Chapter-I

1

INTRODUCTION

Because of the diversity in synthetic procedures, physiological and industrial

significance, heterocyclic chemistry has been and continues to be one of the most

active areas of organic chemistry. As a result numerous heterocyclic compounds such

as thiazoles, thiadiazoles, indoles, oxadiazoles, benzisoxazoles and pyrroles have been

successfully used as antibacterial, anticancer, antipyretic, schistosomicidal,

hypoglycemic, antihypertensive, antitubercular, anti-inflammatory and anti-HIV

agents. In addition, they have also been used in agriculture, plastics, polymers, dyes

and textiles. Hence heterocyclic chemistry still continues to draw the attention of

synthetic organic chemists and is of great scientific interest.

A large number of organo-sulfur compounds occur in living and non-living

objects. They belong to open chain, alicyclic, aromatic and heterocyclic types of

compounds containing sulfur atom or atoms as a part of chain/ring or both in the

structure. Isolation, identification and applications of these organo-sulfur compounds

lead to the fact that some of the compounds are useful in scientific, technical and

industrial growth. During the last three decades organo-sulfur chemistry developed at

a much faster pace than any other branches of organic chemistry. The role of organic

sulphides in rubber vulcanization, hair curling, muscle contraction, natural aromas,

vitamins, hormones, antibiotics, radio-protective agents, dye stuffs, binding materials

organic semiconducting materials1,2

and organic light emitting diodes3,4

etc. may be

cited.

Among the sulfur containing heterocyclic compounds, lot of research in the

field of 1,3,4-thiadiazoles and imidazo[2,1-b][1,3,4]thiadiazoles has been reported.

Some salient features regarding structure, chemical reactivity, spectral studies,

synthetic pathways and biological interest of 1,3,4-thiadiazole and condensed

imidazo[2,1-b][1,3,4]thiadiazole are discussed briefly as background information.

A. Structure and reactivity of 1,3,4-thiadiazoles

Of the four possible thiadiazoles (I, II, III, IV) the chemistry of 1,3,4-

thiadiazole (I) has attracted maximum attention since its discovery by Emil Fischer in

1882 on account of its compounds finding applications in agriculture, drugs, dyes and

photographic materials.

Chapter-I

2

S

NN

SN

N

SN

N

SNN

I (1,3,4-) II (1,2,3-) III (1,2,4-) IV (1,2,5-)

1,3,4-thiadiazole (I) can be looked upon as 4-azathiazole or 3,4-

diazathiophene so far as they are electronically isosteric. However, the replacement of

–CH= by electronegative –N= atom in the 5-membered thiophene ring changes the

chemical/physical behavior considerably. The structure (I) represents π-excessive ring

system as the two adjacent N atoms of the ring carry a lone pair of electrons each.

Actually 1,3,4-thiadiazole molecule does not display a true aromatic behavior as do

benzene, pyridine and thiophene. Bak et al.5 have made analysis of microwave spectra

of this molecule and calculated bond lengths, bond angles and bond orders. They

concluded that the aromatic character as measured by the π-electron delocalization

decreases in the order of 1,2,5-thiadiazole > thiophene > thiazole > 1,3,4-thiadiazole.

Zahardnik and Koutechy6

made a series of M.O. calculations by

HMO method using the Longuet Higgins model for the

sulfur atom of thiadiazole isomers and showed that π-

electron delocalisation is more in 1,2,5-isomer than in I

and thiazole. Bak et al.7

have reported the dipole

moment value of 3.25D for 1,3,4-thiadiazole and 1.61D

for thiazole. These findings suggested that

1,3,4-thiadiazole is a polar symmetric molecule exhibiting pseudoaromatic character.

The molecular geometry figure for 1,3,4-thiadiazole is given here which are

calculated on the bases of M.O. method.

Some important canonical forms of 1,3,4-thiadiazole are written below, of

which I with dienic behavior is the maximum contributing structure.

N

S

N N

S

N N

S

N

I IaIb

+_+

_

The chemistry of 1,3,4-thiadiazoles has been well documented in the form of

books8-11

and review articles.12-16

Hence only a brief account of some characteristic

reactions of the molecule is given.

N

S

N

H H

1.371Ao

1.72Ao

1.302Ao

1.077Ao

a

bcd

e

a =112.2o; b = 86.4

o; c =114.6

o;

d = 123.5o; e = 121.9

o

Chapter-I

3

1. Ring cleavage and rearrangement

1,3,4-thiadiazole is susceptible to the attack by strong nucleophiles, at the

carbon atoms which is explainable on account of the poor electron density created by

electronegative N atoms, e.g. 2-amino and 2-methylamino-1,3,4-thiadiazoles are

rearranged17,18

to the isomeric S-triazole-3-thiones on heating with methylamine at

150oC. Heating 2-aminothiadiazole with benzyl amine afforded a mixture of 2-

benzylamino-1,3,4-thiadiazole and 1-benzyl-S-triazole-3-thione.

S

NN

NHR N

NH

N

S

R

Base

Such rearrangements are reported to take place via ring opening to an

intermediate thio-carbohydrazone derivative (amidrazone), which further recyclises to

S-triazole-3-thione in the basic medium.

