2,4,6-Trimethylphenol → 4-Chloro-2,5-dimethyl-6-(2,4,6-trimethyl-phenoxy)pyridine

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Reaction Steps

To a 2 liter flask equipped with a mechanical stirrer, a reflux condenser and a nitrogen inlet was charged 250 ml of pyridine. The flask was cooled in an ice bath and charged with 42.5 g (0.312 mmol) of 2,4,6-trimethylphenol and 35.1 g (0.313 mol) of potassium t-butoxide. The flask was warmed to room temperature and charged with 50.0 g (0.284 mol) of 2,4-dichloro-3,6-dimethylpyridine and 13.5 g (0.071 mol) of copper (I) iodide. The reaction mixture was heated to reflux for two hours and then cooled to 0° C. The reaction was diluted with 500 ml of hexanes, then mixed with 1000 ml of saturated ammonium chloride (NH4Cl). After warming to room temperature, the mixture was stirred overnight. The layers were separated and the organic layer was washed with 3×125 ml of 1M ammonium hydroxide (NH4OH), 2×250 ml of 3N sodium hydroxide (NaOH), 1×250 ml of 1N hydrochloric acid (HCl) and 1×250 ml of water. After drying over sodium sulfate (Na2SO4), the solids were removed by filtration and washed with hexane. The filtrate was concentrated under vacuum to a brown oil. The residue was mixed with 250 ml methanol and stirred overnight. The resulting slurry was filtered under vacuum. The off-white solids were washed with methanol then dried to obtain 31.6 g (40.4%) of the title compound.

Provenance & Evidence