SYNTHESES AND PHYSICOCHEMICAL STUDIES...
Transcript of 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
2.2 Basis of work and objectives of the present investigations
2.3 Materials, methods and syntheses
2.4 Result and discussion
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-
pyrrole-2-carboxylate
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
3.2 Basis of work and objectives of the present investigations
3.3 Materials, methods and syntheses
3.4 Result and discussion
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
4.2 Basis of work and objectives of the present investigations
4.3 Materials, methods and syntheses
4.4 Result and discussion
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-
pyrazol-3-yl]-3, 5-dimethyl-1H-pyrrole-2-carboxylate
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
1.2 Basis of work and objectives of the present investigations
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.
Solubility: This compound is soluble in chloroform, ethylacetate, ethanol, methanol,
acetone, DMSO and insoluble in hexane, benzene and water.
UV-vis Spectra (ethanol): λmax 308 nm
IR Spectra (KBr):
3495.18 (N-H), 3038.66 (aromatic =C-H), 2973.9 (aliphatic C-H), 2863.16 (aliphatic
C-H), 1675.91 (C=O of ester group), 1630.18(C=O), 1593.53 (C=C) cm-1
.
1H NMR Spectra (CDCl3):
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
Ethyl 4-acetyl-3, 5-dimethyl-1H-pyrrole-2-carboxylate (0.105 g, 0.0005 mol) was
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.
Solubility: This compound is soluble in chloroform, ethylacetate, ethanol, methanol,
acetone, DMSO and insoluble in hexane, benzene and water.
UV-vis Spectra (ethanol): λmax 237, 317 nm
37
IR Spectra (KBr):
3285.83 (N-H), 3108.69 (aromatic =C-H), 2984.62 (aliphatic C-H), 2920.28 (aliphatic
C-H), 1645.95 (C=O of ester group), 1593.53 (C=O), 1556.28 (C=C) cm-1
.
1H NMR Spectra (CDCl3):
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-
pyrrole-2-carboxylate
Ethyl 4-acetyl-3, 5-dimethyl-1H-pyrrole-2-carboxylate (0.105 g, 0.0005 mol) was
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
Solubility: This compound is soluble in chloroform, ethylacetate, ethanol, methanol,
acetone, DMSO and insoluble in hexane, benzene and water.
UV-vis Spectra (ethanol): λmax 228, 247 nm
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
1.5 References
(1) (a) Martins, M. A. P.; Frizzo, C. P.; Moreira, D. N.; Zanatta, N.; Bonacorso, H. G. Chem. Rev. 2008, 108, 2015;
(b) Patil, N. T.; Yamamoto, Y. Chem. Rev. 2008, 108, 3395; (c) Larrosa, I.; Romea, P.; Urpí, F. Tetrahedron
2008, 64, 2683; (d) Nising, C. F.; Br€ase, S. Chem. Soc. Rev. 2008, 37, 1218; (e) Mori, A.; Sugie, A. Bull.
Chem. Soc. Jpn. 2008, 81, 548; (f) Surry, D. S.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 6338; (g)
Wang, M.-X. Chem. Commun. 2008, 4541; (h) Lewis, J. C.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res.
2008, 41, 1013.
(2) Riveira, M. J.; La-Venia, A.; Mischne, M. P. J. Org. Chem. 2008, 73, 8678.
(3) (a) Vereschagin, L. I.; Pokatilov, F. A.; Kizhnyaev, V. N. Chem. Heterocycl. Compd. 2008, 44, 1; (b) Hulme, C.;
Lee, Y.-S. Mol. Diversity 2008, 12, 1.
(4) (a) Isambert, N.; Lavilla, R. Chem.–Eur. J. 2008, 14, 8444; (b) Groenendaal, B.; Ruijter, E.; Orru, R. V. A.
Chem. Commun. 2008, 5474.
(5) (a) Hahn, F. E.; Jahnke, M. C. Angew. Chem., Int. Ed. 2008, 47, 3122; (b) Ma, Y.; Wei, S.; Lan, J.; Wang, J.;
Xie, R.; You, J. J. Org. Chem. 2008, 73, 8256; (c) Tommasi, I.; Sorrentino, F. Tetrahedron Lett. 2009, 50, 104;
(d) Bezerra, C. W. B.; Zhang, L.; Lee, K.; Liu, H.; Marques, A. L. B.; Marques, E. P.; Wang, H.; Zhang, J.
Electrochim. Acta 2008, 53, 4937.
(6) (a) Dooleweerdt, K.; Ruhland, T.; Skrydstrup, T. Org. Lett. 2009, 11, 221; (b) Shawali, A. S.; Farghaly, T. A.
Arkivoc 2008, i, 18; (c)Ye, L.-W.; Zhou, J.; Tang,Y. Chem. Soc. Rev. 2008, 37, 1140; (d) Warkentin, J. Acc.
Chem. Res. 2009, 42, 205; (e) Philip, A.; Gale, P. A. Chem. Commun. 2008, 4525; (f) Flick, A. C.; Padwa, A.
Tetrahedron Lett. 2008, 49, 5739; (g) Corberán, R.; Marrot, S.; Dellus, N.; Merceron-Saffon, N.; Kato, T.; Peris,
E.; Baceiredo, A. Organometallics 2009, 28, 326.
(7) (a) Fukamizu, K.; Miyake, Y.; Nishibayashi, Y. J. Am. Chem. Soc. 2008, 130, 10498; (b) Ma, D.; Qian, C. Q.
Acc. Chem. Res. 2008, 41, 1450; (c) Shen, H. C. Tetrahedron 2008, 64, 3885; (d) Míriam, A.-C.; Manuel, M.-
D.; Ignacio, R.-G. Chem. Rev. 2008, 108, 3174; (e) Rudolph, A.; Rackelmann, N.; Turcotte-Savard, M.-O.;
Lautens, M. J. Org. Chem. 2009, 74, 289; (f) Buchlovič, M.; Man, S.; Potáček, M. Tetrahedron 2008, 64, 9953;
(g) Barluenga, J.; Tomás-Gamasa, M.; Moriel, P.; Aznar, F.; Valdés, C. Chem.–Eur. J. 2008, 14, 4792.
(8) (a) Watson, J. D.; Crick, F. H. C. Nature 1953, 171, 737; (b) Watson, J. D.; Crick, F. H. C. Nature 1953, 171,
964.
(9) Handy, S. T.; Wilson, T. and Muth, A. J. Org. Chem. 2007, 72(22), 8496-8500.
(10) Gómez-Zavaglia, A. and Fausto, R. J. Phys. Chem. A 2004, 108, 6953-6967.
(11) Zhang, Q.; Zhou, X.; Yang, H. J. Power Sources 2004, 125, 141.
(12) Wang, J.; Neoh, K.; Kang, E. Thin Solid Films 2004, 446, 205.
(13) Kim, S.; Oh, K.; Bahk, J. J. Appl. Polym. Sci. 2004, 91, 4064.
(14) Ghosh, P.; Kar, S. J. Appl. Polym. Sci. 2004, 91, 3737.
(15) Bousalem, S.; Yassar, A.; Basinska, T.; Miksa, B.; Slomkowski, S.; Azioune, A.; Chehimi, M. Polym. Adv.
Technol. 2003, 14, 820.
(16) Kanakaraju, R.; Kolandaivel, P. Int. J. Mol. Sci. 2002, 3, 777.
(17) (a) Hayes, R. T.; Wasielewski, M. R.; Gosztola, D. J. Am. Chem. Soc. 2000, 122, 5563–5567; (b) Harmjanz, M.;
Gill, H. S.; Scott, M. J. J. Am. Chem. Soc. 2000, 122, 10476–10477; (c) Rurach, K. Angew. Chem., Int. Ed.
2001, 40, 385–387.
(18) Wagner, R. W.; Lindsey, J. S. Pure Appl. Chem. 1996, 68, 1373–1380.
(19) Rimarčik, J.; Lukeš, V.; Klein, E.; Griesser, M.; Kelterer A. chem. Phys. 2008, 353, 177-184
(20) Fischer, H.; Orth, H. Akademische Verlag: Die Chemie des Pyrrols; Leipzig, 1934, 1937, 1940; Vol. I.
(21) (a) Morrison, M. D.; Hanthorn, J. J.; and Pratt D. A. Org. Lett. 2009, 11(5), 1051-1054; (b) Keifer, P.; Schwartz,
R.; Koker, M.;Hughes, R.; Rittschof, D.; Rinehart, K. J. Org. Chem. 1991, 56, 2965-2975; (c) Palermo, J.;
Rodriguez, B.; Seldes, A.; Tetrahedron 1996, 52, 2727-2734; (d) Waller, C.W.; Wolf, C.F.; Stein, W.J.;
Hutchings, B.L. J. Am. Chem. Soc. 1957, 79, 1265-1266; (e) Bailly, C.; Chaires, J.B. Bioconjugate Chem. 1998,
9, 513-538; (f) Bailly, C.; Henichart, J.P. Bioconjugate Chem. 1991, 2, 379-393; (g) Dervan, P.B. Science 1986,
232, 464-471 and references cited therein.
45
(22) Deidda, D.; Lampis, G.; Fioravanti, R.; Biava, M.; Porretta, G. C.; Zanetti, S.; and Pompei, R. Antimicrobial
Agents And Chemotherapy, 1998, 42(11), 3035–3037.
(23) (a) Furstner, A. Angew. Chem., Int. Ed. 2003, 42, 3582–3603; (b) Fan, H.; Peng, J.; Hamann, M. T.; Hu, J.-F.
Chem. Rev. 2008, 108, 264–287; (c) Nakao, Y.; Fusetani, N. J. Nat. Prod. 2007, 70, 689–710; (d) Urban, S.;
Hickkford, S. J. H.; Blunt, J. W.; Munro, M. H. G. Curr. Org. Chem. 2000, 4, 765–807.
(24) (a) Mohamed, M. S.; Rashad, A. E.; Adbel-monem, M.; Fatahalla, S. S. Z. Naturforsch. 2007, 62c, 27–31; (b)
Berger, M.; Schaecke, H.; May, E.; Skuballa,W.; Kuenzer, H. PCT Int. Appl. WO 2008098798 A1, 2008.
(25) Cocco, M. T.; Congiu, C.; Onnis, V. Bioorg. Med. Chem. 2003, 11, 495–503.
(26) Akiyoshi, A.; Takashi, S.; Naohisa, O.; Yasuo, S.; Motoniro, S.; Junji, N.; Masayosh, K.; PCT Int. Appl.
JP2009179589 (A), 2009.
(27) Onnis, V.; De Log, A.; Cocco, M. T.; Fadda, R.; Meleddu, R. Eur. J. Med. Chem. 2009, 44, 1288–1295.
(28) Chou, D.; Knauf, W.; Maier, M.; Malaska, M. J.; McIntyre, D.; Lochhaas, F.; Huber, S. K. PCT Int. Appl. US
20070281976 A1, 2007.
(29) Ghorab, M. M.; Heimy, H. I.; Khalil, A. I.; Abou El Ella, D. A.; Noaman, E. Phosphorus, Sulfur, Silicon 2008,
183, 90–104.
(30) Wallace, M. B.; Adams, M. E.; Kanouni, T.; Mol, C. D.; Dougan, D. R.; Feher, V. A.; O’Connell, S. M.; Shi, L.;
Halkowycz, P.; Dong, Q. Bioorg. Med. Chem. Lett. 2010, 20, 4156–4158.
(31) Heng, R.; Koch, G.; Schlapbach, A.; Seiler, M. P. PCT Int. Appl. WO 2008034600 A1, 2008.
(32) Ronan, B.; Tabart, M.; Souaille C.; Viviani, F.; Bacque, E. PCT Int. Appl. FR2881742 A1, 2006.
(33) Wang, D.; Kosh, J. W.; Sowell, J. W., Sr.; Wang, T. PCT Int. Appl. WO 2005046676 A1, 2005.
(34) Kenji, K.; Noriko, K. PCT Int. Appl.WO2010024227 A1, 2010.
(35) Bullington, J. L.; Fan, X.; Jackson, P. F.; Zhang, Y.-M. PCT Int. Appl. WO 2004029040 A1, 2004.
(36) Tanaka, M.; Sasaki, Y.; Kimura, Y.; Fukui, T.; Ukai, Y. BJU Int. 2003, 92, 1031–1036.
(37) Mohamed, M. S.; Kamel, R.; Fatahala, S. S. Eur. J. Med. Chem. 2010, 45, 2994–3004.
(38) (a)Diana, P.; Barraja, P.; Lauria, A.;Montalbano, A.; Almerico, M.; Dattolo, G.; Cirrincione Eur. J. Med. Chem.
2002, 37, 267–272; (b) Willemann, C.; Grunert, R.; Bednarski, P. J.; Troschutz, R.; Cocco, M. T.; Congiu, C.;
Onnis, V. Bioorg. Med. Chem. 2009, 17, 4406–4419.
(39) (a) Bennet, S. M.; Nguyen-Ba, N.; Ogilvie, K. K. J. Med. Chem. 1990, 33, 2162–2173; (b) Krawczyk, S. H.;
Nassiri, M. R.; Kucera, L. S.; Kern, E. R.; Ptak, R. G.; Wotring, L. L.; Drach, J. C.; Townsend, L. B. J. Med.
Chem. 1995, 38, 4106–4114; (c) Migawa, M. T.; Drach, J. C.; Townsend, L. B. J. Med. Chem. 2005, 48, 3840–
3851.
(40) El-Gaby, M. S. A.; Gaber, A. M.; Atalla, A. A.; Abd Al-Wahab, K. A. Farmaco 2002, 57, 613–617.
(41) Castelhano, A. L.; McKibben, B.; Witter, D. J. PCT Int. Appl. US 6878716 B1, 2005.
(42) Bookser, B. C.; Ugarkar, B. G.; Matelich, M. C.; Lemus, R. H.; Allan, M.; Tsuchiya, M.; Nakane, M.; Nagahisa,
A.; Wiesner, J. B.; Erion, M. D. J. Med. Chem. 2005, 48, 7808–7820.
(43) Gangjee, A.; Jain, H. D.; Queener, S. F.; Kisliuk, R. L. J. Med. Chem. 2008, 51, 4589–4600.
(44) Gupta, P. K.; Daunert, S.; Nassiri, M.R.; Wotring, L. L.; Drach, J. C.; Townsend, L. B. J. Med. Chem. 1989, 32,
402–408.
(45) (a) Kabayashi, J.; Cheng, J.; Kikuchi, Y.; Ishibashi, M.; Yamamura, S.; Ohizumi, Y.; Ohta, T.; Nozoe, S.
Tetrahedron Lett. 1990, 31, 4617–4620; (b) Tsuda,M.; Nozawa,K.; Shimbo,K.;Kobayashi, J. J. Nat. Prod. 2003,
66, 292–294; (c) Davis, R. A.; Christensen, L. V.; Richardson, A. D.; Moreira da Rocha, R.; Ireland, C. M. Mar.
Drugs 2003, 1, 27–33.
(46) Dimmock, J.R.; Elias, D.W.; Beazely, M.A.; Kandepu, N.M. Curr. Med. Chem. 1999, 6, 1125–1149.
(47) Go, M.L.; Wu, X.; Liu, X.L. Curr. Med. Chem. 2005, 12, 481–499.
(48) Echeverria, C.; Santibanez, J.S.; Donoso-Tauda, O.; Escobar, C.A.; Ramirez-Tagle, R. Int. J. Mol. Sci. 2009, 10,
221–231.
46
(49) Williams, C. A., and Grayer, R. J. Nat. Prod. Rep. 2004, 21, 539–573.
(50) Hsieh, R. J.; Kinsella, J. E., Adv. Food Nutr. Res. 1989, 33, 233.
(51) Meltzer, H.M. and Malterud, K.E. Scand. J. Nutr. 1997, 41, 50-57 and references therein.
(52) Visioli, F.; Bellomo, G.; Galli, C. Biochem. Biophys. Res. Commun. 1998, 247, 60.
(53) Visulli, F.; Galli, C. J. Agric. Food Chem. 1998, 46, 4292.
(54) Kuehnau, J. World Rev. Nutr. Diet 1976, 24, 117.
(55) (a) Kandaswami, C. and Middleton, E. Adv. Exp. Med. Biol. 1994, 366, 351-376; (b) Rice-Evans, C.A.; Miller,
N.J.; Bolwell, P.G.; Bramley, P.M. and Pridham, J.B. Free Rad. Res. 1995, 22, 373-383; (c) Cotelle, N.;
Bernier, J-L.; Catteau, J.P.; Pommery, J. and Wallet, J-C.; Gaydou, W. Free Rad. Biol. Med. 1996, 20, 35-43.
(56) Moroney, M.A.; Alcaraz, M.J.; Forder, R.A.; Carey, F. and Hoult, J.R.S. J. Pharm. Pharmacol., 1988, 40, 787-
792; Laughton, M.J.; Evans, P.J.; Moroney, M.A.; Hoult, J.R.S. and Halliwell, B. Biochem. Pharmacol. 1991,
42, 1673-1681.
(57) Middleton, E. and Kandaswami, C., Biochem. Pharmacol. 1992, 43, 1167-1179.
(58) Lin, Y-M.; Flavin, M.T.; Cassidy, C.S.; Mar, A. and Chen, F-C. Bioorg. Med. Chem. 2001, 11, 2101-2104.
(59) Middleton, E. Flavonoids TIPS 1984, 5, 335.
(60) Harborne, J. B. The Flavonoids: Advances in research since 1980; Chapman and Hall: London, 1988.
