Efficient one-pot synthetic methods for the preparation of 3,4-dihydropyrimidinones and 1,4-dihydropyridine derivatives using BNPs?SiO2(CH2)3NHSO3H as a ligand and metal free acidic heterogeneous nano-catalyst

Article abstract of DOI:10.1016/j.poly.2019.114340

Heterocyclic compounds with biological and pharmacological activates like 3,4-dihydropyrimidin-2-(1H)-ones and 1,4-dihydropyridines have attracted great interest. Boehmite nanoparticles functionalized with silylpropyl sulfamic acid (BNPs?SiO₂(C

Full text of DOI:10.1016/j.poly.2019.114340

Journal Pre-proofs
Efficient One-Pot Synthetic Methods for the Preparation of 3,4-Dihydropyri-
midinones and 1,4-Dihydropyridine Derivatives using
BNPs@SiO (CH ) NHSO H as a Ligand and Metal Free Acidic Heterogeneous
2
2 3
3
Nano-catalyst
Minoo Khodamorady, Samira Sohrabnezhad, Kiumars Bahrami
PII:
S0277-5387(19)30785-5
DOI:
https://doi.org/10.1016/j.poly.2019.114340
POLY 114340
Reference:
To appear in:
Polyhedron
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Revised Date:
Accepted Date:
4 September 2019
29 December 2019
30 December 2019
Please cite this article as: M. Khodamorady, S. Sohrabnezhad, K. Bahrami, Efficient One-Pot Synthetic Methods
for the Preparation of 3,4-Dihydropyrimidinones and 1,4-Dihydropyridine Derivatives using
BNPs@SiO (CH ) NHSO H as a Ligand and Metal Free Acidic Heterogeneous Nano-catalyst, Polyhedron (2020),
2
2 3
3
doi: https://doi.org/10.1016/j.poly.2019.114340
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Efficient One-Pot Synthetic Methods for the Preparation of 3,4-
Dihydropyrimidinones and 1,4-Dihydropyridine Derivatives using
BNPs@SiO
2
(CH
2
)
3
NHSO H as a Ligand and Metal Free Acidic
3
Heterogeneous Nano-catalyst
a
b
a,c
Minoo Khodamorady, Samira Sohrabnezhad and Kiumars Bahrami*
a
Department of Organic Chemistry, Faculty of Chemistry, Razi University, Kermanshah, 67149-
7346, Iran.
Department of Organic Chemistry, Faculty of Science, Lorestan University, Khoramabad, Iran
6
b
c
Nanoscience and Nanotechnology Research Center (NNRC), Razi University, Kermanshah 67149-
7346, Iran. Fax:+98(83)34274559. E-mail: kbahrami2@hotmail.com
6
Abstract
Heterocyclic compounds with biological and pharmacological activates like 3,4-
dihydropyrimidin-2-(1H)-ones and 1,4-dihydropyridines have attracted great interest.
Boehmite
BNPs@SiO
nanoparticles
(CH NHSO
functionalized
with
silylpropyl
sulfamic
acid
(
2
2
)
3
3
H) as a metal free and environmentally friendly catalyst has been
found to be effective for the one pot synthesis of 3,4-dihydropyrimidin-2-(1H)-ones and the
preparation of 1,4-dihydropyridines derivatives. Some features of this protocol are low cost
and available materials, short reaction times, convenient catalyst separation, and no need for a
neutral atmosphere. Moreover, the catalyst can be reused for at least five times with only a 7%
reduction in yield. This study also shows that BNPs@SiO
2
(CH
2
)
3
NHSO H is a sustainable,
3
recoverable and effective heterogeneous catalyst for multicomponent reactions.
Keywords: Boehmite; Acidic heterogeneous nano-catalysts; Biginelli reaction; 1,4-Dihydropyridines.
1. Introduction
In recent years, one of the most important disciplines in synthetic and pharmaceutical
chemistry is the chemistry of heterocyclic compounds [1-3]. Today, science and technology
have changed to develop eco-friendly and cost-effective methods. To this end, the development
of one-pot multi-component reactions under solvent-free conditions and design and synthesis
of stable, active, cost-effective and recyclable heterogeneous nano-catalysts are increasingly
needed. In addition, one-pot Multicomponent reactions (MCPs) are nowadays highly regarded
in organic and medicinal chemistry not only for their time saving, reduce chemical waste,
1

