Regioselective meta-C−H borylation of aryl acetic acid derivatives enabled by iridium-aluminum bifunctional catalysts

Remote C–H functionalization provides a powerful strategy for overcoming the inherent selectivity of arene functionalization. While reversible secondary-sphere interactions have enabled remote regioselective borylation of benzoic acid derivatives, analogous transformations of phenylacetic acid derivatives and higher homologs remain largely unexplored because increased distance from the directing group disfavors metallamacrocyclic transition states. Herein, we report bifunctional iridium catalysts featuring a tunable Lewis-acidic aluminum site in the secondary coordination sphere for highly selective remote meta -C–H borylation of phenylacetamides. Systematic ligand engineering further enables borylation of previously inaccessible arylpropanamides, arylbutanamides, and aryloxyacetamides. The distinct regioselectivity from the conventional [Ir(cod)(OMe)] 2 /dtbpy system highlights the decisive roles of Lewis acid-base interactions and bifunctional catalyst design. Gram-scale synthesis, downstream diversification, and late-stage functionalization of napropamide and ketoprofen demonstrate the method's synthetic utility. Control experiments and DFT studies elucidate the ligand design and the crucial role of aluminum Lewis acidity in controlling selectivity.