Aromatic nitrogen scanning by ipso-selective nitrene internalization

作者：Tyler J. Pearson, Ryoma Shimazumi, Julia L. Driscoll, Balu D. Dherange, Dong-Il Park, M. Levin · 发表于：Science · 年份：2023 · DOI：10.1126/science.adj5331 · 被引用次数：128 · 研究领域：Medicine

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 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. Description Editor’s summary Drug development often requires systematic modifications of molecular structures. A prominent example is transformation of aryl rings into pyridines. However, methods building on photochemical ring expansion of aryl azides tended to scramble the position of the nitrogen in the final product. Pearson et al. report that selection of an optimal oxidant enables precise replacement of the ring carbon bound to the azide with a nitrogen. The method can thereby be applied to ...