Triazoles 1,4-disubstituted, formation

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>. 

Contrasting with the reported formation of fused [l,3,4]thiadiazole rings in the course of the reaction of 3-substituted-4-amino-5-thio-47/-[l,2,4]triazoles 83 with various isothiocyanates (cf. Section 11.07.8.3, Table 3), the reactions with methyl isothiocyanate and with phenylisocyanate afford 3,7-disubstituted-6,7-dihydro-57/-[l,2,4]triazolo[4,3-f] [l,2,4]triazole-6-thiones 110 and -triazole-6-ones 111, respectively (Equation 29) <1986MI607, 1992IJB167>.The same reaction of 4-amino-l-methyl-3,5-bis(methylthio)[l,2,4]triazolium iodide 112 with aryl isothiocyanates yields the mesoionic compounds 113 (Equation 30) <1984TL5427, 1986T2121>. 

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). 

Basic hydrolysis of 1,4-disubstituted l,4-dihydro-l,2,4,5-tetrazines (87) resulted in the formation of 2,4-disubstituted 3-imino-1,2,4-triazoles (88) (78HC(33)1075, p. 1152), and aqueous base converted 3,6-disubstituted dihydro-1,2,4,5-tetrazines (89) into 3,5-disub-stituted 1,2,4-triazoles (90) (56JCS2253). 

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). 

Identically, triazole-based carbenes were found to be able to substitute CO, giving rise to mono- or disubstituted carbene carbonyl complexes (53) and (54) as a function of the reaction stoichiometry (Scheme 8). Reaction between M(CO)e and one equivalent of triazolylidene led to the formation of cis... 

Stankovicova, H., Fabian, W. M. F., Lacova, M. Synthesis and theoretical study of Mannich type reaction products of 3-formylchromones with triazoles and amides and nucleophilic formation of 2,3-disubstituted-4-chromanones. Molecules [Electronic Publication] 1996,1, 223-235. 

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>. 

Other bis azo compounds give y-triazole JV-imines as intermediates. Thus, photolysis of sydnones (58) 94-97 and of 2,5-disubstituted tetrazoles98-99 gives w-triazoles (62). These reactions probably involve the primary formation of nitrilimines (60) which dimerize to the bis azoethylene derivatives (61) which in turn cyclize to form the v-triazole IV-imines. These, under the reaction conditions, cleave at the exocyclic N-N bond (see Section IV,F). 

The 1,3-dipolar character of the azido group has been previously exploited for [2 + 3]-cycloaddition reactions of glycosyl azides with compounds containing triple bonds. It is known that formation of 1,4-disubstituted 1,2,3-triazoles is favored over the 1,5-disubstituted ones. Motivated mainly by pharmacological considerations (in order to obtain compounds with cytostatic properties), syntheses of a great number of 1-A -glycosyl-1,2,3-triazole derivatives have been reported. " " "" ... 

Triazole ring opening of these chiral alcohols with the formation of chiral 2,6-disubstituted pyridines are known. The reactions are performed with acetic acid, 2.5 M sulphuric acid, and selenium dioxide as electrophiles (07T10479). 

These trends correspond to pseudo-first order rate constants of 0.5 x 10 , 2.0 x 10 , >650 X 10 and >30 x lO min" for prodnction of the 3,4- and 3,5-disubstituted isoxa-zoles from reaction of 4-ferf-butylbenzonitrile oxide (ImM) with propynamide (5mM) and the cyclodextrin derivative (5mM), respectively (Fignre 3.14). Thus, the cyclodextrin moiety increases the rate of formation of the 3,4-disubstitnted isoxazole by more than three orders of magnitude. Even the rate of formation of the 3,5-disubstituted isoxazole is increased more than fifteen times by the cyclodextrin, despite templating of the other isomer being preferred. Under analogous conditions, the pseudo-first order rate constants for production of the 1,5- and 1,4-disubstituted triazoles from reaction of A-tert-butylphenylazide with propynamide and the cyclodextrin derivative are <0.1 x 10 , ... 

X 10 40 X 10 and 2 x 10 minrespectively (Figure 3.14). Therefore, in this case, the cyclodextrin moiety increases the rate of formation of the 1,5-disubstituted triazole by a factor of more than four hundred, and even the rate of formation of the 1,4-isomer is accelerated by a factor of at least twenty. 

As 1,4-disubstituted 1,2,3-triazoles are usually prepared through copper-catalyzed 1,3-dipolar cycloadditions of terminal alkynes with organic azides, the use of a single copper complex for a direct arylation-based sequential catalysis was probed. Thereby, a modular chemo- and regioselective synthesis of fully-substituted 1,2,3-triazoles was achieved (Scheme 9.43). Notably, the overall reaction involved the selective coupUng of four components through the formation of one C—C- and three C—N-bonds [58]. 

In 2005, ruthenium cyclopentadienyl complexes were found to catalyze the formation ofthe complementary 1,5-disubstituted triazole from azides and terminal... 

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