A cheap and efficient methodology for the solvent-free, one-pot and multi-component synthesis of 3,4-dihydropyrimidin-2(1h)-ones catalyzed by Mesoporous nh4h2po4/mcm-48 and comparison of its catalytic efficacy with nh4h2po4/mcm-41

Article abstract of DOI:10.1002/jccs.201200503

The catalytic efficiency of ammonium dihydrogenphosphate was evaluated in the two heterogeneous forms of NH4H2PO4/MCM-48 and NH4H2PO4/MCM-41, as mesoporous catalysts, in the solvent free synthesis of 3,4-dihydropyrimidin- 2(1H)-ones through one-pot three-

Full text of DOI:10.1002/jccs.201200503

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Article
A Cheap and Efficient Methodology for the Solvent-Free, One-pot and
Multi-component Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones Catalyzed by
Mesoporous NH H PO /MCM-48 and Comparison of Its Catalytic Efficacy with
4
NH H PO /MCM-41
2
4
4
2
4
Reza Tayebee,* Nasrin Abdollahi and Malihe Ghadamgahi
Department of Chemistry, School of Sciences, Hakim Sabzevari University, Sabzevar 96179-76487, Iran
(Received: Sept. 20, 2012; Accepted: Jan. 28, 2013; Published Online: ??; DOI: 10.1002/jccs.201200503)
The catalytic efficiency of ammonium dihydrogenphosphate was evaluated in the two heterogeneous
4 2 4 4 2 4
forms of NH H PO /MCM-48 and NH H PO /MCM-41, as mesoporous catalysts, in the solvent free syn-
thesis of 3,4-dihydropyrimidin-2(1H)-ones through one-pot three-component condensation of ethyl
acetoacetate, an aryl aldehyde and urea. Different reaction parameters including catalytic efficacy, solvent
effect, and urea concentration are considered.
4 2 4
Keywords: 3,4-Dihydropyrimidin-2(1H)-ones; NH H PO ; MCM-48; MCM-41.
INTRODUCTION
Dihydropyrimidinones are important biologically ac-
Scheme I Three component condensation of urea, al-
dehyde and ethylacetoacetate
tive synthons which have numerous applications in mam-
1
malian cells, and have been considered as a lead for the de-
CHO
R
2
velopment of new anticancer drugs. They also exhibit var-
O
R
O
NH4H2PO4/MCM-48
Solvent free 100 °C
+
EtO
ious types of pharmacological properties such as antibacte-
EtO
NH
H2N
H2N
3
rial and antifungal, antiviral, antioxidative, a-adrenergic
4
5
O
O
Me
Me
N
H
O
6
and neuropeptide Y antagonists, as well as anti-inflamma-
7
tory. Additionally, it has been proved that several structur-
ucts were characterized by comparison of their spectral and phys-
1
1
ally related marine natural products, such as batzelladine,
are effective in the inhibition of binding of HIV gp-120 to
CD4 cells, so offering new insights towards the develop-
ical data with those reported in the literature. Progress of the re-
actions was monitored by TLC. Infrared spectra were recorded
(KBr pellets) on 8400 Shimadzu Fourier Transform spectro-
8
1
13
ment of AIDS therapy. Therefore, development of new
photometer. H and C NMR spectra were recorded on a Bruker
AVANCE instrument using TMS as an internal reference. Melting
points were determined in open capillary tubes in a Stuart BI
Branstead Electrothermal Cat No: IA9200 apparatus and uncor-
and efficient protocols for the preparation of these com-
pounds are of prime importance and still remains a chal-
lenge for organic chemists.
1
rected. Data for H NMR are reported as chemical shift (d) and
Recently, we used NH
4
H
2
PO
4
as a non-toxic, inex-
pensive, and easily available catalyst in synthesis of 3,4-di-
9
hydropyrimidin-2(1H)-one. Moreover, heterogenization
multiplicity (s: singlet, d: doublet, t: triplet, q: quartet, m:
multiplet, qt: quintuple, dq: doublet of quartets, br: broad). Syn-
thesis of MCM-48. n-Hexadecyltrimethylammonium bromide
(C H (CH ) NBr, template) was dissolved in deionized water,
of NH
4
1
H
0
2
PO
4
on the mesoporous MCM-41 is also investi-
gated. From our research on the development of useful
1
6
33
3 3
synthetic methodologies and interest in NH
4
H
2
PO
4
cata-
and sodium hydroxide and tetraethoxysilane (TEOS) were added.
lyzed reactions, we have found a one-pot three component
procedure for the preparation of 3,4-dihydropyrimidin-
The molar composition of the gel was 1 M TEOS/0.25 M Na O/
2
0.65 M C H (CH ) NBr/62 M H O. The solution was stirred for
2
1
6
33
3 3
2
(1H)-one derivatives under solvent-free condition with
about 1 h, charged into a polypropylene bottle and then heated at
383 K for 3 days. The product was filtered, washed with water and
the use of NH H PO grafted on MCM-48 (Scheme I).
4
2
4
1
calcined at 823 K for 6 h. MCM-41 was prepared according to
2
1
0
EXPERIMENTAL
4 2 4
the procedure described before. Preparation of NH H PO /
General remarks. The chemicals, solvents and starting
MCM-48. In order to prepare the heterogeneous catalyst, MCM-
materials were obtained from Aldrich, Merck or Fluka. All prod-
48 (1.5 g) was mixed with a solution of NH H PO (0.6 g) in dis-
4
2
4
*
Corresponding author. Tel: +98-571-4410310; Fax: +98-571-4410300; Email: Rtayebee@yahoo.com
J. Chin. Chem. Soc. 2013, 60, 000-000
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1

