The development of an ecofriendly procedure for alkaline metal (II) sulfate promoted synthesis of N,N′-dimethyl substituted (unsubstituted)-4-aryl-3, 4-dihydropyrimidones (thiones) and corresponding bis-analogues in aqueous medium: evaluation by green che

Article abstract of DOI:10.1002/jhet.283

(Chemical Equation Presented) Different alkaline metal (II) sulfates were used as catalysts for the N,N′-dimethyl substituted as well as unsubstituted 4-aryl-3,4-dihydropyrimidones (thiones) and their corresponding bis-analogues in aqueous medium. Among t

Full text of DOI:10.1002/jhet.283

136
The Development of an Ecofriendly Procedure for Alkaline Metal
(II) Sulfate Promoted Synthesis of N,N0-Dimethyl Substituted
(Unsubstituted)-4-Aryl-3,4-Dihydropyrimidones (Thiones) and
Corresponding Bis-Analogues in Aqueous Medium: Evaluation by
Green Chemistry Metrics
Vol 47
Chhanda Mukhopadhyay* and Arup Datta
Department of Chemistry, University of Calcutta, Kolkata 700009, India
*E-mail: csm@vsnl.net or cmukhop@yahoo.co.in
Received July 8, 2009
DOI 10.1002/jhet.283
Published online 5 January 2010 in Wiley InterScience (www.interscience.wiley.com).
Different alkaline metal (II) sulfates were used as catalysts for the N,N0-dimethyl substituted as well
as unsubstituted 4-aryl-3,4-dihydropyrimidones (thiones) and their corresponding bis-analogues in aque-
ous medium. Among the various salts, MgSO4ꢀ7H2O (Epsom salt) proved to be the best catalyst giving
the desired products in good to excellent yields. This catalyst enables the construction of a series of
compound libraries particularly for N,N0-dimethyl substituted DHPM’s whose synthesis is very rare in
the literature. The reaction on a wide variety substrates was evaluated by the application of green chem-
istry metrics and a very good correlation was obtained.
J. Heterocyclic Chem., 47, 136 (2010).
INTRODUCTION
velopment of future science and technology [4]. Nowa-
days many reactions are being carried out in water for
environmental protection. From this view point, it is de-
sirable, instead of organic solvents, to use water as a
reaction medium as, water is safe, easy handling, abun-
dant and an environmentally benign solvent. Therefore,
we aimed at the synthesis of the N,N0-disubstituted and
N,N0-unsubstituted DHPMs in aqueous medium.
The actual driving force for the development of new
catalysts for the structural motif-N,N0-disubstituted(un-
substituted)-4-aryl-3,4-dihydropyrimidones being a heter-
ocyclic moiety of remarkable pharmacological impor-
tance [1] is to prepare compound libraries for screening in
drug discoveries. The appropriately functionalized dihy-
dropyrimidones (DHPMs) are very prominent as mitotic
kinesin inhibitors, a1-adrenergic antagonists and potent
hypertensive agents [1]. The importance of the N,N0-dis-
ubstituted DHPMs lies in the fact that N,N0-disubstitution
promotes lipophilicity and advances chemozymatic syn-
thesis of enantiopure DHPMs in organic solvents [2].
When three component coupling (3CC) involving an alde-
hyde, alkyl acetoacetate, and N,N0-dimethylurea is per-
formed, the synthesis of the desired dihydropyrimidones
often fail or produces the desired products in very low
yields due to the formation of multiple side products. Sol-
vent-free conditions also fail to produce them [3]. Till
date, the synthesis of N,N0-disubstituted DHPMs remains
a great challenge for organic chemists.
RESULTS AND DISCUSSION
Dihydropyrimidones (DHPMs) possess immense bio-
logical activity [5] and therefore the synthesis of this
nucleus has received much attention. It must be men-
tioned that the synthesis of the N,N0-dimethyl substituted
DHPMs is rather difficult and there are only few refer-
ences in the literature. The simple DHPMs, first synthe-
sized by Biginelli [6], have already been prepared by a
number of methods. In spite of this, very few reports of
the synthesis of this ring system exist in water [7–9].
Thus, exploration for catalysts leading to the synthesis
of this extremely important ring system in aqueous me-
dium is still needed. In continuation of our sincere
Green Chemistry is a rapidly developing new field
that provides a proactive avenue for the sustainable de-
C
V
2010 HeteroCorporation

January 2010 Synthesis of N,N0-Dimethyl Substituted (Unsubstituted)-4-Aryl-3,4-Dihydropyrimidones
(Thiones) and Corresponding Bis-Analogues in Aqueous Medium
137
(entry 13). The yields were much lower when carried
out in organic solvents (entries 1–8). Therefore, water
has a definite role for the green reaction medium as it
has an unique property of inducing hydrophobic interac-
tions between the substrate and the catalyst.
Our next task was the choice of the catalyst for the
model reaction with EAA, urea, and 4-chlorobenzalde-
hyde with 0.5 mL of water at 90ꢁC and the results are
summarized in Table 2.
Figure 1. Monastrol.
efforts in carrying out reactions in aqueous medium
[10–12], we envisaged the construction of a wide variety
of N,N0-unsubstituted and dimethyl substituted dihydro-
pyrimidones and also bis-dihydropyrimidones in water
with variations in all the three components. This catalyst
has been efficiently utilized for the synthesis of the mi-
totic kinesin EG 5 inhibitor Monastrol [13] (Fig. 1) in
excellent yield.
We tried Group IIA metal sulfates as the catalyst for
the dihydropyrimidone formation in water at 90ꢁC. It
was observed that MgSO4ꢀ7H2O (Epsom salt) produced
the desired product in maximum yield. It was also
observed that the solubility of the Group IIA metal sul-
fate decreases down the group in accordance with
Fajan’s rules, which states that solubility decreases with
increasing cationic radius. Therefore, the yield with
Epsom salt was maximum probably due to an optimum
correlation between its solubility and ionic character.
The partial covalent character of Mgþ2 ion helps to
form strong metal-oxygen bonds (similarly as in ref. [5])
thereby increasing the electrophilicity of the carbonyl
carbons of the b-keto esters or b-diketones.
For the initial exploration, the condensation of ethyla-
cetoacetate, 4-chlorobenzaldehyde and urea with MgSO4
(10 mol %) was studied in different solvents to optimize
the reaction condition and to establish the feasibility of
our catalyst (Table 1).
From Table 1, we find that the synthesis of the dihy-
dropyrimidone produced from 4-chlorobenzaldehyde,
EAA and urea proceeds best in water at 90ꢁC in water
(entry 12). Almost no reaction took place in aqueous
medium at lower temperatures (entries 9–11). Use of
higher temperature did not increase the yield further
Once the optimum reaction conditions were finalized,
the catalyst was effectively utilized for the synthesis of
a wide variety of N,N0-unsubstituted-3,4-dihydropyrimi-
din-2(1H)-ones and thiones (Scheme 1, R3 ¼ H) and the
results are summarized in Table 3.
Table 1
Optimization of the reaction conditions of synthesis of dihydropyrimidone from 4-chlorobenzaldehyde, ethylacetoacetate, and urea with
MgSO4 (10 mol %).
Entry
Solvent (0.5 mL)
Temperature (ꢁC)
Reaction time (h)
Yielda (%) (isolated)
1
2
3
CH2Cl2
THF
45
65
70
80
5
4
4
5
6
4
6
5
4
5
6
4
5
8
35
30
35
30
40
45
40
42
00
03
05
90
90
90
MeOH
EtOH
DMF
DMF
DMSO
DMSO
H2O
H2O
H2O
H2O
H2O
4
5
80
6
100
80
100
40
60
70
90
7
8
9
10
11
12
13
14
100
90
H2O
a Yields calculated with respect to starting aldehyde.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

138
C. Mukhopadhyay and A. Datta
Vol 47
Table 2
equally well. Ethylacetoacetate, methylacetoacetate, and
acetylacetone were varied as the b-keto esters or the b-
diketone. Again, urea and thiourea were equally effec-
tive in carrying out the reaction. Table 3, entry 4 depicts
the synthesis of Monastrol (Fig. 1). In all the cases, the
pure product was isolated by simple filtration. Recrystal-
lization from aqueous ethanol produced the pure 3, 4-
dihydropyrimidin-2(1H)-ones. Thus, the products were
obtained in pure form without any column chromatogra-
phy or any cumbersome work-up techniques. In all the
cases, 100% conversion was observed as no starting
materials were present in thin layer chromatography
Choice of catalyst for the reaction of EAA, urea, and
4-chlorobenzaldehyde with 0.5 mL water at 90ꢁC.