pot/atom and step economy and higher yields but also, for ease of product separation and
purification [4-9].
In the past several years, the functionalized dihydropyrimidone compounds (DHPMs) have
known for their multipurpose usages in nature products, chemical building blocks, pharmacy
and therapeutic activities such as antiviral, anti-tumor, antibacterial. and anti-inflammatory
[
10-14], as mitotic kinesin inhibitors [15], antihypertensive agents [16, 17], neuropeptide Y
NPY) antagonists [18], calcium channel blockers [14, 19, 20], as an useful organic
(
intermediates [21, 22] and as a key component in several alkaloids with marine sources. The
batzelladine alkaloids including the DHPM structure is a strong HIVgp-120-CD4 inhibitor [13,
2
3]. Some of these compounds with biological applications were presented in the Fig. 1.
Fig. 1. Examples of biologically active DHPMs
For the first time, in 1893, Italian chemist Pietro Biginelli [14] reported the simple one-pot
three component cyclocondensation synthesis of ethyl acetoacetate, benzaldehyde and urea
under acidic conditions [24]. In the traditional Biginelli conditions, due to the use of strong
acid catalysts, the purification of the products was difficult and the yields were low [25]. In
addition, high temperatures, stoichiometric use of catalysts, costly reagents, environmental
pollution and long reaction times are the operational drawbacks of the classical protocols [26,
2
7]. Ionic liquids [28, 29], ultrasound irradiation [30], H
3
BO
3
[31], VCl
3
[32], nanomagnetic
-CuCl [35],
supported sulfonic acid [33], KAl(SO -12H O supported on silica [34], SiO
4
)
2
2
2
2
2

(MWCNTs) [36, 37], boehmite nanoparticles [38], graphite [39], silica–sulfuric acid [40],
Mn(OAC) -2H O,[41] Ce(NO -6H O [42], ytterbium chloride [43] and graphene oxide [44]
3
2
3
)
3
2
are some of the different catalysts were used for modified Biginelli reactions.
To resolve the problems of previous methods, nowadays, many approaches have been
reported for the synthesis of DHPMs, which in most cases have been attempted to minimize
the dangerous reaction conditions and improve the catalyst separation from the reaction
medium.
1
,4-dihydropyridine compounds (1,4-DHPs) have gained special prominence among
researchers due to the widespread use of these compounds in the biological and pharmaceutical
fields, such as calcium blocker agents in heart disease, anti-tumour [45], antidiabetic agents
[
46], antihypertensive [47], antianginal [48], antimicrobial [49] and drugs to treat many other
diseases [50] (Fig. 2). Also 1,4-dihydropyridines with optical activity used as valid precursors
in various chiral N-heterocycles [51]. More than a century ago, 1,4-DHPs are synthesized by
Hantszch, via cyclocondensation of aldehyde, β-ketoester, and ammonia in EtOH refluxing for
a long time [52].
Fig. 2. Examples of biologically active 1,4-dihydropyridine compounds
In the last decades, many researchers have attempted to expand more efficient approaches
for the preparation of 1,4-DHPs, because the traditional methods had disadvantages such as the
use of strong, toxic and corrosive acids, high temperatures, prolonged reaction times, toxic
solvents, low to moderate yields, difficult to work up and tedious reaction conditions.[53, 54]
Since in most of the reported methods in the scientific literature, catalysts have been non-
recyclable, the development of novel, inexpensive and renewable heterogeneous nano-catalysts
3

is a fundamental issue. In between, solid-phase catalysts are of particular interest because they
have higher yields, easier product purification, catalyst recovery and easier catalytic separation
from the environment which form an economic approach for the multi-component reactions.
Among various supports, boehmite nanoparticles (BNPs) (‐AlOOH) is attractive solid-phase
catalyst because boehmite has remarkable merits containing high specific surface area, ease of
modification due to the many hydroxyl groups on the surface, mechanical, thermal and
chemical stability, cheap and commercially available precursors, high dispersity and air and
moisture insensibility.
Aiming to develop green chemistry and improve the synthetic methods for the preparation
of heterocyclic compounds, in this approach, we introduced a useful acidic metal and ligand
free catalyst (BNPs@SiO
2
(CH
2
)
3
NHSO H) for the solvent-free one-pot multicomponent
3
synthesis of DHPMs from reaction of divergent aldehydes with 1,3-dicarbonyl compounds and
urea/thiourea at 80 °C with decent yields as well as the one-pot atom-economic
multicomponent preparation of 1,4-DHP derivatives via condensation reactions of various
aldehydes, 1,3-dicarbonyl compounds and ammonium acetate at 70 °C in MeOH with efficient
catalytic performance (Scheme 1).
4

