Palladium-Catalyzed Regiodivergent Telomerization of Isoprene With Oxindoles

Transition metal-catalyzed nucleophilic telomerization of isoprene is an efficient strategy for the construction of monoterpene skeletons, yet its development has been impeded by inherent challenges of chemo- and regioselectivity control, especially in reactions with carbon nucleophiles. Herein, we developed a versatile palladium catalysis for the regiodivergent telomerization of isoprene with oxindoles through synergistic control of ligands, solvents, and additives. In the presence of aprotic solvent NMP, we revealed the electron-rich and less bulky tri(2-furyl)phosphine (TFP) ligand can facilitate the exclusive formation of tail-to-tail geranyl oxindoles, meanwhile the reactivity was severely improved by adding base as additive. On the other hand, a newly designed hemilabile phosphine ligand enables selective access to tail-to-head isomer, where the MeOH worked as an irreplaceable solvent choice. Mechanistic experiments and density functional theory (DFT) calculations were conducted, which indicate that protolysis of the η¹,η³-diallyl-Pd(II) complex is speculated to be the rate-determining step. Apart from oxindoles, this regiodivergent protocol could also be applied to the nucleophilic telomerization of isoprene with a broad scope of amines. Furthermore, the synthetic utility of current synthetic strategy was illustrated by late-stage alkene isomerization, as well as various derivatizations that effectively expand the structural diversity of monoterpenoids and complement alkaloid frameworks.