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DESIGN, SYNTHESIS AND SPECTRAL STUDIES OF

NOVEL HETEROCYCLIC COMPOUNDS


A
THESIS
Presented to the Faculty of the Physical Sciences of the
Punjabi University, Patiala
In the Fulfillment of the Requirements for the
Degree of
DOCTOR OF PHILOSOPHY
IN
CHEMISTRY

BY

MAMTA RANI

DEPARTMENT OF CHEMISTRY
PUNJABI UNIVERSITY, PATIALA-147002
MAY, 2012

Dr. Mohamad Yusuf


Assistant Professor (Stage-II)

Department of Chemistry
Tel.: +91-175-3046409 (off)
E-mail: yusuf_sah04@yahoo.co.in

Punjabi
University
Patiala 147002

CERTIFICATE
This is to certify that this thesis entitled Design, Synthesis and Spectral Studies of Novel
Heterocyclic Compounds embodies the work carried out by Mamta Rani herself under my
supervision and that it is worthy of consideration for the award of the Ph. D. degree.

(Dr. Mohamad Yusuf)

..
Day

Month

...
Year

DECLARATION
I hereby affirm that the work presented in this thesis is exclusively my own and there are no
collaborators. It does not contain any work for which a degree/diploma has been awarded by any
other University/Institution.

(MAMTA RANI)
..
Day

..
Month

..
Year

Countersigned

(Dr. Mohamad Yusuf)


Assistant Professor (Stag- II)

Department of Chemistry,
Punjabi University, Patiala
..
Day

.. ..
Month Year

ACKNOWLEDGEMENTS
I gratefully acknowledge my Research Supervisor Dr. Mohamad Yusuf for his advice,
supervision and crucial contribution which made him a backbone of this research and so to this
dissertation.
A special word of appreciation for ever so helpful, cooperative and encouraging attitude of Dr.
Baldev Singh, Professor & Head, Department of Chemistry, for providing the necessary
facilities.
I am highly thankful to Mr. Avtar Singh, RSIC, Panjab University, Chandigarh for providing
the 1H-NMR and 13C-NMR spectra of the research samples.
I am also thankful to Dr. (Mrs.) P. P. Sahota, Department of Microbiology, P. A. U.,
Ludhiana for carrying out the antibacterial analysis of research samples.
The thesis could not have been completed without the love, support, continuous motivation and
encouragement offered by my husband Mr. Manoj Kumar Vimal during this research work. I
also wish to thank my loving daughter Deekshika Vimal.
Words alone are not sufficient to express my feeling about my immense gratitude that I owe to
my dear parents and in laws family for their endless love, deep affection, heartful blessings and
ever encouraging moral support.
Above all, I am grateful to God, Almighty who sustains this beautiful world and without
whose grace nobody can ever succeed.
(Mamta Rani)

PREFACE
Syntheses of heterocyclic compounds have been the subject of major interest among the
synthetic organic chemists in the past and majority of these substrates are widely used in the
pharmaceuticals and biotechnology industries.
Chapter-I is introductory in nature that contains many observations from literature of various
types of heterocyclic compounds like three, four, five membered rings containing one or more
than one heteroatoms. It was observed that five membered heterocyclic compounds (pyrazoles,
thiadiazolines & thiazoles) have been investigated due to their significant applications in the
various pharmacological areas.
Chapter-II has been subdivided into two parts IIa & IIb. The subpart IIa has been devoted to
the investigations pertaining to the cyclization of the alkoxy-chalcones and these reactions lead
to the formation of two series of alkoxy-N-phenyl-pyrazolines which are obtained from the
cyclocondensation reactions of chalcones with phenyl hydrazine. In part IIb, are included the
result of cyclization reactions of alkoxy-chalcones with thiosemicarbazide under the alcoholic
alkaline conditions which could easily provide N-thiocarbamoyl-pyrazolines.
Chapter-III deals with preparation of new alkoxy-thiadiazolines which are obtained from the
cyclization reactions of suitable thiosemicarbazones with acetic anhydride. The reactions of
intermediate thiosemicarbazones with 2,3-dichloroquinoxaline could results in formation of new
thiazole derivatives.
The last Chapter-IV has also been divided into two parts IVa & IVb which contain the
chemical transformations of furyl/thienyl-bischalcones built around the aliphatic chains. In part
IVa, bischalcones are reacted with phenyl hydrazine to furnish N-phenyl-bispyrazolines. The
part IVb describes the synthesis of new N-thiocarbamoyl-pyrazolines which are easily prepared
from the cyclization reactions of bischalcones with thiosemicarbazide.
The structures of intermediates (alkoxy-chalcones, bischalcones & thiosemicarbazones) and final
heterocyclic compounds (N-phenyl-pyrazolines, N-thiocarbamoyl-pyrazolines, thiadiazolines,
thiazoles, N-phenyl-bispyrazolines & N-thiocarbamoyl-bispyrazolines) have been confirmed
from the rigorous analysis of their spectroscopic data (IR, 1H-NMR, 13C-NMR & Mass).

CONTENTS
GENERAL CONSIDERATIONS

CHAPATER-I: HETEROCYCLIC CHEMISTRY: GENERAL


INTRODUCTION

CHAPTER-IIa: SYNTHESIS OF NEW ALKOXY N-PHENYL-5FURYL/THIENYL-PYRAZOLINES

27

CHAPTER-IIb: SYNTHESIS OF NEW ALKOXY-N-THIOCARBAMOYL5-FURYL/THIENYL-PYRAZOLINES

81

CHAPTER-III: SYNTHESIS OF NEW ALKOXY THIADIAZOLINES AND


QUINOXALINE BASED THIAZOLES

107

CHAPTER-IVa: SYNTHESIS OF NEW N-PHENYL-BISPYRAZOLINES

161

CHAPTER-IVb: SYNTHESIS OF NEW N-THIOCARBAMOYLBISPYRAZOLINES

212

SUMMARY

249

LIST OF PUBLICATIONS

259

GENERAL CONSIDERATIONS
The melting points were determined using the open capillaries and are uncorrected.

The Infrared (IR) spectra were scanned in KBr pellets on a Perkin Elmer RXIFT Infrared
spectrophotometer.
The 1H-NMR and

13

C-NMR spectra were recorded in CDCl3/DMSO-d6 solvent on a 400 MHz

Bruker spectrophotometer; the chemical shifts are reported on a scale using tetramethylsilane
(TMS) as the internal standard; s, d, t, dd & td represent singlet, doublet, triplet, doublet of
doublet and triplet of doublet respectively.

The mass spectra have been scanned on the Waters Micromass Q-T of Micro (ESI) spectrometer.

TLC plates were coated with silica gel (suspended in chloroform-methanol, 1:1) and iodine
vapours were used as visualizing agent.

Abstract
The pyrazolines are the five membered heterocyclic compounds which have attracted the
attentions of organic chemists in the past decades due to their immense biological applications.
These compounds are generally prepared from the reactions of chalcones with hydrazine
derivatives under the ordinary conditions. So, this thesis has been devoted upon the synthesis and
antibacterial examinations of variously substituted pyrazolines and bispyrazolines. In the
chapter-I of the thesis are described the examples of various heterocyclic compounds from the
literature and it was found that five membered heterocyclics containing two and three hetero
atoms are associated to the useful pharmacological properties. The chapter-IIa describes results
of investigations relating to the cyclocondensation reactions of the thienyl/furyl-alkoxychalcones
with phenyl hydrazine under the acidic alcoholic medium. These reactions could lead to the
formation of two series of thienyl/furyl substituted alkoxy-N-phenyl-pyrazolines. The chapter IIb
provides the easy synthesis of alkoxy-N-thiocarbamoyl-pyrazolines which are obtained from the
cyclization reactions of alkoxy-chalcones with thiosemicarbazide under the alcoholic alkaline
conditions. In the chapter-III synthesis of new alkoxy substituted 1,3,4-thiadiazolines have been
described and these products are obtained from the cyclization reactions of alkoxythiosemicarbazones with acetic anhydride. The reactions of intermediate thiosemicarbazones
with 2,3-dichloroquinoxaline also resulted in the formation of new thiazoles. The required
thiosemicarbazones were obtained from the reactions of alkoxy-benzaldehydes with
thiosemicarbazide. The Chapter-IVa contains the cyclocondensation reactions of furyl/thienylbischalcones with phenyl hydrazine and these reactions could furnish N-phenyl-bispyrazolines as
the end products. The chapter IVb describes the synthesis of new N-thiocarbamoyl-pyrazolines
which are easily prepared from the cyclization reactions of alkyl chain linked bischalcones with
thiosemicarbazide under alkaline conditions. The structures of the newly synthesized compounds
have been confirmed from the rigorous analysis of their IR, 1H-NMR (400 MHz, CDCl3/DMSOd6),

13

C-NMR (100 MHz, CDCl3/DMSO-d6) and ESI-MS spectral parameters. The products of

these investigations have also been also subjected to their antibacterial analysis against the four
bacteria strains namely A. hydrophila, Y. enterocolitica, L. monocytogenes & S. aureus. Many of
the studied compound exhibited significant activity against the tested microorganisms.

CHAPTER-I
Heterocyclic Compounds: General
Introduction

Heterocyclic compounds are the organic substrates that contain a ring structure having atoms
like nitrogen, oxygen or sulfur in addition to carbon atom as the part of their ring. The cyclic part
(from Greek kyklos, meaning circle) of heterocyclic indicates that at least one ring structure is
present in such a compound and the prefix hetero (from Greek heteros, meaning other or
different) refers to non carbon atom in the ring. The cyclic part of the heterocyclic indicates that
at least one ring structure is cyclic organic compound that incorporate at least one hetero atom in
the rings like cyclopropane or benzene. The presence of the heteroatom gives heterocyclic
compounds many significant physical and chemical properties that are usually distinct from
those of all carbon-ring analogues. These structures may comprise of either simple aromatic
rings or non-aromatic ring. The chemistry of heterocyclic compounds is one of the most
interesting and intriguing branch of the organic chemistry which is of equal interests for its
theoretical implications, for the diversity of its synthetic procedures and for the physiological and
industrial significances.1-2
It is well known that a number of heterocyclic compounds containing nitrogen and sulphur
exhibit a wide variety of biological activities. The majority of pharmaceutical products that
mimic natural products with biological activity are heterocyclic in nature3 and are of great
importance to life because their structural subunits exist in many natural products such as
vitamins, hormones, antibiotics and pigments.4,5 Besides the vast distribution of heterocyclics in
natural products, these substrates are also the major components of biological molecules such as
DNA and RNA, in the form of pyrimidine and purine bases. Hydrolysis of DNA and RNA
produce nucleosides 1.1-1.5 which are composed of an aromatic heterocyclic base, a phosphate
and a ribose moiety.6
O
HO

O
O

OH

Ar

HO

CH3
N

H3C

R = H, OH, Ar =
N

,
1.1

NH2

,
1.2

,
1.3

NH

NH

NH

NH2

,
1.4

1.5

The enzymes possess purely protein structures and the coenzymes incorporate non-amino acid
moieties, most of them are aromatic nitrogen heterocycles. Co-enzymes are involved in many
important metabolic reactions in living cells, nicotinamide adenine dinucleotide 1.6 (NAD
coenzyme-I) and nicotine adenine dinucleotide phosphate (NADP,

coenzyme-II), are derived

from nicotinamide, flavin adenine dinucleotide 1.7 (FAD) and the co-enzyme pyridoxal
phosphate (codecarboxylase) is a physiologically active form of pyridoxine.
O
NH2
O
O

NH 2
N

H3C

CH3
O

NH2
(CHOH) 3

P
O

OH

HO
N

OH

CH 2

OH

O
NH

OH OH

1.6

1.7

New heterocyclic uracil based multifunctional compound 1.8 shows antiviral activity against
dengue virus and is a potent inhibitor of the replication of dengue virus.7
O

OH

N
O

O
OH

1.8
Porphyrins8-10 are the backbone of many major compounds and some of their derivatives are
fundamental to life, such as heme11 derivatives in blood and chlorophyll is essential for
photosynthesis.

The

heme

group

of

the

oxygen-carrying

protein-hemoglobin and

related compounds such as myoglobin; the chlorophyll, which are the light-gathering pigments
of green plants and other photosynthetic organisms, and vitamin B12 are all formed from four
pyrrole units joined in a larger ring system known as a porphyrin, such as that of chlorophyll a
1.9 and chlorophyll b 1.10.

H3C

H3C

H3C

H3C

CH=CH2

CH3

CO2H 3C

CO 2H 3C

CH3

CH 2CH 3

CH3

CHO

N
N......Mg ......

RO 2CCH 2CH 2
CH2CH3

N......
N
Mg......

RO2CCH2CH2

CH=CH 2

CH3
H3C

R=phytyl, C 20H 39

R=phytyl, C20H39

1.9

1.10

Adenosine monophosphate 1.11a, diphosphate 1.11b, and triphosphate12 1.11c are important
participants in energy processes in the living cell. Each of the compounds is composed of the
nucleotide base adenine linked to the sugar ribose, which in turn is linked to a linear tail of
one, two, or three phosphate groups, respectively.
OH OH
H

H
H

CH2 O P OY
OH
N

N
NH2

1.11a 1.11c
a (Y=H), b (Y=PO3H2), c (Y=P2O6H3)
Many vitamins13 like folic acid 1.12, vitamin B5, nicotinic acid 1.13, nicotinamide 1.14, vitamin
B6 pyridoxine 1.15, pyridoxal 1.16, and pyridoxamine 1.17 are well known heterocyclic
compounds.
O

O
N

HN
H2N

NH
N

CH2NH

COOH
COOH

1.12

CH O

CH2OH

HO
OH

H3C

1.13

OH

OH

NH2

CH 2NH 2

HO

H3C

1.14

1.15

HO
OH
H3C

1.16

1.17

Vitamin E (-tocopherol) 1.18 is found in plant oils and the leaves of green vegetables whereas
coumarin 1.19 or 2H-1-benzopyran-2-one is used in perfumes. Psoralen 1.20 consists of
coumarin fused with furan rings, is used in treatment for skin problems and it shows considerable
clinical efficacy.14
CH3
(CH 2CH 2CH 2CH) 3CH 3

HO

H3C

CH3

CH3

1.18

1.19

1.20

Cinchona bark15 has been used for several hundred years for the treatment of malaria where
quinine 1.21 is the active heterocyclic component.
CH

CH2

H
HO
N
H3CO

1.21

Caffeine (1,3,7-trimethylxanthine) 1.22 obtained commercially from methylation of xanthine


with methyl chloride or dimethylsulphate and alkali, is the major stimulant in tea and coffee.
CH3
O

N
N

N
N

H3C
O

1.22

CH3

The best known indole derivatives are the indole alkaloids16 which have been isolated from
plants e.g.- tryptamine 1.23, serotonin 1.24, reserpine 1.25, strychine 1.26 and brucine 1.27.
NH2

NH2

HO

N
H

N
H

1.23

1.24

H
N

N
H3CO

H H

OCH 3

H3CO

OCH 3

OCO

N
O

OCH 3

1.25

OCH 3

1.26
R
R
R

O
H

H
O

1.27
In medicines, aziridine derivatives are used for the treatment of cancer.

17

The mitomycin18 1.28 is

the most well known class of natural product containing the aziridine ring which acts as a
antitumor agent. The compounds 1.32, 1.33 and 1.34 also acts as antibiotics.
O
H3C

NH
O

H2N

R
N

CH3

O
O
H2N

1.28

H3C
O

1.29

N
(CH 2)n

Tr

1.30

1.31

Aziridine derivatives are also employed in plastics, coating and as a curing agent. 19-21 The
naturally occurring compounds containing one or more oxirane rings are quite abundant which
include insect juvenile hormones22-26 and later are associated to the promising therapeutic
applications. An important synthetic oxirane is fosformycin 1.32 which is used as an
antibacterial drug particularly in the treatment of urinary tract infections.
O

HO P

CH3

HO

1.32
Atropine 1.33 is a significant heterocyclic compound which is widely used in medicine for the
muscle relaxant properties and it is also used as an antispasmodic including the dilation of the
pupil by relaxing the eye muscles. The compound 1.34 has similar properties to atropine and at
one time it was used as a local anesthetic agent.
N
N

CH3

H
Ph
OCOCH

CH3

CO 2CO 3
OCOPh

CH 2OH

1.33

1.34

The most important heterocycles with four membered are two related series of antibiotics,
penicillins 1.35 and cephalosporins 1.36 containing -lactum unit.27 Penicillin was first reported
by Fleming in 1929 and demonstrated its powerful effect against bacteria.28-31 Some important
penicillins used in medical practices are-penicillin-G 1.37, oxacillin 1.38, mecillinam 1.39,
theienamycin 1.40, amoxicillin 1.41. Cephalosporin is found to be more useful against
pathogenic bacteria and these products have much wider spectrum of activity than the penicillin.

H
NH

S
N

NH

CH3

CH3

CH 2OAc

COOH

COOH

1.35

1.36
C6H5CH2O CHN

H
S

CH3
CH3

N
O

CO O H

1.37
O

Ph

NH
N
O

CH3

S
N

CH3

C OO H

1.38

1.39

NH2

H
NH

H3C

S
N

NH2

H
S
N

HO

CH3

COOH

HO

CH3

CH3

C OOH

1.40

CH3
CH3

C OOH

1.41

Numerous oxetanes 1.42-1.44, the synthetic analogs of the antiviral natural product oxetanocin32
are under investigations for antifungal, anti-inflammatory, anticancer and antiviral activities.
Oxetanocin like OXT-A, 2-amino-OXT-A, OXT-G, OXT-H and OXT-X are reported as the
inhibitor of the human cytomegavirus.33 Oxetane derivatives are also widely utilized in polymer
manufacturing and in agriculture as herbicides, fungicides and bactericides.

NH2
N

HO

NH2

NH2

HO

HO

OH

NH
N

OH

1.42

NH2

OH

1.43

1.44

Many pyridine derivatives show pharmaceutical properties.34 It has been observed that a number
of more potent synthetic drugs such as chloroquinine 1.45, plasmoquinine 1.46 and atebrin 1.47
are found to possess pyridine ring.
Et

Et

Et

CH 3

Et

CH3

Et

HN

HN

Et

CH3
HN

OCH 3

1.45
35-36

Quinoline

H 3CO

Cl

Cl

1.46

1.47

is also present in some other drugs like plasmoquine 1.48 (antimalarial) and

norfloxacin 1.49 (antibacterial).36


O

H3CO

F
OH
N
N
H

N
CH(CH 2)3N(C 2H5)2
CH3

1.48

HN
H3C

1.49

Lovastatin 1.50 (cholesterol lowering), captopril 1.51, losartan 1.52 (anti-hypertensive),


isoniazid 1.53 (anti-tuberculosis) and tagamet 1.54 (anti-ulcer) are some significant drugs which
are also made from heterocyclic scaffold.

HO

O
Cl

H3C

OH

H 3C
N

H3C

O
CH3

HS

CH3

N
O

H3C

1.50

CO 2H

1.51

1.52
H
N

H3C

NCN
O

N
H

N
N
K

H3C

NH 2

N
H

N
H

N
H

1.53

1.54

Many alkaloids37 contain a pyridine or piperidine ring structure, among them nicotine 1.55, the
main alkaloid constituent of tobacco, is based on the five membered pyrrolidine and six
membered pyridine structures and piperine 1.56 which is one of the sharp-tasting constituents of
white and black pepper and it is obtained from the plant species piper nigrum.
O
N

N
N

CH3

1.55

1.56

Papaverines 1.57 is an alkaloid which acts as a smooth muscle relaxant, coronary vasodilator,
antispasmodic, and also used as analgesics.
MeO
N
MeO
OMe

OMe

1.57
Streptomycin 1.58 is a quinolinequinone antitumour antibiotic which has significant activity
against the broad range of tumours.38 The positive results were reported for streptomycin both as
a single agent and in combination chemotherapy.39

O
CH3O
N
H2N

COOH

N
O

H2N
HO

CH3

CH3O
OCH3

1.58
Zidovudine 1.59 and acylovits are two derivatives which are used to treat acute infections like
AIDS.
O
CH3

HN
O

HO
H

H
+

1.59
Recently, synthesis of novel benzoxazole 1.60-1.63 have been reported40 which are associated
with antimicrobial, anticonvulsant, neurotoxicity and anti-hyperglycemic activities.
O

CO NH NH

NH

O
N

R=H, 2-Cl, 4-Cl

where M= Co, Fe, Mg, Zn, Cd, Ni

R=H, 2-OCH3, 2-CH3, 3-CH3, 4-CH3

1.60

1.61

O
N

R
N

S
O

NH O N
2

R
O

O
O

R= Me, BRL 48432

1.62

R= 4-C6H5F, 2-C6H5F, 4-C6H5Cl, 2-C6H5Cl, 4-C6H5COCH3

1.63

The benzimidazole derivatives 1.64-1.68 having antifungal, antibacterial, anti-inflamatory and


analgesics properties have been successfully prepared.41
O
N

Ph

H5C6
N

H5C6

Br

HN

OH

N
H

1.64

OCH 2C6H5

1.65

1.66
H

N
R

Cl

NH

N
H

Br

R1

N
H

1.67

1.68

Recently, benzopyrazole derivatives 1.69 & 1.70 are prepared to study their biological
properties.42
O
N
S

NH

NHO 2S

NH

R
S
R= -NH3, -OH, -Cl

1.69

1.70

The pyrazoline compounds 1.71-1.73 are found to be associated with potent antimicrobial and
anticancer activities.43
F

HO

Ph

N
N

Cl

CH3

1.71

1.72
O
N
N
S

H3CO
HO

OCH 3

OH

1.73

The quinone fused pyrrolidine derivatives are also exhibited significant anticancer behaviour.44
O
H3C

NH

N
OMe

H2N
O

O
O

H2N

1.74
Some significant five45a,b 1.75 &1.76, seven45c,d 1.77 and eight45e 1.78 & 1.79 membered oxygen
heterocyclic compounds have been synthesized by using photochemical reactions.
R

OH

COOCH 2R
H

OH

Ph

1.75

1.76

O
H3C

Ph

H
O

OH

O
H3C

H CH3

1.77

Ph

1.78
Me
O
O
HO

Ph

1.79
Benzopyrone and their derivatives46 1.80-1.84 have also been prepared due to the significant
biological applications associated to these compounds.

MeO
O

Me

O
R1
R2

1.80

MeO

1.81

1.82
Ph

OMe
N

N
N

Ph

OH
OMe

1.83

1.84

Recently, syntheses of tetracyclic pyronopyran derivatives 1.85-1.88 have been reported47 from
the photocyclization reaction of the suitable 3-alkoxychromones/bischromones.
CH3

CH3

Cl

Cl

COOCH 2CH 3

1.85

COOCH 2CH 3
H

1.86
X

X
O

O
H

H
Y

Cl

Cl

O
H

X = O, S

1.87
X

O
Y

Cl
O

Cl

O
H
(X= S)

Y = -CH=CH-; -C=C-

1.88

Azoles are another category of five membered heterocyclic compounds containing two hetero
atoms in their rings where at least one of the hetero atoms must be nitrogen. The azoles are
derived from pyrrole by replacement of one methylene group by the nitrogen/oxygen/sulfur

atoms. They may contain more than one nitrogen atom of the two electronic types; the pyrrolic,
electron-releasing type, and the pyridinic, electronic-attracting type. Azoles are of two types (1,2
& 1,3) depending upon the placement of two hetero atoms in their rings 1.89 and 1.90.

N
N
X

X
X = (HN, O, S)

1.89

1.90

Pyrazole is the important member of the 1,2-azole family in which the direct linking of the two
hetero atoms has a very marked effect upon its basicity. Pyrazole derivatives are very remotely
formed in nature, probably due to the difficulty in constructing N-N bond by living organisms. 3Nonylpyrazole48 1.91,

-amino--1-pyrazolylpropionic

acid49

1.92

and

4-phenyl-1,5-

trimethylenepyrazole50 1.93 are the exceptional compounds which are isolated from houttuynia
cordata, watermelon seed and withania somnifera respectively.
N

NH2

H
N

HOOC

CH

CH2
N

(CH 2) 8CH 3

1.91

1.92

1.93

In 1884 Knorr discovered the antipyretic action of a pyrazole derivative in human beings which
actually initiated major interest in the study of these heterocycles.51,52 A large number of
pharmaceutical and dyestuff containing this ring system have been synthesized in laboratory.
The pyrazole derivatives are used in the form of some important drugs like antipyrine53
and novalgin54 1.95.

1.94

H3C

CH3
N CH 2

H3C

SO3Na

H3C

H3C

N
N

C6H5

C6H5

1.94

1.95

The isoquiloline derivatives 1.96-1.198 have been used for many centuries as hypnotics and
analgesics.
H3CCOO

H3CO

HO

CH3

1.96
Serotonin

HO
H

CH3

H
HO

HO

55

CH3

1.97

1.98

1.99, an indole derivative which is synthesized and investigated in the lab shows a

wide range of pharmacological applications. Many closely related substances have been
synthesized like sumatripan 1.100, for treatment of migraine and ondansetron56 1.101, for
suppression of nausea and vomiting during cancer chemotherapy.
CH3
H

CH3

N
NH2

HO

N
O

N
H

1.99

CH3

H3C

N
H

1.100

CH3

1.101

Polysubsituted pyrroles are the important constituents of many biologically active compounds
and have emerged as important chemotherapeutics agents.57
Besides these, many other pyrazole derivatives have been used for curing a number of other
ailments. For example, 1.102-1.105 are used as an antimalarial,58 anti-infertility,59 antiviral60 and
antitumour agents61 respectively.

H
N

OCH 3

N
S

1.102
H
N

1.103

F
N

OH

HO

OH

F
O

N
CO 2CH 3

N
CH3

1.104

1.105

The thiophene and related heterocycles are found in coal tar and crude petroleum. The most
important naturally occurring derivative such as B-complex vitamin biotin 1.106 which is an
essential growth factor for animals and human beings.
H

(CH2)4C OOH
N
S

O
N
H

1.106
Ranitidine 1.107 is a heterocyclic derivative having furan ring and it is widely used as a specific
H2-receptor antagonist to treat peptic and duodenal ulcers.62
M e2N

NO 2

S
O

NHM e
CH3

1.107
5-Nitrofurfural semicarbazide 1.108 is a useful antibacterial compound and khellin 1.109 is an
important medicinal agent that has been used for a variety of pharmacological indications
including hypertension, renal, biliary colic and stomach disorders.63

OCH 3 O

O
H3C

CH

N NH

NH2

CH3

OCH 3

1.108

1.109

Manning and coworker64 have made the detailed studies of some heterocycles 1.110 and 1.111
which are found to furnish biological influences on aphids and green bugs.
F 3C

F 3C

Cl

Cl

Cl

Cl

CH3

CH3

H2N

H2N

OCH 3

Ph

SCH 3

1.110

Ph

1.111

Benzothiazole 1.112 moiety is the part of many compounds showing numerous biological
properties such as antimicrobial,65-69 anticancer,70-73 antihelmintic,74 and antidiabetic75 activities.
The amino, hydroxyl and chloro containing derivatives showed better anticancer behaviour.76-78
N
4

R= -NH3, -OH, -Cl

1.112
Celecoxib 1.113, a pyrazole derivatives and veledecoxib 1.114, an isoxazole derivatives are
widely used in the market as anti-inflammatory drugs.79 In addition, a number of pyrazoles
exhibit fluorescence characteristics and act as agrochemical herbicides, soil fungicides,
pesticides and insecticides.80

O
S
H2N

N
N

C F3
N
O

CH3
H 2N

CH3

1.113

S
O

1.114

It is evident from the above literature studies that five membered heterocyclics particularly
pyrazolines and related compounds have been the subject of major attraction for the researchers
in the area of synthetic medicinal chemistry. Major emphasis has been laid down upon the
antibacterial, antifungal, antitubercular, anticancer, antidepressant and anti-inflammatory
behavior of these heterocyclic compounds. By considering this aspect in view we have focused
our investigations upon the detailed syntheses of new pyrazolines, thiadiazolines and thiazole
derivatives.
Thus, in the coming chapters we have presented the result of our investigations upon the
synthesis and antibacterial studies of new alkoxy substituted pyrazolines, thiadiazolines,
thiazoles and bispyrazolines. We have synthesized eight series of heterocyclic derivatives
bearing various substitutents on the alkoxy group. The researches have also been attempted upon
the N-phenyl & N-thiocarbamoyl-bispyrazolines built around the aliphatic chains of varying
lengths.

Chapter-IIa: Synthesis of new-N-phenyl-5-furyl/thienyl-pyrazolines

OCH 2 R
H
H
N
N

X = O, S
R=

CH=CH

, COOC 2H5 ,

Chapter-IIb: Synthesis of new-N-thiocarbamoyl-5-furyl/thienyl-pyrazolines.


OCH 2

R
H
H

N
N

C
NH2

X = O, S

R=

CH=CH2 ,

COOC 2H5 ,

Chapter-III: Synthesis of new-thiadiazolines and quinoxaline based thiazoles.


O

CH2

H
S
O
H3C

CH2

CH3

N
N

H C N NH

H
R=

CH=CH 2 ,

Chapter-IVa: Synthesis of new-N-phenyl-bispyrazolines.

CH 2 ,

CH 2CH3

CH2

(CH 2)n

CH2

O
H

H
H

N
N

X = O, S
n = 0, 2, 3, 4, 6

Chapter-IVb: Synthesis of new-N-thiocarbamoyl-bispyrazolines.


O

CH2

(CH 2)n

CH2

O
H

H
H

N
N

H
S

NH2
X = O, S
n = 0, 2, 3, 4, 6

N
NH2

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CHAPTER-IIa
Synthesis of New Alkoxy-N-phenyl-5furyl/thienyl-pyrazolines

Synthesis,

studies

and

in

5-(furan-2-yl)-phenyl pyrazolines

vitro-antibacterial

activity

of

N-substituted

Mamta Rani, Mohamad Yusuf, Salman Ahamad Khan, P.P. Sahota and
G. Pandove
Arabian Journal of Chemistry 2011, doi:10.1016/j.arabjc.2010.10.036.
Synthesis, studies and in vitro antibacterial activity of some 5-(thiophene-2-yl)phenyl pyrazoline derivatives
Mamta Rani and Mohamad Yusuf
Journal of Saudi Chemical Society 2011, doi:10.1016/j.jscs.2011.09.002.
The studies of heterocyclic compounds had been subject of the major attraction in the past due to
their occurrence in nature and numerous applications in the biological systems.1 The
development of clean procedures for the preparation of heterocyclic compounds is a major
challenge in modern heterocyclic chemistry in view of the environmental, practical and
economic issues. The derivatives of chalcones are the significant compounds which are
associated with a wide range of biological activities.2-11 Chalcones are the compounds having
1,3-diaryl-2-propene moiety, containing an olefinic, ketonic/hyrdoxyl group.2,4,6 Pyrazolines are
an important class of heterocyclic compounds containing two nitrogen atoms in the five
membered ring. Amongst different heteroatomic cycles, pyrazoline have played a crucial part in
the development of the heterocyclic systems and are also extensively used in the organic
synthesis.12-16 Pyrazoline derivatives are the electron rich nitrogen heterocycles which play an
important role in the diverse biological activities. The substituted 2-pyrazolines have found
application as activators for polymerization,17 dyes for wool, nylon,18 as electro photographic
conductors19 and as wavelength shifters in liquid and polymer scintillation.20 Considerable
attention has been focused on the pyrazolines and their derivatives due to their interesting
biological activities. These compounds have been found to possess antifungal,21 antidepressant,
anticonvulsant,22-25 anti-inflammatory,26 antibacterial27 and antitumor28 properties.
Pyrazolines are generally prepared from the condensation reaction of a variety of substituted
chalcones with hydrazine and its derivatives under acidic and basic medium.29-37
One of the most widely used method for the synthesis of pyrazoles involves the condensation of
appropriate hydrazine and 1,3-diketones. It is well known that symmetrical 1,3-diketones give
only one product with hydrazine and its derivatives.38-44 For instance, acetylacetone upon
reaction with substituted hydrazine afforded
the only product (Scheme-2.1).

3,5-dimethyl-N-substituted pyrazole 2.1 as

N
CH3

H3C

NHNH 2
H3C

CH3

2.1
Scheme-2.1

However, problem arised when a substituted hydrazine and unsymmetrical 1,3-diketone were
reacted which produced two isomeric pyrazoles. The reaction of benzoylacetone45 with methyl
hydrazine led to the formation of isomeric pyrazoles 2.2 and 2.3 (Scheme-2.2).

H3C

H3C
N

CH3

+ H3C

NHNH 2

H3C

CH3

2.2

2.3

Scheme-2.2

The reaction of 2,4-dinitrophenyl hydrazine with benzoyl acetone also resulted in the formation
of two isomeric pyrazoles46 2.4 and 2.5 (Scheme-2.3).
O 2N
NO 2
N

N
CH3

NHNH 2
O

2.4

O 2N

O
CH3

+
NO 2

O 2N

NO 2

H3C

2.5

Scheme-2.3
Selivonov et al47-48 have investigated the mechanism of these reactions by demonstrating the
presence of dihydroxypyrazolidine and hydroxypyrazoline as the intermediates.

Thus, reaction of symmetrical 1,3-diketone (R=CH3) with hydrazine proceeds through the
formation of dihydroxypyrazolidines and hydroxypyrazolines as the intermediates. But the
reaction of unsymmetrical 1,3-diketones (R=C2H5, t-Bu, Ph, CF3) with hydrazine provided two
dihydroxypyrazolidines 2.6 & 2.7 and two hydroxypyrazoline 2.8 & 2.9 intermediates (Scheme2.4).
R1

R1
N

OH

CH3

R1

CH3

2.6

HO

HO

R1

OH

N
CH3

HO

2.7

OH
CH3

2.8

2.9

Scheme-2.4
Elguero and Yranzo49 could become successful to isolate the proposed dihydroxypyrazolidine
and hydroxypyrazoline intermediates 2.10 and 2.11 from the condensation of 1,1,1,5,5,5hexafluoropentan-2,4-dione with hydrazine (Scheme-2.5).
H

H
O
F 3C

N
CF 3

NH 2NH 2

CF 3

F 3C

OH

HO

H
N
F 3C
HO

OH
CF 3

2.10
2.11
Scheme-2.5
Zelenin et al50 while investigating the condensation of benzoylacetones with hydrazine hydrate
were also able to isolate monohydroxypyrazoline intermediate 2.12 and this observation again
corroborated the proposed mechanism (Scheme-2.6).
O

O
CF 3

NH 2NH 2

F 3C

H
N

HO

2.12
Scheme-2.6

In the research work diazonium salts of sulfones 2.14a & 2.14b were coupled with malononitrile
to yield hydrazones 2.15a & 2.15b.51 The refluxing of hydrazones with hydrazine hydrate in
EtOH furnished the aminopyrazoles 2.16a & 2.16b. Some of the above said compounds were
tested for their antibacterial activity (Scheme-2.7).
CN
+

NH2

N2 Cl

NH N

NaNO2/ HCl

O 2S

CN

CH2(CN)2

O 2S N

O 2S

2.15
2.13

2.14
NH2NH2

NH2

NH
H2N

a) X= CH2 ; b) X=O

O 2S

X
2.16

Scheme-2.7
The transformation of 1,3,5-trisubstituted-pyrazolines to pyrazoles was carried out efficiently in
the presence of new reagent ni-tetrabromo-benzene-1,3-disulfonylamine [TBBDA] and nidibromo-N,N-1,2-ethanediylbis-(p-toluenesulphonamide) [BNBTS] in solvent-free conditions
with catalytic amounts of SiO2 under microwave irradiation52 (Scheme-2.8) in high yields.
R

R
N

2.17

Ph

MW/ BNBTS or TBBDA

solid phase or presence of SiO2

R
N

H3 C

Ph

H2N

NH

2.18
O

2.19

CH2- ) 2

NH2
S
O

S
O

2.20

Scheme-2.8

The title compounds 2.23 were prepared by reaction of Mannich bases 2.22 with various N-4
substituted thiosemicarbazides.53 All compounds were checked for microbial activity. It was
concluded that 3-chloro and 3-bromo substituents on the phenyl ring at position 3 of the
pyrazoline ring enhanced the antiamoebic activity (Scheme-2.9).

CH3

(HCHO)n

+ (CH ) NH Cl
3 2

HCl

CH3

CH3
O

2.21

2.22
b

X= H, Br, Cl
R= cyclic amine

N
N
S

a) (i) EtOH, HCl, reflux; b) MeOH, NaOH, reflux


X

2.23

.
Scheme-2.9
A series of chlorinated 3,5-diaryl-2-pyrazolines54 has been synthesized by the reaction of
appropriately substituted chlorochalcones and mono-substituted hydrazines in hot acetic acid
solution (Scheme-2.10).
R

XNHNH2/ MeCOOH

2.24

NH2

2.25
X= H, Ph

Scheme-2.10
4-Methylthiobenzaldehyde55 reacts with substituted acetophenones under aldol conditions to
form unsaturated compounds which undergo cyclization with hydrazine to provide pyrazolines
2.29 & 2.30 (Scheme-2.11).

O
CH 3S

CH3

2.26

2.27
KOH/ EtOH

CH 3S
2.28
NH2NH2.H2O, AcOH

NH2NHPh, AcOH

R
N

R
N
N
CH 3S

N
CH 3S

CH3
2.29

2.30

R = H, Cl, OCH3, NO2, CH3, Br, F, 2,4-Cl2

Scheme-2.11
Some N-substituted thiocarbamoyl-3,5-diphenyl-2-pyrazoline derivatives56 2.33 have been
synthesized (Scheme-2.12) by a base catalysed Claisen-Schmidt condensation of benzaldehyde
with acetophenone followed by cyclization with various N-4 substituted thiosemicarbazides. The
palladium(II) complexes of these ligands were obtained by reacting 2.33 with [Pd(DMSO)2Cl2].

O
OHC
CH3

MeOH, NaOH

+
2.32

2.31
H2N

NH

EtOH, NaOH

Pd(DMSO)2Cl2

Cl
Pd
Cl

Dry MeOH

N
S

N
N
S

R
2.33

2.34

Scheme-2.12

A series of 1,3,5-triaryl-2-pyrazolines 2.37 were prepared in good yields through the reaction of
chalcones57and phenyl hydrazine hydrochloride in sodium acetate-acetic acid aqueous solution
under ultrasound irradiation (Scheme-2.13).
Ar1
N
Ar1

Ar2
O

CH3COONa/ AcOH/H2O

N
Ar2

NHNH 2.HCl
2.35

2.37

2.36

Scheme-2.13

Fourteen N-acetylated and non-acetylated 3,4,5-tri- or 2,5-dimethoxypyrazoline analogs of


combretastatin-A4 (1) were synthesized 58 through the protocol as shown in

Scheme-2.14.
R

H3CO

H3CO

OH

OH

i or ii

H3CO

OCH 3
H3CO

2.38
R= H, Ac

i) Hydrazine hydrate, EtOH, reflux ii) Hydrazine hydrate, AcOH, reflux

Scheme-2.14

H3CO

OCH 3
H3CO

2.39

To discover new lead compounds exhibiting both fungicidal and insecticidal activities, a series of
pyrazoline derivatives 2.42 were designed and synthesized (Scheme-2.15) by introducing the
methoxyacrylate pharmacophore into the scaffold of 1-acetyl-3,5-diarylpyrazoline.59
O
R
NH2NH2.H2O/ AcOH

OH

Br

CH3 MeO

N
OH
2.41

2.40

O
O

CH3

K2CO3/ acetone

COO Me

CH3
2.42

CH3

Scheme-2.15

Novel series of 1-(2,4-dimethoxy-phenyl)-3-(1,3-diphenyl-1H-pyrazol-4-yl)propenone 2.45 had


been prepared by the Claisen-Schmidt condensation of 1-(2,4-dimethoxy-phenyl)-ethanone 2.43
and substitued 1,3-diphenyl-1H-pyrazole-4-carbaldehydes 2.44 and the later were prepared by
the Vilsmeir-Haack reaction on acetophenone phenyl hydrazones (Scheme-2.15). All the
compounds were also evaluated for their

anti-inflammatory, antioxidant and antimicrobial

activities.60
R
O

O
CH3
H3C

CH3

EtOH, NaOH, rt

H3C

2.43

H 3C

H
H 3C
H 3C

CHO

H 3C
H 3C

Cl
Br

Cl

H 3CO

H 3C
H 3C

H 3C
H 3C

2.45

2.44
R=

CH3

Cl

H 3C
H 3C

H 3C
H 3C

H 3C
H 3C

Cl H CO
3

Cl

H 3C
H 3C

OCH 3

H 3C
H 3C

Scheme-2.16
A group of 3,5-diaryl-2-pyrazoline derivatives61 2.46 were prepared via the reaction of various
chalcones with hydrazine hydrate in ethanol. A group of 2-pyrazoline derivatives 2.51 & 2.52
were synthesized by carrying different steps as shown in Scheme-2.17.

R1

R2

CH3

+ Ar

R2

CHO

R2

Ar

Ar
N
2.46 H

N
N
Ar

d
R1

R1

N
CH2ONO 2

O
2.48
R1

R2

R2
R2

N
N

Ar

N
Ar

Br

CHONO2
2.52

CH2Br

2.47

Ar

R1

R2

Ar

R2

R2

R1

R1

R1

R1

CH3

N
NH

O
CH3

2.49

NH

CH3
CH3

2.50

2.51

O
a)NaOH,EtOH; b)NH2NH2.H2O, EtOH; c) BrCH2COBr, K2CO3; d) CH3CH(Br)COOH, ClCOOEt, Et3N; e) AgNO3, CH3CN, f) p-NH2 Acetophenone,
K2CO3, acetone g) NH2OH. HCl, EtOH

Scheme-2.17

A novel series of 5-(substituted)aryl-3-(3-coumarinyl)-1-phenyl-2-pyrazolines 2.55 were


synthesized (Scheme-2.18) by reacting various substituted 3-aryl-1(3coumarinyl) propan-1-ones
2.54 withphenyl hydrazine in the presence of hot pyridine.62
O
O

CHO

OH

CH3

+
H3C

CH3

O
2.53
b

H2 N

O
substituted Aryl/phenyl

H
O

substituted Aryl/phenyl
c

2.55

2.54

Reaction conditions: Piperidine, stir, rt, 20min. b) Ar-CHO, piperidine/butanol c) hydrazine derivative, pyridine, reflux

Scheme 2.18

3,5-Diaryl-pyrazolines 2.57 were obtained (Scheme-2.19) and evaluated for their monoamine
oxidase (MAO) inhibitory activity.63

NOH

O
HO

HO
R-C6H4-NCS, MeOH

NH2NH2.H2O, EtOH,reflux

HO

N
H

N
S

2.56

HN
R

2.57

Scheme-2.19
A series of 1,3,5-trisubstituted pyrazolines were prepared (Scheme-2.20) and evaluated for in
vitro antimalarial efficacy against chloroquine sensitive as well as chloroquine resistant strains of
Plasmodium falciparum.64
O

R5
CH3

HO

R4

O
H Methanolic NaOH, r.t.

+
R3

R5

HO

R4

R3
R2

R1
R2

2.58

2.59

NH2
NH

+
N

R1

2.60
n-butanol, reflux

HO
R1

R2
R3

N
N
O

R5

R4

2.60 a

Scheme-2.20

The zwitterionic intermediates generated from dialkyl azodicarboxylates and triphenylphosphine


displayed excellent reactivity65 toward 3-formylchromones to afford chromeno[2,3-c]pyrazolines
2.63 and chromeno[2,3-e]tetrazepines 2.64 (Scheme-2.21).

COOR
R

+
R

CHO

COOR

COOR

3
3

toluene, reflux

COOR

PPh3

2.61

2.62

2.63
COOR
R

R1 = H, Me, i-Pr, Cl

COOR

R3 = i-Pr, Et

R2 = H, Me

COOR

N
O

COOR

2.64

Scheme-2.21
A series of 2-pyrazolines 2.68 have been synthesized66 from ,-unsaturated ketones 2.67 and
hydrazine hydrate with acetic/formic acid in ethanol/DMSO as shown in

H
R

R
2.65

NaOH/ EtOH/ SOCl2/ EtOH

Scheme-2.22.

CH3

2.67

2.66

NH2NH2/ HCOOH NH2NH2/ AcOH

CH 2

R
R

N
O
R

2.68

Scheme-2.22

It is evident from the above literature survey that pyrazolines and their derivatives are
biologically highly significant. Thus, there is an enough scope upon the synthesis of new
pyrazolines and their biological activity need to be explored to investigate the potentially
efficaceous antibacterial compounds. By, keeping this aspect in view, researches have been
focused upon the following alkoxy substituted 5-furyl-pyrazolines 2.74-2.77.

CH2

HM
HA
N
N Hx

2.74 R = -CH=CH2,
2.75 R = -Ph,
2.76 R = -COOEt ,
2.77 R =

Scheme-2.23
The pyrazolines 2.74-2.77 required for this study were prepared starting from chalcone 2.69
which was obtained from the Claisen-Schmidt reaction of 2-hydroxy-acetophenone with 2furaldehyde (Scheme-2.24). The decomposition of the reaction mixture into iced HCl provided a
crude product which was crystallized from MeOH to yield pure chalcone 2.69 (80%, m.p. 8486C).
3'

OH
CH3
O

NaOH/ EtOH/ O0C

4'

2'

OH

4''

3''
2

H
O
O

5'

1'
6'

5''

1
3

O
1''

2.69
Scheme-2.24
The compound 2.69 was identified from its spectral analysis. Its IR spectrum showed major
absorptions at 1634 & 3210 cm-1 due to the conjugated carbonyl and OH groups respectively. In
the 1H-NMR spectrum (400 MHz, CDCl3) of 2.69, a D2O exchangeable singlet was placed at
12.70 that can be ascribed to OH proton. The double bond and furan rings protons were very
well resonating at 8.02 (1H, d, H-3), 7.72 (1H, d, H-2), 7.31 (1H, d, J5,4=1.8Hz, H-5), 7.25
(1H, m, H-3) & 7.02 (1H, dd, J4,3=3.5Hz, J4,5=1.8Hz, H-4). The coupling value of 15.4
Hz between H-3 & H-2 describes the trans geometry around the C-3 & C-2 double bond. Finally,
its structure was confirmed from the

13

C-NMR spectrum which displayed the major resonances

at 192.4 (C=O), 142.6 (C-3) & 120.3 (C-2) and other signals were found to be placed in the
aromatic region at 152.8 (C-2), 150.7 (C-2), 148.6 (C-5), 138.2 (C-1), 136.2 (C-6), 129.4

(C-3), 128.7 (C-4),127.3 (C-5), 125.5 (C-3) & 123.4 (C-4). The mass spectrum of 2.69
exhibited the molecular ion at m/z 215 (60%) which also corroborated its structure.
Synthesis of (5R)-5-(furan-2-yl)-1-phenyl-3-[2-(prop-2-en-1-yloxy) phenyl]-4,5-dihydro-1Hpyrazole 2.74
The compound 2.74 was obtained in two steps:
(i). Synthesis of allyloxy-chalcone 2.70
The chalcone 2.69 was treated with allyl bromide in the presence of anhydrous K2CO3 and
tetrabutyl ammonium iodide (PTC) in dry acetone under the refluxing conditions (Scheme-2.25).
The reaction mixture was poured into iced HCl to give a solid compound. The crude product was
purified by crystallization from MeOH to yield pure compound 2.70 (70%, m.p. 96-980C).
CH2 -CH=CH

3'
2'

4'

1'
5'
6'

OH

3''

+ -

4'

dry acetone

5'

K2CO3/ Bu4N I / RCH2-CH=CH2/

5''

1
3

3'

4''

O
1''

2'

3''

4''

2
1'
6'

5''

1
3

O
1''

2.70
Scheme-2.25
The structure of compound 2.70 was determined from the rigorous analysis of its spectral data.
IR spectrum exhibited absorption bands at 1655 (C=O), 1602 (C=C) & 1250, 1030 (C-O) cm-1.
Its 1H-NMR spectrum (400 MHz, CDCl3) was quite informative. The aromatic protons produced
suitable signals at 7.57 (1H, d{dd}, Jp,m,o=0.9, 1.4, 7.8Hz, H-6), 7.50 (2H, m, H-4, 5), 7.35
(1H, m, H-5), 7.28 (1H, d, J3,4=3.2Hz, H-3), 7.15 (1H, dd, J4,3=3.2Hz, J4,5=1.8Hz, H4) & 6.94 (1H, d, Jo=7.8Hz, H-3). The upfield appearance of the later may be resulted by the
electron releasing effect of the allyloxy group present at C-2 position. In the aromatic region,
two broad doublets were also observed at 7.64 (1H) & 7.43 (1H) which could be furnished by
H-3 & H-2 respectively. The coupling value of 15.6 Hz between these protons describes their
trans relationship. The signals belonging to the allyloxy group were centered at 5.45 (1H, td,
Jvic, trans= 6.7, 15.8Hz, CH=CH2), 5.24 (2H, td, Jallyl,trans=1.0, 15.8Hz, CH=CH2) & 4.64 (2H, dd,
Jallyl, vic =1.0, 6.7Hz, OCH2).
13

C-NMR (100 MHz, CDCl3) spectrum of 2.70 was very instrumental to corroborate its proposed

structure. Here, presence of the enone moiety was confirmed by resonances at 192.2 (C=O),

141.5 (C-3) & 120.8 (C-2) and the signals at 132.0, 118.5 & 69.5 could be emanating from
allyloxy group carbon atoms CH=CH2, CH=CH2 & OCH2 respectively. The carbon atoms
belonging to furan ring furnished suitable signals at

153.6 (C-2), 144.6 (C-5), 131.4

(C-3) & 125.8 (C-4) respectively. The remaining carbon atoms (C-1 to C-6) were found to
be resonating at the expected position in the aromatic region (vide experimental).
The heaviest ion in the mass spectrum of 2.70 was observed at m/z 255 (18.2 %) and other major
ions were found at m/z 214 (20.2 %), 188 (10.3 %) & 134 (14.6 %) due to the loss of allyloxy,
furyl and C=O group respectively. The fragmentation pattern of 2.70 has been depicted in
Chart-1.

.. a
..

.
O ... CH2 CH CH2

+.

..
..
..
..
O
b
O
m/z 255 (18.2 %)

-C4H3O

-CH2-CH=CH2

+.
O

CH2 CH CH2

..
..
..
..

O+
..
..
..
..

CH2

m/z 214 (20.2 %)

m/z 188 (10.3 %)

-HC

+ H.

- C4H5O

CH

O+
O CH2 CH

CH2

..
..
...
.

..
..
... +
.

O
m/z 146 (9.8 %)

O
m/z 163 (100 %)

- CO , -C 2H2
- CO

..
..

.
O ... CH2 CH

+.

+.
OH

CH2
- C3H5

m/z 94 (11.2 %)
m/z 134 (14.6 %)

Chart-1
(ii). Cyclization of chalcone 2.70
The compound 2.70 was refluxed with phenyl hydrazine in EtOH/AcOH solution (Scheme-2.26)
and cooling of the resulting reaction mixture provided a solid compound. The crude product was
crystallized from MeOH to yield pure pyrazoline 2.74 (62%,

m.p. 130-1320C).

3''

CH2 CH=CH
2'

3''

4''

1'
6'

PhNHNH2/ AcOH/EtOH

5''

5''

1
3

3 4

6''
2

2
5'

CH2

2
1''

3'
4'

2''

4''

HM
HA

3'''

1N Hx

1''

1'
6'

4'''

CH=CH

5'''

O
1'''

2'
3'

5'
4'

2.70

2.74

Scheme-2.26
The IR spectrum of 2.74 was very helpful to interpret its structure which did not exhibit any
absorption band at 1655 cm-1 indicating the involvement of carbonyl group during the
cyclization reaction of 2.70. Here, significant absorption band was observed at

1595 cm-1 due

to the C=N moiety of pyrazoline ring. Its mass spectrum furnished the heaviest ion at m/z 344
(34.6 %) which easily describes that a phenyl hydrazine moiety has undergone
cyclocondensation with chalcone in the formation of 2.74. The mass fragmentation pattern of
2.74 also corroborated its structure which has been presented in Chart-2 and here ions were
observed at m/z 303 (30.4 %), 277 (25.1 %) & 227 (23.1 %) due to the loss of allyloxy, C 3phenyl and C5-furyl ring respectively (Chart-2).
A comparison of the 1H-NMR spectra (400 MHz, CDCl3) of 2.70 and 2.74 shows that resonances
present at 7.64 (H-3) & 7.43 (H-2) in former were found missing altogether in the later, thereby
pronouncing the involvement of these hydrogens in the chemical transformation. The protons
(H-6, 5 & 3) appeared at 7.84 (1H, dd, Jm,o=2.4, 7.8Hz), 7.36 (1H, d, J5,4=1.8Hz) &
7.29 (1H, d, J3, 4=3.4Hz) respectively. A doublet placed at 6.89 (Jo= 7.8 Hz) could be given
by H-3 and its upfield appearance might be resulted by electron releasing effect of C 2-allyloxy
group. The remaining aromatic protons (H-2, 3, 4, 5, 6, 4, 5 & 4) appeared as
multiplets in the region of

7.20-6.96 (vide experimental).

The major feature of the 1H-NMR spectrum of 2.74 was the signals of pyrazoline ring protons
(H-X, M & A) which were centered at 5.28 (1H, dd, JXA=6.7Hz, JXM=11.6Hz), 3.58 (1H, dd,
JMX=11.6Hz, JMA=16.7Hz) & 3.27 (1H, dd, JAX=6.7Hz, JAM=16.7Hz) respectively. In a double
resonance experiment, irradiation of doublet of doublet at 5.28 (H-X) converted the doublet of

doublets at 3.58 (H-M) and 3.27 (H-A) to doublet each which clearly describes the coupling
pattern among hydrogens H-X, H-M & H-A.
Finally

13

C-NMR (100 MHz, CDCl3) data of 2.74 provided enough evidence in favor of the

proposed structure. The downfield signals at 156.7, 155.2, 154.4 & 144.2 were designated to
C-3, 2, 5 & 1 respectively due to their direct bonding to the electronegative hetero atoms
(O & N). The remaining aromatic carbon atoms were resonating at 156.2 (C-2), 136.4 (C1), 131.5 (C-3), 130.9 (C-6), 129.8 (C-4), 129.1 (C-5), 128.2 (C-4), 127.5 (C-3,5),
125.5 (C-4), 123.2 (C-2, 6) & 116.7

(C-3). The signals present at 57.3 (C-5) & 43.7 (C-4)

could be easily generated by pyrazoline ring carbons C-5 and C-4 respectively. The carbon
atoms of the allyloxy chain appeared at 133.8 (CH=CH2), 118.2 (CH=CH2) & 76.7 (OCH2).

H2C CH=CH
...... c

+.
2

O
b

......

H
......

N
N

a
-C4H4O

c
m/z 344 (34.6 %)

+
.

H2C CH=CH

O
H
H

H
+

N H

H
H

N
O

N H

m/z 303 (30.4 %)

H
N

......

m/z 277 (25.1 %)


m/z 227 (23.1 %)

-O

+H. -C6H5

-2H.

+.

+.

H2C CH=CH

H
H

......

N
O

......

N H

N
m/z 225 (56.2 %)

H
N
H

m/z 200 (44.0 %)


m/z 288 (12.6 %)
+H.

-C4H3O
-N2H

-C4H3O

......

+.

H
N

H
H

N
N H

H2C CH=CH

O
-C6H5
-H2

m/z 143 (100 %)

H
m/z 170 (18.4 %)
m/z 202 (9.7 %)

Chart-2

Synthesis of (5R)-5-(furyl-2-yl)-1-phenyl-3-[2-(benzyloxy) phenyl]-4,5-dihydro-1H-pyrazole


2.75
The pyrazoline 2.75 was again obtained in the two steps:

(i). Synthesis of alkoxy chalcone 2.71


The reaction of 2.69 with benzyl chloride (Scheme-2.27) under the similar conditions as used
earlier for 2.70 yielded compound 2.71 (72 %, m.p. 118-1200C).
2'''

3'''

1'''
CH2
3'
4'

2'
1'

5'
6'

3'

OH
1

3''
2

K2CO3/Bu4N+I-/BrCH2Ph/dry acetone
5''

4''

6'

1''

2.69

1' 1

5'

2'

4'

4'''
6'''

5'''
3''

4''

5''
3

1''

2.71

Scheme-2.27
The IR spectrum of 2.71 had strong absorptions at 1653 (C=O) & 1603 (C=C) cm-1. In the 1HNMR (400 MHz, CDCl3), the characteristics doublets of the trans double bond were resonating
at 7.62 (1H, Jtrans=15.6Hz, H-3) & 7.41 (1H, Jtrans =15.6Hz, H-2). The downfield placement of
the former hydrogen (H-3) could be ascribed to the electophilic character of the -carbon atom in
the enone moiety. The remaining aromatic hydrogens were suitably placed at 7.54 (1H, d{dd},
Jp,m,o=0.9, 1.4, 7.8Hz, H-6), 7.49 (4H, m,
7.10 (1H, m, H-4), 7.03 (2H, m,

H-4, 5, 3, 5), 7.31 (3H, m, H-5, 3, 4),

H-2, 6) & 6.89 (1H, d, Jo=7.9Hz, H-3); the upfield

resonance of the later again could be ascribed to of the +I effect of the C-2 benzyloxy group.
The OCH2 group produced a two protons sharp singlet at 5.18 and vicinity to the oxygen atom
and benzylic nature of these protons make the downfield appearance.
13

C-NMR (100 MHz, CDCl3) spectrum of 2.71 also exhibited the major resonances at

191.4

(C=O), 154.1 (C-2), 153.5 (C-2), 143.8 (C-5), 141.3 (C-3), 132.6 (C-1) & 130.9 (C-1).
The remaining aromatic carbon atoms were resonating at the expected position in the aromatic
region (vide experimental). The benzyloxy group (OCH2) furnished a suitable signal at 77.4. In
the mass spectrum of 2.71, the molecular ion was present at m/z 305 (20.2 %) and its mass
fragmentation pattern was found to be similar as shown in Chart-1 (vide experimental).

