Solvent-free approach to 3,4-dihydropyrimidin-2(1H)-(thio)ones: Biginelli reaction catalyzed by a Wells-Dawson reusable heteropolyacid

Article abstract of DOI:10.1080/00397910701572332

The Biginelli reaction is performed in an efficient, simple, solvent-free procedure, using a small amount of H6P2W18O62 · 24H2O, a reusable heteropolyacid catalyst with Wells-Dawson structure. Both aromatic and aliphatic aldehydes, and different β-dicarbo

Full text of DOI:10.1080/00397910701572332

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Solvent‐Free Approach to
3,4‐Dihydropyrimidin‐2(1H)‐(thio)ones:
Biginelli Reaction Catalyzed by a
Wells–Dawson Reusable Heteropolyacid
a
a
b c
Gustavo P. Romanelli , Angel G. Sathicq , Juan C. Autino
, Graciela
d
e
Baronetti & Horacio J. Thomas
a
Faculty of Exact Sciences, Department of Chemistry, Center of Research
and Development of Applied Sciences, “Dr. Jorge J. Ronco” (CINDECA)
Universidad Nacional de La Plata‐CONICET, La Plata, Argentina
b
Faculty of Agricultural and Forest Sciences, Course of Organic Chemistry,
UNLP, La Plata, Argentina
c
LADECOR, Faculty of Exact Sciences, Department of Chemistry, UNLP, La
Plata, Argentina
d
Faculity of Engineering, Department of Chemical Engineering, University
of Buenos Aires, Buenos Aires, Argentina
e
Center of Research and Development of Applied Sciences, “Dr. Jorge J.
Rono” (CINDECA), Universidad Nacional de La Plata‐CONICET, La Plata,
Argentina
Published online: 19 Nov 2007.
To cite this article: Gustavo P. Romanelli , Angel G. Sathicq , Juan C. Autino , Graciela Baronetti & Horacio J.
Thomas (2007): Solvent‐Free Approach to 3,4‐Dihydropyrimidin‐2(1H)‐(thio)ones: Biginelli Reaction Catalyzed
by a Wells–Dawson Reusable Heteropolyacid, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 37:22, 3907-3916
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Synthetic Communications , 37: 3907–3916, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701572332
Solvent-Free Approach to
,4-Dihydropyrimidin-2(1H)-(thio)ones:
Biginelli Reaction Catalyzed by a
3
Wells–Dawson Reusable Heteropolyacid
Gustavo P. Romanelli and Angel G. Sathicq
Faculty of Exact Sciences, Department of Chemistry,
Center of Research and Development of Applied Sciences,
“Dr. Jorge J. Ronco” (CINDECA), Universidad Nacional de La
Plata-CONICET, La Plata, Argentina
Juan C. Autino
Faculty of Agricultural and Forest Sciences, Course of Organic
Chemistry, UNLP,La Plata, Argentina and LADECOR, Faculty of Exact
Sciences, Department of Chemistry, UNLP, La Plata, Argentina
Graciela Baronetti
Faculity of Engineering, Department of Chemical Engineering,
University of Buenos Aires, Buenos Aires, Argentina
Horacio J. Thomas
Center of Research and Development of Applied Sciences, “Dr. Jorge J.
Rono” (CINDECA), Universidad Nacional de La Plata-CONICET,
La Plata, Argentina
Abstract: The Biginelli reaction is performed in an efficient, simple, solvent-free
.
procedure, using a small amount of H P W O
6
24H O, a reusable heteropolyacid
2
2
18 62
catalyst with Wells–Dawson structure. Both aromatic and aliphatic aldehydes, and
different b-dicarbonyl compounds and urea or thiourea, were used as starting
materials. Seventeen examples of dihydropyrimidinones and dihydropyrimidinethiones
Received in the USA March 28, 2007
Address correspondence to Juan C. Autino, Faculty of Agricultural and Forest
Sciences, Course of Organic Chemistry, UNLP, Calles 60 y 119, B1904AAN, La
Plata, Republic Argentina. E-mail: autino@agro.unlp.edu.ar
3
907

