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

Robin Klintworth,Willem A L Van Otterlo,Garreth L Morgans,Joseph P Michael,Charles B De Koning,Stefania M Scalzullo

doi:10.3762/bjoc.17.170

Abstract

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.

Highlights

Or fully saturated variants of the pyrrolizine nucleus 1 are widely occurring motifs in natural products
In the course of our attempts at the syntheses of aryl-bearing indolizidine alkaloids via N-phenacyl vinylogous amides such as 11, we fortuitously found substituted 2,3-dihydro1H-pyrrolizines 12 as unexpected products when intermediates 11 were exposed to acidic conditions, including treatment with acetic acid or even during chromatography on silica gel Results and Discussion
Microwave heating at 150 °C for no more than 10 minutes of a solution of 15a in xylene with montmorillonite K10, an acidic layered aluminosilicate clay often used as a catalyst in microwave-assisted organic synthesis [41,42,43,44], afforded the pyrrolizine 19a in a good yield of 84%, prolonged exposure even at ambient temperature led to decomposition (Table 1, entries 22 and 23)

Summary

Introduction

Or fully saturated variants of the pyrrolizine nucleus 1 are widely occurring motifs in natural products. In contrast to the corresponding N-phenacyl analogue 11 (Ar = Ar’ = Ph), the ester-containing enaminone 15a proved to be completely stable during chromatography on silica gel or upon dissolution in acetic acid at room temperature (conditions under which we had observed cyclization of vinylogous amides 11 [18]), and spontaneous cyclization to the expected pyrrolizinone 13a or tautomer 13a' did not take place (Table 1, entry 1).

Results

Conclusion