Scheme 1. Synthesis of DHPMs and 1,4-DHPs using BNPs@SiO
2
(CH
2
)
3
NHSO H as a catalyst
3
2
. Experimental
This nano-catalyst (BNPs@SiO
2
(CH
2
)
3
NHSO H) was synthesized according to
3
previously reported procedure [55].
.1. General
2
Yields refer to isolated products. The purity of the products and the progress of the reactions
were accomplished by TLC. Melting points were determined by a Stuart Scientific SMP2
apparatus. The FT-IR spectra were recorded on Perkin-Elmer 683 spectrometer using pressed
KBr pellets. The materials were purchased from Merck Company and used without any
purification. TEM and SEM recorded using a TESCAN, Model: MIRA3. X-ray powder
diffraction (XRD) was performed on a PANalytical Company X'Pert Pro MPD diffractometer.
Thermogravimetric analyis (TGA) was carried out using a STA PT-1000 Linseis (Germany)
-1
in the temperature range of 25– 800 °C at a heating rate of 10˚C min , under air atmosphere.
All yields refer to isolated products after purification by EtOH.
5

2
.2. General Procedure for the Preparation of 3,4-Dihydropyrimidon-2-(1H)-ones using
BNPs@SiO (CH NHSO
2
2
)
3
3
H
In a round bottom flask, a mixture of aromatic aldehyde (1 mmol), ethyl acetoacetate (1 mmol),
urea or thiourea (1.5 mmol) and BNPs@SiO (CH NHSO H (0.05 g, containing 0.07 mmol
SO H) was heated at 80 °C under solvent-free conditions for the appropriate time. When the
2
2
)
3
3
3
reaction was complete as monitored by TLC (n-hexane/ethyl acetate: 6/4), ethanol was added
to the mixture and it was stirred for 5 min at 80 °C. Then, the catalyst was removed by simple
filtration. After evaporation of the solvent corresponding product was obtained and further
purification was carried out by crystallization in hot ethanol.
3
.3. General Procedure for the Synthesis of 1,4-Dihydropyridines using
BNPs@SiO (CH NHSO
2
2
)
3
3
H
A mixture of the aldehyde (1 mmol), 1,3-dicarbonyl compounds (2 mmol) and ammonium
acetate (1.5 mmol) in the presence of BNPs@SiO (CH NHSO H (0.06 g, containing 0.08
mmol SO H) was heated at 70 °C in EtOH (7 mL) as a solvent. The progress of the reaction
2
2
)
3
3
3
was monitored by TLC (eluent: EtOAc: n-hexane = 3/7)). After completion of the reaction, the
mixture was cooled to room temperature and then ethanol was added to the resulting mixture
and the catalyst was isolated by filtration. After evaporation of solvent, solid product was
obtained and recrystallized from ethanol to give the pure products in excellent yields.
3
. Results and discussion
3
.1. Catalyst characterization
Following the successful synthesis of the BNPs@SiO
2
(CH
2
)
3
NHSO H and its use for the
3
selective oxidation of sulfides in the previous work, we found this to be a stable and efficient
nano-catalyst for the synthesis of heterocyclic compounds including DHPMs and 1,4-DHPs.
The boehmite nanoparticles were synthesized according to the method described in the
literature [55, 56] The schematic pathway for the preparation of sulfonic acid-modified silica-
coated BNPs are depicted in Scheme 2.
6

Scheme 2. The schematic route for synthesis of BNPs@SiO
2
(CH
2
)
3
NHSO H
3
Catalyst was well identified using different methods including FT‐IR, EDX, XRD, mapping,
TEM, SEM, TGA-DTA analysis and pH analysis.
The bonding of different groups onto the catalyst surface and catalyst synthesis were
investigated step by step by the IR technique. FT-IR spectra of a) BNPs b) BNPs-TEOS, c)
BNPs@SiO
2
(CH
2
)
3
NH
2
and d) BNPs@SiO
2
(CH )
2 3
NHSO H are depicted in Fig. 3. As can be
3
seen, all peaks appearing in Fig. 3a for BNPs are repeated in Fig. 3b, with a slight change in
frequency which is due to the grafting of TEOS to the boehmite surface. In addition, in all
-1
spectra (Fig. 3a-d), the peaks appearing in 424, 511, 636 and 778 cm are related to the Al-O
-1
stretching frequency and also the strong peak in 1000-1300 cm is related to the hydrogen
bond (OH…OH) between the boehmite plates and asymmetric and symmetric stretching
vibration of the Si-O-Si band buried below this peak.[55, 57] As can be seen in Fig. 3a,b, OH
-1
bending adsorption and OH stretching adsorption appeared in 1605, 1625 cm and 3370-3580
-1
cm respectively. It should be noted that all Al-O peaks shift to lower frequencies after binding
7

