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) 2 PO 2 H, ( n BuO) 2 PO 2 H) via Pd II -H species, allyl-π-Pd II -O, and indazoles-acid-assisted Pd II -π-allyl. The calculated results show that the Pd II -π-allyl coordinated mechanism is the most preferred one. The noncovalent interactions between the less bulky ligand L1 , substrates, and (PhO) 2 PO 2 - 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 N 1 or N 2 of indazoles is governed by cooperative acid BF 3 and solvent i PrOH rather than BF 3 alone. Overall, our findings might open a new avenue for designing more efficient regioselective 1,2- or 4,3-addition or N 1 -/N 2 -selective nucleophilic reactions.