Catalyst
(10 mol%)
(with water of
hydration)
Yield %
(isolated
w. r. t. starting
aldehyde)
Time
(h)
Entry
1
2
3
4
5
–
10
4
5
90
60
47
20
MgSO4
CaSO4
SrSO4
BaSO4
6
7
10
1
(TLC) or in H NMR (crude) after the reaction. With al-
iphatic aldehydes, only 10% conversion (by TLC) was
observed and the final products cannot be isolated from
the reaction mixture. The reaction was also 100% selec-
tive as a single product was obtained for all cases for ar-
omatic aldehydes. This is possibly due to the higher sta-
bility of the acyl imines (with increasing conjugation)
for aromatic aldehydes than with aliphatic ones. This
methodology in aqueous medium is obviously a green
one as no toxic chemicals or reagents were used and no
side products were obtained.
Our next target was the application of our catalyst for
the synthesis of the dimethyl substituted DHPM’s and
hence to synthesize ‘‘drug-like’’ molecules. This is
because the synthesis of these N,N0-dimethyl DHPMs
are rather difficult and thus references for their synthesis
are very rare. To establish the scope and utility of our
catalyst, a number of reactions (Table 4) were con-
ducted and the products isolated. It was noted that on
scaling up the reaction, the amount of MgSO4 need not
be increased proportionately. After lyophilization of the
water extract obtained from the filtration of the product,
the recovered catalyst could be reused to a maximum of
three successive preparations of the DHPMs with almost
the same yield of the reaction. The water extract
Encouraged by the aforementioned results, we turned
our attention toward the utilization of our catalyst to-
ward the construction of the bis-3,4-dihydropyrimidin-
2(1H)-ones (thiones). We found that the reactions pro-
ceeded smoothly in aqueous medium with MgSO4 (10
mol %) to produce the N,N0-unsubstituted bis-com-
pounds in excellent yields (Scheme 2, Table 5). The
responded to positive tests for both Mgþ2 and SO4
2ꢂ
ions indicating that the catalyst remains intact after the
reaction. The role of the catalyst is therefore to increase
the electrophilicity of the aldehyde carbonyl which is
very obvious as with other metal salts and also to coor-
dinate with the carbonyl oxygen of the b-keto ester and
the b-diketone.
On analysis of Tables 3 and 4, we find that our cata-
lyst produced the N,N0-unsubstituted-3,4-dihydropyrimi-
din-2(1H)-ones in excellent yields and the N,N0-dimethyl
DHPMs in good yields. The reaction also accommo-
dated a wide variety of substrates in the aldehyde part,
both electron-donating and electron-withdrawing acting
0
reaction generated two new chiral centers at C4 and C4 -
positions, the relative stereochemistry of which could be
either RR or RS. X-ray crystallography of these com-
pounds was not possible due to their amorphous nature.
With dimethyl urea and thiourea, the formation of these
bis-compounds did not go to completion. These bis-
compounds are otherwise quite difficult to achieve and
therefore the application of our catalyst provides an easy
access to the construction of these compounds.
The mechanism of the dihydropyrimidone formation
is similar as proposed by Folkers and Johnson [15]. The
Scheme 1. Synthesis of 3,4-dihydropyrimidin-2(1H)-ones (thiones) with MgSO4 (10 mol %) in water at 90ꢁC.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2010 Synthesis of N,N0-Dimethyl Substituted (Unsubstituted)-4-Aryl-3,4-Dihydropyrimidones
(Thiones) and Corresponding Bis-Analogues in Aqueous Medium
139
Table 3
Synthesis of N,N0-unsubstituted-3,4-dihydropyrimidin-2(1H)-ones (thiones) (R3 ¼ H) with MgSO4 (10 mol %) in water at 90ꢁC.
Yield (%)
(isolated)
Entry
R1
R2
X
Time (h)
References
1
2
3
OEt
OMe
OMe
OEt
OMe
Me
4-Cl
4-OMe
4-OH-3-OMe
3-OH
O
O
S
8
9
6
90
88
85
82
80
88
87
83
85
82
80
78
82
78
81
79
75
80
82
78
75
78
79
82
84
86
85
77
73
76
77
76
85
84
83
82
79
[10]
[10]
[10]
[13]
[10]
–
4
S
7
5
6
3-NO2
2,5-(OMe)2
2,5-(OMe)2
4-CN
O
O
O
O
O
S
10
5
7
8
OMe
OMe
OEt
Me
5
6
–
–
9
4-NO2
H
4-CN
10
7
[13]
[13]
–
[13]
–
[13]
–
[13]
–
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
Me
S
8
OEt
OMe
OEt
OEt
Me
OMe
Me
Me
2-furanyl
4-CN
4-OH
4-CN
2-Cl
3-OH
O
S
4
8
S
S
9
10
8
S
S
7
2-NO2
3-NO2
4-OH-3-OMe
H
S
9
–
–
–
S
S
9
8
Me
OEt
OEt
OMe
Me
O
S
9
9
[13]
[13]
[13]
[13]
[13]
[13]
[13]
[13]
[13]
[13]
[13]
[13]
[13]
[13]
[13]
[13]
[13]
H
4-OH-3-OMe
4-OMe
4-OMe
3-NO2
4-NMe2
4-NMe2
4-NO2
3-OH
O
O
S
7
5
OEt
Me
OEt
OMe
Me
5
O
O
O
O
O
O
O
S
10
4
4
10
6
OEt
Me
4-Cl
H
H
7
Me
8
8
OMe
OEt
Me
OMe
OMe
4-OMe
4-OH
4-OH
O
O
O
O
6
7
8
4-NO2
8
initial formation of the acylimine intermediate takes
place which reacts subsequently with the b-diketone or
b-ketoester effectively. The partial covalent character of
Mgþ2 helps in forming a strong metal oxygen bond
which helps in increasing the electrophilicity of the b-
diketone or b-ketoester in the same manner as men-
tioned in ref. [5]. Finally, a favorable cyclization and
dehydration path follows to produce the dihydropyrimi-
done system.
matography, (f) this methodology is particularly useful
for the synthesis of the dimethyl dihydropyrimidones
and bis-dihydropyrimidones which are otherwise quite
rare in the literature, and (g) it is a totally green
methodology.
Green metric calculations. The green metrics were
calculated using the procedures reported in the litera-
ture.4 Their definitions are given as follows:
Mass Intensity (MI) ¼ Total mass used in a process
or process step (g)/mass of product (g)
In a nutshell, our methodology has the following dis-
tinct advantages over the earlier reported procedures
[6.9]: (a) the reactions are investigated in water and
hence avoids the hassles of organic solvents, (b) the cat-
alyst is rather simple and cheap, (c) anhydrous reaction
conditions need not be maintained, (d) additional proton
sources are not required, (e) the products are obtained
by simple filtration without the need for column chro-
Reaction mass efficiency (RME) ¼ (R mass of prod-
ucts/R mass of reactants) ꢃ 100
Carbon efficiency (CE) ¼ [(No. of moles of product
ꢃ No. of carbons in product)/R (No. of moles of reac-
tant ꢃ No. of carbons in reactant)] ꢃ 100
Atom economy (AE) ¼ [molecular weight of product/
R molecular weight of reactant] ꢃ100
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

140
C. Mukhopadhyay and A. Datta
Vol 47
Table 4
Synthesis of N,N0-dimethyl-4-aryl-dihydropyrimidones (thiones) (R3 ¼ Me) with MgSO4 (10 mol %) in water at 90ꢁC.
Entry
R1
R2
X
Time (h)
Yielda
References
1
2
OMe
OEt
OMe
OEt
OMe
OMe
OEt
Me
Me
Me
OMe
OMe
Me
40-OMe
40-OH
O
O
O
O
O
O
O
O
O
O
O
O
S
10
8
60
62
60
61
65
62
61
60
62
65
64
61
44
58
60
65
60
61
64
60
–
–
3
4
40-Cl
8
9
–
–
30,40-(OMe)2
20-NO2
20,50-(OMe)2
20,50-(OMe)2
20-Cl
5
9
–
6
7
9
10
6
–
–
8
9
–
–
40-NO2
40-Br
7
10
11
12
13
14
15
16
17
18
19
20
9
10
7
–
–
40-Br
20-Cl
–
40-Br
12
10
7
–
–
Me
20-Cl
S
OEt
Me
40-Cl
O
O
O
O
O
O
–
–
30-NO2
20-NO2
30-NO2
40-NO2
40-OMe
7
OEt
OEt
OEt
OEt
8
9
[2]
[2]
[2]
[2]
9
9
a Isolated.
Mass intensity (MI), reaction mass efficiency (RME),
carbon efficiency (CE), and atom economy (AE) have
been considered as a measure of environmental sustain-
ability in minimizing the amount of theoretical waste.
MI considers the yield stoichiometry, the solvent and
the RME is the natural measure of greenness that takes
into account the yield, excess or catalytic amount of
reactants used but it does not account for any solvent
use. CE is the percentage of carbon gain or loss, that is,
whether all the carbon atoms of the reactant are present
in the product. It is a very important parameter in our
reaction as our reaction involves carbon atoms. Finally,
the AE is a theoretical calculation of the chemical and
environmental efficiency of the reaction which allows
Scheme 2. Synthesis of bis-3,4-dihydropyrimidin-2(1H)-ones (thiones) at 90ꢁC in aqueous medium with MgSO4 (10 mol %).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2010 Synthesis of N,N0-Dimethyl Substituted (Unsubstituted)-4-Aryl-3,4-Dihydropyrimidones
(Thiones) and Corresponding Bis-Analogues in Aqueous Medium
141
Table 5
Synthesis of bis-3,4-dihydropyrimidin-2(1H)-ones (thiones) at 90ꢁC in aqueous medium with MgSO4 (10 mol %).
