Efficient one-pot synthesis of pyrano[2,3-d]pyrimidinone and pyrido [2,3-d] pyrimidine derivatives by using of Mn-ZIF-8?ZnTiO3 nanocatalyst

Article abstract of DOI:10.1016/j.molstruc.2019.127667

Mn-ZIF-8?ZnTiO3 nanocomposite was synthesized by sol-gel method. The morphology and structure of the nanocrystalline Mn-ZIF-8?ZnTiO3 was characterized by SEM, TEM, BET, XRD. The results confirmed the formation of Mn-ZIF-8?ZnTiO3 nanocomposite with particl

Full text of DOI:10.1016/j.molstruc.2019.127667

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Efficient one-pot synthesis of pyrano[2,3‐d]pyrimidinone and pyrido [2,3‐d] pyrimidine
derivatives by using of Mn-ZIF-8@ZnTiO3 nanocatalyst
Tayebeh Farahmand, Saeedeh Hashemian, Ali Sheibani
PII:
S0022-2860(19)31776-4
DOI:
https://doi.org/10.1016/j.molstruc.2019.127667
MOLSTR 127667
Reference:
To appear in: Journal of Molecular Structure
Received Date: 30 October 2019
Revised Date: 14 December 2019
Accepted Date: 28 December 2019
Please cite this article as: T. Farahmand, S. Hashemian, A. Sheibani, Efficient one-pot synthesis of
pyrano[2,3‐d]pyrimidinone and pyrido [2,3‐d] pyrimidine derivatives by using of Mn-ZIF-8@ZnTiO3
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Efficient one-pot synthesis of pyrano[2,3‐d]pyrimidinone and Pyrido [2,3‐d]
pyrimidine derivatives by using of Mn-ZIF-8@ZnTiO3 nanocatalyst
Tayebeh Farahmand, Saeedeh Hashemian , Ali Sheibani
Department of Chemistry, Yazd Branch, Islamic Azad University, Yazd, Iran
mesoporous
Abstract
Mn-ZIF-8@ZnTiO3 nanocomposite was synthesized by sol-gel method. The
morphology and structure of the nanocrystalline Mn-ZIF-8@ZnTiO3 was characterized
by SEM, TEM, BET, XRD. The results confirmed the formation of Mn-ZIF-8@ZnTiO3
naocomposite with particle size about 40 nm. The nanocrystalline Mn-ZIF-8@ZnTiO3
was used for efficient promotion of the synthesis of pyrano[2,3-d]pyrimidinone and
pyrido[2,3-d]pyrimidine derivatives. The three-component condensation of 6-amino
uracil or 1,3-Dimethyluracil with arylaldehydes and malononitrile to generate a series of
pyrido [2,3-d]pyrimidine derivatives has been carried out over nanocrystalline Mn-ZIF-
8@ZnTiO3 in water and ethanol at 70 ºC. Pyrano[2,3‐d]pyrimidinone derivatives were
prepared by three-component of barbuturic acid, arylaldehydes and malononitrile. A
simple procedure, short reaction time, high yields of products, avoiding toxic solvents,
non‐column chromatographic, separation and recyclability of the catalyst are attractive
features of this process.
Keywords: Multicomponent reaction, Pyrano[2,3-d] pyrimidines , Pyrido [2,3-d]
pyrimidines, , Reusable, Mn- ZIF-8, Zinc titanate
Corresponding author; Sa_hashemian@iauyazd.ac.ir
Tel: 0983187575
Fax:0983538214810
1

