Synthesis and antibacterial study of 2-amino-4H-pyrans and pyrans annulated heterocycles catalyzed by sulfated polysaccharide-coated BaFe12O19 nanoparticles

Article abstract of DOI:10.1007/s11164-020-04168-x

Abstract: In this procedure, the synthesis of ecofriendly, magnetically retrievable BaFe₁₂O₁₉ was reported using a sulfated polysaccharide of?algal origin, Irish moss (IM), as bio-matrix and capping agent. The characterization of BaFe₁₂O₁₉@IM was performed by some physicochemical characterization tools, such?as Fourier transform?infrared spectroscopy, X-ray powder diffraction, scanning electron microscopy, energy-dispersive X-ray spectroscopy, vibrating sample magnetometer, and thermogravimetric analysis. The catalytic performance and recyclability of the introduced heterogeneous catalyst have been explored in the one-pot synthesis of 2-amino-4H-pyrans and pyrans annulated heterocyclic compounds via a three-component reaction between aldehydes, malononitrile, and various C–H activated acidic compound under green reaction conditions. This environmentally benign catalyst displayed high catalytic activity and effective reusability and could maintain its high catalytic efficiency even after six recycling runs. Furthermore, the antibacterial activity of BaFe₁₂O₁₉@IM and the selected compound (4a) toward two types of clinically isolated bacterial strains Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) was evaluated. The results revealed that BaFe₁₂O₁₉@IM and 2-amino-4-(4-chlorophenyl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4a) showed an effective antibacterial activity against gram-positive S. aureus. Graphic abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s11164-020-04168-x

Research on Chemical Intermediates
https://doi.org/10.1007/s11164-020-04168-x
Synthesis and antibacterial study of 2‑amino‑4H‑pyrans
and pyrans annulated heterocycles catalyzed by sulfated
polysaccharide‑coated BaFe12O19 nanoparticles
Sara Amirnejat1 · Aliakbar Nosrati1 · Reza Peymanfar1 · Shahrazad Javanshir1
Received: 4 February 2020 / Accepted: 27 April 2020
© Springer Nature B.V. 2020
Abstract
In this procedure, the synthesis of ecofriendly, magnetically retrievable BaFe12O19
was reported using a sulfated polysaccharide of algal origin, Irish moss (IM), as bio-
matrix and capping agent. The characterization of BaFe12O19@IM was performed
by some physicochemical characterization tools, such as Fourier transform infrared
spectroscopy, X-ray powder difraction, scanning electron microscopy, energy-dis-
persive X-ray spectroscopy, vibrating sample magnetometer, and thermogravimetric
analysis. The catalytic performance and recyclability of the introduced heterogene-
ous catalyst have been explored in the one-pot synthesis of 2-amino-4H-pyrans and
pyrans annulated heterocyclic compounds via a three-component reaction between
aldehydes, malononitrile, and various C–H activated acidic compound under green
reaction conditions. This environmentally benign catalyst displayed high catalytic
activity and efective reusability and could maintain its high catalytic efciency even
after six recycling runs. Furthermore, the antibacterial activity of BaFe12O19@IM
and the selected compound (4a) toward two types of clinically isolated bacterial
strains Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) was evalu-
ated. The results revealed that BaFe12O19@IM and 2-amino-4-(4-chlorophenyl)-
7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4a) showed an
efective antibacterial activity against gram-positive S. aureus.
* Sara Amirnejat
shjavan@iust.ac.ir
1
Heterocyclic Chemistry Research Laboratory, Department of Chemistry, Iran University
of Science and Technology, 16846-13114 Tehran, Iran
Vol.:(0123456789)
1 3

