Truly catalytic Gewald synthesis of 2-aminothiophenes using piperidinium borate (Pip borate), a conjugate acid-base pair

Abstract

The Gewald reaction has been well-known for more than half a century as an excellent method providing bioactive 2-aminothiophene heterocycles from the reaction of carbonyl compounds, α cyanoacetates, and elemental sulfur, in the presence of amines in stoichiometric amounts. This work describes the use of salts of boric acid as conjugate acid-base pair in a truly catalytic amount for the cyclocondensation of ketones with active methylenes like malononitrile, ethyl cyanoacetate, and benzoyl acetonitrile with sulfur to give 2-aminothiophenes via Gewald reaction. The present protocol is also applied for synthesizing Tinoridine an anti-peroxidative NSAID with an excellent yield. Additionally, the catalyst has great recyclability and reusability.