Diaryl and heteroaryl ethers are important and common motifs in drug discovery and agrochemicals. Here we present a catalytic system for the copper catalysed arylation of phenols with aryl halides. Bidentate N‐heterocyclic carbene ligands provide a well‐defined catalytic system that enable low loading of copper in effective coupling reactions (0.5 mol% Cu or lower). The reaction scope of aryl iodides and aryl bromides is developed, that is tolerant of functional groups and a library of biaryl ethers with lead‐like properties is prepared. The presence of excess ligand (in a 1:3 ratio) is shown to be optimal to prevent catalyst degradation, presumably by avoiding decomplexation of the ligand. This is also supported by the catalytic results obtained with pre‐formed copper complexes. The kinetics of the reaction are examined and shown to be first order in copper, supportive of a well‐defined catalyst species, first order in phenol and aryl iodide, and zero order in base under the developed conditions. Computational studies performed using Minnesota MN15‐L parametrisation method support an oxidative addition–reductive elimination pathway. Reductive elimination would be turnover limiting and occurr through an intimate ion pair intermediate.

中文翻译：

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含二齿 NHC 的配体，用于铜催化合成功能化二芳基醚


二芳基和杂芳醚是药物发现和农用化学品中重要且常见的基序。在这里，我们提出了一种用于铜催化酚与芳基卤化物芳基化反应的催化系统。Bidentate N-杂环卡宾配体提供了一个明确的催化系统，可在有效的偶联反应中实现低铜负载量（0.5 mol% Cu 或更低）。开发了芳基碘化物和芳基溴化物的反应范围，其对官能团具有耐受性，并制备了具有类似铅性质的联芳基醚库。过量配体（以 1：3 的比例）的存在被证明是防止催化剂降解的最佳选择，可能是通过避免配体的解构。使用预成型铜配合物获得的催化结果也支持了这一点。检查反应的动力学，结果表明在铜中为一级，支持明确定义的催化剂种类，在苯酚和芳基碘化物中为一级，在碱中为零级。使用 Minnesota MN15-L 参数化方法进行的计算研究支持氧化加成-还原消除途径。还原消除将是周转限制，并通过亲密离子对中间体发生。