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<p>Amine functionalization is crucial in pharmaceutical and agrochemical synthesis yet direct enantioselective α-C(<i>sp</i><sup>3</sup>)–H functionalization of <i>N</i>-alkyl anilines remains challenging. Here we show a metallaphotoredox-catalysed radical approach for α-C(<i>sp</i><sup>3</sup>)–H arylation of <i>N</i>-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 <i>N</i>-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.</p><p></p>

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

  • 期刊论文

  • 发表日期：

    2026年1月5日

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  • 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

摘要

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.