Search

The C-N coupling of 1,2,4-triazolo[1,5-a]pyrimidin-7-ones with 1-adamantanol/1-bromoadamantane leads to 1,2,4-triazolo[4,3-a]pyrimidinium-5-olates, which are represented as mesomeric betaines (MBs). The formation of MBs involves not only N-alkylation of heterocyclic framework but also the rearrangement leading to a change in the type of fusion between pyrimidine and 1,2,4-triazole fragments. The structures of the obtained products were confirmed by the X-ray analysis and measurements of 13 C- 13 C (J CC ) coupling constants in the 1D 13 C NMR spectra of selectively 13 C-labeled samples. Treatment of the betaines with lithium bis(trimethylsilyl)amide (LiHMDS) gave anionic carbenes, which were detected by 13 C NMR spectroscopy and were trapped by reactions with phenyl isothiocyanate and sulfur. Density functional theory (DFT) and the quantum theory of atoms in molecules (QTAIM) analyses allowed for an insight into the electronic structure of the obtained betaines and N-heterocyclic carbene derivatives., (© 2023 Wiley-VCH GmbH.)

Selectively 15 N-labeled tetrazolo[1,5- b ][1,2,4]triazines and tetrazolo[1,5- a ]pyrimidines bearing one, two, or three 15 N labels were synthesized. The synthesized compounds were studied by 1 H, 13 C, and 15 N NMR spectroscopy in DMSO and TFA solutions, where the azide-tetrazole equilibrium can lead to the formation of two tetrazole ( T , T' ) isomers and one azide ( A ) isomer for each compound. Incorporation of the 15 N-label(s) leads to the appearance of 15 N- 15 N coupling constants ( J NN ), which can be easily measured via simple 1D 15 N NMR spectra, even at natural abundance between labeled and unlabeled 15 N atoms. The chemical shifts for the 15 N nuclei in the azole moiety are very sensitive to the ring opening and azide formation, thus providing information about the azido-tetrazole equilibrium. At the same time, the 1-2 J NN couplings between 15 N-labeled atoms in the azole and azine fragments unambiguously determine the fusion type between tetrazole and azine rings in the cyclic isomers T and T' . Thus, combined analysis of 15 N chemical shifts and J NN values in selectively isotope-enriched compounds provides an effective diagnostic tool for direct structural determination of tetrazole isomers and azide form in solution. This method was found to be the most simple and efficient way to study the azido-tetrazole equilibrium.

Isotope-labeled antiviral drug Triazavirin containing 2 H, 13 C, and 15 N atoms in its structure has been synthesized. 13 C 2 H 3 I and KS 13 CN served as donors of 13 C isotopes. The use of 13 С-MeI containing 2 H atoms made it possible to additionally incorporate deuterium labels into the structure of the compound. The 15 N atoms were incorporated using 15 N-enriched sodium nitrite, aminoguanidine carbonate, and ethyl nitroacetate. The resulting 2 H 3 , 13 C 2 , 15 N 3 -Triazavirin was characterized by NMR spectroscopy., Supplementary Information: The online version contains supplementary material available at 10.1007/s10593-021-02927-1., (© Springer Science+Business Media, LLC, part of Springer Nature 2021.)

This review provides a generalization of effective examples of 15 N labeling followed by an analysis of 13 C- 15 N ( J CN ) and 1 H- 15 N ( J HN ) coupling constants in solution as a tool to study the structural aspects and pathways of chemical transformations ( e.g. , rearrangements and ring-chain tautomerisms) in monocyclic and fused nitrogen heterocycles. This approach allows us to significantly expand and supplement the scope of NMR techniques for heterocyclic compounds. Moreover, methods for the incorporation of 15 N atoms into the cores of various N-heterocycles have been collected in this work., Competing Interests: The authors declare no conflict of interest., (This journal is © The Royal Society of Chemistry.)

