Aromatic nitrogen scanning by ipso -selective nitrene internalization

• Published in: Science (American Association for the Advancement of Science) Vol. 381; no. 6665; pp. 1474 - 1479
• Main Authors: Pearson, Tyler J, Shimazumi, Ryoma, Driscoll, Julia L, Dherange, Balu D, Park, Dong-Il, Levin, Mark D
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 29.09.2023
• Subjects: Aromatic compounds; Drug development; Internalization; Molecular structure; Nitrogen; Oxidants; Oxidizing agents; Photochemicals; Pyridines
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.adj5331

Nitrogen scanning in aryl fragments is a valuable aspect of the drug discovery process, but current strategies require time-intensive, parallel, bottom-up synthesis of each pyridyl isomer because of a lack of direct carbon-to-nitrogen (C-to-N) replacement reactions. We report a site-directable aryl C-to-N replacement reaction allowing unified access to various pyridine isomers through a nitrene-internalization process. In a two-step, one-pot procedure, aryl azides are first photochemically converted to 3 -azepines, which then undergo an oxidatively triggered C2-selective cheletropic carbon extrusion through a spirocyclic azanorcaradiene intermediate to afford the pyridine products. Because the carbon of the aryl nitrene is excised from the molecule, the reaction proceeds regioselectively without perturbation of the remainder of the substrate. Applications are demonstrated in the abbreviated synthesis of a pyridyl derivative of estrone, as well as in a prototypical nitrogen scan.