Scanning nitrogen in sp3-rich scaffolds enabled by carbonyl-to-nitrogen atom swap

Abstract: Saturated nitrogen heterocycles (SNHs) are prevalent in small-molecule drugs, and the position of the nitrogen atom strongly influences biological activity and physicochemical properties of these compounds. Consequently, medicinal chemistry campaigns routinely require access to series of SNH-based analogues by placing nitrogen at different positions to probe structure–activity relationships (SAR) through nitrogen scanning. However, systematic preparation of N-positional variants remains synthetically burdensome: each analogue typically demands a distinct retrosynthetic plan and de novo synthesis. The lack of a general tactic to access SNH positional isomers has therefore become a persistent obstacle when exploring chemical space surrounding these privileged scaffolds. Here we report an unprecedented strategy that allows convenient nitrogen scanning in sp³-rich scaffolds enabled by exchanging a carbonyl group with an amine moiety, which is termed as CO-to-N atom swap. Because ketone positional isomers can be readily obtained via carbonyl transposition or C–H oxidation from a common carbocyclic precursor, the CO-to-N atom swap greatly streamlines the preparation of SNH positional analogues and obviates the need for multiple de novo syntheses. The transformation is achieved through sequential C–C bond activation of ketones, in which p-tosylphenyldiazene is employed as a nitrogen-centered double radical acceptor. Owing to its radical-mediated bond-forming features, the CO-to-N reaction exhibits exceptional functional group (FG) tolerance and generality, making it well suited for late-stage modification of complex bioactive molecules and for isotope labeling. This method is expected to enrich medicinal chemists’ toolbox for rapid analogue synthesis and for expedited exploration of SNH-based chemical space.