反应详情

温度

115 °C

A mixture of 2-chloro-3-fluoro-4-trifluoromethylpyridine (3.50 g, 17.5 mmol), benzophenone imine (3.50 g, 19.3 mmol), palladium(II) acetate (0.158 g, 0.70 mmol), caesium carbonate (8.00 g, 24.6 mmol) and BINAP (0.66 g, 1.05 mmol) was suspended in toluene (35 ml) and degassed with nitrogen for 1 h. The mixture was then heated at 115° C. for 18 h. The mixture was allowed to cool to ambient temperature, diluted with toluene (100 ml) and the organic phase was washed with water (100 ml) and brine (100 ml), dried over anhydrous sodium sulphate, filtered and evaporated to give an orange oil. The oil was dissolved in propan-2-ol (60 ml), 5N hydrochloric acid (10 ml) added and the mixture heated at 50° C. for 30 min. The mixture was cooled to ambient temperature and solid sodium hydrogencarbonate (7.14 g, 85 mmol) added portionwise over 10 min, followed by addition of chloroacetaldehyde (2.75 g, 35.08 mmol). On complete addition the mixture was heated at 95° C. for 24 h. The mixture was allowed to cool to ambient temperature, filtered through a glass microfibre filter paper, the solid washed with ethanol (30 ml) and the filtrate evaporated. The residue was diluted with ethyl acetate (200 ml) and extracted with 5N hydrochloric acid (2×75 ml). The organics were filtered and then washed with ethyl acetate (2×100 ml). The aqueous phase was then made basic by the addition of solid sodium hydrogen-carbonate and extracted with ethyl acetate (2×150 ml). The organics were washed with brine (100 ml), dried over anhydrous sodium sulphate, filtered and evaporated to give a brown oil. The oil was purified by flash column chromatography on silica eluting with dichloromethane on a gradient of methanol (0-2%). Collecting appropriate fractions gave 8-fluoro-7-trifluoromethylimidazo[1,2-α]pyridine (1.5 g, 42%) as a pale yellow solid: δH (360 MHz, CDCl3) 6.92 (1H, dd, J 7 and 7), 7.75 (1H, d, J 3), 7.80 (1H, d, J 3), 8.04 (1H, d, J 7).

1. customdegassed with nitrogen for 1 h
2. temperatureto cool to ambient temperature
3. additiondiluted with toluene (100 ml)
4. washthe organic phase was washed with water (100 ml) and brine (100 ml)
5. dry with materialdried over anhydrous sodium sulphate
6. filtrationfiltered
7. customevaporated
8. customto give an orange oil
9. temperaturethe mixture heated at 50° C. for 30 min
10. temperatureThe mixture was cooled to ambient temperature
11. additionOn complete addition the mixture
12. temperaturewas heated at 95° C. for 24 h
13. temperatureto cool to ambient temperature
14. filtrationfiltered through a glass microfibre
15. filtrationfilter paper
16. washthe solid washed with ethanol (30 ml)
17. customthe filtrate evaporated
18. additionThe residue was diluted with ethyl acetate (200 ml)
19. extractionextracted with 5N hydrochloric acid (2×75 ml)
20. filtrationThe organics were filtered
21. washwashed with ethyl acetate (2×100 ml)
22. additionThe aqueous phase was then made basic by the addition of solid sodium hydrogen-carbonate
23. extractionextracted with ethyl acetate (2×150 ml)
24. washThe organics were washed with brine (100 ml)
25. dry with materialdried over anhydrous sodium sulphate
26. filtrationfiltered
27. customevaporated
28. customto give a brown oil
29. customThe oil was purified by flash column chromatography on silica eluting with dichloromethane on a gradient of methanol (0-2%)
30. customCollecting appropriate fractions