1

Chapter 1

11 Introduction

Heterocyclic derivatives have long been biologically important in the medicinal

field particularly five and six-membered heterocyclic compounds This research is

particularly focused upon pyrrole pyridine and imidazolidine ring derivatives 124-

Triazole and 134-oxadiazole rings have been attracting wide attention due to their

diverse pharmacological properties such as antimicrobial anti-inflammatory

analgesic and antitumor activities

Heterocyclic derivatives containing the commonly known cyclic N-nucleosides

as well as acyclic analogues have strong biological effects [1-3] and the less

commonly used O S and C-nucleosides are known to have antiproliferating activity

and can be used for antiviral anticancer and anti-AIDS therapies [4]

Pyrrole derivatives and their biological importance

Pyrrole and its derivatives feature widely in natural products drugs polymers

and dyes As a result many efficient synthetic procedures for their preparation have

been developed The synthetic methodology for the preparation of pyrrole and its

derivatives can be possible to form a number of bonds on the pyrrole ring [5] 24-

Dimethyl-5-carbethoxypyrrole (Fig 1) was selected as a starting compound The

pyrrole containing an ester group at the 2-position (Fig 2) is an important anti-

inflammatory drug [6]

2

NH

CH3 CH3

H3CH2CO

O

OCH2CH3O

N

CH3 OCH2CH3

O

CH3

Figure 1 Figure 2

12-Diaryl-substituted pyrrole and pyrazole derivatives have been shown to

possess interesting antiviral and anti-inflammatory activities [78] In recent years

polysubstituted-pyrrole derivatives have been shown to have interesting biological

properties 24-Disubstituted brominated pyrroles which are brominated at positions

3 and 5 along with 234-trisubstituted pyrroles have demonstrated potent in vitro

cytotoxic activity against a variety of marine and human tumor models [9-12]

Atorvastatin (Lipitor R) (Fig 3) is a clinically used hypolipidemic agent containing a

pyrrole ring

N

O

NH

CH3

CH3F

OH

OH

OHO

Figure 3

Justin et al [13] studied the lipid-lowering effects of the pyrrole derivative

ethyl 2-phenacyl-3-aryl-1H-pyrrole-4-carboxylate in rodents (Fig 4) Pyrrole and

fused heterocyclic pyrrole derivatives have received considerable attention owing to

their synthetic and effective biological importance [14 15] in particular those fused

with triazoles to their thermodynamically more stable isomers which have been

discussed in di- and tri-heterocyclics [16-18]

3

NH

O

ClCl

O

H3CH2CO

Figure 4

Pyrrole and related benzo condensed pyrrole derivatives also have significant

biological activities [1920] 1-Hydroxyethoxymethylpyrrole derivatives were reported

to be inactive against HIV-1 HSV-1 and HSV-2 but they showed considerable

promise as cytotoxic and antiviral agents [21] Furthermore 1-methyl-5-[(4-

methylphenyl) carbonyl]-1H-pyrrol-2-ylacetic acid and related compounds (Fig5)

were prepared [22 23] for biological studies on anti-inflammatory and analgesic

activities

N

O

COOH

CH3

CH3

Figure 5

Studies on oligopeptides containing pyrrole rings (Fig6) have reported antiviral

antitumour and cytostatic activities against both human and marine tumor cell lines

Oligopeptides (Fig 7) have also been reported to have potential antibiotic activities in

human and marine cell lines [24]

NNH

Cl

O

CH3

NCH3

NH

O

NH

NH2

Figure 6

4

N

CH3

OHC

CH3O

NH

N

O

NHN

NH

NH2

NH

OCH3

CH3

Figure 7

The heterocyclic molecules containing aromatic compounds are a famous class

of antitumor agents [25-27] They bind to DNA by interactions between the base pairs

of the double helix The synthesis and antitumor activities of distamycin derivatives

have been reported [28]

Since the naturally occurring pyrrole polyamide netropsin was reported in the

literature as having antibiotic activities [29-31] pyrrole polyamide (Fig 8) analogues

have been synthesized and their highly sequence-specific binding to DNA has

triggered the design of novel functional pyrrole polyamides [32] and the search for

new biological functions including anticancer activities [33] Lipid derivatives of

pyrrole polyamides were synthesized and screened for cytotoxicity and anti-HIV

activities Although no anti-HIV activity was found their cytotoxicity against cancer

cells was significantly enhanced by introducing a lipophilic group into the pyrrole

polyamide which also affected their biological activities against the monoamine

oxidize inhibitor [34] and bacterial [35] depressive [36] hypertensive [37] pyretic

and inflammatory diseases [38]

NH

HN NH

OO

NH2

NH

Figure 8

5

Oxadiazole derivatives and their biological importance

134-Oxadiazole derivatives have been produced and constitute an important

family of heterocyclic compounds since many of them display remarkable biological

activities such as antibacterial [39 40] antifungal [41] analgesic anti-inflammatory

[42 43] and hypoglycaemic [44] activities

The 134-oxadiazole derivatives have also shown leprostatic and

tuberculostatic properties analgesic antipyretic antiphlogistic bactericidal

insecticidal fungicidal and several other biological activities [45 46]

Oxadiazole derivatives which belong to an important group of heterocyclic

compounds have been the subject of extensive study over recent years Numerous

reports have highlighted their uses in chemistry [47 48] Diverse biological activities

such as anti-tuberculostatic anti-inflammatory analgesic antipyretic and

anticonvulsant activities have been found to be associated with oxadiazole derivatives

[49 50] The substituted oxadiazoles have potential biological activities [51] such as

pesticide [52] hypertensive [53] insecticidal [54] hypoglycaemic [55] muscle

relaxing [56] and fungicidal activities [57]

134-Oxadiazoles and their analogues were found to be effective insecticides

against houseflies face flies and horn flies This type of compound was shown to

inhibit Drosophlia and Musca domestica in both in vitro and in vivo studies [58]

Furthermore anti-HIV antibacterial and antifungal activities were found for these

compounds [59]

6

Triazole derivatives and their biological importance

The 124-triazoles have significant of biological activities such as anti-

inflammatory activity and triazoles containing -NH-CS-NH- groups have a strong

potential for biological activity since the SH group can be easily converted into their

S-substituted derivatives [60 61]

The synthesis of 124-triazole derivatives has attracted widespread attention

due to their diverse biological activities which include anti-inflammatory analgesic

antitumoural [62-65] and antimicrobial activities [66 67]

124-Triazoles are a ubiquitous feature of many pharmaceutical and

agrochemical products [68] The substituted-124-triazole nucleus is particularly

common and examples of this can be found in marketed drugs such as fluconazole

[69] terconazole [70] and rizatriptan [71] Some other 124-triazole and 134-

thiadiazole heterocyclic entities that are very interesting components in terms of their

biological properties which include antifungal [7273] antibacterial [74] and

herbicidal [75] activities

The 124-triazole derivatives and their N-bridged heterocyclic analogues with

six-membered rings are important in the field of medicine [76 - 79] Triazoles fused

with heterocyclic such as pyridines [80] pyridazines [81] pyrimidines [82] pyrazines

[83] and triazines [84] have been reported This literature survey revealed that there

are not many examples of triazoles fused with thiadiazines However triazoles

triazoles incorporating the NndashCndashS linkage such as in the skeleton of 124-

triazolo[34-b][134]thiadiazine exhibit a broad spectrum of antimicrobial activity

[85]

2

NH

CH3 CH3

H3CH2CO

O

OCH2CH3O

N

CH3 OCH2CH3

O

CH3

Figure 1 Figure 2

12-Diaryl-substituted pyrrole and pyrazole derivatives have been shown to

possess interesting antiviral and anti-inflammatory activities [78] In recent years

polysubstituted-pyrrole derivatives have been shown to have interesting biological

properties 24-Disubstituted brominated pyrroles which are brominated at positions

3 and 5 along with 234-trisubstituted pyrroles have demonstrated potent in vitro

cytotoxic activity against a variety of marine and human tumor models [9-12]

Atorvastatin (Lipitor R) (Fig 3) is a clinically used hypolipidemic agent containing a

pyrrole ring

N

O

NH

CH3

CH3F

OH

OH

OHO

Figure 3

Justin et al [13] studied the lipid-lowering effects of the pyrrole derivative

ethyl 2-phenacyl-3-aryl-1H-pyrrole-4-carboxylate in rodents (Fig 4) Pyrrole and

fused heterocyclic pyrrole derivatives have received considerable attention owing to

their synthetic and effective biological importance [14 15] in particular those fused

with triazoles to their thermodynamically more stable isomers which have been

discussed in di- and tri-heterocyclics [16-18]

3

NH

O

ClCl

O

H3CH2CO

Figure 4

Pyrrole and related benzo condensed pyrrole derivatives also have significant

biological activities [1920] 1-Hydroxyethoxymethylpyrrole derivatives were reported

to be inactive against HIV-1 HSV-1 and HSV-2 but they showed considerable

promise as cytotoxic and antiviral agents [21] Furthermore 1-methyl-5-[(4-

methylphenyl) carbonyl]-1H-pyrrol-2-ylacetic acid and related compounds (Fig5)

were prepared [22 23] for biological studies on anti-inflammatory and analgesic

activities

N

O

COOH

CH3

CH3

Figure 5

Studies on oligopeptides containing pyrrole rings (Fig6) have reported antiviral

antitumour and cytostatic activities against both human and marine tumor cell lines

Oligopeptides (Fig 7) have also been reported to have potential antibiotic activities in

human and marine cell lines [24]

NNH

Cl

O

CH3

NCH3

NH

O

NH

NH2

Figure 6

4

N

CH3

OHC

CH3O

NH

N

O

NHN

NH

NH2

NH

OCH3

CH3

Figure 7

The heterocyclic molecules containing aromatic compounds are a famous class

of antitumor agents [25-27] They bind to DNA by interactions between the base pairs

of the double helix The synthesis and antitumor activities of distamycin derivatives

have been reported [28]

Since the naturally occurring pyrrole polyamide netropsin was reported in the

literature as having antibiotic activities [29-31] pyrrole polyamide (Fig 8) analogues

have been synthesized and their highly sequence-specific binding to DNA has

triggered the design of novel functional pyrrole polyamides [32] and the search for

new biological functions including anticancer activities [33] Lipid derivatives of

pyrrole polyamides were synthesized and screened for cytotoxicity and anti-HIV

activities Although no anti-HIV activity was found their cytotoxicity against cancer

cells was significantly enhanced by introducing a lipophilic group into the pyrrole

polyamide which also affected their biological activities against the monoamine

oxidize inhibitor [34] and bacterial [35] depressive [36] hypertensive [37] pyretic

and inflammatory diseases [38]

NH

HN NH

OO

NH2

NH

Figure 8

5

Oxadiazole derivatives and their biological importance

134-Oxadiazole derivatives have been produced and constitute an important

family of heterocyclic compounds since many of them display remarkable biological

activities such as antibacterial [39 40] antifungal [41] analgesic anti-inflammatory

[42 43] and hypoglycaemic [44] activities

The 134-oxadiazole derivatives have also shown leprostatic and

tuberculostatic properties analgesic antipyretic antiphlogistic bactericidal

insecticidal fungicidal and several other biological activities [45 46]

Oxadiazole derivatives which belong to an important group of heterocyclic

compounds have been the subject of extensive study over recent years Numerous

reports have highlighted their uses in chemistry [47 48] Diverse biological activities

such as anti-tuberculostatic anti-inflammatory analgesic antipyretic and

anticonvulsant activities have been found to be associated with oxadiazole derivatives

[49 50] The substituted oxadiazoles have potential biological activities [51] such as

pesticide [52] hypertensive [53] insecticidal [54] hypoglycaemic [55] muscle

relaxing [56] and fungicidal activities [57]

134-Oxadiazoles and their analogues were found to be effective insecticides

against houseflies face flies and horn flies This type of compound was shown to

inhibit Drosophlia and Musca domestica in both in vitro and in vivo studies [58]

Furthermore anti-HIV antibacterial and antifungal activities were found for these

compounds [59]

6

Triazole derivatives and their biological importance

The 124-triazoles have significant of biological activities such as anti-

inflammatory activity and triazoles containing -NH-CS-NH- groups have a strong

potential for biological activity since the SH group can be easily converted into their

S-substituted derivatives [60 61]

The synthesis of 124-triazole derivatives has attracted widespread attention

due to their diverse biological activities which include anti-inflammatory analgesic

antitumoural [62-65] and antimicrobial activities [66 67]

124-Triazoles are a ubiquitous feature of many pharmaceutical and

agrochemical products [68] The substituted-124-triazole nucleus is particularly

common and examples of this can be found in marketed drugs such as fluconazole

[69] terconazole [70] and rizatriptan [71] Some other 124-triazole and 134-

thiadiazole heterocyclic entities that are very interesting components in terms of their

biological properties which include antifungal [7273] antibacterial [74] and

herbicidal [75] activities

The 124-triazole derivatives and their N-bridged heterocyclic analogues with

six-membered rings are important in the field of medicine [76 - 79] Triazoles fused

with heterocyclic such as pyridines [80] pyridazines [81] pyrimidines [82] pyrazines

[83] and triazines [84] have been reported This literature survey revealed that there

are not many examples of triazoles fused with thiadiazines However triazoles

triazoles incorporating the NndashCndashS linkage such as in the skeleton of 124-

triazolo[34-b][134]thiadiazine exhibit a broad spectrum of antimicrobial activity

[85]

3

NH

O

ClCl

O

H3CH2CO

Figure 4

Pyrrole and related benzo condensed pyrrole derivatives also have significant

biological activities [1920] 1-Hydroxyethoxymethylpyrrole derivatives were reported

to be inactive against HIV-1 HSV-1 and HSV-2 but they showed considerable

promise as cytotoxic and antiviral agents [21] Furthermore 1-methyl-5-[(4-

methylphenyl) carbonyl]-1H-pyrrol-2-ylacetic acid and related compounds (Fig5)

were prepared [22 23] for biological studies on anti-inflammatory and analgesic

activities

N

O

COOH

CH3

CH3

Figure 5

Studies on oligopeptides containing pyrrole rings (Fig6) have reported antiviral

antitumour and cytostatic activities against both human and marine tumor cell lines

Oligopeptides (Fig 7) have also been reported to have potential antibiotic activities in

human and marine cell lines [24]

NNH

Cl

O

CH3

NCH3

NH

O

NH

NH2

Figure 6

4

N

CH3

OHC

CH3O

NH

N

O

NHN

NH

NH2

NH

OCH3

CH3

Figure 7

The heterocyclic molecules containing aromatic compounds are a famous class

of antitumor agents [25-27] They bind to DNA by interactions between the base pairs

of the double helix The synthesis and antitumor activities of distamycin derivatives

have been reported [28]

Since the naturally occurring pyrrole polyamide netropsin was reported in the

literature as having antibiotic activities [29-31] pyrrole polyamide (Fig 8) analogues

have been synthesized and their highly sequence-specific binding to DNA has

triggered the design of novel functional pyrrole polyamides [32] and the search for

new biological functions including anticancer activities [33] Lipid derivatives of

pyrrole polyamides were synthesized and screened for cytotoxicity and anti-HIV

activities Although no anti-HIV activity was found their cytotoxicity against cancer

cells was significantly enhanced by introducing a lipophilic group into the pyrrole

polyamide which also affected their biological activities against the monoamine

oxidize inhibitor [34] and bacterial [35] depressive [36] hypertensive [37] pyretic

and inflammatory diseases [38]

NH

HN NH

OO

NH2

NH

Figure 8

5

Oxadiazole derivatives and their biological importance

134-Oxadiazole derivatives have been produced and constitute an important

family of heterocyclic compounds since many of them display remarkable biological

activities such as antibacterial [39 40] antifungal [41] analgesic anti-inflammatory

[42 43] and hypoglycaemic [44] activities

The 134-oxadiazole derivatives have also shown leprostatic and

tuberculostatic properties analgesic antipyretic antiphlogistic bactericidal

insecticidal fungicidal and several other biological activities [45 46]

Oxadiazole derivatives which belong to an important group of heterocyclic

compounds have been the subject of extensive study over recent years Numerous

reports have highlighted their uses in chemistry [47 48] Diverse biological activities

such as anti-tuberculostatic anti-inflammatory analgesic antipyretic and

anticonvulsant activities have been found to be associated with oxadiazole derivatives

[49 50] The substituted oxadiazoles have potential biological activities [51] such as

pesticide [52] hypertensive [53] insecticidal [54] hypoglycaemic [55] muscle

relaxing [56] and fungicidal activities [57]

134-Oxadiazoles and their analogues were found to be effective insecticides

against houseflies face flies and horn flies This type of compound was shown to

inhibit Drosophlia and Musca domestica in both in vitro and in vivo studies [58]

Furthermore anti-HIV antibacterial and antifungal activities were found for these

compounds [59]

6

Triazole derivatives and their biological importance

The 124-triazoles have significant of biological activities such as anti-

inflammatory activity and triazoles containing -NH-CS-NH- groups have a strong

potential for biological activity since the SH group can be easily converted into their

S-substituted derivatives [60 61]

The synthesis of 124-triazole derivatives has attracted widespread attention

due to their diverse biological activities which include anti-inflammatory analgesic

antitumoural [62-65] and antimicrobial activities [66 67]

124-Triazoles are a ubiquitous feature of many pharmaceutical and

agrochemical products [68] The substituted-124-triazole nucleus is particularly

common and examples of this can be found in marketed drugs such as fluconazole

[69] terconazole [70] and rizatriptan [71] Some other 124-triazole and 134-

thiadiazole heterocyclic entities that are very interesting components in terms of their

biological properties which include antifungal [7273] antibacterial [74] and

herbicidal [75] activities

The 124-triazole derivatives and their N-bridged heterocyclic analogues with

six-membered rings are important in the field of medicine [76 - 79] Triazoles fused

with heterocyclic such as pyridines [80] pyridazines [81] pyrimidines [82] pyrazines

[83] and triazines [84] have been reported This literature survey revealed that there

are not many examples of triazoles fused with thiadiazines However triazoles

triazoles incorporating the NndashCndashS linkage such as in the skeleton of 124-

triazolo[34-b][134]thiadiazine exhibit a broad spectrum of antimicrobial activity

[85]

4

N

CH3

OHC

CH3O

NH

N

O

NHN

NH

NH2

NH

OCH3

CH3

Figure 7

The heterocyclic molecules containing aromatic compounds are a famous class

of antitumor agents [25-27] They bind to DNA by interactions between the base pairs

of the double helix The synthesis and antitumor activities of distamycin derivatives

have been reported [28]

Since the naturally occurring pyrrole polyamide netropsin was reported in the

literature as having antibiotic activities [29-31] pyrrole polyamide (Fig 8) analogues

have been synthesized and their highly sequence-specific binding to DNA has

triggered the design of novel functional pyrrole polyamides [32] and the search for

new biological functions including anticancer activities [33] Lipid derivatives of

pyrrole polyamides were synthesized and screened for cytotoxicity and anti-HIV

activities Although no anti-HIV activity was found their cytotoxicity against cancer

cells was significantly enhanced by introducing a lipophilic group into the pyrrole

polyamide which also affected their biological activities against the monoamine

oxidize inhibitor [34] and bacterial [35] depressive [36] hypertensive [37] pyretic

and inflammatory diseases [38]

NH

HN NH

OO

NH2

NH

Figure 8

5

Oxadiazole derivatives and their biological importance

134-Oxadiazole derivatives have been produced and constitute an important

family of heterocyclic compounds since many of them display remarkable biological

activities such as antibacterial [39 40] antifungal [41] analgesic anti-inflammatory

[42 43] and hypoglycaemic [44] activities

The 134-oxadiazole derivatives have also shown leprostatic and

tuberculostatic properties analgesic antipyretic antiphlogistic bactericidal

insecticidal fungicidal and several other biological activities [45 46]

Oxadiazole derivatives which belong to an important group of heterocyclic

compounds have been the subject of extensive study over recent years Numerous

reports have highlighted their uses in chemistry [47 48] Diverse biological activities

such as anti-tuberculostatic anti-inflammatory analgesic antipyretic and

anticonvulsant activities have been found to be associated with oxadiazole derivatives

[49 50] The substituted oxadiazoles have potential biological activities [51] such as

pesticide [52] hypertensive [53] insecticidal [54] hypoglycaemic [55] muscle

relaxing [56] and fungicidal activities [57]

134-Oxadiazoles and their analogues were found to be effective insecticides

against houseflies face flies and horn flies This type of compound was shown to

inhibit Drosophlia and Musca domestica in both in vitro and in vivo studies [58]

Furthermore anti-HIV antibacterial and antifungal activities were found for these

compounds [59]

6

Triazole derivatives and their biological importance

The 124-triazoles have significant of biological activities such as anti-

inflammatory activity and triazoles containing -NH-CS-NH- groups have a strong

potential for biological activity since the SH group can be easily converted into their

S-substituted derivatives [60 61]

The synthesis of 124-triazole derivatives has attracted widespread attention

due to their diverse biological activities which include anti-inflammatory analgesic

antitumoural [62-65] and antimicrobial activities [66 67]

124-Triazoles are a ubiquitous feature of many pharmaceutical and

agrochemical products [68] The substituted-124-triazole nucleus is particularly

common and examples of this can be found in marketed drugs such as fluconazole

[69] terconazole [70] and rizatriptan [71] Some other 124-triazole and 134-

thiadiazole heterocyclic entities that are very interesting components in terms of their

biological properties which include antifungal [7273] antibacterial [74] and

herbicidal [75] activities

The 124-triazole derivatives and their N-bridged heterocyclic analogues with

six-membered rings are important in the field of medicine [76 - 79] Triazoles fused

with heterocyclic such as pyridines [80] pyridazines [81] pyrimidines [82] pyrazines

[83] and triazines [84] have been reported This literature survey revealed that there

are not many examples of triazoles fused with thiadiazines However triazoles

triazoles incorporating the NndashCndashS linkage such as in the skeleton of 124-

triazolo[34-b][134]thiadiazine exhibit a broad spectrum of antimicrobial activity

[85]

5

Oxadiazole derivatives and their biological importance

134-Oxadiazole derivatives have been produced and constitute an important

family of heterocyclic compounds since many of them display remarkable biological

activities such as antibacterial [39 40] antifungal [41] analgesic anti-inflammatory

[42 43] and hypoglycaemic [44] activities

The 134-oxadiazole derivatives have also shown leprostatic and

tuberculostatic properties analgesic antipyretic antiphlogistic bactericidal

insecticidal fungicidal and several other biological activities [45 46]

Oxadiazole derivatives which belong to an important group of heterocyclic

compounds have been the subject of extensive study over recent years Numerous

reports have highlighted their uses in chemistry [47 48] Diverse biological activities

such as anti-tuberculostatic anti-inflammatory analgesic antipyretic and

anticonvulsant activities have been found to be associated with oxadiazole derivatives

[49 50] The substituted oxadiazoles have potential biological activities [51] such as

pesticide [52] hypertensive [53] insecticidal [54] hypoglycaemic [55] muscle

relaxing [56] and fungicidal activities [57]

134-Oxadiazoles and their analogues were found to be effective insecticides

against houseflies face flies and horn flies This type of compound was shown to

inhibit Drosophlia and Musca domestica in both in vitro and in vivo studies [58]

Furthermore anti-HIV antibacterial and antifungal activities were found for these

compounds [59]

6

Triazole derivatives and their biological importance

The 124-triazoles have significant of biological activities such as anti-

inflammatory activity and triazoles containing -NH-CS-NH- groups have a strong

potential for biological activity since the SH group can be easily converted into their

S-substituted derivatives [60 61]

The synthesis of 124-triazole derivatives has attracted widespread attention

due to their diverse biological activities which include anti-inflammatory analgesic

antitumoural [62-65] and antimicrobial activities [66 67]

124-Triazoles are a ubiquitous feature of many pharmaceutical and

agrochemical products [68] The substituted-124-triazole nucleus is particularly

common and examples of this can be found in marketed drugs such as fluconazole

[69] terconazole [70] and rizatriptan [71] Some other 124-triazole and 134-

thiadiazole heterocyclic entities that are very interesting components in terms of their

biological properties which include antifungal [7273] antibacterial [74] and

herbicidal [75] activities

The 124-triazole derivatives and their N-bridged heterocyclic analogues with

six-membered rings are important in the field of medicine [76 - 79] Triazoles fused

with heterocyclic such as pyridines [80] pyridazines [81] pyrimidines [82] pyrazines

[83] and triazines [84] have been reported This literature survey revealed that there

are not many examples of triazoles fused with thiadiazines However triazoles

triazoles incorporating the NndashCndashS linkage such as in the skeleton of 124-

triazolo[34-b][134]thiadiazine exhibit a broad spectrum of antimicrobial activity

[85]

6

Triazole derivatives and their biological importance

The 124-triazoles have significant of biological activities such as anti-

inflammatory activity and triazoles containing -NH-CS-NH- groups have a strong

potential for biological activity since the SH group can be easily converted into their

S-substituted derivatives [60 61]

The synthesis of 124-triazole derivatives has attracted widespread attention

due to their diverse biological activities which include anti-inflammatory analgesic

antitumoural [62-65] and antimicrobial activities [66 67]

124-Triazoles are a ubiquitous feature of many pharmaceutical and

agrochemical products [68] The substituted-124-triazole nucleus is particularly

common and examples of this can be found in marketed drugs such as fluconazole

[69] terconazole [70] and rizatriptan [71] Some other 124-triazole and 134-

thiadiazole heterocyclic entities that are very interesting components in terms of their

biological properties which include antifungal [7273] antibacterial [74] and

herbicidal [75] activities

The 124-triazole derivatives and their N-bridged heterocyclic analogues with

six-membered rings are important in the field of medicine [76 - 79] Triazoles fused

with heterocyclic such as pyridines [80] pyridazines [81] pyrimidines [82] pyrazines

[83] and triazines [84] have been reported This literature survey revealed that there

are not many examples of triazoles fused with thiadiazines However triazoles

triazoles incorporating the NndashCndashS linkage such as in the skeleton of 124-

triazolo[34-b][134]thiadiazine exhibit a broad spectrum of antimicrobial activity

[85]

7

Thiadiazole derivatives and their biological importance

The therapeutic effects of compounds containing 134-thiadiazole and 124-

triazole rings have been well studied for a number of pathological conditions

including inflammation [85 86] pain [87-89] and hypertension [90] Moreover the

synthesis of thiadiazoles and triazoles has attracted widespread attention due to their

diverse applications as antibacterial [91] antimycobacterial [92 93] antimycotic [94

95] antifungal [96 97] and antidepressant agents [98] Meanwhile N-acylated

aminoacids are known for their hepatoprotective and antimicrobial effects [99 100]

The preparation and anticonvulsant activity of several derivatives of

imidazoles triazoles oxadiazoles and thiadiazoles have been previously reported

[101 102] The 2-aryl-5-hydrazino-134-thiadiazole derivatives have particular

potential for anticonvulsant activity [103] The majority of the literature reporting on

this structure includes substitution of the 5-membered heterocyclic ring of 134-

thiadiazole [104-106]

The antitumor activities of a number of 2-substituted thiadiazoles have been

reported by many investigators [107108] Various substituted 134-thiadiazoles are

associated with diverse pharmacological activities such as antimicrobial bactericidal

anti-inflammatory antiviral antihypertensive anthelmintic and analgesic effects [109-

111]

Pyrazole derivatives and their biological importance

Pyrazole and its derivatives constitute an important class of compounds which

exhibit various biological and pharmaceutical activities ranging from antitumor [112]

anti-inflammatory [113] antipsychotic [114] antimicrobial [115] and antiviral [116]

8

activities to antifungal [117] activities They are also useful intermediates for many

industrial products [118119]

The efficiency of pyrazole as chemotherapeutic agent is well established and its

chemistry has been extensively studied Pyrazole and its synthetic analogues have

been found to exhibit industrial agricultural and biological applications [120-124]

Pyrazoles are an interesting group of compounds many of which possess a broad

spectrum of pharmacological properties such as analgesic antipyretic antidepressant

and antirheumatic [125126] and they are also well known for their pronounced anti-

inflammatory activity They are also used as potent antidiabetic agents Moreover

pyrazoles have played a crucial part in the development of heterocyclic chemistry and

they are extensively used as useful synthons in organic synthesis [127-129]

Thiazole derivatives and their biological importance

The thiazoles and their derivatives have proved their biological activity in

medicinal chemistry Various thiazole derivatives have shown herbicidal anti-

inflammatory antimicrobial and antiparasitic activities [130] 2-Aminothiazoles are

mainly known as biologically active compounds with a broad range of activities and

as intermediates in the synthesis of antibiotics such as the well known sulfa drugs

[131]

14-Dihydropyridine derivatives and their biological importance

Dihydropyridine derivatives [DHPDs] are used as starting materials for

cycloaddition and electrophilic reactions [132 133] Dihydropyridine derivatives

display a broad spectrum of medicinal activities [134] The oxidation of DHPDs to

their corresponding pyridine derivatives constitutes the principle of metabolic

9

pathway in biological systems such as antihypoxic and anti-ischaemic activities [135]

vasodilator bronchodilator anti-atherosclerotic antitumour and antidiabetic agents

[136] anticonvulsant anti-anxiety antidepressive antitumor analgesic hypnotic and

anti-inflammatory agents [137] and calcium channel blockers for the treatment of

hypertension [138] antihypoxic and cardiovascular disorders [139] 4-Aryl-14-

dihydropyridine-35-dicarboxylic diesters of the nifedipine type are widely used in the

treatment of hypertension and coronary heart diseases [140] Nifedipine with

symmetrical substituentrsquos on its dihydropyridine ring is achiral while second-

generation derivatives such as nimodipine amlodipine and nicardipine with

unsymmetrical substitutions are chiral and demonstrate moderate to significant

enantioselectivity in their pharmacological effects [141-143]

Therefore oxidative aromatization of DHPDs has attracted the continuing interest of

organic and medicinal chemists and a plethora of protocols have been developed [144

145] The 14-dihydropyridine derivatives (DHPDs) of the nifedipine compound type

are potential antihypertensive drugs based on their Ca+2

channel antagonistic activity

The precise mode of interaction is believed to involve the insertion of the alpha

subunit of the L-type voltage-gated channels present in skeletal and cardiac muscle

into their binding sites [146] The presence of ester groups at the 3 and 5-positions in

the 14-dihydropyridine ring is of crucial importance for the pharmacological effects

It has been suggested that these groups produce hydrogen bonding with the receptor

site [147] Hantzsch 14-dihydropyridines (DHPDs) continue to attract a lot of

attention due to their use as NAD(P)H (Nicotinamide Adenine Dinucleotide

Phosphate) models for probing the mechanisms of hydrogen transfer [148-150] and

8

activities to antifungal [117] activities They are also useful intermediates for many

industrial products [118119]

The efficiency of pyrazole as chemotherapeutic agent is well established and its

chemistry has been extensively studied Pyrazole and its synthetic analogues have

been found to exhibit industrial agricultural and biological applications [120-124]

Pyrazoles are an interesting group of compounds many of which possess a broad

spectrum of pharmacological properties such as analgesic antipyretic antidepressant

and antirheumatic [125126] and they are also well known for their pronounced anti-

inflammatory activity They are also used as potent antidiabetic agents Moreover

pyrazoles have played a crucial part in the development of heterocyclic chemistry and

they are extensively used as useful synthons in organic synthesis [127-129]

Thiazole derivatives and their biological importance

The thiazoles and their derivatives have proved their biological activity in

medicinal chemistry Various thiazole derivatives have shown herbicidal anti-

inflammatory antimicrobial and antiparasitic activities [130] 2-Aminothiazoles are

mainly known as biologically active compounds with a broad range of activities and

as intermediates in the synthesis of antibiotics such as the well known sulfa drugs

[131]

14-Dihydropyridine derivatives and their biological importance

Dihydropyridine derivatives [DHPDs] are used as starting materials for

cycloaddition and electrophilic reactions [132 133] Dihydropyridine derivatives

display a broad spectrum of medicinal activities [134] The oxidation of DHPDs to

their corresponding pyridine derivatives constitutes the principle of metabolic

9

pathway in biological systems such as antihypoxic and anti-ischaemic activities [135]

vasodilator bronchodilator anti-atherosclerotic antitumour and antidiabetic agents

[136] anticonvulsant anti-anxiety antidepressive antitumor analgesic hypnotic and

anti-inflammatory agents [137] and calcium channel blockers for the treatment of

hypertension [138] antihypoxic and cardiovascular disorders [139] 4-Aryl-14-

dihydropyridine-35-dicarboxylic diesters of the nifedipine type are widely used in the

treatment of hypertension and coronary heart diseases [140] Nifedipine with

symmetrical substituentrsquos on its dihydropyridine ring is achiral while second-

generation derivatives such as nimodipine amlodipine and nicardipine with

unsymmetrical substitutions are chiral and demonstrate moderate to significant

enantioselectivity in their pharmacological effects [141-143]

Therefore oxidative aromatization of DHPDs has attracted the continuing interest of

organic and medicinal chemists and a plethora of protocols have been developed [144

145] The 14-dihydropyridine derivatives (DHPDs) of the nifedipine compound type

are potential antihypertensive drugs based on their Ca+2

channel antagonistic activity

The precise mode of interaction is believed to involve the insertion of the alpha

subunit of the L-type voltage-gated channels present in skeletal and cardiac muscle

into their binding sites [146] The presence of ester groups at the 3 and 5-positions in

the 14-dihydropyridine ring is of crucial importance for the pharmacological effects