3
908
G. P. Romanelli et al.
were prepared by heating the reactants either in refluxing acetonitrile or in the absence
of solvent. Operational simplicity, the use of a noncorrosive, reusable catalyst in sol-
ventless conditions, short reaction times, and very good to excellent yields in most
of the selected examples are the main advantages of the method.
Keywords: Biginelli reaction, clean processes, dihydropyrimidinones, solvent-free,
Wells–Dawson catalyst
INTRODUCTION
Biginelli compounds, 3,4-dihydro-2(1H)-pyrimidinones, are interesting
compounds in the fields of therapeutics, synthesis, and bioorganic
chemistry. Their derivatives exhibit a wide spectrum of biological effects
including antifungal, antiviral, anticancer, antibacterial, anti-inflammatory,
[
1]
and antihypertensive effects. Several bioactive marine alkaloids with the
[
2]
dihydropyrimidine-5-carboxylate core have been isolated;
alkaloids A and B from the sponge Batzella sp. inhibit the binding of HIV
batzelladine
[3]
glycoprotein gp-l2O to human CD4 receptor.
The Biginelli reaction, as it was carried out initially, is a simple, one-pot,
acid-catalyzed cyclocondensation of ethyl acetoacetate, benzaldehyde, and
[1a]
urea (see head of Table 1) in the presence of HCl.
However, the
procedure suffers from low yields, long reaction times, and harsh reaction con-
ditions. These difficulties have aroused chemists’ interest in the development
of alternative processes using novel catalysts as an answer to the environ-
mental problems mainly associated with the handling and disposal of toxic
inorganic acids.
A number of synthetic procedures, reported in the recent years for preparing
dihydropyrimidinones (DHPMs), involve these reagents and catalysis by protic
[
4a]
[4b]
acids such as H SO adsorbed on silica gel, H BO ,
2
KHSO , and PEG-
4
4
3
3
[
4c]
[5a]
[5b]
[5c]
.
SO H;
3
a variety of Lewis acids (VCl ,
[5d]
CeCl3 7H O,
Cu(OTf)2,
), or recoverable catalysts (KSF
3
[5e]
2
[
3b]
LiClO ,
LiBr,
ion-exchange resins,
and Zn(NH SO )
2
4
6a]
3 2
[
[6b]
[6c]
[6d,6e]
clay,
Amberlyst-15,
heteropolyacids,
[6f]
the poly(4-vinylpyridine-co-divinylbenzene)-Cu(II) complex ). Other
and
[
7]
[8]
reaction conditions involve microwaves, ultrasound irradiation, solid-
[
phase synthesis, and use of ionic liquids.
9]
[10]
However, in spite of their
potential use, some of these methods involve expensive reagents, strong acidic
conditions, long reaction times, high temperatures, stoichiometric amounts of
[11]
catalysts, and environmental pollution and give unsatisfactory yields.
[4d,5b,5e,6b]
Solvent-free conditions were also applied.
Heteropolycompounds are useful and versatile for a number of transform-
[12]
ations because of their redox and superacidic properties.
The molecular
structure of the Wells–Dawson (WD) heteropolyacid catalyst
.
H P W O 24H O) shows two identical “half units” of PW linked through
(
the oxygen atoms
6
2
18 62
2
13]
9
[
and consists of a close-packed framework of W(VI)–

