Magnetically retrievable nano crystalline CuFe2O4 catalyzed multi-component reaction: A facile and efficient synthesis of functionalized dihydropyrano[2,3-c]pyrazole, pyrano[3,2-c]coumarin and 4H-chromene derivatives in aqueous media

Article abstract of DOI:10.1039/c3cy00901g

CuFe₂O₄ magnetic nanoparticles were synthesized and recognized as an efficient catalyst for the one-pot synthesis of dihydropyrano[2,3-c]pyrazole, pyrano[3,2-c]coumarin and 4H-chromene derivatives at mild conditions and in excellent yields. The four component reaction (4CRs) of a wide variety of substituted hydrazine derivatives, ethyl acetoacetate, dialkyl acetylenedicarboxylates and alkyl nitrile derivatives (malononitrile and ethyl cyanoacetate) gave the targeted dihydropyrano[2,3-c]pyrazoles. When two equivalents of dialkyl acetylenedicarboxylates were introduced replacing ethyl acetoacetate, a new four-component reaction took place providing another type of dihydropyrano[2,3-c]pyrazole derivatives. An efficient and practical route to pyrano[3,2-c]coumarin and 4H-chromene framework has also been developed by one-pot, three-component reaction (3CRs) of 4-hydroxycoumarin/dimedone/ cyclohexane-1,3-dione, dialkyl acetylenedicarboxylates and alkyl nitriles. CuFe₂O₄ magnetic nanoparticles were prepared by a simple and effective citric acid complex method and characterized by using XRD, FT-IR, EDX and TEM image. The catalyst was recycled for six cycles with almost unaltered catalytic activity. All reactions were easily performed and proceeded with high efficiency under very simple and mild conditions and gave excellent yields avoiding time-consuming, costly syntheses, and tedious workup and purification of products.

Full text of DOI:10.1039/c3cy00901g

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Magnetically retrievable nano crystalline CuFe2O4
catalyzed multi-component reaction: a facile
and efficient synthesis of functionalized
Cite this: Catal. Sci. Technol., 2014,
4, 822
dihydropyrano[2,3-c]pyrazole, pyrano[3,2-c]coumarin
and 4H-chromene derivatives in aqueous media†
*
Koyel Pradhan, Sanjay Paul and Asish R. Das
CuFe2O4 magnetic nanoparticles were synthesized and recognized as an efficient catalyst for the
one-pot synthesis of dihydropyrano[2,3-c]pyrazole, pyrano[3,2-c]coumarin and 4H-chromene derivatives
at mild conditions and in excellent yields. The four component reaction (4CRs) of a wide variety of
substituted hydrazine derivatives, ethyl acetoacetate, dialkyl acetylenedicarboxylates and alkyl nitrile
derivatives (malononitrile and ethyl cyanoacetate) gave the targeted dihydropyrano[2,3-c]pyrazoles. When
two equivalents of dialkyl acetylenedicarboxylates were introduced replacing ethyl acetoacetate, a new
four-component reaction took place providing another type of dihydropyrano[2,3-c]pyrazole derivatives.
An efficient and practical route to pyrano[3,2-c]coumarin and 4H-chromene framework has also been
developed by one-pot, three-component reaction (3CRs) of 4-hydroxycoumarin/dimedone/
cyclohexane-1,3-dione, dialkyl acetylenedicarboxylates and alkyl nitriles. CuFe2O4 magnetic nanoparticles
were prepared by a simple and effective citric acid complex method and characterized by using XRD,
FT-IR, EDX and TEM image. The catalyst was recycled for six cycles with almost unaltered catalytic
activity. All reactions were easily performed and proceeded with high efficiency under very simple and
mild conditions and gave excellent yields avoiding time-consuming, costly syntheses, and tedious
workup and purification of products.