It has been suggested that these groups produce hydrogen bonding with the receptor

site [147] Hantzsch 14-dihydropyridines (DHPDs) continue to attract a lot of

attention due to their use as NAD(P)H (Nicotinamide Adenine Dinucleotide

Phosphate) models for probing the mechanisms of hydrogen transfer [148-150] and

9

pathway in biological systems such as antihypoxic and anti-ischaemic activities [135]

vasodilator bronchodilator anti-atherosclerotic antitumour and antidiabetic agents

[136] anticonvulsant anti-anxiety antidepressive antitumor analgesic hypnotic and

anti-inflammatory agents [137] and calcium channel blockers for the treatment of

hypertension [138] antihypoxic and cardiovascular disorders [139] 4-Aryl-14-

dihydropyridine-35-dicarboxylic diesters of the nifedipine type are widely used in the

treatment of hypertension and coronary heart diseases [140] Nifedipine with

symmetrical substituentrsquos on its dihydropyridine ring is achiral while second-

generation derivatives such as nimodipine amlodipine and nicardipine with

unsymmetrical substitutions are chiral and demonstrate moderate to significant

enantioselectivity in their pharmacological effects [141-143]

Therefore oxidative aromatization of DHPDs has attracted the continuing interest of

organic and medicinal chemists and a plethora of protocols have been developed [144

145] The 14-dihydropyridine derivatives (DHPDs) of the nifedipine compound type

are potential antihypertensive drugs based on their Ca+2

channel antagonistic activity

The precise mode of interaction is believed to involve the insertion of the alpha

subunit of the L-type voltage-gated channels present in skeletal and cardiac muscle

into their binding sites [146] The presence of ester groups at the 3 and 5-positions in

the 14-dihydropyridine ring is of crucial importance for the pharmacological effects

It has been suggested that these groups produce hydrogen bonding with the receptor

site [147] Hantzsch 14-dihydropyridines (DHPDs) continue to attract a lot of

attention due to their use as NAD(P)H (Nicotinamide Adenine Dinucleotide

Phosphate) models for probing the mechanisms of hydrogen transfer [148-150] and

10

their applications in medicine as calcium channel modulators vasodilators and

antihypertensive agents [151 152]

Imidazolidin derivatives and their biological importance

The biological activities of hydantoin and 2-thiohydantoin derivatives have

been known for a long time Hydantoins which are a class of cyclic imides have

demonstrated good anticonvulsant properties depending on the nature of the

substitution on the hydantoin ring and a wide range of other pharmacological

properties such as fungicidal [153] herbicidal [154] antitumor [155] anti-HIV [156]

hypolipidemic [157] and antihypertensive [158] activities have also been identified

The hydantoin nucleus containing an active urea is responsible for a variety of

biological activities such as antineoplastic [159] and anticonvulsant activities [160]

and hydantoins also exhibit platelet aggregation [161] aldose reductase [162] for

example iprodione used for fungicide drug [163] A number of publications have

reported the fungicidal and bactericidal activity of hydantoins and their 2-thio

analogues [164]

Thiohydantoins are sulphur analogues of hydantoins with one or both carbonyl

groups replaced by thiocarbonyl groups [165] Among the known thiohydantoins the

2-thiohydantoins are most notable for their wide ranging applications as

hypolipidemic [166] anticarcinogenic [167] antimutagenic [168] antithyroidal [169]

antiviral for example against the herpes simplex virus HSV [170] and the human

immunodeficiency virus (HIV) [171] antituberculosis [172] antimicrobial (antifungal

and antibacterial) [173] and anti-ulcer agents and it is therefore not surprising that

various synthetic methods have been developed to prepare 2-thiohydantoin and its

11

derivatives One of the most commonly used methods is the treatment of amino acids

with acetic anhydride followed by ammonium thiocyanate [174]

Over the last twenty years a lot of interest has been focused upon the synthesis

of N-aminoheterocycles since this class of compounds has interesting biological

properties Numerous heterocyclic compounds having a thiourea or a

thiosemicarbazide moiety have been found to be active as agrochemicals [175]

Piperidone derivatives and their biological importance

Piperidone derivatives have been found to possess potential biological activities

such central nervous system (CNS) [176 177] and antimicrobial activities [178]

Heterocyclic containing thiosemicarbazone derivatives [179 180] are possibly

associated with antimicrobial activity Previous reports have indicated that the

biological activities of piperidones were associated with substitutions at the 2 3 and 6-

positions These biological activities were found to be significant in compounds

possessing aromatic substituents in the 2 andor 6-positions The presence of the

methyl substitution in the 2 or 3-position was also attributed as the reason for the

biological activities of these compounds Therefore it was envisaged that 26-diaryl-

3-methyl-piperidones and their corresponding thiosemicarbazones and oximes would

result in compounds with potent biological activities

It was found that thiosemicarbazone(TSC) derivatives[181] are tumour inhibitors

that potentially act as N-N-S type ligands In general the N-N-S types are tridentate

donor ligands of substituted thiosemicarbazones and thiosemicarbazides are attributed

to their ability to chelate and form metal complexes [182] In this context Thelander

and Grasland et al [183] undertook a detailed study on the effects of 1-formyl

12

isoquinolone thiosemicarbazone on the mammalian ribonucleotide reductase to

understand the environment of the active site and the reaction mechanism of the

enzyme [184] French and Freelander et al [185] suggested that some antitumor

agents also possess the ability to function as chelating agents Thiosemicarbazone

(TSC) derivatives exhibit a wide spectrum of biological activities such as antitumor

antimalarial [186] antiviral [187] antibacterial [188] and antifertility activities [189]

In addition these derivatives possess non-linear optical properties [190]

13

(12) Literature review

Preparation of starting compound of pyrrole derivatives

Fischer and Noller [191] synthesized the compound diethyl 35-dimethyl-1H-

pyrrole-24-dicarboxylate (Fig 9) and this compound was used as one of the base

compounds in this research

CH3OEt

O O

CH3OEt

O O

NOH

CH3OEt

O O

NOHCH3

OEt

O O

NH2

EtO2C NH2

OHCH3

+

O CH3

O

CO2Et

HOAcNH

CH3

CH3

OEt

O

O

EtO

NaNO2

HOAc H2O

Zn HOAc

H2O

Figure 9

Fischer et al [192] studied the modification of the pyrrole structure using ethyl

2-(4-acetyl-35-dimethyl-1H-pyrrol-2-yl)-2-oxoacetate (Fig 10)

+

O CH3

O

CH3

NH

CH3

CH3

O

O

EtO2C

CH3OCH3

EtO2C NH2

-2H2O

Figure 10

Paine et al [193] proposed regioselectivity of pyrrole synthesis from diethyl

aminomalonate and 13-diketones (Figs 11 and 12)

14

+

CH3 O

EtO2C

Ac

OH

NaNO2 AcOH H2O

Zn AcOH

NH

OEt

O

EtO

O

CH3

CH3

+NH

CH3

O

OEt

Figure 11

+

CH3 O

EtO2CN

OH

Ac

OH

Zn AcOHNH

OEt

O

EtO

O

CH3

CH3

+NH

CH3

O

OEt

Figure 12

Fabiano et al [194] reported on the reactions between ethyl 2-aminoaceto

acetate and an excess of ethyl acetoacetate leading to diethyl 24-dimethylpyrrole-35-

dicarboxylate (Fig13)

+

CH3 O

EtO2CNH2

NH

OEt

O

EtO

O

CH3

CH3

CH3

O

EtO

O

Et3N

Figure 13

Lipshutz et al [195] reported that under catalytic conditions of catalytic Ni(0)

and Me2NHmiddotBH3K2CO3 a (Carbobenzyloxy) Cbz-protected nitrogen which is part of a

heteroaromatic ring can be chemospecifically cleaved without affecting the Cbz

group on the original basic amine (Fig 14)

K2CO3 Me2NHBH3 NiCl2(PPh3)2 PPh3

MeCN

N

OEt

O

EtO

O

CH3

CH3

OO

N

OEt

O

EtO

O

CH3

CH3

H

Figure 14

15

Bennasar et al [196] have studied the tributylstannyl radicals promote the

deprotection of N-Cbz derivatives of amides and nitrogen-containing heteroaromatic

rings These radical conditions do not affect N-Cbz derivatives of basic amines

(Fig15)

Bu3SnHN

OEt

O

EtO

O

CH3

CH3

OON

OEt

O

EtO

O

CH3

CH3

H

30min reflux

Figure 15

Preparation of base compounds of 14-dihydropyridine derivatives

Described more than a century ago by Hussain et al [197] dialkyl 14-

dihydro-26-dimethylpyridine-35-dicarboxylates are recognized as vital drugs in the

treatment of angina and hypertension In 1882 Hantzsch first reported the synthesis of

dialkyl 14-dihydro-26-dimethylpyridine-35-dicarboxylates from a refluxing mixture

of an aldehyde a β-ketoester and aqueous ammonium hydroxide in ethanol More

than a century ago the 14-DHPDs were first obtained by Hantzsch and Liebigs [198]

This reaction involved a one-pot condensation of an aldehyde with ethyl acetoacetate

and ammonia either in acetic acid or refluxing in alcohol for a longer period

Hadizadeh et al [199] synthesized 4-(1-phenylmethyl-5-imidazolyl)-14-dihydropyri

dines as calcium channel antagonists (Fig 16)

16

N

N

NHH3CS

CHOCH3COCH2COOC2H5 NH4OH

NH

CH3 CH3

COOC2H5H5C2OOC

N

N

SCH3

Figure 16

Bhavik Desai et al [200] synthesized 4-substituted phenyl-26-dimethyl-35-

bis-N-(4-chlorophenyl)carbamoyl-14-dihydropyridines and Quantitative structural

activity relationship (QSAR) studies of these compounds showed that they were

potential antitubercular agents (Fig 17)

CH3

NH

O

O

Cl

+CHO

NH3 CH3OH

Reflux

NH

NH

OO

NH

CH3 CH3

Cl Cl

Figure 17

Amini et al [201] carried out the synthesis and confirmed the antitubercular

activity of new NN-diaryl-4-(45-dichloroimidazole-2-yl)-14-dihydro-26-dimethyl-

35-pyridinedicarbox amides (Fig 18)

N

NHCl

Cl

CHO

+CH3 NH

O O

NH4OAc

MeOH reflux

NH

NH

O

NH

N NH

Cl Cl

CH3 CH3

O

Figure 18

17

Shashikant et al [202] studied the synthesis and evaluation of some 1 4-

dihydropyridines and their derivatives as antihypertensive agent (Fig 19)

CH3 NH

O O

+

CHO

Reflux 10 - 12h

Ammonia ( 25 )

Methanol

NH

OC CONH NH

CH3 CH3

Figure 19

Suresh et al [203] studied the synthesis and bronchodilatory activity of new 4-

aryl-35-bis(2-chlorophenyl)-carbonyl-26-dimethyl-14-dihydropyridines and their 1-

substituted analogues (Fig 20)

CH3 NH

O OCl

+

CHONH

NH NH

CH3 CH3

Cl ClO O

+ NH3

AcOH - MeOH

12 - 28 h

Figure 20

Sobin [204] reported the hydrazinolysis method by hydrazine hydrate was

reacted with an ester group and Suresh et al [205] reported that pyrrole derivatives

condense with hydrazine hydrate (Fig 21)

NH

CH3

CH3H3CH2CO

O

OCH 2CH3

O NH

CH3

CH3

O

NH

O

NH

NH2

NH2NH2 NH2

Figure 21

18

Preparation of oxadiazole derivatives

R

O

HN NH2

N

O

N

R

SH-H2S

+ S C

S

KOH

alcoholR

O

HN NH

S

HS

N

O

HN

R

S

H

SH

Figure 22 Mechanism of the oxadiazole preparation

Figure 22 shows the mechanism for the preparation of oxadiazole derivatives

Akhtar et al[206] reported on the in vitro antitumour and antiviral activities of new

benzothiazole and 134-oxadiazole-2-thione derivatives (Fig 23)

OO

NHNH2

CH3Br

KOH CS2O

CH3Br

NN

O

SH

Figure 23

Kalagouda Gudasi et al [207] studied the new ligand for 56-(5-mercapto-

134-oxadiazol-2-yl)pyridin-2-yl-134-oxadiazole-2-thiol (Fig 24)

NO

OCH3 OCH3

O

NH2NH2 C2H5OH

Reflux 4h

NO

NH NH

O

NH2 NH2

KOH 2CS2

Reflux 15 min

NO O

SH SH

Figure 24

19

Preparation of Triazole derivatives

Shipra Baluja et al [208] reported on the work for a facile synthesis and the

antimicrobial activity of some 4-aryltriazoles (Fig 25)

NHNH

O

S-

SH3CO

K+

NH

O

NH2H3CO

CS2 KOH

NHNH2

H3CO

N

N

N

NH

SH

Figure 25

Mohammad Al-Amin et al [209] reported on the synthesis of some bis-

triazole derivatives that were studied for cytotoxicity (Fig 26)

HOOC - (CH2)n -COOH Fusion

+NH2 NH

NH

NH2S

N N

N(CH2)n

N N

NSHSH

NH2NH2

Figure 26

Shivarama et al [210] carried out some trouble site reaction of new bis-

aminomercaptotriazole and bis-triazolothiadiazole as possible anticancer agents (Fig

27)

HOOCH 2CO OCH2COOHON

NN

O

N

N

N

NH2 NH2

SH SH

H2NNHCSNHNH 2

Figure 27

20

Amine reactions with ester groups

For the reactions between amines and esters the reaction is accelerated by

heating it moderately Notice that a stronger base (amine) is used up and a weaker

base (alcohol) is produced Notice also that before the alcohol (leaving group) portion

of the ester departs it picks up an H+ so that it leaves as the weak base alcohol ion

(ROH) rather than as the strong base alkoxide ion (RO-) Weaker bases make better

leaving groups Figure 28 illustrates the mechanism of the amination reaction

Figure 28 Mechanism of the amine reacted with the ester group

Suresh et al [211] studied the amination reaction (Fig 29)

CH3 OEt

O O

+

NH2

ClBuOK

EtOH

0 - 5 h rt

CH3 NH

O O

Cl

Figure 29

Shashikant et al [212] also reported on an amination reaction where a secondary

amine is formed (Fig 30)

CH3 OEt

O O

+ CH3 NH

O O

NH2

EtOH

Figure 30

21

Konstantinos et al [213] studied the fusion method ndash the solvent free reaction

of arylamines with ethyl cyanoacetates is one of the most widely used methods for the

preparation of cyanoacetanilides (Fig 31)

NH2

+

O

EtO

CN

150 degC

NH

O

CN

Figure 31

Metwally et al [214] reported on the reaction using different basic medium

conditions such as sodium ethoxide solution (Fig 32)

+

O

EtO

CN

N

S

NH2

at

EtOH

N

S

NH

O

CN

Figure 32

Bhawal et al [215] reported on the reaction of benzylamine with ethyl

cyanoacetate in tetra hydro furan (THF) containing butyl lithium as the basic catalyst

which formed N-benzylcyanoacetamide (Fig 33)

NH2

+

O

EtO

CN

THF

BuLi

NH

O

CN

Figure 33

Jianguo et al [216] reported that microwave (MW) irradiation has become an

important method in organic synthesis which can be applied to a wide range of

reactions with short reaction times and high yields (Fig 34)

22

NH2

H3CO

+

EtO

CNO

MW

trichlorobenzene

NH

H3CO

CN

O

Figure 34

Hanan et al[217] studied the amination reaction of compound 2-[4-

(ethoxycarbonyl)anilino]-3-methyl quinoxaline with primary amine (Fig 35)

N

N CH3

NH

OEtO

RNH2

N

N CH3

NH

NHOR

Figure 35

Srivastava et al [218] studied the hydrazinolysis reaction in which 124-triazole

containing an ester group reacted with thiosemicarbazide (Fig 36)

N N

N

OC2H5

ONH2 NH

CS NH2

N N

N

NH

O

NH

CS

NH2

Figure 36

Swati ojha et al [219] studied the reaction in which benzotriazole containing

ethyl chloroacetate is converted to carbothioamide by the hydrazinolysis method (Fig

37)

23

N

NN

O

OEt

NH2 NH

CS NH2

N

NN

O

NHNH

CSNH2

Figure 37

Preparation of triazole derivatives

R

S

HN NH

S

HN

R

N

N

HN

R

H

SHR

S

N

N

HN

R

R

S10 NaOH

HCl

-H2S

Figure 38 Mechanism of the triazole preparation

Maymona et al [220] and Barnela et al [221] studied the Vilsmeier-Haack

reaction mechanism of triazole preparation using hydrolysis of 10 sodium hydroxide

solution followed by acidification with dilute hydrochloric acid to give 5-thioxo-

134-triazol derivatives (Fig 39)

Figure 39

Otilia Pintilie et al [222] prepared triazole derivatives via the hydrolysis of

10 sodium hydroxide solution followed by acidification with dilute hydrochloric

acid (Fig 40)

24

H3CS CONH

NH

O2N

NH NH

S

CH3

NaOH

H3CS

NH

O2N

NN

N

CH3

SH

Figure 40

Mohamed Belkadi et al [223] studied the steps involved in the treatment of

(plusmn)-22-dimethyl-[13]dioxolan-4-carboxylic-acid-hydrazide-thioformamido-semicarb

azide with NaOH in absolute ethanol under reflux for five hours to give (plusmn)-5-(22-

dimethyl-[13]dioxolan-4-yl)-4H-[124]triazole-3-thiol (Fig 41)

Figure 41

Hussain et al [224] synthesized thiadiazole and 124-triazole derivatives from

cyclopropane dicarboxylic acid (Fig 42)

HOOCCOOH

SOCl2 H2NNHCSNH2H2NSCHNNOC

CONNHCSNH2

NaOHN

NH

N

NH

NN

SH

SH

Figure 42

25

Sibel Demir et al [225] studied the crystallographic analysis of compound 55rsquo-

pyridine-26-diylbis[4-ethyl-24-dihydro-124-triazole-3(2H)-thione (Fig 43)

NNHNH

OO

NH NH

S

NHNH

O

CH3 CH3

NaOH

NN

N

N

N

N

N

SH SHCH3

CH3

Figure 43

Preparation of thiadiazole derivatives

Foroumadi et al [226] reported on the anticonvulsant activity of novel 2-amino-

5-[4-chloro-2-(2-chlorophenoxy) phenyl]-134-thiadiazole derivatives (Fig 44)

OCl

Cl

NH

O

NH NH2

S H2SO4

NH4OH

OCl

Cl

N

S

N

NH2

Figure 44

Otilia Pintilie et al [227] reported on the synthesis and antimicrobial activity of

some new 134-thiadiazole and 124-triazole compounds which had a DL-

methionine moiety (Fig 45)

Figure 45

26

Srivastava et al [228] studied the synthesis of a new 124- triazolo-thia

diazole as antimicrobial anticonvulsant and anti-inflammatory agents (Fig 46)

N

NN

O

NHNH NH2

SH2SO4

NH3

N

NN

N

S

N

NH2

Figure 46

Swati Ojha et al [229] studied the conversion of benzatriazole containing

thiosemicarbazone into thiadiazole derivatives with the help of H2SO4 by the

cyclization method (Fig 47)

N

NN

O

NHNH NH2

S H2SO4 NH3

N

NN

S

N N

NH2

Figure 47

Hussain et al [230] synthesized thiadiazole and 124-triazole derivatives from

cyclopropane dicarboxylic acid (Fig 48)

N

S

N

S

NN

NH2 NH2

HOOCCOOH POCl3 H2NNHCSNH2

Figure 48

27

Preparation pyrazole and thiazole derivatives

El-Sayed Rashad et al [231] studied the synthesis of the biologically active

pyrazoles and C-nucleosides (Fig 49)

NHNH2

CH3

O

OEt

O

AcOH heatN N

CH3 O

Figure 49

Hamied latif et al [232] Zevrsquoyalow et al [233] and More et al [234] have

reported by thazole derivative (Fig 50) and their biologically importance

CH3

O

I2 CH2I

ONH2

NH2

S

N

SNH2

Figure 50

Preparation of imidazolidin-4-thioxo-2-one derivatives

Renata Jakse et al [235] studied the progresses in the synthesis and reactions

of imidazolidin and its derivatives in particular the stereoselective synthesis of

5-[heteroaryl methylidene]-substituted hydantoins and thiohydantoins as aplysinopsin

analogues (Fig 51)

NH

N

NCH3

CH3

O

S

Figure 51

28

Giulio et al [236] studied the synthesis of CB1 (cannabinoid) receptor ligands

and evaluated their pharmacological properties (Fig 52)

N

NH

CH3

O S

Cl

Cl

Figure 52

Janos Marton et al [237] studied the fungicidal activity of 5-substituted

hydantoins and their 2-thio analogues (Fig 53)

NH

NH

S

S

CHO

NH NH

O

S

Figure 53

2-Thiohydrotoin was reacted with aromatic aldehydes to give the corresponding

arylmethylene derivatives reported by Wheeler et al[238] and Lubomir Floch et al

[239] studied the synthesis of 5- substituted-3-amino-2-thioxo-4-imidazolidinones

(Fig 54)

H

CO2Et

NCS NH2 NH2 H2O

MeOH or EtOH Et2O

H

CO2Et

NH

NHNH2

S

NH

N

O

SH

NH2

Figure 54

29

Zerong Daniel wang et al [240] reported that synthesis of 2-thiohydantoins

derivative (Fig 55)

N N

NH2

CH3

CH3

OH

O

+ NH

S

NH2

CH2

NH

N

CH3CH3

S

O

CH2

+NH

NH

CH3CH3

O

S

Figure 55

Farzin Hadizadeh et al [241] prepared the thiosemicarbazone derivatives (Fig

56)

NH

N

CH3 CHO

NH2 NH

NH2

S NH

N

CH3

NNH

NH2

S

Figure 56

Peesapati Venkateswarlu et al [242] studied the semicarbazone derivatives

from bi-cyclic ketones reacted with semicarbazide hydrochloride (Fig 57)

O

CH3

NH2 NH

NH2

O

N

CH3

NH

NH2O

HCl

AcONa and EtOH

Figure 57

Natesh Ramesh kumar et al [243] reported that thiosemicarbazide reacted

with ketone derivatives to give the corresponding thiosemicarbazone derivatives (Fig

58)

30

CH3

CH3

O

+

HO

Cl

N

O

CH3

CH3

Cl

NH2 NH

NH2

S

N

N

CH3

CH3

NH

NH2S

Cl

HO

CH3COONH4

Figure 58

Sampath et al [244] studied the crystal structure and conformation of

N-methyl-t-3-methyl-R-2C-6-diphenylpipridin-4-one thiosemicarbazone (Fig 59)

CH3

CH3

O

+

HO

+ CH3 NH2

99 Ethanol

N

O

CH3

CH3

NH2 NH

NH2

S

methanol HCl N

N

CH3

CH3

NH

NH2S

Figure 59

Jamal Abdul Nasser et al [245] studied the imidazolidin ring prepared from

thiosemicabazone reacted with ethyl chloroacetate and fused sodium acetate by the

cyclization method (Fig 60)

NNH NH2

S

Cl

OC2H5

O

NaOAc

NN

NH

S

O

Figure 60

31

The above literature findings were taken as the basis on which to synthesize

pyrrole pyridine and imidazolidine derivatives

Pyrrole derivatives are mentioned in schemes 1-3

Pyridine derivatives are mentioned in scheme 3

Imidazolidine derivatives are mentioned in schemes 4 -7

All of the synthetic compounds were characterized by Infrared (IR) Proton Nuclear

magnetic resonance (sup1H-NMR) Carbon Nuclear magnetic resonance (13

C-NMR)

Mass spectral and elemental analyses The selected compounds were screened for the

following biological activities

In vitro antimicrobial anticoagulant anticancer and antioxidant activities

In vivo anti-convulsant anti-inflammatory and analogous activities

Environmental toxicity analysis

11

derivatives One of the most commonly used methods is the treatment of amino acids

with acetic anhydride followed by ammonium thiocyanate [174]

Over the last twenty years a lot of interest has been focused upon the synthesis

of N-aminoheterocycles since this class of compounds has interesting biological

properties Numerous heterocyclic compounds having a thiourea or a

thiosemicarbazide moiety have been found to be active as agrochemicals [175]

Piperidone derivatives and their biological importance

Piperidone derivatives have been found to possess potential biological activities

such central nervous system (CNS) [176 177] and antimicrobial activities [178]

Heterocyclic containing thiosemicarbazone derivatives [179 180] are possibly

associated with antimicrobial activity Previous reports have indicated that the

biological activities of piperidones were associated with substitutions at the 2 3 and 6-

positions These biological activities were found to be significant in compounds

possessing aromatic substituents in the 2 andor 6-positions The presence of the

methyl substitution in the 2 or 3-position was also attributed as the reason for the

biological activities of these compounds Therefore it was envisaged that 26-diaryl-

3-methyl-piperidones and their corresponding thiosemicarbazones and oximes would

result in compounds with potent biological activities

It was found that thiosemicarbazone(TSC) derivatives[181] are tumour inhibitors

that potentially act as N-N-S type ligands In general the N-N-S types are tridentate

donor ligands of substituted thiosemicarbazones and thiosemicarbazides are attributed

to their ability to chelate and form metal complexes [182] In this context Thelander

and Grasland et al [183] undertook a detailed study on the effects of 1-formyl

12

isoquinolone thiosemicarbazone on the mammalian ribonucleotide reductase to

understand the environment of the active site and the reaction mechanism of the

enzyme [184] French and Freelander et al [185] suggested that some antitumor

agents also possess the ability to function as chelating agents Thiosemicarbazone

(TSC) derivatives exhibit a wide spectrum of biological activities such as antitumor

antimalarial [186] antiviral [187] antibacterial [188] and antifertility activities [189]

In addition these derivatives possess non-linear optical properties [190]

13

(12) Literature review

Preparation of starting compound of pyrrole derivatives

Fischer and Noller [191] synthesized the compound diethyl 35-dimethyl-1H-

pyrrole-24-dicarboxylate (Fig 9) and this compound was used as one of the base

compounds in this research

CH3OEt

O O

CH3OEt

O O

NOH

CH3OEt

O O

NOHCH3

OEt

O O

NH2

EtO2C NH2

OHCH3

+

O CH3

O

CO2Et

HOAcNH

CH3

CH3

OEt

O

O

EtO

NaNO2

HOAc H2O

Zn HOAc

H2O

Figure 9

Fischer et al [192] studied the modification of the pyrrole structure using ethyl

2-(4-acetyl-35-dimethyl-1H-pyrrol-2-yl)-2-oxoacetate (Fig 10)

+

O CH3

O

CH3

NH

CH3

CH3

O

O

EtO2C

CH3OCH3

EtO2C NH2

-2H2O

Figure 10

Paine et al [193] proposed regioselectivity of pyrrole synthesis from diethyl

aminomalonate and 13-diketones (Figs 11 and 12)

14

+

CH3 O

EtO2C

Ac

OH

NaNO2 AcOH H2O

Zn AcOH

NH

OEt

O

EtO

O

CH3

CH3

+NH

CH3

O

OEt

Figure 11

+

CH3 O

EtO2CN

OH

Ac

OH

Zn AcOHNH

OEt

O

EtO

O

CH3

CH3

+NH

CH3

O

OEt

Figure 12

Fabiano et al [194] reported on the reactions between ethyl 2-aminoaceto

acetate and an excess of ethyl acetoacetate leading to diethyl 24-dimethylpyrrole-35-

dicarboxylate (Fig13)

+

CH3 O

EtO2CNH2

NH

OEt

O

EtO

O

CH3

CH3

CH3

O

EtO

O

Et3N

Figure 13

Lipshutz et al [195] reported that under catalytic conditions of catalytic Ni(0)

and Me2NHmiddotBH3K2CO3 a (Carbobenzyloxy) Cbz-protected nitrogen which is part of a

heteroaromatic ring can be chemospecifically cleaved without affecting the Cbz

group on the original basic amine (Fig 14)

K2CO3 Me2NHBH3 NiCl2(PPh3)2 PPh3

MeCN

N

OEt

O

EtO

O

CH3

CH3

OO

N

OEt

O

EtO

O

CH3

CH3

H

Figure 14

15

Bennasar et al [196] have studied the tributylstannyl radicals promote the

deprotection of N-Cbz derivatives of amides and nitrogen-containing heteroaromatic

rings These radical conditions do not affect N-Cbz derivatives of basic amines

(Fig15)

Bu3SnHN

OEt

O

EtO

O

CH3

CH3

OON

OEt

O

EtO

O

CH3

CH3

H

30min reflux

Figure 15

Preparation of base compounds of 14-dihydropyridine derivatives

Described more than a century ago by Hussain et al [197] dialkyl 14-

dihydro-26-dimethylpyridine-35-dicarboxylates are recognized as vital drugs in the

treatment of angina and hypertension In 1882 Hantzsch first reported the synthesis of

dialkyl 14-dihydro-26-dimethylpyridine-35-dicarboxylates from a refluxing mixture

of an aldehyde a β-ketoester and aqueous ammonium hydroxide in ethanol More

than a century ago the 14-DHPDs were first obtained by Hantzsch and Liebigs [198]

This reaction involved a one-pot condensation of an aldehyde with ethyl acetoacetate

and ammonia either in acetic acid or refluxing in alcohol for a longer period

Hadizadeh et al [199] synthesized 4-(1-phenylmethyl-5-imidazolyl)-14-dihydropyri

dines as calcium channel antagonists (Fig 16)

16

N

N

NHH3CS

CHOCH3COCH2COOC2H5 NH4OH

NH

CH3 CH3

COOC2H5H5C2OOC

N

N

SCH3

Figure 16

Bhavik Desai et al [200] synthesized 4-substituted phenyl-26-dimethyl-35-

bis-N-(4-chlorophenyl)carbamoyl-14-dihydropyridines and Quantitative structural

activity relationship (QSAR) studies of these compounds showed that they were

potential antitubercular agents (Fig 17)

CH3

NH

O

O

Cl

+CHO

NH3 CH3OH

Reflux

NH

NH

OO

NH

CH3 CH3

Cl Cl

Figure 17

Amini et al [201] carried out the synthesis and confirmed the antitubercular

activity of new NN-diaryl-4-(45-dichloroimidazole-2-yl)-14-dihydro-26-dimethyl-

35-pyridinedicarbox amides (Fig 18)

N

NHCl

Cl

CHO

+CH3 NH

O O

NH4OAc

MeOH reflux

NH

NH

O

NH

N NH

Cl Cl

CH3 CH3

O

Figure 18

17

Shashikant et al [202] studied the synthesis and evaluation of some 1 4-

dihydropyridines and their derivatives as antihypertensive agent (Fig 19)

CH3 NH

O O

+

CHO

Reflux 10 - 12h

Ammonia ( 25 )

Methanol

NH

OC CONH NH

CH3 CH3

Figure 19

Suresh et al [203] studied the synthesis and bronchodilatory activity of new 4-

aryl-35-bis(2-chlorophenyl)-carbonyl-26-dimethyl-14-dihydropyridines and their 1-

substituted analogues (Fig 20)

CH3 NH

O OCl

+

CHONH

NH NH

CH3 CH3

Cl ClO O

+ NH3

AcOH - MeOH

12 - 28 h

Figure 20

Sobin [204] reported the hydrazinolysis method by hydrazine hydrate was

reacted with an ester group and Suresh et al [205] reported that pyrrole derivatives

condense with hydrazine hydrate (Fig 21)

NH

CH3

CH3H3CH2CO

O

OCH 2CH3

O NH

CH3

CH3

O

NH

O

NH

NH2

NH2NH2 NH2

Figure 21

18

Preparation of oxadiazole derivatives

R

O

HN NH2

N

O

N

R

SH-H2S

+ S C

S

KOH

alcoholR

O

HN NH

S

HS

N

O

HN

R

S

H

SH

Figure 22 Mechanism of the oxadiazole preparation

Figure 22 shows the mechanism for the preparation of oxadiazole derivatives

Akhtar et al[206] reported on the in vitro antitumour and antiviral activities of new

benzothiazole and 134-oxadiazole-2-thione derivatives (Fig 23)

OO

NHNH2

CH3Br

KOH CS2O

CH3Br

NN

O

SH

Figure 23

Kalagouda Gudasi et al [207] studied the new ligand for 56-(5-mercapto-

134-oxadiazol-2-yl)pyridin-2-yl-134-oxadiazole-2-thiol (Fig 24)

NO

OCH3 OCH3

O

NH2NH2 C2H5OH

Reflux 4h

NO

NH NH

O

NH2 NH2

KOH 2CS2

Reflux 15 min

NO O

SH SH

Figure 24

19

Preparation of Triazole derivatives

Shipra Baluja et al [208] reported on the work for a facile synthesis and the

antimicrobial activity of some 4-aryltriazoles (Fig 25)

NHNH

O

S-

SH3CO

K+

NH

O

NH2H3CO

CS2 KOH

NHNH2

H3CO

N

N

N

NH

SH

Figure 25

Mohammad Al-Amin et al [209] reported on the synthesis of some bis-

triazole derivatives that were studied for cytotoxicity (Fig 26)

HOOC - (CH2)n -COOH Fusion

+NH2 NH

NH

NH2S

N N

N(CH2)n

N N

NSHSH

NH2NH2

Figure 26

Shivarama et al [210] carried out some trouble site reaction of new bis-

aminomercaptotriazole and bis-triazolothiadiazole as possible anticancer agents (Fig

27)

