Dimethylacetamide → 4-Cyclohexyl-3-(trifluoromethyl)benzonitrile

HRID 1506524Notes

Reaction equation

HRID 1506524 reaction equation
Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].CC(N(C)C)=O.[Br-].[CH:21]1([Zn+])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C1COCC1>[CH:21]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[C:10]([F:13])([F:12])[F:11])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1

Participants

5

Reactant 3

HCID 31374DimethylacetamideHCID 108006474-Bromo-3-(trifluoromethyl)benzonitrileHCID 178418970HCID 178418970, compound

Product 1

HCID 671683274-Cyclohexyl-3-(trifluoromethyl)benzonitrileYield 45.6%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
60 °C

Procedure

A mixture of 4-bromo-3-(trifluoromethyl)benzonitrile (6 g, 24.00 mmol), DMA (30 mL), cuprous iodide (0.914 g, 4.80 mmol) and 1,1′-bis(diphenylphosphino) ferrocenedichloro palladium(II) dichloromethane complex (1.756 g, 2.400 mmol) was bubbled with nitrogen for 5 min. before 0.5 M THF solution of cyclohexylzinc bromide (100 mL, 50.0 mmol) was added over 20 min. via cannula at room temperature. The black reaction mixture was stirred at 60° C. overnight. The reaction mixture was concentrated under reduced pressure. EtOAc (50 mL), water (100 mL) and saturated aqueous ammonium chloride solution (30 mL) were added. The solid was filtered off over a celite pad and washed with ethyl acetate (3×20 mL). The aqueous layer was separated and extracted with ethyl acetate (50 mL). The combined organic solutions were washed with 1 N aqueous HCl (2×40 mL) and then brine (40 mL), dried (sodium sulfate) and concentrated under reduced pressure. Flash chromatography purification (silica gel column, 20→100% ethyl acetate in hexanes) afforded 4-cyclohexyl-3-(trifluoromethyl)benzonitrile (2.77 g, 10.94 mmol, 45.6% yield) as a solid. The compound had an HPLC retention time=3.44 min. (condition C); LC/MS [M+H2O]+1=272.2.

Workup

  1. additionwas added over 20 min. via cannula at room temperature
  2. customThe black reaction mixture
  3. concentrationThe reaction mixture was concentrated under reduced pressure
  4. additionEtOAc (50 mL), water (100 mL) and saturated aqueous ammonium chloride solution (30 mL) were added
  5. filtrationThe solid was filtered off over a celite pad
  6. washwashed with ethyl acetate (3×20 mL)
  7. customThe aqueous layer was separated
  8. extractionextracted with ethyl acetate (50 mL)
  9. washThe combined organic solutions were washed with 1 N aqueous HCl (2×40 mL)
  10. dry with materialbrine (40 mL), dried (sodium sulfate)
  11. concentrationconcentrated under reduced pressure
  12. customFlash chromatography purification (silica gel column, 20→100% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-6145ea2b24bd4d1e9c293a49b142b80c
Source dataset
uspto-grants-2015_12
Patent number
US09216972B2

Reaction notes

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