PAPER	Synthesis 2003: 1683-1692 DOI: 10.1055/s-2003-40888
© Georg Thieme Verlag Stuttgart ˙ New York
A Practical Oxone®-Mediated, High-Throughput, Solution-Phase Synthesis of Benzimidazoles from 1,2-Phenylenediamines and Aldehydes and its Application to Preparative Scale Synthesis
Pierre L. Beaulieu*, Bruno Haché, Elisabeth von Moos
Boehringer Ingelheim (Canada) Ltd., Research and Development, 2100 Cunard Street, Laval (Québec) H7S 2G5, Canada Fax: +1(450)6828434; e-Mail: pbeaulieu@lav.boehringer-ingelheim.com;
Received 31 March 2003

Abstract

Addition of oxone® to a mixture of a 1,2-phenylenediamine and an aldehyde in wet DMF at room temperature results in rapid formation of benzimidazoles under very mild conditions. The reaction is applicable to a wide range of substrates including aliphatic, aromatic and heteroaromatic aldehydes, and is not significantly affected by steric or electronic effects. In most cases, crude products are isolated in good to excellent yields (59-95%) and homogeneities (86-99%) by simple precipitation or extraction from the reaction mixture and do not require additional purification. Limitations to the scope of this methodology were encountered in cases where aldehydes were sensitive to oxone® under the acidic reaction conditions. The features of this methodology make it particularly well suited for the high-throughput, solution-phase synthesis of benzimidazole libraries. The low cost and simplicity of this procedure makes it equally attractive for preparative-scale syntheses where safety and environmental issues are of greater concern.

Key words

benzimidazoles - heterocycles - aldehydes - amines - oxone - combinatorial chemistry