Facile synthesis of tetrazolo[1,5-a]pyrimidine with the aid of an effective gallic acid nanomagnetic catalyst

Article abstract of DOI:10.1016/j.poly.2019.04.015

The present work is the first report of nano-Fe₃O₄@SiO₂-NH-gallic acid in multicomponent reactions as a catalyst. One-pot condensation of various aromatic aldehydes, ?-ketoesters and 5-aminotetrazole to deliver the desired tetrazolo[1,5-a]pyrimidine derivatives is investigated. It involves successful surface modification of Fe₃O₄@SiO₂-NH₂ as a potent magnetic support with a well-known natural acid which attracts considerable interests because of its applications in different sciences. This reusable magnetically separable nanocatalyst provides a convenient and reliable method for high yield tetrazole derivatives synthesis in short reaction times with wide variety range of the products and facile isolation. Acid grafting on the surface of amine-functionalized silica-coated magnetic nanoparticles confirmed by Fourier transform infrared (FT-IR) spectroscopy, thermogravimetric analysis (TGA) and energy-dispersive X-ray (EDX) analysis techniques. Structural characterization included scanning electron microscopy (SEM) images along with transmission electron microscopy (TEM) images and vibrating sample magnetometer (VSM) curve applied for morphology and magnetism type determination of the resulted nanocatalyst, respectively.

Full text of DOI:10.1016/j.poly.2019.04.015

Accepted Manuscript
Facile synthesis of tetrazolo[1,5-a]pyrimidine with the aid of an effective gallic
acid nanomagnetic catalyst
Ali Maleki, Maryam Niksefat, Jamal Rahimi, Sepide Azadegan
PII:
S0277-5387(19)30262-1
https://doi.org/10.1016/j.poly.2019.04.015
POLY 13875
DOI:
Reference:
Polyhedron
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Revised Date:
Accepted Date:
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6 April 2019
11 April 2019
Please cite this article as: A. Maleki, M. Niksefat, J. Rahimi, S. Azadegan, Facile synthesis of tetrazolo[1,5-
a]pyrimidine with the aid of an effective gallic acid nanomagnetic catalyst, Polyhedron (2019), doi: https://doi.org/
10.1016/j.poly.2019.04.015
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Facile synthesis of tetrazolo[1,5-a]pyrimidine with the aid of an effective gallic
acid nanomagnetic catalyst
Ali Maleki*, Maryam Niksefat, Jamal Rahimi, Sepide Azadegan
Catalysts and Organic Synthesis Research Laboratory, Department of Chemistry, Iran
University of Science and Technology, Tehran 16846-13114, Iran
*Corresponding author. E-mail: maleki@iust.ac.ir; Fax: +98-21-73021584; Tel: +98-21-
73228313
Abstract
The present work is the first report of nano-Fe3O4@SiO2-NH-gallic acid in multicomponent
reactions as a catalyst. One-pot condensation of various aromatic aldehydes, ß–ketoesters and 5-
aminotetrazole to deliver the desired tetrazolo[1,5-a]pyrimidine derivatives is investigated. It
involves successful surface modification of Fe3O4@SiO2-NH2 as a potent magnetic support with
a well-known natural acid which attracts considerable interests because of its applications in
different sciences. This reusable magnetically separable nanocatalyst provides a convenient and
reliable method for high yield tetrazole derivatives synthesis in short reaction times with wide
variety range of the products and facile isolation. Acid grafting on the surface of amine-
functionalized silica-coated magnetic nanoparticles confirmed by Fourier transform infrared (FT-
IR) spectroscopy, thermogravimetric analysis (TGA) and energy-dispersive X-ray (EDX)
analysis techniques. Structural characterization included scanning electron microscopy (SEM)
images along with transmission electron microscopy (TEM) images and vibrating sample
magnetometer (VSM) curve applied for morphology and magnetism type determination of the
resulted nanocatalyst, respectively.
Keywords: Gallic acid; Green chemistry; Nanomagnetic catalyst; Multicomponent reactions;
Tetrazolo[1,5-a]pyrimidine.
1

