4-Bromotoluene → Ethyl 4,4,4-trifluoro-3-methyl-2-(4-methylphenyl)butanoate

HRID 1476073Notes

Reaction equation

HRID 1476073 reaction equation
C1(P(C2CCCCC2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2C=CC=CC=2N(C)C)CCCCC1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[F:39][C:40]([F:50])([F:49])[CH:41]([CH3:48])[CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44].BrC1C=CC(C)=CC=1>C1(C)C=CC=CC=1.C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1CCCCC1.ClCCl>[F:39][C:40]([F:49])([F:50])[CH:41]([CH3:48])[CH:42]([C:12]1[CH:11]=[CH:10][C:9]([CH3:14])=[CH:8][CH:13]=1)[C:43]([O:45][CH2:46][CH3:47])=[O:44]

Participants

9

Reactant 4

HCID 78054-BromotolueneHCID 228896Ethyl 3-methyl-4,4,4-trifluorobutanoateHCID 2733832Lithium HexamethyldisilazideHCID 27342172-(Dicyclohexylphosphino)-2'-(dimethylamino)biphenyl

Product 1

HCID 58136599Ethyl 4,4,4-trifluoro-3-methyl-2-(4-methylphenyl)butanoate

Reagents, catalysts & solvents 4

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolvent2×HCID 8028TetrahydrofuranSolventHCID 21916607Dichloromethane cyclohexaneSolvent

Procedure

Under argon, 196.9 mg (0.88 mmol) of palladium(II) acetate and 724.8 mg (1.84 mmol) of 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl were initially charged in 50 ml of anhydrous toluene. 43.8 ml (43.8 mmol) of a 1 M solution of lithium hexamethyldisilazide in THF were then added slowly, and the reaction solution was stirred at RT for 10 min. The reaction solution was then cooled to −10° C., 7 g (38.0 mmol) of (+/−)-ethyl 4,4,4-trifluoro-3-methylbutanoate were added slowly and the mixture was stirred at −10° C. for 10 min 5 g (29.2 mmol) of 4-bromotoluene, dissolved in 50 ml of toluene, were then added dropwise, and the reaction solution was warmed initially to RT and then to 80° C. The mixture was stirred at this temperature for 2 h, then cooled to RT and stirred overnight. After the reaction had gone to completion (monitored by TLC; mobile phase cyclohexane/dichloromethane 2:1), the reaction mixture was filtered through kieselguhr, the residue was washed repeatedly with ethyl acetate and dichloromethane and the combined filtrates were concentrated under reduced pressure. The crude product obtained was purified chromatographically on silica gel (mobile phase petroleum ether/dichloromethane 4:1→3:1). This gave 3.91 g (14.3 mmol, 48.8% of theory) of the title compound as a colourless liquid.

Workup

  1. temperatureThe reaction solution was then cooled to −10° C.
  2. additionwere then added dropwise
  3. temperaturethe reaction solution was warmed initially to RT
  4. customto 80° C
  5. stirringThe mixture was stirred at this temperature for 2 h
  6. temperaturecooled to RT
  7. stirringstirred overnight
  8. filtrationthe reaction mixture was filtered through kieselguhr
  9. washthe residue was washed repeatedly with ethyl acetate and dichloromethane
  10. concentrationthe combined filtrates were concentrated under reduced pressure

Sources & evidence

ORD record
ord-ff244843e1ce4211a7e43049ed52a4e8
Source dataset
uspto-grants-2015_04
Patent number
US09018414B2

Reaction notes

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