S. Amirnejat et al.
Graphic abstract
X
X
X
O
O
O
CN
OSO 3K
CN
CN
CH 2OH
O
NH
Or
O
Or
O
O
O
O
O
NH 2
O
N
H
O
NH 2
O
NH 2
O
OH
OH
+
F e ( N
BaFe
Ba(NO
O
CN
3
12
)
O
+
3
O
O
. 9
O
3
19
)
H
+
2
CN
O
2
O
H
Ar
or
O
O
O
O
HN NH
O
bacteria
aureus
deactived
bacteria
S.
Keywords Biopolymer · Magnetic nanocomposite · Irish moss · 2-Amino-4H-
pyrans · Antibacterial activity
Introduction
The accumulation of metallic nanoparticles in the environment could adversely
afect the ecosystem [1–3]. Therefore, recycling and reuse of metal nanoparticles
can prevent their accumulation and thus minimize their negative efects. Neverthe-
less, the separation and recycling of the metallic nanoparticles from the reaction
medium persist a main defy [4]. Magnetically separable nanoparticles (MSNPs)
[5] were employed as an appropriate solution to overcome sophisticated separation
techniques, such as fltration or centrifugation [6, 7]. This type of nanomaterial can
be efortlessly and rapidly separated from the reaction mixture using a simple mag-
net [8, 9]. As such, mixed, ferrimagnetic hexaferrites oxides, which are classifed
into six categories according to the chemical formulas and crystalline structures (M,
Y, Z, W, X, and U types), are interesting materials that have aroused great interest
[10, 11]. Meanwhile, M-type barium hexaferrite having a good combination of three
advantages, namely high magnetic properties, chemical stability, and low cost, is
considered as a good choice [12–14].
The utilization of polymer-coated magnetic particles as efcient nanocatalysts
has been considered recently. Biopolymer coating of magnetic particles is of interest
to overwhelm the aggregation [15]. The special polysaccharides which have been
extracted from algal origin can be used as natural polymers coating agents [16–18].
In this case, red algae such as IM derived from the Chondrus crispus are extremely
sulfated galactans [19, 20]. In this respect, these carbohydrates are mostly κ- and
ι-carrageenan with both sulfate and OH group reacting as double-acting catalyst.
Multi-component reactions (MCRs) [21, 22] are the series of special types of
synthetically useful organic reactions in which three or more substrates react to
give a fnal product in a one-pot procedure. Owing to an extensive range of MCRs
1 3

Synthesis and antibacterial study of 2-amino-4H-pyrans…
applications in diferent areas like the preparation of diferent structural scafolds
and the detection of new drugs, these types of reactions have drawn considerable
attention in organic synthesis and pharmaceutical chemistry [23]. 4H-pyran deriva-
tives are a remarkable category of heterocyclic compounds, due to their signifcant
properties for the treatment of numerous neurodegenerative diseases, which include
Parkinson, Alzheimer, Huntington, amyotrophic lateral sclerosis, AIDS-associated
dementia, Down’s syndrome, schizophrenia, and also cancer treatment [24–26].
Furthermore, other applications can be mentioned including, laser dyes [27], opti-
cal brighteners, pigment industries [28], and biodegradable agrochemicals proper-
ties [29]. As a result, numerous methods have been reported for the synthesis of
4H-pyrans in the presence of catalysts such as chitosan‐CTAB [30], ZnFe2O4@ alg-
inic acid [31], Fe3O4@xanthan gum [32], MCM-41@Schif base-Co(OAc)2 [33],
Fe3O4@SiO2@TiO2 [34], saccharose [35], and muskmelon fruit shell (WEMFSA)
[36].
Nowadays, the resistance of microorganisms to various antibiotics has become
one of the most serious global health problems [37–39]. The high prevalence of
multidrug-resistant bacteria has put the efectiveness of these drugs in serious dan-
ger. These results indicate that increasing antibiotic resistance, which has always
been one of the most important global health problems, is now an increasing threat,
and the development of a new strategy to overcome this problem is urgently needed
[40–42]. One of these strategies is the use of metallic nanoparticles. In recent years,
there has been an unprecedented explosion of research on the use of metal-based
nanostructures as antibacterial agents [43]. Metallic nanoparticles can afect bacteria
through multiple mechanisms. The best known mechanisms are induction of oxida-
tive stress, interaction and/or permeabilization of the cell membrane, generation of
metal ions, interactions with proteins and/or with DNA [44].
Pursuant to the above-mentioned statements, our research group introduce a new
Irish moss-based nanocomposite, BaFe12O19@IM, which was successfully applied
as a heterogeneous bifunctional catalyst for the synthesis of 4H-pyran derivatives
via one-pot, three-component reaction between various aromatic aldehydes, malon-
onitrile, and dimedone, methyl acetoacetate or malonylurea at room temperature in
ethanol (Scheme 1).
In addition to the catalytic study, the antibacterial properties of BaFe12O19@IM
were investigated on two bacterial strain, S. aureus, and E. coli. The results revealed
good antibacterial activity against gram-positive S. aureus.
Experimental
Chemicals and materials
All materials were purchased from Merck and used without purifcation. IR spectra
were recorded on KBr discs on a Shimadzu FT-IR-8400S spectrometer. X-ray dif-
fraction (XRD) measurements were carried out using Philips X’Pert MPD analyzer
(with a range of 2θ=10–80 degree on 40 kV current and 40 mA with wave length
of λ=1.78897 Å using Co tube). Calcination of catalyst was performed by Exciton
1 3

