Nickel NPs @N-doped titania: an efficient and recyclable heterogeneous nanocatalytic system for one-pot synthesis of pyrano[2,3-d]pyrimidines and 1,8-dioxo-octahydroxanthenes

Article abstract of DOI:10.1007/s13738-019-01669-4

Abstract: Catalysis holds a very important and promising place in chemical industry. In a typical chemical transformation, the use of a catalyst reduces the reagent-based waste and enhances the reaction selectivity, thereby minimizing the chances of getti

Full text of DOI:10.1007/s13738-019-01669-4

Journal of the Iranian Chemical Society
https://doi.org/10.1007/s13738-019-01669-4
ORIGINAL PAPER
Nickel NPs @N‑doped titania: an efcient and recyclable
heterogeneous nanocatalytic system ꢀor one‑pot synthesis
oꢀ pyrano[2,3‑d]pyrimidines and 1,8‑dioxo‑octahydroxanthenes
Yogayta Rajinder · Monika Gupta1 · Jaspreet Kour1
1
Received: 7 December 2018 / Accepted: 5 April 2019
©
Iranian Chemical Society 2019
Abstract
Catalysis holds a very important and promising place in chemical industry. In a typical chemical transformation, the use of
a catalyst reduces the reagent-based waste and enhances the reaction selectivity, thereby minimizing the chances of getting
any side product. In the recent years, the introduction of nanotechnology in the ꢀeld of catalysis has further revolutionized
it. It is the extremely small size, shape and remarkably large surface-area-to-volume ratio which sets apart a nanocatalyst
from its ordinary bulk form and imparts it unique catalytic properties. In the present work, we report the application of
heterogeneous nickel nanoparticles in the synthesis of some biologically important heterocyclic compounds. In brief, we
doped titania nanostructures with nitrogen and then used them as a support material for immobilizing nickel nanoparticles
onto them. The nanoparticles of nickel were prepared by the chemical reduction of nickel acetate. The catalyst thus prepared,
i.e., nickel nanoparticles loaded over nitrogen-doped titania (nickel NPs @N-doped TiO ), was then explored for its catalytic
2
activity toward the synthesis of pyrano[2,3-d]pyrimidines and 1,8-dioxo-octahydroxanthenes. The surface and the elemental
composition of the catalyst was studied by SEM–EDX analysis. TEM analysis was done to study the internal morphology
and the size of the nanostructures formed. The other studies included TGA, FTIR and XPS which gave information regarding
thermal stability, presence of nitrogen in the titania framework and oxidation state of the nickel nanoparticles, respectively.
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s13738-019-01669-4) contains
supplementary material, which is available to authorized users.
*
Monika Gupta
monika.gupta77@rediꢁmail.com
1
Department of Chemistry, University of Jammu,
Jammu 180006, India
Vol.:(0
1
123456789)
3

Journal of the Iranian Chemical Society
Graphical Abstract
Keywords Nickel · Nanoparticles · Catalysis · Recyclability · Doping · Pyrano[2,3-d]pyrimidines · 1,8-dioxo-
octahydroxanthenes
Introduction
One of the revolutionizing applications of nanotechnol-
ogy is in the ꢀeld of catalysis. Catalysis plays a key role in
the organic transformations and can be thought of as pillars
in diꢁerent chemical protocols, whether it is at industrial
level or in research laboratories at academic level [50]. If
there was no catalyst in chemistry, a good number of prod-
ucts that we come across in our daily life such as medicines,
polymers, ꢀbers, fuel and many more would not have been
there. Between homogeneous and heterogeneous catalysis,
the latter one is a blessing to a chemist due to its ease of
recoverability. Following the recent trend in nanocataly-
sis, immobilizing metal or metal oxide nanoparticles on a
modiꢀed support (alumina, titania, silica, clays, zirconia,
etc.) facilitates a highly active and easily separable catalytic
system that can be explored for its catalytic activity in a
number of organic synthesis. Due to their extremely small
size, nanoparticles have large surface area and thus increased
number of active sites. This increases the area that comes in
contact with the reactants and thus enhances the rate of the
reaction involved [34].
Nanotechnology refers to manipulation of matter on the
atomic and molecular level. When we say nanostructures,
it means structures of the size 100 nanometers or smaller.
The area of the practical implications of nanotechnology
is very wide and includes cosmetics, paints, medicines,
energy, environmental remediation, food industry and
much more [41]. Nanomaterials ꢀnd numerous applica-
tions owing to their unique physical, chemical and biologi-
cal properties such as more chemical reactivity, enhanced
strength and improved reꢂection and enhanced thermal
and electrical conduction [13]. The physical properties
of any system change substantially when its dimensions
get reduced from macroscale to nanoscale. This happens
because the surface area increases in comparison with the
volume as the material is miniaturized and also it is sub-
jected to quantum eꢁects. Such materials start behaving
in diꢁerent ways and no longer obey the laws of physics as
larger objects do. Scientists all over the world have fabri-
cated diꢁerent kinds of nanomaterials such as nanorods,
nanoꢀbers, nanobelts, nanoribbons, nanowires, nanotubes,
nanoparticles, quantum dots and hollow spheres which
possess at least one dimension ranging from 1 to 100 nm
Generally, transition metal and/or metal oxide nanopar-
ticles are used as catalytic systems in a chemical synthesis.
