Electrocatalytic reductive deuteration of arenes and heteroarenes.

Abstract

The incorporation of deuterium in organic molecules has widespread applications in medicinal chemistry and materials science^1,2. For example, the deuterated drugs austedo³, donafenib⁴ and sotyktu⁵ have been 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 deuterium oxide (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 ruthenium-deuterium species, generated by electrolysis of D₂O in the presence of a nitrogen-doped ruthenium electrode, are key intermediates that directly reduce aromatic compounds. This quick and cost-effective methodology for the preparation of highly deuterium-labelled saturated (hetero)cyclic compounds could be applied in drug development and metabolism studies.