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MICROWAVE ASSISTED SYNTHESIS OF
SOME NOVEL CHALCONES
A project report submitted in partial fulfillment of requirement for the
degree of
Master of Science
in
ORGANIC CHEMISTRY
by
MUSAAB MOHAMED ALI ELSANOOSI
(100712503079)
Under the Supervision of
PROF. D. ASHOK
DEPARTMENT OF CHEMISTRY
OSMANIA UNIVERSITY
HYDERABAD-500 007
2014
I
Dedicated to
my beloved mother, father,
brothers and sisters
II
ACKNOWLEDGMENT
It gives me great pleasure and profound privilege to place on record
my deep sense gratitude and indebtedness to my supervisor Prof. D. Ashok
whose constructive comments, unflagging optimism and scholarly guidance
throughout the present work has driven me towards the success of this
endeavor. It is pleasure to thank Prof. K. Nageswar Rao, Dean, Faculty of
Science, Osmania University, Prof. V. Uma, Head, Department of
Chemistry, Osmania University. for providing facilities to carry out the work
in the department.
.
It is pleasure to thank Prof. L.N. Sharada, Chairman, Board of Studies
in Chemistry, Department of Chemistry. I acknowledge with pleasure the
encouragement shown by Prof. V. Prabhakar Reddy, Prof. Ch. Prasad Rao,
Prof. Ch. Krishna Reddy, Prof. P. Leelavathi, Dr. M. Vijjualatha and Mr. P.
Vijay Kumar. I thank for the support of Mr. S. Ravi, Mr. A. Ganesh, Mr.
Mohan Gandhi, Mr. A. Vikas,Mrs. R. Kavitha and Mr. G. Srinivas Research
Scholars, in my thesis, without their help this work have been an unfinished
job.
Deeply from my heart with love and faith, I would like to thank my
beloved father Mr. Mohamed Ali Elsanosi and my mother Mrs. Amna
Abdulkarim for their encouragement and prays throughout my life, and my
special tribute goes to my teachers who have taught me to rise this level,
special thanks also to all my graduate friends, My apologies to all those who
have helped me but are not acknowledged. May God bless them all for ever.
III
Re-Accredited by NAAC with ‘A’ Grade
CERTIFICATE
This is to certify that the project work entitled “Microwave Assisted
Synthesis of Some Novel Chalcones” is submitted by Mr. MUSAAB
MOHAMED ALI ELSANOOSI in partial fulfillment for the award of
degree of Master of Science in Organic Chemistry. This work has been
carried out under my guidance and supervision in the Department of
Chemistry, Osmania University, Hyderabad, is original and has not been
submitted for any degree or diploma to this University or any other
University.
Date: 25th
September, 2014 D. Ashok
Dr. D. ASHOK Ph.D.
Professor of Organic Chemistry
Department of Chemistry
Osmania University Campus
Hyderabad - 500 007. India
040- 27682337 (O)
09391024769 (M)
Email : [email protected]
IV
DECLARATION
The project work embodied in this thesis has been carried out in the
Department of Chemistry, Osmania University, Hyderabad, under the
supervision of PROF. D. ASHOK, Department of Chemistry, Osmania
University, Hyderabad. This work is original and has not been submitted for
any degree or diploma to this University or any other University.
Date: 25th
September, 2014 MUSAAB ELSANOOSI
V
List of Abbreviation
br broad
13C NMR Carbon Nuclear Magnetic Resonance
CC Column Chromatography
d doublet
dd doublet of doublet
)))) Ultra sound reaction
DMF Dimethylformamide
EtOH Ethanol
PEEK Poly ether-ether-ketone
MAOS Microwave assisted organic synthesis
1H NMR Hydrogen Nuclear Magnetic Resonance
IR Infrared
DMSO Dimethyl sulfoxide
m multiplet
MORE Microwave induced organic reaction enhancement
Conven. Conventional method
m/z mass to charge ratio
M. P Melting point
ppm parts per million
DMS Dimethyl sulfide
RT Room temperature
s singlet
t triplet
TLC Thin Layer Chromatography
UV Ultraviolet
VI
Table of Contents
No. Title Page
1 Abstract IX
CHAPTER 1
2 Biological activity of heterocyclic compounds
1
3 Microwave assisted organic synthesis (MAOS)-a brief review 7
4 Microwave irradiation method differs from Conventional
heating method
12
5 Advantages of microwave assisted reactions over the
conventional reactions
14
6 Examples for Microwave irradiation reactions 15
7 Objective of current research 18
CHAPTER 2
8 Introduction 19
9 Methods for the synthesis of Chalcones 20
10 Present work
23
CHAPTER 3
11 Experimental 33
12 Conclusion 47
13 References 48
14 Publication 52
VII
List of Tables
Table
No.
Title Page
1.1 Biological activity of Chalcone derivatives 3
1.2 Biological activity of Quinoline derivatives 4
1.3 Biological activity of Piperidine derivatives 5
1.4 Biological activity of Pyrrolidine derivatives 5
1.5 Biological activity of Morpholine derivatives 6
2.1 Physical data of (E)-1-(1-Substituted naphthalen-2-yl)-3-(2-
morpholinoquinolin-3-yl)prop-2-en-1-ones
26
2.2 Physical data of (E)-1-(1-Substituted naphthalen-2-yl)-3-(2-
piperidinoquinolin-3-yl)prop-2-en-1-ones
29
2.3 Physical data of (E)-1-(1-Substituted naphthalen-2-yl)-3-(2-
pyrrolidinoquinolin-3-yl)prop-2-en-1-ones
32
VIII
List of Schemes
Scheme
No.
Title Page
2.1 Synthesis of (E)-1-(4-Aminophenyl)-3-(2-
morpholinoquinolin-3-yl)prop-2-en-1-one
20
2.2 Synthesis of (E)-1-(4-Aminophenyl)-3-(7-methyl-2-
morpholinoquinolin-3-yl)prop-2-en-1-one
20
2.3 Synthesis of (E)-3-(3-Aryl-3-oxoprop-1-en-1-yl)quinolin-
2(1H)-ones
21
2.4 Synthesis of (E)-1-Aryl-3-(2-chloroquinolin-3-yl)prop-2-en-
1-ones
21
2.5 Synthesis of (E)-1-Aryl-3-(2-chloroquinolin-3-yl)prop-2-en-
1-ones
22
2.6 Synthesis of (E)-1-Aryl-3-(2-chloroquinolin-3-yl)prop-2-en-
1-ones
22
2.1 Synthesis of (E)-1-(1-Substituted naphthalen-2-yl)-3-(2-
morpholinoquinolin-3-yl)prop-2-en-1-ones
26
2.2 Synthesis of (E)-1-(1-Substituted naphthalen-2-yl)-3-(2-
piperidinoquinolin-3-yl)prop-2-en-1-ones
29
2.3 Synthesis of (E)-1-(1-Substituted naphthalen-2-yl)-3-(2-
pyrrolidinoquinolin-3-yl)prop-2-en-1-ones
32
IX
ABSTRACT
In the present study, we have investigated the microwave assisted
synthesis of several (E)-1-(1-Substituted naphthalen-2-yl)-3-(2-substituted
quinolin-3-yl)prop-2-en-1-ones by base catalyzed Claisen-Schmidt
condensation reaction of 2-Morpholinoquinoline-3-carbaldehyde/ 2-
Piperidinoquinoline-3-carbaldehyde/ 2-Pyrrolidinoquinoline-3-carbaldehyde
with 1-(1-Hydroxynaphthalen-2-yl) ethanone/ 1-(1-Methoxynaphthalen-2-
yl)ethanone. The structures of the newly synthesized compounds were
confirmed by elemental analysis, and spectral data such as IR, 1H &
13C
NMR and Mass.
1
BIOLOGICAL ACTIVITY OF HETEROCYCLIC COMPOUNDS AND
MICROWAVE ASSISTED ORGANIC SYNTHESIS (MAOS)
- A BRIEF REVIEW
1.1 Biological activity of heterocyclic compounds
Infectious diseases account for about half of the deaths in tropical countries.
Bacterial diseases are type of infectious diseases caused by pathogenic bacteria.
Bacterial infections are one of the prominent causes of health problems, physical
disabilities and mortalities around the world. These results when the harmful
bacteria get into a body area, multiply their and thrash the body’s defensive
mechanism. It is notable that majority of bacteria are non pathogenic and are not
harmful to human health. Some bacteria are even helpful and necessary for the
good health. Millions of bacteria normally live in the intestine, on the skin and the
genitalia. Medicinal plants are a rich source of antimicrobial agents and provide a
safer and cost effective way of treating bacterial infections. Some of the natural
antibacterial compounds generally possess quinolines as a core unit. Thus synthesis
of such heterocycles became main focus for synthetic chemists.
Heterocyclic moiety is a pivotal core of many biologically and
pharmacologically interesting compounds. Any synthetic approach for these
compounds depends upon the availability cost of the starting materials, selection of
ring closure steps and the tolerance of the functional groups present in the
molecule. A vast number of nitrogen containing heterocyclic building blocks have
applications in pharmaceuticals and agro-chemical research and drug discovery.
Heterocyclic compounds have a large number of applications in dyes and polymer
chemistry. Several analogues of heterocycles show different biological activity.
