Carbonyl-to-sulfur swap enabled by sequential double carbon-carbon bond activation.

Abstract

In drug development, replacement of a skeletal carbon with a sulfur atom can result in analogs of bioactive compounds with improved properties. Currently, the sulfur analogs are almost exclusively prepared by de novo synthesis; the existing approach to swap carbon with sulfur is inefficient and involves stoichiometric mercury reagents. In this study, we report a two-step carbonyl-to-sulfur (CO-to-S) atom swap approach, enabled by a rationally designed <i>N</i>'-alkyl-hydrazonamide (NAHA) reagent that promotes forming pre-aromatic intermediates twice sequentially by different mechanisms, thereby achieving homolytic cleavage of both α-C-C bonds of the ketone substrates. A Ts-S-Ts (Ts, <i>p</i>-toluenesulfonyl) reagent mediates this process through successive intermolecular and intramolecular alkyl radical trapping by the central sulfur. This method shows a broad substrate scope and excellent chemoselectivity, providing a streamlined route to sulfur-containing scaffolds from readily available ketones.