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.
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.
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.
A new method was developed for the investigation of an azido tetrazole equilibrium based on using a complex analysis of 13 С-15 N and 1 H-15 N spin spin coupling constants. The use of this approach became possible due to the selective inclusion of 15 N isotopes into the structures of 2 azidopyrimidines and their cyclic analogs tetrazolo[1,5 a]pyrimidines.
A new in principle method for the synthesis of 6 aryl(hetaryl) 3,5 diamino 1,2,4 triazines by decomposition of pre synthesized tetrazolo[1,5 b] [1,2,4]triazines was developed. The ad vantages of this method over traditional methods were demonstrated using the synthesis of a modern antiepileptic preparation lamotrigine, as an example.
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 1H-1H and 1H-13C NMR correlation experiments (COSY and HMBC, respectively) or nuclear Overhauser effect spectroscopy (NOESY or ROESY). The selective incorporation of 15N-labelled atoms in different positions of the heterocyclic core allowed for the use of 1H-15N (J
HN) and 13C-15N (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 1H spin-echo experiments with the selective inversion of the 15N nuclei and line-shape analysis in the 1D 13С spectra acquired with selective 15N decoupling, respectively. Additional spin–spin interactions were detected in the 15N-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 15N-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.
A new procedure was developed for the synthesis of 6 phenyltetrazolo[1,5 b]triazin 7 one. Aza analogs of uracil and isocytosine were prepared by the tetrazole ring cleavage. It was demonstrated that these transformations can be used in the synthesis of anomalous nucleo sides.