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February 9, 20260 citations

Synthesis of 3,5-Disubstituted-(1H-) and (2H-) Heteroaryl-1,2,4-triazoles via an Oxidative Annulation Strategy.

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EAEmmanuel E AimiuwuDDDamian P. DudaAOAllen G. Oliver

Key Points

  • The aim is to develop a convergent and efficient method for synthesizing disubstituted 1,2,4-triazoles.
  • Utilized iodine-mediated oxidative annulation strategy for synthesis.
  • Incorporated functionalized heteroaryl hydrazonimides and carbaldehydes.
  • Conducted single-crystal X-ray diffraction to confirm tautomer presence.
  • Applied density functional theory computations for mechanistic insight.
  • Successfully synthesized 1H- and 2H-3,5-disubstituted-1,2,4-triazoles.
  • Demonstrated complete chemo-selectivity and scalability of the method.
  • Provided rapid access to a variety of sp2- and sp3-hybridized substituents.

Abstract

1,2,4-Triazole is a ubiquitous heterocycle of significance for pharmaceuticals, materials, and ligand design. A convergent, atom-economical strategy for the construction of this important moiety has been developed, leveraging functionalized heteroaryl hydrazonimides and carbaldehydes via iodine-mediated oxidative annulation in an efficient, scalable, and metal-free manner, providing completely chemoselective 1H- or 2H-3,5-disubstituted-1,2,4-triazoles of relevance to separation science and medicinal chemistry. The twenty-nine-example substrate scope is highlighted by rapid access to sp2- and sp3-hybridized substituents through carbaldehyde selection. Diversely functionalized pyridyl- and heteroaryl components were incorporated through a hydrazonimide synthon with several examples having relevance to unsymmetric, soft-N-donor complexant scaffolds utilized in minor actinide extraction in support of improving the sustainability of the nuclear fuel cycle. Single-crystal X-ray diffraction experiments confirmed the presence of 1H- and 2H-tautomers. Density functional theory computations provided support of a proposed mechanistic hypothesis. Method optimization, substrate scope, scale-up experiments, and a preliminary reaction mechanism are reported herein.

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Cite This Study

Aimiuwu et al. (2026) studied this question.

synapsesocial.com/papers/698979e9f0ec2af6756e7f53https://doi.org/10.1021/acs.joc.5c03029
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