Synthesis and application of a novel nanomagnetic catalyst with Cl[DABCO-NO2]C(NO2)3 tags in the preparation of pyrazolo[3,4-b]pyridines via anomeric based oxidation

Article abstract of DOI:10.1007/s11164-018-3576-9

A novel nanomagnetic catalyst with Cl[DABCO-NO₂]C(NO₂)₃ tags was designed, synthesized and fully characterized by several techniques such as Fourier transform infrared spectroscopy, energy-dispersive X-ray spectroscopy, el

Full text of DOI:10.1007/s11164-018-3576-9

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Synthesis and application of a novel nanomagnetic catalyst
with Cl[DABCO-NO2]C(NO2)3 tags in the preparation
of pyrazolo[3,4-b]pyridines via anomeric based oxidation
Javad Afsar1 Mohammad Ali Zolfigol1
Ardeshir Khazaei1
•
•
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Diego A. Alonso2 Abbas Khoshnood2 Yadollah Bayat3 Asiye Asgari3
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Received: 11 June 2018 / Accepted: 25 August 2018
Ó Springer Nature B.V. 2018
Abstract
A novel nanomagnetic catalyst with Cl[DABCO-NO2]C(NO2)3 tags was designed,
synthesized and fully characterized by several techniques such as Fourier transform
infrared spectroscopy, energy-dispersive X-ray spectroscopy, elemental mapping
analysis, thermogravimetric analysis, derivative thermal gravimetric, powder X-ray
diffraction patterns, field scanning electron microscopy, high resolution transmis-
sion electron microscopy, physical adsorption and desorption of N2 isotherms
(BET) and vibrating sample magnetometer. The synthesized nanomagnetic particles
were used as an efficient and recyclable catalyst for the one-pot three component
condensation reaction of 3-methyl-1-phenyl-1H-pyrazol-5-amine or 3-methyl-1H-
pyrazol-5-amine, aryl aldehydes and malononitrile for the synthesis of pyrazolo[3,4-
b]-pyridine derivatives under neat conditions.
Keywords Pyrazolo[3,4-b]pyridine Á Nanomagnetic catalyst Á Fe2O3@SiO2(CH2)3-
Cl[DABCO-NO2]C(NO2)3 Á Solvent-free Á Anomeric-based oxidation
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11164-
018-3576-9) contains supplementary material, which is available to authorized users.
&
Mohammad Ali Zolfigol
zolfi@basu.ac.ir; mzolfigol@yahoo.com
Ardeshir Khazaei
Khazaei_1326@yahoo.com
Diego A. Alonso
diego.alonso@ua.es
Abbas Khoshnood
abbas.khoshnood@ua.es; abbaskhoshnood@yahoo.com
Extended author information available on the last page of the article
123

J. Afsar et al.
Introduction
The outlook of chemical processes is moving towards the goal of sustainable
development. With this aim, the design, synthesis and applications of ‘‘benign’’
catalysts has been one of the serious challenges for chemists and chemical engineers
in recent years. Nowadays, chemical processes that produce the least waste and
pollutants are of paramount importance. One way to achieve this goal is to use
catalysts that increase a chemical reaction’s rate by reducing its activation energy,
simultaneously reducing energy consumption [1]. Homogeneous catalysts have
demonstrated good performance in chemical processes, but their separation from the
reaction mixture is tediously long, so the use of heterogeneous catalysts, especially
highly efficient nano-catalysts, is highly interesting [2–6]. However, nano-sized
catalysts are difficult to separate from the reaction mixture by conventional filtration
techniques. Nanomagnetic catalysts are designed to solve this problem. Generally,
these catalysts can be easily separated from the reaction by using a magnet and
reused several times with only a marginal decrease in reactivity [7–13].
Multi-component reactions (MCRs) have been introduced and developed in order
to increase the efficiency of chemical reactions, simplify processes, save time and
energy, increase the atomic economy and reduce the use of organic solvents and
waste generation [14–16].
The influence of the stereoelectronic anomeric effect on the reactivity of certain
chemical entities has been extensively reviewed [17–20]. Recently, the term
‘‘anomeric based oxidation (ABO)’’ has been introduced to explain the driving force
for the aromatization of susceptible heterocyclic compounds, those which have
heteroatoms at the appropriate sites, by an exceptional hydride transfer mechanism.
In addition to experimental observations, computational evidence also confirms this
mechanism [21]. The systematic study of the anomeric effect in target molecules
allows the design of synthetic strategies based on anomerically driven stereoselec-
tive reactions, or highly biased equilibrium between isomeric products. Many
biological processes involve an oxidation–reduction step of substrates by NAD?/
NADH and/or NADP?/NADPH, respectively (Fig. 1). The key feature of the
oxidation mechanism in these systems is a hydride transferring from carbon to
substrates via anomeric based oxidation. Thus, the development of anomeric based
oxidation and/or aromatization reactions can be expected to lead to a knowledge-
based design of biomimetic reactions in the future. We think that the obtained
results from this field of research will support the idea of rational designs, syntheses
and applications of tasked-specific catalysts and molecules for the development of
anomeric based oxidation and/or aromatization mechanisms [22–25].
Pyrazole derivatives have attracted much interest due to their variety of biological
and pharmacological activities such as antiviral [26], antidiabetic [27], hypotensive
[28], anticancer [29], antitumor, antibacterial [30] and anti-inflammatory [31]. These
compounds can be also effective in the remedy of gastrointestinal disease, drug and
alcohol withdrawal symptoms, anorexia nervosa depression, hemorrhaged stress,
Alzheimer’s disease, infertility and drug addiction [32, 33]. Recently, it has been
found that pyrazolo[3,4-b]pyridines can also be used as FGFR Kinase inhibitors [34]
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Synthesis and application of a novel nanomagnetic…
Fig. 1 Molecular structures of NADH and NADPH
and metabotropic glutamate receptor 5 (mGluR5) [35] (Fig. 2). Therefore, due to
these important biological abilities, any development in the synthetic organic
methodology for the preparation of these compounds is potentially important.
With this aim, we wish to introduce Fe2O3@SiO2(CH2)3-Cl[DABCO-NO2]-
C(NO2)3 as a novel nanomagnetic catalyst and use it as an efficient and reusable
catalyst in the synthesis of pyrazolo[3,4-b]pyridine derivatives via anomeric based
oxidation under solvent-free conditions (Scheme 1).
Experimental
General
All chemicals were obtained from Merck or Sigma-Aldrich and were used without
further purification. Known products were identified by comparison of their melting
(a)
(b)
Fig. 2 a FGFR Kinase Inhibitors, b metabotropic glutamate receptor 5 (mGluR5)
123

