Physics Chemistry Geology Biology - INFLIBNETshodhganga.inflibnet.ac.in/bitstream/10603/43587/6/06_chapter_02.pdfHeterocyclic compounds probably constitute the largest and most varied

Chapter 1: Introduction and Literature Review

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CHAPTER 1

INTRODUCTION AND LITERATURE REVIEW

1.1 Introduction

The synthetic chemistry initiate up to 4,000 years ago by earliest Egyptians.

The earliest society was using technologies that formed the basis of the various

branches of chemistry as wine fermenting, metal extraction, creation of

pigments for makeup and painting [1]. They had also done the extraction of

chemicals from plants for perfume and medicinal purpose. Along with this they

also did the leather tanning, soap preparation from fat, glass making, and

preparation of alloys like bronze [2].

The origin of chemistry can be traced to the widely observed

phenomenon metallurgy. It is the art and science of processing ores to get

metals [3]. Although original principles were not well understood, the hunger

for gold led to the discovery of the process for its purification, it was thought to

be a transformation rather than purification. Many researchers in those days

thought it is rational to means for transforming cheaper metals into gold [4].

This method approaches to alchemy. Chemistry is the science of matter,

particularly its chemical reactions, along with its composition, structure and

properties [5]. Chemistry is associated with atoms and their interactions with

other atoms, and mainly with the properties of chemical bonds. Chemistry is

sometimes called "the central science" (Fig. 1.1) because it connects physics

with other natural sciences such as geology and biology [6].

(Fig. 1.1) Chemistry - The central science

Geology Biology

Physics

Chemistry


2

Traditional chemistry starts with the study of elementary particles,

atoms, metals, crystals and other cumulative of matter. It finds in the isolated or

in combination of solid, liquid, and gas states. The interactions along with

transformation which are studied in chemistry are typically a product of

interaction between atoms, to rearrangements in the chemical bonds [7].

A chemical reaction is a process that leads to the transformation of one

set of chemical substances to another [8]. Chemical reactions either

spontaneous which are not requiring input of energy, or non-spontaneous,

normally requires input of energy, such as heat, light or electricity. Naturally,

chemical reactions include changes that strictly involve the motion of electrons

in the forming and breaking of chemical bonds between atoms, and can

frequently be described by a chemical equation [9]. The broad concept of

chemical reactions between atoms has been be absolute to the non-chemical

reactions between individual smaller than atoms, including nuclear reactions as

explained by quantum field theory.

The substances initially involved in a chemical reaction are called

reactants. Chemical reactions are regularly illustrated by a chemical change,

and they give up one or more products, which typically have different

properties from the reactants. Reactions frequently consist of a sequence of

different steps; the information on the accurate course of action is part of the

reaction mechanism. It is the step by step sequence of elementary reactions by

which overall chemical change occurs [10]. Diverse chemical reactions are

used in combination in chemical synthesis in order to obtain a desired product.

Chemical reactions are illustrated with chemical equations, graphically

showing starting materials, final products along with sometimes intermediates

and reaction conditions. A chemical reaction can be represented through a

chemical equation. In the equation the number of atoms on the left hand side

and the right hand side is equal for a chemical transformation [11]. The

chemical laws are constrained by certain basic rules in which substances

undergo chemical reactions and the energy changes that may accompany it.

Energy and entropy considerations are invariably important in almost all


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chemical studies. The chemical substances are analyzed by spectroscopy and

chromatography techniques. The persons engaged in the chemical research are

called chemist [12]. Most chemists focus in one or more interdisciplinary

subjects.

1.2 History of Heterocyclic Chemistry

The heterocyclic compounds are also known as heterocycles. It is a

major class of organic chemical compounds describe by the fact that some or

all of the atoms in their molecules are joined in rings containing at least one

atom of an element other than carbon. Heterocyclic compounds are a class of

organic compounds whose molecules contains one or more ring of atoms with

at least one heteroatom being an element other then carbon, most frequently

oxygen, nitrogen or sulphur. The cyclic part (from Greek kyklos, meaning

“circle”) of heterocyclic indicates that at least one ring structure is present in

such a compound, while the hetero (from Greek heteros, meaning “other” or

“different”) refers to the heteroatoms [13].

Heterocyclic compounds probably constitute the largest and most varied

family of organic compounds. Although different structure and functionality,

every carbocyclic compound have attitude be converted into a collection of

heterocyclic analogs by replacing one or more of the ring carbon atoms with a

different element. The history of heterocyclic chemistry began in the 1800

century, along with the growth of organic chemistry [14]. If we concentrate to

oxygen, nitrogen and sulfur (the most common heterocyclic elements), the

variation and arrangement of such a substitute are plentiful.

A heterocyclic ring may comprise of three or more atoms which may be

saturated or unsaturated. The chemistry of heterocyclic compounds is as logical

as that of aliphatic or aromatic compounds [15]. Also the ring may contain

more than one hetero atom which may be similar or dissimilar. Their study is

of great interest both from the theoretical as well as practical point of view. In

their general structure, heterocyclic compounds resemble cyclic organic

compounds that incorporate only carbon atoms in the rings e.g. cyclopropane


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or benzene but the presence of the heteroatoms gives heterocyclic compounds

physical and chemical properties that are often quite distinct from those of their

all carbon ring analogs. The most common heterocycles are those having five

or six membered rings and containing heteroatoms of nitrogen (N), oxygen (O),

or sulfur (S) [16].

1.2.1 Nomenclature of Heterocyclic Compounds

Set up a systematic nomenclature system for heterocyclic compounds

presented a difficult challenge, which has not been equally done. Many

heterocycles, especially amines, were recognized near the beginning, and

received trivial names which are still ideal. Some monocyclic compounds of

this kind are shown in the (Fig. 1.2), with the common (trivial) names. The

study of these common names provides an adequate nomenclature background.

O O S NH

NH

O N NH

O

O

N

N

Furan Tetrahydrofuran Thiophene Pyrrole Pyrrolidine

Pyran Pyridine Piperidine Dioxan Pyrimidine

(Fig. 1.2) Varities of heterocyclic componds.

The IUPAC advised the Hantzsch-Widman nomenclature for naming

heterocyclic compounds [17]. The non-carbons usually are considered to

replace carbon atoms; they are called heteroatoms, meaning “different from

carbon and hydrogen”. Heterocyclic compounds may be also classified into

aliphatic and aromatic. Many inorganic compounds may be are heterocyclic but

most contain at least one carbon [18]. The cyclic analogues of amines, ethers,


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thioethers, amides, etc. are aliphatic heterocycles. Their properties are

particularly influenced by the presence of strain in the ring. These compounds

consist of small (3 and 4 membered) and commonly (5 to 7 membered) ring

systems.

The aromatic heterocycles, in contrast, are those which have a

heteroatom in the ring and behave in a manner similar to benzene in some of

their properties. In addition, these compounds also fulfill with the general rule

proposed by Hückel [19]. This rule explain that aromaticity is obtained in

cyclic conjugated and planar systems containing (4n + 2) π electrons. This

extra stabilization results in a diminished tendency of the molecule to react by

addition but a larger tendency to react by substitution in which the aromatic

ring remains intact.

1.2.2 Nitrogen, oxygen containing heterocyclic compounds

Nitrogen, oxygen containing heterocycles are important. We treat it

seriously because most of organic compounds belong to this class and among

them some of the most significant compounds for human beings [20]. Due to

their vital roles heterocyclic compounds have became wide applications in

agriculture [21] and medicine [22] fields. The use of nitrogen, oxygen

containing heterocycles in agriculture for pest management is likely to offer

huge benefit in number of ways like insecticides, fungicides, herbicide, etc [23-

24].

The environmental and food security would remain key issue

confronting mankind in the new millennium. In North America, Europe and

Japan, losses are estimated to be in the range of 10-30%, but in developing

parts of the world, these are substantially higher as order of 40% are common,

and losses of as much as 75% have been reported [25]. Therefore, efforts to

increase the food production to lead the increasing population must rely on eco-

friendly approaches to pest management.

In the words of the committee on the plant and animal pests, NAS

[26],”a major technique such as the use of pesticides can be the very heart and


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core of integrated systems. There are many pest problems for which the use of

chemicals provides the only acceptable solution. Their use is indispensable to

modern society [27].Chemical pesticides will continue to the one of the most

dependable weapons of the entomologist for the projected future”.

1.3 Quinolines

Quinoline is also known as benzpyridine. Nitrogen containing

heterocyclic compounds like quinoline has received considerable attention

in recent years due to their biological and pharmaceutical activities. Quinoline

has a phenyl ring fused to a pyridine ring. The chemistry of quinoline has

gained increasing attention due to its various diverse pharmacological activities

[28-30]. Quinoline ring fused with five or six membered ring in linear fashion

is found in natural products as well as in synthetic compounds of biological

interest. Many derivatives of quinoline have been studied for the different

biological activity such as anti-inflammatory [31], antituberculosis [32]. The

Dictemine and Skimmianine (Fig. 1.3) are the examples of two naturally

occurring compounds which are associated with smooth muscle contracting

properties [33].

N O

OCH3

OCH3

OCH3

(Fig. 1.3) Skimmianine

1.4 Furo-pyrimidines

Investigations of quinoline isosters (furopyridines) in which the benzene

ring is replaced by furan rings have resulted in discovering many biologically

active compounds. New pharmacophores with potential antipsychotic activity

possess the furo[3,2-c]pyridine ring system. Therefore, efficient synthetic

methods for these types of heterocycles are of a great interest. Derivatives of


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furopyrimidines moieties are known to possess antitumor [34] and anti-

inflammatory [35] activity. The furan unit can be found in biologically active

compounds and natural products and is a useful synthetic intermediate.

Furopyrimidines and their nucleosides derivatives has been the subject

of many chemical and biological studies on account of their interesting

pharmacological properties. Recently, furopyrimidines were also known to

inhibit adenosine kinase in very low concentration [36]. Therefore, new

furopyrimidine derivatives to evaluate their potential as protein kinase

inhibitors which in mammals comprises three highly homologous members.

Furopyrimidine derivatives have emerged as the most potent inhibitors of

varicella-zoster virus (VZV). In addition; several series of heterocyclic

compounds possessing a bridgehead pyrrolyl moiety play a vital role in many

biological activities.

1.5 Indino-pyridines

The highly conjugated, yellow alkaloid onychnine was first isolated by

De Almeida et al. in 1976 from Onychopetalum amazonicum (Annonaceae)

[37]. The indinopyridine moiety is like the 4-azafluorenone group of this

alkaloid onychine. The naturally occurring onychnine is having antimicrobial

properties particularly against fungus Candida albicans. The infections caused

by this fungus are resistant to treatment and are opportunistic as they infect

persons of weak immune system like AIDS patients and cancer patients

undergoing chemotherapy [38]. The amphotericin-B which has used against

Candida albicancs has many side effects. Therefore the indinopyridines can be

used as alternative to amphotericin-B. Many indinopyridines are having the

different biological activities like herbicidal, calcium antagonistic activators.

They are also useful in the treatment of the neurological disorder as adenosine

A2a receptor binding active and in the treatment of inflammation related

disease as a phosphodiesterase inhibiting [39]. It has also anticandidal activity

[40]. Along with these activities they are also show wide range of


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pharmaceutical activities such as antimalarial, vasodilator, anesthetic. They

also show agrochemicals use such as fungicide, pesticide, and herbicide [41].

1.6 Applications of Heterocyclic Compounds

A majority of compounds produced by nature have heterocyclic ring as

part of their structures. Many heterocyclic rings are found as key components

in biological system. Five membered heterocyclic rings are present in

chlorophyll (Fig. 1.4), hemoglobin (Fig. 1.5) as well as indigo and other

polymers such as melanin [42].

NN

N N

CH2

CH3

CH3

CH3

CH3

OC 20H39

O

CH3

Mg

OH3CO 2C

HH

H

NN

N N

CH2

CH3

CH3

CH2

CH3

OHO

OH

O

CH3

Fe II

(Fig. 1.4) Chlorophyll (Fig. 1.5) Heamoglobin

The six membered heterocyclic rings take place in pyridine, pyridoxine

along with vitamin E, quinine and the pyran nucleus which is originate in

sugars and the anthrocyanin pigments [43]. The five and six membered

heterocyclic rings present in nicotine (Fig. 1.6) and morphin (Fig. 1.7)

respectively [44]. Additional heterocyclic compounds are purine and

pyrimidine which are close relative compounds of nucleic acid and are found in

barbiturates, caffine [45]. Additionally, heterocycles play important role in dye

chemistry [46] and as chelating agents [47].


