Keggin and Dawson-type polyoxometalates as efficient catalysts for the synthesis of 3,4-dihydropyrimidinones: Experimental and theoretical studies

Article abstract of DOI:10.1016/j.tetlet.2016.02.077

3,4-Dihydropyrimidinones were synthesized by a multicomponent condensation of an aldehyde, a β-keto ester, and urea, in acetonitrile and ethanol using Keggin and Dawson type polyoxometalates as catalysts. Keggin heteropolyacid, H₄SiMO₁₂

Full text of DOI:10.1016/j.tetlet.2016.02.077

Accepted Manuscript
Keggin and Dawson-type polyoxometalates as efficient catalysts for the syn-
thesis of 3,4-dihydropyrimidinones: experimental and theoretical studies
Liza Saher, Malika Makhloufi-Chebli, Leila Dermeche, Baya Boutemeur-
Khedis, Cherifa Rabia, Artur M.S. Silva, Maamar Hamdi
PII:
S0040-4039(16)30186-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.02.077
TETL 47352
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
5 January 2016
16 February 2016
19 February 2016
Please cite this article as: Saher, L., Makhloufi-Chebli, M., Dermeche, L., Boutemeur-Khedis, B., Rabia, C., Silva,
A.M.S., Hamdi, M., Keggin and Dawson-type polyoxometalates as efficient catalysts for the synthesis of 3,4-
dihydropyrimidinones: experimental and theoretical studies, Tetrahedron Letters (2016), doi: http://dx.doi.org/
10.1016/j.tetlet.2016.02.077
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Keggin and Dawson-type polyoxometalates as efficient
catalysts for the synthesis of 3,4-dihydropyrimidin-
ones: experimental and theoretical studies
Liza Saher,a,b Malika Makhloufi-Chebli,a,b Leila Dermeche,a,c Baya Boutemeur-Khedis,b Cherifa Rabia,c Artur
M. S. Silvad,* and Maamar Hamdib,*
3,4-Dihydropyrimidinones were synthesized
by the Biginelli condensation using, using
Keggin and Dawson type polyoxometalates
as catalysts in acetonitrile and ethanol.
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Tetrahedron Letters
Keggin and Dawson-type polyoxometalates as efficient catalysts for the synthesis of
3,4-dihydropyrimidinones: experimental and theoretical studies
Liza Saher,a,b Malika Makhloufi-Chebli,a,b Leila Dermeche,a,c Baya Boutemeur-Khedis,b Cherifa Rabia,c
Artur M. S. Silvad,* and Maamar Hamdib,*
aDépartement de Chimie, Faculté des Sciences, Université Mouloud Mammeri, 15000, Tizi Ouzou, Algeria.
bLaboratoire de Chimie Organique Appliquée (Groupe Hétérocycles), Faculté de Chimie, Université des Sciences et de la Technologie Houari Boumediène,
BP32, El-Alia 16111 Bab-Ezzouar, Alger, Algeria.
cLaboratoire de Chimie du Gaz Naturel, Faculté de Chimie, Université des Sciences et de la Technologie Houari Boumediène, BP 32, El-Alia, 16111 Bab-
Ezzouar, Alger, Algeria.
dQOPNA, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
3,4-Dihydropyrimidinones were synthesized by a multicomponent condensation of an aldehyde,
a β-keto ester and urea, in acetonitrile and ethanol using Keggin and Dawson type
polyoxometalates as catalysts. Keggin heteropolyacid, H4SiMO12O40, is more efficient compared
to Keggin and Dawson salts and to the Biginelli classical reaction conditions. It leads to good
yields and short reaction times. Theoretical calculations let us to confirm the reaction
mechanism.
Available online
Keywords:
Biginelli reaction
2013 Elsevier Ltd. All rights reserved.
Dihydropyrimidinones
Polyoxometalates (POMs)
Multicomponent reactions (MCR)
Environmentally friendly processes
1. Introduction*
The original Biginelli protocol for the DHMPs preparation
consisted in heating a mixture of the three components (1 equiv
Multicomponent reactions (MCRs) are of great importance in
both organic and medicinal chemistry for various reasons.1 They
offer significant advantages compared to conventional synthesis.