J. Afsar et al.
O
R
H
R
H3C
H3C
CN
Cat. 5 mg
N
N
N
N
N
NH2
neat, 100 °C
CN
NH2
NC
R: H, 4-Cl, 4-Me, 4-MeO, 2,4-Cl2, 4-Isopropyle, 4-Br, 4-NO2, 3,4-(MeO)2, 4-F,
3-NO2, 2,6-F2, 3,5-F2, 3,4-F2,4-CN, 2-Naph, 1-Naph
Scheme 1 MCRs Synthesis of pyrazolo[3,4-b]pyridine derivatives using Fe2O3@SiO2(CH2)3-
Cl[DABCO-NO2]C(NO2)3 as novel nanomagnetic catalyst under neat conditions
points and spectral data with those reported in the literature. Progress of the
reactions was monitored by TLC using silica gel SIL G/UV 254 plates. Melting
points were recorded on a Bu¨chi B-545 apparatus in open capillary tubes. Rf values
were measured using a 3/7 mixture of EtOAc/n-Hexane as eluent. Fourier
transformed infrared (FTIR) spectra of the catalyst and the synthesized products
were performed on a Perkin-Elmer spectrum 65 FT-IR spectrometer using KBr
disks. High resolution mass spectra (GC/QTOF, chemical ionization (CI) mode with
20% CH4 and 300 °C source temperature) were obtained using an Agilent 7200
Network spectrometer. Each sample was dissolved in CHCl3 and directly injected
1
into the instrument by using a standard Agilent glass capillary. H NMR (300 and
400 MHz) spectra were obtained on Bruker Avance 300 and Bruker Avance 400
NMR spectrometers under proton coupled mode using CDCl3 as solvent. 13C NMR
(75, 101 and 126 MHz) spectra were acquired on Bruker Avance 300, Bruker
Avance 400 NMR and Bruker Avance DRX 500 NMR spectrometers in the proton
decoupled mode at 20 °C in CDCl3 as solvent. Chemical shifts are given in d (parts
per million) and the coupling constants (J) in Hertz. 19F NMR (282 and 376 MHz)
spectra were recorded on Bruker Avance 300 and Bruker Avance 400 NMR
1
spectrometers, in proton coupled mode. Data for H NMR spectra are reported as
follows: chemical shift (ppm), multiplicity (s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet; and br., broad), coupling constant (Hz), and integration.
Simultaneous thermal gravimetry analysis TG-DSC, were carried out on a Mettler
Toledo device (model TGA/SDTA851and/LF/1600), capable of working between
room temperature and 1600 °C under inert Argon atmosphere and equipped with a
34 position autosampler. The experiment was carried out at 25 °C using a heating
rate of 25 °C min-1 up to 800 °C. The powder X-ray diffraction (XRD) pattern was
recorded with a Bruker D8-Advance with a Goebel mirror (non-planar samples),
high temperature chamber (up to 900 °C), generator of x-ray KRISTALLOFLEX K
760-80F (power: 3000 W, voltage: 20–60 kV and current: 5–80 mA) and with a
tube of RX with copper anode Ka (k = 0.154 nm) in the range 10° \ 2h \ 90°.
123

Synthesis and application of a novel nanomagnetic…
Physical adsorption and desorption of N2 isotherms were measured at 77 K with an
AUTOSORB-iQ-XR-2 analyzer. The catalyst was degassed before the experiment
for 1 day at 100 °C under high vacuum conditions. The Brunauer–Emmett–Teller
(BET) method was used to calculate the specific surface areas (SBET). By using the
Barrett–Joyner–Halenda (BJH) model, the pore volumes and pore size distributions
were derived from the adsorption branches of isotherms. The micropore surface area
(SBET micro) was calculated using the V–t plot method. Scanning electron
microscopy (SEM) studies were performed using a Hitachi S3000N, equipped with
a Bruker XFlash 3001 x-ray detector for microanalysis (EDX) and elemental
mapping. Field emission scanning electron microscopy (FESEM) studies were
performed using a Merlin VP Compact from Zeiss, equipped with a Bruker Quantax
400 EDS microanalysis system. The resolution was 0.8 nm at 15 kV and 1.6 nm at
1 kV. Field emission equipment is able to work at very reduced voltages (from 0.02
to 30 kV) allowing us to observe beam sensitive samples without damaging them
and minimizing the charging effects. High-resolution transmission electron
microscopy (HRTEM) images were obtained using a JEOL JEM-2010 microscope
operating at an accelerating voltage of 200 kV. This microscope was equipped with
an OXFORD INCA Energy TEM 100 x-ray detector for microanalysis (EDS) and
acquisition of the images was made by means of a GATAN ORIUS SC600 digital
camera mounted on-axis, integrated with the program GATAN Digital Micrograph
1.80.70 for GMS 1.8.0. The sample was prepared by drop casting the dispersed
particles in absolute ethanol onto a 300-mesh copper grid from TED PELLA, INC.
model 01883-F, coated with a lacey formvar film enforced by a heavy coating of
carbon. Holes were completely open. The magnetic behavior of the nanomagnetic
catalyst was also measured by a vibrating sample magnetometer (VSM) instrument
from Meghnatis Daghigh Kavir Company, model LBKFB.
General procedure for the preparation of the novel nanomagnetic catalyst
Fe2O3 nanoparticles were prepared according to a previously reported procedure.
Then, 1 g of Fe2O3 nanoparticles (a) was dispersed in toluene. In the next step, to
coat the surface of the Fe2O3 with SiO2, 1.5 mL tetraethyl orthosilicate (TEOS) was
added drop-wise and the reaction was continued for 12 h under reflux conditions.
The resultant Fe2O3@SiO2 (b) was washed with ethanol for three times and dried.
After that, in order to silanate the silica coated nanomagnetic particles, 3-chloro-
propyltrimethoxysilane (1.5 mL) was added to the mixture in toluene under reflux
conditions to give (c). After 12 h, compound (c) was washed with ethanol, then 1,4-
diazabicyclo[2.2.2]octane (DABCO) (6 mmol, 0.67 g) was added and refluxed in
ethanol for 12 h to afford compound (d). Eventually, tetranitromethane (6 mmol,
1.18 g, 0.73 mL) was added to compound (d) in toluene under reflux conditions to
give (e) as a novel nanomagnetic catalyst (Scheme 2).
General procedure for the synthesis of pyrazolo[3,4-b]pyridine derivatives
To a round-bottom flask containing a mixture of the corresponding aldehyde
(1 mmol), 3-methyl-1-phenyl-1H-pyrazol-5-amine or 3-methyl-1H-pyrazol-5-
123

