One-pot, green and efficient synthesis of 3,4-dihydropyrimidin-2(1H)-ones or thiones catalyzed by citric acid

Article abstract of DOI:10.1002/jccs.201300118

One-pot three-component condensation of ethyl acetoacetate, aldehyde and urea or thiourea in refluxing ethanol in the presence of catalytic amounts of citric acid afforded the corresponding 3,4-dihydropyrimidin- 2(1H)-ones/thiones in high yields. The cata

Full text of DOI:10.1002/jccs.201300118

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Article
One-pot, Green and Efficient Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones or Thiones
Catalyzed by Citric Acid
Arash Ghorbani-Choghamarani,a* Tahereh Taghipourb and Gouhar Azadia
aDepartment of Chemistry, Faculty of Science, Ilam University, Ilam, Iran
bSama Technical and Vocational Training College, Islamic Azad University, Ilam Branch, Ilam, Iran
(Received: Mar. 1, 2013; Accepted: May 13, 2013; Published Online: ??; DOI: 10.1002/jccs.201300118)
One-pot three-component condensation of ethyl acetoacetate, aldehyde and urea or thiourea in refluxing
ethanol in the presence of catalytic amounts of citric acid afforded the corresponding 3,4-dihydropyrimi-
din-2(1H)-ones/thiones in high yields. The catalyst is reusable and can be applied several times without
any decrease in product yield.
Keywords: Biginelli reaction; One-pot synthesis; 3,4-Dihydropyrimidin-2(1H)-ones; Citric acid.
INTRODUCTION
Compounds with biological activity are often derived
methods for the synthesis of 3,4-dihydropyrimidin-2(1H)-
ones. The use of reusable catalysts represents one of the
most powerful and green procedures in chemical technol-
ogy.
from heterocyclic structures. 3,4-Dihydropyrimidin-2(1H)-
ones and their sulfur analogs (DHPMs) are an important
class of heterocycles with a wide range of pharmacological
and biological activities including antiviral, antibacterial
and antihypertensive activity,1 as well as efficacy as cal-
cium channel modulators and a1a-antagonists.2 The simple
and direct method for the synthesis of DHPMs reported by
Biginelli in 1893 involves the one-pot condensation of an
aldehyde, a b-ketoester and a urea under strongly acidic
conditions.3
RESULTS AND DISCUSSION
In connection with our previous work for the synthe-
sis of pharmaceutically important heterocyclic compounds,
and introduction of new catalysts for the organic functional
group transformations,30-40 we decided to develop a very
simple, economic and highly efficient strategy for the syn-
thesis of dihydropyrimidinones/thiones through the three-
component one-pot condensation of an aldehyde, ethyl
acetoacetate and urea or thiourea promoted by citric acid as
a catalyst in ethanol under reflux conditions (Scheme I).
In spite of the importance of the reported method, it
suffers from long reaction times, acidic reaction condi-
tions, low yields of the products particularly in the case of
substituted aldehydes and loss of sensitive functional
groups during the reaction.4 Recently, because of the sim-
plicity of the synthesis of DHPMs, the Biginelli reaction
has received renewed interest. To enhance the efficiency of
the Biginelli reaction, various catalysts and reaction condi-
tions have been studied, and many improved procedures
catalyzed by different Lewis and protic acids such as
CeCl3,5 Cu(OTf)2,6 Cu(BF4)2,7 Mg(ClO4)2,8 heteropoly ac-
ids,9 Y(NO3)3,10 Ziegler–Natta,11 PhB(OH)2,12 propane
phosphonic acid anhydride,13 triphenylphosphine,14 hydra-
zine,15 SiCl4,16 ionic liquid,17 graphite–LaCl3,18 polyethyl-
ene glycol (PEG),19 chiral primary amine/HCl,20 K2CO3,21
and uronium hydrogensulfate,22 have been reported. How-
ever, some of these procedures suffer from some draw-
backs such as unsatisfactory yields, cumbersome product
isolation procedures and environmental pollution.23,24-30
Therefore, there is still a need to develop efficient
Synthesis of 3,4-dihydropyrimidin-2(1H)-
ones/thiones
Scheme I
Initially, in order to optimize reaction conditions, the
effect of catalyst quantity was investigated. In this light
p-chlorobenzaldehyde was combined with ethyl acetoace-
* Corresponding author. E-mail: arashghch58@yahoo.com or a.ghorbani@mail.ilam.ac.ir
J. Chin. Chem. Soc. 2013, 60, 000-000
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Article
Ghorbani-Choghamarani et al.
