Disubstituted 1,2,3-triazoles

4-Disubstituted 1,2,3-triazoles are exclusive products of copper catalyzed 1,3-dipolar cycloadditions of terminal alkynes to azides. A variety of substituents can be introduced in this way. Many examples of such reactions are discussed in Section 5.01.9. 

5-Disubstituted 1,2,3-triazoles are formed in 1,3-dipolar cycloaddition of alkynylmagnesium reagents to azides. This reverse regioselectivity is also achieved in ruthenium-catalyzed cycloadditions. Examples of such reactions can be found in Section 5.01.9. 

---

In the presence of copper and palladium catalysts, terminal alkynes 1222 react with trimethylsilyl azide and allyl methyl carbonate to provide 2,4-disubstituted 1,2,3-triazoles 1223 in moderate to good yield. Isomerization of the allyl substituent in the presence of a ruthenium catalyst gives 4-substituted 2-(l-propen-l-yl)-2//-l,2,3-triazoles 1224. 

Disubstituted 1,2,3-triazoles are usually minor components in the product mixtures obtained from reactions of triazole with electrophiles (see Section 5.01.5). The few regioselective syntheses of such compounds include a reaction of aminoacetophenones 1235 with hydrazines. The reaction with methylhydrazine proceeds well without any catalysis, but that with phenylhydrazine requires cupric chloride as a catalyst. It is assumed that hydrazone 1236 that forms in the first step is in a tautomeric equilibrium with its azo form 1237. However, it is not clear how bond formation between the nitrogen atoms and oxidation to the triazole system occurs. 4-Aryltriazoles 1238 are obtained in 50-66% yield (Scheme 205) <2003SC3513>. 

Other 4,5-disubstituted triazoles used as precursors for triazolopyridines are the diacid 118 or its anhydride, reacting with aniline (83IJC(B)125) and the ketoamide 119 (90IZV1392). 

Scheme 18 Click chemistry synthesis of 1,4-disubstituted triazoles...

Canthine skeleton 52 Cardiotonic agent, heart failiu-e 3 Caspase-3 inhibitors, non-peptide 269 Catch and release , 2,4,5-trisubstituted pyrimidines 98 Chloro dehydroxylation 17 Click chemistry, 1,4-disubstituted triazoles 45... 

It appears that treatment of phenacyl bromides 1239 with methylhydrazine in refluxing acetic acid leads also to 1,4-disubstituted triazoles 1244. Fivefold excess of methylhydrazine is used in these reactions. According to the proposed mechanism, structures 1240-1243, methylhydrazine has a double role, as a condensing agent and an oxidant. In the final account, three molecules of methylhydrazine have to be used to produce one molecule of triazole 1244, two molecules of methylamine and one molecule of ammonia. The basic triazole 1244 (X = Y = H) is separated in 59% yield. The reactions go well with electron-donating substituents (for X = OH, the yield is 81%), but electron-withdrawing substituents can lower the yield dramatically (11% for X = N02) (Scheme 206) <2003JCM96>. 

The synthesis of 4,5-disubstituted triazoles shown in Scheme 208, carried out on a polymer support with microwave assistance, is based on a similar principle. In the first step, sulfinate 1248 is converted to sulfone 1249. Condensation with aldehydes provides vinyl sulfones 1250. Cyclocondensation of sulfones 1250 with sodium azide generates corresponding triazoline intermediates that eliminate sulfinate 1248 to provide triazoles 1251 in moderate to good yield <2006OL3283>. 

Reactions of 4,5-disubstituted triazoles with appropriate substrates provide very useful methods for building triazolo fused bicyclic or tricyclic systems. 5-Azido-1,2,3-triazoles bearing an appropriate substituent (e.g., CHO, CN, CO2R) at the 4-position can be transformed with active methylene nitriles into tricyclic heterocycles (e.g., (368)) <86BSB679,87BSB587). A new tricyclic system, 5//-1,2,3-triazolo[5,l-c][l,4]benzodiazepine (e.g., (370) and (371)), is prepared by the intramolecular ring closure of triazoles (369) <89JHC1605). 

Hydrazine hydrate reacts with a-hydroxyacids to give the A -aminodihydrotriazole which is diazotised with sodium nitrite in HCl to the 3,5-disubstituted triazole enantiomer (Scheme 24) <87H(26)989>. These triazoles were converted to macrocyclic derivatives (see Section 4.02.12.3). The ketals of a-oxoesters undergo the same series of reactions to give, after hydrolysis, the 3,5-dicarbonyl derivatives (Scheme 25) <92S398>. 

We found that a catalytic amount of cucurbituril markedly accelerated the reaction shown and rendered it regiospecific, yielding only the 1,3-disubstituted product. This result is explained by formation of a transient ternary complex between the reactants and the receptor. Simultaneous binding of both the alkyne and the azide, with one NH3 coordinated to each set of carbonyls and with the substituents extending into the interior of cucurbituril, results in alignment of the reactive groups within the core of the receptor so as to facilitate production of the 1,3-disubstituted triazole. The proposed mechanism may be visualized with the aid of Fig. 7 (R = H). 