S. Amirnejat et al.
Scheme 1. Synthesis of 2-Amino-3-cyano-4H-pyrans by BaFe12O19@IM
oven. A vibrating-sample magnetometer (VSM) model was recorded by MDKFD
(Danesh Pajohan Kavir Co). Scanning electron microscope (SEM, Tescan Mira3)
was used for analyses from Czech Republic. NMR spectra were recorded using a
German Bruker Avance DRX 500 MHz instrument with CDCl3 solvent. Melting
point was measured by Electrothermal 9100. Sonication for synthesis of catalyst was
performed by Elma at 60 Hz. All thermogravimetric analyses were performed using
a model STA504, BÄHR Thermoanalyse GmbH (Hüllhorst, Germany).
Synthesis of barium hexaferrite (BaFe12O19) magnetic nanoparticles
BaFe12O19 barium hexaferrite was prepared according to our previously reported
method [32]. A mixture of barium nitrate (Ba(NO3)2) (0.52 g, 1.99 mmol), iron(III)
nitrate·nonahydrate (Fe(NO3)3·9H2O) (9.6 g, 23.76 mmol), and 4.5 g of citric acid
in 100 mL of double distillated water was sonicated in ultrasonic bath for 15 min.
Aqueous ammonia solution (25%) was then added until the solution reaches pH 8.
The obtained solids were fltered, washed, dried at 80 °C, and fnally calcined at
750 °C for 2 h to furnish the desired barium hexaferrite magnetic nanoparticles.
Synthesis of BaFe12O19@IM nanocomposite
The Irish moss was washed several times with water to remove residual salts, fl-
tered and dried at room temperature, and ground to obtain IM powder.
1 3

Synthesis and antibacterial study of 2-amino-4H-pyrans…
A mixture of IM powder (7.8 g) and BaFe12O19 (3.12 g, 0.36 mmol) in 15 mL
H2O: ETOH solvent mixture (2:1 volume ratio) was stirred for 2 h, followed by soni-
cation in water bath for 40 min. The achieved product was separated by external
magnet and oven-dried for 6 h to obtain BaFe12O19@IM nanocomposite (Scheme 2).
General procedure for synthesis of pyran derivatives (4a–x)
A mixture of aromatic aldehydes (1 mmol), malononitrile (1 mmol), dimedone or
malonylurea or methyl acetoacetate (1 mmol) and BaFe12O19@IM nanocomposite
(12 mg) in ethanol (5 mL) was stirred under refux condition until completion of the
reaction which was monitored by TLC (eluent: EtOAc/n-hexane, 1:3). The catalyst
was separated from the mixture by an external magnet, washed, and dried for use in
the next run. The crude products were fltered and recrystallized from ethanol.
Spectral data for some products
2 ‑ A m i n o ‑ 4 ‑ ( 2 , 4 ‑ d i c h l o r o p h e n y l ) ‑ 7 , 7 ‑ d i m e t h y l ‑ 5 ‑ oxo ‑ 5 , 6 , 7 , 8 ‑ t e t ra h y ‑
dro‑4H‑chromene‑3‑carbonitrile (4d) pale yellow crystalline solid. m.p.: 180–183 °C.
1HNMR (500 MHz, CDCl3, 25 °C): δ=1.04 (s, 3H, CH3), 1.10 (s, 3H, CH3), 2.25
(s, 2H, CH2), 2.43 (s, 2H, CH2), 4.74 (s, 2H, NH2), 4.79 (s, 1H, CH), 7.13(d, H,
H-Ar, J=8.3), 7.17 (d-d, H, H-Ar, J=2.15), 7.33(d, H, H-Ar, J=2.05).
Scheme 2. Preparation of BaFe12 O19@IM nanocomposite
1 3

