An eco-friendly synthesis of 4-aryl-substituted pyrano-fuzed coumarins as potential pharmacological active heterocycles using molybdenum oxide nanoparticles as an effective and recyclable catalyst

Article abstract of DOI:10.1007/s11164-018-3363-7

A green cascade three-component reaction between 4-hydroxycoumarin, malononitrile and a wide range of arylaldehydes by employing molybdenum oxide nanoparticles (MoO₃ NPs) is described. By this achievement, some medicinally important products have been successfully synthesized in a one-pot under green conditions. Obtaining good to excellent yields of products, environmentally benign procedure, being easily handled, availability of starting materials, use of non-toxic solvents, and high recyclability of nano-catalysts are the most important advantages of this methodology.

Full text of DOI:10.1007/s11164-018-3363-7

Res Chem Intermed
https://doi.org/10.1007/s11164-018-3363-7
An eco-friendly synthesis of 4-aryl-substituted pyrano-
fuzed coumarins as potential pharmacological active
heterocycles using molybdenum oxide nanoparticles
as an effective and recyclable catalyst
Yaghoub Pourshojaei1,2
Mohammad-Hossein Jadidi1
•
•
Khalil Eskandari1
Alireza Foroumadi2,3 Ali Asadipour1
•
•
Received: 25 October 2017 / Accepted: 1 March 2018
Ó Springer Science+Business Media B.V., part of Springer Nature 2018
Abstract A green cascade three-component reaction between 4-hydroxycoumarin,
malononitrile and a wide range of arylaldehydes by employing molybdenum oxide
nanoparticles (MoO3 NPs) is described. By this achievement, some medicinally
important products have been successfully synthesized in a one-pot under green
conditions. Obtaining good to excellent yields of products, environmentally benign
procedure, being easily handled, availability of starting materials, use of non-toxic
solvents, and high recyclability of nano-catalysts are the most important advantages
of this methodology.
Keywords Pyrano-fuzed coumarins Á Molybdenum oxide nanoparticles Á
Recyclable catalyst Á Green protocol
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11164-
018-3363-7) contains supplementary material, which is available to authorized users.
&
&
1
Yaghoub Pourshojaei
y.pourshoja@kmu.ac.ir
Khalil Eskandari
khalileskandari@yahoo.com
Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutics Research Center,
Kerman University of Medical Sciences, Kerman, Iran
2
Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical
Sciences, Kerman, Iran
3
Drug Design and Development Research Center, Tehran University of Medical Sciences,
Tehran, Iran
123

Y. Pourshojaei et al.
Introduction
In the past decades, catalytic technologies have attracted much interest from
chemists and industrialists, especially the use of heterogeneous recyclable eco-
friendly catalysts considering the economic aspects, and from the green chemistry
point of view [1, 2]. Based on the above, environmentally benign heterogeneous
catalysts have been widely used in synthetic methodologies and their scope is being
expanded [3]. Among them, metal oxides have attracted much interest and been
broadly applied by chemists in different types of organic reactions [4–6]. The rate of
reaction progress in the presence of heterogeneous catalysts directly depends on the
total surface area of the catalysts, and also on the number of active sites on them.
Therefore, it is obviously expected that good catalytic activity is achieved with
smaller particle sizes and higher surface areas of the catalysts [7, 8].
Considering the above, using nano-sized heterogeneous, environmentally benign
catalysts in synthetic protocols is of considerable importance. Among metal oxide
nanoparticles, molybdenum oxide nanoparticles (MoO3 NPs) is one of the most
attractive nanomaterials which have extensively attracted the attraction of chemists
because of its special chemical and physical properties. These NPs have been
successfully applied as promising materials in broad areas, especially as reusable
catalysts in synthetic methodologies [9, 10]. From the above, it can be seen that
MoO3 NPs can be successfully applied as heterogeneous Lewis catalysts in organic
synthesis because of their special qualities, including easy separation from the
reaction mixture by simple filtration, the capability for reuse in further cycles, not
producing undesired side products, and thermal stability. In addition, nano-MoO3
shows non-corrosivity and non-toxicity qualities which make it more important
from the green chemistry point of view, and of benefit as an environmentally benign
catalyst in the chemical industries and synthetic methodologies [11–13]. These
important advantages encourage chemists to apply Mo-based heterogeneous
catalysts in organic transformations. For instance, using supported molybdenum
oxides for the fast pyrolysis of lignocellulosic biomass [14], ethanolysis of kraft
lignin to platform chemicals over molybdenum-based catalysts [15], synthesis of
indole alkaloids by employing nanocomposites of MoS2–RGO [16], biodiesel
synthesis by employing molybdenum dioxo catalyst [17], and also selective
hydrodeoxygenation of 2-furancarboxylic acid over a molybdenum oxide-modified
platinum catalyst [18] can be counted as recent developments in Mo-based
heterogeneous catalysis.
