Ethyl Bromide → 5-(4-(Difluoromethoxy)-2-ethoxy-3-methoxyphenyl)isoindolin-1-one

HRID 2171096Notes

Reaction equation

HRID 2171096 reaction equation
BrC1C(O)=C(OC)C(OC(F)F)=CC=1.C(=O)([O-])[O-].[K+].[K+].C(Br)C.Br[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH:32]([F:34])[F:33])=[C:27]([O:35][CH3:36])[C:26]=1[O:37][CH2:38][CH3:39].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:54]2[CH:55]=[C:56]3[C:60](=[CH:61][CH:62]=2)[C:59](=[O:63])[NH:58][CH2:57]3)O1>C(#N)C.CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:33][CH:32]([F:34])[O:31][C:28]1[CH:29]=[CH:30][C:25]([C:54]2[CH:55]=[C:56]3[C:60](=[CH:61][CH:62]=2)[C:59](=[O:63])[NH:58][CH2:57]3)=[C:26]([O:37][CH2:38][CH3:39])[C:27]=1[O:35][CH3:36]

Participants

10

Reactant 6

HCID 6332Ethyl BromideHCID 10796Cesium carbonateHCID 11430Potassium CarbonateHCID 219557955-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-oneHCID 674668041-Bromo-4-(difluoromethoxy)-2-ethoxy-3-methoxybenzeneHCID 674670406-Bromo-3-(difluoromethoxy)-2-methoxyphenol

Product 1

HCID 674629765-(4-(Difluoromethoxy)-2-ethoxy-3-methoxyphenyl)isoindolin-1-oneYield 13%

Reagents, catalysts & solvents 3

HCID 11979704Tetrakis(triphenylphosphine)palladiumCatalystHCID 6228DimethylformamideSolventHCID 6342AcetonitrileSolvent

Conditions

Temperature
80 °C

Procedure

To a stirring solution of 6-bromo-3-(difluoromethoxy)-2-methoxyphenol (200 mg, 0.74 mmol) in acetonitrile (10 mL) was added potassium carbonate (307 mg, 2.23 mmol) and ethyl bromide (0.6 mL, 2.23 mmol) and the resultant reaction mixture was heated to 80° C. for 2 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure to afford 200 mg of crude product, 1-Bromo-4-difluoromethoxy-2-ethoxy-3-methoxy-benzene, as a solid. A stirring solution of 1-bromo-4-(difluoromethoxy)-2-ethoxy-3-methoxybenzene (200 mg, 0.673 mmol) in N,N-dimethylformamide (5 mL) was purged with argon for 1 h, to this cesium carbonate (656 mg, 2.019 mmol), tetrakis(triphenylphosphine) palladium(0) (38 mg, 0.033 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (209 mg, 0.807 mmol) were added and the resultant reaction mixture was heated to 80-90° C. for 3 h. The reaction mixture was cooled to RT, filtered and the filtrate was diluted with water and extracted with ethyl acetate (3×). The combined ethyl acetate layer was washed with brine and dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, 0-20% ethyl acetate in pet ether) afforded the title compound as a solid (30 mg, 13%).

Workup

  1. customthe resultant reaction mixture
  2. temperatureThe reaction mixture was cooled to RT
  3. filtrationfiltered through celite
  4. concentrationthe filtrate was concentrated under reduced pressure
  5. customto afford 200 mg of crude product, 1-Bromo-4-difluoromethoxy-2-ethoxy-3-methoxy-benzene
  6. additionwere added
  7. customthe resultant reaction mixture
  8. temperaturewas heated to 80-90° C. for 3 h
  9. temperatureThe reaction mixture was cooled to RT
  10. filtrationfiltered
  11. additionthe filtrate was diluted with water
  12. extractionextracted with ethyl acetate (3×)
  13. washThe combined ethyl acetate layer was washed with brine
  14. dry with materialdried over anhydrous sodium sulphate
  15. concentrationconcentrated under reduced pressure
  16. customPurification of the residue by column chromatography (silica gel, 0-20% ethyl acetate in pet ether)

Sources & evidence

ORD record
ord-ff9bebd396da48bab6ad2cab4e78b7f3
Source dataset
uspto-grants-2015_06
Patent number
US09051290B2

Reaction notes

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