HOOCH 2CO OCH2COOHON

NN

O

N

N

N

NH2 NH2

SH SH

H2NNHCSNHNH 2

Figure 27

20

Amine reactions with ester groups

For the reactions between amines and esters the reaction is accelerated by

heating it moderately Notice that a stronger base (amine) is used up and a weaker

base (alcohol) is produced Notice also that before the alcohol (leaving group) portion

of the ester departs it picks up an H+ so that it leaves as the weak base alcohol ion

(ROH) rather than as the strong base alkoxide ion (RO-) Weaker bases make better

leaving groups Figure 28 illustrates the mechanism of the amination reaction

Figure 28 Mechanism of the amine reacted with the ester group

Suresh et al [211] studied the amination reaction (Fig 29)

CH3 OEt

O O

+

NH2

ClBuOK

EtOH

0 - 5 h rt

CH3 NH

O O

Cl

Figure 29

Shashikant et al [212] also reported on an amination reaction where a secondary

amine is formed (Fig 30)

CH3 OEt

O O

+ CH3 NH

O O

NH2

EtOH

Figure 30

21

Konstantinos et al [213] studied the fusion method ndash the solvent free reaction

of arylamines with ethyl cyanoacetates is one of the most widely used methods for the

preparation of cyanoacetanilides (Fig 31)

NH2

+

O

EtO

CN

150 degC

NH

O

CN

Figure 31

Metwally et al [214] reported on the reaction using different basic medium

conditions such as sodium ethoxide solution (Fig 32)

+

O

EtO

CN

N

S

NH2

at

EtOH

N

S

NH

O

CN

Figure 32

Bhawal et al [215] reported on the reaction of benzylamine with ethyl

cyanoacetate in tetra hydro furan (THF) containing butyl lithium as the basic catalyst

which formed N-benzylcyanoacetamide (Fig 33)

NH2

+

O

EtO

CN

THF

BuLi

NH

O

CN

Figure 33

Jianguo et al [216] reported that microwave (MW) irradiation has become an

important method in organic synthesis which can be applied to a wide range of

reactions with short reaction times and high yields (Fig 34)

22

NH2

H3CO

+

EtO

CNO

MW

trichlorobenzene

NH

H3CO

CN

O

Figure 34

Hanan et al[217] studied the amination reaction of compound 2-[4-

(ethoxycarbonyl)anilino]-3-methyl quinoxaline with primary amine (Fig 35)

N

N CH3

NH

OEtO

RNH2

N

N CH3

NH

NHOR

Figure 35

Srivastava et al [218] studied the hydrazinolysis reaction in which 124-triazole

containing an ester group reacted with thiosemicarbazide (Fig 36)

N N

N

OC2H5

ONH2 NH

CS NH2

N N

N

NH

O

NH

CS

NH2

Figure 36

Swati ojha et al [219] studied the reaction in which benzotriazole containing

ethyl chloroacetate is converted to carbothioamide by the hydrazinolysis method (Fig

37)

23

N

NN

O

OEt

NH2 NH

CS NH2

N

NN

O

NHNH

CSNH2

Figure 37

Preparation of triazole derivatives

R

S

HN NH

S

HN

R

N

N

HN

R

H

SHR

S

N

N

HN

R

R

S10 NaOH

HCl

-H2S

Figure 38 Mechanism of the triazole preparation

Maymona et al [220] and Barnela et al [221] studied the Vilsmeier-Haack

reaction mechanism of triazole preparation using hydrolysis of 10 sodium hydroxide

solution followed by acidification with dilute hydrochloric acid to give 5-thioxo-

134-triazol derivatives (Fig 39)

Figure 39

Otilia Pintilie et al [222] prepared triazole derivatives via the hydrolysis of

10 sodium hydroxide solution followed by acidification with dilute hydrochloric

acid (Fig 40)

24

H3CS CONH

NH

O2N

NH NH

S

CH3

NaOH

H3CS

NH

O2N

NN

N

CH3

SH

Figure 40

Mohamed Belkadi et al [223] studied the steps involved in the treatment of

(plusmn)-22-dimethyl-[13]dioxolan-4-carboxylic-acid-hydrazide-thioformamido-semicarb

azide with NaOH in absolute ethanol under reflux for five hours to give (plusmn)-5-(22-

dimethyl-[13]dioxolan-4-yl)-4H-[124]triazole-3-thiol (Fig 41)

Figure 41

Hussain et al [224] synthesized thiadiazole and 124-triazole derivatives from

cyclopropane dicarboxylic acid (Fig 42)

HOOCCOOH

SOCl2 H2NNHCSNH2H2NSCHNNOC

CONNHCSNH2

NaOHN

NH

N

NH

NN

SH

SH

Figure 42

25

Sibel Demir et al [225] studied the crystallographic analysis of compound 55rsquo-

pyridine-26-diylbis[4-ethyl-24-dihydro-124-triazole-3(2H)-thione (Fig 43)

NNHNH

OO

NH NH

S

NHNH

O

CH3 CH3

NaOH

NN

N

N

N

N

N

SH SHCH3

CH3

Figure 43

Preparation of thiadiazole derivatives

Foroumadi et al [226] reported on the anticonvulsant activity of novel 2-amino-

5-[4-chloro-2-(2-chlorophenoxy) phenyl]-134-thiadiazole derivatives (Fig 44)

OCl

Cl

NH

O

NH NH2

S H2SO4

NH4OH

OCl

Cl

N

S

N

NH2

Figure 44

Otilia Pintilie et al [227] reported on the synthesis and antimicrobial activity of

some new 134-thiadiazole and 124-triazole compounds which had a DL-

methionine moiety (Fig 45)

Figure 45

26

Srivastava et al [228] studied the synthesis of a new 124- triazolo-thia

diazole as antimicrobial anticonvulsant and anti-inflammatory agents (Fig 46)

N

NN

O

NHNH NH2

SH2SO4

NH3

N

NN

N

S

N

NH2

Figure 46

Swati Ojha et al [229] studied the conversion of benzatriazole containing

thiosemicarbazone into thiadiazole derivatives with the help of H2SO4 by the

cyclization method (Fig 47)

N

NN

O

NHNH NH2

S H2SO4 NH3

N

NN

S

N N

NH2

Figure 47

Hussain et al [230] synthesized thiadiazole and 124-triazole derivatives from

cyclopropane dicarboxylic acid (Fig 48)

N

S

N

S

NN

NH2 NH2

HOOCCOOH POCl3 H2NNHCSNH2

Figure 48

27

Preparation pyrazole and thiazole derivatives

El-Sayed Rashad et al [231] studied the synthesis of the biologically active

pyrazoles and C-nucleosides (Fig 49)

NHNH2

CH3

O

OEt

O

AcOH heatN N

CH3 O

Figure 49

Hamied latif et al [232] Zevrsquoyalow et al [233] and More et al [234] have

reported by thazole derivative (Fig 50) and their biologically importance

CH3

O

I2 CH2I

ONH2

NH2

S

N

SNH2

Figure 50

Preparation of imidazolidin-4-thioxo-2-one derivatives

Renata Jakse et al [235] studied the progresses in the synthesis and reactions

of imidazolidin and its derivatives in particular the stereoselective synthesis of

5-[heteroaryl methylidene]-substituted hydantoins and thiohydantoins as aplysinopsin

analogues (Fig 51)

NH

N

NCH3

CH3

O

S

Figure 51

28

Giulio et al [236] studied the synthesis of CB1 (cannabinoid) receptor ligands

and evaluated their pharmacological properties (Fig 52)

N

NH

CH3

O S

Cl

Cl

Figure 52

Janos Marton et al [237] studied the fungicidal activity of 5-substituted

hydantoins and their 2-thio analogues (Fig 53)

NH

NH

S

S

CHO

NH NH

O

S

Figure 53

2-Thiohydrotoin was reacted with aromatic aldehydes to give the corresponding

arylmethylene derivatives reported by Wheeler et al[238] and Lubomir Floch et al

[239] studied the synthesis of 5- substituted-3-amino-2-thioxo-4-imidazolidinones

(Fig 54)

H

CO2Et

NCS NH2 NH2 H2O

MeOH or EtOH Et2O

H

CO2Et

NH

NHNH2

S

NH

N

O

SH

NH2

Figure 54

29

Zerong Daniel wang et al [240] reported that synthesis of 2-thiohydantoins

derivative (Fig 55)

N N

NH2

CH3

CH3

OH

O

+ NH

S

NH2

CH2

NH

N

CH3CH3

S

O

CH2

+NH

NH

CH3CH3

O

S

Figure 55

Farzin Hadizadeh et al [241] prepared the thiosemicarbazone derivatives (Fig

56)

NH

N

CH3 CHO

NH2 NH

NH2

S NH

N

CH3

NNH

NH2

S

Figure 56

Peesapati Venkateswarlu et al [242] studied the semicarbazone derivatives

from bi-cyclic ketones reacted with semicarbazide hydrochloride (Fig 57)

O

CH3

NH2 NH

NH2

O

N

CH3

NH

NH2O

HCl

AcONa and EtOH

Figure 57

Natesh Ramesh kumar et al [243] reported that thiosemicarbazide reacted

with ketone derivatives to give the corresponding thiosemicarbazone derivatives (Fig

58)

30

CH3

CH3

O

+

HO

Cl

N

O

CH3

CH3

Cl

NH2 NH

NH2

S

N

N

CH3

CH3

NH

NH2S

Cl

HO

CH3COONH4

Figure 58

Sampath et al [244] studied the crystal structure and conformation of

N-methyl-t-3-methyl-R-2C-6-diphenylpipridin-4-one thiosemicarbazone (Fig 59)

CH3

CH3

O

+

HO

+ CH3 NH2

99 Ethanol

N

O

CH3

CH3

NH2 NH

NH2

S

methanol HCl N

N

CH3

CH3

NH

NH2S

Figure 59

Jamal Abdul Nasser et al [245] studied the imidazolidin ring prepared from

thiosemicabazone reacted with ethyl chloroacetate and fused sodium acetate by the

cyclization method (Fig 60)

NNH NH2

S

Cl

OC2H5

O

NaOAc

NN

NH

S

O

Figure 60

31

The above literature findings were taken as the basis on which to synthesize

pyrrole pyridine and imidazolidine derivatives

Pyrrole derivatives are mentioned in schemes 1-3

Pyridine derivatives are mentioned in scheme 3

Imidazolidine derivatives are mentioned in schemes 4 -7

All of the synthetic compounds were characterized by Infrared (IR) Proton Nuclear

magnetic resonance (sup1H-NMR) Carbon Nuclear magnetic resonance (13

C-NMR)

Mass spectral and elemental analyses The selected compounds were screened for the

following biological activities

In vitro antimicrobial anticoagulant anticancer and antioxidant activities

In vivo anti-convulsant anti-inflammatory and analogous activities

Environmental toxicity analysis

12

isoquinolone thiosemicarbazone on the mammalian ribonucleotide reductase to

understand the environment of the active site and the reaction mechanism of the

enzyme [184] French and Freelander et al [185] suggested that some antitumor

agents also possess the ability to function as chelating agents Thiosemicarbazone

(TSC) derivatives exhibit a wide spectrum of biological activities such as antitumor

antimalarial [186] antiviral [187] antibacterial [188] and antifertility activities [189]

In addition these derivatives possess non-linear optical properties [190]

13

(12) Literature review

Preparation of starting compound of pyrrole derivatives

Fischer and Noller [191] synthesized the compound diethyl 35-dimethyl-1H-

pyrrole-24-dicarboxylate (Fig 9) and this compound was used as one of the base

compounds in this research

CH3OEt

O O

CH3OEt

O O

NOH

CH3OEt

O O

NOHCH3

OEt

O O

NH2

EtO2C NH2

OHCH3

+

O CH3

O

CO2Et

HOAcNH

CH3

CH3

OEt

O

O

EtO

NaNO2

HOAc H2O

Zn HOAc

H2O

Figure 9

Fischer et al [192] studied the modification of the pyrrole structure using ethyl

2-(4-acetyl-35-dimethyl-1H-pyrrol-2-yl)-2-oxoacetate (Fig 10)

+

O CH3

O

CH3

NH

CH3

CH3

O

O

EtO2C

CH3OCH3

EtO2C NH2

-2H2O

Figure 10

Paine et al [193] proposed regioselectivity of pyrrole synthesis from diethyl

aminomalonate and 13-diketones (Figs 11 and 12)

14

+

CH3 O

EtO2C

Ac

OH

NaNO2 AcOH H2O

Zn AcOH

NH

OEt

O

EtO

O

CH3

CH3

+NH

CH3

O

OEt

Figure 11

+

CH3 O

EtO2CN

OH

Ac

OH

Zn AcOHNH

OEt

O

EtO

O

CH3

CH3

+NH

CH3

O

OEt

Figure 12

Fabiano et al [194] reported on the reactions between ethyl 2-aminoaceto

acetate and an excess of ethyl acetoacetate leading to diethyl 24-dimethylpyrrole-35-

dicarboxylate (Fig13)

+

CH3 O

EtO2CNH2

NH

OEt

O

EtO

O

CH3

CH3

CH3

O

EtO

O

Et3N

Figure 13

Lipshutz et al [195] reported that under catalytic conditions of catalytic Ni(0)

and Me2NHmiddotBH3K2CO3 a (Carbobenzyloxy) Cbz-protected nitrogen which is part of a

heteroaromatic ring can be chemospecifically cleaved without affecting the Cbz

group on the original basic amine (Fig 14)

K2CO3 Me2NHBH3 NiCl2(PPh3)2 PPh3

MeCN

N

OEt

O

EtO

O

CH3

CH3

OO

N

OEt

O

EtO

O

CH3

CH3

H

Figure 14

15

Bennasar et al [196] have studied the tributylstannyl radicals promote the

deprotection of N-Cbz derivatives of amides and nitrogen-containing heteroaromatic

rings These radical conditions do not affect N-Cbz derivatives of basic amines

(Fig15)

Bu3SnHN

OEt

O

EtO

O

CH3

CH3

OON

OEt

O

EtO

O

CH3

CH3

H

30min reflux

Figure 15

Preparation of base compounds of 14-dihydropyridine derivatives

Described more than a century ago by Hussain et al [197] dialkyl 14-

dihydro-26-dimethylpyridine-35-dicarboxylates are recognized as vital drugs in the

treatment of angina and hypertension In 1882 Hantzsch first reported the synthesis of

dialkyl 14-dihydro-26-dimethylpyridine-35-dicarboxylates from a refluxing mixture

of an aldehyde a β-ketoester and aqueous ammonium hydroxide in ethanol More

than a century ago the 14-DHPDs were first obtained by Hantzsch and Liebigs [198]

This reaction involved a one-pot condensation of an aldehyde with ethyl acetoacetate

and ammonia either in acetic acid or refluxing in alcohol for a longer period

Hadizadeh et al [199] synthesized 4-(1-phenylmethyl-5-imidazolyl)-14-dihydropyri

dines as calcium channel antagonists (Fig 16)

16

N

N

NHH3CS

CHOCH3COCH2COOC2H5 NH4OH

NH

CH3 CH3

COOC2H5H5C2OOC

N

N

SCH3

Figure 16

Bhavik Desai et al [200] synthesized 4-substituted phenyl-26-dimethyl-35-

bis-N-(4-chlorophenyl)carbamoyl-14-dihydropyridines and Quantitative structural

activity relationship (QSAR) studies of these compounds showed that they were

potential antitubercular agents (Fig 17)

CH3

NH

O

O

Cl

+CHO

NH3 CH3OH

Reflux

NH

NH

OO

NH

CH3 CH3

Cl Cl

Figure 17

Amini et al [201] carried out the synthesis and confirmed the antitubercular

activity of new NN-diaryl-4-(45-dichloroimidazole-2-yl)-14-dihydro-26-dimethyl-

35-pyridinedicarbox amides (Fig 18)

N

NHCl

Cl

CHO

+CH3 NH

O O

NH4OAc

MeOH reflux

NH

NH

O

NH

N NH

Cl Cl

CH3 CH3

O

Figure 18

17

Shashikant et al [202] studied the synthesis and evaluation of some 1 4-

dihydropyridines and their derivatives as antihypertensive agent (Fig 19)

CH3 NH

O O

+

CHO

Reflux 10 - 12h

Ammonia ( 25 )

Methanol

NH

OC CONH NH

CH3 CH3

Figure 19

Suresh et al [203] studied the synthesis and bronchodilatory activity of new 4-

aryl-35-bis(2-chlorophenyl)-carbonyl-26-dimethyl-14-dihydropyridines and their 1-

substituted analogues (Fig 20)

CH3 NH

O OCl

+

CHONH

NH NH

CH3 CH3

Cl ClO O

+ NH3

AcOH - MeOH

12 - 28 h

Figure 20

Sobin [204] reported the hydrazinolysis method by hydrazine hydrate was

reacted with an ester group and Suresh et al [205] reported that pyrrole derivatives

condense with hydrazine hydrate (Fig 21)

NH

CH3

CH3H3CH2CO

O

OCH 2CH3

O NH

CH3

CH3

O

NH

O

NH

NH2

NH2NH2 NH2

Figure 21

18

Preparation of oxadiazole derivatives

R

O

HN NH2

N

O

N

R

SH-H2S

+ S C

S

KOH

alcoholR

O

HN NH

S

HS

N

O

HN

R

S

H

SH

Figure 22 Mechanism of the oxadiazole preparation

Figure 22 shows the mechanism for the preparation of oxadiazole derivatives

Akhtar et al[206] reported on the in vitro antitumour and antiviral activities of new

benzothiazole and 134-oxadiazole-2-thione derivatives (Fig 23)

OO

NHNH2

CH3Br

KOH CS2O

CH3Br

NN

O

SH

Figure 23

Kalagouda Gudasi et al [207] studied the new ligand for 56-(5-mercapto-

134-oxadiazol-2-yl)pyridin-2-yl-134-oxadiazole-2-thiol (Fig 24)

NO

OCH3 OCH3

O

NH2NH2 C2H5OH

Reflux 4h

NO

NH NH

O

NH2 NH2

KOH 2CS2

Reflux 15 min

NO O

SH SH

Figure 24

19

Preparation of Triazole derivatives

Shipra Baluja et al [208] reported on the work for a facile synthesis and the

antimicrobial activity of some 4-aryltriazoles (Fig 25)

NHNH

O

S-

SH3CO

K+

NH

O

NH2H3CO

CS2 KOH

NHNH2

H3CO

N

N

N

NH

SH

Figure 25

Mohammad Al-Amin et al [209] reported on the synthesis of some bis-

triazole derivatives that were studied for cytotoxicity (Fig 26)

HOOC - (CH2)n -COOH Fusion

+NH2 NH

NH

NH2S

N N

N(CH2)n

N N

NSHSH

NH2NH2

Figure 26

Shivarama et al [210] carried out some trouble site reaction of new bis-

aminomercaptotriazole and bis-triazolothiadiazole as possible anticancer agents (Fig

27)

HOOCH 2CO OCH2COOHON

NN

O

N

N

N

NH2 NH2

SH SH

H2NNHCSNHNH 2

Figure 27

20

Amine reactions with ester groups

For the reactions between amines and esters the reaction is accelerated by

heating it moderately Notice that a stronger base (amine) is used up and a weaker

base (alcohol) is produced Notice also that before the alcohol (leaving group) portion

of the ester departs it picks up an H+ so that it leaves as the weak base alcohol ion

(ROH) rather than as the strong base alkoxide ion (RO-) Weaker bases make better

leaving groups Figure 28 illustrates the mechanism of the amination reaction

Figure 28 Mechanism of the amine reacted with the ester group

Suresh et al [211] studied the amination reaction (Fig 29)

CH3 OEt

O O

+

NH2

ClBuOK

EtOH

0 - 5 h rt

CH3 NH

O O

Cl

Figure 29

Shashikant et al [212] also reported on an amination reaction where a secondary

amine is formed (Fig 30)

CH3 OEt

O O

+ CH3 NH

O O

NH2

EtOH

Figure 30

21

Konstantinos et al [213] studied the fusion method ndash the solvent free reaction

of arylamines with ethyl cyanoacetates is one of the most widely used methods for the

preparation of cyanoacetanilides (Fig 31)

NH2

+

O

EtO

CN

150 degC

NH

O

CN

Figure 31

Metwally et al [214] reported on the reaction using different basic medium

conditions such as sodium ethoxide solution (Fig 32)

+

O

EtO

CN

N

S

NH2

at

EtOH

N

S

NH

O

CN

Figure 32

Bhawal et al [215] reported on the reaction of benzylamine with ethyl

cyanoacetate in tetra hydro furan (THF) containing butyl lithium as the basic catalyst

which formed N-benzylcyanoacetamide (Fig 33)

NH2

+

O

EtO

CN

THF

BuLi

NH

O

CN

Figure 33

Jianguo et al [216] reported that microwave (MW) irradiation has become an

important method in organic synthesis which can be applied to a wide range of

reactions with short reaction times and high yields (Fig 34)

22

NH2

H3CO

+

EtO

CNO

MW

trichlorobenzene

NH

H3CO

CN

O

Figure 34

Hanan et al[217] studied the amination reaction of compound 2-[4-

(ethoxycarbonyl)anilino]-3-methyl quinoxaline with primary amine (Fig 35)

N

N CH3

NH

OEtO

RNH2

N

N CH3

NH

NHOR

Figure 35

Srivastava et al [218] studied the hydrazinolysis reaction in which 124-triazole

containing an ester group reacted with thiosemicarbazide (Fig 36)

N N

N

OC2H5

ONH2 NH

CS NH2

N N

N

NH

O

NH

CS

NH2

Figure 36

Swati ojha et al [219] studied the reaction in which benzotriazole containing

ethyl chloroacetate is converted to carbothioamide by the hydrazinolysis method (Fig

37)

23

N

NN

O

OEt

NH2 NH

CS NH2

N

NN

O

NHNH

CSNH2

Figure 37

Preparation of triazole derivatives

R

S

HN NH

S

HN

R

N

N

HN

R

H

SHR

S

N

N

HN

R

R

S10 NaOH

HCl

-H2S

Figure 38 Mechanism of the triazole preparation

Maymona et al [220] and Barnela et al [221] studied the Vilsmeier-Haack

reaction mechanism of triazole preparation using hydrolysis of 10 sodium hydroxide

solution followed by acidification with dilute hydrochloric acid to give 5-thioxo-

134-triazol derivatives (Fig 39)

Figure 39

Otilia Pintilie et al [222] prepared triazole derivatives via the hydrolysis of

10 sodium hydroxide solution followed by acidification with dilute hydrochloric

acid (Fig 40)

24

H3CS CONH

NH

O2N

NH NH

S

CH3

NaOH

H3CS

NH

O2N

NN

N

CH3

SH

Figure 40

Mohamed Belkadi et al [223] studied the steps involved in the treatment of

(plusmn)-22-dimethyl-[13]dioxolan-4-carboxylic-acid-hydrazide-thioformamido-semicarb

azide with NaOH in absolute ethanol under reflux for five hours to give (plusmn)-5-(22-

dimethyl-[13]dioxolan-4-yl)-4H-[124]triazole-3-thiol (Fig 41)

Figure 41

Hussain et al [224] synthesized thiadiazole and 124-triazole derivatives from

cyclopropane dicarboxylic acid (Fig 42)

HOOCCOOH

SOCl2 H2NNHCSNH2H2NSCHNNOC

CONNHCSNH2

NaOHN

NH

N

NH

NN

SH

SH

Figure 42

25

Sibel Demir et al [225] studied the crystallographic analysis of compound 55rsquo-

pyridine-26-diylbis[4-ethyl-24-dihydro-124-triazole-3(2H)-thione (Fig 43)

NNHNH

OO

NH NH

S

NHNH

O

CH3 CH3

NaOH

NN

N

N

N

N

N

SH SHCH3

CH3

Figure 43

Preparation of thiadiazole derivatives

Foroumadi et al [226] reported on the anticonvulsant activity of novel 2-amino-

5-[4-chloro-2-(2-chlorophenoxy) phenyl]-134-thiadiazole derivatives (Fig 44)

OCl

Cl

NH

O

NH NH2

S H2SO4

NH4OH

OCl

Cl

N

S

N

NH2

Figure 44

Otilia Pintilie et al [227] reported on the synthesis and antimicrobial activity of

some new 134-thiadiazole and 124-triazole compounds which had a DL-

methionine moiety (Fig 45)

Figure 45

26

Srivastava et al [228] studied the synthesis of a new 124- triazolo-thia

diazole as antimicrobial anticonvulsant and anti-inflammatory agents (Fig 46)

N

NN

O

NHNH NH2

SH2SO4

NH3

N

NN

N

S

N

NH2

Figure 46

Swati Ojha et al [229] studied the conversion of benzatriazole containing

thiosemicarbazone into thiadiazole derivatives with the help of H2SO4 by the

cyclization method (Fig 47)

N

NN

O

NHNH NH2

S H2SO4 NH3

N

NN

S

N N

NH2

Figure 47

Hussain et al [230] synthesized thiadiazole and 124-triazole derivatives from

cyclopropane dicarboxylic acid (Fig 48)

N

S

N

S

NN

NH2 NH2

HOOCCOOH POCl3 H2NNHCSNH2

Figure 48

27

Preparation pyrazole and thiazole derivatives

El-Sayed Rashad et al [231] studied the synthesis of the biologically active

pyrazoles and C-nucleosides (Fig 49)

NHNH2

CH3

O

OEt

O

AcOH heatN N

CH3 O

Figure 49

Hamied latif et al [232] Zevrsquoyalow et al [233] and More et al [234] have

reported by thazole derivative (Fig 50) and their biologically importance

CH3

O

I2 CH2I

ONH2

NH2

S

N

SNH2

Figure 50

Preparation of imidazolidin-4-thioxo-2-one derivatives

Renata Jakse et al [235] studied the progresses in the synthesis and reactions

of imidazolidin and its derivatives in particular the stereoselective synthesis of

5-[heteroaryl methylidene]-substituted hydantoins and thiohydantoins as aplysinopsin

analogues (Fig 51)

NH

N

NCH3

CH3

O

S

Figure 51

28

Giulio et al [236] studied the synthesis of CB1 (cannabinoid) receptor ligands

and evaluated their pharmacological properties (Fig 52)

N

NH

CH3

O S

Cl

Cl

Figure 52

Janos Marton et al [237] studied the fungicidal activity of 5-substituted

hydantoins and their 2-thio analogues (Fig 53)

NH

NH

S

S

CHO

NH NH

O

S

Figure 53

2-Thiohydrotoin was reacted with aromatic aldehydes to give the corresponding

arylmethylene derivatives reported by Wheeler et al[238] and Lubomir Floch et al

[239] studied the synthesis of 5- substituted-3-amino-2-thioxo-4-imidazolidinones

(Fig 54)

H

CO2Et

NCS NH2 NH2 H2O

MeOH or EtOH Et2O

H

CO2Et

NH

NHNH2

S

NH

N

O

SH

NH2

Figure 54

29

Zerong Daniel wang et al [240] reported that synthesis of 2-thiohydantoins

derivative (Fig 55)

N N

NH2

CH3

CH3

OH

O

+ NH

S

NH2

CH2

NH

N

CH3CH3

S

O

CH2

+NH

NH

CH3CH3

O

S

Figure 55

Farzin Hadizadeh et al [241] prepared the thiosemicarbazone derivatives (Fig

56)

NH

N

CH3 CHO

NH2 NH

NH2

S NH

N

CH3

NNH

NH2

S

Figure 56

Peesapati Venkateswarlu et al [242] studied the semicarbazone derivatives

from bi-cyclic ketones reacted with semicarbazide hydrochloride (Fig 57)

O

CH3

NH2 NH

NH2

O

N

CH3

NH

NH2O

HCl

AcONa and EtOH

Figure 57

Natesh Ramesh kumar et al [243] reported that thiosemicarbazide reacted

with ketone derivatives to give the corresponding thiosemicarbazone derivatives (Fig

58)

30

CH3

CH3

O

+

HO

Cl

N

O

CH3

CH3

Cl

NH2 NH

NH2

S

N

N

CH3

CH3

NH

NH2S

Cl

HO

CH3COONH4

Figure 58

Sampath et al [244] studied the crystal structure and conformation of

N-methyl-t-3-methyl-R-2C-6-diphenylpipridin-4-one thiosemicarbazone (Fig 59)

CH3

CH3

O

+

HO

+ CH3 NH2

99 Ethanol

N

O

CH3

CH3

NH2 NH

NH2

S

methanol HCl N

N

CH3

CH3

NH

NH2S

Figure 59

Jamal Abdul Nasser et al [245] studied the imidazolidin ring prepared from

thiosemicabazone reacted with ethyl chloroacetate and fused sodium acetate by the

cyclization method (Fig 60)

NNH NH2

S

Cl

OC2H5

O

NaOAc

NN

NH

S

O

Figure 60

31

The above literature findings were taken as the basis on which to synthesize

pyrrole pyridine and imidazolidine derivatives

Pyrrole derivatives are mentioned in schemes 1-3

Pyridine derivatives are mentioned in scheme 3

Imidazolidine derivatives are mentioned in schemes 4 -7

All of the synthetic compounds were characterized by Infrared (IR) Proton Nuclear

magnetic resonance (sup1H-NMR) Carbon Nuclear magnetic resonance (13

C-NMR)

Mass spectral and elemental analyses The selected compounds were screened for the

following biological activities

In vitro antimicrobial anticoagulant anticancer and antioxidant activities

In vivo anti-convulsant anti-inflammatory and analogous activities

Environmental toxicity analysis

13

(12) Literature review

Preparation of starting compound of pyrrole derivatives

Fischer and Noller [191] synthesized the compound diethyl 35-dimethyl-1H-

pyrrole-24-dicarboxylate (Fig 9) and this compound was used as one of the base

compounds in this research

CH3OEt

O O

CH3OEt

O O

NOH

CH3OEt

O O

NOHCH3

OEt

O O

NH2

EtO2C NH2

OHCH3

+

O CH3

O

CO2Et

HOAcNH

CH3

CH3

OEt

O

O

EtO

NaNO2

HOAc H2O

Zn HOAc

H2O

Figure 9

Fischer et al [192] studied the modification of the pyrrole structure using ethyl

2-(4-acetyl-35-dimethyl-1H-pyrrol-2-yl)-2-oxoacetate (Fig 10)

+

O CH3

O

CH3

NH

CH3

CH3

O

O

EtO2C

CH3OCH3

EtO2C NH2

-2H2O

Figure 10

Paine et al [193] proposed regioselectivity of pyrrole synthesis from diethyl

aminomalonate and 13-diketones (Figs 11 and 12)

14

+

CH3 O

EtO2C

Ac

OH

NaNO2 AcOH H2O

Zn AcOH

NH

OEt

O

EtO

O

CH3

CH3

+NH

CH3

O

OEt

Figure 11

+

CH3 O

EtO2CN

OH

Ac

OH

Zn AcOHNH

OEt

O

EtO

O

CH3

CH3

+NH

CH3

O

OEt

Figure 12

Fabiano et al [194] reported on the reactions between ethyl 2-aminoaceto

acetate and an excess of ethyl acetoacetate leading to diethyl 24-dimethylpyrrole-35-

dicarboxylate (Fig13)

+

CH3 O

EtO2CNH2

NH

OEt

O

EtO

O

CH3

CH3

CH3

O

EtO

O

Et3N

Figure 13

Lipshutz et al [195] reported that under catalytic conditions of catalytic Ni(0)

and Me2NHmiddotBH3K2CO3 a (Carbobenzyloxy) Cbz-protected nitrogen which is part of a

heteroaromatic ring can be chemospecifically cleaved without affecting the Cbz

group on the original basic amine (Fig 14)

K2CO3 Me2NHBH3 NiCl2(PPh3)2 PPh3

MeCN

N

OEt

O

EtO

O

CH3

CH3

OO

N

OEt

O

EtO

O

CH3

CH3

H

Figure 14

15

Bennasar et al [196] have studied the tributylstannyl radicals promote the

deprotection of N-Cbz derivatives of amides and nitrogen-containing heteroaromatic

rings These radical conditions do not affect N-Cbz derivatives of basic amines

(Fig15)

Bu3SnHN

OEt

O

EtO

O

CH3

CH3

OON

OEt

O

EtO

O

CH3

CH3

H

30min reflux

Figure 15

Preparation of base compounds of 14-dihydropyridine derivatives

Described more than a century ago by Hussain et al [197] dialkyl 14-

dihydro-26-dimethylpyridine-35-dicarboxylates are recognized as vital drugs in the

treatment of angina and hypertension In 1882 Hantzsch first reported the synthesis of

dialkyl 14-dihydro-26-dimethylpyridine-35-dicarboxylates from a refluxing mixture

of an aldehyde a β-ketoester and aqueous ammonium hydroxide in ethanol More

than a century ago the 14-DHPDs were first obtained by Hantzsch and Liebigs [198]

This reaction involved a one-pot condensation of an aldehyde with ethyl acetoacetate

and ammonia either in acetic acid or refluxing in alcohol for a longer period

Hadizadeh et al [199] synthesized 4-(1-phenylmethyl-5-imidazolyl)-14-dihydropyri

dines as calcium channel antagonists (Fig 16)

16

N

N

NHH3CS

CHOCH3COCH2COOC2H5 NH4OH

NH

CH3 CH3

COOC2H5H5C2OOC

N

N

SCH3

Figure 16

Bhavik Desai et al [200] synthesized 4-substituted phenyl-26-dimethyl-35-

bis-N-(4-chlorophenyl)carbamoyl-14-dihydropyridines and Quantitative structural

activity relationship (QSAR) studies of these compounds showed that they were

potential antitubercular agents (Fig 17)