In recent decades, the attention being paid to environmental pollution control
programmes and policies and also to green chemistry aspects have led to using
harmless and neat technologies in synthetic methodologies [19, 20]. One of the
harmless and neat technologies is the use of aqueous medium in synthetic
procedures, which can not only sometimes accelerate reaction progress but is also
completely compatible with green chemistry aspects [21, 22]. Furthermore, running
organic reactions in aqueous media has some other important advantages, such as
using harmless, non-toxic, non-corrosive, inexpensive, and easily accessible
solvents [21, 22].
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An eco-friendly synthesis of 4-aryl-substituted pyrano…
The other noteworthy achievement in organic synthetic methodologies is loading
reaction components in a one-pot. Running organic reactions in this way has some
unique advantages which have resulted in attracting the interest of chemists. For
instance, diminishing of reaction waste, saving in time, simplifying practical aspects
and also having atom economy, step economy, and redox economy can be counted
as advantages of one-pot reactions [23–25]. In addition, running in a one-pot, the
economical point of view is important because complicated molecules can be
obtained from simple starting materials, and can be easily separated from the
reaction mixture, purified and characterized [26]. Coumarin, which may be
classified as a,b-unsaturated d-lactones [27] or benzopyrone analogous [28], is one
of the important O-containing heterocycles which have been isolated from natural
products [29], and have attracted great interest from chemists and pharmaceutics
[30–34]. So far, a broad range of works on biological and pharmaceutical activities
of coumarin and its derivatives have been published. For example, they have been
shown to be anti-inflammatory [35], antitumor [36, 37], anticoagulant, anti-oxidant,
antibacterial, and antiHIV [38] activities. Among coumarin analogous 4-hydrox-
ycoumarins which have been found in numerous plants and natural products and
which belong to a class of vitamin K antagonists, have increasingly attracted the
interest of chemists and pharmacologists [39, 40]. For instance, 4-hydroxycoumarin
and its derivatives have also shown antibacterial [41], antiHIV [42–44], antiviral
[45], anti-oxidant [46], and anticoagulant [47] activities. To date, numerous types of
biologically active products are recognized with 4-hydroxycoumarin’s scaffold
being observed in their chemical structures as an obvious motif (Fig. 1) [48]. All the
Fig. 1 Examples of some drugs and biologically active compounds containing 4-hydroxycoumarin or
alkylamine ether motifs
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Y. Pourshojaei et al.
above-mentioned features about the biological and pharmaceutical activities of
4-hydroxycoumarin have encouraged chemists and pharmacologists to synthesize
newly prepared heterocycles based on the 4-hydroxycoumarin framework [49–51].
In addition to the above-mentioned scaffolds, the alkylamine ether moiety has also
been found in some important drugs and biologically active compounds (Fig. 1)
[52–54].
These disclosed properties have encouraged chemists and pharmacologists to
design synthetic routes to obtain newly prepared molecules exhibiting pharmaco-
logical and biological activities which may be applied in the future in the treatment
of human disease as new medicines [43, 55, 56]. Based on the above, and in
continuation of our research studies onthe catalytic synthesis of newly prepared
potentially interesting biologically active heterocyclic compounds, [57–61], here we
wish to report a green one-pot catalytic three-component reaction between
4-hydroxycoumarin (1), malononitrile (2), and a broad range of arylaldehydes (3)
in the presence of catalytic amounts of MoO3 NPs (Scheme 1)
It has been found that MoO3 NPs not only efficiently catalyze the synthesis and
cyclization of 4-phenyl-substituted pyrano-fuzed coumarins via a convenient work-
up but also have some advantages, such as safety, capability for reuse, high stability,
and easy handling. Therefore, in this work, the preparation, high activation, and
regeneration of MoO3 NPs as an eco-friendly and recyclable catalyst in the
synthesis of some medicinally important heterocycles are explained. Furthermore,
the efficiency of the catalyst in the synthesis of target products was compared with
others. The structures of the target products (4) were deduced from and confirmed
by FT-IR, FT-1H and FT-13C NMR spectroscopies and (C,H,N, ) analyses.
