Chloromethyl Methyl Ether → 1-(Dimethoxymethyl)-2-(methoxymethoxy)-3-(trifluoromethyl)benzene

HRID 2076585Notes

Reaction equation

HRID 2076585 reaction equation
[CH:1]([O:6][CH3:7])([O:4][CH3:5])OC.[OH:8][C:9]1[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:14]=[CH:13][C:10]=1C=O.C(=O)([O-])O.[Na+].C(N(C(C)C)CC)(C)C.[CH3:35][O:36][CH2:37]Cl>CO.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.O>[CH3:7][O:6][CH:1]([O:4][CH3:5])[C:10]1[CH:13]=[CH:14][CH:15]=[C:16]([C:17]([F:18])([F:19])[F:20])[C:9]=1[O:8][CH2:35][O:36][CH3:37]

Participants

9

Reactant 5

HCID 7864Chloromethyl Methyl EtherHCID 9005Trimethyl orthoformateHCID 81531DiisopropylethylamineHCID 516892Sodium BicarbonateHCID 27792742-Hydroxy-3-(trifluoromethyl)benzaldehyde

Product 1

HCID 671191561-(Dimethoxymethyl)-2-(methoxymethoxy)-3-(trifluoromethyl)benzeneYield 93%

Reagents, catalysts & solvents 3

HCID 18462Bicyclo[2.2.1]heptane-1-methanesulfonic acid, 7,7-dimethyl-2-oxo-, (1S)-CatalystHCID 887MethanolSolventHCID 962WaterSolvent

Conditions

Temperature
50 °C

Procedure

After trimethyl orthoformate (130 ml, 1.19 mol) and camphorsulfonic acid (1.55 g, 6.67 mmol) were added to a solution of 2-hydroxy-3-(trifluoromethyl)benzaldehyde (31.7 g, 167 mmol) obtained in Example (6-3) in methanol (50 ml), the mixture was stirred at 50° C. for 6 hours. After the reaction mixture was poured into a 1% aqueous sodium hydrogencarbonate solution and the mixture was extracted with ethyl acetate (three times), the organic layer was successively washed with water (twice) and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by concentrating the organic layer was dissolved in methylene chloride (400 ml) and diisopropylethylamine (50.9 ml, 292 mmol) and chloromethyl methyl ether (15.4 ml, 203 mmol) were successively added thereto under ice-cooling, and the mixture was stirred overnight. After the reaction mixture was poured into water and the mixture was extracted with ethyl acetate (twice), the organic layer was successively washed with 0.5N hydrochloric acid, a 5% aqueous sodium hydrogencarbonate solution, water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=14/1-10/1) to give 1-(dimethoxymethyl)-2-(methoxymethoxy)-3-(trifluoromethyl)benzene as a pale yellow oil (42.2 g, yield: 93%).

Workup

  1. extractionthe mixture was extracted with ethyl acetate (three times)
  2. washthe organic layer was successively washed with water (twice) and a saturated aqueous NaCl solution
  3. dry with materialdried with anhydrous sodium sulfate
  4. customThe residue obtained
  5. concentrationby concentrating the organic layer
  6. dissolutionwas dissolved in methylene chloride (400 ml)
  7. temperatureunder ice-cooling
  8. stirringthe mixture was stirred overnight
  9. extractionthe mixture was extracted with ethyl acetate (twice), the organic layer
  10. washwas successively washed with 0.5N hydrochloric acid
  11. dry with materiala 5% aqueous sodium hydrogencarbonate solution, water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate
  12. customThe residue obtained
  13. customby removing the solvent under reduced pressure
  14. customwas purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=14/1-10/1)

Sources & evidence

ORD record
ord-467f64665b24400d8ef8aa0bfa84e801
Source dataset
uspto-grants-2011_04
Patent number
US07923573B2

Reaction notes

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