Facile synthesis of some new functionalized 2-selenoxopyrimidines

Article abstract of DOI:10.1080/10426507.2019.1694023

Some new functionalized 2-selenoxodihydropyrimidines 1–6 were synthesized in good yields via a simple one-pot reaction. The simple method depended on the reaction of selenourea with some nitrile active methylene compounds under basic-catalyzed conditions.

Full text of DOI:10.1080/10426507.2019.1694023

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: https://www.tandfonline.com/loi/gpss20
Facile synthesis of some new functionalized 2-
selenoxopyrimidines
Ahmed M. Fouda, Mohammed A. Assiri & Tarik E. Ali
To cite this article: Ahmed M. Fouda, Mohammed A. Assiri & Tarik E. Ali (2019): Facile synthesis
of some new functionalized 2-selenoxopyrimidines, Phosphorus, Sulfur, and Silicon and the
Related Elements, DOI: 10.1080/10426507.2019.1694023
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PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
https://doi.org/10.1080/10426507.2019.1694023
Facile synthesis of some new functionalized 2-selenoxopyrimidines
Ahmed M. Fouda, Mohammed A. Assiri, and Tarik E. Ali
Department of Chemistry, Faculty of Science, King Khalid University, Abha, Saudi Arabia
ABSTRACT
ARTICLE HISTORY
Received 26 August 2019
Accepted 13 November 2019
Some new functionalized 2-selenoxodihydropyrimidines 1–6 were synthesized in good yields via a
simple one-pot reaction. The simple method depended on the reaction of selenourea with some
nitrile active methylene compounds under basic-catalyzed conditions. Also, treatment of sele-
nourea with each of malononitrile and ethyl cyanoacetate in the presence of benzaldehyde under
the same basic reaction conditions afforded the 2-selenoxopyrimidine-5-carbonitriles 7 and 8,
respectively. Furthermore, selenourea reacted with benzaldehyde and different b-dicarbonyl com-
pounds under Biginelli reaction conditions to afford the 2-selenoxo-1,2,3,4-tetrahydropyrimidine-5-
carboxylates 10, 11 and 13. Using acetylacetone as a substrate in Biginelli reaction yielded the
unexpected 5-benzylidene-4,6-dimethyl-pyrimidine-2(5H)-selenone (14). The structures of the syn-
KEYWORDS
Selenourea;
2-selenoxopyrimidine;
Biginelli reaction
1
thesized compounds were established on the basis of elemental analysis, IR, H- and 13C-NMR and
mass spectral data.
GRAPHICAL ABSTRACT
Introduction
only been described through two reports in the literature. Klein
and coworkers reported the synthesis of a single seleno-ana-
logue of Monastrol and evaluated its ability to inhibit the
Kinesin Eg5 enzyme; however, it caused a twofold decrease in
the activity when compared to Monastrol [29]. In the second
report, Kolb and colleagues evaluated a pyrimidinyl selenourea
and its selenazolopyrimidine derivative as phosphatase inhibi-
tors [30]. The present work was aimed to synthesize some new
functionalized 2-selenoxopyrimidines by reaction of selenourea
with different active methylene compounds in absolute ethanol
containing sodium ethoxide as a catalyst. In addition, treatment
of selenourea with benzaldehyde in the presence of different
active methylene compounds under acidic or basic catalyzed
reaction conditions. The obtained products will be evaluated as
potential inhibitors for cancer cells.
In 1817, the selenium element was discovered. It is a red
amorphous powder [1]. While some organoselenium com-
pounds are less stable and toxic, their distinctive chemical and
biological properties make the chemistry of selenium-contain-
ing heterocycles interesting [2–7]. Organoselenium compounds
are well known for their antioxidant activity with the ability to
mimic selenoenzyme Glutathione Peroxidase (GPx-like activ-
ity) [8, 9]. Also, these compounds are well known to inhibit cell
proliferation and induce cell death in human cancer cells by
apoptosis [10, 11]. In addition, some selenium compounds
showed anti-inflammatory [12, 13], anticancer [14–16], neuro-
protective [17] and antimelanogenesis properties [18, 19]. On
the other hand, selenourea derivatives have found applications
as a chalcogenizing agent [20], high potential dechloroacetyla-
tion reagent [21], and scavenger of superoxide radicals [22].
Selenoureas represent important building blocks for the synthe-
sis of pharmacologically relevant selenium heterocycles espe-
cially 1,3-selenazoles and 1,3,4-selenadiazines [23–28]. To the
Results and discussion
In the present work, selenourea reacted with some nitrile
best of our knowledge, selenoxopyrimidine derivatives have active methylene compounds such as malononitrile, ethyl
CONTACT Tarik E. Ali
tarik_elsayed1975@yahoo.com; tismail@kku.edu.sa
Department of Chemistry, Faculty of Science, King Khalid University, Abha,
Saudi Arabia.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/gpss.
