syntheses and physicochemical studies...

1

SYNTHESES AND PHYSICOCHEMICAL

STUDIES ON PYRROLE DERIVATIVES

Thesis submitted to the

University of Lucknow

For the degree of

Doctor of Philosophy

In

Chemistry

By

Sangeeta Sahu

Under the supervision of

Dr. R. N. Singh

Department of Chemistry

University of Lucknow

Lucknow 226 007 India

August 2012

2

Department of Lucknow University

Chemistry Lucknow – 226007

Certificate

This is to certify that all the regulations necessary for the submission of

the Ph.D. thesis of Sangeeta Sahu have been fully observed. The contents of this

thesis are original and have not been presented anywhere else for award of

Ph.D. degree.

(Dr. R. N. Singh) The Head

The Supervisor Department of Chemistry

3

Glossary (List of Abbreviations)

The following abbreviations have been used throughout this thesis:

Å angstrom

Ac acetyl, acetate

AcOH acetic acid

Ac2O acetic anhydride

Ar aromatic group

aq. aqueous

atm atmosphere

br broad

°C degrees Celsius

Conc. concentrated

calc’d calculated

COD 1, 3-cyclooctadiene

δ chemical shift (NMR)

d doublet (NMR)

dd double doublet (NMR)

dec decomposition

DCM dichloromethane

DEA diethylamine

DMF N, N-dimethylformamide

DMSO dimethyl sulfoxide

equiv equivalent

E entgegen (apart or opposite)

E+

electrophile

eV electron volt

Et ethyl

Et3N triethyl amine

Et2O diethyl ether

EtOAc ethyl acetate

g gram(s)

hr hour(s)

HIV human immunodeficiency virus

Hz hertz

i iso

IR infrared (spectroscopy)

J coupling constant (NMR)

wavelength

l liter

m multiplet

m meta

mg milligram

Me methyl

MHz megahertz

4

ml milliliter

min minute(s)

mol mole(s)

m.p. melting point (°C)

μ micro

NMR nuclear magnetic resonance

p para

Ph phenyl

PhH benzene

ppm parts per million

ppt precipitate

Pr propyl

i-Pr isopropyl

q quartet

r. t. room temperature

s singlet or strong

SAR structure-activity relationship

sat. saturated

sec. second

t triplet (NMR)

temp. temperature

TFA trifluoroacetic acid

THF tetrahydrofuran

TLC thin layer chromatography

TMS trimethylsilane

TosMIC tosylmethylisocyanide

Ts p-toluenesulfonyl (tosyl)

UV ultraviolet

Vis visible

viz. videlicit (namely)

w weak

wt weight

Z zusammen (together)

5

Acknowledgements

The grace of Almighty and my work has made the presentation of this thesis possible.

With deep regards and profound respect, I avail this opportunity to express my deep sense of

gratitude and indebtedness to my supervisor, Dr. R. N. Singh, Department of Chemistry,

University of Lucknow, Lucknow for introducing the present thesis topic and for his inspiring

guidance, constructive criticism and valuable suggestion throughout the work. I most

gratefully acknowledge his constant encouragement and help in different ways to complete

this thesis successfully.

I acknowledge my sincere regards to the Head and all staff’s member of Department of

Chemistry, University of Lucknow, Lucknow for their kindness and support.

I would like to acknowledge Central Drug Research Institute, Lucknow for providing

library and spectral facility (1H NMR,

13C NMR, Mass Spectrometry, Elemental analysis). I

thanks to Indian Institute of Technology, Kanpur for providing IR spectral records. I

express my thanks to Mr. Rakesh Kumar Gupta for providing IR spectral data of my

samples. I express my thanks to Prof. Dr. Poonam Tandon, Department of Physics,

University of Lucknow, Lucknow for providing UV spectral data of my samples.

I will fail in my duty if I forget my friends who always supported me to get through the ups

and downs of this thesis and constantly inspired me during these years. I am obliged to many

of my colleagues, who helped me. I express my heartful thanks to my seniors and juniors

Mrs. Krishna, Mr. Vikas Baboo, Ms. Poonam Rawat, Mr. Amit Kumar and Ms. Divya

Verma for their nice co-operation during my research work.

Today what I am is all due to my most beloved, highly respectable parents, Shri Ram Ratan

Sahu, a strong source of inspiration and supported me financially and morally and I feel a

deep sense of gratitude for my mother Smt. Raj Mati Sahu, who formed part of my vision and

taught me good things that really matter in life. I feel a deep sense of gratitude for my

younger sister, Ms. Smriti Sahu, youngest brother, Mr. Harsh Sahu and other family

members for their constant encouragement, moral support and everlasting love.

Place: Lucknow

Date: (Sangeeta Sahu)

6

Dedicated

To

God, and my Beloved Parents

7

Contents

Certificate

Abbreviations

Acknowledgement

Chapter 1. Syntheses and characterization of pyrrole-chalcone derivatives 1-60

1.1 Introduction

Pyrrole and its derivatives, Chalcones and Pyrrole-chalcone derivatives

1.2 Basis of work and objectives of the present investigations

1.3 Materials, methods and syntheses

1.4 Result and discussion

1.4.1. Ethyl 3, 5-dimethyl-4-(3-oxo-3-phenyl-propenyl)-1H-pyrrole-2-

carboxylate

1.4.2. Ethyl 3, 5-dimethyl-4-(3-phenyl-acryloyl)-1H-pyrrole-2-carboxylate

1.4.3. Ethyl 4-(3-furan-2-yl-acryloyl)-3, 5-dimethyl-1H-pyrrole-2-

carboxylate

1.4.4. Ethyl 4-[3-(4-dimethylamino-phenyl)-acryloyl]-3, 5-dimethyl-1H-

pyrrole-2-carboxylate

1.5 References

Chapter 2. Syntheses and characterization of Pyrrole hydrazide-hydrazones

61-131

2.1 Introduction

Acid hydrazide, Hydrazide-hydrazones




2.4.1 Ethyl 4-{1-[(2-hydrazinocarbonyl-acetyl)-hydrazono]-ethyl}-3, 5-

dimethyl-1H-pyrrole-2-carboxylate

2.4.2 Phenyl sulfonyl hydrazone of Ethyl 4-acetyl-3, 5-dimethyl-1H-


2.4.3 Thiocarbohydrazone of Ethyl 4-acetyl-3, 5-dimethyl-1H-pyrrole-2-

carboxylate

2.4.4 Ethyl 4-[1-(cyanomethyl-hydrazono)-ethyl]-3, 5-dimethyl-1H-pyrrole-

2-carboxylate

2.5 References

Chapter 3. Syntheses and characterization of cyanovinyl ester pyrrole

hydrazide-hydrazones 132-193

3.1 Introduction

Cyanovinyl ester pyrrole




8

3.4.1 Thiocarbohydrazone of ethyl α-cyano-5-formyl-2-pyrroleacrylate

3.4.2 Hydrazone of succinic acid dihydrazide and ethyl α-cyano-5-formyl-

2-pyrroleacrylate

3.4.3Carbohydrazone of ethyl α-cyano-5-formyl-2-pyrroleacrylate

3.4.4Hydrazone of malonic acid dihydrazide and ethyl α-cyano-5-formyl-2-

pyrroleacrylate

3.4.5Hydrazone of 2-hydrazinocarbonyl-N-phenyl-acetamide and ethyl α-

cyano-5-formyl-2-pyrroleacrylate

3.5 References

Chapter 4. Syntheses and characterization of Pyrrole-pyrazoline containing

Heterocycles 194-254

4.1 Introduction

Pyrazoline and its derivatives




4.4.1 Ethyl 4-[5-Furan-2-yl-1-(4-nitro-benzoyl)-4, 5-dihydro-1H-pyrazol-3-

yl]-3, 5-dimethyl-1H-pyrrole-2-carboxylate

4.4.2 Ethyl 4-[1-(2, 4-Dinitro-phenyl)-5-furan-2-yl-4, 5-dihydro-1H-

pyrazol-3-yl]-3, 5-dimethyl-1H-pyrrole-2-carboxylate

4.4.3 Ethyl 4-[5-(4-Chloro-phenyl)-1-(2, 4-dinitro-phenyl)-4, 5-dihydro-1H-


4.4.4 Ethyl 4-[5-(4-Dimethylamino-phenyl)-1-(2, 4-dinitro-phenyl)-4, 5-

dihydro-1H-pyrazol-3-yl]-3, 5-dimethyl-1H-pyrrole-2-carboxylate

4.5 References

Summary and Conclusion 255-261

List of Publications

9

Chapter 1

Syntheses and characterization of

pyrrole-chalcone derivatives

10

1.1 Introduction

Heterocyclic chemistry encompasses one of the largest divisions of chemistry, with

important applications in biological,1 pharmaceutical,

1f,h,2 therapeutic,

3 medicinal,

4

catalytic5, advanced materials

1e,f,h,3a chemistry and the production of (non)-natural

compounds.6 The synthesis of complex heterocycles continues to lead the field of

synthetic organic chemistry, and much focus has been on their efficient production

through novel synthetic protocols,1a,7

with the discovery of the DNA structure in

1950s boosting focus on these systems.8 As a large number of pesticides, antibiotics,

alkaloids, and cardiac glycosides are also based on heterocyclic natural products of

significance to human and animal health, activity has been on the rational design of

heterocyclic analogues of natural models.1a

Pyrrole and its derivatives

Pyrrole (C4H5N) is a five membered nitrogen containing planar heterocyclic ring

system exhibiting aromaticity and π-excessive character. The aromatic character of

this heterocycle is due to the delocalization of the lone pair electrons from the hetero

nitrogen atom to the π-system. Among other five membered ring systems are furan

and thiophene. Pyrrole exhibits greater aromaticity than furan and less aromaticity

than thiophene. This order of aromaticity is due to the extent of the involvement of the

lone pair electrons on the heteroatom to the aromatic sextet and this involvement

depends upon the electronegativity of the heteroatom. The pyrrole moiety is one of the

ubiquitous heterocyclic structures throughout both the plant and animal kingdoms.10

From the point of view of its intense utilization the synthetic pyrrole chemistry has

dominated. Pyrrole is much more reactive than furan, thiophene and benzene towards

electrophilic aromatic substitution as a result of the lone pair at nitrogen and the

consequent stability of σ-complexes. A variety of electrophilic substitution reactions

are known for pyrrole including sulfonation, halogenation, nitration, mercuration,

alkylation and acylation. All of these electrophilic reactions must be performed under

mild reaction environments due to the tendency of pyrrole to polymerize under acidic

11

conditions (e.g., sulfonation and nitration). In the pyrrole family, electrophilic

substitution occurs predominantly at the C-2 or (α)-position. This preference can be

due to the more stable intermediate that is formed upon introduction of an electrophile

to the α-position. This fact has played a crucial role in the synthetic chemistry of

pyrroles for preparations of natural homologs. During attempts for synthesis of natural

homologs, there was frequent formation of many intermediates which were also

utilized for further new synthetic routes.

This widespread appearance of the pyrrole moiety among biological molecules is

mainly due to both its facility to polymerize and capacity to form N-H…....

π hydrogen

bonds with neighboring molecules.11-16

Growing abundance of pyrrolic components in natural products, pharmaceuticals and

new materials lead the chemistry of pyrrole and its derivatives towards centre of

interest. Common naturally occurring substances mostly contain tetrapyrrolic unit

such as hemoglobin, chlorophyll, B12 vitamin etc. Many alkaloid natural products of

varying complexity and biological activity, various naturally occurring drugs

containing pyrrole derivatives have created much more attraction towards it.

Increasing interest towards pyrrole as potential pharmaceutical is because of its less

restricted potent position relative to more common heterocyclic skeleton such as

indole and imidazole. The chemistry of pyrroles is attracting steady attention because

these heterocycles play an important role in nature and, at the same time, possess rich

synthetic potential making them valuable synthons for the design of novel

organometallic magnetic compounds or materials for optoelectronics,17

light-

harvesting systems and photosensitizers for photodynamic cancer diagnostics and

therapy,18

conducting organic polymers, pesticides. Hence a considerable effort has

been focused on the understanding of pyrrole electronic structure and photochemical

properties. Moreover, pyrroles also serve as a source of fuel nitrogen in coals and

heavy oils.19

Furthermore, pyrrolic moieties exhibit a wide variety of useful

compounds having emerging optical and electronic properties.

12

Pyrrole derivatives were often found in biological materials. Porphobilinogen, which

is present in living cells, is the monopyrrole natural derivative and it makes its

utilization in the synthesis of chlorophyll in plant cells and hemin and vitamin B12 in

animal cells. It is also precursor of a number of antibiotics, including the tripyrrolic

prodigiosins, which have an entirely different biosynthetic origin.20

Besides, several

macromolecular antibiotics having pyrrole structure were isolated from biological

sources and their activities were defined.

Pyrrolnitrin (3-Chloro-4-(3-chloro-2-nitro-phenyl)-1H-pyrrole) 1 (Figure 1),21a

naturally occurring antibiotics as being found to display antifungal, antimycotic

activity and is therapeutically useful compound.

Moreover, the Atorvastin Calcium 2 is a pentasubstituted pyrrole and is most

prescribed prescription drug for cholesterol lowering (hypolipidemic agent) without

side effects. Other pyrrolecarboxamide moieties are also common structural motif

amongst a number of biologically important natural products including sceptrin21b

3

(antiviral agent), storniamide21c 4 (antibacterial agent) as well distamycin 5 and

netropsin21d, e, f

6 (antibiotics). Such examples serve to demonstrate the potential of the

pyrrole nucleus as a drug scaffold due to the fact that heterocyclic aromatic ring

pyrrole can provide five points of potential chemical diversity.

13

Among the aforementioned compounds, the antibiotics distamycin 5 and netropsin 6

are crescent-shaped oligopeptides composed of three and two 1-methyl-4-

14

aminopyrrole-2-carboxylic acid residues, respectively. These heterocycles bind in the

minor groove of Β-DNA with a strong preference for A, T-sequences21e, f

presumably

via hydrogen bonding between the amide groups of the antibiotics and lone pair

electrons on the nitrogens of adenines or oxygen atoms of thymines.21g

The pyrrole derivative BM212 (1, 5-diaryl-2-methyl-3-(4-methylpiperazin-1-

yl)methyl-pyrrole) 7 appeared to be endowed with particularly potent and selective

antimycobacterial properties, and consequently, Delia Deidda et al.22

devised some

experiments in order to characterize its activity against both drug resistant and

intramacrophagic mycobacteria.

Polysubstituted pyrroles are an important class of heterocycles that display diverse

pharmacological activities.23

Furthermore, they are useful building blocks in the

synthesis of natural products and heterocyclic chemistry. Known bioactivities for this

class of compounds include anti-inflammatory,24

anticancer,25

antiviral, 26

antifungal,27

pesticidal,28

radioprotective,29

MEK inhibitory,30

MK2 inhibitory,31

FAK, KDR and

Tie2 inhibitory,32

PDE inhibitory,33

anti-interleukin-6,34

TNF-R production

inhibitory,35

and afferent pelvic nerve activity inhibitory.36

Moreover, some of these

polysubstituted pyrroles like 2-aminopyrroles are precursors for the synthesis of

purine analogues; pyrrolopyrimidines, pyrrolotriazines, and pyrrolopyridines.37-43

15

These pyrrole containing heterocycles are widely investigated for their multiple

bioactivities, which, among many others, are known to include anti-inflammatory,37

anticancer,38

antiviral,39

antifungal,40

adenosine A1 receptor inhibitory,41

adenosine

kinase,42

and dihydrofolate reductase43

inhibitory. The pyrrolo[2,3-d]pyrimidine ring

system is also a common motif in several natural products, such as nucleoside

antibiotics tubercidin, toyocamycin, sangivamycin,44

and marine alkaloids rigidins A,

B, C, D, and E.45

Chalcones

Chalcones possess a 1, 3-diaryl-2-propen-1-one skeleton in which two aromatic rings

are linked by a three-carbon α, β-unsaturated carbonyl system.

From a chemical viewpoint, chalcones consist of two aromatic rings (A and B) linked

through a three carbon unit having α, β-unsaturated carbonyl moiety.46-48

The presence

of an α, β-unsaturated bond and the absence of the central C-ring are two specific

characteristics of chalcones, making these compounds chemically different from the

other flavonoids.

Chalcones often entitled ‘open chain flavonoids’ that occupy a variety of structural

forms and in general have the flavan skeleton structurally in common, Figure 5.

16

The numbering in the chalcone framework is reversed from that of the other

flavonoids. The bridge carbons are marked relative to the carbonyl function as C-α

and C-β.

Flavonoids have known for more than a hundred years, and constitute one of the

largest and most diverse groups of natural compounds. Flavonoids are widely

distributed in edible plants and consequently form part of the human diet.

Approximately 9000 different flavonoids from different plant sources have been

described so far, and each year, hundreds of newly identified compounds belonging to

eight different classes of flavonoids are being recorded in the literature.49

Flavonoids

mainly found in a wide variety of fruits, vegetables, leaves, and flowers.50

The

flavonoids are usually yellow-colored compounds, and contribute to the colours of

flowers and fruits. Their biological activity was discovered around 1940 and they

were for a short while designated “P vitamins” because of their ability to heal

capillary fragility, a property similar to that of vitamin C. This effect has never

entirely proven, but since then their biological role has studied extensively, and

thousands of articles and several books have published on the theme.51

Flavonoids show a wide variety of biological activities. Flavonoids act as

antioxidants, by inhibiting biomolecules from undergoing oxidative damage through

free radicals mediated reactions.52

They can act in several ways, including direct

quenching of reactive oxygen species, inhibition of enzymes, chelation of metal ions

(Fe3+

, Cu+), promotion of radical production, and regeneration of membrane-bound

antioxidants such as R-tocopherol. Their beneficial effects are related to diseases in

which oxidative processes are remarkable, i.e., atherosclerosis, coronary heart disease,

17

certain tumors, and aging itself.53

Flavonoids represent the most common and active

edible antioxidants.54

While fat-soluble tocopherols can exhibit their antioxidant

power especially in hydrophobic systems, flavonoids can act both in hydrophilic and

hydrophobic environments.

In addition to their antioxidant effects,55

they have been reported to among other

things modulate enzyme activity,56

have immunomodulating and anti-inflammatory

activities,57

antibiotic effects,58-60

oestrogenic activity,61

anticarcenogenic activity,62

antithrombotic effects63

and counteract vascular permeability.64

Silybin 8 (Figure 6), a

flavonoid from the milk thistle Silybum marianum, has hepatoprotective effect and is

used in combination with penicillin in the treatment of mushroom poisoning. Drugs

containing milk thistle extract are used to treat various types of liver disease.65

Kostanecki first coined the name chalcone in 1899.66

Chalcones are one of the major

classes of natural products with widespread distribution in legumes, soy, spices, tea,

beer, fruits and vegetables.67, 68

A cursory look at the literature cited in relation to chalcones in recent years indicates

that there is a growing interest in evaluating the pharmaceutically important biological

activities of chalcones and its derivatives, presuming their role in the prevention of

various degenerative diseases and other human ailments.69

A naturally occurring chalcone Licochalcone-A 9 (chalcone derivative found in the

licorice root70, 71

) (Figure 7) has been associated with a wide variety of anticancer

18

effects, along with other potential benefits.72

It is active against a wide range of Gram-

positive organisms but not against Gram-negative bacteria and eukaryotes.73, 74

Licochalcone A has been used as a lead compound for the design of more potent

antibacterial agents based on the chalcone template.75

Scientific investigations on the bioavailability of chalcones from food sources are

limited but variety of synthetic chalcones has been reported to possess a wide range of

pharmaceutically important biological activities.76(a)

Chalcones have shown a wide

range of biological activities76(b)

depending on the substitution pattern on the two

aromatic rings around enone moiety. Plethora of literature has accumulated in the

recent years suggesting that chalcones and its derivatives have demonstrated to

possess an impressive array of pharmacological and agrochemical activities,77

namely,

antiprotozoal, antispasmodic,78

immunomodulatory, nitric oxide and lipid

peroxidation inhibition, antiulcer,79, 80

cardiovascular,81

antibiotic,82

analgesic,83

anti-

HIV,84

anti-AIDS agents,85

modulation of enzyme activity,86

modulation of P-

glycoprotein mediated multidrug resistance,87

tuberculostatic,88

antileishmanial,89-91

oestrogenic,92

anticarcinogenic,93

antimalarial activity,94, 95

Anti-Trypanosomal96

and

antimicrobial activities.97

Chalcone derivatives have been described in the literature as

inhibitors of chemoresistance,98

ovarian cancer cell proliferation,99

pulmonary

carcinogenesis,100

proliferation of HGC-27 cells derived from human gastric cancer,

and other tumorigenic effects.101

19

Chalcones have also been reported as inhibitors of angiogenesis, because the process

of angiogenesis (formation of new blood vessels) is proved crucial for the survival and

proliferation of solid tumors. Arresting the angiogenesis process has been considered

as a potential target for the development of anticancer drugs.102

Chemists have long

sought a ‘magic bullet’ for the treatment of cancer, a compound that will selectively

kill cancerous cells without affecting the normal cells. A number of chalcones have

demonstrated cytotoxic and anticancer103, 104

properties because of their preferential

reactivity toward cellular thiols in contrast to amino and hydroxy groups found in

nucleic acids.105-109

Hence, these compounds may be free from the problems of

mutagenicity and carcinogenicity that are associated with a number of alkylating

agents used in cancer chemotherapy, such as chlorambucil and melphalan.110

Recently Gacche et al. have reported series of derivatives of 1-(2 -hydroxy-3-(2-

hydroxy-cyclohexyl)-4, 6-dimethoxy-phenyl)-methanone (chalcone) as an effective

antioxidant agents.111

In fact, because of their chemical structures, these compounds

can promote both antioxidant112-114

and preoxidant effects115

and, as a consequence,

have been shown to be effective chemo-preventive agents116, 117

as well as to exert

antimicrobial activity like antimalarial,118

bactericidal especially more effective

against Gram-positive than Gram-negative bacteria,119-121

antifungal,122,123

antiviral,124

anticarcinogenic125

and anti-inflammatory126

actions. Chalcone derivatives have also

been shown to exhibit in vitro and in vivo antitumor activities84, 127-130

and capacity to

inhibit carcinogenesis induced by chemical agents through enhancement of reduced

glutathione levels.131

Their antimicrobial activity and particularly the antifungal action

have been largely attributed to the reactive enone moiety.132

As a Michael reaction

acceptor, the enone unit binds thiol groups of certain proteins.133

Probably in that

manner, most chalcones inhibit biosynthesis of yeast cell wall and thus unfold their

antifungal potential.134

The Michael reactions of chalcones are facilitated by electron

withdrawing (EW) groups at p-position in ring B. Such substituents increase the

electron deficiency at C- β transforming it into an attractive electrophilic centre for the

thiol attack. The alternative p-electron donating (p-ED) groups hamper this

reaction.132, 135

Introduction of various substituents and / or groups into the two aryl

20

rings / enone moiety is also a subject of interest because it leads to useful SAR

conclusions and thus helps to synthesize pharmacologically active chalcones.136

Several Synthetic Chalcones have been designed, synthesized and tested for inhibition

of activation of mast cells, neutrophils, macrophages and microglial cells which are

important mediators in the initiation of inflammatory disorders.137

It is this reputation

of Synthetic Chalcones in the main stream of pharmaceutical research, which has

attracted researches in the recent years.

They have found numerous applications as pesticides; photo-protectors in plastics;

solar creams and food additives.50

In plants, chalcones are important intermediates in

the biosynthesis of flavonoids and isoflavonoids.138(a)

Subsequently, they are

precursors in biosynthesis of a large number of flavonoid groups, including flavones,

flavonols, dihydroflavonols, aurones, and isoflavones.138(b)

Chalcones constitute an

important group of natural products that serve as precursors for the synthesis of

various heterocyclic compounds like furans,139(a)

pyrroles,139(a,b)

pyrimidines,139(c)

imidazoles,139(c)

pyrazoles,140

2-pyrazolines141

and flavonoids.142

21

The synthesis of chalcones has accomplished using the Claisen-Schmidt condensation

between the appropriate aldehydes and ketones. The Claisen-Schmidt condensation is

a modified aldol condensation. This latter method involves the reaction of two

molecules of an aldehyde or a ketone having α-hydrogen’s, under the influence of

dilute alkali or acid, to a β-hydroxy aldehyde or β-hydroxy ketone, which usually

22

undergoes dehydration to form a α, β-unsaturated ketone, whereas the Claisen-

Schmidt method involves the condensation between an aldehyde, that has no α-

hydrogen, with a ketone. The reaction can be either base catalyzed or acid catalyzed.

