Water → ethyl 4,6-dimethyl-1H-indole-2-carboxylate

HRID 1510168Notes

Reaction equation

HRID 1510168 reaction equation
O.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl.[CH3:14][C:15]1[CH:16]=[C:17]([NH:22]N)[CH:18]=[C:19]([CH3:21])[CH:20]=1.[C:24]([O:29][CH2:30][CH3:31])(=[O:28])[C:25]([CH3:27])=O.O>C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:30]([O:29][C:24]([C:25]1[NH:22][C:17]2[C:16]([CH:27]=1)=[C:15]([CH3:14])[CH:20]=[C:19]([CH3:21])[CH:18]=2)=[O:28])[CH3:31]

Participants

7

Reactant 4

HCID 962WaterHCID 12041Ethyl pyruvateHCID 521998p-Toluenesulfonic acid monohydrateHCID 12651341(3,5-Dimethylphenyl)hydrazine hydrochloride

Product 1

HCID 4714990ethyl 4,6-dimethyl-1H-indole-2-carboxylateYield 82%

Reagents, catalysts & solvents 2

HCID 521998p-Toluenesulfonic acid monohydrateCatalystHCID 241BenzeneSolvent2×

Procedure

In a flask fitted with a Dean-Stark trap, p-toluenesulfonic acid monohydrate (132 g, 0.69 mol) in 500 ml of benzene was heated at reflux for 2 hours. A solution of 3,5-dimethylphenylhydrazine hydrochloride (34.5 g, 0.2 mol), ethyl pyruvate (23.2 g, 0.2 mol), and p-toluenesulfonic acid monohydrate (0.85 g, 0.005 mol) in 500 ml of benzene, which had been refluxed for 2 hours with water removed through a Dean-Stark apparatus was then added. The resulting mixture was heated at reflux and stirred overnight. After cooling, the solution was treated with saturated sodium bicarbonate solution and diluted with methylene chloride. The organic portion was washed twice with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by ISCO (hexane/EtOAc, 0-30%, 40 min) to give yellow solids, which was recrystallized from hexane/ethyl acetate (10%) to give colorless needles (35.6 g, 82%). 1H NMR (DMSO-d6, 400 MHz): δ 11.68 (brs, 1H, exchangeable with D2O, NH), 7.12 (s, 1H), 7.05 (s, 1H), 6.71 (s, 1H), 4.33 (q, J=6.8 Hz, 2H), 2.44 (s, 3H), 2.35 (s, 3H), 1.34 (t, J=6.8 Hz, 3H).

Workup

  1. temperaturewas heated
  2. temperatureat reflux for 2 hours
  3. customremoved through a Dean-Stark apparatus
  4. additionwas then added
  5. temperatureThe resulting mixture was heated
  6. temperatureat reflux
  7. temperatureAfter cooling
  8. additionthe solution was treated with saturated sodium bicarbonate solution
  9. additiondiluted with methylene chloride
  10. washThe organic portion was washed twice with saturated sodium bicarbonate solution
  11. dry with materialdried over anhydrous sodium sulfate
  12. concentrationconcentrated under reduced pressure
  13. customThe residue was purified by ISCO (hexane/EtOAc, 0-30%, 40 min)
  14. customto give yellow solids, which
  15. customwas recrystallized from hexane/ethyl acetate (10%)

Sources & evidence

ORD record
ord-76d9bea5c2dd40df848f72da855c3328
Source dataset
uspto-grants-2012_07
Patent number
US08211918B2

Reaction notes

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