Toluene → (3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopent-2-enyl)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-methylpiperidin-2-one

HRID 932007Notes

Reaction equation

HRID 932007 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[NH:12][C:11](=[O:21])[C@:10]([CH2:23][CH:24]3[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[O:25]3)([CH3:22])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:31]1([CH3:37])[CH:36]=[CH:35][CH:34]=CC=1.C([Li])CCC.BrC1CCC=C1>CCCCC.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([CH:31]3[CH2:36][CH2:35][CH:34]=[CH:37]3)[C:11](=[O:21])[C@:10]([CH2:23][CH:24]3[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[O:25]3)([CH3:22])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1

Participants

7

Reactant 4

HCID 1140TolueneHCID 111826803-BromocyclopenteneHCID 58573060(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-methylpiperidin-2-oneHCID 178418339Butyllithium2×

Product 1

HCID 58573694(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopent-2-enyl)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-methylpiperidin-2-one

Reagents, catalysts & solvents 2

HCID 8003PentaneSolvent2×HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

To (3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-methylpiperidin-2-one (Example 102, Step B) (0.909 g, 2.027 mmol) was added toluene (15 mL) and the mixture was concentrated under reduced pressure. This step was repeated three times. Inhibitor free THF (20 mL) was added and the solution was cooled to −78° C. Butyllithium in pentane (2.0M) (1.014 mL, 2.027 mmol) was added dropwise and the reaction mixture remained colorless. The reaction mixture warmed to 0° C. and the reaction color turned very light yellow. nBuLi in pentane (2.0M) was added dropwise until the reaction mixture remained bright yellow. The reaction mixture was cooled to −78° C. and freshly prepared 3-bromocyclopent-1-ene (0.4 g, 2.72 mmol) in THF (2 mL) was added dropwise. The reaction mixture was wrapped in foil and warmed to 0° C. The reaction mixture was stirred at 0° C. for 1 h and then at rt for 2 days. The reaction was quenched with sat. NH4Cl and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: 0 to 100% EtOAc in hexanes) to give the title compound as a colorless film.

Workup

  1. concentrationthe mixture was concentrated under reduced pressure
  2. additionInhibitor free THF (20 mL) was added
  3. temperatureThe reaction mixture warmed to 0° C.
  4. temperatureThe reaction mixture was cooled to −78° C.
  5. temperaturewarmed to 0° C
  6. waitat rt for 2 days
  7. customThe reaction was quenched with sat. NH4Cl
  8. extractionextracted with EtOAc
  9. dry with materialThe organic layer was dried over Na2SO4
  10. concentrationconcentrated under reduced pressure
  11. customThe residue was purified by flash chromatography on silica gel (eluent: 0 to 100% EtOAc in hexanes)

Sources & evidence

ORD record
ord-a7fb9b63487e412b8793a6d9057f0056
Source dataset
uspto-grants-2016_03
Patent number
US09296736B2

Reaction notes

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