N-methoxy-N-methylprop-2-enamide → (E)-3-[3-(4-Fluorophenyl)-1-isopropyl-1H-indol-2-yl]-N-methoxy-N-methylacrylamide

HRID 352098Notes

Reaction equation

HRID 352098 reaction equation
Br[C:2]1[N:3]([CH:18]([CH3:20])[CH3:19])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.C([O-])(=O)C.[Na+].[CH3:26][O:27][N:28]([CH3:33])[C:29](=[O:32])[CH:30]=[CH2:31]>CN(C=O)C>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]([CH:18]([CH3:20])[CH3:19])[C:2]=2/[CH:31]=[CH:30]/[C:29]([N:28]([O:27][CH3:26])[CH3:33])=[O:32])=[CH:12][CH:13]=1

Participants

5

Reactant 3

HCID 294174N-methoxy-N-methylprop-2-enamide2×HCID 517045Sodium AcetateHCID 227150602-bromo-3-(4-fluorophenyl)-1-isopropyl-1H-indole

Product 1

HCID 22715057(E)-3-[3-(4-Fluorophenyl)-1-isopropyl-1H-indol-2-yl]-N-methoxy-N-methylacrylamide

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

2 g (6.02 mmol) of 2-bromo-3-(4-fluorophenyl)-1-isopropyl-1H-indole and 10 ml of DMF are introduced into a 50 ml three-necked round-bottomed flask, which has been purged with nitrogen and is equipped with a magnetic stirrer, thermometer, reflux condenser, gas inlet tube and nitrogen delivery line, and degassing is carried out for 45 min. by introducing nitrogen. 24 mg (1.0 mol %) of the catalyst K4 from WO-A-99/47474 and 0.539 g (6.59 mmol) of sodium acetate are then added and degassing is carried out for a further 15 min. 1.08 g (8.43 mmol) of N-methoxy-N-methylacrylamide (prepared analogously to a procedure of S. Nahm, Tetrahedron Letters 22, 3815 (1981)) are subsequently added and the suspension is heated at reflux for 1.75 hours. A further 0.5 g (4.34 mmol) of N-methoxy-N-methylacrylamide is added and refluxing is carried out for 1.5 hours. Cooling is then carried out followed by dilution with 50 ml of water and extraction three times with 50 ml of ethyl acetate. The combined organic phases are washed three times with 50 ml of water, dried over magnesium sulfate, filtered and concentrated by evaporation. Purification by means of flash chromatography (hexane/ethyl acetate=2:1) yields a yellow solid that is pure according to NMR. Recrystallisation from 94% ethanol yields slightly yellow crystals having a melting point of from 123 to 124° C.

Workup

  1. customwhich has been purged with nitrogen
  2. customis equipped with a magnetic stirrer
  3. temperaturethermometer, reflux condenser, gas inlet tube
  4. customnitrogen delivery line, and degassing
  5. additionby introducing nitrogen
  6. customdegassing
  7. waitis carried out for a further 15 min
  8. additionNahm, Tetrahedron Letters 22, 3815 (1981)) are subsequently added
  9. temperaturethe suspension is heated
  10. temperatureat reflux for 1.75 hours
  11. temperaturerefluxing
  12. waitis carried out for 1.5 hours
  13. temperatureCooling
  14. extractionis then carried out followed by dilution with 50 ml of water and extraction three times with 50 ml of ethyl acetate
  15. washThe combined organic phases are washed three times with 50 ml of water
  16. dry with materialdried over magnesium sulfate
  17. filtrationfiltered
  18. concentrationconcentrated by evaporation
  19. customPurification by means of flash chromatography (hexane/ethyl acetate=2:1)
  20. customyields a yellow solid
  21. customRecrystallisation from 94% ethanol
  22. customyields slightly yellow crystals
  23. customof from 123 to 124° C.

Sources & evidence

ORD record
ord-119cec0f6e7043a5a7886499d328a7b9
Source dataset
uspto-grants-2004_06
Patent number
US06743926B2

Reaction notes

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