Conditions Method A: 1 (0.4 mmol), Pd(OAc)2 (10 mol%), NaOAc (0.6 mmol), CD3CO2D/dioxane (1.2 mL/3 mL), 120 °C, 16 h. Method B: (i) 1 (0.2 mmol), Pd(OAc)2 (10 mol%), NaOAc (0.3 mmol), CD3CO2D/dioxane (0.6 mL/1.5 mL), 120 °C, 16 h. (ii) K2CO3 (0.2 mmol), MeOH/H2O (1.2 mL / 0.4 mL), 100 °C, 12 h. Grey circles show the labelling positions, with values in square brackets denoting isotope incorporation, as determined by With optimized conditions in hand, we explored the substrate scope of indoles amenable to this selective C2-deuteration methodology (Scheme 3). Indoles with no substituent on the pyrrole ring were submitted to palladium-catalyzed deuteration, followed by reaction with K2CO3 in MeOH/H2O after purification (method B), while indoles with a substituent on C3 did not require this second step (method A). Consistently high deuterium incorporation at C2 was achieved in good yields for unsubstituted indole (6a), as well as indoles bearing electron-donating methyl and methoxy substituents (6b-6d). Some unselective background deuteration was observed for more electron-rich indoles: 6-methoxyindole (6d) underwent 17% C7-deuteration, while 4-hydroxyindole showed unselective deuteration on all free positions (6m). Similarly, the methodology could not be extended to highly electron-rich pyrrole 1n-p (with or without protecting groups on nitrogen) which polymerized under the reaction conditions, or other electron-rich aromatics such as N,Ndimethylaniline 1q, which was recovered without any deuteration. For electron-poor 4-nitroindole, lower levels of deuterium incorporation were observed (6f: 32%), but this result could be improved (to 68%) by increasing the reaction time of step 1 to 32 h. To the best of our knowledge, there are no other examples of selective C2-deuteration of electron-poor 4-nitroindole in the literature. Initial screening results for 4-fluoroindole looked promising (79% deuterium incorporation), but the compound decomposed in our hands. Free hydroxyl groups were tolerated, albeit with lower levels of deuterium incorporation (6g: 60%) and yields (39%). Benzimidazole showed high deuterium incorporation at C2 under these conditions (6h: 95%). However, this result is comparable to results obtained under palladium-free conditions (see Scheme 5 below), suggesting that simple acid-mediated H/D exchange may be taking place. For 7-azaindole, C2 incorporation was low, possibly due to coordination of the palladium catalyst to the nitrogen heterocycle or protonation: 3i was formed with only 9% deuterium incorporation at C2 and 47% at C3, with C3-deuteration reduced to 6% when submitted to K2CO3 twice. To further demonstrate the utility of our methodology for late-stage functionalization, we submitted two high-value products to our deuteration conditions. The Boc/Fmoc-protected amino acid tryptophan showed 54% deuteration at C2 (6k) with concomitant Boc deprotection, promising result for the use of this methodology on indole alkaloid natural products. Efficient C2-and-C3-deuteration of the clinically approved beta blocker pindolol/Visken 33 was achieved (3l: 28%), however no reduction of C3 deuteration was observed after treatment with K2CO3, even when 3 equivalents of the base were used.