3,4-Dihydropyrimidin-2(1H)-(thio)ones
3909
a
Table 1. Wells–Dawson acid-catalyzed preparation of dihydropyrimidinones
Procedure Procedure
A, yield
(%)
B, yield
(%)
1
R
2
Entry
4
R
X
b
1
2
3
4
5
6
7
8
9
a
b
c
C H
6
OEt
OEt
OEt
O
S
83
85
86 [78]
5
5
C
6
H
89
97 [56]
99
c
4-ClC
4-ClC H
6
H
4
O
O
O
O
O
O
O
O
O
O
O
O
O
S
85 (84, 82)
d
d
e
(CH ) CMe
2 2 2
91
98
77
93
77
92
96
91
98
95
40
99
99
38
6
4
2-HOC
3-HOC
6
H
H
4
4
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
Me
88
90
f
6
g
h
i
3-OMe-4-HOC H
6
91 [43]
76
85
3
2-Cl-6-FC H
6
3
4-(CH
3,4-OCH
1-Naphthyl
6-OCH -2-naphthyl
3
S)C
6
H
4
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
j
2
OC
6
H
3
84 [49]
89
97
k
l
3
m
n
o
p
q
Cinnamyl
n-Propyl
82
53 [15]
—
—
6 5
C H
3-HOC
Et
6
H
4
OEt
OEt
O
—
a
Reaction conditions: molar ratio 3:1:2 (2:2:3). Procedure A: heating at 808C with
% mmol WD catalyst for 1.5 h, under solvent-free conditions. Procedure B:
refluxing in acetonitrile for 8 h with 1% mmol WD catalyst.
1
b
In square brackets: yields for the classical Biginelli reaction conditions (catalysis by
[
5a,5b,9a]
HCl in refluxing ethanol for 18 h)
c
In parentheses: yields for the first and second reutilizations of the WD catalyst,
respectively.
d
C -chain from dimedone.
5
oxygen octahedra WO surrounding a central P(V) atom. Wells–Dawson acid
6
[13]
was prepared as described elsewhere
from an aqueous solution of a/b
K P W O 10H O salt, which was treated with ether and concentrated
.
6
2
18 62
2
(37%) HCl solution. Then the ether was eliminated from the addition
compound formed with the heteropolyacid. WD acid can be utilized both in
bulk or supported forms, and both homogeneous and heterogeneous catalyses
are possible.

3
910
G. P. Romanelli et al.
WD acid is useful and versatile for catalyzing a number of reactions.
[
14a]
Mention can be made of the epoxidation of alkenes and alkenols,
protec-
Michael alkylation
solvent-free preparation of cou-
and preparation of 1,3-dioxolane derivatives by the reaction of
[14b]
tion and deprotection of some functional groups,
[14c]
reaction of cyclohexanone with alcohols,
[
14d]
marins,
[14e]
epoxides with carbonyl compounds.
RESULTS
In this work, we report a simple and effective WD-catalyzed Biginelli reaction
that gives high yields of 3,4-dihydro-2(1H)pyrimidinones. We first carried out
the reaction in acetonitrile (procedure B) and then tried solvent-free con-
ditions, improving the results (procedure A). Reactions were optimized by
varying reaction temperature, reaction time, reagent molar ratio, and
solvent. The reaction was found to be nearly complete within 8 h in
refluxing acetonitrile or in 1.5 h when no solvent was used. A catalytic
amount of WD acid (1 mol%) is sufficient to perform the reaction. A series
of DHPMs and their thio-derivatives was obtained by applying both
procedures.
Results are summarized in Table 1. In all of the studied examples, the
reaction proceeded smoothly; aromatic aldehydes having either electron-with-
drawing or electron-releasing substituents, including hydroxyl, reacted effi-
ciently to give very good to excellent yields of the desired
dihydropyrimidinones. As an example, the reaction between 2-hydroxyben-
zaldehyde, ethyl acetoacetate, and urea in the presence of WD acid gave the
corresponding DHPM 4e in 98% yield (no solvent) and 88% (in solution)
(
see Table 1, entry 5). Butyraldehyde, which gives extremely poor yields in
the classical Biginelli reaction, yielded 53% of DHPM 4n in solution and
0% no solvent (Table 1, entry 14). In both 4n and 4q, the reaction time
4
doubled (both procedures) with and no substantial change of yield was
observed. Reutilization of the catalyst was investigated (Table 1, entry 3);
yields of 4c were comparable to that of the first use. Besides, the reaction
was performed using dimedone (see Fig. 1 and Table 1, entry 4), yielding
9
1% of 4d (solvent free) and 99% in acetonitrile solution. Some physical prop-
erties, analytical data, and NMR characterization of various selected DHPMs
are given. All the other products included in Table 1 were also characterized
4
1
13
by H NMR and C NMR and/or by comparison with authentic samples.
Figure 1. Formation of a dihydropyrimidinone.

