Heterogeneous ditopic ZnFe2O4 catalyzed synthesis of 4H-pyrans: Further conversion to 1,4-DHPs and report of functional group interconversion from amide to ester

Article abstract of DOI:10.1039/c3gc42095g

Highly stable, environmentally benign ZnFe₂O₄ nanopowder was prepared, characterized and applied in the one-pot, three-component synthesis of 4H-pyrans in water. The ZnFe₂O ₄ catalyst provides both acidic (Fe

Full text of DOI:10.1039/c3gc42095g

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Heterogeneous ditopic ZnFe2O4 catalyzed
synthesis of 4H-pyrans: further conversion to
1,4-DHPs and report of functional group
interconversion from amide to ester†
Cite this: DOI: 10.1039/c3gc42095g
Paramita Das,a Arghya Dutta,b Asim Bhaumikb and Chhanda Mukhopadhyay*a
Highly stable, environmentally benign ZnFe2O4 nanopowder was prepared, characterized and applied in
the one-pot, three-component synthesis of 4H-pyrans in water. The ZnFe2O4 catalyst provides both
acidic (Fe3+) and basic functionalities (O2−) as the reaction requires. The advantages of this method lie in
its simplicity, cost effectiveness, environmental friendliness and easier scaling up for large scale synthesis.
Water was exploited both as a reaction medium as well as a medium for synthesis of the catalyst. More-
over, water was the only byproduct. The present report puts forward an application of 4H-pyrans for the
synthesis of 1,4-DHPs. This is the first attempt towards the synthesis of 4H-pyran-3-carboxylate from
4H-pyran-3-carboxamide. The corresponding functional group interconversion from amide to ester is rare in
organic synthesis.
Received 9th October 2013,
Accepted 27th November 2013
DOI: 10.1039/c3gc42095g
www.rsc.org/greenchem
Mixed metal oxide nanoparticles (MMONs) have garnered
much attention in recent years and are actively pursued in the
Introduction
Adaptation of synthetic procedures to the requirements of development of modern organic synthesis and greener reac-
combinatorial chemistry has always been an essential task to tion protocols.7 Catalytic processes based on such mixed metal
solve.1 In this context multicomponent reactions (MCRs)2 oxide nanocatalysts are simpler, economically efficient and
provide opportunities to construct the scaffold of natural pro- more environmentally friendly, constituting “green chemistry”
ducts and diverse drug-like molecules in a single operation that produces only the most desirable products.8 These
which make the strategy important.3 As a consequence, MCRs MMONs have emerged as sustainable alternatives to conven-
as well as domino or related reactions have gained increased tional materials, as robust, high surface area heterogeneous
attention.4 However one aspect of MCRs that has received rela- catalysts, cheap and economical. These nano-sized particles
tively little attention is their development in aqueous environ- increase the exposed surface area of the active component of
ments.5 Despite a small number of organic reactions which the catalyst, thereby enhancing the contact between reactants
can be performed in the solid state or solvent-free conditions, and the catalyst dramatically and mimicking the homogeneous
these approaches are restricted due to the easy formation of catalysts. Their insolubility in reaction solvents renders them
undesired side products and the difficult heat flow control. In easily separable from the reaction mixture, which in turn
this regard, water is nature’s reaction medium and constitutes makes the product isolation stage effortless. Notably, the
a nonflammable, nonhazardous, nontoxic, uniquely redox- MMONs are better in terms of their catalytic activity than the
stable, inexpensive solvent.6 For these reasons, the develop- individual component oxides in various reactions because of
ment of synthetically useful, elegant and convergent MCRs their enhanced surface area.9 Thus, in view of modern catalytic
using water as the green reaction medium is of prime interest.
chemistry, MMONs represent one of the most important and
widely employed materials in catalysis science.
4H-Pyran derivatives represent the key building blocks of
many natural products and constitute the core of valuable
compounds exhibiting a broad spectrum of biological activi-
ties. Certain pyran-based motifs are often found as recurring
structures in a variety of natural and biologically relevant pro-
ducts10 along with photochromic materials.11 These interest-
ing features have projected the 4H-pyran framework as a
valuable lead pharmacophore and inspired much effort toward
aDepartment of Chemistry, University of Calcutta, 92 APC Road, Kolkata 700009,
India. E-mail: cmukhop@yahoo.co.in; Tel: +91-9433019610
bDepartment of Materials Science, Indian Association for the Cultivation of Science,
Jadavpur, Kolkata 700 032, India. E-mail: msab@iacs.res.in
†Electronic supplementary information (ESI) available. CCDC 946297, 946296,
946298 and 946299. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c3gc42095g
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the synthesis of its derivatives.12 Consequently, the incorpor- X-ray diffraction (XRD), high resolution transmission electron
ation of the two structural features into interesting motifs, microscopy (HRTEM), EDX with elemental analysis, FTIR,
such as pyranocoumarins and 2-amino-4H-pyran, may have solid state UV spectroscopy, X-ray photoelectron spectroscopy
some significance in the design of new therapeutic agents.13 (XPS) and N2 adsorption analysis. (For the preparation and
Moreover, 4H-benzo[b]pyrans are also potential calcium detailed characterization of the catalyst see ESI†.)
