We hypothesized that homogeneous palladium catalysis could provide directing group free deuteration with high levels of C2-selectivity under mild conditions if competing C3-deuteration could be suppressed (Scheme 2). We aimed to achieve this by fine-tuning of the reaction pH to favor migration of palladium from C3 (complex A in Scheme 2) to C2 (complex B) in the carbopalladated intermediate prior to rearomatization, as reported by Gaunt et al. Initially, both C2-and C3-deuteration were observed: when indole was reacted in the presence of 10 mol% Pd(OAc)2 in an anhydrous dioxane/CD3CO2D solvent mixture at 120 °C for 16 h, we observed 40% C2-deuteration and 52% C3-deuteration by H NMR, with no hydrogen isotope exchange at any other position (Table , entry 1). Deuterium incorporation increased at both positions in the presence of NaOAc to 81% (C2) and 72% (C3) respectively (entry 2). Reducing the amount of deuterated acetic acid (entries 3-4) only had a small effect on C2-deuteration, but saw a significant reduction of the undesired deuterium incorporation at the C3 position. The use of CH3CO2D significantly reduced deuteration at C2 compared with CD3CO2D (entry 5 cf. entry 3)presumably due to proton exchange between the methyl and hydroxyl positions in acetic acid. Low C2-deuteration was also observed with D2O (entry 6). Lower reaction temperatures, alternative solvents and a reduced reaction time all had a negative effect on the reaction outcome (see ESI, Table ). Given the effect of CD3CO2D concentration on C2/C3-deuteration ratio (entries 2-4), and the mechanistic hypothesis in Scheme 2, we wondered if careful balancing of pH would allow for selective deuteration on the C2 position only. Indeed, addition of a large excess of NaOAc (15 equiv.) afforded complete protonation at C3 while deuterium incorporation at C2 remained high (80%, entry 7). Due to the impracticalities of using a large excess of base on scale, we wanted to reduce this amount. Indeed, further optimisation revealed that a similar result could be obtained with a telescoped approach using milder conditions: indole was reacted with 10 mol% Pd(OAc)2 in anhydrous CD3CO2D/dioxane at 120 °C for 16 h. After filtration through silica and removal of solvents in vacuo, 1 equiv. K2CO3 and protic solvents (MeOH/H2O) were added and reacted for a further 16 h (entry 8), resulting in 81% deuterium incorporation at C2 (with no isotopic labelling at C3). A control reaction confirmed that the palladium catalyst was necessary for C2-deuteration: in the absence of Pd(OAc)2, only C3-deuteration was observed (entry 9), as expected from indole's intrinsic acid/base reactivity.