Room-Temperature Palladium-Catalyzed Deuterogenolysis of Carbon Oxygen Bonds towards Deuterated Pharmaceuticals

Site-specific incorporation of deuterium into drug molecules to study and improve their biological properties is crucial for drug discovery and development. Herein, we describe a palladium-catalyzed room-temperature deuterogenolysis of carbon-oxygen bonds in alcohols and ketones with D-2 balloon for practical synthesis of deuterated pharmaceuticals and chemicals with benzyl-site (sp(3) C-H) D-incorporation. The highlights of this deoxygenative deuteration strategy are mild conditions, broad scope, practicability and high chemoselectivity. To enable the direct use of D2O, electrocatalytic D2O-splitting is adapted to in situ supply D-2 on demand. With this system, the precise incorporation of deuterium in the metabolic position (benzyl-site) of ibuprofen is demonstrated in a sustainable and practical way with D2O.

Automated summary

This method involves the palladium-catalyzed introduction of deuterium into carbon-oxygen bonds in alcohols and ketones using D-2 balloon at room temperature, showcasing a practical synthesis of deuterated pharmaceuticals and chemicals. Its advantages include mild conditions, broad scope, and high chemoselectivity. By utilizing electrocatalytic D2O-splitting, D-2 can be supplied on demand, enabling precise incorporation of deuterium in pharmaceuticals in a sustainable and practical way.