Chloromethyl Methyl Ether → 2-(Methoxymethyl)-7-methyl-2H-indazole-5-carbaldehyde

Participants

Reaction Steps

To a solution of 7-methylindazole-5-carboxaldehyde (8.80 g, 54.9 mmol) and N-methyl-dicyclohexylamine (23.6 mL, 110 mmol) in tetrahydrofuran (200 mL) at 0° C. was added chloromethyl methyl ether (7.50 mL, 1.8 equiv). The reaction was allowed to gradually warm to room temperature overnight. The reaction was concentrated, dissolved in diethyl ether, washed with water, then 1 M hydrochloric acid, then water, then brine, dried over magnesium sulfate, and concentrated to give an oil. The oil was dissolved in ethyl acetate and treated with hexanes until lasting turbidity. The suspension was heated until a clear solution was obtained and the flask placed in the freezer. The resulting crystalline solid was crushed with a spatula to break it up, reheated to dissolve some of the solids, and placed in the freezer. The solids were filtered, washed with very cold diethyl ether (−78° C.), and air-dried to give 5.43 g. The mother liquor was concentrated, redissolved in diethyl ether (ca. 20 mL), cooled to −78° C., and treated with a seed crystal of the product. After 1 h, the resulting solids were filtered, washed with cold diethyl ether (−78° C.), and air-dried to give an additional 1.05 g (total yield=58%). 1H-NMR (CDCl3, 500 MHz) δ 2.66 (s, 3H), 3.44 (s, 3H), 5.73 (s, 2H), 7.59 (s, 1H), 8.09 (s, 1H), 8.32 (s, 1H), 9.97 (s, 1H). Mass spec.: 205.19 (MH)+.

Provenance & Evidence