Sustainable Copper-Catalyzed Cyanation of Aryl Iodine through a Design of Experiment Strategy

Aryl nitriles are critical intermediates in organic synthesis, widely utilized in pharmaceuticals, agrochemicals, and other industrial applications. Traditional cyanation methods often rely on highly toxic cyanide sources and demanding conditions, prompting the need for greener alternatives. Here, we report a novel copper catalyst [Cu(CyDMEDA)2Br]Br·H2O allowing cyanation of aryl iodides using sodium nitroprusside as a nontoxic cyanide source in water, operating under mild conditions (75 °C) with high efficiency. A Design of Experiment-based optimization strategy employing Response Surface Methodology enabled the systematic investigation of key reaction parameters, achieving yields exceeding 80% with minimal resource consumption. The robustness of the optimized protocol was validated through the synthesis of Febuxostat, an FDA-approved gout medication, in 79% yield under environmentally friendly conditions. This approach highlights a sustainable and scalable alternative for the preparation of aryl nitriles (13 examples, 29% to 81% yields), advancing the principles of green chemistry in pharmaceutical synthesis.