Heteropolyacid@creatin-halloysite clay: an environmentally friendly, reusable and heterogeneous catalyst for the synthesis of benzopyranopyrimidines

Article abstract of DOI:10.1007/s11164-017-3016-2

A novel hybrid catalyst has been designed and synthesized based on the incorporation of heteropolyacid into creatin-functionalized halloysite clay. The catalyst was characterized by using SEM/EDS, FTIR, XRD, BET, ICP-AES, TGA and DTGA, and successfully applied for promoting the synthesis of two series of benzopyranopyrimidines under ultrasonic irradiation in aqueous media. The results established the efficiency of this protocol in terms of product yield, reaction time and the eco-friendly nature of the process. Moreover, immobilization of heteropolyacid on creatin-functionalized halloysite circumvents heteropolyacid leaching and rendered the catalyst highly reusable.

Full text of DOI:10.1007/s11164-017-3016-2

Res Chem Intermed
DOI 10.1007/s11164-017-3016-2
Heteropolyacid@creatin-halloysite clay:
an environmentally friendly, reusable
and heterogeneous catalyst for the synthesis
of benzopyranopyrimidines
Samahe Sadjadi1
Majid M. Heravi2 Masoumeh Malmir2
•
•
Received: 4 April 2017 / Accepted: 19 June 2017
Ó Springer Science+Business Media B.V. 2017
Abstract A novel hybrid catalyst has been designed and synthesized based on the
incorporation of heteropolyacid into creatin-functionalized halloysite clay. The
catalyst was characterized by using SEM/EDS, FTIR, XRD, BET, ICP-AES, TGA
and DTGA, and successfully applied for promoting the synthesis of two series of
benzopyranopyrimidines under ultrasonic irradiation in aqueous media. The results
established the efficiency of this protocol in terms of product yield, reaction time
and the eco-friendly nature of the process. Moreover, immobilization of
heteropolyacid on creatin-functionalized halloysite circumvents heteropolyacid
leaching and rendered the catalyst highly reusable.
Keywords Halloysite clay Á Heterogeneous catalyst Á Ultrasonic irradiation Á
Benzopyranopyrimidines Á Heteropolyacids Á Reusable catalyst
Introduction
The investigation of multi-component reactions (MCRs) is a cheering and hot topic
in organic chemistry. Using MCRs in the synthesis of heterocyclic molecules and
drug discovery benefits from various advantageous such as high efficiency,
simplicity, atom economic nature and short reaction times [1]. Fused pyrimidines
&
&
1
Samahe Sadjadi
samahesadjadi@yahoo.com
Majid M. Heravi
mmh1331@yahoo.com
Gas Conversion Department, Faculty of Petrochemicals, Iran Polymer and Petrochemical
Institute, PO Box 14975-112, Tehran, Iran
2
Department of Chemistry, School of Science, Alzahra University,
PO Box 1993891176, Vanak, Tehran, Iran
123

S. Sadjadi et al.
and benzopyranopyrimidines are biologically attractive heterocycles with pharma-
cological activity [2]. Some benzopyranopyrimidines are recognized as important
pharmacophores that display in vivo antitumor activity and cytotoxic activity
against cancer cell lines [3]. Owing to the wide applications of benzopyranopy-
rimidines, the development of new approaches for the synthesis of these valuable
scaffolds is an attractive topic of current research in many laboratories [4–7].
Although various protocols have been reported for the synthesis of this class of
heterocycles, very many of them suffer from some drawbacks such as high
temperature, long reaction times, low yields and the use of toxic organic solvents,
reagents and catalysts. Therefore, the development of new strategies and the
exploitation of eco-friendly and heterogeneous catalysts to cleanly and quickly build
this type of heterocyclic compounds is imperative.
Heteropolyacids (HPAs) and their salts are nontoxic catalytic species which
consist of cations and polyanion clusters. These catalysts have received increasing
attention due to their outstanding features such as high thermal stability, non-
corrosive entity, and sensitivity to electricity and light [8]. Of note, HPAs can be
considered as bifunctional catalysts which possess both strong Bronsted acidity and
redox potentiality. HPAs can not only be used as classic catalysts for promoting
various organic transformations [9], such as Friedel–Crafts acylation and alkylation
[10], ring opening reactions, etc. [11], but have also proved to be promising
photocatalysts [12] for the degradation of hazardous chemicals and electro-catalysts
[13]. Moreover, HPAs have been wildly used for developing hybrid catalytic
systems. Despite all the excellent properties of HPAs, their solubility in water and
most organic solvents, as well as their low surface area, renders them homogeneous
and hampers their recovery and reuse, thus restricting their industrial applications.
