3.5- Disubstituted-l,2,4-triazoles

A three-component coupling was used to prepare a series of 1,4-disubstituted-l,2,3-triazoles 129 from the corresponding acetylated Baylis-Hillman adducts 127, sodium azide and terminal alkynes 128 <06TL3059>. This same reaction was also carried out in either water or in... 

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.

In another example employing multiple supported catalysts and reagents, Smith et al. (2007a) presented a modular flow reactor in which 14 1,4-disubstituted-l,2,3-triazoles were synthesized. Coupling an immobilized copper(I) iodide species 148 with two scavenger modules (immobilized thiourea 149 and phosphane resin 150), the authors reported the [3 + 2] cycloaddition of an array of azides and terminal acetylene (30 pi min x) to afford the desired 1,4-disubstituted 1,2,3-triazoles (Scheme 40) in moderate to excellent yield (70-93%). 

Aldehyde 126 was converted to the terminal alkyne (142) in 61% yield by Seyferth-Gilbert homologation (Scheme 23) [60]. These basic conditions were well tolerated and no C-8 epimerization or C-2 deacetylation was observed. Alkyne 142 was coupled with various azides under copper(I)-catalyzed click reaction conditions to afford 1,4-disubstituted-l,2,3-triazoles (143-145) in 88% yield. Similar conditions were used to generate unsubstituted 1,2,3-triazoles. Alkyne 142 was coupled to azidomethyl pivalate under click reaction conditions to give the pivalyl triazole (146) in 88% yield. The pivalyl triazole was then treated with IN NaOH to remove both the pivalyl group and the C-2 acetyl group. These conditions also led to C-8 epimerization. Acetylation of the epimeric mixture under standard conditions (AC2O, pyridine) and preparative scale separation by TLC furnished the C-8 epimeric N-unsubstituted triazoles (147) in 54% yield over three steps in a ratio of 4 6 (C-8 epi-C-8). 

Coupled with the fact that the proportion of trace metal contaminants detected within continuous flow reaction products is inherently low, due to reduced catalyst degradation, the use of a scavenger cartridge at the end of a reaction sequence represents a relatively long-term solution to this problem. Other examples of the use of solid-supported scavengers have been reported by Ley and co-workers [65], where in one example, two scavenger modules, comprising QuadraPure TU (126) and phosphane resin, were used in the synthesis of 1,4-disubstituted-l,2,3-triazoles [66], and by Watts and co-workers [67], where silica-supported copper sulfate was used for the removal of residual dithiol (ppb) in the synthesis of 1,3-dithiolanes and 1,3-dithianes. 

Polystyrene-sulfonyl hydrazide resins 153 reacted with various amines to give regiospecifically 1,4-disubstituted-l,2,3-triazoles 154 via traceless cleavage reactions <04TL6129>. A library of peptidotriazoles were prepared by solid-phase peptide synthesis combined with a regiospecific copper(I)-catalyzed 1,3-dipolar cycloaddition between resin-bound alkynes and protected amino azides <04JCO312>. 

Eokin and Van der Eycken, et al. also described the microwave-assisted three-component one-pot synthesis of 1,4-disubstituted-l,2,3-triazoles 211 (Scheme 11.53) [109]. A suspension of alkyl halides 208, sodium azide 209, and alkynes 210 in a 1 1 mixture of t-BuOH and water, together with a copper catalyst, in a... 

Disubstituted-l,2,3-triazoles ( cHck-triazoles ) as hgands 12THC (28)31. 

Azide additions to a,P-unsatnrated systems are another method for the preparation of 1,2,3-triazoles. Cydoaddition of aryl azides to a,P-unsaturated aldehydes 88 in the presence of catalytic diethylamine and DBU afforded 1,4-disubstituted-l,2,3-triazoles 89 via an inverse electron-demand process (13CC10187). Michael addition of sodium azide with ethyhdene bisphospho-nates 90 in cydoaddition reactions via sonication afforded bisphosphono-1,2,3-triazoles 91 (13T4047).A one-pot protocol for the synthesis of 1,2,3-triazoles was prepared from unactivated alkenes with azidosulfenylation of the carbon-carbon double bond followed by the copper-catalyzed azide—alkyne cycloaddition (13JOC5031). 1,5-Disubstituted-l,2,3-triazoles 93 were synthesized from enamides 92 with tosyl azide (13AG(E)13265). Reaction of ethyl 3-(alkylamino)-4,4,4,-trifluoro-but-2-enoates 94 with mesyl azide in the presence of DBU afforded l,2,3-triazole-4-carboxylates 95 (13EJ02891). 

