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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 chalcones2-4.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
N N
NH2
Ar Ar'
Pyrimidine
GuanidineAr C
O
CH
CH Ar'
NH2OH
NH2NH2
Malononitrile
N
CN
Ar'
Ar
Cyanopyridine
NNH
Ar Ar'
Pyrazoline
NO
Ar Ar'
Iso-oxazole
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.
C CH CH
O
1
2 3
4
56
1'
2'3'
4'
5' 6'
(I)
The British Chemical Abstract and Journal of Chemical Society have
followed the following system.
2
Chapter - I: Introduction
C CH CH
O
1
23
4
5 6
1'
2' 3'
4'
5'6'(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)
C OHC
R
C
O
CH
CH
R'
R'R
+
:OH- -H2O
O
CH3
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 Sipos23 condensed 2-hydroxy-5-nitro-
acetophenone with benzaldehyde using anhydrous AlCl3. 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.
CH3COPh C2H5O CH2COPh C2H5OH
CH2COPh PhCHO Ph C CH2COPh
O
H
Ph C CH2COPh
O
H
H2O Ph C CH2COPh
OH
H
OH
Ph C CH2COPh
OH
H
Ph-CH=CHCOPh H2O
[I]
+
+
+
+
+
+
C2H5OPhCHO Ph C OC2H5
O
H
Ph C OC2H5
O
H
CH3COPh Ph C CH2COPh
OH
H
[II]
+
+
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
O
Ph C CH2
OH
+
Ph C
O
H Ph C
OH
H S[S=Solvent]
SH+
Ph C CH2
OH
Ph C H
OHTransition
+
Ph C
OH
CH2 CH Ph
OH
Ph C
OH
CH2 CH Ph
OH
Ph C
O
CH2 CH Ph
OH
Ph C
O
CH2 CH Ph
OH2
SH
S
+
++
Complex
S
+
+
+ +
+
+
Ph C
O
CH2 CH Ph
OH2
Ph C
O
CH CH Ph H2OH+
+
+ +
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 sweeteners39-43,
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-β'-neohesperdoside55
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
OH
OHO
OHC
O
CH
CH
(III)
It isomerizes to a yellow compound isocarthamin (IV) on treatment with
dil. HCl as reported by Kuroda62.
7
Chapter - I: Introduction
OHC
O
CH
CH
(IV)
OHHO
OGC
OH
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.
CH
CH C
O
OCH3 OH
C
O
OH
CH
CH
OCH3
(V)
CH
CH C
O
OH
C
O
OH
HC CHH3CO OCH3
(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
C
O
OH
CH
CH
NO2
OCH3
(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
CH
CH
C
(X)
CHO C
O
H2CP
OC2H5
C2H5O
O
(VIII) (IX)
+
O
Several workers117-119 prepared chalcones (XIV, XV) from ketones (XII,
XIII) and aromatic aldehyde (XI) in ethanol as energy transfer medium.
Ar1CH3 C
O
Ar1
(XII)
CHO Ar1 CH
CH C
O
CH
CH Ar1
(XIV)(XI)
OH
9
Chapter - I: Introduction
Ar1CH3 C
O
Ar2
(XIII)
CHO
(XI)
OHAr1 C
HCH C
O
Ar2
(XV)
Ar1 = C6H5, Ar2 = -R-C6H4
Mistry and Desai120 synthesized chalcone (XVI) using microwave technique.
H3CO C
Cl
ClCH
O
CH
(XVI)
Naik and Naik121 synthesized chalcone derivative from 2-hydroxy-3-
bromo-5-ethyl acetophenone.
RC CH
O
CH
OH
Br
C2H5C
O
OH
Br
C2H5 CH3
R-CHO
aq. KOH (40%)
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 activity131-132.
It is reported that chalcones exhibited potent activity against human malarial
parasite133. Many workers have reported the different pharmaceutical activities
of chalcones and its derivatives134-137. 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 al143. 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 Dargelos147 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
µg/ml.
OO2N C
HCH C
O
F
(XVII)
Some chalcones containing indole moiety (XVIII) were synthesized and
tested for antibacterial and antifungal activity by Dandia, Sehgal and Singh148.
11
Chapter - I: Introduction
NH
Ar
HC X
X
CH C
O
(XVIII)
where,Ar = Substituted phenyl
Chalcones incorporated with benzopyran moiety (XIX) were reported by
Hismat, El-Diwani and Melek149.
OH3C
OCH3
CH
O
CH
C
O
(XIX)
Salvie, Richard and John150 reported α-substituted chalcones. The α-
methyl compound (XX) was found to be the most active and tested for the
chemotherapy of leukemias.
