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<p>In drug development, the substitution of benzene rings in aniline-based drug candidates with saturated bridged bicyclic ring systems often enhances pharmacokinetic properties while preserving biological activity. However, current efforts predominantly focuses on bicyclo[1.1.1]pentylamines, accessing analogs capable of mimicking <i>ortho</i>- and <i>meta</i>-substituted anilines remains challenging due to the lack of a versatile and modular synthetic methods. Herein, we present a modular approach to access a diverse array of saturated bioisosteres of anilines via photoelectrochemical-induced decarboxylative C(sp<sup>3</sup>)–N Coupling. The success of this reaction hinges on the merging the cooperative ligand-to-metal charge transfer (LMCT) with copper-catalyzed amination. Notably, this net-oxidative C(sp<sup>3</sup>)–N forming reaction operates under mild electrode potentials and proceeds through hydrogen evolution, eliminating the need for external chemical oxidants. Our research enables the facile decarboxylative amination of a set of sp<sup>3</sup>-rich small-ring cage carboxylic acids, thus offering a versatile bioisosteric replacement for <i>ortho</i>-, <i>meta</i>-, and <i>para</i>-substituted anilines and di(hetero)aryl amines.</p>

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Modular access to saturated bioisosteres of anilines via photoelectrochemical decarboxylative C(sp3)–N coupling

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年1月22日

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  • Kang-Ning Yuan,
  • Hongjun Zhuang,
  • Jie Wei,
  • Yu Shen,
  • Hong-Qing Yao,
  • Ming-Hong Li,
  • Lin-Lin Xu,
  • Ming Shang

摘要

In drug development, the substitution of benzene rings in aniline-based drug candidates with saturated bridged bicyclic ring systems often enhances pharmacokinetic properties while preserving biological activity. However, current efforts predominantly focuses on bicyclo[1.1.1]pentylamines, accessing analogs capable of mimicking ortho- and meta-substituted anilines remains challenging due to the lack of a versatile and modular synthetic methods. Herein, we present a modular approach to access a diverse array of saturated bioisosteres of anilines via photoelectrochemical-induced decarboxylative C(sp3)–N Coupling. The success of this reaction hinges on the merging the cooperative ligand-to-metal charge transfer (LMCT) with copper-catalyzed amination. Notably, this net-oxidative C(sp3)–N forming reaction operates under mild electrode potentials and proceeds through hydrogen evolution, eliminating the need for external chemical oxidants. Our research enables the facile decarboxylative amination of a set of sp3-rich small-ring cage carboxylic acids, thus offering a versatile bioisosteric replacement for ortho-, meta-, and para-substituted anilines and di(hetero)aryl amines.