Toluene → Tert-butyl 4-(3-cyclopropyl-5-methylpyridin-2-yl)piperazine-1-carboxylate

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Reaction Steps

To a mixture of 1-Boc-piperazine (7.2 g), 2,3-dichloro-5-methylpyridine (5 g), palladium (II) acetate (179 mg), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (499 mg) and sodium tert-butoxide (4.1 g) was added toluene (30 mL), and the mixture was refluxed for 5 hr. After cooling, 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 residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3-chloro-5-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (9 g). To a mixture of 4-(3-chloro-5-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (9 g), bis(tricyclohexylphosphine)palladium (II) dichloride (1 g), tripotassium phosphate (30 g) and cyclopropylboronic acid (5.5 g) were added toluene (80 mL) and water (4 mL), and the mixture was refluxed for 8 hr. After cooling, 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 residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3-cyclopropyl-5-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (9 g). 4-(3-Cyclopropyl-5-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (9 g) was dissolved in chloroform (25 mL), 4N hydrogen chloride/ethyl acetate (25 mL) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (100 mL) was added and the mixture was filtered to give the title compound (4.6 g).

Provenance & Evidence