Sodium fluoride-assisted, solvent-controlled regioselective synthesis of 2-substituted and 1,2-disubstituted benzimidazoles with diverse substituents, and unveiling mechanistic insights

Abstract

The regioselective formation of 2-substituted benzimidazoles and 1,2-disubstituted benzimidazoles with similar substituents at N1 and C2-positions has been achieved by the reaction of o-phenylenediamine derivatives with different aldehydes in the presence of sodium fluoride (NaF) in two different polar solvents. This method is simple, economical, and applicable to a wide range of aldehydes. The method aids in forming 2-substituted benzimidazoles in anhydrous dimethylformamide and 1,2-disubstituted benzimidazoles with similar substituents in glacial acetic acid in excellent yields when using 4.76 mol% of NaF as the catalyst. Furthermore, we have demonstrated the synthesis of 1,2-disubstituted benzimidazoles with dissimilar substitutions at N1 and C2-positions utilizing a one-pot method that eliminates the need to isolate the intermediate 2-substituted benzimidazole. The structure of 1,2-disubstituted benzimidazole (11p) was confirmed using single crystal X-ray diffraction analysis in addition to the spectral studies. These findings emphasize the practical feasibility of our approach to the production of benzimidazole-based drug molecules.