Water → tert-Butyl 4-(3-(tert-butoxycarbonylamino)-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate

HRID 1808893Notes

Reaction equation

HRID 1808893 reaction equation
Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:3]=1.[N:20]1([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>C1(C)C=CC=CC=1.C(O[Pd]OC(=O)C)(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(OCC)(=O)C>[C:16]([O:15][C:13]([NH:12][C:4]1[CH:3]=[C:2]([N:23]2[CH2:22][CH2:21][N:20]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][CH2:24]2)[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])=[O:14])([CH3:19])([CH3:18])[CH3:17]

Participants

9

Reactant 4

HCID 962WaterHCID 10796Cesium carbonateHCID 143452tert-Butyl piperazine-1-carboxylateHCID 66692382Methyl 4-bromo-2-((tert-butoxycarbonyl)amino)benzoate

Product 1

HCID 66695921tert-Butyl 4-(3-(tert-butoxycarbonylamino)-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylateYield 69%

Reagents, catalysts & solvents 4

HCID 167845palladium(II) acetateCatalystHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylCatalystHCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
110 °C

Procedure

Nitrogen was bubbled into a mixture of methyl 4-bromo-2-(tert-butoxycarbonylamino)benzoate (0.62 g, 1.878 mmol), tert-butyl piperazine-1-carboxylate (0.350 g, 1.878 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.045 g, 0.094 mmol) and cesium carbonate (1.835 g, 5.63 mmol) in toluene (4 mL) for 10 min., followed by the addition of diacetoxypalladium (0.013 g, 0.056 mmol). The reaction mixture was stirred at 110° C. for two hours. The reaction mixture was cooled to RT. Water and ethyl acetate (30 mL/30 mL) were added. The two layers were separated in a separatory funnel The aqueous layer was extracted one more time with 30 mL of ethyl acetate. The product was purified by flash chromatography (1% EtOAc/DCM, Rf 0.44) to give 0.56 g (69% yield) of tert-Butyl 4-(3-(tert-butoxycarbonylamino)-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate. 1H-NMR (CDCl3, 400 MHz): δ 10.48 (1H, s), 8.01 (1H, d, J=2.5 Hz), 7.87 (1H, d, J=9.0 Hz), 6.46 (1H, dd, J1=9.0 Hz, J2=2.5 Hz), 3.86 (3H, s), 3.57 (4H, t, J=5.0 Hz), 3.36 (4H, t, J=5.0 Hz), 1.53 (9H, s), 1.49 (9H, s).

Workup

  1. temperatureThe reaction mixture was cooled to RT
  2. customThe two layers were separated in a separatory funnel The aqueous layer
  3. extractionwas extracted one more time with 30 mL of ethyl acetate
  4. customThe product was purified by flash chromatography (1% EtOAc/DCM, Rf 0.44)

Sources & evidence

ORD record
ord-e30cf58559ee475a8f5aa5514b3ec34e
Source dataset
uspto-grants-2013_01
Patent number
US08362004B2

Reaction notes

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