CH3

NH

O

O

Cl

+CHO

NH3 CH3OH

Reflux

NH

NH

OO

NH

CH3 CH3

Cl Cl

Figure 17

Amini et al [201] carried out the synthesis and confirmed the antitubercular

activity of new NN-diaryl-4-(45-dichloroimidazole-2-yl)-14-dihydro-26-dimethyl-

35-pyridinedicarbox amides (Fig 18)

N

NHCl

Cl

CHO

+CH3 NH

O O

NH4OAc

MeOH reflux

NH

NH

O

NH

N NH

Cl Cl

CH3 CH3

O

Figure 18

17

Shashikant et al [202] studied the synthesis and evaluation of some 1 4-

dihydropyridines and their derivatives as antihypertensive agent (Fig 19)

CH3 NH

O O

+

CHO

Reflux 10 - 12h

Ammonia ( 25 )

Methanol

NH

OC CONH NH

CH3 CH3

Figure 19

Suresh et al [203] studied the synthesis and bronchodilatory activity of new 4-

aryl-35-bis(2-chlorophenyl)-carbonyl-26-dimethyl-14-dihydropyridines and their 1-

substituted analogues (Fig 20)

CH3 NH

O OCl

+

CHONH

NH NH

CH3 CH3

Cl ClO O

+ NH3

AcOH - MeOH

12 - 28 h

Figure 20

Sobin [204] reported the hydrazinolysis method by hydrazine hydrate was

reacted with an ester group and Suresh et al [205] reported that pyrrole derivatives

condense with hydrazine hydrate (Fig 21)

NH

CH3

CH3H3CH2CO

O

OCH 2CH3

O NH

CH3

CH3

O

NH

O

NH

NH2

NH2NH2 NH2

Figure 21

18

Preparation of oxadiazole derivatives

R

O

HN NH2

N

O

N

R

SH-H2S

+ S C

S

KOH

alcoholR

O

HN NH

S

HS

N

O

HN

R

S

H

SH

Figure 22 Mechanism of the oxadiazole preparation

Figure 22 shows the mechanism for the preparation of oxadiazole derivatives

Akhtar et al[206] reported on the in vitro antitumour and antiviral activities of new

benzothiazole and 134-oxadiazole-2-thione derivatives (Fig 23)

OO

NHNH2

CH3Br

KOH CS2O

CH3Br

NN

O

SH

Figure 23

Kalagouda Gudasi et al [207] studied the new ligand for 56-(5-mercapto-

134-oxadiazol-2-yl)pyridin-2-yl-134-oxadiazole-2-thiol (Fig 24)

NO

OCH3 OCH3

O

NH2NH2 C2H5OH

Reflux 4h

NO

NH NH

O

NH2 NH2

KOH 2CS2

Reflux 15 min

NO O

SH SH

Figure 24

19

Preparation of Triazole derivatives

Shipra Baluja et al [208] reported on the work for a facile synthesis and the

antimicrobial activity of some 4-aryltriazoles (Fig 25)

NHNH

O

S-

SH3CO

K+

NH

O

NH2H3CO

CS2 KOH

NHNH2

H3CO

N

N

N

NH

SH

Figure 25

Mohammad Al-Amin et al [209] reported on the synthesis of some bis-

triazole derivatives that were studied for cytotoxicity (Fig 26)

HOOC - (CH2)n -COOH Fusion

+NH2 NH

NH

NH2S

N N

N(CH2)n

N N

NSHSH

NH2NH2

Figure 26

Shivarama et al [210] carried out some trouble site reaction of new bis-

aminomercaptotriazole and bis-triazolothiadiazole as possible anticancer agents (Fig

27)

HOOCH 2CO OCH2COOHON

NN

O

N

N

N

NH2 NH2

SH SH

H2NNHCSNHNH 2

Figure 27

20

Amine reactions with ester groups

For the reactions between amines and esters the reaction is accelerated by

heating it moderately Notice that a stronger base (amine) is used up and a weaker

base (alcohol) is produced Notice also that before the alcohol (leaving group) portion

of the ester departs it picks up an H+ so that it leaves as the weak base alcohol ion

(ROH) rather than as the strong base alkoxide ion (RO-) Weaker bases make better

leaving groups Figure 28 illustrates the mechanism of the amination reaction

Figure 28 Mechanism of the amine reacted with the ester group

Suresh et al [211] studied the amination reaction (Fig 29)

CH3 OEt

O O

+

NH2

ClBuOK

EtOH

0 - 5 h rt

CH3 NH

O O

Cl

Figure 29

Shashikant et al [212] also reported on an amination reaction where a secondary

amine is formed (Fig 30)

CH3 OEt

O O

+ CH3 NH

O O

NH2

EtOH

Figure 30

21

Konstantinos et al [213] studied the fusion method ndash the solvent free reaction

of arylamines with ethyl cyanoacetates is one of the most widely used methods for the

preparation of cyanoacetanilides (Fig 31)

NH2

+

O

EtO

CN

150 degC

NH

O

CN

Figure 31

Metwally et al [214] reported on the reaction using different basic medium

conditions such as sodium ethoxide solution (Fig 32)

+

O

EtO

CN

N

S

NH2

at

EtOH

N

S

NH

O

CN

Figure 32

Bhawal et al [215] reported on the reaction of benzylamine with ethyl

cyanoacetate in tetra hydro furan (THF) containing butyl lithium as the basic catalyst

which formed N-benzylcyanoacetamide (Fig 33)

NH2

+

O

EtO

CN

THF

BuLi

NH

O

CN

Figure 33

Jianguo et al [216] reported that microwave (MW) irradiation has become an

important method in organic synthesis which can be applied to a wide range of

reactions with short reaction times and high yields (Fig 34)

22

NH2

H3CO

+

EtO

CNO

MW

trichlorobenzene

NH

H3CO

CN

O

Figure 34

Hanan et al[217] studied the amination reaction of compound 2-[4-

(ethoxycarbonyl)anilino]-3-methyl quinoxaline with primary amine (Fig 35)

N

N CH3

NH

OEtO

RNH2

N

N CH3

NH

NHOR

Figure 35

Srivastava et al [218] studied the hydrazinolysis reaction in which 124-triazole

containing an ester group reacted with thiosemicarbazide (Fig 36)

N N

N

OC2H5

ONH2 NH

CS NH2

N N

N

NH

O

NH

CS

NH2

Figure 36

Swati ojha et al [219] studied the reaction in which benzotriazole containing

ethyl chloroacetate is converted to carbothioamide by the hydrazinolysis method (Fig

37)

23

N

NN

O

OEt

NH2 NH

CS NH2

N

NN

O

NHNH

CSNH2

Figure 37

Preparation of triazole derivatives

R

S

HN NH

S

HN

R

N

N

HN

R

H

SHR

S

N

N

HN

R

R

S10 NaOH

HCl

-H2S

Figure 38 Mechanism of the triazole preparation

Maymona et al [220] and Barnela et al [221] studied the Vilsmeier-Haack

reaction mechanism of triazole preparation using hydrolysis of 10 sodium hydroxide

solution followed by acidification with dilute hydrochloric acid to give 5-thioxo-

134-triazol derivatives (Fig 39)

Figure 39

Otilia Pintilie et al [222] prepared triazole derivatives via the hydrolysis of

10 sodium hydroxide solution followed by acidification with dilute hydrochloric

acid (Fig 40)

24

H3CS CONH

NH

O2N

NH NH

S

CH3

NaOH

H3CS

NH

O2N

NN

N

CH3

SH

Figure 40

Mohamed Belkadi et al [223] studied the steps involved in the treatment of

(plusmn)-22-dimethyl-[13]dioxolan-4-carboxylic-acid-hydrazide-thioformamido-semicarb

azide with NaOH in absolute ethanol under reflux for five hours to give (plusmn)-5-(22-

dimethyl-[13]dioxolan-4-yl)-4H-[124]triazole-3-thiol (Fig 41)

Figure 41

Hussain et al [224] synthesized thiadiazole and 124-triazole derivatives from

cyclopropane dicarboxylic acid (Fig 42)

HOOCCOOH

SOCl2 H2NNHCSNH2H2NSCHNNOC

CONNHCSNH2

NaOHN

NH

N

NH

NN

SH

SH

Figure 42

25

Sibel Demir et al [225] studied the crystallographic analysis of compound 55rsquo-

pyridine-26-diylbis[4-ethyl-24-dihydro-124-triazole-3(2H)-thione (Fig 43)

NNHNH

OO

NH NH

S

NHNH

O

CH3 CH3

NaOH

NN

N

N

N

N

N

SH SHCH3

CH3

Figure 43

Preparation of thiadiazole derivatives

Foroumadi et al [226] reported on the anticonvulsant activity of novel 2-amino-

5-[4-chloro-2-(2-chlorophenoxy) phenyl]-134-thiadiazole derivatives (Fig 44)

OCl

Cl

NH

O

NH NH2

S H2SO4

NH4OH

OCl

Cl

N

S

N

NH2

Figure 44

Otilia Pintilie et al [227] reported on the synthesis and antimicrobial activity of

some new 134-thiadiazole and 124-triazole compounds which had a DL-

methionine moiety (Fig 45)

Figure 45

26

Srivastava et al [228] studied the synthesis of a new 124- triazolo-thia

diazole as antimicrobial anticonvulsant and anti-inflammatory agents (Fig 46)

N

NN

O

NHNH NH2

SH2SO4

NH3

N

NN

N

S

N

NH2

Figure 46

Swati Ojha et al [229] studied the conversion of benzatriazole containing

thiosemicarbazone into thiadiazole derivatives with the help of H2SO4 by the

cyclization method (Fig 47)

N

NN

O

NHNH NH2

S H2SO4 NH3

N

NN

S

N N

NH2

Figure 47

Hussain et al [230] synthesized thiadiazole and 124-triazole derivatives from

cyclopropane dicarboxylic acid (Fig 48)

N

S

N

S

NN

NH2 NH2

HOOCCOOH POCl3 H2NNHCSNH2

Figure 48

27

Preparation pyrazole and thiazole derivatives

El-Sayed Rashad et al [231] studied the synthesis of the biologically active

pyrazoles and C-nucleosides (Fig 49)

NHNH2

CH3

O

OEt

O

AcOH heatN N

CH3 O

Figure 49

Hamied latif et al [232] Zevrsquoyalow et al [233] and More et al [234] have

reported by thazole derivative (Fig 50) and their biologically importance

CH3

O

I2 CH2I

ONH2

NH2

S

N

SNH2

Figure 50

Preparation of imidazolidin-4-thioxo-2-one derivatives

Renata Jakse et al [235] studied the progresses in the synthesis and reactions

of imidazolidin and its derivatives in particular the stereoselective synthesis of

5-[heteroaryl methylidene]-substituted hydantoins and thiohydantoins as aplysinopsin

analogues (Fig 51)

NH

N

NCH3

CH3

O

S

Figure 51

28

Giulio et al [236] studied the synthesis of CB1 (cannabinoid) receptor ligands

and evaluated their pharmacological properties (Fig 52)

N

NH

CH3

O S

Cl

Cl

Figure 52

Janos Marton et al [237] studied the fungicidal activity of 5-substituted

hydantoins and their 2-thio analogues (Fig 53)

NH

NH

S

S

CHO

NH NH

O

S

Figure 53

2-Thiohydrotoin was reacted with aromatic aldehydes to give the corresponding

arylmethylene derivatives reported by Wheeler et al[238] and Lubomir Floch et al

[239] studied the synthesis of 5- substituted-3-amino-2-thioxo-4-imidazolidinones

(Fig 54)

H

CO2Et

NCS NH2 NH2 H2O

MeOH or EtOH Et2O

H

CO2Et

NH

NHNH2

S

NH

N

O

SH

NH2

Figure 54

29

Zerong Daniel wang et al [240] reported that synthesis of 2-thiohydantoins

derivative (Fig 55)

N N

NH2

CH3

CH3

OH

O

+ NH

S

NH2

CH2

NH

N

CH3CH3

S

O

CH2

+NH

NH

CH3CH3

O

S

Figure 55

Farzin Hadizadeh et al [241] prepared the thiosemicarbazone derivatives (Fig

56)

NH

N

CH3 CHO

NH2 NH

NH2

S NH

N

CH3

NNH

NH2

S

Figure 56

Peesapati Venkateswarlu et al [242] studied the semicarbazone derivatives

from bi-cyclic ketones reacted with semicarbazide hydrochloride (Fig 57)

O

CH3

NH2 NH

NH2

O

N

CH3

NH

NH2O

HCl

AcONa and EtOH

Figure 57

Natesh Ramesh kumar et al [243] reported that thiosemicarbazide reacted

with ketone derivatives to give the corresponding thiosemicarbazone derivatives (Fig

58)

30

CH3

CH3

O

+

HO

Cl

N

O

CH3

CH3

Cl

NH2 NH

NH2

S

N

N

CH3

CH3

NH

NH2S

Cl

HO

CH3COONH4

Figure 58

Sampath et al [244] studied the crystal structure and conformation of

N-methyl-t-3-methyl-R-2C-6-diphenylpipridin-4-one thiosemicarbazone (Fig 59)

CH3

CH3

O

+

HO

+ CH3 NH2

99 Ethanol

N

O

CH3

CH3

NH2 NH

NH2

S

methanol HCl N

N

CH3

CH3

NH

NH2S

Figure 59

Jamal Abdul Nasser et al [245] studied the imidazolidin ring prepared from

thiosemicabazone reacted with ethyl chloroacetate and fused sodium acetate by the

cyclization method (Fig 60)

NNH NH2

S

Cl

OC2H5

O

NaOAc

NN

NH

S

O

Figure 60

31

The above literature findings were taken as the basis on which to synthesize

pyrrole pyridine and imidazolidine derivatives

Pyrrole derivatives are mentioned in schemes 1-3

Pyridine derivatives are mentioned in scheme 3

Imidazolidine derivatives are mentioned in schemes 4 -7

All of the synthetic compounds were characterized by Infrared (IR) Proton Nuclear

magnetic resonance (sup1H-NMR) Carbon Nuclear magnetic resonance (13

C-NMR)

Mass spectral and elemental analyses The selected compounds were screened for the

following biological activities

In vitro antimicrobial anticoagulant anticancer and antioxidant activities

In vivo anti-convulsant anti-inflammatory and analogous activities

Environmental toxicity analysis

14

+

CH3 O

EtO2C

Ac

OH

NaNO2 AcOH H2O

Zn AcOH

NH

OEt

O

EtO

O

CH3

CH3

+NH

CH3

O

OEt

Figure 11

+

CH3 O

EtO2CN

OH

Ac

OH

Zn AcOHNH

OEt

O

EtO

O

CH3

CH3

+NH

CH3

O

OEt

Figure 12

Fabiano et al [194] reported on the reactions between ethyl 2-aminoaceto

acetate and an excess of ethyl acetoacetate leading to diethyl 24-dimethylpyrrole-35-

dicarboxylate (Fig13)

+

CH3 O

EtO2CNH2

NH

OEt

O

EtO

O

CH3

CH3

CH3

O

EtO

O

Et3N

Figure 13

Lipshutz et al [195] reported that under catalytic conditions of catalytic Ni(0)

and Me2NHmiddotBH3K2CO3 a (Carbobenzyloxy) Cbz-protected nitrogen which is part of a

heteroaromatic ring can be chemospecifically cleaved without affecting the Cbz

group on the original basic amine (Fig 14)

K2CO3 Me2NHBH3 NiCl2(PPh3)2 PPh3

MeCN

N

OEt

O

EtO

O

CH3

CH3

OO

N

OEt

O

EtO

O

CH3

CH3

H

Figure 14

15

Bennasar et al [196] have studied the tributylstannyl radicals promote the

deprotection of N-Cbz derivatives of amides and nitrogen-containing heteroaromatic

rings These radical conditions do not affect N-Cbz derivatives of basic amines

(Fig15)

Bu3SnHN

OEt

O

EtO

O

CH3

CH3

OON

OEt

O

EtO

O

CH3

CH3

H

30min reflux

Figure 15

Preparation of base compounds of 14-dihydropyridine derivatives

Described more than a century ago by Hussain et al [197] dialkyl 14-

dihydro-26-dimethylpyridine-35-dicarboxylates are recognized as vital drugs in the

treatment of angina and hypertension In 1882 Hantzsch first reported the synthesis of

dialkyl 14-dihydro-26-dimethylpyridine-35-dicarboxylates from a refluxing mixture

of an aldehyde a β-ketoester and aqueous ammonium hydroxide in ethanol More

than a century ago the 14-DHPDs were first obtained by Hantzsch and Liebigs [198]

This reaction involved a one-pot condensation of an aldehyde with ethyl acetoacetate

and ammonia either in acetic acid or refluxing in alcohol for a longer period

Hadizadeh et al [199] synthesized 4-(1-phenylmethyl-5-imidazolyl)-14-dihydropyri

dines as calcium channel antagonists (Fig 16)

16

N

N

NHH3CS

CHOCH3COCH2COOC2H5 NH4OH

NH

CH3 CH3

COOC2H5H5C2OOC

N

N

SCH3

Figure 16

Bhavik Desai et al [200] synthesized 4-substituted phenyl-26-dimethyl-35-

bis-N-(4-chlorophenyl)carbamoyl-14-dihydropyridines and Quantitative structural

activity relationship (QSAR) studies of these compounds showed that they were

potential antitubercular agents (Fig 17)

CH3

NH

O

O

Cl

+CHO

NH3 CH3OH

Reflux

NH

NH

OO

NH

CH3 CH3

Cl Cl

Figure 17

Amini et al [201] carried out the synthesis and confirmed the antitubercular

activity of new NN-diaryl-4-(45-dichloroimidazole-2-yl)-14-dihydro-26-dimethyl-

35-pyridinedicarbox amides (Fig 18)

N

NHCl

Cl

CHO

+CH3 NH

O O

NH4OAc

MeOH reflux

NH

NH

O

NH

N NH

Cl Cl

CH3 CH3

O

Figure 18

17

Shashikant et al [202] studied the synthesis and evaluation of some 1 4-

dihydropyridines and their derivatives as antihypertensive agent (Fig 19)

CH3 NH

O O

+

CHO

Reflux 10 - 12h

Ammonia ( 25 )

Methanol

NH

OC CONH NH

CH3 CH3

Figure 19

Suresh et al [203] studied the synthesis and bronchodilatory activity of new 4-

aryl-35-bis(2-chlorophenyl)-carbonyl-26-dimethyl-14-dihydropyridines and their 1-

substituted analogues (Fig 20)

CH3 NH

O OCl

+

CHONH

NH NH

CH3 CH3

Cl ClO O

+ NH3

AcOH - MeOH

12 - 28 h

Figure 20

Sobin [204] reported the hydrazinolysis method by hydrazine hydrate was

reacted with an ester group and Suresh et al [205] reported that pyrrole derivatives

condense with hydrazine hydrate (Fig 21)

NH

CH3

CH3H3CH2CO

O

OCH 2CH3

O NH

CH3

CH3

O

NH

O

NH

NH2

NH2NH2 NH2

Figure 21

18

Preparation of oxadiazole derivatives

R

O

HN NH2

N

O

N

R

SH-H2S

+ S C

S

KOH

alcoholR

O

HN NH

S

HS

N

O

HN

R

S

H

SH

Figure 22 Mechanism of the oxadiazole preparation

Figure 22 shows the mechanism for the preparation of oxadiazole derivatives

Akhtar et al[206] reported on the in vitro antitumour and antiviral activities of new

benzothiazole and 134-oxadiazole-2-thione derivatives (Fig 23)

OO

NHNH2

CH3Br

KOH CS2O

CH3Br

NN

O

SH

Figure 23

Kalagouda Gudasi et al [207] studied the new ligand for 56-(5-mercapto-

134-oxadiazol-2-yl)pyridin-2-yl-134-oxadiazole-2-thiol (Fig 24)

NO

OCH3 OCH3

O

NH2NH2 C2H5OH

Reflux 4h

NO

NH NH

O

NH2 NH2

KOH 2CS2

Reflux 15 min

NO O

SH SH

Figure 24

19

Preparation of Triazole derivatives

Shipra Baluja et al [208] reported on the work for a facile synthesis and the

antimicrobial activity of some 4-aryltriazoles (Fig 25)

NHNH

O

S-

SH3CO

K+

NH

O

NH2H3CO

CS2 KOH

NHNH2

H3CO

N

N

N

NH

SH

Figure 25

Mohammad Al-Amin et al [209] reported on the synthesis of some bis-

triazole derivatives that were studied for cytotoxicity (Fig 26)

HOOC - (CH2)n -COOH Fusion

+NH2 NH

NH

NH2S

N N

N(CH2)n

N N

NSHSH

NH2NH2

Figure 26

Shivarama et al [210] carried out some trouble site reaction of new bis-

aminomercaptotriazole and bis-triazolothiadiazole as possible anticancer agents (Fig

27)

HOOCH 2CO OCH2COOHON

NN

O

N

N

N

NH2 NH2

SH SH

H2NNHCSNHNH 2

Figure 27

20

Amine reactions with ester groups

For the reactions between amines and esters the reaction is accelerated by

heating it moderately Notice that a stronger base (amine) is used up and a weaker

base (alcohol) is produced Notice also that before the alcohol (leaving group) portion

of the ester departs it picks up an H+ so that it leaves as the weak base alcohol ion

(ROH) rather than as the strong base alkoxide ion (RO-) Weaker bases make better

leaving groups Figure 28 illustrates the mechanism of the amination reaction

Figure 28 Mechanism of the amine reacted with the ester group

Suresh et al [211] studied the amination reaction (Fig 29)

CH3 OEt

O O

+

NH2

ClBuOK

EtOH

0 - 5 h rt

CH3 NH

O O

Cl

Figure 29

Shashikant et al [212] also reported on an amination reaction where a secondary

amine is formed (Fig 30)

CH3 OEt

O O

+ CH3 NH

O O

NH2

EtOH

Figure 30

21

Konstantinos et al [213] studied the fusion method ndash the solvent free reaction

of arylamines with ethyl cyanoacetates is one of the most widely used methods for the

preparation of cyanoacetanilides (Fig 31)

NH2

+

O

EtO

CN

150 degC

NH

O

CN

Figure 31

Metwally et al [214] reported on the reaction using different basic medium

conditions such as sodium ethoxide solution (Fig 32)

+

O

EtO

CN

N

S

NH2

at

EtOH

N

S

NH

O

CN

Figure 32

Bhawal et al [215] reported on the reaction of benzylamine with ethyl

cyanoacetate in tetra hydro furan (THF) containing butyl lithium as the basic catalyst

which formed N-benzylcyanoacetamide (Fig 33)

NH2

+

O

EtO

CN

THF

BuLi

NH

O

CN

Figure 33

Jianguo et al [216] reported that microwave (MW) irradiation has become an

important method in organic synthesis which can be applied to a wide range of

reactions with short reaction times and high yields (Fig 34)

22

NH2

H3CO

+

EtO

CNO

MW

trichlorobenzene

NH

H3CO

CN

O

Figure 34

Hanan et al[217] studied the amination reaction of compound 2-[4-

(ethoxycarbonyl)anilino]-3-methyl quinoxaline with primary amine (Fig 35)

N

N CH3

NH

OEtO

RNH2

N

N CH3

NH

NHOR

Figure 35

Srivastava et al [218] studied the hydrazinolysis reaction in which 124-triazole

containing an ester group reacted with thiosemicarbazide (Fig 36)

N N

N

OC2H5

ONH2 NH

CS NH2

N N

N

NH

O

NH

CS

NH2

Figure 36

Swati ojha et al [219] studied the reaction in which benzotriazole containing

ethyl chloroacetate is converted to carbothioamide by the hydrazinolysis method (Fig

37)

23

N

NN

O

OEt

NH2 NH

CS NH2

N

NN

O

NHNH

CSNH2

Figure 37

Preparation of triazole derivatives

R

S

HN NH

S

HN

R

N

N

HN

R

H

SHR

S

N

N

HN

R

R

S10 NaOH

HCl

-H2S

Figure 38 Mechanism of the triazole preparation

Maymona et al [220] and Barnela et al [221] studied the Vilsmeier-Haack

reaction mechanism of triazole preparation using hydrolysis of 10 sodium hydroxide

solution followed by acidification with dilute hydrochloric acid to give 5-thioxo-

134-triazol derivatives (Fig 39)

Figure 39

Otilia Pintilie et al [222] prepared triazole derivatives via the hydrolysis of

10 sodium hydroxide solution followed by acidification with dilute hydrochloric

acid (Fig 40)

24

H3CS CONH

NH

O2N

NH NH

S

CH3

NaOH

H3CS

NH

O2N

NN

N

CH3

SH

Figure 40

Mohamed Belkadi et al [223] studied the steps involved in the treatment of

(plusmn)-22-dimethyl-[13]dioxolan-4-carboxylic-acid-hydrazide-thioformamido-semicarb

azide with NaOH in absolute ethanol under reflux for five hours to give (plusmn)-5-(22-

dimethyl-[13]dioxolan-4-yl)-4H-[124]triazole-3-thiol (Fig 41)

Figure 41

Hussain et al [224] synthesized thiadiazole and 124-triazole derivatives from

cyclopropane dicarboxylic acid (Fig 42)

HOOCCOOH

SOCl2 H2NNHCSNH2H2NSCHNNOC

CONNHCSNH2

NaOHN

NH

N

NH

NN

SH

SH

Figure 42

25

Sibel Demir et al [225] studied the crystallographic analysis of compound 55rsquo-

pyridine-26-diylbis[4-ethyl-24-dihydro-124-triazole-3(2H)-thione (Fig 43)

NNHNH

OO

NH NH

S

NHNH

O

CH3 CH3

NaOH

NN

N

N

N

N

N

SH SHCH3

CH3

Figure 43

Preparation of thiadiazole derivatives

Foroumadi et al [226] reported on the anticonvulsant activity of novel 2-amino-

5-[4-chloro-2-(2-chlorophenoxy) phenyl]-134-thiadiazole derivatives (Fig 44)

OCl

Cl

NH

O

NH NH2

S H2SO4

NH4OH

OCl

Cl

N

S

N

NH2

Figure 44

Otilia Pintilie et al [227] reported on the synthesis and antimicrobial activity of

some new 134-thiadiazole and 124-triazole compounds which had a DL-

methionine moiety (Fig 45)

Figure 45

26

Srivastava et al [228] studied the synthesis of a new 124- triazolo-thia

diazole as antimicrobial anticonvulsant and anti-inflammatory agents (Fig 46)

N

NN

O

NHNH NH2

SH2SO4

NH3

N

NN

N

S

N

NH2

Figure 46

Swati Ojha et al [229] studied the conversion of benzatriazole containing

thiosemicarbazone into thiadiazole derivatives with the help of H2SO4 by the

cyclization method (Fig 47)

N

NN

O

NHNH NH2

S H2SO4 NH3

N

NN

S

N N

NH2

Figure 47

Hussain et al [230] synthesized thiadiazole and 124-triazole derivatives from

cyclopropane dicarboxylic acid (Fig 48)

N

S

N

S

NN

NH2 NH2

HOOCCOOH POCl3 H2NNHCSNH2

Figure 48

27

Preparation pyrazole and thiazole derivatives

El-Sayed Rashad et al [231] studied the synthesis of the biologically active

pyrazoles and C-nucleosides (Fig 49)

NHNH2

CH3

O

OEt

O

AcOH heatN N

CH3 O

Figure 49

Hamied latif et al [232] Zevrsquoyalow et al [233] and More et al [234] have

reported by thazole derivative (Fig 50) and their biologically importance

CH3

O

I2 CH2I

ONH2

NH2

S

N

SNH2

Figure 50

Preparation of imidazolidin-4-thioxo-2-one derivatives

Renata Jakse et al [235] studied the progresses in the synthesis and reactions

of imidazolidin and its derivatives in particular the stereoselective synthesis of

5-[heteroaryl methylidene]-substituted hydantoins and thiohydantoins as aplysinopsin

analogues (Fig 51)

NH

N

NCH3

CH3

O

S

Figure 51

28

Giulio et al [236] studied the synthesis of CB1 (cannabinoid) receptor ligands

and evaluated their pharmacological properties (Fig 52)

N

NH

CH3

O S

Cl

Cl

Figure 52

Janos Marton et al [237] studied the fungicidal activity of 5-substituted

hydantoins and their 2-thio analogues (Fig 53)

NH

NH

S

S

CHO

NH NH

O

S

Figure 53

2-Thiohydrotoin was reacted with aromatic aldehydes to give the corresponding

arylmethylene derivatives reported by Wheeler et al[238] and Lubomir Floch et al

[239] studied the synthesis of 5- substituted-3-amino-2-thioxo-4-imidazolidinones

(Fig 54)

H

CO2Et

NCS NH2 NH2 H2O

MeOH or EtOH Et2O

H

CO2Et

NH

NHNH2

S

NH

N

O

SH

NH2

Figure 54

29

Zerong Daniel wang et al [240] reported that synthesis of 2-thiohydantoins

derivative (Fig 55)

N N

NH2

CH3

CH3

OH

O

+ NH

S

NH2

CH2

NH

N

CH3CH3

S

O

CH2

+NH

NH

CH3CH3

O

S

Figure 55

Farzin Hadizadeh et al [241] prepared the thiosemicarbazone derivatives (Fig

56)

NH

N

CH3 CHO

NH2 NH

NH2

S NH

N

CH3

NNH

NH2

S

Figure 56

Peesapati Venkateswarlu et al [242] studied the semicarbazone derivatives

from bi-cyclic ketones reacted with semicarbazide hydrochloride (Fig 57)

O

CH3

NH2 NH

NH2

O

N

CH3

NH

NH2O

HCl

AcONa and EtOH

Figure 57

Natesh Ramesh kumar et al [243] reported that thiosemicarbazide reacted

with ketone derivatives to give the corresponding thiosemicarbazone derivatives (Fig

58)

30

CH3

CH3

O

+

HO

Cl

N

O

CH3

CH3

Cl

NH2 NH

NH2

S

N

N

CH3

CH3

NH

NH2S

Cl

HO

CH3COONH4

Figure 58

Sampath et al [244] studied the crystal structure and conformation of

N-methyl-t-3-methyl-R-2C-6-diphenylpipridin-4-one thiosemicarbazone (Fig 59)

CH3

CH3

O

+

HO

+ CH3 NH2

99 Ethanol

N

O

CH3

CH3

NH2 NH

NH2

S

methanol HCl N

N

CH3

CH3

NH

NH2S

Figure 59

Jamal Abdul Nasser et al [245] studied the imidazolidin ring prepared from

thiosemicabazone reacted with ethyl chloroacetate and fused sodium acetate by the

cyclization method (Fig 60)

NNH NH2

S

Cl

OC2H5

O

NaOAc

NN

NH

S

O

Figure 60

31

The above literature findings were taken as the basis on which to synthesize

pyrrole pyridine and imidazolidine derivatives

Pyrrole derivatives are mentioned in schemes 1-3

Pyridine derivatives are mentioned in scheme 3

Imidazolidine derivatives are mentioned in schemes 4 -7

All of the synthetic compounds were characterized by Infrared (IR) Proton Nuclear

magnetic resonance (sup1H-NMR) Carbon Nuclear magnetic resonance (13

C-NMR)

Mass spectral and elemental analyses The selected compounds were screened for the

following biological activities

In vitro antimicrobial anticoagulant anticancer and antioxidant activities

In vivo anti-convulsant anti-inflammatory and analogous activities

Environmental toxicity analysis

15

Bennasar et al [196] have studied the tributylstannyl radicals promote the

deprotection of N-Cbz derivatives of amides and nitrogen-containing heteroaromatic

rings These radical conditions do not affect N-Cbz derivatives of basic amines

(Fig15)

Bu3SnHN

OEt

O

EtO

O

CH3

CH3

OON

OEt

O

EtO

O

CH3

CH3

H

30min reflux

Figure 15

Preparation of base compounds of 14-dihydropyridine derivatives

Described more than a century ago by Hussain et al [197] dialkyl 14-

dihydro-26-dimethylpyridine-35-dicarboxylates are recognized as vital drugs in the

treatment of angina and hypertension In 1882 Hantzsch first reported the synthesis of

dialkyl 14-dihydro-26-dimethylpyridine-35-dicarboxylates from a refluxing mixture

of an aldehyde a β-ketoester and aqueous ammonium hydroxide in ethanol More

than a century ago the 14-DHPDs were first obtained by Hantzsch and Liebigs [198]

This reaction involved a one-pot condensation of an aldehyde with ethyl acetoacetate

and ammonia either in acetic acid or refluxing in alcohol for a longer period

Hadizadeh et al [199] synthesized 4-(1-phenylmethyl-5-imidazolyl)-14-dihydropyri

dines as calcium channel antagonists (Fig 16)

16

N

N

NHH3CS

CHOCH3COCH2COOC2H5 NH4OH

NH

CH3 CH3

COOC2H5H5C2OOC

N

N

SCH3

Figure 16

Bhavik Desai et al [200] synthesized 4-substituted phenyl-26-dimethyl-35-

bis-N-(4-chlorophenyl)carbamoyl-14-dihydropyridines and Quantitative structural

activity relationship (QSAR) studies of these compounds showed that they were

potential antitubercular agents (Fig 17)

