Simple and ecofriendly synthesis of dihydropyrimidinones (thiones), dihydropyridines, and pyridines using 3-formylchromones as substrates assisted by a recyclable Preyssler heteropolyacid

Article abstract of DOI:10.1002/hc.21340

Several dihydropyrimidinones/thiones, 1,4-dihydropyridines, and pyridine derivatives were prepared in very good yields and purity values. The corresponding reactions were carried out by employing a bulk Preyssler heteropolyacid H₁₄[NaP₅

Full text of DOI:10.1002/hc.21340

Received: 15 February 2016
DOI: 10.1002/hc.21340
Revised: 19 July 2016
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R E S E A R C H A R T I C L E
Simple and ecofriendly synthesis of dihydropyrimidinones
(thiones), dihydropyridines, and pyridines using
3-formylchromones as substrates assisted by a recyclable
Preyssler heteropolyacid
Laura M. Sanchez1
Gustavo Pasquale2
Ángel Sathicq1
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Diego Ruiz2
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Jorge Jios3
Andrea L. Ferreira de Souza4
Gustavo P. Romanelli1
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1Departamento de Química, Facultad de
Ciencias Exactas, Centro de Investigación y
Desarrollo en Ciencias Aplicadas ‘Dr. J. J.
Ronco’ (CINDECA), UNLP-CCT- La Plata-
CONICET, La Plata, Argentina
2Cátedra de Química Orgánica, Facultad de
Ciencias Agrarias y Forestales, Universidad
Nacional de La Plata, La Plata, Argentina
3LaSeISiC, Departamento de Química, Facultad
de Ciencias Exactas, UNLP-CICPBA, La Plata,
Argentina
4Universidade Federal do Rio de Janeiro,
Macaé, Brazil
Abstract
Several dihydropyrimidinones/thiones, 1,4-dihydropyridines, and pyridine deriva-
tives were prepared in very good yields and purity values. The corresponding reac-
tions were carried out by employing
a bulk Preyssler heteropolyacid
H14[NaP5W29MoO110] as an efficient and recyclable catalyst. The preparation of
pyridine derivatives was carried out not through a usual procedure, i.e., the opening
of the γ-pyrone ring of 3-formylchromone. In general, reactions took place in solvent-
free conditions at 80°C during short reaction times.
Correspondence
Laura M. Sanchez and Gustavo P. Romanelli,
Departamento de Química, Facultad de Ciencias
Exactas, Centro de Investigación y Desarrollo
en Ciencias Aplicadas ‘Dr. J. J. Ronco’
(CINDECA), UNLP-CCT- La Plata-CONICET,
La Plata, Argentina.
Emails: lsanchez@mdp.edu.ar;
gpr@quimica.unlp.edu.ar
heteropolycompounds. Heteropolycompounds are effective,
reusable, and stable solid catalysts that have intrinsic multi-
1.
INTRODUCTION
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functionality; they can be designed in order to enhance their
redox or superacidic properties by varying the atoms pres-
ent in their formula.[1–3] Among the heteropolycompounds
is the Preyssler heteropolyanion, which consists of a cy-
clic assembly of five PW6O22 units, each derived from the
Keggin anion [PW12O40]3− by the removal of two sets of
three corner-sharing WO6 octahedra.[4] This material could
be considered as a green catalyst with respect to safety,
noncorrosive properties, quantity of waste separability,
and stability.[5] It was used in several organic transforma-
tions, such as the synthesis of isoxazoles,[6] coumarins,[7]
2,4,6-triarylpyridines,[8] 2-amino-4H-chromenes,[9] and
1,5-benzodiazepine,[10] in the esterification of n-butanol with
acetic acid,[11] in the alkylation of phenol with 1-octene,[12]
The chemist’s attention is focused not only on achiev-
ing an efficient and specific product preparation but also
on the process for compound preparation in order to min-
imize the environmental problems mainly associated with
both the handling of potentially dangerous substances and
the disposal of the generated waste. In this sense, one pos-
sible strategy consists in replacing the mineral acids tra-
ditionally used as catalysts in stoichiometric quantities by
Contract grant sponsor: Universidad Nacional de La Plata (UNLP),
CONICET.