1. Introduction
Azolo-annulated pyrimidines and 1,2,4-triazines have attracted continuing interest due primarily
to their structural similarity to heterocyclic bases of DNA and RNA. As a consequence, these
compounds can act as antimetabolites, being effective biologically active compounds. One of the
categories which can be considerable as isosteres (structural analogues) of purine bases of DNA
and RNA, such as hypoxanthine, adenine, and guanine is azolo[1,5-a]pyrimidines [1].
Substituted compounds of this valuable tetrazolo prymidines can be used as anti-HBV (hepatitis
B virus) [2], anti-tumor [3] and anticancer [4] agents, besides antimicrobial and antioxidant
properties of related metal complexes [5, 6].
Among the strategies used to construct the small molecule, multicomponent reactions (MCRs)
are ideal synthetic tools to generate multiple molecular scaffolds from the same starting materials
or intermediates because of their intrinsic convergence, complexity-generating power, as well as
operational simplicity, resource and energy effectivity from the viewpoint of atom-economy and
sustainable technology [7]. In addition, nature of applied catalyst can be playing a fundamental
role in efficiency of procedure, green chemistry aspects and facility of that. With the rapid
development in the field of catalytic chemistry, researchers have started to pay more attention to
the detrimental effects of non-green processes to the environment. Recently, magnetic
nanoparticles which can be separate magnetically after completion of a reaction, have gained
recognition as potential environmentally benign replacement of the conventional Lewis acid and
base catalysts in various organic synthetic processes [8, 9]. Furthermore, surface modification of
nanoparticles can provide significant features likes stabilization of nanoparticles against
agglomeration, make them compatible with another phase, enable their self-organization and
2

functionalization by the organic groups [10]. Wide range of catalytic protocols have been
reported for heterocyclic compounds synthesis using nanomagnetic catalysts [11-17].
Gallic acid (3,4,5-trihydroxybenzoic acid) (GA) is a naturally occurring polyphenolic compound
which is widely distributed across the plant kingdom such as leaves, roots and bark and also can
be synthesized from phenylalanine via caffeic acid or trihydroxycinnamic acid [18] can be
considered as a valuable acid for functionalizing the magnetic nanoparticles [19, 20].
Due to above mentioned reasons, in the present study, we attempt to design, prepare, characterize
and investigate the application of nano-Fe3O4@SiO2-NH-GA as a heterogeneous catalyst in the
synthesis of tetrazolo[1,5-a]pyrimidine derivatives (Scheme 1).
Scheme 1. (a) Preparation of Fe3O4@SiO2-NH-GA and (b) synthesis of tetrazolo[1,5-
a]pyrimidine derivatives
2. Experimental
2.1. General
4
a–o in the presence of Fe3O4@SiO2-NH-GA.
3

Reagents, chemicals and solvents, were all provided by Merck, Fluka and Aldrich. Melting
points were measured with an Electrothermal 9100 apparatus. The FT-IR spectra were taken
1
via Shimadzu IR-470 spectrometer. H NMR spectra were recorded with a Bruker DRX-500
Avance spectrometer. SEM and TEM measurements were conducted using KYKY-EM3200
and Zeiss-EM10C electron microscopes at an acceleration voltage of 100 kV, respectively.
Elemental analysis of the nanocatalyst was done by EDX analysis using Numerix DXP-X10P.
Magnetic susceptibility measurements were performed by using a Lake Shore VSM 7410. TGA
was recorded under air atmosphere by Bahr-STA 504 instrument.
2.2. Preparation of Fe3O4@SiO2-NH-GA
On the basis of our previous work [21], the target nanocatalyst was synthesized by grafting of
GA on the freshly prepared Fe3O4@SiO2-NH2 nanoparticles. In this regard, 1.0 g of the
Fe3O4@SiO2-NH2 was dispersed in 5 mL of dry toluene. Then, the solution of dispersed GA (0.6
g in 10 mL of dry toluene) was added drop wise to the previously prepared mixture during 10
min under vigorous stirring for 1 h in presence of 10 mol% of ZrCl4 as a co-catalyst for
amidation of carboxylic acids [22]. After that, the obtained mixture was refluxed for 24 h.
Finally, the catalyst was isolated by an external magnet, washed several times with ethanol and
dried at room temperature.
2.3. Typical procedure for synthesis of 5-aminotetrazole
5-Aminotetrazole as an active component for the present procedure of tetrazolo[1,5-a]pyrimidine
derivatives synthesis was achieved by heating the mixture of 2-cyano-guanidine (84 mg, 1
4

