Development of direct C-3 difluoromethylation reaction for application in synthesis of quinoline-related drugs

Abstract

Fluorine holds a prominent position within the realm of drug discovery and development, substantiated by its presence in approximately 25% of drugs approved by the US Food and Drug Administration (FDA). Consequently, the advancement of new fluorination reactions stands as a pivotal area in medicinal chemistry. In particular, the monofluoro-, difluoromethyl-, and trifluoromethyl- are three groups that appear most frequently in drug structure. Quinoline, owing to its privileged structural status, plays a crucial role in drug design and synthesis. Various approaches have been documented for the direct difluoromethylation of the C-2 and C-4 positions of the quinoline ring. However, achieving direct C-3 difluoromethylation has remained an elusive objective. In this study, we introduce a novel method for effecting the direct difluoromethylation at the C-3 position of the quinoline ring. Comprehensive characterizations, including ¹H-NMR, ¹³C-NMR, and ¹⁹F-NMR for all compounds are performed. We believe that this novel method will open a new way to access the hitherto untapped C-3-difluoromethylation active compounds.