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Chapter-1

Department of Chemistry, S.P.University 1

Chapter-1

Introduction

The title of the thesis suggests that it is proper to review the heterocyclic

compounds based on 1,2,4-triazole.

1.1 1,2,4-triazole:

1,2,4-triazoles are cyclic hydrazidines with hydrogen atom (or substituent) on

either hydrazide nitrogen I or on amide nitrogen II. Parent 1,2,4-triazole (1H-form)

is in tautomeric equilibrium with 1,3,4-triazole (4H-form).

NH

N

N NH

NN

NH

NN

1H-1,2,4-triazole 4H-1,2,4-triazole (1H-1,3,4-triazole)

1

2

34

5

1

2

34

5

1

2

34

5

(I) (II)

The interconversion of two tautomeric forms occurs rapidly and their

separation is difficult, however, 1,2,4-triazole tautomer is preferred over 1,3,4-

triazole tautomer (less symmetrical 1H-form is favoured over symmetrical 4H-form).

(1,2,4 > 1,3,4)

Triazole is a five-membered heterocycles containing three nitrogens in the

ring and its derivatives have biological activities such as antiviral, antibacterial,

antifungal and antituberculous.

4-Amino-1,2,4-triazole is used as an intermediate for the synthesis of

antifungal agents such as fluconazole and other organic compounds. Because of its

purity and its chemical structure, 4-amino-1,2,4 triazole is used to increase the

selectivity of the desired active isomers and thus obtain excellent yields. Triazoles are

used for the synthesis of active ingredients for phytosanitary, pharmaceutical and

NH

N

N

NN

NH

1,2,4-triazole

1

2

34

5

1,3,4-triazole

1 2

3

4

5

Chapter-1


veterinary products (especially thanks to the anti-fungal properties of these

Triazoles) also triazoles are used for Photographic products.

Synthesis:

4-amino-1,2,4-triazole is synthesized from Ethyl formate and hydrazine

hydrate [1]. Here, equimolar ratio of ethyl formate and hydrazine hydrate in ethanol

refluxed for 18 hours to form crude formhydrazide. Which is further heated under

atmospheric pressure for 3 hours at temperature range of 1500 to 2000C to give

desired 4-amino-1,2,4-triazole after proper work up the reaction mass.

H

O

OEt H

O

NH

NH2

N

NN

NH2

H

O

NH

NH2

NH2NH2 . H2O

+ C2H5OH H2O+

2

2000C2H2O+

Product identification, physical and chemical Properties of 4-amino-1,2,4-triazole:

Synonyms 4-amino-4H-1,2,4-triazole

4H-1,2,4-triazol-4-amine

1-amino-1,3,4-triazole

CAS Number 584-13-4

Linear Formula C2H4N4

Molecular Weight 84.08

Toxicity Oral rat LD50: 2625 mg/kg

Physical State White crystal

Melting Point 84-860C

Stability Stable under ordinary

conditions. Hygroscopic.

Chapter-1


1.2 1,2,4-triazole: A review.

Pharmacological properties:

The 1H-1,2,4-triazole compounds are considered interesting heterocycles

since they possess important pharmacological activities such as antifungal and

antiviral activities. Examples of antifungal drugs [2,3] are fluconazole (1) [4],

itraconazole (2) [6], ravuconazole (3) [7], voriconazole (4) [8,9], ICI 153066 (5)

[10], and posaconazole (6) [11]. The action of these compounds is based on the

inhibition of biosynthesis of ergosterol, the major steroid in fungal membranes, by

blocking 14-α-demethylation, which occurs with accumulation of 14-α-methyl-

steroids and disruption of the fungal membranes [12, 13]. Fluconazole (1) causes

second bronchialarch anomalies in mice [14].

N

NN N

NN

F

F

OH

N

N

N

O

O

NN

N

NNO

O

Me

Me

Cl

Cl

(1) Fluconazole (2) Itraconazole

S

NN

N

N

Me

F

F

OH

CN

N N

NN

N

Me

F

OH

F

F

(3) Ravuconazole (4) Voriconazole

NN

N

F

OH

Cl

Cl

Cl

Cl

N

N

N

O

NN

N

NNO

O

OH

Me

Me

(5) ICI (6) Posaconazole

Chapter-1


Some 3-amino-1H-1,2,4-triazoles have been used as herbicides and

defoliants; meanwhile they were described as catalase inhibitors [15] and blockers

for certain ethanol-induced behavior effects [16]. It has been reported that only

certain enantiomers of triazoles containing oxazolidine rings (e.g., (7), 4(R), 5(R))

are active against Candida albicans infections in mice [17].

N

NN

O

N

RO

H

X

(7)

Ribose N-glycoside (8) [18-20] is a broad spectrum antiviral agent containing

the 3-aminocarbonyltriazole moiety. It is active against both RNA and DNA viruses

and is used in an aerosol for lower respiratory tract viral disease as well as in the

treatment of influenza, Lassa fever, and Hantaan virus [21]. Amidine and guanidine

derivatives (9) (R = H�HCl, Me, CN) exhibiting a broad spectrum of antiviral activity

[22] have been prepared.

NN

N

O

OHOH

OH

CONH2

NN

N

O

OHOH

OH

NHR

NH

(8) Ribavirin (9)

Some triazole derivatives are considered as angiotensin II receptor

antagonists [23-25]. These compounds, such as (10) and (11), are used to increase

the blood pressure. Furthermore, various 1,2,4-triazole derivatives have been

reported as fungicidal [26], insecticidal [27], antimicrobial [28,29], and antiastmatic

[30] agents, anticonvulsants [31], antidepressants [32], and plant growth regulators

[33]. In addition, it was reported that compounds having triazole moieties, such as

Chapter-1


vorozole (12), letrozole (13), and anastrozole (14), appeared to be very effective

aromatase inhibitors, which in turn prevented breast cancer [34,35]. It is known that

1,2,4-triazole moieties interact strongly with heme iron, and aromatic substituents on

the triazoles are very effective for interacting with the active site of aromatase [36].

Other laboratories reported the same biological activity of the triazole family [37,38].

N

NN

NH

N N

N

Bu

Pr

N

NN

SO2

Bu

CF3

NH

O

(10) (11)

N

N

N

NN

N

Cl

MeN

N

N

ClCl

NN

N

Me Me

Me

Me

CN

NC

(12) Vorozole (13) Letrozole (14) Anastrozole

The derivatives of s-triazolo[1,5-c]pyrimidines are important as potential

therapeutic agents [39]; some 3-amino-1,2,4-triazole (ATZ), 3-mercapto-1,2,4-

triazole (MTZ), and 3-nitro-1,2,4-triazole (NTZ) derivatives showed antithyroid

activity [40]. In recent work [41] thienopyrimido-1,2,4-triazoles (15) have been

synthesized as pharmacologically interesting compounds. Some acyclic 1,2,4-triazole

C-nucleosides [42] lacked antiviral properties against herpes simplex virus 1 and 2

(HSV-1 and -2) along with other viruses.

Chapter-1


N

NN

NS

R

(15)

Synthesis of 1H-1,2,4-triazole compounds:

There are mainly five methods to buildup the 1,2,4-triazole ring.

1.2.1. Methods employing hydrazine derivatives.

The reaction of hydrazine or substituted hydrazines with suitable electrophiles

is the most common method for the preparation of the triazoles. Examples where

hydrazines provide the triazole ring [43-45] are described in Scheme 1.

Scheme 1

YC6H4 NH

NH

SK

S

O

N

NH

N

S

NH2

YC6H4

NN

NH2

Me

NHNH2

O

NH

NNH

NN

NN

NH2

MeMe

N

N

N

CO2Et

N

N

N

CONHNH2

N

NHN

N

N

N

SNH2

NH2NH2.H2O

NH2NH2

NH2NH2KOH/CS2

NH2NH2

Another example of such type of reaction is the interaction of ethyl N

cyanoformimidate with the hydrazine derivative (16) in triethylamine to give the

corresponding 5-aminotriazole (17) [46,47] (Scheme 2).

Chapter-1


Scheme 2

N

NH

NHNH2N

H

EtO

CNN

NH

NH

N

N

H

N

N

NHN

NH

NH

N

N

NN

NH

NH2

....NH

(17)

(16)

Dimova et al. [48] recently synthesized a series of 4-substituted-5-aryl-1,2,4-

triazoles by cyclization of the corresponding substituted thiosemicarbazides.

Carlsen et al. [49] have prepared triazoles (19) and (20) from earlier

described unsymmetrical bis(p-alkylaminobenzylidene)hydrazines (18) [49] using a

modified procedure outlined in Scheme 3.

Scheme 3

X

COCl

CONHNH2

X

NH

NH

O

O

X

NN

Cl

Cl

N

NN

X Me

N

NH

N

X

Et3N/THF

r.t.+

PCl31,2-Cl2C6H4

1200C

MeNH2

reflux

NH32-Propanol

(18)

(19)

(20)

Chapter-1


A series of neat unsymmetrically substituted 3,5-diaryl-4-methyl-4H-1,2,4-

triazoles (19) were next thermolyzed at 330°C for 30 min to investigate the

regioselectivity as a function of the electronic conditions induced by the para-

substituents in one of the phenyl rings. These results were also compared with those

obtained upon alkylation of the corresponding unsymmetrical 3,5-diaryl-1H-1,2,4-

triazoles (20) with MeI. The general reactions are shown in Scheme 4.

Scheme 4

N

N

N

Me

X

NH

NN

X

Me3300C

30 min

NaH, DMF

r.t.

+

(19)

(20)

The rearrangement of 3,5-diaryl-4-methyl-4H-1,2,4-triazoles to the

corresponding 3,5-diaryl-1-methyl-1H-1,2,4-triazoles exhibited a regioselectivity

comparable to that for alkylation of 3,5-diaryl-1H-1,2,4-triazoles, providing further

support to the previously proposed mechanism for the rearrangement [50], which

would involve consecutive nucleophilic displacement steps (Scheme 5).

