1,3-dipolar cycloaddition triazoles synthesis

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. 

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>. 

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). 

The 1,3-dipolar cycloaddition of azides to alkynes is a versatile route to 1,2,3-tri-azoles. Different combinations of substituents on the azide and on the alkyne allow the preparation of diverse N-substitutcd 1,2,3-triazoles. Katritzky and Singh have described the synthesis of C-carbamoyl-1,2,3-triazoles by microwave-induced cydoaddition of benzyl azides to acetylenic amides (Scheme 6.220) [393]. Employing equimolar mixtures of the azide and alkyne under solvent-free conditions, the authors were able to achieve good to excellent isolated product yields by microwave heating at 55-85 °C for 30 min. In general, the triazole products were obtained as mixtures of regioisomers. Control experiments carried out under thermal (oil bath)... 

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>. 

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). 

Deprotection of N-2 by ozonolysis furnishes triazoles 1225 (Scheme 202) <2003JA7786>. Finding that 1,3-dipolar cycloaddition of alkynes 1222 to trimethylsilyl azide, carried out in DMF/MeOH in the presence of Cul as a catalyst, leads directly to products 1225 with much higher yields provides a significant progress to the synthesis of N-unsubstituted 1,2,3-triazoles <2004EJO3789>. 

A mild and greener approach to the synthesis of 1,2,4-triazoles by the dipolar cycloaddition of nitrilimines with nitriles has been reported. The nitrilium intermediates were generated in situ from hydrazonyl chlorides 120 and reacted with the nitriles in a one-pot process. Yields of the 1,3,5-trisubstituted products 121a-o were good in the majority of cases (Equation 37 and Table 20) <2005H(65)1183>. 

The 1,3-dipolar cycloaddition of azido-l,2,5-oxadiazoles (azidofurazans) to dicarbonyl compounds has been studied and a new procedure for the synthesis of (l,2,3-triazol-l-yl)-l,2,5-oxadiazoles was proposed <2002MC159>. The cycloaddition of 4-amino-3-azido-l,2,5-oxadiazole 168 to nitriles with activated methylene groups has been studied, and 3-amino-4-(5-amino-l/7-l,2,3-triazol-l-yl)-l,2,5-oxadiazoles 169 and the products of their Dimroth rearrangement 170 have been synthesized <2004MC76>. 

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... 

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.

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. 

Palacios et al. (31) reported the synthesis of the isomeric 4,5-disubstituted l-(diethoxyphosphorylmethyl)-l,2,3-triazoles 156 and 157 via thermal intermole-cular 1,3-dipolar cycloadditions of the azidoalkylphosphonates 154 with the disubstimted acetylenes 155 (Scheme 9.31). 

An efficient synthesis of the l-aUyl-6-(l, 2, 3 -triazolyl) analogue 170 of 1-[2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (KEPT), an anti-human immunodeficiency virus (HIV) reverse transcriptase inhibitor, was reported using an intermolecular 1,3-dipolar cycloaddition of the azide 169 with acetylenes (35) (Scheme 9.35). Azidouracil (169), when refluxed with an acetylene in equimolar proportions in toluene, gave the corresponding triazoles (170) in excellent yield. 

The synthesis of the l-(D-apio-D-furanosyl)-1,2,3-triazoles 196, structurally related analogues of the antibiotic ribavarin A 176, was achieved through an intermolecular 1,3-dipolar cycloaddition of the azide 193 with the 2-oxoalkylide-netriphenylphosphorane (41) (Scheme 9.41). 

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. 

Zinc chloride-doped natural phosphate was shown to have catalytic behavior in the 1,3-dipolar cycloadditions of nucleoside acetylenes with azides to form triazolonucleosides <99SC1057>. A soluble polymer-supported 1,3-dipolar cycloaddition of carbohydrate-derived 1,2,3-triazoles has been reported <99H(51)1807>. 2-Styrylchromones and sodium azide were employed in the synthesis of 4(5)-aryl-5(4)-(2-chromonyl)-1,2,3-triazoles <99H(51)481>. Lead(IV) acetate oxidation of mixed bis-aroyl hydrazones of biacetyl led to l-(a-aroyloxyarylideneamino)-3,5-dimethyl-l,2,3-triazoles <99H(51)599>. Reaction of 1-amino-3-methylbenzimidazolium chloride with lead(fV) acetate afforded l-methyl-l/f-benzotriazole <99BML961>. Hydrogenation reactions of some [l,2,3]triazolo[l,5-a]pyridines, [l,2,3]triazolo[l,5-a]quinolines, and [l,2,3]triazolo[l,5-a]isoquinolines were studied <99T12881>. 

Cycloaddition reactions can also be used for the synthesis of various triazole derivatives. Thus, for example, the reaction of azidohydrazone (106) with enamines includes a 1,3-dipolar cycloaddition of the azido group to the... 

Katritzky, A.R. and Singh, S.K., Synthesis of C-carbamoyl- 1,2,3-triazoles by microwave-induced 1,3-dipolar cycloaddition of organic azides to acetylenic amides, ]. Org. Chem., 2002,67, 9077-9079. 

A more recently published example of organic microwave synthesis under CF conditions is the 1,3-dipolar cycloaddition chemistry in the CEM CF Voyager system (Fig. 11). Savin and coworkers presented the cycloaddition of dimethyl acetylene dicarboxylate with benzyl azide in toluene, which was first carefully optimized with respect to solvent, temperature, and time under batch conditions. The best protocol was then translated to a CF procedure where a 0.33 M solution of both building blocks was pumped through a Kevlar-enforced Teflon coil (10 mL total capacity) heated in the single-mode reactor at 110 °C (10 min residence time) [66]. This method provided a 91% conversion to the desired triazole product (Scheme 12). 

The formation of triazole rings by the reactions of azides and acetylenes was first described by Huisgen and coworkers [48,49] and has recently been promoted as dick chemistry by Sharpless et al. [50,51]. This versatile [3 + 2] dipolar cycloaddition proved to be useful for the synthesis of hyperbranched polytriazoles via 1,3-dipolar polycydoaddition of AB2-type monomers 28 and 29 (Scheme 14) [52], The monomers exhibited very high reactivity the... 

The difficulty in trying to forecast which way round a 1,3-dipolar cycloaddition will go is well illustrated when a substituted azide adds to an alkyne in the synthesis of 1,2,3-triazolcs. Reaction of an alkyl azide with an unsymmetrical alkyne, having an electron-withdrawing group at one end and an alkyl group at the other, gives mostly a single triazole. 

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