Synthesis of biginelli products of thiobarbituric acids and their antimicrobial activity

Article abstract of DOI:10.2298/JSC090106060D

A simple and efficient method has been developed for the synthesis of 2,4,7-tri(substituted)phenyl-2,4,8,10-tetraza-3,9-dithioxo-5-oxobicyclo-[4.4.0] dec-1(6)-ene (4) and 2,4,7-tri(substituted)phenyl-2,4,8,10-tetraza-3-thioxo-5,9- dioxobicyclo[4.4.0]dec-1

Full text of DOI:10.2298/JSC090106060D

J. Serb. Chem. Soc. 75 (8) 1033–1040 (2010)
JSCS–4028
UDC 547.853’593+547.854:547.571:
615.28–188
Short communication
SHORT COMMUNICATION
Synthesis of Biginelli products of thiobarbituric acids
and their antimicrobial activity
*
VIJAY V. DABHOLKAR and TRIPATHI DILIP RAVI
Organic Research Laboratory, Department of Chemistry, Mumbai University,
K. C. College, Churchgate, Mumbai-400 020, India
(Received 6 January 2009, revised 26 April 2010)
Abstract: A simple and efficient method has been developed for the synthesis
of 2,4,7-tri(substituted)phenyl-2,4,8,10-tetraza-3,9-dithioxo-5-oxobicyclo-
[4.4.0]dec-1(6)-ene (4) and 2,4,7-tri(substituted)phenyl-2,4,8,10-tetraza-3-thio-
xo-5,9-dioxobicyclo[4.4.0]dec-1(6)-ene (5), by a one-pot, three-component
cyclocondensation reaction of a 1,3 dicarbonyl compound (thiobarbituric acid),
an aromatic aldehyde, and urea/thiourea using catalytic a amount of concen-
trated HCl in refluxing ethanol. Representative samples were screened for their
anti-microbial activity against the Gram-negative bacteria, Escherichia coli and
Proteus aeruginosa, and the Gram-positive bacteria, Staphyllococcus aureus
and Corynebacterium diphtheriae using the disc diffusion method. The struc-
tures of the products were confirmed by IR, 1H- and 13C-NMR spectroscopy, as
well as by elemental analysis.
Keywords: aromatic aldehydes; dihydropyrimidine; thiobarbituric acid.
INTRODUCTION
The acid-catalyzed Biginelli reaction, which is a three-component reaction
between an aldehyde, a β-ketoester and urea/thiourea, is a rapid and facile me-
thod for the synthesis of pyrimidones, which are interesting compounds with po-
tential for pharmaceutical applications.
Pyrimidone products have been reported to possess biological activities such
1
as anti-viral, anti-bacterial, anti-hypertensive and anti-tumor. More recently py-
rimidones have emerged as integral backbones of several calcium channel blo-
2
ckers. Certain substituted 2-thiobarbituric acids have been used as intravenous ane-
3
4
5
sthetics, anti-convulsants, immunotropic and anti-inflammatory compounds.
Multicomponent reactions (MCRs) are of increasing importance in organic
6
and medicinal chemistry for various reasons. In times when premium is put on
*Corresponding author. E-mail: vijaydabholkar@gmail.com
doi: 10.2298/JSC090106060D
1033
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DABHOLKAR and DILIP RAVI
7
speed, diversity, and efficiency in the drug discovery process, MCR strategies
offer significant advantages over conventional linear-type synthesis. MCR con-
densations involve three or more compounds reacting in a single event, but con-
secutively to form a new product, which contains the essential parts of all the
8
starting materials. The search and discovery for new MCRs on the one hand,
and the full exploitation of already known multicomponent reactions on the other
are therefore of considerable current interest. One such MCR that belongs in the
latter category is the venerable Biginelli dihydropyrimidine synthesis.
Over the past decade, dihydropyrimidin-2(1H)-ones and their derivatives have
attracted considerable attention in organic and medicinal chemistry, as the dihyd-
ropyrimidine scaffold displays a fascinating array of pharmacological and thera-
peutic properties. They have emerged as integral backbones of several calcium
channel blockers, antihypersentive agents, α-1 antagonists and neuropeptide Y
9
(NPY) antagonists. Moreover, several alkaloids containing the dihydropyrimi-
dine core unit have been isolated from marine sources, which also exhibit inte-
resting biological properties. Most notably, among these are the batzelladine al-
kaloids, which were found to be potent HIV gp-120-CD4 inhibitors. The scope of
this pharmacophore has been further increased by the identification of the 4-(3-
10
-hydroxyphenyl)-2-thione derivative (±)-4i, called monastrol, as a novel cell-per-
meable lead molecule for the development of new anticancer drugs (Fig. 1).
