Starch functionalized magnetite nanoparticles: A green, biocatalyst for one-pot multicomponent synthesis of imidazopyrimidine derivatives in aqueous medium under ultrasound irradiation

Article abstract of DOI:10.1016/j.molstruc.2019.127410

An efficient and environmentally friendly one-pot multicomponent synthesis of biologically fascinating imidazopyrimidine derivatives by the reaction of aromatic aldehydes, active methylene compounds and 2-aminobenzimidazole under ultrasonic irradiation ha

Full text of DOI:10.1016/j.molstruc.2019.127410

Journal Pre-proof
Starch functionalized magnetite nanoparticles: A green, biocatalyst for one-pot
multicomponent synthesis of imidazopyrimidine derivatives in aqueous medium under
ultrasound irradiation
Pratibha Verma, Shaili Pal, Swati Chauhan, Ankush Mishra, Indrajit Sinha, Sundaram
Singh, Vandana Srivastava
PII:
S0022-2860(19)31519-4
DOI:
https://doi.org/10.1016/j.molstruc.2019.127410
MOLSTR 127410
Reference:
To appear in: Journal of Molecular Structure
Received Date: 30 July 2019
Revised Date: 11 November 2019
Accepted Date: 11 November 2019
Please cite this article as: P. Verma, S. Pal, S. Chauhan, A. Mishra, I. Sinha, S. Singh, V. Srivastava,
Starch functionalized magnetite nanoparticles: A green, biocatalyst for one-pot multicomponent
synthesis of imidazopyrimidine derivatives in aqueous medium under ultrasound irradiation, Journal of
Molecular Structure (2019), doi: https://doi.org/10.1016/j.molstruc.2019.127410.
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Starch Functionalized Magnetite Nanoparticles: A Green, Biocatalyst for One-pot Multicomponent Synthesis of
Imidazopyrimidine Derivatives in Aqueous Medium under Ultrasound Irradiation
Graphical Abstract

Starch Functionalized Magnetite Nanoparticles: A Green, Biocatalyst for One-pot
Multicomponent Synthesis of Imidazopyrimidine Derivatives in Aqueous Medium under
Ultrasound Irradiation
Pratibha Verma, Shaili Pal, Swati Chauhan, Ankush Mishra, Indrajit Sinha, Sundaram Singh and
Vandana Srivastava*
Email: vsrivastava.apc@iitbhu.ac.in
Department of Chemistry, Indian Institute of Technology, Banaras Hindu University,
Varanasi 221005, Uttar Pradesh, India
Abstract
An efficient and environmentally friendly one-pot multicomponent synthesis of biologically
fascinating imidazopyrimidine derivatives by the reaction of aromatic aldehydes, active
methylene compounds and 2-aminobenzimidazole under ultrasonic irradiation have been
developed. The reaction is catalyzed by starch functionalized magnetite nanoparticles (s-Fe3O4).
The salient features of the present methodology are mild reaction conditions, easy isolation, high
atom-economy, good to excellent yield of the products, done without column chromatography,
magnetically separable and reusability of the catalyst.
Keywords: Multicomponent reaction, 2-Amino benzimidazole, Active methylene compound,
Ultrasound Irradiation.
1. Introduction
Nitrogen-containing heterocyclic moieties get much more attention due to its biological,
agrochemical, and pharmaceutical properties. Imidazopyrimidines, which have two nitrogen-
containing heterocyclic imidazole and pyrimidine core units, possess several biological activities
1

