Ultrasound aided solvent-free synergy: an improved synthetic approach to access 3,4-dihydropyrimidin-2(1H)-ones

Article abstract of DOI:10.1007/s13738-019-01597-3

Abstract: A remarkably simple synthetic method has been described for the access of structurally diverse 3,4-dihydropyrimidin-2(1H)-ones in excellent yields in the presence of 2,4,6-trichloro-1,3,5-triazine (TCT) as an efficient source of hydrochloric aci

Full text of DOI:10.1007/s13738-019-01597-3

Journal of the Iranian Chemical Society
https://doi.org/10.1007/s13738-019-01597-3
ORIGINAL PAPER
Ultrasound aided solvent-free synergy: an improved synthetic
approach to access 3,4-dihydropyrimidin-2(1H)-ones
Rathinam Ramesh1 · Samikannu Ramesh1 · Jan Grzegorz Malecki2 · Appaswami Lalitha1
Received: 11 September 2018 / Accepted: 7 January 2019
© Iranian Chemical Society 2019
Abstract
A remarkably simple synthetic method has been described for the access of structurally diverse 3,4-dihydropyrimidin-2(1H)-
ones in excellent yields in the presence of 2,4,6-trichloro-1,3,5-triazine (TCT) as an efficient source of hydrochloric acid
under ultrasound radiation. In this tandem reaction, a range of aldehydes, β-diketo esters and urea were made to condense
together via one-pot, solvent-free synthetic strategy. Use of metal-free catalyst, readily accessible substrates, high production
rate and ease of work-up are the imperative features of this protocol.
Graphical abstract
Keywords 3,4-Dihydropyrimidin-2(1H)-ones · Solvent-free synthesis · Trichlorotriazine · X-ray analysis · Ultrasound
Introduction
nitrogen rich heterocycles has special importance because,
they constitute a potent class of natural as well as pharma-
ceutical products. In recent times, considerable attention has
been built-up for the exploration of environmentally benign,
economically accessible and robust materials as catalysts
for the synthesis of fine organic skeletons. In this regard,
2,4,6-trichloro-1,3,5-triazine has been accounted as an inex-
pensive, low toxic and less corrosive substance with poten-
tial uses in medicinal chemistry over various organic solvent
mediated Lewis acid catalytic systems [7, 8]. Because of the
immense remarks, some of the researchers have efficiently
utilized TCT as an efficient catalyst in several organic trans-
formations [9–15]. Gratifyingly, the ultrasonic irradiation
increases molecular attractive forces and stimulate the
molecular mixing. This causes a warm contact between the
molecules to furnish highly reactive species which induces
the formation of target molecules quantitatively in a rapid
manner. Owing to the efficiency, ultrasound radiation has
The constantly emergent concern for the direct access of tar-
get molecules from green and convenient methodology using
less expensive starting materials is a central goal in organic
synthesis [1–4]. The tandem reactions are considered as very
attractive strategy for accessing complex organic frame-
works in a facile and efficient mode [5, 6]. Chemistry of
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s13738-019-01597-3) contains
supplementary material, which is available to authorized users.
* Appaswami Lalitha
lalitha2531@yahoo.co.in
1
Department of Chemistry, Periyar University, Periyar
Palkalai Nagar, Salem, Tamil Nadu 636011, India
2
Department of Crystallography, University of Silesia,
Szkolna 9, 40-007 Katowice, Poland
Vol.:(0123456789)
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Journal of the Iranian Chemical Society
Table 1 Optimization of suitable conditions for the synthesis of 4a
been accounted as a green and expedient tool in molecular
synthesis. By relating with traditional protocols, ultrasound-
assisted organic transformations are well amplified as being
convenient and probably completed in higher rate [16–18].
Dihydropyrimidinones (DHPMs) are well known motifs,
which can be frequently accessed by the Biginelli reaction.