(ii). Cyclization of chalcone 2.71


The reaction of 2.71 with phenyl hydrazine (Scheme-2.28) under the similar conditions as used
earlier for 2.74 resulted in the formation of pure pyrazoline 2.75 (60%,
3'''

2'''
2'''

3'''

1'''

CH2
3'
4'

2'

1' 1

5'
6'

5'''
3''

5''
3

PhNHNH2/ AcOH/EtOH

6''

1'''
4'''
5'''

6'''

1''

5''
4''

CH2

2''

4''

4'''

6'''

3''

1''

HM
HA

3'''

4'''

N Hx
1'

6'

m.p. 128-1300C).

5'''

O
1'''

2'
3'

5'
4'

2.71

2.75

Scheme-2.28
In the IR spectrum of 2.75, the characteristics bands were observed at 3081 (aromatic

C-H) &

1600 (C=N) cm-1. Its 400 MHz 1H-NMR exhibited pyrazoline ring protons (H-X, M & A) at
5.23 (1H, dd), 3.82 (1H, dd) & 3.52 (1H, dd) respectively. The coupling value of JAX=6.5Hz and
JMX=11.2Hz describes that H-A is trans to H-X while H-M has cis relationship to H-X. The
coupling constant of JMA=17.1Hz describes the geminal placement of the H-A and H-M at C-4.
The protons belonging to aromatic rings were resonating at 7.82 (1H, dd, Jm,o=2.3, 7.8Hz, H6), 7.34 (1H, d, J5,4=3.5Hz, H-5), 7.25 (3H, m, H-3, 3, 5), 7.21 (5H, m, H3,5,4,5,4), 7.12 (5H, m, H-2, 4, 6, 2, 6) & 6.94 (2H, m, H-3, 4). In the upfield
region, a singlet integrating for two protons at 5.32 may be allotted to OCH2 group.
The mass spectrum of 2.75 was quite helpful to interpret its structure which had the molecular
ion at m/z 395 (24.4 %) and other major fragments were observed at m/z 327 (28.2 %), 303 (60
%), 222 (42.4 %) & 211 (100 %). Its mass fragmentation pattern was found to be similar as
shown in Chart-2 (vide experimental).
13

C-NMR (100 MHz, CDCl3) of 2.75 produced the resonances of the pyrazoline moiety

(C-3, 5 & 4) at 156.1, 60.2 & 45.3 respectively; the most downfield occurrence of the former
carbon (C-3) could be ascribed to its azomethine nature. Other prominent signals were present at
153.4, 152.3, 142.6, 142.2, 133.2, 130.1 & 129.6 which could be easily provided by C-2, 2,

5, 1, 1, 1 & 6 respectively. The remaining carbon atoms furnished appropriate


resonances at the expected positions in the aromatic and aliphatic regions (vide experimental).
Synthesis of alkoxy-chalcones 2.72 and 2.73
The compounds 2.72 and 2.73 were obtained from the O-alkylation of 2.69 with
2-bromoethylacetate and 1-chloromethylnaphthalene respectively under the similar conditions as
used earlier for 2.70 & 2.71.
R

H2C
3'
2'

4'
5'

1'
6'

O
1

5''
3

4''

3''

1''

7"'
8"'

2.72: R = -COOCH

2CH 3 ; 2.73: R =

9"'
1"'
2"'

6"'
5"'
10"'
4"'
3"'

IR spectra of 2.72 and 2.73 exhibited strong bands at 1650 & 1754 and 1654 cm-1 respectively
which indicated the presence of C=O group. In the 1H-NMR spectra, hydrogens belonging to C-1
and C-3 aryl rings and double bonds were found resonating at the expected positions (Table-1 &
vide experimental). The distinguishing feature in their 1H-NMR spectra was the signal due to
alkoxy group. The OCH2 group produced singlets at 5.18 & 5.49 respectively in 2.72 & 2.73
and the downfield resonance of these hydrogens may be occurring due to their direct linkage to
oxygen atom. In case of former, two additional signals were found at 4.24 (2H, q, Jvic=6.9Hz)
& 1.34 (3H, t, Jvic=6.9Hz) which could be assigned to ethyl group (-CH2CH3) of the carboxylate
moiety.

13

C-NMR spectra of 2.72 and 2.73 were also similar as observed in 2.70 and 2.71

(Table-1 & vide experimental). The OCH2 group in 2.72 and 2.73 were present at 72.4 & 74.0
respectively. Additional signals were present in the former at 68.5 (OOCH2CH3) & 23.4
(OOCH2CH3).
The cyclization reaction of 2.72 and 2.73 with phenyl hydrazine under the similar conditions as
used earlier for 2.74 led to the formation of pyrazolines 2.76 & 2.77 respectively. These
compounds were identified by using their spectroscopic data

(Table-1 & vide experimental).

The significant features in the 1H-NMR spectra of 2.76 and 2.77 were three doublet of doublets
(dd) present at 5.25-5.23 (JXA=6.5Hz, JXM=11.8Hz), 3.82-3.62 (JMX=11.8Hz, JMA=16.2Hz) and
3.42-3.23 (JAX=6.7Hz, JAM=16.2Hz) which could be easily given by pyrazoline ring protons H-

X, H-M & H-A respectively. The signals of the N-1, C-3 & C-5 aryl rings and alkoxy group
protons were found to be present at the expected and J values in the aromatic region (Table-1
& vide experimental).

3''
4''

2''
1''

5''
6''

CH2 R

HM
HA

3'''

4'''

5'''

N
1 N Hx
1'
6'

O
1'''

2'
3'

5'

7"'

4'
8"'

2.76: R = -COOCH

2CH 3 ; 2.77: R =

9"'
1"'
2"'

6"'
5"'
10"'
4"'
3"'

The structures of 2.76 and 2.77 were further corroborated from their

13

C-NMR spectra where

aromatic and aliphatic carbons atoms were placed at the expected positions (Table-1 & vide
experimental). The mass spectra of these compounds exhibited the molecular ions at m/z 391
(2.72) and 445 (2.73) and their mass fragmentation pattern was found to be similar (vide
experimental) as depicted in Chart-2.

Table-1: Physical and characteristics spectral data of alkoxy-chalcones (2.72 & 2.73) and pyrazolines (2.76 & 2.77)
Compound

Yield (%)

No.
2.72

65

H-NMR ()

13

C-NMR ()

m.p.

I.R.

(0C)

max (cm-1)

108- 110

1754 (C=O)

7.82 (H-3), 7.45

191.2 (C=O), 187.8 (C=O), 155.8

1650 (C=O)

(H-2), 5.18

(C-2), 142.5 (C-3), 120.2 (C-2)

ESI-MS
(m/z)
301 (M+, 100 %)

(OCH2)
2.73

72

137-139

1654

7.91 (H-3), 7.47

192.3 (C=O), 154.7 (C-2), 140.6

(C=O)

(H-2), 5.49

(C-3), 120.4 (C-2)

355(M+, 60.3 %)

(OCH2)
2.76

2.77

64

65

150-152

162-164

1755 (C=O)

5.25 (H-X), 4.61

190.5 (C=O), 156.6 (C=N), 155.6

1604 (C=N)

(OCH2), 3.82 (H-

(C-2), 76.7 (C-5), 72.2 (OCH2),

M), 3.42 (H-A),

45.6 (C-4)

5.23 (H-X), 5.04

156.7 (C=N), 155.2 (C-2), 54.6

(OCH2), 3.62 (H-

(C-5), 71.2 (OCH2), 46.2 (C-4)

1598 (C=N)

M), 3.23 (H-A),

413 (M+Na+, 100 %)/


391 (M+, 10.4 %)

445 (M+1+, 100 %)

To generalize the above described cyclization reaction of chalcones, these


investigations have also been extended upon the synthesis of 5-thienyl-pyrazolines
2.83-2.86.

CH2

HM
HA
N
N Hx

2.83 R = - CH=CH2,
2.84 R = - Ph,
2.85 R = - COOEt ,
2.86 R =

The pyrazolines 2.83-2.86 needed for this study were synthesized starting from
chalcone 2.78 which was obtained from the Claisen-Schmidt reaction of 2-hydroxyacetophenone with thiophene-2-carboxaldehyde (Scheme-2.30). The decomposition
of the reaction mixture into iced HCl provided a crude product which was crystallized
from MeOH to yield pure chalcone 2.78 (86%, m.p. 94-96C).
3'

OH
0

CH3

NaOH/ EtOH/ O C

2' OH

4'

4''

3''

5'

1'
6'

1
3

5''

1''

2.78
Scheme-2.30
IR spectrum of 2.78 showed significant absorptions at 1638 (C=O) and 2949 (OH)
cm-1. In the 1H-NMR spectrum (400 MHz, CDCl3), H-2 & H-3 were resonating at
7.82 (1H, d) & 8.04 (1H, d) respectively and the coupling value of 15.1Hz between
these hydrogens describes the trans geometry around C-2 & C-3 double bond. The
protons of the thienyl and phenyl rings were centred at appropriate position in
aromatic region (vide experiemental). In the mass spectrum of 2.78, heaviest ion was
observed at m/z 231

(50.8 %) which also described its structure. In the

13

C-NMR

(100 MHz, CDCl3) spectrum of 2.78, signals of the enone moiety were present at
191.4 (C=O), 149.6 (C-2), 143.8 (C-3) and aromatic carbon atoms were resonating at
expected position (vide experiemental).
Synthesis of (5R)-5-(thienyl -2-yl)-1-phenyl-3-[2-(prop-2-en-1-yloxy) phenyl]-4,5dihydro-1H-pyrazole 2.83
The compound 2.83 was obtained in two steps:
(i). Synthesis of allyloxy-chalcone 2.79
The chalcone 2.78 was reacted with allyl bromide in the presence of anhydrous
K2CO3 and tetrabutyl ammonium iodide (PTC) in dry acetone (Scheme-2.31). The
reaction mixture was decomposed by pouring into iced HCl to give a solid product
which was crystallized from MeOH to yield pure compound 2.79 (78%, m.p. 1131150C).
H2C CH=CH
3'
4'

3'

OH

2'

3''

4''

4'

2'

K2CO3/BrCH2-CH=CH2/dry acetone/
1'

5'
6'

5''
3

2.78

S
1''

Bu4N+I-/

2
3''

4''

2
5'

1'
6'

5''

1
3

S
1''

2.79

Scheme-2.31
The structure of compound 2.79 was based upon of its spectroscopic data. IR
spectrum exhibited the major bands at 3084 (aromatic C-H), 1651 (C=O) & 1596
(C=C) cm-1. Its 1H-NMR spectrum (400 MHz, CDCl3) provided the signals for phenyl
and thiophene rings hydrogens at 7.59 (1H, d{dd}, Jp,m,o=0.9, 1.4, 7.8Hz, H-6),
7.52 (2H, m, H-4, 5), 7.35 (1H, m, H-5), 7.30 (1H, d, J3,4=3.2Hz, H-3), 7.17
(1H, dd, J4,3=3.2Hz, J4,5=5.0Hz, H-4) & 6.98 (1H, d, Jo=7.9Hz, H-3). Two
broad doublets were also found to be placed at 7.68 & 7.44 which were easily
represented by H-3 & H-2 respectively while the coupling value of 15.7 Hz between
these protons describes the trans geometry around C-2 & C-3 double bond. The
protons belonging to allyloxy moiety resulted suitable resonances at 5.49 (1H, td,
Jvic,trans=6.7, 15.8Hz, CH=CH2), 5.23 (2H, td, Jallyl,trans=1.0, 15.8Hz, CH=CH2) & 4.64
(2H, dd, Jallyl,vic=1.0, 6.7Hz, OCH2). The molecular ion in the mass spectrum of 2.79

was observed at m/z 271 (100%) and its fragmentation pattern has been shown in
Chart-3 (vide experimental).
..
..

Ob ... CH2

CH

.
a...
..
.

+.

CH2

O
m/z+1 271 (100%)

- C3H4

-C6SH4
+.

OH

..
..
...

..
..
...

a
.

.
CH2 ... CH

..

S
O

O
m/z 231 (37.4 %)

m/z 162 (26.5 %)


-CH=CH

-CH

CH2

CH
..
..
.. CH 2
.

O
OH

..
..
... +

..
..
...

m/z 135 (11.4 %)

m/z 204 (60.2 %)


-CH 2 , -CO

-C5OSH3
+.
OH

O+

-H

m/z 93 (8.4 %)
m/z 94 (12.2 %)

Chart-3
13

C-NMR (100 MHz, CDCl3) spectrum of 2.79 was very helpful to corroborate its

proposed carbon framework. The most downfield signal at 190.6 could be given by
C=O group and the carbon atoms of the thienyl ring and allyloxy moiety were located
at 152.1 (C-2), 143.8 (C-5), 131.8 (C-3), 127.4 (C-4), 132.1 (CH=CH2),
119.6 (CH=CH2) & 70.5 (OCH2) respectively. Other carbon atoms were found to be
resonating at the expected positions in the aromatic region (see the experimental).

(ii). Cyclization of chalcone 2.79

The compound 2.79 was refluxed with phenyl hydrazine in EtOH/AcOH solution
(Scheme-2.32). The resulting reaction mixture was cooled in an ice bath to yield a
solid compound which was crystallized from MeOH to give pure pyrazoline 2.83
m.p. 133-1350C).

(65%,

3''

CH2
3'
2'

4'

1'

5'
6'

CH=CH

O
1

4''

5''
PhNHNH2/ AcOH/EtOH /

1''
3

CH2

CH=CH

HM
HA

3'''

5''

1N Hx
1'
6'

4'''

S
1''

6''
2

2
3

3''

2''

4''

5'''

S
1'''

2'
3'

5'
4'

2.79

2.83

Scheme-2.32
IR spectrum of 2.83 showed major absorption bands at 3032 (aromatic C-H) & 1594
(C=N) cm-1. 1H-NMR spectrum (400 MHz, CDCl3) of 2.83 was very helpful to
describe its structural features. The hydrogens of the allyloxy group and pyrazoline
moiety were resonating at 5.58 (1H, td, Jvic,trans=6.8, 15.8Hz, CH=CH2), 5.19 (2H,
td, Jallyl,trans=1.0, 15.8Hz, -CH=CH2), 4.68 (2H, dd, Jallyl,vic=1.0, 6.8Hz, OCH2) & 5.24
(1H, dd, JXA=6.7Hz, JXM=11.6Hz, H-X), 3.62 (1H, dd, JMX=11.6Hz, JMA=16.7Hz, HM), 3.34 (1H, dd, JAX=6.7Hz, JAM=16.7Hz, H-A) respectively. In a double irradiation
technique, irradiation of doublet of doublet at 5.24 (H-X) converted the doublet of
doublets at 3.62 (H-A) & 3.34 (H-M) to doublet each which certainly describes that
H-X, M & A are coupling among each other. The signals present at 7.36 (1H, d,
J5,4=5.2Hz, H-5), 7.29 (1H, d, J3,4=3.6Hz, H-3) & 7.02 (1H, m, H-4)
could be generated by thienyl ring protons H-5, 3 & 4 respectively. The nine
hydrogens (H-2-6 & H-3-6) were located at the expected positions in the
aromatic region (vide experimental). In the mass spectrum of 2.83, the heaviest ion
was observed at m/z 360 (60.2 %) and its mass fragmentation pattern has been
presented in Chart-4 (vide experimental).

H2C CH=CH
...... c

+.
2

O
b

......

H
......

a
c
m/z 360 (60.2 %)

+
.

H2C CH=CH

O
H

+.

H
+

N H

H
N

......

N H

m/z 319 (30.4 %)

m/z 276 (15.2 %)


m/z 243 (10.1 %)

-O

+H. -C6H5

-2H.

+.

+
.

H2C CH=CH

......

......

H
N

H
S

N H

N
m/z 241 (100 %)

+H

+.

H
N
H

m/z 200 (25.1 %)

OH
m/z 303 (12.4 %)
+H.

-C4H3S

-N2H

H
N

-O

+.

H
N H
H

m/z 239 (60.2 %)

H2C CH=CH

H
N
N H

O
+

H
H
m/z 171 (38.3 %)

m/z 202 (16.2 %)

Chart-4
In the

13

C-NMR (100 MHz, CDCl3) spectrum of 2.83, the significant signals were

found at 157.2 (C=N), 156.5 (C-2), 155.8 (C-2), 152.6 (C-5), 146.7 (C-1)
and the downfield occurance of these resonances could be attributed to the direct
bonding of these carbons to the hetero atoms (N, O & S). The upfield signals present
at 59.7 & 45.0 might be resulted by pyrazoline ring carbon atoms C-5 & C-4
respectively. The carbon atoms of the allyloxy chain were resonating at 134.4
(CH=CH2), 117.6 (CH=CH2), & 78.3 (OCH2) and the remaining aromatic carbon
atoms were present at the suitable positions (vide experimental).

Synthesis of (5R)-5-(thienyl-2-yl)-1-phenyl-3-[2-(benzyloxy) phenyl]-4, 5-dihydro1H-pyrazole 2.84


The pyrazoline 2.84 was again obtained in the two steps:
(i). Synthesis of alkoxy chalcone 2.80
The chalcone 2.78 was reacted with benzyl chloride (Scheme-2.33) under the similar
conditions as used earlier for 2.79 to yield compound 2.80 (72%, m.p. 130-1320C).
2'''

CH2
3'
2'

4'

OH

3''

3'

4''
K2CO3/BrCH2Ph/ dry acetone/

2
5'

1'
6'

5''

1
3

S
1''

Bu4N+I-/

2'

4'

6'

4'''

6'''

1' 1

5'

3'''

1'''

5'''
3''

5''
3

2.78

4''

1''

2.80

Scheme-2.33
IR spectrum of 2.80 had noticeable absorptions at 1656 (C=O) & 1604 (C=C) cm-1. In
the 1H-NMR (400 MHz, CDCl3), the characteristics doublets of trans double bond
were resonating at 7.71 (1H, Jtrans=15.7Hz, H-3) & 7.40 (1H, Jtrans =15.7Hz, H-2).
Other major signals were found to be present at 7.56 (4H, m, H-6, 3, 3, 4),
7.49 (1H, d, Jo=7.6 Hz, H-5), 7.35 (1H, m, H-4), 7.32 (4H, m, H-5, 2, 4, 6),
7.03 (1H, m, H-4) & 6.89 (1H, d, Jo=7.6Hz, H-3). A sharp singlet integrating for
two hydrogens at 5.18 may be provided by OCH2 group. The mass spectrum of
2.80 had the (M+1)+ ion at m/z 321 (100 %) and its mass fragmentation pattern was
found to be similar as shown in Chart-3 (vide experimental).
13

C-NMR (100 MHz, CDCl3) spectrum of 2.80 exhibited the resonances of the enone

moiety at 190.1 (C=O), 143.7 (C-3) & 120.2 (C-2). The signals placed at 152.3,
151.8, 144.6, 143.7, 133.2, 131.5, 130.9 could be easily furnished by C-2, 2, 5, 3,
1, 1 & 6 respectively. The remaining carbon atoms produced suitable signals at
the expected positions in the aromatic and aliphatic regions (vide experimental).

(ii). Cyclization of chalcone 2.80


The compound 2.84 (68%, m.p. 146-148C) was prepared from the reaction of 2.80
with phenyl hydrazine (Scheme-2.34) under the similar conditions as used earlier for
2.83.
2''''
2'''

3'

2'

4'

2''

1' 1

5'

5''
3

6'

4''

1''

5''
PhNHNH2/ AcOH/EtOH/

6''

HM
4
HA

N Hx
1

1''

4''''
5''''

3'''

4'''

3''''

1''''
6''''

4''

4'''
5'''
3''

6'''

3''

3'''

1'''
CH2

CH2

1'

6'

5'''

S
1'''

2'

5'

3'
4'

2.80

2.84

Scheme-2.34
IR spectrum of 2.84 showed the characteristics bands at 3037 (aromatic C-H) &
1595 (C=N) cm-1. Its 1H-NMR (400 MHz) had the pyrazoline ring protons (H-X, H-M
& H-A) at 5.25 (1H, dd, JXA=6.5Hz, JXM=11.8Hz, H-X), 3.82 (1H, dd, JMX=11.8Hz,
JMA=17.2Hz, H-M) & 3.42 (1H, dd, JAX=6.5Hz, JAM=17.2Hz, H-A) respectively. A
singlet integrating for two hydrogens was also found to be placed at 5.01 which
could be furnished by OCH2 group. The protons belonging to N-phenyl, 3-phenyl and
5-thienyl rings were resonating at the expected & J values in the aromatic region
(see experimental). The mass spectrum of compound 2.84 also corroborated its
structure which showed the heaviest ion at m/z 412 (M+2, 40.4 %) and its mass
fragmentation pattern was found to be samilar as given in Chart-4 (vide
experimental).
In the

13

C-NMR (100 MHz, CDCl3) of 2.84, the signals due to 5-thienyl and

pyrazoline moieties were resonating at 152.9 (C-2), 144.5 (C-5), 129.2 (C3), 128.2 (C-4) and 154.5 (C-3), 62.5 (C-5), 43.8 (C-4) respectively and the most
downfield occurrence of C-3 could be resulted from its azomethine (H-C=N) nature.
The remaining fourteen aromatic carbon atoms (C-2 to C-6, C-3 to C-6 & C-2
to C-6) provided suitable signals at the expected positions in the aromatic region
(vide experimental).

Synthesis of chalcones 2.81 & 2.82 and pyrazolines 2.85 & 2.86
The chalcones 2.81 & 2.82 were again prepared from the reaction 2.78 with suitable
alkylating agent (bromoethylacetate & 1-chloromethylnaphthalene) under the similar
conditions as used earlier for 2.79 & 2.80.
R

CH2
3'

2'

4'

3''
2

5'

5''

1'

6'

4''

1''

7"'
8"'

2.81: R = -COOCH

2CH 3

9"'
1"'

; 2.82: R =

2"'

6"'
5"'
10"'
4"'
3"'

The characteristics physical and spectral data of 2.81 & 2.82 have been given in
Table-2 (vide experimental).
The refluxing of chalcones 2.81 & 2.82 with phenyl hydrazine under acidic alcoholic
medium yielded pyrazolines 2.85 & 2.86 and their structures became evident from
their spectral data (Table-2 & vide experimental). 1H-NMR (400 MHz, CDCl3) and
13

C-NMR (100 MHz, CDCl3) of 2.85 & 2.86 were similar to those of 2.83 & 2.84.

The distinguishing features in their 1H-NMR spectra were the resonances of the
alkoxy groups hydrogens which were present at 4.73 (2H, s, OCH2), 4.25 (2H, q,
Jvic =7.2Hz, CH2CH3) & 1.25 (3H, t, Jvic=7.2Hz, CH2CH3) and 7.93-7.09 (7H, m,
naphthalene-H) & 5.59 (2H, s, OCH2) respectively. The pyrazolines ring (H-X, M &
A) and N-1, C-3 & C-5 aryl rings hydrogens were found to be resonating at the
expected positions (Table-2 & vide experimental).
3''

4''
1''

5''
6''

CH2

HM
HA

3'''

4'''

5'''

N
1N
1'
6'

Hx

1'''

2'
3'

5'

2.85: R = -COOCH

2CH 3

7"'
8"'

4'

; 2.86: R =

9"'
1"'
2"'

6"'
5"'
10"'
4"'
3"'

Table-2: Physical and characteristics spectral data of alkoxy chalcones (2.81 &
2.82) and pyrazolines (2.85 & 2.86)
Compound Yield

m.p.

I.R.

No.

(0C)

max (cm-1)

2.81

(%)

775

H-NMR
()

13

C-NMR
()

ESI-MS
m/z

122-

1751 (C=O) 7.82

(H-3), 191.8 (C=O), 316 (M+, 22.7 %)

124

1655 (C=O) 7.36

(H-2), 189.3 (C=O),

1598 (C=C)

4.73 (OCH2)

156.2 (C-2),
141.8 (C-3),
120.9

C-2),

71.3 (OCH2)
2.82

80

162-

1652 (C=O) 7.80

(H-3), 190.5 (C=O), 370 (M+, 40.3 %)

164

1600 (C=C)

(H-2), 154.2 (C-2),

7.65

5.59 (OCH2)

141.8 (C-3),
121.1

C-2),

74.5 (OCH2)
2.85

62

137-

1755 (C=O) 5.12

139

1597 (C=N)

(H-X),

191.2 (C=O), 429 (M+Na+,

4.73 (OCH2), 157.7 (C=N), 100 %)


3.82 (H-M), 155.8 (C-2),
3.42 (H-A)

71.8 (OCH2),
57.6

(C-5),

44.6 (C-4),
2.86

68

175177

1599 (C=N)

5.49 (OCH2), 158.2 (C=N), 460 (M+, 30.2 %)


5.23

(H-X), 156.6 (C-2),

3.86

(H-M), 72.6 (OCH2),

3.30 (H-A)

56.5

(C-5),

45.6 (C-4)

Mechanistic consideration
The cyclization reactions described above i.e. 2.70-2.73 & 2.78-2.81-2.74-2.77 &
2.82-2.85 can be visualized as having occurred through an initial nucleophilic attack
(path a) of phenyl hydrazine upon the carbonyl group of enone moiety under the
influence of proton followed by dehydration to produce hydrazones 2.70a-2.73a &
2.78a-2.81a. The later further undergo cyclization reactions with the addition of
proton to give 2.74-2.77 & 2.82-2.85 as the end products (Scheme-2.35).
In other way, phenyl hydrazine can also undergo attack upon the enone part of 2.702.73 & 2.78-2.81 in a Michael addition fashion (path b) to give 2.70b-2.73b &
2.78b-2.81b as the intermediates which subsequently may suffer cyclization reactions
followed by dehydration to provide 2.74b-2.77b & 2.82b-2.85b as the final products
(Scheme-2.35).
But in spite of our repeated and best efforts, we were not able to isolate any product
similar to 2.74b-2.77b & 2.82b-2.85b. Thus, in chalcones 2.70-2.73 & 2.78-2.81
direct condensation of phenyl hydrazine with carbonyl group (path a) is preferred
over the Michael addition (path b, Scheme-2.35)

.
O

CH 2 R

CH 2 R

H+

path b
Ar

Ar

H+

cyclization

OH

2.70-2.73 & 2.78-2.81

..

H2N NH Ph

Ar

HO

NH

CH 2 R
H
H

..

HN

N
H

Ph

Ph

-H2O

H+ path a
CH 2 R

O
HO

O CH 2 R
Ar

H
Ar

H N H

H N Ph

Ph

N
H

-H+

CH 2 R

CH 2 R

-H2O

OH

-H+ /+H+

Ar

Ar
H

..
N

..
N

Ph

Ph

2.70a-2.73a & 2.78a-2.81a

Ar =
O

O CH 2 R
H

cyclization

H
N

Ar
H

Ph
2.74-2.77 & 2.82-2.85

R = -CH=CH2, -COOCH2CH3,

Scheme-2.35: Mechanism of the cyclization of chalcones 2.70-2.73 & 2.78-2.81.

Antimicrobial Activities of pyrazoline 2.74-2.77


In vitro antibacterial activities of pyrazoline derivatives 2.74-2.77 were carried out
using the cultures of A. hydrophila, Y. enterocolitica, L. monocytogenes and S. aureus
by disc diffusion method67 under the nutrient broth medium. In this method, sterile
paper disc (5.0 mm) impregnated with compound dissolved in DMSO at a
concentration of 100 g/ml were used. Gentamicin and Tetracycline were used as the
standard drugs, where DMSO poured disc was used as negative control. Then, the
paper disc impregnated with the solution of test compounds were placed on the
surface of the media inoculated with the microorganisms. The plates were incubated
for 18 hrs at 370C. After incubation, the diameters of the inhibition zones (mm) were
measured. The minimum inhibitory concentrations (g/ml) of these compounds were

also determined by using serial tube dilution method.68 The results of the zone of
inhibitions (mm) and MIC (g/ml) determination of these compounds are presented in
Table-3 (2.74-2.77), Table-5

(2.83-2.88) and Table-4 (2.74-2.77), Table-6 (2.83-

2.88) respectively.

Table-3: Zone of inhibitions (mm) of pyrazolines 2.74-2.77.

Compounds

A. hydrophila

Y. enterocolitica,

L.monocytogenes

S. aureus

2.74

15.6

16.4

13.4

14.6

2.75

22.3

21.4

24.3

22.8

2.76

14.6

14.5

15.5

15.5

2.77

21.7

25.2

19.4

23.6

Gentamicin

21.2

----

----

17.1

Tetracycline

13.4

20.3

12.2

14.4

Table-4: Minimum inhibitiory concentrations (g/ml) of pyrazolines 2.74-2.77.

Compounds

A. hydrophila

Y. enterocolitica,

L.monocytogenes

S. aureus

2.74

30

30

30

20

2.75

10

10

20

10

2.76

40

40

30

30

2.77

10

20

10

10

Gentamicin

10

10

10

10

Tetracycline

30

30

30

30

Table-5: Zone of inhibitions (mm) of pyrazolines 2.83-2.86.

Compounds

A. hydrophila

Y. enterocolitica,

L. monocytogenes

S. aureus

2.83

14.5

11.5

13.4

14.6

2.84

20.5

22.4

24.3

22.8

2.85

12.5

14.5

14.5

15.5

2.86

21.7

18.4

21.2

19.4

Gentamicin

21

----

----

17

Tetracycline

13

20

12

14

Table-6: Minimum inhibitory concentrations (MIC, g/ml) of pyrazolines 2.83-2.86.

Compounds

A. hydrophila

Y. enterocolitica,

L. monocytogenes

S. aureus

2.83

30

20

20

30

2.84

10

20

10

10

2.85

40

40

40

40

2.86

20

10

10

10

Gentamicin

10

10

10

10

Tetracycline

30

30

30

30

It is evident from Table-3 & Table-4 that the compounds 2.75 & 2.77 showed better
zone of inhibitions (mm) and MIC (g/ml) against the bacterial strains namely
A. hydrophila, Y. enterocolitica, L. monocytogenes & S. aureus.
Similarly, Table-5 & Table-6 describes that compounds 2.84 & 2.86 mainly
prohibited the growth of the tested bacteria strains. It is also clear from the Table-5
that 2.84 & 2.86 exhibited better zone of inhibitions ranging from 19.4-24.3 mm. The
compound 2.84 was found to be very active (MIC-10 g/ml) against bacteria strains
A. hydrophila, L. monocytogenes and S. aureus respectively (Table-6). The
compound 2.86 also seems to be very active against bacterial strains Y. enterocolitica,
L. monocytogenes & S. aureus (Table-6). It may be concluded that these
investigations describe the genral method for the synthesis of alkoxy N-phenyl-5furyl/thienyl-pyrazoline derivatives under the ordinary conditions. Most of the studied

heterocyclics also exhibited significant antibacterial activity against the tested bacteria
strains.

EXPERIMENTAL

Synthesis of (2E)-l-(2-hydroxyphenyl)-3-(furan-2-yl) prop-2-en-1-one 2.69


A solution of o-hydroxy-acetophenone (4.5 g, 0.008 mol), 2-furaldehyde (4.5 g, 0.008
mol) and NaOH (5.0 g, 0.024 mol) in ethanol (25.0 ml) was stirred in an ice bath for
10 hrs. During the course of reaction, the initially formed greenish mixture changed to
a reddish gummy mass. The resulting mass was poured into iced-HCl to yield a
yellow solid that was filtered, thoroughly washed with water and dried. The crude
product was crystallized from CHCl3:MeOH (1:1) to provide yellow needles of 2.69.

3'
2'

4'
5'

1'
6'

OH
1

3''

4''

5''
3

O
1''

2.69
2.69: Yellow needle; Yield: 80%; m.p. 84-860C; IR (KBr) max (cm-1): 3210 (OH),
3082 (aromatic C-H), 1634 (C=O), 1608 (C=C); 1H-NMR (400 MHz, CDCl3):
12.70 (1H, s, OH), 8.02 (1H , d, Jtrans=15.4Hz, H-3), 7.72 (1H, d, Jtrans=15.4Hz, H-2),
7.34 (1H, d{dd}, Jp,m,o=1.1, 2.8, 8.6Hz, H-6), 7.31 (1H, d, J5,4=1.8Hz, H-5), 7.25
(1H, m, H-3), 7.13 (1H, m, H-4), 7.02 (1H, dd, J4,3=3.4Hz, J4,5=1.8Hz, H-4),
6.92 (1H, m, H-5), 6.74 (1H, d, Jo=8.3Hz, H-3);

13

C-NMR (100 MHz, CDCl3):

192.4 (C=O), 152.8 (C-2), 150.7 (C-2), 148.6 (C-5), 142.6 (C-3), 138.2 (C-1),
136.2 (C-6), 129.4 (C-3), 128.7 (C-4),127.3 (C-5), 125.5 (C-3), 123.4 (C-4),
120.3 (C-2); MS: m/z 215 (60 %), 214; Anal. calc. for C13H10O3: C, 72.89; H, 4.67;
Found: C, 72.76; H, 4.64 %.

Synthesis of (2E)-1-[2-(prop-2-en-1-yloxy) phenyl]-3-(furan-2-yl) prop-2-en-1-one


2.70
A suspension of 2.69 (2.0 g, 0.005 mol), allyl bromide (1.0 g, 0.005 mol), anhydrous
K2CO3 (1.0 g) and tetrabutyl ammonium iodide (1.0 g) in dry acetone (25.0 ml) was
refluxed for 6 hrs with continuous stirring. The progress of reaction was monitored by
TLC. After the completion of reaction, the reaction mixture turned to a colorless mass

which was poured into iced HCl to provide a light yellow solid. The crude product
thus obtained was crystallized from MeOH to afford pure compound 2.70.

CH2 CH=CH
3'
2'

4'
5'

1'
6'

O
1

3''

4''

5''

1''

2.70
2.70: Light yellow solid; Yield: 70%; m.p. 96-98C; IR (KBr) max (cm-1): 3084
(aromatic C-H), 1655 (C=O), 1602 (C=C), 1250 & 1030 (C-O); 1H-NMR (400 MHz,
CDCl3): 7.64 (1H, d, Jtrans=15.6Hz, H-3), 7.57 (1H, d{dd}, Jp,m,o=0.9, 1.4, 7.8Hz, H6), 7.50 (2H, m, H-4, 5), 7.43 (1H, d, Jtrans =15.6Hz, H-2), 7.35 (1H, m, H-5), 7.28
(1H, d, J3,4=3.2Hz, H-3), 7.15 (1H, dd, J4,3=3.2Hz, J4,5=1.8Hz, H-4), 6.94
(1H, d, Jo=7.8Hz, H-3), 5.45 (1H, td, Jvic,trans=6.7, 15.8Hz, CH=CH2), 5.24 (2H, td,
Jallyl,trans=1.0, 15.8Hz, -CH=CH2), 4.64 (2H, dd, Jallyl,vic=1.0, 6.7Hz, OCH2); 13C-NMR
(400 MHz, CDCl3): 192.2 (C=O), 154.5 (C-2), 153.6 (C-2), 144.6 (C-5), 141.5
(C-3), 132.5 (C-1), 132.0 (CH=CH2), 131.4 (C-3), 130.8 (C-6), 128.8 (C-4), 126.7
(C-5), 125.8 (C-4), 120.8 (C-2), 118.5 (CH=CH2), 114.6 (C-3), 69.5 (OCH2); MS:
m/z (M)+ 255 (18.2 %), 214 (20.2 %), 188 (10.3 %), 163 (100 %), 146 (9.8 %), 134
(14.6 %), 94 (11.2 %); Anal. calc. for C16H14O3: C, 75.59; H, 5.51; Found: C, 75.50;
H, 5.45 %.

Synthesis of (2E)-1-[2-(banzyloxy) phenyl]-3-(furan-2-yl) prop-2-en-1-one 2.71


The compound 2.71 was obtained from the reaction of 2.69 (2.0 g, 0.001 mol) with
benzyl chloride (1.5 g, 0.004 mol) under the similar conditions as used for 2.70.
2'''

CH2
3'
4'

2'

6'

4'''

6'''

5'''
3''

4''

1' 1

5'

3'''

1'''

5''
3

1''

2.71
2.71: Light yellow solid; Yield: 72%; m.p. 118-1200C; IR (KBr) max (cm-1): 3079
(aromatic C-H), 1653 (C=O), 1603 (C=C), 1248 & 1028 (C-O); 1H-NMR (400 MHz,
CDCl3): 7.62 (1H, d, Jtrans=15.6Hz, H-3), 7.54 (1H, d{dd}, Jp,m,o=0.9, 1.4, 7.8Hz, H6), 7.49 (4H, m, H-4, 5, 3, 5), 7.41 (1H, d, Jtrans =15.6Hz, H-2), 7.31 (3H, m,
H-5, 3, 4), 7.10 (1H, m, H-4), 7.03 (2H, m, H-2, 6), 6.89 (1H, d, Jo=7.9Hz,

H-3), 5.18 (2H, s, OCH2); 13C-NMR (100 MHz, CDCl3): 191.4 (C=O), 154.1 (C2), 153.5 (C-2), 143.8 (C-5), 141.3 (C-3), 132.6 (C-1), 130.9 (C-1), 130.0 (C6), 129.6

(C-3, 5), 128.1 (C-4), 127.5 (C-4), 125.8 (C-5), 124.9 (C-3),

122.5 (C-4), 121.2 (C-2, 6), 120.4 (C-2), 112.7 (C-3), 77.4 (OCH2); MS: m/z
(M)+ 305 (20.2 %), 238 (30.0 %), 214 (10.8 %), 213 (100 %), 185 (20.4 %), 146 (10.1
%), 94 (12.0 %); Anal. calc. for C20H16O3: C, 78.94; H, 5.26; Found: C, 78.82; H,
5.20 %.

Synthesis of (2E)-1-[2-(ethaloxy) phenyl]-3-(furan -2-yl) prop-2-en-1-one 2.72


The compound 2.72 was prepared from the reaction of 2.70 with bromoethyl acetate
under the similar conditions as used earlier for 2.70.
O
CH2 C OCH 2-CH 3
3'
2'

4'
5'

1'
6'

O
1

3''
2

5''
3

4''

1''

2.72
2.72: Light yellow solid; Yield: 65%; m.p. 108-1100C; IR (KBr) max (cm-1): 3082
(aromatic C-H), 1754, 1650 (C=O), 1598 (C=C), 1243 & 1032 (C-O); 1H-NMR (400
MHz, CDCl3): 7.82 (1H, d, Jtrans =15.2Hz, H-3), 7.56 (1H, d{dd}, Jp,m,o=0.8, 1.7,
7.8Hz, H-6), 7.45 (1H, d, Jtrans =15.2Hz, H-2), 7.38 (1H, d, J5,4 =3.5Hz, H-5),
7.24 (1H, dd, J3,4=3.4Hz, H-3), 7.07 (1H, m, H-4), 7.02 (1H, m, H-5), 6.93 (1H,
m, H-4), 6.82 (1H, d, Jo=7.8Hz, H-3), 5.18 (2H, s, OCH2), 4.24 (2H, q, Jvic=6.9Hz,
OOCH2CH3), 1.34 (3H, t, Jvic=6.9Hz, OOCH2CH3); 13C-NMR (100 MHz, CDCl3):
191.2 (C=O), 187.8 (C=O), 155.8 (C-2), 154.2 (C-2), 143.6 (C-5), 142.5 (C-3),
132.5 (C-1), 131.7 (C-3), 130.3 (C-6), 128.5 (C-4), 126.6 (C-4), 125.4 (C-5),
120.2 (C-2), 114.6 (C-3), 72.4 (OCH2), 68.5 (-CH2CH3), 23.4 (-CH2CH3); MS: m/z
(M+1)+ 301 (100 %), 233 (40.3 %), 214 (16.5 %), 208 (23.6 %), 180 (15.8 %), 146
(8.4 %), 94 (12.7 %); Anal. calc. for C17H16O5 : C, 68.00; H, 5.33; Found: C, 67.91;
H, 5.39 %.

Synthesis of (2E)-1-[2-(naphthalen-2-ylmethoxy) phenyl]-3-(furan -2-yl) prop-2en-1-one 2.73

The

compound

2.73

was

obtained

from

the

reaction

of

2.70

with

1-chloromethylnaphthalene under the similar conditions as used earlier for 2.70.


6'''

7"'
8"'

CH2
3'
2'

4'

1'
5'
6'

10"'
4'''

2"'

O
1

5'''

9"'
1'''

3'"
3''

4''

5''
3

O
1''

2.73
2.73: Light yellow solid; Yield: 72%; m.p. 137-1390C; IR (KBr) max (cm-1): 3087
(aromatic C-H), 1654 (C=O), 1599 (C=C), 1252 & 1026 (C-O); 1H-NMR (400 MHz,
CDCl3): 8.01 (1H, dd, Jm,o=2.4, 7.8Hz, H-8), 7.91 (1H, d, Jtrans=15.7Hz, H-3),
7.80 (1H, d, Jo=7.8Hz, H-7), 7.60 (1H, d{dd}, Jp,m,o=0.7, 1.7, 7.6Hz, H-6), 7.54
(1H, dd, J5,3=1.6, J5,4=3.7Hz, H-5), 7.47 (1H, d, Jtrans=15.7Hz, H-2), 7.31 (1H, d,
J3,4=1.4Hz, H-3), 7.24 (4H, m, H-4, 4, 5, 6), 7.09 (1H, d{dd}, Jp,m,o= 0.9, 1.6,
7.8Hz, H-5), 7.05 (2H, m, H-3, 4), 6.81 (2H, m, H-3, 2), 5.49 (2H, s,
OCH2); 13C-NMR (100 MHz, CDCl3): 192.3 (C=O), 154.7 (C-2), 153.3 (C-2),
142.6 (C-5), 140.6 (C-3), 138.7 (C-1), 132.5 (C-1), 131.4 (C-6), 130.3 (C-9),
129.4 (C-10), 128.8 (C-3), 128.2 (C-8), 127.5 (C-7), 126.6 (C-6), 126.1
(C-5), 125.3 (C-4), 124.5 (C-4), 122.6 (C-5), 121.5 (C-3), 120.4 (C-2), 118.5
(C-4), 114.3 (C-2), 113.8 (C-3), 74.0 (OCH2); MS: m/z (M)+ 355 (60.3 %), 288
(40.5 %), 263 (20.7 %), 235 (13.7 %), 214 (16.7 %), 146 (32.4 %), 94 (6.3 %); Anal.
calc. For C24H18O3: C, 81.36; H, 5.08; Found: C, 81.31; H, 5.02 %.

Synthesis of (5R)-5-(furan-2-yl)-1-phenyl-3-[2-(prop-2-en-1-yloxy) phenyl]-4, 5dihydro-1H-pyrazole 2.74

A mixture of 2.70 (0.5 g, 0.0015 mol) and phenyl hydrazine (0.430 g, 0.004 mol) in
dry EtOH (25 ml) and glacial acetic acid (5 ml) was refluxed for 8 hrs. The progress
of reaction was monitored by TLC. After completion of the reaction, the solvent was
removed under reduced pressure and the residue thus obtained was purified by
crystallization from EtOH to yield compound 2.74.

3''

1''

5''

CH2 CH=CH

2''

4''

3 4

6''
2

HM
HA

3'''

4'''

N
1N
1'

Hx

6'

5'''

O
1'''

2'
3'

5'
4'

2.74
2.74: Brown solid; Yield: 62%; m.p. 130-1320C; IR (KBr) max (cm-1): 3078
(aromatic C-H), 1595 (C=N), 1242 & 1030 (C-O); 1H-NMR (400 MHz, CDCl3):
7.84 (1H, dd, Jm,o=2.4, 7.8Hz, H-6), 7.36 (1H, d, J5,4=1.8Hz, H-5), 7.29 (1H,
d, J3,4=3.4Hz, H-3), 7.20 (4H, m, H-3, 5, 4, 5), 7.15 (3H, m, H-2, 4, 6),
6.96 (1H, m, H-4), 6.89 (1H, d, Jo=7.8Hz, H-3), 5.52 (1H, td, Jvic,trans=6.8, 15.8Hz,
-CH=CH2), 5.28 (1H, dd, JXA=6.7Hz, JXM=11.6Hz, H-X), 5.21 (2H, td, Jallyl,trans=1.0,
15.8Hz, -CH=CH2), 4.62 (2H, dd, Jallyl,vic=1.0, 6.8Hz, OCH2), 3.58 (1H, dd,
JMX=11.6Hz, JMA=16.7Hz, H-M), 3.27 (1H, dd, JAX=6.7Hz, JAM=16.7Hz, H-A);

13

C-

NMR (100 MHz, CDCl3): 156.7(C=N), 156.2 (C-2), 155.2 (C-2), 154.4 (C5), 144.2 (C-1), 136.4 (C-1), 133.8 (-CH=CH2), 131.5 (C-3), 130.9 (C-6),
129.8 (C-4), 129.1 (C-5), 128.2 (C-4), 127.5 (C-3, 5), 125.5 (C-4), 123.2 (C2, 6), 118.2 (-CH=CH2), 116.7(C-3), 76.7 (OCH2), 57.3 (C-5), 43.7 (C-4); MS:
m/z (M)+ 344 (34.6 %), 303 (30.4 %), 277 (25.1 %), 288 (12.6 %), 227 (23.1 %), 225
(56.2 %), 202 (9.7 %), 200 (44.0 %), 170 (18.4 %), 143 (100 %); Anal. calc. for
C22H20O2N2: C, 76.74; H, 5.81; N, 8.13; Found; C, 76.90; H, 5.78; N, 8.09 %.

2.4.2. (5R)-5-(furan-2-yl)-1-phenyl-3-[2-(benzyloxy) phenyl]-4, 5-dihydro-1Hpyrazole 2.75

The compound 2.75 was synthesized from the reaction of 2.71 (0.5 g, 0.0015 mol)
with phenyl hydrazine (0.430 g, 0.00398 mol) under the similar conditions as used for
2.74.

2''''
3''
2''

4''

1''
5''
6''

CH2

3''''

1''''

4''''

6''''

H
3 4 M

HA

5''''

3'''

4'''

N
1

N Hx
1'

6'

5'''

O
1'''

2'
3'

5'
4'

2.75
2.75: Light yellow solid; Yield: 60%; m.p. 128-1300C; IR (KBr) max (cm-1): 3081
(aromatic C-H), 1600 (C=N), 1246 & 1032 (C-O); 1H-NMR (400 MHz, CDCl3):
7.82 (1H, dd, Jm,o=2.3, 7.8Hz, H-6), 7.34 (1H, d, J5,4=3.5Hz, H-5), 7.25 (3H,
m, H-3, 3, 5), 7.21 (5H, m, H-3, 5, 4, 5, 4), 7.12 (5H, m, H-2, 4, 6,
2, 6), 6.94 (2H, m, H-3, 4), 5.32 (2H, s, OCH2), 5.23 (1H, dd, JXA=6.5Hz,
JXM=11.2Hz, H-X), 3.82 (1H, dd, JMX=11.2Hz, JMA=17.1Hz, H-M), 3.52 (1H, dd,
JAX=6.5Hz, JAM=17.1Hz, H-A); 13C-NMR (100 MHz, CDCl3): 156.1 (C=N), 153.4
(C-2), 152.3 (C-2), 142.6 (C-5), 142.2 (C-1), 133.2 (C-1), 130.1 (C-1),
129.6 (C-6), 129.2 (C-3), 128.2 (C-4), 127.9 (C-4), 126.2 (C-3, 5), 125.2
(C-3, 5), 124.7
114.6 (C-2, 6), 114.2

(C-5), 118.2 (C-4), 116.2 (C-4), 115.2 (C-2, 6),


(C-3), 72.4 (OCH2), 60.2 (C-5), 45.3 (C-4); MS: m/z

(M)+ 395 (24.4 %), 327 (28.2 %), 303 (60.0 %), 288 (15.6 %), 251 (10.2 %), 222
(42.4 %), 211 (100 %), 209 (12.6 %), 143 (4.8 %), 142 (3.0 %); Anal. calc. for
C26H22O2N2: C, 79.18; H, 5.58; N, 7.10; Found: C, 79.23; H, 5.54; N, 7.02 %.

Synthesis of (5R)-5-(furan-2-yl)-1-phenyl-3-[2-(ethyloxy) phenyl]-4, 5-dihydro1H-pyrazole 2.76

The compound 2.76 was prepared from the reaction of 2.72 (0.5 g, 0.0015 mol) with
phenyl hydrazine (0.430 g, 0.00398 mol) under the similar conditions as used for
2.74.
O
CH2 C OCH 2-CH 3

3''
2''

4''

1''

5''
6''

3 4

HM
HA

3'''

4'''

5'''

N
1 N Hx
1'
6'

O
1'''

2'

5'

3'
4'

2.76
2.76: Brown solid; Yield: 64%; m.p. 150-1520C; IR (KBr) max (cm-1):

3078

(aromatic C-H), 2878, 2889 (methylene C-H), 1755 (C=O), 1604 (C=N); 1H-NMR
(400 MHz, CDCl3): 7.87 (1H, dd, Jm,o=2.1, 7.9Hz, H-6), 7.35 (1H, m, H-5),
7.23 (3H, m, H-3,5,4), 7.06 (2H, m, H-5,3), 6.88 (5H, m, H-2,4,6,3,5),
5.25 (1H, dd, JXA=6.5Hz, JXM=11.8Hz, H-X), 4.61 (2H, s, OCH2), 4.01 (2H, q,
Jvic=6.4Hz, COOCH2CH3), 3.82 (1H, dd, JMX=11.8Hz, JMA=16.6Hz, H-M), 3.42 (1H,
dd, JAX=6.4Hz, JAM=16.6Hz, H-A), 1.25 (3H, t, Jvic=6.4Hz, COOCH2CH3); 13C-NMR
(100 MHz, CDCl3): 190.5 (C=O), 156.6 (C=N), 155.6 (C-2), 155.2 (C-2), 154.2
(C-5), 144.4 (C-1), 136.7 (C-1), 131.2 (C-3), 130.6 (C-6), 129.4 (C-4),
128.7 (C-4), 127.6 (C-3, 5), 123.4 (C-5), 122.8 (C-2, 6), 120.7 (C-4), 114.7
(C-3), 76.7 (C-5), 72.2 (OCH2), 67.6 (-CH2CH3), 45.6 (C-4), 25.4 (-CH2CH3); MS:
m/z (M+Na)+ 413 (100 %), (M+2)+ 392 (40.8 %), (M)+ 391 (10.4 %), 323 (62.7 %),
303 (62.7 %), 288 (19.6 %), 247 (14.6 %), 222 (45.3 %), 218 (38.3 %), 211 (66.4 %),
209 (14.6 %), 143 (6.8 %), 142

(5.5 %); Anal. calc. for C23H22N2O4: C, 70.76; H,

5.64; N, 7.17; Found: C, 70.62; H, 5.69; N, 7.11 %.

Synthesis of (5R)-5-(furan-2-yl)-1-phenyl-3-[2-(naphthalen-2-ylmethoxy prop-2en-1-yloxy) phenyl]-4, 5-dihydro-1H-pyrazole 2.77


The compound 2.77 was prepared from the reaction of 2.73 (0.5 g, 0.0015 mol) with
phenyl hydrazine (0.430 g, 0.00398 mol) under the similar conditions as used for
2.74.
7''''

3''

2''

4''

1''

5''
6''

6''''

8''''
9''''
1''''
CH2

5''''
10''''
4''''

2''''

HM
4
HA

3''''

3'''

4'''

2N
1 N
1'

Hx

5'''

1'''

2'

6'

3'

5'
4'

2.77
2.77: Light yellow solid; Yield: 65%; m.p. 162-1640C; IR (KBr) max (cm-1): 3082
(aromatic C-H), 1598 (C=N); 1H NMR (400 MHz, CDCl3): 8.02 (2H, m, H-7,
8), 7.52 (1H, d{dd}, Jp,m,o = 0.8Hz, 1.9Hz, 7.6Hz, H-6), 7.49 (5H, m, H-4, 5,
3, 5, 6), 7.10 (6H, m,

H-3, 4, 4, 5, 5, 3), 6.82 (5H, m, H-2, 6,

3, 4, 2), 5.23 (1H, dd, JXA=6.7Hz, JXM=11.8Hz, H-X), 5.04 (2H, s, OCH2),
3.62 (1H, dd, JMX=11.8Hz, JMA=16.2Hz, H-M), 3.23 (1H, dd, JAX=6.7Hz,
JAM=16.2Hz, H-A);

13

C-NMR (400 MHz, CDCl3): 156.7(C=N), 155.2 (C-2),

154.3 (C-2), 144.2 (C-1), 142.6 (C-5), 135.2 (C-1), 131.9 (C-1), 130.7 (C9), 129.9 (C-10), 129.2 (C-6), 128.7 (C-8), 128.2 (C-7), 127.6 (C6), 127.1 (C-5), 126.7

(C-4), 126.2 (C-3), 125.8 (C-5), 125.3 (C-4),

124.3 (C-3, 5), 123.8 (C-3), 123.0 (C-4), 122.6 (C-4), 121.4 (C-2), 120.5
(C-2, 6), 115.5 (C-3), 71.2 (OCH2), 54.6 (C-5), 46.2 (C-4); MS: m/z (M+1)+ 445
(100 %), 377 (24.2 %), 303 (55.8 %), 301 (12.6 %), 288 (17.8 %), 272 (40.6 %), 222
(40.0 %), 211 (40.4 %), 209 (60.4 %), 143 (3.4 %), 142 (4.7 %); Anal. calc. for
C30H24N2O2: C, 81.08; H, 5.40; N, 6.30; Found: C, 81.20; H, 5.37; N, 6.25 %.

Synthesis of (2E)-l-(2-hydroxyphenyl)-3-(thienyl-2-yl) prop-2-en-1-one 2.78

A solution

of o-hydroxy-acetophenone

(4.5 g, 0.008 mol), thiophene-2-

carboxaldehyde (4.5 g, 0.008 mol) and NaOH (5.0 g, 0.024 mol) in ethanol (25.0 ml)
was stirred in an ice bath at 0oC for 12 hrs. The resulting mass thus obtained was
poured into iced HCl to give a yellow solid that was filtered, thoroughly washed with
water and dried. The crude product was crystallized from CHCl3:MeOH (1:1, v/v) to
provide 2.78.
3'
2'

4'
5'

1'
6'

OH
1

4''

3''
2

5''
3

S
1''

2.78
2.78: Yellow needles; Yield: 86%; m.p. 94-960C; IR (KBr) max (cm-1): 3085
(aromatic C-H), 1638 (C=O), 2949 (O-H); 1H-NMR (400 MHz, CDCl3): 12.89 (1H,
s, OH), 8.04 (1H,d, Jtrans=15.1 Hz, H-3), 7.93 (1H, dd, Jm,o=1.5, 8.1 Hz, H-6), 7.82
(1H, d, Jtrans=15.1 Hz, H-2), 7.55 (1H, dd, Jm,o=1.5, 8.5 Hz, H-4), 7.48 (1H, td,
Jm,o=1.5, 8.5 Hz, H-5), 7.03 (2H, dd, Jm,o=0.8, 8.4 Hz, H-3), 6.98 (1H, dd,
J3,4=3.4Hz, J3,5=1.2Hz, H-3), 6.92 (1H, t, J5,4=5.1Hz, H-5), 6.54 (1H, dd,
J4,3=3.4Hz, J4,5=5.1Hz, H-4); 13C-NMR (100 MHz, CDCl3): 191.4 (C=O), 154.7
(C-2), 149.6 (C-2), 148.4 (C-5), 143.8 (C-3), 138.7 (C-1), 133.5 (C-6), 128.8 (C3), 127.8 (C-5), 127.5 (C-4), 125.8 (C-3), 124.7 (C-4), 122.6 (C-2); MS: m/z
(M+1)+ 231 (50.8 %); Anal. calc. for C13H10O2S : C, 67.82; H, 4.34; Found: C, 67.71;
H, 4.30 %.

Synthesis of (2E)-1-[2-(prop-2-en-1-yloxy) phenyl]-3-(thienyl-2-yl) prop-2-en-1one 2.79


A suspension of 2.78 (2.0 g, 0.005 mol), allyl bromide (1.0 g, 0.005 mol), anhydrous
K2CO3 (1.0 g) and tetrabutyl ammonium iodide (1.0 g) in dry acetone (25.0 ml) was
refluxed for 6 hrs with continuous stirring. The progress of reaction was monitored by
TLC. After the completion of reaction, the reaction mixture turned to a colorless mass
which was poured over iced HCl to obtain a light yellow solid. The crude product thus
obtained was crystallized from MeOH to afford pure compound 2.79.

CH2 CH=CH
3'
2'

4'
5'

1'
6'

3''

4''

5''

1''

2.79
2.79: Light yellow solid; Yield: 78%; m.p. 113-115oC; IR (KBr) max (cm-1): 3084
(aromatic C-H), 2923, 2871 (C-H), 1651 (C=O), 1596 (C=C); 1H-NMR (400 MHz,
CDCl3): 7.68 (1H, d, Jtrans=15.7Hz, H-3), 7.59 (1H, d{dd}, Jp,m,o=0.9, 1.4, 7.8Hz, H6), 7.52 (2H, m, H-4, 5), 7.44 (1H, d, Jtrans =15.7Hz, H-2), 7.35 (1H, m, H-5), 7.30
(1H, d, J3,4=3.2Hz, H-3), 7.17 (1H, dd, J4,3=3.2Hz, J4,5=5.0Hz, H-4), 6.98
(1H, d, Jo=7.9Hz, H-3), 5.49 (1H, td, Jvic,trans=6.7, 15.8Hz, CH=CH2), 5.23 (2H, td,
Jallyl,trans=1.0, 15.8Hz, CH=CH2), 4.64 (2H, dd, Jallyl,vic=1.0, 6.7Hz, OCH2); 13C-NMR
(100 MHz, CDCl3): 190.6 (C=O), 155.4 (C-2), 152.1 (C-2), 143.8 (C-5), 142.3
(C-3), 132.9

(C-1), 132.1 (-CH=CH2), 131.8 (C-3), 130.2 (C-6), 129.7 (C-4),

128.3 (C-5), 127.1 (C-4), 121.5 (C-2), 119.6 (-CH=CH2), 113.6 (C-3), 70.5
(OCH2); MS: m/z (M)+ 271 (100 %), 231 (37.4 %), 204 (60.2 %), 162 (26.5 %), 135
(11.4 %), 94 (12.2 %), 93 (8.4 %); Anal. calc. for C16H14O2S: C, 71.11; H, 5.18;
Found: C, 71.25; H, 5.21 %.