2. Substitution reactions

Though 1,3,4-thiadiazole is a weak base, it forms hydrochloride salts. It resists

electrophilic substitution reactions generally, e.g. bromination, nitration, sulfonation

etc. do not take place. However the presence of strong electron donating groups like

NH2 at 2-position activates the 5-position for attack. Bak et al.19

obtained 2-amino-5-

bromo-1,3,4-thiadiazole by bromination and subjected to Sandmeyers reaction to get

the corresponding 2-substituted-5-bromo-1,3,4-thiadiazoles. Halogenation and

nitration of 2-arylamino-5-methyl-1,3,4-thiadiazole occur in aryl nucleus.20

The

halogen at 2-or 5-position is reactive and undergoes a variety of nucleophilic

displacement reactions. Infact 1,3,4-thiadiazole is susceptible to nucleophilic attack at

2- or 5-position as both are activated sites. The sensitivity to nucleophilic attack is

further illustrated by direct nuclear amination 21

of certain 2-aryl-1,3,4-thiadiazoles.

e.g. the reaction of hydroxylamine in the presence of alkali leads to the formation of

2-aryl-5-amino-1,3,4-thiadiazoles in about 45-70% yields. Also a substituent like

methyl, amino, halo, carboxy present at this position undergo characteristic

reactions.22-24

Though weak base, amino group of 2-amino-1,3,4-thiadiazole and its 5-

substituted derivatives can be readily acylated and diazotized. It undergoes Mannich

reaction with variety of reactive methylene compounds. Alkylation25,26

takes place on

Chapter-I

4

ring nitrogen with alkyl halides in most of the cases suggesting the imino structure for

alkylated product.

S

NN

NH2

Ar

N

S

N

NH

R

Ar

RI

Burmistrov et a.l27

have reported an interesting reaction of 2-amino-1,3,4-

thiadiazole with sec- and tert-alcohols in presence of 80-99% sulfuric acid giving the

corresponding 2-alkylamino-1,3,4-thiadiazole in good yields.

S

NN

NH2

Ar

N

S

N

Ar NHR'

R'OH

R = H, alkyl R' = isopropyl, sec-butyl, t-butyl and t-amyl

3. Free radical reactions

Butler et al.28

have reported the following reaction regarded as Gomberg-

Bachman reaction involving homolysis to C6H5• OH

• and nitrogen.

S

NN

NHNOPh

N

S

N

Ph Ph

Benzene+ N2

4. Tautomerism

2-hydroxy-1,3,4-thiadiazole, 2-mercapto-1,3,4-thiadiazole and 2-amino

thiadiazole have been reported29

to exist in the tautomeric forms as shown below.

S

NH

N

X

N

S

N

XH

I II

where X = O, S, NH

Both hydroxyl and mercapto-1,3,4-thiadiazoles exist mostly in ketoform (I) in

free state.30

But their hydroxy/thiol function is often elicited during the chemical

reactions.

Chapter-I

5

5. Mesoionic 1,3,4-thiadiazoles

The interest in the mesoionic 1,3,4-thiadiazoles is reviewed to study the

physico-chemical aspects of varieties of mesoionic compounds containing

heteroaromatic rings. F. Kurzer14, 15

has given a concise account of mesoionic 1,3,4-

thiadiazoles in a review article. Some of the mesoionic thiadiazoles are given below.

N

S

N

S

Ph

Ph

N

S

N

SPh

Me

_

+

+

_

Mesoionic 4-phenyl-5-aryl- Mesoionic 5-phenyl-4-methyl-1,3,4-thiadiazole-2-thione 1,3,4-thiadiazole-2-thione

The mesoionic 1,3,4-thiadiazole-2-thiones are reported to display large dipole

moment values, which is confirmed by X-ray photoelectron spectroscopy. Their

characteristic UV, IR, NMR spectra are reported.31

6. Formation of Macroheterocycles

An interesting reaction of 2,5-diamino-1,3,4-thiadiazole and phthalonitrile in

ethylene glycol at 120oC, leading to the formation of the following macroheterocyclic

product (81%) has been reported. 32

NH

N N

S NN

NH

S

NN

N N

Spectral data

Vast information is cited in the literature33-38

on spectral investigations of

1,3,4-thiadiazole and its derivatives. Bak et al.19

have recorded the IR and NMR

spectra of a number of 1,3,4-thiadiazole derivatives. Reports on the mass spectra39-42

of some 2,5-disubstituted-1,3,4-thiadiazole derivatives have provided data for

fragmentation patterns in the system.

Chapter-I

6

Characteristic Features of 1,3,4-thiadiazole

By the studies on the chemical reactivities and the spectral features of 1,3,4-

thiadiazoles we can summarize their properties as below.

1. 1,3,4-thiadiazole is a typical pseudo-aromatic molecule with dipole moment value

of 3.25D.

2. It is stable to acids but affected by strong bases leading to ring cleavage.

3. It resists electrophilic substitution reactions. Facile nucleophilic attack takes place

at 2- and 5- positions. Groups like CH3, halogen, NH2, COOH present in this

position are reactive and exhibits their typical reactions.

4. 2-hydroxy-, mercapto- and amino derivatives display tautomeric behaviour.

5. It is susceptible to reduction and oxidation in acids/alkali.

6. It forms stable mesoionic betaine type compounds.

Methods of synthesis

The method commonly employed for the synthesis of 1,3,4-thiadiazole is the

cyclisation of thiosemicarbazide derivatives incorporating the basic structural unit.

Other methods involve ring closure of dithiocarbazates, acylhydrazines, bisthioureas

or interconversions of oxadiazoles in to 1,3,4-thiadiazoles have also been reported.

1. From 1,2-diacylhydrazines

Stolle and co workers43

prepared a number of 2,5-dialkyl-1,3,4-thiadiazoles

from 1,2-diacylhydrazines and P2S5. Instead of using P2S5, thioacylation of 1,2-

diacylhydrazine is effected by carboxymethyldithioate which on heating gives 2,5-

disubstituted thiadiazoles.

O

R'

NH

NH

R

O

P2S

5

S

NN

R R'+

2. From cyclisation of acylthiosemicarbazides

E. Hoggarth44

for the first time reported the synthesis of 2-amino-1,3,4-

thiadiazoles, by cyclodehydration of acylthiosemicarbazides in presence of acid

Chapter-I

7

catalyst like H2SO4, H3PO4 etc. The required acylthiosemicarbazides were obtained

by treating an acidhydrazide with an isothiocyanate. They were also prepared in situ

by heating the carboxylic acid and thiosemicarbazide in the acid medium and were

cyclised subsequently.

