The hydroxyacetylpiperidines and their N‐benzyl derivatives. The 2‐hydroxymethyl‐2‐piperidyl‐ and 2‐hydroxymethyl‐2‐pyridyl‐1,3‐dioxolanes

Abstract The hydroxyacetylpiperidines, their ethylene ketals, and the N ‐benzyl derivatives of these new piperidines have been synthesized. Methylolation of 2‐(2‐ and 4‐pyridyl)‐1,3‐dioxolanes by heating with paraformaldehyde at 185° led to 2‐hydroxymethyl‐2‐(2‐ and 4‐pyridyl)‐i,3‐dioxolanes ( 7,8 , respectively). 2‐Hydroxymethyl‐2‐(3‐pyridyl)‐1,3‐dioxolane ( 13 ) was obtained by reaction of 2‐bromomethyl‐2‐(3‐pyridyl)‐1,3‐dioxolane with aqueous sodium hydroxide at 190°. Hydrogenation of these pyridine ketals with rhodium‐charcoal catalyst produced the corresponding piperidine ketals (16,17,18). Acid hydrolysis of the piperidine ketals and their N ‐benzyl derivatives led to the hydroxyacetylpiperidines (1,2,3) and their N ‐benzyl derivatives (25,26,27). The N ‐benzylhydroxyacetylpiperidines undergo rapid hydrogenolysis with palladium‐charcoal catalyst to produce the hydroxyacetylpiperidines. Further hydrogenation produces the piperidyl‐1,2‐ethanediols. The hydroxyacetylpiperidines are somewhat unstable, hygroscopic substances which polymerize with dehydration on standing; in solution they are relatively stable. Their N ‐benzyl, ketal, and hydrochloride salt derivatives, on the other hand, represent stable, synthetically useful intermediates from which the reactive trifunctional hydroxyacetylpiperidines may readily be prepared.