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Carbon-to-nitrogen single-atom transmutation of azaarenes

Abstract

When searching for the ideal molecule to fill a particular functional role (for example, a medicine), the difference between success and failure can often come down to a single atom1. Replacing an aromatic carbon atom with a nitrogen atom would be enabling in the discovery of potential medicines2, but only indirect means exist to make such C-to-N transmutations, typically by parallel synthesis3. Here, we report a transformation that enables the direct conversion of a heteroaromatic carbon atom into a nitrogen atom, turning quinolines into quinazolines. Oxidative restructuring of the parent azaarene gives a ring-opened intermediate bearing electrophilic sites primed for ring reclosure and expulsion of a carbon-based leaving group. Such a ‘sticky end’ approach subverts existing atom insertion–deletion approaches and as a result avoids skeleton-rotation and substituent-perturbation pitfalls common in stepwise skeletal editing. We show a broad scope of quinolines and related azaarenes, all of which can be converted into the corresponding quinazolines by replacement of the C3 carbon with a nitrogen atom. Mechanistic experiments support the critical role of the activated intermediate and indicate a more general strategy for the development of C-to-N transmutation reactions.

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Fig. 1: Introduction.
Fig. 2: Scope of the C-to-N transmutation of azaarenes.
Fig. 3: Synthetic applications of C-to-N transmutation of azaarenes.
Fig. 4: Mechanistic experiments.

Data availability

All data are in the Supplementary Information or are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank the Rawal, Snyder and Dong groups (University of Chicago) for lending chemicals. We thank the Snyder group for use of an ozone generator and the Rawal group for use of a cryocooler. We thank T. Pearson (University of Chicago), A. Neel (Merck) and J. Del Pozo (Merck) for helpful discussions. Financial support for this work was provided by the National Institutes of Health (grant no. R35 GM142768).

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Authors and Affiliations

  1. Department of Chemistry, The University of Chicago, Chicago, IL, USA

    Jisoo Woo, Colin Stein & Mark D. Levin

  2. Discovery Chemistry, Merck & Co., Inc., Boston, MA, USA

    Alec H. Christian

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Contributions

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

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Alec H. Christian or Mark D. Levin.

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Supplementary Materials and Methods; general procedure for transmutation; graphical guide; general procedure for N-oxidation of azaarenes; starting material synthesis; one-pot transmutation; synthetic applications; mechanistic studies; optimization; limitations; references; and nuclear magnetic resonance spectra.

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Woo, J., Stein, C., Christian, A.H. et al. Carbon-to-nitrogen single-atom transmutation of azaarenes.
Nature 623, 77–82 (2023). https://doi.org/10.1038/s41586-023-06613-4

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  • Received: 08 June 2023

  • Accepted: 05 September 2023

  • Published: 01 November 2023

  • Issue Date: 02 November 2023

  • DOI: https://doi.org/10.1038/s41586-023-06613-4

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