Scheme 5

N

NN

Me

Ar PhN

NN

Ar Ph

N

NN

Me

Ar PhN

NN

Me

Ar Ph

Me

N

NN

Ar Ph

N

NN

Me

Ar Ph

Me

N

NN

Ar Ph

Me

N

NN

Ar Ph

Me

_

+..

Re-orientation

Ion-pair _

+

Nair et al. [51] recently reported an extensive review on the synthesis of

1,2,4-triazoles and thiazoles from thiosemicarbazide and its derivatives.

Chapter-1


1.2.2. Methods employing nitrile imines and triazines.

1,3-Dipolar cycloaddition has been extensively used for the synthesis of

triazoles. An example of this method is the reaction of nitrile imine (22) with the

tetrazole ((21), X = NH) to give triazole (23). Reaction of (22) with the tetrazole

((21), X = O) gave (24), which on treatment with a base afforded triazolinone (25)

[52] (Scheme 6).

Scheme 6

N

NN

NXH

RN

N

N

Ar

NH2

Ph

N

NN

N

R

N

NHArPh

O NH

NN

Ar

OPh

+

H

PhH2C C C N NAr+ ..

X = O

NaOH

-RN3

(21)

(22)

(23)

(24)

(25)

An improved synthesis of 1,3,5-trisubstituted 1,2,4-triazoles (27) has been

reported [53] via 1,3-dipolar cycloaddition of nitrile imine, generated in situ from

(26) in the presence of Ag2CO3 and Et3N. In an alternative two-step approach,

Buzykin et al. [54] first prepared intermediate (28) from the reaction of (26) with a

primary amine and Et3N, which was then treated with a solution of 30% H2O2

/aqueous KOH to yield (27) (Scheme 7).

Scheme 7

Cl

H

NN

RN

N

NPh

NH

H

NN

R

R1

R1

R1

R2

R2

Conde's approach

R2CN/ Ag2CO3, Et3N, 1200C

R2CH2NH2

Et3N / MeCNH2O2 / KOH

MeCN / r.t.

Buzykin's approach

(26)(27)

(28)

Chapter-1


1.2.3. Synthesis of triazoles by transformation of other heterocyclic

systems.

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. The

process usually involved nucleophilic ring opening of the heterocycle followed by ring

closure and loss of the other atom. Little new material in this area has appeared

after it was reviewed by Polya [55] in 1984, and only a few typical examples [56, 57]

are illustrated in Scheme 8.

Scheme 8

N

NO

NH2

COOH

NH

NNH

O

COOH

N

NS

Ar

NH

NN

S

COOH

Me

O

N

Ar

O NH

N

N

Ar

HOH2C

NH2NH2

MeNH2

1600C

OH_

There are, so far, only a few published studies about the solid-phase

synthesis of substituted 1,2,4-triazoles. Katritzky reported the synthesis of tri-

substituted 1,2,4-triazoles on a solid support based on the condensation reaction

between an acyl hydrazide and substituted amidines [58]. The yields were 37-90%

and the purities depended on the substituents of the triazole core.

This procedure enables the alkylation of the 1-position, giving the

trisubstituted 1,2,4-triazoles, but suffers from the nontraceless nature of the reaction

sequence. Hence, the synthesized 1,2,4-triazoles contain the 4-hydroxyphenyl linker

of the starting Wang resin. 3,4,5-Trisubstituted 1,2,4-triazoles were also prepared on

solid supports [59].

A traceless synthesis of 3,5-disubstituted 1,2,4-triazoles has been developed

on polymeric supports [60], using immobilized mesoionic 1,3-oxazolium 5-oxides

(münchnones) as key intermediates in the 1,3-dipolar cycloaddition reaction, as

shown in Scheme 9.

Chapter-1


Scheme 9

O

OMe

CHO

O

OMe

NH

O

H

OMe

R

R

O

O

OMe

N

O

H

OMeN

N

N

O

OMe

R

NH

N N

R1R1

RR1

1.2.4. Synthesis of particular classes of compounds and critical comparison

of methods.

Triazolium salts (30) and (31) can be prepared [61] from

methylthiadiazolium salt (29) by treatment with butylamine and aniline, respectively.

The proposed mechanism of transformation of mesoionic 1,3,4-thiadiazole (29) to

mesoionic 1,2,4-triazole (30) by the action of primary amine is explained in terms of

the intermediate (a) ring opening by butylamine to give the iminium salt (b), which

is subsequently deprotonated to the intermediate (c), and by delocalization of the

unpaired electrons of the nitrogen, allowing the butyliminium group to attack the

C=S bond to give the protonated cyclic (d), followed by lose of the proton and SMe

group to give (30). Thiadiazolium salt (32) reacts similarly with phenyl hydrazine

[62] to give the triazolium salt (33), as shown in Scheme 10.

Chapter-1


Scheme 10

N

S

N

SMePh

Ph

N

S

N

SMePh

Ph

H

N NH

NHBu SMe

S

Ph

Ph

HH

N NH

SMe

S

Ph

Ph

NBu

N

NN

H

SMe

S

Bu

Ph

Ph

N

N

N

S

Bu

Ph

Ph

N

N

N

SMePh

Ph

Ph

N

S

N

Ph

Me

PhN

N

N

Ph

Me

NHPh

Ph

I+ _

BuNH2

I_

+

BuNH..

H+

a b

+

++ +

+_

..

..

C

+

d

+

_

PhNH2

+ _I I

+ _

PhNHNH2

+_I

(29)

(30)

(31) (32) (33)

(29)

1.2.5. Synthesis of 1,2,4-triazoles under microwave irradiation.

Microwave irradiation has become a widely used method to synthesize many

useful organic chemicals rapidly, with good yields and high selectivity [63-71]. A

great many relevant works suggest only a thermal nature of the microwave action,

which means that microwaves are considered to be a method to heat chemical

reagents rapidly and without any overheating. Some other works describe specific

non-thermal effects, and these effects are likely to exist. Sometimes the effects are

thought to be only specific forms of heat effects, but not always.

Kappe et al. [72-74] have used this method extensively for the synthesis of

their organic molecules; meanwhile Molteni and Ellis [75] reviewed the work carried

out since 1994 in the field of microwave-assisted synthesis of heterocyclic

Chapter-1


compounds and reactions in which a heteroatom is directly participating in the bond

forming process that gives rise to a heterocyclic core.

By applying the microwave irradiation method, several 1,2,4-triazole

derivatives were recently reported. Bentiss et al. [76] have synthesized 3,5-

disubstituted 4-amino-1,2,4-triazoles (35) from the reaction of aromatic nitriles (34)

with NH2NH2�2HCl in the presence of NH2NH2�2H2O excess in ethylene glycol under

microwave irradiation (Scheme 11).

Scheme 11

N

N N

ArAr

NH2

ArCNEthylene Glycol

NH2NH2. 2HCl

NH2NH2. H2O(34)

(35)

Condensation of acid hydrazide (36) with S-methylisothioamide hydroiodide

(37) and ammonium acetate on the surface of silica gel under microwave irradiation

afforded 1,2,4-triazoles (38) [77] (Scheme 12).

Scheme 12

NHNH2

O SMe

NH2NH

NN

+

NH4OAc, SiO2

Et3N, MWR1

R2+

_I R1 R2

(37) (38)(36)

An efficient microwave-assisted one-pot and three-component synthesis of

substituted 1,2,4-triazoles (39) has been achieved utilizing substituted primary

amines [78] (Scheme 13).

Scheme 13

N

NN

Me

R

AcNHNH2 Me2NCH(OMe)2 RNH2+ +MW

(39)

Chapter-1


A recent publication by Yeung et al. [79] described a convenient and efficient

one-step, base-catalyzed synthesis of 3,5-disubstituted 1,2,4-triazoles (42) by the

condensation of nitriles (40) and hydrazides (41) under microwave irradiation

(Scheme 14). Under the reaction conditions, a diverse range of functionality and

heterocycles are tolerated. The reactivity of the nitrile partner is relatively insensitive

to electronic effects.

Scheme 14

NH2NH

O

NH

N

NR1 CN +

R2

K2CO3, BuOH

MW, 1500C, 1-14 h

R1,R2 = aryl, hetaryl

R1

R2(40)

(41)(42)

Kidwai et al. [80] have synthesized new antifungal azoles including 1,2,4-

triazole derivatives from substituted hydrazide (43) using various solid supports

under microwave irradiation, as shown in Scheme 15.

Scheme 15

CONHNHR

NHCOPh

NH

NN

NHCOPh

R

S

NH4SCN

Basic/ Neutral

alumina, MW

(43) (44)

A simple and fast synthesis of 6-aryl-3-substituted 5H-[1,2,4]-triazolo-[4,3-

b][1,2,4]triazoles (46) in high yields has been developed by microwave assisted

Heterocyclization of N-(3-methylthio-5-substituted- 4H-1,2,4-triazol-4-

yl)benzenecarboximidates (45) [81] (Scheme 16).

Scheme 16

NN

NNH

NHMeS

R

N

NH

NN

N

R

(46)(45)

Chapter-1


1.2.6. Dipolar cycloaddition of 1-aza-2-azoniaallene salts with nitriles.

Recently, Jochims et al. [82] described a synthesis of a new class of

carbenium ions, heterocumulenic cations, namely, 1-aza-2-azoniaallene cations (48),

which was prepared from (E)-1-(2-chloroalkan-2-yl)-2- alkyldiazenes (47) and a

Lewis acid, such as SbCl5. Although the positive charge of (48) is stabilized by the

adjacent atom, the salts are short lived, making their separation impossible.

However, the heterocumulenes salts (48) were found to undergo cycloadition to the

multiple bonds of alkenes, alkynes, isocyanates, carbodiimides, and nitriles to furnish

pyrazolium ions (49), which in most cases undergo a spontaneous successive

transformation [82-86] to afford different heterocycles, including 1,2,4-triazole

derivatives (50), as shown in Scheme 17.

