Sulfuric Acid → 7-Bromo-5-fluorobenzofuran-2-carboxylic acid

HRID 1012691Notes

Reaction equation

HRID 1012691 reaction equation
[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].F[C:11](F)(F)[C:12]([OH:14])=[O:13].[CH2:17]1N2CN3CN(C2)CN1C3.S(=O)(=O)(O)O.C(=O)([O-])[O-].[K+].[K+].ClCC(OC)=O.[OH-].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C1COCC1>[Br:1][C:2]1[C:3]2[O:9][C:11]([C:12]([OH:14])=[O:13])=[CH:17][C:4]=2[CH:5]=[C:6]([F:8])[CH:7]=1

Participants

11

Reactant 7

HCID 1118Sulfuric AcidHCID 4101HexamethylenetetramineHCID 6422Trifluoroacetic acidHCID 7295Methyl chloroacetateHCID 11430Potassium CarbonateHCID 14797Potassium HydroxideHCID 6054722-Bromo-4-fluorophenol

Product 1

HCID 179827017-Bromo-5-fluorobenzofuran-2-carboxylic acid

Reagents, catalysts & solvents 3

HCID 67553Tetrabutylammonium IodideCatalystHCID 962WaterSolvent2×HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
130 °C

Procedure

1.0 g (5.24 mmol) of 2-bromo-4-fluorophenol is introduced into 4.0 ml of trifluoroacetic acid. 1.47 g (10.47 mmol) of hexamethylenetetramine are added in portions over the course of 20 min. The mixture is then boiled under reflux for 28 h. At RT, 6 ml of water and 3 ml of 50% strength sulphuric acid are added. After 2 h, the mixture is extracted twice with a total of 60 ml of ethyl acetate. The combined organic phases are washed four times with 1N hydrochloric acid and once with water. Drying over magnesium sulphate is followed by removal of the solvent under reduced pressure. Finally, the last residues of solvent are removed under high vacuum. The crude product (without further purification) and 0.19 g (0.52 mmol) of tetra-n-butylammonium iodide are mixed with 2.9 g (20.96 mmol) of anhydrous potassium carbonate. 1.19 g (11.0 mmol) of methyl chloroacetate are added. The reaction mixture is heated at 130° C. for 4 h and then cooled to 0° C. in an ice bath. 18 ml of THF and a solution of 1.76 g (31.44 mmol) of potassium hydroxide in 18 ml of water are added. The mixture is stirred at RT overnight. The solvent is removed under reduced pressure. Dilution with water is followed by acidification with concentrated hydrochloric acid. The mixture is extracted twice with ethyl acetate. The combined organic phases are dried over magnesium sulphate, and the solvent is removed in a rotary evaporator under reduced pressure; Silicagel 60 (Merck, Darmstadt; eluent: toluene/acetic acid 40:1) is used for purification. The solvent is removed under reduced pressure. Finally, the last residues of solvent are removed under high vacuum. 257 mg (19% of theory over the two stages) of the title compound are isolated.

Workup

  1. temperatureunder reflux for 28 h
  2. extractionthe mixture is extracted twice with a total of 60 ml of ethyl acetate
  3. washThe combined organic phases are washed four times with 1N hydrochloric acid
  4. dry with materialDrying over magnesium sulphate
  5. customis followed by removal of the solvent under reduced pressure
  6. customFinally, the last residues of solvent are removed under high vacuum
  7. temperaturecooled to 0° C. in an ice bath
  8. customThe solvent is removed under reduced pressure
  9. extractionThe mixture is extracted twice with ethyl acetate
  10. dry with materialThe combined organic phases are dried over magnesium sulphate
  11. customthe solvent is removed in a rotary evaporator under reduced pressure
  12. customSilicagel 60 (Merck, Darmstadt; eluent: toluene/acetic acid 40:1) is used for purification
  13. customThe solvent is removed under reduced pressure
  14. customFinally, the last residues of solvent are removed under high vacuum

Sources & evidence

ORD record
ord-6d42b7e5ebea4d6891cc6ae87cee8bab
Source dataset
uspto-grants-2011_07
Patent number
US07977485B2

Reaction notes

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