Synthesis of Biologically Relevant 1,2,3- and 1,3,4-Triazoles: From Classical Pathway to Green Chemistry

Abstract

Green Chemistry has become in the last two decades an increasing part of research interest. Nonconventional «green» sources for chemical reactions include micro-wave, mechanical mixing, visible light and ultrasound. 1,2,3-triazoles have important applications in pharmaceutical chemistry while their 1,2,4 counterparts are developed to a lesser extent. In the review presented here we will focus on synthesis of 1,2,3 and 1,2,4-triazole systems by means of classical and « green chemistry » conditions involving ultrasound chemistry and mechanochemistry. The focus will be on compounds/scaffolds that possess biological/pharmacophoric properties. Finally, we will also present the formal cycloreversion of 1,2,3-triazole compounds under mechanical forces and its potential use in biological systems.

Keywords: 1,2,3-triazoles; 1,2,4-triazoles; biological properties; green chemistry; mechanochemistry; medicinal chemistry; ultrasound.

Figure 1

A summary of various approaches toward synthesis of 1,2,3-triazoles.

Scheme 1

Synthesis of 2-(2-(4-chlorophenyl)iminohydrazino) acetonitrile 4.

Scheme 2

Synthesis of tacrine and quinoline derivatives 9.

Scheme 3

Synthesis of 1,2,3-triazole-fused spirochromenes 13.

Scheme 4

Synthesis of 4-substituted 1,2,3-triazole-coumarin derivatives 18.

Scheme 5

Synthesis of mono and bis-1,2,3-triazoles, respectively 20 and 23.

Scheme 6

Synthesis of 24 and anti-oxidant activity measured as IC₅₀ by the DPPH procedure.

Scheme 7

Synthesis of new olanzapine based 1,2,3-triazole derivatives 27 via CuAAC method.

Scheme 8

Synthesis of 1,2,3-triazole 30 under ultrasound (US) and conventional methods (CM).

Scheme 9

Synthesis of fluorinated-1,2,4-triazole 36.

Figure 2

2-(4-(((3-(2-fluorophenyl)-4-phenyl-4,5-dihydro-1H-1,2,4-triazol-5-yl)thio)methyl)-1H-1,2,3-triazol-1-yl)-N-(5-(methylsulfonyl)-2,3-dihydro-1H-inden-2-yl)acetamide 37.

Scheme 10

Mechanochemical synthesis of oxindole-triazole hybrid pharmacophores 38.

Figure 3

Most active compound 38m of the series.

Scheme 11

Synthesis of triazolyl compounds from Quinine.

Scheme 12

Synthesis of 1,2,3-Triazole Tethered 3-Hydroxy-2-oxindoles.

Figure 4

Antifungal fluconazole 43, antitumoral letrozole 44, the antiviral ribavirin 45.

Scheme 13

Synthesis of 3,4,5-trisubstituted 1,2,4-triazoles 48.

Scheme 14

Synthesis of 3-C-glycosyl-5-substituted-1,2,4-triazoles 52.

Scheme 15

Syntheses of N¹-arylidene-arenecarboxamidrazones and their transformation into 3,5-diaryl-1,2,4-triazoles 55.

Figure 5

C-glucopyranosyl 1,2,4-triazoles 56.

Scheme 16

Reaction of the Mitsunobu reagent on amidrazones 57.

Scheme 17

Synthesis of 1,2,4-triazole 64 from hydrazides.

Scheme 18

Synthesis of 1,2,4-triazole-3-thione 67 and 68.

Scheme 19

Synthesis of 7-hydroxy-4-phenylchromen-2-linked 1,2,4-triazoles 73.

Figure 6

7-hydroxy-4-phenyl-2H-chromen-2-one 70 (with R = H) and 7-((4-(4-Chlorophenyl)-4H-1,2,4-triazol-3-yl)methoxy)-4-phenyl-2H-chromen-2-one 74.

Scheme 20

Synthesis of 3-(4-alkoxystyryl)-[1,2,4]triazolo[3,4-a]phthalazines 77.

Figure 7

(E)-3-[4-(3-Methylbut-2-enyloxy)styryl]-[1,2,4]triazolo[3,4-a]phthalazine 78.

Scheme 21

Convergent (A) and divergent (B) routes for synthesis of compounds 77.

Scheme 22

Synthesis of alkoxylated trans-styryltriazolophthalazine derivatives 81.

Scheme 23

Synthesis of 3-ethynylated derivative 85.

Scheme 24

One pot two step mechanochemical synthesis of annulated 1,2,4-triazoles 87.

Scheme 25

One pot two step synthesis of phenolic 1,2,3-triazoles 89.

Scheme 26

Syntheses of 3-bromo-[1,2,4]triazolo[3,4-a]phthalazine 91 by classical method (above) and mechanochemical condition (below).

Scheme 27

Effect of ultrasound on the triazole 92.

Scheme 28

Reactions of (a) 1,4-dimethyl 1,2,3-triazole leading to mononuclear Cu^I-catalyzed cycloreversion and (b) 1,5-dimethyl 1,2,3-triazole leading to Ru^II-catalyzed cycloreversions.