Dearomative Difluoromethylation of N-Heterocycles and Pharmaceuticals with Bromo(difluoro)acetic Acid

Given the significant prevalence of N-heterocycles in small-molecule pharmaceuticals, the selective N-difluoromethylation is of paramount importance in drug discovery and development. However, such integrated approaches remain underexplored, presumably due to the lack of efficient synthetic methods. In the present research, for the first time, we introduce a new and broadly applicable technique for the scalable difluoromethylation of N-heterocyclic substrates, including drugs using low-cost and commercially available bromo(difluoro)acetic acid in the presence of K₂CO₃ at room temperature to produce 45 desired complex Het-NCF₂H products featuring an imine functional group, which were hitherto impossible to produce. Depending on the type of N-heterocycle, this advance also permits the inclusion of two CF₂H units. Crucial to success is the nucleophilicity and less steric hindrance on the nitrogen atom of the heteroarene ring that enables N-difluoromethylative dearomatization of N-heterocycles. Overall, this unique transformation was transition metal-free, practical, scalable (>50 g), tolerant to diverse reactive functional groups with excellent chemoselectivity, and adaptable for difluoromethylation of commercial drug molecules. Ultimately, we have also unveiled a prominent synthetic application for rapid hydrodefluorinative reduction in a single step to access complex N-methylated Fsp³-enriched motif. This cost-effective strategy increases the synthetic access of N-difluoromethylated compounds.