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<p>Transition<i>-</i>metal-catalysed asymmetric radical functionalization of N<i>-</i>heteroarene derivatives remains a substantial challenge. The asymmetric azidation of N-heteroarene derivatives remains unattainable with current catalytic systems, probably due to catalyst poisoning. Here we develop a strong chelating tridentate PyAP ligand, which allows the formation of the mono-azido Cu(II) intermediate and further prevents the successive binding of N<i>-</i>heteroarenes that might lead to catalyst poisoning. Thus, the Cu/PyAP catalytic system shows excellent reactivity, together with high enantioselectivity induced by the chiral environment close to the metal centre. Mechanistic studies and density functional theory calculations suggest that the asymmetric azidation proceeds through an intramolecular homolytic substitution pathway, with the pyridyl alkyl radical bound to Cu. The Cu/PyAP catalytic system realizes both the asymmetric azido difunctionalization of N<i>-</i>heteroaryl ethylenes and the azidation of the N-heterobenzyl halides in high yield and enantiomeric excess, thereby expediting the synthesis of various chiral drugs, natural products and bioactive compounds featuring the chiral azido N<i>-</i>heteroarene motif.</p><p></p>

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Unlocking the Cu-catalysed asymmetric radical azidation of N-heterobenzylic sites through rational ligand design

  • 期刊论文

  • 发表日期：

    2026年6月30日

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  • Yifan Lei,
  • Zitong Chen,
  • Hongyou Guo,
  • Qiyang Yuan,
  • Aoping Zhu,
  • Zixin Zhang,
  • Yuhongxu Bai,
  • Xiaotian Qi,
  • Caiyou Chen

摘要

Transition-metal-catalysed asymmetric radical functionalization of N-heteroarene derivatives remains a substantial challenge. The asymmetric azidation of N-heteroarene derivatives remains unattainable with current catalytic systems, probably due to catalyst poisoning. Here we develop a strong chelating tridentate PyAP ligand, which allows the formation of the mono-azido Cu(II) intermediate and further prevents the successive binding of N-heteroarenes that might lead to catalyst poisoning. Thus, the Cu/PyAP catalytic system shows excellent reactivity, together with high enantioselectivity induced by the chiral environment close to the metal centre. Mechanistic studies and density functional theory calculations suggest that the asymmetric azidation proceeds through an intramolecular homolytic substitution pathway, with the pyridyl alkyl radical bound to Cu. The Cu/PyAP catalytic system realizes both the asymmetric azido difunctionalization of N-heteroaryl ethylenes and the azidation of the N-heterobenzyl halides in high yield and enantiomeric excess, thereby expediting the synthesis of various chiral drugs, natural products and bioactive compounds featuring the chiral azido N-heteroarene motif.