반응 #164134

반응 방정식

4-(dimethylamino)-4-(3-fluorophenyl)cyclohexanone

Carbon dioxide

tert-butyl lithium

ammonium chloride

hydrogen chloride

n-butyl lithium

skatole

sodium hydrogencarbonate

sodium hydroxide

→

colourless powder

수율 35.0%

4-(dimethylamino)-4-(3-fluorophenyl)-1-(3-methyl-1H-indol-2-yl)cyclohexanol

수율 35.0%

용매

tetrahydrofuran

반응 조건

후처리

1. 1
   기타A colourless precipitate was formed
2. 2
   기타A colourless solution was formed
3. 3
   기타After 5 min the volatile constituents were completely removed in a vacuum at room temperature (water bath temperature ≦30° C.)
4. 4
   workup.DISSOLUTIONThe colourless solid residue was again dissolved in absolute tetrahydrofuran (20 ml)
5. 5
   온도The light yellow reaction mixture was cooled to −78° C.
6. 6
   기타An orange solution was formed
7. 7
   온도cooled to −78° C
8. 8
   workup.STIRRINGthe resulting solution stirred for 2 h
9. 9
   workup.STIRRINGstirred for 10 min
10. 10
    온도the mixture heated to 0° C.
11. 11
    workup.STIRRINGstirred for 20 min
12. 12
    workup.STIRRINGstirred for 10 min (light gas development)
13. 13
    기타After 10 min the phases were separated
14. 14
    기타The phases were separated
15. 15
    추출The aqueous phase was extracted with dichloromethane/methanol 20:1 (3×50 ml)
16. 16
    기타The volatile constituents were completely removed in a vacuum
17. 17
    추출The remaining light brown powder was extracted with methanol (5×75 ml)
18. 18
    농축The extracts were concentrated
19. 19
    기타until dry in a vacuum
20. 20
    workup.DISSOLUTIONA light-coloured solid did not dissolve
21. 21
    기타This was separated by means of a fritted glass
22. 22
    여과filter
23. 23
    기타dried in a vacuum

실험 절차

n-butyl lithium (8.39 mmol, 3.35 ml, 2.5M in hexane) was slowly added to a solution of skatole (1.00 g, 7.62 mmol) in absolute tetrahydrofuran (25 ml) in an argon atmosphere at −78° C. A colourless precipitate was formed. After 10 min the solution was heated to room temperature. Carbon dioxide was then introduced into the reaction mixture for approx. 3 min. A colourless solution was formed. After 5 min the volatile constituents were completely removed in a vacuum at room temperature (water bath temperature ≦30° C.). The colourless solid residue was again dissolved in absolute tetrahydrofuran (20 ml). The light yellow reaction mixture was cooled to −78° C. and tert-butyl lithium (8.39 mmol, 5.59 ml, 1.5M in pentane) was added in drops. An orange solution was formed. This was stirred for 1 h at −20° C. and then cooled to −78° C. 4-(dimethylamino)-4-(3-fluorophenyl)cyclohexanone [1.97 g, 8.39 mmol, in absolute tetrahydrofuran (20 ml)] was then added in drops and the resulting solution stirred for 2 h. Saturated aqueous ammonium chloride solution (50 ml) was then added in drops to the reaction mixture, stirred for 10 min, the mixture heated to 0° C. and stirred for 20 min. 2N aqueous hydrogen chloride solution (50 ml) was added thereto and stirred for 10 min (light gas development). The pH value of the milky suspension was then basified with saturated sodium hydrogencarbonate solution (50 ml) and 5N sodium hydroxide solution (20 ml). After 10 min the phases were separated. The organic phase contained a colourless solid. The phases were separated. The aqueous phase was extracted with dichloromethane/methanol 20:1 (3×50 ml). The organic solutions were combined. The volatile constituents were completely removed in a vacuum. The remaining light brown powder was extracted with methanol (5×75 ml). The residue was exclusively composed of the non-polar diastereoisomer 6b/7b (450 mg, 1.23 mmol, 16%). The extracts were concentrated until dry in a vacuum. The residue was taken up in methanol (approx. 30 ml). A light-coloured solid did not dissolve. This was separated by means of a fritted glass filter and then dried in a vacuum. 980 mg (2.67 mmol, 35%) of a colourless powder were obtained. This was composed of the two diastereoisomers.

출처