Zn2+/MCM-41 catalyzed Biginelli reaction of heteroaryl aldehydes and evaluation of the antimicrobial activity and cytotoxicity of the pyrimidone products

Article abstract of DOI:10.1016/j.tetlet.2015.09.143

The three component Biginelli condensation of various aryl aldehydes, 1,3-dicarbonyls and urea was investigated in the presence of free or MCM-41 supported ZnNO₃. The pyrimidone products, which were obtained under solvent-free conditions, were

Full text of DOI:10.1016/j.tetlet.2015.09.143

Accepted Manuscript
2
Zn /MCM-41 catalyzed Biginelli reaction of heteroaryl aldehydes and evalu-
+
ation of the antimicrobial activity and cytotoxicity of the pyrimidone products
Zarrin Ghasemi, Farzaneh Farshbaf Orafa, Mahtab Pirouzmand, Gholamreza
Zarrini, Behnaz Nikzad Kojanag, Roya Salehi
PII:
S0040-4039(15)30184-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.09.143
TETL 46815
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
22 March 2015
25 August 2015
28 September 2015
2
+
Please cite this article as: Ghasemi, Z., Orafa, F.F., Pirouzmand, M., Zarrini, G., Kojanag, B.N., Salehi, R., Zn /
MCM-41 catalyzed Biginelli reaction of heteroaryl aldehydes and evaluation of the antimicrobial activity and
cytotoxicity of the pyrimidone products, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.
2
015.09.143
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
2
+
Zn /MCM-41 catalyzed Biginelli reaction
of heteroaryl aldehydes and evaluation of the
antimicrobial activity and cytotoxicity of the
pyrimidone products
Leave this area blank for abstract info.
a
a
b
c
b
Zarrin Ghasemi *, Farzaneh Farshbaf Orafa , Mahtab Pirouzmand , Gholamreza Zarrini , Behnaz Nikzad Kojanag and
Roya Salehi
d

1
Tetrahedron Letters
journal h omepage: www.els evier. com
2+
Zn /MCM-41 catalyzed Biginelli reaction of heteroaryl aldehydes and evaluation of
the antimicrobial activity and cytotoxicity of the pyrimidone products
a
a
b
c
Zarrin Ghasemi *, Farzaneh Farshbaf Orafa , Mahtab Pirouzmand , Gholamreza Zarrini , Behnaz Nikzad
b
d
Kojanag and Roya Salehi
a
Department of Organic and Biochemistry, Faculty of Chemistry, University of Tabriz, Tabriz 5166614766, Iran
Department of Inorganic Chemistry, Faculty of Chemistry, University of Tabriz, Tabriz 5166614766, Iran
Department of Biology, Faculty of Natural Science, University of Tabriz, Tabriz 5166614766, Iran
b
C
d
Reseach Center for Pharmaceutical Nanotechnology and School of Advanced Medical Science, Tabriz University of Medical Sciences, Tabriz, Iran
ARTICLE INFO
ABSTRACT
Article history:
Received
The three component Biginelli condensation of various aryl aldehydes, 1,3-dicarbonyls and urea
was investigated in the presence of free or MCM-41 supported ZnNO . The pyrimidone
3
Received in revised form
Accepted
products, which were obtained under solvent-free conditions, were evaluated for antibacterial
and antifungal activities as well as their cytotoxicities.
Available online
2
009 Elsevier Ltd. All rights reserved.
Keywords:
Biginelli reaction
Solvent-free conditions
MCM-41
3
,4-Dihydropyrimidones
1
. Introduction
4-pyrone (prepared from kojic acid), which represents the first
report of this reaction incorporating the 4-pyrone skeleton.
Finally, the evaluation of antibacterial and antifungal activities as
well as the cytotoxicity data of selected pyrimidone derivatives is
presented.
The three component condensation of an aromatic aldehyde,
urea, and a 1,3-dicarbonyl compound, known as the Biginelli
reaction, offers an efficient methodology for the synthesis of 3,4-
dihydropyrimidine-2-ones.
1
Interesting
synthetic
and
pharmacological properties and the commercial availability or
easy preparation of the individual building blocks have resulted2
in the remarkable popularity of this acid catalyzed reaction.
Development of various synthetic modifications such as the
utilization of heterogeneous reusable catalysts and solvent free
conditions have considerable advantages for overcoming some of
the drawbacks of the classical Biginelli reaction, such as harsh
conditions, long reaction times and low to moderate yields with
2. Results and discussion
We began by examining the Biginelli condensation between
benzaldehyde, urea and ethyl acetoacetate in the presence of
2
+
various Zn species under solvent free conditions (Table 1). The
well known ZnCl catalyzed condensation gave product 1 in 90%
yield (Entry 1), while substitution for the same amount of
Zn(NO .6H O, gave the product in higher yield and shorter
time (Entry 2). To study the catalytic systems containing MCM-
1, we first examined the activity of the mesoporous material in
2
)
3 2
2
3
certain substrates. The incorporation of metal species onto
4
heterogeneous surfaces such as mesostructure materials can
improve the facile diffusion of bulky reactants and efficient
this reaction (Entries 3-5). Because the synthesis of MCM-like
materials is typically based on the self assembly of ionic or non-
ionic surfactant micelles on the silica skeleton, the organic
4
interaction in their nano-size pores. Therefore, these systems can
promote the reaction without the use of solvent and minimise
waste production. MCM-41 (Mobil Composition of Matter) is a
mesoporous material with a high surface area which has been
modified by various metallic ions, and widely utilized as a
7
template can be removed by calcination or extraction techniques.
Testing of both catalyst types (calcinated and with template),
resulted in low yields of product due to the low acidity of the
heterogeneous solid (Entries 3-5). In order to improve the activity
of the silica materials, we attempted to disperse zinc cations onto
the porous support using two methods: direct synthesis (DS) and
wet
5
suitable support in many metal catalyzed reactions. Among the
potential Lewis acids which promote multicomponent reactions,
2+
Zn based systems are interesting due to being efficient,
6
inexpensive and environmentally benign. In this work, we report
2+
the use of Zn incorporated MCM-41 for the Biginelli reaction
2+
and a comparison with other Zn species. We also report the
ZnNO promoted Biginelli reaction with 3-benzyloxy-2-formyl-
3