Determining the accurate chemical structures of synthesized compounds is essential for biomedical studies and computer-assisted drug design. The unequivocal determination of N-adamantylation or N-arylation site(s) in nitrogen-rich heterocycles, characterized by a low density of hydrogen atoms, using NMR methods at natural isotopic abundance is difficult. In these compounds, the heterocyclic moiety is covalently attached to the carbon atom of the substituent group that has no bound hydrogen atoms, and the connection between the two moieties of the compound cannot always be established via conventional 1 H- 1 H and 1 H- 13 C NMR correlation experiments (COSY and HMBC, respectively) or nuclear Overhauser effect spectroscopy (NOESY or ROESY). The selective incorporation of 15 N-labelled atoms in different positions of the heterocyclic core allowed for the use of 1 H- 15 N ( J HN ) and 13 C- 15 N ( J CN ) coupling constants for the structure determinations of N-alkylated nitrogen-containing heterocycles in solution. This method was tested on the N-adamantylated products in a series of azolo-1,2,4-triazines and 1,2,4-triazolo[1,5- a ]pyrimidine. The syntheses of adamantylated azolo-azines were based on the interactions of azolo-azines and 1-adamatanol in TFA solution. For azolo-1,2,4-triazinones, the formation of mixtures of N -adamantyl derivatives was observed. The J HN and J CN values were measured using amplitude-modulated 1D 1 H spin-echo experiments with the selective inversion of the 15 N nuclei and line-shape analysis in the 1D 13 С spectra acquired with selective 15 N decoupling, respectively. Additional spin-spin interactions were detected in the 15 N-HMBC spectra. NMR data and DFT (density functional theory) calculations permitted to suggest a possible mechanism of isomerization for the adamantylated products of the azolo-1,2,4-triazines. The combined analysis of the J HN and J CN couplings in 15 N-labelled compounds provides an efficient method for the structure determination of N-alkylated azolo-azines even in the case of isomer formation. The isomerization of adamantylated tetrazolo[1,5- b ][1,2,4]triazin-7-ones in acidic conditions occurs through the formation of the adamantyl cation.

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.

Two general methods for the selective incorporation of an (15)N-label in the azole ring of tetrazolo[1,5-b][1,2,4]triazines and tetrazolo[1,5-a]pyrimidines were developed. The first approach included treatment of azinylhydrazides with (15)N-labeled nitrous acid, and the second approach was based on fusion of the azine ring to [2-(15)N]-5-aminotetrazole. The synthesized compounds were studied by (1)H, (13)C, and (15)N NMR spectroscopy in both DMSO and TFA solution, in which the azide-tetrazole equilibrium is shifted to tetrazole and azide forms, respectively. Incorporation of the (15)N-label led to the appearance of (13)C-(15)N J coupling constants (J(CN)), which can be measured easily using either 1D (13)C spectra with selective (15)N decoupling or with amplitude modulated 1D (13)C spin-echo experiments with selective inversion of the (15)N nuclei. The observed J(CN) patterns permit unambiguous determination of the type of fusion between the azole and azine rings in tetrazolo[1,5-b][1,2,4]triazine derivatives. Joint analysis of J(CN) patterns and (15)N chemical shifts was found to be the most efficient way to study the azido-tetrazole equilibrium.

A new class of inhibitors of herpes simplex virus replication was found. The compounds under study are derived from condensed 1,2,4-triazolo[5,1-c][1,2,4]triazines and 1,2,4-triazolo[1,5-a]pyrimidines, structural analogues of natural nucleic bases. Antiherpetic activity and cytotoxicity of the compounds were studied. The corresponding triphosphates of several active compounds were prepared and tested as inhibitors of DNA synthesis catalyzed by herpes simplex virus polymerase. The potential mechanism of their action is blocking of DNA dependent DNA polymerase, a key enzyme of viral replication., (Copyright © 2010 Elsevier Inc. All rights reserved.)