Title: Direct enantioselective C(sp3)−H coupling of N-alkyl anilines via metallaphotoredox catalysis

Authors: Weisai Zu, Xiang Wan, Haoran Wu, Jingwen Huo, Cankun Zhang, Chengyang Li, Yongliang Huang, Zhen Xu, Yumin Xu, Tao Li, Junliang Cheng, Jian-Liang Ye, Cheng Wang, Haohua Huo*

Abstract: Amine functionalization is crucial in pharmaceutical and agrochemical synthesis yet direct enantioselective α-C(sp³)–H functionalization of N-alkyl anilines remains challenging. Here we show a metallaphotoredox-catalysed radical approach for α-C(sp³)–H arylation of N-alkyl anilines, introducing a simple, sterically hindered aryl ketone photocatalyst. This key innovation slows undesired back-electron transfer, enabling efficient α-anilinoalkyl radical generation. Our strategy uses a sequential single-electron transfer and proton transfer process, thereby overcoming multiple limitations of existing methods. In conjunction with a chiral nickel catalyst, we have achieved site-selective, enantioselective arylation of diverse N-alkyl anilines with various (hetero)aryl halides. The method exhibits exceptional functional group tolerance, enabling modular functionalization of complex molecular structures. This approach provides an effective route to valuable α-aryl amines, offering significant possibilities for drug discovery and streamlining challenging synthetic sequences.

Full-Link: https://www.nature.com/articles/s41557-025-02018-0