1. Introduction
Nowadays, the Uralic derivatives are considered as effective drugs in the field of
pharmaceutical chemistry. In the meantime, 6-amino-urazils, as raw materials, have a
widespread use in the synthesis of important welded urays such as Pirano-, Pyridou-,
Pyrazolo-, Pyrimidino-, Pyridazino-pyrimidines. Pyrido[2,3- d ]-Pyrimidines are a major
category of compounds associated with oraxylans, which in recent years have resulted in
extensive biological activity such as Anti-infectious, anti-HIV, anti-inflammatory, anti-
cancer, antiparksinson, and antifungal, as well as hypnotic drugs [1, 2]. Uracil and its
fused derivatives, such as pyrano[2,3-d]pyrimidines, pyrido [2,3-d] pyrimidines or
pyrimido[4, 5-d] pyrimidines are well known by synthesis as well as biological
chemists[3]. Pyrido pyrimidine and their derivatives have biological and
pharmacological activities, such as antifolate activity, antibacterial activity,
tyrosinekinase activity, antimicrobial activity, calcium channel antagonists activity, anti-
inflammatory and analgesic activity, antileishmanial activity, tuberculostatic activity,
anticonvulsants activity, antiaggressive activity, diuretic and potassium-sparing activity
[4].
Different catalysts such as Al-HMS-20 [5], NaP5W30O110 [6], ZrO2 nanoparticles [7], L-
proline [8], 4-dimethylaminopyridine as organocatalyst [9] and Zn[(L) proline[10], were
experienced for synthesis of pyrano[2,3-d]pyrimidines and pyrido [2,3-d] pyrimidines
through the reaction between various aromatic aldehydes, malononitrile and pyrimidine
derivatives.
Porous metal-organic frameworks (MOFs) are new groups of catalysis which have been
widely investigated. The MOFs can be used in several research areas such as nonlinear
optics, molecular recognition, sensors, catalysis, gas storage and separation process [11].
The broad application of MOFs is mainly due to the limited micropore dispersion, high
dispersion of metals, prompt mono-dispersion of nanoparticles and high surface area.
All these properties contribute to increase the catalytic activity and selectivity [12].
Zeolitic imidazolate framework (ZIF-8) is a sub-class of MOF. ZIF-8 has uniform pores,
2

channels on the surface and high surface area; therefore, it was used as a catalyst in
photocatalytic reaction, Knoevenagel reaction, cycloadditions and condensation
reactions [13-15].
ZnTiO3 is a perovsktite-type metal oxide and has some unique physical and chemical
properties. ZnTiO3 plays an important role in photocatalysis, microwave dielectric
material, gas sensor and desulphurization [16-18].
Here, a new route for the synthesis of pyrano [2,3-d]pyrimidines 4a–g and pyrido [2,3-d]
pyrimidines 6a–f was developed in the presence of Mn-ZIF-8@ZnTiO3 as the
heterogeneous recyclable catalyst, in water and EtOH (Scheme 1).
Scheme 1
2. Experimental
2. 1. Material and methods
All Chemicals and solvents were purchased from Merck, Aldrich and Fluka Chemical
Companies. The reactions and purity of products were observed by TLC using silica gel
SIL G/UV 254 plates. Melting point measurement was done in open capillary tube
method by using an electrothermal 9200 apparatus. Reactions were prosecuted by TLC.
The IR spectra (4000‐ ‐470
400 cm‐1) were recorded in KBr pellets using a Shimadzu IR
1
13
spectrophotometer (for organic products). H and C NMR spectra were recorded in
DMSO with TMS as an internal standard on Inova 500 MHz.
For characterization of catalyst, Infrared spectra were obtained on a Bruker FTIRTensor
27 spectrophotometer. The crystalline structure of nanocatalyst was investigated by X-
ray diffraction (XRD, Rigaku D/Max 2500) using Cu Kα (λ=1.542 Å) radiation in the
scan range from 5° to 70°. The size and morphology of the nanocrystalline catalyst was
determined using a transmission electron microscope (TEM -Zeiss - EM10C - 80 KV)
and scanning electron microscopy (SEM- (XL-30 FEG, Philips, 20 kV) instrument.
Energy dispersive X-ray analysis (EDX) measurements were performed under standard
conditions. The specific surface area was measured by N2 adsorption–desorption
3

