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

HRID 2411202Notes

Reaction equation

HRID 2411202 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2C(Cl)=CC(Cl)=C[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2CCCCC2)C2C=CC=C[C:30]=2[C:35]2[C:40](OC)=C[CH:38]=[CH:37][C:36]=2OC)CCCCC1.[F-].[K+].CB(O)O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:37]([CH3:38])=[CH:36][C:35]([CH3:30])=[CH:40][N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

8

Reactant 4

HCID 139377Methylboronic AcidHCID 522689Potassium FluorideHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 67380983Tert-butyl 4-(3,5-dichloropyridin-2-yl)piperazine-1-carboxylate

Product 1

HCID 673812824-(3,5-Dimethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl esterYield 449%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

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).

Workup

  1. temperaturewith heating
  2. temperatureunder reflux for 8 hr under a nitrogen stream
  3. extractionthe mixture was extracted with ethyl acetate
  4. washThe organic layer was washed with saturated brine
  5. customthe solvent was evaporated
  6. customThe obtained residue was purified by column chromatography (hexane:ethyl acetate)

Sources & evidence

ORD record
ord-6219351b06d447c086eb633cb681746a
Source dataset
uspto-grants-2014_08
Patent number
US08816079B2

Reaction notes

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