Ethyl Acetate → 2-(1-(Ethylsulfonyl)azetidin-3-ylidene)acetonitrile

Participants

Reaction Steps

tert-Butyl 3-(cyanomethylene)azetidine-1-carboxylate (2, 1000 g, 5.2 mol) was diluted with acetonitrile (7 L) and 3 N aqueous HCl (7 L). This resulting reaction mixture was stirred at room temperature for 18 h. When TLC showed the reaction was deemed complete, the reaction mixture was concentrated under reduced pressure. The residual solids were then suspended in acetonitrile (12 L) and cooled to 5° C. Diisopropyethyl amine (2.7 L, 15. 6 mol, 3 equiv) was slowly added to the suspension while keeping the temperature<15° C. The homogeneous solution was allowed to cool to 5° C. and ethanesulfonyl chloride (730 mL, 7.73 mol, 1.5 equiv) was added over 1 h while keeping the reaction temperature<15° C. The resulting solution was allowed to slowly warm to room temperature and stirred at room temperature for overnight. The additional amount of ethanesulfonyl chloride (100 ml, 1.05 mol, 0.2 equiv) was added and the reaction mixture was stirred for an additional 2 h at room temperature. After the reaction was deemed complete, the reaction mixture was concentrated under reduced pressure to a volume of about 4 L. This solution was then placed in a 50 L separatory funnel, diluted with dichloromethane (10 L) and washed with half saturated brine (10 L). The aqueous phase was extracted with dichloromethane (5 L). The combined organic layers were dried over sodium sulphate and absorbed onto silica gel (1 Kg) under reduced pressure. The material was then loaded onto a silica gel column (2.5 Kg) and eluted with 20% ethyl acetate in heptane (40 L), 40% ethyl acetate in heptane (80 L) and finally 60% ethyl acetate in heptane (40 L) to afford pure 2-(1-(ethylsulfonyl)azetidin-3-ylidene)acetonitrile (4, 567 g, 968.4 g theoretical, 58.6% yield) as a off-white solid. For 4: 1H NMR (300 MHz, CDCl3) δ 1.38 (t, 3H), 3.05 (q, 2H), 4.72 (m, 2H), 4.79 (m, 2H), 5.41 (m, 1H); MS: m/z calcd. 187.05; found: 187.1.

Provenance & Evidence