A Water-Based and Continuous-Flow-Usable Cascade: Sustainable Synthesis of Tetrazolo-Fused Heterocycles

The innovation of energetic materials is frequently hampered by economic inefficiency and safety concerns. Emerging cascade reactions could overcome existing bottlenecks and accelerate next-generation energetic materials with enhanced scalability and reduced risks. In this work, a water-based cascade reaction has been applied to obtain 6-amino-7,8-dihydrotetrazolo[5,1-f][1,2,4]triazin-8-ol (AHTO), a new nitrogen-rich energetic compound. Using water as a green, multifunctional medium, this strategy achieves three critical advances: (1) elimination of intermediate isolation through cascade reaction integration, (2) minimization of toxic solvents and hazardous reagents, and (3) stabilization of sensitive tetrazolo intermediates. The inherent safety benefits of water-mediated chemistry are further amplified through microchannel continuous-flow technology, leading to an all-round improvement. Finally, AHTO was obtained in a 90.8% crystallization yield and a 98.1% HPLC purity in a 3 h flow reaction. After nitroamino derivatization, 6-nitroamino-7,8-dihydrotetrazolo[5,1-f][1,2,4]triazin-8-ol (NHTO) was prepared as a new potential metal-free primary explosive.The integration of cascade with flow chemistry will accelerate the development efficiency of energetic materials while balancing economic, safety, and environmental considerations.