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(Fig. 1.6) Nicotine (Fig. 1.7) Morphin

These compounds are useful in the field of medicine and used as a

starting material for the synthesis of new drugs [48]. Heterocyclic compounds

have great applicability in pharmaceutics because they have specific chemical

reactivity and block the normal functioning of biological receptors [49]. Some

well known drugs (like penicillin, streptomycin, etc.) consist of heterocyclic

ring system. Natural products containing pyrano and furoquinoline moieties are

widely scattered in nature and found to be connected with a wide range of

biological activities such as psychotropic [50], anti-inflammatory [51],

estrogenic [52] activities.

Modern society is dependent on synthetic heterocycles for use as drugs,

pesticides, dyes, and plastics [53]. A molecule of pyridine contains a ring of six

atoms five carbon atoms and one nitrogen atom. A cyclic organic compound

containing all carbon atoms in ring formation is referred to as a carbocyclic

compound. Nitrogen, oxygen and sulfur are the most common heteroatoms but

heterocyclic rings containing other hetero atoms are also widely known. A vast

number of heterocyclic compounds are recognized and this number is growing

speedily. Accordingly the literature on the subject this is very vast area.

The synthetic heterocyclic drugs are still more plentiful and comprise

most of the hypnotic like anticonvulsants [54] and analeptic [55] drugs, also

many antiseptics [56] (9-aminoacridine) (Fig. 1.8), fungicide [57] (8-

hydroxyqinoline) (Fig. 1.9).


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N

NH2

N

OH

(Fig. 1.8) 9-aminoacridine (Fig. 1.9) 8-hydroxyqinoline

Many pesticides are made up of heterocyclic compounds such as the

herbicide paraquat (Fig. 1.10), diquat, and simazine along with insecticides as

rotenome (Fig. 1.11) and diazinon [58].

N+

N+ CH3

CH3Cl

-

Cl-

(Fig. 1.10) Paraquat

O

O

O

O

O

CH3

CH3 O

CH2

CH3

(Fig. 1.11) Rotenome

Among the wide range of heterocycles explored to develop

pharmaceutically important molecules, five membered heterocyclic has turned

out to be potential chemotherapeutic agents [59]. Scrutiny of a literature has

shown that five membered heterocyclic (pyrazole, thiadiazole, oxadiazole, etc.)

present a class of compound of great importance in biological chemistry. For

instance, certain compound bearing oxadiazole nucleus possesses significant

activities such as anti-inflammatory [60], antituberculosis [61], antibacterial

[62], antischistoma [63] etc.


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Similarly differently substituted triazole moieties have fascinating

activities such as antifungal [64], antihaemostatic [65], antimicrobial [66] etc.

At present several-marketed preparation of triazoles are available like Trazonil,

Trazodone (Fig. 1.12), Terconozole, Fluconazole (Fig. 1.13) etc.

N

N

N

N

N

Cl

O

OH

N

NNN

NN

F

F

(Fig. 1.12) Trazodone (Fig. 1.13) Fluconazole

Several pyrazolines are also known to exhibit versatile pharmacological

activities like analgesic [67], anticancer [68], antiproliferative [69],

antimycobacterial [70], antidepressant [71], insecticidal [72] and antioxidant

[73] etc. Heterocyclic compounds include many of the biochemical material

that carries the genetic information controlling inheritance [74].

1.7 Agricultural Impotence of Heterocyclic Compounds

1.7.1 Herbicides

Weeds may be defined as plant growing where man does not wish them

to be [75]. Weed stared to compete with the crop plants for moisture, nutrients,

and light. With the rapid growth of industrialization, the resultant drift of labors

from the countryside to the factories meant a shortage of manpower on the

farms and consequently agricultural wages increased and to try and cut down

weds, not always with success [76]. This situation provides the stimulus for the


12

development both of more efficient mechanical means of weed control and the

introduction of chemical weed killers (herbicides).

With the large-scale use of certain herbicides, such as phenoxyacetic

acid derivatives, for weed control in cereals, the weed develops new strains that

are resistant to these chemicals [77]. Resistance is most likely to develop in

short-lived annual weeds which may go through several generations in one

season, and have been frequently subjected to a particular chemical herbicide

[78]. New products have been developed to control these grass weeds. The

natural flora of the world is more versatile than man himself. The battle with

weeds has a very long history and will probably have a long future.

The idea of controlling weeds with chemicals is not new. For more than

a century chemicals have been employed for the total weed control the removal

of all plants from such places as railway tracts, timber yards, and roadsides

[79]. Crude chemicals such as rock salt, crushed arsenical ores, oil wastes,

sulphuric acid, and copper salts were used in massive doses [80-81]. The weed-

killing properties of other inorganic compounds such as sodium chlorate,

borates, and arsenic compounds (e.g. sodium arsenite) have been known for a

long time [82]. Under these conditions all plants were killed and what were

much more needed were chemicals which would selectively destroy the weeds,

but not damage the crops.

The first important discovery in the field of selective weed control was

the introduction of 2, 4-dinitro-o-cresol (DNOC or Sinox) in France in 1933

[83].This is a contact herbicide and when sprayed onto a cereals crop it killed

the majority of annual weed. A serious disadvantage is that these substances

are very poisonous to mammals and they have caused considerable damage to

wild life and some human fatalities [84]. In 1942 Zimmerman and Hitchcock

showed that certain chlorinated phenoxyacetic acid such as 2, 4- D (Fig. 1.17)

was more active than the natural growth hormone IAA and furthermore was not

rapidly degraded in the plant [85]. They came into use at a time when the

maximum home food production with a much reduced agricultural labor force

was a vital factor in the war effort [86]. Another early example of great


13

importance was 2-methyl-4-chlorophenoxyacetic acid (MCPA) (Fig. 1.18)

[87].

OOH

O

Cl Cl

CH3

Cl

OOH

O

(Fig. 1.17) 2, 4- D (Fig. 1.18) MCPA

Cl

Cl

Cl

O COOH

(Fig. 1.19) 2, 4, 5-T

Another important member of this series of selective herbicide is 2, 4, 5-

trichlorophenoxyacetic acid (2, 4, 5-T) (Fig. 1.19). This Tranlocated herbicide

is employed for control of woody plants and can be used for selective weed

control in conifers [88]; it is more persistence in soil than either MCPA or 2,4-

D. A number of chlorinated aliphatic acids have been recognized for some time

to be herbicidal. Dalapon (sodium 2, 2-dichloropropionate), introduced in 1953

and trichloroacetic acid (TCA) (1974) shows a similar selective herbicidal

action towards grasses but it is less active than Dalapon, since it is only a soil

acting herbicide and not appreciably translocated from foliage [89].

Some aromatic carbamates are Prophan and Chloroprophan used as soil

acting pre-emergence herbicides [90]. In 1951 C. W. Todd of DuPont described

the herbicidal properties of Monuron (Fig. 1.21) and emphasized its toxicity

against annual and perennial grasses [91].

Cl

NH N

O

CH3

CH3

(Fig. 1.21) Monuron


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Several heterocyclic areas have been developed including Spike which

was introduced by Eli Lilly Ltd. in1974 as a persistent broad-spectrum

herbicide for control of herbaceous and woody plants. Substituted amides are

another group of herbicides whose activity is closely related to that of the

ureas. Examples include the anilines such as Propanil (Fig. 1.22) and Solan.

Several acetamide derivatives are useful herbicides: Allidochl (CDAA) and

Alachlor. Several 2, 6-dinitroanilines are very valuable herbicides e.g.

Trifluralin and Balan.

N

H

O

CH3

Cl

Cl

(Fig. 1.22) Propanil

The herbicidal properties of substituted s-triazines were discovered by

the Swiss firm J. R. Geigy Ltd. in 1952 [92]. Two well known examples are

Simazine (Fig. 1.23) and Atrazine or Gesaprin.

N

N

N

CH3

NHCH3 NH CH3

(Fig. 1.23) Simazine

The best known member of triazoles is Amitrole (3-amino-1, 2, 4-

triazole) introduced as herbicide and growth regulator in 1954, and prepared by

condensation of amino guanidine and formic acid. A number of N-

phenylpyridazinones show herbicidal properties; the most active Pyrazon (Fig.

1.24) is a soil-acting herbicide used for pre- or post-emergence weed control in

sugar beet [93]. Some substituted uracils are also herbicidal was developed by

DuPont Ltd. (1966).


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NN

Cl

NH2 O

(Fig. 1.24) Pyrazon

Bentazon, a member of thiadiazine group, containing nitrogen and

sulphur was developed by BASF AG (Germany) (1968) for post-emergence

control of dicotyledonous weeds in cereals, peas, and beans are Bromacil

(Fig. 1.25) and Trebacil (Fig. 1.26) [94].

NH

Br

CH3

O CH3

CH3

O

N

NH

CH3

Cl

O

CH3

CH3

CH3O

(Fig. 1.25) Bromacil (Fig. 1.26) Trebacil

The two most important examples of bipyridylium herbicides are Diquat

and Paraquat were introduced by plant protection division of Imperial chemical

industries Ltd., in 1958. A very large number of nitrogen containing

heterocycles apparently quite unrelated to one another have been reported to

have herbicidal activity viz., Aminotriazole, Bentazone, Benazoline,

Oxadiazon, Mertribuzin, Hexadiazone and etc [95]. Enough has been said to

illustrate the wide range of compounds which exhibit herbicidal activity and

more are being produced every year.

1.7.2 Insect Growth Regulators (IGRs)

Insect growth regulators (IGRs) are one of the fastest developing

chemical classes of insecticides in the past ten years [96]. They are considered

a “reduced risk” pesticide because they are soft on beneficial insects and


16

primarily are target specific for juvenile stages [97]. The first IGRs were

prepared in the 1960, but most that are used today are new products. These

products do not work on the insect nervous system like classic insecticides and

are therefore more worker-friendly within closed greenhouse environments

[98]. They can be either foliar or soil applied (label dependent) and can be used

alone or in combination with an adulticide (kills the adult insect). Odor in many

cases is minimized compared to classic insecticides and thus users have

negligible contact to dermal inhalation [99].

As a consequence, new approaches have been tested and implemented.

In recent years many of the conventional methods of insect control by broad-

spectrum synthetic chemicals have come under attack and scrutiny because of

their undesirable effects on human health and the environment [100]. One of

these approaches which have captured worldwide attention is the use of

analogs and antagonists of insect growth regulators (IGR) such as juvenile

hormones (JH) (Fig. 1.14), ecdysones (Fig. 1.15), chitin synthetic inhibitors

(Fig. 1.16), and related compounds.

O

CH3

CH3

O

OCH3

CH3

CH3

CH3

CH3

CH3

OH

OH

CH3

OH

CH3

O

OH

OH

(Fig. 1.14) Juvenile hormones (Fig. 1.15) Ecdysone

N

H

N

OO

N

N

N

CH3

Cl

CH3 H

Br

CH3

(Fig. 1.16) Chitin synthesis inhibitor


17

It must be understood that compounds of this type are also chemicals,

but because of their little toxicity to mammals, their choosy toxicity to insect

species, and safety to the environment they can assume a prominent role in the

“integrated pest management” program [101].

1.7.2.1 Juvenile Hormone Mimics of Agricultural Importance

Juvenoids of agricultural importance are Fenoxycarb and their derivative

Pyriproxyfen. Pyriproxyfen which proposed to be more potent than Fenoxycarb

on various insect species [102-105] was introduced recently for controlling

white fly in cotton [106-107] Pyriproxyfen is a potent suppresser of

embryogenesis and adult formation of the sweet potato white fly, Bemisia

tabaci (Gennadius), and the green house white fly Trialeurodes vaporaviorum

(Westwood) [108].

1.7.2.2 Ecdysone Agonists of Agricultural Importance

The activities of ecdysones are due to biosynthesis, enzymatic

degradation, and compartmentalization of the hormonally active compounds

[109-110]. During the last decade many investigations have been directed to

elucidate the possible use of the ecdysteroid receptors as target site for

developing insecticides with novel mode of action [111-112]. Several non

steroid ecdysteroid agonists have been developed recently by Rohm and Hass

Co., Spring House, Pennsylvania, USA.