(61) Setchell, K. D. R. J. Am. Coll. Nutr. 2001, 20, 354S-362S.
(62) Barnes, S. J. Nutr. 1995, 125, 777S-783S.
(63) Pulliero, G.; Montin, S.; Bettini, V.; Martino, R.; Mogno, C. and Lo Castro, G. Fitoterapia 1989, 60, 69-75.
(64) Comel, M. and Laszt, L. Clinical Pharmacology: Flavonoids and the vascular wall, Karger, Basel, 1972.
(65) Samuelsson, G. Drugs of Natural Origin, Swedish Pharmaceutical Press, Kristianstad, 1999, p. 232-234.
(66) Kostanecki, S.V.; Tambor, J. Chem Ber, 1899, 32, 1921.
(67) Sawle, P.; Moulton, B. E.; Jarzykowska, M.; Green, C. J.; Foresti, R.; Fairlamb, I. J. S. and Motterlini R. Chem.
Res. Toxicol. 2008, 21, 1484–1494
(68) Calliste C. A.; Le Bail J. C.; Trouilas P.; Pouget C.; Habrioux G.; Chulia A. J.; Duroux J. L. Anticancer Res.
2001, 21, 3949-3956.
(69) Lochi, M. J. Heterocycl. 1989, 24, 1697.
(70) Stoll, R.; Renner, C.; Hansen, S.; Palme, S.; Klein, C.; Belling, A.; Zeslawski, W.; Kamionka, M.; Rehm, T.;
Mühlhahn, P.; Schumacher, R.; Hesse, F.; Kaluza, B.; Voelter, W.; Engh, R. A. and Holak, T. A. Biochemistry
2001, 40, 336-344.
(71) Kumar, S. K.; Hager, E.; Pettit, C.; Gurulingappa, H.; Davidson, N. E. and Khan, S. R. J. Med. Chem. 2003, 46,
2813-2815.
(72) Park, E. J.; Park, H. R.; Lee, J. S.; Kim, J. Planta Med. 1998, 64, 464-466.
(73) Tsukiyama, R.; Katsura, H.; Tokuriki, N.; Kobayashi, M. Antimicrob. Agents Chemother. 2002, 46, 1226-1230.
(74) Nowakowska, Z.; Kędzia, B.; Schroeder, G. Eur. J. Med. Chem. 2008, 43, 707-713
(75) Liu, X.L.; Xu, Y.J.; Go, M.L. Eur. J. Med. Chem. 2008, 43, 1681-1687.
(76) (a) Gacche, R.; Khsirsagar, M.; Kamble, S.; Bandgar, B.; Dhole, N.; Shisode, K.; Chaudhari, A. Chem. Pharm.
Bull. 2008, 56(7), 897-901; (b) (i) Boeck, P.; Leal, P.C.; Yunes, R.A.; Fiiho, V.C.; Lopez, S.; Sortino, M.;
Escalante, A.; Furlan, R.L.E.; Zacchino, S. Arch. Pharm. Chem. Life Sci. 2005, 338, 87-95; (ii) Ni, L.; Meng,
C.Q.; Sikorski, J.A. Expert Opin. Ther. Pat. 2004, 14, 1669-1691; (iii) Lopez, S.N.; Castelli, M.V.; Zacchino,
S.A.; Dominguez, J.N.; Lobo, C.; Charris-Charris, J.; Cortes, J.C.G.; Ribas, J.C.; Devia, C.; Rodriguez, A.M.;
Entriz, R.D.; Bioorg. Med. Chem. 2001, 9, 1999-2013; (iv) Opletalova, V.; Ricicarova, P.; Sedivy, D.;
Meltrova, D.; Krivakova, J. Folia Pharm. Univ. Carol. 2000, XXV, 21-33; (v) Dimmock, J.R.; Elias, D.W.;
Beazely, M.A.; Kandepu, N.M. Curr. Med. Chem. 1999, 6, 1125-1149; (vi) Opletalova, V.; Sedivy, D. Ceska
Slov. Farm. 1999, 48, 252-255.
47
(77) Barros, A. I. R. N. A.; Silva, A. M. S.; Alkortac, I. and Elguero, J. Tetrahedron 2004, 60, 6513–6521 and
references cited therein.
(78) Shoji, S.; Masatoshi, H. and Widago, B. Yakugaku Zasshi, 1960, 80, 620; Chem. Abstr. 1960, 54, 21488e.
(79) Kyogoku, K.; Hatayama, K.; Yokomori, S.; Saziki, R.; Nakane, S.; Sasajima, M.; Sawada, J.; Ohzeki, M. and
Tanaka, I. Chem. Pharm. Bull. 1979, 27(12), 2943; Chem. Abstr. 1980, 93, 26047f.
(80) Yamamoto, K.; Kakegawa, H.; Ueda, H.; Matsumoto, H.; Sudo, T.; Miki, T.; Satoh, T. Planta Med. 1992, 58,
389–393.
(81) Marmo, E.; Caputi, A. P. and Cataldi, S. Farmaco, Ed. Prat. 1973, 28(3), 132; Chem. Abstr., 1973, 79, 13501v.
(82) (a) Tsuchiya, H.; Sato, M.; Akagiri, M.; Takagi, N.; Tanaka, T. and Iinuma, M. Pharmazie, 1994, 49, 756-758;
(b) Brenner, P.D. and Meyer, J.J.M. Planta Med. 1998, 64, 777; (c) Lopez, S.N.; Castelli, M.V.; Zacchino, S.A.;
Dominguez, J.N.; Lobo, G.; Charris-Charris, J.; Cortes, J.C.G.; Ribas, J.C.; Devia, C.; Rodriguez, A.M. and
Enriz, R.D. Bioorg. Med. Chem. 2001, 9, 1999-2013
(83) Viana, G. S.; Bandeira, M. A.; Matos, F. J. Phytomedicine, 2003, 10, 189-195.
(84) Tiwar, N.; Dwivedi, B.; Nizamuddin. Boll. Chim. Farm., 1989, 128, 332-335.
(85) Wu, J. H.; Wang, X. H.; Yi, Y. H.; Lee, K. H. Bioorg. Med. Chem. Lett. 2003, 13, 1813-1815.
(86) Sogawa, S.; Nihro, Y.; Ueda, H.; Izumi, A.; Miki, T.; Matsumoto, H. and Satoh, T. J. Med. Chem. 1993, 36,
3904-3909.
(87) Bois, F.; Beney, C.; Boumendjel, A.; Mariotte, A-M.; Conseil, G. and Pietro, A.D. J. Med. Chem. 1998, 41,
4161-4164.
(88) (a) Lin, Y-M.; Zhou, Y.; Flavin, M.T.; Zhou, L-M.; Nie, W. and Chen, F-C. Bioorg. Med. Chem. 2002, 10,
2795-2802; (b) Sivakumar, P. M.; Geetha Babu, S. K.; Mukesh, D. Chem. Pharm. Bull. 2007, 55, 44-49.
(89) (a) Narender, T.; Khaliq, T.; Shweta, Nishi, Goyal, N.; Gupta, S. Bioorg. Med. Chem. 2005, 13, 6543-6550; (b)
Nielsen, S. F.; Christensen, S. B.; Cruciani, G.; Kharazmi, A.; Liljefors, T. J. Med. Chem. 1998, 41, 4819-4832;
(c) Hermoso, A.; Ignacio, A.; Jiménez; Zulma, A.; Mamani; Isabel, L.; Bazzocchi, J. E.; Piñero, A. G.; Ravelo;
Basilio, V. Bioorg. Med. Chem. 2003, 11, 3975–3980; (d) Sahu, N. P.; Pal, C.; Mandal, N. B.; Banerjee, S.;
Raha, M.; Kundu, A.P.; Basu, A.; Ghosh, M.; Roy, K.; Bandyopadhyay, S. Bioorg. Med. Chem. 2002, 10,
1687-1693.
(90) (a) Liu, M.; Wilairat, P.; Croft, S.L.; Tan, A.L.; Go, M.L. Bioorg. Med. Chem. 2003, 11, 2729–2738; (b) Boeck,
P.; Falcão, C.A.B.; Leal, P.C.; Yunes, R.A.; Cechinel, V.; Torres-Santos, E.C.; Rossi-Bergamann, B. Bioorg.
Med. Chem. 2006, 14, 1538–1545; (c) Liu, M.; Wilairat, P.; Croft, S.L.; Tan, A.L.C.; Go, M.L. Bioorg. Med.
Chem. 2003, 11, 2729–2738; (d) Andrighetti-Fröhner, C. R.; de Oliveira, K. N.; Gaspar-Silva, D.; Pacheco, L.
K.; Joussef, A. C.; Steindel, M.; Simões, C. M. O.; de Souza, A.M.T.; Magalhaes, U. O.; Afonso, I. F.;
Rodrigues, C. R.; Nunes, R. J.; Castro, H. C. Eur. J. Med. Chem. 2009, 44, 755-763
(91) (a) Ni, L.; Meng, C.Q.; Sikorski, J. Expert Opin. Ther. Pat. 2004, 14, 1669-1691; (b) Boeck, P.; Falcão, C.A.B.;
Leal, P.C.; Yunes, R.A.; Cechinel Filho, V.; Torres-Santos, V.E.C.; Rossi-Bergmann, B. Bioorg. Med. Chem.
2006, 14, 1538-1545; (c) (a) Piñero, J.; Temporal, R.M.; Silva-Gonçalves, A.J.; Jiménez, I.A.; Bazzocchi, I.L.;
Oliva, A.; Perera, A.; Leon, L.L.; Valladares, B. Acta Trop. 2006, 98, 59-65; (b) Salem, M.M.; Temporal,
K.A.J. J. Nat. Prod. 2006, 69, 43-49.
(92) Calliste, C.A.; Le Bail, J.C.; Trouillas, P.; Pouget, C.; Habrioux, G.; Chulia, A.J. and Duroux, J. Anticancer Res.
2001, 21, 3949-3956.
(93) Yamamoto, S.; Aizu, E.; Jiang, H.; Nakadate, T.; Kiyoto, I.; Wang, J.C. and Kato, R. Carcinogenesis 1991, 12,
317-323.
(94) (a) Liu, M.; Wilairat, P. and Go, M. J. Med. Chem. 2001, 44, 4443-4452; (b) Domínguez, J.N.; Charris, J.E.;
Lobo, G.; Domínguez, N.G. de; Moreno, M.M.; Riggione, F.; Sanchez, E.; Olson, J. and Rosenthal, P. Eur. J.
Med. Chem. 2001, 36, 555-560.
(95) (a) Narender, T.; Shweta, Tanvir, K.; Rao, M. S.; Srivastava, K.; Puri, S. K. Bioorg. Med. Chem. Lett. 2005, 15,
2453-2455; (b) Liu, M.; Wilairat, P.; Croft, S. L.; Tan, A. L.; Go, M. Bioorg. Med. Chem. 2003, 11, 2729- 2738;
(c) Wu, X.; Wilairat, P.; Go, M. Bioorg. Med. Chem. Lett. 2002, 12, 2299-2302; (d) Ram, V. J.; Saxena, A. S.;
Srivastava, S.; Chandra, S. Bioorg. Med. Chem. Lett. 2000, 10, 2159-2161; (e) Liu, M.; Wilairat, P.; Croft, S.L.;
Tan, A.L.; Go, M.L. Bioorg. Med. Chem. 2003, 11, 2729–2738; (f) Domínguez, J. N.; Charris, J. E.; Lobo, G.;
48
Domínguez, N. G.; Moreno, M. M.; Riggione, F.; Sanchez, E.; Olson, J.; Rosenthal, P. J. Eur. J. Med. Chem.
2001, 36, 555-560; (g) Go, M.L.; Liu, M.; Wilairat, P.; Rosenthal, P.J.; Saliba, K.J.; Kirk, K. Antimicrob. Agents
Chemother. 2004, 48, 3241-3245.
(96) Aponte, J. C.; Verástegui, M.; Málaga, E.; Zimic, M.; Quiliano, M.; Vaisberg, A. J.; Gilman, R. H. and
Hammond, G. B. J. Med. Chem. 2008, 51, 6230–6234
(97) (a) Mokle, S. S.; Sayeed, M. A.; Kothawar, Chopde, Int. J. Chem. Sci. 2004, 2, 96-100; (b) Azad, M.; Munawar,
M. A.; Siddiqui, H.L. J. Appl. Sci. 2007, 7, 2485-2489.
(98) Daskiewicz, J. B.; Comte, G.; Barron, D.; Di Petro, A. and Thomasson, F. Tetrahedron Lett. 1999, 40, 7095-
7098.
(99) Devincenzo, R.; Scambia, G.; Panici, P. B.; Ranelletti, F. O.; Bonanno, G.; Ercoli, A.; Dellemonache, F.;
Ferrari, F.; Piantelli, M. and Mancuso, S. Anti-Cancer Drug Res. 1995, 10, 481-490.
(100) Wattenberg, L. J. Cell. Biochem. Suppl. 1995, 22, 162-168.
(101) Shibata, S. Shibata Lab. Nat. Med. Mater., Minophagen Pharm. Co., Tokyo, Japan, Stem Cells (Dayton), 1994,
12(1), 44-52.
(102) (a) Nam, N. H.; Kim, Y.; You, Y. J.; Hong, D. H.; Kim, H. M.; Ahn, B. Z. J. Med. Chem. 2003, 38, 179-187; (b)
Lee, Y. S.; Lim, S. S.; Shin, K. H.; Kim, Y. S.; Ohuchi, K.; Jung, S. H. Biol. Pharm. Bull. 2006, 29, 1028-1031.
(103) Modzelewska, A.; Pettit, C.; Achanta, G.; Davidson, N. E.; Huang, P.; Khan, S. R. Bioorg. Med. Chem. 2006,
14, 3491-3495.
(104) Francesco, E.; Salvatore, G.; Luigi, M.; Massimo, C. Phytochem. 2007, 68, 939-953.
(105) (a) Jha, A.; Mukherjee, C.; Rolle, A. J.; De Clercq, E.; Balzarini, J. and Stables, J. P. Bioorg. Med. Chem. Lett.
2007, 17, 4545-4550; (b) Yit, C. C.; Das, N. P. Cancer Lett. 1994, 82, 65; (c) Satomi, Y. Int. J. Cancer 1993,
55, 506.
(106) (a) Wattenberg, L. W.; Coccia, J. B.; Galhaith, A. R. Cancer Lett. 1994, 83, 165; (b) De Vincenzo, R.; Ferlini,
C.; Distefano, M.; Gaggini, C.; Riva, A.; Bombardelli, E.; Morazzoni, P.; Valenti, P.; Belluti, F.; Ranelletti, F.
O.; Mancuso, S.; Scambia, G. Cancer Chemother. Pharmacol. 2000, 46, 305.
(107) (a) Edwards, M. L.; Stemerick, D. M.; Sunkara, S. P. J. Med. Chem. 1990, 33, 1948; (b) Achanta, G.;
Modzelewska, A.; Feng, L.; Khan, S. R.; Huang, P. Mol. Pharmacol. 2006, 70, 426.
(108) (a) Go, M. L.; Wu, X. and Liu, X. L. Curr. Med. Chem. 2005, 12(4), 483-499; (b) Miranda, C.L.; Stevens, J.F.;
Helmrich, A.; Henderson, M.C.; Rodriguez, R.J.; Yang, Y.H.; Deinzer, M.L.; Barnes, D.W.; Buhler, D.R. Food
Chem. Toxicol. 1999, 37, 271–285.
(109) (a) Shah, A.; Khan, A.M.; Qureshi, R.; Ansari, F.L.; Nazar, M.F.; Shah, S.S. Int. J. Mol. Sci. 2008, 9, 1424–
1434; (b) Boumendjel, A.; Ronot, X.; Boutonnat, J. Curr. Drug Targets 2009, 10, 363–371; (c) Katsori, A.M.;
Hadjipavlou-Latina, D. Curr. Med. Chem. 2009, 16, 1062–1081.
(110) Benvenuto, A.; Connor, T.H.; Monteith, D.K.; Laid-law, J.L.; Adams, S.C.; Matney, T.S.; Theiss, J.C. J. Pharm.
Sci. 1993, 82, 988–991; (b) Garcia, S.J.; McQuillan, A.; Panasci, L. Biochem. Pharmacol. 1988, 37, 3189–3192.
(111) Gacche, R. N.; Dhole, N. A.; Kamble, S. G.; Bandagar, B. P. J. Enzyme Inhib. Med. Chem. 2007, i, 1-4.
(112) (a) Suksamrarn, A.; Poomsing, P.; Aroonrerk, N.; Punjanon, T.; Suksamrarn, S.; Kongkun, S. Arch. Pharm. Res.
2003, 26, 816-820; (b) John, A. R.; Sukumaran, K.; Kuttan, G.; Rao, M. N. A.; Subbaraju, V.; Kuttan, R.
Cancer Lett. 1995, 97, 33-37; (c) Vaya, R.; Belinky, P. A.; Aviram, M. Free Radic. Biol. Med. 1997, 23, 302-
313; (d) Mukherjee, S.; Kumar, V.; Prasad, A. K.; Raj, H. G.; Brakhe, M. E.; Olsen, C. E.; Jain, S. C.; Parmar,
V. P. Bioorg. Med. Chem. 2001, 9, 337-339.
(113) (a) Arty, I. S.; Timmerman, H.; Samhoedi, M.; Sastrohami, D.; Sugiyanto, H.; Van Der Goot H. Eur. J. Med.
