Aqua-mediated one-pot synthesis of Biginelli dihydropyrimidinone/thiones (DHPMs), Hantzsch dihydropyridines (DHPs), and polysubstituted pyridines sonocatalyzed by metal-supported nanocatalysts

Article abstract of DOI:10.1007/s13738-015-0734-5

In this work, catalyst composition-activity relationship of supported catalysts in Biginelli and Hantzsch reactions was investigated under mild conditions. Biginelli dihydropyrimidinone/thiones were prepared over Fe-Cu/ZSM-5 as an efficient, convenient, and environmentally benign catalyst under ultrasonic irradiation in aqueous media in very good yields. The Fe-Cu/ZSM-5-catalyzed synthesis of 1,4-dihydropyridines and their aromatization to polysubstituted pyridines and also a new one-pot, two-step, and sequential protocol for the synthesis of pyridine derivatives, employing an aldehyde, ethyl acetoacetate, and ammonium acetate under the same green experimental conditions were illustrated. Three-component condensation in the presence of supported reagent with operational simplicity, inexpensive reagents, short reaction time, high yield of products, and use of non-toxic reagents makes this synthetic protocol an attractive one.

Full text of DOI:10.1007/s13738-015-0734-5

J IRAN CHEM SOC
DOI 10.1007/s13738-015-0734-5
ORIGINAL PAPER
Aqua-mediated one-pot synthesis of Biginelli
dihydropyrimidinone/thiones (DHPMs), Hantzsch
dihydropyridines (DHPs), and polysubstituted pyridines
sonocatalyzed by metal-supported nanocatalysts
1
1
1
Kazem D. Safa
•
Maryam Esmaili
•
Maryam Allahvirdinesbat
Received: 17 June 2015 / Accepted: 5 September 2015
Ó Iranian Chemical Society 2015
Abstract In this work, catalyst composition–activity
relationship of supported catalysts in Biginelli and
Hantzsch reactions was investigated under mild conditions.
Biginelli dihydropyrimidinone/thiones were prepared over
Fe–Cu/ZSM-5 as an efficient, convenient, and environ-
mentally benign catalyst under ultrasonic irradiation in
aqueous media in very good yields. The Fe–Cu/ZSM-5-
catalyzed synthesis of 1,4-dihydropyridines and their
aromatization to polysubstituted pyridines and also a new
one-pot, two-step, and sequential protocol for the synthesis
of pyridine derivatives, employing an aldehyde, ethyl
acetoacetate, and ammonium acetate under the same green
experimental conditions were illustrated. Three-component
condensation in the presence of supported reagent with
operational simplicity, inexpensive reagents, short reaction
time, high yield of products, and use of non-toxic reagents
makes this synthetic protocol an attractive one.
One-pot multicomponent reactions have been applied as
an efficient tool in combinatorial chemistry and drug dis-
covery for the synthesis of diverse and complex com-
pounds, as well as small and drug-like heterocycles from
easily available starting materials via a green synthetic
approach by reducing the number of steps, energy con-
sumption, and waste production [4–7].
In recent years, 1,4-dihydropyridines (DHPs) and 3,4-
dihydropyrimidinone/thiones (DHPMs) have occupied an
important place in organic and medicinal chemistry,
mainly due to their diverse therapeutic and pharmacolog-
ical properties [8, 9]. A number of Hantzsch dihydropy-
ridines, namely azelnidipine and nifedipine, have been
introduced as potential drugs for the treatment of conges-
tive heart failure due to their calcium antagonistic effect
(Fig. 1) [10–13]. In addition, DHPs are used as
organocatalysts for asymmetric reactions such as hydro-
genation of quinolones in the synthesis of alkaloids,
asymmetric reductive amination of aldehydes, and hydro-
genation of a,b-unsaturated aldehydes and ketones.
Besides, the oxidation of readily accessible Hantzsch 1,4-
DHP provides one of the shortest routes to polysubstituted
pyridine derivatives [10–13, 32, 33]. The dihydropyrim-
idinone/thione moiety constitutes an active backbone in
exciting medications, e.g., monastrol (anti-cancer agent),
SQ 32926, and SQ 32547 (antihypertensive drugs) (Fig. 1).
Also their particular structure is present in natural marine
alkaloid Batzelladine A and B for the development of
AIDS therapy [9, 14–17].
Keywords Biginelli reaction Á Hantzsch reaction Á Green
synthesis Á Metal-supported nanocatalysts Á Polysubstituted
pyridines Á Oxidative aromatization
Introduction
Green chemistry is a branch of chemistry, which covers all
chemical processes that reduce or preferably eliminate
waste generation and avoid the use of toxic and/or haz-
ardous substances and solvents [1–3].
This versatile applicability highlights the importance of
access to efficient synthetic routes to well benign DHP and
DHPM derivatives. Ultrasonic-irradiation technique pro-
vides an efficient and powerful tool to perform reactions
faster with enhanced product yields with high purity by
reducing the unwanted formation of byproducts [18–20].
&
Kazem D. Safa
dsafa@tabrizu.ac.ir
1
Organosilicon Research Laboratory, Faculty of Chemistry,
University of Tabriz, 5166614766 Tabriz, Iran
123

J IRAN CHEM SOC
Fig. 1 Examples of 1,4-
dihydropyridine- and 3,4-
dihydropyrimidone/thione-
containing drugs
NO2
N
N
Ph
O
NO2
O
N
Ph
MeO C
CO Me i-PrO C
CO Me i-PrO C
2
2
2
2
2
O
Me
N
H
Me
Me
N
H
Me
OH
Me
N
H
Me
Nifedipine
Isradipine
Azelnidipine
O N
2
.
HCl
F3C
O
N
i-PrO C
2
CO NH2
i-PrO C
2
EtO C
2
2
N
N
O
F
NH
Me
N
H
O
Me
N
H
S
Me
N
H
S
SQ-32926
Monastrol
SQ-32547
One of the key areas of green chemistry is green catalysis.
The extensive application of metal oxides supported on
various inorganic solid supports has attracted the attention
of many chemists in different areas of chemistry [19, 21,
one-pot three-component condensation reactions in the
presence of metal-supported nanocatalysts as recyclable
catalysts in water under ultrasonic irradiation (high inten-
sity) at ambient temperature (Scheme 1).
