Bronsted acidic ionic liquid catalyzed highly efficient synthesis of chromeno pyrimidinone derivatives and their antimicrobial activity

Article abstract of DOI:10.1016/j.cclet.2012.06.041

A series of 8,9-dihydro-2-(2-oxo-2H-chromen-3-yl)-5-aryl-3H-chromeno[2,3-d] pyrimidine-4,6(5H,7H)-diones (5a-j) have been synthesized by the reaction of 2-amino-5,6,7,8-tetrahydro-5-oxo-4-aryl-4H-chromene-3-carbonitrile (4a-j) with coumarin-3-catboxylic a

Full text of DOI:10.1016/j.cclet.2012.06.041

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 1015–1018
www.elsevier.com/locate/cclet
Brønsted acidic ionic liquid catalyzed highly efficient synthesis of
chromeno pyrimidinone derivatives and their antimicrobial activity
*
Janardhan Banothu, Rajitha Bavanthula
Department of Chemistry, National Institute of Technology, Warangal 506004, AP, India
Received 4 May 2012
Available online 18 July 2012
Abstract
A series of 8,9-dihydro-2-(2-oxo-2H-chromen-3-yl)-5-aryl-3H-chromeno[2,3-d]pyrimidine-4,6(5H,7H)-diones (5a-j) have
been synthesized by the reaction of 2-amino-5,6,7,8-tetrahydro-5-oxo-4-aryl-4H-chromene-3-carbonitrile (4a–j) with couma-
rin-3-catboxylic acid under neat conditions employing Brønsted acidic ionic liquid (4-sulfobutyl)tris(4-sulfophenyl)phosphonium
hydrogen sulfate as catalyst. Structures of all the compounds were established on the basis of analytical and spectroscopic data. All
the compounds were evaluated for their in vitro antimicrobial activity against different bacterial and fungal strains.
# 2012 Rajitha Bavanthula. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Antimicrobial activity; Ionic liquid; Neat conditions; 8,9-Dihydro-2-(2-oxo-2H-chromen-3-yl)-5-aryl-3H-chromeno[2,3-d]pyrimidine-
4,6(5H,7H)-dione
In recent years ionic liquids (ILs) playing an important role in synthetic chemistry due to their interesting properties
like high thermal stability, non volatility, eco friendly and reusability [1]. Reactions under solvent-free conditions [2]
are also continuously attracted to the researchers both from academia and industry, due to the fact that without solvent,
reactions usually need shorter reaction time, simpler reactors and require simple and efficient workup procedures.
Chromene derivatives represent an important class of compounds. They are often used as structural unit in many
natural products [3] and have been reported to possess various pharmacological activities such as antimicrobial [4],
antitumor [5], antiaggregating [6], antidepressant [7] and antiproliferative activities [8]. It is well known that
pyrimidine and coumarin derivatives were also found to possess antiallergic [9], antimicrobial [10], antioxidant [11],
anti-inflammatory [12] and anticancer activities [13].
In view of the pharmaceutical importance of these compounds, many improved methods have been developed such
as H3PW12O40 [14], Yb(OTf)3 [15], carbon materials [16] and ionic liquid [17] catalyzed reactions, but these ionic
liquid are expensive. To avoid this limitation and for the continuation of our studies on the synthesis of biologically
important heterocyclic compounds [18], in the present work we have designed and synthesized a novel chromeno
pyrimidinone derivatives incorporated coumarin moiety at second position utilizing an eco-friendly, reusable and
inexpensive ionic liquid as a catalyst under neat conditions and evaluated there in vitro antimicrobial activity against
different bacterial and fungal strains.
* Corresponding author.
E-mail address: rajitabhargavi@yahoo.com (R. Bavanthula).
1001-8417/$ – see front matter # 2012 Rajitha Bavanthula. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2012.06.041