Supplemental data for this article can be accessed here.
ß 2019 Taylor & Francis Group, LLC

2
A. M. FOUDA ET AL.
Se
HN
HN
N
X=CN
86%
H2N
NH2
1
Se
EtONa
EtOH
+
NC
X
H2N
NH2
Se
X=CN, COOEt, CONH2
NH
X=COOEt
X=CONH2
77, 81%
H2N
O
2
Scheme 1. Reaction of selenourea with nitrile active methylene compounds.
cyanoacetate and cyanoacetamide in the presence of to the NH proton. On the other hand, the 13C-NMR spectra
ethanolic sodium ethoxide to give 4,6-diaminopyrimidine- of compounds 3–6 displayed signals of the carbon atoms C–5
2(1H)-selenone (1) and 6-amino-2-selenoxo-2,3-dihydropyri- resonating at d 102.6–104.1 (for compounds 3, 4 and 5A) and
midin-4(1H)-one (2), respectively (Scheme 1). Compounds 1 at d 61.9–82.4 (for compounds 5B and 6) ppm. Moreover,
and 2 registered the IR absorption bands for NH2 stretching compounds 3–6 exhibited signals of the carbon atoms of
in the range of 3430–3140 cmꢀ1, beside a carbonyl group at C@Se groups at d 173.5–177.1 ppm [27].
1
1654 cmꢀ1 for compound 2. The H-NMR spectra for these
The chemical modification of the pyrimidine ring can lead
compounds exhibited characteristic signals for the protons to strengthening or changing the pharmacological properties
at position 5 of pyrimidine rings in the region of d by adding bioactive moiety or group [34]. Thus, in this paper,
5.00–4.67 ppm. Their 13C-NMR spectra showed the three we extended selenourea to react with some nitrile active
specific carbon atoms of the pyrimidine rings in the regions methylene compounds in the presence of benzaldehyde. Thus,
of d 74.2–78.7 (C–5), 152.7–154.7 (C–6) and 177.2–175.0 4-amino-6-phenyl-2-selenoxo-1,2-dihydropyrimidine-5-car-
(C@Se) ppm [31], while the carbon atom of C@O in the bonitrile (7) and 4-oxo-6-phenyl-2-selenoxo-1,2,3,4-tetrahy-
product 2 was observed at d 162.0 ppm.
dropyrimidine-5-carbonitrile (8) were synthesized for the first
We turned our attention to study the possibility of treat- time in a one pot reaction from selenourea, benzaldehyde and
ment of selenourea with b-dicarbonyl compounds. Thus, active methylene compounds (namely, malononitrile, ethyl
reaction of selenourea with ethyl acetoacetate and ethyl ben- cyanoacetate or cyanoacetamide) via a base-catalyzed reaction
zoylacetate in the presence ethanolic sodium ethoxide led to conditions (Scheme 3). The structures of the compounds 7
formation of 6-methyl-2-selenoxo-2,3-dihydropyrimidin-4(1H)- and 8 were identified by NMR analysis, IR and mass spectra.
one (3) and 6-phenyl-2-selenoxo-2,3-dihydropyrimidin-4(1H)- Their IR spectra confirmed the presence of the nitrile groups
1
one (4), respectively, in moderate yields (Scheme 2). Similarly, at 2187 and 2240 cmꢀ1, respectively. The H-NMR spectra of
4,6-dimethyl-2-selenoxopyrimidine 5 and 2-selenoxodihydro- compounds
7
and
8
showed singlets in range
d
pyrimidine-4,6(1H,5H)-dione (6) were isolated from reaction 9.98 ꢀ 13.28ppm due to the NH protons, besides a singlet at d
of selenourea with acetylacetone and diethyl malonate, respect- 6.12 ppm was observed in compound 7 which could be attrib-
ively, under the same basic reaction conditions (Scheme 2). uted to the protons of the NH2 group. In addition, their 13C-
Compounds 3 [32] and 6 [33] were previously reported in the NMR spectra exhibited signals of the carbon atoms of the
literature. However, compound 6 has no any reported spectral CBN and C@Se groups at
d
119.9 ꢀ 115.1 and
data. The suggested reaction mechanisms for the formation 174.5 ꢀ 176.7 ppm, respectively, while the carbon atom of
compounds 3–6 were assumed to proceed via cyclocondensa- C@O group in compound 8 was observed at d 161.4 ppm. All
tion reactions through the nucleophilic attack of the NH2 the spectral data of the product 8 confirmed exclusion of the
groups at the carbonyl groups to remove water and ethanol other proposed structure 9 [35, 36]. The computational studies
molecules affording the final products. The IR spectra of com- of the products 8 and 9 are still under investigation. Aiding by
pounds 3–6 revealed the presence of absorption bands at the calculated frequencies and chemical shifts, the observed
3115–3199 cmꢀ1 which were assigned to the NH groups. infrared bands and NMR resonances will confidently assign
Moreover, compounds 3, 4 and 6 exhibited bands of the car- why the product 8 was achieved. In addition, the proposed
1
bonyl groups at 1677–1655 cmꢀ1. In the meantime, the H- mechanism for both reaction pathways will be theoretically
NMR spectra of compounds 3, 4 and 6 displayed singlets of studied based on the calculated electronic structure for reac-
the protons at position 5 at d 5.66, 6.06 and 4.88 ppm, respect- tion intermediates and thermodynamic parameters for the
ively, while the NH protons were observed in the regions d involved steps.