R OH

O

NH2

NH

S

NH2 H

2SO

4

S

NN

R NH2

+ +

Turner et al.45

have prepared 2-amino-5-aryl-1,3,4-thiadiazoles directly by

heating a mixture of the carboxylic acid and thiosemicarbazide with PPA.

Phosphorous oxychloride can also be used instead of PPA.

Fullop et al.46

used ethanolic HCl for cyclodehydration of acylthiosemi-

carbazides.

Mahajanshetti et al.47

synthesized thiadiazoles containing a long alkyl chain

by using H3PO4 as dehydrating agent.

R NH

O

NH2

ArCNSR N

H

O

NH

NHAr

SS

NN

R NHAr

H3PO

4

+

Where R = C7 to C17 alkyl

3. From cyclisation of aminoguinidines and diaminoguinidines

F. Kurzer48,49

prepared a number of 1,3,4-thiadiazoles by acid catalysed

cyclisation of acylthiosemicarbazides obtained from the reaction of aminoguinidine

salts and aroylisothiocyanates.

NH

NHR

NH

NH2

PhCONCSNH

O

NH

S

NH

NHR

NH

PhS

NN

NH

NHR

O

PhNH

3

H+

+ +

4. From carbohydrazide and acylisothiocyanate

F. Kurzer50

prepared a number of 2-hydroxy-5-acylaminothiadiazoles by

heating carbohydrazide with equimolar quantity of an acylisothiocyanate in DMF at

100˚C.

NH

NH

O

NH2

NH2

RCONCS

R NH

O

NH

S

NH

NH

O

NH2

S

NN

NH

OHR

OH+

+

Chapter-I

8

5. From hydrazine and hydrogen sulfide

K. Ruhlmall51

obtained 2,5-dialkyl-1,3,4-thiadiazoles in high yields via

thiadiazolidines prepared from the reaction of hydrazine, aliphatic aldehyde and

hydrogen sulfide. The thiadiazolidinones thus prepared were further dehydrogenated

by sulfur in boiling pyridine.

S

NH

NH

R R S

NN

R R

2RCHO + NH2NH2 + H2SS,

-H2

6. From the oxidation of thiosemicarbazones

Young and Eyre52

prepared 2-amino-5-phenyl-1,3,4-thiadiazoles by oxidative

cyclisation of corresponding aldehyde thiosemicarbazone by ferric chloride.

C6H

5CHO

NH2

NH

S

NH2

NH

NH2

S

NC6H

5

S

NN

H5C

6NH

2

+FeCl3

7. From dithiocarbazates

Various dithiocarbazates readily undergo the desired cyclisation to yield

2-substituted-5-mercapto-1,3,4-thiadiazoles53,54

R NH

O

NH

S

S

R NH

S

NH

S

S

R NH

NOH

NH

S

S

S

NN

R SH

K+

K+

K+

AcOH

AcOH

AcOH

Guha55

synthesized 2-amino-5-mercapto-1,3,4-thiadiazoles by the reaction of

thiosemicarbazide and carbondisulfide in presence of KOH, followed by heating the

intermediate potassium dithiocarbazate.

NH2

NH

S

NH2 CS

2NH

2NH

S

NH

S

S

S

NN

NH2

SHK

+

+ + H2S

130oC

Chapter-I

9

8. From bis thioureas

Bisthiourea and substituted bisthioureas when treated with 3% hydrogen

peroxide are converted to 2,5-diamino-1,3,4-thiadiazole derivatives.56

NH

NH

S

NH

NH

S

RR

H2O

2

S

NN

RHN NHR

9. From 1,3-dipolar addition of diazomethane

An interesting method that involves the addition of diazomethane to an

appropriate thiobenzoylchloride to yield 2-aryl-1,3,4-thiadiazole was reported by

Sartorelli et al. 57

S

NN

C6H

5

CH2

N+

NH

5C

6

S

Cl+

-HCl

In the present investigation we have adopted the method of Hoggarth for the

synthesis of 2-amino-5-alkyl-1,3,4-thiadiazoles using conc.H2SO4 as cyclodehy-

drating agent and POCl3 for the synthesis of various 2-amino-5-aryl-1,3,4-

thiadiazoles.

Thiadiazole derivatives of biological interest

Mohammad amir et al.58

have synthesized thiadiazole derivatives of biphenyl-

4-yloxy acetic acid and the targeted compounds were evaluated for their analgesic

and anti-inflammatory activities.

O

S

NN

R

where R = Ph, p-BrPh, p-FPh, p-ClPh

Padmavati et al.59

have prepared the following novel sulfone-linked

thiadiazoles and reported them as potent antimicrobial agents.

NH

N

S

R

S

NNSH

OO

Chapter-I

10

Pandey and coworkers60

have synthesized thiadiazolo-s-triazines and reported

the anti viral activities of these compounds based on QSAR studies using

physicochemical method.

S

N N

N

N

S

R'

R Ph

Sherman61

prepared a number of 2-amino-5-(5'-nitro-2'-furyl)-1,3,4-

thiadiazoles as antibacterials and tested them orally and by intramuscular route in the

infected animals. He found that the free amino group conferred maximum activity

compared to the 2-substituted amino derivatives. This view was further strengthened

by the observation of Skougius and Zelterberg 62

on I as an active drug against the

infection of gastrointestinal tract. Bonina et al.63

prepared a number of 2-amino-5-(2-

sulfomoylphenyl)-1,3,4-thiadiazoles II (R= H, Me, CH2CH=CH2 and C2H5) and

tested them against DNA and RNA virus. Compound II (R=Me) was active against

RNA virus while rest of them were not very promising.

