PEG-SO3H as catalyst for 3,4-dihydropyrimidones via Biginelli reaction under microwave and solvent-free conditions

Article abstract of DOI:10.1080/00397910500383519

An efficient and environmentally friendly process for the synthesis of 3,4-dihydropyrimidones via the Biginelli-type condensation reaction using poly(ethylene glycol)-bound sulfonic acid as catalyst irradiated by microwave has been developed. The function

Full text of DOI:10.1080/00397910500383519

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PEG‐SO3H as Catalyst for
3,4‐Dihydropyrimidones via Biginelli
Reaction Under Microwave and Solvent‐Free
Conditions
Xicun Wang a , Zhengjun Quan a , Fang Wang a , Mangang Wang a , Zhang
Zhang a & Zheng Li a
a Gansu Key Laboratory of Polymer Materials, College of Chemistry and
Chemical Engineering, Northwest Normal University, Lanzhou, Gansu, China
Published online: 19 Aug 2006.
To cite this article: Xicun Wang , Zhengjun Quan , Fang Wang , Mangang Wang , Zhang Zhang & Zheng
Li (2006) PEG‐SO3H as Catalyst for 3,4‐Dihydropyrimidones via Biginelli Reaction Under Microwave and
Solvent‐Free Conditions, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 36:4, 451-456, DOI: 10.1080/00397910500383519
To link to this article: http://dx.doi.org/10.1080/00397910500383519
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Synthetic Communicationsw, 36: 451–456, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500383519
PEG-SO3H as Catalyst for
3,4-Dihydropyrimidones via Biginelli
Reaction Under Microwave and
Solvent-Free Conditions
Xicun Wang, Zhengjun Quan, Fang Wang, Mangang Wang,
Zhang Zhang, and Zheng Li
Gansu Key Laboratory of Polymer Materials, College of Chemistry
and Chemical Engineering, Northwest Normal University,
Lanzhou, Gansu, China
Abstract: An efficient and environmentally friendly process for the synthesis of
3,4-dihydropyrimidones via the Biginelli-type condensation reaction using poly(ethy-
lene glycol)-bound sulfonic acid as catalyst irradiated by microwave has been
developed. The functionalized poly(ethylene glycol) acted simultaneously as catalyst
and as solvent in the condensation. The workup was easy, and the products were
obtained in good to excellent yields and high purities.
Keywords: Biginelli reaction, 3,4-dihydropyrimidone, microwave, poly(ethylene
glycol) (PEG), polymer-supported catalyst
INTRODUCTION
In recent years, there has been rapid growth in the development of novel
polymer-supported compounds,[1] such as supported catalysts, reagents, and
scavengers. These species allow rapid and simplified procedures, and their
Received in Japan July 11, 2005
Address correspondence to Xicun Wang, Gansu Key Laboratory of Polymer
Materials, College of Chemistry and Chemical Engineering, Northwest Normal
University, Lanzhou, Gansu 730070, China. Tel.: þ86-931-7971971; Fax: 86-931-
7971971; E-mail: wangxicun@nwnu.edu.cn
451

452
X. Wang et al.
use has become widespread in solution-phase organic synthesis and combina-
torial chemistry.[2] After reaction by filtration and multiple washing steps,
reagents, excess starting materials, solvents, and by-products are removed.
Then the desired products are obtained in good purity by simple operation.
The polymer-supported compounds include mainly two types: the
dominated insoluble polymer supported and soluble polymer supported.
However, in recent years, the soluble polymer-bound compounds have
received some interest in various organic reactions.[3] One could envision
that in an ideal case such a functionalized polymer could act as a catalyst
and at the same time as a solvent in the synthesis step. Appropriately functio-
nalized polymeric resins could be utilized that not only mediate a specific
chemical reaction but at the same time act as solvents. However, examples
of such supported polymers that act simultaneously as a catalyst and as
solvent are rare.[3a] Poly(ethylene glycol) (PEG) and its aqueous solutions
represent interesting solvents for solvent replacement and may stand compari-
son to other currently favored systems, such as ionic liquids, supercritical
carbon dioxide, and micellar systems.[4]
We recently reported the synthesis of 1,3,4-oxadiazoles using PEG-
supported dichlorophosphate as catalyst and solvent under microwave
irradiation.[5] Herein we preliminarily report the generation of libraries of
Biginelli-type compounds 3,4-dihydropyrimidones (DHPMs) 5, employing
PEG-bound sulfonic acid that acts simultaneously as reaction promoter in
the Biginelli-type reaction step and as reaction solvent (Scheme 1).
The considerable interest in DHPM-type products stems from their wide
range of biological activities as calcium channel blockers, antihyperten-
sive agents, a1a adrenergic antagonists, and neuropeptide Y antagonists.[6]
DHPMs are generally referred to as Biginelli compounds because in 1893
P. Biginelli reported the synthesis of DHPMs by cyclocondensation of ethyl
acetoacetate, aldehyde, and urea. Because of the strongly acidic conditions,
low yields, and difficult isolation in the original Biginelli conditions,
improved procedures using different types of catalysts and conditions have
been reported with the aim of overcoming the main drawbacks of the
Biginelli reaction.[7]
Scheme 1. Synthesis of 3,4-dihydropyrimidones using PEG-SO3H as catalyst.