2
More than 50% of the drugs used in the modern medicine are based on either
synthetic or natural heterocyclic systems. The quinolines scaffold and it derivatives
represent a major class of heterocycles and are widely found in natural products,
drugs
and exhibit significant role in medicinal chemistry. Several quinoline
derivatives have been reported to exhibit biological activities such as
antibacterial1 antimalarial
2, antiallergenic
3, anti-inflammatory
4 and antitumor
5.
Among the quinolines, 2-chloro-3-formylquinolines find an important place in
synthetic organic chemistry, as these are key intermediates for further β-annelation
of a wide variety of ring systems and for the inter-conversions of many functional
groups6.
Morpholine derivatives present a wide range of biological activities, they can
be used as inhibitors and deactivators of liver alcohol dehydrogenase, antitumor,
antiviral or antimicrobial agents, anti-inflammatory or antifungal drugs7.
Piperidine derivatives were reported for the various pharmacological activities such
as antimicrobials8, anticonvulsants
9, anti-inflammatory
10, antidepressant
(Paroxetine)11
and attention-deficit hyperactivity disorder (ADHD)
(Methylphenidate) agents.
Pyrrolidine derivatives are well known for their versatile pharmacological
activities such as antimicrobial12
, antitumor13
, anti-HIV14
, anticonvulsant15
.
Chalcones are a class of privileged structures that have a wide range of biological
properties such as antimicrobial
16, anti-inflammatory
17 and anticancer
18 activities
etc. Sofalcone is a gastroprotective chalcone based drug promotes healing of gastric
ulcer and they inhibit many types of enzymes. Chalcones constitute an important
class of natural products belonging to the flavonoid families19
, which are also key
3
precursors in the synthesis of many biologically important heterocycles such as
benzothiazepines20
, pyrazolines21
, 1,4-diketones22
and flavones23
.
Table 1.1: Biological activity of Chalcone derivatives
Compound Structure Biological activity Ref
(E)-1-phenyl-3-(2-(piperidin-
1-yl)quinolin-3-yl)prop-2-en-
1-one
Antidepressant
activity
24
Licochalcone
Anticancer activity
25
Xanthohumol
Anticancer activity
26
4
Table 1.2: Biological activity of Quinoline derivatives
Compound Structure Biological activity Ref
Cinchonine
Antimalarial activity
27
Norfloxacin
Antibacterial activity
28
Mefloquite
Antibacterial activity
29
5
Table 1.3: Biological activity of Piperidine derivatives
Compound Structure Biological activity Ref
Paroxetine
Antiprotozoal activity
30
Methylphenidate
Attention Deficit Hyperactivity
Disorder
31
Table 1.4: Biological activity of Pyrrolidine derivatives
Compound Structure Biological activity Ref
Nicotine
Antibacterial activity
32
Desoxy-D2PM
Antimalarial activity
33
6
Table 1.5: Biological activity of Morpholine derivatives
Compound Structure Biological activity Ref
3-(Diphenylmethyl)Morpholine
Stimulant and
Anorectic effect
34
Gefitinib
Anticancer activity
35
7
1.2 Microwave assisted organic synthesis (MAOS)-a brief review
There are major advancements in the last few years in the methodology of
synthetic chemistry, but one element of the process has not much changed since its
inception i.e. the use of conductive heating to perform chemical transformations.
However, with the advent of microwave assisted synthesis, there is for the first
time, a technology that will dramatically, change the way chemical synthesis is
performed by offering a new energy source, powerful enough to complete reactions
in minutes instead of hours or even days.
A microwave is a form of electromagnetic energy, which falls at lower
end of the electromagnetic spectrum and is defined in a measurement of frequency
as 300 to 300,000 MHz. This includes the region that will affect molecular rotation,
though the preferred frequency of 2450 MHz, chosen by microwave
instrumentation manufacturers falls below any of the rotational transitions that will
occur in molecules, one of the four available frequencies for industrial, scientific or
medical applications, 2450 MHz is preferred because it has the right penetration
depth to interact with laboratory scale samples and has become the standard for
bench top systems.
Microwave energy consists of an electric field and a magnetic field
though only the electric field transfers energy to heat a substance. Any interaction
from magnetic field is insignificant. The energy in microwave photons (0.03
K.cal/mole) is very low relative to the typical energies of 80-120 K.cal/mole for
chemical bonds. Thus, microwaves will not directly affect molecular structure. In
8
the excitation of molecules, the effect of microwave absorption is purely increased
kinetic energy.
Traditionally, chemical synthesis has been achieved through conductive
heating with an external heat source, where the temperature is elevated and heat is
driven into the substance, passing first through the walls of the vessel in order to
reach the solvent and reactants. This is a slow and inefficient method for
transferring energy into the system because it depends on the thermal conductivity
of the various materials that must be penetrated. It also results in a higher external
temperature than the final internal temperature, which is problematic as the
required internal temperature can only be reached by sufficiently increasing the
surface temperature of the material over the desired temperature. Microwave
heating is a different process. The microwaves couple directly with the molecules
that are heating, leading to a rapid rise in temperature, because the process is not
dependent upon the thermal conductivity of the materials, the result is an
instantaneous heating of anything that will react to either dipole rotation or ionic
conductions, the two fundamental mechanisms for transferring energy from
microwave to the substance being heated.
One of the most important aspects of microwave energy is the rate at which
it heats. Microwave will transfer energy in 10-9
seconds with each cycle of
electromagnetic energy. The kinetic molecular relaxation from this energy is
approximately 10-5
seconds. The energy transfers faster than the molecules can
relax, resulting in a non-equilibrium condition and high instantaneous temperatures
that effect the kinetics of the system. This enhances the reaction rate as well as the
yields. Activated complexes do not normally exist long enough to have an
9
opportunity to absorb microwave energy although there are a number of stabilized
intermediates, resident stabilized intermediates and other intermediates that are
much longer lived. Many of these have lifetimes longer than 10-9
seconds, so the
opportunity exists for them to couple directly with the microwave and be further
enhanced. Most intermediates are highly polar species and many of them are even
ionic in character, making them excellent candidates for microwave energy
transfer.
Microwave enhanced chemical reactions can be faster by as much as 1,000
fold this is based on experimental data, from numerous works, that have been
performed over the last 15 years. Using the rate equation, calculations were
performed to determine the temperatures required to get these reaction
enhancements, for a 1000 fold rate increase, it was determined that a temperature
enhancement of approximately 55 oC would be needed. For a 100-fold rate increase
the temperature would reach 185 oC and require approximately a 35
oC increase
over the bulk temperature. For a 10-fold enhancement, a 15-20oC increase would
be required. Thus, these instantaneous temperatures are very consistent with the
temperatures that would be expected in these systems and can fully account for the
reaction rate and yield enhancement. These calculations were also performed over a
range of temperatures and as expected, the lines are essentially parallel predicting
the instantaneous versus bulk temperatures.
Microwave heating allows chemical reactions to be shifted from kinetic
control to thermodynamic control because of the energy available. This can change
the product for a particular transformation. This mechanism is a probable
explanation for some of the work that has been done concerning selected
10
stereoisomers, which were generated using microwave versus conventional
heating.. Microwave heating is extremely useful in slower reactions where high
activation energies are required to do various transformations. With the elevated
molecular energy generated by the transfer of microwave energy, reactions that
required many hours or even days to complete have been accomplished in min. It is
also possible to use non-polar solvents to actually reduce the bulk heating and
directly energize the molecule. The solvent acts as a heat sink to pull energy way.
Frequently used processing techniques employed in microwave-assisted
organic synthesis involve solvent less dry-media procedures where the reagents
are readsorbed onto either a more or less microwave transparent (silica, alumina or
clay)36
or strongly absorbing (graphite)37
inorganic support which can additionally
be doped with a catalyst or reagent. The solvent-free approach was very popular
particularly in the early days of microwave assisted organic synthesis (MAOS)
since it allowed the safe use of domestic household microwave ovens and standard
open-vessel technology. Although a large number of interesting transformations
with dry-media reactions have been published in the literature, technical
difficulties relating to non-uniform heating, mixing, and the precise determination
of the reaction temperature remain unsolved, in particular when scale-up issues
need to be addressed. In addition phase-transfer catalysis (PTC) has also been
widely employed as a processing technique in MAOS38
.
Alternatively, microwave-assisted synthesis can be carried out in standard
organic solvents either under open or sealed-vessel conditions. If solvents are
heated by microwave irradiation at atmospheric pressure in an open vessel, the
boiling point of the solvent (as in an oil-bath experiment) typically limits the
11
reaction temperature that can be achieved. In the absence of any specific or non-
thermal microwave effects (such as the superheating effect at atmospheric pressure
which has been reported to be up to 40 °C)39
the expected rate enhancements would
be comparatively small. To nonetheless achieve high reaction rates, high-boiling
microwave-absorbing solvents such as DMSO, N-methyl-2-pyrrolidone (NMP),
1,2-dichlorobenzene (DCB) or ethylene glycol have been frequently used in open-
vessel microwave synthesis40
. However, the use of these solvents presents serious
challenges during product isolation. The recent availability of modern microwave
reactors with on-line monitoring of both temperature and pressure has meant that
MAOS in sealed vessels - a technique pioneered by Strauss in the mid 1990s41
has
been celebrating a comeback in recent years. This is clearly evident from surveying
the recently published literature in the area of MAOS and it appears that the
combination of rapid dielectric heating by microwaves with sealed-vessel
technology (autoclaves) will most likely be the method of choice for performing
MAOS in the future.
