Current Developments in the Syntheses of 1,2,4-Triazole

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Current Organic Chemistry, 2014, 18, 359-406 359

Current Developments in the Syntheses of 1,2,4-Triazole Compounds

Hui-Zhen Zhang, Guri L V Damu†, Gui-Xin Cai* and Cheng-He Zhou*

Laboratory of Bioorganic & Medicinal Chemistry, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, People’s Republic of China

Abstract: Heterocyclic 1,2,4-triazole derivatives possess unusually spacious potentiality as medicinal agents, agricultural chemicals, functional materials, ionic liquids, supramolecular catalysts as well as artificial enzymes and receptors for supramolecular recognition and biomimetic catalysis, and their various researches and developments have been being a quite rapidly developing and active highlight topic with an infinite space. Numerous efforts have been directed toward various types of possible applications of 1,2,4-triazole-based compounds and a lot of important progress has been made, especially their preparations have attracted increasing attention. This review systematically summarized the recent advances in the syntheses of 1,2,4-triazole derivatives, including: (1) Cyclizations to form triazole ring; (2) Transformations of heterocyclic compounds to construct triazole ring; (3) Substitutions on 1,2,4-triazole ring; (4) Structural modifications in side chains of 1,2,4-triazole ring. It was hoped that this review would be helpful for the design and development of highly efficient preparation of 1,2,4-triazole derivatives with various sorts and varieties of extensively potential applications in medicine, agriculture, chemistry, materials, supramolecular sciences and so on.

Keywords: N-Alkylation, cyclization, heterocyclic transformation, hydrazine, hydrazone, N-quaternization, structural modification, 1,2,4-triazole.

1. INTRODUCTION

Triazole compounds have been attracting special interest due to the presence of unusual five-membered tri-nitrogen aromatic het-erocyclic structure which may exert diverse weak interactions such as hydrogen bonds, coordination, ion-dipole, cation-�, �-� stacking, hydrophobic effect, van der Waals force and so on [1, 2], and thereby 1,2,4-triazole-based compounds exhibit extensively poten-tial applications in medicinal, agricultural, chemical, supramolecu-lar as well as materials sciences [3,4]. In medicinal chemistry, the unique structure of triazole ring made its derivatives easily bind with a variety of enzymes and receptors in biological system and show broad biological activities like antibacterial, antifungal, anti-viral, anticoagulant, anti-inflammatory, anticancer and antioxidant properties etc [5-7]. So far, a large number of triazole-based me-dicinal drugs have been extensively used in clinic, such as antifun-gal Fluconazole 1, Voriconazole 2 and Itraconazole 3, anticancer Letrozole 4 and Anastrozole 5 as well as antiviral Ribavirin 6 (Fig. 1) [8, 9]. More importantly, numerous researchers have been devot-ing to triazole compounds as medicinal agents and hopefully dis-cover novel chemical scaffold compounds with broad spectrum, high bioactivity, low toxicity and excellent pharmacokinetic prop-erty. Noticeably, more and more triazole-based compounds as drug candidates are being actively developed [10]. In agriculture, tria-zoles as agrochemicals, for example, fungicides, plant growth regu-lators, herbicides and insecticides etc. play an unusually important role in ensuring the harvest of the crops [11-13]. A lot of triazole pesticides such as insecticide Triazophos 7, fungicides Triadimefon 8 and Prothioconazole 9, plant growth regulators Paclobutrazol 10aand Diniconazole 10b, herbicides Sulfentrazone 11 and Flupoxam

*Address correspondence to this author at the Laboratory of Bioorganic & Medicinal Chemistry, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, People’s Republic of China; Tel: +86-23-68254967; Fax: +86-23-68254967; E-mails: [email protected] and [email protected] † Postdoctoral fellow from Indian Institute of Chemical Technology (IICT), India

12 (Fig. 2) have been extensively employed for agricultural produc tion. In material sciences, triazoles as new types of functional mate-rials have displayed enormous potentiality in luminescent, magnetic and electron transport materials [3,14-19]. In chemical aspects, as corrosion inhibitors, triazole-derived compounds may easily form �-coordination bonds with various metal ions to inhibit the corro-sion of metals [20, 21]; as light stabilizers, triazole derivatives with low volatility and high thermostability have been widespreadly applied in paints, food packages as well as sunscreen agents [11]. As a new type of ionic liquids (ILs), triazoles have exhibited con-spicuous advantages with nonvolatile, wide applicable temperatures and environmentally friendly properties [22,23]. In supramolecular chemistry, the specific 1,2,4-triazole ring as good building block has been frequently employed to construct various artificial cation, anion and molecular receptors [3,24], enzyme models and su-pramolecular catalysts [25, 26] as well as nanometer materials [3,27], especially in supramolecular recognization, assembly [28, 29] and in the development of supramolecular drugs [30-32]. All the above mentions have strongly shown an infinite space for the various applications of triazole compounds. In fact, numerous works have been focusing on various types of possible applications of 1,2,4-triazole-based derivatives, and a large number of excellent achievements have been acquired. The related researches have be-come a quite rapidly developing and increasingly attracting high-light topic [33-35].

The extensive potential applications of 1,2,4-triazole-based compounds have attracted increasingly overwhelming effort to develop their highly efficient syntheses [2,36-38]. Numerous works have been directed toward their syntheses with cheap and easy preparations, and a great deal of progress has been acquired [39, 40]. Throughout current researches, the synthetic methods of tria-zole compounds could be principally divided into two pathways: the formation of triazole ring and the functionalization of triazoles. The constructive routes of triazole ring include the cyclizations or cycloadditions from non-cyclic compounds and transformations of

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360 Current Organic Chemistry, 2014, Vol. 18, No. 3 Zhang et al.

Antifungal Fluconazole

N

N N

NH2

OO

OH

OH

HOAntiviral RibavirinAnticancer Letrozole

NN

N

N NAnticancer Anastrozole

F

F

NOH

N

N

Antifungal Voriconazole

CH3

NN

F

Antifungal Itraconazole

N

CH3

H3CN

H3C

CH3

1 2 3

4 5 6

F

OHN N N

NN

N

F

N N

N

O

O

O N

Cl

Cl

N

N

NN

N N

N

OCH3

H3C

Fig. (1). Some clinical triazole drugs.

Insecticide Triazophos

NN

N

O

P

S

OOC2H5 C2H5

Cl

O

N

N

N

O

CH3

CH3H3C

Fungicide Triadimefon Fungicide Prothioconazole

Plant growth regulatorsCl Cl

NHNN

N

H3C

F2HCO

Herbicide Sulfentrazone

SO O

CH3

Herbicide Flupoxam

7 8 9

11 12

N

NN

NH2O

Cl

O

C2F5

Cl

N N

HN

S

OHCH3

YX

NN

N

HO

H3C CH3

CH3

Cl

R

10a: X-Y = CH-CH2, R = H, Paclobutrazol10b: X-Y = C=CH, R = Cl, Diniconazole

Fig. (2). Some marketed triazole agrochemicals.

other heterocycles. In particular, cyclization approaches, due to good yields, mild reaction conditions and easy operations as well as commercial availability for reactant materials with cheapness and convenience, were the most predominant methods to produce 1,2,4-triazoles especially various substituted triazole derivatives. The structural modifications of triazole compounds were also exten-sively adopted to prepare new triazole derivatives. Noticeably, the N-alkylation modifications of triazole ring have been being preva-lent synthetic strategy to develop bioactive 1,2,4-triazole containing compounds especially antimicrobial drugs with broad active spec-trum, high efficiency and low toxicity. A large number of works have also focused on the structural reconstitutions in the side chains of triazole ring. Furthermore, some synthetic techniques like com-binatorial chemistry, solid-phase synthesis, and microwave-assisted synthetic technology as well as other methods such as one-pot preparation, highly selective reactions and asymmetric synthesis and phase transfer catalysis etc. have been extensively developed

and employed for the preparation of various triazoles. Previously, a few works had partially introduced the synthetic methods for some types of 1,2,4-triazoles [2,36,38,41]. However, so far no compre-hensive review on current synthetic methods of various 1,2,4-triazole compounds has been observed. This review should be of great interest to the readers as it for the first time systematically summarized the current developments in the syntheses of 1,2,4-triazoles, including (1) Cyclizations to form triazole ring; (2) Trans-formations of heterocyclic compounds to construct triazole ring; (3) Substitutions on 1,2,4-triazole ring and (4) Structural modifications in side chains of 1,2,4-triazole ring. The comparable discussion of various types of synthetic methods to access triazoles was done. The perspectives of the foreseeable future in the new trend of syn-thetic developments for the preparation of 1,2,4-triazoles were also presented. It is hoped that this review will be helpful to serve as a stimulant for new thoughts in the quest for rational designs of highly efficient preparation for various sorts and varieties of 1,2,4-

Current Developments in the Syntheses of 1,2,4-Triazole Compounds Current Organic Chemistry, 2014, Vol. 18, No. 3 361

triazole derivatives with diverse potential applications in chemical, medicinal, agricultural, material sciences and so on.

2. CYCLIZATIONS TO FORM TRIAZOLE RING

Cyclization is one of the most important synthetic methods in the preparation of 1,2,4-triazole derivatives with adjustable sub-stituents like mono-, bis- and tri-substituted ones. An increasing number of researches have directed toward the cyclization reactions to prepare 1,2,4-triazole ring with desirable various structural sub-stituents. Among these cyclizations to prepare 1,2,4-triazole deriva-tives, hydrazine and its derivatives are the most common starting materials to form the C=N or C�N bonds and have been extensively investigated. Especially, the dipolar cycloaddition as a predomi-nantly synthetic method is widely employed to build 1,2,4-triazole scaffold with special structures.

The simple non-substituted 1H-1,2,4-triazole is commercially available with very cheapness. So far its preparative methods are mainly involved in four types of synthetic methods [42, 43]: (1) Cyclization of formhydrazide with formamide. This preparative method provides quite low yield. (2) Cyclization of formic acid with hydrazine hydrate and formamide. This type of synthetic pro-cedure takes long reaction time and is not applicable for industry production. (3) Cyclization of formic acid with hydrazine hydrate under ammonia gas. The first step of this method is two phase reac-tion with harsh conditions and long reaction time. (4) Cyclization of formamide with hydrazine hydrate in a mole ratio of 3:1. This ap-proach as the maturely synthetic method with simple operation and high yield has been popularly employed for the preparation of 1H-1,2,4-triazole in industry. In spite of this, some effort has been still directed toward the further synthetic improvement and here the detailed advance will not be described. The present works almost focus on the synthetic developments of 1,2,4-triazole derivatives.

The substituted 1,2,4-triazole compounds, covering specific substituents or substitution patterns, have been attracting special interest due to their extensive applications in many fields. Cur-rently, there are thousands of scientific papers describing the syn-theses of this versatile group of triazoles. The reported synthetic methods of substituted triazoles could be summarized into the fol-lowing categories according to the different precursors of cycliza-tion reactions to form 1,2,4-triazole ring: (1) Hydrazones; (2) Hy-drazides; (3) Hydrazines; (4) Guanidines and so on.

2.1. Cyclizations of Hydrazones

Hydrazones as important synthons have been extensively adopted to construct 1,2,4-triazole ring. The cyclization of hydra-zones with nitrile compounds is an earlier synthetic method for the formation of 1,2,4-triazole backbone. Up to now, a large amount of work has been devoted to hydrazones and their derivatives as pre-cursors for the preparation of triazole derivatives [36-38]. On the basis of the different substituents on hydrazone skeleton, the start-ing reactants for the syntheses of 1,2,4-triazole derivatives may be recapitulated in the following types: amidrazones, acyl hydrazones and other hydrazone derivatives.

2.1.1. Amidrazones Amidrazones, the conjuncted products of imine and hydrazines,

are a class of important reactants for the synthesis of various types of nitrogen-containing compounds with broad bioactive spectrum, interesting luminous and magnetic properties [44,45]. Their cycliza-tion with carbonyl compounds is one of the most important path-ways to access 1,2,4-triazole derivatives [46-48].

It is well known that the preparation of aryl triazoles is a huge challenge to synthetic chemists, and much effort has been contrib-uted to the synthetic developments of this type of triazoles [49]. Currently, the prevalent preparative strategy is the classical syn-thetic method of transition-metal-catalyzed carbon-carbon cross-coupling. However, the costliness and instability of organometallic reactants largely limit their application. Great hope has therefore been invested in multicomponent heterocyclization which is able to readily access aryl triazoles under mild reaction conditions without the preparation of any organometallic intermediates. A practical example was the multicomponent reaction of primary hydrazone 13, substituted iodobenzene 14 and carbon monoxide under the catalysis of palladium diacetate that could facilely produce the sub-stituted 1,2,4-triazole 15 with acceptable yields ranging from 56% to 79% (Scheme 1) [49].

The cyclization of thio substituted amidrazones to afford sulfur triazoles is a special interesting topic because this type of thio tria-zole compounds generally exhibits broad bioactive spectrum. The reaction of sulfur substituted hydrazone 16 with a series of aliphatic and aromatic primary amines in boiling glacial acetic acid was ex-pected to produce N-substituted amides of 3-(3-ethylthio-1,2,4-triazol-5-yl)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid, but it failed. Interestingly, during cyclization reaction nucleophilic ring opened and decomposed. X-ray analysis elucidated that an unex-pected product, the N-substituted amides of 3-(3-ethylthio-1,2,4-triazol-5-yl)propenoic acid 17, was obtained in good yields. The electron withdrawing substituents on benzene ring seemed to be in favor for this conversion and resulted in high yields for 17a (R = 2-Cl) and 17b (R = 4-Br) with 81% and 78% respectively, while compound 17c with electron donating 3-CH3 group gave relatively low yield (67%) (Scheme 2). Additional researches showed that the introduction of sulfur atom into triazole compounds could evidently improve lipophilicity and regulate electron density of triazole ring, thus enhancing anticancer activities [50].

With the advent of ever more sophisticated computational methods for the modeling of molecular skeletons and properties, it is unsurprising that this has opened a new direction in the exploita-tion of novel drug scaffolds and could also predict the possibility for the synthesis of completely new bioactive organic molecules. Theoretical calculations suggested that cyclization of phenyl hydra-zone 18 with commercially available cis-1,2-cyclohexanedicarbo-xylic anhydride could generate antimicrobial 3,4,5-trisubstituted triazole 19 which practically exhibited antimicrobial activity against the tested fungi. The experimental results indicated that the tem-perature largely influenced the formation of target compound 19,and the room temperature was favorable for the formation of the desired product, while the refluxing condition resulted in the cyclic imide with 78% yield under the molar ratio of 1:1 for the two reac-tants (Scheme 3) [51].

Recently, much attention has been directed towards this type of reaction as shown in (Scheme 3) with an aim to extend its applica-ble scope and functional group tolerance. Substituted hydrazone 20,a pyridine analog of compound 18, could react with itaconic anhy-dride 21 in anhydrous diethyl ether at room temperature for 7 days to produce trisubstituted triazole 22a in a quite low yield of 15%, and while the mixture was treated by aqueous sodium hydroxide (2%) under reflux condition to give its isomer 22b in 75% yield. In order to further recognize this reaction, more efforts were done and found that compound 22a could be transformed into the more stable isomer 22b when treated by 2% NaOH solution at room tempera-ture for 12 h or in dimethylformamide (DMF) at 150 °C for 4 h (Scheme 4) [52].


The cyclic substituted hydrazone 23 was obtained through Beckmann rearrangement of oxime in the presence of polyphos-phoric acid (PPA) and subsequent treatment with phosphorous pen-tasulfide and hydrazine hydrate, its cycloaddition with formic acid could favorably produce anticonvulsant oxazepine triazole 24 in yields of 71-83%. The length of alkyl chain had no large effect on the yields of compound 24, but exerted direct impact on anticonvul-sant activity (Scheme 5) [53]. The easy preparation of oxazepine triazole derivatives provides a large possibility for their further exploitation of new oxazepine triazoles with low neurotoxicity and potent anticonvulsant activity.

Morpholine containing hydrazone 25, a six-membered analog of compound 23, was a good precursor for the preparation of tria-zolium compounds. It could easily react with trimethyl orthofor-mate to produce triazolium 26 in almost quantitative yield, and the latter as the precursor of N-heterocyclic carbenes (NHC) was able to form metal complexes with metal ions [54]. This type of tria-zolium metal complexes was generally resistant to decomposition and could be used as catalysts without additional ligands (Scheme 6) [55-57]. Some other triazolium compounds such as pyridine-based triazoliums [58] could also be successfully prepared in high yields by this method and all the triazolium compounds were found

13 14 15

NH2

R2HN

N

CH3

N

NN

R1 = 3-Cl, 4-OCH3R2 = i-Pr, Ph

R1

CH3

R2

+Pd(OAc)2

COI

R1

Scheme 1.

1716

a: R = 2-Cl b: R = 4-Br c: R = 3-CH3

R

NH2 HOAcNO

O

O

N

H3C

S

NH2 N NH

NNH

O

S

R

+

CH3

Scheme 2.

+ O

O

O

Toluene

12 h

18 19(75%)

N N

N

COOH

HNN

H2N

Scheme 3.

+

CH2

O

O

O

rt, 7 d

2221

N N

N RN

a: R =

b: R =

HN N

N

NH2COOH

CH2COOH

CH3

20

Scheme 4.

O

HN

O

HCOOH

23 24

CH3

n = 0�6

H2NN

nO

N

O

CH3

NN

OCH3

OHON

n n

PPAP2S5

NH2NH2

Scheme 5.


to exhibit much potentiality for further utilization in coordination and organometallic chemistry.

