One-pot three-component reaction for facile and efficient green synthesis of chromene pyrimidine-2,4-dione derivatives and evaluation of their anti-bacterial activity

Article abstract of DOI:10.1007/s00706-020-02692-5

Abstract: A facile and highly efficient one-pot three-component synthesis of chromene pyrimidine-2,4-dione derivatives from available substrates catalyzed by heteropoly acid (H₃PW₁₂O₄₀) is described. In this protocol, the

Full text of DOI:10.1007/s00706-020-02692-5

Monatshefte für Chemie - Chemical Monthly
https://doi.org/10.1007/s00706-020-02692-5
ORIGINAL PAPER
One‑pot three‑component reaction for facile and efcient
green synthesis of chromene pyrimidine‑2,4‑dione derivatives
and evaluation of their anti‑bacterial activity
Habib Ollah Foroughi1 · Mansoureh Kargar1 · Zahra Erjaee2 · Elham Zarenezhad3
Received: 4 August 2020 / Accepted: 14 September 2020
© Springer-Verlag GmbH Austria, part of Springer Nature 2020
Abstract
A facile and highly efcient one-pot three-component synthesis of chromene pyrimidine-2,4-dione derivatives from avail-
able substrates catalyzed by heteropoly acid (H3PW12O40) is described. In this protocol, the reaction of diverse aldehydes,
4-hydroxycoumarin, and 4-amino-1,3-dimethyluracil in the mixture of EtOH / H2O (1:2) at room temperature in the presence
of heteropoly acid (H3PW12O40) as a highly efcient catalyst afords the corresponding chromene pyrimidine-2,4-dione in
good to excellent yields. Operational simplicity, low cost, eco-friendly with the environment, easy workup and purifca-
tion, short reaction time, high yield of products, green media of the reaction and mild conditions are the advantages of this
method. The in vitro antibacterial activities of title compounds were obtained against Escherichia coli (ATTC 35218) and
Staphylococcus aureus (ATCC 6538) as Gram-negative and Gram-positive bacteria, respectively, and their activities were
compared to gentamycin and penicillin as reference drugs.
Graphic abstract
Keywords Multicomponent reaction · Heterocycles · Catalysts · Aldehydes
Introduction
Phosphotungstic acid is a heteropoly acid (HPA) with the
chemical formula H3PW12O40 is a well-known catalyst and
Electronic supplementary material The online version of this
has attracted much attention because of its redox and acidic
properties [1]. HPAs have received considerable attention
as an inexpensive, eco-friendly catalyst with pseudo liquid
behavior, good thermal stability, which is easy to prepare
and recyclable. It is widely used as an acid catalyst for dif-
ferent reactions in homogenous liquid media [2].
article (https://doi.org/10.1007/s00706-020-02692-5) contains
supplementary material, which is available to authorized users.
* Habib Ollah Foroughi
foroughihabib@ymail.com
1
Department of Science, Fasa Branch, Islamic Azad
University, P. O. Box: No. 364, Fasa, Fars 7461713591, Iran
Design and synthesis of facile and efcient chemical reac-
tions that build up maximum structural diversity and com-
plexity with a minimum number of synthetic steps to provide
chemical compounds with interesting properties is a key
challenge of modern drug development [3]. Multicomponent
2
Department of Food Science and Technology, Fasa
Branch, Islamic Azad University, P. O. Box: No. 364, Fasa,
Fars 7461713591, Iran
3
Noncommunicable Diseases Research Center, School
of Medicine, Fasa University of Medical Sciences, Fasa, Iran
Vol.:(0123456789)
1 3

H. O. Foroughi et al.
reactions (MCRs) are regarded as powerful synthetic tools
for drug discovery [4]. MCRs are a synthetic methodology
in which three or more diferent starting materials react to
produce complex compounds in a one-pot setup efciently
and with good atom economy [5].
Pyrimidines are used for the synthesis of deoxyribonu-
cleotides which are found in the DNA structure. The ana-
logues of these nucleotide precursors have shown anticancer
activity. The mechanism actions of antimetabolic pyrimidine
antineoplastic drugs are well known and very similar [16].
