Indolizines. II. A facile synthesis of 3-Alkoxycarbonyl-, 3-Cyano-, and 3-Carbamoyl-indolizines and its mechanism

Abstract

Acylative cyclization of 1-benzyl-, 1-alkoxycarbonylmethyl-, 1-cyanomethyl-, and 1-oximinomethyl-2-methylpyridinium salts gives good yields of 2,3-disubstituted, and 1-acyl-2,3-disubstituted, indolizines. This general method provides a novel and convenient route to indolizines bearing those electronegative 3-substituents which can be removed or modified, and hence offers considerable potential for the synthesis of 1,2-disubstituted and 2-substituted indolizines. With appropriately 2-substituted pyridinium salts this method also provides syntheses of 1-acetoxy-2,3-disubstituted and other l,2,3-trisubstituted indolizines. Hydroxypyridines give acetoxyindolizines in good yield. Product studies have shown conclusively that acyl-and diacyl-methines are the major intermediates in this reaction. Ethyl chloroformate reacts selectively with indolizines to give good yields of ethyl indolizine-3-carboxylates. These products and also 3-cyanoindolizines are readily characterized by reaction with acid formaldehyde to give methylene-1,l'-diindolizines. N.m.r. data are reported for a number of indolizines and pyridinium salts.