Entry
R1
Starting dialdehyde
X
Time (h)
Yield (%) (isolated)
References
1
2
3
4
5
6
7
8
OMe
OEt
5
5
5
5
7
7
7
7
O
O
S
O
O
O
S
10
11
15
10
12
11
10
11
85
82
75
80
84
82
76
74
–
–
OMe
Me
–
[14]
[14]
[14]
[14]
[14]
OMe
OEt
OMe
OEt
S
for the effect on stoichiometric equation, not considering
any solvent, excess of reagents and formation of inter-
mediate or any other side product, etc. So from this
aforementioned point, the ideal situation is MI ꢄ 1, %
RME ꢄ 100, % CE ꢄ 100, % AE ꢄ 100.
solvent in the reaction will lead to the ideal situation.
We use only 0.5 mL of water in our reactions which
is the optimum value. Use of lower amount of solvent
(water) in the reaction will lead to increase in MI, but
lower yield, as the catalyst will not react in lesser
amount of solvent used. Thus, the MI values obtained
were highly acceptable. Our reactions have excellent
CE (for reactions with urea and thiourea) and quite
good CE (for reactions with dimethyl counterparts),
which in these cases is equal to the yield because all
the carbon atoms of the reactant are present in the
We have shown the green metrics calculations for
some selected compounds using urea, thiourea, or di-
methyl urea (Table 6). The results reveal that our reac-
tions have excellent MI values for almost all the com-
pounds (Table 6). MI values of the reactions are very
much dependent on solvent. Use of lesser amount of
Table 6
Green metrics calculations of a wide variety of compounds taken from Tables 3–5.
Entry
Substrates used
% Yield
FW (product)
Yield (g)
MI
% RME
% CE
% AE
1
2
3
Table 3, entry 6
Table 3, entry 7
Table 3, entry 8
Table 3, entry 11
Table 3, entry 13
Table 3, entry 15
Table 3, entry 17
Table 3, entry 18
Table 3, entry 19
Table 3, entry 20
Table 4, entry 1
Table 4, entry 2
Table 4, entry 3
Table 4, entry 4
Table 4, entry 5
Table 4, entry 6
Table 4, entry 7
Table 4, entry 8
Table 4, entry 9
Table 4, entry 10
Table 3, entry 11
Table 3, entry 12
Table 3, entry 13
Table 3, entry 14
Table 3, entry 15
Table 3, entry 16
Table 5, entry 1
Table 5, entry 2
Table 5, entry 3
88
87
83
80
82
81
75
80
82
78
60
62
60
61
65
62
61
60
62
65
64
61
44
58
60
65
85
82
75
290.317
306.316
271.275
271.342
287.341
301.368
278.291
291.329
291.329
292.356
304.344
304.344
308.763
348.390
319.320
334.370
348.396
292.764
303.316
337.215
353.210
308.760
353.280
308.830
322.790
303.320
414.416
442.469
446.548
0.255
0.266
0.225
0.217
0.235
0.244
0.208
0.233
0.238
0.228
0.182
0.188
0.185
0.212
0.207
0.207
0.212
0.175
0.188
0.219
0.226
0.188
0.155
0.179
0.193
0.197
0.352
0.362
0.334
3.32
3.43
3.90
3.81
3.80
3.72
4.25
3.64
3.56
3.72
5.00
4.80
4.94
4.50
4.47
4.54
4.50
4.85
4.75
4.08
4.24
4.87
5.87
4.83
4.81
4.36
3.14
3.13
3.41
73.70
64.56
59.68
66.36
59.80
59.95
54.16
67.15
68.59
65.52
44.39
45.85
44.69
46.70
48.70
47.70
46.70
50.29
52.37
55.73
49.24
45.41
37.90
49.18
45.09
54.87
58.08
57.10
52.35
88
87
83
80
82
81
75
80
82
78
60
62
60
61
65
62
61
60
62
65
64
61
44
58
60
65
85
82
75
88.96
89.47
88.28
88.28
88.86
89.32
88.84
88.99
88.99
89.03
89.41
89.42
89.55
90.06
89.86
90.27
90.63
89.04
89.38
90.35
90.74
89.55
90.75
89.55
89.96
89.38
85.19
86.00
86.11
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

142
C. Mukhopadhyay and A. Datta
Vol 47
252–254ꢁC (MeOH). IR (KBr): 3247, 3107, 1705, 1628, 1495,
product. In the same direction, the excellent yields
with the catalyst produced good values of RME while
moderate yield produced moderate RME values. Table
6 shows that all our reactions possess excellent AE
values mostly being 89–90%. Thus all the reactions
carried out using our methodology have very good
green metrics correlations.
1
1454, and 1235 cmꢂ1. H NMR (300 MHz, DMSO-d6) d: 9.12
(s, 1H, NH), 7.33 (s, 1H, NH), 6.90 (d, J ¼ 8.7 Hz, 1H, aro-
matic C3-H), 6.78 (dd, J ¼ 9.0, 3.0 Hz, 1H, aromatic C4-H),
6.53 (d, J ¼ 3.3 Hz, 1H, aromatic C6-H), 5.48 (d, J ¼ 3.0 Hz,
1H, C4-H), 3.72 (s, 3H, C2-OMe), 3.61 (s, 3H, C5-OMe), 2.25
(s, 3H, ACOCH3), 2.00 (s, 3H, C6-CH3). 13C NMR (75 MHz,
DMSO-d6) d: 194.6 (C¼¼O), 153.2 (C2¼¼O), 152.3 (aromatic
C2), 150.5 (aromatic C5), 148.2 (C6), 132.4 (aromatic C1),
113.9 (aromatic C3), 112.3 (aromatic C4), 112.2 (aromatic C6),
108.0 (C5), 56.0 (C2-OMe), 55.4 (C5-OMe), 48.9 (C4), 29.8
(COCH3), 18.7 (C6-CH3). Anal. calcd. for C15H18N2O4; C:
62.06, H: 6.25, N: 9.65. Found: C: 62.17, H: 6.02, N: 9.71%.
5-Methoxycarbonyl-6-methyl-4-(2,5-dimethoxyphenyl)-3.4-
dihydropyrimidin-2(1H)-one (Table 3, entry 7). Off-white
solid; M.p. 240–242ꢁC (MeOH). IR (KBr): 3241, 3106, 2948,
CONCLUSION
It can be concluded that MgSO4ꢀ7H2O (10 mol %) in
0.5 mL water proves to be the best catalyst amongst all
the alkaline Group II metals for dihydropyrimidone, bis-
dihydropyrimidone and particularly, N,N0-dimethyl dihy-
dropyrimidone formation. Since only 10 mol % of the
catalyst and 0.5 mL of water are used, the reaction con-
dition meets several green chemistry principles. The iso-
lation of the reaction products is very simple and does
not require column chromatography for most cases.
1
1703, 1646, 1496, 1440, 1235, and 1092 cmꢂ1. H NMR (300
MHz, DMSO-d6) d: 9.16 (s, 1H, NH), 7.26 (s, 1H, NH), 6.91
(d, J ¼ 9.0 Hz, 1H, aromatic C3-H), 6.79 (dd, J ¼ 8.9, 3.0 Hz,
1H, aromatic C4-H), 6.54 (d, J ¼ 3.0 Hz, 1H, aromatic C6-H),
5.41 (d, J ¼ 3.0 Hz, 1H, C4-H), 3.73 (s, 3H, C2-OMe), 3.64
(s, 3H, C5-OMe), 3.47 (s, 3H, ACOOCH3), 2.27 (s, 3H, C6-
CH3). 13C NMR (75 MHz, DMSO-d6) d: 165.9 (COOMe),
153.0 (C2¼¼O), 152.3 (aromatic C2), 150.8 (aromatic C5),
149.3 (C6), 132.6 (aromatic C1), 113.9 (aromatic C3), 112.4
(aromatic C4), 112.0 (aromatic C6), 97.4 (C5), 56.1 (C2-OMe),
55.3 (C5-OMe), 50.8 (C4), 49.0 (COOCH3), 17.8 (C6-CH3).
Anal. calcd. for C15H18N2O5; C: 58.82, H: 5.92, N: 9.15.
Found: C: 58.71, H: 5.84, N: 9.22%.
EXPERIMENTAL
General. Ethanol was distilled before use. All the chemicals
were purchased from Aldrich Chemical Company and Spectro-
chem (Mumbai, India). Silica Gel G with binder from Spectro-
chem was used for thin layer chromatography. MgSO4ꢀ7H2O
was purchased from Spectrochem was used as such. 1H and
13C NMR spectra were obtained on Bruker 300 MHz instru-
ment at 300 and 75 MHz, respectively. CDCl3 and DMSO-d6
were purchased from Aldrich Chemical Company. Melting
points were determined on an electrical melting point appara-
tus with an open capillary and are uncorrected. IR spectra
were recorded on a Perkin-Elmer spectrophotometer RX/FTIR
system.
