Chapter - I: Introduction

CHALCONE

INTRODUCTION
The chemistry of chalcones has generated intensive scientific studies
throughout the world. Especially interest has been focused on the synthesis and
biodynamic activities of chalcones. The name Chalcones was given by
Kostanecki and Tambor1. These compounds are also known as
benzalacetophenone or benzylidene acetophenone. In chalcones, two aromatic
rings are linked by an aliphatic three carbon chain. Chalcone bears a very good
synthon so that variety of novel heterocycles with good pharmaceutical profile
can be designed.

Chalcones are -unsaturated ketone containing the reactive keto-

ethylenic group CO-CH=CH-. These are coloured compounds because of the
presence of the chromophore -CO-CH=CH-, which depends in the presence of
other auxochromes.

Different methods are available for the preparation of chalcones 2-4.The

most convenient method is the Claisen-Schimdt condensation of equimolar
quantities of arylmethylketone with aryl aldehyde in the presence of alcoholic
alkali5.

Chalcones are used to synthesize several derivatives like cyanopyridines,

pyrazolines isoxazoles and pyrimidines having different heterocyclic ring
systems.6-9

1
Chapter - I: Introduction

Ar Ar'

N
O
Iso-oxazole

NH2OH
Ar'
Ar Ar'
CN
Ar C C CH Ar'
H Guanidine N N
Malononitrile
O
Ar N
Cyanopyridine NH2NH2 NH2
Pyrimidine

Ar Ar'

N
N
H
Pyrazoline

NOMENCLATRURE

Different methods of nomenclatures for chalcone were suggested at

different times. The following pattern has been adopted by Chemical
Abstracts published by American chemical society.

3' 2' 2 3

1' 1
4' C CH CH 4

O 6 5
5' 6'
(I)

The British Chemical Abstract and Journal of Chemical Society have

followed the following system.

2
Chapter - I: Introduction

3 2 2' 3'

1 1'
4 C CH CH 4'

O 5'
5 6 6'
(II)

SYNTHETIC METHODS OF PREPARING CHALCONES

CLAISEN-SCHMIDT REACTION

A variety of methods are available for the synthesis of chalcones, the

most convenient method is the one that involves the Claisen-Schmidt
condensation of equimolar quantities of a substituted acetophenone with
substituted aldehydes in the presence of aqueous alcoholic alkali. 10-17 In the
Claisen-Schmidt reaction, the concentration of alkali used, usually ranges
between 10 and 60 %.18-19 The reaction is carried out at about 50 oC for 12-15
hours or at room temperature for one week. Under these conditions, the
Cannizaro reaction20 also takes place and thereby decreases the yield of the
desired product. To avoid the disproportionation of aldehyde in the above
reaction, the use of benzylidene-diacetate in place of aldehyde has been
recommended.21 (a)

R R'

C CH3 + OHC

:OH - -H 2O

R R'
C C CH
H
O

VARIOUS CONDENSING AGENTS USED IN SYNTHESIS OF CHALCONES

3
Chapter - I: Introduction

[1] Alkali

Alkali has been the most used condensing agents for synthesis of
chalcones. It is used as an aqueous solution of suitable concentration viz. 30 %,
40 %, 50 % and 70 %.

[2] Hydrochloric Acid

Dry hydrochloric gas in a suitable solvent like ethylacetate at 0 oC was

used as a condensing agent in a few syntheses of chalcones from aromatic
ketones. Methanolic solution of dry hydrochloric acid gas at 0 oC was also used
by Lyle, Paradis21 (b) and Marathey21 (c).

[3] Other Condensing Agents

Raval and Shah22 used phosphorous oxychloride as a condensing agent to

synthesize of chalcones. Szell and Sipos 23 condensed 2-hydroxy-5-nitro-
acetophenone with benzaldehyde using anhydrous AlCl 3. Kuroda, Matsukuma
and Nakasmura24 obtained chalcone by condensing acetophenone derived from
anisole and other polymethoxy benzenes with some methoxyaldehydes in
presence of anhydrous aluminium chloride.

Besides the above, other condensing agents used in synthesis of

chalcones have been,

(1) Amino acid 25

(2) Aqueous solution of borax 26

(3) Perchloric acid 27

(4) Piperidine 28

(5) Boron trifloride 29

(6) Alkali metal alkoxide 30

(7) Magnesium tert-butoxide 31

4
Chapter - I: Introduction

(8) Organocadmium compound 32

MECHANISM OF CHALCONE FORMATION

Kinetic studies have been reported for the base-catalyzed formation of

chalcone and its derivatives33-36. Two alternative mechanisms have been
advanced for the reaction of benzaldehyde with acetophenone in the presence
of a basic catalyst.