Scheme 17

N N N N

N

X Y

N

N

X Y

N

R1

R2

R3

Cl

Lewis acid

R1

R2

R3

+ ..

1-aza-2-azoniaallene ion

R1

R2

R3+[1,2] shift

R1

R2

R3

etc.

X = Y = nitrile, alkene, isocyanate, carbodiimide

(47)

(48)

(50) (49)

α,α'-Dichloroazoalkanes (53) were prepared by chlorination of ketazines (52)

[87-91], which were obtained by reaction of 2 eq. of ketone (51) with 1 eq. of

hydrazine [92-95]. The azo compounds (53) have been converted at low

temperature (~-60°C) to the reactive intermediates

(chloroalkyl)azohexachloroantimonates (54) in the presence of SbCl5. During the

addition of the nitrile compounds at ~-30°C the color changed from orange to

brown, indicating that (54) undergoes cycloaddition with the nitrile compounds to

give inseparable 5-alkyl-3H-1,2,4-triazolium hexachloroantimonates (55). When the

temperature is raised to ~0°C, (55) furnishes the protonated triazoles (56) by

Chapter-1


[1,2]-migration [82] of the alkyl group R2 of (55) from C-3 to N-2 associated with

elimination of the (CClR1R2) group from N-1. Hydrolysis of (56) in situ with sodium

hydrogen carbonate and ammonia solution afforded the 1,2,4-triazole derivatives

(57) (Scheme 18).

Scheme 18

N NO N N

N NN NH

N NN

NH

NN

N

R1

R2

+

R1

R2

R1

R2

2NH2NH2 Cl2

R1

R2

R1

R2

ClCl

R1

R2R1

R2

Cl

SbCl6

_

SbCl6

_

R1

R2

R3

SbCl6

_

R1

R2

+

R3

R1

R2

R3

SbCl2 CH2Cl2 , -600C

RCN

CH2Cl200C to r.t

MeCN, 00C, 3 h NaHCO3, NH3

(51) (52) (53)

(55) (56)

(54)

(57)

Since some successful attempts in the synthesis of several 1H-1,2,4-triazole

derivatives have been made, the chemistry of their nucleosides has been explored,

such as the synthesis of acyclic nucleosides [96], 1,3-dialkyl-(D-mannopentitol-1-yl)-

1H-triazole nucleosides, (59), derived from 1-(chloroalkyl)-1-aza-2- azoniaallene

salts (54) and the penta-O-benzoyl-D-mannonic acid (58) [97]. Deblocking of (59)

with NaOMe in MeOH at room temperature proceeded smoothly to give the free

nucleosides (60); their structures were confirmed by 2D-NMR spectroscopy (Scheme

19).

Chapter-1


Scheme 19

NN

N

SbCl5, CH2Cl2, less than -600C

then r.t. NAHCO3

BzO

OR

RO

R1

R2

+

CN

BzOOBz

OBz

OBz

RO

OR

OR

NaOMe / MeOHR = Bz

R = H

(54)

(58)

(59)

(60)

Recently, 1,2,4-triazole nucleosides (62) bearing an unusual thiosugar have

been synthesized [98] from cycloaddition of the 1,5-dithio-1-thiomethyl-

arabinopentulopyranose (61) with the cumulenes (54). Deblocking of (62) with

NaOMe in MeOH afforded free thionucleosides (63), as shown in Scheme 20.

Scheme 20

OAc

OAc

MeS

S

CN

S

OAc

OAc

SMe

CNS

OAc

OAcOAc

OAcSMe

CN

NN

N

S

OAc

OAcOAc

OAcSMe

NN

N

S

OAc

OHOH

OHSMe

R1 R2R1

R2

1. OsO4

2. Ac2O, Pyridine

SbCl5 , CH2Cl2 , -600C

300C , then 230C

NaOMe / MeOH

(61)

(62)(63)

Extensive work has demonstrated the feasibility of using synthetic nucleoside

and non-nucleoside analogues as anticancer and antiviral chemotherapeutic agents,

Chapter-1


and some of them are anti-HIV drugs, with 1-substituted pyrimidines being among

the most widely studied [99]. Based on these biological data, the 1-[(1,5-dialkyl-1H-

1,2,4-triazol-3 yl)methylthymines (65) [100] have been prepared from cycloaddition

of the 1-cyanothymine (64) [101] with the reactive cumulenes (54), as potential

anti-HIV agents since some acyclic 1,2,4-triazole C-nucleosides [102] showed

remarkable antiviral properties against HSV-1 and -2 along with other viruses

(Scheme 21).

Scheme 21

NH

N

O

O

Me

CN

N

N

N

NH

N

O

O

Me

R1

R2


300C, then 230C

(65)

(54)

(64)

Tumor necrosis factor alpha (TNF-α) is an important cytokine secreted by

activated monocytes/macrophages and possesses favorable biological activities,

including direct tumor toxicities [103]. Phthalimide derivative, Thalidomide® [N-(α)-

phthalimidoglutarimide] (66) was selected as a potential inhibitor of TNF-α

production [104]. A series of new 1,2,4-triazoloalkylphthalimides (68) [105] has

been synthesized from cycloaddition of the cyanoalkylphthalimides (alkylmethyl,

ethyl, propyl) (67), respectively, with the reactive cumulenes (54), as promising

inhibitors of TNF-α production (Scheme 22).

Scheme 22

NH

N

O

O O

O

N

O

O

N

O

O

N

N

N

(CH2)nCN (CH2)n

R1

R2SbCl5 , CH2Cl2 , -600C300C, then 230C

Thalidomide

n = 1,2,3n = 1,2,3

(66)

(67) (68)

(54)

Chapter-1


The use of synthetic quinolones as antibacterial [106], antiviral [107], or

anticancer agents [108], and dehydrogenase inhibitors [109] as well as indole

compounds such as the antibiotic rebecamycin as an anticancer agent [110], has

stimulated extensive research in the synthesis of this class of compounds. The

quinolone and indole moieties bearing substituted 1,2,4-triazoles (71) and (72)

have been synthesized [111] from coupling of the 1,2,4-triazolylbenzyl chloride (70)

with indole and quinolone moities, respectively, in the presence of hydride ions,

where (70) was prepared from cycloaddition of the reactive intermediates (54) with

4-cyanobenzyl chloride (69), as shown in Scheme 23. Compound (71a) exhibited a

remarkable toxicity against nine tumor cell lines.

Scheme 23

Cl

CN N

N N

Cl

NH

N

N

N

N

N

N

N

N

NH

O

F

Cl

CO2Et

N

N

N

N

O

F

Cl

CO2Et


300C , then 230C

R1R2

NaH, DMF

R1

R2

R2

R1

NaH, DMF

(69)

(70)

(72) (71a) (71)

(54)

The 1H-benzotriazole compounds possess important pharmacological

activities such as anti-inflammatory, antiviral, antineoplastic, and antidepressant

effects. With respect to the biological activity of these molecules and the structurally

related benzo-fused imidazoles (rifaximin [112] as antineoplastic and anticancer

Chapter-1


agent), attention was focused on the design of a novel type of trisubstituted 1,2,4-

triazoles [113] bearing methyl benzotriazole residues in positions 2 and 3. Thus,

cycloaddition of 1-(cyanomethyl)benzotriazole (73) with (54) afforded, after

spontaneous rearrangements, the N-1-triazolylmethylbenzotriazoles (74), where the

compound (74a) showed a remarkable potential activity against leukemia. Similarly,

the N-2 isomer [114] gave the analogue (75) (Scheme 24), while (75a) showed a

high potency against Mycobacterium tuberculosis growth inhibitor (99%).

Scheme 24

N

N

N

CN

N

N

N

N

N

N

N

N

N

N

N

N

N

N

N CN

N

N

N

N

N

N

N

N

N

N

N

N


300C , then 230C R1

R2


300C , then 230C

R1

R2

(73)

(54)

(74) (74a)

(54)

(75) (75a)

During the last decade, several piperazine derivatives were synthesized as

useful chemotherapeutic agents for various diseases, such as Crivixan® (Indinavir

sulphate) [115] and delaviridine (Rescriptor) [116], powerful inhibitors for the

protease and reverse transcriptase inhibitor of HIV enzymes, respectively. On the

basis of the exciting biological results of the piperazine derivatives, several

substituted 1,2,4-triazole derivatives carrying piperazine residue, (76) and (77)

[117], have been synthesized from cycloaddition of (54) with the 1,4-

bis(cyanomethyl)piperazine [118] and 1-cyanomethyl-4-methylpiperazine [119],

respectively (Scheme 25).

Chapter-1


Scheme 25

N NCN

NC

N

N

N

N

NN

N N

N N MeNC

N

N

N

N N Me

N N Me

N

N

N

N

NN

N N

N

N

N

R1

R2

R1

R2


300C , then 230C


300C , then 230CR1

R2

R1

R2

R1

R2

R1

R2

(54)

(54)

(76)

(77)

(78)

(79)

Compounds (76) and (77) were screened against breast, lung, and CNS

cancers, as well as their DNA affinity assay. More derivatives of 1,2,4-triazoles, such

as (78) and (79) [119], have been synthesized from the precursor (70).

1.3 Work done on 4-Amino-1,2,4-triazole: A Review

Looking after the systematic literature survey reveals that there is extensive

work was reported on 3,5-disubstituted-4-amino-1,2,4-triazole, especially on 3-

mercapto derivatives. While there is not much work or study was done on 4-amino-

1,2,4-triazole. So that, work done on 4-amino-1,2,4-triazole was broadly divided into

five sections.

1.3.1 Triazolothiadiazole from 4-amino-1,2,4-triazole.

Gakhar, H. K. and co-workers [120] prepared triazolo[3,4-b]-1,3,4-

thiadiazoles (80) in a 55-57% yield by treating 5-substituted 4-amino-1,2,4-triazole-

3-thione with dry gaseous hydrogen chloride in cold ether, followed by decantation

Chapter-1


of the ether, the replacement with absolute ethanol, and refluxing the reaction

mixture with aromatic aldehyde in the presence of sodium acetate.