2
Tetrahedron Letters
2
+
Table 1. Zn Catalyzed Biginelli reaction at solvent free conditions
Entry
Catalyst
Amount of cat.
Time
Yield (%)
1
2
3
4
5
6
7
8
9
ZnCl
2
10% mol
10% mol
0.01 gr
0.02 gr
0.02 gr
0.02 gr
0.02 gr
0.02 gr
0.02 gr
0.02 gr
0.02 gr
20 min
15 min
2 h
90
91
40
47
36
92
77
78
49
43
84
Zn(NO .6H O
3
)
2
2
MCM-41 (Calcinated)
MCM-41 (Calcinated)
MCM-41 (with template)
2h
5 h
Zn(NO
Zn(NO
Zn(NO
ZnCl
ZnCl
.6H O /MCM-41/Calcinated/(WI) (Recycled)
3
)
2
.6H
2
O /MCM-41/Calcinated/(WI)
20 min
5 h
3
)
2
.6H
2
O /MCM-41/Extracted/(WI)
O /MCM-41/Calcinated/(DS)
/MCM-41/Calcinated/(WI)
3
)
2
.6H
2
1 h
2
3 h
1
1
0
1
2
/MCM-41/Extracted/(WI)
3 h
Zn(NO
3
)
2
2
25 min
o
Conditions: benzaldehyde (3 mmol), ethyl acetoacetate (3 mmol), urea (4.5 mmol), 80 C.
impregnation (WI) techniques. The catalyst formed by
introduction of the metal into the calcinated silica materials (after
complete removal of the organic template) by the wet
of a supported ZnNO
even at higher temperatures and longer times. However, the use
of free ZnNO gave the corresponding Biginelli products in
acceptable yields (Table 4). Interestingly, the use of ZnCl under
3
species, resulted in only trace conversion,
3
8
impregnation method, gave the highest yield and its efficacy was
2
comparable to free ZnNO
3
(Entry 6). Replacing the thermal
solvent free conditions, produced a complex mixture of products
calcination step with extraction, gave a catalytic system with
relatively poor activity (Entry 7). Furthermore, the direct
synthesis method consisting of addition of the metal catalyst into
the reaction mixture at the beginning of preparation process, also
produced a lower yield (Entry 8). Despite the proven high
which could not be isolated.
9
Table 2. Basicity and percent of metal loading on MCM-41.
catalytic activity of ZnCl
channels of MCM-41, led to a decrease in effectiveness (Entries
,10). Therefore, we focused on an optimized system based on
supported ZnNO (Entry 6) which showed acceptable activity
2
, impregnation onto the hexagonal
Basicity
mmol/g)
Metal loading
(%)
Entry
Catalyst
(
9
3
Zn(NO
3 2
) /MCM-
1
2
3
4
5.16
1.13
2.74
0.97
10.50
11.29
12.54
14.61
even when recycled (Entry 11).
4
1/Template/(DS)
This catalyst was found to have the highest metal loading
Zn(NO
3 2
) /MCM-
(
14.61%) relative to other species as determined by Energy
dispersive X-ray (EDX) (Table 2). Estimation of the acidity of
the active catalytic sites at loaded species of Zn(NO was
4
1/Calcinated/(DS)
)
3 2
Zn(NO
3 2
) /MCM-
10
performed using the Hammett indicator method which showed
the highest acidity for our selected system (Table 2, Entry 4). For
determination of the basic strength of the catalyst the following
41/Extracted/(WI)
Zn(NO
3 2
) /MCM-
4
1/Calcinated/(WI)
Hammett indicators were used: bromothymol blue (H
−
=7.2),
phenolphthalein (H =9.3) and alizarine yellow (H =11.0). H
−
−
−
-
function defined by Eq. (1), where [BH] and [B ] are the
concentration of the indicator and its conjugate base respectively,
and pKBH is the logarithm of the dissociation constant of the
indicator used:
The antimicrobial activity of twelve compounds were
investigated by the disk diffusion method and the antibacterial
and antifungal activities are presented in Table 5. These revealed
that the compounds possessed weak to moderate antimicrobial
activity, with compound 2d possessing a furan ring and
methoxycarbonyl group showing higher antimicrobial activity in
both the bacterial and fungal test strains. Moreover, this
compound exhibited higher activity against Staphylococcus
aureus and Candida kefyr than Escherichia coli.
-
H_= pKBH + log[B ]/[BH] Eq. (1)
A 0.1 N solution of benzoic acid in anhydrous methanol was used
11
for titration of each catalyst sample, see ESI for details.
We next examined this catalytic system with thiophene, furan
and 2-naphthyl carbaldehydes to obtain the products 2a-p (Table
3
). Additionally we utilized 5-benzyloxy-2-formyl-4-pyrone 3
12
(prepared from commercially available kojic acid ) as an
aldehyde partner in the Biginelli condensation reaction (Table 4).
Treatment with urea and various 1,3-dicarbonyls in the presence

