Selective ¹⁵N-Labeling and Analysis of ¹³C−¹⁵N J Couplings as an Effective Tool for Studying the Structure and Azide−Tetrazole Equilibrium in a Series of Tetrazolo[1,5-b][1,2,4]triazines and Tetrazolo[1,5-a]pyrimidines

Abstract

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.

Synthesis of the [2H,15N]-labeled antiviral drug “triazavirine”

“…12 Adiabatic impulses (WURST 20) of 10-20 ms in length and the width of inversion range ~1 kHz (14 ppm for 15 N) were used for the selective 15 N decoupling.…”

NMR Spectroscopic Study of Tautomerism in Solution and in the Solid State

“…Selectively 15 N-labeled derivatives lead to the easy appearance of all 15 N, 13 C coupling constants which, together with 15 N chemical shifts, provide additional structural information [25].…”

Spin-spin coupling constants 13C-15N and 1H-15N in the investigation of azido-tetrazole tautomerism in a series of 2-azidopyrimidines

“…18 Hetaryl azide 2*A (enrichment in 15 N is 86%) containing the isotope label in the  position of the azido group was obtained by the same method from compound 1 (Scheme 2).…”

“…In this case, to introduce the 15 N atom into the azide group/tetrazole fragment, it is necessary to use labeled 5 aminotetrazole, which builds up the azine fragment. 16,18 The 15 N isotope can be included into posi tion 2 of 5 aminotetrazole by the treatment of aminoguani dine with nitrous acid or by the interaction of 15 20 However, in this case, a mixture of 15 N isotopo mers was formed at the  and  positions of the azido group. The use of compound 4** makes it possible to obtain samples of 15 N tetrazolo [1,5 a]pyrimidines with the homogeneous isotope composition.…”

“…Two earlier developed methods 18 were used to measure the 13 С-15 N coupling constants: the method of nonlinear approxi mation of line shapes in the 1D 13 C NMR spectra detected with 15 N nuclear selective decoupling and without it and the method of quantitative SSCCs measurement in amplitude modulated spin echo 1D 13 C experiments accumulated with selective in version of 15 N nuclear magnetization in the spin echo sequence and without it. 18 The 1 H-15 N coupling constant values were quantitatively measured using amplitude modulated spin echo 1D 1 H experiments. Delays (2×) in the range from 0.4 to 1.2 s were used in the spin echo sequence (the total time of mag netization evolution for J C,N and J N,H ).…”