One-pot synthesis of novel pyrano-fused coumarins catalyzed by zinc oxide nanoparticles

Article abstract of DOI:10.3987/COM-14-13006

A new class of pyrano[3,2-c]coumarins containing an aryloylgroup was synthesized via the three-component reactions of 4-hydroxycoumarin with arylglyoxals and malononitrile. The reactions are efficiently catalyzed by zinc oxide nanoparticles as powerful and recyclable catalyst. The green chemistry principles were also considered and the present method has some advantages, such as simplicity, low catalyst loading, and high yields.

Full text of DOI:10.3987/COM-14-13006

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HETEROCYCLES, Vol. 89, No. 7, 2014
HETEROCYCLES, Vol. 89, No. 7, 2014, pp. 1670 - 1677. © 2014 The Japan Institute of Heterocyclic Chemistry
Received, 17th April, 2014, Accepted, 28th May, 2014, Published online, 5th June, 2014
DOI: 10.3987/COM-14-13006
ONE-POT SYNTHESIS OF NOVEL PYRANO-FUSED COUMARINS
CATALYZED BY ZINC OXIDE NANOPARTICLES
Saeed Khodabakhshi,*a Bahador Karami,b and Khalil Eskandaric
aYoung Researchers and Elite Club, Gachsaran Branch, Islamic Azad University,
Gachsaran, Iran; E-mail: saeidkhm@yahoo.com
bDepartment of Chemistry, Yasouj University, Yasouj, Zip Code: 75918-74831
P.O.Box 353, Iran
cYoung Researchers and Elite Club, Shahrekord Branch, Islamic Azad University,
Shahrekord, Iran
Abstract – A new class of pyrano[3,2-c]coumarins containing an aryloylgroup was
synthesized via the three-component reactions of 4-hydroxycoumarin with
arylglyoxals and malononitrile. The reactions are efficiently catalyzed by zinc
oxide nanoparticles as powerful and recyclable catalyst. The green chemistry
principles were also considered and the present method has some advantages, such
as simplicity, low catalyst loading, and high yields.
From the perspective of environmental problems, the avoidance of harmful organic solvents is one of the
efficient ways to decrease the concerns in chemical research and industry. In regard of the fundamental
principles of the green chemistry, the elimination of toxic solvents and the generation of waste are
important items.1-3 In chemical reactions, transition metal oxides are commonly used due to their catalytic
activity.4,5 Among the nano-sized transition metal oxides, zinc oxide nanoparticles (ZnO NPs) have gained
tremendous importance as they exhibit interesting catalytic properties which cannot be achieved by their
bulk counterparts. ZnO nanomaterials are non-toxic and water-insoluble material which can be recovered
and reused, therefore, it can help to reduce the waste.6-8
The pyranocoumarins possess several types of pharmacological properties, such as anti-HIV, antibacterial,
insecticidal, anticancer, and anti-inflammatory activities, thus, they have received considerable
attention.9,10 Among pyranocoumarins, the pyrano[3,2-c]coumarins are the most synthetically feasible.11
Generally, pyrano[3,2-c]coumarins are affordable from commercially available 4-hydroxycoumarin with

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1671
the suitable electrophiles. For example, pyrano[3,2-c]coumarins were prepared via the one-pot, three
component reaction of 4-hydroxycoumarins with carbonyl compounds and active methylenes.12-15
To the best of our knowledge, there is no report describing the synthesis of pyrano[3,2-c]coumarins
containing aryloyl group starting from arylglyoxals via a three-component reaction.
ZnO nanoparticles were prepared through the thermal decomposition method and characterized by
scanning electron microscopy (SEM), transmission electron microscopy (TEM) and selected area electron
diffraction (SAED). The morphology of the ZnO NPs was investigated by scanning electron microscopy
(SEM). The typical SEM image of ZnO NPs shows that the nanoparticles have an average diameter of 20
nm (Figure 1, A). In addition, transmission electron microscopy (TEM) analyses and selected area
diffraction (SAED) pattern were used for more investigation (Figure 1, B).
Figure 1
The TEM image reveals that the spherical ZnO nanoparticles have granular nature with the average size
of 20 nm and clearly shows that the ZnO nanoparticles are in the form of wurtzite crystal structure. The
rings with a dotted pattern in SAED (shown in the inset of Figure 1B) confirm the wide size distribution
of ZnO nanoparticles.
In continuation of our previous studies on synthesis of organic compounds by the use of safe
catalysts,16-20 in this work, we report the three-component synthesis of new pyrano[3,2-c]coumarins 4
using ZnO NPs as powerful catalyst based the condensation reaction of 4-hydroxycoumarin (1) with aryl-
glyoxals 2 and malononitrile (3) (Scheme 1). It is noteworthy to mention that these ZnO-catalyzed
reactions showed the chemoselectivity toward pyranocoumarins 4 instead of biscoumarins 5 which was
reported in the previous literature.21
To determine suitable conditions, the preparation of 4a was selected as a model. In the first attempt,
compound 4a was not produced in absence of catalyst even after 180 min. When ZnO (3 mol%) was
added, the compound 4a was formed in good yield (85%)

