Sequential Ugi four-component/nucleophilic substitution/Staudinger–aza-Wittig/hydrolysis strategy for the efficient construction of 1-benzyl-6-(tetrazolo[1,5-a]quinolin-4-yl)piperazine-2,5-dione

Kiamehr, Mostafa; Fathizadeh, Mohadeseh

doi:10.22091/jaem.2025.13684.1029

Sequential Ugi four-component/nucleophilic substitution/Staudinger–aza-Wittig/hydrolysis strategy for the efficient construction of 1-benzyl-6-(tetrazolo[1,5-a]quinolin-4-yl)piperazine-2,5-dione

Document Type : Research Article

Authors

Department of Chemistry, Faculty of Science, University of Qom, Ghadir Blvd, P.O. Box 37146-6611, Qom, Iran

10.22091/jaem.2025.13684.1029

Abstract

A sequential synthetic strategy integrating multiple transformations has been established for the efficient construction of 1-benzyl-6-(tetrazolo[1,5-a]quinolin-4-yl)piperazine-2,5-dione, a complex heterocyclic scaffold of potential medicinal relevance. The synthetic route commenced with a Ugi four-component reaction (Ugi-4CR) involving 2-chloro-3-formylquinoline (1), an amine (2), 2-chloroacetic acid (3), and an isocyanide (4), furnishing the corresponding Ugi adduct 5 in excellent yield. This intermediate was subsequently subjected to nucleophilic substitution with sodium azide to afford the azide derivative 6. Conversion of 6 through a Staudinger reduction with triphenylphosphine generated the iminophosphorane intermediate 7, which underwent an intramolecular aza-Wittig transformation followed by hydrolysis to provide the desired product 8 in good yield (Scheme 1).
This convergent and modular approach highlights the synthetic versatility of combining multicomponent reactions with post-condensation modifications. The use of readily available starting materials, mild reaction conditions, and the absence of transition-metal catalysts underscore the practicality and cost-effectiveness of the method. Furthermore, the integration of Ugi condensation, azide substitution, Staudinger reduction, and aza-Wittig cyclization demonstrates an efficient bond-forming sequence that rapidly assembles architecturally complex frameworks. Importantly, the developed strategy enables access to heterocycles containing a tetrazole ring, a quinoline core, and a piperazine-2,5-dione motif, structural features frequently encountered in bioactive molecules. Collectively, this work provides not only a valuable synthetic route to a novel heterocyclic system but also a broadly applicable methodology for the construction of nitrogen-rich frameworks with potential pharmaceutical applications.

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