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.

芳基腈（aryl nitriles）是有机合成中的关键中间体，广泛应用于医药、农药及其他工业领域。传统氰化方法通常依赖高毒性氰源且反应条件严苛，因此亟需开发更绿色的替代方案。本研究报道了一种新型铜催化剂[Cu(CyDMEDA)₂Br]Br·H₂O，可在水相中以无毒的硝普钠（sodium nitroprusside）作为氰源，实现芳基碘化物的氰化反应，反应条件温和（75℃）且效率优异。本研究采用基于实验设计（Design of Experiment, DoE）结合响应面法（Response Surface Methodology, RSM）的优化策略，系统考察了关键反应参数，在极低资源消耗下实现了超过80%的反应收率。研究通过以环保条件下79%的收率合成经美国食品药品监督管理局（FDA）批准的痛风治疗药物非布司他（Febuxostat），验证了优化后工艺的稳健性。该方法为芳基腈的制备提供了一种可持续且可规模化的替代路径（共13个反应实例，收率区间29%~81%），推动了绿色化学理念在药物合成中的应用。