Synthesis
To a mixed solution of ethyl piperidine-3-carboxylate (5.94 mL, 38.24 mmol, 1.0 eq.) in dichloromethane (80 mL) and water (40 mL) was added benzyl bromide (4.77 mL, 1.05 eq.) and sodium carbonate (5.06 g, 1.25 eq.) in that order. The reaction mixture was heated to reflux for 3 hours. After completion of the reaction, the organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by fast column chromatography on silica gel, using ethyl acetate/hexane (1:6, v/v) as eluent, to afford ethyl 1-benzylpiperidine-3-carboxylate (9) as a colorless oil in 87% yield.
1H NMR (400 MHz, CDCl3) δ 7.29-7.18 (m, 5H, Ar-H), 4.11 (q, J = 7.2 Hz, 2H, OCH2CH3), 3.51 (d, J = 13.6 Hz, 1H, CHa-Ph), 3.44 (d, J = 13.2 Hz, 1H, CHb-Ph), 2.90 (m, 1H, Piperidine-H), 2.68 (m, 1H, Piperidine-H), 2.54 (m, 1H, Piperidine-H), 2.20 (m, 1H, Piperidine-H), 2.01 (m, 1H, Piperidine-H), 1.90 (m, 1H, Piperidine-H), 1.69 (m, 1H, Piperidine-H), 1.52 (m, 2H, Piperidine-H), 1.19 (t, J = 7.2 Hz, 3H, Piperidine-H), 3.44 (d, J = 13.2 Hz, 1H, CHb-Ph), 1.19 (t, J = 7.2 Hz, 3H, OCH2CH3).
13C NMR (62.5 MHz, CDCl3): δ 174.4, 138.4, 129.1, 128.2, 127.0, 63.3, 60.3, 55.5, 53.7, 42.0, 27.0, 24.6, 14.2; δ
HRESI-MS m/z calcd for [M + H]+ C15H22NO2: 248.1645, found: 248.1646.
References
[1] Journal of Medicinal Chemistry, 2003, vol. 46, # 25, p. 5512 - 5532
[2] Journal of Organic Chemistry, 2016, vol. 81, # 22, p. 11235 - 11249
[3] Tetrahedron Letters, 2001, vol. 42, # 33, p. 5645 - 5649
[4] European Journal of Medicinal Chemistry, 2017, vol. 127, p. 972 - 985
[5] Patent: US6664271, 2003, B1. Location in patent: Page column 15
