Cesium carbonate → tert-Butyl {2-[1-(4-bromo-phenyl)piperidin-4-yl]ethyl}-carbamate

HRID 1019708

Reaction equation

HRID 1019708 reaction equation
[Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[NH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11][CH2:10]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1

Participants

10

Reactant 4

HCID 10796Cesium carbonateHCID 115221-Bromo-4-iodobenzeneHCID 634876Binap, (A+-)-HCID 15018494-(2-Aminoethyl)piperidine, 4-BOC protected

Product 1

HCID 86661351tert-Butyl {2-[1-(4-bromo-phenyl)piperidin-4-yl]ethyl}-carbamateYield 19.8%

Reagents, catalysts & solvents 5

HCID 167845palladium(II) acetateCatalyst2×HCID 634876Binap, (A+-)-CatalystHCID 962WaterSolventHCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Procedure

6.19 g (21.90 mmol) of 1-bromo-4-iodobenzene, 5.00 g (21.90 mmol) of tert-butyl (2-piperidin-4-ylethyl)carbamate, 9.98 g (60.66 mmol) of caesium carbonate and 0.54 g (0.88 mmol) of BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) suspended in 100 mL of toluene are placed under an inert atmosphere. 0.098 g (0.44 mmol) of palladium diacetate is then added. The reaction mixture is then refluxed for 6 hours. 0.045 g (0.20 mmol) of palladium diacetate and 0.25 g (0.40 mmol) of BINAP are added and the mixture is left to stir at reflux for 12 hours. The reaction medium is allowed to cool, and ethyl acetate and water are added. The aqueous phase is separated out and extracted twice with ethyl acetate, and the combined organic phases are washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. After evaporating off the solvent, the residue obtained is purified by chromatography on silica gel, eluting with a 98/2/0.2 mixture of dichloromethane, methanol and 28% aqueous ammonia to give 1.66 g of expected product in the form of a white solid.

Workup

  1. temperatureThe reaction mixture is then refluxed for 6 hours
  2. waitthe mixture is left
  3. temperatureat reflux for 12 hours
  4. temperatureto cool
  5. customThe aqueous phase is separated out
  6. extractionextracted twice with ethyl acetate
  7. washthe combined organic phases are washed with saturated aqueous sodium chloride solution
  8. dry with materialdried over sodium sulfate
  9. customAfter evaporating off the solvent
  10. customthe residue obtained
  11. customis purified by chromatography on silica gel
  12. washeluting with a 98/2/0.2 mixture of dichloromethane, methanol and 28% aqueous ammonia

Sources & evidence

ORD record
ord-f643cf4c1c954478aff3d8023f575c2c
Source dataset
uspto-grants-2014_05
Patent number
US08716289B2

Linked notes

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