Methylboronic Acid → 4-(3,5-Dimethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester

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Reaction Steps

To a mixture of 2,3,5-trichloropyridine (25 g), 1-Boc-piperazine (28.13 g) and potassium carbonate (37.86 g) were added N,N-dimethylformamide (25 mL) and toluene (50 mL), and the mixture was stirred at 100° C. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3,5-dichloropyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (39.13 g). To a mixture of the obtained 4-(3,5-dichloropyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (6.35 g), palladium(II) acetate (0.46 g), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (1.71 g), potassium fluoride (9.56 g) and methylboronic acid (5 g) was added tetrahydrofuran (202 mL), and the mixture was stirred with heating under reflux for 8 hr under a nitrogen stream. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3,5-dimethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (5.45 g). The obtained 4-(3,5-dimethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (5.45 g) was dissolved in chloroform (46 mL), 4N hydrogen chloride/ethyl acetate (18 ml) was added, and the mixture was stirred at room temperature. After completion of the reaction, to the reaction mixture were added water and potassium carbonate, the mixture was extracted with ethyl acetate, and the solvent was evaporated to give the title compound (3.3 g).

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