Immobilized Cu(I) on organic-inorganic hybrid material: An effective and reusable catalyst for Biginelli reaction

Article abstract of DOI:10.2174/157017811797249425

The immobilized Cu(I) on organic-inorganic hybrid material was prepared and used as effective catalyst for the Biginelli reaction. In the presence of immobilized copper catalyst, aromatic aldehydes reacted with β-keto ester and urea (or thiourea) smoothly

Full text of DOI:10.2174/157017811797249425

Letters in Organic Chemistry, 2011, 8, 577-581
577
Immobilized Cu(I) on Organic–Inorganic Hybrid Material: An Effective
and Reusable Catalyst for Biginelli Reaction
#
,a
,a
,a,b
Xiao L. Zhang , Min Wang* and Lei Wang*
a
Department of Chemistry, Huaibei Normal University, Huaibei, Anhui 235000, P.R. China
b
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, Shanghai 200032, P.R. China
Received May 04, 2010: Revised June 04, 2010: Accepted July 06, 2010
Abstract: The immobilized Cu(I) on organic–inorganic hybrid material was prepared and used as effective catalyst for the
Biginelli reaction. In the presence of immobilized copper catalyst, aromatic aldehydes reacted with ꢀ-keto ester and urea
(or thiourea) smoothly to generate the corresponding Biginelli products in good to excellent yields without any additive.
The work-up procedure is very simple and practical. Furthermore, the silica-supported Cu(I) could be recovered and recy-
cled for eight consecutive trials without significant loss of its reactivity.
Keywords: ꢀ-Keto ester, Biginelli reaction, Heterogeneous catalyst, Immobilization of Cu(I), Organic–inorganic hybrid mate-
rial, Urea (thiourea).
INTRODUCTION
However, in spite of their potential utility, most of the
above recommendation reaction procedures were carried out
in homogeneous catalytic conditions, which had intrinsic
problems, such as difficulties in recovery, separation and
recycling of the expensive, toxic catalysts. Such drawbacks
could be obviated by using supported catalyst, which can
facilitate both the isolation and recycling of the catalyst by
filtration thus providing environmentally cleaner processes.
In recent years, among various solid supports, silica is usu-
ally preferred since it displays many advantageous proper-
ties-excellent stability (chemical and thermal), high surface
area, good accessibility, and organic groups can be robustly
anchored to the surface, to provide catalytic centers [36]. In
addition, the development of organic reagents grafted onto
silica has attracted increasing attention because industry
seeks more environmentally friendly chemical manufactur-
ing processes [37]. These catalysts named hybrid catalysts,
which generally consist of matrix, spacer and metal complex
can be easily recovered and reused like heterogeneous cata-
lysts while acting as the homogeneous ones with high activ-
ity [38]. Therefore, the search for milder and environmen-
tally acceptable catalytic system for performing the Biginelli
reaction has been the subject of the recent focus.
Dihydropyrimidin-2(1H)-one (DHPM) and its derivatives
have attracted considerable interest in recent years because
these compounds exhibit diverse pharmacological properties
such as calcium channel blockers, antihypertensive agents,
neuropeptide Y (NPY) antagonists and ꢀ-1a-antagonists [1].
Moreover, several alkaloids containing the dihydro-
pyrimidine unit also exhibit interesting biological properties
[
2]. In 1893, Biginelli first reported the synthesis of 3,4-
dihydropyrimidin-2(1H)-one (DHPM) by a simple one-pot
condensation reaction of an aromatic aldehyde, ꢁ-ketoester
and urea under strongly acidic reaction conditions [3]. How-
ever, this protocol often provides only low to moderate
yields of the desired target molecules, especially in the case
of substituted aromatic aldehyde as one of the substrate. Af-
ter then, the Biginelli reaction for the synthesis of 3,4-
dihydropyrimidin-2(1H)-one has received renewed interest
and a number of improved procedures have been reported
including in the classical reaction conditions, as well as un-
der microwave irradiation [4], solid phase reagents [5], or in
ionic liquids [6], in the presence of Lewis acid catalyst, such
as BF
polyphosphonate ester (PPE) [11], In(OTf)
InCl [13], LaCl •7H O [14], La(OTf) [15], Yb(OTf)
ceric ammonium nitrate [17], Mn(OAc) •2H
19], LiClO [20], CeCl •7H O [21], Ce(NO
FeCl •6H O and NiCl •6H O/HCl [23], ZnCl
and ZrOCl •8H O [25], Sr(OTf) [26], Bi(OTf)
Cl [29], CaF [30], Y(NO •6H O [31], PhB(OH)
32], or SmI [33] et al. Most recently, the application of
3
•OEt
2
/CuCl [7], CuI [8], Cu(OTf)
2
[9], Cu(BF
4
)
2
[10],
and
[16],
3
[12], InBr
3
3
3
2
3
3
Because new types of silica-supported catalysts have
theoretical and practical significance, currently the prepara-
tion of 3-[(2-aminoethyl)amino]propyl-functionalized silica-
anchored copper and subsequently its uses as highly efficient
and recyclable catalysts for the Sonogashira reaction was
reported [39]. In this paper, we wish to report the synthesis
of functionalized silica immobilized Cu(I) catalysts (Scheme
1), which were found to be the effective catalysts for the
Biginelli reaction. In the presence of immobilized Cu(I) cata-
3
2
O [18], BiCl
•6H O [22],
[24], ZrCl
[27], LiBr
3
[
4
3
2
3
)
3
2
3
2
2
2
2
4
2
2
2
3
[
[
28], NH
4
2
3
)
3
2
2
2
Lewis base as catalyst [34] and asymmetric synthesis [35]
for the Bignielli reaction have been investigated.
2 5
lyst (10 mol%) in C H OH, the Biginelli reactions of aro-
*
Address correspondence to this author at the Department of Chemistry,
Huaibei Normal University, Huaibei, Anhui 235000, P.R. China; Tel: + 86-
61-3802-069; Fax: + 86-561-3090-518; E-mail: leiwang@chnu.edu.cn
matic aldehydes with ethyl acetoacetate and urea (or
thiourea) underwent smoothly to generate the corresponding
products in good to excellent yields in the absence of any
additive. To the best of our knowledge, this is the first ex-
5
#
Permanent address: Department of Nursing, Anhui Medical College, Hefei,
Anhui 230061, P. R. China.
1
570-1786/11 $58.00+.00
© 2011 Bentham Science Publishers