[1] like antioxidant, antibiotic and antiarrhythmic, anti-inflammatory, antiviral, antimicrobial,
anti-diabetic, herbicidal, anti-cancer [2], calcium anagostic [3], antineoplastic [4], anti-hepatitis
B and as well as DNA-gyrase inhibitors and lipid peroxidation inhibitor properties [5,6] shown
in Fig. 1.
Fig. 1. Some of the biologically important fused imidazopyrimidine derivatives
Several methods have been reported for the synthesis of imidazopyrimidine derivatives under
different conditions and diverse catalysts like L-proline [7], citric acid [8], silica sulfuric acid[ 9],
sulfamic acid [10], boric acid [11], MgO [12], [PVPH]ClO4 [13], 1,1,3,3-N,N,N,,N,-
tetramethylguanidinium trifluoroacetate [14], ZnClO4 [15], P-TSA [16], NH4OAc [17], H3PO4–
Al2O3 [18], RHA-[pmim]HSO4 [19], Fe3O4@IM [20], [bmim][BF4] [21]. However these
procedures suffer from comparatively harsh reaction conditions, longer reaction time, low yields
2

and use of volatile organic solvents. Therefore, the development of an energy and environment
efficient greener protocol for the synthesis of these heterocyclic compounds is always in demand.
In the last few decades, the construction of biologically active complex structures in a
single step by multicomponent synthesis is one of the most promising areas of green chemistry.
Successful implementation of this single step approach allows high atom economy, reduces
reaction time, low cost due to lesser material consumption as compared to multi-step synthesis.
However, limited methods have been reported for the synthesis of imidazopyrimidine derivatives
via one pot. Imidazopyrimidines could be synthesized via multicomponent reaction (MCR) it
reduces processing time, cost and waste materials. Another aspect of such green synthesis is the
requirement of an alternative solvent like water [22-25], supercritical CO2, ethylene glycol
[26,27], ionic liquids, [28,29] glycerol [30,31] etc which can be used instead of conventional
volatile organic solvents. Among these, water is sustainable, non-toxic, inexpensive and can
dissolve a variety of organic and inorganic compounds. In this respect, water has attracted much
attention due to advantages in term of economic, ecological, and environmental point of view.
Since green synthesis procedures have generally been found to be relatively slower; therefore,
workers have often resorted to strong ultrasound irradiation (>20 Hz) for smooth conduct of the
reaction. Ultrasound radiation brings physical and chemical changes due to the formation and
destruction of cavitation space in the reaction mixture. Ultrasonic radiations are useful for all
type of catalysts but are most effective for the catalysts which are intertwined or magnetic
because ultrasound radiation helps to disperse the catalyst particulates in the reaction mixture
equally [32-36].
Higher efficiency of green synthesis protocols for multicomponent synthesis can be
achieved by using an appropriate nanocatalyst. Nowadays enzymes and biomolecules
3

functionalized nanoparticles are being used extensively in organic synthesis as well as in
biomedical sciences [37-41]. Functionalized nanocatalysts display improved stability against
aggregation, thereby giving access to higher surface area and more catalytically active sites.
Additionally, functionalization also influences the properties of active sites on the nanocatalyst
[42]. Because of this; the present investigation utilizes starch functionalized superparamagnetic
magnetite nanoparticles for multicomponent synthesis of imidazopyridine derivatives. Starch is
an excellent substrate for supporting the nanoparticles because it contains hydroxyl groups which
stabilize the nanoparticles. Besides this, starch is an economical and biodegradable natural
polymer of glucose. Utilization of such natural molecules for the functionalization of
heterogeneous catalysts is one of the most important thrust areas in green chemistry. To the best
of our knowledge, the catalytic activity of starch functionalized magnetite nanoparticles for the
one-pot multicomponent synthesis of imidazopyrimidine derivatives in aqueous medium under
ultrasound irradiations has not been reported till date.
Moreover, superparamagnetic nanoparticles can be easily separated by placing magnet
below the reaction vessel. The nanoparticles can then be reused by re-dispersing them again in
fresh reaction medium after removal of the magnetic field. Thus, a new dimension in organic
synthesis for the devolvement of more efficient and green methodology for the synthesis of
imidazopyridine derivatives (4) (Scheme 1) is achieved.
4

