Synthesis and reactivity of some 6-substituted-2,4-dimethyl-3-pyridinols, a novel class of chain-breaking antioxidants

The synthesis and study of a series of 6-substituted-2,4-dimethyl-3-pyridinols having interesting antioxidant properties is reported. The general synthetic strategy leading to the compounds involved a low-temperature aryl bromide-to-alcohol conversion as the last step. 2,4-dimethyl-3-pyridinol (1a), 2,4,6-trimethyl-3-pyridinol (1b), and 2,4-dimethyl-6-(dimethylamino)-3-pyridinol (1d) were thus prepared from the corresponding 3-bromopyridine precursor. The methoxy derivative 2,4-dimethyl-6-(methoxy)-3-pyridinol (1c) was also prepared by an alternate route via a Baeyer-Villiger reaction on the substituted benzaldehyde precursor. Novel bicyclic pyridinols 2 and 3 required prior construction of the ring structure. Thus, 2 was prepared by the use of a 6-step intramolecular Friedel-Crafts strategy, and 3 required an 11-step sequence with a thermolytic intramolecular inverse-demand Diels-Alder reaction between a pyrimidine ring and an alkyne as the key step. Basicities of the pyridinols approached physiological pH with increasing electron density in the ring. Pyridinols 1a-d were found to be indefinitely stable to air oxidation while 2 and 3 decomposed upon extended exposure to the atmosphere. The reactivities of the pyridinols toward chain-carrying peroxyl radicals in homogeneous organic solution were examined by studying the kinetics of radical-initiated styrene autoxidations under controlled conditions. These experiments revealed that some of the newly synthesized pyridinols are the most effective phenolic chain-breaking antioxidants reported to date.