Iodine → Methyl 4-fluoro-2-iodo-6-methylbenzoate

HRID 1618113Notes

Reaction equation

HRID 1618113 reaction equation
[F:1][C:2]1[CH:10]=C[C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.[C:12](O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.II.[CH3:29][I:30].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.COC(C)(C)C.Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([C:6]([O:8][CH3:12])=[O:7])=[C:29]([I:30])[CH:10]=1

Participants

10

Reactant 5

HCID 807IodineHCID 6328Methyl iodideHCID 11430Potassium CarbonateHCID 38606394-Fluoro-2-methylbenzoic acidHCID 12217721Iodo benzene diacetate

Product 1

HCID 57949477Methyl 4-fluoro-2-iodo-6-methylbenzoateYield 63%

Reagents, catalysts & solvents 4

HCID 167845palladium(II) acetateCatalystHCID 313Hydrochloric AcidSolventHCID 6228DimethylformamideSolvent2×HCID 15413tert-Butyl methyl etherSolvent2×

Conditions

Temperature
100 °C

Procedure

4-Fluoro-2-methylbenzoic acid (5.0 gr, 32.4 mmol), palladium(II) acetate (0.364 g, 1.62 mmol), iodobenzene diacetate (12.54 g, 38.92 mmol) and elemental iodine (9.88 g, 38.92 mmol) were dissolved in N,N-dimethylformamide (130 mL) and stirred at 100° C. overnight. The reaction mixture was cooled to room temperature, diluted with methyl-tert-butylether and aqueous hydrochloric acid and washed with 10% sodium metabisolfite aqueous solution. Organic phase was treated with 2N aqueous sodium hydroxide. The resulting aqueous phase was treated with aqueous hydrochloric acid up to acidic pH and extracted with methyl-tert-butylether. The organic phase was washed with brine, dried over sodium sulfate and concentrated. So obtained iodinated benzoic acid (6.9 g, 24.6 mmol) was dissolved in N,N-dimethylformamide (50 mL) and methyliodide (3 mL, 49.2 mmol) and potassium carbonate (5 g, 36.9 mmol) were added. The reaction mixture was stirred overnight at room temperature, diluted with methyl-tert-butylether and washed with water, 1M sodium hydroxide, water and brine. Solvent was removed under reduced pressure and the crude was purified by flash chromatography (n-hexane/diethyl ether 100:2) to give title compound (5.9 g, 63% yield).

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. washwashed with 10% sodium metabisolfite aqueous solution
  3. additionOrganic phase was treated with 2N aqueous sodium hydroxide
  4. additionThe resulting aqueous phase was treated with aqueous hydrochloric acid up to acidic pH
  5. extractionextracted with methyl-tert-butylether
  6. washThe organic phase was washed with brine
  7. dry with materialdried over sodium sulfate
  8. concentrationconcentrated
  9. stirringThe reaction mixture was stirred overnight at room temperature
  10. washwashed with water, 1M sodium hydroxide, water and brine
  11. customSolvent was removed under reduced pressure
  12. customthe crude was purified by flash chromatography (n-hexane/diethyl ether 100:2)

Sources & evidence

ORD record
ord-aba1dc868f124a4c9ac45c7af50ece5e
Source dataset
uspto-grants-2014_07
Patent number
US08765972B2

Reaction notes

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