isotherm and was obtained with an ASAP- 2010 instrument (Micromeritics). The pore
size distribution was determined by The BJH (Barret–Joyner–Hallender) method. Mean
pore diameter and total pore volume calculated by the BET (Brunauer–Emmett–Teller)
equation.
2.2. Preparation of nanocatalyst (Mn-ZIF-8@ZnTiO3)
The Mn-ZIF-8@ZnTiO3 nano catalyst was prepared [19]. For typical 2 mmol
Mn(NO3)2.4H2O (0.5 g) and 4mmol of 2 methyl imidazole (0.66 g) dissolved at
°
minimum amount of methanol. The mixture stirred at 70 C for 5 hours, dried product
then washed with methanol. The resultant product dried at 80°C for 2h (Mn-ZIF-8).
1mmol (citric acid), 1mmol (zinc acetate), and 1mmol (tetra ethyl orthotitanate) were
separately dissolved in minimum amount of ethanol. Then the tetraethyl orthotitanate
solution was added drop wise to the citric acid solution. Then, after 15 minutes zinc
acetate solution was added to the mixture as a drop of drop and the temperature of the
heater regulated to 60 °C to completely remove the ethanol and as prepared mixture was
dried at 70 °C. Then, the product was heated at 600 °C for 2 hours (ZnTiO3).
Zinc titanate and Mn-ZIF-8 with 2:1 ratio was dissolved in minimum amount ethanol
and was mixed. The mixture was refluxed at 60˚C for 2 hours. The mixture then, dried
for 3 h at 70˚C. The mixture product (Mn-ZIF-8@ZnTiO3) was used as nanocatalyst.
2.3. Synthesis of pyrido [2, 3-d] pyrimidine
For preparation of pyrido [2, 3-d]pyrimidine, three-component condensation of 6-amino
uracil or 1,3-Dimethyluracil with arylaldehydes and malononitrile has been carried out
over nanocrystalline Mn-ZIF-8@ZnTiO3 in water and ethanol. For synthesis 0.02 g Mn-
ZIF-8@ZnTiO3 as catalyst was used. To a magnetically stirred mixture 6-amino uracil
or 1, 3-Dimethyluracil (1 mmol), malononitrile (1 mmol), substituted benzaldehydes (1
mmol) and 0.06 mmol catalyst in ethanol and water (1:1) were mixed. The mixture was
refluxed at 70 ˚C for different times (15-30 min). The progress of the reaction was
4

monitored by TLC. The reaction mixture was allowed to cool down to ambient
temperature. The crude product was filtered and purified by recrystallization from
ethanol (Scheme 2).
Scheme 2
7-Amino-2, 4-dioxo-5-(phenyl)-1, 2, 3, 4-tetrahydropyrido [2, 3-d]pyrimidine-6-
carbonitrile(4a)
IR (KBr, cm-1): ѵmax=3390, 3285, 3135, 2190, 1692, 1612.
1H NMR (500 MHz, Chloroform-d)
7.53 (Sm, 5H), 7.41-7.37 (m, 1H) ppm.
13C NMR (400 MHz, DMSO):
= 84.22, 90.88, 115.20, 128.20, 128.57, 130.05, 135.07,
δ = 11.86 (s, 1H), 10.56 (s, 1H), 7.59 (s, 2H), 7.45-
δ
152.05, 153.10, 160.43, 160.96, 161.24ppm.
7-Amino-2,4-dioxo-5-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrido[ 2,3-d]pyrimidine-
6-carbonitrile(4b)
IR (KBr, cm-1): ѵmax=3405, 3280, 3175, 2195, 1700, 1615.
1H NMR (500 MHz, Chloroform-d)
δ = 11.88 (s, 1H), 10.57 (s, 1H), 7.89 (s, 2H), 7.75
(d, 1H), 7.51 (dd, J= 8.5 , 2.3Hz, 1H), 7.41 (d, J=8.4Hz, 1H) ppm.
7-Amino-2,4-dioxo-5-(4-hydroxyphenyl)-1,2,3,4-tetrahydro pyrido[ 2,3-d]pyrimidine-6-
carbonitrile(4c)
IR (KBr, cm-1): ѵmax=3510, 3180, 3065, 2180, 1706.
1H NMR (500 MHz, Chloroform-d)
δ = 11.86 (s, 1H), 10.56 (s, 1H), 9.59 (s, 1H), 7.78
(S, 2H), 7.38 (d, J=8.6Hz, 2H), 6.82 (d, J=8.6Hz, 2H), 4.79 (s, 2H)ppm.
7-Amino-2,4-dioxo-5-(2-hydroxy-3-methoxyphenyl)-1,2,3,4-tetrahydro pyrido[ 2,3-
d]pyrimidine-6-carbonitrile(4d)
5

