Reaction #67630

Reaction equation

sodium chlorodifluoroacetate

Compound 1005

2-chloro-3-hydroxypyridine

water

potassium carbonate

2-chloro-3-hydroxypyridine

sodium chlorodifluoroacetate

potassium carbonate

→

2-chloro-3-(difluoromethoxy)pyridine

Yield 72.0%

Solvents

DMF

Conditions

Workup

1. 1
   Temperatureheating
2. 2
   TemperatureAfter this time, the reaction was cooled
3. 3
   Otherthe volatiles removed under reduced pressure
4. 4
   OtherThe residue was partitioned between brine and ethyl acetate
5. 5
   Washthe organics washed once more with brine
6. 6
   Dryingdried over Na2SO4
7. 7
   Filtrationfiltered
8. 8
   Otherthe volatiles removed under reduced pressure
9. 9
   OtherThe product was purified by silica gel chromatography
10. 10
    Washeluting with a hexanes/DCM to DCM gradient

Procedure

As shown in step 3-i of Scheme 3, 2-chloro-3-hydroxypyridine (Compound 1005, 2.0 g, 15.4 mmol, obtained from Aldrich Chemical Co.) was dissolved in 40 mL of DMF and 5.0 mL of water along with sodium chlorodifluoroacetate (4.71 g, 30.9 mmol, obtained from Lancaster Synthesis, Inc.) and anhydrous potassium carbonate (2.56 g; 18.5 mmol). The reaction mixture was heated in an oil bath at 100° C. for 2 hours. Another equivalent of sodium chlorodifluoroacetate and 1.2 equiv. of potassium carbonate were added and heating continued for an additional 2.0 hours. After this time, the reaction was cooled and the volatiles removed under reduced pressure. The residue was partitioned between brine and ethyl acetate and the organics washed once more with brine, dried over Na2SO4, filtered, and the volatiles removed under reduced pressure. The product was purified by silica gel chromatography, eluting with a hexanes/DCM to DCM gradient, to produce 2-chloro-3-(difluoromethoxy)pyridine as a white solid (Compound 1006, 2.0 g, 72% yield): ESMS (M+H) 180; 1H NMR (CDCl3) δ 8.05 (m, 1H), 7.45 (m, 1H), 6.90 (m, 1H), 6.60 (t, 1H; J=75 Hz), 4.01 (s, 3H).

Source