Step 1: Synthesis of (3,3-difluorocyclobutyl)methanol
Sodium borohydride (0.556 g, 14.70 mmol) was suspended in tetrahydrofuran (50 mL) and cooled to 0 °C. The methanol was then added to the mixture of sodium borohydride (0.556 g, 14.70 mmol). Subsequently, a solution of 3,3-difluorocyclobutanecarboxylic acid (2 g, 14.70 mmol) in tetrahydrofuran (50 mL) was added dropwise. After the dropwise addition, the reaction flask was removed from the ice bath and the reaction was stirred for 1 hour at room temperature. After that, the reaction mixture was cooled again to 0 °C and boron trifluoride-ether compound (1.862 mL, 14.70 mmol) was slowly added. The reaction was stirred at 0 °C overnight and gradually warmed up to room temperature. After completion of the reaction, the mixture was cooled again to 0 °C and the reaction was quenched with 95% ethanol (25 mL). After stirring in an ice bath for 1 h, the mixture was concentrated in vacuum. The residue was partitioned with dichloromethane and saturated saline and the organic phase was separated. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to afford the title compound (3,3-difluorocyclobutyl) methanol as a light tan oil (1.629 g, 9% yield).
1H NMR (300 MHz, CDCl3) δ: 2.31-2.38 (m, 3H), 2.60-2.66 (m, 2H), 3.67 (m, 2H); MS (DCI) m/z: 123 (M+H)+.
