Carbon Dioxide → 4-Bromo-2,6-difluorobenzoic acid

HRID 2367308Notes

Reaction equation

HRID 2367308 reaction equation
[Li]CCCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:15]=[C:16]([Br:21])[CH:17]=[C:18]([F:20])[CH:19]=1.[C:22](=[O:24])=[O:23]>C1COCC1>[Br:21][C:16]1[CH:15]=[C:14]([F:13])[C:19]([C:22]([OH:24])=[O:23])=[C:18]([F:20])[CH:17]=1

Participants

6

Reactant 4

HCID 280Carbon DioxideHCID 7912DiisopropylamineHCID 1363131-Bromo-3,5-difluorobenzeneHCID 178418339Butyllithium

Product 1

HCID 27732984-Bromo-2,6-difluorobenzoic acidYield 38%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-50 °C

Procedure

n-BuLi (220 mL, 550 mmol, 2.5 M) was added dropwise to a solution of diisopropylamine (61 g) in THF (500 mL) with stirring at −50° C. under N2. After the addition, the reaction mixture was stirred at −50° C. for 15 minutes, and then warmed to 0° C. for 1 hour. The reaction was cooled to −50° C. and then a solution of 3,5-difluorobromobenzene (96 g, 0.5 mole) in THF (500 mL) was added dropwise. After the addition, the reaction mixture was stirred at −50° C. for 2 hours and then dry ice (about 200 g) was added portion-wise. The resulting mixture was warmed gradually to room temperature and stirred overnight. The mixture was concentrated under reduced pressure, and the resulting residue was partitioned between CH2Cl2 (1 L) and water (1 L). An aqueous NaOH solution was added to adjust the pH of the mixture to 10. The organic layer was discarded and the water phase was adjust the pH to 2 with HCl solution. The mixture was extracted with CH2Cl2 (3×400 mL), and the extracts were combined, dried over MgSO4, filtered and evaporated under vacuum to provide the title compound (45 g) as a white solid.

Workup

  1. additionAfter the addition
  2. stirringthe reaction mixture was stirred at −50° C. for 15 minutes
  3. temperaturewarmed to 0° C. for 1 hour
  4. temperatureThe reaction was cooled to −50° C.
  5. additionAfter the addition
  6. stirringthe reaction mixture was stirred at −50° C. for 2 hours
  7. temperatureThe resulting mixture was warmed gradually to room temperature
  8. stirringstirred overnight
  9. concentrationThe mixture was concentrated under reduced pressure
  10. customthe resulting residue was partitioned between CH2Cl2 (1 L) and water (1 L)
  11. additionAn aqueous NaOH solution was added
  12. extractionThe mixture was extracted with CH2Cl2 (3×400 mL)
  13. dry with materialdried over MgSO4
  14. filtrationfiltered
  15. customevaporated under vacuum

Sources & evidence

ORD record
ord-31521304d8dd437195d008722033707c
Source dataset
uspto-grants-2014_04
Patent number
US08697685B2

Reaction notes

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