the acidic groups to the BNPs@SiO
2
(CH
2
)
3
NH surface and OH bending frequency shift to
2
higher frequency, which collaborates the successful synthesis of the catalyst.
−
1
Also, broad adsorption in 3000–3500 cm is prone to the successful attachment of the SO -
3
H groups to the catalyst surface [55]. However, in the 3100 to 3500 region, in addition to the
acidic groups, there is also the possibility of non-functionalized hydroxyl groups of boehmite.
Fig. 3. FTIR spectra of a) BNPs, b) BNPs-TEOS, c) BNPs@SiO
2 2
(CH )
3
NH
2
and d)
BNPs@SiO (CH NHSO
2
2
)
3
3
H
TEM and SEM analyzes were used to obtain accurate information on the morphology and
particle size of the BNPs@SiO (CH NHSO H. According to Fig. 4a, the morphology of
2
2
)
3
3
acidic boehmite is nearly orthorhombic [8] and the particles are irregularly dispersed and there
is little accumulation which is common in bohemite nanoparticles due to hydrogen bonding
between the plates. The average particle size of BNPs@SiO
nm.
2
(CH
2
)
3
NHSO H is between 10-40
3
Also, the structure and particle size of the boehmite and BNPs@SiO
investigated by SEM, the results of which are in agreement with the obtained results from TEM.
SEM images of boehmite and BNPs@SiO (CH NHSO H are shown in Fig. 4b-c. The
2
(CH
2
)
3
NHSO H were
3
2
2
)
3
3
morphology of the initial boehmite is irregular and accumulates due to the many hydroxyl
groups on the boehmite surface (Fig. 4b). It is worth mentioning that, the particle size in the
nano-catalyst is between 15-40 nm, which corroborates the particle size obtained from TEM
8

(Fig. 4c). It is worth noting that after the functionalization of the boehmite surface, the
accumulation is reduced and the structure is spherical and regular.
Fig. 4. a) TEM image of BNPs@SiO
of the BNPs@SiO (CH NHSO
2
(CH
2
)
3
NHSO H, b) SEM image of boehmite and c) SEM image
3
2
2
)
3
3
H
Powerful technique to scrutiny the crystallinity and phase purity of the material is XRD. Fig. 5
showed the XRD pattern of BNPs@SiO (CH NHSO H. According to the diffraction peaks
at the Bragg angles of 14.40° (020), 28.41° (120), 31.96° (110), 40.46° (060), 45.71° (131),
1.94° (200), 56.02° (151), 65.04° (231) and 68.09° (171), the boehmite crystalline phase is
2
2
)
3
3
5
orthorhombic.[55, 58] It is obvious that the boehmite crystalline phase is retained after several
modification steps and after the increase of different groups and linkers, the XRD pattern
changes and as can be seen in the XRD pattern, several peaks at 20-30° are typical for silica
and not seen in the XRD pattern of Boehmitt [59, 60]. Based on the evidence the introduced
catalyst was successfully synthesized.
9

Fig. 5. XRD pattern of BNPs@SiO
2
(CH
2
)
3
NHSO H
3
In the following, energy-dispersive X-ray spectrometry (EDX) analysis was used to
corroborate the presence of all the elements in the catalyst structure and based on the EDX
pattern, the composition of the BNPs@SiO
2
(CH
2
)
3
NHSO H was affirmed by the presence of
3
N (5.56%), O (76.28%), Al (6.10%), S (9.22%) and Si (2.83%) (Fig. 6).
Fig. 6. EDX spectrum of the nano-catalyst
Another useful technique used to illustrate the distribution of elements in the nano-catalyst
structure is mapping. The mapping pattern of the BNPs@SiO
2
(CH
2
)
3
NHSO H is illustrated in
3
Fig. 7 and the identical distribution of all the elements in the structure of the acidic
heterogeneous catalyst is quite evident.
1
0

Fig. 7. Mapping pattern of the BNPs@SiO
2 2
(CH )
3
NHSO H
3
Thermogravimetric analysis (TGA) was used for the survey of the thermal behavior of the
catalyst. Fig. 8 presents a) TGA curve and b) TGA-DTA diagram of the
BNPs@SiO
2
(CH
2
)
3
NHSO H. Based on the literature, boehmite nanoparticles are stable even
3
at temperatures up to 400 °C and retains approximately 90% of its weight.[61] The first weight
losing before 120 °C (3.58%) can be related to the water elimination. A second weight loss
(
14.54%) in the range of 130-300 °C is ascribed to the thermal decomposition of the NHSO
groups and organic solvents. It is worth noting that, a third weight loss that occurred in 300-
00 °C is attributed to the APTES and TEOS removal from the boehmite surface. Finally,
3
H
6
according to the TGA diagram, the last weight loss which observed between 600 to 800 °C is
related to the boehmite crystalline phase change. In addition, based on DTA curve (Fig. 8b),
the process of decomposition of inorganic and organic templates is an exothermic process. In
the DTA diagram, three exothermic peaks are seen and the first peak at 130 °C might be
attributed to the water evaporation and the second peak in 336 °C can be related to the removal
of the organosilane and organic groups from the catalyst surface and the last peak at 490 °C is
probably corresponding to the catalyst crystalline phase variation.
1
1

