Reaktion #51546

Reaktionsgleichung

tert-butyl (±)-cis-6-bromo-4-oxo-1,2,3,4,7b,10,11,11a-octahydro[1,4]diazepino[6,7,1-hi]pyrido[4,3-b]indol-9(8H)-carboxylate

triphenylphosphine

trifluoroacetic acid

ammonium hydroxide

2,6-difluorophenylstannane

→

title compound

Ausbeute 5.2%

(±)-cis-6-(2,6-difluorophenyl)-1,2,3,4,7b,8,9,10,11,11a-decahydro[1,4]diazepino[6,7,1-hi]pyrido[4,3-b]indole

Ausbeute 5.2%

Lösungsmittel

N,N-dimethylformamide

N,N-dimethylformamide

ethyl acetate

N,N-dimethylformamide

N,N-dimethylformamide

chloroform

Reaktionsbedingungen

Aufarbeitung

1. 1
   Sonstigedegassed under nitrogen
2. 2
   Temperaturheated to 140° C. for 10 minutes
3. 3
   workup.STIRRINGto stir at 140° C. for 1 hour
4. 4
   TemperaturThe reaction was cooled to room temperature
5. 5
   Waschenwashed with water (4×260 ml) and brine (2×150 ml)
6. 6
   TrocknenThe organic layer was dried over magnesium sulfate
7. 7
   Filtrationfiltered
8. 8
   EinengenThe filtrate was concentrated under reduced pressure
9. 9
   Sonstigeto give an oil
10. 10
    SonstigePurified oil via silica gel column chromatography
11. 11
    Wascheneluting with (10%) ethyl acetate in hexanes
12. 12
    SonstigeFractions were collected
13. 13
    Einengenconcentrated under reduced pressure
14. 14
    Sonstigeto give an oil
15. 15
    SonstigeThis oil was purified further by high pressure liquid chromatography on a Chiralcel OD column
16. 16
    Wascheneluted with 2% ethyl alcohol in hexanes (0.05% diethyl amine modifier) at 7 ml/min
17. 17
    Sonstigeto afford a colorless oil
18. 18
    Temperaturcooled to 0° C. in an ice bath
19. 19
    workup.STIRRINGstirred for 3 hours, during which time reaction
20. 20
    Temperaturwarmed to room temperature
21. 21
    Extraktionextracted with chloroform (3×20 ml)
22. 22
    SonstigeOrganics were seperated
23. 23
    Waschenwashed with brine
24. 24
    Trocknendried over magnesium sulfate
25. 25
    FiltrationOrganics were filtered
26. 26
    Einengenconcentrated under reduced pressure

Vorschrift

tert-butyl (±)-cis-6-bromo-4-oxo-1,2,3,4,7b,10,11,11a-octahydro[1,4]diazepino[6,7,1-hi]pyrido[4,3-b]indol-9(8H)-carboxylate (500 mg, 1.19 mmol), triphenylphosphine (62 mg, 0.238 mmol), copper (1) bromide (34 mg, 0.238 mmol), and dichlorobis(triphenylphosphine)palladium (II) were dissolved in anhydrous N,N-dimethylformamide (20 ml) and degassed under nitrogen and stirred for 10 minutes. Then 2,6-difluorophenylstannane (1.5 eq, 497 mg) in anhydrous N,N-dimethylformamide (5 ml) was added via cannula and then heated to 60° C. for 30 minutes. Another portion of 2,6-difluorostannane (1.5 eq, 497 mg) in anhydrous N,N-dimethylformamide (2.5 ml) was added via cannula and then heated to 140° C. for 10 minutes. After 10 minutes a final portion of 2,6-difluorostannane (1.5 eq, 497 mg) in anhydrous N,N-dimethylformamide (2.5 ml) was added via cannula and reaction allowed to stir at 140° C. for 1 hour. The reaction was cooled to room temperature, diluted with ethyl acetate (200 ml) and washed with water (4×260 ml) and brine (2×150 ml). The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give an oil. Purified oil via silica gel column chromatography, eluting with (10%) ethyl acetate in hexanes. Fractions were collected and concentrated under reduced pressure to give an oil. This oil was purified further by high pressure liquid chromatography on a Chiralcel OD column, eluted with 2% ethyl alcohol in hexanes (0.05% diethyl amine modifier) at 7 ml/min to afford a colorless oil. The oil was dissolved in chloroform (10 ml) and cooled to 0° C. in an ice bath and trifluoroacetic acid (2 ml) was added and stirred for 3 hours, during which time reaction warmed to room temperature. This was basified with concentrated ammonium hydroxide to pH 12, then extracted with chloroform (3×20 ml). Organics were seperated and washed with brine and dried over magnesium sulfate. Organics were filtered and then concentrated under reduced pressure to give the title compound as an oil (21 mg, 5%). 1H NMR (CDCl3, 300 MHz): δ 7.91 (d, 1H, J=1.5 Hz); 7.83 (s, 1H); 7.74 (s, 1H); 6.90 (t, 2H, J=8.1 Hz); 4.32 (t, 2H, J=9.6 Hz); 4.04 (t, 2H, J=9.54 Hz); 3.47 (s-broad, 2H); 3.31-3.04 (m, 3H); 3.08-3.04 (m, 1H); 2.23-2.10 (m, 1H); 2.08-2.03 (m, 1H) ppm.

Quelle