Experimental
Chemicals were purchased from Merck and Sigma-Aldrich. An elecrtothermal
IA9100 melting point apparatus fixed at 1 °C/min was used for melting point
measurements. A Brucker FT-IR Tensor 27 infrared spectrophotometer with KBr as
Scheme 1 One-pot synthesis of 4-phenyl-substituted pyrano-fuzed coumarins catalyzed by MoO3 NPs
under green conditions
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An eco-friendly synthesis of 4-aryl-substituted pyrano…
the matrix was applied for recording IR spectra, which were recorded in the range of
4000–400 cm-1. A FT-NMR Bruker Avance Ultra Shield Spectrometer at 400.13
1
1
for H NMR and at 100.62 MHz for 13C NMR (In some cases, H NMR 300 MHz
and 13C NMR 75 MHz, was applied) in DMSO as solvent was used for recording 1H
and 13C NMR. Elemental analyses (C,H,N,S) were performed on a Heraeus Rapid
analyzer and the results were found to be in good agreement with the calculated
values ( 0.3%). TLC-Grade silica gel-G/UV (254 nm) plates were used for
monitoring of the reaction progress using CHCl3/CH3OH (10:1) as eluent.
Catalyst characterization
Scanning electron microscopy (SEM) evaluations of the nano-catalyst were
performed on a JEOL JEM 3010 instrument operating at an accelerating voltage
of 300 kV. An X-ray diffraction pattern for the characterization of the heteroge-
neous nano-catalyst was studied with XRD (D8 Avance; Bruker). EDAX analysis
was carried out by NEWXL30 144-2.5 instrument in an active area of 10 mm2.
Thermogravimetric (TG) measurements were carried out using a thermal gravi-
metric analyzer (BAHR, STA 503) from room temperature to 1100 °C in air at a
heating rate of 10 °C min-1. Transmission electron microscopy (TEM) investiga-
tions of the nano-catalyst were performed on a JEOL JEM 3010 instrument
operating at an accelerating voltage of 300 kV. The Brunauer–Emmett–Teller
(BET) surface area was measured on a BELSORP-MR6 (Japan) at 77.4 K. All
samples were first degassed in a vacuum at 100 °C for 4 h before analysis.
Typical procedure to prepare MoO3 NPs
To synthesize MoO3 NPs, to the stirred mixture of 2 g (1.6 mmol) ammonium
heptamolybdate tetrahydrate ((NH4)6Mo7O24 9 4H2O) dissolved in 5 mL ethanol
and 15 mL of deionized water, at room temperature for 20 min, HNO3 (2 M) was
added dropwise until the pH of the mixture reached 1. Then, the formed clear
solution was stirred under reflux conditions at 90 °C for 5 h. Next, the obtained
light-blue precipitates were separated by filtration, washed several times with
deionized water until the washing solution became neutral, and dried in an oven at
90 °C for 12 h. In the final step, the catalyst was calcined at 450 °C for 6 h in an
electric furnace.
General procedure for the preparation of corresponding aldehydes
Corresponding aldehydes containing alkylamine ethers were synthesized according
to the procedure, and the physical and chemical properties of obtained aldehydes
were compared with those reported in the literature [61], and all their structures
were confirmed. Also, p-benziloxybenzaldehyde derivatives were prepared by being
treated with 4-hydroxybenzaldehyde with appropriate benzylchloride/bromide
derivatives in the presence of K2CO3 as the catalyst. The physical and chemical
properties of all the obtained substrates were compared with those reported in the
literature and all their structures were confirmed [68, 69].
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Y. Pourshojaei et al.
Typical procedure to the synthesis of 4a
4-hydroxycoumarin (1 mmol, 0.162 g) was added to a stirred mixture of malonon-
itrile (1.5 mmol 0.01 g), MoO3 NPs (0.007 g, 5 mol%) and para-(4-morpholi-
noethoxy)-benzaldehyde (1 mmol, 0.235 g) in EtOH/H2O (4:1). The mixture was
heated at 80 °C for the times indicated in Table 2 (see ‘‘Results and discussion’’.
After compilation of the reaction progress (which was controlled by TLC CHCl3/
CH3OH (10:1) as eluent), the mixture was precipitated and then filtrated to separate
the crude product., which was dissolved in boiling ethanol and filtrated to separate
the catalyst. Finally, a crystalline pure product was obtained in solution and isolated
by filtration.
