Synthesis
In a 1L three-necked flask, 2-chloroacrylonitrile (39.6 g, 453 mmol) was dissolved in toluene (105 ml). In another vessel, N-benzylethanolamine (66.5 g, 440 mmol) was dissolved in toluene (35 ml) and the solution was slowly added dropwise to the above mentioned 1L three-necked flask. The reaction mixture was stirred at room temperature for 12 hours. Subsequently, toluene (205 ml) was added to dilute the reaction mixture and the system was cooled to -5°C. A solution of potassium tert-butoxide (t-BuOK, 50.84 g, 444 mmol) dissolved in THF (202 ml) was slowly added dropwise while maintaining the temperature at -5 °C. After the dropwise addition, the reaction was continued with stirring at -5°C for 50 min. After completion of the reaction, the reaction mixture was washed once with saturated brine and the organic phase was dried with anhydrous magnesium sulfate (MgSO4) and filtered. After the solvent was removed by distillation under reduced pressure, the reaction was purified by silica gel column chromatography to afford 4-benzylmorpholine-2-carbonitrile (64.1 g, 316.9 mmol, 70% yield). The structure of the product was confirmed by 1H NMR (400 MHz, CDCl3): δ7.39-7.28 (m, 5H, Ar-H), 4.62 (t, J=3.6 Hz, 1H, CH), 4.05 (m, 1H, CH), 3.79 (dt, J=3.6,11.6 Hz, 1H, CH2), 3.59 (dd, J=9.2, 25.2 Hz, 2H, CH2), 2.78 (dd, J=3.6,12.0 Hz, 1H, CH2), 2.66 (m, 1H, CH), 2.58 (dd, J=3.6,12.0 Hz, 1H, CH2), 2.43 (m, 1H, CH2).
References
[1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 7, p. 2022 - 2025
[2] Organic Process Research and Development, 2009, vol. 13, # 2, p. 209 - 224
[3] Journal of Fluorine Chemistry, 2012, vol. 134, p. 136 - 145
[4] Patent: WO2015/164508, 2015, A1. Location in patent: Page/Page column 48
[5] Patent: WO2012/128582, 2012, A2. Location in patent: Page/Page column 27-28
