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

HRID 2403648Notes

Reaction equation

HRID 2403648 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, 364 mmol) in a 2 L 3-neck flask fitted with a Dean-Stark trap was added p-toluenesulfonic acid (6.92 g, 36.4 mmol) with stirring. The reaction was heated to 70° C., and 3-buten-2-one (61.8 mL, 753 mmol) was added. The 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. 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 column chromatography (10-80% ethyl acetate/heptanes) to yield an additional 23.6 g of the title compound as a thick brown oil. A combined yield of 91.7 g, (94.1%) was realized. 1H NMR (400 MHz, CDCl3, δ): 7.27-7.43 (m, 5 H), 6.79 (d, J=10.3 Hz, 1 H), 5.95 (d, J=10.3 Hz, 1 H), 5.13 (s, 2 H), 3.56-3.71 (m, 2 H), 3.39-3.55 (m, 2 H), 2.38-2.50 (m, 2 H), 1.96 (t, J=6.7 Hz, 2 H), 1.52-1.70 (m, 4 H).

Workup

  1. temperatureThe mixture was heated
  2. temperatureat reflux for 24 hours
  3. customcollecting
  4. temperatureThe reaction was cooled to room temperature
  5. washwashed with 500 mL saturated aqueous sodium bicarbonate
  6. dry with materialThe organic phase was dried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated
  9. filtrationfiltered through a silica pad (600 mL silica)
  10. washeluting with 2 L heptane
  11. additionFractions containing clean product
  12. concentrationconcentrated

Sources & evidence

ORD record
ord-84cb1acea8464d12bb9b0490bc199535
Source dataset
uspto-grants-2014_08
Patent number
US08802688B2

Reaction notes

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