Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA.
Chemistry Research Laboratory, University of Oxford, Oxford OX1 3TA, UK.
Science. 2018 Nov 16;362(6416):799-804. doi: 10.1126/science.aas8961.
Heterobiaryls composed of pyridine and diazine rings are key components of pharmaceuticals and are often central to pharmacological function. We present an alternative approach to metal-catalyzed cross-coupling to make heterobiaryls using contractive phosphorus C-C couplings, also termed phosphorus ligand coupling reactions. The process starts by regioselective phosphorus substitution of the C-H bonds para to nitrogen in two successive heterocycles; ligand coupling is then triggered via acidic alcohol solutions to form the heterobiaryl bond. Mechanistic studies imply that ligand coupling is an asynchronous process involving migration of one heterocycle to the ipso position of the other around a central pentacoordinate P(V) atom. The strategy can be applied to complex drug-like molecules containing multiple reactive sites and polar functional groups, and also enables convergent coupling of drug fragments and late-stage heteroarylation of pharmaceuticals.
由吡啶和二嗪环组成的杂双芳基是药物的关键组成部分，通常也是药物发挥药理功能的核心。我们提出了一种替代金属催化交叉偶联的方法，使用收缩磷 C-C 偶联反应（也称为磷配体偶联反应）来构建杂双芳基。该过程首先通过在两个连续的杂环中对位氮的 C-H 键的区域选择性磷取代开始；然后通过酸性醇溶液触发配体偶联，形成杂双芳基键。机理研究表明，配体偶联是一个异步过程，涉及一个杂环围绕中心五配位 P(V)原子迁移到另一个杂环的 ipso 位置。该策略可应用于含有多个反应性位点和极性官能团的复杂类药物分子，并且还能够实现药物片段的收敛偶联和药物后期的杂芳基化。
