Practical Ligand-Enabled C–H Halogenation of (Hetero)Benzoic and (Hetero)Aryl Acetic Acids

For over half a century, <i>ortho</i>-halogenated arenes, widely used in cross-coupling reactions, are mainly synthesized and manufactured by stoichiometric-directed <i>ortho</i>-lithiation/halogenation technology. While catalytic C-H halogenation has emerged as a potentially environmentally friendly method, the need for stoichiometric bases, expensive oxidants, and installation of directing groups prevented its adoption in scalable synthesis. In addition, the ligandless Pd(II)-catalyzed C-H halogenation is incompatible with heterocyclic substrates, thus limiting its use in medicinal chemistry substantially. By the discovery and development of three bifunctional bidentate pyridone ligands, we categorically removed these four detrimental drawbacks, rendering C-H halogenation technology substantially more practical: the reaction conditions require only a ligand-supported Pd(II) catalyst, inexpensive industrial halogenating reagents (NXS), and a commonly used acetonitrile solvent. The utility of this halogenation technology is demonstrated by one-step access to a variety of advanced intermediates for drug molecules that previously involved multistep syntheses.