Except for the preparation of the reversed chalcones that were prepared by the acid

catalyzed method, all other compounds were synthesized by using base catalysis. The

method of the preparation of the chalcones is shown in Scheme 1 mentioned below:

The mechanism of formation of a chalcones is depicted in Figure 9. In the first step,

the alkoxide ion abstracts a α-proton from the ketone resulting in the formation of the

carbanion (I). This carbanion is in resonance with the enolate anion. In the next step,

the carbanion attacks the electropositive carbonyl-carbon of the arylaldehyde to give

an alkoxide, which further abstracts a hydrogen from water to yield a β-hydroxy

ketone. In the final step, the β-hydroxy ketone undergoes dehydration to give the α, β-

unsaturated ketone, namely a chalcone.

23

The α proton appears further upfield compared to the β proton due to the shielding

effect of the carbonyl group. The coupling constant of 16 ppm strongly indicates that

the protons have a trans configuration, which is consistent with the observation that

the more stable trans isomers are produced in the synthesis of chalcones.143

Pyrrole-chalcone derivatives

On taking into account, the enormous areas of applicability of both type of moieties

pyrrole and chalcone, it is matter of great interest to have combined both. So, when

one of the rings of 1, 3-diaryl-2-propen-1-one skeleton is occupied by pyrrole

derivatives, it generates Pyrrole-chalcone.

24

2-Pyrrole-chalcones 12-15 were synthesized by base-catalyzed (Sodium hydroxide or

Potassium hydroxide in ethanol) condensation of 2-formylpyrrole 10 with aromatic

ketones 11.144

These pyrrole-chalcones, like chalcones, are easy targets for various types of reagents

to produce a variety of chemical modifications. For e.g., The pyrrole-chalcone 16

cyclizes into the pyrrolizine 17 in the presence of a complex catalytic system, [(MeLi-

ZnCl2, 1.5:1; 5-10 mol % of Ni(COD)2]. Reductive cyclization (ZnEt2, 5-10 mol % of

Ni(COD)2, 20 mol% of PPh3) of the pyrrole 16 is less efficient: a 1:3 mixture of

pyrroles 18 and 19 is formed (Figure 10).145

25

Sonication of a suspension of 2-pyrrole-chalcones 20 and t-BuOK in acetonitrile

affords a number of 4-(2- pyrrolyl)-3-cyano-2-methylpyridines 21, which can be

readily transformed to nicotinic acids (Figure 11).146

Cyclization of pyrrole-chalcones with hydrazone function 22 gives pyrazolines 23,

which may then be oxidized to the corresponding pyrazoles (Figure 12).147

Cyclization of pyrrole-chalcones with urea, thiourea and guanidine 24 gives

pyrimidine derivatives 25 (Figure 13).

26


The literature survey made readily show that pyrrole and chalcones are two very

valuable classes of substances which have wide usage area; either as starting materials

for drug substances or many other compounds which have fused heterocyclic rings in

their structures and pharmacophore for many complex natural products. Some

derivatives of these compounds are potent drug substances themselves. They are also

present in many biologically active compounds and their derivatives are known to

have a wide range of applications in medicine and agriculture. Their multifunctional

derivatives are extensively used in drug discovery and many pharmacological

activities. They have been widely used to produce pharmaceutical, essences,

biochemicals, etc. It has been observed that challenge for development of shorter,

cheaper and more versatile synthetic pathways for these two substance classes has

been a subject of great challenge for many chemists around the world, beginning from

the early decades of last century and still today many reports about the subject can be

seen since there is a huge number of natural products reported to have these systems

in their structures.

The objective of the present study was the syntheses and characterization of chalcones

containing pyrrole moiety. Since on structural viewpoint, chalcones consist of two

aromatic rings (A and B) linked through a three carbon unit having α, β-unsaturated

carbonyl frame (Figure 14) as given below:

In α, β-unsaturated carbonyl frame pyrrole moiety may have position on β carbon

(side 1) or carbonyl carbon (side 2) depends on reactants functional during synthesis.

27

So, based on pyrrole position in α, β-unsaturated carbonyl frame two categories of

chalcones are formed:

(I) Pyrrole moiety attached to β carbon (side 1) α, β-unsaturated carbonyl frame of

chalcone and

(II) Pyrrole moiety attached to carbonyl carbon (side 2) of α, β-unsaturated carbonyl frame

of chalcone.

Based on the huge literature survey mentioned the versatile method for the synthesis

of chalcones. The factors outlined above directed our efforts towards development of

new and shorter synthetic procedures for synthesis of derivatives of aforementioned

two series. The general methodology utilized for the synthesis of tetra-substituted

pyrrole-chalcones is as shown in Scheme 3. This scheme is aided with calculative

amount of ethanol as a solvent and aqueous solution of base catalyst.

28

This scheme for the syntheses of compounds has been worked out and characterized

by different tools which are described in detail in the further proceedings.

29

1.3 Materials, Methods and Syntheses

A. Reagents and Solvents

The solvents were procured from S.D.Fine Qualigens, Ranbaxy, Himedia and E.

Merck. They were used after purification & drying by conventional method148

. The

commercially available chemicals of BDH, guaranteed reagents of Merck & analytical

reagents or equivalent grade of others were used as such.

Syntheses of Starting Materials or reactants

2, 4-Dimethyl –3-formyl-5-carbethoxy pyrrole

Diethyl eximinomalonate149

: In a 3.0 l, three necked, round bottomed flask, fitted

with a liquid-sealed mechanical stirrer and dropping funnel, are placed 390 g (3 mol)

of diethylmalonate and 900 cc of glacial acetic acid. The solution is cooled in an

efficient freezing mixing to 5° & a cold solution of 170 g (1.47 mol) of 95% sodium

nitrite in 150 cc of water is added drop wise with vigorous stirring at such a rate that

30

temperature remains between 5° and 7°. With efficient cooling about one-half hour

longer and then allowed to stand for 4 hours during which time it warms up to room

temperature.

2-Carbethxoy-3,5-dimethylpyrrole150

: A solution of 5 g of 2, 4-pentanedione in 26

ml of glacial acetic acid was placed in a 100 ml three-neck flask equipped with a

mechanical stirrer, dropping funnel, thermometer and gas exist. The solution was

heated and at 80° C, a mixture of 13 g of anhydrous sodium acetate and 11 g of zinc

dust was added with vigorous stirring. At 95°, the drop wise addition of a solution of

9.47 g of diethyl eximinomalonate in 12 ml of acetic acid and 5 ml of water was

begun. The addition was completed in 30 to 40 min. between 95 and 105°, vigorous

stirring being maintained constantly throughout. After heating to 100-105º for an

additional 20 min. the reaction mixture was poured with stirring into 170ml of ice-

water mixture, then refrigerated. The crude-product was filtered off, washed with

water pressed on the filter then taken up in 50 ml of boiling 95%EtOH. After filtration

of the hot mixture to remove the zinc dust, the filtrate was concentrated to 30ml,

poured into 85 ml of ice-water mixture and refrigerated. Filtration then afforded a

product, which after drying in vacuo weighed 5.03g (60% yields) m.p. 120-124º. Two

recrystallizations from 95% ethanol afforded the analytically pure material of m.p.

124-124.5º, mixed melting point with authentic sample (m.p.124.5-125º) prepared by

the method of Fischer & Walach showed no depression.

2, 4-Dimethyl –3-formyl-5-carbethoxy pyrrole151

: To a cold mixture of 2.68 g

(0.0160 mol) of 2-carbethoxy-3, 5- dimethyl pyrrole and 1.46 g (1.54 ml,0.0199 mol)

of N, N-dimethyl formamide, there was gradually added 3.08 g (1.86 ml, 0.0200

mole) POCl3 through a condenser which was then connected to a calcium chloride

tube. After the vigorous reaction was over, the reaction mixture was refluxed on a

steam bath for 2 hours. The brown mass was then stirred with ice water and

neutralized to Congo red with a saturated solution of sodium acetate. The crude 2, 4-

dimethyl-3-formyl-5-carbethoxy pyrrole was filtered, washed with a small amount of

cold water and recrystallized with 50% alcohol. Yield: 2.65 g (89.5%) Melting point:

140-142ºC observed (145-145.5 ºC reported).

31

2, 4-Dimethyl –3-acetyl-5-carbethoxy pyrrole

2, 4-Dimethyl –3-acetyl-5-carbethoxy pyrrole was prepared by following method152

:

In a 3.0 l, three-necked flask provided with a stirrer & surrounded by an ice-bath are

placed 402 g (3.09 mol) of ethyl acetoacetate (Note 1→The ester used was

commercial product and was not further purified.) and 1.2 l of glacial acetic acid. To

this solution is then added drop wise with stirring a solution of 246 g (3.55 mol) of

sodium nitrite in 400 ml of water. The rate of addition is controlled so that the

temperature does not rise above 12º. After the sodium nitrite solution has been added,

the mixture is stirred an additional 2-3 hours. It is then allowed to warm up to room

temperature and stand about 12 hours, after which 348 g (3.48 mol) of acetyl acetone

is added at one time.

To the reaction mixture 450 g of zinc dust (Note 2→The zinc dust should be at least

80% pure.) is added in portions of about 100 g with vigorous stirring. The rate of

addition is regulated so that the temperature never rises above 60º. After the addition

is complete (Note 3→Before the reaction mixture is refluxed, enough time should be

allowed for the zinc dust to react completely; otherwise considerable trouble with

foaming may be encountered.), the mixture is refluxed for 2-3 hours on a hot plate

until the unreacted zinc dust collects in balls. The hot solution is then poured through

a fine copper sieve, with stirring, into 30 l of ice water. The crude product, which

32

separates, is contaminated with zinc (Note 4→The crude product darkens an exposure

to light especially when exposed to direct sunlight. The recrystallization product is

unaffected by light.). On recrystallization from 1.5l of 95% ethanol 360-390 g of 2, 4-

dimethyl –3-acetyl-5-carbethoxy pyrrole (m.p. 143 -144 º) is obtained (55.60% based

on the ethyl acetoacetate used) (Note 5→The preparation can be carried out in larger

or smaller quantities with proportionate amounts of materials and volumes of

containers without affecting the yield. The amounts specified here are 60% of those

used by the submitter.). A second recrystallization may be necessary to secure a

perfectly white product.

B. Physico-Chemical Techniques

Thin layer chromatography was routinely used to check the formation & status of

products on pre-coated TLC plates (Silica gel 60, Merck) and using various

developers such as spray of 5% H2SO4 solution or keeping in iodine chamber.

Ambassador®

melting point apparatus based on controlled electrically heating device

was used for melting point determination using capillary tubes open on side and are

uncorrected. Ambassador® melting point apparatus provided a temperature range from

room temperature to 360°C. The infrared spectra of products were recorded (4000-500

cm-1

) in KBr disc, using a Schimadzu 8201 PCFT IR spectrometer in Regional

Sophisticated Instrumentation Centre, at Central Drug Research Institute, Lucknow.

For denoting the intensities of infrared vibrational frequencies the used abbreviation

are as follows: br = broad, vbr = very broad, m = medium, s = strong, vs = very

strong, sh = shoulder, w = weak, vw = very weak. Proton nuclear magnetic resonance

(¹HNMR) spectra were recorded on Bruker DRX-300 spectrometer (300 MHz FT

NMR) instrument using TMS (tetramethylsilane) as an internal reference. The ¹H

NMR spectra were taken in CDCl3 and DMSO unless otherwise stated. The chemical

shift values are expressed in δ scale.

33

Experimental Details

Synthesis of Ethyl 3, 5-Dimethyl-4-(3-oxo-3-phenyl-propenyl)-1H-pyrrole-2-

carboxylate

Ethyl 3, 5-dimethyl-4-formyl-1H-pyrrole-2-carboxylate (0.1952 g, 0.001 mol) was

dissolved in ethanol and freshly distilled acetophenone (0.11 ml, 0.12015 g, 0.001

mol) was added in it. 20% KOH (5 ml) solution was added drop wise in the cold

reaction mixture (5-10˚C). It was allowed to stir overnight. It was neutralized with 5%

HCl solution and poured in water and kept in refrigerator for one hour. The yellow

colored precipitate was obtained which was filtered and washed thoroughly with cold

distilled water and kept for air dry.

Yield: 0.0686g (23.07%)

Melting Point: decomposed

Solubility: This compound is soluble in chloroform, ethylacetate, ethanol, methanol,

acetone, DMSO and insoluble in hexane, benzene and water.

34

UV-vis Spectra (ethanol): λmax 287, 370 nm

IR Spectra (KBr):

3292.45 (N-H), 3043.47 (aromatic =C-H), 2927.53 (aliphatic C-H), 2855.07 (aliphatic

C-H), 1653.29 (C=O of ester group), 1558.75 (C=O), 1508.62 (C=C) cm-1

.

1H NMR Spectra (CDCl3):

9.165 (1H, br, s, py-N-H), 6.998 & 6.960 (1H, d, J=11.4 Hz, β-vinyl proton), 6.747 &

6.707 (1H, d, J=12 Hz, α-vinyl proton), 8.000, 7.977, 7.493, 7.470 (5H, m, Phenyl

protons), 4.345 & 4.321 (2H, q, J=8 Hz, methylene proton of ester group), 1.404,

1.380, 1.356 (3H, t, J=7.1 Hz, methyl protons of ester group), 2.575 (3H, s, 3-methyl

group), 2.527 (3H, s, 5-methyl group).

Synthesis of Ethyl 3, 5-Dimethyl-4-(3-phenyl-acryloyl)-1H-pyrrole-2-carboxylate

Ethyl 4-acetyl-3, 5-dimethyl-1H-pyrrole-2-carboxylate (0.105 g, 0.0005 mol) was

dissolved in ethanol and freshly distilled Benzaldehyde (0.053 g, 0.055 ml, 0.0005

35

mol) was added in it. 20% KOH (5ml) solution was added drop wise in the cold

reaction mixture (5-10˚C). It was allowed to stir overnight. It was neutralized with 5%

HCl solution and poured in water and kept in refrigerator for one hour. The light

yellow colored precipitate was obtained which was filtered and washed thoroughly

with cold distilled water.

Yield: 0.0500 g (33.3%)

Melting Point: first decomposed then melted at 164° C to black liquid.



UV-vis Spectra (ethanol): λmax 308 nm

IR Spectra (KBr):


C-H), 1675.91 (C=O of ester group), 1630.18(C=O), 1593.53 (C=C) cm-1

.


9.033 (1H, br, s, py-N-H), 7.656 & 7.602 (1H, d, J=16.2 Hz, β-vinyl proton), 7.206 &

7.154 (1H, d, J=16.2 Hz, α-vinyl proton), 7.414, 7.369, 7.354 (5H, m, Phenyl

protons), 4.367 & 4.344 (2H, q, J=6.9 Hz, methylene proton of ester group), 1.414,

1.391, 1.367 (3H, t, J=7.1 Hz, methyl protons of ester group), 2.591 (3H, s, 3-methyl

group), 2.523 (3H, s, 5-methyl group).

36

Synthesis of Ethyl 4-(3-Furan-2-yl-acryloyl)-3, 5-dimethyl-1H-pyrrole-2-

carboxylate


dissolved in ethanol and freshly distilled Furan-2-carbaldehyde (0.0480 g, 0.04 ml,

0.0005 mol) was added in it. 20% KOH (2.5ml) solution was added drop wise in the

cold reaction mixture (5-10˚C). It was allowed to stir overnight. It was neutralized

with 5%HCl solution and poured in ice. The pale yellow colored precipitate was

obtained which was filtered and washed thoroughly with cold distilled water.

Yield: 0.0400 g (35.9%)

Melting Point: decomposed at 138˚C and at 140˚C melted to black liquid.




37

IR Spectra (KBr):


C-H), 1645.95 (C=O of ester group), 1593.53 (C=O), 1556.28 (C=C) cm-1

.


8.942 (1H, br, s, py-N-H), 7.438 & 7.387 (1H, d, J=15 Hz, β-vinyl proton), 7.119 &

7.067 (1H, d, J=15 Hz, α-vinyl proton), 7.500 (1H, s, furan-5C-H), 6.496 (1H, s,

furan-4C-H), 6.661 & 6.651(1H, d, J=3 Hz, furan-3C-H), 4.379, 4.355, 4.331 & 4.308

(2H, q, J=7.1 Hz, methylene proton of ester group), 1.358, 1.382, 1.406 (3H, t, J=7.2

Hz, methyl protons of ester group), 2.571 (3H, s, 3-methyl group), 2.520 (3H, s, 5-

methyl group).

Synthesis of Ethyl 4-[3-(4-Dimethylamino-phenyl)-acryloyl]-3, 5-dimethyl-1H-



dissolved in ethanol. 4-Dimethylamino-benzaldehyde (0.0746 g, 0.0005 mol) was

38

dissolved in ethanol and added dropwise in the cold solution of first one. 20% KOH

(2.5ml) was added dropwise in cold reaction mixture while stirring. It was allowed to

stir overnight. It was neutralized with ~5ml HCl and poured in ice. The dark yellow-

orange colored precipitate was filtered off, washed thoroughly with distilled water and

recrystallized with ethanol.

Yield: 0.0446 g (23.07%)

Melting Point: decomposed




IR Spectra (KBr):

3257.76 (N-H), 3089.61, 3054.89 (aromatic =C-H), 2958.46, 2928.22 (aliphatic C-H),

2892.89, 2854.32 (aliphatic C-H), 1661.89 (C=O of ester group), 1620.49 (C=O),

1544.66, 1514.34 (C=C) cm-1

.

1H NMR Spectra (DMSO):

11.852 (1H, br, s, py-N-H), 7.699 & 7.670 (2H, d, J = 8.7 Hz, o-protons of phenyl ring

to vinyl group ), 7.356 & 7.305 (1H, d, J=15.3 Hz, β-vinyl proton), 7.061 & 7.009

(1H, d, J=15.6 Hz, α-vinyl proton), 6.807 & 6.778 (2H, d, J = 8.7 Hz, m-protons of

phenyl ring to vinyl group ), 4.291, 4.268, 4.244 & 4.221 (2H, q, J=7.0 Hz, methylene

proton of ester group), 2.858 (6H, s, methyl groups attached to nitrogen), 2.461 (3H, s,

3-methyl group), 2.429 (3H, s, 5-methyl group), 1.325, 1.302, 1.279 (3H, t, J=6.9 Hz,

methyl protons of ester group).

39

1.4 RESULT AND DISCUSSION

I have successfully synthesized and characterized all the four derivatives of pyrrole-

chalcone derivative. All the results obtained for these compounds are discussed below

in detail.

Syntheses of Pyrrole-chalcone compounds

Syntheses of all four derivatives of pyrrole-chalcones were carried out in presence of

base by conventional Claisen-Schmidt condensation. In this type aldehyde and ketone

were mixed in equiv. amount in presence of aq. KOH. These reactions were possible

only in presence of catalyst.

Spectral Characteristics

The structures of compounds were established on the basis of spectral data. A detailed

discussion of the spectral outcome for each and every compound is as below:

1.4.1 Ethyl 3, 5-Dimethyl-4-(3-oxo-3-phenyl-propenyl)-1H-pyrrole-2-carboxylate

(37)

IR spectra

Heteroaromatics containing an N-H group show N-H stretching absorption in the

region of 3500-3220 cm-1

. The exact position of absorption within this general

frequency region depends upon the degree of hydrogen bonding and hence upon the

degree physical state of the sample for frequency record.153

The IR spectra of Ethyl 3,

5-Dimethyl-4-(3-oxo-3-phenyl-propenyl)-1H-pyrrole-2-carboxylate contains

characteristic band at around 3292.45 cm-1

due to pyrrolic N-H stretching modes. In

general, C=O stretching vibrations give rise to absorption band in the region of 1870-

1540 cm-1

. Generally, the C=O of ester group give rise to absorption for its stretching

vibrations at higher wavenumber than that of the carbonyl group. The spectrum shows

characteristic bands at 1653.29 and 1558.75 cm-1

due to C=O of ester group and

carbonyl group, respectively. The C=C stretching vibration or ring stretching

40

vibrations (or skeletal bands) occur in the general region between 1600-1300cm-1

. The

absorption involves stretching and contraction of all of the bonds in the ring and

interaction between these stretching modes. The band pattern and the relative

intensities depend on the substitution pattern and the nature of the substituents.153

The

spectrum shows band at 1508.62 cm-1

and below it within the given range due to C=C

stretching vibrations. The heteroaromatic structure shows the presence of =C-H

stretching vibrations in the region 3100-3000 cm-1

which is characteristic region for

the ready identification of C-H stretching vibrations.154

In this region the bands are not

affected appreciably by the nature of substituents.155

So, the band above 3000 cm-1

for

e.g., 3043.47 corresponds to aromatic =C-H stretching. The absorption arising from

C-H stretching for aliphatic group occurs in the region of 3000-2840 cm-1

, generally

below 3000 cm-1

. The position of the C-H stretching vibrations is among the most

stable in the spectrum. So, bands below 3000 cm-1

corresponds to aliphatic C-H

stretching modes for e.g., 2927.53 and 2855.07 for asymmetrical and symmetrical

stretching of C-CH3 group, respectively. Other bands at lower frequencies are mixed

modes of different vibrations of present groups corresponds to bending vibrations: in-

plane (scissoring, rocking) and out-of-plane deformations (wagging, twisting) and

torsions etc.

1H NMR spectra

1H NMR spectrum of Ethyl 3, 5-Dimethyl-4-(3-oxo-3-phenyl-propenyl)-1H-pyrrole-

2-carboxylate shows the presence of a broad singlet at δ 9.165 corresponding to

pyrrolic N-H. A multiplet for 5 protons at δ 8.000, 7.977, 7.493 and 7.470 corresponds

to phenyl ring. A doublet at δ 6.998 & 6.960 (J=11.4 Hz) confirms the presence of β-

vinyl (=C-H) proton and another doublet at δ 6.747 & 6.707 (J=12 Hz) confirms the

presence of α-vinyl (=C-H) proton. A quartet for 2 protons at δ 4.345 & 4.321 (J = 8

Hz) and a triplet for 3 protons at δ 1.404, 1.380, 1.356 (J = 7.1 Hz) confirms the

presence of methylene and methyl of ester group in the molecule, respectively. Two

singlets at δ 2.575 and 2.527 confirm the presence of 3-methyl and 5- methyl groups

on pyrrole ring, respectively.

41

1.4.2 Ethyl 3, 5-dimethyl-4-(3-phenyl-acryloyl)-1H-pyrrole-2-carboxylate (39)

IR spectra

The IR spectra of ethyl 3, 5-dimethyl-4-(3-phenyl-acryloyl)-1H-pyrrole-2-carboxylate

contains characteristic bands at around 3495.18, 1675.91, 1630.18 and 1593.53 cm-1

due to υ(N-H), υ(C=O of ester group), υ(C=O) and υ(C=C) stretching modes,

respectively. Other main bands above 3000 cm-1

for e.g., 3038.66 corresponds to

aromatic =C-H and below 3000 cm-1

corresponds to aliphatic C-H stretching modes

for e.g., 2973.9 and 2863.16 for asymmetrical and symmetrical stretching of C-CH3

group, respectively. Other bands at lower frequencies are mixed modes of different

vibrations of groups corresponds to in-plane and out-of-plane deformations, wagging,

rocking and torsions.

1H NMR spectra

1H NMR spectrum of ethyl 3, 5-dimethyl-4-(3-phenyl-acryloyl)-1H-pyrrole-2-

carboxylate shows the presence of a broad singlet at δ 9.033 corresponding to pyrrolic

N-H. A multiplet for 5 protons at δ 7.414, 7.369 and 7.354 corresponds to phenyl ring.

A doublet at δ 7.656 & 7.602 (J=16.2 Hz) confirms the presence of β-vinyl (=C-H)

proton and another doublet at δ 7.206 & 7.154 (J=16.2 Hz) confirms the presence of

α-vinyl (=C-H) proton. A quartet for 2 protons at δ 4.367 & 4.344 (J = 6.9 Hz) and a

triplet for 3 protons at δ 1.414, 1.391, 1.367 (J = 7.1 Hz) confirms the presence of

methylene and methyl of ester group in the molecule, respectively. Two singlets at δ

2.591 and 2.523 confirm the presence of 3-methyl and 5- methyl groups on pyrrole

ring, respectively.

