Skeletal Editing of Quinolines by Single-Atom Carbon Insertion-Deletion

In the endeavor to identify a molecule optimally tailored to a specific functional role, the distinction between success and failure often hinges on one or two atoms. Replacing an aromatic carbon with an exogenous one may facilitate the discovery of potential pharmaceuticals; yet, to date, only indirect approaches exist for such C-to-C transformations, most commonly via parallel synthesis. Herein, we report a transformation enabling the direct conversion of two adjacent aromatic carbons remote from the reactive site to two new carbons, thereby reconstructing quinolines. Cyclizative rearrangement of the parent azaarene with an electron-deficient alkyne generates in situ a benzazepine intermediate, which incorporates an isomerizable triene motif priming the subsequent regioselective 6π-azaelectrocyclization and departure of a designated carbon. This method obviates ring opening and recyclization, enabling site-specific editing of azaarenes via single-carbon insertion and deletion. We demonstrate a broad substrate scope encompassing quinolines and associated azaarenes, all undergoing skeletal reconstruction via concurrent 1,2-carbon migration from C3 to C4 and insertion of a new functionalizable C3 carbon. Mechanistic studies validate the pivotal role of the activated intermediate and showcase the utility of this methodology in the late-stage modification of drug molecules.