To furnish a solution to these drawbacks, HPAs can be immobilized on
heterogeneous supports such as clays [14, 15].
Halloysite nanotubes (HNTs), a hydrated layered aluminosilicate of the kaolinite
group, can be found in nature and possess the general formula of (Al2(OH)4Si2-
O5Á2H2O) [16, 17]. The length of HNTs range from about 100 nm to 4000 nm, with
an average of about 1200 nm [18]. The compositions of the interior and exterior
surfaces of HNTs are different. The Al–OH octahedral sheets are located in the
HNTs’ inner surface, whereas the siloxanes are placed in the external surface. A
monolayer of water molecules separates the unit layers of HNTs. This class of clays
has gained particular interest in various research fields, such as catalysis [19, 20],
materials science, drug delivery [20], photo-degradation [17], water treatment [21],
optical, magnetic and electrical applications [20], membranes for gas separation
[22] and enzyme immobilization, due to their properties such as biocompatibility,
high surface area, availability, mechanical strength, capacity of cation exchange and
porous structure. Another interesting feature of HNTs is their capability of
functionalization of their both surfaces [23] and the incorporation of various active
species such as nanoparticles [24, 25].
In continuation of our efforts [26–32] for developing efficient heterogeneous
catalysts for promoting organic transformations, heterogenation of HPA via its
immobilization on creatin-functionalized HNTs is reported here. The catalytic
activity of the obtained catalyst, HPA@HNTs-C, was studied for the synthesis of
123

Heteropolyacid@creatin-halloysite clay: an…
two series of benzopyranopyrimidines from the reaction of aldehydes, urea/thiourea
and 4-hydroxycoumarin (method a) and the reaction of 2-hydroxy benzaldehydes,
malononitrile and amine (method b). The reactions were performed under eco-
friendly reaction conditions, i.e. ultrasonic irradiation in aqueous media.
Experimental
Chemicals and apparatus
All chemicals, including halloysite nanoclay, (3-chloropropyl) trimethoxysilan,
creatin, phosphomolybdic acid, 4-hydroxy coumarine, malononitrile, aldehydes,
amines, urea, thiourea, toluene, acetonitrile, and ethanol, were purchased from
Sigma Aldrich and used without further purification. The synthesized catalyst was
characterized by various techniques including FTIR, SEM/EDX, TGA, DTGA,
XRD and ICP-AES. FTIR spectra were obtained by using a Perkin-Elmer Spectrum
65 instrument. SEM/EDS images as well as elemental mapping were recorded by
employing a Tescan instrument, using Au-coated samples and an acceleration
voltage of 20 kV. Room-temperature powder X-ray diffraction patterns were
collected using a Siemens D5000. CuKa radiation was used from a sealed tube. The
BET analyses were performed using a Belsorp Mini II instrument. Prior to BET
analyses, the samples were degassed at 423 K for 3 h. All the synthesized
heterocycles were known and identified by comparing their melting points
(measured by using the capillary tube method with an electrothermal 9200
apparatus) and FTIR spectra with authentic samples. For some samples, 13CNMR
1
and HNMR were also obtained to prove the formation of the final products.
Cl-Functionalization of HNTs: synthesis of HNTs-Cl
To introduce Cl functionality on HNTs, 1.2 g HNTs was added to a solution of
4 mL (3-chloropropyl) trimethoxysilan in 50 mL dry toluene. The resulting mixture
was subjected to ultrasonic irradiation at 200 W for 0.5 h and then refluxed at
110 °C for 24 h. Upon completion of the process, the precipitate was filtered off and
washed repeatedly with dried toluene and dried at 100 °C overnight.
Conjugation of creatin to HNTs-Cl: synthesis of HNTs-C
To a suspension of HNTs-Cl (1 g) in 60 mL of dried toluene, creatin (0.5 g) was
added. The obtained mixture was then refluxed overnight. At the end of the reaction,
the solid was filtered, washed with dry toluene (20 mL) for several times and dried
at 100 °C in an oven overnight.