[I]
CH3COPh + C 2H 5O CH2COPh + C2H5OH

CH2COPh + PhCHO Ph C CH2COPh

O OH
Ph C CH2COPh + H 2O Ph C CH2COPh + OH

H H
OH

Ph C CH2COPh Ph-CH=CHCOPh + H 2O

[II] O

PhCHO + C2 H5 O Ph C OC2H5

O OH

CH3COPh
+ Ph C OC2H5 Ph C CH2COPh

H H

5
Chapter - I: Introduction

The formation of chalcone by the acid catalyzed condensation of

acetophenone and benzaldehyde has been studied. 37, 38

The following mechanism seems to be operating

Ph C CH3 Ph C CH2

O OH

+
O OH

+ +SH
Ph C H Ph C H
+ S
[S=Solvent]

OH +OH OH OH
Transition
Ph C CH2 + Ph C H Complex Ph C CH2 CH Ph

+OH OH O OH
+SH
Ph C CH2 CH Ph + S Ph C CH2 CH Ph +

O
+OH
2

Ph C CH2 CH Ph + S

O
+OH
2 O
+
Ph C CH2 CH Ph Ph C CH CH Ph + H + H 2O

IMPORTANCE OF CHALCONES

(1) They have close relationship with flavones, aurones, tetralones and
aziridines.

6
Chapter - I: Introduction

(2) Chalcones and their derivatives find application as artificial sweeteners 39-43,
scintillator44, polymerization catalyst 45-46
, fluorescent whitening agent47,
organic brightening agent48-49, stabilizer against heat, visible light, ultraviolet
light and aging.50-54

(3) 3,2,4,6-tetrahydroxy-4-propoxy-dihydrochalcone-4-'-neohesperdoside 55
has been used as synthetic sweetener and is 2200 times sweeter than
glucose.

(4) They contain a keto-ethylenic group and are therefore reactive towards
several reagents e.g. (a) phenyl hydrazine, (b) 2-amino thiophenol etc.

(5) The chalcones have been found useful in elucidating structure of natural
products like hemlock tannin56, cyanomaclurin57, ploretin58, eriodictyol and
homo eriodictyol59, naringenin60 etc.

METHODS OF SYNTHESIS

Carthamin (III), a red pigment was first obtained as red needles with
green iridescence using pyridine solvent from the flowers of cartharmus tinctoria
(safflower) by Kmetaka and Perkin61 and this was the first known example of
chalcone in nature.

OGC

O OH

C C CH OH
H
OH O
(III)

It isomerizes to a yellow compound isocarthamin (IV) on treatment with

dil. HCl as reported by Kuroda62.

7
Chapter - I: Introduction

OGC

HO OH

C C CH OH
H
OH O
(IV)

A variety of methods are available for the synthesis of chalcones. The

most convenient method is the one that involves the Claisen-Schmidt
condensation of equimolar quantities of substituted acetophenone with
substituted aldehydes in presence of aqueous alcoholic alkali.63-98

Venkatraman and Nagrajan99 prepared bis-chalcone (V, VI) from

dihydroxy-diacetylbenzene and anisaldehydes using alkali.

OCH3 OH OH OCH3

C CH C C C CH
H H
O O

(V)

OH OH

H
H3CO C CH C C C CH OCH3
H
O O

(VI)

Several hydroxy-nitrochalcones were prepared using dry hydrogen

chloride gas100-102. Onoda and Sasaki103 used hydrochloric acid to synthesize
hydroxy-nitrochalcone (VII) from 2-hydroxy-5-nitroacetophenone and p-
anisaldehyde.

8
Chapter - I: Introduction

OH

C C CH OCH 3
H
O

NO2 (VII)

The other condensing agents which have been employed are alkali metal
alkoxide104-105, magnesium-t-butoxide106, borax107, piperidine108, aluminium
chloride109, boron trifluoride110, amino acids111 and perchloric acid.112

Chalcones (X) were prepared by reaction of benzaldehyde (VIII) with

phosphonate carbanion (IX) derived from diethyl phenacyl phosphonate. 113-116

H2
CHO + C 2 H5 O P C C

OC 2H5 O
(VIII) (IX)

C C C
H H
O

(X)

Several workers117-119 prepared chalcones (XIV, XV) from ketones (XII,

XIII) and aromatic aldehyde (XI) in ethanol as energy transfer medium.

OH
Ar1 CHO Ar1 C CH C C CH Ar1
H H
CH3 C Ar1
O
O
(XI) (XIV)
(XII)

9
Chapter - I: Introduction

OH
Ar1 CHO Ar1 C CH C Ar2
H
CH3 C Ar2
O
O
(XI) (XV)
(XIII)

Ar1 = C6H5, Ar2 = -R-C6H4

Mistry and Desai120 synthesized chalcone (XVI) using microwave technique.

H3 CO C C CH Cl
H
O

(XVI) Cl

Naik and Naik121 synthesized chalcone derivative from 2-hydroxy-3-

bromo-5-ethyl acetophenone.