S

NN

SO2NH

2

NH2

R

II

O

S

NN

NH2

O2N

I

A series of 2,5-disubstituted-1,3,4-thiadiazoles were synthesized and screened

for the antituberculosis activity against Mycobacterium tuberculosis H37Rv using the

BACTEC 460 radiometric system by Elcin et al.64

Among the tested compounds, 2-

phenylamino-5-(4-fluorophenyl)-1,3,4-thiadiazole I showed the highest inhibitory

activity. The relationship between the structures of compounds and their

antitubercular activity was investigated by Electronic-Topological Method (ETM) and

Feed Forward Neural Networks (FFNN) trained with the back-propagation algorithm.

As a result of the approach, a system of pharmacophores and anti-pharmacophores

has been listed. They have effectively separated compounds under examination into

groups of active and inactive compounds. They concluded that 1,3,4-thiadiazole

system can be applied to the screening and design of new active compounds.

S

NN

NH

FI

Chapter-I

11

Some 2-aryl-5-hydrazino-l,3,4-thiadiazoles have been synthesized and

screened for antihypertensive activity by Turner et al.65

The 2-methylphenyl and 2-

ethylphenyl derivatives I and II were the most potent members of the series.

Preliminary studies indicated that the hypotensive action of these compounds was due

to a direct relaxant effect on vascular smooth muscle.

S

NN

NH

NH2

S

NN

NH

NH2

I II

Miyahara and coworkers66

have tested twenty compounds of the Type I and

reported that I (R=NHN(NO)Me and R1=H, Me, SH or SCH2Ph) were effective

against both mouse lymphoide leukemia and rat asascites hepatoma.

RS

NN

R1Where R = NHCONHMe, NHCONHEt, NHCON (NO) Me

R' = H, Me, SH or SCH2PhI

A review article on the pharmacology of 2-amino-1,3,4-thiadiazole derivatives

in the study of cancer chemotheraphy is given by D. L. Hill.67

Y. Hasegawa et al.68

have synthesized a number of 5-(heteroarylmethylthio)-

1,3,4-thiadiazole derivatives of type I as possible antiulcer agents.

I

S

NN

SR1R2

where R1 = alkyl, NH2, (methoxy)alkylamino, Ph, pyridyl, cyclohexyl etc

and R2 = Ph, pyridyl, quinolyl, thiazolyl etc.

1,3-Bis(5-alkyl-1,3,4-thiadiazol-2-yl)ureas were tested for hypoglycemic

activity by Ermili and Cortese,69

the compounds were found to be good hypoglycemic

agents.

S

NN

RNH

NH

O

S

NNR R = propyl, isopropyl, t -butyl

Mishra et al.70

have reported CNS depressant properties of some substituted

thiadiazoles (I, R=Me, Et, propyl and X=dimethylamino, diethylamino etc.).

Mazzone and associates 71

have prepared following thiadiazoles (II, R = H, C1-3 alkyl

or Ph) and evaluated them for their antipyretic and ant-inflammatory activities.

Chapter-I

12

S

NN

R NHCOCH2X S

NN

Aryl NHR

I II

Turner and associates72

have prepared 2-aryl-5-hydrazino and 2-aryl-5-

guanidino-1,3,4-thiadiazoles having vasodilator activity and screened them for

antihypertensive activity. They observed that 2-substituted phenyl ring enhanced the

activity in both the cases, particularly 2-tolyl and 2-ethylphenyl substituted

derivatives were most potent compounds amongst the series. They have further

concluded that lowering of the blood pressure by these compounds was due to a direct

relaxant effect on vascular smooth muscles.

Stillings et al.73

have reported a set of aminoalkyl-1,3,4-thiadiazoles and

evaluated them for their anticonvulsant activity.

Grant and associates.74

have prepared the compounds of following type and

reported their hypotensive activity after administrating orally as a suspension in 2%

gelatin to conscious male rats. Some of them (R2=NHCOCH3, NHCONHC6H5)

caused significant reduction in blood pressure.

S

NN

R1 R2

Where R1 = H and C2H5

R2 = NHCOCH3, NHCOOCH3, NHCOOC2H5

Reisdorff and coworkers75

prepared a number of 2-arylmercapto-5-tri

fluoromethyl-1,3,4-thiadiazoles (I) and reported their amoebicidal, paraciticidal and

fungicidal activity. Suciu et al.76

have reported the cytostatic active derivatives of

2-amino-5-isopropyl-1,3,4-thiadiazoles (II) (R=H, COCH2Cl, COCH2I, COCHCl2,

COCCl3). Trichloroacetamido derivatives were found to be most effective compound

on radicular meristems of Triticam vulgau at 0.0012% concentration. M. Santus77

has

reported the synthesis of mercapto thiadiazoles (III) (R=Me, Ph, PhCH2, 2-naphthyl,

2- and 4-pyridyl) as potential tuberculostatic drugs.

S

NN

F3C S

ArS

NN

NHRS

NN

R SH

I II III

Chapter-I

13

Recently synthesis and antitubercular activity of the following thiadiazole

derivatives (I, II, III& IV, R = benzyl, pyridyl, cyclohexyl) was also reported from

our laboratory.78

N

S

N

RNH

NH

N N

S

N

RNH

O

N N

S

N

RNH

S

N

I II III

N

S

N

R N NH

HN

IV

B. Structure and reactivity of Imidazo[2,1-b][1,3,4]thiadiazole

Two types of bicyclic imidazo[2,1-b][1,3,4]thiadiazole ring systems are

possible.

