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<p>Aliphatic amines, such as <i>N</i>,<i>N</i>-dialkyl secondary amines, represent important scaffolds in bioactive molecules, driving significant interest in their regio- and stereoselective C–H functionalisation. While hydrogen atom transfer (HAT) provides a powerful radical-based approach to elaborate such amines, achieving controllable, regio-divergent, and enantioselective functionalisation across different <i>N</i>-alkyl groups remains challenging. Herein, we report a Cu-catalyzed <i>α’</i>/<i>β</i>-regiodivergent and <i>β</i>-enantioselective cyanation of secondary amine-derived ureas through tunable 1,4’/1,5-HAT. The utilization of a sterically demanding ligand <b>L14</b> enables the excellent <i>α’</i>-selective C–H cyanation at the <i>N</i>-methyl position, while two developed ligands (<b>L24</b> and <b>L41</b>) promote the <i>β</i>-chirality construction at the other <i>N</i>-alkyl group. The approach is demonstrated for a broad scope of ureas with wide functional group compatibility. Experimental and computational studies reveal two distinct reaction pathways regarding the different reactive sites (<i>α’</i>/<i>β</i>) and the choice of ligands could significantly influence the selectivity in HAT process.</p>

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Ligand-controlled regiodivergent and enantioselective C–H cyanation of secondary amines

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月20日

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  • Yang-Jie Mao,
  • Xiahe Chen,
  • Huan-Le Li,
  • Qi Pan,
  • Kun Zhou,
  • Zhen-Yuan Xu,
  • Yun-Fang Yang,
  • Shao-Jie Lou,
  • Dan-Qian Xu

摘要

Aliphatic amines, such as N,N-dialkyl secondary amines, represent important scaffolds in bioactive molecules, driving significant interest in their regio- and stereoselective C–H functionalisation. While hydrogen atom transfer (HAT) provides a powerful radical-based approach to elaborate such amines, achieving controllable, regio-divergent, and enantioselective functionalisation across different N-alkyl groups remains challenging. Herein, we report a Cu-catalyzed α’/β-regiodivergent and β-enantioselective cyanation of secondary amine-derived ureas through tunable 1,4’/1,5-HAT. The utilization of a sterically demanding ligand L14 enables the excellent α’-selective C–H cyanation at the N-methyl position, while two developed ligands (L24 and L41) promote the β-chirality construction at the other N-alkyl group. The approach is demonstrated for a broad scope of ureas with wide functional group compatibility. Experimental and computational studies reveal two distinct reaction pathways regarding the different reactive sites (α’/β) and the choice of ligands could significantly influence the selectivity in HAT process.