Electrocatalytic reductive deuteration of arenes and heteroarenes

Abstract

The incorporation of deuterium to organic molecules has widespread applications in medicinal chemistry and material science^1,2. For example, deuterated drugs e.g. Austedo³, Donafenib⁴ and Sotyktu⁵ were recently approved. There are various methods for the synthesis of deuterated compounds with high deuterium incorporation⁶. However, the reductive deuteration of aromatic hydrocarbons, ubiquitous chemical feedstocks, to saturated cyclic compounds has rarely been achieved. Here, we describe a scalable and general electrocatalytic method for the reductive deuteration and deuterodefluorination of (hetero)arenes using a prepared nitrogen doped electrode and D₂O, giving perdeuterated and saturated deuterocarbon products. This protocol has been successfully applied to the synthesis of 13 highly deuterated drug molecules. Mechanistic investigations suggest that the Ru-D species, generated by electrolysis of D₂O in the presence of nitrogen-doped Ru electrode, are key intermediates that directly reduce aromatic compounds. This quick and cost-effective methodology for the preparation of highly D-labeled saturated (hetero)cycles compounds could be applied in the drug development and metabolism studies.