When these compounds difuse into cells, enzymatic reac-
tion of the pyrimidine metabolic pathway converts them to
analogues of cellular nucleotides. In conclusion, the metabo-
lites produced by these reactions can inhibit one or more
enzymes responsible for DNA synthesis. This can cause
DNA destruction and induction of apoptosis [17].
Chromene (benzopyran) is an attractive class of hetero-
cyclic compounds because of their wide range of biologi-
cal applications such as antivascular, antitumor [6], TNF-α
inhibitor [7], antimicrobial [8], antifungal, anticoagulant,
antioxidant, anti-viral, anti-infammatory, anti-helminthic,
herbicidal, estrogenic, antitubercular, anti-HIV, and anti-
convulsant activity [9]. Pyrimidine derivatives are a major
and interesting group of heterocyclic drugs, they are well
known in synthetic organic chemistry as well as pharmaceu-
tical chemistry. Additionally, pyrimidine derivatives have
attracted increasing interest owing to the presence of the
heterocycles in the RNA and/or DNA scafold [5, 10]. Het-
erocyclic compounds containing pyrimidine structure are
known as bioactive compounds, exhibiting a broad spectrum
of biological activities, such as anti-proliferative, antiviral,
antitumor, anti-inflammatory, antibacterial, antifungal,
and anti-tubercular properties. Also, the pyrimidine ring is
found in vitamins such as thiamine, ribofavin, barbitone,
and folic acid [11]. Uracil is known as one of the nucle-
obases in the RNA, it is naturally and common occurring
pyrimidine derivative can be used as a pharmaceutical in the
drug discovery process. In addition, many efective antiviral
and anticancer drugs contain uracil scafold [12]. Pyrimi-
dines are most interesting class of antibacterial compound
which have made a major impact on the feld of antibacte-
rial chemotherapy especially in the past few years. Many
groups of chemotherapeutic agents containing pyrimidine
nucleus are in clinical use as antibacterial, as can be seen in
Fig. 1. Trimethoprim is a well-known synthetic antibiotic
that blocks the production of tetrahydro folic acid (THF)
[13], piromidic acid is another synthetic antibacterial agent
which is used to treat infections caused by gram-negative
bacteria and staphylococci [14], and sulfadiazine [15] is
known as an antibiotic, this drug is the treatment of choice
for toxoplasmosis.
One of the serious medical problems humanity faces
today is microbial resistance. Additionally, the levels rate
of resistance is increasing in traditional antibiotics. So, the
development and discovery of novel and potent antibacte-
rial and antifungal medicines with an efective and possibly
novel mechanism of action become essential duties for anti-
biotic research and development programs [18–22].
Recently, a few procedures have been developed for the
synthesis of chromene pyrimidine-2,4-dione derivatives
via three-component condensation reaction of aldehyde,
4-hydroxycoumarin, and 4-amino-1,3-dimethyluracil using
various catalysts, such as Zr(HSO4)4 [23], Fe3O4@TiO2
nanocomposite [24], L-proline [25], organocatalyst [26],
and ZnO nanoparticles [27]. In addition, Cai and co-worker
have reported a method without any catalyst in poly(ethylene
glycol) 200/H2O [28]. However, despite their own merits
some of the reported procedures sufer from certain draw-
backs such as prolonged reaction time, the lower yield of
products, expensive catalysts, relatively harsh reaction con-
ditions, tedious workup and purifcation. Therefore, it is
quite clear that developing new methodologies in terms of
operational simplicity, less expensive catalyst, mild reaction
conditions and applicable to a wide range of substrates could
be desirable. In continuation of our research works on the
development of new procedures for the synthesis of new het-
erocyclic compounds [29–31], herein, we wish to study the
reaction of diverse aldehydes with 4-hydroxycoumarin and
4-amino-1,3-dimethyluracil in the presence of H3PW12O40
as an efcient catalyst in green media to synthesize some
chromene pyrimidine-2,4-dione derivatives (Scheme 1) and
evaluated anti-bacterial activity.