Benzene bridged bis-morpholine hydrazone 27, a condensed product resulting from m-phenylenedihydrazine and the corre-sponding morpholin-3-one, could successfully undergo cyclization with triethyl orthoformate to form triazole compound 28 in overall yields of 51-64%. Bis-triazolium 28 was a good catalyst that could efficiently catalyze the asymmetric intermolecular benzoin conden-sation in the presence of t-BuOK (Scheme 7) [59].

Solvent-free conditions (SFC) have been attracting special in-terest in synthetic chemistry because of no risk to use large amounts of volatile organic solvents and no need to recover, purify and reutilize the solvents [60]. In SFC, the substitution of ethoxy group in pyrazole 29 by aromatic amines under conventional heating (150 °C, 3 h) readily generated intermediate pyrazole hydrazone 30 and subsequently proceeded intramolecular cyclization to produce pyra-

zolyl 1,2,4-triazole 31 which could be easily converted by the use of amino group on pyrazole ring into other 1,2,4-triazole derivatives in good yields (Scheme 8) [61].

Silver salts as catalysts are able to promote the cyclization of hydrazones to access 1,2,4-triazole derivatives. Under the catalysis of silver carbonate, aryl amidrazone 32 easily proceeded an in-tramolecular cyclization in refluxing acetonitrile to successfully afford the desired 1,3,5-trisubstituted 1,2,4-triazole 33 as potential cytochrome P (CYP) enzyme inhibitor (Scheme 9) [62]. This type of preparative method has been usually employed for the formation of triazole ring with low reaction temperature and short reaction time.

Tertiary amino substituted amidrazones are one important type of building blocks for the synthesis of trisubstituted 1,2,4-triazole derivatives which can form coordination polymers by different �-�stacking interactions, especially off-set-face to face arrangements.

NH

O

HN

NH HC(OCH3)3

25 26

Cl

N

NN

O

(100%)Cl

Scheme 6.

HC(OEt)3 N N

NNN

N

O O

R RNHHN

NH NHN

O O

HN RR

2X2X

27 28R = Bn, i-C3H7

CH3OHX = Cl, PF6

Scheme 7.

29 30R1 = CH3, Ph R2 = H, 4-Cl

(77�86%)

150 oC

NH2

R2

31

N N

NN

N

CH3

R1

NH2

R2

N N

R1

H2N

OHN

N

O

CH3

H3C

N N

R1

H2N

OHN

N

HN

CH3

R2

Scheme 8.

RHN

N

HNn

n = 0, 1 X, Y = N, CH R = H, OCH3 32

33

Ag2CO3

X

Y

n

NN

N

RYX

CH3CN

(48�77%)

Scheme 9.


Bis-tertiary amino amidrazone 34 with substituted phenylamine in the presence of p-toluene sulfonic acid (p-TosOH) underwent in-termolecular cyclization to afford 3,4,5-trisubstituted triazole 35.The formed yields were remarkably affected by the substituents on benzene ring (Scheme 10). The presence of bis-carboxyl group resulted in quite low yield of compound 35c (45%), while mono-carboxyl substitution gave high yields up to 70-81% (Table 1). Generally, it was considered that the driving force in this reaction was the release of dimethyl amine as well as the stability of aro-matic heterocycle [63].

Thiocarbonyl diazoles as one of the highly reactive molecules are also used for the preparation of triazolones which are difficult to be prepared under common conditions. Treatment of amidrazone 36with 1,1-thiocarbonyldiimidazole 37 as the donor of the remaining carbon atom in tetrahydrofuran (THF) gave the corresponding 1,2,4-triazol-5-thione 38 in yields of 47-55%, and further conver-sion afforded 3-alkylthio-1,2,4-triazoles in 41-47% overall yields which could be served as artificial cyclooxygenase-2 (COX-2) isozyme (Scheme 11) [64]. This approach provides a convenient synthetic strategy for the preparation of artificial COX-2 isozyme thio triazole derivatives with facile condition, easy operation and moderate yields using thiocarbonyldiimidazole as reaction agent.

The aromatic heterocycles with the emission color tunability have recently received a great deal of interest in a variety of pho-tonic applications. In particular, triazole derivatives have been in-tensely studied as dopants in light-emitting electrochemical cells. Luminescent triazole 40 was prepared by the cyclization of pyridine amidrazone 39 with a series of substituted benzoyl chloride in basic media, and easily isolated by recrystallization without further puri-fication. (Table 2) manifested that substituents on benzene ring exhibited large effect on the formation of triazoles, especially the 4-CH3 substituent was specially favorable for this cyclization with almost quantitative yield up to 97%. Surprisingly, the presence of 4-OCH3 group gave low yield of 58%, and further researches to elucidate the influential factors on this reaction were necessary (Scheme 12) [65].

The combination of different pharmacophores into one mole-cule is a prevalent strategy to design and develop new bioactive compounds. Many works have been contributed to this field to ex-plore the bis-functional drug molecules with the aim to discover highly active drugs. Antitumor benzimidazolyl 1,2,4-triazole 42, a medicinal hybrid of nitrobenzimidazole and triazole, was efficiently prepared in 80% yield by the cyclization of benzimidazole amidra-zone 41 with trimethyl orthoformate. The bioactive assay showed

+

NH2

34

p-TosOH

35

R2NN

NR1 R1

R2

N

NR1

N

R1

NH3C CH3

CH3

CH3

Benzene

Scheme 10.

Table 1. Effects of Substituents on the Formation of Compounds 35a-e

Compound 35 a b c d e

R1 H H H CH3 CH3

R2 4-COOH 3-COOH 3,5-(COOH)2 4-COOH 3-COOH

Yield (%) 70 65 45 77 81

NHN

NH2

SO2CH3X

+

N

N

N

N

S

SO2CH3

N

HN N

S

X

X = H, F, CH3

36 37 38

THF

N2

Scheme 11.

Table 2. Effects of Substituents on the Formation of Compounds 40a-g

Compound 40 a b c d e f g

R H 4-CH3 4-OCH3 4-F 2,6-(F)2 3,5-(F)2 2,3,4,5,6-(F)5

Yield (%) 63 97 58 72 45 68 60


significant anticancer efficacy and its cytotoxic mechanism in-volved with reductive alkylation of DNA accompanied by the cleavaging of G and A bases (Scheme 13) [66]. This type of cycli-zation provides a convenient method for the preparation of novel triazole derivatives with multiple target sites.

Intramolecular cyclization of amidrazones is another alternative strategy to construct triazole compounds. Formyl amidrazone 43,which was obtained by the reaction of ethyl ethoxycarbonyl ace-timide with formyl hydrazine, underwent intramolecular cyclization in vacuo at 29 mm Hg to afford triazole 44 in 78% yield, and the prepared ethyl 3-triazolyl acetate could be further treated by ammo-nia and then dehydrated by P2O5/dry sand/absolute pyridine to gen-erate triazolyl acetonitrile which was an important intermediate of potent inhibitors for vascular endothelial growth factor receptor II (VEGFR-2) (Scheme 14) [67].

Aryl substituted amidrazone 45 could also generate in-tramolecular cyclization under high temperature to produce bis-aryl triazole 46 (Scheme 15) [68]. This reaction is of great use in prepa-ration of pyridine-triazole-benzene based xanthine oxidoreductase (XO) inhibitors with non-purine structures using acyl amidrazones as intermediates to introduce a heterocyclic moiety for reinforce-ment activity. However, no yields were given in this literature.

2.1.2. Acyl Hydrazones Acyl hydrazones also are important starting reactants to con-

struct the backbone of 1,2,4-triazole ring and have been paid large

attention due to the easy operations and highly active reactivities [69-71].

Microwave-assisted synthetic technology has been frequently employed in organic synthesis with shorter reaction time, higher yields and more environmentally friendly properties in comparison with traditional methods [72]. Intramolecular cyclization of com-pound 47 was achieved in water by microwave irradiation without any bases or catalysts to readily produce amino 1,2,4-triazole 48 in excellent yields. Experiments showed that this reaction could be highly affected by the solvents. Water was found to be the best green solvent to promote this reaction, while ethanol was unfavor-able for this transformation (Scheme 16) [73].

Intramolecular cyclization of guanidine containing acyl hydra-zone 49, which was prepared by the reaction of benzohydrazide with cyano guanidine in the presence of hydrochloric acid, afforded guanidino 1,2,4-triazole (50) in 68% yield and further transformed products 1,2,4-triazolo[1,5-a][1,3,5]triazines may be used as potent inhibitors of A1 and A2A adenosine receptors (Scheme 17) [74]. By the same synthetic procedure, indolyl-4H-1,2,4-triazoles as the center ligands of Growth Hormone Secretagogue Receptor 1a (GHS-R1a) with effective anti-obesity activity could also be effi-ciently prepared in good yields ranging from 73% to 79% [75]. This synthetic approach provides a practical and useful procedure with easy operation and mild condition for the construction of guanidino substituted triazole derivatives.

39

Na2CO3

40HN N

NN

R

+N

NHHN ClO

R

H2N

(CH2OH)2

Scheme 12.

41 42

+EtONaNN

CH3

O2N

NHNH2

NHNN

CH3

O2N

HN N

N

OCH3

OCH3

OCH3

HEtOH

Scheme 13.

125�130 oC

29 mm Hg

43 44

1. NH3

2. P2O5

N

HN N

CN

N

HN N

O O

OO

HNHN

NH

CHO

CH3

H3C

Scheme 14.

4645

200 oC

R = H, Cl, CH3, OCH3

NC

O

N

NHN

N

RO

NC

O

NH

NH

HN

O

N

R

OOCH3 OCH3

Scheme 15.


49

NaOH

50

HNO

N NH

NH2

NH2HNN

NHN

NH

NH2HN

Scheme 17.

Phthalocyanines are a family of aromatic macrocycles with de-localized 18-� electron system which are well known as photody-namic reagents for cancer therapy, laser dyes, new red-sensitive photocopying applications, optical computer read/write discs and so on. Triazole ring is incorporated into phthalocyanine molecules due to the strong ability of triazole derivatives to form metal complexes that extend magnetochemical application and other potential uses as optical sensors or molecular memory devices. Amino triazole 52with two substituted benzenes was an important precursor for the preparation of triazole phthalocyanines and was easily synthesized in good yield (85%) via intermolecular cyclization of hydrazine hydrate in n-propanol with the acyl hydrazone 51 which was ob-tained by the condensation of p-chlorobenzohydrazide with ethyl imido-p-methylbenzoate. Further modification of compound 52 by

2-fluoro-4-chlorobenzyl and 3,4-dicyano phenyl groups and subse-quent cyclization afforded triazole derived phthalocyanine which could coordinate with metal ions to form magnetochemical su-pramolecular complexes (Scheme 18) [76]. This synthetic proce-dure presents a practical route for the preparation of triazole derived phthalocyanines with multipurpose potentiality.

Ferrocene containing heterocycles also possess various poten-tial applications as medicinal agents, materials, catalysts and so on, especially triazole ones, due to their strong bioactivity and broad bioactive spectrum, have been attracting considerable attention. 1,2,4-Triazole-based bis-ferrocene 54 was prepared by the in-tramolecular cyclization of 1,5-bis(ferrocenylmethylene)thio-carbonohydrazide 53 under facile methyl iodide and dimethyl ace-tylenedicarboxylate (DMAD) mediated condition (Scheme 19) [77]. This pathway is a easy synthetic route to prepare 1,2,4-triazole-based diferrocenyl heterocycles.

Ester substituted hydrazones can also be served for the prepara-tion of triazole tautomeric forms triazolones with desirable proper-ties. Imidazole derivatives possess diverse potential application in pharmacology, chemistry and materials sciences [78-81]. Recently, the conjunction of triazole ring with imidazoles has also become the subject of debate. Experiments showed that the reaction of com-

NHN

NH2NMicrowave

4748

N

NH

O

NH2

NH2

(84�100%)R

R

R = H, F, Cl, CH3, OCH3

Water

Scheme 16.

350 W175 oC

N

NN N

Cl

CH3

Cl

CN

CNN

N

N

N

N

N

N

N

R

R

R

R =

NN

N

N

ClH3C

Cl

F

5251

NH2NH2

Cl

O

HN NO

H3C

H3Cn-PrOH N

NN NH2

Cl

CH3

Cl

OHN

NH2

NHO

CH3

+EtOH

R

DMAEM2+

M = Ni, Zn, Co, Cu

CH3

F

Scheme 18.


pound 55 with N-(3-aminopropyl)imidazole could not proceed smoothly under traditional conditions, but it was able to go rapidly without solvent in sealed tube to give compound 56 which could be used for the precursor of ionic liquids. The X-ray crystallography showed that the three ring system was on one plane in compounds 56a and 56b, while the ring system in 56c was in parallel (Scheme 20) [82]. It seemed no obvious substituent effect, either the electron withdrawing NO2 group or the electron donating OCH3 substituent in phenyl ring made this reaction occur smoothly.

Continuous researches demonstrated that ethoxylcarbonyl hy-drazone 57 was also able to smoothly perform cyclization with 4-aminoantipyrine to generate the antibacterial pyrazolyl 1,2,4-triazole 58 (78%) which as a hybrid of antipyrine and triazole pharmacophore was expected to display excellent pharmacological profiles with different mechanisms of action, slow metabolic rate, high oral bioavailability and less side effects (Scheme 21) [83]. 2.1.3. Other Hydrazones

Literature has reported that 1,3-dipolar cycloaddition as one type of pericyclic reactions relating to six � electrons could perform a versatile and efficient one-pot reaction to access five-membered

heterocycles [84-89] particularly triazole derivatives starting from available oximes, hydrazones and hydrazonoyl halides [90-92]. The 1,3-dipolar cycloaddition of phenyl substituted hydrazonoyl chlo-ride 59 with oxime 60 in the presence of excess triethylamine could generate triazole derivative 61 with broad antimicrobial spectrum (Scheme 22). As shown in (Table 3), the type of R2 group had great effects on this reaction, the electron donating alkyl oximes 60a-band 60d-e as well as cycloalkyl compound 60g gave high yields up to more than 87%, while the aromatic and aza-heterocyclic sub-stituents seemed to be unfavorable for this cycloaddition, specially the large 2-naphthalyl group made the yield low to 28%. However, the R1 group, which is far away from the reactive center, showed weak effects on the formation of target compound 61 [93, 94].

The phenyl substituted hydrazone 62 could also be readily transformed by amidine into trisubstituted triazole 63 in 63-78% yields through the nucleophilic addition of the imino group in amidine then cyclization at the imine carbon, or by cycloaddition onto C=N of the amidine moiety. Similarly, compound 62 could also smoothly cyclize with oxime to produce triazole compound 63.Researches showed that the substituents on benzenes exhibited little effect on the yields of target compounds (Scheme 23) [95].

The cycloaddition of strongly dipolar 2-arylsulfanylpyridinium N-arylimide 64 with isothiocyanates could form fused thi-oxo[1,2,4]triazolium salt 65 in very good yields (Scheme 24). This transformation may be elucidated as a regular 1,3-dipolar cycload-dition followed by a spontaneous elimination of aryl group [96].

2.2. Cyclizations of Hydrazides As is well known, several hydrazides are commercially avail-

able, and the noncommercial ones could be successfully prepared

HN NH

S

N N

53

1. CH3I

2. DMADFe Fe

N N

N SMe

N

54Fe

Fe

Scheme 19.

55

a: R = Hb: R = 4-NO2c: R = 3,4-(OCH3)2

+

56

(69�73%)

160 oCNN

NH2

N

O

CH3

HN

O

O

CH3

R

HN

NN

O

N N

R

Sealed tube

Scheme 20.

110�120 oC

58

N N

O

NH2

CH3

CH3

+

57

HN

NN

O

N

N

H3C CH3

O

ClCl

N

HN

O

O

CH3

Scheme 21.

+Et3N

59 61

N

NN

R2 R1

60

TolueneNH

NCl

O OCH3

R1

R2 H

N

OH

OOCH3

Scheme 22.


by the reaction of hydrazine with the corresponding ester precur-sors. Up to now, a lot of works have been done by the cyclization of hydrazides or their derivatives, mainly including alkyl, aryl and thio hydrazides, to prepare triazole derivatives.

2.2.1. Alkyl Hydrazides It has been well investigated that alkyl hydrazides as an impor-

tant class of effective building blocks for the preparation of ni-trogenous heterocycles, especially for the synthesis of 1,2,4-triazole

derivatives have caused much interest and a lot of works have been directed towards their developments [97-101]. Cyclization of form-hydrazide with 2,3-dihydro-1H-indene thioamide 66, a product of amide with Lawesson’s reagent in toluene, successfully provided triazole intermediate 67 in yield of 22% under the catalysis of mer-cury acetate (Scheme 25), In comparison with the relatively low yield of this compound, the final target triazole compound as the potent sodium glucose co-transporter 2 (SGLT2) inhibitor unex-pectedly exhibited a highly antidiabetic activity. Undoubtedly, fur-ther work is necessary to improve the yield of compound 67 [102].

Under the catalysis of acetic acid, hydrazide 68 proceeded cy-clization with 4-aminophenol and dimethoxy-N,N-dimethylmetha-namine to give phenol containing triazole 69 in excellent yield by one-pot procedure of the three component which has a wide range of applicability with adjustable substituted primary amines, hydraz-ides and dimethyl acetal as starting materials (Scheme 26) [103]. The maximal electroshock (MES) test showed that this type of syn-thetic compounds exhibited strong potency at a dose of 30 mg/kg against MES induced seizure in mice and also possessed remark-able lower neurotoxicity [104]. By the similar procedure, triazole fragment was coupled with 2-substituted benzooxazole to give molecules with broad bioactive spectrum [105] and other 4-(hydroxyphenyl)-1,2,4-triazole derivatives were also able to be prepared efficiently [106].