Akbari et al. [2] studied the role of diꢁerent transition metal
oxide nanoparticles in the oxidation and synthesis of dif-
ferent sulꢀdes, alcohols, ketones, epoxides and carboxylic
[
25].
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Journal of the Iranian Chemical Society
acids. Rawat et al. [46] used CuO nanoparticles for the syn-
performance. Diꢁerent methods are used to synthesize these
nanoparticles such as sputtering or mechanical dispersion of
bulk substances or chemical reduction of metal salts. However,
the most commonly used method is chemical reduction.
Along with the other compounds, pyrano[2,3-d]pyrimi-
dines and 1,8-dioxo-octahydroxanthenes represent an impor-
tant class of biologically important heterocyclic molecules.
A good number of bacterial strains such as Staphylococcus
aureus, Bacillus cereus, Escherichia coli, Klebsiella pneu-
monia, Pseudomonas aeruginosa (gram-positive as well
gram-negative) were evaluated against pyrano[2,3-d]pyrim-
idine-6-carboxylate, and it was found that these heterocyclic
moieties possessed antimicrobial activity [3]. In addition to
this, the derivatives of pyrano[2,3-d]pyrimidine have been
found to show antitumor [5], antifungal [15], antipyretic,
anti-inflammatory and gastroprotective [6], antioxidant
[44], antimalarial [11], antileishmanial [1], antiviral [48]
and anticonvulsant [42] activities. A great deal of research
has been dedicated to the xanthenes to explore their utility
in biological and pharmaceutical industry [28]. Research
has shown that the derivatives of 1,8-dioxo-octahydroxan-
thene possess anticancer [10], anti-inꢂammatory [36, 47],
antiplasmodial [52], antiviral and antibacterial [47] activi-
ties. Literature shows various protocols developed for the
synthesis of pyrano[2,3-d]pyrimidines [24, 37, 53, 55] and
1,8-dioxo-octahydroxanthenes ([14, 18, 31, 43], Waghamare
et al. 2018).
thesis of imidazo[1,2-a]pyrimidine derivatives. Kour et al.
[
30] synthesized gem-bisamides using silver nanoparticles
supported on modiꢀed TEOS (tetraethyl orthosilicate) xero-
gel. Ghatak et al. [19] immobilized nickel nanoparticles on
alumina and used them as stable catalyst for carrying out
homocoupling of benzylic halides in aqueous media to form
bibenzyls. Delgado et al. [12] immobilized cobalt nano-
particles on titania and tested them for their performance
toward Fischer–Tropsch synthesis. Hierro et al. [20] syn-
thesized a novel iron oxide nanoparticles which were sta-
bilized by ionic liquid silanes possessing choline hydrox-
ide and amino acid functionalities to prevent the magnetic
nanoparticles from clustering together. The catalytic system
thus prepared was used for carrying out Knoevenagel con-
densation between various aldehydes and active methylene
compounds. Kaboudin et al. [26] used gold nanoparticles
supported on amine-functionalized polystyrene as an eꢃ-
cient catalyst in the oxidation of alcohols in water. Elzab
et al. [17] reported the application of palladium nanoparti-
cles on copper oxide as an eꢃcient catalyst for carrying out
Suzuki cross-coupling reaction in aqueous medium. Tad-
2
−
jarodi et al. [51] reported titania nanoparticles (SO /TiO
4
2
NPs) which were prepared by using titanium tetraisopropox-
ide in the synthesis of polyhydroquinoline (PHQ) derivatives
via reaction of various aldehydes, ammonium acetate and
1,3-dicarbonyl compounds. Kalarivalappil et al. [27] synthe-
sized titania nanotubes and decorated them with Pd nano-
particles. The nanostructures thus formed were used as an
eꢃcient catalyst for the catalytic reduction of p-nitrophenol
to p-aminophenol.
This work presents the combined application of nanotech-
nology and heterogeneous catalysis to develop a novel nano-
catalytic system by immobilizing nickel nanoparticles pro-
duced by chemical reduction method onto nitrogen-doped
titania and establishing its role in the one-pot three-com-
ponent synthesis of pyrano[2,3-d]pyrimidines and one-pot
two-component synthesis of 1,8-dioxo-octahydroxanthenes.
Diꢁerent sources of nitrogen such as thiourea, triethylamine,
ammonia and hydrazine hydrate [9, 16] have been used for
doping titania. However, the use of barbituric acid as dopant
has been reported for the ꢀrst time only in our work. For the
characterization of the catalyst, studies such as SEM–EDX,
HR-TEM, TGA, FTIR and XPS were performed and the
reaction products thus obtained were conꢀrmed by spectro-
The main reason behind the catalytic activity of these nano-
particles is that transition metals can exhibit a variety of oxida-
tion states. The availability of d-orbitals and a good number
of valance electrons in them enable the transition elements to
form both σ- and π- bonds which is very important in forming
complexes with a variety of ligands [33]. Moreover, these pos-
sess the ability to shuꢄe between diꢁerent oxidation states and
hence can easily donate as well as accept electrons. Among
diꢁerent metal nanoparticles such as copper, iron, palladium,
nickel, platinum, silver, gold, etc., we focused on exploring
the catalytic importance of nickel nanoparticles in the synthe-
sis of some heterocyclic compounds. Owing to the previous
research work done on the nickel nanoparticles, it has been
established that these metallic nanoparticles can act as excep-
tionally good heterogeneous catalyst because they are cheap,
non-toxic, highly stable, easy to transport and easily recyclable
1
13
scopic techniques such as H NMR, C NMR and IR. One
of the advantages of our catalyst was that it was recyclable
up to ꢀve consecutive runs which made the whole process
cost-eꢁective and fall in the domain of green chemistry.