Synthesis of (2E)-1-[2-(banzyloxy) phenyl]-3-(thienyl-2-yl) prop-2-en-1-one 2.80


The compound 2.80 was prepared from the reaction of 2.78 (2.0 g, 0.001 mol) with
benzyl chloride (1.5 g, 0.004 mol) under the similar conditions as used earlier for
2.79.
CH2
3'

2'

4'
1'

5'
6'

2"'
1"'

3"'

6'"

5"'
3''

4"'
4''

5''

1
3

1''

2.80
2.80: Light yellow solid; Yield: 72%; m.p. 130-1320C; IR (KBr) max (cm-1): 3074
(aromatic C-H), 1656 (C=O), 1604 (C=C); 1H-NMR (400 MHz, CDCl3): 7.71 (1H,
d, Jtrans=15.7Hz, H-3), 7.56 (4H, m, H-6, 3, 3, 5), 7.49 (1H, d, Jo=7.6Hz, H-5),
7.40 (1H, d, Jtrans=15.7Hz, H-2), 7.35 (1H, m, H-4), 7.32 (4H, m, H-5, 2, 4,
6), 7.03 (1H, m, H-4), 6.89 (1H, d, Jo=7.6Hz, H-3), 5.18 (2H, s, OCH2);

13

C-

NMR (100 MHz, CDCl3): 190.1 (C=O), 152.3 (C-2), 151.8 (C-2), 144.6 (C-5),
143.7 (C-3), 133.2 (C-1), 131.5 (C-1), 130.9 (C-3), 129.1 (C-6), 128.7 (C-3,
5), 126.8 (C-4), 126.2 (C-4), 124.9 (C-5), 121.9 (C-4), 121.1 (C-2, 6),
120.2 (C-2), 114.5 (C-3), 71.6 (OCH2); MS: m/z (M+1)+ 321 (100 %), 230 (30.4 %),
212 (28.2 %), 204 (10.4 %), 134 (16.7 %), 93 (40.6 %), 92 (16.3 %); Anal. calc. for
C20H16O2S: C, 75.00; H, 5.00; Found: C, 74.90; H, 5.09 %;.

Synthesis of (2E)-1-[2-(ethaloxy) phenyl]-3-(thienyl-2-yl) prop-2-en-1-one 2.81


The compound 2.81 was obtained from the reaction of 2.78 (2.0 g, 0.01 mol) with
bromoethyl acetate (1.2 g, 0.004 mol) under the similar conditions as used earlier for
2.79.
O
CH2 C OCH 2-CH 3
3'
4'

2'

5'

1'

3''

4''

2
6'

5''

1
3

1''

2.81
2.81: Brown solid; Yield: 75%; m.p. 122-1240C; IR (KBr) max (cm-1): 3075 (aromatic
C-H), 1751, 1655 (C=O), 1598 (C=C); 1H-NMR (400 MHz, CDCl3): 7.82 (1H, d,
Jtrans=15.6Hz, H-3), 7.65 (1H, dd, J5,3=1.1Hz, J5,4=5.1Hz, H-5), 7.45 (1H,
d{dd}, Jp,m,o=0.7, 1.8, 7.5Hz, H-6), 7.40 (2H, dd, J=1.0,7.6, H-4, 5), 7.36 (1H, d,
Jtrans=15.6Hz, H-2), 7.07 (2H, m, H-3, 4), 6.82 (1H, d, Jo=7.6, H-3), 4.73 (2H, s,
OCH2), 4.25 (2H, q, Jvic=7.1 Hz, OCH2CH3), 1.25 (3H, t, Jvic=7.2 Hz, OCH2CH3);
13

C-NMR (100 MHz, CDCl3): 191.8 (C=O), 189.3 (C=O), 156.2 (C-2), 154.7 (C-

2), 145.2 (C-5), 141.8 (C-3), 135.6 (C-1), 133.4 (C-3), 131.7 (C-6), 130.2 (C4), 127.8 (C-4), 125.7 (C-5), 120.9 (C-2), 113.2 (C-3), 71.3 (OCH2), 68.5 (CH2CH3), 25.7 (-CH2CH3); MS: m/z (M+Na)+ 339 (60.7 %), (M)+ 316 (22.7 %), 253
(100 %), 231

(30.8 %), 227 (17.4 %), 158 (16.9 %), 116 (12.4 %); Anal. calc. for

C17H16O4S: C, 64.55; H, 5.06; Found: C, 64.67; H, 5.00 %.

Synthesis of (2E)-1-[2-(naphthalen-2-ylmethoxy) phenyl]-3-(thienyl-2-yl) prop-2en-1-one 2.82


The compound 2.82 was synthesized from the reaction of 2.78 (2.0 g, 0.01 mol) with
1-chloromethylnapthalene (1.4 g, 0.004 mol) under the similar conditions as used for
2.79.
6'''

7'''
8'''

CH2
3'
2'

4'

1'

5'
6'

5'''

9'''
1'''

10'''
4'''

2'''

3'''
3''

4''

5''

1
3

1''

2.82
2.82: Light yellow solid; Yield: 80%; m.p. 162-1640C; IR (KBr) max (cm-1): 3064
(aromatic C-H), 1652 (C=O), 1600 (C=C); 1H-NMR (400 MHz, CDCl3): 8.02 (1H,
m, H-8), 7.83 (1H, d, Jo=8.1Hz, H-6), 7.80 (1H, d, Jtrans=15.4Hz, H-3), 7.74 (1H,
dd, Jm,o=1.8, 7.4Hz, H-4), 7.65 (1H, d, Jtrans=15.4Hz, H-2), 7.61 (1H, d, Jm,o=1.9,
7.6Hz, H-7), 7.24 (4H, m, H-5, 3, 5, 6), 7.42 (1H, d{dd}, Jp,m,o=0.8, 1.9,
7.6Hz, H-5), 7.09 (3H, m, H-4, 3, 4), 6.92 (2H, m, H-3, 2), 5.59 (2H, s,
OCH2);

13

C-NMR (100 MHz, CDCl3): 190.5 (C=O), 154.2 (C-2), 152.8 (C-2),

142.2 (C-5), 141.8

(C-3), 137.4 (C-1), 132.8 (C-1), 131.9 (C-6), 131.1 (C-

9), 129.7 (C-10), 129.2 (C-3), 128.0 (C-8), 127.8 (C-7), 126.9 (C-6),
126.2 (C-5), 125.7 (C-4), 123.6 (C-4), 122.4 (C-5), 121.8 (C-3), 120.9 (C-2),
119.3 (C-4), 116.2 (C-2), 113.6 (C-3), 74.5 (OCH2); MS: m/z (M+1)+ 371 (100
%), (M)+ 370 (40.3 %), 262 (38.3 %), 230 (22.3 %), 204 (12.7 %), 135 (9.8 %), 93
(3.4 %); Anal. calc. for C24H18O2S: C, 77.83; H,4.86; Found: C, 77.89; H, 4.80 %.

Synthesis of (5R)-5-(thienyl-2-yl)-1-phenyl-3-[2-(prop-2-en-1-yloxy) phenyl]-4, 5dihydro-1H-pyrazole 2.83


A mixture of 2.79 (0.5g, 0.0015 mol) was refluxed with phenyl hydrazine (0.430 g,
0.004mol) in dry EtOH (25 ml) and glacial acetic acid (5 ml) for 8 hrs. The progress
of reaction was monitored by TLC. After completion of the reaction, the solvent was

removed under reduced pressure and the residue thus obtained was purified by
recrystalization from EtOH to yield compound 2.83.

3''
2''

4''

1''

5''

CH2 CH=CH

H
3 4 M

HA

6''
2

3'''

4'''

1N Hx
1'
6'

5'''

S
1'''

2'
3'

5'
4'

2.83
2.83: Light yellow solid; yield: 65%; m.p. 133-1350C; IR (KBr) max (cm-1): 3032
(aromatic C-H), 1594 (C=N); 1H-NMR (400 MHz, CDCl3): 7.88 (1H, dd, Jm,o=2.3,
7.8Hz, H-6), 7.36 (1H, d, J5,4=5.2Hz, H-5), 7.29 (1H, d, J3,4=3.6Hz, H3), 7.20 (4H, m, H-3, 5, 4, 5), 7.10 (3H, m, H-2, 4, 6), 7.02 (1H, m, H-4),
6.94 (1H, d, Jo=7.9Hz, H-3), 5.58 (1H, td, Jvic,trans=6.8, 15.8Hz, CH=CH2), 5.24 (1H,
dd, JXA=6.7Hz, JXM=11.6Hz, H-X), 5.19 (2H, td, Jallyl,trans=1.0, 15.8Hz, CH=CH2),
4.68 (2H, dd, Jallyl,vic=1.0, 6.8Hz, OCH2), 3.62 (1H, dd, JMX=11.6Hz, JMA=16.7Hz, HM), 3.34 (1H, dd, JAX=6.7Hz, JAM=16.7Hz, H-A);

13

C-NMR (100 MHz, CDCl3):

157.2 (C=N), 156.5 (C-2), 155.8 (C-2), 152.6 (C-5), 146.7 (C-1), 137.9 (C1), 134.4 (CH=CH2), 132.3 (C-3), 131.5 (C-6), 130.2 (C-4), 129.7 (C-5),
128.6 (C-4), 126.3 (C-3, 5), 125.1 (C-4), 122.8 (C-2, 6), 117.6 (CH=CH2),
113.4 (C-3), 78.3 (OCH2), 59.7 (C-5), 45.0 (C-4); MS: m/z (M)+ 360 (60.2 %), 319
(30.4 %), 303 (12.4 %), 276 (15.2 %), 243 (10.1 %), 241 (100 %), 239 (55.8 %), 202
(16.2 %), 200 (25.1 %), 171 (38.3 %); Anal. calc. for C22H20N2OS: C, 73.33; H, 5.55;
Found: C, 73.49; H, 5.50 %.

2.4.2. (5R)-5-(thienyl-2-yl)-1-phenyl-3-[2-(benzyloxy) phenyl]-4, 5-dihydro-1Hpyrazole 2.84


The compound 2.84 was prepared from the reaction of 2.80 (0.5 g, 0.0015 mol) with
phenyl hydrazine (0.430 g, 0.00398 mol) under the similar conditions as used for
2.83.

2'"'

3'"'

1'"'

3''

2''

4''

1''

5''
6''

CH2

4'"'
6'"'

HM
HA

5'"'

3'''

4'''

N
1

5'''

N Hx

1'''

1'

6'

2'
3'

5'
4'

2.84
2.84: Brown solid; Yield: 68%; m.p. 146-1480C; IR (KBr) max (cm-1): 3037 (aromatic
C-H), 1595 (C=N); 1H-NMR (400 MHz, CDCl3): 7.91 (1H, dd, Jm,o=2.1, 8.4Hz, H6), 7.34 (4H, m, H-4, 5, 3, 5), 7.28 (5H, m, H-3, 5, 5, 3, 4), 7.06
(2H, d{dd}, Jp,m,o=1.0, 1.8, 7.0Hz, H-2, 6), 6.93 (4H, m, H-2, 4, 6, 4), 6.84
(1H, m, H-3), 5.25 (1H, dd, JXA=6.5Hz, JXM=11.8Hz, H-X), 5.01 (2H, s, OCH2),
3.82 (1H, dd, JMX=11.8Hz, JMA=17.2Hz, H-M), 3.42 (1H, dd, JAX=6.5Hz,
JAM=17.2Hz, H-A);

13

C-NMR (100 MHz, CDCl3): 154.5 (C=N), 153.8 (C-2),

152.9 (C-2), 144.5 (C-5), 142.8 (C-1), 135.6 (C-1), 130.8 (C-1), 130.1 (C6), 129.2 (C-3), 128.7 (C-4), 128.2 (C-4), 127.4 (C-3, 5), 126.8 (C-3,
5), 124.2 (C-5), 120.9 (C-4), 116.6 (C-4), 115.9 (C-2, 6), 115.3 (C-2,
6), 113.2 (C-3), 74.6 (OCH2), 62.5 (C-5), 43.8 (C-4); MS: m/z (M+2)+ 412 (40.4
%), 387 (22.6 %), 319 (19.7 %), 311 (14.7 %), 304 (12.4 %), 227 (60.4 %), 225 (100
%), 222 (5.3 %), 143

(10.6 %); Anal. calc. for C26H22N2OS: C, 76.09; H, 5.36;

Found: C, 76.20; H, 5.44 %;.

Synthesis of (5R)-5-(thienyl-2-yl)-1-phenyl-3-[2-(ethyloxy) phenyl]-4, 5-dihydro1H-pyrazole 2.85


The compound 2.85 was synthesized from the reaction of 2.81 (0.5 g, 0.0015 mol)
with phenyl hydrazine (0.430 g, 0.00398 mol) under the similar conditions as used for
2.83.
O
3''
4''

2''
1''

5''
6''

CH2 C OCH 2-CH 3

3 4

HM
HA

3'''

4'''

5'''

N
1N
1'

Hx
2'

6'

3'

5'
4'

2.85

S
1'''

2.85: Brown solid; Yield: 62%; m.p. 137-1390C; IR (KBr) max (cm-1): 3247
(aromatic C-H), 2878, 2889 (methylene C-H), 1755 (C=O), 1597 (C=N); 1H-NMR
(400 MHz, CDCl3): 7.85 (1H, dd, Jm,o=2.1, 8.2Hz, H-6), 7.35 (2H, d{dd},
Jp,m,o=0.8, 1.9, 7.6 Hz, H-3, 5), 7.22 (3H, m, H-4, 3, 5), 7.06 (5H, m, H-2, 4,
6, 5, 4), 6.82 (1H, d, Jo=8.6Hz, H-3), 5.12 (1H, dd, JXA=6.5Hz, JXM=11.8Hz, HX), 4.73 (2H, s, OCH2), 4.01 (2H, q, Jvic=7.2Hz, -CH2CH3), 3.82 (1H, dd,
JMX=11.8Hz, JMA=17.6Hz, H-M), 3.42 (1H, dd, JAX=6.5Hz, JAM=17.6Hz, H-A), 1.25
(3H, t, Jvic=7.1Hz, -CH2CH3);

13

C-NMR (100 MHz, CDCl3): 191.2 (C=O), 157.7

(C=N), 155.8 (C-2), 155.1 (C-2), 154.6 (C-5), 146.1 (C-1), 137.3 (C-1),
134.0 (C-3), 132.8 (C-6), 130.9 (C-4), 128.9 (C-4), 128.2 (C-3, 5), 125.6
(C-5), 123.1 (C-2, 6), 121.3 (C-4), 114.1 (C-3), 71.8 (OCH2), 65.3 (-CH2CH3),
57.6 (C-5), 44.6 (C-4), 23.7 (-CH2CH3); MS: m/z (M+Na)+ 429 (100 %), 339 (28.8
%), 319 (14.5 %), 304 (17.6 %), 263 (21.6 %), 234 (38.4 %), 227 (52.4 %), 225 (60.4
%), 222 (19.7 %), 143 (18.4 %), 142 (29.5 %); Anal. calc. for C23H22N2O3S: C, 67.98;
H, 5.41; N, 6.89; Found: C, 68.12; H, 5.33; N, 6.82 %.

Synthesis of (5R)-5-(thienyl-2-yl)-1-phenyl-3-[2-(naphthalen-2-ylmethoxy prop-2en-1-yloxy) phenyl]-4, 5-dihydro-1H-pyrazole 2.86


The compound 2.86 was prepared from the reaction of 2.82 (0.5 g, 0.0015 mol) with
phenyl hydrazine (0.430 g, 0.00398 mol) under the similar conditions as used for
2.83.
7''''

6''''

8''''

3''

2''

4''

1''

5''

6''

5''''

9''''
CH21''''
2''''

HM
4
HA

10''''
4''''
3''''

3'''

4'''

2N
1 N
1'

Hx

5'''

1'''

2'

6'

3'

5'
4'

2.86
2.86: Light yellow solid; Yield: 68%; m.p. 175-1770C; IR (KBr) max (cm-1): 3257
(aromatic C-H), 1599 (C=N); 1H-NMR (400 MHz, CDCl3): 7.93 (2H, dd, Jm,o =1.8,

7.4Hz, H-6, 8), 7.54 (5H, m, H-4, 5, 5, 6, 7), 7.15 (7H, m, H-3, 4,
5, 5, 3, 3, 4), 7.09 (4H, m, H-2, 6, 4, 2), 6.88 (1H, d, Jo=8.2Hz, H3), 5.49 (2H, s, OCH2), 5.23 (1H, dd, JXA= 6.7Hz, JXM=11.6Hz, H-X), 3.86 (1H, dd,
JMX=11.6Hz, JMA=17.2Hz, H-M), 3.30 (1H, dd, JAX=6.7Hz, JAM=17.2Hz, H-A);
13

C-NMR (100 MHz, CDCl3): 158.2 (C=N), 156.6 (C-2), 155.8 (C-2), 144.1

(C-5), 142.8 (C-1), 136.0 (C-1), 131.2 (C-1), 130.4 (C-9), 129.8 (C10), 129.1 (C-6), 128.8 (C-8), 128.0 (C-7), 127.7 (C-6), 127.1 (C5), 126.8 (C-4), 126.2 (C-3), 125.9 (C-5), 125.2 (C-4), 124.7 (C-3, 5),
123.8 (C-3), 123.0 (C-4), 122.3 (C-4), 121.6 (C-2), 118.5 (C-2, 6), 113.7
(C-3), 72.6 (OCH2), 56.5 (C-5), 45.6 (C-4); MS: m/z (M+2)+ 462 (100 %), (M)+ 460
(30.2 %), 393 (14.2 %), 319 (19.7 %), 317 (29.8 %), 304 (22.4 %), 288 (46.0 %), 227
(40.8 %), 225 (20.1 %), 222 (26.7 %), 161 (7.1 %), 143 (10.7 %), 142 (4.3 %); Anal.
calc. for C30H24N2OS: C, 78.26; H, 5.21; N, 6.08; Found: C,78.08; H, 5.16; N, 6.14%.

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Chapter-IIb
Synthesis of New Alkoxy-Nthiocarbamoyl-5-furyl/thienylpyrazolines

Synthesis and in-vitro-antibacterial activity of [5-(furan-2-yl)-phenyl]-4, 5carbothioamide-pyrazolines


Mamta Rani, Mohamad Yusuf and Salman Ahamad Khan
Journal of Saudi Chemical Society (2011), doi:10.1016/j.jscs.2011.02.012.

In continuation of earlier chapter (IIa), here we have attempted the synthesis of


N-thiocarbamoyl substituted pyrazolines. These heterocyclic derivatives have gained
immense importance in the past due to their structural, synthetic and wide range of
biological applications. These compounds are generally synthesized in the lab from
the

reaction

of

-unsaturated

carbonyl

substrates

with

semicarbazide/thiosemicarbazide and their derivatives. These reactions are generally


carried out in the alkaline condition by using alcohol as the solvent. The normal
reaction condition and easy work up of these procedures have been the major
incentive behind these researches.
Recently synthesis of a series of 1-phenyl-, 1-thiocarbamoyl- and 1-N-substituted
thiocarbamoyl-3-(2-furyl)-5-phenyl/(2-furyl)-2-pyrazoline derivatives1 2.87 have
been described (Scheme-2.35).
O

CH3

Ar CHO
OH-

CH=CH

Ar

NH2-NH2

NH2-NHC6H5

NH2-NHCSNH2

O
O
O

Ar

N
Ar

N
Ar

N
N

N
H

N
H2N

S
R-NCS

O
Ar

N
N
R

NH

Ar: C6H5-, 2-furyl


R: CH3-, C2H5-, C3H5-, C6H5-

2.87
Scheme-2.35

The reaction of neutral NS bidentate ligands, 1-N-substituted thiocarbamoyl-3,5diphenyl-2-pyrazolines,2 isolated by cyclization of chalcone with N-4-substituted
thiosemicarbazide

of

aromatic

amines,

with

[Pd(DMSO)2Cl2]

(DMSO

dimethylsulfoxide) leads to the formation of new complexes of the type [Pd(L)Cl 2]


(Scheme-2.36).
NH2NHCSR
i

CH=CH

CH=CH

HN

N
R

[Pd(DMSO)2Cl2]

ii

N
H

S
Pd
Cl

Cl

2.88
Scheme-2.36
A variety of 3-(3-bromo phenyl)-5-phenyl-1-(thiazolo[4,5-b] quinoxaline-2-yl)-2pyrazoline 2.89 were obtained (Scheme-2.37) by the refluxing of N-thiocarbamoyl3,5-diphenyl-2-pyrazoline with 2,3-dichloroquinoxaline.3
O

O
CH3

CHO

NaOH

Br

Br
NH2NHCSNH2

S
N
N

Br

THF

Cl

Cl

Br
N
N
S

R
NH2

2.89
Scheme-2.37

3,5-Diaryl carbothioamide pyrazolines 2.90 designed as mycobactin analogs


(mycobacterial siderophore)4 are reported to be potent antitubercular agents under
iron limiting condition (Scheme-2.38).

R2

R1

R1

R1

R1

R3

CH3

R3

R2

R4

R4

N
H

R
R1
N

R1

R3

R2

R4

R4

HN

R3

R2

S
S

HN

H2N
R5

R5
R6

X= O, S

R6

2.90
Scheme-2.38
N1-acetyl-5-aryl-3-(substituted styryl)pyrazolines 2.91 were synthesized (Scheme2.38) by the cyclocondensation of 1,5-substituted diphenyl-1,4-pentadien-3-ones with
hydrazine hydrate and a cyclizing agent such as acetic acid in ethanol.5
CHO

+
H3C

CH CH

CH

NH2.NH2.H2O

CH

CH

CH3
CH3COOH

X
CH CH

CH
N

N
C

X= H, 4-Cl, 4-OCH3, 2-OCH3, 3,4,5-(OCH3)3, 4F, 2-Cl, 3-F, 2F, 2,4-(Cl2)

CH3

2.91
Scheme-2.39
Recently, some significant studies are also reported on the synthesis and biological
evaluation of thiocarbamoyl substituted pyrazoline compounds.6-10

It is clear from the above literature examples that thiocarbamoyl substituted


pyrazolines have attracted special significance due to their immense synthetic and
biological applications. By considering this aspect in view, synthesis and antibacterial
studies of the following pyrazolines 2.92-2.95 have been attempted.
CH2

HM
HA
N
O

N Hx
C

NH2

2.92 R = -CH=CH2,
2.93 R = -Ph,
2.94 R = -COOEt ,
2.95 R =

Synthesis of N-thiocarbamoyl-pyrazolines 2.92


The compound 2.70 was refluxed with thiosemicarbazide in EtOH/NaOH medium
and resulting reaction mixture was poured into ice cold water to provide a solid
substance (Scheme-2.40). The crude product thus obtained was crystallized from
EtOH to yield pure compound 2.92 (69%, m.p. 140-1420C).
CH2 CH=CH

3'

CH2 CH=CH
3'
2'

4'

1'

5'
6'

4'

4''

5''

1''

1'

5'
NaOH/EtOH
S
H2N NH

C NH2

HM
HA

6'
2

3''
2

2'

3''

4''

N
1N

Hx

5''

O
1''

NH2

2.70

2.92

Scheme-2.40
The structure of 2.92 was characterized from its spectral parameters. Its IR spectrum
showed major absorption bands at 3452, 3308 (N-H) & 1597 (C=N) cm-1 and another
significant band was also observed at 1160 cm-1 which could be attributed to the C=S
group. 1H-NMR (400 MHz, CDCl3) spectrum of 2.92 also confirmed its structure
which showed the signals due to aromatic rings (furyl & phenyl) at 7.85 (1H, dd,
Jm,o=2.5, 7.8Hz, H-6), 7.62 (1H, m, H-5), 7.50 (2H, m, H-4, 3), 7.22 (1H, m, H-

5), 6.97 (1H, dd, J4,3=2.1Hz, J4,5=3.8Hz, H-4) & 6.90 (1H, d, Jo=8.2Hz, H-3).
A D2O exchangeable broad singlet at 8.42 (2H) could be easily provided by NH2
group. The allyloxy group protons were found to be resonating at 5.32 (1H, td,
Jvic,trans=6.7, 15.8Hz OCH2CH=CH2), 4.64 (2H, dd, Jallyl,vic=1.1, 6.7Hz, OCH2) & 4.52
(2H, td, Jallyl,trans=1.2, 15.8Hz, OCH2CH=CH2). Regarding the rest of the spectrum, it
showed three doublet of doublets (dd) at 5.25 (1H, JXA=6.7Hz, JXM=11.6Hz), 3.52
(1H, JMX=11.6Hz, JMA=16.7Hz) & 3.24 (1H, JAX=6.7Hz, JAM=16.7Hz) which could
be very well represented by pyrazoline ring protons H-X, H-M & H-A respectively.
The mass spectrum of 2.92 furnished molecular ion at m/z 327 (20.1 %) along with an
ion at m/z 329 (M+2, 8.6 %) which also corroborate its structure. The fragments at
m/z 287 (100 %), 259 (30.1 %) & 194 (36.1 %) further lent support to the proposed
structure, as these ions could become available through the loss of allyl, furyl and
phenyl moieties respectively. The mass fragmentation pattern of 2.92 has been
depicted in Chart-1.
Finally, 13C NMR (100 MHz, CDCl3) data of 2.92 provided enough evidence in favor
of the proposed expression. The downfield signals at 178.3 & 158.4 were assignable
to C=S & C=N groups and the resonances of allyloxy chain were found to be
resonating at

132.9 (CH=CH2), 120.6 (CH=CH2) & 73.8 (OCH2). The signals

present at 58.8 & 43.2 could be easily generated by pyrazoline ring carbons C-5 and
C-4 respectively. The signals belonging to phenyl and furyl rings were found at
157.1 (C-2), 155.8 (C-2), 153.7 (C-5), 138.8 (C-1), 131.2 (C-3), 130.3 (C-6),
128.4 (C-4), 126.1 (C-5), 125.2 (C-4) & 115.8 (C-3). The upfield resonance of the
later seems to be decided by the electron releasing effect of the C-2 allyloxy group.

H2C CH=CH
...... c

+.
2

O
b
......

H
H

(M+2)

......

N H
S

m/z 329 (8.6 %)

NH2

2.92 m/z 327 (20.1 %)


c

-C4H3O

+.
+.

H2C CH=CH

OH

O
H
H

......

N H

N
O

N H
NH2

NH2

m/z 287 (100 %)


m/z 194 (36.1 %)

H
N

......

NH2
S
m/z 259 (30.1 %)

-CSNH2
+H -C4H3O

+H. -C4H3O
+

H2C CH=CH

+.

OH
H
N
N H
S

H
H
H

N
N

H
N

H
N
H

NH2

NH2

m/z 128 (22.1 %)

m/z 200 (15.1 %)

m/z 221 (12.4 %)


-NH
+

-O

H2C CH=CH

O
+.

N
N

......

H
H

m/z 126 (10.2 %)

H
N

m/z 185 (25.1 %)

N
N H
S

NH2

S
H

+H. -CSNH2

+.

NH2

m/z 205 (15.1 %)

.
+H -N

H2C CH=CH
+

N
N
H

O
H

m/z 67 (9.8 %)

H
H
H
m/z 172 (12.3 %)

Chart-1
Synthesis of (5R)-5-(furyl-2-yl)-1-phenyl-3-[2-(benzyloxy) phenyl]-4, 5-dihydro1H-pyrazole 2.93
The reaction of 2.71 with thiosemicarbazide (Scheme-2.41) under the similar
conditions as used earlier for 2.92 yielded 2.93 (68%, m.p. 118-1200C).

2'''
2'''

CH2
3'
2'

4'

3'

3'''

1'''

4'''
5'''
3''

6'"

NaOH/EtOH
1' 1 2

5'
6'

5''

1'

5'
4''

1''

S
H2N NH

2'

4'

6'

4'''

6'"
4

HM
HA

5'''

3''

4''

N
1

C NH2

3'''

CH2 1'''

N Hx
C

5''

O
1''

NH2

.71

2.93

Scheme-2.41
The structure of compound 2.93 was consistent to its spectral parameters. IR spectrum
showed noticeable absorptions at 3438, 3317 (N-H), 1596 (C=N) & 1165 (C=S) cm-1.
Its 400 MHz 1H-NMR (DMSO-d6) had characteristics pyrazoline ring protons (H-X,
H-M & H-A) at 5.20 (1H, dd), 3.78 (1H, dd) & 3.57 (1H, dd) respectively. The
coupling value of JMX=11.2Hz and JAX=6.5Hz describes that H-A is trans to H-X
while H-B has cis relationship to H-X and geminal coupling constant between H-M &
H-A was found to be 17.1Hz. NH2 group hydrogens furnished a broad singlet at
8.32 which was also exchangeable with D2O. The aromatic and benzyloxy group
protons were found to be resonanting at 7.87 (1H, dd, Jm,o=2.3, 7.8Hz, H-6), 7.38
(1H, d, J5,4=3.5Hz, H-5), 7.29 (3H, m, H-3, 3, 5), 7.20 (3H, m, H-4, 5,
4), 7.14 (2H, m, H-2, 6), 7.01 (2H, m, H-3, 4) & 5.35 (2H, s, OCH2)
respectively.
13

C-NMR (100 MHz, CDCl3) of 2.93 was also very helful to interpret its carbon

framework which exhibited the significant resonances of the pyrazolines moiety (C-3,
5 & 4) at 158.4, 59.4 & 43.8 respectively. The presence of C=S & OCH2 groups
were confirmed by the appearance of signals at 177.4 & 71.7 respectively and the
resonances present at 152.3 , 142.3, 129.2 & 125.9 could be provided by furan ring
carbon atoms (C-2, 5, 3 & 4) respectively. The remaining carbon atoms were
found to be resonating at the suitable positions in the aromatic region (vide
experimental).
The mass spectrum of compound 2.93 exhibited molecular ion at m/z 377 (100 %)
and the characteristics ions due to the loss of the benzyloxy and furyl moieties were
observed at m/z 287 (21.6 %) & 310 (28.9 %) respectively. The mass fragmentation
of 2.93 was found to similar as shown in Chart-1 (vide experimental).

Synthesis of pyrazolines 2.94 & 2.95


The compounds 2.94 & 2.95 were prepared from the reactions of chalcones 2.72 &
2.73 with thiosemicarbazide under the similar conditions as used earlier for 2.92.
These compounds were also characterized on the basis of their spectroscopic
parameters and their IR, 1H-NMR &

13

C-NMR spectra were comparable to those of

2.92 & 2.93. The aromatic and alkoxy groups protons and carbon atoms were
resonating at the usual palces in their 1H-NMR &

13

C-NMR spectra. IR sepectra of

these products also displayed the bands of the required functional groups at the
expected frequencies (vide experimental). The significant physical and spectral data
of 2.94 & 2.95 have been given in Table-1.
3'
4'

2'
1'

5'
6'

CH2 R

O
3

HM
HA

3''

4''

5''

N
O

1 N Hx

1''

NH2
7"'
8"'

2.94: R = -COOCH

2CH 3

; 2.95: R =

9"'
1"'
2"'

6"'
5"'
10"'
4"'
3"'

Table-1: Physical and characteristics spectral data of N-thiocarbamoylpyrazolines 2.94 & 2.95
1

Compound

Yield

m.p.

I.R.

H-NMR

No.

(%)

(oC)

max (cm-1)

()

2.94

72

130-132

3438, 3369

8.50 (brs,

(N-H)

NH2),

1755(C=O)

5.32 (dd, HX), 4.65 (s,

1604 (C=N)

OCH2), 3.80
1163 (C=S)

(dd, H-M),

13

C-NMR
()

ESI-MS
(m/z)

179.2 (C=S), 170.0 374 (M+1+,


(C=O), 158.8

100 %)

(C=N), 152.9 (C-2),


74.1 (OCH2), 55.8
(C-5),
44.7 (C-4)

3.39 (dd, HA)


2.95

70

163-165

3428, 3314

8.48 (brs,

178.9 (C=S), 157.4

(N-H)

NH2),

(C=N), 156.8 (C-2),

1599 (C=N)

5.26 (dd, H-

71.8 (OCH2), 55.3

X), 5.02 (s,

1167 (C=S)

(C-5), 45.2 (C-4)

OCH2), 3.70
(dd, H-M),
3.31 (dd, HA),

To generalize above discribed heterocyclization reactions, the researches have also


been oriented upon the following pyrazolines 2.96-2.99:
CH2

HM
HA
N
N Hx
C

NH2

2.96 R = -CH=CH2,
2.97 R = -Ph,
2.98 R = -COOEt ,
2.99 R =

450
(M+Na+,
100 %)

Synthesis of N-thiocarbamoyl-pyrazolines 2.96


The chalcone 2.79 was refluxed with thiosemicarbazide in the presence of
EtOH/NaOH medium (Scheme-2.42). The reaction mixture thus obtained was poured
into ice cold water to provide a solid substance which was crystallized from EtOH to
yield pure compound 2.96 (74%, m.p. 148-1500C).
3'

CH2 CH=CH
3'
4'

2'
1'

5'
6'

3''

4''

2
3

H2N NH

5''

CH2

CH=CH

HM
HA

3''

2
S

2'

4'

1'

5'

C NH2 /

NaOH/EtOH/

6'
2

5''

1N Hx

1''

4''

5 2''

1''

NH2

2.79

2.96

Scheme-2.42
The compound 2.96 in its IR spectrum revealed four major absorptions at 3420, 3308
& 1594 and 1162 cm-1 showing the presence of N-H, C=N & C=S functionalities. Its
mass spectrum furnished the (M+2)+ and M+ ions at m/z 345 (100 %) & 343 (20.1 %)
which

easily

describes

that

thiosemicarbazide

moiety

has

undergone

cyclocondensation with chalcone 2.79 in the formation of 2.96. The ions present at
m/z 303 (18.7 %), 259

(30.1 %) & 210 (15.3 %) also corroborated to the proposed

expression of 2.96 and its mass fragmentation pattern has been depicted in Chart-2.

+.

H2C CH=CH

...... c

O
b
......

H
(M+2)

H
......

m/z 345 (100 %)

N H
S

NH2

2.92 m/z 343 (20.1%)


c

-C4H3S

+.

+
.

H2C CH=CH

OH

O
H
H

......

N H

H
N

N
S

N H
NH2

NH2

m/z 303 (18.7 %)


m/z 210 (36.1 %)

H
N

......

NH2
S
m/z 259 (30.1%)
-CSNH2

-C4H3S

-C4H3S
+
.

H2C CH=CH

+.

OH
H
N

N
N

H
N H

H
+

NH2

H
H
H

H
N

NH2

m/z 128 (22.1 %)

H
N
H

m/z 201 (15.3 %)

m/z 221 (12.4 %)


-N2H
-O

H
N
N H
S

......

NH2

S
H

+.

H2C CH=CH

m/z 126 (10.2 %)

H
H

m/z 171 (12.3 %)

NH2

m/z 205 (15.1 %)

N
N
H

m/z 67 (9.8 %)

Chart-2

A comparison of the 1H-NMR spectra (400 MHz, CDCl3) of 2.79 and 2.96 shows that
resonances present at 7.61 (H-3) & 7.52 (H-2) in former were found missing

altogether in the later, thereby describing the involvement of these hydrogens in the
chemical transformation. The noticeable signals were resonating at 5.28 (1H, dd,
JXM=6.6Hz, JXA=11.7Hz), 3.54 (1H, dd, JMX=6.7Hz, JMA=16.7Hz), 3.27 (1H, dd,
JAX=11.7Hz, JAM=16.7Hz) which were belonging to H-X, H-M & H-A respectively of
the pyrazoline ring. The most downfield broad singlet at 8.23 could be generated by
NH2 group and this signal was also exchangeable with D2O. In the aromatic region,
signals present at 7.91 (1H, dd, Jm,o=2.5, 7.8Hz), 7.52 (1H, m), 7.20 (1H, m) & 6.89
(1H, d, Jo=8.6Hz) and 7.68 (1H, m), 7.44 (1H, d, J3,4=3.7Hz) & 7.02 (1H, dd,
J4,3=3.7Hz, J4,5=5.0Hz) could be ascribed to phenyl ring (H-6, 4, 5 & 3) and
thienyl ring (H-5, 3 & 4) protons respectively. The hydrogens of the allyloxy
group were resonating at the expected positions (vide experimnatal).
13

C-NMR (100 MHz, CDCl3) spectrum of 2.96 exhibited significant resonances at

178.8 (C=S), 157.6 (C-2), 156.2 (C-2), 152.8 (C-5) and the downfield
appearance of these carbon atoms could be happening due to their direct bonding to
the hetero atoms (O & S). The signals of the pyrazoline moiety were placed at 159.3
(C-3), 58.4 (C-5) & 44.5 (C-4) and allyloxy group could provide suitable signals at
134.3 (CH=CH2), 120.1 (CH=CH2) & 74.3 (OCH2). The remaining carbon atoms
associated to the phenyl and thiophene rings also resulted suitable signals at the
expected positions in the aromatic region (see experimental).

Synthesis of (5R)-5-(furyl-2-yl)-1-phenyl-3-[2-(benzyloxy) phenyl]-4, 5-dihydro1H-pyrazole 2.97


The compound 2.97 (70%, m.p. 125-1270C) was prepared from the reaction of
chalcone 2.80 with thiosemicarbazide (Scheme-2.43) under the similar conditions as
described earlier for 2.96.

6''
6''

CH2
3'

2'

4'

1' 1

5'

4''

6'

5''
3

1'

5'

4''

3''

H2N NH

C NH2 /

6'

CH2

2'

4'

3''

2''

3'

5''

1''

HM
HA

3'''

4'''

1''

4''
3''

2''

NaOH/EtOH/

5''

1''

N Hx
C

5'''

S
1'''

NH2

2.80

2.97

Scheme-2.43
In the IR spectrum of 2.97, the characteristics bands were present at 3460, 3317 (NH), 1596 (C=N) & 1166 (C=S) cm-1. Its 1H-NMR (400 MHz, CDCl3) spectrum had
pyrazoline ring protons (H-X, H-A & H-M) at 5.24 (1H, dd, JXA=6.5Hz,
JXM=11.2Hz, H-X), 3.80 (1H, dd, JMX=11.2Hz, JMA=17.1Hz, H-M), 3.60(1H, dd,
JAX=6.5Hz, JAM=17.1Hz, H-A). The coupling value of JAX=6.5Hz and JMX=11.2Hz
describes that

H-A is trans to H-X while H-M has cis relationship to H-X. The

coupling constant of JMA=17.1Hz describes the geminal placement of the H-A and HM at C-4. The aromatic and OCH2 group hydrogens were observed at the expected
positions (see experimental).
13

C-NMR (100 MHz, CDCl3) of 2.97 exhibited signals of the pyrazolines moiety (C-

3, 5 & 4) at 158.9, 58.8 & 44.3 respectively. The most downfield occurrence of the
carbon (C-3) could be ascribed to its azomethine nature. The OCH2 group provided a
signal at

72.3 and remaining carbon atoms were found resonating at the suitable

positions in the aromatic region (see experimental).


The (M+2)+ and (M)+ ions in the mass spectrum of 2.97 were observed at m/z 395
(40%) & 393 (30.1 %) and its mass fragmentation was found to be similar as shown
in Chart-2 (vide experimental).
Synthesis of pyrazolines 2.98 & 2.99
The compounds 2.98 & 2.99 were obtained from the reactions of chalcones 2.81 &
2.82 with thiosemicarbazide under the similar conditions as used earlier for 2.96. The
structures of these pyrazolines were determined from the rigereous analysis of their
spectroscopic data and their spectral parameters were comparable to those of 2.96 &
2.97. The hydrogen and carbon atoms belonging to aromatic rings and alkoxy groups

were found to be resonating with expexted & J values in their 1H-NMR &

13

C-

NMR spectra. The important physical and characteristics spectral data of 2.98 & 2.99
have been provided in Table-2.

3'
4'

2'
1'

5'
6'

CH2 R

HM
HA
5

3''

5''

1 N Hx

4''

2''
1''

7"'

NH2
2.98: R = -COOCH

8"'

2CH 3

; 2.99: R =

9"'
1"'
2"'

6"'
5"'
10"'
4"'
3"'

Table-2: Physical and characteristics spectral data of pyrazolines 2.98 & 2.99
Compoun Yield

m.p.

d No.

(%)

(oC)

2.98

72

I.R.
max (cm-1)

H-NMR
()

13

C-NMR

()

ESI-MS
(m/z)

148-

3442, 3369 8.40 (brs, NH2), 179.6 (C=S), 390 (M+1+,

150

(N-H)

5.38 (dd, H-X), 170.5 (C=O), 42.4 %)/389

1755

4.62 (s, OCH2), 158.3 (C=N), (M+,30.6%)

(C=O)

3.78 (dd, H-M), 152.4


3.35 (dd, H-A)

1598
(C=N)

(C-2),

72.5 (OCH2),
56.1

(C-5),

44.2

(C-4)

1161
(C=S)
2.99

75

173-

3478, 3314 8.62 (brs, NH2), 179.2 (C=S),

175

(N-H)

5.29 (dd, H-X), 158.6 (C=N), (M+2+,

1602

5.08 (s, OCH2), 156.3 (C-2), 100

(C=N)

3.75 (dd, H-M), 70.5 (OCH2), %)/444


3.34 (dd, H-A),

1164
(C=S)

56.4

445

(C-5), (M+1+,

43.8 (C-4)

40.2 %)

Antimicrobial studies of N-thiocarbamoyl-pyrazolines 2.92-2.95 & 2.96-2.99


In vitro antimicrobial activities of 2.92-2.95 & 2.96-2.99 have been performed using
the similar methods as described earlier in Chapter-IIa (page no.-34, 35) [disc
diffusion and serial tube dilution method]. The results of their zone of inhibitions and
minimum inhibitory concentrations are summarized in Table-3, Table-5 and Table-4,
Table-6 respectively.

Table-3: Zone of inhibitions (mm) of N-thiocarbamoyl-pyrazolines 2.92-2.95.


Compounds

A. hydrophila

Y. enterocolitica

L. monocytogenes

S. aureus

2.92

16.5

14.7

15.6

17.6

2.93

21.5

24.4

21.3

22.8

2.94

14.5

15.7

18.6

16.8

2.95

25.3

18.6

20.8

24.5

Gentamicin

21

..

17

Tetracycline

13

20

12

14

DMSO

Table-4: Minimum inhibitory concentrations (MIC, g/ml) of N-thiocarbamoylpyrazolines 2.92-2.95.

Compounds

A. hydrophila

Y. enterocolitica

L. monocytogenes

S. aureus

2.92

10

20

30

20

2.93

10

30

30

20

2.94

20

30

30

10

2.95

30

40

40

20

Gentamicin

10

10

10

10

Tetracycline

30

30

30

30

Table-5: Zone of Inhibitions (mm) of N-thiocarbamoyl-pyrazolines 2.96-2.99.

Compounds

A. hydrophila

Y. enterocolitica,

L. monocytogenes

S. aureus

2.96

16.5

14.7

15.6

17.6

2.97

21.5

24.4

21.3

22.8

2.98

14.5

15.7

18.6

16.8

2.99

25.3

18.6

20.8

24.5

Gentamicin

21

..

17

Tetracycline

13

20

12

14

DMSO

Table-6: Minimum inhibitory concentrations (MIC, g/ml) of N-thiocarbamoylpyrazolines 2.96-2.99.

Compounds

A. hydrophila

Y. enterocolitica

L. monocytogenes

S. aureus

2.96

30

40

20

10

2.97

30

40

30

40

2.98

20

20

20

40

2.99

20

10

10

30

Gentamicin

10

10

10

10

Tetracycline

30

30

30

30

It is evident from Table-3 & Table-5 that compounds 2.93, 2.95, 2.97 and 2.99
provided better zone of inhibitions against the bacteria strains namely A. hydrophila,
Y. enterocolitica, L. monocytogenes & S. aureus. Table-4 & Table-6 describes that
compounds 2.94 & 2.99 showed significant MIC against S. aureus & L.
monocytogenes respectively.
It may be concluded that this study describes the genral method for the preparation of
N-thiocrbamoyl-thienyl/furyl-pyrazolines.

These

heterocyclic

compounds

exhibited significant antibacterial behavior against the tested bacteria strains.

also

EXPERIMENTAL
Synthesis of (5R)-5-(furan-2-yl)-1-phenyl-3-[2-(prop-2-en-1-yloxy) phenyl]-4, 5dihydro-1H-pyrazole 2.92
A mixture of chalcone 2.70 (0.5 g, 0.0015 mol) was refluxed with thiosemicarbazide
(0.800 ml, 0.004 mol) in dry EtOH (30 ml) and NaOH (1.0 g) for 10 hrs. The progress
of reaction was monitored by TLC. After completion of the reaction, the solvent was
removed under reduced pressure and the resulted residue was poured into iced cold
water to give a solid compound which was filtered and thoroughly washed with water.
The crude product thus obtaned was crystallized from EtOH to yield pure 2.92.

3'
2'

4'

1'

5'

CH2

O
3

6'
2

HM
HX

CH=CH

3''

4''

1N Hx

5''

O
1''

NH2

2.92
2.92: Brown solid; Yield: 69%; m.p. 140-1420C; IR (KBr) max (cm-1): 3452, 3308
(N-H), 3065 (aromatic C-H), 1597 (C=N), 1160 (C=S); 1H-NMR (400 MHz, CDCl3):
8.42 (2H, brs, NH2), 7.85 (1H, dd, Jm,o=2.5, 7.8Hz, H-6), 7.62 (1H, m, H-5), 7.50
(2H, m, H-4, 3), 7.22 (1H, m, H-5), 6.97 (1H, dd, J4,3=2.1Hz, J4,5=3.8Hz, H4), 6.90 (1H, d, Jo=8.2Hz, H-3), 5.32 (1H, td, Jvic=6.7Hz, Jtrans=15.8Hz
OCH2CH=CH2), 5.25 (1H, dd, JXA=6.7Hz, JXM=11.6Hz, H-X),

4.64 (2H, dd,

Jallyl,vic=1.2, 6.1Hz, OCH2), 4.52 (2H, td, Jallyl,trans=1.2, 15.8Hz, OCH2CH=CH2), 3.52
(1H, dd, JMX=11.6Hz, JMA=16.7Hz, H-M), 3.24 (1H, dd, JAX=6.7Hz, JAM=16.7Hz, HA);

13

C-NMR (100 MHz, CDCl3): 178.3 (C=S), 158.4 (C=N), 157.1 (C-2), 155.8

(C-2), 153.7 (C-5), 138.8 (C-1), 132.9 (-CH=CH2), 131.2 (C-3), 130.6 (C-6),
128.4 (C-4), 126.1 (C-5), 125.2 (C-4), 120.6 (-CH=CH2), 115.8

(C-3), 73.8

(OCH2), 58.8 (C-5), 43.2 (C-4); MS: m/z (M+) 327 (20.1 %), (M+2)+ 329 (8.6 %) 287
(100 %), 259 (30.1 %), 221 (12.4 %), 205 (15.1 %), 200 (15.1 %), 194 (36.1 %), 185
(25.1 %), 172 (12.3 %), 128 (22.1 %), 126 (10.2 %), 67 (9.8 %); Anal. calc. for

C17H17O2SN3: C, 62.38; H, 5.20; N, 12.84; S, 9.79; Found; C, 61.98; H, 5.18; N,


9.69%.

2.4.2. (5R)-5-(furan-2-yl)-1-phenyl-3-[2-(benzyloxy) phenyl]-4, 5-dihydro-1Hpyrazole 2.93


The compound 2.93 was obtained from the reaction of 2.70 (0.5 g, 0.0015 mol) with
thiosemicarbazide (0.430 g, 0.00398 mol) under the similar conditions as used for
2.92.

2'"
3'

1'

5'
6'

CH2

2'

4'

3'''

1'''

4'''
5'''

6'"
4

HM
HA

3''

4''

N Hx
1
C

5''

O
1''

NH2

2.93
2.93: Light yellow solid; Yield: 68%; m.p. 118-1200C; IR (KBr) max (cm-1): 3438,
3317 (N-H), 3078 (aromatic C-H), 1596 (C=N), 1165 (C=S); 1H-NMR (400 MHz,
CDCl3):

8.32 (2H, brs, NH2), 7.87 (1H, dd, Jm,o=2.3, 7.8Hz, H-6), 7.38 (1H, d,

J5,4=3.5Hz, H-5), 7.29 (3H, m, H-3, 3, 5), 7.20 (3H, m, H-4, 5, 4), 7.14
(2H, m, H-2, 6), 7.01 (2H, m, H-3, 4), 5.35 (2H, s, OCH2), 5.20 (1H, dd,
JXA=6.5Hz, JXM=11.2Hz, H-X), 3.78 (1H, dd, JMX=11.2Hz, JMA=17.1Hz, H-M), 3.57
(1H, dd, JAX=6.5Hz, JAM=17.1Hz, H-A);

13

C-NMR (100 MHz, CDCl3): 177.4

(C=S), 158.4 (C=N), 153.4 (C-2), 152.3 (C-2), 142.3 (C-5), 133.2 (C-1), 130.1
(C-1), 129.8 (C-6), 129.2 (C-3), 128.2 (C-4), 125.9 (C-4), 125.2 (C-3, 5),
124.7 (C-5), 116.2 (C-4), 115.2 (C-2, 6), 114.6 (C-3), 71.7 (OCH2), 59.4 (C5), 43.8 (C-4); MS: m/z (M)+ 377 (100 %), 310 (28.9 %), 287 (21.6 %), 250 (18.4 %),
235 (18.6 %), 222 (10.6 %), 221 (15.4 %), 205 (18.5 %), 194 (42.0 %), 128 (26.2 %),
126 (14.6 %), 67 (10.3 %); Anal. calc. for C21H19O2N3S: C, 66.84; H, 5.04; N, 11.14;
S, 8.49; Found: C, 67.02; H, 5.08; N, 11.09; S, 8.46%.

Synthesis of (5R)-5-(furan-2-yl)-1-phenyl-3-[2-(ethyloxy) phenyl]-4, 5-dihydro1H-pyrazole 2.94


The compound 2.94 was prepared from the reaction of 2.70 (0.5 g, 0.0015 mol) with
thiosemicarbazide (0.430 g, 0.00398 mol) under the similar conditions as used for
2.92.
O
3'
4'

2'
1'

5'
6'

CH2 C OCH 2CH 3

O
3

HM
HA

3''

4''

5''

N
1N

Hx

O
1''

NH2

2.94
2.94: Brown solid; Yield: 72%; m.p. 130-1320C; IR (KBr) max (cm-1): 3438, 3369
(N-H), 3046 (aromatic C-H), 1755 (C=O), 1604 (C=N), 1163 (C=S); 1H-NMR (400
MHz, CDCl3): 8.50 (2H, brs, NH2), 7.90 (1H, dd, Jm,o=2.2, 7.8Hz, H-6), 7.40 (1H,
d, J5,4=3.8Hz, H-5), 7.28 (2H, m, H-4,3), 7.02 (2H, m, H-5, 4), 6.92 (1H, d,
Jo=7.8Hz H-3), 5.32 (1H, dd, JXA=6.5Hz, JXM=11.8Hz, H-X), 4.65 (2H, s, OCH2),
4.02 (2H, q, Jvic=6.4Hz, OOCH2CH3), 3.80 (1H, dd, JMX=11.8Hz, JMA=16.6Hz, HM), 3.39 (1H, dd, JAX=6.5Hz, JAM=16.6Hz, H-A), 1.23 (3H, t, Jvic=6.4Hz,
OOCH2CH3);

13

C-NMR (100 MHz, CDCl3): 179.2 (C=S), 170.0 (C=O), 158.8

(C=N), 152.9 (C-2), 152.1 (C-2), 143.5 (C-5), 133.8 (C-1), 130.2 (C-6), 129.9
(C-3), 129.2 (C-4), 128.8 (C-4), 123.4 (C-5), 114.2 (C-3), 74.1 (OCH2), 67.2
(OCH2CH3), 55.8 (C-5), 44.7 (C-4), 25.8 (OCH2CH3); MS: m/z (M+1)+ 374 (100 %),
(M+) 373 (20.1 %), 306 (50.4 %), 287 (12.4 %), 246 (22.2 %), 231 (15.0 %), 221
(19.6 %), 205 (30.2 %), 194 (31.9 %), 128 (19.0 %), 126 (17.6 %), 67 (12.1 %); Anal.
calc. for C18H19N3SO4: C, 57.90; H, 5.09; N, 11.26; S, 8.58; Found: C, 58.09; H, 5.06;
N, 11.23; S, 8.60 %.
Synthesis of (5R)-5-(furan-2-yl)-1-phenyl-3-[2-(naphthalen-2-ylmethoxy prop-2en-1-yloxy) phenyl]-4, 5-dihydro-1H-pyrazole 2.95
The compound 2.95 was synthesized from the reaction of 2.71 (0.5 g, 0.0015 mol)
with thiosemicarbazide (0.430 g, 0.00398 mol) under the similar conditions as used
for 2.92.

7"'

6"'

8"'
3'

2'

4'

CH2

5"'

1"'
2"'

1'

5'

6'

HM
4
HA
5

2N
1

N Hx

4"'
3"'

3''

4''

2''

5''

O
1''

C S
NH2

2.95
2.95: Light yellow solid; Yield: 70%; m.p. 163-1650C; IR (KBr) max (cm-1): 3428,
3314 (N-H), 3052 (aromatic C-H), 1599 (C=N), 1167 (C=S); 1H-NMR (400 MHz,
CDCl3):

8.48 (2H, brs, NH2), 8.02 (2H, m, H-7, 8), 7.72 (1H, dd, Jm,o= 2.6,

7.9Hz, H-6), 7.59 (4H, m, H-4, 5, 5, 6), 7.39 (1H, d, J3,4=3.0Hz, H-3),
7.08 (3H, m, H-5, 4, 3), 6.98 (2H, m, H-2, 4), 6.87 (IH, d, Jo=8.6Hz, H-3),
5.26 (1H, dd, JXA=6.7Hz, JXM=11.8Hz, H-X), 5.02 (2H, s, OCH2), 3.70 (1H, dd,
JAX=6.7Hz, JAM=16.2Hz, H-A), 3.31 (1H, dd, JMX=11.8Hz, JMA=16.2Hz, H-M);

13

C-

NMR (100 MHz, CDCl3): 178.9 (C=S), 157.4 (C=N), 156.8 (C-2), 154.9 (C-2),
142.2 (C-5), 139.5 (C-1), 132.1 (C-1), 131.8 (C-9), 130.2 (C-10), 129.9 (C6), 129.2 (C-8), 128.8 (C-7), 127.6 (C-6), 127.0 (C-5), 126.9 (C-4), 126.1
(C-3), 125.8 (C-5), 125.2 (C-4), 123.7 (C-3), 122.4 (C-4), 120.5 (C-2),
116.3 (C-3), 71.8 (OCH2), 55.3 (C-5), 44.6 (C-4); MS: m/z (M+Na)+ 450 (100 %),
(M+1)+ 428 (30.6 %), 360 (48.1 %), 300 (21.0 %), 287 (20.8 %), 285 (30.7 %), 221
(7.2 %), 205 (29.9 %), 194 (42.8 %), 128 (30.6 %), 126 (11.6 %), 67 (14.5 %); Anal.
calc. for C25H21N3O2S: C, 70.26; H, 4.92; N, 9.84; S, 7.49; Found: C, 70.52; H, 4.95;
N, 9.87; S, 7.46 %.
Synthesis of (5R)-5-(furan-2-yl)-1-phenyl-3-[2-(prop-2-en-1-yloxy) phenyl]-4, 5dihydro-1H-pyrazole 2.96
A mixture of 2.80 (0.5g, 0.0015 mol) was refluxed with thiosemicarbazide (0.8 ml,
0.004mol) in dry EtOH (30 ml) and NaOH (1.0 g) for 8 hrs. The progress of reaction
was monitored by TLC. After completion of the reaction, the solvent was removed
under reduced pressure and the residue obtained was poured into ice cold water to

yield a solid substance which was filtered , washed thoroughly with H2O and dried.
The crude product was crystallized from EtOH to yield 2.96.
3'

2'

4'

1'

5'

CH=CH

HM
HA

3''

6'
2

CH2

4''

5 2''

1N Hx

5''

S
1''

NH2

2.96
2.96: Brown solid; Yield: 74%; m.p. 148-1500C; IR (KBr) max (cm-1): 3420, 3308
(N-H), 3082 (aromatic C-H), 1594 (C=N), 1162 (C=S); 1H-NMR (400 MHz, CDCl3):
8.23 (2H, brs, NH2), 7.91 (1H, dd, Jm,o=2.5, 7.8Hz, H-6), 7.68 (1H, m, H-5), 7.52
(1H, m, H-4), 7.44 (1H, d, J3,4=3.7Hz, H-3), 7.20 (1H, m, H-5), 7.02 (1H, dd,
J4,3=3.7Hz, J4,5=5.0Hz, H-4), 6.89 (1H, d, Jo=8.6Hz, H-3), 5.35 (1H, td,
Jvic=6.6Hz, Jtrans=15.8Hz OCH2CH=CH2), 5.28 (1H, dd, JXM=6.6Hz, JXA=11.7Hz, HX), 4.61 (2H, d, Jvic=6.1Hz, OCH2), 4.54 (2H, dd, Jallyl,

trans=1.1,

15.8Hz,

OCH2CH=CH2), 3.54 (1H, dd, JMX=6.7Hz, JMA=16.7Hz, H-M), 3.27 (1H, dd,
JAX=11.7Hz, JAM=16.7Hz, H-A); 13C-NMR (100 MHz, CDCl3): 178.8 (C=S), 159.3
(C=N), 157.6 (C-2), 156.2 (C-2), 152.8 (C-5), 138.0 (C-1), 134.3 (-CH=CH2),
132.6 (C-3), 131.8 (C-6), 129.7 (C-4), 126.4 (C-5), 124.5 (C-4), 120.1 (CH=CH2), 118.9 (C-3), 74.3 (OCH2), 58.4 (C-5), 45.2 (C-4); MS: m/z (M+2)+ 345
(100 %), (M)+ 343 (20.1 %), 303 (18.7 %), 259 (30.1 %), 221 (12.4 %), 210 (36.1 %),
205 (15.4 %), 201 (25.6 %), 171 (12.3 %), 128 (22.1 %), 126 (10.2 %), 67 (9.8 %) ;
Anal. calc. for C17H17OS2N3: C, 59.47; H, 4.96; N, 12.24; S, 18.66; Found; C, 59.62;
H, 4.97; N, 12.28; S, 18.53%.

2.4.2. (5R)-5-(furan-2-yl)-1-phenyl-3-[2-(benzyloxy) phenyl]-4, 5-dihydro-1Hpyrazole 2.97


The compound 2.97 was obtained from the reaction of 2.80 (0.5 g, 0.0015 mol) with
thiosemicarbazide (0.430 g, 0.00398 mol) under the similar conditions as used for
2.96.