1.4.3 Ethyl 4-(3-Furan-2-yl-acryloyl)-3, 5-dimethyl-1H-pyrrole-2-carboxylate (41)

IR spectra

The IR spectra of ethyl 4-(3-Furan-2-yl-acryloyl)-3, 5-dimethyl-1H-pyrrole-2-

carboxylate contains characteristic bands at around 3285.83, 1645.95, 1593.53 and

42

1556.28 cm-1

due to υ(N-H), υ(C=O of ester group), υ(C=O) and υ(C=C) stretching

modes, respectively. Other main bands above 3000 cm-1

for e.g., 3108.69 corresponds

to aromatic =C-H and below 3000 cm-1

corresponds to aliphatic C-H stretching modes

for e.g., 2984.62 and 2920.28 for asymmetrical and symmetrical stretching of C-CH3

group, respectively. Other bands at lower frequencies are mixed modes of different

vibrations of groups corresponds to in-plane and out-of-plane deformations, wagging,

rocking and torsions.

1H NMR spectra

1H NMR spectrum of ethyl 4-(3-Furan-2-yl-acryloyl)-3, 5-dimethyl-1H-pyrrole-2-

carboxylate shows the presence of a broad singlet at δ 8.942 corresponding to pyrrolic

N-H. There is presence of two singlets and one doublet at δ 7.500, 6.496, and 6.661 &

6.651 (J=3 Hz) ppm corresponding to furan ring protons attached to 5C, 4C, 3C

respectively. A doublet at δ 7.438 & 7.387 (J=15 Hz) confirms the presence of β-vinyl

(=C-H) proton and another doublet at δ 7.119 & 7.067 (J=15 Hz) confirms the

presence of α-vinyl (=C-H) proton. A quartet for 2 protons at δ 4.379, 4.355, 4.331 &

4.308 (J = 7.1 Hz) and a triplet for 3 protons at δ 1.358, 1.382, 1.406 (J = 7.2 Hz)

confirms the presence of methylene and methyl of ester group in the molecule,

respectively. Two singlets at δ 2.571 and 2.520 confirm the presence of 3-methyl and

5- methyl groups on pyrrole ring, respectively.

1.4.4 Ethyl 4-[3-(4-Dimethylamino-phenyl)-acryloyl]-3, 5-dimethyl-1H-pyrrole-2-

carboxylate (43)

IR spectra

The IR spectra of Ethyl 4-[3-(4-Dimethylamino-phenyl)-acryloyl]-3, 5-dimethyl-1H-

pyrrole-2-carboxylate contains characteristic bands at around 3257.76, 1661.89,

1620.49 and 1544.66, 1514.34 cm-1

due to υ(N-H), υ(C=O of ester group), υ(C=O)

and υ(C=C) stretching modes, respectively. Other main bands above 3000 cm-1

for

e.g., 3089.61, 3054.89 corresponds to aromatic =C-H and below 3000 cm-1

corresponds to aliphatic C-H stretching modes for e.g., 2958.46, 2928.22 and 2892.89,

43

2854.32 for asymmetrical and symmetrical stretching of C-CH3 and N-CH3 group,

respectively. Other bands at lower frequencies are mixed modes of different vibrations

of groups corresponds to in-plane and out-of-plane deformations, wagging, rocking

and torsions.

1H NMR spectra

1H NMR spectrum of Ethyl 4-[3-(4-Dimethylamino-phenyl)-acryloyl]-3, 5-dimethyl-

1H-pyrrole-2-carboxylate in DMSO-d6 shows the presence of a broad singlet at δ

11.852 corresponding to pyrrolic N-H. A doublet at 7.699 & 7.670 (J = 8.7 Hz) for

protons of phenyl ring o- to vinyl group and another doublet at 6.807 & 6.778 (J = 8.7

Hz) for protons of phenyl ring m- to vinyl group. A doublet at δ 7.356 & 7.305

(J=15.3 Hz) confirms the presence of β-vinyl (=C-H) proton and another doublet at δ

7.061 & 7.009 (J=15.6 Hz) confirms the presence of α-vinyl (=C-H) proton. A quartet

for 2 protons at δ 4.291, 4.268, 4.244 & 4.221 (J = 7.0 Hz) and a triplet for 3 protons

at δ 1.325, 1.302, 1.279 (J = 6.9 Hz) confirms the presence of methylene and methyl

of ester group in the molecule, respectively. A singlet for 6 protons at δ 2.858

corresponds to methyl groups attached to amino nitrogen. Two singlets at δ 2.461 and

2.429 confirm the presence of 3-methyl and 5- methyl groups on pyrrole ring,

respectively.

44

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51

Chapter 2

Synthesis and characterization of

Pyrrole hydrazide-hydrazones

52

2.1 Introduction

Acid Hydrazide

The functional group -C(=O)NHNH2 containing acid hydrazides covers a vast

numbers of organic compounds. In recent years the N-N linkage has been used as a

key structural motif in various bioactive agents. In particular, an increasing number of

N-N bond-containing heterocycles and peptidomimetics have made their way into

commercial applications as pharmaceutical and agricultural agents.1 Hydrazides find

wide applications as drugs, chemical preservers for plants; in industry – for

manufacturing polymers, glues etc.; in analytical chemistry of organic and inorganic

substances and for many other purposes.2

Hydrazides are known to have different biological activities.3

Hydrazide

derivatives have been claimed to possess antimicrobial,4 antimycobacterial,

5

antitumour,6 anti-inflammatory,

7 trypanocidal,

8 antimalarial

9 and anti-HIV activities.

10

Aromatic hydrazides are also important intermediates in heterocyclic chemistry

and have been used for the synthesis of various biologically active five-

membered heterocycles such as 2, 5-disubstituted-1, 3, 4-oxadiazoles11

and 5-

substituted-2-mercapto-1, 3, 4-oxadiazoles.12

Hydrazides are important key intermediates in the synthesis of many series of

biologically active heterocycles and their synthesis has attracted significant attention

due to their utility as building blocks13(a-e)

and aroused interest in exploring the utility

of hydrazides as versatile precursors for the synthesis of a variety of substituted

heterocycles. 14-16

Organic hydrazide compounds have been widely used as synthetic starting materials

to construct various heterocycles containing nitrogen. Hydrazides of carboxylic acids

are used for the synthesis of hydrazones,17

pyrroles,18

pyrazoles,18

oxadiazoles,19

thiadiazoles19b, 20, 21

and triazoles.19a, 21

Several of these compounds have wide variety

of pharmaceutical continuum such as analgesic, antitubercular, antidepressive,

53

anticonvulsive, antitumor, and bactericidal activity. Cumulative presentation of

general synthesis of acid hydrazides starting from an ester derivative and many

reactions which use hydrazides as one of the starting material are shown in figure 1.

The influence of a few organic hydrazide compounds, namely, lauric hydrazide,

undecenoic hydrazide (Figure 2) on corrosion behavior of mild steel in simulated

corrosive environments encountered in paper industries was also studied.22

These

compounds have been chosen as corrosion inhibitors because they contain hetero

atoms (like N) and π-electrons through which they are readily adsorbed on metal

surface.23

54

Hydrazides are rather reactive substances; they are bidentate as ligands. Depending on

medium acidity, reagents form complexes in either amide (type I) or imide (type II)

forms (Figure 3).24

Since 1970-s, the complexation of a number of carbonic acid hydrazides with ions of

non-ferrous and other metals was studied, significant quantity of papers was

published, dozens of complexes were obtained. However, hydrazides were not used

for separation and concentration of elements for a long time. Obviously, the first

attempt of such type of use was the extraction of Cu (II) from ammoniac mediums

with 2-hydroxybenzoic acid hydrazides as per the general formula shown in figure 4.25

The importance of many aromatic hydrazides is closely related to their

biological activity and to the fact that they can be used for the syntheses of

55

several other biologically active compounds. Nicotinohydrazide (Figure 5), for

example, is an efficient peroxidase-activated inhibitor of the POX activity of

PGHS-2.26

Many acyl hydrazides were widely reported as biologically active compounds, and

similar properties were shown for their derivatives, e.g., hydrazones, semicarbazones,

and thiosemicarbazones.17,27

Furthermore, acid hydrazides are privileged starting

materials for the preparation of various heterocycles like 1, 2, 4-triazoles, 1, 3, 4-

thiadiazoles, 1, 3, 4-oxadiazoles, etc.28

In view of the versatility of these

compounds, Wang et al., obtained 1H-Pyrrole-2-carbohydrazide 20 (Figure 6) and

also presented its crystal data.29

Another type of hydrazide for example, thiocarbohydrazide, having thiocarbamide

group is a key feature with common structure in a variety of natural and synthetic

copounds with interesting biological or chemical properties, and therefore has been

known for its important medicinal,30

bioorganic31

and supramolecular chemistry32

applications. Recently, thiocarbamide derivatives have been used for asymmetric

synthesis33

and they play an important role as chiralcatalysts for highly

enantioselective Michael reactions34

and a new type of herbicides for weed control.35

56

Hydrazide-Hydrazones

Schiff base hydrazide-hydrazones: In chemical terminology, a hydrazone is a

substance with the structure R1R2C=NNR3R4, differing from aldehydes or ketones by

the replacement of the double bonded oxygen with the =NNR3R4 functional group. A

member of the Schiff base family with triatomic >C=N–N< linkage is termed as schiff

base hydrazones and when this linkage is formed by a hydrazide, the product is coined

by the term schiff base hydrazide-hydrazone.

Hydrazones are used as intermediates in synthesis,36

as functional groups in metal

carbonyls,37

in organic compounds38

and in particular in hydrazone schiff base

ligands,39

which are among others employed in dinuclear catalysts.40

It is well

established that the biological activity of hydrazide-hydrazone compounds is

associated with the presence of the active (-CO-NHN=CH-) pharmacophore and these

compounds form a significant category of compounds in medicinal and

pharmaceutical chemistry with several biological applications that include

anticonvulsant,41

antidepressant,42

anti-inflammatory,43

antimalarial,44

antimycobacterial,45

anticancer46

and antimicrobial47

activities. All these physiological

activities are attributed to the formation of stable chelate complexes with transition

metals which catalyze physiological processes.48, 49

Hydrazone linkage is extensively utilized for pH-dependent release of drugs from

polymer-drug conjugates.50

They also act as herbicides, insecticides, nematocides,

rodenticides, plant growth regulators, sterilants for houseflies, among other

57

applications.48, 49, 51

In analytical chemistry hydrazones find applications as

multidentate ligands for transition metals in colorimetric or fluorimetric

determinations.52

Overall, hydrazides, hydrazones and their adducts, hydrazide-hydrazones have

displayed diverse range of biological properties such as potential biological

activities,53

anti-viral,54

anti-tuberculosis,55

anti-tumor,56

cardiovascular,57

anti-

fungal,58

anticonvulsant,49

anti-helminthic,60

analgesic,60

anti-leprotic,61

anti-malerial,62

antidepressant,63

leishmanicidal,64

vasodilator65

and anti-inflammatory66,67

activities.

Therapeutic protocols for the treatment of HIV infection are mainly based on the

combined use of reverse transcriptase, protease, and more recently, of cell fusion and

entry inhibitors. Although drugs targeting reverse transcriptase and protease are in

wide use and have shown effectiveness, the rapid emergence of resistant variants,

often cross-resistant to the members of a given class, limits the efficacy of existing

antiretroviral drugs. Therefore, it is critical to develop new agents directed against

alternate sites in the viral life cycle, anticancer68

and anti-HIV.69

The inhibitory action

of these compounds is attributed to their chelating properties.70

Moreover, many

selectively substituted organic hydrazone compounds show peculiar pharmacological

and agrochemical properties.

Several Schiff’s bases, hydrazones and hydrazides of isoniazid have shown good

activity against tubercular, fungal and bacterial infections.71

For example, Isonicotinic

acid hydrazide (isoniazid, INH) 21 (Figure 8) has itself very high in vivo inhibitory

activity towards M. tuberculosis H37Rv.

58

Sah and Peoples synthesized INH hydrazide-hydrazones 22 (Figure 9) by reacting

INH with various aldehydes and ketones. Isonicotinoyl hydrazones are antitubercular.

Salicylaldehyde benzoylhydrazone 23 inhibits DNA synthesis and cell growth.72

Salicylaldehydeacetylhydrazone 24 displays radioprotective properties.73

4-hydroxybenzoic acid [(5-nitro-2-furyl)methylene]-hydrazide (nifuroxazide) 25(a) is

an intestinal antiseptic; 4-fluorobenzoic acid [(5-nitro-2-furyl)methylene]-hydrazide74

25(b) and 2, 3, 4-pentanetrione-3-[4-[[(5-nitro-2-furyl) methylene] hydrazino]

carbonyl] phenyl]-hydrazone,75

have antibacterial activity against both Staphylococcus

aureus ATCC 29213 and Mycobacterium tuberculosis H37Rv. N1-(4-

Methoxybenzamido)benzoyl]-N2-[(5-nitro-2-furyl)methylene]hydrazine,76

demonstrated antibacterial activity.

59

N1-(4-methoxybenzamido)benzoyl]-N

2-[(5-nitro-2-furyl)methylene]hydrazine 26

(Figure 12) inhibited the growth of several bacteria and fungi.76

The INH hydrazide-hydrazone of 2-acetylimidazo[4,5-b]pyridine 27 exhibited activity

against M. tuberculosis H37 Rv, M. tuberculosis 192, M. tuberculosis 210, isolated

from patients and resistant against INH, ethambutol, rifampicine at 3.13 μg/mL.77(a)

Sriram et al.77(b)

synthesized a new series of antimycobacterial agents containing INH

hydrazide-hydrazones. Amongst them, 1-(4-Fluorophenyl)-3-(4-{1-[pyridine-4-

carbonyl)hydrazono]ethyl}phenyl)thiourea 28 was found to be most potent

compound, with MIC of 0.49 μM against M. tuberculosis H37Rv and INH-resistant

M. tuberculosis. N'-{1-[2-hydroxy-3-(piperazine-1-yl-methyl)phenyl] ethylidene}

isonicotinohydrazide 29 was found to be the most active compound with the MIC of

0.56 μM, and it was more potent than INH (MIC of 2.04 μM).67

60

On the other hand, hydrazide-hydrazone ligand possesses N-donor with favorable

coordination ability and can easily construct hydrogen bonds in supramolecular

chemistry derivatives.78

These compounds can act as multidentate ligands depending

on the nature of the substituent attached to the hydrazone unit.79

So the coordination

properties of hydrazides and hydrazones are used as forming them metal extracting

agents.80

They are also used as analytical reagents, polymer-coating, ink, pigments,

and fluorescent materials.81

They can form very stable complexes with different metal

ions giving well-characterized metal complexes.82

They form a coloured chelates with

transition elements which are then used in the selective and sensitive determination of

these metal ions.83

Accordingly several hydrazone compounds were synthesized and

their applications in the spectrophotometric determination of trace amounts of metal

ions such as cobalt,84

calcium,85

lanthanides86

and anions such as acetate87

were

61

reported. In addition, Schiff base complexes have been extensively studied in great

detail as a result of their prospective applications in catalysis, magnetic properties,

molecular architectures and materials chemistry by coordination chemists at all

times.88

Hydrazones contain two connected nitrogen atoms of different nature and a C-N

double bond that is conjugated with a lone electron pair of the terminal nitrogen atom.

These structural fragments are mainly responsible for the physical and chemical

properties of hydrazones (Figure 14). Both nitrogen atoms of the hydrazone group are

nucleophilic, although the amino type nitrogen is more reactive. The carbon atom of

hydrazone group has both electrophilic and nucleophilic character.

The utility of hydrazides as key intermediates in the synthesis of several series of

heterocyclic compounds and the broad spectrum of biological activities that have been

reported for their cyclized products89

has aroused interest in exploring the utility of

hydrazides as versatile precursors for the synthesis of a variety of substituted

heterocycles.90

Hydrazide-hydrazones compounds are not only intermediates but they

are also very effective organic compounds in their own right. When they are used as

intermediates, coupling products can be synthesized by using the active hydrogen

component of (–CONHN=CH-) azometine group.91

N-Alkyl hydrazides can be

synthesized by reduction of hydrazones with NaBH4,92

substituted 1, 3, 4-

oxadiazolines can be synthesized when hydrazones are heated in the presence of acetic

anhydride.93

2-Azetidinones can be synthesized when hydrazones react with

62

triethylamine chloro acetylchloride.94

4-Thiazolidinones are synthesized when

hydrazones react with thioglycolic acid/ thiolactic acid.76,95

Many effective compounds, such as isocarboxazide 30 and iproniazide 31, are

synthesized by reduction of hydrazide-hydrazones. Iproniazide, like INH, is used in

the treatment of tuberculosis. It has also displays an antidepressant effect and patients

appear to have a better mood during the treatment. For example, another clinically

effective hydrazide-hydrazones is nifuroxazide, which is used as an intestinal

antiseptic.

2.1.3 Strategies for syntheses of Hydrazones from ketone functional group

63

(1) Hydrazones are formed usually by the reaction of hydrazides, hydrazines or their

derivatives with ketones or aldehydes. Generalized reaction for hydrazone formation

from aromatic ketone and aliphatic hydrazine is shown in scheme 1 and an example of

hydrazone formation from aromatic ketone with aromatic hydrazide is shown in

scheme 2.

Andrade et al.96

have used benzhydrazide (34a), salicyloylhydrazide (34b), and

isonicotinic hydrazide (34c) (Figure 17) to react with a wide range of ketones and

aldehydes.

64

They have tested the protocol with several types of ketones: cyclic aliphatic ketones

(cyclohexanone, cyclopentanone), linear aliphatic ketones (butan-2-one, pentan-3-one,

4-methylpentan-2-one), aromatic ketones (acetophenone, isobutyrophenone) and

heteroaromatic ketones (2acetylfuran, 2-acetylthiophene, 2-acetylpyridine). The

protocol employed consists in placing equivalent amounts of hydrazide and ketone in

a quartz tube, which was then subjected to microwave irradiation to give various

derivatives of hydrazones 35-44 (Figure 18).

(2) With the aim of obtaining hydrazones with wide spectrum of pharmaceutical

applications, Mohareb et al.97

report the synthesis of a series of hydrazones 47a-c via

the reaction of cyanoacetylhydrazine 45 with bromoketones (46a-c).

65

(3) Mabkhot et al.98

have chosed to combine the N-terminal of hydrazine derivative

and central portions of acetyl bis-heterocycle first. An example of initial synthetic

approach is outlined in Scheme 4. [2,3-b]thienothiophene hydrazine 49a was prepared

from 1-(5-Acetyl-3,4-dimethyl-thieno[2,3-b]thiophen-2-yl)-ethanone 48 with N-

nucleophile such as hydrazine in EtOH under reflux for 4h in the presence of catalytic

amount of TFA (trifluoro acetic acid) afforded 49a in high yield.

(4) With respect to the synthesis of acyl hydrazone derivatives, although three

representative methods have been reported, they have been used in only limited

appications. For example, strongly acidic media is necessary to generate a diazonium

salt in a typical von Richter synthesis,99

and regiocontrolled cyclization is still

difficult in Barber synthesis.100

Furthermore, intramolecular aromatic substitution

sometimes requires the protection of hydrazones to avoid a Wolff- Kishner-type

process.101

To overcome these disadvantages, Hasegawa et al.;102

planned to develop a

general synthetic method to produce such hydrazones using 3-haloaryl-3-hydroxy-

2diazopropanoates,103

which have been shown to be useful building blocks for the

synthesis of nitrogen-containing molecules (Scheme 5).104

An aldol-type reaction of 2-

bromo or 2-iodobenzaldehydes 50 with tosyl chloride in a one-pot synthesis gave 51

66

in respective yields of 81% and 88% using our procedure that has been reported

previously.104

After conversion to silyl ethers 52 , stereoselective reduction of diazo

group by LiEt3BH gave (E )-53. Subsequent acylation of terminal nitrogens with acid

chlorides gave 54 and 55 in reasonable yields.

(5) Synthesis of some pyrrole hydrazones from reaction of ethyl 4-[(E)-1-chloro-3-

oxoprop-1-en-1-yl]-3, 5-dimethyl-1H-pyrrole-2-carboxylate (56) with 4-

nitrophenylhydrazine (57a), having an electron-withdrawing nitro group (which

reduces the nucleophilicity of the amino nitrogen atom) and 4-bromophenylhydrazine

(57b) under reflux for 2 hour to give hydrazone 58a and 58b, respectively, while

hydrazone 58c was formed in the reaction of 56 with 2, 4-dinitrophenylhydrazine

(57c) only in the presence of excess sulfuric acid (Scheme 6).105

67

(6) Synthesis of pyrrole-hydrazone 60 from acetylpyrrole 59 was done in presence of

polyphosphoric acid in anhydrous alcohol under reflux for 40 hours (Scheme 7).105

This method was found best for the synthesis of pyrrole hydrazones when starting

with the acetylpyrrole substrate.

(7) The cyanoacetohydrazone derivative 63 was formed through the reaction of

cyanoacetic acid hydrazide 61 with 2-acetylfuran 62 (Scheme 8).106

68

2.2 Basis of work and objectives of the present investigations or aim of the work:

Development of novel chemotherapeutic agents is an important and challenging task

for the medicinal chemists and many research programs are directed towards the

design and synthesis of new drugs for their chemotherapeutic usage. Hydrazone

compounds constitute an important class for new drug development in order to

discover an effective compound against multidrug resistant microbial infection. A

number of hydrazide and hydrazone derivatives have gained significance owing to

their application in pharmaceutical chemistry. They have been demonstrated to

possess antibacterial, antifungal, anticonvulsant, antidepressant, anti-inflammatory,

antimalarial, antimycobacterial, anticancer, analgesic, antiplatelets, antiproliferative,

antituberculosis and antimicrobial activities. These reports prompted us to synthesize

the novel hydrazide-hydrazone derivatives.

The hydrazine molecule and its many derivatives represent an intermediate valence

state for nitrogen suggesting that hydrazine can function both as an oxidizing and as a

reducing agent. With four replaceable hydrogens and two unbonded electron pairs,

hydrazine can form many alkyl/aryl or acyl derivatives, including mono-, di-, tri-, and

tetra-substituted derivatives and their isomers. Many hydrazine derivatives retain

some of hydrazine toxicity and form the basis for perhaps practical significance in

pharmaceuticals, such as antituberculants, as well as in textile dyes and photography.

The remarkable biological activity of acid hydrazides R-CO-NHNH2, their

corresponding aroylhydrazones R-CO-NHN=CH-Ar, and the dependence of their

mode of chelation with transition metal ions present in the living system are of

significant importance. Pyrrole based Schiff bases offer the versatile ligand donor

groups. Amido-imine conformational frame change and as a consequence varying the

number of donor sites that can interact with other substrate has biological importance.

The free side of hydrazide group present in product can be further utilized for other

reactions.

The main objective of the work was to synthesize pyrrole-hydrazide-hydrazone of

varying frame containing substituted pyrrole moiety and characterize those using

http://en.wikipedia.org/wiki/Pharmaceutical

http://en.wikipedia.org/w/index.php?title=Antituberculant&action=edit

http://en.wikipedia.org/wiki/Dye

69

spectroscopic techniques. Based on the literature survey the versatile method for the

synthesis has been adopted. Hydrazone derivatives containing electron rich variable

functional groups may alter the activity and chemical properties. They may found

wide utility as drugs, chemical preservers for plants; in industry – for manufacturing

polymers, glues etc.; in organic synthesis; in analytical chemistry of organic and

inorganic substances and for many other purposes. In this chapter Pyrrole hydrazide-

hydrazones have been synthesized from keto-pyrrole derivative and acid hydrazide.

The combination of acid hydrazides and acetyl pyrrole generated the highly applicable

product. The synthesized derivatives are schematically presented as below:

These final products may be useful for various pharmaceutical applications as well as

for further synthetic purpose. These may have variety of functional utilizations.

70




Merck. They were used after purification & drying by conventional method.107

The



Syntheses of Starting Materials or reactants:

Malonic acid dihydrazide108

10.55g (10 ml, 0.06585 mol) of Diethylmalonate 64 was dissolved in absolute ethanol,

with stirring. Then there was dropwise addition of solution of 12.5178g (12.17 ml,

0.2500 mol) NH2NH2.H2O in EtOH, at reflux temperature. The mixture was refluxed

again for 7 hrs. After cooling white crystals appeared which were filtered out, washed

with EtOH and recrystallized with distilled H2O.

Yield: 6.1012g (70%)

Melting point: 147ºC observed (152ºC reported).

