Diethyl (cyanomethyl)phosphonate → 1-(tert-Butoxycarbonyl)-3-(cyanomethylene)azetidine

Participants

Reaction Conditions

Reaction Steps

Diethyl cyanomethyl phosphonate (745 g, 4.20 mol, 1.20 eqiv) and anhydrous THF (9 L) was added to a four-neck flask equipped with thermowell, addition funnel and nitrogen protection tube. The solution was cooled with an ice-methanol bath to −14° C. and a 1.0 M solution of t-BuOK in THF (3.85 L, 3.85 mol, 1.1 equiv) was added over 20 min keeping the temperature<−5° C. The mixture was stirred for 3 hr at −10° C. and a solution of 1-tert-butoxycarbonyl-3-azetidinone (1, 600 g, 3.50 mol) in THF (2 L) was added over 2 hr while keeping the reaction temperature<−5° C. The reaction mixture was stirred at −5 to −10° C. over 1 hr and then slowly warmed up to room temperature and stirred at room temperature for overnight. The reaction mixture was then diluted with water (4.5 L) and saturated brine (4.5 L) and extracted with ethyl acetate (2×9 L). The combined organic layers were combined and washed with brine (6 L), dried over anhydrous Na2SO4. The organic solvent was removed under reduced pressure, diluted with dichloromethane (4 L) and adsorbed onto silica gel (1.5 kg). The product was purified by flash column chromatography (SiO2, 3.5 kg×2), each column was eluted with (8 L of heptane, 8 L of 5% AcOEt/heptane, 12 L of 10% AcOEt/heptane, 40 L of 25% AcOEt/heptane) to give the pure tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (2, 414.7 g, 679.8 g theoretical, 61% yield) as white solid. For 2: 1H NMR (300 MHz, CDCl3) δ 1.46 (s, 9H), 4.62 (m, 2H), 4.72 (m, 2H), 5.41 (m, 1H).

Provenance & Evidence