Azide-tetrazole Equilibrium Research Articles

Structural study of azide-tetrazole equilibrium in pyrido[2,3-d]pyrimidines

C-5 Substituted pyrido[3,2-e]tetrazolo[1,5-a]pyrimidines were obtained by simple azidation of 2,4-dichloropyrido[2,3-d]pyrimidine followed by SNAr reactions with S-, N- and O-nucleophiles. Their NMR and IR studies revealed that the mono-azido products undergo azide-tetrazole equilibrium, whereas 2,4-diazidopyrido[2,3-d]pyrimidine exists in four tautomeric forms in various solutions, and its solid phase tautomer was established by the X-ray analysis. In total, nine of the obtained products are fully characterized by their single crystal X-ray structures and seven of them revealed a novel annulated pyrido[3,2-e]tetrazolo[1,5-a]pyrimidine skeleton. Among the studied products the amino derivatives - 5-aminopyrido[3,2-e]tetrazolo[1,5-a]pyrimidines - exist mainly in their tetrazole form both in the solid phase and in the solutions. However, also the latter enter the tautomeric equilibrium and the liberated azido group is able to undergo copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction and form the corresponding 1,2,3-triazole derivatives. Free Gibbs energies of the tautomerization of C-5 substituted cyclohexylmercapto-, isopropyloxy- and phenoxy-pyrido[3,2-e]tetrazolo[1,5-a]pyrimidines were found to be -21.30, -23.19 and -17.02 kJ/mol, respectively.

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

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 (JNN), 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 1-2JNN 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 JNN 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 and antimicrobial evaluation of novel polyheterocyclic systems derived from cyclopenta[4',5']pyrido[3',2':4,5]furo[3,2-d]pyrimidine

The synthesis of new cyclopenta[4',5']pyrido[3',2':4,5]furo[3,2-d]pyrimidin-7-amines have been carried out to study their antimicrobial activity. The biological tests evidenced that some of the synthesized compounds exhibit pronounced antimicrobial properties. A study of the structure–activity relationship revealed that the 3,5-dimethyl-1H-pyrazol-1-yl moiety linked to the carbon C-9 of the pyrimidine plays a decisive role in the manifestation of activity. The influence of 3,5-dimethyl-1H-pyrazol-1-yl group on the Dimroth rearrangement and azide-tetrazole equilibrium has also been examined.

4-Azidotetrahydroquinazoline derivatives in CuAAC reaction

4-Azido-2-methyltetrahydroquinazoline N-oxide cleanly undergoes the copper( i )-catalyzed azide–alkyne cycloaddition (CuAAC) reaction with alkynes to give new conjugates with pyrimidine N-oxide and triazole moieties. Its deoxygenated analogue, 4-azido-2-methyltetrahydroquinazoline, is inert in CuACC process due to the shift of imidoyl azide–tetrazole equilibrium towards the tetrazole tautomer.

Efficient Synthesis and Some Transformations of 1-Hydrazinyl-5,6,7,8-tetrahydroisoquinolines Involving Rearrangement of the Pyridine Ring

—A procedure was developed for the synthesis of 1-hydrazinyl-3-arylamino-5,6,7,8-tetrahydroisoquinoline- 4-carbonitriles via recyclization of the pyridine ring in 3-amino-2-aryl-1-sulfanylidene-1,2,5,6,7,8- hexahydroisoquinoline-4-carbonitriles by the action of hydrazine hydrate. The recyclization products were converted to new heterocyclic systems, 7,8,9,10-tetrahydro[1,2,4]triazolo[3,4-a]isoquinolines and 1-(3,5-dimethyl- 1H-pyrazol-1-yl)-5,6,7,8-tetrahydroisoquinolines, by reactions with triethyl orthoformate and acetylacetone, respectively. Treatment of 1-hydrazinyl-3-arylamino-5,6,7,8-tetrahydroisoquinoline-4-carbonitriles with sodium azide in acetic acid gave 1-azido-3-arylamino-5,6,7,8-tetrahydroisoquinoline-4-carbonitriles, and azide–tetrazole isomerism of the latter was studied. The state of the azide–tetrazole equilibrium was found to depend on the solvent polarity and substituent nature in the arylamino group. The structure of 5-(2-methoxyanilino)- 7,8,9,10-tetrahydro[1,2,4]triazolo[3,4-a]isoquinoline-6-carbonitrile was confirmed by X-ray analysis, and intermolecular hydrogen bonds were detected in its crystal structure. The synthesized compounds were evaluated for antimicrobial activity.

