JARED L. PIPER¹,*, STANLEY P. KOLIS¹, CHAOYU XIE¹, MARTIAL BERTRAND², PASCAL BOQUEL²
*Corresponding author
1. Eli Lilly and Company, Lilly Corporate Centre, Chemical Product Research and Development, Indianapolis, IN 46285, USA
2. Eli Lilly & Company, Lilly Development Centre, Chemical Product Research and Development, S.A., Rue Granbonpré 11, Mont-Saint-Guibert, B-1348, Belgium

Abstract

2-aryl pyrrolidine 1 was efficiently prepared in three steps starting from N-vinylpyrrolidinone and ethyl 3,5-dimethylbenzoate. The key steps highlight the use of a rearrangement and an iridium catalysed hydrogenation to afford the desired compound. This methodology was utilised to prepare several differentially 2-aryl-substituted pyrrolidines in good yield and enantiomeric excess, and is complimentary to existing methods to prepare molecules of this type.

INTRODUCTION

Chemical compounds containing the pyrrolidine structural motif are ubiquitous in nature, and are present in both the core of the amino acids proline and hydroxyproline, and the natural alkaloids nicotine and ficine. These heterocycles have been used by the pharmaceutical industry in the search for therapeutic agents (1). For this reason, methods to synthesize the pyrrolidine skeleton have received considerable attention (2). Substituted 2-phenylpyrrolidines are also used as intermediates for the preparation of tricyclic systems such as pyrrolo(2,1-a)isoquinolines which can exhibit pharmacological activities. A recent requirement to prepare an active pharmaceutical ingredient (API) for evaluation required the synthesis of the 2-aryl substituted pyrrolidine 1 (Figure 1) as a starting material.
Our initial synthesis of 1 is depicted in Scheme 1. It commenced with a Grignard reaction of 1-bromo-3,5-dimethylbenzene (2) and N-Boc-2-pyrrolidinone (3) to provide ketone 4 in 32 percent yield. Corey-Bakshi-Shibata (3) reduction of 4 using (S)-2-methyl-CBS-oxazaborolidine was followed by exposure to methanesulfonylchloride in dichloromethane to ...