Synthesis of Nitrogen Heterocycles from Methyl α‐ and β‐d‐Glucopyranosides

Eight nitrogen heterocycles, mono and disubstituted tetrazoles and oxadiazoles, were synthesized from methyl d‐glucopyranoside anomers. The monosubstituted tetrazoles resulted from the reaction of 6‐cyanoglucopyranoside derivatives with sodium azide. By alkylation of the monosubstituted tetrazoles, the 1,5 and 2,5 disubstituted tetrazoles were obtained. The monosubstituted tetrazoles were reacted with acetic anhydride to give the oxadiazoles.     

Synthesis of New Tetrazole Derivatives of α,α‐Trehalose

Five new nitrogen heterocycles, mono‐and disubstituted tetrazoles with potential synthetic and pharmacological interest, were synthesized from α, α‐trehalose via the alkylation of commercial tetrazoles. This method appears to have broad scope with respect to the variations at positions 1 and 2 of tetrazole.     

Synthesis of polynuclear heterocyclic polynitrogen systems based on cyanuric chloride and its derivatives

Polynuclear structures containing several heterocycles of various types were synthesized by the reaction of cyanuric chloride and its mono- and dichloro derivatives with triazoles and tetrazoles in the presence of bases.     

Iron(II)‐Based Metalloradical Activation: Switch from Traditional Click Chemistry to Denitrogenative Annulation

A unique concept for the intermolecular denitrogenative annulation of 1,2,3,4‐tetrazoles and alkynes was discovered by using a catalytic amount of Fe(TPP)Cl and Zn dust. The reaction precludes the traditional, more favored click reaction between an organic azide and alkynes, and instead proceeds by an unprecedented metalloradical activation. The method is anticipated to advance access to the construction of important basic nitrogen heterocycles, which will in turn enable discoveries of new drug candidates.     

Features of the synthesis of 1,1′-Phenylenebis(1H-tetrazoles) and their transformations in basic environment

Reactions of substituted 1,3- and 1,4-phenylenediamines with sodium azide and triethyl orthoformate in the presence of acetic acid led to the formation in high yields of the corresponding 1,12 -phenylenebis(1Htetrazoles). The presence of electron-acceptor groups in the molecules of the initial diamines reduces the yield of the target heterocycles. With 2-nitro-1,4-phenylenediamine the prevailing product was 2-nitro-4-(1H-tetrazol-1-yl)aniline. The obtained bistetrazoles in basic environment suffer an opening of one or both heterocycles forming cyanamides.     

Direct electrophilic N-trifluoromethylation of azoles by a hypervalent iodine reagent

Effective CF(3) transfer: Various electron-rich nitrogen heterocycles (pyrazoles, triazoles, and tetrazoles) can be directly N-trifluoromethylated by a hypervalent iodine reagent in an efficient manner. The optimized procedure, which includes an in situ silylation of the substrate followed by an acid-catalyzed CF(3) transfer, provides ready access to a series of new and previously challenging or inaccessible NCF(3) compounds.     

Fast microwave-assisted preparation of aryl and vinyl nitriles and the corresponding tetrazoles from organo-halides

Aryl and vinyl nitriles have been prepared in very high yields from the corresponding bromides using palladium-catalyzed reactions with microwave irradiation employed as the energy source. Furthermore, flash heating was used successfully for the conversion of these nitriles into aryl and vinyl tetrazoles by cycloaddition reactions. One-pot transformation of aryl halides directly to the aryl tetrazoles could be accomplished both in solution and on solid support. All reactions were completed in minutes rather than in hours or days as previously reported with the standard thermal heating technique. A very potent HIV-1 protease inhibitor (K(i) = 0. 56 nM), comprising two tetrazole heterocycles as carboxyl group bioisosteres, was prepared in one pot by microwave-promoted cyanation of a bromo precursor and a subsequent cycloaddition reaction. The temperature-time profiles at 13, 20, and 60 W magnetron input power in DMF are presented.     

Synthesis of tetrazoles,triazoles, and imidazolines catalyzed by magnetic silica spheres grafted acid

The magnetically separable catalysts are used in the synthesis of N-containing heterocycles, including tetrazoles, triazoles, and imidazolines. The magnetic silica sphere grafted sulfonic acid (MSS-SO₃H) is suitable for the synthesis of 1,2,3-triazole via the cycloaddition of nitroalkene with NaN₃, whereas the zinc-modified silica sphere catalyst (MSS-SO₃Zn) is more suitable for the synthesis of tetrazoles. The MSS-SO₃Zn catalyst also works well for the synthesis of 2-substituted imidazoline via the condensation of nitriles with ethylenediamine. Both of the MSS-SO₃H and MSS-SO₃Zn catalysts can be recovered easily by a magnet, and they can be reused without further tedious activation.     

