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

HRID 916000Notes

Reaction equation

HRID 916000 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 5.2 g (39.4 mmol) of aluminum chloride in several portions. 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 1 N aqueous HCl and extracted with three 150 mL portions of EtOAc. The combined organic layers were washed with 50 mL of 1 N 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 1 N 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-cb462e7488044527a93c93dc4605d932
Source dataset
uspto-grants-2007_09
Patent number
US07268152B2

Reaction notes

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