Advancing Dearomative Difluoromethylation of N-heterocycles and Pharmaceuticals

Given the significant prevalence of N-heterocycles in small-molecule pharmaceuticals, the selective incorporation of a difluoromethyl (−CF2H) motif and the creation of a new functional group within the same molecular framework are 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, we introduce a new platform and broadly applicable technique for the difluoromethylation of various N-heterocyclic substrates using low-cost and commercially available bromo(difluoro)acetic acid in the presence of K2CO3 at room temperature to produce >70 desired complex Het−NCF2H products featuring either imine and/or ketone 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 more 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 grams), tolerant to diverse reactive functional groups with excellent chemoselectivity, adaptable to diversities of challenging N-heteroaromatic ring systems, and could be used for the late-stage diversification of 18 commercial drug molecules. Mechanistic investigation revealed the formation of N-difluoromethylquinolinium salt as a key intermediate, which occurs via nucleophilic substitution followed by decarboxylation with bromo(difluoro)acetic acid. 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 encompasses a full package of medicinally important functionalities (heterocycle, −NCF2H, and imine/keto), making them highly valuable in the preparation of chemical libraries and effective drugs.