Article
Tayebee et al.
tilled water (10 mL). The resulting mixture was stirred for 12 h to
via a self-assembled liquid crystal mechanism involving
absorb NH
4
H
2
PO
4
on the surface of MCM-48. The mixture was
sol-gel precursors which form a hexagonally packed rod-
1
5
dried at 120 °C for 12 h to remove the water. The drying tempera-
shaped micelle structure. The cubic MCM-48 is another
member of the M41S family. Silica is widely carried out as
the main building block of mesoporous materials since it is
ture was maintained below the decomposition temperature of the
1
ammonium salt. Infrared spectra of MCM-48 and the supported
3
1
6
catalyst was compared. Appearance of absorption related to P=O
inexpensive, chemically inert, thermally stable, harmless
-
1
stretching vibrations of OPO
the supported catalysts spectra proved that NH
successfully supported. NH PO /MCM-41 was prepared simi-
larly. (Infrared spectra of MCM-48 and NH PO /MCM-48
are shown in Fig. 1). General procedure for the preparation of
,4-dihdropyrimidin-2(1H)-ones. A mixture of ethyl aceto-
3
H
2
groups in the region 1400 cm in
and abundantly available in the Earth’s crust. These meso-
porous materials are highly ordered with large specific sur-
face area and uniform mesoporous channel. Especially for
MCM-41 and MCM-48, the pore size could be controlled
4
H
2
PO has been
4
4
H
2
4
1
0
4
H
2
4
1
7
and widely used as adsorbent, catalyst, and support.
3
The main objective of this report is focused on the
acetate (2 mmol), aldehyde (2 mmol) and urea (2.5 mmol) was
comparison of MCM-48 with MCM-41 as supporting ma-
heated to 100 °C under solvent-free condition in the presence of
4 2 4
terials for NH H PO and studying their catalytic efficacy
NH
4
H
2
PO
4
/MCM-48 (0.04 g). Progress of the reaction was moni-
for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones.
Studying efficacy of MCM-41 versus MCM-48 as the
supporting materials
tored by TLC. At the end of the reaction, the resulting mixture
was filtered and the heterogeneous catalyst was separated. Then,
the filtrate was poured into cold water and the solid product was
separated by filtration. The impure product, if necessary, was
re-crystallized from n-hexane/ethyl acetate (3:1).
Efficiency of the synthesis of 3,4-dihdropyrimidin-
2(1H)-ones was mainly affected by the amount of catalyst.
Our previous findings revealed that the target reaction is
obviously dependent to the presence of catalyst and simple
heating of a neat mixture of aldehyde, acetoacetate and
RESULTS AND DISCUSSION
Comparison of the structural features of MCM-48
with MCM-41
urea at 100 °C under solvent free condition obtained a
9
highly impure product after 9 h. 0.02 g of NH
4
H
2
PO
4
/
Several drawbacks such as difficulties in separation
of products, reusing and recycling of catalyst, production
of acidic wastes, and low product selectivity limited the
practical applications of homogeneous catalytic systems.
Therefore, immobilization of homogeneous catalysts on
solid supports would be an effective solution to the above
problems.
MCM-48 catalyst (containing 2.5 mol% of NH
4
H
2
PO
4
)
provided 28% of product after 4.4 h; While 74% yield was
afforded in the presence of 0.04 g NH PO /MCM-48 af-
ter 4.4 h. It should be mentioned that NH PO /MCM-41
4
H
2
4
4
H
2
4
has been shown the best catalytic activity and 85% of con-
version was obtained after 2.5 h under the same reaction
1
conditions. Enhancing amount of the heterogeneous cata-
0
The investigation for new molecular sieves in the late
lyst directly affected conversion. 0.08 g of catalyst sup-
1
980s led Mobil researchers to the finding of a family of
ported on MCM-48 (involving 10 mol % NH
duced 87% yield after 4.4 h; Whereas, the same amount of
