Organic Synthesis. Functional Group Interconversion
Organic Synthesis. Functional Group Interconversion
Pere Romea
Department of Organic Chemistry
I. Nucleophilic Substitutions
Electrophilic Additions to C=C
Addition-Eliminations on Carboxylic Acids and Derivatives
II. Reductions
Mechanism!!! III. Oxidations
Pere Romea, 2014 2
Nucleophilic Substitutions
+ Nu + X
X Nu
Csp3
RX
Chap. 15
Pere Romea, 2014 3
Nucleophilic Substitutions
+ Nu + X
X Nu
X + Nu Nu + X
Nu
Sulfonates ROSO2R RNu
Nu
Alcohols ROH RNu
Alkyl halides Nu
RX RNu
X: I, Br, Cl
A wide array of structures can be synthesized from sulfonates and alkyl halides through
nucleophilic substitution of X = OSO2R, I, Br, Cl in CC bond forming reactions and FGI
R Y
R R R OH
Y
R H 2O
or OH
R N R OR
ROH
CN or RO
R X
O
N3 O
R N3 O R R
O R
NH3 H 2S
RSH or HS
or RS
R NH 2 R SH
Nu
Sulfonates ROSO2R RNu
Nu
Alcohols ROH RNu
Alkyl halides Nu
RX RNu
X: I, Br, Cl
pyridine
+ RSO2Cl or (RSO 2 )2O
OH CH 2Cl 2 or Et2O OSO 2R
0 C rt
Primary and secondary ROH OK, but the reaction is sensitive to steric hindrance
OH
TsCl, pyr Me
Me
Me
H Me
The reaction does not affect the CO bond: the configuration of the carbon remains the same
Mesylates and tosylates are largely employed.Triflates are the most reactive sulfonates
Rearrangements of the carbon backbone are not frequent
8 Pere Romea, 2014
Sulfonic Esters and Alkyl Halides
X
OH SN2 X X: Cl, Br, I
Pr 2) LiCl, DMF Pr
83%
Sulfonates ROSO2R
RSO2Cl
Alcohols ROH X
?
Alkyl halides
RX
X: I, Br, Cl
OH X X: Cl, Br, I
H Br
OH OH2 Br
SN2 single
OH OH2
H
Br Br
SN1
Br
86% 14% Br
Cl
H Cl
OH OH2
single
Pere Romea, 2014 12
Alcohols and Alkyl Halides
The most used options are based on the conversion of alcohols into alkoxyphosphonium salts,
highly reactive in SN2 substitutions
E
Ph3P + ENu Ph3P Ph3P E + Nu
Nu
Ph3P E + HO Ph3P O + HE
H H
Alkoxyphosphonium salt
Ph3P O + Nu Ph3P=O + Nu
H H
Alkoxyphosphonium salt
13 Pere Romea, 2014
Alcohols and Alkyl Halides
HBr Ph3P=O
Ph3P Br + HO Ph3P O Br
H H Br H
SN2
This transformation is very useful for secondary alcohols and those systems that easily produce transpositions, as neopentylic alcohols
The control on the configuration is very good.
Br
Br PBr3 Ph3P/Br2
+ + Br OH Br
OMe OMe
Ph3P, Br2 Ph 3P, I 2
O R O R OH I
O O Imidazole
OH Br Et 2O, rt
85% 96%
14 OBn OBn
Alcohols and Alkyl Halides
HO
CCl3 H Ph3P=O
Ph3P + ClCCl3 Ph3P Cl Ph3P O Cl
HCl H H
Cl
carbon tetrachloride
O O
Ph3P + Cl CCl3
Cl
CCl3
Cl Cl Cl
hexachloroacetone
Ph3P/Cl2 OH Ph3P/CCl4 Cl
OH Cl
92% 70%
Ph3P/CCl3COCCl3
OH Cl
99%
Nu
Sulfonates ROSO2R RNu
Nu
Alcohols ROH RNu
Alkyl halides Nu
RX RNu
X: I, Br, Cl
O O O
R NH2 R OH R H R Me
Amine 1 Carboxylic Acid Aldehyde Methyl ketone
R CN R C CH
+C +2C
Attention!
