Sonochemical synthesis of alkyne-functionalized 1,5-disubstituted tetrazoles via Ugi-azide reaction

Nitrogen-containing heterocycles are present in natural products and synthetic drugs and are among the most relevant target molecules in organic synthesis due to their wide range of valuable applications across several fields. 1,5-disubstituted tetrazoles (1,5-Ds-T) have attracted interest as bioisosteres of carboxylic acid and amide bonds because they enhance pharmacokinetic and pharmacodynamic properties and have found applications in medicinal chemistry, coordination chemistry, materials science, and chemical biology.

Isocyanide-based multicomponent reactions (IMCRs) are efficient and versatile tools for the sustainable synthesis of nitrogen-containing heterocycles, offering high convergence, atom- and step-economy, mild conditions, broad scope, operational simplicity, high overall yields, reduced waste generation, and use of readily accessible starting materials. Specifically, the four-component Ugi-azide reaction (UA-4CR) is an effective one-pot process for accessing 1,5-Ds-Ts under eco-friendly conditions. Furthermore, incorporating orthogonal reagents as inputs expands their synthetic versatility. The use of alternative energy sources, such as ultrasound irradiation, in IMCRs is emerging as a highly efficient approach that aligns with several principles of green chemistry, enabling accelerated reaction rates, reduced reaction times, and improved yields.

Herein, we report the development of a sonochemical UA-4CR for the synthesis of alkyne-functionalized 1,5-Ds-Ts under mild conditions, which could serve as versatile synthetic platforms for further post-transformations.