Where, R = Me, Ph,

3-NO2C6H4, 3,4-(CH2O2)C6H3,

2-NH2-4,5-(CH2O2)C6H2

(80)

Ammar, Y. A. and co-workers [121] reported that reaction of

aminotriazolthiones containing naphthalene constituent with formic acid and/or ethyl

aceto acetate yielded the corresponding triazolothiadiazole derivative (81) or (82)

respectively.

SN

N

NNCH3

MeO

SN

N

NNCH3

MeO

COCH3

(81) (82)

Demirbas, N. and co-workers [122] reported that 5-alkyl-4-amino-2-[4-amino-

4H-3-oxo-1,2,4-triazol-3-yl]-2,4-dihydro-3H-1,2,4-triazol-5-thiones was led to react

with acetic acid to produce 5-alkyl-4-amino-2-[(6-methyl-1,2,4-triazolo[3,4-b]-1,3,4-

thiadiazol-3-yl)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-ones (83), while its

condensation with carbon disulphide or formic acid afforded the triazolothiadiazoles,

respectively, compounds (84) and (85).

N

NN SN

N

NN

O

NH2

RN

NN SN

N

NN

O

NH2

RSH

N

NN SN

N

NN

O

NH2

R

(83) (84) (85)

S

N N

N

N R

HCH3

Chapter-1


Holla, B. S. and co-workers [123] doing cyclization of bis(4-amino-5-thioxo-

1,2,4-triazol-3-yl)alkanes with substituted aromatic carboxylic acids, substituted

aryloxyacetic acids, and substituted anilinoacetic acids yielded the condensed

triazolothiadiazolyl alkanes (86) and (87).

SN

N

NN

Ar

N

N

N

NN

Ar

SN

N

NN

XAr

N

N

N

NN

XAr

(CH2)n (CH2)n

Where, Ar = C6H5, 2-, 3-, and 4-ClC6H4, 4-F-C6H4, 4-CH3 C6H4 ; n = 1,2 ; X = O, NH

(86) (87)

Awad, L. F. and co-workers [124] reported cyclised products 1,2,4-

triazolo[3,4-b]-1,3,4-thiadiazoles (88 a-e).

N NN

N

R S

N NN

N

CH3 S

CH2OBz

OBz

R1R2

BzO

OBz

CH2OAc

OAc

OAc

AcO

OAc

OAcR = Me, Ph

88 a, R1 = OBz, R2 = H, (88 e)

b, R1 = H, R2 = OBz,

c, R1 = OAc, R2 = H,

d, R1 = H, R2 = OAc

Holla, B. S. and co-workers [125,126] prepared Triazolothiadiazole derivatives

(89) in a better yield by the cyclization of 4-amino-4H-1,2,4-triazol-3-thiones with

arylfuroic acid.

Chapter-1


O

N

N

N

S

N

R

R1

(89)

Where, R = Me, Et, Pr, C6H5, 4-ClC6H4, 2-OH-C6H4

R1 = NO2, Cl, Br

Dong, H. S. and co-workers [127] synthesize 3-[1-(4-ethoxyphenyl)-5-methyl-

1,2,3-triazol-4-yl]-6-substituted-s-triazolo[3,4-b]-1,3,4-thiadiazoles (90) by the

condensation of triazolethiols containing substituted 1,2,3-triazole moiety with

various 5-methyl-1-substituted–1,2,3-triazol-4-carboxylic acid in the presence

of phosphorous oxychloride.

N

N

N

N

N

N

S

N

N

NN

CH3

Ar

CH3

OEt

(90)

Where, Ar = 4-CH3-C6H4, 3- and 4-ClC6H4 , 3, and 4-BrC6H4 , 2,5-Cl2C6H3 ,

4-CH3OC6H4 , 4-C2H5C6H4

Husain, M. I. and co-workers [128] reported new 1,2,4-triazolo[3,4-b]-1,3,4-

thiadiazole derivatives (91).

N

S

SS

N

N

NN

Ar

(91)

Where, Ar = C6H5, 4-OHC6H4, 3- and 4-NO2C6H4, 2- and 4-ClC6H4, 2- and 4-NH2 C6H4

Chapter-1


Qiao, R. Z. and co-workers [129] reported that reaction of quinoline-3-

carboxylic acids with 3-aroyldithiocarbazates in the presence of phosphorous

oxychloride on refluxing or under M.W. irradiation gave (4-chloroquinoline-3-yl)-

1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles (92).

N

S

NN

N

NCl

R

R1

(92)

Where, R = C6H5, 3- and 4-CH3C6H4, 3- and 4-CH3C6H4, 4-Cl C6H4

R1 = 6-Cl, 6-CH3, 6-CH3O, 8-CH3

Li, M. and co-workers [130] prepared 3-(alkyl or 3’-chlorophenyl)-6-

pipemidic-s-triazolo[3,4-b]-1,3,4-thiadiazoles (93) by the condensation of 4-

aminotriazol-3-thiones with pipemidic acid in the presence of phosphorous

oxychloride.

NN

N

N

N

S

NN

N

N

R

O

Et

H

(93)

Where, R = Me, Et, 3-Cl-C6H4

Chande, M. S. and Joshi, R. M. [131] reported synthesis of triazolo[3,4-b]-

1,3,4-thiadiazolidine-spiro[6’,4]-isoxazol-5-one (95). The key of their successful

preparation depended on reacting (94) with 4-anilino-3-substituted-1,2,4-triazol-5-

thione. Where as Chadha, V. K. [132] reported that refluxing compound 3-

substituted 4-amino-1,2,4-triazole-5-thione with oxalic acid yielded the bis-

triazolothiadiazole (96).

O N

Br

OR

ON

SN

N

NN

O

R

Ph

N

N

N

S

NS

NN

NN

Ph

Ph

R1

(94) (95) (96)

Chapter-1


Gakhar, H. K. and co-workers [133] synthesized Triazolothiadiazole (97) by

reacting isatoic anhydride with 4-amino-3-methyl-1,2,4-triazol-5-thione and the

subsequent cyclization of the intermediate (98) with phosphorous oxychloride and

phosphorous trichloride.

NN

N

S

N

N

CH3O

N

NN

SHCH3

N NH

O

COOH

H

(97) (98)

El-Barbary, A. A. and co-workers [134] reported some new 4-amino-1,2,4-

triazole derivatives (99) as potential anti-HIV and anti-HBV.

N

N

S

NN

CH N

O

O

R1

R2

(99)

Matichyk, B. C. and co-workers [135] New 3-phenyl[1,2,4]triazolo[3,4-

b][1,3,4]thiadiazole derivatives containing pharmacophores (100) have been

synthesized in good yield by the reaction of 4-amino-5-phenyl-4H-1,2,4-triazole-3-

thiol with a series of carboxylic acids in phosphorous oxychloride.

N

N

S

NN

R

(100)

Rangappa, S. and co-workers [136] synthesized two series of 4,6-

disubstituted 1,2,4-triazolo-1,3,4-thiadiazole derivatives (101 a–e) and (102 a–e).

Chapter-1


The title compounds were checked for their efficacy as antimicrobials in vitro.

Compounds 101b, 101c, 101d, 102b, 102c and 102d showed significant

inhibition against all the strains tested, when compared to standard drugs.

N

N

S

NN

R

Cl

N

N

S

NN

R

(101 a-e) (102 a-e)

Where, R = -CH3, -C2H5, -C6H5, CH3-C6H5, Cl-C6H5

Prasad, D. J. and co-workers [137] synthesized a series of substituted

triazolothiadiazoles (103 and 104) by condensing 4-amino-3-[4-methylthiobenzyl]-

4H-1,2,4-triazole-5-thiol with substituted aryl furoic acids/aromatic acids in the

presence of POCl3. The triazole was obtained by the fusion of 4-methylthiophenyl

acetic acid with thiocarbohydrazide.

S

NN

NNCH3S

OS

NN

NNCH3S

R1R2

(103) (104)

Where, R1 and R2 = various substituents

Ibrahim, D. A. [138] synthesized a new series of Bis-[1,2,4]triazolo[3,4-

b][1,3,4]thiadiazole derivatives (105) as a novel class of potential anti-tumor

agents.

N

N

N

S

NS

NN

N

N S

S

R

R

(105)

Where, R = various substituents

Chapter-1


Shukla, S. R. and co-workers [139] reported a novel series of 1,4-bis(6-

(substituted phenyl)-[1,2,4]-triazolo[3,4-b]-1,3,4-thiadiazoles (107) synthesized

from terephthalic dihydrazide (106) through multistep reaction sequence.

Terephthalic dihydrazide (106) was obtained from poly(ethylene terephthalate)

waste from reaction with hydrazine hydrate in good yield (86%). All the synthesized

compounds were screened for their antibacterial activities against various bacteria

and fungi strains. Several of these compounds showed potential antibacterial activity.

S

N

N SN

N

NN NN

ArAr

O

O

NH

NH

NH2

NH2

(106) (107)

1.3.2 Triazolothiadiazine from 4-amino-1,2,4-triazole.

Triazolo[3,4-b]-1,3,4-thiadiazine (108) were prepared by treating 4-amino-

4H-1,2,4-triazole-thiones with substituted phenacyl bromide [140-142]. Raslan, M. A.

and co-workers [143] reported 6-aryl-3-[2H-2-oxobenzo[b]pyran-3-yl]-7H-1,2,4-

triazolo[3,4-b]-1,3,4-thiadiazines (109a,b) by treatment of 4-amino-5-[2H-2-

oxobenzo[b]pyran-3-yl]-1,2,4-triazole-3-thione with 4-substituted phenacyl chloride

in absolute ethanol containing potassium carbonate.

