Hydrochloric Acid → 3-Chloro-2-hydroxy-5-methoxybenzaldehyde

HRID 854894Notes

Reaction equation

HRID 854894 reaction equation
[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].[Mg+2].[Cl-].[Cl-].[CH2:14]=[O:15].Cl>C(#N)C>[Cl:1][C:2]1[C:3]([OH:10])=[C:4]([CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1)[CH:14]=[O:15]

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 712Formaldehyde3×HCID 874592-Chloro-4-methoxyphenolHCID 5360315Magnesium Chloride2×

Product 1

HCID 220401323-Chloro-2-hydroxy-5-methoxybenzaldehydeYield 102.8%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

To a solution of 2-chloro-4-methoxyphenol (25.0 g, 158 mmole) in anhydrous acetonitrile (625 mL) under a dry N2 atmosphere was added MgCl2 (22.5 g, 236 mmole) and TEA (82.3 mL, 591 mmole). The mixture warmed slightly as the MgCl2 was added. Paraformaldehyde (32.0 g, 1.06 mmiole) was then added, the mixture was refluxed for 4.5 h and allowed to stand at room temperature overnight. Additional paraformaldehyde (14.2 g, 474 mmole) was added and reflux was resumed. After 4 h, the mixture was cooled, additional paraformaldehyde (32.0 g, 1.06 mmole) was added and reflux was resumed for another 2.25 h. The mixture was then cooled to room temperature, acidified with 1 N HCl and extracted with ethyl ether (4×500 mL). The combined extracts were washed with brine (250 mL), dried over MgSO4, filtered and concentrated in vacuo to give 30.3 g of a yellow crystalline solid. Recrystallization from isopropanol-H2O gave 11.9 g (41% yield) of the product as a yellow crystalline solid: 1H NMR (dmso-d6/300MHz) 10.47 (brs, 1H, 10.11 (s, 1H), 7.36 (d, 1H, J=3.0 Hz), 7.19 (d, 1H, J=3.0 Hz), 3.73 (s, 3H).

Workup

  1. additionwas added
  2. temperaturethe mixture was refluxed for 4.5 h
  3. temperaturereflux
  4. waitAfter 4 h
  5. temperaturethe mixture was cooled
  6. temperaturereflux
  7. waitwas resumed for another 2.25 h
  8. extractionextracted with ethyl ether (4×500 mL)
  9. washThe combined extracts were washed with brine (250 mL)
  10. dry with materialdried over MgSO4
  11. filtrationfiltered
  12. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-d0fa1c092c2b4f4fb871ee715116804d
Source dataset
uspto-grants-2007_08
Patent number
US07259266B2

Reaction notes

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