Efficient and green synthesis of 3,4-dihydropyrimidin-2(1H)-ones/thiones using imidazol-1-yl-acetic acid as a novel, reusable and water-soluble organocatalyst

Article abstract of DOI:10.1016/j.catcom.2011.08.022

A practical and green chemistry route to the Biginelli multicomponent cyclocondensation reaction using imidazol-1-yl-acetic acid as a novel bifunctional and efficient organocatalyst is described under two different sets of reaction conditions.

Full text of DOI:10.1016/j.catcom.2011.08.022

Catalysis Communications 15 (2011) 123–126
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Short Communication
Efficient and green synthesis of 3,4-dihydropyrimidin-2(1H)-ones/thiones using
imidazol-1-yl-acetic acid as a novel, reusable and water-soluble organocatalyst
b
a
Mojgan Kargar a, Rahim Hekmatshoar a, , AbdolJalil Mostashari , Zahra Hashemi
⁎
a
School of Chemistry, College of Science, University of Alzahra, Tehran, Iran
b
Industrial Chemical R&D Organization, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 31 May 2011
Received in revised form 25 July 2011
Accepted 21 August 2011
Available online 2 September 2011
A practical and green chemistry route to the Biginelli multicomponent cyclocondensation reaction using
imidazol-1-yl-acetic acid as a novel bifunctional and efficient organocatalyst is described under two different
sets of reaction conditions.
© 2011 Elsevier B.V. All rights reserved.
Keywords:
Organocatalyst
Imidazol-1-yl-acetic acid
Biginelli reaction
3,4-Dihydropyrimidin-2(1H)-ones/thiones
1. Introduction
reactions was the discovery of efficient L-proline-mediated asymmetric
Robinson annulation in the early 1970s [29]. However, the big potential
Dihydropyrimidinones/thiones, primary products of the re-
nowned multicomponent “Biginelli reaction”, occupy an important
place in the realm of natural and synthetic organic chemistry because
of their therapeutic and pharmacological properties [1–5].
of proline as an organocatalyst was discovered at the beginning of the
21st century [30]. Overall, more than 1500 manuscripts report the use
of organocatalysts in over 130 discrete reaction types, including car-
bon–carbon bond formation, oxidation, reduction, pericyclic, halogena-
tion and widely applicable asymmetric reactions [31]. Organocatalytic
reactions are becoming powerful tools in the construction of complex
molecular skeletons [32].
Organocatalysts such as BINOL-derived phosphoric acids [33], L-
proline [34] as well as L-proline-derived tetrazole catalysts [35] and
a trans-4-hydroxyproline-derived secondary amine catalysts com-
bined with a Brønsted acid [36] were applied to the classical Biginelli
reactions with excellent control of the enantioselectivity of the
products.
Although great success has been achieved in previous works [33–36],
the design and synthesis of new organocatalysts remains an interesting
challenge. In this paper, we describe a simple and green organocatalytic
Biginelli reaction that involves the use of imidazol-1-yl-acetic acid
(Fig. 1) as a new organocatalyst. The reactions afforded various 3,4-dihy-
dropyrimidin-2(1H)-ones/thiones (Scheme 1), with good-to-excellent
yields (87–94%).
The Biginelli reaction is the most effective route to 3,4-dihydro-
pyrimidin-2(1H)-ones/thiones through simple condensation reac-
tions of aldehyde, urea or thiourea and easily enolizable carbonyl
compounds. For Biginelli condensations, more than 100 different
experimental conditions are now known [6]. During the past few
years, numerous catalytic methods have been developed in order
to improve the yield and scope of the Biginelli reaction. Most of
them are based on protic or Lewis acid-catalyzed reactions [7–26].
Water is the most environmentally friendly and least expensive
solvent. Since many organic compounds have limited solubility in
water, the reaction can be conducted in aqueous suspensions [27],
particularly when some of the reactants and the catalyst(s) are to
some extent water-soluble.
The use of small organic molecules as catalysts has been known for
more than a century, when J. Von Liebig found–accidentally–that dicyan
is transformed into oxamide in the presence of an aqueous solution of
acetaldehyde [28]. Another key event in the history of organocatalytic
2. Experimental
The physical data of all compounds were known and were com-
pared with those of authentic samples and found to be identical.
Structure and identity of 3,4-dihydropyrimidin-2(1H)-ones/thiones
were confirmed by spectroscopic methods such as IR and 1H NMR.
⁎
Corresponding author. Tel.: +98 2188041344; fax: +98 2188047861.
E-mail address: rhekmatus@yahoo.com (R. Hekmatshoar).
1566-7367/$ – see front matter © 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.catcom.2011.08.022

