Carbene-Catalyzed α,γ-Deuteration of Enals under Oxidative Conditions

Abstract

Organic compounds with deuterated allyl groups are very attractive for drug entities to enhance pharmacokinetic properties, since allylic C–H bonds are prone to metabolic oxidation and the deuterated versions can be less prone to such metabolism. However, direct deuteration at allylic C–H moieties is still a challenge. Few examples have been reported by transition-metal catalysis and no such reports have been documented in an organocatalytic fashion. Herein, a carbene-catalyzed C–H deuteration of enal at allylic C(sp3) and C(sp2) centers is disclosed. Addition of the carbene catalyst to the aldehyde moiety of enals to eventually activate the α- and γ-carbon atom under oxidative conditions is critical to achieve high deuterium incorporation. Key mechanistic steps of our reaction include carbene catalyst addition, azolium ester formation, remote γ-carbon activation, reversible α- and γ-carbon enolization, and iterative H/D exchanges. The reaction is performed under mild conditions using D2O as the deuterium source to efficiently afford α,γ-deuterated 2-alkenoic acids and their derivatives in good to excellent yields and high deuterium incorporation. These labeled products containing carbonyl and allyl bifunctionalities are valuable building blocks for further transformations, eventually leading to otherwise challenging labeled targets including deuterated allylic derivatives, aliphatic derivatives and polydeuterated drugs (e.g., Ibuprofen). The convenient and scalable synthesis has application potential for materials and pharmaceuticals.