Fig. 1. The structure of monastrol.
In 1893, the Italian chemist Pietro Biginelli reported on the acid-catalyzed
11
cyclocondensation reaction of ethyl acetoacetate, benzaldehyde and urea. The
reaction was performed simply by heating a mixture of the three components dis-
solved in ethanol with a catalytic amount of HCl at reflux temperature. The pro-
duct of this novel one-pot, three-component synthesis that precipitated on cooling
of the reaction mixture was identified correctly by Biginelli as 3,4-dihydropyri-
midin-2(1H)-one (DHPM).
12
Thiobarbituric acid derivatives are known to possess antibacterial activity,
13
14
some are claimed to be sedatives, and herbicides, while some are classified as
15
antiviral agents.
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BIGINELLI PRODUCTS OF THIOBARBITURIC ACIDS
1035
16
In addition, it was reported that the insertion of an aryl, amino, or a methyl
moiety at 5-position of thiobarbituric acid enhances the antidepressant activities
of the resulting compounds.
Bearing in mind the high synthetic utility and pharmacological importance,
the synthesis of substituted pyrimidones (DHPMs) is reported herein.
Thus, the pharmacophoric activity of pyrimidones and thiobarbituric acid
prompted the design and synthesis of 2,4,7-tri(substituted)phenyl-2,4,8,10-tet-
raza-3,9-dithioxo-5-oxo-bicyclo [4.4.0] dec-1(6)-ene (4) and 2,4,7-tri(substitu-
ted)phenyl-2,4,8,10-tetraza-3-thioxo-5,9-dioxo-bicyclo [4.4.0] dec-1(6)-ene (5)
(Scheme I).
Scheme 1. The synthesis of the compounds 4 and 5.
RESULTS AND DISCUSSION
The original Biginelli protocol for the preparation of DHPMs consisted of
heating a mixture of the three components thiobarbituric acid (β-keto-ester) (1),
aromatic aldehyde (2), and urea/thiourea (3) in ethanol containing a catalytic
17
amount of HCl. This procedure leads in one-step one pot to the desired DHMP.
The target molecules, 2,4,7-tri(substituted)phenyl-2,4,8,10-tetraza-3,9-dithi-
oxo-5-oxobicyclo[4.4.0]dec-1(6)-ene 4(a–d) and 2,4,7-(substituted)triphenyl-
-2,4,8,10-tetraza-3-thioxo-5,9-dioxobicyclo[4.4.0]dec-1(6)-ene 5(a–d) were syn-
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DABHOLKAR and DILIP RAVI
thesized in good yield by the one pot reaction of thiobarbituric acid, aromatic al-
dehydes, and urea/thiourea in refluxing ethanol using few drops of concentrated
HCl as the catalyst. Compound 1 was prepared by the solid phase equimolar ad-
18
19
dition of thiocarbanilide, malonic acid and acetyl chloride.
The physical characterization data of the derivatives of 4(a–d) and 5(a–d)
are reported in Table I.
TABLE I. Characterization data of compounds 4 (X = S) and 5 (X = O)
Compound
4a
R1
R2
p-OCH3
M.p., °C
160
Yield, %
62
CH3
4b
4c
4d
p-Cl
H
88
77
67
57
67
NO2
Cl
o-OH
125
5a
5b
o-OH
155
110
72
68
CH3
p-OCH3
5c
p-OCH3
o-OH
128
108
77
72
Cl
Cl
5d
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BIGINELLI PRODUCTS OF THIOBARBITURIC ACIDS
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2,4-Diphenyl-7-p-methyoxyphenyl-2,4,8,10-tetraza-3,9-dithioxo-5-oxobicyc-
lo[4.4.0]dec-1(6)-ene (4a). Orange crystals; Anal. Calcd. for C H N O S : C,
25 20
4 2 2
63.56; H, 4.24; N, 11.86 %; Found: C, 63.54; H, 4.23; N, 11.84 %. IR (KBr, cm–1):
1
1680, 1740, 3310. H-NMR (500 MHz, DMSO-d , δ / ppm): 3.8 (3H, s, OCH ),
6
3
13
4.4 (1H, s, CH), 6.8–7.8 (14H, m, Ar–H), 8.6 (1H, s, NH), 8.7 (1H, s, NH). C-
-NMR (500 MHz, DMSO-d , δ / ppm): 52.3 (C–H), 55.1 (OCH ), 85.2 (C=C),
6
3
153.4 (C=C), 172.2 (C=O), 183.4 (C=S), 191.8 (C=S).