1.7.2.3 Chitin Synthetic Inhibitors of Agricultural Importance

Synthesis of chitin and deposition of the cuticle in insects are regulated

by the molting hormones (ecdysones). The enzyme chitin synthetase is the key

enzyme in chitin formation. Obviously, any interference with chitin synthesis

and degradation can lead to derangement of metamorphosis and growth of the

organism. Compounds which interface with chitin biosynthesis exert their toxic

effects at the time of molting.

The first potent chitin synthesis inhibitor of the benzoylphenyl urea type

was discovered by scientists at Philips-Duphar in Holland [113]. This


18

compound named Diflubenzuron was found to affect mainly the larval stage

[114]. Buprofezin suppresses embryogenesis and progeny formation of B.

tabaci [115]. It has no ovicidal activity, but suppresses embryogenesis through

adults. Vapor phase toxicity of buprofezin persists at least 10 days after

application, enabling control of whitefly larvae which are present on the lower

surface of the leaves and are difficult to control under standard spray conditions

of other pesticides [116]. Buprofezin is harmless to aphelinid parasite as

Encarsia formosa and Cales noaki and to predacious mites and as such it is a

potential component to be used in IPM programs [117].

1.8 Objectives

The present research work will be concerned with the

development of new heterocyclic compounds in terms of chemical structure

and biological activities. We hope that product development involves

application of the existing drug to meet the emerging therapeutic needs in

addition to the discovery of new chemical entities. The literature survey on

synthesis and biological activities of quinoline, furo-pyrimidine and indino-

pyridine compounds gives us way for synthesis of different derivatives of

above said compounds of biological importance. The single step multi-

component reactions have more advantages as compared with multi-step

synthesis methods. We have attempted to synthesize new heterocyclic moieties

with good biological activities.


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References

[1] http://www.newscientist.com/article/mg16121734.300-first-chemists.html

First chemists, New Scientist, February 13, 1999.

[2] http://en.wikipedia.org/wiki/Chemistry, 2013.

[3] http://www.chemheritage.org/explore/ancients-time.html Alchemy

Timeline, Chemical Heritage Society, June 2011.

[4] http://www.alchemylab.com/history of alchemy.htm, 2013.

[5] Pauling, L. General Chemistry. Dover Publications, Inc. 1947.

[6] Brown, T.L.; Lemay, H.E.; Bursten, B.E.; Lemay, H. Chemistry: The

Central Science. Prentice Hall, 8th edition, pp. 3, 1999.

[7] http://www.visionlearning.com/library/module_viewer.php?mid=49, 2013.

[8] Hill, J.W.; Petrucci, R.H.; McCreary, T.W.; Perry, S.S. General Chemistry

4th edition, Upper Saddle River, NJ: Pearson Prentice Hall, pp. 37, 2005.

[9] Chemical bonding, Britannica Encyclopedia Britannica Retrieved 1

November 2012.

[10] March, J. Advanced Organic Chemistry: Reactions, Mechanisms, and

Structure 3rd edition, New York, Wiley, 1985.

[11] Clayden, J.; Greeves, N.; Warren, S.; Wothers, P. Organic Chemistry, 1st

edition, Oxford University Press, 2001.

[12] California Occupational Guide Number 22: Chemists. Calmis.ca.gov. 1999.

[13] http://www.britannica.com/EBchecked/topic/264227/heterocyclic-

compound

[14] Campaigne, E. J Chem Edu 1986, 6, 860.

[15] Bansal, R.K. Heterocyclic Chemistry, 3rd edition, New Age International,

pp. 1, 1999.

[16] Arora, P.; Arora, V.; Lamba, H.S.; Wadhwa, D. Int J Pharm Res Sci 2012,

3(9) 2947.

[17] IUPAC, Compendium of Chemical Terminology, 2nd edition. (the "Gold

Book") 1997.


20

[18] Eicher, T.; Hauptmann, S. The Chemistry of Heterocycles: Structure,

Reactions, Syntheses, and Applications, 2nd edition, Wiley-VCH Verlag

GmbH, Weinheim. 2003.

[19] Hückel, E. Z Phys 1931, 70 (3/4) 204–86.

[20] Czarnik, A. Acc Chem Res 1996, 29, 112.

[21] Denton, T.T.; Zhang, X.; Cashman, J.R. J Med Chem 2005, 48, 224.

[22] Rudi, A.; Kashman. Y. J Org Chem 1989, 54, 5331.

[23] Aly, M.R.E; El-Mageed, A.E.A; El Kafafy, A.K.M.A.; Nawwar, G.A.M. J

Plant Prot Res 2011, 51(2), 114.

[24] Zhu, M.; Fu, W.; Xun, C.; Zou, G Bull Korean Chem Soc 2012, 33(1) 43.

[25] Atwal, A.S.; Dhariwal, G.S. Agricultural pests of south Asia and their

management, 4th Edition, Kalyani Publishers, New Delhi, 2002.

[26] National Academy of sciences (NAS). Insect-pest management and

control.publ.1695.NAS, Washington, DC. 1969, 245.

[27] Metcalf, R.L.; Luckmen, W.H. Introduction to insect pest management, 3rd

Edition, A Wiley-Interscience Publication, 1994, 312.

[28] Harrison, E.A.; Jr. Rice, K.C.; Rogers, M.E. J Heterocycl Chem 1977, 14,

909.

[29] Morgan, L.R.; Jursic, B. S.; Hopper, C.L.; Neumann, D.M.; Thangaraj, K.;

LeBlanc, B. Bioorg. Med Chem Lett 2002, 12, 3407.

[30] Ryckebusch, A.; Derprez-Poulain, R.; Maes, L.; Debreu-Fontaine, M.;

Mouray, E.; Grellier, P.; Sergheraert, C. J Med Chem 2003, 46, 542.

[31] Sun, X.Y.; Wei, C.X.; Chai, K.Y.; Piao, H.R.; Quan, Z.S. Archiv der

Pharmazie 2008, 341, 5, 288.

[32] Tong, J.; Chen, Y.; Liu, S.; Xu, X. Med Cem Res 2013,

DOI=10.1007/s00044-013-0502-y

[33] Ratheesh, M.; Sindhu, G. Antony, H. Inflamm Res 2013, 62, 4, 367.

[34] Cody, V.; Galitsky, N.; Luft, D.; Pangborn, W.; Blakley, R.; Gangjee, A.

Anti-cancer drug design 1998, 13(4), 307.

[35] Mahadevan, K.M.; Vaidya, V.P.; Vagdevi, H.M. Ind J Chem Sec B 2003,

42(8), 1931.


21

[36] McGaraughty, S.; Cowart, M.; Jarvis, M.F.; Berman, R.F. Cur Topics Med

Chem, 2005, 5(1), 43.

[37] De Almeida, M.E.L.; Braz F.R.; von Btilow, M.V.; Gottlieb, 0.R.; Maia,

J.G.S. Phytochemistry 1976, 15, 1186.

[38] Hufford, C.D.; Clark, A.M. U.S. Pat. US 4873250, 1989.

[39] Heintzelman, G.R.; Averill, K.M.; Dodd, J.H.; Demarest, K.T.; Tang, Y.;

Jackson, P.F. U.S. Pat. US 20040082578, 2004.

[40] De Almeida, M.E.I.; Braz, F.R.; von Bulow, M.V.; Gottleib, O.R.; Maia,

J.G.S. Phytochemistry 1976, 15, 1186.

[41] Kim, B.Y.; Ahn, J.B.; Lee, H.W.; Kang, S.K.; Lee, J.H.; Shin, J.S.; Ahn,

S.K.; Hong,C.I.; Yoon, S.S. Eur J Med Chem 2004, 39, 433.

[42] Arzillo, M.; Pezzella, A.; Crescenzi, O.; Napolitano, A.; Land, E.J.; Barone,

V.; Ischia, M. Org Lett 2010, (12), 14, 325.

[43] Agarwal V.K. The Modern Ayurveda: Milestones beyond the Classical

Age, 2012, 189.

[44] Ji, K.G.; Zhu, H.T.; Yang, F.; Shaukat, A.; Xia, X.F.; Yang, Y.F.; Liu,

X.Y.; Liang, Y.M. J Org Chem 2010, (75)16, 5670.

[45] Sidorov, G.V.; Myasoedov, N.F. Russ Chem Rev 1999, (68)3, 229.

[46] Pal, M.; Garcia S.J.; Santiago, P.; Pal, U. J Physical Chem C 2007, (111)1,

96.

[47] Tron, G.C.; Pirali, T.; Sorba, G.; Pagliai, F.; Busacca, S.; Genazzani, A.A. J

Med Chem 2006, (49), 11, 3033.

[48] Langer, R.; Tirrell, D.A. Nature, 2004, (428)6982, 487.

[49] Antonello, A.; Tarozzi, A.; Morroni, F.; Cavalli, A.; Rosini, M.; Hrelia, P.;

Bolognesi, M.L.; Melchiorre, C. J Med chem 2006, (49)23, 6642.

[50] Leipzig, R.M.; Cumming, R.G.; Tinetti, M.E. J American Geriatrics Soc

1999, (47)1, 30.

[51] Silverstein, F.E.; Faich, G.; Goldstein, J.L.; Simon, L.S.; Pincus, T.;

Whelton, A.; Makuch, R.; Eisen, G.; Agrawal, N.M.; Stenson, W.F.; J

American Med Asso 2000, (284)10, 1247.


22

[52] Desbrow, C.E.J.R.; Routledge, E.J.; Brighty, G.C.; Sumpter, J.P.; Waldock,

M. Environment Sci Tech 1998, (32)11, 1549.

[53] Dua, R.; Shrivastava, S.; Sonawane, S.K.; Srivastava, S.K.; Advance Bio

Res 2011, (5)3, 120.

[54] Ucar, H.; Van derpoorten, K.; Cacciaguerra, S.; Spampinato, S.; Stables,

J.P.; Depovere, P.; Isa, M.; Masereel, B.; Delarge, J.; Poupaert, J.H. J Med

Chem 1998, (41)7, 1138.

[55] Hinkle, P.M.; Pekary, A.E.; Senanayaki, S.; Sattin, A. Brain Res 2002,

(935)1, 59.

[56] McDonnell, G.; Russell, A.D. Clinical Micro Rev 1999, (12)1, 147.

[57] Ostby, J.; Monosson, E.; Kelce, William R.; Gray, L.E. Toxicol Ind Health

1999, (15)1, 48.

[58] Heaton, A. The Chemical Industry 1994, 214.

[59] Grunberg, E.; Titsworth; Edith, H. Annual Rev Microbio 1973, 27(1), 317.

[60] Amir, M.; Javed, S.A.; Kumar, H. Ind J Chem Sec B, 2007, 46(6), 1014.

[61] Maddry, J.A.; Subramaniam, A.; Goldman, R.C.; Hobrath, J.V.; Kwong,

C.D.; Maddox, C.; Rasmussen, L.; Reynolds, R.C.; Secrist III, J.A.; Sosa,

M.I. Tuberculosis 2009, 89(5), 354.

[62] Maslat, A.O.; Abussaud, M.; Tashtoush, H.; Al-Talib, M. Polish J

Pharmacol 2002, 54(1), 55.

[63] Saha, R.; Tanwar, O.; Marella, A.; Alam, M.M.; Akhter, M. Mini Rev Med

Chem 2013, 13(7), 1027.

[64] Aher, N.G.; Pore, V.S.; Mishra, N.N.; Kumar, A.; Shukla, P.K.; Sharma, A.;

Bhat, M.K. Bioorg Med Chem Lett 2009, 19(3), 759.

[65] De Candia, M.; Lopopolo, G.; Altomare, C. Expert Opinion on Therapeutic

Patents 2009, 19(11), 1535.

[66] Eswaran, S.; Adhikari, A.V.; Shetty, N.S. E J Med Chem 2009, 44,(11),

4637.

[67] Joshi, R.S.; Mandhane, P.G.; Diwakar, S.D.; Dabhade, S.K.; Gill, C.H.

Bioorg Med Chem lett 2010, 20(12), 3721.


23

[68] Bashir, R.; Ovais, S.; Yaseen, S.; Hamid, H.; Alam, M.S.; Samim, M.;

Singh, S.; Javed, K. Bioorg Med Chem lett 2011, 21(14), 4301.

[69] Ovais, S.; Yaseen, S.; Bashir, R.; Rathore, P.; Samim, M.; Singh, S.; Nair,

V.; Javed, K. J Enzyme Inhib Med Chem 2012 ,1-8

[70] El-Hashash, M.A.; Soliman, F.M.A.; Souka, L.M.; Salman, A.S.S. Chem

Inform 1995, 26, 46.

