1H-Indazole-5-carboxaldehyde, 7-methyl- (9CI) synthesis

Yield: 65%

Reaction Conditions:

with hydrogenchloride;sec.-butyllithium;sodium hydrogencarbonate in tetrahydrofuran;N-methyl-acetamide;cyclohexane;mineral oil

Steps:

11 7-methylindazole-5-carboxaldehyde
7-methylindazole-5-carboxaldehyde 5-Bromo-7-methylindazole (6.10 g, 28.9 mmol) and sodium hydride (60% in mineral oil, 1.27 g, 1.1 equiv) were weighed into a flame-dried round-bottom flask containing a magnetic stir bar. Under a nitrogen atmosphere at room temperature, dry tetrahydrofuran (30 mL) was added. The mixture was stirred at room temperature for 15 min, during which time it became homogeneous. The stirred mixture was cooled to -70° C. and a solution of sec-butyllithium in cyclohexane (1.4M, 45 mL, 2.2 equiv) was added over several minutes. After 1 h at -70° C., dimethylformamide (10 mL) was added over several minutes. The mixture was allowed to warm to room temperature and was stirred overnight. It was then cooled to 0° C. and carefully treated with 1N hydrochloric acid (60 mL). After a few minutes, solid sodium bicarbonate was added to basify the mixture to pH 9-10. The layers were separated and the aqueous phase washed twice with ethyl acetate. The combined organic phases were extracted with 0.8M sodium hydrogen sulfate (3*125 mL). The combined aqueous phases were washed with ethyl acetate (100 mL) and then the pH was adjusted to ca. 10 with solid sodium hydroxide. The resulting suspension was extracted with ethyl acetate (3*150 mL). The combined organic phases were washed with brine, dried (magnesium sulfate) and evaporated to give the product as a light-tan solid (3.01 g, 65%). ¹H-NMR (CDCl₃, 500 MHz) δ 2.63 (3H, s), 7.73 (1H, s), 8.12 (1H, s), 8.25 (1H, s), 10.03 (1H, s). Mass spec.: 161.06 (MH)⁺.

References:

Chaturvedula, Prasad V.;Chen, Ling;Civiello, Rita;Conway, Charles Mark;Degnan, Andrew P.;Dubowchik, Gene M.;Han, Xiaojun;J. Jiang, Xiang Jun;Karageorge, George N.;Luo, Guanglin;Macor, John E.;Poindexter, Graham;Tora, George;Vig, Shikha US2004/204397, 2004, A1