4-Toluenesulfonyl chloride → (R)-N-(2-(3,3-Diphenyl-2-propen-1-yloxy)ethyl)-3-piperidinecarboxylic acid ethyl ester

HRID 1614805Notes

Reaction equation

HRID 1614805 reaction equation
[C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH2:9][O:10][CH2:11][CH2:12]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[NH:36]1[CH2:41][CH2:40][CH2:39][C@@H:38]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:37]1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[CH2:45]([O:44][C:42]([C@@H:38]1[CH2:39][CH2:40][CH2:41][N:36]([CH2:12][CH2:11][O:10][CH2:9][CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:37]1)=[O:43])[CH3:46]

Participants

8

Reactant 5

HCID 73974-Toluenesulfonyl chlorideHCID 11430Potassium CarbonateHCID 185582ethyl (3R)-piperidine-3-carboxylateHCID 108009482-(3,3-Diphenyl-2-propen-1-yloxy)ethanolHCID 178418339Butyllithium

Product 1

HCID 53658393(R)-N-(2-(3,3-Diphenyl-2-propen-1-yloxy)ethyl)-3-piperidinecarboxylic acid ethyl esterYield 33%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
10 °C

Procedure

A solution of 2-(3,3-diphenyl-2-propen-1-yloxy)ethanol (3.0 g, 11.8 mmol) in dry THF (30 ml) kept under a nitrogen atmosphere was cooled to 10° C. and a solution of n-butyllithium in hexanes (5.0 ml, 2.5 M) was added dropwise. The reaction mixture was stirred for 0.5 h at room temperature and p-toluenesulphonyl chloride (2.3 g, 12.1 mmol) was added. The mixture was stirred at room temperature for 1 h. Ethyl (R)-3-piperidinecarboxylate (2.7 g, 17.7 mmol) and potassium carbonate (2.5 g, 17.7 mmol) were added and the mixture was heated at reflux temperature for 5 h. The cooled reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (2×75 ml). The combined organic phases was washed with water and a sodium citrate buffer solution (2×100 ml, pH 6). The organic phase was then extracted with a 5% citric acid solution (3×75 ml) and the combined acidic aqueous extracts was washed with ethyl acetate (25 ml). To the acidic aqueous solution was added a 4 N sodium hydroxide solution until pH 11 and this solution was immediately extracted with ethyl acetate (3×50 ml). The combined organic extracts was dried over sodium sulphate and the solvent evaporated in vacuo to give 1.5 g (33%) of the title compound as an oil. TLC: rf=0.20 (SiO2 ; n-heptane/THF=7:3). 1H NMR (CDCl3)δ 4.08 (d, 2H); 6.22 (t, 1H).

Workup

  1. stirringThe mixture was stirred at room temperature for 1 h
  2. temperaturethe mixture was heated
  3. temperatureat reflux temperature for 5 h
  4. customThe cooled reaction mixture
  5. extractionextracted with ethyl acetate (2×75 ml)
  6. washThe combined organic phases was washed with water
  7. extractionThe organic phase was then extracted with a 5% citric acid solution (3×75 ml)
  8. washthe combined acidic aqueous extracts was washed with ethyl acetate (25 ml)
  9. additionTo the acidic aqueous solution was added a 4 N sodium hydroxide solution until pH 11
  10. extractionthis solution was immediately extracted with ethyl acetate (3×50 ml)
  11. dry with materialThe combined organic extracts was dried over sodium sulphate
  12. customthe solvent evaporated in vacuo

Sources & evidence

ORD record
ord-ecad0d7781844ea18776a3baa6a7f507
Source dataset
uspto-grants-1993_03
Patent number
US05198451

Reaction notes

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