Novel Magnetically Separable Sulfated Boric Acid Functionalized Nanoparticles for Hantzsch Ester Synthesis

Article abstract of DOI:10.1055/s-0035-1561441

A novel, separable, solid-acid catalyst consisting of sulfated boric acid nanoparticles immobilized on a silica-coated magnetite support was prepared. This catalyst permits the preparation of dihydropyridine derivatives (Hantzsch esters) by condensation of an aldehyde with two equivalents of a β-keto ester in the presence of ammonium acetate. The catalyst can be recovered and recycled.

Full text of DOI:10.1055/s-0035-1561441

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–D
letter
A
K. Azizi et al.
Letter
Synlett
Novel Magnetically Separable Sulfated Boric Acid Functionalized
Nanoparticles for Hantzsch Ester Synthesis
Kobra Azizi
O
OSO3H
Jamshid Azarnia
Fe3O4
O
O
Si O B
R2CHO
OSO3H
O
R2
O
Meghdad Karimi
Elahe Yazdani
concd H+
0.68 mmol/g
R1
R1
O
O
O
O
R1
2
O
Akbar Heydari*
EtOH, 60 °C
N
H
short reaction time, ease of catalyst isolation,
high chemoselectivity, no side reaction,
low costs, simplicity in process
NH4OAc
Department of Chemistry, Tarbiat Modares University,
P.O. Box 14115-4838, Tehran, Iran
heydar_a@modares.ac.ir
12 examples
up to 98% yield
This article is dedicated to the memory of Mansour Sattari.
Received: 24.02.2016
Accepted after revision: 18.03.2016
Published online: 26.04.2016
ca. The resulting silica shell can be readily modified with
various functional groups through covalent bonding.6 Fur-
thermore, such silica coatings improve the aqueous com-
patibility and biocompatibility of MNPs.5
DOI: 10.1055/s-0035-1561441; Art ID: st-2016-d0131-l
Abstract A novel, separable, solid-acid catalyst consisting of sulfated
boric acid nanoparticles immobilized on a silica-coated magnetite sup-
port was prepared. This catalyst permits the preparation of dihydropyr-
idine derivatives (Hantzsch esters) by condensation of an aldehyde with
two equivalents of a β-keto ester in the presence of ammonium ace-
tate. The catalyst can be recovered and recycled.
Homogeneous catalysts can be replaced by solid cata-
lysts as reusable and environmentally safe acid catalysts.7
There has been increased interest in the use of solid materi-
als as catalysts in the preparation of fine chemicals,8 be-
cause this approach frequently results in less expensive and
less polluting processes.
Key words magnetic separation, nanostructures, catalyst, dihydropy-
Boric acid has been found to be effective in various or-
ganic transformations, such as esterification of hydroxycar-
boxylic acids,9 aza-Michael reactions,10 and thia-Michael
additions.11 Silica-supported boric acid has been applied in
Mannich reactions12 and in syntheses of dihydropyrimidin-
2-ones and bis(indolyl)methanes, and for acetylation of al-
cohols, amines, and phenols.13
The dihydropyridine unit has been widely employed as
a hydride source for reductive amination.14 In addition, het-
erocycles containing 1,4-dihydropyridyl moieties have
pharmaceutical and industrial applications.15 These com-
pounds exhibit various biological properties, such as vaso-
dilatory, bronchodilatory, geroprotective, hepatoprotective,
antitumor, antiatherosclerotic, antidiabetic, neuroprotec-
tive, and neuropeptide YY1 antagonist activities.16
Hantzsch esters have been used as photoreductants (as
both electron- and hydrogen-atom donors) for selective de-
bromination and hydroxylation of α-bromo ketones in the
absence of any additional reagents.17 A recent report on the
synthesis of Hantzsch esters described the use of lithium
bromide as a catalyst.18
ridines, boric acid
Magnetic nanoparticles (MNPs) can be produced with
appropriate chemical and surface properties for various ap-
plications, such as drug delivery, biosensing, biochemical
separations, or bioanalysis,1 and the range of applications of
MNPs has developed dramatically during the last 30 years.2
Multifunctional MNPs can be produced by coupling MNPs
with moieties that make them suitable for use as catalysts.3
The MNPs facilitate separation of the catalyst and purifica-
tion of the product, and their large specific surface area en-
hances their catalytic activity. Supported catalysts of this
type act as quasi-homogeneous species, providing a bridge
between homogeneous and heterogeneous phases.4
Among MNPs, magnetite (Fe3O4) is the most widely
used support in catalysis because of its low cost and ease of
preparation. Magnetite is inert and possesses an active sur-
face for immobilization or adsorption of various catalytic
species, including metal catalysts (Au, Pd, Pt, Cu, Ni, Co, or
Ir), organocatalysts, or enzymes, to give robust catalysts.5
The surface of unmodified MNP does not have suitable
functionality to permit the formation of strong covalent
bonds with other molecules. However, the reactivity of
MNPs can be improved by coating them with a layer of sili-
Here we describe the preparation of a magnetically re-
coverable sulfated boric acid catalyst (Fe3O4–SiO2–SB) and
its application in a high-yielding (<90%) Hantzsch synthesis
of various 1,4- dihydropyridines (Scheme 1).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

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K. Azizi et al.
Letter
Synlett
The Fe3O4 nanoparticles were synthesized according to
a previously reported procedure, then coated with silica,
functionalized with boric acid, and sulfated by treatment
with chlorosulfonic acid.19
The EDS spectrum showed no peaks other than those
for Fe, O, Si, B, and S, indicating a high purity for the com-
posites. The elemental composition was B, 3.68; O, 17.54;
Si, 20.26; S, 12.42, Fe, 48.09%.
The sulfated boric acid-functionalized MNPs were char-
acterized by Fourier-transform IR spectroscopy, X-ray dif-
fraction (XRD), thermogravimetric analysis (TGA), differen-
tial thermal analysis (DTA), scanning electron microscopy
(SEM), energy-dispersive X-ray spectroscopy (EDS), vibrat-
ing sample magnetometry, and inductively coupled-plasma
mass spectrometry (ICP-MS). The acid capacity of the sili-
ca-sulfated boric acid MNPs (as an assay for H+ sites) was
determined by back titration. Triplicate ~100 mg samples
were added to 5 mL of 0.1 N aqueous NaOH, and the mix-
ture was sonicated for 10 minutes. Two drops of phenol-
phthalein were added to each vessel as a pH indicator, and
the residual base was back-titrated with 0.1 M aqueous HCl
to the first permanent cloudy pink color. In this way, the
acidity value was estimated to be 0.7 mmol/g of catalyst.
This result was confirmed by titration of proton-exchanged
brine solutions. The MNP-sulfated boric acid (100 mg) was
added to 1 M aqueous NaCl (25 mL) with an initial pH of 5.9,
and the resulting mixture was stirred for 24 hours, after
which the pH of the solution decreased to 3.2. This corre-
sponds to a loading of 0.65 mmol H+ per gram of catalyst.
The crystal structure of the Fe3O4–SB NPs and their
phase purity were determined by powder XRD (Figure 1).
The XRD pattern of the MNPs indexed to the spinel phases
of iron oxide, and six peaks (2θ = 30.1, 35.5, 43.2, 53.5, 57.0,
and 62.8) relate to the indices (220), (311), (400), (422),
(511), and (440), respectively. The weaker diffraction lines
indicated that the Fe3O4 nanoparticles were covered by
amorphous silica. The positions of all diffraction peaks
matched well with those from the appropriate JCPDS card.
The presence of the sulfated boric acid did not significantly
affect the phase properties of the Fe3O4.
To explore and quantify the surface modifications of the
MNP that occurred during the grafting steps, TGA measure-
ments were carried out under a nitrogen purge (Figure 2).
Approximately 10 mg of each sample was heated at a rate of
20 °C/min. Both Fe3O4–SiO2–boric acid and Fe3O4–sulfated
boric acid samples began to undergo thermal degradation
at around 350 °C, with mass losses of 10 and 40%, respec-
tively. The loading of boric acid calculated from these TGA
results was 1.2 mmol/g. ICP-MS determined the amount of
boron in solution to be 1.218 mmol/g.
Figure 2 TGA/DTA analysis of Fe3O4–SiO2, Fe3O4–SiO2–boric acid,
Fe3O4–sulfated boric acid
SEM of the Fe3O4–boric acid and Fe3O4–sulfated boric
acid MNPs clearly revealed their structure (Figure 3).
Figure 3 SEM of the coated nanoparticles after addition of B(OH)3
(left) and HSO3Cl (right)
First, we investigated the Hantzsch synthesis by using
benzaldehyde, methyl acetoacetate, and ammonium ace-
tate. When the reaction was carried out in the absence of
catalyst, the corresponding dihydropyridine 1a was ob-
tained in low yield (30%). Increasing the temperature sig-
nificantly enhanced the yield (45%), and this could be im-
proved to 53% and 60%, respectively, when ethanol was
used. When the reaction was carried out in the presence of
10 mg of catalyst, the yield increased further to 95%. Vary-
ing the amount of catalyst did not markedly affect the yield.
The yield could be further improved to 98% by extending
Figure 1 Powder X-ray diffraction pattern of Fe3O4–SiO2–BOSO3H.
Characteristic diffraction peaks of Fe3O4:
peaks of SiO2:
·; characteristic diffraction
·.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

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K. Azizi et al.
Letter
Synlett
the reaction time to 30 minutes. To explore the scope of the
reaction, we examined the reaction of methyl and ethyl aceto-
acetate with various aldehydes and ammonium acetate un-
der the optimized conditions (Scheme 1).
Acknowledgements
We are grateful to Tarbiat Modares University for partial financial
support of this work.
R2CHO
O
R2
O
Supporting Information
O
O
Catalyst
(SB-MNPs)
R1
R1
R1
O
O
2
O
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561441.
EtOH
60 °C
N
H
NH4OAC
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
Me
References
Cl
O
O
O
O
O
O
(1) Reddy, H.; Arias, J. L.; Nicolas, J.; Couvreur, P. Chem. Rev. 2012,
112, 5818.
Me
Me Me
Me Me
Me
O
O
O
O
O
O
(2) Svoboda, J. Magnetic Techniques for the Treatment of Materials;
Kluwer Academic: Dordrecht, 2004.
(3) Wang, L.; Bao, J.; Wang, L.; Zhang, F.; Li, Y. Chem. Eur. J. 2006, 12,
6341.
N
N
H
N
H
H
30 min, 98 %
20 min 95%
1 h, 90%
1a
1b
1c
OMe
(4) Dalpozzo, R. Green Chem. 2015, 17, 3671.
NO2
O
(5) Wang, D.; Astruc, D. Chem. Rev. 2014, 114, 6949.
(6) Kralja, S.; Makoveca, D.; Čampelja, S.; Drofenik, M. J. Magn.
Magn. Mater. 2010, 322, 1847.
O
O
O
O
O
O
Me
Me Me
Me Me
Me
O
O
O
O
O
O
(7) (a) Hara, M.; Yoshida, T.; Takagaki, A.; Takata, T.; Kondo, J. N.;
Hayashi, S.; Domen, K. Angew. Chem. Int. Ed. 2004, 43, 2955.
(b) Devi, B. L. A. P.; Prasad, K. N.; Jagannadh, P. S. S.; Prasad, B.;
Gangadhar, R. B. N. ChemSusChem 2009, 2, 617. (c) Suganuma, S.
S.; Nakajima, K.; Kitano, M.; Yamaguchi, D.; Kato, H.; Hayashi, S.;
Hara, M. J. Am. Chem. Soc. 2008, 130, 12787.
N
H
N
H
N
H
1 h, 88 %
30 min, 92 %
1 h, 85 %
1d
1e
1f
OMe
(8) (a) Hutchings, G. Chem. Commun. 1999, 301. (b) Corma, A. Chem.
Rev. 1995, 95, 559.
Cl
O
O
O
O
O
O
Et
Et
Et
Et Et
Et
(9) Houston, T. A.; Wilkinson, B. L.; Blanchfield, J. T. Org. Lett. 2004,
6, 679.
(10) Chaudhuri, M. K.; Hussain, S.; Kantam, M. L.; Neelima, B. Tetra-
hedron Lett. 2005, 46, 8329.
O
O
O
O
O
O
N
N
N
H
H
H
30 min, 96%
30 min, 90%
45 min, 90 %
2a
2b
2c
(11) Chaudhuri, M. K.; Hussain, S. J. J. Mol. Catal. A: Chem. 2007, 269,
214.
Me
(12) Kumar, V.; Sharma, U.; Verma, P. K.; Kumar, N.; Singh, B. Chem.
Pharm. Bull. 2011, 59, 639.
(13) Kumar, V.; Singh, C.; Sharma, U.; Verma, P. K.; Singh, B.; Kumar,
N. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 2014, 53,
83.
(14) Itoh, T.; Nagata, K.; Miyazaki, M.; Ishikawa, H.; Kurihara, A.;
Ohsawa, A. Tetrahedron 2004, 60, 6649.
(15) Heydari, A.; Khaksar, S.; Tajbakhsh, M.; Bijanzadeh, H. R. J. Fluo-
rine Chem. 2009, 130, 609.
NO2
O
O
O
O
O
O
O
Et
Et
Et
Et
O
O
Et
Et
O
O
O
O
N
H
N
H
N
H
30 min, 95 %
1 h, 86 %
1 h, 88 %
2d
2e
2f
Scheme 1 Synthesis of Hantzsch esters 1a–f and 2a–f by using Fe3O4–
(16) (a) Stilo, A. D.; Visentin, S.; Cena, C.; Gasco, A. M.; Ermondi, G.;
Gasco, A. J. Med. Chem. 1998, 41, 5393. (b) Mager, P. P.; Coburn,
R. A.; Solo, A. J.; Triggle, D. J.; Rothe, H. Drug Des. Discovery 1992,
8, 273.
(17) Jung, J.; Kim, J.; Park, G.; You, Y.; Cho, J. E. Adv. Synth. Catal. 2016,
358, 74.
(18) Gopinath, R.; Rajendraprasad, K.; Nagabhushana, K. J.;
Krishnappa, B. M. Indo Am. J. Pharm. Res. 2015, 5, 3024;
http://www.iajpr.com/archive/volume-5/august-2015/15sep-
tember39.html.
(19) Silica-Coated Magnetite Nanoparticles
Fe3O4 magnetic nanoparticles were prepared by dissolving
FeCl3·6H2O (10 mmol) and FeCl2·4H2O (5 mmol) in deionized
H2O (100 mL) with vigorous stirring (800 rpm), and then adding
25% aq NH4OH (30 mL) at r.t. until the pH increased to 11. Drop-
wise addition of NH4OH was continued to maintain a pH of 11–
SiO2–SB catalyst at 60 °C in ethanol
The desired pure products 1a–f and 2a–f were charac-
terized by comparison of their physical data with those of
known compounds.20
In summary, we have described a synthesis of sulfated
boric acid magnetic nanoparticles tailored for use as an acid
catalyst for the Hantzsch reaction. In contrast to previous
methods, this new method has the advantages of short re-
action times, ease of catalyst isolation, lack of side reac-
tions, simplicity of the process, and recoverability of the
catalyst.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

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12. The resulting black dispersion was continuously stirred for 1
h at r.t., and then the mixture was refluxed for 1 h.
under argon, and the mixture was refluxed for 12 h. The result-
ing nanoparticles were collected by using a magnet, washed
with deionized H2O, EtOH, and Et2O (×5), and dried at 80 °C for
12 h.
EtOH (40 mL) was added to the nanoparticles and the mixture
was heated for 1 h at 40 °C. Tetraethyl orthosilicate (10 mL) was
then added and the mixture was continuously stirred for 24 h.
The silica-coated nanoparticles were collected by using a
magnet, washed with EtOH and Et2O (×5), and then dried in a
vacuum at 100 °C for 12 h.
(21) Preparation of Sulfated Boric Acid–Silica-Coated Magnetite
Nanoparticles
Boric acid–silica-coated Fe3O4 nanoparticles (2 g) in anhydrous
CH2Cl2 (100 mL) were stirred for 10 min under argon. Chlorosul-
fonic acid (5 mL) was added dropwise to the suspension at r.t.,
and the mixture was stirred for 4 h. The sulfated particles was
separated from the mixture with a magnet and washed several
times with CH2Cl2 and then with H2O, and finally dried at 80 °C
overnight.
(20) Boric Acid–Silica-Coated Magnetite Nanoparticles
SOCl2 (1 mL) was added slowly to the silica-coated magnetite
nanoparticles (1 g) in anhydrous CH2Cl2 (50 mL) cooled in an ice
bath, and the mixture was stirred for 1 h. The solvent was then
removed under reduced pressure. The nanoparticles (1g) were
suspended in anhydrous acetone (50 mL), a sat. solution of boric
acid (0.5 g) in anhydrous acetone (50 mL) was added at r.t.
(22) Kumar, A.; Maurya, R. A. Synlett 2008, 6, 883.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D