Representative spectral data
2-Amino-4-(4-(2-morpholinoethoxy)phenyl)-5-oxo-4H,5H-pyrano[3,2-c]chromene-
3-carbonitrile (4a)
Light yellow crystals; m.p: 191–193 °C; FT-IR (KBr) (mmax, cm-1): 3413, 3272,
3148, 2937, 2860, 2189, 1729, 1679, 1605, 1375, 1171, 1110, 1035, 763. H NMR
1
(500 MHz, DMSO-d6) d (ppm): 7.94 (d, 1H, J = 7.5 Hz, CHAr), 7.70 (t, 1H,
J = 7.5 Hz, CHAr), 7.50–7.44 (m, 2H, CHAr), 7.38 (brs, 2H, NH2), 7.15 (d, 2H,
J = 8 Hz, CHAr), 6.86 (d, 2H, J = 8 Hz, CHAr), 4.38 (s, 1H, CH), 4.01 (t, 2H,
J = 5.5 Hz, OCH2), 3.56 (brs, 4H, 2CH2), 2.67 (brs, 2H, CH2), 2.46 (brs, 4H,
2CH2); 13C NMR (75 MHz, DMSO-d6) d (ppm): 160.0, 158.4, 157.9, 153.6, 152.6,
135.9, 133.3, 129.2, 125.1, 122.9, 119.8, 117.0, 114.9, 113.5, 104.8, 66.5, 65.6,
58.9, 57.4, 53.9, 36.7. Anal Calcd. for (C25H23N3O5): C, 67.41; H, 5.20; N, 9.43;
Found: C, 67.39; H, 5.15; N, 9.46%.
2-Amino-5-oxo-4-(4-(2-(piperidin-1-yl)ethoxy)phenyl)-4H,5H-pyrano[3,2-
c]chromene-3-carbonitrile (4b)
Light yellow crystals; m.p: 185–186 °C; FT-IR (KBr) (mmax, cm-1): 3349, 3153,
2954, 2192, 1721, 1677, 1606, 1377, 1242, 1174, 1113, 1048, 766. 1H NMR
(500 MHz, DMSO-d6) d (ppm): 7.91–7.89 (m, 1H, CHAr), 7.73–7.70 (m, 1H,
CHAr), 7.51–7.42 (m, 4H, CHAr, NH2), 7.20 (d, 2H, J = 8.5 Hz, CHAr), 6.93 (d,
J = 8.5 Hz, 2H, CHAr), 4.41 (s, 1H, CH), 4.33 (brs, 2H, OCH2), 2.95 (brs, 6H,
3CH2), 1.74–1.50 (m, 6H, 3CH2); 13C NMR (75 MHz, DMSO-d6) d (ppm): 160.0,
158.4, 157.1, 153.7, 152.6, 136.7, 133.4, 129.4, 125.2, 123.0, 119.8, 117.0, 115.1,
113.5, 104.6, 62.8, 58.5, 55.2, 53.1, 38.7, 22.9, 21.7; Anal Calcd. for (C26H25N3O4):
C, 70.41; H, 5.68; N, 9.47; Found: C, 70.44; H, 5.59; N, 9.51%.
2-Amino-4-(4-(3-morpholinopropoxy)phenyl)-5-oxo-4H,5H-pyrano[3,2-
c]chromene-3-carbonitrile (4c)
Light yellow crystals; m.p: 170–173 °C; FT-IR (KBr) (mmax, cm-1): 3415, 3331,
3141, 2866, 2192, 1702, 1671, 1605, 1466, 1379, 1237, 1178, 1111, 767. H NMR
1
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An eco-friendly synthesis of 4-aryl-substituted pyrano…
(500 MHz, DMSO-d6) d (ppm): 7.90 (d, 1H, J = 8 Hz, CHAr), 7.71 (t, 1H,
J = 8 Hz, CHAr), 7.51–7.42 (m, 4H, CHAr, NH2), 7.17 (d, J = 8.5 Hz, 2H, CHAr),
6.87 (d, J = 8.5 Hz, 2H, CHAr), 4.40 (s, 1H, CH), 4.02 (t, 2H, J = 5 Hz, OCH2),
3.92–3.78 (brs, 4H, 2CH2) 3.50 (brs, 2H, CH2), 3.21 (brs, 2H, CH2), 3.06 (brs, 2H,
CH2), 2.15 (brs, 2H, CH2). 13C NMR (125 MHz, DMSO-d6) d (ppm): 160.0, 158.4,
157.8, 153.6, 152.5, 136.2, 133.3, 129.2, 125.1, 123.0, 119.7, 117.0, 114.9, 113.4,
104.7, 65.4, 63.7,58.6, 54.0, 51.5, 36.6, 23.5; Anal Calcd. for (C26H25N3O5): C,
67.96; H, 5.48; N, 9.14; Found: C, 68.04; H, 5.41; N, 9.20%.
