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Skeletal editing through direct nitrogen deletion of secondary amines


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.

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Fig. 1: Background.
Fig. 2: Development of an anomeric amide reagent.
Fig. 3: Scope of the nitrogen-deletion reaction promoted by reagent 1c.
Fig. 4: Mechanistic experiments.

Data availability

All data are available from the corresponding author upon reasonable request.


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We thank D. Nagib, F. D. Toste, M. Johnson and Z. Wickens for discussions. Financial support for this work was provided by start-up funding from the University of Chicago.

Author information




S.H.K., K.J.B. and B.D.D. designed and conducted experiments, and collected and analysed the data. M.D.L. supervised the research, conceived of the project and wrote the manuscript with input from all authors.

Corresponding author

Correspondence to Mark D. Levin.

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Competing interests

Reagent 1c is under development for commercialization with Sigma-Aldrich (product number 919799), but the authors have retained no financial interest and no patents have been filed.

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Supplementary information

Supplementary Information

This file contains Supplementary Sections 1-59, including Supplementary Materials and Methods, Procedures, Supplementary Figures 1-17, Supplementary References and NMR Spectra data – see contents page for details.

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Kennedy, S.H., Dherange, B.D., Berger, K.J. et al. Skeletal editing through direct nitrogen deletion of secondary amines. Nature 593, 223–227 (2021).

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