jo052532+_si_017.pdb (1.71 kB)

Synthesis of 3,4-Disubstituted Piperidines by Carbonyl Ene and Prins Cyclizations:  Switching between Kinetic and Thermodynamic Control with Brønsted and Lewis Acid Catalysts

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posted on 17.03.2006 by Jodi T. Williams, Perdip S. Bahia, Benson M. Kariuki, Neil Spencer, Douglas Philp, John S. Snaith
A novel approach to cis and trans 3,4-disubstituted piperidines is described. Carbonyl ene cyclization of aldehydes 4ae catalyzed by MeAlCl2 in refluxing chloroform afforded the trans piperidines 7ae 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 4ae catalyzed by concentrated hydrochloric acid in CH2Cl2 at low temperature afforded cis piperidines 6ae 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 4g also 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, with the cis carbocation being more stable than the trans carbocation. DFT calculations (B3LYP/6-31G(d)) of the transition state energies for concerted cyclization show that the cis piperidine is also the favored product from cyclization through a more concerted mechanism.