3,4-Dihydropyrimidones via Biginelli Reaction
453
As described in Scheme 1, the PEG-bound sulfonic acid 1 was prepared
by reacting PEG with excess chlorosulfonic acid at 08C to room temperature.
The conversion of terminal hydroxyl groups on PEG was determinated by
1H NMR analysis to be quantitative, and the appearance of singlets at
d 12.85 and d 4.23 ppm due to the proton of SO3H and the a-methylene
protons at the polymer attached site, respectively. Biginelli-type condensation
took place by subjecting a mixture of an equivalent of aldehyde 2 and ethyl
acetoacetate 3 and an excess of urea/thiourea 4 (1.2 equiv) to microwave
irradiation in the presence of a catalytic amount of PEG-SO3H under
open-vessel conditions to facilitate the removal of water formed during the
reaction. Finally, by adding hot water, filtration, and multiple washing with
hot water and diethyl ether, reagents, excess starting materials, and
by-products were removed and the desired products obtained in good
purities and good yields. PEG was readily recovered from the aqueous
solution by extraction. The results are listed in Table 1.
In the initial studies of screening of catalysts, we found the application of
PEG-6000–bound sulfonic acid as catalyst in the Biginelli reaction of 5a
resulted in excellent yield: 91% (Table 1, entry 1). Various solvents were
tested including toluene, MeCN, and C2H5OH under microwave irradiation
using an equivalent of aldehyde and dicarbonyl compound, a catalytic
amount of PEG-6000–bound sulfonic acid, and an excess of urea, affording
the product 5a in yields of 71%, 82%, and 86%, respectively. On the other
Table 1. Synthesis of 3,4-dihydropyrimidones using PEG-SO3H
as catalyst
Yield
(%)a
Purity
(%)b
Entry
Ar
X
Product
1
2
C6H5
O
O
O
O
O
O
O
S
5a
5b
5c
5d
5e
5f
91
85
89
78
79
83
82
88
83
89
77
79
82
88
90
90
85
85
85
85
88
89
90
89
85
83
85
85
85
88
4-HOC6H4
4-CH3OC6H4
4-NO2C6H4
2-ClC6H4
3
4
5
6
4-ClC6H4
2,4-Cl2C6H3
C6H5
7
5g
5h
5i
8
9
4-HOC6H4
4-CH3OC6H4
4-NO2C6H4
2-ClC6H4
S
10
11
12
13
14
15
S
5j
S
5k
5l
S
4-ClC6H4
2,4-Cl2C6H3
2-CH3OC6H4
S
5m
5n
5o
S
S
aDetermined based on weight of isolated sample.
bDetermined by HPLC analysis of crude products.