Br Br

OH OH
R-CHO
aq. KOH (40%)

C2H 5 C CH 3 C2H 5 C C CH R
H
O O

The chalcones are associated with different biological activities like

insecticidal122, anticancer123, anti-inflammatory124, bactericidal125, fungicidal126,
antiviral127, antitumor128, antimalarial129 and antiulcer130. Literature shows that
lieochalcone and oxygenated chalcone has strong antileishmanial activity 131-132.
It is reported that chalcones exhibited potent activity against human malarial
parasite133. Many workers have reported the different pharmaceutical activities
of chalcones and its derivatives 134-137. The antibacterial activities of some
substituted chalcones have been studied by Modi et al138. De vincenzo et al139

10
Chapter - I: Introduction

reported anti-inflammatory activity of some chalcone derivatives. Aldose

reductase inhibitor activity of chalcone derivatives has also been reported by
Okuyama et al140, Toru et al141 reported anticancer activities of chalcones and
Ceo et al142 reports the chalcones as a-glucosidase inhibitors. Antiplasmodial
activity of ferrocenyl chalcones was reported by Xiang et al 143. Bhatt and co-
workers reported cytotoxic properties of chalcones and their pyrazoles
derivatives.144

BIOLOGICAL IMPORTANCE

The presence of -unsaturated carbonyl system of chalcone makes it

biologically active145. They have shown antibacterial activity against S. aureus,
E. coli, C. albicans, T. utilis, S. sake, W. anomala and some other organisms146.

Devaux, Nuhrich and Dargelos 147 synthesized some nitrofuryl chalcones

and tested for their antibacterial activity. Among all those derivatives the most
efficient was (XVII), which inhibited Staphylococcus landon at concentration 1
g/ml.

O2 N C CH C
H
O
O
(XVII)

Some chalcones containing indole moiety (XVIII) were synthesized and

tested for antibacterial and antifungal activity by Dandia, Sehgal and Singh 148.

11
Chapter - I: Introduction

HC CH C X

Ar

N
H
(XVIII)
where,
Ar = Substituted phenyl

Chalcones incorporated with benzopyran moiety (XIX) were reported by

Hismat, El-Diwani and Melek149.

O OCH3

C C C
H H
H3C O
O
(XIX)

Salvie, Richard and John150 reported -substituted chalcones. The -

methyl compound (XX) was found to be the most active and tested for the
chemotherapy of leukemias.

OCH3

H3CO C C CH OCH3

O CH3

OCH3 (XX) OH

12
Chapter - I: Introduction

Heterocyclic substituted chalcones (XXI) were prepared by Bombardeli

and Valenti151. They reported that some of them were introduced for the
treatment of breast cancer, menopausal disorders and osteoporosis.

C C C Ar
H H
O
R1 O

O (XXI)
Where, Ar = Heteroaryl
R = -OH, -OR', where R' = alkyl
R1 = -H, -alkyl

Uenaka, Kawata, Nagai and Endoh 152 synthesized -hydroxy chalcones

(XXII). Compounds having fluoro substitution showed considerable activity
against Human Immuno Virus (HIV).

R4 R2 R1
N NH
H
C C R3
N
C CH3

O
(XXII)
Where,
R 1, R2 , R 3 = H, (un) substituted alkyl, alkoxy, halo
R 4 = H, (un) substituted alkyl or aryl

Seele153 reported chalcone having heterocyclic moiety (XXIII) and

reported their insecticidal activity.

13
Chapter - I: Introduction

R C C C Ar
H
O H2C

N
Where, (XXIII)
R, R1 = alkyl, phenyl, bi-phenyl, naphthyl, furyl
X = N, CH

Some other biological activity of chalcone such as antiviral 154, anti-

inflammatory155-156, prostaglandin binding157, antiulcer158, anti-tumor159,
cardiovascular160 and anti-cancer161 were also reported.

14
Chapter - I: Introduction

PYRIMIDINE

Pyrimidine nucleus exhibited remarkable pharmacological activities.

Literature indicates that compounds having pyrimidine nucleus have wide range
of therapeutic uses that include anti-inflammatory, antibacterial, anticancer,
antiviral, anti-HIV, antimalarial, antihypertensive, sedatives and hypnotics,
anticonvulsant and antihistaminic.

In medicinal chemistry pyrimidine derivatives have been very well known

for their therapeutic applications. The presence of a pyrimidine base in thymine,
cytosine and uracil, which are the essential binding blocks of nucleic acids, DNA
and RNA is one possible reason for their activity. The literature indicated that
compounds having pyrimidine nucleus possess broad range of biological
activities. Like 5-fluorouracil as anticancer; idoxuridine and trifluoridine as
antiviral; zidovudine and stavudine as antiHIV, trimethoprim, sulphamethiazine
and sulphadiazine as antibacterial; sulphadoxin as antimalarial and antibacterial;
minoxidil and prazosin as antihypertensive; barbiturates e.g. phenobarbitone as
sedative, hypnotics and anticonvulsant; propylthiouracil as antihyroid;
thionzylamine as H1-antihistamine; and toxoflavin and fervennuline as
antibiotics.

The replacement of two -CH units in benzene by nitrogen atoms gives

pyrimidines (I).

N N

(I)

15
Chapter - I: Introduction

Pyrimidines are considered to be 'important' if they occur naturally as

such or as part of a natural molecule from which the Pyrimidine can be obtained
easily; they are used as drugs; as agricultural chemicals.

During the last 160 years, many trivial names have been used for
pyrimidine and its derivatives, such as Miazine (I) and Cytosine (II) etc.