Received 7th November 2013,
Accepted 30th November 2013
DOI: 10.1039/c3cy00901g
www.rsc.org/catalysis
calanone, calophyllolides etc.12 4H-Chromene derivatives are
also considered as a venerable pharmacophore and has a wide
Introduction
Dihydropyrano[2,3-c]pyrazoles are one of the most well-
known heterocyclic scaffold, since a large number of these
molecular frameworks show interesting biological activities
and are often part of various pharmaceutical compositions.1
Pyrano-[3,2-c]coumarins, the fused tricyclic derivatives of cou-
marin are also known for their medicinal properties. These
derivatives show antihyperglycemic and antidyslipidemic,2
cytotoxic,3 molluscicidal,4 anti-inflammatory,5 and antifungal
activities.6 These compounds also exhibit a wide spectrum
of biological activities,7 including anticancer,8 antimalarial9
and are also widely employed as cosmetics, pigments10 and
potential biodegradable agrochemicals.11 Furthermore
pyrano-[3,2-c]coumarin and 4H-chromene derivatives are
components of numerous natural products like calanolides,
range of biological applications (compounds A–C, Fig. 1) e.g.
inhibitors of EAAT1 (excitatory amino acid transporters),
anticancer agent and Bcl-2 inhibitor, respectively.13
To the best of our knowledge, only a few references exist
concerning their synthesis.14 Although these reported reac-
tions have developed some useful synthetic procedures, still
several limitations have remained. For example, most of the
procedures involve low yields, or use of organic solvents, or
non-recoverable organo catalysts. Thus, a simple, efficient,
and green method to synthesize these highly important
heterocycles would be attractive.
Department of Chemistry, University of Calcutta, Kolkata 700009, India.
E-mail: ardchem@caluniv.ac.in, ardas66@rediffmail.com; Fax: +91 3323519754;
Tel: +91 3323501014, +91 9433120265
† Electronic supplementary information (ESI) available: 1H and 13C NMR spectra of
all the compounds. CCDC 959948, 959885, and 968630. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c3cy00901g
Fig. 1 Biologically active 4H-chromene derivatives.
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Catalytic processes in aqueous medium are important
in many areas of the fine and specialty chemical industries,
and the use of solid catalysts means easier catalyst separa-
tion and recovery, hence facilitating their reuse. It is widely
accepted that a smaller catalyst particle means a higher
activity.15 As a result, both the activity and the stability of a
solid catalyst suspended in a liquid media can benefit
greatly with the use of these small particles. Nano-catalysts
mimic homogeneous (high surface area, easily accessible) as
well as heterogeneous (stable, easy to handle) catalyst sys-
tems. The main difficulty, however, is that such small parti-
cles are almost impossible to separate by conventional
means, which can lead to the blocking of valves by the cata-
lyst. To overcome this issue, the use of magnetic nano-
particles has emerged as a viable solution; their insoluble
and paramagnetic nature enables easy and efficient separa-
tion of the catalysts from the reaction mixture by using an
external magnet. Other exciting properties of these magnetic
materials include their highly active and specific centers;
these features serve to encourage this relatively novel but
vastly expanding field. They offer a promising option that can
meet the requirements of high accessibility with improved
reusability. One of the most attractive features of magneti-
cally separable nanoparticles (MSNPs) is their separation
properties. Most heterogeneous systems require a filtration
or centrifugation step and/or a tedious workup of the final
reaction mixture to recover the catalyst. However, magneti-
cally supported catalysts can be recovered with an external
magnet due to their paramagnetic character. Magnetically
recoverable materials have been applied in a wide range of
catalytic reactions, including oxidations, hydrogenations,
photocatalysis, and C–C bond formation, as well as in novel
applications in asymmetric synthesis, hydration, Knoevenagel
condensations, and CO2 cycloaddition reactions.16–18 There
has been an increasing trend toward the use of MSNPs in
increasingly efficient green chemical synthesis.
Results and discussion
Due to very wide spectrum of biological potency, our efforts
were directed in exploring a more simple and efficient method
for the synthesis of substituted dihydropyrano[2,3-c]pyrazole,
pyrano[3,2-c]coumarin and 4H-chromene derivatives. To intro-
duce more structural diversity and to develop a more efficient
protocol, we have tried to synthesize dihydropyrano[2,3-c]pyrazole
core by advocating a four component coupling reaction of
substituted hydrazines (IA), ethyl acetoacetate (IB), dialkyl
acetylenedicarboxylates (IIA) and malononitrile or ethyl
cyanoacetate (IIB, Scheme 1).
