Reacción #582615

Ecuación de reacción

1-amino-4-methoxyindole

nitrobenzene

5-methoxycinnoline

HBr

→

title compound

Rendimiento 53.0%

5-Hydroxycinnoline

Rendimiento 53.0%

Disolventes

HCl

Condiciones de reacción

Tratamiento posterior

1. 1
   Temperaturawas heated
2. 2
   Temperaturaat reflux for 76 h
3. 3
   Temperaturacooled
4. 4
   Otropartitioned between 10% aqueous NaOH (50 mL) and dichloromethane (3×30 mL)
5. 5
   SecadoThe combined organic extracts were dried (Na2SO4)
6. 6
   Otroevaporated in vacuo
7. 7
   Otroto give an oil which
8. 8
   Otrowas purified by chromatography on silica with 5-100% ether in hexane gradient elution
9. 9
   Temperaturathe resulting solution heated
10. 10
    Temperaturaat reflux for 18 h
11. 11
    TemperaturaThe mixture was cooled
12. 12
    Otroevaporated in vacuo
13. 13
    workup.DISSOLUTIONthe residue dissolved in water (10 mL)
14. 14
    workup.ADDITIONAqueous ammonia (d=0.880) was added until pH 6
15. 15
    Otrowas obtained
16. 16
    FiltraciónThe precipitated solid was collected by filtration
17. 17
    Otropurified by charcoal-methanol treatment

Procedimiento

To a mixture of 4-methoxyindole (1.26 g, 8.57 mmol), powdered potassium hydroxide (10.05 g, 0.179 mol) and dry dimethylformamide (20 mL) at 15° C. under argon was added, portionwise over 0.2 h, hydroxylamine-O-sulfonic acid. Internal temperature was kept ≦30° C. by external ice bath cooling. The mixture was stirred at 20° C. for 4 h, then was extracted with toluene (4×50 mL). The combined extracts were washed with water (4×50 mL) and brine (50 mL), then dried (Na2SO4) and evaporated in vacuo to give an oil. Chromatography of the residue on silica with 5-50% ether in hexane gradient elution gave 1-amino-4-methoxyindole (0.79 g, 56%). A mixture of 1-amino-4-methoxyindole (0.78 g, 4.8 mmol), nitrobenzene (3.4 g, 27.8 mmol), and methanolic HCl (3% w/w, 180 mL) was heated at reflux for 76 h, then cooled and partitioned between 10% aqueous NaOH (50 mL) and dichloromethane (3×30 mL). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give an oil which was purified by chromatography on silica with 5-100% ether in hexane gradient elution. The resulting 5-methoxycinnoline (0.56 g, 3.5 mmol) was mixed with 48% aqueous HBr (35 mL) and the resulting solution heated at reflux for 18 h. The mixture was cooled, then evaporated in vacuo, and the residue dissolved in water (10 mL). Aqueous ammonia (d=0.880) was added until pH 6 was obtained, and the resulting mixture cooled to 0° C. The precipitated solid was collected by filtration and purified by charcoal-methanol treatment to give the title compound (0.37 g, 53%) as a yellow solid.

Fuente