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Letters in Organic Chemistry, 2013, 10, 693-714

693

1,2,4-Triazoles: A Review of Synthetic Approaches and the Biological


Activity
Suresh Maddila, Ramakanth Pagadala and Sreekanth B. Jonnalagadda*
School of Chemistry & Physics, University of KwaZulu-Natal, Westville Campus, Chiltern Hills, P. Bag X 54001,
Durban 4000, South Africa
Received May 21, 2013: Revised July 18, 2013: Accepted July 19, 2013

Abstract: 1,2,4-Triazoles and their derivatives have a distinct place in the field of medicinal and pharmaceutical chemistry. These are used as lead compounds for the synthesis of numerous heterocyclic compounds which possess diverse
biological activities and play pivotal roles. This review covers the latest literature and knowledge on the synthetic
procedures for various triazoles derivatives, their activities and pharmacological applications.

Keywords: 1,2,4-Traizole, synthesis, biological activity, review.


INTRODUCTION
Heterocyclic chemistry is most challenging and amply
rewarding field, and by far heterocycles are the largest class
in organic chemistry. A majority of pharmaceuticals, biologically active agrochemicals, additives and modifiers used
in industrial applications are heterocyclic by nature [1]. Synthetic organic chemists made significant progresses in discovering and developing wide range of heterocyclic compounds for the benefit of mankind. One remarkable structural feature and characteristic to heterocycles, which continue to be exploited, is their capability to accommodate the
substituents around a central frame. Ever since their initial
use in agriculture which began a century ago, the chemistry
of nitrogen and sulfur containing heterocycles has made remarkable advances [2]. The pesticidal, fungicidal, antiviral
and potential chemotherapeutic properties have been the inspiration for the overwhelming curiosity into the heterocyclic compounds in general, and the thiadiazoles, oxadiazoles,
pyrazoles and triazoles in particular. Among the heterocyclic
compounds, triazoles are one of the most key heterocycles
exhibiting remarkable pharmacological activity as they are
an essential constituent of all cells and living matter [3]. Triazole is a five-membered heterocyclic ring, which possesses
three nitrogen atoms 1,2 and 4 positions. It is a much basic
aromatic compound soluble in all organic solvents. The parent compound, triazole was synthesised for the first time by
Fischer in 1878. Over 0.2 million 1,2,4-triazole derivatives
have been reported in the literature and this class of organic
compounds has become extraordinarily important due to
their wide-ranging biological, agrochemical and chemical
properties. The advances in the synthesis and biological activity of 1,2,4-triazoles from time to time have also been
reviewed [4-8]. This review mainly aims at the recent advances in the field of synthesis and biological activity of
1,2,4-triaozles and their derivatives.
*Address correspondence to this author at the School of Chemistry & Physics, University of KwaZulu-Natal, Westville Campus, P Bag X 54001,
Durban 4000, SOUTH AFRICA; Tel: + 2731 260 7325 (Direct), 3090 (Secretary); Fax: + 2731 260 3091; E-mail: jonnalagaddas@ukzn.ac.za.

1875-6255/13 $58.00+.00

Triazoles form an important cluster among the heterocyclic compounds which possess a wide range of biological applications. While Pellizari et al. [9, 10] have reported the
ability of 4-phenyl-1,2,4-triazoles to produce convulsions,
indeed 1-phenyl-1,2,4-triazole was found to exhibit anticonvulsant property [11]. Benzimidazolyl-1,2,4-triazole acts as
central nervous system depressant [12]. Besides these, the
nitrofuryltriazoles (1) display potential urinary track antibacterial activity [13]. The -amino--phenyl-o-tolyl-1,2,4triazoles (2) were reported as sedative and anticonvulsant
agents [14].
Apart from these, the 1,2,4-triazole derivatives possess
important pharmacological activities such as antifungal and
antiviral [15] properties. Examples of antifungal drugs are
fluconazole (3) [16, 17], itraconazole (4) [18], ravuconazole
(5) [19], voriconazole (6) [20-22] and posaconazole (7) [23].
Some triazole derivatives are considered as angiotensin II
receptor antagonists [24-27].
Furthermore, various 1,2,4-triazole derivatives are reported as insecticides [28], antiasthmatics [29], anticonvulsants [30], antidepressants [31], anti-inflammatory [32], insecticidal [33] and plant growth regulators [34]. In addition,
compounds having triazole moieties, such as vorozole (8),
letrozole (9), and anastrozole (10) are found to be very effective aromatase inhibitors, which could prevent breast cancer
[35-37]. 1,2,4-triazole moiety is reported to interact strongly
with heme iron, and aromatic substituents on the triazole are
very effective in interacting with the active site of aromatase
[38, 39].
In fact, there are various drugs, which contain 1,2,4triazole nucleus viz., triazolam (11) [40], alprazolam (12)
[41], etizolam (13) [42] and furacylin [43]. Many sulfur
containing heterocycles are quite promising with several
practical applications. The mercapto and thione substituted
1,2,4-triazole derivatives possess antibacterial [44-47], antifungal [48-50], antitubercular [51], antimycobacterial [52],
anticancer [53, 54], diuretic [55, 56] and hypoglycemic [57]
properties.
2013 Bentham Science Publishers

694 Letters in Organic Chemistry, 2013, Vol. 10, No. 10

Maddila et al.