In order to find the best reaction conditions for the syn-
thesis of dihydropyrano[2,3-c]pyrazole, pyrano[3,2-c]coumarin
and 4H-chromene derivatives, our preliminary investigations
focused on the search for a suitable catalyst. At the outset of
our studies, we tested representative Brønsted and Lewis acid
catalysts ZnO, nano Al2O3, InCl3, H6P2W18O62, 18H2O,
p-toluenesulphonic acid, CF3CO2H, SiO2, Fe2O3 and CuO for
the four-component reaction of phenylhydrazines, ethyl
acetoacetate, diethyl acetylenedicarboxylates and malononitrile
(Scheme 2). It was evident that in absence of any catalyst the
reaction was unable to proceed to give the expected product
even after heating the reaction mixture for about 24 h (Table 1,
entry 1) in aqueous medium at 60 °C. It is also noteworthy to
mention that no product was detected when ZnO, nano Al2O3
and InCl3 were applied for the four component coupling reac-
tion (Table 1, entries 2, 3, 4). As shown in Table 1, the influ-
ence of Brønsted and Lewis acid catalysts (H6P2W18O62, 18H2O,
p-toluenesulphonic acid, CF3CO2H and SiO2) in the above reac-
tion was marginal (entries 5, 6, 7, 8). Entries 9 and 10 in Table 1
clearly showed that Fe2O3 and CuO were superior to other con-
ventional Brønsted and Lewis acid catalysts applied for the
desired synthesis of dihydropyrano[2,3-c]pyrazole derivative
(5a). From Scheme 1 it was evident that the reaction passes
through two component (hydrazine and ethyl acetoacetate)
condensation and Michael reaction (diethyl acetylenedicarboxy-
lates and malononitrile) steps and probably Cu2+ catalyzes
these two steps and Lewis acidic Fe3+ catalyzes the final intra-
molecular cyclization step. The above observations (Table 1,
entries 9, 10) encouraged us to think about a catalyst having
both metal ions, Fe3+ and Cu2+ to catalyze two component con-
densation, Michael reaction and intramolecular cyclization
step concurrently. For this we advocated CuFe2O4 magnetic
Multicomponent reactions19 (MCRs) have emerged as a
highly valuable tools for the rapid generation of molecular
complexity and diversity with predefined functionality in
chemical biology and drug discovery, due to its straightfor-
ward reaction design, convergent, and atom efficient nature
resulting in substantial minimization of waste, labour, time,
and cost.20,21 In continuation of our research program dedi-
cated to the design and synthesis of novel heterocyclic sys-
tems,22 we have started our investigation with the objective
of developing a clean, efficient and straightforward method-
ology for the synthesis of dihydropyrano[2,3-c]pyrazole,
pyrano[3,2-c]coumarin and 4H-chromene derivatives. In addi-
tion to the previous report for the synthesis of functionalized
dihydropyrano[2,3-c]pyrazole and 4H-chromene derivatives,23
in this paper, we report our design of such a direct synthesis
of dihydropyrano[2,3-c]pyrazole, pyrano[3,2-c]coumarin and
4H-chromene derivatives. The syntheses of these heterocyclic
systems have been performed by assembling the basic build-
ing blocks using nano CuFe2O4 as the efficient magnetically
recoverable catalyst.
Scheme 1 Retrosynthesis of dihydropyrano[2,3-c]pyrazole derivatives.
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To find the optimized amount of magnetic nanoparticles for
the four component coupling reaction, the reaction was carried
out by varying the amount of the catalyst on the model reaction
(Scheme 2). The conversion of dihydropyrano[2,3-c]pyrazole
derivative 5a increased linearly with the catalyst weight up
to 8 mol% and became almost steady when the amount of
catalyst was further increased beyond this. Therefore 8 mol%
catalyst was sufficient to catalyze the reaction leading to
expected heterocyclic molecules in excellent yield.
Nano CuFe2O4 was characterized by X-ray diffraction
study, TEM, FT-IR spectra and EDX. The XRD patterns of
CuFe2O4 calcined at 500 °C temperature is shown in Fig. 2.
The crystalline nature of the spinel CuFe2O4 appears in the
XRD pattern of the sample calcined at 500 °C. Six peaks at
18.3, 30.3, 35.6, 42.8, 57.1, and 62.98 can be assigned to the
(101), (200), (211), (221), (303), and (224) diffraction peaks of
CuFe2O4 spinel, respectively.24 The morphology and micro-
structure of CuFe2O4 was investigated by HR-TEM (Fig. 3).