S

NN

N S

NN

N

1

2

3 4 5

6

7 1

2

3 4 5

6

7

I II

Imidazo[2,1-b][1,3,4]thiadiazole imidazo[5,1-b][1,3,4]thiadiazole

Both the systems contain nitrogen as a bridgehead atom at 4-position. Only a

brief account of imidazo[2,1-b][1,3,4]thiadiazole ring system is discussed here. Ban

and coworkers79-83

have reported the synthesis of some imidazo[2,1-b][1,3,4]

thiadiazole derivatives in 1952 and since then many reports have been published

covering different aspects of this bicyclic system. But no systematic study covering

all aspects of physical and chemical properties of the bicyclic system is made. A brief

survey of the information on the structure and chemical reactivity of this system (I) is

given below.

Important resonance structures of (I) are given below.

S

NN

N S

NN

+

NS

NN

+

N S

NN

+

N S

NN

NI IIIII IV V

__

_

_+

These resonance structures indicate greater delocalization of π-electrons in the

imidazole ring, while the double bond of the thiadiazole ring is almost localized.

Structure I is the maximum contributing structure.

The imidazo[2,1-b][1,3,4]thiadiazole ring system is pseudoaromatic in

behavior containing imidazole moiety as electron rich center. Chlorine or bromine

Chapter-I

14

does not add to the double bond at 2,3-position. On the other hand electrophilic

substitution reactions like bromination, nitration etc. take place at 5-position.

This bicyclic system with desired substituents at 2-, 5- and 6-positions can be

built by starting with appropriate synthons. For introduction of substituents at 5-and

6-positions the synthon R1COCHR

2Br is employed. For substituents at 2-position, 5-

substituted-2-aminothiadiazole is required.

S

NN

R NH2

NH

N

SR NH

NN

S

R

NHO

S

NN

N

R+ R1COCHR2Br

.HBrR1

R2

-H2O R1

R2

The ring nitrogen of the iminoform of thiadiazole attacks carbon-carrying

bromine in the synthon.

Schenetti et al.84

have reported a detailed study on the structure and

protonation of the imidazo[2,1-b][1,3,4]thiadiazole ring system by means of 1HNMR,

X-ray analysis, ring current model performance and M.O calculations. Some of the

important conclusions of their study are summarized here.

1. Electronic delocalization as deduced from experimental measurements, both

NMR and MO calculations involve electrons moving from thiadiazole to

imidazole ring. This causes the deshielding of H-2 whereas

H-5 and H-6 appear at low field with respect to the parent

thiadiazole and imidazole system85, 86

respectively.

2. Of the three nitrogen atoms of structure I, N-7 is the most basic center. The order

of basicity is N-7 > N-3 > N-4. Therefore protonation occurs first at N-7 and then

at N-3 position.

3. π electron charge density measurements indicated that the imidazole ring is rich in

π- electron density having maximum at N-7 position and then at 5- position. This

accounts for the preferable electrophilic substitution reaction at 5-position.

4. The measurement of intramolecular bond distances and bond angles concluded

that the structure I shows a small but significant deviation from the planarity,

although the thiadiazole and imidazole rings are planar individually.

S

NN

N

H

HH

1

2

34

5

68.56 7.38

7

7.82

Chapter-I

15

This accounts for some overall reduction of aromaticity of I. Infact this system

is less aromatic than the corresponding electronically isosteric imidazo[2,1-b]

thiazole. This is further supported by the measurements of magnetic susceptibility

normal to the molar plane, which is of the order of –2.5 x 10-5

for I while it is –3.12 x

10-5

for imidazo[2,1-b]thiazole and –5.36 x 10-5

c.g.s., e.m.u for imidazo[1,2-a]

pyrimidine. These values show that the latter two systems are more aromatic than I.

The system I is bioisosteric and electronically isosteric with imidazo[2,1-b]

thiazole. However the presence of N at 3-position of I causes a lot of difference in

electronic and chemical behaviour. e.g, H-2 of unsubstituted I appears at δ 8.56 where

as that of thiazole analogue87

appears at δ 6.73. The bridgehead nitrogen in both

systems is responsible for downfield shift of 5-H compared to 6-H.

1. Substitution reactions

S. Kano88

, Pentimalli et al.89

and G. Mazzone et al.90

have reported the

following type of electrophilic substitution reactions of 2,6-diaryl and 2-alkyl-6-

arylimidazo[2,1-b][1,3,4]thiadiazole I taking place at 5-position.

S

NN

N

R R1

S

NN

N

R

Br

R1

S

NN

N

R R1

NO2

S

NN

N

R R1

NO

S

NN

N

R R1

CHO

S

N NN

R

R1

O2N

NN

Br2 /CH3COONa

HNO3+

H2SO4

HNO2

DMF/POCl3

p-nitrobenzenediazonium chloride

I

2. Nucleophilic displacement reactions

Ingendoh et al.91

prepared 2-alkylaminoimidazo[2,1-b][1,3,4]thiadiazole by

treating I with an appropriate alkylamine.

S

NN

N

Br Ph

S

NN

N

RR'N Ph+ RR'NH

I

Chapter-I

16

Kano et al.88

have prepared 5-thiocyanato derivatives of I by the reaction of

the 5-bromoderivative with potassium thiocyanate.

S

NN

N

Br

R'R

S

NN

N

R'R+ KCNS

SCN

T. L. Hough92

obtained 5-cyanoderivatives by heating the 5-bromoderivative

with cuprous cyanide in DMF. He has also reported that bromine of 2,6-di-t-butyl-5-

bromo-imidazo[2,1-b][1,3,4]thiadiazole could not be displaced by the reaction with

ammonia or alkylamine.

