Allyl bromide → (5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-1-((S)-1-hydroxybutan-2-yl)piperidin-2-one

HRID 932142Notes

Reaction equation

HRID 932142 reaction equation
[Si]([O:18][CH2:19][C@@H:20]([N:23]1[C@H:28]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[C@@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[CH2:26][CH:25]([CH2:43][CH3:44])[C:24]1=[O:45])[CH2:21][CH3:22])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:46]([N-]C(C)C)([CH3:48])[CH3:47].[Li+].C(Br)C=C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C1(C)C=CC=CC=1>[CH2:48]([C:25]1([CH2:43][CH3:44])[CH2:26][C@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[C@@H:28]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)[N:23]([C@@H:20]([CH2:21][CH3:22])[CH2:19][OH:18])[C:24]1=[O:45])[CH:46]=[CH2:47]

Participants

7

Reactant 4

HCID 7841Allyl bromideHCID 2724141Tetrabutylammonium FluorideHCID 2724682Lithium diisopropylamideHCID 67998674(5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethylpiperidin-2-one

Product 1

HCID 67998816(5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-1-((S)-1-hydroxybutan-2-yl)piperidin-2-one

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
0 °C

Procedure

(5R,6S)-1-((S)-1-(Tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethylpiperidin-2-one (421 mg, 0.639 mmol; Example 202, Step A) was azeotroped with toluene (3×). THF (1.6 mL) was added. The mixture was sparged with argon for 5 minutes and then cooled to 0° C. 1.0 M lithium diisopropylamide solution in THF (1.246 mL, 1.246 mmol) was added dropwise. After 25 minutes, allyl bromide (0.166 mL, 1.917 mmol) was added dropwise. After 20 minutes, the mixture was quenched with sat. aq. NH4Cl solution. The mixture was extracted with ethyl acetate. The organic layer was washed with sat. aq. NaCl solution, dried over Na2SO4, and concentrated. The residue was dissolved in THF (3 mL) and 1.0M tetrabutylammonium fluoride solution in THF (2.335 mL, 2.335 mmol) was added. After stirring overnight, the mixture was partitioned between 5% aq. HCl and ethyl acetate. The organic layer was washed with sat. aq. NaCl solution, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography on silica gel (eluent: 20 to 50% ethyl acetate/hexanes) to afford the title compound as the more polar major diastereomer.

Workup

  1. customThe mixture was sparged with argon for 5 minutes
  2. waitAfter 20 minutes
  3. customthe mixture was quenched with sat. aq. NH4Cl solution
  4. extractionThe mixture was extracted with ethyl acetate
  5. washThe organic layer was washed with sat. aq. NaCl solution
  6. dry with materialdried over Na2SO4
  7. concentrationconcentrated
  8. dissolutionThe residue was dissolved in THF (3 mL)
  9. customthe mixture was partitioned between 5% aq. HCl and ethyl acetate
  10. washThe organic layer was washed with sat. aq. NaCl solution
  11. dry with materialdried over Na2SO4
  12. concentrationconcentrated
  13. customThe residue was purified by flash chromatography on silica gel (eluent: 20 to 50% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-a3152625ed874388ad29f2ac47bd2950
Source dataset
uspto-grants-2016_03
Patent number
US09296736B2

Reaction notes

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