12.15 ꢀ 12.50 ppm. Furthermore, the 1H-NMR spectrum of
As one of the most important multicomponent reactions
compound 5 confirmed its existence in two tautomeric forms (MCRs), Biginelli reaction provided an easy and effective
5A and 5B due to the presence of the protons of position 5 as process to prepare 3,4-dihydropyrimidin-2(1H)-ones [37].
two singlets at d 6.40 (1H, form A) and 2.41 (2H, form B) As reported, the acid catalyst played a key role in Biginelli
ppm, beside a characteristic singlet at d 12.47 ppm attributed reaction to performing the reaction of aromatic aldehydes

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
3
Se
HN
NH
X=Me, Ph
Y=OEt
X
O
3, X=Me (69%)
4, X=Ph (75%)
Se
Se
Se
X
Y
X=Y=Me
X=Y=OEt
+
EtONa
EtOH
H2N
NH2
HN
N
N
N
O
O
H3C
CH3
(72%)
CH3
H3C
X=Me, Y=OEt
X=Ph,
Y=OEt
5B
5A
X=Me, Y=Me
X=OEt, Y=OEt
Se
HN
NH
O
O
6 (67%)
Scheme 2. Reaction of selenourea with b-dicarbonyl compounds.
(Scheme 4). On the contrary, using diethyl malonate
afforded the 4-oxo-2-selenoxo-1,2,3,4-tetrahydropyrimidine
-5-carboxylate 13 (Scheme 4). Although the product 10 was
known in the literature [40], it was synthesized by reaction
of ethyl 6-methyl-4-phenyl-2-thioxo-1,2,3,4-tetrahydro- pyr-
imidine-5-carboxylate with methyl iodide and NaSeH. This
known method needed more than 15 h to give the product
[40]. The structure of compounds 10 and 11 was obtained
Se
HN
N
X=CN
Ph
NH2
CN
7 (88%)
Se
+
H2N
NC
NH2
X
Se
from their H-NMR, 13C-NMR and mass spectra. In the H-
NMR spectra, besides the signals due to the ester groups,
three singlets appeared at regions d 5.15–5.26, 9.62–9.73 and
10.30–10.45 ppm which could be attributed to the
C4ꢀHpyrimidine and two types of NH protons, respectively.
The 13C-NMR spectra of 10 and 11 showed signals at d
165.6–165.3 ppm which corresponded to the carbonyls of
1
1
X=COOEt
K2CO3 X=CONH2
HN
NH
EtOH
Ph
O
X=CN, COOEt, CONH2
CN
8 (76, 73%)
+
PhCHO
Se
ester groups, as well as signals at
d
54.5 and
X=CONH2
HN
N
174.7–174.9 ppm due to the C ꢀ 4pyrimidine and C@Se
Ph
NH2
NH2
atoms [27].
Interestingly, using acetylacetone to react with benzalde-
hyde and selenourea under the acidic-catalyzed conditions,
O
9
the
unexpected
5-benzylidene-4,6-dimethylpyrimidine-
Scheme 3. Reaction of selenourea with benzaldehyde and nitrile active methy-
2(5H)-selenone (14) was isolated and not the desired com-
pound 15 (Scheme 5). The structure of 14 was in agreement
with elemental analysis and spectral data. Its IR spectrum
confirmed the absence of any intense absorption bands due
lene compounds.
1
and b-dicarbonyl compounds with urea and thiourea [38].
The synthesis of 3,4-dihydropyrimidin-2(1H)-selenones by
Biginelli reaction, was rarely mentioned in the literature [29,
39]. Thus, we studied the possibility of using selenourea in
Biginelli reaction with benzaldehyde and b-dicarbonyl com-
pounds (including ethyl acetoacetate, ethyl benzoylacetate,
diethyl malonate and acetylacetone) under acidic catalyzed
reaction conditions (Schemes 4 and 5).
By using ethyl acetoacetate and ethyl benzoylacetate as
substrates in Biginelli reaction, to react with benzaldehyde
and selenourea in absolute ethanol containing drops of con-
centrated HCl, the 2-selenoxo-1,2,3,4-tetrahydropyrimidine-
5-carboxylates 10 and 11, respectively, were isolated and
to carbonyl group. Its H-NMR spectrum exhibited two sig-
nals due to methyl protons at d 1.89 and 2.09 ppm, multiplet
signals at d 7.30–7.49 ppm owing to the aromatic protons,
beside
a singlet due to CHexocyclic at d 7.77 ppm.
