Carbon-to-nitrogen single-atom transmutation of azaarenes

• Published in: Nature (London) Vol. 623; no. 7985; pp. 77 - 82
• Main Authors: Woo, Jisoo, Stein, Colin, Christian, Alec H., Levin, Mark D.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.11.2023; NATURE PORTFOLIO; Nature Publishing Group
• Subjects: 140/131; 639/638/309/2144; 639/638/403/933; 639/638/403/934; Carbon; Carbon - chemistry; Chemistry Techniques, Synthetic; Development strategies; Direct conversion; Drug Design; Editing; Expulsion; FDA approval; Humanities and Social Sciences; Light emitting diodes; multidisciplinary; Multidisciplinary Sciences; Nitrogen; Nitrogen - chemistry; Organic compounds; Oxidation; Oxidation-Reduction; Perturbation; Pharmaceutical Preparations - chemical synthesis; Pharmaceutical Preparations - chemistry; Quinazolines - chemical synthesis; Quinazolines - chemistry; Quinolines; Quinolines - chemistry; Science; Science & Technology; Science & Technology - Other Topics; Science (multidisciplinary); Skeleton; Transmutation; OZONOLYSIS; QUINOLINE N-OXIDES; DESIGN; HETEROCYCLES; TRANSFORMATIONS; DELETION
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-023-06613-4

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 atom 1 . Replacing an aromatic carbon atom with a nitrogen atom would be enabling in the discovery of potential medicines 2 , but only indirect means exist to make such C-to-N transmutations, typically by parallel synthesis 3 . 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. A new type of transformation converting a heteroaromatic carbon atom into a nitrogen atom, turning quinolines into quinazolines to enable manipulation of molecular properties, is reported.