Thus, MCR condensations involve three or more compounds that
react in a one-pot reaction to form a new product. The Biginelli
reaction is one of the most important multicomponent reactions
for the synthesis of dihydropyrimidinones, consisting in the acid-
catalyzed cyclocondensation reaction of an aldehyde, a β-keto
ester, and a urea (or thiourea).2
of an aldehyde 1, 1 equiv of a β-keto ester 2, and 1.5 equiv of
urea 3), in ethanol with a catalytic amount of HCl.2,4 This
procedure leads in one-pot reaction to the desired DHMPs, but in
low yields, particularly for substituted aromatic and aliphatic
aldehydes.7 This drawback led to modifications of the classical
Biginelli’s protocol in the development of multistep synthetic
strategies involving Lewis acids, e.g. BF3.OEt2, polyphosphate
esters, and reagents like InCl3, Mn(OAc)3, trimethylsilyltriflate,
LaCl3.7H2O, CeCl3.7H2O, LiClO4, Yb(OTf)3, ZrCl4 or ZrOCl2
clays, among others.8,10-24 However, many of these methods use
longer reaction times, strong acidic conditions, and
stoichiometric amounts of catalysts, and in addition are difficult
to handle especially on a large scale.
Over the past decade, dihydropyrimidin-2(1H)-ones (DHPMs)
and derivatives have attracted considerable attention in organic
and medicinal chemistry because of their pharmacological and
therapeutic properties.3 Certain derivatives have emerged due to
their potential antiviral, antitumor, antibacterial and anti-
inflammatory activities.3-5 More recently, functionalized DHPMs
The Keggin-type polyoxometalates are believed to have
extensive prospects of application in synthetic chemistry. Their
acidic and oxidizing properties are dependent of the composition
and nature of components and can be modified according to the
reaction needs. Moreover, they are easily to handle, non-volatile
and non-explosive. Heteropolyacids (HPA) have been
extensively studied as acid catalysts for many reactions in our
laboratory,25-27 and have also found industrial applications in
several processes.28 Herein we will report on the synthesis of
DHPMs by the Biginelli reaction, in the presence of an acid
are
considered
potent
calcium
channel
blockers,6
antihypertensive agents,7 α-1a adrenergic antagonists8 and
neuropeptide Y (NPY) antagonists.9
———
* Corresponding author. Tel.: +351 234370714 / +21 321 508 581;
fax: +351 234370084. Email address: artur.silva@ua.pt (A.M.S.
Silva) prhamdi@gmail.com (M. Hamdi).

In order to evaluate the effect of the catalyst the synthesis of
3,4-dihydropyrimidin-2(1H)-ones 4a-j was also performed with
H3PMo12O40. In this case the highest yields were obtained in
MeCN and using electron-withdrawing 4i,j and electron-donating
4d,e substituents (Table 2, entries 4, 5, 9 and 10). However, these
results were lower than those obtained with H4SiMo12O40. The
difference in the obtained yields are more pronounced (up to
10%) in the case of other substituents, showing that H4SiMo12O40
is more active than H3PMo12O40 (Table 2). This catalytic
behaviour could be explained by the number of protons existing
in SiMo12O40 (4H+) that is greater than that of PMo12O40 (3H+)
and not by the acidity strength. In the Keggin-type
heteropolyacid, all protons are equivalent and have the same
strength unlike conventional acids (H2SO4, H3PO4).
catalyst of Keggin-type (H4SiMo12O40) and of Dawson-type (α-
K6P2W18O62, β-(NH4)6P2W18O62, K6P2W12Mo6O62) and in the
presence of
(H3PMo12040,
a
series of Keggin-type phosphomolybdates
H4PMo11VO40, K3HPMo11VO40 and
(NH4)3PMo12O40).
