Carbon-to-nitrogen single-atom transmutation of azaarenes

Jisoo Woo, Colin Stein, Alec H. Christian () and Mark D. Levin ()
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Jisoo Woo: The University of Chicago
Colin Stein: The University of Chicago
Alec H. Christian: Merck & Co., Inc.
Mark D. Levin: The University of Chicago

Nature, 2023, vol. 623, issue 7985, 77-82

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41586-023-06613-4

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