Chem. 2000, 35, 449-457; (b) Zhan, C.; Yang, J. Pharmacol. Res. 2006, 53, 303–309; (c) Ni, L.M.; Meng, C.Q.;
Sikorski, J.A. Expert Opin. Ther. Pat. 2004, 14, 1669–1691; (d) Simirgiotis, M. J.; Adachi, S.; To, S.; Yang, H.;
Reynertson, K. A.; Basile, M. J.; Gil, R. R.; Weinstein, I. B.; Kennelly, E. J. Food Chemistry 2008, 107, 813–
819.
(114) (a) Han, A. R.; Kang, Y. J.; Windono, T.; Lee, S. K. and Seo, E. K. Journal of Natural Products 2006, 69(4),
719-721; (b) Anto, R.J.; Sukumaran, K.; Kuttan, G.; Rao, M.N.A.; Subbaraju, V.; Kuttan, R. Cancer Lett. 1995,
97, 33–37.
49
(115) Mirinda, C. L.; Stevens, J. F.; Ivanov, V.; McCall, M.; Frei, B.; Deinzer, M. L.; Buhler, D. R. J. Agric. Food
Chem. 2000, 48, 3876-3884.
(116) Go, M. L.; Wu, X. and Liu, X. L. Curr. Med. Chem. 2005, 12, 481–499.
(117) (a) Makita, H.; Tanaka, T.; Fujitsuka, H.; Tatematsu, N.; Satoh, K.; Hara, A.; Mori, H. Cancer Res. 1996, 56,
4904-4909; (b) Rui, H. J. Cell. Biochem. 1997, 67, 7-11; (c) Wattenberg, L. W.; Coccia, J. B.; Galbraith, A. R.
Cancer Lett. 1994, 83, 165-169.
(118) Dominguez, J. N.; Leon, C.; Rodrigues, J.; Dominguez, N. G. D.; Gut, J.; Rosenthal, P. J. J. Med. Chem. 2005,
48, 3654-3658.
(119) Opletalova, V. Ceska Slov. Farm. 2000, 49, 278-284.
(120) (a) Lin, Y.M.; Zhou, Y.; Flavin, M.T.; Zhou, L.M.; Nie, W.; Chen, F.C. Bioorg. Med. Chem. 2002, 10, 2795–
2802; (b) Liu, X.L.; Xu, Y.J.; Go, M.L. Eur. J. Med. Chem. 2008, 43, 1681-1687.
(121) Nielsen, S.F.; Boesen, T.; Larsen, M.; Schonning, K.; Kromann, H. Bioorg. Med. Chem. 2004, 12, 3047-3054.
(122) (a) Dimmock, J. R.; Elias, D. W.; Beazely, M. A.; Kandepu, N. M. Curr. Med. Chem. 1999, 6, 1125-1149; (b)
Go, M. L.; Wu, X.; Liu, X. L. Curr. Med. Chem. 2005, 12, 483-499; (c) Nowakowska, Z. Eur. J. Med. Chem.
2007, 42, 125-137; (d) Bhakuni, D. S.; Chaturvedi, R. J. Nat. Prod. 1984, 47, 585-591.
(123) Svetaz, L.; Tapia, A.; Lopez, S. N.; Furlan, R. L. E.; Petenatti, E.; Pioli, R.; et al. J. Agricultural and Food
Chem. 2004, 52(11), 3297–3300.
(124) (a) Trivedi, J. C.; Bariwal, J. B.; Upadhyay, K. D.; Naliapara, Y. T.; Joshi, S. K.; Pannecouque, C. C.; Clercq, E.
D.; Shah, A. K. Tetrahedron Lett. 2007, 48, 8472-8474; (b) Uchiumi, F.; Hatano, T.; Ito, H.; Yoshida, T.;
Tanuma, S. I. Antiviral Res. 2003, 58, 89-98; (c) Wu, J. H.; Wang, X. H.; Yi, Y. H.; Lee, K. H. Bioorg. Med.
Chem. 2003, 13, 1813- 1818; (d) Kiat, T. S.; Pippen, R.; Yusof, R.; Ibrahim, H.; Khalid, N. and Rahman, N. A.
Bioorg. Med. Chem. Lett. 2006, 16(12), 3337–3340.
(125) (a) Statomi, Y. Int. J. Cancer 1993, 55, 506-514; (b) Yamamoto, S.; Aizu, E.; Jian, H.; Nakadate, T.; Kiyoto, I.;
Wang, J. C.; Kato, R. Carcinogenesis 1991, 12, 317-323.
(126) (a) Jahng, Y.; Zhao, L.; Moon, Y.; Basnet, A.; Kim, E.; Chang, H. W.; Ju, H. K.; Jeong, T. C.; Lee, E. S. Bioorg.
Med. Chem. Lett. 2004, 14, 2559-2562; (b) Ballesteros, J. F.; Sanz, M. J.; Ubeda, A.; Miranda, M. A.; Iborra, S.;
Paya, M.; Alcaraz, M. J. Med. Chem. 1995, 38, 2794-2797; (c) Liu, Y.C.; Hsieh, C.W.; Wu, C.C.; Wung, B.S.
Life Sci. 2007, 80, 1420–1430; (d) Hsieh, H. K.; Lee, T. H.; Wang, J. P.; Wang, J. J.; Lin, C. N. Pharm. Res.
1998, 15, 39-46; (e) Lespagnol, A.; Lespagnol, C.; Lesieur, D.; Cazin, J. C.; Cazin, M.; Beerens, H.; et al.
Chimica Therapeutica 1972, 7(5), 365–369; (f) Herencia, F.; Ferrandiz, L.; Ubeda, A.; Dominguez, J.N.;
Charris, J.; Lobo, G.M. and Alcaraz, M.J. Bioorg. Med. Chem. Lett. 1998, 8, 1169-1174; (g) Nowakowska, Z.
Eur. J. Med. Chem. 2007, 42, 125-137.
(127) (a) Xia, Y.; Yang, Z. Y.; Xia, P.; Bastow, K. F.; Nakanishi, Y.; Lee, K. H. Bioorg. Med. Chem. Lett. 2000, 10,
699-701; (b) Ducki, S.; Forrest, R.; Hadfield, J. A.; Kendall, A.; Lawrence, N. J.; McGown, A. T.; Rennison, D.
Bioorg. Med. Chem. Lett. 1998, 8, 1051-1056.
(128) (a) Kobori, M.; Iwashita, K.; Shinmoto, H.; Tsushida, T. Biosci. Biotechnol. Biochem. 1999, 63, 719-725; (b)
Sabzevari, O.; Galati, G.; Moridani, M.Y.; Siraki, A.; Brien, P.J.O. Chem. Biol. Interact. 2004, 148, 57-67; (c)
Iwashita, K.; Kobori, M.; Yamaki, K.; Tsushida, T. Biosci. Biotechnol. Biochem. 2000, 64, 1813-1820; (d) Hsu,
Y.L.; Kuo, P.L.; Lin, C.C. Life Sci. 2005, 77, 279-292.
(129) Cabrera, M.; Simoens, M.; Falchi, G.; Lavaggi, M.L.; Piro, O.E.; Castellano, E.E.; Vidal, A.; Azqueta, A.;
Monge, A.; Ceráin, A.L.; Sagrera, G.; Seoane, G.; Cerecetto, H.; González, M. Bioorg. Med. Chem. 2007, 15,
3356-3367.
(130) (a) De Vincenzo, R.; Scambia, G.; Benedetti Panici, P.; Ranelletti, F.O.; Bonanno, G.; Ercoli, A.; Monache, F.
D.; Ferrari, F.; Piantelli, M.; Mancuso, S. Anti-cancer Drug Des. 1995, 10, 481-490; (b) Shibata, S. Stem Cells
1994, 12, 44-52; (c) Yamamoto, S.; Aizu, E.; Jiang, H.; Nakadate, T.; Kiyoto, I.; Wang, J.C.; Kato, R.
Carcinogenesis 1991, 12, 317-323; (d) Satomi, Y.J. Int. J. Cancer 1993, 55, 506-514.
(131) (a) Wattenberg, L.W.; Coccia, J.B.; Galbraith, A.R. Cancer Lett. 1994, 83, 165-169; (b) Makita, H.; Tamaka, T.;
Fujitsuka, H.; Tatematsu, N.; Satoh, K.; Hara, A.; Mori, H. Cancer Res. 1996, 56, 4904-4909.
(132) Batovska, D.; Parushev, S.; Stamboliyska, B.; Tsvetkova, I.; Ninova, M.; Najdenski, H. Eur. J. Med. Chem.
2009, 44, 2211-2218.
50
(133) Opletalova, V.; Ricicarova, P.; Sedivy, D.; Meltrova, D.; Krivakova, J. Folia Pharm. Univ. Carol. 2000, XXV,
21.
(134) (a) Bowden, K.; Pozzo, A. D.; Duah, C. K. J. Chem. Res., Synop. 1990, 12, 2801-2830; (b) Lahtchev, K.;
Batovska, D.; Parushev, S.; Ubiyvovk, V.; Sibirny, A. Eur. J. Med. Chem. 2007.
doi:10.1016/j.ejmech.2007.12.2007.
(135) Lahtchev, K.L.; Batovska, D.I.; Parushev, St. P.; Ubiyvovk, V. M.; Sibirny, A.A. Eur. J. Med. Chem. 2008, 43,
2220-2228.
(136) (a) Dimmock, J.R.; Elias, D.W.; Beazely, M.A.; Kandepu, N.M. Curr. Med. Chem. 1999, 6, 1125; (b) Ni, L.;
Meng, C.Q.; Sikorski, J.A. Expert Opin. Ther. Pat. 2004, 14, 1669.
(137) Won, S. J.; Liu, C. T.; Tsao, L. T.; Weng, J. R.; Ko, H. H.; Wang, J. P.; Lin, C. N. Eur. J. Med. Chem. 2005, 40,
103-112.
(138) (a) Strachan, J.-P.; O’Shea, D. F.; Balasubramanian, T. and Lindsey, J. S. J. Org. Chem. 2000, 65(10), 3160-
3172; (b) Harborne, J. B.; Mabry, T. J.; Mabry, H. The Flavonoids; Chapman and Hall: London, 1975.
(139) (a) Mattson, A. E.; Bharadwaj, A. R.; Zuhl, A. M. and Scheidt, K. A. J. Org. Chem. 2006, 71, 5715-5724; (b)
Tafi, A.; Costi, R.; Botta, M.; Di Santo, R.; Corelli, F.; Massa, S.; Ciacci, A.; Manetti, F. and Artico, M. J. Med.
Chem. 2002, 45, 2720-2732; (c) Varga, L.; Nagy, T.; Köesdi, I.; Benet-Buchholz, J.; Dormán, G.; Ürge, L.;
Darvas, F. Tetrahedron 2003, 59, 655-662.
(140) Bhat, B. A.; Dhar, K. L.; Puri, S. C.; Saxena, A. K.; Shanmugavel, M.; Qazi, G. N. Bioorg. Med. Chem. Lett.
2005, 15, 3177-3180.
(141) (a) Azarifar, D.; Ghasemnejad, H. Molecules 2003, 8, 642-648; (b) Lévai, A. Arkivoc 2005, 9, 344-352.
(142) (a) Lakshmi, K. M.; Veda, P. B.; Venkat, R. Ch. Synth. Commun. 2005, 35, 1971-1978; (b) Lin, Y. M.; Zhou,
Y.; Flavin, M. T.; Zhou, L. M.; Nie, W.; Chen, F. C. Bioorg. Med. Chem. 2002, 10, 2795-2802; (c) Kozlowski,
D.; Trouillas, P.; Calliste, C.; Marsal, P.; Lazzaroni, R. and Duroux, J.-L. J. Phys. Chem. A 2007, 111, 1138-
1145.
(143) Arlt, W. Chem. Ber. 1964, 97, 1910.
(144) Sobenina, L. N.; Demenev, A. P.; Mikhaleva, A. I.; Trofimov, B. A. Russ. Chem. Rev. 2002, 71, 563–591.
(145) Montgomery, J.; Chevliakov, M. V.; Brielmann, H. L. Tetrahedron 1997, 53, 16449.
(146) Shibata, K.; Katsuyama, I.; Matsui, M.; Muramatsu, H. J. Heterocycl. Chem. 1991, 28, 161.
(147) El Sadek, M. M.; Faidallah, H. M.; El Soccary, N. N.; Hassan, S. Y. Egypt. J. Chem. 1995, 38, 403.
(148) Vogel, A. I. Practical Organic Chemistry, New York (1956).
(149) (a) Organic Synthesis, Coll. Vol. 2, 1943, 202; (b) Organic Synthesis 1935, 15, 17.
(150) Kleinspehn, G. G. J. Am. Chem. Soc. 1955, 77, 1546-1548.
(151) Ju-Hwa Chu, E. Chu, T. C. J. Org. Chem. 1954, 19(feb), 266-269.
(152) (a) Organic Synthesis, Coll. Vol. 3, 1955, 513; (b) Organic Synthesis 1941, 21, 67.
(153) Silverstein, Basler and Morrill Spectrometric identification of organic compounds, IV edition, 134.
(154) Varsanyi, G. Assignments for vibrational spectra of seven hundred benzene derivatives, Vol 1-2, Adam Hilger,
1974.
(155) Kavitha, E.; Sundaraganesan, N. and Sebastian, S. Ind. J. of Pure and Appl. Phy. 2010, 48(January), 20-30.
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
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
2.3 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 method.107
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:
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
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. 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
Experimental Details
Synthesis of Ethyl 4-{1-[(2-Hydrazinocarbonyl-acetyl)-hydrazono]-ethyl}-3, 5-
dimethyl-1H-pyrrole-2-carboxylate
Ethyl 4-acetyl-3, 5-dimethyl-1H-pyrrole-2-carboxylate (0.1000 g, 0.00047 mol) was
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%)
Melting point: 255ºC
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-
pyrrole-2-carboxylate
Ethyl 4-acetyl-3, 5-dimethyl-1H-pyrrole-2-carboxylate (0.1000 g, 0.00047 mol) was
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,
dichloromethane, chloroform, benzene and water.
UV-vis Spectra (DMSO): λmax 216, 299 nm
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
.
1H NMR Spectra (300 MHz, DMSO):
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).
13C NMR Spectra (75.5 MHz, DMSO):
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
Ethyl 4-acetyl-3, 5-dimethyl-1H-pyrrole-2-carboxylate (0.1000 g, 0.00047 mol) was
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%)
Melting point: 243ºC
Solubility: soluble in hot methanol and DMSO; insoluble in hexane,
dichloromethane, chloroform, benzene and water.
UV-vis Spectra (DMSO): λmax 213, 268 nm
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
.
1H NMR Spectra (300 MHz, DMSO):
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).
13C NMR Spectra (75.5 MHz, DMSO):
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-
pyrrole-2-carboxylate
Ethyl 4-acetyl-3, 5-dimethyl-1H-pyrrole-2-carboxylate (0.1000 g, 0.00047 mol) was
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%)
Melting point: 247ºC
Solubility: soluble in hot methanol and DMSO; insoluble in hexane,
dichloromethane, chloroform, benzene and water.
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
.
1H NMR Spectra (300 MHz, DMSO):
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).
13C NMR Spectra (75.5 MHz, DMSO):
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
2.4 RESULT AND DISCUSSION
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.
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:
2.4.1 Ethyl 4-{1-[(2-Hydrazinocarbonyl-acetyl)-hydrazono]-ethyl}-3, 5-dimethyl-
1H-pyrrole-2-carboxylate (71)
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. 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 N-H stretching and other bands at 1665.76, 1565.31 and 1503.94 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
NH protons in the whole molecule viz., a broad singlet at δ 11.779 ppm corresponding
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
hydrazone (C=NNH) linkage (C3), δ 13.17 and 12.26 corresponding to methyl groups
at 5 and 3-position of pyrrole ring, (C6) and (C8) respectively.
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 to N-H stretching and other bands at 1681.16, 1556.24 and 1510.86 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
deformations and their mixed modes.
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
NH protons in the whole molecule viz., a broad singlet at δ 11.778 ppm corresponding
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
methylene and methyl of the ester group in the molecule, respectively. A singlet at δ
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
hydrazone (C=NNH) linkage (C5), δ 13.19 and 12.26 corresponding to methyl groups
at 5 and 3-position of pyrrole ring, (C8) and (C9) respectively.
89
2.5 References
(1) (a) Vicini, P.; Zani, F.; Cozzini, P.; Doytchinova, I. Eur. J. Med. Chem. 2002, 37, 553-564; (b) Mamolo, M.G.;
Falagiani, V.; Zampieri, D.; Vio, L.; Banfo, E. II Farmaco 2001, 56, 587-592.
(2) Grekov, A.P. Organic Chemistry of Hydrazine. Technika Publishers, Kiev, 1966, 23.
(3) (a) Ashiq, U.; Ara, R.; Mahroof-Tahir, M.; Maqsood, Z. T.; Khan, K. M.; Khan, S. N.; Siddiqui, H. and
Choudhary, M. I. Chem. Biodivers. 2008, 5, 82-92; (b) Ara, R.; Ashiq, U.; Mahroof-Tahir, M.; Maqsood, Z. T.;
Khan, K. M.; Lodhi, M. A. and Choudhary, M. I. Chem. Biodivers. 2007, 4, 58-71.
(4) Vittorio, F.; Ronsisvalle, G.; Marrazzo, A.; Blandini, G. Farmaco 1995, 50, 265-272.
(5) Nayyar, A.; Monga, V.; Malde, A.; Coutinho, E.; Jain, R. Bioorg. Med. Chem. 2007, 15, 626-640.