2
2]. The use of various copper-exchanged zeolites as active
We initiated our study with the supported catalysts with
different transition metals (Mn, Fe, Co, and Cu) and sup-
ports (c-Al O , ZSM-5, and SAPO-34) on the Hantzsch
condensation reaction. In order to optimize the reaction
parameters, the cyclo-condensation reaction of benzalde-
hyde (1 equiv.), ethyl acetoacetate (2 equiv.), and ammo-
nium acetate (1 equiv.) was investigated in water at room
temperature for preparation of diethyl 1,4-dihydro-2,6-
dimethyl-4-phenylpyridine-3,5-dicarboxylate (5b) as a
model reaction.
and stable heterogeneous catalysts in synthetic organic
chemistry can make the synthetic process more efficient
from both environmental and economic points of view [23,
2
3
2
4]. On the other hand, the catalysis of organic reactions in
aqueous medium is fully compatible with green chemistry
[
2, 3, 21, 22].
In this work, we have investigated Biginelli and
Hantzsch condensation reactions in the presence of sup-
ported catalysts with different transition metals (Mn, Fe,
Co, and Cu) and c-alumina (c-Al O ), Zeolite Socony
Mobil-5 (ZSM-5), as an aluminosilicate zeolite, and sili-
coaluminophosphate molecular sieve (SAPO-34) under
ultrasonic irradiation in various solvents. The desired
products were obtained in excellent yields using Cu–Fe/
ZSM-5 bimetallic oxide nanocatalyst as an ‘‘E’’ catalyst
Acidity of catalysts is one of the important parameters to
determine their performance during cyclo-condensation
processes. Among the zeolite-supported metal nitrates,
Cu(NO3)2 has attracted much attention because of its
suitable acidity, eco-friendliness, easy availability, and low
cost, thereby acting as a promising reagent. Also the
activity of catalysts with metal loading of 10 wt% is lower
with 5 wt%. This decrease can be attributed to excessive
metal agglomeration, leading to the formation of large
metal particles. Besides, further content of metal blocks the
pores and active sites of the catalyst so the catalytic activity
decreases. Therefore, the metal content was kept at 5 wt%
for monometallic catalysts. To evaluate and optimize the
catalytic system, three-component condensation was
examined with different supported Lewis acid catalysts to
2
3
(
efficient, eco-friendly, and economic) via zeolite-cat-
alyzed multicomponent reactions (ZCMCRs) in aqueous
medium. Also some of the Hantzsch-polysubstituted
pyridines were prepared efficiently by Cu–Fe/ZSM-5 under
the same green conditions in very good yields.
Result and discussion
give 5b. Interestingly, it was found that Cu(NO ) sup-
3 2
Because of the wide use of solid acid catalysts in different
areas of organic chemistry and due to our continuing
interest to use various catalysts in multicomponent reac-
tions transformation [8, 25–31], here we wish to report an
efficient and environmentally benign method for the syn-
thesis of DHPs, DHPMs, and polysubstituted pyridines via
ported on zeolite H-ZSM-5 with low loading (5 wt%) was
proved to be an efficient catalyst, and gave 5b in 61 %
yield under ultrasonic irradiation in water. The sequence of
acidic property of supports is as follows:
ZSM-5 [ SAPO-34 [ c-Al O
2
3
1
23

J IRAN CHEM SOC
Scheme 1 Preparation of
O
O
O
Ar
O
Biginelli dihydropyrimidinone/
thiones (DHPMs), Hantzsch
dihydropyridines (DHPs), and
polysubstituted pyridines using
metal-supported nanocatalysts
H C
OR
OR
3
RO
OR
CH3
2
H C
N
H
NH OAc 3
3
5(a-f)
4
M/support
H O, ((((
2
O
O
O
O
Ar
N
O
O
O
H C
3
+
M/support
H O, ((((
2
RO
OR
Ar
H
H3C
OR
1
2
NH OAc 3
4
2
H C
CH3 6(a-c)
3
R=OMe, OEt
X= O, S
M= Mn, Co, Fe, Cu
X
O
Ar
support= Al O , ZSM-5, SAPO-34
2
3
H N
2
NH2
RO
H C
NH
4
7(a-i)
N
H
X
3
The c-Al O has the least acidity, and the acidity of
Table 1 Optimization of the
reaction conditions
2
3
H-ZSM-5 is more than H-SAPO-34. Therefore, Cu-ZSM-5
has shown higher activity than Cu-SAPO-34. Mn-based
catalysts show poor activity during the cyclo-condensation
reaction due to the formation of many other side products.
More investigation of the metal-supported nanocatalysts
revealed that metal has more influence than support on
catalyst activity at supported catalysts. Hence, Cu-ZSM-5
has shown higher activity than Cu-SAPO-34 for the
preparation of 5b. However, the reaction proceeded rather
slowly, and no significant acceleration was observed.
