Selective Halogenation of Pyridines Using Designed Phosphine Reagents

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 SNAr 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（Halopyridines）是合成药物、农用化学品及金属配合物配体的关键合成砌块，但目前仍缺乏可选择性卤化吡啶C–H前体的有效策略。我们设计了一类杂环膦化合物，该类化合物以鏻盐的形式被安装至吡啶的4号位，随后可被卤化物亲核试剂取代。该方法可实现多种未活化吡啶的卤化修饰，且适用于复杂药物的后期卤化。计算研究表明，C–卤键的形成经由芳香亲核取代（SNAr）路径，而膦的消除为反应决速步。C–P键断裂过程中的空间位阻相互作用，是2-取代与3-取代吡啶反应活性产生差异的根源。