Origin of Ligand and Acid Effects on the Pd-Catalyzed Regiodivergent Coupling Reaction of Indazoles and Isoprene: A DFT Study

Comprehensive computational studies were carried out to explore the mechanisms and origin of regioselectivity in the Pd-catalyzed regiodivergent coupling reaction of indazoles and isoprene. Three different insertion models were investigated for regioselectivity 1,2- or 4,3-insertion with respect to the electrophilic sites on isoprene under two different ligands (L1 and L2) and acids ((PhO)2PO2H, (nBuO)2PO2H) via PdII-H species, allyl-π-PdII-O, and indazoles-acid-assisted PdII-π-allyl. The calculated results show that the PdII-π-allyl coordinated mechanism is the most preferred one. The noncovalent interactions between the less bulky ligand L1, substrates, and (PhO)2PO2- are found to be key factors for 1,2-insertion. The 4,3-insertion selectivity is primarily controlled by the steric repulsion of the t-Bu group of bulky ligand L2 and substrate, as well as the geometry distortion. Therefore, the regioselectivity difference of the 1,2- and 4,3-insertion on electrophilic sites is controlled by the synergistic effect of ligands and acids instead of the size of the ligand. Similarly, nucleophilic site selectivity at N1 or N2 of indazoles is governed by cooperative acid BF3 and solvent iPrOH rather than BF3 alone. Overall, our findings might open a new avenue for designing more efficient regioselective 1,2- or 4,3-addition or N1-/N2-selective nucleophilic reactions.