2-Amino-4-(4-((4-bromobenzyl)oxy)phenyl)-5-oxo-4H,5H-pyrano[3,2-c]chromene-
3-carbonitrile (4d)
Navajo white crystals; m.p: 249–250 °C; FT-IR (KBr) (mmax, cm-1): 3398, 3284,
3177, 2911, 2861, 2193, 1710, 1671, 1598, 1377, 1236, 1170, 1056, 1013, 873, 806,
757; 1H NMR (300 MHz, DMSO-d6) d (ppm): 7.91 (dd, 1H, 1J = 6 Hz, 2J = 3 Hz,
CHAr), 7.75–7.64 (m, 1H, CHAr), 7.59 (dd, 2H, 1J = 6 Hz, 2J = 3 Hz, CHAr),
7.53–7.39 (m, 6H, CHAr, NH2), 7.20 (d, 2H, J = 9 Hz, CHAr), 6.96 (d, J = 9 Hz,
2H, CHAr), 5.06 (s, 2H, CH2Bn), 4.42 (s, 1H, CH); 13C NMR (75 MHz, DMSO-d6) d
(ppm): 160.0, 158.4, 157.8, 153.6, 152.4, 137.1, 136.3, 133.3, 131.9, 130.2, 129.3,
125.1, 122.9, 121.4, 119.8, 117.0, 115.1, 113.5, 104.7, 68.9, 58.6, 36.7. Anal Calcd.
for (C26H17BrN2O4): C, 62.29; H, 3.42; N, 5.59; Found: C, 62.34; H, 3.39; N,
5.63%.
2-Amino-4-(4-((4-chlorobenzyl)oxy)phenyl)-5-oxo-4H,5H-pyrano[3,2-c]chromene-
3-carbonitrile (4e)
Navajo white crystals, m.p: 246–148 °C; FT-IR (KBr) (mmax, cm-1): 3398, 3286,
3180, 2911, 2863, 2193, 1714, 1672, 1600, 1378, 1237, 1208, 756. 1H NMR
(300 MHz, DMSO-d6) d (ppm): 7.92 (dd, 1H, 1J = 6 Hz, 2J = 3 Hz, CHAr),
7.75–7.69 (m, 1H, CHAr), 7.53–7.43 (m, 6H, CHAr), 7.39 (brs, 2H, NH2), 7.21 (d,
J = 9 Hz, 2H, CHAr), 6.97 (d, J = 9 Hz, 2H, CHAr), 5.08 (s, 2H, CH2Bn), 4.42 (s,
1H, CH). 13C NMR (75 MHz, DMSO-d6) d (ppm): 160.0, 158.4, 157.8, 153.6,
152.5, 136.6, 136.2, 133.3, 132.8, 129.9, 129.2, 128.9, 125.1, 122.9, 119.7, 117.0,
114.8, 113.4, 104.7, 68.8, 58.6, 36.6. Anal Calcd. for (C26H17ClN2O4): C, 68.35; H,
3.75; N, 6.13; Found: C, 68.33; H, 3.69; N, 6.15%.
2-Amino-4-(4-((3-chlorobenzyl)oxy)phenyl)-5-oxo-4H,5H-pyrano[3,2-c]chromene-
3-carbonitrile (4f)
Navajo white crystals; m.p: 223–225 °C; FT-IR (KBr) (mmax, cm-1): 3393, 3325,
3197, 2922, 2853, 2201, 1711, 1672, 1605, 1490, 1380, 1264, 1173, 1052, 805, 757;
1H NMR (300 MHz, DMSO-d6) d (ppm): 7.92 (dd, 1H, 1J = 6 Hz, 2J = 3 Hz,
CHAr), 7.76–7.71 (m, 1H, CHAr), 7.49–7.39 (m, 8H, 3CHAr, NH2), 7.26 (t, 1H,
J = 9 Hz, CHAr), 6.92–6.86 (m, 3H, CHAr), 5.07 (s, 2H, CH2Bn), 4.45 (s, 1H, CH).
13C NMR (75 MHz, DMSO-d6) d (ppm): 160.0, 158.8, 158.5, 153.9, 152.6, 145.4,
136.4, 133.4, 132.8, 130.1, 130.0, 128.8, 125.1, 122.9, 120.7, 117.0, 114.8, 113.4,
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Y. Pourshojaei et al.
