Ultrasound-assisted rapid synthesis of 2-aminopyrimidine and barbituric acid derivatives

Article abstract of DOI:10.1080/00397911.2019.1705349

Novel, inexpensive, and relatively expeditious procedure to achieve the synthesis of different 2-aminopyrimidine and barbituric acid derivatives is presented here, starting from readily available compounds such as guanidine hydrochloride, urea, 1,3-dialkylurea, or thiourea. Under ultrasonic irradiation, base-driven (Na₂CO₃, NaOH, or NaOC₂H₅) heterocyclization reactions of the aforementioned substrates with diethyl malonate, diethyl-2-alkyl malonate, pentane-2,4-dione, or ethyl-3-oxobutanoate yielded corresponding products. Significant advantages of this sonochemical synthetic protocol with regard to the conventional thermal methods include easy reaction setup and work-up steps, reasonably mild conditions, shorter reaction times (～30 min) and comparably high product yields. The characterization of the synthesized compounds was based on melting points, FT-IR, GC-MS, ¹H-NMR techniques, and the obtained data were also checked from the previously published studies.

Full text of DOI:10.1080/00397911.2019.1705349

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Ultrasound-assisted rapid synthesis of 2-
aminopyrimidine and barbituric acid derivatives
Duygu Bayramoğlu, Gülbin Kurtay & Mustafa Güllü
To cite this article: Duygu Bayramoğlu, Gülbin Kurtay & Mustafa Güllü (2020): Ultrasound-assisted
rapid synthesis of 2-aminopyrimidine and barbituric acid derivatives, Synthetic Communications,
DOI: 10.1080/00397911.2019.1705349
To link to this article: https://doi.org/10.1080/00397911.2019.1705349
Published online: 03 Feb 2020.
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SYNTHETIC COMMUNICATIONSV
https://doi.org/10.1080/00397911.2019.1705349
Ultrasound-assisted rapid synthesis of 2-aminopyrimidine
and barbituric acid derivatives
ꢀ
€
€ €
Duygu Bayramoglu , Gulbin Kurtay , and Mustafa Gullu
Department of Chemistry, Faculty of Science, Ankara University, Ankara, Turkey
ABSTRACT
ARTICLE HISTORY
Received 25 August 2019
Novel, inexpensive, and relatively expeditious procedure to achieve
the synthesis of different 2-aminopyrimidine and barbituric acid
derivatives is presented here, starting from readily available com-
pounds such as guanidine hydrochloride, urea, 1,3-dialkylurea, or
thiourea. Under ultrasonic irradiation, base-driven (Na2CO3, NaOH, or
NaOC2H5) heterocyclization reactions of the aforementioned sub-
strates with diethyl malonate, diethyl-2-alkyl malonate, pentane-2,4-
dione, or ethyl-3-oxobutanoate yielded corresponding products.
Significant advantages of this sonochemical synthetic protocol with
regard to the conventional thermal methods include easy reaction
setup and work-up steps, reasonably mild conditions, shorter reac-
tion times (ꢀ30 min) and comparably high product yields. The char-
acterization of the synthesized compounds was based on melting
points, FT-IR, GC-MS, 1H-NMR techniques, and the obtained data
were also checked from the previously published studies.
KEYWORDS
2-Aminopyrimidine; barbitu-
ric acid; cyclization reaction;
sonochemistry
GRAPHICAL ABSTRACT
€ €
CONTACT Mustafa Gullu
gullu@ankara.edu.tr
Department of Chemistry, Faculty of Science, Ankara University,
Ankara, Turkey
Supplemental data for this article is available online at https://doi.org/10.1080/00397911.2019.1705349
ß 2020 Taylor & Francis Group, LLC