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HETEROCYCLES, Vol. 89, No. 7, 2014
OH
N
N
NH2
C
CN
Ar
OH
O
O
O
H
H
O
O
O
O
O
+
3
1
O
O
Ar
OH
O
OH
Ar
O
4
H
OH
2
5
Conditions: EtOH:H2O (50/50), ZnO NPs (3 mol%), rt to reflux
Scheme 1
Subsequently, the amount of catalyst was varied. As shown in Figure 2, when 6 mol% of ZnO NPs was
employed, the desired product 4a was isolated in 85% yield and no appreciable effect observed on the
reaction rate. In order to compare the ZnO nanoparticles with bulk case, an experiment was also
investigated. However, it was found that the model reaction proceeds slowly using ZnO bulk and needs
140 min to be completed.
Figure 2
A series of common solvents (THF, CH2Cl2, H2O, EtOH, and MeOH) was also investigated. Amongst the
solvents experimented, an equal mixture of EtOH and H2O provided the best yield.
Using the optimized conditions, we studied the domino Knoevenagel-Michael type reaction of
4-hydroxycoumarin, malononitrile and different arylglyoxals. It should be noted that both electron
donating/withdrawing groups on arylglyoxal reacted well. The results are summarized in Table 1.
During our experiments, it was found that the reactions are independent from electron
donating/withdrawing substitutions on the phenyl ring.
As a mechanistic pathway, Scheme 2 indicates a catalytic cycle for synthesis of compounds 4. It seems
that in the first step, the reaction undergoes the Knoevenagel condensation between arylglyoxal and
malononitrile in which ZnO can promote the condensation as the versatile catalyst. In the next step,
Michael type addition of 4-hydroxycoumarin to the corresponding aroylidene malononitriles followed by
interamolecular heterocyclization reaction lead to the formation of 4.

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1673
Table 1. Synthesis of pyrano fused coumarins catalyzed by ZnO NPs (3 mol%) in H2O/EtOH (1:1)
Entry
Product
Ar
Time (min) Yield (%)a
Mp (ºC)
1
2
4a
4b
4c
4d
4e
4f
C6H5
85
85
90
85
80
95
80
80
95
97
80
85
80
85
100
80
95
90
75
75
272-274
253-255
263-265
263-265
248-250
273-275
268-270
266-268
271-273
278-280
4-F-C6H4
3
4-Cl-C6H4
4-Br-C6H4
3-NO2-C6H4
4-NO2-C6H4
3-MeO-C6H4
4-MeO-C6H4
1-naphthyl
2-naphthyl
4
5
6
7
4g
4h
4i
8
9
10
4j
aIsolated yields.
O
OH
Ar
OH
H
H
ZnO
O
H
HO
ZnO
CN
CN
H
O
H
Ar
TM
H
N
Z
n
H2O
O
C
NC
H
H
H
O
O
NC
O
O
Ar
Ar
O
N
OZn
H
O
O
O
Scheme 2