Contract grant number: PIP 003.
Contract grant sponsor: ANPCyT.
Contract grant number: PICT 0409.
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Heteroatom Chemistry 2016; 1–11
wileyonlinelibrary.com/journal/hc
© 2016 Wiley Periodicals, Inc.
1

2
Sanchez et al.
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and in oxidation reactions, such as alcohols,[13] primary ar-
omatic amines,[14] and thiols using air as an oxidant,[15] and
also in alkene epoxidation.[16]
carbonyl group at C3 and, above all, a very reactive elec-
trophilic center at C2;[37] second, they possess reactivity
toward nucleophiles, such as hydrazine, phenylhydrazine,
amidines, and aminopyrazoles;[38–41] and third, the deriva-
tives of chromones are important natural products possess-
ing a wide range of valuable physiological activities.[42]
In addition, 3-formylchromones represent useful synthetic
building blocks in organic and medicinal chemistry.[43] As
a result, it was observed that 3-formylchromones showed
an alternative direction of the Hantzsch condensation reac-
tion. A functionalized pyridine in the 2-, 3-, and 5-positions
was formed by opening the γ-pyrone ring after nucleo-
philic attack and subsequent cyclodehydration.[36] The
tendency to opening of the pyrone ring is well known[44]
and was also observed in 3-formylchromones and in sub-
stituted 3-formylchromones when amines or C-nucleophilic
anilines were used as nucleophiles.[45–47] Ammonium and
primary amines also act as nucleophiles on other closely
related activated chromones. 2-Methylchromones[48] and
2-trifluoromethylchromones[49] afford aminoenones by at-
tack at the C2 position.
In the above-mentioned previous work, the desired
1,4-DHP was finally prepared through a multistep proce-
dure. Inspired on the mechanism for 1,4-DHPs formation
suggested by Shen et al.,[50] we separately synthesized
2-acetyl-3-(3-chromonyl)acrylic acid ethyl ester as the α,β-
unsaturatedcarbonylcompoundandmethyl3-aminocrotonate
as enamine. These two reactants were stirred at 80°C for
30 min in the presence of 1 mmol % of a Wells–Dawson
heteropolyacid. The course of the reaction was monitored
by TLC, yielding the corresponding 1,4-dihydropyridine
86%.[36]
The synthesis of heterocyclic compounds is an area of
interest in the search for new drugs because of their wide
spectrum of significant biological activity. Among these
compounds, it is possible to cite dihydropyrimidinones
(DHPMs)/thiones, 1,4-dihydropyridines (1,4-DHPs), and
pyridines. DHPMs are commonly known as Biginelli com-
pounds, and they are medicinally important as antibacterial,
antitumor, antiviral, and anti-inflammatory agents.[17–20]
More recently, these compounds have emerged as poten-
tial calcium channel blockers, antihypertensives, α1a-
adrenergic antagonists, and neuropeptide antagonists.[21] In
addition, the 2-oxodihydropyrimidine-5-carboxylate core
unit is found in nature and in potent HIV gp-120-CD4 in-
hibitors.[22–24] However, 1,4-DHPs also have significant
biological applications since they can function as neuropro-
tectants, antianginal,[25–27] analgesic,[28] antitubercular,[29]
antithrombotic,[30,31] and anti-inflammatory agents,[32,33]
among many other applications. Regarding pyridines, they
are present in the important niacin and B6 vitamins, and also
in highly toxic alkaloids, such as nicotine.[34] They are im-
portant as anti-inflammatory, antiasthmatic,[31] antidepres-
sant,[34] antitubercular, and antibacterial agents.[30] There
also are examples of pyridines that act as potent HIV prote-
ase inhibitors.[35]
Pyridine derivatives are mostly prepared through one of
the following two procedures: by an oxidation reaction or
through a condensation-type reaction. In the case of DHPMs/
thiones and 1,4-DHPs, traditional methods for their prepa-
ration include the use of a multicomponent reaction that re-
quires the use of an aldehyde, a 1,3-dicarbonyl compound,
and urea/thiourea or ammonia, respectively, as starting
materials.