Isotopic hydrogen exchange in methyl derivatives of five-membered aromatic heterocycles

The kinetics of isotopic exchange of the hydrogen atoms of the methyl groups in an alcohol solution of potassium ethoxide were studied for an extensive series of methyl derivatives of azoles and di-, tri-, and tetrazoles. The electronic effect of one or several heteroatoms and substituents on the rate of deuterium exchange of five-membered heterocycles is satisfactorily conveyed by the correlation relationship previously established for a series of substituted toluenes and six-membered heteroaromatic compounds ( _25°=7.6). The limitations that exist in a number of cases are discussed in connection with the peculiarities of the electron-density distribution in five- and six-membered heterocycles.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1196–1201, September, 1977.     

Dimethylheptyl [3-(N-hetaryl)propyl]silanes: Synthesis,antimicrobial and antiblastic activity

The alkylation of monoazoles, diazoles, triazoles and tetrazoles with dimethylheptyl(3-iodopropyl)silane using liquid/liquid phase-transfer catalysis affords the corresponding [3-(N-azolyl)propyl]silanes in high yield, by which means the nonsymmetric ambident heterocycles 1,2,4-triazole and tetrazole undergo alkylation regiospecifically in position 1 and 2, respectively. Dimethylheptyl[3-(N-imidazolyl)propyl]silane demonstrated high fungistatic activity with respect to S. cerevisiae and T.rubrum in combination with high cytotoxicity.     

Mass spectrometry of methyltetrazoles

The mass spectra of tetrazole, all isomers of monomethyl- and dimethyltetrazole, several trifluoromethyl substituted tetrazoles, as well as deuterated analogs, were recorded. Loss of N₂ was the important fragmentation of the molecular ions of tetrazole and 2-methyl substituted tetrazoles; however, HN₂ loss was more important for 1-methyl substituted tetrazoles. The 1-methyl-tetrazoles showed molecular ion peaks while the 2-methyltetrazoles exhibited an unprecedented [M + 1] peak with no molecular ion.     

Quantum-Chemical Study of the Relative Stability of N-Substituted Tetrazole Isomers

The enthalpies of formation and total energies of a series of 1- and 2-substituted tetrazoles in the gas phase and in solution were calculated by MNDO and AM1 semiempirical methods and by a set of nonempirical procedures. The effect of solvent on the relative stability of N-substituted tetrazoles was estimated in terms of the PCM, SM5, and SCRF models. The possibility for isomerization of N-substituted tetrazoles, depending on the substituent in position 1 or 2, was studied at the MP2/6-31G*//HF/6-31G* level. According to the results of nonempirical calculations, 2-substituted tetrazoles are more stable in the gas phase, in keeping with the experimental data for the corresponding isomers. The solvent nature is an important factor affecting isomerization of N-substituted tetrazoles: Rise in the solvent polarity leads to displacement of the equilibrium toward 1-substituted isomers.     

Synthesis of Polynuclear Nonfused Azoles

Polynuclear blocks consisting of nonfused heterocycles of the azole series, connected through methylene bridges, were synthesized by successive addition of azole units via cycloaddition of organic azides to the triple bond of N-(2-propynyl)azoles, as well as via reaction of azide ion at the cyano group of cyanomethylazoles. Initial N-(2-propynyl)azoles were prepared by reaction of 2-propynyl bromide with 1,2,3-triazoles, benzotriazole, and tetrazoles; cyanomethylazoles were obtained by alkylation of azoles with chloroacetonitrile. An analogous scheme was used to add heterocyclic units to 2-phenyl-1,2,3-triazole-4-carbonitrile. In this case, the first two heterocyclic units are linked through the ring carbon atom.     

A Physical Organic Approach towards Statistical Modeling of Tetrazole and Azide Decomposition**

Nitrogen atom-rich heterocycles and organic azides have found extensive use in many sectors of modern chemistry from drug discovery to energetic materials. The prediction and understanding of their energetic properties are thus key to the safe and effective application of these compounds. In this work, we disclose the use of multivariate linear regression modeling for the prediction of the decomposition temperature and impact sensitivity of structurally diverse tetrazoles and organic azides. We report a data-driven approach for property prediction featuring a collection of quantum mechanical parameters and computational workflows. The statistical models reported herein carry predictive accuracy as well as chemical interpretability. Model validation was successfully accomplished via tetrazole test sets with parameters generated exclusively in silico. Mechanistic analysis of the statistical models indicated distinct divergent pathways of thermal and impact-initiated decomposition.     

Clicking the Arsenic–Carbon Triple Bond: An Entry into a New Class of Arsenic Heterocycles

Arsaalkynes can undergo regioselective and quantitative [3+2] cycloaddition reactions with organic azides to give hitherto unknown 3H‐1,2,3,4‐triazaarsole derivatives. The reaction product was obtained as a white, air‐ and moisture‐stable solid, and the presence of a planar, five‐membered arsenic heterocycle was unambiguously verified by means of X‐ray crystallography. DFT calculations gave insight into the electronic structure of these novel compounds compared to tetrazoles and triazaphospholes. The coordination chemistry towards Re^I was investigated and compared with the structurally related phosphorus‐containing ligand. These preliminary investigations pave the way for a new class of arsenic heterocycles and fill the gap between the azaarsoles already known.     