2,4-Di-o-methylphenyl-7-p-chlorophenyl-2,4,8,10-tetraza-3,9-dithioxo-5-oxo-
bicyclo[4.4.0]dec-1(6)-ene (4b). Yellow crystals; Anal. Calcd. for C H N OS Cl:
26 21
4
2
C, 61.84; H, 4.16; N, 11.10 %; Found: C, 61.82; H, 4.14; N, 11.09 %. IR (KBr,
–1
1
cm ): 1670, 1730, 3330. H-NMR (500 MHz, DMSO-d , δ / ppm): 2.1 (3H, s,
6
CH ), 2.2 (3H, s, CH ), 4.5 (1H, s, CH), 6.5–7.9 (12H, m, Ar–H), 8.8 (1H, s, NH),
3
3
13
8.9 (1H, s, NH). C-NMR (500 MHz, DMSO-d , δ / ppm): 31.2 (CH ), 37.8
6
3
(CH ), 54.3 (C–H), 79.2 (C=C), 152.1 (C=C), 162.3 (C=O), 178.4 (C=S), 201.1
3
(C=S).
2,4-Di-o-nitrophenyl-7-phenyl-2,4,8,10-tetraza-3,9-dithioxo-5-oxobicyclo[4.4.0]-
dec-1(6)-ene (4c). Brick red crystals, Anal. Calcd. for C H N O S : C, 54.13;
24 16
6 5 2
–1
H, 3.01; N, 15.79 %; Found: C, 54.11; H, 3.00; N, 15.78 %. IR (KBr, cm ):
1680, 1780, 3360. H-NMR (500 MHz, DMSO-d , δ / ppm): 4.5 (1H, s, CH), 6.5–
–7.5 (13H, m, Ar–H), 7.9 (1H, s, NH), 8.1 (1H, s, NH). C-NMR (?MHz, DMSO-
1
6
13
-d , δ / ppm): 55.1 (C–H), 83.2 (C=C), 147 (C=C), 159.2 (C=O), 182.6 (C=S),
6
199.3 (C=S).
2,4-Di-o-chlorophenyl-7-(o-hydroxyphenyl)-2,4,8,10-tetraza-3,9-dithioxo-5-
-oxobicyclo[4.4.0]dec-1(6)-ene (4d). Light green crystals; Anal. Calcd. for
C H Cl N O S : C, 54.65; H, 3.04; N, 10.63 %; Found: C, 54.63; H, 3.02; N,
24 16
2 4 2 2
–1
1
10.61 %. IR (KBr, cm ): 1660, 1730, 3290. H-NMR (500 MHz, DMSO-d , δ /
6
/ ppm): 4.3 (1H, s, CH), 5.6 (1H, s, OH), 6.5–7.8 (12H, m, Ar–H), 8.4 (1H, s,
13
NH), 8.7 (1H, s, NH). C-NMR (500 MHz, DMSO-d , δ / ppm): 52.4 (C–H),
6
82.2 (C=C), 154.3 (C=C), 166.4 (C=O), 182.4 (C=S), 200.5 (C=S).
2,4-Diphenyl-7-(o-hydroxyphenyl)-2,4,8,10-tetraza-3-thioxo-5,9-dioxobicyclo-
[4.4.0]dec-1(6)-ene (5a). Red crystals; Anal. Calcd. for C H N O S: C, 70.24;
24 18
4 3
–1
H, 4.39; N, 13.66 %; Found: C, 70.23; H, 4.37; N, 13.64 %. IR (KBr, cm ):
1660, 1750, 3290. H-NMR (500 MHz, DMSO-d , δ / ppm): 4.4 (1H, s, CH), 4.7
(1H, s, OH), 6.5–7.7 (14H, m, Ar–H), 8.6 (1H, s, NH), 8.9 (1H, s, NH). C-NMR
1
6
13
(500 MHz, DMSO-d , δ / ppm): 59.6 (C–H), 87.1 (C=C), 155.3 (C=C), 163.2
6
(C=O), 168.3 (C=O), 179.1 (C=S).