2
D. BAYRAMOĞLU ET AL.
Introduction
The past 30 years have seen increasingly rapid advances to develop environmentally
benign, “green” synthetic methods to obtain a myriad of organic compounds by
using nontoxic starting materials, catalysts, and/or solvents.[1] Therefore, the use of
sonochemical methods in organic synthesis as an alternative energy input to improve
and accelerate synthetically valuable reactions has gained considerable importance.
Ultrasound-assisted reactions differentiate from the traditional synthetic methods by
their potential to be an effective instrument to building-up even the complex molecules
with ultimate simplicity and brevity.[2–5] Pyrimidine and barbituric acid derivatives have
been extensively studied compounds due to their biocompatibility, and there is extensive
literature exploring their structural properties and similarity to the pyrimidine bases of
DNA. Therefore, these pharmaceutically active compounds are broadly used in the
development of numerous antibacterial, anti-allergic, antimicrobial, anti-HIV, and anti-
cancer drug ingredients.[6,7] Several studies have revealed that 2-aminopyrimidine deriv-
atives containing different substituents on their 5-position possess unusual
biological activity.[8]
Furthermore, 2-amino-4,6-dihydroxypyrimidine derivatives are also known for their
excellent ligand formation capabilities with copper.[9,10] Moreover, barbituric acid deriv-
atives are the most potent central nervous system depressant agents known.[11] Even
then, the synthesis of these compounds by known typical cyclization reactions, mostly
involving the use of toxic chemicals, high reaction temperatures, and long reaction
times restrict the effectiveness and applicability of the methods.[12,13] As an alternative
approach, recent developments in ultrasound-assisted heterocyclic chemistry have
heightened the need for an appropriate synthesis method to overcome the disadvantages
of the conventional cyclization reactions.[14,15] Up to now, the preparation of pyrimidine
and barbituric acid derivatives via ultrasound-assisted reactions has received limited
attention in the literature. For this purpose, in the presented study, we aimed at exam-
ining the emerging role of ultrasound waves in the cyclization reactions and on
that account, our primary challenge faced by many experiments is the synthesis of 2-
aminopyrimidine and barbituric acid derivatives by following an atom economic reac-
tion procedure preferably ends up with good to excellent yields. In this concept, an
extended explanation of the whole procedures is given in the following subtitles. The
target 2-aminopyrimidine and barbituric acid derivatives were obtained by following the
synthetic pathway illustrated in Figure 1.
Results and discussion
In this study, our primary objective is to ascertain the efficacy of the ultrasonic radi-
ation and the use of different bases on specific heterocyclization reactions and compare
the gathered data with the experimental results obtained from the conventional heating
processes. Regarding the previous studies, the synthesis of 2-aminopyrimidine and bar-
bituric acid derivatives carried out by the condensation reactions of ß-diketo com-
pounds with nitrogenous compounds such as urea and guanidine in
basic medium.[16–23]

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Figure 1. Scope of the experimental procedures.
Preparation of 2-aminopyrimidine derivatives
While designing the experimental setup to be carried out, we aimed to obtain alkyl- or
hydroxyl- (–OH) substituted 2-aminopyrimidine derivatives following the condensation
reactions of guanidine hydrochloride with different b-diketone compounds. The appro-
priate heterocyclic ring closure reaction mechanism was shown in Figure 2.
Notably, the targeted 2-aminopyrimidine derivatives possessing hydroxyl groups are
crucial starting materials because of their susceptibility to derivatization reactions, and
thus, their ability to be converted into distinct functional groups. Therefore, primarily,
literature data were evaluated and parameters such as reaction temperature, reaction
time, and the molar ratio of substrate to reactive were fully optimized (Table 1).
In the following step, the optimized reaction conditions were maintained in order to
accomplish the synthesis of the desired 2-aminopyrimidines (1–6), and the correspond-
ing reactions were performed under both conventional and ultrasonic irradiation condi-
tions. It is well known from the previous studies that most of the pyrimidine derivatives
could be synthesized under reflux by conventional methods, which possess long reaction
times (at least 1 h to overnight), and the crude product yields varied between 54% and
78%.[9,16,19,24] In comparison to these synthetic strategies, the ultrasound-assisted

