Triazole chemistry

Perhaps the most important issues to consider now are the application of novel methodologies, molecular diversity, and synthetic convenience. There have been several reports of novel, one-pot procedures for the preparation of 1,2,4-triazoles with diverse structures. Synthesis of 1,2,4-triazoles on polymeric supports, in both solution and solid phase, represents a step toward the combinatorial synthesis of these heterocycles. It is these novel applications of technology to organic synthesis that perhaps lead the way in 1,2,4-triazole chemistry. 

The present review, which surveys the literature to mid-1972, has been restricted to monocyclic 1,2,3-triazoles, since much of the chemistry of benzotriazoles and other fused systems has little in common with monocyclic triazole chemistry. The aim has been to give a broad survey of methods of synthesis and reactions of triazoles few references are included from before 1960, as these are available from earlier reviews. 

This monograph aims to present a composite picture of the chemistry of 1,2,4-triazoles through examples chosen to display the variety of its problems and methods. It is also intended to draw attention to some critical matters that tend to be overlooked by those whose main concern is the ordering of a vast amount of material. Since the voluminous controversy on some points of triazole chemistry is beyond the scope of this monograph, it is hoped that readers irritated by seemingly dogmatic arbitration without full references will consult the appropriate sections of the reviews quoted above. 

At present the major value of mass spectrometry to structural triazole chemistry appears to be in intricate heterocyclic reactions giving rise simultaneously not only to triazoles but many other heterocycles at the same time <81kgs694). Identification of unstable triazolines has been aided by mass spectrometry as well as by their NMR data (71BSF3296, 73bcj125o). 

An unusual feature of triazole chemistry is the ready exchange of nitro groups of nitro-and dinitro-triazoles and nitrotriazolinones (67cb2250, 70KGS269, 70KGS1701). The reaction of l-methyl-3,5-dinitro-l,2,4-triazole with hydrazine (7OKGS997) exemplifies such reactions... 

Conversion of existing functions include the oxidation of aliphatic or aromatic side-chains, one of the earliest preparative techniques of triazole chemistry. Hydrolysis of cyanides obtained by displacement of halo, nitro and diazo groups is of comparable importance. 

In the early development of n-triazole chemistry a number of reactions leading to the 4,5-dicarboxylic acids and their derivatives were discovered and should be explored further. Fries oxidized benzotriazoles (Eqs. 46,47) and prepared a broad range of acid derivatives. Some especially promising compounds in this series have been prepared from what was then called a hydrazoic acid polymer (4.3-1) by reaction with nitrous acid (Eqs. 48,49). Although the yields were not reported, the chemistry is intriguing. The oxidation of a 1,2,3-triazole methyl group and conversion to acid... 

Despite the weak basicity of isoxazoles, complexes of the parent methyl and phenyl derivatives with numerous metal ions such as copper, zinc, cobalt, etc. have been described (79AHC(25) 147). Many transition metal cations form complexes with Imidazoles the coordination number is four to six (70AHC(12)103). The chemistry of pyrazole complexes has been especially well studied and coordination compounds are known with thlazoles and 1,2,4-triazoles. Tetrazole anions also form good ligands for heavy metals (77AHC(21)323). 

In azole chemistry the total effect of the several heteroatoms in one ring approximates the superposition of their separate effects. It is found that pyrazole, imidazole and isoxazole undergo nitration and sulfonation about as readily as nitrobenzene thiazole and isothiazole react less readily ica. equal to m-dinitrobenzene), and oxadiazoles, thiadiazoles, triazoles, etc. with great difficulty. In each case, halogenation is easier than the corresponding nitration or sulfonation. Strong electron-donor substituents help the reaction. 

The most important chemistry of azidoazoles is the fragmentation of derived nitrenes of which the prototypes are (453) (454) and (455) (456). Thus 5-azido-l,4-diphenyltriazole (457) evolves nitrogen at 50 °C (70JOC2215). 4-Azido-pyrazoles and -1,2,3-triazoles (458) undergo fragmentation with formation of unsaturated nitriles (8lAHC(28)23l). 

The classical age of preparative organic chemistry saw the exploration of the extensive field of five-membered heterocyclic aromatic systems. The stability of these systems, in contrast to saturated systems, is not necessarily affected by the accumulation of neighboring heteroatoms. In the series pyrrole, pyrazole, triazole, and tetrazole an increasing stability is observed in the presence of electrophiles and oxidants, and a natural next step was to attempt the synthesis of pentazole (1). However, pentazole has eluded the manifold and continual efforts to synthesize and isolate it. 