[71] Palaska, E.; Aytemir, M.; Uzbay, İ.T. Erol, D. Eur J Med Chem 2001, 36(6),

539.

[72] Silver, K.S.; Soderlund, D.M. Pesticide Biochem Physiol, 2005, 81(2), 136.

[73] Kumar, A.; Varadaraj, B.G.; Singla, R.K. Bulletin of Faculty of Pharmacy,

Cairo University, 2013.

[74] Wolf, C.; Rentsch, J.H.; Philipp J Agric Food Chem 1999, 47(4), 1350.

[75] Akiyama, K.; Hayashi, H. Annal Botany 2006, 97(6), 925.

[76] Harriss, J. Economic and Political Weekly 1999, 3367.

[77] Holt, J.S.; Powles, S.B.; Holtum, J.A. Annual Rev Plant Bio 1993, 44(1),

203.

[78] Murphy, C.E.; Lemerle, D. Euphytica 2006, 148(1), 61.

[79] Willoughby, I.; Clay, D.; Dixon, F. Forestry, 2003, 76(1), 83.

[80] Kearney, P.C.; Kaufmann, D.D. Herbicides-chemistry, Degradation and

mode of action, 2nd edition, vol.1, Dekker, New York, 1975.

[81] Gysin, H.; Knusli, E. Adv in Pest Control Res 1960, 3, 289.

[82] Pesticide Manual (Ed. Martin, H.; Worthing, C.R., 4th edition, British Crop

Protection council, 1974.

[83] Church, J.M.F.; Henson, H.M.G. Int J of Pest Manage A 1969, 15(4), 578.

[84] Turner, D.J.; Loader, M.P.C. Pesticide Sci 1975, 6(1), 1.

[85] Cetin, H.; Erler, F.; Yanikoglu, A. J Vect Ecology 2009, 34(2), 329.

[86] Khater, H.F. Advances in integrated pest management. In Tech, Croatia

2011, 17.

[87] Denis, B.H. Techniques for testing microbials for control of arthropod pests

in greenhouses, Field Manual of Techniques in Invertebrate Pathology,

Springer 2007, pp. 463.


24

[88] Regnault-Roger, C.; Vincent, C.; Arnason, J.T. Annual Rev Entomol, 2012,

57, 405.

[89] Fitzner, M.S. Pesticides in Agriculture and the Environment, 2002, 90, 1.

[90] Penrose, L.J.; Thwaite, W.G.; Bower, C.C. Crop Prot, 1994, 13(2), 146.

[91] Ward, R.K. Total weed control, Proc 13th NZ Weed Control Conf 1960, pp-

66.

[92] Whitten, J.L. that we may live, Van Nostrand, Pinceton, U.S.A., 1996, 31.

[93] Hartley, G.S.; West, T. F., Chemicals for Pest control, Pergamon Press,

Oxford, 1969.

[94] Timmons, F.L.; Weed Science 1970, 294.

[95] Schwendiman, A.; Torrie, J.H.; Briggs, G.M. Agronomy Journal 1943,

35(10), 901.

[96] Hassall, K.A. World Crop Protection: Pesticides, Iliffe Books Ltd., London.

1969, 2.

[97] Green, M.B. ‘heteroaromatics of industrial importance’ in

Polychloroaromatics Compounds Polychloroaromatics (Ed. Suschitzky, H.),

Plenum Press, London. 1974, 419.

[98] Martin, H. The Scientific Principles of Crop Protection, 6th Edition. Arnold,

London, 1973.

[99] Weed control Handbook (Eds. Fryer, J.D.; Evans, S.A.), 5th edition,

Blackwell, Oxford, 1962.

[100] Approved Products for Farmers and Growers, Ministry of Agriculture,

Fisheries and Food, 1978.

[101] Klingman, G.G. Weed Control as a Science, 2nd edition, Wiley, New York,

1963.

[102] Itaya, N. Sumitomo Parathyroid World 1987, 8, 2.

[103] Kawada, H. Sumitomo Parathyroid World 1988, 11, 2.

[104] Langley, P.A. Sumitomo Parathyroid World 1990, 15, 2.Koehler, P.G.;

Pattreson, R.J. J Econ Entomol 1991, 84, 917.

[105] Horowitz, A.R.; Ishaaya, I. J Econ Entomol 1992, 85, 318.

[106] Horowitz, A.R.; Forer, G.; Ishaaya, I. Pestic Sci 1994, 42, 113.


25

[107] Ishaaya, I.; Horowitz, A.R. Pesic Sci 1995, 43, 227.

[108] Gilbert, L.I.; Bollenbacher, W.E.; Goodman, W.; Smith, S.L.; Agui, N.;

Sedlak, B.J. Recent Prog Horm Res 1980, 36, 401.

[109] Koolman, J.; Kaisen, P. Regulation of ecdysteroid titer: degradation. In:

Kerkut, G.A.; Gilbert, L.I. (eds) Comprehensive Insect Physiology,

biochemistry and pharmacology. Vol. 7 Pergamon Press, Oxford,pp , 1985,

343.

[110] Robbins, W.E.; Kaplanis, J.N.; Thompson, M.J.; Shortino, T.J.; Joyner, S.C.

Steroids 1970, 16, 105.

[111] Bergamasco, R.; Horn, D.H.S. The biological activities of ecdystreroid s and

ecdystreroid analogues. In: Hoffman JA (Ed) Progress in ecdysone research.

Elsevier, Amsterdam, 1980, 299.

[112] Van Daalen, J.J.; Meltzer, J.; Mulder, R.; Wellinga, K. 1972, 59, 312.

[113] Grosscurt, A.C. Pestic Sci 1978, 9, 373.

[114] Issaya, I.; Medelson, Z.; Melamed-Madjar, V. J Econ Entomol 1988, 81,

781.

[115] DeCock, A.; Ishaaya, I.; Degheele, D.; Veierov, D. J Econ Entomol 1990,

83, 1254.

[116] Mendel, Z.; Blumberg, D.; Ishaaya, I. Entomophaga 1994, 39, 199.

[117] Joule, J.A.; Mills, K. Heterocyclic Chemistry 5th edition; John Wiley & Sons

Ltd; UK, 2010; pp. 177-198.

Chapter 2: Synthesis of substituted quinoline derivatives

26

CHAPTER 2

SYNTHESIS OF SUBSTITUTED QUINOLINE DERIVATIVES

2.1 Introduction

Quinoline was first extracted from coal tar by Friedlieb Ferdinand

Runge (1834) [1]. Like other nitrogen containing heterocylic compounds

quinoline is often reported as an environmental contaminant associated with

processing oil or coal. The principal source of commercial quinoline is

leftovers of coal tar [2]. Due to high water solubility quinoline has significant

potential for mobility in the environment. The quinoline is readily degradable

by microorganisms, such as Strain Q1 of Rhodococcus species, which was

isolated from soil and paper mill sludge [3].

Most of the today’s drugs in the market are heterocyclic compounds.

Among them one of the important heterocycle is quinoline. The quinoline

containing compounds have wide range of applications such as antibacterial [4]

anticancer [5], anti-malarial [6] and antifungal [7]. It is used in the

manufacturing of dyes [8], preparation of hydroxyquinoline sulfate and niacin

[9]. Quinoline is mainly used as a building block in the production of other

specialty chemicals [10]. Its principal use is as a precursor to 8-

hydroxyquinoline, which is a flexible chelating agent and precursor to

pesticides [11]. Its 2- and 4-methyl derivatives are originator to cyanine dyes

[12]. Oxidation of quinoline give quinolinic acid (Pyridine-2,3-dicarboxylic

acid), a precursor to the herbicide.

In the sequence of study it has seen that the activity of such nucleus may

be due to the presence of fused pyridine [13]. The different substituted schiff

bases were prepared to enhance the antimicrobial activity of quinoline [14].

Some fused derivatives prepared by combining these potent organic fragments

which have reported for their antimicrobial activity to produce more potent

derivatives [15]. Quinoline and its fused heterocyclic derivatives tested for

diverse pharmacological activity constitute an important class of compounds


27

for new drug development [16]. Therefore, many workers have synthesized

quinolines as target structures and evaluated their biological activities.

Due to such enormous importance, it has becomes the synthetic targets

of many organic and medicinal chemistry groups [17]. Recently, it has been

observed that certain bacteria had resistance against well-known antibiotics

[18]. This fact decreases the efficiency of today’s antibiotics which inspired us

to search for new antibacterial molecule with high efficiency and less toxicity

[19-20]. With continuation of our previous work [21] encouraged us to

synthesize different derivatives of quinoline.

2. 2 Literature Review

The quinolines are generally synthesized from the different methods. In

Combes synthesis [22] 1,3-dicarbonyl compound reacted with aryl amine to

give β-aminoenone which then clyclised to give desired quinoline (Scheme

2.1).

NH2

+

R1

R

O

O

N

R

R1

H2SO4

(Scheme 2.1)

In the Conrad-Limpach synthesis [23-24] anilines and β-keto esters

react at lower temperatures to give the kinetic product, a β-aminoacrylate,

which on cyclisation gives a 4-quinolone. At higher temperatures, β - keto acid

anilides are formed and on cyclisation of this gives 2-quinolones (Scheme 2.2).

NH2

+

CH3

EtO

O

ORT

NH CH3

OEtO

70 %

250 oC

NH

O

CH3

140oC

NH O

CH3O

250 oC

NH

CH3

O50 %

(Scheme 2.2)


28

In the Skraup synthesis [25], quinoline is produced when aniline,

concentrated sulfuric acid, glycerol and a mild oxidising agent are heated

together (Scheme 2.3).

NH2

+ PhNO2

OHOH

OH

H2SO4 N

(Scheme 2.3)

The Doebner – Miller Synthesis [26-27] involves the aniline and α, β-

unsaturated carbonyl compounds. The isolation of reaction product is not easy

[28] due to extensive acid catalyzed polymerization of starting α, β-unsaturated

aldehydes (Scheme 2.4).

NH2

R H

O

N R

(Scheme 2.4)

The Friedlander Synthesis [29-30] is widely used for substituted

quinolines. In this reaction the o-acyl-arylamine reacted with ketone or

aldehyde (which must contain α – methylene group) by base or acid catalysis to

yield the quinoline (Scheme 2.5).

O

NH2

+ -H2OR

1

R2

O

N

R1

R2

(Scheme 2.5)


29

Pfitzinger-Borsche reaction [31-32] is the chemical reaction of isatin

with base and a carbonyl compound to yield substituted quinoline-4-carboxylic

acids (Scheme 2.6).

NH

O

OR

1 R2

O

KOHN

OHO

R2

R1

(Scheme 2.6)

Heteroaromatic tosylates and phosphates are suitable electrophiles in

iron-catalyzed cross-coupling reactions with alkyl Grignard reagents (Scheme

2.7). These reactions are carrying out at low temperature allowing good

functional group tolerance with full conversion within minutes [33].

N

OTs

R

+ Br-Mg-R'N

OTs

R

1.5 eq.

5 mol % Fecl 3,

9 eq. NMP

THF

-100C, 9-20 min

R: alkyl

(Scheme 2.7)

The progression of 2,4-disubstituted quinolines were simply prepared

through a one-pot reaction of structurally diverse 2-aminoaryl ketones with

various arylacetylenes in the presence of K5CoW12O40•3H2O as a reusable and

environmentally benign catalyst (Scheme 2.8) under microwave irradiation and

solvent-free conditions [34].

O

R1

NH2

R +CH

Ar

R

N Ar

R1

R1 : Ar, Me

o.1 eq. K5CoW12O40.3H2O

neat, MW (100 W)

1100C, 5-20 min

(Scheme 2.8)


30

An eco-friendly method allows the synthesis of 2,4-disubstituted quinolines

by Meyer-Schuster rearrangement of 2-aminoaryl ketones and

phenylacetylenes in the presence of a catalytic amount of zinc

trifluoromethanesulfonate in the ionic liquid [hmim]PF6 (Scheme 2.9).The

ionic liquid can be recycled [35].