4
D. BAYRAMOĞLU ET AL.
Figure 2. The proposed reaction mechanism for the synthesis of 1.
Table 1. Optimization studies of 2-aminopyrimidine derivatives.
Model reactiona
†
1: 0.5
1: 1
1: 1.5
20 30 45
32 47 43
1: 1.5
A:B
5
0
20 30 45
10 12 13
1: 0.5
60
12
5
8
20 30 45
37 55 52
1: 1
60
48
5
9
60
42
Na2CO3
NaOH
Time (min.)
Yield (%)
A:B
5
0
20 30 45
60
0
5
5
20 30 45
11 24 22
1: 1
60
20
5
6
20 30 45
12 16 15
1: 1.5
60
16
Time (min.)
Yield (%)
A:B
0
0
0
1: 0.5
NaOC2H5
Time (min.)
Yield (%)
5
20 30 45
60
38
5
20 30 45
60
76
5
20 30 45
60
70
10 28 35 36
18 45 78 75
20 47 74 72
OH
NH.HCl
NH2
)))
O
O
N
+
H2N
NH2
C2H5O
OC2H5
HO
N
base
(A)
(B)
3
aModel reaction was also carried out without base for 60 min of reaction time, and we did not isolate any product.
bMolar ratio.
cIn order to visualize the reaction outputs, we have analyzed the obtained product yields by 3-color conditional format-
ting (red: poor, yellow to orange: moderate, green: good reaction yields).

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5
Table 2. Comparison between conventional and sonochemical procedures for the synthesis of 2-ami-
nopyrimidine derivatives.
Conventional procedure
Sonochemical procedure
Base
Entry
Time
5 h
Base
Yield (%)
75
Time
Yield (%)
1
Na2CO3
30 min
Na2CO3
NaOH
66
45
72
76
56
80
55
24
78
80
54
79
72
57
75
61
26
73
NaOC2H5
Na2CO3
NaOH
NaOC2H5
Na2CO3
NaOH
NaOC2H5
Na2CO3
NaOH
NaOC2H5
Na2CO3
NaOH
2
3
4
5
6
5 h
Overnight
1 h
Na2CO3
79
92
95
86
88
NaOC2H5
NaOC2H5
NaOC2H5
NaOC2H5
1 h
NaOC2H5
Na2CO3
NaOH
1 h
NaOC2H5
cyclization reactions facilitated the formation of target molecules in less than 1 h and
furthermore, in several experiments with an addition of a strong base, such as
NaOC2H5, final yields were close to those obtained by these antecedent methods. As
aforementioned, in this section, numerous experimental parameters have been examined
to ensure that synthetic procedures are optimized. To this aim, our first objective is to
determine the most suitable base in order to achieve the desired cyclization reactions.
Since it is well known from the literature that the most commonly used bases for the
synthesis of pyrimidine derivatives are Na2CO3, NaOH, and NaOC2H5, these com-
pounds have also been studied in our sonochemical experiments, and we have found
that Na2CO3 is sufficiently reactive to act directly for the cyclization reactions of 2-
amino-4,6-dimethylpyrimidine and 2-amino-4-hydroxy-6-methylpyrimidine. Whereas,
in order to prepare 2-amino-4,6-dihydroxypyrimidine and its derivatives containing dif-
ferent alkyl or alkylidene groups in their 5-position, we have found that it is essential to
use a stronger base (NaOC2H5). The model reaction was also carried out without add-
ing any base for 60 min of reaction time, under ultrasonic conditions, and we could not
be able to isolate any product, and this phenomenon clearly demonstrated the necessity
of the base catalysis during the targeted syntheses.
Model reactions were also carried out without adding a base for 60 min of reaction
time under ultrasonic conditions, and we could not isolate any material, and this phe-
nomenon clearly demonstrated the need for baseline catalysis during the tar-
geted synthesis.
Moreover, we observed that the molar ratio of the starting materials also has a signifi-
cant influence on our cyclization reactions. Following the determination of the ideal
base type, another important aspect is to predict the molar ratio of the respective sub-
strate to base. For this reason, we made several attempts by increasing the base propor-
tion versus 2-aminopyrimidine derivatives albeit we observed that considerably better
results were achieved by using 1:1 equivalent quantity. Additionally, in the conventional
synthesis of 2-aminopyrimidines, we have found to be essential to keep the temperature

