Reaction #1747899

Reaction equation

paraformaldehyde

2-methoxy-4-methylpyridine

n-BuLi

→

4-(2-hydroxyethyl)-2-methoxypyridine

Yield 51.0%

Solvents

THF

Conditions

Workup

1. 1
   Temperaturewarmed slowly to 0° C.
2. 2
   workup.STIRRINGstirred at 0° C. for 30 min
3. 3
   Otherwas recooled to −78° C.
4. 4
   TemperatureThe mixture was warmed slowly to room temperature
5. 5
   workup.STIRRINGstirred at room temperature for 8 h
6. 6
   OtherThe reaction was quenched by addition of saturated aq. NH4Cl
7. 7
   Extractionextracted with EtOAc (150 mL×3)
8. 8
   WashThe combined organic layers were washed with brine
9. 9
   Dryingdried (MgSO4)
10. 10
    Concentrationconcentrated
11. 11
    OtherThe residue was purified by chromatography with hexane/EtOAc (2:1)

Procedure

To a stirred solution of 2-methoxy-4-methylpyridine (6 g, 49 mmol) in anhydrous THF (200 mL) at −78° C. under nitrogen was added dropwise 29.4 mL (73.5 mmol) of n-BuLi (2.5 M solution in hexanes). The mixture was stirred at −78° C. for 1 h, and then warmed slowly to 0° C. and stirred at 0° C. for 30 min. The mixture was recooled to −78° C. and paraformaldehyde (10 g) was added in one portion. The mixture was warmed slowly to room temperature and stirred at room temperature for 8 h. The reaction was quenched by addition of saturated aq. NH4Cl and extracted with EtOAc (150 mL×3). The combined organic layers were washed with brine, dried (MgSO4), and concentrated. The residue was purified by chromatography with hexane/EtOAc (2:1) to afford 4-(2-hydroxyethyl)-2-methoxypyridine as a colorless oil (3.8 g, 51%). 1H NMR (CDCl3) δ 8.06 (d, 1H, J=5.1 Hz), 6.77 (d, 1H, J=5.1 Hz), 6.62 (s, 1H), 3.92 (s, 3H), 3.87 (t, 2H, J=6.6 Hz), 2.81 (t, 2H, J=6.6 Hz), 1.98 (br s, 1H); 13C NMR (CDCl3) δ 164.48, 150.63, 146.71, 117.76, 110.91, 62.43, 53.34, 38.30. MS m/z (%): 153 (M, 73), 152 (100), 123 (48).

Source