J. Afsar et al.
Scheme 2 Synthetic route for synthesis of novel nanomagnetic catalyst Fe2O3@SiO2(CH2)3-
Cl[DABCO-NO2]C(NO2)3
amine (1 mmol) and malononitrile (1.2 mmol, 79 mg) 5 mg of Fe2O3@SiO2(-
CH2)3-Cl[DABCO-NO2]C(NO2)3 were added. The resulting mixture was stirred
magnetically under neat conditions at 100 °C. After completion of the reaction,
which was monitored by TLC, the mixture was cooled to room temperature. Then,
acetone was added to separate the catalyst by an external magnet. After evaporation
of the solvent, the resulting solid was recrystallized in ethanol to give the
corresponding pure products. Finally, the nanomagnetic catalyst was reused for the
next run (Scheme 1).
Spectroscopic and analytical data for the synthesized products
6-Amino-3-methyl-1,4-diphenyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (1a) Iso-
lated as white solid, (290 mg, 89%), Rf: 0.52; Melting point: 210–212 °C; FT-IR: t
1
(cm-1) = 3366, 3219, 2217, 1626, 756; H NMR (300 MHz) d 8.11 (dd, J = 8.6,
1.1, 2H), 7.66–7.39 (m, 7H), 7.35–7.27 (m, 1H), 5.42 (br. s, 2H), 2.03 (s, 3H). 13C
NMR (101 MHz) d 158.3, 152.8, 150.9, 144.4, 138.8, 134.0, 129.9, 129.0, 128.6
(2c), 126.2, 121.5, 116.8, 109.5, 88.5, 14.7; HRMS calcd. for C20H15N5 [M?]
325.1327, found: 325.1343.
6-Amino-4-(3,4-dimethoxyphenyl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-
carbonitrile (1b) Isolated as white solid, (354 mg, 92%), Rf: 0.35; Melting point:
218–220 °C; FT-IR: t (cm-1) = 3332, 3222, 2210, 1626, 765; 1H NMR (300 MHz)
d 8.10 (dd, J = 8.6, 1.1, 2H), 7.58–7.42 (m, 2H), 7.35–7.27 (m, 1H), 7.11–7.00 (m,
2H), 6.98 (d, J = 1.5, 1H), 5.41 (br. s, 2H), 3.98 (s, 3H), 3.94 (s, 3H), 2.13 (s, 3H).
13C NMR (101 MHz) d 158.4, 152.7, 150.9, 150.3, 148.8, 144.4, 138.8, 129.0, 126.2
(2C), 121.7, 121.5, 117.1, 111.9, 111.0, 109.6, 88.6, 56.1, 56.0, 15.0; HRMS calcd.
for C22H19N5O2 [M?] 385.1539, found: 385.1557.
6-Amino-3-methyl-4-(4-nitrophenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboni-
trile (1c) Isolated as pale yellow solid, (333 mg, 90%), Rf: 0.60; Melting point:
223–225 °C; FT-IR: t (cm-1) = 3350, 3208, 2214, 1619, 1581, 1348, 769; 1H NMR
(300 MHz) d 8.53–8.34 (m, 2H), 8.10 (d, J = 7.7, 2H), 7.79–7.59 (m, 2H), 7.51 (t,
J = 7.9, 2), 7.33 (t, J = 7.4, 1H), 5.47 (br. s, 2H), 2.03 (s, 3H). 13C NMR (101 MHz)
d 158.1, 150.8, 149.7, 148.8, 143.6, 140.4, 138.5, 129.9, 129.0, 126.4, 124.0, 121.5,
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Synthesis and application of a novel nanomagnetic…
116.1, 109.0, 88.0, 14.8; HRMS calcd. for C20H14N6O2 [M?] 370.1178, found:
370.1187.
6-Amino-4-(4-chlorophenyl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-car-
bonitrile (1d) Isolated as white solid, (327 mg, 91%), Rf: 0.74; Melting point:
194–198 °C; FT-IR: t (cm-1) = 3308, 3187, 2214, 1633, 824; 1H NMR (300 MHz)
d 8.10 (dd, J = 8.5, 1.0, 2H), 7.61–7.45 (m, 4H), 7.45–7.38 (m, 2H), 7.31 (t, J = 7.4,
1H), 5.43 (br. s, 12H), 2.06 (s, 3H). 13C NMR (101 MHz) d 158.3, 151.3, 150.9,
144.1, 138.7, 136.3, 132.4, 130.0, 129.0 (2C), 126.3, 121.5, 116.6, 109.4, 88.4, 14.8;
HRMS calcd. for C20H14ClN6 [M?] 359.0938, found: 370.0951.
6-Amino-4-(4-bromophenyl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-car-
bonitrile (1e) Isolated as white solid, (372 mg, 92%), Rf: 0.77; Melting point:
216–217 °C; FT-IR: t (cm-1) = 3369, 2920, 2217, 1637, 760; 1H NMR (300 MHz)
d 8.10 (dd, J = 8.6, 1.1, 2H), 7.75–7.67 (m, 2H), 7.54–7.45 (m, 2H), 7.38–7.28 (m,
3H), 5.43 (br. s, 2H), 2.06 (s, 3H). 13C NMR (101 MHz) d 158.3, 151.3, 150.9,
144.1, 138.7, 132.8, 132.0, 130.2, 129.0, 126.3, 124.5, 121.5, 116.6, 109.3, 88.3,
14.8; HRMS calcd. for C20H14BrN5 [M?] 403.0433, found: 403.0437.
6-Amino-4-(4-isopropylphenyl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-car-
bonitrile (1f) Isolated as white solid, (320 mg, 87%), Rf: 0.71; Melting point:
198–200 °C; FT-IR: t (cm-1) = 3308, 3190, 2211, 1635, 709; 1H NMR (300 MHz)
d 8.11 (dd, J = 8.6, 1.1, 12H), 7.53–7.45 (m, 2H), 7.40 (br. s, 4H), 7.34–7.27 (m,
1H), 5.42 (br. s, 2H), 3.10–2.93 (m, 1H), 2.06 (s, 3H), 1.34 (s, 3H), 1.32 (s, 3H). 13
C
NMR (101 MHz) d 158.4, 153.1, 150.9, 144.657, 138.8, 131.2, 129.0, 128.7, 126.6,
126.1, 121.5, 117.1, 109.6, 88.5, 34.0, 23.9, 14.8; HRMS calcd. for C23H21N5 [M?]
367.1797, found: 367.1812.
6-Amino-4-(2,4-dichlorophenyl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-car-
bonitrile (1g) Isolated as white solid, (359 mg, 91%), Rf: 0.82; Melting point:
167-169 °C; FT-IR: t (cm-1) = 3350, 3213, 2214, 1614, 757; 1H NMR (300 MHz)
d 8.11 (dd, J = 8.7, 1.1, 2H), 7.63 (d, J = 2.0, 1H), 7.55–7.42 (m, 3H), 7.35–7.27
(m, 2H), 5.45 (br. s, 2H), 2.02 (s, 3H). 13C NMR (101 MHz) d 158.2, 150.8, 148.2,
144.1, 138.7, 136.7, 133.5, 131.7, 130.8, 130.1, 129.0, 127.7, 126.3, 121.5, 115.9,
109.6, 88.8, 13.5; HRMS calcd. for C20H13Cl2N5 [M?] 393.0548, found: 393.0564.
6-Amino-3-methyl-1-phenyl-4-(p-tolyl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile
(1h) Isolated as white solid, (315 mg, 93%), Rf: 0.72; Melting point: 200–202 °C;
1
FT-IR: t (cm-1) = 3325, 3216, 2211, 1629, 762; H NMR (300 MHz) d 8.16–8.07
(m, 2H), 7.54–7.44 (m, 2H), 7.36 (br. s, 4H), 7.33–7.27 (m, 1H), 5.39 (br. s, 2H),
2.47 (s, 3H), 2.07 (s, 3H). 13C NMR (101 MHz) d 158.4, 153.1, 150.9, 144.5, 140.0,
138.8, 131.0, 129.3, 129.0, 128.5, 126.2, 121.6, 117.0, 109.5, 88.5, 21.5, 14.8;
HRMS calcd. for C21H17N5 [M?] 339.1484, found: 339.1495.
6-Amino-4-(4-fluorophenyl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboni-
trile (1i) Isolated as white solid, (302 mg, 88%), Rf: 0.61; Melting point:
214–216 °C; FT-IR: t (cm-1) = 3328, 3222, 2214, 1629, 768; 1H NMR (300 MHz)
d 8.16–8.02 (m, 2H), 7.56–7.41 (m, 4H), 7.39–7.16 (m, 2H), 5.43 (br. s, 2H), 2.06
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J. Afsar et al.
(s, 3H). 13C NMR (101 MHz) d 163.6 (d, J = 250.4), 158.3, 151.6, 150.9, 144.2,
138.7, 130.6 (d, J = 8.5), 129.9 (d, J = 3.3), 129.0, 126.3, 121.5, 116.7, 115.9 (d,
J = 22.0), 109.5, 88.5, 14.8. 19F NMR (282 MHz) d -110.51; HRMS calcd. for
C20H14FN5 [M?] 343.1233, found: 343.1244.
6-Amino-3-methyl-4-(3-nitrophenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboni-
trile (1j) Isolated as white solid, (315 mg, 85%), Rf: 0.52; Melting point:
157–159 °C; FT-IR: t (cm-1) = 3357, 3224, 2216, 1617, 753; 1H NMR (400 MHz)
d 8.46 (m, 1H), 8.38 (t, J = 1.8, 1H), 8.19–8.02 (m, 2H), 7.89–7.77 (m, 2H),
7.58–7.46 (m, 2H), 7.34 (m, 1H), 5.55 (br. s, 2H), 2.04 (s, 3H). 13C NMR (75 MHz)
d 158.2, 149.4, 148.1, 143.6, 138.5, 138.1, 135.6, 134.5, 130.0, 129.0, 126.5, 124.8,
123.9, 122.8, 121.6, 116.2, 88.2, 14.8; HRMS calcd. for C20H14N6O2 [M?]
370.1178, found: 393.1195.
6-Amino-4-(4-methoxyphenyl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-car-
bonitrile (1k) Isolated as white solid, (323 mg, 91%), Rf: 0.47; Melting point:
195–197 °C; FT-IR: t (cm-1) = 3353, 3224, 2216, 1629, 765; 1H NMR (400 MHz)
d 8.17–8.04 (m, 2H), 7.52–7.46 (m, 2H), 7.44–7.39 (m, 2H), 7.33–7.27 (m, 1H),
7.09–7.05 (m, 2H), 5.40 (br. s, 2H), 3.90 (s, 3H), 2.10 (s, 3H). 13C NMR (101 MHz)
d 160.9, 158.4, 152.8, 151.0, 144.5, 138.8, 130.2, 129.0, 126.1 (2C), 121.5, 117.2,
114.0, 109.7, 88.5, 55.4, 15.0.
6-Amino-4-(2,6-difluorophenyl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-car-
bonitrile (1l) Isolated as white solid, (307 mg, 85%), Rf: 0.55, Melting point:
227–229 °C; FT-IR: t (cm-1) = 3318, 3202, 2213, 1630, 768; 1H NMR (300 MHz)
d 8.17–8.04 (m, 2H), 7.62–7.45 (m, 3H), 7.36–7.27 (m, 1H), 7.19–7.10 (m, 2H),
5.43 (br. s, 2H), 2.11 (s, 3H). 13C NMR (101 MHz) d 159.54 (dd, J = 252.0, 6.0),
158.2, 150.9, 143.9, 139.7, 138.6, 132.4 (t, J = 10.0), 129.0, 126.3, 121.6, 116.0,
112.0 (dd, J = 19.5, 6.0), 111.3 (t, J = 20.0), 110.0, 89.9, 13.0. 19F NMR
(282 MHz) d -111.00; HRMS calcd. for C20H13F2N5 [M?] 361.1139, found:
361.1151.
6-Amino-3-methyl-4-(naphthalen-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-car-
bonitrile (1m) Isolated as white solid, (319 mg, 85%), Rf: 0.55; Melting point:
195–197 °C; FT-IR: t (cm-1) = 3385, 3319, 2210, 1621, 776; 1H NMR (300 MHz)
d 8.19–8.11 (m, 2H), 8.07–7.95 (m, 2H), 7.64 (dd, J = 8.2, 7.1, 1H), 7.59–7.43 (m,
26H), 7.36–7.28 (m, 1H), 5.47 (br. s, 2H), 1.59 (s, 3H). 13C NMR (101 MHz) d
158.5, 151.5, 150.7, 144.7, 138.8, 133.4, 131.6, 131.0, 130.2, 129.0, 128.6, 127.3,
126.6 (2C), 126.2, 125.2, 124.8, 121.5, 116.5, 110.8, 89.7, 13.4; HRMS calcd. for
C24H17N5 [M?] 375.1484, found: 375.1503.
6-Amino-3-methyl-4-(naphthalen-2-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-car-
bonitrile (1n) Isolated as white solid, (338 mg, 90%), Rf: 0.58, Melting point:
270–272 °C; FT-IR: t (cm-1) = 3356, 3219, 2217, 1623, 744; 1H NMR (300 MHz)
d 8.19–8.06 (m, 12H), 8.03 (d, J = 8.5, 1H), 7.99–7.92 (m, 3H), 7.66–7.47 (m, 5H),
7.35–7.27 (m, 1H), 5.45 (br. s, 2H), 2.02 (s, 31H). 13C NMR (101 MHz) d 158.4,
152.7, 150.9, 144.5, 138.8, 133.7, 132.7, 131.4, 129.0, 128.5 (2C), 128.0, 127.4,
123