Yamaguchi, K., Kotani, M., Kamata, K., et al. (2008). An Efficient One-Pot Three-Component Reaction to Produce 1,4-Disubstituted-l,2,3-triazoles Catalyzed by a Dicopper-Substituted SU-icotungstate, Chem. Lett., 37, pp. 1258-1259. 

The 1,3-dipolar cycloaddition of primary, secondary, tertiary or aromatic azides and terminal alkynes to give triazole is possibly the most useful cycloaddition. This reaction has only recently been popularized under the name of click chemistry by Sharpless upon finding that it can be regioselectively catalyzed by Cu to quantitatively provide only 1,4-disubstituted l,2,3-triazoles. ... 

Also, reactions of terminal alkynes with sodium azide and aryl iodide afford 5-aryl-1,4-disubstituted l,2,3-triazoles °. In the reaction of a,/3-acetylenic aldehydes with sodium azide in DMSO at room temperature, 5-substituted-4-carbaldehyde-1,2,3-triazoles are obtained in quantitative yields... 

Click-Triazole Coordination Chemistry Exploiting 1,4-Disubstituted-l,2,3-Triazoles as Ligands... 

While the aqueous Cu(II)/ascorbate method is ubiquitous, the reducing conditions are not always compatible with sensitive substrates. For this reason, alternative approaches to 1,4-disubstituted-l,2,3-triazole ligands have been... 

It is clear that the CuAAC click reaction can be exploited to rapidly synthesize families of functionalized ligand architectures, and this synthetic versatility could lead to many potential applications. However, before the full potential of these click ligands can be realized, an understanding of the coordination properties of 1,4-disubstituted-l,2,3-triazoles is required. In the following sections, we will examine the coordination properties of monodentate, bidentate, tridentate, and polydentate ligands containing 1,4-disubstituted-l,2,3-triazole units. 

Fig. 3 X-ray structures of the Pd(ll) complexes 10a (a) [109] and 12b (b) [111] showing the monodentate coordination through the N3 nitrogen of 1,4-disubstituted-l,2,3-triazole ligands. Hydrogen atoms and counter ions have been omitted for clarity...

In a final example, Osuka, Shinokubo, and coworkers have synthesized the 1,4-disubstituted-l,2,3-triazole appended Zn(II)-porphyrin, 15, and showed using NMR studies that it dimerizes in solution. X-ray crystallography confirmed that the dimerization is driven by coordination of the 1,4-disubstituted-l,2,3-triazole donor on one porphyrin to the Zn(ll) ion of the adjacent porphyrin (Fig. 5) [113]. As with the previously discussed Pd(II) and Re(I) complexes, the triazole unit interacts with the Zn(ll) ions through the N3 nitrogen. 

There are a number of other reported 1,4-disubstituted-l,2,3-triazole metal complexes in which monodentate binding is presumed [114—119]. None of these compounds have been structurally characterized, and as such, it is unknown whether the coordination is through the N2 or N3 nitrogen of the 1,2,3-triazole unit. However, on the basis of the previously discussed structurally characterized... 

While the most obvious coordinatimi sites on the 1,4-disubstituted-l,2,3-triazole unit are the N2 and N3 nitrogen atoms, the acidic nature of the hydrogen on the C5 carbon means that it can be readily deprotmiated to provide anionic 1,4-disubstituted-1,2,3-triazolide Ugands. Straub and coworkers [123] were able to isolate a stable copperOD 1,4-disubstituted-l,2,3-triazolide complex (19a) by reacting the bulky NHC-stabdized copper(T) acetyUde 18a with azidodi-4-tolylmethane in toluene at RT for 24 h (Fig. 7). 19a was stable in air and water, and its molecular structure was confirmed by X-ray crystallography (Fig. 7). The copper(I) 1,2,3-triazolide... 

The anionic l,4-disubstituted-l,2,3-triazolides are not the only click triazole ligands which display the C5 coordination mode. 1,4-Disubstituted-l,2,3-triazoles (C) are readily and regioselectively alkyl/benzylated at the N3 position providing easy... 

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