NN

SN

N

Ar

R O

O

N

N

S

NN

Ar

(108) (109)

Where, R = H, Me, Et, Pr, Bu, CF3, Ph, PhCH2, 4-MeC6H4, a, Ar=C6H5

4-MeOCH3, 2- and 4-ClC6H4, 2-, 3- and 4-BrC6H4 b, Ar=4-CH3-C6H4

Ar = Ph, 4-MeC6H4, 2,3-Me2C6H3, 2- and 4-MeOC6H4,

2-EtC6H4, 3-CF3C6H4, 4-ClC6H4, 4-BrC6H4, 4-NO2C6H4, 3,4-Cl2C6H3

Chapter-1


The cyclization of 4-amino-5-aryl-3-cyanomethylthio-1,2,4-triazoles (110) in

the presence of conc. sulfuric acid gave 60–81% of 7H-6-amino-s-triazolo[3,4-b]-

1,3,4-thiadiazines (111) [140].

N

NN

NH2

SR

CN

NN

SN

N

NH2

R

(110) (111)

Where, R= C6H5CH2, C6H5, 4-CH3C6H4, 4-BrC6H4

Yanchenko, V. A. and Heravi, M. M. and co-workers [144,145] said that

heating (5-alkyl-4-amino-4H-1,2,4-triazol-3-ylsulfanyl)acetanilide (112) in boiling

phosphorous oxychloride resulted in an intramolecular ring closure with the

formation of 7H-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines (113). Similarly, several 7-

carbethoxy-methyl-s-triazolo[3,4-b]thiadiazines (114) [146] have been synthesized

by the reaction of appropriate ethyl β-aroyl-β-bromopropionates with 4-amino-4H-

1,2,4-triazole-3-thiones.

N

NN

NH2

S

R

NHAr

ON

N

SN

N NHAr

R

NN

SN

N

R

CO2Et

R1

(112) (113) (114)

R = various aliphatic substituent R = H, Me;

Ar = various aromatic substituent R1 = H, Cl, OMe

Shawali, A. S. and co-workers [147] reported conversion of thiohydrazonate

esters into the triazolothiadiazines (115) was affected by their treatment with acetic

acid. Triazolothiadiazines (116) were prepared in a 60–80% yield by the reaction of

hydrazones with α-bromomethylene derivatives in the presence of triethyl amine and

chloroform [148]. 7H-1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazines (117) were obtained

by condensing triazole with phenacyl bromides in ethanol [149].

Chapter-1


N

N

S

NN

R

NNH

Ar

PhN

NH

SN

N

CH3

COR

Ph

NS

N

NN

O

R

R1

R2

(115) (116) (117)

R = 2-naphthyl R = C6H5, 4-CH3C6H4, 4-ClC6H4 R = Substituted phenyl

Ar = Substituted phenyl R1 = H, OH; R2 = H, Cl

Yanchenko, V. A. and co-workers [150] reported new 6,7-dihydro-1,2,4-

triazolo[3,4-b]-1,3,4-thiadiazines (119) and (120) compounds were prepared by the

alkylation of the Schiff bases (118) using ethylchloroacetate or substituted α-chloro-

acetanilides.

N

N

N

NCH3

SH

H

O

O

NN

SN

N

H

O

OH

HCH3

NN

SN

N

H

NH

OH

HCH3

R1

R2

R1

R2

R3

R4

(118) (119) (120)

R1R2 = -OCH2O- R1 = R3 = Cl, R2 = R4 = H

R1 = Cl, R2 = H R1 = Cl, R2 = R3= H, R4 = CF3

The reaction of 4-amino-3-(D-glycero-D-gulo-hexitol-1-yl)-1,2,4-triazol-5-

thione with phenacyl bromide afforded 3-(D-gluco-,D-galacto-pentitol-1-yl)- and 3-

(D-glycero-, D-gulohexitol-1-yl)-6-phenyl-7H-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine

[151]. The 4-amino-4H-1,2,4-triazole-3-thione underwent a cyclocondensation

reaction with 2-bromoacetyl-5-nitrofuran or 2-bromoacetyl-5-nitrothiophene to give

the corresponding s-triazolo[3,4-b]-1,3,4-thiadiazines (121a) and (121b)

respectively [152,153].

XN

N

SN

N

RNO2

(121) a, X = O, R = H, alkyl, Ph, 4-OHC6H4, 4-ClC6H4, tolyl, anisyl, NO2C6H4, PhCH2

b, X = S, R = H, Me, Ph, 2-tolyl, 2-naphthyloxymethylene

Chapter-1


In the same manner, the reaction of (122) with chloroacetaldehyde or 2-

bromo-4’-substituted-acetophenone or 2-bromocyclohexanone afforded 1,2,4-

triazolo[3,4-b]-1,3,4-thiadiazines (123) and 6,7,8,9-tetrahydro-1,2,4-triazolo[4,3-b]-

4,1,2-benzothiadiazine (124) [154].

ON

N

NHN

NH2CH3

SN

N

S

O

N

NN

CH3

R

N

N

S

O

N

NN

CH3

(122) (123) (124)

Where, R = H, C6H5, 4-BrC6H4, 4-CH3C6H4, 4-ClC6H4

7H-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines (227-131) [155-158] were

obtained during the reactions of (125) and (126) with chloroacetaldehyde or ω-

bromoacetophenones, or 2-bromo-cyclohexanone.

N

N

N N

NH

N

S

NH2

ArMe

N

Ph

N

NH

N

S

NH2

N

N

S

N

N

N

NN

ArMe

RN

NN

N

N

S

N

N

N

NN

ArMe

R

N

N

S

N

N

N

NN

ArMe

N

N

S

N

Ph

NN

R

N

N

S

N

Ph

NN

(125) (126)

(127)

(128) (129)

(130) (131)

R and Ar = various substituent

Chapter-1


Demirbas, N. and co-workers [159] reported the synthesis of 5-alkyl-4-amino-

2-[(6-phenyl-7H-[1,2,4]triazolo[3,4-b]-1,3,4-thiadiazin-3-yl)-methyl]-2,4-dihydro-3H-

1,2,4-triazol-3-ones (133) were performed by the treatment of compound (132)

with α-bromoacetophenone.

N

NN

N

NNSH

NH2O

NH2

R

N S

NN

N

NN

O

NH2

R

Ph

(132) (133)

Where, R = CH3, CH3CH2, C3H7, CH2C6H5, C6H5

A series of 3-coumarinyl-s-triazolo-1,3,4-thiadiazines (134) was synthesized

by the cyclocondensation of bromoacetylcoumarins with aminotriazolthiones

[160,161].

Where, R = Me, Et, Ph, 4-NO2C6H4,

4-pyridyl;

R1 = H, Br

(134)

Farghaly, A. A. H. [162] reported in his work refluxing triazole (135) with

phenacyl bromide in ethanol produced 7H-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine

(136).

NPh

N

N N

NH2

S

H

N

N S

NPh

N N

Ph

(135) (136)

OO

NN

SN

N

R

R1

Chapter-1


Ammar, Y. A. and co-workers [163] reported the reaction of 1-(6-methoxy-2-

naphthyl)-1-(5’-amino-s-triazol-3-yl)ethane-4’-thione with ethyl chloroacetate yielded

the corresponding triazolothiadiazine derivative (137).

NNH

SNN

O

CH3

MeO

(137)

Holla, B. S. and co-workers [164] reported in his work that 2,3-dibromo-1-

aryl-3-[5-(p-nitrophenyl)furyl]-propan-1-ones were dehydro-brominated in the

presence of triethyl amine and were then condensed with methyl 3-

aroyldithiocarbazates to give 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines (138).

O

N

N

S

NN

R

ClNO2

(138)

Shawali, A. S. and co-workers [165] reported that 1,2-bis(7-arylhydrazono-

7H-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazin-3-yl)ethane derivatives (139) were

synthesized by the reaction of bis(4-amino-5-thioxo-1,2,4-triazol-3-yl)alkanes (n=2)

with two equivalents of N-aryl-2-oxopropane-hydrazonoyl chloride in ethanol in the

presence of sodium ethoxide.

N

N

S

NN

CH3

N

NHR

2

(139)

Chapter-1


4-bromo-3-arylisoxazol-5(4H)-ones (140) or bromomethylpyrazolones (141)

underwent cyclocondensation with 4-amino-4H-1,2,4-triazole-3-thiones to give 5H-s-

triazolo[3,4-b]isoxazolo[5,4-e]-1,3,4-thia-diazines (142) [166] and

pyrazolotriazolothiadiazines (143), [167] respectively.

ON R

Br

O

NN

R

CH3Br

O

O N

N

N

NN

R

HN

NN

N

SN

N

CH3

RH

R1

R1

(140) (141) (142) (143)

R = H, Cl R = H, Ph

R1 = Me, Aryl R1 = Me, Et, Pr, Ph,

2-OHC6H4, 3-NO2C6H4

Rao, M. S. and co-workers [168] reported that cyclization of (144) with

compound 4-amino-4H-1,2,4-triazole-3-thiones gave 69–93% of naphtha[2,3-e]-s-

triazolo[3,4-b]-1,3,4-thiadiazine-6,11-diones (145).

O

O

R

OHN

N

N

S

N

O

O

H R1

(144) (145)

Where, R1 = Me, Et, Pr, Ph, 4-tolyl, 3- and 4-NO2C6H4, 2- and 4-ClC6H4, C6H5CH2, 4-pyridyl

When ethanolic solutions of substituted 4-amino-4H-1,2,4-triazole-3-thione

were treated with chloranil in the presence of anhydrous sodium acetate, bis-1,2,4-

triazolo[3,4-b]-1,3,4-thiadiazino[5’,6’-b:5’,6’-e]cyclo-hexyl-1,4-dienes (146) were

obtained [143,154,155].

N

NN

N

N

N

N

S

S

N

Cl

Cl

R

R

(146)

Chapter-1


O

N

CH3

N

N

N

Ar

Me

N Ph O O

R =

Mekuskiene, G.; and Vainilavicius, P. co-workers [169] said in his work that 4-

amino-5-(4,6-diphenyl-2-pyrimidinyl)-3,4-dihydro-2H-1,2,4-triazole-3-thione is

formed from the reaction of 4,6-diphenylpyrimidinecarboxylic acid or its ethyl ester

with thiocarbonyl hydrazide. Alkylation of the product leads to S-alkyl derivaties or 6-

substituted 3-(4,6-diphenyl-2-pyrimidinyl)-7H-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine

(147, 148).