Synthesis and study of the azide-tetrazole tautomerism in 2-azido-4-(trifluoromethyl)-6-R-pyrimidines (R = H, 4-ClC6H4)

Azide-tetrazole equilibrium in azidopyrimidines bearing trifluoromethyl group on the example of 2-azidopyrimidines has been studied. The latter were synthesized via nitrosation of 2-hydrazino-4-trifluoromethylpyrimidine and reaction of NaN3 with 4-trifluoromethyl-2- chloro-6-(4-chlorophenyl)pyrimidine. The tautomeric equilibrium 5-trifluoro methyl tetrazolo[1,5-a]pyrimidine ⇆ 2-azido-4-trifluoromethylpyrimidine was observed in the absence of solvent and in DMSO-d6 solution, whereas in CDCl3 only an azide form exists. For 2-azido- 4-trifluoromethyl-6-(4-chlorophenyl)pyrimidine, only an azide isomer was detected in CDCl3 solution, and in DMSO-d6 solution it is in equilibrium with 5-(trifluoromethyl)-7-(4-chlorophenyl) tetrazolo[1,5-a]pyrimidine (the tautomer ratio is 99 : 1). Thermodynamic and kinetic parameters of 5-trifluoromethyltetrazolo[1,5-a]pyrimidine ⇆ 2-azido-4-trifluoromethylpyri midine tautomeric rearrangement in DMSO-d6 for 5-trifluoromethyltetrazolo[1,5-a]pyrimidine were determined using the exchange spectroscopy (EXSY) technique.

Synthesis and antimicrobial activity of new amino derivatives of pyrano[4’’,3’’:4’,5’]pyrido[3’,2’:4,5]thieno[3,2-d]pyrimidine

Annulated thienopyrimidine derivatives attracted big interest of the scientific community due to their broad spectrum of biological activities among which are the inhibition of phosphodiesterase, antiproliferative and antimicrobial activities. As a continuation of our studies on the synthesis and biological activity of fused thieno[3,2-d]pyrimidine derivatives, the goal of this paper is the synthesis and study of the properties of compounds containing different heterocycles such as fused thieno[2,3-b]pyridine and tetrazolo[1,5-c]pyrimidine in the same molecule. Thus, starting from the ethyl 1-amino-5-isopropyl-8,8-dimethyl-8,9-dihydro-6H-pyrano[4,3-d]thieno[2,3-b]pyridine-2-carboxylate 1, efficient methods for obtaining new 8-amino-5-isopropyl-2,2-dimethyl-10-(methylthio)-1,4-dihydro-2H-pyrano[4'',3'':4',5']pyrido[3',2':4,5]thieno[3,2-d]pyrimidines 6 and thieno[2,3-e]tetrazolo[1,5-c]pyrimidine 8 are described. The spectroscopic results showed that compound 8 in the solid state is exclusively in the tetrazolo tautomeric form, while in solution an azide-tetrazole equilibrium is present 8A/T. The possible antimicrobial activity of newly synthesized compounds against some gram-positive and gram-negative bacilli strains has been evaluated. The biological tests evidenced that some of them showed promising antimicrobial activity. Two compounds showed similar activity to the one of the used reference drug. The study of structure-activity relationships revealed that the activity of a compound depends mostly on the nature of substituent R1R2. According to the predicted docking studies our compounds could be DnaG inhibitors.

Effective synthesis of 6-substituted 7H-tetrazolo[5,1-b][1,3,4]thiadiazines via a one-pot condensation/nitrosation/azide-tetrazole tautomerism reaction sequence

A new, simple, and general method for the synthesis of 6-R-7H-tetrazolo[5,1-b][1,3,4]thiadiazines (R=Ar, Het, Alk) has been developed. The described method is based on the one-pot condensation of α-haloketones with thiocarbohydrazide, nitrosation of the formed hydrazinylthiadiazine using NaNO2/HCl, and intramolecular cyclization of the nitrosation product via azide-tetrazole tautomerism. Spectroscopic and structural investigations revealed that the azide-tetrazole equilibrium is completely shifted to the tetrazole form both in solution and the solid state.

A structural study on the azide–tetrazole equilibrium in the azidobenzothiazole system. DFT-treatment

Many 2-substituted benzothiazole derivatives are reported to possess a broad spectrum of biological activities, 2-azidobenzothiazole is scarely reported in the literature. This study investigates the structural properties of some azidobenzothiazoles, in addition to the azido–tetrazole isomerism. All calculations were carried out using a Gaussian 09 package and the DFT-B3LYP/6-311+G(d,p) procedure.The optimized geometry, the NBO-charge density, and the molecular orbitals, of all the studied species were investigated and discussed. The azide–tetrazole isomerism proved to be initiated by a “π-atomic orbital” overlap process rather than by an “electrostatic” attraction process. Solvent effect on the studied isomerism for the parent 2-azidobenzothiazole has been investigated. The Self Consistent Reaction Field (SCRF) theory and the Polarizable Continuum Model (PCM) at the B3LYP/6-311+G(d,p) level were used.