71

Phenyl sulphonyl hydrazide134

Phenylsulfonyl chloride 66 (8.8117 g, 6.4 ml, 0.05 mol) was dissolved in dry C6H6

with stirring and hydrazide hydrate (0.5006 g, 0.486 ml, 0.01 mol) was added

dropwise. After few seconds, white suspension was obtained. The white precipitate of

67 was separated after vigorous stirring which was washed with cold H2O and then

with petroleum ether.

Yield: 1.5912 g (77%)

Melting point: 178ºC (204-206ºC reported)

Cyanoacetohydrazide108

2.26g (2.12 ml, 0.0199 mol) of Ethyl cyanoactate 68 and 1.0g (0.97 ml, 0.0199 mol)

of 100% hydrazine hydrate were dissolved in 10 ml ethanol each. There was dropwise

addition of the solution of ethyl cyanoacetate to hydrazine solution with stirring at

0ºC. After 5 minutes, white coloured precipitate of 69 obtained. It was filtered and

washed with 10 ml of diethylether and dried in air.

Yield: 1.60g (81%)

Melting point: 107ºC

72





Ambassador®



uncorrected. Ambassador ® melting point apparatus provided a temperature range

from room temperature to 360°C. The infrared spectra of products were recorded

(4000-500 cm-1

) in KBr disc, using a Schimadzu 8201 PCFT IR spectrometer. For

denoting the intensities of infrared vibrational frequencies the used abbreviation are as

follows: br = broad, vbr = very broad, m = medium, s = strong, vs = very strong, sh =

shoulder, w = weak, vw = very weak. Proton nuclear magnetic resonance (¹H NMR)

and carbon nuclear magnetic resonance (13

C NMR) spectra were recorded on Bruker

DRX-300 spectrometer (300 MHz FT NMR) instrument in Regional Sophisticated

Instrumentation Centre, at Central Drug Research Institute, Lucknow. In Proton

nuclear magnetic resonance (¹H NMR), TMS (tetramethylsilane) is used as an internal

reference. The ¹H NMR and 13

C NMR spectra were taken in DMSO unless otherwise

stated. The chemical shift values are expressed in δ scale.

73


Synthesis of Ethyl 4-{1-[(2-Hydrazinocarbonyl-acetyl)-hydrazono]-ethyl}-3, 5-

dimethyl-1H-pyrrole-2-carboxylate


dissolved in ethanol. Malonic acid dihydrazide (0.0621 g, 0.00047 mol) was dissolved

in boiling water. 1 Drop of polyphosphoric acid was added as catalyst. The mixed

solution was allowed to reflux for 4 days. The colour of solution turned to yellow

colour. After completion of reaction, the solvent was distilled off. Dark yellow

coloured solid was washed thoroughly with boiling water and crystallized twice with

ethanol.

Yield: 0.0826 g (54.38%)


Solubility: soluble in hot methanol, hot ethanol and DMSO; insoluble in hexane,

dichloromethane, chloroform, benzene and water.

74

UV-vis Spectra (DMSO): λmax 218, 274 nm

IR Spectra:

3300.31 (N-H), 3201.92 (N-H), 3133.41 (N-H), 1648.52 (C=O), 1605.27 (C=N),

1555.42 (C=C), 2989.27 (aliphatic C-H), 2879.33(aliphatic C-H) cm-1

.

1H NMR Spectra (300 MHz, DMSO):

12.479 (1H, br, s, NH proton of CONHNH2), 12.105 (1H, br, s, NH proton of

C=NNH), 11.779 (1H, br, s, py-N-H proton), 5.321 (2H, s, NH2 protons of

CONHNH2), 4.279, 4.253, 4.232 & 4.210 (2H, q, J = 6.9 Hz, methylene protons of

ester group), 2.908 (2H, s, methylene protons of malonic moiety), 2.452 (3H, s, 3-

methyl group), 2.355 (3H, s, 5-methyl group), 2.154 (3H, s, protons of methyl group

on C=NNH), 1.315, 1.292, 1.269 (3H, t, J = 6.9 Hz, methyl protons of ester group).

13C NMR Spectra (75.5 MHz, DMSO):

174.86 (C3), 171.01 (C1), 164.46 (C12), 160.81 (C4), 138.80 (C7), 126.44 (C10), 122.51

(C11), 116.83 (C6), 59.49 & 59.09 (C13), 31.12 (C2), 18.85 (C5), 14.38 & 14.29 (C14),

13.18 (C8), 12.26 (C9).

75

Synthesis of Phenyl sulfonyl hydrazone of Ethyl 4-acetyl-3, 5-dimethyl-1H-



dissolved in methanol. Phenylsulfonyl hydrazide (0.08094 g, 0.00047 mol) was

dissolved in methanol. 1 Drop of polyphosphoric acid was added as catalyst. The

mixed solution was allowed to reflux for 4 days. The colour of solution turned to

yellow colour. After completion of reaction, the solvent was distilled off. Light brown

coloured solid was washed thoroughly with water and crystallized twice with

methanol.

Yield: 0.0948 g (55.50%)

Melting point: 188-190 ºC

Solubility: soluble in hot methanol and DMSO; insoluble in hexane,



76

IR Spectra:

3281.28 (N-H), 3205.20 (N-H), 1648.22 (C=O), 1584.04 (C=N), 1515.34 (C=C),

3066.89 (=C-H), 2980.02(υasC-H), 2936.19 (υasC-H), 2811.47 (υsC-H), 1335.16,

1171.46 (S=O) cm-1

.


11.777 (1H, br, s, NH proton of C=NNH), 11.403 (1H, br, s, py-N-H proton), 7.798 &

7.774 (2H, d, J = 7.2 Hz, o-protons of Phenyl ring), 7.715, 7.690 & 7.666 (1H, t, J =

7.35 Hz, p-proton of Phenyl ring), 7.624, 7.599 & 7.575 (2H, t, J = 7.35 Hz, m-protons

of Phenyl ring), 4.281, 4.257, 4.234 & 4.210 (2H, q, J = 7.1 Hz, methylene protons of

ester group), 2.451 (3H, s, 3-methyl group), 2.354 (3H, s, 5-methyl group), 2.144 (3H,

s, protons of methyl group on C=NNH), 1.316, 1.293, 1.269 (3H, t, J = 7.05 Hz,

methyl protons of ester group).


164.46 (C15), 160.81 (C7), 139.83 (C4), 138.80 (C10), 131.72 (C1), 129.04 (C2, 6),

126.43 (C12), 125.80 (C3, 5), 122.51 (C14), 116.83 (C9), 59.49 & 59.09 (C16), 18.86

(C8), 14.38 & 14.29 (C17), 13.18 (C11), 12.26 (C13).

77

Synthesis of Thiocarbohydrazone of Ethyl 4-acetyl-3, 5-dimethyl-1H-pyrrole-2-

carboxylate


dissolved in methanol. Thiocarbohydrazide (0.0498 g, 0.00047 mol) was dissolved in

methanol. 1 Drop of polyphosphoric acid was added as catalyst. The mixed solution

was allowed to reflux for 4 days. The colour of solution turned to yellow colour. After

completion of reaction, the solvent was distilled off. Light yellow coloured solid was

washed thoroughly with water and crystallized twice with methanol.

Yield: 0.0844 g (60.41%)





IR Spectra:

78

3279.05 (N-H), 3226.54 (N-H), 3214.97(N-H), 1665.76 (C=O), 1565.31 (C=N),

1503.94 (C=C), 2978.66(aliphatic C-H), 2925.20 (aliphatic C-H), 2869.75 (aliphatic

C-H), 1275.00 (C=S) cm-1

.


11.779 (1H, br, s, NH proton of C=NNH), 11.438 (1H, br, s, py-N-H proton), 9.683

(1H, br, s, NH proton of C(=S)NHNH2), 5.821 (2H, s, NH2 protons of C(=S)NHNH2),

4.279, 4.254, 4.232 & 4.210 (2H, q, J = 6.6 Hz, methylene protons of ester group),

2.450 (3H, s, 3-methyl group), 2.354 (3H, s, 5-methyl group), 2.155 (3H, s, protons of

methyl group on C=NNH), 1.315, 1.292, 1.268 (3H, t, J = 7.05 Hz, methyl protons of

ester group).


190.04 (C1), 164.46 (C10), 160.82 (C2), 138.81 (C5), 126.44 (C7), 122.51 (C9), 116.84

(C4), 59.49 & 59.09 (C11), 20.15 (C3), 14.38 & 14.29 (C12), 13.17 (C6), 12.26 (C8).

79

Synthesis of Ethyl 4-[1-(Cyanomethyl-hydrazono)-ethyl]-3, 5-dimethyl-1H-



dissolved in methanol. Cyanoacetohydrazide (0.0466 g, 0.00047 mol) was dissolved

in methanol. 1 Drop of polyphosphoric acid was added as catalyst. The mixed

solution was allowed to reflux for 4 days. The colour of solution turned to yellow

colour. After completion of reaction, the solvent was distilled off. Light yellow

coloured solid was washed thoroughly with water and crystallized twice with

methanol.

Yield: 0.0828 g (60.70%)




UV-vis Spectra (DMSO+Ethanol): λmax 255 nm

80

IR Spectra:

3346.72 (N-H), 3281.78 (N-H), 2259.65 (C≡N), 1681.16 (C=O), 1556.24 (C=N),

1510.86 (C=C), 2980.95 (aliphatic C-H), 2929.18 (aliphatic C-H) cm-1

.


11.778 (1H, br, s, NH proton of C=NNH), 11.433 (1H, br, s, py-N-H proton), 4.279,

4.256, 4.232 & 4.209 (2H, q, J = 7.0 Hz, methylene protons of ester group), 4.074

(2H, s, methylene protons attached to cyano group), 2.449 (3H, s, 3-methyl group),

2.353 (3H, s, 5-methyl group), 2.152 (3H, s, protons of methyl group on C=NNH),

1.315, 1.292, 1.268 (3H, t, J = 7.05 Hz, methyl protons of ester group).


174.85 (C3), 164.44 (C12), 160.88 (C4), 138.83 (C7), 126.44 (C10), 122.52 (C11), 116.89

(C6), 115.03 (C1), 59.49 & 59.09 (C13), 24.54 (C2), 19.53 (C5), 14.38 & 14.29 (C14),

13.19 (C8), 12.26 (C9).

81


We have synthesized and characterized all the four derivatives of hydrazide-

hydrazones of Ethyl 4-acetyl-3, 5-dimethyl-1H-pyrrole-2-carboxylate. All the results

obtained for these compounds are discussed below in detail.

Syntheses of hydrazide-hydrazones of Ethyl 4-acetyl-3, 5-dimethyl-1H-pyrrole-2-

carboxylate

Syntheses of all four derivatives of hydrazide-hydrazones of Ethyl 4-acetyl-3, 5-

dimethyl-1H-pyrrole-2-carboxylate was carried out by refluxing equiv. amount of

both reactants in appropriate single solvent or mixed solvents. This type of reaction

was not possible without catalyst. So, catalytic amount of polyphosphoric acid was

utilized for these reactions.




2.4.1 Ethyl 4-{1-[(2-Hydrazinocarbonyl-acetyl)-hydrazono]-ethyl}-3, 5-dimethyl-

1H-pyrrole-2-carboxylate (71)

IR spectra





degree physical state of the sample for frequency record. There is observation of wave

number ranging from 3520-3070 for amide N-H stretching depending upon the

presence of either primary or secondary and either free or bonded. In case of primary

amides, there is presence of two N-H stretching bonds resulting for symmetrical and

asymmetrical N-H stretching.109

The IR spectra of Ethyl 4-{1-[(2-Hydrazinocarbonyl-

acetyl)-hydrazono]-ethyl}-3,5-dimethyl-1H-pyrrole-2-carboxylate contains

82

characteristic bands at around 3300.31, 3201.92 and 3133.41 cm-1

due to N-H

stretching of different types of N-H present in the whole molecule. In general, C=O

stretching vibrations give rise to absorption band in the region of 1870-1540 cm-1

. The

spectrum shows band at 1648.52 cm-1

for this stretching. Schiff’s bases, imines etc.

show the C=N stretch in the 1689-1471 cm-1

region. The band at 1605.27 cm-1

is for

the C=N stretching vibration for the hydrazone linkage. The C=C stretching vibration

or ring stretching vibrations (or skeletal bands) occur in the general region between

1600-1300cm-1

. The absorption involves stretching and contraction of all of the bonds

in the ring and interaction between these stretching modes. The band pattern and the

relative intensities depend on the substitution pattern and the nature of the

substituents.109

The presence of bands at 1555.42 cm-1

and below it in the above

mentioned range confirms for the presence of C=C group in the molecule. The

absorption arising from C-H stretching for aliphatic group occurs in the region of

3000-2840 cm-1

, generally below 3000 cm-1

. The position of the C-H stretching

vibrations is among the most stable in the spectrum. The bands below 3000 cm-1

corresponds to aliphatic C-H stretching modes for e.g., 2989.27 and 2879.33 for

asymmetrical and symmetrical stretching of C-CH3 group, respectively. Other bands

at lower frequencies are mixed modes of different vibrations of groups corresponds to

bending vibrations: in-plane (scissoring, rocking) and out-of-plane deformations

(wagging, twisting) and torsions etc.

1H NMR spectra

1H NMR spectrum of Ethyl 4-{1-[(2-Hydrazinocarbonyl-acetyl)-hydrazono]-ethyl}-3,

5-dimethyl-1H-pyrrole-2-carboxylate shows the presence of four singlets for four

different types of NH protons in the whole molecule viz., a broad singlet at δ 12.479

ppm corresponding to NH proton of free site of hydrazide (CONHNH2) group, a broad

singlet at δ 12.105 ppm corresponding to NH proton of hydrazone (C=NNH) linkage,

a broad singlet at δ 11.779 ppm corresponding to pyrrolic NH proton and a broad

singlet at δ 5.321 ppm corresponding to 2 protons of NH2 of remained free site of

hydrazide (CONHNH2) group. A quartet at δ 4.279, 4.253, 4.232 & 4.210 (J = 6.9

Hz) and a triplet at δ 1.315, 1.292, 1.269 (J = 6.9 Hz) confirms the presence of

83

methylene and methyl of the ester group in the molecule, respectively. A singlet at δ

2.908 ppm for CH2 group of malonic moiety and two singlets at δ 2.452 and 2.355

ppm corresponds to methyl groups at 3- and 5-position of pyrrole ring, respectively. A

singlet at δ 2.154 ppm corresponds to protons of methyl group directly attached to

carbon of hydrazone (C=NNH) linkage.

13C NMR spectra

The 13

C NMR data of Ethyl 4-{1-[(2-Hydrazinocarbonyl-acetyl)-hydrazono]-ethyl}-3,

5-dimethyl-1H-pyrrole-2-carboxylate shows the presence of δ 174.86, 171.01 and

164.46 corresponding to carbonyl groups of directly attached to hydrazone linkage

(C3), of free site of hydrazide (C1) and of ester group (C12), respectively. The presence

of δ 160.81 confirms the hydrazone (C=NNH) linkage (C4). The presence of δ 138.80

(C7), 126.44 (C10), 122.51 (C11), 116.83 (C6) corresponds to pyrrole carbons. δ 59.49

& 59.09 (C13) and 14.38 & 14.29 (C14) shows the presence of methylene and methyl

carbons of ester group. Spectra shows the presence of δ 31.12 corresponding to CH2

group of malonic moiety (C2), δ 18.85 corresponding to CH3 group directly attached

to carbon of hydrazone (C=NNH) linkage (C5), δ 13.18 and 12.26 corresponding to

methyl groups at 5 and 3-position of pyrrole ring, (C8) and (C9) respectively.

2.4.2 Phenyl sulfonyl hydrazone of Ethyl 4-acetyl-3, 5-dimethyl-1H-pyrrole-2-

carboxylate (73)

IR spectra

The IR spectra of Phenyl sulfonyl hydrazone of Ethyl 4-acetyl-3, 5-dimethyl-1H-

pyrrole-2-carboxylate contains characteristic bands at around 3281.28 and 3205.20

cm-1

due to N-H stretching and other bands at 1648.22, 1584.04 and 1515.34 cm-1

due to υ(C=O), υ(C=N) and υ(C=C) stretching modes, respectively. The aromatic

structure shows the presence of =C-H stretching vibrations in the region 3100-3000

cm-1

which is characteristic region for the ready identification of C-H stretching

vibrations.110

In this region the bands are not affected appreciably by the nature of

substituents.111

So, the band above 3000 cm-1

for e.g., 3066.89 corresponds to aromatic

84

=C-H stretching. The bands below 3000 cm-1

corresponds to aliphatic C-H stretching

modes for e.g., 2980.02, 2936.19 cm-1

for asymmetrical and 2811.47 cm-1

for

symmetrical stretching of aliphatic C-H group. The asymmetric and symmetric S=O

stretching frequency ranges from 1372-1335 cm-1

and 1195-1168 cm-1

, respectively. In

these compounds, asymmetric stretch usually occurs as a doublet.112

The IR spectrum

of the compound shows a doublet at 1335.16 cm-1

and 1171.46 cm-1

for asymmetric

and symmetric S=O stretching, respectively. Other bands at lower frequencies are

mixed modes of different vibrations of groups corresponds to in-plane and out-of-

plane deformations and their mixed modes.

1H NMR spectra

1H NMR spectrum of Phenyl sulfonyl hydrazone of Ethyl 4-acetyl-3, 5-dimethyl-1H-

pyrrole-2-carboxylate shows the presence of two singlets for two different types of

NH protons in the whole molecule viz., a broad singlet at δ 11.777 ppm corresponding

to NH proton of hydrazone (C=NNH) linkage and a broad singlet at δ 11.403 ppm

corresponding to pyrrolic NH proton. Spectral data shows the presence of one doublet

at δ 7.798 & 7.774 (J = 7.2 Hz) corresponding to two o-protons of phenyl ring, two

triplets at 7.715, 7.690 & 7.666 (J = 7.35 Hz) and 7.624, 7.599 & 7.575 (J = 7.35 Hz)

for 1 p- and 2 m-protons of phenyl ring, respectively. A quartet at δ 4.281, 4.257,

4.234 & 4.210 (J = 7.1 Hz) and a triplet at δ 1.316, 1.293, 1.269 (J = 7.05 Hz)

confirms the presence of methylene and methyl of the ester group in the molecule,

respectively. Two singlets at δ 2.451 and 2.354 ppm corresponds to methyl groups at

3- and 5-position of pyrrole ring, respectively. A singlet at δ 2.144 ppm corresponds to

protons of methyl group directly attached to carbon of hydrazone (C=NNH) linkage.

13C NMR spectra

The 13

C NMR data of Phenyl sulfonyl hydrazone of Ethyl 4-acetyl-3, 5-dimethyl-1H-

pyrrole-2-carboxylate shows the presence of δ 164.46 corresponding to carbonyl

groups of ester group (C15). The presence of δ 160.81 confirms the hydrazone

(C=NNH) linkage (C7). The presence of δ 138.80 (C10), 126.43 (C12), 122.51 (C14),

85

116.83 (C9) corresponds to pyrrole carbons. Spectra shows the presence of δ 139.83

corresponding to Carbon of phenyl ring directly attached to sulfonyl group(C4), δ

131.72 corresponding to Carbon of phenyl ring p- to sulfonyl group(C1), δ 129.04

corresponding to Carbon of phenyl ring m- to sulfonyl group(C2, 6), δ 125.80

corresponding to Carbon of phenyl ring o- to sulfonyl group(C3, 5), δ 59.49 & 59.09

(C16) and 14.38 & 14.29 (C17) corresponding to methylene and methyl carbons of ester

group, respectively, δ 18.86 corresponding to CH3 group directly attached to carbon of

hydrazone (C=NNH) linkage (C8), δ 13.18 and 12.26 corresponding to methyl groups

at 5 and 3-position of pyrrole ring, (C11) and (C13) respectively.

2.4.3 Thiocarbohydrazone of Ethyl 4-acetyl-3, 5-dimethyl-1H-pyrrole-2-

carboxylate (75)

IR spectra

The IR spectra of Thiocarbohydrazone of Ethyl 4-acetyl-3, 5-dimethyl-1H-pyrrole-2-

carboxylate contains characteristic bands at around 3279.05, 3226.54 and 3214.97

cm-1


due to υ(C=O), υ(C=N) and υ(C=C) stretching modes, respectively. Other main bands

below 3000 cm-1

correspond to aliphatic C-H stretching modes for e.g., 2978.66,

2925.20 cm-1

for asymmetrical and 2869.75 cm-1

for symmetrical stretching of

aliphatic C-H group. Compounds that contain a thiocarbonyl group show absorption

in the 1280-1020 cm-1

region. Since the absorption occurs in the same general region

as C-O and C-N stretching, considerable interaction can occur between these

vibrations within a single molecule.113

The IR spectrum of this compound shows a

band at 1275.00 cm-1

for C=S stretching. Other bands at lower frequencies are mixed

modes of different vibrations of groups corresponds to in-plane and out-of-plane

deformations and their mixed modes.

1H NMR spectra

1H NMR spectrum of Thiocarbohydrazone of Ethyl 4-acetyl-3, 5-dimethyl-1H-

pyrrole-2-carboxylate shows the presence of four singlets for four different types of

86


to NH proton of hydrazone (C=NNH) linkage, a broad singlet at δ 11.438 ppm

corresponding to pyrrolic NH proton, a broad singlet at δ 9.683 ppm corresponding to

NH proton of free site of hydrazide (C(=S)NHNH2) group, and a broad singlet at δ

5.821 ppm corresponding to 2 protons of NH2 of remained free site of hydrazide

(C(=S)NHNH2) group. A quartet at δ 4.279, 4.254, 4.232 & 4.210 (J = 6.6 Hz) and a

triplet at δ 1.315, 1.292, 1.268 (J = 7.05 Hz) confirms the presence of methylene and

methyl of the ester group in the molecule, respectively. Two singlets at δ 2.450 and

2.354 ppm corresponds to methyl groups at 3- and 5-position of pyrrole ring,

respectively. A singlet at δ 2.155 ppm corresponds to protons of methyl group directly

attached to carbon of hydrazone (C=NNH) linkage.

13C NMR spectra

The 13

C NMR data of Thiocarbohydrazone of Ethyl 4-acetyl-3, 5-dimethyl-1H-

pyrrole-2-carboxylate shows the presence of δ 190.04 corresponding to carbon of thio

group (C1), 164.46 corresponding to carbonyl groups of ester group (C10),

respectively. The presence of δ 160.82 confirms the hydrazone (C=NNH) linkage

(C2). The presence of δ 138.81 (C5), 126.44 (C7), 122.51 (C9), 116.83 (C4)

corresponds to pyrrole carbons. δ 59.49 & 59.09 (C11) and 14.38 & 14.29 (C12) shows

the presence of methylene and methyl carbons of ester group. Spectra shows the

presence of δ 20.15 corresponding to CH3 group directly attached to carbon of



2.4.4 Ethyl 4-[1-(Cyanomethyl-hydrazono)-ethyl]-3, 5-dimethyl-1H-pyrrole-2-

carboxylate (77)

IR spectra

The IR spectra of Ethyl 4-[1-(Cyanomethyl-hydrazono)-ethyl]-3, 5-dimethyl-1H-

pyrrole-2-carboxylate contains characteristic bands at around 3346.72 and 3281.78

cm-1


due

87

to υ(C=O), υ(C=N) and υ(C=C) stretching modes, respectively. Other main bands

below 3000 cm-1

correspond to aliphatic C-H stretching modes for e.g., 2980.95,

2929.18 cm-1

. The spectra of nitriles (R-C≡N) are characterized by weak to medium

absorption in the triple bond stretching region of the spectrum. Aliphatic nitriles

absorb near 2260-2240 cm-1

.114

The IR spectrum of this compound shows a band at

2259.65 cm-1

for C≡N stretching. Other bands at lower frequencies are mixed modes

of different vibrations of groups corresponds to in-plane and out-of-plane


1H NMR spectra

1H NMR spectrum of Ethyl 4-[1-(Cyanomethyl-hydrazono)-ethyl]-3, 5-dimethyl-1H-

pyrrole-2-carboxylate shows the presence of two singlets for two different types of


to NH proton of hydrazone (C=NNH) linkage, a broad singlet at δ 11.433 ppm

corresponding to pyrrolic NH proton. A quartet at δ 4.279, 4.256, 4.232 & 4.209 (J =

7.0 Hz) and a triplet at δ 1.315, 1.292, 1.268 (J = 7.05 Hz) confirms the presence of


4.074 ppm for 2 CH2 protons attached to cyano group and two singlets at δ 2.449 and

2.353 ppm corresponds to methyl groups at 3 and 5-position of pyrrole ring,

respectively. A singlet at δ 2.152 ppm corresponds to protons of methyl group directly

attached to carbon of hydrazone (C=NNH) linkage.

