2,2,2-Trifluoroethyl trifluoromethanesulfonate → 5-(2,3-Difluorophenyl)-1-(2,2,2-trifluoroethyl)piperidin-2-one

HRID 1481820Notes

Reaction equation

HRID 1481820 reaction equation
[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][NH:13][C:12](=[O:15])[CH2:11][CH2:10]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O([CH2:34][C:35]([F:38])([F:37])[F:36])S(C(F)(F)F)(=O)=O>C1COCC1.CN1C(=O)CCC1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][N:13]([CH2:34][C:35]([F:38])([F:37])[F:36])[C:12](=[O:15])[CH2:11][CH2:10]1

Participants

6

Reactant 3

HCID 803662,2,2-Trifluoroethyl trifluoromethanesulfonateHCID 2733832Lithium HexamethyldisilazideHCID 687484265-(2,3-Difluorophenyl)piperidin-2-one

Product 1

HCID 687471945-(2,3-Difluorophenyl)-1-(2,2,2-trifluoroethyl)piperidin-2-one

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
0 °C

Procedure

To a stirred solution of 5-(2,3-difluorophenyl)piperidin-2-one (8.88 g, 42 mmol) in THF (250 mL) and NMP (170 mL) at 0° C. was added lithium bis(trimethylsilyl)amide (1.0 M in THF, 48 mL, 48 mmol) over 5 min, keeping the internal temperature of the reaction mixture below 5° C. The resulting mixture was stirred at 0° C. for 15 min, then 2,2,2-trifluoroethyl triflate (11.2 g, 48 mmol) was added dropwise, keeping the internal temperature of the reaction mixture below 5° C. The reaction mixture was allowed to warm slowly to ambient temperature and stirring was continued for 3 h. The resulting mixture was partitioned between saturated aqueous sodium bicarbonate (800 mL) and EtOAc (1 L). The organic layer was removed and the aqueous phase was extracted further with EtOAc (500 mL). The combined organic extracts were washed with water, then brine, then dried over sodium sulfate, filtered, and concentrated to dryness in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc—100:0 to 0:100, to give the title compound. MS: m/z=293.9 (M+1).

Workup

  1. customthe internal temperature of the reaction mixture below 5° C
  2. customthe internal temperature of the reaction mixture below 5° C
  3. temperatureto warm slowly to ambient temperature
  4. stirringstirring
  5. waitwas continued for 3 h
  6. customThe resulting mixture was partitioned between saturated aqueous sodium bicarbonate (800 mL) and EtOAc (1 L)
  7. customThe organic layer was removed
  8. extractionthe aqueous phase was extracted further with EtOAc (500 mL)
  9. washThe combined organic extracts were washed with water
  10. dry with materialbrine, then dried over sodium sulfate
  11. filtrationfiltered
  12. concentrationconcentrated to dryness in vacuo
  13. customThe crude product was purified by silica gel chromatography
  14. washeluting with a gradient of hexanes

Sources & evidence

ORD record
ord-6209d42f106d4762ab9402dfb3128952
Source dataset
uspto-grants-2016_08
Patent number
US09409916B2

Reaction notes

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