The intriguing biological profiles in the field of drug discov-
ery have encouraged the development of elegant synthetic
methods for their preparation and chemical transformations
[19–21]. DHPM and its components have attracted consid-
erable attention as they exhibit several pharmaceutical and
therapeutic activities (Fig. 1), such as anticancer, anti-HIV,
antioxidant, antiviral, antibacterial, antitumor, antihyperten-
sive, anti-inflammatory, antifungal, anthelmintic and most
prominently, as calcium channel modulators [22–24]. Due to
their diverse range of biological activities and unique prop-
erties, the progress of new improved methodologies for the
Biginelli reaction is in vast deal [25–35].
using TCT as catalyst
Entry Mol% Solvent
Temperature Time (min) Yielda (%)
(°C)
1
2
3
4
5
6
7
8
10
10
10
10
10
10
10
10
10
10
5
EtOH
MeOH
CH3CN
(CH3)2CHOH Reflux
H2O
–
–
–
–
–
–
–
–
Reflux
Reflux
Reflux
90
120
120
120
150
12
120
45
12
6
18
9
9
81
77
74
69
72
96
38
83
80
80
RT
60
100
60
60
60
60
60
9
96
10
11
12
13
14
97b
84b
96b
95b
18b
15
20
–
–
90
Furthermore, multicomponent reactions (MCRs) are pow-
erful and highly privileged synthetic tool for the construc-
tion of complex and novel organic molecules with reduced
synthetic steps [36, 37]. Ease of handling, minimization of
chemical wastes, accelerating chemical reactions in faster
rate, high degrees of atom economy and environmental
friendliness are the valuable specifics of MCRs over conven-
tional step by step synthetic strategies. Following our con-
tinuous effort devoted to the synthesis of medicinally desired
scaffolds using green solvents or catalysts [38–42], herein
we have described an efficient and convenient protocol for
the three-component synthesis of 3,4-dihydropyrimidin-
2(1H)-ones via a one-pot, solvent-free reaction using TCT
as a source of hydrochloric acid under ultrasonic irradiation.
Reaction conditions: benzaldehyde (5 mmol), urea (6 mmol),
β-diketoester (5 mmol) and TCT at various conditions
aIsolated yield
bUnder ultrasound irradiation
solvents including methanol, acetonitrile, 2-propanol and
water which also provided moderate yields of 4a in rea-
sonable times (Table 1, entries 2–5). To improve the reac-
tion efficacy, the model experiment was further prompted at
80 °C under solvent-free condition, the expected 4-phenyl-
3,4-dihydropyrimidin-2(1H)-one-5-carboxylate (4a) was
formed quantitatively in 12 min (96%, Table 1, entry 6).
After achieving this initial success, we have screened the
model reaction at different thermal conditions, from ambi-
ent to 100 °C and it was noticed that 80 °C would be the
appropriate temperature for the preparation of 4a in good
yields (Table 1, entries 7–9).
Results and discussion
To begin with, the three-component reaction of benza-
ldehyde (1a) with urea (2) and ethyl acetoacetate (3) in
ethanol using a catalytic amount of 2,4,6-trichloro-1,3,5-
triazine (10 mol%) as a source of HCl for the synthesis of
3,4-dihydropyrimidin-2(1H)-one (4a) at reflux tempera-
ture was performed. The reaction furnished the product 4a
in a good yield (81%) in 90 min (Table 1, entry 1). Then,
we have examined the same reaction with different polar
On the other hand, the reaction time was shortened to
6 min while the same reaction has been performed under
ultrasonic irradiation at 60 °C (Table 1, entry 10). From
this observation, we accomplish that the present domino
reaction was strongly promoted by the ultrasound. Encour-
aged by this result, we have also screened the charge of cata-
lyst required for the maximum conversion by carrying out
the above reaction with different mol% of TCT (5, 15 and
Fig. 1 Biologically active
DHPM based compounds
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Journal of the Iranian Chemical Society
20%) under ultrasound condition and found that 10 mol%
of the catalyst was proficient to this tandem reaction for
the convenient access of 3,4-dihydropyrimidin-2(1H)-ones
(Table 1, entries 11–13). Moreover, the model reaction when
attempted without any catalyst resulted in a poor yield of
the product (Table 1, entry 14). From the results outlined in
Table 1, we have selected 10 mol% of TCT as a suitable and
efficient catalyst in the presence of ultrasonic radiation due
to the increased yield in shorter reaction time for this three-
component reaction under solvent-free conditions.
free methyl (–CH3) group and benzylic methine (–CH)
proton, respectively. Aromatic protons showed peaks in
the range δ 7.23–7.34 ppm (J = 7.6 Hz). The amide (–NH)
protons exhibited singlets at δ 7.74 and 9.20 ppm. In 13C
NMR spectrum, the methyl (–CH3) carbon is observed at
δ 14.5 ppm and the benzylic methine carbon showed a
peak at δ 99.7 ppm. The carboxylate and amide carbons
appeared correspondingly at δ 152.5 and 165.7 ppm which
helped to confirm the structure of compound 4a. Moreo-
ver, the compound 4 g was further confirmed by X-ray
diffraction method (Figs. 2, 3) and their crystal refinement
parameters are depicted in Table 3.