Synthesis and application of a novel nanomagnetic…
127.0, 126.2, 125.7, 121.6, 116.9, 109.7, 88.7, 14.8; HRMS calcd. for C24H17N5
[M?] 375.1484, found. 375.1501.
6-Amino-4-(3,5-difluorophenyl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-car-
bonitrile (1o) Isolated as white solid, (314 mg, 87%), Rf: 0.67; Melting point:
198–200 °C; FT-IR: t (cm-1) = 3348, 3227, 2219, 1632, 744; 1H NMR (300 MHz)
d 8.17–8.06 (m, 2H), 7.57–7.48 (m, 2H), 7.37–7.30 (m, 1H), 7.12–6.97 (m, 3H),
5.47 (br. s, 2H), 2.10 (s, 3H). 13C NMR (126 MHz) d 162.89 (dd, J = 252.0, 13.0),
158.2, 150.8, 149.6, 143.8, 138.6, 136.9 (t, J = 10.0), 129.0, 126.4, 121.5, 116.1,
112.1 (dd, J = 20.0, 7.0), 109.1, 105.5 (t, J = 25.0), 88.1, 14.5; 19F NMR
(376 MHz) d -107.5; HRMS calcd. for C20H13F2N5 [M?] 361.1139, found:
361.1150.
6-Amino-4-(3,4-difluorophenyl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-car-
bonitrile (1p) Isolated as white solid, (322 mg, 89%), Rf: 0.57; Melting point:
203–205 °C; FT-IR: t (cm-1) = 3369, 3227, 2215, 1634, 764; 1H NMR (300 MHz)
d 8.15–8.08 (m, 2H), 7.56–7.48 (m, 2H), 7.43–7.30 (m, 3H), 7.27–7.21 (m, 1H),
5.46 (br. s, 2H), 2.10 (s, 3H). 13C NMR (126 MHz) d 158.2, 151.4 (dd, J = 252.6,
12.2), 150. 9, 150.24 (dd, J = 251.6, 12.8), 150.0 (d, J = 0.9), 143.8, 138.6, 130.7
(dd, J = 6.0, 4.3), 129.0, 126.3, 125.2 (dd, J = 6.6, 4.0), 121.5, 118.1 (dd, J = 25.0,
18.0), 116.3, 109.3, 88.4, 14.7; 19F NMR (376 MHz) d -135.15 (dd, J = 311.5,
21.3); HRMS calcd. for C20H13F2N5 [M?] 361.1139, found: 361.1152.
6-Amino-4-(4-cyanophenyl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-car-
bonitrile (1q) Isolated as white solid, (326 mg, 93%), Rf: 0.50; Melting point:
237–239 °C; FT-IR: t (cm-1) = 3338, 3216, 2228, 2211, 1619; 1H NMR
(300 MHz) d 8.13–8.06 (m, 2), 7.93–7.85 (m, 2H), 7.65–7.58 (m, 2H), 7.55–7.47
(m, 2H), 7.36–7.29 (m, 1H), 5.47 (br. s, 2H), 2.02 (s, 3H). 13C NMR (126 MHz) d
158.2, 150.9, 150.0, 143.6, 138.6, 132.5, 129.5, 129.0, 126.4, 121.5, 117.9, 116.2,
114.1, 109.0, 88.0, 14.7; HRMS calcd. for C21H14N6 [M?] 350.1280, found:
350.1303.
6-Amino-3-methyl-4-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (1r) Isolated
as white solid, (219 mg, 88%), Melting point: 267–269 °C; FT-IR: t (cm-1)-
1
= 3460, 3423, 3347, 3199, 2211, 1652; H NMR (400 MHz) d 12.94 (s, 1H),
7.71–7.60 (m, 3H), 7.56 (dd, J = 6.4, 2.9 Hz, 2H), 6.98 (s, 2H), 1.87 (s, 3H). 13C
NMR (101 MHz, DMSO) d 158.89, 153.19, 151.95, 142.13, 134.50, 129.38, 128.52,
128.31, 127.40, 116.97, 106.08, 86.74, 14.23.
6-Amino-3-methyl-4-(p-tolyl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (1s) Iso-
lated as white solid, (226 mg, 86%), Melting point: 263–265 °C; FT-IR: t (cm-1)-
= 3463, 3440, 3314, 2212, 1639; 1H NMR (400 MHz) d 12.83 (s, 1H), 7.38 (s, 4H),
6.88 (s, 2H), 2.42 (s, 3H), 1.84 (s, 3H). 13C NMR (101 MHz, DMSO) d 158.90,
153.17, 152.16, 147.12, 142.16, 138.95, 131.56, 128.85, 128.50, 117.06, 106.12,
86.82, 20.91, 14.37.
6-Amino-4-(3,4-dimethoxyphenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboni-
trile (1t) Isolated as white solid, (275 mg, 89%), Melting point: 273–275 °C; FT-
123

