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

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Reaction Steps

1-(Methoxycarbonyl)-2-(2-methyl-4-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (7.79 g, 22.56 mmol) (reference compound 31) was dissolved in THF (60 mL) and then di(1H-imidazol-1-yl)methanone (5.49 g, 33.84 mmol) was added. The reaction was stirred overnight at room temperature (flask 1). In a separate flask potassium 3-ethoxy-3-oxopropanoate (7.68 g, 45.12 mmol) and anhydrous magnesium chloride (4.30 g, 45.12 mmol) were suspended in THF (60.0 mL) and stirred at 50° C. under nitrogen overnight and then allowed to cool to room temperature (flask 2). The content of flask 1 was added to flask 2 and stirred under nitrogen for 48 h. The reaction was quenched by addition of 2 M HCl. The mixture was extracted three times with EtOAc, the combined organic phases were evaporated and purified by column chromatography on silica (100 g Biotage column with heptane/EtOAc 88/12-33/67 over 9 column volumes) to give cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-methyl-4-(trifluoromethyl)phenyl)piperidine-1-carboxylate (6.28 g, 67%). 1H NMR (400 MHz, cdcl3) δ 1.23-1.33 (m, 3H), 1.68-1.97 (m, 2H), 2.08-2.21 (m, 2H), 2.44 (s, 3H), 2.87-2.98 (m, 1H), 3.46 (s, 2H), 3.44-3.66 (m, 1H), 3.58 (s, 3H), 4.15-4.29 (m, 3H), 4.91-5.01 (m, 1H), 7.24-7.32 (m, 1H), 7.36-7.43 (m, 2H). MS m/z 416 (M+H)+

Provenance & Evidence