channel antagonists, which are structurally similar to biologi-
cally active 1,4-dihydropyridines.14 It is therefore little surpris-
Characterization of the catalyst
ing that an enormous amount of research has been carried out
to develop efficient synthetic methods for their assembly.15
XRD analysis. The XRD pattern of the sample obtained by
Thus, based on the above facts and as a part of our research calcining at 800 °C (Fig. S1D, see ESI†) clearly depicts the
program to develop mild and greener methodologies involving good-quality polycrystalline nature of the single spinel phase
nanoparticle derived catalysts16 we report herein the appli- of ZnFe2O4. The diffraction peaks at 2θ values of 18.0, 30.0,
cation of ZnFe2O4 nanoparticles for the library synthesis of 35.3, 36.9, 42.8, 53.2 and 56.7 assigned to the reflection of the
4H-pyrans.
(111), (220), (311), (222), (400), (422) and (511) planes have
In light of the numerous applications of 4H-pyrans, the been indexed to Fd3m cubic spinel structure of ZnFe2O4. The
present report puts forward an application of nucleophilic mean crystallite size (coherent diffraction domain size) was
vinylic substitution followed by intramolecular cyclization of estimated to be 24 nm from the half-maximum full width of
4H-pyran compounds for the synthesis of 1,4-dihydropyridines the (311) peak by the modified Scherrer formula.
that provides easy access to two nitrogen–carbon (N–C) bonds
HRTEM and EDX elemental analysis. TEM images of the
in a single operation.
synthesized ZnFe2O4 obtained by calcining at 800 °C (Fig. S2,
In this report, an assembly of 88 compounds was syn- see ESI†) clearly show the uniform formation of ZnFe2O4 nano-
thesized and well characterized by 1H & 13C NMR, 2D NMR, particles with only one type of particle morphology, indicating
FTIR, elemental analysis and X-ray crystallographic analysis.
the formation of one phase, i.e. the spinel structure having
dimensions of ca. 25–30 nm which is also in accordance with
the result calculated using the Scherrer formula. The presence
of Zn, Fe and O atoms was observed in the EDX spectrum
(Fig. S2d, see ESI†).
Results and discussion
Since we were interested in finding an efficient heterogeneous
FT-IR analysis. The presence of the spinel structure for
catalyst for 4H-pyran synthesis we therefore, conducted a ZnFe2O4 was further confirmed by FT-IR spectroscopy (Fig. S3,
careful literature survey to fully understand the mechanistic see ESI†). In the present study, the absorption bands for the
interpretation of 4H-pyran formation. We realized that the synthesized zinc ferrite are in the expected range. No band
beforehand reported methodologies overlooked the synergistic around 3400 cm−1 and 1640 cm−1 indicates the absence of any
effect of the combined use of an acid–base ditopic catalyst OH vibrations of water molecules resulting from the crystalline
since in pyran formation some steps are base catalyzed (Knoe- spinel phase of ZnFe2O4. According to Waldron, the high fre-
venagel condensation) whereas some others are assisted by an quency bands around 667 cm−1 and 540 cm−1 and the low fre-
acid (namely the addition, cyclization and dehydration leading quency band around 417 cm−1 are attributed to that of the
to the 4H-pyran ring system). Therefore, there is still a need to tetrahedral and octahedral groups, respectively. Moreover, the
design a more sustainable protocol to afford functionalized low frequency band also appeared in the expected range of
4H-pyran. Again, mixed metal oxides exhibit activity and 332 cm−1. The peak at 1272 cm−1 is due to overtones.
selectivity superior to those shown by individual oxides.
UV spectrum. UV-vis diffuse reflectance spectroscopy of
Chemical properties of the active sites can be attuned by ZnFe2O4 showed a steep absorption edge (Fig. S4, see ESI†).
mixing an oxide catalyst with another metal oxide, so the inter- ZnFe2O4 is highly photoresponsive in both the UV and visible
action between two metal cations is highly critical to catalytic light ranges (>400 nm) as expected, especially in the wave-
performance. For example, iron oxide possesses a Lewis acidic length range of 300–500 nm. The dark brown color of ZnFe2O4
character17 whereas zinc oxide enjoys a basic character18 but did demonstrate the visible light absorption ability of these
mixing iron oxide with zinc oxide to form spinel zinc ferrite materials.
