反应详情

温度

-40 °C

4-(tert-Butyldimethylsilyloxymethyl)-pyridine (T. F. Gallagher et al, Bioorganic and Medicinal Chemistry; 1997, 5, 49) (67 g, 0.3 mol) was dissolved in THF (250 ml) and cooled to −40° C. The solution was treated with a 2M solution of lithuim diusopropylamide in THF (200 ml, 0.4 mol) and stirred for 45 minutes maintaining a temperature of −40 to −20° C., before the dropwise addition of 3,4-dichlorobenzaldehyde (55.13 g, 0.32 mol) in THF (250 ml). The mixture was allowed to warm to room temperature then stirred for a further 18 hours. After re-cooling to 0° C. the reaction was quenched with saturated ammonium chloride solution (500 ml), and the resulting two phase mixture separated. The aqueous phase was extracted with ethyl acetate and the combined organics concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate solution, water and brine, dried (MgSO4) and concentrated under reduced pressure to an oil (129 g). The oil was dissolved in THF (300 ml) and a 1M solution of tetrabutylammonium fluoride (360 ml, 0.36 mol) added dropwise. The solution was stirred at room temperature for 45 minutes, then concentrated to an oil under reduced pressure. The oil was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution, water and brine, dried (MgSO4) and evaporated under reduced pressure. The oil was triturated with hexane and the resulting solid filtered and washed with hexane to afford the title compound (67.58 g 79%) as a tan solid; MS(AP+) m/e 284/286/288 [M+H]+.

1. temperaturemaintaining a temperature of −40 to −20° C.
2. temperatureto warm to room temperature
3. stirringthen stirred for a further 18 hours
4. temperatureAfter re-cooling to 0° C. the reaction
5. customwas quenched with saturated ammonium chloride solution (500 ml)
6. customthe resulting two phase mixture separated
7. extractionThe aqueous phase was extracted with ethyl acetate
8. concentrationthe combined organics concentrated under reduced pressure
9. dissolutionThe residue was dissolved in ethyl acetate
10. washwashed with saturated sodium bicarbonate solution, water and brine
11. dry with materialdried (MgSO4)
12. concentrationconcentrated under reduced pressure to an oil (129 g)
13. dissolutionThe oil was dissolved in THF (300 ml)
14. stirringThe solution was stirred at room temperature for 45 minutes
15. concentrationconcentrated to an oil under reduced pressure
16. dissolutionThe oil was dissolved in ethyl acetate
17. washwashed with saturated sodium bicarbonate solution, water and brine
18. dry with materialdried (MgSO4)
19. customevaporated under reduced pressure
20. customThe oil was triturated with hexane
21. filtrationthe resulting solid filtered
22. washwashed with hexane