Design, synthesis, characterization, and antimicrobial activity of biginelli products of indandione

Article abstract of DOI:10.1002/jhet.860

A simple and efficient method has been developed for the synthesis of 4-(substituted phenyl)-3,4-dihydro-1H-indeno [1,2-d] pyrimidine-2,5-dione (5) and 4-(substituted phenyl)-2-thioxo-1,2,3,4-tetrahydroindeno [1,2-d] pyrimidine-5-one (6), by a one-pot three component cyclocondensation reaction of 1,3 dicarbonyl compound (Indandione) (1), aromatic aldehyde (2), and urea/thiourea (3/4) using catalytic amount of conc. HCl in refluxing ethanol. Representative samples were screened for their antimicrobial activity against gram-negative bacteria, E coli and Paeruginosa and gram-positive bacteria, S aureus, and C diphtheriae using disc diffusion method. The structures of the products were confirmed by IR, ¹H, ¹³C NMR, and elemental analysis.

Full text of DOI:10.1002/jhet.860

July 2012
Design, Synthesis, Characterization, and Antimicrobial Activity of Biginelli
Products of Indandione
929
*
Vijay V. Dabholkar, Sunil R. Patil, and Rajesh V. Pandey
Organic Research Laboratory, Department of Chemistry, Mumbai University, K.C. College,
Churchgate, Mumbai 400 020, India
*
E-mail: vijaydabholkar@gmail.com
Received November 11, 2010
DOI 10.1002/jhet.860
View this article online at wileyonlinelibrary.com.
A simple and efficient method has been developed for the synthesis of 4‐(substituted phenyl)‐3,4‐dihydro‐
1H‐indeno [1,2‐d] pyrimidine‐2,5‐dione (5) and 4‐(substituted phenyl)‐2‐thioxo‐1,2,3,4‐tetrahydroindeno
[1,2‐d] pyrimidine‐5‐one (6), by a one‐pot three component cyclocondensation reaction of 1,3 dicarbonyl
compound (Indandione) (1), aromatic aldehyde (2), and urea/thiourea (3/4) using catalytic amount of conc.
HCl in refluxing ethanol. Representative samples were screened for their antimicrobial activity against
gram‐negative bacteria, E coli and Paeruginosa and gram‐positive bacteria, S aureus, and C diphtheriae using
1
disc diffusion method. The structures of the products were confirmed by IR, H, 13C NMR, and elemental
analysis.
J. Heterocyclic Chem., 49, 929 (2012).
INTRODUCTION
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 consider-
able attention in organic and medicinal chemistry as the
dihydropyrimidine scaffold displays a fascinating array
of pharmacological and therapeutic properties. They have
emerged as integral backbones of several calcium channel
blockers, antihypersentive agents, α‐1 antagonists, and neu-
ropeptide Y antagonists [6]. Moreover, several alkaloids
containing the dihydropyrimidine core unit have been iso-
lated from marine sources, which also exhibit interesting
biological properties. Most notably, among these are the
batzelladine alkaloids, which were found to be potent
HIV gp‐120‐CD4 inhibitors. The scope of this pharmaco-
phore has been further increased by the identification of
the 4‐(3‐hydroxyphenyl)‐2‐thione derivative ( )‐4i called
monastrol as a novel cell‐permeable lead molecule for the
development of new anticancer drugs [7].
The acid‐catalyzed Biginelli reaction, which is a three‐
component reaction between aldehyde, ß ketoester and
urea/thiourea, is a rapid and facile method for the synthesis
of pyrimidones, which are interesting compounds with a
potential pharmaceutical applications.
The pyrimidone products have been reported to possess
biological activities such as antiviral, antibacterial, antihy-
pertensive, and antitumor [1]. More recently pyrimidones
have emerged as the integral backbones of several calcium
channel blockers [2].
Multicomponent reactions (MCRs) are of increasing
importance in organic and medicinal chemistry for
various reasons [3]. In times where a premium is put on
speed, diversity, and efficiency in the drug discovery
process [4], MCR strategies offer significant advantages
over conventional linear‐type synthesis. MCR condensa-
tions involve three or more compounds reacting in a
single event, but consecutively to form a new product,
which contains the essential parts of all the starting
materials. The search and discovery for new MCR’s on
one hand [5] and the full exploitation of already known
MCRs on the other hand, is therefore of considerable
Keeping in view the high synthetic utility and pharma-
cological importance, we report here the synthesis of
substituted Pyrimidones 3,4‐dihydropyrimidin‐2(1H)‐one
(DHPMs).
