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<p>Arene difunctionalization offers a powerful strategy for the simultaneous installation of two functional groups in a single step. Despite recent advances, <i>ipso</i>/<i>para</i>-selective arene transformations remain underdeveloped. Herein, we report an <i>N</i>-heterocyclic carbene (NHC)-catalyzed radical protocol that addresses this challenge. The process features a unique generation of acyl-inserting Smiles rearrangement, wherein radical Meisenheimer intermediates are intercepted by NHC-bound radicals prior to rearomatization. Subsequent ketone deprotonation regenerates ionic Meisenheimer intermediates, thereby completing the rearrangement and affording 1,4-difunctionalized arenes. This organocatalytic protocol exhibits broad substrate scope, tolerates diverse functional groups, and delivers acylated aniline derivatives in excellent yields (96 examples, up to 98% yield). The synthetic potential is further showcased by a ring-expansion strategy to benzo[<i>b</i>]azepines and by late-stage functionalization of drug-like molecules. Mechanistic insights from combined experimental and computational studies shed light on the unique reactivity and the observed excellent site-selectivity.</p>

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Arene difunctionalization through an acyl-inserting Smiles rearrangement enabled by N-heterocyclic carbene catalysis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月15日

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  • Qing-Zhu Li,
  • Yan-Qing Liu,
  • Long-Hai Hong,
  • Ting Qi,
  • Mei-Hao He,
  • Peng-Tao Wang,
  • Xin-Xin Kou,
  • Jun-Long Li

摘要

Arene difunctionalization offers a powerful strategy for the simultaneous installation of two functional groups in a single step. Despite recent advances, ipso/para-selective arene transformations remain underdeveloped. Herein, we report an N-heterocyclic carbene (NHC)-catalyzed radical protocol that addresses this challenge. The process features a unique generation of acyl-inserting Smiles rearrangement, wherein radical Meisenheimer intermediates are intercepted by NHC-bound radicals prior to rearomatization. Subsequent ketone deprotonation regenerates ionic Meisenheimer intermediates, thereby completing the rearrangement and affording 1,4-difunctionalized arenes. This organocatalytic protocol exhibits broad substrate scope, tolerates diverse functional groups, and delivers acylated aniline derivatives in excellent yields (96 examples, up to 98% yield). The synthetic potential is further showcased by a ring-expansion strategy to benzo[b]azepines and by late-stage functionalization of drug-like molecules. Mechanistic insights from combined experimental and computational studies shed light on the unique reactivity and the observed excellent site-selectivity.