Abstract

A novel, simple and efficient laboratory scale continuous flow protocol has been elaborated for one-pot benzimidazole synthesis via a reductive cyclization method using the commercially available H-Cube Pro. Coupling with a stainless steel microreactor (4mL reactor volume), the acylation of o-nitroaniline was successfully joined in the hydrogenation step without any isolation or purification steps. This concept enabled a fully integrated process using a standard 5% Pt/C, sulfide catalyst for the reductive cyclization of 2-nitroacetanilide with quantitative yield. Compared with the previously reported batch processes, the present procedure facilitated efficient synthesis of a broad range of benzimidazole derivatives bearing functionalities sensitive to reductive cleavage and acidic conditions (10 compounds, 82 to >99% selectivity).

Keywords: Benzimidazole, continuous flow, reductive cyclization, one-pot, selective synthesis, heterocycles