Work

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

Year: 2025

Type: article

Abstract: -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.

Source: Journal of the American Chemical Society

DOI: 10.1021/jacs.5c05774

Authors: Haiwei Zhao, Zhen Li, Xinyu Zhu, Jin-Quan Yu

Institution: Scripps Research Institute

Language: English

Topic: Catalytic C–H Functionalization Methods

Subfield: Organic Chemistry

Field: Chemistry

Domain: Physical Sciences

Open Access status: green

Funders: Scripps Research Institute, George E. Hewitt Foundation for Medical Research, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, National Institute of General Medical Sciences

Awards: G1584591046, Enantioselective and site-selective C-H activation reactions with Bifunctional ligands