Ammonium Chloride → 4-(4-Hydroxytetrahydro-2H-pyran-4-yl)benzenecarbonitrile

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Reaction Conditions

Reaction Steps

To a solution of 4-iodobenzonitrile (5.0 g, 21.8 mmol) in dry THF (100 mL) was added 2-propyl magnesium chloride (2M solution in diethyl ether, 11 mL, 21.8 mmol) dropwise at −40° C. After stirring for 1.5 h at this temperature, the reaction mixture was cooled to −78° C. before it was canulated to a solution of 4-oxotetrahydro-2H-pyrane (3.28 g, 32.8 mmol) in dry THF (100 mL) which was likewise cooled to −78° C. After the slow addition of the Grignard reagent was completed, the reaction mixture was stirred at −78° C. for additional 10 minutes, then at 0° C. for 2 h, and finally at rt for 30 minutes. A few mL saturated aqueous NH4Cl were added, and then most of the solvent was evaporated. The residue was partitioned between water and ethyl acetate (200 mL each). After separation, the aqueous layer was extracted using ethyl acetate. The combined organic layers were successively washed with water and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the crude material was purified by MPLC (silica, cyclohexane/ethyl acetate 2:1→1:1). The title compound was obtained as a highly viscous oil (1.19 g, 27%): 1H NMR (400 MHz, DMSO-d6) δ 7.80 (d, 2H), 7.70 (d, 2H), 5.30 (s, 1H), 3.81-3.70 (m, 4H), 2.02-1.94 (m, 2H), 1.51-1.48 (m, 2H); DCI(NH3)-MS m/z 204 (MH)+, 221 (M+NH4)+; HPLC RT (Method I) 3.35 min.

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