近日，厦门大学霍浩华团队报道了直接对映选择性C(sp³)金属光氧化还原催化N-烷基苯胺的H偶联。相关论文于2026年1月5日发表在《自然-化学》杂志上。

胺官能团化在药物和农药合成中至关重要，然而，N-烷基苯胺的直接对映选择性α-C(sp³)–H官能团化仍然具有挑战性。

研究组展示了一种金属光氧化还原催化自由基方法，用于N-烷基苯胺的α-C(sp³)–H芳基化，引入了一种简单且位阻较大的芳基酮光催化剂。这一关键创新减缓了不希望的反向电子转移，从而能够高效生成α-苯胺基烷基自由基。该策略采用顺序的单电子转移和质子转移过程，从而克服了现有方法的多种局限性。

结合手性镍催化剂，研究组实现了多种N-烷基苯胺与各种（杂）芳基卤化物的位点选择性和对映选择性芳基化。该方法具有优异的官能团耐受性，能够对复杂分子结构进行模块化官能团化。该方法为制备有价值的α-芳基胺提供了一条有效途径，为药物发现和简化具有挑战性的合成序列提供了重要可能性。

附：英文原文

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

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

Issue&Volume: 2026-01-05

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.

DOI: 10.1038/s41557-025-02018-0

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