Rapid, Sequential Synthesis of 5-Acetoxy-1-Substituted Tetrazoles Via Heterogeneous FeCl3-Al2O3 Catalysis and Hypervalent Iodine Functionalization
Satheeshkumar Nagaraj, Karpagam Ezhilarasan, Gopalakrishnan Mannathusamy, Rajalakshmi RamarajanAbstract:
The 1,5-disubstituted tetrazole moiety is a critical pharmacophore in medicinal chemistry, valued as a metabolically stable carboxylic acid bioisostere. Existing synthetic routes often suffer from slow kinetics, high costs, or harsh conditions. We report a rapid, sustainable protocol for synthesising 5-acetoxy-1-substituted tetrazoles in two reaction sequences. The first sequence involves a cost-effective FeCl3-Al2O3 heterogeneous catalyst that drives the multicomponent condensation of amines, sodium azide, and triethyl orthoformate, reducing reaction times to ~90 minutes. In the second sequence, the tetrazole core undergoes direct C-5 acetoxylation using iodobenzene diacetate (IBDA) and KOH, proceeding via a hypervalent iodine intermediate. Docking studies against the muscular dystrophy target 2VD5 reveal that the methyl-substituted derivative exhibits superior binding affinity (-5.9 kcal/mol) compared to the standard drug Prednisone (-5.22 kcal/mol). This method offers an efficient, metal-free pathway to bioactive tetrazole derivatives.