Synthetic strategies for 1,4,5/4,5-substituted azoles: A perspective review

Azole nucleus represents an important class of biologically active compounds that are gaining more attention in the field of medicinal chemistry due to large number of structure diversity. Among azoles, pyrazoles, and isoxazoles five-membered nitrogen containing heterocyclic compounds are associated wide range of biological activities such as anticancer, antimicrobial, anti-inflammatory, antioxidant, etc. Some of azole derivatives (e.g., 1,4,5-trisubstituted pyrazoles, 4,5-disubstituted isoxazoles, and 4,5-disubstituted-1H-pyrazoles) are still unexplored in literature, these unexplored azoles have fascinated the consideration of many researchers to study their framework synthetically and biologically. This present review is an attempt to update and understand the chemistry of unexplored pyrazoles and isoxazoles along with their medicinal importance. This article would definitely help the researchers to bring further enhancement in the synthesis of biologically active pyrazoles and isoxazoles.     

Research in the field of unsaturated derivatives of azoles. 12. Reaction of benzimidazole-2-thione with 1,2-dibromoethane; template synthesis of coronands

Benzimidazole-2-thione and 2-(mercaptomethyl)benzimidazole react with 1,2-dibromoethane in the presence of caustic under conditions of interfacial catalysis, forming macrocyclic compounds along with linear compounds.For communication 11, see [1].Rostov State University, Rostov-on-Don 344090. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 571–574, April, 1995. Original article submitted March 11, 1995.     

Diazocarbonyl and Related Compounds in the Synthesis of Azoles

Diazocarbonyl compounds have found numerous applications in many areas of chemistry. Among the most developed fields of diazo chemistry is the preparation of azoles from diazo compounds. This approach represents a useful alternative to more conventional methods of the synthesis of azoles. A comprehensive review on the preparation of various azoles (oxazoles, thiazoles, imidazoles, pyrazoles, triazoles, and tetrazoles) from diazocarbonyl and related compounds is presented for the first time along with discussion of advantages and disadvantages of «diazo» approaches to azoles.     

Thermal latent coordination compounds

Complexes of the type M(Pa)₂(HAz)₂ and M(QA)₂(HAz)₂ (M=cobalt(II) and nickel(II); HPa=picolinic acid, HQa=quinaldic acid; HAz=azoles like imidazole (Him), pyrazole (HPz), benzimidazole (HBzIm) etc.) show a similar thermal behaviour. In the first step of decomposition the corresponding azolinium picolinates or quinaldinates (H₂AzPa, H₂AzQa) are split off with formation of polymeric mixed ligand complexes M(Pa)(Az) or M(Qa)(Az). X-ray analysis of Co(Qa)₂(HBzIm)₂ XIIIa illustrates a proton transfer and a subsequent thermal removal of benzimidazolinium quinaldinate (H₂BzImQa): Hydrogen bridges from pyrrole nitrogen of the benzimidazole to the non-coordinated oxygen of the quinaldinate predetermine the thermal initiated proton transfer. The high volatility of the heterocyclic acids and the nitrogen coordination are responsible for the formation of the mixed ligand complex Co(Qa)(BzIm) XIVa. Exceptions are the complexes M(Pa)₂(HPz)₂ XIa-b and M(Qa)₂(HIm)₂ XVIIa-b. Pyrazole is eliminated from the complexes XIa-b with formation of the solvent-free inner complex M(Pa)₂ XIIa-b. From compounds XVIIIa-b quinaldic acid or their decomposition products are split off and a high temperature modification of M(Im)₂ XVIIIa-b is formed at elevated temperature. XVIIIa-b are decomposed to the cyanides M(CN)₂ similarly to the thermal behaviour of Cu(Im). In the first step the thermal degradation of imidazole and pyrazole adducts of copper(II) picolinates and quinaldinates is characterized by the elimination of azoles. The reason for this thermal behaviour is the weaker coordination of the azole heterocycles in copper chelate compounds.     

Fluorescent Pyrene‐Based Bis‐azole Compounds: Synthesis and Photophysical Analysis

A rational synthetic procedure for the preparation of a series of pyrene‐based neutral and dicationic bis‐azole compounds is reported. The method allows the tailored design of pyrene‐based azoles with different substituents at the nitrogen atoms of the heterocycles, for which the relative conformation of the resulting bis‐azoles can be easily controlled. The bis‐azoliums were used for the preparation of the related diplatinum complexes by reaction with [{Pt(ppy)(μ‐Cl)₂}₂] (ppy=2‐phenylpyridinate). The X‐ray molecular structure of one of the resulting compounds, a diplatinum(II) bis(N‐heterocyclic carbene) complex, is described. Studies on the photophysical properties of all new species are described. The emission of the bis‐azole‐based compounds seems to be independent of their substitution patterns, which basically indicates that physical properties such as solubility, melting point, and viscosity can be fine‐tuned while maintaining the luminescence properties. Finally, the energies associated with the HOMO and LUMO levels suggest that this family provides versatility to match the energy levels of a wide range of host materials, which is important for the preparation of organic light‐emitting devices.     