124
M. Kargar et al. / Catalysis Communications 15 (2011) 123–126
methanol was added. The resulting suspension was cooled to 0 °C and
N
O
stirred for 10 min. The obtained precipitate was isolated by vacuum fil-
tration, washed with methanol (2×20 mL) and dried at 50 °C for 1 h
to obtain 2.9 g (97%) of imidazol-1-yl-acetic acid (catalyst) as a white
crystalline. The performance of the recovered catalyst was found to be
as good as the same amount of fresh catalyst. The recovered catalyst
was used for seven runs without appreciable loss in its catalytic activity
(Table 2).
N
OH
2.3.2. Route 2
After completion of the reaction, CH2Cl2 (200 mL) was added to
the reaction mixture and stirred for 20 min. The undissolved solid
(imidazol-1-yl-acetic acid) was filtered. The filtrate was then evapo-
rated to dryness and re-crystallized from ethanol to afforded pure
product.
Fig. 1. Imidazol-1-yl-acetic acid.
2.1. Chemicals and apparatus
2.4. Spectral data for selected compounds
IR spectra were recorded as KBr disk on the FT-IR Brucker Tensor 27
spectrometer. 1H NMR spectra were recorded on a Bruker DRX-500
AVANCE Spectrometer.
5-(Ethoxycarbonyl)-6-methyl-4-phenyl-3,4-dihydropyrimidin-2
(1H)-one (Entry 1):
mp 206–208 °C; 1H NMR (500 MHz, DMSO-d6): δ=9.20 (s, 1H,
NH), 7.75 (s, 1H, NH), 7.28 (m, 5H, arom CH), 5.14 (s, 1H, CH), 3.97
(q, J 7.1 Hz, 2H, OCH2), 2.25 (s, 3H, CH3), 1.09 (t, J 7.1 Hz, 3H, CH3);
IR (KBr): 3242, 1721, 1637 cm−1. Anal. Calcd for C14H16N2O3: C,
64.60; H, 6.20; N, 10.76. Found: C, 64.64; H, 6.25; N, 10.92.
5-(Ethoxycarbonyl)-6-methyl-4-(4-chlorophenyl)-3,4-dihydro-
pyrimidin-2(1H)-one (Entry 2):
2.2. General procedure for synthesis of 3,4-dihydropyrimidin-2(1H)-
ones/thiones
2.2.1. Water reflux process
A solution of ethyl acetoacetate (10 mmol), aldehyde (10 mmol) and
urea or thiourea (15 mmol) in 10 mL water was heated under reflux in
the presence of imidazol-1-yl-acetic acid (2.4 mmol, 0.3 g). The progress
of the reaction was monitored by TLC (hexane/ethyl acetate 8:3). After
completion of the reaction, the reaction mixture was cooled to room
temperature and filtered. Resulting crude product was washed with
water and re-crystallized from ethanol. The imidazol-1-yl-acetic acid is
soluble in water and simply is separated from product.
mp 215–217 °C; 1H NMR (500 MHz, DMSO-d6): δ=9.26 (s, 1H,
NH), 7.79 (s, 1H, NH), 7.40 (d, J 8.5 Hz, 2H arom CH), 7.25 (d, J
8.5 Hz, 2H; arom CH), 5.14 (s, 1H, CH), 3.99 (q, J 7.0 Hz, 2H, OCH2),
2.25 (s, 3H, CH3),1.09 (t, J 7.0 Hz, 3H, CH3); IR (KBr): 3241, 1700,
1645 cm−1. Anal. Calcd for C14H15N2O3Cl: C, 57.14; H, 5.10; N 9.52.
Found: C, 56.99; H, 5.09; N, 9.60.
5-(Ethoxycarbonyl)-6-methyl-4-(4-methoxyphenyl)-3,4-dihy-
dropyrimidin-2(1H)-one (Entry 3):
2.2.2. Solvent free process
mp 203 °C; 1H NMR (500 MHz, DMSO-d6): δ=9.17 (s, 1H, NH),
7.68 (s, 1H, NH), 7.15 (d, J 8.6 Hz, 2H; arom CH), 6.88 (d, J 8.5 Hz,