Me

N
N
O 2N

R2

Me
NH2

N
O

Cl

R1

R3

1
2
F
OH

N
N

N
3
N

O
N

Cl

N
O

Me
OH
N

N
CN

FS

Me
OH
N
NF

F
6

F
5
N

Me

Cl

Me

O
N

N
O

Cl

OH
Me

Me

Cl

N
N
N

NC

N
Me

Me

Me

N
N
N

Cl
8

Cl

Cl
9

Me

Me
CN
10

Triazole Derivatives

Letters in Organic Chemistry, 2013, Vol. 10, No. 10

H 3C

Cl

N
N
N

Cl

H 3C

N
Cl

N
13

12

11
Ribavirin (14), a substituted 1,2,4-triazole-3-carboxamide
possesses antiviral activity against RNA and DNA viruses
[58]. It inhibits the replication of HIV in human T lymphocytes [59]. Isopropylidene ribavirin (15) acts as an inhibitor
of several viruses [60]. Trisubstituted 1,2,4-triazoles (16)
reportedly exhibit potent antiviral activity against efavirenzand nevirapine-resistant viruses [61]. While, diarylthiazolotriazole (17) demonstrates selectivity against human
COX-1 and COX-2 enzymes [62], Maraviroc [63] (18) is
known as an antiretroviral drug in the treatment of HIV infection. Deferasirox [64] (19) is a rationally-designed oral
iron chelator, which is used to reduce chronic iron overload
in patients and other chronic anemias.

Cl

solvent produced 1,2,4-triazoles, which proceed through


acylhydrazidines as intermediates [69]. However, the yield
was found to be low due to the loss of amides through dehydration into the corresponding nitriles which do not participate in the Pellizari reaction. The acyl interchange between
amide and hydrazide may complicate the reaction processes.
O
HO

N N

In addition to these, triazoles fused with pyridines, pyridazines, pyrimidines, pyrazines and triazines exhibit diverse
applications in the field of medicine, agriculture and industry. The pyrazolo triazoles (20) are found to have analgesic
activity [65].

OH

N
OH

19

HN N

I. FROM HYDRAZONE DERIVATIVES


R

HO

N
N

RO

OH
14

N
S

(
)

N
R'

N
17

Ar'

NH2
R

16

15

Ar

R2

R1

N
N

N
N

H
N

N N

Me

20

CH2CH2OH

HO

CONH2

CONH2

Me

N N

The formation of 1,2,4-triazoline was first observed by


Pinner [66-68] during the synthesis of amidrazones from an
imidate and hydrazine. The Pellizari reaction between hydrazides and amides at high temperature in the absence of

695

18

N
X

696 Letters in Organic Chemistry, 2013, Vol. 10, No. 10

Maddila et al.

Ph
N N

i
Et

Me

O
Et

H
N

N
H

Ph

Me

NH2

Ph
N N

ii
Me

Me

(i) 210 C (ii) >210 C


Eqn. 1
O
H

N
H

NH2

Ph

H
N

N N

i
Ph

N
Ph

(i)

Eqn. 2
O
H

N
H

H
N

HCONH2

R
N N

i
RNHNH2.HCl

HCONH2
Eqn. 3

(i)

NH2
N
N
H

H
NHNH2 +
EtO

N CN

(i) Et3N

It was observed that acyl interchange did not occur when


acetamide was heated with 1-phenyl-2-propionylhydrazine
until the temperature was around 210C. The product formed
was found to be 1-phenyl-3-ethyl-5-methyl-1,2,4-triazole,
whereas at high temperatures, 1-phenyl-3,5-dimethyl-1,2,4triazole was obtained [70] (Eqn. 1).
However, the reaction between cyanoacetylhydrazine or
formylhydrazine and N,N-diphenylformamidine led to the
formation of 3-cyanomethyl-4-phenyl-1,2,4-triazole or 4phenyl-1,2,4-triazole [71, 72] (Eqn. 2). The fusion of Nformyl-N-alkyl/arylhydrazines with formamide at high temperature produced N-substituted triazoles [73, 74]. The Pellizari reaction of formamide with substituted hydrazine hydrochloride also gave N-substituted triazoles [75] (Eqn. 3).
Similarly, 1,5-diphenyl-1,2,4-triazole was obtained by the
reaction between N-formylbenzamide and phenylhydrazine
[70,75,76]. The interaction of ethyl N-cyanoformimidate
with benzimidazole-2-hydrazine in triethylamine gave the
corresponding 5-aminotriazole [77, 78]. (Eqn. 4).
The Einhorn-Brunner reaction of hydrazine with diacylamines was exploited to get 1,2,4-triazoles [70,78,79]. The
treatment of hydrazine or its mono substituted derivatives
with symmetrical or unsymmetrical diacylamines in an or-

N
N
H

N
Eqn. 4

ganic acid or in an acid-buffered solution or in the presence


of pyridine hydrochloride produced 1,2,4-triazoles. However, its reaction mechanism involving an amidrazone intermediate was later reported [80] (Eqn. 5). Similarly, the reaction of unsubstituted hydrazine with an amide derivative
yielded amidrazone. The amidrazone, either on reaction with
one more mole of amide derivative or self-condensation led
to N2-(acetimidoyl)acetimidohydrazide, which on heating
cyclized to triazole [81] (Eqn. 6). However, there was an
ambiguity of cyclization to oxadiazole or triazole. The conversion of amidrazone into triazole was effected in basic
medium, while oxadiazole was obtained in the presence of
an acid [82]. On the other hand, dehydration of amidrazone
to triazole takes place in the presence of polyphosphoric
acid.
The treatment of arenenitrile with arenesulfonate of an
aroylhydrazine afforded 3,5-diaryltriazole [83]. This method
was extended to the reaction of arenenitriles with alkylhydrazide benzenesulfonates [84] (Eqn. 7). However, the reaction failed with alkenenitriles and aroylhydrazine arenesulfonates. Contrary to this, 3,5-dialkyl-1,2,4-triazoles were
obtained in good yield by the treatment of alkylnitriles with
zinc chloride complex of hydrazine at 140C [85].

Triazole Derivatives

Letters in Organic Chemistry, 2013, Vol. 10, No. 10


2

H
N

O
NH2

O
N
H

R
NH

N N

R HN N

697

Eqn. 5
NH
R

NH

NH

i
X

N
H

NH2 +

HN NH

ii

NH HN
ii

(i) N2H4 .H2O (ii)

N NH
R

R
Eqn. 6

N NH

O
R

N
H

NH2.

