¹⁵N Chemical Shifts and J_NN-Couplings as Diagnostic Tools for Determination of the Azide–Tetrazole Equilibrium in Tetrazoloazines

Abstract

Selectively 15N-labeled tetrazolo­[1,5-b]­[1,2,4]­triazines and tetrazolo­[1,5-a]­pyrimidines bearing one, two, or three 15N labels were synthesized. The synthesized compounds were studied by 1H, 13C, and 15N 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 15N-label(s) leads to the appearance of 15N–15N coupling constants (J NN), which can be easily measured via simple 1D 15N NMR spectra, even at natural abundance between labeled and unlabeled 15N atoms. The chemical shifts for the 15N 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 15N-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 15N 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.

Synthesis of a New 1,2,4‐Triazine Derived Azidoxime

“…Neither the azido or the N4-tetrazolo isomers were observed in the solid state or in solution for compounds 2-4. The observed regiochemistry of azide / tetrazolo tautomerization has been documented previously and is preferred thermodynamically over the N4-tetrazolo isomer [10]. Several attempts were made to cyclize 4 to its 1-hydroxytetrazole isomer 5 by screening numerous acids, solvents, and temperatures, however no product was observed.…”

SnAr Reactions of 2,4-Diazidopyrido[3,2-d]pyrimidine and Azide-Tetrazole Equilibrium Studies of the Obtained 5-Substituted Tetrazolo[1,5-a]pyrido[2,3-e]pyrimidines

“…1 H and 13 C NMR spectra were recorded on a Bruker Avance 500 spectrometer (Bruker BioSpin GmbH, Rheinstetten, Germany). Chemical shifts (δ) were reported in ppm and coupling constants (J) in Hz.…”

“…From the synthesis perspective, heterocycles with an azido-azomethine structural entity are interesting due to their intrinsic dynamic azide-tetrazole tautomeric equilibrium in the solution phase (Figure 1a) [8][9][10][11][12][13][14][15] alongside rich azide functional group chemistry [16].…”

Destabilizing Predictive Copper‐Catalyzed Click Reactions by Remote Interactions with a Zinc‐Porphyrin Backbone

“…Ligand L displays substrate‐preorganization features since the zinc‐porphyrin site serves for molecular recognition of nitrogen‐containing substrates whereas the triazolopyridine fragment is able to coordinate by chelation catalytically active iridium sites leading to excellent levels of meta ‐selectivity when applied in iridium‐catalyzed C−H bond borylation reactions [22,23] . However, the access to 2‐azidopyridine derivative reagents is not trivial due to tautomerism and many functional groups are not tolerated during the synthesis process starting from 2‐bromopyridine derivatives [24–43] . Consequently, and in view to obtain supramolecular ligands featuring different substitution patterns in the triazolopyridine site, we envisioned an alternative route that also involves copper‐catalyzed click chemistry, but this time, relying on the treatment of 1 with tosyl azide and further stoichiometric reaction with pyridine N ‐oxides ( Scheme 1, bottom) [44–46] .…”

“…[22,23] How-ever, the access to 2-azidopyridine derivative reagents is not trivial due to tautomerism and many functional groups are not tolerated during the synthesis process starting from 2-bromopyridine derivatives. [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43] Consequently, and in view to obtain supramolecular ligands featuring different substitution patterns in the triazolopyridine site, we envisioned an alternative route that also involves copper-catalyzed click chemistry, but this time, relying on the treatment of 1 with tosyl azide and further stoichiometric reaction with pyridine N-oxides (Scheme 1, bottom). [44][45][46] However, as it is herein presented, the copper-catalyzed click reaction involving the alkyne zinc-porphyrin 1 with tosyl azide did not afford the expected compound 1' but delivered products resulting from nucleophile addition such as sulfonyl imidates or sulfonyl amides (2).…”