Dual-Ligand Strategy in Rh-Catalyzed Sequential Hydrofunctionalization of Valylene

Controlling regio- and chemo-selectivity in transition-metal-catalyzed reactions involving coupling reagents with multiple reactive sites remains a significant challenge. In this study, a dual-ligand strategy is introduced to orthogonally regulate both nucleophilic and electrophilic sites in the rhodium-catalyzed sequential hydrofunctionalization of valylene. Leveraging the synergistic effects of bidentate and monodentate phosphine ligands, cyclic prenylation of 4-hydroxycoumarins is achieved with outstanding regio- and chemo-selectivity under basic conditions. Conversely, structurally reversed prenylation is selectively obtained using a dppb (1,4-bis(diphenylphosphino)butane)/DME (1,2-dimethoxyethane) ligand combination under acidic conditions. This efficient and versatile protocol is also applicable to pyrazol-5-one substrates, yielding high-value dihydropyrano[2,3-c]pyrazole analogs. Mechanistic studies suggest that the cyclic prenylation proceeds via C3- or O-propargylation, followed by Rh- or acid-promoted intermolecular annulation. It is hoped that this strategy will provide valuable insights for addressing selectivity challenges in transition-metal catalysis and inspire further developments in this field.