4-Bromo-2-fluoro-benzoic acid methyl ester → Methyl 4-cyano-2-fluorobenzoate

HRID 2041484Notes

Reaction equation

HRID 2041484 reaction equation
Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1.[Cu][C:14]#[N:15]>CN(C=O)C.CCCCCC.CCOC(C)=O.O>[C:14]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1)#[N:15]

Participants

6

Reactant 2

HCID 113453114-Bromo-2-fluoro-benzoic acid methyl esterHCID 178418546HCID 178418546, compound

Product 1

HCID 15278726Methyl 4-cyano-2-fluorobenzoateYield 76%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 21226206Ethyl acetate hexaneSolvent

Procedure

Slurry methyl 4-bromo-2-fluoro-benzoate (5 g, 21.5 mmol) and copper(I) cyanide (3.8 g, 42.9 mmol) in anhydrous DMF (90 mL). Heat the mixture to reflux for 20 h under a nitrogen atmosphere. Cool the mixture to room temperature, dilute with hexane/EtOAc (1:1, 300 mL) and water (150 mL). Filter the mixture through Celite® washing with hexane/EtOAc (1:1) to reduce the emulsion layer. Separate the organic layer and extract the aqueous layer with hexane/EtOAc (1:1, 2×200 mL). Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (9:1 to 1:1 gradient) to obtain the desired intermediate (2.9 g, 76%). GC-MS m/z: 179 (M).

Workup

  1. temperatureHeat the mixture
  2. temperatureto reflux for 20 h under a nitrogen atmosphere
  3. filtrationFilter the mixture through Celite®
  4. washwashing with hexane/EtOAc (1:1)
  5. customSeparate the organic layer
  6. extractionextract the aqueous layer with hexane/EtOAc (1:1, 2×200 mL)
  7. dry with materialDry the combined organic extracts over Na2SO4
  8. filtrationfilter
  9. concentrationconcentrate in vacuo
  10. customPurify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (9:1 to 1:1 gradient)

Sources & evidence

ORD record
ord-c132149a31614ced8d82349e9c623089
Source dataset
uspto-grants-2013_11
Patent number
US08580780B2

Reaction notes

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