Polymer-supported 4-aminoformoyldiphenylammonium triflate (PS-AFDPAT): An effective and recyclable catalyst for the Biginelli reaction

Article abstract of DOI:10.1080/00397910802393109

Polymer-supported 4-aminoformoyldiphenylammonium triflate (PS-AFDPAT) was used as an effective catalyst for the synthesis of 3,4-dihydropyrimidin-2(1H)- ones (DHPMs) via the Biginelli reaction. This immobilized catalyst could be easily recovered by simple

Full text of DOI:10.1080/00397910802393109

1
Synthetic Communications , 39: 475–483, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910802393109
Polymer-Supported 4-Aminoformoyldiphenyl-
ammonium Triflate (PS-AFDPAT): An Effective
and Recyclable Catalyst for the
Biginelli Reaction
1
1
2
Ming Lei, Dong-Dong Wu, He-Geng Wei, and Yan-Guang Wang
1
1
Department of Chemistry, Zhejiang University, Hangzhou, China
2
Zhejiang Hisun Pharmaceutical Co., Taizhou, China
Abstract: Polymer-supported 4-aminoformoyldiphenylammonium triflate (PS-
AFDPAT) was used as an effective catalyst for the synthesis of 3,4-dihydropyri-
midin-2(1H)-ones (DHPMs) via the Biginelli reaction. This immobilized catalyst
could be easily recovered by simple filtration and recycled for 10 runs without
significant decrease of the catalytic activity.
Keywords: Biginelli reaction, 3,4-dihydropyrimidin-2(1H)-ones (DHPMs),
immobilized catalyst, polymer-supported 4-aminoformoyldiphenylammonium
triflate (PS-AFDPAT)
INTRODUCTION
The Biginelli reaction furnishes 3,4-dihydropyrimidin-2(1H)-ones
(DHPMs) via a one-pot, three-component condensation of aromatic
aldehyde, ethyl acetoacetate, and urea in ethanol under strongly acidic
[
1]
conditions. Multifunctionalized DHPMs exhibit significant pharma-
ceutical and therapeutic properties, such as antiviral, antitumor, antibac-
[2]
terial, and anti-inflammatory activities. They have emerged as potent
[3]
[4]
calcium channel blockers and adrenergic. Moreover, some marine
natural products containing the dihydropyrimidine core unit such as the
alkaloid Batzelladine B have been found to be potent HIV gp-120-CD4
Received April 7, 2008.
Address correspondence to Ming Lei, Department of Chemistry, Zhejiang
University, Hangzhou 310027, China. E-mail: leiming@zju.edu.cn
4
75

476
M. Lei et al.
[
5]
inhibitors. Therefore, the Biginelli reaction has received renewed inter-
est because it is suitable for the generation of DHPM libraries in a high-
throughput or combinatorial format. However, this method suffers from
several drawbacks such as harsh conditions, long reaction times, and fre-
quently low yields (20–50%), particularly in the case of substituted aro-
matic and aliphatic aldehydes and loss of sensitive functional
groups during the reaction. In the past decade, a number of techniques
[
6]
[7]
and catalysts, such as microwave
and ultrasound irradiation,
[8]
[9]
[10]
[11]
[16]
[20]
solvent-free techniques, BF ꢀ OEt =CuCl, ZrCl4,
LaCl ꢀ H O,
2
3
[13]
2
3
2
[12]
[14]
[15]
Mn(OAc) ꢀ 2H O,
InCl ,
3
NH Cl,
4
Cu(OTf) ,
2
Zn(OTf) ,
[19]
RuCl3,
3
2
[17]
[18]
Ln(OTf) (Ln ¼ Yb, Sc, La),
NiCl ꢀ 6H O,
CdCl2,
3
2
2
[
21]
and 1-n-butyl-3-methylimidazolium tetra-fluoroborate ([Bmim][BF ]),
4
have been used for the synthesis of multifunctionalized DHPMs.
22]
[
Additionally, heteropoly acids Ag PW O
3
have been employed as
12 40
heterogeneous catalysts for the Biginelli reactions. Although there is pro-
gress for the Biginelli reactions, developing economical and environmen-
tally friendly procedures remains a challenge. Therefore, we are interested
in the recyclable and metal-free catalysts for the Biginelli reactions.
Previously, we reported the polymer-supported 4-aminoformoyldi-
phenylammonium triflate (PS-AFDPAT, 1), a diphenylammonium
[
23]
triflate resin.
was also developed by Ishihara et al.
Thereafter, the pentafluorobenzenesulfonate analog (2)
It was found that 1 and 2 were
[24]
effective and recyclable catalysts for the esterification of carboxylic acids
with equimolar amounts of alcohols. In continuation of our work on
PS-AFDPAT applications, we herein describe a synthesis of dihydropyr-
imidinones and their thione analogs via the Biginelli reaction using
PS-AFDPAT (1) as the recyclable organocatalyst.
RESULTS AND DISCUSSION
Initially, the efficacy of the catalyst was investigated on the model reaction
of benzaldehyde (1.0 equiv), ethyl acetoacetate (1.0 equiv), and urea
(1.2 equiv) in different solvents in the presence of catalyst 1 (0.05 equiv)
under reflux conditions (Scheme 1). We examined several solvents, such
Figure 1. Polymer-supported diphenylammonium triflate catalysts.

