Hydrochloric Acid → 1-Benzyl-3,3-dimethylpiperidin-4-one

HRID 1760616Notes

Reaction equation

HRID 1760616 reaction equation
C=O.[CH2:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][CH:12](C)[C:13](=[O:15])C.Cl.C=O.[CH2:20](N)C1C=CC=CC=1.C(N([CH:34]([CH3:36])[CH3:35])CC)(C)C.[OH-].[K+]>C(O)C.O>[CH2:3]([N:10]1[CH2:11][CH2:12][C:13](=[O:15])[C:34]([CH3:35])([CH3:36])[CH2:20]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1

Participants

10

Reactant 7

HCID 313Hydrochloric AcidHCID 712Formaldehyde2×HCID 7504BenzylamineHCID 112513-Methyl-2-butanoneHCID 14797Potassium HydroxideHCID 81531DiisopropylethylamineHCID 8659040590367-39-8

Product 1

HCID 97944131-Benzyl-3,3-dimethylpiperidin-4-one

Reagents, catalysts & solvents 2

HCID 702EthanolSolvent2×HCID 962WaterSolvent

Conditions

Temperature
10 °C

Procedure

In a 1 liter 3-neck flask equipped with a mechanical stirrer, an addition funnel and a calcium chloride drying tube was added a 37% weight solution of formaldehyde (168.5 mL, 2.25 mole) dissolved in 500 mL of absolute ethanol. The resulting solution was cooled in an ice-water bath to 10° C., and benzylamine (109 mL, 1 mole) was added dropwise over a one hour period. In a separate 3-liter 3-neck flask equipped with a mechanical stirrer, an addition funnel and two condensers was added 3-methyl-2-butanone (113 mL, 1.06 mole) dissolved in 500 ml of absolute ethanol and concentrated hydrogen chloride (92 mL, 1.11 mole). The resulting solution was brought to reflux and the formaldehyde/benzylamine solution is added dropwise over a 2 hour period. This solution was heated at reflux overnight, and then cooled to ambient temperature. Diisopropylethylamine (142.2 g, 1.1 mole) and formaldehyde (22.46 mL, 0.3 mole) were added and the resulting solution was heated to reflux for six hours, and then cooled to ambient temperature. The solution was quenched with potassium hydroxide (61.6 g, 1.1 mole) in 200 mL of water, and then extracted 3 times with 500 ml ethyl acetate. The organic layers were concentrated under vacuum to give 225 g of a red oil. The crude oil was dissolved in 1 liter of methylene chloride. This solution was carefully poured over 1 kg of silica gel on a sintered glass filter. The silica gel was washed with 4 L of methylene chloride. The methylene chloride was concentrated under vacuum to provide 142 g of a yellow oil which was crystallized in a freezer overnight. Yield=65.4%. MS(ion spray)=218.3(M+1)

Workup

  1. customIn a 1 liter 3-neck flask equipped with a mechanical stirrer, an addition funnel and a calcium chloride drying tube
  2. customIn a separate 3-liter 3-neck flask equipped with a mechanical stirrer, an addition funnel
  3. temperatureto reflux
  4. temperatureThis solution was heated
  5. temperatureat reflux overnight
  6. temperaturecooled to ambient temperature
  7. temperaturethe resulting solution was heated
  8. temperatureto reflux for six hours
  9. temperaturecooled to ambient temperature
  10. extractionextracted 3 times with 500 ml ethyl acetate
  11. concentrationThe organic layers were concentrated under vacuum

Sources & evidence

ORD record
ord-17b1600d42ff4edf9153200217b9b973
Source dataset
uspto-grants-2005_01
Patent number
US06844344B2

Reaction notes

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