Synthesis of 4,4‐disubstituted piperidine analogs of (±)‐cis‐N‐[1‐(2‐hydroxy‐2‐phenylethyl)‐3‐methyl‐4‐piperidyl]‐N‐phenylpropanamide

Condensation of (±)‐1‐benzyl‐3‐methyl‐4‐piperidone (1) with aniline followed by trapping of the intermediate imine with cyanide generated a mixture of isomeric nitriles 2A and 2B, the structures of which were established unambiguously by obtaining an X‐ray crystal structure on nitrile 2B. Subsequent elaboration of the nitrile intermediates provided analogs of (±)‐cis‐N‐[1‐(2‐hydroxy‐2‐phenylethyl)‐3‐methyl‐4‐piperidyl]‐N‐phenylpropanamide having a second substituent (carbomethoxyl, carboethoxyl, methoxymethyl) at the piper‐idine 4‐position. The conversion of the carboxamide intermediates 3A and 3B to the carboalkoxyl intermediates 5A, 5B and 6A was accomplished utilizing a modified esterification procedure. Proton nmr data are presented for both the final products and the key synthetic intermediates.