biostudies-literatureWoo JNIGMS NIH HHS77-82https://www.ebi.ac.uk/biostudies/studies/S-EPMC10907950biostudies-literatureUnknown623(7985)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.NatureCarbon-to-nitrogen single-atom transmutation of azaarenes.PMC10907950R35 GM142768Levin MDChristian AHStein CWoo JfalseCarbon-to-nitrogen single-atom transmutation of azaarenes.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.2023-01-01T00:00:00Z2023 Nov2025-04-26T17:07:15.293Z2025-04-06T15:24:11.779ZS-EPMC109079503791494610.1038/s41586-023-06613-4