12
1.3 Microwave irradiation method differs from Conventional
heating method
1.3.1 Conventional heating method
In all conventional heating reactions, heating proceeds from a surface,
usually the inside surface of the reaction vessel. Whether one uses a heating mantle,
oil bath, steam bath or oven an immersion heater, the mixture must be in physical
contact with a surface that is at a higher temperature than the rest of the mixture.
In conventional heating, energy is transferred from a surface, to the bulk
mixture and eventually to the reacting species. The energy can either make the
reaction thermodynamically allowed or it can increase the reaction kinetics.
In conventional heating, spontaneous mixing of the reaction mixture may
occur through convection or mechanical means (stirring) can be employed to
homogenously distribute the reactants and temperature throughout the reaction
vessel. Equilibrium temperature conditions can be established and maintained.
Although it is an obvious point, it should be noted here that in all
conventional heating of open reaction vessels, the highest temperature that can be
achieved is limited by the boiling point of the particular mixture. In order to reach
higher temperature in the open vessel, a higher-boiling solvent must be used.
In conclusion, compared to conventional heating, microwave heating
enhances the rate of certain reactions by 10 to 1000 times. This is due to its ability
to substantially increase the temperature of a reaction.
13
1.3.2 Microwave irradiation method
Microwave heating occurs somewhat differently from conventional heating.
First, the reaction vessel must be substantially transparent to the passage of
microwaves. The selection of vessel material is limited to fluoropolymers and only
a few other engineering plastics such as polypropylene or glass fiber filled poly
ether-ether-ketone (PEEK).
Heating of the reaction mixture does not proceed from the surface of the
vessel; the vessel wall is almost always at a lower temperature than the reaction
mixture. In fact the vessel wall can be an effective route for heat loss from the
reaction mixture.
Second, for microwave heating to occur, there must be some component of
the reaction mixture that absorbs the penetrating microwaves. Microwaves will
penetrate the reaction mixture, and if they are absorbed, the energy will be
converted into heat. Just as with conventional heating, mixing of the reaction
mixture may occur through mechanical means (stirring) can be employed to
homogeneously distribute the reactants and temperature throughout the reaction
vessel.
14
1.4 Advantages of microwave assisted reactions over the
conventional reactions
Microwave-assisted reactions are emerging as an important tool in chemical
synthesis, the main advantages are:
o Reduction in reaction temperatures
o Increases in reaction rates over 10-10,000 times.
o Increased yields of 10-30% on an average.
o Increased selectivity in the product.
o Minimum side reactions due to rapid quenching
o Reduced solvent usage creates less wastage
o Environmentally clean solvent free processes.
In the field of organic synthesis it is mainly applied to drastically reduce the
reaction times of many synthetic reactions like Diels-Alder, Claisen, Ene reactions
etc.
There has been considerable interest in the application of microwave heating
upon chemical reactions. After much debate there seem to be general agreement
that in most cases microwave heating can only give rise to different temperature
regimes, which can be used in a profitable way. For instance when the reaction
need to be rapid incase of the synthesis of radiopharmaceuticals or when high
temperature need to be reached for the preparation of some inorganic compounds41
.
In addition microwave heating is ideal for solvent-free reaction systems, so called
“dry reactions”. Temperature effects are also the origin of the fact that a power
input change can cause a different.
15
1.5 Examples for Microwave irradiation reactions
1.5.1 Synthesis of 1-phenylpiperidine (1.3)42
.
Conventional: 15%- 20%
Microwave: 80%- 90%
1.5.2 Synthesis of methyl 3-phenyl-4,5-dihydroisoxazole-5-carboxylate (1.6) 43
.
Conventional: 60%- 75%
Microwave: 90%- 98%
16
1.5.3 Synthesis of (E)-(2-nitroprop-1-en-1-yl)benzene (1.9) 44
.
Conventional: 65%- 74%
Microwave:84%- 92%
1.5.4 Synthesis of (2E,2'E)-3,3'-(1,4-phenylene)bis(1-(4-hydroxyphenyl)prop-2-en-
1-one) (1.12) 45
.
Conventional: 70%- 78%
Microwave: 85%- 98%
17
1.5.5 Synthesis of 9-phenyl-3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-dione
(1.15) 46
.
Conventional: 65%- 75%
Microwave: 84%- 95%
18
1.6 Objective of current research
The project report entitled “Microwave Assisted Synthesis of Some Novel
Chalcones” has been divided into three chapters. The first chapter deliberates a
brief review on biological activity of chalcones, heterocyclic compounds and a
brief review on microwave assisted organic synthesis. The second chapter intrigues
introduction and synthesis of quinoline chalcones. The third chapter deals with the
experimental.
Therefore the aim of the present investigation is to synthesize some novel
quinoline chalcones. As a part of our ongoing program towards the microwave
irradiation approach47
to the experimental set ups of induced organic reactions, the
concept of microwave induced organic reaction enhancement (MORE) chemistry
has been utilized for rapid and efficient synthesis of some novel heterocyclic
Chalcones.
19
MICROWAVE ASSISTED SYNTHESIS OF
SOME NOVEL CHALCONES
2.1 Introduction
Several quinoline derivatives exhibit a wide variety of biological activities. It
was also observed from the literature that chalcones are associated with various
biological activities. This leads to the conclusion that the combined effect of both
quinoline and chalcone moieties play an important role in imparting various
biological activities to title compounds. The microwave irradiation methods have
gained popularity as a nonconventional technique for rapid organic synthesis. It
offers a clean, cheap and convenient method of heating which often results in
higher yields and shortens reaction times. These prompted us to take up the
conventional and microwave irradiation synthesis of (E)-1-(1-Substituted
naphthalen-2-yl)-3-(2- Substituted quinolin-3-yl)prop-2-en-1-ones (2.1-2.3)
under
conventional and microwave irradiation.
R= H, Me
20
2.2 Methods for the synthesis of Chalcones
1) H. Kishor Chikhalia et al.,48
have reported the synthesis of (E)-1-(4-
Aminophenyl)-3-(2-morpholinoquinolin-3-yl)prop-2-en-1-one (2.6) by the
condensation of 2-morpholinoquinoline-3-carbaldehyde (2.4) and 4-
aminoacetophenone (2.5) in the presence of KOH in methanol at room temperature.
Scheme-2.1: Synthesis of (E)-1-(4-Aminophenyl)-3-(2-morpholinoquinolin-3-
yl)prop-2-en-1-one (2.6)
2) K. J. Mayan Patel et al.,48
have been reported the synthesis of (E)-1-(4-
Aminophenyl)-3-(7-methyl-2-morpholinoquinolin-3-yl)prop-2-en-1-one (2.8) by
Claisen-Schmidt condensation of 7-methyl-2-morpholinoquinoline-3-carbaldehyde
(2.7) and 4-aminoacetophenone (2.5) in the presence of 20% NaOH in methanol at
room temperature.
Scheme-2.2: Synthesis of (E)-1-(4-Aminophenyl)-3-(7-methyl-2-
morpholinoquinolin-3-yl)prop-2-en-1-one (2.8)
21
3) D. Karthik Kumar and S. P. Rajendra49
have synthesized (E)-3-(3-Aryl-3-
oxoprop-1-en-1-yl)quinolin-2(1H)-ones (2.11) by the condensation of 2-oxo-1,2-
dihydroquinoline-3-carbaldehyde (2.9) and aryl methyl ketone (2.10) in methanolic
KOH at room temperature.
Scheme-2.3: Synthesis of (E)-3-(3-Aryl-3-oxoprop-1-en-1-yl)quinolin-2(1H)-ones
(2.11)
4) S. Abdel-Sattar Hamad Elgazwy50
have synthesized (E)-1-Aryl-3-(2-
chloroquinolin-3-yl)prop-2-en-1-ones (2.13) by Claisen-Schmidt condensation of
2-chloroquinoline-3-carbaldehyde (2.12) and aryl methyl ketones (2.10) in the
presence of piperidine.
Scheme-2.4: Synthesis of (E)-1Aryl-3-(2-chloroquinolin-3-yl)prop-2-en-1-ones
(2.13)
22
5) Vandana Tiwari et al.,51
describes the synthesis of (E)-1-Aryl-3-(2-
chloroquinolin-3-yl)prop-2-en-1-ones (2.13) by the condensation of 2-
chloroquinoline-3-carbaldehyde (2.12), aryl methyl ketones (2.10) in the presence
of K2CO3 under microwave irradiation.
Scheme-2.5: Synthesis of (E)-1-Aryl-3-(2-chloroquinolin-3-yl)prop-2-en-1-ones
(2.13)
6) Vandana Tiwari et al.,52
have reported the synthesis of of (E)-1-Aryl-3-(2-
chloroquinolin-3-yl)prop-2-en-1-ones (2.13) by condensation of 2-chloroquinoline-
3-carbaldehyde (2.12), aryl methyl ketones (2.10) in the pressence K2CO3 & neutral
alumina in dichloromethane in the presence of ultrasound irradiation.
