Formaldehyde → 4-Fluoro-2-hydroxybenzaldehyde

HRID 1357745Notes

Reaction equation

HRID 1357745 reaction equation
[CH3:1][O-:2].[Mg+2].C[O-].[F:6][C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1.C=O>CO.C1(C)C=CC=CC=1>[F:6][C:7]1[CH:12]=[CH:11][C:10]([CH:1]=[O:2])=[C:9]([OH:13])[CH:8]=1

Participants

6

Reactant 3

HCID 712FormaldehydeHCID 97433-FluorophenolHCID 164537Methanol, magnesium salt (2:1)

Product 1

HCID 27792684-Fluoro-2-hydroxybenzaldehydeYield 46.2%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 1140TolueneSolvent

Conditions

Temperature
25 °C

Procedure

To a stirred solution of magnesium methoxide (13 g, 150 mmol, 6% in methanol) in methanol (50 mL) was added 3-fluorophenol (22.4 g, 200 mmol). The solution was heated to reflux, approximately half the methanol distilled off, toluene (300 mL) added, and the reaction heated with azeotropic removal of solvent until the temperature of the distillate reached 95 ° C.. A slurry of paraformaldehyde powder (22 g, 720 mmol) in toluene (20 mL) was added in small portions over 1 hour to the reaction with concurrent removal of volatile materials by distillation. Stirring was continued at 95 ° C. for 1 hour, cooled to 25 ° C., the reaction quenched by slow addition to 10% sulfuric acid and stirred at 30-40 ° C. for 2 hours. The layers were separated and the aqueous portion extracted with toluene (2×50 mL). The combined organic layers were washed with 10% sulfuric acid, water, dried with sodium sulfate, filtered and solvent evaporated. The resulting yellow oil was purified by flash chromatography over silica gel eluting with hexane:ethyl acetate (5: 1) to provide 9.7 g of the title compound as a white solid.

Workup

  1. temperatureThe solution was heated
  2. temperatureto reflux
  3. distillationapproximately half the methanol distilled off
  4. additiontoluene (300 mL) added
  5. temperaturethe reaction heated with azeotropic removal of solvent until the temperature of the distillate
  6. customreached 95 ° C.
  7. customthe reaction quenched by slow addition to 10% sulfuric acid
  8. stirringstirred at 30-40 ° C. for 2 hours
  9. customThe layers were separated
  10. extractionthe aqueous portion extracted with toluene (2×50 mL)
  11. washThe combined organic layers were washed with 10% sulfuric acid, water
  12. dry with materialdried with sodium sulfate
  13. filtrationfiltered
  14. customsolvent evaporated
  15. customThe resulting yellow oil was purified by flash chromatography over silica gel eluting with hexane:ethyl acetate (5: 1)

Sources & evidence

ORD record
ord-995eab27b87f4572bde176469477d098
Source dataset
uspto-grants-2003_07
Patent number
US06593335B1

Reaction notes

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