13C NMR spectra

The 13

C NMR data of Ethyl 4-[1-(Cyanomethyl-hydrazono)-ethyl]-3, 5-dimethyl-1H-

pyrrole-2-carboxylate shows the presence of δ 174.85 corresponding to carbon of

carbonyl group (C3) and δ 164.44 corresponding to carbonyl groups of ester group

(C12). The presence of δ 160.88 confirms the hydrazone (C=NNH) linkage (C4). The

presence of δ 138.80 (C7), 126.44 (C10), 122.52 (C11), 116.89 (C6) corresponds to

pyrrole carbons, δ 115.03 corresponds to the cyano carbon (C1). δ 59.49 & 59.09 (C13)

and 14.38 & 14.29 (C14) shows the presence of methylene and methyl carbons of ester

88

group. Spectra shows the presence of δ 24.54 corresponding to CH2 group of

hydrazide (C2), δ 19.53 corresponding to CH3 group directly attached to carbon of



89

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48(January), 20-30.




95

Chapter 3

Synthesis and characterization of cyanovinyl ester pyrrole

hydrazide-hydrazones

96

3.1 Introduction

Cyanovinyl ester Pyrrole

Vinylpyrroles are extensively studied building blocks for the synthesis of versatile

members of the pyrrole series, especially of fused heterocycles related to pyrrole.1-3

Their structure is present in the molecules of many life-supporting systems

(porphyrins, vitamin B12, bile pigments, prodigiosins, myoglobin and haemoglobin

performing oxygen transport in live bodies of mammals, and chlorophyll playing the

key role in photosynthesis processes, i.e., in the photocatalytic transformation of the

solar energy).4-7

There are 2 main streams of vinylpyrroles:

(a) N-vinylpyrroles or 1-vinylpyrroles

(b) C-vinylpyrroles or 2- and 3-vinylpyrroles

(a) N-vinylpyrroles or 1-vinylpyrroles

N-Vinylpyrroles are promising as monomers for the preparation of materials for

photoelectronics, as well as highly reactive building blocks for the synthesis of

variously functionalized pyrrole derivatives and biologically active species.8-10

N-

Vinylpyrroles 1 (Figure 1) having several alkyl or aryl substituents and polymers

derived therefrom attract specific attention due to their enhanced ability to transmit

electronic excitation. In addition, di- and tri-arylpyrroles exhibit specific biological

activity, and they are widely used in the design of hypoglycaemic and antisclerotic

drugs (an example is atorvastatin).11

N-Vinylpyrroles became readily available thanks

to the discovery and development of simple methods of their synthesis by vinylation

of NH-pyrroles with acetylene12

or by one-pot Trofimov reaction from ketone oximes

and acetylene in a MOH-DMSO system (M = Li, Na, K).8-10,13

The results of

investigations about synthesis, activity and reactivity of N-Vinylpyrroles have been

summarized in a number of monographs and reviews.13,14

97

Compounds R1 R2 R3 R4 R5 R6

(a) H H H H H H

(b) H H H Me H H

(c) Me Me H H H H

(d) Me Me H Me H H

(e) Me Me Me H H H

(f) Me Me Me Me H H

(g) Ph H H H H H

(h) Ph H H Me H H

(i) (CH2)4 H H H H

(j) (CH2)4 H Me H H

(k) (CH2)4 Me H H H

(l) (CH2)4 Me Me H H

(m) (CH)4 H H H H

(n) (CH)4 H Me H H

(o) H H H Me Ph H

(p) H H H Me 4-t-BuC6H4 H

(q) H H H Me 4-MeOC6H4 H

(r) H H H Me MeO H

(s) H H H H Me H

(t) Ph H H H Me H

(u) H H H H H Me

(v) Ph H H H H Me

Figure 1: Some known N-vinylpyrroles

98

(b) C-vinylpyrroles

C-vinylpyrroles are key structural unit of natural chromophores such as chlorophylls,

hemoglobin, vitamin B12 and related macrocyclic tetrapyrrole pigments which play

vital roles in plants and animals15

as well as being valuable intermediates for the

construction of diverse pyrrole assemblies.1,3,16

Besides, these are found useful as

molecular optical switches, in particular, as ultrafast ones, for design of photo- and

electroconducting materials3 and micro- and nanodevices and also as ligands for new

photocatalysts and biologically active complexes.

C-vinylpyrroles are of two types (Figure 2):

(I) 2-Vinylpyrrole: 2-Vinylpyrrole structure is found in molecules of many vital

natural compounds (porphyrins, chlorophylls, vitamin B12, prodigiosins, etc.).

(II) 3-Vinylpyrrole: 3-Vinylpyrrole structural elements compose molecules of

haemoglobin and chlorophylls a, b, c, and d.

C-Vinylpyrroles bearing functional groups on the double bond (or those without them)

are highly reactive precursors for the targeted synthesis of conjugated and fused

heterocycles similar to natural pyrrole assemblies. Consequently, growing interest in

the development of synthetic methods for the preparation of C-vinylpyrroles and

understanding their reactivity seems quite obvious and explicable.

C-Vinylpyrroles are also of interest as vinyl monomers,17

although this aspect remains

so far less developed. For example, in multistep processes of syntheses of porphyrins,

99

different derivatives of pyrrole which were formed as intermediates not attracted

much attention for other utilization purposes at the time of their synthesis. But, in fact

these separate derivatives are very important for reactive synthetic utility such as

pyrrole derivatives containing general reactive groups like halogens, carbonyls,

amides, amines, etc., different reactive vinyl groups, some protective groups, some

heteroatom /atoms containing groups etc. So synthesis of such pyrrole derivatives of

synthetic efficacy and of bioactive and pharmaceutical importance is a demanding

goal.

In series of reactive intermediates, Pyrrole-2-carboxaldehyde plays an important role

in synthetic chemistry. It is soluble in both organic solvents and in water. Its

solubility in water is due to its resonance hybrid structures:

Its water solubility property leads its many reactions in aqueous reaction medium

providing a solid base for more economical (as there is no use of organic solvent) and

environmental friendly conversion processes. Thus water is a medium that is fully

compatible with green chemistry and such reactions lead the behaviour of research

towards green chemistry.

The reaction methods used to prepare pyrrole aldehydes and ketones rely heavily on

acylation.18

These reactions have been reported using a wide range of reagents and

conditions. One improved procedure for the formylation of pyrrole and N-

methylpyrrole employed an equimolecular mixture of phosphorus oxychloride and

dimethylformamide.19

100

The aldehyde function is one of great importance in the chemistry of pyrroles.20

Alone, its electron-withdrawing properties can confer considerable stability on an

otherwise sensitive system. 2-Formylpyrroles condense readily with 2-unsubstituted

pyrroles in the presence of acid to form the very stable and synthetically useful 2, 2'-

dipyrromethene salts.21

This reaction forms the basis for several well-known routes to

porphyrins including the regiospecific synthesis of Johnson et al.22

Although 2-

formylpyrroles are resistant to autoxidation or Cannizzaro disproportionation, they are

very susceptible to decomposition under acidic conditions and in the presence of many

of the reagents commonly used in pyrrole syntheses (bromine, sulfuryl chloride, lead

tetraacetate).23

Pyrrole aldehydes are widely used in many synthetic procedures like

condensation reactions, leading to the formation of porphyrins of various structures,

dipyrromethanes, dipyrromethenes, various types of vinylpyrroles.

2-Vinylpyrroles were synthesized by Wittig reaction in which appropriate pyrrole-2-

carboxaldehyde and ylide in dry benzene or toluene was heated at reflux under

nitrogen atmosphere.24

For example, a solution of 2-formylpyrrole and

methoxycarbonylmethylenephosphorane in dry benzene gave methyl 3-(pyrrol-2-yl)

prop-2-enoate (2a) (Figure 5).

101

Stobbe condensation is also good method for ketovinyl synthesis. In this procedure

appropriate aldehyde 3 and dimethyl succinate 4 were refluxed in a solution of LiOMe

in anhydrous MeOH (freshly prepared by slow addition of finely divided lithium) to

yield the corresponding monoester or the carboxylic acid 5 which can be used as

precursor for other vinylpyrroles25

(Scheme 1).

3-Vinylpyrrole 8 can be synthesized by using TosMIC (Tosyl methylisocyanide) 7

and non-pyrrolic reagent 6 in presence of sodium hydride26

as shown in scheme 2.

102

2-Nitrovinyl pyrroles 10 may be synthesized by treating 2-formylpyrrole 9 with

nitromethane in presence of sodium or potassium acetate and methylamine

hydrochloride27, 28

(Scheme 3).

A pyrrole acrylic lactam 13 (Scheme 4) was synthesized.29

The first step involved a

Knoevenagel condensation via a nucleophilic addition of the malonic carbanion to the

unsaturated carbon atom of the aldehyde, followed by dehydration.18

Pyrrole-2-carboxaldehyde and its derivatives were condensed with active methylene

compounds in presence of piperidine base30, 31

(Scheme 5). In the same way pyrrole-3-

aldehydes and 3, 4-dialdehyde derivatives have tendency to give the corresponding

vinyl in presence of piperidine in benzene solvent with diethylmalonate.32

103

Cyanovinyl pyrrole derivatives 16a-g, 17a-f, 18a-h (Figure 6) were prepared from the

Knoevenagel reaction of 2-formylpyrroles and its various derivatives with

malononitrile or esters of cyanoacetic acid, in the presence of a basic catalyst, usually

a primary or secondary amine.33, 23

The applications of the cyanovinyl groups were as

a protecting group which were first employed by Fisher.34

in, for example, the

synthesis of 2, 5-diformyl-3, 4-dimethylpyrrole, and later by Woodward35

in the

synthesis of chlorophyll. Similar use of these protecting groups has been made by

Davies36

and by Badger37

in an unsuccessful assault on porphyrin.

104

Knoevenagel condensation of formylthienylpyrroles 19 with malononitrile38

in

refluxing ethanol gave dicyanovinyl derivatives 20 (Scheme 6) in moderate to

excellent yields (36-100%).39

Pyrrole, being the most electron rich five-membered

heteroaromatic ring, counteracts the electron-withdrawing effect of the dicyanovinyl

group.39

The most reactive site in the C-vinylpyrrole molecules is the outer double bond, which

governs their chemical transformations. A lot of articles and reviews covered many

reactions with participation of the vinyl group (including those involving the pyrrole

ring) and its functional substituents. C-Vinylpyrroles are used for the synthesis of new

heterocycles,1-3, 16, 40

polymers,17

photocatalysts and biologically active complexes.41

Recent investigations into the reactivity of C-ethenylpyrroles with vinyl groups

polarized by a push–pull combination of substituents, such as 2-(1-alkylthio-2-

cyanoethenyl) pyrroles, have confirmed that these compounds possess synthetic

potential, which may be utilized for a variety of synthetic needs.3, 42-45

(Note: Hydrazide-hydrazones are described in chapter 2 of this thesis.)

105

Strategies for syntheses of hydrazide-hydrazones from aldehydic functional

group

The most important hydrazide-hydrazone formation reaction is the modification of

aldehydes with hydrazide or bishydrazide compounds. Aldehydes spontaneously react

with hydrazides to form a hydrazone linkage (Scheme 7). The hydrazone bond is a

type of Schiff base, but the linkage between a hydrazide and an aldehyde is more

stable than the linkage between an aldehyde and an amine. Further stabilization can be

achieved under reductive conditions. The hydrazone linkage formed from a hydrazine

and an aldehyde is much more stable than the bond formed between a hydrazide and

an aldehyde.46

(1) Aakash Deep et al.,47

have prepared a series of biphenyl-4carboxylic acid

hydrazide-hydrazones. The reaction between biphenyl-4-carboxylic acid 21 and

methanol in the presence of sulfuric acid yielded corresponding methyl ester of

biphenyl-4carboxylic acid 22, which on reaction with hydrazine hydrate in presence of

a catalytic amount of glacial acetic acid afforded the corresponding hydrazides 23 in

appreciable yield. Further, the hydrazides were condensed with substituted aldehydes

to yield the title compounds 24 (scheme 8).

106

(2) Machakanur et al.48

have utilized the similar above-mentioned procedure for the

synthesis of a series of hydrazide-hydrazones. p-Hydroxylbenzaldehyde was added to

a solution of 4-Bromo- or 4-Chloro- or 4-Fluoro-benzoic acid hydrazide in methanol.

The mixture was stirred at refluxing temperature for 3 h and then concentrated under

vacuum.

(3) Rajput et al.49

have condensed benzhydrazide with 4-methoxybenzaldehyde, 4-

hydroxybenzaldehyde, 2-nitro benzaldehyde and benzaldehyde respectively in

methanol containing catalytic amount of acetic acid formed 4-methoxybenzaldehyde

phenyl-1-carbonyl hydrazone, 4-hydroxybenzaldehyde phenyl-1-carbonylhydrazone,

2-nitrobenzaldehyde phenyl-1-carbonylhydrazone and benzaldehyde phenyl-1-

carbonylhydrazone. Revanasiddappa et al.50

prepared a novel series of schiff bases

hydrazide-hydrazones by refluxing a solution of hydrazide in absolute alcohol,

substituted aldehydes with a few drops of glacial acetic acid for about 8 hours.

(4) G. Nagalakshmi et al.,51

have taken a mixture of benzohydrazide 25 (0.01 mol) and

different aromatic aldehydes 26a-g (4-chlorobenzaldehyde (26a), 2,3-

dichlorobenzaldehyde (26b), 2, 4-dichlorobenzaldehyde (26c), 4-bromobenzaldehyde

107

(26d), 2-nitrobenzaldehyde (26e), 3-nitrobenzaldehyde (26f) and 4-nitrobenzaldehyde

(26g)) in absolute ethanol in presence of catalytic amount of conc. hydrochloric acid.

After refluxing for 4-5 h, seven different schiff’s base hydrazide-hydrazones 27a-g

were synthesized (scheme 9).

(5) Y. N. Mabkhoot52

used an ester Diethyl 3-methyl-4-phenylthieno[2,3-b]thiophene-

2,5-dicarboxylate 28 with hydrazine hydrate in refluxing ethanol to give the bis-

hydrazide 29. Subsequent treatment of compound 29 with appropriate aldehydes in

refluxing ethanol yielded the corresponding hydrazones 30a-c (Scheme 10).

108

(6) Gašparová et. al.,53

have used microwave technology for synthesis of these

compounds. N' -[5-(R1-Phenyl)furan-2-yl)methylene]-2-R-4-H-furo[3,2-b]pyrrole-5-

carboxhydrazides 35a-i, N' -[(thiophen-2-yl)methylene]-2-R-4-H-furo[3,2-b]pyrrole-

5-carboxhydrazides 36a, 36b and N'-{[(5-methoxycarbonyl-4-methyl)furo[3,2-

b]pyrrol-2-yl]methylidene}-2-(3-trifluoromethylphenyl)-4-H-furo[3,2-b]pyrrole-5-

carbohydrazide 37 were synthesized by microwave assisted reaction of 2-R-furo[3,2-

b]pyrrole-5-carboxhydrazides 31 with 5-R1-phenylfuran2-carboxaldehydes 32 or

thiophene-2-carboxaldehyde 33, 2-formyl-4-methylfuro[3,2-b]pyrrole-5-carboxylate

34 in ethanol in the presence of p-toluenesulfonic acid using a power output of 90 W

over different reaction time period (Scheme 11).

109

(7) The chemistry of thiocarbazones and thiocarbazides has received considerable

attention because of their biological activity and industrial applications.54-57

Thiocarbazone analogues substituted with sulfur and nitrogen are more versatile

intermediates with respect to the oxygenated ones.58, 59

Thiocarbazones form a class of

mixed hard-soft oxygen/nitrogen-sulphur chelating ligands that show a variety of

coordination modes in metal complexes. The thiocarbazones can act as a monodentate

ligand that binds to the metal ion through the sulphur atom or as a bidentate ligand

that coordinates to the metal ion through the sulphur atom and one of the nitrogen

110

atoms of the hydrazine moiety to form four or five membered chelate rings. Besides

their interesting coordination chemistry, thiocarbazones have attracted considerable

interest because of their potentially beneficial biological activities. So, L. N. Suvarapu

et. al.60

and Rao et. al.61

etc. have synthesized Benzyloxybenzaldehyde

thiosemicarbazone 40 by refluxing a methanolic solution containing

benzyloxybenzaldehyde 38 and thiosemicarbazide 39 (scheme 12).

Thiosemicarbazone derivatives were also synthesized from thioglycolic acid

intermediate 41 as shown in Scheme 13.62-65

Reaction of carbon disulfide with a

primary/ secondary amine in aqueous ethanolic solution of potassium hydroxide and

sodium chloroacetate followed by acidification gave thioglycolic acid 41, which was

then refluxed with aqueous sodium hydroxide and hydrazine hydrate to give

substituted thiosemicarbazide 42. Treatment of 42 with heterocyclic aldehyde gave the

corresponding thiosemicarbazone 43. A large number of thiosemicarbazones were

prepared using a variety of aliphatic, aromatic, and cyclic amines along with different

heterocyclic aldehydes.

111

(8) Different pyrrole derivatives containing hydrazide have been prepared which are

susceptible for condensation to form schiff base hydrazide-hydrazones. For example,

3, 5-dimethyl-1H-pyrrole-2, 4-dicarbo hydrazide 47 was prepared from hydrazinolysis

method.66

A mixture of 2, 4-dimethyl-3, 5-dicarbethoxypyrrole 44 and

thiosemicabarzide 45 in ethanol, added few drops of conc. HCl, the reaction mixture

was heated and refluxed to give 2, 2'-[(3, 5-dimethyl-1H-pyrrole-2,4-diyl) dicarbonyl]

dihydrazinecarbo thioamide 46 (scheme 14).

112

A variety of pyrrole hydrazones67-71

are also known and are well studied, e. g. (Figure

7),

113


The remarkable biological activity of acid hydrazides Ar–CO–NH–NH2, their

corresponding aryolhydrazide-hydrazone Ar–CO–NH–N=CHAr, and also their mode

of chelation with transition metal ions has aroused interest in the past due to possible

biomimetic applications. Their Cobalt and Nickel complexes have a variety of

applications in biological, clinical and analytical fields. Recently there has been a

considerable interest in the coordination chemistry of transition metals especially,

Cobalt and Nickel with O-N donor hydrazone ligands because of their potential

biological and pharmacological applications. The coordination chemistry of aroyl

hydrazones are quite interesting as it presents a combination of donor sites such as

protonated / deprotonated amide oxygen, an imine nitrogen of hydrazone moiety and

additional donor site (usually N or O) provided from the aldehyde or ketone forming

the Schiff base. In short, we can say that hydrazones and their derivatives constitute a

versatile class of compounds in organic chemistry. These compounds have interesting

biological properties, such as anti-inflammatory, analgesic, anticonvulsant,

antituberculous, antitumor, anti-HIV and antimicrobial activity. Hydrazones are

important compounds for drug design, as possible ligands for metal complexes,

organocatalysis and also for the syntheses of heterocyclic compounds. The ease of

preparation, increased hydrolytic stability relative to imines, and tendency toward

crystallinity are all desirable characteristics of hydrazones. Due to these positive traits,

hydrazones have been under study for a long time, but much of their basic chemistry

remains unexplored.

In this way, one can also see that Aroylhydrazide-hydrazones play a vital role in

medicinal chemistry.72-74

2-pyrrole and its vinyl compounds give good

pharmacological properties.75-79

Important biological properties of pyrrole derivatives

stimulate the incessant search for syntheses of new pyrrole derivatives. Hence, it was

thought of interest to merge both of pyrrole and hydrazide moieties which may

enhance the drug activity of compounds to some extent, or they might possess some of

the above mentioned biological activities. From this point of view, the objective of the

present work is to prepare hydrazide-hydrazone containing pyrrole moiety. Hence the

114

present work comprises the synthesis hydrazide-hydrazones of vinylpyrrole. A very

special and important thing in the designed products is that these compounds contain

two different type of reactive series namely, vinyl group and hydrazide group.

The objective of this chapter of thesis includes the moiety derived from formyl

cyanovinyl ester pyrrole that has many reactive centers in itself. This compound has

been easily transformed into the desired hydrazide-hydrazones. This chapter includes

synthesis and characterization of following newly synthesized cyanovinyl ester

pyrrole hydrazide-hydrazone derivatives. Pyrrole derivatives containing a greater

number of -electrons, a greater number of donating groups or a larger binding group,

have properties which differ substantially from other studies systems. The synthetic

approach for cyanovinyl ester pyrrole hydrazide-hydrazones is shown in scheme 9.

All the designed molecules are carrying variety of functionalities which are further

useful for pharmaceutical importance and synthetic utilizations.

115





The



Syntheses of Starting Materials or reactants

Ethyl α-cyano-5-formyl-2-pyrroleacrylate81

Phosphoryl chloride (1.50 g, 0.90 ml, 0.0098 moles) was added over 20 minutes to N,

N-dimethylformamide (0.72 g, 0.76 ml, 0.0098 moles), stirred and kept at 10-20°C by

cooling with an ice-salt bath. After stirring for another 15 min without cooling, 1, 2-

dichloroethane (4.50 ml) was added. The stirring and cooling were continued while a

suspension of ethyl α-cyano-2-pyrrole-acrylate 52 (1.54 g, 0.0081 moles) in 1, 2-

dichloroethane (6.75 ml) was added over 30 min at ca. 5°C. The mixture was then

refluxed for 15 min (HCl evolution!). Aqueous 4.0 M sodium acetate (12.5 ml) was

added over ca. 5 min at 25-30°C to the vigorously stirred mixture, which was then

refluxed for another 15 min. Crystallization overnight yielded ethyl α-cyano-5-formyl-

2-pyrroleacrylate 53 (1.41 g, 80%).

Succinic acid dihydrazide82

116

Succinic anhydride 54 (5.0 g, 0.04997 moles) was dissolved in EtOH, with stirring.

Hydrazine hydrate (7.19 g, 6.899 ml, 0.12 moles) in ethanol was added dropwise in

the solution of succinic anhydride. The reaction mixture was allowed to reflux for 24

hours. The obtained precipitate of succinic acid dihydrazide 55 was filtered out.

2-Hydrazinocarbonyl-N-phenyl-acetamide (malonilic acid hydrazide) 82

N-Phenyl-malonamic acid ethyl ester:83

A mixture of aniline 56 (5.0 g, 4.88 ml,

0.0536 mole) and diethylmalonate 57 (8.5992 g, 8.15 ml, 0.0536 mole) was refluxed

overnight in a round bottomed flask fitted with an air condenser of such a length that

ethanol formed escaped and diethylmalonate flowed back into the flask. The obtained

precipitate N-Phenyl-malonamic acid ethyl ester 58 was filtered out. On

recrystallization from aqueous ethanol (50%), ester (m.p. 39°C) was obtained.

Malonilic acid hydrazide: N-Phenyl-malonamic acid ethyl ester 58 (1.238 g, 0.0059

moles) and hydrazine hydrate (0.60072 g, 0.58 ml, 0.012 moles) in ethanol were

mixed via dropwise addition. The reaction mixture was allowed to reflux overnight. It

was then cooled in refrigerator for one day. White precipitate of malonic acid

hydrazide 59 was obtained which was filtered out and washed with water and air

dried.

117

Yield: 0.580 g (51%)

Melting point: 186°C





Ambassador®





cm-1

) in KBr disc, using a Schimadzu 8201 PCFT IR spectrometer in Regional

Sophisticated Instrumentation Centre, at Central Drug Research Institute, Lucknow.

For denoting the intensities of infrared vibrational frequencies the used abbreviation

are as follows: br = broad, vbr = very broad, m = medium, s = strong, vs = very

strong, sh = shoulder, w = weak, vw = very weak. Proton nuclear magnetic resonance

(¹HNMR) spectra were recorded on Bruker DRX-300 spectrometer (300 MHz FT

NMR) instrument using TMS (tetramethylsilane) as an internal reference. The ¹H

NMR spectra were taken in DMSO unless otherwise stated. The chemical shift values

are expressed in δ scale.