Additionally, its 13C-NMR spectrum showed the presence of
two methyl carbons at d 20.4 and 21.9 ppm and CHexocyclic
at d 138.3 ppm, as well as C ꢀ 4, C ꢀ 6 and C@Se of pyrimi-
dine ring at d 150.3, 152.1 and 179.4 ppm, respectively. Its
mass spectrum revealed the molecular ion peak at m/z 275
(Mþ, 15%).
The synthesized 2-selenoxopyrimidines 1–14 could have
promising applications in drug discovery as potential inhibi-
tors for cancer cells. This aspect is currently under study in
not the 2-selenoxo-1,2-dihydropyrimidine-5-carboxylates 12 our laboratory and will be reported in due course.

4
A. M. FOUDA ET AL.
Se
Se
Se
+
X=Me, Ph
N
NH
HN
H
NH
and not
Ph
X
H2N
O
NH2
X
Ph
COOEt
12
COOEt
O
10, X=Me, (82%)
11, X=Ph, (85%)
EtOH
HCl
X
OEt
X=Me, Ph, OEt
Se
+
X=OEt
HN
NH
PhCHO
Ph
O
COOEt
13 (90%)
Scheme 4. Reaction of selenourea with benzaldehyde and b-dicarbonyl compounds.
O
O
Experimental
Se
+
PhCHO
+
The melting points were determined in an open capillary
tube on a digital Stuart SMP-3 apparatus. Infrared spectra
were measured on FT-IR (Nicolet IS10) spectrophotometer
using KBr disks and Perkin-Elmer 293 spectrophotometer
Me
Me
HCl EtOH
H2N
NH2
1
using KBr disks. H- and 13C-NMR spectra were measured
on Gemini-300BB spectrometer (400 and 100 MHz), using
DMSO-d6 as a solvent and TMS (d) as an internal standard.
Mass spectra were recorded on a Gas Chromatographic
GCMSqp 1000 ex Shimadzu instrument at 70 ev and direct
probe controller inlet part to single quadropole mass ana-
lyzer in (Thermo Scientific GCMS). Elemental microanalysis
was performed on Perkin-Elmer 2400II at the Chemical War
department, Ministry of Defense. The purity of the synthe-
sized compounds was checked by thin layer chromatography
(TLC) and elemental microanalysis. The Supplemental
Materials contains sample 1H and 13C NMR spectra for
products 1 – 14 (Figures S1–S24).
Se
Se
HN
N
N
N
Ph
CH3
CH3
H3C
CH3
O
Ph
14 (59%)
15
Scheme 5. Reaction of selenourea with benzaldehyde and acetylacetone.
(C ꢀ 2). MS (m/z, I %): 189 (Mþ, 6%). Anal. Calcd for
C4H6N4Se (189.08): C, 25.41; H, 3.20; N, 29.63. Found: C,
25.12; H, 2.96; N, 29.32.
General procedure for reaction of selenourea with
appropriate nitrile active methylene or b-dicarbonyl
compounds: Synthesis of the products 1-6
6-Amino-2-selenoxo-2,3-dihydropyrimidin-4(1H)-one (2):
white solid; yield 77% and 81%; mp >300 ꢁC. IR (KBr,
cmꢀ1): 3430, 3324 (NH2), 3220 (br, 2 NH), 1654 (C@O),
1628 (C@N), 1552 (C@C). 1H-NMR (d ppm, DMSO-d6):
4.67 (s, 1H, C5ꢀHpyrimidine), 6.34 (br, 2H, NH2), 11.48 (s,
1H, NH), 11.59 (s, 1H, NH). 13C-NMR (d ppm, DMSO-d6):
78.7 (C ꢀ 5), 154.7 (C ꢀ 6), 162.0 (C ꢀ 4), 175.0 (C ꢀ 2). MS
(m/z, I %): 190 (Mþ, 16%). Anal. Calcd for C4H5N3OSe
(190.06): C, 25.28; H, 2.65; N, 22.11. Found: C, 25.06; H,
2.46; N, 21.93.
