Cesium carbonate → cis-3,5-Dimethyl-1-[4-(methyloxy)-3-nitrophenyl]piperazine

HRID 130399Notes

Reaction equation

HRID 130399 reaction equation
C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:54]1[CH:59]=[CH:58][C:57]([O:60][CH3:61])=[C:56]([N+:62]([O-:64])=[O:63])[CH:55]=1.[CH3:65][C@H:66]1[CH2:71][NH:70][CH2:69][C@@H:68]([CH3:72])[NH:67]1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:65][C@H:66]1[NH:67][C@@H:68]([CH3:72])[CH2:69][N:70]([C:54]2[CH:59]=[CH:58][C:57]([O:60][CH3:61])=[C:56]([N+:62]([O-:64])=[O:63])[CH:55]=2)[CH2:71]1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 1185334-Bromo-2-nitroanisoleHCID 634876Binap, (A+-)-HCID 6950261rel-(2R,6S)-2,6-dimethylpiperazine

Product 1

HCID 59007052cis-3,5-Dimethyl-1-[4-(methyloxy)-3-nitrophenyl]piperazine

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 312751,4-DioxaneSolvent

Procedure

Palladium (II) acetate (941 mg, 4.2 mmol) and rac-2,2′-bis(diphenylphosphino)-1,1′-binapthyl (3.93 g, 6 mmol) were heated to 50° C. in dioxane (200 ml) for 30 minutes. Cesium carbonate (20.48 g, 63 mmol), 4-bromo-2-nitroanisole (9.75 g, 42 mmol) and cis-2,6-dimethylpiperazine (14.39 g, 126 mmol) were added and the mixture heated at reflux for 18 hours. The solids were filtered through celite and washed with ethyl acetate. The residue was concentrated and dissolved in ethyl acetate and extracted with 2N hydrochloric acid (×5). The combined extracts were washed in ethyl acetate (×3), basified with 0.880 ammonia and extracted with dichloromethane (×5). The combined organic extracts were concentrated, redissolved in ethyl acetate and washed with water (×3), saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (Biotage Horizon, dichloromethane to 1:9 2M ammonia in methanol:dichloromethane) to afford the title product (D3). MS (ES+) m/e 266 [M+H]+.

Workup

  1. temperaturethe mixture heated
  2. temperatureat reflux for 18 hours
  3. filtrationThe solids were filtered through celite
  4. washwashed with ethyl acetate
  5. concentrationThe residue was concentrated
  6. dissolutiondissolved in ethyl acetate
  7. extractionextracted with 2N hydrochloric acid (×5)
  8. washThe combined extracts were washed in ethyl acetate (×3)
  9. extractionextracted with dichloromethane (×5)
  10. concentrationThe combined organic extracts were concentrated
  11. dissolutionredissolved in ethyl acetate
  12. washwashed with water (×3), saturated brine
  13. dry with materialdried over anhydrous sodium sulfate
  14. concentrationconcentrated
  15. customThe residue was purified by column chromatography (Biotage Horizon, dichloromethane to 1:9 2M ammonia in methanol:dichloromethane)

Sources & evidence

ORD record
ord-0fdb102c1c4849a88d3f7edd0b990ca0
Source dataset
uspto-grants-2008_06
Patent number
US07381728B2

Reaction notes

Loading…