With the optimal conditions in hand, we have focused our
attention to examine the scope of the present reaction with
a variety of aldehydes (1b–h) bearing both electron donat-
ing and electron withdrawing substituents in the aromatic
ring (Scheme 1). These reactions revealed that a range of
aldehydes bearing halides or alkyl groups were compatible
and efficiently immersed with the strategy. All the studied
reactions underwent smoothly at standard reaction condi-
tions and provided the desired 3,4-dihydropyrimidin-2(1H)-
one derivatives (4b–h) in the range of about 92–97% yield
(Table 2, entries 2–8). Moreover, benzyl acetoacetate (3,
R′ = CH2C6H5) has also been explored in place of ethyl
ester where too the respective products (4i-l) were formed in
excellent yields under the optimal conditions and the results
are furnished in Table 2 (Entries 9–12). Subsequently, the
efficacy of this synthetic protocol was further investigated
by extending the reaction with different hetero aldehydes
1 l and 1 m which also condensed smoothly with urea (2)
and benzyl acetoacetate (3) under optimized conditions, in
which 92% and 90% yields of the corresponding 3,4-dihy-
dropyrimidin-2(1H)-one were formed, respectively (Table 2,
entries 13 and 14). Furthermore, it would be interesting to
state that, the work-up of the present methodology was found
to be simple and effortless. After completion of the reaction,
the reaction mixture was treated with water and stirred well
for few minutes then filtered.
A tentative mechanism that accounts for the synthesis
of 3,4-dihydropyrimidin-2(1H)-ones has been presented
in Scheme 2. Initially, the TCT reacts with atmospheric
moisture to give three molecules of HCl with cyanuric
acid as a by-product. The formed HCl take part in the
reaction, which activates the aldehyde (1a) followed by
nucleophilic addition of urea (2) resulting the formation of
N-acylimine intermediate I which undergoes the elimina-
tion of water molecule to afford the reactive intermediate
II. Then the generated iminium intermediate (II) acts as
an electrophile for the nucleophilic addition of the enol
form of the ethyl acetoacetate (3) furnished the adduct III.
Finally, the carbonyl group of the open chain intermediate
(III) undergoes intramolecular cyclocondensation by the
free -NH2 group of urea moiety results the cyclic adduct
(IV) which further involves the dehydration to afford the
desired cyclized product 4a.
In this scenario, the generality of this TCT catalysed
solvent-free, ultrasound aided synergy for the preparation
of 3,4-dihydropyrimidin-2(1H)-one was compared with
various catalytic methods and found that the efficacy of
TCT is probably effective than the number of existing syn-
thetic reports (Table 4, entry 12).
To showcase the versatility and effectiveness of this
TCT catalysed cascade reaction in the preparation of
3,4-dihydropyrimidin-2(1H)-ones, the model experiment
was performed in large scale (30 mmol) under the standard
procedure. As expected, the corresponding product (4a)
could be achieved remarkably with 96% yield in 6 min and
it reveals a new direction to access the target molecules for
industrial applications in a benign way.
The synthesized compounds (4a–n) were character-
1
ized by H, 13C NMR and X-ray single crystal analysis.