S

NN

N

Br

t-BuBu-t

S

NN

N

t-BuBu-t

CN

Cu2CN

2

3. Ring cleavage of imidazo[2,1-b][1,3,4]thiadiazoles

Pyl et al.93

have reported the cleavage of thiadiazole ring of I when heated

with ethanolic hydrazine hydrate.

S

NN

N

R

R'S

N

N

NH2

R

R'SH

NH2NH2

Where, R = H, CH3; R' = Me, Ph, p-bromoPhI

Similarly, Barnish et al.94

have reported the cleavage of thiadiazole ring by

heating with 5N. NaOH in the following compound.

S

NN

N

H2NO

2S t-Bu

N

N

NH2

SH t-Bu

NaOH

Hough92

subjected 2,6-di-t-butyl-5-nitroimidazo[2,1-b][1,3,4]thiadiazole to

reduction with sodium dithionite. An unexpected cleavage of the imidazole ring is

reported as shown below which is quite unusual.

S

NN

N

t-BuBu-t

NO2

S

NN

Bu-t NHCO-t-Bu

Na2SO

4

NaHCO3

Chapter-I

17

Spectral data

The spectral studies involving UV, IR, 1HNMR,

13CNMR, Mass spectral data

of imidazo[2,1-b][1,3,4]thiadiazoles have been reported by Torogova et al.95

and the

mass spectral fragmentation of some 2-arylamino-5-alkyl-1,3,4-thiadiazoles and 2-

alkyl-6-arylimidazo[2,1-b][1,3,4]thiadiazoles was studied by Khazi et al.95a

wherein

they observed the McLafferty rearrangement in many of these molecules.

N

S

N

N

C7H15 Ph

N

Ph

+

+

N

NPhS

PhC N

C7H15C N

S C N C Ph

*

*

*

-CSN-HCN

-C2HS

C7H5N2

*m/z 147

m/z 174 m/z 116

m/z 103 m/z 117

Methods of synthesis

The bicyclic imidazo[2,1-b][1,3,4]thiadiazole ring system I can be constructed

with an appropriately substituted 2-amino-1,3,4-thiadiazole moiety and building the

imidazole ring or vice versa. The first method is commonly adopted.

1. From the condensation of 2-amino-1,3,4-thiadiazoles with α-haloketones

A mixture of an appropriately substituted 2-amino-1,3,4-thiadiazole and α-

haloketones is heated in a suitable solvent medium for 6 to 10 hrs. Hydrohalides are

obtained in good yields. The respective free bases are obtained by neutralization of

salts with sodium carbonate solution. The method provides required substituent at 2-,

5- and 6-position, by starting with appropriately substituted synthons.

Chapter-I

18

S

NN

R NH2

S

NN

R2

R1

O

NH

R

H

S

NN

N

RR2

R1

OH

H

S

NN

N

R2

R1R

.HBr

S

NN

N

R2

R1R

Na2CO

3

+ R1COCHBrR2Solvent

.HBr

.HBr

-H2O

The ring nitrogen of the thiadiazole is involved in the nucleophilic

displacement of halogen of α-haloketone forming the intermediate as shown above. It

undergoes further cyclodehydration on heating in a suitable medium like ethanol,

dimethylformamide to afford imidazo[2,1-b][1,3,4]thiadiazoles in good yields. The

cyclodehydration involves intramolecular nucleophilic addition of the 2-imino group

to carbonyl function of the intermediate followed by the elimination of water.

Various reports are available in the literature which involve this method for

the synthesis of imidazo[2,1-b][1,3,4]thiadiazoles.96,97

2. From cyclisation of N-(1,3,4-thiadiazol-2-yl)formamidines

Fajgelj et al.98

have reported a method for synthesis of imidazo[2,1-b]

[1,3,4]thiadiazoles. The method involves the transformation of N-(1,3,4-thiadiazol-2-

yl)formamidines to the corresponding bicyclic system by cyclisation with phenacyl

bromides.

S

N+

N

R NN

CH3

CH3

O

Ph

Br

S

NN

R NH2

N

CH3

CH3

OMe

OMeS

NN

R NN

CH3

CH3

S

NN

N

R

OPh

+

PhCOCH2Br

-(Me)2NH.HBr

This route provides a convenient method for the synthesis of imidazo[2,1-b]

[1,3,4]thiadiazoles having a benzoyl group at 5-position without any substituent at 6-

position.

Chapter-I

19

3. From 1-amino-2-mercapto-4, 5-disubstituted imidazoles

Pyl et al.,93

reported that 2-benzylmercapto-5,6-disubstituted imidazo[2,1-

b][1,3,4]thiadiazole on heating with hydrazine hydrate is cleaved into the

corresponding 1-amino-2-mercapto-4,5-disubstituted imidazole. Further they built

thiadiazole ring on this moiety by cyclisation of 1-acylderivative in phosphorous

oxychloride as shown below.

N

N

R2

R1

NH2

SHN

N

R2

R1

NH

SH

O

CH3

S

NN

N

R2

R1CH3-H

2O

(CH3CO)2O

-CH3COOH

POCl3

For the present work we have adopted the first method for the synthesis of

various imidazo[2,1-b][1,3,4]thiadiazoles.

Imidazo[2,1-b][1,3,4]thiadiazoles of biological interest

There are number of reports in the literature on the synthesis and biological

activities of the condensed imidazo[b]thiazoles 99

appeared particularly after the

discovery of novel broad spectrum anthelmintic tetramisole.100

S

N N

N

Imidazothiadiazole ring

S

N

N

.HCl

Tetramisole

After this discovery, research activities started on bioisosteric thiadiazole ring

in place of thiazole ring of tetramisole. So, imidazo[2,1-b][1,3,4]thiadiazole nucleus

has come into picture and thereafter tremendous work on such molecules being

carried out in search of biologically active molecules. An important review article on

the chemistry of imidazo[2,1-b][1,3,4]thiadiazoles has been recently published from

our group.

