Ethyl Acetate → methyl (R)-1-(2-phenoxyethyl)piperidine-2-carboxylate

HRID 1476743Notes

Reaction equation

HRID 1476743 reaction equation
[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([O:9][CH3:10])=[O:8].C([O-])([O-])=O.[K+].[K+].Br[CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCOC(C)=O>CN(C=O)C>[O:20]([CH2:19][CH2:18][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([O:9][CH3:10])=[O:8])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1

Participants

6

Reactant 4

HCID 8857Ethyl AcetateHCID 11430Potassium CarbonateHCID 68526Benzene, (2-bromoethoxy)-HCID 7408456methyl (R)-piperidine-2-carboxylate

Product 1

HCID 52294458methyl (R)-1-(2-phenoxyethyl)piperidine-2-carboxylateYield 64%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
100 °C

Procedure

Dissolve methyl (R)-piperidine-2-carboxylate (5.00 g, 34.9 mmol) in DMF (87 mL) and treat with K2CO3 (14.48 g, 104.8 mmol) and β-bromophenetole (7.16 g, 34.9 mmol). Stir the mixture overnight at 100° C. Cool the mixture to room temperature and add EtOAc (250 mL). Wash the organic phase with water (4×100 mL) and saturated aqueous NaCl (100 mL). Dry the organic phase over K2CO3, filter to remove the solids, and concentrate the filtrate under reduced pressure to furnish a yellow oil. Subject this crude material to flash chromatography on silica gel eluting with a gradient of 20% to 100% EtOAc/hexanes. Concentrate the fractions containing the desired product under reduced pressure to furnish the title compound as a colorless oil in ca. 90% purity by 1H NMR analysis (6.50 g, 64% yield). Mass spectrum (m/z) 264 (M+H)+. 1H NMR (400 MHz, CDCl3): δ 7.27 (dd, J=8.5, 7.3 Hz, 2H), 6.93 (t, J=7.3 Hz, 1H), 6.88 (d, J=8.8 Hz, 2H), 4.10 (app t, J=6.1 Hz, 2H), 3.72 (s, 3H), 3.29 (dd, J=8.4, 4.0 Hz, 1H), 3.14 (app dt, J=11.3, 6.4 Hz, 1H), 2.95 (app dt, J=13.7, 6.1 Hz, 1H), 2.89 (app dt, J=13.7, 6.1 Hz, 1H), 2.42 (ddd, J=11.6, 7.9, 3.7 Hz, 1H), 1.90-1.82 (m, 1H), 1.79 (app td, J=8.9, 3.8 Hz, 1H), 1.67-1.59 (m, 3H), 1.39 (app td, J=8.8, 4.0 Hz, 1H).

Workup

  1. temperatureCool the mixture to room temperature
  2. washWash the organic phase with water (4×100 mL) and saturated aqueous NaCl (100 mL)
  3. dry with materialDry the organic phase over K2CO3
  4. filtrationfilter
  5. customto remove the solids
  6. concentrationconcentrate the filtrate under reduced pressure
  7. customto furnish a yellow oil
  8. concentrationConcentrate the fractions
  9. additioncontaining the desired product under reduced pressure

Sources & evidence

ORD record
ord-e90f454a6c3443d2a7575c19289d91bc
Source dataset
uspto-grants-2016_08
Patent number
US09402838B2

Reaction notes

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