R
CN
NH
NH2
N
N
2a
4a-l
O
s-Fe3O4
H
Water, rt, ))))
2b
R
3
1
4m-p
O
R
O
O
2c
N
NH
N
4q-u
Scheme 1. s-Fe3O4 catalyzed synthesis of imidazopyrimidines
2. Results and discussion
2. (a) Nano-catalyst characterization
The starch functionalized superparamagnetic nanoparticles s-Fe3O4 were synthesized by co-
precipitation method as reported by Prakash et al. and characterized by using different analytical
and spectroscopic techniques [43]. How starch was attached to the magnetite nanoparticles was
investigated by FT-IR spectroscopy. The FT-IR spectrum of pure soluble starch shows
characteristic peaks at 1,155 cm-1 for the stretching frequency of glycosidic C-O-C and 1,023 cm-
1 for C-O bonds another peak, due to O-H stretching mode of starch, is observed at 3412 cm-1. In
contrast to this, the FT-IR of s-Fe3O4 displays the stretching frequencies of the C-O-C and
5

C-O bonds at 1,150 and 1,025 cm-1 respectively, and appearance of an intense peak at 584 cm-1 is
due to the stretching frequency of Fe-O bond supports the formation of s-Fe3O4 [ESI Fig. S1].
Fig. 2. XRD pattern of s-Fe3O4
The XRD diffraction spectrum of s-Fe3O4 is shown in Fig. 2. The indexed planes (220), (311),
(400), (422), (511), and (440) agree very well with the magnetite phase as per JCPDS card no-
89-0688. The absence of any other peak indicates that only pure magnetite phase nanoparticles
have been formed. Moreover, starch functionalization does not impact the XRD pattern of the
magnetite phase. The SEM analysis of s-Fe3O4 was performed to investigate the effect of starch
on magnetite particle morphology (Fig. 3). The SEM image clearly shows the homogenous
morphology and small particle size of s-Fe3O4. The presence of C, along with Fe and O in the
Energy Dispersive X-Ray Analysis (EDAX), reaffirms the attachment of starch to magnetite
(Fig. 4). The TEM images of both nanoparticles Fe3O4 and s-Fe3O4 are spherical in nature and
very fine particles in the case of s-Fe3O4 shows nano Fe3O4 are functionalized with starch (ESI-
Fig. S3a & 3b).
6

Fig. 3. SEM image of s-Fe3O4
Fig. 4. EDAX of s-Fe3O4.
The magnetic properties of the starch functionalized magnetite nanoparticles were analyzed by
Mission Planning and Monitoring System (MPMS) Fig. 5 shows the magnetization curve of s-
Fe3O4. The absence of hysteresis loop shows that s-Fe3O4 is superparamagnetic. Furthermore, the
magnetic moment of s-Fe3O4 (51.9 emu/g) is lower than Fe3O4 (71.3 emu/g) due to starch
functionalization.
Fig. 5. MPMS analysis; Magnetic moment versus magnetic field graph of Fe3O4 and s- Fe3O4
7

2 (b). Optimization of reaction conditions
To establish the optimized conditions benzaldehyde (1a), malononitrile (2a) and 2-
aminobenzimidazole (3) in (1.2: 1.2: 1 molar ratio) was chosen as a model reaction for the
synthesis of imidazopyrimidine (4a) (Scheme 1).
The model reaction was carried out in reflux and ultrasound irradiation method to compare the
effectiveness of this methodology. When model reaction was done under reflux, the reaction was
completed in 2h and gave 80% yield of the product. While in ultrasound irradiation method it
gave 98% of the product in 3 min because catalyst s-Fe3O4 was homogenized in reaction mixture
by ultrasound irradiation so all other optimization was carried out by ultrasound method. To find
a suitable solvent the model reaction was carried out with 5 mg of s-Fe3O4 in various solvents at
room temperature under ultrasound irradiation. In non-polar solvents such as xylene, toluene,
benzene no product was obtained after 1 hour (Table 1, entries 1-3). Polar-aprotic solvents such
as 1,4-dioxane, acetonitrile, dichloromethane gave the imidazopyrimidine (4a) in 25-40% yield
after one hour (Table 1, entries 4-6). In the case of polar- protic solvents like methanol, ethanol,
and water gave the product (4a) in 40-98% yield (Table 1, entries 7-9). The best result was
obtained in water almost complete conversion of the reactants into the product (4a) was achieved
with an isolated yield of 98% in 3 minutes (Table 1, entry 9). To understand the effectiveness of
s-Fe3O4 nano catalyst in the synthesis of imidazopyrimidines some controlled experiments have
been done with the model reaction under the same reaction conditions. The model reaction
mixture was irradiated under ultrasound without catalyst s-Fe3O4 in water at r.t. However, there
was no formation of 2-amino-4-phenyl-1,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine-3-
carbonitrile (4a) in 1h (Table 1, entry 10). In another controlled experiment, the reaction was
also performed in the presence of starch only (no s-Fe3O4) but no product was formed in this
8