(ZnFe2O4) causes the generation of new active sites having
XPS spectrum. From X-ray photoelectron spectroscopy the
enhanced Lewis acidic as well as basic sites.17 The Lewis acidic binding energy of O 1s was found to be 533.8 eV (Fig. S5a, see
behaviour of ZnFe2O4 is derived from the strong Lewis acceptor ESI†). XPS signals at 715.19 and 723.0 eV could be attributed
properties of Fe3+ of Fe2O3. On the other hand the basic char- to the Fe 2p3/2 and Fe 2p1/2 oxidized states of Fe(III) (Fig. S5b,
acter of ZnFe2O4 is due to the O2− of ZnO. This dual catalytic see ESI†), whereas signals at 1025.56 and 1048.53 eV could be
property of mixed metal oxides makes ZnFe2O4 nanoparticles attributed to the Zn 2p1/2 and Zn 2p3/2 states of Zn(II) (Fig. S5c,
very interesting for use as a heterogeneous “E” catalyst see ESI†). Binding energies of Fe 2p3/2 and Fe2p1/2 states of Fe(III)
(Eco-friendly, Efficient and Economic).
and Zn 2p1/2 and Zn 2p3/2 states of Zn(II) are found to be
For this purpose we have prepared zinc ferrite nanoparticles different from the binding energies of those states in α-Fe2O3
as described by Sato et al.19 and characterized them by powder and ZnO oxide. These clearly reflect that Zn, Fe and O are not
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present in the form of individual zinc oxide, ferrous oxide or temperature (Table 1, entries 4, 5, 6). On the other hand, the
ferric oxide but as spinel zinc ferrite. use of ZnO in combination with Fe2O3 as an acid–base dual
N2 adsorption analysis. Mixed oxides have greater surface catalyst showed a significant improvement in the yield of 4H-
area, smaller particle sizes and higher generation of new cata- pyran (4h) (73%) at room temperature (Table 1, entry 7). This
lytic active sites than the corresponding oxide homologues. In implies that the initial Knoevenagel condensation is a base
the present investigation the surface area of ZnFe2O4 nanopowder catalyzed reaction. Subsequent addition via the attack of an
obtained by calcining at 800 °C was 16 m2 g−1 (Fig. S6a, see active methylene compound (here indane-1,3-dione) on ortho-
ESI†). The pore volume and average pore diameter were found quinone methides (5), cyclization and dehydration to afford
to be 0.02 cm3 g−1 and 6.09 nm, respectively (Fig. S6b, see ESI†). the desired xanthene are acid catalyzed reactions. Interestingly,
carrying out the same experiment with only ZnO NP at 70 °C
yielded the desired compound (4h) in 80% yield (Table 1,
entry 8). This could probably be due to the fact that after Knoe-
venagel condensation in the presence of ZnO, the addition,
cyclization and dehydration steps are assisted at higher temp-
eratures. Therefore, we see that though ZnO/Fe2O3 is a good
catalyst for carrying out this reaction at room temperature, it
leads to a yield that is not as high as that of spinel ZnFe2O4
NPs (Table 1, entry 9). Albeit other mixed oxide spinel NPs like
ZnTiO3 offered quantitative conversion to 4h (Table 1, entry
14), ZnFe2O4 was a more attractive alternative since it can be
created from cheaper materials available in a common class
laboratory. With ZnFe2O4 as a good catalyst in hand, we next
examined whether 40 mg of the catalyst was the optimum
quantity for this reaction (Table 1, entry 9).
Optimization of the reaction conditions
To optimize the reaction conditions, a series of experiments
were conducted with a representative reaction of β-naphthol
(1) (1 mmol), 4-nitrobenzaldehyde (2) (1 mmol) and indane-
1,3-dione (3) (1 mmol) with the variation of reaction para-
meters, such as catalyst, reaction temperature, etc., and the
results are summarized in Table 1.
It was found that 40 mg of ZnO or MgO NPs as the base
catalyst could mainly afford the ortho-quinone methides (5)
(formed by Knoevenagel condensation of β-naphthol with
aldehyde) along with a small amount of the target compound
(4h) (Table 1, entries 1, 2) after 24 h stirring at room tempera-
ture. However the starting materials were mostly unaffected by
acidic catalysts like Fe2O3, TiO2 and CeO2 NPs at room
Good to excellent conversion was also achieved with
different homogeneous catalysts like NaOAc/AcOH, NH4OAc/
AcOH, piperidinium benzoate, etc. However, they required
Table 1 Optimization of reaction conditions for the multicomponent
coupling reactionsa
repeated work-up, neutralization of acids and bases, and exten-
sive chromatographic purification. Ultimately the isolated
yields were not very high (Table 1, entries 15, 16, 17). There-
fore, the homogeneous catalysts were replaced with a hetero-
geneous reusable catalyst. Thus, ZnFe2O4 was found to be the
right choice of catalyst for this particular reaction in generat-
ing 4H-pyran at room temperature. Importantly, no product
was observed without any catalyst (Table 1, entry 18) which
further necessitates the use of ZnFe2O4 in this transformation.
Moreover, this simple procedure allowed easy scale-up of
the reaction, and as shown in Table 1, 82% yield was obtained
in the 150 mmol scale reaction (Table 1, entry 19), indicating
the practicability of our protocol.