Polymer-Supported Catalyst
477
Scheme 1. PS-AFDPAT catalyzed model Biginelli reaction.
asCH CN, tetrahydrofuran(THF), CH Cl , andethanol(EtOH) (Table1).
3
2
2
We found that EtOH gave the best yield (Table 1, entries 4 and 5).
Subsequently, we examined a wide range of reactants using the estab-
lished procedure, and the results are presented in Table 2. We found that
the aromatic aldehydes bearing either the electron-donating or electron-
withdrawing groups afforded DHPMs 3 in good to excellent yields
(70–94%) (Table 2, entries 1–12). Thiourea was also used as one of the
substrates to provide the corresponding 3,4-dihydropyrimidinethiones
Table 1. Solvent effect on the model Biginelli reaction
a,b
catalyzed by 1
c
Reaction
time (h)
Yield
(%)
Entry
Solvent
1
2
3
4
5
6
CH
THF
CH Cl
EtOH
EtOH
EtOH
3
CN
6.5
6
10
5
5.5
4
81
83
55
90
90
86
2
2
a
Reaction conditions: benzaldehyde (10 mmol); ethyl aceto-
acetate (10 mmol); urea (12 mmol); 1 (0.5 mmol), reflux.
b
The reactions were monitored by TLC.
Isolated yield after recrystallization.
c
Scheme 2. PS-AFDPAT catalyzed Biginelli reactions.

478
M. Lei et al.
a
Table 2. PS-AFDPAT–catalyzed synthesis of DHPMs
Mp
ꢁ
ꢁ
Reaction Yield
time (h) (%) found
( C)
Mp ( C)
reported
Entry Product
R
1
R
2
X
O
[
9]
1
2
3
4
5
6
7
8
9
0
1
3a
3b
3c
3d
3e
3f
Ph
Ph
OEt
5
90 203–204
204
[
[
9]
9]
OMe O
OEt
OMe O
OEt
OMe O
OEt
OMe O
OEt
OMe O
5
5
5
5.5
6
8
8
8
8
88 209–210 207–210
94 200–202 201–203
4-MeOC
4-MeOC H
4-ClC H
6
6
H
4
O
[
9]
88 191–193 192–194
80 214–215 214–215
6
4
[
9]
O
4
4
[
18]
4-ClC
4-O
4-O NC H
6
H
89 204–206 204–207
76 207–208 206–208
74 234–236 235–237
[
[
7]
9]
3g
3h
3i
2
NC
6
H
4
O
2
6
4
[
15]
12]
2-HOC
4-HOC
6
H
H
4
O
81 200–202 200–202
75 227–229 227–228
[
1
1
3j
3k
6
5
3,4-(OCH O) OMe O
2
8
70 196–198
—
6 3
C H
[
7c]
14]
22]
22]
12
13
14
15
16
17
3l
C
Ph
6
H
5
CH=CH- OEt
OEt
O
S
S
S
S
S
6
6
6
6
7
8
82 232–234 232–235
[
[
[
3m
3n
3o
3p
3q
83 206–207 205–206
82 151–153 153–154
82 192–194 192–194
75 234–235 —
75 194–195 193–194
4-MeOC
4-ClC
4-NO
4-HOC H
6
H
4
OEt
OEt
OEt
OEt
6
H
4
2
C
6
H
4
[
10]
6
4
a
b
c
In 10-mmol scale.
The reactions were monitored by TLC.
Isolated yield after recrystallization.
in high yields (Table 2, entries 13–17), which are also of much interest
with respect to their biological activities. This procedure is fairly general,
and several functionalities including methoxy, nitro, halide, ester,
hydroxyl, and C=C groups could survive under the present reaction con-
ditions, representing an obvious improvement to the classical Biginelli
methodologies.
Scheme 3. Model Biginelli reaction catalyzed by recyclable PS-AFDPAT.

