Sustainable Synthesis of 3,4-Dihydro-2 H -1,2,4-benzothiadiazine-1,1-dioxides by Graphene Oxide Catalysts

Abstract A sustainable transition metal-free catalytic route for the synthesis of pharmacologically relevant 3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxides (DHBDs) was developed under ambient reaction conditions. The prepared graphene oxide was characterised using PXRD, FE-TEM, FE-SEM, EDX, FT-IR, BET and Raman analysis. The prepared graphene oxide exhibited a sheet-like structure comprising of several layers with a specific surface area of 30.83 m2 g−1 and an average pore radius of 19.15 Å. The developed methodology employs an environmentally benign EtOH/H2O (2:1) solvent system under ambient reaction conditions and exhibits wide substrate tolerability, including difficult aliphatic substrates. Furthermore, the developed catalytic route is ligand-, base- or oxidant-free, operationally simple without the need for a special reaction atmosphere and eliminates the issue of metal contamination in the target products. The established metal-free catalytic route is also amenable to late-stage derivatisation of natural products, highlighting its relevance to pharmaceutical applications. The scalability of the metal-free catalytic protocol was validated through a scale-up reaction, which delivered the target product in efficient yield, demonstrating industrial feasibility. The green chemistry metrics for the scale-up process were calculated and it validates the environmentally sustainable nature of the developed protocol. Notably, the metal-free graphene oxide catalyst could be efficiently recovered and reused for five consecutive cycles, highlighting its economic viability and environmental sustainability.