© 2012 HeteroCorporation

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V. V. Dabholkar, S. R. Patil, and R. V. Pandey
Vol 49
—
RESULTS AND DISCUSSION
ppm): 6.48 (s,1H, CH), 6.89–7.64 (m,8H, Ar H), 8.91 (s,2H,
2xNH), 13C NMR(DMSO‐d6,δ/ ppm): 113.89 (CH), 117.98‐
134.84 (C—C, Ar C), 180.43 (C—O), 188.45 (C—O):
Anal. Calcd for C17H11N202Cl: C, 65.70; H, 3.54; N,
9.01%. Found: C, 65.62; H, 3.42, N, 9.12%.
4‐(4‐Methoxyphenyl phenyl)‐3,4‐dihydro‐1H‐indeno [1,2‐d]
pyrimidine‐2,5‐dione (5c). Yield: 88%; m.p. = 180–183°C:
IR (cm ): 1660(C——O), 1730(C—O), 3290 (NH), H NMR
In 1983, the Italian Chemist Pietro Biginelli reported on
the acid‐ catalyzed cyclocondensation reaction of ethylace-
toacetate, benzaldehyde and Urea [8]. The reaction was per-
formed simply by heating a mixture of the three components
dissolved in ethanol with catalytic amount of HCl at refluxed
temperature. Product of these novel one pot, three compo-
nent synthesis that precipitated on cooling of the reaction
mixture was identified correctly by Biginelli as DHPM.
Thus, the target molecules 4‐(substituted phenyl)‐3,4‐
dihydro‐1H‐indeno [1,2‐d] pyrimidine‐2,5‐dione (5a‐e) and
4‐(substituted phenyl)‐2‐thioxo‐1,2,3,4‐tetrahydroindeno
[1,2‐d] pyrimidine‐5‐one (6a‐e) were synthesized in
good yield by the one pot reaction of aromatic aldehydes,
Indandione [9] and urea/thiourea in refluxing ethanol using
few drops of conc. HCl as catalyst. The pathway of synthe-
sis of compounds 5 and 6 is given in Scheme 1.
—
—
—
—
−1
1
—
(DMSO‐d6,δ/ ppm): 3.88 (s, 3H, OCH3), 6.63 (s, 1H,
CH),7.11–7.93 (m, 8H, Ar H), 8.6 (s, 2H, 2xNH), 13C
—
NMR(DMSO‐d6,δ/ppm): 55.70 (OCH3), 115.10 (CH),
—
—
—
—
116.36‐131.7 (C—C, Ar C),179.56 (C—O), 187.9 (C—O):
Anal. Calcd for C18H14N203: C, 70.59; H, 4.58; N, 9.15%.
Found: C, 70.62; H, 4.52, N, 9.24%.
4‐(2‐Hydroxy phenyl)‐3,4‐dihydro‐1H‐indeno [1,2‐d]
pyrimidine‐2,5‐dione (5d).
Yield:83%; m.p. = 200–202°
−1
—
—
C: IR (cm ): 1657 (C—O), 1765 (C—O), 3310 (NH),
1H NMR (DMSO‐d6,δ/ppm): 4.12 (s,1H, OH),6.82 (s,
The spectral Analysis of Some representative com-
pounds is given below:
—
1H, CH), 7.42–8.13 (m, 8H, Ar H), 8.86 (s, 2H,
2xNH), 13C NMR(DMSO‐d6,δ/ppm): 114.25 (CH),
4‐Phenyl‐3,4‐dihydro‐1H‐indeno [1,2‐d] pyrimidine‐2,5‐
—
—
—
117.46–130.8 (C—C, Ar C), 178.82 (C—O), 184.47
(C—O): Anal. Calcd for C17H12N203: C, 69.86; H, 4.11;
N, 9.59%. Found: C, 69.82; H, 4.21, N, 9.54%.
