One-pot synthesis of 3-tetrazolylmethyl-4H-chromen-4-ones via Ugi-azide reaction

1,5-disubstituted tetrazoles (1,5-Ds-T) are heterocyclic bioisosteres of the cis-amide bond and are widely employed in medicinal chemistry to enhance the pharmacokinetic and pharmacodynamic properties of peptidomimetics. Their incorporation can improve potency, selectivity, and metabolic stability while reducing toxicity. Beyond their biomedical applications, 1,5-Ds-T have been used as ligands, chelating agents, metal-organic framework precursors (MOFs), and bioimaging probes.

On the other hand, chromones are privileged scaffolds found in a wide range of natural products and are well recognized for their broad spectrum of biological activities, including anticancer, antimicrobial, antidiabetic, anti-inflammatory and antioxidant properties.

Isocyanide-based multicomponent reactions (IMCR) are efficient tools to synthesize nitrogen heterocycles, such as 1,5-Ds-T. Among them, the Ugi-azide four-component reaction (UA-4CR) stands out for its versatility and mild reaction conditions for the one-pot synthesis of 1,5-Ds-T. This UA-4CR involves an aldehyde or ketone, an amine, an isocyanide, and an azide source, commonly trimethylsilyl azide (TMSN₃), which generates hydrazoic acid in situ.

Herein, we report a one-pot process via the UA-4CR for the synthesis of 1,5-Ds-T incorporating a chromone moiety, under mild conditions, affording moderate overall yields (46-59%). This strategy approach provides a valuable platform for generating novel tetrazole–chromone analogs with potential application in medicinal chemistry and materials science.