Yieldc (%)
Temp.b Time
Entry Catalyst (amount)
(°C)
(h)
4h
5
1
2
3
4
5
6
7
8
ZnO NPS (40 mg)
MgO NPs (40 mg)
CuO (40 mg)
Fe2O3 (40 mg)
TiO2 (40 mg)
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
70
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
24
24
24
24
24
24
5
6
3
3
3
3
3
3
8
8
10
24
23
—
—
—
—
73
80
91
49
18
8
91
88
75
72
72
69
68
31
16
18
14
14
12
—
—
—
—
—
—
—
—
—
Synthetic application of spinel ZnFe2O4 nanopowder
CeO2 (40 mg)
Synthesis of 2-amino-4H-pyrans. With the optimized con-
ditions in hand, to delineate this approach, the scope and gen-
erality of this protocol was next examined by employing
various aldehydes, carbonyl compounds possessing a reactive
α-methylene group and alkylmalonates. An assembly of 44
2-amino-4H-pyran compounds was synthesized using this proto-
col (Scheme 1). Among the aldehydes, aliphatic as well as aro-
matic aldehydes afforded excellent yields. Aromatic aldehydes
with electron-withdrawing as well as electron-donating groups
in o, m, p positions of the aromatic ring were converted into
desired products in good to excellent yields. It was pleasing to
find that acid-sensitive aldehydes (containing heteroatom,
methoxy, and hydroxy groups) and highly activated aromatic
aldehydes (containing –NO2 groups) also reacted very efficiently
ZnO/Fe2O3 (40 mg)
ZnO NPS (40 mg)
ZnFe2O4 NPs (40 mg)
ZnFe2O4 NPs (20 mg)
ZnFe2O4 NPs (10 mg)
ZnFe2O4 NPs (5 mg)
ZnFe2O4 NPs (50 mg)
ZnTiO3 NPs (40 mg)
NaOAc/AcOH (0.2 mmol)
NH4OAc/AcOH (0.2 mmol)
Piperidinium benzoate
(0.2 mmol)
9
10
11
12
13
14
15
16
17
18
—
r.t.
r.t.
24
6
—
82
—
—
19d
ZnFe2O4 NPs (3 g)
a β-Naphthol 1 (1 mmol), 4-nitrobenzaldehyde 2 (1 mmol), indane-
1,3-dione 3 (1 mmol), water (2 mL). b Here r.t. corresponds to 30 °C.
c Isolated yields. d 150 mmol scale.
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with no side reactions. Therefore, the present spinel ZnFe2O4
nanoparticle catalyzed protocol has general applicability
accommodating a variety of substitution patterns. To further
expand the scope of the reaction, the use of different alkyl-
malonates was investigated. To our surprise, all the active methy-
lene compounds (namely malononitrile, ethyl cyanoacetate,
methyl cyanoacetate and cyanoacetamide) were easily trans-
formed into the desired products in good to excellent yields.
Besides, our methodology has been used successfully with
diverse carbonyl compounds possessing a reactive α-methylene
group, and corresponding 4H-pyrans were obtained in excel-
lent yields without any byproducts. Therefore, this mixed
metal oxide catalyst showed an excellent distribution of acid–
base sites. The synthetic route is facile, convergent, and allows
easy placement of a variety of substituents around the
periphery of the heterocyclic ring system. The structures of
compounds 7am and 7ay were clearly elucidated using X-ray
crystallography (Fig. S7 and S8, see ESI†).
Synthesis of the bis-4H-pyran system. The rapid generation
of molecular complexity in a controlled and predictable
manner from simple and readily available starting materials is
a contemporary topic in modern organic synthesis. The com-
plexity and brevity mostly rely on the coupling of individual
transformations into one synthetic process. In these lines, we
speculated that the use of bis-1,4-aldehyde would result in the
creation of complex molecules by doubling the efficacy of the
above process. The efficiency of this process is further
extended to demonstrate the double multicomponent process
by utilizing bis-1,3-aldehyde in an analogous manner. The bis-
aldehyde was reacted with carbonyl compounds possessing a
reactive α-methylene group and alkylmalonates to furnish the
respective bis-4H-pyran system (Scheme 2). This reaction
Scheme 1 Library of 4H-Pyrans synthesized. Reaction conditions: car-
bonyl compounds possessing a reactive α-methylene group 1 (1 mmol),
aldehyde 2 (1 mmol), alkylmalonates 6 (1 mmol), 40 mg of ZnFe2O4,
water (2 mL), 3 h stirring at r.t. (30 °C).
Scheme 2 Scope exploration: generation of bis-4H-pyran system.
Reaction conditions: carbonyl compounds possessing a reactive α-
methylene group 1 (1 mmol), bis-aldehyde 8 (0.5 mmol), alkylmalonates
6 (1 mmol), 40 mg of ZnFe2O4, water (2 mL), 3 h stirring at r.t. (30 °C).
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efficiently resulted in the formation of six chemical bonds, two The low reactivity of ketones in this reaction is also reflected in
stereocenters and two 4H-pyran units in a single operation. the reaction temperature since there was only about 15%
The complex bis-4H-pyran systems are skillfully and profi- spiro-4H-pyrans formation after stirring the reaction mixture at
ciently synthesized from simple, readily available starting 30–35 °C for 8 h in water instead of nearly 90% yield at
materials.
