反应详情

温度

70 °C

Sodium hydride (6.63 g, 166 mmol, 60% in mineral oil) was washed with hexanes (100 mL) to remove the mineral oil and was then suspended in dry acetonitrile (1500 mL) at room temperature. 3,6-Dimethyl-5-nitropyridin-2-ol (27.9 g, 166 mmol) was added in portions over 30 minutes to give a yellow suspension. During the addition there was some bubbling but negligible temperature change. Cesium fluoride (2.50 g, 16.6 mmol) was then added followed by the slow addition of trimethylsilyl 2-(fluorosulfonyl)difluoroacetate (36.0 mL, 182 mmol) over 30 minutes. During the addition there was some bubbling, the temperature rose from 23° C. to 30° C., and the suspension became noticeably less turbid. After stirring for 15 min, TLC indicated that starting material still remained, so additional trimethylsilyl 2-(fluorosulfonyl)difluoroacetate (6.5 mL, 33 mmol) was added over 10 minutes. After an additional 15 min, TLC indicated consumption of starting material. The reaction was quenched by the addition of water (20 mL) dropwise at such a rate that the bubbling did not become too vigorous. After bubbling ceased, additional water (200 mL) was added. Most of the solvent was removed in vacuo and the aqueous residue was extracted with ethyl acetate (3×200 mL). The combined organic layers were dried over Na2SO4 and evaporated to a brown syrup which solidified upon standing. This residue was dissolved in ethanol (400 mL) and decolorizing charcoal (15 g) was added. The suspension was heated at 70° C. for 20 min and then filtered through a pad of Celite and sand. The filtrate was collected and the solvent was evaporated. The residue was dissolved in methylene chloride and the solution was evaporated to give 2-(difluoromethoxy)-3,6-dimethyl-5-nitropyridine (33.4 g, 92% yield) as a pale yellow solid: mp 51-52° C.; 1H NMR (400 MHz, CDCl3) δ8.21 (s, 1H), 7.55 (t, J=72.0 Hz, 1H), 2.76 (s, 3H), 2.30 (s, 3H). Anal. calcd. for C8H8N2O3F2: C, 44.04; H, 3.69; N, 12.84. Found: C, 43.78; H, 3.55; N, 12.58.

1. customto remove the mineral oil
2. customwas then suspended in dry acetonitrile (1500 mL) at room temperature
3. customto give a yellow suspension
4. additionDuring the addition there
5. additionDuring the addition there
6. customrose from 23° C. to 30° C.
7. waitAfter an additional 15 min
8. customconsumption of starting material
9. customThe reaction was quenched by the addition of water (20 mL) dropwise at such a rate that the bubbling
10. customAfter bubbling
11. additionadditional water (200 mL) was added
12. customMost of the solvent was removed in vacuo
13. extractionthe aqueous residue was extracted with ethyl acetate (3×200 mL)
14. dry with materialThe combined organic layers were dried over Na2SO4
15. customevaporated to a brown syrup which
16. dissolutionThis residue was dissolved in ethanol (400 mL)
17. additionwas added
18. filtrationfiltered through a pad of Celite and sand
19. customThe filtrate was collected
20. customthe solvent was evaporated
21. dissolutionThe residue was dissolved in methylene chloride
22. customthe solution was evaporated