Polymer-Supported Catalyst
479
a
Table 3. Recyclability of catalyst 1 in the model reaction
b
Run
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
5
5
5
5
5.5
5.5
5.5
5.5
6
90
90
90
88
88
87
86
86
86
86
1
0
6
a
b
In 10-mmol scale.
Isolated yield after recrystallization.
As the next step, the recyclability of catalyst 1 was evaluated using
the model reaction (Table 3). We found that our catalyst could be reused
for 10 runs without significant decrease of the catalytic activity. It is
noteworthy that the resin catalyst could be easily recovered by simple
filtration, which facilitated the separation of the products.
CONCLUSION
In summary, we have demonstrated that PS-AFDPAT could effectively
catalyze the one-pot, three-component synthesis of DHPMs as well as
their thione analogs in high yields. It is noteworthy that this immobilized
organocatalyst possesses several advantages including high catalytic
activity, low toxicity, easy recovery, and excellent reusability. Therefore,
the present procedure is environmentally friendly and will be of great
value for the preparation of the Biginelli compounds.
EXPERIMENTAL
1
All chemicals were reagent grade and used as purchased. H NMR
spectra were recorded in deuterated solvent on Bruker Avance 500 spec-
1
3
trometer operating at 500 MHz. C NMR spectra were recorded at
25 MHz. Infrared (IR) spectra were recorded on a Nicolet 470 Nexus
1
FT-IR spectrometer and measured as thin film or in KBr. Electrospray
ionization-mass spectrometry (ESI-MS) spectra were recorded on a
Bruker Daltonics Esquire 3000 plus instrument. Melting points were

