Isobutyraldehyde → 2-[2-(4-Methoxy-benzyl)-1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl]-2-methyl-propionaldehyde

HRID 2069817Notes

Reaction equation

HRID 2069817 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH2:6][CH2:5]2.C[O:23][C:24]1C=CC=[C:28](OC)[C:29]=1[C:30]1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)C(C)C>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:29]([CH3:30])([CH3:28])[CH:24]=[O:23])[CH:3]=3)[C:8]2=[O:12])=[CH:15][CH:16]=1

Participants

7

Reactant 4

HCID 6561Isobutyraldehyde2×HCID 10796Cesium carbonateHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl3×HCID 592164816-Bromo-2-(4-methoxy-benzyl)-3,4-dihydro-2H-isoquinolin-1-one

Product 1

HCID 592164762-[2-(4-Methoxy-benzyl)-1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl]-2-methyl-propionaldehydeYield 144.3%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalyst3×HCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

6-Bromo-2-(4-methoxy-benzyl)-3,4-dihydro-2H-isoquinolin-1-one (5 g, 14.4 mmol), SPHOS (361 mg, 0.06 eq), cesium carbonate (5.65 g, 1.2 eq) and palladium acetate (130 mg, 0.04 eq) were placed in an open sealed tube and taken up in dioxane (58 mL). Argon was bubbled through the solution for about 15 minutes and then isobutyraldehyde (2.9 mL, 2 eq) was added and the mixture was capped and stired at 80° C. overnight. The next day the reaction still was not complete, so additional palladium acetate (65 mg) and SPHOS (181 mg) and isobutyraldehyde (1.5 mL) were added and the reaction was stirred at 80° C. for another 24 hours. At this point the reaction still was not complete so additional palladium acetate (30 mg) and SPHOS (90 mg) were added and the reaction was stirred at 100° C. for another 24 hours. After 3 days, there was no starting material remaining and the reaction was cooled to room temperature. Added ethyl acetate (300 ml) and water 100 mL) and partitioned and separated the layers. The ethyl acetate layer was washed with brine (100 mL) and dried over magnesium sulfate, filtered and concentrated to give the crude product. Purification on silica gel eluting with 20% ethyl acetate in hexanes afforded the title compound as a thick colorless oil (428 mg). MS (ESI) 338.0 (M+H)+.

Workup

  1. customArgon was bubbled through the solution for about 15 minutes
  2. customthe mixture was capped
  3. customThe next day the reaction
  4. customAt this point the reaction
  5. additionwere added
  6. stirringthe reaction was stirred at 100° C. for another 24 hours
  7. waitAfter 3 days
  8. temperaturethe reaction was cooled to room temperature
  9. customAdded ethyl acetate (300 ml) and water 100 mL) and partitioned
  10. customseparated the layers
  11. washThe ethyl acetate layer was washed with brine (100 mL)
  12. dry with materialdried over magnesium sulfate
  13. filtrationfiltered
  14. concentrationconcentrated
  15. customto give the crude product
  16. customPurification on silica gel eluting with 20% ethyl acetate in hexanes

Sources & evidence

ORD record
ord-a5c1d0d7bec54718a83180ff8754e842
Source dataset
uspto-grants-2012_10
Patent number
US08299077B2

Reaction notes

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