Incorporation of different transition metals into
Cu(NO ) /H-ZSM-5 for preparation of a series of M–Cu/
O
O
O
O
H
O
catalyst
H O, ((((
2
OC
2
H
5
C
2
H
5
O
OC
2 5
H
C H O
2
5
+
H C
O
H C
3
N
CH
3
O
3
H C
H
3
4
NH OAc
5b
a
Entry
Catalyst
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
9
Mn/c-Al
2
O
3
20
20
20
20
15
15
15
15
10
10
10
10
5
10
21
29
35
24
36
47
50
35
46
54
61
70
78
95
20
31
35
2 3
Co/c-Al O
Fe/c-Al
2 3
O
3
2
Cu/c-Al
2 3
O
ZSM-5 (M: Mn, Co, and Fe) bimetallic oxide nanocatalysts
has become a target for optimizing the catalytic system of
monometallic oxide catalysts for the synthesis of DHP
derivatives. The study of catalytic ability of Fe–Cu/ZSM-5
catalyst showed that incorporation of Fe over Cu/ZSM-5
increased the product yield to 95 %, and the reaction time
Mn/SAPO-34
Co/SAPO-34
Fe/SAPO-34
Cu/SAPO-34
Mn/ZSM-5
1
1
0
1
Co/ZSM-5
(
5 min) was decreased with the decrease of the catalyst
Fe/ZSM-5
loading (3 wt%) (Table 1, entry 15). This result is in
agreement with our working hypothesis that the favorable
synergetic effects of iron and copper, acidity, and reactant
adsorption ability of the support might be the main factors
for improving the cyclo-condensation reaction on Fe–Cu/
ZSM-5. The other reason may be the phenomenon called
12
13
14
15
16
17
18
Cu/ZSM-5
Mn–Cu/ZSM-5
Co–Cu/ZSM-5
Fe–Cu/ZSM-5
5
5
c-Al
2
O
3
1 h
1 h
1 h
‘
acoustic cavitations&produced by ultrasound irradiation. It
is worthy to note that ultrasound with frequencies less than
0 kHz and using solid catalysts in the reaction mixture
H-SAPO-34
H-ZSM-5
5
Reaction conditions 4-nitrobenzaldehyde (1 equiv.), ethylacetoacetate
2 equiv.), and ammonium acetate (1 equiv.), and (5 wt% from
monometallic catalyst) and (3 wt% from bimetallic catalyst) in water
under ultrasonic irradiation at ambient temperature at 20 % power of
the processor
could increase the reaction rate. Molecules of the liquid are
separated during the rarefaction cycle of the wave, gener-
ating bubbles that undergo subsequent implosive collapse
in a liquid that produces unusual chemical and physical
environments. These rapid and violent implosions of the
(
a
Indicated yields refer to isolated products
123

J IRAN CHEM SOC
Table 2 Synthesis of diethyl 1,4-dihydro-2,6-dimethyl-4-phenylpyr-
idine-3,5-dicarboxylate (5b)
protocol will provide new alternative in the synthesis of
polysubstituted pyridines. In this work, for example, DHPs
a
(
5b, 5e, and 5f) were converted to the corresponding
Entry
Conditions
Time/min
Yield/%
pyridines 6(a–c) efficiently in excellent yields by Fe–Cu/
ZSM-5 (6 wt%) in water under ultrasonic irradiation in the
presence of oxygen in air at ambient temperature
1
2
3
4
5
6
7
8
Ethanol
20
20
20
20
5
50
52
48
70
95
20
10
84
Ethanol/water
Acetonitrile
Acetonitrile/water
Water
(Scheme 2).
This work proposes a mechanism for the formation of
polysubstituted pyridines 6a, 6b, and 6c (Scheme 3). In
analogy to the mechanisms involving high-valence metal
ions, the oxidation of 1,4-DHP is presumed to be initiated
by a single electron transfer to acceptor Cu(II) and/or
Fe(III) to produce a radical cation a, and Cu(I) and/or Fe(II).
This is followed by a proton loss from radical cation a, to
generate radical b. The latter is further oxidized by another
molecule of Cu(II) and/or Fe(III) to form the oxidized
pyridine c (in the protonated form) and Cu(I) and/or Fe(II).
Cu(I) and/or Fe(II) is oxidized by molecular oxygen to
regenerate Cu(II) and/or Fe(III) along with the formation of
hydroperoxide radical via superoxide ion. Hydroperoxide
radical can, in turn, oxidize another Cu(I) and/or Fe(II) ion
to produce H O . Both the hydroperoxide radical and H O
2 2
DCM
50
50
10
Toluene
Solvent-free (120 °C)
Reaction conditions: (3 wt%) Fe–Cu/ZSM-5 bimetallic catalyst in
water under ultrasonic irradiation at ambient temperature
a
Indicated yields refer to isolated product
bubbles generate localized ‘hot spots.&Such localized hot
spots can be considered as microreactors in which the
energy of sound is transformed into a useful chemical form
next to the surface of the catalyst/reactants [18–20].
We studied the effect of various solvents under ultra-
sound irradiation and also solvent-free conditions on the
model reaction. As shown in Table 2, polar solvents and
solvent-free conditions afforded better yield than the non-
polar ones, and the best result was obtained in aqueous
medium in which Fe–Cu/ZSM-5 catalyst worked most
efficiently by phasing out of the desired product.
2
2
can oxidize 1,4-DHP, thereby accounting for less than the
stoichiometric consumption of O in the oxidation [32].
2
Encouraged by these results, we next focused our efforts
to study the effect of the supported catalysts with different
transition metals (Mn, Fe, Co, and Cu) and supports (c-
Al O , H-ZSM-5 and H-SAPO-34) under ultrasonic irra-
To further show the applicability of this method, the
preparation of derivatives 5(a–f) with variety of aromatic
aldehydes bearing electron-withdrawing or electron-do-
nating groups was investigated under the same experi-
mental conditions, and the corresponding products were
obtained in high yields without the formation of any side
products (Table 3). Some of the Hantzsch dihydropyridines
was confirmed by IR, NMR, elemental analyses, and
melting points.
2
3
diation in various solvents on the Biginelli condensation
reaction for the synthesis of dihydropyrimidinone/thiones
(DHPMs) (Scheme 1). In order to achieve the optimum
conditions, the reaction of benzaldehyde (1 equiv.) with
ethylacetoacetate (1 equiv.) and urea (1.5 equiv.) was
selected as a model. The trials were begun by comparing
the catalytic efficiency of Fe-Cu/ZSM-5 with other Cu-
supported nanocatalysts in this work. The yield of Biginelli
product is up to 42, 53, and 65 % with Cu/c-Al O , Cu/
In addition to the benefits from economical point of
view, reuse of catalysts is very important to avoid wastes.
Therefore, we investigated the catalytic performance of the
recycled Fe–Cu/ZSM-5 in the model reaction. For this
purpose, all the water added for filtering and washing the
product was collected and washed with ethanol
2
3
SAPO-34, and Cu/ZSM-5, respectively. The effect of dif-
ferent solvents was then studied. Biginelli product is
obtained in moderate to good yields in CH3CN, THF,
ethanol, and water. However, the reaction in water under
ultrasonic irradiation at ambient temperature gave very
good yield of the desired product.
(
2 9 10 mL) to remove the organic impurities. Then the
water was evaporated, and the extracted catalyst was dried.
As shown in Fig. 2, the recovered catalyst could be reused
three times without significant decrease in its catalytic
activity.