J. Afsar et al.
IR: t (cm-1) = 3413, 3325, 2924, 2213, 1652; 1H NMR (400 MHz) d 12.94 (s, 1H),
7.21 (d, J = 8.3 Hz, 1H), 7.19 (d, J = 1.9 Hz, 1H), 7.12 (dd, J = 8.2, 1.9 Hz, 1H),
6.92 (s, 2H), 3.94 (s, 3H), 3.88 (s, 3H), 1.99 (s, 3H). 13C NMR (101 MHz, DMSO) d
158.94, 153.25, 151.97, 149.52, 148.15, 142.23, 126.62, 121.34, 117.28, 112.40,
111.21, 106.23, 86.92, 55.65, 55.46, 14.59.
Results and discussion
Characterization of the novel nanomagnetic catalyst
To confirm the successful synthesis of the nanomagnetic heterogeneous catalyst, the
structure was fully characterized by various techniques such as Fourier transform
infrared spectroscopy (FT-IR), elementals mapping survey with energy-dispersive
X-ray spectroscopy (EDX), thermal gravimetric analysis (TGA), derivative thermal
gravimetric (DTG), powder x-ray diffraction patterns (XRD), field scanning
electron microscopy (FESEM), high resolution transmission electron microscopy
(HRTEM), physical adsorption and physisorption of N2 isotherms (BET) and
vibrating sample magnetometer (VSM).
The FT-IR spectrum of the catalyst and its comparison with the starting materials
is presented in Fig. 3. As shown, the absorption peak observed at 586 cm-1 is
related to the formation of magnetic nanoparticles, which is attributed to the Fe–O
bonds. The depicted sharp and broad band at 1076 is related to Si–O–Si stretching in
the silica layer. The absorption bands at 1384 and 1629 cm-1 are connected to the
vibrational modes of the –NO2 bonds (Fig. 3).
Next, the energy-dispersive X-ray spectroscopy (EDX) and elemental mapping
analyses were used to prove the organic content as well as the elemental
composition of the MNPs, which could be explained by the DABCO ionic liquid
tags attached to the MNPs (Figs. 4a–h). As shown, the results confirmed the
presence of carbon (C: 23.73%), nitrogen (N: 12.70%), oxygen (O: 48.33%),
Fig. 3 FT-IR spectra of a Fe2O3@SiO2(CH2)3-Cl[DABCO], and b Fe2O3@SiO2(CH2)3-Cl[DABCO-
NO2]C(NO2)3
123