O

R1

NH2

R +CH

Ph

R

N Ph

R1

R1

: Ar, Me

1 mol % Zn(OTf)2

[hmim]PF6

~ 85oC, 2 - 2.5 h

(Scheme 2.9)

An efficient single-step approach toward the synthesis of 2-

alkylquinolines is mediated by a Lewis acid through [3 + 3] annulation reaction

between 3-ethoxycyclobutanones and aromatic amines (Scheme 2.10). A

variety of multi-substituted 2-alkylquinoline derivatives were prepared

regioselectively at room temperature [36].

R

NH2

+O R

1

R2

OEt1 eq. BF3 OEt

DCM, r.t., 6 - 24 hR

N

R1

R2

R1 : alkyl, Bn, Ph

R2 : H, alkyl

2 eq.

(Scheme 2.10)

An environmentally friendly and highly efficient method gives 2,4-

disubstituted quinoline derivatives by a simple alkynylationcyclization reaction

of 2-aminoaryl ketones with phenylacetylenes in the presence of indium(III)

trifluoromethanesulfonate (Scheme 2.11). In (OTf)3 quinoline synthesis under

microwave irradiation and solvent-free conditions. The catalyst can be reused

[37].


31

O

R1

NH2

R +CH

Ph

R

N Ph

R1

R1

: Ar, Me

1 mol % In(OTf)3

neat, MW

1100C, 3.5-5 min

(Scheme 2.11)

A cooperative catalytic system, consisting of CuI and pyrrolidine

enables an efficient synthesis of 2-substituted quinolines (Scheme 2.12). A

mixture of both catalysts is needed; the use of either catalyst alone does not

give the product [38].

CHO

NH2

+CH

Ph N R

1.2 eq.

0.1 eq. CuI0.25 eq. pyrrolidine

MeCN100oC, 12 h

R: Ar, alkyl, vinyl

(Scheme 2.12)

A three-component reaction of nitroarenes, aldehydes, and

phenylacetylene in the existence of indium in dilute hydrochloric acid produces

quinoline derivatives under reflux condition (Scheme 2.13). The conversion

occupies reduction of the nitroarenes to anilines followed by coupling of the

anilines, aldehydes, and phenylacetylene. The cyclization of the resulting

species and dehydrogenation of the cyclic intermediates is carries out [39].

R

NO 2

+ R1CHO

CH

Ph

1.5 eq.+2 eq. In

1 eq. HCl (0.17 M eq.) reflux, 18- 22 h

R

N R1

Ph

R1 : Ar, Et

(Scheme 2.13)


32

A straightforward and efficient Yb(OTf)3 catalyzed three-component

reaction of aromatic aldehydes, alkynes, and amines beneath microwave

irradiation in an ionic liquid gives 2,4-disubstituted quinolines in admirable

yield under placid reaction condition (Scheme 2.14). The catalyst can be

recycled four times [40].

R

NH2

+CH

Ar`

+ R

N

Ar`

Ar

[bmim] [BF4], MW (80 W)

80 oC, 5.5 bar, 3 min.

O

H

Ar

(Scheme 2.14)

A Fe(acac)3/TBAOH-catalyzed three-component coupling cycloiso-

merization reaction of aldehydes, terminal alkynes, and amines (Scheme 2.15)

provides a diverse range of heterocyclic compounds such as aminoindolizines

and quinoline derivatives in good yields [41].

R

NH2

+O

H

R` DMSO60 oC, 2 h

0.1 eq. TBAOHr.t. , o.n.

CH Ar1.4 eq.

R: H, Cl R`: Ar, alkyl

N

Ar

R`

R

(Scheme 2.15)

A modified Larock method permit a one-pot synthesis of substituted

quinolines via a Heck reaction of 2-bromoanilines and allylic alcohols followed

by dehydrogenation with diisopropyl azodicarboxylate (DIAD) (Scheme 2.16)

[42].


33

RBr

NH2

+

R`CH2

OH R``

1) 0.5 mol % [Pd(allyl)Cl2]2

3 mol % ligand.1.8 eq. Cy2NMe

MeCN, 90 oC, 0.25 - 19 h

2) 0.6 eq. AcOH, 1 eq. DIAD90 oC, 15 min.

R

N

R`

R``

R``: alkyl, PhR`: H, Me

(Scheme 2.16)

Highly substituted 3-iodoquinolines bearing different alkyl and aryl

moieties can be synthesized in good yields by a regioselective 6-endo-dig

iodocyclization of 2-tosylaminophenylprop-1-yn-3-ols with molecular iodine

under gentle conditions (Scheme 2.17). The resulting 3-iodoquinolines can be

more functionalized by various coupling reactions [43].

2 eq. I2

MeOH60 oC, 6 -12 h

R

N

I

R``

R`

R`: Ar, PrR``: Ar, MeR

OH

NHTs

R`

R

(Scheme 2.17)

Upon photoirradiation of o-alkynylaryl isocyanides in the presence of

iodine, an intramolecular cyclization gives the consequent 2,4-diiodoquinolines

in excellent yields (Scheme 2.18). 2,4-Diiodoquinolines can be employed in

regioselective transition metal-catalyzed cross-coupling reactions [44].

R`

R

NC

+ I2hv (Hg, Pyrex filter, > 300 nm)

CHCl3, r.t., 4 hN

R R`

I

I

R: H, Me, CF 3

R`: Ar, alkyl, vinyl, TMS

(Scheme 2.18)


34

A Wacker-type oxidative cyclization was done by Pd-catalyzed under

air allows the construction of 2-methylquinolines in good yields under mild

conditions (Scheme 2.19) [45].

R

NH2

CH2

OH

R`R``

0.1 eq. Pd(OAc)20.2 eq. 1,10-phenanthroline

airMeOH, 25 or 40 oC, 36 h

R

N CH3

R``

R`

R`: H, Me, Ph

R``: H, Me

(Scheme 2.19)

A straight reaction (Scheme 2.20) between 2-aminobenzylic alcohol

derivatives and either ketones or alcohols in the presence of a base and

benzophenone as hydride scavenger allows the synthesis of polysubstituted

quinolines without any transition-metal catalyst [46].

OH

R

NH2

+R``O

R` 1 eq. KOtBu1 eq. Ph2CO

1,4-dioxane90 oC, 30 min N

R`

R

R``

R: H, Ph R`: H, alkylR``: alkyl, Ar

(Scheme 2.20)

An efficient and convenient nickel-catalyzed cyclization of 2-

iodoanilines with alkynyl aryl ketones gives 2,4-disubstituted quinolines

(Scheme 2.21). The mechanism is discussed [47]. Naturally take place

quinoline derivatives have been prepared in good yields.

NH2

IR

+ R``R`

O2 eq. 5 mol % NiBr2(dppe)2 eq. Zn

Ch3CN. 80 oC, 12 h

N

R

R`

R``

(Scheme 2.21)


35

A straight two component synthesis of quinolines from α,β-unsaturated

ketones and o-aminophenylboronic acid derivatives (Scheme 2.22) is

regiocomplementary to the traditional Skraup-Doebner-Von Miller synthesis

and proceeds under basic rather than strongly acidic conditions [48].

B(OH)2

NH2

+

R'

R

O

2 eq.

3 mol % [RhCl(cod)2]

2 eq. KOH (3.8 M)toluene, r.t., 24 h N R

R`

R: Me, Ar

0.2 eq. Pd / C (5%)

airreflux, 4 h N R

R`

R`: H, alkyl, Ar

(Scheme 2.22)

An efficient reductive cyclization of o-nitrocinnamoyl compounds was

achieved by employing 1,4-dihydropyridine diethyl ester as a reducing agent in

the presence of catalytic palladium on carbon (Scheme 2.23). This approach

was fruitfully practical to the synthesis of substituted quinolines [49].

NO2

R'

R

O

1.7 mol %Pd/C(10 wt %)

AcOH,1200C,15h

R:Ar,alkyl,H

R':Ar,alkyl,COR

3.6 eq.Hantzsch Ester

N R

R'

(Scheme 2.23)

The reduction of secondary and tertiary o-nitrophenyl propargyl

alcohols followed by acid-catalyzed Meyer-Schuster rearrangement (Scheme

2.24) gave 2-substituted and 2,4-disubstituted quinolines, respectively in good

yields [50].

1) 4.8 eq.FeEtOH,conc.HCl(cat),80

0C,>2h

2)EtOH/10%HCl(pH<4),800C,25h

RNH

RR

OH

NO2

R

(Scheme 2.24)


36

A one-pot dehydrogenative Povarov/oxidation tandem reaction of N-

alkyl anilines with mono- and 1,2-disubstituted aryl and alkyl olefins allow the

synthesis of a various substituted quinolines (Scheme 2.25). The simple

procedure uses inexpensive iron (III) chloride as the Lewis acid catalyst and a

TEMPO oxoammonium salt as a nontoxic, mild, efficient oxidant [51].

RNH COOEt

+R'

2 eq.2 eq.T

+BF4

-

0.1 eq.FeCl3

DCM60

0C,6-20 h

RN COOEt

R'

R' : Ar.C6H13

N+

OT+:

(Scheme 2.25)

A domino reaction of benzimidoyl chlorides with 1,6-enynes offer

quinoline derivatives via palladium-catalyzed Sonogashira coupling and

subsequent cyclization (Scheme 26). The reaction conditions and the extent of

the process are examined, and a probable mechanism is proposed. The

procedure is easy, speedy and the substrates are readily available [52].

N

Ar-

Cl

R

+O

Ar'

5mol -%

Pd(PPh3)2Cl2

2.5mol -%CuI

Et3N,800C,7h

N

Ar-

R

Ar'

O

N

O

Ar-

Ar-

R

(Scheme 2.26)

The intramolecular cyclization of 1-azido-2-(2-propynyl)benzene

proceeds smoothly in the presence of electrophilic reagents in CH3NO2 at room

temperature or in the presence of catalytic amounts of AuCl3/AgNTf2 in THF at

100°C to afford the corresponding quinolines (Scheme 2.27) in good to high

yields [53].


37

E: I(EX=NIS),

Br (EX=Br2)

R':H, OAc

R":alkyl,Ar

R'

RN3

R 5eq.Ex

CH3NO2,r.t,1 - 60h N R"

ER'

R

(Scheme 2.27)

4-Aryl and 4-vinyl quinolines were synthesized by sequential procedure

involving regioselective rhodium-catalyzed hydroarylation/hydrovinylation of

β-(2-aminophenyl)-α,β-ynones with arylboronic acids or potassium aryl and

vinyl trifluoroborates, followed by nucleophilic attack of the amino group onto

the carbonyl (Scheme 2.28) [54].

+NH2

R''

O

R

5 eq.

Y2B -R'

3.3 mol -%Rh(acac)(C2H4)2

6.6 mol -%dppf

dioxane/H2O(10:1)

1000C,4.5 -20 h

N

R'

R"R

Y2B -R':

(HO)2B -Ar,

R' R":Ar, vinyl

BF3KPh

(Scheme 2.28)

An easy copper-catalyzed method allows the synthesis of quinoline-2-

carboxylate derivatives (Scheme 2.29) through sequential intermolecular

addition of alkynes onto imines and subsequent intramolecular ring closure by

arylation at room temperature [55].

R

N COOEt

2 eq.

+0.2 eq.Cu(OTf)2

CH2Cl2,r.t,16h

R

N

R'

COOEt

R:Me,OMe,OBn

R':Ar,BnR

(Scheme 2.29)

A single-step conversion of various N-vinyl and N-aryl amides to the

corresponding pyridine and quinoline derivatives involves amide activation

with trifluoromethanesulfonic anhydride in the presence of 2-chloropyridine

followed by π-nucleophile addition to the activated intermediate and


38

annulations (Scheme 2.30). The compatibility of this chemistry with various

functional groups is striking [56].

NH

R O

R'R''

1.2 -2 eq.

2 -Cl -pyridine

1.1 eq.Tf2O

CH2Cl2. -780C,5 min

N+

R

Cl

N+HR'

R''

2TfO

R''' Riv

R'''

Riv

ORv

1.1-2eq

or

0oC r.t.,1h

N

Riv

R R'''

R''R'

(Scheme 2.30)

The synthesis transfer of amides, including sensitive N-vinyl amides, to

the corresponding trimethylsilyl alkynyl imines (Scheme 2.31) followed by a

Quinoline synthesis ruthenium-catalyzed protodesilylation and

cycloisomerization gives various substituted pyridines and quinolines [57].

