Chloromethyl Methyl Ether → 2-Methoxy-5-(methoxymethoxy)pyridine

HRID 1847948Notes

Reaction equation

HRID 1847948 reaction equation
[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[H-].[Na+].[CH3:12][O:13][CH2:14]Cl>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][CH2:12][O:13][CH3:14])=[CH:7][N:8]=1

Participants

5

Reactant 3

HCID 7864Chloromethyl Methyl EtherHCID 24758Sodium hydrideHCID 116223355-Hydroxy-2-methoxypyridine

Product 1

HCID 120277842-Methoxy-5-(methoxymethoxy)pyridineYield 89.3%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
2.5 °C

Procedure

To a solution of 6-methoxypyridin-3-ol (20 g, 0.16 mol) in DMF (200 mL) was added NaH (60% in mineral oil; 9.6 g, 0.24 mol) at 0-5° C. portion-wise. Upon the completion of addition, the mixture was continued to stir at 0-5° C. for 15 min followed by additional of chloromethyl methyl ether. The mixture was stirred at 0-5° C. for another 20 min and quenched with aqueous NH4Cl(sat.). The aqueous layer was extracted with EtOAc (3×100 mL) and the combined organic layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified on silica gel with 25% EtOAc/hexanes as eluent to give 2-methoxy-5-(methoxymethoxy)pyridine (24.1 g, 89.3%) as a colorless oil. 1H NMR (400 MHz; CDCl3) 7.97 (d, 1H), 7.35 (dd, 1H), 6.70 (d, 1H), 5.12 (s, 2H), 3.91 (s, 3H), 3.51 (s, 3H); MS (ESI) m/z 170.1 [M+H]+.

Workup

  1. additionUpon the completion of addition
  2. stirringThe mixture was stirred at 0-5° C. for another 20 min
  3. customquenched with aqueous NH4Cl(sat.)
  4. extractionThe aqueous layer was extracted with EtOAc (3×100 mL)
  5. washthe combined organic layer was washed with water and brine
  6. dry with materialdried over Na2SO4
  7. concentrationconcentrated under reduced pressure
  8. customThe residue was purified on silica gel with 25% EtOAc/hexanes as eluent

Sources & evidence

ORD record
ord-d257feb73b9f4acc97e2052f0898db4e
Source dataset
uspto-grants-2015_02
Patent number
US08952171B2

Reaction notes

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