General experimental procedure for dihydropyrimidone/
bis-dihydropyrimidone formation. A mixture of aromatic
aldehyde (1 mmol), b-keto ester or b-diketone (1.3 mmol/2.6
mmol), urea/thiourea/N,N0-dimethyl urea/N,N0-dimethyl thiou-
rea (1.5 mmol/3.0 mmol) and MgSO4ꢀ7H2O (10 mol %) and
0.5 mL water were mixed thoroughly and then taken in a 5
mL conical flask. It was next placed in water bath at 90ꢁC and
heated for the specified time as mentioned in Tables 3–5. The
reactions were monitored by TLC for the absence of the start-
ing aldehyde. After completion of the reaction, the crude mass
was cooled, poured into crushed ice, and stirred for further 10
min, when the dihydropyrimidones (solids) precipitated out.
They were directly filtered and crystallized from hot aqueous
ethanol to obtain the finally pure products. The liquid DHPMs
products were extracted with (2 ꢃ 5) mL ethyl acetate, washed
with brine, solvent removed to obtain the crude products. The
pure products (liquids) were obtained by column chromatogra-
phy with silica gel (100–200 mesh) and elution with ethyl ace-
tate/petroleum ether (60–80ꢁC). All the products were charac-
terized by their spectral and analytical data.
5-Methoxycarbonyl-6-methyl-4-(4-cyanophenyl)-3.4-dihy-
dropyrimidin-2(1H)-one (Table 3, entry 8). White solid;
M.p. 176–178ꢁC (MeOH). IR (KBr): 3329, 3120, 2235, 1634,
1
1223, and 1089 cmꢂ1. H NMR (300 MHz, DMSO-d6) d: 9.33
(s, 1H, NH), 7.85 (d, J ¼ 1.2 Hz, 1H, NH), 7.80 (d, J ¼ 8.4 Hz,
2H, aromatic C3-, C5-H), 7.38 (d, J ¼ 8.1 Hz, 2H, aromatic C2-,
C6-H), 5.18 (d, J ¼ 3.3 Hz, 1H, C4-H), 3.49 (s, 3H, ACOCH3),
2.22 (s, 3H, C6-CH3). 13C NMR (75 MHz, DMSO-d6) d: 165.7
(COOMe), 152.0 (C2¼¼O), 149.9 (aromatic C1), 149.7 (C6),
132.7 (aromatic C3, C5), 127.4 (aromatic C2, C6), 118.8 (C5),
110.3 (aromatic C4), 98.2 (CN), 53.8 (C4), 51.0 (COOCH3),
18.0 (C6-CH3). Anal. calcd. for C14H13N3O3; C: 61.99, H: 4.83,
N: 15.49. Found: C: 61.84, H: 4.71, N: 15.63%.
5-Acetyl-6-methyl-4-(4-cyanophenyl)-3.4-dihydropyrimidin-
2(1H)-thione (Table 3, entry 11). White solid; M.p. 130–
132ꢁC (MeOH). IR (KBr): 3277, 3181, 2228, 1617, 1577, 1455,
and 1186 cmꢂ1 1H NMR (300 MHz, DMSO-d6) d: 10.38 (s,
.
1H, NH), 9.81 (d, J ¼ 2.4 Hz, 1H, NH), 7.80 (d, J ¼ 8.4 Hz, 2H,
aromatic C3-, C5-H), 7.35 (d, J ¼ 8.1 Hz, 2H, aromatic C2-, C6-
H), 5.32 (d, J ¼ 3.9 Hz, 1H, C4-H), 2.31 (s, 3H, COCH3), 2.18
(s, 3H, C6-CH3). 13C NMR (75 MHz, DMSO-d6) d: 194.7
(C¼¼O), 174.6 (C¼¼S), 148.1 (aromatic C1), 145.5 (C6), 132.8
(aromatic C3, C5), 127.6 (aromatic C2, C6), 118.8 (C5), 110.5
(aromatic C4), 110.3 (CN), 53.4 (C4), 30.8 (COCH3), 18.5 (C6-
CH3). Anal. calcd. for C14H13N3OS; C: 61.97, H: 4.83, N: 15.49.
Found: C: 61.84, H: 4.75, N: 15.61%.
5-Methoxycarbonyl-6-methyl-4-(4-cyanophenyl)-3.4-dihy-
dropyrimidin-2(1H)-thione (Table 3, entry 13). White solid;
M.p. 158–160ꢁC (MeOH). IR (KBr): 3327, 3146, 2926, 2228,
1689, 1526, and 1173 cmꢂ1 1H NMR (300 MHz, DMSO-d6)
.
The data for all the previously unknown compounds are
given later:
5-Acetyl-6-methyl-4-(2,5-dimethoxyphenyl)-3,4-dihydropyr-
imidin-2(1H)-one (Table 3, entry 6). Light brown solid; M.p.
d: 10.45 (s, 1H, NH), 9.72 (d, J ¼ 2.1 Hz, 1H, NH), 7.80 (d, J
¼ 8.4 Hz, 2H, aromatic C3-, C5-H), 7.35 (d, J ¼ 8.1 Hz, 2H,
aromatic C2-, C6-H), 5.20 (d, J ¼ 3.3 Hz, 1H, C4-H), 3.51 (s,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2010 Synthesis of N,N0-Dimethyl Substituted (Unsubstituted)-4-Aryl-3,4-Dihydropyrimidones
(Thiones) and Corresponding Bis-Analogues in Aqueous Medium
143
3H, COOCH3), 2.25 (s, 3H, C6-CH3). 13C NMR (75 MHz,
DMSO-d6) d: 175.1 (C¼¼S), 165.3 (C¼¼O), 147.0 (aromatic
C1), 143.6 (C6), 132.8 (aromatic C3, C5), 127.5 (aromatic C2,
C6), 118.3 (C5), 112.4 (aromatic C4), 102.0 (CN), 55.6 (C4),
51.7 (COOCH3), 18.6 (C6-CH3). Anal. calcd. for
C14H13N3O2S; C: 58.52, H: 4.56, N: 14.62. Found: C: 58.64,
H: 4.68, N: 14.74%.
5-Ethoxycarbonyl-6-methyl-4-(4-cyanophenyl)-3.4-dihydro-
pyrimidin-2(1H)-thione (Table 3, entry 15). White solid;
M.p. 242–244ꢁC (MeOH). IR (KBr): 3319, 3145, 2229, 1532,
1428, 1172, and 772 cmꢂ1 1H NMR (300 MHz, CDCl3) d:
.
8.27 (s, 1H, NH), 7.85 (s, 1H, NH), 7.63 (d, J ¼ 8.1 Hz, 2H,
aromatic C3-, C5-H), 7.42 (d, J ¼ 8.4 Hz, 2H, aromatic C2-,
C6-H), 5.46 (d, J ¼ 3.0 Hz, 1H, C4-H), 4.12 (q, J ¼ 6.8 Hz,
2H, OCH2CH3), 2.38 (s, 3H, C6-CH3), 1.20 (t, J ¼ 7.2 Hz,
3H, OCH2CH3). 13C NMR (75 MHz, CDCl3) d: 174.7 (C¼¼S),
164.9 (C¼¼O), 147.1 (aromatic C1), 143.6 (C6), 132.7 (aro-
matic C3, C5), 127.5 (aromatic C2, C6), 118.3 (C5), 112.2 (aro-
matic C4), 102.1 (CN), 60.8 (OCH2), 55.6 (C4), 18.4 (C6-
CH3), 14.1 (OCH2CH3). Anal. calcd. for C15H15N3O2S; C:
59.78, H: 5.02, N: 13.94. Found: C: 59.64, H: 5.16, N:
14.04%.
130.8 (aromatic C5), 123.1 (aromatic C2), 121.7 (aromatic C4),
110.8 (C5), 53.4 (C4), 31.2 (COCH3), 18.9 (C6-CH3). Anal.
calcd. for C13H13N3O3S: C: 53.60, H: 4.50, N: 14.42. Found:
C: 53.51, H: 4.54, N:14.39%.
5-Acetyl-4-(4-hydroxy-3-methoxyphenyl)-6-methyl-3,4-dihy-
dropyrimidin-2(1H)-thione (Table 3, entry 20). Yellowish-
white solid; M.p. 228–230ꢁC (EtOH). IR (KBr):3485, 3255,
3194, 1589, 1518, 1458, 1193, and 796 cmꢂ1 1H NMR (300
.
MHz, DMSO-d6) d: 10.20 (s, 1H, NH), 9.65 (brs, 1H, NH), 9.05
(s, 1H, OH), 6.85 (d, J ¼ 1.8 Hz, 1H, aromatic C2-H), 6.72 (d, J
¼ 7.8 Hz, 1H, aromatic C5-H), 6.58 (dd, J ¼ 8.1, 1.8 Hz, 1H,
aromatic C6-H), 5.20 (d, J ¼ 3.6 Hz, 1H, C4-H), 3.74 (s, 3H, ar-
omatic AOMe), 2.32 (s, 3H, ACOCH3), 2.11 (s, 3H, C6-CH3).
