Ethyl propiolate → (2S,3R)-3-(Ethoxycarbonylethynyl)-3-hydroxy-2-phenylpiperidine

HRID 1976073Notes

Reaction equation

HRID 1976073 reaction equation
C([Li])CCC.[C:6]([O:10][CH2:11][CH3:12])(=[O:9])[C:7]#[CH:8].[C:13]1([C@H:19]2[C:24](=[O:25])[CH2:23][CH2:22][CH2:21][NH:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1>[CH2:11]([O:10][C:6]([C:7]#[C:8][C@:24]1([OH:25])[CH2:23][CH2:22][CH2:21][NH:20][C@H:19]1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:9])[CH3:12]

Participants

5

Reactant 3

HCID 12182Ethyl propiolateHCID 9812895(2S)-2-phenyl-3-piperidoneHCID 178418339Butyllithium

Product 1

HCID 70226356(2S,3R)-3-(Ethoxycarbonylethynyl)-3-hydroxy-2-phenylpiperidine

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A solution of n-butyllithium (55.4 ml, 1.4 M in hexanes, 77.6 mmol) was added dropwise to a stirred solution of ethyl propiolate (7.9 ml, 77.7 mmol) in tetrahydrofuran (200 ml), keeping the temperature of the reaction below −65° C. The mixture was stirred for 10 min and a solution of (2S)-2-phenyl-3-piperidone in tetrahydrofuran (50 ml) added dropwise at −72° C. over 15 min. The reaction mixture was stirred at this temperature for 40 min, quenched with acetic acid (10 ml) and warm up to room temperature. Solvent was removed in vacuo. The residue was treated with saturated aqueous NaHCO3 (200 ml) and extracted with ethyl acetate (3×100 ml). The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (210 g, hexane:diethyl ether 5-40%) to afford the product (11.9 g, 83%, 96% ee) as a colourless oil.

Workup

  1. customthe temperature of the reaction below −65° C
  2. stirringThe reaction mixture was stirred at this temperature for 40 min
  3. customquenched with acetic acid (10 ml)
  4. customSolvent was removed in vacuo
  5. additionThe residue was treated with saturated aqueous NaHCO3 (200 ml)
  6. extractionextracted with ethyl acetate (3×100 ml)
  7. dry with materialThe combined organic extracts were dried (Na2SO4)
  8. concentrationconcentrated
  9. customThe residue was purified by chromatography on silica gel (210 g, hexane:diethyl ether 5-40%)
  10. customto afford the product (11.9 g, 83%, 96% ee) as a colourless oil

Sources & evidence

ORD record
ord-136287b8ace64e6598ba8ab65426d5e5
Source dataset
uspto-grants-2001_05
Patent number
US06225320B1

Reaction notes

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