mmol) and NaN3 (71.5 mg, 1.1 mmol) in 2 mL of distilled water in the presence of Fe3O4@SiO2-
NH-GA (45 mg). Then, the nanocatalyst was separated from the reaction mixture by an external
magnet. Next, washing the filtered precipitate with distilled water made it ready to use for
intended purpose.
2.4. General procedure for the synthesis of tetrazolo[1,5-a]pyrimidine derivatives (4a-o)
Fe3O4@SiO2-NH-GA was added to a mixture of an aromatic aldehyde (1 mmol), ß–ketoester (1
mmol), 5-aminotetrazole (93 mg, 1.1 mmol) in ethanol and refluxed for appropriate time. After
completion of reaction (monitored by thin-layer chromatography, TLC (EtOAc/n-hexane 4:1),
nanomagnetic catalyst was separated by an external magnet and rest of the reaction mixture was
filtered, washed, dried and purified by recrystallization from ethanol to yield target products
4a-
o. Introducing a new tetrazolo[1,5-a]pyrimidine derivative ( i) could be considered as a
4
noteworthy feature of present work (related spectral data is described as well). Other resulted
products are known compounds and confirmed by melting points comparison with literature
authentic samples.
2.5. Spectral data of the selected products
Methyl 7-(4-cyanophenyl)-5-methyl-4,7-dihydrotetrazolo-[1,5-a]pyrimidine-6-carboxylate (4i):
IR (potassium bromide): 3394, 3099, 2977, 2229, 1704, 1654, 1573, 1415, 1377, 1311, 1280,
1
1224, 1147, 1107, 1008, 838, 767, 698, 557. H NMR (500 MHz, CDCl3): δH (ppm) = 1.16 (t, J
= 6.85 Hz, 3H, OCH2CH3), 1.67 (s, 3H, 5-methyl-H), 2.66 (s, 3H, OCH3), 4.12 (q, 2H,
5

OCH2CH3), 6.78 (s, 1H, -CH), 7.5 (d, 2H, J = 7.6 Hz ArH), 7.67(d, 2H, J = 7.8 Hz ArH), 11.02
(s, 1H, NH).
3. Results and discussion
3.1. Characterization of the nanocomposite
3.1.1. FT-IR Analysis
Comparative FT‐ IR spectra of Fe3O4, Fe3O4@SiO2, Fe3O4@SiO2-NH2 and Fe3O4@SiO2-NH-
GA are shown in Fig. 1. All spectra have absorption peaks attributed to silica shell and magnetic
core in common. Based on bands at 1607 and 1388 cm-1 which are assigned to the C-C stretching
and C-H bending vibrations, respectively, existence of aromatic ring in the synthesized
nanocatalyst could be verified. Besides that, appeared bands at 1504 cm-1 attributed to the N-H
and C=O at 1680 cm-1 corresponded to formation of amide group in final catalyst.
Fig. 1. Comparative FT-IR spectra of Fe3O4@SiO2-NH-GA and its components
manufacturing steps.
6

3.1.2. Energy-dispersive X-ray (EDX)
The elemental composition of the synthesized Fe3O4@SiO2-NH-GA was analysed using energy
dispersive spectroscopy (EDX) in Fig 2. The results illustrated that Fe3O4 was coated with silica
shell and the inorganic compound functionalized surface of the catalyst successfully.
Furthermore, higher intensity of the Si peak compared with the Fe ones indicates that
nanomagnetic core was covered satisfyingly by silica layer and strong Si linkages were presented
in intended catalyst.
Fig. 2. EDX analysis of Fe3O4@SiO2-NH-GA
.
3.1.3. Scanning electron microscopy (SEM)
7

With regards to SEM images of Fe3O4@SiO2-NH-GA, formation of uniform spherical
particles without any agglomeration was confirmed (Fig. 3). The calculated average diameter of
52 particles in chart c reveal that the catalyst was mostly made up of ~20 nm particles and
nearly-uniform sized structure was obtained.
Fig. 3. a,b) SEM images of Fe3O4@SiO2-NH-GA in different magnifications and c) related
particle size distribution diagram.
3.1.4. Transmission electron microscopy (TEM)
8

As revealed by TEM image (Fig. 4) the silica shell is fully coated on the magnetic core through
all particles uniformly. The magnetic core can be easily distinguished as dark regions from the
shell according to different density and core-shell structure is clearly indicated.
Fig. 4. TEM image of Fe3O4@SiO2-NH-GA
.
3.1.5. Thermogravimetric analysis (TGA)
Thermal stability of Fe3O4@SiO2-NH-GA was investigated by thermogravimetric analysis
(TGA) (Fig. 5). Weight loss observed in the first area (at temperatures below 200 °C) can be
attributed to water desorption from the surface of the silica layer, while weight loss above 600 °C
is associated with the release of the structural water of Fe3O4@SiO2 [23]. Furthermore, gallic
9