13C NMR (75 MHz, DMSO-d6) d: 195.6 (C¼¼O), 174.2 (C¼¼S),
148.0 (aromatic C3), 146.7 (aromatic C4), 144.6 (C6), 134.3 (aro-
matic C1), 119.2 (aromatic C6), 115.9 (aromatic C5), 111.8 (aro-
matic C2), 110.6 (C5), 56.1 (OCH3), 54.2 (C4), 30.6 (COCH3),
18.6 (C6-CH3). Anal. calcd. for C14H16N2O3S: C: 57.52, H: 5.52,
N: 9.58. Found: C: 57.39, H: 5.65, N: 9.47%.
1,3,6-Trimethyl-4-(4-methoxyphenyl)-2-oxo-1,2,3,4-tetrahy-
dropyrimidine-5 carboxylic acid methyl ester (Table 4, entry
1). Light yellow solid; M.p. 68–70ꢁC (ethylacetate þ petro-
leum ether). IR (KBr): 2949, 1669, 1506, 1431, and 1353
4-(3-Hydroxyphenyl)-5-methoxycarbonyl-6-methyl-3,4-dihy-
dropyrimidin-2(1H)-thione (Table 3, entry 17). Off-white
solid; M.p. 220–222ꢁC (EtOH). IR (KBr): 3315, 3189, 1669,
.
1576, 1478, 1284, 1194, 1117, and 752 cmꢂ1 1H NMR (300
cmꢂ1
.
1H NMR (CDCl3, 300 MHz) d: 7.13 (td, J ¼ 8.4 Hz
and 3 Hz, 2H, C2-H, C6-H), 6.81 (td, J ¼ 8.7 Hz and 3 Hz,
2H, C3-H, C5-H), 5.17 (s, 1H, C4-H), 3.77 (s, 3H, –OCH3),
3.67 (s, 3H, ACOOCH3), 3.28 (s, 3H, N1-CH3), 2.89 (s, 3H,
N3-CH3), 2.47 (s, 3H, C6-CH3). 13C NMR (CDCl3, 75 MHz)
d: 166.4 (ACOOCH3), 159.2 (C2¼¼O), 153.8 (aromatic-C4),
149.1 (C1), 133.9 (vinylic C6), 127.7 (2C, C2 þ C3), 114.0
(2C, C3 þ C5), 103.7 (vinylic C5), 60.2 (C4), 55.2 (AOCH3),
51.2 (ACOOCH3), 34.3 (N1-CH3), 31.0 (N3-CH3), 16.6 (C6-
CH3). Anal. calcd. for C16H20N2O4; C: 63.15, H: 6.62, N:
9.20. Found: C: 63.04, H: 6.77, N: 9.45%.
MHz, DMSO-d6) d: 10.32 (s, 1H, NH), 9.62 (brd, J ¼ 1.8 Hz,
1H, NH), 9.47 (s, 1H, OH), 7.12 (t, J ¼ 7.8 Hz, 1H, aromatic
C5-H), 6.65 (d, J ¼ 8.7 Hz, 3H, aromatic C2-, C4-, and C6-H),
5.09 (d, J ¼ 3.6 Hz, 1H, C4-H), 3.57 (s, 3H, ACOOMe), 2.29 (s,
3H, C6-CH3). 13C NMR (75 MHz, DMSO-d6) d: 174.7 (C¼¼S),
166.2 (C¼¼O), 158.0 (aromatic C3), 145.6 (C6), 145.1 (aromatic
C1), 130.1 (aromatic C5), 117.4 (aromatic C6), 115.2 (aromatic
C2), 113.7 (aromatic C4), 101.0 (C5), 54.3 (C4), 51.6 (COOCH3),
17.7 (C6-CH3). Anal. calcd. for C13H14N2O3S: C: 56.10, H:
5.07, N: 10.06. Found: C: 56.03, H: 5.05, N: 10.10%.
1,3,6-Trimethyl-4-(4-hydroxyphenyl)-2-oxo-1,2,3,4-tetrahy-
dropyrimidine-5-carboxylic acid ethyl ester (Table 4, entry
2). Off-white solid; M.p.184–186ꢁC (ethylacetate þ petroleum
5-Acetyl-6-methyl-4-(2-nitrophenyl)-3,4-dihydropyrimidin-
2(1H)-thione (Table 3, entry 18). Brown solid; M.p. 254–
256ꢁC (EtOH). IR (KBr): 3419, 2927, 1719, 1607, 1527, 1355,
.
1268, 1202, 1093, 1013, and 668 cmꢂ1 1H NMR (300 MHz,
1
ether). IR (KBr): 3209, 2373, 1704, 1641, and 1449 cmꢂ1. H
NMR (CDCl3, 300 MHz) d: 7.02 (d, J ¼ 8.7 Hz, 2H, C2-H,
C6-H), 6.68 (d, J ¼ 8.4 Hz, 2H, C3-H, C5-H), 5.16 (s, 1H, C4-
H), 4.13 (dq, J ¼ 7.8 Hz and 2.4 Hz, 2H, AOCH2CH3), 3.27
(s, 3H, N1-CH3), 2.91 (s, 3H, N3-CH3), 2.47 (s, 3H, C6-CH3),
1.73 (brs, 1H, OH), 1.22 (t, J ¼ 7.2 Hz, 3H, AOCH2CH3). 13C
NMR (CDCl3, 75 MHz) d: 166.1 (ACOOCH3), 156.1 (C2¼¼O),
154.2 (aromatic C4), 148.6 (C1), 132.4 (vinylic C6), 127.9 (2C,
C2 þ C6), 115.5 (2C, C3 þ C5), 104.3 (vinylic C5), 60.4 (C4),
60.3 (AOCH2), 34.5 (N1-CH3), 31.1 (N3-CH3), 16.6 (C6-CH3),
14.2 (AOCH2CH3). Anal. calcd. for C16H20N2O4; C: 63.15, H:
6.62, N: 9.20. Found: C: 63.03, H: 6.88, N: 9.37%.
DMSO-d6) d: 10.41 (s, 1H, NH), 9.60 (s, 1H, NH), 7.92 (dd, J ¼
9.0, 0.9 Hz, 1H, aromatic C3-H), 7.72 (td, J ¼ 7.5,1.2 Hz, 1H, C4-
H), 7.54 (td, J ¼ 8.4, 1.2 Hz, 1H, aromatic C5-H), 7.46 (dd, J ¼
9.0, 1.2 Hz, 1H, aromatic C6-H), 5.98 (d, J ¼ 3.0 Hz, 1H, C4-H),
2.36 (s, 3H, ACOCH3), 2.16 (s, 3H, C6-CH3). 13C NMR (75
MHz, DMSO-d6) d: 194.0 (C¼¼O), 173.7 (C¼¼S), 147.0 (aromatic
C2), 144.6 (C6), 137.0 (aromatic C1), 133.6 (aromatic C5), 128.7
(aromatic C6), 128.6 (aromatic C4), 123.9 (aromatic C3), 110.1
(C5), 48.9 (C4), 30.3 (COCH3), 17.9 (C6-CH3). Anal. calcd. for
C13H13N3O3S: C, 53.60; H,4.50; N, 14.42%. Found: C, 53.53; H,
4.48; N,14.45%.
5-Acetyl-6-methyl-4-(3-nitrophenyl)-3,4-dihydropyrimidin-
2(1H)-thione (Table 3, entry 19). Brown solid; M.p. 280–
281ꢁC (EtOH). IR (KBr): 3294, 3183, 2374, 1612, 1576, 1527,
1450, 1346, and 1186 cmꢂ1 1H NMR (300 MHz, DMSO-d6)
.
d: 10.45 (s, 1H, NH), 9.88 (brs, 1H, NH), 8.13–8.17 (m, 1H,
aromatic C4-H), 8.09 (brs, 1H, aromatic C2-H), 7.63–7.70 (m,
2H, aromatic C5-, C6-H), 5.44 (d, J ¼ 3.9 Hz, 1H, C4-H), 2.37
(s, 3H, ACOOMe), 2.28 (s, 3H, C6-CH3). 13C NMR (75 MHz,
DMSO-d6) d: 195.1 (C¼¼O), 175.0 (C¼¼S), 148.4 (aromatic
C3), 146.1 (C6), 145.4 (aromatic C6), 133.5 (aromatic C1),
1,3,6-Trimethyl-4-(4-chlorophenyl)-2-oxo-1,2,3,4-tetrahy-
dropyrimidine-5-carboxylic acid methyl ester (Table 4,
entry 3). Off-white solid; M.p. 86–88ꢁC (ethylacetate þ petro-
leum ether). IR (KBr): 2927, 1660, 1604, 1464, 1434, and
1
1268 cmꢂ1. H NMR (CDCl3, 300 MHz) d: 7.06 (d, J ¼ 8.4
Hz, 2H, C2-H, C6-H), 6.96 (d, J ¼ 8.4 Hz, 2H, C3-H, C5-H),
5.03 (s, 1H, C4-H), 3.48 (s, 3H, AOCH3), 3.06 (s, 3H, N1-
CH3), 2.71 (s, 3H, N3-CH3), 2.28 (s, 3H, C6-CH3). 13C NMR
(CDCl3, 75 MHz) d: 166.0 (ACOOCH3), 153.4 (C2¼¼O), 149.6
(C4), 139.3 (vinylic C6), 133.4 (aromatic C1), 128.6 (2C, C2 þ
C6), 127.7 (2C, C3 þ C5), 102.8 (vinylic C5), 60.0 (C4), 51.1
(AOCH3), 34.3 (N1-CH3), 30.9 (N3-CH3), 16.5 (C6-CH3).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

144
C. Mukhopadhyay and A. Datta
Vol 47
Anal. calcd. for C15H17N2O3Cl; C:58.35, H: 5.55, N: 9.07.
