Acetic Acid → HCID 178516504, compound

HRID 271551Notes

Reaction equation

HRID 271551 reaction equation
CO/[CH:3]=[CH:4]/[C:5](=[O:7])[CH3:6].[F:8][CH:9]([F:15])[C:10](OCC)=O.CC(C)([O-])C.[K+].C(O)(=O)C.[NH3:26]>O.C(OCC)C>[F:8][CH:9]([F:15])[C:10]1[CH:6]=[C:5]([OH:7])[CH:4]=[CH:3][N:26]=1

Participants

8

Reactant 5

HCID 176Acetic AcidHCID 222AmmoniaHCID 9961Ethyl difluoroacetateHCID 639675(3E)-4-Methoxy-3-buten-2-oneHCID 23665647Potassium tert-butoxide

Product 1

HCID 178516504HCID 178516504, compoundYield 32%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 3283Diethyl EtherSolvent

Procedure

A mixture of (E)-4-methoxy-but-3-en-2-one (20 mmol) and ethyl difluoroacetate (24 mmol) is added dropwise to a mixture of potassium tert-butoxide (26 mmol) and diethyl ether (50 ml) under nitrogen atmosphere at −15° C. over 30 min. The mixture is allowed to warm up to room temperature slowly over 3 h. After cooling to 0° C., acetic acid (26 mmol) and H2O (10 ml) are successively added dropwise to the reaction mixture. The organic layer is separated, washed with sat. aq. NaHCO3, dried over MgSO4, and evaporated in vacuo. The residue is dissolved in i-propanol (30 ml). To the solution, conc. HCl (2 ml) is added and the mixture is refluxed for 3 h. After cooling, the reaction mixture is neutralised with sat. aq. NaHCO3 and extracted with CH2Cl2. The organic layer is dried over MgSO4 and evaporated in vacuo. The residue is dissolved in i-propanol (20 ml). To the solution, 28% aq. NH3 (50 mmol) is added and the mixture is refluxed for 20 h. After cooling, the reaction mixture is diluted with H2O and extracted with AcOEt. The organic layer is dried over MgSO4 and evaporated in vacuo. The residue is purified by silica gel column chromatography (n-hexane:AcOEt=1:1) to give 2-difluoromethyl-pyridin-4-ol in 32% yield.

Workup

  1. temperatureAfter cooling to 0° C.
  2. customThe organic layer is separated
  3. washwashed with sat. aq. NaHCO3
  4. dry with materialdried over MgSO4
  5. customevaporated in vacuo
  6. dissolutionThe residue is dissolved in i-propanol (30 ml)
  7. additionTo the solution, conc. HCl (2 ml) is added
  8. temperaturethe mixture is refluxed for 3 h
  9. temperatureAfter cooling
  10. extractionextracted with CH2Cl2
  11. dry with materialThe organic layer is dried over MgSO4
  12. customevaporated in vacuo
  13. dissolutionThe residue is dissolved in i-propanol (20 ml)
  14. temperaturethe mixture is refluxed for 20 h
  15. temperatureAfter cooling
  16. extractionextracted with AcOEt
  17. dry with materialThe organic layer is dried over MgSO4
  18. customevaporated in vacuo
  19. customThe residue is purified by silica gel column chromatography (n-hexane:AcOEt=1:1)

Sources & evidence

ORD record
ord-8bb50111d27644538900f741fc8d4404
Source dataset
uspto-grants-2008_11
Patent number
US07452886B2

Reaction notes

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