IR (KBr, cm-1): ѵmax=3430, 3310, 3190, 2160, 1704, 1599.
1H NMR (500 MHz, Chloroform-d)
= 11.84 (s, 1H), 10.55 (s, 1H), 9.60 (s, 31H), 7.15-
δ
7.13 (dd, j= 8.5 , 2.3Hz, 1H), 6.97 – 6.92 (m, 2H), 3.84(s, 3H)ppm.
7-Amino-1,3-dimethyl-2,4-dioxo-5-(4-methoxyphenyl-1,2,3,4-tetrahydro-pyrido[2,3-
d]pyrimidine-6-carbonitrile(4f)
IR (KBr, cm-1): ѵmax=3390, 3235, 3090, 2190, 1704, 1671, 1597.
1H NMR (500 MHz, Chloroform-d)
δ = 7.87 (s, 2H), 7.42 (d, J=8.3Hz, 2H), 7.01 (d,
J=8.3Hz, 2H), 3.81 (S, 3H), 3.53 (S, 3H), 3.34 (s, 3H)ppm.
7-Amino-1,3-dimethyl-2,4-dioxo-5-(2-chlorophenyl-1,2,3,4-tetrahydro-pyrido[2,3-
d]pyrimidine-6-carbonitrile(4g)
IR (KBr, cm-1): ѵmax=3325, 3195, 3095, 2175, 1701.
1H NMR (500 MHz, Chloroform-d)
δ = 7.70 (s, 1H), 7.64-7.61 (td, J=8 , 1.4Hz, 2H),
3.55 (s, 3H), 3.36 (S, 3H)ppm.
7-Amino-1,3-dimethyl-2,4-dioxo-5-(4-methylphenyl-1,2,3,4-tetrahydro-pyrido[2,3-
d]pyrimidine-6-carbonitrile
IR (KBr, cm-1): ѵmax=3395, 3080, 2190, 1701, 1664.
1H NMR (500 MHz, Chloroform-d)
δ = 7.74 (s, 2H), 7.51 (d, J=7.5Hz, 2H), 7.20 (d, J =
7.5, Hz, 2H), 3.56 (s, 3H), 3.36 (s, 3H), 2.34 (s, 3H) ppm.
2.4. Synthesis of pyrano[2,3-d]pyrimidine
Pyrano[2,3‐d]pyrimidinone derivatives were prepared by three-component of barbuturic
acid, arylaldehydes and malononitrile. For synthesis of pyrano [2,3-d] pyrimidine with
0.06 mmol Mn-ZIF-8@ZnTiO3 as catalyst was used. To a magnetically stirred mixture
Barbituric acid (1 mmol), malononitrile (1 mmol), substituted benzaldehydes (1 mmol)
6

and 0.06 mmol catalyst in ethanol and water (1:1) were mixed. The mixture was
refluxed at 70 ˚C for different times (10-18 min). The progress of the reaction was
monitored by TLC. The reaction mixture was allowed to cool down to ambient
temperature. The crude product was filtered and purified by recrystallization from
ethanol (Scheme 3).
Scheme 3
7-Amino-2,4-dioxo-5-phenyl-1,3,4,5-tetrahydro-2H-pyrano[2,3-d]pyrimidine-6-
carbonitrile(6a)
IR (KBr, cm-1): ѵmax=3300, 3170, 2155, 1674, 1632.
1H NMR (500 MHz, Chloroform-d)
(t, J=7.5Hz, 2H), 7.16-7.10 (m, 3H), 4.92 (s, 1H)ppm.
13C NMR (400 MHz, DMSO):
= 44.72, 57.98, 91.08,119.48, 127.34, 127.93, 128.41,
δ = 11.13 (S, 1H), 11.03 (s, 1H), 8.89 (S, 2H), 7.31
δ
144.64, 151.58, 152.18,158.45, 162.01ppm.
7-Amino-2,4-dioxo-5-(4-bromophenyl)-1,3,4,5-tetrahydro-2H-pyrano[2,3-d]pyrimidine-
6-carbonitrile(6b)
IR (KBr, cm-1): ѵmax=3295, 3170, 3040, 2175, 1706, 1667.
1H NMR (500 MHz, Chloroform-d) = 11.14 (S, 1H), 11.00 (s, 1H), 8. 31 (S, 2H), 7.55
(d, J=8.3Hz, 2H), 7.45 (d, J=8.7Hz, 2H), 4.90 (s, 1H)ppm.
7-Amino-2,4-dioxo-5-(3-nitrophenyl)-1,3,4,5-tetrahydro-2H-pyrano[2,3-d]pyrimidine-6-
carbonitrile(6c)
IR (KBr, cm-1): ѵmax=3440, 3325, 3180, 2183, 1662, 1584.
1H NMR (500 MHz, Chloroform-d) = 11.15 (s, 1H), 11.06 (s, 1H), 8.30-7.96 (m, 5H),
7.60 (t, J=7.5Hz, 1H), 4.90 (s, 1H)ppm.
7

