[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[C:6]#[N:7].[H-].[Na+].[CH3:15]I>O1CCCC1>[CH3:12][O:11][C:9]1[CH:8]=[C:5]([CH:4]=[C:3]([CH2:2][O:1][CH3:15])[CH:10]=1)[C:6]#[N:7]To a solution of 3-hydroxymethyl-5-methoxy-benzonitrile (261.1 mg, 1.6 mmol, example 33) in tetrahydrofuran (5 mL) cooled to 0° C. was added sodium hydride (43 mg, 1.68 mmol). The ice-bath was removed and the reaction mixture was stirred at room temperature for 15 min before methyl iodide (149 μL, 2.4 mmol) was added. The reaction mixture was stirred at room temperature for 3 h before being quenched with several drops of saturated ammonium chloride solution. The solvent was removed and the residue was taken up in diethyl ether. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solid was then filtered off, and the filtrate was concentrated in vacuo. Purification of the residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 12% ethyl acetate in hexanes yielded 3-methoxy-5-methoxymethyl-benzonitrile as a colorless oil (213 mg, 75%).
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