Synthesis and application of a novel nanomagnetic…
chlorine (Cl: 0.06%), iron (Fe: 11.63%) and silicon (Si: 3.56%), as the expected
elements in the catalyst structure. Morover, the selected-area elemental analysis
displays the regular uniformity of the synthesized MNPs.
To investigate the morphology and topography and to resolve the internal
structure of the catalyst, high-resolution transmission electron microscopy
(HRTEM) and field emission scanning electron microscopy (FESEM) analyses
were carried out (Fig. 5). As shown in figures a and b, Fe2O3 has been coated with
tetraethyl orthosilicate (TEOS), 3-chloropropyltrimethoxysilane, 1,4-diazabicy-
clo[2.2.2]octane (DABCO) and tetranitromethane respectively. The shape of
Fe2O3@SiO2(CH2)3-Cl[DABCO-NO2]C(NO2)3 were seperated, arranged and
improved to a symmetrical double spherical MNPs. As shown in Fig. 5b, the
crystal Fe2O3-MNPs distance layer of final nanoparticles is around 0.26 nm.
Moreover, the FESEM results clearly proved the spherical and uniform shape of the
MNPs in the sample (Fig. 5c).
Thermogravimetric (TG) analysis, derivatives thermal gravimetric analysis
(DTG), and the differential thermal analysis (DSC) were performed to analyze
the content of DABCO ionic tags in the catalyst under argon atmosphere (Fig. 6).
From the performed studies, it can be inferred that of the two main weight losses
that occurred upon heating, the first, from ambient temperature to 110 °C with a
weight loss of * 1 wt% could be related to the removal of surface-adsorbed water
and organic solvents applied during the catalyst preparation, and the second part
from 200 to 300 °C with weight loss of [ 11 wt% could be reason for the ionic
molten salt nature of DABCO with different NO2 parts. Moreover, the analysis of
the results of DSC (Fig. 6b) showed that the catalyst has three different thermal
behaviours. Initially, it showed a downward and exothermic pattern from 25 to
110 °C. Then, a second upwards and endothermic pattern from 110 to * 400 °C,
and finally, in the last part from * 400 to 800 °C it showed again a downward and
endothermic behaviour.
Further observations were obtained by powder X-ray diffraction (XRD) to
illustrate the crystalline structure of the MNPs in a range of 10 \ 2h \ 90° (Fig. 7).
The upward typical iron oxide spectrum pattern showed peaks at 2h values of
14.96°, 18.38°, 30.24°, 35.63°, 43.28°, 53.73°, 57.27°, 62.93° and 74.47° related to
(110), (111), (220) (311), (400), (422), (511), (440) and (533) corresponding to
planes of iron oxide (FexOy). Moreover, as is clear from the maghemite (Fe2O3)
with blue standard lines (JCP2: 00-039-1346) and magnetite (Fe3O4) with red
standard lines (JCP2: 01-075-1609) as the standard references, the center of every
peak may be adjusted with maghemite (Fe2O3) structures more than magnetite
(Fe3O4). Also, the sharpest peak in the XRD spectrum of the catalyst has been
˚
correlated to plane (311) at 30.24° with a 2.51 A layer distance, and the largest layer
˚
distance is correlated to layer (220) at 30.24° with 2.95 A.
Next, N2 adsorption/desorption isotherm was performed to characterize the
porosity and total surface area of the magnetic nanoparticles. As shown in Fig. 8a,
catalyst exhibited type II isotherm according to the IUPAC definition and with H3
type hysteresis loop, which displayed the presence of a nanoporous structure. The
surface area and pore volume of the catalyst are listed in Table 1. The obtained
Brunauer–Emmett–Teller (BET), BJH and DR specific surface areas of
123