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To investigate the recyclability of ZnO NPs, a recycling experiment was conducted by the use of above
mentioned model reaction. After separation, the catalyst was reused in the next run. It was revealed that
the ZnO NPs could be reused at least three times without the apparent loss of catalytic activity (Figure 3).
Figure 3
In summary, we developed the first method for synthesis of novel pyrano[3,2-c]coumarins by employing
arylglyoxals. This research presents a green and efficient method catalyzed by ZnO NPs as safe and
recyclable catalyst. It should be mentioned that the present strategy enables the access to a wide variety of
pyranocoumarins bearing an aryloyl group which are unexplored compounds with a high potential for
synthetic and biological applications.
EXPERIMENTAL
The reactions were monitored by TLC (silica gel 60 F254). IR spectra (in KBr discs) were recorded on a
FTIR Shimadzu-470 spectrometer (Shimadzu, Japan) in the scanning range of 400–4000 cm−1 and the 1H
NMR spectra (300 MHz) were obtained on a Bruker Avance DPX-300 NMR spectrometer (Bruker,
USA).
Starting Materials. Arylglyoxals were prepared as detailed in the previous paper.22 All other chemicals
used in this study were commercially available.
General procedure for the preparation of ZnO nanoparticles
In a typical two step procedure, firstly, zinc acetate dihydrate (2.19 g, 0.01 mol) and oxalic acid (1.08 g,
0.012 mol) were combined by grinding in an agate mortar for 30 min at room temperature. Afterwards, in
the second step, the prepared ZnC2O4·2H2O nanoparticles were calcinated at 450 ºC for 30 min to
produce ZnO nanoparticles (0.78 g) under thermal decomposition conditions.
General procedure for the synthesis of compounds 4
To a 25 mL round-bottomed flask, 4-hydroxycoumarin (1.0 mmol), arylglyoxal (1.2 mmol), malononitrile
(1.2 mmol), EtOH/H2O (1:1, 10 mL) and ZnO NPs (0.03 mmol) were added. The reaction was stirred at

HETEROCYCLES, Vol. 89, No. 7, 2014
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room temperature for 30 min, then, vigorously stirred under reflux conditions for a special time. The
progress of the reaction was monitored by TLC. After completion, the reaction mixture was cooled to
room temperature and the precipitates were filtered, dried and dissolved in THF to separate the catalyst.
The solvent was removed under reduced pressure and the pure product was obtained after
