We report a ligand-controlled, regiodivergent deuteration of indoles. Both ligands exhibit anti-selectivity against the electron-rich C3 position: the indazole-pyridone ligand enables deuteration at all sites, except C3, while the NAP ligand delivers exclusive C2 selectivity. Density functional theory (DFT) calculations reveal that site selectivity is governed by two concerted rate-determining steps (RDS): C-H bond activation and AcOH-bridged intermolecular proton transfer. Notably, as the electron density of the substrate increases, the energy barrier of the proton transfer step becomes increasingly dominant. The interplay of these two cooperative steps dictates selectivity, explaining the absence of deuteration at the C3 position. This work thus provides a versatile deuteration strategy and reveals how ligands govern selectivity by modulating the energetics of key steps.
Zhang et al. (Fri,) studied this question.