Found: C: 58.13, H: 5.83, N: 9.27%.
1,3,6-Trimethyl-4-(2-chlorophenyl)-5-acetyl-6-methyl-1,2,3,4-
tetrahydropyrimidin-2(1H)-one (Table 4, entry 8). Brown
solid; M.p. 80–82ꢁC (ethylacetate þ petroleum ether). IR
1,3,6-Trimethyl-4-(3, 4-dimethoxyphenyl)-2-oxo-1,2,3,4-tet-
rahydropyrimidine-5-carboxylic acid ethyl ester (Table 4,
entry 4). Light brown sticky liquid; IR (KBr): 3499, 2935,
1670, 1511 1031, and 753 cmꢂ1. 1H NMR (CDCl3, 300 MHz) d:
6.77–6.71 (m, 3H, C2-H, C5-H, C6-H), 5.16 (s, 1H,C4-H), 4.13
(q, J ¼ 7.2 Hz, 2H, AOCH2), 3.82 (s, 3H, AOCH3), 3.81 (s, 3H
AOCH3), 3.23 (s, 3H, N1-CH3), 2.90 (s, 3H, N3-CH3), 2.44 (s,
3H, C6-CH3), 1.24 (t, J ¼ 7.2 Hz, 3H, ACH2CH3). 13C NMR
(CDCl3, 75 MHz) d: 166.0 (ACOOCH2CH3), 153.8 (C2¼¼O),
148.9, 148.8, 148.6 (3C, aromatic C4, C3, C1), 133.6 (vinylic
C6), 118.6 (C6), 111.9 (C2), 109.9 (C5), 103.9 (vinylic C5), 60.4
(C4), 60.1 (AOCH2), 55.8 (AOCH3), 55.7 (AOCH3), 34.3 (N1-
CH3), 30.9 (N3-CH3), 16.5 (C6-CH3), 14.2 (AOCH2CH3). Anal.
calcd. for C18H24N2O5; C: 62.05, H: 6.94, N: 8.04, O: 22.96%.
Found: C: 62.13, H: 6.73, N: 8.27%.
(KBr): 2926, 1660, and 1610 cmꢂ1 1H NMR (CDCl3, 300
.
MHz) d: 7.38–7.33 (m, 1H, aromaticC4-H), 7.31–7.22 (m, 3H,
C3-H, C5-H, C6-H), 5.78 (s, 1H, C4-H), 3.30 (s, 3H, N1-CH3),
2.96, 2.95 (2s, 3H, N3-CH3), 2.49 (2s, 3H, C6-CH3), 2.14 (S,
3H, ACOCH3). 13C NMR (CDCl3, 75 MHz) d: 196.3
(ACOCH3), 152.7 (C2¼¼O), 148.6 (C1), 137.7 (C2), 132.5
(vinylic C6), (129.8, 129.7, 129.4) (C3, aromatic C4, C6), 128.3
(C5), 112.1 (vinylic C5), 57.5 (C4), 33.9 (N1-CH3), 30.9 (N3-
CH3), 30.1 (COCH3), 17.1 (C6-CH3). Anal. calcd. for
C15H17N2O2Cl; C: 61.54, H: 5.85, N: 9.57, O: 10.93, Cl:
12.11%. Found: C: 61.33, H: 5.83, N: 9.27%.
1,3,6-Trimethyl-4-(4-nitrophenyl)-5-acetyl-6-methyl-1,2,3,4-
tetrahydropyrimidine-2(1H)-one (Table 4, entry 9). Light
brown solid; M.p. 142–144ꢁC (ethylacetate þ petroleum ether).
IR (KBr): 2931, 1675, 1621, and 1518 cmꢂ1 1H NMR
.
1,3,6-Trimethyl-4-(2-nitrophenyl)-2-oxo-1,2,3,4-tetrahydro-
pyrimidine-5-carboxylic acid methyl ester (Table 4, entry
5). Light brown sticky liquid; IR (KBr): 2944, 1670, 1618,
(CDCl3,300 MHz) d: 8.16 (td, J ¼ 8.7 Hz and 2.4 Hz, 2H, C2-H,
C6-H), 7.39 (td, 8.7 Hz and 1.8 Hz, 2H, C3-H, C5-H), 5.46 (s,
1H, C4-H), 3.34 (S, 3H, N1-CH3), 2.99 (s, 3H, N3-CH3), 2.42 (s,
3H, C6-CH3), 2.34 (s, 3H, ACOCH3). 13C NMR (CDCl3, 75
MHz) d: 194.8 (ACOCH3), 153.5 (C2¼¼O), 149.0 (aromatic C4),
147.6 (C1/vinylic C6), 147.5 (vinylic C6/C1), 127.3 (C2, C6),
124.0 (C3, C5), 114.2 (vinylic C5), 59.9 (C4), 34.8 (N1-CH3),
31.4 (N3-CH3), 31.4 (ACOCH3), 17.9 (C6-CH3). Anal. calcd. for
C15H17N3O4; C: 59.40, H: 5.65, N: 13.85, O: 21.10%. Found: C:
59.53, H: 5.83, N: 13.77%.
1
1534, and 1202 cmꢂ1. H NMR (CDCl3, 300 MHz) d: 7.44 (dd,
J ¼ 9 Hz and 0.9 Hz, 1H, C3-H), 7.31–7.23 (m, 2H, aromatic
C4 and C6H), 7.13 (dt, J ¼ 7.4 Hz and 2.4 Hz, 1H, C5H), 5.71
(s, 1H, C4-H), 3.24 (s, 3H, N1-CH3), 3.08 (s, 3H, AOCH3), 2.74
(s, 3H, N3-CH3), 2.26 (s, 3H, C6-CH3). 13C NMR (CDCl3, 75
MHz) d: 165.3 (ACOOCH3), 152.8 (C2¼¼O), 150.4 (C2), 148.8
(C1) 137.0 (vinylic C6), 133.2 (C5), 128.7 (aromatic-C4þC6),
123.4 (C3), 102.1 (vinylic C5), 54.6 (C4), 51.0 (AOCH3), 33.7
(N1-CH3), 30.8 (N3-CH3), 16.3 (C6-CH3). Anal. calcd. for
C15H17N3O5; C: 56.42, H: 5.37, N: 13.16, O: 25.05%. Found: C:
56.33, H: 5.43, N: 13.27%.
1,3,6-Trimethyl-4-(4-bromophenyl)-5-acetyl-6-methyl-1,2,3,4-
tetrahydropyrimidine-2(1H)-one (Table 4, entry 10). Light
brown sticky liquid; IR (KBr): 2929, 1665, 1601, and 1403
1
cmꢂ1. H NMR (CDCl3,300 MHz) d: 7.44 (td, J ¼ 8.4 Hz and
1,3,6-Trimethyl-4-(2,5-dimethoxyphenyl)-2-oxo-1,2,3,4-tetra-
hydropyrimidine-5-carboxylic acid methyl ester (Table 4,
entry 6). White solid; M.p. 100–102ꢁC (ethylacetate þ petro-
1.8 Hz, 2H, C2-H, C6-H), 7.09 (td, J ¼ 8.4 Hz and 1.8 Hz, 2H,
C3-H, C5-H), 5.23 (s, 1H, C4-H), 3.26 (s, 3H, N1-CH3), 2.95 (s,
3H, N3-CH3), 2.42 (s, 3H, vinylic C6-CH3), 2.25 (s, 3H,
ACOCH3). 13C NMR (CDCl3, 75 MHz) d: 195.3 (ACOCH3),
153.4 (C2¼¼O), 148.3 (C1), 139.1 (vinylic C6), 131.9 (C2, C6),
128.3 (C3, C5), 122.0 (C4), 113.8 (vinylic C5), 60.5 (C4), 34.5
(N1-CH3), 31.2 (N3-CH3), 30.9 (ACOCH3), 17.5 (C6-CH3).