CH3

NH

O

O

Cl

+CHO

NH3 CH3OH

Reflux

NH

NH

OO

NH

CH3 CH3

Cl Cl

Figure 17

Amini et al [201] carried out the synthesis and confirmed the antitubercular

activity of new NN-diaryl-4-(45-dichloroimidazole-2-yl)-14-dihydro-26-dimethyl-

35-pyridinedicarbox amides (Fig 18)

N

NHCl

Cl

CHO

+CH3 NH

O O

NH4OAc

MeOH reflux

NH

NH

O

NH

N NH

Cl Cl

CH3 CH3

O

Figure 18

17

Shashikant et al [202] studied the synthesis and evaluation of some 1 4-

dihydropyridines and their derivatives as antihypertensive agent (Fig 19)

CH3 NH

O O

+

CHO

Reflux 10 - 12h

Ammonia ( 25 )

Methanol

NH

OC CONH NH

CH3 CH3

Figure 19

Suresh et al [203] studied the synthesis and bronchodilatory activity of new 4-

aryl-35-bis(2-chlorophenyl)-carbonyl-26-dimethyl-14-dihydropyridines and their 1-

substituted analogues (Fig 20)

CH3 NH

O OCl

+

CHONH

NH NH

CH3 CH3

Cl ClO O

+ NH3

AcOH - MeOH

12 - 28 h

Figure 20

Sobin [204] reported the hydrazinolysis method by hydrazine hydrate was

reacted with an ester group and Suresh et al [205] reported that pyrrole derivatives

condense with hydrazine hydrate (Fig 21)

NH

CH3

CH3H3CH2CO

O

OCH 2CH3

O NH

CH3

CH3

O

NH

O

NH

NH2

NH2NH2 NH2

Figure 21

18

Preparation of oxadiazole derivatives

R

O

HN NH2

N

O

N

R

SH-H2S

+ S C

S

KOH

alcoholR

O

HN NH

S

HS

N

O

HN

R

S

H

SH

Figure 22 Mechanism of the oxadiazole preparation

Figure 22 shows the mechanism for the preparation of oxadiazole derivatives

Akhtar et al[206] reported on the in vitro antitumour and antiviral activities of new

benzothiazole and 134-oxadiazole-2-thione derivatives (Fig 23)

OO

NHNH2

CH3Br

KOH CS2O

CH3Br

NN

O

SH

Figure 23

Kalagouda Gudasi et al [207] studied the new ligand for 56-(5-mercapto-

134-oxadiazol-2-yl)pyridin-2-yl-134-oxadiazole-2-thiol (Fig 24)

NO

OCH3 OCH3

O

NH2NH2 C2H5OH

Reflux 4h

NO

NH NH

O

NH2 NH2

KOH 2CS2

Reflux 15 min

NO O

SH SH

Figure 24

19

Preparation of Triazole derivatives

Shipra Baluja et al [208] reported on the work for a facile synthesis and the

antimicrobial activity of some 4-aryltriazoles (Fig 25)

NHNH

O

S-

SH3CO

K+

NH

O

NH2H3CO

CS2 KOH

NHNH2

H3CO

N

N

N

NH

SH

Figure 25

Mohammad Al-Amin et al [209] reported on the synthesis of some bis-

triazole derivatives that were studied for cytotoxicity (Fig 26)

HOOC - (CH2)n -COOH Fusion

+NH2 NH

NH

NH2S

N N

N(CH2)n

N N

NSHSH

NH2NH2

Figure 26

Shivarama et al [210] carried out some trouble site reaction of new bis-

aminomercaptotriazole and bis-triazolothiadiazole as possible anticancer agents (Fig

27)

HOOCH 2CO OCH2COOHON

NN

O

N

N

N

NH2 NH2

SH SH

H2NNHCSNHNH 2

Figure 27

20

Amine reactions with ester groups

For the reactions between amines and esters the reaction is accelerated by

heating it moderately Notice that a stronger base (amine) is used up and a weaker

base (alcohol) is produced Notice also that before the alcohol (leaving group) portion

of the ester departs it picks up an H+ so that it leaves as the weak base alcohol ion

(ROH) rather than as the strong base alkoxide ion (RO-) Weaker bases make better

leaving groups Figure 28 illustrates the mechanism of the amination reaction

Figure 28 Mechanism of the amine reacted with the ester group

Suresh et al [211] studied the amination reaction (Fig 29)

CH3 OEt

O O

+

NH2

ClBuOK

EtOH

0 - 5 h rt

CH3 NH

O O

Cl

Figure 29

Shashikant et al [212] also reported on an amination reaction where a secondary

amine is formed (Fig 30)

CH3 OEt

O O

+ CH3 NH

O O

NH2

EtOH

Figure 30

21

Konstantinos et al [213] studied the fusion method ndash the solvent free reaction

of arylamines with ethyl cyanoacetates is one of the most widely used methods for the

preparation of cyanoacetanilides (Fig 31)

NH2

+

O

EtO

CN

150 degC

NH

O

CN

Figure 31

Metwally et al [214] reported on the reaction using different basic medium

conditions such as sodium ethoxide solution (Fig 32)

+

O

EtO

CN

N

S

NH2

at

EtOH

N

S

NH

O

CN

Figure 32

Bhawal et al [215] reported on the reaction of benzylamine with ethyl

cyanoacetate in tetra hydro furan (THF) containing butyl lithium as the basic catalyst

which formed N-benzylcyanoacetamide (Fig 33)

NH2

+

O

EtO

CN

THF

BuLi

NH

O

CN

Figure 33

Jianguo et al [216] reported that microwave (MW) irradiation has become an

important method in organic synthesis which can be applied to a wide range of

reactions with short reaction times and high yields (Fig 34)

22

NH2

H3CO

+

EtO

CNO

MW

trichlorobenzene

NH

H3CO

CN

O

Figure 34

Hanan et al[217] studied the amination reaction of compound 2-[4-

(ethoxycarbonyl)anilino]-3-methyl quinoxaline with primary amine (Fig 35)

N

N CH3

NH

OEtO

RNH2

N

N CH3

NH

NHOR

Figure 35

Srivastava et al [218] studied the hydrazinolysis reaction in which 124-triazole

containing an ester group reacted with thiosemicarbazide (Fig 36)

N N

N

OC2H5

ONH2 NH

CS NH2

N N

N

NH

O

NH

CS

NH2

Figure 36

Swati ojha et al [219] studied the reaction in which benzotriazole containing

ethyl chloroacetate is converted to carbothioamide by the hydrazinolysis method (Fig

37)

23

N

NN

O

OEt

NH2 NH

CS NH2

N

NN

O

NHNH

CSNH2

Figure 37

Preparation of triazole derivatives

R

S

HN NH

S

HN

R

N

N

HN

R

H

SHR

S

N

N

HN

R

R

S10 NaOH

HCl

-H2S

Figure 38 Mechanism of the triazole preparation

Maymona et al [220] and Barnela et al [221] studied the Vilsmeier-Haack

reaction mechanism of triazole preparation using hydrolysis of 10 sodium hydroxide

solution followed by acidification with dilute hydrochloric acid to give 5-thioxo-

134-triazol derivatives (Fig 39)

Figure 39

Otilia Pintilie et al [222] prepared triazole derivatives via the hydrolysis of

10 sodium hydroxide solution followed by acidification with dilute hydrochloric

acid (Fig 40)

24

H3CS CONH

NH

O2N

NH NH

S

CH3

NaOH

H3CS

NH

O2N

NN

N

CH3

SH

Figure 40

Mohamed Belkadi et al [223] studied the steps involved in the treatment of

(plusmn)-22-dimethyl-[13]dioxolan-4-carboxylic-acid-hydrazide-thioformamido-semicarb

azide with NaOH in absolute ethanol under reflux for five hours to give (plusmn)-5-(22-

dimethyl-[13]dioxolan-4-yl)-4H-[124]triazole-3-thiol (Fig 41)

Figure 41

Hussain et al [224] synthesized thiadiazole and 124-triazole derivatives from

cyclopropane dicarboxylic acid (Fig 42)

HOOCCOOH

SOCl2 H2NNHCSNH2H2NSCHNNOC

CONNHCSNH2

NaOHN

NH

N

NH

NN

SH

SH

Figure 42

25

Sibel Demir et al [225] studied the crystallographic analysis of compound 55rsquo-

pyridine-26-diylbis[4-ethyl-24-dihydro-124-triazole-3(2H)-thione (Fig 43)

NNHNH

OO

NH NH

S

NHNH

O

CH3 CH3

NaOH

NN

N

N

N

N

N

SH SHCH3

CH3

Figure 43

Preparation of thiadiazole derivatives

Foroumadi et al [226] reported on the anticonvulsant activity of novel 2-amino-

5-[4-chloro-2-(2-chlorophenoxy) phenyl]-134-thiadiazole derivatives (Fig 44)

OCl

Cl

NH

O

NH NH2

S H2SO4

NH4OH

OCl

Cl

N

S

N

NH2

Figure 44

Otilia Pintilie et al [227] reported on the synthesis and antimicrobial activity of

some new 134-thiadiazole and 124-triazole compounds which had a DL-

methionine moiety (Fig 45)

Figure 45

26

Srivastava et al [228] studied the synthesis of a new 124- triazolo-thia

diazole as antimicrobial anticonvulsant and anti-inflammatory agents (Fig 46)

N

NN

O

NHNH NH2

SH2SO4

NH3

N

NN

N

S

N

NH2

Figure 46

Swati Ojha et al [229] studied the conversion of benzatriazole containing

thiosemicarbazone into thiadiazole derivatives with the help of H2SO4 by the

cyclization method (Fig 47)

N

NN

O

NHNH NH2

S H2SO4 NH3

N

NN

S

N N

NH2

Figure 47

Hussain et al [230] synthesized thiadiazole and 124-triazole derivatives from

cyclopropane dicarboxylic acid (Fig 48)

N

S

N

S

NN

NH2 NH2

HOOCCOOH POCl3 H2NNHCSNH2

Figure 48

27

Preparation pyrazole and thiazole derivatives

El-Sayed Rashad et al [231] studied the synthesis of the biologically active

pyrazoles and C-nucleosides (Fig 49)

NHNH2

CH3

O

OEt

O

AcOH heatN N

CH3 O

Figure 49

Hamied latif et al [232] Zevrsquoyalow et al [233] and More et al [234] have

reported by thazole derivative (Fig 50) and their biologically importance

CH3

O

I2 CH2I

ONH2

NH2

S

N

SNH2

Figure 50

Preparation of imidazolidin-4-thioxo-2-one derivatives

Renata Jakse et al [235] studied the progresses in the synthesis and reactions

of imidazolidin and its derivatives in particular the stereoselective synthesis of

5-[heteroaryl methylidene]-substituted hydantoins and thiohydantoins as aplysinopsin

analogues (Fig 51)

NH

N

NCH3

CH3

O

S

Figure 51

28

Giulio et al [236] studied the synthesis of CB1 (cannabinoid) receptor ligands

and evaluated their pharmacological properties (Fig 52)

N

NH

CH3

O S

Cl

Cl

Figure 52

Janos Marton et al [237] studied the fungicidal activity of 5-substituted

hydantoins and their 2-thio analogues (Fig 53)

NH

NH

S

S

CHO

NH NH

O

S

Figure 53

2-Thiohydrotoin was reacted with aromatic aldehydes to give the corresponding

arylmethylene derivatives reported by Wheeler et al[238] and Lubomir Floch et al

[239] studied the synthesis of 5- substituted-3-amino-2-thioxo-4-imidazolidinones

(Fig 54)

H

CO2Et

NCS NH2 NH2 H2O

MeOH or EtOH Et2O

H

CO2Et

NH

NHNH2

S

NH

N

O

SH

NH2

Figure 54

29

Zerong Daniel wang et al [240] reported that synthesis of 2-thiohydantoins

derivative (Fig 55)

N N

NH2

CH3

CH3

OH

O

+ NH

S

NH2

CH2

NH

N

CH3CH3

S

O

CH2

+NH

NH

CH3CH3

O

S

Figure 55

Farzin Hadizadeh et al [241] prepared the thiosemicarbazone derivatives (Fig

56)

NH

N

CH3 CHO

NH2 NH

NH2

S NH

N

CH3

NNH

NH2

S

Figure 56

Peesapati Venkateswarlu et al [242] studied the semicarbazone derivatives

from bi-cyclic ketones reacted with semicarbazide hydrochloride (Fig 57)

O

CH3

NH2 NH

NH2

O

N

CH3

NH

NH2O

HCl

AcONa and EtOH

Figure 57

Natesh Ramesh kumar et al [243] reported that thiosemicarbazide reacted

with ketone derivatives to give the corresponding thiosemicarbazone derivatives (Fig

58)

30

CH3

CH3

O

+

HO

Cl

N

O

CH3

CH3

Cl

NH2 NH

NH2

S

N

N

CH3

CH3

NH

NH2S

Cl

HO

CH3COONH4

Figure 58

Sampath et al [244] studied the crystal structure and conformation of

N-methyl-t-3-methyl-R-2C-6-diphenylpipridin-4-one thiosemicarbazone (Fig 59)

CH3

CH3

O

+

HO

+ CH3 NH2

99 Ethanol

N

O

CH3

CH3

NH2 NH

NH2

S

methanol HCl N

N

CH3

CH3

NH

NH2S

Figure 59

Jamal Abdul Nasser et al [245] studied the imidazolidin ring prepared from

thiosemicabazone reacted with ethyl chloroacetate and fused sodium acetate by the

cyclization method (Fig 60)

NNH NH2

S

Cl

OC2H5

O

NaOAc

NN

NH

S

O

Figure 60

31

The above literature findings were taken as the basis on which to synthesize

pyrrole pyridine and imidazolidine derivatives

Pyrrole derivatives are mentioned in schemes 1-3

Pyridine derivatives are mentioned in scheme 3

Imidazolidine derivatives are mentioned in schemes 4 -7

All of the synthetic compounds were characterized by Infrared (IR) Proton Nuclear

magnetic resonance (sup1H-NMR) Carbon Nuclear magnetic resonance (13

C-NMR)

Mass spectral and elemental analyses The selected compounds were screened for the

following biological activities

In vitro antimicrobial anticoagulant anticancer and antioxidant activities

In vivo anti-convulsant anti-inflammatory and analogous activities

Environmental toxicity analysis

16

N

N

NHH3CS

CHOCH3COCH2COOC2H5 NH4OH

NH

CH3 CH3

COOC2H5H5C2OOC

N

N

SCH3

Figure 16

Bhavik Desai et al [200] synthesized 4-substituted phenyl-26-dimethyl-35-

bis-N-(4-chlorophenyl)carbamoyl-14-dihydropyridines and Quantitative structural

activity relationship (QSAR) studies of these compounds showed that they were

potential antitubercular agents (Fig 17)

CH3

NH

O

O

Cl

+CHO

NH3 CH3OH

Reflux

NH

NH

OO

NH

CH3 CH3

Cl Cl

Figure 17

Amini et al [201] carried out the synthesis and confirmed the antitubercular

activity of new NN-diaryl-4-(45-dichloroimidazole-2-yl)-14-dihydro-26-dimethyl-

35-pyridinedicarbox amides (Fig 18)

N

NHCl

Cl

CHO

+CH3 NH

O O

NH4OAc

MeOH reflux

NH

NH

O

NH

N NH

Cl Cl

CH3 CH3

O

Figure 18

17

Shashikant et al [202] studied the synthesis and evaluation of some 1 4-

dihydropyridines and their derivatives as antihypertensive agent (Fig 19)

CH3 NH

O O

+

CHO

Reflux 10 - 12h

Ammonia ( 25 )

Methanol

NH

OC CONH NH

CH3 CH3

Figure 19

Suresh et al [203] studied the synthesis and bronchodilatory activity of new 4-

aryl-35-bis(2-chlorophenyl)-carbonyl-26-dimethyl-14-dihydropyridines and their 1-

substituted analogues (Fig 20)

CH3 NH

O OCl

+

CHONH

NH NH

CH3 CH3

Cl ClO O

+ NH3

AcOH - MeOH

12 - 28 h

Figure 20

Sobin [204] reported the hydrazinolysis method by hydrazine hydrate was

reacted with an ester group and Suresh et al [205] reported that pyrrole derivatives

condense with hydrazine hydrate (Fig 21)

NH

CH3

CH3H3CH2CO

O

OCH 2CH3

O NH

CH3

CH3

O

NH

O

NH

NH2

NH2NH2 NH2

Figure 21

18

Preparation of oxadiazole derivatives

R

O

HN NH2

N

O

N

R

SH-H2S

+ S C

S

KOH

alcoholR

O

HN NH

S

HS

N

O

HN

R

S

H

SH

Figure 22 Mechanism of the oxadiazole preparation

Figure 22 shows the mechanism for the preparation of oxadiazole derivatives

Akhtar et al[206] reported on the in vitro antitumour and antiviral activities of new

benzothiazole and 134-oxadiazole-2-thione derivatives (Fig 23)

OO

NHNH2

CH3Br

KOH CS2O

CH3Br

NN

O

SH

Figure 23

Kalagouda Gudasi et al [207] studied the new ligand for 56-(5-mercapto-

134-oxadiazol-2-yl)pyridin-2-yl-134-oxadiazole-2-thiol (Fig 24)

NO

OCH3 OCH3

O

NH2NH2 C2H5OH

Reflux 4h

NO

NH NH

O

NH2 NH2

KOH 2CS2

Reflux 15 min

NO O

SH SH

Figure 24

19

Preparation of Triazole derivatives

Shipra Baluja et al [208] reported on the work for a facile synthesis and the

antimicrobial activity of some 4-aryltriazoles (Fig 25)

NHNH

O

S-

SH3CO

K+

NH

O

NH2H3CO

CS2 KOH

NHNH2

H3CO

N

N

N

NH

SH

Figure 25

Mohammad Al-Amin et al [209] reported on the synthesis of some bis-

triazole derivatives that were studied for cytotoxicity (Fig 26)

HOOC - (CH2)n -COOH Fusion

+NH2 NH

NH

NH2S

N N

N(CH2)n

N N

NSHSH

NH2NH2

Figure 26

Shivarama et al [210] carried out some trouble site reaction of new bis-

aminomercaptotriazole and bis-triazolothiadiazole as possible anticancer agents (Fig

27)

HOOCH 2CO OCH2COOHON

NN

O

N

N

N

NH2 NH2

SH SH

H2NNHCSNHNH 2

Figure 27

20

Amine reactions with ester groups

For the reactions between amines and esters the reaction is accelerated by

heating it moderately Notice that a stronger base (amine) is used up and a weaker

base (alcohol) is produced Notice also that before the alcohol (leaving group) portion

of the ester departs it picks up an H+ so that it leaves as the weak base alcohol ion

(ROH) rather than as the strong base alkoxide ion (RO-) Weaker bases make better

leaving groups Figure 28 illustrates the mechanism of the amination reaction

Figure 28 Mechanism of the amine reacted with the ester group

Suresh et al [211] studied the amination reaction (Fig 29)

CH3 OEt

O O

+

NH2

ClBuOK

EtOH

0 - 5 h rt

CH3 NH

O O

Cl

Figure 29

Shashikant et al [212] also reported on an amination reaction where a secondary

amine is formed (Fig 30)

CH3 OEt

O O

+ CH3 NH

O O

NH2

EtOH

Figure 30

21

Konstantinos et al [213] studied the fusion method ndash the solvent free reaction

of arylamines with ethyl cyanoacetates is one of the most widely used methods for the

preparation of cyanoacetanilides (Fig 31)

NH2

+

O

EtO

CN

150 degC

NH

O

CN

Figure 31

Metwally et al [214] reported on the reaction using different basic medium

conditions such as sodium ethoxide solution (Fig 32)

+

O

EtO

CN

N

S

NH2

at

EtOH

N

S

NH

O

CN

Figure 32

Bhawal et al [215] reported on the reaction of benzylamine with ethyl

cyanoacetate in tetra hydro furan (THF) containing butyl lithium as the basic catalyst

which formed N-benzylcyanoacetamide (Fig 33)

NH2

+

O

EtO

CN

THF

BuLi

NH

O

CN

Figure 33

Jianguo et al [216] reported that microwave (MW) irradiation has become an

important method in organic synthesis which can be applied to a wide range of

reactions with short reaction times and high yields (Fig 34)

22

NH2

H3CO

+

EtO

CNO

MW

trichlorobenzene

NH

H3CO

CN

O

Figure 34

Hanan et al[217] studied the amination reaction of compound 2-[4-

(ethoxycarbonyl)anilino]-3-methyl quinoxaline with primary amine (Fig 35)

N

N CH3

NH

OEtO

RNH2

N

N CH3

NH

NHOR

Figure 35

Srivastava et al [218] studied the hydrazinolysis reaction in which 124-triazole

containing an ester group reacted with thiosemicarbazide (Fig 36)

N N

N

OC2H5

ONH2 NH

CS NH2

N N

N

NH

O

NH

CS

NH2

Figure 36

Swati ojha et al [219] studied the reaction in which benzotriazole containing

ethyl chloroacetate is converted to carbothioamide by the hydrazinolysis method (Fig

37)

23

N

NN

O

OEt

NH2 NH

CS NH2

N

NN

O

NHNH

CSNH2

Figure 37

Preparation of triazole derivatives

R

S

HN NH

S

HN

R

N

N

HN

R

H

SHR

S

N

N

HN

R

R

S10 NaOH

HCl

-H2S

Figure 38 Mechanism of the triazole preparation

Maymona et al [220] and Barnela et al [221] studied the Vilsmeier-Haack

reaction mechanism of triazole preparation using hydrolysis of 10 sodium hydroxide

solution followed by acidification with dilute hydrochloric acid to give 5-thioxo-

134-triazol derivatives (Fig 39)

Figure 39

Otilia Pintilie et al [222] prepared triazole derivatives via the hydrolysis of

10 sodium hydroxide solution followed by acidification with dilute hydrochloric

acid (Fig 40)

24

H3CS CONH

NH

O2N

NH NH

S

CH3

NaOH

H3CS

NH

O2N

NN

N

CH3

SH

Figure 40

Mohamed Belkadi et al [223] studied the steps involved in the treatment of

(plusmn)-22-dimethyl-[13]dioxolan-4-carboxylic-acid-hydrazide-thioformamido-semicarb

azide with NaOH in absolute ethanol under reflux for five hours to give (plusmn)-5-(22-

dimethyl-[13]dioxolan-4-yl)-4H-[124]triazole-3-thiol (Fig 41)

Figure 41

Hussain et al [224] synthesized thiadiazole and 124-triazole derivatives from

cyclopropane dicarboxylic acid (Fig 42)

HOOCCOOH

SOCl2 H2NNHCSNH2H2NSCHNNOC

CONNHCSNH2

NaOHN

NH

N

NH

NN

SH

SH

Figure 42

25

Sibel Demir et al [225] studied the crystallographic analysis of compound 55rsquo-

pyridine-26-diylbis[4-ethyl-24-dihydro-124-triazole-3(2H)-thione (Fig 43)

NNHNH

OO

NH NH

S

NHNH

O

CH3 CH3

NaOH

NN

N

N

N

N

N

SH SHCH3

CH3

Figure 43

Preparation of thiadiazole derivatives

Foroumadi et al [226] reported on the anticonvulsant activity of novel 2-amino-

5-[4-chloro-2-(2-chlorophenoxy) phenyl]-134-thiadiazole derivatives (Fig 44)

OCl

Cl

NH

O

NH NH2

S H2SO4

NH4OH

OCl

Cl

N

S

N

NH2

Figure 44

Otilia Pintilie et al [227] reported on the synthesis and antimicrobial activity of

some new 134-thiadiazole and 124-triazole compounds which had a DL-

methionine moiety (Fig 45)

Figure 45

26

Srivastava et al [228] studied the synthesis of a new 124- triazolo-thia

diazole as antimicrobial anticonvulsant and anti-inflammatory agents (Fig 46)

N

NN

O

NHNH NH2

SH2SO4

NH3

N

NN

N

S

N

NH2

Figure 46

Swati Ojha et al [229] studied the conversion of benzatriazole containing

thiosemicarbazone into thiadiazole derivatives with the help of H2SO4 by the

cyclization method (Fig 47)

N

NN

O

NHNH NH2

S H2SO4 NH3

N

NN

S

N N

NH2

Figure 47

Hussain et al [230] synthesized thiadiazole and 124-triazole derivatives from

cyclopropane dicarboxylic acid (Fig 48)

N

S

N

S

NN

NH2 NH2

HOOCCOOH POCl3 H2NNHCSNH2

Figure 48

27

Preparation pyrazole and thiazole derivatives

El-Sayed Rashad et al [231] studied the synthesis of the biologically active

pyrazoles and C-nucleosides (Fig 49)

NHNH2

CH3

O

OEt

O

AcOH heatN N

CH3 O

Figure 49

Hamied latif et al [232] Zevrsquoyalow et al [233] and More et al [234] have

reported by thazole derivative (Fig 50) and their biologically importance

CH3

O

I2 CH2I

ONH2

NH2

S

N

SNH2

Figure 50

Preparation of imidazolidin-4-thioxo-2-one derivatives

Renata Jakse et al [235] studied the progresses in the synthesis and reactions

of imidazolidin and its derivatives in particular the stereoselective synthesis of

5-[heteroaryl methylidene]-substituted hydantoins and thiohydantoins as aplysinopsin

analogues (Fig 51)

NH

N

NCH3

CH3

O

S

Figure 51

28

Giulio et al [236] studied the synthesis of CB1 (cannabinoid) receptor ligands

and evaluated their pharmacological properties (Fig 52)

N

NH

CH3

O S

Cl

Cl

Figure 52

Janos Marton et al [237] studied the fungicidal activity of 5-substituted

hydantoins and their 2-thio analogues (Fig 53)

NH

NH

S

S

CHO

NH NH

O

S

Figure 53

2-Thiohydrotoin was reacted with aromatic aldehydes to give the corresponding

arylmethylene derivatives reported by Wheeler et al[238] and Lubomir Floch et al

[239] studied the synthesis of 5- substituted-3-amino-2-thioxo-4-imidazolidinones

(Fig 54)

H

CO2Et

NCS NH2 NH2 H2O

MeOH or EtOH Et2O

H

CO2Et

NH

NHNH2

S

NH

N

O

SH

NH2

Figure 54

29

Zerong Daniel wang et al [240] reported that synthesis of 2-thiohydantoins

derivative (Fig 55)

N N

NH2

CH3

CH3

OH

O

+ NH

S

NH2

CH2

NH

N

CH3CH3

S

O

CH2

+NH

NH

CH3CH3

O

S

Figure 55

Farzin Hadizadeh et al [241] prepared the thiosemicarbazone derivatives (Fig

56)

NH

N

CH3 CHO

NH2 NH

NH2

S NH

N

CH3

NNH

NH2

S

Figure 56

Peesapati Venkateswarlu et al [242] studied the semicarbazone derivatives

from bi-cyclic ketones reacted with semicarbazide hydrochloride (Fig 57)

O

CH3

NH2 NH

NH2

O

N

CH3

NH

NH2O

HCl

AcONa and EtOH

Figure 57

Natesh Ramesh kumar et al [243] reported that thiosemicarbazide reacted

with ketone derivatives to give the corresponding thiosemicarbazone derivatives (Fig

58)

30

CH3

CH3

O

+

HO

Cl

N

O

CH3

CH3

Cl

NH2 NH

NH2

S

N

N

CH3

CH3

NH

NH2S

Cl

HO

CH3COONH4

Figure 58

Sampath et al [244] studied the crystal structure and conformation of

N-methyl-t-3-methyl-R-2C-6-diphenylpipridin-4-one thiosemicarbazone (Fig 59)

CH3

CH3

O

+

HO

+ CH3 NH2

99 Ethanol

N

O

CH3

CH3

NH2 NH

NH2

S

methanol HCl N

N

CH3

CH3

NH

NH2S

Figure 59

Jamal Abdul Nasser et al [245] studied the imidazolidin ring prepared from

thiosemicabazone reacted with ethyl chloroacetate and fused sodium acetate by the

cyclization method (Fig 60)

NNH NH2

S

Cl

OC2H5

O

NaOAc

NN

NH

S

O

Figure 60

31

The above literature findings were taken as the basis on which to synthesize

pyrrole pyridine and imidazolidine derivatives

Pyrrole derivatives are mentioned in schemes 1-3

Pyridine derivatives are mentioned in scheme 3

Imidazolidine derivatives are mentioned in schemes 4 -7

All of the synthetic compounds were characterized by Infrared (IR) Proton Nuclear

magnetic resonance (sup1H-NMR) Carbon Nuclear magnetic resonance (13

C-NMR)

Mass spectral and elemental analyses The selected compounds were screened for the

following biological activities

In vitro antimicrobial anticoagulant anticancer and antioxidant activities

In vivo anti-convulsant anti-inflammatory and analogous activities

Environmental toxicity analysis

17

Shashikant et al [202] studied the synthesis and evaluation of some 1 4-

dihydropyridines and their derivatives as antihypertensive agent (Fig 19)

CH3 NH

O O

+

CHO

Reflux 10 - 12h

Ammonia ( 25 )

Methanol

NH

OC CONH NH

CH3 CH3

Figure 19

Suresh et al [203] studied the synthesis and bronchodilatory activity of new 4-

aryl-35-bis(2-chlorophenyl)-carbonyl-26-dimethyl-14-dihydropyridines and their 1-

substituted analogues (Fig 20)

CH3 NH

O OCl

+

CHONH

NH NH

CH3 CH3

Cl ClO O

+ NH3

AcOH - MeOH

12 - 28 h

Figure 20

Sobin [204] reported the hydrazinolysis method by hydrazine hydrate was

reacted with an ester group and Suresh et al [205] reported that pyrrole derivatives

condense with hydrazine hydrate (Fig 21)

NH

CH3

CH3H3CH2CO

O

OCH 2CH3

O NH

CH3

CH3

O

NH

O

NH

NH2

NH2NH2 NH2

Figure 21

18

Preparation of oxadiazole derivatives

R

O

HN NH2

N

O

N

R

SH-H2S

+ S C

S

KOH

alcoholR

O

HN NH

S

HS

N

O

HN

R

S

H

SH

Figure 22 Mechanism of the oxadiazole preparation

Figure 22 shows the mechanism for the preparation of oxadiazole derivatives

Akhtar et al[206] reported on the in vitro antitumour and antiviral activities of new

benzothiazole and 134-oxadiazole-2-thione derivatives (Fig 23)

OO

NHNH2

CH3Br

KOH CS2O

CH3Br

NN

O

SH

Figure 23

Kalagouda Gudasi et al [207] studied the new ligand for 56-(5-mercapto-

134-oxadiazol-2-yl)pyridin-2-yl-134-oxadiazole-2-thiol (Fig 24)

NO

OCH3 OCH3

O

NH2NH2 C2H5OH

Reflux 4h

NO

NH NH

O

NH2 NH2

KOH 2CS2

Reflux 15 min

NO O

SH SH

Figure 24

19

Preparation of Triazole derivatives

Shipra Baluja et al [208] reported on the work for a facile synthesis and the

antimicrobial activity of some 4-aryltriazoles (Fig 25)

NHNH

O

S-

SH3CO

K+

NH

O

NH2H3CO

CS2 KOH

NHNH2

H3CO

N

N

N

NH

SH

Figure 25

Mohammad Al-Amin et al [209] reported on the synthesis of some bis-

triazole derivatives that were studied for cytotoxicity (Fig 26)

HOOC - (CH2)n -COOH Fusion

+NH2 NH

NH

NH2S

N N

N(CH2)n

N N

NSHSH

NH2NH2

Figure 26

Shivarama et al [210] carried out some trouble site reaction of new bis-

aminomercaptotriazole and bis-triazolothiadiazole as possible anticancer agents (Fig

27)

HOOCH 2CO OCH2COOHON

NN

O

N

N

N

NH2 NH2

SH SH

H2NNHCSNHNH 2

Figure 27

20

Amine reactions with ester groups

For the reactions between amines and esters the reaction is accelerated by

heating it moderately Notice that a stronger base (amine) is used up and a weaker

base (alcohol) is produced Notice also that before the alcohol (leaving group) portion

of the ester departs it picks up an H+ so that it leaves as the weak base alcohol ion

(ROH) rather than as the strong base alkoxide ion (RO-) Weaker bases make better

leaving groups Figure 28 illustrates the mechanism of the amination reaction

Figure 28 Mechanism of the amine reacted with the ester group

Suresh et al [211] studied the amination reaction (Fig 29)

CH3 OEt

O O

+

NH2

ClBuOK

EtOH

0 - 5 h rt

CH3 NH

O O

Cl

Figure 29

Shashikant et al [212] also reported on an amination reaction where a secondary

amine is formed (Fig 30)

CH3 OEt

O O

+ CH3 NH

O O

NH2

EtOH

Figure 30

21

Konstantinos et al [213] studied the fusion method ndash the solvent free reaction

of arylamines with ethyl cyanoacetates is one of the most widely used methods for the

preparation of cyanoacetanilides (Fig 31)

NH2

+

O

EtO

CN

150 degC

NH

O

CN

Figure 31

Metwally et al [214] reported on the reaction using different basic medium

conditions such as sodium ethoxide solution (Fig 32)

+

O

EtO

CN

N

S

NH2

at

EtOH

N

S

NH

O

CN

Figure 32

Bhawal et al [215] reported on the reaction of benzylamine with ethyl

cyanoacetate in tetra hydro furan (THF) containing butyl lithium as the basic catalyst

which formed N-benzylcyanoacetamide (Fig 33)

