63071-22-7Relevant academic research and scientific papers
Selective Halogenation of Pyridines Using Designed Phosphine Reagents
Alegre-Requena, Juan V.,Levy, Jeffrey N.,Liu, Renrong,McNally, Andrew,Paton, Robert S.
, p. 11295 - 11305 (2020)
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.
