Indolizines. I. A direct synthesis of acylindolizines from substituted pyridinium salts

Abstract

Several routes to 1-formylmethyl-2-methylpyridinium bromide have been investigated. Chichibabin cyclization of this salt to indolizine fails because the reaction system favours an intermolecular aldol condensation. A general one-step synthesis of acyl-and diacyl-indolizines from 1-(β-oxo)-alkyl-2-alkyl- and 1-(β-oxo)alkyl-2-benzyl-pyridinium salts is described. This synthesis, as effected by the anhydride of a weak aliphatic acid and its sodium salt, also gives isomeric products and these have provided a mechanistic reaction scheme of three competing pathways. 1-Acyl-2,3-disubstituted and 3-acyl-1,2-disubstituted indolizines are formed from the relevant salts by Chichibabin cyclization and subsequent in situ acylation. 1-Acetonyl-2-methylpyridinium bromide gives useful yields of 3-acyl-and 1,3-di-acyl-indolizines by this pathway and also via 1-acetonyl-2-acetylmethylene-l,2-dihydropyridine. The reaction of the corresponding 1-phenacyl salt involves acylated intermediates of type (14) and (15), and has provided evidence for the rearrangement of the diacylmethylides (15) to acylmethines (14). A facile thermal cyclization of 2-phenylpyridinium diphenacylmethylide to 3-benzoyl-1,2-diphenylindolizine is reported.