Methyl Acrylate → Methyl (2E)-3-(1-acetyl-1H-pyrazol-4-yl)prop-2-enoate

HRID 1850073Notes

Reaction equation

HRID 1850073 reaction equation
I[C:2]1[CH:3]=[N:4][N:5]([C:7](=[O:9])[CH3:8])[CH:6]=1.[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12].C(N(CC)CC)C.P(OC)(OC)OC>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[C:7]([N:5]1[CH:6]=[C:2](/[CH:12]=[CH:11]/[C:10]([O:14][CH3:15])=[O:13])[CH:3]=[N:4]1)(=[O:9])[CH3:8]

Participants

7

Reactant 4

HCID 7294Methyl AcrylateHCID 8471TriethylamineHCID 8472Trimethyl phosphite2×HCID 153665251-(4-Iodo-1H-pyrazol-1-yl)ethan-1-one

Product 1

HCID 25137630Methyl (2E)-3-(1-acetyl-1H-pyrazol-4-yl)prop-2-enoateYield 84.8%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalyst2×HCID 6228DimethylformamideSolvent

Conditions

Temperature
110 °C

Procedure

A 5-L multineck flask was fitted with a mechanical stirrer, a gas inlet adapter, and a thermometer and cooled in a salt-ice bath to between −10 and −15° C. The system was purged with dry nitrogen for a few minutes. A solution of 1-(4-iodo-1H-pyrazol-1-yl)ethanone (100 g, 0.425 mol) 1.2 L of N,N-dimethylformamide (DMF) was added followed by methyl acrylate (110 g, 1.275 mol), triethylamine (64 mL, 0.458 mol), trimethyl phosphite (5.27 g, 42.5 mmol), and palladium acetate (4.76 g, 21.25 mmol). The mixture was then warmed to 110° C. under dry nitrogen atmosphere and stirred for 1 hour. LC/MS analysis of an aliquot showed only 10% product formation. Trimethyl phosphite (5.27 g, 42.5 mmol), and palladium acetate (4.76 g, 21.25 mmol) were then added to the reaction mixture. The reaction went to completion after another 1.5 h as monitored by LC/MS. The mixture was allowed to cool to room temperature and the DMF was removed under reduced pressure. The residue was stirred with 1.5 L of methylene chloride, and the suspension was filtered through a plug of silica gel. The filtrate was collected and washed with 1 L of 3% hydrochloric acid, 1 L of water, and 1 L of saturated brine. The solution was dried over magnesium sulfate and filtered. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (Hexane/EtOAc 10:1 to 1:1) to give (E)-methyl 3-(1-acetyl-1H-pyrazol-4-yl)acrylate as a solid (70 g, 84%).

Workup

  1. customA 5-L multineck flask was fitted with a mechanical stirrer, a gas inlet adapter
  2. temperaturea thermometer and cooled in a salt-ice bath to between −10 and −15° C
  3. customThe system was purged with dry nitrogen for a few minutes
  4. waitThe reaction went to completion after another 1.5 h
  5. temperatureto cool to room temperature
  6. customthe DMF was removed under reduced pressure
  7. stirringThe residue was stirred with 1.5 L of methylene chloride
  8. filtrationthe suspension was filtered through a plug of silica gel
  9. customThe filtrate was collected
  10. washwashed with 1 L of 3% hydrochloric acid, 1 L of water, and 1 L of saturated brine
  11. dry with materialThe solution was dried over magnesium sulfate
  12. filtrationfiltered
  13. customThe solvent was removed under reduced pressure
  14. customthe residue was purified by silica gel column chromatography (Hexane/EtOAc 10:1 to 1:1)

Sources & evidence

ORD record
ord-67ea2d8525b049f0b25b5b9b4220b730
Source dataset
uspto-grants-2015_02
Patent number
US08957066B2

Reaction notes

Loading…