N

N

S

NH

N

N

ON

N

S

N

N

N

R1

(147) (148)

Where, R1 = Ph, CH2CO2Et

Kaplancıklı, Z. A. and co-workers [170] reported in his work that reaction of

1H-indol-3-acetic acid with thiocarbohydrazide gave the 4-amino-3-mercapto-5-[(1H-

indol-3-yl)methyl]- 4H-1,2,4-triazole. The reaction of triazole with arylaldehydes in

ethanol gave the 4-arylideneamino-3-mercapto-5-[(1H-indol-3-yl)methyl]- 4H-1,2,4-

triazoles (149). The 3-[(1H-indol-3-yl)methyl]-6-aryl-7H-1,2,4-triazolo[3,4-

b][1,3,4]thiadiazines (150) were obtained by condensing triazole with phenacyl

bromides in absolute ethanol. Their antimicrobial activities against Micrococcus luteus

(NRLL B-4375), Bacillus cereus (NRRL B-3711), Proteus vulgaris (NRRL B-123),

Salmonella typhimurium (NRRL B-4420), Staphylococcus aureus (NRRL B-767),

Escherichia coli (NRRL B-3704), Candida albicans and Candida glabrata (isolates

obtained from Osmangazi University, Faculty of Medicine) were investigated and

significant activity was obtained.

Chapter-1


N

N

S

NN

N

R

H

N

N

S

NN

N

R

H

H

(149) (150)

1.3.3 Triazolothiadiazepine from 4-amino-1,2,4-triazole.

Holla, B. S. and co-workers [171] said in his work that α-bromochalcones

were utilized, which were prepared by the dehydrobromination of RCOCHBrCHBrR1,

in a reaction with 4-amino-4H-1,2,4-triazole-3-thione in alcoholic potassium

hydroxide and produced triazolothiadiazepines (151).

S

N

N

NN

R

R1

R2

(151)

Where, R = Ph; R1 = 4-MeOC6H4NH, R2 = H, Me, Et, Pr, 4-MeC6H4OCH2, 4-ClC6H4OCH2,

2-MeC6H4OCH2, 2-ClC6H4OCH2

Ammar, Y. A. and co-workers [172] reported reaction of compound 1-(6-

methoxy-2-naphthyl)-1-(5’-amino-s-triazol-3-yl)ethane-4’-thione with acetylacetone

gave the triazolothiadiazepine derivative (152).

S

N

N

NN

CH3CH3

CH3

MeO

(152)

Chapter-1


Kalluraya, B. and co-workers [173] reported new thiadiazepine derivatives

(153) were synthesized from the reaction of heterocyclic α-bromochalcone

derivatives, i.e., 5-nitro-2-thienyl, with 4-amino-4H-1,2,4-triazole-3-thione using

sodium acetate as a catalyst.

S

S

N

N

NN

R

NO2

R1

(153)

Where, R = Me, Et, (un)substituted Ph; R1 = (un)substituted Ph

Kidwai, K. and co-workers [174] reported the reaction of aminotriazolthiones

and substituted chalcones supported by basic alumina or in a solution phase under

microwave irradiation afforded 5-substituted-1,2,4-triazolo[3,4-b]-1,3,4-

thiadiazepines (154).

S

N

N

NN

H

R

Ar1

Ar2

(154)

Ar1 = 4-CH3COC6H5, 3,4-O2H2CC6H3, Ar2 = C6H5, 4-BrC6H4

N

NN

NN

CH2

S

NN

SCH2CH3 N

CH

2

H

N

OCH2

N

CH3

OCH2

R =

, , , ,

4,6-dichloro-2-methylthio-pyrimidine-5-carbaldehyde reacted with 4-amino-

4H-1,2,4-triazole-3-thione that led to the formation of 7-substituted-9-

methylthiopyrimido-[4,5-f ]-1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazepines [175].

Dandia, A. and co-workers [176] synthesized a series of 6a,7-dihydro-6H-7(4-

aryl)-6-phenyl[1]-benzo-pyrano-1,2,4-triazolo[3,4-b]-benzothiadiazepines was

prepared by the reaction of triazoles with (E)-6-chloro-3-(4-

Chapter-1


chlorobenzylidine)flavanone and (E)-6-chloro-3-(4-methoxy-benzylidine)-flavanone in

refluxing toluene, containing piperidine as catalyst [176].

The reaction of 6-substituted-2-chloro-3-formyl-quinoline and

aminotriazolthiones afforded 1,2,4-triazolo[3,4-b]-1,3,4-quinolinothiadiazepines

(155) rather than the expected Schiff bases. Compounds (155) could also be

prepared by the reaction of 4-amino-4H-1,2,4-triazole-3-thiones with 6-substituted

quinolines [177]. The synthesis of s-triazolothiadiazepinoquinolines (156) and the

facile intramolecular rearrangement of (156) to s-triazolothiazinoquinolines (157)

involving N, N-bond scission is reported [178].

N

NN

N

SN

R

N

NN

N

SNRN

NN

N

SNR

NH

R1

R1

R1

(155) (156) (157)

R = H, Me, OMe; R = H, Me, Cl;

R1 = Me, Pr, Ph, 4-ClC6H4 R1 = Me, (un)substituted phenyl

1.3.4 Miscelanious work done on 4-amino-1,2,4-triazole.

Bernand, P. and co-workers [179] reported new investigation of their

chemical and physiochemical properties associated with their particular exocyclic

amide function of 4-Acylamino-4H-1,2,4-triazoles and related structures (158).

NN

NNH2 N

N

NNHCOCH2C6H5

C6H5CH2COCl

Pyridine

Dioxane

(158)

Glushkov, V. A. and co-workers [180] reported new path for synthesis of 5,5-

dialkyl-3-perfluroalkyl-5,6-dihydro-1,2,4-triazolo[3,4-a]isoquinolines (159).

N

SMe

Me

Me N

N N

NH2

NN

N

NH

Me

Me

NCF3

+CF3

(159)

Chapter-1


Eser, I. and co-workers [181] reported new thiorea and azomethine

derivatives of 4-amino-5-[hydroxyl(diphenyl)mehtyl]-2,4-dihydro-3H-1,2,4-triazol-3-

thione (160,161,162) as a potential antimicrobial agent.

OH N

NHN

SN

OH N

NHN

SNH

NH

RS

OH N

NS

NN

NH

R

(160) (161) (162)

Labanauskas, L. and co-workers [182] reported synthesis of 7-methyl-3-

methylthio-7,8-dihydro[1,2,4]triazolo[3,4-f][1,2,4]triazine (164) from 4-amino-5-

methylthio-4H-1,2,4-triazol-3-ylmethanol (163).

N N

N

NN

Me

SMeN

NH

N

S

NH2

OHCH2

(163) (164)

Zafer, A. K. and co-workers [183] reported synthesis and antituberculosis

activity of new 3-alkylsulfanyl-1,2,4-triazole derivatives (165).

S N

NN

NH2

CH2 S

R

S CH CH2 C

O

Where, R = H, F, Cl, Br, OH, NO2, CH3, OCH3

(165)

Chapter-1


El-Zemity, S. R. and co-workers [184] reported fungicidal and bactericidal

Properties of chiral N-[(S,S)-3,5-bis(1-methoxyethyl)-1,2,4-triazol-4-yl]arylimines

(166). Here (R)-configuration has shown better fungicidal activity against the tested

fungi than (S)-configuration. The presence of chlorine atom as in compound also

improved their fungicidal activity. Lengthen the carbon chain (n = 1 and/ or 2)

reduced the fungicidal activity.

N

NNCH3CH3

NOMeMeO

R''

R'

( )n

(166)

Where, n = 0, 1, 2; R’ = H, Cl, CH3; R’’ = H, CH3

Al-Amin, M. and Islam, M. R. [185] reported a series of bis–[4-N-amino-5-

mercapto-1,2,4-triazol-3-yl] alkanes and their Schiff bases with 2-adamanta-none

(167).

N

NN

N

NN

(CH2)nSHSH

NN

(167)

[n = 1, 2, 3 & 5]

Bekircan, O. and Bektas, H. [186] reported a series of new 1,2/1,3-bis[o-(N-

methylidenamino-3-aryl-5-phenyl-4H-1,2,4-triazole-4-yl)phenoxy]ethane/propane

derivatives (168) in good yields by treatment of 4-amino-3-aryl-5-phenyl-4H-1,2,4-

triazoles with certain bis-aldehydes. Compounds (168) were reduced with NaBH4 to

Chapter-1


afford the corresponding 1,2/1,3-bis[o-(N-methylamino-3-aryl-5-phenyl-4H-1,2,4-

triazole-4-yl)phenoxy]ethane/propane derivatives (169).

N

NN

N

NN

N H

O

Y

O

NHR

R

N

NN

N

NN

N

O

Y

O

NR

R

(168) (169)

Rzadkowska, M. [187] reported synthesis of new derivatives of 1H-3-

arylosulfonyloamino-4-amino-1,2,4-triazolin-5-one (170).

N

NN

O

NH2

H

R

SO2 NH

(170)

R = H, 2-CH3, 4-CH3, 4-NHCOCH3, 4-Cl

Hussain, S. and co-workers [188] reported new 1,2,4-triazole derivatives

(171) derived from 5-amino-2-hydroxybenzoic acid. These derivatives were

evaluated for their antibacterial and antifungal activity. The compounds showed

significant antibacterial activity against S. aureus (gram-positive) and E.coli (gram-

negative) bacteria and antifungal activity against A. niger fungi using cup plate

technique.