A microwave-assisted three-component reaction has been used to prepare a series of 1,4-disubstituted-1,2,3-triazoles with complete control of regiose-lectivity by click chemistry , a fast and efficient approach to novel functionalized compounds using near perfect reactions [76]. In this user-friendly procedure for the copper(l) catalyzed 1,3-dipolar cycloaddition of azides and alkynes, irradiation of an alkyl halide, sodium azide, an alkyne and the Cu(l) catalyst, produced by the comproportionation of Cu(0) and Cu(ll), at 125 °C for 10-15 min, or at 75 °C for certain substrates, generated the organic azide in situ and gave the 1,4-disubstituted regioisomer 43 in 81-93% yield, with no contamination by the 1,5-regioisomer (Scheme 18). 

Scheme 18 Click chemistry synthesis of 1,4-disubstituted triazoles...

In another paper, the same authors investigated the 1,3-dipolar cycloaddition on 2-(lH)-pyrazine scaffolds 72 and electron-rich azides, using Cu(0) and CUSO4 as pre-catalysts. To demonstrate the versatility of this approach, they reported the generation of different templates (73 in Scheme 25) as an application of cUck chemistry . They also investigated the Diels-Alder reaction of the so obtained triazoles with dimethyl acetylenedicarboxylate (DMAD), under microwave irradiation. The latter reaction allowed obtaining various pyridinones in good yields (74 and 75 in Scheme 25) [57]. 

Canthine skeleton 52 Cardiotonic agent, heart failiu-e 3 Caspase-3 inhibitors, non-peptide 269 Catch and release , 2,4,5-trisubstituted pyrimidines 98 Chloro dehydroxylation 17 Click chemistry, 1,4-disubstituted triazoles 45... 

In this review, general and efficient approaches to a diverse series of triazoles and coumarin derivatives have been developed and discussed. The obtained products have been characterized with the help of spectroscopic techniques and were screened for their antiviral and antitumor activity. The methods could provide valuable routes to various coumarin derivatives and enrich the organic and medicinal chemistry of coumarins. The synthesized triazoles and coumarin derivatives showed moderate to good antiviral and antitiunor activities. 

We have also been successful in developing a new method for the synthesis of [l,2,3]-triazoles by regioselective 1,3-dipolar cycloaddition of 2-diazopropane with imidates in good yields. These compoimds may find wide use in medicinal chemistry. 

Kellum [115] has described a class-selective oxidation chemistry procedure for the quantitative determination of secondary antioxidants in extracts of PE and PP with great precision (better than 1 %). Diorgano sulfides and tertiary phosphites can be quantitatively oxidised with /-chloropcroxybenzoic acid to the corresponding sulfones and phosphates with no interference from other stabilisers or additives. Hindered phenols, benzophenones, triazoles, fatty acid amides, and stearate... 

Process development of the synthesis of iodoaniline 28 began with an improved synthesis of l-(4 -aminobenzyl)-l,2,4-triazole (6) (Scheme 4.7), which was prepared in the medicinal chemistry synthesis, albeit with poor regioselectivity (Scheme 4.1). We found that this aniline intermediate 6 could be readily prepared in three steps in >90% overall yield from 4-amino-l,2,4-triazole (30) and 4-nitrobenzyl bromide (4) based on a modified literature procedure [9]. The condensation of 30 and 4 in isopropyl alcohol followed by deamination gave the nitro... 

The triazole derivative, in turn, produces an intensely colored substance, III, with a diazonium compound under the experimental conditions devised for this analysis. The reactions leading to the formation of the colored substance have not yet been fully elucidated, but it appears that opening of the triazole ring as well as coupling is involved. The chemistry of the color formation will be discussed in another publication. 

A different result was obtained in the cycloaddition to methylenecyclo-propanes 216-218 tearing alkoxycarbonyl substituents on the cyclopropyl ring. In this instance, 1,2,3-triazoles 220 isomeric with the triazolines 219 were formed in the reaction [57]. The formation of triazoles 220 is rationalised by the intermediate formation of triazolines 219, which are unstable under the reaction conditions and undergo a rearrangement to the aromatic triazoles via a hydrogen transfer that probably occurs with the assistance of the proximal ester carbonyl (Scheme 35). The formation of triazoles 220 also confirms the regio-chemistry of the cycloaddition for the methylene unsubstituted methylene-cyclopropanes, still leaving some doubt for the substituted ones 156 and 157. 

The synthesis and chemistry of pyrazoles, imidazoles, and 1,2,3-triazoles were actively pursued in 2006. A review on the cross-coupling reactions on azoles with two and more heteroatoms for pyrazoles and imidazoles has been published <06EJO3283>. Publications relating to 1,2,4-triazole and tetrazole chemistry were not particularly well represented this year. The solid-phase and combinatorial chemistry of these ring systems have not been investigated compared to past years. No attempt has been made to incorporate all the exciting chemistry or biological applications that have been published this year. 

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