dione (5a). Yield: 84 %; m.p.=175–178°C: IR (cm−1):
—
1
—
—
1658(C—O), 1715(C—O), 3268(NH), H NMR(DMSO‐
—
d6,δ/ ppm): 6.74 (s, 1H, CH), 7.24–8.03 (m, 9H, Ar H),
4‐(4‐Hydroxy‐3‐methoxyphenyl)‐3,4‐dihydro‐1H‐indeno [1,2‐d]
8.73 (s, 2H, 2xNH), 13C NMR(DMSO‐d6,δ/ ppm): 114.29
pyrimidine‐2,5‐dione (5e). Yield: 87%; m.p. = 220–223°C:
—
—
IR (cm ): 1660 (C—O), 1750 (C——O), 3290 (NH), 1H
−1
—
(CH), 119.46–132.9 (C—C,Ar C),180.28 (C—O),186.2
(C——O): Anal. Calcd for C17H12N202: C, 73.91; H, 4.35; N,
—
NMR (DMSO‐d6,δ/ppm): 3.56 (s, 3H, OCH3), 5.24 (s, 1H,
10.14%.Found: C, 73.87; H, 4.32, N, 10.24%.
—
OH), 6.63 (s, 1H, CH),7.4–7.9 (m, 7H, Ar H), 8.8 (s, 2H,
4‐(4‐Chlorophenyl)‐3, 4‐dihydro‐1H‐indeno [1,2‐d] pyrimidine‐
2xNH). Anal. Calcd for C18H14N204: C, 67.08; H, 4.35; N,
8.72%. Found: C, 67.12; H, 4.42, N, 8.64%.
2,5‐dione (5b). Yield: 86%; m.p. = 215–217°C: IR (cm−1):
1667(C——O), 1742(C——O), 3275(NH), 1H NMR(DMSO‐d6,δ/
4‐(Phenyl)‐2‐thioxo‐1,2,3,4‐tetrahydroindeno [1,2‐d]
pyrimidine‐5‐one (6a). Yield: 82%; m.p. = 249–252°C: IR
(cm ): 1680 (C—O), 1240 (C—S), 3310 (NH), H NMR
(DMSO‐d6,δ/ ppm): 6.85 (s,1H, CH),7.05–7.46 (m, 9H,
−1
1
—
—
Scheme 1. Pathway of synthesis of compounds 5 and 6.
—
Ar H), 9.26 (s, 2H, 2xNH): Anal. Calcd for C17H12N20S:
C, 69.86; H, 4.11; N, 9.59%. Found C, 69.82; H, 4.18, N,
9.54%.
4‐(4‐Chlorophenyl)‐2‐thioxo‐1,2,3,4‐tetrahydroindeno [1,2‐d]
pyrimidine‐5‐one (6b).
Yield: 88%; m.p. = 185–187°C:
−1
IR (cm ): 1662 (C—O), 1218 (C——S), 3328 (NH): 1H
—
NMR (DMSO‐d6,δ/ppm): 6.54 (s,1H, H), 7.86–8.65 (m,
8H, Ar H), 10.2(s, 2H, 2xNH): 13C NMR (DMSO‐d6,δ/
—
—
—
ppm): 116.12 (CH), 119.96–138.67 (C—C, Ar C),184.8
(C—O), 189.65 (C——S): Anal. Calcd for C17H11N20SCl: C,
—
62.48; H, 3.37; N, 8.58%. Found: C, 62.35; H, 3.32, N,
8.64%.
4‐(4‐Methoxyphenyl)‐2‐thioxo‐1,2,3,4‐tetrahydroindeno
[1,2‐d] pyrimidine‐5‐one (6c). Yield: 87%; m.p. = 144–147°C :
1
IR (cm−1): 1670 (C——O), 1230(C——S), 3330(NH): H NMR
(DMSO‐d6,δ/ppm): 3.88 (s,3H, OCH3), 6.72 (s,1H, H), 7.75–
8.70 (m,8H, Ar H), 10.6 (s, 2H, 2xNH): 13C NMR(DMSO‐
—
d6,δ/ppm): 55.65 (OCH3), 114.29 (CH), 120.56–139.8 (C——C,
—
—
—
Ar C), 182.7 (C—O), 184.34 (C—S): Anal. Calcd for
C18H14N202S: C, 67.08; H, 4.35; N, 8.70%. Found: C, 67.15; H,
4.22, N, 8.74%.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2012
Design, Synthesis, Characterization, and Antimicrobial Activity of Biginelli Products of Indandione
931
Table 1
Physical data of compounds 5 and 6.