Also the different experiments showed that the best
result was obtained by the application of Fe-Cu/ZSM-5
(3 wt%) in water under ultrasonic irradiation (high inten-
sity) at ambient temperature within 5 min.
To our knowledge, the use of metal-supported
nanocatalyst to oxidize 1,4-DHPs has never been reported
before. Herein, we examined the possibility of using Fe–
Cu/ZSM-5 as a novel environmentally benign reagent to
effect the oxidative aromatization of Hantzsch 1,4-dihy-
dropyridines. Also a one-pot, two-step, and sequential
In order to study the scope and generality of this
methodology, ferrocenecarboxaldehyde was tested in the
previous reaction. Unfortunately, it was observed that even
under optimized conditions, the corresponding 1,4-DHPM
was isolated in very low yield due to the formation of many
other side products. Also the starting material was still
1
23

J IRAN CHEM SOC
Table 3 Synthesis of Hantzsch 1,4-dihydropyridines (DHPs) and polysubstituted pyridines
a
Yield /%
Entry
1
1(aldehyde)
R
Product IV
M.p. (lit. m.p.)/°C
Et
H3C
EtO
97
95
96
130–132 (128–129 [34])
O
NH
O
H
CH3
OEt 5a
O N
2
O N
2
O
2
3
O
Et
H3C
150–152 (152–154 [35])
EtO
NH
O
H
CH3
OEt 5b
O
Me
CH3
144–146 (143–145 [36])
O
OMe
O
NH
H
CH3
Cl
Cl
O
OMe
5c
4
O
Et
H C
3
95
200–203
EtO
O
NH
H
CH3
OEt
O
O
O
O
5
d
O
5
6
7
8
Et
Et
Et
Et
OEt CH3
NH
93
93
229–232 (229–231 [35])
159–161 (160–161 [34])
59–61 (60–61 [37])
O
O
H
CH3
OEt
HO
HO
O
5
e
OEt CH3
O
O
NH
Figb
H
CH3
H C
3
H C
O
OEt
3
5f
OEt CH3
99
O
O
N
H
CH3
OEt
O
6
a
O
CH3
100
172–174 (172–173 [37])
O
EtO
N
H
CH3
OEt 6b
HO
HO
O
123

J IRAN CHEM SOC
Table 3 continued
a
Yield /%
Entry
9
1(aldehyde)
R
Product IV
M.p. (lit. m.p.)/°C
Et
O
CH3
98
72–74 (72–73 [38])
O
EtO
N
H
CH3
OEt 6c
H C
3
H C
O
3
Reaction conditions: aldehyde (1 mmol), b-ketoester (2 mmol), ammonium acetate (1 mmol), and 3 wt% of Fe–Cu/ZSM-5 for the synthesis of
(a–f), and aldehyde (1 mmol), b-ketoester (2 mmol), ammonium acetate (1 mmol), and 6 wt% of Fe–Cu/ZSM-5 for the synthesis of 6(a–c) in
water under ultrasonic irradiation at ambient temperature at 20 % power of the processor within 5 min
5
a
Indicated yields refer to isolated products
Conclusion
9
5
95
9
4
9
3
1
00
8
6
4
2
0
0
0
0
In summary, for investigation of the relationship between
catalyst composition and catalytic performance in a cyclo-
condensation process, one-pot three-component synthesis
of dihydropyrimidinone/thione and dihydropyridine
derivatives via Biginelli and Hantzsch condensations was
studied using the catalysts with different metals (Mn, Fe,
Co, and Cu) and supports (c-Al O , ZSM-5, and SAPO-34)
5
5
6
7
0
1
2
3
4
Time (min)
2
3
Isolated Yield (%)
at ambient temperature. The results revealed that Fe–Cu/
ZSM-5 bimetallic oxide nanocatalyst is the best and least
expensive catalyst for the preparation of 1,4-DHPs and 3,4-
DHPMs in water as a suitable green solvent under ultra-
sonic irradiation in excellent yields. Also we successfully
developed a new and easy to perform method for efficient
oxidation of Hantzsch 1,4 dihydropyridines, and a new
one-pot potentially efficient, absolutely clean, versatile,
green procedure for the synthesis of polysubstituted
pyridines under the same experimental conditions. These
simple procedures combined with easy recovery and reuse
of this catalyst make this method economically and envi-
ronmentally benign.
Fig. 2 Results of the reusability of Fe–Cu/ZSM-5 in the synthesis of
diethyl 1,4-dihydro-2,6-dimethyl-4-phenylpyridine-3,5-dicarboxylate
(
5b) in water under ultrasonic irradiation (Table 3, entry 2)
1
present in the crude products (according to H NMR
spectrum). In comparison, the reaction was amenable to a
wide range of aromatic aldehydes bearing either electron-
donating or electron-withdrawing groups, and in all cases,
gave the desired products in very good yields (Table 4). By
replacing urea with thiourea in the reaction system, the
corresponding Biginelli products were also obtained in
high yields.
R'
R'
R'
H
O
O
O
(
3 wt%)
EtO C
2
CO Et
2
(3 wt%)
EtO C
CO Et
H
O
O
2
2
Fe-Cu/ZSM-5
Fe-Cu/ZSM-5
EtO
H C
OEt
+
O (via air), H O, ((((
H O, ((((
2
H C
N
H
CH3
2
2
3
H C
N
CH3
3
H C
3
3
NH OAc
4
6
6
6
a
b
c
R'=H
5
5
5
b
e
f
R'=H
R'=OH
R'=Me
R'=OH
R'=Me
Fe-Cu/ZSM-5 (6 wt%)
O (via air), H O, ((((
2
2
Scheme 2 Oxidative aromatization of 1,4-DHPs by Fe–Cu/ZSM-5
1
23

J IRAN CHEM SOC
Scheme 3 Proposed
R'
mechanism for the oxidative
aromatization of 1,4-DHPs by
Fe–Cu/ZSM-5 for preparation
of pyridine derivatives
R'
R'
H
H
EtO C
CO Et
EtO C
CO Et
EtO C
CO Et
2
.
2
2
2
Cu(II) and/or Fe(III)
-Cu(I) and/or Fe(II)
2
2
.
-H.
.
+
.
.