Fig. 8. a) TGA diagram of the catalyst and b) TGA-DTA diagram of the catalyst
.2. pH analysis of the catalyst
To measure the acidity of the catalyst surface, (0.1 g) of the prepared catalyst was added to
3
the aqueous solution of NaCl (1 M, 10 mL) with an initial pH of 7.62. The mixture was stirred
continuously for 30 min during which the pH of the mixture diminished to 1.84, denoting an
ion exchange between protons of NHSO
3
H groups and sodium ions, this represents 1.44 mmol
-1
g of acidic groups on the boehmite surface [55]. In this way, the acidity was measured for the
1
2

catalyst surface after the fifth run (pH = 1.95), and the surface acidity of the catalyst 1.12
-1
mmol/g was obtained. Also, the acidity of the surface was evaluated by titration with a NaOH
0.1 M), and the acidity was found to be 1.42 mmol per gram of catalyst, which is in good
agreement with the value obtained with the PHM apparatus.
(
3
.3. Catalytic studies
To optimize the reaction conditions, as a model, the condensation of benzaldehyde (1
mmol), ethyl acetoacetate (1 mmol) and urea (1.5 mmol) was examined in the presence of
different quantities of the catalyst under solvent-free conditions at different temperatures. The
respective results are summarized in Table 1. The reaction was tested in the presence of 0.02-
0
.08 g of BNPs@SiO
were achieved in the presence of 0.05 g (0.05 g, containing 0.07 mmol SO
Table 1, entry 4). Also, using a lower amount of the catalyst resulted in a lower yield, while a
2
(CH
2
)
3
NHSO
3
H. The best results regarding the reaction time and yield
3
H) of the catalyst
(
higher amount did not affect the reaction time and yield (Table 1, entries 3 and 5). To evaluate
the temperature influence, the model reaction was performed in 70, 80 and 100 °C. It was found
that 80 °C was the optimal reaction temperature and the reaction was incomplete at lower than
8
0 °C (Table 1, entry 7).
Table 1. Effect of the catalyst amount and temperature on the reaction between ethyl acetoacetate, urea,
and benzaldehydea
Entry
BNPs@SiO
2
(CH
2
)
3
NHSO
3
H (g)
Temp (°C)
Yield (%)b
1
2
3
4
5
6
7
-
80
80
80
80
80
Trace
60
30
97
98
0.02
0.03
0.05
0.08
0.08
0.05
100
70
98
80
a
Reaction conditions: Benzaldehyde (1 mmol), ethylacetoacetate (1 mmol) and urea
(
1.5 mmol), solvent-free.
Isolated yields.
b
To survey the solvent effect on the time and reaction yield, we studied varied solvents,
containing CH CN, H O, CH Cl , DMF and EtOH at 80 °C using 0.05 g (0.07 mmol SO H) of
3
2
2
2
3
the catalyst. The results of these examinations revealed that polar solvents led to a significant
decrease in the yield of the desired product compared to solvent-free conditions (Table 2,
entries 1–5).
1
3

Table 2. Effect of various solvents on the preparation of 3,4-dihydropyrimidinonesa
Entry
Solvent
Yield (%)a
1
2
3
4
5
6
H
2
O
30
65
50
60
70
97
EtOH
CH Cl
CH CN
2
2
3
DMF
-
a
Reaction conditions: Benzaldehyde (1 mmol), ethylacetoacetate (1
mmol) and urea (1.5 mmol), catalyst (05 g) (0.05 g, containing 0.07
mmol SO H), 30 min.
3
a
Isolated yields.
With optimized conditions in hand, synthesis of 3,4-dihydropyrimidinones with variety of
functionalized aromatic aldehydes was performed to explore the scope and the generality of
this protocol and the corresponding results are summarized in Table 3. Aromatic aldehydes
bearing either electron donating or electron-withdrawing substituents reacted efficiently and
gave excellent yields (Table 3, entries 3,5,12-13). Also. furane-2-carbaldehyde and thiophene-2-
carbaldehyde as Heterocycle aldehydes, produced corresponding compounds with remarkable
yields (Table 3, entries 6,7). It is noteworthy that, BNPs@SiO
2
(CH
2
)
3
NHSO H was an efficient
3
and reusable acidic heterogeneous catalyst for the preparation of the 3,4-dihydropyrimidinones.
It is noted that the reaction time is shorter in the presence of aldehydes with electron-poor
groups.
In addition, to evaluate the efficiency of this approach, comparison of this procedure with
previous methods was performed and the results are summarized in Table 4. As the Table
demonstrates, BNPs@SiO
2
(CH
2
)
3
NHSO H is superior to former methods and has indeed
3
improved the synthesis of 3,4-dihydropyrimidinones.
A plausible mechanism for the synthesis of 3,4-dihidropyrimidones using the
BNPs@SiO
2
(CH
2
)
3
NHSO
3
H catalyst is as follows: The BNPs@SiO
2
(CH
2
)
3
NHSO H as a
3
Bronsted acidic catalyst participates in the reaction by activating the aldehyde (1). This is
pursued by nucleophilic addition of urea or thiourea (2) forming the intermediate (4). Then,
this intermediate interacts with ketoester (5) to produce an open chain intermediate (6), which
is followed by cyclization and dehydration to produce 3,4-dihidropyrimidone (8) (Scheme 3).
1
4