PhSO3H + ArCN

Ar

N NH
R

Ar

NH2 O

(i)

Eqn. 7
NH
Ph

N
H

H
N

Me

O
Me

N N

+
Cl

OEt

HO

Ph
Eqn. 8

Cyclization of N-benzimidoyl-N-methylhydrazine with


ethyl chloroformate led to 5-hydroxy-1-methyl-3-phenyl1,2,4-triazole (Eqn. 8). However, the reaction of former
compound with formic acid or acetic anhydride afforded 1methyl-3-phenyl- and 1,5-dimethyl-3-phenyl-1,2,4-triazoles,
respectively [85].
1,2,4-Triazole-3,5-diamine derivatives were produced in
one-pot reaction from the corresponding isothiocyanates,
monosubstituted hydrazines and sodium hydrogencyanamide
in
the
presence
of
1-(3-dimethylaminopropyl)-3ethylcarbodiimide hydrochloride (EDC) [86] (Eqn. 9). Similarly, 3-mercapto-4,5-disubstituted 1,2,4-triazoles were obtained by the interaction between aryloxyacetic acid hydrazides and aryl isothiocyanates [87, 88] (Eqn. 10). The treatment of acid hydrazide with carbon disulfide in the presence
of potassium hydroxide gave potassium salt of 2acyldithiocarbazic acid, which was further converted into its
methyl ester with methyl iodide. The later on reaction with
hydrazine gave 4-amino-5-mercapto-3-substituted 1,2,4triazole [89] (Eqn. 11).
Apart from these, pyrazinyl substituted 5-mercapto-1,2,4triazoles were prepared form the corresponding potassium
dithiocarbazinates in the presence of pyrazinic acid hydrazide [90] (Eqn. 12). Similarly, ethanolic potassium hydroxide
solution of thiophene carbohydrazide with carbon disulfide
yielded the corresponding dithiocarbazate, which subse-

quently reacted with hydrazine to give 4-amino-5-mercapto3-(2-thienyl)-1,2,4-triazole [91].


The aliphatic and aromatic diacylhydrazines upon treatment with ammonia gave 3,5-disubstituted 1,2,4-triazoles
[77]. The reaction of dibenzoylhydrazine with aniline in the
presence of phosphorus pentoxide [92] or phenylphosphazoanilide [93] afforded 3,4,5-triphenyl-1,2,4-triazole (Eqn. 13).
Under similar conditions, a mixture of hydrazine, ammonia
and formaldehyde yielded 1,2,4-triazole, in which diformylhydrazine was initially formed [94, 95]. The treatment of Nsubstituted acetamides with oxalyl chloride generated imidoyl chlorides which on reaction with acylhydrazines followed by cyclization led to triazoles [96]. 4-Substituted
1,2,4-triazoles were also prepared by fusing diformylhydrazine with amino phenols [97].
One of the choicest methods for the preparation of 1,2,4triazole derivatives was the condensation of thiocarbohydrazides with aliphatic and aromatic carboxylic acids [98100] (Eqn. 14). The reaction of benzhydrazide benzenesulfonate with N,N-dimethylformamide resulted in formation of
4-benzamido-3-phenyl-1,2,4-triazolium
benzenesulfonate
and 1-benzoyl-4-formamidobenzhydrazidine as the major
products. The reaction of latter compound with benzenesulfonic acid in N,N-dimethylformamide gave 1,2,4-triazolium
benzenesulfonate. Alkaline hydrolysis of triazolium derivative produced 4-benzamido-3-phenyl-1,2,4-triazole [101,
102] (Eqn. 15).

698 Letters in Organic Chemistry, 2013, Vol. 10, No. 10

R2

H
N

Maddila et al.

N N

NH2

+ R NCS

R HN

R2
N N

+
R1 HN

NH2

NH2

(i) NaNHCN / EDC

Eqn. 9

O
O

N N
NCS

NHNH2

+
R'

SH

R
R'

(i) aq. NaOH

Eqn. 10

N
H

NH2 + CS2 + KOH

HN

N N

NH

R
OS

ii

SCH3

SH
N
NH2

(i) MeI (ii) N2H4.H2O

Eqn. 11

N N
O
Ar

Ar

H
N

N
H

S- K +

SH

N
HN

S
N
N

(i) Pyrazinic acid hydrazide / water /


HN
PhNH2 +

Eqn. 12

NH

Ph

N N

Ph

Ph

OO

Ph

N
Ph

Eqn. 13

(i) PhN=PNHPh

S
H2N

N
N
H
H
(i) RCOOH /

NH2

N N

i
R

SH
N
NH2

Eqn. 14

N N
Ph
O
Ph

N
H

NH2 . PhSO3H +(Me)2NCHO

(i) PhSO3H (ii) NaOH

The 3,5-disubstituted 1,2,4-triazoles were also prepared


by the reaction of S-methyl-N-arylisothiouronium iodide
with substituted hydrazides [103] (Eqn. 16). The reaction of
N-acetyl-N,N-dimethylhydrazonoformamide with primary

. PhSO H
3
N
NHCOPh

ii
N N
Ph

i
NNHCHO
H
N
Ph
N
H

ii

N
NHCOPh

Ph
O

Eqn. 15

amines followed by acid catalyzed cyclization resulted in


substituted 1,2,4-triazoles. The former compound was generated in situ from acid hydrazide and N,N-dimethylformamide
dimethyl acetal [104]. On the other hand, an efficient mi-

Triazole Derivatives

Letters in Organic Chemistry, 2013, Vol. 10, No. 10

N NH

S Me
NH

N
H

NH2

+
R'

OMe
N
H

NH2 +

(i) CH2Cl2 /

R'
Eqn. 16
N N

i
N
H

OMe

ii

N
R

(ii) RNH2 / AcOH / MW

crowave irradiation (Eqn. 22). Kidwai et al. [125] have reported a new antifungal 1,2,4-triazole derivatives from substituted hydrazide using various solid supports under microwave irradiation. Several potentially bioactive 1,2,4-triazole
derivatives were prepared adopting 1,3-cycloaddition methodology between different nitriles and 1-(chloroalkyl)azo
salts in the presence of SbCl5 as a Lewis acid [126-129].