S. Amirnejat et al.
2 ‑ A m i n o ‑ 4 ‑ ( 4 ‑ m e t h o x y p h e n y l ) ‑ 7 , 7 ‑ d i m e t h y l ‑ 5 ‑ o x o ‑ 5 , 6 , 7 , 8 ‑ t e t ‑
rahydro‑4H‑chromene‑3‑carbonitrile (4j) White crystalline solid. m.p.: 199–
201 °C. 1HNMR (500 MHz, CDCl3, 25 °C): δ=1.02 (s, 3H, CH3),1.09 (s, 3H, CH3),
2.25 (s, 2H, CH2), 2.43 (s, 2H, CH2), 3.75 (s, 3H,O-CH3), 4.34 (s, 1H, CH), 4.56 (s,
2H, NH2), 6.81 (d, 2H, H-Ar, J=8.65 Hz), 7.14 (d, 2H, H-Ar, J=8. 65 Hz).
7‑Amino‑5‑(4‑chlorophenyl)‑2,4‑dioxo‑1,3,4,5‑tetrahydro‑2H‑pyrano [2, 3-d]pyrimi-
dine-6-carbonitrile (4q) white crystalline solid. m.p.: 230 °C. 1 H NMR (500 MHz,
DMSO-d6): δ=4.24 (s, 1H, CH), 7.15 (s, 2H, NH2), 7.23 (d, J=5 Hz, 2H, Ar-),
7.34 (d, J=10 Hz, 2H, Ar–H), 11.07 (s, 1H, NH), 12.08 (s, 1H, NH).
Methyl 6‑amino‑5‑cyano‑2‑methyl‑4‑phenyl‑4H‑pyran‑3‑carboxylate (4s) White crys-
talline solid. m.p.: 177–178 °C. 1HNMR (500 MHz, CDCl3, 25 °C): δ=3.31 (s, 3H,
CH3), 3.58 (s, 3H, CH3), 4.17 (s, 1H, CH), 7.13–7.28 (m, 5H, H–Ar and NH2).
Evaluation of antibacterial activities
The antibacterial activities of samples were measured using disc difusion method.
Two diferent bacterial strains, E. coli, and S. aureus, were cultured in Müeller-Hin-
ton broth Agar using a sterile loop and incubated at 37 °C for 24 h before the test.
The inoculum turbidity was standardized to equivalent of a 0.5 McFarland standard.
Disc-shaped samples of samples with 1cm2 dimension were prepared and subjected
to the inhibition zone tests. The discs were placed on culture plates. The diameter of
the zones of growth inhibition around each disk was measured.
Results and discussion
Characterization of BaFe12O19@IM magnetic nanocomposites
The synthesized nanocomposites were characterized by FT-IR spectroscopy, EDX
analysis, XRD pattern, SEM image, and TGA analysis. The FT-IR spectra of the IM,
BaFe12O19 nanoparticles and BaFe12O19@IM nanocomposite are shown in Fig. 1.
The peak at 842.4 cm−1 is related to the α(1,3) d-galactose C–O–S stretching vibra-
tions. The C–O and C–OH stretching vibrations observed around 1010–1065 cm−1,
also the S–O asymmetric sulfate stretching exhibited at 1249 cm−1. In addition
to these peaks, the broadband stretching vibrations of hydroxyl groups appeared
around 3400 cm−1. The OH bending vibration peaks become manifest at 1650.7
and 1537.6 cm−1. According to the BaFe12O19 spectrum, the peaks at 426.1 and
584.0 cm−1 are related to the metal-oxide stretching vibration emanated from the
BaFe12O19 crystalline structure. Furthermore, all depicted peaks above, the presence
of the metal oxide peaks and biopolymer absorption bands, also exhibited in FT-IR
of BaFe12O19@IM acknowledged that the chemical structure of the polysaccharide
and BaFe12O19 nanoparticles have been preserved after the heat treatments.
1 3

