Ni-Catalyzed Cyanation of (Hetero)Aryl Electrophiles Using the Nontoxic Cyanating Reagent K₄[Fe(CN)₆]

A Ni-catalyzed cyanation of aryl halides using potassium ferrocyanide (K₄[Fe(CN)₆]) as a nontoxic cyanide source has been developed. Key features of this method include the use of biphasic aqueous conditions to overcome the innate insolubility of K₄[Fe(CN)₆] in organic solvents and the use of a bench-stable Ni(II) precatalyst combined with a commercially available JosiPhos ligand that enhances the practicality and scalability of this cyanation reaction. The inclusion of the acidic additive tetrabutylammonium hydrogen sulfate was found to improve the reaction rate and conversion. The initial scope of this Ni-catalyzed cyanation reaction was successfully demonstrated on a range of (hetero)aryl bromides, chlorides, and sulfamates using catalyst loadings as low as 2.5 mol %. This base-metal-catalyzed methodology was further translated to the decagram synthesis of a pharmaceutical intermediate, usurping the prior Pd-catalyzed process that employed a hazardous cyanide source and solvent pair (Zn(CN)₂, DMAc).