1
As a representative example, the H NMR spectrum of
compound 4a shows a triplet at δ 1.09 (J = 6.8 Hz) and a
quartet at δ 3.95 (J = 7.2 Hz) ppm representing the pres-
ence of ethoxy (–OCH2CH3) moiety of ester group. The
two singlets appeared at δ 2.25 ppm and 5.14 ppm for the
Scheme 1 TCT assisted syn-
thesis of 3,4-dihydropyrimidin-
2(1H)-one derivatives
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Journal of the Iranian Chemical Society
a
Table 2 TCT catalysed
one-pot synthesis of
3,4-dihydropyrimidin-2(1H)-
ones
b
b
b
b
b
12
CH2C6H5
15
93b
13
CH2C6H5
15
15
92b
90b
14
CH2C6H5
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Journal of the Iranian Chemical Society
Table 2 (continued)
Reaction conditions: aromatic aldehyde (5 mmol), urea (6 mmol), β-diketoester (5 mmol) and TCT
(10 mol%) under ultrasonic irradiation at 60 °C
aIsolated yield
bNovel compound
Table 3 Crystal data and structure refinement parameters for com-
pound 4g
4g
CCDC number
Empirical formula
Formula weight
1579292
C14H15N3O5
305.29
T (K)
Wavelength (Å)
Crystal system
Space group
295
0.71073
Monoclinic
P 21/n
Unit cell dimensions
a (Å)
b (Å)
8.6734 (4)
11.8296 (5)
13.7613 (7)
90
93.374 (5)
90
1409.50 (11)
4
1.439
c (Å)
α (o)
β (o)
γ (o)
Volume (Å3)
Z
Density (calculated) Mg m−3
Absorption coefficient mm−1
F (000)
0.111
640.0
Fig. 2 ORTEP of compound 4g (CCDC 1579292)
Scan range for data collection (deg)
Index ranges
3.7440 to 27.1200
−11≤ h ≤ 11
−16≤ k ≤16
−19≤ l ≤18
Reflections collected/unique, Rint
Completeness to thetamax
Data/restraints/parameters
Goodness-of-fit on F2
7320/2462,0.0554
0.867
2462/0/209
0.945
Final R indices [I>2σ(I)]a
R1 =0.0554
wR2 =0.1293
R indices (all data)
R1 =0.1070
wR2 =0.1447
2
2 2
aStructures were refined on Fo2: wR2 = [∑[w(Fo − Fc ) ]/∑w
(Fo2)2]1/2, where w−1 = [∑(Fo ) + (aP)2 + bP] and P = [max(Fo ,
2
2
2
0)+2Fc ]/3
Experimental
Fig. 3 Packing diagram of compound 4g
Materials and instruments
Ethyl acetoacetate, benzyl acetoacetate, substituted aro-
matic aldehydes, urea, TCT and solvents were purchased
from commercial sources (Sigma-Aldrich) and were used
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Journal of the Iranian Chemical Society
Scheme 2 Plausible mechanis-
tic approach
Table 4 Comparison of efficacy
of TCT with reported catalytic
methods to access 4a
Entry
Catalyst
Conditions
Time (min)
Yield (%)
1
2
3
4
[BMIM(SO3H)]OTf
CG (n:1)
nFe3O4@ZrO2/HPW
[bmim][PF6], 60 °C
Neat, 130 °C
Solvent-free, 100 °C
240
10
15
86 [25]
94 [26]
97 [27]
90 [28]
Fe3O4@SiO2–(CH2)3–NH2– Neat, 85 °C
15
Fe(OH)2
5
6
7
8
Nano-γ-Fe2O3–SO3H
AT-Montmorillonite
β-CD-PSA
Solvent-free, 60 °C
EtOH, 78 °C
Solvent-free, 80 °C
Solvent-free, 100 °C
CH3CN, Reflux
Solvent-free, 90 °C
EtOH, 65 °C
180
120
20
10
120
30
95 [29]
98 [30]
91 [31]
92 [32]
92 [33]
98 [34]
96 [35]
97 [This work]
Co@Imine-Na+-MMT
A-15-X
9
10
11
12
Nano-Zr-SA
ZnO@SBA-15
TCT (10 mol%)
150
6
US, Solvent-free, 60 °C
as received. Reactions were monitored by TLC using
pre-coated silica gel 60 F254 aluminium sheets with ethyl
acetate/hexane (1:4) mixture as the mobile phase. Melt-
ing points are uncorrected and were determined using an
electrothermal apparatus. NMR spectra were recorded on
a BRUKER DRX-400 MHz spectrometer as DMSO-d6
solution and δ values are expressed in ppm using CH4Si
as an internal standard. The crystal of compound 4g was
mounted on a Gemini A Ultra Oxford Diffraction auto-
matic diffractometer equipped with a CCD detector for
X-ray analysis. The percentage of CHN elements were
measured by varioMICRO elemental analyser. Ultra-
sound cleaning bath (IMECO ICW) was used to perform
the sonication with a frequency of 40 kHz and an output
power of 250 W.
Typical procedure for the synthesis of 3,4‑dihydro‑
pyrimidin‑2(1H)‑ones
A mixture of aldehyde (5 mmol), urea (6 mmol), ethyl/
benzyl acetoacetate (5 mmol) and TCT (10 mol%) was
mixed thoroughly in a petri dish at room temperature.