N NH

H 2N

(II)

Preliminary IR spectra suggested that Pyrimidones (III) existed as

pyrimidinols (IV).162-163

O OH

N NH N N

(III) (IV)

Similarly pyrimidine thiones (V) existed as pyrimidine thiols (VI).

S SH

N NH N N

(V) (VI)

There are various methods for synthesis of pyrimidines; some of them are
described here.

16
Chapter - I: Introduction

1. Condensation of 1,1,3,3-tetraethoxy propane (VII) with thiourea in alcoholic

hydrochloric acid gave pyrimidine-2-(1H)-thione (VIII) 164 and with N-methyl

urea under similar conditions gave 1-methyl pyrimidine-2-(1H)-one (IX) 165.

CH(OEt) 2

CH 2

CH(OEt) 2

S (VII) O

H 2N C NH2 H3C HN C NH2

N N

N S N O
H
CH3
(VIII) (IX)

2. Pyrimidone (XI) and pyrimidine thione (XII) have been prepared by heating

chalcone (X) with urea and thiourea respectively either with conc. HCl in
ethanol166 or with ethanol and Na-ethoxide167.

17
Chapter - I: Introduction

R C C CH R'
H
O
(X) H2N C NH2
H2N C NH2

O S

O S

N NH N NH

R R' R R'

(XI) (XII)

Most drugs in the pyrimidine series fall in to four categories; the

barbiturates, the sulphonamide; the antimicrobials and antitumor agents.

Barbituric acid was made conveniently from diethyl malonate and urea in
ethanolic sodium ethoxide168 and it has a variety of biological properties. Luminol
(R1 - Et, R2-Ph) (XIII) was prepared in 1904 but used as a long active CNS
depressant only from 1912 until the present day.

O
R1
NH
R2

O N O
H
(XIII)

Hyperthyroidism may be treated in several ways. One of these is

interference with the synthesis of the thyroid hormones, possibly or by removal
of iodine. Thiouracil (XIV) and thiobarbital (XV) are effective thyroid drugs.
Compound (XIV) is widely used probably because it has fewer side effects than
the others169.

18
Chapter - I: Introduction

O O

NH Et2 NH

R N O N S
H O H

(XIV) (XV)

Cytosine arabinoside (XVI) is established drug for the treatment of acute

leukemia's of childhood and adult granulocytic. It has also incidental antiviral
activity against herpes and herpes zaster types170.

NH2

CH2OH N
O

CH3 HO

H3C CH3

OH CH3

(XVI)

El-Gaby, Adel-Hamide and Gharab 171 prepared some new pyrimidine-2-

thiones (XVII). Some of these compounds were tested for in vitro anticancer
activity against Ehrlich Ascites Carcinoma Cells.

19
Chapter - I: Introduction

N NH

R CH3

C2 H5OOC
(XVII)
where,
R= 4-F-C 6H4 , 4-(F2 )-C6 H3, 1-Naphthyl

Wada and Yoshida172 prepared pyrimidine derivatives having general

structure (XVIII). They reported their use as herbicide which gave complete
control of Amaranthus retroflexus.

OCH3 R2

N N

O O

N N

OCH3 R2 R1 HCOOC R3

(XVIII)

Several pyrazolo[3,4-d]pyrimidine derivatives were synthesized as

potential inhibitor of adenosine kinase by Cottom et al173. One of the compounds
(XIX) was found to display good anti-inflammatory activity.

NH2
I

N
N

N
N

HO O

HO
OH
(XIX)

20
Chapter - I: Introduction

Lee et al174 synthesized and studied some 6-substituted pyridopyrimidine

analogous as potential AK inhibitors, led to the identification of 4-amino-5-(3-
bromophenyl)-7-(6-morpholinopyridin-3-yl)pyrido[2,3-d]-pyrimidine (XX, ABT-
702), a novel and potent non-nucleoside AK inhibitor with oral activity in animal
models of pain and inflammation The ABT-702 was further studied in details by
Boyle et al175 to evaluate its potential utility in chronic inflammation.

Br

NH2

N N

N
N
(XX)
O

Molina et al176 synthesized a number of pyrido[1,2- C] pyrimidines (XXI-

XXIII) and tested for effects on leukocyte function in vitro and anti-inflammatory
activity.

COOC2 H5

N N

(XXI) R

R=H, CH3, OCH3, F, Cl, Br

21
Chapter - I: Introduction

COOC2 H5

N N

X
X=O, S
(XXII)

N N

(XXIII)

Vidal et al177 have studied the effects of some hexahydroimidazo[1,2-

C]pyrimidine derivatives (XIV) on leukocyte functions in vitro and screened for
anti-inflammatory activity in two models of inflammation.

O2
H S CH3
N N

N
O

R
HN
O
H3C O
CH3
R=H, 4-Br, 4-F, 2-Cl
(XXIV)

22
Chapter - I: Introduction

Bruno et al178 reported the synthesis of some new 2,5-cycloamino-5H -

benzopyrano[4,3-d]pyrimidines (XXV) and screened them for anti-inflammatory,
analgesic and antipyretic activities and in vitro antiplatelet activity. All the
compounds failed to exhibit anti-inflammatory, analgesic and antipyretic
activities but they showed an interesting antiplatelet activity.