[
8]. However, literature does not have much reports on the
Experimental
role of nickel nanoparticles in catalysis although these have
been used to grow carbon nanotubes [35] and in a number of
other organic reactions [21, 22, 40, 49]. Also, it is quite dif-
Chemicals
ꢀ
cult to generate nanoparticles of nickel in zero oxidation state
Titania (TiO ), barbituric acid (C H N O ), nickel acetate
2
4
4
2
3
since they easily get oxidized, thereby altering their catalytic
(Ni (CH COO) .4 H O) and d-Glucose (C H O ) were
3 2 2 6 12 6
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Journal of the Iranian Chemical Society
purchased from Sigma-Aldrich and used as such without any
puriꢀcation. Deionized water was used for all experiments.
room temperature. After 1 h, 40 ml of liquid ammonia was
added dropwise to the mixture and the resultant mixture was
reꢂuxed at 80 °C for about 8 h. With the passage of time,
the color of the solution turned from green to deep blue and
Synthesis of catalyst (nickel NPs @N‑doped TiO2)
2
+
ꢀ
nally to black indicating the reduction of Ni ions to Ni
Synthesis oꢀ TiO nanospheres
metal. The nickel NPs thus formed were now loaded on the
2
N-doped TiO nanospheres by adding the nanospheres to the
2
TiO nanospheres were prepared following a method [32]
solution containing Ni NPs and stirred for 12 h. Finally, the
mixture was cooled to room temperature, ꢀltered, washed
with anhydrous EtOH and dried in an oven at 60 °C for 24 h
(Fig. 2).
2
reported in the literature with slight modiꢀcation. Four
grams of TiO was dissolved in 200 ml of 10 M KOH solu-
2
tion. The solution was then sonicated for about 1 h followed
by reꢂuxing on an oil bath at 110 °C for 24 h. After reꢂux-
ing, the solution was ꢀltered and washed with distilled water
repeatedly until the pH value of the washing solution was
lower than 7. The ꢀnal products were then dried in an oven
at a very high temperature of 500 °C.
General procedure ꢀor the synthesis oꢀ pyrano[2,3‑d]
pyrimidines
Aldehyde (1 mmol), ethyl cyanoacetate (1 mmol) and bar-
bituric acid (1 mmol) were taken in a round-bottomed ꢂask,
Synthesis oꢀ N‑doped TiO nanospheres
and to these, nickel NPs @N-doped TiO nanocatalyst (0.1 g
2
2
)
and MeOH (8–10 mL) as solvent were added. This reaction
Barbituric acid was selected as the nitrogen source for dop-
mixture was then stirred on a magnetic stirrer in an oil bath
at 65 °C for appropriate time. After the completion of the
reaction as monitored by thin-layer chromatography (petro-
leum ether: ethyl acetate as solvent system), the reaction
was worked up. The workup involved ꢀltering the reaction
mixture and washing it with ice-cold water. As soon as the
reaction mixture was washed with ice-cold water, formation
of some solid product in the ꢀltrate was observed. Once the
solid product was formed, it was separated from the ꢀltrate
by further ꢀltration using Whatman ꢀlter paper. The prod-
uct thus obtained was crude product. It was further puriꢀed
by recrystallization using hot petroleum ether. The melting
points of the products were also checked and compared to
those reported earlier in the literature. Finally, the products
ing titania nanospheres. Equal amounts of TiO nanospheres
2
and barbituric acid (1:1) were taken together in a pestle and
ground well with a mortar for about 30 min. to ensure uni-
form mixing. The resultant mixture was then transferred to a
silica glass crucible followed by heating in a muꢄe furnace
at 245 °C for 1 h. A blackish gray powder material was
obtained indicating complete mixing (Fig. 1). An attempt
to heat the equimolar mixture of TiO nanospheres and bar-
2
bituric acid at lower temperatures of 100 °C, 150 °C and
2
00 °C was also made but the results were not satisfying as
an incomplete mixing of the two components was observed.
Synthesis oꢀ nickel nanoparticles @N‑doped TiO (nickel
2
1
13
NPs @N‑doped TiO2)
were characterized by H NMR, C NMR and IR spectral
data.
Nickel nanoparticles were synthesized by chemical reduc-
tion method [45] and subsequently loaded on the nitrogen-
doped titania. In a typical procedure, 2.96 g of nickel ace-
tate and 160 ml of 0.15 M d-glucose solution were taken
together in a round-bottomed ꢂask and stirred well for 1 h at
General procedure ꢀor the synthesis
oꢀ 1,8‑dioxo‑octahydroxanthenes
Aldehyde (1 mmol) and dimedone (2 mmol) were taken
together in a round-bottomed ꢂask, and to this, nickel NPs
@
N-doped TiO (0.1 g) and EtOH (8–10 mL) were added.
