Practical Preparation of Ethyl 2-Methylthiophene-3-carboxylate

Abstract

NoteThiophenes serve as the central pharmacophore in drug discovery and their bioisosteric replacement of a benzene ring is widely accepted as a powerful strategy to improve biological activities and pharmacodynamic and pharmacokinetic properties.1) Therefore, use of thiophenes as building blocks undoubtedly continues to receive much attention in the pharmaceutical industry.In connection with an ongoing program, we needed kilogram quantities of 2-methylthiophene-3-carboxylic acid (1) and its esters as starting raw materials. A medicinal researchbased route was based on C-2 methylation 2-4) of dianion of commercially available 3-thiophenecarboxylic acid (2). However, because of both the expense of the reagent 2 and the use of more than 2 eq of n-butyllithium at low temperature, this route is far from ideal for large-scale preparation of these raw materials. Among several precedent methods for preparation of the corresponding acid or esters, the Grignard approach is thought to be a straightforward solution. In this note, we describe a practical synthesis of 2-methylthiophene-3-carboxylic acid ethyl ester, capitalizing on the LiCl-mediated halogen-magnesium exchange reactions.This synthesis began with 2-methylthiophene, which was converted into 3-bromo-2-methylthiophene (3) according to literature methods. 5) As for preparation of the Grignard reagent from 3, the original work of Steinkopf and Jacob [6][7][8] involved treatment of 3 with magnesium by an entrained method, followed by coupling with carbon dioxide. However, all our attempts failed when using an array of the usual activators such as iodine and 1,2-dibromoethane, which was consistent with the findings of Rieke.9,10) In recent years, there have been several publications regarding the LiCl-mediated halogen-magnesium exchange reactions (TurboGrignard reagents) of 3-bromothiophenes, and therefore we turned our attention to this technology.11) Exchange reaction of 3 with 1.5 eq of i-PrMgCl/LiCl in tetrahydrofuran (THF) reached a maximum conversion of 94% after 3 h at reflux, while reaching plateaus of 81% and 50% of the conversions after 5 h at 40°C and room temperature, respectively. The ratios were determined by quantitative HPLC analysis of reaction aliquots after quenching with an excess of aqueous ammonium chloride. Extensive survey of other inexpensive Grignard reagents including EtMgBr and i-PrMgBr provided poor conversions (20-45%), illustrating the superiority of TurboGrignard. Conveniently, similar acceleration was observed when addition of LiCl to a THF solution of 3 was followed by treatment with i-PrMgCl. 12)With the successful conversion of 3 into the corresponding Grignard reagent 4 in hand, several electrophiles were examined for installation of an ethyl ester group, and ethyl chloroformate was found to be the choice of electrophile in terms of cost and efficacy. It should be noted that the use of inexpensive diethyl carbonate gave a decreased yield (70%) accompanied by formation of symmetrical ketone 6 (3%).The initial scale-up runs indicate...