Dimethylformamide → Methyl 3-amino-5-(3-chlorophenyl)thiophene-2-carboxylate

HRID 900415Notes

Reaction equation

HRID 900415 reaction equation
P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:8]=[C:9]([C:13](=O)[CH3:14])[CH:10]=[CH:11][CH:12]=1.Cl.NO.[SH:19][CH2:20][C:21]([O:23][CH3:24])=[O:22].C[O-].[Na+].[CH3:28][N:29](C)C=O>CO.O>[NH2:29][C:28]1[CH:14]=[C:13]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([Cl:6])[CH:8]=2)[S:19][C:20]=1[C:21]([O:23][CH3:24])=[O:22]

Participants

9

Reactant 6

HCID 6228DimethylformamideHCID 149331-(3-Chlorophenyl)ethanoneHCID 16907Methyl ThioglycolateHCID 24813Phosphorus oxychlorideHCID 443297Hydroxyamine hydrochlorideHCID 10942334Sodium Methoxide

Product 1

HCID 11994772Methyl 3-amino-5-(3-chlorophenyl)thiophene-2-carboxylate

Reagents, catalysts & solvents 2

HCID 887MethanolSolvent2×HCID 962WaterSolvent2×

Conditions

Temperature
50 °C

Procedure

Phosphorous oxychloride (6.7 mL) was added to dimethylformamide (11 mL) with ice cooling to keep the internal temperature below 25° C. After 20 minutes, (3-chlorophenyl)ethanone (5 g) was added portionwise keeping the internal temperature below 30° C. The reaction mixture was heated to 50° C. and then treated cautiously with hydroxylamine hydrochloride (10 g). The reaction mixture was stirred for 20 minutes at room temperature and water (50 mL) was added. After a further 30 minutes, the reaction mixture was extracted three times with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4) and evaporated to give an oil. This oil was dissolved in methanol (50 mL) and treated with methyl mercaptoacetate (2.7 mL) and sodium methoxide (7.3 mL of a 25% solution in methanol). After reflux for 1 h, the cooled reaction mixture was reduced to one third volume and water was added. The reaction mixture was extracted three times with ethyl acetate. The combined extracts were dried (MgSO4), the solvent was evaporated and the residue was chromatographed on silica eluting with dichloromethane/isohexane mixtures to give the sub-title ester (2.0 g).

Workup

  1. customthe internal temperature below 25° C
  2. customthe internal temperature below 30° C
  3. waitAfter a further 30 minutes
  4. extractionthe reaction mixture was extracted three times with ethyl acetate
  5. washThe combined extracts were washed with brine
  6. dry with materialdried (MgSO4)
  7. customevaporated
  8. customto give an oil
  9. temperatureAfter reflux for 1 h
  10. customthe cooled reaction mixture
  11. additionwas added
  12. extractionThe reaction mixture was extracted three times with ethyl acetate
  13. dry with materialThe combined extracts were dried (MgSO4)
  14. customthe solvent was evaporated
  15. customthe residue was chromatographed on silica eluting with dichloromethane/isohexane

Sources & evidence

ORD record
ord-633da105725b4a8e91e35c4724159f2f
Source dataset
uspto-grants-2008_04
Patent number
US07358376B2

Reaction notes

Loading…