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

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 N′-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, p-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. Editor's summary: Site-selective modification of molecular frameworks can streamline drug discovery. Peripheral substituents have conventionally been easiest to manipulate, but there has been major recent progress in editing core atoms as well. Most of these methods have focused on carbon, nitrogen, and oxygen swaps. Zhang and Dong now report a protocol to introduce sulfur in place of the carbon and oxygen in cyclic ketones. A custom reagent promotes radical scission of both framework bonds to the ketone carbon, which is driven by aromatization of a triazole precursor. —Jake S. Yeston [ABSTRACT FROM AUTHOR]