反応 #339673

反応方程式

Diisopropylamine

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

n-Butyllithium

4-iodoaniline

triphenylphosphine

→

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

溶媒

THF

THF

反応条件

後処理

1. 1
   その他A nitrogen-purged flask
2. 2
   その他fitted 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
   温度is cooled to −78° C
6. 6
   workup.ADDITIONis added slowly
7. 7
   温度the resulting solution is maintained at −78° C. for 30 min
8. 8
   その他The flask is then transferred to a water-ice bath
9. 9
   温度The solution is once again cooled to −78° C.
10. 10
    workup.ADDITIONis added
11. 11
    workup.WAITAfter about 10 minutes
12. 12
    その他to come to room temperature
13. 13
    その他The septum is removed
14. 14
    その他A reflux condenser is fitted to the flask
15. 15
    その他the solution is degassed by three successive cycles of vacuum
16. 16
    温度The solution is then heated
17. 17
    温度to reflux overnight
18. 18
    温度After 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
    ろ過filtered through celite (with ethyl acetate washing)
22. 22
    その他to remove solid Zn- and Pd-
23. 23
    workup.ADDITIONcontaining material
24. 24
    その他The phases are separated
25. 25
    抽出the aqueous phase is extracted with more ethyl acetate
26. 26
    洗浄The organic phases are washed in sequence with saturated brine
27. 27
    乾燥dried over anhydrous sodium sulfate
28. 28
    ろ過filtered
29. 29
    その他evaporated
30. 30
    ろ過is collected by trituration with ether and filtration
31. 31
    その他The remaining material is purified by column chromatography (eluting 1:2 ethyl acetate-hexane on silica gel 60)

実験手順

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%).

出典