4-Iodotoluene → Ethyl 2,2-difluoro-2-(p-tolyl)acetate

HRID 271390Notes

Reaction equation

HRID 271390 reaction equation
I[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.Br[C:10]([F:17])([F:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].P([O-])([O-])(O)=O.[K+].[K+]>CS(C)=O.C(OC(C)C)(=O)C.O.[Cu]>[F:16][C:10]([F:17])([C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]

Participants

8

Reactant 3

HCID 122074-IodotolueneHCID 24450Potassium Phosphate, DibasicHCID 69585Ethyl bromodifluoroacetate

Product 1

HCID 14888699Ethyl 2,2-difluoro-2-(p-tolyl)acetateYield 69.8%

Reagents, catalysts & solvents 4

HCID 23978CopperCatalystHCID 679Dimethyl SulfoxideSolventHCID 962WaterSolventHCID 7915Isopropyl AcetateSolvent

Conditions

Temperature
55 °C

Procedure

The compound was prepared by modification to the procedure of Sato, K.; Kawata, R.; Ama, F.; Omote, M.; Ando, A. Chemical & Pharmaceutical Bulletin 47(7), 1013-1016 (1999). To a solution of 1-iodo-4-methylbenzene (25.1 g, 115 mmol) in DMSO (125 mL) was added ethyl bromo(difluoro)acetate (24.7 g, 122 mmol) and copper (16.8 g, 264 mmol), and the resulting solution was heated to 55° C. After 14 h the reaction was cooled to room temperature and diluted with isopropyl acetate, then cooled to 0° C. and treated with a solution of potassium hydrogen phosphate (23.3 g) in water (250 mL). The mixture was filtered through a pad of Celite, rinsing with isopropyl acetate. The phases were separated and the aqueous layer was washed with isopropyl acetate. The combined organic layers were washed with brine, dried (sodium sulfate), filtered and concentrated. The residue was purified by silica gel chromatography (5% methylene chloride, 1-8% ethyl acetate/hexanes gradient) gave the title compound (17.2 g) as an oil.

Workup

  1. customThe compound was prepared by modification to the procedure of Sato, K
  2. temperatureAfter 14 h the reaction was cooled to room temperature
  3. temperaturecooled to 0° C.
  4. filtrationThe mixture was filtered through a pad of Celite
  5. washrinsing with isopropyl acetate
  6. customThe phases were separated
  7. washthe aqueous layer was washed with isopropyl acetate
  8. washThe combined organic layers were washed with brine
  9. dry with materialdried (sodium sulfate)
  10. filtrationfiltered
  11. concentrationconcentrated
  12. customThe residue was purified by silica gel chromatography (5% methylene chloride, 1-8% ethyl acetate/hexanes gradient)

Sources & evidence

ORD record
ord-7861dc9ab7ff42dfb46121eac6620463
Source dataset
uspto-grants-2008_11
Patent number
US07452893B2

Reaction notes

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