Cooperative Ligand-Enabled Facile Synthesis of γ-C(sp3 )-H Alkenylated Aliphatic Amides: A Comprehensive Protocol to Free N-H Tolerance

Site-selective distal C(sp(3))-H functionalization of aliphatic amides is one of the longstanding challenges in synthetic methodology. Herein, we report a palladium-catalyzed gamma-C(sp(3))-H alkenylation of native aliphatic amide, exploiting a cooperative ligand approach to harness the weak coordinating ability of the amide functional group. Apart from tertiary amides, the protocol developed by us is also suitable for secondary, primary, and relatively unbiased beta-C-H bond-containing amides, which remain unexplored till date. Theoretical calculations revealed that the combination of ligands is crucial for the reaction. Monoprotected amino acid (MPAA) ligand is essential for the concerted metalation-deprotonation (CMD) step of the C-H activation, occurring via a distinctive [5,6]-palladacyclic transition state. Meanwhile, the pyridone ligand plays a key role in forming the catalyst resting state, promoting beta-hydride elimination, and facilitating product release. Both experimental and computational mechanistic studies confirm that C-H activation is the rate-limiting step in this process, providing crucial insights into the factors governing regioselective functionalization at the distant gamma-site.