Immobilization of HPA on HNTs-C: synthesis of HPA@HNTs-C
Incorporation of phosphomolybdic acid on HNTs-C was achieved via the incipient
wetness impregnation method. Typically, a solution of H3PMo12O40 20% w/w
123

S. Sadjadi et al.
(0.2 g of HPA in 10 mL of acetonitrile) was dropwise added to a suspension of the
HNTs-C (1 g) in acetonitrile (25 mL). The resulting mixture was stirred vigorously
at room temperature overnight. Subsequently, the obtained precipitate was filtered,
washed with acetonitrile (20 mL) and dried in an oven at 90 °C overnight. The
schematic synthesis of the catalyst is depicted in Scheme 1.
Synthesis of benzopyranopyrimidines via two methods of a and b
Method a
A mixture of aldehydes (1 mmol), urea/thiourea (1 mmol), 4-hydroxycoumarin
(1 mmol) and catalyst (0.03 g) in 10 mL water was subjected to ultrasonic
irradiation at room temperature for the appropriate reaction time. Upon completion
of the reaction as monitored by TLC, the mixture was cooled to room temperature
and the solid catalyst was separated by filtration, washed with H2O/EtOH (1:1)
(20 mL) and dried at 90 °C overnight for reusing in consecutive reaction runs. The
white solution was recrystallized from hot EtOH to afford the pure product.
Method b
Another series of benzopyranopyrimidines was also synthesized from the reaction of
2-hydroxybenzaldehydes (2 mmol), malononitrile (1 mmol) and amines (1 mmol)
in the presence of the catalyst (0.03 g) through a procedure similar to method a
(Scheme 2).
O
Si
(MeO)3
Cl
O
Si
Si
Cl
Cl
OH
OH
OH
O
Toluene
ultrasound, 30 min
O
O
O
OH
OH
OH
heated, reflux, overnight
washed by Toluene
dried, overnight
O
H2N
N
OH
HNTs
O
NH
NH
OH
O
Si
N
N
O
Toluene
H
O
overnight
heated, reflux
H3PMo12O40
washed by Toluene
NH
H3PMo12O40/CH3CN
Et3N, dropwise
O
OH
OH
O
Si
Si
N
H
NH N
N
O
O
O
O
O
N
H
O
overnight
r.t., stirrered
Scheme 1 Synthesis of HPA@HNTs-C as catalyst
123

Heteropolyacid@creatin-halloysite clay: an…
Scheme 2 Synthesis of benzopyranopyrimidine by two different methods a (blue line) and b (pink lime).
(Color figure online)
Spectral data from some of the compounds
3,4-Dihydro-4-phenyl-1H-chromeno [4,3-d] pyrimidine-2,5-dione (4a)
White solid, m.p. 160–162 °C; IR: (KBr) (m cm-1) = 3409, 2920, 2730, 2365,
1
1648, 1450, 1354, 1300, 1120, 1068, 972, 722; H-NMR (DMSO): d(ppm) 6.35 (s,
1H, CH), 7.10–7.55 (m, 9H, Ar–H), 7.75 (brs, 1H, NH), 7.85 (brs, 1H, NH).
4-(4-Chlorophenyl)-3,4-dihydro-1H-chromeno [4, 3-d] pyrimidine-2, 5-dione (4b)
White solid, m.p. 162–164 °C; IR: (KBr) (m cm-1) = 3400, 3075, 2888, 2825,
2730, 2610, 1659, 1604, 1556, 1490, 1446, 1343, 1309, 1217, 1086, 1034, 1010,
1
760, 671; H-NMR (DMSO): d(ppm) 6.34 (s, 1H, CH), 7.28–7.66 (m, 8H, ArH),
7.89 (brs, 1H, NH), 7.95 (brs, 1H, NH).
1,2,3,4-Tetrahydro-4-(2-hydroxyphenyl)-2-thioxochromeno[4, 3-d]pyrimidin-5-one
(4g)
Pale yellow, m.p. 169–171 °C; IR: (KBr) (m cm-1) = 3413, 3067, 2360, 1748,
1600, 1475, 1441, 1380, 1336, 1240, 1262, 1021, 940, 870, 760, 465. H-NMR
1
(300 MHz, DMSO): d(ppm) 3.35 (brs, 1H, OH), 6.9–7.76 (m, 9H, Ar–H), 8.40 (brs,
1H, NH), 10.75 (brs, 1H, NH).