recrystallization from EtOH/THF (3:1).
2-Amino-4-(benzoyl)-3-cyano-4H,5H-pyrano[3,2-c]chromen-5-one (4a): mp 272-274 ºC; IR 3402,
3292, 2201, 1708, 1678, 1606, 1373, 1064 cm-1; 1H NMR:  8.16 (d, 2H, J = 7.2 Hz), 7.90 (dd, 1H, J1 =
8.2, J2 = 1.6 Hz), 7.81-7.73 (m, 2H), 7.69 (s, 2H), 7.62 (t, 2H, J = 8.2 Hz), 7.57-7.53 (m, 2H), 5.42 (s,
1H); 13C NMR:  198.1, 160.0, 159.5, 154.7, 152.1, 135.3, 134.1, 133.3, 129.1, 128.8, 125.0, 122.1, 118.5,
116.8, 112.5, 101.9, 51.9, 37.1. Anal. Calcd for C20H12N2O4: C, 69.76; H, 3.51; N, 8.14. Found: C, 69.55;
H, 3.41; N, 8.09.
2-Amino-4-(4-fluorobenzoyl)-3-cyano-4H,5H-pyrano[3,2-c]chromen-5-one (4b): mp 253-255 ºC; IR
3474, 3404, 2205, 1712, 1677, 1595, 1371, 1218, 1061 cm-1; 1H NMR:  8.27 (m, 2H), 7.90 (dd, 1H, J =
8.2, 1.8 Hz), 7.82-7.76 (m, 1H), 7.70 (s, 2H), 7.58-7.53 (m, 2H), 7.46 (t, 2H, J = 8.8 Hz), 5.44 (s, 1H); 13C
NMR:  196.7, 160.0, 159.5, 154.7, 152.1, 133.3, 132.3, 132.1, 125.0, 122.1, 118.5, 116.8, 116.1, 115.8,
112.5, 101.7, 51.8, 37.1. Anal. Calcd for C20H11FN2O4: C, 66.30; H, 3.06; N, 7.73. Found: C, 66.37; H,
3.00; N, 7.61.
2-Amino-4-(4-chlorobenzoyl)-3-cyano-4H,5H-pyrano[3,2-c]chromen-5-one (4c): mp 263-265 ºC; IR
3319, 3186, 3027, 2871, 2205, 1713, 1673, 1587, 1375, 1058, 759 cm-1; 1H NMR:  8.20 (d, 2H, J = 8.4
Hz), 7.89 (dd, 1H, J1 = 8.2, J2 = 1.4 Hz), 7.81-7.69 (m, 5H), 7.57-7.52 (m, 2H), 5.43 (s, 1H); 13C NMR: 
197.2, 160.0, 159.5, 154.7, 152.1, 139.2, 134.1, 133.3, 130.9, 129.0, 125.0, 122.1, 118.4, 116.8, 112.5,
101.6, 51.7, 37.2. Anal. Calcd for C20H11ClN2O4: C, 63.42; H, 2.93; N, 7.40. Found: C, 63.61; H, 2.99; N,
7.35.
2-Amino-4-(4-bromobenzoyl)-3-cyano-4H,5H-pyrano[3,2-c]chromen-5-one (4d): mp 263-265 ºC; IR
3316, 3186, 3027, 2871, 2203, 1715, 1673, 1582, 1374, 1057, 620 cm-1; 1H NMR:  8.10 (d, 2H, J = 8.6
Hz), 7.91-7.76 (m, 4H), 7.71 (s, 2H), 7.58-7.53 (m, 2H), 5.42 (s, 1H); 13C NMR: 197.5, 159.5, 154.7,
152.1, 134.4, 133.4, 132.0, 131.0, 125.0, 122.1, 116.8, 112.5, 101.6, 51.7, 37.2. Anal. Calcd. for
C20H11BrN2O4: C, 56.76; H, 2.62; N, 6.62. Found: C, 56.89; H, 2.51; N, 6.58.
2-Amino-4-(3-nitrobenzoyl)-3-cyano-4H,5H-pyrano[3,2-c]chromen-5-one (4e): mp 248-250 ºC; IR
3415, 3086, 2928, 2197, 1712, 1673, 1609, 1525, 1385, 1352, 1063 cm-1; 1H NMR:  8.83 ( t, 1H, J = 1.8
Hz), 8.65 (d, 1 H, J = 7.8 Hz), 8.61-8.57 (m, 1H), 7.98-7.89 (m, 2H), 7.82-7.77 (m, 3H), 7.59-7.53 (m,
2H), 5.57 (s, 1H); 13C NMR:  197.0, 160.1, 159.5, 154.8, 152.1, 148.1, 136.6, 135.2, 133.5, 130.9, 128.3,