Few examples from literature are given here.

A series of 2-sulfamoyl-imidazo[2,1-b][1,3,4]thiadiazole derivatives were

synthesized by Barnish and associates.94

They have reported them as carbonic

anhydrase inhibitors.

Chapter-I

20

S

NN

N

R2

R1S

NH2

OO

R1 = H, CH3, C2H5, isopropyl, n-butyl, Ph, t-butyl

R2 = H, CH3, Ph,

Many of these compounds showed the same degree of ionization as

acetazolamide and methazolamide with higher lipophilic character. They were tested

for anticonvulsant activities, compound I (R = t-butyl and R2 = H) had an

anticonvulsant ED50 of 2.6mg/kg when administered orally to mice. This compound

selectively increased cerebral blood flow in animals without producing a high level of

metabolic acidosis.

Mazzone et al.101

have reported a number of imidazo[2,1-b][1,3,4]

thiadiazoles and screened them for their anti-inflammatory, antipyretic, analgesic and

antimicrobial activities.

S

NN

N

R

Ar

ArR = H, Me, Br, SCN, CHO.

Abignentae et al.102

have reported the antipyretic, analgesic and ulcerogenic

activities associated with imidazo[2,1-b][1,3,4]thiadiazoles of the following type I.

Li-Xue Zhang and associates103

have reported the synthesis and biological activity 3-

(2-furanyl)-6-aryl-1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles (II).

S

NN

N

R2

R1

R

R = H, R1= Me, COOH, CH2COOH,

R2 = H, COOH.

S

NN

NN

OR

R = 4-NH2, 3-Cl, etc.

Gadad et al.104

have synthesized a series of 2-sulfonamido/trifluoromethyl-6-

(4'-substituted aryl/heteroaryl)imidazo[2,1-b][1,3,4]thiadiazole derivatives (I).

Recently from our laboratory105

new series of imidazo[2,1-b][1,3,4]thiadiazole

derivatives of types II and III have been reported. All these novel derivatives (I, II

and III) were evaluated for their preliminary in vitro antitubercular activity against

Mycobacterium tuberculosis H37Rv strain using radiometric BACTEC and broth

dilution assay methods and have exhibited good activity. Compounds II and III have

shown 100% activity in the preliminary screening level.

Chapter-I

21

S

NN

NO

CHO

S

NN

N

OH

S

NN

N

R1 aryl/heteroaryl

R2

R1 = SO2NH2, CF3

R2 = Br, SCN.

I II III

Khazi et al.,106

have reported the synthesis of following series of imidazo[2,1-

b][1,3,4] thiadiazole derivatives and the compounds were evaluated for their

preliminary in vitro antitubercular activity against M. tuberculosis H37Rv strain using

broth microdilution and microplate alamar blue assay methods. Further they have

reported few of the compounds emerged with moderate to good antitubercular

activity.

S

N N

N

R'

R''

R

R = cyclohexyl, thienyl, 2-furyl

R' = H, Br

R'' = CH2OH, C=NOH, CN

Gadad et al.,107

have synthesized a series of 2-sulfonamido/trifluoromethyl-6-

(4'-substituted aryl/heteroaryl)imidazo[2,1-b][1,3,4]thiadiazole derivatives and the

selected compounds were screened for their preliminary in vitro cyclooxygenase

inhibitory activity against COX-2 and COX-1 enzymes using colorimetric method.

The compounds tested showed selective inhibitory activity toward COX-2 over COX-

1. These compounds also exhibited significant anti-inflammatory activity.

S

NN

N

R1R2

R

R = H, OCH3, R1 = H, F, CH3, SO2CH3, R2 = CF3,

SO2NH2

Methylene bridged benzofuranyl imidazo[2,1-b][1,3,4]thiadiazoles and their

mannich bases of morpholine derivative have been synthesized by Jadhav et al.,108

and they have reported them as potent anti-inflammatory agents.

O

N

S

N

N

R R = Br, Cl, NO2

Chapter-I

22

Schwarz109

and Hewitt et al.110

have disclosed the synthesis and insecticidal

activity of 3-[6-(2,4-dichloro-phenyl)-2-trifluoromethylimidazo[2,1-b][1,3,4]

thiadiazol-5-yl]-N-substituted-acrylamides. Some of these compounds exhibited

100% protection after 7 days in a Phaedon cochleariae protection assay at 500 ga.i./ha

(sic).

S

NN

N

F

F

F

Cl Cl

NR1

R

O

R, R1 = alkyl, aryl

Claffey et al.111

have disclosed the synthesis of arylsubstituted-imidazo[2,1b]

[1,3,4] thiadiazoles as antagonists of the mammalian C3a receptor and their use for

the treatment of chronic inflammatory diseases. Several imidazo[2,1-

b][1,3,4]thiadiazole derivatives have been disclosed as leukotriene biosynthesis

inhibitors useful for the treatment of atherosclerotic diseases,112

tyrosine kinase

modulators,113

mineraralocorticoid receptor antagonists,114

IKK enzyme inhibitors

useful for the treatment of inflammatory diseases and cancer,115

and Btk kinase

inhibitors.116

A non-coplanar imidazothiadiazole ring system and a 6-methoxyphenyl ring

with an angle of 31.60(7)0 between their mean planes was reported by Begum et al.

117

in the X-ray crystal structure of 2-ethyl-6-(4-methoxyphenyl)imidazo[2,1-

b][1,3,4]thiadiazole-5-carbaldehyde (1). In the crystal structure, intermolecular C-H--

O hydrogen bonding linked the molecules into dimmers, while π-π staking

interactions reinforced the crystal

cohesion

S

NN

N

CHO

Et

0Me

S

NN

N

O

CHO

O

(1) (2)

Chapter-I

23

In the single-crystal X-ray crystal structure of 2-cyclohexyl-6-(2-oxo-2H-

chromen-3-yl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde (2), the imidazo

thiadiazole and coumarin ring systems have reported to be planar and inclined at an

angle of 31.60(7)0 towards each other, whilst the crystal structure was stabilized by

intermolec ular C-H--O interactions 118.