(6) Sztanke, K.; Pasterhak, K.; Rzymowska, J.; Sztanke, M.; Kandefer-Szerszen, M. Eur. J. Med. Chem. 2007,
43(2), 404-419.
(7) Radhwan, M. A. A.; Ragab, E.A.; Sabry, N.M.; El-Shenawy, S.M. Bioorg. Med. Chem. 2007, 15, 3832-3841.
(8) Leite, A. C. L.; Lima, R. S. D.; Moreira, D. R.; Cardoso, M. V.; Brito, A. C. G. D.; Santos, L. M. F. D.;
Hernandes, M. Z.; Kipustok, A. C.; Lima, R. S. D.; Soares, M. B. P. Bioorg. Med. Chem. 2006, 14, 3749-3757.
(9) Gemma, S.; Kukreja, G.; Fattorusso, C.; Persico, M.; Romano, M. P.; Altarelli, M.; Savini, L.; Campiani, G.;
Fattorusso, E.; Basilico, N.; Taramelli, D.; Yardley, V.; Butini, S. Bioorg. Med. Chem. Lett. 2006, 16, 5384-
5388.
(10) Al-Mawsawi, L. Q.; Dayam, R.; Taheri, L.; Witvrouw, M.; Debyser, Z.; Neamati, N. Bioorg. Med. Chem. Lett.
2007, 17, 6472-6475.
(11) (a) Zheng, X.; Li, Z.; Wang, Y.; Chen, W.; Huang, Q.; Liu, C. and Song, G. J. Fluorine Chem. 2003, 117, 163-
169; (b) Al-Talib, M.; Tastoush, H. and Odeh, N. Synth. Commun. 1990, 20, 1811-1814.
(12) (a) Yousif, M. Y.; Ismail, A. M.; Elman, A. A. and El-Kerdawy, M. M. J. Chem. Soc. Pak. 1986, 8, 183-187;
(b) Ahmad, R.; Iqbal, R.; Akhtar, R. H.; Haq, Z. U.; Duddeck, H.; Stefaniak, L. and Sitkowski, J. Nucleosides
Nucleotides Nucleic Acids 2001, 20, 1671-1682; (c) Al-Soud, Y. A.; Al-Deeri, M. N. and Al-Mosoudi, N. A.
Farmaco 2004, 59, 775-783; (d) El-Emam, A. A.; Al-Deeb, O. A.; Al-Omar, M. and Lehmann, J. Bioorg. Med.
Chem. 2004, 12, 5107-5113.
(13) (a) Koz’minykh, V. O. Pharm. Chem. J. 2006, 40, 8-17; (b) Kidawi, M.; Misra, P.; Kumma, R.; Saxena, R. K.;
Gupta, R.; Bardoo, S. Monatsh. Chem. 1998, 129, 961-965; (c) Fuquang, L. I. U.; Palmer, D.C.; Sorgi, K. L.
Tetrahedron Lett. 2004, 45, 1877-1880; (d) Demirbas, N.; Ugurluoglu, R.; Demirbas, A. Bioorg. Med. Chem.
2002, 10, 3717-3723; (e) Holla, B.S.; Akberali, P.M.; Shivananda, M.K. Farmaco 2001, 56, 919-927.
(14) (a) Aboul-Fadl, T.; Mohammed, F.A.; Hassan, E.A. Arch. Pharm. Res. 2003, 26, 778-784; (b) Hussein, M.A.;
Aboul-Fadl, T.; Hussein, A. Bull. Pharm. Sci. Assiut Univ. 2005, 28, 131-136; (c) Abdel-Aziz, H.A.; Hamdy,
N.A.; Farag, A.M.; Fakhr, I.M.I. J. Chin. Chem. Soc. 2007, 54, 1573-1582; (d) Abdel-Aziz, H.A.; Gamal-
Eldeen, A.M.; Hamdy, N.A.; Fakhr, I.M.I. Arch. Pharm. 2009, 342, 230-237; (e) Abdel-Aziz, H.A.; Abdel-
Wahab, B.F.; Badria, F.A. Arch. Pharm. 2010, 343, 152-159.
(15) (a) Abdel-Aziz, H. A.; Mekawey, A. A. I. Eur. J. Med. Chem. 2009, 44, 3985-4997; (b) Abdel-Aziz, H. A.;
Mekawey, A. A. I.; Dawood, K. M. Eur. J. Med. Chem. 2009, 44, 3637-3644.
(16) (a) Abdel-Wahab, B.F.; Abdel-Aziz, H.A.; Ahmed, E.M. Monatsh. Chem. 2009, 140, 601-605; (b) Abdel-
Wahab, B.F.; Abdel-Aziz, H.A.; Ahmed, E.M. Arch. Pharm. 2008, 341, 734-739.
(17) Rollas, S.; Küçükgüzel, S. G. Molecules 2007, 12, 1910.
(18) Mickevičius, V.; Vaickelionienė, R. Chem. Heterocycl. Comp. 2008, 44, 170.
(19) (a) Theocharis, A. B.; Alexandrou, N. E. J Heterocycl Chem 1990, 27, 1685; (b) Charistos, D. A.; Vagenas, G.
V.; Tzavellas, L. C.; Tsoleridis, C. A.; Rodios, N. A. J Heterocycl Chem 1994, 31, 1593; (c) James, C. A.;
Poirier, B.; Grisé, C.; Martel, A.; Ruediger, E. H. Tetrahedron Lett 2006, 47, 511.
(20) (a) Karthikeyan, M. S.; Holla, B. S.; Kalluraya, B.; Kumari, N. S. Monatsh Chem 2007, 138, 1309; (b)
Karabasanagouda, T.; Adhikari, A. V.; Shetty, N. S. Eur J Med Chem 2007, 42, 521.
(21) Pintilie, O.; Profire, L.; Sunel, V.; Popa, M.; Pui, A. 2007, Molecules 12, 103.
90
(22) Quraishi, M. A.; Ahamad, I.; Lal, B. and Singh, V. The Arabian Journal for Science and Engineering, 2009,
34(2A)(July), 87-92.
(23) (a) Desai, M. N.; Shah, V. K. and Gandhi, M. H. Anti-Corros. Meth. Mater. 1974, 21, 10-12; (b) Quraishi, M.
A.; Jamal, D. and Saeed, M. T. J. Am. Oil Chem. Soc. 2000, 77, 265-268; (c) Quraishi, M. A.; Bhardwaj, V. and
Rawat, J. J. Am. Oil Chem. Soc. 2002, 79, 603-609.
(24) Machkhoshvili, R. I. Coordinative compounds of metals with hydrazines. Doctoral Thesis. M.; 1983, p.457.
(25) Patent of France 2213271. Cl.C 22 B 3/00//C 22 B5/0. Les sels de hydrazides, leurs obtention et application/
Ciba-Geigi AG (Suisse).
(26) Ouelleta, M.; Aitkenb, S. M.; Englishc, A. M. and Percivala, M. D. Arch. Biochem. Biophys. 2004, 431, 107-
118.
(27) (a) Abel-Aziza, H. A.; Abel-Wahab, B. F.; Badira, F. A. Arch. Pharm; (Weinheim) 2010, 343, 152; (b) Zheng,
L.; Wub, L.; Zhao, B.; Dong, W.; Miao, J. Bioorg. Med. Chem. 2009, 17, 1957; (c) Xia, Y.; Fan, C.; Zhao, B.;
Zhao, J.; Shin, D.; Miao, J. Eur. J. Med. Chem. 2008, 43, 2347; (d) Dimmocka, J. R.; Vashishthaa, S. C.;
Stablesb, J. P. Eur. J. Med. Chem. 2000, 35, 241.
(28) (a) Narasimhan, B.; Kumar, P.; Sharma, D. Acta Pharm. Sci. 2010, 52, 169; (b) Chandrakantha, B.; Shetty, P.;
Nambiyar, V.; Isloor, N.; Isloor, A. M. Eur. J. Med. Chem. 2010, 45, 1206; (c) Reichelt, A.; Falsey, J. R.;
Rzasa, R. M.; Thiel, O. R.; Achmatowicz, M. M.; Larsen, R. D.; Zhang, D. Org. Lett. 2010, 12, 792; (d) Abd-
alla, S. M.; Hegab, M. I.; Abo-Taleb, N. A.; Hasabelnaby, S. M.; Goudah, A. Eur. J. Med. Chem. 2010, 45,
1267.
(29) Wang, L.; Liu, X.; Yang, C.; Zhao S. and Li, K. Acta. Cryst. 2011, E67, o493.
(30) (a) Di Grandi, M. J.; Curran, K. J.; Feigelson, G.; Prashad, A.; Ross, A. A.; Visalli, R.; Fairhurst, J.; Feld, B.;
Bloom, J. D. Bioorg. Med. Chem. Lett. 2004, 14, 4157-4160; (b) Han, T.; Cho, J. H.; Oh, C. H. Eur. J. Med.
Chem. 2006, 41, 825-832; (c) Kaymakçioglu, B. K.; Rollas, S.; Körceg ez, E.; Ari ci og lu. F. Eur. J. Pharm.
Sci. 2005, 26, 97-103.
(31) Rostom, S. A. F. Bioorg. Med. Chem. 2006, 14, 6475-6485.
(32) Heck, R.; Marsura, A. Tetrahedron Lett. 2003, 44, 1533-1536.
(33) Cao, C. L.; Ye, M. C.; Sun, X. L.; Tang, Y. Org. Lett. 2006, 8, 2901-2904.
(34) Liu, K.; Cui, H. F.; Nie, J.; Dong, K. Y.; Li, X. J.; Ma, J. A. Org. Lett. 2007, 9, 923-925.
(35) Wang, X. M.; Zhu, T.; Zheng, L. Y.; Li, Y. X.; Zheng, J. F.; Zhang, S. Q.; Bai, J. Chin. J. Org. Chem. 2006, 26,
660-665.
(36) Armbruster, F.; Klingebiel, U.; Noltemeyer, M. Z. Naturforsch 2006, 61b, 225.
(37) Senturk, O. S.; Sert, S.; Ozdemir, U. Z. Naturforsch 2003, 58b, 1124.
(38) (a) Amr, A. E. G. E.; Mohamed, A. M.; Ibrahim, A. A. Z. Naturforsch 2003, 58b, 861; (b) Mohrle, H.; Keller,
G. Z. Naturforsch 2003, 58b, 885; (c) Rollas, S.; Küçükgüzel, S.G. Molecules, 2007, 12, 1910-1939.
(39) (a) Chakraborty, J.; Singh, R. K. B.; Samanta, B.; Choudhury, C. R.; Dey, S. K.; Talukder, P.; Borah, M. J.;
Mitra, S. Z. Naturforsch 2006, 61b, 1209; (b) Lozan, V.; Lassahn, P.-G.; Zhang, C.; Wu, B.; Janiak, C.;
Rheinwald, G.; Lang, H. Z. Naturforsch 2003, 58b, 1152; (c) Zeyrek, C. T.; Elmali, A.; Elerman, Y. Z
Naturforsch 2006, 61b, 237; (d) Dey, D. K.; Samanta, B.; Lycka, A.; Dahlenburg, L. Z. Naturforsch 2003, 58b,
336.
(40) Janiak, C.; Lassahn, P.-G.; Lozan, V. Macromol. Symp. 2006, 236, 88.
(41) Ragavendran, J.; Sriram, D.; Patel, S.; Reddy, I.; Bharathwajan, N.; Stables, J.; Yogeeswari, P. Eur. J. Med.
Chem. 2007, 42, 146.
(42) Ergenc, N.; Gunay, N. S. Eur. J. Med. Chem. 1998, 33, 143.
(43) Todeschini, A.R.; Miranda, A.L.; Silva, C.M.; Parrini, S.C.; Barreiro, E. J. Eur. J. Med. Chem. 1998, 33, 189.
(44) Gemma, S.; Kukreja, G.; Fattorusso, C.; Persico, M.; Romano, M. et. al. Bioorg. Med. Chem. Lett. 2006, 16,
5384.
(45) Bijev, A. Lett. Drug. Des. Discov. 2006, 3, 506.
91
(46) Gursoy, E.; Guzeldemirci-Ulusoy, N. Eur. J. Med. Chem. 2007, 42, 320.
(47) (a) Masunari, A.; Tavaris, L. C. Bioorg. Med. Chem. 2007, 15, 4229; (b) Loncle, C.; Brunel, J.; Vidal, N.;
Dherbomez, M.; Letourneux, Y. Eur. J. Med. Chem. 2004, 39, 1067; (c) Kucukguzel, S.G.; Mazi, A.; Sahin,
F.; Ozturk, S.; Stables, J. P. Eur. J. Med. Chem. 2003, 38, 1005; (d) Vicini, P.; Zani, F.; Cozzini, P.;
Doytchinova, I. Eur. J. Med. Chem. 2002, 37, 553.
(48) Katyal , M.; Dutt, Y. Talanta 1975, 22, 151.
(49) (a) Mohan, M.; Gupta, M. P.; Chandra, L.; Jha, N. K. Inorg. Chim. Acta 1988, 151, 61; (b) Sinh, R. B.; Jain, P.
Talanta 1982, 29, 77.
(50) Ulbrich, K.; Subr, V. Adv. Drug Del. Rev. 2004, 56, 1023-1050.
(51) Molodykh, Zh. V.; Buzykin, B. I.; Bystrykn, N. N.; Kitaev, Y. P. Khim. Farm. Zh. 1978, 11, 37.
(52) (a) Suez, I.; Pehkonen, S. O.; Hoffmann, M. R. Sci. Technol. 1994, 28, 2080; (b) Terra, L. H.; Areias, A. M. C.;
Gaubeur, I.; SuezIha, M. E. V. Spectroscopy Letters 1999, 32, 257.
(53) (a) Kutyrev, A.; Kappe, T. J. Heter. Chem. 1997, 34, 969-972; (b) Nishino, H.; Ishida K.; Hashimoto, H.;
Kurosawa, K. Synthesis, 1996, 888-896; (c) Sotriffer, C. A.; Ni, H.; McCammon, A. J. J. Am. Chem. Soc. 2000,
122, 6136-6137; (d) Ni, H.; Sotriffer, C. A.; McCammon, A. J. J. Med. Chem. 2001, 44, 3043-3047; (e)
Semenova, E. A.; Marchand, C.; Pommier, Y. Adv. Pharmacol. 2008, 56, 199-228; (f) Sechi, M.; Bacchi, A.;
Carcelli, M.; Compari, C.; Duce, E.; Fisicaro, E.; et al. J. Med. Chem. 2006, 49, 4248-4260; (g) Grimm, J.;
Harrington, P.; Heidebrecht, R.; Jr Miller, T.; Otte, K.; Siliphaivanh, P.; et al. PCT Int Appl, WO 2007002248;
2007.
(54) (a) Neamati, N.; Lin, Z.; Karki, R. G.; Orr, A.; Cowansage, K.; Strumberg, D. J. Med. Chem. 2002, 45, 5661-
5670. (b) David, L.; Rusu, M.; Cozar, O.; Rusu, D.; Todica, M.; Balan, C. J. Mol. Struct. 1999, 482-483; (c)
Shulgin, V. F.; Pevzner, N. S.; Zub, V. Y.; Strizhakova, N. G.; Maletin, Y. A. Inorg. Chem. Comm. 2001, 3,
134-137; (d) Neamati, N.; Marchand, C.; Pommier, Y. In Advances in Pharmacology, Academic Press San
Diego, USA, 2000, 49, 147-165.
(55) (a) Cavier, R.; Rips, R. J. Med. Chem. 1965, 8(5), 706-708; (b) Martynovskii, A. A.; Samura, B. A.; et al. Khim.
Farm. Zh. 1990, 24(7,113), 31-32; (c) Strokin, Yu. V.; Karasovskii, I. A.; et al. Khim. Farm. Zh. 1990, 24(7),
45-48.
(56) (a) Ragavendran, J.; Sriram, D.; Patel, S.; Reddy, I.; Bharathwajan, N.; Stables, J.; Yogeeswari, P. Eur. J.
Med. Chem. 2007, 42, 146-151; (b) Salgin-Goksen, U.; Gokhan-Kelekci, N.; Goktas, O.; Koysal, Y.; Kilic, E.;
Isik, S.; et al. Bioorg. Med. Chem. 2007, 15, 5738-5751; (c) Kucukguzel, S. G.; Mazi, A.; Sahin, F.; Ozturk, S.;
Stables, J. P. Eur. J. Med. Chem. 2003, 38, 1005-1009; (d) Loncle, C.; Brunel, J.; Vidal, N.; Dherbomez, M.;
Letourneux, Y. Eur. J. Med. Chem. 2004, 39, 1067-1071; (e) Amos, B. S. J. Org. Chem. 2008, 73(4), 1201-
1208; (f) Sreeja, P. B. and Prathapachandra Kurup, M. R. Spectrochimica Acta Part A, Molecular and
Biomolecular Spectroscopy 2005, 61(1), 331-336.
(57) Uchida, K. Free Radic. Biol. Med. 2000, 28, 1685-1696.
(58) Omar, A.; Mohsen, M. E.; Farghaly, A. M.; Hazzai, A. A. B.; Eshba, N. H. Pharmazie, 1980, 95, 25382a.
(59) (a) Rollas, S.; Kucukguzel, S. G. Molecules, 2007, 12, 1910-1939; (b) Kaymakcioglu, K. B.; Oruc, E. E.;
Unsalan, S.; Kandemirli, F.; Shvets, N.; Rollas, S.; et al. Eur. J. Med. Chem. 2006, 41, 1253-1261; (c)
Shivananda, W. Eur J Med Chem, 2009, 44(3), 1135-1143.