N

NN

NH2

NHAr

OH

NH2

(171)

Where, Ar = 4-methyl phenyl, 4-methoxy phenyl, 4-chloro phenyl, 2,6-di methyl phenyl,

4-flouro-3-chloro phenyl, 4-flouro phenyl, 4-bromo phenyl

Chapter-1


Bekircan, O. and Bektas, H. [189] synthesized Schiff and Mannich bases of

Isatin derivatives with 4-amino-4,5-Dihydro-1H-1,2,4-triazole-5-ones (172).

NN

N

NN

H

O

N O

X

R

(172)

Where, R = 2-F, 4-F; and X = H, Cl

Rzadkowska, M. and co-workers [190] synthesized a new derivatives of 1H-3-

arylsulfonylhydrazono-4,5-diamino-1,2,4-triazole derivatives (173).

N

NNH

NH2

NH2

NH NSO2

R

(173)

Where, R = H, 2-CH3, 4-CH3, 4-NHCOCH3, 4-Cl

Singh, R. J. and Singh, D. K. [191] synthesized a series of 3-alkyl-4- amino-5-

cyanomethyl-4H-1,2,4-triazoles (174) with active methylene groups. The newly

synthesized compounds were characterized by spectral and elemental analysis. Some

compounds were screened for their antibacterial activity against S. aureus, E. coli, B.

subtilis and P. aeruginosa. All the compounds carrying 1,2,4- triazole moiety showed

significant biological activity.

N

NN

NH2

CH2CNR

(174)

Chapter-1


Ts. Mavrova, A. and co-workers [192] synthesized 4-amino-5-(4,5,6,7-

tetrahydro-1-benzothien-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (175) which

possessed high cytotoxicity in vitro against thymocytes. The tested compounds

showed a general stimulation effect on B-cells’ response.

SN

NN

S

NH2R

R1

(175)

Where, R = R1 = -(CH2)CH3

Foroughifar, N. and co-workers [193] synthesized a new series of new 1,2

/1,3–bis[o-(N–methylidenamino–5–aryl–3–thiol-4H–1,2,4–triazole-4–yl)phenoxy]

alkane derivatives were prepared by condensation of 4-amino-5-(aroyl)-4H-1,2,4-

triazole-3-thiols with bis-aldehydes. Further reaction of these compounds with

dibromoalkanes afforded the new macrocycles (176). The cyclization does not

require high dilution techniques and provides the expected azathia macrocycles in

good yields, ranging from 55% to 68%.

OOX

N

NN

N

NN

ArSY

SAr

N N

(176)

Xiang, J. and co-workers [194] synthesized a new series of d-glucopyranosyl-

1,2,4-triazole-3-thione derivatives (178) were synthesized by the reaction of 1,2,4-

triazole-3-thione Schiff bases (177) with 2,3,4,6-tetra-o-acetyl-σ-d-glucopyranosyl

bromide. These analogues (177) and (178) have shown cytotoxic activity against

human MCF-7 and Bel-7402 malignant cell lines.

Chapter-1


N NH

N

S

NR R

O

AcO

OAcOAc

AcO

N N

N

S

N

(177) (178)

Where, R = H, 4-Cl, 3-OCH3-4-OH, 4-OH

1.3.5 Schiff bases and Mannich derivatives of 4-amino-1,2,4-triazole.

Kahveci, B., Bekircan, O., Serdar, M., Ikizler, A, A. [195] synthesize a series

of 3-alkyl-4-(arylmethyleneamino)-4,5-dihydro-1H-1,2,4-triazol-5-ones (179). These

compounds of type have recently described as a new class of antitumor agents.

Where, (a) R = CH3, Ar = m-Cl-C6H4

(b) R = CH3, Ar = p-Cl-C6H4 (c) R = CH3, Ar = p-Br-C6H4

(d) R = CH3, Ar = p-F-C6H4

(e) R = CH2CH3, Ar = m-Cl-C6H4 (f) R = CH2CH3, Ar = p-Cl-C6H4

(g) R = CH2CH3, Ar = m-Br-C6H4 (179) (h) R = CH2CH3, Ar = p-F-C6H4

Yuksek, H. and co-workers [196] prepared eight 3-alkyl(aryl)-4-(3,4-

dihydroxybenzylideneamino)-4,5-dihydro-1H-1,2,4-triazol-5-ones (180) synthesized

by the reactions of 3-alkyl(aryl)-4-amino-4,5-dihydro-1H-1,2,4-triazol-5-ones with

3,4-dihydroxy-benzaldehyde and their antioxidant activities are investigated. In

addition, compounds are titrated potentiometrically with tetrabutylammonium

hydroxide in non-aqueous solvents and the half-neutralization potential values and

the corresponding pKa values are determined.

Where, R= (a) CH3

(b) CH2CH3

(c) CH2C6H5 (d) CH2C6H5CH3(4-)

(e) CH2C6H5Cl(4-) (f) CH2C6H5OCH3(4-)

(g) C6H5

(180) (h)

N

NH

N

OR

N CHAr

NNH

N

O

R

OH

OH

N CH

Chapter-1


El-Sayed, R. [197] reported Sodium 1-[4-(substituted benzylidine-amino)-5-

mercapto-4H-[1,2,4]triazol-3-yl] heptadecane-1-sulfonate (181) synthesize by facile

condensation reaction of Sodium 1-[4-amino-5-mercapto-4H-(1,2,4)triazol-3-yl]

heptadecane-1-sulfonate with different substituted aromatic aldehydes. All these

products have antimicrobial activity and they can be used as surface active agents.

Where, R = CH3(CH2)15CH(SO3Na)-

Ar = (a) C6H5

(b) C6H4Cl(p) (c) C6H4OCH3(p)

(181)

Kalluraya, B. and co-workers [198] said in his work that 4-amino-3-

substituted-5-mercapto[1,2,4]-triazole condensed with substituted pyrazole

containing formyl group to give 3-(substituted)-4-(1-phenyl-3-methyl-5-chloro-4-

pyrazolidene)amino-1,2,4-triazole-5-thione (182). All these compounds were tested

for their antifungal and antibacterial activity.

Where, R = (a) Methyl (b) Ethyl

(c) Phenyl

(d) p-Cresyloxymethyl (e) p-Chlorophenoxymethyl

(182)

Holla, B. S. And co-workers [199] synthesize a series of 3-substituted-4-(5-

nitro-2-furfuralidene)amino-5-mercapto-1,2,4-triazoles (183) and their mannich

bases were prepared. These new synthesized compounds were evaluated for their

antibacterial activities. The title compounds are highly active against Gram-positive

bacteria at 5 µg/ml concentation.

(183)

N

NN

SHR

N CH Ar

N

NN

SHR

N

NN

CH3

Cl

CH

Ph

N

NN CH2

S

N

R

O

NO2

NR'

R''

CH

Chapter-1


Number of scientists [200-203] synthesized or reported azomethine of

mercapto derivatives (184) and mercapto furan derivatives of amino triazole (185).

Where, R = C6H5, 4-CH3C6H4, 4-Cl-C6H4, 3-NO2-C6H4, 2-Naphthyl

R1 = H, Me, 4-CH3O-C6H4, 4-Cl-C6H4, 4-Br-C6H4,

2-Furanyl

(184)

Where, R = C6H5, 4-CH3C6H4, 4-Cl-C6H4, 3,4(CH3O)2C6H3, 2-nitrofuryl

(185)

Ammar, Y. A., Ghorab, M. M., Sh. El-Sharief, A. M., and Mohamed S. I. [204]

reported reaction of 4-amino mercapto triazole bearing naphthalene ring with 4-

anisaldehyde in acetic acid afforded the Schiff base (186).

N

NN

S

N

H

CH3

MeO

OMe

(186)

Turan-Zitouni, G. and co-workers [205] reacted 3-[(5,6,7,8-tetrahydro-

naphthalen-2-yl)-oxymethyl]-4-amino-1,2,4-triazol-5-thione with different aromatic

aldehydes in the presence of conc. sulfuric acid using dioxane as a reaction solvent

gave the corresponding Schiff bases (187).

N

NN

SH

N

R

H

R1

ON

NN

SH

N

R

H

Chapter-1


N

NN

S

N

H

O

R (187)

Where, R = C6H5, 4-Cl-C6H4, 4-NO2-C6H4, 4-(CH3)2N-C6H3, 4-OCH3-C6H4

Similarly El-Masry, A. H. [206] reported Schiff bases of 1,2,4-triazole having

benzimidazole moiety (188) synthesized by similar procedure as in [205].

N

N

CH3

N

NN

SH

N

R

(188)

Where, R = 2-Cl-C6H4, 4-CH3-C6H4

Yadawe, M. S. and Patil, S. A. [207] prepared N,N’-1,2-ethanediylidene-bis[3-

thioxo-1,2,4-triazol-4-amines] (189) in a 60% yield by condensation of 4-amino-3-

mercapto-5-substituted-1,2,4-triazole with diacetyl.

NN

N

R

NN

N

SH

NN

R

SH

(189)

Naik, A. D. and co-workers [208] reported that condensation of 2,6-diformyl-

p-cresol and two equivalents of 4-amino-1,2,4-triazol-5-thiones gave the Schiff bases

(190).

Chapter-1


NN

N

N

NNOH

CH3

NN

S

R

HSH

R

(190)

Where, R = CH3, CH2SH, SH

Holla, B. S. and co-workers [209] as well as Wu, T. X. and co-workers [210]

reported Schiff bases of 4-amino-5-alkyl/aryl-2,4-dihydro-3H-1,2,4-triazole-3-thiones

(191) were prepared via a facile method in glacial acetic acid as a solvent and

catalyst.

O

N

N

N

SH

NR

H

R1

(191)

Zhang, Y. and co-workers [211] synthesize a Schiff base of 3-mercapto-1,2,4-

triazole bearing 1,2,3-triazole ring (192).

Where, R = H, CH3

R1 = H, CH3 R2 = CH3, C6H5

(192)

Holla, B. S. [212] described in his work that on reacting aminotriazolthione

with 2,4-dichlorophenylfurfural in the presence of a few drops of conc. sulfuric acid

NN

NN

NN

SN

H

Me

R R1

R2

Chapter-1


as a catalyst produced Schiff bases (193) in good yields. These Schiff bases were

then treated with a primary/secondary amine in the presence of formaldehyde to

produce Mannich bases.