Scheme-2.6: Synthesis of (E)-1-Aryl-3-(2-chloroquinolin-3-yl)prop-2-en-1-ones
(2.13)
23
2.3 Present work
2.3.1 Synthesis of (E)-1-(1-Substituted naphthalen-2-yl)-3-(2-
morpholinoquinolin-3-yl)prop-2-en-1-ones (2.22-2.23) involves five steps:
2.3.1.1 Synthesis of 2-Chloroquinoline-3-carbaldehyde (2.17)
2-Chloroquinoline-3-carbaldehyde (2.17) is synthesized by Vilsmeier-Haack
reaction of acetanilide (2.16).
2.3.1.2 Synthesis of 2-Morpholinoquinoline-3-carbaldehyde (2.18)
2-Morpholinoquinoline-3-carbaldehyde (2.18) is synthesized by the reaction of 2-
Chloroquinoline-3-carbaldehyde (2.17) with morpholine.
24
2.3.1.3 Synthesis of 1-(1-Hydroxynaphthalen-2-yl)ethanone (2.20)
1-Naphthol on acetylation followed by Fries migration afforded 1-(1-Hydroxy
naphthalen-2-yl)ethanone (2.20)
2.3.1.4 Synthesis of 1-(1-Methoxynaphthalen-2-yl)ethanone (2.21)
1-(1-Hydroxynaphthalen-1-yl)ethanone (2.20) on methylation with dimethyl
sulphate afforded 1-(1-Methoxynaphthalen-1-yl)ethanone (2.21)
25
2.3.1.5 Synthesis of (E)-1-(1-Substituted naphthalen-2-yl)-3-(2-
morpholinoquinolin-3-yl)prop-2-en-1-ones (2.22-2.23) under conventional and
microwave irradiation methods
26
Table 2.1: Physical data of (E)-1-(1-Substituted naphthalen-2-yl)-3-
(2-morpholinoquinolin-3-yl)prop-2-en-1-ones
S.No Compound M. P.
(oC)
Reaction time Yield (%)
Conven.
(hr)
MWI
(min) Conven. MWI
1
(E)-1-(1-Hydroxynaphthalen-2-yl)-3-(2-
morpholinoquinolin-3-yl)prop-2-en-1-
one (2.22)
133-136 5 3 70 88
2
(E)-1-(1-Methoxynaphthalen-2-yl)-3-(2-
morpholinoquinolin-3-yl)prop-2-en-1-
one (2.23)
126-129 5 3.5 72 92
27
2.3.2 Synthesis of (E)-1-(1-Substituted naphthalen-2-yl)-3-(2-
piperidinoquinolin-3-yl)prop-2-en-1-ones (2.25-2.26) involves five steps:
2.3.2.1 Synthesis of 2-Chloroquinoline-3-carbaldehyde (2.17)
(Discussed earlier in 2.3.1.1)
2.3.2.2 Synthesis of 2-Piperidinoquinoline-3-carbaldehyde (2.24)
2-Piperidinoquinoline-3-carbaldehyde (2.24) is synthesized by the reaction of 2-
Chloroquinoline-3-carbaldehyde (2.17) with piperidine.
2.3.2.3 Synthesis of 1-(1-Hydroxynaphthalen-2-yl)ethanone (2.20)
(Discussed earlier in 2.3.1.3)
2.3.2.4 Synthesis of 1-(1-Methoxynaphthalen-2-yl)ethanone (2.21)
(Discussed earlier in 2.3.1.4)
28
2.3.2.5 Synthesis of (E)-1-(1-Substituted naphthalen-2-yl)-3-(2-
piperidinoquinolin-3-yl)prop-2-en-1-ones (2.25-2.26) under conventional and
microwave irradiation methods
29
Table 2.2: Physical data of (E)-1-(1-Substituted naphthalen-2-yl)-3-
(2-piperidinoquinolin-3-yl)prop-2-en-1-ones
S.No Compound M. P.
(oC)
Reaction time Yield (%)
Conven.
(hr)
MWI
(min) Conven. MWI
1
(E)-1-(1-Hydroxynaphthalen-2-yl)-3-(2-
(piperidin-1-yl)quinolin-3-yl)prop-2-en-1-
one (2.25)
137-140 5 3 75 80
2
(E)-1-(1-Methoxynaphthalen-2-yl)-3-(2-
(piperidin-1-yl)quinolin-3-yl)prop-2-en-1-
one (2.26)
125-128 5 3.5 74 95
30
2.3.3 Synthesis of (E)-1-(1-Substituted naphthalen-2-yl)-3-(2-
pyrrolidinoquinolin-3-yl)prop-2-en-1-ones (2.28-2.29) involves five steps:
2.3.3.1 Synthesis of 2-Chloroquinoline-3-carbaldehyde (2.17)
(Discussed earlier in 2.3.1.1)
2.3.3.2 Synthesis of 2-Pyrrolidinoquinoline-3-carbaldehyde (2.27)
2-Pyrrolidinoquinoline-3-carbaldehyde (2.27) is synthesized by the reaction of 2-
Chloroquinoline-3-carbaldehyde (2.17) with pyrrolidine.
2.3.3.3 Synthesis of 1-(1-Hydroxynaphthalen-2-yl)ethanone (2.20)
(Discussed earlier in 2.3.1.3)
2.3.3.4 Synthesis of 1-(1-Methoxynaphthalen-2-yl)ethanone (2.21)
(Discussed earlier in 2.3.1.4)
31
2.3.3.5 Synthesis of (E)-1-(1-Substituted naphthalen-2-yl)-3-(2-
pyrrolidinoquinolin-3-yl)prop-2-en-1-ones (2.28-2.29) under conventional and
microwave irradiation methods
32
Table 2.3: Physical data of (E)-1-(1-Substituted naphthalen-2-yl)-3-
(2-pyrrolidinoquinolin-3-yl)prop-2-en-1-ones
S.No Compound M. P.
(oC)
Reaction time Yield (%)
Conven.
(hr)
MWI
(min) Conven. MWI
1
(E)-1-(1-Hydroxynaphthalen-2-
yl)-3-(2-(pyrrolidin-1-
yl)quinolin-3-yl)prop-2-en-1-
one (2.28)
129-132 4.5 3.5 68 91
2
(E)-1-(1-Methoxynaphthalen-2-
yl)-3-(2-(pyrrolidin-1-
yl)quinolin-3-yl)prop-2-en-1-
one (2.29)
122-124 5 4 72 93
33
Experimental
2.3.1 Synthesis of (E)-1-(1-Substituted naphthalen-2-yl)-3-(2-
morpholinoquinolin-3-yl)prop-2-en-1-ones (2.22-2.23)
2.3.1.1 Synthesis of 2-Chloroquinoline-3-carbaldehyde (2.17)
A Vilsmeier-Haack adduct was obtained from Phosphorus oxytrichloride (6.5
ml, 70 mmol) and N,N-dimethylformamide (2.3 ml, 30 mmol) at 0°C. N-
phenylacetamide (2.16) (1.35 g, 10 mmol) was added to the Vilsmeier-Haack
adduct and it was stirred at room temperature for overnight. Progress of the
reaction was monitored by TLC, after completion of the reaction, the reaction
mixture was poured in ice cold water and the white product was filtered and dried.
The compound was purified by recrystallization from petroleum ether : ethyl
acetate to yield 0.16 gm of pure 2-Chloroquinoline-3-carbaldehyde (2.17)
M. P. : 145-148 °C.
2.3.1.2 Synthesis of 2-Morpholinoquinoline-3-carbaldehyde (2.18)
A mixture of 2-Chloroquinoline-3-carbaldehyde (2.17) (0.19 gm, 1 mmol),
morpholine (0.10 gm, 1.2 mmol) and K2CO3 (0.55 gm, 4 mmol) in DMF (20 ml)
was heated to 80-90 °C. Progress of the reaction was monitored by TLC, after
completion of the reaction, the reaction mixture was poured in ice cold water. The
solid separated was filtered, washed with water, dried and purified by column
chromatography using silica-gel (hexane: ethyl acetate, 10 : 1, v/v) to yield 0.18 gm
of pure 2-Morpholinoquinoline-3-carbaldehyde (2.18)
M. P. : 158-160 °C.
34
1H NMR data of 2-Morpholinoquinoline-3-carbaldehyde:
1H NMR spectrum, δ, ppm: 3.48-3.51 (t, 4H, N-CH2), 3.92-3.94 (t, 4H, O-
CH2), 7.39-7.42 (t, 1H, ArH), 7.70-7.74 (t, 1H, ArH), 7.81-7.85 (t, 2H, ArH), 8.52
(s, 1H, C4-H), 10.19 (s, 1H, -CHO).
2.3.1.3 Synthesis of 1-(1-Hydroxynaphthalen-2-yl)ethanone (2.20)
In 80ml hot glacial acetic acid, 50gm of zinc chloride was added and the
reaction mixture was refluxed till it is dissolved. Then 30 gm of 1-naphthol (2.19)
was added to reaction mixture and was refluxed for 8 hrs. The reaction mixture was
cooled and poured in ice cold water. The crude product was filtered, washed with
water and recrystallized from ethanol to obtain 17 gm of pure 1-(1-
Hydroxynaphthalen-2-yl)ethanone (2.20)
M. P. : 95-97 °C .
1H NMR data of 1-(1-Hydroxynaphthalen-2-yl)ethanone:
1H NMR spectrum, δ, ppm: 8.69 (s, 3H, COCH3), 7.24-7.27 (m, 1H, ArH),
7.50-7.56 (m, 1H, ArH), 7.60-7.64 (m, 2H, ArH), 7.74-7.76 (d, 1H, ArH), 8.44-
8.46 (d, 1H, ArH), 14.01 (s, 1H, Ar-OH).