Alkyl halides are very useful for R X R OH
the construction of CC bonds
R X HX
R NH2 R2 NH2 X R2 NH Secondary Amine
+ HX
R X HX
R2 NH R3 NH X R3 N Tertiary Amine
+ HX
R X
R3 N R4 N X Ammonium Salt
Such an alkylation only becomes efficient when the resulting amine is much less nucleophile than the initial one,
for steric or electronic reasons
CO2Et
CO2Et CO2Et 1) Br CO2Et
1) RCH2Cl
NH N
H2N 2) NaHCO3 R N 2) NaHCO3
R: C15H31 H
18 Pere Romea, 2014
Nitrogen Nucleophiles: Primary Amines
Azide, N3
The azide anion is an excellent nucleophile that participates in a large number of SN2 processes
The reduction of the azide group affords a primary amine
NaN3
I N3 NH2
Bu Bu Bu
DMSO,
90%
O O O O
1) MsCl, Et3N
OTBDPS OTBDPS
2) NaN3, DMF
OH N3
85% 19
Nitrogen Nucleophiles: Primary Amines
Ph3P
CO2Et Ph3P CO2Et
N N N N
EtO2C EtO2C
N3 O PPh3 N3 + O=PPh3
H H
20 Pere Romea, 2014
Nitrogen Nucleophiles
Reduction Mitsunobu
O
LiAlH4, H2 cat, Ph3P/H2O Ph3P/DEAD/ HN3 or DPPA
R N R1 R NH2 R N3 R OH
H
Amide Amine 1 Azide
SN2 SN2
Phthalimide N3
R X R OSO2R'
O O O O
Ph3P, DEAD, HN3
O N OH O N N3
CH2Cl2, 0 C
Bn 97% Bn
O O O
1) H2, Pd/C, THF/MeOH/TFA, ta
O N N Ph
H 2) PhCOCl, Et3N, CH2Cl2, 0 C
Bn 97% 21
Oxygen Nucleophiles: Alcohols
H2O, OH
X OH
X: Cl, Br, I
RO
X RO SN2
H H
X: Cl, Br, I
O O O
Ar + XCH2R2 R1 R2 R1 + MeX o BnX
NO2 NO2
O O
OH OBu O O
BuBr, K2CO3 1) NaH, THF
O O O O
H2O H 2) BnCl, H
HO O BnO O
80% 95%
Carboxilates, RCO2
RCO2
X RCO2 SN2
H H
X: Cl, Br, I, OSO2R
O O
OK Br 18-crown-6 O
+
O 95% O
Br Br
why KF?
O O CO2H O O CO2Me
MeI, KF
O O
O DMF O
O O
84%
Ph3P
CO2Et Ph3P CO2Et
N N N N
EtO2C EtO2C
RCO2H
H CO2Et
N N RCO2 RCO2
EtO2C H H
OH PhCO2
Ph3P, DEAD
CO2Me CO2Me
O PhCO2H O
Pere Romea, 2014 25
89%
Oxygen Nucleophiles
Configuration inversion
SN2 Hidrolysis
RCO2 OH
OH OSO2R' RCO2 HO
H H H H
Mitsunobu Hidrolysis
Ph3P/DEAD/RCO2H OH
OH RCO2 HO
H H H
OH O OH
Ph Ph Ph
Ph 3P, DEAD O2N KOH
p-O2NPhCO 2H MeOH
99% overall
O O O
NaOH Ph3P
Ph3P + Br Ph3P
OEt OEt OEt
Br
BuLi Ph3P
Ph3P + Br Ph3P
OPh OPh OPh
Br
Ph3P
Attention: no E2 occurs OPh
27
Phosphorus Nucleophiles: in Route to Wittig Reactions
Phosphites are also good nucleophiles and react with alkyl halides:
Michaelis-Arbuzov reaction
RR R1 OCHR2 O
(R2CHO)3P + R1X P P
H O OCHR2 (R2CHO)2 R1
X
phosphite alkylphosphonate
alkyltrialkoxyphosphonium halide
Attention:
Horner-Wadsworth-Emmons reaction
O O O O O
EtO
(EtO)3P + Br (EtO)2P (EtO)2P
OEt OEt OEt
EtBr
O O
(EtO)2P
OEt
O O
(EtO)2P
Pere Romea, 2014 28 OEt
Sulfur Nucleophiles: Thiols
H RX
RX + HS R SH R S R S R
+H
S
thiourea NH2
H2N NH2 NaOH
H S NH2
O
X H H SH
O
S NaOH
thioacetate H S or LiAlH4
1) Thiourea AcSCs
Br HS
C10H 21 C10H 21 Br H
2) NaOH DMF
i-Pr i-Pr
H SAc
80% 84%
Thiolates are the best option since they are excellent nucleophiles ...
