A Protocol for the Ortho-Deuteration of Acidic Aromatic Compounds in D₂O Catalyzed by Cationic Rh^III

Abstract

Methods to catalytically introduce deuterium in synthetically useful yields ortho to a carboxylic acid directing group on arenes typically requires D2 or high catalyst loadings, which makes using these approaches cost prohibitive for large-scale synthesis (equipment and reagent costs respectively). Herein, we present a simplified approach using low catalyst loadings of cationic RhIII and D2O as both deuterium source and solvent and show its application to H/D exchange on various carboxylic acid substrates.

Versatile Regioselective Deuteration of Indoles via Transition-Metal-Catalyzed H/D Exchange

“…Interestingly, raising the temperature to 130 °C and replacing DCE with MeCN resulted in a satisfactory isolated yield of 13 Next, we investigated the substrate scope for preparation of the C2/C3/C7 trideuterated product 4 using various indoles. Most of the reactions showed very deep (4a, 4d, 4h−4q) to almost complete (4a, 4k, 4l, 4p, and 4q) conversion on all three positions.…”

Regioselective α-Deuteration of Michael Acceptors Mediated by Isopropylamine in D2O/AcOD

“…The aldehyde was converted to the nitrile via oxidative amination using iodine and ammonium hydroxide to afford product 8 in 77% yield with 92% deuterium incorporation after the reaction. Furthermore, 2a was used for condensation reactions to prepare a dieneone (9) and dieneal (10), though notably with some loss in deuterium labeling. Deuterated primaquine derivative 11 can be easily prepared via the reductive amination of primaquine and 2n.…”

“…respectively . Subsequently, our group reported the β-H/D exchange on cinnamic acid derivatives, using low catalyst loadings of rhodium and D 2 O as a deuterium source . However, cheap and metal-free approaches toward deuterium incorporation are still sought to reduce the cost of deuterated drugs .…”

“…9 Subsequently, our group reported the β-H/D exchange on cinnamic acid derivatives, using low catalyst loadings of rhodium and D 2 O as a deuterium source. 10 However, cheap and metal-free approaches toward deuterium incorporation are still sought to reduce the cost of deuterated drugs. 11 Styrenes and cinnamate esters, which are not very electrophilic, can undergo selective α-H/D exchange using organocatalytic systems.…”

Ortho-Selective Hydrogen Isotope Exchange of Phenols and Benzyl Alcohols by Mesoionic Carbene-Iridium Catalyst

“…Because of the prevalence of aryl moieties in drug candidates and natural products, the selective incorporation of a hydrogen isotope into aryl moieties has always been a hot research topic. The transition-metal-catalyzed, such as Ir, Ru, Rh, and Pd, direct ortho hydrogen isotope exchange (HIE) of arenes assisted by chelate directing groups has been well studied and established as a major method for its simplicity and value for the late-stage incorporation of deuterium or tritium. However, research on the selective deuteration of compounds without chelate directing groups remains rare …”