Selective Halogenation of Pyridines Using Designed Phosphine Reagents

• DOI: 10.1021/jacs.0c04674
• Publication Date: 2020-05-29T13:48:15Z
• Authors: Jeffrey N. Levy; Juan V. Alegre-Re...; Renrong Liu; Robert S. Paton; Andrew McNally
• Keywords: Bromides; Halogenation; Phosphines; Pyridines; Iodides; 01 natural sciences; 0104 chemical sciences; Onium Compounds; Models, Chemical; Lithium Compounds; Indicators and Reagents; Lithium Chloride; Density Functional Theory

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.