Then the reaction mixture was irradiated in the ultrasonic
bath at 60 °C in open air for the time specified in Table 2.
After completion of the reaction (monitored by TLC), the
residue obtained was washed with water (4 × 25 ml) and
then filtered. The formed solid was collected, dried and
recrystallized from ethanol which afforded the desired
3,4-dihydropyrimidin-2(1H)-ones in excellent purity for
further characterizations.
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Journal of the Iranian Chemical Society
Ethyl-6-methyl-2-oxo-4-phenyl-3,4-dihydropyrimi-
dine-5-carboxylate (4a)
Ethyl-6-methyl-4-(naphthalene-1-yl)-2-oxo-3,4-dihydropy-
rimidine-5-carboxylate (4e)
White solid; mp: 206–208 °C; 1H-NMR (400 MHz, DMSO-
d6): ppm δ 1.09 (t, 3H, CH3, J=7.2 Hz), 2.25 (s, 3H, CH3),
3.95 (q, 2H, CH2, J=7.2 Hz), 5.14 (s, 1H, CH), 7.23 (t, 3H,
ArH, J = 7.2 Hz), 7.30 (d, 2H, ArH, J= 7.2 Hz), 7.74 (s,
1H, NH), 9.20 (s, 1H, NH); 13C-NMR (100 MHz, DMSO-
d6): ppm δ 14.5, 18.2, 54.4, 59.6, 99.7, 126.7, 127.7, 128.8,
145.3, 148.8, 152.5, 165.7; Anal. Calcd. For C14H16N2O3
(260.29 g/mol): C, 64.60; H, 6.20; N, 10.76. Found: C,
64.39; H, 6.10; N, 10.48.
White solid; 1H-NMR (400 MHz, DMSO-d6): ppm δ 0.82
(t, 3H, CH3, J = 6.8 Hz), 2.36 (s, 3H, CH3), 3.83 (q, 2H,
CH2, J = 7.2 Hz), 6.05 (s, 1H, CH), 7.40–7.96 (m, 7H,
ArH, J = 7.6 Hz), 8.30 (s, 1H, NH), 9.24 (s, 1H, NH);
13C-NMR (100 MHz, DMSO-d6): ppm δ 14.2, 18.2, 50.2,
59.4, 99.5, 124.1, 124.6, 126.0, 126.4, 128.3, 128.9,
130.5, 133.9, 140.8, 149.1, 152.1, 165.7; Anal. Calcd. For
C18H18N2O3 (310.35 g/mol): C, 69.66; H, 5.85; N, 9.03.
Found: C, 70.14; H, 6.26; N, 9.61.
Ethyl-4-(4-methoxyphenyl)-6-methyl-2-oxo-3,4-dihydropy-
rimidine-5-carboxylate (4f)
Ethyl-4-(4-bromo-2-fluorophenyl)-6-methyl-2-oxo-3,4-di-
hydropyrimidine-5-carboxylate (4b)
1
White solid; mp: 202–204 °C; H-NMR (400 MHz,
White solid; 1H-NMR (400 MHz, DMSO-d6): ppm δ 1.04 (t,
3H, CH3, J=6.8 Hz), 2.26 (s, 3H, CH3), 3.93 (q, 2H, CH2,
J=7.2 Hz), 5.41 (s, 1H, CH), 7.21 (t, 1H, ArH, J=8.0 Hz),
7.40 (d, 1H, ArH, J=8.0 Hz), 7.49 (d, 1H, ArH, J=8.0 Hz),
7.73 (s, 1H, NH), 9.31 (s, 1H, NH); 13C-NMR (100 MHz,
DMSO-d6): ppm δ 14.6, 18.1, 48.1, 59.6, 97.2, 105.7,
110.7, 142.5, 149.7, 152.8, 156.4, 165.4; Anal. Calcd. For
C14H14BrFN2O3 (357.17 g/mol): C, 47.08; H, 3.95; N, 7.84.
Found: C, 47.51; H, 4.24; N, 7.95.
DMSO-d6): ppm δ 1.10 (t, 3H, CH3, J = 7.2 Hz),
2.24 (s, 3H, CH3), 3.72 (s, 3H, OCH3), 3.97 (q, 2H,
CH2, J = 7.2 Hz), 5.09 (s, 1H, CH), 6.86 (d, 2H, ArH,
J = 8.8 Hz), 7.13 (d, 2H, ArH, J = 8.4 Hz), 7.67 (s, 1H,
NH), 9.15 (s, 1H, NH); 13C-NMR (100 MHz, DMSO-d6):
ppm δ 14.5, 18.2, 53.7, 55.5, 59.6, 100.0, 114.1, 127.8,
137.5, 148.4, 152.6, 158.9, 165.8; Anal. Calcd. For
C15H18N2O4 (290.31 g/mol): C, 62.06; H, 6.25; N, 9.65.