3,5-Disubstituted 1,2,4-triazoles were also obtained by


treating nitriles with zinc hydrazine complexes [106]. Dialkylamino-1,2,4-triazole was obtained from aliphatic nitrile
and hydrazine [107] (Eqn. 18). The formation of 1,3,5triphenyl-1,2,4-triazole by the reaction between phenylhydrazine and benzonitrile in the presence of sodium proceeded
through amidrazone as probable intermediate [108]. 1,2,4Triazoles were also obtained by oxidative intramolecular
cyclization of heterocyclic hydrazones with copper (II) chloride [109] (Eqn. 19).

II. FROM SEMICARBAZONE DERIVATIVES


The ring closure of acyl derivatives of semicarbazides,
thiosemicarbazides or aminoguanidines in alkaline solution
was one of the widely applied methods for the preparation of
1,2,4-triazoles [130-132] (Eqn. 23). Triazoles were also afforded by the cyclization of S-alkylthiosemicarbazides in the
presence of acetic anhydride [133] (Eqn. 24). In fact, this
reaction resembles the formation of 1-phenyl-3-hydroxy1,2,4-triazole from 1-phenylsemicarbazide in the presence of
triethoxymethane [134-136] (Eqn. 25).

Microwave irradiation has become a widely used method


to rapidly synthesize many useful organic molecules with
good yield and high selectivity [110-120]. Bentiss et al.
[121] have reported 3,5-disubstituted 4-amino-1,2,4-triazoles
from aromatic nitriles and NH2NH22HCl in the presence of
excess NH2NH22H2O in ethylene glycol under microwave
irradiation (Eqn. 20). Symmetrical 3,5-disubstituted 4amino-1,2,4-triazoles were prepared from aromatic aldehydes via nitriles by two-step reaction under microwave irradiation with no need to separate the intermediate [122]
(Eqn. 21). An efficient microwave-assisted one-pot and
three-component synthesis of substituted 1,2,4-triazoles was
also reported from substituted primary amines [123]. Yeung
et al. [124] described an efficient one-step procedure, the
synthesis of 3,5-disubstituted 1,2,4-triazoles by basecatalyzed condensation of nitriles and hydrazides under mi-

The literature survey reveals that the cyclization of substituted thiosemicarbazides can occur in the presence of sodium carbonate [98,137-139], alkoxides [140, 141], sodium
hydroxide [142-147], triethylamine [148] or by their fusion
[149]. The bis(1,2,4-triazolyl) derivatives were prepared by
the
base
catalzsed
cyclodehydration
of
bis(thiosemicarbazide) derivatives [150, 151] (Eqn. 26).
However, the cyclization of 1,4-disubstituted thiosemicarbazides in acidic medium has also been a concept, which
attracted overwhelming interest. In this case the product was
found to be thiadiazole derivative instead of triazole [152,

HN NH

RCN

N N
R

R
N
NH2

HN NH

(i) N2H4. H2O

N
H

Eqn. 18
N

C
H

(i) 2CuCl2 / DMF /

CH3

Eqn. 17

crowave assisted one-pot and three-component synthesis of


1,2,4-triazoles was accomplished by the reaction of acid hydrazide with N,N-dimethylformamide dimethyl acetal and
primary amine in the presence of acetic acid [105] (Eqn. 17).

NH

NH
.HI

699

N N
N

R
Eqn. 19

700 Letters in Organic Chemistry, 2013, Vol. 10, No. 10

Maddila et al.

N N
i

ArCN

Ar

Ar

N
NH2

(i) Ethylene glycol / NH2NH2.2HCl / NH2NH2.H2O / MW


H H
N N

ArCHO

Eqn. 20

ii

ArCN

Ar

N N
Ar

Ar
N N

(i) NH2OH.HCl /

Ar

N
NH2

O / MW

N
Me

(ii) Ethylene glycol / NH2NH2.2HCl / NH2NH2.H2O / MW

Eqn. 21

O
1

NH2

N
H

HN N

R CN

R2

(i) K2CO3 / BuOH / MW

O
H2N

H
N

N
H

(i) OH

Eqn. 22

N N

Ph

HO

Ph

N
Ph

Ph

Eqn. 23
N

Me

H
N

NH

N N

N
H

MeS

S
Me

(i) Ac2O

Eqn. 24

O
N
H

H 2N

H
N

Ph
i

N N

Ph

OH

Eqn. 25

(i) HCO2H
S
RHN
(i) OH

N
H
-

H
N

H
N

( )n
O

S
N
H

N NH

HN N
i
NHR

153]. On the other hand, thiosemicarbazide on treatment


with benzoyl chloride in boiling pyridine or alkali undergoes
in situ benzoylation and cyclization, resulting in the formation of 4-benzoyl-3-phenyl-1,2,4-triazoline-5-thione [154]
(Eqn. 27).
Thermal [155] and acetic anhydride [145] catalyzed reactions of 4-alkyl/aryl-1-oxamoyl/carbamoylthiosemicarbazides were known to give 1,2,4-triazoline-5-thione derivatives with reasonable yield. These reactions were also carried
out with sulfur monochloride. Apparently, its reaction with
1-benzylidene-4-methylthiosemi-carbazone at 115C in ace-

N
R

( )n

R
Eqn. 26

tic acid gave 4-methyl-3-phenyl-1,2,4-triazoline-5-thione


[156]. The 3-fluoroalkyl-4,5-dihydro-1,2,4-triazole-5-(1H)thiones were produced by treating 4-substituted thiosemicarbazides with di- and trifluoroacetic acids [157]. (Eqn. 28).
The reaction of terephthalic acid hydrazide with
phenyl/benzyl isothiocyanate gave the corresponding
bis(thiosemicarbazide), which in the presence of NaOH was
cyclized to bis 1,2,4-triazoles [158] (Eqn. 29).
Herbst and Klingbeil [159] observed that the treatment of
1-acetyl-4-phenyl- thiosemicarbazide with lead oxide resulted in the formation of 3-methyl-4-phenyl-1,2,4-