3
3
Table 3. Catalytic Biginelli reactions in the presence of ZnNO /MCM-41.
Product
Yield
Product
Yield
Product
Yield
Product
Yield
2
a
2b
2c
2d
9
3%
85%
77%
78%
2
e
2f
2g
2h
8
7
9
0%
76%
88%
87%
2
i
2j
2k
2l
6%
79%
82%
69%
2
m
2n
2o
2p
1%
84%
81%
86%
o
Conditions: aldehyde (3 mmol), urea (4.5 mmol), 1,3-dicarbonyl (3 mmol), cat (0.06 g), 80 C, 3-6 h.
Table 4. Yields of Biginelli products obtained from aldehyde 3.
Table 5. Antimicrobial activity of selected compounds.
Zone of inhibition (mm)
Compound
Escherichia
coli
Staphylococcus
aureus
Candida
kefyr
2
2
a
7.6
12
6.4
7
8
14.4
7
6.4
d
14
7
2
e
Entry
R
Product 4 (Yield %)
4a (57)
2
f
6.4
7.2
7
6.8
7
1
OCH
3
2
2
g
6.8
7
2
3
4
5
OCH
2
CH
3
4b (67)
h
7
OC(CH
3
)
3
4c (50)
2
2
i
7
7.4
7
6.4
7
CH
Ph
3
4d (66)
j
7
4e (80)
2
k
7.3
7.1
9
6.4
6.8
7
Conditions: aldehyde 3 (1.3 mmol), urea (1.9 mmol), 1,3-
dicarbonyl (1.3 mmol), Zn(NO .6H O (0.036 g, 10% mol),
0 C, 24 h.
3
)
2
2
2
l
6.4
o
8
2
m
9
7
9
7
4
e
8.4