5
78 Letters in Organic Chemistry, 2011, Vol. 8, No. 8
Zhang et al.
(
EtO) Si(CH ) NH(CH ) NH
3 2 3 2 2 2
OH
OH
OH
O
O
O
O
O
O
H
N
(AAPTS)
CuI
Si
N
Si
NH2
NH2
H
Toluene
DMF
Cu(I)
Catal. A
Silica-AAPTS
OH
O
O
O
O
OH (EtO)
Si(CH
)
NH
Si
NH
Si
NH2
NH2
3
2
3
2
2
OH
OH
(APTS)
Toluene
O
O
CuI
DMF
O
O
Cu(I)
OH
OH
O
O
Si
NH2
O
O
Si
Silica-APTS
Catal. B
Ar
N
H
RO C
2
X
O
O
Catal. A (10 mol%)
ArCHO
+
+
H N
2
NH2
CH3
OR
EtOH, reflux 4-5 h
Me
N
H
X
X = O, S
R = CH
i-C H , n-C H
4 9
3 2 5
, C H ,
3
7
Scheme 1.
ample of supported catalyst for the Biginelli reaction. It is
noteworthy that the silica-supported Cu(I) catalyst could be
recovered and recycled for 8 consecutive trials without
significant loss of its reactivity.
To probe the generality of this reaction, a series of aro-
matic aldehydes with ethyl acetoacetate and urea (thiourea)
were investigated under the optimized reaction conditions (in
2 5
the presence of 10 mol% Catal. A in C H OH at 80 ꢀ for 5
h without acid, base, ligand and additive). The results in Ta-
ble 1 indicated that aromatic aldehydes with both electron-
donating and electron-withdrawing functional groups on the
RESULTS AND DISCUSSION
3 3 2 3
benzene rings, such as CH , CH O, NO , CF , F, Cl and Br
groups reacted smoothly with ethyl acetoacetate and urea to
afford the corresponding products in excellent yields (Table
The synthesis of the organic–inorganic hybrid materials
immobilized copper catalysts illustrated in Scheme 1. This
was readily prepared through a two-step procedure. The sil-
ica gel (100–200 mesh, from Aldrich) was reacted with (3-
aminopropyl)triethoxysilane or 3-(2-aminoethylamino)pro-
pyltriethoxysilane in dry toluene at 120 °C for 24 h to afford
the 3-aminopropyl or 3-(2-aminoethylamino)propyl func-
tionalized silica gel. The organic–inorganic hybrid materials
then reacted with CuI in DMF at room temperature for 4 h to
generate the silica-supported copper(I) catalyst, Catal. A and
Catal. B respectively.
1
, entries 1ꢀ10). It was worth noting that sterically demand-
ing ortho substituent did not hamper the reaction and the
corresponding products were isolated in good yields (Table
1
, entries 8 and 10). Fortunately, a reaction of benzaldehyde
with ethyl acetoacetate and thiourea also gave a high yield of
the desired product (Table 1, entry 11). However, when ali-
phatic aldehyde, such as n-butanal was treated with ethyl
acetoacetate and urea under the present reaction conditions,
moderate yield of the desired condensation product was ob-
tained (Table 1, entry 12). The effect of substituents on ꢁ-
keto esters for the Biginelli reactions was also investigated.
The results indicated that activity of methyl acetoacetate, iso-
propyl acetoacetate and n-butyl acetoacetate towards the
Biginelli reaction with benzaldehyde and urea was similar to
the activity of ethyl acetoacetate under the standard reaction
conditions (Table 1, entries 13ꢀ15 vs entry 1).
For the optimization of reaction conditions for Biginelli
reaction, a model reaction of ethyl acetoacetate, benzalde-
hyde with urea was chosen for the investigation. In our ini-
tial screening experiments, when the model reaction was
performed in ethanol at reflux temperature for 5 h in the
presence of 10 mol% of Catal. A without any additive, the
desired three-component condensation product was isolated
in 95% yield. When Catal. B was instead of Catal. A for the
model reaction, 90% yield of the desired three-component
condensation product was isolated. So, the optimized reac-
tion conditions for this Biginelli reaction are silica-supported
To screen the recyclability of silica-supported Cu(I) cata-
lyst, a more practical method was applied to the reaction of
benzaldehyde, ethyl acetoacetate and urea under present re-
action conditions. After separation of the product and the
recovery of the silica-supported Cu(I), fresh starting materi-
2 5
Cu(I) Catal. A (10 mol% of Cu), in refluxing C H OH for 5
h.

