Carbon Dioxide → 3-Bromo-5-chloro-2-fluorobenzoic acid

HRID 885715Notes

Reaction equation

HRID 885715 reaction equation
C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[F:21].[C:22](=[O:24])=[O:23]>C1COCC1>[Br:13][C:14]1[C:15]([F:21])=[C:16]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[C:22]([OH:24])=[O:23]

Participants

6

Reactant 4

HCID 280Carbon DioxideHCID 7912DiisopropylamineHCID 27732642-Bromo-4-chloro-1-fluorobenzeneHCID 178418339Butyllithium

Product 1

HCID 510344623-Bromo-5-chloro-2-fluorobenzoic acid

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
-78 °C

Procedure

To a cooled solution of diisopropylamine (2.4 mL, 17.2 mmol) in dry THF (15 mL) under Argon at 0° C. was added n-butyllithium (7.5 mL, 2.0 M in pentane, 15.0 mmol). After 30 minutes the solution was cooled to −78° C. and a solution of 2-bromo-4-chloro-1-fluorobenzene (3 g, 14.3 mmol) in dry THF (15 mL) was added over 15 minutes. After 1 hour, this solution was transferred via cannula over 10 minutes to a mixture of solid carbon dioxide and THF (30 mL) at −78° C. After 45 minutes the cold bath was removed and excess carbon dioxide was allowed to vent while the solution warmed to room temperature. The reaction mixture was then quenched with aqueous 0.5 M HCl solution (60 mL). After concentrating, the remaining aqueous phase was basified with aqueous 0.5 M NaOH solution and was washed with ethyl acetate (100 mL). The aqueous phase was then acidified with aqueous 1.0 M HCl solution and extracted with chloroform (2×75 mL). The combined organic portions were washed with brine, dried (Na2SO4) and concentrated to give 3.34 g of a semi-crystalline solid as a mixture of regioisomers with the desired isomer as the major: LCMS(m/z) not observed (MH+), tR=0.66 minute; 1H NMR (400 MHz, CDCl3) δ 7.80 (dd, J=5.5, 2.7 Hz, 1H), 7.95 (dd, J=5.5, 2.7 Hz, 1H).

Workup

  1. customAfter 45 minutes the cold bath was removed
  2. temperaturewarmed to room temperature
  3. customThe reaction mixture was then quenched with aqueous 0.5 M HCl solution (60 mL)
  4. concentrationAfter concentrating
  5. washwas washed with ethyl acetate (100 mL)
  6. extractionextracted with chloroform (2×75 mL)
  7. washThe combined organic portions were washed with brine
  8. dry with materialdried (Na2SO4)
  9. concentrationconcentrated
  10. customto give 3.34 g of a semi-crystalline solid
  11. additionas a mixture of regioisomers with the desired isomer as the major: LCMS(m/z) not

Sources & evidence

ORD record
ord-38bff3fb5c8b49b1b92ccf9b06078fcf
Source dataset
uspto-grants-2012_08
Patent number
US08242260B2

Reaction notes

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