Water → 1'-benzyl-5-chloro-3H-spiro[isobenzofuran-1,4'-piperidin]-3-one

HRID 270091Notes

Reaction equation

HRID 270091 reaction equation
Br[C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([Li])CCC.[CH2:17]([N:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>O1CCCC1.CCCCCC.C(OCC)C>[CH2:17]([N:24]1[CH2:29][CH2:28][C:27]2([C:2]3[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=3[C:4](=[O:5])[O:6]2)[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1

Participants

8

Reactant 4

HCID 962WaterHCID 192201-Benzyl-4-piperidoneHCID 890272-Bromo-5-chlorobenzoic acidHCID 178418339Butyllithium

Product 1

HCID 598336431'-benzyl-5-chloro-3H-spiro[isobenzofuran-1,4'-piperidin]-3-oneYield 37.2%

Reagents, catalysts & solvents 3

HCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolvent2×HCID 8058HexaneSolvent

Conditions

Temperature
-78 °C

Procedure

To a solution of 2-bromo-5-chlorobenzoic acid (2.35 g, 10.0 mmol) in tetrahydrofuran (THF) (15 mL) was added, a 1.6 M solution in hexane, n-butyllithium (20 mL, 32.0 mmol) slowly at −78° C. under nitrogen. After addition was complete the reaction mixture was kept on stirring at −78° C. for 3 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 kept on stirring at room temperature overnight. The reaction mixture was poured into a mixture of water (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 aqueous 6M hydrochloric acid (HCl) to pH 2 and boiled for 1 h, cooled to 0° C., pH was adjusted to 10.0 by addition of aqueous sodium hydroxide (NaOH) (6M) and rapidly extracted with trichloromethane (CHCl3). The organic layer was washed with water, dried over sodium sulphate (Na2SO4), filtered and concentrated in vacuo to give the subtitled 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. stirringon stirring 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 10.0 by addition of aqueous sodium hydroxide (NaOH) (6M)
  11. extractionrapidly extracted with trichloromethane (CHCl3)
  12. washThe organic layer was washed with water
  13. dry with materialdried over sodium sulphate (Na2SO4)
  14. filtrationfiltered
  15. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-c939a2f578e8451881a916358a2d0398
Source dataset
uspto-grants-2008_11
Patent number
US07449475B2

Reaction notes

Loading…