Long-Range 1H–15N J Couplings Providing a Method for Direct Studies of the Structure and Azide–Tetrazole Equilibrium in a Series of Azido-1,2,4-triazines and Azidopyrimidines

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 theoretical DFT study on the structural parameters and azide–tetrazole equilibrium in substituted azidothiazole systems

Azido–tetrazole equilibrium is sensitive to: substitution, solvent, temperature and phase. In this work, the effects of the type and position of substitution on the thiazole ring of azidothiazoles on its structural parameters and on the azido–tetrazole equilibrium have been theoretically investigated using the density functional procedures at the B3LYP/6-311G∗∗ level of theory. This study includes the investigation of the equilibrium geometry, the transformation of the trans-conformer to the cis one then the ring closure to the tetrazole isomer. The transition states of the two steps were located, confirmed and the structural parameters were calculated. In all the steps of calculations, geometry optimization was considered.The results obtained indicate that substitution by: –NO2 and –CN group shifts the equilibrium to the azide side and in some cases the tetrazole isomer is not obtained. On the other hand, substitution by: –NH2 and –OH groups shifts the equilibrium to the tetrazole side and in some cases the azide isomer is not obtained and if formed changes spontaneously to the tetrazole isomer.The decisive parameters which determine the position of the equilibrium are: charge density on atoms N3 and N8, rearrangement of bond length and bond angles during the process of cyclization and variation of dipole moment as a result of cyclization.Results of this work indicate that substitution on C5 is more efficient than substitution on C4 of the thiazole ring.

Nitrenes, Diradicals, and Ylides. Ring Expansion and Ring Opening in 2-Quinazolylnitrenes

Tetrazolo[1,5-a]quinazoline (9) is converted to 2-azidoquinazoline (10) on sublimation at 200 degrees C and above, and the azide-tetrazole equilibrium is governed by entropy. 2-Quinazolylnitrenes 11 and 27 and/or their ring expansion products 14 and 29 can undergo type I (ylidic) and type II (diradicaloid) ring opening. Argon matrix photolysis of 9/10 affords 2-quinazolylnitrene (11), which has been characterized by ESR, UV, and IR spectroscopy. A minor amount of a second nitrene, formed by rearrangement or ring opening, is also observed. A diradical (19) is formed rapidly by type II ring opening and characterized by ESR spectroscopy; it decays thermally at 15 K with a half-life of ca. 47 min, in agreement with its calculated facile intersystem crossing (19T --> 19OSS) followed by facile cyclization/rearrangement to 1-cyanoindazole (21) (calculated activation barrier 1-2 kcal/mol) and N-cyanoanthranilonitrile (22). 21and 22 are the isolated end products of photolysis. 21 is also the end product of flash vacuum thermolysis. An excellent linear correlation between the zero-field splitting parameter D (cm(-1)) and the spin density rho on the nitrene N calculated at the B3LYP/EPRIII level is reported (R2 = 0.993 for over 100 nitrenes). Matrix photolysis of 3-phenyltetrazolo[1,5-a]quinazoline (25) affords the benzotriazacycloheptatetraene 29, which can be photochemically interconverted with the type I ring opening product 2-isocyano-alpha-diazo-alpha-phenyltoluene (33) as determined by IR and UV spectroscopy. The corresponding carbene 37, obtained by photolysis of 33, was detected by matrix ESR spectroscopy.

Effect of intramolecular hydrogen bond on the azide-tetrazole equilibrium of 5-(2?-hydroxyphenyl)tetrazolo[1,5-a]pyrimidine,-tetrazolo[1,5-c]pyrimidme, -tetrazolo[1,5-c]quinazoline, and 7-(2?-hydroxyphenyl)tetrazolo[1,5-c]pyrimidine

The intramolecular hydrogen bond between the phenolic hydroxyl and the pyrimidine nitrogen atom in the title compounds exerts a destabilizing effect on the tetrazole ring and shifts the azide-tetrazole equilibrium toward the azide form, especially in the case of tetrazolo[c]pyrimidine and -[c]quinazoline. It has been found that the introduction of a methoxy group into theortho-position of the phenyl fragment stabilizes the tetrazole tautomer more efficiently than introduction of this group into thepara-position.