Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, United States.
J Am Chem Soc. 2020 Jun 24;142(25):11295-11305. doi: 10.1021/jacs.0c04674. Epub 2020 Jun 10.
Halopyridines are key building blocks for synthesizing pharmaceuticals, agrochemicals, and ligands for metal complexes, but strategies to selectively halogenate pyridine C-H precursors are lacking. We designed a set of heterocyclic phosphines that are installed at the 4-position of pyridines as phosphonium salts and then displaced with halide nucleophiles. A broad range of unactivated pyridines can be halogenated, and the method is viable for late-stage halogenation of complex pharmaceuticals. Computational studies indicate that C-halogen bond formation occurs via an SAr pathway, and phosphine elimination is the rate-determining step. Steric interactions during C-P bond cleavage account for differences in reactivity between 2- and 3-substituted pyridines.
卤代吡啶是合成药物、农用化学品和金属配合物配体的关键结构单元，但选择性卤化吡啶 C-H 前体的策略还很缺乏。我们设计了一组杂环膦，将其作为磷翁盐安装在吡啶的 4 位，然后用卤代亲核试剂取代。未活化的吡啶可以被卤化，该方法适用于复杂药物的后期卤化。计算研究表明，C-卤键的形成是通过 SAr 途径进行的，膦消除是速率决定步骤。C-P 键断裂过程中的空间相互作用解释了 2-和 3-取代吡啶之间反应性的差异。