0.1 eq.SPhos

1 eq.NH4PF6

toluene,1050C,18h

NR

R"

R'

PCy2

OMe

MeO

SPhos:SiMe3

R N

R''

R'

(Scheme 2.31)

The present chapter divided into two sections:

� Section I: Synthesis of dicarboxyquinoline derivatives

� Section II: Synthesis of dihydroxypyridazinoquinoline derivatives


39

Section I

SYNTHESIS OF DICARBOXYQUINOLINE DERIVATIVES

2. I.1 Present Work

With respect to the effectiveness of quinoline derivatives as biological

active molecules we decided to synthesize some more quinoline molecules with

continuation of our previous work. By transforming di-ester quinoline to

dicarboxyquinoline derivatives we used different aromatic amino

benzophenone as starting materials which provides use variability in the final

products as target molecules for study of different biological activities.

The synthesis of target compounds involves preparation of 2,3,4-

trisubstituted quinolines (3A-D). They were synthesized from different

aromatic amino ketone (1A-D) and diethyl acetelylenedicarboxylate (DEAD)

(2) in ethanol as reported by Patil et al (scheme 2.32) [58]. The newly

synthesized compounds were confirmed on the basis of spectroscopic data.

O

O

O

O CH3

CH3

R1

R2

O

NH2

+N

R1

R2

O

OO

O

CH3CH3

1A-D 2 3A-D

+ OH

CH3 H2SO4, Reflux.

(Scheme 2.32)

When we use different alcohol there is possibility of formation of trans-

esterification product. Therefore use of ethanol as solvent we maintain the

same di-ester functional group for all starting materials. It gives easy access to

transform the starting material into final dicarboxyquinoline (Section I) and

dihydroxypyridazinoquinoline (Section II) derivatives.

Putting this view in mind the dicarboxyquinoline derivatives (4A-D) are

synthesized by using ethanol as a solvent in reflux condition from the

corresponding quinoline dicarboxylates (3A-D) by alkaline hydrolysis with

good yield. The reaction is monitored by TLC method. The solvent system


40

used was Hexane: Ethyl acetate (8:2). The salt obtained was acidified with 1:1

HCl at low temperature [59]. The final product was oven dried.

2. I.2 General Procedure for Synthesis of Dicarboxyquinoline Derivatives

(4A-4D)

To a stirred solution of 5 ml ethanol, dicarboxylic acid ester 3a (0.767 g,

2 mmoles) and aq. potassium hydroxide (20 mole % in 0.5 ml water) was

refluxed for 2 hr. The reaction mixture was then cooled at room temperature.

The isolated desired solid material was filtered and washed with 10 ml of

ethanol. The obtained product dissolved in distilled water and acidified with

1:1 HCl. The formed precipitate was filtered and washed with distilled water.

It is then recrystalized from ethanol. (Scheme 2.33)

N

R1

R2

O

O

O

CH3

O

CH3

i

ii N

R1

R2

OH

O

OH

O

3A-D4A-D

R1: 3A,3D:Cl-; 3B,3C:H-

R2:3A,3B:C6H5-: 3C:CH3-; 3D:Cl-C6H6-

R1: 4A,4D:Cl-; 4B,4C:H-

R2:4A,4B:C6H5-: 4C:CH3-; 4D:Cl-C6H4-

i) EtOH, aq. KOH, Reflux 2hrs. ii) Water, 1:1 HCl, 0-5 0C

(Scheme 2.33)

The different synthesized dicarboxyquinoline derivatives are

summarized in the (Table 2.1). The compounds (4A-D) are confirmed by

spectroscopic technique like IR, 1H NMR, 13C NMR, GCMS and LCMS data.

The data obtained is in good agreement with the proposed structure.


41

(Table 2.1) The physical and analytical data of synthesized dicarboxyquinoline

derivatives

Sr.

No. Entry Structure

Time

(min) Color

M. P.

(oC)

Isolated

Yield (%)

1 4A

N

ClOH

O

OH

O

30 White

210 87

2 4B

N

O

O

OH

OH

35 White

195 85

3 4C N

CH3 O

O

OH

OH

30 White

190 82

4 4D

N

OH

OH

O

O

Cl

Cl

30 White

120 80

2. I.3 Experimental

This experimental part is same for (Section I) and (Section II) also. The

melting points are uncorrected and were determined in an open capillary

method. Infrared spectra (in KBr pellets) were measured with on a Perkin

Elmer Spectrum 100 spectrophotometer and 1H and 13C NMR spectra were


42

recorded on a Bruker Spectrospin Avance II-300 MHz spectrophotometer using

CDCl3 and DMSO-d6 solvents and tetramethylsilane as an internal standard.

Chemical shifts are given in the delta scale (ppm).

Mass spectra were analyzed on a Shimadzu QP 2010 GCM. The

LCMSMS used from Applied Bio-system API-4000 AB-SCIEX. Diethyl

acetylenedicarboxylate was purchased from Aldrich chemicals. The purity of

the compounds was checked by using TLC Silica gel 60-F254 plates. A X-ray

powder diffraction pattern was recorded at room temperature on PW 3710/1710

Philips-Holland, Tube anode used was Cr and wavelength α1 [Å] was 2.28970.

2. I.4 Result and Discussion

The structures of dicarboxyquinoline (4A-D) derivatives were confirmed

from IR, 1H NMR, 13C NMR and Mass spectrometry data. The IR spectrum

(4A) was showed the broad stretching vibration bands for acidic –OH group at

3426 cm-1 resembling the formation of dicarboxyquinoline derivatives. The 1H

NMR of same compound didn’t exhibited the signals of ethyl esters suggest the

formation of hydrolysis product. Similarly the 13C NMR spectra have given all

the corresponding carbons presents in the structure.

Finally, the structure of formed compound was confirmed from the

GCMS analysis which gives the peak at 309 corresponding to the molecular

weight due to loss of water molecule from the parent compound having

molecular formula C17H10ClNO4. The data obtained is in good agreement with

the proposed structure. In the LCMS analysis compounds (4C) and (4D) gives

the desired molecular weights as 232.1 and 362 respectively.

2. I.5 Conclusions

The dicarboxyquinoline derivatives are new entries in the substituted

quinolines. The process has mild reaction conditions. These compounds are

used in different biological activities. The use of cheap catalysts is an important

aspect of the development of new process. Here we used aq. KOH as easily

available and cheap catalyst for hydrolysis reaction.


43

2. I.3.1 Spectral Data for Representative Compound

Diethyl 4-phenyl-6-chloroquinoline-2,3-dicarboxylate

(Scheme 2.32, Entry 3A)

N

ClO

O

O

O

CH3

CH3

(Fig. 2.1)

White solid; Yield=78%; M.P.= 140 0C; IR (Fig. 2.2) (KBr,cm-1) 3442,

2985, 2936,1734, 1719, 1215, 1051, 831, 701; 1H NMR (Fig. 2.3) (300 MHz,

CDCl3) δ (ppm): 8.28-8.25 (d, 1H, Ar-H), 7.77-7.73 (dd, 1H, Ar-H), 7.57-7.56

(d, 1H, Ar-H), 7.55-7.50 (m, 3H, Ar-H), 7.37-7.34 (m, 2H, Ar-H), 4. 57-4.49

(q, 2H, CH2, J =7.2 Hz), 4.12-4.05 (q, 2H, CH2, J =7.2 Hz), 1.51-1.46 (t, 3H,

CH3, J = 7.2 Hz), 1.03-0.98 (t, 3H, CH3, J =7.2 Hz); 13C NMR (Fig. 2.4) (300

MHz, CDCl3) δ(ppm) 166.46, 164.74, 146.87, 146.09, 145.46, 135.29, 134.17,

132.20, 131.82, 129.36x2, 128.96, 128.36x2, 128.27, 127.94, 125.27, 62.41,

61.44, 14.19, 13.59; MS (Fig. 2.5a & 2.5b):(m/z) 383 (M+).

XRD data (Fig. 2.6): Molecular formula= C21H18ClNO4, Formula

weight= 383.82, Temperature= 298K, Tube anode= Cr, Wavelength= 2.28970

Å, Crystal System= Monoclinic, Unit cell dimensions; a= 6.9177 Å, b=21.5289

Å, c= 8.6812 Å, β= 98.671 Å, Volume= 1278.11 Å3, Crystal size (t) =

18942.11 Å.

2. I.3.2 Spectral data for compounds (4A-D)

6-Chloro-4-phenylquinoline-2,3-dicarboxylic acid (Table 2.1, Entry 4A)


44

N

ClOH

O

OH

O

(Fig. 2.7)

Compound (4A) Colorless solid; Yield=87%; M.P. = 210 0C; IR (Fig. 2.8)

(KBr, cm-1) 3426, 2922, 1923, 1746, 1636; 1H NMR (Fig. 2.9) (300 MHz,

CDCl3) δ (ppm): 11.23 (s, 1H, Ar-COOH), 11.13 (s, 1H, Ar-COOH), 8.18-

8.15 (d, 1H, Ar-H), 7.76-7.72 (1H, dd, Ar-H), 7.51-7.49 (m, 3H, Ar-H), 7. 41 -

7.40 (d, 1H, Ar-H), 7.33-7.32 (m, 2H, Ar-H); 13C NMR (Fig. 2.10) (300 MHz,

CDCl3) δ (ppm):167.90, 166.53, 147.34, 145.87, 144.98, 134.54, 134.41,

132.09, 131.62, 129.51, 129.05, 128.68, 128.55, 128.23, 125.15; MS (Fig.

2.11a & 2.11b): (m/z-18) 309.

4-Phenylquinoline-2,3-dicarboxylic acid (Table 2.1, Entry 4B)

N

O

O

OH

OH

(Fig. 2.12)

Compound (4B) White solid; Yield=85%; M.P. = 195 0C; IR (Fig. 2.13)

(KBr, cm-1) 3436, 3080, 2541, 2012, 1740, 1615, 1597; 1H NMR (Fig. 2.14)

(300 MHz, CDCl3) δ (ppm): 11.32 (s, 1H, Ar-COOH), 11.21 (s, 1H, Ar-

COOH), 8.19-8.16 (d, 1H, Ar-H), 7.87 -7.82 (t, 1H, Ar-H), 7.65-7.60 (m, 2H,

Ar-H), 7.51-7.49 (m, 3H, Ar-H), 7.35-7.33 (m, 2H, Ar-H); 13C NMR (Fig.

2.15) (300 MHz, CDCl3) δ (ppm): 168.16, 167.01, 147.41, 146.74, 146.50,

135.09, 131.20, 130.12, 129.63, 129.28, 128.90, 128.54, 127.67, 127.24,

126.61; MS (Fig. 2.16): (m/z-19) 274.


45

4-Methylquinoline-2,3-dicarboxylic acid (Table 2.1, Entry 4C)

N

CH3 O

O

OH

OH

(Fig. 2.17)

Compound (4C) White solid; Yield=82%; M.P. = 190 0C; IR (Fig. 2.18)

(KBr, cm-1): 3495, 2924, 2499, 1942, 1720, 1719; 1H NMR (Fig. 2.19) (300

MHz, CDCl3) δ (ppm): 10.40 (s, 1H, Ar-COOH), 9.96 (s, 1H, Ar-COOH),

8.25-8.23 (d, 1H, Ar-H), 8.12-8.06 (d, 1H, Ar-H), 7.91-7.86 (t, 1H, Ar-H), 7.81

-7.76 (t, 1H, Ar-H), 2.73 (s, 3H, CH3); 13C NMR (Fig. 2.20) (300 MHz,

CDCl3) δ (ppm): 169.02, 167.42, 148.00, 145.86, 143.44, 131.46, 130.36,

129.30, 127.76, 125.38, 15.75; MS (Fig. 2.21a & 2.21b): (m/z) 232.1 (MH+).

6-Chloro-4-(2-chlorophenyl)quinoline-2,3-dicarboxylic acid

(Table 2.1, Entry 4D)

N

OH

OH

O

O

Cl

Cl

(Fig. 2.22)

Compound (4D) White solid; Yield=80%; M.P. = 120 0C; IR (Fig. 2.23)

(KBr, cm-1): 3427, 2923, 2565, 1934, 1727, 1559; 1H NMR (Fig. 2.24) (300

MHz, CDCl3) δ (ppm): 11.33 (s, 1H, Ar-COOH), 11.01 (s, 1H, Ar-COOH),

8.21- 8.12 (t, 1H, Ar-H), 7.82-7.79 (d, 1H, Ar-H), 7.61-7.45 (m, 3H, Ar-H), 7.

