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Synthesis and Reactivity of Some 6-Substituted-2,4-dimethyl-3-pyridinols, a Novel Class of Chain-Breaking Antioxidants

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journal contribution
posted on 24.12.2004, 00:00 by Maikel Wijtmans, Derek A. Pratt, Johan Brinkhorst, Remigiusz Serwa, Luca Valgimigli, Gian Franco Pedulli, Ned A. Porter
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 1ad 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.