Immobilized Cu(I) on Organic–Inorganic Hybrid Material
Letters in Organic Chemistry, 2011, Vol. 8, No. 8
579
a
Table 1. Silica-Supported Cu(I) Catalyzed Biginelli Reaction
Ar
H
RO C
2
X
O
O
N
Catal. A (10 mol%)
EtOH, reflux 4-5 h
ArCHO
+
+
H
2
N
NH
2
CH3
OR
Me
N
H
X
b
Entry
ArCHO
CHO
X
R
Yield (%)
1
2
3
4
5
6
7
8
9
C
6
H
5
O
O
O
O
O
O
O
O
O
O
S
C
2
2
2
2
2
2
2
2
2
2
2
2
H
5
5
5
5
5
5
5
5
5
5
5
5
96
91
86
94
97
90
86
94
97
91
88
65
95
93
94
4-CH
4-CH OC
4-FC
4-NO
3
C
6
H
4
CHO
C
C
C
C
C
C
C
C
C
C
C
H
H
H
H
H
H
H
H
H
H
H
3
6
H
4
CHO
6
H
4
CHO
CHO
2
C
6
H
4
3 6 4
4-CF C H CHO
3-BrC
6
6
H
H
4
4
CHO
CHO
CHO
CHO
2-BrC
4-ClC
6
6
H
H
4
4
1
1
1
1
1
1
0
1
2
3
4
5
2-ClC
C
6
H
5
CHO
3
n-C H
7
CHO
O
O
O
O
C
6
C
6
C
6
H
H
H
5
5
5
CHO
CHO
CHO
CH
i-C
3
3
H
7
4 9
n-C H
a
Silica-supported Cu(I) catalyst Catal. A (containing Cu 0.10 mmol), ꢁ-keto ester (1.0 mmol), aromatic aldehyde (1.0 mmol) and urea or thiourea (1.0 mmol) was carried out in
b
2 5
refluxing C H OH (5.0 mL) for 5 h. Isolated yields.
als and C
2
H
5
OH were charged into the reaction system. The
with a reflux condenser, 80 mL of concentrated H
2 4
SO and
reactions still proceeded well and no unreacted substrates
were detected at the end of the reaction. The silica-supported
Cu(I) catalyst was recovered and recycled for eight consecu-
tive trials without any decreases in its activity.
15 mL of HNO were added and the mixture was heated in
3
oil-bath at 140 °C for 24 h. The solution was filtered and the
white powder was washed with distilled water until neutral
pH was attained. The solid was again washed with acetone,
methanol and dichloromethane respectively, and dried under
vacuum at 150°C for 48 h.
EXPERIMENTAL SECTION
In a 50 mL round-bottom flask were introduced succes-
sively 20 mL of anhydrous toluene, 3.00 g of activated silica
and 10 mL of 3-(2-aminoethylamino)propyltriethyoxylsilane
General Remarks
Melting points were recorded on a WRS-2B melting
1
13
(
AAPTS). The solution was refluxed for 24 h. The solution
point apparatus and were uncorrected. All H and C NMR
spectra were recorded on a Bruker 400 MHz FT-NMR spec-
trometer. Chemical shifts were given as ꢀ value with refer-
ence to tetramethylsilane (TMS) as the internal standard.
Products were purified by flash column chromatography on
was filtered and the solid was washed with acetone and di-
chloromethane respectively, and dried under reduced pres-
sure at 60°C. 3.38 g of Silica-AAPTS material was obtained.
ꢁ1
ꢁ1
FT-IR (KBr): 2941 cm (ꢀ C-H
)
,
.
1088 cm (ꢀ Si-O) The load-
ing of Silica-AAPTS was readily quantified via CHN micro-
analysis and was found to be 0.918 mmol/g of
2
30–400 mesh silica gel, SiO
2
.
The chemicals were purchased from commercial suppli-
ers (Aldrich, USA and Shanghai Chemical Company, China)
and were used without purification prior to use.
CH
age.
2
CH
2
CH
2
NHCH
2
CH
2
NH
2
based on the nitrogen percent-
In a small Schlenk tube, 1.00 g of Silica-AAPTS (con-
tains 0.918 mmol CH CH CH NHCH CH NH /g) was
2
2
2
2
2
2
Preparation of Catal. A
mixed with 0.191 g (1.0 mmol) of CuI in 5 mL of DMF. The
mixture was stirred for 4 h under nitrogen atmosphere at
room temperature. The solution was filtered and the solid
was washed with acetone and methanol respectively, and the
solid was dried under reduced pressure at room temperature
This catalyst was prepared in the following steps from
commercial silica gel.
Activation of silica 10.00 g of silica (100–200 mesh, Ald-
rich) were introduced in a round-bottomed flask equipped