NR2

N N

O NR'2
NR2 & NR'2 = pyrrolo, piperidino, morpholino

(XXV)

Bahekar et al179 reported the synthesis of some [2-amino-6-(4-substituted

aryl)-4-(4-substituted phenyl)-1,6-dihydropyrimidin-5-yl]acetic acid derivatives
(XXVI) and evaluated for anti-inflammatory activity. Only few of them showed
remarkable anti-inflammatory activity.

HOOCH2 C
NH

N NH2

R1 R1= Phenyl, 4-chloro phenyl, furfural, 4-methoxy phenyl,

2-thiophene, 3-nicotine

(XXVI)

23
Chapter - I: Introduction

Ferri et al180 synthesized some 2-tosylamino (XXVII-A) and 2-

tosyliminopyrimidine (XXVII-B) derivatives and studied their interference with
some leukocyte functions.

Ts

N N
CH2 CONHR

(XXVII -A)

N N Ts

N CH2 CONHR

(XXVII -B)

where,
R= H, C2H5 , C6 H5 , 4-OH-C6H4 , 2-4Cl2-C6H3 , C6 H5 CH2 CH2 , 4-OH-C6H4 CH2 CH2
4-F-C6H4 CH2 CH2 , 2-4-Cl2-C6H4 CH2 CH2

Jakubkiene et al181 reported the synthesis of some 5-(6-methyl-2-

substituted-4-pyrimidinyloxymethyl)-2,3-dihydro-1,3,4-oxadiazole-2-thiones
(XXVIII-A) and their 3-morpholinomethyl derivatives (XXVIII-B) and evaluated
them for anti-inflammatory activity. Most of the tested compounds were found
to be active and some of them were more active than acetylsalicylic acid.

CH3

N N NH

O CH2
R N O S

(XXVIII-A)

24
Chapter - I: Introduction

CH3
O
N
N N N

O CH2
R N O S

(XXVIII-B)

R= thiomethyl, benzylamino, pyrrolidino, piperidino, morpholino

Bruno et al182 synthesized two different series N-methyl-N-pyrimidin-2-yl

glycine and N-5H-[1]benzopyrano[4,3-d]pyrimidin-2-yl substituted amino acids
and tested for anti-inflammatory activity. All the compounds showed significant
anti-inflammatory activity.

Sacchi et al183 synthesized a series of imidazo[1,2- a]pyrimidine 2-

carboxylic acid and 20 acetic acid analogs (XXIX-A-B) and tested them for anti-
inflammatory activity. Almost all the carboxylic acid derivatives showed a
remarkable anti-inflammatory activity.

H 3C N R1 N N
N

CH 2COOEt CH 2COOH
N N

R 1= OCH3, CH 3
Cl R2
R 2= OCH3, OC2H5
(XXIX-A) (XXIX-B)

Abignente et al184 synthesized a group of imidazo[1,2-a]pyrimidine-2-

carboxylic acid esters, acids and amides. Some of them showed anti-
inflammatory activity, while almost all compounds displayed significant analgesic
activity.

25
Chapter - I: Introduction

Laneri et al185 reported the synthesis and anti-inflammatory activity of

some new 2-methylimidazo-[1,2-a]pyrimidine-3-carboxylic esters, acids and
amides. The compounds (XXX-XXXII) displayed maximum anti-inflammatory
activity.

R1 N N
CH3
N

COOC 2H5 R1 = OCH3, CH3, H

R2
R2 = OCH3, CH3, OC 2H 5
(XXX)

N N
CH3
N

CONH2

(XXXI)

R1 N N
CH3
N

COOH
R2 R1 , R 2 = H

R1 , R 2 = CH3
(XXXII)

26
Chapter - I: Introduction

2-AMINO PYRIMIDINE BASED ON CHALCONE

Pyrimidine derivatives are prepared in view of the fact that a number of

related compounds are known to be associated with biodynamic properties 186.
Pyrimidine derivatives are reported to be prepared by condensing chalcone with
guanidine carbonate in methanol to give 2-Amino-dihydro pyrimidine 187.
Recently condensation of chalcone with guanidine nitrate is also reported 188.

Kadu and Doshi et al189 prepared 2-amino-pyrimidine by condensing 2-

hydroxy-4-benzo substituted chalcone and guanidine nitrate in ethanol in
presence of sodium hydroxide solution. There are few reports concerning
pyrimidine condensed with oxygen heterocycles190.

Amol et al191 reported the synthesis and antimicrobial activity of some

new 4-furyl-6-(4-substituted)-2-(OH)-pyrimidine (XXXIII) by reaction of sodium
nitrite and acetic acid with 2-Amino-4-furyl-6-(substituted)pyrimidine (XXXIV).
Almost all the compounds showed a remarkable antimicrobial activity.