2H; arom CH), 5.09 (s, 1H, CH), 3.98 (q, J 7.0 Hz, 2H, OCH2), 3.71 (s,
3H, OCH3), 2.24 (s, 3H, CH3), 1.10 (t, J 7.0 Hz, 3H, CH3); IR (KBr):
3241,1700, 1637 cm−1. Anal. Calcd for C15H18N2O4: C, 62.07; H,
6.20; N, 9.66. Found: C, 61.65; H, 6.21; N 9.58.
Heterogeneous mixture of ethyl acetoacetate (10 mmol), aldehyde
(10 mmol), urea or thiourea (15 mmol) and imidazol-1-yl-acetic acid
(2.4 mmol, 0.3 g) was heated at 100 °C for appropriate time (Table 2).
After completion of the reaction, to the mixture, water (20 mL) was
added and stirred 15 min. The undissolved crude product was filtered,
washed with water and re-crystallized from ethanol to obtain pure
3,4-dihydropyrimidin-2(1H)-ones/thiones.
3. Result and discussion
2.3. Large scale reactions for the synthesis of 5-(ethoxycarbonyl)-6-
methyl-4-phenyl-3,4-dihydropyrimidin-2(1H)-one, catalyst recovery
and reuse
The success of these small molecules (organocatalysts) may largely
be attributed to their bifunctionality, bearing a Lewis/Brønsted acidic
moiety for the activation of electrophiles, and a Lewis/Brønsted basic
moiety for the activation of nucleophiles For example in Takemoto's
catalyst (Scheme 2), the thiourea moiety activates the electrophile
and the amine moiety activates the nucleophile [37].
In order to have more precise idea of the recoverability of the catalyst,
a 100 mmol scale reaction, using imidazol-1-yl-acetic acid (24 mmol, 3 g)
was run under solventless condition.
In the course of our studies on the industrial processes for the pro-
duction of Zoledronic acid (Antihypercalcemic drug) [38], we were
able to find a simple, low cost and rather benign procedure for the
production of the key precursor, imidazol-1-yl-acetic acid. This
amino acid is almost always in ionized form (Scheme 3).
2.3.1. Route 1
After completion of the reaction, water (120 mL) was added to the
reaction mixture and stirred for 15 min. The undissolved solid (product)
was filtered. The filtrate was then evaporated to dryness and (120 mL)
This molecule contains both acidic and basic functionalities. It
seemed to be an ideal bifunctional catalyst for condensation reactions
such as the ones encountered in the “Biginelli” protocol. This assumption
encouraged us to evaluate potential of imidazol-1-yl-acetic acid as a
simple bifunctional organocatalyst in this reaction. Extensive literature
survey indicates that imidazol-1-yl-acetic acid has never been reported
as a catalyst for “Biginelli reaction” or any other organic transformation
and the present work is the first report that introduces it as a catalyst.
This water-soluble catalyst is eco-friendly and easily accessible. Facile
recoverability in pure state and good yield makes it infinitely reusable.
Scheme 1. Imidazol-1-yl-acetic acid catalyzed synthesis of 3,4-dihydropyrimidin-2
(1H)-ones/thiones.

