Tetrahydrofuran → (1-methyl-1H-imidazol-2-yl){4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methanone Formic Acid Salt

Participants

Reaction Conditions

Reaction Steps

A stirring mixture of 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (200 mg; 1.05 mmol), 4-bromoiodobenzene (297 mg; 1.05 mmol), K2CO3 (302 mg; 2.18 mmol), CuI (20 mg; 0.11 mmol) and N,N-dimethyl glycine (30 mg; 0.29 mmol) in DMSO (4 mL) was heated at 130° C. for 5 hours 30 minutes. The reaction mixture was partitioned between DCM and water, the organic phase filtered through silica (eluent—methanol), and concentrated in vacuo, giving a brown oil (411 mg). This was purified by column chromatography, giving a mixture of 1-(4-bromophenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole and 1-(4-iodophenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (205 mg). Under an inert atmosphere of argon, 95 mg of this mixture was dissolved in anhydrous THF (2 mL), cooled to −78° C., and n-butyl lithium (2.5 M in hexanes, 330 μL; 0.82 mmol) was added dropwise over 2 minutes. After stirring for 1 hour, N,1-dimethyl-N-(methyloxy)-1H-imidazole-2-carboxamide (93 mg; 0.55 mmol) was added in one portion to the cold (−78° C.) mixture and the reaction stirred at this temperature for a further 40 minutes. The reaction was warmed to 0° C. and stirred at this temperature for 5 hours 20 minutes. Additional N,1-dimethyl-N-(methyloxy)-1H-imidazole-2-carboxamide (58 mg; 0.34 mmol) was added in one portion, and the reaction stirred at 0° C. for a further 1 hour. The reaction was quenched with aqueous hydrochloric acid (1M, 2 mL), and purified by SCX column chromatography, yielding a white solid (32 mg). This was further purified by MDAP, giving the title compound as white solid (1.14 mg; 0.29% [2 steps]).

Provenance & Evidence