acid mass loss was occurred at temperature ~210-300 °C [24] and the other degradation took
place at ~400-600 °C is due to organic part of 3-aminopropylsilica.
Fig. 5. TGA curve of Fe3O4@SiO2-NH-GA.
3.1.6. Vibrating sample magnetometer (VSM)
Magnetization curves of Fe3O4, Fe3O4@SiO2, Fe3O4@SiO2-NH2 and Fe3O4@SiO2-NH-GA
are compared in Fig. 6. The saturation magnetization (Ms) of Fe3O4, Fe3O4@SiO2, Fe3O4@SiO2-
NH2 and Fe3O4@SiO2-NH-GA were measured 61.50, 40.28, 21.30 and 19.1 emu g−1,
respectively. The observed decrease in saturation magnetization was most likely due to the
existence of coated layers on the surface of the magnetic nanoparticles which formed during the
nanocatalyst manufacturing process [25]. Facile separation of the nanocatalyst from final mixture
could be resulted from high magnetic saturation character of resulted Fe3O4@SiO2-NH-GA.
10

Fig. 6. Study of magnetization behavior.
3.2.1. Optimizing the reaction conditions
In order to develop a better catalytic system, preliminary screening was performed on the
reaction of benzaldehyde (106.1 mg, 1 mmol), ethyl acetoacetate (130.1 mg, 1 mmol) and 5-
amino tetrazole (93.5 mg, 1.1 mmol) as a model reaction.
As solvent has impressive effect in these reactions, solvent screening was carried out (Table 1,
entries 2-6) in which EtOH and CH3CN afforded good yields. By considering green and safe
aspects, EtOH was chosen as suitable solvent (Table 1, entry 2). Experiments on catalyst amount
affirmed that 45 mg of Fe3O4@SiO2-NH-GA should be selected as minimum required catalyst
amount to achieve high expected yield (Table 1, entry 13). Besides that, in case of catalyst-free
condition, the reaction did not proceed (Table 1, entry 7). The results reported in Table 1
11

revealed that in comparison with prolonged reaction times of some reported procedures (Table
1, entries 15-17), present study can be considered as a time-saving, environmentally friendly and
efficacious approach to tetrazolo[1,5-a]pyrimidine derivatives synthesis.
Table 1. Screening of reaction condition and catalyst efficiency investigation
.
Entry
Catalyst
Temp.
(°C)
Time
(min)
15
Solvent
Yield (%)
1
2
Fe3O4@SiO2-NH-GA
Fe3O4@SiO2-NH-GA
Fe3O4@SiO2-NH-GA
Fe3O4@SiO2-NH-GA
Fe3O4@SiO2-NH-GA
r.t.
EtOH
EtOH
65
90
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
85
15
3
15
H2O
76
4
15
CH3CN
PEG-400
CH2Cl2
EtOH
85
5
15
83
6
Fe3O4@SiO2-NH-GA
15
30
-
7
120
15
Trace
35
8
Fe3O4@SiO2-NH-GA (5 mg)
Fe3O4@SiO2-NH-GA (10 mg)
Fe3O4@SiO2-NH-GA (20 mg)
Fe3O4@SiO2-NH-GA (30 mg)
Fe3O4@SiO2-NH-GA (40 mg)
Fe3O4@SiO2-NH-GA (45 mg)
Fe3O4@SiO2-NH-GA (50 mg)
Sulfamic acid
EtOH
9
15
EtOH
49
10
11
12
13
14
15
16
15
EtOH
60
15
EtOH
73
15
EtOH
81
15
EtOH
90
14
EtOH
90
420
540
Solvent-free
Solvent-free
85 [26]
46 [26]
FeCl3.6H2O
85
12

17
Concentrated HCl
GA
Reflux
45
120
15
EtOH
EtOH
60.9 [27]
66
18
a Isolated yields.
3.2.2. Study the scope of present catalytic reaction
Various aromatic aldehydes were employed to study the generality of optimized conditions.
The results were summarized in Table 2. The results revealed efficiency of the procedure against
both electron-withdrawing and donating groups substituted aromatic aldehydes. Furthermore, the
reaction was extended to di- and tri-substituted aromatic aldehydes and related tetrazolo[1,5-
a]pyrimidine derivatives were generated in excellent yields. On the other hand, reliability of the
present study was increased via successful synthesis of a new derivative (Table 2, Entry 9).
13

