Hydrochloric Acid → trans-Methyl 2-(4-tert-butylphenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate

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Reaction Conditions

Reaction Steps

Magnesium chloride (5.38 g, 56.51 mmol) and potassium 3-ethoxy-3-oxopropanoate (9.62 g, 56.51 mmol) were suspended in methyl THF (100 mL) and heated to 50° C. under nitrogen for 18 h using an oversized stirring bar, then cooled to room temperature (flask 1). In a separate flask was to a suspension of 2-(4-tert-butylphenyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (9.5 g, 29.74 mmol) (reference compound 15) in methyl THF (100 mL) added di(1H-imidazol-1-yl)methanone (7.23 g, 44.62 mmol) under nitrogen. The resulting mixture was stirred at room temperature for 4 h (flask 2). Then, the contents of flask 2 is transferred into flask 1 by transfer needle. Wash with methyl THF (30 mL). Resulting suspension stirred at room temperature for 18 h. 3.8 M HCl was added (ca. 150 mL) and the resulting biphasic mixture stirred vigorously for 2 h. The phases were separated. The organic phase was washed with water, satd NaHCO3 and brine, then dried over MgSO4 and evaporated. The residue was purified via Biotage in two equal portions (Biotage® KP-SIL 340 g column, 1 CV 20% EtOAc in heptanes, then 20%=>60% over 7 CV). Trans-methyl 2-(4-tert-butylphenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.09 g, 9.4%) was isolated as a pale yellow oil. 1H NMR (400 MHz, cdcl3) δ 1.22-1.31 (m, 3H), 1.31 (s, 9H), 1.50-1.99 (m, 4H), 2.50-2.96 (m, 2H), 3.47 (s, 2H), 3.74 (s, 3H), 4.08-4.23 (m, 3H), 5.46-5.71 (m, 1H), 7.09-7.16 (m, 2H), 7.34-7.40 (m, 2H).

Provenance & Evidence