Citric Acid → beta-[[(3-methoxyphenyl)thio]methyl]benzenepropanoic Acid, Ethyl Ester

HRID 2307903Notes

Reaction equation

HRID 2307903 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.[C:10]1([CH:16]2[CH2:21]CO[C:17]2=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:22](=[O:25])([O-])[O-:23].[K+].[K+].[C:28](O)(=O)[CH2:29]C(CC(O)=O)(C(O)=O)O>CN(C=O)C.C(OC(=O)C)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9][CH2:21][CH:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:17][C:22]([O:23][CH2:28][CH3:29])=[O:25])[CH:6]=[CH:7][CH:8]=1

Participants

7

Reactant 4

HCID 311Citric AcidHCID 11430Potassium CarbonateHCID 232693-Phenyloxolan-2-oneHCID 849893-Methoxybenzenethiol

Product 1

HCID 21306343beta-[[(3-methoxyphenyl)thio]methyl]benzenepropanoic Acid, Ethyl EsterYield 40%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
75 °C

Procedure

To a solution of 3-methoxy-thiophenol (1.4 g, 0.01 mol) and 2-phenylbutyrolactone 2a (1.5 g, 0.0093 mol, (Tetrahedron 47, (8) 1525-40, 1991) in DMF (10.0 mL) were added potassium carbonate (1.4 g, 0.01 mol) and 18-crown-C (0.05 g), and the mixture was heated at 75° C. for 12 h under an atmosphere of argon. The reaction mixture was cooled, and partioned between 5% citric acid (25 mL) and ethylacetate (50 mL). The organic phase was washed with water (2×25 mL), dried dried (Na2SO4) and concentrated under reduced pressure to give a yellow syrup. This was purified by silica gel flash chromatography using 20% EtOAc in hexane. Fractions containing the desired acid as monitored by ES mass spectrometry, [m/z=303 (M+H)] were combined and concentrated. This material was dissolved in EtOH (5 mL), added 4N HCl/dioxane (5.0 mL) and stirred at room temperature for 1 h, and at 70° C. for 1 h. The resulting solution was concentrated to dryness and the residue was purified by silica gel flash chromatography using 20% EtOAc in hexane to give 1.2 g (40%) of the desired ester as a pale yellow liquid: 1H-NMR (400 Mz, CDCl3) δ 7.35-7.15 (m, 5H), 6.87 (m, m 1H), 6.85 (m, 1H), 6.70(m, 1H), 4.02 (m, 2H), 3.77 (m, 3H), 3.18 (d, 2H, J=7.2 Hz), 2.92 (dd, 1H, J=6.4 Hz), 2.65 (dd, 1H, J=8.0 Hz), and 1.11 (t, 3H, J=6.8 Hz); ES-MS m/z 331 (M+H)+; HR-MS Calcd C19H23O3S 331.1100, found 331.1377.

Workup

  1. temperatureThe reaction mixture was cooled
  2. washThe organic phase was washed with water (2×25 mL)
  3. customdried
  4. dry with materialdried (Na2SO4)
  5. concentrationconcentrated under reduced pressure
  6. customto give a yellow syrup
  7. customThis was purified by silica gel flash chromatography
  8. additionFractions containing the desired acid
  9. concentrationconcentrated
  10. dissolutionThis material was dissolved in EtOH (5 mL)
  11. additionadded 4N HCl/dioxane (5.0 mL)
  12. waitat 70° C. for 1 h
  13. concentrationThe resulting solution was concentrated to dryness
  14. customthe residue was purified by silica gel flash chromatography

Sources & evidence

ORD record
ord-7e4e3b16003f48bfbd3dc08a16a7d5cb
Source dataset
uspto-grants-2004_12
Patent number
US06833366B1

Reaction notes

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