104.3, 68.8, 58.3, 37.3. Anal Calcd. for (C26H17ClN2O4): C, 68.35; H, 3.75; N, 6.13;
Found: C, 68.37; H, 3.80; N, 6.09%.
2-(4-((4-chlorobenzyl)oxy)benzylidene)malononitrile (int. 7e) m.p. 174–176 °C;
IR (KBr) (mmax, cm-1): 3032, 2924, 2853, 2221, 1603, 1582, 1433, 1274, 1178,
1
1013, 828, 798; H NMR (300 MHz, DMSO-d6) d (ppm): 8.41 (1H, s, CHvinylic),
7.99 (2H, d, J = 9 Hz, CHAr), 7.53–7.46 (4H, m, CHAr), 7.27 (2H, d, J = 9 Hz,
CHAr), 5.26 (2H, s, OCH2). 13CNMR (75 MHz, DMSO-d6) d (ppm): 163.6, 160.8,
135.5, 133.8, 133.2, 130.2, 129.0, 124.8, 116.4, 115.7, 115.2, 114.3, 77.6, 69.4.
Anal. Calcd for (C17H11ClN2O): C, 69.28; H, 3.76; N, 9.50; Found: C, 69.25; H,
3.77; N, 9.55.
Results and discussion
Characterization of catalyst
Molybdenum(VI) oxide nanoparticles were synthesized by a slight modification of
the solvothermal method [62]. The functional groups of the MoO3 with the best
crystalline degree were identified by FT-IR (Supplementary materials: Fig. S29).
The FT-IR spectrum of MoO3 NPs shows three strong peaks at 990 cm-1 attributed
to the stretching vibration of the terminal M=O bond with an indicator of the layered
orthorhombic MoO3 lattice, 855 cm-1 attributed to the stretching vibration of Mo–
O–Mo bonds, and a broad band at 558 cm-1 corresponding to the bending
stretching vibration of an oxygen atom linked to three Mo atoms [63, 64].
Figure 2 shows the X-ray diffraction pattern (XRD) of the MoO3 NPs. In the
XRD pattern, the distinguished diffraction peaks centered at 2h * 23.7°, 25.9°,
27.1°, 33.7°, 33.9°, 35.8°, 39.1°, and 49.2° related,respectively, to the (001), (011),
(021), (101), (111), (121), (051) and (002) planes of the MoO3 with an rutile phase
which is in agreement with the standard data for the MoO3 orthorhombic lattice
structure (JCPDS: 05-0506) [9b].
Also, an EDAX study of the MoO3 NPs showed peaks corresponding to
molybdenum and oxygen only which proves that the catalyst is essentially pure
(Fig. 3). Furthermore, to support the stability of the catalyst at higher temperatures,
thermogravimetric analysis (TGA) of MoO3 NPs was performed (Fig. 4). The TGA
curve shows that the weight percent remains constant until about 780 °C. Therefore,
it was found that the catalyst is stable at temperatures below 780 °C.
SEM was used to observe the morphology of MoO3 NPs (Fig. 5). SEM images of
MoO3 NPs show that they have a diameter of about 40 nm without any amorphous
or other kinds of crystallized phase particles. In addition, the TEM images of the
nanoparticles were studied for more investigation of their morphology (Fig. 6) and
showed the MoO3 NPs have a homogeneous diameter size of about 40 nm.
Synthesis of pyrano-fuzed coumarins using MoO3 NPs
Before running this three-component reaction, it was necessary to prepare
benzaldehydes containing alkylamine ethers. For this aim, 4-hydroxybenzaldehyde
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An eco-friendly synthesis of 4-aryl-substituted pyrano…
Fig. 2 X-ray diffraction pattern of the MoO3 NPs
Fig. 3 EDAX spectrum of MoO3 nanoparticles
was reacted with appropriate alkylhalides to obtain the desired aldehydes containing
alkylamine ethers. This procedure was run according to a previously reported
methodology [61], and the chemical structures of obtained aldehydes were strongly
confirmed by comparing their physical and spectroscopic data with those reported in
the literature [61].
After the MoO3 NPs, and desired aldehydes were prepared and characterized,
they were applied to the synthesis of 4-phenyl-substituted pyrano-fuzed coumarins
via a green, one-pot reaction (Scheme 1).
Before starting to expand and examine the scope of the reaction, compound 4g
was selected as model to find best conditions for running the reaction (Table 1).