35
2.3.1.4 Synthesis of 1-(1-Methoxynaphthalen-2-yl)ethanone (2.21)
1-(1-Hydroxynaphthalen-2-yl)ethanone (2.20) (0.18 gm, 1 mmol), K2CO3
(0.69 gm, 5 mmol) and dimethyl sulphate (0.14 gm, 1.1 mmol) was taken in 20 ml
of DMF and stirred for 4 hrs at room temperature. After completion of reaction, as
indicated by TLC, the reaction mixture was poured into ice cold water and
extracted with dichloromethane (2×20 ml), dried over Na2SO4 and the crude
product obtain 0.14 gm, was recrystallized from methanol.
M. P. : 108-109 °C.
1H NMR data of 1-(1-Methoxynaphthalen-2-yl)ethanone:
1H NMR spectrum, δ, ppm: 2.78 (s, 3H, COCH3), 4.01 (s, 3H, O-CH3), 7.56-
7.64 (m, 3H, ArH), 7.73-7.75 (d, 1H, ArH), 7.84-7.87 (m, 1H, ArH), 8.21-8.24 (m,
1H, ArH).
36
Synthesis of (E)-1-(1-Hydroxynaphthalen-2-yl)-3-(2-morpholinoquinolin-3-
yl)prop-2-en-1-one (2.22)
a. Conventional method
A mixture of 2-Morpholinoquinoline-3-carbaldehyde (2.18) (0.24 gm, 1
mmol), 1-(1-Hydroxynaphthalen-2-yl)ethanone (2.20), (0.18 gm, 1 mmol) and
potassium hydroxide (0.12 gm, 3 mmol) was dissolved in ethanol (10 ml) and
stirred at room temperature. Progress of the reaction was monitored by TLC, after
completion of the reaction, the reaction mixture was poured in ice cold water and
neutralized with dil. HCl solution. The solid separated was filtered, washed with
water, dried and purified by column chromatography using silica-gel (hexane :
ethyl acetate, 10 : 1, v/v) to yield 0.29 gm of pure compound (2.22)
b. Microwave irradiation method
A mixture of 2-Morpholinoquinoline-3-carbaldehyde (2.18) (0.24 gm, 1
mmol), 1-(1-Hydroxynaphthalen-2-yl)ethanone (2.20) (0.18 gm, 1 mmol) and
potassium hydroxide (0.12 gm, 3 mmol) was dissolved in ethanol (5 ml), and
subjected to microwave irradiation at 180 W with 30 sec intervals. Progress of the
reaction was monitored by TLC, after completion of the reaction, the reaction
mixture was poured in ice cold water and neutralized with dil. HCl solution. The
solid separated was filtered, washed with water, dried and purified by column
chromatography using silica-gel (hexane : ethyl acetate, 10 : 1, v/v) to yield 0.36
gm of pure compound (2.22)
37
(E)-1-(1-Hydroxynaphthalen-2-yl)-3-(2-morpholinoquinolin-3-yl)prop-2-
en-1-one (2.22)
IR spectrum v, cm-1
: 1573 (C=C), 1625 (C=O). 1H NMR spectrum, δ, ppm:
3.43-3.45 (t, 4H, 2 X N-CH2-), 3.94-3.97 (t, 4H, 2 X O-CH2-), 7.33-7.35 (d, 1H,
ArH), 7.61-7.68 (m, 3H, ArH), 7.77-7.80 (m, 2H, ArH), 7.86-7.94 (m, 3H, ArH&
Hα), 8.17-8.21 (d, 1H, ArH& Hβ), 8.32 (s, 1H, ArH), 8.51-8.53 (d, 2H, ArH), 14.85
(s, 1H, ArOH). 13
C NMR spectrum, δc, ppm: 57.0, 66.9, 121.5, 123.7, 124.4, 124.5,
124.8, 124.9, 125.9, 126.0, 127.3, 127.4,126.7, 127.9, 130.0, 130.3, 130.6, 130.7,
142.1, 147.7, 164.6, 192.9 .Found, %: C, 76.25; H, 5.30; N, 6.30. C26H22N2O3.
Calculated, %: C, 76.82; H, 5.43; N, 6.48. M 411[M+H]+.
Synthesis of (E)-1-(1-Methoxynaphthalen-1-yl)-3-(2-morpholinoquinolin-3-
yl)prop-2-en-1-one (2.23)
a. Conventional method
A mixture of 2-Morpholinoquinoline-3-carbaldehyde (2.18) (0.24 gm, 1
mmol), 1-(1-Methoxynaphthalen-2-yl)ethanone (2.21) (0.20 gm, 1 mmol) and
potassium hydroxide (0.12 gm, 3 mmol) was dissolved in ethanol (10 ml) and
stirred at room temperature. Progress of the reaction was monitored by TLC, after
completion of the reaction, the reaction mixture was poured in ice cold water and
neutralized with dil. HCl solution. The solid separated was filtered, washed with
water, dried and purified by column chromatography using silica-gel (hexane :
ethyl acetate, 20 : 1, v/v) to yield 0.30 gm of pure compound (2.23)
38
b. Microwave irradiation method
A mixture of 2-Morpholinoquinoline-3-carbaldehyde (2.18) (0.24 gm, 1
mmol), 1-(1-Methoxynaphthalen-2-yl)ethanone (2.21) (0.20 gm, 1 mmol) and
potassium hydroxide (0.12 gm, 3 mmol) was dissolved in ethanol (5 ml), and
subjected to microwave irradiation at 180 W with 30 sec intervals. Progress of the
reaction was monitored by TLC, after completion of the reaction, the reaction
mixture was poured in ice cold water and neutralized with dil. HCl solution. The
solid separated was filtered, washed with water, dried and purified by column
chromatography using silica-gel (hexane : ethyl acetate, 20 : 1, v/v) to yield 0.40
gm of pure compound (2.23)
(E)-1-(1-Methoxynaphthalen-2-yl)-3-(2-morpholinoquinolin-3-yl)prop-2-
en-1-one (2.23)
IR spectrum v, cm-1
: 1593 (C=C), 1645 (C=O). 1H NMR spectrum, δ, ppm: 3.38-
3.40 (t, 4H, 2 X N-CH2-), 3.81-3.83 (t, 4H, 2 X O-CH2-), 3.97 (s, 3H, -OCH3), 7.37-7.41
(m, 1H, ArH), 7.60-7.71 (m, 6H, ArH), 7.75-7.77 (d, 1H, ArH), 7.82-7.86 (m, 2H, ArH),
7.90-7.92 (m, 1H, ArH& Hα), 8.25-8.28 (m, 1H, ArH& Hβ), 8.30 (s, 1H, C4-H). 13
C NMR
spectrum, δc, ppm: 51.0, 64.0, 66.9, 122.6, 122.9, 124.4, 124.8, 125.0, 125.7,126.8, 127.6,
127.9, 128.1, 128.2, 130.6, 136.5, 137.0, 141.7, 147.7, 156.4, 159.6, 193.7. Found, %: C,
76.38; H, 5.69; N, 6.55. C27H24N2O3. Calculated, %: C, 76.34; H, 5.28; N, 6.52. M
425[M+H]+.
39
2.3.2 Synthesis of (E)-1-(1-Substituted naphthalen-2-yl)-3-(2-
piperidinoquinolin-3-yl)prop-2-en-1-ones (2.25-2.26)
2.3.2.1 Synthesis of 2-Chloroquinoline-3-carbaldehyde (2.17)
(Discussed earlier in 2.3.1.1)
2.3.2.2 Synthesis of 2-Piperidinoquinoline-3-carbaldehyde (2.14)
A mixture of 2-Chloroquinoline-3-carbaldehyde (2.17) (0.19 gm, 1 mmol),
piperidine (0.10 gm, 1.2 mmol) and K2CO3 (0.55 gm, 4 mmol) in DMF (20 ml) was
heated to 80-90 °C. Progress of the reaction was monitored by TLC, after
completion of the reaction, the reaction mixture was poured in ice cold water. The
solid separated was filtered, washed with water, dried and purified by column
chromatography using silica-gel (hexane : ethyl acetate, 10 : 1, v/v) to yield 0.21
gm of pure 2-Piperidinoquinoline-3-carbaldehyde (2.24)
M. P. : 123-125 °C.
1H NMR data of 2-Piperidinoquinoline-3-carbaldehyde:
1H NMR spectrum, δ, ppm: 1.69-1.70 (m, 2H, -CH2), 1.78-1.79 (m, 4H, N-
CH2-CH2), 3.43-3.46 (t, 4H, N-CH2), 7.33-7.35 (t, 1H, ArH), 7.66-7.69 (t, 1H,
ArH), 7.76-7.83 (m, 2H, ArH), 8.47 (s, 1H, C4-H), 10.15 (s, 1H, -CHO).
