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<p>The construction of quaternary carbon centers at the <i>para</i>-position of benzamide derivatives is of significant importance for the synthesis of pharmaceutical agents and their key precursors. Such structural motifs can serve directly as small-molecule targeted compounds or be further elaborated into complex ligand architectures to meet diverse pharmacological requirements. However, achieving high selectivity in the formation of these quaternary carbon centers remains a long-standing challenge. We herein report a method for the <i>para</i>-selective construction of quaternary carbon centers on benzamide derivatives via iron catalysis. This transformation proceeds at room temperature using benzamide derivatives and tertiary alkyl Grignard reagents. By employing a catalytic system comprising inexpensive iron(II) salt and <i>tert</i>-butylmagnesium chloride, this method enables the introduction of sterically demanding tertiary alkyl groups at the <i>para</i>-position with high regioselectivity, effectively suppressing common side reactions such as alkyl group isomerization or <i>ortho</i>-alkylation. This approach exhibits a diverse range of applicable aryl amides, though <i>N</i>-alkyl substrates are not tolerated.</p> Graphical abstract <p></p>

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Iron-catalyzed para-selective alkylation of aryl amides with tertiary Grignard reagents

  • 期刊论文

  • 发表日期：

    2026年3月22日

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  • Bohao Wang,
  • Baowei Wu,
  • Deng Deng,
  • Hongfeng Ji,
  • Pei Liu,
  • Jie Kong

摘要

The construction of quaternary carbon centers at the para-position of benzamide derivatives is of significant importance for the synthesis of pharmaceutical agents and their key precursors. Such structural motifs can serve directly as small-molecule targeted compounds or be further elaborated into complex ligand architectures to meet diverse pharmacological requirements. However, achieving high selectivity in the formation of these quaternary carbon centers remains a long-standing challenge. We herein report a method for the para-selective construction of quaternary carbon centers on benzamide derivatives via iron catalysis. This transformation proceeds at room temperature using benzamide derivatives and tertiary alkyl Grignard reagents. By employing a catalytic system comprising inexpensive iron(II) salt and tert-butylmagnesium chloride, this method enables the introduction of sterically demanding tertiary alkyl groups at the para-position with high regioselectivity, effectively suppressing common side reactions such as alkyl group isomerization or ortho-alkylation. This approach exhibits a diverse range of applicable aryl amides, though N-alkyl substrates are not tolerated.

Graphical abstract