反应详情

温度

-25 °C

To a 1.0 Molar solution of potassium t-butoxide in tetrahydrofuran (3000 mL, 3.000 moles) was added diisopropylamine (425 mL, 306.8 g, 3.032 moles). The resulting solution was cooled by a dry ice/acetone bath to −50° C. n-Butyllithium solution (980 mL of 2.5 Molar, 2.450 moles) was added drop wise over a period of 40 minutes, giving a bright orange solution. The mixture was allowed to stir for an additional 20 minutes at −25° C., then was cooled back down to −55° C. 2-isopropylpyridine (1) (240.0 g, 1.981 moles) was then added drop wise over a period of 20 minutes while maintaining the internal temperature between −50° C. to −55° C., giving a deep, reddish-purple solution. The mixture was allowed to stir for an additional 2 hours at −50° C., then was used directly in the next step. To the cooled (−50° C.) mixture containing the 2-Isopropylpyridyl anion was added a solution of (R,E)-N-benzylidene-2-methylpropane-2-sulfinamide (2) (360.0 g, 1.720 moles) in anhydrous tetrahydrofuran (3000 mL), drop wise over a period of 3 hours while maintaining the internal temperature between −50° C. and −55° C. The reaction mixture was allowed to warm gradually over 3 hours to 0° C., then checked for completion by working up an aliquot and checking by HPLC. The reaction was quenched by treatment with saturated sodium bicarbonate solution (3000 mL), added drop wise over 20 minutes. After stirring for an additional 30 minutes, the mixture was further diluted with water (3000 mL), and divided into three portions (˜4500 mL each). Each portion was partitioned with ethyl acetate (1000 mL), and the layers separated. The combined aqueous layer was further extracted with ethyl acetate (3×1000 mL). The combined organic extracts were washed with saturated brine (1500 mL), then dried (anhydrous magnesium sulfate). Filtration, followed by removal of the solvent under reduced pressure, left the crude product as a cream-colored solid (575.8 g, 101.3% crude yield), which was a 9:1 mixture of diastereomers. The crude material was recrystallized from a mixture of Hexane/EtOAc (2:1) to give pure desired single diastereomer (371.9 g, 65.4% yield). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 8.62 (dd, J=4.85, 1.05 Hz, 1 H) 7.52 (td, J=7.80, 2.11 Hz, 1H) 7.09-7.19 (m, 4 H) 6.99 (d, J=8.01 Hz, 1 H) 6.85-6.94 (m, 2 H) 5.80 (d, J=8.01 Hz, 1 H) 4.49 (d, J=8.43 Hz, 1 H) 1.46 (s, 3 H) 1.33 (s, 3 H) 1.10 (s, 9 H). MS: m/z 331.

1. additionwas added drop wise over a period of 40 minutes
2. customgiving a bright orange solution
3. temperaturewas cooled back down to −55° C
4. temperaturewhile maintaining the internal temperature between −50° C. to −55° C.
5. customgiving a deep, reddish-purple solution
6. stirringto stir for an additional 2 hours at −50° C.
7. temperatureTo the cooled (−50° C.) mixture
8. waitdrop wise over a period of 3 hours
9. temperaturewhile maintaining the internal temperature between −50° C. and −55° C
10. temperatureto warm gradually over 3 hours to 0° C.
11. customThe reaction was quenched by treatment with saturated sodium bicarbonate solution (3000 mL)
12. additionadded drop wise over 20 minutes
13. stirringAfter stirring for an additional 30 minutes
14. additionthe mixture was further diluted with water (3000 mL)
15. customEach portion was partitioned with ethyl acetate (1000 mL)
16. customthe layers separated
17. extractionThe combined aqueous layer was further extracted with ethyl acetate (3×1000 mL)
18. washThe combined organic extracts were washed with saturated brine (1500 mL)
19. dry with materialdried (anhydrous magnesium sulfate)
20. filtrationFiltration
21. customfollowed by removal of the solvent under reduced pressure
22. waitleft the crude product as a cream-colored solid (575.8 g, 101.3% crude yield), which
23. additiona 9:1 mixture of diastereomers
24. customThe crude material was recrystallized from a mixture of Hexane/EtOAc (2:1)
25. customto give pure desired single diastereomer (371.9 g, 65.4% yield)