6-Methyl-2-selenoxo-2,3-dihydropyrimidin-4(1H)-one (3):
white solid; yield 69%; mp 288 ꢀ 290 ꢁC (Lit. [32] mp
>250 ꢁC). IR (KBr, cmꢀ1): 3115 (br, 2 NH), 2934, 2884
(CꢀHaliph), 1671 (C@O), 1632 (C@N), 1560 (C@C). 1H-
NMR (d ppm, DMSO-d6): 2.04 (s, 3H, CH3), 5.66 (s, 1H,
C5ꢀHpyrimidine), 12.21 (s, 1H, NH), 12.26 (s, 1H, NH). 13C-
NMR (d ppm, DMSO-d6): 18.5 (CH3), 104.1 (C ꢀ 5), 153.5
(C ꢀ 6), 161.4 (C ꢀ 4), 176.3 (C ꢀ 2). MS (m/z, I %): 189
(Mþ, 30%). Anal. Calcd for C5H6N2OSe (189.08): C, 31.76;
A mixture of selenourea (2.5 mmol, 0.31 g) and appropriate
nitrile active methylene (including malononitrile, ethyl cya-
noacetate and cyanoacetamide) or b-dicarbonyl compounds
(including ethyl acetoacetate, ethyl benzoylacetate, acetylace-
tone and diethyl malonate) (2.5 mmol) in ethanolic sodium
ethoxide solution (0.1 g of Na in 20 mL of absolute EtOH)
was heated under reflux for 4–10 h. The reaction mixtures
were cooled, poured into ice and acidified with diluted
hydrochloric acid (10%). The resulting precipitates 1–6 were
filtered off, washed with water several times and crystallized
from EtOH.
4,6-Diaminopyrimidine-2(1H)-selenone (1): white solid;
yield 86%; mp >300 ꢁC. IR (KBr, cmꢀ1): 3418, 3333, 3281,
1
3140 (2 NH2), 3108 (NH), 1622 (C@N), 1572 (C@C). H-
NMR (d ppm, DMSO-d6): 5.00 (s, 1H, C5ꢀHpyrimidine), 6.53
(br, 4H, 2 NH2), 10.92 (s, 1H, NH). 13C-NMR (d ppm,
DMSO-d6): 74.3 (C ꢀ 5), 152.7 (C ꢀ 6), 155.6 (C ꢀ 4), 177.8 H, 3.20; N, 14.82. Found: C, 31.50; H, 3.01; N, 14.59.

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
5
6-Phenyl-2-selenoxo-2,3-dihydropyrimidin-4(1H)-one (4):
yellow solid; yield 75%; mp 252 ꢀ 254 ꢁC. IR (KBr, cmꢀ1): 3199
(br, 2 NH), 3096 (CꢀHarom), 2934 (CꢀHaliph), 1667 (C@O),
4-Oxo-6-phenyl-2-selenoxo-1,2,3,4-tetrahydropyrimidine-
5-carbonitrile (8): pale yellow solid; yield 76% and 73%; mp
296 ꢀ 297 ꢁC. IR (KBr, cmꢀ1): 3182 (br, 2 NH), 3070
(CꢀHarom), 2240 (CBN), 1695 (C@O), 1666 (C@N), 1573
(C@C). 1H-NMR (d ppm, DMSO-d6): 7.42–7.66 (m, 5H,
Ph–H), 13.14 (s, 1H, NH), 13.28 (brs, 1H, NH). 13C-NMR
(d ppm, DMSO-d6): 91.2 (C ꢀ 5), 115.1 (CBN), 127.1
(C ꢀ 4 phenyl), 128.9 (C ꢀ 2 ,6 phenyl), 129.2 (C ꢀ 3 ,5 phenyl),
132.6 (C ꢀ 1 phenyl), 158.9 (C ꢀ 6), 161.4 (C ꢀ 4), 176.7
(C ꢀ 2). MS (m/z, I %): 276 (Mþ, 28%). Anal. Calcd for
C11H7N3OSe (276.16): C, 47.84; H, 2.55; N, 15.22. Found: C,
47.59; H, 2.37; N, 14.98.