The N-ethylmorpholine substituted hydrazide 70 was treated in trifluoroacetic acid (TFA) by S-methyl isothiourea 71, which was prepared by the conversion of thioureas and secondary amine, to successfully afford the desired antimicrobial 3-N,N-dialkylamino-1,2,4-triazole 72 in 68% yield (Scheme 27) [107]. This synthetic method has been common strategy for the preparation of 1,2,4-triazole bioactive molecules involved the condensation of hydraz-ides with S-methyl isothiourea because of the relatively mild condi-tion, acceptable yields and good functional group tolerances includ-ing various heterocyclic derivatives like morpholine.

The cyclization of substituted hydrazide 73 with azetidine thioamide 74, a tautomeric form of S-methyl isothiourea, in the presence of trifluoroacetic acid produced compound 75 in low yield of 35% (Scheme 28) [108]. Further optimization of the reaction conditions to improve the yields of this transformation is necessary for potential clinical application of compound 75 as a potent oxyto-cin antagonist.

Computer aided design for organic molecules has attracted great interest and promoted the progress of synthetic chemistry [109]. The theoretical calculation predicted that the reaction of disubstituted hydrazide 76 with compound 77 could smoothly oc-cur, the experimental result showed that triazole 78 was success-fully obtained in the presence of potassium carbonate as antici-pated, and could be further transformed in THF at room tempera-ture into azabicyclo[3.1.0]hexyl triazole derivative as potent an-tagonist of dopamine D3 receptor (Scheme 29) [110].

The ester type of methoxyl substituted hydrazide 79 could also readily proceed cyclization with 4-nitroaniline and trimethyl ortho-

Table 3. Effects of Substituents on the Formation of Compounds 61a-g

Compound 61 a b c d e f g

R1 4-F 4-F 4-F 4-CF3 3-CF3 4-CF3 4-CF3

R2 CH3 i-Pr 2-naphthyl CH3 CH3 2-pyrrolyl cyclopentyl

Yield (%) 91 90 28 87 87 51 94

O

N

NH

R1 NH2

NR3R2

Et3N

N

N

N

H

NHR3

R2

O

R1

R1

N

HO

R2

H

N

N

N

OH

H

R2

O

R1

R1

N

N

N

O

R1

R1

R2

63

62

R1 = H, F, Cl, Br, CH3; R3 = H, PhR2 = CH3, Ph, SBn, SCH2COOH

R1

Et3N

Scheme 23.

NN

SR1 R2

N

N N

S

SR1

R3

N

NN

SR2

R3

Cl

64 65

N

NN

SR2

R3

S R1

R2

R1 = Et, Bn, 4-ClPh; R2 = Cl, CH3, OCH3; R3 = Et, 4-NO2Ph

(73�88%)R3NCS

CH2Cl2S C N R3

CH2Cl2

Scheme 24.


66

Hg(OAc)2

67

Reflux

NN

NN

O

H3C

H3CO

O

HN

NH2

+ NH

S

CH3

H3C

N N

N

H3C

Scheme 25.

OH

NH2

CH3CN

69

N

OCH3H3CO

CH3H3CH2N

HN

H3C

O

(93%)

N

NN

OH

+ +HOAc CH3

68

Scheme 26.

70

TFA+

NH

NNH2

O

71 72

NN

SCH3

Cl

O

NN

NN

NN

N

Cl

O

O

NNTHF

O

Scheme 27.

CF3COOH

73 74

+ THF

75

HN

O

NH2 O

CH3

NH

N

O

S

N

O

Cl

F

N N

NN

N

O

O

Cl

FCH3 CH3

OCH3

(35%)

Scheme 28.

K2CO3

60 oC

76 77 78R1 = H, F, CH3

+

CH2

R1R1

O

HN

NH2n

HN N

CH3CH3

R2 N

NNH3C

R2

R1R1N

n

N

NN CH3

R2

R1 R1 CH2

n

CF3R2 = H, 2-Cl, 2,4-(F)2

Scheme 29.

formate in refluxing methanol and following by addition of sodium methoxide via a succinct and easy operation of one-pot synthesis to conveniently produce N-nitrophenyl triazolone 80 with high yields

of 76-86%, and subsequently the latter was treated by oxirane to generate Fluconazole analogues with excellent activities against the evaluated fungi (Scheme 30) [111].


NO2

NH2

1. HC(OCH3)3

2. CH3ONa

79 80NO2

N

NHN

O

+

HN

OO

NH2

CH3

Scheme 30.

It has been over the past decade that N-heterocyclic carbenes as important ligands for transition metal-based homogeneous catalysis have emerged in the field of asymmetric catalysis, and triazole de-rivatives with multiple nitrogen atoms have played important roles in asymmetric technology as chiral carbene ligands. The cycloaddi-tion of N-isopropyl substituted hydrazide 81 with imidoyl chloride 82 was able to quantitatively yield chiral 1,4-disubstituted tria-zolium 83 which could be further transformed into chiral [RhCl(N-HC)(COD)] catalyst by the coordination with [RhCl(COD)]2(Scheme 31) [112].

2.2.2. Aryl Hydrazides Aryl hydrazides as an important type of industrial materials ex-

hibit higher reactivity than alkyl ones, and they easily perform cy-clization reactions to produce 1,2,4-triazole derivatives. The highly reactive methyl thioamide 84 was able to cyclize with substituted phenyl hydrazide 85 by the catalysis of trimethylsilyl triflate/silver triflate (TMSOTf/AgOTf) to give the potent inhibitor of 11�-Hydroxysteroid Dehydrogenase Type 1 (HSD1) cyclobutane tria-zole 86 which could conquer a cluster of health problems like hy-pertension, obesity and diabetes as well as dyslipidemias. However, no yields were reported for this transformation (Scheme 32) [113].

Triazole thiones display analgesic activity, and a lot of work has been directed towards development of new triazole thione de-rivatives as anti-inflammatory agents. Triazole thione 88 as new type of potential analgesic compound with significant activity was successfully prepared by the cyclization of hydrazide 87, a sulfur containing phenyl derivative on phenyl ring in compound 85, with potassium thiocyanate and hydrochloric acid followed by cycliza-tion of thiosemicarbazide. When compound 87 was treated by car-

bon disulfide or cyanogen bromide, this reaction gave 5-aryl-1,3,4-oxadiazole-2(3H)-thiones and 5-aryl-2-amino-1,3,4-oxadiazoles respectively in moderate to high yields (Scheme 33) [114].

Our recent work showed that amino substituted N-phenyl hy-drazide 89, a condensed product of phenylhydrazine with urea, was able to perform cyclization with formic acid under solvent free condition for 16-20 h at 125 °C to efficiently produce hydroxy 1,2,4-triazole 90 which was further modified to afford a new class of halobenzyloxy or alkoxy 1,2,4-triazole derivatives and their hy-drochlorides with superior inhibitory activity against bacteria to reference drug Chloramphenicol (Scheme 34) [115].

2.2.3. Thio Hydrazides Thio hydrazides, including amino and thiol hydrazides, have

been extensively employed as cyclization reactants for the construc-tion of sulfur containing 1,2,4-triazole derivatives with intriguing properties.

2.2.3.1. Amino Thio Hydrazides

Amino substituted thio hydrazides have usually been served as general intermediates for the preparation of thio triazole derivatives, and a lot of achievements have been acquired [116-119] such as anti-inflammatory phthalazine containing triazoles [120], antimi-crobial phenyl imidazole bearing thiazole-3H-1,2,4-triazole-3-thiones [121], anticonvulsant thiazole containing 1H-1,2,4-triazoles [122], antitubercular thiadiazole fused triazoles [123], antidepres-sant pyrazoline triazoles [124] as well as benzoxazine-4H-1,2,4-triazoles as ligands of A Disintegrin and Metalloproteinase with Thrombospondin Motifs 5 (ADAMTS-5) [125].

H2N

O

N

H3C CH3

81

N NHCl

N

83

ClO4

(90%)

NN

N

CH3

CH382

NaClO4

(AcO)2O+

ClO4

Scheme 31.

R2

R1

HN

NH2

O

84 85 86

TMSOTf

AgOTf

R1 = H, F, Cl, OCH3R2 = Br, NO2

+

N N

N

R2

R1

CH3

Cl

NH

CH3

S

Cl

Scheme 32.

KSCN

8788

X = S, SO2R = H, Cl

NH

NHN

S

X

R

X

R

NH

O

NH2HCl

Scheme 33.


Numerous researches have manifested that thio triazole deriva-tives should be associated with efficient antibacterial and antifungal activities [121, 126]. In continuation of ongoing interest in the de-velopment of new antimicrobial agents, sulfur containing triazoles have attracted much attention. The reaction of halobenzyl halide with thiosemicarbazide 91 successfully produced halobenzyl hydra-zine carbothioamide A1, and then the nucleophilic reaction with formic acid afforded intermediate A2. The following cyclization under acid condition produced triazole thione 92a, and its further transformation provided the isomer triazole thiol 92b in 73-82% yields. In the process of reaction conditions screening, it was found that the solvent and base played remarkable influence on the forma-tion of compound 92 (Scheme 35). Notably, ethanol led to rela-tively high yields in contrast to acetonitrile which might be attrib-uted to the good dissolvability of thiosemicarbazide in this solvent, but the presence of base resulted in low yields of target compounds due to formation of by-products [126]. This method provides a newly developed multicomponent procedure to prepare triazole thiol derivatives and triazole thiones with easy and convenient op-eration, short reaction time and high yields.

Thiocarbohydrazide 93 could undergo cyclization with 5-nitro-2-furoic acid through a one-step procedure to afford furane 4-

amino-1,2,4-triazole-3-thiol 94 in 78% yield (Scheme 36). Antitu-mor precursor 94 as a lead compound was of much potentiality to be further modified by aromatic aldehydes, alkyl/aryl isothiocy-anates or phenacyl bromides via condensation to afford thiadiazole or thiadiazine fused triazoles with strong cytotoxicity against hepa-tocarcinoma (Hep-G2) and human colon tumor (HCT-116) cell lines [127].

As is well known, acyl containing amino thio hydrazides can perform intramolecular cyclization under basic conditions to give functional triazole thione derivatives, and this synthetic procedure is widely employed for the construction of triazoles skeletons bear-ing special fragments [128-132] such as benzimidazoles, pyridazi-nones, sulfanilamides and so on. The intramolecular cyclization of benzimidazolyl thio hydrazide 95, which was prepared by the reac-tion of hydrazide with methylisothiocyanate, successfully provided hybrid of triazole and benzimidazole 96 with potent antioxidant activity in the presence of sodium hydroxide (Scheme 37) [133]. The similar synthetic procedure was applied to prepare pyridazi-none substituted 1,2,4-triazoles which showed highly significant reduction in mean arterial blood pressure but with higher dose in comparison to standard drugs Hydralazine and Propanolol [134]. Moreover, a series of novel sulfonamide-1,2,4-triazolones (26-65%), triazole thiones (53-96%) and benzodioxane triazoles (96%) as well as phenyl triazoles were conveniently developed in the simi-lar preparative method, and these intriguing molecules exhibited interesting bioactivities like antibacterial, antifungal and antitumor properties [135-137]. This type of synthetic strategy provides a fast (several minutes), facile and efficient method to access substituted 1,2,4-triazole thione derivatives [138-142].

HN

HN

NH2

O

+H OH

ON

HO

125 oC

8990

NHNH2

H2N NH2

O

(88%)

N

N

Scheme 34.

R2

HN

R1 A1

H OH

ONHS

H2N

R2

R1

H2N NH

SHCOOH

HCOOH

N NH

NS

R1

N N

NSH

R1

N

A2

HN

S

OH2

OH2

NH2

R1

R2

+

NH2

X

R2 R2

R1 = F, ClR2 = 2-F, 2-Cl, 3-Cl

92a 92b

H

91

X = Cl, Br

Scheme 35.

+

93

170�180 oCHN

NH2

NH

S

NH2

94

O

COOH

NO2

NN

NHS

NH2

O NO2

Scheme 36.


Recently, epidemiological studies have shown that the highly selective COX-2 inhibitors have serious side effects in clinical use. In the search for new anti-inflammatory agents with low toxicity and little resistance, special attention has been paid towards a wide variety of heterocycles like pyridazinones, 1,3,4-thiadiazoles, espe-cially 1,2,4-triazole thione derivatives. Therefore, the sodium bicar-bonate catalyzed intramolecular cyclization of compound 97 was carried out which highly yielded the corresponding pyridazinone containing triazole thione 98 as anti-inflammatory agent with supe-rior gastrointestinal safety (Scheme 38), and while the presence of acid resulted in pyridazinone thiadiazoles in 40-90% yields [143].

It is well known that the same starting materials can always lead to various types of products under diversified reaction condi-tions in synthetic chemistry, and this might be attributed to the dif-ferent synthetic mechanisms. Bis-phenylsulfone containing thio hydrazide 99 could generate intramolecular cyclization when re-fluxed in sodium hydroxide solution and followed by treatment with hydrochloric acid solution to give triazole thiol 100a and its tautomer triazole thione 100b in overall yields of 62-80%. How-ever, intramolecular cyclization in the presence of concentrated sulphuric acid and subsequent ammonia solution provided thiadia-zoles in 74-92% yields (Scheme 39). It was noticeable that this transformation could proceed smoothly to produce triazole com-pound with yield up to 80% when the substituents R1 and R2 are Br and 4-OCF3 respectively [144].

2.2.3.2. Thiol Thio Hydrazides

The cyclization of thiol thio hydrazides with hydrazine hydrate has also attained the status of an important pathway in preparation of triazole derivatives. The investigation and application of this strategy have prepared several interesting 1,2,4-triazole-based com-pounds bearing both amino and thiol groups [145]. This type of synthetic method provides practical access to amino triazole thiols which may favorably react with 1,3,4-thiadiazoles or 1,3,4-thiadiazines to prepare new types of fused heterocyclic compounds with broad bioactive spectrum such as antimicrobial [146-149], anti-inflammatory, analgesic [150,151] as well as antiepileptic ac-tivity [152].

Naturally, the chemistry of 1,2,4-triazole derivatives and their fused heterocyclic ones has received considerable attention owing to their effective biological properties. Thiol thio hydrazide 101, a condensed product of hydrazide with carbon disulphide, reacted with hydrazine hydrate to efficiently provide anti-inflammatory precursor 4-amino-5-substituted-4H-1,2,4-triazole-3-thiol 102 in high yield of 85%, and the latter could be further treated by various aromatic carboxylic acids in phosphorous oxychloride to yield thiadiazole containing triazoles or by a series of phenacyl bromides to produce thiadiazines bearing triazoles in good yields of 80-86% (Scheme 40) [153].

Fluoroquinolone structure as an important type of pharmacody-namic fragment is a popular scaffold in lots of pharmacologically

N

NNaOH

R2

95

R1 HN

HN

O

NH

S

N

N

96

R2

NHN

N

SCH3R1 = H, 3,5-(Cl)2

R2 = H, 4-Cl, 4-OCH3, 3,4-(OCH3)2

(51�64%)

R1CH3

Scheme 37.

N

NN

O

H3C O

R1

HN

NH

NH

R2O

S

97 98

NaHCO3

R1 = H, NO2, OCH3R2 = CH3, Et, Ph

N

NN

O

H3C O

R1

(85�95%)

N NH

N S

R2

Scheme 38.

1. NaOH

R1 = H, BrR2 = 4-OCF3, 3,4,5-(OCH3)3

99 100a 100b

S

HNNH

O

SHN

R2

O O

R1S

N N

N SH

O

O

R1

S

NHN

NS

O

O

R1

R2 R2

2. HCl

Scheme 39.


active artificial and natural compounds. Many researches have modified the C-3 carboxylic group of fluoroquinolones to develop novel antitumor drugs. Cyclization of Ofloxacin thio hydrazide 103with hydrazine hydrate at the catalysis of sodium hydroxide pro-vided anticancer precursor quinolone triazole derivative 104 in 72% yield (Scheme 41). Further modification of this important interme-diate successfully afforded the double functional compound bearing side chains of both Schiff and Mannich bases with excellent in vitroantitumor activity against the tested cell lines [154]. This research opens a new strategy to develop novel antitumor fluoroquinolone candidates from antibacterial analogs by introducing a triazole ring as bioisostere of the C-3 carboxylic group via convenient proce-dures.

Pyridine bridged dithiol thio hydrazide 105 could also success-fully generate molecular cyclization to produce pyridine bis-1,2,4-triazole 106 in 63% yield in the presence of excess hydrazine hy-drate, and then subsequently was reacted with aromatic acid in the catalysis of phosphorus oxychloride to provide fused triazole de-rivatives which possessed large conjugated plane for accepting or transporting charge and could also be used as hole transport materi-als (Scheme 42). This method was frequently applied for the syn-thesis of bis-triazole compounds with large conjugated planes of

high ionization or low electron affinities which could be used as good transferring holes materials in organic light emitting diodes (OLEDs) [155]. In same fashion, pyridine mono thiol thio hydraz-ides were also transformed into the corresponding triazoles, and could be subsequently glycosylated to afford glucoside bearing triazoles with good antibacterial and antifungal activities [156].

Various types of substituted hydrazides as starting materials have been extensively employed to construct functional triazole derivatives and a lot of remarkable progress has been acquired. It is foreseeable that more and more types of hydrazides including cyclic ones will be continuously served as reactants to prepare novel tria-zole derivatives with special properties, and the related researches will become increasingly active in future [157-160].

