biostudies-literatureHu LScripps Research InstituteNational Institute of General Medical SciencesNIGMS NIH HHS20550-20553https://www.ebi.ac.uk/biostudies/studies/S-EPMC10243520biostudies-literatureUnknown144(45)Ligand development has enabled rapid advances in Pd(II)-catalyzed β-methyl C(sp³)-H activation of free carboxylic acids. However, there are only a handful of reports of free-acid-directed β-methylene C(sp³)-H activation, all of which are limited to intramolecular reactions. Herein, we report the first Pd(II)-catalyzed intermolecular β-methylene C(sp³)-H arylation of free aliphatic acids, which is enabled by bidentate pyridine-pyridone ligands. The bite angle of this ligand has been discovered to play a key role in promoting β-methylene C-H activation of free carboxylic acid. This new transformation provides a disconnection for alkylation of arenes with simple aliphatic acids. A variety of free aliphatic acids, including the antiasthmatic drug seratrodast, wJournal of the American Chemical SocietyLigand-Enabled Pd(II)-Catalyzed β-Methylene C(sp³)-H Arylation of Free Aliphatic Acids.PMC10243520R01 GM084019R01GM084019Yu JQHu LMeng GfalseLigand-Enabled Pd(II)-Catalyzed β-Methylene C(sp³)-H Arylation of Free Aliphatic Acids.Ligand development has enabled rapid advances in Pd(II)-catalyzed β-methyl C(sp³)-H activation of free carboxylic acids. However, there are only a handful of reports of free-acid-directed β-methylene C(sp³)-H activation, all of which are limited to intramolecular reactions. Herein, we report the first Pd(II)-catalyzed intermolecular β-methylene C(sp³)-H arylation of free aliphatic acids, which is enabled by bidentate pyridine-pyridone ligands. The bite angle of this ligand has been discovered to play a key role in promoting β-methylene C-H activation of free carboxylic acid. This new transformation provides a disconnection for alkylation of arenes with simple aliphatic acids. A variety of free aliphatic acids, including the antiasthmatic drug seratrodast, w2022-01-01T00:00:00Z2022 Nov2025-04-04T21:13:51.647Z2025-04-04T21:13:51.647ZS-EPMC102435203634246610.1021/jacs.2c09205