γ-Lactams form important structural cores of a range of medicinally-relevant natural products and clinical drugs, principal examples being the new generation of immunomodulatory imide drugs (IMiDs) and the brivaracetam family. Compared to conventional multistep synthesis, an intramolecular γ-C−H amination of aliphatic amides would allow for the direct construction of valuable γ-lactam motifs from abundant amino acid precursors. Herein we report a novel pyridone ligand enabled Pd(II)-catalyzed γ-C(sp3)−H lactamization of native amides, enabling the convenient synthesis of γ-lactams, isoindolinones, and imidazolidinones. This protocol features 1) the use of native amides, which serve as both the directing group and cyclization partner, 2) practical and inexpensive tert-butyl hydrogen peroxide (TBHP) as the sole bystanding oxidant, and 3) a broad substrate scope.

Ligand enabled Pd(II)-catalyzed γ-C(sp3)−H lactamization of native amides

ACS Spring 2022

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