反应详情

温度

-78 °C

Dimethyl zinc (117 mL, 2.0 M in toluene, 234 mmol) was added to an oven-dried and nitrogen-purged 500 mL round bottom flask with stir bar. Isobutylmagnesium bromide (103 mL, 2.0 M in ether, 206 mmol) was added over 5 min with stirring and the solution was allowed to stir at room temperature for 30 minutes. (S)-2-Methyl-propane-2-sulfinic acid 1-[2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-meth-(E)-ylideneamide (48.83 g, 137.4 mmol) was placed in an oven dried nitrogen-purged 2 L 3-necked flask with addition funnel, overhead stirring, and internal temperature. The solid was dissolved in anhydrous THF (690 mL) and cooled to −78° C. where it was a white suspension. The zincate solution was cannulated into the addition funnel and then added dropwise over 75 min to the sulfinyl imine, maintaining an internal temperature of less than −72° C. The reaction was then allowed to stir at −78° C. as a yellow solution. At 75 min, the reaction was quenched with saturated NH4Cl, adding 100 mL over 45 min, keeping the internal temperature below-70° C. A second 400 mL was then added more quickly (˜20 min), keeping the internal temperature below −47° C. Gas evolution was observed at these higher temperatures indicating perhaps a latency period. Upon adding a final 100 mL, no gas evolution was observed indicating the reaction was quenched. The cold bath was removed, another 300 mL of water was added and the reaction allowed to warm to 5° C. at which point the contents were added to an addition funnel, along with ethyl acetate and some additional water. The layers were separated and the aqueous layer extracted with three additional portions of ethyl acetate. The combined organics were dried over MgSO4. Purification was done on half the material in two batches by silica gel flash chromatography (ethyl acetate/heptane) to give (S)-2-methyl-propane-2-sulfinic acid {(S)-3-methyl-1-[2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-butyl}-amide (38.83 g, 68%) as a yellow solid. 1H NMR (400 MHz, CDCl3, δ): 8.82 (s, 2H) 8.57 (d, J=8.2 Hz, 2H) 7.75 (d, J=8.4 Hz, 2H) 4.49 (q, J=7.2 Hz, 1H) 3.44 (d, J=5.7 Hz, 1H) 1.99 (dt, J=13.9, 7.3 Hz, 1H) 1.51-1.77 (m, 2H) 1.24 (s, 9H) 0.99 (d, J=6.6 Hz, 3H) 0.95 (d, J=6.4 Hz, 3H); MS (M+1): 414.3.

1. customan oven-dried
2. customnitrogen-purged 500 mL round bottom flask
3. stirringwith stirring
4. stirringto stir at room temperature for 30 minutes
5. customdried nitrogen-purged 2 L 3-necked flask
6. additionwith addition funnel
7. stirringoverhead stirring
8. dissolutionThe solid was dissolved in anhydrous THF (690 mL)
9. additionadded dropwise over 75 min to the sulfinyl imine
10. temperaturemaintaining an internal temperature of less than −72° C
11. stirringto stir at −78° C. as a yellow solution
12. customthe reaction was quenched with saturated NH4Cl
13. additionadding 100 mL over 45 min
14. custom70° C
15. additionA second 400 mL was then added more quickly (˜20 min)
16. customthe internal temperature below −47° C
17. waitindicating perhaps a latency period
18. additionUpon adding a final 100 mL
19. customwas quenched
20. customThe cold bath was removed
21. additionanother 300 mL of water was added
22. temperatureto warm to 5° C. at which point the contents
23. additionwere added to an addition funnel, along with ethyl acetate
24. customThe layers were separated
25. extractionthe aqueous layer extracted with three additional portions of ethyl acetate
26. dry with materialThe combined organics were dried over MgSO4
27. customPurification