In previous work, we introduced the use of 3-formyl
chromones as a starting aldehyde in the Hantzsch reaction,
replacing the traditionally used benzaldehyde derivatives,
in order to give a new perspective to this reaction.[36]
3-Formylchromones were selected due to several reasons:
first, they represent a very reactive system owing to the pres-
ence of an unsaturated keto function, a conjugated second
Herein, we report the preparation of DHPMs/thiones
and 1,4-DHPs derivatives using a bulk Preyssler het-
eropolyacid (HPA) as catalyst through multicomponent
solvent-free and multistep reactions, respectively. We
also report a nontypical method for preparation of pyr-
idines, i.e., through the opening of the γ-pyrone ring of
3-formylchromone working with the above-mentioned
catalyst and under similar reaction conditions. The three
above-mentioned synthetic procedures are shown in
Schemes 1–3.
R
O
2
O
O
O
O
X
O
O
HPA 0.5 mmol %
+
+
R1
NH
H2N
NH2
R
H
C O
R1
R
O
2
R
Solvent-free
80 °C, 90 min
HN
O
=
X
X
R = -H -CH
R1 = -CH3, -Ph
R2 = -CH3, -CH2CH3
O S
,
,
,
3
SCHEME 1 General outcome of solvent-free Biginelli-like condensation reaction with 3-formylchromone as starting aldehyde

Sanchez et al.
3
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R
H
-
O
O
3C
O
O
O
NH2
O
HPA 0.5 mmol %
+
O
O
C
H
3C
R
O
1
Solvent-free
80 °C, 30 min
R
O
O
H
R
1
R
1O
OR1
= -
-
C
R
H
H
l
C
,
,
H
3C
N
H
H
3
3
= -
-
R1
H
H
C
H
3
C
2C
,
3
SCHEME 2 General outcome of the final step in the multistep solvent-free 1,4-dihydropyridines synthesis
H
O
O
O
O
O
O
HPA 0.5 mmol %
R
O
2
+
+
AcONH4
R
H
C O
R1
R
O
Solvent-free
80 °C, 30 min
2
N
R1
O
R
= -
-
H
C
-
l
C
= -
= -
-
Ph
R
H
,
R1
R2
H
H
C
,
,
,
3
3
-
H
C
H
2C
3
C
3
SCHEME 3 General outcome of solvent-free substituted pyridine synthesis using 3-formylchromone as a substrate
obtained (Table 1, entry 1). When the catalyst amount was
increased from 0.25 to 0.5 mmol %, the product yield also
increased, but no significant change was observed by em-
ploying 2 mmol % of HPA (Table 1, entries 2–4). If the
reaction temperature increases or decreases from 80°C,
product yields are lower (Table 1, entries 5 and 6). Since
the use of reaction times of 60 and 120 min did not give
better results (Table 1, entries 7 and 8), the optimal reaction
conditions were established as 80°C, 0.5 mmol % of HPA
for 90 min (Table 1, entry 3). It was demonstrated that after
three catalytic cycles the catalytic material maintained its
activity (Table 1, entries 9 and 10).
By employing the optimal reaction conditions and vary-
ing the starting materials, six different dihydropyrimidinones
(thiones) were prepared (Table 2). In all cases, the desired
product was obtained with high selectivity, achieving product
yields greater than 80%.
In order to quantify the sustainability of the methodology,
the atomic economy (AE), atomic efficiency factor (E), process
mass intensity (PMI), and EcoScale were calculated for each
reaction product, and the results are also presented in Table 2.
The resulting parameters indicate an improvement in the syn-
thetic method from a green chemistry point of view, with bet-
ter yield, AE, environmental factor, PMI, and EcoScale factors
than those obtained by traditional synthetic procedures.
2.
RESULTS AND DISCUSSION
Preparation of dihydropyrimidinones
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2.1.
