1,1'-Carbonyldiimidazole → HCID 131730468, compound

Participants

Reaction Conditions

Reaction Steps

Ethyl potassium malonate (3.42 g, 20.16 mmol) and MgCl2 (1.599 g, 16.80 mmol) were added to dry THF (50 ml). The reaction flask was stirred vigorously overnight at 50° C. (flask 1). 1-(Methoxycarbonyl)-2-(3-(trifluoromethyl)benzyl)piperidine-4-carboxylic acid (5.8 g, 16.80 mmol) (reference compound 48) and carbonyldiimidazole (4.09 g, 25.19 mmol) were added to dry THF (50 mL) at 5° C. and was stirred overnight at room temperature (flask 2). The contents of flask 2 was added to flask 1 at room temperature and stirred for 3 days. The reaction mixture was dissolved between water and diethyl ether. The organic phase was evaporated to remove most of the THF. Dissolved the crude between water and diethyl ether again. The organic phase was isolated, dried with Na2SO4, filtered through celite and the solvent was evaporated. Chromatography using the Biotage equipment. Gradient eluation using ethyl acetate-heptane, started 0-100 and ended 100-0. Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-(trifluoromethyl)benzyl)piperidine-1-carboxylate (1.8 g, 26%) and cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-(trifluoromethyl)benzyl)piperidine-1-carboxylate (2.45 g, 35%) were isolated. Cis-isomer: 1H NMR (400 MHz, cdcl3) δ 1.20-1.32 (m, 3H), 1.63-1.99 (m, 4H), 2.67-2.86 (m, 2H), 2.92-3.12 (m, 2H), 3.47 (s, 2H), 3.59 (s, 3H), 3.89-4.00 (m, 1H), 4.09-4.29 (m, 3H), 7.32-7.51 (m, 4H). MS m/z 416 (M+H)+. Trans-isomer: 1H NMR (400 MHz, cdcl3) δ 1.19-1.35 (m, 3H), 1.42-2.08 (m, 4H), 2.51-3.09 (m, 4H), 3.35-3.78 (m, 5H), 4.04-4.38 (m, 3H), 4.47-4.79 (m, 1H), 7.23-7.56 (m, 4H). MS m/z 416 (M+H)+

Provenance & Evidence