2.3.2.3 Synthesis of 1-(1-Hydroxynaphthalen-2-yl)ethanone (2.20)
(Discussed earlier in 2.3.1.3)
2.3.2.4 Synthesis of 1-(1-Methoxynaphthalen-2-yl)ethanone (2.21)
(Discussed earlier in 2.3.1.4)
40
Synthesis of (E)-1-(1-Hydroxynaphthalen-2-yl)-3-(2-piperidinooquinolin-3-
yl)prop-2-en-1-one (2.25)
a. Conventional method
A mixture of 2-Piperidinoquinoline-3-carbaldehyde (2.24) (0.24 gm, 1
mmol), 1-(1-Hydroxynaphthalen-2-yl)ethanone (2.20) (0.18 gm, 1 mmol) and
potassium hydroxide (0.12 gm, 3 mmol) was dissolved in ethanol (10 ml) and
stirred at room temperaturer. Progress of the reaction was monitored by TLC, after
completion of the reaction, the reaction mixture was poured in ice cold water and
neutralized with dil. HCl solution. The solid separated was filtered, washed with
water, dried and purified by column chromatography using silica-gel (hexane :
ethyl acetate, 10 : 1, v/v) to yield 0.27 gm of pure compound (2.25)
b. Microwave irradiation method
A mixture of 2-Piperidinoquinoline-3-carbaldehyde (2.24) (0.24 gm, 1
mmol), 1-(1-Hydroxynaphthalen-2-yl)ethanone (2.20) (0.18 gm, 1 mmol) and
potassium hydroxide (0.12 gm, 3 mmol) was dissolved in ethanol (5 ml), and
subjected to microwave irradiation at 160 W with 30 sec intervals. Progress of the
reaction was monitored by TLC, after completion of the reaction, the reaction
mixture was poured in ice cold water and neutralized with dil. HCl solution. The
solid separated was filtered, washed with water, dried and purified by column
chromatography using silica-gel (hexane : ethyl acetate, 10 : 1, v/v) to yield 0.36
gm of pure compound (2.25)
41
(E)-1-(1-Hydroxynaphthalen-2-yl)-3-(2-(piperidin-1-yl)quinolin-3-yl) prop-
2-en-1-one (2.25)
IR spectrum v, cm-1
: 1593 (C=C), 1625 (C=O). 1H NMR spectrum, δ, ppm:
1.66-1.69 (m, 2H, -CH2-), 1.75-1.81 (m, 4H, 2 X N-CH2-CH2-), 3.36-3.38 (t, 4H, 2
X N-CH2-), 7.19-7.21 (d, 1H, ArH), 7.31-7.35 (m, 1H, Ar-H), 7.41-7.45 (m, 1H,
ArH), 7.56-7.68 (m, 5H, ArH), 7.82-7.84 (d, 1H, C5-H), 7.92-7.94 (d, 1H, Hα),
8.08-8.13 (m, 2H, ArH& Hβ), 8.19 (s, 1H, C4-H), 14.98 (s, 1H, Ar-OH). 13
C NMR
spectrum, δc, ppm: 24.6, 26.0, 29.7, 42.3, 51.9, 113.4, 118.2, 120.8, 123.0, 123.8,
124.6,125.5, 125.9, 127.5, 127.8, 130.2, 130.5, 135.5, 137.3, 139.8, 145.3, 147.9,
160.7, 164.5, 193.1. Found, %: C, 79.36; H, 5.89; N, 6.85. C27H24N2O2. Calculated,
%: C, 79.39; H, 5.98; N, 6.22. M 409[M+H]+.
Synthesis of (E)-1-(1-Methoxynaphthalen-2-yl)-3-(2-(piperidin-1-
yl)quinolin-3-yl)prop-2-en-1-one (2.26)
a. Conventional method:
A mixture of 2-Piperidinoquinoline-3-carbaldehyde (2.24) (0.24 gm, 1
mmol), 1-(1-Methoxynaphthalen-2-yl)ethanone (2.21) (0.20 gm, 1 mmol) and
potassium hydroxide (0.12 gm, 3 mmol) was dissolved in ethanol (10 ml) and
stirred at room temperature. Progress of the reaction was monitored by TLC, after
completion of the reaction, the reaction mixture was poured in ice cold water and
neutralized with dil. HCl solution. The solid separated was filtered, washed with
water, dried and purified by column chromatography using silica-gel (hexane :
ethyl acetate, 20 : 1, v/v) to yield 0.31 gm of pure compound (2.26)
42
b. Microwave irradiation method
A mixture of 2-Piperidinoquinoline-3-carbaldehyde (2.24) (0.24 gm, 1
mmol), 1-(1-Methoxynaphthalen-2-yl)ethanone (2.21) (0.20 gm, 1 mmol) and
potassium hydroxide (0.12 gm, 3 mmol) was dissolved in ethanol (5 ml), and
subjected to microwave irradiation at 160 W with 30 sec intervals. Progress of the
reaction was monitored by TLC, after completion of the reaction, the reaction
mixture was poured in ice cold water and neutralized with dil. HCl solution. The
solid separated was filtered, washed with water, dried and purified by column
chromatography using silica-gel (hexane : ethyl acetate, 20 : 1, v/v) to yield 0.40
gm of pure compound (2.26)
(E)-1-(1-Methoxynaphthalen-2-yl)-3-(2-(piperidin-1-yl)quinolin-3-yl) prop-
2-en-1-one (2.26)
IR spectrum v, cm-1
: 1590 (C=C), 1670(C=O). 1H NMR spectrum, δ, ppm:
1.55-1.69 (m, 6H, -CH2-), 3.30-3.39 (m, 4H, 2 X N-CH2-), 3.98 (s, 3H, -OCH3),
7.35-7.43 (m, 2H, ArH), 7.59-7.74 (m, 5H, ArH), 7.83-7.90 (m, 3H, ArH& Hα),
8.08-8.12 (m, 1H, ArH& Hβ), 8.19 (d, 1H, ArH), 8.27 (s, 1H, ArH). 13
C NMR
spectrum, δc, ppm: 24.3, 29.7, 52.0, 52.6, 118.7, 119.4, 122.8, 124.0, 124.3, 125.1,
125.9, 127.3, 127.8, 128.4, 128.6, 129.4, 129.8, 130.5, 136.8, 136.9, 137.6, 140.6,
147.9, 162.8, 194.5. Found, %: C, 79.76; H, 6.43; N, 6.40. C28H26N2O2. Calculated,
%: C, 79.29; H, 6.45; N, 6.34. M 423[M+H]+.
43
2.3.3 Synthesis of (E)-1-(1-Substituted naphthalen-2-yl)-3-(2-
pyrrolidinoquinolin-3-yl)prop-2-en-1-ones (2.28-2.29)
2.3.3.1 Synthesis of 2-Chloroquinoline-3-carbaldehyde (2.17)
(Discussed earlier in 2.3.1.1)
2.3.3.2 Synthesis of 2-Pyrrolidinoquinoline-3-carbaldehyde (2.27)
A mixture of 2-Chloroquinoline-3-carbaldehyde (2.17) (0.19 gm, 1 mmol),
pyrrolidine (0.10 gm, 1.2 mmol) and K2CO3 (0.55 gm, 4 mmol) in DMF (20 ml)
was heated to 80-90 °C. Progress of the reaction was monitored by TLC, after
completion of the reaction, the reaction mixture was poured in ice cold water. The
solid separated was filtered, washed with water, dried and purified by column
chromatography using silica-gel (hexane : ethyl acetate, 10 : 1, v/v) to yield 0.20
gm of pure 2-Pyrrolidinoquinoline-3-carbaldehyde (2.27)