OCH3
H3CO
OCH3
OCH3
OH
C
O
C
CH3
CH
(XX)
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.
O
C
R
R1
O
O
CH
CH
Ar
(XXI)
Where, Ar = HeteroarylR = -OH, -OR', where R' = alkylR1= -H, -alkyl
Uenaka, Kawata, Nagai and Endoh152 synthesized β-hydroxy chalcones
(XXII). Compounds having fluoro substitution showed considerable activity
against Human Immuno Virus (HIV).
NHN
NC
O
HC C
CH3
R3
R1R2R4
Where,R1, R2, R3 = H, (un) substituted alkyl, alkoxy, halo
R4 = H, (un) substituted alkyl or aryl
(XXII)
Seele153 reported chalcone having heterocyclic moiety (XXIII) and
reported their insecticidal activity.
13
Chapter - I: Introduction
R C
O
C CH
Ar
Where,R, R1 = alkyl, phenyl, bi-phenyl, naphthyl, furyl
X = N, CH
H2C
N
X
(XXIII)
Some other biological activity of chalcone such as antiviral154, 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
H2N
O
(II)
Preliminary IR spectra suggested that Pyrimidones (III) existed as
pyrimidinols (IV).162-163
N NH
O
(III)
N N
OH
(IV)
Similarly pyrimidine thiones (V) existed as pyrimidine thiols (VI).
N NH
S
(V)
N N
SH
(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
CH2
CH(OEt)2
(VII)
NH
N
N
N
NH2C
S
H2N NH2C
O
HNH3C
(VIII) (IX)
S O
CH3
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
(X)
N NH
O
N NH
S
NH2C
O
H2N NH2C
S
H2N
(XI) (XII)
CH
C
O
R CH R'
R'R R R'
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.
NH
NH
O
OO
R1
R2
(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
NH
NH
NH
NH
O S
O
Et2
OR
O
(XV)(XIV)
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.
O
CH3OH
CH3 HO
H3C
CH2OH N
N
NH2
CH3
(XVI)
El-Gaby, Adel-Hamide and Gharab171 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
C2H5OOC
N NH
S
R CH3
(XVII)
where,R= 4-F-C6H4, 4-(F2)-C6H3, 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.
R2R1HCOOC
(XVIII)
N
N
N
N
OO
OCH3
OCH3
R2
R3
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.
N
N
NH2
N
N
I
OHO
HOOH
(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.
N
N N
N
N
O
Br
NH2
(XX)
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.
N N
COOC2H5
R
N
(XXI)
R=H, CH3, OCH3, F, Cl, Br
21
Chapter - I: Introduction
N N
COOC2H5
XX=O, S
(XXII)
N N
S
(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.
HN
N
HN
CH3
O2S
N
O
OOH3C
CH3
R
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.
O NR'2
N N
NR2
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.
N
NH
R
(XXVI)
R1
HOOCH2C
NH2
R1= Phenyl, 4-chloro phenyl, furfural, 4-methoxy phenyl,2-thiophene, 3-nicotine
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.
N
N
(XXVII -A)
NCH2 CONHR
Ts
N
N
CONHRCH2
N Ts
(XXVII -B)
where,R= H, C2H5, C6H5, 4-OH-C6H4, 2-4Cl2-C6H3, C6H5CH2CH2, 4-OH-C6H4CH2CH2
4-F-C6H4CH2CH2, 2-4-Cl2-C6H4CH2CH2
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.
N
N
NHN
OR
CH3
O CH2S
(XXVIII-A)
24
Chapter - I: Introduction
N
N
NN
OR
CH3
O CH2S
(XXVIII-B)
ON
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.
N
N N
N
N N
CH2COOEt
Cl
H3C R1
R2
CH2COOH
(XXIX-A) (XXIX-B)
R1= OCH3, CH3
R2= OCH3, OC2H5
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.
N
N N
CH3
R2
R1
(XXX)
R1= OCH3, CH3, H
R2= OCH3, CH3, OC2H5
COOC2H5
N
N N
CH3
(XXXI)
CONH2
N
N N
CH3
(XXXII)
COOH
R1
R2R1, R2 = H
R1, R2 = CH3
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 properties186.
Pyrimidine derivatives are reported to be prepared by condensing chalcone with
guanidine carbonate in methanol to give 2-Amino-dihydro pyrimidine187.
Recently condensation of chalcone with guanidine nitrate is also reported188.
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.
