Methyl Ethyl Ketone → Tert-butyl 4-(3,5-dibromopyridin-2-yl)piperazine-1-carboxylate

HRID 1803988Notes

Reaction equation

HRID 1803988 reaction equation
Br[C:2]1[C:7]([Br:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[C:10]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>O>[C:13]([O:12][C:10]([N:17]1[CH2:22][CH2:21][N:20]([C:2]2[C:7]([Br:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=2)[CH2:19][CH2:18]1)=[O:11])([CH3:16])([CH3:14])[CH3:15]

Participants

6

Reactant 4

HCID 6569Methyl Ethyl KetoneHCID 11430Potassium CarbonateHCID 143452tert-Butyl piperazine-1-carboxylateHCID 6287982,3,5-Tribromopyridine

Product 1

HCID 49871619Tert-butyl 4-(3,5-dibromopyridin-2-yl)piperazine-1-carboxylateYield 97.5%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

To a mixture of 2,3,5-tribromopyridine (10 g), 1-Boc-piperazine (6 g) and potassium carbonate (20 g) was added 2-butanone (80 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 to give 4-(3,5-dibromopyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (13 g). To a mixture of 4-(3,5-dibromopyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (13 g), bis(tricyclohexylphosphine)palladium (II) dichloride (1.3 g), tripotassium phosphate (38 g) and cyclopropylboronic acid (8.4 g) were added toluene (100 mL) and water (5 mL), and the mixture was refluxed for 8 hr. After cooling, 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-(3,5-dicyclopropylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (7 g). 4-(3,5-Dicyclopropylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (7 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. To the reaction mixture was added 1N aqueous sodium hydroxide solution (100 mL), and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was dissolved in ethyl acetate (50 mL), 4N hydrogen chloride/ethyl acetate (8 mL) was added, and the mixture was filtered to give the title compound (3.2 g).

Workup

  1. temperaturethe mixture was refluxed for 8 hr
  2. temperatureAfter cooling
  3. extractionthe mixture was extracted with ethyl acetate
  4. washThe organic layer was washed with saturated brine
  5. customthe solvent was evaporated

Sources & evidence

ORD record
ord-65bcdae0933d4adca3a68f3ecb25dd59
Source dataset
uspto-grants-2013_01
Patent number
US08354401B2

Reaction notes

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