tert-Butyl piperazine-1-carboxylate → Tert-butyl 4-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-1-piperazinecarboxylate

HRID 1972444Notes

Reaction equation

HRID 1972444 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:14])([CH3:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[C:15]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>O.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].C1(C)C=CC=CC=1>[F:10][C:9]([F:12])([F:11])[C:8]([C:5]1[CH:6]=[CH:7][C:2]([N:25]2[CH2:24][CH2:23][N:22]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:27][CH2:26]2)=[CH:3][CH:4]=1)([OH:14])[CH3:13]

Participants

8

Reactant 4

HCID 143452tert-Butyl piperazine-1-carboxylateHCID 162179852-Dicyclohexylphosphino-2',6'-diisopropoxybiphenylHCID 23676156Sodium t-butoxideHCID 583472902-(4-Bromophenyl)-1,1,1-trifluoropropan-2-ol

Product 1

HCID 66582454Tert-butyl 4-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-1-piperazinecarboxylateYield 85.8%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

A 350 mL pressure tube was charged with 2-(4-bromophenyl)-1,1,1-trifluoro-2-propanol (7.22 g, 26.8 mmol, Example 27, step 1), N-Boc-piperazine (5.00 g, 26.8 mmol), sodium tert-butoxide (3.87 g, 40.3 mmol), 50 mL of toluene, dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (1.253 g, 2.68 mmol, Strem Chemical Inc, Newburyport, Mass.) and tris(dibenzylideneacetone)dipalladium (0) (1.229 g, 1.342 mmol, Strem Chemical Inc, Newburyport, Mass.). The tube was sealed and heated at 100° C. for 2 h. After that time, the mixture was diluted with water (50 mL) and extracted with EtOAc (2×100 mL) to give a dark oil. Purification via column chromatography (120 g of silica gel, 0 to 40% EtOAc in hexanes) gave tert-butyl 4-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-1-piperazinecarboxylate (8.61 g) as an off-white brittle foam.

Workup

  1. customThe tube was sealed
  2. extractionextracted with EtOAc (2×100 mL)
  3. customto give a dark oil
  4. customPurification via column chromatography (120 g of silica gel, 0 to 40% EtOAc in hexanes)

Sources & evidence

ORD record
ord-877a751f6416471db4d364d9f674b534
Source dataset
uspto-grants-2013_04
Patent number
US08431563B2

Reaction notes

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