p-Toluenesulfonic acid → 2-chloro-4-((tetrahydro-2H-pyran-2-yloxy)methyl)pyridine

HRID 517557Notes

Reaction equation

HRID 517557 reaction equation
[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1.[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1.CC1C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][O:10]2)[CH:5]=[CH:4][N:3]=1

Participants

5

Reactant 3

HCID 6101p-Toluenesulfonic acidHCID 80803,4-dihydro-2H-pyranHCID 7062237(2-Chloropyridin-4-yl)methanol

Product 1

HCID 860901042-chloro-4-((tetrahydro-2H-pyran-2-yloxy)methyl)pyridineYield 78.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a mixture of (2-chloropyridin-4-yl)methanol (7.0 g, 48.8 mmol) and 3,4-dihydro-2H-pyran (20.5 g, 244 mmol) in THF (80 mL), 4-methylbenzenesulfonic acid (840 mg, 4.88 mmol) was added. The reaction mixture was stirred at reflux overnight, and the solvent was removed under reduced pressure. The residue was diluted with H2O (200 mL), and the aqueous phase was extracted with EtOAc (3×200 mL). The combined organic layers were washed with H2O (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated to afford the crude product, which was purified by silica gel column chromatography (Petroleum ether:EtOAc=4:1) to afford 2-chloro-4-((tetrahydro-2H-pyran-2-yloxy)methyl)pyridine as a yellow oil (8.7 g, 78%). MS (ES+) C11H14ClNO2 requires: 227, found: 228[M+H]+.

Workup

  1. additionwas added
  2. temperatureat reflux overnight
  3. customthe solvent was removed under reduced pressure
  4. additionThe residue was diluted with H2O (200 mL)
  5. extractionthe aqueous phase was extracted with EtOAc (3×200 mL)
  6. washThe combined organic layers were washed with H2O (20 mL) and brine (20 mL)
  7. dry with materialdried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customto afford the crude product, which
  11. customwas purified by silica gel column chromatography (Petroleum ether:EtOAc=4:1)

Sources & evidence

ORD record
ord-2a70c0d3ac074bcca5a60b9ad87a5d77
Source dataset
uspto-grants-2015_08
Patent number
US09115120B2

Reaction notes

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