60–70 °C.
Synthesis of spiro-4H-pyrans. A survey of the literature
Synthesis of benzopyrans. Being inspired by the above
revealed that albeit the condensation between alkylmalonates, results, it was thought worthwhile to replace alkylmalonates
carbonyl compounds possessing reactive α-methylene group with cyclic-1,3-dione in order to show the versatility of this pro-
and highly reactive ketones (isatin, ninhydrin or acenaphthene- tocol (Scheme 5). For this aim, we have examined the reaction
quinone) is frequently reported20 (Scheme 3), to the best of of aldehydes, carbonyl compounds possessing a reactive
our knowledge to date there has been only one report21 of α-methylene group and dimedone. Notably, a wide range of R1
spiro-4H-pyrans with cyclic aliphatic ketones (cyclopentanone, groups (aromatic and heteroaromatic) were well tolerated and
cyclohexanone, and cycloheptanone) using morpholine as a incorporated. After the successful coupling of carbonyl com-
catalyst with inherent limitations involved in the separation pounds possessing a reactive α-methylene group 1, aromatic
and recycling of the homogeneous catalysts. Therefore, our aldehydes 2 and dimedone, under the same previous reaction
strategy enabled us to overcome the negative aspects of catalyst conditions, cyclohexane-1,3-dione, 5-phenylcyclohexane-1,3-
leaching in spiro-4H-pyrans formation from aliphatic cyclic dione and indane-1,3-dione were also utilized in place of dime-
ketones. To our surprise, despite distinct steric hindrance, done to show the versatility of this protocol. In this experi-
ring tension and lower reactivity cyclic ketones reacted mentally simple process three new bonds (two C–C and one
smoothly under the present conditions. Both 3- and 4-hydroxy- C–O) and one stereocenter are generated in a single operation
coumarin were totally consumed in this reaction affording with all reactants efficiently utilized.
moderate to good yield of 13 (Scheme 4). Unlike the reaction
Synthesis of xanthenes. Xanthenes are biologically impor-
with aldehydes, in the reaction with ketones the starting tant heterocyclic compounds, which possess antiviral anti-
materials were mostly unconsumed with α- and β-naphthol. inflammatory22a and antibacterial activities.22b These are
being utilized as antagonists for the paralyzing action of zoxa-
zolamine22c and in photodynamic therapy.22d Furthermore,
these compounds can be used as dyes, in laser technologies22e
and as pH sensitive fluorescent materials for visualization of
biomolecules.22f As can be seen from Scheme 6, for precursors
2 bearing either electron-donating or electron-withdrawing
substituents on the aromatic ring, the reactions all proceeded
very smoothly to provide the corresponding xanthene deriva-
Scheme 3 Synthesis of spirooxindoles 11. Reaction conditions: carbo-
nyl compounds possessing a reactive α-methylene group 1 (1 mmol),
isatin 10 (1 mmol), alkylmalonates 6 (1 mmol), 40 mg of ZnFe2O4, water
tives. The property of substituents on the aromatic ring of the
aldehydes did not exert an obvious effect on the reaction yield.
(2 mL), 3 h stirring at r.t. (30 °C).
Scheme 4 Formation of spiropyrano[3,2-c]chromene using cyclic ali-
phatic ketones as carbonyl compounds. Reaction conditions: carbonyl
compounds possessing a reactive α-methylene group 1 (1 mmol), cyclic
aliphatic ketones 12 (1 mmol), alkylmalonates 6 (1 mmol), 40 mg of
ZnFe2O4, water (2 mL), 3 h, 60–70 °C.
Scheme 5 ZnFe2O4 nanoparticle catalyzed one-pot synthesis of benzo-
xanthenes. Reaction conditions: carbonyl compounds possessing a reac-
tive α-methylene group 1 (1 mmol), aldehyde 2 (1 mmol), cyclic-1,3-dione
3 (1 mmol), 40 mg of ZnFe2O4, water (2 mL), 3 h stirring at r.t. (30 °C).
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Scheme 6 ZnFe2O4 nanoparticle catalyzed efficient protocol for
xanthene synthesis. Reaction conditions: aldehyde 2 (1 mmol), cyclic-
1,3-dione 3 (2 mmol), 40 mg of ZnFe2O4, water (2 mL), 3 h stirring at r.t.
(30 °C).
Scheme 7 Synthetic transformation of xanthene to 1,4-DHPs. Reaction
conditions: xanthenes 14 (1 mmol), nitrogen-centered nucleophile 15
(1 mmol), 40 mg of ZnFe2O4, water (2 mL), 3 h, 50–55 °C.
Our attempt to use isatin as a carbonyl group in this MCR was
also successful attesting to the flexibility of the present
protocol.
