Ascorbic Acid: An Organocatalyst for Metal-free Benign Synthesis of Biologically Active 5-substituted 1H-tetrazole

Introduction: The synthesis of physiologically significant 5-substituted 1H-tetrazoles is an important area in medicinal and industrial chemistry due to their wide range of biological and pharmacological applications. Conventional synthetic methods often rely on hazardous reagents and transition-metal catalysts, raising environmental and safety concerns. The objective of this study is to develop a sustainable, metal-free, and environmentally benign method for the synthesis of 5- substituted 1H-tetrazoles. Method: A [3 + 2] cycloaddition reaction between various organic nitriles and azide sources was carried out using ascorbic acid as an organocatalyst. Polyethylene glycol (PEG-300) was employed as a green solvent. The reactions were performed under mild conditions without the use of hazardous acidic reagents or metal catalysts. Result: A wide range of organonitrile substrates were successfully converted into the corresponding 5-substituted 1H-tetrazoles in good to excellent yields. The reaction showed reduced reaction times and smooth conversion under mild conditions. Discussion: The use of ascorbic acid enhanced the efficiency of the [3 + 2] cycloaddition process while maintaining cost-effectiveness and simplicity. PEG-300 contributed to the environmental sustainability of the method, making the process safer and greener compared to traditional approaches. Conclusion: The developed method provides a practical, efficient, and eco-friendly route for synthesizing 5-substituted 1H-tetrazoles. Its broad substrate scope, high yields, and green reaction conditions make it a promising approach for potential industrial and medicinal applications.