Stereochemical aspects of the synthesis of 4-benzoyl-1,3-dimethyl-4-phenylpiperidine from 1,3-dimethyl-4-piperidone

Abstract

1,3-Dimethyl-4-piperidone reacts stereospecifically with potassium cyanide to give the trans (3-Me/4-OH) cyanohydrin. This was converted to 1,3-dimethyl-4-hydroxy-4-diphenylhydroxymethylpiperidine which rearranged with zinc chloride – acetic anhydride to cis (3-Me/4-Ph) 4-benzoyl-1,3-dimethyl-4-phenylpiperidine. The stereochemistry of all the products was established from proton magnetic resonance (p.m.r.) data and from the properties of diastereoisomeric 4-benzoyl-4-phenylpiperidines prepared from isomeric 4-cyano-1,3-dimethyl-4-phenylpiperidines of known configuration. Stable epimeric (+NH) hydrochlorides of 4-carboxylate and 4-carbethoxy analogues of the cyanohydrin of 1,3-dimethyl-4-piperidone were detected in DMSO-d6 (p.m.r. evidence), and epimer formation in this series is discussed. The hot-plate activities in mice of some piperidine derivatives prepared during this work are reported.