Synthesis of 1,2,3-Triazoles

Further disadvantage of the alkyne-azide cycloaddition is the lack of regiospecificity. On the other hand, cycloadditions of azides to alkenes are, in most cases, regioselective and afford 1,5-disubstituted triazolines B-84Ml 40l-0l . Therefore, the regioselective cycloaddition of an azide to an alkene, followed by aromatization (see Section 4.01.5.3.1) is an alternative method for the synthesis of 1,2,3-triazoles. 

5-Amino-1,2,3-triazoles with a substituent at the 4-position have been prepared (i) from azides and active methylene nitriles (ii) from azides and ynamines (iii) from diazomethane and carbo-diimides (iv) from azides and 1,1-diaminoethenes and (v) from the rearrangement of 3-hydrazono-1,2,4-oxadiazoles. Among these, the first method, a regiospecific process, is the most versatile and convenient although it is suitable only for 5-NH2-substituted triazoles. Other methods are used to prepare 5-NHR , 5-NR R - and 5-NHCOR-substituted triazoles. Intramolecular cyclization of suitable precursors also gives 5-aminotriazoles. For example, a-imino-a-piperidyl phenylhydrazones (838), in the presence of copper acetate, give 5-piperidyl-triazoles (839) (Equation (85)) 94H(38)739 . 

5-Hydroxy-1,2,3-triazoles with an aryl or carbonyl function at C(4) are similarly synthesized from azides and 1,3-dicarbonyl compounds. 

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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. 

In one approach to catalytic synthesis of 1,2,3-triazoles, copper(l) is introduced to the reaction mixture as Cul. Compounds 1109-1115 are obtained this way. As can be seen in Table 12, a tertiary amine is often added as a base. The reaction conditions are mild and yields of the products are high. In some cases, the reaction can be carried out in water (compound 1115). For the synthesis of triazole 1116, addition of Cu powder is enough to generate catalytic amounts of Cu(l). 

The synthesis of 1,2,3-triazole-fused tetracyclic compounds via intramolecular click chemsitry approach was presented (Fig. 49).65... 

Scheme 7.2 Synthesis of 1,2,3-triazoles by the 1,3-dipolar cycloaddition reaction of organic azides with terminal acetylenes.

Patent One Step Synthesis of 1,2,3-Triazole Carboxylic Acids... 

Finally, the new aromatic system (a triazole) can be formed by elimination of the amir. Protonation of the most basic nitrogen is followed by expulsion of morpholine and aromatiza by deprotonation. This synthesis of 1,2,3-triazoles was discovered in Milan during a mechanic study of the reactions of azides and enamines. 

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 aUcyne in the synthesis of 1,2,3-triazoles. 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. 

Triazoles can also be prepared from in situ formation of azides from halo compormds. For example, 1,4-disubstituted-1,2,3-triazoles 138 were obtained in excellent yields by a convenient one-pot procedure from a variety of aryl and alkyl iodides 136 and terminal alkynes 137 without isolation of potentially unstable organic azide intermediates 05SL2941>. Efficient one-pot synthesis of 1,2,3-triazoles from in situ formation of azides from benzyl and alkyl halides with alkynes has also been reported <05SL943>. 

Dipolar cycloaddition of polyethylene glycol-supported azide with various dipolarophiles followed by acidic cleavage afforded 4- and 5-substituted-1,2,3-triazoles 05T4983>. Trimethylsilyl-directed 1,3-dipolar cycloaddition reactions in the solid-phase synthesis of 1,2,3-triazoles have been developed <05OL1469>. 

The following methods are particularly applicable to the synthesis of 1,2,3-triazoles. 

Based on an aminoalkylurethane linker attached to the Wang resin 155, Zaragoza et al. developed a solid-phase synthesis of 1,2,3-triazoles. Thus, as shown in Scheme 4.1.30, Wang resin 84 was primarily treated with 4-nitrophenyl chloroformate 153 in the presence of pyridine to give 154 and then reacted with piperazine in DMF to produce 155. Subsequent reaction with a freshly prepared solution of 3-oxobutyric acid phenyl ester afforded resin-bound 3-oxobutyryl piperazine 156. In the presence of triethylorthoformate, the condensation of 156 with primary aliphatic amines readily produced the corresponding 3-amino-2-butenoic acid amides attached to the solid support (157). 

From these examples, the versatility of 1,3-cycloaddition reactions in the synthesis of 1,2,3-triazoles is apparent. Other strategies, however, are available. Greif and coworkers developed perfluoroalkyl-substituted p-chlorovinylaldehydes as new building blocks for a number of fluorinated heterocyclic systems such as thiazoles, pyridines, pyrazoles, and benzimidazoles. Reaction of the chlorovinylaldehydes with sodium azide leads to the formation of moderate to good yields of 4-perfluor-... 

The use of a reducing agent, most commonly sodium ascorbate, introduced by Fokin and coworkers [6], is a convenient and practical alternative to oxygen-free conditions. Its combination with a copper(II) salt, such as the readily available and stable copper(II) sulfate pentahydrate or copper(ll) acetate, has become the method of choice for preparative synthesis of 1,2,3-triazoles. Water appears to be an ideal solvent, capable of supporting copper(l) acetylides in their reactive state, especially when they are formed in situ. The aqueous ascorbate procedure often furnishes triazole products in nearly quantitative yield and greater than 90% purity, without the need for ligands or protection of the reaction mixture from oxygen (Scheme 10.2C). Of course, copper(I) salts can also be used in combination with ascorbate, wherein it converts any oxidized copper(ll) species back to the catalytically active -Hi oxidation state. 

General procedure 2, copper metal-catalyzed synthesis of 1,2,3-triazoles [6, 23]. Phenylacetylene (2.04g, 20mmol) and 2,2-bis(azidomethyl)propane-l,3-diol (1.86g, lOmmol) were dissolved in 1 2 tert-butanol/water mixture (50mL). About 1 g of copper metal turnings was added, and the reaction mixture was stirred for 24 h, after which time TLC analysis indicated complete consumption of starting materials. Copper was removed, and the white product was filtered off, washed with water, and dried to yield 3.85 g (98%) of pure bis-triazole product. 

Reproduced from Mukherjee N, Ahammed S, Bhadraa S, Ranu BC. Solvent-fiee one-pot synthesis of 1,2.3-triazole derivatives by the Click reaction of akyl halides or ary boronic ackis, sodium azide and terminal akynes over a Cu/AlyOs surface under ball-milling. Green Chem 2013 15 389-97 with permission from the Royal Society of Chemistry. 

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