Table 2. Green synthesis of 5-methyl-7-aryl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-
carboxylic ester derivatives 4a-o in the presence of 5 mol% of Fe3O4@SiO2-NH-GA.
Entry R1
R2
Product
Time (min) Yielda (%)
Mp (°C)
Reported
Found
1
2
3
4
5
6
C6H5
C2H5
C2H5
C2H5
15
20
15
20
20
20
90b
82
84
80
83
82
202-204
226-228
204-206
200-202
256-258
220-223
204-205 [28]
225-227 [29]
203-208 [30]
199-201 [26]
252-256 [28]
221-223 [28]
4
4
a
4‐ NO2C6H4
3‐ NO2C6H4
b
4
c
3,4,5-(CH3O)3C6H4 C2H5
4
d
2,4‐ Cl2C6H3
4‐ BrC6H4
C2H5
C2H5
4
e
4
f
7
3‐ ClC6H3
4-FC6H4
C2H5
C2H5
C2H5
15
15
15
20
15
15
20
15
15
90
88
90
81
89
86
85
88
89
182-184
196-198
238
180-185 [30]
197-198 [26]
This work
4
4
g
8
h
9
4-CNC6H4
4
i
10
11
12
13
14
15
3,4,5-(CH3O)3C6H2 CH3
C6H5 CH3
3-NO2-4-HOC6H3 CH3
217-218
190-191
250-251
219-220
192-195
256-258
200-202[26]
196-198 [31]
248-250 [30]
210-212 [26]
209-211 [32]
257-259 [26]
4
j
4
k
4
i
3,4-(CH3O)2C6H3
4‐ MeC6H4
CH3
CH3
CH3
4
m
4
n
o
2,4-Cl2C6H3
4
a Isolated yield.
14

3.2.3. Mechanism evaluation
A suggested mechanism for the formation of tetrazolopyrimidines using Fe3O4@SiO2-NH-GA is
shown in Scheme 2. Initially, activated aldehyde by nanomagnetic catalyst may participate in
Knoevenagel condensation with elimination of water and forms intermediate A. In the next step,
intermediate B forms by consequent imine-enamine tautomerization of 5-aminotertrazole and
intermediate A. Intermolecular cyclization of intermediate B and release a H2O molecule leads to
desired products [4a-o].
15

Scheme 2. Plausible mechanism for the synthesis of tetrazolo[1,5-a]pyrimidines using
Fe3O4@SiO2-NH-GA.
Reusability of Fe3O4@SiO2-NH-GA magnetic nanocatalyst
Owing to the magnetic properties of synthesized Fe3O4@SiO2-NH-GA and accordingly facile
separation from the crude reaction, impel us to persist in green aspects of present work. The
recovered catalyst from reaction mixture was washed with EtOH and dried to be ready for later
run. Six subsequent runs were investigated by recovered nanomagnetic catalyst. Slight decrease
was observed in obtained yields after 6 time reuse of magnetic catalyst (Fig. 7).
Fig. 7. Reusability studies of the nanocatalyst for the model reaction.
4. Conclusions
16

The main goal of the present study was to extend the application domain of gallic acid by
proving the catalytic potency of Fe3O4@SiO2-NH-GA in multicomponent and cycloaddition
reactions, excellent performance of Fe3O4@SiO2-NH-GA as catalyst makes it worthy to apply in
other MCRs. Surface modifying of nanomagnetic particles by a significant natural phenolic acid
is a remarkable feature of this work. TGA results exhibited that the nanocomposite was stable at
least until ~210-300 °C without considerable mass loss and gallic acid successfully incorporated
into the structure. EDX analysis showed the presence of Si, C, N, O and Fe elements. According
to the collected data, by adding an extra layer to the core shell system the magnetic power was
substantially declined which was confirmed by VSM analysis. The obtained results indicated that
the current vigorous acid-modified nanomagnetic catalyst has superparamagnetic properties and
monotonous structure with an average particle diameter of around 20 nm. Besides that, core-shell
structure and uniform coat of silica layer inferred from TEM analysis. To the best of our
knowledge in comparison with the long time, hard reaction conditions previously reported
procedures, this simple protocol offers several advantages including one-pot multicomponent
synthesis, outstanding catalytic performance in terms of yields, brief time period of the reactions,
lack of hazardous catalyst or solvent, facile work-up procedure, ease of separation, broad
substrates scope, recyclability of the magnetic catalyst at least for 7-times, carrying out reactions
with approximately low loading of the catalyst (0.045 g) and good accordance with some of the
green chemistry principles.
Acknowledgements
The authors gratefully acknowledge the partial support from the Research Council of the Iran
University of Science and Technology.
Supplementary Information
17

Additional supporting information including spectroscopic characterization data of some
products can be found in the online version of this article at the publisher’s web site.
18

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Graphical abstract
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Abstract
The first report of nano-Fe3O4@SiO2-NH-gallic acid in multicomponent reactions as a reusable
magnetically separable nanocatalyst for one-pot condensation of various aromatic aldehydes, ß–
ketoesters and 5-aminotetrazole to deliver the desired tetrazolo[1,5-a]pyrimidine derivatives is
investigated.
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