1-(3,5-Bis(trifluoromethyl)phenyl)ethan-1-one → (alphaR)-alpha-Methyl-3,5-bis(trifluoromethyl)benzenemethanol

HRID 1836804Notes

Reaction equation

HRID 1836804 reaction equation
[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:13](=[O:15])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>[Ru].CC(O)C>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:4]=[C:5]([C@H:13]([OH:15])[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1

Participants

4

Reactant 1

HCID 1216161-(3,5-Bis(trifluoromethyl)phenyl)ethan-1-one

Product 1

HCID 2779031(alphaR)-alpha-Methyl-3,5-bis(trifluoromethyl)benzenemethanolYield 75%

Reagents, catalysts & solvents 2

HCID 23950RutheniumCatalystHCID 3776IsopropanolSolvent

Procedure

The ruthenium salt [RuCl2(P-Cymene)]2 and (S,R)-cis-aminoindanol were added to IPA at RT and aged 0.5 h. The solution generally turned bright yellow-orange over the age period. 1-(3,5-Bis(trifluoromethyl)phenyl)ethan-1-one was added and the reaction was degassed under vacuum. Base was then added and the reaction was aged until >98% complete by HPLC (4-6h). The reaction was then quenched by pouring it into 1 N HCl and extracted with heptane (2×10.5 L) and washed with 15 L brine. 1,4-Diazabicyclo[2.2.2]octane (DABCO) was added and the solution was concentrated to a volume of ˜4 mL/g of alcohol. At this point the KF was less than 200 and less than 5% IPA remains. The reaction can be flushed with additional heptane if these criteria are not met. Optionally, the reaction was seeded with the DABCO complex at 40° C. and the reaction was allowed to slowly cool to RT. Crystallization began to occur immediately. The reaction was then cooled to 0° C. and filtered. The cake was washed with cold heptane. The DABCO complex was isolated in 75-80% yield with an enantiomeric excess of >99%.

Workup

  1. customthe reaction was degassed under vacuum
  2. additionBase was then added
  3. customThe reaction was then quenched
  4. additionby pouring it into 1 N HCl
  5. extractionextracted with heptane (2×10.5 L)
  6. washwashed with 15 L brine
  7. addition1,4-Diazabicyclo[2.2.2]octane (DABCO) was added
  8. concentrationthe solution was concentrated to a volume of ˜4 mL/g of alcohol
  9. customThe reaction
  10. customcan be flushed with additional heptane if these criteria
  11. customwas seeded with the DABCO complex at 40° C.
  12. customCrystallization
  13. temperatureThe reaction was then cooled to 0° C.
  14. filtrationfiltered
  15. washThe cake was washed with cold heptane
  16. customThe DABCO complex was isolated in 75-80% yield with an enantiomeric excess of >99%

Sources & evidence

ORD record
ord-2cb44e396c474201b265d77c50c67b99
Source dataset
uspto-grants-2004_08
Patent number
US06777580B2

Reaction notes

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