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S. Sadjadi et al.
2-(4-Morpholino-5H-chromeno[2,3-d]pyrimidin-2-yl)phenol (8a)
White powder, m.p. 160–162 °C; IR: (KBr) (m cm-1) = 3449, 3098, 2990,
1605.1H-NMR (400 MHz, CDCl3): d (ppm) 3.51 (t, J = 4.5 Hz, 4H), 3.89 (t,
J = 4.5 Hz, 4H), 3.90 (s, 2H), 6.96 (t, J = 8.0 Hz, 1H), 6.99 (d, J = 8.0 Hz, 1H),
7.11 (t, J = 7.3 Hz, 1H), 7.20–7.32 (m, 3H), 7.38 (t, J = 7.3 Hz, 1H), 8.40 (d,
J = 8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3): d (ppm) 25, 48.9, 66.2, 96.6, 115.5,
115.4, 118.5, 118.7, 118.9, 124, 128, 128.2, 129.5, 133.7, 149.2, 161.2, 161.9, 163,
164.7 ppm.
2-Methoxy-6-(9-methoxy-4-morpholino-5H-chromeno[2,3-d]pyrimidin-2-yl)phenol
(8b)
White powder, m.p. 162–164 °C; IR: (KBr) (m cm-1) = 3444, 3043, 2950, 1600.
1H-NMR (400 MHz, CDCl3): d (ppm) 3.45 (t, J = 4.4 Hz, 4H), 3.90 (t,
J = 4.4 Hz, 4H) 3.94 (s, 8H), 6.70 (d, J = 7.7 Hz, 1H), 6.80–6.90 (m, 2H), 6.91
(d, J = 7.7 Hz, 1H), 6.99 (t, J = 8.0 Hz, 1H), 8.07 (d, J = 8.0 Hz, 1H). 13C-NMR
(100 MHz, CDCl3): d (ppm) 25.1, 48.7, 55.9, 55.91, 66.43, 97.6, 111.5, 113.5, 118,
118.4, 119.6, 119.9, 121, 124.5, 139.7, 148, 148.5, 150.9, 162.5, 165.3.
2-Methoxy-6-(9-methoxy-4-(piperidin-1-yl)-5H-benzopyrano[2,3-d]pyrimidin-2-
yl)phenol (8e)
White powder, m.p. 181–183 °C; IR: (KBr) (m cm-1) = 3415, 3044, 2926,
1604;1H-NMR (400 MHz, CDCl3): d (ppm) 1.65–1.81 (m, 6H), 3.45 (t,
J = 4.9 Hz, 4H), 3.76 (s, 2H), 3.95 (s, 6H), 6.80 (d, J = 7.7 Hz, 1H), 6.85–6.91
(m, 2H), 6.95 (d, J = 7.7 Hz, 1H), 7.06 (t, J = 8.0 Hz, 1H), 8.12 (d, J = 8.0 Hz,
1H). 13C-NMR (100 MHz, CDCl3): d (ppm) 24.5, 25.6, 27.7, 50.3, 55.7, 55.9, 99.6,
110.1, 114.7, 118.2, 118.5, 120.1, 120.2, 120.8, 124, 138.9, 146.7, 149, 150.2,
162.3, 165.1, 166.4.
Results and discussion
Characterizations of catalyst
The SEM/EDX images of the HPA@HNTs-C are depicted in Fig. 1. As can be seen,
upon functionalization of the HNTs with creatin and incorporation of HPA, the
morphology of the HNTs changed to a more aggregate one. According to previous
reports [19], this observation can be attributed to the presence of organic
functionalities which can anchor the HPA and keep the HNTs nano-rods more
packed. Notably, in the SEM images of the HPA@HNTs-C, the rod-like
morphology is still observable, indicating that upon functionalization the tubular
morphology of the HNTs did not collapse. This observation was also confirmed via
XRD analysis. The EDX analysis of the catalyst established the presence of Si, Al
and O atoms which can be attributed to the HNTs framework. Moreover, the C, O
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Heteropolyacid@creatin-halloysite clay: an…
Fig. 1 The SEM/EDX images of HPA@HNTs-C (a) and SEM image of pure HNTs (b) [11, 19]
123

S. Sadjadi et al.
and N atoms can demonstrate the successful conjugation of creatin to the HNTs.