(60) Kalsi, R.; Shrimali, M.; Bhalla, T. N.; Barthwal, J. P. Indian J. Pharm. Sci. 2006, 41, 353-359.
(61) Masunari, A.; Tavares, L. C. Bioorg. Med. Chem. 2007, 15, 4229-4236.
(62) (a) Shriram, D.; Yogeeswari, P; Madhu, K. Bioorg. Med. Chem. Lett. 2005, 15, 4502-4505; (b) Bijev, A. Lett.
Drug. Des. Discov. 2006, 3, 506-512.
(63) Singh, V.; Srivastava, V. K.; Palit, G.; Shanker, K. Arzneim- Forsch Drug Res. 1992, 42, 993- 996.
(64) Bernardino, A.; Gomes, A.; Charret, K.; Freitas, A.; Machado, G.; Canto- Cavalheiro, M.; et al. Eur. J. Med.
Chem. 2006, 41, 80-87.
(65) Silva, A. G.; Zapata-Suto, G.; Kummerle, A. E.; Fraga, C. A. M.; Barreiro, E. J.; Sudo, R. T. Bioorg. Med.
Chem. 2005, 13, 3431-3437.
92
(66) (a) Eissa, A. A. M. Bioorg. Med. Chem. 2009, 17(14), 5059-5070; (b) Rasras, A. J. M. Eur. J. Med. Chem.
2010, 45(6), 2307-2313.
(67) Sriram, D. Bioorg. Med. Chem. Lett. 2005, 15(20), 4502-4505.
(68) (a) Nayyar, A.; Jain, R. J. Med. Chem. 2005, 12, 1873-1886; (b) Scior, T.; Garces-Eisele, S. J. Curr. Med.
Chem. 2006, 13, 2205-2219; (c) Janin, Y. Bioorg. Med. Chem. 2007, 15, 2479-2513; (d) Ulusoy, N.; Gursoy,
A.; Otuk, G.; Kiraz, M. IL Farmaco 2001, 56, 947-952; (e) Linhong, J.; Jiang, C.; Baoan, S.; Zhuo, C.; Song,
Y.; Qianzhu, L.; et al. Bioorg. Med. Chem. Lett. 2006, 16, 5036-5040; (f) Caleta, I.; Grdisa, M.; Mrvos, D. S.;
Cetina, M.; Tralic, K. V.; Pavelic, K.; et al. IL Farmaco 2004, 59, 297-305; (g) Geoffrey, W.; Tracey, D. B.;
Patrizia, D.; Angela, S.; Dong, F. S.; Andrew, D. W.; et al. Bioorg. Med. Chem. Lett. 2000, 10, 513-515; (h)
Terzioglu, N.; Gursoy, A. Eur. J. Med. Chem. 2003, 38, 781-786; (i) Hall, I. H. Anticancer Drugs 1995, 6(1),
147-53.
(69) (a) Savini, L.; Chiasserini, L.; Travagli, V.; Pellerano, C.; Novellino, E.; Cosentino, S.; et al. Eur. J. Med.
Chem. 2004, 39, 113-122; (b) Sechi, M.; Azzena, U.; Delussu, M. P.; Dallocchio, R.; Dessì, A.; Cosseddu, A.;
et. al. Molecules 2008, 13, 2442-2461; (c) Neamati, N. Expert. Opin. Ther. Pat. 2002, 12, 709-724; (d) Cotelle,
P. Recent Patents Anti-Infect Drug Disc. 2006, 1, 1-15; (e) Wang, Y.; Serradell, N.; Bolos, J.; Rosa, E. Drugs
Fut. 2007, 32, 118-122; (f) Pais, G. C. G.; Burke, T. R. Drugs Fut. 2002, 27, 1101-1111.
(70) (a) Singh, N. K.; Singh, S. B. Indian J. Chemistry. 2001, 40(10), 1070-1075; (b) Afrasiabi, Z.; Sinn, E. J. Chem.
Inorg. Chim. Acta. 2004, 357(1), 271-278; (c) Labisbal, E.; Haslow, K. D.; Sousa-Pedrares, A.; Valdes-
Martinez, J.; Hernandez-Ortega, S.; West, D. X.. Polyhedron 2003, 22(20), 2831-2837; (d) Ajay kumar, D. K.;
Sangamesh, A. P.; Prema, S. B. Int. J. Electrochem. Sci. 2009, 4, 717-729; (e) Singh, R. V.; Fahmi, N.; Biyala,
M. K. J. Iran. Chem. Soc. 2005, 2(1), 40-46.
(71) (a) Joshi, S. D.; Vagdevi, H. M.; Vaidya, V. P.; Gadaginamath, G. S. Eur. J. Med. Chem. 2008, 43, 1989-1996;
(b) Mamolo, M. G. Farmaco 2003, 78, 631-637.
(72) (a)Johnson, D. K.; Murphy, T. B.; Rose, N. J.; Goodwin, W. H.; Pickart, L. Inorg. Chim. Acta 1982, 67, 159-
165; (b) Pickart, L.; Goodwin, W. H.; Burgua, W.; Murphy, T. B.; Johnson, D. K. Biochem. Pharmacol. 1983,
32, 3868-3871.
(73) Arapov, O. V.; Alferva, O. F.; Levocheskaya, E. I.; Krasil’nikov, I. Radiobiologiya 1987, 27, 843-846.
(74) Rollas, S.; Gülerman, N.; Erdeniz, H. Farmaco 2002, 57, 171-174.
(75) Küçükgüzel, S. G.; Rollas, S.; Küçükgüzel, I ; Kiraz, M. Eur. J. Med. Chem. 1999, 34, 1093-1100.
(76) Küçükgüzel, S.G.; Oruç E.E.; Rollas S.; Sahin, F.; Özbek, A. Eur. J. Med. Chem. 2002, 37, 197-206.
(77) (a) Bukowski, L.; Janowiec, M.; Zwolska-Kwiek, Z.; Andrzejczyk, Z. Pharmazie 1999, 54, 651-654; (b) Sriram,
D.; Yogeeswari, P.; Madhu, K. Bioorg. Med. Chem. 2006, 14, 876-878.
(78) Li, C. H.; Wang, Q.; Xu, Y. Q.; Hu, C. W. Chin. J. Struct. Chem. 2008, 27, 187-190.
(79) Kuriakose, M.; Prathapachandra Kurup, M. R. and Suresh, E. Polyhedron, 2007, 26(12), 2713-2718.
(80) Vidrio, H.; Fernandez, G.; Medina, M.; Alvarez, E.; Orallo, F.; Vascul Pharmacol. 2003, 40, 13.
(81) El-Tabl, A. S.; El-Saied, F. A.; Plass, W. and Al-Hakimi, A. N. Spectrochimica Acta A 2008, 71(1), 90-99.
(82) (a) El-Behery, M. and El-Twigry, H. Spectrochimica Acta A 2007, 66(1), 28-36; (b) Bessy Raj, B. N. and
Kurup, M. R. P. Spectrochimica Acta A 2007, 66(4-5), 898-903.
(83) Vasilikiotis, G. S. and Stratis, J. Analytica Chimica Acta 1975, 75(1), 227-230.
(84) Park, C. I. and Cha, K.W. Talanta 1998, 46(6), 1515-1523.
(85) Silva, M. and Valcárcel, M. The Analyst 1980, 105(248), 193-202.
(86) (a) Ganjali, M. R.; Matloobi, P.; Ghorbani, M.; Norouzi, P. and Salavati-Niasari, M. Bulletin of the Korean
Chemical Society 2005, 26(1), 38-42; (b) Ganjali, M. R.; Norouzi, P.; Daftari, A.; Faridbod, F. and Salavati-
Niasari, M. Sensors and Actuators B 2007, 120(2), 673-678; (c) Ganjali, M. R.; Mirnaghi, F. S.; Norouzi, P. and
Adib, M. Sensors and Actuators B 2006, 115(1), 374-378; (d) Zamani, H. A.; Ganjali, M. R.; Norouzi, P.; Adib,
M. and Aceedy, M. Analytical Sciences 2006, 22(7), 943-948; (e) Zamani, H. A.; Ganjali, M. R. and Adib, M.
Sensors and Actuators B 2007, 120(2), 545-550.
(87) (a) Shao, J.; Lin, H.; Yu, M.; Cai, Z. and Lin, H. Talanta 2008, 75(2), 551-555; (b) Gupta, V. K.; Goyal, R. N.
and Sharma, R. A. Talanta 2008, 76(4), 859-864.
93
(88) (a) Kasai, K.; Aoyagi, M.; Fujita, M. J. Am. Chem. Soc. 2000, 122, 2140-2141; (b) Kitagawa, S.; Kitaura, R.;
Noro, S. I. Angew. Chem. Int. Ed. 2004, 43, 2334-2375; (c) Hoshino, N.; Ito, T.; Nihei, M.; Oshio, H. Inorg.
Chem. Commun. 2003, 6, 377-380; (d) Khandar, A. A.; Nejati, K. Polyhedron 2000, 19, 607-613.
(89) (a) Tozkoparan, B.; Gökhan, N.; Aktay, G.; Yesilada, E.; Ertan, M. Eur. J. Med. Chem. 2000, 35, 743-750; (b)
Demirbas, N.; Ugurluoglu, R.; Demirbas, A. Bioorg. Med. Chem. 2002, 10, 3717-3723; (c) Holla, B. S.;
Akberali, P. M.; Shivananda, M. K. Farmaco 2001, 56, 919-927; (d) Holla, B. S.; Kalluraya, B.; Sridhar, K. R.;
Drake, E.; Thomas, L. M.; Bhandary, K. K.; Levine, M. J. Eur. J. Med. Chem. 1994, 29, 301-308; (e) Dawood,
K. M.; Farag, A. M.; Abdel-Aziz, H. A. J. Chin. Chem. Soc. 2006, 53, 873-880.
(90) (a) Dawood, K. M.; Farag, A. M.; Abdel-Aziz, H. A. Heteroatom Chem. 2005, 16, 621-627; (b) Dawood, K.
M.; Farag, A. M.; Abdel-Aziz, H. A. Heteroatom Chem. 2007, 18, 294; (c) Farag, A. M.; Dawood, K. M.;
Abdel-Aziz, H. A. J. Chem. Res. 2004, 808-810; (d) Dawood, K. M.; Farag, A. M.; Abdel-Aziz, H. A. J. Chem.
Res. 2005, 378-381.
(91) Singh, V.; Srivastava, V.K.; Palit, G.; Shanker, K. Arzneim-Forsch. Drug. Res. 1992, 42, 993-996.
(92) Ergenç, N.; Günay, N.S. Eur. J. Med. Chem. 1998, 33, 143-148.
(93) (a) Rollas, S.; Gülerman, N.; Erdeniz, H. Farmaco 2002, 57, 171-174; (b) Rollas, S. and Küçükgüzel, S. G.
Molecules 2007, 12(8), 1910-1939; (c) Durgun B. B.; Çapan G.; Ergenç, N.; Rollas, S. Pharmazie 1993, 48,
942-943.
(94) Dooan H.N.; Duran, A.; Rollas, S. ; Sener, G. ; Armutak, Y.; Keyer-Uysal, M. Med. Sci. Res. 1998, 26, 755-758.
(95) Kalsi, R.; Shrimali, M.; Bhalla, T.N.; Barthwal, J.P. Indian J. Pharm. Sci. 2006, 41, 353-359.
(96) Andrade, M. M. and Barros, M. T. J. Comb. Chem. 2010, 12, 245-247.
(97) Mohareb, R. M.; Ibrahim, R. A. and Moustafa, H. E. The Open Org. Chem.J. 2010, 4, 8-14.
(98) Mabkhot, Y. N.; Barakat, A.; Al-Majid, A. M.; Al-Othman, Z. A. and Alamary, A. S. Int. J. Mol. Sci. 2011, 12,
7824-7834.
(99) (a) von Richter, V. Chem. Ber. 1883, 16, 677-683; (b) Li, J.-J.; Cook, J. M. Name Reactions in Heterocyclic
Chemstry; Wiley-Interscience, Hoboken, NJ, 2005; 540-543; (c) Vasilevsky, S. F.; Tretyakov, E. V. Liebigs
Ann. 1995, 775-779; (d) Schofield, K.; Swain, T. J. Chem. Soc. 1949, 2393-2399; (e) Kimball.; D. B.; Hayes, A.
G.; Haley, M. M. Org. Lett. 2000, 2, 3825-3827.
(100) (a) Barber, H. J.; Washbourn, K.; Wragg, W. R.; Lunt, E. J. Chem. Soc. 1961, 2828-2843; (b) Shoup, R. R.;
Castle, R. N. J. Heterocycl. Chem. 1965, 2, 63-66; (c) Al-Awadi, N. A.; Elnagdi, M. H.; Ibrahim, Y. A.; Kaul,
K.; Kumar, A. Tetrahedron 2001, 57, 1609-1614; (d) Sereni, L.; Tato´ , M.; Sola, F.; Brill, W. K.-D.
Tetrahedron 2004, 60, 8561-8577 .
(101) (a) Miyamoto, T.; Matsumoto, J. Chem. Pharm. Bull. 1988, 36, 1321-1327; (b) Sandison, A. A.; Tennant, G. J.
Chem. Soc.; Chem. Commun. 1974, 752-753; (c) Ames, D. E.; Leung, O. T.; Singh, A. G. Synthesis 1983, 52-53
.
(102) Hasegawa, K.; Kimura, N.; Arai, S. and Nishida, A. J. Org. Chem. 2008, 73, 6363-6368.
(103) (a) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods for Organic Synthesis with Diazo
Compounds; Wiley Interscience, New York, 1998; (b) Ye, T.; McKervey, M. A. Chem. Rev . 1994, 94, 1091-
1160; (c) Zhao, Y.; Wang, J. Synlett 2005, 2886-2892; (d) Yasui, E.; Wada, M.; Takamura, N. Tetrahedron Lett.
2006, 47, 743-746 .
(104) (a) Arai, S.; Hasegawa, K.; Nishida, A. Tetrahedron Lett. 2004, 45, 1023-1026; 2005, 46, 6171; (b) Hasegawa,
K.; Arai, S.; Nishida, A. Tetrahedron 2006, 62, 1390-1401.
(105) Mikhed’kina, E. I.; Bylina, O. S.; Mel’nik, I. I. and Kozhich, D. T. Russ. J. Org. Chem. 2009, 45(4), 564-571.
(106) Mohareb, R. M.; El-Arab, E. E.; El-Sharkawy, K. A. Sci Pharm. 2009, 77, 355-366.
(107) Vogel, A. I. Practical Organic Chemistry, New York (1956).
(108) Vogel, A. I. Practical Organic Chemistry, New York (1956), 344.
(109) Silverstein, Basler and Morrill Spectrometric identification of organic compounds, IV edition, 134.
(110) Varsanyi, G. Assignments for vibrational spectra of seven hundred benzene derivatives, Vol 1-2, Adam Hilger,
1974.
94
(111) Kavitha, E.; Sundaraganesan, N. and Sebastian, S. Indian Journal of Pure and Applied Physics 2010,
48(January), 20-30.
(112) Silverstein, Basler and Morrill Spectrometric identification of organic compounds, IV edition, 133.
(113) Silverstein, Basler and Morrill Spectrometric identification of organic compounds, IV edition, 132.
(114) Silverstein, Basler and Morrill Spectrometric identification of organic compounds, IV edition, 129.
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
3.2 Basis of work and objectives of the present investigations
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
3.3 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 method.80
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
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
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 DMSO unless otherwise stated. The chemical shift values
are expressed in δ scale.
118
Experimental Details
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%)
Melting point: 271ºC
Solubility: soluble in DMSO; insoluble in hexane, dichloromethane, chloroform,
benzene, methanol, ethanol and water.
UV-vis Spectra (DMSO+Ethanol): λmax 369 nm
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
.
1H NMR Spectra (300 MHz, DMSO):
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%)
Melting point: 263ºC
Solubility: soluble in DMSO; insoluble in hexane, dichloromethane, chloroform,
benzene, methanol, ethanol and water.
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
.
1H NMR Spectra (300 MHz, DMSO):
12.588 (1H, br, s, NH proton of CONHNH2), 12.057 (1H, br, s, NH proton of
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
CONHNH2), 4.290, 4.266, 4.242 & 4.220 (2H, q, J = 7.0 Hz, methylene 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
Ethyl α-cyano-5-formyl-2-pyrroleacrylate (0.0218 g, 0.0001 mole) was dissolved in
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%)
Melting point: 269ºC
Solubility: soluble in DMSO; insoluble in hexane, dichloromethane, chloroform,
benzene, methanol, ethanol and water.
UV-vis Spectra (DMSO+Ethanol): λmax 372 nm
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
1H NMR Spectra (300 MHz, DMSO):
12.818 (1H, br, s, NH proton of CONHNH2), 12.421 (1H, br, s, NH proton of
C=NNH), 11.012 (1H, br, s, py-N-H proton), 8.155 (1H, s, vinyl proton attached to
cyanoester groups), 7.908 (1H, s, vinyl proton attached to hydrazone linkage), 7.444
& 7.417 (2H, d, J = 8.1 Hz, py-3 C-H & -4 C-H), 5.389 (2H, s, NH2 protons of
CONHNH2), 4.290, 4.266, 4.244 & 4.220 (2H, q, J = 7.0 Hz, methylene protons of
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%)
Melting point: 274ºC
123
Solubility: soluble in DMSO; insoluble in hexane, dichloromethane, chloroform,
benzene, methanol, ethanol and water.