Fig. 1. Molecular structure and atom-labelling scheme for compound 2.

Novel methylene bridged benzisoxazolyl imidazo[2,1-b][1,3,4]thiadiazoles

and their bromo, nitroso and thiocyanato derivative have been synthesized by Ravi et

al.,119

These derivatives were screened for their antibacterial and antifungal activities

by agar well diffusion method.

ON

N N

SN

RBr

ON

N N

SN

R

ON

N N

SN

R

NO

SCN

R = H, Cl , NO2, Br, OMe, 3-Coumarinyl

Badiger et al.,120

synthesized 5-[6-aryl-2-(4-methoxybenzyl)imidazo[2,1-b]

[1,3,4] thiadiazol-5-yl-methylene]-pyrimidine-2,4,6-triones (2) and 5-[6-aryl-2-(4-

methoxy benzyl)imidazo[2,1-b][1,3,4] thiadiazol-5-yl]methylene-2-

thioxoimidazolidin-4-one (1) derivatives from 5-formyl derivatives of 2-(4-

methoxybenzyl)-6-aryl imidazo [2,1-b][1,3,4]thiadiazole by the knoevenagel

condensation with barbituric acid & thiohydantoin. These newly synthesized

compounds were screened for their antibacterial and antifungal activities.

Chapter-I

24

S

NN

N

R

H3CO

NH

NH

O

OO

S

NN

N

R

H3CO NH

NH

S

O

(1) (2)

R = H, Cl , NO2, Br, Me, OMe, 3-Coumarinyl

Afshan banu et al.,121

analysed the structure of 2-(4-fluoro benzyl)-6-phenyl-

imidazo-[2,1-b][1,3,4]thiadiazole-5-carbaldehyde(I) & 2-(fluoro benzyl)-6-(4-nitro

phenyl)imidazo-[2,1-b][1,3,4]thiadiazole (II) by crystallographic structure elucidation.

S

N N

N

FCHO

S

N N

N

F

NO2

(I)(II)

Afshan banu et al.,122,123

analysed the crystal structure of 3-{[5-(4-

Bromophenyl)imidazo[2,1-b]-[1,3,4]thiadiazol-2-yl]methyl}-1,2-benzoxazole by

crystallographic structure elucidation.

O

NN N

SN

R

R= Br, Cl

The detailed discussion on the synthesis, structure & physicochemical

properties, reactivity and interesting pharmacological properties of imidazo[2,1-

b][1,3,4]thiadiazole ring systems has been revealed in the review article “Chemistry

of imidazo[2,1-b][1,3,4]thiadiazoles” by Khazi et al.,124

.

Afshan banu et al.,125

analysed the crystal structure of 6-(4-Bromophenyl)-2-(4-

fluorobenzyl)imidazo[2,1-b][1,3,4]thiadiazole by crystallographic structure

elucidation.

Chapter-I

25

NN

S N

Br

F

6-(4-Bromo-phenyl)-2-(4-fluoro-benzyl)-imidazo[2,1-b][1,3,4]thiadiazole

Salimon et al 126

introduced some new 2,5-(dithioacetic acid)-1,3,4-thidiazole

and 2,5-di-[5-amino-1,3,4-thiadiazole-2-thiomethyl]-1,3,4-thiadiazole which were

screened for their in vitro antibacterial activities against the Gram-positive (S. aureus,

S. cerevisiae and C. diphtheriae) and the Gram-negative, (E.coli and P.aeruginosa)

bacteria.

Sevgi et al 127

were synthesized 5-[-4-(fluorobezoylolamino)phenyl]-2-subsituted

amino-1,3,4-thiadiazole and evaluate the cytotoxic activity.

NN

SNH-R

HN

HO

R

(Ar)

Shahar Yar et al 128

have synthesized 2-Phenylamino-5-(4-pyridyl)-1,3,4-

thiadiazole derivatives. All the newly synthesized compounds were evaluated for their

anticonvulsant activity by MES method. Among of these compounds 13(a-e) showed

maximal activity whereas compounds 13a showed good activity.

Chapter-I

26

NN

SNH

NR

13 (a) = O-CH3 13 (b) = P -CH3

13 (c) = O-OC2H5 13 (d) = P -OC2H5

13 (e) = Cl

Moise et al 129

were showed the 1,3,4-thiadiazole, that containing a

phenylalnine moiety were synthesized by intramolecular cyclization of 1,4-

thiosmicrbazides, in acid and alkaline media and the synthesized compounds was

evaluated by anti-inflammatory activity.

NN

SNH-R

NH

O

N

O

O

Alegaon & Alagawadi et al 130

synthesized new imidazo[2,1-

b][1,3,4]thiadiazoles from 3,4,5 trimethoxybenzoic acid. All compounds were

screened for their antibacterial & antifungal activities using twofold serial dilution

technique against two Gram negative Escherichia Coli (ATCC-35218) Pseudomonas

aeruginosa (ATCC-25619) & two Gram positive Staphylococcus aureus (ATCC-

25923) Enterococcus faecalis (ATCC-35550) bacterial strains.

S

N

NN

SN

H3CO

H3CO

H3CO

R

O

X

OH

O

X = O, S

A total analysis reveals that pharmacological activity of imidazothiadiazoles

were enhanced by the introduction of electron withdrawing groups at 6th

position of

imidazo[2,1-b][1,3,4]thiadiazole moiety.

Chapter-I

27

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