Table 3. One pot synthesis of various 3,4-dihydropyrimidinonesa
Entry
Aryl aldehyde
-CHO
-CHO
-CHO
-CHO
-CHO
X
O
O
O
O
O
O
O
S
S
S
O
O
S
R
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Me
Me
Et
Et
Et
Time (min)
Yield (%)b
M.p [Ref]
1
2
3
4
5
6
7
8
9
C
6
H
5
30
27
25
40
45
55
60
70
40
45
25
20
35
30
55
97
96
95
94
96
95
95
98
95
96
97
96
95
96
97
201-203 [61]
211-213 [62]
207-209 [61]
170-171 [61]
200-202 [63]
204-206 [61]
207-208 [61]
150-152 [63]
202-204 [63]
202-204 [63]
210-212 [61]
190-192 [63]
193-195 [63]
192-193 [63]
150-152 [62]
4-ClC
4-NO
4-MeC
4-MeOC
6 4
H
2
6 4
C H
6
H
4
6
H
4
2-Furyl-CHO
2-Thienyl-CHO
4-MeOC
-CHO
-CHO
-CHO
-CHO
-CHO
-CHO
-CHO
6
H
4
-CHO
C
6
H
5
1
1
1
1
1
1
0
1
2
3
4
5
4-MeC
6
H
5
C
6
H
5
4-FC
4-NO
4-ClC
3-MeOC
6 4
H
2
6 4
C H
6
H
4
S
O
6
H
4
aReaction conditions: Aryl aldehyde (1 mmol), ethyl acetoacetate (1 mmol), urea (1.5 mmol), catalyst: 0.05 g
(
0.05 g, containing 0.07 mmol SO
3
H), solvent-free, 80 °C.
bIsolated products.
Table 4. Comparison of methods for the synthesis of 3,4-dihydropyrimidone compounds
Entry
1
Product
Conditions
Time/ min
360
Yield (%)Ref
85 [64]
Fe
3
O
4
@SBA-15/ Solvent-free/85 °C
2
3
4
5
6
PTA@MIL-101/Solvent-free/100 °C
Cu@PMO-IL/Solvent-free/70 °C
60
50
30
20
30
90 [65]
92 [66]
85 [27]
92 [67]
97
PTA@ZIF‐9(NH
GO-PO / Solvent-free/ 80 °C
BNPs@SiO (CH NHSO H/ Solvent-free/80 °C
2
)/Solvent-free/110 °C/
3
H
2
2
2
)
3
3
1
5

Scheme 3. Proposed mechanism for the synthesis of 3,4-dihydropyrimidones
For practical purposes, the ability to easily recycle the catalyst is highly valuable. The
recyclability of the BNPs@SiO
2
(CH
2
)
3
NHSO H has great importance for both the economic
3
and the synthetic aspects. To check this issue, the recyclability of the catalyst was tested for
the preparation of DHPMs. Therefore, the reusability of the catalyst was investigated by
isolation of the BNPs@SiO
2
(CH
2
)
3
NHSO H from the reaction mixture with simple filtration,
3
washing with ethanol and drying in a vacuum oven at 80 °C for 10 h and reuse it in subsequent
runes. The recovered catalyst can be reused at least five times with a small loss in catalyst
activity (Fig. 9).
1
6

Yield (%) Time (min)
97
97
95
93
90
100
80
60
40
20
0
40
40
35
30
30
Run 1
Run 2
Run 3
Run number
Run 4
run 5
Fig. 9. The reusability of the BNPs@SiO
2
(CH
2
)
3
NHSO H in the reaction of benzaldehyde, ethyl
3
acetoacetate, and urea
Since the prepared catalyst showed excellent catalytic activity for the Biginelli reaction, we
decided to employ it for the preparation of 1,4-dihydropyridines. For this regard, to achieve the
best reaction conditions, BNPs@SiO
2
(CH
2
)
3
NHSO H was added to a solution of aromatic
3
aldehyde, 1,3-dicarbonyl compounds and ammonium acetate in EtOH at 70 °C as a model
reaction (Table 5). First, the reaction was studied in the presence of different quantities of the
catalyst (0.02, 0.04, 0.06 and 0.08 g). The best results were obtained in the yield and reaction
time in the presence of 0.06 g (0.08 mmol SO
entry 7). Lower temperatures increased the reaction time and reduced yield of product (Table
, entries 5-6). Furthermore, increasing the amount of catalyst to 0.8 g did not lead to significant
3
H) of BNPs@SiO
2
(CH
2
)
3
NHSO H (Table 5,
3
5
increase in the yield of product (Table 5, entry 8).
Then, we focused on solvent influence and studied several solvents including CH
3
CN, H O,
2
DMF, CH
2
Cl and EtOH under optimum reaction conditions (Table 6). As can be seen, the
2
nature of solvent has a considerable effect on the reaction rate and the yield of product and
EtOH works better (Table 6, entry 5) and other solvents are less effective.
1
7