R R
O O

N N N N

(XXXIII) OH (XXXIV) NH2

Nimavat and Joshi et al 192 synthesized 2-amino-4-(3-bromo phenyl)-6-

aryl-pyrimidine (XXXV) from 1-aryl-3-(3-bromo phenyl)-2-propen-1-ones

27
Chapter - I: Introduction

(chalcone) and guanidine hydrochloride. All the synthesized compounds

screened for their antitubercular activity.

N N

Br
NH 2

(XXXV)

28
Chapter - I: Introduction

QUINOLINE

INTRODUCTION

The synthesis of 4-hydroxyquinoline derivatives consists of a -ketoester

with aryl amines and cyclisation of the acrylates or the crotonates.

Ethylacetoacetate and ethylbenzoylacetate were the first two -

ketoesters, investigated for the synthesis of 2-and 4-hydroxyquinolines. These
hydroxyquinolines may carry a OH group in either 2- or 4-position. Earlier
workers have shown that ethylacetoacetate and an aryl amine react at room
temperature in presence of catalyst to form ethyl--arylaminocrotonate or the
anil193-196 where as at higher temperatures (130-140 C) anilides are
produced.197-200

The anilides have also been prepared by refluxing the reactants for one
and half hour201. Houser and Reynolds202 employed different methods which
were more or less modified over the original Conrad-Limpach method. 194

Coffey et al.196, Misani and Bogert203 have reported that aryl amines,
containing a nitro group, could not form anilides. However, three years later,
Kaslow and Stayner204 condensed p-nitroaniline with ethylacetoacetate to form
ethyl--(p-nitro-anilino)crotonate by refluxing ethylacetoacetate and p-nitro-
aniline dissolved in chloroform.

Backeberg205 obtained ethyl--(p-acetamidoanilino)-crotonate by heating

p-aminoacetanilide with ethylacetoacetate at 100 C for thirty minutes. Similarly,
the crotonate was obtained by refluxing the ester with p-aminoacetanilide in
methanol for 5 hours.204-206 Backeberg205, Kermack and Webster207 prepared and
cyclized ethyl--(m-acetamidoanilino)-crotonate. Conard and Limpach 208

29
Chapter - I: Introduction

obtained ethyl--(1- and 2-naphthyl-amino)-crotonates by condensing

ethylacetoacetate with 1- and 2-naphthylamines.

Staskum and Israelstam209 obtained directly 2-phenyl-4-hydroxy-

quinolines from ethylbenzoylacetate and aryl amines using Polyphosphoric acid;
under these conditions a mixture, benzoylacetanilide and -arylaminocinnamate
was also obtained. Mallams and Israelstam 210 synthesized directly 4-

hydroxyquinaldines from ethylacetoacetate or its -alkyl derivatives and

arylamines using polyphosphoric acid. It may be noted that they could not
cyclise by this method meta- or ortho-nitroanilines and ethylacetoacetate
directly. Desai and Desai211 however, found that acetoacetanilides could be
cyclised to 4-hydroxyquinaldines and also 2-hydroxy-lepidines by adjusting
temperature conditions. They also improved the yields of 4-hydroxyquinaldines
by the modification of the polyphosphoric acid method. They also modified the
procedure and were successful in cyclising o-nitroaniline or m-nitroaniline into 8-
nitro-4-hydroxyquinaldine and 7-nitro-4-hydroxyquinaldine directly, in very good
yield. Mehta and Desai212 refluxed a mixture of nitro-arylamine and
ethylacetoacetate in ethylacetate as solvent for two hours and the residue,
obtained after evaporation of the solvent was cyclised with polyphosphoric acid;
they have reported that the yields of 8-nitro, 7-nitro and 5-chloro-4-
hydroxyquinolines were higher.

Bangadiwala and Desai213 employed acetic anhydride and concentrated

sulphuric acid to cyclise anils of different -ketoesters, such as ethyl-
acetoacetate, ethylbenzoylacetate, ethylacetylmalonate, ethylacetylcyanoacetate
and obtained 4-hydroxyquinolines.

Quinoline derivatives possess wide therapeutic activity, viz; antiseptic,

analgesic, trypanocidal, germicidal, amoebicidal, antitubercular, anthelmintic,
pyroplasmosis, schistomiasis, antiserotonin, cytokinin and antispasmodic.214-219

The recent researches in chemotherapy have revealed that sulfanilamide

and its derivatives have been found to possess definite bacteriostatic action

30
Chapter - I: Introduction

against various coccal infections. Basu and Das Gupta 220 prepared some (4-
amidobenzenesulfonyl)-aminoquinolines which are expected to have some
therapeutic importance since the replacement of one H-atom of sulfonamido
group of p-aminobenzenesulfonamide often widens the range of activity of the
drug221-223. Some 5,6 and 8-sulfonamidoquinolines have been synthesized 224.

A large number of quinoline derivatives are the most effective and best
tolerated amoebicides known so far225-229. Among them, those quinoline moieties
with a methoxy or a methyl substituent (at position-8) are the most effective
one.

Maheshvari and Thaker230 synthesized 2-aryl/styryl-6-acetyl- quinolino-4-

yl-N2-phenyl/benzyl hydrazides and tested against bacteria, viz., E. coli, S.
aureus and M. tuberculosis.

