Organic Letters· 2026Q1
Cu-Catalyzed Cross-Coupling of (Hetero)Aryl Halides with Malonates: One-Pot Assembly of α-Arylacetic Acid Scaffolds
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Short summary
A new one-pot method directly synthesizes α-arylacetic acids from aryl halides and malonates using a Cu/oxalamide catalyst, enabling gram-scale production and late-stage drug modification.
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Key points
- Direct synthesis of α-arylacetic acids from aryl halides and malonates achieved via Cu/oxalamide catalysis.
- The reaction involves cross-coupling followed by tandem hydrolysis and decarboxylation.
- A tailored oxalamide ligand (L4) enables mild conditions, low catalyst loadings, and broad substrate scope.
- The method is scalable to gram quantities and applicable to late-stage modification of drug intermediates.
- DFT calculations identify an ortho-sp2-hybridized nitrogen atom on the ligand as essential for catalytic activity by stabilizing the oxidative addition transition state.
AI-generated from the title and abstract; the full text is not read.
Abstract
Abstract A direct synthesis of α-arylacetic acids from (hetero)aryl chlorides and bromides and malonates via Cu/oxalamide-catalyzed cross-coupling with tandem hydrolysis and decarboxylation is described. Enabled by tailored oxalamide ligand L4, the reaction proceeds smoothly under mild conditions with low catalyst loadings, exhibits a broad substrate scope, and can be scaled to the gram scale and applied in the late-stage modification of complex drug intermediates. Systematic evaluation of the steric and electronic properties of oxalamide ligands, combined with density functional theory (DFT) calculations, elucidates that the ortho-sp2-hybridized nitrogen atom on the ligand is indispensable for catalytic activity. The nitrogen atom coordinates with the sodium cation in the oxidative addition transition state (TS-OA-1a), stabilizing the transition state and lowering the activation barrier through favorable noncovalent interaction.
The authors' abstract, as published at the source. Organic Letters, 2026 · DOI ↗
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Field: Organic Chemistry
Organic ChemistryChemistry