Synthesis and antibacterial study of 2-amino-4H-pyrans…
BaFe12O19@IM
BaFe12O19
IM
4400
3900
3400
2900
2400
1900
1400
900
400
Wave number (cm-1)
Fig. 1 FTIR analysis of IM, the BaFe12O19 nanoparticles, and BaFe12O19@IM nanocomposite
Thermal gravimetric analysis was achieved to assess the thermal stability and
characteristic decomposition of IM and BaFe12O19/IM, from ambient to 600 °C
at a heating rate of 10 °C/min, under air atmosphere (Fig. 2). As can be seen
from Fig. 2, the TG curve of IM shows an initial weight loss (about 6%) from
50 to 170 °C which is due to the loss of moisture. The second degradation stage
7.5
TGA
7
6.5
6
5.5
5
4.5
IM
4
BaFe12O19@IM
3.5
3
0
100
200
300
400
500
600
700
Temperature (oC)
Fig. 2 The thermogravimetric analysis of IM and BaFe12O19@IM
1 3

S. Amirnejat et al.
occurred in the range of 170–600 °C (ca. 30.0% weight loss) and may be attrib-
uted to the loss of sulfate group and also carbohydrate fragmentation. This result
indicated that there remained many inorganic salts in IM. These results are in
agreement with the previous studies carried out on the thermal behavior of car-
rageenan [44, 45]. For BaFe12O19/IM, around 30% weight loss occurred between
270 and 600 °C, indicating that BaFe12O19/IM exhibit better thermal stabil-
ity than IM.
The magnetic properties of BaFe12O19@IM and BaFe12O19 nanoparticles were
investigated by VSM analysis with an applied feld of 10 kOe at room tempera-
ture (Fig. 3). The VSM curve of the hard magnetic BaFe12O19 discloses an intrin-
sic coercivity (Hci) of 5 kOe and the saturation magnetization of 48.60 emu/g.
The magnetic hysteresis loops of BaFe12O19/IM nanocomposite indicated a
decrease in Hci and the Ms value, 2.5 kOe and 39.93 emu/g, respectively, due to
the existence of polysaccharide in the composite. However, the magnetic property
is at the appropriate level, to be easily separated from the reaction medium by an
external magnet.
SEM images and EDS analysis of BaFe12O19, IM and BaFe12O19@IM nano-
composite are shown in Fig. 4a–c. The SEM image alongside with EDS analysis
of BaFe12O19 nanoparticles is presented in Fig. 4a. The SEM image revealed the
hexagonal and lace-like morphology of synthesized BaFe12O19, while the EDS
analysis of BaFe12O19 showed the presence of Ba, Fe, O elements. The amor-
phous morphology of IM was revealed in SEM micrograph (Fig. 4b), beside the
EDS analysis displaying the presence of O, C, and S elements in IM. The SEM
image of BaFe12O19@IM nanocomposite showed uniform surface coverage of
IM by hexagonal BaFe12O19 nanoparticles presenting an average size of ~ 85 nm
Fig. 3 Magnetic hysteresis loops of the BaFe12O19 nanoparticles and BaFe12O19@IM nanocomposite+
1 3

