Mechanistic Analysis of Organocatalytic Transfer Borylations: Sacrificial Protodeboronation, Catalyst Aggregation, and Product Inhibition

The mechanism of borylation of N-methylindole (1aH) with aryl catecholboranes (2Bcat), mediated by the N-aryl-1,3-imidazole-2-thione organocatalyst (3aH), has been investigated using a combination of in situ 1H and 19F NMR reaction monitoring, titration experiments, kinetic analysis, kinetic modeling, and computational studies. The study shows that rapid and unproductive catalytic protodeboronation removes trace impurities of water, boronic acid, and catechol prior to the catalytic arene C−H borylation. The catalytic cycles for protodeboronation and arene C−H borylation are linked to one another, with differences in their catalyst resting states resulting in different kinetics. The catalyst resting state for protodeboronation is dominated by a rapid and thermodynamically favorable dimerization equilibrium of the protonated species (3aH). The dimer acts as a reservoir, with irreversible protonation of the C−B bond occurring at the monomeric species through a cyclic concerted transition state. The rates of catalytic protodeboronation are independent of water and catechol concentrations, and correlation of experimental and computational linear free-energy relationships within a series of (2-anisyl)catecholboranes suggests mechanistic continuity across electronic variations in the arene, with important contributions of resonance substituent effects (ρ+ = −2.1). The subsequent electrophilic C−H borylation step involves the monomeric borylated catalyst species (3aBcat), with reaction kinetics influenced by the reversible and thermodynamically favored self-aggregation of 3aBcat. The protodeboronation of the newly formed borylated indole (1aBcat) is faster compared to the organoboron reagent (2Bcat), which causes a stark and progressive rate inhibition. These findings provide a mechanistic basis for the observed choice of reagents, stoichiometry, high temperatures, and narrow scope of approaches relying on transfer borylation, while informing key targets that can assist the design of improved FLP-based organocatalytic C−H borylations.