2.3. Cyclizations of Hydrazines

Hydrazines as raw materials of hydrazones and hydrazides can also be used to prepare triazole derivatives via direct cyclization with carbon containing compounds. The reaction of hydrazine with amidine 107, a substituted aniline with diphenyl cyanocarbonimi-date, conveniently produced diamino triazole 108 which possessed higher selectivity to tyrosine kinase 2 (TYK2) than Janus associated kinase 1-3 (JAK1-3) (Scheme 43) [161]. This synthetic strategy is

101

NH2NH2

102Cl Cl

Cl

O NH

HN

S

SH

Cl Cl

Cl

N

N

N NH2

SH

CH3OH

Cl Cl

Cl

HN O

NH2

CS2

CH3OH

Scheme 40.

104

NaOH

NH2NH2

103

N

O

F

CH3

N

O NN

N SH

NH2

NH3C

N

O

F

CH3

N

O O

NH3C

NH

HN

S

SH

Scheme 41.

105

NH2NH2

106

N

N

NN

NN

N

SH

SH

NH2

NH2

N

NH

NHS

O

SH

NH

NHO

SSH

KOHN

N

NN

NN

N

N

S

S

N

Ar

Ar

POCl3

ArCOOH

Ar = CH3NN

Scheme 42.


hopeful to be used as a starting point to develop anti-inflammatory triazole candidates with excellent selectivity.

Acyl amidines as important active building blocks have fre-quently appeared in biomolecules, and recently they have been found with ability to construct nitrogenous heterocycles [162]. The facile, practical and efficient one-pot reaction of acyl amidine 109with hydrazine hydrate reliably provided potent PI3K inhibitor 110with a special structure of thiophene triazole, but the reaction mechanism was not mentioned (Scheme 44) [163]. Another synthe-sis was the conversion of amides with N,N-dimethylformamide dimethyl acetal (DMF-DMA) at 100 °C to the corresponding ylideneamide, followed by the reaction with hydrazine to form desired triazole derivative 110. However, the yields for this cycliza-tion step are not mentioned in the experimental part, and only the total yield for the totally synthetic scheme was indicated as 70% [164].

Compound 111, a coupled product of commercially available carboxylic acid with amidine, easily reacted with cyclohexyl hydra-zine 112 in one-pot procedure under the catalysis of acetic acid to give 1,3,5-trisubstituted 1,2,4-triazole 113 (78%) as pharmaceuti-cally active molecule (Scheme 45) [165]. The reaction optimization and substrate scope studies for this one-pot synthesis revealed that the incorporation of aryl and alkyl substituents at 5-position, and heterocycloalkyl group at the 3-position of triazole ring are viable substrates for this transformation [166]. This type of coupling reac-tions provides a practical synthetic pathway with substituent com-patibility under mild conditions to produce considerable diversity of 1,3,5-trisubstituted 1,2,4-triazole skeletons.

Moreover, some aryl hydrazines are also employed as building blocks to construct 1,2,4-triazole derivatives. The mixture of phen-ylhydrazine 114 and N-cyanobenimidate 115, which was obtained by the reaction of inexpensive reagents aldehydes using cyanamide as nitrogen source and N-bromosuccinimide as oxidant, could pro-

ceed the cyclization of intermolecular C-N and C-O bonds by one-pot synthesis to afford 1,3,5-trisubstituted triazole 116 (82%) (Scheme 46) [167]. This synthesis could be further extended to the preparation of aniline substituted 1,2,4-triazoles in yields of 67-90% [71]. This method is an efficient one-pot procedure with the mild cyclization reaction of hydrazines to produce l,2,4-triazole derivatives in good yields.

Noticeably, the one-pot multicomponent reaction (MCR) of substituted phenyl hydrazine 117, ammonium thiocyanate and acid chlorides could efficiently produce triazole-3-thione 118 in high yields under solvent free conditions at room temperature. A possi-ble mechanism for this transformation was proposed that the reac-tion was started from the formation of isothiocyanate B1, followed by the addition of aryl hydrazine to construct B2, and subsequently cyclized to generate B3. The latter was converted to compound 118by elimination of water. Continuous researches showed that the different types of substituents could also accomplish this cycliza-tion in excellent yields, and this clearly pointed out that the substi-tution on benzene ring exhibited weak effects on the formation of target triazoles (Scheme 47) [168].

The discovery of new and safe anti-inflammatory drugs is be-coming a challenge. It has been reported that phthalazine containing triazoles possessed anti-inflammatory potentiality, and this has attracted much attention to prepare phthalazine derived anti-inflammatory candidates. The intermolecular cyclization of phtha-lazine containing hydrazine 119 with cyanogen bromide provided fused amino triazole 120 in low yield of 30%, and subsequent O-alkylation with a series of alkanols or substituted phenols afforded anti-inflammatory 6-alkoxy(phenoxy)-1,2,4-triazolyl-3-amine (Scheme 48) [169]. Further researches are necessary to improve the low yields of this synthetic method.

Additionally, some other hydrazine derivatives like N-Boc compounds have also been used as reactants to prepare 1,2,4-

107 108

NH2NH2

NH

N

N

NH

NH2R

R= 3-COOH, 3-COOEt, 4-COOH, 4-SO2NH2

NH

NCN

ORTHF

(50�73%)

Scheme 43.

(55�86%)

NH2NH2

S

CN

N

O

R1R2

N

N NH

110

S

CN

N

O

NN

O

R1R2

109

H3C

CH3

R1, R2 = F, Cl, CN, OCH3

EtOH

Scheme 44.

111 113

HOAc

NHNH2

+

N

N

N

N

O

NH2

OCF3

N

N

N

N N

N

OCF3

DMF

112

Scheme 45.


triazole derivatives. Recently, N-linked different heterocycles have received much attention because they are difficult to prepare under alternative conditions and represent previously unexplored hetero-cyclic cores. Fortunately, internal alkyne containing hydrazines were found to be able to undergo regioselective Ru-catalyzed cy-cloaddition of azide with alkyne to yield substituted hydrazine 1,2,3-triazole 121 and then the resulting heterocycle was rapidly transformed into an unusual N-1,2,3-triazole functionalized 1,2,4-triazole 122 (54%) by simple addition of formamide and anhydrous hydrogen chloride (Scheme 49). Further work displayed that these heterocyclic systems would be difficult to disconnect via alternative chemistry which demonstrated the significant promise of ynehydra-zines for the preparation of N-linked bis-heterocycles [170].

2.4. Cyclizations of Guanidines

Guanidines as starting reactants have been widely used in or-ganic synthesis and medicinal industry. Much literature has mani-fested that guanidines can be easily transformed into amino-1,2,4-triazole derivatives with high reactivity and intriguing properties.

Amino guanidine 123 could react with hot malonic acid by gradual addition to produce malonyl amino guanidine intermediate, and the latter underwent intramolecular cyclization in the presence of potassium hydroxide and subsequently acidified with concen-trated hydrochloric acid to pH = 4-5 to give desired 5-amino-1H-1,2,4-triazole-3-acetic acid 124 in 65% yield. Further transforma-tion of compound 124 could produce potential energetic material nitro triazole in yield of 70% (Scheme 50) [171,172]. Compound 123 could also condense with oxalic acid, and then performed cy-clization to afford bis[3-(5-amino-1,2,4-triazolyl)] compound [173].

Guanidine derivative 125 was prepared via substitution of thioether by hydrazine derivatives in microwave oven and its puri-fication was done by reverse phase HPLC (using acetic acid in wa-ter and acetonitrile as eluents) (Scheme 51). The intramolecular

N

NNCOCH3

CH3OH

115 116

NHNH2

+

N

N

NN

NH2

Reflux

114

Scheme 46.

NH4SCNR1 Cl

O

R1 N

O

118

B1 B2B3

a: R1 = Ph, R2 = H (95%) b: R1 = Et, R2 = 2,4-(NO2)2 (95%)c: R1 = Et, R2 = H (92%) d: R1 = Ph, R2 = 4-NO2 (94%)

+ +

NHNH2

R2N

N

NH

SR1

R2

NHNH2

R2

R1 N NNH

O S

H H

R2 HN

NHN

SR1

OH

R2C

S

117

Scheme 47.

N

N

Cl

NHNH2119 120

N

N

N N

NH2

Cl

Na2CO3BrCN+

Dioxane

Scheme 48.

H NH2

OHCl

121 122

+N N

N

NHN

Boc

BocH3C

NN

N

N CH3

N

N

Dioxane

Scheme 49.


cyclization of this compound under microwave irradiation success-fully accessed amino triazole derivative 126. Experiments pointed out that substituents showed large effects on this transformation. When R2 was 4-fluorobenzyl group, compound 126 was obtained in yields of 48-70%. In this case, when the substituent R1 is 2,4-dichlorobenzyl group, this reaction gave the highest yield up to 70%. However, if R2 was benzyl or alkyl groups, the conversion yields would decrease to 34-65% [174].

Intramolecular cyclization of compound 127 in ethanol pro-vided benzylthio substituted 1,2,4-triazole 128 in good yield with the concomitant expulsion of acetone and aniline. Compound 128was found to have potentiality to be served as inhibitor of the me-thionine aminopeptidase-2 (Co2+-MetAP2) enzyme (Scheme 52)[175]. Although this synthetic route is easy to perform, however, this reaction is limited because the substituted aniline guanidine intermediates are difficult to prepare.

2.5. Cyclizations of Other Compounds Some other compounds like nitriles and amidines etc. can also

proceed cyclization to generate 1,2,4-triazole derivatives. The reac-tion of benzonitrile with isoquinoline amidine 129 in the presence of copper ions formed the coordinated intermediate C1, subse-quently, copper complex promoted nucleophilic attack of amino isoquinoline on the nitrile to provide amidine C2, then oxidative cyclization was developed using molecular oxygen (air at 1 atm) as oxidant which was induced by copper ions to give isoquinoline triazole 130 that was known as a potent nonhormonal antifertility agent, and the water was produced as the sole theoretical by-product (Scheme 53). Further studies of substituents effects demon-strated that the electron withdrawing groups like halogens and

trifluoromethyl group on benzene ring gave the corresponding tria-zoles with good yields, while benzonitrile was substituted by methoxy group, the transformation efficiency was quite low to 55%. Acetonitrile could also be employed instead of benzonitrile to prepare triazoles in similar yield (52%) [176].

Cyclization of diethyl azodicarboxylate (DEAD) 131 with the N-protected imine 132 in the presence of triphenylphosphine was able to produce triazole derivative 133a in yield of 23% and its isomer 133b with relative high yield of 58% when the molar ratio of 132, DEAD and triphenylphosphine was 1:1.5:1.5. Experiments revealed that the reactant concentration highly influenced the for-mation of products, and the high concentration resulted in the for-mation of products in almost quantitative yields (75% and 25% respectively). The possible mechanism was shown in (Scheme 54). Initially, the reaction of triphenylphosphine with DEAD 131 pro-duced the zwitterionic intermediate D1, which underwent nucleo-philic addition of N-Boc protected imine to form intermediate D2.The intramolecular addition of intermediate D2 yielded intermediate D3 and the latter subsequently generated the elimination of triphen-ylphosphine oxide to give the product 133b via intermediate D4.The elimination of t-BuO- group from intermediate D2 afforded intermediate D5 and the released t-BuO- anion attacked DEAD to give intermediate D6, which underwent the elimination of EtO-

anion to provide compound D7. The released EtO- anion hit the intermediate D5 to generate intermediate D8, and then the resulting compound could experience similar intramolecular nucleophilic attack and eliminate the triphenylphosphine oxide to give product 133a [177].

The tremendous success of cyclization to access 1,2,4-triazole derivatives has prompted numerous efforts towards the cyclizations

123 124

H2N

NH

NH

NH2 COOH

COOH

+1. KOH

NH

NN

H2N

COOH

2. HCl

NH

NN

O2N

NO2NO2

NO2

NaNO2HNO3

Fuming HNO3

Scheme 50.

NHNH2R2N

N

N

R2

R1 NH2

125 126

(34�70%)

R1 = i-Pr, 2,4-(Cl)2PhR2 = Et, i-Bu, 4-FPh, CH2CH2OH

O

O N

S

NH

CH3

R1 O

O

O N

HN

NH

R1 O

NH

R2

160 oC

Scheme 51.

10% HCl

128

EtOH NN

HN S

HN

127

HNHN

N S

N

N

CH3

CH3

(70%)

Scheme 52.


of hydrazines and their derivatives. So far some good preparative methods for triazole derivatives have been successfully found and established, in particular, the cyclization of hydrazones, hydrazides and guanidines as well as their derivatives have already shown large prospects in preparation of triazoles. Undoubtedly, cyclization or cycloaddition preparative methods will continue to play impor-tant roles in the developments of various sorts and varieties of 1,2,4-triazole derivatives with novel structures and extensive poten-tial applications.

3. TRANSFORMATIONS OF HETEROCYCLIC COM-POUNDS TO CONSTRUCT TRIAZOLE RING

The interconversions of heterocyclic compounds represent an-other alternative strategy to prepare some special structures which

are difficult to develop through traditional strategies in heterocyclic chemistry. Up to now, some rare triazole derivatives have been successfully prepared via the transformations of heterocycles in-cluding five- and six-membered ones, and this type of synthetic strategy has contributed practical methods to construct some special 1,2,4-triazoles. Among these reported heterocycles, oxazoles and azines as transformation precursors to prepare 1,2,4-triazole deriva-tives have been paid special attention.

3.1. Transformations of Five-Membered Heterocyclic Com-pounds

Recently, rearrangements of five-membered heterocycles such as oxadiazoles, oxazolones, tetrazoles and thiazoles to prepare 1,2,4-triazole derivatives have attracted much interest in synthetic chemistry.

N

NH2+

N N N

N

129 130

N

NH2

N

Cun+

N

HN

NH

Cun+

Cu(n-2)+

or 2 Cu(n-1)+

Cun+

C1 C2

(55�87%)

R

R

R

R

R = H, Cl, Br, CF3, OCH3

Scheme 53.

BocN

Ph

N

N

NN

N

N

Boc

EtO2C

Ph OEt

EtO2C

Ph

CO2Et

OEt +

131 133b133a

CO2EtN

NEtO2C

PPh3path a

path b

NN

OEtNHPh

EtO2CPPh3

OBu-tO

O N

NN

EtO2C

Ph

PPh3

OEt

OH

BocN

NNEtO2C

Ph

PPh3

OEt

O

Boc

NN

OEtNPh

EtO2C

PPh3

OBu-tO

O

N

N

EtO

OEt

O

O

NN

OEtNPh

EtO2C

PPh3

CO2Et

ON

NNEtO2C

Ph

PPh3

OEt

O

CO2Et

EtO2CN

NCO2Et +

132

PPh3PPh3

BocN

Ph

D1

D2

D2 D3 D4

131

D8D9

N

N

N

EtO2C

Ph OEt

133a CO2Et

OBu-t

N

N

EtO

OEt

O

O

t-BuO

D6EtO

N

N

O

OBu-t

OEt

O

NN

OEtNPh

EtO2C

PPh3

O

O

D5

D7

Scheme 54.


Oxadiazoles, including 1,2,4-oxadiazoles and 1,3,4-oxadiazoles which possess various bioactivities like antibacterial, antifungal and antitumor potencies [178], have relatively high reactivity due to the inductive effect of oxygen atom in the oxadiazole ring, and they have been investigated very well to transform into more stable het-erocycles, especially 1,2,4-triazole derivatives [179-187]. In recent years, the prepared triazoles via rearrangement of oxadiazoles usu-ally exhibited wide applications in medicinal chemistry especially as antitubercular [188] and antiproliferative agents [189], and also in supramolecular chemistry as progesterone receptors and ligands of coordination polymers [64,190,191].

As anticipated, 1,2,4-oxadiazole 134 could undergo ring open-ing and subsequent closure with hydrazine via two pathways to produce amino 1,2,4-triazole 135. In path a, the initial nucleophilic attack on the C(5) of the oxadiazole ring caused ring-opening into intermediate E1, and subsequent ring-closure of the former C(3) of the oxadiazole with loss of the leaving group led to hydroxyl aminotriazole E3; and in path b, the initial attack at the C(3) of the oxadiazole 134 generated the dihydrooxadiazole derivative E2, and then nucleophilic attack at C(5) followed by ring-opening and ring-closure involving either the intramolecular 3-hydrazino moiety or another external hydrazine molecules to produce compound E3,which is then reduced into amino triazole 135 (Scheme 55) [192]. Optimization of reaction conditions found that the mole ratio (hy-drazine/compound 134) had remarkable influence on this transfor-mation and the type of C(5) substituent exhibited few effects on this rearrangement (75-90%). As shown in (Table 4), when the reactant mole ratio was up to 100, the yields of target compounds were largely increased, and while it was 12 times hydrazine excess, the yield was quite low to 8% for product 135e. Indeed, the observed reactivity of 134 seemed to be strongly dependent on the leaving group ability of the C(3) substituent R rather than on its electronic effect. Moreover, it was also found that the substituents on benzene ring had some influences on this transformation, and non-substituted benzene gave the highest yield of 90%, while 4-CH3 and

4-Cl groups produced lower yield with 85% and 75% respectively (Table 4).

Dichlorophenyl 1,3,4-oxadiazole 136 as the isomer of 1,2,4-oxadiazole could also generate ring transformation by the treatment of 2-methylbenzyl amine to produce triazole derivative 137 which was easily separated from by-products (Scheme 56). The conver-sion yield did not exceed 50%, but it was worthy to notice that compound 137 may be further converted into the corresponding salt which had sufficient solubility for pharmacokinetic and efficacy studies in vivo, and exhibited anti-nociceptive activity in the rat of neuropathic pain [193].

