Cesium carbonate → Methyl 3-Fluoro-4-(4-methyl-1-piperazinyl)benzoate

HRID 906065Notes

Reaction equation

HRID 906065 reaction equation
[CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:61]1[CH:70]=[CH:69][C:64]([C:65]([O:67][CH3:68])=[O:66])=[CH:63][C:62]=1[F:71]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:71][C:62]1[CH:63]=[C:64]([CH:69]=[CH:70][C:61]=1[N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)[C:65]([O:67][CH3:68])=[O:66]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 531671-MethylpiperazineHCID 634876Binap, (A+-)-HCID 21951878Methyl 4-bromo-3-fluorobenzoate

Product 1

HCID 57703850Methyl 3-Fluoro-4-(4-methyl-1-piperazinyl)benzoateYield 81.1%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
105 °C

Procedure

To 1-methylpiperazine (980 μl, 8.80 mmol) in toluene (15 ml) was added tris(dibenzylidene acetone)dipalladium (201 mg, 0.22 mmol), BINAP (550 mg, 0.88 mmol), and cesium carbonate (4.30 g, 13.2 mmol). The mixture was stirred for 30 minutes before the addition of methyl 4-bromo-3-fluorobenzoate (2.05 g, 8.80 mmol), after which, the temperature was increased to 105° C. and stirred for an additional 18 h. The mixture was cooled and filtered through Celite, washed with ethyl acetate, and the resultant filtrate concentrated in vacuo to afford an orange oil. The residue was purified by column chromatography eluting with 5% methanol in dichloromethane. Pure fractions were concentrated to afford (1.80 g, 81%) of methyl 3-fluoro-4-(4-methylpiperazin-1-yl)benzoate as a colorless oil. 1H NMR (400 MHz, CD3OD): 7.78-7.73 (d, 1H), 7.64-7.59 (d, 1H), 7.09-7.03 (m, 1H), 3.86 (s, 3H), 3.26-3.20 (m, 4H), 2.65-2.59 (m, 4H), 2.35 (s, 3H). MS (EI) for C13H17FN2O2: 253 (MH+).

Workup

  1. temperatureThe mixture was cooled
  2. filtrationfiltered through Celite
  3. washwashed with ethyl acetate
  4. concentrationthe resultant filtrate concentrated in vacuo
  5. customto afford an orange oil
  6. customThe residue was purified by column chromatography
  7. washeluting with 5% methanol in dichloromethane
  8. concentrationPure fractions were concentrated

Sources & evidence

ORD record
ord-a22e4957e8a547dcab0e3c4946c24619
Source dataset
uspto-grants-2011_09
Patent number
US08012956B2

Reaction notes

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