Reaction #1006

Reaction equation

2-methoxy-5-amino-pyridine

ammonium chloride

4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid

triethylamine

ethyl chloroformate

→

N-(4-methoxy-3-pyridyl)-4-oxo-4,5,6,7-tetrahydro-1H-indole 3-carboxamide

Yield 19.6%

Solvents

N,N-dimethylformamide

N,N-dimethylformamide

Conditions

Workup

1. 1
   workup.STIRRINGto stir for an additional 75 minutes
2. 2
   Extractionextracted 2× with ethyl acetate
3. 3
   WashThe combined organic layers were washed with water
4. 4
   Dryingdried over magnesium sulfate
5. 5
   Filtrationfiltered
6. 6
   Concentrationconcentrated in vacuo
7. 7
   workup.ADDITIONTo the residue was added aqueous 5N sodium hydroxide (5 mL) and ethyl alcohol (1 mL)
8. 8
   Temperatureheated
9. 9
   Temperatureat reflux for 1 hour
10. 10
    TemperatureAfter cooling in an ice water bath
11. 11
    workup.ADDITIONthe reaction mixture was poured into saturated aqueous ammonium chloride
12. 12
    Extractionextracted 2× with ethyl acetate
13. 13
    DryingThe combined organic layers were dried over magnesium sulfate
14. 14
    Filtrationfiltered
15. 15
    Concentrationconcentrated in vacuo
16. 16
    Otherthe residue recrystallized from ethyl acetate

Procedure

To a stirring solution of 4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (179 mg, 1 mmol) and triethylamine (293 μl, 2.1 mmol) in N,N-dimethylformamide (3 mL) at 0° C. was added ethyl chloroformate (191 μl, 2 mmol). After stirring an additional 30 minutes, a solution of 2-methoxy-5-amino-pyridine (216 mg, 2 mmol) in N,N-dimethylformamide (3 mL) was added. The reaction mixture was allowed to stir for an additional 75 minutes, then poured into saturated aqueous ammonium chloride and extracted 2× with ethyl acetate. The combined organic layers were washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo. To the residue was added aqueous 5N sodium hydroxide (5 mL) and ethyl alcohol (1 mL), then heated at reflux for 1 hour. After cooling in an ice water bath, the reaction mixture was poured into saturated aqueous ammonium chloride and extracted 2× with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, concentrated in vacuo, and the residue recrystallized from ethyl acetate to give N-(4-methoxy-3-pyridyl)-4-oxo-4,5,6,7-tetrahydro-1H-indole 3-carboxamide (56 mg); m.p. 209°-210° C. (Compound 1).

Source