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Halogencarbene-free Ciamician-Dennstedt single-atom skeletal editing

Author

Listed:
  • Shaopeng Liu

    (Northeast Normal University)

  • Yong Yang

    (Northeast Normal University)

  • Qingmin Song

    (Northeast Normal University)

  • Zhaohong Liu

    (Northeast Normal University)

  • Paramasivam Sivaguru

    (Northeast Normal University)

  • Yifan Zhang

    (Northeast Normal University)

  • Graham Ruiter

    (Technion—Israel Institute of Technology)

  • Edward A. Anderson

    (University of Oxford)

  • Xihe Bi

    (Northeast Normal University
    Nankai University)

Abstract

Single-atom skeletal editing is an increasingly powerful tool for scaffold hopping-based drug discovery. However, the insertion of a functionalized carbon atom into heteroarenes remains rare, especially when performed in complex chemical settings. Despite more than a century of research, Ciamician-Dennstedt (C-D) rearrangement remains limited to halocarbene precursors. Herein, we report a general methodology for the Ciamician-Dennstedt reaction using α-halogen-free carbenes generated in situ from N-triftosylhydrazones. This one-pot, two-step protocol enables the insertion of various carbenes, including those previously unexplored in C-D skeletal editing chemistry, into indoles/pyrroles scaffolds to access 3-functionalized quinolines/pyridines. Mechanistic studies reveal a pathway involving the intermediacy of a 1,4-dihydroquinoline intermediate, which could undergo oxidative aromatization or defluorinative aromatization to form different carbon-atom insertion products.

Suggested Citation

  • Shaopeng Liu & Yong Yang & Qingmin Song & Zhaohong Liu & Paramasivam Sivaguru & Yifan Zhang & Graham Ruiter & Edward A. Anderson & Xihe Bi, 2024. "Halogencarbene-free Ciamician-Dennstedt single-atom skeletal editing," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54379-8
    DOI: 10.1038/s41467-024-54379-8
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    References listed on IDEAS

    as
    1. Mark Peplow, 2023. "‘Almost magical’: chemists can now move single atoms in and out of a molecule’s core," Nature, Nature, vol. 618(7963), pages 21-24, June.
    2. Hongyu Zhong & Dominic T. Egger & Valentina C. M. Gasser & Patrick Finkelstein & Loris Keim & Merlin Z. Seidel & Nils Trapp & Bill Morandi, 2023. "Skeletal metalation of lactams through a carbonyl-to-nickel-exchange logic," Nature Communications, Nature, vol. 14(1), pages 1-9, December.
    3. Aaron Sattler & Gerard Parkin, 2010. "Cleaving carbon–carbon bonds by inserting tungsten into unstrained aromatic rings," Nature, Nature, vol. 463(7280), pages 523-526, January.
    4. Sean H. Kennedy & Balu D. Dherange & Kathleen J. Berger & Mark D. Levin, 2021. "Skeletal editing through direct nitrogen deletion of secondary amines," Nature, Nature, vol. 593(7858), pages 223-227, May.
    5. Jose B. Roque & Yusuke Kuroda & Lucas T. Göttemann & Richmond Sarpong, 2018. "Deconstructive diversification of cyclic amines," Nature, Nature, vol. 564(7735), pages 244-248, December.
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