Ethyl Acetoacetate → 1-(2,3-Difluoro-6-nitrophenyl)propan-2-one

HRID 1791738Notes

Reaction equation

HRID 1791738 reaction equation
[H-].[Na+].[C:3](OCC)(=O)[CH2:4][C:5]([CH3:7])=[O:6].[F:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=C(F)[C:14]=1[F:23]>C1COCC1>[C:5]([CH2:4][C:3]1[C:14]([F:23])=[C:13]([F:12])[CH:18]=[CH:17][C:16]=1[N+:19]([O-:21])=[O:20])(=[O:6])[CH3:7]

Participants

5

Reactant 3

HCID 8868Ethyl AcetoacetateHCID 24758Sodium hydrideHCID 698711,2,3-Trifluoro-4-nitrobenzene

Product 1

HCID 142688761-(2,3-Difluoro-6-nitrophenyl)propan-2-oneYield 72%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
5 °C

Procedure

To a suspension of sodium hydride (5.42 g, 226 mmol) (prewashed with pentane) in THF (100 ml) cooled at 101C was added ethyl acetoacetate (29.4 g, 226 mmol) while keeping the temperature below 15C. After completion of addition, the mixture was further stirred for 15 minutes and cooled to 5° C. A solution of 1,2,3-trifluoro-4-nitrobenzene (20 g, 113 mmol) in THF (150 ml) was added while keeping the temperature below 5C. The mixture was then left to warm up to ambient temperature and stirred for 24 hours. The volatiles were removed under vacuum and the residue was partitioned between ethyl acetate and 2N aqueous hydrochloric acid. The organic layer was washed with water, brine, dried (MgSO4) and evaporated. The residue was dissolved in concentrated hydrochloric acid (650 ml) and acetic acid (600 ml) and the mixture was refluxed for 15 hours. After cooling, the volatiles were removed under vacuum and the residue was partitioned between aqueous sodium hydrogen carbonate (5%) and ethyl acetate. The organic layer was washed with sodium hydrogen carbonate, water, brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography eluting with ethylacetate/petroleum ether (75/25) to give 3-acetylmethyl-1,2-difluoro-4-nitrobenzene (17.5 g, 72%).

Workup

  1. additionAfter completion of addition
  2. waitThe mixture was then left
  3. temperatureto warm up to ambient temperature
  4. stirringstirred for 24 hours
  5. customThe volatiles were removed under vacuum
  6. customthe residue was partitioned between ethyl acetate and 2N aqueous hydrochloric acid
  7. washThe organic layer was washed with water, brine
  8. dry with materialdried (MgSO4)
  9. customevaporated
  10. dissolutionThe residue was dissolved in concentrated hydrochloric acid (650 ml)
  11. temperatureacetic acid (600 ml) and the mixture was refluxed for 15 hours
  12. temperatureAfter cooling
  13. customthe volatiles were removed under vacuum
  14. customthe residue was partitioned between aqueous sodium hydrogen carbonate (5%) and ethyl acetate
  15. washThe organic layer was washed with sodium hydrogen carbonate, water, brine
  16. dry with materialdried (MgSO4)
  17. customevaporated
  18. customThe residue was purified by column chromatography
  19. washeluting with ethylacetate/petroleum ether (75/25)

Sources & evidence

ORD record
ord-eb0dcc849300485fb45634be45243899
Source dataset
uspto-grants-2006_07
Patent number
US07074800B1

Reaction notes

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