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

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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.