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125.1, 123.1, 122.2, 118.5, 116.8, 112.5, 101.3, 51.2, 37.6. Anal. Calcd for C20H11N3O6: C, 61.70; H,
2.85; N, 10.79. Found: C, 61.88; H, 2.77; N, 10.83.
2-Amino-4-(4-nitrobenzoyl)-3-cyano-4H,5H-pyrano[3,2-c]chromen-5-one (4f): mp 273-275 ºC; IR
3461, 3336, 2192, 1720, 1681, 1613, 1517, 1383, 1326, 1070, 1064 cm-1; 1H NMR:  8.46-8.38 (m, 4H),
13
7.90 (dd, 1H, J = 8.2, 1.4 Hz), 7.82-7.77 (m, 3H), 7.59-7.54 (m, 2H), 5.51 (s, 1H); C NMR:  197.7,
160.1, 159.5, 154.8, 152.1, 150.4, 140.2, 133.5, 130.4, 125.1, 124.0, 122.2, 116.8, 112.5, 101.3, 51.2, 37.9.
Anal. Calcd for C20H11N3O6: C, 61.70; H, 2.85; N, 10.79. Found: C, 61.79; H, 2.72; N, 10.71.
2-Amino-4-(3-methoxybenzoyl)-3-cyano-4H,5H-pyrano[3,2-c]chromen-5-one (4g): mp 268-270 ºC;
IR 3477, 3344, 3072, 2934, 2196, 1721, 1674, 1577, 1386, 1065 cm-1; 1H NMR:  7.90 (dd, 1H, J1 = 8.2, J2
=1.8 Hz), 7.815-7.75 (m, 2H), 7.70 (s, 2H), 7.62 (t, 1H, J = 2.4 Hz), 7.57-7.52 (m, 3H), 7.32 (dd, 1H, J1 =
13
7.8, J2 = 2.1 Hz), 5.40 (s, 1H), 3.87 (s, 3H); C NMR:  197.7, 160.0, 159.6, 159.4, 154.7, 152.1, 136.6,
133.3, 130.0, 125.0, 122.1, 121.6, 120.2, 118.5, 116.8, 113.5, 112.6, 101.9, 55.3, 52.0, 37.4. Anal. Calcd
for C21H14N2O5: C, 67.38; H, 3.77; N, 7.48. Found: C, 67.48; H, 3.70; N, 7.56.
2-Amino-4-(4-methoxybenzoyl)-3-cyano-4H,5H-pyrano[3,2-c]chromen-5-one (4h): mp 266-268 ºC;
IR 3426, 3320, 2926, 2200, 1714, 1673, 1597, 1383, 1062 cm-1; 1H NMR:  8.15 (d, 2H, J = 9.0 Hz), 7.89
(dd, 1H, J1 = 8.2, J2 = 1.4 Hz), 7.80-7.74 (m, 1H), 7.65 (s, 2H), 7.57-7.52 (m, 2H), 7.14 (d, 2H, J = 9.0
Hz), 5.36 (s, 1H), 3.90 (s, 3H); 13C NMR:  196.2, 163.9, 160.0, 159.5, 154.6, 152.0, 133.2, 131.6, 128.1,
124.9, 122.1, 118.6, 116.7, 114.1, 112.6, 102.1, 55.6, 52.2, 36.7. Anal. Calcd for C21H14N2O5: C, 67.38; H,
3.77; N, 7.48. Found: C, 67.40; H, 3.73; N, 7.40.
2-Amino-4-(1-naphthoyl)-3-cyano-4H,5H-pyrano[3,2-c]chromen-5-one (4i): mp 271-273 ºC; IR 3477,
3327, 3050, 2923, 2191, 1727.91, 1674.87, 1573.63, 1381.75, 1177 cm-1; 1H NMR:  8.37 (m, 2H), 8.24 (d,
1H, J = 8.4 Hz), 8.09-8.05 (m, 1H), 7.92 (dd, 1H, J = 8.2, J2 = 1.8 Hz), 7.83-7.70 (m, 4H), 7.66-7.54 (m,
4H), 5.43 (s, 1H); 13C NMR:  200.3, 160.2, 159.6, 154.6, 152.2, 134.2, 133.4, 133.3, 133.2, 129.8, 129.0,
128.5, 128.0, 126.5, 125.1, 125.0, 124.7, 122.2, 118.3, 116.8, 112.6, 101.7, 51.4, 38.6. Anal. Calcd for
C24H14N2O4: C, 73.09; H, 3.58; N, 7.10. Found: C, 73.13; H, 3.55; N, 7.01.
2-Amino-4-(2-naphthoyl)-3-cyano-4H,5H-pyrano[3,2-c]chromen-5-one (4j): mp 278-280 ºC; IR 3428,
3321, 2938, 2199, 1714, 1674, 1631, 1597, 1569, 1382, 1172 cm-1; 1H NMR:  8.44 (s, 1H), 7.98-7.95 (m,
2H), 7.84-7.82 (d, 1H, J = 8.4 Hz), 7.76-7.72 (m, 1H), 7.62-7.52 (m, 3H), 7.49-7.42 (m, 2H), 7.39 (s, 2H),
7.33 (d, 1H, J =7.2 Hz), 5.47 (s, 1H); 13C NMR:  199.6, 159.5, 157.8, 153.8, 152.0, 133.2, 132.9, 130.9,
128.4, 127.4, 126.1, 126.1, 126.0, 125.8, 125.7, 124.7, 123.4, 122.4, 119.1, 116.6, 112.9, 104.6, 53.6, 37.2.
Anal. Calcd for C24H14N2O4: C, 73.09; H, 3.58; N, 7.10. Found: C, 73.17; H, 3.60; N, 7.04.
ACKNOWLEDGEMENTS

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We gratefully acknowledge the Yasouj University Research Council for their support. We are also grateful
to the Iranian Nanotechnology Initiative Council for financial support.
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