A Rationally Designed Iron(II) Catalyst for C(sp³)-C(sp²) and C(sp³)-C(sp³) Suzuki-Miyaura Cross-Coupling

Despite the paramount importance of the Suzuki-Miyaura coupling (SMC) in academia and industry, and the great promise of iron to offer sustainable catalysis, iron-catalyzed SMC involving sp³-hybridized partners is still in its infancy. We herein report the development of a versatile, well-defined electron-deficient anilido-aldimine iron(II) catalyst. This catalyst effectively performed C(sp³)-C(sp²) and C(sp³)-C(sp³) SMC of alkyl halide electrophiles and (hetero)aryl boronic ester and alkyl borane nucleophiles respectively, in the presence of a lithium amide base. These couplings operated under mild reaction conditions and displayed wide functional group compatibility including various medicinally relevant N-, O- and S-based heterocycles. They also tolerated primary, secondary and tertiary alkyl halides (Br, Cl, I), electron-neutral, -rich and -poor boronic esters and primary and secondary alkyl boranes. Our methodology could be directly and efficiently applied to synthesize key intermediates relevant to pharmaceuticals and a potential drug candidate. For C(sp³)-C(sp²) couplings, radical probe experiments militated in favor of a carbon-centered radical derived from the electrophile. At the same time, reactions run with a pre-formed activated boron nucleophile coupled to competition experiments supported the involvement of neutral, rather than an anionic, (hetero)aryl boronic ester in the key transmetalation step.