Acetic Acid → Ethyl 1-methylpiperidine-4-carboxylate

Participants

Reaction Steps

Ethyl isonipecotate (20) (5.00 g, 31.8 mmol) was dissolved in an ice-cold mixture of glacial acetic acid (3.80 g, 63.6 mmol) and water (11 mL). Then, a 37% aqueous formaldehyde solution (2.85 mL, 38.2 mmol) was added and the reaction mixture was hydrogenated over Pd/C (10%, 338 mg) at 58 psi H2 for 3.5 h at room temperature. The solid was removed by filtration through Celite, which was washed thoroughly with water (50 mL) and the filtrate was adjusted to pH 11 with 1 M NaOH under cooling. The resulting solution was extracted with Et2O (5×100 mL), the combined organic fractions were dried (MgSO4), and the solvent was removed under reduced pressure to provide 21 (5.44 g, quant.) as a colorless liquid that was used for the next step without further purification. 1H NMR (300 MHz, CDCl3): δ=1.25 (t, J=7.1 Hz, 3 H, OCH2CH3), 1.69-2.06 (m, 6 H, 2-Hax, 3-H2, 5-H2, 6-Hax), 2.18-2.32 (m, 1 H, 4-H), 2.27 (s, 3 H, NMe), 2.75-2.87 (m, 2 H, 2-Heq, 6-Heq), 4.13 (q, J=7.1 Hz, 2 H, OCH2CH3) ppm. —13C NMR (75.5 MHz, CDCl3): δ=14.1 (OCH2CH3), 28.2 (C-3, C-5), 40.5 (C-4), 46.3 (NMe), 54.9 (C-2, C-6), 60.2 (OCH2CH3), 175.0 (C═O) ppm. −MS (70 eV, EI): m/z (%)=171 (31) [M]+, 142 (59) [M-CH2CH3]+, 126 (40) [M-OCH2CH3]+, 98 (56) [M-CO2Et]+. —C9H17NO2 (171.24).

Provenance & Evidence