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Y. Pourshojaei et al.
Fig. 4 Thermogravimetric analysis of MoO3 NPs
Fig. 5 Scanning electron
microscopy of MoO3 NPs
Fig. 6 TEM image of MoO3
NPs
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An eco-friendly synthesis of 4-aryl-substituted pyrano…
At first, the reaction was loaded in catalyst-free condition. It was observed that no
remarkable target product was obtained. Also, among the examined acidic and basic
catalysts, MoO3 NPs showed better efficiency than the others. Furthermore, the mix
of EtOH and H2O with a 1:1 ratio was not only more effective than other pure
solvents such as EtOH, H2O, CH3CN, CH2Cl2 or CHCl3 but also showed more
efficiency than other ratios of mixed EtOH and H2O. Among different examined
conditions, the use of MoO3 NPs in aqueous medium [EtOH/H2O (4:1)] at 80 °C
disclosed the best efficiency tofor the synthesis of the product (Table 1).
On the other hand, further investigations to find the optimum amounts of the
required catalyst im the model reaction revealed that the yield of the product was at
a maximum (90%) when 5 mol% of MoO3 NPs was used, while using another
amounts of the catalyst (for instance 3, 4, 6 and 7 mol%) did not lead to maximum
yield.
From the above, it was decided to carry out the reaction in aqueous medium
[EtOH/H2O (4:1)] in the presence of MoO3 NPs (5 mol%) at 80 °C. To examine the
generality of the reaction, compound 3 as one of the starting materials in this three-
component reaction was exchanged to lead to the synthesis of some novel and
known heterocycles with good to excellent yields. The results are summarized in
Table 2 [65–67].
As can be seen from Table 2, the use of aryl aldehydes bearing either electron-
donating or electron-withdrawing groups leads to obtaining products with good to
excellent yields without remarkable differences in the yields. However, for
compounds 4a–c, the yields of cproducts are slightly less than others in which aryl
aldehydes bearing alkyl amine side chains have been used.
Table 1 Effect of different
conditions to the synthesis of 4g
Entry
Conditionsa
Yieldb (%)
1
Catalyst-free, EtOH, reflux
MoO3 NPs, EtOH, r.t.
Trace
37
2
3
MoO3 NPs, EtOH, reflux
MoO3 NPs, H2O, reflux
82
4
68
5
MoO3 NPs, EtOH/H2O (1:1), 80 °C
MoO3 NPs, EtOH/H2O (2:1), 80 °C
MoO3 NPs, EtOH/H2O (4:1), 80 °C
MoO3 NPs, EtOH/H2O (5:1), 80 °C
SSA, EtOH/H2O (4:1), 80 °C
p-TSA, EtOH/H2O (4:1), 80 °C
p-TSA, CH3CN, reflux
70
6
79
7
90
8
84
9
83
10
11
12
13
14
15
16
73
50
SSA, CH3CN, reflux
57
SSA, CH2Cl2, reflux
Trace
37
aReaction time: 30 min; catalyst
amount: 5 mol%; amount of
solvent: 10 mL
In(OTf)3, CHCl3, reflux
Na2CO3, CH2Cl2, reflux
Trace
30
Na2HPO4, CHCl3, reflux
bIsolated yield
123

Y. Pourshojaei et al.
This innovation in the synthesis of different kinds of potentially interesting
biologically active heterocycles which were obtained by the exchange of two
starting materials may attract the attention of pharmacologists and pharmacists in
the future, especially when these products show important biological and
pharmacological activities. It is believed that these compounds will be biologically
active because there is strong evidence that their analogues are biologically active
[35–38].
It is believed that demonstrating the biological and pharmacological activities of
these compounds is appropriate because there are proven biologically active
fragments in their chemical structures.
Investigation of reaction mechanism
An admissible mechanism for the synthesis of phenyl-substituted pyranocoumarins
is given in Scheme 2. In this proposed pathway, in a first step, malononitrile (2) and
aldehyde (3) are reacted together in the presence of MoO3 NPs to give intermediate
(7). In the next step, 4-hydroxycoumarin is attacked to (7) and followed by an enol-
keto tautomerization, Intermediate (8) is formed. Finally, (8) is converted to product
(4) by the attack of enolic OH to the nitrile group via an intramolecular cyclization
procedure. It can be obviously seen from the reaction mechanism that MoO3 NPs
play a key role in the activation of reactants to interact with each other in all the
steps that subsequently lead to accelerating the reaction progress.