118


Synthesis of Thiocarbohydrazone of ethyl α-cyano-5-formyl-2-pyrroleacrylate

Ethyl α-cyano-5-formyl-2-pyrroleacrylate (0.0218 g, 0.0001 moles) was dissolved in

methanol. Thiocarbohydrazide (0.0106 g, 0.0001 moles) was dissolved in methanol

and added dropwise in the solution at room temperature. The reaction mixture was

allowed to stir whole night after addition of catalytic amount of conc. HCl. The

reaction was followed up by T.L.C. time to time. When the product formation

occurred, the solvent methanol was distilled off and got the solid mass of very light

brown colour. It was washed with cold methanol, then with hot methanol.

Yield: 0.0214 g (69.8661%)


Solubility: soluble in DMSO; insoluble in hexane, dichloromethane, chloroform,

benzene, methanol, ethanol and water.


119

IR Spectra:

3307.68 (N-H), 3208.66 (N-H), 3125.50, 3111.24 (N-H), 2209.87 (C≡N), 1695.87

(C=O), 1580.98 (C=N), 1529.37 (C=C), 3031.15 (=C-H), 2992.99, 2965.60 (υasC-H),

2905.07 (υsC-H), 1280.25 (C=S) cm-1

.


12.699 (1H, br, s, NH proton of C=NNH), 12.060 (1H, br, s, py-N-H proton), 9.671

(1H, br, s, NH proton of C(=S)NHNH2), 8.156 (1H, s, vinyl attached to cyanoester

groups), 7.906 (1H, s, vinyl attached to hydrazone linkage), 7.441 & 7.414 (2H, d, J =

8.1 Hz, py-3 C-H & -4 C-H), 5.682 (2H, s, NH2 protons of C(=S)NHNH2), 4.290,

4.266, 4.243 & 4.220 (2H, q, J = 7.0 Hz, methylene protons of ester group), 1.300,

1.277, 1.253 (3H, t, J = 7.05 Hz, methyl protons of ester group).

Synthesis of Hydrazone of succinic acid dihydrazide and ethyl α-cyano-5-formyl-

2-pyrroleacrylate

Ethyl α-cyano-5-formyl-2-pyrroleacrylate (0.0218 g, 0.0001 mole) was dissolved in

ethanol. Succinic acid dihydrazide (0.0146 g, 0.0001 mole) dissolved in hot water and

added dropwise in the solution. The reaction mixture was stirred whole night at room

temperature after addition of 1 drop of conc. HCl. Very light yellow coloured

precipitate formed. The precipitate was filtered and washed with hot water and then

with methanol.

120

Yield: 0.0106 g (30.64%)




UV-vis Spectra (DMSO+Ethanol): λmax 260, 370 nm

IR Spectra:

3307.78 (N-H), 3210.28 (N-H), 3125.69, 3111.32 (N-H), 2209.90 (C≡N), 1696.45

(C=O), 1582.24 (C=N), 1521.66 (C=C), 3032.45 (=C-H), 2993.21 (υasC-H), 2965.89

(υsC-H) cm-1

.



C=NNH), 10.908 (1H, br, s, py-N-H proton), 8.155 (1H, s, vinyl proton attached to

cyanoester groups), 7.925 (1H, s, vinyl proton attached to hydrazone linkage), 7.441

& 7.419 (2H, d, J = 6.6 Hz, py-3 C-H & -4 C-H), 5.466 (2H, s, NH2 protons of


ester group), 2.348 (4H, s, methylene protons of succinic group), 1.300, 1.277, 1.253

(3H, t, J = 7.05 Hz, methyl protons of ester group).

121

Synthesis of Carbohydrazone of ethyl α-cyano-5-formyl-2-pyrroleacrylate


methanol. Carbohydrazide (0.0090 g, 0.0001 mole) was dissolved methanol and added

dropwise in the solution. The reaction mixture was stirred at room temperature whole

night after addition of catalytic amount of conc. HCl. After completion of reaction,

the solvent was distilled off. Very light brown coloured solid was obtained. It was

washed thoroughly with hot methanol.

Yield: 0.0118 g (40.65%)





IR Spectra:

3307.98 (N-H), 3207.25 (N-H), 3125.52, 3111.24 (N-H), 2209.98 (C≡N), 1696.16

(C=O), 1581.43 (C=N), 1552.52 (C=C), 3031.75 (=C-H), 2993.21 (υasC-H), 2965.89

(υsC-H) cm-1

.

122







ester group), 1.300, 1.276, 1.253 (3H, t, J = 7.05 Hz, methyl protons of ester group).

Synthesis of Hydrazone of malonic acid dihydrazide and ethyl α-cyano-5-formyl-

2-pyrroleacrylate

Ethyl α-cyano-5-formyl-2-pyrroleacrylate (0.0218 g, 0.0001 moles) was dissolved in

ethanol. Malonic acid dihydrazide (0.0132 g, 0.0001 moles) was dissolved in boiling

water and added dropwise in the solution. The reaction mixture was allowed to stir

whole night at room temperature after addition of 1 drop of conc. HCl. The colour of

solution turned light yellow. The reaction was followed up by routine T.L.C. check

up. After completion of the reaction the solvent was distilled off. Dark yellow

coloured solid found which was washed thoroughly with boiling water and methanol.

Yield: 0.0164 g (49.39%)


123




IR Spectra:

3307.86 (N-H), 3205.33 (N-H), 3125.61, 3111.20 (N-H), 2210.07 (C≡N), 1696.74,

1638.36 (C=O), 1581.86 (C=N), 1500.11 (C=C), 3030.48 (=C-H), 2993.03 (υasC-H),

2965.61 (υsC-H) cm-1

.







ester group), 2.904 (2H, s, methylene protons of malonic group), 1.300, 1.276, 1.252

(3H, t, J = 7.2 Hz, methyl protons of ester group).

Synthesis of Hydrazone of 2-hydrazinocarbonyl-N-phenyl-acetamide and ethyl α-

cyano-5-formyl-2-pyrroleacrylate

124


ethanol. 2-Hydrazinocarbonyl-N-phenyl-acetamide (malonilic acid hydrazide) (0.0194

g, 0.0001 mole) was dissolved boiling methanol and added dropwise in the solution of

the first one. 1 Drop of conc. HCl was added in the reaction mixture as a catalyst. The

reaction mixture was allowed to stir whole night at room temperature. Pale yellow

colour appeared. After completion of reaction the solvent was distilled off. Light

brown coloured solid was separated which was washed thoroughly with hot methanol.

Yield: 0.0184 g (46.77%)





IR Spectra:

3305.83 (N-H), 3203.40 (N-H), 3126.30 (N-H), 2210.02 (C≡N), 1695.07, 1645.46

(C=O), 1582.12 (C=N), 1536.03 (C=C), 3035.22 (=C-H), 2992.96 (υasC-H), 2880.44

(υsC-H) cm-1

.


12.619 (1H, br, s, CONH proton attached to phenyl ring), 12.059 (1H, br, s, NH

proton of C=NNH), 11.710 (1H, br, s, py-N-H proton), 8.156 (1H, s, vinyl proton

attached to cyanoester groups), 7.916 (1H, s, vinyl proton attached to hydrazone

linkage), 7.617, 7.590 & 7.562 (2H, t, J = 8.25 Hz, o-protons of Phenyl ring), 7.443 &

7.421 (2H, d, J = 6.6 Hz, py-3 C-H & -4 C-H), 7.316 & 7.303 (2H, m, J = 3.9 Hz, m-

protons of Phenyl ring), 7.060 & 7.048 (1H, m, J = 3.6 Hz, p-proton of Phenyl ring),

4.290, 4.267, 4.243 & 4.220 (2H, q, J = 7.0 Hz, methylene protons of ester group),

3.182 (2H, s, methylene protons of malonic group), 1.300, 1.277, 1.253 (3H, t, J =

7.05 Hz, methyl protons of ester group).

125


I have synthesized and characterized all the five derivatives of hydrazide-hydrazones

of Ethyl α-cyano-5-formyl-2-pyrroleacrylate. All the results obtained for these

compounds are discussed below in detail.

Syntheses of hydrazide-hydrazones of Ethyl α-cyano-5-formyl-2-pyrroleacrylate

Syntheses of all five derivatives of hydrazide-hydrazones of Ethyl α-cyano-5-formyl-

2-pyrroleacrylate was carried out by taking equiv. amount of both reactants in

appropriate solvent or in mixed solvents and stirring at room temperature. Catalytic

amount of hydrochloric acid was utilized for these reactions.




3.4.1 Thiocarbohydrazone of ethyl α-cyano-5-formyl-2-pyrroleacrylate (61)

IR spectra





degree physical state of the sample for frequency record. There is observation of wave

number ranging from 3520-3070 for amide N-H stretching depending upon the

presence of either primary or secondary and either free or bonded. In case of primary

amides, there is presence of two N-H stretching bonds resulting for symmetrical and

asymmetrical N-H stretching.84

The IR spectra of Thiocarbohydrazone of ethyl α-

cyano-5-formyl-2-pyrroleacrylate contains characteristic bands at around 3307.68,

3208.66, 3125.50 and 3111.24 cm-1

due to N-H stretching of different types of N-H

present in the whole molecule. In general, C=O stretching vibrations give rise to

absorption band in the region of 1870-1540 cm-1

. The spectrum shows band at

126

1695.87 cm-1

for C=O stretching. Schiff’s bases, imines etc. show the C=N stretch in

the 1689-1471 cm-1


is for the C=N stretching

vibration for the hydrazone linkage. The C=C stretching vibration or ring stretching

vibrations (or skeletal bands) occur in the general region between 1600-1300cm-1

. The

absorption involves stretching and contraction of all of the bonds in the ring and

interaction between these stretching modes. The band pattern and the relative

intensities depend on the substitution pattern and the nature of the substituents.84

The

presence of bands at 1529.37 cm-1

and below it in the above mentioned range

confirms for the presence of C=C group in the molecule. The heteroaromatic structure

shows the presence of =C-H stretching vibrations in the region 3100-3000 cm-1

which

is characteristic region for the ready identification of C-H stretching vibrations.85

In

this region the bands are not affected appreciably by the nature of substituents.86

The


corresponds to aromatic =C-H stretching. The absorption arising

from C-H stretching for aliphatic group occurs in the region of 3000-2840 cm-1

,

generally below 3000 cm-1

. The position of the C-H stretching vibrations is among the

most stable in the spectrum. The bands below 3000 cm-1


streching modes for e.g., 2992.99, 2965.60 for asymmetrical and 2905.07 for

symmetrical stretching of C-H group, respectively. The spectra of nitriles (R-C≡N) are

characterized by weak to medium absorption in the triple bond stretching region of the

spectrum. Aliphatic nitriles absorb near 2260-2240 cm-1

. Conjugation, such as occurs

in aromatic nitriles, reduces the frequency of absorption to 2240-2222 cm-1

and

enhances the intensity. Further extended conjugation reduces the frequency much

more.87

Hence, the IR spectrum of this compound shows a band at 2209.87 cm-1

for

C≡N stretching. Compounds that contain a thiocarbonyl (C=S) group show absorption

in the 1280-1020 cm-1

region. Since the absorption occurs in the same general region

as C-O and C-N stretching, considerable interaction can occur between these

vibrations within a single molecule.88

The IR spectrum of this compound shows a


for C=S stretching. Other bands at lower frequencies are mixed

modes of different vibrations of groups corresponds to bending vibrations: in-plane

(scissoring, rocking) and out-of-plane deformations (wagging, twisting) and torsions

etc.

127

1H NMR spectra

1H NMR spectrum of Thiocarbohydrazone of ethyl α-cyano-5-formyl-2-

pyrroleacrylate showed the presence of four singlets for four different types of NH

protons in the whole molecule viz., a broad singlet at δ 12.699 ppm corresponding to

NH proton of hydrazone (C=NNH) linkage, a broad singlet at δ 12.060 ppm

corresponding to pyrrolic NH proton, a broad singlet at δ 9.671 ppm corresponding to

NH proton of free site of hydrazide (C(=S)NHNH2) group, and a broad singlet at δ

5.682 ppm corresponding to 2 protons of NH2 of remained free site of hydrazide

(C(=S)NHNH2) group. A quartet at δ 4.290, 4.266, 4.243 & 4.220 (J = 7.0 Hz) and a

triplet at δ 1.300, 1.277, 1.253 (J = 7.05 Hz) confirmed the presence of methylene and

methyl of the ester group in the molecule, respectively. A singlet at δ 8.156 ppm for

vinyl (=C-H) attached to cyanoester groups and a singlet at δ 7.906 ppm corresponds

to vinyl (=C-H) attached to hydrazone linkage. A doublet at δ 7.441 & 7.414 ppm (J =

8.1 Hz) corresponds to protons of pyrrole ring carbons.

3.4.2 Hydrazone of succinic acid dihydrazide and ethyl α-cyano-5-formyl-2-

pyrroleacrylate (63)

IR spectra

The IR spectra of Hydrazone of succinic acid dihydrazide and ethyl α-cyano-5-

formyl-2-pyrroleacrylate contains characteristic bands at around 3307.78, 3210.28,

3125.69 and 3111.32 cm-1

due to N-H stretching of different types of N-H present in

the whole molecule and other bands at 1696.45, 1582.24 and 1521.66 cm-1

due to

υ(C=O), υ(C=N) and υ(C=C) stretching modes, respectively. Other main bands above

3000 cm-1

corresponds to aromatic C-H stretching for e.g., 3032.45 cm-1

and below

3000 cm-1

corresponds to aliphatic C-H stretching modes for e.g., 2993.21, 2965.89

cm-1

. The IR spectrum of this compound shows a band at 2209.90 cm-1

for C≡N

stretching. Other bands at lower frequencies are mixed modes of different vibrations

of groups corresponds to in-plane and out-of-plane deformations and their mixed

modes.

128

1H NMR spectra

1H NMR spectrum of Hydrazone of succinic acid dihydrazide and ethyl α-cyano-5-

formyl-2-pyrroleacrylate showed the presence of four singlets for four different types

of NH protons in the whole molecule viz., a broad singlet at δ 12.588 ppm

corresponding to NH proton of free site of hydrazide (CONHNH2) group, a broad





Hz) and a triplet at δ 1.300, 1.277, 1.253 (J = 7.05 Hz) confirmed the presence of


8.155 ppm for vinyl (=C-H) attached to cyanoester groups and a singlet at δ 7.925

ppm corresponded to vinyl (=C-H) attached to hydrazone linkage. A doublet at δ

7.441 & 7.419 ppm (J = 6.6 Hz) corresponded to protons of pyrrole ring carbons. A

singlet at δ 2.348 ppm corresponded to 4 protons of two CH2 group of succinic

moiety.

3.4.3 Carbohydrazone of ethyl α-cyano-5-formyl-2-pyrroleacrylate (65)

IR spectra

The IR spectra of Carbohydrazone of ethyl α-cyano-5-formyl-2-pyrroleacrylate

contains characteristic bands at around 3307.98, 3207.25, 3125.52 and 3111.24 cm-1

due to N-H stretching of different types of N-H present in the whole molecule and

other bands at 1696.16, 1581.43 and 1552.52 cm-1

due to υ(C=O), υ(C=N) and υ(C=C)

stretching modes, respectively. Other main bands above 3000 cm-1

corresponds to

aromatic C-H stretching for e.g., 3031.75 cm-1

and below 3000 cm-1

corresponds to

aliphatic C-H stretching modes for e.g., 2993.21, 2965.89 cm-1

. The IR spectrum of

this compound shows a band at 2209.98 cm-1

for C≡N stretching. Other bands at lower

frequencies are mixed modes of different vibrations of groups corresponds to in-plane

and out-of-plane deformations and their mixed modes.

129

1H NMR spectra

1H NMR spectrum of Carbohydrazone of ethyl α-cyano-5-formyl-2-pyrroleacrylate

showed the presence of four singlets for four different types of NH protons in the

whole molecule viz., a broad singlet at δ 12.818 ppm corresponding to NH proton of

free site of hydrazide (CONHNH2) group, a broad singlet at δ 12.421 ppm

corresponding to NH proton of hydrazone (C=NNH) linkage, a broad singlet at δ

11.012 ppm corresponding to pyrrolic NH proton and a broad singlet at δ 5.389 ppm

corresponding to 2 protons of NH2 of remained free site of hydrazide (CONHNH2)

group. A quartet at δ 4.290, 4.266, 4.244 & 4.220 (J = 7.0 Hz) and a triplet at δ 1.300,

1.276, 1.253 (J = 7.05 Hz) confirmed the presence of methylene and methyl of the

ester group in the molecule, respectively. A singlet at δ 8.155 ppm for vinyl (=C-H)

attached to cyanoester groups and a singlet at δ 7.908 ppm corresponds to vinyl (=C-

H) attached to hydrazone linkage. A doublet at δ 7.444 & 7.417 ppm (J = 8.1 Hz)

corresponds to protons of pyrrole ring carbons.

3.4.4 Hydrazone of malonic acid dihydrazide and ethyl α-cyano-5-formyl-2-

pyrroleacrylate (67)

IR spectra

The IR spectra of Hydrazone of malonic acid dihydrazide and ethyl α-cyano-5-formyl-

2-pyrroleacrylate contains characteristic bands at around 3307.86, 3205.33, 3125.61

and 3111.20 cm-1

due to N-H stretching of different types of N-H present in the whole

molecule and other bands at 1696.74, 1638.36 due to υ(C=O), 1581.86 and 1500.11

cm-1

, due to υ(C=N) and υ(C=C) stretching modes, respectively. Other main bands

above 3000 cm-1


and

below 3000 cm-1

corresponds to aliphatic C-H stretching modes for e.g., 2993.03,

2965.61 cm-1


for

C≡N stretching. Other bands at lower frequencies are mixed modes of different

vibrations of groups corresponds to in-plane and out-of-plane deformations and their

mixed modes.

130

1H NMR spectra

1H NMR spectrum of Hydrazone of malonic acid dihydrazide and ethyl α-cyano-5-

formyl-2-pyrroleacrylate showed the presence of four singlets for four different types

of NH protons in the whole molecule viz., a broad singlet at δ 12.589 ppm

corresponding to NH proton of free site of hydrazide (CONHNH2) group, a broad





Hz) and a triplet at δ 1.300, 1.276, 1.252 (J = 7.2 Hz) confirmed the presence of


8.156 ppm for vinyl (=C-H) attached to cyanoester groups and a singlet at δ 7.922

ppm corresponded to vinyl (=C-H) attached to hydrazone linkage. A doublet at δ

7.440 & 7.419 ppm (J = 6.3 Hz) corresponded to protons of pyrrole ring carbons. A

singlet at δ 2.904 ppm corresponded to 2 protons of CH2 group of malonic moiety.

3.4.5 Hydrazone of 2-hydrazinocarbonyl-N-phenyl-acetamide and ethyl α-cyano-

5-formyl-2-pyrroleacrylate (69)

IR spectra

The IR spectra of Hydrazone of 2-hydrazinocarbonyl-N-phenyl-acetamide and ethyl

α-cyano-5-formyl-2-pyrroleacrylate contains characteristic bands at around 3305.83,

3203.40 and 3126.30 cm-1

due to N-H stretching of different types of N-H present in

the whole molecule and other bands at 1695.07, 1645.46 due to υ(C=O), 1582.12 and

1536.03 cm-1

, due to υ(C=N) and υ(C=C) stretching modes, respectively. Other main

bands above 3000 cm-1


and below 3000 cm-1

corresponds to aliphatic C-H stretching modes for e.g., 2992.96,

2880.44 cm-1


for

C≡N stretching. Other bands at lower frequencies are mixed modes of different

131

vibrations of groups corresponds to in-plane and out-of-plane deformations and their

mixed modes.

1H NMR spectra

1H NMR spectrum of Hydrazone of 2-hydrazinocarbonyl-N-phenyl-acetamide and

ethyl α-cyano-5-formyl-2-pyrroleacrylate showed the presence of three singlets for

three different types of NH protons in the whole molecule viz., a broad singlet at δ

12.619 ppm corresponding to CONH group attached to phenyl ring, a broad singlet at

δ 12.059 ppm corresponding to NH proton of hydrazone (C=NNH) linkage and a

broad singlet at δ 11.710 ppm corresponding to pyrrolic NH proton. A quartet at δ

4.290, 4.267, 4.243 & 4.220 (J = 7.0 Hz) and a triplet at δ 1.300, 1.277, 1.253 (J =

7.05 Hz) confirmed the presence of methylene and methyl of the ester group in the

molecule, respectively. A singlet at δ 8.156 ppm for vinyl (=C-H) attached to

cyanoester groups and a singlet at δ 7.916 ppm corresponded to vinyl (=C-H) attached

to hydrazone linkage. A doublet at δ 7.443 & 7.421 ppm (J = 6.6 Hz) corresponded to

protons of pyrrole ring carbons. A singlet at δ 3.182 ppm corresponded to 2 protons of

CH2 group of malonic moiety. Spectral data showed the presence of one triplet at δ

7.617, 7.590 & 7.562 (J = 8.25 Hz) corresponding to two o-protons of phenyl ring,

two multiplets at 7.316 & 7.303 (J = 3.9 Hz) and 7.060 & 7.048 (J = 3.6 Hz) for 2 m-

and 1 p-protons of phenyl ring, respectively.

132

3.5 References

(1) Trofimov, B. A. The Chemistry of Heterocyclic Compounds, Jones, R. A. Ed., New York: Wiley, 1992, 48, 131.

(2) Sobenina, L. N.; Demenev, A. P.; Mikhaleva, A. I. and Trofimov, B. A. Usp. Khim. 2002, 71, 641.

(3) Trofimov, B. A.; Sobenina, L. N.; Demenev, A. P. and Mikhaleva, A.I. Chem. Rev. 2004, 104, 2481.

(4) Falk, J. E. Porphyrins and Metalloporphyrin, Smith, K. M. Ed., Amsterdam: Elsevier, 1975, 757.

(5) Dolphin, D. The Porphyrins, New York: Academic Press, 1979, 7, 6.

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136

Chapter 4

Synthesis and characterization of

Pyrrole-pyrazoline containing

heterocycles

137

4.1 Introduction

Pyrazoline and its derivatives

Nitrogen heterocycles are of special interest as they constitute an important class of

natural and non-natural products, many of which exhibit useful biological activities.

Pyrrole is the most concerned heterocycle containing single nitrogen in a 5-membered

ring. Pyrroles and their derivatives exhibit different important biological activities like

antibacterial, antioxidant, cytotoxic, insecticidal, anti-inflammatory, anticoagulant,

antiallergic, antiarhythmic, hypotensive and anticonvulsant 1-7

etc.

Another heterocycle containing two nitrogen atoms is Pyrazole which has been widely

studied. Pyrazoles represent a class of heterocyclic compounds of significant

importance and are considered as extremely versatile building blocks in organic

chemistry.8, 9

Pyrazole ring is a prominent structural motif found in numerous

pharmaceutically active compounds. This is mainly due to the ease preparation and

the important biological activity. Pyrazole framework plays an essential role in

biologically active compounds and therefore represents an interesting template for

combinatorial as well as medicinal chemistry.10-19

Pyrazole derivatives possess wide

range of pharmacological activities like antioxidant, anxiolytics,20

GABA receptor

antagonists and insecticides,21

a potential PET ligand for CB1 receptors,22

antimicrobial agents,23

growth inhibition activity,24

antimalarial activity,25

antihyperglycemic activity,26

antipyretic activities6 anti-invasive, antiviral,

antipyretic, antiinflammatory, antidepressant, and blood pressure lowering 8 etc.

Pyrazoles are also used as agrochemicals, for instance, as insecticides,27

dyestuff’s in

sunscreen materials28,29

etc. Pyrazole derivatives have become increasingly important

in the past few years because they have proven to be extremely useful intermediates

for the preparation of new biological materials.

Many natural and synthetic pyrrole and pyrazole derivatives are known to be involved

in many pharmacological activities. For example, Distamycin-A is a naturally

occurring antibiotic characterized by the presence of N-methylpyrrole-2-carboxamide

138

units ending with an amidino moiety,30

which binds to the DNA minor groove,

preferentially to AT-rich sequence, and in a reversible manner.31

Three mixed

pyrazole-pyrrole compounds 1a-c (Figure 1), called lexitropsins (or information-

reading oligopeptides), consisting of a varying number of pyrrole amide units (from

one to three) tethered on the N-terminus to a 3,5-pyrazole dicarboxylic acid moiety

and structurally related to the DNA minor groove binder distamycin A.