4
Tetrahedron Letters
The cytotoxicity studies and inhibitory effects of the selected
3. Conclusion
compounds were also studied using MDA-MB-231 and MCF7
cell lines and the cytotoxicity was evaluated using the MTT
assay, an approach which is generally applied to measure
mitochondrial activity to quantify cell growth or cell death. To
assess the in vitro cytotoxicity of selected Biginelli products, cell
viabilities of human breast cancer cell lines (MDA-MB-231)
In summary we have reported the solvent free Biginelli
reaction in the presence of free or MCM-41 incorporated ZnNO .
3
The easy workup and high yields of products as well as the
reusability of the solid catalyst were the advantages of our
method. These reactions were examined with furan, thiophene
and naphthyl carbaldehydes which were catalyzed in the presence
under 48
h incubation with different concentrations of
of ZnNO
benzyloxy-2-formyl-4-pyrone (prepared from kojic acid) was
optimized in the presence of free ZnNO . Antimicrobial studies
3
impregnated on calcinated MCM-41. Reaction of 3-
compounds (4000, 2000, 1000, 500, 250, 50 and 25 μg/mL) were
studied using the MTT assay. As seen in Figure 1, compounds
3
2p, 2l and 2b showed inhibitory activities against MDA-MB-231.
of the products showed relatively good activity for the derivative
obtained from furfural and methyl acetoacetate. The cytotoxicity
studies and inhibitory effects of selected products using MDA-
MB-231 and MCF7 cell lines, showed inhibitory activities for
compounds 2b, 2l and 2p, and nontoxic effects of other
derivatives.
However, the degree of inhibition of 2l was stronger (IC50=2000
μg/mL) than 2p and 2b (IC50=4000 μg/mL). The cell viabilities
for other compounds, revealed the nontoxic effects on MDA-
MB-231 breast cancer cell lines. Similar results were obtained for
MCF7 cell lines.
Acknowledgments
The authors thank Research Affairs of University of Tabriz
and also Tabriz University of Medical Sciences for financial
supports.
References
1
.
(a) Qu, H.; Li, X.; Mo, F.; Lin, X. Beilstein J. Org. Chem. 2013, 9,
2
2
7
846–2851; (b) Wan, J. P.; Pan, Y. J. Chem. Commun. 2009, 45,
768–2770; (c) Shen, Z. L.; Xu, X. P.; Ji, S. J. J. Org. Chem. 2010,
5, 1162–1167; (d) Chitra, S.; Devanathan, D.; Pandiarajan, K. Eur.
J. Med. Chem. 2010, 45, 367–371. (e) Liu, Q.; Xu, J.; Teng, F.;
Chen, A.; Pan, N.; Zhang, W. J. Heterocycl. Chem. 2014, 51, 741–
7
46.
2
.
(a) Lal, J.; Gupta, S. K.; Thavaselvam, D.; Agarwal, D. D. Bioorg.
Med. Chem. Lett. 2012, 22, 2872–2876; (b) Lusch, M. J.; Tallarico,
J. A. Org. Lett. 2004, 6, 3237-3240; (c) Hegedüs, A.; Hell, Z.; Vígh,
I. Synth. Commun. 2006, 36, 129–136; (d) Shen, Z. L.; Xu, X. P.; Ji,