M. Kargar et al. / Catalysis Communications 15 (2011) 123–126
125
Table 1
Imidazol-1-yl-acetic acid catalyzed synthesis of 3,4-dihydropyrimidin-2(1H)-ones/thiones.
Entry
Ar
X
Time
(min)
Yield (%)a
Mp °C
Mp °C lit.
[Ref.]
foundb
Solvent free
Water reflux
1
2
3
4
5
6
7
8
C6H5
4-Cl-C6H4
O
O
O
O
O
O
O
O
O
S
S
S
S
S
S
S
S
S
35
30
38
30
35
40
40
35
38
30
35
30
40
45
45
30
30
50
90
89
91
91
90
89
88
89
89
91
90
91
85
87
88
90
91
87
92
94
90
92
92
90
89
91
91
92
88
92
87
88
89
91
90
87
206–208
215–217
203
228–230
211–213
213–215
200–202
253–254
208–210
206
202–204 [10]
215–216 [10]
203 [17]
228 [17]
214 [17]
4-OCH3-C6H4
3-NO2-C6H4
4-CH3-C6H4
4-Br-C6H4
2-OH-C6H4
4-N(CH3)2-C6H4
2-Furyl
215 [17]
201–202 [24]
253–254 [10]
208–210 [10]
206 [17]
153 [17]
205 [10]
162–164 [24]
192–194 [23]
122–124 [23]
196–198 [23]
211–213 [18]
150–152 [22]
9
10
11
12
13
14
15
16
17
18
C6H5
4-OCH3-C6H4
3-NO2-C6H4
2-OH-C6H4
4-CH3-C6H4
3-OH-C6H4
2-Furyl
153
205
162–164
192–194
122–124
197–198
209–211
150–152
4-N(CH3)2-C6H4
4-OCH3-C6H4
a
Yields refer to isolated crude products.
Recrystallized products.
b
imidazol-1-yl-acetic acid (24 mol%) for a certain period of time re-
quired to complete the reaction (TLC), resulting in the formation of
5-(ethoxycarbonyl)-6-methyl-4-phenyl-3,4-dihydropyrimidin-2
(1H)-one. The solid product was then filtered. The imidazol-1-yl-acetic
acid is soluble in water and is simply separated from the product.
To study the generality of this process, several examples illustrating
this novel and general method for the synthesis of dihydropyrimidi-
nones were studied and are summarized in Table 1. It is seen that several
aromatic aldehydes carrying either electron-releasing or electron-with-
drawing substituents in the ortho and para positions afforded good
yields of the products. Acid sensitive aldehydes such as furfural worked
well without the formation of any side products. Thiourea has been used
with similar success to provide the corresponding dihydropyrimidine-
(2H)-thiones.
Table 2
Reusability of the catalyst after 35 min.
Run no.
Product yield (%)
Fresh
90
89
89
90
90
89
89
90
First recycle
Second recycle
Third recycle
Fourth recycle
Fifth recycle
Sixth recycle
Seventh recycle
Several publications indicate a competition between Biginelli and
Hantzsch condensations in this type of reactions, leading to the tem-
perature dependent production of 3,4-dihydropyrimidin-2(1H)-ones
(DHPMs) and 1,4-dihydropyridines (DHPs) respectively. Increasing
temperature favors the decomposition of urea into ammonia, thus
promoting Hantzsch reaction. Hantzsch reaction products were not
observed, in our protocol.
In our final series of experiments, we set out to examine the sol-
vent-free reaction. β-Ketoester, aldehyde, urea or thiourea and
imidazol-1-yl-acetic acid (24 mol%) were mixed together, and the
heterogeneous mixture was stirred at 100 °C. After cooling the reac-
tion mixture, water (20 mL) was added and the mixture stirred
15 min. The undissolved solid was filtered and washed with water.
The corresponding dihydropyrimidinones and -thiones were isolated
in a typically good yield (85–91%). Re-crystallization from ethanol
afforded pure 3,4-dihydropyrimidin-2(1H)-ones/thiones.
Scheme 2. Takemoto's catalyst; a bifunctional organocatalyst.
Kappe [1] proposed that the first step of the Biginelli reaction, the
acid catalyzed formation of acyliminium intermediate 1 formed by
the reaction of aldehyde with urea, is the rate-determining step. Fur-
ther reaction of the iminium ion by the activated β-Ketoester gives
an ureido 3 which is subsequently cyclized to dihydropyrimidinone
4 with expulsion of water. The catalytic effect of imidazol-1-yl-acetic
acid probably arises from dual action of imidazol-1-yl-acetic acid, par-
ticipating in acid catalyzed formation of 1, as well as base catalyzed ac-
tivation of the β-Ketoester and stabilizing the resulting “enolate ion”
through hydrogen bonding. The suggested mechanism is illustrated
in Scheme 4.
Scheme 3. Bifunctionality of imidazole-1-yl-acetic acid in the reaction medium.
In order to evaluate the catalytic efficiency of imidazol-1-yl-acetic
acid; a solution of benzaldehyde, ethyl acetoacetate and urea in water
was heated under reflux in the presence of a catalytic amount of

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M. Kargar et al. / Catalysis Communications 15 (2011) 123–126
Scheme 4. Plausible mechanism for catalytic effect of imidazol-1-yl-acetic acid in Biginelli reaction.
In order to show the merit of the present work, we compared
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Table 3
Comparison the results of the synthesis of 5-(ethoxycarbonyl)-6-methyl-4-phenyl-3,4-
dihydropyrimidin-2(1H)-one using different catalysts.
Entry
Catalyst
Reaction time
Yield% [Ref.]
1
2
3
4
5
6
7
8
Bi (NO3)3
BiCl3 (10%)
H3BO3 (20%)
VCl3 (10%)
Sc(OTf)2 (1%)
PPh3 (10%)
InBr3 (10%)
Mn(OAC)3·2H2O
H3PMoO40 (2%)
Montmorilonite KSF
Zeolite
6 h
5 h
0.5 h
2 h
80 [14]
44 [14]
97 [10]
96 [12]
97 [15]
70 [11]
79 [19]
96 [13]
80 [28]
82 [7]
4 h
10 h
10 h
2 h
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9
5 h
10
11
12
48 h
12 h
35 min
80 [8]
92 (this work)
Imidazol-1-yl-acetic acid (20%)