2,4-Di-o-methylphenyl-7-(p-methoxyphenyl)-2,4,8,10-tetraza-3-thioxo-5,9-di-
oxobicyclo[4.4.0]dec-1(6)-ene (5b). Orange crystals, Anal. Calcd. for C H N O S:
27 24
4 3
C, 66.94; H, 4.96; N, 11.57 %; Found: C, 66.92; H, 4.95; N, 11.55 %. IR (KBr,
–1
1
cm ): 1680, 1770, 3330. H-NMR (500 MHz, DMSO-d , δ / ppm): 2.1 (3H, s,
6
CH ), 2.4 (3H, s, CH ), 3.9 (1H, s, OCH ), 4.5 (1H, s, C–H), 6.5–7.9 (12H, m,
3
3
3
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DABHOLKAR and DILIP RAVI
13
Ar–H), 9.2 (1H, s, NH), 9.8 (1H, s, NH). C-NMR (500 MHz, DMSO-d , δ /
6
/ ppm): 31.2 (CH ), 33.1 (CH ) 56.6 (C–H), 58.3 (OCH ), 87.4 (C=C), 147.4
3
3
3
(C=C), 171.9 (C=O), 187.7 (C=O), 200.8 (C=S).
2,4-Di-p-chlorophenyl-7-(2’-hydroxy-4’-methoxyphenyl)-2,4,8,10-tetraza-3-
-thioxo-5,9-dioxobicyclo[4.4.0]dec-1(6)-ene (5c). Orange crystals, Anal. Calcd.
for C H Cl N O S: C, 55.45; H, 3.33; N, 10.35 %; Found: C, 55.42; H, 3.31;
25 18
2 4 4
–1
1
N, 10.33 %. IR (KBr, cm ): 1650, 1780, 3340. H-NMR (500 MHz, DMSO-d ,
6
δ / ppm): 3.9 (1H, s, OCH ), 4.5 (1H, s, C–H), 6.8–7.8 (11H, m, Ar–H), 8.3 (1H,
3
13
s, NH), 8.9 (1H, s, NH), 9.8 (1H, s, OH). C-NMR (500 MHz, DMSO-d , δ /
6
/ppm): 56.3 (C–H), 62.1 (OCH ), 63.3 (C=C), 152.2 (C=C), 163.7 (C=O), 167.1
3
(C=O), 187.3 (C=S).
2,4-di-o-chlorophenyl-7-(o-hydroxyphenyl)-2,4,8,10-tetraza-3-thioxo-5,9-di-
oxobicyclo[4.4.0]dec-1(6)-ene (5d). Purple crystals; Anal. Calcd. for
C H Cl N O S: C, 56.36; H, 3.13; N, 10.96 %; Found: C, 56.35; H, 3.11; N,
24 16
2 4 3
–1
1
10.94 %. IR (KBr, cm ): 1680, 1730, 3330. H-NMR (500 MHz, DMSO-d , δ /
6
/ ppm): 4.6 (1H, s, CH), 6.7–7.9 (12H, m, Ar–H), 8.3 (1H, s, NH), 8.8 (1H, s, NH).
13
C-NMR (500 MHz, DMSO-d , δ / ppm): 55.5 (C–H), 83.7 (C=C), 157.2 (C=C),
6
159.2 (C=O), 164.3 (C=O), 191.3 (C=S).
Antimicrobial and antifungal activities
The activities of representative compounds are reported in Table II.