NH2

+

O

EtO

CN

THF

BuLi

NH

O

CN

Figure 33

Jianguo et al [216] reported that microwave (MW) irradiation has become an

important method in organic synthesis which can be applied to a wide range of

reactions with short reaction times and high yields (Fig 34)

22

NH2

H3CO

+

EtO

CNO

MW

trichlorobenzene

NH

H3CO

CN

O

Figure 34

Hanan et al[217] studied the amination reaction of compound 2-[4-

(ethoxycarbonyl)anilino]-3-methyl quinoxaline with primary amine (Fig 35)

N

N CH3

NH

OEtO

RNH2

N

N CH3

NH

NHOR

Figure 35

Srivastava et al [218] studied the hydrazinolysis reaction in which 124-triazole

containing an ester group reacted with thiosemicarbazide (Fig 36)

N N

N

OC2H5

ONH2 NH

CS NH2

N N

N

NH

O

NH

CS

NH2

Figure 36

Swati ojha et al [219] studied the reaction in which benzotriazole containing

ethyl chloroacetate is converted to carbothioamide by the hydrazinolysis method (Fig

37)

23

N

NN

O

OEt

NH2 NH

CS NH2

N

NN

O

NHNH

CSNH2

Figure 37

Preparation of triazole derivatives

R

S

HN NH

S

HN

R

N

N

HN

R

H

SHR

S

N

N

HN

R

R

S10 NaOH

HCl

-H2S

Figure 38 Mechanism of the triazole preparation

Maymona et al [220] and Barnela et al [221] studied the Vilsmeier-Haack

reaction mechanism of triazole preparation using hydrolysis of 10 sodium hydroxide

solution followed by acidification with dilute hydrochloric acid to give 5-thioxo-

134-triazol derivatives (Fig 39)

Figure 39

Otilia Pintilie et al [222] prepared triazole derivatives via the hydrolysis of

10 sodium hydroxide solution followed by acidification with dilute hydrochloric

acid (Fig 40)

24

H3CS CONH

NH

O2N

NH NH

S

CH3

NaOH

H3CS

NH

O2N

NN

N

CH3

SH

Figure 40

Mohamed Belkadi et al [223] studied the steps involved in the treatment of

(plusmn)-22-dimethyl-[13]dioxolan-4-carboxylic-acid-hydrazide-thioformamido-semicarb

azide with NaOH in absolute ethanol under reflux for five hours to give (plusmn)-5-(22-

dimethyl-[13]dioxolan-4-yl)-4H-[124]triazole-3-thiol (Fig 41)

Figure 41

Hussain et al [224] synthesized thiadiazole and 124-triazole derivatives from

cyclopropane dicarboxylic acid (Fig 42)

HOOCCOOH

SOCl2 H2NNHCSNH2H2NSCHNNOC

CONNHCSNH2

NaOHN

NH

N

NH

NN

SH

SH

Figure 42

25

Sibel Demir et al [225] studied the crystallographic analysis of compound 55rsquo-

pyridine-26-diylbis[4-ethyl-24-dihydro-124-triazole-3(2H)-thione (Fig 43)

NNHNH

OO

NH NH

S

NHNH

O

CH3 CH3

NaOH

NN

N

N

N

N

N

SH SHCH3

CH3

Figure 43

Preparation of thiadiazole derivatives

Foroumadi et al [226] reported on the anticonvulsant activity of novel 2-amino-

5-[4-chloro-2-(2-chlorophenoxy) phenyl]-134-thiadiazole derivatives (Fig 44)

OCl

Cl

NH

O

NH NH2

S H2SO4

NH4OH

OCl

Cl

N

S

N

NH2

Figure 44

Otilia Pintilie et al [227] reported on the synthesis and antimicrobial activity of

some new 134-thiadiazole and 124-triazole compounds which had a DL-

methionine moiety (Fig 45)

Figure 45

26

Srivastava et al [228] studied the synthesis of a new 124- triazolo-thia

diazole as antimicrobial anticonvulsant and anti-inflammatory agents (Fig 46)

N

NN

O

NHNH NH2

SH2SO4

NH3

N

NN

N

S

N

NH2

Figure 46

Swati Ojha et al [229] studied the conversion of benzatriazole containing

thiosemicarbazone into thiadiazole derivatives with the help of H2SO4 by the

cyclization method (Fig 47)

N

NN

O

NHNH NH2

S H2SO4 NH3

N

NN

S

N N

NH2

Figure 47

Hussain et al [230] synthesized thiadiazole and 124-triazole derivatives from

cyclopropane dicarboxylic acid (Fig 48)

N

S

N

S

NN

NH2 NH2

HOOCCOOH POCl3 H2NNHCSNH2

Figure 48

27

Preparation pyrazole and thiazole derivatives

El-Sayed Rashad et al [231] studied the synthesis of the biologically active

pyrazoles and C-nucleosides (Fig 49)

NHNH2

CH3

O

OEt

O

AcOH heatN N

CH3 O

Figure 49

Hamied latif et al [232] Zevrsquoyalow et al [233] and More et al [234] have

reported by thazole derivative (Fig 50) and their biologically importance

CH3

O

I2 CH2I

ONH2

NH2

S

N

SNH2

Figure 50

Preparation of imidazolidin-4-thioxo-2-one derivatives

Renata Jakse et al [235] studied the progresses in the synthesis and reactions

of imidazolidin and its derivatives in particular the stereoselective synthesis of

5-[heteroaryl methylidene]-substituted hydantoins and thiohydantoins as aplysinopsin

analogues (Fig 51)

NH

N

NCH3

CH3

O

S

Figure 51

28

Giulio et al [236] studied the synthesis of CB1 (cannabinoid) receptor ligands

and evaluated their pharmacological properties (Fig 52)

N

NH

CH3

O S

Cl

Cl

Figure 52

Janos Marton et al [237] studied the fungicidal activity of 5-substituted

hydantoins and their 2-thio analogues (Fig 53)

NH

NH

S

S

CHO

NH NH

O

S

Figure 53

2-Thiohydrotoin was reacted with aromatic aldehydes to give the corresponding

arylmethylene derivatives reported by Wheeler et al[238] and Lubomir Floch et al

[239] studied the synthesis of 5- substituted-3-amino-2-thioxo-4-imidazolidinones

(Fig 54)

H

CO2Et

NCS NH2 NH2 H2O

MeOH or EtOH Et2O

H

CO2Et

NH

NHNH2

S

NH

N

O

SH

NH2

Figure 54

29

Zerong Daniel wang et al [240] reported that synthesis of 2-thiohydantoins

derivative (Fig 55)

N N

NH2

CH3

CH3

OH

O

+ NH

S

NH2

CH2

NH

N

CH3CH3

S

O

CH2

+NH

NH

CH3CH3

O

S

Figure 55

Farzin Hadizadeh et al [241] prepared the thiosemicarbazone derivatives (Fig

56)

NH

N

CH3 CHO

NH2 NH

NH2

S NH

N

CH3

NNH

NH2

S

Figure 56

Peesapati Venkateswarlu et al [242] studied the semicarbazone derivatives

from bi-cyclic ketones reacted with semicarbazide hydrochloride (Fig 57)

O

CH3

NH2 NH

NH2

O

N

CH3

NH

NH2O

HCl

AcONa and EtOH

Figure 57

Natesh Ramesh kumar et al [243] reported that thiosemicarbazide reacted

with ketone derivatives to give the corresponding thiosemicarbazone derivatives (Fig

58)

30

CH3

CH3

O

+

HO

Cl

N

O

CH3

CH3

Cl

NH2 NH

NH2

S

N

N

CH3

CH3

NH

NH2S

Cl

HO

CH3COONH4

Figure 58

Sampath et al [244] studied the crystal structure and conformation of

N-methyl-t-3-methyl-R-2C-6-diphenylpipridin-4-one thiosemicarbazone (Fig 59)

CH3

CH3

O

+

HO

+ CH3 NH2

99 Ethanol

N

O

CH3

CH3

NH2 NH

NH2

S

methanol HCl N

N

CH3

CH3

NH

NH2S

Figure 59

Jamal Abdul Nasser et al [245] studied the imidazolidin ring prepared from

thiosemicabazone reacted with ethyl chloroacetate and fused sodium acetate by the

cyclization method (Fig 60)

NNH NH2

S

Cl

OC2H5

O

NaOAc

NN

NH

S

O

Figure 60

31

The above literature findings were taken as the basis on which to synthesize

pyrrole pyridine and imidazolidine derivatives

Pyrrole derivatives are mentioned in schemes 1-3

Pyridine derivatives are mentioned in scheme 3

Imidazolidine derivatives are mentioned in schemes 4 -7

All of the synthetic compounds were characterized by Infrared (IR) Proton Nuclear

magnetic resonance (sup1H-NMR) Carbon Nuclear magnetic resonance (13

C-NMR)

Mass spectral and elemental analyses The selected compounds were screened for the

following biological activities

In vitro antimicrobial anticoagulant anticancer and antioxidant activities

In vivo anti-convulsant anti-inflammatory and analogous activities

Environmental toxicity analysis

18

Preparation of oxadiazole derivatives

R

O

HN NH2

N

O

N

R

SH-H2S

+ S C

S

KOH

alcoholR

O

HN NH

S

HS

N

O

HN

R

S

H

SH

Figure 22 Mechanism of the oxadiazole preparation

Figure 22 shows the mechanism for the preparation of oxadiazole derivatives

Akhtar et al[206] reported on the in vitro antitumour and antiviral activities of new

benzothiazole and 134-oxadiazole-2-thione derivatives (Fig 23)

OO

NHNH2

CH3Br

KOH CS2O

CH3Br

NN

O

SH

Figure 23

Kalagouda Gudasi et al [207] studied the new ligand for 56-(5-mercapto-

134-oxadiazol-2-yl)pyridin-2-yl-134-oxadiazole-2-thiol (Fig 24)

NO

OCH3 OCH3

O

NH2NH2 C2H5OH

Reflux 4h

NO

NH NH

O

NH2 NH2

KOH 2CS2

Reflux 15 min

NO O

SH SH

Figure 24

19

Preparation of Triazole derivatives

Shipra Baluja et al [208] reported on the work for a facile synthesis and the

antimicrobial activity of some 4-aryltriazoles (Fig 25)

NHNH

O

S-

SH3CO

K+

NH

O

NH2H3CO

CS2 KOH

NHNH2

H3CO

N

N

N

NH

SH

Figure 25

Mohammad Al-Amin et al [209] reported on the synthesis of some bis-

triazole derivatives that were studied for cytotoxicity (Fig 26)

HOOC - (CH2)n -COOH Fusion

+NH2 NH

NH

NH2S

N N

N(CH2)n

N N

NSHSH

NH2NH2

Figure 26

Shivarama et al [210] carried out some trouble site reaction of new bis-

aminomercaptotriazole and bis-triazolothiadiazole as possible anticancer agents (Fig

27)

HOOCH 2CO OCH2COOHON

NN

O

N

N

N

NH2 NH2

SH SH

H2NNHCSNHNH 2

Figure 27

20

Amine reactions with ester groups

For the reactions between amines and esters the reaction is accelerated by

heating it moderately Notice that a stronger base (amine) is used up and a weaker

base (alcohol) is produced Notice also that before the alcohol (leaving group) portion

of the ester departs it picks up an H+ so that it leaves as the weak base alcohol ion

(ROH) rather than as the strong base alkoxide ion (RO-) Weaker bases make better

leaving groups Figure 28 illustrates the mechanism of the amination reaction

Figure 28 Mechanism of the amine reacted with the ester group

Suresh et al [211] studied the amination reaction (Fig 29)

CH3 OEt

O O

+

NH2

ClBuOK

EtOH

0 - 5 h rt

CH3 NH

O O

Cl

Figure 29

Shashikant et al [212] also reported on an amination reaction where a secondary

amine is formed (Fig 30)

CH3 OEt

O O

+ CH3 NH

O O

NH2

EtOH

Figure 30

21

Konstantinos et al [213] studied the fusion method ndash the solvent free reaction

of arylamines with ethyl cyanoacetates is one of the most widely used methods for the

preparation of cyanoacetanilides (Fig 31)

NH2

+

O

EtO

CN

150 degC

NH

O

CN

Figure 31

Metwally et al [214] reported on the reaction using different basic medium

conditions such as sodium ethoxide solution (Fig 32)

+

O

EtO

CN

N

S

NH2

at

EtOH

N

S

NH

O

CN

Figure 32

Bhawal et al [215] reported on the reaction of benzylamine with ethyl

cyanoacetate in tetra hydro furan (THF) containing butyl lithium as the basic catalyst

which formed N-benzylcyanoacetamide (Fig 33)

NH2

+

O

EtO

CN

THF

BuLi

NH

O

CN

Figure 33

Jianguo et al [216] reported that microwave (MW) irradiation has become an

important method in organic synthesis which can be applied to a wide range of

reactions with short reaction times and high yields (Fig 34)

22

NH2

H3CO

+

EtO

CNO

MW

trichlorobenzene

NH

H3CO

CN

O

Figure 34

Hanan et al[217] studied the amination reaction of compound 2-[4-

(ethoxycarbonyl)anilino]-3-methyl quinoxaline with primary amine (Fig 35)

N

N CH3

NH

OEtO

RNH2

N

N CH3

NH

NHOR

Figure 35

Srivastava et al [218] studied the hydrazinolysis reaction in which 124-triazole

containing an ester group reacted with thiosemicarbazide (Fig 36)

N N

N

OC2H5

ONH2 NH

CS NH2

N N

N

NH

O

NH

CS

NH2

Figure 36

Swati ojha et al [219] studied the reaction in which benzotriazole containing

ethyl chloroacetate is converted to carbothioamide by the hydrazinolysis method (Fig

37)

23

N

NN

O

OEt

NH2 NH

CS NH2

N

NN

O

NHNH

CSNH2

Figure 37

Preparation of triazole derivatives

R

S

HN NH

S

HN

R

N

N

HN

R

H

SHR

S

N

N

HN

R

R

S10 NaOH

HCl

-H2S

Figure 38 Mechanism of the triazole preparation

Maymona et al [220] and Barnela et al [221] studied the Vilsmeier-Haack

reaction mechanism of triazole preparation using hydrolysis of 10 sodium hydroxide

solution followed by acidification with dilute hydrochloric acid to give 5-thioxo-

134-triazol derivatives (Fig 39)

Figure 39

Otilia Pintilie et al [222] prepared triazole derivatives via the hydrolysis of

10 sodium hydroxide solution followed by acidification with dilute hydrochloric

acid (Fig 40)

24

H3CS CONH

NH

O2N

NH NH

S

CH3

NaOH

H3CS

NH

O2N

NN

N

CH3

SH

Figure 40

Mohamed Belkadi et al [223] studied the steps involved in the treatment of

(plusmn)-22-dimethyl-[13]dioxolan-4-carboxylic-acid-hydrazide-thioformamido-semicarb

azide with NaOH in absolute ethanol under reflux for five hours to give (plusmn)-5-(22-

dimethyl-[13]dioxolan-4-yl)-4H-[124]triazole-3-thiol (Fig 41)

Figure 41

Hussain et al [224] synthesized thiadiazole and 124-triazole derivatives from

cyclopropane dicarboxylic acid (Fig 42)

HOOCCOOH

SOCl2 H2NNHCSNH2H2NSCHNNOC

CONNHCSNH2

NaOHN

NH

N

NH

NN

SH

SH

Figure 42

25

Sibel Demir et al [225] studied the crystallographic analysis of compound 55rsquo-

pyridine-26-diylbis[4-ethyl-24-dihydro-124-triazole-3(2H)-thione (Fig 43)

NNHNH

OO

NH NH

S

NHNH

O

CH3 CH3

NaOH

NN

N

N

N

N

N

SH SHCH3

CH3

Figure 43

Preparation of thiadiazole derivatives

Foroumadi et al [226] reported on the anticonvulsant activity of novel 2-amino-

5-[4-chloro-2-(2-chlorophenoxy) phenyl]-134-thiadiazole derivatives (Fig 44)

OCl

Cl

NH

O

NH NH2

S H2SO4

NH4OH

OCl

Cl

N

S

N

NH2

Figure 44

Otilia Pintilie et al [227] reported on the synthesis and antimicrobial activity of

some new 134-thiadiazole and 124-triazole compounds which had a DL-

methionine moiety (Fig 45)

Figure 45

26

Srivastava et al [228] studied the synthesis of a new 124- triazolo-thia

diazole as antimicrobial anticonvulsant and anti-inflammatory agents (Fig 46)

N

NN

O

NHNH NH2

SH2SO4

NH3

N

NN

N

S

N

NH2

Figure 46

Swati Ojha et al [229] studied the conversion of benzatriazole containing

thiosemicarbazone into thiadiazole derivatives with the help of H2SO4 by the

cyclization method (Fig 47)

N

NN

O

NHNH NH2

S H2SO4 NH3

N

NN

S

N N

NH2

Figure 47

Hussain et al [230] synthesized thiadiazole and 124-triazole derivatives from

cyclopropane dicarboxylic acid (Fig 48)

N

S

N

S

NN

NH2 NH2

HOOCCOOH POCl3 H2NNHCSNH2

Figure 48

27

Preparation pyrazole and thiazole derivatives

El-Sayed Rashad et al [231] studied the synthesis of the biologically active

pyrazoles and C-nucleosides (Fig 49)

NHNH2

CH3

O

OEt

O

AcOH heatN N

CH3 O

Figure 49

Hamied latif et al [232] Zevrsquoyalow et al [233] and More et al [234] have

reported by thazole derivative (Fig 50) and their biologically importance

CH3

O

I2 CH2I

ONH2

NH2

S

N

SNH2

Figure 50

Preparation of imidazolidin-4-thioxo-2-one derivatives

Renata Jakse et al [235] studied the progresses in the synthesis and reactions

of imidazolidin and its derivatives in particular the stereoselective synthesis of

5-[heteroaryl methylidene]-substituted hydantoins and thiohydantoins as aplysinopsin

analogues (Fig 51)

NH

N

NCH3

CH3

O

S

Figure 51

28

Giulio et al [236] studied the synthesis of CB1 (cannabinoid) receptor ligands

and evaluated their pharmacological properties (Fig 52)

N

NH

CH3

O S

Cl

Cl

Figure 52

Janos Marton et al [237] studied the fungicidal activity of 5-substituted

hydantoins and their 2-thio analogues (Fig 53)

NH

NH

S

S

CHO

NH NH

O

S

Figure 53

2-Thiohydrotoin was reacted with aromatic aldehydes to give the corresponding

arylmethylene derivatives reported by Wheeler et al[238] and Lubomir Floch et al

[239] studied the synthesis of 5- substituted-3-amino-2-thioxo-4-imidazolidinones

(Fig 54)

H

CO2Et

NCS NH2 NH2 H2O

MeOH or EtOH Et2O

H

CO2Et

NH

NHNH2

S

NH

N

O

SH

NH2

Figure 54

29

Zerong Daniel wang et al [240] reported that synthesis of 2-thiohydantoins

derivative (Fig 55)

N N

NH2

CH3

CH3

OH

O

+ NH

S

NH2

CH2

NH

N

CH3CH3

S

O

CH2

+NH

NH

CH3CH3

O

S

Figure 55

Farzin Hadizadeh et al [241] prepared the thiosemicarbazone derivatives (Fig

56)

NH

N

CH3 CHO

NH2 NH

NH2

S NH

N

CH3

NNH

NH2

S

Figure 56

Peesapati Venkateswarlu et al [242] studied the semicarbazone derivatives

from bi-cyclic ketones reacted with semicarbazide hydrochloride (Fig 57)

O

CH3

NH2 NH

NH2

O

N

CH3

NH

NH2O

HCl

AcONa and EtOH

Figure 57

Natesh Ramesh kumar et al [243] reported that thiosemicarbazide reacted

with ketone derivatives to give the corresponding thiosemicarbazone derivatives (Fig

58)

30

CH3

CH3

O

+

HO

Cl

N

O

CH3

CH3

Cl

NH2 NH

NH2

S

N

N

CH3

CH3

NH

NH2S

Cl

HO

CH3COONH4

Figure 58

Sampath et al [244] studied the crystal structure and conformation of

N-methyl-t-3-methyl-R-2C-6-diphenylpipridin-4-one thiosemicarbazone (Fig 59)

CH3

CH3

O

+

HO

+ CH3 NH2

99 Ethanol

N

O

CH3

CH3

NH2 NH

NH2

S

methanol HCl N

N

CH3

CH3

NH

NH2S

Figure 59

Jamal Abdul Nasser et al [245] studied the imidazolidin ring prepared from

thiosemicabazone reacted with ethyl chloroacetate and fused sodium acetate by the

cyclization method (Fig 60)

NNH NH2

S

Cl

OC2H5

O

NaOAc

NN

NH

S

O

Figure 60

31

The above literature findings were taken as the basis on which to synthesize

pyrrole pyridine and imidazolidine derivatives

Pyrrole derivatives are mentioned in schemes 1-3

Pyridine derivatives are mentioned in scheme 3

Imidazolidine derivatives are mentioned in schemes 4 -7

All of the synthetic compounds were characterized by Infrared (IR) Proton Nuclear

magnetic resonance (sup1H-NMR) Carbon Nuclear magnetic resonance (13

C-NMR)

Mass spectral and elemental analyses The selected compounds were screened for the

following biological activities

In vitro antimicrobial anticoagulant anticancer and antioxidant activities

In vivo anti-convulsant anti-inflammatory and analogous activities

Environmental toxicity analysis

19

Preparation of Triazole derivatives

Shipra Baluja et al [208] reported on the work for a facile synthesis and the

antimicrobial activity of some 4-aryltriazoles (Fig 25)

NHNH

O

S-

SH3CO

K+

NH

O

NH2H3CO

CS2 KOH

NHNH2

H3CO

N

N

N

NH

SH

Figure 25

Mohammad Al-Amin et al [209] reported on the synthesis of some bis-

triazole derivatives that were studied for cytotoxicity (Fig 26)

HOOC - (CH2)n -COOH Fusion

+NH2 NH

NH

NH2S

N N

N(CH2)n

N N

NSHSH

NH2NH2

Figure 26

Shivarama et al [210] carried out some trouble site reaction of new bis-

aminomercaptotriazole and bis-triazolothiadiazole as possible anticancer agents (Fig

27)

HOOCH 2CO OCH2COOHON

NN

O

N

N

N

NH2 NH2

SH SH

H2NNHCSNHNH 2

Figure 27

20

Amine reactions with ester groups

For the reactions between amines and esters the reaction is accelerated by

heating it moderately Notice that a stronger base (amine) is used up and a weaker

base (alcohol) is produced Notice also that before the alcohol (leaving group) portion

of the ester departs it picks up an H+ so that it leaves as the weak base alcohol ion

(ROH) rather than as the strong base alkoxide ion (RO-) Weaker bases make better

leaving groups Figure 28 illustrates the mechanism of the amination reaction

Figure 28 Mechanism of the amine reacted with the ester group

Suresh et al [211] studied the amination reaction (Fig 29)

CH3 OEt

O O

+

NH2

ClBuOK

EtOH

0 - 5 h rt

CH3 NH

O O

Cl

Figure 29

Shashikant et al [212] also reported on an amination reaction where a secondary

amine is formed (Fig 30)

CH3 OEt

O O

+ CH3 NH

O O

NH2

EtOH

Figure 30

21

Konstantinos et al [213] studied the fusion method ndash the solvent free reaction

of arylamines with ethyl cyanoacetates is one of the most widely used methods for the

preparation of cyanoacetanilides (Fig 31)

NH2

+

O

EtO

CN

150 degC

NH

O

CN

Figure 31

Metwally et al [214] reported on the reaction using different basic medium

conditions such as sodium ethoxide solution (Fig 32)

+

O

EtO

CN

N

S

NH2

at

EtOH

N

S

NH

O

CN

Figure 32

Bhawal et al [215] reported on the reaction of benzylamine with ethyl

cyanoacetate in tetra hydro furan (THF) containing butyl lithium as the basic catalyst

which formed N-benzylcyanoacetamide (Fig 33)

NH2

+

O

EtO

CN

THF

BuLi

NH

O

CN

Figure 33

Jianguo et al [216] reported that microwave (MW) irradiation has become an

important method in organic synthesis which can be applied to a wide range of

reactions with short reaction times and high yields (Fig 34)

22

NH2

H3CO

+

EtO

CNO

MW

trichlorobenzene

NH

H3CO

CN

O

Figure 34

Hanan et al[217] studied the amination reaction of compound 2-[4-

(ethoxycarbonyl)anilino]-3-methyl quinoxaline with primary amine (Fig 35)

N

N CH3

NH

OEtO

RNH2

N

N CH3

NH

NHOR

Figure 35

Srivastava et al [218] studied the hydrazinolysis reaction in which 124-triazole

containing an ester group reacted with thiosemicarbazide (Fig 36)

N N

N

OC2H5

ONH2 NH

CS NH2

N N

N

NH

O

NH

CS

NH2

Figure 36

Swati ojha et al [219] studied the reaction in which benzotriazole containing

ethyl chloroacetate is converted to carbothioamide by the hydrazinolysis method (Fig

37)

23

N

NN

O

OEt

NH2 NH

CS NH2

N

NN

O

NHNH

CSNH2

Figure 37

Preparation of triazole derivatives

R

S

HN NH

S

HN

R

N

N

HN

R

H

SHR

S

N

N

HN

R

R

S10 NaOH

HCl

-H2S

Figure 38 Mechanism of the triazole preparation

Maymona et al [220] and Barnela et al [221] studied the Vilsmeier-Haack

reaction mechanism of triazole preparation using hydrolysis of 10 sodium hydroxide

solution followed by acidification with dilute hydrochloric acid to give 5-thioxo-

134-triazol derivatives (Fig 39)

Figure 39

Otilia Pintilie et al [222] prepared triazole derivatives via the hydrolysis of

10 sodium hydroxide solution followed by acidification with dilute hydrochloric

acid (Fig 40)

24

H3CS CONH

NH

O2N

NH NH

S

CH3

NaOH

H3CS

NH

O2N

NN

N

CH3

SH

Figure 40

Mohamed Belkadi et al [223] studied the steps involved in the treatment of

(plusmn)-22-dimethyl-[13]dioxolan-4-carboxylic-acid-hydrazide-thioformamido-semicarb

azide with NaOH in absolute ethanol under reflux for five hours to give (plusmn)-5-(22-

dimethyl-[13]dioxolan-4-yl)-4H-[124]triazole-3-thiol (Fig 41)

Figure 41

Hussain et al [224] synthesized thiadiazole and 124-triazole derivatives from

cyclopropane dicarboxylic acid (Fig 42)

HOOCCOOH

SOCl2 H2NNHCSNH2H2NSCHNNOC

CONNHCSNH2

NaOHN

NH

N

NH

NN

SH

SH

Figure 42

25

Sibel Demir et al [225] studied the crystallographic analysis of compound 55rsquo-

pyridine-26-diylbis[4-ethyl-24-dihydro-124-triazole-3(2H)-thione (Fig 43)

NNHNH

OO

NH NH

S

NHNH

O

CH3 CH3

NaOH

NN

N

N

N

N

N

SH SHCH3

CH3

Figure 43

Preparation of thiadiazole derivatives

Foroumadi et al [226] reported on the anticonvulsant activity of novel 2-amino-

5-[4-chloro-2-(2-chlorophenoxy) phenyl]-134-thiadiazole derivatives (Fig 44)

OCl

Cl

NH

O

NH NH2

S H2SO4

NH4OH

OCl

Cl

N

S

N

NH2

Figure 44

Otilia Pintilie et al [227] reported on the synthesis and antimicrobial activity of

some new 134-thiadiazole and 124-triazole compounds which had a DL-

methionine moiety (Fig 45)

Figure 45

26

Srivastava et al [228] studied the synthesis of a new 124- triazolo-thia

diazole as antimicrobial anticonvulsant and anti-inflammatory agents (Fig 46)

N

NN

O

NHNH NH2

SH2SO4

NH3

N

NN

N

S

N

NH2

Figure 46

Swati Ojha et al [229] studied the conversion of benzatriazole containing

thiosemicarbazone into thiadiazole derivatives with the help of H2SO4 by the

cyclization method (Fig 47)

N

NN

O

NHNH NH2

S H2SO4 NH3

N

NN

S

N N

NH2

Figure 47

Hussain et al [230] synthesized thiadiazole and 124-triazole derivatives from

cyclopropane dicarboxylic acid (Fig 48)

N

S

N

S

NN

NH2 NH2

HOOCCOOH POCl3 H2NNHCSNH2

Figure 48

27

Preparation pyrazole and thiazole derivatives

El-Sayed Rashad et al [231] studied the synthesis of the biologically active

pyrazoles and C-nucleosides (Fig 49)

NHNH2

CH3

O

OEt

O

AcOH heatN N

CH3 O

Figure 49

Hamied latif et al [232] Zevrsquoyalow et al [233] and More et al [234] have

reported by thazole derivative (Fig 50) and their biologically importance

CH3

O

I2 CH2I

ONH2

NH2

S

N

SNH2

Figure 50

Preparation of imidazolidin-4-thioxo-2-one derivatives

Renata Jakse et al [235] studied the progresses in the synthesis and reactions

of imidazolidin and its derivatives in particular the stereoselective synthesis of

5-[heteroaryl methylidene]-substituted hydantoins and thiohydantoins as aplysinopsin

analogues (Fig 51)

NH

N

NCH3

CH3

O

S

Figure 51

28

Giulio et al [236] studied the synthesis of CB1 (cannabinoid) receptor ligands

and evaluated their pharmacological properties (Fig 52)

N

NH

CH3

O S

Cl

Cl

Figure 52

Janos Marton et al [237] studied the fungicidal activity of 5-substituted

hydantoins and their 2-thio analogues (Fig 53)

NH

NH

S

S

CHO

NH NH

O

S

Figure 53

2-Thiohydrotoin was reacted with aromatic aldehydes to give the corresponding

arylmethylene derivatives reported by Wheeler et al[238] and Lubomir Floch et al

[239] studied the synthesis of 5- substituted-3-amino-2-thioxo-4-imidazolidinones

(Fig 54)

H

CO2Et

NCS NH2 NH2 H2O

MeOH or EtOH Et2O

H

CO2Et

NH

NHNH2

S

NH

N

O

SH

NH2

Figure 54

29

Zerong Daniel wang et al [240] reported that synthesis of 2-thiohydantoins

derivative (Fig 55)

N N

NH2

CH3

CH3

OH

O

+ NH

S

NH2

CH2

NH

N

CH3CH3

S

O

CH2

+NH

NH

CH3CH3

O

S

Figure 55

Farzin Hadizadeh et al [241] prepared the thiosemicarbazone derivatives (Fig

56)

NH

N

CH3 CHO

NH2 NH

NH2

S NH

N

CH3

NNH

NH2

S

Figure 56

Peesapati Venkateswarlu et al [242] studied the semicarbazone derivatives

from bi-cyclic ketones reacted with semicarbazide hydrochloride (Fig 57)

O

CH3

NH2 NH

NH2

O

N

CH3

NH

NH2O

HCl

AcONa and EtOH

Figure 57

Natesh Ramesh kumar et al [243] reported that thiosemicarbazide reacted

with ketone derivatives to give the corresponding thiosemicarbazone derivatives (Fig

58)

30

CH3

CH3

O

+

HO

Cl

N

O

CH3

CH3

Cl

NH2 NH

NH2

S

N

N

CH3

CH3

NH

NH2S

Cl

HO

CH3COONH4

Figure 58

Sampath et al [244] studied the crystal structure and conformation of

N-methyl-t-3-methyl-R-2C-6-diphenylpipridin-4-one thiosemicarbazone (Fig 59)

CH3

CH3

O

+

HO

+ CH3 NH2

99 Ethanol

N

O

CH3

CH3

NH2 NH

NH2

S

methanol HCl N

N

CH3

CH3

NH

NH2S

Figure 59

Jamal Abdul Nasser et al [245] studied the imidazolidin ring prepared from

thiosemicabazone reacted with ethyl chloroacetate and fused sodium acetate by the

cyclization method (Fig 60)

NNH NH2

S

Cl

OC2H5

O

NaOAc

NN

NH

S

O

Figure 60

31

The above literature findings were taken as the basis on which to synthesize

pyrrole pyridine and imidazolidine derivatives

Pyrrole derivatives are mentioned in schemes 1-3

Pyridine derivatives are mentioned in scheme 3

Imidazolidine derivatives are mentioned in schemes 4 -7

All of the synthetic compounds were characterized by Infrared (IR) Proton Nuclear

magnetic resonance (sup1H-NMR) Carbon Nuclear magnetic resonance (13

C-NMR)

Mass spectral and elemental analyses The selected compounds were screened for the

following biological activities

In vitro antimicrobial anticoagulant anticancer and antioxidant activities

In vivo anti-convulsant anti-inflammatory and analogous activities

Environmental toxicity analysis

20

Amine reactions with ester groups

For the reactions between amines and esters the reaction is accelerated by

heating it moderately Notice that a stronger base (amine) is used up and a weaker

base (alcohol) is produced Notice also that before the alcohol (leaving group) portion

of the ester departs it picks up an H+ so that it leaves as the weak base alcohol ion

(ROH) rather than as the strong base alkoxide ion (RO-) Weaker bases make better

leaving groups Figure 28 illustrates the mechanism of the amination reaction

Figure 28 Mechanism of the amine reacted with the ester group

Suresh et al [211] studied the amination reaction (Fig 29)

