Ligand-Enabled Ag-Free Cross-Coupling of Methylene C(sp3)-H Bonds in Aliphatic Acids with C(sp2) Bromides.

Despite decades of progress, the use of methylene C(sp3)-H bonds from readily available native substrates as secondary alkyl coupling partners in C(sp3)-C(sp2) bond-forming reactions has remained largely confined to arylation. The requirement for stoichiometric silver salts to scavenge the iodides from the aryl or vinyl iodide coupling partners is another persistent hurdle in achieving practicality and scalability. Here we report C(sp3)-C(sp2) cross-coupling of remote methylene C(sp3)-H bonds as secondary alkyl surrogates with C(sp2) bromides. The development of a bifunctional electron-rich pyridine-pyridone ligand that can promote both the C(sp3)-H activation and the oxidative addition of alkenyl and (hetero)aryl bromides is crucial to achieve this Ag free cross-coupling, addressing a long-standing challenge in C(sp3)-H coupling reactions. Moreover, the successful modification of structurally complex natural products and pharmaceutical derivatives highlights its broad functional group tolerance and utility in late-stage C(sp3)-C(sp2) bond construction.