O
N N
NH2
R
(XXXIV)
O
N N
OH
R
(XXXIII)
Nimavat and Joshi et al192 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
NH2
R
(XXXV)
28
Chapter - I: Introduction
QUINOLINE
INTRODUCTION
The synthesis of 4-hydroxyquinoline derivatives consists of a β-ketoester
with aryl amines and cyclisation of the acrylates or the crotonates.
Ethylacetoacetate and ethylbenzoylacetate were the first two β-
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-β-arylaminocrotonate or the
anil193-196 where as at higher temperatures (130-140 ºC) 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-β-(p-nitro-anilino)crotonate by refluxing ethylacetoacetate and p-nitro-
aniline dissolved in chloroform.
Backeberg205 obtained ethyl-β-(p-acetamidoanilino)-crotonate by heating
p-aminoacetanilide with ethylacetoacetate at 100 ºC 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-β-(m-acetamidoanilino)-crotonate. Conard and Limpach208
29
Chapter - I: Introduction
obtained ethyl-β-(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 β-arylaminocinnamate
was also obtained. Mallams and Israelstam210 synthesized directly 4-
hydroxyquinaldines from ethylacetoacetate or its α-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 β-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 Gupta220 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 synthesized224.
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 compounds244, Patel and
Desai245 synthesized 2-(6’-methoxy-2’-styryl-4’-quinolin-oxy)-4-phenylureido-6-
arylthioureido-s-triazine (I).
31
Chapter - I: Introduction
N
N
N
N
H3CO
CH
CH
O
NHCONHR
NHCSNHR
(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.
N
OCH3
Cl
OCH3
NR
N
OCH3
Cl
OCH3 N
R
O
Cl
(II) (III)
Synthesis and antibacterial screening of 2-chloro-8-methylquinolin-3-yl-N-
(2’-phenyl-4’-arylidene-5’-oxoimidazolin-1’-yl) azomethines248 have been very
recently reported. A series of azetidinones249 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-quinolinesulfonamides250 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 derivatives254 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.
CH3
Cl
HC N NHSO2R
(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 derivatives257
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.
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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 compounds1. 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
N S S N
OHHO
R R
(I)NH2NH2
N N N N
OHHO
R R
(II)NH2NH2
Where,R=H, 4-OMe, 4-Cl, 4-NO2, 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.
N
N
O
R
NH2
(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
HN
NH RO
(IV)
NH
HN
NH RS
(V)
Several pyrimidine derivatives possess a broad spectrum of biological
effectiveness such as calcium channel blockers6, 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 acids9 have been prepared and
screened for antibacterial activity. Some new 2-aryl-6,7-substituted quinolines10
of type (VI) and (VII) having 4-aminoantipyrine and 1,3,4-oxadiazole moiety
have been prepared and tested for antimicrobial activity.
N
N
N
CH2
R1
R2
R3
C6H5
(VI)
N R1
R2
R3
(VII)
CONH
C6H5
NN
CH3
O CH3
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.
N
(VIII)X
NHC
SN
R
O
R =aryl, X= H/ CH3/ CH2COOH
HO
Very recently a number of substituted-4-hydroxy-3-(p-azobenzene-
sulfonamido)-2-phenylquinoline12, 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 derivatives14 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-α-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-α-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-N2-4-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 chloride24-26 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
COCH3 OHC+
KOH/ C2H5OHOH-
N N
NH2
(1) Conventional heating
(2) Heterocyclization
C2H5OH
40% NaOH
H2N C
NH
NH2
C
O
CH
CH
THF
Anhy. K2CO3NR3
R2
R1
Cl
NR3
R2
R1
N N
HN
R R'
R R'
R'R
R R'
Scheme-I
Ar y l acet ophenone Ar y l al d ehy d e
S ubs t i t ut ed chal cone
4,6 -Di ar y l subs t i t ut ed -2 -py r imi d i namine
Guani d i ne
4-C hl or oqu ino l i ne d er i v at i v e
N4-[ 4 ,6-D i ar y l subs t i t ut ed pheny l -2-py r i mi d i ny l ] -subs t i t ut ed -4-qui no l i nami ne
R= 2,4-(Cl)2-5-F, 4-Cl, 4-OCH3, 4-CH3
R'= 4'-F, 4'-Cl, 3'-NO2, 3'-Br
R1= -H, -CH3, R2 = -H, -Cl, -CH3, -OCH3, R3 = -H, -Cl
where
51
Chapter - I: Introduction
Scheme-I I
N N
NH2
Br
H3COCold brand reactive dye +
H2O + THF
NaHCO3
N N
NHBr
H3CO
Cold brand reactive dye
-HCl
4 -( 3 -br omopheny l ) -6 -( 4 -met hox y pheny l )py r i mi d i n -2 -ami ne
52
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