Water → 1'-Benzyl-6-chloro-3H-spiro[2-benzofuran-1,4'-piperidin]-3-one

HRID 270048Notes

Reaction equation

HRID 270048 reaction equation
Br[C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:12]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O.C(OCC)C>O1CCCC1.CCCCCC.C([Li])CCC>[CH2:12]([N:19]1[CH2:24][CH2:23][C:22]2([C:2]3[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=3[C:4](=[O:5])[O:6]2)[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1

Participants

8

Reactant 4

HCID 962WaterHCID 3283Diethyl EtherHCID 192201-Benzyl-4-piperidoneHCID 331262-Bromo-4-chlorobenzoic acid

Product 1

HCID 122130471'-Benzyl-6-chloro-3H-spiro[2-benzofuran-1,4'-piperidin]-3-oneYield 37.2%

Reagents, catalysts & solvents 3

HCID 8028TetrahydrofuranSolvent2×HCID 8058HexaneSolventHCID 178418339ButyllithiumSolvent

Conditions

Temperature
-78 °C

Procedure

To a solution of 2-bromo-4-chlorobenzoic acid (2.35 g, 10.0 mmol) in tetrahydrofuran (THF) (15 mL) was added, a 1.6 M solution in hexane, n-butyllithium (Parham, W. E; Egberg, D. C.; Sayed, Y. A; Thraikill, R. W; Keyser, G. E; William, M. N; Montgomery, M. C; Jones, L. D., J. Org. Chem., 1976, 41, 2628-2633) (20 mL, 32.0 mmol) slowly at −78° C. under nitrogen. After addition was complete the reaction mixture was stirred at −78° C. for 3 hours (h). Then a solution of 1-benzylpiperidin-4-one (3.78 g, 20.0 mmol) in THF (10 mL) was added slowly to the reaction mixture at −78° C. After addition was complete the reaction temperature was raised to room temperature and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into a mixture of water (H2O) (60 mL) and diethyl ether (60 mL), layers were separated. The aqueous layer was extracted with diethyl ether (2×20 mL). The aqueous layer was acidified with aq 6 M HCl to pH 2 and boiled for 1 h, cooled to 0° C., pH was adjusted to 10 by addition of aqueous sodium hydroxide (NaOH) (6M) and rapidly extracted with trichloromethane (CHCl3). The organic layer was washed with H2O, dried over sodium sulphate (Na2SO4), filtered and concentrated in vacuo to give sub-titled compound (1.22 g) and it was pure enough for the next step.

Workup

  1. customslowly at −78° C.
  2. additionAfter addition
  3. additionAfter addition
  4. temperaturewas raised to room temperature
  5. stirringthe reaction mixture was stirred at room temperature overnight
  6. customwere separated
  7. extractionThe aqueous layer was extracted with diethyl ether (2×20 mL)
  8. waitboiled for 1 h
  9. temperaturecooled to 0° C.
  10. additionpH was adjusted to 10 by addition of aqueous sodium hydroxide (NaOH) (6M)
  11. extractionrapidly extracted with trichloromethane (CHCl3)
  12. washThe organic layer was washed with H2O
  13. dry with materialdried over sodium sulphate (Na2SO4)
  14. filtrationfiltered
  15. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-6f3b5c0078254db7b218495532b5c691
Source dataset
uspto-grants-2008_11
Patent number
US07449475B2

Reaction notes

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