Synthesis and antibacterial study of 2-amino-4H-pyrans…
(a)BaFe12O19
Elt
O
W%
59.56
32.13
8.30
Fe
Ba
700
600
500
400
300
200
100
0
Elt
C
N
O
S
W%
A%
(b)IM
S K β
S K α
O K α
keV
0
5
10
15
20
700
Elt
W%
A%
(c)BaFe12O19@IM
C
600
500
400
300
200
100
0
N
O
S
Fe
Ba
FeL α
O K α
FeKα
BaL γ 11
BaL β 2
BaL β
BaL α
BaLl
S Kβ
S Kα
FeKβ
BaLγ 1
keV
0
5
10
15
20
Fig. 4 SEM images and the EDX analysis of a BaFe12O19@IM, b IM and c BaFe12O19@IM nanocom-
posite
(Fig. 4c). The EDS analysis of BaFe12O19@IM nanocomposite revealed the pres-
ence of both IM and BaFe12O19 nanoparticles. Spectrum shows expected major
elements such as Ba, Fe, O but also C and S (Fig. 4c).
1 3

S. Amirnejat et al.
Fig. 5 X-ray difraction patterns of a the bare BaFe12O19 and b BaFe12O19@IM and IM
X-ray difraction patterns of the bare BaFe12O19, BaFe12O19@IM, and IM are
shown in Fig. 5. The difraction peaks observed at 2θ values of 29.92, 31.68,
33.54, 34.84, 36.54, 54.61, 56.18, and 62.84 correspond to the crystal planes
(110), (107), (114), (203), (217), (2011), and (220) and confrmed that BaFe12O19
nanoparticles were synthesized in hexagonal crystal system based on the stand-
ard XRD pattern (JCPDS, card number 01-072-0738). According to the Scherrer
equation, the size of the nanoparticles was 85 nm. The XRD pattern of IM dis-
plays a bump at 2θ around 22 which are referred to the amorphous nature of IM
(Fig. 5b). The XRD pattern of BaFe12O19@IM nanocomposite indicates that the
crystal structure of barium hexaferrite has been preserved after modifcation, and
1 3

Synthesis and antibacterial study of 2-amino-4H-pyrans…
at the same time, the existence of a small bump in 2θ around 22 might confrm
the presence of IM in nanocomposite.
For the overall study of the catalytic property of BaFe12O19@IM magnetic
nanocomposites, at frst, the synthesis of the pyrans derivatives was optimized by
the reaction of 4-methoxy benzaldehyde, malononitrile, and dimedone as a model
reaction. To check the efect of the amount of catalyst, the reaction launched
using a diferent amount of the BaFe12O19@IM (5, 10, 12, 15 mg) under certain
reaction condition. Increasing the amount of catalyst from 5 to 12 mg resulted in a
moderate improvement in the yield of the model reaction. Nevertheless, a higher
amount of catalyst did not lead to a signifcant increase in yields. Thus, 12 mg of
catalyst is sufcient for the synthesis of pyran annulated compounds with high
yields. The model reaction has been studied in various protic and aprotic solvents
such as ethanol, water, chloroform, and toluene. Ethanol has proved to be the best
solvent for this reaction. The efect of temperature was also tested for the model
reaction at three diferent temperatures: room temperature, 50 °C, and refux con-
ditions. As shown in Table 1, by raising the temperature from room temperature
to refux temperature, the reaction yield was improved. Optimum circumstances
were achieved in refuxing ethanol, in the presence of 12 mg of catalyst. The reac-
tion was unsuccessful in the absence of catalyst, but the results obtained through
the separate use of IM and BaFe12O19 showed the synergistic efect of the nano-
particles and the sulfated polysaccharide.
A series of pyrans were synthesized under refux conditions in the presence
of 12 mg catalyst. Diferent type of aromatic aldehydes containing electron
Table 1 Optimization of the catalyst and the solvent amounts for the synthesis of pyrans heterocyclic
compounds
Entry
Temperature (°C)
Solvent
Catalyst loading (mg)
Time (min)
Yielda (%)
1
2
3
4
5
6
7
8
Refux
Refux
Refux
Refux
r.t
Refux
Refux
Refux
r.t
Ethanol
Ethanol
Ethanol
Ethanol
Water
Chloroform
Ethanol/water
Toluene
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
BaFe12O19@IM (5 mg)
BaFe12O19@IM (10 mg)
BaFe12O19@IM (12 mg)
BaFe12O19@IM (15 mg)
BaFe12O19@IM (12 mg)
BaFe12O19@IM (12 mg)
BaFe12O19@IM (12 mg)
BaFe12O19@IM (12 mg)
BaFe12O19@IM (12 mg)
BaFe12O19@IM (12 mg)
IM (12 mg)
50
35
15
15
25
40
20
60
35
30
20
45
120
80
85
95
95
70
55
85
55
70
80
85
65
30
9
10
11
12
13
50
Refux
Refux
Refux
BaFe12O19 (12 mg)
–
Model reaction conditions: 4-methoxy benzaldehyde (1 mmol), dimedone (1 mmol), malononitrile
(1 mmol)
aIsolated yields
1 3

