2-(4-Bromophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol → HCID 86670448, compound

HRID 1972697Notes

Reaction equation

HRID 1972697 reaction equation
[CH2:1]([O:8][CH2:9][C@@H:10]1[NH:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:24]1[CH:29]=[CH:28][C:27]([C:30]([OH:39])([C:35]([F:38])([F:37])[F:36])[C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=1.CC([O-])(C)C.[Na+]>CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.CC(OC)(C)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].C1(C)C=CC=CC=1>[CH2:1]([O:8][CH2:9][C@@H:10]1[N:15]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([OH:39])([C:35]([F:36])([F:38])[F:37])[C:31]([F:34])([F:32])[F:33])=[CH:26][CH:25]=2)[CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1

Participants

6

Reactant 3

HCID 232335702-(4-Bromophenyl)-1,1,1,3,3,3-hexafluoropropan-2-olHCID 23676156Sodium t-butoxideHCID 70659797HCID 70659797, compound

Product 1

HCID 86670448HCID 86670448, compoundYield 83.6%

Reagents, catalysts & solvents 2

HCID 66572931HCID 66572931, compoundCatalystHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

A 20 mL vial was charged with tert-butyl (3R)-3-((benzyloxy)methyl)-1-piperazinecarboxylate (1.19 g, 3.88 mmol), 2-(4-bromophenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (1.39 g, 4.31 mmol, Bioorg. Med. Chem. Lett. 2002, 12, 3009), RuPhos Palladacycle (0.047 g, 0.039 mmol, Strem Chemical Inc, Newburyport, Mass.), NaOtBu (0.938 g, 9.76 mmol, Sigma-Aldrich, St. Louis, Mo.) and toluene (12 mL). The mixture was degassed by bubbling Ar through the solution for 10 min. The vial was sealed and the mixture was heated at 100° C. for 3 h. Water (100 mL) was added and the aqueous phase was extracted with EtOAc (2×60 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (100 g of silica, 0-30% EtOAc in hexanes) to afford tert-butyl (3R)-3-((benzyloxy)methyl)-4-(4-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-1-piperazinecarboxylate (1.78 g) as an off-white foam.

Workup

  1. customThe mixture was degassed
  2. customby bubbling Ar through the solution for 10 min
  3. customThe vial was sealed
  4. additionWater (100 mL) was added
  5. extractionthe aqueous phase was extracted with EtOAc (2×60 mL)
  6. dry with materialThe combined organic phases were dried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customThe crude product was purified by column chromatography (100 g of silica, 0-30% EtOAc in hexanes)

Sources & evidence

ORD record
ord-7339ed69cfa6431d9e5600c76b7e32f5
Source dataset
uspto-grants-2013_04
Patent number
US08431563B2

Reaction notes

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