Practical and Scalable Synthesis of a Benzonitrile Derivative via Palladium-Catalyzed Cyanation with Potassium Ferrocyanide

A practical and reproducible synthetic method for the preparation of a benzonitrile derivative (1) from an aryl bromide (2) via Pd-catalyzed cyanation was established with dimethylacetamide (DMAc)–toluene as a mixed solvent. Optimization was examined by a design of experiments (DoE) technique to enhance reaction conversion and reduce the dimeric impurity 3, and desired benzonitrile derivative 1 was successfully obtained in high yields with excellent quality control on a 117 kg scale.