Methane → (3R)-1-(3,4-dimethoxyphenyl)-3-methylpiperazine

HRID 1677751Notes

Reaction equation

HRID 1677751 reaction equation
[CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.Br[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C>C1(C)C=CC=CC=1.CCOCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(Cl)Cl.CCOCC>[CH3:16][O:15][C:12]1[CH:13]=[C:14]([N:6]2[CH2:5][CH2:4][NH:3][C@H:2]([CH3:1])[CH2:7]2)[CH:9]=[CH:10][C:11]=1[O:17][CH3:18]

Participants

10

Reactant 5

HCID 297MethaneHCID 76114Benzene, 4-bromo-1,2-dimethoxy-HCID 634876Binap, (A+-)-HCID 73304342-Methylpiperazine, (R)-HCID 23676156Sodium t-butoxide

Product 1

HCID 58487959(3R)-1-(3,4-dimethoxyphenyl)-3-methylpiperazineYield 28.1%

Reagents, catalysts & solvents 4

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolventHCID 3283Diethyl EtherSolventHCID 21881112Ethyl ether methylene chlorideSolvent

Procedure

A mixture of (R)-(−)-2-methylpiperazine (2.0 g, 20 mmol), 4-bromo-1,2-dimethoxybenzene (4.33 g, 20 mmol) and sodium tert-butoxide (2.88 g, 30 mmol) was prepared in anhydrous toluene (50 mL). The solution was degassed by argon bubbling for 10 min. Then palladium(II) acetate (220 mg, 1 mmol) and (+/−)-BINAP (500 mg, 0.8 mmol) were added. The resulting mixture was heated at reflux for 4 hours. Then the reaction mixture was cooled to RT and diluted with Et2O (50 mL). The salts were removed by filtration on Celite and the solvents were removed under reduced pressure to give a dark brown oil. Purification by flash chromatography (CHCl3/MeOH) gave a brown oil. This oil was taken up with DCM/Et2O, treated with activated charcoal at RT for 10 min and filtered on Celite. The solvents were removed under reduced pressure to give 1.33 g (28%) of the title compound as a yellow oil. M+(ESI): 237.2. HPLC (Condition A), Rt: 1.2 min (HPLC purity: 93.2%).

Workup

  1. customThe solution was degassed by argon bubbling for 10 min
  2. temperatureThe resulting mixture was heated
  3. temperatureat reflux for 4 hours
  4. customThe salts were removed by filtration on Celite
  5. customthe solvents were removed under reduced pressure
  6. customto give a dark brown oil
  7. customPurification by flash chromatography (CHCl3/MeOH)
  8. customgave a brown oil
  9. filtrationfiltered on Celite
  10. customThe solvents were removed under reduced pressure

Sources & evidence

ORD record
ord-933eddd1f69748e5b5c823b4b6a9d425
Source dataset
uspto-grants-2011_08
Patent number
US08008302B2

Reaction notes

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