Reacción #159458

Ecuación de reacción

3-(5-bromo-2-ethylphenyl)bicyclo[3.2.2]non-6-ene-2,4-dione

4-chloro-2-fluorophenylboronic acid

Cesium fluoride

→

3-(4′-chloro-4-ethyl-2′-fluorobiphen-3-yl)bicyclo[3.2.2]non-6-ene-2,4-dione

Disolventes

dimethoxyethane

Condiciones de reacción

Tratamiento posterior

1. 1
   OtroThe reaction mixture is then evacuated
2. 2
   Otroflushed with nitrogen (degassing cycle repeated 4 times)
3. 3
   Temperaturathe reaction mixture is heated at 80° C. for 21.5 hours
4. 4
   TemperaturaAfter cooling to room temperature the suspension
5. 5
   Filtraciónis filtered through diatomaceous earth
6. 6
   Lavadowashed with 2M hydrochloric acid (20 ml) and dichloromethane (20 ml)
7. 7
   OtroThe organic phase is separated
8. 8
   Extracciónthe aqueous phase is extracted with dichloromethane (10 ml×2)
9. 9
   Secadodried over magnesium sulfate
10. 10
    Filtraciónfiltered
11. 11
    Concentraciónthe filtrate concentrated under reduced pressure
12. 12
    Otroto give a brown gum
13. 13
    OtroThe crude product is purified by flash column chromatography on silica gel (100% to 0% hexane/ethyl acetate eluant ratio)
14. 14
    Otrofurther purified by preparative reverse-phase HPLC

Procedimiento

A solution of 3-(5-bromo-2-ethylphenyl)bicyclo[3.2.2]non-6-ene-2,4-dione (0.180 g, 0.54 mmol) and 4-chloro-2-fluorophenylboronic acid (0.133 g, 0.76 mmol) in anhydrous dimethoxyethane (5 ml) is stirred at room temperature under an atmosphere of nitrogen. The reaction mixture is then evacuated and flushed with nitrogen (degassing cycle repeated 4 times). Cesium fluoride (0.246 g, 1.62 mmol) is added, and the suspension is stirred at room temperature for 45 minutes. Next [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II) (0.066 g, 0.081 mmol) is added in one portion, and the reaction mixture is heated at 80° C. for 21.5 hours. After cooling to room temperature the suspension is filtered through diatomaceous earth, then washed with 2M hydrochloric acid (20 ml) and dichloromethane (20 ml). The organic phase is separated, and the aqueous phase is extracted with dichloromethane (10 ml×2). All organics are combined, dried over magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to give a brown gum. The crude product is purified by flash column chromatography on silica gel (100% to 0% hexane/ethyl acetate eluant ratio), then further purified by preparative reverse-phase HPLC to afford 3-(4′-chloro-4-ethyl-2′-fluorobiphen-3-yl)bicyclo[3.2.2]non-6-ene-2,4-dione.

Fuente