Nickel-Catalyzed Asymmetric Reductive Arylation of α-Amino-CF 3 Acetates: A Strategy for the Enantioselective Synthesis of α-Trifluoromethyl Amine Derivatives

作者：Xue Chen, Yanran Yang, Shuli Li, Tianhao Chen, Hegui Gong, Xiaotai Wang, Weichen Huang · 发表于：ACS Catalysis · 年份：2025 · DOI：10.1021/acscatal.5c06406 · 被引用次数：4 · 研究领域：Fluorine in Organic Chemistry、Asymmetric Hydrogenation and Catalysis、Chemical Synthesis and Analysis

Enantioenriched α-trifluoromethyl (α-CF 3 ) amines are highly valuable as amide bioisosteres in medicinal chemistry; however, their general synthesis remains a challenge. We hereby report a Ni-catalyzed asymmetric reductive coupling of α-CF 3 amino acetates with (hetero)aryl halides, providing an efficient and versatile route to these chiral building blocks. Notably, the strategy is adaptable for the enantioselective synthesis of structurally related derivatives, including α-CF 2 H, α-CF 2 CF 3, and α-CF 2 Me-substituted amines, demonstrating broad utility. DFT studies have revealed Ni(III) to Ni(I) reductive elimination as the rate-determining step and elucidated the observed enantioselectivity. This approach overcomes the limitations of traditional methods, which often rely on linear synthetic routes, precious metal catalysts, and stoichiometric auxiliaries, thereby providing a practical strategy for accessing pharmaceutically relevant α-fluoroalkyl amines.