Triazoles cycloadditions

Methods for the synthesis of these systems include the following cyclocondensation (1,2,3- ind 1,2,4-thiadiazoles, benzotriazoles, 1,2,4-triazoles), cycloaddition (1,2,3-triazoles, tetrazoles), cyclodehydration (1,2,5-oxadiazoles) and cyclization (l,2,5-oxadiazole-2-oxides, 1,2,4-thiadiazoles, 1,2,3-triazoles, tetrazoles). 

A related method with a resin-bound miinchnone intermediate was applied to the synthesis of 1,2,4-triazoles. Cycloaddition of resin-bound miinchnones with the N=N double bond of the dipolarophilic diethyl diazocarboxylate (DEAD) or 4-phenyl-4//-1,2,4-triazohne-3,5-dione gave resin-bound 1,2,4-triazoles. Traceless cleavage of the products from the 2-methoxy-substituted resin was achieved with 30% trifluoroacetic acid (Scheme 11.22). ... 

Thieno[3,4-d][ 1,2,3]triazole, tetramethyl-synthesis, 6, 1015 Thieno[3,4-c][ 1,2,3]triazoles synthesis, 6, 1042 Thieno[3,4-d][ 1,2,3]triazoles reactions, 6, 1036 synthesis, 6, 1044 Thienyl radicals generation, 4, 832 Thiepane, 2-acetoxy-synthesis, 7, 574 Thiepane, 2-chloro-nucleophilic substitution, 7, 573 synthesis, 7, 574 Thiepane, 2-methyl-synthesis, 7, 573 Thiepane, 2-phenyl-synthesis, 7, 573 Thiepane, 3,3,6,6-tetramethyl-cycloaddition reactions, 7, 574 Thiepanes, 7, 547-592 applications, 7, 591... 

Azides can use enamines as dipolarophiles for ],3 cycloadditions to form triazolines. These azides can be formate ester azides (186), phenyl azides (187-195), arylsulfony] azides (191-193,196), or benzoylazides (197,198). For example, the reaction between phenyl azide (138) and the piperidine enamine of propionaldehyde (139) gives 1 -phenyl-4-methy l-5-( 1 -piperidino)-4,5-dihydro-l,2,3-triazole (140), exclusively, in a 53% yield (190). None of the isomeric l-phenyl-5-methyl product was formed. This indicates that the... 

Azidofurazans and -furoxans undergo dipolar cycloaddition reactions with unsaturated compounds, in some cases regiospecifically. Thus, reaction of 3-amino-4-azidofurazan with l-morpholinyl-2-nitroethene (toluene, reflux, 70 hours) gives 4-nitro-l,2,3-triazole 204 in 87% yield (99MI1, 000KGS406). Cycloaddition of the same azide to alkynes was accomplished by formation of a mixture of position isomers 205 and 206. Regiospecific addition was observed only in singular cases... 

Free carbenes based on 1,2,4-triazole are not as numerous as those based on imidazole (70ZN(B)1421, 95AGE1021, 97JA6668, 98JA9100). The carbene complex 169 (Ar = Ph, p-Tol) is prepared by the [3 + 2] cycloaddition route from [W(CO)j(C+=NC-HCOOEt)]- and aryldiazonium (930M3241). Oxidative decomplexation causes tautomerization of the 1,2,4-triazole ligand, the products being 170 (Ar= Ph, i-Tol). 

Intramolecular dipolar azide-olefin cycloaddition of 723 took place upon heating in benzene to afford 724 (83JA3273). An alternative rearrangement process can take place upon photolysis of 724 to give 725. Mesylation of 4-(3-hydroxypropyl)-2,4,6-trimethyl-2,5-cyclohexadiene-l-one (78JA4618) and subsequent treatment with sodium azide in DMF afforded the respective azide 726 which underwent intramolecular cycloaddition to afford the triazoline 727 (83JOC2432). Irradiation of 727 gave the triazole derivative 728 (Scheme 126). 

Ethyl l//-azepine-l-carboxylate (1) undergoes slow cycloaddition with diethyl diazenedicar-boxylate to give the [4 + 2] 7t-adduct 14 and not, as was first thought, the [6 + 2] 7t-adduct.257 4-Phenyl-l,2-dihydro-l,2,4-triazole-3,5-dione257 258 and phthalazine-1,4-dione257 react likewise. 

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). 

Triazoles have been obtained via microwave-assisted [3-i-2] cycloaddition, under solvent-free conditions [54], starting from organic azides and acetylenic amides at 55 °C for 30 min (Scheme 23). The complete conversion of the reagents into AT-substituted-1,2,3-triazoles 69 was achieved without decomposition and side products. A control reaction carried out at the same temperature in an oil bath did not give the cycHc products, not even after 24 h of reaction time. 

The same azide 67 was utiUzed to study the microwave-assisted synthesis of triazoles using the thermal cycloaddition with acetylenes. To achieve high yields in a short time and avoiding side reactions, the authors analyzed the effects of time, temperature, and concentration (in toluene) on the synthesis of triazoles [55]. 

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]. 

