Acetic Acid → 3-Azido-6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-2-one

HRID 406567Notes

Reaction equation

HRID 406567 reaction equation
C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][CH:12]1[N:17]([CH2:18][C:19]([F:22])([F:21])[F:20])[C:16](=[O:23])[CH2:15][CH2:14][CH:13]1[C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[C:25]=1[F:32].C(C1C=C(C(C)C)C=C(C(C)C)C=1S([N:51]=[N+:52]=[N-:53])(=O)=O)(C)C.CC(O)=O.C(=O)(O)[O-].[Na+]>C1COCC1>[N:51]([CH:15]1[CH2:14][CH:13]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[C:25]=2[F:32])[CH:12]([CH3:11])[N:17]([CH2:18][C:19]([F:22])([F:20])[F:21])[C:16]1=[O:23])=[N+:52]=[N-:53]

Participants

7

Reactant 5

HCID 176Acetic AcidHCID 3717072,4,6-Triisopropylbenzenesulfonyl azideHCID 516892Sodium BicarbonateHCID 2733832Lithium HexamethyldisilazideHCID 866652096-Methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-2-one

Product 1

HCID 866652103-Azido-6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-2-one

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
-78 °C

Procedure

To a stirred solution of lithium bis(trimethylsilyl)amide (1.0 M in THF, 36 mL, 36 mmol) in THF (180 mL) at −78° C. was added a cold (−78° C.) solution of (5S,6R & 5R,6S)-6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-2-one (9.68 g, 29.8 mmol) in THF (100+20 mL) dropwise, keeping the internal temperature of the reaction mixture below −65° C. The resulting mixture was stirred at −78° C. for 30 min, then a cold (−78° C.) solution of 2,4,6-triisopropylbenzenesulfonyl azide (Harmon et al. (1973) J. Org. Chem. 38, 11-16) (11.97 g, 38.7 mmol) in THF (100 mL) was added dropwise, keeping the internal temperature of the reaction mixture below −65° C. The reaction mixture was stirred at −78° C. for 45 min, then AcOH (7.8 mL, 140 mmol) was added. The resulting mixture was allowed to warm slowly to ambient temperature and was poured into saturated aqueous sodium bicarbonate (750 mL) and the mixture was extracted with CH2Cl2 (2×750 mL). The combined organic layers were washed with 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:Et2O—100:0 to 0:100, to give the title compound. MS: m/z=367.1 (M+1).

Workup

  1. customthe internal temperature of the reaction mixture below −65° C
  2. customthe internal temperature of the reaction mixture below −65° C
  3. stirringThe reaction mixture was stirred at −78° C. for 45 min
  4. temperatureto warm slowly to ambient temperature
  5. extractionthe mixture was extracted with CH2Cl2 (2×750 mL)
  6. washThe combined organic layers were washed with brine
  7. dry with materialdried over sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated to dryness in vacuo
  10. customThe crude product was purified by silica gel chromatography
  11. washeluting with a gradient of hexanes

Sources & evidence

ORD record
ord-a981faa28022426d95a2562240f2eb44
Source dataset
uspto-grants-2014_06
Patent number
US08754096B2

Reaction notes

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