1016
J. Banothu, R. Bavanthula / Chinese Chemical Letters 23 (2012) 1015–1018
1. Results and discussion
Ionic liquid (IL) has prepared according to the literature procedure [19]. The synthetic pathway of the title
compounds was shown in Scheme 1. The intermediate 4a–j were obtained by the three component condensation of
cyclohexane-1,3-dione, aryl aldehyde 2a–j with malononitrile under basic conditions in alcohol at refluxing
temperature. Desire products 5a–j were obtained by the reaction of 4a–j with coumarin-3-carboxylic acid under neat
conditions at 120 8C utilizing ionic liquid (IL) as catalyst.
Initially the reaction between compound 4a and coumarin-3-catboxylic acid was carried out under neat conditions
at 120 8C without and with different acid catalyst (sulfuric acid, silica sulfuric acid, cellulose sulfuric acid, ionic liquid
each 10 mol%) and observed maximum yield with ionic liquid. Also observed, the change in the amount of the catalyst
(ionic liquid) has no effect on the product yield and reaction time.
At these optimistic conditions (solvent-free, 120 8C, 10 mol% of IL) we synthesized various chromeno
pyrimidinones 5a–j (Table 1). After completion of the reaction the catalyst was recovered by evaporating the aqueous
layer, washed with acetone, dried and reused for subsequent reactions without significant loss in its activity. All the
synthesized compounds were confirmed by their analytical and spectroscopic data (see the supporting information).
1.1. Antimicrobial activity
All the newly synthesized compounds 5a–j were screened for their in vitro antibacterial and antifungal activities
against Bacillus subtilis (Bs), Staphylococcus aureus (Sa), Staphylococcus epidermidis (Se) (Gram-positive),
O
R
O
O
R
O
Coumarin-
CN
3-carboxylic acid
CN
NH
O
Methanol
R
CHO
IL (10 mol%)
Neat, 120 oC,
10-12 h
Piperidine
Reflux, 1-4 h
O
N
CN
O
NH2
O
O
2 (a-j)
3
1
4 (a-j)
5 (a-j)
SO3H
Compound
4a/5a
4b/5b
4c/5c
4d/5d
4e/5e
4f/5f
R
C6H5
2-ClC6H4
4-ClC6H4
SO3H
-
HSO4
P
3-NO2C6H4
4-CH3C6H4
4-OCH3C6H4
HO3S
SO3H
4g/5g
4h/5h
4i/5i
3,4-(OCH2)3C6H3
4-OHC6H4
Ionic liquid (4-sulfobutyl)tris(4-sulfophenyl)
phosphonium hydrogen sulphate (IL)
4-OH-3-OCH3C6H3
4-N(CH3)2C6H4
4j/5j
Scheme 1. Synthetic pathway of the chromeno pyrimidinones.
Table 1
Synthesis of chromeno pyrimidinones 5(a–j) using ionic liquid (IL).a
Analog
R
Time (h)
Yieldb (%)
M.p. (8C)
5a
5b
5c
5d
5e
5f
C6H5
12
12
10
12
10
10
10
12
12
12
68, (68, 67, 65, 64)c
276–278
235–236
248–250
269–270
234–236
220–222
242–244
230–232
267–269
273
2-ClC6H4
65
74
69
71
68
65
70
75
67
4-ClC6H4
3-NO2C6H4
4-CH3C6H4
4-OCH3C6H4
3,4-(OCH2)3C6H3
4-OHC6H4
5g
5h
5i
4-OH-3-OCH3C6H3
4-N(CH3)2C6H4
5j
a
Reaction conditions: Compounds 4a–j (1 mmol), coumarin-3-catboxylic acid (1 mmol), ionic liquid (10 mol%), neat, 120 8C.
Yields refer to the pure isolated products.
b
c
Yields refer to the reusability of catalyst over additional four times.

