Silica gel and microwave-promoted synthesis of dihydropyrrolizines and tetrahydroindolizines from enaminones

A wide range of N-(ethoxycarbonylmethyl)enaminones, prepared by the Eschenmoser sulfide contraction between N-(ethoxycarbonylmethyl)pyrrolidine-2-thione and various bromomethyl aryl and heteroaryl ketones, underwent cyclization in the presence of silica gel to give ethyl 6-(hetero)aryl-2,3-dihydro-1H-pyrrolizine-5-carboxylates within minutes upon microwave heating in xylene at 150 °C. Instead of functioning as a nucleophile, the enaminone acted as an electrophile at its carbonyl group during the cyclization. Yields of the bicyclic products were generally above 75%. The analogous microwave-assisted reaction to produce ethyl 2-aryl-5,6,7,8-tetrahydroindolizine-3-carboxylates from (E)-ethyl 2-[2-(2-oxo-2-arylethylidene)piperidin-1-yl]acetates failed in nonpolar solvents, but occurred in ethanol at lower temperature and microwave power, although requiring much longer time. A possible mechanism for the cyclization is presented, and further functionalization of the newly created pyrrole ring in the dihydropyrrolizine core is described.