Table 5. Effect of increasing amount of BNPs@SiO
2
(CH
2
)
3
NHSO H and temperature on the
3
preparation of 1,4-dihydropyridinea
Entry
BNPs@SiO
2
(CH
2
)
3
NHSO
3
H (g)
Temp (°C)
Time (min)
Yield (%)b
1
2
3
4
5
6
7
8
-
-
25
70
70
70
25
50
70
70
60
60
60
40
60
45
30
30
-
Trace
50
75
60
80
97
98
0.02
0.04
0.06
0.06
0.06
0.08
aReaction conditions: Benzaldehyde (1 mmol), 1,3-dicarbonyl compounds (2 mmol), NH
OAc (1 mmol),
4
EtOH (7 mL).
Yields refer to pure isolated products.
b
Table 6. Effect of various solvents on the synthesis of 1,4-dihydropyridine derivativesa
Entry
Solvent
Yield (%)a
1
2
3
4
5
CH
H
CH Cl
2 2
DMF
EtOH
3
CN
O
85
50
55
85
97
2
a
4
Reaction conditions: Benzaldehyde (1 mmol), ethylacetoacetate (2 mmol) NH OAc (1
mmol), catalyst (06 g) (0.06 g, containing 0.08 mmol SO
Isolated yields.
3
H), solvent (7 mL).
a
In order to scrutiny the activity of BNPs@SiO
aromatic aldehydes were treated with different 1,3-dicarbonyl compounds and ammonium
acetate in the presence of BNPs@SiO (CH NHSO H and the desired 1,4-dihydropyridines
2
(CH
2
)
3
NHSO
3
H as a catalyst, a range of
2
2
)
3
3
were formed in excellent yields (90-97 %) (Table 7). The position and nature of the substituent
on the aromatic ring had a negligible effect on the yields of the final products. But in general,
aldehydes with electron-withdrawing groups have shorter reaction times (Table 7, entries 4,8
and 10). In addition, under optimized reaction conditions, heterocycle aldehydes reacted
perfectly and generated desired products with high yields (Table 7, entries 5-7 and 12-13).
Furthermore, cyclohexyl aldehyde (as an aliphatic aldehyde) works well in this procedure and
produces the desired product in excellent yield (Table 7, entry 14)
1
8