NH PO /MCM-41 led to 88% yield after 2.4 h. Thus,
4 2 4
H PO ) pro-
nano-structured mesoporous materials known as M41S
1
Fig. 2). MCM-41 is undoubtedly the best known and
4
(
4
H
2
4
most widely studied of this family of materials, synthesized
MCM-41 acted better than MCM-48 as supporting material
considering time and conversion% (Fig. 3).
Fig. 1. Infrared spectra of (a) MCM-48 and (b)
NH PO /MCM-48.
Fig. 2. The M41S family of materials including MCM-
9
41 and MCM-48.
4
H
2
4
2
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JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
4 2 4
Synthesis of Dihydropyrimidinones with NH H PO
9
,10,11
As we reported before,
one of the most impor-
Table 1. Comparison of NH H PO /MCM-48 and NH H PO /
4
4
2
4
4
2
tant points in synthesis of 3,4-dihdropyrimidin-2(1H)-ones
is that aldehydes with electron donating and electron with-
drawing groups took part in the Biginelli reaction uni-
MCM-41 on the solvent-free condensation of ethyl
acetoacetate, urea and different aldehydes
O
Ar
O
C
O
C
O
O
NH4H2PO4/Support
EtO
NH
formly. Some sensitive functional groups such as -NO
2
,
+
+
Me
OEt
Ar
H
H N
2
N
H
O
NH2
Me
-
Cl, -Br attached to the ring were compatible with this re-
action protocol. The aliphatic aldehydes participated in the
reaction very smoothly. Table 1 compares efficiency of the
[a]
-1
Time (h)
MCM-41
Yield (%)
MCM-41
/MCM-48
TOF (h )
MCM-41
/MCM-48
ArCHO
Product
/
MCM-48
two heterogeneous catalysts (NH
4 2 4
H PO /MCM-48 versus
NH H PO /MCM-41) on the preparation of some 3,4-di-
2
4
4
CHO
O
hydropyrimidin-2(1H)-ones using different aromatic alde-
6/6
72/45
C H O
NH
2.4/1.5
2
5
Me
N
H
O
hydes bearing electron withdrawing and electron releasing
NO
2
C H O
4 2 4
substituents on the phenyl ring. NH H PO /MCM-48 made
O
2
.5/4.4
85/74
58/25
6.8/3.3
2.3/1.0
lower yields than MCM-41 and need more time to complete
the reaction.
C
2
H
5
O
NH
N O
2
M e
N
O
H
Cl
CHO
To study role of solvents on the synthesis of 3,4-di-
O
5
/5
C
2
H
5
O
NH
hydropyrimidin-2(1H)-ones in the presence of NH
4
H
2
PO
4
Cl
Me
N
H
O
Cl
supported on MCM-48 and MCM-41 (0.04 g), the control
reaction was performed with different solvents at 60 °C. As
presented in Table 2, chloroform and acetonitrile behaved
as the most preferred solvents (entry 3 and 4). However, the
catalytic system resulted in the best yield in the absence of
solvent (entry 5).
CHO
O
3
.7/3.7
72/74
47/53
3.9/4.0
1.9/2.1
C
2
H
5
O
NH
Cl
Me
N
H
O
CHO
O
Me
NH
CH
3
5
/5
2 5
C H O
Me
N
H
O
4 2 4
NH H PO was immobilized on different supporting
Reaction condition: 4-nitrobenzaldehyde (2 mmol), ethyl
materials to compare their catalytic efficacy. Findings re-
vealed that MCM-41 is the most favored bed considering
reaction time and yield% (Fig. 4). MCM-41 led to 85%
conversion after 2.5 h. Whereas, commercial silica-gel
acetoacetate (2 mmol), urea (2.5 mmol) and 0.04 g catalyst. 0.04
g of NH
a]: Turn over frequency is defined as moles of substrate
converted per mole of catalyst per hour.
H PO /MCM's involves 5 mol% NH H PO (0.1 mmol).
4
2 4 4 2 4
[
(
mesh 70-230) produced 76% (after 5.6 h). SBA-15 and
ZrO showed moderate efficiency and produced 77-80%
2
conversion after 3.3-3.5 h. The effect of supporting mate-
rial structure on the catalytic reactivity of this catalyst was
approved by these experiments.
Fig. 4. Condensation of 4-nitrobenzaldehyde, ethyl
acetoacetate and urea in the presence of
Fig. 3. Effect of (a) NH
NH PO /MCM-48 amount on the Biginelli
reaction under solvent free condition.
4 2 4
H PO /MCM-41 and (b)
4
H
2
4
NH
als.
4 2 4
H PO supported on different solid materi-
J. Chin. Chem. Soc. 2013, 60, 000-000
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3