Fig. 1 Antibacterial compounds
containing pyrimidine structure
1 3

One‑pot three‑component reaction for facile and efcient green synthesis of chromene…
Scheme 1
of the product improved to 85% after 60 min under refux
Results and discussion
(Table 1, entry 2). As can be seen in Table 1, the yield of
desired product was increased to 93% when 2 mol% tung-
stophosphoric acid (H3PW12O40) was added to the reaction
media as a catalyst at room temperature (Table 1, entry
4). In addition, the yield of the product and reaction time
was changed to some extent by increasing the amount of
tungstophosphoric acid (H3PW12O40) under the same con-
dition (Table 1, entries 5, 7). Further attempts to decrease
catalyst loading lead to lower product yields and longer
reaction times (Table 1, entry 6). To evaluate the efect of
the reaction temperature, the model reaction was also car-
ried out under refux. It increases the product yield and the
reaction rate to a certain extent (Table 1, entry 3). In con-
tinuation of our study, the model reaction was performed
in diferent solvents such as H2O, EtOH, EtOH / H2O (1:2),
CH2Cl2, and CH3CN. According to the obtained results,
the mixture of EtOH / H2O (1:2) was selected as the best
solvent (Table 1, entries 4 and 8–12). However, remarkable
yields were obtained using mixtures of ethanol and water
Chemistry
In this study, facile and efcient conversion of diverse
aldehydes, 4-hydroxycoumarin, and 4-amino-1,3-di-
methyluracil in the presence of a catalytic amount of
H3PMo12O40 for preparing chromene pyrimidine-2,4-di-
ones in one-pot is presented. At frst, we performed the
reaction between benzaldehyde, 4-hydroxycoumarin, and
4-amino-1,3-dimethyluracil as a model reaction to aford
6-amino-5-[(4-hydroxy-2-oxo-2H-chromen-3-yl)(phe-
nyl)methyl]-1,3-dimethylpyrimidine-2,4(1H,3H)-dione
(4a) (Table 1). In our initial selection, we tried this model
reaction without any catalyst in the mixture of EtOH /
H2O (1:2) at refux condition but the desired product 4a
obtained in trace amount after 120 min (Table 1, entry1).
When the reaction was accomplished in the presence of
2 mol% molybdatophosphoric acid (H3PMo12O40) the yield
Table 1 Optimization of
three-component reaction
between benzaldehyde,
4-hydroxycoumarin, and
4-amino-1,3-dimethyluracil
Entry
Catalyst (mol%)
Solvent
Temp /°C
Time /min
Yield /%a
1
2
3
4
5
6
7
None
EtOH/H2O (1:2)
EtOH/H2O (1:2)
EtOH/H2O (1:2)
EtOH/H2O (1:2)
EtOH/H2O (1:2)
EtOH/H2O (1:2)
EtOH/H2O (1:2)
MeCN
CH2Cl2
EtOH
EtOH
H2O
refux
refux
refux
r.t
r.t
r.t
120
60
12
15
13
70
12
100
120
25
30
60
120
150
120
153
Trace
85
97
93
95
65
96
76
67
91
90
85
73
67
42
35
H3PMo12O40 (2)
H3PW12O40 (2)
H3PW12O40 (2)
H3PW12O40 (3)
H3PW12O40 (1)
H3PW12O40 (4)
H3PW12O40 (2)
H3PW12O40 (2)
H3PW12O40 (2)
H3PW12O40 (2)
H3PW12O40 (2)
SSA (25)
r.t
8
9
refux
refux
refux
r.t
refux
refux
refux
refux
refux
10
11
12
13
14
15
16
EtOH/H2O (1:2)
EtOH/H2O (1:2)
EtOH/H2O (1:2)
EtOH/H2O (1:2)
p-TSA (58)
FeCl3 (30)
ZnCl2 (40)
Amount of reagents in all reactions: benzaldehyde (1 mmol), 4-hydroxycoumarin (1 mmol), 4-amino-
1,3-dimethyluracil (1 mmol), and 5 cm3 solvent
The best optimized condition for the reaction are highlighted with bold
aIsolated yield
1 3

H. O. Foroughi et al.
(Table 1, entries 10–12). During optimization of the reac-
tion conditions, various catalysts were used to compare
catalytic activity of H3PW12O40. As shown in Table 1, sil-
ica sulfuric acid (SSA) and p-toluenesulfonic acid showed
a signifcant reactivity under the same reaction conditions
(Table 1, entries 13, 14). Also, FeCl3 and ZnCl2 as Lewis
acid catalysts were tested in the model reaction and the
products obtained with 42% and 35% yields, respectively,
after long reaction time (Table 1, entries 15 and 16). Thus,
H3PW12O40 was chosen as the best catalyst for three-com-
ponent reaction between aldehydes, 4-hydroxycoumarin
and 4-amino-1,3-dimethyluracil.
