反应详情

温度

-78 °C

Tert-Butyl-4-acetylpiperazine-1-carboxylate (3.90 g, 17.1 mmol) is dissolved in anhydrous THF and cooled to −78° C. in nitrogen atmosphere. To this solution is added MeTi(OiPr)3 (1.0 M in THF, 20.5 mL, 20.5 mmol) over a period of 3 min, followed by EtMgBr (3.0 M in Et2O, 22.0 mL, 66.0 mmol) over a period of 7 min. The reaction mixture is allowed to warm to room temperature during which time it changes from a clear red to a viscous black liquid and gas evolution is observed. The flask can be shaken intermittingly to ensure continuous stirring and LCMS analysis can be used to show the absence of the starting amide. Typically, the reaction is complete after 30 min of stirring. The reaction mixture is then carefully diluted with water (20 mL) and a Rochelle salt solution (20% aq., 50 mL). The mixture is stirred vigorously for 15 min, the upper layer liquid decanted off and the precipitate triturated with EtOAc (3×50 mL). The precipitate is then filtered off using a celite plug (10 g) that has been washed well with EtOAc (20 mL). The initially decanted liquid, the triturates and the filtrate are then combined and extracted with EtOAc (4×50 mL). The combined extracts are dried (MgSO4), filtered and concentrated in vacuo to afford the crude product as a clear oil (4.0 g). Column chromatography (250 g SiO2, hexanes-ethyl acetate 4:1, 2 L) affords tert-butyl-4-(1-methylcyclopropyl)piperazine-1-carboxylate as a white solid (2.46 g, 60%). 1H NMR (400 MHz, DMSO-D6) δ ppm 0.29-0.33 (m, 2H), 0.43-0.47 (m, 2H), 0.97 (s, 3H), 1.38 (s, 9H), 2.44-2.48 (m, 4H), 3.17-3.27 (m, 4H); ESI-MS: m/z 229.2 (M+H)+.

1. temperatureto warm to room temperature during which time it
2. stirringto ensure continuous stirring
3. stirringof stirring
4. stirringThe mixture is stirred vigorously for 15 min
5. customthe upper layer liquid decanted off
6. customthe precipitate triturated with EtOAc (3×50 mL)
7. filtrationThe precipitate is then filtered off
8. washhas been washed well with EtOAc (20 mL)
9. extractionextracted with EtOAc (4×50 mL)
10. dry with materialThe combined extracts are dried (MgSO4)
11. filtrationfiltered
12. concentrationconcentrated in vacuo
13. customto afford the crude product as a clear oil (4.0 g)