반응 #994281

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 was charged with dry THF (all additions performed by syringe) (20 mL)
4. 4
   workup.ADDITIONwas added slowly
5. 5
   온도was cooled to −78° C
6. 6
   workup.ADDITIONwas added slowly
7. 7
   온도the resulting solution was maintained at −78° C. for 30 min
8. 8
   기타The flask was then transferred to a water-ice bath
9. 9
   온도The solution was once again cooled to −78° C.
10. 10
    workup.ADDITIONwas added
11. 11
    workup.WAITAfter about 10 minutes
12. 12
    기타to come to room temperature
13. 13
    기타The septum was removed
14. 14
    기타A reflux condenser was fitted to the flask
15. 15
    기타the solution was degassed by three successive cycles of vacuum
16. 16
    온도The solution was then heated
17. 17
    온도to reflux overnight
18. 18
    온도After cooling to room temperature
19. 19
    workup.ADDITIONthe solution was poured into 4 volumes of water, and 4 volumes of ethyl acetate
20. 20
    workup.ADDITIONwere 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 were separated
25. 25
    추출the aqueous phase was extracted with more ethyl acetate
26. 26
    세척The organic phases were washed in sequence with saturated brine
27. 27
    건조dried over anhydrous sodium sulfate
28. 28
    여과filtered
29. 29
    기타evaporated
30. 30
    기타A solid precipitate formed at this point, which
31. 31
    여과was collected by trituration with ether and filtration
32. 32
    기타The remaining material was 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 was charged with dry THF (all additions performed by syringe) (20 mL). Diisopropylamine (Aldrich Sure-Seal, 2.00 mL, 14.3 mmol) was added, and the solution was cooled to 0° C. n-Butyllithium (8.50 mL of 1.6 M solution in hexane, 13.6 mmol) was added slowly. The flask was allowed to warm to room temperature briefly, and then was 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) was added slowly, and the resulting solution was maintained at −78° C. for 30 min. The flask was then transferred to a water-ice bath and allowed to come to 0° C. for about 15 minutes. The solution was once again cooled to −78° C., and ZnCl2 (0.5 M solution in THF, 27.0 mL, 13.5 mmol) was slowly added. A precipitate was observed at this point, which may have been the bis(indole)zinc compound, but the solution became homogeneous when the entire volume of zinc chloride solution was added. After about 10 minutes, the solution was 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) was added. The septum was removed, and solid Pd2(dba)3 (295 mg, 0.322 mmol) was added. A reflux condenser was fitted to the flask, and the solution was degassed by three successive cycles of vacuum pumping/N2 purging. The solution was then heated to reflux overnight. After cooling to room temperature, the solution was poured into 4 volumes of water, and 4 volumes of ethyl acetate were added. The resulting mixture was vigorously stirred for 30 minutes, then filtered through celite (with ethyl acetate washing) to remove solid Zn-and Pd-containing material. The phases were separated, and the aqueous phase was extracted with more ethyl acetate. The organic phases were washed in sequence with saturated brine, combined, dried over anhydrous sodium sulfate, filtered and evaporated. A solid precipitate formed at this point, which was sufficiently pure product and was collected by trituration with ether and filtration. The remaining material was 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, was 2.75 g (8.99 mmol, 70%).

출처