3,3-Difluoroazetidine hydrochloride (5.60 mmol, 0.726 g) was dissolved in dichloromethane/methanol (20 mL; 1/1) and 15 g Si-Carbonate (Silicycle, Loading 0.7 mmol/g) was added. After 20 minutes this slurry was put on a column with 7 g of Si-Carbonate (Silicycle, Loading 0.7 mmol/g) and eluated with dichloromethane/methanol (40 mL; 1/1). The solution was concentrated (900 mbar, bath 45 deg) to a volume of 30 mL. To this solution N-((3-chloropyrazin-2-yl)methyl)-4-oxocyclohexanecarboxamide (3.74 mmol, 1 g), acetic acid (0.1 mL) and sodium cyanoborohydride (7.47 mmol, 0.469 g) were added and the reaction mixture stirred at room temperature. After 3 days the reaction mixture was concentrated, dichloromethane added and washed with aqueous sodium hydrogencarbonate and water. Both aqueous layers were extracted four times with dichloromethane. The combined organic extracts were dried (sodium sulfate) and concentrated in vacuo. Purification by column chromatography (silica gel, gradient heptanes/ethyl acetate 2/1 to ethyl acetate) yielded (trans)-N-((3-chloropyrazin-2-yl)methyl)-4-(3,3-difluoroazetidin-1-yl)cyclohexanecarboxamide (0.47 g) and (cis)-N-((3-chloropyrazin-2-yl)methyl)-4-(3,3-difluoroazetidin-1-yl)cyclohexanecarboxamide (0.49 g).
