Directed C-O Activation of Nitrile Functionalized Alkyl Ethers: C-C Cross Coupling Using Redox-active Cobalt Catalysts

Abstract

The utility of palladium in cross coupling is driving efforts to find alternatives based on inexpensive, abundant first-row transition metals. Beyond mimicking Pd, base metal catalysts can access entirely new reactions unknown to precious metals. A recently discovered coupling of ether nitriles and aryl Grignards was herein optimized with CoII bis(phenol)-substituted N-heterocyclic carbene complexes. Reactivity was explored with a variety of directed, activated, and both unactivated and undirected ether reagents. Coupling seemed specific to nitrile directing groups, with a 3-carbon linker being optimal, with optimized yields of >70% at 5 mol% catalyst loading at 70 °C. A variety of organometallic coupling partners were also explored, with aryl- and alkyl-lithium, Grignard, and organozinc reagents. The activation and functionalization of C-O bonds is of special importance, as it can play a powerful role in late-stage fine chemical synthesis. This system is of interest, as it activates sp3 C-O bonds, a rare process, and constitutes the first non-aryl containing ether C-O activation for C-C bond formation. Mechanistic investigations of this system determined it followed a redox-active pathway instead of an acid-base activation. Tests using Kumada reagents suggest that the redox-active pathway that C-O reagents pass through is fundamentally different.