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.     

Research in the field of unsaturated derivatives of azoles. 11. Reaction of benzimh)azole-2-thione with 1,2,3-tribromopropane

In the interaction of benzimidazole-2-thione with 1, 2, 3-tribromopropane under conditions of interfacial catalysis in an alkaline medium, 2-(2-bromo-2-propenylthio)benzimidazole is formed; debromination of this compound affords 3-methylthiazolo[3,2-a]benzimidazole, which is subsequently converted as a result of thermolysis to 2-propadienylthio)benzimidazole.For communication 10, see [1].Rostov State University, Rostov-on-Dan 344090. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 567–570, April, 1995. Original article submitted March 11, 1995.     

Investigation of the electrosurface properties of NiO and Fe2O3 in azole solutions

The electrokinetic study of heterogeneous system consisting of Ni(II) and Fe(III) oxide powders in aqueous azole solutions is presented. Diazole, triazole and tetrazole were used in our experiments. Various combinations of operating conditions such as pH, electrolyte and azole concentrations were employed. Zeta-potentials of powders with adsorbed azoles were obtained in order to investigate the interactions occurring between azoles and the oxide surfaces. In the presence of azoles the equilibration process of zeta-potential of oxide surfaces has a very special “damping oscillation” character and the equilibration process continues for around a week. However, kinetics of adsorption of azoles is completed in approximately 3 h. The latter shows a complex behaviour of adsorbed azoles on oxide surfaces.     

How do azoles inhibit cytochrome P450 enzymes? A density functional study

To examine how azole inhibitors interact with the heme active site of the cytochrome P450 enzymes, we have performed a series of density functional theory studies on azole binding. These are the first density functional studies on azole interactions with a heme center and give fundamental insight into how azoles inhibit the catalytic function of P450 enzymes. Since azoles come in many varieties, we tested three typical azole motifs representing a broad range of azole and azole-type inhibitors: methylimidazolate, methyltriazolate, and pyridine. These structural motifs represent typical azoles, such as econazole, fluconazole, and metyrapone. The calculations show that azole binding is a stepwise mechanism whereby first the water molecule from the resting state of P450 is released from the sixth binding site of the heme to create a pentacoordinated active site followed by coordination of the azole nitrogen to the heme iron. This process leads to the breaking of a hydrogen bond between the resting state water molecule and the approaching inhibitor molecule. Although, formally, the water molecule is released in the first step of the reaction mechanism and a pentacoordinated heme is created, this does not lead to an observed spin state crossing. Thus, we show that release of a water molecule from the resting state of P450 enzymes to create a pentacoordinated heme will lead to a doublet to quartet spin state crossing at an Fe-OH(2) distance of approximately 3.0 A, while the azole substitution process takes place at shorter distances. Azoles bind heme with significantly stronger binding energies than a water molecule, so that these inhibitors block the catalytic cycle of the enzyme and prevent oxygen binding and the catalysis of substrate oxidation. Perturbations within the active site (e.g., a polarized environment) have little effect on the relative energies of azole binding. Studies with an extra hydrogen-bonded ethanol molecule in the model, mimicking the active site of the CYP121 P450, show that the resting state and azole binding structures are close in energy, which may lead to chemical equilibrium between the two structures, as indeed observed with recent protein structural studies that have demonstrated two distinct azole binding mechanisms to P450 heme.     

Basicity of azoles. IV. Empirical relationships between basicity and ionization potential for aromatic five membered rings containing nitrogen or oxygen

A plot of pK_a values for eleven azoles and benzazoles vs the experimental ionization energy of the nitrogen lone pair shows the existence of three groups of compounds: simple unsubstituted azoles (imidazole, pyrazole, oxazole, isoxazole), unsubstituted benzazoles (benzimidazole, 1H-indazole and benzoxazole, including imidazo [1,2-a]pyridine) and benzazoles carrying a methyl group α- to the basic centre (2-methylbenzimidazole, 2-methylindazole and 2-methylbenzoxazole).     

