Continuous-Flow Direct Azidation of Alcohols and Peroxides for the Synthesis of Quinoxalinone, Benzooxazinone, and Triazole Derivatives

Continuous-flow reactors provide an ideal tool for the synthesis of potentially explosive but synthetically useful organic substances like organic azides due to their intrinsically small volume leading to very effective collision and highly controlled reaction conditions. Herein, we report the continuous-flow direct azidation of various alcohols by using TMSN3 as an azide transfer reagent in the presence of Amberlyst-15 as a recyclable catalyst. Numerous 3-hydroxy-2-oxindoles effectively undergo azide transfer to afford azidefunctionalized quaternary stereocenters in a continuous-flow module. Interestingly, peroxyoxindole undergoes sequential skeletal rearrangement to generate a carbocation followed by nucleophilic azidation to afford a library of substituted 2-azido-2H-benzo[b][1,4]oxazin-3(4H)-one derivatives under continuous flow. Furthermore, a continuous-flow Cu-catalyzed click reaction afforded triazole-functionalized deivatives. Next, reduction of azide in the presence of PPh3 affords the amine derivatives in good yields. The continuous-flow application was extended further for the thermolytic skeletal rearrangement of 3-azide-2-oxindole for the synthesis of biologically important quinoxalin-2(1H)-ones without any reagents. Furthermore, this continuous-flow direct azidation reaction is scaled up to 6.144 g of azides with a turnover number of 9.24 under safer conditions.

Automated summary

Continuous-flow reactors are an ideal tool for synthesizing potentially explosive but synthetically useful organic substances. This study reports the continuous-flow direct azidation of alcohols using TMSN3 as a transfer reagent and Amberlyst-15 as a recyclable catalyst. The study also explores the application of continuous-flow reactors in other organic reactions.