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(thiones)
Several catalytic tests were conducted in order to deter-
mine the optimal reaction conditions. 3-Formylchromone,
methyl acetoacetate, and urea were employed as starting
materials. Temperature was varied between 60 and 100°C,
while catalyst amounts, from 0 to 2 mmol %. After 120 min
of working at 80°C without catalyst, a very low yield was
TABLE 1 HPA-catalyzed multicomponent synthesis of
dihydropyrimidinones by reaction between 3-formylchromone, methyl
acetoacetate and urea
Temperature
(°C)
Catalyst
amount (%)
Entry
1a
Time (min)
Yields (%)
80
80
120
90
–
15
80
88
87
78
75
82
87
87
86
2
0.25
0.5
2
3
80
90
4
80
90
5
100
60
90
0.5
0.5
0.5
0.5
0.5
0.5
6
90
7
80
60
8
80
120
90
9b
10c
80
80
90
2.2.
Preparation of 1,4-dihydropyridines
|
aReaction without catalyst. bFirst and csecond reuse, respectively.
Optimum reaction conditions for this preparation were de-
termined by carrying out a series of catalytic tests. With this
The bold values correspond to the obtained yield under the optimal reaction con-
ditions for each presented reaction.

4
Sanchez et al.
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TABLE 2 HPA-catalyzed synthesis of 3,4-dihydropyrimidin-2-(1H)-ones/thiones containing 3-formylchromone moietya
Eco
scale
Comp.
3-formylchromone
Dihydropyrimidinones (thiones)
Yield (%)
AE (%)
E factor
PMI
1
88
100
13.69
16.45
91
88
7
O
O
O
O
O
O
HN
O
O
CHO
NH
O
O
O
2
3
82
80
100
100
14.06
12.67
16.94
15.45
HN
NH
S
O
O
O
O
HN
NH
O
4
89
100
12.99
15.65
1.5
O
O
O
O
O
O
H
3C
CHO
H
3C
HN
NH
O
5
6
85
81
100
100
13.02
12.09
15.73
14.76
89.5
87.5
O
O
O
O
O
H
3C
CHO
O
H
3C
HN
NH
S
O
O
O
O
H
3C
HN
NH
O
aReaction conditions: HPA (0.5 mmol %), 3-formylchromone (1 mmol), 1,3-dicarbonylcompounds (1 mmol), and urea or thiourea (1.5 mmol). The mixture was stirred
at 80°C for 90 min.
purpose, 2-acetyl-3(-chromonyl)-acrylic acid methyl ester
and 3-amino-2-butenoic acid methyl ester (previously pre-
pared) were employed as reactants. After 30 min of reaction
at 80°C without catalyst, a poor product yield was obtained
(Table 3, entry 1). Then, the catalyst amount was varied from
0.25 to 2 mmol % of HPA: the results showed that yields in-
creased when the catalytic material amount increased from
0.25 to 0.5 mmol %, but no difference was observed when
2 mmol % of HPA was employed (Table 3, entries 2–4).
The effect of reaction temperature was also evaluated when
the reaction temperature increased to 100°C or decreased to
60°C, the product yield was lower (Table 3, entries 5 and 6).
As the use of shorter and longer reaction times did not give
better results (Table 3, entries 7 and 8), the optimal reaction

Sanchez et al.
5
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TABLE 3 HPA-catalyzed synthesis of 1,4-dihydropyridines by
reaction between 3-2-acetyl-3(-chromonyl)-acrylic acid methyl ester and
3-amino-2-butenoic acid methyl ester
Pathway B: The carbonyl group that comes from 3-formyl-
chromone is activated by the HPA, and a nucleophilic
attack to the 2-position of the γ-pyrone ring takes place,
producing its opening to give V.
Temperature
(°C)
Catalyst
amount (%)
Entry
Time (min)
Yields (%)
1a
80
80
80
80
100
60
80
80
80
80
30
30
30
30
30
30
15
60
30
30
–
35
83
87
87
59
50
82
85
87
87
In the case of intermediate IV, it not only produces the 1,4-
DHP but could also form the corresponding pyridine derivative.
The difference is due to the taken pathway: A1 or A2. Then,
V could only give the pyridine derivative after cyclization and
dehydration reactions.
