1,2,3 triazole cycloaddition reaction

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... 

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... 

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... 

A variety of triazole-based monophosphines (ClickPhos) 141 have been prepared via efficient 1,3-dipolar cycloaddition of readily available azides and acetylenes and their palladium complexes provided excellent yields in the amination reactions and Suzuki-Miyaura coupling reactions of unactivated aryl chlorides <06JOC3928>. A novel P,N-type ligand family (ClickPhine) is easily accessible using the Cu(I)-catalyzed azide-alkyne cycloaddition reaction and was tested in palladium-catalyzed allylic alkylation reactions <06OL3227>. Novel chiral ligands, (S)-(+)-l-substituted aryl-4-(l-phenyl) ethylformamido-5-amino-1,2,3-triazoles 142,... 

Figure 7.7 The synthesis of dendrimer molecules using click chemistry proceeds with high yield. Each step results in the cycloaddition reaction between azide-containing molecules and alkyne molecules to form triazole linkages.

The 1,3-dipolar cycloaddition reactions to unsaturated carbon-carbon bonds have been known for quite some time and have become an important part of strategies for organic synthesis of many compounds (Smith and March, 2007). The 1,3-dipolar compounds that participate in this reaction include many of those that can be drawn having charged resonance hybrid structures, such as azides, diazoalkanes, nitriles, azomethine ylides, and aziridines, among others. The heterocyclic ring structures formed as the result of this reaction typically are triazoline, triazole, or pyrrolidine derivatives. In all cases, the product is a 5-membered heterocycle that contains components of both reactants and occurs with a reduction in the total bond unsaturation. In addition, this type of cycloaddition reaction can be done using carbon-carbon double bonds or triple bonds (alkynes). 

Use of unsubstituted acetylene as a substrate in 1,3-dipolar cycloadditions with azides results in 4,5-unsubstituted triazoles. The reactions have to be carried out under pressure. In an example given in Equation (23) showing synthesis of an antibacterial agent, a solution of azide 1049 in dimethoxyethane is transferred to a pressure bomb that is then charged with acetylene and heated at 90 °C for 12 h to give triazole derivative 1050 in 74% yield <2003BMC35>. 

Table 8 Cycloaddition reactions of 5-azido-1,2,4-triazole derivatives with alkynes (Equation 22)... 

Table 20 Cycloaddition reaction of in s/ fu-generated nitrilimines with nitriles to give 1,3,5-trisubstituted 1,2,4-triazole derivatives (Equation 37)...

The 1,3-dipolar cycloaddition reaction of l,2-0-isopropylidene-a-D-xylopentodialdo-l,4-furanose oxime 262 with 3-(2-propynylthio)-l/f-l,2,4-triazole affords 3,4-bis-(l,2-0-isopropylidene-a-D-threofuranos 4-yl)-l,2,5-oxadiazole-2-oxide 263 as a main product (Scheme 68) <2000CHC393>. Synthesis of 3,4-bis(alkylamino)-l,2,5-oxadiazoles 265... 

The reaction of phenylazoalkenes 424 with an excess of potassium thiocyanate in acetic acid produces the cycloadducts 425 that undergo further [3+2]-cycloaddition reaction with thiocyanic acid at the azomethine imine function giving rise to the bicyclic product imidazo[l,5-3][triazole]-2,5-dithiones 41 (Equation 87) <1998SL786>. 

Scheme 7.1 Click chemistry synthesis of 1,4-disubstituted-l,2,3-triazoles by a 1,3-dipolar cycloaddition reaction of organic azides with terminal acetylenes.

Baryshnikov and co-workers synthesized some nitro-substituted 1,2,3-triazoles using an ingenious cycloaddition reaction between sodium azide and 1,1-dinitroethene the latter prepared in situ from a number of precursors including 2,2-dinitroethyl acetate (Section 1.10.2.3). 

In the reactions with phosphonio-a-methoxycarbonyl-alkanides, the products of type 261 derived from 1,3-cycloaddition can rearrange to the tautomeric lif-pyrazolo-triazole (87MI2). The reaction of 3-diazopyra-zoles and 3-diazoindazole with acyl-substituted phosphonium ylides led to pyrazolo-triazine and indazolo-triazine derivatives 266 instead of the expected triazole compounds (8IJHC675). In this case, the ylides, which can exist as phosphonium enolates, possess nucleophilic and electrophilic centers in a /8-relationship, giving [7 + 2] or [11 -I- 2]cycloaddition reactions. With dimethylsulfonio-a-aroyl-methanides, very complex, temperature-dependent mixtures were obtained, in some cases with sulfur retention (87MI3). 

