4-Fluorophenol → 3-(4-Fluoro-phenoxy)-2-methyl-benzoic acid ethyl ester

HRID 409201Notes

Reaction equation

HRID 409201 reaction equation
[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7](I)[C:6]=1[CH3:12])[CH3:2].[F:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(C)(C(=O)CC(=O)C(C)(C)C)C>CN1CCCC1=O.[Cu]Cl>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:21][C:18]2[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=2)[C:6]=1[CH3:12])[CH3:2]

Participants

7

Reactant 4

HCID 97324-FluorophenolHCID 10796Cesium carbonateHCID 707002,2,6,6-Tetramethyl-3,5-heptanedioneHCID 54051219Ethyl 3-iodo-2-methylbenzoate

Product 1

HCID 671103423-(4-Fluoro-phenoxy)-2-methyl-benzoic acid ethyl esterYield 54.5%

Reagents, catalysts & solvents 2

HCID 62652Cuprous chlorideCatalystHCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
130 °C

Procedure

A mixture of 3-iodo-2-methyl-benzoic acid ethyl ester (6.29 g, 0.02 mol), para-fluorophenol (4.86 g, 0.04 mol), cesium carbonate (14.14 g, 0.04 mol), 2,2,6,6-tetramethylheptane-3,5-dione (447 μL, 2 mmol) and copper (I) chloride (1.07 g, 0.01 mol) in anhydrous N-methyl-2-pyrrolidone (38 mL) was heated at 130° C. for 3 days before it was cooled to room temperature, quenched with water and filtered. The filtrate was extracted with ethyl acetate. The organic layer was washed twice with 0.5 N sodium hydroxide, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a pale green oil (2.99 g): 1H NMR (CDCl3, 200 MHz): δ=7.63 (m, 1H), 7.18 (m, 2H), 6.98 (m, 2H), 6.85 (m, 2H), 4.37 (q, J=7.0 Hz, 2H), 2.45 (s, 3H), 1.40 (t, J=7.0 Hz, 3H).

Workup

  1. temperaturewas cooled to room temperature
  2. customquenched with water
  3. filtrationfiltered
  4. extractionThe filtrate was extracted with ethyl acetate
  5. washThe organic layer was washed twice with 0.5 N sodium hydroxide, brine
  6. dry with materialdried over anhydrous sodium sulfate
  7. concentrationconcentrated in vacuo
  8. customThe residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes

Sources & evidence

ORD record
ord-34b70b0315e245778a3815847620df1a
Source dataset
uspto-grants-2014_06
Patent number
US08759373B2

Reaction notes

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