2. Results and discussion
Biginelli protocol was carried out using two solvents EtOH
(polar protic) and MeCN (polar aprotic) and HPA catalysts under
reflux conditions (Scheme 1). The condensation of methyl/ethyl
acetoacetate, benzaldehyde and urea in refluxing ethanol (or
acetonitrile), for 1.5 h in the presence of H4SiMo12O40 catalyst (5
mol %), yielded various 3,4-dihydropyrimidin-2(1H)-ones 4a-j in
moderate to good yield (52-82%) (Table 1). Higher yields were
obtained in the case of using aldehydes with electron-
withdrawing 4i,j and electron-donating 4d,e substituents (Entries
4, 5, 9 and 10) and also using acetonitrile as the solvent. These
results show that this method using H4SiMo12O40 as the catalyst is
effective and permit an improvement in the classical Biginelli’s
methodology.
Table 2. Synthesis of DHPMs 4a-j using H3PMo12O40 (5 mol%) as
catalyst, under refluxing ethanol or MeCN.
Yield (%)
Entry
Product
EtOH
51
MeCN
61
1
2
4a
4b
4c
4d
4e
4f
61
65
3
62
66
4
75
77
5
70
72
6
58
59
7
4g
4h
4i
62
68
8
61
68
9
77
78
10
4j
67
70
Scheme 1. Synthesis of various substituted 3,4-dihydropyrimidin-
2(1H)-ones using heteropolyacid catalyst, using refluxing EtOH or
CH3CN.
All the aforementioned reactions delivered excellent product
yields and accommodated a wide range of aromatic aldehydes
bearing both, electron-donating and electron-withdrawing
substituents. Substrates with electron-withdrawing groups gave
relatively higher yields (Table 1 and 2), and this fact was
confirmed by theoretical calculations using the PM6 semi-
empirical Hamiltonian method,29 which proved to give useful
evidence for the yields by estimating the Mulliken charges. The
results show that the aldehyde carbon (CHO) is more positive in
both solvents when the substituent is an electron-withdrawing
group (Table 3). Hence the ranking of increasing reactivity of
the aldehyde carbonyl group are as follows: Ph < 4-ClPh < 4-
OHPh < 4-OCH3Ph) < 4-NO2Ph. Therefore the obtained yields
have varied in the same direction.
Table 1. Synthesis of 3,4-dihydropyrimidin-2(1H)-ones 4a-j
(structural characterisation at SI) using H4SiMo12O40 (5 mol%)
heteropolyacid as catalyst, under refluxing ethanol or MeCN.
Compound
(solvent)
Yield
(%)
Mp (°C)
(Mp)Lit
Entry
Ar
R
4a (EtOH)
(MeCN)
52
64
70
76
73
77
78
80
74
76
60
65
63
70
65
68
79
82
69
75
207-209
(209-211)32
238-240
1
2
C6H5
OMe
OMe
OMe
OMe
OMe
OEt
4b (EtOH)
(MeCN)
4-OHC6H4
4-ClC6H5
-
4c (EtOH)
(MeCN)
201-203
(204-207)32
Table 3: Carbon Mulliken charge of the aldehyde group in the two
different solvents.
3
4d (EtOH)
(MeCN)
233-236
4
4-NO2C6H4
4-OCH3C6H3
C6H5
(236-238)32
194-195
(192-194)32
Aldehyde
Substituent
R
Charge of CHO
MeCN
EtOH
4e (EtOH)
(MeCN)
5
4-NO2PhCHO
PhCHO
4-NO2
H
0.192
-0.039
-0.019
0.192
-0.039
-0.019
4f (EtOH)
(MeCN)
203-205
6
(202-204)30
225-228
(228-230)31
4-ClPhCHO
4-Cl
4g (EtOH)
(MeCN)
4-OHPhCHO
4-OH
0.041
0.095
0.041
0.095
7
4-OHC6H4
4-ClC6H5
OEt
4-OCH3PhCHO
4-OCH3
4h (EtOH)
(MeCN)
210-212
8
OEt
(209-211)31
207-209
(209-212)31
In order to evaluate the effect of other catalysts the synthesis
of 4i was also carried out in MeCN under the same conditions in
the presence of K3HPMo11VO40, H4PMo11VO40 and
(NH4)3PMo12O40 (5mol %) (Table 4). The results evidenced the
efficiency (82%) of the H4SiMo12O40 catalyst compared to the
4i (EtOH)
(MeCN)
9
4-NO2C6H4
4-OCH3C6H3
OEt
4j (EtOH)
(MeCN)
200-202
(199-202)31
10
OEt
a
b
phosphomolybdate-based
catalysts
H3PMo12O40
and
Isolated yields.