+
H C
3
N
CH3
H C
3
N
H
CH3
H C
3
N
H
CH3
H
b
a
R'
R'
EtO C
CO Et
EtO C
CO Et
2
2
2
2
-
H+
+
H C
N
H
CH3
H C
3
N
CH3
3
c
d (V)
H.
Cu(II) and/or Fe(III) + HO2.
Cu(I) and/or Fe(II) + O (via air)
2
Cu(I) and/or Fe(II) + HO2.
Cu(II) and/or Fe(III) + H O
2
2
Experimental
bimetallic catalysts, and the second metal content was kept
at 3 wt%. The first determined amount of precursors was
dissolved in 30 mL of the mixture of distilled water and
ethanol with a volume ratio of 50 %. Then the support was
added to the solution, and the suspension was stirred at
45 °C until the solvent was totally evaporated. Subse-
quently, the catalysts were dried in an oven at 100 °C
overnight and then calcined at 550 °C for 4 h. Under these
conditions, complete decomposition of metal nitrate into
metal oxide occurred. The prepared catalysts were kept in
desiccator until testing time to prevent water and contam-
inant adsorption.
Material and technique
Chemicals were either prepared in our laboratory or pur-
chased from Merck, Fluka, and Aldrich. Commercial
products were used without further purification. The 1H
1
3
and C NMR spectra were recorded with a Bruker FT-
00 MHz spectrometer at room temperature and with
CDCl and/or DMSO-d as solvent. The FTIR spectra were
4
3
6
recorded on a Bruker Tensor 270 spectrometer. The reac-
tions were carried out using an ultrasonic processor probe
(
SONOPULS Ultrasonic Homogenizers). The elemental
analyses were carried out with an Elementar Vario EL III
instrument. The abbreviations used for NMR signals are
s = singlet, d = doublet, t = triplet, and m = multiplet.
The melting points were recorded on a B u¨ chi B-545
apparatus in open capillary tubes.
General procedure for preparation of Hantzsch
1,4-dihydropyridine (DHP) derivatives 5(a–f)
In a typical experiment, aromatic aldehyde (1 mmol), b-
ketoester (2 mmol), ammonium acetate (1 mmol), and Fe-
Cu/ZSM-5 (3 wt%) in 2 ml water were introduced in a
20-mL heavy-walled pear-shaped two-necked flask with
nonstandard-tapered outer joint. The flask was attached to a
12-mm tip diameter probe, and the reaction mixture was
sonicated at ambient temperature at 20 % power of the
processor. After completion of the reaction (monitored by
TLC, within 5–8 min), the solid product was filtered,
washed with water and ethanol, dried, and recrystallized
from ethanol. The supported reagent was washed thrice with
water and ethanol and dried under vacuum before reuse.
Data for the selected compounds are as shown below:
Synthesis of nanocatalysts
All mono and bimetallic nanocatalysts were prepared
through the excess-solution impregnation method. The
precursors of used metals were Cu(NO ) Á3H O,
3
2
2
Co(NO ) Á6H O, Fe(NO ) Á9H O, and Mn(NO ) Á4H O,
3
2
2
3 3
2
3 2
2
and the used supports were H-ZSM5 (Si/Al = 50), c-
2
Al O , and SAPO-34. The type of metal was chosen based
2 3
on our previous research results [28]. The metal content
was kept at 5 wt% for monometallic catalysts and for
123

J IRAN CHEM SOC
Table 4 Synthesis of Biginelli 3,4-dihydropyrimidinone/thiones (DHPMs)
a
Yield /%
Entry
1
1(aldehyde)
R
X
Product IV
M.p. (lit. m.p.)/°C
Me
S
S
95
211–213 (209–213 [15])
O
HN
O
NH
H
CH3
OMe
S
7
a
2
3
Et
S
S
94
95
205–206 (205–207 [39])
O
HN
O
NH
H
CH3
OEt
HO
HO
7b
O
Me
S
193–195
HN
NH
CH3
OMe
7c
H
O
O
O
O
O
4
Me
S
S
92
154–156 [40])
O
HN
NH
CH3
H
H
H C
3
H C
O
OMe
3
7d
5
Et
S
S
93
187–189 (190–192 [40])
O
HN
NH
CH3
H C
3
H C
O
O
OEt
3
7e
6
7
8
O
Et
O
O
O
95
93
97
201–203 (203–205 [39])
226–227 (229–230 [41])
236–238 (233–235 [42])
HN
O
NH
H
CH3
OEt
7
f
Et
O
O
HN
NH
H
CH3
HO
HO
O
OEt
7
g
Me
O
O
HN
NH
H
CH3
OMe
O N
2
O N
O
2
7h
1
23

J IRAN CHEM SOC
Table 4 continued
a
Yield /%
Entry
9
1(aldehyde)
R
X
Product IV
M.p. (lit. m.p.)/°C
O
Me
O
O
94
189–191 (189–192 [42])
H
HN
O
NH
MeO
CH3
OMe
MeO
7
i
Reaction conditions: aldehyde (1 mmol), b-ketoester (1 mmol), urea or thiourea (1.5 mmol), and 3 wt% of Fe–Cu/ZSM-5 in water under
ultrasonic irradiation at ambient temperature at 20 % power of the processor within 5 min
a
Indicated yields refer to isolated products
Diethyl 1,4-dihydro-2,6-dimethyl-4-phenylpyridine-3,5-
dihydropyridine (1 mmol), and Fe–Cu/ZSM-5 (3 wt%) in
2 ml water were introduced in a 20-mL heavy-walled pear-
shaped two-necked flask with nonstandard-tapered outer
joint. The flask was attached to a 12-mm tip diameter
probe, and the reaction mixture was sonicated at ambient
temperature at 20 % power of the processor. After com-
pletion of the reaction (monitored by TLC, within
10–15 min), the solid product was filtered, washed with
water and ethanol, dried, and recrystallized from ethanol.
