p-Toluenesulfonic acid → Benzyl 9-oxo-3-azaspiro(5.5)undec-7-ene-3-carboxylate

HRID 2064271Notes

Reaction equation

HRID 2064271 reaction equation
[CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:30][C:31](=[O:34])[CH:32]=[CH2:33]>C1C=CC=CC=1>[O:34]=[C:31]1[CH2:32][CH2:33][C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH2:5][CH2:4]2)[CH:1]=[CH:30]1

Participants

5

Reactant 3

HCID 6101p-Toluenesulfonic acidHCID 6570Methyl vinyl ketoneHCID 2776272Benzyl 4-formylpiperidine-1-carboxylate

Product 1

HCID 23435732Benzyl 9-oxo-3-azaspiro(5.5)undec-7-ene-3-carboxylateYield 62.5%

Reagents, catalysts & solvents 1

HCID 241BenzeneSolvent

Conditions

Temperature
70 °C

Procedure

To a benzene (700 mL) solution of benzyl 4-formylpiperidine-1-carboxylate (90.0 g, 363.9 mmol) stirring in a 2 L 3-neck flask fitted with a Dean-Stark trap was added p-toluenesulfonic acid (6.92 g, 36.4 mmol). The reaction was heated to 70° C., 3-buten-2-one (61.8 mL, 753 mmol) was added and mixture was heated at reflux for 24 hours collecting expelled water in the trap. The reaction was cooled to room temperature and washed with 500 mL saturated aqueous sodium bicarbonate. The organic phase was dried over sodium sulfate, filtered and concentrated. The resultant dark brown oil was taken up in 200 mL dichloromethane and filtered through a silica pad (600 mL silica), eluting with 2 L heptane followed by 3 L 50% ethyl acetate/heptane and then 3 L ethyl acetate, collecting by 1 L fractions. Fractions containing clean product were combined and concentrated to yield 68.1 g of the title compound as a thick brown oil. The fractions containing impure product were combined and concentrated and purified by flash chromatography (10-80% ethyl acetate/heptane, 340 g silica gel) to yield an additional 23.6 g of the title compound as a thick brown oil. Combined yield of 91.7 g, (94.1%) was realized. 1H NMR (400 MHz, CDCl3) δ ppm 7.27-7.43 (m, 5H), 6.79 (d, J=10.3 Hz, 1H), 5.95 (d, J=10.3 Hz, 1H), 5.13 (s, 2H), 3.56-3.71 (m, 2H), 3.39-3.55 (m, 2H), 2.38-2.50 (m, 2H), 1.96 (t, J=6.7 Hz, 2H), 1.70-1.52 (m, 4H).

Workup

  1. customfitted with a Dean-Stark trap
  2. temperaturemixture was heated
  3. temperatureat reflux for 24 hours
  4. customcollecting
  5. temperatureThe reaction was cooled to room temperature
  6. washwashed with 500 mL saturated aqueous sodium bicarbonate
  7. dry with materialThe organic phase was dried over sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated
  10. filtrationfiltered through a silica pad (600 mL silica)
  11. washeluting with 2 L heptane
  12. custom3 L ethyl acetate, collecting by 1 L fractions
  13. additionFractions containing clean product
  14. concentrationconcentrated

Sources & evidence

ORD record
ord-3dd98aa248af4e4eac7ad7487d441ae9
Source dataset
uspto-grants-2012_10
Patent number
US08288405B2

Reaction notes

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