7-Amino-2,4-dioxo-5-(2-nitrophenyl)-1,3,4,5-tetrahydro-2H-pyrano[2,3-d]pyrimidine-6-
carbonitrile(6d)
IR (KBr, cm-1): ѵmax=3400, 3240, 3130, 2160, 1692, 1647.
1H NMR (500 MHz, Chloroform-d) = 11.13 (s, 1H), 10.96 (s, 1H), 8.81 (s, 2H), 7.95-
7.63 (m, 4H), 4.87 (s, 1H)ppm
7-Amino-2,4-dioxo-5-(4-methylphenyl)-1,3,4,5-tetrahydro-2H-pyrano[2,3-
d]pyrimidine-6-carbonitrile(6e)
IR (KBr, cm-1): ѵmax=3460, 3345, 3225, 2185, 1666, 1603.
1H NMR (500 MHz, Chloroform-d)= 11.15 (S, 1H), 11.01 (s, 1H), 8.55 (S, 2H), 7.34 (d,
J=7.5Hz, 2H), 6.94 (d, J=7.5Hz, 2H), 4.91 (s, 1H), 2.529 (s,3H)ppm
7-Amino-2,4-dioxo-5-(2-hydroxyphenyl)-1,3,4,5-tetrahydro-2H-pyrano[2,3-
d]pyrimidine-6-carbonitrile(6f)
IR (KBr, cm-1): ѵmax=3290, 3165, 2172, 1710, 1675.
1H NMR (500 MHz, Chloroform-d) =11.12 (S, 1H), 11.02 (s, 1H), 9.62 (S, 1H) 8.88 (S,
2H), 7.41 (d, J=8.3Hz, 2H), 7.17 (t, J=7.5Hz, 1H), 6.96 (t, J=7.5Hz, 1H), 6.86 (d,
J=7.5Hz, 1H), 5.01 (s, 1H)ppm.
3. Results and discussion
3. 1. Characterization of catalyst
The FTIR spectra of ZIF-8 and Mn-ZIF-8@ZnTiO3 are shown in Fig. 1. As is observed,
the broad band due to symmetric stretching vibration of water appears at 3420 cm-1. The
vibrations of C-H bonds in the aromatic imidazole ring and methyl group of aliphatic
chain was observed in 3118 cm-1 in the spectra of the ZIF. The bands in the range of
600−1500 cm−1 can be assigned to the stretching and bending modes of the aromatic
imidazole ring, whereas the band at 1584 cm−1 to the stretching mode of C
═N bonding
8

of 2- methyl imidazole. The stretching band of Mn–N was observed at stretching
vibrations 622 cm–1 [19, 20].
The FTIR of Mn-ZIF-8@ZnTiO3 (Fig 2b), shows the peaks below 800 cm-1, that are
assigned to the Ti-O stretching vibration, and corresponding to the formation of zinc
titanate. For all of samples the appearance of bands below 1000 cm-1 is associated to
stretching mode of Zn-O and Ti-O. The Fig. 1b shows the formation of ZIF on the
surface of zinctitanate [19].
Fig. 1. FTIR of a- ZIF-8 and b- Mn-ZIF-8@ZnTiO3
The particle size and the morphology evolution of the Mn-ZIF-8@ZnTiO3 nanoparticles
were visualized by Field Emission Scanning Electron Microscopy (FESEM) and
transmission electron microscopy (TEM) analysis. The FESEM and TEM images of
Mn-ZIF-8@ZnTiO3 are shown in Fig. 2a and Fig. 2b, respectively. Results show
uniform distribution of the ZIF-8 nanoparticles on the zinc titanate substrate and more
particles are granular. The FESEM also shows some aggregations on the surface of Mn-
ZIF-8@ZnTiO3 (Fig. 2.a). The nanoparticles are homogeneous in shape and distribution.
The ZIF-8 particles are located in brighter color on the darker particles of zinc titanate.
ZIF-8@ZnTiO3 has particles about 40 nm.
Energy Dispersive X-Ray Spectroscopy (EDS) was showed the 38.57 % Zn, 29.73 Ti%
and 31.7 O% for ZnTiO3 and Zn 11.94%, Mn 4.46%, Ti 2.70.56%, O 23.15%, N
27.18% and C 31.56%, respectively. Thus, EXD of ZnTiO3 and ZIF-8@ZnTiO3 also
confirmed the existence of ZIF-8 crystals on the surface of ZIF-8@ZnTiO3.
Fig. 2. a- FESEM and b-of TEM image of ZIF-8@ZnTiO3
9

