4-Fluoroanisole → 4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentanoic acid ethyl ester

HRID 2105979Notes

Reaction equation

HRID 2105979 reaction equation
[CH2:1]([O:3][C:4](=[O:15])[C:5]([OH:14])([C:10]([F:13])([F:12])[F:11])[CH2:6][C:7]([CH3:9])=[CH2:8])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[F:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1>>[CH2:1]([O:3][C:4](=[O:15])[C:5]([OH:14])([C:10]([F:13])([F:12])[F:11])[CH2:6][C:7]([C:25]1[CH:26]=[C:21]([F:20])[CH:22]=[CH:23][C:24]=1[O:27][CH3:28])([CH3:9])[CH3:8])[CH3:2]

Participants

4

Reactant 3

HCID 99874-FluoroanisoleHCID 6451240Aluminum(III) ChlorideHCID 17935595Ethyl 2-hydroxy-4-methyl-2-(trifluoromethyl)pent-4-enoate

Product 1

HCID 179356104-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentanoic acid ethyl esterYield 71%

Procedure

To a mixture of 5.9 g (26.1 mmol) of the above 2-hydroxy-4-methyl-2-trifluoromethylpent-4-enoic acid ethyl ester in 30 mL of 4-fluoroanisole was added in several portions 5.2 g (39.4 mmol) of aluminum chloride. The mixture became exothermic and turned black with the first addition and was cooled with an ice-water bath. The mixture was stirred for 3 days and was then poured into 200 mL of ice-cold 1N aqueous HCl and extracted with three 150 mL portions of EtOAc. The combined organic layers were washed with 50 mL of 1N aqueous hydrochloric acid, three 50 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography eluting with EtOAc-hexanes (1:9, then 2:8, then 3:7, then 4:6) to afford 6.6 g (71%) of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentanoic acid ethyl ester.

Workup

  1. additionturned black with the first addition
  2. temperaturewas cooled with an ice-water bath
  3. extractionextracted with three 150 mL portions of EtOAc
  4. washThe combined organic layers were washed with 50 mL of 1N aqueous hydrochloric acid, three 50 mL portions of brine
  5. dry with materialdried over magnesium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe crude residue was purified by silica gel chromatography
  9. washeluting with EtOAc-hexanes (1:9

Sources & evidence

ORD record
ord-4b468ce64b5d43058e49d3b77ac3eaa0
Source dataset
uspto-grants-2009_08
Patent number
US07579469B2

Reaction notes

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