S. J. J. Org. Chem. 2010, 75, 1162–1167; (e) Srivastava, V. P.;
Yadav, L. D. S. Tetrahedron Lett. 2010, 51, 6436–6438. (f) Azizian,
J.; Mohammadi, M. K.; Firuzi, O.; Mirza, B.; Miri, R. Chem. Biol.
Drug Des. 2010; 75, 375–380. (g) Chitra, S.; Devanathan, D.;
Pandiarajan, K. Eur. J. Med. Chem. 2010, 45, 367–371.
3
4
5
.
.
.
(a) Panda, S. S.; Khanna, P.; Khanna, L. Current Org. Chem. 2012,
1
6, 507-520; (b) Karade, H. N.; Sathe, M.; Kaushik, M. P.
Molecules 2007, 12, 1341-1351; (c) Lee, K. Y.; Ko, K. Y. Bull.
Korean Chem. Soc. 2004, 25, 1929-1931. (d) Atar, A. B.; Jeong, Y.
T. Mol. Divers. 2014, 18, 389-401.
(a) Shobha, D.; Chari, M. A.; Mano, A.; Selvan, S. T.; Mukkanti, K.;
Vinu, A. Tetrahedron 2009, 65, 10608–10611. (b) Cai, M.; Xu, Q.;
Sha, J. J. Mol. Catal, A-Chem. 2007, 272, 293–297; (c) Oskooie, H.
A.; Heravi, M. M.; Karimi, N.; Monjezy, M. H. Synth. Commun.
2
011, 41, 826–831.
(a) Tamaddon, F.; Moradi, S. J. Mol. Catal. A-Chem. 2013, 370,
1
17. (b) Iwanami, K.; Sakakura, T.; Yasuda, H. Catal. Commun.
009, 10, 1990–1994. (c) Thitsartarn, W.; Gulari, E.; Wongkasemjit,
2
S. Appl. Organometal. Chem. 2008, 22, 97–103; (d) Parida, K. M.;
Rath, D.; Dash, S. S. J. Mol. Catal. A-Chem. 2010, 318, 85–93; (e)
Iwanami, K.; Seo, H.; Choi, J. C.; Sakakura, T.; Yasuda, H.
Tetrahedron 2010, 66, 1898–1901.
Figure1. Cytotoxicity data of selected compounds against the
MDA-MB-231 cell line.
6.
(a) Tamaddon, F.; Moradi, S. J. Mol. Catal. A- Chem. 2013, 370,
117-122. (b) Sun, Q.; Wang, Y. Q.; Ge, Z. M.; Cheng, T. M.; Li, R.
T. Synthesis 2004, 7, 1047–1051; (c) Wang, C. F.; Jiang, H.; Gong,
H.; Wang, M.; Wang, Z. C. Chin. J. Org. Chem. 2006, 26, 333-336.
Derylo-Marczewska, A.; Gac, W.; Popivnyak, N.; Zukocinski, G.;
Pasieczna, S. Catal. Today 2006, 114, 293–306.
7
.
8
9
.
.
Parida, K. M.; Dash, S. S. J. Mol. Catal. A-Chem 2009, 306, 54-61.
(a) Selvaraj, M.; Pandurangan, A.; Seshadri, K. S.; Sinha, P. K.; Lal,
K. B. Appl. Catal. A-Gen. 2003, 242, 347–364; (b) Savidha, R.;

5
Pandurangan, A.; Palanichamy, M.; Murugesan, V. J. Mol. Catal. A-
Chem. 2004, 211, 165–177.
1
0. Carvalho, L.; Abreu, W.; Silva, M.; Lima, J.; Oliveira, J.; Matos, J.;
Moura, C.; E. Moura, E. J. Braz. Chem. Soc. 2013, 24, 550-557.
1. Tanabe, K.; Yamaguchi, T. J. Res. Inst. Catal. 1964, 11, 179-184.
2. (a) Ghasemi, Z.; Kalantar Esfangare, H. Heterocycl. Commun. 2015,
1
1
2
1, 37–41; (b) Shahrisa, A.; Ghasemi, Z. Chem. Heterocycl. Compd.
010, 46, 30-36.
2
Supplementary Material
1
13
Spectra and characterization data (IR, H, and C NMR) of
compounds (2a-p) and also (4a-e), the preparation and analytical
data of the catalysts, as well as the procedures for biological
studies are available via the Internet at www.sciencedirect.com.