DFT – Proposed mechanism of Friedel–Crafts acylation of indole using metal triflate catalysts

The Friedel-Crafts acylation of indole with propionic anhydride using a metal-triflate catalyst is an efficient and environmentally friendly method for synthesizing 3-acylindole, an important pharmaceutical intermediate. Despite its high selectivity for the C-3 position without requiring NH protection, the exact mechanism by which the metal-triflate catalyst promotes regioselective acylation remains unclear. In this study, density functional theory (DFT) calculations were employed to explore acyl substitution at three positions on the indole ring, both in the presence and absence of the catalyst. Two possible mechanisms were proposed: (i) an indirect pathway, where the catalyst forms an electrophilic intermediate (PrOTf) to acylate indole, and (ii) a direct pathway, where indole reacts directly with propionic anhydride at the metal core. The results indicated that the indirect pathway favored N-acylation, while the direct pathway preferred 3-acylindole. Both pathways were observed across several metal triflate catalysts (M = Y, In, Bi, La), in line with experimental data.