Synthesis of 2,5-Substituted Piperidines: Transposition of 1,4-Substitution Pattern for the Analgesic Drug R6582.

Article abstract of DOI:10.1016/S0040-4020(01)89901-4

This report describes the synthesis of cis 5-(1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)-2-p-fluorophenyl-1-methylpiperidine (1a) and the analogous cis and trans 1-benzylpiperidines 2a,b.Key steps in the synthesis were the α-chlorination of the lactams 5 and 6 (1-methyl- and 1-benzyl-6-p-fluorophenyl-2-piperidinone), and nucleophilic substitution of the resulting cis and trans 3-chloro lactams 8a,b and 9a,b. 1H NMR analysis for the epimeric 3,6-substituted lactam compounds revealed a preferred axial orientation for the 3-chloro substituent and an equatorial orientation for the 3-(oxobenzimidazolyl) group.For the reduced compound, cis N-methyl piperidine 1a, a conformational equilibrium was observed.This was shifted to the <2ax,5eq> form for the cis N-benzyl analogue 2a. Keywords: 2,5-substituted piperidines, synthesis and conformational analysis, 3-chloro-2-piperidinones, Friedel-Crafts reaction, reductive amination