Article
Tayebee et al.
Table 2. Effect of solvent on the synthesis of Ethyl-6-methyl-4-
Scheme II The proposed reaction mechanisms for the
synthesis of 3,4-dihydropyrimidin-2(1H)-
ones
(
4-nitrophenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-
carboxylate catalyzed by NH H PO /MCM-48 and
4
2
4
NH H PO /MCM-41
4
2
4
Yield(%)
Entry Solvent Time (h)
NH H PO /
4
NH H PO /
4 2 4
2
4
MCM-48
MCM-41
1
2
3
4
5
MeOH
EtOH
CHCl3
MeCN
free
5
5
33
55
82
71
48
50
58
79
73
85
5
5
2.5
Reaction condition is described below Table 1.
Effect of urea concentration was also investigated on
the Biginelli reaction of 4-nitrobenzaldehyde (2 mmol) and
4 2 4
ethyl acetoacetate (2 mmol) in the presence of NH H PO /
MCM-48 (0.04 g) at 100 °C under solvent free condition
after 4.4 h (Fig. 5). Clearly, yield% was enhanced with in-
creasing urea concentration from 1.5 to 4.5 mmol.
iminium ion route, however, our new data showed more
ambiguity and obviously more distinct and precise mecha-
nistic studies should be carried out.
As described in Scheme II, three mechanistic routes
could be suggested for the preparation of 3,4-dihydropyr-
Studying reusability of NH
Recycling of NH PO
4
H
2
PO
4
/MCM-48
1
8
imidinones. According to our previous findings, we think
the second route using iminium intermediate would be the
most plausible route for the synthesis of 3,4-dihydropyr-
imidinone in presence of catalyst. Further investigations
are underway to clarify the exact route. Obviously, yield%
of the desired product was higher in the presence of catalyst
and reaction goes in forward direction effectively. Al-
4
H
2
4
/MCM-48 was studied in the
1
0
4 2 4
same manner as described for NH H PO /MCM-41. For
this purpose, condensation of 4-nitrobenzaldehyde, ethyl
acetoacetate and urea was carried out in the presence of
0
4 2 4
.04 g NH H PO /MCM-48 as model reaction. After com-
pletion of the reaction, the reaction mixture was diluted
with hot methanol and the catalyst separated and reused in
subsequent reactions. No significant reduction was ob-
served in yield even after five runs. In conclusion,
1
0
though, in our previous report, we emphasized on the
NH
NH
4
H
2
PO
4
/MCM-48 is also a recyclable catalyst as
4
H
2
PO
4
/MCM-41.
CONCLUSIONS
A simple methodology is described for the synthesis
of some biologically important 3,4-dihydropyrimidin-
(1H)-ones through one-pot three-component reaction of
ethyl acetoacetate, aryl aldehyde and urea under solvent
free condition using the heterogeneous NH PO /MCM-
8 catalyst. Effect of supporting material MCM-48 versus
2
4
H
2
4
4
MCM-41 was fully studied in this report. Both catalysts
could be reused after a simple work-up and reused several
times without noticeable reduction in the catalytic activity.
Different reaction parameters including catalytic efficacy,
solvent effect and urea concentration were considered in
the comparison of MCM-48 with MCM-41. Clearly, MCM-
Fig. 5. Effect of urea concentration on the condensa-
tion of 4-nitrobenzaldehyde with ethyl aceto-
acetate and urea in the presence of NH
MCM-48 after 4.4 h.
4 2 4
H PO /
4
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J. Chin. Chem. Soc. 2013, 60, 000-000

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
4 2 4
Synthesis of Dihydropyrimidinones with NH H PO
K.; Westley, J. W.; Potts, B. C. M. J. Org. Chem. 1995, 60,
4
1 showed better efficacy than MCM-48 as supporting ma-
1
182. (b) Rovnyak, G. C.; Atwal, K. S.; Hedberg, A.;
terial considering time and conv%.
Kimball, S. D.; Moreland, S.; Gougoutas, J. Z.; O’Reilley, B.
C.; Schwartz, J.; Malley, M. F. J. Med. Chem. 1992, 35,
ACKNOWLEDGEMENTS
3
254.
. Tayebee, R.; Maleki, B.; Ghadamgahi, M. Chin. J. Catal.
012, 33, 659.
0. Tayebee, R.; Ghadamgahi, M. Arab. J. Chem. In press.
1. Tayebee, R.; Amini, M. M.; Ghadamgahi, M.; Armaghan, M.
Partial financial support from the Research Council
of Hakim Sabzevari University is greatly appreciated.
9
2
1
1
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5