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

Abstract 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.