4-Bromo-2-methylpyridine → HCID 22710417, compound

Participants

Reaction Steps

At room temperature, tetrakis(triphenylphosphine)palladium (470 mg) was added to a solution of 4-bromo-2-methylpyridine (1.65 g) and (5-thiazolyl)trimethyltin (1.56 g) in benzene (80 ml), followed by heating under reflux for 14 hours. After allowed to cool down to room temperature, the reaction mixture was washed with a saturated aqueous solution (100 ml) of sodium bicarbonate. The water layer was extracted with ethyl acetate (50 ml). The organic layers were combined, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (methylene chloride:ethyl acetate=4:1→1:1), whereby 2-methyl-4-(5-thiazolyl)pyridine was obtained as a colorless solid. The resulting solid was dissolved in diethyl ether (30 ml) and tetrahydrofuran (30 ml), followed by the dropwise addition of n-butyl lithium (a 1.52N hexane solution, 4.35 ml) at −78° C. After stirring for 30 minutes, a carbon dioxide gas was blown into the reaction mixture. Thirty minutes later, the reaction mixture was heated gradually to room temperature. The reaction mixture was concentrated, whereby the residue of lithium 5-(2-methylpyridin-4-yl)thiazole-2-carboxylate was obtained as a colorless solid. To a solution of the resulting residue in N,N-dimethylformamide (40 ml) were added 1-(tert-butoxycarbonyl)piperazine (1.30 g), 1-hydroxybenzotriazole monohydrate (945 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.34 g) at room temperature. After stirring for 3 days, ethyl acetate (200 ml) and water (800 ml) were added to the reaction mixture to separate it into layers. The water layer was extracted with ethyl acetate (2×100 ml). The organic layers were combined, washed with water (800 ml) and a saturated aqueous solution (200 ml) of sodium bicarbonate, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (methylene chloride:acetone=6:1), whereby the title compound (810 mg) was obtained as a colorless transparent viscous substance.

Provenance & Evidence