Difluorocarbene-Promoted Regioselective Ring-Opening of Benzimidazoles

This study presents a regioselective ring-opening method for 2-substituted benzimidazoles, utilizing in situ-generated difluorocarbene as a key electrophile. Employing sodium chlorodifluoroacetate as the carbene precursor and Na₂CO₃ as the base, the reaction directly affords valuable 2-carbonyl phenyl isocyanides. Mechanistic studies, including HRMS (using ¹⁸O-labeled water) and Hammett analysis, confirm that the reaction proceeds via a difluorocarbene-derived N-CF₂ ylide intermediate, followed by water nucleophilic attack at the C2 position. This cascade process results in the simultaneous introduction of an isocyanide and a carbonyl group, demonstrating a novel hydrolysis/functionalization strategy. The methodology features a broad substrate scope, successful gram-scale synthesis, and versatile downstream derivatization of the isocyanide products, offering a new and practical approach for heterocycle editing and drug synthesis.