The Cu(I)-catalyzed Huisgen [3 + 2] dipolar cycloaddition was also utilized by Van der Eycken and co-workers to obtain a new class of glycopep-tidomimetics based on the 1,2,3-triazole ring system 78 starting from glu-copyranosyl azide 75 and the pyrazinone compound 76 (Scheme 26) [58]. 

A few syntheses of the 1,2,4-triazole ring were reported in 1996. Treatment of the (1,1-dichloropropyl)azo compound 8 with SbCls gave the chloro-substituted allenium salt 9. This salt was found to undergo cycloaddition with MeCN to give a 76% yield of the 1,2,4-triazolium salt 10 <96S274>. Reaction of 3-[3-chlorophenyl]-l-[4-(3,4-... 

Intramolecular cycloaddition between an azide and an unsaturated ester (see 300) was the key step in the synthesis of triazole carboxylic acids 302 a, b, prospective anionic sugar mimics (Eq. 33) [79]. 

Cycloaddition reactions catalysed by transition metal complexes are an important tool in the construction of a wide range of carbo- and hetero-cyclic systems, such as benzene, pyridines, triazoles, etc. [7]. In general, these reactions are extremely atom-efficient and involve the formation of several C-C bonds in a single step. Among the innumerable possible catalytic systems for the cycloaddition reaction the NHC-metal complexes have received special attention [7c]. 

The NHCs have been used as ligands of different metal catalysts (i.e. copper, nickel, gold, cobalt, palladium, rhodium) in a wide range of cycloaddition reactions such as [4-1-2] (see Section 5.6), [3h-2], [2h-2h-2] and others. These NHC-metal catalysts have allowed reactions to occur at lower temperature and pressure. Furthermore, some NHC-TM catalysts even promote previously unknown reactions. One of the most popular reactions to generate 1,2,3-triazoles is the 1,3-dipolar Huisgen cycloaddition (reaction between azides and alkynes) [8]. Lately, this [3h-2] cycloaddition reaction has been aided by different [Cu(NHC)JX complexes [9]. The reactions between electron-rich, electron-poor and/or hindered alkynes 16 and azides 17 in the presence of low NHC-copper 18-20 loadings (in some cases even ppm amounts were used) afforded the 1,2,3-triazoles 21 regioselectively (Scheme 5.5 Table 5.2). 

The lH-l,2,4-triazole compounds possess important pharmacological activities such as antifimgal and antiviral activities [18-20]. In the present study, the reactive intermediates 45a-c, prepared in situ from the dichlorides 44a-c, were reacted via the cycloaddition reaction with ethyl cyanoacetate 40 to give, after spontaneous rearrangement, the triazole hydrazides 41a-c. These compoimds were used as starting materials for the synthesis of the... 

In conclusion, we have been successful in developing a new method for the synthesis of [ 1,2,3]-triazoles by regioselective 1,3-dipolar cycloaddition of 2-diazopropane with imidates 60 in good yields. 

Recently, Li et al. have reported an efficient 1,3-dipolar cycloaddition of azides with electron-deficient alkynes without any catalysts at room temperature in water.128 The reaction has been applied successfully to the coupling of an azido-DNA molecule with electron-deficient alkynes for the formation of [l,2,3]-triazole heterocycle (Eq. 4.66). 

Another important click reaction is the cycloaddition of azides. The addition of sodium azide to nitriles to give l//-tetrazoles is shown to proceed readily in water with zinc salts as catalysts (Eq. 11.71).122 The scope of the reaction is quite broad a variety of aromatic nitriles, activated and nonactivated alkyl nitriles, substituted vinyl nitriles, thiocyanates, and cyanamides have all been shown to be viable substrates for this reaction. The reaction of an arylacetylene with an azide in hot water gave 1,4-disubstituted 1,2,3-triazoles in high yields,123 while a similar reaction between a terminal aliphatic alkyne and an azide (except 111 - nitroazidobenzcnc) afforded a mixture of regioisomers with... 

The general procedure used for the synthesis of [l,2,3]triazolo[l,2-tf][l,2,4]benzotriazin-l-5(6//)-dione derivatives 506 is shown in Scheme 86. Ionic 1,3-dipolar cycloaddition of the appropriate azide 503 to ethyl phenylacetates gives l-(2-nitrophenyl)-4-aryl-5-oxo[l,2,3]triazoles 504. Catalytic reduction of these compounds affords the corresponding amines 505. Cyclocondenzation of these amines to the final tricyclic compounds 506 is performed using triphosgene in anhydrous tetrahydrofuran solution at room temperature (Scheme 86) <2005JME2936>. 

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. 

Photolysis of the azirines 68 in the presence of DEAZD gives 1,2,4-triazolines (69, R = Et) via cycloaddition to the nitrile ylid.114 The nitrile ylid generated thermally from 70 gives 1,2,4-triazolines (69, R = Me, R1 = R2 = CF3) (Scheme 7).11S The cycloadditions proceed in good yield, and the triazolines 69 are readily converted into aromatic 1,2,4-triazoles. 

Triazole derivatives also result from the cycloaddition of DEAZD to azomethine ylids derived from electrocyclic ring opening of aziridines.117 121 For example, the tetrahydro-1,2,4-triazole 73 was prepared by thermolysis of the cts-aziridine in the presence of DEAZD in 96% yield (Eq. 8), and... 

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