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<p>Direct <i>meta</i>-halogenation of pyridines and their derivatives remains a formidable challenge in synthesis. Temporary dearomatization strategies provide potential solutions, while multistep synthetic routes with substantial generation of chemical waste raise costs for installing a single halogen atom into pyridines. Here we report visible-light-induced single-step <i>meta</i>-selective radical bromination and chlorination of pyridines using commercial reagents. We show how the key intermediates—pyridinium radical cations, with their tendency to undergo radical coupling—overcome the reluctant halogenation reactivity of pyridines, which differs conceptually from previous umpolung temporary dearomatization strategies. Simultaneously, the spin density distribution on pyridinium radical cations, combined with the suggested π–π stacked structure of intermediates, controls the <i>meta</i>-selective reaction with halogen radicals. These simple, mild and robust reaction conditions distinguish this transformation from other reported <i>meta</i>-selective halogenation reactions.</p><p></p>

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Spin-density-controlled radical coupling for meta-selective C–H halogenation of pyridines

  • 期刊论文

  • 发表日期：

    2025年9月2日

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  • Jihua Zhang,
  • Guozhen Wu,
  • Yifei Zhao,
  • Xinlian Liu,
  • Hance Zhu,
  • Armido Studer,
  • Xiaotian Qi,
  • Qiang Cheng

摘要

Direct meta-halogenation of pyridines and their derivatives remains a formidable challenge in synthesis. Temporary dearomatization strategies provide potential solutions, while multistep synthetic routes with substantial generation of chemical waste raise costs for installing a single halogen atom into pyridines. Here we report visible-light-induced single-step meta-selective radical bromination and chlorination of pyridines using commercial reagents. We show how the key intermediates—pyridinium radical cations, with their tendency to undergo radical coupling—overcome the reluctant halogenation reactivity of pyridines, which differs conceptually from previous umpolung temporary dearomatization strategies. Simultaneously, the spin density distribution on pyridinium radical cations, combined with the suggested π–π stacked structure of intermediates, controls the meta-selective reaction with halogen radicals. These simple, mild and robust reaction conditions distinguish this transformation from other reported meta-selective halogenation reactions.