for three-component coupling reaction between aldehyde,
4-hydroxycoumarin, and 4-amino-1,3-dimethyluracil using
heteropoly acid (HPA) as catalyst (Scheme 2). At frst, het-
eropoly acid (H3PW12O40) promotes the aldehyde with pro-
tonation and then 4-amino-1,3-dimethyluracil reacts with
promoted aldehyde and produces the Knoevenagel interme-
diate I. Next, intermediate I reacts with 4-hydroxycoumarin
via Michael addition and creates the desired product.
Bactericide activity
The antimicrobial activity of the synthetized compounds is
shown in Table 3. DMSO is used as a negative control. The
To illustrate the scope of the designed protocol for the
preparation of chromene-pyrimidine 2,4-dione derivatives,
we extended the optimized reaction conditions for various
aromatic and heteroaromatic aldehydes and the results are
summarized in Table 2. As depicted in Table 2, it seems
that the aromatic aldehydes with electron releasing groups
reduced the yield and reaction rate to some extent (Table 2,
entries 6–9). In the other hand, aromatic aldehydes with
electron-withdrawing groups increased the reaction rate and
the yield of products to a certain degree (Table 2, entries 2–5
and 10, 11). In addition, we used pyridine-4-carbaldehyde
as a heteroaromatic aldehyde in the reaction and the desired
product obtained in 90% yield after 15 min (Table 2, entry
12). Some of the synthesized compounds were known and
their identity was confrmed by a comparison of their melt-
ing points and their spectral properties with literature data
[19–21]. In addition, some compounds (4c, 4 g, and 4i) were
new and were characterized by spectroscopic techniques.
Scheme 2
1
Their structures were confrmed by IR, H and 13C NMR
spectroscopic techniques, and elemental analysis. According
to the obtained results, we propose the following mechanism
Table 2 Synthesis of chromene
pyrimidine-2,4-dione
derivatives via three component
reaction
Entry
Aldehyde
Product
Time/min
Yielda
/%
M.p. /°C
Found
Reported [Lit]
1
2
3
4
5
6
7
8
Benzaldehyde
4a
4b
4c
4d
4e
4f
4g
4h
4i
15
13
20
18
12
25
17
25
23
14
10
15
93
95
90
89
96
88
90
86
89
91
93
90
190–192
193–195
252–254
235–237
245–247
204–206
170–173
199–202
245–246
255–257
238–239
226–228
192–193 [19]
193–194 [19]
–
233–234 [19]
248–250 [21]
203–205 [19]
–
205–207 [19]
–
257–259 [19]
240–242 [20]
227–229 [19]
4-Chlorobenzaldehyde
3-Chlorobenzaldehyde
4-Bromobenzaldehyde
4-Fluorobenzaldehyde
4-Methylbenzaldehyde
3-Methylbenzaldehyde
4-Methoxybenzaldehyde
4-t-Butylbenzaldehyde
3-Nitrobenzaldehyde
2- Nitrobenzaldehyde
Pyridin-4-carbaldehyde
9
10
11
12
4j
4k
4l
Reaction conditions: aldehyde (1 mmol), 4-hydroxycoumarin (1 mmol), 4-amino-1,3-dimethyluracil
(1 mmol), and 0.056 g H3PW12O40 (2 mol%) in 5 cm3 EtOH / H2O (1:2)
aIsolated yield
1 3

One‑pot three‑component reaction for facile and efcient green synthesis of chromene…
Table 3 MIC and MBC of synthetic compounds against Staphylococ-
Conclusions
cus aureus and Escherichia coli
In summary, we explained the design and synthesis of
a series of chromene pyrimidine-2,4-dione derivatives
4a–4 l as a new type of antibacterial agent and evalua-
tion of their antibacterial activity. In this procedure, the
reaction of diverse aldehydes, 4-hydroxycoumarin, and
4-amino-1,3-dimethyluracil in the presence of heteropoly
acid in green media that lead to the synthesis of a series
of chromene pyrimidine-2,4-dione derivatives has been
reported. We have now realized that the reaction can be
carried out much more rapidly and in good to excellent
yields using H3PMo12O40 as a catalyst. Bactericide activity
of this result confrms that Compounds 4i, 4j, 4 l showed
inhibition at concentrations of 62.5 mg/cm3, which exhib-
ited better antimicrobial properties than reference drugs.