2''
3'
4'

1'

5'
6'

CH2

2'

3''

1''

4''

6''

HM
4
HA

5''
4''

3''

5 2''

N Hx
1
C

5''

S
1''

NH2

2.97
2.97: Light yellow solid; Yield: 70%; m.p. 125-1270C; IR (KBr) max (cm-1): 3460,
3317 (N-H), 3072 (aromatic C-H), 1596 (C=N), 1166 (C=S); 1H-NMR (400 MHz,
CDCl3): 8.36 (2H, brs, NH2), 7.88 (1H, dd, Jm,o=2.4, 7.6Hz, H-6), 7.40 (1H, d,
J5,4=5.0Hz, H-5), 7.31 (3H, m, H-3, 3, 5), 7.23 (3H, m, H-4, 5, 4), 7.15
(2H, m, H-2, 6), 7.06 (1H, dd, J4,3=3.7Hz, J4,5=5.0Hz, H-4), 6.92 (1H, d,
Jo=8.6Hz, H-3), 5.32 (2H, s, OCH2), 5.24 (1H, dd, JXA=6.5Hz, JXM=11.2Hz, H-X),
3.80 (1H, dd, JMX=11.2Hz, JMA=17.1Hz, H-M), 3.60 (1H, dd, JAX=6.5Hz,
JAM=17.1Hz, H-A); 13C-NMR (100 MHz, CDCl3): 179.5 (C=S), 158.9 (C=N), 154.7
(C-2), 152.6 (C-2), 142.8 (C-5), 132.5 (C-1), 131.4 (C-1), 130.8 (C-6), 129.1
(C-3), 128.6 (C-4), 126.2 (C-4), 125.8

(C-3, 5), 123.5 (C-5), 118.4 (C-

4), 116.7 (C-2, 6), 114.2 (C-3), 72.3 (OCH2), 58.8 (C-5), 44.3 (C-4); MS: m/z
(M+2)+ 395 (40.0 %), (M)+ 393 (30.1 %), 310 (33.6 %), 303 (19.7 %), 250 (20.7 %),
221 (10.6 %), 210 (100 %), 205 (20.0 %), 128 (24.6 %), 126 (17.5 %), 67 (18.3 %);
Anal. calc. for C21H19ON3S2: C, 64.12; H, 4.83; N, 10.69; S, 16.28; Found: C, 64.36;
H, 4.81; N, 10.72; S, 16.23%.

Synthesis of (5R)-5-(furan-2-yl)-1-phenyl-3-[2-(ethyloxy) phenyl]-4, 5-dihydro1H-pyrazole 2.98


The compound 2.98 was prepared from the reaction of 2.80 (0.5 g, 0.0015 mol) with
thiosemicarbazide (0.430 g, 0.00398 mol) under the similar conditions as used for
2.96.

O
3'
4'

2'
1'

5'
6'

CH2 C OCH 2CH 3

O
3

HM
HA
5

Hx

4''

2''

N
1N

3''

5''

S
1''

NH2

2.98
2.98: Brown solid; Yield: 72%; m.p. 148-1500C; IR (KBr) max (cm-1): 3442, 3369
(N-H), 3062 (aromatic C-H), 1755 (C=O), 1598 (C=N), 1161 (C=S); 1H-NMR (400
MHz, CDCl3): 8.40 (2H, brs, NH2), 7.86 (1H, dd, Jm,o=2.1, 7.9Hz, H-6), 7.43 (1H,
d, J5,4=5.1Hz, H-5), 7.28 (1H, m, H-4), 7.19 (1H, d, J3,4=3.8Hz, H-3), 7.11
(1H, m, H-5), 7.02 (1H, dd, J4,3=3.8Hz, J4,5=5.1Hz, H-4), 6.98 (1H, d,
Jo=8.6Hz H-3), 5.38 (1H, dd, JXA=6.6Hz, JXM=11.8Hz, H-X), 4.62 (2H, s, OCH2),
4.05 (2H, q, Jvic=6.5Hz, OCH2CH3), 3.78 (1H, dd, JMX=6.6Hz, JMA=16.6Hz, H-M),
3.35 (1H, dd, JAX=11.8Hz, JAM=16.6Hz, H-A), 1.26 (3H, t, Jvic=6.5Hz, OCH2CH3);
13

C-NMR (100 MHz, CDCl3): 179.6 (C=S), 170.5 (C=O), 158.3 (C=N), 152.4 (C-

2), 151.2 (C-2), 143.8 (C-5), 134.2 (C-1), 130.7 (C-6), 129.1 (C-3), 128.3 (C4), 125.9 (C-4), 122.1 (C-5), 113.4 (C-3), 72.5 (OCH2), 67.8 (OCH2CH3), 56.1
(C-5), 44.2 (C-4), 25.1 (OCH2CH3); MS: m/z (M+1)+ 390 (42.4 %), (M)+ 389 (30.6
%), 306 (100 %), 303 (15.5 %), 246 (12.6 %), 221 (16.3 %), 217 (18.0 %), 205 (25.3
%), 128 (13.7 %), 126 (24.3 %), 67 (7.2 %); Anal. calc. for C18H19N3S2O3: C, 55.53;
H, 4.88; N, 10.80; S, 16.45; Found: C, 55.76; H, 4.86; N, 10.83; S, 16.50%.

Synthesis of (5R)-5-(furan-2-yl)-1-phenyl-3-[2-(naphthalen-2-ylmethoxy prop-2en-1-yloxy) phenyl]-4, 5-dihydro-1H-pyrazole 2.99


The compound 2.99 was synthesized from the reaction of 2.80 (0.5 g, 0.0015 mol)
with thiosemicarbazide (0.430 g, 0.00398 mol) under the similar conditions as used
for 2.95.

7'''

6'''

8'''

3'

2'

4'

1'

5'

6'

CH2

10'''
4'''

2'''
4

HM
HA

3'''

3''

4''

2''

2N
1

5'''

9'''
1'''

N Hx

5''

S
1''

C S
NH2

2.99
2.99: Light yellow solid; Yield: 75%; m.p. 173-1750C; IR (KBr) max (cm-1): 3478,
3314 (N-H), 3075 (aromatic C-H), 1602 (C=N), 1164 (C=S); 1H NMR (400 MHz,
CDCl3):

8.62 (2H, brs, NH2), 8.05 (2H, m, H-7, 8), 7.75 (1H, dd, Jm,o= 2.3,

7.8Hz, H-6), 7.63 (4H, m, H-4, 5, 5, 6), 7.37 (1H, d, J3,4=3.7Hz, H-3),
7.11 (2H, m, H-5, 3), 7.03 (1H, dd, J4,3=3.7Hz, J4,5=5.0Hz, H-4), 6.95 (2H,
m, H-2, 4), 6.88 (IH, d, Jo=8.8Hz, H-3), 5.29 (1H, dd, JXA=6.7Hz, JXM=11.8Hz,
H-X), 5.08 (2H, s, OCH2), 3.75 (1H, dd, JMX=11.8Hz, JMA=16.2Hz, H-M), 3.34 (1H,
dd, JAX=6.7Hz, JAM=16.2Hz, H-A);

13

C-NMR (100 MHz, CDCl3): 179.2 (C=S),

158.6 (C=N), 156.3 (C-2), 154.2 (C-2), 143.1 (C-5), 139.8 (C-1), 132.6 (C-1),
131.2 (C-9), 130.8 (C-10), 129.7 (C-6), 129.0 (C-8), 128.2 (C-7), 127.9 (C6), 127.2 (C-5), 126.7 (C-4), 126.0 (C-3), 125.9 (C-5), 125.1 (C-4), 124.6
(C-3), 121.5 (C-4), 120.8 (C-2), 114.6 (C-3), 70.5 (OCH2), 56.4 (C-5), 43.8
(C-4); MS: m/z (M+2)+ 445 (100 %), (M+1)+ 444 (40.2%), 376 (42.6 %), 316 (25.4
%), 303 (60.2 %), 287 (19.8 %), 221 (18.3 %), 210 (48.7 %), 205 (24.4 %), 128 (26.5
%), 126 (7.1 %), 67 (12.2 %); Anal. calc. for C25H21N3S2O: C, 67.72; H, 4.74; N,
9.48; S, 14.45; Found: C, 67.98; H, 4.72; N, 9.45; S, 14.42 %.

REFERENCES
1. Zdemir, Z. O.; Kandilci, H. B. and Gumusxel, B.; Alsx, U. C. and Bilgin, A. A.
Eur. J. Med. Chem. 2007, 42, 373.
2. Budakoti, A.; Abid, M. and Azam, A. Eur. J. Med. Chem. 2007, 42, 544-551.
3. Budakoti, A.; Bhat, A. R.; Athar, F. and Azam, A. Eur. J. Med. Chem. 2008, 43,
1749.
4. Jayaprakash, V.; Sinha, B. N.; Ucar, G. and Ercan, A. Bioorg. Med. Chem. Lett.
2008, 18, 6362.
5. Pathak, V. N.; Joshi, R.; Sharma, J.; Gupta, N. and Rao, V. M. Phosphorous,
Sulfur & Silicon 2009, 184, 1854.
6. Shailendra, Bharti, N.; Naqvi, F. and Azam, A. Bioorg. Med. Chem. Lett. 2003,
13, 689.
7. Bharti N.; Athar, F.; Mauryab, M. R. and Azam, A. Bioorg. Med. Chem. 2004, 12,
4679.
8. Sharma, S.; Athar, F.; Mauryab, M. R.; Naqvi, F. and Azam A. Eur. J. Med.Chem.
2005, 40, 557.
9. Mauryab, M. R.; Kumar, A.; Abid, M. and Azam, A. Inorg. Chim. Acta 2006,
359, 2439.
10. Sharma, S.; Athar, F.; Mauryab, M. R. and Azam, A. Eur. J. Med. Chem. 2005,
40, 1414.

CHAPTER-III
Synthesis of New alkoxythiadiazolines and quinoxaline
based thiazoles

"Synthesis and biological evalutions of thiadiazoline derivatives".


Mamta Rani and Mohamad Yusuf
Hetrocyclic communication (Communicated Manuscript- ID: HC.2011.0059)

Five membered aromatic systems having three heteroatoms at the symmetrical


positions have been studied because of their interesting physiological properties.1 In
the recent decades, the synthesis of substituted thiadiazolines2-4 and related
compounds has attracted considerable attention because these compounds constitute
the structural frameworks of several naturally occurring alkanoids that show a wide
range of pharmaceutical and industrial importances.5 The techonological uses of these
compounds include dyes, optically active liquid crystals and photographic materials.
Thiadiazolines, thiadiazoles and oxadiazolines possess a wide range of biological
properties and they act as anthelminitics,6-8 antihypertensive,9 antitumor,10-12
analgesic, anticancer, anti-inflammatory and antibacterial,13-17 tyrosinase inhibitory
activities.18 The macrocycles containing thiadiazoline & thiadiazole subunits are
found to be interesting host guest complexation characterstics19 and also exhibit
antibacterial activities.20
The synthesis of new 1,3,4-thiadiazole21 3.4 derivatives endowed with analgesic and
anti-inflammatory activities have been reported. Two series of N-[5-oxo-4(arylsulfonyl)-4,5-dihydro-1,3,4-thiadiazol-2-yl]-amides

3.4

(Scheme-3.1)

were

synthesized and tested in vivo for their analgesic and anti-inflammatory activities. All
the new compounds were found to exhibit good analgesic action and some
compounds also showed fair anti-inflammatory activity in the carrageenan rat paw
edema test. Ulcerogenic and irritative action on the gastrointestinal mucose, in
comparison with indomethacin was observed to be low.
O

O
R

S NH NH 2

S C N C R'

3.1

3.2

O
a

S NH NH

NH

R
R'

3.3

SO2

N
O

O
NH

R'

3.4

Reagents and Conditions: a) THF anhyd, rt, 3 days; b) CH3COONa anhyd, posgene, THF anhyd, 12h, rt

Scheme-3.1
Yasser H. Zaki and et al22 have prepared 2,3-dihydro-1,3,4-thiadiazoles 3.8 & 3.12 in
good yields from the reactions of hydrazonoyl halides with alkyl carbodithioates,
pyrimidine-2-thione and substituted prop-2-ene-1-one respectively (Scheme-3.2 &
3.3). Some of these compounds were also tested against the bacteria and fungi strains.

..
[RCOC-N=NAr]

X
R

3.7

3.5

PhNHC(S)SCH3
3.6

NNHAr

Ph
R

-CH3SH

N
N

S
N

NPh

Ar

Ar

3.8

3.9

a) Ar= C6H6, X= Br, b) Ar= 4-CH3C6H4, X=Br, R= 2, 4-dimethylthiazol-5-yl

Scheme-3.2
Y

SH

R'

RCOC(Br):NNHAr

SCH 3

R'

3.10

COR

Et3N

Ar

3.11

3.12

Scheme-3.3
Noureddine Mazoir and co-workers23 have reported the synthesis of some steroidal
based spirocyclic thiadiazolines under the ordinary conditions as shown in Scheme3.4.
H3C

CH3

H3C

CH3
S

H2N

CH3

CH3

CH3

CH3

Ac

CH3

CH3
HN

H3C

N
N

Ac2O/ pyridine/ 1h

H3C

N
H3C

S
AcHN

H3C

3.14

3.13

Scheme-3.4

The

heterocyclic

derivatives24

7-(substituted

aryl/aryloxy

methyl-3-(4-

methylthiobenzyl)-4H-1,3,4-thiadiazolo [2, 3-c]-1, 2, 4-triazin-4-ones 3.19 were


prepared

by

reacting

4-amino-6-(4-methylthiobenzyl)-3-mercapto-1,2,4-triazin-

5(4H)-one with substituted benzoic acids/aryloxy acetic acids in the presence of


phosphorus oxychloride. 4-Amino-6-(4-methylthiobenzyl)-3-mercapto-1,2,4-triazin5(4H)-one was obtained by reacting 4-(4-methylthiobenzylidene)-2-methyl-oxazol-5one(3) with thiocarbohydrazide by refluxing in aqueous EtOH (Scheme-3.5). The
antibacterial and antifungal activities of these compounds were carried out and all the
tested products exhibited moderate activity for both microbes.

NH
H3C

Ac2O/ NaOAc/heat

COOH

H3CS

SCH 3

3.16

3.15

N
3.17

CH3

NH2NHCSNHNH2/ aq EtOH, heat

3.18

N
N

Ar'

H3CS

Ar'-COOH/ POCl3

3.20

N
N

H3CS

NH2
SH

N
3.19

Ar-COOH/ POCl3

N
N

H3CS

N
Ar
S

N
3.21

Ar= C6H5, 4-OCH3C6H4, 4-ClC6H4, 2,4-Cl2C6H3


Ar= C6H5OCH2, 4-CH3C6H4OCH2, 4-ClC6H4OCH2, 2,4-Cl2C6H3OCH2

Scheme-3.5

The compound 3.22 was converted into 1,3,4-thiadiazolines 3.25 through three step
reaction 25 which is shown in Scheme-3.6.

HN

H2NHN
O
O
NHCOPh

S
NHCOPh

NH

Ar

Ar

SK

O
O

CS2/ KOH

NH

- +

NH

3.23

3.22

N2H4.H2O/ stirring

S
N
NH2
O

AcOH/ POCl3
or PhCOCl

NH
O

H
N

NHCOPh

NH

NHCOPh
H
H

3.24

Ar
3.25

OMe

H3 C

a) R= CH3; b, R=Ph

Ar=

OMe
OMe

Ar

Scheme-3.6

New thiophene substituted products were synthesized by the reaction of thiophene


substituted amidoxime 3.30 with ethyl chloroformate according to the protocol as
described below in Scheme-3.7 & Scheme-3.8.
O
S

NH2OH.HCl

RNH2

NCS

NOH

NaOH

3.26

NOH

DMF

NOH
S

Cl

3.28

3.27

3.29

HN
R

R) a=Ph, b=4-Me-C6H4, c=4-Cl-C6H4, d=4-MeO-C6H4, e= 4-Br-C6H4, f=1-Naphthyl, g= 4-I-C6H4

Scheme-3.7
Cl
NOH
S

Et3N

Xylene, Reflux

OCH 2CH 3

HN

3.31

3.30

3.32
R) a=Ph, b=4-Me-C6H4, c=4-Cl-C6H4, d=4-MeO-C6H4, e= 4-Br-C6H4, f=1-Naphthyl, g= 4-I-C6H4

Scheme-3.8
The spirocyclic oxadiazole27 3.38 were synthesized successfully starting from
p-chloroaniline through the sequence of reactions as shown in Scheme-3.9.
X
i) Cl3CCH(OH)2, NH2OH.HCl

NOH
O

iii) conc. HCl, iv) Na2SO4 sol.

NH

NH2

N
H

3.35

3.34

3.33

Conc. H2SO4, 70-80 0C, reflux

NH2NHCONHNH2/ CH3COOH, reflux

COCH 3

H
N

NHNH 2

NHNHCOCH 3

3.38

NNHCONHNH

O
N
H

NH2NH2.H2O, stirring 3-4 hrs

N
H

3.37

Ac2O/ reflux, 4h

O
N
H

3.36

X= H, Cl

Scheme-3.9
The cyclization28 reactions of 3-aryl-4-amino-5-mercapto-1,2,4-triazoles with
hexanedioic acid in the presence of POCl3 and Bu4N+I- as a catalyst provided 1,4bis(3-aryl)-1,2,4-triazolo[3,4-b][1,3,4]thiadiazole-6-yl]butane (Scheme-3.10).

HOOC

(CH 2)4

COOH

Ar
3.39

(n-C4H9)4N+IPOCl3

SH

Ar

NH2

Ar

(CH 2)4

3.40

3.41
Ar=Ph, 2-Cl-Ph, 4-Cl-Ph, 3-CH3-Ph, 3-CH3-Ph, 3-Br-Ph, 4-Br-Ph, 2-I-Ph, 3-I-Ph, 4-I-Ph, 4-OCH3-Ph, 4-pyridyl, 3-pyridyl

Scheme-3.10

The inhibition activity on carbonic anhydrase I of some substituted thiadiazole and


thiadiazoline-disulfonamides29 have been studied. The structure activity relationships
based upon an original molecular descriptors family method has been developed and
applied on a sample of substituted 1,3,4-thiadiazole and 1,3,4-thiadiazolinedisulfonamides. Forty compounds were studied for their inhibition activity on
carbonic anhydrase I.
In order to investigate a better antimicrobial agent, 1,3,4-thiadiazoles30 3.44 bearing
long alkenyl and hydroxyl-alkenyl chain have been synthesized (Scheme-3.11) and
their antibacterial activity has also been examined.

O
C N

O
C NH

R C NH NH2

O
C NH NH

Conc. H2SO4

O
C NH

N
R
S

3.42

3.44

3.43

Scheme-3.11

It is evident from the above literature studies that thiadiazolines are very significant
compounds from the synthetic and biological point of view. By keeping this aspect in
view, the researches have been focussed upon the synthesis of new alkoxy
thiadiazolines

3.57-3.62.
OCH 2 R
4'
5'

3'

6'

2'
1'
2

N3

N4

O
C CH3

H3C C NH
O
O
R = -CH=CH2, -Ph,

3.57

3.58

C OCH2CH3 ,

3.59

, -CH3,

3.60

3.61

-CH2CH3

3.62

The thiadiazolines 3.57-3.62 required for the present study were synthesized from
cyclization reactions of thiosemicarbazones by refluxing under Ac2O medium. The
thiosemicarbazones 3.51-3.56 were obtained from the condensation reaction of
alkoxy- benzaldehydes 3.45-3.50 with thiosemicarbazide in the presence of dry
EtOH/HCl. The later were prepared in good yields from the O-alkylation of 4hydroxybenzaldehyde with suitable alkylating agents (allyl bromide, benzyl chloride,
bromoethyl acetate, 1-chloromethyl-naphthalene, methyl iodide & ethyl iodide) under
anhydrous K2CO3/dry acetone medium. The structures of the prepared compounds
were determined from the rigorous analysis of their spectral data (IR, 1H-NMR, 13CNMR & ESI-MS) and their purity was confirmed with help of satisfactory elemental
analysis results.

Synthesis of thiadiazoline 3.57


The compound 3.57 was synthesized in three steps:

(i) Synthesis of 4-allyoxy-benzaldehyde 3.45


4-Hydroxybenzaldehyde was reacted with allyl bromide in the presence of anhydrous
K2CO3 and tetrabutyl ammonium iodide (PTC) in dry acetone under refluxing
conditions (Scheme-3.12). The resulting reaction mixture was poured over iced HCl
to obtain a crude substance that was recrystallized from MeOH to yield pure
compound 3.45 (72%, m.p. 102-1040C).
OH

OCH 2 CH CH2

4
5

3
2
1

H C O

+ -

K2CO 3 / dry acetone / Bu 4N I


CH2=CH-CH2-Br /

2
1

H C O

3.45
Scheme-3.12
The compound 3.45 was identified from its spectral analysis. Its IR spectrum showed
strong absorption at 1662 cm-1 due to conjugated carbonyl group along with two
bands at 2850 & 2742 cm-1 (aldehyde C-H). In the 1H-NMR spectrum (400 MHz,
CDCl3) of 3.45, the lowest downfield resonance was placed at 9.80 that can be
ascribed to CHO proton. The protons of phenyl ring (H-2, 6 & H-3, 5) were
resonating at 7.78 (2H, d) & 7.07 (2H, d) respectively and their coupling values was

found to be 8.1Hz (Jo). The allyloxy group produced suitable signals at 5.35 (1H, td,
Jvic,trans=6.7, 15.8Hz, CH=CH2), 5.20 (2H, dd, Jallyl,vic=1.0, 6.7Hz, OCH2) & 5.18 (2H,
td, Jallyl,trans=1.0, 15.8Hz, CH=CH2).
13

C-NMR (100 MHz, CDCl3) spectrum of 3.45 had the downfield signal at 190.4

due to aldehydic C=O group. Another resonance at 163.1 was observed due to C-4
and its downfield appearance can be explained due to the direct linkage of this carbon
to the electronegative oxygen atom. The aromatic carbon atoms showed suitable
signals at 134.9 (C-1), 128.0 (C-2, 6) & 114.8 (C-3, 5) and allyloxy group generated
three signals at 129.8 (CH=CH2), 118.6 (CH=CH2) & 69.0 (OCH2). The ESI-MS
spectrum of 3.45 exhibited the (M+Na)+ ion at 185 (60 %) which also corroborated its
structure.
(ii) Synthesis of allyloxy-thiosemicarbazone 3.51
The compound 3.45 was treated with thiosemicarbazide in dry EtOH and HCl under
refluxing conditions (Scheme-3.13). The cooling of the resulting reaction mixture in
an ice bath provided a solid product which was crystallized from MeOH to yield pure
compound 3.51 (68%, m.p. 156-1580C).

O CH2 CH CH2
4

3
2

6
1

H C O

3.45

H2N NH

O CH2 CH CH2

S
C NH2

HCl /

/ dry EtOH

2
1

H C N NH
1'

2'

3'

C
4'

NH2
5'

3.51

Scheme-3.13

The structure of 3.51 was determined from the rigorous analysis of its spectral data.
IR spectrum exhibited absorption bands at 3374, 3350, 3150 (N-H), 1602 (C=N) &
1177 (C=S). Its 1H-NMR spectrum (400 MHz, DMSO-d6) was quite informative. The
resonance placed at 11.23 was assignable to 3-NH protons and a broad singlet
resonating at 7.78 could be assigned to NH2 group. The azomethine hydrogen (H1) was resonating at 8.00 (1H) as a sharp singlet. The aromatic protons (H-2, 6 &
H-3, 5) exhibited suitable signals at 7.53 (2H, d, Jo=8.7Hz) & 6.91 (2H, d,
Jo=8.7Hz) respectively. The upfield resonance of later could be occuring due to the +I
effect of C-4 allyloxy group. A doublet of doublet (dd) integrating for two hydrogens

at 4.65 may be alloted to OCH2 group and remaining resonances of the allyloxy
group appeared at 5.42 (1H, td, Jvic,trans=6.7, 15.8Hz, CH=CH2) & 5.27 (2H, td,
Jallyl,trans=1.0, 15.8Hz, CH=CH2). The mass spectrum of 3.51 showed (M+1)+ & (M)+
ions at m/z 236 (100 %) & 235

(69.1 %) and its fragmentation pattern has been

shown in Chart-1.
13

C-NMR (100 MHz, DMSO-d6) spectrum of 3.51 was very instrumental to

corroborate its carbon framework. The presence of C=S group was confirmed by the
appearance of a signal at 175.6 and other downfield resonance present at 148.3
could be furnished by C-4 due to its direct linkage to the electronegative oxygen
atom. The C=N group could provide a suitable resonance at 150.2. The remaining
signals in aromatic region were found to be placed at 138.6 (C-1), 134.2 (C-2, 6),
130.5 (CH=CH2), 119.7 (CH=CH2) & 116.8 (C-3, 5). The signal at 69.4 was
assignable to OCH2 group.
+
-----

+.

CH2

-----

CH2

CH2 CH

(M + 2)
m/z 237 (100 %)

NH C NH2

H C

-----

---------

H C

S
c

m/z 235 (69.1 %)

- CS

CH2

+.

OH

H
N NH NH2

m/z 164 (24.9 %)

-----

H C

CH2 CH CH2

m/z 160 (31.3 %)

NH C NH2

m/z 195 (10.4 %)

-----

+
O

NH C NH2

m/z 208 (20.5 %)

S
-C3H4

-CSNH2

OH

OH

H
H C

N NH

m/z 135 (15.8 %)


-N2

+
OH

H C H
m/z 107 (49.3 %)

Chart-1

m/z 120 (40.8 %)

(iii) Cyclization of thiosemicarbazone 3.51


The compound 3.51 was refluxed with acetic anhydride and the resulting reaction
mixture was poured into crushed ice to provide a solid substance. The crude product
was crystallized from EtOH to yield pure compound 3.57 (72%, m.p. 103-1050C).

O CH2 CH CH2

OCH 2 CH CH2

4'"
3

Ac2O /

H C
1'

N NH C
2'

3'

4'

6'"

2'"

5'"

3'"

1'"
2

NH2
5'

3' 2'

H3C C
O

3.51

N3

N4

O
C CH3
1''

2"

NH
1'

3.57

Scheme-3.14

IR spectrum of 3.57 was very helpful to interpret its structure which exhibited the
major bands at 1692, 1646 (C=O) & 1605 (C=N) cm-1. Its structure was further
supported by ESI-MS spectrum which exhibited the (M)+ & (M+2)+ ions at m/z 321
(10.4 %) & 319 (66.6 %) respectively. Other major ions were observed at m/z 203
(24.2%), 187 (36.6%), 173 (60.4 %), 147 (26.6 %), 116 (16.6 %), 107 (44.2 %) & 102
(10.1 %). The mass fragmentation pattern of 3.57 has been depicted in Chart-2.
A comparison of 1H-NMR spectra (400 MHz, DMSO-d6) of 3.51 & 3.57 shows that
resonances present at 7.78 (NH2) in former compound were found missing
altogether in the later thereby pronouncing the involvement of these hydrogens in the
chemical transformation. At the most downfield position a sharp singlet at 11.35
(1H) could be assigned to 1-NH proton. The aromatic protons (H-2, 6 & H-3,
5) were located at 7.30 (2H, d, Jo=8.7Hz) & 6.89 (2H, d, Jo=8.7Hz) respectively.
A singlet integrating for one hydrogen at 6.70 could be assigned to H-2 and two
singlets at 2.28 & 2.17 were easily provided by 3-CH3 & 2-CH3 groups
respectively. The hydrogens of allyloxy group were centred at 5.47 (1H, td,
Jvic,trans=6.5, 15.8Hz, CH=CH2), 5.23 (2H, td, Jallyl,trans=1.0, 15.8Hz, CH=CH2) & 4.65
(2H, dd, Jallyl,vic=1.1, 6.5Hz, OCH2) respectively.

In the 13C-NMR (100 MHz, CDCl3) spectrum of 3.57 downfield signals at 170.9 &
169.2 were designated to two C=O groups and C=N moiety of thiadiazoline ring
exhibited a resonance at 148.1. The signals in the aromatic region were very well
resonating at 156.6 (C-4), 134.4 (C-1), 131.2 (CH=CH2), 129.5 (C-2, 6),

118.9 (CH=CH2) & 114.6 (C-3, 5). The noticeable signals in the aliphatic region
were placed at 69.8 (OCH2), 68.2 (C-2), 26.7 (3-CH3) & 24.5 (2-CH3).
OCH 2

CH CH2

3'

5'

2'

6'
1'
2

H3C C NH

C CH
3

C CH
3

m/z 187 (36.6 %)

+
.

+.

m/z 319 (66.6 %)

OCH 2

CH CH2

m/z 321 (10.4 %)

N
N

O
3

N4

H3C C NH

(M + 2)

1S

+ H

4'

H3C C NH
O

m/z 116 (16.6 %)

O
H

CH3

m/z 203 (24.2 %)

+.

OCH 2 CH CH2

O
S

C CH
3

H3C C NH

OH

-C3H4

O CH2 CH CH2

+.

+.

O
+

H C H
+

m/z 173 (60.4 %)

m/z 107 (44.2 %)

m/z 147 (26.6 %)

+.
O
N

......

C CH
3

+.
-N2, -C2H3O

......

H3C C NH

C S

H3C C NH

m/z 102 (10.1 %)

O
.

Chart-2

Synthesis of thiadiazoline 3.58


The compound 3.58 was again prepared in three step:
(i). Synthesis of benzyloxy-benzaldehyde 3.46
The compound 3.46 (76%, m.p. 120-1220C) was obtained from the reaction of
4-hydroxybenzaldehyde with benzyl chloride (Scheme-3.15) under the similar
conditions as used earlier for 3.45.

2'

OH
5

CH2

+ -

K2CO 3 / dry acetone / Bu 4N I


Ph-CH2-Cl /

5'

3
2

4'

6'

3'

1'

H C O

H C

3.46
Scheme-3.15

IR spectrum of 3.46 showed major absorptions at 2940 (methylene C-H), 2852, 2738
(aldehyde C-H) & 1662 (C=O) cm-1. Its 1H-NMR spectrum (400 MHz, CDCl3)
showed most downfield resonance at 9.80 (1H, s) which may be given by CHO
group. The aromatic ring protons were found to be placed at 7.76 (2H, d, Jo=8.1Hz,
H-2, 6), 7.39 (3H, m, H-3, 4, 5), 7.06 (2H, dd, Jm,o=2.3, 7.9Hz, H-2, 6) & 6.92
(2H, d, Jo=8.2Hz, H-3, 5). In the upfield region, a signal integrating for two protons at
5.18 could be easily assigned to OCH2 group hydrogens.
13

C-NMR (100 MHz, CDCl3) spectrum of 3.46 had the most downfield resonance at

189.8 due to the presence of CHO group. The aromatic carbon (C-4) directly linked
to oxygen atom provided a signal at 163.0. The remaining aromatic carbon atoms
were found at 135.0 (C-1), 130.0 (C-1), 129.4 (C-3, 5), 128.0 (C- 2, 6), 119.8 (C2, 6), 116.2 (C-4) & 115.0 (C-3, 5). The carbon atoms of the benzyloxy group
(OCH2) appeared at 69.0.
The mass spectrum of 3.46 had (M+Na)+ ion at m/z 235 (40.3 %) which also
confirmed its structure.

(ii) Synthesis of benzyloxy thiosemicarbazone 3.52


The compound 3.52 (70%, m.p. 171-1730C) was prepared from the reaction of
compound 3.46 with thiosemicarbazide (Scheme-3.16) under the similar conditions as
described earlier for 3.51.
2"

CH2

4
5

6"
3

2
1

H C

3"

1"

2"
4"

O
4

5"
H2N NH

C NH2 /

CH2

dry EtOH /HCl/

6"

5"

H C
1'

3.46

4"

3"

1"

N NH
2'

3.52

3'

C NH2
4'

5'

Scheme-3.16

IR spectrum of 3.52 displayed major absorptions at 3387, 3360, 3155 (N-H), 1608
(C=N) & 1175 (C=S) cm-1. In the 400 MHz 1H-NMR (DMSO-d6), the protons
belonging to phenyl ring (H-2, 6 & H-3, 5) were resonating at the expected positions
in aromatic regions (vide experimental). Other protons H-3, 4, 5 & H-2, 6
appeared at 7.45 (3H, m) & 7.08 (2H, dd, Jm,o=2.3, 7.9Hz) respectively.
The downfield resonances in the

13

C-NMR (100 MHz, DMSO-d6) spectrum of 3.52

were placed at 177.6 & 152.4 which could be furnished by C=S & C-1 respectively
and the carbon atom of the OCH2 group was present at 70.2. The carbon atoms
belonging to the phenyl rings (C-1 to C-6 & C-1 to C-6) were resonating at the
appropriate positions in the aromatic region (vide experimental). The mass spectrum
of 3.52 showed (M+1)+ & (M)+ ions at m/z 286 (30.6 %) & 285 (7.3 %) respectively
and its mass fragmentation pattern was found be similar as shown in Chart-1 (vide
experimental).
(iii) Cyclization of benzyloxy-thiosemicarbazone 3.58
The compound 3.58 (75%, m.p. 133-1350C) was obtained by reacting 3.52 with acetic
anhydride (Scheme-3.17) under the similar conditions as used earlier for 3.57.
2""
3"

2"

CH2

4
5

1"

1'

4"

6"

5"

N NH
2'

3'

1""

6"'

3'

2'

H3C C

1"'
2

1S

N3

N4

1'

NH

5""

2"'

H
5'

3""
4""

6""

3"'

5"'

Ac2O /

C NH2
4'

CH2

4"'

H C

C CH3
1"

2"

3.52

3.58

Scheme-3.17
The structure of 3.58 was characterized from the rigorous analysis of its spectroscopic
data. Its IR spectrum exhibited expected absorption bands at 3286 (N-H), 1688, 1642
(C=O) & 1602 (C=N) cm-1. 1H-NMR (400 MHz, DMSO-d6) spectrum of 3.58 was
highly amenable to its interpretation and was similar to that of 3.57. At the lowest
downfield a singlet was observed at 11.31 (1H) due to 1-NH proton. Here again the

signal present at 7.75 (NH2) in 3.58 was found missing which clearly describes that
these protons have reacted during the cyclization reaction. The aromatic protons (H2, 6 & H-3, 5) were located at 7.28 (2H, d, Jo=8.7Hz) & 6.93 (2H, d,
Jo=8.7Hz) respectively. A singlet placed at 6.76 may be assigned to H-2 and two
methyl groups present at C-3 & 2 positions appeared at 2.25 (s) & 2.18 (s)
respectively. A singlet integrating for two protons at 5.23 could be furnished by
OCH2 group. The protons belonging to phenyl ring (H-2, 3, 4, 5 & 6) of
the benzyloxy group were resonating at the usual positions in the aromatic region
(vide experimental).
13

C-NMR (100 MHz, DMSO-d6) data of 3.58 was comparable to that of 3.57. The

downfield signals at 169.8 & 168.3 were attributed to 3-C=O & 2-C=O
respectively and C=N group showed a suitable resonance at 149.8. The aromatic
carbon atoms were found resonating at 156.2 (C-4), 134.7 (C-1), 133.4 (C1), 130.1 (C-2, 6), 128.3 (C-3, 5), 125.7 (C-4), 123.6 (C-2, 6)
& 116.4 (C-3, 5). The signals in the aliphatic region were located at 71.5
(OCH2), 67.8 (C-2), 25.3 (3-CH3) & 24.8 (2-CH3). The mass fragmentation pattern
of compound 3.58 was found to be similar as shown in Chart-2 and major ions in its
mass spectrum were observed at m/z 370 (M+1+, 100 %) & 369 (M+, 43.8 %) (vide
experimental).

Synthesis of thiadiazoline 3.59


(i) Synthesis of ethylacetyloxy-benzaldehyde 3.47
The reaction of 4-hydroxybenzaldehyde with bromoethyl acetate under similar
conditions (Scheme-3.18) as described for 3.45 yielded 3.47 (68%, m.p. 112-1140C).
O
O CH2 C OCH 2CH 3

OH

4
5

3
2
1

H C O

+ -

K2CO 3 / dry acetone / Bu 4N I


C2H5COOCH2-Br /

C O

3.47
Scheme-3.18

IR spectrum of 3.47 had noticeable absorption bands at 2942 (methylene C-H), 2842,
2730 (aldehyde C-H) & 1760, 1663 cm-1 (C=O). In its 1H-NMR spectrum (400 MHz,
CDCl3), a singlet was found to be placed at 9.91 due to CHO group. The aromatic
protons (H-2, 6 & 3, 5) were seen resonating at the expected positions (vide
experimental). The signals of 4-alkoxy group were placed at 5.16 (2H, s, OCH2),
4.26 (2H, q, Jvic=6.7Hz, OCH2CH3) & 1.32 (3H, t, Jvic=6.7Hz, OCH2CH3).
13

C-NMR (100 MHz, DMSO-d6) spectrum of 3.47 confirmed the presence of CHO

group as a signal was found on the extreme left hand side of the spectrum at 189.8.
The aromatic carbon atoms (C-1 to C-6) were present at the similar positions as
observed in 3.45 & 3.46 (vide experimental). The suitable resonances were found in
aliphatic region at 69.2 (OCH2), 67.4 (OOCH2CH3) & 22.0 (OOCH2CH3) which
also corroborate the carbon framework of the 4-alkoxy group.

(ii) Synthesis of thiosemicarbazone 3.53


4-alkoxybenzaldehyde 3.47 was treated with thiosemicarbazide under the same
conditions (Scheme-3.19) as used above for 3.51 to furnish 3.53 (65%, m.p. 1431450C).
O

O CH2 C OCH 2CH 3


4

O CH2 C OCH 2CH 3


4

H2N NH

C NH2 / dry EtOH


/HCl/

5
6

3
2

C O

1'

C N NH C NH2
1'

2'

3'

3.47

4'

5'

3.53

Scheme-3.19

IR spectrum of 3.53 revealed significant absorptions at 3165 (N-H), 1622 (C=N) &
1174 (C=S) cm-1. Its 400 MHz 1H-NMR (DMSO-d6) spectrum showed characteristics
signals at 11.23 (1H, s, 3-NH), 7.99 (1H, s, HC=N) & 7.69 (2H, brs, NH2-5). The
signals for the aromatic protons (H-2, 6 & 3, 5) were found at appropriate positions in
the aromatic region (vide experimental).
The structure of 3.53 was also supported by

13

C-NMR (100 MHz, DMSO-d6) data

which was similar to that of 3.51 & 3.52. C=S, C-1 & C-1 produced suitable
resonances at 179.3, 152.7 & 139.2 respectively. The carbon atoms belonging to 4-

alkoxy group were resonating at 170.4 (C=O), 72.4 (OCH2), 67.8 (OOCH2CH3) &
22.6 (OOCH2CH3). The phenyl ring carbon atoms (C-2, 3, 4, 5 & 6) were found to be
placed at expected positions in the aromatic region (vide experimental). The mass
spectrum of 3.54 exhibited (M+2)+ & (M)+ ions at m/z 283 (100 %) & 281 (47.3 %)
and its mass fragmentation pattern has been found to be similar as shown in Chart-1
(vide experimental).
(iii) Cyclization of thiosemicarbazone 3.53
The compound 3.59 (70%, m.p. 154-1560C) was prepared by reacting 3.53 with acetic
anhydride (Scheme-3.20) under the similar conditions as used earlier for 3.57.
O

4"'

O CH2 C OCH 2CH 3


3

Ac2O/

H
S

2"'

6"'

3"'

5"'

2'

3'

4'

1S
5'

3'

2'

H3C C

1'

NH

1"'
2

C N NH C NH2
1'

CH2 C O CH2 CH3

C
3

1"

CH3
2"

3.53

3.59

Scheme-3.20

IR spectrum of 3.59 exhibited characteristics bands at 3288 (N-H), 1684, 1646 (C=O)
& 1605 (C=N) cm-1. 1H-NMR (400 MHz, DMSO-d6) spectrum of 3.59 was found to
be similar to that of 3.57. The aromatic protons (H-2, 6 & H-3, 5) and
alkoxy group hydrogens (-OCH2COOCH2CH3) were observed at the usual positions
(vide experimental). The signal resonating at 6.77, 2.29 & 2.20 were certainly
assignable to H-2, 3-CH3 & 2-CH3 respectively.
In the

13

C-NMR (100 MHz, DMSO-d6) spectrum of 3.59, downfield resonances at

169.8, 168.3 & 149.8 were attributed to 2-C=O, 1-C=O & C=N groups
respectively. The carbon atoms belonging to aromatic ring were found to be
resonating at 156.2 (C-4), 134.7 (C-1), 130.1 (C-2, 6), 116.4 (C-3, 5)
and a signal at 67.8 was contributed by C-2 carbon of thiadiazoline ring. The
(OCH2) and (OOCH2CH3) carbon atoms of the alkoxy group also resulted suitable
resonances at the expected positions in the aliphatic region (vide experimental). ESIMS spectrum of 3.59 had (M+1)+ & (M+Na)+ at m/z 366 (68.4 %) & 388 (100 %)

respectively and its fragmentation pattern was similar as shown in Chart-2 (vide
experimental).

Synthesis of alkoxy-benzaldehyde 3.48-3.50


The compounds 3.48-3.50 were obtained from the O-alkylation of 4-hydroxybenzaldehyde with 1-chloromethylnaphthalene, methyl iodide and ethyl iodide
respectively under the similar conditions as used earlier for 3.45. The physical and
characteristics spectral data of compounds 3.48-3.50 are given in Table-1 & Table-2
(vide experimental).
OCH 2 R
4
5

2
1

H C

R=

3.48

-CH3,
3.49

-CH2CH3
3.50

Table-1: Physical and characteristics spectral data of alkoxy-benzaldehydes 3.48-3.50

Compound

m.p.(0C)

IR(max cm-1)

Yield(%)

H-NMR()

m/z
(M+1)+/(M+Na)+

C-H

C=O

CHO

H-2, 6

H-3, 5

OCH2

667

9.79

7.71

7.02

5.20

(aldehyde)
3.48

152-154

70

2850, 2742

263 (25.6 %) / 285


(100 %)

3.49

125-127

65

2856, 2752

662

9.82

7.67

7.04

4.92

151 (20.8 %) / 173


(100 %)

3.50

118-120

68

2858, 2760

669

9.89

7.72

7.06

5.24

165 (32.4 %) / 187


(100 %)

Table-2: Characteristics

13

C-NMR (100 MHz) data () of alkoxy-benzaldehydes

3.48-3.50
Compound CHO

C-3, 5

C-1

C-2, 6

C-4

OCH2

3.48 189.8

114.9

134.9

128.6

164.2

69.6

3.49 190.0

114.8

134.8

128.2

164.0

69.0

3.50 189.7

115.0

134.6

128.4

164.8

69.1

Synthesis of thiosemicarbazone 3.54-3.56


The compounds 3.54-3.56 were prepared in good yields from the condensation reactions
of alkoxy-benzaldehydes 3.48-3.50 with thiosemicarbazide under the similar condition as
described earlier for 3.51. These compounds were also characterized by means of their
spectral data (Table-3 & Table-4) and their spectroscopic data was found to be similar to
that of 3.52 & 3.53 (vide experimental).
O CH2 R
4
3

C N
1'

R=

2'

NH C NH2
3'

4'

5'

, -CH3, -CH2CH3
3.54

3.55

3.56

Table-3: Physical and characteristics spectral data of alkoxy-thiosemicarbazones 3.54-3.56


Compound

m.p.

Yield

No.

(0C)

(%)

3.54

196-198

72

IR(max cm-1)

H-NMR()

ESI-MS
(m/z)

N-H

C=S

C=N

NH2

HC=N

OCH2

3-NH

3370,

1179

1602

7.63

7.93

5.45

11.23

358 (M+Na+, 54.3 %)/


335 (M+, 10.7 %)

3320,
3150
3.55

168-170

67

3340,

1176

1608

7.84

7.96

4.09

11.31

224 (M+1+, 39.1 %)/


223 (M+, 7.8 %)

3310,
3167
3.56

158-160

64

3346,
3308,
3158

1174

1605

7.70

7.96

4.02

11.28

260 (M+Na+, 100 %)

Table-4: Characterstics

13

C-NMR (100 MHz) data () of alkoxy-thiosemicarbazone

3.54-3.56
Compound C=S

C=N

C-3, 5

C-2, 6

C-1

C-4

OCH2

3.54

180.7

154.2

114.8

138.1

138.9

151.4

75.3

3.55

179.2

150.4

117.4

135.7

140.3

148.9

66.5

3.56

179.9

151.8

118.6

136.2

140.7

149.1

68.4

Synthesis of thiadiazolines 3.60-3.62


The compounds 3.60-3.62 were synthesized from the cyclization reactions of the
corresponding thiosemicarbazones 3.54-3.56 with Ac2O under the similar reaction
conditions as described earlier for 3.57. The physical and significant spectral parameters
of these compounds are summarised in Table-5 & Table-6 (vide experimental).

CH2

4"'
3"'

5"'
6"'

2"'

3'

2'

H3C C

1"'
2

1S

N3

N4

1'

NH

C CH3
1"

2"

O
R=

, -CH3, -CH2CH3
3.60

3.61

3.62

Table-5: Physical and characteristics spectral data of alkoxy-thiadiazolines 3.60-3.62

Compound

m.p

Yield

No.

(0C)

(%)

3.60

165-167

78

IR (max cm-1)

H-NMR()

ESI-MS
(m/z)

N-H

C=O

C=N

1-NH

33240

1675,

1609

11.35

H -2

6.78

OCH2

3-CH3

2-CH3

5.42

2.25

2.04

1640
3.61

126-128

74

3290

1689,

138-140

70

3256

1684,
1642

(M+1+,

100 %)
1605

11.30

6.72

4.06

2.30

2.21

1645
3.62

420

309

(M+2+,

40.8 %)
1602

11.27

6.75

4.01

2.28

2.19

344 (M+Na+,
100 %)

Table-6: Characteristics 13C-NMR (100 MHz) data () alkoxy-thiadiazolines 3.60-3.62

Compound

C=N

C-2, 6

OCH2

C-2

3-CH3

2CH3

116.7

75.3

68.5

25.8

24.6

132.8

117.2

68.1

67.5

25.4

24.3

132.3

115.6

69.7

67.5

26.2

23.8

C=O

C=O

(2)

(1)

3.60

171.3

169.7

149.1

131.6

3.61

169.8

168.3

149.7

3.62

168.1

167.3

148.2

C-3, 5

Mechanistic consideration
The formation and cyclization reactions of the thiosemicarbazones 3.51-3.56 can be
visualized as having occurred through an initial nucleophilic attack of thiosemicarbazide
upon the carbonyl group of 3.45-3.50 under the influence of protons followed by
dehydration to produce 3.51-3.56. The azomethine nitrogen captures acetyl group from
the acetic anhydride to give N-acetyl intermediates 3.51-3.56 which further undergoes
cyclization to give another intermediates 3.51-3.56. The 2-imino group of later finally
undergoes acetylation with Ac2O to provide final products 3.57-3.62 (Scheme-3.21).
CH 2 R

O
CH2

CH2 R

S
+

EtOH/HCl/

3.45-3.50

-H2O

H2N NH C NH2

H
O

HO

..

H N

NH

C NH2

3.51-3.56

CH3 H +

H3C

H2N NH C NH2

NH N

H 2N

-AcOH

O
O CH 2 R
H3C

O
NH

..

H 2N
N

3.57-3.62

+
H

H
N

S
H 2N

CH 2 R

CH 3

CH 3

CH 3
O

CH 2 R

-H+

CH3

-AcOH

H
N

H+

S
H 3C

3.51'-3.56'

3.51''-3.56''

Scheme-3.21

Antibacterial activities of compounds 3.51-3.56 & 3.57-3.62


The compounds 3.51-3.56 & 3.57-3.62 were tested for their antibacterial activities by
disc-diffusion method31 using nutrient broth medium [contained (g/L): beef extract 3 g;
peptone 5 g; pH 7.0]. The gram positive bacteria and gram-negative bacteria utilized in
this study consisted of Aeromonas hydrophila, Yersinia enterocolitica, Listeria
monocytogenes and Staphylococcus aureus. In the disc-diffusion method, sterile paper
discs (5 mm) impregnated with compound dissolved in dimethylsulfoxide (DMSO) at
concentration 100 g/mL were used. Gentamicin and Tetracycline were used as the

standard drugs, where as DMSO poured disk was used as negative control. Then, the
paper discs impregnated with the solution of the compound tested were placed on the
surface of the media inoculated with the microorganism. The plates were incubated at
37C for 24 hrs. After incubation, the growth of inhibition zones were recorded which are
shown in Table-7 (3.51-3.56) & Table-9 (3.57-3.62). The minimum inhibitory co
ncentrations of compounds 3.51-3.56 & 3.57-3.62 were also determined by using serial
tube dilution method.32 The MIC of these compounds have been presented in Table-8
(3.51-3.56) & Table-10 (3.57-3.63).

Table-7: Zone of inhibitions (mm) of thiosemicarbazones 3.51-3.56.


Compounds

A. hydrophila

Y. enterocolitica

L. monocytogenes

S. aureus

3.51

11.5

12.4

10.3

13.8

3.52

14.5

16.5

15.4

22.6

3.53

12.5

13.5

13.5

14.5

3.54

15.2

17.6

20.8

18.6

3.55

12.5

11.4

12.6

15.7

3.56

13.5

14.5

11.5

12.5

Gentamicin

21

----

----

17

Tetracycline

13

20

12

14

Table-8: Minimum inhibitory concentrations (MIC, g/ml) of thiosemicarbazones 3.513.56.


Compounds

A. hydrophila

Y. enterocolitica

L. monocytogenes

S. aureus

3.51

30

40

30

20

3.52

10

20

30

10

3.53

20

20

40

20

3.54

40

30

10

30

3.55

50

30

50

20

3.56

20

30

10

10

Gentamicine

10

10

10

10

Tetracycline

30

30

30

30

Table-9: Zone of inhibitions (mm) of thiadiazolines 3.57-3.62.


Compounds

A. hydrophila

Y. enterocolitica

L. monocytogenes

S. aureus

3.57

17.5

12.4

14.3

13.8

3.58

24.5

21.5

23.4

22.6

3.59

12.5

16.5

15.5

14.5

3.60

19.2

22.6

20.8

21.6

3.61

15.5

13.4

14.6

15.7

3.62

10.5

15.5

13.5

14.5

Gentamicine

21

----

----

17

Tetracycline

13

20

12

14

Table-10: Minimum inhibitory concentrations (MIC, g/ml) of thiadiazolines 3.57-3.62.


Compounds

A. hydrophila

Y. enterocolitica

L. monocytogenes

S. aureus

3.57

20

20

10

10

3.58

30

10

10

20

3.59

10

10

20

10

3.60

40

20

40

50

3.61

30

30

40

50

3.62

50

40

50

50

Gentamicine

10

10

10

10

Tetracycline

30

30

30

30

It is concluded from the Table-7 that compound 3.52 and 3.54 showed better zone of
inhibitions than the other derivatives & Table-8 describes that 3.52 is found to be very
active against A. hydrophila,

L. Monocytogenes & S. aureus. The compound 3.56

exhibited significant MIC (10 g/ml) against L. Monocytogenes and S. aureus


(Table-8). Similarly Table-9 & Table-10 indicates that 3.58 & 3.60 could exhibit better
activity against the studied bacterial strains.
It is clear from the above data (Table-7, 8, 9 & 10) that thiosemicarbazones and
thiadiazolines containing benzyloxy and naphthyloxy groups are better antibacterial
agents than the other derivatives.
In order to explore the synthetic utility of the thiosemicarbazones, the researches have
also been focused upon the preparation of quinoxaline based thiazoles 3.63-3.69. The
major interest in this study was that how the quinoxaline moiety upon the thiazole ring
would affect the antibacterial behavior of the final heterocyclic products.

Synthesis of allyloxy-thiazoles 3.63


The compound 3.51 was refluxed with 2,3-dichloroquinoxaline under the alcoholic
medium and resulting reaction mixture was poured into crushed ice to provide a solid
substance (Scheme-3.22). The crude product was crystallized from EtOH to yield pure
compound 3.63 (68%, m.p. 255-2570C).
O

CH2 CH=CH

O
2

H C

N NH

CH=CH

5
2,3-dichloroquinoxaline/

CH2

2
1

H C

C NH2

3.51

N 5'

6'

1'
2'

N NH

3'
4'

3.63

Scheme-3.22

IR spectrum of 3.63 was very helpful to interpret its structure which exhibited the major
bands at 3351 (NH) & 1596, 1590, 1585 (C=N) cm-1. Its structure was further supported
by ESI-MS spectrum which exhibited the (M+1)+ & (M)+ ions at m/z 362 (100 %) & 361
(25.4 %) respectively. Other major ions were observed at m/z 334 (14.2 %), 321 (10.9
%), 305 (19.1 %), 273 (38.7 %), 135 (12.7 %), 120 (39.1 %) & 107 (20.6 %). The mass
fragmentation pattern of 3.63 has been depicted in Chart-3.
A comparison of 1H-NMR spectra (400 MHz, DMSO-d6) of 3.51 & 3.63 shows that
resonances present at 7.78 (NH2) in former compound were found missing altogether in
the later thereby describing the involvement of these hydrogens in the chemical
transformation. The aromatic protons were located at 7.80 (2H, m, H-1, 4), 7.65 (2H,
m, H-2, 3), 7.60 (2H, d, Jo=7.9Hz, H-2, 6) & 6.84 (2H, d, Jo=7.9Hz, H-3, 5). A singlet
integrating for one hydrogen at 7.98 could be assigned to azomethine proton (HC=N).
The hydrogens of the allyloxy group were centred at 5.40 (1H, td, Jvic,trans= 6.5Hz,
15.9Hz, CH=CH2). 5.25 (2H, td, Jallyl,trans=1.0, 15.9Hz, CH=CH2) & 4.62 (2H, dd,
Jallyl,vic=1.0, 6.5Hz, OCH2) respectively.
In the

13

C-NMR (100 MHz, DMSO-d6) spectrum of 3.63, downfield signals at 154.2,

150.4, 148.0 could be assigned to three C=N moieties of the compound. The aromatic
carbon atoms were very well resonating at 146.8 (C-4), 145.6 (C-5), 143.3 (C-S),
141.0 (C-6), 139.4 (C-1), 132.5 (C-2, 6), 131.2 (CH=CH2), 130.2 (C-1), 129.1 (C-4),

128.3 (C-2), 126.5 (C-3), 120.2 (CH=CH2) & 114.7 (C-3, 5). The noticeable signals in
the aliphatic region were placed at 68.7 (OCH2).
-----

CH2

CH

CH2
(M + 1)

m/z 362 (100 %)

NH

m/z 361 (25.4 %)

+
O
+
.

OH

NH

-----

CH2

NH

m/z 334 (14.2 %)

m/z 321 (10.9 %)


-N2

+
OH

+
.

OH

H
H

NH

CH3

m/z 120 (39.1 %)

m/z 305 (19.1 %)

m/z 135 (12.7 %)

-S

+.
O

OH

CH3

C
+

NH
N

m/z 273 (38.7 %)

m/z 107 (20.6 %)

Chart-3
Synthesis of bezyloxy-thiazole 3.64
The compound 3.64 (64%, m.p. 240-2420C) was prepared by reacting 3.52 with
2,3-dichloroquinoxaline under the similar conditions as used earlier for 3.57
(Scheme-3.23).
2"
2"

CH2

3"

1"

O CH2

4"

6"

1'

S
N NH
2'

3'

3.52
Scheme-3.23

6"

5"

5"

2,3-dichloroquinoxaline/

H C

4"

4
5

3"

1"

2
1

C NH2
4'

6'

5'

1'
2'

H C N NH
5'

3.64

3'
4'

The structure of 3.64 was characterized from the rigorous analysis of its spectroscopic
data. Its IR spectrum exhibited expected absorption bands at 3353 (N-H) & 1598, 1593,
1587 (C=N) cm-1. 1H-NMR (400 MHz, DMSO-d6) spectrum of 3.64 was highly
amenable to its interpretation and was similar to that of 3.63. At the lowest downfield a
singlet was observed at 9.28 (1H) due to NH proton. Here again the signal present at
7.75 (NH2) in 3.64 was found missing which clearly describes that these protons have
undergone transformation during the cyclization reaction. The aromatic protons (H-2, 6
& H-3, 5) were located at 7.61 (2H, d, Jo=7.9 Hz) & 6.81 (2H, d, Jo=7.9 Hz)
respectively. A singlet placed at 7.92 could be assigned to CH=N moiety. A singlet
integrating for two protons at 4.57 was assignable to OCH2 group. The protons
belonging to phenyl ring of the benzyloxy group (H-2 to H-6) and quinoxaline moiety
(H-1 to H-4) were resonating at the expected positions in the aromatic region (vide
experimental).
13

C-NMR (100 MHz, DMSO-d6) data of 3.64 was comparable to that of 3.63. The C=N

groups showed three resonances at 156.4, 149.7 & 148.9 and in aliphatic region OCH2
group was located at 66.6. The aromatic carbon atoms were found to be resonating at
147.3 (C-4), 144.1 (C-5), 143.9 (C-S), 142.7 (C-6), 138.3 (C-1), 130.0 (C-2, 6), 129.4
(C-1), 128.7 (C-3, 5), 128.1 (C-4), 127.8 (C-2), 125.4 (C-4), 124.1 (C-3), 123.4
(C-2, 6) & 113.6 (C-3, 5). The ESI-MS spectrum of 3.64 exhibited (M+1)+ & (M)+
ions at m/z 412 (10.8 %) & 411 (25.8 %) respectively (vide experimental).

Synthesis of thiazoles 3.65-3.68


The compounds 3.65-3.68 were obtained in good yields from the cyclization reactions of
the corresponding thiosemicarbazones 3.53-3.56 with 2,3-dichloroquinoxaline under the
similar reaction conditions as described earlier for 3.63. The structures of these
compounds were also determined from the analysis of their spectral parameters (Table- 5
& Table- 6) and their spectroscopic data was similar to that of 3.63 & 3.64.