2
0.25
0.5
2
3
4
5
0.5
0.5
0.5
0.5
0.5
0.5
6
Pathway A1: The carbonyl group that comes from the
1,3-dicarbonylic compound is activated by the HPA
to react with the intermediate of structure IV. The
subsequent dehydration and cyclization produces the
1,4-DHP.
Pathway A2: Intermediate IV undergoes cyclization and de-
hydration to give the pyridine derivative functionalized in
2, 3, and 5 positions.
7
8
9b
10c
aReaction without catalyst. bFirst and csecond reuse, respectively.
The bold values correspond to the obtained yield under the optimal reaction con-
ditions for each presented reaction.
conditions were established as 30 min at 80°C with 0.5 mmol
% of HPA (Table 3, entry 3). It was seen that the catalytic
material did not lose its activity after three catalytic cycles
(Table 3, entries 9 and 10).
Five different 1,4-DHP derivatives (Table 4) were effi-
ciently prepared using the optimal reaction conditions. Product
yields were equal to or greater than 80%. In order to quantify
the sustainability grade of the proposed methodology, the AE,
E, PMI, and EcoScale were calculated for each reaction prod-
uct and the results are also presented in Table 4. The resulting
parameters indicate an improvement in the synthetic proce-
dure from a green chemistry point of view, with better yield,
AE, environmental factor, PMI, and EcoScale factors than
those obtained by traditional synthetic procedures.
1,4-Dihydropyridines must be prepared through this mul-
tistep reaction instead of using a multicomponent reaction
if 3-formylchromones are employed as reactants, in order to
minimize the formation of the corresponding pyridine deriv-
ative by γ-pyrone ring opening.[36] When the multicompo-
nent reaction takes place, a competitive mechanism appears
(Scheme 4).
First, 3-formylchromone I is activated by the HPA and reacts
withthe1,3-dicarbonyliccompoundinaKnoevenagelcondensa-
tion. After a dehydration step, a 2-acetyl-3(-chromonyl)-acrylic
acid alkyl ester II is obtained (Scheme 4). Then, two different
carbonyl groups of II could be activated by the HPA, giving
two possible reaction pathways A and B.
From this, it can be said that intermediates IV and V are
key structures in the mechanisms competition. Structure V
could be more stable due to a more intense conjugation effect
and, furthermore, from V it could be possible to prepare the
pyridine derivative by simple intramolecular cyclization (with
high probability of occurrence) without the need of an addi-
tional condensation step, as occurs with 1,4-DHP formation
from intermediate IV. As can be seen, pyridine formation is
much more favored than 1,4-DHP formation if this prepara-
tion strategy is employed.
However, when a multistep reaction is applied to pre-
pare 1,4-DHPs, the possible reaction mechanism changes
(Scheme 5). In its last step, 2-acetyl-3(-chromonyl)-acrylic
acid alkyl diester II reacts with 3-amino-2-butenoic acid
alkyl ester through Michael condensation to give, after cy-
clization and dehydration, the corresponding 1,4-DHP deriv-
ative, avoiding the above-mentioned side reactions.
2.3.
Preparation of substituted pyridines
|
In order to find a convenient method for pyridine
synthesis, several catalytic tests were carried out.
3-Formylchromone, methyl acetoacetate, and ammonium
acetate were used as starting materials. Temperature
varied from 60 to 100°C, while the catalyst amount was
established between 0 and 2 mmol %. After 30 min of
working at 80°C without catalyst, a 39% product yield
was obtained (Table 5, entry 1). When the catalyst amount
was increased from 0.25 to 0.5 mmol %, the product yield
increased slightly, but no change was observed by em-
ploying 2 mmol % of HPA with respect to the system with
0.5 mmol % (Table 5, entries 2–4). If the reaction tem-
perature increases or decreases from 80°C, product yield
Pathway A: The carbonyl group that comes from the
1,3-dicarbonylic compound is activated by the HPA to
give the corresponding enamine by condensation reac-
tion with ammonia. After its dehydration, structure IV
is obtained.