6
D. BAYRAMOĞLU ET AL.
around 100 ꢁC for about 5–8 h, but in the ultrasonic-assisted reactions, we have enlight-
ened that a temperature range of 60–70 ꢁC is sufficient and the reaction time period has
drastically decreased to 30 min (Table 2).
Preparation of barbituric acid derivatives
In the scope of the study, similar optimization studies that we conducted for the prepar-
ation of 2-aminopyrimidine derivatives were also carried out for the target barbituric
acid derivatives. Thus, in the initial stage, we have tried to predict the convenient base
to be used for the condensation reactions that occurred between diethyl malonate and
(thio)urea. To this aim, a series of experiments have been performed again by using
Na2CO3, NaOH, and NaOC2H5. The base strength of Na2CO3 and NaOH were found
to be inefficient for the condensation reactions, and following the work-up processes,
the obtained product yields were found to be insufficient. Therefore, NaOC2H5 was
selected in order to be used for further experiments. Following this step, a number of
additional experiments have been conducted to determine the exact molar ratio of the
substrate to base. When we tried to use an equal ratio (1:1), it was found that the start-
ing material was not totally consumed in the reaction environment. On the other hand,
when the experiments were repeated with higher base proportion (1:1.5), it was found
that the excess of the base remained in the medium and resulted in the formation of
by-products. On this basis, the equivalent ratio of the base was gradually reduced, and
it was observed that the highest yields were obtained when the substrate to base ratio
was set to 1:1.2. When the ideal molar ratio was identified, we focused on determining
the optimal reaction temperature. In conventional methods, the ring formation of the
barbituric acid derivatives occurs approximately at 100 ꢁC. In our case, we first tried to
accomplish the reactions aforementioned above at room temperature, but a significant
amount of starting materials remained unreacted. Therefore, the reaction temperature
was gradually increased, and we determined that the optimum reaction temperature
range varies between 60 ꢁC and 70 ꢁC. In the last step, we aimed to optimize the reac-
tion time. Thus, we have first exposed the reaction mixtures to ultrasound irradiation
for 10 min but the obtained product yields were not satisfying. Thereby, the reaction
durations were prolonged to 30 min whereas no significant increase was detected in the
product yields during the experiments exceeding 30 min In this way when compared to
conventional thermal methods that needed at least 5 h, we notably shortened the
required reaction time. The summary of our optimized reaction conditions is depicted
in Table 3.
In the case of compounds 7 and 8, the obtained yields were found relatively low
when compared to corresponding conventional methods (Table 4).[20,25–27]
Conclusion
This study set out to evaluate a feasible and inexpensive strategy to enhance the prepar-
ation of 2-aminopyrimidine and barbituric acid derivatives. Moreover, in order to pre-
dict the optimal conditions for our cyclization reactions, we intended to detect the
appropriate base, the molar ratio of substrate to base, reaction time and temperature

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SYNTHETIC COMMUNICATIONSV
7
Table 3. Optimization studies of barbituric acid derivatives.
Model reactiona
†
1:0.5
1:1
1:1.2
1:1.5
A:B
Na2CO3
NaOH
Time (min.)
Yield (%)
A:B
60
0
5
0
20 30 45 60
5
0
20 30 45 60
5
0
20 30 45 60
< 5
< 5
<5
1:0.5
60
0
1:1
1:1.2
20 30 45 60
1:1.5
20 30 45 60
Time (min.)
Yield (%)
A:B
5
20 30 45 60
5
0
5
< 5
< 5
< 5
1:0.5
1:1
1:1.2
1:1.5
NaOC2H5 Time (min.)
60
5
8
20 30 45 60
5
20 30 45 60
5
20 30 45 60
Yield (%)
0
32 46 40 41 12 43 52 50 49 13 35 50 52 51
O
O
O
O
HN
NH
)))
C2H5O
OC2H5
H2N
NH2
+
base
(B)
O
O
(A)
7
aModel reaction was also carried out without base for 60 min of reaction time, and we did not isolate any product.
bMolar ratio.
cIn order to visualize the reaction outputs, we have analyzed the obtained product yields by 3-color conditional format-
ting (red: poor, yellow to orange: moderate, green: good reaction yields).
Table 4. Comparison between conventional and sonochemical procedures for the synthesis of barbi-
turic acid derivatives.
Conventional procedure
Sonochemical procedure
Base
Entry
Time
16 h
Base
Yield (%)
64
Time
Yield (%)
7
NaOC2H5
30 min
Na2CO3
NaOH
<5
<5
52
<5
<5
47
<5
<5
79
NaOC2H5
Na2CO3
NaOH
NaOC2H5
Na2CO3
NaOH
8
9
16 h
16 h
NaOC2H5
NaOC2H5
78
38
NaOC2H5
parameters. In this context, synthesis of the target compounds has been completed in
low-economic, mild conditions with reaction durations reduced to minute scale. In view
of the findings we have obtained, we are persuaded that this new ultrasound-assisted
technique will find a broad application for the preparation of larger or condensed rings
in further studies.
Experimental section
General procedure for the sonochemical synthesis of 2-aminopyrimidine
derivatives
Into the round-bottom reaction vessels having an appropriate thickness for the sono-
chemical reactions; guanidine hydrochloride (0.052 mol) and corresponding b-diketone

