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Divergent alkynylative difunctionalization of amide bonds through C–O deoxygenation versus C–N deamination

Author

Listed:
  • Feng Liu

    (Hunan University
    Hunan First Normal University)

  • Xueyuan Yan

    (Tianjin University)

  • Fangfang Cai

    (Hunan University)

  • Wenjuan Hou

    (Hunan University)

  • Jianyu Dong

    (Hunan University
    Hunan First Normal University)

  • Shuang-Feng Yin

    (Hunan University)

  • Genping Huang

    (Tianjin University)

  • Tieqiao Chen

    (Hainan University)

  • Michal Szostak

    (73 Warren Street)

  • Yongbo Zhou

    (Hunan University)

Abstract

The transformation and utilization of amides are significant in organic synthesis and drug discovery. Here we demonstrate a divergent alkynylative difunctionalization of amides in a single transformation. In this reaction, amides react with an organometallic nucleophile to form a tetrahedral intermediate. By altering the N-substitution or the acyl group, the tetrahedral intermediate species selectively undergoes C–O or C–N cleavage with a concomitant capture by an alkynyl nucleophile generated in situ. This process enables the selective introduction of two different functional groups into the amide molecular architecture, producing valuable propargyl amine and propargyl alcohol products. The selectivity between deoxygenation and deamination process has been further elucidated by DFT calculations. Overall, this reaction successfully transforms the traditional mode of nucleophilic acyl addition to amides to a divergent C–O/C–N cleavage. The particularly wide substrate scope, including late-stage modification of bioactive molecules, demonstrates its potential broad applications in organic synthesis.

Suggested Citation

  • Feng Liu & Xueyuan Yan & Fangfang Cai & Wenjuan Hou & Jianyu Dong & Shuang-Feng Yin & Genping Huang & Tieqiao Chen & Michal Szostak & Yongbo Zhou, 2025. "Divergent alkynylative difunctionalization of amide bonds through C–O deoxygenation versus C–N deamination," Nature Communications, Nature, vol. 16(1), pages 1-11, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-024-55618-8
    DOI: 10.1038/s41467-024-55618-8
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    References listed on IDEAS

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    1. Liana Hie & Noah F. Fine Nathel & Tejas K. Shah & Emma L. Baker & Xin Hong & Yun-Fang Yang & Peng Liu & K. N. Houk & Neil K. Garg, 2015. "Conversion of amides to esters by the nickel-catalysed activation of amide C–N bonds," Nature, Nature, vol. 524(7563), pages 79-83, August.
    2. Fang-Fang Xu & Jin-Quan Chen & Dong-Yang Shao & Pei-Qiang Huang, 2023. "Catalytic enantioselective reductive alkynylation of amides enables one-pot syntheses of pyrrolidine, piperidine and indolizidine alkaloids," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    3. Wei Sun & Lu Wang & Yue Hu & Xudong Wu & Chungu Xia & Chao Liu, 2020. "Chemodivergent transformations of amides using gem-diborylalkanes as pro-nucleophiles," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    4. Vijaya R. Pattabiraman & Jeffrey W. Bode, 2011. "Rethinking amide bond synthesis," Nature, Nature, vol. 480(7378), pages 471-479, December.
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