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 azide-functionalized
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.