8
D. BAYRAMOĞLU ET AL.
compound (0.052 mol) were placed in water (15 mL) and Na2CO3 (0.052 mol). The reac-
tion vessel has been put in a hot water bath at 60 ꢁC, and the flask content was exposed
to ultrasonic waves for 30 min. The solid product obtained at the end of the experiment
was treated with a small quantity of water and filtered through the Nuche funnel.
2-Amino-4,6-dimethylpyrimidine (1)
White solid, yield: 75%, m.p.: 152–155 ꢁC (Lit. m.p.: 153 ꢁC).24 FT-IR (KBr), ꢀmax/cmꢂ1
:
3395–3310 (s, NH2 stretching), 3175 (w, aromatic, C–H stretching), 1633 (w, N–H
bending), 1575, 1537 (conjugated C ¼ C stretching), 1459, 1381 (aliphatic C–H bend-
ing), 1243 (C–NH2 stretching), 1026, 952, 793. MS (DI) m/z (%) calcd for C6H9N3:
1
123.1; found: 123. H-NMR (CDCl3, 400 MHz) d: 2.25 (s, 6H, CH3), 5.36 (bs, 2H,
NH2), 6.33 (s, 1H, Ar–H).
General procedure for the sonochemical synthesis of barbituric acid derivatives
This method consists of two steps. Accordingly, during the first step, NaOC2H5 was
prepared in N2 atmosphere as described in the previous sections dedicated to conven-
tional methods. In the second step, the prepared base was taken into the reaction vessel
for the sonication process, and the base solution interacted with the appropriate
reagents. In this concept, first of all, the two-necked flask fitted with a dropping funnel
was purified from moisture purging with N2 for several times and sodium metal slices
(0.75 g, 0.016 mol) was added. After then, 20 mL of absolute ethyl alcohol was added
dropwise to the reaction mixture at 0 ꢁC. Following the preparation of the NaOC2H5
solution, a 10 mL of this solution was poured into the reaction vessel in which the sonic
probe will be immersed, and guanidine hydrochloride (0.052 mol) -or urea/thiourea-
and diethyl malonate derivatives (0.052 mol) were added. The reaction mixture was
exposed to ultrasound waves into a water bath at 60 ꢁC and different reaction times.
After the completion of the reaction, the crude products were dissolved in a small
amount of ice-water, and with the addition of the HCl, the pH of the solution was care-
fully adjusted to 2. The crude products were filtered off and purified by recrystallization
from the appropriate solvent system.
Barbituric acid (7)
White solid, yield: 64%, m.p.: 245–248 ꢁC (Lit. m.p.: 252–253 ꢁC).25 FT-IR (KBr),
ꢀmax/cmꢂ1: 3198, 3086 (s, N–H stretching), 2870 (w, aliphatic C–H stretching), 1673 (s,
C ¼ O stretching), 1423, 1344, 1296, 1240, 1030, 903, 775. MS (DI) m/z (%) calcd for
1
C4H4N2O3: 128.02; found: 128. H-NMR (DMSO-d6, 400 MHz) d: 3.46 (s, 2H, CH2),
11.08 (s, 2H, NH).
1
Supplementary data (Full experimental details and copies of FT-IR, GC-MS, and H-
NMR spectra of all the synthesized compounds) associated with this article can be
found via the “Supplementary Content” section of this article’s webpage.
Acknowledgment
_
The authors thank Dr. E. Ku€bra Inal for performing MS analysis.

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SYNTHETIC COMMUNICATIONSV
9
Funding
ꢀ
Mustafa Gu€llu€ and Duygu Bayramoglu acknowledge here with the support provided by AU-
BAP [15L0430001].
ORCID
ꢀ
Duygu Bayramoglu
Gu€lbin Kurtay
Mustafa Gu€llu€
http://orcid.org/0000-0002-0613-3539
http://orcid.org/0000-0003-0920-8409
http://orcid.org/0000-0003-3905-1094
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