1
1620 (C@N), 1548 (C@C). H-NMR (d ppm, DMSO-d6): 6.06
(s, 1H, C5ꢀHpyrimidine), 7.45–7.55 (m, 3H, Ph–H), 7.67–7.69 (m,
2H, Ph–H), 12.44 (s, 1H, NH), 12.50 (s, 1H, NH). 13C-NMR (d
ppm, DMSO-d6): 103.5 (C ꢀ 5), 127.9 (C ꢀ 2 ,6 phenyl), 129.1
(C ꢀ 3 ,5 phenyl), 131.4 (C ꢀ 4 phenyl), 131.6 (C ꢀ 1 phenyl), 153.6
(C ꢀ 6), 161.4 (C ꢀ 4), 177.1 (C ꢀ 2). MS (m/z, I %): 251 (Mþ,
4%). Anal. Calcd for C10H8N2OSe (251.15): C, 47.82; H, 3.21; N,
11.15. Found: C, 47.59; H, 3.02; N, 10.94.
4,6-Dimethylpyrimidine-2(5H)-selenone (5A) and 4,6-
dimethylpyrimidine-2(1H)-selenone (5B): yellow solid; yield
72%; mp 168 ꢀ 170 ꢁC. IR (KBr, cmꢀ1): 3138 (br, NH), 2880
(CꢀHaliph), 1628 (C@N), 1596 (C@C). 1H-NMR (d ppm,
DMSO-d6): 2.11 (s, 6H, 2 CH3 form B), 2.27–2.34 (m, 6H, 2
CH3 form A), 2.41 (s, 2H, CH2 form B), 6.40 (s, 1H,
C5ꢀHpyrimidine form A), 12.47 (s, 1H, NH form A). 13C-
NMR (d ppm, DMSO-d6): 18.5 (CH3, form A), 23.8 (CH3,
form B), 61.9 (CH2, form B), 102.6 (C ꢀ 5, form A), 148.1
(C ꢀ 6, form A), 152.3 (C ꢀ 4, form A), 159.5 (C ꢀ 4,6, form
B), 171.3 (C ꢀ 2, form A), 173.5 (C ꢀ 2, form B). MS (m/z, I
%): 187 (Mþ, 4%). Anal. Calcd for C6H8N2Se (187.10): C,
38.52; H, 4.31; N, 14.97. Found: C, 38.14; H, 4.09; N, 14.74.
2-Selenoxodihydropyrimidine-4,6(1H,5H)-dione (6): white
solid; yield 67%; mp 203 ꢀ 205 (dec.) oC (Lit. [33] mp
195–210 ꢁC). IR (KBr, cmꢀ1): 3164 (br, 2 NH), 2977,
General procedure for reaction of selenourea with
appropriate b-dicarbonyl compounds and benzaldehyde
(Biginelli reaction): synthesis of the products 10, 11, 13
and 14
A mixture of selenourea (2.5 mmol, 0.31 g), benzaldehyde
(2.5 mmol, 0.24 mL), and appropriate b-dicarbonyl com-
pounds (including ethyl acetoacetate, ethyl benzoylacetate,
diethyl malonate and acetylacetone) (2.5 mmol) in absolute
ethanol (20 mL) containing concentrated HCl (0.5 mL), was
heated under reflux for 3–6 h. The reaction mixtures were
cooled. The resulting precipitates 10–14 were filtered off,
washed with ethanol several times and crystallized
from EtOH.
Ethyl 6-methyl-4-phenyl-2-selenoxo-1,2,3,4-tetrahydropyri-
midine-5-carboxylate (10): white solid; yield 82%; mp
204 ꢀ 206 ꢁC (Lit. [40] mp 196-198 ꢁC). IR (KBr, cmꢀ1):
3329, 3174 (2 NH), 3106 (CꢀHarom), 2980 (CꢀHaliph), 1671
(C@O), 1575 (C@C), 1028 (OꢀC). 1H-NMR (d ppm,
DMSO-d6): 1.08 (t, 3H, J@6.8 Hz, CH3), 2.27 (s, 3H, CH3),
3.99 (q, 2H, J@6.8 Hz, CH2), 5.15 (s, 1H, C4ꢀHpyrimidine),
7.19–7.35 (m, 5H, Ph–H), 9.62 (s, 1H, NH), 10.30 (s, 1H,
NH). 13C-NMR (d ppm, DMSO-d6): 14.4 (CH3), 17.6 (CH3),
54.5 (C ꢀ 4), 60.0 (CH2O), 101.1 (C ꢀ 5), 126.8
(C ꢀ 2 ,6 phenyl), 128.1 (C ꢀ 4 phenyl), 128.9 (C ꢀ 3 ,5 phenyl),
143.9 (C ꢀ 1 phenyl), 145.4 (C ꢀ 6), 165.6 (C@O), 174.7
(C ꢀ 2). MS (m/z, I %): 323 (Mþ, 14%). Anal. Calcd for
C14H16N2O2Se (323.26): C, 52.02; H, 4.99; N, 8.67. Found:
C, 51.83; H, 4.72; N, 8.41.
1
(CꢀHaliph), 1655 (C@O). H-NMR (d ppm, DMSO-d6): 4.88
(s, 2H, CH2), 12.15 (s, 2H, 2 NH). 13C-NMR (d ppm,
DMSO-d6): 82.4 (Cꢀ 5), 162.5 (C ꢀ 4,6), 175.5 (C ꢀ 2). MS
(m/z, I %): 191 (Mþ, 22%). Anal. Calcd for C4H4N2O2Se
(191.05): C, 25.15; H, 2.11; N, 14.66. Found: C, 24.83; H,
2.02; N, 14.39.
General procedure for reaction of selenourea with
appropriate nitrile active methylene compounds and
benzaldehyde: Synthesis of the products 7 and 8
A mixture of selenourea (2.5 mmol, 0.31 g), benzaldehyde
(2.5 mmol, 0.24 mL), and appropriate nitrile active methy-
lene (including malononitrile, ethyl cyanoacetate and cya-
noacetamide) (2.5 mmol) in absolute ethanol (20 mL)
containing anhydrous potassium carbonate (0.3 mL), was
heated under reflux for 4–9 h. The reaction mixtures were
cooled. The resulting precipitates were filtered off, washed
with ethanol several times and crystallized from EtOH.