Infrared data have been tabulated for benzotriazole and a wide range of its transition metal complexes or adducts (172). Far infrared spectra have been recorded for copper(II) benzotriazole adducts and bands at 270-320 cm-1 have been assigned to Cu-N vibrations (172). Infrared absorptions at approximately 825, 800, and 775 cm-1 in the spectra of cobalt(III)/4,5-disubstituted triazolate complexes have been attributed to triazolate ring vibrations (109). Infrared data have been reported and assignments made for palladium and platinum thiatriazoline-5-thionate complexes (37) and for the parent thione (127). Vibrational spectroscopy has been employed in an attempt to determine coordination sites for a range of 8-azapurine complexes (108). 

Proton and I3C NMR spectra have been used to distinguish between symmetrically (N-2) and asymmetrically (N-l) coordinated benzotriazole (209) or 4,5-disubstituted triazolate (109, 146) ligands, and to measure equilibrium constants for the N-l/N-2-coordinated benzotriazole system [Fe(CN)5(btaH)]3 (209). Hydrogen bond formation and proton transfer reactions in [Fe(taH)(C5H5)(CO)2][HSOJ have been followed by variable-temperature 1H and 13C NMR (5,146). 

In azide addition to quinones, the triazoline adducts are spontaneously oxidized to the triazoles.1-8 9,279-281,317,392 393 Potassium permanganate32,155,286,288 and nickel peroxide394 also effect triazoline oxidation. Permanganate oxidation of 1,5-substituted triazolines in a two-phase system using a phase-transfer catalyst provides a convenient route to the synthesis of 1,5-disubstituted triazoles (Scheme 118).395,396 Triazoline 4-carboxylic esters32,287,288 and a 4-carboxamide397 are converted to triazoles by potassium permanganate and nickel peroxide, respectively. 

The discovery of copper catalysis in 1,3-dipolar cycloadditions of terminal alkynes to azides (click chemistry) in 2002 <2002AGE2596, 2002JOC3057> has revolutionized the field . It is not only that the catalyzed reactions proceed faster under mild conditions, but full regioselectivity of the products is also achieved. Terminal alkynes generate only 1,4-disubstituted triazoles. A brief outline of the reaction mechanism is given in Scheme 253 . Some aspects of this new methodology are discussed in a review <2007ALD7>. 

Various miidazo[l,5-a]imidazoles (35), itnidazo[l,5-a] pyridines (36), and iniidazo[5,l-a]isoquinolmes (37), important ligands or precursors to pharmaceuticals," can be constructed via copper-catalyzed heterocyclization of Schiff s bases. A stepwise cycloaddition between azides and terminal alkynes is also catalyzed by copper salts in what has now been termed click chemistry, producing 1,4-disubstituted triazoles (38) in excellent yields." ... 

Polymers derived from triazoles can be formed by three fundamental methods. In the simplest way 3,5-disubstituted triazoles are treated with acetylene to obtain 1-vinyl derivatives which are then polymerized with free radical catalysts. The resulting polymers do not appear to be used on their own but mixed with other polymerized alkenes they facilitate the dyeing of synthetic fabrics. 

A [l,2,4]triazolo[l,5-a]pyrazine analog of guanine has been prepared by cyclization of a 1,5-disubstituted triazole (77JHC697). 

Reaction of l-benzyl-4-acetylimino-l,2,4-triazolium (493) with aryl isothiocyanates in benzene yields a mixture of 1,3-cycloaddition product (494) and 1,5-disubstituted triazole (495). However, in DMF, mainly the... 

Dabco-based ionic liquids have been recently used, together other basic and neutral ILs, in the copper(i)-catalyzed azide-alkyne click reaction (Scheme 4.3). The model cycloaddition of a sugar azide with a sugar acetylene has been carried out in ten ILs. With one exception, in all investigated ILs the reaction afforded exclusively the 1,4-disubstituted triazole, namely a triazole-linked C-dis-accharide, in high yields. 

AAMonosubsti luted triazole arylation resulted in product mixture. Arylation of 1,5-disubstituted triazole afforded the product in low yield consistent with results reported by Yorimitsu. 

An analogous effect was observed for 1,3-disubstituted triazoles where the bromine atom is located at the N4 heteroatom of intermediate 47 (75BSF647) (Scheme 19). 

Disubstituted triazoles are brominated to give unstable intermediates, said to have structure 48. Subsequent treatment leads to their decom-... 

A somewhat different but mechanistically related reaction is the [2 -f 3] cycloaddition of a functionalized alkyne or nitrile to an azide to form a disubstituted triazole (120) or tetrazole ring (121, 122), linking the respective functionalities irreversibly (Scheme 14b). This click chemistry was used by Sharpless and co-workers (120) in 2001 as a tool to probe biochemical catalysis and substrate activation. The ease of the Cu(I)-catalyzed reaction has created a true explosion (120-160) of simple coupling-functionalization chemistry of all types of biochemical components (sugars, DNA, proteins, enzymes, substrates, inhibitors) (131, 135, 136, 139, 142, 155, 157-160), polymers (126, 134, 140, 147, 154),... 

Michael reaction Enantioselective addition of ketones to p-nitrostyrene is performed with the disubstituted triazole 1. Surprisingly, 1 is not a good catalyst for the aldol reaction. 

The 1,2,3-triazoles have interesting biological properties [86, 87]. 1,4-Disubstituted triazoles 45 can be synthesized in a one-pot three-component MW-assisted reaction from corresponding alkyl halides, sodium azide, and alkynes (Scheme 17.34) [88]. 

---