2
This reaction mixture was then stirred on a magnetic stir-
rer in an oil bath at a temperature of 80 °C. The reaction
was monitored using thin-layer chromatography (ethyl ace-
tate: pet ether as solvent system). When the reaction was
complete, 20–25 ml of ethyl acetate was added to the reac-
tion mixture and then ꢀltered oꢁ while hot to separate the
catalyst from the reaction mixture. This was followed by
giving washing to the ꢀltrate with water using a separating
funnel. The ꢀltrate was then dried over anhydrous sodium
sulfate for overnight. Then, the sodium sulfate was sepa-
rated by simple ꢀltration and the left ꢀltrate was reduced
Fig. 1 Photographs of TiO nanospheres (a) before doping and (b)
2
after doping
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Journal of the Iranian Chemical Society
Fig. 2 Proposed scheme for
the preparation of nickel NPs
@N-doped TiO2
to one-third of its original volume to get the crude product
which was further recrystallized from ethyl acetate: pet
ether. The products were conꢀrmed by comparing their
melting points to those already reported in the literature.
Finally, the structures of the products were characterized
TEM analysis
This study tells us about the internal morphology of a mate-
rial such as shape and size. Figure 5 shows the TEM images
of the nickel NPs @N-doped TiO . The image shown in
2
1
13
by H NMR, C NMR and IR spectral studies.
Fig. 5a shows the presence of some dark and hexagonal
particle which could be the nickel nanoparticle. Figure 5b
shows the metallic nanoparticles of diꢁerent sizes in nm.
A dark-ꢀeld image has also been obtained (Fig. 5d) which
indicated the crystalline nature of the nickel nanoparticles
and thus conꢀrmed the presence of very small-sized nano-
particles, the smallest being 16 nm.
Characterization of nickel NPs @N‑doped
TiO
2
SEM–EDX analysis
Thermogravimetric analysis
SEM analysis gives us information regarding the surface
topography of a material. Figure 3 shows the SEM images
of the nanocatalyst at diꢁerent magniꢀcations. The image
TGA analysis showed an initial weight loss of 3.2% at
155 °C which might be due to loss of physically adsorbed
water, and then the catalyst was stable up to 370 °C. Then,
the weight loss reached up to 10.5% which could be pos-
sibly due to the loss of structural features. The weight loss
continued to 34.9% at 561 °C and further to 49.9% at 894 °C
(Fig. 6).
(
Fig. 3a) obtained at magniꢀcation of 13,000 X shows the
presence of some bright agglomerated structures which
corresponds to metallic nanoparticles against a dull non-
shiny background which corresponds to the titania sup-
port. At a magniꢀcation of 70,000 X (Fig. 3c), a bright
ꢂower-like structure was observed.
An EDX analysis was done for elemental identiꢀca-
tion and to get an idea about their quantitative composi-
tion. Figure 4 shows the EDX analysis spectrum which
conꢀrmed the presence of titanium, oxygen, nitrogen and
nickel elements in the catalyst, and Table 1 shows their
corresponding percentage amount.
FTIR analysis
−
1
The FTIR spectrum showed peaks at 508 cm and
−
1
603 cm which corresponded to Ti–O and Ti-O-Ti stretch-
−
1
ing vibrations. The peak at 1388 cm could be attributed
to nitrogen doping of TiO framework since it indicates
2
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Journal of the Iranian Chemical Society
Fig. 3 SEM images of nickel
NPs @N-doped TiO2
Fig. 4 EDX spectrum of nickel
NPs @N-doped TiO2
Table 1 EDX analysis of nickel NPs @N-doped TiO2
the presence of Ti-N bonding [7]. Thus, we can conclude
that nitrogen has replaced some of the oxygen atoms from
the titanium dioxide framework and has been incorporated
substitutionally and does not occupy any of the interstitial
Element
Weight (%)
Atomic (%)
Ti K
O K
N K
Ni K
Total
36.58
54.28
8.14
1.00
100.00
16.06
71.36
12.22
0.36
−
1
sites. The peak at 1564 cm corresponded to the bend-
−
1
ing vibration of –OH bond, and those at 2806 cm and
−
1
3
039 cm corresponded to the –OH stretching vibration,
thus indicating the presence of hydroxyl group on the
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Journal of the Iranian Chemical Society
Fig. 5 TEM images of nickel
NPs @N-doped TiO2
Fig. 6 TGA of nickel NPs
@N-doped TiO2
surface due to the physically adsorbed water molecules
Fig. 7).
binding energy of 852.7 eV which corresponded to metallic
nickel, i.e., Ni (0). Further, the presence of nickel (0) nanopar-
ticles in the prepared catalyst was conꢀrmed by comparing the
results to the previous reports on nanocrystalline nickel [54].
(
XPS analysis
2+
However, the nanocatalyst contained a very few Ni species
which were still unreduced.
