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<p>Pyridines, as privileged scaffolds in drug design, can exhibit improved metabolic stability and target affinity through the strategic installation of fluorine or trifluoromethylamino groups at the C4 position. However, existing methods face fundamental challenges: the weak nucleophilicity of fluoride, low C4-site electrophilicity in pyridines and the lack of efficient approaches for NCF₃ moiety installation. Here we report an oxidative activation strategy that overcomes these limitations through oxidation of pyridyl phosphonium salts. This method not only enables the synthesis of both C4-fluorinated and C4-trifluoromethylaminated pyridines from common precursors but also exhibits exceptional functional group tolerance and practicality for bioactive molecules. The markedly enhanced bioactivity observed in the resulting analogues underscores the method’s transformative promise for medicinal chemistry. In addition, mechanistic studies suggest the formation of radical cation species, which lowers the activation barrier of nucleophilic attack.</p><p></p>

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Late-stage synthesis of C4-fluorinated and C4-trifluoromethylaminated pyridines

  • 期刊论文

  • 发表日期：

    2026年3月24日

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  • Longhui Chen,
  • Chenming Zu,
  • Fengyuan Zhang,
  • Yahui Ding,
  • Yu-Xin Luan,
  • Li Chen,
  • Pingping Tang

摘要

Pyridines, as privileged scaffolds in drug design, can exhibit improved metabolic stability and target affinity through the strategic installation of fluorine or trifluoromethylamino groups at the C4 position. However, existing methods face fundamental challenges: the weak nucleophilicity of fluoride, low C4-site electrophilicity in pyridines and the lack of efficient approaches for NCF₃ moiety installation. Here we report an oxidative activation strategy that overcomes these limitations through oxidation of pyridyl phosphonium salts. This method not only enables the synthesis of both C4-fluorinated and C4-trifluoromethylaminated pyridines from common precursors but also exhibits exceptional functional group tolerance and practicality for bioactive molecules. The markedly enhanced bioactivity observed in the resulting analogues underscores the method’s transformative promise for medicinal chemistry. In addition, mechanistic studies suggest the formation of radical cation species, which lowers the activation barrier of nucleophilic attack.