Triazole Derivatives

Letters in Organic Chemistry, 2013, Vol. 10, No. 10

HN N

S
H 2N

N
H

NH2 + PhCOCl

S
O

S
N
H

N
H

NH2

+ CF3COOH

S
R

N
H

Ph

N
Ph

(i) Pyridine or NaOH, pH>7

701

N
H

Eqn. 27

HN N

H
N

CF3

CF3

(i)

Eqn. 28

O
O

Ar

N C S

NH

HN

NHAr
SNa

NaS

O
ii

ArHN

H2N

NH2

NH

HN

iii

NH

HN
NH

HS

HN
NHAr

ArHN
S

N N

N N

Ar

Ar

(i) NaH/DMF (ii) H+ (iii) NaOH

Eqn. 29

HN N

i
R

SH

(i) Pb(SCN)2 / N2H4.H2O

triazoline-5-thione. Thus, oxidative cyclization of substituted


aldehyde thiosemicarbazones induced by different metallic
salts afforded 1,2,4-triazoline derivatives. The reaction of
carboxylic acid chlorides with thiosemicarbazide gave
acylthiosemicarbazides, which in alkaline medium were cyclized to 2,4-dihydro-3H-1,2,4-triazole-3-thiones [160-174].
The triazoles were also prepared by treating acid halides with
lead (II) thiocyanate and hydrazine hydrate [175] (Eqn. 30).
Goswami et al. [176] reported that the oxidative cyclization
of 1-(2,4-dichlorobenzoyl)-thiosemicarbazide resulted in 3(2,4-dichlorophenyl)-1H-1,2,4-triazole-5-thiol (Eqn. 31).
The reaction of benzothiozolyl hydrazide with ammonium
thiocyanate in boiling hydrochloric acid produced 1-(2benzothiazolylcarbonyl)thiosemicarbazide and the latter
compound in the presence of sodium hydroxide underwent
intramolecular cyclization to 3-(2-benzothiazolyl)-1,2,4triazoline-5-thione [177]. (Eqn. 32).
Interestingly, the cyclization of 4-benzoyl-1-carbamoyl3-thiosemicarbazide resulted differently with substituted
1,2,4-triazole derivatives, depending on the reaction conditions. The former, when treated with 20% NaOH yielded 5mercapto-3-phenyl-1,2,4-triazole, whereas in the presence of
conc. H2SO4 gave 3-benzamido-5-hydroxy-1,2,4-triazole. On
the other hand, with hot acetic anhydride and acetic acid

SH
Eqn. 30

mixture, 3-benzamido-5-methyl-1,2,4-triazole was obtained


[178] (Eqn. 33). Similar results were reported in the cyclocondensation of substituted thiosemicarbazides with formic,
acetic and triflouroacetic acids [98,179].
The reactions involving alkyl imidates also proceeded in
a like-wise manner. Subsequently, treatment of 4phenylthiosemicarbazide with ethylphenyl imidate hydrochloride at pH > 7 led to the formation of 3,4-bis(phenyl)1,2,4-triazoline-5-thione [180] (Eqn. 34). Extension of this
approach to substituted ethyl imidate hydrochloride in the
presence of hydrazine yielded 3-alkyl/aryl-1,2,4-triazoline-5thiones [181].
Cyclization of morpholinoacetyl- or naphthylthiosemicarbazides with sodium hydroxide afforded 1,2,4-triazoles
[144,182-184]. Upon heating 4-alkylthiosemicarbazides with
arylcyanamides,
4-alkyl-3-arylamino-1,2,4-triazoline-5thiones were formed. It was observed that initially formed 1(N-arylamidino)-4-alkylthiosemicarbazide underwent in situ
cyclization by the attack of alkyl substituted nitrogen on arylamidino carbon followed by the elimination of ammonia
[185]. On the other hand, the reaction of 4-alkyl/
arylthiosemicarbazides with cyanamide in the presence of
acid produced 3-amino-4-alkyl/aryl-5-mercapto-1,2,4-triazo-

702 Letters in Organic Chemistry, 2013, Vol. 10, No. 10

O
N
H

Cl

H
N

Cl

Maddila et al.

NH2

N N
i

Cl

SH

N
H
Cl

(i) NaOH

NH NH2

N
S

HN NH

+ NH4SCN

Eqn. 31

NH2
S

O
ii

N NH

(i) HCl /

(ii) NaOH /

Ph
HN

NH

SH

N
HN N

ii

NHCOPh

Eqn. 32

N NH

H 2N

N
H

HO

OS

NHCOPh

N
HN N

iii
H3C

NHCOPh

(i) 20% NaOH (ii) conc. H2SO4 (iii) Ac2O / AcOH

S
Ph

N
H

HN N

EtO
N
H

NH2 +

Eqn. 33

NH.HCl
Ph

(i) pH>7

les and 2-alkyl/arylamino-5-amino-1,3,4-thiadiazoles. The


formation of these products was explained by the nucleophilic displacement of ammonia from the intermediate, 1amidino-4-alkyl/arylthiosemicarbazide either by the attack of
sulfur or nitrogen atom carrying alkyl/aryl substituent [186]
(Eqn. 35).
Among different methods employed for the synthesis of
triazoles, considerable attention was devoted to the cyclocondensation of 2,4-disubstituted thiosemicarbazides with
carbonyl compounds (Eqn. 36). Analogously, the reaction of
4-(2-methylallyl)-2-phenylthiosemicarbazides with ketones
afforded 3,3-dimethyl-4-(2-methylallyl)-1-phenyl-1,2,4-triazolidine-5-thiones [187].
Kurzer et al. described the formation of 3-hydroxy-1,2,4triazoline-5-thione from 1,4-diethoxycarbonylthiosemicarbazide under alkaline conditions [188] (Eqn. 37). The reaction
of phenylhydrazine with potassium thiocyanate produced
phenylthiosemicarbazide. An acylation of latter by benzoyl
chloride followed by cyclization gave 1,2,4-triazoline-5thione [189].

