Hydrochloric Acid → ethyl 7-ethyl-3-methyl-1H-indole-2-carboxylate

HRID 1362443Notes

Reaction equation

HRID 1362443 reaction equation
N([O-])=O.[Na+].[CH2:5]([C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[NH2:9])[CH3:6].Cl.C([O-])(=O)C.[Na+].[CH2:20]([CH:22](C(C)=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:21].[OH-].[K+]>C(O)C.O>[CH2:5]([C:7]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:8]=1[NH:9][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:20]2[CH3:21])[CH3:6]

Participants

9

Reactant 6

HCID 313Hydrochloric AcidHCID 113572-EthylanilineHCID 14797Potassium HydroxideHCID 79065Butanoic acid, 2-ethyl-3-oxo-, ethyl esterHCID 517045Sodium Acetate2×HCID 23668193Sodium Nitrite

Product 1

HCID 59277626ethyl 7-ethyl-3-methyl-1H-indole-2-carboxylateYield 11.5%

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 962WaterSolvent2×

Conditions

Temperature
0 °C

Procedure

A solution of sodium nitrite (6.24 g, 90.64 mmol) was added dropwise to a mixture of 2-ethyl aniline (10.2 mL, 82.4 mmol), conc.HCl (20 mL) and water (30 mL) at −5° C. After the addition, the mixture was stirred at 0° C. for 15 min and brought to pH 34 by addition of sodium acetate. In a separate flask, a solution of ethyl α-ethylacetoacetate (14.6 mL, 90.64 mmol) in ethanol (50 mL) at 0° C. was treated with a solution of potassium hydroxide (5.08 g, 90.64 mmol) in water (20 mL) followed by addition of ice. The diazonium salt was immediately added to this alkaline solution. The mixture was adjusted to pH 5-6 by adding sodium acetate and stirred at 0° C. for 3 h. The solution was kept overnight at 4° C. and extracted with ethyl acetate, washed with brine, dried over magnesium sulfate and most of the solvent removed. The crude mixture was added dropwise to a solution of ethanolic HCl (50 mL) at 78° C. and stirred for 2 h at 78° C. The mixture was evaporated and chromatographed over silica gel eluting with ethyl acetate/hexane (3%) to afford the title compound (2.2 g, 11%). 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 7.48 (d, J=8 Hz, 1H), 7.12 (d, J=6.8 Hz, 1H), 7.06 (t, J=7.2 Hz, 1H), 4.38 (q, J=7.3 Hz, 2H), 2.82 (q, J=7.6 Hz, 2H), 2.58 (s, 3H), 1.40 (t, J=7.2 Hz, 3H), 1.33 (t, J=7.6 Hz, 3H)

Workup

  1. customat −5° C
  2. additionAfter the addition
  3. additionfollowed by addition of ice
  4. stirringstirred at 0° C. for 3 h
  5. waitThe solution was kept overnight at 4° C.
  6. extractionextracted with ethyl acetate
  7. washwashed with brine
  8. dry with materialdried over magnesium sulfate and most of the solvent
  9. customremoved
  10. additionThe crude mixture was added dropwise to a solution of ethanolic HCl (50 mL) at 78° C.
  11. stirringstirred for 2 h at 78° C
  12. customThe mixture was evaporated
  13. customchromatographed over silica gel eluting with ethyl acetate/hexane (3%)

Sources & evidence

ORD record
ord-f2fbfdbb039a4d519917f67c7dca64ad
Source dataset
uspto-grants-2011_02
Patent number
US07879872B2

Reaction notes

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