6
Sanchez et al.
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TABLE 4 HPA-catalyzed synthesis of 1,4-dihydropyridine derivatives containing 3-formylchromone moietya
2-Acetyl-3(-chromonyl)-acrylic
acid alkyl esters
3-Amino-2-butenoic
acid alkyl esters
Yield
(%)
AE
(%)
Eco
scale
Comp.
1,4-Dihydropyridine
E factor
PMI
7
87
83
86
95.7
95.8
95.3
11.33
13.78
14.00
14.91
0.5
88.5
0
H
NH2
O
O
3C
O
O
H
3C
O
O
H
O
O
O
O
O
O
O
N
H
8
11.47
12.33
12.78
CH3
H
O
3C
O
O
O
O
H
3C
H
O
O
O
O
O
O
N
H
9
H
O
O
3C
O
NH2
O
O
H
3C
O
O
O
O
H
O
O
O
O
O
O
N
H
10
80
83
95.5
95.7
15.51
14.28
87
H
CH3
O
O
3C
H
O
O
H
3C
O
O
O
O
O
O
N
H
11
11.68
88.5
Cl
H
O
3C
H
O
O
O
Cl
O
O
O
O
O
O
N
H
aReaction conditions: HPA (0.5 mmol %), 2-acetyl-3(-chromonyl)-acrylic acid alkyl ester (1 mmol), and 3-amino-2-butenoic acid alkyl ester (1 mmol). The mixture was
stirred at 80°C for 30 min.
values are lower (Table 1, entries 5 and 6). Therefore,
the optimal reaction conditions were established as
80°C, 0.5 mmol % of HPA and 15 min (Table 1, entry 3).
Finally, the results showed that after 3 catalytic cycles the
catalytic material maintained its activity (Table 5, entries
8 and 9).
As is shown in Table 6, seven different pyridine deriva-
tives were efficiently prepared by using the optimal reaction
conditions, achieving, in almost all cases, product yields
greater than 85%.
In order to quantify the sustainability grade of the pro-
posed methodology, the AE, E, PMI, and EcoScale were
calculated for each reaction product, and the results are also
presented in Table 6. The resulting parameters indicate an
improvement in the synthetic procedure from a green chemis-
try point of view, with better yield, AE, environmental factor,
PMI, and EcoScale factors than those obtained by traditional
synthetic procedures.
Based on present and previous results,[36] a possi-
ble reaction mechanism for pyridine preparation from

Sanchez et al.
7
|
O
O
O
H
O
O
O
O
R
R
R2
O
O
HPA
H
O
+
R2
R1
O
I
-
H
2O
R1
II
HPA
A
B
PA-
H
O+
PA-
H
H
H
O
O
O
H
O
O
O
O
O
H
O
O
R
R2
R
R2
O
O
H
R2
R
R
R2
O
+
O
O+
R1
R1
O
+
O
PA-
R1
O
R1
O
H
PA-
NH3
NH3
H
O
O
O
O
H
H
O
O
OH
O
H
H
O
R2
R2
R
R2
R
R2
R
R
O
O
O
OH
R1
O
+
+
+
O
H
OH2
+
R
R
H3N
O
O
O
H2N
NH31
NH21
O
R1
-
H2O
H
O
O
O
H
R
R2
O+
H
O
O
R2
R
+
O
HN
R1
H
R
O
NH21
OH
PA-
PA-
O
O
R2
HPA
R1
O
HPA
O
HPA
H
O
O
O
H
H
O
O
O
R
R2
R2
PA-
H
PA-
O
O
O
H
O+
O
O
+
HN
R1
R1
H2N
IV
A2
V
R2
R2
R
R
R1
O
R1
O
A1
HPA
HPA
H
O+
PA-
H
PA-
H
O
H
O
+
OH
O
H
O
O
H
O
R2
R2
O
O
O
H
O
O
O
O
R
R2
R2
+
O
R
O
O
R2
R1
R1
H2N
H2N
OH
H
OH
H
R2
O
H
PA-
+
PA-
O
R
R
HN
R1
O
R1
+
HN
O
R1
N
OH
R1
H
-
PA
H
OH
O
H
N
OH
O
HPA
R
O
H
O
H
O
R
R2
R
R2
O
R2
O
O
+
+
O
H
+
N
R1
O
R1
OH
R1
O
NH
H
H
R
O
O
O
R2
R2
O
H
O
PA-
R1
N
OH
R1
H
+
O
H
O
HPA
H
O
H
O
O
R
R2
O
R2
O
R
N
R1
OH
OH
R1
N
H
R
O
PA-
-
H2O
O
O
O
