Benzyl 4-oxopiperidine-1-carboxylate → Benzyl 4-[(4-fluorophenyl)methyl]-4-hydroxypiperidine-1-carboxylate

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Reaction Conditions

Reaction Steps

To a round bottom flask equipped with a magnetic stirring bar was added 2.94 g of 4-oxo-piperidine-1-carboxylic acid benzyl ester (12.6 mmol, 1.0 equiv) and 25 mL of ether. The flask was fitted with a septum and a nitrogen inlet and cooled to −40° C. A 0.25 M solution of (4-fluoro)benzylmagnesium chloride (50 mL, 12.5 mmol, 1.0 equiv.) was added via syringe over 10 minutes to the reaction solution. After 1 h, the mixture was warmed to room temperature and stirred for 20 h. Then the solution was cooled to 0° C. and quenched with 30 mL of saturated aqueous ammonium-chloride. The aqueous layer was extracted with 100 mL of EtOAc. The combined organic layers were washed with saturated aqueous NaCl (3×25) and dried over MgSO4. The resultant yellow oil was purified by flash chromatography to afford 1.058 g of 4-(4-Fluoro-benzyl)-4-hydroxy-piperidine-1-carboxylic acid benzyl ester (3.08 mmol, 25% yield). The crude product was diluted in methanol (12 mL) and added to a round bottom flask containing a magnetic stirring bar and 200 mg of 10% Pd/C. The flask was evacuated, and back-filled with hydrogen (1 atm). After 24 h of vigorous stirring under nitrogen atmosphere, the solution was filtered through celite and concentrated in vacuo to afford 4-(4-fluoro-benzyl)-piperidin-4-ol (67) in quantitative yield (644 mg): HPLC retention time=0.26 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 mL/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected=210.1, found 210.1.

Provenance & Evidence