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 (1 a), 2 ,4,6-trimethyl-3-pyridinol (ib), and 2 ,4-dimethyl-6-(dimethylamino)-3-pyridinol (1 d) were thus prepared from the corresponding 3-bromopyridine precursor. The methoxy derivative 2,4-dimethyl- 6-(methoxy)-3-pyridinol (ic) 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 la-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. [ABSTRACT FROM AUTHOR]