反应详情

温度

-70 °C

A suspension of 231 g (1.06 moles) of 1-6 in 11 L of THF in a 20 L jacketed reactor was stirred vigorously with overhead stirring for 1 h, then cooled to −70° C. To this suspension was added dropwise 1.28 L (1.28 moles) of a 1M solution of NaHMDS in THF. After stirring for 3 h, 478.9 g (1.28 moles) of solid N-phenylbis(trifluoro-methanesulphonimide) was added, followed by an additional 1.5 h of stirring, before being quenched by the addition of 2 L of a saturated aqueous NH4Cl solution. After the solution reached room temperature, 2 L of water and 2 L of EtOAc were added, the layers were separated, and the aqueous layer was extracted with 2 L of EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated by rotary evaporation. The residue was dissolved in 6 L of DME and 1.2 L of water in a 20 L jacketed reactor with overhead stirring, and the solution was degassed with a strong flow of N2 for 1 h. To the reactor was then added 201.6 g (1.28 moles) of 2,5-difluorophenylboronic acid, 134 g (3.19 moles) of LiCl, 338 g (3.19 moles) of Na2CO3, and 24.6 g (21 mmol) of tetrakis(triphenylphospine)palladium(O), and the reaction was heated at 90° C. for 2 h. Following this period of time, approximately 4.5 L of DME was distilled off, the remaining solution was cooled to room temperature, and dumped into 6 L of water and 8 L of CH2Cl2. The layers were separated, the aqueous layer was extracted with 2 L of CH2Cl2, the organic layers were combined, washed with 4 L of water, dried over Na2SO4 and concentrated by rotary evaporation to provide a dark red solid mass. This residue was swished with 500 mL of CHCl3, and filtered to provide a tan solid. The filtrate was concentrated to ˜300 mL and a second crop of solid was collected, combined with the first crop, and the combined material was swished with 500 mL of EtOAc overnight. This suspension was filtered to provide an off-white solid, the filtrate was concentrated to ˜250 mL and a second crop was collected, combined with the first crop, and the combined material (˜205 g) was recrystallized from 1.6 L of EtOAc to provide 1-7 as a white solid. Data for 1-7: 1HNMR (500 MHz, CDCl3) δ 7.5-7.3 (mn, 5H), 7.1-6.9 (m, 3H), 6.8 (s, 1H), 4.9 (d, 1H), 4.75 (d, 1H), 4.5 (d, 1H), 4.25 (d, 1H) ppm. HRMS (ES) calc'd M+H for C18H13F2NO2: 314.0987. Found: 314.0993.

1. stirringstirring for 1 h
2. stirringAfter stirring for 3 h
3. stirringof stirring
4. custombefore being quenched by the addition of 2 L of a saturated aqueous NH4Cl solution
5. customreached room temperature
6. addition2 L of water and 2 L of EtOAc were added
7. customthe layers were separated
8. extractionthe aqueous layer was extracted with 2 L of EtOAc
9. washThe combined organic layers were washed with brine
10. dry with materialdried over Na2SO4
11. concentrationconcentrated by rotary evaporation
12. dissolutionThe residue was dissolved in 6 L of DME
13. customthe solution was degassed with a strong flow of N2 for 1 h
14. temperaturethe reaction was heated at 90° C. for 2 h
15. distillationwas distilled off
16. temperaturethe remaining solution was cooled to room temperature
17. customThe layers were separated
18. extractionthe aqueous layer was extracted with 2 L of CH2Cl2
19. washwashed with 4 L of water
20. dry with materialdried over Na2SO4
21. concentrationconcentrated by rotary evaporation
22. customto provide a dark red solid mass
23. filtrationfiltered
24. customto provide a tan solid
25. concentrationThe filtrate was concentrated to ˜300 mL
26. customa second crop of solid was collected
27. customwas swished with 500 mL of EtOAc overnight
28. filtrationThis suspension was filtered
29. customto provide an off-white solid
30. concentrationthe filtrate was concentrated to ˜250 mL
31. customa second crop was collected
32. customthe combined material (˜205 g) was recrystallized from 1.6 L of EtOAc