A Practical Oxone®-Mediated, High-Throughput, Solution-Phase Synthesis of Benzimidazoles from 1,2-Phenylenediamines and Aldehydes and its Application to Preparative Scale Synthesis

Addition of oxone ® to a mixture of a 1,2-phenylenedi- amine 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 ali- phatic, aromatic and heteroaromatic aldehydes, and is not signifi- cantly affected by steric or electronic effects. In most cases, crude products are isolated in good to excellent yields (59-95%) and ho- mogeneities (86-99%) by simple precipitation or extraction from the reaction mixture and do not require additional purification. Lim- itations 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 proce- dure makes it equally attractive for preparative-scale syntheses where safety and environmental issues are of greater concern.