Hydrochloric Acid → 1-Carbethoxy-4-[2-(1-methylethoxy)phenyl]-4-piperidinol

HRID 865931Notes

Reaction equation

HRID 865931 reaction equation
BrCCBr.Br[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH:13]([CH3:15])[CH3:14].[C:16]([N:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1)([O:18][CH2:19][CH3:20])=[O:17].Cl>CCOCC>[C:16]([N:21]1[CH2:22][CH2:23][C:24]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:12][CH:13]([CH3:15])[CH3:14])([OH:27])[CH2:25][CH2:26]1)([O:18][CH2:19][CH3:20])=[O:17]

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 78391,2-DibromoethaneHCID 34767Ethyl 4-oxo-1-piperidinecarboxylateHCID 219254271-Bromo-2-[(propan-2-yl)oxy]benzene

Product 1

HCID 105188151-Carbethoxy-4-[2-(1-methylethoxy)phenyl]-4-piperidinolYield 91.7%

Reagents, catalysts & solvents 1

HCID 3283Diethyl EtherSolvent2×

Conditions

Temperature
22 °C

Procedure

To a suspended solution of Mg chips (10.07 g, 0.414 mol) in anhydrous ether (150 mL) at 22° C. under argon was added ca. 0.15 mL of 1,2-dibromoethane. Then 43.7 g (0.200 mol) of XIV in 200 mL of ether was added dropwise. After 50% of the aryl halide was added, the reaction began to reflux vigorously. The flask was cooled in an ice bath. After the refluxing had subsided somewhat, the ice bath was removed and the remaining aryl halide was added over a 1.5 h period. The resultant Grignard reagent was cooled in a dry ice/ether bath for 2 h and then treated with 34.0 mL (0.221 mol) of 98% 1-carbethoxy-4-piperidone. Upon complete addition of ketone, the reaction mixture was allowed to warm to 22° C. and stirred for 2 h. The reaction was then quenched with cold aqueous ammonium chloride which resulted in an emulsion. Addition of 1M aqueous HCl solution separated the two layers. The aqueous phase was extracted with additional ether and the combined organic solution was washed with 10% aqueous sodium bisulfite, 1.0M HCl, saturated NaHCO3, and dried (K2CO3). Filtration concentration yielded 56.36 g of XV as a yellow viscous oil which was carried on without further purification The structure of this oil was supported by 1H NMR.

Workup

  1. temperatureto reflux vigorously
  2. temperatureThe flask was cooled in an ice bath
  3. customthe ice bath was removed
  4. additionthe remaining aryl halide was added over a 1.5 h period
  5. temperatureThe resultant Grignard reagent was cooled in a dry ice/ether bath for 2 h
  6. customThe reaction was then quenched with cold aqueous ammonium chloride which
  7. customresulted in an emulsion
  8. customseparated the two layers
  9. extractionThe aqueous phase was extracted with additional ether
  10. washthe combined organic solution was washed with 10% aqueous sodium bisulfite, 1.0M HCl, saturated NaHCO3
  11. dry with materialdried (K2CO3)
  12. filtrationFiltration concentration

Sources & evidence

ORD record
ord-c6f1d52043954f619d674aa736199be5
Source dataset
uspto-grants-1996_10
Patent number
US05569659

Reaction notes

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