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<p>The direct synthetic approach from versatile and abundantly sourced carboxylic acids to nitriles has garnered considerable attention for a long time. However, the highly unfavourable thermodynamics of this process make it challenging to achieve under mild conditions and with broad functional-group tolerance. Here, inspired by biosynthetic pathways of nitrile synthesis and urea activation, we present a mild Mg- and Pd-cocatalysed nitrile synthesis from carboxylic acids with the simple, inexpensive and readily available urea as the nitrogen source. A pathway involving nucleophilic addition of carboxylic acid to urea is supported by both mechanistic studies and density functional theory calculations. This chemistry also demonstrates efficiency for the late-stage modification of complex drugs and natural products and offers substantial opportunities for the synthesis and optimization of valuable compounds.</p><p></p>

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Late-stage conversion of carboxylic acids to nitriles with Mg and Pd cocatalysis

  • 期刊论文

  • 发表日期：

    2025年11月18日

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  • Junhong Meng,
  • Mithun C. Madhusudhanan,
  • Teng Wang,
  • Zengrui Cheng,
  • Binzhi Zhao,
  • Hongwei Shi,
  • Licheng Yang,
  • Peng Liu,
  • Ning Jiao

摘要

The direct synthetic approach from versatile and abundantly sourced carboxylic acids to nitriles has garnered considerable attention for a long time. However, the highly unfavourable thermodynamics of this process make it challenging to achieve under mild conditions and with broad functional-group tolerance. Here, inspired by biosynthetic pathways of nitrile synthesis and urea activation, we present a mild Mg- and Pd-cocatalysed nitrile synthesis from carboxylic acids with the simple, inexpensive and readily available urea as the nitrogen source. A pathway involving nucleophilic addition of carboxylic acid to urea is supported by both mechanistic studies and density functional theory calculations. This chemistry also demonstrates efficiency for the late-stage modification of complex drugs and natural products and offers substantial opportunities for the synthesis and optimization of valuable compounds.