Reaktion #167020

Reaktionsgleichung

Ethoxyvinyl-tributyl tin

N-bromo succinimide

2,7-Dibromo-9,9-difluoro-9H-fluorene

N-Cbz-4-cyclopropyl(L)Proline

DIEA

→

5-Aza-spiro[2.4]heptane-5,6-dicarboxylic acid 5-benzyl ester 6-[2-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-2-oxo-ethyl]ester

Ausbeute 35.1%

Lösungsmittel

EtOAc

EtOAc

dioxane

MeCN

water

Reaktionsbedingungen

Aufarbeitung

1. 1
   TemperaturThe reaction was cooled to room temperature
2. 2
   Sonstigeafter which the majority of the dioxane was removed in vacuo
3. 3
   SonstigeThe crude reaction mixture
4. 4
   Waschenwas washed with water
5. 5
   SonstigeAll volatiles were removed in vacuo
6. 6
   workup.ADDITIONToluene was added
7. 7
   Sonstigeall volatiles were removed in vacuo for a second time
8. 8
   workup.DISSOLUTIONThe crude material was dissolved in DMF/MeCN (2 mL, 1:1) at room temperature
9. 9
   workup.STIRRINGstirring at room temperature
10. 10
    workup.WAITAfter 14 hours
11. 11
    Sonstigemost of the MeCN was removed in vacuo
12. 12
    Sonstigethe crude reaction mixture
13. 13
    WaschenThe mixture was washed with aqueous HCl (1M), aqueous LiCl solution (5%), brine
14. 14
    Trocknenwas dried over sodium sulfate
15. 15
    FiltrationFiltration and evaporation of solvents
16. 16
    Sonstigegave the crude
17. 17
    Sonstigereaction product, which
18. 18
    Sonstigewas purified via silica gel chromatography (eluent: EtOAc/hexanes)

Vorschrift

2,7-Dibromo-9,9-difluoro-9H-fluorene (372 mg, 1.04 mmol), Pd(PPh3)4 (30.0 mg, 0.026 mmol), PdCl2(PPh3)2 (18.2 mg, 0.026 mmol), As(PPh3)3 (5.0 mg) were dissolved in dioxane (10 mL) under an argon atmosphere. Ethoxyvinyl-tributyl tin (376.4 mg, 1.04 mmol) was added. The mixture was heated for 140 minutes at 85° C. (oil bath). The reaction was cooled to room temperature. N-bromo succinimide (177 mg, 1.0 mmol) was added followed by water (2 mL). The reaction was stirred at room temperature for 3 hours, after which the majority of the dioxane was removed in vacuo. The crude reaction mixture was diluted with EtOAc and was washed with water. All volatiles were removed in vacuo. Toluene was added and all volatiles were removed in vacuo for a second time. The crude material was dissolved in DMF/MeCN (2 mL, 1:1) at room temperature. A solution of N-Cbz-4-cyclopropyl(L)Proline (0.84 mmol) and DIEA (268 mg, 2.08 mmol) in MeCN (2 mL) was added and stirring at room temperature was continued. After 14 hours, most of the MeCN was removed in vacuo and the crude reaction mixture was diluted with EtOAc. The mixture was washed with aqueous HCl (1M), aqueous LiCl solution (5%), brine, and was dried over sodium sulfate. Filtration and evaporation of solvents gave the crude reaction product, which was purified via silica gel chromatography (eluent: EtOAc/hexanes) to yield the product 5-Aza-spiro[2.4]heptane-5,6-dicarboxylic acid 5-benzyl ester 6-[2-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-2-oxo-ethyl]ester (176 mg). LCMS-ESI+: calc'd for C30H24BrF2NO5: 596.4 (M+). Found: 595.2/597.2 (M+H+).

Quelle