In addition, before adding 4-hydroxycoumarin to the reaction mixture, interme-
diate (7e) was separated as the sole material and successfully characterized by FT-
IR, 1H NMR, 13C NMR and elemental analysis (see representative spectral data and
supplementary materials: Figs. S27, S28). This observation strongly confirms the
above proposed reaction mechanism.
Investigation of catalyst recycling
In the other investigation, as one of the noteworthy aspects of this methodology is
the capability of catalyst to be reused which makes it industrially and economically
important, the recyclability of MoO3 NPs was also evaluated on a model reaction
(Fig. 7). This investigation reveals that MoO3 NPs can efficiently catalyze the
reaction up to six times without remarkable loss of its activity.
In addition, the BET method was applied to identify the specific surface area
(SBET) of the catalyst before the first and after the sixth runs, respectively
(Supplementary materials, Figs S30, S31). The BET analysis ofthe catalyst before
the first run showed a specific surface area of 47 m2 g-1. Also, this analysis of the
specific surface area of the catalyst after the sixth run was 41 m2 g-1. Therefore, the
results from the BET analyses revealed that there is no significant decline in the
surface area of the catalyst before and after use, which results are completely
compatible with those obtained from the reusability of catalyst. Furthermore, the
TEM image and XRD pattern of the catalyst after use clearly demonstrated that no
remarkable agglomeration or changes in the crystalline phase have occurred over
each run (Supplementary materials, Figs S32, S33). From both these observations, it
123

An eco-friendly synthesis of 4-aryl-substituted pyrano…
Table 2 Investigations of the scope of substrates to the synthesis of 4-phenyl-substituted pyrano-fuzed
coumarinsa
Entry Product
Time
(min)
Yieldb
(%)
M.P. (lit.)
191–193c
1
45
50
50
88
87
88
4a
2
185–186c
4b
3
170–173c
4c
4
5
6
40
40
40
93
90
92
249–250c
246–248c
223–225c
4d
4e
4f
123

Y. Pourshojaei et al.
Table 2 continued
Entry Product
Time
(min)
Yieldb
(%)
M.P. (lit.)
7
30
90
260–262
(261–263) [65]
4g
8
35
88
259–260
(258–260) [65]
4h
9
30
90
253–256
(257–259) [65]
4i
10
30
95
251–254
(250–252) [65]
4j
11
30
91
247–249 (248–249)
[66]
4k
12
45
89
269–270 (266–267)
[67]
4l
13
30
93
273–275 (274–275)
[66]
4m
123

An eco-friendly synthesis of 4-aryl-substituted pyrano…
Table 2 continued
Entry Product
Time
(min)
Yieldb
(%)
M.P. (lit.)
14
30
95
256–257 (255–257)
[66]
4n
4o
15
30
91
264–265
(265–267) [65]
aReaction conditions: 4-hydroxycoumarin 1 (1 mmol), malononitrile 2 (1.5 mmol), appropriate aldehyde
3 (1 mmol), MoO3 NPs (5 mol%), EtOH/H2O (4:1) at 80 °C
bIsolated yield
cNovel compound
can be better understood that reuse of MoO3 NPs over six successive runs furnished
(4g) in comparable yields to that obtained with a freshly prepared catalyst.
Conclusion
In summary, a green nanocatalytic approach for the synthesis of newly prepared
potentially interesting and biologically active heterocycles has been described by
the use of MoO3 NPs as a highly efficient nano-catalyst, and in addition the scope of
potentially biologically active heterocycles was developed. By this procedure, some
novel products were obtained which can be candidates for medicinally important
compounds or even important drugs in the future. It is believed that this
methodology will attract the interest of chemists, biologists and pharmacologists
in the future. Also, a new application of MoO3 NPs as an eco-friendly, highly
efficient, recyclable, and easily handled nano-catalyst for the synthesis of
heterocyclic compounds has been introduced. The merit of this protocol is the
synthesis of new kinds of organic compounds by the use of an efficient nano-Lewis
acid catalyst and environmentally benign conditions with good to excellent yields.
123

Y. Pourshojaei et al.
Scheme 2 A proposed mechanism for the catalytic synthesis of product (4) by MoO3 NPs
Fig. 7 Reusability of MoO3 NPs over six runs
123

An eco-friendly synthesis of 4-aryl-substituted pyrano…
Acknowledgement The authors gratefully thank the Pharmaceutics Research Center, Institute of
Neuropharmacology and Research Central Labratory, Kerman University of Medical Sciences for
supporting this work.
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