S. Amirnejat et al.
Table 2 One-pot synthesis of pyran derivatives with BaFe12O19@IM magnetic nanocomposites
Entry Aldehyde
C–H acid
Product
Time Yield
m.p. (oC)
(min)
(%)
cal./ref.
10
97
213–215
208–210
[47]
1
4a
20
81
213–216
210–213
[36]
2
4b
4c
15
10
92
95
196–194
202–203
[48]
3
4
180–183
192–194
[49]
4d
20
15
88
90
228–232
230–232
[32]
5
6
4e
216–215
210–214
[50]
4f
15
87
208
209–211
[51]
7
4i
1 3

Synthesis and antibacterial study of 2-amino-4H-pyrans…
Table 2 (continued)
15
95
199–201
202–203
[36]
8
4j
15
15
92
94
228–231
228–230
[52]
9
4k
187–190
181–182
[53]
10
4l
15
15
87
85
216–218
217–218
[54]
11
4m
215–219
222–224
[33]
12
13
14
4n
4o
15
15
90
92
275–278
278–279
[55]
272–274
266–270
[50]
4P
1 3

S. Amirnejat et al.
Table 2 (continued)
10
15
95
89
230
228–230
[56]
15
4q
200 – 202
204 – 206
[57]
16
4r
4s
15
15
93
94
178
176
[58]
17
18
151–153
149
[58]
4t
15
97
161–164
160–163
[59]
19
4x
Reaction conditions: benzaldehyde derivatives (1 mmol), dimedone or malonylurea or methyl acetoac-
etate (1 mmol), malononitrile (1 mmol), BaFe12O19@ IM magnetic (12 mg) as a catalyst, in EtOH under
refux
Table 3 Comparison of the present with some literature reported the synthesis of 4H-pyrans in the pres-
ence of the diferent catalyst
Entry Catalyst
Conditions
Yield (%) Time
Ref
1
Hydroxyapatite or modifed sodium
Solvent free, r.t
61–96
2–6 h
[60]
apatite
2
3
4
5
6
7
MNP-DMAP
FSM-16/AEPC-SO3H
WEMFSA
MCM-41@Schif-based- Co(OAc)2
MgFe2O4 nanoparticles
BaFe12O19@ IM
Solvent free
Solvent free, 120 °C 88
EtOH, r.t
H2O, 50 °C
EtOH, 65 °C
Refux in EtOH
96
1–3 h
15 min
45 min
3 h
10–15 min [63]
15 min This work
[61]
[62]
[36]
[33]
92
93
74–92
96
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Synthesis and antibacterial study of 2-amino-4H-pyrans…
withdrawing and electron releasing substituent were used successfully in the
reaction providing the corresponding products in high yield (Table 2).
In addition, the current green protocol is compared with other published reports
in the literature for the synthesis of pyran derivatives (Table 3). The BaFe12O19@
Scheme 3. Proposed mechanism for the synthesis of 2-Amino-3-cyano-4H-pyrans (4H-chromene-3-car-
bonitriles, 4H-pyran-3-carbonitriles, 2H-pyrano[2, 3-d]pyrimidine-6-carbonitrile derivatives)
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S. Amirnejat et al.
IM catalyst ofers several advantages over some previous reported methods such
as lower reaction time, simple work-up procedure, and higher performance.
The proposed mechanism for the synthesis of pyrans based on the literature [32,
62] is shown in Scheme 3. According to this mechanism, the arylidene malononitrile
intermediate (I) was frstly formed by Knoevenagel condensation reaction between
aldehyde and malononitrile in the presence of the BaFe12O19@IM. The intermedi-
ate (I) reacts with activated C–H acid compounds such as dimedone, malonylurea
or methyl acetoacetate giving rise to the intermediate (II) which leads to the desired
product after cyclization.
Catalyst recycling possibility has also been investigated. For this purpose, the
magnetic BaFe12O19@IM nanocatalyst was removed from the reaction mixture by