UV-vis Spectra (DMSO+Ethanol): λmax 261, 370 nm
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
.
1H NMR Spectra (300 MHz, DMSO):
12.589 (1H, br, s, NH proton of CONHNH2), 12.059 (1H, br, s, NH proton of
C=NNH), 10.909 (1H, br, s, py-N-H proton), 8.156 (1H, s, vinyl proton attached to
cyanoester groups), 7.922 (1H, s, vinyl proton attached to hydrazone linkage), 7.440
& 7.419 (2H, d, J = 6.3 Hz, py-3 C-H & -4 C-H), 5.462 (2H, s, NH2 protons of
CONHNH2), 4.289, 4.266, 4.242 & 4.220 (2H, q, J = 6.9 Hz, methylene protons of
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
Ethyl α-cyano-5-formyl-2-pyrroleacrylate (0.0218 g, 0.0001 mole) was dissolved in
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%)
Melting point: 258ºC
Solubility: soluble in DMSO; insoluble in hexane, dichloromethane, chloroform,
benzene, methanol, ethanol and water.
UV-vis Spectra (DMSO+Ethanol): λmax 370 nm
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
.
1H NMR Spectra (300 MHz, DMSO):
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
3.4 RESULT AND DISCUSSION
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.
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:
3.4.1 Thiocarbohydrazone of ethyl α-cyano-5-formyl-2-pyrroleacrylate (61)
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. 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
region. The band at 1580.98 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
band at 3031.15 cm-1
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
corresponds to aliphatic C-H
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
band at 1280.25 cm-1
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
singlet at δ 12.057 ppm corresponding to NH proton of hydrazone (C=NNH) linkage,
a broad singlet at δ 10.908 ppm corresponding to pyrrolic NH proton and a broad
singlet at δ 5.466 ppm corresponding to 2 protons of NH2 of remained free site of
hydrazide (CONHNH2) group. A quartet at δ 4.290, 4.266, 4.242 & 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
8.155 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
corresponds to aromatic C-H stretching for e.g., 3030.48 cm-1
and
below 3000 cm-1
corresponds to aliphatic C-H stretching modes for e.g., 2993.03,
2965.61 cm-1
. The IR spectrum of this compound shows a band at 2210.07 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
singlet at δ 12.059 ppm corresponding to NH proton of hydrazone (C=NNH) linkage,
a broad singlet at δ 10.909 ppm corresponding to pyrrolic NH proton and a broad
singlet at δ 5.462 ppm corresponding to 2 protons of NH2 of remained free site of
hydrazide (CONHNH2) group. A quartet at δ 4.289, 4.266, 4.242 & 4.220 (J = 6.9
Hz) and a triplet at δ 1.300, 1.276, 1.252 (J = 7.2 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 7.922
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
corresponds to aromatic C-H stretching for e.g., 3035.22 cm-1
and below 3000 cm-1
corresponds to aliphatic C-H stretching modes for e.g., 2992.96,
2880.44 cm-1
. The IR spectrum of this compound shows a band at 2210.02 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.
(6) Lagarias, J. C. and Raproport, H. J. Am. Chem. Soc. 1980, 102, 4821.
(7) Williams, R. C.; Yeh, S. W. and Clark, J. H. Science 1985, 230, 1051.
(8) Trofimov, B. A. and Mikhaleva, A. I., N-Vinilpirroly (N-Vinylpyrroles), Novosibirsk: Nauka, 1984.
(9) Trofimov, B. A. Adv. Heterocycl. Chem. 1990, 51, 177.
(10) Trofimov, B. A., Pyrroles. Part 2. The Synthesis, Reactivity, and Physical Properties of Substituted Pyrroles,
Jones, R. A., Ed., New York: Wiley, 1992, 131-298.
(11) Bellina, F. and Rossi, R. Tetrahedron, 2006, 62, 7213.
(12) (a) Trofimov, B. A.; Mikhaleva, A. I.; Korostova, S. E.; Vasil’ev, A. N. and Balabanova, L. N. Khim.
Geterotsikl. Soedin. 1977, 213; (b) Trofimov, B. A.; Korostova, S. E.; Shevchenko, S. G.; Polubentsev, E. A.
and Mikhaleva, A. I. Zh. Org. Khim. 1990, 26, 1110.
(13) Trofimov, B. A.; Korostova, S. E.; Balabanova, L. N. and Mikhaleva, A. I. Zh. Org. Khim. 1978, 14, 2182.
(14) (a) Trofimov, B. A.; Mikhaleva, A. I. Khim. Geterotsikl. Soed. 1980, 1299; (b) Trofimov, B. A. Z. Chem. 1986,
26, 41; (c) Trofimov, B. A.; Sobenina, L. N.; Mikhaleva, A. I. Organicheskaya Khimiya (Itogi Nauki i Tekhniki)
[Organic Chemistry (Advances in Science and Engineering Series)]; VINITY: Moscow, 1987; 7, 78; (d)
Sobenina, L. N.; Mikhaleva, A. I.; Trofimov, B. A. Usp. Khim. 1989, 58, 275; (e) Sobenina, L. N.; Mikhaleva,
A. I.; Trofimov, B. A. Khim. Geterotsikl. Soed. 1989, 291; (f) Trofimov, B. A.; Mikhaleva, A. I. Heterocycles
1994, 37, 1193; (g) Trofimov, B. A. Phosphorus, Sulfur, Silicon 1994, 95-97, 145; (h) Trofimov, B. A.;
Mikhaleva, A. I. Zh. Org. Khim. 1996, 32, 1127; (i) Korostova, S. E.; Mikhaleva, A. I.; Vasil’tsov, A. M.;
Trofimov, B. A. Zh. Org. Khim. 1998, 34, 967; (j) Korostova, S. E.; Mikhaleva, A. I.; Vasil’tsov, A. M.;
Trofimov, B. A. Zh. Org. Khim. 1998, 34, 1767; (k) Korostova, S. E.; Mikhaleva, A. I.; Trofimov, B. A. Usp.
Khim. 1999, 68, 506.
(15) (a) Falk, J. E. In Porphyrins and Metalloporphyrin; Smith, K. M., Ed.; Elsevier: Amsterdam, 1975; (b) Dolphin,
D. In The Porphyrins; Academic Press: New York, 1979; Vols. VI and VII; (c) Lagarias, J. C.; Rapoport, H. J.
Am. Chem. Soc. 1980, 102, 4821-4828; (d) Williams, R. C.; Yeh, S. W.; Clark, J. H. Science 1985, 230, 1051.
(16) Sobenina, L. N.; Demenev, A. P.; Mikhaleva, A. I.; Trofimov, B. A. Russ. Chem. Rev. 2002, 71, 563-591.
(17) (a) Bakhshi, A. K.; Lovleen, A. Superlattices Microstruct. 1993, 13, 437; (b) Berlin, A.; Canavesi, A.; Pagani,
G.; Schiavon, G.; Zecchin, S.; Zotti, G. Synth. Met. 1997, 84, 451; (c) Entezami, A.; Rahmatpour, A. Eur.
Polym. J. 1998, 34, 871; (d) Kim, I. T.; Elsenbaumer, R. L. Macromolecules 2000, 33, 6407.
(18) Baltazzi, E. and Krimen, L. I. Chem. Rev. 1963, 63(5), 511-556.
(19) Anthony, W. C. J. Org. Chem. 1960, 25, 2049.
(20) Fischer H. and Orth, H.; “Die Chemie des Pyrrols”, Johnson Reprint Go., New York, N.Y., 1968.
(21) Harris, R. L. N.; Johnson, A. W. and Kay, I. T.; Rev., Q. Chem. Soc. 1966, 20, 211.
(22) Harris, R. L. N.; Johnson, A. W. and Kay, I. T. J. Chem. Soc. C 1966, 22.
(23) Paine, J. B.; Woodward, R. B.and Dolphin, D. J. Org. Chem. 1976, 41(17), 2826-2835.
(24) McNab, H. and (the late) Thornley, C. J. Chem. Soc., Perkin Trans. 1, 1997, (12-15), 2200.
(25) del Corral, J. M. M.; Gordaliza, M.; Castro, M. A.; Salinero, M. A.; Dorado, J. M.; San Feliciano, A. Synthesis
2000, (1-3), 157.
(26) Nair, V.; Maliakal, D.; Treesa, P. M.; Rath, N. P.; Eigendorf, G. K. Synthesis 1996, (7-9), 851.
(27) Strachan, J.-P.; O’Shea, D. F.; Balasubramanian, T. and Lindsey, J. S. J. Org. Chem. 2000, 65(10), 3160-3172.
133
(28) Battersby, A. R.; Dutton, C. J. and Christopher, J. R. F. J. Chem. Soc., Perkin Trans. 1, 1988, (APR-JUNE),
1569-1576.
(29) Agosta, W. C. J. Am. Chem. Soc. 1960, 82, 2258.
(30) Campbell, S. E.; Comer, M. C.; Derbyshire, P. A.; Despinoy, X. L. M.; McNab, H.; Morrison, R.; Sommerville,
C. C. and (the late) Thornley, C. J. Chem. Soc., Perkin Trans. 1, 1997, (12-15), 2195-2202.
(31) Kwon , O. P.; Jazbinsek, M; Seo, J.I.; Kim, P. J.; Choi, E. Y; Lee , Y. S.; Günter P. Dyes and Pigments 2010,
85, 162-170.
(32) Sha, C.-K.; Liu, J.-M.; Chiang, R.-K. and Wang, S.-L. Heterocycle 1990, 31(Apr-June), 603-609.
(33) (a) Olssen, K. and Per-Ǻke Pernemalm, Acta. Chemica Scandinavica, 1979, B33, 125; (b) Miller, R. and Olssen,
K. Acta. Chemica Scandinavica 1981, B35, 303-310.
(34) Fischer, H. and Hofelmann, H. Justus Liebigs Ann. Chem. 1938, 533, 216.
(35) Woodward, R. B. Angew. Chem. 1960, 72, 651.
(36) Davies, J. L. J. Chem. Soc. C 1968, 1392.
(37) Badger, G. M.; Harris, R. L. N. and Jones, R. A. Aust. J. Chem. 1964, 17, 987, 1002, 1022.
(38) Comprehensive Organic Synthesis; Trost B. M., Ed.; Pergamon Press: Oxford, 1991; Coll. Vol. 2, pp 358-359.
(39) Raposo, M. M. M.; Sousa, A. M. R. C.; Kirsch, G.; Cardoso, P.; Belsley, M.; Gomes, E. de M. and Fonseca, A.
M. C. Org. Lett. 2006, 8(17), 3681-3684.
(40) (a) Burns, D. H.; Smith, K. M. J. Chem. Res. Miniprint 1990, 1349-1372; (b) Murase, M.; Yoshida, S.; Hosaka,
T.; Tobinaga, S. Chem. Pharm. Bull. 1991, 39, 489-492; (c) Selim, M. A. Aswan Sci. Technol. Bull. 1992, 13,
60-72; (d) Xiao, D.; Ketcha, D. M. J. Heterocycl. Chem. 1995, 32, 499-504.
(41) Sour, A.; Boillot, M.-L.; Riviere, E.; Lesot, P. Eur. J. Inorg. Chem. 1999, 2117-2119.
(42) Sobenina, L. N.; Mikhaleva, A. I.; Toryashinova, D.-S.D.; Kozyreva,O. B.; Trofimov, B. A. Sulfur Lett. 1996,
20, 9-14.
(43) Sobenina, L. N.; Mikhaleva, A. I.; Toryashinova, D.-S.D.; Kozyreva, O. B.; Trofimov, B. A. Sulfur Lett. 1997,
20, 205-212.
(44) Sobenina, L. N.; Demenev, A. P.;Mikhaleva, A. I.; Petrova, O. V.; Larina, L. I.; Chernyhk, G. P.; Toryashinova,
D.-S.D.; Vashchenko, A. V.; Trofimov, B. A. Sulfur Lett. 2000, 24, 1-12.
(45) Sobenina, L. N.; Demenev, A. P.;Mikhaleva, A. I.; Ushakov, I. A.; Afoninn, A. V.; Petrova, O. V.; Elokhina, V.
N.; Volkova, K. A.; Toryashinova, D.-S.D.; Trofimov, B. A. Sulfur Lett. 2002, 25, 87-93.
(46) Hermanson, G. T. Bioconjugate Techniques, Academic Press, Inc., San Diego, CA, 1996.
(47) Deep, A.; Jain, S.; Verma, P.; Sharma, P. C.; Kumar, M. and Dora, C. P. Acta Poloniae Pharm. Drug Res. 2010,
67(3), 255-259.
(48) Machakanur, S. S.; Patil, B. R.; Pathan, A. H.; Naik, G. N.; Ligade, S. G.; Gudasi, K. B. Der Pharma Chemica
2012, 4(2), 600-607.
(49) Rajput, A. P. and Rajput, S. S. International J. Pharm. Tech. Res. 2009, 1(4)(Oct-Dec), 1605-1611.
(50) Revanasiddappa, B. C.; Subrahmanyam, E. V. S.; Satyanarayana, D.; Thomas, J. International J. Chem. Tech.
Res. 2009, 1(4)(Oct-Dec), 1100-1104.
(51) Nagalakshmi, G.; Maity, T. K. and Maiti, B. C. Der Pharmacia Lettre 2011, 3(1), 476-489.
(52) Mabkhoot, Y. N. Molecules 2010, 15, 3329-3337.
(53) Gašparová, R.; Moncman, M.; Zbojek, D.; Králová K. and Krutošíková, A. 10th International Electronic
Conference on Synthetic Organic Chemistry (ECSOC-10). 2006, 1-30 November.
http://www.usc.es/congresos/ecsoc/10/ECSOC10.htm and http://www.mdpi.org/ecsoc-10/
(54) Beraldo, H.; Gambino, D. Mini-Rev. Med. Chem. 2004, 4, 31.
(55) Tenorio, R. P.; Goes, A. J. S.; de Lima, J. G.; de Faria, A. R.; Alves, A. J.; Aquino, T. M. Quim. Nova 2005, 28,
1030.
134
(56) Agarwal, K. C.; Sartorelli, A. C. J. Med. Chem. 1969, 12, 771.
(57) Liu, M. C.; Lin, T. S.; Cory, J. G.; Cory, A. H.; Sartorelli, A. C. J. Med. Chem. 1996, 39, 2586.
(58) Bellesia, F.; Boni, M.; Ghelfi, F. Tetrahedron 1993, 49, 199.
(59) Bernardi, F.; Csizmadia, I. G.; Mangini, A. Organic Sulphur Chemistry; Elsevier: Amsterdam, The Netherlands,
1985.
(60) Suvarapu, L. N.; Reddy, A V.; Kumar, G. S. and Baek, S. O. e-Journal of Chemistry 2011, 8(4), 1848-1858.
(61) Rao, Y. S.; Prathima, B.; Hariprasad, O.; Reddy, N. N.; Jagadeesh, M. and Varada, A. Reddy J. Chem. Pharm.
Res., 2010, 2(1), 292-299.
(62) (a) Sharma, S.; Athar, F.; Maurya, M. R.; Naqvi, F.; Azam, A. Eur. J. Med. Chem. 2005, 40, 557; (b) Sharma,
S.; Athar, F.; Maurya, M. R.; Azam, A. Eur. J. Med. Chem. 2005, 40, 1414.
(63) Shailendra; Bharti, N.; Gonzalez Garza, M. T.; Cruz-Vega, D. E.; Castro-Garza, J.; Saleem, K.; Naqvi, F.;
Azam, A. Bioorg. Med. Chem. Lett. 2001, 11, 2675.
(64) (a) Singh, S.; Athar, F.; Maurya, M. R.; Azam, A. Eur. J. Med. Chem. 2006, 41, 592; (b) Singh, S.; Bharti, N.;
Naqvi, F.; Azam, A. Eur. J. Med. Chem. 2004, 39, 459; (c) Singh, S.; Athar, F.; Azam, A. Bioorg. Med. Chem.
Lett. 2005, 15, 5424.
(65) (a) Bharti, N.; Husain, K.; Gonzalez Garza, M. T.; Cruz-Vega, D. E.; Castro-Garza, J.; Mata-Cardenas, B. D.;
Naqvi, F.; Azam, A. Bioorg. Med. Chem. Lett. 2002, 12, 3475; (b) Bharti, N.; Shailendra; Sharma, S.; Naqvi, F.;
Azam, A. Bioorg. Med. Chem. 2003, 11, 2923; (c) Shailendra; Bharti, N.; Naqvi, F.; Azam, A. Bioorg. Med.
Chem. Lett. 2003, 13, 689.
(66) Idhayadhulla, A.; Kumar, R. S.; Nasser, A. J. A. and Manilal, A. Der Pharma Chemica, 2011, 3(4), 210-218.
(67) (a) He, R. H. Y.; Jiang, X. K. Chinese Chemical Letters 1999, 10(6), 499-502; (b) He, H. Y.; Lin, C.; Zhao, C.
X.; Jiang, X. K. Chinese Chemical Letters 2001, 12(12), 1097-1100.
(68) Kwon, O-P.; Jazbinsek, M.; Yun, H.; Seo, J.-I.; Kim, E.-M.; Lee, Y.-S. and Günter, P. Crystal Growth &
Design, 2008, 8(11), 4021-4025.
(69) Bijev, A.; Georgieva, M. Journal of the University of Chemical Technology and Metallurgy 2010, 45(2), 111-
126.
