Telescoped continuous flow synthesis of benzimidazoles from o-phenylenediamines and carboxylic acids

Abstract

Benzimidazole and its derivatives are a versatile class of scaffolds found in a variety of pharmaceuticals and synthetic chemistry. Herein, we describe a continuous flow method for the telescoped synthesis of benzimidazoles from o-phenylenediamines and carboxylic acids via monoacylation and subsequent acid-catalyzed cyclization. This protocol enables efficient and straightforward access to benzimidazoles under mild conditions and short residence times (20 minutes). The wide substrate scope of this continuous flow synthetic method was confirmed through the synthesis of 32 different benzimidazoles. Moreover, the scalability of this methodology was further established through the gram-scale synthesis of the respective key intermediates for ravidasvir and ledipasvir, demonstrating its potential for industrial pharmaceutical applications.