The HR-TEM image reveals that the nanoparticle catalyst has
a spherical shape and the nanoparticles are almost uniform
in size with a narrow distribution. The size of the CuFe2O4
particles is approximately 15–18 nm. As shown in Fig. 4, the
FT-IR spectra of CuFe2O4 calcined at 500 °C temperature
clearly indicates the presence of the peaks (559 cm−1) for the
Fe–O stretching vibration.
Scheme 2 Synthesis of dihydropyrano[2,3-c]pyrazole derivative.
nanoparticles for the MCR and to our delight CuFe2O4 spinel
provided a satisfactory result (Table 1, entry 11). There is a
maiden report14c for the L-proline catalyzed synthesis of
dihydropyrano[2,3-c]pyrazole derivatives. One apparent advan-
tage of the CuFe2O4 magnetic nanoparticles was that the cata-
lyst catalyzed specific steps of the four component coupling
reaction by using its explicit metal ions. Hence only the desired
product was obtained with almost quantitative yield in a
shorter reaction time. The non-recoverable organo catalysts
generated larger amounts of bi-products by the polymerization
of the catalyst and starting materials which in turn decreased
the yield of the desired product and made the product purifica-
tion complicated. The problems were resolved by using the
magnetically retrievable nano-CuFe2O4.
In an effort to enhance the capacity of the chosen catalyst
candidate we next sought to find the effect of different solvents
(H2O, MeOH, EtOH, CH3CN and DMF) for the four component
coupling protocol (Table 1, entries 11–15). The reaction using
EtOH (81%) or H2O (95%) as the solvents gave the correspond-
ing product 5a in high yields (Table 1, entries 11, 13). From the
economical and environmental point of view, H2O was chosen
as the reaction medium for all further reactions.
Elemental analyses of the as-synthesized CuFe2O4 NPs
were performed at EDX equipped onto TEM. Quantitative EDX
Table 1 Optimization of reaction conditions for the synthesisa of
dihydropyrano[2,3-c]pyrazole derivative 5a
Catalyst load
(mol%)
Time Yieldb
Entry Catalyst
Solvent (h)
%
1
2
3
4
5
6
—
ZnO
10
10
10
10
H2O
H2O
H2O
H2O
H2O
H2O
24
10
10
10
6
—
—
—
—
18
24
Nano Al2O3
InCl3
H6P2W18O62, 18H2O 10
p-Toluenesulphonic 10
acid
Fig. 2 XRD patterns of CuFe2O4 (a) before reaction and (b) after six
run (c) crystal planes.
6
7
8
9
CF3CO2H
SiO2
Fe2O3
CuO
Nano CuFe2O4
Nano CuFe2O4
Nano CuFe2O4
Nano CuFe2O4
Nano CuFe2O4
Nano CuFe2O4
Nano CuFe2O4
Nano CuFe2O4
10
10
10
10
10
10
10
10
10
3
H2O
H2O
H2O
H2O
6
6
5
5
2
3
14
10
42
30
95
61
81
49
53
69
77
95
10
11
12
13
14
15
16
17
18
H2O
MeOH
EtOH
CH3CN
DMF
H2O
2.5
3
3
2
2
2
5
8
H2O
H2O
a
All reactions were carried out with phenylhydrazines (1 mmol), ethyl
acetoacetate (1 mmol), diethyl acetylenedicarboxylates (1 mmol),
malononitrile (1 mmol) and specified catalyst in 5 ml solvent at 60 °C.
b
The yield of isolated products.
Fig. 3 HR-TEM image of CuFe2O4.
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active methylene intermediate I (Scheme 1) which was gener-
ated from substituted hydrazine and ethyl acetoacetate dur-
ing the four component condensation reaction (Scheme 2).
As revealed in Table 3, the reaction of dimedone or cyclohex-
ane-1,3-dione or 4-hydroxycoumarin, (6) dialkyl acetylenedi-
carboxylates (3) and malononitrile or ethyl cyanoacetate (4)
resulted in corresponding desired pyrano[3,2-c]coumarin and
4H-chromene derivatives in excellent yields.