3,4-Dihydropyrimidin-2(1H)-(thio)ones
3911
EXPERIMENTAL PROCEDURES
General Procedures
Commercially available aldehydes, b-ketoesters, urea, and thiourea (Aldrich
or Fluka) were distilled or recrystallized before use. Melting points of the
compounds were determined in open capillary tubes and are uncorrected.
1
13
H NMR and C NMR spectra (DMSO-d ) were recorded in Bruker
6
spectrometers at 250 or 400 MHz and 62 or 100 MHz, respectively,
using TMS as internal standard. Spectral data agree with the expected
values. The purity determination of the products was accomplished by high-
performance thin-layer chromatography (HPTLC) (silica-gel matrix),
compared with authentic samples prepared by known methods.
Catalyst Preparation
.
The Dawson acid (H P W O
6
24H O) was prepared by the Drechsel
2
2
18 62
[
13]
.
method
Dawson-type salt was prepared according to the technique reported by Lyon
from an a/b K P W O
10H O isomer mixture. This
6
2
18 62
2
[15]
et al.
aqueous solution of Na WO 2H O, and the mixture was kept boiling in a
Concentrated H PO in a 4:1 acid/salt ratio was added to a boiling
3 4
.
2
4
2
reflux system for 8 h. The salt was precipitated by adding KCl, then purified
by recrystallization and cooled overnight to 58C. The product, which is a
mixture of the a and b isomers, was filtered, washed, and then vacuum
dried for 8 h.
The acid was obtained from an aqueous solution of a/b K P W
18
6
2
.
O62 10H O salt, which was treated with ether and concentrated HCl (37%)
2
solution. The Dawson acid so released formed an addition compound with the
ether, which allows its separation from the solution. After obtaining the ether
solution with the acid, the ether was eliminated by flowing dry air, and the
remaining solution was placed in a vacuum desiccator until crystallization.
Typical Procedures for the Preparation of DHPMs: Representative
Procedures for 4-(4-Chlorophenyl)-5-ethoxycarbonyl-6-methyl-3,4-
dihydropyrimidin-2(1H)-one 4c
Procedure A
A mixture of ethyl acetoacetate (260 mg, 2 mmol), 4-chlorobenzaldehyde
.
281 mg, 2 mmol), urea (180 mg, 3 mmol), and P W O H 24H O
2 18 62 6 2
(
(
48 mg, 1% mmol) was thoroughly mixed, and the mixture was heated at
08C for 1.5 h (to completion of the reaction, checked by thin-layer chromato-
graphy, TLC). On cooling, the reaction mixture was washed with water
8