Ph

Ph
Eqn. 34

During the reaction of thiosemicarbazide with phenyl


isocyanide, it was observed that the substituents in the 4position of thiosemicarbazide play a major role. While the
treatment of 4-methylthiosemicarbazide with phenyl isocyanide produced only 4-methyl-1,2,4-triazoline-5-thione, the 4phenylthiosemicarbazide
gave
2-phenylamino-1,3,4thiadiazole, in addition to 4-phenyl-1,2,4-triazoline-5-thione
[190] (Eqn. 38). On the other hand, the reaction of
acylthiosemicarbazide with sodium methoxide [95] or sodium carbonate [138] resulted in 3-alkyl-5-mercapto-1,2,4triazole only. Furthermore, bis(4-aryl-3-thio-1,2,4-triazol-5yl)alkanes were prepared by the base induced cyclization of
corresponding bis(4-arylthiosemicarbazido)alkanes [191193] (Eqn. 39).
The oxidation of S-alkylthiosemicarbazones with H2O2 or
FeCl3 also gave triazoles. Thus, oxidation of Smethylthiosemicarbazone of benzaldehyde with hydrogen
peroxide yielded 3-phenyl-5-methylthio-1,2,4-triazole [194].
Similarly, aldehyde semicarbazones on heating in an alcoholic solution of ferric chloride led to the formation of 1,2,4-

Triazole Derivatives

Letters in Organic Chemistry, 2013, Vol. 10, No. 10

703

N N
HS
S

S
RHN

N
H

H
N

NH2.HCl

RHN

N
H

N
R

NH2.HCl

N N
NH
RHN

NH

(i)

Cl

NH2

NH2

Eqn. 35
R

S
1

N
H

N
R

N NH

NH2

N
R1

R
R

(i) R COR / H2SO4


O
EtO

S
N
H

(i) OH

N
H

Eqn. 36

H
N

OEt

HN N

i
S

N
H

OH

N
H

Eqn. 37

S
Ph

NH2

NH2

N
H

HN N

N N

+
PhHN

N
Ph

(i) PhNC
CONHNHCSNHR
(CH2)n

( )n

CONHNHCSNHR
(i) OH

N NH

HN N
i

Eqn. 38

Eqn. 39

O
H 2N

N
H

N N
ii

N N
NH2
O O
(i) alc. FeCl3 (ii) FeCl2
H2N

+ RCHO

HO

N
H

Eqn. 40

triazoles. The latter compounds were also obtained by the


treatment of aldehydes and azodicarbamides with ferrous
chloride [195] (Eqn. 40).
The reaction of 2-methyl-4-phenylthiosemicarbazides
with cupric perchlorate in methanol gave 1,2,4-triazolines
[196] (Eqn. 41). On the other hand, oxidation of 4benzylthiosemicarbazones with Br2/CHCl3 gave 1,2,4triazole derivatives along with 1,3,4-thiadiazoles in minor
amounts. Interestingly, a treatment with bromine in acetic
acid resulted in exclusively 3-mercapto-1,2,4-triazoles
[197].

The
reaction
of
thiosemicarbazide
with
Ncyanoguanidine in an acidic medium afforded 3,5-diamino1-thiocarbamoyl-1,2,4-triazole [198] (Eqn. 42). The treatment of hydrazide derivative of pyrrolyl ester with phenyl
isothiocyanate followed by cyclization of the resulting semicarbazide derivative produced 1,2,4-triazole [199] (Eqn. 43).
However, cyclocondensation of 1-benzoylsemicarbazide and
1-isonicotinylsemicarbazide with primary amines in the
presence of anhydrous zinc chloride gave 3,4,5-trisubstituted
1,2,4-triazoles [200] (Eqn. 44).

704 Letters in Organic Chemistry, 2013, Vol. 10, No. 10

Maddila et al.

Me

S
R

N
H

N N

Ar

i
S

H 2N

H 2N
NH2

N
H

Ar

Me
(i) Cu(ClO4)2 / MeOH

H
N

RN

Eqn. 41

H
N

H2N

NR

H
N
NH

S
N
H

NH2

S
NH2

N N
H 2N

NHR

Eqn. 42

CONHNH2
i

N
N

S
N

ii

Ph

NH

CONHNHCSNHPh

Ph
N

Ph

Ph
Eqn. 43

(i) PhCNS / EtOH (ii) KOH / EtOH


HN

NH

R
OO

N N

NH2

Eqn. 44
N N

N N

i
Ar

NHR1

R1

(i) R1 NH2 / an. ZnCl2

Ar

HN N

Ar

Ar
H2N NH2

(i) NaNH2

III. MISCELLANEOUS METHODS


The Chichibabin amidation of azines led to 3,5diaryltriazoles [201], with bisamidrazone as an intermediate
(Eqn. 45). The use of six membered ring systems as a source
of amidrazones for synthesis of triazoles was scarcely reported. The transformations of 4,6-dihydrazinopyrimidine
hydrazines formed from haloaminopyridazine [202] and
1,2,4-triazines to triazoles proceeded through amidrazone
intermediates. The reaction of 3-aminofurazan-4-amidrazone
with cyanogen bromide resulted in bicyclic 1,2,4-triazolyl1,2,5-oxadiazole [203] (Eqn. 46). The condensation of substituted amidrazones with maleic anhydride yielded 1,2,4triazoles [204] (Eqn. 47).
Triazoles were also obtained by the reaction between phydroxy phenylbiguanide and hydrazine [205] (Eqn. 48).