Pyrazolines are well known nitrogen containing heterocyclic compounds.32

Pyrazolines are the reduced form of pyrazole and can be represented as:

The above three represent heterocyclic nomenclature to pyrazolines require that

nitrogen atoms to be numbered one and two in each structure. Numbering of the 2-

pyrazolines begins with the amino nitrogen and pyrazolines are numbered to obtain

for the double bond the lower of the two possible numbers. Thus, this structure may

be referred as:

139

They display a broad spectrum of biological activities.33-36

They are an important class

of heterocyclic compounds that attracted considerable attention due to their significant

biological activity which includes potential application as, anti-inflammatory,37

antimicrobial,38

antifungal,39

anti-tumor,40

anti-histamic,41

anti-depressant,42

anticonvulsant,42d,e

anti-viral activities,43

antibacterial,44

antidiabetic,45

anticancer,46

cytotoxic,47

cerebroprotective effect,48

antiamoebic49

and platelet aggregation

inhibiting50

properties. Pyrazoline derivatives have been found to be effective as

herbicidal & insecticidal,51

pesticide,52

cardiovascular,53

hypoglycemic,54

anticoagulant,55

immunosuppressive56

and tranquillizer57

agents. Many class of

chemotherapeutic agents containing pyrazoline nucleus are in clinical use such as

orisul 3 (bacterostatic), antipyrine 4 (antipyretic), butazolidine 5 (anti-

inflammatory).The pyrazole derivative celebrex 6 (celecoxib) is also used widely as

anti-inflammatory drug in the market.58

140

3-(4-Fluorophenyl)-4,5-dihydro-N-[4-(trifluoromethyl)-phenyl]-4-[5-(trifluoromethyl)

-2-pyridyl]-1H-pyrazole-1-carboxamide 7 (figure 5) has potent contact and foliar

activity against both lepidoptera and orthoptera insects.59

Extensive SAR studies

focused on varying the heterocycle at position 4 resulted in the identification of

pyrazoline-1-carboxamide as a potential candidate for commercialization. 60

Pyrazolines are also used in the treatment of Parkinson’s, Alzehimer’s disease and

Cerebral edema.61

Certain pyrazolines due to their non toxic properties have been used

as local anesthetics also.62

Besides, fluorinated pyrazolines find application as

antifertility, antibacterial and antifungal agents.63,64

It has been reported that

introduction of acetyl group at 1st position enhance the mollucicidal

65 activity as well

as increases the stability of pyrazolines. All their known pharmaceutical activities

rendered them important compounds in drug research.

One of the important applications of pyrazoline is the use of pyrazolines as effective

bleaching agents, luminescent and a fluorescent brightening agent.66

They can absorb

light of 300-400 nm and emit blue fluorescence with high quantum yields67

and are

used as optical brighteners and whiteners.68

Especially, 2-Pyrazolines possessing aryl

substituents at positions 1, 3 and 5 exhibit fluorescence properties and have been

found to act as hole transporting media in photoconductive as well as emitting

141

materials69,70

and in organic electro luminescent devices (OELDs)71,72

because of

formation of p-л conjugated system due to one of the nitrogen atom. Organic

electroluminescent devices find potential use in various displays73,74

and have many

advantages over inorganic ones, such as high luminous efficiency, low cost, wide

range of emission colors via specialized molecular design of organic compounds, and

easy processing. 1, 3, 5-Triaryl-2-pyrazolines are also utilized as optical brightening

agents for textiles, fabrics, plastics, papers,75

fluorescent switches76

and as fluorescent

probes in many chemosensors.77

Many pyrazolines also find variety of industrial application78

viz., they are used as

polymer intermediates in industry. Pyrazolines are used extensively as useful synthon

in organic synthesis.79-81

The pyrazoline function is quite stable and has inspired

chemists to utilize this stable fragment in bioactive moieties to synthesize new

compounds. Hence, much importance is given to the synthesis and structural aspect of

pyrazolines as witnessed by continued activity in this area.

Strategies for syntheses of pyrazoline ring

Among various pyrazoline derivatives, 2-pyrazolines seem to be most frequently

studied and useful pyrazoline. A variety of methods have been reported for the

preparation of this class of compounds.82

Some of them are accounted here for review:

(1) One of the general methods to accomplish the synthesis of pyrazolines is 1, 3-

dipolar cycloaddition of an ylide to an alkene.83

Several methods are employed in the

synthesis of pyrazolines, such as, the cycloaddition of nitrilimines, generated in situ

from the corresponding hydrazonoyl halides by the action of a suitable base, to

carbon-carbon double bonds of a suitable dipolarophile.84, 85

142

(2) Several methods are employed in the synthesis of pyrazolines, including the

condensation of chalcones with thiosemicarbazide under acidic86

or basic87

conditions.

Recently, a series of 1-N -substituted thiocarbamoyl-3, 5-diphenyl-2-pyrazoline

derivatives were reported by Budakoti et al. (Scheme 2).88

Cyclization of chalcone 14

with various N-4 substituted thiosemicarbazides in presence of NaOH gave the

desired pyrazoline derivatives 15 with a wide variety of aliphatic and aromatic

amines.

143

The 1-thiocarbamoyl-3, 5-diaryl-4, 5-dihydro-(1H)-pyrazoles were synthesized by

reacting chalcone, thiosemicarbazide and KOH in ethanol by Chimenti et. al.89

and

Zen et. al.90

(3) The α, β-unsaturated ketones can play the role of versatile precursors in the

synthesis of the corresponding pyrazolines.91

Numerous methods have been reported

for the preparation of pyrazoline compounds. After the pioneering work of Fischer

and Knövenagel in the late nineteenth century, the reaction of α, β-unsaturated

aldehydes and ketones with hydrazines became one of the most popular methods for

the preparation of 2-pyrazolines.92-96

The regioselective formation of pyrazolines has

been synthesized by the reaction of substituted hydrazine with α, β-unsaturated

ketones.97

(4) Condensation of the chalcone systems 16 with hydrazine hydrate,

phenylhydrazine, and methylhydrazine, resulted in the formation of the corresponding

compounds 17, 1H-pyrazoline as well as N-phenyl- and N-methylpyrazolines,

respectively (Scheme 3). 98

144

(5) Starting from chalcones, Chimenti et. al.99

have obtained the new 1-acetyl-3,5-

diphenyl-4,5-dihydro-(1H)-pyrazole derivatives 18-29 (Scheme 4) by addition of

hydrazine hydrate in acetic acid according to a previous method.100

The similar procedure was applied by Solankee et. al.101

to synthesize the compound

31 starting from chalcone 30 (Scheme 5).

145

(6) In 1998, Powers et al.102(a)

have reported the reaction of chalcones with phenyl

hydrazine hydrochloride in the presence of sodium hydroxide and absolute ethanol at

70°C, where the longer reaction time is the disadvantage of the reaction. Bilgin et

al.102(b)

have synthesized different pyrazoline derivatives 33 starting from chalcone

containing furan 32 in presence of ethanolic sodium hydroxide (Scheme 6).

(7) Recently, many organic reactions in aqueous media have been described in the

literature.103

In 2007, Li et al.104

have synthesized 1, 3, 5-triaryl-2pyrazoline with

chalcones and phenyl hydrazine hydrochloride in sodium acetate-acetic acid aqueous

solution under ultrasound irradiation.

(8) High speed microwave assisted chemistry is being utilized in recent years

successfully in various field of synthetic organic chemistry.105

Kamble et al.106

have

used the clean cyclization of chalcones with hydrazine hydrate under microwave

irradiation to afford pyrazolines. 15 Chalcones undergo a rapid cyclization with

hydrazine hydrate under microwave irradiations at 80±5°C (240 W) to give

pyrazolines quantitatively in 4–12 min. Sometimes, poly(ethylene glycol) (PEG 200)

and formic acid were used as the solvent for these preparations. K2CO3-mediated

microwave irradiation has been shown to be an efficient method for the synthesis of

pyrazolines.107(a)

Thirunarayanan et al.107(b)

have taken efforts to synthesize a series of

1-phenyl-3(5-bromothiophen-2-yl)-5-(substituted phenyl)-2-pyrazolines 35 from 5-

bromo-2thienyl chalcones 34 and phenyl hydrazine hydrochloride in presence of fly

ash:H2SO4 in microwave irradiations for 5 to 6 min in a microwave oven (Scheme 7).

146

(9) The reaction of α, β-unsaturated aldehydes and ketones with phenyl hydrazine in

acetic acid by refluxing provides 2-pyrazolines.108

For example, Kaushik et al.109(a)

and Revanasiddappa et al.109(b)

have prepared pyrazoline derivatives 38 by reaction of

chalcone 36 and isonicotinic acid hydrazide (isoniazid; INH; 37) in glacial acetic acid

(Scheme 8).

147

(10) A facile synthesis of a range of 1, 3, 5-trisubstituted-2-pyrazolines 39 from α, β-

unsaturated ketones (chalcones) and phenylhydrazine in the presence of methanoic

acid is described herein (Scheme 9).110

(11) A variety of conditions and reagents have been used for cyclizing α, β-

unsaturated carbonyl compounds with phenylhydrazine to produce pyrazolines,

through phenylhydrazone 40 formation (Figure 6).111

The condensation of

phenylhydrazine with chalcone compound in the presence of hydrochloric acid gave

the corresponding pyrazoline.112

148


Heterocyclic aromatic compounds are unique sources of building blocks in natural

product synthesis. Pyrazoline derivatives have attracted the attention of research

scholars on account of their wide range of applications in medicine. Pyrrole and

pyrazoline derivatives are two major five-membered heterocycles, whose compounds,

with these nuclei, are known to possess anticonvulsant, antidepressant, antibacterial,

analgesic, antimicrobial, and anticancer activities. Taking into consideration of the

above properties as well as the combination principles for drug design, we herein

report the synthesis of some new pyrrole-pyrazoline derivatives, which might exhibit

enhanced activities.

Numbers of pyrazoline derivatives have been found to posses considerable biological

activities, which stimulated the research activity in this field. 2-Pyrazolines seem to be

the most frequently studied pyrazoline type compounds. The work of this chapter

presents the synthesis of substituted pyrrole-pyrazoline derivatives. Our approach to

the synthesis of target molecules started from preparation of chalcones. Chalcones and

its derivatives have attracted particular interest during the last few decades due to use

of such ring system as the core structure in many drug substances covering wide range

of pharmacological application.113-116

Chalcones have been very attractive starting

compounds in organic chemistry, they are easy to prepare with large variability at the

two aromatic rings and the enone provides a bifunctional site for 1, 3-dinucleophiles

affording several heterocyclic ring systems.117

The objective of this chapter was to synthesize and characterize pyrrole-pyrazoline

derivatives. The chalcones were prepared in presence of base by conventional Claisen-

Schmidt condensation. 1, 3, 5-trisubstituted-2-pyrazolines are prepared by choosing

the appropiate chalcone and phenylhydrazine derivatives were prepared in presence of

acid catalyst, HCl and represented in Scheme 10.

150





The



Syntheses of Starting Materials or reactants:

p-Nitro-benzoic acid hydrazide119

Step I: In 100ml round bottomed flask placed 3 g of p-nitro benzoic acid 41 and

dissolved in dry methanol and 1 ml of conc. H2SO4 was added. The mixture was

refluxed for about 10 hr. The colour of solution changed to yellow and the solution

was diluted with saturated solution of NaHCO3, large amount of CO2 evolution was

observed. The yellow coloured precipitate (42) was filtered and washed with methanol

and dried in air. The precipitate again dissolved in methanol and again diluted with

saturated NaHCO3, finally filtered and dried in air. The light yellow coloured solid

was obtained. Melting point = 90°C (96°C).

Step II: The obtained ester 42 was again dissolved in dried methanol and added

NH2NH2.H2O. The colour of the solution changes to orange. The solution was

refluxed in oil bath for 6 hours. The yellow coloured precipitate (43) was obtained,

filtered, washed with methanol and dried in air. Melting point = 198°C (211-212°C).

151

4-[3-(4-Chloro-phenyl)-acryloyl]-3, 5-dimethyl-1H-pyrrole-2-carboxylic acid

ethyl ester

4-Acetyl-3, 5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester 44 (0.105 g, 0.0005

moles) was dissolved in ethanol and p-chloro-benzaldehyde 45 (0.154 g, 0.001 moles)

was added in it. 20% KOH (5ml) solution was added drop wise in the cold reaction

mixture (5-10˚C). It was allowed to stir overnight. It was neutralized with 5% HCl

solution and poured in water and kept in refrigerator for one hour. The light yellow

coloured precipitate (46) was obtained which was filtered and washed thoroughly with

cold distilled water.

Yield: 0.200 g (60%)

Melting Point: 178ºC



152





Ambassador®





cm-1

) in KBr disc, using a Schimadzu 8201 PCFT IR spectrometer. For denoting the

intensities of infrared vibrational frequencies the used abbreviation are as follows: br

= broad, vbr = very broad, m = medium, s = strong, vs = very strong, sh = shoulder, w

= weak, vw = very weak. Proton nuclear magnetic resonance (¹H NMR) and carbon

nuclear magnetic resonance (13

C NMR) spectra were recorded on Bruker DRX-300

spectrometer (300 MHz and 75.5 MHz FT NMR, respectively) instrument in Regional

Sophisticated Instrumentation Centre, at Central Drug Research Institute, Lucknow. In

Proton nuclear magnetic resonance (¹H NMR), TMS (tetramethylsilane) is used as an

internal reference. The ¹H NMR and 13

C NMR spectra were taken in DMSO unless

otherwise stated. The chemical shift values are expressed in δ scale.

153


Synthesis of Ethyl 4-[5-Furan-2-yl-1-(4-nitro-benzoyl)-4, 5-dihydro-1H-pyrazol-

3-yl]-3, 5-dimethyl-1H-pyrrole-2-carboxylate

Ethyl 4-(3-Furan-2-yl-acryloyl)-3, 5-dimethyl-1H-pyrrole-2-carboxylate (0.05746 g,

0.0002 moles) was dissolved in ethanol. 4-Nitrobenzoic acid hydrazide (0.05746 g,

0.0002 moles) was dissolved in ethanol and added dropwise. The mixed solution was

stirred and refluxed for 12 hours after addition of 1 drop of 35% HCl. Black shining

precipitate formed which was filtered and washed with water thoroughly and then

with methanol (~2 ml). It was allowed for air dryness.

Yield: 0.0426 g (47.30%)

Melting point: decomposed at 235ºC



154


IR Spectra:

3454.54 (N-H), 1677.72 (C=O), 1631.46 (C=N), 1579.07 (C=C), 2967, 2927.53 (υasC-

H), 2864 (υsC-H), 1579.07 (υasNO2), 1378.55 (υs NO2) cm-1

.

NMR Spectra (DMSO):

11.852 (1H, br, s, py-N-H), 8.312 & 8.283 (2H, d, J = 8.7 Hz, o-protons of phenyl ring

to nitro group), 8.060 & 8.031 (2H, d, J = 8.7 Hz, m-protons of phenyl ring to nitro

group),7.848 (1H, s, furan-5C-H), 6.983 & 6.973 (1H, d, J = 3.0 Hz, furan-3C-H),

6.649 (1H, s, furan-4C-H), 4.323, 4.299, 4.273 & 4.252 (2H, q, J = 7.1 Hz, methylene

proton of ester group), 2.307 & 2.272 (1H, d, J = 10.5 Hz, Hx of pyrazoline group),

2.128, 2.084, 2.038 & 2.019 (1H, dd, J = 19.5 Hz, J = 13.5 Hz, Hb of pyrazoline group

and 6H, merged singlet of 3- & 5- methyl groups), 1.352, 1.326, 1.304 (3H, t, J = 7.2

Hz, methyl protons of ester group), 1.304 & 1.232 (1H, d, J = 21.6 Hz, Ha of

pyrazoline group).

155

Synthesis of Ethyl 4-[1-(2, 4-Dinitro-phenyl)-5-furan-2-yl-4, 5-dihydro-1H-


Ethyl 4-(3-Furan-2-yl-acryloyl)-3, 5-dimethyl-1H-pyrrole-2-carboxylate (0.05746 g,

0.0002 mole) was dissolved in methanol. 2, 4-Dinitrophenyl hydrazine (2, 4-DNP)

(0.0396 g, 0.0002 mole) was dissolved in boiling methanol and added dropwise. The

mixed solution was stirred and refluxed for 12 hours after addition of 1 drop of 35%

HCl. Black shining particles were separated out which were filtered and washed with

water thoroughly and then with methanol (~2 ml). It was allowed for air dryness.

Yield: 0.0623 g (66.52%)

Melting point: decomposed at 198ºC

Solubility: soluble in DMSO and boiling methanol; insoluble in hexane,

dichloromethane, chloroform, benzene, ethanol and water.


156

IR Spectra:

3289.85 (N-H), 1655.35 (C=O), 1602 (C=N), 1559.20 (C=C), 3059 (=C-H), 2975,

2922.74 (υasC-H), 2847.82 (υsC-H), 1559.20 (υasNO2), 1374.94 (υs NO2) cm-1

.

NMR Spectra (DMSO):

11.992 (1H, br, s, py-N-H), 8.482 & 8.453 (1H, d, J = 8.7 Hz, o-proton of phenyl ring

to both nitro group), 8.070 & 8.041 (1H, d, J = 8.7 Hz, o-proton of phenyl ring to one

nitro group),7.847 (1H, s, furan-5C-H), 7.320 & 7.302 (1H, d, J = 5.4 Hz, m-proton of

phenyl ring to nitro group), 6.984 & 6.974 (1H, d, J = 3.0 Hz, furan-3C-H), 6.648 (1H,

s, furan-4C-H), 5.032, 5.018, 4.991 & 4.977 (1H, dd, Jbx = 12.3 Hz, Jax = 4.2 Hz, Hx of

pyrazoline group), 4.291, 4.268, 4.244 & 4.221 (2H, q, J = 7.0 Hz, methylene proton

of ester group), 3.941, 3.899, 3.882 & 3.840 (1H, dd, Jab = 17.7 Hz, Jbx = 12.6 Hz, Hb

of pyrazoline group), 3.941, 3.899, 3.882 & 3.840 (1H, dd, Jab = 18.0 Hz, Jax = 4.8 Hz,

Ha of pyrazoline group), 2.454 (3H, s, py-3-methyl group), 2.354 (3H, s, py-5-methyl

group), 1.325, 1.303, 1.278 (3H, t, J = 7.05 Hz, methyl protons of ester group).

13C NMR Spectra (DMSO):

160.56 (C20), 156.53 (C4), 152.61 (C13), 143.36 (C6), 141.07 (C1), 136.16 (C9), 134.75

(C15), 133.34 (C7), 130.17 (C10), 125.74 (C17), 122.97 (C19), 118.91 (C8), 116.32 (C14),

111.40 (C11), 110.02 (C2), 105.15 (C3), 59.48 (C21), 52.82 (C5), 40.50 (C12), 14.44

(C22), 11.68 (C16), 11.28 (C18).

157

Synthesis of Ethyl 4-[5-(4-Chloro-phenyl)-1-(2, 4-dinitro-phenyl)-4, 5-dihydro-

1H-pyrazol-3-yl]-3, 5-dimethyl-1H-pyrrole-2-carboxylate

Ethyl 4-[3-(4-Chloro-phenyl)-acryloyl]-3, 5-dimethyl-1H-pyrrole-2-carboxylate

(0.0414 g, 0.000125 mole) was dissolved in methanol and 2, 4-dinitrophenyl

hydrazine (2, 4-DNP) (0.0248 g, 0.000125 mole) was dissolved in boiling methanol

and added dropwise in the solution of first one while stirring. 1 Drop of 35% HCl was

added and the reaction mixture was refluxed for 48 hours. After the complete product

formation, the solvent was distilled off, washed with water and recrystallized with

methanol. Dark brick red shining crystals were obtained.

Yield: 0.0328 g (51.26%)





158

IR Spectra:

3310.81 (N-H), 1684.51 (C=O), 1656.75 (C=N), 1544.32 (C=C), 2978.26, 2927.53

(υasC-H), 2858 (υsC-H), 1544.32 (υasNO2), 1378.75 (υs NO2), 1097.67 (C-Cl) cm-1

.

1H NMR Spectra (DMSO):



nitro group), 7.693 & 7.665 (2H, d, J = 8.4 Hz, o-protons of phenyl ring to chloro

group), 7.350 & 7.319 (2H, d, J = 9.3 Hz, m-protons of phenyl ring to chloro group),

7.319 & 7.303 (1H, d, J = 4.8 Hz, m-protons of phenyl ring to nitro group), 4.323,

4.299, 4.276 & 4.252 (2H, q, J = 7.1 Hz, methylene proton of ester group), 2.307 &

2.272 (1H, d, J = 10.5 Hz, Hx of pyrazoline group), 2.128, 2.084, 2.038 & 2.017 (1H,

dd, Jab = 20.1 Hz, Jbx = 13.5 Hz, Hb of pyrazoline group and 6H, merged singlet of 3-

& 5- methyl groups), 1.350, 1.326, 1.304 (3H, t, J = 6.9 Hz, methyl protons of ester

group), 1.304 & 1.235 (1H, d, Jab = 20.7 Hz, Ha of pyrazoline group).

13C NMR Spectra (DMSO):

160.55 (C22), 152.61 (C15), 143.36 (C8), 137.39 (C4), 136.16 (C11), 134.76 (C19),

133.31 (C9), 132.15 (C1), 130.17 (C12), 129.06 (C2, 6), 128.78 (C3, 5), 125.74 (C17),

159

122.97 (C18), 118.90 (C10), 116.32 (C16), 111.40 (C13), 59.47 (C23), 52.92 (C7), 41.81

(C14), 14.43 (C24), 11.67 (C20), 11.28 (C21).

Synthesis of Ethyl 4-[5-(4-Dimethylamino-phenyl)-1-(2, 4-dinitro-phenyl)-4, 5-

dihydro-1H-pyrazol-3-yl]-3, 5-dimethyl-1H-pyrrole-2-carboxylate

Ethyl 4-[3-(4-Dimethylamino-phenyl)-acryloyl]-3, 5-dimethyl-1H-pyrrole-2-

carboxylate (0.0306 g, 0.00009 mole) was dissolved in methanol. 2, 4-Dinitrophenyl

hydrazine (2, 4-DNP) (0.0178 g, 0.00009 mole) was dissolved in boiling methanol

and added dropwise. The mixed solution was stirred and refluxed for 24 hours after

addition of 1 drop of 35% HCl. The reaction progression was checked up by routine

T.L.C. after completion of reaction the solvent was distilled off. Dark brown shining

solid mass was formed. It was washed with water thoroughly and then with methanol

(~2 ml).

Yield: 0.0198 g (42.30%)

160

Melting point: decomposed above 120-122ºC




IR Spectra:

3285.58 (N-H), 1657.79 (C=O), 1648 (C=N), 1595.75 (C=C), 3061, 3028 (=C-H),

2919.41 (υasC-H), 2850.56 (υsC-H), 1595.75 (υasNO2), 1378.55 (υs NO2) cm-1

.

NMR Spectra (DMSO):



nitro group), 7.549 & 7.520 (2H, d, J = 8.7 Hz, o-protons of phenyl ring to

dimethylamino group), 7.318 & 7.302 (1H, d, J = 4.8 Hz, m-proton of phenyl ring to

nitro group), 6.788 & 6.758 (2H, d, J = 9.0 Hz, m-protons of phenyl ring to

dimethylamino group), 5.031, 5.017, 4.990 & 4.976 (1H, dd, Jbx = 10.5 Hz, Jax = 4.2

Hz, Hx of pyrazoline group), 4.292, 4.267, 4.243 & 4.222 (2H, q, J = 7.0 Hz,

methylene proton of ester group), 3.940, 3.898, 3.881 & 3.839 (1H, dd, Jab = 17.7 Hz,

Jbx = 12.6 Hz, Hb of pyrazoline group), 3.005, 2.989, 2.945 & 2.929 (1H, dd, Jab = 18.0

Hz, Jax = 4.8 Hz, Ha of pyrazoline group), 2.752 (6H, s, methyl protons attached to

nitrogen), 2.454 (3H, s, py-3-methyl group), 2.353 (3H, s, py-5-methyl group), 1.326,

1.303, 1.279 (3H, t, J=7.05 Hz, methyl protons of ester group).

161


I have synthesized and characterized all the four derivatives of pyrrole-pyrazoline

heterocycles. All the results obtained for these compounds are discussed below in

detail.