Found: C, 62.71; H, 6.58; N, 10.06.
Ethyl-4-(4-fluoro-3-methylphenyl)-6-methyl-2-oxo-3,4-di-
hydropyrimidine-5-carboxylate (4c)
Ethyl-4-(2-chlorophenyl)-6-methyl-2-oxo-3,4-dihydropy-
rimidine-5-carboxylate (4h)
White solid; 1H-NMR (400 MHz, DMSO-d6): ppm δ 1.10
(t, 3H, CH3, J = 7.2 Hz), 2.19 (s, 3H, CH3), 2.25 (s, 3H,
CH3), 4.0 (q, 2H, CH2, J=7.2 Hz), 5.12 (s, 1H, CH), 6.92 (s,
1H, ArH), 6.96 (d, 1H, ArH, J=8.0 Hz), 7.23 (d, 1H, ArH,
J=8.0 Hz), 7.77 (s, 1H, NH), 9.23 (s, 1H, NH); 13C-NMR
(100 MHz, DMSO-d6): ppm δ 14.2, 14.5, 18.2, 53.7, 59.7,
99.3, 113.1, 122.2, 123.5, 132.0, 145.3, 149.1, 152.5, 159.7,
165.7; Anal. Calcd. For C15H17FN2O3 (292.31 g/mol): C,
61.63; H, 5.86; N, 9.58. Found: C, 62.07; H, 6.16; N, 9.89.
White solid; mp: 216–218 °C; 1H-NMR (400 MHz,
DMSO-d6): ppm δ 0.99 (t, 3H, CH3, J = 7.2 Hz), 2.29 (s,
3H, CH3), 3.88 (q, 2H, CH2, J=7.2 Hz), 5.62 (s, 1H, CH),
7.25–7.41 (m, 4H, ArH, J=8.4 Hz), 7.70 (s, 1H, NH), 9.27
(s, 1H, NH); 13C-NMR (100 MHz, DMSO-d6): ppm δ 14.3,
18.1, 51.9, 59.5, 98.3, 128.2, 129.8, 132.1, 142.2, 149.7,
151.8, 165.4; Anal. Calcd. For C14H15ClN2O3 (260.29 g/
mol): C, 57.05; H, 5.13; N, 9.50. Found: C, 57.62; H, 5.57;
N, 9.94.
Benzyl-4-(2,4-dimethoxyphenyl)-6-methyl-2-oxo-3,4-dihy-
dropyrimidine-5-carboxylate (4i)
Ethyl-4-(4-bromo-3-fluorophenyl)-6-methyl-2-oxo-3,4-di-
hydropyrimidine-5-carboxylate (4d)
White solid; 1H-NMR (400 MHz, DMSO-d6): ppm δ 2.31
(s, 3H, CH3), 3.74 (s, 3H, OCH3), 3.77 (s, 3H, OCH3), 4.94
(d, 1H, CH2, J = 12.8 Hz), 4.99 (d, 1H, CH2, J = 12.8 Hz),
5.49 (s, 1H, CH), 6.42 (d, 1H, ArH, J = 8.4 Hz), 6.53 (s,
1H, ArH), 6.94 (d, 1H, ArH, J = 8.4 Hz), 7.07 (d, 1H,
ArH, J = 7.2 Hz), 7.09 (s, 1H, NH), 7.26 (m, 4H, ArH),
9.18 (s, 1H, NH); 13C-NMR (100 MHz, DMSO-d6): ppm δ
14.5, 18.2, 21.2, 48.7, 55.6, 55.8, 64.9, 97.8, 104.9, 124.6,
White solid; 1H-NMR (400 MHz, DMSO-d6): ppm δ 0.99
(t, 3H, CH3, J = 6.8 Hz), 2.29 (s, 3H, CH3), 3.90 (q, 2H,
CH2, J=7.2 Hz), 5.63 (s, 1H, CH), 7.26–7.41 (m, 3H, ArH,
J=8.4 Hz), 7.70 (s, 1H, NH), 9.27 (s, 1H, NH); 13C-NMR
(100 MHz, DMSO-d6): ppm δ 14.3, 18.2, 48.9, 59.6, 97.4,
119.3, 121.0, 128.2, 131.0, 149.7, 151.8, 158.4, 160.4,
165.3; Anal. Calcd. For C14H14BrFN2O3 (357.17 g/mol): C,
47.08; H, 3.95; N, 7.84. Found: C, 46.71; H, 3.57; N, 7.39.