Both 3-diazO 1,2,4-triazoles and 4-diazo-l,2,3-triazoles easily give cycloaddition reactions with ynamine leading to 4-aminotriazolo-triazine 284 and the yields are generally higher than in the pyrazole and imidazole series (77S556) (Scheme 85). 

Diazo-substituted 1,2,3-triazoles undergo regiospecific dipolar cycloaddition reactions with electron-rich unsaturated compounds. Thus, 4-diazo-5-phenyl-4//-1,2,3-triazole (272, R = Ph) reacts with 1 -morpholinyl-2-nitroethene (273) in CH2CI2 at 20 °C by a net 1,7-cycloaddition and elimination of morpholine to give the product (274) (Scheme 53). 4-Diazo-5-cyano-4/f-1,2,3-triazole (272, R = CN) similarly adds to phenylacetylene to form compound (275) <87JOC5538>. 

Extension of the linkage to hve atoms as in 285 provides routes to pyrazolines or pyrazoles 286, or 1,2,4-triazoles 287, fused to a seven-membered ring. The products are potentially biologically active and examples have been reported for X=N (177-181), X = 0 (181-185) and for a pyrazolo fused analogue (186) and X = S (187). In some cases, [e.g., (183)], these reactions are accompanied by tandem intramolecular-intermolecular reactions leading to the formation of macrocycles (see the section Tandem Intermolecular-Intramolecular Cycloaddition Reactions). 

Since the discovery of triazole formation from phenyl azide and dimethyl acetylenedicarboxylate in 1893, synthetic applications of azides as 1,3-dipoles for the construction of heterocychc frameworks and core structures of natural products have progressed steadily. As the 1,3-dipolar cycloaddition of azides was comprehensively reviewed in the 1984 edition of this book (2), in this chapter we recount developments of 1,3-dipolar cycloaddition reactions of azides from 1984 to 2000, with an emphasis on the synthesis of not only heterocycles but also complex natural products, intermediates, and analogues. 

Hlasta and Ackerman (72) reported a synthesis of the triazoles 379, related to the human leuokocyte elastase inhibitor WIN 62225 (380), based on an inter-molecular 1,3-dipolar cycloaddition of the azide 378 with alkynes (Scheme 9.72). They also investigated in detail the effect of steric and electronic factors on the regioselectivity of the cycloaddition reaction. (Azidomethyl)benzisothiazolone (378) underwent smooth 1,3-dipolar cycloaddition with various disubstituted acetylenes to give the corresponding triazoles (379) in 37-84% yields. Electron-deficient acetylenic dipolarophiles reacted more rapidly with the azide to give the respective triazoles. 

TABLE 10.4. 1,3-DIPOLAR CYCLOADDITION REACTIONS OF MUNCHNONES AND METHYLENE TRIAZOLES ... 

Bis(phenylazo)phenanthrene 174, for which the cyclic form 175 dominates reactivity at low concentrations, reacts with acrylonitrile in dry toluene at 55 °C for 48h to give the o o-adduct 2,4-diphenyl-3a,6a-(biphenyl-2,2 -yl)-6-exo-cyano-l,3a,4,5,6,6a-hexahydropyrrolo[2,3-r7 -2,3-triazol-2-ium-l-ide 176 (60% ) as the only product of cycloaddition. Reaction with other alkenes, for example, A -phenylmaleimide, leads to a mixture of endo- and o ti-products, cf. 177 and 178 <1996J(P1)1623>. 

Cyclization of 3-Amino-1,2,4-triazoles by Reaction with Alkylidene- or Arylidenemalononitrile. [3 + 3] Cycloaddition of 3-amino-l,2,4-triazole (65) onto 4-methoxybenzylidenemalononitrile produced only the 7-amino-6-cyano-5-(4-methoxyphenyl)-l,2,4-triazolo[4,3-a]pyrimidine (66) [88IJC(B) 478)]. The alternative addition that may afford the 5-amino-6-cyano-7-(4-methoxyphenyl)-l,2,4-triazolo[4,3-a]pyrimidine (110) did not take place. Utilization of ethoxymethylene malononitrile in place of arylidenemalononitrile in this reaction gave 66 (R = H) in addition to 7-amino-6-cyano-l,2,4-triazolo[l,5-a]pyrimidine 67 (R = H) (70JPR254) (Scheme 46). 

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