R2
R2
PA-
H
O
H
N
O
O
O
H
O
H
R2
+
O
R1
N
O
R
1H
R1
-
-
PA
R
R
R
O
R
R
O
O
O
O
-
PA
-
PA
O
O
H
PA
O
O
O
HPA H O
,
-
PA
HPA H O
2
,
O
O
O
O
O
2
O
O
O
H
R2
H
H
R2
R2
O
H
R2
R2
R2
R2
R2
H
O
O
O
O
O
H
R1
+
R1
N
OH2
R1
R1
N
R1
N
R1
N
R1
R1
H
H
SCHEME 4 Possible reaction mechanisms competition in the multicomponent synthesis of 1,4-DHP

8
Sanchez et al.
|
TABLE 5 HPA-catalyzed synthesis of substituted pyridines
R
Temperature
(°C)
Catalyst
Entry
1a
Time (min)
amount (%)
Yield (%)
O
R2
O
80
80
30
15
15
30
30
30
60
30
30
–
39
83
87
87
59
50
85
87
87
O
O
O
2
0.25
0.5
2
R2
H
O
3
80
4
80
H2N
R1
II
R1
R
O
5
100
60
0.5
0.5
0.5
0.5
0.5
6
7
80
R
8b
9c
80
80
O
O
aReaction without catalyst. bFirst and csecond reuse, respectively.
O
O
R2
O
R2
R2
R2
O
The bold values correspond to the obtained yield under the optimal reaction con-
ditions for each presented reaction.
O
O
O
O
O
O
times under mild conditions. The employed catalytic material
is a noncorrosive and it could be reused without significant
loss of activity. A multistep synthetic strategy that allows ob-
taining more structurally complex 1,4-dihydropyridines from
3-formylchromones as main reaction product was presented.
Furthermore, pyridine derivatives were prepared through
a nontypical method, i.e., by opening the γ-pyrone ring of
3-formylchromone.
+
R1
R1
R1
R1
-
H2N
H2N
O
O
R
R
O
O
O
O
R2
O
R2
O
R2
O
R2
O
O
O
O
O
R1
H
+
R1
4.
EXPERIMENTAL
General
N
R1
|
N
R1
-O
O
H
H2
4.1
|
-
H
2O
All chemicals were purchased commercially and used with-
out further purification. The yields were calculated from
crystallized products. All the products were identified by
comparison of analytical data, melting point (mp), elemental
microanalyses, thin layer chromatography (TLC), and
nuclear magnetic resonance (NMR) data with those reported.
The starting materials are commercial products.
2-Acetyl-3(-chromonyl)-acrylic acid alkyl esters were pre-
pared using a literature procedure[36] and 3-amino-2-butenoic
acid alkyl esters by warming a 1:5 mixture of alkyl acetoac-
etate and ammonium acetate at 80°C for 120 min. Melting
points of the compounds were determined in open capillary
R
O
O
O
O
O
R2
R2
O
R1
N
H
R1
1
tubes and are uncorrected. 13C NMR and H NMR spectra
SCHEME 5 Possible reaction mechanism in the final step of the
multistep synthesis of 1,4-DHP
were recorded at room temperature on a Bruker AC 400 using
tetramethylsilane (TMS) as internal standard. Elemental mi-
croanalyses were performed in a F & M instrument.
3-formylchromones is proposed, and it was exhaustively
described in the previous section (Scheme 4).
4.2.
Catalyst preparation
|
The heteropolyacid used in the present paper was syn-
thesized essentially following a procedure performed
by us with slight modifications.[4] The Preyssler salt,
3.