33 -7.30 (d, 1H, Ar-H), 7.18 (s, 1H, Ar-H); 13C NMR (Fig. 2.25) (300 MHz,

CDCl3) δ (ppm): 167.36, 166.76, 144.98, 143.74, 134.81, 133.57, 133.12,

132.32, 132.02, 131.33, 130.98, 129.73, 128.43, 127.59, 127.39, 124.75; MS

(Fig. 2.26): (m/z) 362 (MH+)


46

Section II

SYNTHESIS OF DIHYDROXYPYRIDAZINOQUINOLINE

DERIVATIVES

2. II.1 Present Work

The hydrazine hydrate is a good synthon for preparation of nitrogen

containing heterocyclic compounds by carrying cyclization reaction. We used

different aromatic amino benzophenone as starting materials for di-ester

derivatives, which provide use variability in the final products as target

molecules for study of different biological activities. The reaction is monitored

by TLC method. The solvent system used was Hexane: Ethyl acetate (8:2).

The solid product is then oven dried.

For the synthesis of dihydroxypyridazinoquinoline derivatives (5A-D)

the reaction of corresponding dicarboxylicacidesters (3A-D) and hydrazine

hydrate was carried out in ethanol as a solvent. The salt obtained was then

refluxed with excess of glacial acetic acid to form desired products. All the

products were obtained in good yield and in high purity [60].

2. II.2 General Procedure for Synthesis of Dihydroxypyridazinoquinoline

Derivatives (5A-D)

In the stirred solution of 5 ml ethanol, the dicarboxylic acid ester 3A

(0.767 g, 2 mmoles) and (0.303 g, 6 mmoles) hydrazine hydrate were refluxed

for 2 hrs. Then the reaction mixture cooled at room temperature. The separated

solid was filtered and washed with 10 ml of ethanol. The solid product then

reacted with glacial acetic acid (15 ml) and refluxed for 2 hrs (Scheme 2.34).

After cooling the crystalline precipitate obtained were filtered and washed with

ethanol and air dried.


47

N

R1

R2

O

O

O

O

CH3

CH3

i

ii N

R1

R2

NH

O

NH

O

3A-D5A-D

R1: 3A,3D:Cl-; 3B,3C:H-

R2:3A,3B:C6H5-: 3C:CH3-; 3D:Cl-C6H6-

R1: 5A,5D:Cl-; 5B,5C:H-

R2:5A,5B:C6H5-: 5C:CH3-; 5D:Cl-C6H4-

i) EtOH, hydrazine hydrate, Reflux 2hrs. ii) Glacial acetic acid, Reflux 2hrs

(Scheme 2.34)

The Structures of synthesized dihydroxypyridazinoquinoline derivatives

are summarized in the (Table 2.2).

(Table 2.2) The physical and analytical data of synthesized dihydroxy-

pyridazinoquinoline derivatives.

Sr.

No. Entry Structure

Time

(min) Color

M. P.

(oC)

Isolated

Yield (%)

1 5A

N

ClNH

NH

O

O

35 Yellow

>320 80

2 5B

N

NH

NH

O

O

40 Yellow

>320 78


48

3 5C N

CH3

NH

NH

O

O

35

Creamy

>320 75

4 5D

N

NH

NH

O

O

Cl

Cl

30 Brown

>320 70

2. II.3 Result and Discussion

The synthesized dihydroxypyridazinoquinoline derivatives (5A-D) were

confirmed by all the available spectroscopic techniques. The IR spectra of (5B)

showed a strong absorption at 3132 cm-1 due to –NH stretching and 1694 and

1645 cm-1 due amide ketone. The 1H NMR of same compounds exhibited two

doublets instead of triplet and quartets due two –NH protons support the

desired product.

The 13C spectra also confirmed the structure by giving all the signals

instead of ethyl function. Finely, the compound was interpreted on the basis of

GCMS analysis which shows a molecular ion peak at 289 (M+) of molecular

formula C17H11N3O2. In this way, the synthesized dihydroxypyridazino-

quinoline derivatives (5A-D) were confirmed by all the available spectroscopic

techniques.

2. II.4 Conclusions

Herewith we are prepared dihydroxypyridazinoquinoline derivatives by

cyclization reaction using hydrazine hydrate. The compounds are new in this

quinoline series. The procedure is simple in execute with mild reaction

conditions. Time period for reaction is less and not required any special

instrument.


49

2. II.4.1 Spectral data for compounds

8-Chloro-10-phenyl-2,3-dihydropyridazino[4,5-b]quinoline-1,4-dione

(Table 2.2, Entry 5A)

N

ClNH

NH

O

O

(Fig. 2.27)

Compound (5A) Yellow solid; Yield=80%; M.P. = >3200C; IR (Fig.

2.28) (KBr, cm-1): 3216, 3066, 1656, 1603; 1H NMR (Fig. 2.29) (300 MHz,

CDCl3) δ (ppm): 8.29-8.26 (d, 1H, Ar-H), 7.78-7.77 (d, 1H, Ar-H), 7.75-7.74

(d, 1H, Ar-H), 7.71-7.69 (d, 1H, -NH), 7.45-7.43 (m, 3H, Ar-H), 7.39-7.38 (d,

1H, -NH), 7.19-7.16 (m, 2H, Ar-H); 13C NMR (Fig. 2.30) (300 MHz, CDCl3) δ

(ppm): 189.45, 134.96, 134.62, 133.76, 133.08, 131.96, 129.64, 128.51,

128.10, 127.90, 127.08, 126.36, 125.99, 124.52, 122.65, 121.08; MS (Fig.

2.31a & 2.31b): (m/z) 323 (M+).

10-Phenyl-2,3-dihydropyridazino[4,5-b]quinoline-1,4-dione

(Table 2.2, Entry 5B)

N

NH

NH

O

O

(Fig. 2.32)

Compound (5B) Yellow solid; Yield=78%; M.P. = >320 0C; IR (Fig. 2.33)

(KBr, cm-1): 3133, 3058, 1694, 1645, 1553; 1H NMR (Fig. 2.34) (300 MHz,

CDCl3) δ (ppm): 8.31-8.28 (d, 1H, Ar-H), 7.96 (t, 1H, Ar-H), 7.63 (t, 1H, Ar-


50

H), 7.48-7.46 (m, 4Ar-H, 1-NH), 7.23 (s, 2H, Ar-H), 1.88 (s, 1H, -NH); 13C

NMR (Fig. 2.35) (300 MHz, CDCl3) δ (ppm): 172.33, 162.00, 149.50, 137.02,

132.61, 130.10, 128.89, 128.75, 127.90, 127.85, 127.53, 102.00; MS: (Fig.

2.36) (m/z) 289 (M+).

10-Methyl-2,3-dihydropyridazino[4,5-b]quinoline-1,4-dione

(Table 2.2, Entry 5C)

N

CH3

NH

NH

O

O

(Fig. 2.37)

Compound (5C) Creamy solid; Yield=75%; M.P. = >320 0C; IR (Fig.

2.38) (KBr, cm-1): 3167, 3029, 2927, 1659, 1602, 1559; 1H NMR (Fig. 2.39)

(300 MHz, CDCl3) δ (ppm): 11.55 (br s, 1H, -NH), 10.89 (br s, 1H, -NH), 8.51-

8.48 (d, 1H, Ar-H), 8.23-8.20 (d, 1H, Ar-H), 8.06-7.79 (m, 1H, Ar-H), 7.59-

7.53 (t, 1H, Ar-H), 2.07 (s, 3H, -CH3); 13C (Fig. 2.40)NMR (300 MHz, CDCl3)

δ (ppm): 192.52, 182.08, 130.49, 128.80, 126.03, 116.53, 15.76.


51

(Fig

. 2.2

) IR

Spe

ctru

m o

f D

ieth

yl 4

-phe

nyl-

6-ch

loro

quin

olin

e-2,

3-di

carb

oxyl

ate

(Sch

eme

2..3

3, E

ntry

3A

)


52

(Fig

. 2.3

) 1 H

NM

R S

pect

rum

of

Die

thyl

4-p

heny

l-6-

chlo

roqu

inol

ine-

2,3-

dica

rbox

ylat

e (S

chem

e 2.

.33,

Ent

ry 3

A)


53

(Fig

. 2.4

) 13

C N

MR

Spe

ctru

m o

f D

ieth

yl 4

-phe

nyl-

6-ch

loro

quin

olin

e-2,

3-di

carb

oxyl

ate

(Sch

eme

2..3

3, E

ntry

3A

)


54

(Fig

. 2.5

a) G

as C

hrom

atog

ram

of

Die

thyl

4-p

heny

l-6-

chlo

roqu

inol

ine-

2,3-

dica

rbox

ylat

e (S

chem

e 2.

.33,

Ent

ry 3

A)


55

(Fig

. 2.5

b) M

ass

Spec

trum

of

Die

thyl

4-p

heny

l-6-

chlo

roqu

inol

ine-

2,3-

dica

rbox

ylat

e (S

chem

e 2.

.33,

Ent

ry 3

A)

M. W

. = 3

83


56

(Fig

. 2.6

) X

RD

of

Die

thyl

4-p

heny

l-6-

chlo

roqu

inol

ine-

2,3-

dica

rbox

ylat

e (S

chem

e 2.

33,

Ent

ry 3

A)


57

(Fig

. 2.8

) IR

Spe

ctru

m o

f 6-

Chl

oro-

4-ph

enyl

quin

olin

e-2,

3-di

carb

oxyl

ic a

cid

(Tab

le 2

.1,

Ent

ry 4

A)


58

(Fig

. 2.9

) 1 H

NM

R S

pect

rum

of

6-C

hlor

o-4-

phen

ylqu

inol

ine-

2,3-

dica

rbox

ylic

aci

d (T

able

2.1

, E

ntry

4A

)


59

(Fig

. 2.1

0) 13

C N

MR

Spe

ctru

m o

f 6-

Chl

oro-

4-ph

enyl

quin

olin

e-2,

3-di

carb

oxyl

ic a

cid

(Tab

le 2

.1,

Ent

ry 4

A)


60

(Fig

. 2.1

1a)

Gas

Chr

omat

ogra

m o

f 6-

Chl

oro-

4-ph

enyl

quin

olin

e-2,

3-di

carb

oxyl

ic a

cid

(Tab

le 2

.1,

Ent

ry 4

A)


61

(Fig

. 2.1

1b)

Mas

s Sp

ectr

um o

f 6-

Chl

oro-

4-ph

enyl

quin

olin

e-2,

3-di

carb

oxyl

ic a

cid

(Tab

le 2

.1,

Ent

ry 4

A)

M. W

. = 3

27-1

8 =

309


62

(Fig

. 2.1

3) I

R S

pect

rum

of

4-P

heny

lqui

nolin

e-2,

3-di

carb

oxyl

ic a

cid

(Tab

le 2

.1,

Ent

ry 4

B)


63

(Fig

. 2.1

4) 1 H

NM

R S

pect

rum

of

4-P

heny

lqui

nolin

e-2,

3-di

carb

oxyl

ic a

cid

(Tab

le 2

.1,

Ent

ry 4

B)


64

(Fig

. 2.1

5) 13

C N

MR

Spe

ctru

m o

f 4-

Phe

nylq

uino

line-

2,3-

dica

rbox

ylic

aci

d (T

able

2.1

, E

ntry

4B

)


65

(Fig

. 2.1

6) M

ass

Spec

trum

of

4-P

heny

lqui

nolin

e-2,

3-di

carb

oxyl

ic a

cid

(Tab

le 2

.1,

Ent

ry 4

B)

M. W

. = 2

93


66

(Fig

. 2.1

8) I

R S

pect

rum

of

4-M

ethy

lqui

nolin

e-2,

3-di

carb

oxyl

ic a

cid

(Tab

le 2

.1,

Ent

ry 4

C)


67

(Fig

. 2.1

9) 1 H

NM

R S

pect

rum

of

4-M

ethy

lqui

nolin

e-2,

3-di

carb

oxyl

ic a

cid

(Tab

le 2

.1,

Ent

ry 4

C)


68

(Fig

. 2.2

0) 13

C N

MR

Spe

ctru

m o

f 4-

Met

hylq

uino

line-

2,3-

dica

rbox

ylic

aci

d (T

able

2.1

, E

ntry

4C

)


69

(Fig

. 2.2

1) M

ass

Spec

trum

of

4-M

ethy

lqui

nolin

e-2,

3-di

carb

oxyl

ic a

cid

(Tab

le 2

.1,

Ent

ry 4

C)

