Mechanistically Agnostic Aliphatic N–H Transmutations Enabled by Interrupted Nitrogen Deletion

Abstract Reactions which promote the replacement of skeletal atoms are emerging as a valuable class of synthetic tools. Despite significant recent progress on transmutations of aromatic systems, aliphatic replacements are comparatively underexplored. Herein, we demonstrate three aliphatic transmutations on heteroaryl-fused piperidines via an interrupted nitrogen deletion. These piperidines react with an anomeric amide to form dearomatized vinylcyclopropanes that can undergo Rh-catalyzed [5 + 1] cycloadditions with carbon monoxide to afford the corresponding cyclohexanone, polar ring-opening in the presence of I2 and H2O followed by base-mediated ring closure to give the corresponding dihydropyran, or photochemically promoted radical cyclization with a sulfonothioate to provide the corresponding thiane. The propensity for the key isodiazene intermediate to partition to the requisite vinylcyclopropane or its isomeric cyclopentene deletion product was systematically examined across a range of heterocycles. The dearomatization penalty of each heterocycle, measured computationally via isodesmic calculations, was found to predict the likelihood of productive vinylcyclopropane formation. This work demonstrates three novel aliphatic transmutations: NH-to-CO, NH-to-O, and NH-to-S, leveraging the unique reactivity of an interrupted nitrogen deletion to allow access to ketones, dihydropyrans, and thianes from the corresponding piperidines.