1,1'-Carbonyldiimidazole → HCID 131730437, compound

Participants

Reaction Conditions

Reaction Steps

A suspension of magnesium chloride (2.085 g, 21.89 mmol) and ethyl potassium malonate (3.73 g, 21.89 mmol) in dry THF (80 mL) was stirred under nitrogen atmosphere at 50° C. for 2.5 h (flask 1). In another flask di(1H-imidazol-1-yl)methanone (2.96 g, 18.24 mmol) was added portionwise to a solution of 2-cyclohexyl-1-(methoxycarbonyl)piperidine-4-carboxylic acid (3.28 g, 12.16 mmol) (reference compound 35) in dry THF (20 mL) at 0° C. and put under nitrogen atmosphere. The ice bath was removed and the solution was stirred for 2 h at room temperature (flask 2). Then the contents of flask 1 was added to flask 2 and the resulting mixture was stirred overnight (20 h). The reaction mixture was concentrated and the residue was taken up in EtOAc and H2O. The aqueous phase was extracted once with EtOAc and the combined organic phase was washed with water, 10% Na2CO3 and then dried over Na2SO4. The organic phase was washed with 0.1 M NaOH and dried again and evaporated to give a yellow oil. The compound was purified further via Biotage, 2 runs, SNAP 340 g KP-SIL, linear gradient heptanes/ethyl acetate 9:1 to 1:1 over 7CV. Trans-methyl 2-cyclohexyl-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (349 mg, 6.9%) and cis-methyl 2-cyclohexyl-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (2.501, 49%) were isolated. Cis-isomer: 1H NMR (400 MHz, cdcl3) δ 0.90-1.29 (m, 5H), 1.26 (t, 3H), 1.37-2.05 (m, 10H), 2.57-2.70 (m, 1H), 2.85-3.02 (m, 1H), 3.48 (s, 2H), 3.67 (s, 3H), 3.71-3.84 (m, 1H), 3.86-3.99 (m, 1H), 4.18 (q, 2H). MS m/z 340 (M+H)+. Trans-isomer: 1H NMR (400 MHz, cdcl3) δ 0.80-1.30 (m, 5H), 1.26 (t, 3H), 1.33-1.90 (m, 9H), 1.96-2.12 (m, 1H), 2.69-2.86 (m, 2H), 3.46 (s, 2H), 3.67 (s, 3H), 3.84-4.33 (m, 2H), 4.21 (q, 2H). MS m/z 340 (M+H)+

Provenance & Evidence