Reaction development. Initially, we tested commercially available heterogeneous catalysts, such as Pd/C, Ir/C, Pt/C, Rh/C and Ru/C which are widely used for hydrogenation reactions, combining with electricity to reductive hydrogenation of 3,5-di-tert-butyl-1,1'-biphenyl using H2O (Supplementary Table S1). The benchmark substrate was chosen because the deuterium incorporation could be determined by 1H NMR using the tBu group as an internal calibration. Pd/C as well as Pt/C showed no activity, and only trace amount of desired product was observed using Rh/C, Ir/C and Ru/C as the catalyst. 99% yield of hydrogenated product was obtained using our developed nitrogen-doped Ru electrode (Ru-N/CF, see Supplementary Information, Section 2 and 5 for general procedure of nitrogen-doped electrocatalyst preparation and electrode materials characterization). As expected, deuterated product was obtained with 99% yield using D2O instead of H2O, and the total deuterium labeling number was 7.2/molecule. Control experiment showed that nitrogen doped carbon felt (N/CF) without loading Ru metal has no activity for the reduction reaction. No product was detected when the reaction was performed under 1 atm H2 atmosphere without electrolysis.
Synthetic scope. With the optimized conditions in hand, we then evaluated the substrate scope of the electrocatalytic system (Fig. 2, see Supplementary Information, sections 1 and 6 for the determination of deuterium incorporation and positions). Amide bonds are included in many important biological compounds and materials, as well as drugs. Consequently, we started to explore the reductive deuteration of aryl amides. In general, the Ru-N/CF electrode permitted smooth reductive deuteration of various aryl amides and corresponding products were isolated with high yields (1b-15b). Remarkably, in many cases, for example in the β and δ positions of the amide group in 1b, the D-incorporation were >100%, H/D exchange might occur during the reductive procedure on the Ru electrode surface. Specifically, excellent yields and high D-incorporation on each position were obtained for N-substituted amides (2b-4b), and fluorin atoms on the cycloalkane ring could be retained (5b). Notable, α and β amino acids containing aryl amides could be reduced with high yields and D-labeling (6b-8b). Next, N, N-dialkyl-substituted and azacycloalkyl amides bearing CF3, ether and amine groups were investigated, and the catalytic labeling provided the corresponding products (9b-15b). As shown in 16b-18b, aryl esters could also be converted to the deuterated products. Besides, polycyclic aromatic hydrocarbons could be reduced with high D-incorporation (18b and 19b). Like the model system, acyl anilines were successfully reductive deuterated (20b-26b). In the case of substrate containing 1,3-dicarbonyl group, H/D exchange was observed with 99% D-incorporation, and one ketone group was reduced to hydroxyl group (21b). Noteworthy, H/D exchange on the methyl group was occurred in the substrate of 24b. Next, biaryl compounds were employed as the starting materials. Interestingly, the aromatic ring without substitutes was more easily reductive deuterated, this may because of the steric effect on the substituted rings (27b-31b). Furthermore, biphenyl and alkyl substituted arenes were transformed with total D-labeling of 7.1-11.0 D/molecular (32b-35b).
By applying our Ru catalyst, we performed reductive deuteration of various N-containing heteroarenes. Quinolines bearing different substitutes were transformed with moderated to excellent yields and only the nitrogen-containing heterocyclic rings were reduced (36b-42b). Heteroarenes bearing two nitrogen atoms, such as quinoxalines, naphthyridines, and 2-hydroxypyridine were compatible (43b-47b). Besides, D-labeling piperazine (48b) was obtained with satisfied yield and D-incorporation. N-containing five-membered heterocyclic rings, including pyrroles, indoles and azaindoles could be reductive deuterated and give the D-labeling products (49b-54b), and H/D exchange on the aromatic ring was also observed.
Fully deuterated cyclohexyl building blocks. To further showcase the generality of our electrocatalytic reductive deuteration reaction, the synthesis of saturated deuterocarbons was investigated (Fig. 3). Firstly, perdeuterated arenes were prepared through transition-metal catalyzed H/D exchange reaction using D2O (see details in Supplementary Information, Section 7)39. The prepared D-labeling arenes were applied into the electrocatalytic reductive deuteration. For example, D-labeling product with >96% D-incorporation on cyclohexyl group (1d) was obtained by using perdeuterated acetanilide. Arenes bearing ester, Boc-N, ether, hydroxyl and amide groups could be reductive deuterated to corresponding products with high D-incorporation and a total D labeling >10/molecule (2d-8d). Diphenyl substrate was reduced to bicyclohexyl product with 20 D/molecule (9d). Importantly, D-piperazine could be isolated with 96% D- incorporation from deuterated pyrazine (10d), which was a common structure motif in drugs. To our delight, deuterodefluorination as well as reduction of the inexpensive and readily available polyfluoroarenes40, readily gave saturated deuterocarbons by just extending the reaction time and no further conditions optimization was performed. In general, the D-labeling products were isolated with good to excellent yields and >10 D/molecule on the cyclohexane ring. Pentafluoro benzamides containing different substitutes such as cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl and morpholinyl group et al. on the nitrogen were reduced to deuterated cyclic products (1f-13f). Moreover, pentafluoro acyl anilines and alkyl substituted arenes could also be transformed to the desired products with excellent D-ratio and yields (14f-20f).