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Journal of the Iranian Chemical Society
127.5, 128.1, 128.6, 137.1, 150.0, 152.6, 157.9, 165.5;
Anal. Calcd. For C21H22N2O5 (382.41 g/mol): C, 65.96; H,
5.80; N, 7.33. Found: C, 66.49; H, 6.17; N, 7.84.
7.05 (d, 2H, ArH, J=7.6 Hz), 7.13 (d, 1H, ArH, J=7.6 Hz),
7.22 (s, 1H, NH), 7.55 (m, 3H, ArH), 7.93 (d, 1H, ArH,
J=8.0 Hz), 8.41 (d, 1H, ArH, J=8.0 Hz), 8.95 (d, 1H, ArH,
J=8.0 Hz), 9.32 (s, 1H, NH); 13C-NMR (100 MHz, DMSO-
d6): ppm δ 18.3, 49.7, 64.8, 98.0, 122.0, 126.5, 126.9, 127.2,
127.8, 128.2, 128.4, 128.6, 136.9, 150.4, 150.9, 152.5,
165.5; Anal. Calcd. For C22H19N3O3 (373.40 g/mol): C,
70.76; H, 5.13; N, 11.25. Found: C, 71.19; H, 5.47; N, 11.84.
Benzyl-4-(5-chloro-2-(trifluoromethyl)phenyl)-6-me-
thyl-2-oxo-3,4-dihydropyrimidine-5-carboxylate (4j)
White solid; 1H-NMR (400 MHz, DMSO-d6): ppm δ 2.36 (s,
3H, CH3), 4.82 (d, 1H, CH2, J=12.8 Hz), 5.01 (d, 1H, CH2,
J=12.8 Hz), 5.59 (s, 1H, CH), 6.87 (d, 2H, ArH, J=6.4 Hz),
7.19 (t, 3H, ArH, J = 7.6 Hz), 7.42 (s, 1H, NH), 7.50 (s,
1H, ArH), 7.58 (d, 2H, ArH, J=8.8 Hz), 7.68 (d, 1H, ArH,
J=8.8 Hz),9.47 (s, 1H, NH); 13C-NMR (100 MHz, DMSO-
d6): ppm δ 18.3, 51.1, 65.0, 97.5, 122.8, 124.8, 125.1, 127.7,
128.0, 128.5, 128.7, 136.8, 138.5, 146.1, 151.0, 151.4,
164.7; Anal. Calcd. For C20H16ClF3N2O3 (424.80 g/mol): C,
56.55; H, 3.80; N, 6.59. Found: C, 56.06; H, 3.51; N, 6.25.
Benzyl-6-methyl-4-(3-methylthiophen-2-yl)-2-oxo-3,4-di-
hydropyrimidine-5-carboxylate (4n)
White solid; 1H-NMR (400 MHz, DMSO-d6): ppm δ 2.07 (s,
3H, CH3), 2.27 (s, 3H, CH3), 4.98 (d, 1H, CH2, J=12.8 Hz),
5.04 (d, 1H, CH2, J=12.8 Hz), 5.48 (s, 1H, CH), 6.75 (d,
1H, ArH, J = 4.8 Hz), 7.12 (t, 2H, ArH, J = 3.6 Hz), 7.24
(m, 4H, ArH), 7.80 (s, 1H, NH), 9.36 (s, 1H, NH); 13C-
NMR (100 MHz, DMSO-d6): ppm δ 13.6, 18.1, 47.8,
65.2, 99.9, 123.4, 127.8, 128.1, 128.7, 130.3, 133.5, 137.0,
142.9, 149.6, 152.0, 165.2; Anal. Calcd. For C18H18N2O3S
(342.41 g/mol): C, 63.14; H, 5.30; N, 8.18. Found: C, 62.73;
H, 4.91; N, 7.69.