After this successful endeavor with the synthesis of
dihydropyrano[2,3-c]pyrazole, pyrano[3,2-c]coumarin and 4H-
chromene derivatives, we changed the 1,3-diketo component
from ethyl acetoacetate (2) to another equivalent of dialkyl
acetylenedicarboxylate (Table 4). Interestingly, the one-pot
reaction of substituted hydrazines, two equivalent dialkyl
acetylenedicarboxylates and malononitrile produced new
dihydropyrano[2,3-c]pyrazoles in the presence of nano
CuFe2O4 (Table 4). The four component reaction passed
through another intermediate (II or III, Scheme 3) which was
more reactive than intermediate I (Scheme 1) due to the pres-
ence of electron withdrawing –CO2R group. Hence we were
able to perform the reactions at room temperature. When R2
and R3 were different, four different sets of products (9a–9d,
9e–9h, 9i–9l, 9m–9p) were isolated by using four hydrazine
derivatives. During our studies on the scope of the reaction,
it was found that the isolated yields of all the four products
were almost the same in aqueous media. However different
results were obtained when the reactions were performed in
ethanol media. In ethanol media 9a, 9e, 9i were the major
products and 9c, 9d, 9g, 9h, 9k, 9l were the minor products.
This observation led us to conclude that in ethanol media,
intermediate II (releasing MeOH) was formed in greater
extent than III (releasing EtOH), leaving a greater amount of
unreacted diethyl acetylenedicarboxylate which in turn
reacted with intermediate II to produce the major products
(9a, 9e, 9i). Hence by introducing different solvents the yield
of the products of this four component reaction could be
changed. Unsubstituted hydrazine was very much reactive
compared to substituted hydrazines and formed both the
intermediates (II and III) in almost equal amount in ethanol
and water. Hence in both the solvents, the yields of dihydro-
pyrano[2,3-c]pyrazoles (9m, 9n, 9o, 9p) were almost the same.
This result is significant since there is no literature precedent
for the synthesis of such highly functionalized dihydro-
pyrano[2,3-c]pyrazoles.
Fig. 4 FT-IR spectra of CuFe2O4 before reaction and after six run.
analysis showed Fe, Cu and O were the main elemental compo-
nents (Fig. 5). The Cu–ferrite NPs analyzed as Fe = 29.28%,
Cu = 13.99%, O = 56.69%. The analysis indicates that NPs in
the array are of initial formula CuFe2O4.
The series of experiments revealed that the optimal results
were obtained when phenylhydrazines (1 mmol), ethyl
acetoacetate (1 mmol), diethyl acetylenedicarboxylates
(1 mmol), malononitrile (1 mmol) and 8 mol% CuFe2O4 in
5 ml water was stirred at 60 °C for 2 h and the corresponding
dihydropyrano[2,3-c]pyrazole derivative was obtained in
95% yield.
Under the established reaction conditions, the scope of
the CuFe2O4-mediated synthesis of dihydropyrano[2,3-
c]pyrazole derivatives was investigated (Table 2). To delineate
this approach, particularly in regard to library construction,
this methodology was evaluated by using a variety of hydra-
zine derivatives, equipped with aryl-halo, aryl-nitro and aryl-
cyano groups, ethyl acetoacetate, dialkyl acetylenedicarboxy-
lates and alkyl nitriles. Five hydrazine derivatives, two dialkyl
acetylenedicarboxylates and two alkyl nitrile derivatives
(malononitrile and ethyl cyanoacetate) were chosen for the
library construction. As revealed in Table 2, the reaction
resulted in corresponding desired dihydropyrano[2,3-
c]pyrazole derivatives by the tandem four-component conden-
sation reaction in good to excellent yields in presence of
nano-crystalline CuFe2O4.
Since pyran and coumarin framework show important bio-
activities, we turned our attention to the synthesis of series
of polyfunctionalized pyrano[3,2-c]coumarin and 4H-
chromene derivatives. For this, dimedone, cyclohexane-1,3-
dione and 4-hydroxycoumarin were examined to replace the
According to our previous studies and the experimental
results mentioned above, we proposed a possible mecha-
nism (Scheme 3) for the 4CRs and 3CRs. The first step of
the current 4CRs was the formation of pyrazolone intermedi-
ate (I, II, III ≡ Y) through Cu2+ (active species of nano-
CuFe2O4)-promoted condensation of phenylhydrazine and
ethyl acetoacetate or dialkyl acetylenedicarboxylate. Cu2+ of
the magnetic nanoparticle (CuFe2O4) has shown excellent cat-
alytic activity in promoting the condensation reaction for the
formation of the intermediate Y by enhancing the electrophi-
licity of carbonyl groups of ethyl acetoacetate and polarizing
the π-electron cloud of dialkyl acetylenedicarboxylate. Cu2+
Fig. 5 EDX spectra of CuFe2O4 NPs.