Ar

Ar
Eqn. 45

The cyclization of N-alkyl or aryl-N-guanidinothioureas or


guanidinodithiocarbamic acids to mercaptotriazole amines
was effected in the presence of alkali [206] (Eqn. 49).
The conversion of a non-triazole ring system into a triazole usually included the substitution of nitrogen for another
heteroatom in a five-membered ring. This process involved
nucleophilic ring opening of the heterocycle, followed by the
ring closure and loss of other atom. The reaction of 1,3,4oxadiazoles with ammonia and methylamine afforded respective triazoles in good yield [207]. (Eqn. 50) Similarly,
the recyclization of 2-amino-1,3,4-oxadiazoles on heating
with hydrazine hydrate led to the corresponding 3,4diaminotriazoles [208-210]. The conversion of 1,3,4oxadiazoles and bis-1,3,4-oxadiazoles into 1,2,4-triazole
derivatives was carried out with substituted anilines or aromatic diamines in the presence of trifluoroacetic acid. A

Triazole Derivatives

Letters in Organic Chemistry, 2013, Vol. 10, No. 10

NNH2
H2N

N NH

NH2

H2N

N
O
(i) BrCN / KHCO3

N N

i
O

NHR

N
Eqn. 46

NNH2

NH2

705

COOH

N
2

(i)

Eqn. 47
H
N

H
N

N
H

N
H

NH2

N
HO

Eqn. 48

(i) N2H4.H2O
S
R

N NH

H
N

NH

NH

HO

NH2

H
N

N N

NH2

HS

N
R

NH

NH2
Eqn. 49

(i) NaOH
N

CF3

CF3

ii

N NH

iii
F 3C

H 2N O

N N
F 3C

NH

F3C

F3C

CF3

N N
CF3

iii
F3C

MeHN NHMe

N
Me

(i) NH3 (ii) MeNH2 (iii) P2O5

CF3

Eqn. 50
R'

F15C7

R'

R'

F15C7

ii
NO
+
OO

F15C7

N
OH NHR"
R'
N

F15C7
(i) hv, 254 nm (ii) R"NH2

similar reaction has also transpired with aniline hydrochloride in pyridine [211]. The fluorinated 1,2,4-oxadiazoles in
the presence of methylamine or propylamine on irradiation
in methanol or acetonitrile led to the corresponding fluorinated 1-methyl or 1-propyl-1,2,4-triazoles [212] (Eqn. 51).
The rearrangement of 1,3,4-thiadiazoles to triazoles was
similar to that of oxa analogs, but the former were less reliable, partly because they require higher temperatures below
which by-products were favored. Thus, 2-methylamino-

N
N
R"

Eqn. 51

1,3,4-thiadiazole were rearranged to triazolinethione in the


presence of methylamine or hydrazine [213] (Eqn. 52).
Isomerization of 3,6-diaryl-1,2-dihydro-1,2,4,5-tetrazines
in the presence of conc. HCl gave 4-amino-3,5-diaryl-1,2,4triazoles [214,215]. On the other hand, employing the reducing agents such as zinc and acetic acid or sodium alkoxides,
3,5-diaryl-1,2,4-triazoles were formed [214]. In contrast to
this, 1,4-diaryl-1,4-dihydro-1,2,4,5-tetrazines under the influence of sodium ethoxide were isomerized to 1-aryl-3-

706 Letters in Organic Chemistry, 2013, Vol. 10, No. 10

Maddila et al.

N N

N NH

i
NHMe

N
Me

(i) MeNH2 / 160 C

Eqn. 52

Ar

Ar

N N

N N

i
ArHN

N N

Ar
(i) NaOEt

Eqn. 53

R1

N NHR1

N N

Ph

Cl
ii

N NHR1

R2

iii

R
NH

(i) R2CN / Ag2CO3 / Et3N


(ii) R2CH2NH2 / Et3N / MeCN
(iii) H2O2 / KOH / MeCN

H
N

R2

Eqn. 54
R

Cl

CO2Me

- +
N N C CO2Me

ii

N N
R1

CO2Me

(i) aq. NaHCO3 / THAC (ii) R CN

Eqn. 55
R2

NNHR2
1

Cl

R CN

(i) Yb(OTf)3

arylamino-1,2,4-triazole by the rupture of nitrogen-nitrogen


bond [216] (Eqn. 53).
An improved method for synthesis of 1,3,5-trisubstituted
1,2,4-triazoles was reported via 1,3-dipolar cycloaddition of
nitrile imines, generated in situ from alkyl substituted 1chloroethylidene-2-alkylhydrazines in the presence of
Ag2CO3 and Et3N [217]. In an alternative two-step approach,
Buzykin et al. [218, 219] first prepared an intermediate from
hydrazonyl chlorides and primary amines in the presence of
Et3N, which was then treated with a solution of 30% H2O2
and aqueous KOH to get 1,5-disubstituted-3-phenyl-1,2,4triazoles (Eqn. 54). The 1,3-dipolar cycloaddition between
nitrile imines and the cyano group of activated nitriles produced 1-aryl-3,5-disubstituted 1,2,4-triazoles. The nitrile
imines were generated in situ from the corresponding hydrazonoyl chlorides in aq. NaHCO3 in the presence of tetrahexylammonium chloride (THAC) [220] (Eqn. 55). 1,3,5Trisubstituted 1,2,4-triazoles were also synthesized by the
intermolecular cyclization of hydrazonyl chlorides with ni-

N N

i
1

Eqn. 56

triles in the presence of ytterbium triflate as catalyst [221]


(Eqn. 56).
Synthesis of 1,2,4-triazoles Using Common Intermediates
The synthesis of thiadiazoles, oxadiazoles and triazoles
was accomplished from a common intermediate, sulfonylacetic acid via acid hydrazide. The methyl ester of phenacylsulfonylacetic acid and benzylsulfonylacetic acid on
treatment with hydrazine hydrate in the presence of pyridine
gave the corresponding acid hydrazides. The potassium
dithiocarbazate of acid hydrazides upon refluxing in acetic
acid got cyclized to thiadiazoles. Acid catalyzed hydrolysis
of the former compounds led to oxadiazoles. On the other
hand, base induced cyclization of potassium dithiocarbazate
with hydrazine hydrate afforded triazoles [222, 223] (Eqn.
57).
Intriguingly, when phenacylsulfonylacetic acid methyl
ester was treated with hydrazine hydrate, a substituted thiadi-