4-Amino-6-phenyl-2-selenoxo-1,2-dihydropyrimidine-5-car-
bonitrile (7): pale yellow solid; yield 88%; mp 218 ꢀ 219 ꢁC.
IR (KBr, cmꢀ1): 3423, 3329 (NH2), 3215 (br, NH), 3027
(CꢀHarom), 2187 (CBN), 1663 (C@N), 1583 (C@C). 1H-
NMR (d ppm, DMSO-d6): 6.12 (s, 2H, NH2), 7.12–7.39 (m,
5H, Ph–H), 9.98 (s, 1H, NH). 13C-NMR (d ppm, DMSO-
d6): 89.9 (C ꢀ 5), 119.9 (CBN), 126.6 (C ꢀ 2 ,6 phenyl), 128.3
(C ꢀ 4 phenyl), 129.1 (C ꢀ 3 ,5 phenyl), 130.7 (C ꢀ 1 phenyl),
143.7 (C ꢀ 6), 149.2 (C ꢀ 4), 174.5 (C ꢀ 2). MS (m/z, I %):
275 (Mþ, 8%). Anal. Calcd for C11H8N4Se (275.17): C,
48.01; H, 2.93; N, 20.36. Found: C, 47.83; H, 2.72; N, 20.11.
Ethyl
4,6-diphenyl-2-selenoxo-1,2,3,4-tetrahydropyrimi-
dine-5-carboxylate (11): white solid; yield 85%; mp
183 ꢀ 185 ꢁC. IR (KBr, cmꢀ1): 3173 (br, 2 NH), 2980
1
(CꢀHaliph), 1698 (C@O), 1571 (C@C), 1029 (O–C). H-NMR
(d ppm, DMSO-d6): 0.71 (t, 3H, J@7.2 Hz, CH3), 3.72 (q, 2H,
J@7.2 Hz, CH2), 5.26 (s, 1H, C4ꢀHpyrimidine), 7.27–7.42 (m,
10H, Ph–H), 9.73 (s, 1H, NH), 10.45 (s, 1H, NH). 13C-NMR (d
ppm, DMSO-d6): 13.8 (CH3), 54.5 (C ꢀ 4), 59.9 (CH2O), 102.2
(C ꢀ 5), 126.8 (C ꢀ 2 ,6 phenyl), 128.1 (C ꢀ 2 ,6 phenyl), 128.2
(C ꢀ 4 phenyl), 129.0 (C ꢀ 3 ,5 phenyl), 129.1 (C ꢀ 3 ,5 phenyl),
129.5 (C ꢀ 4 phenyl), 134.4 (C ꢀ 1 phenyl), 143.4 (C ꢀ 1 phenyl),
146.3 (C ꢀ 6), 165.3 (C@O), 174.9 (C ꢀ 2). MS (m/z, I %): 385
(Mþ, 9%). Anal. Calcd for C19H18N2O2Se (385.33): C, 59.23; H,
4.71; N, 7.27. Found: C, 58.97; H, 4.52; N, 6.95.
Ethyl 4-oxo-6-phenyl-2-selenoxo-1,2,3,4-tetrahydropyrimi-
dine-5-carboxylate (13): white solid; yield 90%; mp

6
A. M. FOUDA ET AL.
250 ꢀ 252 ꢁC. IR (KBr, cmꢀ1): 3478, 3191 (br, 2 NH), 3080
(CꢀHarom), 2878 (CꢀHaliph), 1719 (C@O), 1690 (C@O), 1615
(C@C), 1033 (O-C). 1H-NMR (d ppm, DMSO-d6): 1.03 (t, 3H,
J@7.2 Hz, CH3), 3.42 (q, 2H, J@7.2 Hz, CH2), 7.33–7.91 (m, 5H,
Ph–H), 10.00 (s, 1H, NH), 11.89 (s, 1H, NH). 13C-NMR (d
ppm, DMSO-d6): 18.9 (CH3), 56.5 (CH2O), 102.7 (C ꢀ 5), 129.6
(C ꢀ 2 ,6 phenyl), 129.4 (C ꢀ 4 phenyl), 129.9 (C ꢀ 3 ,5 phenyl),
130.2 (C ꢀ 1 phenyl), 151.3 (C ꢀ 6), 165.1 (C ꢀ 4), 171.0 (C@O),
176.4 (C ꢀ 2). MS (m/z, I %): 323 (Mþ, 14%). Anal. Calcd for
C13H12N2O3Se (323.21): C, 48.31; H, 3.74; N, 8.67. Found: C,
48.06; H, 3.48; N, 8.46.
