Functionalized Tetrahydropyridines by Enantioselective Phosphine-Catalyzed Aza - (4 + 2) Cycloaddition of N Sulfonyl-1-Aza-1,3-Dienes With Vinyl Ketones
Functionalized Tetrahydropyridines by Enantioselective Phosphine-Catalyzed Aza - (4 + 2) Cycloaddition of N Sulfonyl-1-Aza-1,3-Dienes With Vinyl Ketones
Functionalized Tetrahydropyridines by Enantioselective Phosphine-Catalyzed Aza - (4 + 2) Cycloaddition of N Sulfonyl-1-Aza-1,3-Dienes With Vinyl Ketones
pubs.acs.org/OrgLett
ABSTRACT: The development of electron-demand disfavored [4 + 2] cycloaddition of two electron-deficient reacting partners
poses a considerable challenge. An enantioselective aza-[4 + 2] cycloaddition of electron-deficient N-sulfonyl-1-aza-1,3-dienes is
possible with vinyl ketones via phosphine catalysis, which provides facile access to a wide range of enantioenriched
trifluoromethylated tetrahydropyridines in up to 97% yield with 97% ee and >20:1 dr. The mechanistic study indicated that this
cycloaddition proceeds via a tandem intermolecular aza-Rauhut−Currier/intramolecular aza-Michael addition reaction.
Scheme 1. Enantioselective Phosphine-Catalyzed Aza [4 + 2] Table 1. Variation of Aza Diene and Aryl Vinyl Ketone
Cycloaddition Components
ketones, catalyst P6 was identified as the best catalyst, and the Scheme 2. Gram-Scale Synthesis of 3a and Further Synthetic
substrate scope was then examined (Table S2). In general, the Transformationsa
reaction worked quite well, delivering the corresponding
products with excellent ee values and high dr values. Similar
to the reaction with aryl vinyl ketone, in general, β-
fluoroalkylated enone derived imines with electronically and
sterically different aromatic groups were also examined, and the
reaction could proceed smoothly to afford the desired products
(3bn−fo) with high stereoselectivity (Table S2, entries 1−13).
The absolute configuration of 3dn was established by single-
crystal X-ray diffraction analysis10 (see the SI).
The enantioselective cycloaddition between chalcone-derived
imines (4) and methyl vinyl ketone (2n) poses considerable
challenges due to their relatively lower reactivity.7a,7d Inspired a
Gram-scale reaction and synthetic applications. Reaction conditions:
by above results and with diverse catalysts in hand, we made (a) P7 (5 mol %), 1a (2.8 mmol), 2a (1.5 equiv), acetone (0.1 M), rt,
our efforts to this cycloaddition. Gratifyingly, as shown in Table 88% yield, 94% ee, dr > 20:1; (b) NaBH4, 0 °C, 90% yield, 90% ee, dr
2, the corresponding cycloadducts 5an−fn could be obtained in > 20:1; (c) RuCl3, NaIO4, 0 °C, 75% yield, 92% ee, dr > 20:1; (d)
TFA/thioanisole, rt, 70% yield, 93% ee, dr > 20:1; (e) BF3·Et2O,
Table 2. [4 + 2] Cycloaddition of Methyl Vinyl Ketones with Et3SiH, 70 °C, 80% yield, 94% ee, dr > 20:1; (f) NaCNBH3, MeOH/
Chalcone-Derived Iminesa AcOH, rt, 94% ee, dr >20:1.
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60−70% yields with 90−92% ee’s regardless of the substituent,
from electron-donating group MeO to weak electron-with-
ASSOCIATED CONTENT
drawing groups such as F, Cl, and Br and even strong electron-
withdrawing group CF3 with the chiral sulfinamide phosphine * Supporting Information
S
P2 as the catalyst, indicating that this type of cycloaddition is The Supporting Information is available free of charge on the
sensitive to the structure of the substrate and an appropriate ACS Publications website at DOI: 10.1021/acs.or-
catalyst must be correctly chosen. In addition, pentafluoro- glett.7b00489.
substituted N-tosyl ketimine gave the product 5gn with 75% Experimental procedures; spectroscopic data for the
yield and 92% ee (Table 2, entry 7). substrates and products (PDF)
In order to display the potential synthetic applications of this X-ray data for (−)-3dn (CIF)
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methodology, a gram-scale reaction of 1a and 2a was also
carried out to furnish 1.2 g of the desired product 3aa in 88% AUTHOR INFORMATION
yield and 94% ee with the use of 5 mol % of P7 as the catalyst
Corresponding Author
(Scheme 2). The selective reduction of carbonyl group
provided effective access to valuable chiral alcohol 6a in 90% *E-mail: [email protected].
yield as a single diastereomer (>20:1 dr) and 90% ee. The ORCID
diastereoselective dihydroxylation of the olefin moiety with Junliang Zhang: 0000-0002-4636-2846
RuCl3/NaIO4 delivered a functionalized piperidine 6b in 75%
yield with 92% ee. The deprotection of tosyl group was realized Notes
The authors declare no competing financial interest.
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by treatment of 3aa with TFA/thioanisole, and the imine
product 6c was obtained as single diastereomer in 70% yield
with 93% ee and trifluoromethylated piperidine 7c was ACKNOWLEDGMENTS
furnished in 90% yield with 94% ee by subsequent reduction We are grateful to the 973 Program (2015CB856600), the
with sodium cyanoborohydride. The enantioenriched piper- National Natural Science Foundation of China (21425205,
C DOI: 10.1021/acs.orglett.7b00489
Org. Lett. XXXX, XXX, XXX−XXX
Organic Letters Letter
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Adv. Synth. Catal. 2013, 355, 3351. (c) Zhang, X. N.; Dong, X.; Wei,
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D DOI: 10.1021/acs.orglett.7b00489
Org. Lett. XXXX, XXX, XXX−XXX