an external magnet, washed with ethanol, and then dried at room temperature. Sub-
sequently, the recycled catalyst was reused in subsequent experiments. The results
showed that the catalyst could be used successfully in six consecutive cycles without
remarkable change in its catalytic activity (Fig. 6).
The antimicrobial activity of BaFe12O19@IM
and 2‑amino‑4‑(4‑chlorophenyl)‑7,7‑dimethyl‑5‑oxo‑5,6,7,8‑tet‑
rahydro‑4H‑chromene‑3‑carbonitrile (4a)
The antibacterial activity of BaFe12O19@IM and 2-amino-4-(4-chlorophenyl)-
7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4a) was also
investigated against gram-positive bacteria S. aureus and gram-negative bacteria E.
coli. The plate of Mueller-Hinton (MH) supplemented with Tween 80 surfactants
(fnal concentration of 0.05% v/v) using agar medium was applied. Suspensions of
each bacterium were accumulated to obtain in the vicinity of 108 colony-forming
units (cfu) per mL for agar plating. For this purpose, an amount of 50 mg of the
◦
sample is to be examined. Then, for 2 h it was maintained at 4 C and afterward was
incubated at 37 °C for overnight. The size of inhibition zones (clear rings) around
the antimicrobial samples was measured in millimeters after overnight incubation.
The results showed that both BaFe12O19@IM and product (4a) have inhibition activ-
ity against S. aureus (inhibition zone diameter 10 mm and 9 mm respectively), while
it does not have any efect on E. coli (Figs. 7a, b, 8).
100
80
60
97
97
95
94
91
88
40
20
0
1
2
3
4
5
6
Run number
Fig. 6 Catalyst reusability study showing the conversion and yield of products in model reaction
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Synthesis and antibacterial study of 2-amino-4H-pyrans…
(a)
(b)
s.aureus
E.coli
10mm
Fig. 7 Antibacterial activity of BaFe12O19@IM against a S. aureus and b against E. coli
s.aureus
9mm
Fig. 8 Antibacterial activity of 2-amino-4-(4-chlorophenyl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-
chromene-3-carbonitrile (4a) against S. aureus
Conclusions
In summary, BaFe12O19@IM magnetic bio-nanocomposites have been used
as a novel and efcient heterogeneous catalyst in the synthesis of biologically
active pyran derivatives. This heterogeneous bio-based catalyst has the promis-
ing potential to synthesize other heterocyclic compounds due to its unique fea-
tures, precisely the reactive functional groups in its structure. Furthermore,
a study on the antibacterial activity of BaFe12O19@IM, and the synthesized
products, carried out on a bacterial strain, revealed that BaFe12O19@IM and
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S. Amirnejat et al.
2-amino-4-(4-chlorophenyl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-
3-carbonitrile (4a) have good antibacterial activity against gram-positive Staphylo-
coccus aureus.
Supporting information
1HNMR Spectral data of the selected products are shown in supporting information
fle.
Acknowledgements The authors wish to express their gratitude for the fnancial support provided by the
Research Council of Iran University of Science and Technology (IUST), Tehran, Iran
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