O

N

NN

S

N

H

H

R Cl

Cl

O

N

NN

S

N

H

R Cl

Cl

R1

(193)

Kalluraya, B. and co-workers [213,214] reported reaction of 5-nitro-2-

(diacetoxymethyl)-thiophene with aminotriazolthione to yield the Schiff bases (194).

Treating the upper mentioned Schiff bases with formaldehyde and amines dialkyl

amines gave the expected Mannich bases (195).

S

N

NN

S

N

H

H

R

NO2

S

N

NN

S

N

H

R

NO2

R1

(194) (195)

Where, R = H, Alkyl, (un)substituted Ph, PhOCH2, PhCH2

R1 = R2R3NCH2 (R2=R3=Ph, R2=4-Cl-C6H4, R

3=H, R2R3NH=Morpholine, Piperidine)

Rahiman, M. A. and co-workers [215] reported Mannich reaction of 3-

substituted-4-(3-aryl-4-sydnonylidene)-amino-1,2,4-triazol-5-thiones with

formaldehyde and the appropriate amines resulted in the formation of 1-amino-

methyl-3-substituted-4-(3-aryl-4-sydnonylidene)amino-1,2,4-triazole-5-thiones.

Chapter-1


Holla, B. S. and co-workers [216,217] reported on the synthesis of 3-

substituted-4-[5-(4-methoxy-2-nitrophenyl)-2-furfurylidene]amino-1,2,4-triazol-5-

thiones (196). On the treatment of (196) with formaldehyde and various secondary

amines, the reaction furnished the formation of the Mannich bases (197).

ON

N

N

S

N

H

H

R

O2NOMe

NX

ON

N

N

S

N

H

R

O2NOMe

(196) (197)

Where, R = H, Me, Et, Pr, 2-Cl-C6H4OCH2, 4-Cl-C6H4OCH2, 2,4-Cl2-C6H3OCH2,

4-Cl-3-MeC6H4OCH2.; X = O, NMe

Liu, X. Y. and co-workers [218] reported new 4-amino-5-furyl-2-yl-4H-1,2,4-

triazole-3-thiol Derivatives (198) as a Novel Class of Endothelin (ET) Receptor

Antagonists.

ON

NN S

N

R1

R2

(198)

Where, R1 = Ph, 3-OCH3-Ph, 4-CN-Ph, C2H5OCO

R2 = 2-NO2Furyl, 3,4-(OCH3)2Ph

Serdar, M. and co-workers [219] reported some new 4-arylidenamino-3,5-

dialkyl-1,2,4-triazoles (199,200). These compounds showed good antifungal activity

only against yeast-like fungi.

N

NN

N

CH

R

CH3

CH3

N

N

NN

N

CH

R

CH3

(199) (200)

Where, R = 4-Chloro phenyl, 4-Hydroxy-3-methoxy, 4-methoxy phenyl, 2,4,6-trimethoxy

phenyl, 2-nephthoyl

Chapter-1


Reddy, V., Patil, N., Reddy, T., and Angadi, S. D. co-workers [220]

synthesized, characterized Cu(II), Co(II), Ni(II), Mn(II) and Fe(III) complexes (202)

with Schiff bases derived from 3-(4-Chlorophenoxymethyl)-4-amino-5-mercapto-

1,2,4-triazole (201). The antibacterial activities of ligand and its complexes were

screened by cup plate method.

N

NN

SH

N

O

Cl

CH

OH

N

NN

SH

N

O

Cl

CH

ON

N N

SH

N

O

Cl

CH

O

M

OH2

OH2

(201) (202)

Almajan, G. L. and co-workers [221] reported a series of Mannich bases of 4-

substituted 5-[4-(4-X-phenylsulfonyl)phenyl]-2,4-dihydro-3H-1,2,4-triazole-3-thiones

(203), X = H, Cl, Br, were synthesized and characterized on the basis of IR, NMR

and elemental analyses and potential antibacterial effects were investigated.

SX

ON

N

NN

N

S

CH2

O

O CH

Ar'

(203)

1.4 Research gaps about the derivatization of

4-amino-1,2,4-triazole:

The usage of most antimicrobial agents is limited, not only by the rapidly

developing drug resistance, but also by the unsatisfactory status of present

treatments of bacterial and fungal infections and drug side-effects [222]. Therefore,

the development of new and different antimicrobial drugs is a very important

objective and many research programs are directed the design of new antimicrobial

agents.

Chapter-1


As per the review about the derivatization of 4-amino-1,2,4-triazole, It is a

five-membered heterocycles containing three nitrogens in the ring and its derivatives

have biological activities such as antibacterial, antifungal, antimycobacterial, anti-

inflammatory, analgesic, anticancer, antihypertensive, anticonvulsant, antiviral,

antidepressant, antiasthmatic, diuretic and hypoglycemic [184, 191, 170, 134, 218,

198, 199, 195]. All these facts were driving force to develop novel 1,2,4-triazole

derivatives with wide structural variation. Thus 1,2,4-triazole derivatives plays pivotal

role in medicinal chemistry.

As part of interest in heterocycles derived from Schiff bases that have been

explored for developing pharmaceutically important molecules, 2-azetidinones

[223,224], 4-thiazolidinones [224,225], fused thiazolidinones [226,227], 2-pyrrole

and 2-pyrrolidinones [228,229], 1,3,5-oxadiazine [225] and tetrazole [230] have

played a pivotal role in medicinal chemistry. Moreover they have been studied

extensively because of their ready accessibility, diverse chemical reactivity and broad

spectrum of biological activity. The area in which derivatization of 4-amino-1,2,4-

triazole into above heterocycles has not been reported so far. Hence, it was thought

to undertaken such study.

1.5 Objectives of the present work:

In view of above review, the prime objectives of the present thesis are,

[1] Derivatization of 4-amino-1,2,4-triazole into heterocycles like 2-azetidinone, 4-

thiazolidinone, fused thiazolidinone, 2-pyrrole, 2-pyrrolidinone, 1,3,5-oxadiazine

and tetrazole.

[2] Evaluation of antibacterial and antifungal activity of above prepared

heterocycles.

1.6 The present work:

According to the above objectives, research work was carried and distributed

into following chapters of the present thesis.

Chapter-1


Chapter-2 of the thesis comprises into two sections.

Section-A comprises the details about techniques used for characterization.

Section-B deals with the formation and characterization of Schiff bases of 4-amino-

1,2,4-triazole (ATZ).

The 2-azetidinone and 4-thiazolidinone derivatives were derived from 4-

amino-1,2,4-triazole (ATZ). Their synthesis and characterization are included into

Chapter-3.

The pyrazolo[3,4-d]thiazole and thiazolo[4,5-b]quinolin-9-one derivatives

were derived from 4-thiazolidinone derivatives of 1,2,4-triazole. Their synthesis and

characterization are summarized into Chapter-4.

The 2H-pyrrole-2-one and 2-pyrrolidinone derivatives were derived from 4-

amino-1,2,4-triazole (ATZ). Further more some of these derivatives were reacted

with o-phenylene diamine to form corresponding 1H-benzimidazole derivatives.

Synthetic details and characterization of these compounds are included into Chapter-

5 of the thesis.

The 1,3,5-oxadiazine and tetrazole derivatives were derived from 4-amino-

1,2,4-triazole (ATZ). Their synthesis and characterization are summarized into

Chapter-6 of the thesis.

All the prepared compounds mentioned in chapters-3 to 6 were screened for

their antibacterial and antifungal activity. The common biospecies have been

selected. The results of such study are discussed in chapter-7.

The entire synthetic route is scanned in Chart 1.1.

Chapter-1


N

NN

NH2

N

NN

N Ar

NN

NN

Ar

O COOH

NN

NN

Ar

O COOH

NN

NN

Cl

Ar

N

NN

N Ar

Cl

N

N

NN

ArN

N

N

N

O

Ar

S

NNN

N

NN

NS

N

O

Ar

NN

N

Br

S

N

O

Ar

Ar

NBr

N

N

S

NNN

N

Ar

NS

NNN

N

O

NO2

NN

N

NH

NN

Ar

O

NN

N

NH

NN

Ar

O4-Amino-1,2,4-triazole (ATZ)

[1]

Ar-CHOEthanol/Conc.H2SO4

CH

Schiff base of ATZ [3a-h]

[2a-h]

2-pyrrole derivatives of ATZ [9a-h] 2-pyrrolidinone derivatives of ATZ [11a-h]

Maleic anhydride Succinic anhydride

O

2-azetidinone derivatives of ATZ [4a-h]

ClCH2COCl

-HCl

PhCONCS

1,3,5-oxadiazine derivatives of ATZ [13a-h]Ph

C

PCl5

NaN3

Tetrazole derivatives of ATZ [15a-h]

4-thiazolidinone derivatives of ATZ [5a-h]

4-Bromo benzaldehyde

5-arylidine derivatives of [5a-h] [6a-h]

4-hydrazino pyridine

Pyrazolo[3,4-d]thiazole derivatives of ATZ [7a-h]

4-nitro anthranilic acid

Thiazolo[4,5-b]quinolin-9-one derivatives of ATZ [8a-h]

Chart 1.1: Synthetic route

HSCH2COOH-H2O

-phenylene diamine

1H-benzimidazole derivatives of [9a-d] [10a-d]

Chlorinated schiff base of ATZ [14a-h]

1H-benzimidazole derivatives of [11a-d] [12a-d]

Where, Ar = (a) C6H5

(b) 4-OH-C6H4

(c) 2-OH-C6H4

(d) 4-OCH3-C6H4

(e) 4-OH-3-OCH3-C6H3

(f) 4-Cl-C6H4

(g) 2-NO2-C6H4

(h) 5-Br-2-OH-C6H3

O -phenylene diamineO

Chapter-1


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