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Table 2 Four component synthesis of 3-methyl-1,4-dihydropyrano[2,3-c]pyrazole derivatives
5a, 95%, 2.0 h
5b, 90%, 3.0 h
5c, 94%, 2.5 h
5d, 94%, 2.5 h
5e, 97%, 2.0 h
5f, 93%, 2.5 h
5g, 88%, 3.0 h
5h, 92%, 2.5 h
5j, 96%, 2.0 h
5k, 85%, 2.5 h
5i, 92%, 2.5 h
of CuFe2O4 also catalyzed the Michael addition reaction of
dialkyl acetylenedicarboxylate with alkyl nitrile derivatives
(malononitrile and ethyl cyanoacetate) during the formation
of the intermediate X. The nucleophilic attack by the inter-
mediate Y at the β position (with respect to nitrile group)
of the intermediate X was enhanced by Cu2+ may be due to
the polarization of the π-electron cloud. Finally, the Lewis
acidic Fe3+ interacted with enolate intermediate Z which in
turn facilitates intramolecular electrophilic cyclization with
the formation of the six member ring (P). The nano-
CuFe2O4 catalyzed activation of condensation, Michael
reaction and subsequent ring annulations leading to the
pyran derivatives were confirmed by the isolation of the
intermediate Y.
The various products 5, 7, 9 thus obtained, were character-
ized by IR, 1H and 13C NMR spectroscopic analyses. Finally,
the structures of three different type of synthesized
heterocyclic core (3-methyl-1,4-dihydropyrano[2,3-c]pyrazole,
pyrano[3,2-c]coumarin
and
alkyl-1,4-dihydropyrano[2,3-
c]pyrazole-3-carboxylate derivatives) were confirmed by single-
crystal X-ray diffraction of three representative compounds
5j, 7i, 9a (Fig. 6–8).25
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Table 3 Synthesis of pyrano[3,2-c]coumarin and 4H-chromene derivatives
7a, 92%, 2.0 h
7b, 88%, 2.5 h
7c, 91%, 2.0 h
7d, 86%, 2.5 h
7e, 94%, 2.0 h
7f, 89%, 2.5 h
7g, 92%, 2.0 h
7h, 86%, 2.5 h
7i, 90%, 2.5 h
7j, 87%, 3.0 h
7k, 88%, 2.5 h
7l, 84%, 3.0 h
A heterogeneous catalyst is more interesting when it can be
easily recovered and re-used. Separation of the catalyst and isola-
tion of the desired product from the reaction mixture is one of
the most crucial aspects of organic synthesis. Catalyst recovery,
which is generally performed by filtration, is relatively inefficient.
Another technique, extractive isolation of products, also requires
excessive amounts of organic solvents. However, in the aforemen-
tioned protocol, after completion of the reaction, water was
removed under reduced pressure from the reaction mixture and
was stirred with 5 mL ethanol and within a few seconds after stir-
ring was stopped, the catalyst was deposited on the magnetic bar
and then easily removed using an external magnet, leaving a clear
reaction mixture. The recovered catalyst was then washed with
ethanol and distilled water and dried under vacuum. The catalyst
was recovered in excellent yield (92–97%) after each of the new
set of reaction. This recycled catalyst was used for the synthesis
of dihydropyrano[2,3-c]pyrazole applying the developed protocol.
For this purpose, the reusability of the catalyst was tested for the
reaction of phenylhydrazines, ethyl acetoacetate, diethyl
acetylenedicarboxylates and malononitrile (Scheme 2). The cata-
lyst was found to be reusable for at least six cycles without any
considerable loss of activity. We also investigated the structural
stability of CuFe2O4 catalyst by comparing its XRD and FT-IR
spectra before and after six run in the one-pot synthesis of
dihydropyrano[2,3-c]pyrazole derivatives (5a). The results obtained
are illustrated in Fig. 2 and 4 respectively. It can be seen that the
XRD and FT-IR spectra of the catalyst obtained before and after
six run was almost same indicating that the MSNPs was structur-
ally stable under the applied reaction conditions.
