1,2,3 triazole cycloaddition approach

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). 

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]. 

In a quite different approach, shown in Scheme 204, cycloaddition of nitrile 1232 to trimethylsilyldiazomethane provides silylated triazole 1233, isolated in 75% yield. Treatment with tetrabutylammonium fluoride removes the trimethylsilyl group and simultaneously the silyl protection of the carboxylic group to afford 4-substituted triazole derivative 1234 in 81% yield <2003PEN699>. 

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 [3 + 2] cycloaddition of diazo compounds to imines or nitriles is an alternative approach to the preparation of 1,2,3-triazoles and 1,2,3-triazolines. For reviews, see CHEC-I <84CHEC-I(5)7I7>. 

More recently, an approach to replace the thioether in FTP with a triazole was attempted utilizing a dipolar cycloaddition to join the prenyl and carboxylate groups [57]. These analogs are not substrates for Icmt, but all possess some activity as inhibitors. Despite the dramatic shift from the thioether to the triazole, the most potent compound retains significant binding affinity and is able to reduce Icmt activity by approximately 50%... 

The cycloadditions of diethyl diazenedicarboxylate and 3//-1,2,4-triazole-3,5(47/)-diones to 1,3-dienes where one only double bond is part of a fused or bridged bicyclic structure occurs with complete diastcrcoselectivity, since the diazene approaches the diene from the least hindered side, e.g., formation of 22 and 33. 

Steric and electronic effects are responsible for the diaslcrcoselectivity observed in the Diels Alder cycloaddition of 4-methyl- and 4-phenyl-3/f-l,2,4-triazole-3,5(4//)-dione to propellanes (Table 4). The dienophile can approach the diene syn or anti, i.e., above or below the plane, respectively. 

A recent very flexible approach for the preparation of TSOS has been published by Liebscher [34], It relies on a two step procedure with one so-called click chemistry step, which is a regioselective copper catalyzed [3 + 2] Huisgen cycloaddition between an azide and a terminal alkyne, followed by quatemarisation of resulting triazoles. Both reagents can be functionalized prior to cyclisation and furthermore such triazolium synthesis can tolerate a large variety of substituents owing to its chemoselectivity (Fig. 14). 

The Huisgen 1,3-dipolar cycloaddition of azides to alkynes or nitriles as dipolaro-philes, resulting in 1,2,3-triazoles or tetrazoles, is one of the most powerful click reactions . A limitation of this approach, however, is the absence of regiospecificity normally found in thermal 1,3-cycloaddition of nonsymmetrical alkynes this leads to mixtures of the different possible regioisomers. In other reports, classical 1,3-dipolar cycloadditions of azides to metal acetylides, alkynic Grignard reagents, phosphonium salts and acetylenic amides have been described. Extended reaction times and high temperatures are required in most of the reactions, but they can also be performed more effectively with the aid of microwave irradiation. The main results reported are reviewed in this section. 

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