(70) Atanas, B.; Georgieva, M. Letters in Drug Design & Discovery 2010, 7(6), 430-437.
(71) Mikhaleva, A. I.; Ivanov, A. V.; Vasil'tsov, A. M.; Ushakov, I. A.; Ma, J. S. and Yang, G. Chemistry of
Heterocyclic Compounds 2008, 44(9), 1117-1122.
(72) Al-Mawsawi, L. Q.; Dayam, R.; Taheri, L.; Witvrouw, M.; Debyser, Z.; Neamati, N. Bioorg. Med. Chem. Lett.
2007, 17(23), 6472.
(73) Plasencia, C.; Daym, R.; Wang, Q.; Pinski, J.; Burke, T. R. Jr.; Quinn, D. I. and Neamati, N. Mol. Cancer Ther.
2005, 4(7), 1105.
(74) Zhao, H.; Neamati, N.; Sunder, S.; Hong, H.; Wang, S.; Milne, G. W.; Pommier, Y.; Burke, T. R. Jr. J. Med.
Chem. 1997, 40(6), 937.
(75) (a) Bijev, A. Lett.Drug Des. Discov. 2006, 3, 506; (b) Thaker, K. M.; et. al., Ind. J. Chem. 2003, 42B, 1544.
(76) (a) Sharma, R. C. and Kumar, D. I. Ind. Chem. Soc. 2000, 77, 492; (b) Ingle, V. S.; Sawale, A. R.; Ingle, R. D.
and Mane, R. A. Ind. J. Chem. 2000, 40, 124.
(77) R. M. Fikry, N. A. Ismael, El-Bahnasawy, A. A. and El-Ahl, A. A. S. Phosphorous, Sulfur and Silicon 2004,
179, 122.
(78) Patel, H. S. Phosphorous, Sulfur and Silicon 2008, 183, 2391.
(79) (a) Patel, H. S.; Mistry, H. J. Phosphorous, Sulfur and Silicon 2004, 179, 1085; (b) Bhatt, J. J.; Shah, B. R. and
Desai, N. C. Ind .J. Chem. 1994, 33B, 189.
(80) Vogel, A. I. Practical Organic Chemistry, New York (1956).
(81) Miller, R. and Olsson, K. Acta. Chem. Scand. B 1981, 35, 303-310.
135
(82) Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G. and Tatchell., A. R. “Vogel’s Text Book of Practical Organic
Chemistry” 1989, 5, 1269.
(83) J. Chem. Soc. 1960, 37, 591.
(84) Silverstein, Basler and Morrill Spectrometric identification of organic compounds, IV edition, 134.
(85) Varsanyi G, Assignments for vibrational spectra of seven hundred benzene derivatives, Vol 1-2, Adam Hilger,
1974.
(86) Kavitha, E.; Sundaraganesan, N. and Sebastian, S. Indian Journal of Pure and Applied Physics 2010,
48(January), 20-30.
(87) Silverstein, Basler and Morrill Spectrometric identification of organic compounds, IV edition, 129.
(88) Silverstein, Basler and Morrill Spectrometric identification of organic compounds, IV edition, 132.
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
4.2 Basis of work and objectives of the present investigations
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.
149
150
4.3 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 method.118
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:
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
Solubility: This compound is soluble in chloroform, ethylacetate, ethanol, methanol,
acetone, DMSO and insoluble in hexane, benzene and water.
152
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. 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
Experimental Details
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
Solubility: soluble in DMSO; insoluble in hexane, dichloromethane, chloroform,
benzene, methanol, ethanol and water.
154
UV-vis Spectra (DMSO+Ethanol): λmax 269 nm
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-
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 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.
UV-vis Spectra (DMSO+Ethanol): λmax 268 nm
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%)
Melting point: 204ºC
Solubility: soluble in DMSO and boiling methanol; insoluble in hexane,
dichloromethane, chloroform, benzene, ethanol and water.
UV-vis Spectra (DMSO+Ethanol): λmax 227, 248 nm
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):
11.077 (1H, br, s, py-N-H), 8.484 & 8.452 (1H, d, J = 9.6 Hz, o-proton of phenyl ring
to both nitro group), 8.060 & 8.031 (1H, d, J = 9.6 Hz, o-proton of phenyl ring to one
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
Solubility: soluble in DMSO and boiling methanol; insoluble in hexane,
dichloromethane, chloroform, benzene, ethanol and water.
UV-vis Spectra (DMSO+Ethanol): λmax 381 nm
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):
11.177 (1H, br, s, py-N-H), 8.485 & 8.453 (1H, d, J = 9.6 Hz, o-proton of phenyl ring
to both nitro group), 8.074 & 8.046 (1H, d, J = 8.4 Hz, o-proton of phenyl ring to one
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
4.4 RESULT AND DISCUSSION
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.
Spectral Characteristics
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
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.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
region. The band at 1631.46 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
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
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
corresponds to aliphatic C-H
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 asymmetric stretching and at 1374.94 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
band at 1544.32 cm-1
for asymmetric stretching and at 1378.75 cm-1
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 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 in-plane and out-of-plane
deformations and their mixed modes.
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,
a doublet at δ 7.318 & 7.302 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 7.549 & 7.520
ppm (J = 8.7 Hz) corresponding to protons of phenyl ring o- to dimethylamino group,
a doublet at δ 6.788 & 6.758 ppm (J = 9.0 Hz) corresponding to protons of phenyl ring
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
4.5 References
(1) Hersheson, F. M. J. Org. Chem. 1972, 20, 3111-3113.
(2) Hania, M. M. Asian Journal of Chemistry, 2002, 2, 1074-1075.
(3) Guy, R. H.; Jeffrey, T. K. Chem. Rev. 2006, 106, 2875-2911.
(4) Jaime, N. D.; William, A. R. Text book of organic medicinal and pharmaceutical chemistry, 10th Ed. 1997, 37-
38.
(5) Sharda, G. Indian J. Heterocyclic Chem. 2006, 15, 401-402.
(6) Dave, C. G.; Shah, P. R.; Upadhyaya, S. P. Indian J. Chemistry, 1988, 27B, 778-780.
(7) Dave, C. G.; Shah, P. R.; Upadhyaya, S. P. Indian J. Chemistry, 1988, 27B, 1046-1048.
(8) Sachse, A.; Penkova, L.; Noel, G.; Dechert, S.; Varzatskii, O. A.; Fritsky, I. O.; Meyer, F. Synthesis 2008, 800-
806.
(9) Dvorak, C. A.; Rudolph, D. A.; Ma, S.; Carruthers, N. I. J. Org. Chem. 2005, 70, 4188- 4190.
(10) Alessandro, B.; Maria, A.; Mauro, M.; Mariangela, M.; Maria, B.; Luciano, O.; Franco. D.
Bioorg. Med. Chem. 2006, 14, 5152.
(11) John, M. F.; Joseph, C.; Joseph, B. J.; Karen, A. R.; Robert, K. M.; Joseph, M. L.;
Pancras, C. W.; Stephen, A. B.; Ruth, R. W. Bioorg. Med. Chem. Lett. 2006, 16, 3755.
(12) Michael, G. C.; Kahn, K. E.; Francis, D. D.; Labaree, R. B.; Robert. M. H.; Bioorg. Med.
Chem. Lett. 2006, 16, 3454.
(13) Thomas, D. P.; Albert, K.; Barbara, B. C.; Mark, A. R.; Mark, L. B.; Yaping, W.; Tiffany,
D. V.; Wayne, E.; Mary, B. F.; Sandra, K. F. Bioorg. Med. Chem. Lett. 2006, 16, 3156.
(14) Manuela, V.; Valeria, P.; Paola, V.; Alexander, C.; Marina, C.; Ciro, M. Bioorg. Med.
Chem. Lett. 2006, 16, 1084.
(15) Bhat, B. A.; Dhar, K. L.; Puri, S. C.; Saxena, A. K.; Shanmugavel, M.; Qazi, G. N.
Bioorg. Med. Chem. Lett. 2005, 15, 3177.
(16) Petra, C.; Giang, V. T.; Viktor, M.; André, L.; Soña, J.; Marica, T. Tetrahedron 2005,
61, 5379.
(17) Gabriele, M.; Stefania, R.; Jean-Mario, M.; Giovanni, L.; Giuseppe, E. G.; Mauro, A. M.;
Paolo, L.; Pani, P. L.; Gérard, A. P. Bioorg. Med. Chem. Lett. 2005, 19, 3309.
(18) Selvam, C.; Sanjay M., M. J.; Ramasamy, T.; Asit, K. C. Bioorg. Med. Chem. Lett.
2005, 15, 1793.
(19) Laxminarayan, B.; Bernd, J.; Tracy, M. D.; Tristen L. Moors, L. M.; Mark, A. G. Bioorg. Med. Chem. Lett.
2005, 15, 85.
(20) Athina, G.; Eugeni, B.; John, D.; Wim, D.; Dmitrii, F.; Galaeva, G. I.; Valentina, K.;
Alexey, L.; Fliur, M.; Guenadiy, M. Bioorg. Med. Chem. 2004, 12, 6559.
(21) Robert, E.; Sammelson, P. C.; Durkin, A. D. K. A.; John, E. C. Bioorg. Med. Chem.
2004, 12, 3345.
(22) Dileep, J. S.; Jaya, P.; Victoria, A.; Ramin, V. P.; Mark, D. U.; Norman, R. S.; Suham,
A. K.; Vattoly, J. M.; Ronald L., L.; Heertum, H. V.; Mann, J. J. Bioorg. Med. Chem. Lett.
2004, 14, 2393.
(23) Adnan, A. B.; Tarek, A. A. Bioorg. Med. Chem. 2004, 12, 1935.
(24) Pier, G. B.; Italo, B.; Paolo, C.; Nicoletta, B.; Roberto Gambari, G.; Romeo, R. Bioorg. Med. Chem. 2003, 11,
965.
(25) Garg, H. G.; Singhal, A.; Mathur, J. M. L. J. Pharm. Sci. 1973, 62, 494.
(26) Kees, K. L.; Fitzgerald, J. J. Jr.; Steiner, K. E.; Mattes, J. F.; Mihan, B.; Tosi, T.; Mondoro, D.; Mccaleb, M. L.
J. Med. Chem. 1996, 39, 3920.
169
(27) Gandhale, D. N.; Patil, A. S.; Awate, B. G.; Naik, L. M. Pesticides 1982, 16, 27-28.
(28) Lokhande, P. D.; Waghamare, B. Y.; Sakate, S. S. Indian J. Chem. 2005, 44B, 2338-2342.
(29) Reddy, G. J.; Mahjula, D.; Rao, S. K.; Khalilullan, M.; Latha, D.; Indian J. Chem. 2005, 44B, 2295-2300.
(30) (a) Arcamone, F.; Orezzi, P. G.; Barbieri, W.; Nicolella, V.; Penco, S. Gazz. Chim. Ital. 1967, 97, 1097-1115;
(b) Arcamone, F.; Penco, S.; Orezzi, P. G.; Nicolella, V.; Pirelli, A. Nature 1964, 203, 1064-1065.
(31) (a) Pelton, J. G.; Wemmer, D. E. J. Am. Chem. Soc. 1990, 112, 1393-1399; (b) Kopka, M. L.; Yoon, C.;
Goodsell, D.; Pjura, P.; Dickerson, R. E. Proc. Natl. Acad. Sci. U.S.A. 1985, 82, 1376-1380; (c) Abu-Daya, A.;
Brown, P. M.; Fox, K. R. Nucleic Acids Res. 1995, 23, 3385-3392.
(32) (a) Katritzky, A. R.; Rees, C. W.; Elguero, J. Comprehensive Heterocyclic Chemistry II, Volume 5; Pergamon
Press: Oxford, U.K., 1984; p 167; (b) Katritzky, A. R.; Rees, C. W.; Scriven, E. F.; Elguero, J. Comprehensive
Heterocyclic Chemistry II, Volume 3; Pergamon Press: Oxford, U.K., 1996; p 1.
(33) (a) Elguero, J.; Goya, P.; Jagerovic, N.; Silva, A. M. S. Italian Society of Chemistry: Rome, Italy, 2002, 6, 52;
(b) Gokhan, N.; Yesilada, A.; Ucar, G.; Erol, K.; Bilgin, A. A. Arch. Pharm. Pharm. Med. Chem. 2003, 336,
362.
(34) Holla, B. S.; Akbarali, P. M.; Shivanada, M. K. IL Farmaco 2000, 55, 256.
(35) Plaska, E.; Aytemir, M.; Uzbay, T.; Erol, D. Eur. J. Med. Chem. 2001, 36, 539.
(36) Turan-Zitouni, G.; Chevallet, P.; Killic, F. S.; Erol, K. Eur. J. Med. Chem. 2000, 35, 635.
(37) (a) Hoffman, Benz, R. E. J.; Shappim, F. J.; Furie, B.; Cohn, H. G.; Berspein, F. E. and Al-Hajjar, F.
Abstract Book of 7th Jordanian Chemical Conference, 2007, 12; (b) Udupi, R. H.; Kushnoor, A.S.; Bhat, A. R.
Indian J. Heterocycl. Chem. 1998, 8, 63-66.
(38) (a) Habib, S. I.; Kulkarni, P. A. and Konda, S. J. Appl. Sci. Res. 2010, 6(12), 1960-1985; (b) Khider, A.K. Br.
J. Pharmacol. Toxicol. 2011, 2(2), 92-96.
(39) (a) Nassar, E. J. Am. Sci. 2010, 6(8), 463-471; (b) Korgaokar, S. S.; Patil, P. H.; Shah, M. J; Parekh, H. H.
Indian J. Pharm. Sci. 1996, 58, 222-225.
(40) (a) Abunada, N. M.; Hassaneen, H. M.; Kandile, N. G. and Miqdad, O. A. Molecules 2008, 13(4), 1011-1024;
(b) Taylor, E. C.; Patel, H. H. Tetrahedron 1992, 48, 8089-8100.
(41) Sridevi, C.; Balaji, K.; Naidu, A. and Karimaris, S. Int. J. Pharm Tech. Res. 2009, 1(3), 816.
(42) (a) Li, J. T.; Zhang, X. H. and Lin, Z.P. Beilstein J. Org. Chem. 2007, 3(13), 1; (b) Palaska, E.; Aytemir, M.;
Uzbay, IT.; Erol, D. Eur. J. Med. Chem. 2001, 36, 539-543; (c) Rajendra, P. Y.; Lakshmana, R. A.; Prasoona,
L.; Murali, K.; Ravi, K. P. Bioorg. Med. Chem. Lett. 2005, 15, 5030-5034; (d) Ozdemir, Z.; Kandilici, H. B.;
Gumusel, B.; Calis, U.; Bilgin, A. A. Eur. J. Med. Chem. 2007, 42, 373-379; (e) Ruhogluo, O.; Ozdemir, Z.;
Calis, U.; Gumusel, B.; Bilgin, A. A. Arzneimittelforschung 2005, 55, 431-436.
(43) (a) Hajos, G. 2nd
Eurasian Meeting on Hetrocyclic Chemistry 2002, 21; (b) Alam, S. and Mostahar, S. J. Appl.
Sci. 2005, 5(2), 327.
(44) (a) Nauduri, D.; Reddy, G. B. Chem. Pharm. Bull. (Tokyo) 1998, 46, 1254-1260; (b) Khali, H. Z. and Yanni,
S.A. J. Indian Chem. Soc. 1981, 58, 168; (c) Patel, P.; Koregaokar, S.; Shad, M. and Parekh, H. I L Farmaco
1955, 50.
(45) (a) Ahn, J. H.; Kim, H. M.; Jung, S. H.; Kang, S. K.; Kim, K. R.; Rhee, S. D.; Yang, S. D.; Cheon, H.G.; Kim,
S. S. Bioorg. Med. Chem. Lett. 2004, 14, 4461; (b) Ahn, J. H.; Kim, H. M.; Jung, S. H.; Kang, S. K.; Kim, K.
R.; Rhee, S. D.; Yang, S. D.; Cheon, H. G.; Kim, S. S. Bioorg. Med. Chem. Lett. 2004, 14, 4461.
(46) Manna, F.; Chimenti, F.; Fioravanti, R.; Bolasco, A.; Seecci, D.; Chimenti, P.; Ferlini, C.; Scambia, G. Bioorg.
Med. Chem. Lett. 2005, 15, 4632.
(47) Cuadro, A.M.; Elguero, J.; Navarro, P. Chem Pharm Bull. 1985, 33, 2535-2540.
(48) Kawazuara, H.; Takahashi, F.; Shinga, Y.; Shimada, F.; Ohto, N.; Tamura, A. Jpn J. Pharmaol. 1997, 73(4),
317.
(49) (a) Budakoti, A.; Abid, M.; Azam, A. Eur. J. Med. Chem. 2006, 41, 63-70; (b) Mbarki, S.; Dguigui, K.;
Hallaoui, M. E. J. Mater. Environ. Sci. 2011, 2(1), 61-70; (c) Rao, N. S.; Kumar, R.; Srivastava, Y. K. Rasayan
J. Chem. 2009, 2(3), 716-719.
170
(50) Palaska, E.; Aytemir, M.; Uzbay, I.T.; Erol, D. Eur. J. Med. Chem. 2001, 36, 539-543.
(51) (a) Van Hes, R.; Wellinga; Kobus and Grosscurt; Arnold, C. J. Agri. Food Clum. 1978, 26(4), 915; (b) Eussen;
Jac, H. H. and Wellinga, K.; Stork, B. Pesticide sci. 1990, 29(1), 101.
