Selective methods for the incorporation of stable isotopes 15 N and 2 H into the structure of antiviral medicine "triazavirine" 1 were developed. The synthesized isotopically modified "tri azavirine" 1 2 H 3 , 15 N 3 contained the labeled atoms in both the azole and the azine rings. 13 C and 15 N NMR spectra of the isotope containing sample 1 2 H 3 , 15 N 3 were thoroughly analyzed.

ABSTRACT:The selectively 15 N labeled azido-1,2,4-triazine 2*A and azidopyrimidine 4*A were synthesized by treating hydrazinoazines with 15 N-labeled nitrous acid. The synthesized compounds were studied by 1 H, 13 C, and 15 N NMR spectroscopy in DMSO, TFA, and DMSO/TFA solutions, where the azide−tetrazole equilibrium could lead to the formation of two tetrazoles (T, T′) and one azide (A) isomer for each compound. The incorporation of the 15 N label led to the appearance of long-range 1 H− 15 N coupling constants (J HN ), which can be measured easily by using amplitude-modulated 1D 1 H spin−echo experiments with selective inversion of the 15 N nuclei. The observed J HN patterns enable the unambiguous determination of the mode of fusion between the azole and azine rings in the two groups of tetrazole isomers (2*T′, 4*T′ and 2*T, 4*T), even for minor isoforms with a low concentration in solution. However, the azide isomers (2*A and 4*A) are characterized by the absence of detectable J HN coupling. The analysis of the J HN couplings in 15 N-labeled compounds provides a simple and efficient method for direct NMR studies of the azide−tetrazole equilibrium in solution.

A Pot, Atom, Step Economic (PASE) approach is reported towards [1, 2,4]triazolo[1, 5‐d][1, 2,4]triazines, substituted with the azole ring with pharmacophore residues, such as 1‐adamantyl or 2‐furanyl moieties, naproxen residues, as well aliphatic and (het)aromatic substituents, starting from easily available 1,2,4‐triazine‐5‐carbonitriles and carboxylic acids hydrazides. This approach involves a sequence of two solvent‐free reactions accompanied by the Dimroth rearrangement on the last step. The structures of the final Dimroth rearrangement products were confirmed based on the DFT studies as well as the single crystal X‐ray analysis for the admantane‐substituted product. In addition, this method possesses lower E‐factors.

This review provides a generalization of effective examples of 15N labeling followed by an analysis of JCN and JHN couplings in solution as a tool to study the structural aspects and pathways of chemical transformations in nitrogen heterocycles.

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