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<p>Methylene-selective C–H functionalization at distal positions is a challenge in the field of Pd(II) catalysis. We have previously reported a ligand-enabled β,γ-C–H coupling with dihaloarenes for the synthesis of benzocyclobutenes (BCBs) as a promising class of scaffolds in drug discovery. Here we report a Pd(II)-catalysed method for the γ,δ-methylene C–H activation of free aliphatic acids and subsequent coupling with dihaloarenes, which offers an efficient route for the synthesis of diversely functionalized BCBs. The development of a carboxyl-pyridone ligand is crucial for the remote C(<i>sp</i><sup>3</sup>)–H activation. Notably, previous γ,δ-methylene C–H activation reactions of monoaliphatic acids are limited to carbocyclic substrates. The site-selective activation of γ,δ-C–H bonds installs the BCB pharmacophores that are one carbon atom further away from the carboxyl group than in previous studies. Given the carboxyl group can serve as hydrogen-bond donor or acceptor, such alternation of distance between two interactions can impact bioactivity.</p><p></p>

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Regiocontrollable [2 + 2] benzannulation of γ,δ-C(sp3)–H bonds with dihaloarenes using palladium catalysis

  • 期刊论文

  • 发表日期：

    2025年9月16日

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  • Liang Hu,
  • Jie-Lun Yan,
  • Yu-Kun Lin,
  • Daniel A. Strassfeld,
  • Jin-Quan Yu

摘要

Methylene-selective C–H functionalization at distal positions is a challenge in the field of Pd(II) catalysis. We have previously reported a ligand-enabled β,γ-C–H coupling with dihaloarenes for the synthesis of benzocyclobutenes (BCBs) as a promising class of scaffolds in drug discovery. Here we report a Pd(II)-catalysed method for the γ,δ-methylene C–H activation of free aliphatic acids and subsequent coupling with dihaloarenes, which offers an efficient route for the synthesis of diversely functionalized BCBs. The development of a carboxyl-pyridone ligand is crucial for the remote C(sp3)–H activation. Notably, previous γ,δ-methylene C–H activation reactions of monoaliphatic acids are limited to carbocyclic substrates. The site-selective activation of γ,δ-C–H bonds installs the BCB pharmacophores that are one carbon atom further away from the carboxyl group than in previous studies. Given the carboxyl group can serve as hydrogen-bond donor or acceptor, such alternation of distance between two interactions can impact bioactivity.