1,5-disubstituted tetrazoles are bioisosteres of cis-amide bond in peptides by adopt their steric conformation, which have contributed to decrease toxicity, increase potency, improve stability, selectivity, and pharmacokinetic properties in peptidomimetics. Additionally, they have been used as bidentate ligands, chelating agents, metal-organic framework precursors, bioimaging agents, energetic materials such as explosives, propellants and pyrotechnics. Isocyanide based multicomponent reactions have proven to be versatile synthetic tools for the synthesis of heterocycles, specifically the Ugi-azide reaction is the best tool to access 1,5-disustituted tetrazoles under mild conditions, in which orthogonal reagents can be included into components to increase its synthetic potential. The Ugi-azide reaction involve an aldehyde or ketone, an amine, an isocyanide and replaced the carboxylic acid used in the classical Ugi reaction by hydrazoic acid. In that the imine is protonated by hydrazoic acid and the remaining azide anion captures the intermediate nitrilium ion, leading to the formation of the final 1,5-disubstituted tetrazole. In the past, Ugi was using isolated hydrazoic acid in a benzene stock solution. Nowadays, trimethylsilyl azide is often used as a safer alternative to azide source, generating hydrazoic acid in situ in protic solvents. Herein we developed a one-pot synthesis under mild conditions to access functionalized 1,5-disubstituted tetrazoles which could be synthetic platforms for further post-transformations.
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Multicomponent one-pot synthesis of 1,5-disubstituted tetrazoles functionalized with azides
Published:
14 November 2024
by MDPI
in The 28th International Electronic Conference on Synthetic Organic Chemistry
session General Organic Synthesis
https://doi.org/10.3390/ecsoc-28-20137
(registering DOI)
Abstract:
Keywords: 1,5-disubstituted tetrazoles (1,5-DS-T), azides, IMCR, Ugi-azide, one-pot