Cesium carbonate → 1-[2-Fluoro-5-(methyloxy)-4-nitrophenyl]-4-(1-methylethyl)piperazine

HRID 1014215Notes

Reaction equation

HRID 1014215 reaction equation
[CH3:1][O:2][C:3]1[CH:8]=[C:7](Br)[C:6]([F:10])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].[CH3:14][CH:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)[CH3:16].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C(OCC)(=O)C>[F:10][C:6]1[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[N:20]1[CH2:21][CH2:22][N:17]([CH:15]([CH3:16])[CH3:14])[CH2:18][CH2:19]1

Participants

9

Reactant 4

HCID 10796Cesium carbonateHCID 780131-IsopropylpiperazineHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 223473121-Bromo-2-fluoro-5-methoxy-4-nitrobenzene

Product 1

HCID 594420111-[2-Fluoro-5-(methyloxy)-4-nitrophenyl]-4-(1-methylethyl)piperazineYield 70%

Reagents, catalysts & solvents 4

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

To 5-bromo-4-fluoro-2-nitrophenyl methyl ether (4.0 g, 16.0 mmol) in dioxane (150 mL) was added 1-(1-methylethyl)piperazine (4.1 g, 32.0 mmol), XANTPHOS (0.9 g, 1.6 mmol), and Cs2CO3 (10.4 g, 32.0 mmol). The mixture was bubbled with N2 for 15 min prior to the addition of Pd2(dba)3 (0.7 g, 0.8 mmol). The reaction was stirred at 100° C. for 18 h. Ethyl acetate (100 mL) was used to dilute the reaction mixture, followed by the addition of water (80 mL). After partitioning, extraction with Ethyl acetate (2×75 mL), drying (Na2SO4), filtration and concentration, silica gel chromatography afforded 1-[2-fluoro-5-(methyloxy)-4-nitrophenyl]-4-(1-methylethyl)piperazine as a yellow solid (3.3 g, 70% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.98 (d, J=6.6 Hz, 6 H), 2.54-2.61 (m, 4 H), 2.68 (dt, J=13.2, 6.6 Hz, 1 H), 3.24-3.31 (m, 4 H), 3.91 (s, 3 H), 6.64 (d, J=7.7 Hz, 1 H), 7.82 (d, J=13.6 Hz, 1 H).

Workup

  1. customThe mixture was bubbled with N2 for 15 min
  2. additionto dilute the reaction mixture
  3. customAfter partitioning
  4. extractionextraction with Ethyl acetate (2×75 mL)
  5. customdrying
  6. filtration(Na2SO4), filtration and concentration, silica gel chromatography

Sources & evidence

ORD record
ord-20c7cdfa4f104033813f8f8e6a9827f5
Source dataset
uspto-grants-2011_07
Patent number
US07981903B2

Reaction notes

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