Enantioselective Dearomatization–Rearomatization Strategy to Access Tertiary Alkyl Fluorides

作者：Hui-Ling Qian, Hongdan Deng, Saisai Yu, Yang Lei, Zhen‐Hua Wang, Yong You, Yu Zhao, Shengwen Yang, Wei‐Cheng Yuan, Jian‐Qiang Zhao · 发表于：ACS Catalysis · 年份：2025 · DOI：10.1021/acscatal.5c05643 · 被引用次数：8 · 研究领域：Fluorine in Organic Chemistry、Catalytic C–H Functionalization Methods、Catalytic Cross-Coupling Reactions

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 HNO 2 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.