反应详情

温度

0 °C

A solution of diisopropylamine (98.85 g, 136.9 mL, 976.9 mmol) in THF (1.350 L) was cooled to −65° C. n-BuLi (2.5 M in hexanes) (375.8 mL of 2.5 M, 939.4 mmol) was added dropwise via cannula over 1 h at such a rate as to maintain reaction temperature below −60° C. Once the addition was complete the cooling bath was removed and the reaction mixture was allowed to warm up to 0° C. The reaction mixture was stirred for 15 min at 0° C., then re-cooled to −78° C. 2,3,5-trifluoropyridine (100 g, 751.5 mmol) was added dropwise via cannula over 20 min at such a rate to maintain the reaction temperature below −69° C. The reaction mixture was stirred for 45 min at −78° C. during which time the solution turned orange brown. A solution of tert-butyl-chloro-dimethyl-silane (147.2 g, 976.9 mmol) in THF (150 mL) was then added via cannula over 30 min. The reaction mixture was stirred at −78° C. for 90 minutes during which time the solution darkened. Lc/Ms after this time indicated that the reaction was complete. A saturated ammonium chloride solution (300 ml) was then added and mixture was allowed to warm up to RT. The reaction mixture was diluted with water (100 ml) and extracted with EtOAc (1.5 L then 2×500 ml). The combined organics were washed with saturated NaHCO (500 ml) and brine (400 ml). The crude mixture was partially concentrated in vacuo, dried over magnesium sulfate, filtered and concentrated in vacuo to an oil. The crude was purified by flash chromatography (CombiFlash Companion XL, 1.5 kg column, 0-20% ethyl acetate in petroleum ether). This afforded the title compound as a colourless oil (136.2 g, 73%); 1H NMR (CDCl3) 0.34 (6H, s), 0.89 (9H, s), 7.73 (1H, s); MS ES(+) 248.25 (M+1).

1. additionwas added dropwise via cannula over 1 h at such a rate as
2. temperatureto maintain
3. customreaction temperature below −60° C
4. additionOnce the addition
5. customwas removed
6. temperaturere-cooled to −78° C
7. temperatureto maintain the reaction temperature below −69° C
8. stirringThe reaction mixture was stirred for 45 min at −78° C. during which time the solution
9. stirringThe reaction mixture was stirred at −78° C. for 90 minutes during which time the solution
10. temperatureto warm up to RT
11. extractionextracted with EtOAc (1.5 L
12. washThe combined organics were washed with saturated NaHCO (500 ml) and brine (400 ml)
13. concentrationThe crude mixture was partially concentrated in vacuo
14. dry with materialdried over magnesium sulfate
15. filtrationfiltered
16. concentrationconcentrated in vacuo to an oil
17. customThe crude was purified by flash chromatography (CombiFlash Companion XL, 1.5 kg column, 0-20% ethyl acetate in petroleum ether)