Fig. 3 shows the XRD patterns of samples. The XRD patterns of ZnTiO3 are shown
at Fig.3a. The samples heat treated at 700 °C for 3 h exhibit the pure crystalline phase
of ZnTiO3 ( reflections of 311 and 220 at 2θ of about 33º, and 35º) [16].
Fig.3b shows the XRD patterns of ZIF-8. A very sharp peak below 10˚at Fig. 3.b (2
θ
of 7.2º) was observed in the XRD pattern of the Mn-ZIF-8, indicating that a highly
crystalline material was achieved. This XRD pattern can be well-indexed to the
reported pattern of ZIF-8. This confirms that ZIF was successfully synthesized [20].
The XRD patterns of ZIF-8@ZnTiO3 are shown at Fig.3c. Patterns show the
formation of composite. The both of reflections ZIF-8 and zinc titanate are observed
at Fig. 3b (011 plan of ZIF-8 and 311 and 220 plans of zinc titanate).
Fig. 3. XRD pattern of a- ZnTiO3, b-ZIF-8 and c- ZIF-8@ZnTiO3
The N2 adsorption–desorption isotherms and pore size distributions of ZIF-8@ZnTiO3 is
shown in Fig. 4. The sample exhibited typical IV type isotherms and H1 type hysteresis
loops at high relative pressures. This indicates that ZIF-8@ZnTiO3 with relatively large
pore size distribution was successfully prepared. Table 1 shows the characterization of
ZnTiO3 and Mn-ZIF-8@ZnTiO3.
The BET measurement revealed that the catalysts had a relatively high specific surface
area of 10.5 m2 g-1and 115 m2 g-1 for ZnTiO3 and Mn-ZIF-8@ZnTiO3, respectively. The
higher specific surface area of Mn-ZIF-8@ZnTiO3 causes the higher catalytic activity of
nanocatalyst for preparation of pyrano[2,3
pyrimidine derivatives.
‐d]pyrimidinone and Pyrido [2,3‐d]
Fig. 4. N2 adsorption–desorption isotherms of Mn-ZIF-8@ZnTiO3
10

Table 1. Characterization of N2 adsorption–desorption isotherms for ZnTiO3 and Mn-
ZIF-8@ZnTiO3
3.2.Synthesis of pyrano[2,3
derivatives
‐d]pyrimidinone and Pyrido [2,3‐d] pyrimidine
Effect of different solvents for synthesis of pyrano[2,3
‐d]pyrimidinone and Pyrido [2,3‐
d] pyrimidine derivatives were examined for benzaldehyde (4a and 6a).
Mn-ZIF-8@ZnTiO3 was used as catalyst. Results are shown at Table 2. The green
solvent of H2O and Et-OH with ratio of 1:1 had highest yield and lowest time reaction.
Therefore, H2O/Et-OH (1:1) was selected as best solvent for further reaction.
Table 2. Effects of different solvents on the reaction yield for the synthesis of 4a and 6a
Effect of mass of nano catalyst on the rate and yield% reaction coordinate for synthesis
of 4a and 6a was studied (0.03- 0.24 mmol). Results are presented at Table. 3. The best
result was obtained 0.06 mmol with a yield of 97 % and 95 % for a product of 4a and 6a,
respectively.
Table. 3. Evaluation of optimum amount of catalyst ZIF-8@ZnTiO3 for the synthesis of
4a and 6a
Effect of numerous catalysts for preparation of 4a and 6a was investigated. In
comparative with other catalysis, ZIF-8 based zinc titanate had higher activity (lower
time of reaction with higher yield and green solvent EtOH/H2O. In comparative with
other catalysis, our catalyst had acceptable reason for preparation of prido and pyrano
derivatives (Table. 4).
11