Oxazolones are an important class of electron rich heterocycles and the presence of electronegativity nitrogen atom decreases the electron density of the entire system, especially � electron density on the C-2 position, which is easily attacked by nucleophiles and results in the ring-opening, following by ring-closure to produce other heterocyclic compounds [36]. Electrophilic attack of oxa-zolone 138 to azodicarboxylate led to the formation of intermediate F2 in acetonitrile, subsequently underwent ring opening to generate nitrilium intermediate F3 which proceeded the cycloaddition upon nucleophilic attack by the other nitrogen of azodicarboxylate via a 5-endo-dig-type ring closure to give the expected triazole derivative 139 without the assistance of any catalysts at room temperature. Further decarboxylation and aromatization in catalysis of alcoholic sodium hydroxide in refluxing ethanol gave triazole compounds (Scheme 57). The in-depth investigation of the reaction progress revealed that substituents highly affected the transformation effi-ciency. This conversion proceeded smoothly in very good yields for H, 4-F, and 4-OCH3 moieties of R1 especially the production of 139a with yield up to 100%. The transformation was significantly hampered when the oxazolones were substituted by the electron withdrawing 4-NO2 moiety. The R2 and R3 positions were substi-tuted by CH3, Et, i-Pr or Bn moieties, all provided the triazoline products in very good yields (Table 5) [194].

135

path a

path b+

NH2NH2

HN Ar

N

N

NH2

R

OH

HN

ON

R

Ar

NH

NH2

134

N

ON

R

Ar

HN

NN

Ar

HNOH

HN

NN

Ar

NH2

HClE1

E2

E3

Scheme 55.

Table 4. Effects of Different Factors on the Formation of Compounds 135a-f

Compound 135 a b c d e f

R Cl OCH3 N(CH3)NH2 Cl N(CH3) 2 Cl

Ar Ph Ph Ph 4-CH3Ph Ph 4-ClPh

Mole Ratio (Hydrazine/Compound 134)

100 84 57 100 12 100

Yield (%) 90 69 51 85 8 75


Moreover, the rearrangement of tetrazole 140 under participa-tion of imine 141 in toluene was able to generate phenyl triazole 142 with good activity against 11�-hydroxysteroid dehydrogenase type 1 (11�-HSD1) enzymes. The mechanism of this transformation was considered to involve the nucleophilic attack of the tetrazole ring on the imidoyl chloride of compound 141 followed by the loss of nitrogen atom (Scheme 58). The structure activity relationship demonstrated that the introduction of 2-Cl and 2-CF3 groups could highly increase the activity which was mainly because the 2-substitution forced the phenyl moiety out of the triazole ring and helped it to be more efficiently to fill into the hydrophobic pocket of the enzyme active site [195].

3.2. Transformations of Six-Membered Heterocyclic Com-pounds

Six-membered heterocyclic compounds can also be readily at-tacked by nucleophilic moiety to be transformed into triazole con-taining compounds accompanying with reduction of atom in the rings, during which azines as representative ones have been investi-gated very swell [36]. The nucleophilic attack of phenyl hydrazine proceeded at position 2 of pyrimidinium 143, and subsequent par-ticipation of the second nitrogen atom of hydrazine formed 1,2,4-triazole 144 in 31-43% yields (Scheme 59), and this type of trans-

formation reaction brought an excellent addition for the synthesis of 1,3,5-trisubstituted triazoles although the yields were relatively low [196].

The transformation of 1,2,4,5-tetrazine compounds also is a powerful synthetic pathway to access triazole compounds. By the catalysis of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 3,6-substituted 1,2,4,5-tetrazine 145 may be transformed into the corre-sponding 3,5-substituted 1,2,4-triazole by the attack of nucleophilic substituted phenyl acetonitrile. Experiments showed that the sub-stituents on benzene ring had a large effect on the ring opening of 145 and formation of triazole ring. In comparison with 146b, either the introduction of 4-Br substituent in R1 of compound 146a or the substitution of 2-NO2 group in R2 of 146c would decrease yields low to 43% and 51% respectively, further introduction of 5-CH3moiety led to a lower yield of 146d (36%) (Scheme 60) [197].

The transformations of heterocycles are an important synthetic strategy for the construction of structurally special 1,2,4-triazole derivatives. Though some synthetic technologies such as photocata-lysis and microwave-assistance have vastly expanded the applica-tion scope of this approach, the difficult preparation of precursor heterocycles has largely hampered their transformations to access triazoles to some extent.

+

137136

NN

OCl

Cl

Toluene

NN

N

Cl

ClNH2

CH3CH3

Scheme 56.

N

O

R2

O N

NN

COOHR2

R3O

O

R3O

O

N

N

OR3

O

OR3

O

CH3CN

N

O

R2

O

N

N

COOR3

COOR3

NR2

N

HO O

N

R3OOC

R3OOC

138

139

F2 F3

+rt

R1

R1

R1

R1

N

O

R2

OHR1

N

N

COOR3

COOR3F1

Scheme 57.

Table 5. Effects of Substituents on the Formation of Compounds 139a-f

Compound 139 a b c d e f

R1 H H 4-NO2 4-OCH3 4-F H

R2 CH3 CH3 CH3 CH3 CH3 Bn

R3 Et i-Pr Et Et Et CH3

Yield (%) 100 99 50 85 98 82


4. SUBSTITUTIONS ON 1,2,4-TRIAZOLE RING

The highly reactive unique three-nitrogen five-membered aro-matic heterocycle is readily modified by various types of functional groups to generate novel 1,2,4-triazole derivatives with multiple purpose applications. In fact, the structural modification of 1,2,4-triazole ring has been one of the most convenient and efficient strategies to build new triazole molecules with a variety of substitu-

ents and has been developed vigorously and increased actively. The lone pair of electrons in nitrogen atoms make 1,2,4-triazole ring easily proceed N-alkylation, N-arylation, N-acylation and N-quaternization with a variety of electron deficient centers to effi-ciently prepare 1,2,4-triazole-based derivatives. However, the struc-tural modifications of carbon atoms in triazole ring are relatively seldom reported mainly involving C-substitution of triazole ring because of their inertia properties [198, 199].

CF3

NH

N

NN Cl

N

CH3

Cl Cl

N

NN

CH3

CF3

140

Toluene

141 142

+

Cl

NH3CN

CF3

NNH

NN

N N

N

F3C

N2

Scheme 58.

N

N

CH3

CH3

H3CCOX

I143

144

NN

N

COX

CH3

X = OEt, NH2

+

HNNH2

RR

NHN

N

H3C

H3C

CH3

COXN

H

NN

NCOXH

H3CHN CH3

H3C

R

NN

CH3H3C

H3C

COX

N

NH

H

R R

R = H, 4-COOH

Scheme 59.

R2 CNDBU

N N

HNR1 R2

N

HN N

N

R1

R1

H

CN

R2

N

R2

N

N

R1

R1

CN

NH2

N

NN

N

R1 H

R1NC R2

H

145146

N N

NNR1R1

N

N

R1

NN

H

R2

R1

+

a: R1 = 4-BrPh, R2 = Ph (43%) b: R1 = Ph, R2 = Ph (60%)c: R1 = Ph, R2 = 2-NO2Ph (51%) d: R1 = Ph, R2 = 2-NO2-5-CH3Ph (36%)

DBU

THF

DBU

Scheme 60.


4.1. N-Alkylation of 1,2,4-Triazole Ring

N-alkylation modifications of 1,2,4-triazole ring have been be-ing prevalent synthetic methods in developing bioactive triazole compounds, which not only exhibit a variety of biological activities, but also are widely used in supramolecular chemistry like artificial cation and anion receptors as well as luminescent and magnetic materials [3].

4.1.1. N-Alkylation of 1H-1,2,4-Triazole 1,2,4-Triazole exhibits weak acidity with three nitrogen atoms

in the aromatic azole ring as well as a tautomeric equilibrium with 4H-1,2,4-triazole. In the presence of base, both 1H-1,2,4-triazole and 4H-1,2,4-triazole display five resonance forms (G1, G2, G3, G4 and G5). Among them, patterns G1 and G2, G3 and G5 are the same forms respectively. Moreover, patterns G1, G2 and G4 are more stable than patterns G3 and G5 [200]. Therefore, N-alkylation of 1,2,4-triazoles can yield two products, and the N-1 alkylated prod-ucts are the predominant ones in the presence of weak base (Fig. 3). A large amount of literature has manifested that N-alkylation reac-tions of 1H-1,2,4-triazole with halides, oxiranes and alcohols as well as alkenes mainly produce the 1-substituted products, accom-panying with a small amount of 4-substituted by-products [2]. Cur-rently, N-alkylation of 1,2,4-triazole ring is still one of the most convenient and common ways to prepare new triazole derivatives [201, 202].

4.1.1.1. N-Alkylation with Halides

As reported that the combination of 1,2,4-triazoles with other functional fragments such as sulfamides, benzimidazoles, piperazi-nes, thiazoles as well as 1,2,3-triazoles [203-209] via N-alkylation reaction has been widely employed to prepare 1,2,4-triazole deriva-tives with broad spectrum and good bioavailability [210, 211]. Al-kyl halides with high reactivity are of great significance in synthetic chemistry for N-alkylation to prepare diverse functional molecules, especially in developments of bioactive 1,2,4-triazoles [212,213].

Carbazole and its derivatives possess desirable electronic and charge transport properties as well as large �-conjugated system, and these special structural characteristics endow them to have unique functional properties and biological activities [211]. More importantly, their structures are easily modified to afford newly bioactive compounds. The conjunction of triazole with carbazole ring into one molecule may generate a novel type of bioactive com-pounds. N-alkylation of 1,2,4-triazole with carbazole bromide 147 was able to be carried out in acetonitrile at 45 °C to provide triazole derivative 148 in high yields of 76-91%. Experiments showed that

the carbazole aralkyl bromides gave higher yields than alkyl ones. Particularly, the high reactivity of carbazole derived p-benzyl bro-mide made the corresponding yield up to 91%, but the hexyl substi-tuted one gave the lowest yield of 76% (Scheme 61) [214].

A large number of researches have focused on further investiga-tion of Fluconazole in order to broaden its antimicrobial spectrum and increase its therapeutic indexes [215-217]. N-Alkylation of 1H-1,2,4-triazole with amine derived dibromide 149 in the presence of potassium carbonate afforded novel tertiary amine type of Flucona-zole analogues bis-triazoles 150a-c in good yields ranging from 76% to 84%. Researches found that the types of substituents and substituted patterns on benzene ring had little effect for this trans-formation, but they displayed remarkable influence on the bioactiv-ity [218, 219]. The reaction of 1H-1,2,4-triazole with amine dibro-mide 149 in the mole ratio of 1:1 could also be controlled to pro-duce mono-triazole derivative 151 in moderate yields of 40-63%. Further reaction of compound 151 with berberrubine gave berberine triazole 152 with excellent antimicrobial activities which was 2- and 16-fold more potent activity than the reference drugs Chloro-mycin and Berberine against MRSA respectively, and equipotent to Norfloxacin (MIC = 8 �g/mL) (Scheme 62) [220,221]. This strat-egy provides a practical way for the construction of completely new type of Fluconazole analogues to explore the ideal lead compounds for clinical therapy [222].

The combination of coumarins with some nitrogen heterocycles such as pyrrole and thiazole can effectively increase the bioactivity and broaden antimicrobial spectrum [223-226]. Recently, the intro-duction of triazole ring into coumarins has also been reported to display excellent bioactivity. Reaction of 1,2,4-triazole with cou-marin dibromide 153 successfully provided coumarin bis-triazole 154 in yields of 71-83% (Scheme 63). The bridged linkers exhibited little effect on the formation of bis-triazole 154, but showed an obvious influence on antimicrobial efficacy [227]. This preparative method provides an easy, convenient and economic synthetic pro-cedure with a large potentiality for further development of cou-marin triazole derivatives as antimicrobial candidates for clinic.

Piperazine ring is an attractive pharmacological scaffold present in various potent marketed drugs. Because of easy modificability, proper alkality, water solubility, the capacity for the formation of hydrogen bonds and adjustment of molecular physicochemical properties, piperazine ring has been frequently employed in design and development of new drugs [228-231]. Compound 155 is a piperazine-based chloride which was obtained by the coupled reac-tion of chloroactyl chloride with 1-((4-chlorophenyl)(phenyl)me-

NH

NNbase

1H-1,2,4-triazole 4H-1,2,4-triazole

N

NHN12

34

5G2

N

NN

N

NN

N

NN

N

N N

N

NN

G1 G5G3 G4 Fig. (3). Tautomeric equilibrium and resonance forms of 1,2,4-triazole.

N R Br+K2CO3

N R N

NN

R =

147148

(n = 2�18)

N NH

N(CH2)n ,

Scheme 61.


thyl)piperazine, and could also successfully generate N-alkylation with 1H-1,2,4-triazole in the presence of anhydrous potassium car-bonate to access piperazine triazole 156 with remarkable antimicro-bial efficacy and broad antimicrobial spectrum (Scheme 64) [232].

Substituted or unsubstituted benzyl halides as highly active al-kyl reactants are very easy to perform the N-alkylation of triazole. Benzofuran containing benzyl chloride 157 was obtained by the treatment of benzofuran methanol with thionyl chloride, and could

react with 1,2,4-triazole via N-alkylation to provide potential anti-cancer aryl triazole 158 (27-85%) (Scheme 65). The type of sub-stituent R showed remarkable influence on the yields of this reac-tion, and the presence of methoxy group gave the high yield up to 85%, while nitro, methyl and trifluoromethyl derivatives produced the target compounds with quite low yields (lower than 30%), and the influential factors on this transformation were under investiga-tion (Table 6) [233].

K2CO3

N

Br

Br

149 150

R1

R3

R2a: R1 = Cl, R2 = H, R3 = Clb: R1 = F, R2 = H, R3 = Fc: R1 = H, R2 = Cl, R3 = Cl

NHN

N

N

N

NN

R1

R3

R2

NN

N

+ CH3CN

N

O

O

H3CO

Cl

151

N

BrR1

R3

R2

NN

N N

OR1

R3

R2

NN

N

DMF

20 h 152

K2CO3

CH3CN

110 oC

Scheme 62.

HN

N

N K2CO3

OO

CH3 O

O

153 154

R

R Br

Br

OO

CH3 O

O

R

R N

NN

N

NN

+

(n = 2�4)R = (CH2)n ,

Scheme 63.

NHN

NN N

Cl155

Cl

OK2CO3

156

N NO

Cl

NN

N

+CH3CN

(60%)

Scheme 64.

158

SOCl2

K2CO3

157

HN N

NOH

O

OCH3

R

Cl

O

OCH3

R

O

OCH3

R

NN

N

Scheme 65.


4.1.1.2. N-Alkylation with Oxiranes

Oxirane compounds, a special class of three-membered ring systems, are easy to open ring by nucleophiles to prepare intriguing organic molecules. Especially in the developments of Fluconazole derivatives, oxirane compounds have been extensively employed for the preparation of tertiary alcohol fragments [234, 235].

Fluconazole 160a as a clinical antifungal drug with good activ-ity, safety profile and pharmacokinetics has been the first choice to treat infections caused by Candida albicans and Cryptococcus neo-formans [236]. Its preparation including the synthesis of its analogs 160b-c (19%) was performed through the N-alkylation of triazole with epoxide 159 which was obtained from halobenzene viaFriedel-Crafts acylation, N-alkylation with 1H-1,2,4-triazole and then epoxidation with trimethyl sulfoxonium iodide (Scheme 66)[237]. The experimental results showed that the substituents on benzene ring should have no obvious effect on this transformation, but they displayed remarkable influences on the antimicrobial activity.

The poor efficacy of Fluconazole against Aspergillus infections promotes the development of its derivatives to search for new and clinically useful antifungal azoles with broad bioactive spectrum [5,10]. In the presence of sodium hydride, reaction of oxirane com-pound 161, prepared by treatment of amide with phenyl magnesium bromide and subsequent epoxidation, with 1H-1,2,4-triazole suc-cessfully provided triazole derivative 162 in 61% yield, and the latter could be further modified with indazoles to afford two new isomers of antifungal compounds with excellent anti-Aspergillus fumigatus activity (MIC80 = 0.25-4 �g/mL) which were 32- to 512-fold more potent than Fluconazole (Scheme 67) [238].

Flutriafol as a broad spectrum triazole fungicide is widely em-ployed for the control of many cereal diseases, and researches have demonstrated that (+)-isomer is more active than the (-)-isomer.

Therefore, the development of Flutriafol in enantiopure form is of great interest. Fluorophenyl epoxide 163 was obtained by the selec-tive tosylation of diol with p-toluenesulfonyl chloride (TsCl) and subsequent treatment by DBU. Nucleophilic reaction of compound 163 with 1,2,4-triazole successfully produced antimicrobial flutria-fol triazole 164 in yield of 77% (Scheme 68) [239]. This synthetic method has been widely employed for the preparation of potent chiral triazole fungicides.

4.1.1.3. N-Alkylation with Alcohols

Generally, hydroxyl group is usually difficult to leave and can not be easily replaced in organic synthesis. However, in certain conditions, N-alkylation of 1,2,4-triazoles with alcohols can suc-cessfully proceed to generate new triazole derivatives.

A simple and one-stage method for N-alkylation of 3,5-disubstituted 1H-1,2,4-triazole with salicyl alcohol was reported in high yields. Salicyl alcohol was firstly transformed into o-methylenequinone H1, followed by treatment with triazole deriva-tive 165 to give alkylation product H2, and then underwent in-tramolecular cyclization to afford triazole fused benzoxazine 166 in refluxing DMF (Scheme 69) [240]. This effective method can be served for the preparation of novel triazole fused derivatives.