When a precursor that is either commercially not available or
less available is used, the E-factor of synthesizing 4H-pyran
will be increased. In order to circumvent these problems, a
general, efficient, and environmentally benign method for
synthesizing 4H-pyran-3-carboxylate with a wide range of alkyl
substituents of the ester group is required. Moreover, the
amide substituents in the 3-positions of the pyran ring are
quite reactive; this makes these compounds good candidates
as precursors for further synthetic transformations to meet the
need for various useful purposes. In the presence of a catalytic
amount of ZnFe2O4, a functional group transformation of car-
boxamides with ester was achieved (Scheme 8). A mechanistic
scheme for the conversion of amide to ester is depicted herein
for clarity (Scheme 9). Here probably Fe3+ remaining in the
octahedral holes of ZnFe2O4 coordinates with the carbonyl
carbon of amide increasing its electrophilicity and thereby
facilitates the attack of alcohol (R2OH) on the amide carbonyl
carbon. It has been established that structurally ZnFe2O4 is a
normal spinel where it can be written as (Zn2+) (Fe3+)2 (O2−)4.
In the ZnFe2O4 spinel structure Fe3+ ions occupy the octa-
hedral holes defined by the O2− ions whereas Zn2+ remains in
the tetrahedral holes defined by the O2− ions.25 Thus in
ZnFe2O4 the O2− ions remaining in the lattice site in the
ZnFe2O4 spinel act as a base in the reaction. As shown in
Scheme 9, in the third step O2− remaining in the lattice site in
ZnFe2O4 acting as a base abstracts proton from intermediate
20 and produces the target compound 18 after elimination of
NH3. The functional group interconversion from amide to
Application of the compounds
One-step synthesis of 1,4-DHPs from xanthenes. 1,4-Dihy-
dropyridines (1,4-DHPs) have potential pharmaceutical activi-
ties and could be used as antimalarial, vasodilator, anesthetic,
anticovulsant, antiepileptic, and antitumor; and as agrochem-
ical such as fungicide, pesticide, and herbicide.23 In light of
their potential versatility as active determining building blocks
of some biologically active natural products, the present report
puts forward an application24 of nucleophilic vinylic substi-
tution (SNV) followed by intramolecular cyclization of 4H-pyran
compounds for the one-step synthesis of 1,4-DHPs that pro-
vides easy access to two nitrogen–carbon (N–C) bonds in a
single operation (Scheme 7). We have confirmed the structure
of compound (16a) unambiguously by X-ray crystallographic
analysis (CCDC 946299) (Fig. S14, see ESI†).
Functional group interconversion from amide to ester. Pre-
vious synthetic methodologies for the construction of a 4H-
pyran scaffold have focused primarily on the combination of
carbonyl compounds possessing a reactive α-methylene group,
aldehyde and active methylene compounds (namely propane-
dinitrile, cyanoacetamide and alkyl cyanoacetate). However a
synthesis involving alkyl cyanoacetate suffers from limited
variety because of the limited availability of the alkyl group of
the starting alkyl cyanoacetate (namely methyl and ethyl
groups). Although other active methylene groups are commer-
cially available, their use is limited due to their high price.
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Fig. 1 The reusability of ZnFe2O4 for the reaction of α-naphthol 1
(1 mmol), pyridine-4-aldehyde
2 (1 mmol), ethyl cyanoacetate 3
(1 mmol) in water (2 mL) at r.t. (30 °C ) for 3 h.
ZnFe2O4 nanopowder catalyst (40 mg) in H2O (2 mL) for 3 h
at r.t. producing 7bm.
A nearly quantitative catalyst (up to 98%) could be recov-
ered from each run. In a test of six cycles, the catalyst could be
reused without significant loss of catalytic activity (Fig. 1). The
slight reduction in yield is probably due to the loss of some
catalyst at the time of filtration. The recovered catalyst after six
runs had no obvious change in structure according to the
FT-IR spectrum in comparison with the fresh catalyst
(Fig. S11, see ESI†). The XRD observation of the recovered cata-
lyst was also made and there was no obvious change in mor-
phology (Fig. S12, see ESI†). In order to prove that the reaction
is heterogeneous, a standard leaching experiment was con-
ducted by means of XPS analysis. β-Naphthol, 4-nitrobenzalde-
hyde and indane-1,3-dione were allowed to react for
15–20 minutes in the presence of ZnFe2O4 at room tempera-
ture. After this 15–20 minutes period, the reaction mixture was
filtered (hot). The filtered reaction mixture was then stirred
without a catalyst for the next 12 h; no formation of the corres-
ponding product was observed, indicating that no homo-
geneous catalyst was involved. XPS analysis of the filtrate (hot)
revealed the absence of Fe and Zn species in the filtrate. These
results revealed that the metal ions are not leached into the
solvent.
Scheme 8 Synthetic transformation of 4H-pyran-3-carboxamide to
4H-pyran-3-carboxylate. Reaction conditions: 4H-pyran-3-carboxamide
7 (1 mmol), 40 mg of ZnFe2O4, alcohol 17 (2 mL), 3 h, 70–80 °C.
Scheme 9 A plausible reaction scenario to explain the conversion of
amide to ester.
ester is compatible with a wide range of alcohols. This obser-
vation is rare and very interesting in organic chemistry. In this
reaction, the alcohol is not only playing the role of a solvent,
but also taking part in the reaction as a reagent. Therefore, we
disclose the successful outcome of this endeavor in which a
new class of densely substituted 4H-pyran-3-carboxylates
was prepared in good to excellent yield from 4H-pyran-
3-carboxamide.