XR2
R1SH + OH R1 S R1 S R2
NaOH Br
SH S S
95%
O O O
MsCl, Et3N BnSH, K2CO3
Me Me Me
N N N
CH2Cl2 CH3CN
HO OMe MsO OMe BnS OMe
100% 80%
Weinreb Amide
O
EtMgBr
BnS
I. Nucleophilic Substitutions
Chap. 19
Electrophilic Additions to C=C
Addition-Eliminations on Carboxylic Acids and Derivatives
II. Reductions
Mechanism!!! III. Oxidations
Pere Romea, 2014 31
Hydroboration of C=C
The regiochemistry for the addition of BH3 to an olefin is controlled by steric as well as electronic factors:
the boron atom binds to the less substituted carbon atom
H
R R R
BH3 BH2 B B
R R R R R
Alkylborane Dialkylborane Trialkylborane
3 + BH3 B
2 + BH3 B Sia2BH
H
H R H H R R
H > H > H > R > R > R
R R R R R R
H H R H H H
BH3 94 80 99 57
% atack B
Sia2BH 99 98 97 to the less
substituted
99.9 98.5 99.5 99.8 carbon atom
9-BBN
34 9-BBN 97 3
Hydroboration of C=C
H
1) B2H6 OH It looks like
an anti-Markovnikov hydration
2) H2O2, OH with a syn stereochemistry
35 85% Pere Romea, 2014
Hydroboration of C=C
Hidroboration of alkynes
RCO2H H H
R1 R2 Alqu Z
H2O (HO)2B H
R1 R2
Vinilboronic acid
O
1) B H
O Br
OH
B
2) H2O OH Pd(0) cat
75%
Suzuki Coupling
36 Pere Romea, 2014
Dr. Pere Romea
Department of Organic Chemistry
R1 OH R1 L
O O O O O O O
R2
R1 Cl R1 O R2 R1 N3 R1 SR2 R1 OR2 R1 N
R3
Acid chloride Anhydride Acyl azide Thioester Ester Amide
R1 C N Nitrile
Addition-elimination mechanism
O Addition Nu O Elimination O
R1 R1 + L
Trigonal Planar L R1 L Nu
Remember: The lower the pKa (HL), the better the leaving group
LA LA LA LA
O O HNu O Nu O O O
LA LH LA
R1 L R1 L R1 L R1 LH R1 Nu R1 Nu
Remember: synthesis of esters by addition of alcohols to acid chlorides in the presence of DMAP
O
H2O
R1 Cl
Very easy
Chap. 16 Chap. 10
R2CO2
O O
R2CO2 H2O
R1 O R2 O
Easy
R2OH R1 OH
R2OH O H2O
R1 OR2 Moderate
R2R3NH
O
R2R3NH H2O
R2
R1 N Difficult
R3
5 Pere Romea, 2014
Addition-Elimination Processes
O
?
R1 Cl
Chap. 16 Chap. 10
R2CO2
R2CO2
O O
?
R1 O R2 O
R2OH R1 OH
R2OH O ?
R1 OR2
R2R3NH
R2R3NH
O
R2
?
R1 N
R3
6 Pere Romea, 2014
Acid Chlorides from Carboxylic Acids
Via (COCl)2
Useful for systems sensitive to acid media.
It is usually used with the sodium salt (neutral media) or with catalytic amounts of DMF.
O Bn O Bn
O (COCl)2 O
N N N N
CO2Na 83% COCl
HO O HO O
O O O Cl O O O O O
P P P
(OMe) Cl (OMe) H OBn (OMe)
Cl Cl HO O
BnO
PMBO O Et 3N, DMAP PMBO O O Cl PMBO O H
95%
THFPhMe, rt
PMBO OH PMBO O PMBO O
Cl Cl
Nu
Pere Romea, 2014 8
Esters from Carboxylic Acids and Derivatives
The retrosynthetic analysis shows two ways of deconnecting the ester group ...
O b) O a) O
+ HOR2 R2 + R2X
R1 L R1 O R1 O
HH
CH2N2
RCO2H RCO2
H
Pere Romea, 2014 9
Esters through SN2 Transformations
Diazomethane is a highly volatile (it must be handled in etherial solutions), toxic, and explosive compound ...