3
912
G. P. Romanelli et al.
(
3 ꢀ 4 mL), filtered, and dried under vacuum (508C). The crude product was
recrystallized from methanol or isopropanol (15 mL) to afford 4c (501 mg,
5% yield, mp 212–2138C). The procedure was followed for the preparation
8
of all compounds listed in Table 1.
Reusing of the catalyst: The reaction was carried out as stated previously;
then the reaction mixture was refluxed with dichloromethane (three times,
1
.5 mL each). The catalyst (insoluble) was dried under vacuum (208C) and
reused, repeating this procedure. Yields of the first and second reuse were
4 and 82%, respectively.
8
Procedure B
A solution of ethyl acetoacetate (260 mg, 2 mmol), 4-chlorobenzaldehyde
.
24H O
18 62 2
(
281 mg, 2 mmol), urea (180 mg, 3 mmol), and H P W O
6
2
(
48 mg, 1% mmol) in acetonitrile (5 mL) was heated under reflux for 8 h;
control of the reaction was made as in procedure A. On cooling to room temp-
erature, the product spontaneously crystallized from the solution. The suspen-
sion was concentrated; the solid was filtered and recrystallized from methanol
to afford 4c (571 mg, 97% yield). The procedure was followed for the prep-
aration of all compounds listed in Table 1. Melting points and spectral and
analytical data for representative products are given next.
Data
5
-Ethoxycarbonyl-6-methyl-4-phenyl-3,4-dihydropyrimidin-2(1H)-one, 4a.
1
[16a]
White crystals, mp 202–2048C (i-PrOH), lit.
202–2048C; H NMR: d
400 MHz) 9.22 (br s, 1H), 7.78 (br s, 1H), 7.41–7.22 (m, 5H), 5.17 (s, 1H),
(
1
3
4
.03 (q, J ¼ 6.5 Hz, 2H), 2.28 (s, 3H), 1.12 (t, J ¼ 6.5 Hz, 3H). C NMR:
d (100 MHz): 166.2, 153.0, 149.2, 145.7, 129.3, 128.1, 127.1, 100.1, 60.1,
54.8, 18.6, 14.9. Anal. calcd. for C H N O : C, 64.60; H, 6.20; N, 10.76.
Found: C, 64.41; H, 6.28; N, 10.71.
14 16 2 3
5
4
-Ethoxycarbonyl-6-methyl-4-phenyl-3,4-dihydropyrimidin-2(1H)-thione,
1
[16b]
b. White crystals, mp 206–2088C (MeOH), lit.
2038C; H NMR: d
(
200 MHz) 10.25 (br s, 1H), 9.60 (br s, 1H), 7.35–7.19 (m, 5H), 5.20 (d, 1H,
1
3
J ¼ 3.5), 4.03 (q, 2H, J ¼ 7 Hz), 2.25 (s, 3H), 1.10 (t, 3H, J ¼ 7 Hz). C
NMR: d (50 MHz): 172.5, 163.3, 145.0, 143.1, 126.7, 125.6, 124.6, 99.0, 58.1,
52.3, 15.5, 12.0.
4
-(4-Chlorophenyl)-5-ethoxycarbonyl-6-methyl-3,4-dihydropyrimidin-2
1
[16a]
(1H)-one, 4c. White crystals, mp 212–2138C (MeOH), lit.
NMR: d (250 MHz, acetone-d ): 9.24 (br s, 1H), 7.77 (br s, 1H), 7.37 (d, 2H,
212–2138C; H
6
J ¼ 8.5 Hz), 7.23 (d, 2H, J ¼ 8.5 Hz), 5.13 (d, 1H, J ¼ 2.8 Hz), 3.95 (q, 2H,
1
3
J ¼ 7 Hz), 2.24 (s, 3H), 1.08 (t, 3H, J ¼ 7 Hz). C NMR: d (62 MHz,