Table 4. Comparative synthesis of 4a and 6a using the reported methods versus present
method
Using the optimized reaction conditions for the synthesis of pyrido[2,3-d]pyrimidine and
pyrano[2,3-d]pyrimidine derivatives, various aromatic aldehydes, were used [Table 5,
Table. 6]. Results are shown our catalyst had good catalytic activity (short reaction time
and high yield) for all of aldehydes and different derivatives did not sufficient effect on
the time and yield of products.
.
Table 5. Effect of different derivatives (Ar, R) for preparation of pyrido[2,3-
d]pyrimidine.a
Table 6. Effect of different derivatives (Ar) for preparation of pyrano[2,3-
d]pyrimidine.a
3. 3.Recyclability of catalyst
The probability of reusing the catalyst was studied. The reaction was done in the
presence of 0.06 mmol of Mn-ZIF-8@ZnTiO3 nanocatalyst. After that end of the
reaction, as indicated by TLC, the reaction mixture was filtered. The catalyst was
separated by a simple filtration from the resulting heterogeneous mixture, washed with
water 3–4 times, dried, and reused for next runs under the same reaction conditions.
Following, the Mn-ZIF-8@ZnTiO3 nanocatalyst was recycled by physical method
(calcination to 300 ºC). From the results, the recycled ZIF-8 based zinc titanate catalyst
can be used by calcination as a minimum five times with no significant decrease in
catalytic activity (the yields from 91-88 % and 86-82 % for 4a and 6a, respectively). The
structure of the recycled Mn-ZIF-8@ZnTiO3 nanocatalyst was also studied with
investigation of FTIR technique. The FTIR of the reused ZIF-8 based zinc titanate
12

catalyst was similar to fresh Mn-ZIF-8@ZnTiO3 nanocatalyst and remains unaffected in
its structure.
4. Conclusion
This multi-component approach is a very efficient and economical kind process. In
conclusion, we have reported an efficient method for the synthesis of pyrano [2, 3-
d]pyrimidines and pyrido[2,3-d]pyrimidines under mild reaction conditions in the
presence of Mn-ZIF-8@ZnTiO3 nanocatalyst in H2O:EtOH as a solvent with good
yields. The present route has the advantages such as good yields and recyclability of the
catalyst without loss of performance. The work-up procedure is very simple, and the
products do not require further purification. Short reaction period, operational
simplicity, good to high yield of the desired products and recyclability of the catalyst for
this multi-component reaction makes it an interesting alternative to other approaches.
Acknowledgments
The authors wish to thank Islamic Azad University of Yazd (IAUY) for the financial
support of this work.
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16

Caption Figs
NH2
NC
N
R
R
O
N
N
R
Catalyst
N
O
EtOH/H2O(1:1)
O
O
N
O
NH2
R
4a-g
CN
R= H or CH3
3
+
H
+
CN
2
NH2
NC
O
O
1
HN
HN
Catalyst
NH
O
EtOH/H2O(1:1)
O
O
N
H
O
R= H or CH3
6a-f
5
Scheme 1
NH2
NC
N
R
R
O
O
CN
N
N
R
Catalyst(0.06 mmol)
EtOH/H2O(1:1)
N
+
O
H
+
CN
2
O
O
N
NH2
R
R= H or CH3
4
1
3
Scheme 2
NH2
NC
O
O
O
CN
HN
HN
NH
Catalyst
(0.06 mmol)
EtOH/H2O(1:1)
+
H
+
O
CN
O
O
N
H
O
3
1
2
6
Scheme 3
17

Fig. 1. FTIR of a- ZIF-8 and b- Mn-ZIF-8@ZnTiO3
a
b
Fig. 2. a- FESEM and b-of TEM image of Mn-ZIF-8@ZnTiO3
18

a
b
c
Fig. 3. XRD pattern of a- ZnTiO3, b-ZIF-8 and c- ZIF-8@ZnTiO3
19

Fig. 4. N2 adsorption–desorption isotherms of Mn-ZIF-8@ZnTiO3
Table 1. Characterization of ZnTiO3 and Mn-ZIF-8@ZnTiO3
samples
Characterization
ZnTiO3
Mn-ZIF-8@ZnTiO3
Surface area (m2/g)
10.5
115
Correlation coefficient
0.984
0.991
(R2)
94.62
0.22
97.2
0.32
18.2
BJH adsorption summary
Surface area (m2/g)
Pore volume (cm3/g)
Pore diameter (nm)
113.3
0.355
BJH desorption summary
Surface area (m2/g)
Pore volume (cm3/g)
Pore diameter (nm)
2.1
115.5
0.38
24.5
0.348
19.20
20

