反应详情

4-Nitrobenzoyl chloride (93 g, 0.50 mol) and malononitrile (33 g, 0.50 mol) were dissolved in toluene (400 mL) and THF (70 mL) in a flask equipped with an addition funnel, a thermometer, a stir bar, and argon atmosphere. The flask was immersed in a −30° C. bath. When the internal temperature reached −10° C., DIPEA (129 g, 1.0 mol) in 300 mL of toluene was added dropwise over 40 min. After an additional 1 hr, the bath was removed. After ca. 14 hr, the mixture had 2 layers. The bottom layer was concentrated in vacuo, dissolved in 400 mL of EtOAc, washed with 10% aqueous citric acid (2×250 mL), dried over Na2SO4, and concentrated in vacuo. The residue was mostly dissolved in THF (100 mL) and left 30 min in a freezer. The resulting solid was collected with the aid of additional freezer-cold THF and pressed well with rubber dam. The isolated solid (60 g) was suspended in 1 M H2SO4, collected, pressed, and washed with water. After drying, the solid weighed 36 g. This solid was dissolved in EtOAc (400 mL), washed with 1 M H2SO4 (200 mL) and water (200 mL), filtered through phase separation paper, and concentrated. The solid residue was reconcentrated successively from dichloromethane and toluene and dried at high vacuum. At this stage, 25 g were isolated. The HPLC purity was 94%. Analysis of a 60 MHz NMR spectrum showed about 18 mol % DIPEA. The material was used in the next step without further purification. Another 15 g portion of solid of 95% HPLC purity but containing 30 mol % DIPEA was eventually isolated from the THF filtrate. This material was set aside. The estimated overall yield of the reaction was about 42% NMR (60 MHz) (CDCl3) δ 8.0 (AB, 4H)

1. customwas immersed in a −30° C.
2. customreached −10° C.
3. customthe bath was removed
4. waitAfter ca. 14 hr
5. concentrationThe bottom layer was concentrated in vacuo
6. dissolutiondissolved in 400 mL of EtOAc
7. washwashed with 10% aqueous citric acid (2×250 mL)
8. dry with materialdried over Na2SO4
9. concentrationconcentrated in vacuo
10. dissolutionThe residue was mostly dissolved in THF (100 mL)
11. waitleft 30 min in a freezer
12. customThe resulting solid was collected with the aid of additional freezer-cold THF
13. customcollected
14. washwashed with water
15. customAfter drying
16. dissolutionThis solid was dissolved in EtOAc (400 mL)
17. washwashed with 1 M H2SO4 (200 mL) and water (200 mL)
18. filtrationfiltered through phase separation paper
19. concentrationconcentrated
20. customdried at high vacuum
21. customAt this stage, 25 g were isolated
22. customThe material was used in the next step without further purification
23. additionAnother 15 g portion of solid of 95% HPLC purity but containing 30 mol % DIPEA
24. customwas eventually isolated from the THF filtrate