3,4-Dihydropyrimidin-2(1H)-(thio)ones
3913
acetone-d ): 165.1, 151.8, 148.5, 143.7, 131.7, 128.3, 128.1, 98.8, 59.2, 53.3,
6
17.7, 14.0. Anal. calcd. for C H Cl N O : C, 57.05; H, 5.13; N, 9.50.
14 15 2 3
Found: C, 57.01; H, 5.11; N 9.48.
5
-Ethoxycarbonyl-4-(3-hydroxyphenyl)-6-methyl-3,4-dihydropyrimidin-2
[16c]
(
1H)-one, 4f. White crystals, mp 164–1658C (MeOH), lit.
163–1658C;
H NMR: d (400 MHz) 9.37 (br s, 1H), 9.16 (s, 1H), 7.69 (s, 1H), 7.12–6.61
m, 4H), 5.07 (s, 1H), 3.99 (q, 2H, J ¼ 7 Hz), 2.24 (s, 3H), 1.12 (t, 3H,
1
(
1
3
J ¼ 7 Hz); C NMR: d (100 MHz) 166.2, 158.2, 153.1, 148.9, 147.1, 130.2,
17.7, 115.0, 113.9, 100.2, 60.1, 54.7, 18.6, 15.0. Anal. calcd. for
C H N O : C, 60.86; H, 5.84; N, 10.14. Found: C, 60.84; H, 5.81; N, 10.10.
1
1
4 16 2 4
5
-Ethoxycarbonyl-4-(4-hydroxy-3-methoxyphenyl)-6-methyl-3,4-dihydro-
[16d]
pyrimidin-2(1H)-one, 4g. White crystals, mp 235–2368C (EtOH), lit.
2
1
30–2328C; H NMR: d (400 MHz) 9.12 (br s, 1H), 8.91 (br s, 1H), 7.64 (br
s, 1H), 6.80 (d, 1H, J ¼ 1.9 Hz), 6.69 (d, 1H, J ¼ 8.1 Hz), 6.61 (dd, 1H,
J ¼ 8.1 Hz, J ¼ 1.9 Hz), 5.07 (d, 1H, J ¼ 3.1 Hz), 3.99 (q, 2H, J ¼ 7 Hz),
1
3
3
1
5
9
.73 (s, 3H), 2.24 (s, 3H), 1.12 (t, 3H, J ¼ 7.1 Hz). C NMR: d (100 MHz)
66.3, 153.1, 148.8, 148.1, 146.6, 136.8, 119.1, 116.1, 111.7, 100.4, 60.0,
6.4, 54.4, 18.6, 15.0. Anal. calcd. for C H N O : C, 58.82; H, 5.92; N,
1
5 18 2 5
.15. Found: C, 58.78; H, 5.89; N 9.11.
5
-Ethoxycarbonyl-6-methyl-4-styryl-3,4-dihydropyrimidin-2(1H)-one, 4m.
[16e]
1
White crystals, mp 232–2348C (i-PrOH), lit.
400 MHz) 9.13 (br s, 1H), 7.51 (br s, 1H), 7.48–7.23 (m, 5H), 6.36 (d, 1H,
J ¼ 15.8 Hz), 6.20 (dd, 1H, J ¼ 16 Hz, J ¼ 6 Hz), 4.72 (d, 1H, J ¼ 6 Hz), 4.11
232–2358C; H NMR: d
(
13
(
m, 2H), 2.20 (s, 3H), 1.15 (t, 3H, J ¼ 7 Hz); C NMR: d (100 MHz) 164.8,
1
52.3, 148.1, 136.2, 130.1, 128.8, 128.0, 127.5, 126.0, 97.8, 59.1, 51.7, 17.7, 14.4.
5
-Acetyl-6-methyl-4-phenyl-3,4-dihydropyrimidin-2(1H)-one, 4o. White
1
[16e]
crystals, mp 234–2368C (i-PrOH), lit.
233–2368C; H NMR: d
400 MHz) 9.18 (s, 1H), 7.79 (s, 1H), 7.35–7.20 (m, 5H), 5.25
(
1
3
(
d, J ¼ 2.8 Hz), 2.23 (s, 3H), 2.07 (s, 3H); C NMR: d (100 MHz) 194.6,
1
58.4, 152.0, 147.8, 136.7, 127.7, 113.8, 109.6, 55.2, 53.3, 30.16, 18.5.
CONCLUSIONS
The described procedure provides a useful one-pot alternative for the prep-
aration of dihydropyrimidinones 4 from aromatic aldehydes 1, ethyl acetoace-
tate 3, and urea or thiourea 2, without solvent and under catalysis by a small
.
amount of Wells–Dawson acid, H P W O
2
24H O. Yields are very good,
2
6
18 62
even for aromatic aldehydes substituted by electron-releasing groups; in
general, the reaction times using no solvent are shorter by a factor of 5 than

3
914
G. P. Romanelli et al.
those for the reactions in solution. Yields achieved in the absence of solvent
are often similar to those attained in acetonitrile solution. The main advan-
tages of this procedure are the operational simplicity, the use of a non
corrosive, reusable catalyst in mild, solvent-free reaction conditions, and the
very good yields attained. The use of an insoluble catalyst instead of
soluble inorganic acids contributes to the reduction of waste.
Further investigations about the use of the supported catalyst are in progress.
ACKNOWLEDGMENTS
Financial support from CONICET (Argentina), Fundaci o´ n Antorchas, and
Universidad Nacional de La Plata (Projects 11-X341 and 11-A135) is grate-
fully acknowledged. A. G. S. also thanks CONICET for a grant. G. P. R.,
G. B., and H. J. T. are members of CONICET.
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5, 249–255; (c) Shivarama Holla, B.; Sooryanarayana Rao, B.; Sarojini, B. K.;
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. Heys, L.; Moore, C. G.; Murphy, P. J. The guanidine metabolites of Ptilocaulis
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000, 29, 57–67.
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