Enantioselective Dearomatization–Rearomatization Strategy to Access Tertiary Alkyl Fluorides

Fluorinated quaternary stereocenters have emerged as indispensable structural motifs in the development of pharmaceuticals. However, strategies for accessing enantioenriched fluorinated gem-diarylmethanes remain largely underdeveloped, with efficient catalytic enantioselective approaches for gem-diheteroaryl tertiary alkyl fluorides being particularly scarce. Herein, we report a general copper–biphosphine catalytic system for the enantioselective heteroarylation of 2-alkyl azaarenes with 2-nitroheteroarenes via a dearomatization–rearomatization process, enabling the modular synthesis of enantioenriched gem-diheteroarylalkanes featuring a fluorinated quaternary stereocenter. Mechanistic experimental studies and density functional theory (DFT) calculations suggest that the reaction proceeds through asymmetric dearomatized addition of chiral copper-ligated α-fluoro aza-heteroarenyl enolates to 2-nitroheteroarenes, followed by HNO2 elimination-driven rearomatization. This protocol features a wide substrate scope and high ee values (>60 examples, up to >99% ee), and its synthetic application is further demonstrated by downstream transformations and successful late-stage functionalization of complex bioactive molecules.