The supported reagent was washed thrice with water and
ethanol and dried under vacuum before reuse. Data for the
selected compound are as shown below:
dicarboxylate (5b)
White powder; yield 95 %; M.P. = 150–152 °C; FTIR
-
KBr, cm ): 3416 (str, N–H), 3093 (str, ArCH), 2981 (str,
1
(
Aliphatic C–H), 1692 (str, O–C=O), 1490 (str, C=C), 1211
1
(
str, C–O). H NMR (400 MHz, CDCl , ppm): d 1.21 (t,
3
J = 8.0 Hz, 6H, 2 O–CH CH ), 2.32 (s. 6H, 2CH ),
2
3
3
4
.04–4.09 (q, J = 8.0 Hz, 4H, 2 O–CH CH ), 4.98 (s, H,
2 3
1
3
C –H), 5.64 (s, 1H, N–H), 7.11–7.28 (m, 5H, Ar–H).
4
C
NMR (100 MHz, CDCl , ppm): d 13.22, 18.60, 38.57,
3
5
8.70, 103.14, 125.07, 126.79, 126.99, 127.08, 127.41,
1
42.80, 146.72, 166.59 (C=O). Anal. Calc. for C H NO :
1
9
23
4
C 69.28, H 7.04, N 4.25 %. Found: C 69.41, H 6.99, N
.12 %.
Diethyl 4-(4-hydroxyphenyl)-2,6-dimethylpyridine-3,5-
4
dicarboxylate (6b)
Diethyl 4-(benzo[d] [1, 3] dioxol-5-yl)-1,4-dihydro-2,6-
White powder; yield 100 %; M.P. = 172–174 °C; FTIR
(KBr, cm ): 3414 (str, O–H), 3054 (str, ArCH), 2983 (str,
-
1
dimethylpyridine-3,5-dicarboxylate (5d)
Aliphatic C–H), 1720 (str, O–C=O), 1612, 1564, 1512,
White powder; yield 95 %; M.P. = 200–203 °C; FTIR
1441 (str, C=C), 1372, 1331, 1239, 1168 (str, C–O), 835,
1
-
KBr, cm ): 3352 (str, N–H), 3096 (str, ArCH), 2979 (str,
1
(
763. H NMR (400 MHz, CDCl , ppm): d 1.00 (t,
3
Aliphatic C–H), 1690 (str, O–C = O), 1651, 1559, 1489
1
str, C=C), 1237, 1211 (str, C–O). H NMR (400 MHz,
J = 7.1 Hz, 6H, 2 O–CH CH ), 2.59 (s. 6H, 2CH ),
3
2
3
(
4.04–4.09 (q, J = 7.1 Hz, 4H, 2 O–CH CH ), 6.30 (s, 1H,
2 3
CDCl , ppm): d 1.23 (t, J = 7.1 Hz, 6H, 2 O–CH CH ),
O–H), 6.74–6.84 (m, 2H, Ar–H), 7.09–7.12 (m, 2H, Ar–H),
1
3
2
3
3
2
.31 (s. 6H, 2CH ), 4.09–4.13 (q, J = 7.1 Hz, 4H, 2 O–
3
6.77. C NMR (100 MHz, CDCl , ppm): d 12.71, 21.65,
3
CH CH ), 4.90 (s, H, C –H), 5.71 (s, 1H, N–H), 5.87 (s,
2
60.53, 114.15, 114.46, 126.34, 127.27, 128.48, 128.84,
3
4
2
H, O–CH –O), 6.64 (d, J = 8.4 Hz, 1H, Ar–H), 6.74 (d,
2
154.13, 155.35, 167.19 (C=O). Anal. Calc. for C H NO :
19 21 5
1
J = 8.4 Hz, 1H, Ar–H), 6.77 (s, 1H, Ar–H). C NMR
3
C 66.46, H 6.16, N 4.08 %. Found: C 66.31, H 6.28, N
4.22 %.
(
100 MHz, CDCl , ppm): d 13.29, 18.63, 38.31, 58.74,
3
9
1
6
9.62, 103.35, 106.54, 107.58, 119.98, 140.99, 142.49,
66.57 (C=O). Anal. Calc. for C H NO : C 64.33, H
2
General procedure for preparation of Biginelli 3,4-
0
23
6
.21, N 3.75 %. Found: C 64.10, H 6.35, N 3.70 %.
dihydropyrimidinone/thione (DHPM) derivatives 7(a–i)
General procedure for the oxidation of 1,4-
dihydropyridines to the corresponding polysubstituted
pyridines 6(a–c)
In a typical experiment, aromatic aldehyde (1 mmol), b-
ketoester (1 mmol), urea, or thiourea (1.5 mmol) and of
Fe–Cu/ZSM-5 (3 wt%) in 2 ml water were introduced in a
20-mL heavy-walled pear-shaped two-necked flask with
In a typical experiment, aromatic aldehyde (1 mmol), b-
ketoester (2 mmol), ammonium acetate (1 mmol) and Fe–
Cu/ZSM-5 (6 wt%) and/or the Hantzsch 1,4-
nonstandard-tapered outer joint. The flask was attached to a
12-mm tip diameter probe, and the reaction mixture was
sonicated at ambient temperature at 20 % power of the
123

J IRAN CHEM SOC
processor. After completion of the reaction (monitored by
TLC, within 5–8 min), the solid product was filtered
washed with water and ethanol, dried, and recrystallized
from ethanol. The supported reagent was washed thrice
with water and ethanol and dried under vacuum before
reuse. Data for selected compounds are as shown below:
164.75 (C=O), 173.40 (C=S). Anal. Calc. for C H N
4 16 2-
1
O S: C 60.85, H 5.84, N 10.14, S 11.60 %. Found: C 60.64,
2
H 5.99, N 10.31, S 11.51 %.
