Aromatic nitrogen scanning by ipso-selective nitrene internalization

• 成果类型: Article
• 署名作者: Pearson, Tyler J.; Shimazumi, Ryoma; Driscoll, Julia L.; Dherange, Balu D.; Park, Dong-Il; Levin, Mark D.
• 署名单位: University of Chicago
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8591
• DOI: 10.1126/science.adj5331
• 发表日期: 2023-09-29
• 页码: 1474-1479
• 关键词: aryl azides; efficient synthesis; ring-contraction; basis-sets; DESIGN; photolysis; chemistry; rearrangement; methylation; derivatives

摘要

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 nitreneinternalization process. In a two-step, one-pot procedure, aryl azides are first photochemically converted to 3H-azepines, which then undergo an oxidatively triggered C2-selective cheletropic carbon extrusion through a spirocyclic azanorcaradiene intermediate to afford the pyridine products. Because the ipso 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.