反应详情

温度

-78 °C

To a solution of (R)-1-benzyl-3-cyanopyrrolidine (10 g, 53.4 mmol) in anhydrous ether (200 mL) was added Ti(OiPr)4 (17.2 mL, 58.8 mmol) and the resulting solution was cooled to −78° C. EtMgBr (3.0 M in Et2O, 35 mL, 105 mmol, Aldrich) was added drop-wise during a period of 40 min at −78° C. Anhydrous THF* (50 mL) was added to the resultant yellow suspension to facilitate stirring and the solution was stirred for 20 min at −78° C. The reaction mixture was allowed slowly to warm up to room temperature, then BF3-Et2O (13.4 mL, 107 mmol) was added and the resultant dark brown suspension was stirred at room temperature for 2 hrs. Both 1N HCl (100 mL) and Et2O (200 mL) were introduced subsequently to the reaction mixture and stirring was kept for 20 min until both organic and aqueous phases became clear. It was basified using aqueous 20% NaOH (100 mL) and stirred for 30 min. The organic phase was separated and the aqueous phase was extracted with Et2O (2×100 mL). The combined organic phase was dried over Na2SO4 and concentrated under reduced pressure to give (R)-1-(1-benzyl-pyrrolidin-3-yl)-cyclopropylamine as brown oil (10.5 g, 90%), which was vacuum distilled to give a colorless liquid (9 g, 77%). The product is sufficiently pure to use in next step. For characterization, a small amount of sample was purified by PTLC using solvent NH4OH/MeOH/CH2Cl2 (1/60/340): [α]23 −10.0° (c=2.5, MeOH); 1H NMR (400 MHz, CDCl3) δ 7.33-7.23 (m, 5H), 3.62 (d, JAB=12.8 Hz, 1H), 3.56 (d, JAB=12.8 Hz, 1H), 2.66-2.57 (m, 3H), 2.40-2.37 (m, 1H), 1.96-1.91 (m, 2H), 1.69-1.62 (m, 1H), 0.55-0.48 (m, 2H), 0.41-0.36 (m, 2H).

1. stirringthe solution was stirred for 20 min at −78° C
2. temperatureto warm up to room temperature
3. stirringthe resultant dark brown suspension was stirred at room temperature for 2 hrs
4. stirringstirring
5. stirringstirred for 30 min
6. customThe organic phase was separated
7. extractionthe aqueous phase was extracted with Et2O (2×100 mL)
8. dry with materialThe combined organic phase was dried over Na2SO4
9. concentrationconcentrated under reduced pressure