Cesium carbonate → 5(4-(Difluoromethoxy)-2-isobutoxy-3-methoxyphenyl)isoindolin-1-one

HRID 2171100Notes

Reaction equation

HRID 2171100 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([F:11])[F:10])=[C:4]([O:12][CH3:13])[C:3]=1[O:14][CH2:15][CH:16]([CH3:18])[CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:33]2[CH:34]=[C:35]3[C:39](=[CH:40][CH:41]=2)[C:38](=[O:42])[NH:37][CH2:36]3)O1>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:10][CH:9]([F:11])[O:8][C:5]1[CH:6]=[CH:7][C:2]([C:33]2[CH:34]=[C:35]3[C:39](=[CH:40][CH:41]=2)[C:38](=[O:42])[NH:37][CH2:36]3)=[C:3]([O:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:4]=1[O:12][CH3:13]

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 219557955-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-oneHCID 674655061-Bromo-4-(difluoromethoxy)-2-isobutoxy-3-methoxybenzene

Product 1

HCID 674678315(4-(Difluoromethoxy)-2-isobutoxy-3-methoxyphenyl)isoindolin-1-one

Reagents, catalysts & solvents 2

HCID 11979704Tetrakis(triphenylphosphine)palladiumCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
85 °C

Procedure

To a stirring solution of 6-bromo-3-(difluoromethoxy)-2-methoxyphenol (100 mg, 0.371 mmol) in acetonitrile (10 mL), was added potassium carbonate (153.8 mg, 1.114 mmol) and isobutyl bromide (152.6 mg, 1.114 mmol) and the resultant reaction mixture was heated to 80° C. for 3 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure to afford 300 mg of 1-Bromo-4-(difluoromethoxy)-2-isobutoxy-3-methoxybenzene as a solid. To a stirring solution of 1-bromo-4-(difluoromethoxy)-2-isobutoxy-3-methoxybenzene (200 mg, 0.615 mmol) in dimethylformamide (5 mL) was purged with argon for 1 h. To this cesium carbonate (599 mg, 1.84 mmol), tetrakis(triphenylphosphine) palladium(0) (35 mg, 0.030 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (191 mg, 0.738 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 (30 mg, 13%).

Workup

  1. customthe resultant reaction mixture
  2. temperatureThe reaction mixture was cooled to RT
  3. filtrationfiltered
  4. additionthe filtrate was diluted with water
  5. extractionextracted with ethyl acetate (3×)
  6. washThe combined ethyl acetate layer was washed with brine
  7. dry with materialdried over anhydrous sodium sulphate
  8. concentrationconcentrated under reduced pressure
  9. customPurification of the residue by column chromatography (silica gel, 0-20% ethyl acetate in pet ether)

Sources & evidence

ORD record
ord-e17c5acec0504c169f0e5946c8e81316
Source dataset
uspto-grants-2015_06
Patent number
US09051290B2

Reaction notes

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