反应详情

温度

-15 °C

A 22 L 4-neck flask equipped with a mechanical stirrer, thermowell, addition funnel, and N2 inlet was charged with 1-(ethoxyethyl)-4-iodo-1H-pyrazole (20, 700.0 g, 2.63 mol) and THF (5.5 L). The resulting solution was cooled to between −12° C.-−15° C. A solution of 2 M i-PrMgCl in THF (1513 mL, 3.03 mol, 1.15 equiv) was added via an addition funnel over 30 min while maintaining the reaction temperature at <−5° C. and the tan suspension was stirred at <−5° C. for 0.75 hr. The resulting reaction mixture was further cooled to −15° C. and 2-isopropoxy-4,4,5,5-tetramethyl[1,3,2]dioxaborolane (16, 734 g, 805 mL, 3.95 mol, 1.5 equiv) was added rapidly via an addition funnel with the reaction temperature increasing to ˜−5°. [Note: previous work with the analogous TMS-protected pyrazole has shown that slow addition of 2-isopropoxy-4,4,5,5-tetramethyl[1,3,2]dioxaborolane results in a lower yield.] A nearly clear light brown solution was developed followed by reformation of grayish light suspension. The cooling bath was then removed and the reaction mixture was allowed to warm to 16° C. over 0.75 hr. The mixture was poured into 50 L reparatory funnel containing a stirred saturated aqueous NH4Cl solution (4 L). The mixture was diluted with toluene (8 L), heptane (8 L) and H2O (2 L). The aqueous phase was removed and the organic phase was washed with warm (30° C.) H2O (4×3 L) and saturated brine (2×3 L). The organic phase was dried over Na2SO4, and the solvents were removed under reduced pressure. The residual toluene was further removed by co-evaporation with heptane (2 L). The residual oil was transferred to a 4 L beaker using a minimum amount of heptane (100 mL) and scratched to induce crystallization. The solid was filtered, washed with heptane (200 mL) and dried overnight in a vacuum oven at 30-40° C. The filtrate was concentrated under reduced pressure and the residue was allowed to stand overnight. The resulting solid was filtered, washed with heptane (100 mL) and dried overnight in a vacuum oven at 30-40° C. The two crops were combined to afford 1-(ethoxyethyl)-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (19, 596 g, 700 g theoretical, 85.1%) as a white to off-white solid. For 19: 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.09 (s, 1H), 8.58 (s, 1H), 7.62 (s, 1H), 5.55 (q, 1H, J=6.1 Hz), 3.37 (dq, 1H, J=7.1, 9.6 Hz), 3.12 (dq, 1H, J=7.0, 9.7 Hz), 1.56 (d, 3H, J=6.0 Hz), 1.24 (s, 12H), 1.00 (t, 3H, J=7.0 Hz); C13H23BN2O3 (MW, 266.14), LCMS (EI) m/e 267 (M++H).

1. customA 22 L 4-neck flask equipped with a mechanical stirrer
2. additionthermowell, addition funnel, and N2 inlet
3. temperatureThe resulting solution was cooled to between −12° C.-−15° C
4. temperaturewhile maintaining the reaction temperature at <−5° C.
5. customThe resulting reaction mixture
6. temperatureincreasing to ˜−5°
7. customresults in
8. customa lower yield
9. customThe cooling bath was then removed
10. temperatureto warm to 16° C. over 0.75 hr
11. additionThe mixture was poured into 50 L reparatory funnel
12. additioncontaining a stirred saturated aqueous NH4Cl solution (4 L)
13. additionThe mixture was diluted with toluene (8 L), heptane (8 L) and H2O (2 L)
14. customThe aqueous phase was removed
15. washthe organic phase was washed
16. temperaturewith warm (30° C.) H2O (4×3 L) and saturated brine (2×3 L)
17. dry with materialThe organic phase was dried over Na2SO4
18. customthe solvents were removed under reduced pressure
19. customThe residual toluene was further removed by co-evaporation with heptane (2 L)
20. customcrystallization
21. filtrationThe solid was filtered
22. washwashed with heptane (200 mL)
23. customdried overnight in a vacuum oven at 30-40° C
24. concentrationThe filtrate was concentrated under reduced pressure
25. waitto stand overnight
26. filtrationThe resulting solid was filtered
27. washwashed with heptane (100 mL)
28. customdried overnight in a vacuum oven at 30-40° C