454
X. Wang et al.
hand, when conducting the reaction under solvent-free conditions by
microwave irradiation, the yield of 5a was 91%. Here, the PEG-bound
sulfonic acid acts as an acidic mediator to facilitate the Biginelli-type con-
densation and at the same time as reaction solvent. This approach was used
to prepare 3,4-dihydropyrimidone in good purities and good yield. This
clearly demonstrates the success of the PEG-bound sulfonic acid simul-
taneously acting as catalyst and as solvent in the Biginelli-type condensation.
Not only is the product easily isolated, this method also does not need any
organic solvents. This method presents a remarkable technique toward an
environmentally clean synthesis of DHPMs. Unfortunately, the use of
recycled PEG-SO3H resulted in a substantial loss of its activity as the yield
of 5a dropped to a low value (50%).
CONCLUSION
In summary, we have developed a simple, efficient, and environmentally
friendly process for the synthesis of 3,4-dihydropyrimidones via a Biginelli-
type condensation reaction using PEG-SO3H as catalyst in which the functio-
nalized PEG acts simultaneously as catalyst and as solvent. The procedure
afforded 3,4-dihydropyrimidones within a shorter period in high purities
and improved yields compared with the classical solution-phase reaction.
Furthermore, the solvent-free preparation of DHPMs is an environmentally
benign method.
EXPERIMENTAL
Preparation of PEG-Bound Sulfonic Acid 1
At 08C, chlorosulfonic acid (10 mmol) was added to a solution of PEG-6000
(1 mmol) in CH2Cl2 (10 mL). Then the resulting solution was stirred at room
temperature overnight, and the solution was concentrated under vacuum.
Appropriate ether was added, and the precipitate filtered and washed with
1
ether three times to afford the PEG-SO3H. H NMR (400 MHz, CDCl3):
d 12.85 (s, 1H, SO3H), 4.23 (s, 2H, CH2SO3H), 3.49–3.66 (m, PEG).
General Procedure for Compound 5
A mixture of aldehyde 2 (1 mmol), ethyl acetoacetate 3 (1 mmol), urea
(1.2 mmol), and PEG-bound sulfonic acid 1 (0.05 mmol) was heated at
1008C for 6 min in a microwave oven under open-vessel conditions. After
reaction hot water (10 mL) was added and the suspension was filtered. The
residue was washed with hot water and diethyl ether and recrystallized
from ethanol to give pure dihydropyrimidone 5. All the compounds were

3,4-Dihydropyrimidones via Biginelli Reaction
455
characterized by FT-IR, 1H NMR, and 13C NMR. For compound 5a: mp 206–
1
2078C. H NMR (400 MHz, CDCl3): d 1.14 (t, 3H, J ¼ 7.2 Hz, CH3CH2O),
2.34 (s, 3H, CH3), 4.06 (q, 2H, J ¼ 7.2 Hz, CH3CH2O), 5.37 (s, 1H, CH),
7.24–7.31 (m, 5H, ArH), 7.16 (s, NH), 7.76 (s, NH). 13C NMR (100 MHz,
CDCI3): d 14.70, 17.85, 54.72, 60.27, 94.70, 101.40, 127.06, 128.35,
129.24, 144.17, 145.69, 165.80, 174.92. IR (KBr) (cm21): v 3320, 3160,
3100, 2980, 1665, 1570, 1460, 1365, 1320, 1280, 1190, 1170, 1115, 1020,
755. 5o: mp 190–1928C. 1H NMR (400 MHz, CDCI3) d 1.07 (t, 3H,
J ¼ 7.2 Hz CH3CH2O), 2.42 (s, 3H, CH3), 3.88 (s, 3H, CH3O), 4.06 (q, 2H,
J ¼ 7.2 Hz, CH3CH2O), 5.75 (s, 1H, CH), 6.87–7.28 (m, 4H, ArH), 7.37
(s, NH), 8.01 (s, NH); 13C NMR (100 MHz, CDCI3): d 14.03, 18.24, 50.68,
55.46, 60.24, 99.95, 110.65, 120.65, 126.79, 128.39, 129.53, 144.40, 156.62,
165.36, 174.58. IR (KBr) (cm21): v 3320, 3172, 3108, 3068, 1682, 1606,
1526, 1492, 1464, 1374, 1320, 1284, 1268, 1244, 1172, 1108, 1016, 840.
ACKNOWLEDGMENTS
We are thankful for the financial support from the Natural Science Foundation
of Gansu Province (ZS021-A25-006-Z), the Scientific and Technological
Innovation Engineering of Northwest Normal University (NWNU-
KJCXGC-02-08), and the Youth Foundation of Northwest Normal University
(NWNU-QN-04-28).
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