H H H
C N N C N N C N N
H H H
O O
CH2N2
HO O MeO O
Et2O
O O
95%
pKa 10 pKa 16
PhOH + CH2N2 PhOMe PrOH + CH2N2 PrOMe
Fischer esterification O
H + HOR2
R1 O
A problem
H
H H 2 H
O
H
O O HO O 2 HO O R O
H O
R
H H H R2 R2
R1 O R1 O R1 O R1 OH R1 O H R1 O R1 O
H
Activation
HO R2
O O
H
H + HOR2 R2 + H2O
R1 O R1 O
O O O O
HCl cat TsOH cat
OH + MeOH OMe OH + HO Cl O Cl
solvent H 2O azeotropic
95%
85%
11 Pere Romea, 2014
Esters through Addition-Elimination Transformations
O O O
H + R N C N R + HOR2 R2 + R R
R1 O R1 O N N
Carbodiimide H H
O O
H O NHR O O
R1 O R1 O
H R2 + R R
R1 O NR R1 O N N
R N C N R R N C N
R H H
R OH Good leaving group
Neutral and aprotic apolar medium
DMAP is usually used as catalyst
O DCC: DiCiclohexylCarbodiimide O
O
OH O N C N O
H H
+ HO
DMAP cat, CH2Cl2
97%
H 12 H Pere Romea, 2014
Esters through Addition-Elimination Transformations
O O O O
R2OH
o R2
R1 Cl R1 O R1 R3N R1 O
Good leaving groups
O O
O PhCOCl O
O O pyr, DMAP cat O O
Ac O CH2Cl2 Ac O
HO O
85% O
Ph
CO2Me CO2Me
Ac2O
OH OAc
Et3N, DMAP cat
OH OAc
CH2Cl2
95%
OH OAc
R1 O R1 O
Mixed anhydrides are usually prepared quantitatively
Cl Cl O2N
from acid chlorides or other anhydrides.
They are not isolated. Nu Nu
Yamaguchi Method Shiina Method
J. Org. Chem. 2004, 69, 1822
O O O Cl O O O O O
P P P
(OMe) Cl (OMe) H OBn (OMe)
Cl Cl HO O
BnO
PMBO O Et3N, DMAP PMBO O O Cl PMBO O H
95%
THFPhMe, ta
PMBO OH PMBO O PMBO O
Cl Cl
Nu
Me O O Me
X X
TBSO O TBSO O
X: NO2
Ph OH + HO Ph Ph O Ph
Et3N, DMAP cat, CH2Cl2
HO OH O OH Bafilomycin A (16)
OH NMe2
O O O OMe
O OH
O O OMe
O OH O
Erythromycin A (14) O OH
HO
HO
OMe
O
HO (C)n L
O (C)n
? O
Campagne, J. -M.
Pere Romea, 2014 15 Chem. Rev. 2006, 106, 911 & 2013, 113, PR1
Lactones in Natural Products
... but as the size of the ring increases, the cyclization mets the selectivity problem
O O O
k1 inter k2inter
L (C)n OH L (C)n O (C)n OH
vintra >> vinter
O
k1intra k2intra vintra = k1intra [S] vinter = k1inter [S]2
O O
vintra 1
O (C)n si k1intra k1inter =
monmer dmer vinter [S]
O O
O Cl
O O
Cl
O O
Cl Cl
O 1) Et3N, THF, rt O
OH O 1) PhMe, DMAP, 60 C O O
[S] = 30 mM
HOOC
O O O
78%
Me O O Me
O X X O
X: NO2
O OH O O O
O O
Et3N, DMAP, CH2Cl2, 40 C
HO [S] = 2.7 mM
O O
O 42%
O b) O a) O
+ HNR2R3 R2 + R2X
R1 L R1 N R1 NR3
R3
Acylation with acid chlorides and anhydrides No very common, but N-substitutions using
Via coupling agents: carbodiimides, HATU sterically unindexed alkyl halides are useful options.
Attention with E2
O O
H NaH, MeI Me
N N
Benz
O O O O
R2R3NH
o R2
R1 Cl R1 O R1 R3N R1 N
Good leaving groups R3
O O
1) SOCl2
OH NH 2
2) NH 3 excess
70%
O O
2 eq Me2NH Me
Cl N + Me2NH2 Cl
Me
85%
O O
Ac2O, pyr H
NH2 N
HO HO
90% O
19 Pere Romea, 2014
Amides through Addition-Elimination Transformations
O O O
H + R N C N R + HNR2R3 R2 + R R
R1 O R1 N N N
Carbodiimide
R3 H H
O O
H O NHR O O
R1 O R1 O
H R2 + R R
R1 O NR R1 N N N
R N C N R R N C N
R R3 H H
R2 NH Good leaving group
Neutral and aprotic apolar medium
R3
DMAP is usually used as catalyst
R2
HO Boc
O H N O H R2 O H R2
N O H N Boc TFA N H
RO H RO N RO N
DCC
R1 R1 O H R1 O H
Coupling Deprotection
Peptide synthesis
20 Pere Romea, 2014
Amides through Addition-Elimination Transformations
O NHR O O
HOXt
Xt R2
R1 O NR R1 O R1 N
O HOXt R3
R2 NH
R R
N N R3
H H
HOXt
O
N N
N N N OH
N N N
OH OH O
HOBt HOAt HOSu