THE CONTINUOUS-FLOW SYNTHESIS OF 1H-INDAZOLES VIA REACTION OF o-FLUOROBENZALDEHYDES WITH tert-BUTYL CARBAZATE UNDER HIGH TEMPERATURE

- Large amounts of 1H-indazoles have been developed and widely used in the production of diverse drugs. The reaction of 4-bromo-2,6-difluorobenzaldehyde with tert-butyl carbazate was selected as model transformation for the application of continuous-flow strategy to realize the efficient syntheses of 1H-indazoles in a highly controlled and safe manner. Various conditions (reaction temperature, residence time, solvent amount, the amount of tert-butyl carbazate, water content) were investigated under continuous-flow conditions to elucidate the benefits of using the continuous-flow strategy. The Box-Behnken design in response surface methodology was employed for the optimization of reaction conditions, and over 85% yield of 6-bromo-4-fluoro-1H-indazole could be achieved. Furthermore, the generality of the reaction conditions found optimal for the synthesis of 6-bromo-4-fluoro-1H-indazole was evaluated for the synthesis of several different 1H-indazoles.