A practical oxone-mediated high-throughput solution-phase synthesis of benzimidazoles from 1,2-phenylenediamines and aldehydes and its application to preparative scale synthesis

ORGN 381

Pierre L. Beaulieu, Bruno Haché, and Elisabeth von Moos. Department of Chemistry, Boehringer Ingelheim Canada Ltd, 2100 Cunard Street, Laval, QC H7S2G5, Canada
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.