N-polyazolylmethanes. 1. Synthesis and nmr study of N,N′-diazolylmethanes

Thirteen N,N-diazolylmethanes, including derivatives of pyrazole, imidazole, 1,2,4-triazole, benzimidazole and indazole were prepared by reaction of azoles with methylene chloride under phase transfer catalysis conditions. The relative amounts of isomeric mixtures obtained with ‘asymmetric’ azoles or with equimolar mixtures of azoles are compared with literature results on monoalkylation of azoles. Proton and carbon-13 nmr spectra of the N,N'-diazolylmethanes are discussed.     

Investigations of unsaturated azoles. 14*. Reaction of benzimidazole and its derivatives with p-nitrostyrene oxide. Quaternary ammonium bases

The reactions of benzimidazole and its 2- and 1-alkyl, 2-mercapto, and 2-amino derivatives with p-nitrostyrene oxide have been studied.Rostov State University, Rostov-on-Don, 344090. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1352–1357, October, 1996. Original article submitted February 21, 1996.     

Etude dans la serie des organogallylazoles I. Synthese et structure

A series of N-dimethylgallylazoles have been prepared by treatment of azoles (imidazoles, benzimidazoles, pyrazoles, s-triazole and benzotriazole) with trimethylgallium.The structure (monomeric, dimeric, polymeric) of the resulting compounds depends on the position of the nitrogen atoms in the azole moiety. In the case of pyrazolyl derivatives, the NMR study in acetone or acetonitrile shows the existence of an equilibrium between the monomeric and dimeric forms.     

A ceric ammonium nitrate N-dearylation of N-p-anisylazoles applied to pyrazole, triazole, tetrazole, and pentazole rings: release of parent azoles. generation of unstable pentazole, HN5/N5-, in solution

The reaction of cerium(IV) ammonium nitrate (CAN) with a range of N-(p-anisyl)azoles in acetonitrile or methanol solvents leads to N-dearylation releasing the parent NH-azole and p-benzoquinone in comparable yields. The scope and limitations of the reaction are explored. It was successful with 1-(p-anisyl)pyrazoles, 2-(p-anisyl)-1,2,3-triazoles, 2-(p-anisyl)-2H-tetrazoles, and 1-(p-anisyl)pentazole. The dearylation renders the p-anisyl group as a potentially useful N-protecting group in azole chemistry. The azole released in solution from 1-(p-anisyl)pentazole is unstable HN5, the long-sought parent pentazolic acid. p-Anisylpentazole samples were synthesized with combinations of one, two, and three 15N atoms at all positions of the pentazole ring. The unstable HN5/N5- produced at -40 degrees C did not build up in the solution but degraded to azide ion and nitrogen gas with a short lifetime. The 15N-labeling of the N3- ion obtained from all samples proved unequivocally that it came from the degradation of HN5 (tautomeric forms) and/or its anion N5- in the solution.     

Are Point Mutations in HMG-CoA Reductases (Hmg1 and Hmg2) a Step towards Azole Resistance in Aspergillus fumigatus?

Invasive aspergillosis, mainly caused by Aspergillus fumigatus, can lead to severe clinical outcomes in immunocompromised individuals. Antifungal treatment, based on the use of azoles, is crucial to increase survival rates. However, the recent emergence of azole-resistant A. fumigatus isolates is affecting the efficacy of the clinical therapy and lowering the success rate of azole strategies against aspergillosis. Azole resistance mechanisms described to date are mainly associated with mutations in the azole target gene cyp51A that entail structural changes in Cyp51A or overexpression of the gene. However, strains lacking cyp51A modifications but resistant to clinical azoles have recently been detected. Some genes have been proposed as new players in azole resistance. In this study, the gene hmg1, recently related to azole resistance, and its paralogue hmg2 were studied in a collection of fifteen azole-resistant strains without cyp51A modifications. Both genes encode HMG-CoA reductases and are involved in the ergosterol biosynthesis. Several mutations located in the sterol sensing domain (SSD) of Hmg1 (D242Y, G307D/S, P309L, K319Q, Y368H, F390L and I412T) and Hmg2 (I235S, V303A, I312S, I360F and V397C) were detected. The role of these mutations in conferring azole resistance is discussed in this work.     