Table 1. Effect of different amount of catalyst on the formation
of 4aa
tate and urea in the presence of different amounts of citric
acid (Scheme II, Table 1).
No.
Catalyst (mmol)
Time (h)
Yield (%)b
Scheme II Optimization of reaction conditions
1
2
3
4
5
0.05
0.25
0.35
0.40
0.45
6
6
6
6
6
29
63
78
93
83
a Reaction condition: p-Chlorobenzaldehyde (1 mmol), Ethyl
acetoacetate (1.1 mmol), urea (1.5 mmol), EtOH (10 mL), Reflux
conditions. b Isolated yield.
Mechanism of 3,4-dihydropyrimidin-
2(1H)-ones/thione synthesis catalyzed by
citric acid
Scheme III
As shown in Table 1 (entry 4), 0.4 mmol of the cata-
lyst presented the maximum activity and yield. Using these
optimized reaction conditions, the reaction of ethyl aceto-
acetate, and urea/thiourea with a variety of aldehydes in the
presence of citric acid as efficient, and thermally stable cat-
alyst was investigated. The reactions proceeded smoothly
in ethanol under reflux conditions and completed within 6
h. The results of the transformation of differently substi-
tuted aryl aldehydes to DHPM derivatives 4a–m are sum-
marized in Table 2.
The feasibility of the reusability and recycling of the
citric acid was examined through a series of sequential con-
densations of ethyl acetoacetate and p-chlorobenzaldehyde
with urea. In a typical reaction, the catalyst was recovered
by washing reaction mixture with water. Followed by evap-
oration and concentration of water, catalyst extracts reused
in the next run avoiding any purification. The reaction pro-
ceeded smoothly with a yield of 85-93% and this result
shows that the catalyst does not lose its activity even after
four runs (Table 3).
physical data with authentic samples.
General procedure for the synthesis of 3,4-Dihydropyr-
imidin-2(1H)-ones/thiones: A mixture of aldehyde (1 mmol),
ethyl acetoacetate (1.1 mmol), urea or thiourea (1.5 mmol) and
citric acid (0.4 mmol) in ethanol (10 mL) was stirred under reflux
conditions for a certain period of time as required to complete the
reaction. The progress of the reaction was monitored by TLC. On
completion, solvent was removed under reduced pressure and the
reaction mixture washed with water (4 × 20 mL) to separate cata-
lyst. Finally, resulting product recrystallized from hot ethanol to
afford high pure 3,4-dihydropyrimidin-2(1H)-ones/thiones.
Representative NMR Data
Suggested mechanism for this transformation has
been outlined in Scheme III.
To investigate and develop the scope and limitation of
this procedure we decided to examine different organic ac-
ids instead of citric acid in the described system (Table 4).
As is evidence from Table 4 a variety of organic acids
are capable of this transformation as well as citric acid.
Ethyl 4-(4-chlorophenyl)-6-methyl-2-oxo-1,2,3,4-tetra-
hydropyrimidine-5-carboxylate 4a: 1H NMR (400 MHz,
DMSO): d = 9.26 (br, 1H), 7.78 (br, 1H), 7.38 (d, J = 8.4 Hz, 2H),
7.23 (d, J = 8.4 Hz, 2H), 5.13 (s, 1H), 3.96 (q, J = 7 Hz, 2H), 2.23
(s, 3H), 1.07 (t, J = 7 Hz, 3H) ppm. Ethyl 4-(4-p-tolyl)-6-methyl-
2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate 4b: 1H
NMR (400 MHz, DMSO): d = 9.16 (br, 1H), 7.68 (br, 1H), 7.11 (s,
4H), 5.09 (s, 1H), 3.96 (q, J = 7 Hz, 2H), 2.25 (s, 3H), 2.23 (s, 3H),
EXPERIMENTAL
General. The chemicals and solvents were purchased from
Fluka, Merck and Aldrich chemical companies without further
purifications. All products are known and were characterized by
1
comparison of their spectral (IR, H NMR, or 13C NMR) and
2
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Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones or Thiones
Table 2. Three-component condensation of aldehydes, urea or thiourea, and ethyl acetoacetate for the
synthesis of DHPMsa,b
Entry
1
Prouduct
Cl
Yield (%)c
Mp found (°C) Mp reported (°C)
Ref.
