3- Aryl-substituted 1,2,3-triazole

The triazoles previously obtained from jS-keto-ylides and acyl azides or ethyl azidoformate are the 2-acyltriazoles (80) formed by isomerization under the basic conditions of the initially formed 1-substituted triazoles (79). The latter can be isolated in some cases if the reactions are interrupted. Aryl mono- and bis-azides have also been used in the preparation of the triazolcs (81). 

Reactions of salts of 1,2,3-triazole with electrophiles provide an easy access to 1,2,3-triazol-jV-yl derivatives although, usually mixtures of N-l and N-2 substituted triazoles are obtained that have to be separated (see Section 5.01.5). Another simple method for synthesis of such derivatives is addition of 1,2,3-triazole to carbon-carbon multiple bonds (Section 5.01.5). N-l Substituted 1,2,3-triazoles can be selectively prepared by 1,3-dipolar cycloaddition of acetylene or (trimethylsilyl)acetylene to alkyl or aryl azides (Section 5.01.9). 

The direction of MCR involving pyruvic acid, aldehyde, and l-aryl substituted l,2,4-triazole-3,5-diamine was different from the directions of all other processes that were discussed earher. It was established [53] that this treatment yielded 3-(5-ammo-lH-l,2,4-triazol-3-ylamino)furan-2(5H)-one 39 instead of triazolopyri-midine carboxylic acids 38 (Scheme 16). 

Diazo(trimethylsilyl)methyl lithium (3) was found to be the reagent of choice for the synthesis of azoles from heterocumulenes (Scheme 8.43). The reaction is typically carried out in ether at 0-20 °C. Thus, alkyl- (or aryl-)substituted keteni-mines are transformed into 1,2,3-triazoles 188 (246), while C-acceptor-substituted ketenimines yield either 4-aminopyrazoles 189 or 1,2,3-triazoles, depending on the substituents (247). Isocyanates are converted into 5-hydroxy-1,2,3-triazoles 190 (248). Reaction of 3 with isothiocyanates are strongly solvent dependent. 

Cyclocondensation of aminoazoles and a,(3-unsaturated carbonyl compounds or Mannich bases is the most common method for the synthesis of dihydroa-zolopyrimidines [99, 155, 156, 157]. Various alkyl- and aryl-substituted dihy-dropyrimidines were prepared in this way. For example, cyclocondensation of 3-amino-1,2,4-triazole 147 with chalcones 148 leads to 5,7-diaryl-4,7-dihydro-l,2,4-triazolo[l,5-a]pyrimidines 149 [158], while reaction with hydrochlorides of Mannich bases 150 leads to heterocycles 151 (Scheme 3.46). 

The 3-alkyl- or aryl-substituted 1,2,3-triazole 1-oxides 448 are usually stable, crystalline, polar, and somewhat hygroscopic compounds. 3-Sub-stituted 1,2,3-triazole 1-oxides 448 are weak bases being subject to protonation at the negatively charged oxygen atom. 3-Hydroxy-l,2,3-triazole 1-oxide 456 (R=OH) acts both as a base and as an acid. No pKa values for 3-substituted 1,2,3-triazole 1-oxide have been reported. 

The similarity of the UV spectra of s-triazolo[3,2-c]-s-triazoles (see equation 44) and 3-aryl-s-triazoles indicates a lack of electronic interaction between the two fused s-triazole rings. In lH-2,6-diphenyl-s-triazolo[3,2-c]-1s-triazole, the UV spectrum exhibits the resultant effects of the two triazole rings each substituted with an aryl group (66JHC119). 

Azomethine imines have been postulated as intermediates in the reaction of aryl-substituted diazo compounds with N-phenyltriazolinedione (PTAD) and DMAD, leading to pyrazolo[l,2-a][l,2,4]triazoles (Scheme 11) (81TL2535). 

In contrast to benzenesulfonyl azide, the reaction between 8 and aryl azides gives only a small amount of 226. Instead, highly substituted triazoles 228 are formed as the major products176,177. When 4-nitrophenyl azide is used, the reaction furnishes 228 exclusively. It has been believed that the reaction involves two competitive pathways and benzoyl-substituted 1,1-enediamines 8 act mainly as nucleophiles rather than as 1,3-dipolarophiles toward aryl azides. Consequently, they add to the azide group and, following intramolecular cyclocondensation, give products 228. Only in the case of unfavorable electronic factors does 1,3-cycloaddition reaction to give 226 take place (Scheme 13)177. 

The energies of activation increase from about 21.5 to 34 kcal.mole and the heats of reaction vary from —11.84 kcal.mole" to about +2.20 kcal.mole" For aryl substituted amino-1,2,3-triazoles there is a good correlation between the logarithm of the rates of isomerization and Hammett s a value for substituents. 

Consequently, ruthenium-catalyzed direct arylations with aryl halides in less coordinating apolar solvents, such as toluene, were probed. Notably, a catalytic system derived from SPO preligand 59 enabled regioselective C-H bond functionalizations at the aromatic moieties of /V-aryl substituted 1,2,3-triazoles (Scheme 32) [88],... 

Two groups of compounds appear to show the most promise as selective xanthine oxidase inhibitors those based on a pyrazolo[l,5-a]pyrimidine nucleus, which show mixed or non-competitive inhibition and substituted triazoles, which are competitive inhibitors [192, 193]. The 3-position of the pyrazolo[l,5-a]pyrimidines (48) is spatially equivalent to the 9-position of purine, and 3-aryl-substituted compounds were found to be 30-160-times better inhibitors than allopurinol (Table 3.8) [ 194]. In contrast, the hetero-rings in the potent substituted triazole inhibitors (49) are no longer fused, but those compounds with substituted aryl groups in the 3-position have the highest levels of intrinsic activity (Table 3.8) [195]. 

As with the other aromatic and heteroaromatic systems, functional group transformations can also be used to produce fluorinated 1,2,3-triazoles. A series of 1-aryl-1,2,3-triazole-4-carbaldehydes were converted to the corresponding difluoromethyl-substituted triazoles by the action of DAST (Fig. 3.96). The difluoromethylene derivatives as well as the precursor aldehydes were studied with respect to antitubercular activity. 

As carboxylic acid additives increased the efficiency of palladium catalysts in direct arylations through a cooperative deprotonation/metallation mechanism (see Chapter 11) [45], their application to ruthenium catalysis was tested. Thus, it was found that a ruthenium complex modified with carboxylic acid MesC02H (96) displayed a broad scope and allowed for the efficient directed arylation of triazoles, pyridines, pyrazoles or oxazolines [44, 46). With respect to the electrophile, aryl bromides, chlorides and tosylates, including ortho-substituted derivatives, were found to be viable substrates. It should be noted here that these direct arylations could be performed at a lower reaction temperatures of 80 °C (Scheme 9.34). 

Copper(I) chloride can be an effective catalyst in multicomponent reactions, such as in the synthesis of 5-alkoxycarbonyl-4-aryl-3,4-dihydrop3nimidine-2-(l//)-ones, the synthesis of quinoline derivatives (eq 69), and the synthesis of fully substituted triazoles. The use of CuCl as an additive is also reported in cross-metathesis reactions leading to significant turnover enhancement. ... 

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