XPS analysis was performed to conꢀrm the oxidation state of
nickel nanoparticles. Figure 8 shows the XPS peak located at
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Journal of the Iranian Chemical Society
Fig. 7 FTIR spectrum of nickel NPs @N-doped TiO2
of catalyst and obtained the reaction product in a good
amount. However, a further increase in the amount of the
catalyst from 0.1 to 0.15 g had no change in the yield of
the reaction product obtained. Thus, we found that 0.1 g of
catalyst was the most appropriate quantity of the catalyst
required for carrying out the reaction. In order to select the
most suitable solvent, we tried the model reaction using
benzaldehyde as test substrate under diꢁerent reaction
conditions such as solvent-free, water and methanol and
observed that the best yield of the product was obtained
in methanol, whereas results obtained under solvent-free
and aqueous conditions were not satisfying. After optimiz-
ing the solvent conditions, we went ahead to optimize the
temperature condition. Again a model reaction with ben-
zaldehyde as aldehyde variant was monitored at r.t., 60 °C
and 65 °C, and it was found that 65 °C was the optimized
reaction temperature. All this is summed up in Table 2. A
comparison with some catalytic parallels such as catalyst-
free conditions, only titania, nitrogen-doped titania and
only nickel nanoparticles was also done, and the results
are shown in Table 3. So the optimized reaction conditions
for the synthesis of pyrano[2,3-d]pyrimidines were found
Fig. 8 XPS spectrum of nickel NPs @N-doped TiO2
Results and discussions
Nanocatalyst testing for the synthesis
of pyrano[2,3‑d]pyrimidines
First, we tried to ꢀnd the most appropriate reaction condi-
tions for the synthesis of pyrano[2,3-d]pyrimidines. Our
initial eꢁorts aimed at selecting the minimum amount of
the nanocatalyst to get the reaction products in appreci-
able yields. We started with 0.05 g of the catalyst and
carried out a model reaction of benzaldehyde (1 mmol),
ethyl cyanoacetate (1 mmol) and barbituric acid (1 mmol)
but obtained no product. Then, we proceeded with 0.1 g
to be 0.1 g of nickel NPs @N-doped TiO (nanocatalyst)
2
in MeOH at 65 °C. Once the reaction conditions were set,
our next aim was to check the reactivity of a range of alde-
hydes which included aromatic, hetero-aromatic as well
as unsaturated aromatic aldehydes also (Table 4). Hetero-
aromatic and unsaturated aromatic aldehydes gave no
products. Table 5 shows the various variants of aromatic
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Journal of the Iranian Chemical Society
Table 2 Optimization of reaction conditions using benzaldehyde
and we decided to perform a test reaction with both the
compounds (taking benzaldehyde and anisaldehyde as test
entries) and compare their reactivity and thus the yield of
the products obtained. Benzaldehyde gave product with
(
1 mmol), ethyl cyanoacetate (1 mmol), barbituric acid (1 mmol) and
0
.1 g of nickel NPs @N-doped TiO
2
o
S. no.
Solvent
Temp ( C)
Time (h)
% yield
4
0% yield in 2.5 h, and with anisaldehyde, product was
1
2
3
4
5
6
7
8
9
1
.
.
.
.
.
.
.
.
Solvent-free
Solvent-free
Solvent-free
MeOH
MeOH
MeOH
Water
Water
Water
Water
R.T.
60
65
R.T.
60
65
R.T.
60
70
15
15
15
15
10
1
15
15
15
15
–
–
–
40
70
90
–
–
45
60
obtained in 50% yield in 3 h. Since ethyl cyanoacetate
gave better results than malononitrile (both in terms of
yield and time), we continued to synthesize the rest of
the products of the series with ethyl cyanoacetate only.
1
13
The products obtained were conꢀrmed by H NMR,
C
NMR and IR spectral studies. Also their melting points
were checked and compared to those already reported in
the literature.
.
0.
100
Nanocatalyst testing for the synthesis
of 1,8‑dioxo‑octahydroxanthenes
Table 3 Control experiments with counterparts of nickel NPs
N-doped TiO under the optimized and similar set of conditions
Nickel NPs @N-doped TiO was explored for its role in
2
@
2
the synthesis of 1,8-dioxo-octahydroxanthenes. To reach
up to the optimized conditions for carrying out the reac-
tion, the conditions of amount of the catalyst, solvent and
temperature were varied. First, we performed a model
reaction using benzaldehyde as test substrate under sol-
vent-free conditions at r.t., 60 °C, 70 °C and 80 °C and
got reaction product in very poor yields. Next, we tried
the same model reaction in water with 0.5 g of catalyst
at r.t., 60 °C, 70 °C and 80 °C and got product in very
less yield which did not increase even with the increase
in the amount of the catalyst to 0.1 g, 0.15 g and 0.2 g.
When we carried out the reaction in ethanol at diꢁer-
ent temperatures and with diꢁerent amounts of catalyst,
we found that the reaction product was obtained in the
best yield at 80 °C with 0.1 g of catalyst (Table 6). A
comparison of the catalytic activity of the nickel nano-
S. no.
Catalyst
Time (h)
% yield
1.
2.
3.
4.
5.