Product
MIC /μg cm−3
MBC /μg cm−3
S. aureus
E. coli
S. aureus
E. coli
4a
250
250
250
125
125
125
125
125
250
62.5
62.5
62.5
125
1.95
500
500
500
500
250
250
250
250
500
500
500
500
500
250
125
500
500
500
500
250
500
250
500
500
500
125
125
125
500
125
1000
500
500
500
250
500
250
250
1000
1000
1000
1000
1000
1000
500
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
Penicillin
Tetracycline
DMSO
1000
Experimental
Chemicals were purchased from Fluka, Merck, and Aldrich
1
chemical companies. H NMR and 13C NMR were run on
a Bruker Avanc DRX (250 MHz) in pure deuterated CDCl3
and DMSO-d6 solvents with tetramethylsilane (TMS) as
internal standards. Chemical shifts are given in the δ scale in
part per million (ppm) and J in Hz. The bonds are assigned
as singlet (s), doublet (d), triplet (t), quartet (q), multiplet
(m), broad (br), doublet of doublet (dd), doublet of triplet
(dt) and complex. FT-IR spectroscopy (Shimadzu FT-IR
8300 spectrophotometer), was employed for characteriza-
tion of the compounds. Microanalyses were performed on
a Perkin-Elmer 240-B microanalyzer. Melting points were
determined in open capillary tubes in a Büchi B 545 appa-
ratus. The reaction monitoring was accomplished by TLC
on silica gel PolyGram SILG/UV254 plates).
MIC and MBC of the compounds are compared to gentamycin
and penicillin as reference drugs.
In general, the efect of these compounds on Gram-negative
bacteria (Escherichia coli) was less than that of Gram-positive
bacteria (Staphylococcus aureus) (Table 3). This maybe due to
the diferences in the bacterial cell wall; Gram-negative bacte-
ria in have an outer membrane in addition to the peptidoglycan
wall. Gram-positive bacteria, however, have only peptidogly-
can walls [32]. The bacterial cell surface has a negative charge,
which is more available in gram-positive bacteria. The nega-
tive charge on the cell surface gives the bacterium an attractive
charge. Therefore, it is expected that with drawing electron
groups such as halogens, nitro groups and also the pyrimidine
rings be a good factor for destroying these bacteria. The inhibi-
tory efect and bactericidal efect of some of the compounds
in Tables 1 and 2 are better than the reference antibiotic used
in this study. By comparing the compounds, it is clear that the
halogens did not signifcantly afect the MIC and MBC. Some
even have no inhibition as compared to the negative control.
Only 4d had the same efect as penicillin. Compounds 4i, 4j,
4 l showed inhibition at concentrations of 62.5 mg/cm3, which
exhibited better antimicrobial properties than penicillin. This
may be due to the strong with drawing electron groups such as
NO2, which has been able to establish surface attraction with
bacteria and prevent them from growing.
General procedure for the synthesis of chromene
pyrimidine‑2,4‑dione derivatives in presence
of H3PW12O40 catalyst
To a stirred solution of 0.162 g 4-hydroxylcoumarin
(1 mmol), aldehyde (1 mmol), and 0.155 g 4-amino-1,3-di-
methyluracil (1 mmol) in the mixture of ethanol/H2O (1:2,
5 cm3) was added 0.056 g H3PW12O40 catalyst (2 mol%)
and then the reaction mixture was stirred at room tempera-
ture for the indicated time in Table 2. After completion
of the reaction, as indicated by TLC (eluent: EtOAc/n-
hexane), the reaction mixture was fltered of and washed
with H2O (2 × 5 cm3) and hot EtOH (5 cm3) and the pure
products were obtained 4a–4 l (yields 86–96%).
