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.