(52) Kini, S.; Gandhi, A. M. Indian J. Pharm. Sci. 2008, 70(1), 105-108.
(53) Burger, A. Burger’s Medicinal Chemistry and drug discovery, John Wiley Publications Inc. 1995, Volume 2-6,
5th
edition.
(54) Sridevi, C.; Balaji, K.; Naidu, A.; Kavimani, S.; Venkappayya, D.; Suthakaran, R.; Parimala, S. Int. J. Pharm.
Tech. Res. 2009, 1(3), 816-821.
(55) Levai, A.; Jeko, J. Arkivoc 2009, VI, 63-70.
(56) Lombardino, J. G. and Otterrness, I. G. J. Med. Chem. 1981, 24, 830.
(57) Bruderer, H.; Richle, R. and Ruegg, R. (Hoffmann-La Roche, Inc.) U. S. 3, 822, 283 (C1. 260-310R; C07d),
1974, 02 Jul, Appl. 296-691, 11 Oct (1972); 9 pp; Chem. Abstr. 1974, 81, 105495r.
(58) Foye, W. O. in Principles of Medicinal Chemistry (Lea and Febiger, London), 1989, p. 159.
(59) Leonard, P. K.; Hertlein, M. B.; Thompson, G. D.; Paroonagian, D. L. BCPC Monograph 1994, 59, 67.
(60) (a) McLaren, K. L.; Hertlein, M. B.; Pechacek, J. T.; Ricks, M. J.; Tong, Y. C.; Karr, L. L. Eur. Pat. Appl.
508469; Chem. Abstr. 1993, 118, 101947; (b) Renga, J. M.; McLaren, K. L.; Pechacek, J. T.; Ricks, M. J.; Tong,
Y. C. U.S. Patent 5,324,837; Chem. Abstr. 1994, 121, 205339; (c) Ricks, M. J.; Tong, Y. C. U.S. Patent
5,338,856; Chem. Abstr. 1994, 121, 300887.
(61) Kawazura, H.; Takahashi, Y.; Shiga, Y.; Shimad, F.; Ohto, N.; Tamura, A. Jpn. J. Pharmacol 1997, 73(4), 317.
(62) Rao, K. S. and Subbaraju, G. V. Indian J. Heterocyclic Chem. 1994, 56, 6948.
(63) (a) Fahmy, A. M.; Hassan, K. M.; Khalaf, A. A. and Ahmed, R. A. Indian Journal of Chemistry 1987, 26B, 884;
(b) Mandal, N. K.; Sinha, R. and Banerjee, K. P. Journal of Indian Chemical Society 1984, 61, 979; (c)
Sachchar, S. P. and Singh, A. K. Journal of Indian Chemical Society 1985, 62, 142.
(64) (a) Tsuboi, S.; Wada, K.; Mauror, F.; Hatton, Y. and Sone, S. European Patent 1993, 537, 581; (b) Nugent, R.
A.; Murphy, M.; Schlachter, S. T.; Dunn, C. J.; Smith, J. R.; Staite, N. D.; Galinet, A. L.; Asper, D. G. and
Richard, K. A. J. Med. Chem. 1993, 36, 134; (c) Rangari, V.; Gupta, V. N. and Atal, C. K. Indian J. Pharm. Sci.
1990, 52, 158; (d) Mancera, M.; Rodriguez, E.; Roffe, I.; Galbis, A. J.; Conde, C. F. and Conde, A.
Carbohydrate Res. 1991, 210, 327; (e) Holla, B. S.; Shivananda, M. K.; Akberali, P. M. and Shalini Shenoy, M.
Indian J. Chem. 2000, 39B, 440-447.
(65) Mishriky, N.; Asaad, F. M.; Ibrahim, Y. A. and Girgis, A. S. Indian J. Chem. 1996, 35B, 935.
(66) Udupi, R. H.; Narayan rao, S.; Bhar, A. R. Ind. J. Hetero. Chem. 1998, 7, 217.
(67) (a) Bian, B. S.; Ji, S.; Shi, H. Dye. Pigment. 2008, 76, 348-352. 9. Lu, Z.; Jiang, Q.; Zhu, W.; Xie, M.; Hou, Y.;
Chen, X.; Wang, Z. Synth. Met. 2000, 111-112, 465-468; (b) Wang, P.; Onozawa-Komatsuzaki, N.; Himeda, Y.;
Sugihara, H.; Arakawa, H.; Kasuga, K. Tetrahedron Lett. 2001, 42, 9199-9201; (c) Wilkinson, F.; Kelly, G.P.;
Micheal, C.; Oelkrug, D. J. Photochem. Photobiol. A Chem. 1990, 52, 309-320.
(68) Wang. P.; Onozawa-Kamatsuzaki, N.; Himeda, Y.; Sugihara, H.; Arakawa, H.; Kasuga, K. Tetrahedron Lett.
2001, 42, 9199.
(69) (a) Wiley, R. H.; Jarboe, C.H.; Hayes, F. N.; Hanbury, E.; Nielsen, J. T.; Callahan, P. X.; Sellars, M. C. J. Org.
Chem. 1958, 23, 732-738; (b) Zhenglin, Y.; Shikang, W. J. Luminesc. 1993, 54, 303-308; (c) Gong, Z.-L.; Xie,
Y.-S.; Zhao, B.-X.; Lv, H.-S.; Liu, W.-Y.; J. Fluoresc. 2011, 21, 355-364.
(70) (a) Gong, Z.-L.; Zhao, B.-X.; Liu, W.-Y.; Lv, H.-S. J. Photochem. Photobiol. A Chem. 2011, 218, 6-10; (b) Liu,
W.-Y.; Xie, Y.-S.; Zhao, B.-X.; Wang, B.-S.; Lv, H.-S.; Gong, Z.-L.; Song, L.; Zheng, L.-W. J. Photochem.
Photobiol. A Chem. 2010, 214, 135-144.
(71) (a) Gao, Z. Q.; Lee, C. S.; Bello, I.; Lee, S. T.; Wu, S. K.; Yan, Z. L.; Zhang, X.H. Synthet. Metal. 1999, 105,
141-144; (b) Jhun, M. S.; Sakaki, Y.; Ogino, K.; Sato, H. Electron Dev. IEEE Trans. 1997, 44, 1307-1314.
(72) (a) Tao, Y. T.; Balasubramaniam, E. J. Matr. Chem. 2001, 13, 1207-1212; (b) Gao, X.; Cao, H.; Zhang, L.;
Zhang, B.; Cao, Y.; Huang, C. H. J. Mater. Chem. 1999, 9, 1077-1080.
171
(73) (a) Tasch, S.; Niko, A.; Leising, G.; Scherf, U. Appl. Phys. Lett. 1996, 68, 1090-1092; (b) Chang, C.; Chen, J.;
Hwang, S.; Chen, C. H. Appl. Phys. Lett. 2005, 87, 253501, doi:10.1063/1.2147730(3 pages).
(74) Susan, F. J.; Appleyard, S. R.; Day, R. D. P.; Willis, M. R. J. Mater. Chem. 2000, 10,169-173.
(75) Xiao, D.; Xi, L.; Yang, W.; Fu, H.; Shuai, Z.; Fang, Y.; Yao, J. J. Am. Chem. Soc. 2003, 125, 6740-6745.
(76) Poteau, X.; Brown, A. I.; Brown, R. G.; Holmes, C.; Matthew, D. Dye. Pigment. 2000, 47, 91-105.
(77) Shi, H. B.; Ji, S. J.; Bian, B. Dye. Pigment. 2007, 73, 394-396.
(78) Rao, K. S.; Subbaraju, G. V. Indian J. Heterocycl. Chem. 1994, 4, 19.
(79) (a) Tomilovi, Yu. U.; Okonnishnikova, G. P.; Shulishov, E. V. and Nfedov, O. M. Russ. Chem. Bt. 1995, 44,
2114; (b) Klimova, E. I.; Marcos, M.; Klimova, T. B.; Cecilio, A. T.; Ruben, A. T. and Lena, R. R. J.
Organomet Chem. 1999, 585, 106; (c) Padmavathi, V.; Sumathi, R. P.; Chandrasekhar, B. N. and Bhaskarreddy,
D. J. Chem. Res. 1999, 610; (d) Bhaskarreddy, D.; Chandrasekhar, B. N.; Padmavathi, V. and Sumathi, R. P.
Synthesis 1998, 491.
(80) (a) Klimova, E. I.; Marcos, M.; Klimova, T. B.; Cecilio, A. T.; Ruben, A. T.; Lena, R. R. J. Organomet. Chem.
1999, 585, 106; (b) Padmavathi, V.; Sumathi, R. P.; Chandrasekhar, B. N.; Bhakarreddy, D. J. Chem. Res. 1999,
610; (c) Bhaskarreddy, D.; Chandrasekhar, B. N.; Padmavathi, V.; Sumathi, R. P. Synthesis 1998, 491.
(81) (a) Ferigolo, M.; Barros, H. M.; Marquardt, A. R.; Tannhauser, M. Pharmacol. Biochem. Behav. 1998, 60(2),
431-437; (b) Palaskaa, E.; Aytemira, M.; Uzbay, I. T.; Erola, D. Eur. J. Med. Chem. 2001, 36, 539-543.
(82) Gothwal, P. and Srivastava, Y. K. J. Chem. Bio. Phy. Sci. Sec. A. 2012, 2(2), 622-627.
(83) Padmavathi, V.; Radha Lakhmi, T.; Sudhakar Reddy, G.; Padmaja, A. J. heterocycl. chem. 2008, 45, 1579.
(84) (a) Hassaneen, H. M; Shawali, A. S.; Elwaln, N. M.; Abunada, N. M.; Algharib, M. S. Arch. Pharm. Res. 1992,
15, 292-297; (b) Hassaneen, H. M.; Hilal, R. H.; Elwan, N. M.; Harhash, A.; Shawali, A. S. J. Heterocycl.
Chem. 1984, 21, 1013-1016.
(85) (a) Hassaneen, H. M.; Mousa, H. A. H.; Shawali, A. S. J. Heterocycl. Chem.
1987, 24, 1665-1668; (b) Hassaneen, H. M.; Mousa, H. A. H.; Abed, N. M.; Shawali, A. S. Heterocycles 1988, 27,
695-706.
(86) (a) Azarifar, D.; Ghasemnejad, H. Molecules 2003, 8, 642-648; (b) Azarifar, D.; Shaebanzadeh, M. Molecules
2002, 7, 885-895.
(87) Patel, V. M.; Desai, K. R. Arkivoc (i) 2004, 123-129.
(88) (a) Budakoti, A.; Abid, M.; Azam, A. Eur. J. Med. Chem. 2006, 41, 63; (b) Budakoti, A.; Abid, M.; Azam, A.
Eur. J. Med. Chem. 2007, 42, 544.
(89) Chimenti, F.; Maccioni, E.; Secci, D.; Bolasco, A.; Chimenti, P.; Granese, A.; Befani, O.; Turini, P.; Alcaro, S.;
Ortuso, F.; Cirilli, R.; La Torre, F.; Cardia, M. C. and Distinto, S. J. Med. Chem. 2005, 48, 7113-7122.
(90) Zen, Y.-M.; Chen, F. and Liu, F.-M. Phosphorus, Sulfur and Silicon 2012, 187, 421-431.
(91) Rajendra Prasad, Y.; Lakshmana Rao, A.; Prasoona, L.; Murali, K.; Ravikumar, P. Bioorg. Med. Chem. Lett.
2005, 15(22), 5030-5034.
(92) (a) Levai, A. Chem. Heterocyclic Comp. 1997, 33, 647-659; (b) Raiford, L. C.; Peterson, W. J. J. Org. Chem.
1936, 1, 544.
(93) (a)L. C. Raiford, G. V. Gundy, J. Org. Chem. 1938, 3, 265; (b) Raiford, L. C.; Manley, R. H. J. Org. Chem.,
1940, 5, 590; (c) Ried, W.; Dankert, G. Chem. Ber. 1957, 90, 2707.
(94) (a) Wiley, R. H.; Jarboe, C. H.; Hayes, F. N.; Hansbury, E.; Nielsen, J. T.; Callahan, P. X.; Sellars, M. C. J. Org.
Chem. 1958, 23, 732; (b) Sammour, A. E. A. Tetrahedron 1964, 20, 1067.
(95) (a) Bhatnagar, I.; George, M. V. Tetrahedron 1968, 24, 1293; (b) Aubagnac, J. L.; Elguero, J.; Jacquier, R.; Bull.
Soc. Chim., Fr. 1969, 3292.
(96) F. G. Weber, K. Brosche, C. Seedorf, A. Rinow, Monatsh. Chem. 1969, 100, 1924.
(97) (a) Katritzky, A. R.; Wang, M.; Zhang, S.; Voronkov, M. V.; Steel, P. J. J. Org. Chem. 2001, 66(20), 6787-
6791; (b) Kuz’menok, N. M.; Koval’chuk, T. K.; Zvonok, A. M. Syn Lett 2005, 3, 485-486.
172
(98) El-Rayyes, N. and Ai-Johary, A. J. A. J. Chem. Eng. Data 1985, 30, 500-502.
(99) Chimenti, F.; Bolasco, A.; Manna, F.; Secci, D.; Chimenti, P.; Befani, O.; Turini, P.; Giovannini, V.; Mondovi,
B.; Cirilli, R. and La Torre, F. J. Med. Chem. 2004, 47, 2071-2074.
(100) Manna, F.; Chimenti, F.; Bolasco, A.; Secci, D.; Bizzarri, B.; Befani, O.; Mondovı`, B.; Turini, P.; Alcaro, S.;
Tafi, A. Bioorg. Med. Chem. Lett. 2002, 12, 3629-3633.
(101) Solankee, A.; Patel, G. and Solankee, S. Rasayan J. Chem 2008, 1(3), 591-595.
(102) (a) Powers, D. G.; Casebier, D. S.; Fokas, D.; Ryan, W. R.; Troth, J. R.; Coffen, D. L. Tetrahedron 1998,
54(16), 4085-4096; (b) Özdemir, Z.; Kandilci, H. B.; Gümüşel, B.; Çaliş, Ü.; Bilgin, A. A. European Journal of
Medicinal Chemistry 2007, 42, 373-379.
(103) Li, C. J. Chem. Rev. 2008, 105(3), 3095-3165.
(104) Li, J. T.; Zhang, X. H.; Lin, Z. P. Beli J Org Chem. 2007, doi:10.1186/1860-5397-3-13.
(105) Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron 2001, 57, 9222-9283.
(106) Kamble, R. R.; Sudha, B. S. and Bhadregowda, D. G. J. Serb. Chem. Soc. 2008, 73 (2), 131-138.
(107) (a) Kidwar, K.; Kukreja, S.; Thakur, R. Lett. Org. Chem. 2006, 3(2), 135-139; (b) Sasikala, R.; Thirumurthy, K.;
Mayavel, P.; Thirunarayanan, G. Organic and Medicinal Chemistry Letters 2012, 2, 20.
(108) (a) Levai, A. Arkivoc 2005, 9, 344; (b) Li, J. T.; Zhang, X. H.; Lin, Z. P. Beilstein J. Org. Chem. 2007, 3, 1; (c)
Kamble, R. R.; Sudha, B. S.; Bhadregowda, D. G. J. Serb. Chem. Soc. 2008, 73, 131.
(109) (a) Kaushik, D.; Nagpal, U.; Verma, T. and Madan, K. Molbank 2011, M714; doi:10.3390/M714; (b)
Revanasiddappa, B. C.; Nagendra Rao, R.; Subrahmanyam, E. V. S. and Satyanarayana, D. e-Journal of
Chemistry 2010, 7(1), 295-298.
(110) Maleki, B.; Azarifar, D.; Moghaddam, M. K.; Hojati, S. F.; Gholizadeh, M. and Salehabadi, H. J. Serb. Chem.
Soc. 2009, 74(12), 1371-1376.
(111) Elderfield, R. C. Heterocyclic Compounds, Wiley: New York, 1957, 5, 48-49.
(112) Catsoulacos, P.; Stassinopoulou, C. I. J. Heterocycl. Chem. 1978, 75, 313.
(113) Lochi, M. J. Heterocycl. 1989, 24, 1697.
(114) (a) Kyogoku, K.; Hatayama, K.; Yokomori, S.; Saziki, R.; Nakane, S.; Sasajima, M.; Sawada, J.; Ohzeki, M. and
Tanaka, I. Chem. Pharm. Bull. 1979, 27(12), 2943; (b) Chem. Abstr. 1980, 93, 26047r.
(115) (a) Marmo, E.; Caputi, A. P. and Cataldi, S. Farmaco, Ed. Prat. 1973, 28(3), 132; (b) Chem. Abstr. 1973, 79,
13501v.
(116) (a) Shoji, S.; Masatoshi, H. and Widago, B. Yakugaku Zasshi 1960, 80, 620; (b) Chem. Abstr. 1960, 54, 2148e.
(117) Powers, D. G.; Fokas, D.; Ryan, W. J. J. and Coffen, D. I. Tetrahedron, 1998, 54, 4085-4096.
(118) Vogel, A. I. Practical Organic Chemistry, New York (1956).
(119) Vogel, A. I. Practical Organic Chemistry, New York (1956), 344.
(120) Silverstein, Basler and Morrill Spectrometric identification of organic compounds, IV edition, 134.
(121) Silverstein, Basler and Morrill Spectrometric identification of organic compounds, IV edition, 130.
(122) Silverstein, Basler and Morrill Spectrometric identification of organic compounds, IV edition, 133.
173
Summary and Conclusion
174
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.
175
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:
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:
178
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.