Dimethylformamide → 3-(4-Fluorophenyl)-1-methyl-1H-indole-2-carbaldehyde

HRID 1707697Notes

Reaction equation

HRID 1707697 reaction equation
P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH3:22])[CH:14]=2)=[CH:9][CH:8]=1.[OH-].[Na+].CN(C)[CH:27]=[O:28]>>[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH3:22])[C:14]=2[CH:27]=[O:28])=[CH:9][CH:8]=1

Participants

5

Reactant 4

HCID 6228Dimethylformamide2×HCID 14798Sodium HydroxideHCID 24813Phosphorus oxychlorideHCID 111388001H-Indole, 3-(4-fluorophenyl)-1-methyl-

Product 1

HCID 134488973-(4-Fluorophenyl)-1-methyl-1H-indole-2-carbaldehyde

Conditions

Temperature
80 °C

Procedure

78.5 ml. (0.84 mole) of phosphorus oxychloride is added dropwise over a 20 min. period to 213 ml. of dimethylformamide stirred at 0° C. under nitrogen, the temperature of the reaction mixture not being allowed to exceed 10° C. The reaction mixture is heated to 80° C., a solution of 163.5 g. (0.727 mole) of 3-(4'-fluorophenyl)-1-methylindole in 270 ml. of dimethylformamide is added at a rate such that the temperature of the reaction mixture is maintained at 81°-83° C., the reaction mixture is maintained at 80°-81° C. for 5 hours and cooled to 10° C., and 1 l. of 15% sodium hydroxide solution is added dropwise at a rate such that the temperature of the reaction mixture is maintained at 35°-40° C., the reaction mixture being stirred under nitrogen throughout. The reaction mixture is cooled to 25° C., and the solids are collected by filtration, washed three times with 500 ml. portions of water and dissolved in 500 ml. of methylene chloride. The methylene chloride solution is filtered through 500 ml. of silica gel (70-230 mesh A.S.T.M.) and the silica gel is carefully washed with 2 l. of methylene chloride. The methylene chloride solutions are combined and concentrated to a volume of 300 ml. at reduced pressure, 300 ml. of absolute ethanol is added, and the reaction mixture is distilled until the internal temperature reaches 78° C. The reaction mixture is cooled to 0° C. and the precipitated bright yellow product is collected by filtration and vacuum dried at room temperature (153.9 g. (84%)), m.p. 80.5°-81.5° C. A slightly less pure second crop may be obtained from the mother liquor.

Workup

  1. customto exceed 10° C
  2. temperatureis maintained at 81°-83° C.
  3. temperaturethe reaction mixture is maintained at 80°-81° C. for 5 hours
  4. temperaturecooled to 10° C.
  5. temperatureis maintained at 35°-40° C.
  6. temperatureThe reaction mixture is cooled to 25° C.
  7. filtrationthe solids are collected by filtration
  8. washwashed three times with 500 ml
  9. dissolutionportions of water and dissolved in 500 ml
  10. filtrationThe methylene chloride solution is filtered through 500 ml
  11. washof silica gel (70-230 mesh A.S.T.M.) and the silica gel is carefully washed with 2 l
  12. concentrationconcentrated to a volume of 300 ml
  13. additionof absolute ethanol is added
  14. distillationthe reaction mixture is distilled until the internal temperature
  15. customreaches 78° C
  16. temperatureThe reaction mixture is cooled to 0° C.
  17. filtrationthe precipitated bright yellow product is collected by filtration and vacuum
  18. customdried at room temperature (153.9 g. (84%)), m.p. 80.5°-81.5° C
  19. customA slightly less pure second crop may be obtained from the mother liquor

Sources & evidence

ORD record
ord-b7def709ccdb47c0a0f3d319bcbe5bd0
Source dataset
uspto-grants-1994_10
Patent number
US05354772

Reaction notes

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