Synthesis and applications of bi ‐ and bis ‐ triazole systems

The current review article represents the synthetic routes to all possible classes of bi ‐ and bis ‐ triazole systems along with their research and biological applications. The classification is based on the connection between the two triazole rings

7][18][19] Nonsymmetric 1,3`-Bitriazole derivatives were reported to have antiviral activity against tobacco mosaic virus and exhibited powerful antiproliferative effects on different cancer cell lines. 20The application of bitriazoles as chelating N-heterocyclic carbene ligands for ruthenium(II), palladium(II), and rhodium and their applications in catalytic organic synthesis have also been reported. 21,224][25][26][27] In the view of the above results and in connection with our previous review articles about biologically active heterocyclic systems, [28][29][30][31][32][33] we prepared this review to disclose the intensive survey on the synthetic routes to symmetrical and nonsymmetrical bi-and bis-triazole systems (Figure 2) and their applications reported in the literature until the end of 2017.

Scheme 5
The synthesis of the 1,5`-bitriazole derivatives 18 was conducted under mild conditions, where the azidotriazole derivative 17 was readily engaged in a copper(I)-catalyzed Huisgen reaction with various terminal acetylenes 5. Treatment the bi-triazolyl compounds 18 with NH 3 /MeOH led to the formation of the corresponding amides 19 (Scheme 6). 39,40The 1,5`-bitriazole derivatives 18 and 19 constituted interesting leads for the development of new antiviral candidates where they were more potent antiviral than the commercial products, DHT and ribavirin.

Scheme 33
The 4,5`-bitriazolyl acyclonucleosides 109 were synthesized in excellent yields via the copper catalyzed cycloaddition reaction of aryl azides and the 5-acetynylyltriazole acyclonucleoside 108 in THF-water followed by ammonolysis with NH 3 /MeOH mixture (Scheme 34).The synthesized compounds exhibited powerful antiproliferative effects on numerous cancer cell lines. 76

Scheme 57
The "click" reaction of diazeniumdiolate prodrugs having terminal alkyne groups with the bis-azide 187 was performed using CuSO 4 /Na-ascorbate in THF/water.The reaction proceeded quickly (15-45 min) and gave a mixture of two products.The major product was in each case the bis-triazole derivative 189 and the minor product was 5,5′-triazolo-triazole 190.The use of CuI and diisopropylethylamine (DIPEA) as base predominantly gave the cycloaddition/oxidative coupling products; 5,5′-triazolo-triazole 189 as major products (Scheme 58). 109The products were reported to have potential biological applications as NO-donors.

Scheme 63
Reaction of terephthalic acid bis-hydrazide 207 with aryl iso(thio)cyanate in DMF in the presence of sodium hydride followed by treatment with concentrated HCl afforded the corresponding (thio)semicarbazide 208.The bis-(thio)semicarbazides on treatment with sodium hydroxide led to the formation of the bis(1,2,4triazole) derivatives 209 in 64-69% yields (Scheme 64).