Carbon Dioxide → 4-Bromo-2,5-difluorobenzoic acid

HRID 1640940Notes

Reaction equation

HRID 1640940 reaction equation
C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([F:13])[C:10]([Br:14])=[CH:9][C:8]=1[F:15].[C:16](=[O:18])=[O:17].Cl>C(OCC)C>[Br:14][C:10]1[C:11]([F:13])=[CH:12][C:7]([C:16]([OH:18])=[O:17])=[C:8]([F:15])[CH:9]=1

Participants

6

Reactant 4

HCID 280Carbon DioxideHCID 313Hydrochloric AcidHCID 675961,4-Dibromo-2,5-difluorobenzeneHCID 178418339Butyllithium

Product 1

HCID 8228574-Bromo-2,5-difluorobenzoic acid

Reagents, catalysts & solvents 1

HCID 3283Diethyl EtherSolvent

Conditions

Temperature
-78 °C

Procedure

Freshly titrated n-butyl lithium (27.0 ml, 1.39 M in hexanes) is added slowly (over about 30 minutes) to a −78° C. solution of diethyl ether (90 ml) containing 1,4-dibromo-2,5-difluorobenzene (1, 10.22 g, 0.038 mol). The resulting yellow solution is stirred at −78° C. for 2 hours to give a yellow suspension. Several pellets (˜10) of dry ice are added to the suspension, which is then allowed to warm slowly to room temperature as it degasses (approximately 40 minutes). The resulting suspension is acidified with a 1 M aqueous solution of hydrochloric acid (500 ml), and the product extracted with diethyl ether (5×200 ml). The combined organics are washed with water (4×100 ml) and filtered. The ether solution is concentrated to approximately 200 ml under reduced pressure, and the product extracted into a saturated aqueous solution of sodium bicarbonate (3×200 ml). The combined aqueous extracts are washed with methylene chloride (3×100 ml) and acidified with hydrochloric acid. The product is extracted with diethyl ether (3×200 ml), and the combined organic extracts washed with water (2×200 ml), dried over magnesium sulfate, and concentrated under reduced pressure to give (2) as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6): δ 7.74 (dd, JH-F=8.5 Hz, 6.5 Hz, 1H), 7.84 (dd, JH-F=10.0 Hz, 5.5 Hz, 1H), 13.7 (br, 1H, CO2H). 19F{1H} NMR (282 MHz, DMSO-d6): δ −114.0 (d, JF-F=17.0 Hz, 1F), −113.6 (d, JF-F=17.0 Hz, 1F). 13C{1H} NMR (75 MHz, DMSO-d6): δ 113.6 (dd, JC-F=23.5 Hz, 10.0 Hz), 118.4 (dd, JC-F=26.5 Hz, 2.5 Hz, CH), 120.0 (dd, JC-F=19.0 Hz, 12.0 Hz), 122.2 (d, JC-F=28.0 Hz, CH), 154.4 (dd, JC-F=245.0 Hz, 5.5 Hz, CF), 156.8 (dd, JC-F=251.5 Hz, 4.0 Hz, CF), 163.4 (m, CO2H).

Workup

  1. customto give a yellow suspension
  2. temperatureto warm slowly to room temperature as it
  3. custom(approximately 40 minutes)
  4. extractionthe product extracted with diethyl ether (5×200 ml)
  5. washThe combined organics are washed with water (4×100 ml)
  6. filtrationfiltered
  7. concentrationThe ether solution is concentrated to approximately 200 ml under reduced pressure
  8. extractionthe product extracted into a saturated aqueous solution of sodium bicarbonate (3×200 ml)
  9. washThe combined aqueous extracts are washed with methylene chloride (3×100 ml)
  10. extractionThe product is extracted with diethyl ether (3×200 ml)
  11. washthe combined organic extracts washed with water (2×200 ml)
  12. dry with materialdried over magnesium sulfate
  13. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-f020deaa857b4ec9b2d75069fe01168c
Source dataset
uspto-grants-2012_02
Patent number
US08114888B2

Reaction notes

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