Conclusions
In conclusion, ZnFe2O4 nanopowder performs efficiently as a
recyclable ditopic heterogeneous catalytic system for the one-
pot construction of the 4H-pyran moiety in aqueous media. In
the present instance the dual catalytic activity of ZnFe2O4 was
essential for the room temperature synthesis of 4H-pyran with
a shorter reaction time. Indeed, to the best of our knowledge
there are no previous reports on the library synthesis of 4H-
pyran in the presence of a mixed metal oxide nanocatalyst
Catalyst stability and recyclability
In order to validate the recyclability of the current ZnFe2O4 having both acidic and basic character. The present report
nanopowder catalyst, the re-use investigation was performed in puts forward an application of 4H-pyran compounds for the
a model reaction of α-naphthol (1) (1 mmol), pyridine-4-alde- synthesis of 1,4-DHPs. In particular an attractive feature of
hyde (2) (1 mmol) and ethyl cyanoacetate (3) (1 mmol) and the this report is the functional group interconversion from amide
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of 4H-pyran-3-carboxamide to ester leading to 4H-pyran- recovered catalyst was washed several times with water and
3-carboxylate.
then acetone, dried in a desiccator and stored for another con-
secutive reaction run. Organic compounds were afforded by
evaporation of the solvent in a rotary evaporator and the solid
residue was finally recrystallized from ethyl acetate–pet. ether.
The products were characterized by standard analytical tech-
Experimental
General procedure for the synthesis of 7aa–7br
1
niques such as H & 13C NMR, FTIR, elemental analysis, and
Carbonyl compounds possessing a reactive α-methylene group
1 (1 mmol), aldehyde 2 (1 mmol), alkylmalonates 6 (1 mmol)
and 40 mg of ZnFe2O4 nanopowder catalyst obtained by calcin-
ing at 800 °C were added to 2 mL water and the reaction
mixture was stirred at r.t. for 3 h. After completion of the reac-
tions (monitored by disappearance of the starting material in
thin layer chromatography), ethyl acetate (5 mL) was added to
the whole reaction mixture and the solid catalyst was separated
from the mixture by filtering through a sinter funnel. The
recovered catalyst was washed several times with water and
then acetone, dried in a desiccator and stored for another con-
secutive reaction run. Organic compounds were afforded by
evaporation of the solvent in a rotary evaporator and the solid
residue was finally recrystallized from ethyl acetate–pet. ether.
The products were characterized by standard analytical tech-
melting point determination and all gave satisfactory results.
General synthetic procedure for the preparation of 13a–13d
Carbonyl compounds possessing a reactive α-methylene group
1 (1 mmol), cyclic aliphatic ketones 12 (1 mmol), alkylmalo-
nates 6 (1 mmol) and 40 mg of the ZnFe2O4 nanopowder cata-
lyst obtained by calcining at 800 °C in water were heated at
60–70 °C for 3 h. After completion of the reactions (monitored
by disappearance of the starting material in thin layer chrom-
atography), ethyl acetate (5 mL) was added to the whole reac-
tion mixture and the solid catalyst was separated from the
mixture by filtering through a sinter funnel. The recovered
catalyst was washed several times with water and then acetone,
dried in a desiccator and stored for another consecutive reac-
tion run. Pure organic compounds were afforded by evapor-
ation of the solvent in a rotary evaporator and the crude
product was further purified by silica gel column chromato-
graphy using ethyl acetate–petroleum ether as an eluent. The
products were characterized by standard analytical techniques
1
niques such as H & 13C NMR, 2D NMR, FTIR, elemental ana-
lysis, melting point determination, and X-ray crystallographic
analysis and all gave satisfactory results.
General synthetic procedure for the preparation of 9a–9e
1
such as H & 13C NMR, FTIR, elemental analysis, and melting
Carbonyl compounds possessing a reactive α-methylene group
1 (1 mmol), bis-1,4 and bis-1,3-aldehyde 8 (0.5 mmol), alkyl-
malonates 6 (1 mmol) and 40 mg of the ZnFe2O4 nanopowder
catalyst obtained by calcining at 800 °C were added to 2 mL
water and the reaction mixture was stirred at r.t. for 3 h. After
completion of the reactions (monitored by disappearance of
the starting material in thin layer chromatography), ethyl
acetate (5 mL) was added to the whole reaction mixture and
the solid catalyst was separated from the mixture by filtering
through a sinter funnel. The recovered catalyst was washed
several times with water and then acetone, dried in a desicca-
tor and stored for another consecutive reaction run. Organic
compounds were afforded by evaporation of the solvent in a
rotary evaporator and the solid residue was finally recrystal-
lized from ethyl acetate–pet. ether. The products were charac-
terized by standard analytical techniques such as 1H & 13C
NMR, FTIR, elemental analysis, and melting point determi-
nation and all gave satisfactory results.
point determination and all gave satisfactory results.