A number of quinoline derivatives like vioform, chloroquin and intestopan

are well-known amoebicides231-232. Many substituted sulfonamides also exhibit
potent amoebicidal activity.233-238

Quinoline derivatives have been reported to possess various

pharmacological activity239-240. In view of this, quinolinoazetidinones,
thiazolidinones, triazolines and formazans have been synthesized and found to
be better cardiovascular agents241.

Urea derivatives of quinoline are used as analgesic and central nervous

system depressant and 8-aminoquinolines as antimalarial. 242-243

With a view to synthesis biologically active compounds 244, Patel and

Desai245 synthesized 2-(6-methoxy-2-styryl-4-quinolin-oxy)-4-phenylureido-6-
arylthioureido-s-triazine (I).

31
Chapter - I: Introduction

NHCSNHR
N

O N

H3CO N

NHCONHR

N CH
C
H
(I)

Quinoline derivatives are drugs of therapeutic importance showing wide

spectrum of biological activities. Some work has been done on the synthesis and
screening of some N-substituted quinoline derivatives. In view of this,
heterocyclic moiety has been incorporated in the N-position of 6-methyl-4-
phenylquinolin-2(1H)-one246 to study the effect of N-substitution on
antimicrobial activity.

Synthesis and biological screening of some azomethines and 2-

azitidinones247 of type (II) and (III) have been very recently reported.

R
OCH 3 O
OCH 3 N

R
N

Cl
N Cl N Cl

OCH 3 OCH 3
(II) (III)

Synthesis and antibacterial screening of 2-chloro-8-methylquinolin-3-yl-N-

(2-phenyl-4-arylidene-5-oxoimidazolin-1-yl) azomethines 248 have been very
recently reported. A series of azetidinones 249 bearing 2-chloroquinoline-3-

32
Chapter - I: Introduction

carboxaldehyde moiety have been synthesized and their antimicrobial activities

have been studied.

Synthesis of certain N-substituted-8-quinolinesulfonamides 250 structurally

related to antimalarials was reported. Synthesis and properties of sulfonamides
of quinoline series251 had been reported. The chemistry of quinoline and p-
toluenesulfonamide has attracted special attention because of their therapeutic
properties252-253. Recently some sulfonamidoquinoline derivatives 254 have been
found to possess enhanced antibacterial activity.

Some new sulfonamides of type (IV) have been prepared having

pharmaceutically important chloroquin moiety by condensing with different
carboxyaryl sulfonylchlorides. The products were screened for antimicrobial
activity255.

H
C N NHSO2 R

Cl

CH3
(IV)

Desai and Desai256 coupled o-, m-, p-cresols with diazotized sulfanilamide
and sulfathiazole and examined their antibacterial activity against different
organisms. 2,4-Dihydroxy-3-(p-azobenzenesulfamido)-quinoline derivatives 257
had been prepared and screened for their antibacterial activity.

Some new sulfonamides like, N-arylsulfonamido-2-chloro-7-methoxy- and

8-methylquinolin-3-yl-azomethine258-259 have been synthesized and screened for
their antibacterial activity.

33
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45
Chapter - I: Introduction

PARTICULAR INTRODUCTION AND PRESENT WORK

Heterocycles are abundant in nature and are of great significance to life

because their structural subunits exist in many natural products such as
vitamins, hormones, antibiotics and alkaloids, as well as pharmaceuticals,
herbicides, dyes, and many more compounds 1. Hence, they have attracted
considerable attention in the design of biologically active molecules. 2

Some new Bis-thiazines (I) and Bis-pyrimidines (II) have been

synthesized from Bis-chalcone and screened for their antibacterial, antifungal
and anti-inflammatory activities.3

HO OH

R R

N S S N

(I)
NH 2 NH2

HO OH

R R

N N N N

(II)
NH2 NH 2

Where,
R=H, 4-OMe, 4-Cl, 4-NO 2, 4-Br, 2-Cl

46
Chapter - I: Introduction

K. M. Mahadevan et al4 reported a new method for the synthesis of

substituted benzofuran derivatives containing pyrimidine ring at 2 position (III).
This method is less time consuming and environmental friendly as compared to
the existing conventional method of synthesis.

NH2
N

N
O

(III)

Where,
R= H, NO2 , Cl, CH3 , OCH3

M. Amir et al5 synthesized 4-(1H-indol-3-yl)-6-phenyl-1,2,3,4-

tetrahydropyrimidin-2-ones/ thiones as potent anti-inflammatory agent (IV, V).

NH NH

HN HN

N S N R
O H R H

(IV) (V)

Several pyrimidine derivatives possess a broad spectrum of biological

effectiveness such as calcium channel blockers 6, antitubercular7, anticancer7 and
antibacterial8.
Quinoline derivatives are also drugs of therapeutic importance showing a
wide spectrum of biological activities.

47
Chapter - I: Introduction

Some 2-aryl-4-carboxyquinoline-6-arsonic acids 9 have been prepared and

screened for antibacterial activity. Some new 2-aryl-6,7-substituted quinolines 10
of type (VI) and (VII) having 4-aminoantipyrine and 1,3,4-oxadiazole moiety
have been prepared and tested for antimicrobial activity.