All the compounds are known and were
H4PMo11VO40 (78 and 56%, respectively). K3HPMo11VO40 and
(NH4)3PMo12O40 salts were found inactive toward 4i formation.
These results show that the synthesis of DHPM 4i requires a
strong medium acidity.
characterized by NMR and IR spectroscopy and mass spectrometry.

Table 4. Synthesis of 4i as function of POM composition.
empirical Hamiltonian method to identify the entities that react
first and deduced the most likely intermediate (Figure 1 reports
the charges of each atom that participate in the reaction).
Catalyst (5%mol)
H3PMo12O40
Yield %
78
H4SiMo12O40
82
Table 7. Synthesis of 4i (yield, %) using Dawson type POMs α-
K6P2W18O62, β-(NH4)6P2W18O62, K6P2W12Mo6O62 as catalysts.
H4PMo11VO40
K3HPMo11VO40
(NH4)3PMo12O40
56
< 10
Traces
Catalyst
5%mol
20
8%mol
30
α-K6P2W18O62
β-(NH4)6P2W18O62
K6P2W12Mo6O62
35
60
We have also evaluated the effect of the catalyst amount (2-8
mol %) on the synthesis of DHPMs 4a (EtOH) and 4j (MeCN)
using H4SiMo12O40 and H3PMo12O40 (Table 5). In the presence of
H4SiMo12O40, the yields of 4a and 4j increase from 18 to 74%
and from 25 to 78% respectively, with the increase of catalyst
from 2 to 8 mol%, unlike to H3PMo12O40 where the highest yields
towards 4a (51%) and 4j (70%) were obtained with an amount of
5 mol% and decreases with an amount of 8 mol%, which is
probably due to the oxidizing power of H3PMo12O40 that is higher
than that of H4SiMo12O40.
17
27
In our previous work,46 we have shown that β-diketones can
exist in a tautomeric equilibrium, being the diketo form more
stable in polar solvents against the keto-enol form that is more
stable in non-polar solvents. Here we have chosen two polar
solvents, being one protic (EtOH) and the other aprotic (MeCN).
The protic solvent can replace the hydrogen of the enol function
by a hydrogen bond with the β-diketone which can give the keto
enol form, unlike in acetonitrile diketone form is more abundant.
Table 5. Effect of the amount of catalysts on the synthesis of
DHPMs 4a (EtOH) and 4j (MeCN).
The calculations of the atom loads of each reagent in both
solvents show firstly that the urea nitrogen atoms do not change
much in both EtOH and MeCN solvents, being slightly more
negative in MeCN than in EtOH, and that the carbon of ethyl
acetoacetate of the diketo form is more positive than in the keto-
enol form in both solvents which increases the reactivity and the
yield in MeCN (Figure 1).
Yields (%) at
2%mol
Yields (%) at
5%mo
Yields (%) at
8%mol
H3PMo
H4SiMo
H3PMo
H4SiMo
H3PMo
H4SiMo
12O40
12O40
12O40
12O40
12O40
12O40
4a
EtOH
4j
12
18
51
52
24
74
21
25
70
75
50
78
MeCN
The influence of stoichiometric amounts of the reactants on
the synthesis of 4j was also examined; being the reaction carried
in reflux MeCN and using H3PMo12O40 as the catalyst (5 mol%)
(Table 6). An excess of ethyl acetoacetate (EtAcOAc) does not
affect the yield, while an aldehyde excess increases the yield of
4j in 12%.
Figure 1. Charges of urea and ethyl acetoacetate in ethanol and
acetonitrile using the Gaussion calculations.
Table 6. Effect of the reagents amount on the yields of DHPM 4j.
