1,1'-Carbonyldiimidazole → cis-Methyl 2-(cyclohexylmethyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate

Participants

Reaction Conditions

Reaction Steps

Ethyl potassium malonate (1.75 g, 10.3 mmol) and MgCl2 (0.665 g, 6.88 mmol) were added to dry THF (50 mL). The reaction flask was stirred vigorously 4 h at 50° C. (flask 1). 2-(Cyclohexylmethyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (1.95 g, 6.88 mmol) (Reference Compound 8) and carbonyldiimidazole (1.34 g, 8.26 mmol) were added to dry THF (50 mL) at 5° C. (flask 2). The contents of flask 2 was added to flask 1 at room temperature. The reaction mixture was evaporated to remove most of the THF. The crude was partitioned between water and diethyl ether. The organic phase was isolated, dried with MgSO4, filtered through Celite® and the solvent was evaporated. The residue was purified by automated column chromatography using the Biotage equipment. Gradient eluation using ethylacetate-heptane, started 15-85 and ended 40-60 which gave trans-methyl 2-(cyclohexylmethyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (0.38 g, 16%) and cis-methyl 2-(cyclohexylmethyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.28 g, 53%). Trans-isomer: 1H NMR (600 MHz, cdcl3) δ 0.88 (d, 2H), 0.99-1.32 (m, 8H), 1.38-1.56 (m, 2H), 1.68 (dd, 8H), 2.80 (t, 2H), 3.45 (s, 2H), 3.66 (s, 3H), 3.93-4.21 (m, 3H), 4.47 (d, 1H). Cis-isomer 1H NMR (600 MHz, cdcl3) δ 0.72-0.95 (m, 2H), 1.04-1.31 (m, 8H), 1.38-1.49 (m, 1H), 1.53-1.69 (m, 6H), 1.70-1.92 (m, 3H), 2.02 (dt, 1H), 2.61-2.71 (m, 1H), 2.95-3.07 (m, 1H), 3.48 (s, 2H), 3.66 (s, 3H), 3.85 (dd, 1H), 4.09-4.21 (m, 3H).

Provenance & Evidence