1 3

H. O. Foroughi et al.
6‑Amino‑5‑[(3‑chlorophenyl)(4‑hydroxy‑2‑oxo‑2H‑chromen‑
3‑yl)methyl]‑1,3‑dimethylpyrimidine‑2,4(1H,3H)‑dione
(4c, C22H18ClN3O5) White solid; yield 0.396 g (90%); m.p.:
252–254 °C; 1H NMR (250 MHz, DMSO-d6): δ=3.13 (s,
3H, N-CH3), 3.36 (s, 3H, N-CH3), 5.63 (s, 1H, CH), 7.12
(d, 1H, J=7 Hz, Ar–H), 7.19–7.25 (m, 3H, Ar–H and NH2),
7.28–7.36 (m, 3H, Ar–H and NH2), 7.41 (d, 1H, J=8.25 Hz,
Ar–H), 7.62 (dt, 1H, J1 =8.5 Hz, J2 =1.25 Hz, Ar–H), 7.83
(dd, 1H, J1 =8 Hz, J2 =1.25 Hz, Ar–H), 13.97 (br, 1H, OH)
ppm; 13C NMR (62.5 MHz, DMSO-d6): δ=28.18 (N-CH3),
30.50 (N-CH3), 35.90 (CH), 86.31, 104.32, 116.08, 116.84,
123.68, 124.25, 125.20, 125.75, 126.27, 129.78, 132.42,
132.95, 141.25, 149.98, 151.92, 155.17, 163.76 (C = O),
164.01 (C = O), 165.58 (C = O) ppm; IR (KBr): ꢀ = 3386,
3354, 3232, 1701, 1643, 1604, 1562, 1508, 1353, 1203,
1064, 894, 775 cm−1.
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Med Chem Res 23:3810
6‑Amino‑5‑[(4‑tert‑butylphenyl)(4‑hydroxy‑2‑oxo‑2H‑
c h r o m e n ‑ 3 ‑ y l ) m e t h y l ] ‑ 1 , 3 ‑ d i m e t h y l p y r i m i ‑
dine‑2,4(1H,3H)‑dione (4i, C26H27N3O5) Cream solid; yield
1
0.41 g (89%); m.p.: 245–246 °C; H NMR (250 MHz,
23. Abdolmohammadi A, Balalaie S, Barari M, Rominger F (2013)
Comb Chem High Throughput Screen 16:150
DMSO-d6): δ=1.22 (s, 9H, t-Bu), 3.14 (s, 3H, N-CH3), 3.37
(s, 3H, N-CH3), 5.57 (s, 1H, CH), 7.04 (d, 2H, J=8.25 Hz,
Ar–H), 7.23 (d, 2H, J=8.5 Hz, Ar–H), 7.31 (s, 2H, NH2),
7.35–7.44 (m, 2H, Ar–H), 7.60–7.67 (m, 1H, Ar–H), 7.83
(dd, 1H, J1 =7.87 Hz, J2 =1.5 Hz, Ar–H), 13.96 (s, 1H, OH)
ppm; 13C NMR (62.5 MHz, DMSO-d6): δ=28.18 (N-CH3),
30.51 (N-CH3), 31.12 (3 CH3), 33.92 (C-3CH3), 35.59 (CH),
86.64, 104.73, 116.09, 116.87, 123.65, 124.27, 124.82, 126,
132.37, 135.08, 147.81, 150, 151.87, 155.05, 163.67 (C=O),
164 (C=O), 165.74 (C=O) ppm; IR (KBr): ꢀ =3398, 3244,
2981, 1685, 1639, 1608, 1569, 1504, 1203, 1064, 760 cm−1.
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(2018) Z Naturforsch B 73:545
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Acknowledgements We would like to offer our special thanks
to Islamic Azd University Fasa branch for partial support of this
research work.
Publisher’s Note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional afliations.
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