Synthetic applications of azolium ylides to a traceless solid-phase synthesis of 2-substituted azoles

A new approach for the preparation of 2-substituted azole libraries using a polystyrene-carbamyl chloride resin in a traceless fashion is described. Azole substrates II are assembled in a one-pot condensation reaction of azoles and aldehydes with a resin-bound carbamyl chloride. Treatment of the azolyl-carbamate II with boron trifluoride etherate under thermal or microwave-assisted solvolysis conditions afforded 2-substituted azoles. [reaction: see text]     

Electrosynthesis of N-Arylazoles by Electrolyzing a Mixture of Azole and 1,4-Dimethoxybenzene in a Diaphragmless Cell

An analysis is performed and data are compared on the electrosynthesis of N-arylazoles and regularities of this process in conditions of a diaphragmless galvanostatic electrolysis (Pt, MeCN, Bu₄NClO₄) of a mixture of 1,4-dimethoxybenzene (DMB) with azoles (pyrazole, triazole, their derivatives, tetrazole). Electrolysis of an azole/DMB mixture leads to the formation of products of an ortho-substitution—1,4-dimethoxy-2-(azolyl-1)benzenes—and, simultaneously, hydrolytically unstable products of an ipso-bis-attachment—1,4-dimethoxy-1,4-di-(azolyl-1)cyclohexa-2,5-dienes. The overall yield of these compounds increases upon adding a base (collidine) or an acid (AcOH) into the initial mixture, and the basicity of initial azoles substantially affects the electrosynthesis results. New notions on the nature of nucleophilic species interacting with radical cation of DMB are considered. The species in question are complexes of azoles with one another or with collidine generated at the expense of the hydrogen bond, rather than azolate ions. Furthermore, the cathodic process is largely connected not with the generation of azolate ions (as a result of the reduction of initial azoles) but with the deprotonation of onium compounds (BH⁺)—products of the interaction of azoles or collidine with protons. The mechanism of electrosynthesis of N-arylazoles is discussed. The key stages of the synthesis are the attack of a nucleophile on the ipso- and, possibly, ortho-positions of the benzene ring of radical cation of DMB, as well as the rearrangement of the intermediate cation of 1,4-dimethoxy-1-(azolyl-1)arenonium into the cation of 1-(azolyl-1)-2,5-dimethoxyarenonium, which affects both the yield and ratio of final products of the reaction mixture.     

Molecularly imprinted polymers: An analytical tool for the determination of benzimidazole compounds in water samples

Molecularly imprinted polymers (MIPs) for benzimidazole compounds have been synthesized by precipitation polymerization using thiabendazole (TBZ) as template, methacrylic acid as functional monomer, ethyleneglycol dimethacrylate (EDMA) and divinylbenzene (DVB) as cross-linkers and a mixture of acetonitrile and toluene as porogen. The experiments carried out by molecularly imprinted solid phase extraction (MISPE) in cartridges demonstrated the imprint effect in both imprinted polymers. MIP–DVB enabled a much higher breakthrough volume than MIP–EDMA, and thus was selected for further experiments. The ability of this MIP for the selective recognition of other benzimidazole compounds (albendazole, benomyl, carbendazim, fenbendazole, flubendazole and fuberidazole) was evaluated. The obtained results revealed the high selectivity of the imprinted polymer towards all the selected benzimidazole compounds.An off-line analytical methodology based on a MISPE procedure has been developed for the determination of benzimidazole compounds in tap, river and well water samples at concentration levels below the legislated maximum concentration levels (MCLs) with quantitative recoveries. Additionally, an on-line preconcentration procedure based on the use of a molecularly imprinted polymer as selective stationary phase in HPLC is proposed as a fast screening method for the evaluation of the presence of benzimidazole compounds in water samples.     

Determination of azoles in sewage sludge from Spanish wastewater treatment plants by liquid chromatography-tandem mass spectrometry

A simple and rapid analytical method for the determination of 16 azoles in sewage sludge has been developed and validated. The method was based on ultrasound-assisted extraction followed by dispersive solid-phase extraction cleanup and liquid chromatography-electrospray tandem mass spectrometric detection. The azoles were selected by their intensive usage as biocides (tebuconazole, propiconazole, cyproconazole and thiabendazole), antimycotic pharmaceuticals (ketoconazole, econazole, fluconazole and clotrimazole) or fungicides in agriculture (difenoconazole, flusilazole, hexaconazole, prochloraz, bromuconazole, epoxiconazole and triticonazole). The recoveries of these compounds through the method were between 71.9 and 115.8%, with relative standard deviations lower than 20%. Detection limits were in the range of 0.5-5.0 ng/g. The developed method was applied to the analysis of azoles in sewage sludge samples collected from 19 Spanish wastewater treatment plants. Although azoles used as biocides or agriculture fungicides were present in a few sludge samples, the pharmaceuticals ketoconazole, econazole and clotrimazole were present in all of the analyzed sludge samples, being ketoconazole the one found at the highest level, representing the 68.6% of the total azole content found in the 19 sludge samples studied.