CH3 OEt

O O

+

NH2

ClBuOK

EtOH

0 - 5 h rt

CH3 NH

O O

Cl

Figure 29

Shashikant et al [212] also reported on an amination reaction where a secondary

amine is formed (Fig 30)

CH3 OEt

O O

+ CH3 NH

O O

NH2

EtOH

Figure 30

21

Konstantinos et al [213] studied the fusion method ndash the solvent free reaction

of arylamines with ethyl cyanoacetates is one of the most widely used methods for the

preparation of cyanoacetanilides (Fig 31)

NH2

+

O

EtO

CN

150 degC

NH

O

CN

Figure 31

Metwally et al [214] reported on the reaction using different basic medium

conditions such as sodium ethoxide solution (Fig 32)

+

O

EtO

CN

N

S

NH2

at

EtOH

N

S

NH

O

CN

Figure 32

Bhawal et al [215] reported on the reaction of benzylamine with ethyl

cyanoacetate in tetra hydro furan (THF) containing butyl lithium as the basic catalyst

which formed N-benzylcyanoacetamide (Fig 33)

NH2

+

O

EtO

CN

THF

BuLi

NH

O

CN

Figure 33

Jianguo et al [216] reported that microwave (MW) irradiation has become an

important method in organic synthesis which can be applied to a wide range of

reactions with short reaction times and high yields (Fig 34)

22

NH2

H3CO

+

EtO

CNO

MW

trichlorobenzene

NH

H3CO

CN

O

Figure 34

Hanan et al[217] studied the amination reaction of compound 2-[4-

(ethoxycarbonyl)anilino]-3-methyl quinoxaline with primary amine (Fig 35)

N

N CH3

NH

OEtO

RNH2

N

N CH3

NH

NHOR

Figure 35

Srivastava et al [218] studied the hydrazinolysis reaction in which 124-triazole

containing an ester group reacted with thiosemicarbazide (Fig 36)

N N

N

OC2H5

ONH2 NH

CS NH2

N N

N

NH

O

NH

CS

NH2

Figure 36

Swati ojha et al [219] studied the reaction in which benzotriazole containing

ethyl chloroacetate is converted to carbothioamide by the hydrazinolysis method (Fig

37)

23

N

NN

O

OEt

NH2 NH

CS NH2

N

NN

O

NHNH

CSNH2

Figure 37

Preparation of triazole derivatives

R

S

HN NH

S

HN

R

N

N

HN

R

H

SHR

S

N

N

HN

R

R

S10 NaOH

HCl

-H2S

Figure 38 Mechanism of the triazole preparation

Maymona et al [220] and Barnela et al [221] studied the Vilsmeier-Haack

reaction mechanism of triazole preparation using hydrolysis of 10 sodium hydroxide

solution followed by acidification with dilute hydrochloric acid to give 5-thioxo-

134-triazol derivatives (Fig 39)

Figure 39

Otilia Pintilie et al [222] prepared triazole derivatives via the hydrolysis of

10 sodium hydroxide solution followed by acidification with dilute hydrochloric

acid (Fig 40)

24

H3CS CONH

NH

O2N

NH NH

S

CH3

NaOH

H3CS

NH

O2N

NN

N

CH3

SH

Figure 40

Mohamed Belkadi et al [223] studied the steps involved in the treatment of

(plusmn)-22-dimethyl-[13]dioxolan-4-carboxylic-acid-hydrazide-thioformamido-semicarb

azide with NaOH in absolute ethanol under reflux for five hours to give (plusmn)-5-(22-

dimethyl-[13]dioxolan-4-yl)-4H-[124]triazole-3-thiol (Fig 41)

Figure 41

Hussain et al [224] synthesized thiadiazole and 124-triazole derivatives from

cyclopropane dicarboxylic acid (Fig 42)

HOOCCOOH

SOCl2 H2NNHCSNH2H2NSCHNNOC

CONNHCSNH2

NaOHN

NH

N

NH

NN

SH

SH

Figure 42

25

Sibel Demir et al [225] studied the crystallographic analysis of compound 55rsquo-

pyridine-26-diylbis[4-ethyl-24-dihydro-124-triazole-3(2H)-thione (Fig 43)

NNHNH

OO

NH NH

S

NHNH

O

CH3 CH3

NaOH

NN

N

N

N

N

N

SH SHCH3

CH3

Figure 43

Preparation of thiadiazole derivatives

Foroumadi et al [226] reported on the anticonvulsant activity of novel 2-amino-

5-[4-chloro-2-(2-chlorophenoxy) phenyl]-134-thiadiazole derivatives (Fig 44)

OCl

Cl

NH

O

NH NH2

S H2SO4

NH4OH

OCl

Cl

N

S

N

NH2

Figure 44

Otilia Pintilie et al [227] reported on the synthesis and antimicrobial activity of

some new 134-thiadiazole and 124-triazole compounds which had a DL-

methionine moiety (Fig 45)

Figure 45

26

Srivastava et al [228] studied the synthesis of a new 124- triazolo-thia

diazole as antimicrobial anticonvulsant and anti-inflammatory agents (Fig 46)

N

NN

O

NHNH NH2

SH2SO4

NH3

N

NN

N

S

N

NH2

Figure 46

Swati Ojha et al [229] studied the conversion of benzatriazole containing

thiosemicarbazone into thiadiazole derivatives with the help of H2SO4 by the

cyclization method (Fig 47)

N

NN

O

NHNH NH2

S H2SO4 NH3

N

NN

S

N N

NH2

Figure 47

Hussain et al [230] synthesized thiadiazole and 124-triazole derivatives from

cyclopropane dicarboxylic acid (Fig 48)

N

S

N

S

NN

NH2 NH2

HOOCCOOH POCl3 H2NNHCSNH2

Figure 48

27

Preparation pyrazole and thiazole derivatives

El-Sayed Rashad et al [231] studied the synthesis of the biologically active

pyrazoles and C-nucleosides (Fig 49)

NHNH2

CH3

O

OEt

O

AcOH heatN N

CH3 O

Figure 49

Hamied latif et al [232] Zevrsquoyalow et al [233] and More et al [234] have

reported by thazole derivative (Fig 50) and their biologically importance

CH3

O

I2 CH2I

ONH2

NH2

S

N

SNH2

Figure 50

Preparation of imidazolidin-4-thioxo-2-one derivatives

Renata Jakse et al [235] studied the progresses in the synthesis and reactions

of imidazolidin and its derivatives in particular the stereoselective synthesis of

5-[heteroaryl methylidene]-substituted hydantoins and thiohydantoins as aplysinopsin

analogues (Fig 51)

NH

N

NCH3

CH3

O

S

Figure 51

28

Giulio et al [236] studied the synthesis of CB1 (cannabinoid) receptor ligands

and evaluated their pharmacological properties (Fig 52)

N

NH

CH3

O S

Cl

Cl

Figure 52

Janos Marton et al [237] studied the fungicidal activity of 5-substituted

hydantoins and their 2-thio analogues (Fig 53)

NH

NH

S

S

CHO

NH NH

O

S

Figure 53

2-Thiohydrotoin was reacted with aromatic aldehydes to give the corresponding

arylmethylene derivatives reported by Wheeler et al[238] and Lubomir Floch et al

[239] studied the synthesis of 5- substituted-3-amino-2-thioxo-4-imidazolidinones

(Fig 54)

H

CO2Et

NCS NH2 NH2 H2O

MeOH or EtOH Et2O

H

CO2Et

NH

NHNH2

S

NH

N

O

SH

NH2

Figure 54

29

Zerong Daniel wang et al [240] reported that synthesis of 2-thiohydantoins

derivative (Fig 55)

N N

NH2

CH3

CH3

OH

O

+ NH

S

NH2

CH2

NH

N

CH3CH3

S

O

CH2

+NH

NH

CH3CH3

O

S

Figure 55

Farzin Hadizadeh et al [241] prepared the thiosemicarbazone derivatives (Fig

56)

NH

N

CH3 CHO

NH2 NH

NH2

S NH

N

CH3

NNH

NH2

S

Figure 56

Peesapati Venkateswarlu et al [242] studied the semicarbazone derivatives

from bi-cyclic ketones reacted with semicarbazide hydrochloride (Fig 57)

O

CH3

NH2 NH

NH2

O

N

CH3

NH

NH2O

HCl

AcONa and EtOH

Figure 57

Natesh Ramesh kumar et al [243] reported that thiosemicarbazide reacted

with ketone derivatives to give the corresponding thiosemicarbazone derivatives (Fig

58)

30

CH3

CH3

O

+

HO

Cl

N

O

CH3

CH3

Cl

NH2 NH

NH2

S

N

N

CH3

CH3

NH

NH2S

Cl

HO

CH3COONH4

Figure 58

Sampath et al [244] studied the crystal structure and conformation of

N-methyl-t-3-methyl-R-2C-6-diphenylpipridin-4-one thiosemicarbazone (Fig 59)

CH3

CH3

O

+

HO

+ CH3 NH2

99 Ethanol

N

O

CH3

CH3

NH2 NH

NH2

S

methanol HCl N

N

CH3

CH3

NH

NH2S

Figure 59

Jamal Abdul Nasser et al [245] studied the imidazolidin ring prepared from

thiosemicabazone reacted with ethyl chloroacetate and fused sodium acetate by the

cyclization method (Fig 60)

NNH NH2

S

Cl

OC2H5

O

NaOAc

NN

NH

S

O

Figure 60

31

The above literature findings were taken as the basis on which to synthesize

pyrrole pyridine and imidazolidine derivatives

Pyrrole derivatives are mentioned in schemes 1-3

Pyridine derivatives are mentioned in scheme 3

Imidazolidine derivatives are mentioned in schemes 4 -7

All of the synthetic compounds were characterized by Infrared (IR) Proton Nuclear

magnetic resonance (sup1H-NMR) Carbon Nuclear magnetic resonance (13

C-NMR)

Mass spectral and elemental analyses The selected compounds were screened for the

following biological activities

In vitro antimicrobial anticoagulant anticancer and antioxidant activities

In vivo anti-convulsant anti-inflammatory and analogous activities

Environmental toxicity analysis

21

Konstantinos et al [213] studied the fusion method ndash the solvent free reaction

of arylamines with ethyl cyanoacetates is one of the most widely used methods for the

preparation of cyanoacetanilides (Fig 31)

NH2

+

O

EtO

CN

150 degC

NH

O

CN

Figure 31

Metwally et al [214] reported on the reaction using different basic medium

conditions such as sodium ethoxide solution (Fig 32)

+

O

EtO

CN

N

S

NH2

at

EtOH

N

S

NH

O

CN

Figure 32

Bhawal et al [215] reported on the reaction of benzylamine with ethyl

cyanoacetate in tetra hydro furan (THF) containing butyl lithium as the basic catalyst

which formed N-benzylcyanoacetamide (Fig 33)

NH2

+

O

EtO

CN

THF

BuLi

NH

O

CN

Figure 33

Jianguo et al [216] reported that microwave (MW) irradiation has become an

important method in organic synthesis which can be applied to a wide range of

reactions with short reaction times and high yields (Fig 34)

22

NH2

H3CO

+

EtO

CNO

MW

trichlorobenzene

NH

H3CO

CN

O

Figure 34

Hanan et al[217] studied the amination reaction of compound 2-[4-

(ethoxycarbonyl)anilino]-3-methyl quinoxaline with primary amine (Fig 35)

N

N CH3

NH

OEtO

RNH2

N

N CH3

NH

NHOR

Figure 35

Srivastava et al [218] studied the hydrazinolysis reaction in which 124-triazole

containing an ester group reacted with thiosemicarbazide (Fig 36)

N N

N

OC2H5

ONH2 NH

CS NH2

N N

N

NH

O

NH

CS

NH2

Figure 36

Swati ojha et al [219] studied the reaction in which benzotriazole containing

ethyl chloroacetate is converted to carbothioamide by the hydrazinolysis method (Fig

37)

23

N

NN

O

OEt

NH2 NH

CS NH2

N

NN

O

NHNH

CSNH2

Figure 37

Preparation of triazole derivatives

R

S

HN NH

S

HN

R

N

N

HN

R

H

SHR

S

N

N

HN

R

R

S10 NaOH

HCl

-H2S

Figure 38 Mechanism of the triazole preparation

Maymona et al [220] and Barnela et al [221] studied the Vilsmeier-Haack

reaction mechanism of triazole preparation using hydrolysis of 10 sodium hydroxide

solution followed by acidification with dilute hydrochloric acid to give 5-thioxo-

134-triazol derivatives (Fig 39)

Figure 39

Otilia Pintilie et al [222] prepared triazole derivatives via the hydrolysis of

10 sodium hydroxide solution followed by acidification with dilute hydrochloric

acid (Fig 40)

24

H3CS CONH

NH

O2N

NH NH

S

CH3

NaOH

H3CS

NH

O2N

NN

N

CH3

SH

Figure 40

Mohamed Belkadi et al [223] studied the steps involved in the treatment of

(plusmn)-22-dimethyl-[13]dioxolan-4-carboxylic-acid-hydrazide-thioformamido-semicarb

azide with NaOH in absolute ethanol under reflux for five hours to give (plusmn)-5-(22-

dimethyl-[13]dioxolan-4-yl)-4H-[124]triazole-3-thiol (Fig 41)

Figure 41

Hussain et al [224] synthesized thiadiazole and 124-triazole derivatives from

cyclopropane dicarboxylic acid (Fig 42)

HOOCCOOH

SOCl2 H2NNHCSNH2H2NSCHNNOC

CONNHCSNH2

NaOHN

NH

N

NH

NN

SH

SH

Figure 42

25

Sibel Demir et al [225] studied the crystallographic analysis of compound 55rsquo-

pyridine-26-diylbis[4-ethyl-24-dihydro-124-triazole-3(2H)-thione (Fig 43)

NNHNH

OO

NH NH

S

NHNH

O

CH3 CH3

NaOH

NN

N

N

N

N

N

SH SHCH3

CH3

Figure 43

Preparation of thiadiazole derivatives

Foroumadi et al [226] reported on the anticonvulsant activity of novel 2-amino-

5-[4-chloro-2-(2-chlorophenoxy) phenyl]-134-thiadiazole derivatives (Fig 44)

OCl

Cl

NH

O

NH NH2

S H2SO4

NH4OH

OCl

Cl

N

S

N

NH2

Figure 44

Otilia Pintilie et al [227] reported on the synthesis and antimicrobial activity of

some new 134-thiadiazole and 124-triazole compounds which had a DL-

methionine moiety (Fig 45)

Figure 45

26

Srivastava et al [228] studied the synthesis of a new 124- triazolo-thia

diazole as antimicrobial anticonvulsant and anti-inflammatory agents (Fig 46)

N

NN

O

NHNH NH2

SH2SO4

NH3

N

NN

N

S

N

NH2

Figure 46

Swati Ojha et al [229] studied the conversion of benzatriazole containing

thiosemicarbazone into thiadiazole derivatives with the help of H2SO4 by the

cyclization method (Fig 47)

N

NN

O

NHNH NH2

S H2SO4 NH3

N

NN

S

N N

NH2

Figure 47

Hussain et al [230] synthesized thiadiazole and 124-triazole derivatives from

cyclopropane dicarboxylic acid (Fig 48)

N

S

N

S

NN

NH2 NH2

HOOCCOOH POCl3 H2NNHCSNH2

Figure 48

27

Preparation pyrazole and thiazole derivatives

El-Sayed Rashad et al [231] studied the synthesis of the biologically active

pyrazoles and C-nucleosides (Fig 49)

NHNH2

CH3

O

OEt

O

AcOH heatN N

CH3 O

Figure 49

Hamied latif et al [232] Zevrsquoyalow et al [233] and More et al [234] have

reported by thazole derivative (Fig 50) and their biologically importance

CH3

O

I2 CH2I

ONH2

NH2

S

N

SNH2

Figure 50

Preparation of imidazolidin-4-thioxo-2-one derivatives

Renata Jakse et al [235] studied the progresses in the synthesis and reactions

of imidazolidin and its derivatives in particular the stereoselective synthesis of

5-[heteroaryl methylidene]-substituted hydantoins and thiohydantoins as aplysinopsin

analogues (Fig 51)

NH

N

NCH3

CH3

O

S

Figure 51

28

Giulio et al [236] studied the synthesis of CB1 (cannabinoid) receptor ligands

and evaluated their pharmacological properties (Fig 52)

N

NH

CH3

O S

Cl

Cl

Figure 52

Janos Marton et al [237] studied the fungicidal activity of 5-substituted

hydantoins and their 2-thio analogues (Fig 53)

NH

NH

S

S

CHO

NH NH

O

S

Figure 53

2-Thiohydrotoin was reacted with aromatic aldehydes to give the corresponding

arylmethylene derivatives reported by Wheeler et al[238] and Lubomir Floch et al

[239] studied the synthesis of 5- substituted-3-amino-2-thioxo-4-imidazolidinones

(Fig 54)

H

CO2Et

NCS NH2 NH2 H2O

MeOH or EtOH Et2O

H

CO2Et

NH

NHNH2

S

NH

N

O

SH

NH2

Figure 54

29

Zerong Daniel wang et al [240] reported that synthesis of 2-thiohydantoins

derivative (Fig 55)

N N

NH2

CH3

CH3

OH

O

+ NH

S

NH2

CH2

NH

N

CH3CH3

S

O

CH2

+NH

NH

CH3CH3

O

S

Figure 55

Farzin Hadizadeh et al [241] prepared the thiosemicarbazone derivatives (Fig

56)

NH

N

CH3 CHO

NH2 NH

NH2

S NH

N

CH3

NNH

NH2

S

Figure 56

Peesapati Venkateswarlu et al [242] studied the semicarbazone derivatives

from bi-cyclic ketones reacted with semicarbazide hydrochloride (Fig 57)

O

CH3

NH2 NH

NH2

O

N

CH3

NH

NH2O

HCl

AcONa and EtOH

Figure 57

Natesh Ramesh kumar et al [243] reported that thiosemicarbazide reacted

with ketone derivatives to give the corresponding thiosemicarbazone derivatives (Fig

58)

30

CH3

CH3

O

+

HO

Cl

N

O

CH3

CH3

Cl

NH2 NH

NH2

S

N

N

CH3

CH3

NH

NH2S

Cl

HO

CH3COONH4

Figure 58

Sampath et al [244] studied the crystal structure and conformation of

N-methyl-t-3-methyl-R-2C-6-diphenylpipridin-4-one thiosemicarbazone (Fig 59)

CH3

CH3

O

+

HO

+ CH3 NH2

99 Ethanol

N

O

CH3

CH3

NH2 NH

NH2

S

methanol HCl N

N

CH3

CH3

NH

NH2S

Figure 59

Jamal Abdul Nasser et al [245] studied the imidazolidin ring prepared from

thiosemicabazone reacted with ethyl chloroacetate and fused sodium acetate by the

cyclization method (Fig 60)

NNH NH2

S

Cl

OC2H5

O

NaOAc

NN

NH

S

O

Figure 60

31

The above literature findings were taken as the basis on which to synthesize

pyrrole pyridine and imidazolidine derivatives

Pyrrole derivatives are mentioned in schemes 1-3

Pyridine derivatives are mentioned in scheme 3

Imidazolidine derivatives are mentioned in schemes 4 -7

All of the synthetic compounds were characterized by Infrared (IR) Proton Nuclear

magnetic resonance (sup1H-NMR) Carbon Nuclear magnetic resonance (13

C-NMR)

Mass spectral and elemental analyses The selected compounds were screened for the

following biological activities

In vitro antimicrobial anticoagulant anticancer and antioxidant activities

In vivo anti-convulsant anti-inflammatory and analogous activities

Environmental toxicity analysis

22

NH2

H3CO

+

EtO

CNO

MW

trichlorobenzene

NH

H3CO

CN

O

Figure 34

Hanan et al[217] studied the amination reaction of compound 2-[4-

(ethoxycarbonyl)anilino]-3-methyl quinoxaline with primary amine (Fig 35)

N

N CH3

NH

OEtO

RNH2

N

N CH3

NH

NHOR

Figure 35

Srivastava et al [218] studied the hydrazinolysis reaction in which 124-triazole

containing an ester group reacted with thiosemicarbazide (Fig 36)

N N

N

OC2H5

ONH2 NH

CS NH2

N N

N

NH

O

NH

CS

NH2

Figure 36

Swati ojha et al [219] studied the reaction in which benzotriazole containing

ethyl chloroacetate is converted to carbothioamide by the hydrazinolysis method (Fig

37)

23

N

NN

O

OEt

NH2 NH

CS NH2

N

NN

O

NHNH

CSNH2

Figure 37

Preparation of triazole derivatives

R

S

HN NH

S

HN

R

N

N

HN

R

H

SHR

S

N

N

HN

R

R

S10 NaOH

HCl

-H2S

Figure 38 Mechanism of the triazole preparation

Maymona et al [220] and Barnela et al [221] studied the Vilsmeier-Haack

reaction mechanism of triazole preparation using hydrolysis of 10 sodium hydroxide

solution followed by acidification with dilute hydrochloric acid to give 5-thioxo-

134-triazol derivatives (Fig 39)

Figure 39

Otilia Pintilie et al [222] prepared triazole derivatives via the hydrolysis of

10 sodium hydroxide solution followed by acidification with dilute hydrochloric

acid (Fig 40)

24

H3CS CONH

NH

O2N

NH NH

S

CH3

NaOH

H3CS

NH

O2N

NN

N

CH3

SH

Figure 40

Mohamed Belkadi et al [223] studied the steps involved in the treatment of

(plusmn)-22-dimethyl-[13]dioxolan-4-carboxylic-acid-hydrazide-thioformamido-semicarb

azide with NaOH in absolute ethanol under reflux for five hours to give (plusmn)-5-(22-

dimethyl-[13]dioxolan-4-yl)-4H-[124]triazole-3-thiol (Fig 41)

Figure 41

Hussain et al [224] synthesized thiadiazole and 124-triazole derivatives from

cyclopropane dicarboxylic acid (Fig 42)

HOOCCOOH

SOCl2 H2NNHCSNH2H2NSCHNNOC

CONNHCSNH2

NaOHN

NH

N

NH

NN

SH

SH

Figure 42

25

Sibel Demir et al [225] studied the crystallographic analysis of compound 55rsquo-

pyridine-26-diylbis[4-ethyl-24-dihydro-124-triazole-3(2H)-thione (Fig 43)

NNHNH

OO

NH NH

S

NHNH

O

CH3 CH3

NaOH

NN

N

N

N

N

N

SH SHCH3

CH3

Figure 43

Preparation of thiadiazole derivatives

Foroumadi et al [226] reported on the anticonvulsant activity of novel 2-amino-

5-[4-chloro-2-(2-chlorophenoxy) phenyl]-134-thiadiazole derivatives (Fig 44)

OCl

Cl

NH

O

NH NH2

S H2SO4

NH4OH

OCl

Cl

N

S

N

NH2

Figure 44

Otilia Pintilie et al [227] reported on the synthesis and antimicrobial activity of

some new 134-thiadiazole and 124-triazole compounds which had a DL-

methionine moiety (Fig 45)

Figure 45

26

Srivastava et al [228] studied the synthesis of a new 124- triazolo-thia

diazole as antimicrobial anticonvulsant and anti-inflammatory agents (Fig 46)

N

NN

O

NHNH NH2

SH2SO4

NH3

N

NN

N

S

N

NH2

Figure 46

Swati Ojha et al [229] studied the conversion of benzatriazole containing

thiosemicarbazone into thiadiazole derivatives with the help of H2SO4 by the

cyclization method (Fig 47)

N

NN

O

NHNH NH2

S H2SO4 NH3

N

NN

S

N N

NH2

Figure 47

Hussain et al [230] synthesized thiadiazole and 124-triazole derivatives from

cyclopropane dicarboxylic acid (Fig 48)

N

S

N

S

NN

NH2 NH2

HOOCCOOH POCl3 H2NNHCSNH2

Figure 48

27

Preparation pyrazole and thiazole derivatives

El-Sayed Rashad et al [231] studied the synthesis of the biologically active

pyrazoles and C-nucleosides (Fig 49)

NHNH2

CH3

O

OEt

O

AcOH heatN N

CH3 O

Figure 49

Hamied latif et al [232] Zevrsquoyalow et al [233] and More et al [234] have

reported by thazole derivative (Fig 50) and their biologically importance

CH3

O

I2 CH2I

ONH2

NH2

S

N

SNH2

Figure 50

Preparation of imidazolidin-4-thioxo-2-one derivatives

Renata Jakse et al [235] studied the progresses in the synthesis and reactions

of imidazolidin and its derivatives in particular the stereoselective synthesis of

5-[heteroaryl methylidene]-substituted hydantoins and thiohydantoins as aplysinopsin

analogues (Fig 51)

NH

N

NCH3

CH3

O

S

Figure 51

28

Giulio et al [236] studied the synthesis of CB1 (cannabinoid) receptor ligands

and evaluated their pharmacological properties (Fig 52)

N

NH

CH3

O S

Cl

Cl

Figure 52

Janos Marton et al [237] studied the fungicidal activity of 5-substituted

hydantoins and their 2-thio analogues (Fig 53)

NH

NH

S

S

CHO

NH NH

O

S

Figure 53

2-Thiohydrotoin was reacted with aromatic aldehydes to give the corresponding

arylmethylene derivatives reported by Wheeler et al[238] and Lubomir Floch et al

[239] studied the synthesis of 5- substituted-3-amino-2-thioxo-4-imidazolidinones

(Fig 54)

H

CO2Et

NCS NH2 NH2 H2O

MeOH or EtOH Et2O

H

CO2Et

NH

NHNH2

S

NH

N

O

SH

NH2

Figure 54

29

Zerong Daniel wang et al [240] reported that synthesis of 2-thiohydantoins

derivative (Fig 55)

N N

NH2

CH3

CH3

OH

O

+ NH

S

NH2

CH2

NH

N

CH3CH3

S

O

CH2

+NH

NH

CH3CH3

O

S

Figure 55

Farzin Hadizadeh et al [241] prepared the thiosemicarbazone derivatives (Fig

56)

NH

N

CH3 CHO

NH2 NH

NH2

S NH

N

CH3

NNH

NH2

S

Figure 56

Peesapati Venkateswarlu et al [242] studied the semicarbazone derivatives

from bi-cyclic ketones reacted with semicarbazide hydrochloride (Fig 57)

O

CH3

NH2 NH

NH2

O

N

CH3

NH

NH2O

HCl

AcONa and EtOH

Figure 57

Natesh Ramesh kumar et al [243] reported that thiosemicarbazide reacted

with ketone derivatives to give the corresponding thiosemicarbazone derivatives (Fig

58)

30

CH3

CH3

O

+

HO

Cl

N

O

CH3

CH3

Cl

NH2 NH

NH2

S

N

N

CH3

CH3

NH

NH2S

Cl

HO

CH3COONH4

Figure 58

Sampath et al [244] studied the crystal structure and conformation of

N-methyl-t-3-methyl-R-2C-6-diphenylpipridin-4-one thiosemicarbazone (Fig 59)

CH3

CH3

O

+

HO

+ CH3 NH2

99 Ethanol

N

O

CH3

CH3

NH2 NH

NH2

S

methanol HCl N

N

CH3

CH3

NH

NH2S

Figure 59

Jamal Abdul Nasser et al [245] studied the imidazolidin ring prepared from

thiosemicabazone reacted with ethyl chloroacetate and fused sodium acetate by the

cyclization method (Fig 60)

NNH NH2

S

Cl

OC2H5

O

NaOAc

NN

NH

S

O

Figure 60

31

The above literature findings were taken as the basis on which to synthesize

pyrrole pyridine and imidazolidine derivatives

Pyrrole derivatives are mentioned in schemes 1-3

Pyridine derivatives are mentioned in scheme 3

Imidazolidine derivatives are mentioned in schemes 4 -7

All of the synthetic compounds were characterized by Infrared (IR) Proton Nuclear

magnetic resonance (sup1H-NMR) Carbon Nuclear magnetic resonance (13

C-NMR)

Mass spectral and elemental analyses The selected compounds were screened for the

following biological activities

In vitro antimicrobial anticoagulant anticancer and antioxidant activities

In vivo anti-convulsant anti-inflammatory and analogous activities

Environmental toxicity analysis

23

N

NN

O

OEt

NH2 NH

CS NH2

N

NN

O

NHNH

CSNH2

Figure 37

Preparation of triazole derivatives

R

S

HN NH

S

HN

R

N

N

HN

R

H

SHR

S

N

N

HN

R

R

S10 NaOH

HCl

-H2S

Figure 38 Mechanism of the triazole preparation

Maymona et al [220] and Barnela et al [221] studied the Vilsmeier-Haack

reaction mechanism of triazole preparation using hydrolysis of 10 sodium hydroxide

solution followed by acidification with dilute hydrochloric acid to give 5-thioxo-

134-triazol derivatives (Fig 39)

Figure 39

Otilia Pintilie et al [222] prepared triazole derivatives via the hydrolysis of

10 sodium hydroxide solution followed by acidification with dilute hydrochloric

acid (Fig 40)

24

H3CS CONH

NH

O2N

NH NH

S

CH3

NaOH

H3CS

NH

O2N

NN

N

CH3

SH

Figure 40

Mohamed Belkadi et al [223] studied the steps involved in the treatment of

(plusmn)-22-dimethyl-[13]dioxolan-4-carboxylic-acid-hydrazide-thioformamido-semicarb

azide with NaOH in absolute ethanol under reflux for five hours to give (plusmn)-5-(22-

dimethyl-[13]dioxolan-4-yl)-4H-[124]triazole-3-thiol (Fig 41)

Figure 41

Hussain et al [224] synthesized thiadiazole and 124-triazole derivatives from

cyclopropane dicarboxylic acid (Fig 42)

HOOCCOOH

SOCl2 H2NNHCSNH2H2NSCHNNOC

CONNHCSNH2

NaOHN

NH

N

NH

NN

SH

SH

Figure 42

25

Sibel Demir et al [225] studied the crystallographic analysis of compound 55rsquo-

pyridine-26-diylbis[4-ethyl-24-dihydro-124-triazole-3(2H)-thione (Fig 43)

NNHNH

OO

NH NH

S

NHNH

O

CH3 CH3

NaOH

NN

N

N

N

N

N

SH SHCH3

CH3

Figure 43

Preparation of thiadiazole derivatives

Foroumadi et al [226] reported on the anticonvulsant activity of novel 2-amino-

5-[4-chloro-2-(2-chlorophenoxy) phenyl]-134-thiadiazole derivatives (Fig 44)

OCl

Cl

NH

O

NH NH2

S H2SO4

NH4OH

OCl

Cl

N

S

N

NH2

Figure 44

Otilia Pintilie et al [227] reported on the synthesis and antimicrobial activity of

some new 134-thiadiazole and 124-triazole compounds which had a DL-

methionine moiety (Fig 45)

Figure 45

26

Srivastava et al [228] studied the synthesis of a new 124- triazolo-thia

diazole as antimicrobial anticonvulsant and anti-inflammatory agents (Fig 46)

N

NN

O

NHNH NH2

SH2SO4

NH3

N

NN

N

S

N

NH2

Figure 46

Swati Ojha et al [229] studied the conversion of benzatriazole containing

thiosemicarbazone into thiadiazole derivatives with the help of H2SO4 by the

cyclization method (Fig 47)

N

NN

O

NHNH NH2

S H2SO4 NH3

N

NN

S

N N

NH2

Figure 47

Hussain et al [230] synthesized thiadiazole and 124-triazole derivatives from

cyclopropane dicarboxylic acid (Fig 48)

N

S

N

S

NN

NH2 NH2

HOOCCOOH POCl3 H2NNHCSNH2

Figure 48

27

Preparation pyrazole and thiazole derivatives

El-Sayed Rashad et al [231] studied the synthesis of the biologically active

pyrazoles and C-nucleosides (Fig 49)

NHNH2

CH3

O

OEt

O

AcOH heatN N

CH3 O

Figure 49

Hamied latif et al [232] Zevrsquoyalow et al [233] and More et al [234] have

reported by thazole derivative (Fig 50) and their biologically importance

CH3

O

I2 CH2I

ONH2

NH2

S

N

SNH2

Figure 50

Preparation of imidazolidin-4-thioxo-2-one derivatives

Renata Jakse et al [235] studied the progresses in the synthesis and reactions

of imidazolidin and its derivatives in particular the stereoselective synthesis of

5-[heteroaryl methylidene]-substituted hydantoins and thiohydantoins as aplysinopsin

analogues (Fig 51)

NH

N

NCH3

CH3

O

S

Figure 51

28

Giulio et al [236] studied the synthesis of CB1 (cannabinoid) receptor ligands

and evaluated their pharmacological properties (Fig 52)

N

NH

CH3

O S

Cl

Cl

Figure 52

Janos Marton et al [237] studied the fungicidal activity of 5-substituted

hydantoins and their 2-thio analogues (Fig 53)

NH

NH

S

S

CHO

NH NH

O

S

Figure 53

2-Thiohydrotoin was reacted with aromatic aldehydes to give the corresponding

arylmethylene derivatives reported by Wheeler et al[238] and Lubomir Floch et al

[239] studied the synthesis of 5- substituted-3-amino-2-thioxo-4-imidazolidinones

(Fig 54)

H

CO2Et

NCS NH2 NH2 H2O

MeOH or EtOH Et2O

H

CO2Et

NH

NHNH2

S

NH

N

O

SH

NH2

Figure 54

29

Zerong Daniel wang et al [240] reported that synthesis of 2-thiohydantoins

derivative (Fig 55)