CONCLUSIONS
|
The three desired heterocyclic families were efficiently pre-
pared through clean and simple procedures in short reaction
K12.5Na1.5[NaP5W30O110].15H2O
(HPAK),
was

Sanchez et al.
9
|
TABLE 6 HPA-catalyzed synthesis of substituted pyridinesa
Eco
scale
Comp.
3-Formylchromones
Substituted pyridines
Yield (%)
AE (%)
E factor
PMI
12
90
74.8
15.25
18.43
92
O
OH
O
O
O
CHO
N
O
CH3
O
13
14
88
87
75.7
76.9
14.88
14.07
18.03
17.12
91
O
O
OH
O
O
H
3C
CHO
N
CH3
CH3
90.5
O
OH
O
O
O
Cl
CHO
O
N
CH3
Cl
15
16
90
91
73.8
74.8
16.03
15.10
19.31
18.25
92
O
O
OH
O
O
O
CHO
N
CH3
O
92.5
O
O
OH
O
O
H
3C
CHO
N
CH3
CH3
17
18
92
68
76.1
77.6
13.92
17.31
16.90
21.24
93
81
O
OH
O
O
O
Cl
CHO
O
N
CH3
Cl
O
O
H
O
O
O
O
CHO
N
aReaction conditions: HPA (0.5 mmol %), 3-formylchromone (1 mmol), 1,3-dicarbonylic compound (1 mmol), and ammonium acetate (1 mmol). The mixture was stirred
at 80°C for 15 min.
prepared from Na2WO4.2H2O according to a previously
reported method and converted to the corresponding acid
H14[NaP5W29MoO110] (HPA), by passing it through a
Dowex-50Wx8 ion-exchange column. In a typical experi-
ment, 66.27 g (0.2 mol) Na2WO4.2H2O was dissolved in
100 mL water and mixed at 60°C for 30 min. The solution
was cooled to room temperature, and 50 mL concentrated
phosphoric acid was added. The solution was refluxed for
18 h. Then, it was brought to room temperature, diluted with
35 mL water, and then 23.5 g potassium chloride was added
with stirring. The mixture was stirred for 30 min and then
heated up to dryness, and a solid was obtained. This raw

10
Sanchez et al.
|
product was dissolved in 85 mL warm water and upon cool-
ing to room temperature crystals formed, which were col-
lected and recrystallized from boiling water (yield, 18%).
The heteropolyanion was converted to its corresponding
acid H14[NaP5W30MoO110] (HPA) by passing an aqueous
solution of HPAMoK through a Dowex-50Wx8 ion-exchange
column. The catalyst was properly characterized.
test, the catalyst was separated from the reaction mixture by
filtration, washed with toluene (2 × 2 mL), dried under vac-
uum, and then reused.
4.7
Green metrics
|
In order to quantify the sustainability for the methodology
presented, various green metric parameters were calculated
for each reaction performed. Thus, relevant quantitative
factors such as atom economy (AE), atomic efficiency fac-
tor (E), process mass intensity (PMI), and semiquantitative
EcoScale were determined.
4.3.
General procedure for the preparation
|
of dihydropyrimidinones (thiones)
The solid catalyst (0.5 mmol %) was added to a mixture of
3-formylchromones (1 mmol), 1,3-dicarbonyl compounds
(1 mmol), and urea or thiourea (1.5 mmol). The mixture was
stirred at 80°C for 90 min. The progress of the reaction was
monitored by TLC. After completion of the reaction, hot tolu-
ene was added (2 × 2.5 mL) and the catalyst was filtered. The
extracts were combined dried with anhydrous sodium sulfate,
and the solvents concentrated in vacuum. All the solid crude
products were recrystallized (Compounds 1–6).
ACKNOWLEDGMENTS
We thank Universidad Nacional de La Plata (UNLP),
CONICET (PIP 003) and ANPCyT (PICT 0409) for financial
support. A. S. and G. R. are members of CONICET.
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SUPPORTING INFORMATION
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the supporting information tab for this article.
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