O CH 2-R
4
3

1'
6'
2'

NH

3'

5'
4'

O
R=

C OCH2CH3 ,
3.65

, -CH 3 , -CH2CH3
3.66

3.67

3.68

Table-11: Physical and characteristics spectral data of alkoxy-thiazoles 3.65-3.68


Compound

3.65

3.66

3.67

3.68

m.p.

Yield

(0C)

(%)

210-212

265-267

220-222

238-240

66

68

69

65

IR(max cm-1)

H-NMR()

ESI-MS
(m/z)

N-H

C=N

N-H

HC=N OCH2

356

1592,

9.31

7.90

358

352

355

4.60

409 (M+2+, 20.6

1589,

%)/ 407 (M+, 40.8

1584

%)

1601,

9.33

7.96

4.66

463 (M+2+, 30.6

1599,

%)/ 461 (M+, 18.0

1592

%)

1603,

9.30

7.94

4.63

351 (M+2+, 60.4

1596,

%)/ 349 (M+, 10.8

1590

%)

1607,

9.37

7.87

4.59

386 (M+Na+, 100

1595,

%)/ 363 (M+, 14.6

1588

%)

Table-12: Characteristics 13C-NMR (100 MHz) data () alkoxy-thiazoles 3.65-3.68

Compound

C=N

C=N

C=N

C-4

C-1

C-2, 6

C-3, 5

OCH2

3.65

155.5

150.1

148.3

147.

137.

131.5

114.4

67.9

132.4

113.9

68.2

131.5

113.3

67.5

130.9

112.9

69.2

1
3.66

3.67

3.68

156.8

155.9

154.6

150.9

149.8

150.0

149.6

148.4

149.2

148.

138.

147.

139.

148.

139.

Antibacterial activities of 3.63-3.68


The in vitro antibacterial analysis of 3.63-3.68 was also carried out by using
disc-diffusion method (zone of inhibition) and serial tube dilution method (MIC)
according to the similar procedures as described earlier for 3.56-3.62 (pp. no. 21-22). The
results of zone of inhibitions (mm) & MIC (g/ml) data of these compounds have been
presented in Table-13 & Table-14 respectively.

Table-13: Zone of inhibitions (mm) of alkoxy-thiazoles 3.63-3.68

Compounds

A. hydrophila Y.enterolitica

L.monocytogenes

S. aureus

3.63

17.5

12.4

14.3

13.8

3.64

24.5

21.5

23.4

22.6

3.65

12.5

16.5

15.5

14.5

3.66

19.2

22.6

20.8

21.6

3.67

15.5

13.4

14.6

15.7

3.68

10.5

15.5

13.5

14.5

Gentamicin

21

----

----

17

Tetracycline

13

20

12

14

Table-14: Minimum inhibitory concentrations (MIC, g/ml) of thiazoles 3.63-3.68

Compounds

A. hydrophila Y.enterolitica

L. monocytogenes

S. aureus

3.63

20

30

20

10

3.64

10

10

10

20

3.65

40

10

10

30

3.66

40

10

10

20

3.67

20

30

20

30

3.68

50

20

50

30

Gentamicin

10

10

10

10

Tetracycline

30

30

30

30

It is evident from Table-13 that compounds 3.64 & 3.66 exhibited better zone of
inhibitions against the bacteria strains namely A. hydrophila, Y. enterocolitica, L.
monocytogenes & S. aureus. Table-14 describe that compounds 3.64 & 3.66 could
provide better MIC (10 g/ml) against the above said microorganisms and compound
3.65 was found to be very active against Y. enterocolitica & L. monocytogenes.
It may be concluded that this study describes the general method for the preparation of
new alkoxy-thiadiazolines and quinoxaline based thiazoles. The distinct differences in the
antibacterial property of these compounds further justify the purpose of this study. The
importance of such work lies in the possibility that thorough investigations regarding the
structureactivity relationship, toxicity and biological effects of these compounds could
be helpful in designing more potent antibacterial agents for therapeutic use.

EXPERIMENTAL
Synthesis of 4-(allyloxy) benzaldehyde 3.45
A suspension of 4-hydroxybenzaldehyde (2.0 g, 0.0153 mol), allyl bromide (1.85 g,
0.0153 mol), anhydrous K2CO3 (1.0 g) and tetrabutyl ammonium iodide (1.0 g) in dry
acetone (25 ml) was refluxed for 6 hrs with continuous stirring. The progress of the
reaction was monitored by TLC. After the completion of reaction, the reaction mixture
was poured into iced HCl to provide a solid product which was crystallised from MeOH
to yield pure compound 3.45.
O CH2 CH CH2
4
3

5
6

2
1

3.45
3.45: Off white solid; Yield 72%; m.p. 102-1040C; IR (KBr) max (cm-1): 3042 (aromatic
C-H), 2930 (methylene C-H), 2850, 2742 (aldehydic C-H), 1662 (C=O); 1H-NMR (400
MHz, CDCl3): 9.80 (1H, s, 1-CHO), 7.78 (2H, d, Jo=8.1Hz, H-2, 6), 7.07 (2H, d,
Jo=8.1Hz, H-3, 5), 5.35 (1H, td, Jvic,trans=6.7, 15.8Hz, CH=CH2), 5.20 (2H, dd,
Jallyl,vic=1.0, 6.7Hz, OCH2), 5.18 (2H, td, Jallyl,trans=1.0, 15.8Hz, CH=CH2); 13C-NMR (100
MHz, CDCl3): 190.4 (CHO), 163.1 (C-4), 134.9 (C-1), 129.8 (CH=CH2), 128.0 (C-2,
6), 118.6 (CH=CH2), 114.8 (C-3, 5), 69.0 (OCH2); MS: m/z (M+Na)+ 185 (60 %); Anal.
Calc. for C10H10O2: Calc. C, 74.07; H, 6.17; Found C, 73.83; H, 6.02 %.

Synthesis of 4-(benzyloxy) benzaldehyde 3.46


The compound 3.46 was obtained from the reaction of 4-hydroxybenzaldehyde (2.0 g,
0.0153 mol) and benzyl chloride (2.0 g, 0.0153 mol) under the similar conditions as used
earlier for 3.45.
2'

O CH2
4
3
2

6
1

4'
6'

3.46

3'

1'
5'

3.46: Cream solid; Yield 76%; m.p. 120-1220C; IR (KBr) max (cm-1): 3051 (aromatic
C-H), 2940 (methylene C-H), 2852, 2738 (aldehydic C-H), 1662 (C=O); 1H-NMR (400
MHz, CDCl3): 9.80 (1H, s, 1-CHO), 7.76 (2H, d, Jo=8.1Hz, H-2, 6), 7.39 (3H, m, H-3,
4, 5), 7.06 (2H, dd, Jm,o=2.3, 7.9Hz, H-2, 6), 6.92 (2H, d, Jo=8.2Hz, H-3, 5), 5.18 (2H,
s, OCH2); 13C-NMR (100 MHz, CDCl3): 189.8 (CHO), 163.0 (C-4), 135.0 (C-1), 130.0
(C-1), 129.4 (C-3, 5), 128.0 (C-2, 6), 119.8 (C-2, 6), 116.2 (C-4), 115.0 (C-3, 5),
69.0 (OCH2); MS: m/z (M+Na)+ 235 (40.3 %); Anal. Calc. for C14H12O2: Calc. C, 79.24;
H, 5.66; Found C, 78.92; H, 5.72 %.

Synthesis of ethyl 2-(4-formyphenoxy) benzaldehyde 3.47


The compound 3.47 was prepared from the reaction of 4-hydroxybenzaldehyde (2.0 g,
0.0153 mol) with bromoethylacetate (2.55 g, 0.0153 mol) under the similar conditions as
described above for 3.45.
O
O CH2 C OCH 2CH 3
4

6
1

3.47
3.47: Off white solid; Yield 68%; m.p. 112-1140C; IR (KBr) max (cm-1): 3048 (aromatic
C-H), 2942 (methylene C-H), 2842, 2730 (aldehydic C-H), 1760, 1663 (C=O); 1H-NMR
(400 MHz, CDCl3): 9.91 (1H, s, 1-CHO), 7.68 (2H, d, Jo=8.1Hz, H-2, 6), 6.96 (2H, d,
Jo=8.2Hz, H-3, 5), 5.16 (2H, s, OCH2), 4.26 (2H, q, Jvic=6.7Hz, OCH2CH3), 1.32 (3H, t,
Jvic=6.6Hz, OCH2CH3);

13

C-NMR (100 MHz, CDCl3): 189.8 (CHO), 172.0 (C=O),

163.0 (C-4), 135.0 (C-1), 128.0 (C-2, 6), 114.9 (C-3, 5), 69.2 (OCH2), 67.4 (OCH2CH3),
22.0 (OCH2CH3); MS: m/z (M+Na)+ 231; Anal. Calc. for C11H12O4: Calc. C, 63.46; H,
5.76; Found C, 63.32; H, 5.74 %.

Synthesis of 4-(naphthalene-1-ylmethoxy) benzaldehyde 3.48


The

reaction

of

4-hydroxybenzaldehyde

(2.0

g,

0.0153

mol)

with

1-chloromethylnaphthalene (2.7 g, 0.0153 mol) under similar conditions as described


earlier for 3.45 yielded 3.48.
7'

6'
5'

8'
1'

O CH2
4

2'

4'
3'

6
1

H C

3.48
3.48: Cream solid; Yield 70%; m.p. 152-1540C; IR (KBr) max (cm-1): 3042 (aromatic
C-H), 2950 (methylene C-H), 2850, 2742 (aldehydic C-H), 1667 (C=O); 1H-NMR (400
MHz, CDCl3): 9.79 (1H, s, CHO), 8.02 (1H, dd, Jm,o=2.3, 7.6Hz, H-8), 7.71 (2H, d,
Jo=8.1Hz, H-2, 6), 7.68 (1H, d, Jo=7.9Hz, H-7), 7.26 (2H, m, H-5, 6), 7.12 (1H, dd,
Jm,o=2.4, 8.4Hz, H-3), 7.02 (2H, d, Jo=8.2 Hz, H-3, 5), 6.92 (2H, m, H-2, 4), 5.20 (2H,
s, OCH2); 13C-NMR (100 MHz, CDCl3): 189.8 (CHO), 164.2 (C-4), 134.9 (C-1), 133.8
(C-1), 132.0 (C-9), 131.3 (C-10), 130.4 (C-8), 128.7 (C-7), 128.6 (C-2, 6), 126.5
(C-6), 125.2 (C-5), 119.8 (C-3), 117.8 (C-4), 116.3 (C-2), 114.9 (C-3, 5), 69.6
(OCH2); MS: m/z (M+Na)+ 285 (100 %), (M+1)+ 263 (25.6 %); Anal. Calc. for
C18H14O2: Calc. C, 82.44; H, 5.34; Found C, 82.73; H, 5.37 %.

Synthesis of 4-ethoxybenzaldehyde 3.49


The compound 3.49 was prepared the reaction of 4-hydroxybenzaldehyde (2.0 g, 0.0153
mol) with methyl iodide (2.2 g, 0.0153 mol) under the similar conditions as described
above for 3.45.
O

CH2 CH3

4
5

3
2

6
1

3.49

3.49: Off white solid; Yield 65%; m.p. 125-1270C; IR (KBr) max (cm-1): 3050 (aromatic
C-H), 2952 (methylene C-H), 2856, 2752 (aldehydic C-H), 1662 (C=O); 1H-NMR (400
MHz, CDCl3): 9.82 (1H, s, CHO), 7.67 (2H, d, Jo=8.1Hz, H-2, 6), 7.04 (2H, d,
Jo=8.2Hz, H-3, 5), 4.92 (2H, s, OCH2), 1.86 (3H, t, Jvic=6.7Hz, OCH3);

13

C-NMR (100

MHz, CDCl3): 190.0 (CHO), 164.0 (C-4), 134.8 (C-1), 128.2 (C-2, 6), 114.8 (C-3, 5),
69.0 (OCH2), 21.2 (OCH2CH3); MS: m/z (M+Na)+ 173 (100 %), (M+1)+ 151 (20.8 %);
Anal. Calc. for C9H10O2: Calc. C, 72.00; H, 6.67; Found C, 71.71; H, 6.64 %.

Synthesis of 4-propoxybenzaldehyde 3.50


The compound 3.50 was prepared from the reaction of 4-hydroxybenzaldehyde (2.0 g,
0.0153 mol) with ethyl iodide (1.6 g, 0.0153 mol) under the similar conditions as
described above for 3.45.
.
O CH2 CH2 CH3
4
5

3
2

6
1

3.50
3.50: Cream solid; Yield 68%; m.p. 118-1200C; IR (KBr) max (cm-1): 3053 (aromatic
C-H), 2956 (methylene C-H), 2858, 2760 (aldehydic C-H), 1669 (C=O); 1H-NMR (400
MHz, CDCl3): 9.89 (1H, s, CHO), 7.72 (2H, d, Jo=8.1Hz, H-2, 6), 7.06 (2H, d,
Jo=8.2Hz, H-3, 5), 5.24 (2H, t, Jvic=6.5Hz, OCH2CH2CH3), 1.86 (2H, m, OCH2CH2CH3),
1.09 (3H, t, Jvic=6.5Hz, OCH2CH2CH3);

13

C-NMR (100 MHz, CDCl3): 189.7 (CHO),

164.8 (C-4), 134.6 (C-1), 128.4 (C-2, 6), 115.0 (C-3, 5), 69.1 (OCH2CH2CH3), 24.8
(OCH2CH2CH3), 23.4 (OCH2CH2CH3); MS: m/z (M+Na)+ 187 (100 %), (M+1)+ 165
(32.4 %); Anal. Calc. for C10H12O2: Calc. C, 73.17; H, 7.31; Found C, 73.26; H, 7.29 %.
Synthesis of 2-[4-(prop-2-en-1-yloxy) benzylidene] hydrazinecarbothioamide 3.51
A mixture of 4-allyloxy-benzaldehydes 3.45 (0.162 g, 0.001 mol) and thiosemicarbazide
(0.091 g, 0.001 mol) in dry EtOH (20 ml) and HCl (1.0 ml) was refluxed for 6 hrs at
80C. After the completion reaction, the reaction mixture was cooled in an ice bath and a

solid was separated out. The resulting product was filtered under suction and crystallized
from MeOH to yield compound 3.51.
O CH2 CH CH2
4
5

3
2

H C
1'

N NH C
2'

3'

4'

NH2
5'

3.51
3.51: Yellow solid; Yield 68%; m.p. 156-1580C; IR (KBr) max (cm-1): 3374, 3350 (NH2),
3150 (NH), 1602 (C=N), 1177 (C=S); 1H-NMR (400 MHz, DMSO-d6): 11.23 (1H, s,
NH-3), 8.00 (1H, s, HC=N), 7.78 (2H, brs, NH2-5), 7.53 (2H, d, Jo=8.7Hz, H-2, 6),
6.91 (2H, d, Jo=8.7Hz, H-3, 5), 5.42 (1H, td, Jvic,trans=6.7, 15.8Hz, CH=CH2), 5.27 (2H,
td, Jallyl,trans=1.0, 15.8Hz, CH=CH2), 4.65 (2H, dd, Jallyl,vic=1.0, 5.1Hz, OCH2); 13C-NMR
(100 MHz, DMSO-d6): 175.6 (C=S), 150.2 (C-1), 148.3 (C-4), 138.6 (C-1), 134.2
(C-2, 6), 130.5 (CH=CH2), 119.7 (CH=CH2), 116.8 (C-3, 5), 69.4 (OCH2); MS:
m/z (M+2)+ 237 (100 %), (M)+ 235 (69.1 %), 208 (20.8 %), 195 (10.4 %), 164 (24.9 %),
160 (31.3 %), 135 (15.8 %), 120 (40.8 %), 107 (49.3 %); Anal. calc. for C11H13N3OS: C,
56.17; H, 5.53; N, 17.87; S, 13.62; Found: C, 56.32; H, 5.57; N, 17.83; S, 13.59 %.
Synthesis of 2-[4-(benzyloxy)benzylidene]hydrazinecarbothioamide 3.52
The compound 3.52 was synthesized from the reaction of 4-benzyloxybenzalaldehyde
3.46 (0.212 g, 0.001 mol) with thiosemicarbazide (0.001 g, 0.091 mol) under the similar
conditions as described above for 3.51.

2"

3"

1"

CH2

4"

6"

5"

H C

N NH

1'

2'

3'

C NH2
4'

5'

3.52
3.52: Yellow solid; Yield 70%; m.p. 171-1730C; IR (KBr) max (cm-1): 3387, 3360 (NH2),
3155 (NH), 1608 (C=N), 1175 (C=S); 1H-NMR (400 MHz, DMSO-d6): 11.29 (1H, s,
NH-3), 7.98 (1H, s, HC=N), 7.75 (2H, brs s, NH2-5), 7.58 (2H, d, Jo=8.7Hz, H-2, 6),
7.45 (3H, m, H-3, 4, 5), 7.08 (2H, dd, Jm,o=2.3, 7.9Hz, H-2, 6), 6.95 (2H, d,
Jo=8.7Hz, H-3, 5), 5.26 (2H, s, OCH2); 13C-NMR (100 MHz, DMSO-d6): 177.6 (C=S),
152.4 (C-1), 149.8 (C-4), 138.9 (C-1), 136.5 (C-2, 6), 132.1 (C-1), 129.6 (C-3, 5),
124.8 (C-4), 120.3 (C-2, 6), 118.4 (C-3, 5), 70.2 (OCH2); MS: m/z (M+1)+ 286
(30.6 %), (M)+ 285 (7.3 %), 210 (38.3 %), 208 (57.8 %), 195 (16.1 %), 164 (10.2 %), 135
(100 %), 120 (44.7 %), 107 (21.4 %); Anal. calc. for C15H15N3OS: C, 63.15; H, 5.26; N,
14.73; S, 11.23; Found: C, 63.28; H, 5.32; N, 14.78; S, 11.28 %.
Synthesis of 2-[4-(ethylacetyloxy)benzylidene]hydrazinecarbothioamide 3.53
The compound 3.53 was obtained from the reaction of 4-ethylacetyloxy-benzaldehyde
3.47 (0.208 g, 0.001 mol) with thiosemicarbazide (0.091 g, 0.001 mol) under the similar
conditions as described above for 3.51.

O
O CH2 C OCH 2CH 3
4
3

5
6

C N NH C NH2
1'

2'

3.53

3'

4'

5'

3.53: Yellow solid; Yield 65%; m.p. 143-1450C; IR (KBr) max (cm-1): 3350, 3320 (NH2),
3165 (NH), 1622 (C=N), 1174 (C=S); 1H-NMR (400 MHz, DMSO-d6): 11.23 (1H, s,
NH-3), 7.99 (1H, s, HC=N), 7.69 (2H, brs s, NH2-5), 7.54 (2H, d, Jo=8.8Hz, H-2, 6),
6.97 (2H, d, Jo=8.8Hz, H-3, 5), 5.20 (2H, s, OCH2), 4.29 (2H, q, Jvic=6.8Hz,
OOCH2CH3), 1.36 (3H, t, Jvic=6.8Hz, OOCH2CH3);

13

C-NMR (100 MHz, DMSO-d6):

179.3 (C=S), 170.4 (C=O), 152.7 (C-1), 150.5 (C-4), 139.2 (C-1), 136.9 (C-2, 6),
118.7 (C-3, 5), 72.4 (OCH2), 67.8 (OOCH2CH3), 22.6 (OOCH2CH3); MS: m/z (M+2)+
283 (100 %), (M)+ 281 (47.3 %), 214 (60.5 %), 206 (53.7 %), 195 (7.0 %), 170 (33.4 %),
135 (12.8 %), 120 (64.5 %), 107 (21.9 %); Anal. calc. for C12H15N3O3S: C, 51.24; H,
5.33; N, 14.94; S, 11.38; Found: C, 51.12; H, 5.38; N, 14.90; S, 11.42 %.
Synthesis of 2-[4-(naphthalen-2-ylmethoxy) benzylidene] hydrazinecarbothioamide
3.54
The compound 3.54 was prepared from the reaction of 4-naphthylmethoxy-benzaldehyde
3.48 (0.262 g, 0.001 mol) with thiosemicarbazide (0.091 g, 0.001 mol) under the similar
conditions as described above for 3.51.
7"

6"

8"

O CH2
4

5''

1"

4"
3"

2"

3
2

H C N
1'

2'

NH
3'

C NH2
4'

5'

3.54
3.54: Light orange solid; Yield 72%; m.p. 196-1980C; IR (KBr) max (cm-1): 3370, 3320
(NH2), 3150 (NH), 1602 (C=N), 1179 (C=S); 1H-NMR (400 MHz, DMSO-d6): 11.23
(1H, s, NH-3), 8.06 (1H, dd, Jm,o=2.3, 7.6Hz, H-8), 7.93 (1H, s, HC=N), 7.76 (1H, d,
Jo=7.9Hz, H-7), 7.63 (2H, brs, NH2-5), 7.49 (2H, d, Jo=8.9Hz, H-2, 6), 7.30 (2H, m,
H-5, 6), 7.16 (1H, dd, Jm,o=2.4, 8.4Hz, H-3), 7.01 (2H, m, H-2, 4), 6.94 (2H, d,
Jo=8.9Hz, H-3, 5), 5.45 (2H, s, OCH2), 13C-NMR (100 MHz, DMSO-d6): 180.7 (C=S),

154.2 (C-1), 151.4 (C-4), 138.9 (C-1), 138.1 (C-2, 6), 134.6 (C-1), 132.2 (C-9), 131.9
(C-10), 130.5 (C-8), 128.9 (C-7), 126.8 (C-6), 125.3 (C-5), 120.8 (C-3), 118.1
(C-4), 116.4 (C-2), 114.8 (C-3, 5), 75.3 (OCH2); MS: m/z (M+Na)+ 358 (54.3 %),
(M)+ 335 (10.7 %), 266 (70.7 %), 214 (16.6 %), 195 (39.0 %), 170 (59..8 %), 135
(19.5 %), 120 (8.1 %), 107 (24.7 %); Anal. calc. for C19H17N3OS: C, 68.05; H, 5.07; N,
12.53; S, 9.55; Found: C, 68.18; H, 5.12; N, 12.50; S, 9.59 %.
Synthesis of 2-(4-methoxybenzylidene)hydrazinecarbothioamide 3.55
The compound 3.55 was prepared from the reaction of 4-methoxy-benzalaldehyde 3.49
(0.150 g, 0.001 mol) with thiosemicarbazide (0.091 g, 0.001 mol) under the similar
conditions as described above for 3.51.
O CH2 CH3
4
3

N NH

1'

2'

3'

C NH2
4'

5'

3.55
3.55: Orange solid; Yield 67%; m.p. 168-1700C; IR (KBr) max (cm-1): 3340, 3310 (NH2),
3167 (NH), 1608 (C=N), 1176 (C=S); 1H-NMR (400 MHz, DMSO-d6): 11.32 (11H, s,
NH-3), 7.96 (1H, s, HC=N), 7.84 (2H, brs s, NH2-5), 7.50 (2H, d, Jo=8.8Hz, H-2, 6),
6.95 (2H, d, Jo=8.7Hz, H-3, 5), 4.09 (2H, q, Jvic=6.7Hz, OCH2), 1.92 (2H, t, Jvic=6.7Hz,
OCH2CH3); 13C-NMR (100 MHz, DMSO-d6): 179.2 (C=S), 150.4 (C-1), 148.9 (C-4),
140.3 (C-1), 135.7 (C-2, 6), 117.4 (C-3, 5), 66.5 (OCH2), 22.3 (OCH2CH3); MS: m/z
(M+1)+ 224 (39.1 %), (M)+ 223 (7.8 %), 208 (27.3 %), 195 (10.4 %), 164 (23.4 %), 148
(100 %), 135 (39.6 %), 120 (13.8 %), 107 (42.3 %); Anal. calc. for C 10H13N3OS: C,
53.81; H, 5.82; N, 18.83; S, 14.34; Found: C, 53.67; H, 5.78; N, 18.80; S, 14.39 %.

Synthesis of 2-(4-ethoxybenzylidene)hydrazinecarbothioamide 3.56


The compound 3.56 was synthesized from the reaction of 4-ethoxy-benzaldehyde 3.50
(0.164 g, 0.001 mol) with thiosemicarbazide (0.091 g, 0.001 mol) under the similar
conditions as described above for 3.51.
O CH2 CH2 CH3
4
3

C N

NH C NH2

1'

2'

3'

4'

5'

3.56
3.56: Yield 64%; light yellow solid; m.p. 158-1600C; IR (KBr) max (cm-1): 3346, 3308
(NH2), 3158 (NH), 1605 (C=N), 1174 (C=S); 1H-NMR (400 MHz, DMSO-d6): 11.28
(1H, s, NH-3), 7.96 (1H, s, HC=N), 7.70 (2H, brs, NH2-5), 7.52 (2H, d, Jo=8.8Hz, H-2,
6), 6.93 (2H, d, Jo=8.7Hz, H-3, 5), 4.02 (2H, t, Jvic=6.7Hz, OCH2CH2CH3), 1.92 (2H, m,
OCH2CH2CH3), 1.12 (3H, t, Jvic=6.5Hz, OCH2CH2CH3);

13

C-NMR (100 MHz,

DMSO-d6): 179.9 (C=S), 151.8 (C-1), 149.1 (C-4), 140.7 (C-1), 136.2 (C-2, 6), 118.6
(C-3, 5), 68.4 (OCH2CH2CH3), 24.9 (OCH2CH2CH3), 23.6 (OCH2CH2CH3); MS:
m/z (M+Na)+ 260 (100 %), 208 (10.7 %), 195 (19.1 %), 164 (26.7 %), 162 (26.7 %), 135
(40.2 %), 120 (28.8 %), 107 (16.3 %); Anal. calc. for C11H15N3OS: C, 55.69; H, 6.32; N,
17.72; S, 13.50; Found: C, 55.82; H, 6.28; N, 17.69; S, 13.56 %.

4.2.1 Synthesis of N-[4-acetyl-5-[4-(prop-2-en-1-yloxy) phenyl]-4,5-dihydro-1,3,4thiadiazol-2-yl] acetamide 3.57.


A mixture of thiosemicarbazone 3.51 (1.0 g, 0.0042 mol) with acetic anhydride (30 ml)
and H2SO4 (1.0 ml) was refluxed for 10 hrs. The progress of reaction was monitored by
TLC. The resulting reaction mixture was poured into crushed ice to obtain a solid product

which was filtered under suction and finally crystallized from EtOH to yield pure
compound 3.57.

OCH 2 CH CH2
4"'
5"'

3"'
2"'

6"'

H
1S
3'

2'

H3C C

1'

NH

1"'
2

C CH3
3

1"

2"

N4

3.57
3.57: Brown solid; Yield 72%; m.p. 103-1050C; IR (KBr) max (cm-1): 3352 (NH), 1692,
1646 (C=O), 1605 (C=N); 1H-NMR (400 MHz, DMSO-d6): 11.35 (1H, s, NH-1), 7.30
(2H, d, Jo=8.7Hz, H-2, 6), 6.89 (2H, d, Jo=8.7Hz, H-3, 5), 6.70 (1H, s, H-2),
5.47 (1H, td, Jvic,trans=6.5, 15.8Hz, CH=CH2), 5.23 (2H, td, Jallyl,trans=1.0, 15.8Hz,
CH=CH2), 4.65 (2H, dd, Jallyl,vic=1.1, 6.5Hz, OCH2), 2.28 (3H, s, CH3-3), 2.17 (3H, s,
CH3-2); 13C-NMR (100 MHz, DMSO-d6): 170.9 (C=O), 169.2 (C=O), 156.6 (C-4),
148.1 (C-5), 134.4 (C-1), 131.2 (CH=CH2), 129.5 (C-2, 6), 118.9 (CH=CH2),
114.6 (C-3, 5), 69.8 (OCH2), 68.2 (C-2), 26.7 (CH3-3), 24.5 (CH3-2); MS: m/z
(M+2)+ 321 (10.4 %), (M)+ 319 (66.6 %), 203 (24.2 %), 187 (36.6 %), 173 (60.4 %), 147
(26.6 %), 116 (16.6 %), 107 (44.2 %), 102 (10.1 %); Anal. calc. for C15H17N3O3S: C,
56.42; H, 5.32; N, 13.16; S, 10.03; Found: C, 56.30; H, 5.28; N, 13.19; S, 10.07 %.
4.2.2. Synthesis of N-[4-acetyl-5-[4-(benzyloxy) phenyl]-4,5-dihydro-1,3,4-thiadiazol2-yl]acetamide 3.58
The compound 3.58 was synthesised by refluxing thiosemicarbazone 3.52 (1.0 g, 0.0036
mol) with acetic anhydride (30 ml) under the similar conditions as described above for
3.57.

2""

O CH2

1""

4"'

6"'

3'

2'

1"'
2

1S

N3

N4

1'

NH

5""

2"'

H3C C

4""
6""

3"'

5"'

3""

O
C CH3
1"

2"

3.58
3.58: Brown solid; Yield 75%; m.p. 133-1350C; IR (KBr) max (cm-1): 3286 (NH), 1688,
1642 (C=O), 1602 (C=N); 1H-NMR (400 MHz, DMSO-d6): 11.31 (1H, s, NH-1), 7.42
(3H, m, H-3, 4, 5), 7.28 (2H, d, Jo=8.7Hz, H-2, 6), 7.08 (2H, dd, Jm,o=2.1,
7.6Hz, H-2, 6), 6.93 (2H, d, Jo=8.7Hz, H-3, 5), 6.76 (1H, s, H-2), 5.23 (2H, s,
OCH2), 2.25 (3H, s, CH3-3), 2.18 (3H, s, CH3-2);

13

C-NMR (100 MHz, DMSO-d6):

169.8 (C=O), 168.3 (C=O), 156.2 (C-4), 149.8 (C-5), 134.7 (C-1), 133.4 (C-1),
130.1 (C-2, 6), 128.3 (C-3, 5), 125.7 (C-4), 123.6 (C-2, 6), 116.4
(C-3, 5), 71.5 (OCH2), 67.8 (C-2), 25.3 (CH3-3), 24.8 (CH3-2); MS: m/z (M+1)+
370 (100 %), (M)+ 369 (43.8 %), 253 (21.6 %), 197 (31.6 %), 187 (39.8 %), 173 (69.4
%), 116 (19.8 %), 107 (40.8 %), 102 (6.4 %); Anal. calc. for C19H19N3O3S: C, 61.78; H,
5.14; N, 11.38; S, 8.67; Found: C, 61.92; H, 5.11; N, 11.34; S, 8.64 %.

4.2.3. Synthesis of N-[4-acetyl-5-[4-(ethyloxy) phenyl]-4,5-dihydro-1,3,4-thiadiazol-2yl]acetamide 3.59


The compound 3.59 was prepared by refluxing thiosemicarbazone 3.53 (1.0 g, 0.0035
mol) with acetic anhydride (30 ml) under the similar conditions as described above for
3.57.

CH2 C O CH2 CH3

O
4"'

3"'

5"'

2"'

6"'

H
1S
3'

2'

H3C C

1'

NH

1"'
2

C
3

1"

CH3
2"

3.59
3.59: Brown solid; Yield 70%; m.p. 154-1560C; IR (KBr) max (cm-1): 3288 (NH), 1684,
1646 (C=O), 1605 (C=N); 1H-NMR (400 MHz, DMSO-d6): 11.34 (1H, s, NH-1), 7.22
(2H, d, Jo=8.7Hz, H-2, 6), 6.99 (2H, d, Jo=8.7Hz, H-3, 5), 6.77 (1H, s, H-2),
5.21 (2H, s, OCH2), 4.26 (2H, q, Jvic=6.7Hz, OOCH2CH3), 1.39 (3H, t, Jvic=6.7Hz,
OOCH2CH3), 2.29 (3H, s, CH3-3), 2.20 (3H, s, CH3-2);

13

C-NMR (100 MHz,

DMSO-d6): 171.2 (C=O), 169.8 (2-C=O), 168.3 (1-C=O), 156.2 (C-4), 149.8
(C-5), 134.7 (C-1), 130.1 (C-2, 6), 116.4 (C-3, 5), 71.5 (OCH2), 67.8 (C-2),
65.3 (OOCH2CH3), 26.9 (CH3-3), 25.2 (CH3-2), 21.9 (OOCH2CH3); MS: m/z (M+Na)+
388 (100 %), (M+1)+ 366 (68.4 %), 245 (28.3 %), 193 (24.7 %), 187 (32.8 %), 173 (72.6
%), 116 (18.2 %), 107 (46.3 %), 102 (12.6 %); Anal. calc. for C16H19N3O5S: C, 52.60; H,
5.20; S, 8.77; N, 11.51; Found: C, 52.73; H, 5.24; S, 8.73; N, 11.47 %.

4.2.4. Synthesis of N-[4-acetyl-5-[4-(napthloxy) phenyl]-4,5-dihydro-1,3,4-thiadiazol2-yl]acetamide 3.60


The compound 3.60 was obtained by refluxing thiosemicarbazone 3.54 (1.0 g, 0.0035
mol) with acetic anhydride (30 ml) under the similar conditions as described above for
3.57.

7""

6""
5""

8""

CH2

1""
4""

4"'

H
1S
3'

2'

1'

NH

3""

2"'

6"'

H3C C

2""

3"'

5"'

1"'
2

C
3

1"

CH3
2"

3.60
3.60: Brown solid; Yield 78%; m.p. 165-1670C; IR (max cm-1): 3240 (NH), 1675, 1640
(C=O), 1609 (C=N); 1H-NMR (400 MHz, DMSO-d6): 11.35 (1H, s, NH-1), 8.01 (1H,
dd, Jm,o=2.4, 7.9Hz, H-8), 7.70 (1H, d, Jo=7.9Hz, H-7), 7.34 (2H, m, H-5,
6), 7.22 (2H, d, Jo=8.8Hz, H-2, 6), 7.12 (1H, dd, Jm,o=2.4, 8.7Hz, H-3), 7.05
(2H, m, H-2, 4), 6.95 (2H, d, Jo=8.8Hz, H-3, 5), 6.78 (1H, s, H-2), 5.42 (2H,
s, OCH2), 2.25 (3H, s, CH3-3), 2.04 (3H, s, CH3-2); 13C-NMR (100 MHz, DMSO-d6):
171.3 (C=O), 169.7 (C=O), 154.7 (C-4), 149.1 (C-5), 134.9 (C-1), 133.4 (C-1),
132.9 (C-9), 131.6 (C-2, 6), 130.2 (C-10), 129.4 (C-8), 128.5 (C-7),
127.3 (C-6), 125.6 (C-5), 122.1 (C-3), 120.6 (C-4), 118.4 (C-2), 116.7
(C-3, 5), 75.3 (OCH2), 68.5 (C-2), 25.8 (CH3-3), 24.6 (CH3-2); MS: m/z (M+1)+
420 (100 %), (M)+ 419 (40.3 %), 303 (19.7 %), 247 (18.9 %), 187 (30.6 %), 173 (70.3
%), 116 (22.8 %) 107 (50.2 %), 102 (17.3 %); Anal .calc. for C23H21N3O3S: C, 51.55; H,
5.01; N, 10.02; S, 7.64; Found: C, 51.67; H, 5.06; N, 9.96; S, 7.62 %.

4.2.5. Synthesis of N-[4-acetyl-5-(4-methoxyphenyl)-4,5-dihydro-1,3,4-thiadiazol-2yl]acetamide 3.61


The compound 3.61 was synthesised by refluxing thiosemicarbazone 3.55 (1.0 g, 0.0044
mol) with acetic anhydride (30 ml) under the similar conditions as described above for
3.57.

O CH2 CH3
4"'
3"'

5"'

2"'

6"'

1S
3'

2'

1'

H3C C

C
1"

CH3
2"

N4

NH

1"'
2

3.61
3.61: Off white solid; Yield 74%; m.p. 126-1280C; IR (max cm-1): 3290 (NH), 1689,
1645 (C=O), 1605 (C=N); 1H-NMR (400 MHz, CDCl3): 11.30 (1H, s, NH-1), 7.32
(2H, d, Jo=8.9Hz, H-2, 6), 6.92 (2H, d, Jo=8.9Hz, H-3, 5), 6.72 (1H, s, H-2),
4.06 (2H, q, Jvic=6.7Hz, OCH2CH3), 2.30 (3H, s, CH3-3), 2.21 (3H, s, CH3-2), 1.94
(3H, t, Jvic=6.7Hz, OCH2CH3);

13

C-NMR (100 MHz, DMSO-d6): 169.8 (C=O), 168.3

(C=O), 155.9 (C-4), 149.7 (C-5), 136.2 (C-1), 132.8 (C-2, 6), 115.6 (C-3,
5), 68.1 (OCH2CH3), 67.5 (C-2), 25.4 (CH3-3), 24.3 (CH3-2), 20.6 (OCH2CH3); MS:
m/z (M+2)+ 309 (40.8 %), (M)+ 307 (100 %), 187 (27.4 %), 173 (62.2 %), 135 (20.2 %),
116 (20.3 %), 107 (35.2 %), 102 (16.5 %); Anal. calc. for C14H17N3O3S: C, 54.72; H,
5.54; N, 13.68; S, 10.42; Found: C, 54.85; H, 5.50; N, 13.65; S,10.45 %.

4.2.6. Synthesis of N-[4-acetyl-5-(4-ethoxyphenyl)-4,5-dihydro-1,3,4-thiadiazol-2yl]acetamide 3.62


The compound 3.62 was prepared by refluxing thiosemicarbazone 3.56 (1.0 g, 0.0042
mol) with acetic anhydride (30 ml) under the similar conditions as described above for
3.57.
O CH2 CH2 CH3
4"'
3"'

5"'

2"'

6"'
1"'

H
1
3'

2'

H3C C

1'

NH

S
5

N3
N4

3.62

O
C
1"

CH3
2"

3.62: Off white solid; Yield 70%; m.p. 138-1400C; IR (KBr) max (cm-1): 3256 (NH),
1684, 1642 (C=O), 1602 (C=N); 1H-NMR (400 MHz, CDCl3): 11.27 (1H, s, NH-1),
7.31 (2H, d, Jo=8.7Hz, H-2, 6), 6.95 (2H, d, Jo=8.7Hz, H-3, 5), 6.75 (1H, s, H2), 4.01 (2H, q, Jvic=6.7Hz, OCH2CH2CH3), 2.28 (3H, s, CH3-3), 2.19 (3H, s, CH3-2),
1.84 (2H, t, m, OCH2CH2CH3), 1.07 (3H, t, Jvic=6.5Hz, OCH2CH2CH3); 13C-NMR (100
MHz, DMSO-d6): 168.1 (C=O), 167.3 (C=O), 155.9 (C-4), 148.2 (C-5), 136.2 (C1), 132.3 (C-2, 6), 115.6 (C-3, 5), 69.7 (OCH2CH2CH3), 67.5 (C-2), 26.2
(CH3-3), 23.8 (CH3-2), 22.4 (OCH2CH2CH3), 21.8 (OCH2CH2CH3); MS: m/z (M+Na+)
344 (100 %), (M+) 321 (59.3 %), 201 (26.8 %), 187 (34.6 %), 173 (64.3 %), 149 (25.2
%), 116 (21.5 %), 107 (28.4 %), 102 (8.9 %); Anal. calc. for C15H19N3O3S : C, 56.07; H,
5.92; N, 13.08; S, 9.97; Found: C, 55.96; H, 5.90; N, 13.12; S, 9.94 %.

2.2.1 Synthesis of N-[4-acetyl-5-[4-(prop-2-en-1-yloxy) phenyl]-4,5-dihydro-1,3,4thiadiazol-2-yl]acetamide 3.63.


A mixture of thiosemicarbazone 3.51 (1.0 g, 0.0024 mol) and 2,3-dichloroquinoxaline
(1.0 g, 0.0024 mol) was refluxed in dry EtOH (25.0 ml) for 15 hrs. The progress of
reaction was monitored by TLC. The resulting reaction mixture was poured into crushed
ice to obtain a solid product which was crystallized from EtOH to yield compound 3.63.
OCH 2 CH CH2
4
3

6
N

H C N

6'

1'

NH
S

2'
3'

5' 4'

3.63
3.63: Light Orange solid; Yield: 68%; m.p. 255-2570C, IR (KBr) max (cm-1): 3351 (NH),
1596 (C=N), 1590 (C=N), 1585 (C=N); 1H-NMR (400 MHz, CDCl3): 9.36 (1H, s, NH),
7.98 (1H, s, HC=N), 7.80 (2H, m, H-1, 4), 7.65 (2H, m, H-2, 3), 7.60 (2H, d, Jo=
7.9Hz, H-2, 6), 6.84 (2H, d, Jo= 7.9Hz, H-3, 5), 5.40 (1H, td, J vic,trans= 6.5Hz, 15.9Hz,

CH=CH2). 5.25 (2H, td, Jallyl,trans=1.0, 15.9 Hz, CH=CH2), 4.62 (2H, dd, Jallyl,vic=1.0,
6.5Hz, OCH2);

13

C-NMR (100 MHz, DMSO-d6): 154.2 (C=N), 150.4 (C=N), 148.0

(C=N), 146.8 (C-4), 145.6 (C-5), 143.3 (C-S), 141.0 (C-6), 139.4 (C-1), 132.5 (C-2, 6),
131.2 (CH=CH2), 130.2 (C-1), 129.1 (C-4), 128.3 (C-2), 126.5 (C-3), 120.2
(CH=CH2), 114.70 (C-3, 5), 68.7 (OCH2); MS: m/z (M+1)+ 362 (100 %), (M)+ 361 (25.4
%), 334 (14.2 %), 321 (10.9 %), 305 (19.1 %), 273 (38.7 %), 135 (12.7 %), 120 (39.1 %),
107 (20.6 %); Anal. calc. for C19H15N5OS: C, 63.15; H, 4.15; N, 19.18; Found: C, 63.26;
H, 4.12; N, 19.15.

2.2.2 Synthesis of 2-[-4(benzyloxy)benzylidene]-1,3thiazolo-[4,5-b]quinoxaline-2-ylhydrazone 3.64


The compound 3.64 was prepared from the reaction of 3.52 (1.0 g, 0.0024 mol) with 2,3dichloroquinoxaline (1.0 g, 0.0024 mol) under the similar as used earlier for 3.63.
2"

CH2

4
5

3"

1"

4"
6"

5"

2
N

6'

1'
2'

H C N NH
S

N 5'

3'
4'

3.64
3.64: Light Orange solid; Yield: 64%; m.p. 240-2420C; IR (KBr) max (cm-1): 3353 (NH),
1598 (C=N), 1593 (C=N), 1587 (C=N); 1H-NMR (400 MHz, CDCl3): 9.28 (1H, s, NH),
7.92 (1H, s, HC=N), 7.78 (2H, m, H-1, 4), 7.63 (2H, m, H-2, 3), 7.61 (2H, d, Jo=
7.9Hz, H-2, 6), 7.48 (3H, m, H-3, 4, 5), 7.13 (2H, dd, Jm,o=2.1, 7.5Hz, H-2, 6),
6.81 (2H, d, Jo=7.9Hz, H-3, 5), 4.57 (2H, dd, Jallyl,vic=1.0, 6.5Hz, OCH2); 13C-NMR (100
MHz, DMSO-d6): 156.4 (C=N), 149.7 (C=N), 148.9 (C=N), 147.3 (C-4), 144.1 (C-5),
143.9 (C-S), 142.7 (C-6), 138.3 (C-1), 130.0 (C-2, 6), 129.4 (C-1), 128.7 (C-3, 5),
128.1 (C-4), 127.8 (C-2), 125.4 (C-4), 124.1 (C-3), 123.4 (C-2, 6), 113.6 (C-3, 5),
66.6 (OCH2); MS: m/z (M+1)+ 412 (10.8 %), (M)+ 411 (25.8 %), 334 (29.3 %), 321 (39.2
%), 305 (100 %), 291 (11.0 %), 273 (10.2 %), 135 (20.8 %), 120 (18.2 %), 107 (35.4 %);
Anal. calc. for C23H17N5OS: C, 67.15; H, 4.13; N, 17.03; Found: C, 67.03; H, 4.11; N,
17.00 %.

2.2.3 Synthesis of 2-[-4(ethyloxy)benzylidene]-1,3thiazolo-[4,5-b]quinoxaline-2-ylhydrazone 3.65


The compound 3.65 was obtained by the reacting 3.52 (1.0 g, 0.0024 mol) with 2,3dichloroquinoxaline (1.0 g, 0.0024 mol) under the similar as used earlier for 3.63.
O
O

CH2 C OCH 2 CH3

4
5

3
2

6
1

6'

1'
2'

C N NH
S

5'

3'
4'

3.65
3.65: Yellow solid; Yield 66%; m.p. 210-2120C; IR (KBr) max (cm-1): 3356 (NH), 1592
(C=N), 1589 (C=N), 1584 (C=N); 1H-NMR (400 MHz, CDCl3): 9.31 (1H, s, NH), 7.90
(1H, s, HC=N), 7.82 (2H, m, H-1, 4), 7.58 (2H, m, H-2, 3), 7.53 (2H, d, Jo= 7.9Hz, H2, 6), 6.78 (2H, d, Jo= 7.9Hz, H-3, 5), 4.60 (2H, dd, Jallyl, vic=1.0, 6.5Hz, OCH2), 4.20
(2H, q, Jvic=6.8Hz, OOCH2CH3), 1.35 (3H, t, Jvic=6.8Hz, OOCH2CH3); 13C-NMR (100
MHz, DMSO-d6): 155.5 (C=N), 150.1 (C=N), 148.3 (C=N), 147.1 (C-4), 145.3 (C-5),
144.2 (C-S), 141.8 (C-6), 137.4 (C-1), 131.5 (C-2, 6), 130.7 (C-1), 128.5 (C-4), 127.0
(C-2), 125.6 (C-3), 114.4 (C-3, 5), 67.9 (OCH2), 64.9 (OOCH2CH3), 21.2
(OOCH2CH3); MS: m/z (M+2)+ 409 (20.6 %), (M)+ 407 (40.8 %), 334 (38.9 %), 321
(100 %), 305 (32.4 %), 273 (7.7 %), 135 (22.4 %), 120 (30.6 %), 107 (18.8 %); Anal.
calc. for C20H17N5O3S: C, 58.96; H, 4.17; N, 17.19; Found: C, 58.82; H, 4.14; N, 17.10
%.

2.2.4 Synthesis of 2-[-4(napthayloxy)benzylidene]-1,3thiazolo-[4,5-b]quinoxaline-2yl- hydrazone 3.66


The compound 3.66 was prepared from the reaction of thiosemicarbazone 3.54 (1.0 g,
0.0024 mol) with 2,3-dichloroquinoxaline (1.0 g, 0.0024 mol) under similar conditions as
used for 3.63.

6"

7"

5"

8"

CH2

1"

3"

2"

4"

6
1

H C N

N 6'

N 5'

1'
2'

NH
3'
4'

3.66
3.66: Light orange solid; Yield: 68%; m.p. 265-2670C; IR (KBr) max (cm-1): 3358 (NH),
1601 (C=N), 1599 (C=N) , 1592 (C=N); 1H-NMR (400 MHz, CDCl3): 9.33 (1H, s,
NH), 8.03 (1H, dd, Jm,o=2.4, 7.9Hz, H-8), 7.96 (1H, s, HC=N), 7.76 (2H, m, H-1, 4),
7.73 (1H, d, Jo=7.9Hz, H-7), 7.62 (2H, m, H-2, 3), 7.55 (2H, d, Jo= 7.9Hz, H-2, 6),
7.40 (2H, m, H-5, 6), 7.09 (1H, dd, Jm,o=2.4, 8.7Hz, H-3), 7.00 (2H, m, H-2,4),
6.80 (2H, d, Jo= 7.9Hz, H-3, 5), 4.66 (2H, dd, Jallyl, vic=1.0, 6.5Hz, OCH2); 13C-NMR (100
MHz, DMSO-d6): 156.8 (C=N), 150.9 (C=N), 149.6 (C=N), 148.2 (C-4), 145.9 (C-5),
143.4 (C-S), 142.1 (C-6), 138.4 (C-1), 133.9 (C-1), 132.7 (C-9), 132.4 (C-2, 6), 130.1
(C-10), 130.0 (C-1), 129.8 (C-4), 129.3 (C-8), 128.9 (C-7), 128.4 (C-2), 127.9 (C6), 126.2 (C-3), 125.2 (C-5), 122.7 (C-3), 120.1 (C-4), 113.9 (C-3, 5), 117.1 (C2), 68.2 (OCH2); MS: m/z (M+2)+ 463 (30.6 %), (M)+ 461 (18.0 %), 334 (36.3 %), 305
(8.9 %), 291 (100 %), 273 (14.2 %), 321 (40.2 %), 135 (24.6 %), 120 (50.1 %), 107 (12.7
%); Anal. calc. for C27H19N5OS: C, 70.28; H, 4.12; N, 15.18; Found: C, 70.40; H, 4.12;
N, 15.14.
2.2.5 Synthesis of 2-[-4(methyloxy)benzylidene]-1,3thiazolo-[4,5-b]quinoxaline-2-ylhydrazone 3.67
The compound 3.67 was obtained from the reaction of thiosemicarbazone 3.55 (1.0 g,
0.0024 mol) with
as used for 3.63.

2,3-dichloroquinoxaline (1.0 g, 0.0024 mol) under similar condition

O CH2 CH3

4
5

3
2

H C

N 6' 1'

2'

NH

3'

N 5'

4'

3.67
3.67: Light Orange solid; Yield: 69%; m.p. 220-2220C; IR (KBr) max (cm-1): 3352 (NH),
1603 (C=N), 1596 (C=N), 1590 (C=N); 1H-NMR (400 MHz, CDCl3): 9.30 (1H, s, NH),
7.94 (1H, s, HC=N), 7.84 (2H, m, H-1, 4), 7.66 (2H, m, H-2, 3), 7.59 (2H, d, Jo=
7.9Hz, H-2, 6), 6.83 (2H, d, Jo= 7.9Hz, H-3, 5), 4.63 (2H, dd, Jallyl,vic=1.0, 6.5Hz,
OCH2CH3), 1.90 (3H, t, Jvic=6.5Hz, OCH2CH3);

13

C-NMR (100 MHz, DMSO-d6):

155.9 (C=N), 149.8 (C=N), 148.4 (C=N), 147.6 (C-4), 144.6 (C-5), 144.0 (C-S), 141.4
(C-6), 139.2 (C-1), 131.5 (C-2, 6), 129.6 (C-1), 128.4 (C-4), 127.2 (C-2), 125.5 (C3), 113.3 (C-3, 5), 67.5 (OCH2CH3), 20.2 (OCH2CH3); MS: m/z (M+2)+ 351 (60.4 %),
(M)+ 349 (10.8 %), 334 (100 %), 321 (28.9 %), 305 (15.9 %), 291 (16.8 %), 273 (6.4 %),
135 (14.6 %), 120 (10.2 %), 107 (42.1 %); Anal. calc. for C18H15N5OS: C, 61.89; H,
4.29; N, 20.05; Found: C, 61.98; H, 4.25; N, 20.01.

2.2.6 Synthesis of 2-[-4(ethyloxy)benzylidene]-1,3thiazolo-[4,5-b]quinoxaline-2-ylhydrazone 3.68


The compound 3.68 was obtained from the reaction of 3.56 (1.0 g, 0.0024 mol) with
2,3-dichloroquinoxaline (1.0 g, 0.0024 mol) under similar conditions as used earlier for
3.63.
O CH2 CH2 CH3
4
3

6
1

6' 1'
2'

H C N NH
S

3.68

N 5'

3'
4'

3.68: Light orange solid; Yield: 65%; m.p. 238-2400C; IR (max cm-1): 3355 (NH), 1607
(C=N), 1595 (C=N), 1588 (C=N); 1H-NMR (400 MHz, CDCl3): 9.37 (1H, s, NH), 7.87
(1H, s, HC=N), 7.79 (2H, m, H-1, 4), 7.64 (2H, m, H-2, 3), 7.57 (2H, d, Jo=7.9Hz,
H-2, 6), 6.73 (2H, d, Jo=7.9Hz, H-3, 5), 4.59 (2H, dd, Jvic=6.5Hz, OCH2), 1.89 (2H, m,
Jvic=6.5Hz, OCH2CH3), 1.00 (3H, t, Jvic=6.5Hz, OCH2CH2CH3); 13C-NMR (100 MHz,
DMSO-d6): 154.6 (C=N), 150.0 (C=N), 149.2 (C=N), 148.7 (C-4), 145.0 (C-5), 144.2
(C-S), 142.2 (C-6), 139.6 (C-1), 130.9 (C-2, 6), 129.8 (C-1), 128.7 (C-4), 127.3 (C-2),
126.8 (C-3), 112.9 (C-3, 5), 69.2 (OCH2), 22.9 (OCH2CH2CH3), 21.3 (OCH2CH2CH3);
MS: m/z (M+Na)+ 386 (100 %), (M)+ 363 (14.6 %), 334 (50.9 %), 321 (12.8 %), 291
(14.9 %), 273 (13.6 %), 135 (20.1 %), 120 (40.6 %), 107 (10.9 %); Anal. calc. for
C19H17N5OS: C, 62.81; H, 4.68; N, 19.28; Found: C, 62.68; H, 4.64; N, 19.25.

REFERENCES
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Elizabeth, A. J.; Eric, E. S. A.; Osgood, A. M.; Lisa, M. R. and Lawrence, B. B.


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CHAPTER-IVa
Synthesis of New N-phenylbispyrazolines

Synthesis and in-vitro antibacterial activity of some alkoxy based


N-substituted-5-(furan-2-yl)-phenyl-bis-pyrazolines
Mamta Rani and Mohamad Yusuf
European Journal of Chemistry 2012, 3(1), 21-25.

The studies of heterocyclic compounds had been subject of the major attraction in the
past decades due to their occurrence in nature and numerous applications in the biological
systems.1 The derivatives of chalcones are the significant compounds which are
associated with a wide range of biological activities.2-11 Amongst different heteroatomic
cycles, pyrazoline have played a crucial part in the development of the heterocyclic
systems and are also extensively used in the organic synthesis.12-16 Pyrazolines are
generally prepared from the condensation reaction of a variety of substituted chalcones
with hydrazine and its derivatives under acidic and basic medium.17-25 These compounds
have also gained much interest because of their wide range of applications in biological
and pharmaceutical chemistry. Bispyrazolines are the molecules which are formed by
joining two pyrazoline moieties together through the carbon chains of varying lengths. In
the recent past, we have been actively engaged in the synthesis of heterocyclic
compounds having more than one heteroatom.26
Braulio Insuasty and et al27 have synthesized new bis-3,5-diphenylpyrazolines 4.4 from
the cyclization of bischalcones 4.3 with hydrazine hydrate in acetic acid medium. The
later were prepared from the Claisen-Schmidt reaction of bisacetophenone 4.1 with
suitable aromatic aldehydes (Scheme-4.1).
O

O
CH3
CHO

EtOH/ NaOH

4.2
CH3

R
O

4.3

4.1`

N2H4/ AcOH

COCH
N

X
O

R
N

N
COCH

R= 3,4,5-tri-OMe, 4-OMe, 4-CF3, 3,4,5,tri-OMe, 4-OMe, 4-CF 3 ; X = alkyl chains

Scheme-4.1

4.4

Some biologically significant bisheterocycles28 bearing pyrazoline moieties 4.8 have been
prepared starting from pyrazolyl aldehyde 4.6 through the reactions sequence as
described in Scheme-4.2.
Cl

N
NC

H3C

H3C
NC

K2CO3/ DMF

CHO

N
H

CHO

Br

Cl

4.5

4.6
PhNHNH2/ NaOAc

Cl

Ph

Cl

N
H3C

Ph

X
CAT, EtOH

Z
NC

Z
H2C

NH

N
H3C

NC

4.8

4.7

X = H, CH3, H, H, H, H, H, H
Y= Ph, Ph, CH3CN, CH2Cl, CH2Br, CH2OH, COOMe, COOEt

Scheme-4.2
One pot and regioselective synthesis29 of a novel series of 3-aryl(heteroaryl)-5triflouromethyl-5-hydroxy-4,5-dihydro-1H-pyrazolyl-carbohydrazides 4.11 and bis-(3aryl-5-triflouromethyl-5-hydroxy-4,5-dihydro-1H-pyrazol-1-yl)methanones

4.12

have

been reported from the reaction of 4-alkoxy-4-aryl(heteroaryl)-1,1,1-triflouro-3-en-2ones 4.10 under the reaction conditions which are shown in Scheme-4.3.
R
F 3C

O
EtOH

H2NHN

NHNH 2

N
N

HO

4.9

NH

4.11

NH2

OMe

HO
EtOH

F 3C

CF 3 O F3C
N

R
4.10

N
R

R
4.12

R = H, Me, Ph, 4-OMePh, 4-ClPh, 4-BrPh, 4,4'-biphenyl, 2-thienyl, 2-furyl

Scheme-4.3

OH

variety

of

bis(3-aryl-4,5-dihydro-1H-pyrazole-1-thiocarboxamides)

4.14

and

bis(3-aryl-4,5-dihydro-1H-pyrazole-1-carboxamides) 4.15 were prepared30 via the


reaction

of

bis(2-propen-1-ones)

4.13

with

thiosemicarbazide/KOH

and

semicarbazide/AcOH respectively (Scheme-4.4).


A

R
O

4.13

S
NH2

H2N

NH

H2N

AcOH

KOH, EtOH

NH2
NH

R
R

R
N

N
S

NH2

N
NH2

H2N

H2N

4.15

4.14
A= 2-O(CH2)2O-2', 4-O(CH2)2O-4'
R= Ph, 4-ClC6H4, 4-FC6H4, 4-H3CC6H4, 2-thienyl, Ph

Scheme-4.4
It is evident from the above literature survey that bisheterocyclic compounds are very
significant in context of synthetic, structural and biological studies. These observations
have prompted us to investigate the synthesis of new bispyrazolines 4.21-4.25.
O

CH2

(CH2) n

HM

HM
HA

Ar'
N H
X

HA
N

Ar'
HX

Ar

4.21

N
Ar

, Ar' =

Ar =

n = 2,

CH2

3,

4,

4.22

4.23

6,
4.24

8
4.25

The bispyrazolines 4.21-4.25 needed for the present studies were synthesized from the
cyclization reactions of bischalcones 4.16-4.20 with phenyl hydrazine by refluxing under

EtOH/AcOH medium. The bischalcones were obtained from the O-alkylation of chalcone
2.69

with

suitable

alkylating

agents

(1,4-dibromobutane,

1,5-dibromopentane,

1,6-dibromohexane, 1,8-dibromooctane & 1,10-dibromodecane). The structures of


prepared compounds were determined from the rigorous analysis of their spectral data
(IR, 1H-NMR,

13

C-NMR & ESI-MS). The results of elemental analysis also confirmed

the purity of these products.