General procedure for the synthesis of 4a–4h
Carbonyl compounds possessing a reactive α-methylene group
1 (1 mmol), aldehyde 2 (1 mmol), cyclic-1,3-dione 3 (1 mmol)
and 40 mg of ZnFe2O4 nanopowder catalyst obtained by calcin-
ing at 800 °C were added to 2 mL water and the reaction
mixture was stirred at r.t. for 3 h. After completion of the reac-
tions (monitored by disappearance of the starting material in
thin layer chromatography), ethyl acetate (5 mL) was added to
the whole reaction mixture and the solid catalyst was separated
from the mixture by filtering through a sinter funnel. The
recovered catalyst was washed several times with water and
then acetone, dried in a desiccator and stored for another con-
secutive reaction run. Organic compounds were afforded by
evaporation of the solvent in a rotary evaporator and the solid
residue was finally recrystallized from ethyl acetate–pet. ether.
The products were characterized by standard analytical tech-
1
niques such as H & 13C NMR, FTIR, elemental analysis, and
General synthetic procedure for the preparation of 11
melting point determination and all gave satisfactory results.
Carbonyl compounds possessing a reactive α-methylene group Along with the first intermediate (5), another intermediate
1 (1 mmol), isatin 10 (1 mmol), alkylmalonates 6 (1 mmol) (2nd) was also isolated, both of which were well characterized
and 40 mg of ZnFe2O4 nanopowder catalyst obtained by calcin- by standard analytical techniques such as 1H & 13C NMR,
ing at 800 °C were added to 2 mL water and the reaction FTIR, elemental analysis, melting point determination and
mixture was stirred at r.t. for 3 h. After completion of the reac- X-ray crystallographic analysis (2nd intermediate).
tions (monitored by disappearance of the starting material in
General synthetic procedure for the synthesis of 14a–14i
thin layer chromatography), ethyl acetate (5 mL) was added to
the whole reaction mixture and the solid catalyst was separated Aldehyde 2 (1 mmol), cyclic-1,3-dione 3 (2 mmol) and 40 mg
from the mixture by filtering through a sinter funnel. The of ZnFe2O4 nanopowder catalyst obtained by calcining at
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800 °C were added to 2 mL water and the reaction mixture was water and the reaction mixture was stirred by a mechanical
stirred at r.t. for 3 h. After completion of the reactions (moni- stirrer at r.t. for 6 h. After completion of the reactions, ethyl
tored by disappearance of the starting material in thin layer acetate (300 mL) was added to the whole reaction mixture and
chromatography), ethyl acetate (5 mL) was added to the whole the solid catalyst was separated from the mixture by filtering
reaction mixture and the solid catalyst was separated from the through a sinter funnel. Organic compounds were obtained by
mixture by filtering through a sinter funnel. The recovered evaporation of the solvent in a rotary evaporator and the solid
catalyst was washed several times with water and then acetone, residue was finally recrystallized from ethyl acetate–pet. ether
dried in a desiccator and stored for another consecutive reac- to afford 49.86 g (82%) of product.
tion run. Organic compounds were afforded by evaporation of
the solvent in a rotary evaporator and the solid residue was
finally recrystallized from ethyl acetate–pet. ether. The pro-
Acknowledgements
ducts were characterized by standard analytical techniques
1
such as H & 13C NMR, FTIR, elemental analysis, and melting One of the authors (PD) thanks the Council of Scientific and
point determination and all gave satisfactory results.
Industrial Research, New Delhi for her fellowship (SRF). We
thank the CAS Instrumentation Facility, Department of Chem-
istry, University of Calcutta for spectral data. We also acknowl-
General procedure for the synthesis of 16a–16h
Xanthenes 14 (1 mmol), nitrogen-centered nucleophile 15 edge the grant received from the UGC funded Major project,
(1 mmol), and 40 mg of ZnFe2O4 nanopowder catalyst obtained F. no. 37-398/2009 (SR) dated 11-01-2010.
by calcining at 800 °C in water were heated at 50–55 °C for 3 h.
After completion of the reactions (monitored by disappearance
of the starting material in thin layer chromatography), ethyl
acetate (5 mL) was added to the whole reaction mixture and
Notes and references
the solid catalyst was separated from the mixture by filtering
through a sinter funnel. The recovered catalyst was washed
several times with water and then acetone, dried in a desicca-
tor and stored for another consecutive reaction run. Organic
compounds were afforded by evaporation of the solvent in a
rotary evaporator and the solid residue was finally recrystal-
lized from ethyl acetate–pet. ether. The products were charac-
terized by standard analytical techniques such as 1H & 13C
NMR, FTIR, elemental analysis, melting point determination,
and X-ray crystallographic analysis and all gave satisfactory
results.
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4H-Pyran-3-carboxamide 7 (1 mmol) and 40 mg of ZnFe2O4
nanopowder catalyst obtained by calcining at 800 °C were
heated at 70–80 °C in various alcohols (2 mL) for 3 h. After
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