Potassium Hydroxide → ethyl 5-bromo-3,6-dimethyl-1H-indole-2-carboxylate

HRID 1362448Notes

Reaction equation

HRID 1362448 reaction equation
N([O-])=O.[Na+].[Br:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][C:7]=1[CH3:13].CC([O-])=O.[Na+].[CH2:19]([CH:21](C(=O)C)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:20].[OH-].[K+].BrC1C(C)=C2C(=CC=1)NC(C(OCC)=O)=C2C>O.CCO>[Br:5][C:6]1[CH:12]=[C:11]2[C:9](=[CH:8][C:7]=1[CH3:13])[NH:10][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:19]2[CH3:20]

Participants

9

Reactant 6

HCID 14797Potassium HydroxideHCID 233594-Bromo-3-methylanilineHCID 79065Butanoic acid, 2-ethyl-3-oxo-, ethyl esterHCID 517045Sodium Acetate2×HCID 23668193Sodium NitriteHCID 86606148HCID 86606148, compound

Product 1

HCID 59277624ethyl 5-bromo-3,6-dimethyl-1H-indole-2-carboxylate

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 962WaterSolvent

Procedure

A solution of NaNO2 (1.52 g, 22 mmol) in water (4 mL) was added to a vigorously stirred mixture of 4-bromo-3-methylaniline (3.72 g, 20 mmol) at −5° C. After 30 min stirring, the solution was adjusted to pH 5 with NaOAc (1.40 g). A cold solution of ethyl 2-ethyl-3-oxobutanoate (4.0 g, 22 mmol) and KOH (1.36 g, 22 mmol) in EtOH (16 mL) were added followed by crushed ice (30 g). NaOAc was added if necessary to adjust the pH to 5. The mixture was stirred for 5 h at 0° C. then kept at this temperature overnight. The solution was extracted with EtOAc, washed with brine, dried and evaporated to 8 mL. This solution was added to a solution of HCl (25 mL, 7M in EtOH). It was further refluxed for 3 h. Upon cooling in an ice bath, water (200 mL) was added slowly. The precipitate was filtered, washed with water and dried to afford 5.36 g (91%) as a 1:1 mixture of the title compound and its ethyl 5-bromo-3,4-dimethyl-1H-indole-2-carboxylate isomer. 1H NMR (300 MHz, CDCl3), δ, mix 8.66 and 8.54 (2s, br, 1H), 7.83 and 7.23 (2s, 2×0.5H), 7.42 and 7.05 (2d, J=8.7 Hz, 2×0.5H), 4.41 (q, J=7.2 Hz, 2H), 2.81, 2.79, 2.53 and 2.49 (4s, 4×1.5H), 1.42 (t, J=7.2 Hz, 3H).

Workup

  1. stirringThe mixture was stirred for 5 h at 0° C.
  2. customthen kept at this temperature overnight
  3. extractionThe solution was extracted with EtOAc
  4. washwashed with brine
  5. customdried
  6. customevaporated to 8 mL
  7. additionThis solution was added to a solution of HCl (25 mL, 7M in EtOH)
  8. temperatureIt was further refluxed for 3 h
  9. temperatureUpon cooling in an ice bath
  10. additionwater (200 mL) was added slowly
  11. filtrationThe precipitate was filtered
  12. washwashed with water
  13. customdried
  14. customto afford 5.36 g (91%)

Sources & evidence

ORD record
ord-679ce56384634bb88ba5730dfb7a412b
Source dataset
uspto-grants-2011_02
Patent number
US07879872B2

Reaction notes

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