Table 2. Effects of different solvents on the reaction yield for the synthesis of 4a and 6a
Enery
Solvent
Condition
4a
6a
Time(min) Yield(%)a Time(min)
Yield(%)a
Solvent-free
CH3CN
CHCL3
Acetone
Me-OH
Et-OH
H2O
EtOH/H2O(1:1)
120
100
80
70
80
50
40
30
15
50
44
46
55
70
85
90
97
100
80
75
80
50
30
22
13
50
55
55
60
80
85
90
95
1
2
3
4
5
7
8
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
a Isolated yields
Reaction conditions: benzaldehyde (1 mmol), malononitrile (1 mmol) and pyrimidines, Mn-ZIF-8@ZnTiO3, temp70 °C
Table. 3. Evaluation of optimum amount of catalyst Mn-ZIF-8@ZnTiO3 for the
synthesis of 4a and 6a
Entry
Catalyst(g)
4a
6a
Time(min)
22
Yield (%)a
92
Time(min)
20
Yield (%)a
89
1
0.01
2
0.02
0.03
0.04
0.05
0.06
0.07
0.08
15
17
20
22
23
23
23
97
94
91
90
86
84
80
15
13
18
20
23
25
27
92
95
91
86
82
81
77
3
4
5
6
7
8
a Isolated yields
Reaction conditions: benzaldehyde (1 mmol), malononitrile (1 mmol) and pyrimidines, Mn-ZIF-8@ZnTiO3, EtOH:H2O
(1:1), temp70 °C
21

Table 4. Comparative synthesis of 4a and 6a using the reported methods versus present
method
Entry Product
Catalyst
Solvent
Time(mi Yield(%)a References
n)
1
2
4a
4a
4a
ZrO2
MgO
-
120
96
92
82
[21]
[22]
23
H2O
DMF
18
4-Dimethylaminopyridine
(DMAP)
20
3
4
5
6
4a
6a
Mn-ZIF-8@ZnTiO3
EtOH/H2O(1:1)
EtOH
15
20
97
95
This work
[24]
[Fe3O4@SiO2@(CH2)3-1-
methyl imidazole] HSO4
6a
6a
6a
(SBA-Pr-SO3H)
ZnO
-
20
180
13
61
89
95
[25]
[26]
-
Mn-ZIF-8@ZnTiO3
EtOH/H2O(1:1)
This work
a Isolated yields
.
Table 5
Effect of different derivatives (Ar, R) for preparation of pyrido[2,3-d]pyrimidine.a
Entry
Ar
R
Product
Time(min) Yield(%)b
Mp (
◦C)
FoundReported
1
2
3
4
C6H5
H
H
H
H
4a
4b
4c
4d
15
20
17
25
95
87
94
91
>300
>300[22]
>300[3]
>300 -
2,4-Cl2C6H4
>300
>300
>300
4-OHC6H4
2-OH ,3-OCH3C6H4
>300 -
5
6
4-OCH3C6H4
2-ClC6H4
CH3
CH3
4e
4f
30
20
88
90
>300
>30
>300 -
>300[3]
7
4-CH3C6H4
CH3
4g
25
89
>300
>300 -
a Reaction conditions: benzaldehyde (1 mmol), malononitrile (1 mmol) and 6-amino uracil or1,3-Dimethyluracil (1 mmol),
Mn-ZIF-8@ZnTiO3 (0.06 mmol), solvent EtOH:H2O (1:1), temp.70 °C
22

b Isolated yields
Table 6. Effect of different derivatives (Ar) for preparation of pyrano[2,3-d]pyrimidine.a
Entry
Ar
Product
Time(min) Yield(%)b
Mp (◦C)
FoundReported
1
C6H5
6a
13
95
204-206
206-208[24]
2
3
4-BrC6H4
6b
6c
15
10
91
93
235-237
272-274
236-238[24]
271-272[24]
3-NO2C6H4
4
5
6
2-NO2C6H4
4-CH3C6H4
2-OHC6H4
6d
6e
6f
15
18
16
92
89
90
253-256
225-227
162-163
-
226-227[25]
-
a Reaction conditions: benzaldehyde (1 mmol), malononitrile (1 mmol) and
Barbituric acid (1 mmol), Mn-ZIF-8@ZnTiO3 (0.06mmol), solvent EtOH:H2O (1:1), temp.70 °C
b Isolated yields
23

Highlights
• Mn-ZIF-8 based zinc titanate nano catalyst was prepared by simple
method.
• Mn-ZIF-8 based zinc titanate nano catalyst exhibit excellent
catalytic activity for synthesis of pyrano[2,3-d]pyrimidinone and
pyrido[2,3-d]pyrimidine derivatives
• Mn-ZIF-8@ZnTiO3 nano catalyst had low reaction time with high
yields of products and was reusable

Confl icts of Interest Statement
Author contribution section
Saeedeh Hashemia (Adviser, wrote the manuscript)
Tayebeh Farahmand (did experiments )
Ali Sheibani ( heplsfor some explanations and characterization of catalyst )

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