[5] Bodtke, A.; Kandt, M.; Pfeiffer, W. D.; Langer, P. Synthesis of
4-Aryl-2-Imino-2H-Selenazolines by Reaction of
a
a
a-(Selenocyanato)Acetophenones with Anilines. Phosphorus
Sulfur Silicon Relat. Elem. 2007, 182, 209–217. DOI: 10.1080/
10426500600892685.
[6] Below, H.; Pfeiffer, W. D.; Geisler, K.; Lalk, M.; Langer, P. 1,3-
Selenazole. Eur. J. Org. Chem. 2005, 2005, 3637–3639. DOI: 10.
1002/ejoc.200500456.
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Langer, P. Synthesis and Reactivity of 2-Acyl-1,3-Selenazoles.
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Peroxidase: Bioinspired Synthetic Antioxidants. Acc. Chem. Res.
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5-Benzylidene-4,6-dimethylpyrimidine-2(5H)-selenone (14):
orange solid; yield 59%; mp 220 ꢀ 222 ꢁC. IR (KBr, cmꢀ1): 3030
1
(CꢀHarom), 2950 (CꢀHaliph), 1605 (C@N), 11560 (C@C). H-
NMR (d ppm, DMSO-d6): 1.89 (s, 3H, CH3), 2.09 (s, 3H, CH3),
7.30 (d, 2H, Ph–H), 7.45–7.49 (m, 3H, Ph–H), 7.77 (s, 1H,
CHexocyclic). 13C-NMR (d ppm, DMSO-d6): 20.4 (CH3), 21.9
(CH3),
112.2
(C ꢀ 5),
127.1
(C ꢀ 4 phenyl),
128.5
(C ꢀ 2 ,6 phenyl), 129.9 (C ꢀ 3 ,5 phenyl), 131.9 (C ꢀ 1 phenyl),
138.3 (CHexocyclic), 150.3 (C ꢀ 4), 152.1 (C ꢀ 6), 179.4 (C ꢀ 2).
MS (m/z, I %): 275 (Mþ, 15%). Anal. Calcd for C13H12N2Se
(275.21): C, 56.74; H, 4.39; N, 10.18. Found: C, 56.51; H, 4.13;
N, 9.93.
[13] Choi, S. Y.; Jo, Y. O.; Koketsu, M.; Ishihara, H.; Kim, S. H.;
Kim, S. Y. Inhibitory Effects of 2-(4-Chlorophenyl)-1,3-
Selenazol-4-One on Lipopolysaccharide-Induced Nitric Oxide
Production in RAW 264.7 Cells. J. Korean Soc. Appl. Biol.
Chem. 2009, 52, 371–374. DOI: 10.3839/jksabc.2009.066.
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2004, 551, 181–197. DOI: 10.1016/j.mrfmmm.2004.02.023.
[15] Block, E.; Bird, S.; Tyson, J. F.; Uden, P. C.; Zhang, X.;
Denoyer, E. The Search for Anticarcinogenic Organoselenium
Compounds from Natural Sources. Phosphorus Sulfur Silicon
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[16] Ahn, H. J.; Koketsu, M.; Yang, E. M.; Kim, Y. M.; Ishihara, H.;
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Apoptosis by Different Mechanisms in SKOV3 and HL 60
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20973.
Conclusion
In summary, we have suggested facile synthesis of some new
2-selenoxopyrimidines. The methods include reaction of
selenourea with each different active methylene compounds.
Addition of benzaldehyde to the previous components under
basic and acidic catalyzed conditions gave some novel func-
tionalized 2-selenoxopyrimidine-5-carbonitriles and 2-sele-
noxopyrimidine-5-carboxylates in moderate to good yields.
Funding
The authors extend their appreciation to the deanship of scientific
research at King Khalid University for funding this work through gen-
eral research project under grant number (R.G.P/142/40).
[17] Nishina, A.; Sekiguchi, A.; Fukumoto, R.; Koketsu, M.;
Furukawa, S. Selenazoles (Selenium Compounds) Facilitate
Survival of Cultured Rat Pheochromocytoma PC12 Cells after
ORCID
Serum-Deprivation
and
Stimulate
Their
Neuronal
Differentiation via Activation of Akt and Mitogen-Activated
Protein Kinase, Respectively. Biochem. Biophys. Res. Commun.
2007, 352, 360–365. DOI: 10.1016/j.bbrc.2006.11.025.
Tarik E. Ali
http://orcid.org/0000-0002-7992-3478
[18] Koketsu, M.; Choi, S. Y.; Ishihara, H.; Lim, B. O.; Kim, H.;
Kim, S. Y. Inhibitory Effects of 1,3-Selenazol-4-One Derivatives
on Mushroom Tyrosinase. Chem. Pharm. Bull. 2002, 50,
1594–1596. DOI: 10.1248/cpb.50.1594.
[19] Lee, E. H.; Lim, Y. J.; Ha, S. K.; Kang, T. H.; Koketsu, M.;
Kang, C. H.; Kim, S. Y.; Park, J. H. Inhibitory Effects of 5-
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