The Mo and P atoms represent the presence of HPA in the structure of the final
catalyst.
The FTIR spectrum of the catalyst is illustrated in Fig. 2. The spectrum contains
the characteristic bands of HNTs, i.e. 3705 and 3631 cm-1, which can be assigned
to internal and external hydroxyl groups of HNT. According to the literature, the
deformation vibration of Al–O–Si at 528 cm-1 is due to Al–O tetrahedral sheets and
the Si–O–Si deformation vibration at 458 cm-1 can be assigned to Si–O tetrahedral
sheets [33].
The bands at 3093 and 1047 cm-1, which are representative of –CH2 stretching
and Si–O stretching, can prove the successful attachment of (3-chloro-
propyl)trimethoxysilan. The bands at 1679, 1699 and 3274 cm-1, which are due
to the stretching vibration of C = N, C = O and –NH2, establish the presence of
creatin in the structure of the catalyst. Moreover, the bands at 1047, 810, 609, and
916 cm-1 can be assigned to the symmetric stretching of P–O, Mo–Oc–Mo, Mo–
Oe–Mo and Mo–Ot, respectively, and prove the HPA incorporation [34]. The FTIR
spectrum of the catalyst is distinguished from the pure HNTs [35], in which no
characteristic band can be observed for C = N, C = O, –CH2 stretching.
The XRD pattern of the catalyst and pure HNTs are shown in Fig. 3. The
reflections observed at 7.53°, 13.74°, 23.44°, 28.78°, 32.48°, 58.94° and 67.18° can
be assigned to HNTs (JCPDS No. 29-1487). This pattern is in good accordance with
the XRD patterns, reported for HNTs in the literature [36, 37]. Comparing these two
XRD patterns clearly establishes their similarity. This observation indicated that,
upon HNTs functionalization and HPA incorporation, the tubular structure of HNTs
did not collapse. Notably, the interlayer distance of the HPA@HNTs-C remained
unchanged compared to pure HNTs, implying that the incorporation of the creatin
and HPA did not take place between the interlayer of the HNTs. This result is in
good accordance with previous reports [37]. All the observed peaks can be assigned
to HNTs and no distinguished peak was detected for the HPA. According to the
Fig. 2 FTIR spectra of pure HNTs and HPA@HNTs-C [26, 35]
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Heteropolyacid@creatin-halloysite clay: an…
Fig. 3 XRD pattern of pure HNTs and HPA@HNTs-C
previous reports, this can be due to the low amount of HPA as well as its high
dispersion on the functionalized HNTs [34].
To provide more insight into the catalyst structure, DTGA and TGA thermo-
grams of the catalyst were obtained (Fig. 4). As shown, two degradation stages can
be detected over the range of 45–600 °C. The first degradation can be due to the loss
of adsorbed water molecules. The other observed weight losses (at about 480 °C)
can be assigned to the thermal decomposition of other components. Notably, the
TGA thermogram of the HPA@HNTs-C is totally distinguished from pure HNTs
[38, 39], in which one degradation step occurred in the range of 45–600 °C due to
loss of lattice water. TGA analysis was also exploited for calculating the content of
the organic motif of the catalyst. This value was about 16 w/w%.
To calculate the content of HPA in the final catalyst, the HPA was digested in
concentrated hydrochloric and nitric acids solution. Then, the resulting extract was
Fig. 4 The TGA (a) and DTGA (b) analysis of HPA@HNTs-C
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S. Sadjadi et al.
analyzed using ICP-AES. The result showed that the loading of HPA was about
6 w%.
A nitrogen adsorption–desorption isotherm of the final catalyst was also recorded
to investigate the textural properties of HPA@HNTs-C (Fig. 5). The shape of the
isotherm is indicative of the type II nitrogen adsorption–desorption isotherms with
H3 hysteresis loops [37], and demonstrated that HPA@HNTs-C possesses thae
porous structure. To elucidate whether the HNTs functionalization and incorpora-
tion of HPA affect the textural properties of the pure HNTs, the average pore
diameter, specific surface area and total pore volume of the HNTs and
HPA@HNTs-C were compared (Table 1). The results indicate that incorporation
of creatin and HPA reduced the specific surface area and pore volume while
increasing the average pore diameter. This observation can imply that functional-
ization and immobilization of HPA can occur both on the surface and within the
cavity of the HNTs.