M. P. : 141-143 °C.
2.3.3.3 Synthesis of 1-(1-Hydroxynaphthalen-2-yl)ethanone (2.20)
(Discussed earlier in 2.3.1.3)
2.3.3.4 Synthesis of 1-(1-Methoxynaphthalen-2-yl)ethanone (2.21)
(Discussed earlier in 2.3.1.4)
44
Synthesis of (E)-1-(1-Hydroxynaphthalen-2-yl)-3-(2-pyrrolidinoquinolin-3-
yl)prop-2-en-1-one (2.28)
a. Conventional method
A mixture of 2-Pyrrolidinoquinoline-3-carbaldehyde (2.27) (0.22 gm, 1
mmol), 1-(1-Hydroxynaphthalen-2-yl)ethanone (2.20) (0.18 gm, 1 mmol) and
potassium hydroxide (0.12 gm, 3 mmol) was dissolved in ethanol (10 ml) and
stirred at room temperature. Progress of the reaction was monitored by TLC, after
completion of the reaction, the reaction mixture was poured in ice cold water and
neutralized with dil. HCl solution. The solid separated was filtered, washed with
water, dried and purified by column chromatography using silica-gel (hexane :
ethyl acetate, 10 : 1, v/v) to yield 0.27 gm of pure compound (2.28)
b. Microwave irradiation method
A mixture of 2-Pyrrolidinoquinoline-3-carbaldehyde (2.27) (0.22 gm, 1
mmol), 1-(1-Hydroxynaphthalen-2-yl)ethanone (2.20) (0.18 gm, 1 mmol) and
potassium hydroxide (0.12 gm, 3 mmol) was dissolved in ethanol (5 ml), and
subjected to microwave irradiation at 160 W with 30 sec intervals. Progress of the
reaction was monitored by TLC, after completion of the reaction, the reaction
mixture was poured in ice cold water and neutralized with dil. HCl solution. The
solid separated was filtered, washed with water, dried and purified by column
chromatography using silica-gel (hexane : ethyl acetate, 10 : 1, v/v) to yield 0.35
gm of pure compound (2.28)
45
(E)-1-(1-Hydroxynaphthalen-2-yl)-3-(2-(pyrrolidin-1-yl)quinolin-3-yl)
prop-2-en-1-one (2.28)
IR spectrum v, cm-1
: 1591 (C=C), 1639 (C=O). 1H NMR spectrum, δ, ppm:
1.98-1.99 (t, 4H, N-CH2-CH2), 3.72-3.76 (t, 4H, N-CH2), 7.33-7.35 (m, 1H, ArH),
7.61-7.90 (m, 9H, ArH), 8.33-8.41 (m, 2H, C4-H& Hα), 8.50-8.52 (d, 1H, ArH&
Hβ), 14.89 (s, 1H, Ar-OH). 13
C NMR spectrum, δc, ppm: 29.6, 50.9, 122.5, 122.7,
123.3, 124.0, 125.0, 125.5, 126.5, 127.2, 127.8, 127.9, 128.6, 129.0, 129.3, 130.7,
133.9, 134.6, 136.8, 148.4, 156.8, 162.8, 194.2. Found, %: C, 79.10; H, 5.56; N,
7.05. C26H22N2O2. Calculated, %: C, 79.44; H, 5.52; N, 7.06. M 395[M+H]+.
Synthesis of (E)-1-(1-Methoxynaphthalen-2-yl)-3-(2-(pyrrolidin-1-yl)
quinolin-3-yl) prop-2-en-1-one (2.29)
a. Conventional method
A mixture of 2-Pyrrolidioquinoline-3-carbaldehyde (2.27) (0.22 gm, 1
mmol), 1-(1-Methoxynaphthalen-2-yl)ethanone (2.21) (0.20 gm, 1 mmol) and
potassium hydroxide (0.12 gm, 3 mmol) was dissolved in ethanol (10 ml) and
stirred at room temperature. Progress of the reaction was monitored by TLC, after
completion of the reaction, the reaction mixture was poured in ice cold water and
neutralized with dil. HCl solution. The solid separated was filtered, washed with
water, dried and purified by column chromatography using silica-gel (hexane :
ethyl acetate, 20 : 1, v/v) to yield 0.30 gm of pure compound (2.29)
46
b. Microwave irradiation method
A mixture of 2-Pyrrolidinoquinoline-3-carbaldehyde (2.27) (0.22 gm, 1
mmol), 1-(1-Methoxynaphthalen-2-yl) ethanone (2.21) (0.20 gm, 1 mmol) and
potassium hydroxide (0.12 gm, 3 mmol) was dissolved in ethanol (5 ml), and
subjected to microwave irradiation at 160 W with 30 sec intervals. Progress of the
reaction was monitored by TLC, after completion of the reaction, the reaction
mixture was poured in ice cold water and neutralized with dil. HCl solution. The
solid separated was filtered, washed with water, dried and purified by column
chromatography using silica-gel (hexane : ethyl acetate, 20 : 1, v/v) to yield 0.40
gm of pure compound (2.29)
(E)-1-(1-Methoxynaphthalen-2-yl)-3-(2-(pyrrolidin-1-yl)quinolin-3-yl)
prop-2-en-1-one (2.29)
IR spectrum v, cm-1
: 1593 (C=C), 1654 (C=O). 1H NMR spectrum, δ, ppm:
1.92-1.95 (m, 4H, N-CH2-CH2), 3.68-3.71 (t, 4H, N-CH2), 3.99 (s, 3H, O-CH3),
7.20-7.24 (m, 1H, ArH), 7.52-7.64 (m, 5H, ArH), 7.70-7.73 (m, 3H, ArH), 7.90-
7.91 (m, 1H, ArH& Hα), 8.04-8.08 (d, 1H, Hβ), 8.14 (s, 1H, C4-H), 8.26-8.29 (m,
1H, ArH). 13
C NMR spectrum, δc, ppm: 25.3, 50.7, 64.1, 121.8, 122.6, 123.0,
123.3, 124.2, 125.9, 126.0, 126.6, 126.7, 126.9, 127.8, 128.0, 128.1, 128.5, 130.5,
131.0, 136.6, 137.0, 143.4, 157.2, 192.5. Found, %: C, 79.40; H, 5.90; N, 6.84.
C27H24N2O2. Calculated, %: C, 79.33; H, 5.94; N, 6.22. M 409[M+H]+.
47
CONCLUSION
We have established an easy, high yielding convenient and green methods for
the synthesis of (E)-1-(1-Hydroxynaphthalen-2-yl)-3-(2-morpholinoquinolin-3-
yl)prop-2-en-1-one (2.22), (E)-1-(1-Methoxynaphthalen-2-yl)-3-(2-
morpholinoquinolin-3-yl)prop-2-en-1-one (2.23), (E)-1-(1-Hydroxynaphthalen-2-
yl)-3-(2-(piperidin-1-yl)quinolin-3-yl)prop-2-en-1-one (2.25), (E)-1-(1-
Methoxynaphthalen-2-yl)-3-(2-(piperidin-1-yl)quinolin-3-yl)prop-2-en-1-one
(2.26), (E)-1-(1-Hydroxynaphthalen-2-yl)-3-(2-(pyrrolidin-1-yl)quinolin-3-yl)prop-
2-en-1-one (2.28), and (E)-1-(1-Methoxynaphthalen-2-yl)-3-(2-(pyrrolidin-1-
yl)quinolin-3-yl)prop-2-en-1-one (2.29)
48
References
1. Piao, H., Zheng, C., Guo, M. and Song, M., Faming Zhuanli Shenqing
(2014), CN 103570706 A 20140212.
2. Singh, S. K. and Singh, Sh., Int. J. of Pharmaceutica Sciences Review and
Research (2014), 25, 295-302.
3. Takagaki, H., Nakanishi, Sh., Kimura, N., Yamaguchi, Sh. and Aoki, Y.,
Eur. Pat. Appl. (1999), EP 933378 A1 19990804.
4. Mukherjee, S. and Pal, M., Curr. Med. Chem. (2013), 20, 4386-4410.
5. Tang, Y., Wang, L. and Xiang, J., Faming Zhuanli Shenqing (2014), CN
103601719 A 20140226.
6. O. Meth-Cohn., Heterocycles, (1993), 35, 539-557.
7. Sherrett, W. L.U.S. Pat. Appl. Publ. (2008), US 20080249088 A1 20081009.
8. Altintop, M. D., Ozdemir, A., Kaplancikli, Z. A., Turan Z., G. Iscan, G. and
Ciftci, G. A., Lett. Drug Des. Disc. (2013), 10, 453-461.
9. Vinaya, K., Veeresh, B., Ananda Kumar, C. S., Prasanna, D. S., Ranganatha,
S. R., Benaka Prasad, S. B., Patil, B. M. and Rangappa, K. S., Lett. Drug
Des. Disc. (2010), 7, 109-115.
10. Sorokina, I. V., Tolstikova, T. G., Zhukova, T. A., Bessergeneva, E. P.,
Mainagashev, I. Ya., Salakhutdinov, N. F. and Tolstikov, G. A., Russ.
(2012), RU 2466136 C1 20121110.
11. Lundbeck, J. M., Treppendahl, S. and Jakobsen, P., Eur. Pat. Appl. (1990),
EP 374675 A2 19900627.
12. Arun, Y., Bhaskar, G., Balachandran, C., Ignacimuthu, S. and Perumal, P.
T., Bioorg. Med. Chem. Lett. (2013), 23, 1839-1845.
13. Higgins, B., Nichols, G. and Chen, L. Ch., U.S. Pat. Appl. Publ. (2014), US
20140200255 A1 20140717.
49
14. Ma, D., Yu, S., Li, B., Chen, L., Chen, R., Yu, K., Zhang, L., Chen, Z.,
Zhong, D. and Gong, Z., Chem. Med. Chem. (2007), 2, 187-193.
15. Kenda, B., Quesnel, Y., Ates, A., Michel, Ph., Turet, L. and Mercier, J.,
PCT Int. Appl. (2006), WO 2006128693 A2 20061207.
16. Yin, B. T., Yan, C. Y., Peng, X. M., Zhang, Sh. L., Rasheed, S., Geng, R. X.,
and Zhou, Ch .H., Eur. J. of Med. Chem. (2014), 71, 148-159.
17. Balasubramanian, R. and Gopal, R., V. Bull. of Pharm. Res. (2012), 2, 70-
77.
18. Wan, M., Xu, L., Hua, L., Li, A., Li, Sh., Lu, W., Pang, Y.; Cao, Ch.; Liu,
X. and Jiao, P., Bioorg. Chem. (2014), 54, 38-43.
19. N. Y. Sreedhar, M. R. Jayapal, Sreenivasa P. and P. Prasad Reddy, Res. J.
Pharm. Bio. Chem. Sci., 2010, 1, 480-484.