J. Afsar et al.
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Synthesis and application of a novel nanomagnetic…
bFig. 4 a EDX spectroscopy quantitative analysis; b total elemental maps and displays of C (c), N (d), O
(e), Si (f), Fe (g), and Cl (h) atoms in the MNPs of catalyst
Fe2O3@SiO2(CH2)3-Cl[DABCO-NO2]C(NO2)3 are 112.766, 61.676 and 108.923
m2 g-1 , respectively. Moreover, the total pore volume was determined to be 0.31
cm3 g-1. The corresponding pore-size distribution (PSD) of nanopores (inset of
Figs. 8b) was calculated from the adsorption branch on the basis of BJH model
(Fig. 8b) and is centered at 15 nm, according to the (BJH) model.
The magnetic measurement of Fe2O3@SiO2(CH2)3-Cl[DABCO-NO2]C(NO2)3
was also studied. Its VSM was compared with its precursors Fe2O3, Fe2O3@SiO2
and Fe2O3@SiO2(CH2)3Cl. As shown in Fig. 9, after the addition of each layer, the
saturation magnetization reduced from 70.55 emu g-1 for Fe2O3 to 50.01 emu g-1
for the described Fe2O3@SiO2(CH2)3-Cl[DABCO-NO2]C(NO2)3.
After the full characterization and investigation of the catalyst’s structure, it was
used as nanomagnetic catalyst in the condensation reaction of 3-methyl-1-phenyl-
1H-pyrazol-5-amine or 3-methyl-1H-pyrazol-5-amine, malononitrile and various
aromatic aldehydes for the synthesis of pyrazolo[3,4-b]pyridine derivatives.
Initially, the reaction of benzaldehyde, 3-methyl-1-phenyl-1H-pyrazol-5-amine
and malononitrile was selected as a model by which to optimize the reaction
conditions. The results for the optimization of temperature, catalyst loading and
solvents are summarized in Table 2. As shown, the best results for the synthesis of
pyrazolo[3,4-b]pyridines were achieved when the reaction was carried out at 100 °C
in the presence of 5 mg of Fe2O3@SiO2(CH2)3-Cl[DABCO-NO2]C(NO2)3 under
neat conditions.
After optimizing the reaction conditions, to assess the scope and limitations of
the catalyst, 3-methyl-1-phenyl-1H-pyrazol-5-amine or 3-methyl-1H-pyrazol-5-
amine was reacted with various aromatic aldehydes (bearing electron-donating
and electron-withdrawing groups) and malononitrile. As shown in Table 3, the
results indicated that this method is appropriate for the synthesis of pyrazolo[3,4-
b]pyridine derivatives, regardless of the structure of the aromatic aldehyde
employed in the reaction. Aliphatic aldehyde was also tested; the target products
were not synthesized. The reaction was sluggish.
In accord with previously reported methods [28, 31], an applicable mechanism
for the synthesis of pyrazolo[3,4-b]pyridines is proposed (Scheme 2). Firstly,
malononitrile reacts with the catalyst-activated aldehyde to afford 2-benzylidene-
malononitrile (II), after losing nitric acid [36]. Then, 3-methyl-1-phenyl-1H-
pyrazol-5-amine or 3-methyl-1H-pyrazol-5-amine attacks to intermediate II as a
Michael acceptor to afford III. Next, the intramolecular cyclization of III creates
intermediate IV which is converted to the desired product via hyperconjugative-like
anomeric-based oxidation (Scheme 3). Previously reported studies have proposed
an aerobic oxidation of intermediate V towards the target molecule VII. In contrast
to the previously reported mechanistic route [31] for the final step of the
aforementioned described organic mechanism, we suggest that this step might
proceed via an unusual hydride transfer/Cannizzaro reaction (Scheme 4) [37] such
as those proposed for pyranose acetals (Scheme 5) [38] and the H2 releasing from
123

J. Afsar et al.
Fig. 5 a) High resolution transmission electron microscopy (HRTEM) images of a) Fe2O3@SiO2(CH2)3-
Cl[DABCO-NO2]C(NO2)3 in 5 nm scale; inlet: b) 2 nm selected scale area (V); and c) field emission
scanning electron microscopy (FESEM) of final catalyst nanoparticles in 100 nm scale
123

Synthesis and application of a novel nanomagnetic…
Fig. 6 a Thermal gravimetric analysis (TG/DTG), and b (TGA/DSC) of MNPs
tricyclic orthoamides (Scheme 6) [39–41]. As presented in Scheme 7, the isomer
with an equatorial methoxy group is more reactive than its axial counterpart due to
the presence of two lone pair anomeric assistance, which facilitates the departure of
the hydride leaving group [38].
As mentioned above, we have introduced an ‘‘anomeric-based oxidation (ABO)’’
terminology for the final step towards the synthesis of various molecules such as:
1,4-dihydropyrano-[2,3-c]pyrazoles [42, 43], 2,4,6-triarylpyridines [44, 45], 2-
amino-3-cyanopyridines [46, 47], 2-sbstituted benz-(imida, oxa and othia)-zole
derivatives [36], the oxidative aromatization of pyrazolines and 1,4-dihydropyridi-
nes [48], sulfanylpyridines [49], and 2-amino-4-aryl-6-(arylamino)pyridine-3,5-
dicarbonitriles [50]. To validate this idea, the model reaction was carried out under
123

J. Afsar et al.
Fig. 7 Powder XRD pattern of MNPs, inlet blue solid lines: JCP2: 00-039-1346 for standard data base of
Fe2O3 and inlet red solid lines: (JCP2: 01-075-1609) for standard data base of Fe3O4
250
0,45
0,4
(b)
(a)
0,35
0,3
200
150
100
50
0,25
0,2
0,15
0,1
0,05
0
0,1 15,1 30,1 45,1 60,1 75,1 90,1 105,1120,1135,1150,1
Pore Diameter (nm)
0
0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1
Relaꢀve Pressure(P/P°)
Fig. 8 a Nitrogen adsorption/desorption isotherms and b inset: BJH pore size distribution of
Fe2O3@SiO2(CH2)3-Cl[DABCO-NO2]C(NO2)3
both nitrogen and argon atmosphere in the absence of any molecular oxygen. Under
these conditions, the reaction progressed under atmosphere of nitrogen and argon
slightly slower than under normal reaction conditions (air atmosphere). On the basis
123

Synthesis and application of a novel nanomagnetic…
Table 1 Textural properties of Fe2O3@SiO2(CH2)3-Cl[DABCO-NO2]C(NO2)3
SaBET (m2 g-1
)
SbBJH (m2 g-1
)
Scm (m2 g-1
)
Vdt (cm3 g-1
)
Pore sizee (nm)
14.826
112.766
61.676
108.923
0.31
aSBET: total surface area
bSBJH: surface area estimated by BJH model applied to the desorption branch of the isotherm
cSm: Micropore surface area estimated by DR model
dVt: total pore volume
eObtained from BJH
Vibraꢀng sample magnetometer(VSM)
70
50
30
10
-15000
-10000
-5000
0
5000
10000
15000
-10
-30
-50
-70
Fe2O3
Fe2O3@SiO2
Fe2O3@SiO2(CH2)3Cl
Final MNPs
Applied Field (Oe)
Fig. 9 VSM magnetization curves of catalyst compared to the catalyst precursors Fe2O3, Fe2O3@SiO2,
Fe2O3@SiO2(CH2)3Cl
of this evidence, the conversion of intermediate V to the target molecule VII might
occur by unusual hydride transfer and the release of molecular hydrogen (H2). The
C–H bond is weakened via hyperconjugation, like that of the nitrogen lone pairs into
the anti-bonding of C–H (rÃ
orbital) which can be broken by reaction with a
C–H
proton to give molecular hydrogen.
The recovery and reuse of Fe2O3@SiO2(CH2)3-Cl[DABCO-NO2]C(NO2)3 were
investigated under the optimized conditions for the reaction of benzaldehyde,
3-methyl-1-phenyl-1H-pyrazol-5-amine and malononitrile. In these conditions, the
nanomagnetic catalyst was reused up to nine times with only a marginal decrease in
its reactivity. After each use, in order to recover the catalyst, acetone was added to
123