No catalyst
24
12
7
4
1
–
TiO nanospheres
20
75
70
90
2
Nitrogen-doped TiO nanospheres
Nickel nanoparticles
Nickel NPs @N-doped TiO2
2
aldehydes used and the corresponding reaction products
obtained with them. Further a comparison of reactivity
among the diꢁerent entries of aromatic aldehydes selected
revealed that those entries with the electron-donating
groups were more reactive and yielded the corresponding
reaction product in lesser time than those entries with elec-
tron-withdrawing groups. In the last, we came up with the
idea to establish the role of active methylene compound
in the synthesis of pyrano[2,3-d]pyrimidines catalyzed by
particles @N-doped TiO with diꢁerent parallels such as
2
only TiO nanospheres, nitrogen-doped TiO , only nickel
2
2
nanoparticles was also done in order to ꢀnd out the most
suitable catalyst so that we could synthesize xanthenes in
best possible yields (Tables 7, 8). Along with the simple
aromatic aldehydes, the catalytic activity of the prepared
nanocatalyst was evaluated for hetero-aromatic as well as
nickel NPs @N-doped TiO . Some of the previous research
2
work on the synthesis of pyrano[2,3-d]pyrimidines reports
the use of ethyl cyanoacetate while other reports malo-
nonitrile as the source of active methylene compound,
Table 4 Comparison of the catalytic activity of the nickel NPs @N-doped TiO with other reported catalysts for the one-pot synthesis of
2
pyrano[2,3-d]pyrimidines
Catalyst
Conditions
Time (h)
%Yield
Drawback
DABCO (5 mol %) [24]
H O:EtOH
90 °C
EtOH, R.T.
3
1
12
1
84–97
46–84
94
Longer reaction time, low yields
Very low yields, harsh reaction conditions
Longer reaction time
2
[
Bmim]BF [53]
4
Al-HMS-20 [56]
Mn\ZrO [37]
EtOH:H O, R.T.
90
Non-recyclable catalyst
2
2
Nickel NPs @N-doped TiO
MeOH, 65 °C, reꢂux
1
90
Easy workup, recyclable catalyst, lesser period of
time, mild reaction conditions, good to excellent
yields
2
(
present work)
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Journal of the Iranian Chemical Society
Table 5 Nickel NPs @N-doped TiO catalyzed one-pot synthesis of pyrano[2,3-d]pyrimidines
2
Yield (%)a
M.pt/Lit. M.pt ( C)
o
Entry Ar
Ar
Product
Time (min.)
1
2
3
4
5
6
7
8
9
C H
4-Me-C H
4-MeO-C H
4-OH-C H
4-Cl-C H
3,4-MeO-C H
3-NO C H
4-NO -C H
4
4a
4b
4c
4d
4e
4f
4g
4h
4i
60
40
48
75
50
30
70
85
57
90
90
94
88
78
90
95
80
85
76
78
198-200/206-210 [4]
290-296/296-298 [4]
285-290/290-293 [4]
165-170/163-167 [4]
280-282/295-300 [4]
288-290/303-306 [4]
230-235/237-240 [4]
285-288/289-293 [4]
200-205/209-211 [39]
232-236/235-237[4]
6
5
6
4
6
4
6
4
6
4
6
3
2
-
6
4
2
6
4-Br-C H
3-Br- C H
6
4
1
0
4j
6
4
Optimized reaction conditions: aldehyde (1 mmol), ethyl cyanoacetate (1 mmol), barbituric acid (1 mmol), nanocatalyst (0.1 g) in MeOH at
6
5 °C
a
Isolated yields: refer to the yields obtained by crystallization from petroleum ether
Table 7 Comparison of catalytic activity of nickel NPs @N-doped
Table 6 Optimization of reaction conditions using benzaldehyde
1 mmol), dimedone (2 mmol) and 0.1 g of nickel NPs @N-doped
TiO
TiO with diꢁerent parallels in the synthesis of 1,8-dioxo-octahydrox-
2
(
anthene derivatives
2
Entry Catalyst
Time (h) Yield (%)
o
S. No.
Solvent
Temp ( C)
Time (h)
% yield
1
2
3
4
5
No catalyst
24
24
12
4
–
–
1
2
3
4
5
6
7
8
9
1
1
1
1
.
.
.
.
.
.
.
.
.
0.
1.
2.
3.
Solvent-free
Solvent-free
Solvent-free
Solvent-free
EtOH
EtOH
EtOH
EtOH
Water
Water
Water
R.T.
60
70
80
R.T.
60
70
80
R.T.
60
70
18
18
16
16
15
12
9
2.5
18
18
16
15
15
–
TiO nanospheres
2
20
40
40
–
30
50
85
–
N-doped TiO nanospheres
Nickel nanoparticles
Nickel NPs @N-doped TiO2 2.5
Product in traces
50
85
2
Optimized reaction conditions: benzaldehyde (1 mmol), dimedone
2 mmol), nanocatalyst (0.1 g) in EtOH
(
Proposed mechanisms
–
45
60
60
Proposed mechanism ꢀor the synthesis oꢀ pyrano[2,3‑d]
pyrimidines catalyzed by nickel NPs @N‑doped TiO2
Water
Water
80
100
The reaction initiation step basically involves the abstrac-
tion of proton from the active methylene compound, i.e.,
ethyl cyanoacetate. Since our nanocatalyst has been doped
with nitrogen, it acts as base and readily abstracts a proton
from ethyl cyanoacetate and generates a negative charge
on it. This negatively charged moiety acts as a nucleophile
and attacks at the carbonyl carbon of the aldehyde followed
by the removal of a water molecule. Meanwhile, the mol-
ecule of barbituric acid loses a proton due to the abstrac-
tion by nitrogen present in the catalyst and combines with
the ene type of intermediate to form a new nitrile kind of
unsaturated aromatic aldehydes and found that unsaturated
aromatic aldehyde gave no product. Table 9 shows the
diꢁerent aldehydes selected for exploring the role of the
catalyst in the synthesis of 1,8-dioxo-octahydroxanthenes
and the corresponding product obtained. The products
1
13
obtained were conꢀrmed by H NMR, C NMR and IR
spectral studies. Also their melting points were checked
and compared to those already reported in the literature.