Conclusions
Overall, we have succeeded in developing a novel, convenient
and efficient protocol for the preparation of dihydropyrano[2,3-
c]pyrazole, pyrano[3,2-c]coumarin and 4H-chromene derivatives
using readily available starting materials by tandem one-pot four-
and three-component reaction. Again this protocol, combining
construction and modification of the dihydropyrano[2,3-
c]pyrazole skeleton, increases the structural diversity of the final
products by forming a new library of dihydropyrano[2,3-c]pyrazole
derivatives. The nano-catalyst system encompassing a paramag-
netic core allows rapid and selective chemical transformations
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Table 4 Four component synthesis of alkyl-1,4-dihydropyrano[2,3-c]pyrazole-3-carboxylate derivatives
9a, 23%,a 42%,b 4.0 h
9e, 26%,a 43%,b 4.0 h
9i, 25%,a 42%,b 4.0 h
9b, 26%,a 34%,b 4.0 h
9c, 25%,a 11%,b 4.0 h
9d, 26%,a 13%,b 4.0 h
9f, 27%,a 31%,b 4.0 h
9g, 25%,a 13%,b 4.0 h
9h, 22%,a 13%,b 4.0 h
9j, 24%,a 33%,b 4.0 h
9k, 25%,a 13%,b 4.0 h
9l, 26%,a 12%,b 4.0 h
9m, 24%,a ,b 2.0 h
9n, 26%,a ,b 2.0 h
9o, 23%,a ,b 2.0 h
9p, 27%,a ,b 2.0 h
a
Isolated yield of the when the reaction was performed in water. b Isolated yield of the when the reaction was performed in EtOH.
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Scheme 3 The proposed mechanisms for the formation of the products (5, 7, 9).
with excellent product yield. The use of CuFe2O4 magnetic nano-
Experimental
Preparation of catalyst
particles as catalyst solves the basic problems of catalyst separa-
tion. This is a promising approach from sustainable and
practical chemistry viewpoints. We believe that the convenient
and efficient CuFe2O4 catalyzed 4CRs and 3CRs, the mechanism
and the interesting activities of the catalyst described here will be
helpful for practical application and a new protocol design.
CuFe2O4 was prepared by using a simple modified literature
method.26 Fe(NO3)3·9H2O (4 mmol), Cu(NO3)2·3H2O (2 mmol)
and citric acid (9 mmol) were dissolved completely in dis-
tilled water (50 mL). The solution was heated up to 90 °C to
Fig. 6 ORTEP diagram of compound 5j (CCDC no. 959948).
Fig. 7 ORTEP diagram of compound 7i (CCDC no. 959885).
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the reaction, water was removed under reduced pressure
from the reaction mixture and was stirred with 5 mL ethanol
and within a few seconds after stirring was stopped, the cata-
lyst was deposited on the magnetic bar and removed using
an external magnet, leaving a clear reaction mixture. After
removing the catalyst the solvent was evaporated under vac-
uum to give the crude product, which was purified by column
chromatography.
Acknowledgements
Fig. 8 ORTEP diagram of compound 9a (CCDC no. 968630).
We gratefully acknowledge the financial support from U.G.C
and Calcutta University. K. P. and S. P. thank U.G.C, New
Delhi, India for the grant of Junior and Senior Research fel-
lowships, respectively.
evaporate the water in an oil bath under continuous stirring
and the citric acid was then decomposed at 300 °C. After the
reaction, the resultant powder was calcined at 500 °C for 2 h
to give the CuFe2O4 samples.
Notes and references
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General procedure for the synthesis of
3-methyl-1,4-dihydropyrano[2,3-c]pyrazole derivatives
A
mixture of substituted hydrazines (1 mmol), ethyl
acetoacetate (1 mmol), dialkyl acetylenedicarboxylates
(1 mmol), malononitrile or ethyl cyanoacetate (1 mmol) and
CuFe2O4 (8 mol%) was stirred at 60 °C for a required period
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General procedure for the synthesis of pyrano[3,2-c]coumarin
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A
mixture of dimedone or cyclohexane-1,3-dione or
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leaving a clear reaction mixture. After removing the catalyst
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product, which was purified by column chromatography.
General procedure for the synthesis of alkyl-1,4-
dihydropyrano[2,3-c]pyrazole-3-carboxylate derivatives
A
mixture of substituted hydrazines (1 mmol), dialkyl
acetylenedicarboxylates (1 mmol + 1 mmol), malononitrile
(1 mmol) and CuFe2O4 (8 mol%) was stirred at room temper-
ature for a required period of time (TLC). After completion of
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