Anal. calcd. for C15H17N2O2Br; C:53.45, H: 5.08, N: 8.31, O:
9.49, Br: 23.69%. Found: C: 53.33, H: 5.13, N: 8.27%.
leum ether). IR (KBr): 2940, 2845, 1659, and 1434 cmꢂ1 1H
.
NMR (CDCl3, 300 MHz) d: 6.76 (d, J ¼ 8.7 Hz, 1H, C3-H),
6.70 (dd, J ¼ 9 Hz and 2.7 Hz, 1H, aromatic C4-H), 6.67 (d, J
¼ 2.7 Hz, 1H, C6-H), 5.55 (s, 1H, C4-H), 3.73, 3.68 (2S, 6H,
2AOCH3), 3.57 (S, 3H, N1-CH3), 3.25, 3.23 (2s, 6H, N3-CH3,
AOCH3), 2.45 (s, 3H, C6-CH3). 13C NMR (CDCl3, 75 MHz) d:
166.4 (ACOOCH3), 153.6 (C2¼¼O), 151.3 (C2/C5), 149.2 (C5/
C2), 129.7 (vinylic C6), 115.1 (C3), 112.8 (aromatic C4/C6),
112.0 (C6/aromatic-C4), 102.1 (vinylic C5), 56.2 (C4), 55.5, 55.4
(2 ꢃ OCH3), 50.9 (COCH3), 31.0 (N1-CH3), 30.8 (N3-CH3),
16.4 (C6-CH3). Anal. calcd. for C17H22N2O5; C: 61.07, H: 6.63,
N: 8.38, O: 23.92%. Found: C: 61.13, H: 6.53, N: 8.27%.
1,3,6-Trimethyl-4-(4-bromophenyl)-2-oxo-1,2,3,4-tetrahydro-
pyrimidine-5-carboxylic acid methyl ester (Table 4, entry
11). Light grey sticky liquid; IR (KBr): 2949, 1672, 1633, and
1
1415 cmꢂ1. H NMR (CDCl3, 300 MHz) d: 7.42 (d, J ¼ 8.4
Hz, 2H, C2-H, C6-H), 7.11 (d, J ¼ 8.4 Hz,2H, C3-H, C5-H),
5.22 (s, 1H, C4-H), 3.68 (s, 3H, N1-CH3), 3.26 (s, 3H, N3-
CH3), 2.91 (s, 3H, AOCH3), 2.48 (s, 3H, C6-CH3). 13C NMR
(CDCl3, 75 MHz) d: 166.0 (ACOOCH3), 153.4 (C2¼¼O), 149.6
(C1), 139.8 (vinylic C6), 131.6 (C2, C6), 128.1 (C3, C5), 121.5
(aromatic C4), 102.7 (vinylic C5), 60.1 (C4), 51.1 (AOCH3),
34.3 (N1-CH3), 30.9 (N3-CH3), 16.5 (C6-CH3). Anal. calcd. for
C15H17N2O3Br; C: 51.01, H: 4.85, N: 7.93, O: 13.59, Br:
22.63%. Found: C: 51.13, H: 4.83, N: 8.17%.
1,3,6-Trimethyl-4-(2,5-dimethoxyphenyl)-2-oxo-1,2,3,4-tetra-
hydropyrimidine-5-carboxylic acid ethyl ester (Table 4, entry
7). White solid; M.p. 68–70ꢁC (ethylacetate þ petroleum ether).
1
IR (KBr): 2934, 1666, and 1492 cmꢂ1. H NMR (CDCl3, 300
MHz) d: 6.78–6.73 (m, 2H, C3-H, C4-H), 6.71 (d, J ¼ 1.2 Hz,
1H, C6-H), 5.59 (s, 1H, C4-H), 4.02 (dq, J ¼ 7.2 Hz, 0.9 Hz,
AOCH2), 3.57 (s, 3H, AOCH3), 3.26 (s, 3H, N1-CH3), 2.84 (s,
3H, N3-CH3), 2.48 (s, 3H, vinylicC6), 1.14(t, J ¼ 7.2 Hz, 3H,
AOCH2CH3). 13C NMR (CDCl3, 75 MHz) d: 166.1
(ACOOCH2CH3), 153.6 (C2¼¼O, C1), 151.3 (C2/C5), 149.2 (C5/
C2), 129.9 (vinylic C6), 115.5 (C3), 112.8 (aromatic-C4/C6),
111.6 (C6/aromatic-C4), 102.3 (vinylic C5), 59.8 (C4), 56.0
(AOCH3), 55.5 (AOCH3,AOCH2), 33.9 (N1-CH3), 30.8 (N3-
CH3), 16.4 (C6-CH3), 14.0 (AOCH2-CH3). Anal. calcd. for
C18H24N2O5; C: 62.05, H: 6.94, N: 8.04, O: 22.96%. Found: C:
62.13, H: 6.83, N: 8.27%.
1,3,6-Trimethyl-4-(2-chlorophenyl)-2-oxo-1,2,3,4-tetrahydro-
pyrimidine-5-carboxylic acid methyl ester (Table 4, entry
12). Light brown solid; M.p. 54–56ꢁC (ethyl acetate þ petroleum
ether). IR (KBr): 3596, 1661, 1604, and 1464 cmꢂ1 1H NMR
.
(CDCl3, 300 MHz) d: 7.35–7.28 (m, 2H, aromaticC4-H, C6-H),
7.24–7.16 (m, 2H, C3-H, C5-H), 5.82 (s, 1H, C4-H), 3.60 (s, 3H,
N1-CH3), 3.32, 3.31 (2s, 3H, N3-CH3), 2.88 (s, 3H, AOCH3), 2.57,
2.56 (2s, 3H, C6-CH3). 13C NMR (CDCl3, 75 MHz) d: 166.1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2010 Synthesis of N,N0-Dimethyl Substituted (Unsubstituted)-4-Aryl-3,4-Dihydropyrimidones
(Thiones) and Corresponding Bis-Analogues in Aqueous Medium
145
(ACOOCH3), 152.9 (C2¼¼O), 149.9 (C1), 139.0 (C2) 132.0 (vinylic
(RR/RS) 4,4-(1,3-phenylene)-bis[5-methoxycarbonyl-3,4-
dihydro-6-methyl]-pyrimidin-2(1H)-one (Table 5, entry
C6), 129.4,129.2, 129.0 (C3, aromatic C4,C6), 127.8 (C5), 102.4
(vinylic C5), 57.1 (C4), 51.1 (ACOOCH3), 33.7 (N1-CH3), 30.7
(N3-CH3), 16.4 (C6-CH3). Anal. calcd. for C15H17N2O3Cl; C:
58.35, H: 5.55, N: 9.07, O: 15.55, Cl: 11.48%. Found: C: 58.23, H:
5.73, N: 9.27%.
1). White solid; M.p. 309–311ꢁC (MeOH). IR (KBr): 3339,
1
3304, 1668, 1441, 1343, 1237, and 1091 cmꢂ1. H NMR (300
MHz, DMSO-d6) d: 9.19 (s, 2H, 2 ꢃ NH), 7.71 (s, 2H, 2 ꢃ NH),
7.25 (t, J ¼ 7.8 Hz, 1H, aromatic C5-H), 7.20–7.05 (m, 3H, aro-
matic C2, C4, and C6-H), 5.08 (d, J ¼ 3.0 Hz, 2H, 2 ꢃ C4-H),
3.50 (s, 6H, 2 ꢃ OCH3), 2.20 (s, 6H, 2 ꢃ C6-CH3). 13C NMR
(75 MHz, DMSO-d6) d: 165.9 (2 ꢃ COOMe), 152.4 (2 ꢃ
C2¼¼O), 148.6 (aromatic C1, C3), 145.2 (2 ꢃ C6), 128.7 (aro-
matic C5), 125.4 (aromatic C4, C6), 124.1 (aromatic C2), 99.3 (2
ꢃ C5), 54.0 (2 ꢃ C4), 50.9 (2 ꢃ COOCH3), 17.9 (2 ꢃ C6-CH3).
Anal. calcd. for C20H22N4O6; C: 57.97, H: 5.35, N: 13.52.
Found: C: 57.84, H: 5.45, N: 13.61%.
1,3,6-Trimethyl-4-(4-bromophenyl)-5-acetyl-6-methyl-1,2,3,4-
tetrahydropyrimidine-2(1H)-thione (Table 4, entry 13). Light
1
yellow sticky liquid; IR (KBr): 3133, 1612, and 1400 cmꢂ1. H
NMR (CDCl3, 300 MHz) d: 7.14 (dd, J ¼ 9.3 Hz and 1.8 Hz, 2H,
C2-H, C6-H), 6.98 (dd, J ¼ 8.1 and 1.5 Hz, 2H, C3-H, C5-H), 5.61
(s, 1H, C4-H), 3.56 (s, 3H, N1-CH3), 3.49 (s, 3H, N3-CH3), 2.41
(s, 3H, C6-CH3), 2.39 (s, 3H, ACOCH3). 13C NMR (CDCl3, 75
MHz) d:196.3 (ACOCH3), 179.3 (C2¼¼S), 146.4 (C1), 138.2
(vinylic C6), 132.0 (C2, C6), 127.6 (C3,C5), 122.0 (aromatic C4),
116.3 (vinylic C5), 60.6 (C4), 43.1 (N1-CH3), 38.2 (N3-CH3), 31.1
(ACOCH3), 17.9 (C6-CH3). Anal. calcd. for C15H17N2OSBr; C:
51.00, H: 4.85, N: 7.93, O: 4.53, S: 9.08, Br: 22.62%. Found: C:
51.13, H: 4.93, N: 8.17%.