1
3

Journal of the Iranian Chemical Society
Table 8 Comparison of the catalytic activity of the nickel NPs @N-doped TiO with other reported catalysts for the one-pot synthesis of
2
1
,8-dioxo-octahydroxanthenes
Catalyst
Conditions
Time (h)
%Yield
Drawback
C/TiO -SO H [31]
Cyclodextrins [29]
ZnO [38]
Water, 100 °C
Water, 60–65 °C
Acetonitrile
3
94
95
85
85
Longer reaction time
Harsh reaction conditions, longer reaction time
Longer reaction time
2
3
12
12
2.5
Nickel NPs @N-doped TiO
EtOH, 80 °C, reꢂux
Recyclable catalyst, lesser period of time, mild
2
(
present work)
reaction conditions, good to excellent yields
Table 9 Nickel NPs @N-doped TiO catalyzed one-pot synthesis of 1,8-dioxo-octahydroxanthenes
2
1
2
3 (a-j)
Yield (%)a
M.pt/Lit.M.pt ( C)
o
Entry
Ar
Product
Time (h)
1
2
3
4
5
6
7
8
9
C H
4-NO -C H
4-CH -C H
4-Br-C H
3-NO -C H
4
4-OMe-C H
4-Cl-C H
2-Cl-C H
3a
3b
3c
3d
3e
3f
3g
3h
3i
2.5
2
1
1
2.5
2
2.5
1
2.5
1.5
85
90
85
95
90
80
92
91
89
80
183-185/186-188 [23]
190-192/194-196 [23]
135-140/139-141 [23]
220-222/220-222 [31]
200-205/201-203 [23]
145-149/149-150 [31]
145-146/142-144 [23]
199-203/199-201 [31]
186-188/188-190 [23]
143-145/141-143 [31]
6
5
2
6
4
4
3
6
6
4
2
6
6
4
6
4
6
4
4-OH-C H
6
4
1
0
3j
Optimized reaction conditions: benzaldehyde (1 mmol), dimedone (2 mmol), nanocatalyst (0.1 g) in EtOH
a
Isolated yields: refer to the yields obtained by crystallization from ethyl acetate : petroleum ether
intermediate which ꢀnally undergoes cyclization to form the
the previous step to form a moiety which through tautomeri-
zation forms the required product (Scheme 2).
pyrano[2,3-d]pyrimidine (Scheme 1).
Recyclability of nickel NPs @N‑doped TiO2
Proposed mechanism ꢀor the synthesis
oꢀ 1,8‑dioxo‑octahydroxanthenes catalyzed by nickel NPs
For the synthesis oꢀ pyrano[2,3‑d]pyrimidines
@
N‑doped TiO2
Recyclability of the catalyst was tested for ꢀve consecu-
tive runs using benzaldehyde (1 mmol), ethyl cyanoacetate
(1 mmol) and barbituric acid (1 mmol) as the test substrates
(Fig. 9).
Since our nanocatalyst contains nitrogen, the reaction mech-
anism starts with the abstraction of a proton from a dime-
done molecule and its conversion into enol form. This enol
type of moiety then attacks at the carbonyl carbon of an alde-
hyde molecule, and the intermediate thus formed undergoes
loss of a water molecule and leads to formation of another
bicyclic intermediate. In the meantime, catalyst abstracts a
proton from the second molecule of dimedone and the enol
form thus obtained reacts with the bicyclic intermediate of
For the synthesis oꢀ 1,8‑dioxo‑octahydroxanthenes
Recyclability of the catalyst was evaluated using benzalde-
hyde (1 mmol) and dimedone (2 mmol) as test substrates for
ꢀve continuous runs (Fig. 10).
1
3

Journal of the Iranian Chemical Society
Scheme 1 Plausible mechanism
for the synthesis of pyrano[2,3-
d] pyrimidines catalyzed by
O
O
HN NH
HN NH
nickel NPs @N-doped TiO
2
O
O
H O
O
H
N (cat.)
nickel @N-
doped TiO2
O
Ar
O
H
H
C
O
COOC2H5
HN
HN NH
N
C H OOC CN
O
N
H
O
Ar
2
5
H
C
O
O
COOC H5
2
HN
Ar
H
O
N
H
OH
N
H O
2
Ni (cat.)
O
O Ar
Ar
H
H
C
COOC H5
2
HN
COOC H5
O
N
H
NH
2
O
CN
nickel @N-
O
Ar
O
doped TiO2
COOC H5
2
HN
COOC H5
2
(
cat.) N
CN
O
N
H
NH2
H
Scheme 2 Plausible mechanism
for the synthesis of 1,8-dioxo-
octahydroxanthenes catalyzed
by nickel NPs @N-doped TiO
2
1
3

Journal of the Iranian Chemical Society
are the mild reaction conditions and good to excellent yields
of the reaction products which reꢂect the activity and selec-
tivity of the nanocatalyst we have prepared. Moreover, our
work involves a catalyst (nickel NPs @N-doped TiO ) which
2
is cost-eꢁective and the preparation, application or disposal
of which does not involve or generate any toxic condition.