Catalytic activity of HPA@HNTs-C catalyst for the synthesis
of benzopyranopyrimidines
To investigate the catalytic activity of the catalyst, the synthesis of two series of
benzopyranopyrimidines (Schemes 3, 4) which are biologically attractive were
selected as model organic transformations.
Initially, the reaction of 4-hydroxycumarine, benzaldehyde and urea and the
reaction of 2-hydroxybenzaldehyde, morpholine and malononitrile were selected as
the model reactions and performed in the absence of the catalyst. The results
established that the presence of the catalyst was essential for promoting the reaction
(Figs. 5, 6). Subsequently, the model reactions were performed in the presence of a
Fig. 5 Nitrogen adsorption–desorption isotherms of HPA@HNTs-C
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Heteropolyacid@creatin-halloysite clay: an…
Table 1 The BET surface area of the catalyst and pure HNTs
Sample
SBET (m2 g-1
)
Total pore volume (cm3 g-1
)
Average pore diameter (nm)
HPA@HNTs-C
HNTs
16.5
51
0.11
0.19
27.29
15.23
X
OH
HN
O
NH
O
O
H
X
R1
Catlyst (0.03 g)
Water/r.t./200 W
H2N
NH2
R1
O
O
1a
R1 (2a-e); aryl
(3a,b); N,O
Entreis (4a-j)
Scheme 3 Synthesis of benzopyranopyrimidines using 4-hydroxycoumarine under ultrasonic irradiation
R4
R3
N
OH
O
N
N
R2
H
N
H
OH
Catalyst (0.03 g)
Water/r.t./200 W
R3
R4
NC
CN
R2
R2 (5a-c)
Scheme 4 Synthesis of benzopyranopyrimidines using salicylaldehydes under ultrasonic irradiation
O
R2
R3, R4 (6a-c)
7
Entreis (8a-i)
Fig. 6 Effects of loading of catalyst, duration of reaction and solvent on the yield of
benzopyranopyrimidines prepared from reaction of 4-hydroxycumarine (1 equiv.), benzaldehyde
(1 equiv.) and urea (1 equiv.)
123

S. Sadjadi et al.
catalytic amount (0.01 g) of the catalyst in aqueous media under ultrasonic
irradiation. Gratifyingly, the desired products were obtained under eco-friendly
conditions after relatively short reaction times (Figs. 6, 7).
Motivated by these results, the reaction variables, the solvent, the amount of the
catalyst and the power of the ultrasonic, were optimized (Figs. 6, 7). The highest
yields were obtained by using the power of 200 W in the presence of 0.03 g catalyst
in water.
Armed with the optimum reaction variables, two series of benzopyranopyrim-
idines were synthesized by using various aldehydes and amines to demonstrate the
generality of the protocols. Moreover, the thio-functionlized derivatives were
achieved by replacing urea with thiourea.
As is clear, aldehydes with electron-withdrawing and electron-donating groups
could be successfully used in method a (Table 2) to furnish the desired products in
high yields and in very short reaction times. Of note, both urea and thiourea resulted
in products in competitive yields. Regarding method b (Table 3), 2-hydroxyben-
zaldehydes with different electron densities could be applied. However, 2-hydrox-
ybenzaldehyde with electron-withdrawing groups led to corresponding products
with slightly lower yields.
Based on the literature [7], the suggested mechanism for the synthesis of
benzopyranopyrimidines is demonstrated in Scheme 5. In the case of method b,
initially, the reaction starts via formation of a Knoevenagel adduct derived from
reaction of salicylaldehyde and malononitrile to form the intermediate I on the
acidic active surface of HPA@HNTs-C. Then, the cyano group of intermediate I is
attacked by the cyclic secondary amine to produce intermediate II. Finally,
intermediate II reacts with another molecule of salicylic aldehyde involving rapid
hydrogen ion transfers III to furnish benzopyrano[2,3-d]pyrimidine IV. Regarding
Fig. 7 Effects of loading of catalyst, duration of reaction and solvent on the yield of
benzopyranopyrimidines prepared from reaction of 2-hydroxybenzaldehyde 5a (2 equiv.), morpholine
6a (1 equiv.) and malononitrile (7) (1 equiv.)