Reaction of adamantane 167 with ammonium nitrate in sulfuric acid readily yielded alcohol intermediate 168, and the latter could further react with 1,2,4-triazole to give the potential antiviral ada-mantly triazole 169 in moderate yields (43-67%) (Scheme 70). Researches found that the substituent R1 of compound 168 could affect the yields to some extent. The -NH2 group was favorable for the transformation with yield up to 67% [241]. This reaction pro-vides a practical synthetic route for the preparation of triazole ada-mantanes with large steric hindrance to overcome the serious aman-tadine/rimantadine resistance of influenza viruses.

Table 6. Effects of Substituents on the Formation of Compounds 158a-h

Compound 158 a b c d e f g h

R F Cl OCH3 CN NO2 CH3 CF3 Et

Yield (%) 83 80 85 73 30 27 28 77

159 160

N

N NH

K2CO3

+

a: R1 = F, R2 = H, R3 = Fb: R1 = H, R2 = Cl, R3 = Clc: R1 = H, R2 = H, R3 = Cl

O R1

R2

R3N

N

N

NN

OH

R1

R2

R3

N

NN

NEtOH

Scheme 66.

N

NHN

161 162

NaH

OOH3C

OHN

F

NN

F

F

OO

CH3

O

+ FDMF

Scheme 67.


Thionyl bis-triazole can also be employed to N-alkylate with alcohols to produce novel triazole derivatives [242,243]. Reaction between compound 170 and N,N�-thionylditriazole 171 successfully afforded potential CYP26 inhibitor 1,2,4-triazole derivative 172(Scheme 71) [244]. This method was easier to perform than that shown in (Scheme 65). Surprisingly, the yields of benzofuran phenyl triazoles are highly affected by the substituents on benzene ring far from reactive site. The isopropyl substituent gave the best yield up to 78%, while n-propyl group gave the lowest yield of 2% (Table 7). It is displayed that the electron rich density of substitu-ents was favorable for this transformation and the short chain made this reaction perform smoothly.

4.1.1.4. N-Alkylation with Alkenes

Michael addition as one of the most important organic reactions has been widely employed to prepare various types of interesting

compounds via formation of C-Z bonds (Z = C, N, O, S, etc.). �,�-Unsaturated aldehydes are also able to be employed in N-alkylation of triazole compounds via Michael addition [245]. The reaction of 2-butenal with 1H-1,2,4-triazole in the presence of benzoic acid and catalyst 173 could successfully produce triazole derivative 174, and the latter was reduced by sodium borohydride and subsequently reacted with acyl chloride to prepare a series of antifungal benzoate 1,2,4-triazoles in total yields of 53-91%. Experiments showed that electron donating methyl group on benzene ring was favorable for this transformation with the excellent yield up to 91%, and also the unsubstituted one gave good yield (72%), while the presence of electron withdrawing chlorine decreased the yield low to 53% (Scheme 72) [246].

Ionic liquids have been recognized as attractive candidates for new type of good propellants [247] and explosives [248,249] be-

+t-BuOK

163

N

N

NH

164

HO

N

N

N

F

FF

OF

DMF

Scheme 68.

OH

OHK2CO3

DMF

O

H2C

165166 (84�87%)

HN N

NX Y

N

O

N

NX

NO

NN

XH

YNN

NH

YX

O

X= H, Br; Y = Cl, Br

H1H2 H3

+HN N

NX Y

Scheme 69.

H2SO4

OH

R1R1R1

167 168169

R1 = NH2, CH(CH3)NH2R2 = H, Cl, Br, CH3, NO2

NN

N R2

NHN

N R2

NH4NO3

Scheme 70.

170

CH3CN

172171

+

N

O

R

N

N

HO

R

O

N

S

N

O

NN

NN

Dioxane

Scheme 71.


cause of several ideal features as energetic materials such as low vapor pressures, broad liquid ranges, low melting points and so on. More importantly, the unique functional nature of ionic liquids permits the independent modification of ions in their structures [250]. Great interest is directed towards triazole ionic liquids in combination with tetrazoles due to their excellent energetic proper-ties. The reaction of triazole with acrylonitrile in the presence of triethylamine effectively produced 1-(2-cyanoethyl)-1,2,4-triazole 175, and further transformation with sodium azide afforded triazole containing tetrazole salt 176 which could be served as excellent ionic liquid (Scheme 73) [251]. This synthetic strategy has opened a new direction to develop novel diheterocyclic energetic ionic liq-uids.

The N-alkylation of amino triazoles with unsaturated esters af-fords different products. Reaction of 3-amino triazole with diethyl benzylidenemalonate in refluxing methanol occurred in triazole ring not in amino group, which provided the product 177a and isomer 177b with low yields of 28% and 10% respectively, and the struc-tures of the obtained compounds were clarified by X-ray crystallog-raphy (Scheme 74) [252]. Further works for this reaction are neces-sary to improve the yields of desired products.

4.1.1.5. N-Alkylation with Other Compounds

Some other compounds such as aldehydes, quaternary ammo-nium salts, esters and so on can also perform the N-alkylation of triazoles. The one-pot N-alkylation reaction of 4-methoxybenzaldehyde and methyl acetoacetate with amino 1,2,4-triazole could efficiently give pyrimidine fused triazole compound 178a in 46% yield and its trace isomer 178b (Scheme 75) [253]. This reaction exhibits some advantages with convenience, good selectivity and easy operations [254].

Quaternary ammonium salts have also been found to success-fully perform N-alkylation with triazole, because of the easy cleav-age of C-N bond in the presence of strong electron withdrawing permanent positive charge. The reaction of 3-isoxazolyl triazole 179 with pyrimidine-2-yl-trimethylammonium chloride 180 could generate N-alkylation in acetone to efficiently produce compound 181 with much potentiality as pesticide in agriculture production (Scheme 76) [255].

Diethyl sulfate as alkylation agent is scarely investigated due to its high toxicity. However, currently its high reactivity has attracted increasing interest. N-alkylation of nitro triazole with diethyl sulfate successfully proceeded to give N(2)-ethyl substituted nitro triazole



R CH3 Et n-Pr i-Pr t-Bu

Yield (%) 28 67 2 78 62

N

N

NH

CH3

CHOCH3

CHO

NN

N

174

173

173

PhCOOH+

NH

Si

CF3F3C

CF3F3C

CH3

CH3

CH3

O

O

CH3

NR

N

N

Scheme 72.

N N

HN

H2C

N

+N N

NCN

Na

Et3N NaN3

175 176(93%) (80%)

N N

N N

N N

NToluene HOAc

Scheme 73.

+CH3OH

177a: R1 = H, R2 = NH2b: R1 = NH2, R2 = H

O

O

N

NN

R2

R1

CH3

O OO

O

O CH3

ON

NNH

NH2

CH3CH3

Scheme 74.


182a and N(4)-substituted isomer 182b in overall yields of 53-73% (Scheme 77). Researches demonstrated that when dimethyl sulfate was employed as alkylation agent, this reaction would gave low yields of target compounds (26-45%) [256].

As is well known, glycosides with high reactivity have been widely used in organic synthesis and drug design [257]. Reaction of tetra-ester �-D-xylopyranose 183 with dihalo triazole under activa-tion of boron trifluoride effectively provided glycosyl triazole 184in 53-71% yields, in which 3,5-dibromo-1H-1,2,4-triazole gave the highest yield up to 71% (Scheme 78). Further researches showed that compound 184 could undergo further C-alkylation to give the corresponding C-alkylated products [258]. This method opens a new synthetic direction to achieve the glycose containing triazole derivatives via efficient N-alkylation.

4.1.2. N-Alkylation of Thio 1,2,4-Triazoles Mannich reaction has been playing an important role in devel-

oping biologically active compounds because of its convenient operations, mild reaction conditions and so on. Numerous works have been directed towards aminomethylation of formaldehydes and development of interesting molecules [259, 260], especially

Mannich reaction of heterocycles via N-alkylation has been attract-ing special interest [261,262]. Multicomponent Mannich reaction of 1,2,4-triazole-3-thione 185, morpholine and formaldehyde was performed in ethanol to give antibacterial triazole thione 186 with good yields of 79-87% (Scheme 79) [263]. All the substituents on benzene ring which were far away from the reaction site displayed weak influence on the formation of triazole derivatives.

Recently, some clinical drugs like Itraconazole containing both piperazine and azole rings are prevalent antifungal agents which have been playing important role in the treatment of microbial in-fections. This promotes much effort towards the combination of different heterocyclic rings with unique properties into one mole-cule to explore bioactive molecules. Bis-triazole compound 187was treated by formaldehyde and piperazine derivative to favorably produce antimicrobial piperazine bis-triazole 188 by a facile Man-nich reaction in DMF (Scheme 80) [264].

In all, Mannich reaction with convenient operations, mild con-ditions and good yields has provided an efficient pathway to access aminomethyl 1,2,4-triazole derivatives, and this method will con-tinuously be one of important active topics in developing diverse triazoles with special functional applications especially bioactive medicinal compounds.

4.2. N-Arylation of 1,2,4-Triazole Ring

It is well known that N-arylation of 1,2,4-triazole ring is usually difficult to perform due to the relatively weak reactivity of aryl compounds. However, N-arylation of triazole ring with aryl halides has been successfully carried out under relatively harsh conditions

OCH3

CHO

+N

HNN

NH2

178

OCH3

N

HN

CH3

YXN

a: X = CH, Y = Nb: X = N, Y = CH

O

OCH3

O O

CH3

CH3

O+

HCl

EtOH

Scheme 75.

179

+

181(90%)

180

Acetone

ClN NH

NS

NO

CH3CH3

N N

N CH3CH3

CH3

NN

N

N

N

S

NO

CH3

CH3

KOH

Scheme 76.

N NH

N RO2N Et2SO4

N N

N RO2NN N

N RO2N

+

182a 182bR = H, CH3

CH3

CH3

78�80 oC

Scheme 77.

X1, X2 = Cl, Br184

+

183

Et2O·BF3O

OO

OOt-Bu

OBu-tO

t-Bu

O

O

N

O

O

O Bu-t

N

N

X1

X2

t-Bu O

O

Bu-t

O

Bu-tO

NHN

N

X1

X2

CH3CN

Scheme 78.


such as high temperature, high pressure and so on. Notably, the presence of strong electron withdrawing groups on aromatic ring and special catalysts make this transformation become relatively easier [265].

Generally, fluorine atom which is directly linked to the benzene ring is particularly difficult to be substituted. However, if the elec-tron withdrawing groups are directly linked with the benzene ring, this reaction will become very easy. In the presence of potassium carbonate, an environmentally benign nucleophilic substitution of fluorine atom in 4-fluorobenzaldehyde with 1,2,4-triazole could readily occur and efficiently produce N-substituted phenyl triazole 189 in 72% yield. Compound 189 proceeded further cyclization with 3,5-difluorobenzene-1,2-diamine via a fast, highly efficient, eco-friendly and catalyst free chemical transformation to afford benzimidazole containing 1,2,4-triazole compound 190 with good antitubercular activity (Scheme 81) [266].

In the presence of sodium, compound 191 with large conjugated system could react with 1,2,4-triazole ring to produce anticancer aryl triazole 192 in low yields ranging from 30% to 38% (Scheme 82) [267]. The occurrence of this N-arylation substitution might be attributed to the presence of electron withdrawing conjugated car-bonyl group and five-membered heterocycle in linkage with ben-zene ring. However, the low yields of this reaction probably re-sulted from the large hindrance of adjacent 3,4,5-tri(methyloxy) phenyl substituent which is unfavorable for this N-arylation.

In comparison with fluorine atom, bromide was easy to be sub-stituted generally. The reaction of 1,2,4-triazole with sulfonamide containing aryl bromide 193 using tris(dibenzylideneacetone) dipalladium (Pd2(dba)3) as catalyst via a mild and easy operation smoothly produced sulfonamide triazole derivative 194 with po-tency as inhibitor of 11�-Hydroxysteroid Dehydrogenase Type 1 (11�-HSD1) (Scheme 83). In this reaction, the fluorine atom was not substituted, this was probably attributed to the existence of the electron donating piperazine moiety at the para position [268]. Continuous researches found that replacement of catalyst Pd2(dba)3by copper iodide was favorable for the N-arylation reaction with largely increased yields up to 81-98% [269].

Iodine containing compounds as important reactants are usually used to couple different fragments to build difunctional molecules due to the easily leaving reactivity of iodine atom. They have been frequently employed to perform N-arylation of 1,2,4-triazole ring to prepare interesting ionic liquids. Coupling reaction of iodobenzene with 1,2,4-triazole under the catalysis of cuprous oxide efficiently afforded 1-phenyl-1H-1,2,4-triazole 195 which could be used to constitute a new generation of 1,2,4-triazolium-based ionic liquids with a high degree of flexibility (Scheme 84) [23]. This reaction is an efficient method with good yields and easy operations for the preparation of phenyl triazoles.

Deoxyuridines play a vital role in the epigenetic regulation of genetic information and in the control of many cellular processes.

HN O

HCHO

X = H, Cl, Br

S

X

O

O N

NN

Pr-n

S

N

O

S

X

O

O N

NHN

S

185 186Pr-n

Scheme 79.

187

HCHO

188

HN

N CH3

N N

N SH

CH3

SN

N N

N

N N

N S

CH3

SN

N N

N

N

N

CH3

(66%)

Scheme 80.

189

190

HN

N

F

NN

N

NN

N+F

K2CO3NHN

N

F F

H2NNH2

110 oC

DMFCHO CHO

Scheme 81.


N

N

NH Cu2O

K2CO3

IN N

N

195

+(65%)

Scheme 84.

O

TBSO

OTBS

N

NH

O

O

D3C

HN N

N

O

TBSO

OTBS

N

N

O

N

D3C

N

N

O

TBSO

OTBS

N

N

O

OH

D3C

POCl3Et3N

TBS = Si

CH3

CH3

Bu-t

196

197Scheme 85.

Therefore, many researches have been dedicated to this type of compounds. Recent work found that triazole incorporated deoxyu-ridine derivatives could generate efficient DNA strand cleavage activity. Experiments showed that compound 196 could be success-fully transformed into the deoxyuridine derived triazole 197 in yield of 72% via N-arylation with 1,2,4-triazole in the presence of phos-phorus oxychloride and triethylamine, and compound 197 could be oxidated to give compounds with efficient strand cleavage in a DNA duplex (Scheme 85). This synthetic method provides useful strategy for the preparation of deoxyuridines containing triazole derivatives in good yields [270].

4.3. N-Acylation of 1,2,4-Triazole Ring The N-acylation reaction of 1,2,4-triazole ring is an easy syn-

thetic method to prepare acyl triazole derivatives. This type of preparative strategy with good reactivity has been extensively used in practical synthesis. Amino triazole is a commercial reactant and is often used to perform N-acylation with acyl halides for the prepa-ration of ring acylated products rather than the amino acylated ones. The reaction of amino triazole 198 with (un)substituted benzoyl chloride at room temperature efficiently gave the acylation product anti-inflammatory 1-benzoylated-1,2,4-triazole 199 in 63-75% yields (Scheme 86), and the electron donating or withdrawing groups on benzene ring displayed little effect on the N-acylation of triazole ring. Interestingly, compound 199 could take place thermal rearrangement at 200-250 °C to give the amino acylated 1,2,4-triazole derivatives [171].

Triazole derivatives with special properties have attracted much attention for the development of anti-inflammatory drugs. The N-acylation of diamino triazole 200 with (un)substituted benzoyl chlo-rides efficiently produced potential anti-inflammatory compound 201a and its trace isomer 201b in total yields of 60-80%. Further researches are necessary to elucidate the effect of substituents on this reaction (Scheme 87) [161].

4.4. N-Quaternization of 1,2,4-Triazole Ring

Many researches have shown that triazoliums as the N-quaternization products of triazole ring possess extensive potential-ity as energy materials, ionic liquids, artificial receptors etc. [271, 272]. Particularly in medicinal chemistry, the permanent positive charge rigid triazolium ring can easily form hydrogen bonds, accept electrons and produce electrostatic interaction with biological target sites leading to the enhancement of water solubility and membrane permeability, and thereby improving biological efficiency and broadening antimicrobial spectrum. Therefore, the transformation of triazoles into triazoliums has been becoming an important strat-egy for the preparation of triazole medicinal drugs [273-277].

Triazoliums are very easy to prepare. For example, 1H-1,2,4-triazole could react with the highly reactive �-bromoketone 202 to

Na

191 192

N

N

NHX = O, SY = N, CH

+

FX

Y

O

OCH3

OCH3

H3CO

NX

Y

O

OCH3

OCH3

H3CO

NN

DMF

Scheme 82.

N

N

NH

+

193

K2CO3

Pd2(dba)3

194 (70%)

NN

S

CH3

O

O

NN

N

NN

S

CH3

O

O

BrFF3C

F3C F

Scheme 83.


provide the N-alkylated product, and subsequently underwent N-quaternization of 1,2,4-triazole ring to successfully give triazolium 203 in 49% yield. Bioactivity screening found that mono-triazolium bromide 203 gave excellent antimicrobial activities with broad bioactive spectrum, and its anti-Saccharomyces cerevisiae activity was 8-fold more potent than that of reference drug Fluconazole (MIC = 32 �g/mL) (Scheme 88) [278].

Naphthalimides with strong hydrophobicity and desirable large �-conjugated backbone could easily interact with various active sites in biological system via non-covalent forces to exhibit diversely biological activities. Recently, much effort has been directed toward naphthalimide derived compounds as medicinal agents. Experiment results demonstrated that naphthalimide containing triazole 204 (MIC � 256 �g/mL) could be easily subjected N-quaternization of triazole ring with (un)substituted benzyl halides to afford triazolium product 205 with improved water solubility and good antimicrobial activity (MIC = 1-32 �g/mL) (Scheme 89), and the substituents had little effect on the formation of triazolium ring [279].

