[Synthesis]
General procedure for the synthesis of 4,6-difluoro-1H-indazoles from 2,4,6-trifluorobenzaldehyde:
Step 1: Synthesis of 4,6-difluoro-1H-indazole
2,4,6-Trifluorobenzaldehyde (0.80 g, 5.0 mmol) was dissolved in 1,2-dimethoxyethane (10 mL) and potassium carbonate (1.04 g, 7.5 mmol) and O-methylhydroxylamine hydrochloride (438 mg, 5.25 mmol) were added sequentially. The reaction mixture was heated at 50 °C for 5 h. After cooling to room temperature, it was filtered and washed with dichloromethane. The filtrate was concentrated and the residue was redissolved in 1,2-dimethoxyethane (10 mL) and hydrazine (0.17 mL, 5.5 mmol) was added. The reaction mixture was heated at 100 °C for 1.5 h. Hydrazine (0.17 mL, 5.5 mmol) was added and heating was continued for 30 min. After completion of the reaction, it was cooled to room temperature, poured into water and extracted with ethyl acetate. The organic layer was washed sequentially with saturated LiCl solution and brine, dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography (eluent: 20% to 50% EtOAc/heptane) to afford 358 mg (47% yield) of 4,6-difluoro-1H-indazole as a light yellow solid.
1H NMR (DMSO-d6, 300 MHz) δ (ppm): 13.47 (br.s, 1H), 8.19 (s, 1H), 7.22 (d, J = 9.1 Hz, 1H), 6.96 (td, J = 10.0, 1.9 Hz, 1H). |