Synthesis of bispyrazoline 4.21


The compound 4.21 was prepared in two steps:
(i). Synthesis of bischalcone 4.16
The chalcone 2.69 was reacted with 1,4-dibromobutane in the presence of anhydrous
K2CO3 and tetrabutyl ammonium iodide (PTC) in dry acetone (Scheme-4.5). The crude
product thus obtained was purified by crystallization from CHCl3:MeOH (1:1) to yield
pure compound 4.16 (80%, m.p. 114-1160C).
3'

OH

4'

5'
6'

3
O

2.69

Anhyd. K2CO 3/ dry acetone/ Bu4N+I - / Br-(CH2)4-Br/

3'

CH2

CH2

2'

3"

4'
1'

5'

1
6'

CH2

4"

2"
3

CH2

5"
O
1"

4.16
Scheme-4.5
The structure of bischalcone 4.16 was determined from the rigorous analysis of its
spectral data. IR spectrum exhibited absorption bands at 3085 (aromatic C-H),

1656 (C=O), 1604 (C=C) & 1248, 1059 (C-O) cm-1. The 1H-NMR (400 MHz, CDCl3)
spectrum of 4.16 was quite helpful to interpret its structure. The aromatic protons (H-6
& H-3) produced resonating signals at 7.56 (2H, dd, Jm,o=2.4, 7.8Hz) & 6.82 (2H, d,
Jo=8.0Hz) respectively whereas the protons H-4, 5 & 5 appeared as a multiplet at
7.43. The downfield resonance of H-6 as compared to other protons could be ascribed
to its proximity to the C=O group and ortho relationship of H-3 to C2-OCH2 group
suggests its upfield placement. In this region, two broad doublets centered at 7.60 (2H)
and 7.38 (2H) were denoted by H-3 and H-2 respectively. The coupling value of 15.4Hz
between these protons describes the trans geometry around C-2 and C-3 double bond.
Regarding the remaining signals, a doublet due to two protons at 7.22 (J3,4=3.6Hz)
and another doublet of doublet integrating for two hydrogens at 7.10 (J4,5=1.8Hz,
J4,3=3.6Hz) can be easily ascribed to H-3 & 4 respectively. The internal methylene
chain hydrogens generated well defined signals at 4.02 (4H, t, Jvic=6.2Hz, OCH2CH2)
& 2.01 (2H, quintet, Jvic=6.2Hz, OCH2CH2). The ESI-MS spectrum also confirmed the
structure of 4.16 which exhibited the (M+Na)+ and (M)+ ions at m/z 505 (60.4 %) & 482
(13.4 %) respectively (vide experimental).
13

C-NMR (100 MHz, CDCl3) spectrum of 4.16 was very instrumental to corroborate its

proposed structure. Here, presence of carbonyl group was confirmed by the appearance of
a signal at 192.6. The carbon atoms belonging to double bond appeared at 140.2 (C-3)
& 119.4 (C-2) and the downfield occurrence of former can be ascribed to its -position in
the enone system. Other downfield resonances present at 152.8 & 151.9 could be
furnished by C-2 and C-2 respectively due to their direct linkage to the electronegative
oxygen atom. The remaining signals in the aromatic region were found at 143.7 (C-5),
134.3 (C-1), 132.5 (C-3), 130.6 (C-6), 127.2 (C-4), 126.9 (C-5) & 124.2 (C-4). The
upfield appearance of the C-3 at 113.9 could be occurring due to its ortho placement
with respect to C2-OCH2 group. The internal chain furnished suitable signals at 68.4
(OCH2CH2) & 26.7 (OCH2CH2).
(ii). Cyclization of bischalcone 4.16
The compound 4.16 was refluxed with phenyl hydrazine in EtOH/AcOH solution
(Scheme-4.6) and cooling of the resulting reaction mixture in an ice bath provided a solid

substance. The crude product was crystallized from MeOH to yield pure compound 4.21
(62%, m.p. 180-1820C).
4.16

PhNHNH2 / EtOH/ AcOH/

CH2

3"
2"

4"

6"
2

CH2

CH2

HM

HM

1"
5"

CH2

3'''

4
5

N
1N
1'

6'

HA

HX

2''' O
1'''

HA

4'''
5'''

HX

2'
3'

5'
4'

4.21
Scheme-4.6
The IR spectrum of 4.21 was very helpful to interpret its structure which did not exhibit a
strong absorption band at 1656 cm-1 indicating the involvement of carbonyl group during
the cyclization reaction of 4.16 and here significant absorption was observed at 1596 cm-1
due to C=N moiety of the pyrazoline ring. Its mass spectrum furnished the heaviest ion at
m/z 662 (M+, 22.8 %) and other ions were present at m/z 660 (15.4 %), 606 (12.0 %), 529
(28.1 %), 345 (16.4 %), 317 (10.4 %), 315 (100 %) & 248 (20.7 %). The mass
fragmentation pattern of 4.21 has been shown in Chart-1.
A comparison of the 1H-NMR spectra (400 MHz, CDCl3) of 4.16 and 4.21 shows that
resonances present at 7.38 (H-3) & 7.60 (H-2) in former were found missing altogether
in the later, thereby pronouncing the involvement of these hydrogens in the chemical
transformation. The aromatic protons (H-6 & 3) were located at 7.82 (2H, dd,
Jm,o=2.2, 8.4Hz) & 6.84 (2H, d, Jo=8.4Hz) respectively. The furyl ring protons furnished
two doublets at 7.42 (2H, J5,4=2.0Hz, H-5) & 7.30 (2H, J3,4=3.2Hz, H-3) and
one doublet of doublet at 6.95 (2H, J4,3=3.2Hz, J4,5=2.0Hz, H-4). The protons of
the N-phenyl ring were also resonating in the aromatic region at 7.16 (6H, m, H-2, 4,
6) & 7.12 (4H, m, H-3, 5). The major feature of this spectrum was the signals of

pyrazoline ring protons (H-X, M & A) which were found to be centred at 5.32 (2H, dd,
JXA=6.7Hz, JXM=11.6Hz), 3.52 (2H, dd, JMX=11.7Hz, JMA=16.7Hz) & 3.34 (2H, dd,
JAX=6.7Hz, JAM=16.7Hz) respectively. In a double resonance experiment, irradiation of
doublet of doublet at 5.32 (H-X) converted the doublet of doublets at 3.52 (H-M) &
3.34 (H-A) to doublet each which clearly describes the inter-relationship among the
H-X, M & A. The internal spacer protons were found to be placed at 3.98 (4H, t,
Jvic=6.5Hz, OCH2CH2) & 1.96 (4H, quintet, Jvic=6.5Hz, OCH2CH2).
Finally, 13C-NMR (400 MHz, CDCl3) data of 4.21 provided enough evidence in favour of
the proposed expression. The downfield signals at 152.4, 151.6 & 150.4 were
designated to C-2, C-2 & C-5 respectively due to the direct bonding of these
carbons to the electronegative oxygen atom. Again, carbon atoms C-3 and C-1 directly
connected to nitrogen atom produced resonances at 158.2 & 146.5 respectively.
Remaining aromatic carbon atoms were placed at 134.9 (C-1), 132.4 (C-3), 131.4
(C-6), 130.6 (C-4), 128.1 (C-5), 127.8 (C-4), 127.0 (C-3, 5), 124.9 (C-4), 121.5
(C-2, 6) & 118.4 (C-3). The signals present at 58.7 & 45.2 could be easily generated
by pyrazoline ring carbon C-5 and C-4 respectively. The carbon atoms of the internal
chain appeared at 67.3 (OCH2CH2) due to its proximity to the oxygen atom while a
signal at 24.6 can be allotted to other methylene group (OCH2CH2).

CH 2

CH 2

CH 2

CH2

CH 2

CH 2

CH2

CH 2

H
H

-2H

H
N

Ar'

N H

Ar'

H N

Ar

Ar

Ar

+.

m/z 662 (22.8 %)

Ar'

Ar'

H N
Ar

m/z 660 (15.4 %)

+
O
O

CH 2

CH 2

CH 2

CH2

+.

N H

- (CH2)4

+
Ar'

N H

Ar'

H N

Ar

H N

Ar

m/z 529 (28.1 %)

Ar

m/z 317 (10.4 %)

Ar

N H Ar'
Ar

-(CH2)2, -2H

H
H

m/z 345 (16.4 %)

+.

H
Ar'

CH 2

N
H N
Ar

N
N

m/z 606 (12.0 %)


-Ar'

+
O

Ar =

CH 2 O

H
H

H2 C

H
H

CH2

CH 2

Ar'

Ar

m/z 315 (100%)

CH 2

, Ar' =

Ar

m/z 248 (20.7 %)

Chart-1

Synthesis of bispyrazoline 4.22


The compound 4.22 was again obtained in the two steps:
(i). Synthesis of bischalcone 4.17
The chalcone 2.69 was reacted with 1,5-dibromopentane (Scheme-4.7) under the similar
conditions as used earlier for 4.16 to yield pure compound 4.17 (72%, 120-1220C).

3'

OH

4'

5'
6'

2
O

3
O

2.69

+ -

Anhyd K2CO3/ dry acetone Bu 4N I / Br-(CH 2)5-Br/

3'
4'

6'

CH2
3"

1'
5'

CH2

2'

CH2

CH2

4"

2"

5"

O
3

CH2

1"

4.17
Scheme-4.7
IR spectrum of 4.17 displayed major absorptions at 1652 (C=O), 1600 (C=C) & 1240,
1060 (C-O) cm-1. Its 400 MHz 1H-NMR (CDCl3) spectrum was similar to that of 4.16
except those of methylene hydrogens which appeared at 3.88 (4H, t, Jvic=6.0Hz,
OCH2CH2CH2), 1.96 (4H, quintet, Jvic=6.0Hz, OCH2CH2CH2) & 1.60 (2H, quintet,
Jvic=6.7Hz, OCH2CH2CH2). The former protons were found slightly upfield as compared
to similar hydrogens in 4.16 ( 4.02), obviously due to the +I effect of the extra
methylene group present in 4.17. In the aromatic region, two doublets were observed at
7.63 (2H, Jtrans=15.4Hz) & 7.32 (2H, Jtrans=15.4Hz) due to H-3 and H-2 respectively.
Other protons belonging to phenyl rings (H-6, 5, 4, 3) and furyl ring (H-3, 4, 5)
were resonating at the expected positions in the aromatic region (vide experimental).
ESI-MS spectrum of 4.17 had the molecular ion (M+1)+ at m/z 497 (9.3 %) and (M+Na)+
ion at m/z 519 (59.6 %) which also confirmed its structure (vide experimental).
The gross structure of compound 4.17 has been further supported by its

13

(100

of

MHz,

CDCl3)

data

which

was

again

similar

to

that

C-NMR
4.16.

The downfield resonances placed at 191.2, 154.1 & 148.1 could be given by C-1, C-2
and C-2 respectively. The carbon atoms (C-3 & C-2) associated to the double bond
were located at 139.2 & 118.2 respectively. The methylene chain carbon atoms were

resonating at 69.9 (OCH2CH2CH2), 28.9 (OCH2CH2CH2) & 24.7 (OCH2CH2CH2). The


carbon atoms of the phenyl ring (C-3, 4, 5, 6) and furyl ring (C-3, 4, 5) were found
at the appropriate positions in the aromatic region (vide experimental).
(ii). Cyclization of bischalcone 4.17
The compound 4.22 (67%, m.p. 173-1750C) was prepared from the reaction of 4.17 with
phenyl hydrazine (Scheme-4.8) under the similar conditions as used earlier for 4.21.
The structure of 4.22 was characterized from the rigorous analysis of its spectroscopic
data. Its IR spectrum displayed expected absorption bands at 1599 (C=N) & 1245, 1050
(C-O) cm-1.
4.17
PhNHNH 2/ EtOH/AcOH/

CH2

3"
2"

4"

1"
5"
6"

HM
3 4

CH2 CH2

HA

HX

5'

2''' O

HA

4'''

5'''

1'
6'

CH2

HM
3'''

CH2

HX

2'
3'
4'

4.22
Scheme-4.8
1

H-NMR (400 MHz, CDCl3) spectrum of 4.22 was highly amenable to its interpretation

and was similar to that of 4.21. Here again, the double bond protons H-3 ( 7.63) and H-2
( 7.32) present in 4.17, were found missing which clearly describes that double bond has
reacted during the cyclization reaction. At the lowest downfield, a ddd resonating at
7.76 (2H) could be generated by H-6 due to its vicinity to the pyrazoline ring. The
pyrazoline ring protons (H-X, M, & A) produced resonances at 5.39 (2H, dd,
JXA=6.7Hz, JXM=11.6Hz), 3.58 (2H, dd, JMX=11.6Hz, JMA=16.7Hz) & 3.39 (2H, dd,
JAX=6.7Hz, JAM=16.7Hz) respectively. The phenyl rings protons (H-2 to 6 & 3 to 6)

and furyl ring protons (H-3, 4 & 5) were found to be present at the similar
positions as observed in 4.21 (vide experimental).
The 100 MHz

13

C-NMR (CDCl3) spectrum of 4.22 finally proved very helpful to

corroborate its structure. On the left hand side, the resonances placed at 154.0, 150.9 &
144.2 were assignable to C-2, 2 and 1 respectively. The internal chain carbon atoms
were found to be resonating at 68.4 (OCH2CH2CH2), 25.8 (OCH2CH2CH2) &
22.3 (OCH2CH2CH2). The carbon atoms (C-3, 4 & 5) belonging to pyrazoline ring
resulted suitable signals at 156.9, 47.0 & 55.1 respectively. The downfield resonance of
C-5 as compared to C-4 could be attributed to its benzylic nature and proximity to the
nitrogen atom. The carbon atoms of the phenyl and furyl rings present at the N-1, C-3 and
C-5 were placed at the expected positions in the aromatic region (vide experimental). The
mass spectrum of 4.22 also confirmed its structure which exhibited the (M+1)+ ion at m/z
677 (100 %) and its fragmentation pattern was found to be similar as shown in Chart-1
(vide experimental).
Encouraged by these facile cyclization reactions, it was considered to be of major interest
to extend this study on the bischalcone 4.18-4.20. The major interest in these reactions
was to investigate the effect of lengthy internal chains upon the formation and
stereochemical features of the bispyrazoline.
The compounds 4.18-4.20 were prepared in good yields from the O-alkylation of
chalcone 2.69 with suitable 1,-dibromoalkane (1,6-dibromohexane, 1,8-dibromooctane
& 1,10-dibromodecane respectively) under the similar conditions as described earlier for
4.16-4.17. The spectral data (IR, 1H-NMR,

13

C-NMR & ESI-MS) of 4.18-4.20 were

consistant to their proposed structures. The significant physical and spectral parameters
of 4.18-4.20 have been given in Table-1 & Table-2 (vide experimental).
3'
2'

4'

CH2

(CH 2)n

1'
5'
6'

2"
3

CH2

4"

3"

O
1''

5"

4.18 (n = 4), 4.19 (n = 6), 4.20 (n = 8)

Table-1: Physical and characteristics spectral data of bischalcone 4.18-4.20

Compound

4.18

m.p. (0C)

Yield

IR(max cm-1)

(%)

(C=O)

75

1658

106-108

(OCH2)

(M+1)+/(M+Na)+

(C=C)
1602

(m/z)

3.76

511 (38.8 %)/


533 (38.6 %)

4.19

102-104

72

1656

1605

3.68

539 (100 %)/


561 (30.4 %)

4.20

118-120

78

1660

1608

3.62

567 (40.3 %)/


589 (100 %)

Table-2: Characteristics 13C-NMR (100 MHz) data of bischalcones 4.18-4.20

Compound

OCH2

C-1

C-2

C-3

C-1

C-2

C-2

4.18

66.7

193.6

120.9

137.7

140.8

151.4

152.3

4.19

67.8

191.9

121.8

138.1

139.1

153.9

150.2

4.20

68.6

192.3

122.4

139.8

137.7

152.0

152.8

Synthesis of bispyrazoline 4.23


The compound 4.23 (70%, m.p. 165-1670C) was obtained from the reaction of
bischalcone 4.18 with phenyl hydrazine (Scheme-4.9) under the similar conditions as

used earlier for 4.21. The structure of 4.23 was identified by comparing its spectral data
(IR, 1H-NMR, 13C-NMR & ESI-MS) with those of 4.21 & 4.22.

4.18

PhNHNH 2/ EtOH/AcOH/

2"

4"

1"
5"
6"

CH2

CH2

3"

HM
3 4

CH2

CH2

HA

4'''

N H 2''' O1'''
1
X
1'
6'
2'
5'

CH2

HM
H A3'''

CH2

5'''

HX

3'
4'

4.23
Scheme-4.9
IR spectrum of 4.23 revealed usual absorptions at 3048 (aromatic C-H), 1602 (C=N) &
1245, 1050 (C-O) cm-1. Its ESI-MS spectrum exhibited the (M+2)+ ion at m/z 691
(40.4 %) and other ions were found to be present according to the similar pattern as
shown in Chart-1 (vide experimental).
1

H-NMR spectrum (400 MHz, CDCl3) of 4.23 in addition to resonances due to phenyl

and furyl rings (N-1, C-3 & C-5) at the expected positions in the aromatic region (vide
experimental), protons of the pyrazoline ring (H-X, M & A) were placed at 5.31 (2H,
dd, JXA=6.7Hz, JXM=11.6Hz), 3.63 (2H, dd, JMX=11.6Hz, JMA=16.7Hz) & 3.43 (2H, dd,
JAX=6.7Hz, JAM=16.7Hz) respectively. The hydrogens belonging to internal six
methylene groups were also characterized through the appropriate signals in the aliphatic
region (vide experimental).

13

C-NMR (100 MHz, CDCl3) data of 4.23 was fully in concurrence to its proposed

structure and was similar to those of 4.21 & 4.22. The significant signals in this spectrum
were located at 156.3 (C-2), 155.1 (C-3) & 152.8 (C-2). The carbon atoms of the
phenyl rings (N-1 & C-3) and furan ring (C-5) were resonating at the suitable positions in
the aromatic region (vide experimental). The resonances placed at 66.7, 26.2 & 24.9
could

be

assigned

to

internal

chain

(OCH2CH2CH2),

(OCH2CH2CH2)

and

(OCH2CH2CH2) groups respectively.


Synthesis of bispyrazolines 4.24-4.25
The compounds 4.24 & 4.25 were prepared in good yields from the cyclization reaction
of the bischalcones 4.19 & 4.20 respectively with phenyl hydrazine under the same
conditions as described earlier for 4.21.

O CH2

3"
2"

4"

6"
2

CH2 O

HM

1"
5"

(CH 2)n

3'''

4
5

N
1N
1'

6'

HA

HX

HA

4'''

2''' O
1'''

5'''

HM
N

HX N

2'
3'

5'
4'

n = 6,
4.24

8
4.25

The structures of compounds 4.24 & 4.25 were based upon their spectral parameters. A
comparison of their 1H and

13

C-NMR (CDCl3) spectra with those of similar products

4.21-4.23 shows that protons belonging to pyrazolines, two phenyl (N-1 & C-3) and furyl
rings (C-5) and the internal methylene chain also furnished their resonances at the
expected positions (vide experimental). The physical and significant spectral data of 4.24
& 4.25 have been presented in Table-3 & Table-4 (vide experimental).

The stereochemical features of pyrazoline rings were determined from the consideration
of coupling constants (J). The vicinal coupling constant (3J) between H-X and H-M was
found to be 11.6Hz which reflects that these hydrogens are cis to each other while
coupling value JXA=6.7Hz describes the trans relationship between H-X and H-A. The
coupling value of 16.7 Hz between H-M and H-A, evidently explain their geminal
placement at C-4. The phenyl rings placed at N-1 and C-5 are certainly trans oriented to
avoid any intramolecular repulsion.

Table-3: Physical and characteristics spectral data of bispyrazolines 4.24-4.25


Compound

4.24

m.p.

Yield

IR(max cm-1)

(0C)

(%)

C=N

174-176

64

1592

(H-X)

(H-M)

(H-A)

ESI-MS
(m/z)

5.42

3.51

3.24

719 (M+1+, 30.5 %)/ 720


(M+2+, 100 %)

4.25

182-184

66

1602

5.45

3.54

3.34

747 (M+1+, 18.4 %)/ 769


(M+Na+, 100 %)

Table-4: Characteristics 13C-NMR (100 MHz) data of bispyrazolines 4.24-4.25

Cmpound

OCH2

C-3

C-4

C-5

C-1

C-2

C-1

C-2

4.24

68.8

154.8

45.8

55.9

144.5

150.7

136.3

151.1

4.25

69.2

157.6

46.1

57.4

145.8

148.0

136.6

151.9

To generalise the syntheses of aliphatic chain linked bispyrazoline, the researches have
also been carried out upon the thienyl bispyrazolines 4.31-4.35.

2"

HM
3'''

6"

CH2 O

HM

1"
5"

(CH 2)n

O CH2

3"
4"

N
1N
1'

HA

HX

6'

2''' S
1'''

HA

4'''

5'''

HX

2'
3'

5'
4'

n = 2,
4.31

3,
4.32

4,

6,

4.33

4.34

4.35

The bispyrazolines 4.31-4.35 were again obtained from the cyclocondensation reactions
of bischalcones 4.26-4.30 with phenyl hydrazine. The later were prepared from the
reaction of chalcone 2.78 with suitable 1,-dibromoalkanes in presence of anhydrous
K2CO3 and Bu4N+I- in dry acetone. The structures of these compounds were also based on
their spectroscopic data (IR, 1H-NMR, 13C-NMR & Mass).

(i). Synthesis of bischalcone 4.26


The chalcone 2.78 was reacted with 1,4-dibromobutane (0.950 g, 0.0043 mol) in the
presence of anhydrous K2CO3 and tetrabutyl ammonium iodide (PTC) in dry acetone
(Scheme-4.10). The crude product of this reaction was purified by crystallization from
CHCl3:MeOH (1:1) to yield pure compound 4.26 (76%, m.p. 128-1300C).

3'

OH

4'

5'

6'

2.78
+ -

Anhydrous K 2CO 3/acetone/ Bu 4N I / Br-(CH 2)4-Br/

3'
4'

CH2

CH2

2'
1

6'

2"
3

CH2

4"

3"
1'

5'

CH2

5"
S
1"

4.26
Scheme-4.10
The structure of 4.26 became evident from its spectral analysis. IR spectrum exhibited
major absorptions at 3066 (aromatic C-H), 1652 (C=O), 1602 (C=C) & 1248,
1050 (C-O) cm-1. In the 1H-NMR spectrum (400 MHz, CDCl3) of 4.26, the aromatic
protons (H-3, 4, 5 & 6) produced well defined signals at 6.86 (2H, d, Jo=8.0Hz,
H-3), 7.58 (4H, ddd, Jp,m,o=0.7, 1.8, 7.6Hz, H-4, 5) & 7.63 (2H, dd, Jm,o=2.3, 6.6Hz,
H-6). The downfield resonance of later as compared to other protons could be ascribed
to its proximity to the C=O group. In this region, two broad doublets placed at 7.72
(2H) & 7.42 (2H) could be easily ascribed to H-3 and H-2 respectively. The coupling
value of 15.4Hz between these protons describes the trans geometry around C-2 and C-3
double bond. The signals due to thienyl ring protons appeared at 7.61 (2H, m, H-5),
7.36 (2H, d, J3,4=3.4Hz, H-3) & 7.22 (2H, dd, J4,5=4.9Hz, J4,3=3.4Hz, H-4). A
triplet at 4.01 (2H, Jvic=6.4Hz) and a quintet at 2.07 (4H, Jvic=6.4Hz) were provided
by internal chain methylene (OCH2CH2) and (OCH2CH2) groups respectively. The ESIMS spectrum of 4.26 exhibited (M+Na)+ and (M+1)+ ions at m/z 537 (100%) & 515
(43.0 %) respectively (vide experimental).
13

C-NMR (100 MHz, CDCl3) spectrum of 4.26 also corroborated its proposed structure

which exhibited the C=O group resonance at 190.8 (C=O). The carbon atoms belonging
to the double bond appeared at 139.4 (C-3) & 118.5 (C-2). Other noticeable signals

present at 151.6 & 149.9 could be generated by C-2 and C-2. The remaining signals
in the aromatic region were resonating at 142.6 (C-5), 135.3 (C-1), 131.2 (C-3),
130.9 (C-6), 126.8 (C-4), 116.2 (C-5), 122.9 (C-4) & 112.6 (C-3). The internal butyl
chain resulted two signals at 67.6 (OCH2CH2) & 25.2 (OCH2CH2).
(ii). Cyclization of bischalcone 4.26
The compound 4.26 was refluxed with phenyl hydrazine in EtOH/AcOH medium
(Scheme-4.11) and cooling of the resulting reaction mixture provided a solid product
which was crystallized from MeOH to yield pure compound 4.31 (63%, m.p. 185-1870C).
4.26

PhNHNH

CH2

3"
2"

4"

6"
2

CH2

EtOH/ AcOH/

CH2

HM

HM

1"
5"

CH2

4
5

N
1N
1'

6'

3'''
HA

HX

2''' S
1'''

HA

4'''

5'''

HX

2'
3'

5'
4'

4.31
Scheme-4.11
The IR spectrum of 4.31 did not exhibit a strong absorption band at 1652 cm-1 indicating
the involvement of carbonyl group during the cyclization reaction of 4.26. The C=N
moiety of pyrazoline became evident from the absorption band at 1595 cm-1.
A comparison of the 1H-NMR spectra (400 MHz, CDCl3) of 4.26 and 4.31 shows that
resonances present at 7.72 (H-3) & 7.42 (H-2) in former were found missing altogether
in the later, thereby describing the involvement of these hydrogens in the chemical
transformation. The thienyl ring protons furnished signals at 7.48 (2H, d, J5,4=5.0Hz,
H-5), 7.38 (2H, d, J3,4=3.6Hz, H-3) & 6.99 (2H, dd, J4,3=3.2Hz, J4,5=5.0Hz,
H-4). The protons of the N-phenyl ring were also resonating in the aromatic region at
7.19 (4H, m, H-3, 5) & 7.13 (6H, m, H-2, 4, 6). The hydrogen H-6, H-4, 5 and H-

3 resulted suitable resonances at 7.86 (2H, dd, Jm,o=2.2, 8.4Hz), 7.31 (4H, m) & 6.90
(2H, d, Jo=8.4Hz) respectively. The pyrazoline ring protons (H-X, M & A) were very
well located at 5.39 (2H, dd, JXA=6.7Hz, JXM=11.6Hz), 3.56 (2H, dd, JMX=11.7Hz,
JMA=16.7Hz) & 3.36 (2H, dd, JAX=6.7Hz, JAM=16.7Hz) respectively. The signals in
aliphatic region were placed at 3.99 (4H, t, Jvic=6.5Hz, OCH2CH2) & 1.98 (4H, quintet,
Jvic=6.5Hz, OCH2CH2).
The proposed expression of 4.31 further became evident from its ESI-MS spectrum
which showed heaviest ion m/z 694 (M+, 22.8 %) and its mass fragmentation has been
depicted in Chart-2.
Finally, 13C NMR (400 MHz, CDCl3) data of 4.21 provided enough evidence in favour of
the proposed structure. The carbon atoms C-3, 2, 2, 5 & 1 could provide suitable
resonances at 158.9, 154.6, 153.6, 152.8 & 148.2 respectively. The direct bonding of
these carbon atoms to electronegative atoms (O & N) resulted their downfield placement.
Other aromatic carbon atoms were resonating at 136.7 (C-1), 134.8 (C-3), 131.9
(C-6), 131.2 (C-4), 130.4 (C-5), 129.1 (C-4), 128.2 (C-3, 5), 125.4 (C-4), 122.6
(C-2, 6) & 120.4 (C-3). The signals present at 59.2 & 47.9 could be easily designated
to pyrazoline ring carbon C-5 and C-4 respectively. The carbon atoms of the intermediate
chain appeared at 68.6 (OCH2CH2) & 25.2 (OCH2CH2).

CH 2

CH 2

CH 2

CH2

CH 2

CH 2

CH2

CH 2

H
H

-2H

H
N

Ar'

N H

Ar'

Ar'

Ar'

H N

Ar

Ar

Ar

+.

N
H N
Ar

m/z 694 (22.8 %)

m/z 692 (25.6 %)

- (CH2)4

+
O

CH2

CH 2

H2 C

H
O

H
H

N
N H

+
Ar'

Ar'

H N

H
H

+.

CH 2 O

N H Ar'

Ar

H
Ar'

Ar

m/z 333 (14.8 %)

m/z 361 (25.2 %)

H N

Ar

Ar

-(CH2)2, -2H

m/z 638 (100 %)

+
O

CH 2

CH 2

-Ar'
N
N

Ar'

Ar

m/z 331 (40.3 %)


Ar =

Ar

m/z 254 (18.1 %)

, Ar' =
S

Chart-2
Synthesis of bispyrazoline 4.32
The compound 4.32 was again obtained in the two steps as follows:
(i). Synthesis of bischalcone 4.27
The chalcone 2.78 was treated with 1,5-dibromopentane (Scheme-4.12) under the similar
conditions as used earlier for 4.26 to yield pure compound 4.27 (65 %, 136-1380C).

2.78

K2CO 3/acetone/ Bu 4N+I-/ Br-(CH 2)5-Br/

3'
4'

6'

CH2
3"

1'
5'

CH2

2'

CH2

CH2

4"

2"

5"

S
3

CH2

1"

4.27
Scheme-4.12
IR spectrum of 4.27 exhibited major absorptions at 3056 (aromatic C-H), 1656 (C=O),
1604 (C=C) & 1246, 1048 (C-O) cm-1. Its 1H-NMR spectrum (400MHz, CDCl3)
produced two resonances at 7.57 (2H, dd, Jm,o=2.4, 7.8Hz) & 6.89 (2H, d, Jo=8.0Hz)
which were easily furnished by H-6 & H-3 respectively. A multiplet integrating for six
hydrogens placed 7.54 could be produced by H-4, 5 & 5. The hydrogen atoms (H-3
& 2) of the double bond were resonating at 7.66 (2H) & 7.49 (2H) respectively as two
broad doublets and the trans relationship between these hydrogens was confirmed from
the coupling value (Jtrans=15.6Hz). The hydrogens H-3 & H-4 of thienyl ring appeared
at 7.29 (2H, d, J3,4=3.6Hz) & 7.18 (2H, m) respectively. The upfield signal at 3.92
as a triplet integrating for four hydrogens could be ascribed to OCH2 group and other
methylene groups were found at 2.01 (OCH2CH2CH2) & 1.60 (OCH2CH2CH2). The
presence of (M+Na)+, (M+2)+ & (M+1)+ ions at m/z 551 (100 %), 530 (20.5 %) & 529
(32.8 %) respectively in the ESI-MS spectrum of 4.27 also corroborated its structure and
its mass fragmentation pattern was found to be similar as shown in Chart-2 (vide
experimental).
13

C-NMR (100 MHz, DMSO-d6) spectrum of 4.27 exhibited the signals of the enone

moiety at 191.4 (C=O), 138.6 (C-3) & 119.6 (C-2). The carbon atom (C-2) bonded to
oxygen atom generated suitable signal at 150.6. The resonances of phenyl ring were
placed at 135.9 (C-1), 131.3 (C-6), 128.7 (C-4), 116.9 (C-5) & 114.9 (C-3) whereas
the signals at 147.8, 140.8, 130.2 & 122.1 were designated to thienyl ring carbon atoms
C-2, 5, 3 & 4 respectively. A signal present at 66.9 could be represented by the
OCH2 group of the internal alkyl chain and other signals in aliphatic region were
observed at 24.6 (OCH2CH2CH2) & 22.8 (OCH2CH2CH2).

(ii). Cyclization of bischalcone 4.27


The compound 4.32 (60%, m.p. 214-2160C) was obtained by reacting 4.27 with phenyl
hydrazine (Scheme-4.8) under the similar conditions as used earlier for 4.31.
4.27
PhNHNH 2/ EtOH/AcOH/

CH2

3"
2"

4"

1"
5"
6"

HM
3 4

CH2

HX

HA

4'''

2''' S
1'''

5'''

1'
6'
5'

CH2

HM
H A3'''

CH2 CH2

HX

2'
3'
4'

4.32
Scheme-4.8
The structure of 4.32 was characterized from the rigorous analysis of its spectroscopic
data. Its IR spectrum displayed expected absorption bands at 1598 (C=N) & 1248, 1053
(C-O) cm-1. In the 1H-NMR (400 MHz, CDCl3) spectrum of 4.32, a downfield ddd
resonating at 7.89 (2H) could be generated by H-6 due to its proximity to the
pyrazoline ring. The resonances placed at 5.47 (2H, dd, JXA=6.7Hz, JXM=11.6Hz), 3.65
(2H, dd, JMX=11.6Hz, JMA=16.7Hz) & 3.45 (2H, dd, JAX=6.7Hz, JAM=16.7Hz) were
allotted to pyrazoline ring hydrogens (H-X, M, & A) respectively. The phenyl rings (N-1
& C-3) and thienyl ring (C-5) hydrogens furnished suitable signals at the expected
positions in aromatic region (vide experimental).
The 100 MHz

13

C-NMR (CDCl3) spectrum of 4.32 finally proved very helpful to

corroborate the proposed expression. The resonances placed at 155.3, 154.8 & 147.0
were assignable to C-2, 2 & 1 respectively. The methylene chain carbon atoms were
resonating at 67.4 (OCH2CH2CH2), 25.6 (OCH2CH2CH2) & 23.9 (OCH2CH2CH2). The
signals of pyrazoline ring carbon atoms (C-3, 4 & 5) appeared at 157.9, 48.3 & 59.8

respectively. The downfield resonance of C-5 as compared to C-4 could be attributed to


its benzylic nature and proximity to the nitrogen atom. The carbon atoms due to two
phenyl rings present at the N-1 & C-3 and thienyl ring at C-5 also provided suitable
signals at the expected positions in the aromatic region (vide experimental).
The ESI-MS spectrum of 4.32 also confirmed its structure which exhibited the (M+Na)+
ion at m/z 731 (100 %) and its fragmentation pattern was similar as shown in Chart-2
(vide experimental).
The above described cyclization reactions have also been attempted upon the
bischalcones 4.28-4.30 built around the lengthy spacer units. The compounds 4.28-4.30
were prepared in good yields from the O-alkylation of chalcone 2.78 with suitable 1,dibromoalkane

(1,6-dibromohexane,

1,8-dibromooctane

&

1,10-dibromodecane

respectively) under the similar conditions as explained earlier for 4.26 & 4.27. The
structures of 4.28-4.30 were determined from their spectroscopic parameters (Table-5 &
Table-6, vide experimental).
3'
2'

4'

CH2

(CH 2)n

1'
5'
6'

2"
3

CH2

4"

3"

5"

1''

n = 4,
4.28

6,
4.29

8
4.30

Table -5: Physical and characteristics spectral data of bischalcones 4.28-4.30

Compound

4.28

m.p. (0C)

110-112

IR(max cm-1)

Yield
(%)

(C=O)

(C=C)

80

1662

1604

(OCH2)

m/z
(M+1)+/(M+Na)+

3.89

543

(40.0

%)/

565 (100 %)
4.29

120-122

75

1656

1605

3.86

571

(45.8

%)/

593 (10.4 %)
4.30

118-120

78

1668

1600

3.82

599

(7.4

621 (38.2 %)

Table-6: Characteristics 13C-NMR (100 MHz) data of bischalcones 4.28-4.30


Compound

OCH2

C=O

C-2

C-3

C-1

C-2

C-2

4.28

66.1

192.8

122.4

138.2

134.7

151.2

148.9

4.29

65.8

191.7

120.9

137.4

134.2

150.8

148.4

4.30

65.1

192.5

121.8

137.9

135.0

150.3

148.0

Synthesis of bispyrazolines 4.33-4.35


The compounds 4.33-4.35 were obtained from the cyclization reactions of the
corresponding bischalcones 4.28-4.30 with phenyl hydrazine under the same conditions
as described earlier for 4.31. The spectral data of 4.33-4.35 was found to be similar to
those of 4.31 & 4.32. The physical and characteristics spectral parameters of these
compounds have been presented in Table-7 & Table-8 (vide experimental).

%)/

O CH2

3"
2"

4"

6"
2

CH2 O
HM

HM

1"
5"

(CH 2)n

3'''

4
5

N
1N
1'

HA

HX

6'

HA

4'''

2''' S
1'''

5'''

HX

2'
3'

5'
4'

n = 4,

6,

4.33

4.34

4.35

Table-7: Physical and characteristics spectral data of bispyrazoline 4.34-4.35


Compound

m.p.

No.

(0C)

4.33

225-227

Yield

IR(max cm-1)

(%)

C=N

67

1604

(H-X)

(H-M)

(H-A)

ESI-MS
(m/z)

5.39

3.69

3.49

722

(M+,

100 %)
230-232

4.34

60

1596

5.49

3.56

3.20

752 (M+2+,
100 %)

182-184

4.35

65

1602

5.59

3.52

3.45

778
13.3 %)

Table-8: Characteristics 13C-NMR (100 MHz) data of bispyrazolines 4.34-4.35


Compound

OCH2

C-3

C-4

C-5

C-1

C-2

C-1

C-2

4.33

69.2

157.2

48.9

59.6

146.4

156.9

136.3

154.4

4.34

68.3

158.3

48.1

58.2

145.8

156.1

136.9

153.2

4.35

68.4

157.6

45.3

58.1

146.9

155.5

135.3

153.0

No

(M+,

Mechanistic consideration
The cyclization reactions described above i.e. 4.16-4.20 & 4.26-4.304.21-4.25 &
4.31-4.35 can be visualized as having occurred through an initial attack (path a) of
phenyl hydrazine upon the carbonyl group of enone moiety under the influence of
protons followed by dehydration to produce 4.16-4.20 & 4.26-4.30. The later further
undergo cyclization with the addition of proton to give 4.21-4.25 & 4.30-4.35 as end
product (Scheme-4.9). In other way, phenyl hydrazine can also undergo addition upon
the enone part of 4.16-4.20 in a Michael fashion (path b) to give 4.16-4.20 & 4.264.30 as the intermediate which subsequently undergo cyclization followed by
dehydration to give 4.21-4.25 & 4.31-4.35 (Scheme-4.9).
But inspite of our repeated and best efforts, we were not able to isolate any product
similar to 4.21-4.25 & 4.31-4.35. Thus, in bischalcones 4.16-4.20 & 4.26-4.30, direct
condensation of phenyl hydrazine with carbonyl group (path a) is preferred over the
Michael addition (path b, Scheme-4.9).

CH 2 (CH 2) n-}

O CH 2(CH 2) n -}

path a
H

H2N

HN

Ar

NH

NH

Ar
4.16'-4.20' (X=O) & 4.26'-4.30' (X=S)

Ar

4.16-4.20 (X=O)

..

NH

CH 2(CH 2) n -}
H+

OH

..

-H 2O

4.26-4.30 (X=S)

cyclisation

-H

CH 2(CH 2) n-}

O
path b

H
H
N
N
O

CH 2(CH 2) n -}

CH 2(CH 2) n-}
H
H

H+
X

OH

NH
..
HN
Ar

-H 2O

CH 2(CH 2) -}
n

N
H

N
H

4.16"-4.20" (X=O)

Ar
4.21'-4.25' (X=O)

4.26"-4.30" (X=S)

4.31'-4.35' (X=S)

Ar

Ar
4.21-4.25 (X=O)

4.31-4.35 (X=S)

cyclisation

HO

(n = 2, 3, 4, 6, 8)

Ar =

Scheme-4.9
Antibacterial Activity of bispyrazolines 4.21-4.25 & 4.31-4.35
The compounds 4.21-4.25 & 4.31-4.35 were tested for their antibacterial activities by
disc-diffusion method31 using nutrient broth medium against four bacterial strains (Gram-

negative and Gram-positive) viz., A. hydrophila, Yersinia enterocolitica, Listeria


monocytogenes and Staphylococcus aureus. In this method, sterile paper discs (5 mm)
impregnated with compound dissolved in dimethylsulfoxide (DMSO) at concentration
100 g /mL were used. Gentamicin and Tetracycline were used as the standard drugs,
whereas DMSO poured disk was used as negative control. Then, the paper discs were
placed on the surface of the media inoculated with the microorganism. The plates were
incubated for 24 h at 37oC. After incubation, the diameters of the inhibition zones were
measured. The minimum inhibitory concentrations of 4.21-4.25 & 4.31-4.35 were also
determined by using serial tube dilution32 method at conc. of 50, 40, 30, 20, 10 g/ml.
The results of zone of inhibitions and minimum inhibitory concentrations (MIC) of these
compounds are summarized in Table-9 & Table-10 respectively.

Table-9: Zone of inhibitions (mm) of bispyrazolines 4.21-4.25 & 4.31-4.35.


Compounds

A. hydrophila

Y. enterocolitica

L. monocytogenes
21.3

S. aureus

4.21

24.5

22.4

25.8

4.22

14.5

15.5

18.4

14.6

4.23

19.5

18.5

16.5

15.5

4.24

15.2

17.6

15.8

14.6

4.25

25.2

23.6

24.2

22.7

4.31

24.5

21.5

23.4

22.6

4.32

17.5

22.4

24.3

22.8

4.33

22.5

18.5

17.5

18.5

4.34

19.2

17.6

18.8

19.6

4.35

21.5

23.4

20.6

25.7

Tetracycline

13

20

12

14

Gentamicin

11

16

15

14

It is evident from Table-9 that the compounds 4.21-4.25 and 4.31-4.35 were very active
against the tested bacterial strains (zone of inhibition, 25.8-17.5 g/ml). Here compound
4.21, 4.23, 4.25, 4.31, 4.33, 4.34 & 4.35 were found to be very active (zone of
inhibition-25.2-17.5 mm) against bacterial strain A. hydrophila. The compounds 4.21,
4.23, 4.25, 4.31, 4.32, 4.33 & 4.35 were active against Y. enterocolitica and zone of
inhibition were found in the range of 23.6-18.5 mm. Further 4.21, 4.22, 4.25, 4.31, 4.32,
4.34 & 4.35 seems to be active against L. monocytogens with zone of inhibition in
range of 24.3-17.5 mm. The 4.21, 4.25, 4.31, 4.32, 4.33, 4.34 & 4.35 could exhibit
significant activity against S. aureus (zone of inhibition: 25.8-18.5 mm)

Table-10: Minimum inhibitory concentrations (MIC, g/ml) of bispyrazolines 4.21-4.25


& 4.31-4.35.
Compounds

A. hydrophila

Y. enterocolitica

4.21

10

20

10

20

4.22

20

30

10

20

4.23

20

10

20

20

4.24

40

40

20

30

4.25

30

20

30

40

30

20

20

20

4.32

20

20

10

30

4.33

10

10

30

20

4.34

40

30

20

10

4.35

30

40

20

40

Tetracycline

30

30

30

30

Gentamicin

10

10

10

10

4.31

L. monocytogenes S. aureus

Similarly, Table-10 describes that compounds 4.21, 4.22, 4.23, 4.32, 4.33 & 4.34 were
found to be very active (MIC-10 g/ml) against the tested bacterial strains A. hydrophila,
Y. enterocolitica, L. monocytogens & S. aureus. Thus zone of inhibitions (Table-9) and
MIC (Table-10) data indicate that most of the studied compounds exhibited significant
activity against the tested microorganisms.
It may be concluded that this study provides a general method for the synthesis of
methylene chain linked furyl/thienyl-bispyrazolines under the ordinary conditions. These
compounds also exhibited significant antibacterial behaviour against the tested bacterial
strains.

EXPERIMENTAL
Synthesis of 1, 4-bis[(2E)-1-(2-oxyphenyl)-3-(furan-2-yl) prop-2-en-1-one] butane
4.16
A suspension of chalcone 2.69 (2.0 g, 0.0093 mol), 1,4-dibromobutane (1.0 g, 0.0046
mol), anhydrous K2CO3 (1.0 g) and tetra butyl ammonium iodide (1.0 g,) in dry acetone
was refluxed with stirring for 8 hrs at room temperature. The progress of reaction was
monitored by TLC. After the completion of reaction, the reaction mixture was turned
white was pour into iced HCl. The precipitated solid was filtered and crystallized from
CHCl3:MeOH (1:1) to yield pure compound 4.16.
3'

CH2

CH2

4'

CH2

4"

3"
1'

5'

CH2

2'
2

2"

1
6'

5"

1"

4.16
4.16: Brown solid; Yield 80%; m.p. 114-1160C; IR (KBr) max (cm-1): 3085
(aromatic

C-H), 1656 (C=O), 1604 (C=C), 1248, 1059 (C-O); 1H-NMR (400 MHz,

CDCl3): 7.60 (2H, d, Jtrans=15.4Hz, H-3), 7.56 (2H, dd, Jm.o=2.4, 7.8Hz, H-6), 7.43
(6H, m, H-4, 5, 5), 7.38 (2H, d, Jtrans=15.4Hz, H-2), 7.22 (2H, d, J3,4=3.6Hz, H-3),
7.10 (2H, dd, J4,3=3.6Hz, J4,5=1.8Hz, H-4), 6.82 (2H, d, Jo=8.0Hz, H-3), 4.02 (4H,
t, Jvic=6.2Hz, OCH2CH2), 2.01 (4H, quintet, Jvic=6.2Hz, OCH2CH2); 13C-NMR (100 MHz,
CDCl3): 192.6 (C=O), 152.8 (C-2), 151.9 (C-2), 143.7 (C-5), 140.2 (C-3), 134.3
(C-1), 132.5 (C-3), 130.6 (C-6), 127.2 (C-4), 126.9 (C-5), 124.2 (C-4), 119.4
(C-2), 113.9 (C-3), 68.4 (OCH2CH2), 26.7 (OCH2CH2); MS: m/z (M+Na)+ 505 (60.4 %),
(M)+ 482 (13.4 %), 241 (100 %), 214 (14.6 %), 175 (12.3 %), 148 (30.2 %), 122 (22.8
%); Anal. calc. for C30H26O6: C, 74.68; H, 5.39; Found: C, 74.82; H, 5.36 %.

Synthesis of 1, 5-bis[(2E)-1-(2-oxyphenyl)-3-(furan-2-yl) prop-2-en-1-one] pantane


4.17
The compound 4.17 was prepared from the reaction of chalcone 2.69 (2.0 g, 0.0093 mol)
with 1,5-dibromopentane (1.0 g, 0.0046 mol) under the similar conditions as used for
4.16.

3'
4'

CH2

2'

3"

1'
5'

6'

CH2

CH2

CH2

5"

1"

4"

2"

CH2

4.17
m.p. 120-1220C; IR (KBr)

4.17: Brown solid; Yield 72%;

max (cm-1): 3050

(aromatic C-H), 1652 (C=O), 1600 (C=C), 1240, 1060 (C-O); 1H-NMR (400 MHz,
CDCl3): 7.63 (2H, d, Jtrans=15.4Hz, H-3), 7.59 (2H, dd, Jm.o=2.4, 7.8Hz, H-6), 7.50
(6H, m, H-4, 5, 5), 7.32 (2H, dd, Jtrans=15.4Hz, H-2), 7.19 (2H, d, J3,4=3.5Hz,
H-3), 6.98 (2H, dd, J4,3=3.5Hz, J4,5=1.9Hz, H-4), 6.78 (2H, d, Jo=8.0Hz, H-3),
3.88 (4H, t, Jvic=6.0Hz, OCH2CH2CH2), 1.96 (4H, quintet, Jvic=6.0Hz, OCH2CH2CH2),
1.60 (2H, quintet, Jvic= 6.0 Hz, OCH2CH2CH2); 13C-NMR (100 MHz, CDCl3): 191.2
(C=O), 154.1 (C-2), 148.1 (C-2), 142.4 (C-5), 139.2 (C-3), 136.3 (C-1), 132.7 (C6), 130.9 (C-3), 129.9 (C-4), 128.0 (C-4), 123.5 (C-5), 118.2 (C-2), 110.1 (C-3),
69.9 (OCH2CH2CH2), 28.9 (OCH2CH2CH2), 24.7 (OCH2CH2CH2); MS: m/z (M+Na)+
519 (59.6 %), (M+1)+ 497 (9.3 %), 255 (15.8 %), 241 (100 %), 214 (28.4 %), 175 (10.8
%), 148 (21.4 %), 122 (30.4 %); Anal. calc. for C31H28O6: C, 75.00; H, 5.64; Found: C,
74.80; H, 5.60%.

Synthesis of 1, 6-bis[(2E)-1-(2oxyphenyl)-3-(furan-2-yl)prop-2-en-1-one] hexane 4.18


The compound 4.18 was obtained from the reaction of chalcone 2.69 (2.0 g, 0.0093 mol)
with 1,6-dibromohexane (1.1 g, 0.0046 mol) under the similar conditions as used for
4.16.
O

3'
4'

CH2
3"

2'

5'
6'

1'

CH2

CH2

CH2

CH2

4"

2"
3

CH2

5"

1"

4.18
4.18: Dark Brown solid; Yield 75%; m.p. 106-1080C; IR (KBr) max (cm-1): 3098
(aromatic C-H), 1658 (C=O), 1602 (C=C), 1222, 1035 (C-O); 1H-NMR (400 MHz,
CDCl3): 7.64 (2H, dd, Jm,o=2.4, 7.8Hz, H-6), 7.58 (6H, m, H-4, 5, 5), 7.54 (2H, d,
Jtrans=15.4Hz, H-3) 7.45 (2H, d, Jtrans=15.4Hz, H-2), 7.20 (2H, d, J3,4=3.4Hz, H-3),

6.91 (2H, dd, J4,3=3.4Hz, J4,5=1.8Hz, H-4), 6.80 (2H, d, Jo=8.0Hz, H-3), 3.76 (4H,
t, Jvic=6.0Hz, OCH2CH2CH2), 1.80 (4H, quintet, Jvic=6.0Hz, OCH2CH2CH2), 1.58 (4H,
quintet, Jvic= 6.0 Hz, OCH2CH2CH2);

13

C-NMR (100 MHz, CDCl3): 193.6 (C=O),

151.4 (C-2), 152.3 (C-2), 140.9 (C-5), 140.8 (C-1), 137.7 (C-3), 131.4 (C-3), 135.4
(C-6), 127.7 (C-4), 123.6 (C-4), 120.9 (C-2), 118.0 (C-5), 113.3 (C-3), 66.7
(OCH2CH2CH2), 26.8 (OCH2CH2CH2), 20.1 (OCH2CH2CH2); MS: m/z (M+Na)+ 533
(38.6 %), (M+1)+ 511 (38.8 %), 269 (100 %), 255 (23.4 %), 241 (12.8 %), 214 (19.4 %),
175 (26.2 %), 148 (40 %); Anal. calc. for C32H30O6: C, 55.29; H, 5.88; Found: C, 55.40;
H, 5.93%.

Synthesis of 1, 8-bis[(2E)-1-(2-oxyphenyl)-3-(furan-2-yl) prop-2-en-1-one] octane


4.19
The compound 4.19 was synthesized from the reaction of 2.69 (2.0 g, 0.0093 mol) with
1,8-dibromooctane (1.2 g, 0.0046 mol) under the similar conditions as used for 4.16.

3'
4'

CH2

CH2

6'

CH2

CH2

CH2

CH2

CH2

4"

3"
1'

5'

CH2

2'

2"

1
3

5"

1"

4.19
4.19: Light brown solid; Yield 72%; m.p.102-1040C; IR (KBr) max (cm-1): 3090
(aromatic C-H), 1656 (C=O), 1605 (C=C), 1255, 1052 (C-O); 1H NMR (400 MHz,
CDCl3): 7.62 (2H, dd, Jm,o=2.4, 7.8Hz, H-6), 7.54 (6H, m, H-4, 5, 5), 7.58 (2H, d,
Jtrans=15.4Hz, H-3), 7.43 (2H, d, Jtrans=15.4Hz, H-2), 7.11 (2H, d, J3,4=3.5Hz, H-3),
6.95 (2H, dd, J4,3=3.5Hz, J4,5=2.0Hz, H-4), 6.79 (2H, d, Jo=8.1Hz, H-3), 3.68 (4H,
t, Jvic=6.0Hz, OCH2CH2CH2CH2), 1.88 (4H, quitentet, Jvic=6.0Hz, OCH2CH2CH2CH2),
1.50 (4H, quintet, Jvic= 6.0Hz, OCH2CH2CH2CH2), 1.34 (4H, m, OCH2CH2CH2CH2);
13

C-NMR (100 MHz, CDCl3): 191.9 (C=O), 153.9 (C-2), 150.2 (C-2), 144.0 (C-5),

139.1 (C-1), 138.1 (C-3), 136.8 (C-6), 130.3 (C-3), 129.2 (C-4), 117.7 (C-5), 126.0
(C-4), 121.8 (C-2), 115.9 (C-3), 67.8 (OCH2CH2CH2CH2), 28.8 (OCH2CH2CH2CH2),

23.0 (OCH2CH2CH2CH2), 19.2 (OCH2CH2CH2CH2); MS: m/z (M+Na)+ 561 (20.4 %)


(M+1)+ 539 (100 %), 325 (26.4 %), 311 (10.2 %), 269 (20.2 %), 255 (11.8 %), 214
(45.2 %), 175 (60.4 %); Anal. calc. for C34H34O6: C, 75.83; H, 6.31; Found: C, 75.70; H,
6.28%.

Synthesis of 1,10-bis[(2E)-1-(2-oxyphenyl)-3-(furan-2-yl)prop-2-en-1-one] decane


4.20
The compound 4.20 was prepared from the reaction of 2.69 (2.0 g, 0.0093 mol) with
1,10-dibromodecane (1.4 g, 0.0046 mol) under the similar conditions as used for 4.16.

3'

CH2

CH2

CH2

CH2

CH2

CH2

CH2

CH2

CH2

CH2

2'

4'

3"

1'
5'

2
1

6'

4"

2"

5"

1"

4.20
4.20: Light Brown solid; Yield 78%; m.p. 118-1200C; IR (KBr) max (cm-1): 3076
(aromatic C-H), 1660 (C=O), 1608 (C=C), 1238, 1023 (C-O); 1H-NMR (400 MHz,
CDCl3): 7.69 (2H, dd, Jm,o=2.4, 7.8Hz, H-6), 7.56 (6H, m, H-4, 5, 5), 7.51 (2H, d,
Jtrans=15.4Hz, H-3), 7.36 (2H, d, Jtrans=15.4Hz, H-2), 7.14 (2H, d, J3,4=3.6Hz, H-3),
6.92 (2H, dd, J4,3=3.6Hz, J4,5=1.9Hz, H-4), 6.76 (2H, d, Jo=8.0Hz, H-3), 3.62 (4H,
t,

Jvic=6.0Hz,

OCH2CH2CH2CH2CH2),

1.74

(4H,

quintet,

Jvis=6.0Hz,

OCH2CH2CH2CH2CH2), 1.38 (4H, quintet, Jvic= 6.0 Hz, OCH2CH2CH2CH2CH2), 1.31


13

(8H, quintet, Jvic= 6.0 Hz, OCH2CH2CH2CH2CH2);

C-NMR (100 MHz, CDCl3):

192.3 (C=O), 152.8 (C-2), 152.0 (C-2), 142.0 (C-5), 139.8 (C-3), 137.7 (C-1),
131.8 (C-3), 132.1 (C-6), 128.7 (C-4), 119.7 (C-5), 128.3 (C-4), 122.4 (C-2), 114.8
(C-3),

68.6

(OCH2CH2CH2CH2CH2),

29.7

(OCH2CH2CH2CH2CH2),

28.1

(OCH2CH2CH2CH2CH2), 24.2 (OCH2CH2CH2CH2CH2), 19.5 (OCH2CH2CH2 CH2CH2);


MS: m/z (M+Na)+ 589 (100 %), (M+1)+ 567 (40.3 %), 283 (14.6 %), 255 (28.2 %), 241
(13.4 %), 214 (9.8 %), 175 (19.1 %), 148 (30.2 %), 122 (35.4 %); Anal. calc. for
C36H38O6: C, 76.32; H, 6.71; Found: C, 76.20; H, 6.65%.

Synthesis of 1,4-bis[1-(2-oxyphenyl)-5-(furan-2-yl)-4,5-dihydro-1H-pyrazole] butane


4.21
A mixture of 4.16 (0.5 g, 0.001 mol), phenyl hydrazine (0.75 ml, 0.00175 mol) and
glacial acetic acid (5.0 ml) in dry ethanol (25.0 ml) was refluxed for 10 hrs. The progress
of reaction was monitored by TLC. After completion the reaction, the reaction mixture
was cooled in an ice bath, to obtain a solid product. The crude substrate was crystallized
from MeOH to yield pure compound 4.21.
CH2

3"
2"

4"

6"
2

CH2

CH2

HM

HM

1"
5"

CH2

3'''

4
5

N
1N
1'

6'

HA

HX

2''' O
1'''

HA

4'''

5'''

HX

2'
3'

5'
4'

4.21
4.21: Brown solid, Yield 62%; m.p. 180-1820C; IR (KBr) max (cm-1): 3051 (aromatic
C-H), 1596 (C=N), 1240, 1056 (C-O); 1H-NMR (400 MHz, CDCl3): 7.82 (2H, dd,
Jm,o=2.2, 8.4Hz, H-6), 7.42 (2H, d, J5,4=2.0Hz, H-5), 7.30 (2H, d, J3,4=3.6Hz,
H-3), 7.21 (4H, m, H-4, 5), 7.16 (6H, m, H-2, 4, 6), 7.12 (4H, m, H-3, 5), 6.95
(2H, dd, J4,3=3.2Hz, J4,5=2.0Hz, H-4), 6.84 (2H, d, Jo=8.4Hz, H-3), 5.32 (2H,
dd, JXA=6.7Hz, JXM=11.6Hz, H-X), 3.98 (4H, t, Jvic=6.5Hz, OCH2CH2), 3.52 (2H, dd,
JMX=11.6Hz, JMA=16.7Hz, H-M), 3.34 (2H, dd, JAX=6.7Hz, JAX=16.7Hz, H-A), 1.96
(4H, quintet, Jvic=6.5Hz, OCH2CH2);

13

C-NMR (100 MHz, CDCl3): 158.2 (C=N),

152.4 (C-2), 151.6 (C-2), 150.4 (C-5), 146.5 (C-1), 134.9 (C-1), 132.4 (C-3),
131.4 (C-6), 130.6 (C-4), 128.1 (C-5), 127.8 (C-4), 127.0 (C-3, 5), 124.9 (C-4),
121.5 (C-2, 6), 118.4 (C-3), 67.3 (OCH2CH2), 58.7 (C-5), 45.2 (C-4), 24.6
(OCH2CH2); MS: m/z (M+) 662 (22.8 %), 660 (15.4 %), 606 (12.0 %), 529 (28.1 %), 345
(16.4 %), 317 (10.4 %), 315 (100 %), 248 (20.7 %); Anal. calc. for C42H38O4N4: C,
76.13; H, 5.74; N, 8.46; Found: C, 76.02; H, 5.79; N, 8.42%.