case. The reaction was attempted with nano Fe3O4 (without starch functionalization) separately
again, in this case, only 30% of the product was obtained under the same reaction conditions
(Table 1, entry 11, 12).
Furthermore, optimization of catalyst loading was investigated with catalyst
concentration 2, 3 and 4 mg gave 50%, 80%, and 98% yields of the desired product respectively
(Table 1, entries 13–15), the results show that 4 mg of s-Fe3O4 was optimal and excessive
amount of catalyst did not increase the rate and yield of the product. The product (4a) was
characterized by spectral data (IR, 1H, 13C NMR) and confirmed by comparing with the reported.
Table 1 Evaluation of solvents and amount of the catalyst for the synthesis of 4aa
Entry Solvent
Catalyst
s-Fe3O4
s-Fe3O4
s-Fe3O4
s-Fe3O4
s-Fe3O4
Catalyst
Amount (mg)
Time (min) % Yieldb
1
2
3
4
5
6
Xylene
5
5
5
5
5
5
60
60
60
60
40
60
NA
NA
NA
25
Toluene
Benzene
1,4-Dioxane
Acetonitrile
35
Dichloromethane s-Fe3O4
40
9

7
Ethanol
Methanol
Water
s-Fe3O4
s-Fe3O4
s-Fe3O4
-
5
5
5
-
40
60
3
50
40
98
NA
30
NA
98
80
50
8
9
10
11
12
13
14
15
Water
60
60
60
3
Water
nano-Fe3O4
Starch
5
5
4
3
2
Water
s-Fe3O4
s-Fe3O4
s-Fe3O4
Water
Water
10
15
Water
a Reaction conditions: benzaldehyde 1a (1.2 mmol), malononitrile 2a (1.2 mmol) and 2-aminobenzimidazole 3 (1.0
mmol) in the presence of s-Fe3O4 at room temperature under ultrasound irradiation, b Isolated yield.
With optimized conditions in hand (Table 1, entry 13), the scope of this s-Fe3O4 catalyzed
protocol was investigated with a variety of aromatic aldehydes (1a-l) and malononirile (2a) with
2-aminobenzimidazole (3) which leads to a series of imidazopyrimidine derivatives (4a-l) in
high-to-excellent yields. All aromatic aldehydes carrying either electron donating or electron-
withdrawing substituents reacted efficiently and gave excellent yields, Results in Table 2, reveal
that nitro, chloro, fluoro, bromo electron-withdrawing groups on benzaldehyde (Table 2, entries
5-12) leads to excellent yields in shorter reaction time than electro donating groups like methoxy,
methyl (Table 2, entries 2-4). Further under the same optimized conditions the reaction of
different active methylene compounds like ethyl acetoacetate (2b), dimedone (2c) with various
aldehydes (1) and 2-aminobenzimidazole (3) gave desired products in excellent yields (Table 2,
10

entries 13-21) but it took slightly longer reaction time than malanonitrile. Excellent
chemoselectivity is an important aspect of this reaction it gave only (4) as the major product in
very high yields and the other possible product (5) was not observed in this methodology.
Scheme 2. Chemoselective synthesis of 4
Table 2 Starch functionalized magnetite nanoparticles catalyzed the multicomponent synthesis
of imidazopyrimidines (4a-u).
Entry
Reactant
Product
Time (min)
% Yieldb
1
3
98
11

