tert-Butyl piperazine-1-carboxylate → 4-(3-Fluoro-4-trifluoromethyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester

HRID 1727049Notes

Reaction equation

HRID 1727049 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([F:25])[CH:16]=1.[Cl-].C(C1C=CC=C(C(C)C)C=1[N+]1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C=1)(C)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[C:17]([F:25])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

6

Reactant 4

HCID 143452tert-Butyl piperazine-1-carboxylateHCID 27349131,3-Bis(2,6-diisopropylphenyl)imidazolium chlorideHCID 27829044-Bromo-2-fluorobenzotrifluorideHCID 23676156Sodium t-butoxide

Product 1

HCID 597936284-(3-Fluoro-4-trifluoromethyl-phenyl)-piperazine-1-carboxylic acid tert-butyl esterYield 86%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

Tert-butyl-1-piperazine-carboxylate (740 mg, 3.05 mmol) and 4-bromo-2-fluoro-1-trifluoromethyl-benzene (530 mg. 2.85 mmol) were dissolved in anhydrous toluene (6 mL, degassed). In a separate, septum-equipped vial were placed tri(dibenzylideneacetone)dipalladium(0) (152 mg, 0.17 mmol), 1,3-bis(2,6-di-i-propylphenyl)imidazolium chloride (283 mg, 0.67 mmol) and sodium t-butoxide (400 mg, 4.2 mmol). This “catalytic” vial was equipped with a magnetic stirbar and flushed with dry nitrogen. The reactant solution was next transferred to the “catalytic” vial and the mixture was stirred at 100° C. for 5 hours. After this period the mixture was combined with 20 mL of hexane/EtOAc (2:1) and was passed through a pad of Celite. The resulting filtrate was concentrated and purified using silica gel chromatography (0-20% EtOAc/Hexane) to yield 853 mg (86%) of 4-(3-Fluoro-4-trifluoromethyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester as a yellow residue. 1H NMR (400 MHz. CDCl3) 7.44-7.40 (m, 1H), 6.65-6.58 (m, 2H), 3.59-3.56 (m, 4H), 3.27-3.25 (m, 4H), 1.49 (s, 9H).

Workup

  1. customIn a separate, septum-equipped vial
  2. customThis “catalytic” vial was equipped with a magnetic stirbar
  3. customflushed with dry nitrogen
  4. waitAfter this period the mixture was combined with 20 mL of hexane/EtOAc (2:1)
  5. concentrationThe resulting filtrate was concentrated
  6. custompurified

Sources & evidence

ORD record
ord-6e8547f606c94243925cf361c84b7f17
Source dataset
uspto-grants-2009_02
Patent number
US07494999B2

Reaction notes

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