GENERAL STEPS: 4-Hydroxymethylpiperidine (1.0 g, 8.6 mmol) was dissolved in water (15 mL) and cooled to 0°C. To this solution a solution of potassium carbonate (4.8 g, 34.7 mmol) in water (10 mL) was slowly added dropwise, followed by methyl chloroformate (2.68 mL, 34.7 mmol). The reaction mixture was stirred vigorously and gradually warmed to room temperature over 2 hours. After continued stirring for 16 hours, the reaction mixture was acidified with 6 M aqueous hydrochloric acid and subsequently extracted with dichloromethane (3 x 60 mL). The organic phases were combined, dried over sodium sulfate, filtered and the solvent evaporated to give methyl 4-(hydroxymethyl)piperidine-1-carboxylate (1.4 g, 8.1 mmol, 93% yield) as a colorless oil. Mass spectrum (m/z): C8H15NO3 calculated value 173.11; measured value 156.2 [M-H2O + H]+. 1H NMR (300 MHz, DMSO-d6): δ (ppm) 0.98 (m, 2H), 1.52 (m, 1H), 1.63 (br d, 2H), 2.72 (br m, 2H), 3.23 (d, 2H ), 3.56 (s, 3H), 3.95 (br d, 2H), 4.48 (br s, 1H).
In another experiment, 4-hydroxymethylpiperidine (47.6 g, 1.0 equiv.) with water (300 mL) was added to a flask and cooled to 0-10 °C. Potassium carbonate (85.7 g, 1.5 eq.) and methyl chloroformate (38.4 mL, 1.1 eq.) dissolved in water (150 mL) were added while keeping the temperature below 10 °C. After addition, the reaction mixture was warmed to 20-30 °C and maintained for 1 hour. Upon completion of the reaction, dichloromethane (500 mL) was added for extraction. The organic phase was washed sequentially with 1 M phosphoric acid solution (200 mL), saturated sodium bicarbonate solution (200 mL) and saturated sodium chloride solution (200 mL). The organic layer was dried with sodium sulfate (50 g, 1 w/w eq) and the solvent was removed by distillation under reduced pressure to give the target product (67.0 g, 90% yield).