TABLE II. Antibacterial activity of compounds 4 and 5
Zone of inhibition, mm
Gram-positive
Gram-negative
Compound
S. aureus
C. diphtheria
P. aeruginosa
E. coli
4a
4b
4c
4d
5a
5b
5c
5d
22
21
19
21
20
15
13
22
26
0
25
26
20
27
22
17
16
23
28
0
22
25
22
28
30
22
25
20
24
0
27
28
23
32
29
23
25
24
21
0
Ampiciline trihydrate
DMSO
EXPERIMENTAL
The melting points of all synthesized compounds were determined in open capillary
tubes on an electro thermal apparatus and are uncorrected. The purity of the compounds was
monitored by thin layer chromatography on silica gel coated aluminum plates (Merck) as the
1
adsorbent and UV light as the visualizing agent. The H-NMR spectra were recorded on Va-
rian 500 MHz NMR spectrophotometer using CDCl /DMSO-d6 as solvent and TMS as an
3
internal standard. The C, H, N estimations were recorded on Carlo Erba 1108 (CHN) elemen-
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BIGINELLI PRODUCTS OF THIOBARBITURIC ACIDS
1039
tal analyzer. 13C-NMR was performed on a Varian 500 MHz spectrophotometer using DMSO-d6
as solvent and IR was performed on PerkinElmer Spectrum 100 FT-IT using a KBr pellet.
Synthesis of 3,4-dihydropyrimidin-2(1H)-ones
Aromatic aldehydes (0.050 mol), substituted thiobarbituric acid (0.050 mol) and urea/
/thiourea (0.050 mol) were dissolved in ethanol and the mixture refluxed on a water bath in
the presence of a catalytic amount of concentrated HCl. The progress of the reaction was
monitored by TLC. After completion of the reaction, the concentrated reaction mixture was
cooled and poured onto ice-cold water. The solid that separated was filtered off, dried, and
recrystallized from absolute alcohol to obtain the pure compounds 4 and 5.
Antimicrobial and antifungal activities
The newly synthesized compounds 4(a–d) and 5(a–d) were screened for their antibac-
terial activity against Staphyllococcus aureus (ATTC-27853), Corynebacterium diphtheria
(ATTC-11913), Proteus aeruginosa (recultured) and Escherichia coli (ATTC-25922) bac-
terial strains by the disc diffusion method.20,21 Discs (6 mm) were prepared from Whatman
filter paper No. 41 and used after autoclaving at 121 psi for 15 min and drying in a hot air
oven. The bacterial inoculums equivalent to the 0.5 McFarland turbidity standard were pre-
pared in normal saline and subsequently diluted. The compounds were dissolved in DMSO
and tested at a concentration of 100 µg ml-1. The zone of inhibition after 24 h incubation was
measured in mm and the potency was compared with standard drug (ampiciline trihydrate).
Acknowledgements. The authors are thankful to the Principal Ms Manju J Nichani and
the Management of K. C. College, Churchgate, Mumbai, India, for the constant encoura-
gement and providing the necessary facilities. The authors are also thankful to the Director,
Institute of Science Mumbai for the spectral data.
И З В О Д
СИНТЕЗА BIGINELLI-ЈЕВИХ ПРОИЗВОДА ТИОБАРБИТУРНИХ КИСЕЛИНА
И ЊИХОВА АНТИМИКРОБНА АКТИВНОСТ
VIJAY V. DABHOLKAR и TRIPATHI DILIP RAVI
Organic Research Laboratory, Department of Chemistry, Mumbai University,
K.C. College, Churchgate, Mumbai-400 020, India
Развијен је једноставан и ефикасан метод за синтхезу 2,4,7-три(супститутисаног)фенил-
-2,4,8,10-тетраза-3,9-дитиоксо-5-оксобицикло[4.4.0]дец-1(6)-ена (4) и 2,4,7-три(супституи-
саног)фенил)-2,4,8,10-тетраза-3-тиоксо-5,9-диоксобицикло[4.4.0]дец-1(6)-ена (5), једнофаз-
ном трикомпонентном циклокондензационом реакцијом 1,3-дикарбонилног једињења (тио-
барбитурне киселине), ароматичног алдехида и урее/тиоурее, користећи каталитичку коли-
чину концентроване HCl у рефлуктујућем етанолу. Одабрани узорци тестирани су на анти-
-микробну активност према грам-негативним бактеријама, E. coli и P. aeruginosa, и грам-по-
зитивних бактерија, S, aureus и C. diphtheriae, применом диск-дифузионог поступка. Струк-
туре производа су потврђене помоћу IR, 1H, 13C-NMR и елементалне анализе.
(Примљено 6. јануара 2009, ревидирано 26. априла 2010)
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