Synthesis

of

1,5-bis[1-(2-oxyphenyl)-5-(furan-2-yl)-4,5-dihydro-1H-pyrazole]

pantane 4.22
The compound 4.22 was obtained from the reaction of bischalcone 4.17 (0.5g, 0.00087
mol) with phenyl hydrazine (0.75ml, 0.00175 mol) under the similar conditions as used
earlier for 4.21.
CH2

3"
2"

4"

1"
5"
6"

HM
3 4

CH2

CH2

CH2

HM
H A3'''

HX

HA

4'''

CH2

2''' O
1'''

5'''

HX

1'
6'
5'

2'
3'
4'

4.22
4.22: Brown solid; Yield 67%; m.p. 173-1750C; IR (KBr) max (cm-1): 3048 (aromatic
C-H), 1599 (C=N), 1245, 1050 (C-O); 1H-NMR (400 MHz, CDCl3): 7.76 (2H, dd,
Jm,o=2.4, 8.5Hz, H-6), 7.48 (2H, d, J5,4=1.9Hz, H-5), 7.38 (2H, d, J3,4=3.5Hz,
H-3), 7.32 (4H, m, H-4, 5), 7.08 (4H, m, H-3, 5), 7.12 (6H, m, H-2, 4, 6), 6.87
(2H, dd, J4,3=3.2Hz, J4,5=1.9Hz, H-4), 6.80 (2H, d, Jo=8.4Hz, H-3), 5.39 (2H,
dd, JXA=6.7Hz, JXM=11.6Hz, H-X), 3.93 (4H, t, Jvic=6.5Hz, OCH2CH2CH2), 3.58 (2H,
dd, JMX=11.6Hz, JMA=16.7Hz, H-M), 3.39 (2H, dd, JAX=6.7Hz, JAM=16.7Hz, H-A), 1.94
(4H, quintet, Jvic=6.5Hz, OCH2CH2CH2), 1.68 (2H, quintet, Jvic=6.5Hz, OCH2CH2CH2);
13

C-NMR (100 MHz, CDCl3): 156.9 (C=N), 154.0 (C-2), 150.9 (C-2), 148.6

(C-5), 144.2 (C-1), 135.1 (C-1), 133.2 (C-3), 132.8 (C-6), 128.4 (C-4), 126.9
(C-5), 129.3 (C-4), 127.2 (C-3, 5), 125.9 (C-4), 120.4 (C-2, 6), 116.9 (C-3),
68.4

(OCH2CH2CH2),

55.1

(C-5),

47.0

(C-4),

25.8

(OCH2CH2CH2),

22.3

(OCH2CH2CH2); MS: m/z (M+1+) 677 (100 %), (M)+ 676 (55.6 %), 674 (22.4 %), 606
(16.0 %), 544 (35.4 %), 359 (28.5 %), 317 (20.2 %), 315 (60.0 %), 248 (26.8 %); Anal.
calc. for C43H40O4N4: C, 76.33; H, 5.91; N, 8.28; Found: C, 76.21; H, 5.88; N, 8.24%.

Synthesis of 1,6-bis[1-(2-oxyphenyl)-5-(furan-2-yl)-4,5-dihydro-1H-pyrazole] hexane


4.23
The compound 4.23 was prepared from the reaction of bischalcone 4.18 (0.5g, 0.00087
mol) with phenyl hydrazine (0.75ml, 0.00175 mol) under the similar conditions as used
earlier for 4.21.

2"

4"

1"
5"
6"

HM
3 4

5'

CH2

CH2

CH2

CH2

O
HM

H A3'''

HA

4'''

6'

CH2

CH2

3"

N H 2''' O1'''
X
1'
2'

5'''

HX

3'
4'

4.23
4.23: Dark Brown solid; Yield 70%; m.p. 165-1670C; IR (KBr) max (cm-1): 3048
(aromatic C-H), 1602 (C=N), 1245, 1050 (C-O); 1H-NMR (400 MHz, CDCl3): 8.00
(2H, dd, Jm,o=2.2, 8.4Hz, H-6), 7.51 (2H, d, J5,4=1.8Hz, H-5), 7.36 (2H, d,
J3,4=3.4Hz, H-3), 7.34 (4H, m, H-4, 5), 7.02 (4H, m, H-3, 5), 7.06 (6H, m,
H-2, 4, 6), 6.82 (2H, dd, J4,3=3.4Hz, J4,5=1.8Hz, H-4), 6.76 (2H, d, Jo=8.4Hz,
H-3), 5.31 (2H, dd, JXA=6.7Hz, JXM=11.6Hz, H-X), 3.90 (4H, t, Jvic=6.5Hz,
OCH2CH2CH2), 3.63 (2H, dd, JMX=11.6Hz, JMA=16.7Hz, H-M), 3.43 (2H, dd,
JAX=6.7Hz, JAM=16.7Hz, H-A), 1.88 (4H, quintet, Jvic=6.5Hz, OCH2CH2CH2), 1.60 (4H,
quintet, Jvic=6.5Hz, OCH2CH2CH2);

13

C-NMR (100 MHz, CDCl3): 156.3 (C-2),

155.1 (C=N), 152.8 (C-2), 149.7 (C-5), 145.1 (C-1), 135.8 (C-1), 131.8 (C-3),
130.9 (C-6), 129.7 (C-4), 127.2 (C-4), 126.3 (C-5), 126.6 (C-4), 125.1 (C-3, 5),
119.2 (C-2, 6), 117.2 (C-3), 66.7 (OCH2CH2CH2), 56.3 (C-5), 46.6 (C-4), 26.2
(OCH2CH2CH2), 24.9 (OCH2CH2CH2); MS: m/z (M+Na)+ 713 (100 %), (M+2)+ 692
(40.4 %), 688 (24.4 %), 606 (19.2 %), 558 (31.6 %), 373 (20.5 %), 317 (28.3 %), 315
(44.7 %), 248 (19.3 %); Anal. calc. for C44H42O4N4: C, 76.52; H, 6.08; N, 8.11; Found:
C, 76.64, H, 6.04, N, 8.08%.

Synthesis of 1,8-bis[1-(2-oxyphenyl)-5-(furan-2-yl)-4,5-dihydro-1H-pyrazole] octane


4.24
The compound 4.24 was synthesized from the reaction of bischalcone 4.19 (0.5 g,
0.00087 mol) with phenyl hydrazine (0.75 ml, 0.00175 mol) under the similar conditions
as used earlier for 4.21.

CH2

3"
2"

4"

1"
5"
6"

HM
3 4

5'

CH2

CH2

CH2

CH2 CH2

CH2

O
HM

HA

3'''

N H
X
1'
2'

2'''

HA

4'''

6'

CH2

5'''

O
1'''

HX

3'
4'

4.24
4.24: Light brown; Yield 64%; m.p. 174-1760C; IR (KBr) max (cm-1): 3082
(aromatic C-H), 1592 (C=N), 1240, 1032 (C-O); 1H-NMR (400 MHz, CDCl3): 7.94
(2H, dd, Jm,o=2.2, 8.4Hz, H-6), 7.58 (2H, d, J5,4=1.8Hz, H-5), 7.49 (2H, d,
J3,4=3.5Hz, H-3), 7.39 (4H, m, H-4, 5), 7.01 (6H, m, H-2, 4, 6), 6.92 (4H, m,
H-3, 5), 6.79 (2H, dd, J4,3=3.5Hz, J4,5=1.8Hz, H-4), 6.77 (2H, d, Jo=8.4Hz,
H-3), 5.42 (2H, dd, JXA=6.7Hz, JXM=11.6Hz, H-X), 3.68 (4H, t, Jvic=6.5Hz,
OCH2CH2CH2CH2), 3.51 (2H, dd, JMX=11.6Hz, JMA=16.7Hz, H-M), 3.24 (2H, dd,
JAX=6.7Hz, JAX=16.7Hz, H-A), 1.84 (4H, quintet, Jvic=6.5Hz, OCH2CH2CH2CH2), 1.43
(4H, quintet, Jvic=6.5Hz, OCH2CH2CH2CH2), 1.31 (4H, quintet, Jvic= 6.5 Hz,
OCH2CH2CH2CH2); 13C-NMR (100 MHz, CDCl3): 154.8 (C=N), 151.1 (C-2), 150.7
(C-2), 148.3 (C-5), 144.5 (C-1), 136.3 (C-1), 132.7 (C-3), 130.4 (C-6), 128.0
(C-4), 127.6 (C-5), 122.3 (C-4), 126.1 (C-3, 5), 128.2 (C-4), 118.7 (C-2, 6),
117.4 (C-3), 68.8 (OCH2CH2CH2), 55.9 (C-5), 45.8 (C-4), 25.9 (OCH2CH2CH2CH2),
21.4 (OCH2CH2CH2CH2), 19.8 (OCH2CH2CH2CH2); MS: m/z (M+2)+ 720 (100 %),
(M+1)+ 719 (30.3 %), 716 (19.8 %), 606 (10.6 %), 586 (22.5 %), 387 (13.7 %), 331 (32.6
%), 315 (40.6 %), 248 (29.6 %); Anal. calc. for C46H46O4N4: C, 76.88; H, 6.41; N, 7.80;
Found: C, 77.12; H, 6.35; N, 7.84%.

Synthesis

of

1,10-bis[1-(2-oxyphenyl)-5-(furan-2-yl)-4,5-dihydro-1H-pyrazole]

decane 4.25
The compound 4.25 was obtained from the reaction of bischalcone 4.20 (0.5 g, 0.00087
mol) with phenyl hydrazine (0.75 ml, 0.00175 mol) under the similar conditions as used
earlier for 4.21.

4"

2"
1"

5"
6"

CH2

3"

HM

CH2

CH2

CH2 CH2

CH2

CH2

CH2

CH2
HM

3'''

3 4
HA
2N 1 5
2''' O
N H
X
1'''
1'
6'
2'
5'

CH2

HA

4'''

5'''

HX

3'
4'

4.25
4.25: Light brown solid; Yield 66%; m.p. 182-1840C; IR (KBr) max (cm-1): 3130
(aromatic C-H), 1602 (C=N), 1240, 1032 (C-O); 1H-NMR (400 MHz, CDCl3): 7.87
(2H, dd, Jm,o=2.2, 8.4Hz, H-6), 7.61 (2H, d, J5,4=1.9Hz, H-5), 7.51 (2H, d,
J3,4=3.4Hz, H-3), 7.31 (4H, m, H-4, 5), 6.97 (4H, m, H-3, 5), 7.02 (6H, m,
H-2, 4, 6), 6.90 (2H, dd, J4,3=3.4Hz, J4,5=1.9Hz, H-4), 6.78 (2H, d, Jo=8.4Hz,
H-3), 5.45 (2H, dd, JXA=6.7Hz, JXM=11.6Hz, H-X), 3.61 (4H, t, Jvic=6.5Hz,
OCH2CH2CH2CH2CH2), 3.54 (2H, dd, JMX=11.6Hz, JMA=16.7Hz, H-M), 3.34 (2H, dd,
JAX=6.7Hz, JAM=16.7Hz, H-A), 1.79 (4H, quintet, Jvic=6.5Hz, OCH2CH2CH2CH2CH2),
1.73 (4H, quintet, Jvic=6.5Hz, OCH2CH2CH2CH2CH2), 1.49 (4H, quintet, Jvic=6.5Hz,
OCH2CH2CH2CH2CH2), 1.25 (4H, quintet,

Jvic=6.5Hz, OCH2CH2CH2CH2CH2);

13

C-NMR (100 MHz, CDCl3): 157.6 (C=N), 151.9 (C-2), 149.6 (C-5), 148.0

(C-2), 145.8 (C-1), 136.6 (C-1), 132.3 (C-6), 130.8 (C-3), 129.9 (C-4), 127.0
(C-5), 125.7 (C-4), 125.9 (C-3, 5), 127.2 (C-4), 120.9 (C-2, 6), 116.5 (C-3),
69.2 (OCH2CH2CH2CH2CH2), 57.4 (C-5), 46.1 (C-4), 29.8 (OCH2CH2CH2CH2CH2),
28.4

(OCH2CH2CH2CH2CH2),

24.7

(OCH2CH2CH2CH2CH2),

20.1

(OCH2CH2CH2CH2CH2); MS(ESI): m/z (M+Na)+ 769 (100 %), (M+1)+ 747 (18.4 %),
744 (24.4 %), 614 (24.3 %), 606 (15.2 %), 415 (9.4 %), 331 (29.6 %), 315 (28.2 %), 248

(14.7 %); Anal. calc. for C48H50O4N4: C, 77.21; H, 6.70; N, 7.50; Found: C, 77.10; H,
6.66; N, 7.46%.

Synthesis

of

1,4-bis[(2E)-1-(2-oxyphenyl)-3-(thiophene-2-yl)

prop-2-en-1-one]

butane 4.26
A suspension of chalcone 2.78 (2.0 g, 0.0086 mol), 1,4-dibromobutane (0.93 g, 0.0043
mol), anhydrous K2CO3 (1.0 g) and tetra butyl ammonium iodide (1.0 g) in dry acetone
was refluxed with continuous stirring for 6 hrs. The progress of reaction was monitored
by TLC. After the completion of reaction, the reaction mixture was poured into iced HCl
to provide a solid product which was recrystallized from CHCl3:MeOH (1:1) to yield
pure compound 4.26.
3'

CH2

CH2

4'

3"
1'

5'

CH2

CH2

2'
2

2"

1
6'

4"

5"

1"

4.26
4.26: Light brown; Yield 76%; m.p. 128-1300C; IR (KBr) max (cm-1): 3066 (aromatic
C-H), 1652 (C=O), 1602 (C=C), 1248, 1050 (C-O); 1H-NMR (400 MHz, CDCl3): 7.72
(2H, d, Jtrans=15.4Hz, H-3), 7.63 (2H, dd, Jm,o=2.3, 6.6Hz, H-6), 7.61 (2H, m, H-5),
7.58 (4H, ddd, Jp,m,o=0.7, 1.8, 8.4Hz, H-4, 5), 7.42 (2H, d, Jtrans=15.4Hz, H-2), 7.36
(2H, d, J3,4=3.4Hz, H-3), 7.22 (2H, dd, J4,5=4.9Hz, J4,3=3.4Hz, H-4), 6.86 (2H,
d, Jo=8.0Hz, H-3), 4.01 (4H, t, Jvic=6.4Hz, OCH2CH2), 2.07 (4H, quintet, Jvic=6.4Hz,
OCH2CH2); 13C-NMR (100 MHz, CDCl3): 190.8 (C=O), 151.6 (C-2), 149.9 (C-2),
142.6 (C-5), 139.4 (C-3), 135.3 (C-1), 131.2 (C-3), 130.9 (C-6), 126.8 (C-4), 122.9
(C-4), 118.5 (C-2), 116.2 (C-5), 112.6 (C-3), 67.6 (OCH2CH2), 25.2 (OCH2CH2); MS:
m/z (M+Na)+ 537 (100 %), (M+1)+ 515 (43.0 %), 257 (32.4 %), 230 (16.2 %), 175
(10.4 %), 148 (38.3 %), 122 (43.6 %); Anal. calc. for C30H26O4S2: C, 70.03; H, 5.05; S,
12.45; Found: C, 70.18; H, 5.02; S, 12.48 %.

Synthesis

of

1,5-bis[(2E)-1-(2-oxyphenyl)-3-(thiophene-2-yl)

prop-2-en-1-one]

pantane 4.27
The compound 4.27 was prepared from the reaction of chalcone 2.78 (2.0 g, 0.0086 mol)
with 1,5-dibromopentane (0.99 g, 0.0043 mol) under the similar conditions as used
earlier for 4.26.
3'
4'

CH2

2'

3"

1'
5'
6'

CH2

CH2

CH2

4"

2"

5"

S
3

CH2

1"

4.27
4.27: Brown solid; Yield 65%; m.p. 136-1380C; IR (KBr) max (cm-1): 3056
(aromatic C-H), 1656 (C=O), 1604 (C=C), 1246, 1048 (C-O); 1H NMR (400 MHz,
CDCl3): 7.66 (2H, d, Jtrans=15.6Hz, H-3), 7.57 (2H, dd, Jm,o=2.4, 7.8Hz, H-6), 7.54
(6H, m, H-4, 5, 5), 7.49 (2H, d, Jtrans=15.6Hz, H-2), 7.29 (2H, d, J3,4=3.6Hz, H-3),
7.18 (2H, m, H-4), 6.89 (2H, d, Jo=8.0Hz, H-3), 3.92 (4H, t, Jvic=6.6Hz,
OCH2CH2CH2), 2.01 (4H, quintet, Jvic=6.5Hz, OCH2CH2CH2), 1.60 (2H, quintet,
Jvic= 6.0Hz, OCH2CH2CH2); 13C-NMR (100 MHz, CDCl3): 191.4 (C=O), 150.6 (C-2),
147.8 (C-2), 140.8 (C-5), 138.6 (C-3), 135.9 (C-1), 131.3 (C-6), 130.2 (C-3), 128.7
(C-4), 122.1 (C-4), 119.6 (C-2), 116.9 (C-5), 114.9 (C-3), 66.9 (OCH2CH2CH2), 24.6
(OCH2CH2CH2), 22.8 (OCH2CH2CH2); MS: m/z (M+Na)+ 551 (100 %), (M+2)+ 530
(20.5 %), (M+1)+ 529 (32.8 %), 271 (42.1 %), 257 (53.4 %), 230 (30.8 %), 175 (12.6 %),
148 (27.3 %); Anal. calc. for C31H28O4S2: C, 70.45; H, 5.30; S, 12.12; Found: C, 70.65;
H, 5.19; S, 12.06%.

Synthesis of 1,6-bis[(2E)-1-(2oxyphenyl)-3-(thiophene-2-yl)prop-2-en-1-one] hexane


4.28
The compound 4.28 was obtained from the reaction of chalcone 2.78 (2.0 g, 0.0086 mol)
with 1,6-dibromohexane (1.06 g, 0.0043 mol) under the similar conditions as used earlier
for 4.26.

3'
4'

CH2

2'

5'
6'

1'

CH2
3"

CH2

CH2

2"

CH2

5"

CH2

4"

1"

4.28
4.28: Brown solid; Yield 80%; m.p. 110-1120C; IR (KBr) max (cm-1): 3092
(aromatic C-H), 1662 (C=O), 1604 (C=C), 1232, 1042 (C-O); 1H-NMR (400 MHz,
CDCl3): 7.67 (2H, dd, Jm,o=2.4, 7.7Hz, H-6), 7.63 (2H, d, Jtrans=15.4Hz, H-3), 7.59
(4H, ddd, Jp,m,o=0.7, 1.8, 8.0Hz, H-4, 5), 7.52 (2H, d, Jtrans=15.4Hz, H-2), 7.47 (2H, d,
J5,4=5.2Hz, H-5), 7.31 (2H, d, J3,4=3.6Hz, H-3), 7.19 (2H, dd, J4,5=5.2Hz,
J4,3=3.6Hz, H-4), 6.95 (2H, d, Jo=8.1Hz, H-3), 3.89 (4H, t, Jvic=6.1Hz,
OCH2CH2CH2), 1.96 (4H, quintet, Jvic=6.0Hz, OCH2CH2CH2), 1.54 (4H, quintet,
Jvic=6.1Hz, OCH2CH2CH2); 13C-NMR (100 MHz, CDCl3): 192.8 (C=O), 151.2 (C-2),
148.9 (C-2), 141.3 (C-5), 138.2 (C-3), 134.7 (C-1), 132.0 (C-6), 131.8 (C-3), 127.6
(C-4), 122.4 (C-2), 121.4 (C-4), 115.5 (C-5), 114.2 (C-3), 66.1 (OCH2CH2CH2), 29.0
(OCH2CH2CH2), 20.4 (OCH2CH2CH2); MS: m/z (M+Na)+ 565 (100 %), (M+1)+ 543
(40.0 %), 285 (25.2 %), 271 (42.3 %), 230 (53.4 %), 175 (36.0 %), 148 (58.2 %);
Anal. calc. for C32H30O4S2: C, 70.84; H, 5.53; S, 11.80; Found: C, 71.02; H, 5.56; S,
11.74%.

Synthesis of 1,8-bis[(2E)-1-(2-oxyphenyl)-3-(thiophene-2-yl) prop-2-en-1-one] octane


4.29
The compound 4.29 was synthesized from the reaction of chalcone 2.78 (2.0 g, 0.0086
mol) with 1,8-dibromooctane (1.18 g, 0.0043 mol)under the similar conditions as used for
4.29.
3'
4'

CH2

CH2

6'

CH2

CH2

CH2

CH2

CH2

4"

3"
1'

5'

CH2

2'

2"

1
3

5"

1"

4.29

4.29: Light brown solid; Yield 75%; m.p.120-1220C; IR (KBr) max (cm-1): 3090
(aromatic C-H), 1656 (C=O), 1605 (C=C), 1255, 1052 (C-O); 1H-NMR (400 MHz,
CDCl3): 7.69 (2H, d, Jtrans=15.6HZ, H-3), 7.53 (2H, dd, Jm,o=2.3, 7.8Hz, H-6), 7.49
(6H, m, H-4, 5, 5), 7.45 (2H, d, Jtrans=15.6Hz, H-2), 7.26 (2H, d, J3,4=3.5Hz, H-3),
7.24 (2H, m, H-4), 6.87 (2H, d, Jo=8.0Hz, H-3), 3.86 (4H, t, Jvic=6.1Hz,
OCH2CH2CH2CH2), 1.93 (4H, quintet, Jvis=6.0Hz, OCH2CH2CH2CH2), 1.49 (4H,
quintet, Jvic= 6.0 Hz, OCH2CH2CH2CH2), 1.32 (4H, m, OCH2CH2CH2CH2); 13C-NMR
(100 MHz, CDCl3): 191.7 (C=O), 150.8 (C-2), 148.4 (C-2), 141.7 (C-5), 134.2
(C-1), 137.4 (C-3), 131.8 (C-6), 130.5 (C-3), 127.9 (C-4), 120.7 (C-4), 120.9 (C-2),
115.2 (C-5), 113.6 (C-3), 65.8 (OCH2CH2CH2CH2), 29.8 (OCH2CH2CH2CH2), 22.0
(OCH2CH2CH2CH2), 19.3 (OCH2CH2CH2CH2); MS(ESI): m/z (M+Na)+ 593 (10.4 %),
(M+1)+ 571 (45.8 %), 341 (44.3 %), 327 (12.8 %), 285 (100 %), 271 (46.2 %), 230
(33.4 %), 175 (28.2 %), 148 (40.3 %); Anal. calc. for C34H34O4S2: C, 71.58; H, 5.96; S,
11.22; Found: C, 71.72; H, 5.99; S, 11.17%.

Synthesis

of

1,10-bis[(2E)-1-(2-oxyphenyl)-3-(thiophene-2-yl)prop-2-en-1-one]

decane 4.30
The compound 4.30 was prepared from the reaction of chalcone 2.78 (2.0 g, 0.0086 mol)
with 1,10-dibromodecane (1.30 g, 0.0043 mol) under the similar conditions as described
earlier for 4.26.
O

3'

CH2

CH2

CH2

CH2

CH2

CH2

CH2

CH2

CH2

CH2

2'

4'

6'

4"

3"

1'
5'

2"

1
3

5"

1"

4.30
4.30: Light brown solid; Yield 78%; m.p. 118-120oC; IR (KBr) max (cm-1): 3082
(aromatic C-H), 1668 (C=O), 1600 (C=C), 1248, 1040 (C-O); 1H-NMR (400 MHz,
CDCl3): 7.65 (2H, d, Jtrans=15.4Hz, H-3), 7.60 (2H, dd, Jm,o=2.4, 7.8Hz, H-6), 7.52
(6H, m, H-4, 5, 5), 7.34 (2H, d, Jtrans=15.4Hz, H-2), 7.24 (2H, d, J3,4=3.6Hz, H-3),
7.15 (2H, dd, J4,3=3.5Hz, J4,5=5.0Hz, H-4), 6.92 (2H, d, Jo=8.0Hz, H-3), 3.82 (4H,
t,

Jvic=6.0Hz,

OCH2CH2CH2CH2CH2),

1.88

(4H,

quintet,

Jvic=6.1Hz,

OCH2CH2CH2CH2CH2), 1.44 (4H, quintet, Jvic= 6.1Hz, OCH2CH2CH2CH2CH2), 1.29


(8H, m, OCH2CH2CH2CH2CH2); 13C-NMR (100 MHz, CDCl3): 192.5 (C=O), 150.3
(C-2), 148.0 (C-2), 142.1 (C-5), 137.9 (C-3), 135.0 (C-1), 131.6 (C-6), 131.4
(C-3), 127.3 (C-4), 121.8 (C-4), 120.6 (C-2), 115.8 (C-5), 112.7 (C-3), 65.1
(OCH2CH2CH2CH2CH2), 29.5 (OCH2CH2CH2CH2CH2), 28.4 (OCH2CH2CH2CH2CH2),
21.8 (OCH2CH2CH2CH2CH2), 19.1 (OCH2CH2CH2CH2CH2); MS: m/z (M+Na)+ 621
(38.2 %), (M+1)+ 599 (7.4 %), 299 (25.4 %), 271 (38.0 %), 257 (100 %), 230 (58.4 %),
175 (41.3 %), 148 (18.2 %); Anal. calc. for C36H38O4S2: C, 72.24; H, 6.35; S, 10.70;
Found: C, 72.41; H, 6.38; S, 10.76 %.

Synthesis

of

1,4-bis[1-(2-oxyphenyl)-5-(thiophene-2-yl)-4,5-dihydro-1H-pyrazole]

butane 4.31
A mixture of 4.16 (0.5 g, 0.00087 mol), phenyl hydrazine (0.75 ml, 0.00175 mol) and
glacial acetic acid (5.0 ml) in dry ethanol (25.0 ml) was refluxed for 8 hrs. The progress
of reaction was monitored by TLC. After completion the reaction, the reaction mixture
was cooled in an ice bath to obtain a solid product which was crystallized from MeOH to
yield pure compound.
CH2

3"
2"

4"

6"
2

CH2

CH2

HM

HM

1"
5"

CH2

3'''

4
5

N
1N
1'

6'

HA

HX

2''' S
1'''

HA

4'''
5'''

HX

2'
3'

5'
4'

4.31
4.31: Light brown solid; Yield 63%; m.p. 185-1870C; IR (KBr) max (cm-1): 3055
(aromatic C-H), 1595 (C=N), 1245, 1053 (C-O); 1H-NMR (400 MHz, CDCl3): 7.86
(2H, dd, Jm,o=2.2, 8.4Hz, H-6), 7.48 (2H, d, J5,4=5.0Hz, H-5), 7.38 (2H, d,
J3,4=3.6Hz, H-3), 7.31 (4H, m, H-4, 5), 7.19 (4H, m, H-3, 5), 7.13 (6H, m,
H-2, 4, 6), 6.99 (2H, dd, J4,3=3.2Hz, J4,5=5.0Hz, H-4), 6.90 (2H, d, Jo=8.4Hz,
H-3), 5.39 (2H, dd, JXA=6.7Hz, JXM=11.6Hz, H-X), 3.99 (4H, t, Jvic=6.5Hz, OCH2CH2),
3.56 (2H, dd, JMX=11.6Hz, JMA=16.7Hz, H-M), 3.36 (2H, dd, JAX=6.7Hz, JAX=16.7Hz,

H-A), 1.98 (4H, quintet, Jvic=6.5Hz, OCH2CH2); 13C-NMR (100 MHz, CDCl3): 158.9
(C=N), 154.6 (C-2), 153.6 (C-2), 152.8 (C-5), 148.2 (C-1), 136.7 (C-1), 134.8
(C-3), 131.9 (C-6), 131.2 (C-4), 130.4 (C-5), 129.1 (C-4), 128.2 (C-3, 5),
125.4 (C-4), 122.6 (C-2, 6), 120.4 (C-3), 68.6 (OCH2CH2), 59.2 (C-5), 47.9 (C-4),
25.2 (OCH2CH2); MS: m/z (M+2)+ 696 (30.8 %), (M+) 694 (22.8 %), 692 (25.6 %), 638
(100 %), 361 (25.2 %), 333 (14.8 %), 331 (40.3 %), 254 (18.1 %); Anal. calc. for
C42H38O2N4S2: C, 72.62; H, 5.47; N, 8.06; S, 9.22; Found: C, 72.80; H, 5.43; N, 8.09;
S, 9.26 %.

Synthesis

of

1,5-bis[1-(2-oxyphenyl)-5-(thiophene-2-yl)-4,5-dihydro-1H-pyrazole]

pantane 4.32
The compound 4.32 was obtained from the reaction of bischalcone 4.17 (0.5 g, 0.00087
mol) with phenyl hydrazine (0.75 ml, 0.00175 mol) under the similar conditions as used
earlier for 4.31.
CH2

3"
2"

4"

1"
5"
6"

HM
3 4

CH2

CH2

CH2

HM
H A3'''

HX

HA

4'''

CH2

2''' S
1'''

5'''

HX

1'
6'
5'

2'
3'
4'

4.32
4.32: Brown solid; Yield 60%; m.p. 214-2160C; IR (KBr) max (cm-1): 3049 (aromatic
C-H), 1598 (C=N), 1248, 1053 (C-O); 1H-NMR (400 MHz, CDCl3): 7.89 (2H, dd,
Jm,o=2.4, 8.5Hz, H-6), 7.56 (2H, d, J5,4=4.9Hz, H-5), 7.44 (2H, d, J3,4=3.5Hz,
H-3), 7.38 (4H, m, H-4, 5), 7.22 (6H, m, H-2, 4, 6), 7.09 (4H, m, H-3, 5), 6.92
(2H, dd, J4,3=3.2Hz, J4,5=4.9Hz, H-4), 6.84 (2H, d, Jo=8.4Hz, H-3), 5.47 (2H,
dd, JXA=6.7Hz, JXM=11.6Hz, H-X), 3.88 (4H, t, Jvic=6.5Hz, OCH2CH2CH2), 3.65 (2H,
dd, JMX=11.6Hz, JMA=16.7Hz, H-M), 3.45 (2H, dd, JAX=6.7Hz, JAM=16.7Hz, H-A), 1.90
(4H, quintet, Jvic=6.5Hz, OCH2CH2CH2), 1.73 (2H, quintet, Jvic=6.5Hz, OCH2CH2CH2);
13

C-NMR (100 MHz, CDCl3): 157.9 (C=N), 155.3 (C-2), 154.8 (C-2), 148.9

(C-5), 147.0 (C-1), 135.9 (C-1), 135.2 (C-3), 132.2 (C-6), 130.2 (C-4), 128.6
(C-4), 128.3 (C-5), 127.5 (C-3, 5), 126.2 (C-4), 121.8 (C-2, 6), 119.6 (C-3),

67.4

(OCH2CH2CH2),

59.8

(C-5),

48.3

(C-4),

25.6

(OCH2CH2CH2),

23.9

(OCH2CH2CH2); MS: m/z (M+Na)+ 731 (100 %), (M)+ 708 (8.9 %), 706 (30.2 %), 638
(73.8 %), 375 (10.4 %), 361 (15.3 %), 345 (20.9 %), 331 (30.4 %), 254 (19.1 %);
Anal. calc. for C43H40O2N4S2: C, 72.88; H, 5.65; N, 7.90; S, 9.03; Found: C, 72.70; H,
5.68; N, 7.94; S, 9.06 %.

Synthesis

of

1,6-bis[1-(2-oxyphenyl)-5-(thiophene-2-yl)-4,5-dihydro-1H-pyrazole]

hexane 4.33
The compound 4.33 was prepared from the reaction of bischalcone 4.18 (0.5g, 0.00087
mol) with phenyl hydrazine (0.75ml, 0.00175 mol) under the similar conditions as used
earlier for 4.31.

2"

4"

1"
5"
6"

CH2

CH2

3"

HM
3 4

CH2

CH2

HA

4'''

N H 2''' S1'''
1
X
1'
6'
2'
5'

CH2

HM
H A3'''

CH2

5'''

HX

3'
4'

4.33
4.33: Dark Brown; Yield 67%; m.p. 225-2270C; IR (KBr) max (cm-1): 3050 (aromatic
C-H), 1604 (C=N), 1240, 1060 (C-O); 1H-NMR (400 MHz, CDCl3): 8.02 (2H, dd,
Jm,o=2.2, 8.4Hz, H-6), 7.74 (2H, d, J5,4=5.0Hz, H-5), 7.48 (2H, d, J3,4=3.4Hz,
H-3), 7.34 (4H, m, H-4, 5), 7.28 (6H, m, H-2, 4, 6), 6.98 (4H, m, H-3, 5), 6.89
(2H, dd, J4,3=3.4Hz, J4,5=5.0Hz, H-4), 6.81 (2H, d, Jo=8.4Hz, H-3), 5.39 (2H,
dd, JXA=6.7Hz, JXM=11.6Hz, H-X), 3.83 (4H, t, Jvic=6.5Hz, OCH2CH2CH2), 3.69 (2H,
dd, JMX=11.6Hz, JMA=16.7Hz, H-M), 3.49 2H, dd, JAX=11.6Hz, JAM=16.7Hz, H-A), 1.87
(4H, quintet, Jvic=6.5Hz, OCH2CH2CH2), 1.69 (4H, quintet, Jvic=6.5Hz, OCH2CH2CH2);
13

C-NMR (100 MHz, CDCl3): 157.2 (C=N), 154.4 (C-2), 156.9 (C-2), 149.0

(C-5), 146.4 (C-1), 136.3 (C-1), 135.9 (C-3), 131.0 (C-6), 130.7 (C-4), 128.9
(C-5), 128.5 (C-4), 127.8 (C-3, 5), 126.8 (C-4), 120.9 (C-2, 6), 118.5 (C-3),
69.2

(OCH2CH2CH2),

59.6

(C-5),

48.9

(C-4),

26.1

(OCH2CH2CH2),

24.3

(OCH2CH2CH2); MS: m/z (M+2)+ 724 (20.4 %), (M)+ 722 (100 %), 720 (13.5 %), 638
(53.2 %), 389 (9.2 %), 333 (26.3 %), 345 (10.4 %), 331 (4.6 %), 254 (12.2 %); Anal.
calc. for C44H42O2N4S2: C, 73.13; H, 5.81; N, 7.75; S, 8.86; Found: C, 73.30; H, 5.78; N,
7.71; S, 8.89 %.

Synthesis

of

1,8-bis[1-(2-oxyphenyl)-5-(thiophene-2-yl)-4,5-dihydro-1H-pyrazole]

octane 4.34
The compound 4.34 was synthesized from the reaction of bischalcone 4.19 (0.5 g,
0.00087 mol) with phenyl hydrazine (0.75 ml, 0.00175 mol) under the similar conditions
as used earlier for 4.31.

CH2

3"
2"

4"

1"
5"
6"

HM
3 4

5'

CH2

CH2

CH2

CH2 CH2

CH2

O
HM

HA

3'''

N H
X
1'
2'

2'''

HA

4'''

6'

CH2

5'''

S
1'''

HX

3'
4'

4.34
4.34: Light brown solid; Yield 60%; m.p. 230-2320C; IR (KBr) max (cm-1): 3080
(aromatic C-H), 1596 (C=N), 1242, 1035 (C-O); 1H-NMR (400 MHz, CDCl3): 7.97
(2H, dd, Jm,o=2.2, 8.4Hz, H-6), 7.67 (2H, d, J5,4=4.8Hz, H-5), 7.59 (2H, d,
J3,4=3.5Hz, H-3), 7.45 (4H, m, H-4, 5), 7.21 (6H, m, H-2, 4, 6), 7.06 (4H, m,
H-3, 5), 6.95 (2H, dd, J4,3=3.5Hz, J4,5=4.8Hz, H-4), 6.78 (2H, d, Jo=8.4Hz,
H-3), 5.49 (2H, dd, JXA=6.7Hz, JXM=11.6Hz, H-X), 3.73 (4H, t, Jvic=6.5Hz,
OCH2CH2CH2CH2), 3.56 (2H, dd, JMX=11.6Hz, JMA=16.7Hz, H-M), 3.20 (2H, dd,
JAX=6.7Hz, JAX=16.7Hz, H-A), 1.79 (4H, quintet, Jvic=6.5Hz, OCH2CH2CH2CH2), 1.47
(4H, quintet, Jvic=6.5Hz, OCH2CH2CH2CH2), 1.36 (4H, quintet, Jvic= 6.5 Hz,
OCH2CH2CH2CH2); 13C-NMR (100 MHz, CDCl3): 158.3 (C=N), 153.2 (C-2), 156.1
(C-2), 148.3 (C-5), 145.8 (C-1), 136.9 (C-1), 134.2 (C-3), 131.3 (C-6), 130.1
(C-5), 129.4 (C-4), 127.7 (C-4), 127.1 (C-3, 5), 125.9 (C-4), 119.6 (C-2, 6),
118.7

(C-3),

68.3

(OCH2CH2CH2CH2),

58.2

(C-5),

48.1

(C-4),

26.3

(OCH2CH2CH2CH2), 20.5 (OCH2CH2CH2CH2), 19.1 (OCH2CH2CH2CH2); MS: m/z


(M+2)+ 752 (100 %), (M+) 750 (30.1 %), 748 (9.3 %), 638 (69.4 %), 417 (13.9 %), 345
(12.8 %), 331 (6.9 %), 254 (18.7 %); Anal. calc. for C46H46O2N4S2: C, 73.60; H, 6.13; N,
7.46; S, 8.56; Found: C, 73.45; H, 6.17; N, 7.43; S, 8.60%.

Synthesis of 1,10-bis[1-(2-oxyphenyl)-5-(thiophene-2-yl)-4,5-dihydro-1H-pyrazole]
decane 4.35
The compound 4.35 was obtained from the reaction of bischalcone 4.20 (0.5g, 0.00087
mol) with phenyl-hydrazine (0.75ml, 0.00175 mol) under the similar conditions as used
earlier for 4.31.

2"
1"

5"
6"

CH2

3"
4"

HM

CH2

CH2

CH2 CH2

CH2

CH2

CH2

CH2
HM

3'''

3 4
HA
5
2N 1
2''' S
N H
X
1'''
1'
6'
2'
5'

CH2

HA

4'''

5'''

HX

3'
4'

4.35
4.35: Light brown; Yield 65%; m.p. 182-1840C; IR (KBr) max (cm-1): 3137
(aromatic C-H), 1602 (C=N), 1245, 1039 (C-O); 1H-NMR (400 MHz, CDCl3): 7.96
(2H, dd, Jm,o=2.2, 8.4Hz, H-6), 7.75 (2H, d, J5,4=4.9Hz, H-5), 7.62 (2H, d,
J3,4=3.4Hz, H-3), 7.40 (4H, m, H-4, 5), 7.03 (4H, m, H-3, 5), 7.16 (6H, m,
H-2, 4, 6), 6.98 (2H, dd, J4,3=3.4Hz, J4,5=4.9Hz, H-4), 6.86 (2H, d, Jo=8.4Hz,
H-3), 5.59 (2H, dd, JXA=6.7Hz, JXM=11.6Hz, H-X), 3.67 (4H, t, Jvic=6.5Hz,
OCH2CH2CH2CH2CH2), 3.52 (2H, dd, JMX=11.6Hz, JMA=16.7Hz, H-M), 3.45 (2H, dd,
JAX=6.7Hz, JAM=16.7Hz, H-A), 1.95 (4H, quintet, Jvic=6.5Hz, OCH2CH2CH2CH2CH2),
1.79 (4H, quintet, Jvic=6.5Hz, OCH2CH2CH2CH2CH2), 1.58 (4H, quintet, Jvic=6.5Hz,
OCH2CH2CH2CH2CH2), 1.16 (4H, quintet,

Jvic=6.5Hz, OCH2CH2CH2CH2CH2);

13

C-NMR (100 MHz, CDCl3): 157.6 (C=N), 155.5 (C-2), 153.0 (C-2), 147.3

(C-5), 146.9 (C-1), 135.3 (C-1), 132.7 (C-6), 133.6 (C-3), 128.6 (C-4), 127.4
(C-5), 126.7 (C-4), 126.3 (C-3, 5), 127.8 (C-4), 120.1 (C-2, 6), 119.9 (C-3),
68.4 (OCH2CH2CH2CH2CH2), 58.1 (C-5), 45.3 (C-4), 28.4 (OCH2CH2CH2CH2CH2),

27.8

(OCH2CH2CH2CH2CH2),

23.3

(OCH2CH2CH2CH2CH2),

19.3

(OCH2CH2CH2CH2CH2); MS: m/z (M+Na)+ 801 (20.4 %), (M+1)+ 779 (6.4 %), (M)+
778 (13.3 %), 776 (60.4 %), 638 (24.2 %), 445 (19.4 %), 331 (28.4 %), 254 (48.9 %);
Anal. calc. for C48H50O2N4S2: C, 74.03; H, 6.43; N, 7.19; S, 8.22; Found: C, 74.20; H,
6.39; N, 7.22; S, 8.18%.

REFERENCES
1. Bart, S.; Halkes, A.; Vrasidas, I. and Rooijer, G. R. Bioorg. Med. Chem. Lett. 2002,
12, 1567.
2. Dhar, D. N. The Chemistry of Chalcones and Related Compounds, John Wiley &
Sons, New York 1981.
3. Grayer, R. J. Methods in Plant Biochemistry, vol. 1 (Eds.: P. M. Dey, J. B. Harborne),
Academic Press, London 1989, 283.
4. Bohm, B. A. Methods in Plant Biochemistry, vol. 1 (Eds.: P. M. Dey, J. B. Harborne),
Academic Press, London 1989, 237.
5. (a) Krutosikova, A.; Uher, M. Natural and Synthetic Sweet Substances (Translation,
Ed.: J. Hudec), Ellis Horwood, New York 1992, 99; (b) Duboism, G. E.; Crosby, G.
A.; Stephenson, R. A. and Wingard, Jr. R. E. J. Agric. Food Chem. 1977, 25, 763.
(c) Dubois, G. E.; Crosby, G. A. and Stephenson, R. A. J. Med. Chem. 1981, 24, 408.
(d) Kinghorn, A. D. and Kennelly, E. J. J. Chem. Educ. 1995, 72, 676.
6. Bohm, B. A. The Flavonoids-Advances in Research Since 1986 (Ed.: J. B. Harborne),
Chapman and Hall, London 1994, 387.
7. Harborne, J. B. and Williams, C. A. Phytochemistry 2002, 55, 481.
8. Parmar, V. S.; Bisht, K. S.; Jain, R.; Singh, S.; Sharma, S. K.; Gupta, S.; Malhotra, S.;
Tyagi, O. D.; Vardhan, A.; Pati, H. N.; Berghe, D. V. and Vlietinck, A. J. Ind. J.
Chem. 1996, 35B, 220.
9. (a) Lewis, D. A. Chem. Br. 1992, 141. (b) Esaki, S.; Nishiyama, K.; Sugiyama, N.;
Nakajima, R.; Takao, Y. and Kamiya, S. Biosci. Biotech. Biochem. 1994, 58 1479.
(c) Bois, F.; Beney, C.; Boumendjel, A.; Mariotte, A.-M.; Conseil, G. and Pietro, A.
Di. J. Med. Chem. 1998, 41, 4161.
10. Gadow, A.; Joubert, E. and Hansmann, C. F. J. Agric. Food Chem. 1997, 45, 632.
11. (a). Pincemail, J.; Deby, C.; Drieu, K.; Anton, R. and Goutier, R. Proceedings of the
3rd International Symposium on Flavonoids in Biology and Medicine, Singapore,
1989, 161; (b). Jovanovic, S. V.; Steenken, S.; Tosic, M.; Marjanovic, B. and Simic,
M. G. J. Am. Chem. Soc. 1994, 116, 4846. (c) Bors, W.; Heller, W.; Michel, C. and
Stettmaier, K. in Handbook of Antioxidants (Eds.: E. Cadenas, L. Packer), Marcel
Dekker, New York 1996, 409. (d) Rice-Evans, C. A.; Miller, N. J. and Paganga, G.

Free Rad. Biol. Med. 1996, 20, 933.


12. Tomilovi, Y. V.; Okonnishnikova, G. P.; Shulishov, E. V. and Nefedov, O. M. Russ.
Chem. Bull. 1995, 44, 2114.
13. Klimova, E. I.; Marcos, M.; Klimova, T. B., Cecilio, A. T.; Ruben, A. T. and Lena, R.
R. J. Organomet. Chem. 1999, 585, 106.
14. Bhaskarreddy, D.; Padmaja, A.; Ramanareddy, P. V. and Seenaiah, B. Sulfur Lett.
1993, 16, 227.
15. Padmavathi, V.; Sumathi, R. P.; Chandrasekhar, B. N. and Bhaskarreddy, D. J. Chem.
Res. 1999, 610.
16. Bhaskarreddy, D.; Chandrasekhar, B. N.; Padmavathi, V. and Sumathi, R. P.
Synthesis 1998, 491.
17. Knorr, L. B. Dt. Chem. Ges. 1893, 26, 100.
18. Thakare, V. G. and Wadodkar, K. N. Ind. J. Chem. Sect.B 1986, 25, 610.
19. Ankhiwala, M. D. and Hathi, M. V. J. Ind. Chem. Soc. 1994, 71, 587.
20. Vounauwers, K. and Muller, B. Dt. Chem. Ges. 1908, 41, 4230.
21. Baker, A. and Butt, V. S. J. Chem. Soc. 1949, 2142.
22. Bauer, H. and Piatert, G. German Patent, (DOS) 3039311, 1981; Chem Abstr. 1981,
95, 63146.
23. Evans, N. A. and Waters, P. J. J. Soc. Dyers Colour 1978, 94, 252.
24. Murayama, T. New Mater. New Processes Electrochem.Technol. 1981, 1, 92.
25. Poduzhailo, V. F.; Pareyaslova, D. F.; Shripkina, V. I.; Verezubora, S. A. and
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CHAPTER-IVb
Synthesis of New Nthiocarbamoyl-bispyrazolines

Synthesis and in-vitro antibacterial activity of some bis-5-(thiophen-2-yl)carbothioamide-pyrazoline derivatives


Mamta Rani and Mohamad Yusuf
European Journal of Chemistry 2012 (Accepted Manuscript, MS No. 476-34622-CE -1).

The study of heterocyclic systems has attracted the attention of organic chemists in the
past decades because of their natural occurrence and large numbers of their derivatives
are essential to human life in various fashions. Many of these molecules exhibit
numerous beneficial biological activity like anti-inflammatory1 and anti-invasive.2
Pyrazolines have gained much interest because of wide range of applications in clinical
and pharmaceutical chemistry such as bacterial,3 depression,4 pyretic and antiinflammatory,1 and many industrial applications.5-9 Thus chalcones10-13 are the valuable
synthones for the synthetic organic chemist and with proper planning and designing these
molecules can be subjected to the synthesis of many exotic heterocyclic compounds.
Bischalcones10,14-17 are the molecules which are formed by joining two chalcone moieties
together through the carbon chains of varying lengths and structures.
1-Benzimidazolyl-3-aryl-prop-2-ene-1-ones

4.36

have

been

transformed

into

substituted pyrazoline derivatives18 by reacting with phenyl hydrazine, hydrazine hydrate


in the presence of formic acid under solvent free microwave induced protocol to give
4.37 and 4.38 respectively while the reaction of 4.36 with thiosemicarbazide could
provide 4.39 (Scheme-4.9).
Ar

ArCHO, M. W.

CH3
N
H

N
4.36 H

O
PhNHNH2

N
N
H

Anhd. K2CO3; NH2CSNHNH2

NH2NH2/ HCOOH

Ar
N

Ar

Ar
N
H

Ph

CHO

4.38

4.37

N
H

N
4.39

NH2

N
S

Scheme-4.9

In the earlier chapter (4a), syntheses of N-phenyl-bispyrazolines have been described. It


would

be

advantageous

here

to

investigate

the

synthesis

of

N-thiocarabamoyl-bispyrazolines. The major interest in this study was how the


replacement of phenyl by thiocarbamoyl group would affect the formation and
antibacterial behaviour of the the resulting bisheterocyclic compounds 4.40-4.44.

CH2

(CH2) n

CH2

HM

HM
HA

HA

Ar

Ar

N H
X
C S

N
HX
S C

NH2

NH2
Ar =
O

n = 2,
4.40

3,
4.41

4,
4.42

6,
4.43

8
4.44

The bispyrazolines 4.40-4.44 needed for this study was obtained from the
cyclocondensation reactions of bischalcones 4.16-4.20 with thiosemicarbazide by
refluxing under EtOH/NaOH medium. The structures of the prepared compounds were
determined from the rigorous analysis of their spectral data (IR, 1H-NMR,

13

C-NMR &

ESI-MS).

Synthesis of N-thiocarbamoyl-bispyrazoline 4.40


The compound 4.16 was refluxed with thiosemicarbazide in EtOH/NaOH medium and
resulting reaction mixture was poured into crushed ice to obtain a solid product
(Scheme-4.11). The crude substrate was crystallized from MeOH to yield pure
compound 4.40 (68%, m.p. 195-1970C).

3'
4'

CH2

CH2

2'
1'

5'

2"

6'

CH2

5"
O
1"

CH2

4"

3"

4.16
S
H 2N C

CH2

3'
2'

4'

6'
2

/EtOH/ NaOH/

CH2

CH2

4
5

CH2

HM

HM

1'
5'

NH NH 2

HA

3''

2''

1N

HX

HA

4''

5''

1''

HX

S C
NH2

NH2

4.40
Scheme-4.11

The IR spectrum of 4.40 had significant absorption bands at 3480, 3375, 1596 & 1148
cm-1 due to NH2, C=N and C=S groups respectively. 1H-NMR spectrum (400 MHz,
DMSO-d6) of 4.40 shows that resonances present at 7.60 (H-3) & 7.38 (H-2) in
compound 4.16 were found missing altogether in the former hereby describing the
involvement of these hydrogens in the chemical transformation. A broad singlet
integrating for 4Hs at 8.26 could be assigned to NH2 protons which were also
exchangeable with D2O. In the aromatic region, major resonances were placed at 7.53
(2H, dd, Jm,o=2.2, 7.7Hz, H-6), 7.45 (4H, m, H-4, 5), 7.38 (2H, d, J5,4=2.0Hz, H-5),
7.31 (2H, d, J3,4=3.2Hz, H-3), 7.08 (2H, dd, J4,3=3.2Hz, J4,5=2.0Hz, H-4) &
6.87 (2H, d, Jo=8.2Hz, H-3). The downfield placement of H-6 as compared to other
protons could be explained on the basis of its proximity to pyrazoline ring. The
pyrazoline ring protons (H-X, M & A) were found to be placed at 5.28 (2H, dd,
JXA=6.6Hz, JXM=11.4Hz), 3.40 (2H, dd, JMX=11.4Hz, JMA=16.4Hz) & 3.26 (2H, dd,
JAX=6.6Hz, JAM=16.7Hz) respectively. A triplet at 3.96 (4H) and a quintet at 1.90
(4H) were observed in the aliphatic region due to OCH2CH2 and OCH2CH2 groups
respectively.

13

C-NMR (100MHz, DMSO-d6) data of 4.40 was also very helpful to corroborate its

structure. The downfield signals present at 176.8, 154.8 & 152.6 were assignable to
C=S, C=N and C-2 respectively due to their placement adjacent to heteroatoms like S, N
& O respectively. Other aromatic carbon atoms were found to be placed at 148.3
(C-2), 136.8 (C-5), 134.2 (C-1), 131.2 (C-6), 130.9 (C-3), 129.2 (C-4), 127.8
(C-5), 126.7 (C-4) & 115.8 (C-3). The pyrazoline rings carbons C-5 and C-4 were
present at 62.7 & 47.0 respectively and downfield resonance of former may be
attributed to its benzylic nature and its bonding to the nitrogen atom. The ESI-MS
spectrum of 4.40 had (M+1)+ and (M)+ ions at m/z 629 (100 %) & 628 (16.2 %)
respectively and its mass fragmentation pattern has been shown in Chart-1.
O

CH2

CH2

CH2

CH2

-----

-----

N H
S

(M + 1)
m/z 629 (100 %)

+.

CH2

CH2

+.

O
H

H
N

- (CH2)4

-----

H N
H2N

NH2

CH2

CH 2

CH2

m/z = 628 (16.2 %)

CH2

-2H

H2N

NH2

H N

m/z = 626 (25.7 %)


O

+.

H
H

N H

CH2

-C2H4

CH2

CH2

CH2

+.

N
H N

H2N

NH2

-(CSNH 2)2
NH2

OH

CH2

CH2

CH2

CH2

H
N

H
NH2

m/z 221 (10.0 %)

Chart-1

N H
N

+.

O
H

m/z 287 (10.8 %)

+.

+.

NH2

m/z = 546 (18.5 %)

-4H

N H

-----

H2N

m/z = 572 (10.3 %)

H
H

+.

O
H

H
H

OH

H N

NH2

S
O

N H

m/z 314 (40.4 %)

H.

NH2

N
H N
H

m/z = 424 (13.6 %)

N
H2N

m/z = 568 (90.2 %)

Synthesis of N-thiocarbamoyl-bispyrazoline 4.41


The compound 4.17 was refluxed with thiosemicarbazide (Scheme-4.13) under the
similar conditions as used earlier for 4.40 to yield 4.41 (61%, 182-1840C).

3'
4'

CH2

2'

CH2
3"

1'
5'

6'

CH2

CH2

CH2

4"

2"

5"

1"

4.17
S
H 2N C

CH2

3'
4'

NH NH 2

CH2

/EtOH/ NaOH/

CH2

CH2

CH2

2'
1'

5'
6'

3 4

HM

HM
HA

3''

N
1

N
C

HX

HA

4''

5''

O
1''

HX
S

N
C
NH 2

NH2

4.41
Scheme-4.13
The IR spectrum of 4.41 showed a strong absorption at 1594 cm-1 indicating the presence
of the C=N moiety of the pyrazoline ring and bands at 3460, 3356 & 1158 cm-1 appeared
due to NH2 & C=S group respectively. A comparison of the 1H-NMR spectra (400 MHz,
DMSO-d6) of 4.17 and 4.41 proved very helpful to assign the structural feature of the
later. The signals at 7.63 (H-3) & 7.32 (H-2) in 4.17 were found missing altogether in
4.41 which describes the involvement these protons in the formation of pyrazoline ring.
A broad singlet was observed at 8.42 due to NH2 protons and this signal was also
exchangeable with D2O. The aromatic protons were centred at 7.65 (2H, dd, Jm,o=2.4,
7.6Hz, H-6), 7.48 (4H, m, H-4, 5) & 6.82 (2H, d, Jo=8.2Hz, H-3). The hydrogens of
furyl ring appeared at 7.43 (2H, d, J5,4=2.0Hz, H-5), 7.24 (2H, d, J3,4=3.6Hz, H-3)
& 7.12 (2H, dd, J4,3=3.6Hz, J4,5=2.0Hz, H-4). The protons belonging to pyrazoline
ring (H-X, M & A) furnished suitable signals at 5.22 (2H, dd, JXA=6.7Hz,

JXM=11.6Hz), 3.56 (2H, dd, JMX=11.6Hz, JMA=16.6Hz) & 3.25 (2H, dd, JAX=6.7Hz,
JAM=16.6Hz) respectively. The internal spacer protons were found to be resonating at
3.92 (4H, t, Jvic=6.5Hz, OCH2), 1.88 (4H, quintet, Jvic=6.2Hz, OCH2CH2CH2) & 1.74
(2H, quintet, Jvic=6.2Hz, OCH2CH2CH2).
In the

13

C-NMR (100MHz, DMSO-d6) spectrum of 4.41, signals at 178.2, 156.1 &

153.4 could be easily represented by C=S, C-3 and C-2 respectively. Other significant
signals were present at 148.3 (C-2), 133.8 (C-1), 129.8 (C-3), 132.4 (C-6), 130.5
(C-4), 128.0 (C-4), 127.3 (C-5) & 116.4 (C-3). The characteristics pyrazoline ring
carbon atoms C-5 and C-4 were observed at 61.8 & 48.3 and internal chain OCH2
group produced a signal at 65.4 and other signals in aliphatic region at 24.9 & 20.8
were assignable to OCH2CH2CH2 & OCH2CH2CH2 groups respectively. The ESI-MS
spectrum of 4.41 showed (M)+ and (M+Na)+ ions at 642 (20.4 %) & 665 (100 %)
respectively and its mass fragmentation pattern was found to be similar as shown in
Chart-1 (vide experimental).

Synthesis of N-thiocarbamoyl-bispyrazolines 4.42-4.44


The compounds 4.42-4.44 were prepared from the cyclization reactions of corresponding
bischalcones 4.18-4.20 with thiosemicarbazide under the similar reaction conditions as
described earlier for 4.40. The structural features of these compounds were similar to
those of 4.40 & 4.41.
O CH2

3"
2"

4"

6"
2

CH2 O
HM

HM

1"
5"

(CH 2)n

3'''

4
5

N
1N

HA

HX

2''' O
1'''

HA

4'''
5'''

HX
S

C S

N
C
NH2

H2N

n = 4,
4.42

6,

4.43

4.44

The physical and characteristics spectral data of 4.42-4.44 have been summed up in
Table-1 & Table-2.

Table-1: Physical and characteristics spectral data of bispyrazolines 4.42-4.44

Compound

m.p.

Yield

IR

No.