5
80 Letters in Organic Chemistry, 2011, Vol. 8, No. 8
Zhang et al.
for 16 h, leading to a pale blue powder Catal. A (1.06 g).
DISCLOSURES
ꢀ1
ꢀ1
FT-IR (KBr): 2937 cm (ꢀ C-H
)
,
.
1053 cm (ꢀ Si-O) The cop-
Xiao Lai Zhang, Permanent address: Department of
Nursing, Anhui Medical College, Hefei, Anhui 230061, P. R.
China
per metal amount of Catal. A was found to be 5.28 wt %
based on AAS analysis.
†
As our study on the immobilized transition metal on or-
Preparation of Catal. B
ganic–inorganic hybrid material, the related manuscript has
been previously published in “SCIENCE CHINA Chemistry,
2011, 54, 74ꢂ80 DOI: 10.1007/s11426-010-4178-6.”
In a 50 mL round-bottom flask were introduced succes-
sively 20 mL of anhydrous toluene, 3.00 g of activated silica,
which obtained from the above procedure and 10 mL of 3-
aminopropyltrimethyoxylsilane (APTS). The solution was
refluxed for 24 h. The solution was filtered and the solid was
washed with acetone and dichloromethane respectively, and
dried under reduced pressure at 60 °C. 3.26 g of Silica-APTS
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[
[
16]
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We gratefully acknowledge financial support by the Na-
tional Natural Science Foundation of China (20972057), and
the Natural Science Foundation of the Education Department
of Anhui Province (KJ2008B008), China.
2
001, 1939ꢂ1941.

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