Organic Letters· 2026Q1
γ-Selective Deuteration of Unactivated C(sp3)–H Bonds of Aliphatic Amines via Pd Catalysis in D2O
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- 2026year
Short summary
A new Pd-catalyzed method achieves selective deuteration at the γ-position of unactivated C(sp3)–H bonds in aliphatic amines using D2O as the deuterium source and 3-formyl-2-pyridone as a transient directing group.
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Key points
- Selective γ-deuteration of unactivated C(sp3)–H bonds in aliphatic amines is achieved using Pd catalysis.
- D2O is used as the sole deuterium source, and 3-formyl-2-pyridone acts 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 with up to 89% D incorporation.
- The method enables the synthesis of deuterated drug scaffolds and a one-pot γ-deuteration/γ-arylation sequence.
AI-generated from the title and abstract; the full text is not read.
Abstract
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.
The authors' abstract, as published at the source. Organic Letters, 2026 · DOI ↗
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Field: Pharmaceutical Science
Pharmaceutical SciencePharmacology, Toxicology and Pharmaceutics