N N

NH2

CH3

CH3

OH

O

+ NH

S

NH2

CH2

NH

N

CH3CH3

S

O

CH2

+NH

NH

CH3CH3

O

S

Figure 55

Farzin Hadizadeh et al [241] prepared the thiosemicarbazone derivatives (Fig

56)

NH

N

CH3 CHO

NH2 NH

NH2

S NH

N

CH3

NNH

NH2

S

Figure 56

Peesapati Venkateswarlu et al [242] studied the semicarbazone derivatives

from bi-cyclic ketones reacted with semicarbazide hydrochloride (Fig 57)

O

CH3

NH2 NH

NH2

O

N

CH3

NH

NH2O

HCl

AcONa and EtOH

Figure 57

Natesh Ramesh kumar et al [243] reported that thiosemicarbazide reacted

with ketone derivatives to give the corresponding thiosemicarbazone derivatives (Fig

58)

30

CH3

CH3

O

+

HO

Cl

N

O

CH3

CH3

Cl

NH2 NH

NH2

S

N

N

CH3

CH3

NH

NH2S

Cl

HO

CH3COONH4

Figure 58

Sampath et al [244] studied the crystal structure and conformation of

N-methyl-t-3-methyl-R-2C-6-diphenylpipridin-4-one thiosemicarbazone (Fig 59)

CH3

CH3

O

+

HO

+ CH3 NH2

99 Ethanol

N

O

CH3

CH3

NH2 NH

NH2

S

methanol HCl N

N

CH3

CH3

NH

NH2S

Figure 59

Jamal Abdul Nasser et al [245] studied the imidazolidin ring prepared from

thiosemicabazone reacted with ethyl chloroacetate and fused sodium acetate by the

cyclization method (Fig 60)

NNH NH2

S

Cl

OC2H5

O

NaOAc

NN

NH

S

O

Figure 60

31

The above literature findings were taken as the basis on which to synthesize

pyrrole pyridine and imidazolidine derivatives

Pyrrole derivatives are mentioned in schemes 1-3

Pyridine derivatives are mentioned in scheme 3

Imidazolidine derivatives are mentioned in schemes 4 -7

All of the synthetic compounds were characterized by Infrared (IR) Proton Nuclear

magnetic resonance (sup1H-NMR) Carbon Nuclear magnetic resonance (13

C-NMR)

Mass spectral and elemental analyses The selected compounds were screened for the

following biological activities

In vitro antimicrobial anticoagulant anticancer and antioxidant activities

In vivo anti-convulsant anti-inflammatory and analogous activities

Environmental toxicity analysis

24

H3CS CONH

NH

O2N

NH NH

S

CH3

NaOH

H3CS

NH

O2N

NN

N

CH3

SH

Figure 40

Mohamed Belkadi et al [223] studied the steps involved in the treatment of

(plusmn)-22-dimethyl-[13]dioxolan-4-carboxylic-acid-hydrazide-thioformamido-semicarb

azide with NaOH in absolute ethanol under reflux for five hours to give (plusmn)-5-(22-

dimethyl-[13]dioxolan-4-yl)-4H-[124]triazole-3-thiol (Fig 41)

Figure 41

Hussain et al [224] synthesized thiadiazole and 124-triazole derivatives from

cyclopropane dicarboxylic acid (Fig 42)

HOOCCOOH

SOCl2 H2NNHCSNH2H2NSCHNNOC

CONNHCSNH2

NaOHN

NH

N

NH

NN

SH

SH

Figure 42

25

Sibel Demir et al [225] studied the crystallographic analysis of compound 55rsquo-

pyridine-26-diylbis[4-ethyl-24-dihydro-124-triazole-3(2H)-thione (Fig 43)

NNHNH

OO

NH NH

S

NHNH

O

CH3 CH3

NaOH

NN

N

N

N

N

N

SH SHCH3

CH3

Figure 43

Preparation of thiadiazole derivatives

Foroumadi et al [226] reported on the anticonvulsant activity of novel 2-amino-

5-[4-chloro-2-(2-chlorophenoxy) phenyl]-134-thiadiazole derivatives (Fig 44)

OCl

Cl

NH

O

NH NH2

S H2SO4

NH4OH

OCl

Cl

N

S

N

NH2

Figure 44

Otilia Pintilie et al [227] reported on the synthesis and antimicrobial activity of

some new 134-thiadiazole and 124-triazole compounds which had a DL-

methionine moiety (Fig 45)

Figure 45

26

Srivastava et al [228] studied the synthesis of a new 124- triazolo-thia

diazole as antimicrobial anticonvulsant and anti-inflammatory agents (Fig 46)

N

NN

O

NHNH NH2

SH2SO4

NH3

N

NN

N

S

N

NH2

Figure 46

Swati Ojha et al [229] studied the conversion of benzatriazole containing

thiosemicarbazone into thiadiazole derivatives with the help of H2SO4 by the

cyclization method (Fig 47)

N

NN

O

NHNH NH2

S H2SO4 NH3

N

NN

S

N N

NH2

Figure 47

Hussain et al [230] synthesized thiadiazole and 124-triazole derivatives from

cyclopropane dicarboxylic acid (Fig 48)

N

S

N

S

NN

NH2 NH2

HOOCCOOH POCl3 H2NNHCSNH2

Figure 48

27

Preparation pyrazole and thiazole derivatives

El-Sayed Rashad et al [231] studied the synthesis of the biologically active

pyrazoles and C-nucleosides (Fig 49)

NHNH2

CH3

O

OEt

O

AcOH heatN N

CH3 O

Figure 49

Hamied latif et al [232] Zevrsquoyalow et al [233] and More et al [234] have

reported by thazole derivative (Fig 50) and their biologically importance

CH3

O

I2 CH2I

ONH2

NH2

S

N

SNH2

Figure 50

Preparation of imidazolidin-4-thioxo-2-one derivatives

Renata Jakse et al [235] studied the progresses in the synthesis and reactions

of imidazolidin and its derivatives in particular the stereoselective synthesis of

5-[heteroaryl methylidene]-substituted hydantoins and thiohydantoins as aplysinopsin

analogues (Fig 51)

NH

N

NCH3

CH3

O

S

Figure 51

28

Giulio et al [236] studied the synthesis of CB1 (cannabinoid) receptor ligands

and evaluated their pharmacological properties (Fig 52)

N

NH

CH3

O S

Cl

Cl

Figure 52

Janos Marton et al [237] studied the fungicidal activity of 5-substituted

hydantoins and their 2-thio analogues (Fig 53)

NH

NH

S

S

CHO

NH NH

O

S

Figure 53

2-Thiohydrotoin was reacted with aromatic aldehydes to give the corresponding

arylmethylene derivatives reported by Wheeler et al[238] and Lubomir Floch et al

[239] studied the synthesis of 5- substituted-3-amino-2-thioxo-4-imidazolidinones

(Fig 54)

H

CO2Et

NCS NH2 NH2 H2O

MeOH or EtOH Et2O

H

CO2Et

NH

NHNH2

S

NH

N

O

SH

NH2

Figure 54

29

Zerong Daniel wang et al [240] reported that synthesis of 2-thiohydantoins

derivative (Fig 55)

N N

NH2

CH3

CH3

OH

O

+ NH

S

NH2

CH2

NH

N

CH3CH3

S

O

CH2

+NH

NH

CH3CH3

O

S

Figure 55

Farzin Hadizadeh et al [241] prepared the thiosemicarbazone derivatives (Fig

56)

NH

N

CH3 CHO

NH2 NH

NH2

S NH

N

CH3

NNH

NH2

S

Figure 56

Peesapati Venkateswarlu et al [242] studied the semicarbazone derivatives

from bi-cyclic ketones reacted with semicarbazide hydrochloride (Fig 57)

O

CH3

NH2 NH

NH2

O

N

CH3

NH

NH2O

HCl

AcONa and EtOH

Figure 57

Natesh Ramesh kumar et al [243] reported that thiosemicarbazide reacted

with ketone derivatives to give the corresponding thiosemicarbazone derivatives (Fig

58)

30

CH3

CH3

O

+

HO

Cl

N

O

CH3

CH3

Cl

NH2 NH

NH2

S

N

N

CH3

CH3

NH

NH2S

Cl

HO

CH3COONH4

Figure 58

Sampath et al [244] studied the crystal structure and conformation of

N-methyl-t-3-methyl-R-2C-6-diphenylpipridin-4-one thiosemicarbazone (Fig 59)

CH3

CH3

O

+

HO

+ CH3 NH2

99 Ethanol

N

O

CH3

CH3

NH2 NH

NH2

S

methanol HCl N

N

CH3

CH3

NH

NH2S

Figure 59

Jamal Abdul Nasser et al [245] studied the imidazolidin ring prepared from

thiosemicabazone reacted with ethyl chloroacetate and fused sodium acetate by the

cyclization method (Fig 60)

NNH NH2

S

Cl

OC2H5

O

NaOAc

NN

NH

S

O

Figure 60

31

The above literature findings were taken as the basis on which to synthesize

pyrrole pyridine and imidazolidine derivatives

Pyrrole derivatives are mentioned in schemes 1-3

Pyridine derivatives are mentioned in scheme 3

Imidazolidine derivatives are mentioned in schemes 4 -7

All of the synthetic compounds were characterized by Infrared (IR) Proton Nuclear

magnetic resonance (sup1H-NMR) Carbon Nuclear magnetic resonance (13

C-NMR)

Mass spectral and elemental analyses The selected compounds were screened for the

following biological activities

In vitro antimicrobial anticoagulant anticancer and antioxidant activities

In vivo anti-convulsant anti-inflammatory and analogous activities

Environmental toxicity analysis

25

Sibel Demir et al [225] studied the crystallographic analysis of compound 55rsquo-

pyridine-26-diylbis[4-ethyl-24-dihydro-124-triazole-3(2H)-thione (Fig 43)

NNHNH

OO

NH NH

S

NHNH

O

CH3 CH3

NaOH

NN

N

N

N

N

N

SH SHCH3

CH3

Figure 43

Preparation of thiadiazole derivatives

Foroumadi et al [226] reported on the anticonvulsant activity of novel 2-amino-

5-[4-chloro-2-(2-chlorophenoxy) phenyl]-134-thiadiazole derivatives (Fig 44)

OCl

Cl

NH

O

NH NH2

S H2SO4

NH4OH

OCl

Cl

N

S

N

NH2

Figure 44

Otilia Pintilie et al [227] reported on the synthesis and antimicrobial activity of

some new 134-thiadiazole and 124-triazole compounds which had a DL-

methionine moiety (Fig 45)

Figure 45

26

Srivastava et al [228] studied the synthesis of a new 124- triazolo-thia

diazole as antimicrobial anticonvulsant and anti-inflammatory agents (Fig 46)

N

NN

O

NHNH NH2

SH2SO4

NH3

N

NN

N

S

N

NH2

Figure 46

Swati Ojha et al [229] studied the conversion of benzatriazole containing

thiosemicarbazone into thiadiazole derivatives with the help of H2SO4 by the

cyclization method (Fig 47)

N

NN

O

NHNH NH2

S H2SO4 NH3

N

NN

S

N N

NH2

Figure 47

Hussain et al [230] synthesized thiadiazole and 124-triazole derivatives from

cyclopropane dicarboxylic acid (Fig 48)

N

S

N

S

NN

NH2 NH2

HOOCCOOH POCl3 H2NNHCSNH2

Figure 48

27

Preparation pyrazole and thiazole derivatives

El-Sayed Rashad et al [231] studied the synthesis of the biologically active

pyrazoles and C-nucleosides (Fig 49)

NHNH2

CH3

O

OEt

O

AcOH heatN N

CH3 O

Figure 49

Hamied latif et al [232] Zevrsquoyalow et al [233] and More et al [234] have

reported by thazole derivative (Fig 50) and their biologically importance

CH3

O

I2 CH2I

ONH2

NH2

S

N

SNH2

Figure 50

Preparation of imidazolidin-4-thioxo-2-one derivatives

Renata Jakse et al [235] studied the progresses in the synthesis and reactions

of imidazolidin and its derivatives in particular the stereoselective synthesis of

5-[heteroaryl methylidene]-substituted hydantoins and thiohydantoins as aplysinopsin

analogues (Fig 51)

NH

N

NCH3

CH3

O

S

Figure 51

28

Giulio et al [236] studied the synthesis of CB1 (cannabinoid) receptor ligands

and evaluated their pharmacological properties (Fig 52)

N

NH

CH3

O S

Cl

Cl

Figure 52

Janos Marton et al [237] studied the fungicidal activity of 5-substituted

hydantoins and their 2-thio analogues (Fig 53)

NH

NH

S

S

CHO

NH NH

O

S

Figure 53

2-Thiohydrotoin was reacted with aromatic aldehydes to give the corresponding

arylmethylene derivatives reported by Wheeler et al[238] and Lubomir Floch et al

[239] studied the synthesis of 5- substituted-3-amino-2-thioxo-4-imidazolidinones

(Fig 54)

H

CO2Et

NCS NH2 NH2 H2O

MeOH or EtOH Et2O

H

CO2Et

NH

NHNH2

S

NH

N

O

SH

NH2

Figure 54

29

Zerong Daniel wang et al [240] reported that synthesis of 2-thiohydantoins

derivative (Fig 55)

N N

NH2

CH3

CH3

OH

O

+ NH

S

NH2

CH2

NH

N

CH3CH3

S

O

CH2

+NH

NH

CH3CH3

O

S

Figure 55

Farzin Hadizadeh et al [241] prepared the thiosemicarbazone derivatives (Fig

56)

NH

N

CH3 CHO

NH2 NH

NH2

S NH

N

CH3

NNH

NH2

S

Figure 56

Peesapati Venkateswarlu et al [242] studied the semicarbazone derivatives

from bi-cyclic ketones reacted with semicarbazide hydrochloride (Fig 57)

O

CH3

NH2 NH

NH2

O

N

CH3

NH

NH2O

HCl

AcONa and EtOH

Figure 57

Natesh Ramesh kumar et al [243] reported that thiosemicarbazide reacted

with ketone derivatives to give the corresponding thiosemicarbazone derivatives (Fig

58)

30

CH3

CH3

O

+

HO

Cl

N

O

CH3

CH3

Cl

NH2 NH

NH2

S

N

N

CH3

CH3

NH

NH2S

Cl

HO

CH3COONH4

Figure 58

Sampath et al [244] studied the crystal structure and conformation of

N-methyl-t-3-methyl-R-2C-6-diphenylpipridin-4-one thiosemicarbazone (Fig 59)

CH3

CH3

O

+

HO

+ CH3 NH2

99 Ethanol

N

O

CH3

CH3

NH2 NH

NH2

S

methanol HCl N

N

CH3

CH3

NH

NH2S

Figure 59

Jamal Abdul Nasser et al [245] studied the imidazolidin ring prepared from

thiosemicabazone reacted with ethyl chloroacetate and fused sodium acetate by the

cyclization method (Fig 60)

NNH NH2

S

Cl

OC2H5

O

NaOAc

NN

NH

S

O

Figure 60

31

The above literature findings were taken as the basis on which to synthesize

pyrrole pyridine and imidazolidine derivatives

Pyrrole derivatives are mentioned in schemes 1-3

Pyridine derivatives are mentioned in scheme 3

Imidazolidine derivatives are mentioned in schemes 4 -7

All of the synthetic compounds were characterized by Infrared (IR) Proton Nuclear

magnetic resonance (sup1H-NMR) Carbon Nuclear magnetic resonance (13

C-NMR)

Mass spectral and elemental analyses The selected compounds were screened for the

following biological activities

In vitro antimicrobial anticoagulant anticancer and antioxidant activities

In vivo anti-convulsant anti-inflammatory and analogous activities

Environmental toxicity analysis

26

Srivastava et al [228] studied the synthesis of a new 124- triazolo-thia

diazole as antimicrobial anticonvulsant and anti-inflammatory agents (Fig 46)

N

NN

O

NHNH NH2

SH2SO4

NH3

N

NN

N

S

N

NH2

Figure 46

Swati Ojha et al [229] studied the conversion of benzatriazole containing

thiosemicarbazone into thiadiazole derivatives with the help of H2SO4 by the

cyclization method (Fig 47)

N

NN

O

NHNH NH2

S H2SO4 NH3

N

NN

S

N N

NH2

Figure 47

Hussain et al [230] synthesized thiadiazole and 124-triazole derivatives from

cyclopropane dicarboxylic acid (Fig 48)

N

S

N

S

NN

NH2 NH2

HOOCCOOH POCl3 H2NNHCSNH2

Figure 48

27

Preparation pyrazole and thiazole derivatives

El-Sayed Rashad et al [231] studied the synthesis of the biologically active

pyrazoles and C-nucleosides (Fig 49)

NHNH2

CH3

O

OEt

O

AcOH heatN N

CH3 O

Figure 49

Hamied latif et al [232] Zevrsquoyalow et al [233] and More et al [234] have

reported by thazole derivative (Fig 50) and their biologically importance

CH3

O

I2 CH2I

ONH2

NH2

S

N

SNH2

Figure 50

Preparation of imidazolidin-4-thioxo-2-one derivatives

Renata Jakse et al [235] studied the progresses in the synthesis and reactions

of imidazolidin and its derivatives in particular the stereoselective synthesis of

5-[heteroaryl methylidene]-substituted hydantoins and thiohydantoins as aplysinopsin

analogues (Fig 51)

NH

N

NCH3

CH3

O

S

Figure 51

28

Giulio et al [236] studied the synthesis of CB1 (cannabinoid) receptor ligands

and evaluated their pharmacological properties (Fig 52)

N

NH

CH3

O S

Cl

Cl

Figure 52

Janos Marton et al [237] studied the fungicidal activity of 5-substituted

hydantoins and their 2-thio analogues (Fig 53)

NH

NH

S

S

CHO

NH NH

O

S

Figure 53

2-Thiohydrotoin was reacted with aromatic aldehydes to give the corresponding

arylmethylene derivatives reported by Wheeler et al[238] and Lubomir Floch et al

[239] studied the synthesis of 5- substituted-3-amino-2-thioxo-4-imidazolidinones

(Fig 54)

H

CO2Et

NCS NH2 NH2 H2O

MeOH or EtOH Et2O

H

CO2Et

NH

NHNH2

S

NH

N

O

SH

NH2

Figure 54

29

Zerong Daniel wang et al [240] reported that synthesis of 2-thiohydantoins

derivative (Fig 55)

N N

NH2

CH3

CH3

OH

O

+ NH

S

NH2

CH2

NH

N

CH3CH3

S

O

CH2

+NH

NH

CH3CH3

O

S

Figure 55

Farzin Hadizadeh et al [241] prepared the thiosemicarbazone derivatives (Fig

56)

NH

N

CH3 CHO

NH2 NH

NH2

S NH

N

CH3

NNH

NH2

S

Figure 56

Peesapati Venkateswarlu et al [242] studied the semicarbazone derivatives

from bi-cyclic ketones reacted with semicarbazide hydrochloride (Fig 57)

O

CH3

NH2 NH

NH2

O

N

CH3

NH

NH2O

HCl

AcONa and EtOH

Figure 57

Natesh Ramesh kumar et al [243] reported that thiosemicarbazide reacted

with ketone derivatives to give the corresponding thiosemicarbazone derivatives (Fig

58)

30

CH3

CH3

O

+

HO

Cl

N

O

CH3

CH3

Cl

NH2 NH

NH2

S

N

N

CH3

CH3

NH

NH2S

Cl

HO

CH3COONH4

Figure 58

Sampath et al [244] studied the crystal structure and conformation of

N-methyl-t-3-methyl-R-2C-6-diphenylpipridin-4-one thiosemicarbazone (Fig 59)

CH3

CH3

O

+

HO

+ CH3 NH2

99 Ethanol

N

O

CH3

CH3

NH2 NH

NH2

S

methanol HCl N

N

CH3

CH3

NH

NH2S

Figure 59

Jamal Abdul Nasser et al [245] studied the imidazolidin ring prepared from

thiosemicabazone reacted with ethyl chloroacetate and fused sodium acetate by the

cyclization method (Fig 60)

NNH NH2

S

Cl

OC2H5

O

NaOAc

NN

NH

S

O

Figure 60

31

The above literature findings were taken as the basis on which to synthesize

pyrrole pyridine and imidazolidine derivatives

Pyrrole derivatives are mentioned in schemes 1-3

Pyridine derivatives are mentioned in scheme 3

Imidazolidine derivatives are mentioned in schemes 4 -7

All of the synthetic compounds were characterized by Infrared (IR) Proton Nuclear

magnetic resonance (sup1H-NMR) Carbon Nuclear magnetic resonance (13

C-NMR)

Mass spectral and elemental analyses The selected compounds were screened for the

following biological activities

In vitro antimicrobial anticoagulant anticancer and antioxidant activities

In vivo anti-convulsant anti-inflammatory and analogous activities

Environmental toxicity analysis

27

Preparation pyrazole and thiazole derivatives

El-Sayed Rashad et al [231] studied the synthesis of the biologically active

pyrazoles and C-nucleosides (Fig 49)

NHNH2

CH3

O

OEt

O

AcOH heatN N

CH3 O

Figure 49

Hamied latif et al [232] Zevrsquoyalow et al [233] and More et al [234] have

reported by thazole derivative (Fig 50) and their biologically importance

CH3

O

I2 CH2I

ONH2

NH2

S

N

SNH2

Figure 50

Preparation of imidazolidin-4-thioxo-2-one derivatives

Renata Jakse et al [235] studied the progresses in the synthesis and reactions

of imidazolidin and its derivatives in particular the stereoselective synthesis of

5-[heteroaryl methylidene]-substituted hydantoins and thiohydantoins as aplysinopsin

analogues (Fig 51)

NH

N

NCH3

CH3

O

S

Figure 51

28

Giulio et al [236] studied the synthesis of CB1 (cannabinoid) receptor ligands

and evaluated their pharmacological properties (Fig 52)

N

NH

CH3

O S

Cl

Cl

Figure 52

Janos Marton et al [237] studied the fungicidal activity of 5-substituted

hydantoins and their 2-thio analogues (Fig 53)

NH

NH

S

S

CHO

NH NH

O

S

Figure 53

2-Thiohydrotoin was reacted with aromatic aldehydes to give the corresponding

arylmethylene derivatives reported by Wheeler et al[238] and Lubomir Floch et al

[239] studied the synthesis of 5- substituted-3-amino-2-thioxo-4-imidazolidinones

(Fig 54)

H

CO2Et

NCS NH2 NH2 H2O

MeOH or EtOH Et2O

H

CO2Et

NH

NHNH2

S

NH

N

O

SH

NH2

Figure 54

29

Zerong Daniel wang et al [240] reported that synthesis of 2-thiohydantoins

derivative (Fig 55)

N N

NH2

CH3

CH3

OH

O

+ NH

S

NH2

CH2

NH

N

CH3CH3

S

O

CH2

+NH

NH

CH3CH3

O

S

Figure 55

Farzin Hadizadeh et al [241] prepared the thiosemicarbazone derivatives (Fig

56)

NH

N

CH3 CHO

NH2 NH

NH2

S NH

N

CH3

NNH

NH2

S

Figure 56

Peesapati Venkateswarlu et al [242] studied the semicarbazone derivatives

from bi-cyclic ketones reacted with semicarbazide hydrochloride (Fig 57)

O

CH3

NH2 NH

NH2

O

N

CH3

NH

NH2O

HCl

AcONa and EtOH

Figure 57

Natesh Ramesh kumar et al [243] reported that thiosemicarbazide reacted

with ketone derivatives to give the corresponding thiosemicarbazone derivatives (Fig

58)

30

CH3

CH3

O

+

HO

Cl

N

O

CH3

CH3

Cl

NH2 NH

NH2

S

N

N

CH3

CH3

NH

NH2S

Cl

HO

CH3COONH4

Figure 58

Sampath et al [244] studied the crystal structure and conformation of

N-methyl-t-3-methyl-R-2C-6-diphenylpipridin-4-one thiosemicarbazone (Fig 59)

CH3

CH3

O

+

HO

+ CH3 NH2

99 Ethanol

N

O

CH3

CH3

NH2 NH

NH2

S

methanol HCl N

N

CH3

CH3

NH

NH2S

Figure 59

Jamal Abdul Nasser et al [245] studied the imidazolidin ring prepared from

thiosemicabazone reacted with ethyl chloroacetate and fused sodium acetate by the

cyclization method (Fig 60)

NNH NH2

S

Cl

OC2H5

O

NaOAc

NN

NH

S

O

Figure 60

31

The above literature findings were taken as the basis on which to synthesize

pyrrole pyridine and imidazolidine derivatives

Pyrrole derivatives are mentioned in schemes 1-3

Pyridine derivatives are mentioned in scheme 3

Imidazolidine derivatives are mentioned in schemes 4 -7

All of the synthetic compounds were characterized by Infrared (IR) Proton Nuclear

magnetic resonance (sup1H-NMR) Carbon Nuclear magnetic resonance (13

C-NMR)

Mass spectral and elemental analyses The selected compounds were screened for the

following biological activities

In vitro antimicrobial anticoagulant anticancer and antioxidant activities

In vivo anti-convulsant anti-inflammatory and analogous activities

Environmental toxicity analysis

28

Giulio et al [236] studied the synthesis of CB1 (cannabinoid) receptor ligands

and evaluated their pharmacological properties (Fig 52)

N

NH

CH3

O S

Cl

Cl

Figure 52

Janos Marton et al [237] studied the fungicidal activity of 5-substituted

hydantoins and their 2-thio analogues (Fig 53)

NH

NH

S

S

CHO

NH NH

O

S

Figure 53

2-Thiohydrotoin was reacted with aromatic aldehydes to give the corresponding

arylmethylene derivatives reported by Wheeler et al[238] and Lubomir Floch et al

[239] studied the synthesis of 5- substituted-3-amino-2-thioxo-4-imidazolidinones

(Fig 54)

H

CO2Et

NCS NH2 NH2 H2O

MeOH or EtOH Et2O

H

CO2Et

NH

NHNH2

S

NH

N

O

SH

NH2

Figure 54

29

Zerong Daniel wang et al [240] reported that synthesis of 2-thiohydantoins

derivative (Fig 55)

N N

NH2

CH3

CH3

OH

O

+ NH

S

NH2

CH2

NH

N

CH3CH3

S

O

CH2

+NH

NH

CH3CH3

O

S

Figure 55

Farzin Hadizadeh et al [241] prepared the thiosemicarbazone derivatives (Fig

56)

NH

N

CH3 CHO

NH2 NH

NH2

S NH

N

CH3

NNH

NH2

S

Figure 56

Peesapati Venkateswarlu et al [242] studied the semicarbazone derivatives

from bi-cyclic ketones reacted with semicarbazide hydrochloride (Fig 57)

O

CH3

NH2 NH

NH2

O

N

CH3

NH

NH2O

HCl

AcONa and EtOH

Figure 57

Natesh Ramesh kumar et al [243] reported that thiosemicarbazide reacted

with ketone derivatives to give the corresponding thiosemicarbazone derivatives (Fig

58)

30

CH3

CH3

O

+

HO

Cl

N

O

CH3

CH3

Cl

NH2 NH

NH2

S

N

N

CH3

CH3

NH

NH2S

Cl

HO

CH3COONH4

Figure 58

Sampath et al [244] studied the crystal structure and conformation of

N-methyl-t-3-methyl-R-2C-6-diphenylpipridin-4-one thiosemicarbazone (Fig 59)

CH3

CH3

O

+

HO

+ CH3 NH2

99 Ethanol

N

O

CH3

CH3

NH2 NH

NH2

S

methanol HCl N

N

CH3

CH3

NH

NH2S

Figure 59

Jamal Abdul Nasser et al [245] studied the imidazolidin ring prepared from

thiosemicabazone reacted with ethyl chloroacetate and fused sodium acetate by the

cyclization method (Fig 60)

NNH NH2

S

Cl

OC2H5

O

NaOAc

NN

NH

S

O

Figure 60

31

The above literature findings were taken as the basis on which to synthesize

pyrrole pyridine and imidazolidine derivatives

Pyrrole derivatives are mentioned in schemes 1-3

Pyridine derivatives are mentioned in scheme 3

Imidazolidine derivatives are mentioned in schemes 4 -7

All of the synthetic compounds were characterized by Infrared (IR) Proton Nuclear

magnetic resonance (sup1H-NMR) Carbon Nuclear magnetic resonance (13

C-NMR)

Mass spectral and elemental analyses The selected compounds were screened for the

following biological activities

In vitro antimicrobial anticoagulant anticancer and antioxidant activities

In vivo anti-convulsant anti-inflammatory and analogous activities

Environmental toxicity analysis

29

Zerong Daniel wang et al [240] reported that synthesis of 2-thiohydantoins

derivative (Fig 55)

N N

NH2

CH3

CH3

OH

O

+ NH

S

NH2

CH2

NH

N

CH3CH3

S

O

CH2

+NH

NH

CH3CH3

O

S

Figure 55

Farzin Hadizadeh et al [241] prepared the thiosemicarbazone derivatives (Fig

56)

NH

N

CH3 CHO

NH2 NH

NH2

S NH

N

CH3

NNH

NH2

S

Figure 56

Peesapati Venkateswarlu et al [242] studied the semicarbazone derivatives

from bi-cyclic ketones reacted with semicarbazide hydrochloride (Fig 57)

O

CH3

NH2 NH

NH2

O

N

CH3

NH

NH2O

HCl

AcONa and EtOH

Figure 57

Natesh Ramesh kumar et al [243] reported that thiosemicarbazide reacted

with ketone derivatives to give the corresponding thiosemicarbazone derivatives (Fig

58)

30

CH3

CH3

O

+

HO

Cl

N

O

CH3

CH3

Cl

NH2 NH

NH2

S

N

N

CH3

CH3

NH

NH2S

Cl

HO

CH3COONH4

Figure 58

Sampath et al [244] studied the crystal structure and conformation of

N-methyl-t-3-methyl-R-2C-6-diphenylpipridin-4-one thiosemicarbazone (Fig 59)

CH3

CH3

O

+

HO

+ CH3 NH2

99 Ethanol

N

O

CH3

CH3

NH2 NH

NH2

S

methanol HCl N

N

CH3

CH3

NH

NH2S

Figure 59

Jamal Abdul Nasser et al [245] studied the imidazolidin ring prepared from

thiosemicabazone reacted with ethyl chloroacetate and fused sodium acetate by the

cyclization method (Fig 60)

NNH NH2

S

Cl

OC2H5

O

NaOAc

NN

NH

S

O

Figure 60

31

The above literature findings were taken as the basis on which to synthesize

pyrrole pyridine and imidazolidine derivatives

Pyrrole derivatives are mentioned in schemes 1-3

Pyridine derivatives are mentioned in scheme 3

Imidazolidine derivatives are mentioned in schemes 4 -7

All of the synthetic compounds were characterized by Infrared (IR) Proton Nuclear

magnetic resonance (sup1H-NMR) Carbon Nuclear magnetic resonance (13

C-NMR)

Mass spectral and elemental analyses The selected compounds were screened for the

following biological activities

In vitro antimicrobial anticoagulant anticancer and antioxidant activities

In vivo anti-convulsant anti-inflammatory and analogous activities

Environmental toxicity analysis

30

CH3

CH3

O

+

HO

Cl

N

O

CH3

CH3

Cl

NH2 NH

NH2

S

N

N

CH3

CH3

NH

NH2S

Cl

HO

CH3COONH4

Figure 58

Sampath et al [244] studied the crystal structure and conformation of

N-methyl-t-3-methyl-R-2C-6-diphenylpipridin-4-one thiosemicarbazone (Fig 59)

CH3

CH3

O

+

HO

+ CH3 NH2

99 Ethanol

N

O

CH3

CH3

NH2 NH

NH2

S

methanol HCl N

N

CH3

CH3

NH

NH2S

Figure 59

Jamal Abdul Nasser et al [245] studied the imidazolidin ring prepared from

thiosemicabazone reacted with ethyl chloroacetate and fused sodium acetate by the

cyclization method (Fig 60)

NNH NH2

S

Cl

OC2H5

O

NaOAc

NN

NH

S

O

Figure 60

31

The above literature findings were taken as the basis on which to synthesize

pyrrole pyridine and imidazolidine derivatives

Pyrrole derivatives are mentioned in schemes 1-3

Pyridine derivatives are mentioned in scheme 3

Imidazolidine derivatives are mentioned in schemes 4 -7

All of the synthetic compounds were characterized by Infrared (IR) Proton Nuclear

magnetic resonance (sup1H-NMR) Carbon Nuclear magnetic resonance (13

C-NMR)

Mass spectral and elemental analyses The selected compounds were screened for the

following biological activities

In vitro antimicrobial anticoagulant anticancer and antioxidant activities

In vivo anti-convulsant anti-inflammatory and analogous activities

Environmental toxicity analysis

31

The above literature findings were taken as the basis on which to synthesize

pyrrole pyridine and imidazolidine derivatives

Pyrrole derivatives are mentioned in schemes 1-3

Pyridine derivatives are mentioned in scheme 3

Imidazolidine derivatives are mentioned in schemes 4 -7

All of the synthetic compounds were characterized by Infrared (IR) Proton Nuclear

magnetic resonance (sup1H-NMR) Carbon Nuclear magnetic resonance (13

C-NMR)

Mass spectral and elemental analyses The selected compounds were screened for the

following biological activities

In vitro antimicrobial anticoagulant anticancer and antioxidant activities

In vivo anti-convulsant anti-inflammatory and analogous activities

Environmental toxicity analysis