123

Heteropolyacid@creatin-halloysite clay: an…
Table 2 Preparation of benzopyranopyrimidines (4a–j) from reaction of 4-hydroxycumarine, aldehyde
and urea/thiourea catalyzed by HPA@HNTs-Ca [4, 40]
Entry
R1
X
Time (min)
Yield (%)b
m.p. References
4a
4b
4c
4d
4e
4f
4g
a
2a:H
3a:O
3a
4
13
17
10
15
22
15
95
95
85
85
80
90
92
160–162 °C (Ref. [4] 160–162 °C)
162–164 °C (Ref. [31] 160–162 °C)
172–174 °C (Ref. [31] 172–174 °C)
188–190 °C (Ref. [4] 188–190 °C)
188–190 °C (Ref. [31] 188–190 °C)
185–187 °C (Ref. [31] 183–185 °C)
169–171 °C (Ref. [4] 170 °C)
2b:p-Cl
2c:m-NO2
2a
3a
3b:S
3b
2b
2c
3b
2d:o–OH
3b
Reaction condition: a mixture of 4-hydroxycumarine 1a (1 equiv.), aldehydes (2a–e; R1 = aryl)
(1 equiv.), urea/thiourea (3a, b) (1 equiv.) and HPA@HNTs-C (0.03 g) was reacted by ultrasonic irra-
diation (Method A)
b
Isolated yield
Table 3 Preparation of benzopyranopyrimidines (8a–h) from reaction of 2-hydroxybenzaldehyde,
amines and malononirtile catalyzed by HPA@HNTs-Ca [5, 41]
Entry R2
R3, R4
Time Yield m.p. References
(min) (%)b
8a
8b
8c
8d
8e
8f
8g
8h
a
5a:H
6a:–(CH2)2–O–(CH2)2– 40
95
90
80
85
83
78
92
80
160–162 °C (Ref. [5] 160–162 °C)
162–164 °C (Ref. [5] 160–162 °C)
198–200 °C (Ref. [29] 198–200 °C)
178–180 °C (Ref. [5] 178–180 °C)
181–183 °C (Ref. [5] 180–182 °C)
187–189 °C (Ref. [29] 188–190 °C)
178–180 °C (Ref. [5] 178–190 °C)
200–202 °C (Ref. [5] 200–202 °C)
5b:3-MeO 6a
30
70
60
50
70
60
40
5c:5-Br
5a
6a
6b:–(CH2)5–
5b
6b
5c
6b
5a
6c:CH3, CH3
5b
6c
Reaction condition: a mixture of 2-hydroxybenzaldehydes 5a (2 equiv.), amines 6a (1 equiv.),
malononitrile 7 (1 equiv.) and HPA@HNTs-C (0.03 g) was reacted by ultrasonic irradiation (Method A)
and heated (Method B) at 90 °C
b
Isolated yield
method a, based on the literature [4], it is believed that the salicylic aldehyde can be
activated by the catalyst (V). Subsequently, the reaction proceeds via a Knoevenagel
condensation to produce intermediate VI. Then, the latter tolerated the Michael
addition with 4-hydroxycumarine to generate intermediate VII. Finally, cyclization
of VII gives product VIII, after dehydration.
In order to demonstrate the efficiency of our protocol, the yields of two model
benzopyrano[2,3-d]pyrimidinesins (procedures a and b) under HPA@HNTs-C
catalysis was compared with those of previously reported procedures and catalysts
(Table 4). As shown in this table, the efficiency of HPA@HNTs-C in procedure b is
superior to silica-bonded N-propylpiperazine sodium N-propionat, ZrOCl2Á8H2O
123

S. Sadjadi et al.
Scheme 5
HPA@HNTs-C
A
plausible mechanism of synthesis of benzopyranopyrimidine in the presence of
and Na2MoO4Á2H2O. Moreover, compared to conventional thermal methods, this
catalyst could furnish the desired product in a shorter reaction time and more eco-
friendly procedure. Regarding procedure a, the previously reported procedures and
catalysts led to comparative yields in less than 5 min. However, HPA@HNTs-C
benefits from some advantages such as being a heterogeneous, non-corrosive and
non-toxic entity.
