A Steric Threshold for Tetrazole Annulation: Rationalizing the Reactivity of Heterocyclic Amides With Triazidochlorosilane via Buried Volume

ABSTRACT In this study, an in situ generated triazidochlorosilane reagent (SiCl 4 –NaN 3 ) was employed as a highly efficient and adaptable system for the direct conversion of heterocyclic amides into tetrazole‐fused frameworks. Cyclization of pyridazin‐3‐one derivatives 1a–f and phthalazinone analogues 5a–d proceeded smoothly to afford tetrazolo[1,5‐b]pyridazines 2a–f and tetrazolo[5,1‐ a ]naphthalenes 6a–d , respectively. The structures of the synthesized products were confirmed through elemental analysis and a comprehensive set of spectroscopic techniques. The study revealed that both steric and electronic influences critically govern the annulation efficiency: electron‐withdrawing groups enhanced the transformation, whereas bulky or electron‐releasing substituents led to a reduction in yield. Computational analysis based on percent buried volume (%V bur ) provided a quantitative explanation for these effects, establishing a steric threshold beyond which cyclization is inhibited. Specifically, substrates exhibiting a %V bur greater than 56% experienced significant steric congestion at the amide carbonyl, suppressing the key intramolecular closure and favoring formation of stable azido intermediates. These insights establish a quantitative steric threshold (%V bur > 56%) that predicts the feasibility of tetrazole annulation, providing a valuable design rule for synthetic chemists.