Benzyl-4-(4-bromo-2-fluorophenyl)-6-methyl-2-oxo-3,4-di-
hydropyrimidine-5-carboxylate (4k)
White solid; 1H-NMR (400 MHz, DMSO-d6): ppm δ 2.29 (s,
3H, CH3), 4.92 (d, 1H, CH2, J=12.8 Hz), 5.03 (d, 1H, CH2,
J=12.8 Hz), 5.44 (s, 1H, CH), 7.05 (d, 2H, ArH, J=8.8 Hz),
7.07 (s, 1H, ArH), 7.26 (t, 3H, ArH, J=8.0 Hz), 7.36 (d, 1H,
ArH, J=7.6 Hz), 7.47 (d, 1H, ArH), 7.76 (s, 1H, NH), 9.37
(s, 1H, NH); 13C-NMR (100 MHz, DMSO-d6): ppm δ 18.3,
48.8, 65.1, 96.8, 119.2, 121.0, 127.9, 128.1, 128.2, 128.6,
130.9, 131.5, 136.8, 150.6, 151.6, 158.5, 165.0; Anal. Calcd.
For C19H16BrFN2O3 (419.24 g/mol): C, 54.43; H, 3.85; N,
6.68. Found: C, 55.06; H, 4.38; N, 7.11.
X‑ray crystallography
The crystal of compound 4g was mounted on a Gemini A
Ultra Oxford Diffraction automatic diffractometer equipped
with a CCD detector and used for data collection. X-ray
intensity data were collected with graphite monochromated
MoKα radiation (λ=0.71073 Å) at a temperature of 295 K,
with ω scan mode. Lorentz, polarization and empirical
absorption correction using spherical harmonics imple-
mented in SCALE3 ABSPACK scaling algorithm were
applied. The structure was solved by the direct method and
subsequently completed by the difference Fourier recycling.
All the non-hydrogen atoms were refined anisotropically
using full-matrix, least-squares technique. All the hydrogen
atoms were found from difference Fourier synthesis after
four cycles of anisotropic refinement, and refined as “rid-
ing” on the adjacent carbon atom with individual isotropic
temperature factor equal 1.2 times the value of equivalent
temperature factor of the parent atom. The Olex2 [43] and
SHELXS, SHELXL [44] programs were used for all the
calculations.
Benzyl-4-(2-hydroxy-3-methoxyphenyl)-6-me-
thyl-2-oxo-3,4-dihydropyrimidine-5-carboxylate (4l)
White solid; 1H-NMR (400 MHz, DMSO-d6): ppm δ 2.26 (s,
3H, CH3), 3.73 (s, 3H, OCH3), 5.0 (d, 1H, CH2, J=12.8 Hz),
5.04 (d, 1H, CH2, J=12.8 Hz), 5.08 (s, 1H, CH), 6.58 (d,
1H, ArH, J= 8.0 Hz), 6.70 (d, 1H, ArH, J= 8.0 Hz), 6.80
(d, 1H, ArH, J=8.0 Hz), 7.17 (t, 2H, ArH, J=6.4 Hz), 7.28
(d, 3H, ArH, J=8.0 Hz), 7.65 (s, 1H, NH), 8.95 (s, 1H, OH)
9.20 (s, 1H, NH); 13C-NMR (100 MHz, DMSO-d6): ppm
δ 18.3, 53.9, 56.1, 65.1, 99.5, 112.5, 114.1, 117.4, 127.8,
128.1, 128.7, 137.0, 137.8, 146.9, 147.4, 149.2, 152.4,
165.6; Anal. Calcd. For C20H20N2O5 (368.38 g/mol): C,
65.21; H, 5.47; N, 7.60. Found: C, 65.83; H, 5.92; N, 8.09.
Conclusions
Benzyl-6-methyl-2-oxo-4-(quinolin-8-yl)-3,4-dihydropy-
rimidine-5-carboxylate (4m)
An efficient, convenient and high yielding three-component
reaction for the synthesis of 3,4-dihydropyrimidin-2(1H)-
ones in an attractive manner through the one-step, solvent-
free conditions is described. The reactions are performed
under ultrasonic irradiation which produces the desired
White solid; 1H-NMR (400 MHz, DMSO-d6): ppm δ 2.41 (s,
3H, CH3), 4.87 (d, 1H, CH2, J=12.8 Hz), 4.93 (d, 1H, CH2,
J=12.8 Hz), 6.58 (s, 1H, CH), 6.82 (d, 2H, ArH, J=8.0 Hz),
1 3

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