Syntheses of Pyrrole-pyrazoline heterocycles

Syntheses of all four derivatives of pyrrole-pyrazoline heterocycles was carried out by

refluxing equiv. amount of both reactants pyrrole chacones and either 4-nitrobenzoic

acid hydrazide or 2, 4-dinitrophenyl hydrazine (2, 4-DNP) in appropriate solvent. For

this type of reaction, a catalyst is essential because hydrazone formation occurs in first

step and for second step cyclization of hydrazone, catalyst play a vital role. So,

catalytic amount of hydrochloric acid was utilized for these reactions.


The spectral data elucidated the structures of compounds. A detailed discussion of the

spectral outcome for each and every compound is as below:

4.4.1 Ethyl 4-[5-Furan-2-yl-1-(4-nitro-benzoyl)-4, 5-dihydro-1H-pyrazol-3-yl]-3,

5-dimethyl-1H-pyrrole-2-carboxylate (49)

IR spectra





degree physical state of the sample for frequency record.120

The IR spectra of Ethyl 4-

[5-Furan-2-yl-1-(4-nitro-benzoyl)-4, 5-dihydro-1H-pyrazol-3-yl]-3, 5-dimethyl-1H-

pyrrole-2-carboxylate contains characteristic band at around 3454.54 cm-1

due to

pyrrolic N-H stretching. In general, C=O stretching vibrations give rise to absorption

band in the region of 1870-1540 cm-1

. The spectrum shows band at 1677.72 cm-1

for

C=O stretching. Schiff’s bases, imines etc. show the C=N stretch in the 1689-1471

162

cm-1


is for the C=N stretching vibration for the

hydrazone linkage. The C=C stretching vibration or ring stretching vibrations (or

skeletal bands) occur in the general region between 1600-1300cm-1

. The absorption

involves stretching and contraction of all of the bonds in the ring and interaction between

these stretching modes. The band pattern and the relative intensities depend on the

substitution pattern and the nature of the substituents.120

The presence of bands at 1579.07

cm-1

and below it in the above mentioned range confirms for the presence of C=C group in

the molecule. The absorption arising from C-H stretching for aliphatic group occurs in the


, generally below 3000 cm-1

. The position of the C-H stretching

vibrations is among the most stable in the spectrum. The bands below 3000 cm-1

correspond to aliphatic C-H stretching modes for e.g., 2967, 2927.53 for asymmetrical

and 2864 for symmetrical stretching of C-H group, respectively. Nitro compounds

show absorptions due to asymmetrical and symmetrical stretching of the NO2 group.

Asymmetrical absorptions results in a strong band in the 1661-1499 cm-1

region;

symmetrical absorptions occurs in the region 1389-1259 cm-1

. The exact position of

the band is dependent on substitution and unsaturation in the vicinity of the NO2

group. Interaction between the NO2 out-of-plane bending and ring C-H out-of-plane

bending frequencies destroys the reliabilities of the substitution pattern observed for

nitro-aromatics in the long wavelength region of the spectrum.121

The spectrum of this

compound shows band at 1579.07 cm-1

for asymmetric stretching and at 1378.55 cm-1

for symmetric stretching of NO2 group. Other bands at lower frequencies are mixed

modes of different vibrations of groups corresponds to bending vibrations: in-plane

(scissoring, rocking) and out-of-plane deformations (wagging, twisting) and torsions

etc.

1H NMR spectra

1H NMR spectrum of Ethyl 4-[5-Furan-2-yl-1-(4-nitro-benzoyl)-4, 5-dihydro-1H-

pyrazol-3-yl]-3, 5-dimethyl-1H-pyrrole-2-carboxylate showed the presence of a broad

singlet at δ 11.852 ppm corresponding to pyrrolic NH proton. Spectral data showed

the presence of a doublet at δ 8.312 & 8.283 ppm (J = 8.7 Hz) corresponding to

protons of phenyl ring o- to nitro group, a doublet at δ 8.060 & 8.031 ppm (J = 8.7

163

Hz) corresponding to protons of phenyl ring m- to nitro group. A singlet at δ 7.848, a

doublet at δ 6.983 & 6.973 (J = 3.0 Hz) and a singlet at δ 6.649 ppm corresponded to

furan ring protons of 5C, 3C and 4C, respectively. A quartet at δ 4.323, 4.299, 4.273

& 4.252 (J = 7.1 Hz) and a triplet at δ 1.352, 1.326, 1.304 (J = 7.2 Hz) confirmed the

presence of methylene and methyl of the ester group in the molecule, respectively. A

doublet at δ 2.307 & 2.272 ppm (Jbx = 10.5 Hz) corresponded to Hx of pyrazoline

group, a double doublet at δ 2.128, 2.084, 2.038 & 2.019 ppm (Jab = 19.5 Hz, Jbx =

13.5 Hz) corresponded to Hb of pyrazoline group and merged singlets of methyl

groups at 3- and 5-position of pyrrole ring and a doublet at δ 1.304 & 1.232 ppm (Jab =

21.6 Hz) corresponded to Ha of pyrazoline group merged with methyl group of ester.

4.4.2 Ethyl 4-[1-(2, 4-Dinitro-phenyl)-5-furan-2-yl-4, 5-dihydro-1H-pyrazol-3-yl]-

3, 5-dimethyl-1H-pyrrole-2-carboxylate (51)

IR spectra

The IR spectra of Ethyl 4-[1-(2, 4-Dinitro-phenyl)-5-furan-2-yl-4, 5-dihydro-1H-

pyrazol-3-yl]-3, 5-dimethyl-1H-pyrrole-2-carboxylate contains characteristic bands at

around 3289.85 cm-1

due to pyrrolic N-H stretching and other bands at 1655.35 cm-1

,

due to υ(C=O), 1602 cm-1

due to υ(C=N) and at 1559.20 cm-1

, due to υ(C=C)

stretching modes. Other main bands above 3000 cm-1

corresponds to aromatic C-H

stretching for e.g., 3059 cm-1

and below 3000 cm-1


stretching modes for e.g., at 2975, 2922.74cm-1

for asymmetric and at 2847.82 cm-1

for symmetric C-H stretching vibrations. The spectrum of this compound shows band

at 1559.20 cm-1


for symmetric

stretching of NO2 group. Other bands at lower frequencies are mixed modes of

different vibrations of groups corresponds to in-plane and out-of-plane deformations

and their mixed modes.

1H NMR spectra

1H NMR spectrum of Ethyl 4-[1-(2, 4-Dinitro-phenyl)-5-furan-2-yl-4, 5-dihydro-1H-

pyrazol-3-yl]-3, 5-dimethyl-1H-pyrrole-2-carboxylate showed the presence of a broad

164

singlet at δ 11.992 ppm corresponding to pyrrolic NH proton. Spectral data showed

the presence of a doublet at δ 8.482 & 8.453 ppm (J = 8.7 Hz) corresponding to proton

of phenyl ring o- to both nitro group, a doublet at δ 8.070 & 8.041 ppm (J = 8.7 Hz)

corresponding to proton of phenyl ring o- to one nitro group, a doublet at δ 7.320 &

7.302 ppm (J = 5.4 Hz) corresponding to proton of phenyl ring m- to nitro group. A

singlet at δ 7.847, a doublet at δ 6.984 & 6.974 (J = 3.0 Hz) and a singlet at δ 6.648

ppm corresponded to furan ring protons of 5C, 3C and 4C, respectively. A quartet at δ

4.291, 4.268, 4.244 & 4.221 (J = 7.0 Hz) and a triplet at δ 1.325, 1.303, 1.278 (J =

7.05 Hz) confirmed the presence of methylene and methyl of the ester group in the

molecule, respectively. A double doublet at δ 5.032, 5.018, 4.991 & 4.977 ppm (Jbx =

12.3 Hz, Jax = 4.2 Hz) corresponded to Hx of pyrazoline group, a double doublet at δ

3.941, 3.899, 3.882 & 3.840 ppm (Jab = 17.7 Hz, Jbx = 12.6 Hz) corresponded to Hb of

pyrazoline group and a double doublet at δ 3.941, 3.899, 3.882 & 3.840 ppm (Jab =

18.0 Hz, Jax = 4.8 Hz) corresponded to Ha of pyrazoline group merged with methyl

group of ester. Two singlets were present at δ 2.454 and 2.354 corresponding to

methyl groups at 3- and 5-position of pyrrole ring, respectively.

13C NMR spectra

The 13

C NMR data of Ethyl 4-[1-(2, 4-Dinitro-phenyl)-5-furan-2-yl-4, 5-dihydro-1H-

pyrazol-3-yl]-3, 5-dimethyl-1H-pyrrole-2-carboxylate showed the presence of δ

160.56 corresponding to carbonyl groups of ester group (C20). The presence of δ

152.61 for the C=N-N linkage (C13), δ 40.50 for CH2 (C12) and δ 52.82 for CH (C5)

within the pyrazoline ring confirmed the structure of the compound. The presence of δ

134.75 (C15), 125.74 (C17), 122.97 (C19), 116.32 (C14) corresponded to pyrrole ring

carbons. δ 59.48 (C21) and 14.44 (C22) showed the presence of methylene and methyl

carbons of ester group. Spectra showed the presence of δ 143.36 (C6), 133.34 (C7),

118.91 (C8), 136.16 (C9), 130.17 (C10), 111.40 (C11) corresponding to 2, 4-

dinitrophenyl ring, δ 141.07 (C1), 110.02 (C2), 105.15 (C3), 156.53 (C4) corresponding

to furan ring. The spectra showed presence of δ 11.68 (C16) and 11.28 (C18)

corresponding to methyl groups at 5 and 3-position of pyrrole ring, respectively.

165

4.4.3 Ethyl 4-[5-(4-Chloro-phenyl)-1-(2, 4-dinitro-phenyl)-4, 5-dihydro-1H-

pyrazol-3-yl]-3, 5-dimethyl-1H-pyrrole-2-carboxylate (53)

IR spectra

The IR spectra of Ethyl 4-[5-(4-Chloro-phenyl)-1-(2, 4-dinitro-phenyl)-4, 5-dihydro-

1H-pyrazol-3-yl]-3, 5-dimethyl-1H-pyrrole-2-carboxylate contains characteristic

bands at around 3310.81 cm-1

due to pyrrolic N-H stretching and other bands at

1684.51 cm-1

, due to υ(C=O), 1656.75 cm-1

due to υ(C=N) and at 1544.32 cm-1

, due to

υ(C=C) stretching modes. Other main bands below 3000 cm-1

corresponds to aliphatic

C-H stretching modes for e.g., at 2978.26, 2927.53 cm-1

for asymmetric and at 2858

cm-1

for symmetric C-H stretching vibrations. The spectrum of this compound shows



for symmetric

stretching of NO2 group. Chlorobenzenes absorb in the 1099-1089 cm-1

region. The

position within the region depends on the substitution pattern.122

So, spectrum of this

molecule shows band at 1097.67 cm-1

for Ar-Cl group. Other bands at lower

frequencies are mixed modes of different vibrations of groups corresponds to in-plane

and out-of-plane deformations and their mixed modes.

1H NMR spectra

1H NMR spectrum of Ethyl 4-[5-(4-Chloro-phenyl)-1-(2, 4-dinitro-phenyl)-4, 5-

dihydro-1H-pyrazol-3-yl]-3, 5-dimethyl-1H-pyrrole-2-carboxylate showed the

presence of a broad singlet at δ 11.077 ppm corresponding to pyrrolic NH proton.

Spectral data showed the presence of a doublet at δ 8.484 & 8.452 ppm (J = 9.6 Hz)

corresponding to proton of phenyl ring o- to both nitro group, a doublet at δ 8.060 &

8.031 ppm (J = 9.6 Hz) corresponding to protons of phenyl ring o- to one nitro group,

a doublet at δ 7.319 & 7.303 ppm (J = 4.8 Hz) corresponding to protons of phenyl ring

m- to nitro group. Spectral data showed the presence of a doublet at δ 7.693 & 7.665

ppm (J = 8.4 Hz) corresponding to protons of phenyl ring o- to chloro group, a

doublet at δ 7.350 & 7.319 ppm (J = 9.3 Hz) corresponding to protons of phenyl ring

m- to chloro group. A quartet at δ 4.323, 4.299, 4.276 & 4.252 (J = 7.1 Hz) and a

166

triplet at δ 1.350, 1.326, 1.304 (J = 6.9 Hz) confirmed the presence of methylene and

methyl of the ester group in the molecule, respectively. A doublet at δ 2.307 & 2.272

ppm (Jbx = 10.5 Hz) corresponded to Hx of pyrazoline group, a double doublet at δ

2.128, 2.084, 2.038 & 2.017 ppm (Jab = 20.1 Hz, Jbx = 13.5 Hz) corresponded to Hb of

pyrazoline group and merged singlets of methyl groups at 3- and 5-position of pyrrole

ring and a doublet at δ 1.304 & 1.235 ppm (Jab = 20.7 Hz) corresponded to Ha of

pyrazoline group merged with methyl group of ester. These proton signals confirmed

the pyrazoline ring formation.

13C NMR spectra

The 13

C NMR data of Ethyl 4-[5-(4-Chloro-phenyl)-1-(2, 4-dinitro-phenyl)-4, 5-

dihydro-1H-pyrazol-3-yl]-3, 5-dimethyl-1H-pyrrole-2-carboxylate showed the

presence of δ 160.55 corresponding to carbonyl groups of ester group (C22). The

presence of δ 152.61 for the C=N-N linkage (C15), δ 41.81 for CH2 (C14) and δ 52.92

for CH (C7) within the pyrazoline ring confirmed the structure of the compound. The

presence of δ 134.76 (C19), 125.74 (C17), 122.97 (C18), 116.32 (C16) corresponded to

pyrrole ring carbons. δ 59.47 (C23) and 14.43 (C24) showed the presence of methylene

and methyl carbons of ester group. Spectra showed the presence of δ 143.36 (C8),

133.31 (C9), 118.90 (C10), 136.16 (C11), 130.17 (C12), 111.40 (C13) corresponding to 2,

4-dinitrophenyl ring, δ 132.15 (C1), 129.06 (2C, C2, 6), 128.78 (2C, C3, 5), 137.39 (C4)

corresponding to p-chlorophenyl ring, δ 11.67 (C20) and 11.28 (C21) corresponding to

methyl groups at 5 and 3-position of pyrrole ring, respectively.

4.4.4 Ethyl 4-[5-(4-Dimethylamino-phenyl)-1-(2, 4-dinitro-phenyl)-4, 5-dihydro-

1H-pyrazol-3-yl]-3, 5-dimethyl-1H-pyrrole-2-carboxylate (56)

IR spectra

The IR spectra of Ethyl 4-[5-(4-Dimethylamino-phenyl)-1-(2, 4-dinitro-phenyl)-4, 5-

dihydro-1H-pyrazol-3-yl]-3, 5-dimethyl-1H-pyrrole-2-carboxylate contains

characteristic bands at around 3285.58 cm-1

due to pyrrolic N-H stretching and other

bands at 1657.79 cm-1

, due to υ(C=O), 1648 and 1595.75 cm-1

, due to υ(C=N) and

167

υ(C=C) stretching modes, respectively. Other main bands above 3000 cm-1

corresponds to aromatic C-H stretching for e.g., 3061, 3028 cm-1

and below 3000 cm-1

corresponds to aliphatic C-H stretching modes for e.g., at 2919.41 cm-1

for asymmetric

and at 2850.56 cm-1

for symmetric C-H stretching vibrations. The spectrum of this

compound shows band at 1595.75 cm-1


for symmetric stretching of NO2 group. Other bands at lower frequencies are mixed

modes of different vibrations of groups corresponds to in-plane and out-of-plane


1H NMR spectra

1H NMR spectrum of Ethyl 4-[5-(4-Dimethylamino-phenyl)-1-(2, 4-dinitro-phenyl)-4,

5-dihydro-1H-pyrazol-3-yl]-3, 5-dimethyl-1H-pyrrole-2-carboxylate showed the

presence of a broad singlet at δ 11.177 ppm corresponding to pyrrolic NH proton.

Spectral data showed the presence of a doublet at δ 8.485 & 8.453 ppm (J = 9.6 Hz)

corresponding to proton of phenyl ring o- to both nitro group, a doublet at δ 8.074 &

8.046 ppm (J = 8.4 Hz) corresponding to protons of phenyl ring o- to one nitro group,


m- to nitro group. Spectral data showed the presence of a doublet at δ 7.549 & 7.520

ppm (J = 8.7 Hz) corresponding to protons of phenyl ring o- to dimethylamino group,


m- to dimethylamino group. A quartet at δ 4.292, 4.267, 4.243 & 4.222 (J = 7.0 Hz)

and a triplet at δ 1.326, 1.303, 1.279 (J = 7.05 Hz) confirmed the presence of

methylene and methyl of the ester group in the molecule, respectively. A double

doublet at δ 5.031, 5.017, 4.990 & 4.976 ppm (Jbx = 10.5 Hz, Jax = 4.2 Hz)

corresponded to Hx of pyrazoline group, a double doublet at δ 3.940, 3.898, 3.881 &

3.839 ppm (Jab = 17.7 Hz, Jbx = 12.6 Hz) corresponded to Hb of pyrazoline group and a

double doublet at δ 3.005, 2.989, 2.945 & 2.929 ppm (Jab = 18.0 Hz, Jax = 4.8 Hz)

corresponded to Ha of pyrazoline group. Two singlets were present at δ 2.454 and

2.353 corresponding to methyl groups at 3- and 5-position of pyrrole ring,

respectively. There is presence of a singlet at δ 2.752 for 6 protons of methyl groups

attached to amino nitrogen.

168

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Summary and Conclusion

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The development of pyrrole chemistry has largely been associated with the natural

products- porphyrins that play par excellence functional role in life, has developed

into an interdisciplinary area of research comprising chemistry, the biosciences,

medicine and even material science. Porphyrins are best arguable ligands in existence,

forming coordination complexes with the most elements of the periodic table.

Porphyrin, a heterocyclic macrocycle derived from four pyrrole units interconnected

via their α carbon atoms through methine bridges (=CH-) forming highly conjugated

and consequently deeply coloured, hence the name porphyrin, from a Greek word for

purple. Different classes of pyrrole containing compounds appearing in natural

products show very interesting biological properties. However, the major limitation

of natural pyrrole derivatives are due to difficulty in their 1) isolation in bulk in pure

form 2) stability of isolated natural products 3) in some cases their limited availability

and 4) synthesis of natural products in laboratory in bulk in pure form. During the

attempt of synthesis of natural products vast number of pyrrole derivatives have been

synthesized which are attracting interests as precursors, model system and other

application due to their various physical and chemical properties. With increasing

number of pyrrole derivatives of diverse structure and properties, attempts are being

made in directions of both simplifying the synthetic strategies as well as synthesizing

of new pyrrole based compounds. The major synthetic strategies are 1)

Combinatorial approach that is most commonly utilized, involves appending

different building blocks around a common structural core. The appendage diversity

that is achieved by varying substituents around a common core is thought to limit the

compounds to a narrow chemical space. Very often, and particularly in the

pharmaceutical company setting, the molecules accessed in this manner are designed

to fall within defined physico-chemical parameters that increase their chances of

becoming drug candidates. 2) Diversity-oriented synthesis (DOS) adapts existing

synthetic methodologies and aims to develop new and structurally diverse molecules

specifically for biological screening. It is designed and deliberate synthesis of

collections of small molecules populating novel chemical space. DOS efforts put the

main emphasis on the diversity of the molecular scaffolds that are accessed and not on

the numbers of compounds.

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The relative stability of the synthesized pyrrole derivatives has marvellously enabled

diverse organic chemistry. Both the biological significance and material importance

are the targeted objectives for a chemist involved in synthesis or production. In order

to obtain the number of pyrrole derivatives of high yield, diverse structure and

properties, attempts are being made in directions of adopting new strategies,

simplifying the previous synthetic strategies as well as understanding the finer aspects

of reported compounds for synthesizing of new pyrrole based compounds. This thesis

presents synthesis and physicochemical studies of few diversified structural pyrrole

derivatives. The synthesized compounds have been characterized by few

physicochemical methods.

The first chapter of the thesis covers synthesis and physicochemical studies of pyrrole-

chalcones that are in fact combination of two very diversely applicable branches of

synthetic chemistry. An efficient method was utilized for the preparation of these

derivatives. The conventional Claisen-Schmidt condensation methodology permits the

controlled formation of trans- isomer on a large scale. The synthesized compounds

have been concisely represented as below:

These compounds are characterized by UV-visible, IR and 1H NMR techniques. Their

UV-visible spectra show wavelength for π→π*and n→π* transitions. Their IR spectra

176

show characteristic C=C and C=O as a prof of link formation at wavenumber 1500-

1600 cm-1

. The most characteristic of these compounds is the presence of its α and β

protons’ chemical shift and coupling constant. Their α proton appears further upfield

compared to the β proton due to the shielding effect of the carbonyl group. The

coupling constant of 11-16 ppm strongly indicates that the protons have a trans

configuration, which is consistent with the observation that the more stable trans

isomers are produced in the synthesis of chalcones. These compounds are having a

versatile reactive skeleton for further synthetic use and they easily can be used as

synthons. This fact led to the development of methods for generation of more

structural heterocyclic moieties.

The hydrazine molecule and its many derivatives represent an intermediate valence

state for nitrogen suggesting that hydrazine can function both as an oxidizing and as a

reducing agent. With four replaceable hydrogens and two unbonded electron pairs,

hydrazine can form many alkyl/aryl or acyl derivatives, including mono-, di-, tri-, and

tetra-substituted derivatives and their isomers. Many hydrazine derivatives retain

some of hydrazine toxicity and form the basis for perhaps practical significance in

pharmaceuticals, such as antituberculants, as well as in textile dyes and photography.

The remarkable biological activity of acid hydrazides R-CO-NHNH2, their

corresponding aroylhydrazones R-CO-NHN=CH-Ar and the dependence of their

mode of chelation with transition metal ions present in the living system are of

significant importance. Second chapter includes the synthesis and characterization of

Pyrrole hydrazide-hydrazones. They have been synthesized from keto-pyrrole

derivative and acid hydrazide resulting into hydrazide-hydrazones. The combination

of acid hydrazides and acetyl pyrrole generated the highly applicable product. Pyrrole

based Schiff bases offer the versatile ligand donor groups. Amido-imine

conformational frame change and as a consequence varying the number of donor sites

that can interact with other substrate has biological importance. The free side of

hydrazide group present in product can be further utilized for other reactions. The

synthesized derivatives are schematically presented as below:

http://en.wikipedia.org/wiki/Pharmaceutical

http://en.wikipedia.org/w/index.php?title=Antituberculant&action=edit

http://en.wikipedia.org/wiki/Dye

177

UV-visible, IR, 1H NMR and

13C NMR spectral data have been recorded to

characterize all of these compounds. All their spectral data show characteristic

hydrazone linkage and confirm the occurrence of link formation.

Over the past few years, functionalized C-vinylpyrroles attracting attention as

molecular optical switches, in particular, as ultra fast ones, for design of photo and

electroconducting materials and micro and nanodevices and also as ligands for new

photocatalysts and biologically active complexes. Pyrrole derivatives containing a

greater number of -electrons, a greater number of donating groups, or a larger

binding group, have properties which differ substantially from other studied systems.

The third chapter of this thesis includes the moiety derived from formyl cyanovinyl

ester pyrrole that has many reactive centers in itself. This compound has been easily

transformed into the desired hydrazide-hydrazones. This chapter includes synthesis

and characterization of following newly synthesized cyanovinyl ester pyrrole

hydrazide-hydrazone derivatives:

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The formation of hydrazone linkage of these compounds is confirmed by their UV-

visible, IR and 1H NMR spectral data which show the characteristic peaks at generally

observed values.

In this thesis, fourth chapter presents the formation of bi- and tri-heterocyclic

derivatives containing pyrrole and pyrazoline essentially. For their synthesis, we used

method which involves the in situ generation of hydrazones derived from pyrrole-

chalcones and their further cyclization to generate pyrazoline moiety in a single step

reaction. The synthesized pyrrole-pyrazoline derivatives have been characterized by

spectroscopic techniques and presented as following structure:

179

UV-visible, IR, 1H NMR and

13C NMR spectral data have been used to characterize

all of these compounds. All these spectra show all characteristic peaks at general

region for the particular functional group. The most characteristic observation for

these compounds is in their 1H NMR spectra which show disappearance of peaks for

vinylic protons of chalcones and appearance of peaks for the three protons of central

pyrazoline ring.

syntheses and physicochemical studies...

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