We investigated the performance of the introduced catalyst by some of the previously
selected protocols and the results are collected in Table 8. It should be noted that, according to
Table, the BNPs@SiO
2
(CH
2
)
3
NHSO H is a more efficient catalyst with respect to times and
3
yields than these reported catalysts.
Table 7. Direct synthesis of various 1,4-dihydropyridines with different 1,3-dicarbonyl compoundsa
Entry
Aldehyde
-CHO
4-MeOC -CHO
4-MeC -CHO
4-ClC -CHO
2-Furyl-CHO
2-Thienyl-CHO
3-Pyridyl-CHO
1,3-dicarbonyl compounds
Ethylacetoacetate
Time (min)
Yield (%)b
M.p [Ref]
1
2
3
4
5
6
7
8
9
C
6
H
5
30
45
30
25
30
25
35
20
35
25
35
40
30
50
97
93
95
92
91
95
92
97
97
90
95
92
95
90
159-161 [68]
159-160 [68]
131-133 [69]
146-148 [68]
160-162 [68]
154-156 [70]
191-192 [71]
163-165 [68]
203-204 [72]
176-178 [73]
263-265 [73]
246-248 [72]
239-241 [72]
222-224 [73]
6
H
4
Ethylacetoacetate
Ethylacetoacetate
Ethylacetoacetate
Ethylacetoacetate
Ethylacetoacetate
Ethylacetoacetate
Ethylacetoacetate
6
H
4
6
H
4
3-NO
2
C
6
H
4
-CHO
-CHO
-CHO
-CHO
C
6
H
5
Dimedone and Ethylacetoacetate
Dimedone and Ethylacetoacetate
Dimedone and Ethylacetoacetate
Dimedone and Ethylacetoacetate
Dimedone and Ethylacetoacetate
Dimedone and Ethylacetoacetate
1
1
1
1
1
0
1
2
3
4
3-NO
2
C
6
H
4
4-BrC
6
H
4
2-Furyl-CHO
2-Thienyl-CHO
C H11-CHO
6
a
4
Reaction conditions: Aldehyde (1 mmol), 1,3-dicarbonyl compound (2 mmol), NH OAc (1 mmol), EtOH (7 mL),
7
0 C.
b
Isolated yields.
Table 8. Comparison of different catalytic systems for the synthesis of 1,4-DHPs
Time
Entry
Product
Coditions
Yield (%)
(min)
1
2
3
PEG1000-DAIL/ Toluene/80 °C
40
300
390
91 [74]
72 [75]
73 [76]
PPh
3
/EtOH/Reflux
3 4
Fe O NPs/Solvent-free/r.t:
Fe
2
O
3
@HAP@Melamine/Solvent-
ftee/80 °C
4
15
94 [77]
5
6
7
ZnO NPs/Solvent free/80 °C
Nicotinic acid/ Solvent free/80 °C
BNPs@SiO (CH NHSO
120
5
30
82 [78]
95 [9]
97
2
2
)
3
3
H
The suggested mechanism for the synthesis of 1,4-DHPs is shown in Scheme 4. First,
BNPs@SiO (CH NHSO H, which is a Bronsted acidic catalyst, activates aldehyde. Then,
2
2
)
3
3
synthesis of 1,4-DHP proceeds through the formation of a Knoevenagel condensation product
as a key intermediate (3). A second key intermediate (4) is an ester enamine, which is formed
by condensation of the second equivalent of the 1,3-dicarbonyl compound with ammonia.
Further condensation between these two key fragments, gives the 1,4-DHP derivatives.
In another survey, reusability and durability of BNPs@SiO
2
(CH
2
)
3
NHSO H was checked.
3
For this regard, model reaction was studied in the presence of catalyst. After completion of the
1
9

reaction, the catalyst was isolated by filtration, washed by EtOH and dried to use for the
subsequent run. It is noteworthy that, catalytic activity of BNPs@SiO (CH NHSO H was
2
2
)
3
3
maintained within 5 successive recycle runs (Fig. 10). To confirm the catalyst recyclability, the
recovered catalyst by EDX and IR techniques was investigated. It should be noted that FT- IR
th
of recovered catalyst after 5 run is similar to the fresh catalyst and EDX pattern of the reused
catalyst represents the presence of the all elements in the structure of the catalyst, which affirms
the BNPs@SiO
2
(CH
2
)
3
NHSO H is recyclable (Fig. 11).
3
Scheme 4. A possible mechanism for the synthesis of 1,4-DHPs in the presence of
BNPs@SiO (CH NHSO
2
2
)
3
3
H
2
0

100
80
60
40
20
0
Run 1 Run 2 Run 3 Run 4 run 5
Yield (%)
97
97
95
95
92
Time (min)
30
30
30
30
30
Fig. 10. The reusability of the catalyst for the reaction of benzaldehyde, ethyl acetoacetate, and
ammonium acetate
Fig. 11. a) EDX pattern of fresh catalyst b) EDX pattern of recovered catalyst after 5th run c)
th
comparison of FT-IR fresh catalyst and FT-IR 5 run
In another study to confirm the non-leaching of acidic groups to the reaction medium, we
performed a hot filtration test. For this purpose, the model reaction for Biginelli synthesis was
performed in the presence of the catalyst and after half a reaction time (15 min) (70% yield),
the catalyst was removed by simple filtration and residue transferred to another quartz tube and
the reaction was stirred in the absence of the catalyst. After several hours, the reaction yield
did not change significantly (72% yield as screened by TLC). This test is a good reason for the
stability of the catalyst and the leaching of acid groups from the catalyst surface is not seen.
2
1

4
. Conclusion
In conclusion, this research displays one-pot multicomponent syntheses of 3,4-
dihydropyrimidones and 1,4-dihydropyridines catalyzed by efficient and recyclable
BNPs@SiO
2
(CH
2
)
3
NHSO H in mild reaction condition. Catalytic results showed that
3
boehmite can be a stable, active and effective solid-phase support for the heterogenization of
homogeneous catalysts. This solid catalyst demonstrates high acidic strength which leads to
greater catalyst efficiency. It is noteworthy that, several unique advantages for the synthesis of
DHPM and DHP derivatives are short times, excellent yields, use of mild conditions, easy
catalyst separation, simple workup and catalyst recovery up to at least five times with small
drop in activity. According to the results, BNPs@SiO
2
(CH
2
)
3
NHSO H is superior to many of
3
the reported catalysts in the scientific literature for the preparation of 3,4-DHPMs and 1,4-
DHPs.
Acknowledgments
We appreciate Razi University Research Council for partial support to this work.
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