Ethyl 1,2,3,4-tetrahydro-6-methyl-2-thioxo-4-p-
tolylpyrimidine-5-carboxylate (7e)
Methyl 1,2,3,4-tetrahydro-6-methyl-4-phenyl-2-
White powder; yield 93 %; M.P. = 187–189 °C; FTIR
(KBr, cm ): 3326, 3174 (str, N–H), 3105 (str, ArCH),
-
1
thioxopyrimidine-5-carboxylate (7a)
2981 (str, Aliphatic C–H), 1673 (str, O–C=O), 1575(str,
White powder; yield 95 %; M.P. = 211–213 °C; FTIR
C=C), 1284 (str, CO–O), 1180 (str, C–N), 1118 (C–O),
1
1113 (str, C=S), 803, 759, 739. H NMR (400 MHz,
-
1
(
KBr, cm ): 3312, 3178 (str, N–H), 3098 (str, ArCH),
925 (str, Aliphatic C–H), 1670 (str, O–C=O), 1567 (str,
C=C), 1338 (str, C–O), 1232 (str, C–N), 1104 (str, C=S),
2
DMSO-d , ppm): d 1.10 (t, J = 7.1 Hz, 3H, CH –CH –O),
6
3
2
2.26 (s, 3H, CH ), 2.28 (s, 3H, CH ), 3.97–4.03 (q,
3
3
1
7
50. H NMR (400 MHz, CDCl , ppm): d 2.36 (s, 3H,
J = 7.1 Hz, 2H, CH –CH –O), 5.13 (s, H, C –H), 7.09 (d,
3 2 4
3
CH ), 3.64 (s, 3H, O–CH ), 5.40 (s, H, C –H), 7.26–7.35
4
J = 8.0 Hz, 2H, Ar–H), 7.14 (d, J = 8.0 Hz, 2H, Ar–H),
3
3
1
m, 6H, Ar–H and 3-NH), 7.95 (s, 1H, 1-NH). C NMR
3
(
9.61 (s, 1H, 3-NH), 10.30 (s, 1H, 1-NH).
(
100 MHz, CDCl , ppm): d 17.51, 50.47, 55.18, 101.78,
3
1
25.64, 127.45, 127.79, 127.97, 141.17, 141.75, 164.65
Ethyl 1,2,3,4-tetrahydro-6-methyl-2-oxo-4-
(
C=O), 173.81 (C=S). Anal. Calc. for C H N O S: C
13 14 2 2
phenylpyrimidine-5-carboxylate (7f)
5
5
9.52, H 5.38, N 10.68, S 12.22 %. Found: C 59.29, H
.21, N 10.75, S 12.01 %.
White powder; yield 95 %; M.P. = 201–203 °C; FTIR
-
KBr, cm ): 3242, 3113 (str, N–H), 3109 (str, ArCH),
1
(
Methyl 4-(benzo[d][1, 3]dioxol-5-yl)-1,2,3,4-tetrahydro-6-
2978 (str, Aliphatic C–H), 1726 (str, O–C=O),1700 (N–
C=O, 1648, 1599 (str, C=C), 1220 (str, CO–O), 1174 (str,
1
C–N), 1090 (Et–O), 783, 757. H NMR (400 MHz,
methyl-2-thioxopyrimidine-5-carboxylate (7c)
White powder; yield 95 %; M.P. = 193–195 °C; FTIR
DMSO-d , ppm): d 1.09 (t, J = 7.0 Hz, 3H, CH –CH –O),
2.24 (s, 3H, CH ), 3.95–4.01 (q, J = 7.0 Hz, 2H, CH –
3 3
6
3
2
-
KBr, cm ): 3313, 3187 (str, N–H), 3088 (str, ArCH),
1
(
2
997 (str, Aliphatic C–H), 1671 (str, O–C=O), 1579 (str,
CH –O), 5.17 (s, H, C –H), 7.23–7.33 (m, 5H, Ar–H), 7.74
2 4
C=C), 1485, 1343 (str, C–O), 1191 (str, C–N), 1120 (str,
1
(s, 1H, 3-NH), 9.19 (s, 1H, 1-NH).
C=S), 803. H NMR (400 MHz, CDCl , ppm): d 2.36 (s,
3
3
2
3
H, CH ), 3.65 (s, 3H, O–CH ), 5.30 (s, H, C –H), 5.94 (s,
3
Methyl 1,2,3,4-tetrahydro-4-(4-methoxyphenyl)-6-methyl-
3
4
H, O–CH –O), 6.74–6.75 (m, 3H, Ar–H), 7.37 (s, 1H,
2
2-oxopyrimidine-5-carboxylate (7i)
1
3
-NH). 7.96 (s, 1H, 1-NH). C NMR (100 MHz, CDCl3,
ppm): d 17.46, 50.52, 54.91, 100.27, 101.74, 106.08,
07.40, 119.27, 135.20, 141.73, 146.67, 147.12, 164.65
C=O), 173.36 (C=S). Anal. Calc. for C H N O S: C
White powder; yield 94 %; M.P. = 189–191 °C; FTIR
(KBr, cm ): 3250, 3114 (str, N–H and str, ArCH), 2956
-
1
1
(
(str, Aliphatic C–H), 1722 (str, O–C=O and N–C=O), 1650,
1
4 14 2 4
5
4.89, H 4.61, N 9.14, S 10.47 %. Found: C 54.74, H 4.77,
1589 (str, C=C), 1237 (str, CO–O), 1180 (str, C–N), 1096
1
N 9.08, S 10.40 %.
(Me–O), 779. H NMR (400 MHz, DMSO-d , ppm): d
6
2.24 (s, 3H, CH ), 3.52 (s, 3H, CH –O), 3.72 (s, 3H, CH –
3 3 3
Methyl 1,2,3,4-tetrahydro-6-methyl-2-thioxo-4-p-
O–Ar), 5.08 (s, H, C –H), 6.87 (d, J = 8.6 Hz, 2H, Ar–H),
4
tolylpyrimidine-5-carboxylate (7d)
7.14 (d, J = 8.6 Hz, 2H, Ar–H), 7.69 (s, 1H, 3-NH), 9.18
(s, 1H, 1-NH).
White powder; yield 92 %; M.P. = 154–156 °C; FTIR
-
KBr, cm ): 3339, 3189 (str, N–H), (str, ArCH), 2926 (str,
1
Acknowledgments The authors would like to acknowledge the
financial support from the University of Tabriz, and Iranian Nan-
otechnology Initiative.
(
Aliphatic C–H), 1668 (str, O–C=O), 1562 (str, C=C), 1343
1
str, C–O), 1178 (str, C–N), 1111 (str, C=S), 803. H NMR
(
(
400 MHz, CDCl , ppm): d 2.31 (s, 3H, CH ), 2.35 (s, 3H,
3
3
CH ), 3.63 (s, 3H, O–CH ), 5.35 (s, H, C –H), 7.12 (d,
3
3
4
References
J = 7.8 Hz, 2H, Ar–H), 7.20 (d, J = 7.8 Hz, 2H, Ar–H),
1
3
.59 (s, 1H, 3-NH), 8.35 (s, 1H, 1-NH). C NMR
7
1
. F. Shirini, A. Yahyazadeh, K. Mohammadi, C.R. Chimie, Chin.
