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<p>Skeleton diversity is an important feature of compound libraries and plays a key role in the success of biological screening. Ligand-controlled divergent synthesis can transform the same substrate into different molecular skeletons, which not only can endow compound libraries with diverse biological activities but also reveal new catalytic modes, and therefore has received extensive attention. Herein, we disclose a Ni-catalyzed, ligand-controlled switchable skeletal rearrangement reaction of acryloyl <i>o</i>-bromobenzamides and activated alkenes. In this protocol, modification of the ligand backbone allows the conversion of the same starting material into four structurally distinct scaffolds of pharmacological importance. Specifically, the use of terpyridine ligand favors the 6-<i>exo</i> cyclization and subsequent 1,2-acyl/Ni dyotropic rearrangement to generate highly functionalized cyclohexenols, while the sterically hindered <sup>iPr</sup>PDI ligand facilitates the 6-<i>exo</i> cyclization and subsequent 1,2-aryl/Ni dyotropic rearrangement to form highly functionalized cycloheptenols. Furthermore, isoquinoline-1,3-diones were obtained through alkene diarylation in the absence of additional activated alkenes. More strikingly, the bidentate ligand promotes nucleophilic addition of the aryl halides to the amide carbonyl, followed by 1,4-acyl transfer and cross-coupling to afford 2-benzazepin-5-ones.</p>

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Nickel-catalyzed ligand-controlled switchable skeletal rearrangements: divergent synthesis of isoquinoline-1,3-diones, cyclohexenols, cycloheptenols, and 2-benzazepin-5-ones

  • 期刊论文

  • 发表日期：

    2025年2月6日

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  • Yongli Liu,
  • Yuanyuan Ping,
  • Wangqing Kong

摘要

Skeleton diversity is an important feature of compound libraries and plays a key role in the success of biological screening. Ligand-controlled divergent synthesis can transform the same substrate into different molecular skeletons, which not only can endow compound libraries with diverse biological activities but also reveal new catalytic modes, and therefore has received extensive attention. Herein, we disclose a Ni-catalyzed, ligand-controlled switchable skeletal rearrangement reaction of acryloyl o-bromobenzamides and activated alkenes. In this protocol, modification of the ligand backbone allows the conversion of the same starting material into four structurally distinct scaffolds of pharmacological importance. Specifically, the use of terpyridine ligand favors the 6-exo cyclization and subsequent 1,2-acyl/Ni dyotropic rearrangement to generate highly functionalized cyclohexenols, while the sterically hindered iPrPDI ligand facilitates the 6-exo cyclization and subsequent 1,2-aryl/Ni dyotropic rearrangement to form highly functionalized cycloheptenols. Furthermore, isoquinoline-1,3-diones were obtained through alkene diarylation in the absence of additional activated alkenes. More strikingly, the bidentate ligand promotes nucleophilic addition of the aryl halides to the amide carbonyl, followed by 1,4-acyl transfer and cross-coupling to afford 2-benzazepin-5-ones.