Since the inorganic support that we chose for loading of
nickel nanoparticles (i.e., titania) has been doped ꢀrst with
nitrogen, the catalyst is supposed to show some photocata-
lytic activity also. However, in the present work, we have
explored only the catalytic activity of the prepared catalyst
in the synthesis of some organic moieties. The advantage of
this method lies in the fact we are able to synthesize a cata-
lyst in which we could carry out some substitutional changes
in the basic lattice structure of the support material and fur-
ther modify it via loading of nanoparticles of nickel. When
we tried to evaluate the activity of our catalyst toward the
synthesis of some organic compounds, we found that cata-
lyst was highly active. Moreover, the reaction products were
obtained in good to excellent yields showing that there was
an appreciable amount of conversion of the starting mate-
rial to the ꢀnal products conꢀrming the eꢃciency of our
catalyst. In this protocol, right from the preparation of the
nanocatalyst to employing it for carrying out the synthesis
of pyrano[2,3-d]pyrimidines and 1,8-dioxo-octahydroxan-
thenes, we made sure that we avoid any harmful and toxic
condition and do not produce any undesirable by-product. So
we can consider our protocol to fall in the domain of green
chemistry. Recyclability of the catalyst up to ꢀve continu-
ous reaction runs makes this work even more economic and
green.
Fig. 9 Recyclability of nickel NPs @N-doped TiO , reaction condi-
2
tions: benzaldehyde (1 mmol), ethyl cyanoacetate (1 mmol), barbitu-
ric acid (1 mmol), nanocatalyst (0.1 g) in MeOH (8-10 mL) at 65 °C
for 1 h
Spectral data of some of the synthesized compounds
Ethyl7-amino-2,4-dioxo-5-phenyl-1,3,4,5-tetrahydro-
2
H-pyrano[2,3-d]pyrimidine-6-carboxylate (4a)
1
H NMR (400 MHz, DMSO-d ): δ (ppm) 1.26–1.30
6
Fig. 10 Recyclability of nickel nanoparticles @N-doped TiO , reac-
2
(t, 3H, CH ), 4.25–4.28 (q, 2H, CH ), 4.60 (s, 1H, CH),
3
2
tion conditions: benzaldehyde (1 mmol), dimedone (2 mmol), nano-
7
7
.13–7.16 (d, 2H, J=12 Hz, ArH), 7.18–7.22 (t, 1H, ArH),
catalyst (0.1 g) in EtOH (8–10 mL) for 2.5 h
.25 (bs, 2H, NH ), 7.28–7.32 (t, 2H, ArH), 8.38 (bs, 1H,
2
NH), 9.01 (bs, 1H, NH).
1
3
Each time the catalyst was washed with EtOH (2×10 mL)
and then vacuum dried. It was observed that there was a loss
in the quantity of the catalyst after each run which could be
due to the manual mishandling. So to check the recyclability,
the amounts of the corresponding reactants were adjusted.
C NMR (100 MHz, DMSO-d ): δ (ppm) 14.7, 39.2,
6
61.3, 82.5, 91.2, 127.2, 128.4, 128.7, 137.9, 150.2, 152.5,
164.6, 168.5.
−
1
IR (KBr, υ ): 1568, 1674, 1702, 2212, 2280, 3162,
cm
3380.
Ethyl7-amino-5-(4-methoxyphenyl)-2,4-dioxo-1,3,4,5-
tetrahydro-2H-pyrano[2,3-d]pyrimidine-6-carboxylate
Conclusion
(4c)
1
H NMR (400 MHz, DMSO-d ): δ (ppm) 1.28- 1.32 (t,
6
So the present work is concluded with some new applica-
tions of nickel nanoparticles loaded on a modiꢀed support
material in the synthesis of two important members of heter-
ocyclic family, i.e., pyrano[2,3-d]pyrimidines and 1,8-dioxo-
octahydroxanthenes. The important features of this protocol
3H, CH ), 3.87 (s, 3H, OCH ), 4.27–4.33 (q, 2H, CH ), 4.63
3
3
2
(s, 1H, CH), 7.15- 7.17 (d, 2H, J=8 Hz, ArH), 8.07–8.10
(d, 2H, J=12 Hz, ArH), 8.31 (bs, 2H, NH ), 8.97 (bs, 1H,
2
NH), 9.25 (bs, 1H, NH).
1
3

Journal of the Iranian Chemical Society
1
3
C NMR (100 MHz, DMSO-d ): δ (ppm) 14.1, 35.7,
Compliance with ethical standards
6
5
1
4.2, 62.9, 103.8, 115.6, 129.9, 130.7, 132.9, 138.4, 154.0,
62.1, 169.7.
Conꢀlict oꢀ interest There are no conꢂicts to declare.
−
1
IR (KBr, υ ): 1559, 1583, 1712, 2215, 2994, 3102.
cm
Ethyl7-amino-5-(4-chlorophenyl)-2,4-dioxo-1,3,4,5-tet-
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