M. W

. = 2

31


70

(Fig

. 2.2

3) I

R S

pect

rum

of

6-C

hlor

o-4-

(2-c

hlor

ophe

nyl)

quin

olin

e-2,

3-di

carb

oxyl

ic a

cid

(Tab

le 2

.1,

Ent

ry 4

D)


71

(Fig

. 2.2

4) 1 H

NM

R S

pect

rum

of

6-C

hlor

o-4-

(2-c

hlor

ophe

nyl)

quin

olin

e-2,

3-di

carb

oxyl

ic a

cid

(Tab

le 2

.1,

Ent

ry 4

D)


72

(Fig

. 2.2

5) 13

C N

MR

Spe

ctru

m o

f 6-

Chl

oro-

4-(2

-chl

orop

heny

l)qu

inol

ine-

2,3-

dica

rbox

ylic

aci

d (T

able

2.1

, E

ntry

4D

)


73

(Fig

. 2.2

6) M

ass

Spec

trum

of

6-C

hlor

o-4-

(2-c

hlor

ophe

nyl)

quin

olin

e-2,

3-di

carb

oxyl

ic a

cid

(Tab

le 2

.1,

Ent

ry 4

D)

M. W

. = 3

62


74

(Fig

. 2.2

8) I

R S

pect

rum

of

8-C

hlor

o-10

-phe

nyl-

2,3-

dihy

drop

yrid

azin

o[4,

5-b]

quin

olin

e-1,

4-di

one

(Tab

le 2

.2,

Ent

ry 5

A)


75

(Fig

. 2.2

9) 1 H

NM

R S

pect

rum

of

8-C

hlor

o-10

-phe

nyl-

2,3-

dihy

drop

yrid

azin

o[4,

5-b]

quin

olin

e-1,

4-di

one

(Tab

le 2

.2,

Ent

ry 5

A)


76

(Fig

. 2.3

0) 13

C N

MR

Spe

ctru

m o

f 8-

Chl

oro-

10-p

heny

l-2,

3-di

hydr

opyr

idaz

ino[

4,5-

b]qu

inol

ine-

1,4-

dion

e (T

able

2.2

, E

ntry

5A

)


77

(Fig

. 2.3

1a)

Gas

Chr

omat

ogra

m o

f 8-

Chl

oro-

10-p

heny

l-2,

3-di

hydr

opyr

idaz

ino[

4,5-

b]qu

inol

ine-

1,4-

dion

e (T

able

2.2

, E

ntry

5A

)


78

(Fig

. 2.3

1b)

Mas

s Sp

ectr

um o

f 8-

Chl

oro-

10-p

heny

l-2,

3-di

hydr

opyr

idaz

ino[

4,5-

b]qu

inol

ine-

1,4-

dion

e (T

able

2.2

, E

ntry

5A

)

M. W

. = 3

23


79

(Fig

. 2.3

3) I

R S

pect

rum

of

10-P

heny

l-2,

3-di

hydr

opyr

idaz

ino[

4,5-

b]qu

inol

ine-

1,4-

dion

e (T

able

2.2

, E

ntry

5B

)


80

(Fig

. 2.3

4) 1 H

NM

R S

pect

rum

of

10-P

heny

l-2,

3-di

hydr

opyr

idaz

ino[

4,5-

b]qu

inol

ine-

1,4-

dion

e (T

able

2.2

, E

ntry

5B

)


81

(Fig

. 2.3

5) 13

C N

MR

Spe

ctru

m o

f 10

-Phe

nyl-

2,3-

dihy

drop

yrid

azin

o[4,

5-b]

quin

olin

e-1,

4-di

one

(Tab

le 2

.2,

Ent

ry 5

B)


82

(Fig

. 2.3

6b)

Mas

s Sp

ectr

um o

f 10

-Phe

nyl-

2,3-

dihy

drop

yrid

azin

o[4,

5-b]

quin

olin

e-1,

4-di

one

(Tab

le 2

.2,

Ent

ry 5

B)

M. W

. = 2

89


83

(Fig

. 2.3

8) I

R S

pect

rum

of

10-M

ethy

l-2,

3-di

hydr

opyr

idaz

ino[

4,5-

b]qu

inol

ine-

1,4-

dion

e (T

able

2.2

, E

ntry

5C

)


84

(Fig

. 2.3

9) 1 H

NM

R S

pect

rum

of

10-M

ethy

l-2,

3-di

hydr

opyr

idaz

ino[

4,5-

b]qu

inol

ine-

1,4-

dion

e (T

able

2.2

, E

ntry

5C

)


85

(Fig

. 2.4

0) 13

C N

MR

Spe

ctru

m o

f 10

-Met

hyl-

2,3-

dihy

drop

yrid

azin

o[4,

5-b]

quin

olin

e-1,

4-di

one

(Tab

le 2

.2,

Ent

ry 5

C)


86

References

[1] Quinoline. Encyclopedia. 1911.

[2] Gerd Collin; Hartmut Höke Quinoline and Isoquinoline, Ullmann's

Encyclopedia of Industrial Chemistry, Weinheim: Wiley-VCH, 2005.

[3] O'Loughlin, E.J.; Kehrmeyer, S.R..; Sims, G.K. Int Biodeter Biode 1996,

38(2), 107.

[4] Harrison, E.A.; Jr., Rice, K.C.; Rogers, M.E. J Heterocycl Chem 1977, 14,

909.

[5] Morgan, L.R.; Jursic, B.S.; Hopper, C.L.; Neumann, D.M.; Thangaraj, K.;

LeBlanc B. Bioorg Med Chem Lett 2002, 12, 3407.

[6] Ryckebusch, A.; Derprez-Poulain, R.; Maes, L.; Debreu-Fontaine, M.;

Mouray, E.; Grellier, P.; Sergheraert, C. J Med Chem 2003, 46, 542.

[7] Denton, T.T.; Zhang, X.; Cashman, J.R. J Med Chem 2005, 48, 224.

[8] Gupta, V.K.; Mittal, A.; Gajbe, V. J colloid interface sci 2005, 284(1), 89.

[9] Sven, J.; Lundin, S.T. J Appl Chem Biotech 1977, 27(4), 499.

[10] http://www.hmdb.ca/metabolites/HMDB33731

[11] Pandeya, S.N.; Tyagi, A. Chem Inform 2012, 43(3), 53.

[12] Bergstrom, F.W. Chem Rev 1944, 35(2), 77.

[13] Meth-Cohn, O.; Narine, B.; Tarnowski, B. J Chem Soc Perkin Trans 1 1981,

1520.

[14] Adsule, S.; Barve, V.; Chen, D.; Ahmed, F.; Dou, Q.P.; Padhye, S.; Sarkar,

F.H. J Med Chem 2006, 49(24), 7242.

[15] Madkour, H.M.F.; Mahmoud, M.R.; Sakr, A.M.; Habashy, M.M. Chem

Inform 2001, 32, 31.

[16] Bruneton, J. Saudi Pharma J 2003, 11, 1.

[17] Abadi, A.H.; Hegazy, G.H.; El-Zaher, A.A. Bioorg Med Chem 2005, 13,

5759.

[18] Otzen, T.; Wempe, E.G.; Kunz, B.; Bartels, R.; Lehwark-Yvetot, G.; Hansel,

W.; Schaper, K.; Seydel, J.K. J Med Chem 2004, 47, 240.

[19] Karlowsky, J.A.; Kelly, L.J.; Thornsberry, C.; Jones, M.E.; Sahm, D.F.

Antimicrob Agents Chemother 2002, 46, 2540.


87

[20] Levy, S.B.; Marshall, B. Nat Med 2004, 10, s112.

[21] Deshmukh, M.B.; Salunkhe, S.M.; Patil, D.R.; Anbhule, P.V. Eur J Med

Chem 2009, 44, 265.

[22] Combes, A. Bull. Chim Soc France 1888, 49, 89.

[23] Conrad, M.; Limpach, L Ber 1887, 20, 944.

[24] Conrad, M.; Limpach, L Ber 1891, 24, 2990.

[25] Skraup, Z.H. Berichte. 1880, 13, 2086.

[26] Doebner, O.; Miller, W. V. Ber 1881, 14, 2812.



[29] Friedlander, P. Ber 1882, 15, 2572.

[30] Friedlander, P.; Gohring, C.F. Ber 1883, 16, 1833.

[31] Pfitzinger, W. J. Prakt Chem 1886, 33, 100.

[32] Pfitzinger, W. J. Prakt Chem 1888, 38, 582.

[33] Gøgsig, T.M.; Lindhardt, A.T.; Skrydstrup, T. Org Lett 2009, 11, 4886.

[34] Baltork, M.; Tangestaninejad, S.; Moghadam, M.; Mirkhani, V.; Anvar, S.;

Mirjafari, A. Synlett 2010, 3104.

[35] Sarma, R.; Prajapati, D. Synlett 2008, 3001.

[36] Shan, G.; Sun, X.; Xia, Q.; Rao, Y.; Org Lett 2011, 13, 5770.

[37] Lekhok, K.C.; Prajapati, D.; Boruah, R.C. Synlett 2008, 655.

[38] Patil, N. T.; Raut, V. S. J. Org Chem 2010, 75, 6961.

[39] Das, B.; Jangili, P.; Kashanna, J.; Kumar, R.A. Synthesis 2011, 3267.

[40] Kumar, A.; Rao, V.K. Synlett 2011, 2157.

[41] Patil, S.S.; Patil, S.V.; Bobade, V.D. Synlett 2011, 2379-2383.

[42] Stone, M.T. Org Lett 2011, 13, 2326.

[43] Ali, S.; Zhu, H.-T.; Xia, X.-F.; Ji, K.-G.; Yang, Y.-F.; Song, X.-R.; Liang, Y.-

M. Org Lett 2011, 13, 2598.

[44] Mitamura, T.; Ogawa, A.; Pan, X. J Org Chem 2011, 76, 1163.

[45] Zhang, Z.; Tang, J.; Wang, Z. Org Lett 2008, 10, 173.

[46] Martínez, R.; Ramón, D.J.; Yus, M. J Org Chem 2008, 73, 9778.

[47] Korivi, R. P.; Cheng, C.-H. J Org Chem 2006, 71, 7079.


88

[48] Horn, J.; Marsden, S.P.; Nelson, A.; House, D.; Weingarten, G.G. Org Lett

2008, 10, 4117.

[49] Xing, R.-G.; Li, Y.-N.; Liu, Q.; Han, Y.-F.; Wei, X.; Li, J.; Zhou, B.

Synthesis 2011, 2066.

[50] Sandelier, M. J.; DeShong, P. Org Lett 2007, 9, 3209.

[51] Richter, H.; Mancheño, O.G. Org Lett 2011, 13, 6066.

[52] Gao, G.-L.; Niu, Y.-N.; Yan, Z.-Y.; Wang, H.-L.; Wang, G.-W.; Shaukat, A.;

Liang, Y.-M. J. Org Chem 2010, 75, 1305.

[53] Huo, Z.; Gridnev, I. D.; Yamamoto Y. J. Org Chem 2010, 75, 1266.

[54] Abbiati, G.; Arcadi, A.; Marinelli, F.; Rossi, E.; Verdecchia, M. Synlett 2006,

3218.

[55] Huang, H.; Jiang, H.; Chen, K.; Liu H. J Org Chem 2009, 74, 5476.

[56] Movassaghi, M.; Hill, M.D.; Ahmad, O.K. J Am Chem Soc 2007, 129,

10096.

[57] Movassaghi, M.; Hill, M.D J Am Chem Soc 2006, 128, 4592.

[58] Patil, D.R.; Deshmukh, M. B.; Salunkhe, S.M.; Anbhule, P.V. J Heterocycl

Chem 2011, 48, 1342.

[59] Vogel A.I. In Textbook of practical organic chemistry: 5th edition; Furniss,

B.S.; Hannaford, A.J.; Smith, P.W.G.; Tatchell, A.R., Ed.; Longman

Scientific and Technical; UK, 1989; pp. 1266-1267.

[60] Rozhkov, E.; Piskunova, I.; Gol’d, M. Chem Heterocycl Compd 1998, 34,

222.

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Physics Chemistry Geology Biology - INFLIBNETshodhganga.inflibnet.ac.in/bitstream/10603/43587/6/06_chapter_02.pdfHeterocyclic compounds probably constitute the largest and most varied