Unanticipated formation of a novel octaazacyclodecane ring upon oxidation of a 1,1‐bis‐urazole

Tetrahydrotetrazoles are a little‐explored class of five‐membered heterocycles with four contiguous singly‐bonded N atoms. Recent work in our labs has demonstrated that urazole radicals are amenable to N—N bond formation via radical combination to form such a chain of four N atoms. Previously described 1,1‐bis‐urazole compounds appeared to be convenient precursors to the target tetrazoles via their oxidation to intermediate urazole diradicals, which upon N—N bond formation would complete the tetrazole framework. While oxidation proceeded smoothly, the novel 10‐membered octaaza heterocycle 7,7,18,18‐tetraacetyl‐4,10,15,21‐tetraphenyl‐1,2,4,6,8,10,12,13,15,17,19,21‐dodecaazapentacyclo[17.3.0.0^2,6.0^8,12.0^13,17]docosan‐3,5,9,11,14,16,20,22‐octone, C₄₂H₃₂N₁₂O₁₂, was obtained (36% yield) instead of the expected tetrazole product, as confirmed by X‐ray crystallography. Calculations at the (U)B3LYP/6‐311G(d,p) level of theory suggest that the desired tetrazoles have weak N—N bonds connecting the two urazole units.     

Local aromaticity study of heterocycles using n-center delocalization indices: the role of aromaticity on the relative stability of position isomers

A quantitative study on local aromaticity based on n-center electron delocalization indices, n being the number of atoms in the ring, is performed on a series of heterocycles containing N, O or S. The results indicate that the order of stability within a series of position isomers is not controlled by aromaticity but by other structural factors. Thus, for a certain series of monocycles position isomers (diazoles, triazoles, tetrazoles, diazines, triazines, and tetrazines) the most stable compound is the least aromatic one and vice versa. However, aromaticity controls the stability for series of isomers where these structural factors are similar. For the case of isocompounds, like isobenzopyrrole, isobenzofuran or isobenzothiophene, the large decrease in the aromaticity of the benzene ring with regard to their isomers makes them less stable.     

Azo coupling of benzenesulfonylhydrazones of heterocyclic aldehydes

The reaction of aldehyde phenylsulfonylhydrazones (VII-XI) with diazotized aromatic and heterocyclic primary amines gave the tetrazoles (XIV-XIX). The yield of the tetrazoles was found to depend to some extent on the nature of the substituent present in the aldehyde moiety. The structures of the tetrazoles obtained was established on the basis of their analytical and spectral data. A tentative explanation for their formation is proposed. The acid dissociation constants of the tetrazoles (XIV) were also determined.     

Organometallic Tetrazole Derivatives: Preparation and Application to Organic Synthesis

The data are integrated and systematized on preparation procedures and application to the organic synthesis of organometallic tetrazole derivatives, including 5-metallated tetrazoles and tetrazoles with a metal-carbon bond in a substituent, and also organotin tetrazoles.     

Synthesis of Glycaro‐1,5‐lactams and Tetrahydrotetrazolopyridine‐5‐carboxylates: Inhibitors of β‐D‐Glucuronidase and α‐L‐Iduronidase

The known glucaro‐1,5‐lactam 8 , its diastereoisomers 9 – 11 , and the tetrahydrotetrazolopyridine‐5‐carboxylates 12 – 14 were synthesised as potential inhibitors of β‐D ‐glucuronidases and α‐L ‐iduronidases. The known 2,3‐di‐O‐benzyl‐4,6‐O‐benzylidene‐D ‐galactose ( 16 ) was transformed into the D ‐galactaro‐ and L ‐altraro‐1,5‐lactams 9 and 11 via the galactono‐1,5‐lactam 21 in twelve steps and in an overall yield of 13 and 2%, respectively. A divergent strategy, starting from the known tartaric anhydride 41 , led to the D ‐glucaro‐1,5‐lactam 8 , D ‐galactaro‐1,5‐lactam 9 , L ‐idaro‐1,5‐lactam 10 , and L ‐altraro‐1,5‐lactam 11 in ten steps and in an overall yield of 4–20%. The anhydride 41 was transformed into the L ‐threuronate 46 . Olefination of 46 to the (E)‐ or (Z)‐alkene 47 or 48 followed by reagent‐ or substrate‐controlled dihydroxylation, lactonisation, azidation, reduction, and deprotection led to the lactams 8 – 11 . The tetrazoles 12 – 14 were prepared in an overall yield of 61–81% from the lactams 54, 28 , and 67 , respectively, by treatment with Tf₂O and NaN₃, followed by saponification, esterification, and hydrogenolysis. The lactams 8 – 11 and 40 and the tetrazoles 12 – 14 are medium‐to‐strong inhibitors of β‐D ‐glucuronidase from bovine liver. Only the L ‐ido‐configured lactam 10 (K_i = 94 μM ) and the tetrazole 14 (K_i = 1.3 mM ) inhibit human α‐L ‐iduronidase.