Some bis-triazoliums with two positive charge groups are also successfully prepared by the N-quaternization of triazole ring. The mono-triazole 206 reacted with a series of dihalides, which were commercially available or were prepared by conventional method via bromination of the corresponding precursors, via N-quaternization to readily produce bis-triazolium 207 in good yields of 74-95%. Notably, the reaction temperature obviously affected the formation of target compounds, and only when the temperature was controlled above 80 °C, this reaction would proceed smoothly (Scheme 90) [280, 281].

The poor water solubility of clinical drug Fluconazole highly precludes its development and utilization as antifungal agent, thus much work is directed towards its further structural modifications for water soluble improvements, and the N-quaternization strategy is able to successfully achieve this goal with convenience. N-Quaternization of compound 208 with a series of excess halides afforded Fluconazole bis-triazolium 209 with superior bioactivity against Aspergillus fumigatus (MIC = 16-32 �g/mL) to its precursor

NHN

N NH2 Pyridine

198 199X = H, Cl, Br, NO2, OCH3

+O O

CH3 X

ClO

Dioxane

N

NN

H2N

X

O

O

O CH3

Scheme 86.

Pyridine

200

HN

N

N

NH

NH2

ClO

201b201a

R1

R2 = H, 2-F, 4-F 2,4-(F)2

R2

R1

NH

N

N

N

NH2

O

R2

NH

N

N

N

NH2

R1

O

R2

++

R1 = 3-N(CH3)2 4-COOH

Scheme 87.

NHN

N

DMF

202

BrO

HO

OCH3 203

Br

ON

NN

O

HO

OCH3

OH

OCH3

+

Scheme 88.

204

Br

R1

R2

R3

205

Br

CH3CN

80 oC

(58�69%)R1, R2, R3 = H, F, Cl, NO2

+N

Br

O O

N

NN

n

N

Br

O O

NN

N

R2

R3

R1

n

n = 2, 3

Scheme 89.


208 (Scheme 91). Experiments displayed that substituent R1 had obvious influence on the yields of target compounds, and the vari-ous halobenzyl appended ones were especially favorable for the formation of target triazoliums with high yields more than 90%, while the large naphthalimide fragment highly limited this quater-nization transformation due to its large blockade [282].

The transformation of triazoles through N-quaternization into the corresponding triazoliums has been an important pathway with convenient operations, mild conditions and good yields in the preparation of triazole derivatives with high water solubility.

4.5. C-Substitution of 1,2,4-Triazole Ring

The structural modification on the carbon atoms of the aromatic 1,2,4-triazole ring is another alternative access to produce triazole derivatives. However, the weak reactivity of C-substitution on tria-zole ring due to lower electronegativity in contrast with nitrogen atoms results in the few developments of C-substitution. Recently, researches have found that the metal catalyzed coupling reaction as a classical synthetic strategy can efficiently realize C-substitution on triazole ring, and much effort has been contributed to widen the application scope of C-C cross coupling reactions on aryl rings [283-289], especially on 1,2,4-triazole ring in organic chemistry. The reported C-substitution on 1,2,4-triazole ring is systematically involving cleavage of C-H and C-X bonds.

4.5.1. Cleavage of C-H Bonds It has been an effective strategy by the use of coupling reaction

to prepare aryl-aryl compounds in the presence of metal catalyst, and various multicomponent one-pot methods for triazoles synthe-ses using metal catalysts have been reported. The coupling reaction of methyl triazole 210 with iodobenzene in the presence of CuI/phenanthroline successfully prepared 1-methyl-5-phenyl-1H-1,2,4-triazole 211 in 88% yield (Scheme 92). The used base for this reaction was depended on the acidity of the C-H bond. For rela-tively acidic C-H bonds with pKa below 27, potassium phosphate

210

N

N N

t-BuOLi

CuIPhenanthroline

211

CH3

N

N NCH3

+

I

Scheme 92.

was employed; when pKa is between 27-35, strong lithium alkoxide base was required [290]. This copper catalyzed arylation is a com-plementary methodology to existing coupling methods for the preparation of aryl triazole derivatives and offers advantages with regards to the number of synthetic steps and functional group toler-ance.

When the catalyst was CuI/PPh3 and sodium carbonate was used as base, the arylation of bis-phenyl triazole 212 with phenyl iodides could occur in 75-81% yields via one-pot manner to afford compound 213 with functionalized triazole core � systems which was widely used in material and pharmaceutical chemistry owing to the good electron transporting and hole blocking abilities [291, 292]. It was worthy to notice that compound 212 could easily real-ize C-alkylation with paraformaldehyde in neutral conditions to prepare its hydroxymethylation derivative 214 in good yield of 81%. The hydroxymethyl triazole 214 could be further converted to the corresponding functional alkyl chloride 215a and aldehyde 215b (Scheme 93). Further researches displayed that the 3-methyl group in this compound could also undergo nucleophilic reaction with formaldehyde to give the corresponding diol when 3,4-dimethyl-1,2,4-triazole was employed as substrate [293].

4.5.2. Cleavage of C-X Bonds The cleavage of C-X bonds of aromatic heterocycles is relatively

easy in comparison with the corresponding C-H bonds. Recently, some effort has been directed towards the cleavage of halogenated 1,2,4-triazole derivatives to develop structurally novel triazole derivatives.

207206

+ CH3CN

2BrBr Br

R

R1, R2 = F, Cl

R

N N

NN N

NR1

R2

R1

R2

NN

N

R =

(n = 2, 4, 8)

R1

R2

(CH2)n

Scheme 90.

209208

NN

OHN

NNN

(53�94%)

R4 Xn

2X

NN

OHN

NNN

R4n

R4n

N

O

O

CH3,R4 =

Br

X = Cl, Brn = 2�17R1, R2, R3, R5, R6, R7 = F, Cl

R1

R2

R3

R1

R2

R3

R5 R6

R7,

CH3CN

Scheme 91.


212

I

CuI/PPh3

213

R1

R1= H, F, Cl, Br, CN, OCH3

N

N N

R1

(CH2O)n 110 oC

214 a: R2 = CH2Clb: R2 = CHO

N

N N

N

N N

OH

N

N N

R2

215

Scheme 93.

Under the catalysis of CuI/Pd(PPh3)4, 3-carbamoyl triazole bromide 216 could react with a series of substituted phenylacety-lenes in aqueous media via one-pot synthesis using microwave irradiation to give benzynyl triazole acyclonucleoside 217 (Scheme 94) [294]. Experimental results displayed that electron withdrawing groups such as CF3, Cl, Br, or CN at the 3- or 4-position on benzene ring resulted in low yields, which probably due to the reduced nu-cleophilicity and increased electrophilicity of the alkyne fragment. However, the electron donating n-butyl group at 4-position seemed to be specifically beneficial for this reaction which resulted in com-pound 217a with excellent yield up to 90% (Table 8).

Nucleoside analogues exhibit important antiviral and anticancer activities. A lot of effort has been engaged in developing various

triazole nucleosides as potent antiviral and anticancer agents. How-ever, the synthesis of N-aryl amino triazole nucleosides is a particu-lar challenge due to the low reactivity of triazole ring, the multiple coordinating N- and O-atoms and the labile glycosidic bond. In the catalysis of unique mixed ligand system of Pd/Synphos/Xantphos, 5-bromotriazole ribonucleoside 218 successfully reacted with ani-line to afford N-aryl aminotriazole nucleoside 219 (Scheme 95).Further evaluation of the reaction parameters demonstrated that the mole ratio of Synphos/Xantphos could highly affect this transfor-mation. Compound 219 would be prepared in high yield of 92% when the mole ratio was 2/1. However, if Synphos or Xantphos was employed as the sole ligand, poor yields of 21-42% would be ob-tained [295].

Typical Suzuki coupling conditions were employed in the reac-tion of aryl boronic acid 220 with glycoside triazole 221 to generate aryl 1,2,4-triazole 222 as main product in moderate yield. In most cases, arylation took place predominantly at 5-position of triazole ring, though some 3-substituted and 3,5-disubstituted products were also observed as minor by-products. 1-Iodo-perfluorohexane was added to the dibrominated 1,2,4-triazole glycoside 221 by use of copper catalyzed coupling reaction to produce the 3-perfluorohexyl-1,2,4-triazole 223 in yield of 37%, while 5-position was substituted by hydrogen. As part of the program directed toward the introduc-tion of trifluoromethyl substituent to 5-position of triazole ring, compound 221 was treated with trimethyl(trifluoromethyl)silane. Unexpectedly, this reaction did not occur while an Ullman-type coupling product 224 was obtained. It was generally considered that 5-position of the 1,2,4-triazole ring was the most reactive site that the perfluoroalkyl group would be expected to attach here, instead, the competing hydrodebromination at 5-position proceeded at a faster rate than the coupling reaction, so the perfluoroalkyl group appeared at the 3-position (Scheme 96) [258].

217

CuIPd(PPh3)4

Li2CO3

R

NN

N

H2N

O

O

HO

Br+

NN

NNH2

O

OHO

R216

Scheme 94.



R 4-Bu-n 4-Cl 4-Br 3-CF3 4-CN

Yield (%) 90 67 48 72 53

O

AcO

OAc OAc

N N

NBr

OCH3

O

+

NH2

O

AcO

OAc OAc

N N

NHN

OCH3

O

Pd2(dba)3

K2CO3

218 219

Synphos/Xantphos

Scheme 95.


Dendrimers as monodisperse and well-defined macromolecules are prepared by divergent or convergent iterative procedures with different sizes and generations. The unique properties associating with the perfectly branched dendritic architecture are highly appre-ciated and have been widely used in various aspects, but their syn-theses are crucially difficult. In the presence of potassium carbon-ate, the disubstituted 1,2,4-triazole 225 reacted with the substituted phenol in a refluxing mixture of DMF and toluene (V/V = 2/1) to efficiently produce 1,2,4-triazole dendrimer 226 in 80% yield. Compound 226 may be used as novel rigid homogeneous dendritic catalyst and organic light emitting diode (Scheme 97) [296].

Very recently, C-substitution of aromatic ring through cleavage of C-H or C-X bonds has attracted substantial interest and becomes one of the most straightforward and useful methods to prepare in-novative compounds especially aryl triazole derivatives with envi-ronmentally green and benign advantages [286].

5. STRUCTURAL MODIFICATIONS IN SIDE CHAINS OF 1,2,4-TRIAZOLES

Structural modifications in side chains of 1,2,4-triazole ring as another practical method are prevalently used to construct 1,2,4-triazole derivatives. Due to the high reactivity of amino and thiol groups in 1,2,4-triazoles, they easily proceed diverse reactions to

modify the side chains of 1,2,4-triazole ring to construct novel het-erocycles [39,297,298]. According to the modified functional groups, this type of structural modifications principally included the following aspects: (1) Modification of Thiol Groups; (2) Modifica-tion of Amino Groups; (3) Modification of both Thiol and Amino Groups; (4) Modification of Active Methylene Groups; (5) Modifi-cation of Other Functional Groups.

5.1. Modification of Thiol Groups

The presence of the sulfur moiety as an electron rich center is able to improve lipophilicity and modulate electron density of the triazole ring, thereby influencing its transmembrane diffusion abil-ity to the anticipant targets, as well as its interaction with hydrogen bond donors of the organism. Naturally, the introduction of sulfur moiety attracts special interest in the design of new drugs. Triazole thiols are in tautomeric equilibrium with triazole thiones, and both of them have two resonance forms (I1 and I2) in the presence of base. Researches have revealed that thermodynamic products tria-zole thiones are obtained as major products at high temperature (80 °C) via the formation of compound I2, while the thiol group is gen-erally converted into thioether at room temperature (Fig. 4)[126,299]. Recently, modification of thiol group of 1,2,4-triazole derivatives has been becoming one of the leading directions to search for biologically active compounds.

[HPAd2Bu]

220222

(44�78%)

223 (37%) (51%)

C6F13I/Cu KF/CuI

221

224

+

X = Cl, Br

O

N

OPiv

PivO

PivO

N

N

X

X

BOHHO

RI

(CH3)3SiCF3

ONPivO

PivO OPivN

N

(CF2)5CF3

Br

N

NN

N

NN

Br

Br

O

OPiv

OPivO

OPiv

PivO

PivO

OPiv

ON OPiv

OPivPivON

N

X

R

Pd(OAc)2

Scheme 96.

N

N N

ClCl

OCH3

K2CO3

225 226

N

NN OCH3

O

O

Bu-t

Bu-t

Bu-t

Bu-t

HO

Bu-t

Bu-t

+

Scheme 97.


It is well known that thiol groups in triazole thiols have high re-activity, and they can easily react with a series of halides in the presence of base. The reaction of 3,4-disubstituted 5-thiol-1,2,4-triazole 227, which was provided by the intramolecular cyclization of thiosemicarbazides in alkaline medium and subsequent acidifica-tion with acetic acid, with benzyl or isoamyl chlorides under basic condition could afford S-substituted triazole 228 in 50-95% yields (Scheme 98) [300]. Researches demonstrated that substituents on benzene ring had large influence on this transformation. The substi-tution pattern of compound 228c gave the highest yield of 95%, while compound 228a provided the lowest one (50%) (Table 9).

The classical preparative methods for thioether triazoles nor-mally proceed in the presence of strong base under refluxing condi-tion. However, this type of reactions requires long refluxing time and the yields are usually very low. Therefore, metal catalyzed reactions are employed because of mild reaction conditions and high yields. In the presence of indium trichloride, triazole thiol 229could react with a series of halides to give potential fungicidal thioether triazole 230 in excellent yields (Scheme 99) [301]. Sev-eral catalysts like InCl3, AlCl3, ZnCl2, PdCl2, CuI and metal Cu were screened to investigate their effects on this reaction. The re-sults showed that the best catalytic activity was achieved when InCl3 was used to promote the reaction and the yields were up to 84-91%.

The incorporation of ferrocene fragments into molecules par-ticularly heterocyclic ring often give hybrids with unexpected bio-logical activity, and which has been recognized as an attractive way to prepare novel molecules. The conjunction of triazole thiol 231with ferrocene containing �-halo-substituted ketone 232 in the presence of sodium hydride and potassium iodide successfully pro-duced compound 233 which possessed unique membrane permea-tion properties and anomalous metabolism (Scheme 100). The ex-perimental results manifested that substituents on benzene ring influenced the product yields to a large extent, and the electron donating group 4-OCH3 was more favorable for the thio etherifica-tion than the electron withdrawing 4-NO2 one, unexpectedly, 3-Br substituent was also helpful for the progress of this reaction (Table 10) [302].

Fe

O

Cl

231232

+

233

NaH

KI

HN

NN

SH

R

NH

NN

S

R

O

Fe

Scheme 100.

N

N

NH

S

RN

N

N

SH

RBase N

N

N

S

RN

N

N

S

R

I1 I2

Fig. (4). Tautomerism of triazole thiols in the presence of base.

R4CH2Cl

227 228

R2

R1O

N

NN

SH

R3

R2

R1O

N

NN

S

R3

R4

KOH

Scheme 98.



R1 Et i-Pr CH3 CH3 n-Bu

R2 H H Br Br H

R3 CH3 CH3 CH3 Ph CH3

R4 3-Br-4-CH3OPh 3-Br-4-CH3OPh 3-Br-4-CH3OPh i-Bu 3-Br-4-CH3OPh

Yield (%) 50 65 95 59 84

RX

229 230

InCl3

R = CH3, Et, Ph, 3-NO2Ph, 3-CH3OPh, 4-CH3OPh

N

NN

SHH3COC

H3COC

OH3C

NH3COC

H3COC

OH3C

NN

SR

NaOH/H2O

Scheme 99.


As is reported, triazole thiol can react with chlorine gas to con-veniently and efficiently afford sulfonyl derivatives with interesting properties. Reaction of 3,4,5-trisubstituted triazole thiol 234 with chlorine gas conveniently produced sulfonyl triazole 235, and the latter subsequently reacted with amine to provide compound 236with superior antimicrobial activity to its precursor (Scheme 101)[303]. This strategy presents an important way for the preparation of sulfonyl triazole derivatives and also extends the development space of novel sulfanilamide compounds.

In addition, thiol group in 3-thiol-1,2,4-triazole 237 could be removed by hydrogen peroxide in presence of acetic acid via mild oxidation to yield the corresponding 3-unsubstituted triazole 238 in 82-86% yields. Experiments showed that compound 238 readily underwent hydroxymethylation at triazole ring under neutral condi-tion to generate triazole alcohols and subsequent oxidation with manganese dioxide to afford corresponding triazole aldehydes in good yields ranging from 71% to 94% (Scheme 102) [293].

5.2. Modification of Amino Groups

Amino 1,2,4-triazoles as important reactants with high reactiv-ity have large potential applications in synthetic chemistry. Gener-ally, they easily undergo condensation with unsaturated compounds such as aldehydes, ketones, thiocyanate and isothiocyanate esters to construct intriguing molecules with spacious application in various fields like organic, medicinal and material chemistry.

A lot of researches have demonstrated that thiourea fragments play unusual contribution to bioactivity and are frequently intro-duced into drug molecules. Experiment results displayed that the condensation of 3-amino 1,2,4-triazole with aryl isothiocyanates efficiently afforded thiourea triazole 239a in yields of 71-93%, while alkyl isothiocyanates were employed as materials, the N-2 atom of 1,2,4-triazole ring might take part in the reaction to give product 239b with unsubstituted amino group in excellent yields (81-92%) (Scheme 103). Further theoretical calculations confirmed that this phenomenon was only for hydrophilic solvent acetonitrile, while in hydrophobic solvents both amino substituted compound 239a and unsubstituted 239b would be obtained [304].