J. Afsar et al.
Table 2 Reaction of benzaldehyde, 3-methyl-1-phenyl-1H-pyrazol-5-amine and malononitrile under
different conditions
Entry
Solvent
Catalyst loading (mg)
Temp. (°C)
Time (min)
Yield (%)a
1
–
10
10
10
8
80
30
81
2
–
100
25
89
3
–
100
25
89
4
–
100
25
89
5
–
5
100
25
89
6
–
3
100
40
75
7
–
–
100
180
240
180
240
180
38
8
EtOH
EtOAc
H2O
CH3CN
5
Reflux
Reflux
Reflux
Reflux
35
9
5
32
10
11
5
Trace
38
5
Reaction conditions: aryl aldehyde (1 mmol), malononitrile (1.2 mmol, 79 mg), 3-methyl-1-phenyl-1H-
pyrazol-5-amine (1 mmol, 173 mg) and [Fe2O3@SiO2(CH2)3-Cl[DABCO-NO2]C(NO2)3] (5 mg)
Bold value indicates the optimized conditions
aIsolated yield
the reaction mixture. Then, the catalyst was recovered by using an external magnet
and reused in the subsequent reactions after washing with acetone. As shown in
Fig. 10, the activity of the catalyst was maintained up to nine times without any
significant changes in the yields and reaction times.
Efficiency and applicability of [Fe2O3@SiO2(CH2)3-Cl[DABCO-NO2]C(NO2)3]
for the synthesis of pyrazolo[3,4-b]pyridines compared with some other reported
nanomagnetic catalysts. As shown in Table 4, [Fe2O3@SiO2(CH2)3-Cl[DABCO-
NO2]C(NO2)3] is better than those previously reported catalysts in yields and
reaction times for the reactions of benzaldehyde, 3-methyl-1-phenyl-1H-pyrazol-5-
amine and malononitrile.
Conclusion
In summary, as a continuation of our studies with new nanomagnetic catalysts
[51–56], the magnetic nanoparticles (MNPs) surface was chemically modified with
Cl[DABCO-NO2]C(NO2)3 tags and the obtained Fe2O3@SiO2(CH2)3-Cl[DABCO-
NO2]C(NO2)3 was fully characterized by several techniques such as, FT-IR, EDX/
123

Synthesis and application of a novel nanomagnetic…
Table 3 Synthesis of pyrazolo[3,4-b]pyridine derivatives using Fe2O3@SiO2(CH2)3-Cl[DABCO-NO2]-
C(NO2)3 as a new nanomagnetic catalyst under neat conditions
Reaction conditions: aryl aldehyde (1 mmol), malononitrile (1.2 mmol, 79 mg), 3-methyl-1-phenyl-1H-
pyrazol-5-amine or 3-methyl-1H-pyrazol-5-amine (1 mmol) and [Fe2O3@SiO2(CH2)3-Cl[DABCO-
NO2]C(NO2)3] (5 mg)
123

J. Afsar et al.
Scheme 3 The proposed mechanism for the synthesis of pyrazolo[3,4-b]-pyridines in the presence of
Fe2O3@SiO2(CH2)3-Cl[DABCO-NO2]C(NO2)3
mapping, FESEM, HRTEM, TGA, DTG, DSC, powder XRD, N2 adsorption (BET)
and VSM. The described nanomagnetic particles were used as an efficient catalyst
for the three-component condensation reaction of aryl aldehydes, 3-methyl-1-
phenyl-1H-pyrazol-5-amine or 3-methyl-1H-pyrazol-5-amine and malononitrile
under neat conditions. Short reaction times, good yields, easy work-up and
reusability of catalyst are also major advantages of this methodology. Finally, an
anomeric-based oxidation was suggested for the final step of the pyrazolo[3,4-
b]pyridines synthesis.
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Synthesis and application of a novel nanomagnetic…
Scheme 4 Suggested mechanism for the in situ oxidation–reduction Cannizzaro reaction by an
uncommon hydride transfer via ABO mechanism [37]
R
R
R
O
O
CH3
O
OCH3
CrVI
O
CH3
O
H2O
H
O
H
R
CrVI
OH
OCH3
RCCH2CH2CH2CO2CH3
O
O
Scheme 5 Unusual hydride transfer from 2-methoxypyranose by ABO mechanism [38]
Scheme 6 Unusual hydride transfer from tricyclic orthoamide (A) by ABO mechanism [39–41]
123

J. Afsar et al.
Scheme 7 Isomer with equatorial 2-methoxy group is more reactive than its axial isomer due to the
presence of two lone pair anomeric assistance to the departure of the hydride leaving group [38]
Fig. 10 Reactions of benzaldehyde, 3-methyl-1-phenyl-1H-pyrazol-5-amine and malononitrile using the
recycled catalyst
Table 4 Evaluation of various catalyst for the synthesis of pyrazolo[3,4-b]pyridines in solvent free
conditions
Entry Catalyst
Catalyst
loading
Time
(min)
Yield
(%)
Refs.
a
1
[Fe2O3@SiO2(CH2)3-Cl[DABCO-
NO2]C(NO2)3]
5 mg
25
89
2
3
4
5
[Fe3O4@SiO2(CH2)3-DABCO-SO3H]Cl2
[Fe3O4@SiO2(CH2)3S-SO3H]
[Fe3O4@SiO2(CH2)3-Im-SO3H]Cl
[Fe3O4@SiO2(CH2)3NH2]
5 mg
5 mg
5 mg
5 mg
30
30
30
60
86
84
85
45
[57]
[58]
[59]
[60]
aThis work
Acknowledgements We thank Bu-Ali Sina University, Iran National Science Foundation (INSF) (Grant
Number: 95831207), National Elites Foundation, University of Alicante (VIGROB-173, UAUSTI16-03),
´
and the Spanish Ministerio de Economıa y Competitividad (CTQ2015-66624-P) for financial support to
our research groups.
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Synthesis and application of a novel nanomagnetic…
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Affiliations
Javad Afsar1 Mohammad Ali Zolfigol1
Ardeshir Khazaei1
•
•
•
Diego A. Alonso2 Abbas Khoshnood2 Yadollah Bayat3 Asiye Asgari3
•
•
•
1
Department of Organic Chemistry, Faculty of Chemistry, Bu-Ali Sina University,
Hamedan 6517838683, Iran
2
Organic Chemistry Department, Organic Synthesis Institute, Alicante University, Apdo. 99,
03080 Alicante, Spain
3
Faculty of Chemistry and Chemical Engineering, Malek Ashtar University of Technology,
Tehran, Iran
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