Toluene → 5-Bromo-2-(2,3-difluoro-4-methoxyphenoxy)benzoic acid

HRID 335937

Reaction equation

HRID 335937 reaction equation
Br[C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C1(C)C=CC=CC=1.[F:19][C:20]1[C:25]([F:26])=[C:24]([O:27][CH3:28])[CH:23]=[CH:22][C:21]=1[OH:29].C(=O)([O-])[O-].[Cs+].[Cs+]>CCOC(C)=O.O>[Br:11][C:8]1[CH:9]=[CH:10][C:2]([O:29][C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[C:25]([F:26])[C:20]=2[F:19])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]

Participants

7

Reactant 4

HCID 1140TolueneHCID 10796Cesium carbonateHCID 118912,5-Dibromobenzoic acidHCID 27741202,3-Difluoro-4-methoxyphenol

Product 1

HCID 673832405-Bromo-2-(2,3-difluoro-4-methoxyphenoxy)benzoic acidYield 64.4%

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateCatalystHCID 962WaterSolvent

Procedure

To a 500 mL flask charged with 2,5-dibromobenzoic acid (14 g, 50.0 mmol) and copper (I) trifluoromethanesulfonate toluene complex (1.29 g, 2.50 mmol) were added toluene (100 mL, 50.0 mmol) followed by EtOAc (0.25 mL, 2.50 mmol) and 2,3-difluoro-4-methoxyphenol (8.41 g, 52.5 mmol). To the resulting green mixture was added cesium carbonate (34.2 g, 105 mmol) in two portions. The mixture was stirred at rt for 5 minutes before being placed in a 110° C. oil bath where it was maintained for 12 h. The reaction was cooled to rt and poured into a separatory funnel containing 1 L of water. The layers were separated and the aqeuous layer was washed with ethyl acetate (2×200 mL). The aqeuous layer was acidified with 6 N HCl and extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to provide a brown oil. The derived oil was triturated with ethyl acetate (100 mL) and hexanes (1000 mL). The slurry was cooled to −10° C. for 4 hours then filtered to provide 5-bromo-2-(2,3-difluoro-4-methoxyphenoxy)benzoic acid (11.55 g, 32.2 mmol, 64.3% yield) as a light tan solid.

Workup

  1. custombefore being placed in a 110° C.
  2. temperaturewas maintained for 12 h
  3. temperatureThe reaction was cooled to rt
  4. additionpoured into a separatory funnel
  5. customThe layers were separated
  6. washthe aqeuous layer was washed with ethyl acetate (2×200 mL)
  7. extractionextracted with ethyl acetate (3×500 mL)
  8. washThe combined organic layers were washed with brine
  9. dry with materialdried over sodium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated
  12. customto provide a brown oil
  13. customThe derived oil was triturated with ethyl acetate (100 mL) and hexanes (1000 mL)
  14. temperatureThe slurry was cooled to −10° C. for 4 hours
  15. filtrationthen filtered

Sources & evidence

ORD record
ord-196970bd21ab45ceb6ee01dc57b2a4a3
Source dataset
uspto-grants-2014_11
Patent number
US08883782B2

Linked notes

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