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γ-Selective Deuteration of Unactivated C(sp3)-H Bonds of Aliphatic Amines via Pd Catalysis in D2O
Jian-Fei Bai1, Hao Hu1, Ru Bo1
1NingboTech-Cuiying Joint Laboratory of Stable Isotope Technology, School of Biological and Chemical Engineering, NingboTech University, Ningbo, 315100, P. R. China.
Abstract:
Selective γ-deuteration of unactivated C(sp3)-H bonds in aliphatic amines is achieved using D2O as the sole deuterium source via Pd catalysis with 3-formyl-2-pyridone as a transient directing group. The reaction proceeds in aqueous medium without acidic or fluorinated co-solvents. Branched and cyclic amines are deuterated regioselectively at γ-methyl sites (up to 89% D). The utility is demonstrated by concise synthesis of deuterated scaffolds (rimantadine, ethambutol, and dobutamine) otherwise inaccessible by conventional methods, together with a one-pot γ-deuteration/γ-arylation sequence. Mechanistic studies establish that the pyridone moiety dominates the CMD step and intrinsically favors H/D exchange.
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