23
O
4a
93
209-212
213-215
213-215
215-216
EtO
NH
O
N
H
O
2
3
4b
4c
98
90
41
23
EtO
NH
N
H
O
F
O
181-183
185-186
EtO
NH
N
H
O
OMe
OMe
O
4
5
6
4d
4e
4f
92
80
99
178
178
23
29
41
EtO
NH
N
H
O
NO2
O
O
208-210
202-204
206-208
202-204
EtO
NH
N
H
OMe
O
EtO
NH
N
O
H
NO2
O
7
8
4g
4h
98
91
222-224
182-184
226-227
179-182
42
39
EtO
NH
N
O
H
Cl
O
EtO
NH
N
H
S
O
9
4i
4j
90
93
99
208-210
188-190
202-204
208-210
191-193
206-207
28
43
43
EtO
NH
N
H
S
O
10
EtO
NH
N
H
S
NO2
O
11
4k
EtO
NH
N
H
S
a Reaction conditions: aldehyde (1 mmol); ethyl acetoacetate (1.1 mmol); urea/thiourea (1.5 mmol);
citric acid (0.4 mmol); EtOH (10 mL); Reflux conditions. b Reaction time: 6 h. c Isolated yield.
J. Chin. Chem. Soc. 2013, 60, 000-000
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Article
Ghorbani-Choghamarani et al.
Table 3. The recyclability of citric acid of the preparation of
ethyl 4-(4-chlorophenyl)-6-methyl-2-oxo-1,2,3,4-
tetrahydropyrimidine-5-carboxylate
60.1, 53.9, 17.6, 14.4 ppm. Ethyl 4-phenyl-6-methyl-2-thioxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate 4i: 1H NMR (400
MHz, DMSO): d = 10.34 (br, 1H), 9.66 (br, 1H), 7.24-7.35 (m,
5H), 5.15 (s, 1H), 3.99 (q, J = 7 Hz, 2H), 2.27 (s, 3H), 1.08 (t, J = 7
Hz, 3H) ppm. Ethyl 4-(4-tolyl)-6-methyl-2-thioxo-1,2,3,4-
Run No.
Yield (%)a
1
2
3
4
5
93
90
86
90
85
1
tetrahydropyrimidine-5-carboxylate 4j: H NMR (400 MHz,
DMSO): d = 10.30 (br, 1H), 9.61 (br, 1H), 7.13 (d, J = 8 Hz, 2H),
7.08 (d, J = 8 Hz, 2H), 5.12 (s, 1H), 3.99 (q, J = 7 Hz, 2H), 2.27 (s,
3H), 2.25 (s, 3H), 1.09 (t, J = 7 Hz, 3H) ppm; 13C NMR (100 MHz,
DMSO): d = 174.6, 165.6, 145.3, 141.1, 137.3, 129.5, 126.7,
101.3, 60, 54.2, 21.1, 17.6, 14.4 ppm.
a Isolated yield
Table 4. Three-component condensation of 4-chlorobenzalde-
hyde, urea and ethyl acetoacetate for the synthesis of
corresponding DHPM catalyzed by different organic
acidsa
CONCLUSIONS
In summary, this report describes a green, simple, and
efficient one-pot procedure for the synthesis of Biginelli
DHPMs using citric acid as a catalyst. High yields of the
products, operation simplicity, easy work-up and an inex-
pensive and commercially available catalyst make this
method attractive for organic chemists.
Entry
Organic acid
Yield (%)b
1
2
3
4
5
6
Citric acid
Acetic acid
93
68
99
88
54
45
Benzoic acid
p-nitrobenzoic acid
Maleic acid
Oxalic acid
ACKNOWLEDGEMENTS
a Reaction conditions: 4-chlorobenzaldehyde (1 mmol); ethyl
acetoacetate (1.1 mmol); urea (1.5 mmol); organic acid (0.4
mmol); EtOH (10 mL); reflux conditions; Reaction time 6 h.
b Isolated yield.
This work was supported by the research facilities of
Ilam University, Ilam, Iran.
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