(RR/RS) 4,4-(1,3-phenylene)-bis[5-ethoxycarbonyl-3,4-dihy-
dro-6-methyl]-pyrimidin-2(1H)-one (Table 5, entry 2). White
solid; M.p. 296–298ꢁC (MeOH). IR (KBr): 3361, 3237, 3114,
1
1700, 1643, 1457, 1226, and 1093 cmꢂ1. H NMR (300 MHz,
DMSO-d6) d: 9.14 (s, 2H, 2 ꢃ NH), 7.72 (s, 2H, 2 ꢃ NH), 7.24
(t, J ¼ 7.2 Hz, 1H, aromatic C5-H), 7.16–7.03 (m, 3H, aromatic
C2, C4-, and C6-H), 5.06 (s, 2H, 2 ꢃ C4-H), 3.92 (s, 4H, 2 ꢃ
AOCH2CH3), 2.19 (s, 6H, 2 ꢃ C6-CH3), 1.04 (t, J ¼ 6.3 Hz,
6H, 2 ꢃ AOCH2CH3). 13C NMR (75 MHz, DMSO-d6) d: 165.3
(2 ꢃ COOMe), 152.2 (2 ꢃ CO), 148.4 (aromatic C1, C3), 145.2
(2 ꢃ C6), 128.6 (aromatic C5), 125.4 (aromatic C4, C6), 124.2
(aromatic C2), 99.4 (2 ꢃ C5), 59.3 (2 ꢃ OCH2), 54.1 (2 ꢃ C4),
17.8 (2 ꢃ C6-CH3), 14.2 (2 ꢃ OCH2CH3). Anal. calcd. for
C22H26N4O6; C: 59.72, H: 5.92, N: 12.66. Found: C: 59.87, H:
5.85, N: 12.81%.
1,3,6-Trimethyl-4-(2chlorophenyl-5-acetyl-6-methyl-1,2,3,4-
tetrahydropyrimidine-2(1H)-thione (Table 4, entry 14). Light
yellow sticky liquid; IR (KBr): 3138, 1669, 1625, and 1399 cmꢂ1
.
1H NMR (CDCl3, 300 MHz) d: 7.39–7.36 (m, 1H, aromatic-C4-
H), 7.27–7.23 (m, 2H, C6-H, C3-H), 7.17–7.14 (m, 1H, C5-H),
5.95 (s, 1H, C4-H), 3.66 (s, 3H, N1-CH3), 3.50 (s, 3H, N3-CH3),
2.45 (C6-CH3), 2.24 (ACOCH3). 13C NMR (CDCl3, 75 MHz) d:
196.4 (ACOCH3), 179.1 (C2¼¼S), 145.3 (C1), 136.4 (C2), 132.2
(vinylic C6), (130.1, 130.0, 128.8, 128.3) (C3, aromatic C4,C6,C5),
114.6 (vinylic C5), 58.5 (C4), 42.5 (N1-CH3), 38.1 (N3-CH3), 30.1
(ACOCH3), 17.4 (C6-CH3). Anal. calcd. for C15H17N2OSCl; C:
58.34, H: 5.55, N: 9.07, O: 5.18, S: 10.38, Cl: 11.48%. Found: C:
58.23, H: 5.83, N: 9.27%.
(RR/RS)
4,4-(1,3-phenylene)-bis[5-methoxycarbonyl-3,4-
dihydro-6-methyl]-pyrimidin-2(1H)-thione (Table 5, entry
3). White solid; M.p. 280–282ꢁC (MeOH). IR (KBr):3301,
3186, 2373, 1699, 1567, 1437, 1321, 1186, and 1108 cmꢂ1
.
1,3,6-Trimethyl-4-(4-chlorophenyl)-2-oxo-1,2,3,4-tetrahydro-
pyrimidine-5-carboxylic acid ethyl ester (Table 4, entry
15). Off-white solid; M.p. 60–62ꢁC (ethylacetate þ petroleum
1H NMR (300 MHz, DMSO-d6) d: 10.39 (s, 2H, 2 ꢃ NH),
9.60 (s, 2H, 2 ꢃ NH), 7.31 (t, J ¼ 7.8 Hz, 1H, aromatic C5-
H), 7.11 (d, J ¼ 7.8 Hz, 2H, aromatic C4, C6-H), 7.02 (s, 1H,
aromatic C2-H), 5.10 (d, J ¼ 3.3 Hz, 2H, 2ꢃC4-H), 3.54 (s,
6H, 2ꢃAOCH3), 2.30 (s, 6H, 2 ꢃ -CH3). 13C NMR (75 MHz,
DMSO-d6) d: 174.4 (2 ꢃ C¼¼S), 165.6 (2 ꢃ COOMe), 145.3
(aromatic C1, C3), 143.9 (2 ꢃ C6), 129.0 (aromatic C5), 125.9
(aromatic C4, C6), 124.2 (aromatic C2), 100.5 (2 ꢃ C5), 54.0
(2 ꢃ C4), 51.2 (2ꢃCOOMe), 17.3 (2ꢃC6-CH3). Anal. calcd.
for C20H22N4O4S2; C: 53.80, H: 4.97, N: 12.55. Found: C:
53.94, H: 5.15, N: 12.41%.
ether). IR (KBr): 3500, 1670, and 1427 cmꢂ1 1H NMR
.
(CDCl3,300 MHz) d: 7.27 (d, J ¼ 8.4 Hz, 2H, C2-H, C6-H),
7.16 (d, J ¼ 8.4 Hz, 2H, C3-H,C5-H), 5.22 (s, 1H, C4-H), 4.12
(q, J ¼ 7.2 Hz, 2H, AOCH2), 3.26 (s, 3H, N1-CH3), 2.89 (s,
3H, N3-CH3), 2.47 (s, 3H, C6-CH3), 1.24 (t, J ¼ 7.2 Hz, 3H,
AOCH2CH3). 13C NMR (CDCl3, 75 MHz) d: 164.7
(ACOOCH2CH3), 152.6 (C2¼¼O), 148.7 (C1), 138.9 (C4),
132.5 (vinylic C6), 127.9 (C2, C6), 127.3 (C3,C5), 102.2
(vinylic C5), 59.4 (C4), 59.3 (AOCH2), 33.5 (N1-CH3), 30.1
(N3-CH3), 15.2 (C6-CH3), 13.4 (AOCH2CH3). Anal. calcd. for
C16H19N2O3Cl; C: 59.54, H: 5.93, N: 8.68, O: 14.87, Cl:
10.98%. Found: C: 59.43, H: 5.83, N: 8.77%.
Acknowledgment. The authors thank the CAS Instrumentation
Facility, University of Calcutta for spectral data. Thanks are also
due to the Centre for Research in Nanoscience and Nanotechnol-
ogy, University of Calcutta [Ref. No. Conv./006/nano RAC
(2009), dt. 25/2/09] for funding.
1,3,6-Trimethyl-4-(3-nitrophenyl)-5-acetyl-6-methyl-1,2,3,4-
tetrahydropyrimidine-2(1H)-one (Table 4, entry 16). Light
1
brown liquid; IR (KBr): 3485, 1672, 1605, and 1529 cmꢂ1. H
NMR (CDCl3,300 MHz) d: 8.14 (qd, J ¼ 8.1 Hz and 1.5 Hz, 1H,
C6-H), 8.08 (t, J ¼ 1.8 Hz, 1H, C2-H), 7.58 (td, J ¼ 7.5 Hz and
1.5 Hz, 1H, aromatic-C4-H), 7.50 (t, J ¼ 7.8 Hz, 1H, C5-H), 5.41
(s, 1H,C4-H), 3.31 (S, 3H, N1-CH3), 2.99 (s, 3H, N3-CH3), 2.47
(S, 3H, C6-CH3), 2.32 (s, 3H, ACOCH3). 13C NMR (CDCl3, 75
MHz) d:194.8 (ACOCH3), 153.2 (C2¼¼O), 149.1 (C4), 148.6
(C1), 142.5 (vinylic-C6), 132.7 (C6), 129.8 (C5), 123.0 (C2/aro-
matic C4), 121.6 (aromatc C4/C2), 113.9 (vinylic C5), 60.2 (C4),
34.7 (N1-CH3), 31.3 (N3-CH3), 31.2 (C6-CH3), 17.8 (ACOCH3).
Anal. calcd. for C15H17N3O4; C: 59.40, H: 5.65, N: 13.85, O:
21.10%. Found: C: 59.33, H: 5.83, N: 13.77%.
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