tert-Butyl piperazine-1-carboxylate → 1,1-Dimethylethyl 4-[2-Methoxy-4-(trifluoromethoxy)phenyl]-1-piperazinecarboxylate

HRID 1058952Notes

Reaction equation

HRID 1058952 reaction equation
Br[C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1OC.[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C[C:29](C)([O-:31])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:29][O:31][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:10])([F:11])[F:12])[CH:5]=[CH:4][C:3]=1[N:18]1[CH2:19][CH2:20][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:17]1

Participants

6

Reactant 3

HCID 143452tert-Butyl piperazine-1-carboxylateHCID 186690522-Bromo-1-methoxy-4-(trifluoromethoxy)benzeneHCID 23676156Sodium t-butoxide

Product 1

HCID 186690671,1-Dimethylethyl 4-[2-Methoxy-4-(trifluoromethoxy)phenyl]-1-piperazinecarboxylateYield 82.1%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
80 °C

Procedure

A solution of 2-bromo-1-methoxy4-(trifluoromethoxy)benzene (Description 16, 3 g, 11 mmol), 1,1-dimethylethyl 1-piperazinecarboxylate (2.47 g) and sodium tert-butoxide (1.49 g) in toluene (100 mL) was degassed with bubbling argon. (RS)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (56 mg) and tris(dibenzylideneacetone)dipalladium (0) (13.8 mg) were added and the mixture was degassed and stirred at 80° C. for 72 h. The mixture was cooled, diluted with ether (150 mL) and filtered through celite. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with hexane/EtOAc (95:5 increasing to 85:15), to give the title compound (3.4 g, 82%). 1H NMR (250 MHz, CDCl3) δ1.48 (9H, s), 2.98-3.01 (4H, m), 3.58-3.61 (4H, m), 3.87 (3H, s), and 6.74-6.85 (3H, m). m/z (ES+) 377 (M+1).

Workup

  1. customthe mixture was degassed
  2. temperatureThe mixture was cooled
  3. additiondiluted with ether (150 mL)
  4. filtrationfiltered through celite
  5. customThe solvent was evaporated under reduced pressure
  6. customthe residue was purified by flash column chromatography on silica gel
  7. washeluting with hexane/EtOAc (95:5 increasing to 85:15)

Sources & evidence

ORD record
ord-275b1e8529ed41c597e2d48a5093c5cf
Source dataset
uspto-grants-2003_02
Patent number
US06518273B1

Reaction notes

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