Hydrochloric Acid → Ethyl 4-oxo-4-(2-pyridyl)butyrate

HRID 2299728Notes

Reaction equation

HRID 2299728 reaction equation
[C:1](N1C=CN=C1)(N1C=CN=C1)=O.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([OH:21])=O.[C:22]([O:25][C:26]([CH3:29])(C)C)(=[O:24])[CH3:23].C([N-]C(C)C)(C)C.[Li+].Cl.[H-].[Na+].BrCC(OCC)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>O1CCCC1.C1(C)C=CC=CC=1.C(OCC)(=O)C.CCCCCC>[O:21]=[C:19]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=1)[CH2:1][CH2:23][C:22]([O:25][CH2:26][CH3:29])=[O:24]

Participants

13

Reactant 9

HCID 313Hydrochloric Acid2×HCID 1018Picolinic acidHCID 6101p-Toluenesulfonic acidHCID 7748Ethyl bromoacetateHCID 10908tert-Butyl acetate2×HCID 24758Sodium hydrideHCID 682631,1'-CarbonyldiimidazoleHCID 516892Sodium BicarbonateHCID 2724682Lithium diisopropylamide

Product 1

HCID 10104463Ethyl 4-oxo-4-(2-pyridyl)butyrateYield 19%

Reagents, catalysts & solvents 3

HCID 1140TolueneSolventHCID 8028TetrahydrofuranSolvent2×HCID 21226206Ethyl acetate hexaneSolvent

Procedure

Carbonyldiimidazole (7.25 g) was added to a solution of 2-pyridinecarboxylic acid (5.00 g) in tetrahydrofuran (200 ml) at 0° C. After stirring at room temperature for 2 hours, the mixture was added dropwise to a solution of lithiated tert-butyl acetate prepared from tert-butyl acetate (17.5 ml) and lithium diisopropylamide (2N tetrahydrofuran solution, 65 ml) at −78° C. over 1 hour. After stirring for 15 minutes, 1N hydrochloric acid (250 ml) was added and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain an oil from an ethyl acetate-hexane(1:4, v/v)-eluted fraction. This was dissolved in tetrahydrofuran (100 ml), and sodium hydride (60% in oil, 1.06 g) was added at 0° C., and then the reaction mixture was stirred for 10 minutes. Further ethyl bromoacetate (2.00 ml) was added, stirred at 0° C. for 8 hours, 0.1N hydrochloric acid (300 ml) was added and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain an oil from an ethyl acetate-hexane (1:5, v/v)-eluted fraction. This was dissolved in toluene (200 ml), and p-toluenesulfonic acid (2.00 g) was added, and then the reaction mixture was stirred at 80° C. for 20 hours. An aqueous saturated solution of sodium bicarbonate was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain ethyl 4-oxo-4-(2-pyridyl)butyrate (1.56 g, yield 19%) from an ethyl acetate-hexane (1:2, v/v)-eluted fraction as a colorless oil.

Workup

  1. stirringAfter stirring for 15 minutes
  2. extractionextracted with ethyl acetate
  3. washThe ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride
  4. dry with materialdried (MgSO4)
  5. concentrationconcentrated
  6. customto obtain an oil from an ethyl acetate-hexane(1:4, v/v)-eluted fraction
  7. stirringthe reaction mixture was stirred for 10 minutes
  8. stirringstirred at 0° C. for 8 hours
  9. extractionextracted with ethyl acetate
  10. washThe ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride
  11. dry with materialdried (MgSO4)
  12. concentrationconcentrated
  13. customto obtain an oil from an ethyl acetate-hexane (1:5, v/v)-eluted fraction
  14. stirringthe reaction mixture was stirred at 80° C. for 20 hours
  15. extractionextracted with ethyl acetate
  16. washThe ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride
  17. dry with materialdried (MgSO4)
  18. concentrationconcentrated

Sources & evidence

ORD record
ord-f4d6fb2a96774e80bff27f33b57c968b
Source dataset
uspto-grants-2002_12
Patent number
US06495581B1

Reaction notes

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