1-Bromo-3,5-bis(trifluoromethyl)benzene → (3S)-1-[3,5-bis(trifluoromethyl)phenyl]pyrrolidin-3-ol

HRID 2198027Notes

Reaction equation

HRID 2198027 reaction equation
[F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[OH:17][C@H:18]1[CH2:22][CH2:21][NH:20][CH2:19]1.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.CC(C)([O-])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].O>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([N:20]2[CH2:21][CH2:22][C@H:18]([OH:17])[CH2:19]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1

Participants

8

Reactant 4

HCID 676021-Bromo-3,5-bis(trifluoromethyl)benzeneHCID 634876Binap, (A+-)-HCID 22309122(S)-3-Hydroxypyrrolidine hydrochlorideHCID 23676156Sodium t-butoxide

Product 1

HCID 46941682(3S)-1-[3,5-bis(trifluoromethyl)phenyl]pyrrolidin-3-olYield 28%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 1140TolueneSolvent

Procedure

A solution of 3,5-bis(trifluoromethyl)phenyl bromide (44.0 g), (S)-3-hydroxypyrrolidine hydrochloride (17.8 g), tris(dibenzylideneacetone)dipalladium(0) (5.88 g), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (8.00 g) and sodium tert-butoxide (36.0 g) in toluene (280 ml) was refluxed with stirring under an argon gas atmosphere for 16 hr. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate 20:1-2:1) to give the title compound (12.0 g, yield 28%) as a white solid.

Workup

  1. extractionthe mixture was extracted with ethyl acetate
  2. washThe organic layer was washed with saturated brine
  3. dry with materialdried over anhydrous sodium sulfate
  4. filtrationfiltered
  5. concentrationThe filtrate was concentrated
  6. customthe residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate 20:1-2:1)

Sources & evidence

ORD record
ord-e645636b00b045c4adfdb98b6337d8c4
Source dataset
uspto-grants-2012_12
Patent number
US08338622B2

Reaction notes

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