480
M. Lei et al.
measured on WRS-1B digital melting-point apparatus. Elemental
analyses were determined on a EA1110 elemental analysis instrument.
Procedure for Synthesis of Catalyst 1
A mixture of aminomethyl polystyrene resin 3 (1 g, 1.1 mmol), 4-iodoben-
0
zoic acid (1.2 mmol), N,N -dicyclohexylcarbodiimide (DCC) (1.6 mmol),
4
(
-dimethylaminopyridine (DMAP) (0.16 mmol), and dichloromethane
DCM) (5 ml) was stirred at temperature for 12 h. Filtration and washing
with DCM, THF, and methanol (MeOH) for several cycles afforded resin
4
. Then a mixture of resin 4 (1.1 mmol), phenyl amine (5.5 mmol), Pd(OAc)
0
2
(0.22 mmol), 1,1 -bis(diphenylphosphino) ferrocene (DPPF) (0.88 mmol),
and Cs CO (11 mmol) in dry toluene (20 ml) was stirred under nitrogen
at 100 C for 48 h. After cooling, the mixture was filtered and washed subse-
quently with water, DMF, DCM, and MeOH for several cycles afforded
resin 5. Then resin 5 was treated with CF SO H (1.05 equiv.) in DCM: the
2
3
ꢁ
3
3
mixture was stirred at room temperature for 1 h, filtered and washed with
DCM, and then dried in vacuo for 1 h to afford resin 1.
General Procedure for Synthesis of 3,4-Dihydropyrimidin-2-one
A solution of benzaldehyde (10 mmol, 1.07 g), ethyl acetoacetate (10 mmol,
1
.3 g), urea (15 mmol, 0.9 g), and PS-AFDPAT (0.5 mmol, 0.65 g) in etha-
nol (50 mL) was stirred and refluxed for 5 h. The progress of the reaction
was monitored by thin-layer chromotography (TLC) using ethyl aceta-
te=hexane (2:3) as eluent. After completion the reaction, the catalyst resin
was removed from the hot mixture by filtration, and then the filtrate was
poured into ice water. The resulting solid was collected by filtration and
recrystallized from ethanol to give pure 5-ethoxycarbony-6-methyl-4-phe-
ꢁ
nyl-3,4-dihydro-pyrimidin-2-one (3a) in 90% yield. Mp 203–204 C.
Data
Spectral Data for New Compound 5-Methoxycarbony-6-methyl-4-
(benzo[d][1,3]dioxol-5-yl)-3,4-dihydro-pyrimidin-2-one (3k)
ꢁ
Pale yellow solid; mp 196–198 C; IR (KBr): 3367, 3220, 3012, 2952, 1712,
ꢂ1
1
692, 1644, 1488, 1459, 1436, 1231, 1099 cm ; H NMR (500 MHz,
1

Polymer-Supported Catalyst
481
DMSO-d ): d ¼ 2.25 (s, 3H, CH ), 3.53 (s, 3H, OCH ), 5.06 (d, 1H,
6
3
3
J ¼ 3.2 Hz, CH), 5.98 (s, 2H, CH ), 6.67–6.85 (m, 3H, ArH), 7.68 (s,
2
1
3
1
1
1
H, NH), 9.19 (s, 1H, NH) ppm; C NMR (125 MHz, DMSO-d ): d
6
8.5, 51.1, 53.9, 99.5, 101.3, 107.0, 108.4, 119.6, 139.1, 146.7, 147.7,
48.9, 152.4, 166.2 ppm; MS (ESI): m=z 603 [2M þ Na]; anal. calcd. for
C H N O : C, 57.93; H, 4.86; N, 9.65. Found: C, 57.98; H, 4.95; N, 9.55.
1
4
14
2
5
Spectral Data for New Compound 5-Ethoxycarbony-6-methyl-4-(4-
nitrophenyl)-3,4-dihydro-pyrimidin-2-thione (3p)
ꢁ
Pale purple solid; mp 234–235 C; IR (KBr) 3324, 3173, 2918, 1679, 1655,
ꢂ1
1
576, 1522, 1466, 1350, 1201, 1176, 1123 cm ; H NMR (500 MHz,
1
DMSO-d ): d ¼ 1.10 (t, 3H, J ¼ 7.1 Hz, CH ), 2.31 (s, 3H, CH ), 4.02
6
3
3
(
q, 2H, J ¼ 7.1 Hz, CH ), 5.31 (d, 1H, J ¼ 3.5 Hz, CH), 7.48 (d, 2H,
2
J ¼ 8.7 Hz, ArH), 8.23 (d, 2H, J ¼ 8.7 Hz, ArH), 9.76 (d, 1H, J ¼ 1.2 Hz,
1
3
NH), 10.49 (s, 1H, NH) ppm; C NMR (125 MHz, DMSO-d ): d 14.7,
6
1
7.7, 54.1, 60.3, 100.2, 124.5, 128.3, 146.4, 147.5, 150.86, 165.3,
þ
1
C, 52.33; H, 4.70; N, 13.08. Found: C, 52.38; H, 4.80; N, 13.02.
74.9 ppm; MS (ESI): m=z 320 [M ꢂ H ]. Anal. calcd. for C H N O S:
1
4
15
3
4
ACKNOWLEDGMENT
The authors thank the National Natural Science Foundation of China
No. 20672093) as well as the Science Research Program of Educational
Bureau of Zhejiang Province (No. 20061311).
(
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