R2 = OOCH2

CH3

,

N NH

N NH2

R1 NCS

R2 NCS

NH

N

NHN

HN

SR1 = H, Cl, CH3, OCH3

(71�93%)R1

N NH

S

R2N

N

H2N

239a

239b

(81�92%)

Scheme 103.

Thiosemicarbazones with thione-thiol tautomerisms are a very promising class of compounds showing a broad spectrum of thera-peutic properties. Recent researches showed that the hybrids of thiosemicarbazone with triazoles could effectively inhibit the growth of Entamoeba histolytica. The condensation of 4-amino-5-phenyl-4H-1,2,4-triazole-3-thiol 240 with various substituted aro-matic aldehydes in the presence of hydrochloric acid afforded tria-zole 241 in good yields (62-70%) (Scheme 104). Further studies demonstrated that substituents on benzene ring such as methyl, methoxy or nitro groups gave little influence on this transformation, but they showed obvious effect on inhibiting the growth of Enta-moeba histolytica [305]. In the same conditions, coumarin triazoles were prepared in yields of 74-76%, and the produced compounds were further transformed into Co(II), Ni(II), and Cu(II) complexes with good DNA cleavage activity [306].

Amino triazole can also easily react with sulfonyl group to af-ford special triazole derivatives. Reaction of amino 1,2,4-triazole with compound 242 through deprotonation with lithium bis(trimethylsilyl)amide (LiN(TMS)2) successfully afforded triazole derivative 243 in yield of 73% and then deprotection of the side chain via sequential treatment by hydrogen chloride and sodium



R H 4-CH3 4-OCH3 4-NO2 3-Br

Yield (%) 57 73 87 24 80

234

NN

N RNH2Cl2

H3C SH

235

NN

NH3C SO2Cl

236

NN

NH3C SO2NHR

(37%) (60%)

AcOH/H2O

Scheme 101.

N N

N

N N

NSHR1

R2

R1

R2

H2O2

237 238R1, R2 = CH3, Ph

AcOHN N

NR1

R2

CHO(CH2O)n

MnO2

Scheme 102.


microwavemicrowave

40 oC

245+OHC

HO 244

N NH

N NH2

+

R

R = H, Cl, Br, OCH3, OEt

EtOH

CH3OHH3C

H3CO

R

O

N

NH

N

N

H3C

246

OH

RHN

N

H3C OH

N

N

Scheme 106.

hydroxide provided a novel potent and efficacious 3-hydroxy-3-methylglutaryl coenzyme-A reductase (HMGR) inhibitor, which might be used in treating hypercholesterolemia and dyslipidemia with potentially excellent safety profile (Scheme 105) [307].

By the use of microwave irradiation, the one-pot reaction of salicylic aldehyde 244, 3-amino 1,2,4-triazole and acetone in etha-nol at 170 °C gave triazole derivative 245 in moderate yield (47%). If the reaction was performed at 40 °C in methanol, the diol product 246 would be obtained as main product in 60% yield. The struc-tures confirmed by single crystal X-ray diffraction clearly showed that the condensation of 3-amino 1,2,4-triazole with aldehyde oc-curred in the exocyclic amino group not on the endocyclic nitrogen of triazole ring (Scheme 106) [308].

An increasing interest has recently been focusing on heterocyc-lic macrocycles because of their large potentiality as medicinal drugs like magnetic resonance imaging agents Magnevist and MultiHance, anticancer agents cyclodextrin- and porphyrin-based supermolecules, etc. [30,31]. Multinitrogen triazoles with strong coordination ability have been of great importance in the develop-ment of macrocyclic complexes. The reaction of bis(2-formylphenyl)hexane 247 with 3-substituted-4-amino-5-hydrazino-1,2,4-triazole 248 in 1:1 molar proportion by adding a few drops of

hydrochloric acid have successfully provided macrocyclic Schiff base triazole 249 in yields ranging from 55% to 60%, and its com-plexes with metal Co(II), Ni(II) and Cu(II) ions exhibited magnetic properties and among them Co(II) complexes had highest magnetic moments (4.70-4.94 BM) than the other ones (Scheme 107) [309].

In addition, the amino group on triazole ring could also be transformed into diazonium salts, nitro and other derivatives [173,310-313]. These studies may lead to the rational design of even more effective and stable molecules with potential valuable application in various aspects.

5.3. Modification of Both Thiol and Amino Groups The thiol and amino substituted triazoles as one of the most im-

portant molecular fragments to develop bioactive compounds are widely employed to construct fused heterocycles [314]. In sulphuric acid medium, the N-alkylation of amino group in compound 250with aromatic aldehydes and thioglycolic acid gave triazole inter-mediate J1, and then was dehydrated and converted into thiazoli-done triazole J2, which was subsequently transformed into its iso-mer J3. The final cyclodehydration produced thiazole-, thiadiazole- and triazole-fused compound 251 with high yields of 77-94% (Scheme 108). No obvious effect of substituents on benzene ring on this reaction was found, since the results showed that the yields of final products did not depend on the substituents [315].

The structural modification of macrocycles by incorporating oxygen, nitrogen and sulfur donor atoms to afford crown ethers with interesting properties has been coming into visual field. Trans-formation of 4-amino-5-(aroyl)-4H-1,2,4-triazole-3-thiol by bis-aldehydes 252 afforded corresponding compound 253 in yields of 66-70% and then the products were converted into crown ether 254with remarkable host-guest complexation characteristics and anti-bacterial activities (Scheme 109). As an extension of this study, 1,3,4-thiadiazole containing crown macrocycles were also success-fully prepared in moderate yields (55-80%) [316].

5.4. Modification of Active Methylene Groups

It is well known that �-hydrogens in active methylene groups which are activated by electron withdrawing groups can easily be

N

NN

SH

NH2

NN

N

SH

N

R = 2-CF3, 4-NO2, 4-CH3, 4-OCH3

R

240 241

R

CHO

+

EtOH

Reflux

Scheme 104.

243242

LiN(TMS)2N N

N NH2

+

CH3

N

N

Pr-i

SO2CH3

O

O CH3

CH3

O

N

N

Pr-i

NH

O

O CH3

CH3

NN

N

CH3

THF

O

CH3H3C

H3C

OO

CH3H3C

H3C

F F

Scheme 105.


R = H, CH3, Et

+HCl

248 249247

O

O O

O

N

NN

R

NO

NHN

O

N

NN

R

H2N

NHH2N

CH3OH

Scheme 107.

H2SO4

R = H, 4-F, 4-OCH3, 4-N(CH3)2, 2-OH-5-Br

CHO

R

250

N N

N CH3HS

NH2

+OH

O

+

SH

N N

S

N

N

S

CH3

251

R

N N

N CH3HS

HN S

R

OH

O

N NN

NS

CH3

R

SH O

N NN

NS

CH3

R

SH HOJ1 J2 J3

Scheme 108.

NN

N

HS

H2N

Ar O O

N N

N N

NN N N

HSSH ArAr

O O

N N

N

N N

S S Ar

253

254

252

O

O

OHC

OHC

Br Br

(65�68%)

N

NN

Ar

(66�70%)

+KOH

EtOH

Ar = NH

NH

Scheme 109.

modified to provide special structures containing chalcone frag-ments. These chalcone structures have typical acyclic conjugated backbone, desirable intramolecular charge transfer and unusual fluorescence emission properties as well as easy structural modifi-cation by various functional groups. It is of great interest to incor-porate these special fragments into 1,2,4-triazole to give the new

skeleton with broad bioactive spectrum [317]. The chalcone con-taining triazole 256 was prepared via aldol condensation of com-pound 255 with benzaldehyde in toluene under the cocatalysis of both glacial acetic acid and piperidine. The key intermediate etha-none in 1,2,4-triazole 255 was efficiently obtained in excellent yield of 93% starting from commercially available m-difluorobenzene


through Friedel-Crafts acylation and then N-alkylation with 1,2,4-triazole in one-pot synthesis (Scheme 110). Further observations indicated that the amount of piperidine was quite an important fac-tor in the formation of amino chalcone hybrids [318, 319]. In addi-tion, compound 255 could be brominated by bromine to give antim-icrobial 2-bromo-2-(5-bromo-1H-1,2,4-triazol-1-yl)-1-(2,4-difluor-ophenyl)ethanone in the presence of acetic acid [320].

As presented in (Scheme 110), mixture of triazole compound 257 and equimolar aromatic aldehydes produced two compounds with architectonic E-chalcone-triazole 258a (38-55%) and its iso-mer Z-one 258b (8-10%) in the catalysis of piperidine and glacial acetic acid. Single crystals of target compounds were successfully cultivated and the structures were measured by X-ray diffraction (Scheme 111). It could be seen from the stereoscopic configuration that the Z type compound was a forceps-shaped structure in which the distance between molecules was far and the intermolecular in-teraction was weak due to the influence of steric effects. However, the E type one could efficiently generate self-assembly via intermo-lecular �-� stacking interactions. It was generally considered that this transformation would be highly affected by the blockade of the substituents, and the large anthracene ring was unfavorable for this reaction with yields low to 38% and 8% for E- and Z- types respec-tively [321-324].

Recently, metal complex inhibitors have extensively been used to treat human immunodeficiency virus (HIV) infections, the emer-gence of serious toxicity and drug resistant strains has highly pro-moted the need for new inhibitors that can resolve these issues.

Reaction of ester containing tetrahydropyranyl 1,2,4-triazole 259with compound 260 successfully produced �,�-unsaturated car-bonyl triazole 261 with potent anti-HIV activity using a low cost and reliable synthetic procedure (Scheme 112) [325].

Additionally, chloromethyl triazoles display strong reactivity for that the electron withdrawing aromatic triazole ring largely de-creases electron density of C-Cl bond. In the presence of potassium carbonate, dichloromethyl triazole 262 smoothly reacted via etheri-fication with 2 equivalent salicylaldehyde to give chemosensor precursor 263, and the latter as semirigid ligand containing lone electron pairs on nitrogen atom, could easily coordinate with cop-per(II) to construct highly sensitive and selective “off-on” che-mosensor chelates (Scheme 113) [326]. It is anticipated that this synthetic reaction may be served for the developments of new che-mosensors for other transition metal ions, and which will signifi-cantly promote the investigation of the effects on cations in biologi-cal systems.

5.5. Modification of Other Functional Groups

Except for the above mentioned structural modifications of functional groups, some other groups such as hydroxyl, azide ones and so on in side chains of triazole ring can also be converted to provide various intriguing triazole derivatives with potential appli-cations.

Etherification of 1-phenyl-1,2,4-triazole-3-ol 90 with a variety of alkyl bromides and benzyl halides afforded alkoxy 1,2,4-triazole 264 and halobenzyloxy derivative 265 in yields ranging from 56%

255 256

HOAcCHO

Piperidine+

O

N

F

F N

N

F

F

O

NN

N

Scheme 110.

NO

N

N

R1

Ar CHOHOAc

NAr

O

N

N

R1

258b258a257

++

N

O

N

N

R1

Ar

Ar = R2,

R1, R2 = H, F, Cl, CH3

Scheme 111.

260

CH3ONa

259 261

+CH3OH O

O

N

NNHO

FO

N

N

NO

O

H3CO

OCH3

O

F

(86%)

Scheme 112.


to 89%, and then they were further treated by hydrochloric acid (4 mol/L) in ethyl ether to produce their corresponding hydrochlorides in high yields (81% to 88%) which gave significantly improved antimicrobial activities in comparison with their precursor triazoles (Scheme 114) [115]. It should be noted that the ratio of reactants, solvents, reaction time, amount of catalyst as well as the addition rate of sulfuric acid exerted important influences on the yields of target triazoles, and experiments confirmed that the presence of weak base such as potassium carbonate in acetonitrile at 70-75 °Cwas favorable for this O-alkylation reaction.

Click chemistry is now being extensively studied, and is easy to perform quickly and reliably by joining small units together. Click reaction as one of the most popular reactions in click chemistry is defined as Cu(I) catalyzed 1,3-dipolar cycloaddition of azide moi-ety and alkyne to build 1,2,3-triazole ring. This efficient coupling reaction is of great potential to build multifunctional molecules due to its high regioselectivity, quantitative yields and mild reaction conditions without by-products [206,207,327]. Recently, double triazole compounds have been attracting considerable interest due to their unique structures and properties, among which Fluconazole is the representative one with powerful antifungal activity, and also 1,2,3-triazoles with excellent properties have attracted much atten-tion. Therefore, the interest in developing conjuncted molecules of both 1,2,4- and 1,2,3-triazole rings was highly increased. The click reaction of azido-1,2,4-triazole 266 with phenylacetylene 267 under mild copper catalyzed conditions favorably produced 1,2,4-triazole derivative 270, and subsequent transformation gave amide ditria-zoles as novel antiviral candidates against Tobacco Mosaic Virus(Scheme 115) [328].

267266 268

Cu2SO4

(85%)

+THF

HN

NN

N3

H3COO NH

NN

H3CO O

N

NN

Scheme 115.

Selenium microelement is introduced into triazole skeletons to produce compounds with good bioactivity and high safety. Herbi-cide precursor arylselenonyl-1H-1,2,4-triazole 270 was prepared by the reaction of diazonium salt, which was obtained by the transfor-mation of arylamine, with compound 269, and target compounds were further oxidated by oxone and subsequently N-acylated with diethylcarbamoyl chloride to produce diethylamide triazole with herbicidal activity. In order to ensure the process of the reaction, the pH values must be strictly kept at 12 (Scheme 116) [329]. This transformation is highly affected by the temperature, pH and com-plicated operations, and only exhibits narrow application scope, but it can provide rare triazole selenium herbicides and much effort should be dedicated to this strategy to optimize the harsh reaction conditions.

269

N2Cl

R

pH = 12

N

NHN

SeK

270

0�5 oC

R= H, F, Cl, NO2, CH3 CF3, OCH3

N NH

NSeR

+

Scheme 116.

Additionally, the modification of functional groups which are far from triazole ring has been reported vastly due to the easily coupling reactions, and numerous 1,2,4-triazole-based su-pramolecular aggregates have been prepared with special properties and biological activities, and display a wide range of potential ap-plication as cation and anion artificial receptors [330-335], lumi-nescent [336-340] and magnetic [341-344] materials as well as medicinal agents [3,30-32].

6. CONCLUSION

The above mentions have clearly demonstrated that the highly efficient syntheses of 1,2,4-triazole derivatives have been fast de-veloped, and a great amount of effort has been directed towards synthetic strategies and lots of excellent achievements have been acquired. Particularly excited is that an increasingly number of new synthetic technologies have been developed to prepare triazole

N N

NCl Cl

O+

K2CO3

262263

(85%)CHO

OH

DMF

N N

NO O

CHO OHC

O

Scheme 113.

90

n = 2�15

264 265

NN

NO

CH3

n

NN

NOH

NN

NO

RR = 2-Cl, 4-Cl, 2,4-(F)2, 2,4-(Cl)2

R

X

H3C Brn

Scheme 114.


compounds in actively ongoing researches. All these clearly pointed out that preparation of triazole containing compounds will provide an infinite space for synthetic chemists. It is undoubtedly believed that the researches and developments of synthetic methods of 1,2,4-triazoles will still be one of the most active areas in a long time. From current researches, the active topics in syntheses of 1,2,4-triazole derivatives in near future might mainly include the follow-ing aspects:

(1) Increasing effort will continuously contribute to cyclizations to form 1,2,4-triazole derivatives.

Cyclizations of hydrazines and their derivatives as starting ma-terials will still be one of the most important synthetic routes to access novel 1,2,4-triazoles with variation of substituents. More and more work will extend to commercially available non-hydrazine compounds to construct 1,2,4-triazoles with completely new chemi-cal structures. Particularly, one-pot synthetic methods to produce triazoles will become important direction.

(2) The substitutions of triazole ring will continuously be an unusually prevalent topic for the preparation of 1,2,4-triazole-based compounds. Especially, with the rapid progress of C-H synthetic methodology, the functionalization of triazole C-H bonds by elec-trophilic attack of metal ions might become active area to prepare novel triazole compounds.

(3) Transformations of heterocycles might still be an important strategy to access novel 1,2,4-triazoles with special structures. However, this type of synthetic pathway is highly limited due to the difficult preparation of precursor heterocycles.

(4) Structural modifications in side chains of triazole ring by a variety of biologically important structural fragments including other azole rings [7] like imidazole [81], tetrazole [345], oxazole [178], benzimidaozle [129,130] etc. will still be a highly prevalent pathway to access 1,2,4-triazole derivatives with novel chemical structures and variable properties. In particular, the moieties with unstable and sensitive properties can be easily improved to generate more stable triazoles.

Clearly, with increasing effort towards the synthesis of 1,2,4-triazole derivatives, more and more synthetic technologies with mild conditions, convenient operations, high efficiencies and so on will be contributed to the preparation of various sorts and varieties of 1,2,4-triazoles with diverse potential applications in chemical, medicinal, agricultural, material sciences and so on.

CONFLICT OF INTEREST

The authors confirm that this article content has no conflicts of interest.

ACKNOWLEDGEMENTS

This work was partially supported by National Natural Science Foundation of China [No. 21172181, 21004075, 21372186, 81350110338, 81250110089, 81250110554 (The Research Fellow-ship for International Young Scientists from International (Re-gional) Cooperation and Exchange Program)], the Key Program from Natural Science Foundation of Chongqing (CSTC2012jjB10026), the Specialized Research Fund for the Doc-toral Program of Higher Education of China (SRFDP 20110182110007), the Fundamental Research Funds for the Central Universities (XDJK2011D007, XDJK2012B026) and the Doctoral Fund of Southwest University (SWU111075, SWUB2006018).

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Received: December 31, 2012 Revised: May 13, 2013 Accepted: May 13, 2013

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Current Developments in the Syntheses of 1,2,4-Triazole