Triazole Derivatives

Letters in Organic Chemistry, 2013, Vol. 10, No. 10

O O

O
S

( )n

O O

O
( )n

OMe

NHNH2

ii
R

O O

O
S

( )n

NHNHCS K +
S

R
O

( )n

iv

iii
R

R
O

SH

( )n

( )n

SH

S
N

SH

NH2

(i) N2H4.H2O / Pyridine / MeOH (ii) CS2 / KOH / EtOH


(iii)

H+

Eqn. 57

(iv) AcOH (v) N2H4.H2O


O

NOH
O

NOH
O

N
S

OMe

H
N

ii

OMe

O
NHNH2

iii

O
NOH
O

O
- +
NHNHCSK
S

R
v

iv
NOH
O

S
R

N N
N
NH2

vii
O

N N
S

SH

vii
O

NOH
O

N N

vi

O
SH
R

NOH
O
SH

vii

N
NH2

SH

N N
O

N N

SH

N N
O

SH

(i) N2H4.H2O / Pyridine / EtOH (ii) NH2OH.HCl / EtOH (iii) CS2 / KOH /
(iv) AcOH (v) N2H4.H2O (vi) H+ (vii) -CD / H2O

Eqn. 58

707

708 Letters in Organic Chemistry, 2013, Vol. 10, No. 10

Maddila et al.

azepinone was obtained instead of the expected acid hydrazide. However, the desired heterocycles were prepared by
protecting the carbonyl group as oxime derivative followed
by treatment of potassium dithiocarbazate with respective
reagents. The deprotection was effected with -cyclodextrin
in the presence of iodoxybenzoic acid [224] (Eqn. 58).

cyclized to thiadiazoles, oxadiazoles and triazoles [226, 227]


(Eqn. 60).
Furthermore, arylsulfonylethenesulfonyl acetic acid
methyl ester was also utilized for the synthesis of pyrrolyloxadiazoles, thiadiazoles and triazoles. The treatment of
former compound with tosylmethylisocyanide resulted in (3arylsulfonyl-1H-pyrrole-4-sulfonyl)acetic acid methyl ester.
The potassium dithiocarbazate of the latter compound in the
presence of acetic acid get cyclized to pyrrolylthiadiazole,
but under strong acidic conditions pyrrolyloxadiazole was
produced. On the other hand, the potassium dithiocarbazate
in the presence of hydrazine hydrate afforded pyrrolyltriazole [228, 229] (Eqn. 61).

Apart from these, phenacylsulfonylacetic acid methyl ester was also used to develop bis-heterocycles, 1,2,3selenadiazolyl/thiadiazolyl/diazaphosphonyl
oxadiazoles,
thiadiazoles and triazoles. The -ketomethylene group in the
former compound was exploited for the construction of selenadiazole, thiadiazole and diazaphosphole rings and ester
functionality for thiadiazole, oxadiazole and triazole moieties
[225] (Eqn. 59). In addition to these, novel sulfone linked bis
heterocycles pyrazolines in combination with thiadiazoles,
oxadiazoles and triazoles were prepared by appropriate functionalization of olefin and ester moieties in Estyrylsulfonylacetic acid methyl ester and aroylethenesulfonylacetic acid methyl ester. Thus, 1,3-dipolar cycloaddition of diazomethane to the latter compounds resulted in (4phenyl-4,5-dihydro-1H-pyrazole-3-sulfonyl)acetic
acid
methyl ester and (3-aroyl-4,5-dihydro-1H-pyrazole-4sulfonyl)acetic acid methyl ester. The ester group in these
compounds through potassium salt of acid hydrazides was
O

CONCLUSION
Triazoles have pronounced biological and medicinal significance, and occupy unique place in the organic chemistry
and our lives. With the enormous literature continuously
accumulating over the years, the chemistry of triazoles sustains to be a promising field in the years to come. The multipurpose synthetic applicability and biological activity of
these heterocycles will facilitate the medicinal chemists to
plan, design and implement new approaches towards the
discovery of novel drugs.
H2NOCHN N

OMe

O
OMe

ii

R
O
N

O
OMe

Se
N
R
O

iv

O
S

- +
NHNHCS K
S

vi

vii

R
O

N N

S
O

Se
N

NHNH2

Se

Se

iii

N N

S
S

SH
N

Se
N

(i) NH2NHCONH2.HCl / NaOAc / MeOH (ii) SeO2 / AcOH


(iii) N2H4.H2O / Pyridine / EtOH (iv) CS2 / KOH / EtOH / US
(v) HCl / H2O (vi) AcOH (vii) N2H4.H2O / H2O

R
O
SH

N N

S
N

Se
N

SH

NH2

Eqn. 59

Triazole Derivatives

Letters in Organic Chemistry, 2013, Vol. 10, No. 10


R

ii

OMe

O
S

OMe
N

709

N
H

R
O

NHNH2

iii

NHNHCS K

N
H

N
H

iv
R

N
O

vi
N

Ar
S
O
O

O
Ar

O
i

Ar

OMe

O O

O O

O O

O
NHNH2

iii

Ar

Ar

O O

O O

O O

NHNHCS K+
S

N N
O

N
H

ii

OMe

N
H

iv
O O

Eqn. 60

N
H

N
H

SH

NH2

N
H

N
H

(i) CH2N2 / Et2O / Et3N (ii) N2H4.H2O / MeOH (iii) CS2 / KOH / EtOH
(iv) HCl (v) AcOH (vi) N2H4.H2O

N
N

SH

N
H

SH

O
SH

Ar

O O

vi
N N
O
S

SH

Ar

N
H

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

N N
N

N
H

(i) TosMIC / NaH /Et2O / DMSO (ii) N2H4.H2O / Pyridine / EtOH


(iii) CS2 / KOH / EtOH / US (iv) HCl / H2O (v) AcOH (vi) N2H4.H2O / H2O

CONFLICT OF INTEREST

O O

SH

NH2

Eqn. 61

from the University of KwaZulu-Natal in the form of postdoctoral bursaries to SM and RP.
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ACKNOWLEDGEMENTS

[1]

Authors acknowledge the amenities received from the


School of Chemistry and Physics and the financial support

[2]

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