Water → tert-Butyl 4-(2-(pyridin-3-ylmethoxy)ethyl)piperidine-1-carboxylate

HRID 2095386Notes

Reaction equation

HRID 2095386 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26]Cl)[CH:21]=1.O>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][CH2:26][C:22]2[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

7

Reactant 4

HCID 962WaterHCID 233943-(Chloromethyl)pyridine hydrochlorideHCID 24758Sodium hydrideHCID 8541401-(tert-Butoxycarbonyl)-4-(2-hydroxyethyl)piperidine

Product 1

HCID 59371585tert-Butyl 4-(2-(pyridin-3-ylmethoxy)ethyl)piperidine-1-carboxylateYield 89.6%

Reagents, catalysts & solvents 2

HCID 67553Tetrabutylammonium IodideCatalystHCID 6228DimethylformamideSolvent

Procedure

A solution of 1-(tert-butoxycarbonyl)-4-(2-hydroxyethyl)piperidine (459 mg, 2.0 mmol) in anhydrous DMF (10 mL) was cooled to 0° C., and NaH (60% dispersion in oil, 200 mg, 5 mmol, 2.5 equiv.) was added all at once. Alkoxide formation was effected by stirring at room temperature for 2 h under N2, then 3-picolyl chloride hydrochloride (345 mg, 2.1 mmol, 1.05 equiv.) and tetra-n-butylammonium iodide (7.4 mg, 20 μmol, 0.01 equiv.) were added. The mixture was warmed to 80° C. and stirred at that temperature for 4 h. After cooling to room temperature, H2O was added, and the product was extracted into EtOAc. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by CC (SiO2, EtOAc/hexane 1:1) to afford 1-(tert-butoxycarbonyl)-4-[2-(3-pyridylmethoxy)ethyl]piperidine (574 mg, 80%) after evaporation as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 8.39 (s, 1H), 8.33 (d, 1H, J=4.8 Hz), 7.54 (d, 1H, J=8.0 Hz), 7.11 (m, 1H), 4.71 (s, 2H), 3.89 (m, 2H), 3.46 (t, 2H, J=6.4 Hz), 2.74 (m, 2H), 1.44 (m, 3H), 1.31 (m, 2H), 1.24 (s, 9H), 0.88 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 154.6, 149.1, 149.0, 136.2, 133.2, 123.5, 78.9, 59.2, 42.8, 39.0, 32.3, 31.9, 28.2.

Workup

  1. temperatureThe mixture was warmed to 80° C.
  2. stirringstirred at that temperature for 4 h
  3. temperatureAfter cooling to room temperature
  4. extractionthe product was extracted into EtOAc
  5. dry with materialThe organic layer was dried over Na2SO4
  6. concentrationconcentrated
  7. customThe residue was purified by CC (SiO2, EtOAc/hexane 1:1)

Sources & evidence

ORD record
ord-0b240e72460545b99d7963534847cebc
Source dataset
uspto-grants-2013_05
Patent number
US08445684B2

Reaction notes

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