반응 #1096710

반응 방정식

Diisopropylamine

6-methoxy-1-propyl-1H-indole-3-carbonitrile

compound 5

1-ethyl-6-methoxy-1H-indole-3-carbonitrile

n-Butyllithium

4-iodoaniline

triphenylphosphine

→

2-(4-aminophenyl)-6-methoxy-1-propyl-1H-indole-3-carbonitrile

용매

THF

THF

반응 조건

후처리

1. 1
   기타A nitrogen-purged flask
2. 2
   기타fitted with a septum
3. 3
   workup.ADDITIONa nitrogen needle is charged with dry THF (all additions performed by syringe) (20 mL)
4. 4
   workup.ADDITIONis added slowly
5. 5
   온도is cooled to −78° C
6. 6
   workup.ADDITIONis added slowly
7. 7
   온도the resulting solution is maintained at −78° C. for 30 min
8. 8
   기타The flask is then transferred to a water-ice bath
9. 9
   온도The solution is once again cooled to −78° C.
10. 10
    workup.ADDITIONis added
11. 11
    workup.WAITAfter about 10 minutes
12. 12
    기타to come to room temperature
13. 13
    기타The septum is removed
14. 14
    기타A reflux condenser is fitted to the flask
15. 15
    기타the solution is degassed by three successive cycles of vacuum
16. 16
    온도The solution is then heated
17. 17
    온도to reflux overnight
18. 18
    온도After cooling to room temperature
19. 19
    workup.ADDITIONthe solution is poured into 4 volumes of water, and 4 volumes of ethyl acetate
20. 20
    workup.ADDITIONare added
21. 21
    여과filtered through celite (with ethyl acetate washing)
22. 22
    기타to remove solid Zn- and Pd-
23. 23
    workup.ADDITIONcontaining material
24. 24
    기타The phases are separated
25. 25
    추출the aqueous phase is extracted with more ethyl acetate
26. 26
    세척The organic phases are washed in sequence with saturated brine
27. 27
    건조dried over anhydrous sodium sulfate
28. 28
    여과filtered
29. 29
    기타evaporated
30. 30
    여과is collected by trituration with ether and filtration
31. 31
    기타The remaining material is purified by column chromatography (eluting 1:2 ethyl acetate-hexane on silica gel 60)

실험 절차

A nitrogen-purged flask fitted with a septum and a nitrogen needle is charged with dry THF (all additions performed by syringe) (20 mL). Diisopropylamine (Aldrich Sure-Seal, 2.00 mL, 14.3 mmol) is added, and the solution is cooled to 0° C. n-Butyllithium (8.50 mL of 1.6 M solution in hexane, 13.6 mmol) is added slowly. The flask is allowed to warm to room temperature briefly, and then is cooled to −78° C. A concentrated THF solution of 6-methoxy-1-propyl-1H-indole-3-carbonitrile (2.77 g, 12.9 mmol; prepared analogously to compound 5 of Example 1A) is added slowly, and the resulting solution is maintained at −78° C. for 30 min. The flask is then transferred to a water-ice bath and allowed to come to 0° C. for about 15 minutes. The solution is once again cooled to −78° C., and ZnCl2 (0.5 M solution in THF, 27.0 mL, 13.5 mmol) is slowly added. A precipitate is observed at this point, which may be the bis(indole)zinc compound, but the solution becomes homogeneous when the entire volume of zinc chloride solution is added. After about 10 minutes, the solution is allowed to come to room temperature, and a THF solution (5 mL) of 4-iodoaniline (3.47 g, 15.8 mmol) and triphenylphosphine (338 mg, 1.29 mmol) is added. The septum is removed, and solid Pd2(dba)3 (295 mg, 0.322 mmol) is added. A reflux condenser is fitted to the flask, and the solution is degassed by three successive cycles of vacuum pumping/N2 purging. The solution is then heated to reflux overnight. After cooling to room temperature, the solution is poured into 4 volumes of water, and 4 volumes of ethyl acetate are added. The resulting mixture is vigorously stirred for 30 minutes, then filtered through celite (with ethyl acetate washing) to remove solid Zn- and Pd-containing material. The phases are separated, and the aqueous phase is extracted with more ethyl acetate. The organic phases are washed in sequence with saturated brine, combined, dried over anhydrous sodium sulfate, filtered and evaporated. A solid precipitate forms at this point, which is sufficiently pure product and is collected by trituration with ether and filtration. The remaining material is purified by column chromatography (eluting 1:2 ethyl acetate-hexane on silica gel 60). Total yield of the product, 2-(4-amino-phenyl)-6-methoxy-1-propyl-1H-indole-3-carbonitrile, is 2.75 g (8.99 mmol, 70%).

출처