To investigate the catalyst reusability, the model reactions were performed in the
presence of the fresh and reused catalysts. The comparison of the yields of the
desired products (Fig. 8) established that the catalyst could be recovered and reused
with only slight loss of the catalytic activity. This promising result motivated us to
study the HPA leaching to disclose whether the catalysis is heterogeneous. To this
purpose, a hot filtration test was used and established only a negligible loss of HPA,
detected by ICP-AES. This result not only proved the heterogeneous catalysis but
also confirmed the efficient immobilization of HPA on functionalized HNTs. The
low leaching of the HPA can be attributed to the interaction of HPA with the
heteroatoms present in creatin. It is postulated that these interactions preserved the
HPA on the HNTs surface and control the HPA leaching. To elucidate whether these
interactions are responsible for low leaching of HPA, HPA was immobilized on
pure HNTs, HPA@HNTs, via a simple incipient wetness impregnation method
(‘‘Immobilization of HPA on HNTs-C: synthesis of HPA@HNTs-C’’ section).
Subsequently, the content of the HPA on the catalyst was calculated by the ICP-
AES method. Interestingly, the loading of the HPA on the pure HNTs was
remarkably lower (1 w/w%) than that of the creatin-functionalized HNTs (6 w/
w%). This result indicated the role of creatin functionality in efficient immobiliza-
tion of HPA on the HNTs surface. Notably, the catalytic activity of HPA@HNTs-C
was higher than HPA@HNTs which can be related to the higher content of HPA.
123

Heteropolyacid@creatin-halloysite clay: an…
Table 4 Comparison of the efficiencies of various protocols for the synthesis of benzopyrano[2,3-
d]pyrimidinea,b [4–6, 41, 42]
Entry Catalyst (amount)
Reaction conditions Yield (%) Time
(h:min)
References
[4]
1a
2a
3b
Chlorosulfonic acid (2.5 mol%)
Hydrochloric acid (4 drops)
Ultrasonic/r.t./S.F.
Microwave/EtOH
96
94
86
00:05
00:02.6 [6]
Silica-bonded N-propylpiperazine Thermal/r.t./S.F.
sodium N-propionat (0.05 g)
6:00
[30]
4b
5b
6a
7b
a
ZrOCl2Á8H2O (30 mol%)
Na2MoO4Á2H2O (10 mol%)
HPA@HNTs-C (0.03 g)
HPA@HNTs-C (0.03 g)
Thermal/r.t./S.F.
90
90
95
95
15:00
10:00
00:04
00:40
[29]
Thermal/r.t./EtOH
Ultrasonic/r.t./H2O
Ultrasonic/r.t./H2O
[5]
[This work]
[This work]
Reaction condition: a mixture of 4-hydroxycumarine (1 equiv.), benzaldehyde (1 equiv.), urea
(1 equiv.) was reacted by ultrasonic or microwave irradiation
b
Reaction condition: a mixture of 2-hydroxybenzaldehyde (2 equiv.), malonitrile (1 equiv.), morpholine
(1 equiv.) was reacted by ultrasonic irradiation or heated
Fig. 8 The results of studying the reusability of the catalyst for the synthesis of benzopyranopyrimidine
by two different methods a and b
Moreover, studying the reusability of the HPA@HNTs established its inferior
reusability compared to HPA@HNTs-C which implied the necessity of creatin for
preserving HPA on the HNTs surface.
Conclusions
In summary, a novel method for the heterogenization of HPA via immobilization on
the creatin-functionalized HNTs is presented. The hybrid system was successfully
applied for promoting the synthesis of biologically attractive benzopyranopyrim-
idines under eco-friendly ultrasonic-assisted procedure. The hot filtration method
established the efficiency of this hybrid system for controlling the HPA leaching and
developing a heterogeneous and reusable catalyst. Compared to the previously
reported methods for the synthesis of benzopyranopyrimidines, the presented
123

S. Sadjadi et al.
protocol benefits from advantages such as short reaction time, high yields, excellent
reusability and simplicity of the work-up procedure.
Acknowledgements The authors appreciate partial financial supports from Alzahra University and Iran
Polymer and Petrochemical Institute. MMH is also grateful to Iran National Science Foundation for the
Individual given grant.
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