CH2 C6H5
N

N CH3
CONH
R2 R2
N
O N CH3
C6H5
R3 N R1 R3 N R1
(VI) (VII)

R1, R2, R3= methyl, methoxy, chloro, nitro

Some new 4-thiazolidinone derivatives of the type (VIII) bearing 8-

hydroxyquinoline moiety were prepared and screened for their antibacterial
activity11.

R
H
HO C N

S
N O

X
(VIII)

R =aryl, X= H/ CH3 / CH2 COOH

Very recently a number of substituted-4-hydroxy-3-(p-azobenzene-

sulfonamido)-2-phenylquinoline 12, 4-[4-(2,6-disubstituted-quinolin-4-yl-amino)-2-
hydroxy-phenylazo]-sulfonamide13 and 4-hydroxy-3-(substituted arylazo)-2-
phenyl-6/7-substituted quinoline derivatives 14 have been found to be active
against gram positive and gram negative bacteria.

48
Chapter - I: Introduction

Formazons are known to be useful agent in various diseases like viral and
bacterial infection and Parkinson diseases. A number of formazons have been
tested and reported as antibacterial15-17 and antitubercular agents.18

Some new N-p-acetylphenyl--arylazo-2-chloro-7-methoxyquinolin-3'-yl-

azomethines have been synthesized and screened for their antimicrobial
activities.19 All the compounds showed moderate activity.

A number of quinolinyl hydrazinobenzylidine azobenzenes(formazons) 20-21

have been prepared and screened for antitubercular and antibacterial activity.

Several N-o-carboxyphenyl--aryl-azo-4-dimethyl-aminophenyl-azomethine
(formazones) have been synthesized and screened for antimicrobial activity.
Some of them showed good antibacterial activity. 22

Some N'-substituted-[(2'-hydroxy-benzylidine)-amino-N 2-4-phenyl-5-(aryl-

azo)-thiazoyl]-azobenzene (formazons) have been very recently reported and
screened for antibacterial activity against Gram positive and Gram negative
bacteria.23

In our efforts to discover new chemical pharmacophores which may be

responsible for the antibacterial as well as antifungal activity, we have described
our studies on the reaction of aromatic aldehyde with aromatic acetophenone to
form chalcone which were further reacted with guanidine nitrate to give 4,6-
diarylsubstituted-2-pyrimidinamine. These compounds were further coupled with
4-chloroquinoline derivative to get corresponding compound pyrimidine-quinoline
clubbed molecule.

Considering the versatile chemistry of cyanuric chloride 24-26 and its

reactions with various nucleophiles such as amines, amino-sulfonamides,
alcohols, phenols, etc., the attempts were also made to couple 4-(3'-
bromophenyl)-6-(4-methoxyphenyl)pyrimidin-2-amine with cold brand reactive dyes.

49
Chapter - I: Introduction

Realizing the medicinal importance of 2-amino-pyrimidine, quinoline and

triazine derivatives it was considered worthwhile to incorporate these moieties.
It was therefore thought interesting to synthesize the title compounds with an
object of ascertaining whether they could augment the microbicidal efficacy.

The structures of the various synthesized compounds were assigned on

the basis of elemental analysis, IR and 1H NMR spectral data. These compounds
were also screened for antibacterial and antifungal activity. The research work is
scanned in Scheme 1 and Scheme-2.

50
Chapter - I: Introduction

Scheme-I
R R'

COCH3 + OHC

Ar y l ac et o p h en on e Ar y l al d eh y d e

OH- KOH/ C2H5OH

R R'
C C CH
H
O
S u b s t i t u t e d c h al c o ne

(1) Conventional heating

H2N C NH2
(2) Heterocyclization

NH C2 H5OH
G u a ni d i n e 40% NaOH
R R'

N N

NH2
4,6 -Di ar y l s u b s t i t u t ed -2 -p y r i mi d i nam i n e
Cl
R2
THF
Anhy. K 2CO3 R3 N R1
4 -C hl o r oq u i n o l i ne d er i v at i v e
R R'

N N

HN

R2

R3 N R1
N 4 -[ 4 ,6 -D i ar y l s u b s t i t u t e d p he ny l -2 -p y r i mi d i n y l ] -s u bs t i t u t ed -4 -q u i no l i n ami n e

where

R= 2,4-(Cl)2 -5-F, 4-Cl, 4-OCH3 , 4-CH3

R'= 4'-F, 4'-Cl, 3'-NO 2, 3'-Br

R1 = -H, -CH3 , R2 = -H, -Cl, -CH3 , -OCH3 , R3 = -H, -Cl

51
Chapter - I: Introduction

Scheme-I I

Cold brand reactive dye + H3 CO

N N
Br
NH2
4 -( 3 -br omo ph e ny l ) -6 -( 4 -m et h ox y p hen y l )p y r i mi d i n -2 -ami n e

H2O + THF
-HCl
NaHCO 3

H3 CO
N N
Br
NH

Cold brand reactive dye

52
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