Preparation of deuterated drug molecules. To demonstrate the utility and to further highlight the saturated deuterocarbons, we undertook preparation of several deuterated existing drug molecules (Fig. 4a and Supplementary Information, section 8). Following standard conditions, various cyclohexyl building blocks with high D-incorporation were prepared. Consequently, representative deuterated drugs and natural products can be conveniently prepared from the corresponding deuterated starting materials. For instance, deuterated cyclohexyl amide 1f could be oxidized to deuterated cyclohexyl isocyanate and then be attacked by sulfonamide 1g to give D-labeled hypoglycemic drug Glipizide ([D]1h). In addition, such deuterated cyclohexyl amide could also be readily converted to deuterated cyclohexyl chloride, which was widely used in the organic synthesis with high react activity, and it then reacted with amine 2g to generate D-labeled Praziquantel ([D]2h). D-labeled expectorant Bromhexine ([D]3h) could be synthesized from deuterated N-methyl-Boc-cyclohexylamine 17f in two steps. The precursor of D-labeled antithrombotic drug Cilostazol ([D]4h’) was obtained from deuterated Boc-cyclohexylamine 16f with high yield and D-incorporation41. As an oral anticoagulant drug, Apixaban is listed on the first position in the top 200 selling drugs in 202127. Electrocatalytic deuterodechlorination combining with reductive deuteration gave the D-labeled 1-arylpiperidin-2-one 5g’, which was further transformed to D-labeled Apixaban ([D]5h) with total 7 D/molecule. In combination with H/D exchange of arene and reductive deuteration, the deuterated Propylhexedrine ([D]6h) was produced from Ac- protected N-methyl-1-phenylpropan-2-amine 6g with high D-incorporation. Via electroreduction, quinoline 7g was converted to D-labeled tetrahydroquinoline 7g’, which was further transformed to deuterated Quinfamide ([D]7h).
Having established the electrocatalytic reductive deuteration of a variety of (hetero)arenes, we then evaluated some practical aspects of our catalyst system. Firstly, the Ru electrode could be readily scaled up to a size of 13.5 x 7.5 x 0.3 cm3 for amplification reaction (Supplementary Information, section 2). Chemical compounds contain a core piperazine functional group generally present important pharmacological properties. To further showcase the application potential of the electrode, synthesis of deuterated piperazine hydrochloride was scaled up to 100 mmol by using a flow electrochemical device under 2A current. 10.9 g D-labeled piperazine was isolated with 95% D-incorporation (Fig. 4b and Supplementary Information, section 9), which was then employed to prepare several pharmaceuticals. As an example, deuterated Aripiprazole ([D]8h) and Brexpiprazole ([D]9h), the unlabeled analogues for treating schizophrenia, were synthesized with average 95% D-incorporation by two steps from D-labeled piperazine hydrochloride. The D-incorporated Trimetazidine ([D]10h), Buspirone ([D]11h), Fipexide ([D]12h) and 2C-B-BZP ([D]13h), were prepared from deuterated piperazine without decreased deuterium labeling, respectively (Fig. 4c).
In conclusion, we have developed a general methodology for the preparation of D-labeled (hetero)cycloalkanes with D2O as the deuterium source. Various of arenes and heteroarenes, including quinolines, naphthyridines, azoles, indoles, pyrazines and so on, were reductive deuterated using a reusable cathode Ru-N/CF. Furthermore, full-deuterated (hetero)cyclohexyl products were produced from D-labeled arenes or polyfluoroaromatics. In addition, the electrocatalytic reductive deuteration approach could run up to 100 mmol scale with excellent deuterium incorporation. We believe this practical electrocatalytic protocol paves the way for practical labeling processes and synthesis of specific deuterated compounds. The obtained full-deuterated products could be applied into synthesizing a variety of D-incorporated pharmaceuticals. We anticipate that facile access to highly D-labeled saturated (hetero)cycles compounds based on the electrocatalytic method described herein could enable accelerated and broader interrogation of the development of new drug molecules.