(0C)

(%)

(max cm-1)

4.42

176-178

64

H-NMR ()

ESI-MS
(m/z)

N-H

C=N & C=S

H-X

H-M

H-A

OCH2

3472, 3380

1608

5.22

3.32

3.18

3.92

656 (M+, 12.3 %)

1150

4.43

204-206

70

3470, 3365

1602

5.39

3.35

3.12

3.78

193-195

66

3478, 3362

1600
1154

685 (M+1+, 100 %) /


684 (M+, 10.6 %)

1162

4.44

658 (M+2+, 100 %) /

5.34

3.29

3.15

3.74

735 (M+Na+, 10.8 %),


712 (M+, 100 %)

Table-2: Characteristics 13C-NMR data () of bispyrazolines 4.42-4.44

Compound

C=S

C-3

C-2

C-1

C-6

C-4

C-5

C-3

C-4

C-5

4.42

178.5

157.4

152.1

133.2

131.5

130.1

126.8 115.2

48.9

58.9

4.43

177.8

157.6

153.9

134.6

130.8

129.6

126.2 116.0

47.4

60.2

4.44

177.4

155.8

153.0

132.8

130.2

128.9

125.8 116.2

47.5

59.6

No

In order to generalise the syntheses of above described bispyrazolines, it would be


advantageous here to explore these reactions for the preparation of thienylbispyrazolines 4.45-4.49.
O CH2

3"
2"

4"

6"
2

CH2 O
HM

HM

1"
5"

(CH 2)n

3'''

4
5

N
1N
1'

HA

HX

HA

4'''

2''' S
1'''

5'''

4.45

N
C
NH 2

H2N

n = 2,

HX

3,
4.46

4,

6,

4.47

4.48

4.49

Synthesis of N-thiocarbamoyl-bispyrazoline 4.45


The compound 4.26 was refluxed with thiosemicarbazide (Scheme-4.11) under
similar conditions as used for 4.40 to provide pure compound 4.45 (72%, m.p. 1701720C).

3'

CH2

CH2

CH2

CH2

2'

4'

4"

3"
1'

5'

2"

1
6'

5"

1"

4.26
S
H 2N C

CH2

3'
2'

4'

6'
2

/EtOH/ NaOH/

CH2

CH2

4
5

CH2

HM

HM

1'
5'

NH NH 2

HA

3''

2''

1N

HX

HA

4''

5''

1''

HX

S C
NH2

NH2

4.45
Scheme-4.11

In IR spectrum of 4.45 major absorption bands were observed at 3482, 3386 (N-H)
and 3071 (C-H), 1604 (C=N) & 1148 (C=S) cm-1. In the 1H-NMR spectra (400 MHz,
DMSO-d6) of 4.45, a D2O exchangeable broad singlet integrating for four hydrogens
at

8.32 could be assigned to NH2 protons. The aromatic hydrogens (H-6), (H-4,

5), (H-5), (H-3), (H-4) and (H-3) were found to be placed at 7.68 (2H, dd,
Jm,o=2.2, 7.7Hz), 7.57 (4H, m), 7.49 (2H, d, J5,4=5.0Hz), 7.39 (2H, d, J3,4=3.6Hz),
7.24 (2H, dd, J4,3=3.6Hz, J4,5=5.0Hz) & 6.88 (2H, d, Jo=8.2Hz) respectively. The
protons

(H-X, M & A) belonging to the pyrazoline ring were very well resonating

at 5.36 (2H, dd, JXA=6.6Hz, JXM=11.4Hz), 3.49 (2H, dd, JMX=11.4Hz, JMA=16.4Hz)
& 3.32 (2H, dd, JAX=6.6Hz, JAM=16.7Hz) respectively. The double irradiation of a
signal at 5.36 converted the doublets of doublets at 3.49 & 3.32 to doublet each
which also describe the coupling behaviour among H-X, M & A. A triplet at 3.98
(4H, Jvic=6.5Hz) and a quintet at 1.96 (4H, Jvic=6.5Hz) were assignable to
OCH2CH2 and OCH2CH2 groups respectively. The structure of compound 4.45 also

fully lent support from its ESI-MS spectrum which had noticeable ions at m/z 662
(M+2, 30.4 %) & 661 (M+1, 24.6 %) and its mass fragmentation pattern has been
given in Chart-2.
In the 13C-NMR (100MHz, DMSO-d6) data of 4.45, the signals at 177.5, 158.6 &
154.7 could be allotted to C=S, C=N & C-2 respectively. Other aromatic carbon
atoms were found to be placed at 148.6 (C-2), 139.8 (C-5), 135.6 (C-1), 131.7
(C-6), 132.4

(C-3), 129.9 (C-4), 127.6 (C-5), 126.2 (C-4) & 116.4 (C-3). The

signals present at 57.2 & 47.9 could be ascribed to pyrazoline ring carbons C-5 and
C-4 respectively.
CH2

-----

CH2

CH2

CH2

NH2

H2N

N
aH
O

4.45
m/z = 660 (12.2 %)

(M + 2)
m/z 662 (30.4 %)

-----

-----

N H
a

CH4

(M + 1)
m/z 661 (24.6 %)

+.

CH2

CH2

CH2

CH2

-2H

O
H

H
H 2C

H 2C CH 2 O

N
a

H N
H2N

NH2

m/z = 658 (100 %)


N

H N

C
H2N
S
m /z 344 (22 .1 %)
O

CH2

CH2

CH2

CH2

-C2H4, -2H
N

H
H

N
H N

N H

H2N

NH2

S
O

m/z = 546 (18.5 %)

-(CSNH 2)2

N
NH2

+.

m/z 314 (31.3 %)

CH2

CH2

CH2

CH2

H
N

H
H

N H
H
O

CH 2

N
N
S

NH2

m/z 231 (10.0 %)

O
H

-C4H3S

Chart-2

CH 2

+.

O
H

N
H N
H

m/z = 424 (13.6 %)

Synthesis of N-thiocarbamoyl-bispyrazoline 4.46


The compound 4.27 was reacted with thiosemicarbazide (Scheme-4.12) under the
similar conditions as used earlier for 4.40 to yield 4.46 (70%, 187-1890C).

3'

CH2

CH2

2'

4'

3"

1'
5'

6'

CH2

5"

1"

CH2

4"

2"

CH2

4.27
S
H 2N C

CH2

3'
2'

4'

1'
5'
6'

HM
3 4

N
C

CH2

/EtOH/ NaOH/

CH2

CH2

CH2

HM
HA 3''

HX

HA

4''

NH NH 2

5''

S
1''

HX
S

N
C
NH2

NH2

4.46
Scheme-4.12
IR spectrum of 4.46 did not exhibit any strong absorption at 1656 cm-1 indicating the
absence of carbonyl group in this compound and C=N, NH2 & C=S moieties
generated

suitable bands at 1590, 3472, 3358 & 1156 cm-1 respectively. A

comparison of the 1H-NMR spectra (400 MHz, DMSO-d6) of 4.27 and 4.46 proved
very fruitful to assign the structural feature of later. The significant feature of 1HNMR spectrum of 4.46 was the appearance of broad singlet (exchangeable with D2O)
at 8.40 due to NH2. The aromatic protons H-3 and H-6 were centred at 6.90 (2H,
d, Jo=8.0Hz) & 7.62 (2H, dd, Jm,o=2.4, 7.6Hz) respectively whereas H-4 and H-5
appeared together at 7.54 in the form of a multiplet. The hydrogens of thienyl ring
were found at 7.51 (2H, d, J5,4=4.9Hz, H-5), 7.32 (2H, d, J3,4=3.6Hz, H-3) &
7.20 (2H, dd, J4,3=3.6Hz, J4,5=4.9Hz, H-4). The protons belonging to pyrazoline
ring (H-X, M & A) provided suitable signals at 5.29 (2H, dd, JXA=6.7Hz,

JXM=11.6Hz), 3.52 (2H, dd, JMX=11.6Hz, JMA=16.7Hz) & 3.24 (2H, dd, JAX=6.7Hz,
JAM=16.7Hz) respectively. The internal chain methylene group hydrogens were found
to be resonating at 3.94 (4H, t, Jvic=6.5Hz, OCH2), 1.96 (4H, quintet, Jvic=6.2Hz,
OCH2CH2CH2) & 1.86 (2H, quintet, Jvic=6.2Hz, OCH2CH2CH2).
In the

13

C-NMR (100MHz, DMSO-d6) spectrum of 4.46, the downfield signals at

176.6, 156.2 & 153.8 were represented by C=S, C-3 and C-2 respectively. The
aromatic carbon atoms were resonating at suitable positions (vide experiemental). The
characteristic pyrazoline ring carbon atoms C-5 and C-4 were observed at 58.4 &
46.8 and internal chain OCH2, OCH2CH2CH2 and OCH2CH2CH2 groups appeared at
65.2, 24.2 & 22.8 respectively. The ESI-MS spectrum of 4.46 also confirmed its
structure which had (M+Na)+ and (M+1)+ ions at 697 (42.1 %) & 675 (26.4 %)
respectively and its mass fragmentation pattern was found to be similar as shown in
Chart-2 (vide experimental).

Synthesis of bispyrazolines 4.47-4.49


The compounds 4.47-4.49 were prepared from the cyclization reaction of
bischalcones 4.26-4.30 with thiosemicarbazide under the similar reaction conditions
as described earlier for 4.40. The spectral data of these compounds exhibited similar
features as observed in those of 4.45 & 4.46.
O CH2

3"
2"

4"

6"
2

CH2 O
HM

HM

1"
5"

(CH 2)n

3'''

4
5

N
1N

HA

HX

HA

4'''

2''' S
1'''

5'''

HX
S

C S

N
C
NH2

H2N

n = 4,
4.47

6,
4.48

8
4.49

The physical and characteristics spectral data of 4.47-4.49 have been presented in
Table-3 & Table-4 (vide experimental).

Table-3: Physical and characteristic spectral data of bispyrazolines 4.47-4.49

Compound

m.p.

Yield

No.

(0C)

(%)

IR (max cm-1)

H-NMR ()

ESI-MS
(m/z)

N-H

C=N

H-X

H-M

H-A

OCH2

5.32

3.43

3.27

3.91

&
C=S

4.47

162-

74

164

4.48

174-

68

176

3478,

1597

3362

1164

3465,

1592

3368

1168

690

(M+2+,

100 %)

5.24

3.46

3.29

3.86

739 (M+Na+,
100 %)/
717

(M+1+,

30.2 %)

4.49

196198

69

3458,

1598

3374

1152

5.27

3.39

3.19

3.84

767 (M+Na+,
10.8 %)/
745

(M+1+,

10.1 %)

Table-4: 13C-NMR data () of bispyrazolines 4.47-4.49

Compound C=S

C-3

C-2

C-1

C-6

C-4

C-5

C-3

C-4

C-5

4.47

177.2

157.3 152.9 135.1 132.8 130.8 126.3 117.2 47.4

57.9

4.48

177.5

156.2 154.1 134.9 131.8 130.4 126.7 116.8 45.2

56.2

4.49

177.8

156.4 153.2 136.3 132.0 131.6 127.1 116.0 46.1

56.7

Antibacterial activities of N-thiocarbamoyl-bispyrazolines 4.40-4.44 & 4.45-4.49


Antibacterial activities of prepared compounds 4.40-4.44 & 4.45-4.49 were carried
out by using disc diffusion method.19 The bacteria were inoculated in 50 ml of
nutrient broth medium and cultured for 5 hrs at 370C. Agar plates were streaked with
a sterile swab moistened with the bacterial suspension. The synthesized compounds
were dissolved in DMSO and spread on discs made of filter paper and incubated
overnight at 370C. The measurements were done in triplicates and the value averaged.
The compounds were also tested for MIC by using serial tube dilution method20
against above said microorganisms. The susceptibility of the bacteria to the test
compounds was determined by the appearance of turbidity after 24 hrs of incubation
at 370C. The observed zone of inhibitions and minimum inhibitory concentrations
(MIC-g/ml) of the tested compounds are presented in Tables-5 & Tables-6
respectively.

Table-5: Zone of inhibitions (mm) of bispyrazolines 4.40-4.44 & 4.45-4.49


A. hydrophila

Y. enterocolitica

L. monocytogenes

S. aureus

4.40

20

12

22

23

4.41

16

13

14

11

4.42

22

17

19

22

4.43

11

19

11

17

4.44

18

10

20

4.45

17

14

20

18

4.46

16

11

16

17

4.47

14

20

18

20

4.48

18

10

17

18

4.49

20

19

12

16

Tetracycline

13

20

12

14

Gentamicin

11

16

15

14

Compounds

It is evident from Table-5 that the compounds 4.40-4.44 shows significant activity
against bacterial strains having zone of inhibition of 23-19 mm against the strains
namely; A. hydrophila, Y. enterocolitica, L. monocytogens and S. aureus. Here
compound 4.40 was found to be very active (zone of inhibition-23 mm) against
bacterial strain S. aureus. The compounds 4.42 & 4.49 were active against A.
hydrophila having zone of inhibition 22 & 20 mm respectively. Further compound
4.47 and 4.49 seems to be active against Y. enterocolitica (zone of inhibition-20 &
19 mm). The compounds 4.40, 4.42 & 4.45 could exhibit good activity against L.
monocytogens having zone of inhibition-20 mm and significant activity is shown
by compounds 4.40 (23 mm), 4.42 (20 mm), 4.44 (20 mm) & 4.47 (20 mm)
against S. aureus.

Table-6: Minimum inhibitory concentrations (MIC, (g/ml) of bispyrazoline 4.404.44 and 4.45-4.49
A. hydrophila

Y.enterocolitica

L.monocytogenes

S. aureus

4.40

10

30

10

10

4.41

20

10

20

20

4.42

20

30

20

20

4.43

40

20

40

30

4.44

30

10

30

20

4.45

20

30

20

10

4.46

10

20

10

20

4.47

20

20

30

30

4.48

30

20

20

20

4.49

10

10

20

10

Tetracycline

30

30

30

30

Gentamicin

10

10

10

10

Compounds

Similarly, Table-8 describes that compounds 4.40-4.44 prohibited the growth of the
all bacterial strains. The compounds 4.40, 4.41, 4.44, 4.45, 4.46 & 4.49 were found to
be very active (MIC-10 g/ml) against tested bacterial strains.
So, it may be concluded that this study describes the general method for the synthesis
of N-thiocarbamoyl-furyl/thienyl-bispyrazolines and most of the prepared compounds
showed good antibacterial behavior against the tested bacterial strains.

EXPERIMENTAL
Synthesis

of

1,4-bis[1-(2-oxyphenyl)-5-(furan-2-yl)-4,5-dihydro-1H-pyrazole]

butane 4.40
A mixture of bischalcone 4.16 (0.5 g, 0.00087 mol), thiosemicarbazide (0.16 g,
0.00175 mol), dry ethanol (25 ml) and NaOH (1.0 g) was refluxed for 12 hrs. The
progress of reaction was monitored by TLC. After completion the reaction, the
reaction mixture was poured into crushed ice to give a solid substance which was
crystallized from MeOH to yield compound 4.40.
CH2

3'
2'

4'

6'
2

CH2

CH2

HM

HM

1'
5'

CH2

3''

4
5

HA

1N

HX

2''

HA

4''

5''

1''

HX
S

N
C
NH2

NH2

4.40
4.40: Brown solid; Yield 68%; m.p. 195-1970C; IR (KBr) max (cm-1): 3480, 3375 (NH), 3071 (aromatic C-H), 1596 (C=N), 1246, 1020 (C-O), 1148 (C=S); 1H-NMR (400
MHz, CDCl3): 8.26 (4H, brs, NH2), 7.53 (2H, dd, Jm,o=2.2, 7.7Hz, H-6), 7.45 (4H,
m, H-4, 5), 7.38 (2H, d, J5,4=2.0Hz, H-5), 7.31 (2H, d, J3,4=3.2Hz, H-3), 7.08
(2H, dd, J4,3=3.2Hz, J4,5=2.0Hz, H-4), 6.87 (2H, d, Jo=8.2Hz, H-3), 5.28 (2H,
dd, JXA=6.6Hz, JXM=11.4Hz, H-X), 3.96 (4H, t, Jvic=6.5Hz, OCH2CH2), 3.40 (2H, dd,
JMX=11.4Hz, JMA=16.4Hz, H-M), 3.26 (2H, dd, JAX=6.6Hz, JAM=16.7Hz, H-A), 1.90
(4H, quintet, Jvic=6.5Hz, OCH2CH2);

13

C-NMR (100 MHz, CDCl3): 176.8 (C=S),

154.8 (C=N), 152.6 (C-2), 148.3 (C-2), 136.8 (C-5), 134.2 (C-1), 131.2 (C-6),
130.9 (C-3), 129.2 (C-4), 127.8 (C-5), 126.7 (C-4), 115.8 (C-3), 66.2
(OCH2CH2), 62.7 (C-5), 47.0 (C-4), 26.2 (OCH2CH2); MS: m/z (M+1)+ 629 (100 %),
(M)+ 628 (16.2 %), 626 (25.7 %), 572 (10.3 %), 568 (90.2 %), 546 (18.5 %), 424
(13.6 %), 314 (40.4 %), 287 (10.8 %), 221 (10.0 %); Anal. calc. for C32H32O4N6S2:
C, 61.14; H, 5.09; N, 13.37; S, 10.19; Found: C, 61.32; H, 5.06; N, 13.41; S, 10.16 %.

Synthesis

of

1,5-bis[1-(2-oxyphenyl)-5-(furan-2-yl)-4,5-dihydro-1H-pyrazole]

pantane 4.41
The compound 4.41 was obtained from the reaction of bischalcone 4.17 (0.5 g,
0.00087 mol) with thiosemicarbazide (0.16 g, 0.00175 mol) under the similar
condition as used earlier for 4.40.

CH2

3'
2'

4'

1'
5'
6'

HM
3 4

N
C

CH2

CH2

CH2

HM

HX

HA

4''

HA3''

CH2

5''

O
1''

HX
S

N
C

H2N

H2N

4.41
4.41: Brown solid; Yield 61%; m.p. 182-1840C; IR (KBr) max (cm-1): 3460, 3356 (NH), 3042 (aromatic C-H), 1594 (C=N), 1238, 1028 (C-O), 1158 (C=S); 1H-NMR (400
MHz, CDCl3): 8.42 (4H, brs, NH2), 7.65 (2H, dd, Jm,o=2.4, 7.7Hz, H-6), 7.48 (4H,
m, H-4, 5), 7.43 (2H, d, J5,4=2.0Hz, H-5), 7.24 (2H, d, J3,4=3.6Hz, H-3), 7.12
(2H, dd, J4,3=3.6Hz, J4,5=2.0Hz, H-4), 6.82 (2H, d, Jo=8.0Hz, H-3), 5.22 (2H,
dd, JXA=6.7Hz, JXM=11.6Hz, H-X), 3.92 (4H, t, Jvic=6.5Hz, OCH2CH2CH2), 3.56
(2H, dd, JMX=11.6Hz, JMA=16.6Hz, H-M), 3.25 (2H, dd, JAX=6.7Hz, JAM=16.6Hz, HA), 1.88 (4H, quintet, Jvic=6.2Hz, OCH2CH2CH2), 1.74 (2H, quintet, Jvic=6.2Hz,
OCH2CH2CH2);

13

C-NMR (100 MHz, CDCl3): 178.2 (C=S), 156.1 (C=N), 153.4

(C-2), 148.3 (C-2), 135.7 (C-5), 133.8 (C-1), 132.4 (C-6), 130.5 (C-4), 129.8
(C-3), 128.0 (C-4), 127.3 (C-5), 116.4 (C-3), 65.4 (OCH2CH2CH2), 61.8 (C-5),
48.3 (C-4), 24.9 (OCH2CH2CH2), 20.8 (OCH2CH2CH2); MS: m/z (M+Na)+ 665 (100
%), (M)+ 642 (20.4 %), 560 (53.0 %), 438 (6.4 %), 328 (10.4 %), 287 (90.8 %), 286
(28.2 %), 220 (33.3 %); Anal. calc. for C33H34O4N6S2: C, 61.68; H, 5.29; N, 13.08; S,
9.96; Found: C, 61.86; H, 5.26; N, 13.04; S, 9.93 %.

Synthesis

of

1,6-bis[1-(2-oxyphenyl)-5-(furan-2-yl)-4,5-dihydro-1H-pyrazole]

hexane 4.42
The compound 4.42 was prepared by treating bischalcone 4.18 (0.5 g, 0.00087 mol)
with thiosemicarbazide (0.16 g, 0.00175 mol) under the similar conditions as used
earlier for 4.40.
2'

4'

1'
5'
6'

CH2

CH2

3'

HM
3 4

CH2

CH2

CH2

O
HM

N H 2"
1
X

HA

4"

H A3''

CH2

5"

O1''

HX
S

N
C
NH 2

NH2

4.42
4.42: Brown solid; Yield 64%; m.p. 176-1780C; IR (KBr) max (cm-1): 3472, 3380 (NH), 3056 (aromatic C-H), 1608 (C=N), 1242, 1030 (C-O), 1150 (C=S); 1H-NMR (400
MHz, CDCl3): 8.28 (4H, brs, NH2), 7.72 (2H, dd, Jm,o=2.4, 7.6Hz, H-6), 7.43 (4H,
m, H-4, 5), 7.36 (2H, d, J5,4=2.1Hz, H-5), 7.16 (2H, d, J3,4=3.4Hz, H-3),
7.06 (2H, dd, J4,3=3.4Hz, J4,5=2.1Hz, H-4), 6.94 (2H, d, Jo=8.4Hz, H-3), 5.22
(2H, dd, JXA=6.7Hz, JXM=11.7Hz, H-X), 3.92 (4H, t, Jvic=6.5Hz, OCH2CH2CH2),
3.32 (2H, dd, JMX=6.7Hz, JMA=16.7Hz, H-M), 3.18 (2H, dd, JAX=11.7Hz,
JAX=16.6Hz, H-A), 1.82 (4H, quintet, Jvic=6.5Hz, OCH2CH2CH2), 1.72 (4H, quintet,
Jvic=6.5Hz, OCH2CH2CH2);

13

C-NMR (100 MHz, CDCl3): 178.5 (C=S), 157.4

(C=N), 152.1 (C-2), 147.4 (C-2), 135.9 (C-5), 133.2 (C-1), 131.5 (C-6), 130.4
(C-3), 130.1 (C-4), 127.6 (C-4), 126.8 (C-5), 115.2 (C-3), 64.2 (OCH2CH2CH2),
58.9 (C-5), 48.9 (C-4), 24.2 (OCH2CH2CH2), 22.7 (OCH2CH2CH2); MS: m/z (M+2)+
658 (100 %), (M)+ 656 (12.3 %), 574 (77.8 %), 452 (24.7 %), 342 (18.3 %), 314 (20.4
%), 287 (40.3 %), 286 (90.3 %), 220 (22.9 %); Anal. calc. for C34H36O4N6S2: C,
62.19; H, 5.48; N, 12.80; S, 9.75; Found: C, 62.02; H, 5.52; N, 12.76; S, 9.78 %.

Synthesis

of

1,8-bis[1-(2-oxyphenyl)-5-(furan-2-yl)-4,5-dihydro-1H-pyrazole]

octane 4.43
The compound 4.43 was obtained from the reaction of bischalcone 4.19 (0.5 g,
0.00087 mol) with thiosemicarbazide (0.16 g, 0.00175 mol) under the similar
conditions as used earlier for 4.43.

CH2

3'
2'

4'

1'
5'
6'

HM
3 4

CH2

CH2 CH2

CH2

O
HM

HA

N H
X
C

CH2

CH2

2''

HA

4''

3''

CH2

5''

O
1''

HX
S

NH2

N
C
NH 2

4.43
4.43: Light brown solid; Yield 70%; m.p. 204-2060C; IR (KBr) max (cm-1): 3470,
3365 (N-H), 3060 (aromatic C-H), 1602 (C=N), 1252, 1045 (C-O), 1162 (C=S); 1HNMR (400 MHz, CDCl3): 8.30 (4H, brs, NH2), 7.69 (2H, dd, Jm,o=2.2, 8.2Hz, H6), 7.51 (4H, m, H-4, 5), 7.32 (2H, d, J5,4=2.0Hz, H-5), 7.24 (2H, d,
J3,4=3.4Hz, H-3), 7.17 (2H, dd, J4,3=3.4Hz, J4,5=2.0Hz, H-4), 6.92 (2H, d,
Jo=8.4Hz, H-3), 5.39 (2H, dd, JXA=6.7Hz, JXM=11.6Hz, H-X), 3.78 (4H, t,
Jvic=6.6Hz, OCH2CH2CH2CH2), 3.35 (2H, dd, JMX=11.6Hz, JMA=16.7Hz, H-M), 3.12
(2H, dd, JAX=11.6Hz, JAM=16.7Hz, H-A), 1.78 (4H, quintet, Jvic=6.5Hz,
OCH2CH2CH2CH2), 1.69 (4H, quintet, Jvic=6.5Hz, OCH2CH2CH2CH2), 1.52 (4H,
quintet, Jvic=6.5 Hz, OCH2CH2CH2CH2);

13

C-NMR (100 MHz, CDCl3): 177.8

(C=S), 157.6 (C=N), 153.9 (C-2), 147.7 (C-2), 136.1 (C-5), 134.6 (C-1), 131.2
(C-3), 130.8 (C-6), 129.6 (C-4), 127.0 (C-4), 126.2 (C-5), 116.0 (C-3), 63.9
(OCH2CH2CH2CH2), 60.2 (C-5), 47.4 (C-4), 23.6 (OCH2CH2CH2CH2), 21.0
(OCH2CH2CH2CH2), 19.5 (OCH2CH2CH2CH2); MS: m/z (M+1)+ 685 (100 %), (M)+
684 (10.6 %), 602 (20.2 %), 480 (17.1 %), 370 (15.6 %), 314 (56.3 %), 287 (68.6 %),
286 (33.1 %), 220 (39.5 %); Anal. calc. for C36H40O4N6S2: C, 63.15; H, 5.84; N,
12.28; S, 9.35; Found: C, 62.98; H, 5.87; N, 12.33; S, 9.31 %.

Synthesis

of

1,10-bis[1-(2-oxyphenyl)-5-(furan-2-yl)-4,5-dihydro-1H-pyrazole]

decane 4.44
The compound 4.44 was synthesized from the reaction of bischalcone 4.20 (0.5 g,
0.00087 mol) with thiosemicarbazide (0.16 g, 0.00175 mol) under the similar
conditions as used earlier for 4.40.
4'

CH2

3'
2'
1'
6'

HA

3''

2N 1
N H 2'' O
X
1''
C

CH2

CH2

CH2 CH2

CH2

CH2

CH2

CH2
HM

HM
3 4

5'

CH2

HA

4''

5''

HX
S

N
C
NH2

NH2

4.44
4.44: Light brown solid; Yield 66%; m.p. 193-1950C; IR (KBr) max (cm-1): 3478,
3362 (N-H), 3076 (aromatic C-H), 1600 (C=N), 1236, 1050 (C-O), 1154 (C=S); 1HNMR (400 MHz, CDCl3): 8.36 (4H, brs, NH2), 7.57 (2H, dd, Jm,o=2.2, 8.4Hz, H-6),
7.40 (4H, m, H-4, 5), 7.26 (2H, d, J5,4=2.0Hz, H-5), 7.18 (2H, d, J3,4=3.4Hz,
H-3), 7.02 (2H, dd, J4,3=3.4Hz, J4,5=2.0Hz, H-4), 6.86 (2H, d, Jo=8.2Hz, H-3),
5.34 (2H, dd,

JXA=6.7Hz,

JXM=11.7Hz, H-X), 3.74 (4H, t,

Jvic=6.2Hz,

OCH2CH2CH2CH2CH2), 3.29 (2H, dd, JMX=6.7Hz, JMA=16.7Hz, H-M), 3.15 (2H, dd,
JAX=11.6Hz,

JAX=16.7Hz,

H-A),

1.76

(4H,

quintet,

Jvic=6.2Hz,

OCH2CH2CH2CH2CH2), 1.63 (4H, quintet, Jvic=6.5Hz, OCH2CH2CH2CH2CH2), 1.49


(4H, quintet, Jvic= 6.5Hz, OCH2CH2CH2CH2CH2), 1.32 (4H, quintet, Jvic= 6.5Hz,
OCH2CH2CH2CH2CH2); 13C-NMR (100 MHz, CDCl3): 177.4 (C=S), 155.8 (C=N),
153.0 (C-2), 148.6 (C-2), 136.3 (C-5), 132.8 (C-1), 130.5 (C-3), 130.2 (C-6),
128.9 (C-4), 126.0 (C-4), 125.8 (C-5), 116.2 (C-3), 62.7 (OCH2CH2CH2CH2CH2),
59.6 (C-5), 47.5 (C-4), 22.8 (OCH2CH2CH2CH2CH2), 19.9 (OCH2CH2CH2CH2CH2),
19.2 (OCH2CH2CH2CH2CH2), 18.4 (OCH2CH2CH2CH2CH2); MS: m/z (M+Na)+ 735
(10.8 %), (M)+ 712 (100 %), 630 (61.3 %), 452 (21.2 %), 398 (48.2 %), 356 (10.2 %),
314 (65.6 %), 287 (52.8 %), 286 (38.4 %), 220 (7.2 %); Anal. calc. for
C38H44O4N6S2: C, 64.04; H, 6.17; N, 11.79; S, 8.99; Found: C, 64.22; H, 6.14; N,
11.83; S, 8.95 %.

Synthesis of 1,4-bis[1-(2-oxyphenyl)-5-(thiophene-2-yl)-4,5-dihydro-1H-pyrazole]
butane 4.45
A mixture of bischalcone 4.26 (0.5 g, 0.00097 mol), thiosemicarbazide (0.17 g,
0.00194 mol), dry ethanol (25ml) and NaOH (1.0 g) was refluxed for 14 hrs. The
progress of reaction was monitored by TLC. After completion the reaction, the
reaction mixture was poured into crushed ice to provide a solid substance which was
crystallized from CH3OH to yield compound 4.45.
CH2

3'
2'

4'

6'
2

CH2

CH2

HM

HM

1'
5'

CH2

3''

4
5

HA

1N

HX

2''

HA

4''

5''

1''

HX
S

N
C
NH2

NH2

4.45
4.45: Brown solid; Yield 72%; m.p. 170-1720C; IR (KBr) max (cm-1): 3482, 3386 (NH), 3071 (aromatic C-H), 1604 (C=N), 1240, 1042 (C-O), 1148 (C=S); 1H-NMR
(400 MHz, CDCl3): 8.32 (4H, brs, NH2), 7.68 (2H, dd, Jm,o=2.2, 7.7Hz, H-6), 7.57
(4H, m, H-4, 5), 7.49 (2H, d, J5,4=5.0Hz, H-5), 7.39 (2H, d, J3,4=3.6Hz, H3), 7.24 (2H, dd, J4,3=3.6Hz, J4,5=5.0Hz, H-4), 6.88 (2H, d, Jo=8.2Hz, H-3),
5.36 (2H, dd, JXA=6.6Hz, JXM=11.4Hz, H-X), 3.98 (4H, t, Jvic=6.5Hz, OCH2CH2),
3.49 (2H, dd, JMX=11.4Hz, JMA=16.4Hz, H-M), 3.32 (2H, dd, JAX=6.6Hz,
JAM=16.7Hz, H-A), 1.96 (4H, quintet, Jvic=6.5Hz, OCH2CH2); 13C-NMR (100 MHz,
CDCl3): 177.5 (C=S), 158.6 (C=N), 154.7 (C-2), 148.6 (C-2), 139.8 (C-5), 135.6
(C-1), 132.4 (C-3), 131.7 (C-6), 129.9 (C-4), 127.6 (C-5), 126.2 (C-4), 116.4
(C-3), 66.9 (OCH2CH2), 57.2 (C-5), 47.9 (C-4), 24.8 (OCH2CH2); MS: m/z (M+2)+
662 (30.4 %), (M+1)+ 661 (24.6 %), 660 (12.2 %), 658 (100 %), 546 (18.5 %), 424
(13.6 %), 344 (22.1 %), 314 (31.3 %), 231 (10.0 %); Anal. calc. for C32H32O2N6S4:
C, 58.18, H, 4.85, N, 12.73; S, 19.39; Found: C, 58.36, H, 4.88; N, 12.77; S, 19.42 %.

Synthesis of 1,5-bis[1-(2-oxyphenyl)-5-(thiophene-2-yl)-4,5-dihydro-1H-pyrazole]
pantane 4.46
The compound 4.46 was obtained from the reaction of bischalcone 4.27 (0.5 g,
0.00094 mol) with thiosemicarbazide (0.17 g, 0.00189 mol) under the similar
condition as used earlier for 4.45.

CH2

3'
2'

4'

1'
5'
6'

HM
3 4

N
C

CH2

CH2

CH2

HM

HX

HA

4''

HA3''

CH2

5''

S
1''

HX
S

N
C

H2N

H2N

4.46
4.46: Light brown solid; Yield 70%; m.p. 187-1890C; IR (KBr) max (cm-1): 3472,
3358 (N-H), 3051 (aromatic C-H), 1590 (C=N), 1250, 1032 (C-O), 1156 (C=S); 1HNMR (400 MHz, CDCl3): 8.40 (4H, brs, NH2), 7.62 (2H, dd, Jm,o=2.4, 7.6Hz, H-6),
7.54 (4H, m, H-4, 5), 7.51 (2H, d, J5,4=4.9Hz, H-5), 7.32 (2H, d, J3,4=3.6Hz,
H-3), 7.20 (2H, dd, J4,3=3.6Hz, J4,5=4.9Hz, H-4), 6.90 (2H, d, Jo=8.0Hz, H3), 5.29 (2H, dd, JXA=6.7Hz, JXM=11.6Hz, H-X), 3.94 (4H, t, Jvic=6.5Hz,
OCH2CH2CH2), 3.52 (2H, dd, JMX=11.6Hz, JMA=16.7Hz, H-M), 3.24 (2H, dd,
JAX=6.7Hz, JAM=16.7Hz, H-A), 1.96 (4H, quintet, Jvic=6.2Hz, OCH2CH2CH2), 1.86
(2H, quintet, Jvic=6.2Hz, OCH2CH2CH2);

13

C-NMR (100 MHz, CDCl3): 176.6

(C=S), 156.2 (C=N), 153.8 (C-2), 138.2 (C-5), 146.7 (C-2), 134.6 (C-1), 132.5
(C-6), 131.4 (C-3), 129.6 (C-4), 128.9 (C-4), 125.8 (C-5), 117.9 (C-3), 65.2
(OCH2CH2CH2), 58.4 (C-5), 46.8 (C-4), 24.2 (OCH2CH2CH2), 22.8 (OCH2CH2CH2);
MS: m/z (M+Na)+ 697 (26.4 %), (M+1)+ 675 (42.1 %), 672 (33.1 %), 560 (21.4 %),
440 (17.7 %), 358 (18.4 %), 314 (28.3 %), 231 (14.6 %); Anal. calc. for
C33H34O2N6S4: C, 58.75; H, 5.04; N, 12.46; S, 18.99; Found: C, 58.60; H, 5.08; N,
12.42; S, 18.93 %.

Synthesis of 1,6-bis[1-(2-oxyphenyl)-5-(thiophene-2-yl)-4,5-dihydro-1H-pyrazole]
hexane 4.47
The compound 4.47 was prepared from the reaction of bischalcone 4.28 (0.5 g,
0.00092 mol) with thiosemicarbazide (0.16 g, 0.00184 mol) under the similar
conditions as used earlier for 4.45.

2'

4'

1'
5'
6'

CH2

CH2

3'

HM
3 4

CH2

CH2

CH2

O
HM

H A3''

N H 2"
1
X

HA

4"

CH2

5"

S1''

HX
S

N
C
NH 2

NH2

4.47
4.47: Dark Brown solid; Yield 74%; m.p. 162-1640C; IR (KBr) max (cm-1): 3478,
3362 (N-H), 3074 (aromatic C-H), 1597 (C=N), 1245, 1050 (C-O), 1164 (C=S); 1HNMR (400 MHz, CDCl3): 8.22 (4H, brs, NH2), 7.64 (2H, dd, Jm,o=2.2, 7.6Hz, H6), 7.56 (2H, d, J5,4=5.1Hz, H-5), 7.47 (4H, m, H-4, 5), 7.26 (2H, d,
J3,4=3.5Hz, H-3), 7.15 (2H, dd, J4,3=3.5Hz, J4,5=5.1Hz, H-4), 6.94 (2H, d,
Jo=8.4Hz, H-3), 5.32 (2H, dd, JXA=6.7Hz, JXM=11.7Hz, H-X), 3.91 (4H, t,
Jvic=6.5Hz, OCH2CH2CH2), 3.43 (2H, dd, JMX=6.7Hz, JMA=16.7Hz, H-M), 3.27 (2H,
dd, JAX=11.7Hz, JAX=16.6Hz, H-A), 1.92 (4H, quintet, Jvic=6.5Hz, OCH2CH2CH2),
1.52 (4H, quintet, Jvic=6.5Hz, OCH2CH2CH2); 13C-NMR (100 MHz, CDCl3): 177.2
(C=S), 157.3 (C=N), 152.9 (C-2), 149.4 (C-2), 137.2 (C-5), 135.1 (C-1), 133.2
(C-3), 132.8 (C-6), 130.8 (C-4), 128.3 (C-4), 126.3 (C-5), 117.2 (C-3), 64.8
(OCH2CH2CH2), 57.9 (C-5), 47.4 (C-4), 23.9 (OCH2CH2CH2), 21.8 (OCH2CH2CH2);
MS: m/z (M+2)+ 690 (100 %), 686 (44.3 %), 524 (46.2 %), 404 (24.4 %), 358 (60.4
%), 314 (31.5 %), 231 (12.6 %); Anal .calc. for C34H36O2N6S4: C, 59.30; H, 5.23; N,
12.21; S, 18.60; Found: C, 59.44; H, 5.27; N, 12.25; S, 18.56 %.

Synthesis of 1,8-bis[1-(2-oxyphenyl)-5-(thiophene-2-yl)-4,5-dihydro-1H-pyrazole]
octane 4.48
The compound 4.48 was obtained from the reaction of bischalcone 4.29 (0.5 g,
0.00087 mol) with thiosemicarbazide (0.16 g, 0.00175 mol) under the similar
conditions as used earlier for 4.45.

CH2

3'
2'

4'

1'
5'
6'

HM
3 4

CH2

CH2 CH2

CH2

O
HM

HA

N H
X
C

CH2

CH2

2''

HA

4''

3''

CH2

5''

S
1''

HX
S

NH2

N
C
NH 2

4.48
4.48: Light brown solid; Yield 68%; m.p. 174-1760C; IR (KBr) max (cm-1): 3465,
3368 (N-H), 3082 (aromatic C-H), 1592 (C=N), 1240, 1032 (C-O), 1168 (C=S); 1HNMR

(400 MHz, CDCl3): 7.92 (4H, brs, NH2), 7.58 (2H, dd, Jm,o=2.2, 8.2Hz, H-

6), 7.53 (2H, d, J5,4=5.0Hz, H-5), 7.49 (4H, m, H-4, 5), 7.28 (2H, d,
J3,4=3.6Hz, H-3), 7.17 (2H, dd, J4,3=3.6Hz, J4,5=5.0Hz, H-4), 6.92 (2H, d,
Jo=8.4Hz, H-3), 5.24 (2H, dd, JXA=6.7Hz, JXM=11.6Hz, H-X), 3.86 (4H, t,
Jvic=6.6Hz, OCH2CH2CH2CH2), 3.46 (2H, dd, JMX=11.6Hz, JMA=16.7Hz, H-M), 3.29
(2H, dd, JAX=11.6Hz, JAM=16.7Hz, H-A), 1.86 (4H, quintet, Jvic=6.5Hz,
OCH2CH2CH2CH2), 1.46 (4H, quintet, Jvic=6.5Hz, OCH2CH2CH2CH2), 1.29 (4H,
quintet, Jvic=6.5 Hz, OCH2CH2CH2CH2);

13

C-NMR (100 MHz, CDCl3): 177.5

(C=S), 156.2 (C=N), 154.1 (C-2), 147.9 (C-2), 137.8 (C-5), 134.9 (C-1), 132.8
(C-3), 131.8 (C-6), 130.4 (C-4), 127.3 (C-4), 126.7 (C-5), 116.8 (C-3), 64.2
(OCH2CH2CH2CH2), 56.2 (C-5), 45.2 (C-4), 23.2 (OCH2CH2CH2CH2), 21.2
(OCH2CH2CH2CH2), 19.4 (OCH2CH2CH2CH2); MS: m/z (M+Na)+ 739 (100 %),
(M+1)+ 717 (30.2 %), (M+) 717 (10.4 %), 714 (29.4 %), 552 (42.3 %), 432 (29.9 %),
400 (52.7 %), 314 (27.1 %), 231 (9.1 %); Anal. calc. for C36H40O2N6S4: C, 60.33; H,
5.59; N, 11.73; S, 17.88; Found: C, 60.42; H, 5.56; N, 11.68; S, 17.81 %.

Synthesis

of

1,10-bis[1-(2-oxyphenyl)-5-(thiophene-2-yl)-4,5-dihydro-1H-

pyrazole] decane 4.49


The compound 4.49 was synthesized from the reaction of 4.30 (0.5 g, 0.00083 mol)
with thiosemicarbazide (0.15 g, 0.00167 mol) under the similar conditions as used
earlier for 4.45.
4'

CH2

3'
2'
1'
6'

HA

3''

CH2 CH2

CH2

CH2

CH2

CH2

HA

4''

2N 1
N H 2'' S
X
1''
C

CH2

HM

HM
3 4

5'

CH2

CH2

5''

HX
S

N
C
NH2

NH2

4.49
4.49: Light brown solid; Yield 69%; m.p. 196-1980C; IR (KBr) max (cm-1): 3458,
3374 (N-H), 3080 (aromatic C-H), 1598 (C=N), 1248, 1040 (C-O), 1152 (C=S);
1

H-NMR (400 MHz, CDCl3): 7.86 (4H, brs, NH2), 7.55 (2H, dd, Jm,o=2.2, 8.4Hz, H-

6), 7.51 (4H, m, H-4, 5), 7.47 (2H, d, J5,4=5.1Hz, H-5), 7.31 (2H, d,
J3,4=3.5Hz, H-3), 7.10 (2H, dd, J4,3=3.5Hz, J4,5=5.1Hz, H-4), 6.86 (2H, d,
Jo=8.2Hz, H-3), 5.27 (2H, dd, JXA=6.7Hz, JXM=11.7Hz, H-X), 3.84 (4H, t,
Jvic=6.2Hz, OCH2CH2CH2CH2CH2), 3.39 (2H, dd, JMX=6.7Hz, JMA=16.7Hz, H-M),
3.19 (2H, dd, JAX=11.6Hz, JAX=16.7Hz, H-A), 1.79 (4H, quintet, Jvic=6.2Hz,
OCH2CH2CH2CH2CH2), 1.42 (4H, quintet, Jvic=6.5Hz, OCH2CH2CH2CH2CH2), 1.32
(4H, quintet, Jvic= 6.5Hz, OCH2CH2CH2CH2CH2), 1.22 (4H, quintet, Jvic= 6.5Hz,
OCH2CH2CH2CH2CH2);

13

C-NMR (100 MHz, CDCl3): 177.8 (C=S), 156.4 (C=N),

153.2 (C-2), 147.1 (C-2), 136.3 (C-5), 134.2 (C-1), 132.0 (C-6), 131.6 (C-4),
131.0

(C-3),

127.9

(C-4),

127.1

(C-5),

116.0

(C-3),

63.6

(OCH2CH2CH2CH2CH2), 56.7 (C-5), 46.1 (C-4), 29.2 (OCH2CH2CH2CH2CH2), 22.9


(OCH2CH2CH2CH2CH2),

20.9

(OCH2CH2CH2CH2CH2),

19.8

(OCH2CH2CH2CH2CH2); MS: m/z (M+Na)+ 767 (100 %), (M+1)+ 745 (10.1 %), 742
(24.4 %), 580 (60.1 %), 460 (19.5 %), 414 (18.6 %), 330 (20.5 %), 314 (40.8 %), 231
(30.7 %); Anal. calc. for C38H44O2N6S4: C, 61.29; H, 5.91; N, 11.29; S, 17.20 Found:
C, 61.52; H, 5.96; N, 11.34; S, 17.25 %.

REFERENCES
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SUMMARY

The chemistry of heterocyclic compounds is as logical as the chemistry of aliphatic


and olefinic compounds. Out of the more than twenty million chemical compounds
currently registered, about one half contains heterocyclic system. Some of the
significant organic compounds like alkaloids, antibiotics, essential amino acids,
vitamins, hemoglobin, hormones, chlorophyll and dye stuffs contain heterocyclic ring.
Heterocycles are important because of their natural abundance and these are also
significant due to their chemical, biological and technological applications. The
heterocyclic substrates have great applicability in pharmaceutics and most of the
drugs in clinical uses are based on heterocyclic constitution as they have specific
chemical reactivity. The majority of synthetic heterocyclics have found widespread
use, for example as anticancer agents, antitubercular, analgesics, hypnotics,
pesticides, insecticides and weed killers. These compounds are the integral part of the
synthetic organic chemistry and most of these substrates are of the immense
importance to the biological and industrial purposes. The majority of pharmaceuticals
and biologically active agrochemicals are the heterocyclic products while countless
additives and modifiers used in industrial applications ranging from cosmetics,
reprography, information storage and plastics are the heterocyclic substrates in nature.
The Chapter-I presents many examples from the literature in the area of general
heterocyclic chemistry. Majority of heterocyclic systems described here are
significant due to their biological activities. Major emphasis has been laid down upon
the various applications of the variety of the five membered heterocyclic derivatives
containing the two nitrogen atoms at the 1,2 and 1,3-positions and compounds
particularly pyrazoline, thiadiazolines and related derivatives are very significant from
the synthetic and biological significance point of view. It was evident from the
literature studies that chalcones and thiosemicarbazones are found to be very
important synthones and with proper designing these intermediates can be subjected
to the synthesis of the variety of heterocyclic compounds. Hence the chapters (IIa,
IIb, III, IVa & IVb) of the thesis have been devoted upon the chemical
transformations of chalcones, bischalcones and thiosemicarbazones for the generation
of novel heterocyclic compounds.
The Chapter-II has been divided into two parts IIa & IIb. In part IIa, synthesis of
alkoxy substituted furyl/thienyl-pyrazolines have been described. These compounds
were obtained starting from O-hydroxy-acetophenone which was reacted with furfural

and thiophene-2-carboxaldehyde in the presence of NaOH/EtOH at 0C to provide


chalcone 2a & 2b respectively which were O-alkylated with suitable alkylating
agents (allyl bromide, benzyl chloride, bromo ethylacetate & 1-chloromethylnapthalene) to furnish alkoxy-chalcones 3a-3d & 4a-4d. The later further underwent
cyclization reactions with phenyl hydrazine in the presence of EtOH/AcOH under
refluxing conditions to yield pyrazolines 5a-5d and 6a-6d in good yields (Scheme-1).

OH

CH3

OH

NaOH/ EtOH/ O0C

H
X

X
O

(X= O & S)

CH2

O
3 4

2a (X = O) & 2b (X = S)
Dry acetone/

HM
HA

K2CO3/ Bu4N+I-/ BrCH2R

2N

N Hx

CH2 R

O
3a-3d (X=O)
4a-4d (X=S)

5a-5d (X=O)
6a-6d (X=S)

a = - CH=CH2, b = - Ph, c = - COOEt , d =

Scheme-1

In the Chapter-IIb, the investigations have been carried out upon the synthesis of
alkoxy N-thiocarbamoyl-pyrazolines. These significant heterocyclics have been
prepared from the cyclocondensation reactions of chalcones 3a-3d and 4a-4d with
thiosemicarbazide under the EtOH/NaOH conditions to furnish 7a-7d and 8a-8d as
the final pyrazoline derivatives (Scheme-2).

CH2 R

HA

NaOH/EtOH
S

H2N NH

CH2 R
HM

C NH2

2N
1

N
C

Hx

NH2
3a-3d (X=O)

7a-7d (X=O)

4a-4d (X=S)

8a-8d (X=S)

a = - CH=CH2, b = - Ph, c = - COOEt , d =

Scheme-2
The trans geometry around C-2 & C-3 double bond in alkoxy-chalcones was
confirmed from the coupling value of J2,3=15.8 Hz. The IR spectra of these
compounds exhibited strong absorption at 1660-1650 cm-1 due to the presence of
conjugated carbonyl group.
The sterochemical disposition of the hydrogens H-X, H-M & H-A belonging to the
pyrazoline ring (alkoxy-pyrazolines) have been ascertained from the study of coupling
constant (J). The vicinal coupling between H-X & H-M was found to be 12.1 Hz
which describes that these hydrogens are cis to each other while trans relationship
between H-X & H-A was evident from the coupling constant of JXA=6.5 Hz. The
coupling value of 17.5 Hz between H-M & H-A evidently indicates their geminal
placement at C-4. The phenyl rings at N-1 and C-5 are certainly trans oriented to
avoid any intramolecular repulsion. The C=N moiety of the pyrazoline ring became
evident from the strong absorption in the IR spectra at 1602-1594 cm-1.
This

study

represents

general

method

for

the

synthesis

of

alkoxy

N-phenyl/thiocarbamoyl- pyrazolines under the ordinary conditions.


The Chapter-III includes the cyclization reactions of the alkoxy-thiosemicarbazones
which lead to the formation of new thiadiazolines and quinoxaline based thiazoles.
The reaction of p-hydroxybenzaldehyde 9 with suitable alkylating agent (allyl
bromide, benzyl chloride, bromo ethyl acetate, 1-chloromethyl-napthalene, ethyl
iodide and propyl iodide) provided 4-alkoxy-bezaldehyde 10a-10f which were easily
condensed with thiosemicarbazide by refluxing in EtOH/HCl medium to give
thiosemicarbazones 11a-11f. The later were refluxed under Ac2O medium to yield
new thiadiazolines 12a-12f (Scheme-3).

O CH2 R

OH

H2N NH

Br-CH2R

S
C NH2

CH2

/ dry EtOH

HCl /
H C O

S
H C N NH

H C O

NH2

11a-11f

10a-10f

Ac2O /

O CH2 R

H
S

O
C CH3

N
H3C

NH

O
12a-12f
a = -CH=CH2, b = -Ph, c = -COOEt , d =

, e = -CH3 , f = -CH2CH3

Scheme-3
To investigate the cyclization behavior of 11a-11f, these intermediates were also
reacted with 2,3-dichloroquinoxaline in alcoholic medium to furnish thiazoles 13a-13f
as the final products (Scheme-4).

CH2 R

CH2 R

2,3-dichloroquinoxaline/

S
H C

N NH

C NH2

11a-11f

a = -CH=CH2, b = -Ph, c = -COOEt , d =

Scheme-4

H C N NH
13a-13f

, e = -CH3, f = -CH2CH3

The final products (12a-12f & 13a-13f) of the above reactions (Scheme-3 & Scheme4) have been obtained in very good yield by using simple protocols.
Bischalcones are the molecules which are formed by joining two chalcone moieties
together through the carbon chains of varying lengths and structures. The easy
cyclization reactions of chalcones have prompted us to investigate the chemical
transformations of the bischalcones in order to obtained novel bisheterocyclic
compounds. The results of chemical transformations of the bischlcones are presented
in Chapter-IV that has been further sub divided into two parts IVa and IVb.
In Chapter-1Va synthesis of the furyl-bischalcones 14a-14e built around the aliphatic
chains of varying lengths have been described. The cyclocondensation reactions of
14a-14e with phenyl hydrazine under the usual alcoholic and AcOH medium resulted
in the formation of novel bispyrazolines 16a-16e (Scheme-5).

OH

X
O
2a (X = O) & 2b (X = S)
+ -

K2CO 3/acetone/ Bu 4N I / Br-(CH ) -Br/


2 4

CH2

(CH2) n

CH2

2
X

O
14a-14e (X = O) & 15a-15e (X= S)

(CH 2)n

O CH2

CH2 O
HM

HM

3 4

HA

HA

2N
1N

HX

HX

16a-16e (X = O) & 17a-17e (X= S)

n = 2, 3, 4, 6, 8

Scheme-5
To generalize above syntheses, the researches have also been focused upon the
thienyl- bischalcones 15a-15e which were also converted to bispyrazolines 17a-17e
by reacting with phenyl hydrazine (Scheme-5).
The bischalcones 14a-14e & 15a-15e required for above study were obtained in good
yields from the O-alkylation of furyl/thienyl-chalcone 2a & 2b respectively with
suitable 1,-dibromoalkanes in the presence of anhydrous K2CO3/dry acetone and
Bu4N+I- as the phase transfer catalyst. The use of PTC in these syntheses not only

reduced the reaction times drastically but also improved the yield of bischalcones.
The Chapter-IVb concerns with the extensive reactions of bischalcones (14a-14e &
15a-15e) with thiosemicarbazide in the presence of NaOH/EtOH under refluxing
conditions and these reactions could furnish new N-thiocarbamoyl-bispyrazolines
18a-18e & 19a-19e in good yields (Scheme-6). The main purpose of this study was to
investigate the utility of thiosemicarbazide as the cyclizing agent in place of phenyl
hydrazine and also to investigate the effect of thiocarbamoyl group upon the
antibacterial behavior of the resulting bispyrazolines.
O

CH2

(CH 2)n

CH2

14a-14e (X=O) & 15a-15e (X= S)

EtOH/ NaOH/

NH2CSNHNH2

(CH 2)n

O CH2

CH2 O
HM

HM

3 4
2N

HA

HA

1N

HX

HX
S

N
C
NH2

NH2

18a-18e (X= O) & 19a-19e (X = S)


a

n = 2, 3,

4, 6,

Scheme-6
The values of coupling constant (Jvic & Jgem) were used to ascertain the
stereochemical features of the bischalcones 14a-14e & 15a-15e (H-2 & H-3;
Jtrans=15.7 Hz) and bispyrazolines 16a-16e, 17a-17e, 18a-18e & 19a-19e (H-X, H-M
& H-A; JA,X=6.5 Hz, JM,X=12.2 Hz & JM,A=17.7 Hz).

To investigate the biological significance of the final products, the compounds 5a-5d,
6a-6d, 7a-7d, 8a-8d, 12a-12d, 13a-13d, 16a-16e, 17a-17e, 18a-18e and 19a-19e
were also subjected to their antibacterial analysis against the four bacteria strains
namely A. hydrophila, Y. enterocolitica, L. monocytogenes & S. aureus.
In vitro antibacterial activities of above heterocyclics were carried out using the
culture by the disc diffusion method using nutrient broth medium [contained
(mcg/ml): beef extract 1 g; peptone 5 g; pH 7.0]. In the disc-diffusion method, sterile
paper discs (5 mm) impregnated with compound dissolved in dimethylsulfoxide
(DMSO) at the concentration of 100 g/ml were used. Gentamicin and Tetracycline
were used as the standard drugs, whereas DMSO poured disc was used as negative
control. Then, the paper discs impregnated with the solution of the compounds were
placed on the surface of the media inoculated with the microorganisms (A.
hydrophila, Y. enterocolitica, L. monocytogenes & S. aureus). The susceptibility of
the bacteria to the test compounds were determined by the formation of an inhibitory
zone after 24 hrs of incubation at 37oC. After incubation, the diameters of the
inhibition zones (mm) were measured. The MIC (g/ml) of these compounds were
also determined by using Serial tube dilution method at the concentration of 50, 40,
30, 20 & 10 g/ml.

Most of the studied compounds exhibited good to excellent activity against the tested
microorganisms which was evident from their zone of inhibitions (mm) and MIC
(g/ml) results. The distinct differences in the antibacterial property of these
compounds further justify the purpose of this study. The importance of such work lies
in the possibility that the new compounds might be more efficacious drugs against
bacteria for which a thorough investigation regarding the structureactivity
relationship, toxicity and their biological effects could be helpful in designing more
potent antibacterial agents for therapeutic use.

Thus, in these studies variety of the alkoxy substituted pyrazolines, bispyrazolines,


thiadiazolines and thiazoles have been prepared in good yields under the ordinary
conditions which are also associated to the good antibacterial activities.

The chalcones and bischalcones used in these studies have been synthesized through a
sequence of several steps. The N-phenyl-pyrazolines, N-thiocarbamoyl-pyrazolines,
N-phenyl-bispyrazolines,

N-thiocarbamoyl-bispyrazolines,

thiadiazolines

and

thiazoles obtained in this study were thoroughly purified by crystallizations in


appropriate solvents. The structures of the newly synthesized intermediates and final
heterocyclic/bisheterocyclic compounds have been confirmed from the rigorous
analysis of their IR, 1H-NMR (400 MHz, CDCl3/DMSO-d6) and 13C-NMR (100 MHz,
CDCl3/DMSO-d6) spectral parameters. The mass spectral fragmentation data have
also been utilized to confirm the structures of the prepared compounds.

LIST OF PUBLICATIONS
1.

Synthesis, studies and in vitro-antibacterial activity 4 of N-substituted 5(furan-2-yl)- phenyl-pyrazolines


Mamta Rani, Mohamad Yusuf, Salman Ahamad Khan, P.P. Sahota and G. andove
Arabian Journal of Chemistry 2011 (doi:10.1016/j.arabjc.2010.10.036).

2. Synthesis and in-vitro-antibacterial activity of [5-(furan-2-yl) - phenyl]-4, 5carbothioamide-pyrazolines


Mamta Rani, Mohamad Yusuf and Salman Ahamad Khan
Journal of Saudi Chemical Society 2011 (doi:10.1016/j.jscs.2011.02.012).
3. Synthesis and biological evalutions of thiadiazoline derivatives
Mamta Rani and Mohamad Yusuf
Hetrocyclic communication (Communicated Manuscript-ID: HC.2011.0059)
4. Synthesis, studies and in vitro antibacterial activity of some 5-(thiophene-2yl)- phenyl-pyrazoline derivatives
Mamta Rani and Mohamad Yusuf
Journal of Saudi Chemical Society 2011 (doi:10.1016/j.jscs.2011.09.002).
5. Synthesis and in-vitro antibacterial activity of some alkoxy based Nsubstituted 5-(furan-2-yl)-phenyl-bispyrazolines
Mamta Rani and Mohamad Yusuf
European Journal of Chemistry 2012, 3(1), 21-25, doi: 10.5755/j.eurochem.
6. Synthesis and in-vitro antibacterial activity of some bis-5-(thiophen-2-yl)carbothioamide-pyrazoline derivatives
Mamta Rani and Mohamad Yusuf
European Journal of Chemistry 2012 (Accepted Manuscript, MS No. 476-3462-2CE-1).