Ethyl Acetoacetate → ethyl 2-methyl-1H-indole-3-carboxylate

HRID 642259

Reaction equation

HRID 642259 reaction equation
I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:8].[Na].[C:10]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:11][C:12]([CH3:14])=O>CN(C=O)C.C(OC)(C)(C)C.O.N>[CH2:17]([O:16][C:10]([C:11]1[C:2]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[NH:8][C:12]=1[CH3:14])=[O:15])[CH3:18]

Participants

8

Reactant 3

HCID 8868Ethyl AcetoacetateHCID 119952-IodoanilineHCID 5360545Sodium

Product 1

HCID 4072358ethyl 2-methyl-1H-indole-3-carboxylateYield 26.4%

Reagents, catalysts & solvents 4

HCID 222AmmoniaSolventHCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 15413tert-Butyl methyl etherSolvent

Conditions

Temperature
120 °C

Procedure

A mixture of 2-iodo-phenylamine (44.30 g, 202 mmol), sodium salt of ethyl acetoacetate (42.1 g, 263 mmol), and Cu(I)I (50.1 g, 263 mmol) in DMF (200 mL) was stirred at 120° C. overnight. Then the reaction mixture was cooled to room temperature, then diluted with methyl tert-butyl ether (MTBE) and water, and concentrated ammonia was added to dissolve the solid, the two layers were separated, the water layer was back extracted with MTBE; all MTBEs were combined and washed with sat. NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated sequentially. The residue was crystallized in hexanes/EtOAc, giving the desired product (10.84 g), the mother liquor was concentrated and purified on column to give an additional batch of product (4.76 g). The title compound, 1H NMR (200 MHz, CDCl3): δ (ppm)=8.32 (1H), 8.09 (m, 1H), 7.31-7.13 (m, 3H), 4.39 (q, 2H, J=6.8 Hz), 2.74 (s, 3H), 1.45 (t, 3H, J=6.8 Hz).

Workup

  1. temperatureThen the reaction mixture was cooled to room temperature
  2. additionwas added
  3. dissolutionto dissolve the solid
  4. customthe two layers were separated
  5. extractionthe water layer was back extracted with MTBE
  6. washwashed with sat. NaCl aqueous solution
  7. dry with materialdried over anhydrous sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated sequentially
  10. customThe residue was crystallized in hexanes/EtOAc

Sources & evidence

ORD record
ord-afd5d3a8e9184f71b977a6b7f82c2303
Source dataset
uspto-grants-2010_04
Patent number
US07696223B2

Linked notes

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