Regioselectivity in Metal-Free Indole C–H Borylation: A DFT Investigation

The selective C–H borylation of indoles represents an important class of organic transformations. Although extensively studied experimentally, the factors governing regioselectivity remain poorly understood. In this study, we employed density functional theory (DFT) calculations to investigate two representative reactions: (1) the B(C6F5)3​-catalyzed C–H borylation of N-methylindole with HBcat at room temperature, which yields 3-Bcat-indole; and (2) the catalyst-free borylation with HBpin at 180 °C, which yields 2-Bpin-indole. For the first reaction, our results indicate an electrophilic aromatic substitution mechanism where regioselectivity is thermodynamically controlled, with the C3-borylated isomer being the most stable product. For the second reaction—where thermodynamic is believed to govern regioselectivity at elevated temperature—calculations surprisingly showed the C3-isomer remains more stable. We resolved this discrepancy by identifying that in situ-generated BH3​ species coordinate to the indole nitrogen, reversing the relative thermodynamic stabilities and favoring the C2-borylated product. Overall, this study provides a coherent theoretical explanation for the experimentally observed temperature-dependent regioselectivity in metal-free indole C–H borylation reactions.