Compounds
R
Molecular formula
M.p. (°C)
Yield (%)
5a
5b
5c
5d
5e
6a
6b
6c
6d
6e
H
4—Cl
4—OCH3
2 OH
C
17H12N202
175–178
215–217
180–183
200–202
220–223
249–252
185–187
144–147
240–243
196–198
84
86
88
83
87
82
88
87
84
89
C17H11N202Cl
C18H14N203
C17H12N203
C18H14N204
C17H12N20S
C17H11N20SCl
C18H14N202S
C17H12N202S
C18H14N203S
4—OCH3, 2—OH
H
4—Cl
4—OCH3
2—OH
4—OCH3, 2—OH
4‐(2‐Hydroxyphenyl)‐2‐thioxo‐1,2,3,4‐tetrahydroindeno [1,2‐
uncorrected. The progress of reaction was monitored by thin
layer chromatography on silica gel coated aluminum plates
(Merck) as adsorbent and UV light as visualizing agent. 1H
NMR spectra were recorded on Varian 500 MHz NMR spec-
trophotometer using CDCl3/DMSO‐d6 as solvent and TMS as
an internal standard (chemical shifts in δ ppm). C, H, N esti-
mation was recorded on Carlo Erba 1108 (CHN) Elemental
Analyzer.
Synthesis of 3, 4‐dihydropyrimidin‐2(1H)‐one. Indandione
1(0.05 mol), (0.05 mol) Aromatic aldehydes 2 and urea/thiourea 3/
4 (0.05 mol) was refluxed on a water bath in ethanol in the presence
of catalytic amount of conc. 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, solid separated was filtered off, dried, and
recrystallized from absolute alcohol to obtain pure compound (5/6).
d] pyrimidine‐5‐one (6d). Yield: 84%; m.p. = 240–243°C:
−1
IR (cm ): 1680 (C—O), 1245 (C—S), 3290 (NH): 1H
—
—
NMR (DMSO‐d6,δ/ppm): 4.82 (s,1H, OH), 6.87 (s,1H, H),
7.58–8.46 (m,8H, Ar H), 10.42 (s, 2H, 2xNH): 13C NMR
—
—
(DMSO‐d6,δ/ ppm): 115.48 (CH), 121.86–136.54 (C—C,
—
—
—
Ar C), 181.6(C—O), 188.28 (C—S): Anal. Calcd for
C17H12N202S: C, 66.23; H, 3.89; N, 9.09%. Found: C,
66.25; H, 3.97, N, 8.98%.
4‐(4‐Hydroxy‐3‐methoxyphenyl)‐2‐thioxo‐1,2,3,4‐
tetrahydroindeno [1,2‐d] pyrimidine‐5‐one (6e).
Yield:
−1
—
89%; m.p. = 196–198°C: IR (cm ): 1680 (C—O), 1280
1
—
(C—S), 3360 (NH), H NMR (DMSO‐d6,δ/ ppm): 3.92 (s,
3H, OCH3), 5.24 (s, 1H, OH) 6.72 (1H, s, CH), 7.75–8.70
—
(m, 7H, Ar H), 10.6 (2H, s, 2xNH), Anal. Calcd for
The physical data is given in Table 1.
C18H14N203S: C, 63.91; H, 4.14; N, 8.28%. Found: C,
63.98; H, 4.18, N, 8.35%.
Antimicrobial and antifungal activities.
All the newly
synthesized compounds were evaluated for their antibacterial
activity against gram‐negative bacteria, E coli and P aeruginosa
and gram‐positive bacteria, S aureus, and C diphtheriae using
disc diffusion method [10,11]. The zone of inhibition was
measured in mm and the activity was compared with standard
drug. The data is given in Table 2.
EXPERIMENTAL
Melting points of all synthesized compounds were determined
in open capillary tubes on an electro thermal apparatus and are
Table 2
Antibacterial activity of compound 5 and 6.
Zone of inhibition (in mm)
Gram positive
Gram negative
Comp.
S. aureus
C. diphtheria
P. aeruginosa
E. coli
5b
5c
5d
5e
6b
6c
6d
6e
22
21
18
16
21
20
18
17
26
0
20
18
19
18
22
21
19
21
28
0
21
20
18
17
16
18
21
21
24
0
19
18
14
18
17
15
14
16
21
0
Amphicilin trihydrate
DMSO
Concentration of the compounds taken was about 100 μg/mL.
a
Diameter of the disc was 6 mm.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

932
V. V. Dabholkar, S. R. Patil, and R. V. Pandey
Vol 49
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Acknowledgments. The authors than the Principal Ms. Manju J.
Nichani and Management of K.C. College, Churchgate, Mumbai
for constant encouragement and providing necessary facilities.
They are also thankful to the Director, Institute of Science,
Mumbai for the spectral data.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet