Heterogeneous bimetallic ZnFe2O4nanopowder catalyzed synthesis of Hantzsch 1,4-dihydropyridines in water

Article abstract of DOI:10.1016/j.tetlet.2016.07.071

The mixed metal oxide ZnFe₂O₄nanopowder, a dual Lewis acid–base combined catalyst is found to efficiently catalyze a multicomponent synthesis of 1,4-dihydropyridines from aldehydes, ethyl acetoacetate, and ammonium acetate in water. This procedure offers several advantages including high yields, short reaction times, a simple work-up procedure, and a benign eco-footprint. This method takes advantage of the fact that water, a green solvent is used in combination with ZnFe₂O₄nanoparticles as catalyst which can be easily recovered magnetically and reused for further runs.

Full text of DOI:10.1016/j.tetlet.2016.07.071

Accepted Manuscript
Heterogeneous bimetallic ZnFe2O4 nanopowder catalyzed synthesis of
Hantzsch 1,4-dihydropyridines in water
T.R. Ravikumar Naik, S.A. Shivashankar
PII:
S0040-4039(16)30930-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.07.071
TETL 47933
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
14 June 2016
21 July 2016
22 July 2016
Please cite this article as: Ravikumar Naik, T.R., Shivashankar, S.A., Heterogeneous bimetallic ZnFe2O4
nanopowder catalyzed synthesis of Hantzsch 1,4-dihydropyridines in water, Tetrahedron Letters (2016), doi: http://
dx.doi.org/10.1016/j.tetlet.2016.07.071
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Tetrahedron Letters
journal homepage: www.els evier.com
Heterogeneous bimetallic ZnFe2O4 nanopowder catalyzed synthesis of Hantzsch 1,4-
dihydropyridines in water.
T. R. Ravikumar Naika∗ and S. A. Shivashankara
aDepartment of Centre for Nano Science and Engineering, Indian Institute of Science, Bangalore 560 012, India
ARTICLE INFO
ABSTRACT
Article history:
Received
The mixed metal oxide ZnFe2O4 nanopowder, a dual Lewis acid–base combined catalyst is
found to efficiently catalyse a multicomponent synthesis of 1,4-dihydropyridines from
Received in revised form
Accepted
aldehydes, ethyl acetoacetate and ammonium acetate in water. This procedure offers several
advantages including high yields, short reaction times, a simple work-up procedure, and a
benign eco-footprint. This method takes advantage of the fact that water, a green solvent is used
in combination with ZnFe2O4nanoparticles as catalyst which can be easily recovered
magnetically and reused for further runs.
Available online
Keywords:
Microwave-irradiation
Nano crystalline ZnFe2O4
1,4-Dihydropyridines
2009 Elsevier Ltd. All rights reserved.
1. Introduction
heterocyclic compounds, and approaches to their synthesis, have
been important topics of interest to medicinal chemists. Thus,
Multicomponent reactions (MCRs) have emerged as an
efficient and powerful tool in modern synthetic organic
chemistry. MCRs contribute to the requirements of an
environmentally friendly process by reducing the number of
synthetic steps, energy consumption and waste production.
Therefore, researchers have transformed this powerful
technology into one of the most efficient and economic tools for
combinatorial and parallel synthesis.1
ever since the first report of the Hantzsch synthesis of 1,4-
dihydropyridines (DHP), a number of strategies have been
developed for their synthesis2 because of the wide range of their
biological and pharmacological actions, such as for their calcium
channel blocking and antitumor, anti-inflammatory, and
analgesic activities.3 Specifically, 1,4-DHP compounds play
important roles in medicinal chemistry, for example in
nifedipine, amlodipine, diludine, felodipine, and oxodipine (Fig-
1), which are the best selling drugs used in the treatment of
cardiovascular diseases.4
Cl
Cl
O
NO2
O
C
O
O
C
O
O
H5
C
C2H5
O
CH3
H5
C
2 O
H3
2 O
H3
O
H3C
CH3
O
O
R
O
O
Kasi
et all
N
H
CH3
N
H
CH3
O
O
H3C
N
H
CH3
CuFe2O4, Ethanol
4.5 h, Reflux
O
O
O
NH4OAc
NH4OAc
RCHO
+
+
+
Diludine
Felodipine
Nifedipine
N
H
R
O
O
O
O
Pal
et all
F3O4@SiO2, H2
30 min, Reflux
O
Cl
O
O
O
O
O
RCHO
C2H5
H3C
+
O
CH3
O
H3C
O
O
O
N
H
O
H3C
N
H
NH2
H3
C
N
H
CH3
Present Work
O
O
R
Amlodipine
Oxodipine
O
O
ZnFe2O4, H2O
30 min, rt
O
O
Figure 1. Drugs containing 1,4-DHP moieties.
NH4OAc
O
RCHO
+
+
N
H
For several decades, five- and six-membered heterocyclic
compounds containing nitrogen, sulphur and oxygen have been
very significant in the field of medicinal chemistry. As they
Scheme 1. Magnetic nanopowder catalysed synthesis of 1,4-
dihydropyridine.
display considerable pharmacological activity, these bioactive
———
∗ Corresponding author. Tel.: +91-99007-92675; e-mail: naikravi@cense.issc.earnet.in, naikravi7@gmial.com

Generally, 1,4-DHPs are synthesized by the Hantszch method,
which involves cyclocondensation of aryl or alkyl aldehyde, a β-
dicarbonyl compound and ammonia in the presence of mineral
acids at room temperature or reflux condition for a long time.
bioseparation,21cd biomolecular sensors21e and magneto-thermal
therapy.21fg Despite their wide use in biological systems, much
less attention has been focused on the catalytic behavior of
magnetic nanoparticles in organic transformations.22
On the other hand, much effort has been expended to develop
more efficient methods for the synthesis of 1,4-DHPs, such as
using microwave irradiation,5 solar thermal energy,6 ultrasound
irradiation,7 solid support,8 metal triflates as catalyst,9 reactions
in ionic liquid,10 InCl3,11 I2,12 SiO2/NaHSO4,13 SiO2/HClO4,14
CAN,15 ZnO16 and Grignard reagents.17 It is noteworthy that all
these protocols have employed thermal reaction conditions,
disposal of toxic solvents and catalysts often poses a problem.
For these reasons, effort has been made to replace conventional
catalysts with eco-friendly and green process catalysts.
Figure 3. (a) SEM images of ZnFe2O4 nano catalyst; (b) TEM
images of noanocrystals (c) HRTEM of ZnFe2O4 nano catalyst
(d) EDX analysis spectrum of obtained ZnFe2O4 nano catalyst.
Recently, Pal and co-workers exploited the high surface area
and reactive morphology of the Fe3O4@SiO2 nanoparticles for
1,4-DHPs synthesis at refluxed temperature in water (Scheme
1).23a Kasi and co-workers also used catalytic amounts of
magnetic CuFe2O4 nanoparticles for 1,4-DHPs synthesis at
refluxed temperature in ethanol (Scheme 1).23b Although these
results are promising, there is still room for further development
of an environment friendly, less expensive and easily separable,
reusable catalytic system for 1,4-DHPs synthesis.
Figure 2. Powder XRD of obtained ZnFe2O4 nano catalyst by
microwave method
One of the most attractive synthetic strategies favoured by
organic chemists is the use of heterogeneous catalysts in
increasing the efficiency of a wide range of organic syntheses.
Heterogeneous catalysis is being used in the fine chemicals
industry because of the need and demand for more environment-
friendly production technology. This trend is assisted by the
availability of catalytic materials and modern techniques of
creating and investigating specific active sites on catalyst
surfaces.19 In particular, mixed metal oxides nanoparticles have
emerged as an efficient catalyst in modern synthetic organic
chemistry.20 These nanoparticles exhibit both the Lewis acid and
the Lewis base character at their surface.20
ZnFe2O4 nanoparticles are inexpensive, effective, safe,
recyclable, and require only mild reaction conditions to produce
high yields of products in shorter duration than that is possible
with traditional catalysts.20 Therefore, in continuation of our
efforts on nanomaterials,24 we herein present a green and efficient
method for the synthesis of 1,4-DHPs using ZnFe2O4
nanoparticles as a catalyst at room temperature (Scheme 1).
H3
C
Table 1: Synthesis of 1,4-dihydropyridines.
O
R
O
O
Nano ZnFe2O4
H2O, rt, 30 min
R1
Time
(min)
Yield(%) a,b
O
OR1
H3
OR1
AcONH
Entry
R
+
4
+
H
3a
O
R
C
N
H
CH3
OR1
1a-p
2a-c
R = Aromatic, R1 = -C(CH3)3, -C2H5, -CH3
4a-p
1a
1b
1c
1d
1e
1f
C6H5
t-Bu
t-Bu
t-Bu
t-Bu
Et
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
90
96
95
95
94
93
90
95
92
92
95
95
90
87
90
90
4-MeO-C6H5
4-Cl-C6H5
4-F-C6H5
C6H5
Scheme 2. Synthesis of 1,4-dihydropyridine (ESI†).
In literature, there are several methods known for the
synthesis of spinel zinc ferrite. The ZnFe2O4 used in this work
was synthesized according to a modified method (ESI†).24b The
prepared crystalline ZnFe2O4-NPs was characterized by FTIR,
powder X-ray diffraction (XRD), scanning electron microscopy
(SEM), highresolution transmission electron microscopic
(HRTEM) analysis, EDX with elemental analysis and solid state
UV spectroscopy (for the preparation and other characterization
see ESI†).
4-MeO-C6H5
4-OH-C6H5
4-F-C6H5
2-Pyridyl
2-Furyl
Et
Et
1g
1h
1i
Et
Et
1j
Et
1k
1l
C6H5
Me
Me
Me
Me
Me
Me
4-MeO-C6H5
4-OH-C6H5
4-F-C6H5
2-Pyridyl
2-Furyl
1m
1n
1o
1p
Nanocrystalline structure of the prepared ZnFe2O4-Nps was
determined by powder X-ray diffraction (XRD) as shown in Fig
2. All the observed reflections could be assigned to cubic spinel
lattice indicating their single phase structure with no traces of
other impurity phases (e.g. Fe2O3, ZnO etc.). The peaks could be
indexed as (220), (311), (400), (422), (511), (440) and (533),
which are characteristics of single-phase cubic spinel structure
aAll the products were characterized by 1H NMR,13C NMR and mass
spectroscopy studies and compared with the literature mps.
bYields of isolated products.
Magnetic nanoparticles have received considerable attention
in recent years owing to their interesting biological applications
such as drug delivery,21a magnetic resonance imaging,21b

(JCPDS card no. 22-1012).25 The morphology and structure of
the product were investigated by scanning electron microscopy as
shown in Fig. 3a. It is clear from the image in Figure 3a that, the
spherically shaped ZnFe2O4 nanoparticles have diameter within
the range of ∼160-200 nm. High-resolution transmission electron
microscopy (HRTEM) at an accelerating voltage of 200 kV was
employed to know the morphology and size of prepared ZnFe2O4
nanoparticles (Fig. 3b) and the individual particles appear to be
single-crystalline, as shown by lattice imaging in Fig. 3c.
Elemental analyses of the as-synthesized ZnFe2O4 nanoparticles
were performed at EDX equipped onto SEM. Quantitative EDX
showed that Fe, Zn and O were the main elemental components
(Fig. 3d).26
was directly used in Hantzsch synthesis of 1.4-DHPs and it was
observed that, the catalyst can be reused for five times and
product obtained (Fig. S6, ESI†) in good yields. It should be
pointed out that no extra care needs to be taken in order to store
or handle the catalyst since it is not air or moisture sensitive.
In conclusion, we have developed an efficient, rapid, high-
yielding, and eco-friendly methodology for the Hantzsch
synthesis of 1,4-DHPs with ZnFe2O4-NPs as the catalyst. The
advantage of ZnFe2O4-NPs catalyst over Lewis acids lies in its
stability, moisture-insensitivity, and low cost. Further efforts will
be devoted to extend the scope of the ZnFe2O4-NPs catalyst in
other kinds of transformations. We believe that the present
improved modification is a convenient and efficient alternative to
the existing methods for the multicomponent synthesis of 1,4-
DHPs.
To examine the versatility of the ZnFe2O4-NPs, the
preparation of 1,4-DHPs was tested using a modified Hantzsch
procedure. Treatment of one equivalent of benzaldehyde 1a and
ammonium acetate 3a with 2 equiv of tert-butyl acetoacetate
(tbob) 2a in the presence of 40mg of ZnFe2O4 in water afforded
the corresponding 1,4-DHP 4a (Scheme 2,Table 1, entry 1) in
90% yield at room temperature.27 Under similar conditions,
various substituted aromatic aldehydes carrying either electron-
donating or electron-withdrawing substituents were converted
into the expected 1,4-DHPs in good to excellent yields, and the
results are summarized in Table 1. To the best of our knowledge,
this is the first report of the preparation of 1,4-DHPs catalysed by
nano crystalline ZnFe2O4 in water at room temparature.
Acknowledgements
The authors thank DeitY, Govt. of India, for a research grant
and the Department of Organic Chemistry, Indian Institute of
Science, Bangalore for providing the NMR and mass spectra.
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1
The products were characterized by H NMR, 13C NMR and
mass spectroscopy and also by comparison with authentic
samples. The advantages of the present protocols are the shorter
reaction times at room temperature, mild reaction conditions and
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in high yields. From a mechanistic point of view, the first step of
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cyclizes to the 1,4-dihydropyridine 4 (Scheme S1, ESI†).
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27. A mixture of benzaldehyde 1a (5 mmol), tert-butyl acetoacetate 2a
(10 mmol), and ammonium acetate 3a (10 mmol) and ZnFe2O4 (40
mg) was dissolved in 30 mL of water. The resultant mixture was
stirred for 30 min at room temperature. After completion of the
reaction (when the starting materials were completely disappeared
as per thin layer chromatography projection), the reaction mixture
was ultrasonicated by ethyl acetate (15 ml) for 10 min. The
separated organic phase was concentrated to get the crude product
which was purified by silica gel column chromatography (ethyl
acetate/hexanes) to afford the title compounds (4a–p) (Scheme 2,
Table 1). The solid catalyst was collected from water layer by
centrifugation. The recovered catalyst was washed several times
with water, ethanol and finally by acetone to remove organic
impurities, dried at 60 ⁰C for 20 min and used for another run (for
the preparation and other characterization see ESI†).

Graphical Abstract
Heterogeneous bimetallic ZnFe2O4
nanopowder catalyzed synthesis of Hantzsch
1,4-dihydropyridines in water.
Leave this area blank for abstract info.
T. R. Ravikumar Naika, ∗ and S. A. Shivashakara

Highlights
• CEM-Microwave assisted synthesis of
ZnFe2O4 nano-catalyst.
• A simple procedure for the conversion of
1,4-Dihydropyridines using ZnFe2O4 in
aqueous medium is described.
• Magnetically recovered heterogeneous
catalyst.
• The reaction exhibits generally good yields,
mild conditions and broad substrate
tolerance.