Palladium-catalyzed carbonylative synthesis of 13C-labeled flavones

Abstract

¹³C-labeled compounds are invaluable in drug discovery as lead compounds and as tracers for studying drug bioavailability and pharmacodynamics. However, these approaches are mainly limited to high-value chemical labeling materials and low atom economy multistep synthesis. Herein, we report a highly efficient Pd-catalyzed reductive carbonylation method for the synthesis of ¹³C-labeled flavones using near-stoichiometric [¹³C]CO₂. With aromatic alkynes, aliphatic alkynes and substituted 2-iodophenols as the reaction partners, the corresponding ¹³C-labeled flavones were obtained in good yields with excellent functional group tolerance. Mechanistic studies suggest that the phenolic group accelerates CO₂ mass transfer, followed by intramolecular migration and the formation of key acylpalladium intermediates. Notably, para-tBu substituted ¹³C-flavone results in a more pronounced enhancement of antitumor efficacy compared to ester or OMe substitutions, relative to their ¹²C analogs.