One-pot synthesis of tetrahydroindolizines by catalytic intra- and intermolecular alkylation of 1,2-disubstituted pyrroles

Abstract

Tetrahydroindolizine fragment is a structural unit of many natural and unnatural compounds possessing diverse biological activity [1–3]. Known methods for the preparation of tetrahydroindolizine derivatives are tedious, and the yields of the target products are poor [4, 5]. Therefore, development of new procedures for their synthesis is an important problem in medicinal and organic chemistry. In the present communication we report on a new convenient one-step procedure for the synthesis of tetrahydroindolizines via successive intraand intermolecular alkylations of 2-methyland 2-phenyl-1(4,4-diethoxybutyl)pyrroles I and II in the presence of a catalytic amount of Yb(OTf)3 (Scheme 1). The yields of compounds III and IV were 40–45% when the reactions were carried out in tetrahydrofuran at room temperature over a period of three days. A probable mechanism of formation of tetrahydroindolizines III and IV (Scheme 2) involves intramolecular nucleophilic addition of C in the pyrrole ring at the acetal carbon atom in the side chain, which bears a partial positive charge enhanced by interaction with the catalyst. Intramolecular ring closure in intermediate complex A gives complex B which reacts with the second substrate molecule, and subsequent elimination of ethanol yields the final product.