Chem. Lett. 25, 341 (2014)
2. S.S. Panda, S.C. Jain, Mini. Rev. Org. Chem. 8, 455 (2011)
(
100 MHz, CDCl , ppm): d 17.29, 20.12, 50.44, 54.71,
3
1
01.79, 125.55, 128.13, 128.55, 137.20, 138.32, 141.96,
1
23

J IRAN CHEM SOC
3
4
. S.S. Panda, Mini. Rev. Med. Chem. 13, 784 (2013)
. N. Isambert, M. Del Mar Sanchez Duque, J.-C. Plaquevent, Y.
G e´ nisson, J. Rodriguez, T. Constantieux, Chem. Soc. Rev. 40,
24. M.J. Climent, A. Corma, S. Iborra, RSC Adv. 2, 16 (2012)
25. S.R. Mistry, K.C. Maheria, J. Mol. Catal. A 355, 210 (2012)
26. K.D. Safa, M. Allahvirdinesbat, H. Namazi, Mol. Divers. 19, 29
(2015)
27. K.D. Safa, M. Abolfathi, K. Ghorbanpour, J. Chem. Res. 36, 575
(2012)
1
. C.O. Kappe, Acc. Chem. Res. 33, 879 (2000)
347 (2011)
5
6
. S.R. Shaikh, G.M. Nazeruddin, J. Chem. Pharm. Res. 6, 505
(
2014)
28. K.D. Safa, L. Sarchami, M. Allahvirdinesbat, A. Feyzi, P.
Nakhostin Panahi, J. Chem. Res. 38, 571 (2014)
29. K.D. Safa, M. Allahvirdinesbat, H. Namazi, Synth. Commun. 45,
1205 (2015)
30. K.D. Safa, A. Zeinolabedini, H. Abbasi, R. Teimuri-Mofrad, J.
Iran. Chem. Soc. 10, 447 (2013)
7
8
. B.B. Shingate, Organic Chem. Curr. Res. 1, 3 (2012)
. S.D. Bajaj, O.A. Mahodaya, P.V. Tekada, Pharm. Chem. J. 48,
681 (2015)
. B. Schnell, U.T. Strauss, P. Verdino, K. Faber, C.O. Kappe,
Tetrahedron 11, 1449 (2000)
9
1
1
0. R.H. Bockert, F.P. Guengerich, J. Med. Chem. 29, 1596 (1986)
1. C. L o´ pez-Alarc o´ n, L.J. N u´ n˜ ez-Vergara, J.A. Squella, Elec-
trochim. Acta 48, 2505 (2003)
31. K.D. Safa, T. Shokri, H. Abbasi, R. Teimuri-Mofrad, J. Hetero-
cyclic Chem. 51(1), 80–84 (2013)
32. S.H. Mashraqui, M.A. Kamik, Tetrahedron Lett. 39, 4895 (1998)
33. N. Nakamichi, Y. Kawashita, M. Hayashi, Org. Lett. 4, 3955
(2002)
34. A.S. ParaSkar, A. Sudalai, Indian J. Chem. 46B, 331 (2007)
35. S.-X. Wang, Z.-Y. Li, J.-C. Zhang, J.-T. Li, Ultrason. Sonochem.
15, 680 (2008)
36. M. Nasr-Esfahani, M. Montazerozohori, R. Raeatikia, Maejo Int.
J. Sci. Technol. 8, 32 (2014)
1
1
1
1
2. M.M. Heravi, FSSh Moosavi, YSh Beheshtiha, M. Ghas-
semzadeh, Heterocycl. Commun. 10, 415 (2004)
3. S. Dehghanpour, M.M. Heravi, F. Derikvand, Molecules 12, 433
2007)
4. S.R. Mistry, R.S. Joshi, S.K. Sahoo, K.C. Maheria, Catal. Lett.
41, 1541 (2011)
5. K.R. Kumar, V.L. Harika, A.B. Shaik, Indo. Am. J. Pharm. Res.
, 2773 (2014)
(
1
4
37. X. Liao, W. Lin, J. Lu, C. Wang, Tetrahedron Lett. 51, 3859
(2010)
38. M. Mahmoodi Hashemi, M.S. ZaKeri, S. Arianfar, Iran. J. Chem.
Chem. Eng. 22, 9 (2003)
16. F.S. Falsone, C.O. Kappe, ARKIVOC 2(2), 122 (2001)
17. S.S. Panda, P. Khanna, L. Khanna, Curr. Org. Chem. 16, 507
(2012)
1
1
2
8. D. Azarifar, D. Sheikh, Helv. Chim. Acta 95, 1217 (2012)
9. J. Safari, L. Javadian, Ultrason. Sonochem. 22, 341 (2014)
0. G.–.F. Chen, H.–.Y. Li, N. Xiao, B.–.H. Chen, Y.–.L. Song, J.–.T.
Li, Z.–.W. Li, Aust. J. Chem. 60, 146 (2014)
39. F. Heidarizadeh, E. Rezaee Nezhada, S. Sajjadifar, Scientia
Iranica C 20, 561 (2013)
40. C. Ramalingan, Y.-W. Kwak, Tetrahedron 64, 5023 (2008)
41. B. Boumoud, I. Mennana, T. Boumoud, A. Debachea, Lett. Org.
Chem. 10, 8 (2013)
2
2
2
1. B.S.P. Anil Kumar, K. Harsha Vardhan Reddy, B. Madhav, K.
Ramesh, Y.V.D. Nageswar, Tetrahedron Lett. 53, 4595 (2012)
2. D.I. MaGee, M. Dabiri, P. Salehi, L. Torkianb, ARKIVOC 11,
56 (2011)
3. K. Sivakumar, A. Kathirvel, A. Lalitha, Tetrahedron Lett. 51,
018 (2010)
42. P. Salehi, M. Dabiri, M.A. Zolfigol, M.A. Bodaghi, Fard. Tetra-
hedron Lett. 44, 2889 (2003)
1
3
123