Practical Synthesis of C-1 Deuterated Aldehydes Enabled by NHC Catalysis.

Abstract

The recent surge in applications of deuterated pharmaceutical agents has created an urgent demand for synthetic methods that efficiently generate deuterated building blocks. Here we show that N-heterocyclic carbenes (NHC) promote a reversible hydrogen-deuterium exchange (HDE) reaction with simple aldehydes, which leads to a practical approach to synthetically valuable C-1 deuterated aldehydes. The reactivity of the well-established NHC catalysed formation of Breslow intermediates from aldehydes is reengineered to overcome the overwhelmingly kinetically favorable, irreversible benzoin condensation reaction and achieve the critical reversibility to drive the formation of desired deuterated products when an excess of D2O is employed. Notably, this operationally simple and cost-effective protocol serves as a general and truly practical approach to all types of 1-D-aldehydes including aryl, -alkyl and -alkenyl aldehydes and enables chemoselective late-stage deuterium incorporation into complex, native therapeutic agents and natural products with uniformly high levels (>95%) of deuterium incorporation for a total of 104 substrates tested.