Direct Arylation of Unactivated Arenes Using Earth-Abundant Iron/Tetra-Aza Macrocyclic Complexes

High Resolution Image Download MS PowerPoint Slide Biaryl motifs are central in pharmaceutical drug design, yet conventional synthesis via palladium-catalyzed cross-coupling poses increasing sustainability and cost concerns. The study presented herein explores a greener alternative to palladium using iron(II) complexes supported by tetra-aza macrocyclic ligands for direct arylation of pyrrole with phenylboronic acids. Under aerobic conditions, the optimized [Fe 2+ L1 (Cl) 2 ] complex of ligand Me 2 Cyclam ( L1; 1,8-dimethyl-1,4,8,11-tetraazacyclotetradecane) showed broad substrate compatibility across 23 derivatives, achieving yields up to 66%, and excellent tolerance for functional groups including halides, esters, and strong electron-deficient substituents. Systematic analysis of these results suggests that meta-substitution and mild electron-withdrawing effects favor reactivity, while bulky ortho-steric hindrance suppresses coupling. Mechanistic studies ruled out outer-sphere radical pathways and high-valent iron complexes but do suggest iron(III)-hydroperoxo species as the operative oxidant. Density functional theory (DFT) analysis was carried out on the boronic acid substrates to show that electron-withdrawing substituents enhance the boron electrophilicity and promote the proposed transmetalation step, positioning this step as a key target for mechanistic activation of the substrate. These findings highlight the potential of earth-abundant iron catalysts as sustainable, cost-effective platforms for C–C bond formation in complex molecular scaffolds.