On the other hand, the ketone carbon of ethyl acetoacetate in
the diketo form is more positive (Figure 1) than the carbon of the
aldehyde function in both solvents (Table 2), suggesting that the
reactivity of urea 3 with methyl/ethyl acetoacetate 2 is the first
step of the reaction, then intermediate 5 reacts with the aldehydes
Reagents amounts
1 mmol 4-OCH3C6H4CHO + 1 mmol EtAcOAc + 1.5
mmol urea
Yield (%)
70
1 mmol 4-OCH3C6H4CHO + 1.5 mmol EtAcOAc + 1.5
mmol urea
69
82
1
to give 3,4-dihydropyrimidinones 4a-j, confirming the
mechanism proposed by Cepanec41 and Litvic,45 thus opposing to
1.5 mmol 4-OCH3C6H4CHO + 1 mmol EtAcOAc + 1.5
mmol urea
that proposed by Folkers and Johnson33 and Kappe.38
The
catalytic
effect
of
tungsten-based
Dawson
polyoxometalates
(α-K6P2W18O62,
β-(NH4)6P2W18O62,
K6P2W12Mo6O62), on the synthesis of 4j in refluxing MeCN for
1.5 h [4-nitrobenzaldehyde (1.5 mmol), ethyl acetoacetate (1
mmol) and urea (1.5 mmol)] was also studied (Table 7). The
experimental results show that α-K6P2W18O62, β-(NH4)6P2W18O62
and K6P2W12Mo6O62 are much less efficient compared to Keggin
POMs. We found that the yields are too low because the
Dawson-type salts does not present the required Bronsted acidity
[such as the case of (NH4)3PMo12O40], which plays a major role
in this type of reaction as opposed to its presence in Keggin-type
catalysts giving them a greater advantage.
The mechanism of this reaction was studied by several
researchers,33-45 and each of them gave arguments for the
formation of an intermediate from which DHPMs are formed. In
order to explain the formation of the DHPMs, we have calculated
the charges of the electrophilic and nucleophilic sites of the
reagents via theoretical calculations using the PM6 semi-
Scheme 2. Proposed mechanism for the synthesis of 3,4-
dihydropyrimidin-2(1H)-ones 4a-j using heteropolyacids as
catalysts.

3. Conclusion
Supplementary Material
Keggin-type polyoxometalates (phospho and silicomolybdic
based HPAs) in an amount of 5 mol% have shown to be excellent
acid catalysts for the one-pot synthesis of 3,4-
dihydropyrimidinones in good yields, using an excess of
aldehyde. The theoretical calculations have confirmed the
mechanism of the reaction including the formation of the so
called ‘ureido-crotonate’. Tungsten-based Dawson POMs α-
K6P2W18O62, β-K6P2W18O62 and K6P2W12Mo6O62, in an amount of
5-8 mol% are less acidic and give lower yields than the Keggin-
type POMs.
Experimental procedures and structural characterization of
3,4-dihydropyrimidin-2(1H)-ones 4a-4j.
References and notes
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4.1. Materials and Method
Melting points were determined on a Stuart scientific SPM3
apparatus fitted with a microscope and are uncorrected. H and
1
13C NMR spectra were recorded in DMSO-d6 solutions on Bruker
Avance 300 (300.13 MHz for 1H and 75.47 MHz for 13C)
spectrometer. Chemical shifts are reported in ppm (δ) using TMS
as internal reference and coupling constants (J) are given in Hz.
13C assignments were made using NOESY, HSQC, and HMBC
(delays for one bond and long-range JC/H couplings were
optimized for 145 and 7 Hz, respectively) experiments. Mass
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nebulizer gas and argon as the collision gas. The needle voltage
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heteropolyacids
H3PMo12O40,
H4PMo11VO40 and H4SiMo12O40 were prepared according to the
classic methods [47-49]. (NH4)3PMo12O40 was precipitated at pH
<
1
as described by Cavani et al.50 K6P2W18O62 and
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[H2P2W12O56]12- according to the method described by Contant et
al.52
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washed with water and the resulting solid was treated with hot
ethanol and filtered again. The filtrate was concentrated to afford
the recrystallized product. The products were characterized by
1
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Highlights
- 3,4-Dihydropyrimidinones were synthesized by a
multicomponent condensation reaction
- Keggin-type polyoxometalates (5 mol%) were
excellent acid catalysts for synthesis
- The semi-empirical theoretical calculations have
confirmed the reaction mechanism