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Skeletal editing through direct nitrogen deletion of secondary amines

Author

Listed:
  • Sean H. Kennedy

    (University of Chicago)

  • Balu D. Dherange

    (University of Chicago)

  • Kathleen J. Berger

    (University of Chicago)

  • Mark D. Levin

    (University of Chicago)

Abstract

Synthetic chemistry aims to build up molecular complexity from simple feedstocks1. However, the ability to exert precise changes that manipulate the connectivity of the molecular skeleton itself remains limited, despite possessing substantial potential to expand the accessible chemical space2,3. Here we report a reaction that ‘deletes’ nitrogen from organic molecules. We show that N-pivaloyloxy-N-alkoxyamides, a subclass of anomeric amides, promote the intermolecular activation of secondary aliphatic amines to yield intramolecular carbon–carbon coupling products. Mechanistic experiments indicate that the reactions proceed via isodiazene intermediates that extrude the nitrogen atom as dinitrogen, producing short-lived diradicals that rapidly couple to form the new carbon–carbon bond. The reaction shows broad functional-group tolerance, which enables the translation of routine amine synthesis protocols into a strategy for carbon–carbon bond constructions and ring syntheses. This is highlighted by the use of this reaction in the syntheses and skeletal editing of bioactive compounds.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:nature:v:593:y:2021:i:7858:d:10.1038_s41586-021-03448-9
    DOI: 10.1038/s41586-021-03448-9
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    Cited by:

    1. Qixue Qin & Liang Zhang & Jialiang Wei & Xu Qiu & Shuanghong Hao & Xiao-De An & Ning Jiao, 2024. "Direct oxygen insertion into C-C bond of styrenes with air," Nature Communications, Nature, vol. 15(1), pages 1-7, December.
    2. Haitao Qin & Ting Guo & Ken Lin & Guigen Li & Hongjian Lu, 2023. "Synthesis of dienes from pyrrolidines using skeletal modification," Nature Communications, Nature, vol. 14(1), pages 1-8, December.
    3. 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.
    4. Hanah Na & Liviu M. Mirica, 2022. "Deciphering the mechanism of the Ni-photocatalyzed C‒O cross-coupling reaction using a tridentate pyridinophane ligand," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    5. Hong Lu & Yu Zhang & Xiu-Hong Wang & Ran Zhang & Peng-Fei Xu & Hao Wei, 2024. "Carbon–nitrogen transmutation in polycyclic arenol skeletons to access N-heteroarenes," Nature Communications, Nature, vol. 15(1), pages 1-8, December.

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