Ammonium Chloride → (S)-6-(5-fluoro-2-methylphenyl)-6-methyl-4-trifluoromethylhept-1-yn-4-ol

HRID 2387303Notes

Reaction equation

HRID 2387303 reaction equation
[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C@:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[Li].[F-].[CH2:22]([N+](CCCC)(CCCC)CCCC)[CH2:23]CC.[Cl-].[NH4+]>CS(C)=O.C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C@@:10]([C:13]([F:16])([F:15])[F:14])([OH:11])[CH2:12][C:22]#[CH:23])[CH:7]=1

Participants

8

Reactant 4

HCID 25517Ammonium ChlorideHCID 2724141Tetrabutylammonium FluorideHCID 3028194LithiumHCID 11701812(R)-2-[2-(5-Fluoro-2-methylphenyl)-2-methylpropyl]-2-trifluoromethyloxirane

Product 1

HCID 58026173(S)-6-(5-fluoro-2-methylphenyl)-6-methyl-4-trifluoromethylhept-1-yn-4-olYield 65.2%

Reagents, catalysts & solvents 3

HCID 679Dimethyl SulfoxideSolventHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of (R)-2-[2-(5-fluoro-2-methylphenyl)-2-methylpropyl]-2-trifluoromethyloxirane (18.5 g, 67.0 mmol) in 200 mL of anhydrous DMSO was added lithium trimethylsilylacetylide (0.5 M in THF, 201 mL, 101 mmol). The resulting brown solution was stirred at room temperature for 5 hours. The reaction mixture was poured into 500 mL of water and extracted with three 500 mL portions of 10% ethyl acetate/hexanes. The combined organic phases were washed with two 500 mL portions of water and one 500 mL portion of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was redissolved in 200 mL of THF and cooled to 0° C. A solution of tetrabutylammonium fluoride (1.0 M in THF, 67.0 mL, 67.0 mmol) was added over 5 minutes. The reaction mixture was stirred for 1 hour, poured into 150 mL of saturated aqueous ammonium chloride solution, and extracted with three 300 mL portions of diethyl ether. The combined organic phases were washed with 300 mL of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography with silica gel (eluted with 0%-3% EtOAc/hexanes) afforded (S)-6-(5-fluoro-2-methylphenyl)-6-methyl-4-trifluoromethylhept-1-yn-4-ol as a yellow oil (13.2 g, 65%).

Workup

  1. extractionextracted with three 500 mL portions of 10% ethyl acetate/hexanes
  2. washThe combined organic phases were washed with two 500 mL portions of water and one 500 mL portion of brine
  3. dry with materialdried over magnesium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. dissolutionThe crude material was redissolved in 200 mL of THF
  7. temperaturecooled to 0° C
  8. stirringThe reaction mixture was stirred for 1 hour
  9. extractionextracted with three 300 mL portions of diethyl ether
  10. washThe combined organic phases were washed with 300 mL of brine
  11. dry with materialdried over magnesium sulfate
  12. filtrationfiltered
  13. concentrationconcentrated in vacuo
  14. customPurification by column chromatography with silica gel (eluted with 0%-3% EtOAc/hexanes)

Sources & evidence

ORD record
ord-38f27e14002841d28203a944b1f3447c
Source dataset
uspto-grants-2012_09
Patent number
US08268859B2

Reaction notes

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