2
5
95
3
6
93
4
4
96
5
3
96
12

6
2
3
98
95
7
8
5
94
9
3
97
13

10
4
96
11
12
13
3
4
6
98
97
95
14

14
8
96
15
16
17
6
6
9
97
97
96
15

18
19
20
21
9
8
7
7
98
95
98
98
a Reaction conditions: Benzaldehyde derivatives 1a-l (1.2 mmol), active methylenic compounds 2a-c (1.2), 2-amino
b
benzimidazole 3 (1.0 mmol) and s-Fe3O4 (4 mg) in 5 mL water under ultrasound irradiation method, isolated
yields.
16

The reusability of s-Fe3O4 nanocatalyst was also examined under the optimized reaction
conditions up to 6 runs (Fig. 6). The catalyst was separated by an external magnet after
o
completion of the reaction, first washed with water and then methanol (3x10mL), dried at 60 C
and used in next reaction. The collected catalyst could be reused numerous times in the
succeeding runs without a significant loss of catalytic activities. Comparison of FT-IR, XRD and
TEM image of the fresh and recycled catalyst s-Fe3O4 has shown that the reaction conditions do
not affect the structure and chemical nature of the catalyst [ESI Fig. S1 & Fig. S3c].
Fig. 6. Recyclability of catalyst
We have also calculated turnover number (TON) and turnover frequency (TOF) of catalyst
s-Fe3O4 and compared with the previously reported catalysts for the synthesis of (4a). The results
show better catalytic activity of s-Fe3O4 in terms of TON and TOF than other studied catalysts
are shown in (ESI-Table 1). TON and TOF of recycled catalyst s-Fe3O4 up to five consecutive
runs have been calculated indicates an insignificant loss of activity are shown in (ESI-Table 2).
A proposed mechanism for the s-Fe3O4 catalyzed synthesis of imidazopyrimidine based on the
product analysis is shown in scheme 3. In the presence s-Fe3O4 catalyst the carbonyl group of
17

aldehyde get polarized and its electrophillicity that help the condensation with malanonitrile to
from arylidenemalononitrile intermediate (I) by Knoevenagel reaction. In the next step, Michael
addition by ring nitrogen atom of 2-aminobenzimidazole (3) to arylidenenitrile (I) followed by
intermolecular cyclization (II) in situ and gives the product (4).
I
4
II
Scheme 3. Plausible mechanism for s-Fe3O4 catalyzed synthesis of imidazopyrimidine
3. Conclusions
In summary, we have developed a simple and efficient ultrasound assisted multicomponent
synthesis of the biologically active imidazopyrimidine derivatives catalyzed by starch
functionalized magnetite nanoparticles in the aqueous medium at room temperature. Broad
18

substrate scope, high atom economy, easy isolation of products and catalyst from the reaction
mixture, excellent conversion, shorter period, chemoselectivity, green solvent, and biocatalyst
make this protocol an efficient alternative to the previously reported protocols. An important key
feature of the present methodology is recyclability of the catalyst successfully up to 6 runs. It is
the leap of faith for environmentally benign synthesis.
Acknowledgments
Authors gratefully acknowledge the Central instrumental facility (CIFC) IIT (BHU) for NMR,
facilities. P. V. thanks CSIR, New Delhi for senior research fellowship (SRF), (CSIR Award
No.: 09/013(0609)/2015-EMR-I) and IIT (BHU) for financial support.
Supporting Information summary
1
Complete characterization of catalyst and all synthesized compounds (M.P., IR, H, 13C NMR)
are provided in the supporting information
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25

Highlights
•
•
•
•
•
s-Fe3O4 biocatalyst
Low catalyst loading
Water as a solvent
Reaction at room temperature
21examples (93-98% yield)

Vandana Srivastava: Supervision, Conceptualization Pratibha Verma: Methodology,
Validation, Investigation Shaili Pal: Data Curation Swati Chauhan: Writing - Original Draft
Ankush Mishra: Writing - Review & Editing Indrajit Sinha: Resources Sundaram Singh:
Conceptualization

Declaration of Interest Statement
The authors declare no conflict of interest.