Synthesis of 3,4-disubstituted piperidines by carbonyl ene and prins cyclizations: switching between kinetic and thermodynamic control with Brønsted and Lewis acid catalysts

The Journal of Organic Chemistry
Jodi T WilliamsJohn S Snaith

Abstract

A novel approach to cis and trans 3,4-disubstituted piperidines is described. Carbonyl ene cyclization of aldehydes 4a-e catalyzed by MeAlCl(2) in refluxing chloroform afforded the trans piperidines 7a-e with diastereomeric ratios of up to 93:7, while aldehyde 4f afforded solely the cis product 6f, which was resistant to isomerization to the trans isomer. It was demonstrated for 4a that the cyclization catalyzed by a variety of Lewis acids at low temperature proceeded under kinetic control to afford predominantly the cis piperidine 6a, and this isomerized to the thermodynamically more stable trans piperidine 7a on warming. In contrast, Prins cyclization of 4a-e catalyzed by concentrated hydrochloric acid in CH2Cl2 at low temperature afforded cis piperidines 6a-e with diastereomeric ratios of up to >98:2. The yield and diastereoselectivity of these cyclizations could be improved by using HCl-saturated CH2Cl2 to form the corresponding chloride, followed by elimination of HCl effected by ammonia. Aldehydes 4f and 4galso cyclized in good yield under the latter conditions. Mechanistic studies supported by DFT calculations (B3LYP/6-31G(d)) suggest that the cyclizations proceed via a mechanism with significant carbocationic character,...Continue Reading

Citations

Oct 9, 2015·Journal of the American Chemical Society·Luping LiuBenjamin List
Jun 4, 2016·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Heidi A DahlmannLindsey O Davis
Apr 29, 2015·Organic & Biomolecular Chemistry·Hisanori ItohMasami Sakamoto
Mar 30, 2018·Organic & Biomolecular Chemistry·Pipas Saha, Anil K Saikia
Sep 20, 2008·Organic & Biomolecular Chemistry·Claire A M CariouJohn S Snaith
Nov 4, 2008·Journal of the American Chemical Society·Yuji KikukawaNoritaka Mizuno
Jan 5, 2011·The Journal of Organic Chemistry·Christoph SchnabelMartin Hiersemann
Jun 12, 2013·Journal of the American Chemical Society·Robert J ComitoDavid W C MacMillan

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