Cesium fluoride → 3-(4'-Chloro-4-ethyl-2'-fluorobiphen-3-yl)bicyclo[3.2.2]non-6-ene-2,4-dione

HRID 72276Notes

Reaction equation

HRID 72276 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:19][CH3:20])=[C:6]([CH:8]2[C:14](=[O:15])[CH:13]3[CH2:16][CH2:17][CH:10]([CH:11]=[CH:12]3)[C:9]2=[O:18])[CH:7]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[C:24]([F:31])[CH:23]=1.[F-].[Cs+]>C(COC)OC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[CH:3]=[CH:4][C:5]([CH2:19][CH3:20])=[C:6]([CH:8]3[C:14](=[O:15])[CH:13]4[CH2:16][CH2:17][CH:10]([CH:11]=[CH:12]4)[C:9]3=[O:18])[CH:7]=2)=[C:24]([F:31])[CH:23]=1

Participants

6

Reactant 3

HCID 25953Cesium fluorideHCID 4193595(4-Chloro-2-fluorophenyl)boronic acidHCID 684883343-(5-Bromo-2-ethylphenyl)bicyclo[3.2.2]non-6-ene-2,4-dione

Product 1

HCID 1317318293-(4'-Chloro-4-ethyl-2'-fluorobiphen-3-yl)bicyclo[3.2.2]non-6-ene-2,4-dione

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 80711,2-DimethoxyethaneSolvent

Procedure

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.

Workup

  1. customThe reaction mixture is then evacuated
  2. customflushed with nitrogen (degassing cycle repeated 4 times)
  3. temperaturethe reaction mixture is heated at 80° C. for 21.5 hours
  4. temperatureAfter cooling to room temperature the suspension
  5. filtrationis filtered through diatomaceous earth
  6. washwashed with 2M hydrochloric acid (20 ml) and dichloromethane (20 ml)
  7. customThe organic phase is separated
  8. extractionthe aqueous phase is extracted with dichloromethane (10 ml×2)
  9. dry with materialdried over magnesium sulfate
  10. filtrationfiltered
  11. concentrationthe filtrate concentrated under reduced pressure
  12. customto give a brown gum
  13. customThe crude product is purified by flash column chromatography on silica gel (100% to 0% hexane/ethyl acetate eluant ratio)
  14. customfurther purified by preparative reverse-phase HPLC

Sources & evidence

ORD record
ord-d28897e5c028425ca9121de952ca6023
Source dataset
uspto-grants-2014_09
Patent number
US08828908B2

Reaction notes

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