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

HRID 2222403Notes

Reaction equation

HRID 2222403 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
10 °C

Procedure

To a suspension of sodium hydride (5.42 g, 226 mmol) (prewashed with pentane) in THF (100 ml) cooled at 10° C. was added ethyl acetoacetate (29.4 g, 226 mmol) while keeping the temperature below 15° C. 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 5° C. 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 ethyl acetate/petroleum ether (75/25) to give 3-acetylmethyl-1,2-difluoro-4-nitrobenzene (17.5 g, 72%).

Workup

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

Sources & evidence

ORD record
ord-ec3471cae34e4c2bb6e6e63dd7a79fb0
Source dataset
uspto-grants-2008_05
Patent number
US07371765B2

Reaction notes

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