J. Banothu, R. Bavanthula / Chinese Chemical Letters 23 (2012) 1015–1018
1017
Table 2
In vitro antimicrobial activity of compounds 5a–j.
Analog
Minimum inhibitory concentration (MIC) in mg/mL
Bacterial strains
Fungal strains
Bs
Sa
Se
Ec
Pa
Kp
Af
Rsp
An
Ca
5a
5b
150
150
25
150
150
100
150
150
100
50
150
150
50
75
50
50
75
75
50
12.5
50
75
75
25
–
150
150
100
150
150
100
50
150
150
100
150
150
50
150
150
150
100
100
100
100
150
100
100
–
150
150
150
100
150
100
100
100
100
50
150
150
150
100
150
100
100
100
100
100
–
50
50
50
25
50
50
50
50
50
25
–
5c
5d
150
150
100
50
150
150
100
100
150
150
150
22
5e
5f
5g
50
5h
5i
150
150
150
24
150
150
150
25
150
150
150
150
150
150
25
5j
CPF
AMP-B
12.5
–
–
–
–
–
–
50
25
50
25
–, not performed.
Standard drugs: Ciprofloxacin (CPF), Amphotericin-B (AMP-B).
Escherichia coli (Ec), Pseudomonas aeruginosa (Pa), Klebsiella pneumonia (Kp) (Gram-negative) bacterial strains
and Aspergillus flavus (Af), Rhizopus schipperae (Asp), Aspergillus niger (An), Candida albicans (Ca) fungal strains
by the liquid dilution method [20] using Ciprofloxacin (for bacterial) and Amphotericin-B (for fungal) as standard
drugs.
Different concentrations of analogs and the positive control drugs were prepared in DMSO. Inoculums of the
bacterial and fungal cultures were also prepared. Inoculum (0.2 mL) and sterile water (3.8 mL) were added to a series
of test tubes each containing 1 mL of test solution at different concentrations. The tubes were incubated for 24 h at
37 8C and carefully observed for the presence of turbidity. The minimum concentration at which no growth was
observed was taken as the MIC value (Table 2).
From the activity report (Table 2) it was notified that, most of the compounds showed moderate activity against all
the bacterial and fungal strains but compounds 5c (MIC: 25 mg/mL) and 5g (MIC: 12.5 mg/mL) has shown excellent
antibacterial activity against B. subtilis and E. coli respectively on par with standard drug Ciprofloxacin. Similarly
compounds 5d (MIC: 25 mg/mL) and 5j (MIC: 25 mg/mL) has shown good antifungal activity against C. albicans
compared with standard drug Amphotericin-B.
2. Experimental
The melting points were recorded in open capillaries and are uncorrected. IR spectra were recorded on Thermo
Nicolet Nexus 670 spectrophotometer using KBr pellet, values are expressed in cmÀ1. NMR spectra were recorded on
Brucker 300-MHz spectrometer using DMSO as solvent and TMS as internal standard, chemical shifts are expressed
in ppm. The C, H and N analysis of the compounds were done on a Carlo Erba modal EA1108. Mass spectra were
recorded on a Jeol JMSD-300 spectrometer.
2.1. General procedure for the synthesis of 5a–j
Ionic liquid (10 mol%) was added to a mixture of 4a–j (1 mmol) and coumarin-3-carboxylic acid (1 mmol), heated
at 120 8C for about 10–12 h. After completion of the reaction 2 mL of water was added and stirred at RT for 5 min. The
precipitated product was filtered, washed with water, dried and purified over column chromatography using silica gel
(230–400 mesh) with n-hexane and ethyl acetate (8:2) as eluent. The aqueous layer containing catalyst was recovered,
washed with acetone, dried and reused for subsequent reactions without loss in its activity and product yield.
8,9-Dihydro-2-(2-oxo-2H-chromen-3-yl)-5-p-tolyl-3H-chromeno[2,3-d]pyrimidine-4,6 (5H,7H)-dione (5e): Pale
yellow solid; IR (KBr, cmÀ1): 3298 (NH), 1724 (CO of lactone), 1685 (CO of ketone), 1641 (CO of lactum), 1604

1018
J. Banothu, R. Bavanthula / Chinese Chemical Letters 23 (2012) 1015–1018
1
(C N), 1202 (C–O–C); H NMR (300 MHz, DMSO-d6): d 1.89–1.95 (m, 2H), 2.26 (s, 3H), 2.56 (t, 4H), 4.33
(s, 1H), 7.03–7.13 (m, 2H), 7.39–7.45 (m, 2H), 7.71–7.92 (m, 4H), 8.75 (s, 1H), 10.71 (s, 1H); 13C NMR (75 MHz,
DMSO-d6): d 193.9, 170.5, 163.9, 163.4, 156.6, 154.4, 153.6, 136.8, 134.9, 134.2, 130.1, 129.1, 127.4, 124.7,
118.3, 117.9, 116.0, 113.5, 100.6, 37.0, 36.2, 26.2, 20.7, 20.5; MS (ESI), 70 eV, m/z: 453 (M+1); Anal. Calcd. For
C27H20N2O5: C, 71.67; H, 4.46; N, 6.19; Found: C, 71.56; H, 4.55; N, 6.42.
3. Conclusion
Various chromeno pyrimidinones (5a–j) were synthesized using an efficient, eco-friendly, reusable and inexpensive
Brønsted acidic ionic liquid (4-sulfobutyl)tris(4-sulfophenyl)phosphonium hydrogen sulfate as a catalyst. All the
synthesized compounds were screened for their in vitro antimicrobial activity. Compound 5g has shown excellent
antibacterial activity against E. coli with MIC 12.5 mg/mL compared to the standard drug ciprofloxacin (MIC 25 mg/
mL). Similarly, compounds 5d (MIC 25 mg/mL) and 5j (MIC 25 mg/mL) have shown good antifungal activity against
C. albicans with respect to positive control drug Amphotericin-B (MIC 25 mg/mL).
Acknowledgment
One of the authors B.J. thanks the Ministry of Human Resource Development for the research fellowship.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/
j.cclet.2012.06.041.
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