20. Om Prakash, Ajay K., Anil S., Richa, P., S. P. Singh, R. M. , Claramunt, D.
S., Ibon, A., and José, E., Tetrahedron, (2005), 61, 6642-6651.
21. R. Y. Prasad, L. A. Rao, L. Prasoona, K. Murali and R. P. Kumar, Bioorg.
Med. Chem. Lett.,(2005), 15, 5030-5034.
22. S. Raghavan and K. Anuradha, Tetrahedron Lett., (2002), 43, 5181-5183.
23. B. A. Bohn, Introduction to Flavonoids, Harwood Academic, Amsterdam,
Harwood Academic, (1998).
24. Afzal, O., Bawa, S., Kumar, S., Kumar, R. and Hassan, M. Q., Lett. Drug
Des. Disc. (2013), 10, 75-85.
25. Zeng, G., Shen, H., Yang, Y., Cai, X. and Xun, W., Tumor Biology (2014),
35, 6549-6555.
26. Liu, Y., Gao, X., Deeb, D., Arbab, A. S., Dulchavsky, S. A. and Gautam, S.
C., J. of Exp. Ther. Oncol. (2012), 10, 1-8.
50
27. Carroll, A.M., Kavanagh, D. J., McGovern, F.P., Reilly, J.W. and Walsh, J.
J., J. Chem. Educ. (2012), 89, 1578-1581.
28. Igarashi, M. and Hiramatsu, K., PCT Int. Appl. (2011), WO 2011058923 A1
20110519.
29. Jonet, A., Dassonville, K. A., Sonnet, P. and Mullie, C., J. Antibiot. (2013),
66, 683-686.
30. Praharaj, S. K. and Arora, M., Ann. Pharmacother. (2006), 40, 1884-1886.
31. Guo, T., Yang, Ch., Guo, L. and Liu, K., Neurosci. Lett. (2012), 528, 11-15.
32. He, J., Dai, J., Yin, K., Chang, Z. and Chang, P., Faming Zhuanli Shenqing
(2010), CN 101716492 A 20100602.
33. Wood, D. M. and Dargan, P. I., Clin. Toxicol. (2012), 50, 727-732.
34. Wu, J. G., Dong, H. R., Dong, H. Sh. and Ng, S., Weng Acta
Crystallographica, Section E: Structure Reports Online (2008), 64, o1067,
o1067/1-o1067/8.
35. Kaur, J. and Tikoo, K. Biochimica et Biophysica Acta, Mol. Cell Res.
(2013), 1833, 1028-1040.
36. Van Thorre, D. M. and Catto, M., L.U.S. Pat. Appl. Publ. (2014), US
20140208638 A1 20140731.
37. Yan, X. and Xiaoyue, X., J. Mater. Res., (1995), 10, 334-338
38. Guiheneuf, S., Paquin, L., Carreaux, F., Durieu, E., Benedettid, H., Le
Guevel, R., Corlu, A., Meijer, L. and Bazureau, Jean-Pierre. Current
Microwave Chem., (2014), 1, 33-40
39. Nagashima, I.and Shimizu, H., Yuki Gosei Kagaku Kyokaishi (2012), 70,
250-264.
40. Nyutu, E. K., Chen, Chun-Hu., Sithambaram, Sh., Crisostomo, Vincent
Mark B. and Suib, S. L., J. Phys. Chem. (2008), 112, 6786-6793.
51
41. Zrinski, I. and Eckert-Maksic, M., Kemija u Industriji (2005), 54, 469-476.
42. Salmoria, G. V., Dall'Oglio, E.M. and Zucco, c., tetrahedron lett. (1998), 39,
2471- 2474.
43. Touaux, B., Texier-Boullet, F. and Hamellin, J. Heteroatom Chem. (1998), 9,
351- 354.
44. Varma, R. S., Dahiya, R. and Kumar, S., Tetrahedron Lett.(1997), 38, 5131-
5134.
45. D. R. Jonathan, M. Chitra, T. V. Rajendra, V. Duraipandiyan and Y. C.
Rajan, Ind. J. Sci. And twch., (2010), 8, 890-894.
46. Suarez, M., Loupy, A., Salfran, E., Moran, L. and Rolanda, E., Heterocycles
(1999), 51, 21-27.
47. D. Ashok and K. Aravind, E-J.Chem., (2009), 6, 323-331.
48. H. Chikhalia Kishor, J. Patel Mayank and B. Vashib Dhaval, Arkivoc,
(2008), 13, 189-197.
49. G. Venkat Reddy, D. Maitraie, B. Narsaiah, Y. Rambabu and P. Shanthan
Rao, Synth. Commun. (2001), 31, 2881-2884.
50. D. K. Kumar and S. P. Rajendran, Synth. Commun., (2012), 42, 2290.
51. S. Abdel-Sattar Hamad Elgazwy., Monatsh. Chem., (2008), 139, 1285-
1297.
52. Vandana, T., Parvez, A. and Jyotsna, M., Int. J. Chem. Tech. Res., (2010), 2,
1031-1035.
52
Publication
Microwave assisted synthesis of (E)-1-(Substituted naphthalenyl)-3-(2-substituted
quinolin-3-yl) prop-2-en-1-ones. (Communicated to Russian Journal of General
Chemistry).
-2-200224466881010121214141616
1.0 1.1 1.1
2.1
1.0
1.2
3.3
1H NMR spectrum of 1-(1-hydroxynaphthalen-2-yl)ethanone (2.20)
-2-200224466881010121214141616
1.0 1.0 1.0
3.1 3.2
3.1
1H NMR spectrum of 1-(1-methoxynaphthalen-2-yl)ethanone (2.21)
-2-200224466881010121214141616
1.0
2.4
1.3
1.1 1.2
4.6 4.6
1H NMR spectrum of 2-Morpholinoquinoline-3-carbaldehyde (2.18)
-2-200224466881010121214141616
1.0 1.1
2.1
1.1 1.0
6.9
3.3
1H NMR spectrum of 2-Piperidinoquinoline-3-carbaldehyde (2.24)
IR spectrum of (E)-1-(1-hydroxynaphthalen-2-yl)-3-(2-morpholinoquinolin-3-yl) prop-2-
en-1-one (2.22)
IR spectrum of (E)-3-(1-methoxynaphthalen-2-yl)-1-(2-morpholinoquinolin-3-yl)
prop-2-en-1-one (2.23)
IR spectrum of (E)-1-(1-hydroxynaphthalen-2-yl)-3-(2-piperidinooquinolin-3-yl) prop-
2-en-1-one (2.25)
IR spectrum of (E)-1-(1-methoxynaphthalen-2-yl)-3-(2-(piperidin-1-yl)quinolin-3-
yl) prop-2-en-1-one (2.26)
IR spectrum of (E)-1-(1-hydroxynaphthalen-2-yl)-3-(2-pyrrolidinoquinolin-3-yl)
prop-2-en-1-one (2.28)
-2-200224466881010121214141616
1H NMR spectrum of (E)-1-(1-methoxynaphthalen-2-yl)-1-(2-morpholinoquinolin-3-yl)prop-2-en-1-
one (2.23)
Aromatic Rrgion of (E)-1-(1-methoxynaphthalen-2-yl)-3-(2-morpholinoquinolin-3-yl)prop-2-
en-1-one (2.23)
-2-200224466881010121214141616
0.9 1.0 1.0 1.0
2.0
1.0
2.2
3.4
2.1
3.9 4.0
2.1
1H NMR spectrum of (E)-1-(1-hydroxynaphthalen-2-yl)-3-(2-piperidinoquinolin-3-yl)prop-2-en-1-one
(2.25)
-2-200224466881010121214141616
1H NMR spectrum of (E)-1-(1-hydroxynaphthalen-2-yl)-3-(2-pyrrolidinoquinolin-3-yl)prop-2-en-1-
one (2.28)
Aromatic Region of (E)-1-(1-Hydroxynaphthalen-2-yl)-3-(2-pyrrolidinoquinolin-3-yl)prop-2-
en-1-one (2.28)
00252550507575100100125125150150175175200200
13C NMR spectrum of (E)-1-(1-methoxynaphthalen-2-yl)-3-(2-morpholinoquinolin-3-yl)prop-2-en-
1-one (2.23)
00252550507575100100125125150150175175200200
13C NMR spectrum of (E)-1-(1-hydroxynaphthalen-2-yl)-3-(2-piperidinoquinolin-3-yl)prop-2-en-1-one
(2.25)
Aromatic Region of (E)-1-(1-Hydroxynaphthalen-2-yl)-3-(2-piperidinoquinolin-3-yl)prop-2-
en-1-one (2.25)
00252550507575100100125125150150175175200200
13C NMR spectrum of (E)-1-(1-methoxynaphthalen-2-yl)-3-(2-(pyrrolidin-1-yl)quinolin-3-yl)prop-2-en-
1-one (2.29)
Mass spectrum of (E)-1-(1-hydroxynaphthalen-2-yl)-3-(2-morpholinoquinolin-3-yl) prop-2-en-1-one (2.22)
Mass spectrum of (E)-1-(1-hydroxynaphthalen-2-yl)-3-(2-pyrrolidinoquinolin-3-yl) prop-2-en-1-one (2.28)