenson, E. K.; Cava, M. P.; Jackson, Y.

Iwao, M.; Kuraishi, T. "Synthesis of 7-Subtituted Indolines

III. Amine Protection

Garner, P.; Park, J. M. "1,1-Dimethylethyl (S)- or (R)-4Formyl-2,2-dimethyl-3-oxazolidinecarboxylate: A Useful Serinal

Lakner, F. J.; Chu, K. S.; Negrete, G. R.; Konopelski, J. P.

Lenz, G. R. Lessor, R. A. "Tetrahydro-3-benzazepin-2-ones:

Hutchison, D. R.; Khau, V. V.; Martinelli, M. J.; Nayyar, N. K.;

Avoid Skin Contact with All Reagents

ORGANIC SYNTHESES REFERENCES

Krakowiak, K. E.; Bradshaw, J. S. "4-Benzyl-10,19-diethyl-4,10,19-triaza-1,7,13,16-tetraoxacycloheneicosane (Triaza21-Crown-7)" OS, (1991), 70, 129.

Nikolaides, N.; Schipor, I.; Ganem, B. "Conversion of Amines

Carrasco, M.; Jones, R. J.; Kamel, S.; Rapoport, H. Truong,

Barton, D. H. R.; MacKinnon, J.; Perchet, R. N.; Tse, C.-L.

Hubschwerlen, C ; Specklin, J.-L. "(35, 4S)-3-Amino-l-(3,4dimethoxybenzyl)-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-azetidinone" OS, (1993), 72, 14.

Pikal, S.; Corey, E. J. "Enantioselective, Catalytic Diels-Alder

Schultz, A. G.; Alva. C. W. " Asymmetric Synthesis

Lists of Abbreviations and Journal Codes on Endpapers

Wang, X.; deSilva, S. O.; Reed, J. N.; Billadeau, R.; Griffen,