Methyl iodide → HCID 59199339, compound

Participants

Reaction Conditions

Reaction Steps

To a solution of LiAlH4 (171 mg, 4.48 mmol) in THF (100 mL) at 0° C. is added a solution of 3-isothiochroman-4-yl-3H-imidazole-4-carboxylic acid methyl ester [which can be prepared from isothiochroman-4-ol (CAS#109819-33-2) as described in Example 2; MS: (ESI) m/z 275.2 (M+H)+] (1.23 g, 4.48 mmol) in THF (50 mL). The reaction is permitted to stir for 4 hours, at which time it is quenched by the slow addition of water. The reaction mixture is then filtered, diluted with ethyl acetate and washed with saturated aqueous NaHCO3. The organic layer is dried with Na2SO4, filtered, and concentrated. A portion of the resulting residue containing (3-isothiochroman-4-yl-3H-imidazol-4-yl)-methanol (240 mg, ca. 0.5 mmol) is then dissolved in THF (25 mL) and cooled to 48° C. The reaction mixture is then charged with a 1 M THF solution of potassium t-butoxide (0.75 mL, 0.75 mmol). The reaction is permitted to stir for 30 minutes and then charged with iodomethane (0.2 mL, 0.61 mmol). After 3.5 hours the reaction is quenched with saturated aqueous NaHCO3 and further diluted with ethyl acetate. The organic layer is washed with saturated aqueous NaHCO3, and then dried with Na2SO4, filtered, and concentrated. The resulting residue is purified by silica gel flash chromatography (methanol-dichloromethane, 0:1 to 1:19) to provide 1-isothiochroman-4-yl-5-methoxymethyl-1H-imidazole; MS: (ESI) m/z 261.1 (M+H); 1H NMR (400 MHz, CDCl3) δ ppm 3.07-3.30 (m, 2 H), 3.33 (s, 3 H), 3.88 (br. s., 2 H), 4.35-4.57 (m, 2 H), 5.64 (t, J=5.2 Hz, 1 H), 6.93 (d, J=7.1 Hz, 1 H), 7.07 (s, 1 H), 7.15-7.28 (m, 3 H), 7.39 (s, 1 H). The HCl salt of the title compound can be prepared by dissolution in diethyl ether followed by treatment with an excess of 1N HCl in diethyl ether. The resulting heterogeneous solution is concentrated to furnish the HCl salt of 1-isothiochroman-4-yl-5-methoxymethyl-1H-imidazole.

Provenance & Evidence