Synthesis of some substituted pyrimidines derived from 3-acetyl coumarin

Article abstract of DOI:10.14233/ajchem.2015.18925

This study targets mainly the synthesis of a number of derivatives of coumarin containing ring pyrimidin-2-one substitutes different aromatic rings, taking advantage of the Biginelli reaction which includes the reaction of 3-acetyl coumarin with suitable

Full text of DOI:10.14233/ajchem.2015.18925

Asian Journal of Chemistry; Vol. 27, No. 10 (2015), 3687-3691
A
SIAN
J
OURNAL OF HEMISTRY
C
http://dx.doi.org/10.14233/ajchem.2015.18925
Synthesis of Some Substituted Pyrimidines Derived from 3-Acetyl Coumarin
*
NABEEL A.A. AL-RADHA and QASSIM A.H. JABER
Department of Chemistry, College of Education, Al-Qadisiyah University, Al Diwaniyah, Qadisiyyah Province, Iraq
*Corresponding author: Tel: +964 7903620810; E-mail: nabeel1959@yahoo.com; kas888alshibany777@gmail.com
Received: 11 December 2014;
Accepted: 2 February 2015;
Published online: 22 June 2015;
AJC-17328
This study targets mainly the synthesis of a number of derivatives of coumarin containing ring pyrimidin-2-one substitutes different
aromatic rings, taking advantage of the Biginelli reaction which includes the reaction of 3-acetyl coumarin with suitable aromatic aldehydes
and urea in the presence of AlCl3 and absolute ethanol as a solvent. It has been indicated that the biological activity is important and
diverse to these kinds of compounds, which is the preparation of compound 3-acetyl coumarin (7) to be used as a compound base. The
compounds having heterocyclic ring are expected to have various important biological and therapeutic applications. This proves structural
formulae for each of new synthetic compounds on the basis of chemical reactions, analysis of the elements, the infrared spectra and
nuclear magnetic resonance (1H NMR and 13C NMR).
Keywords: Coumarin derivatives, Substituted pyrimidines, 4,3-Dihydro-(4-aryl-6-coumarin)pyrimidin-2-one.
known as 4,3-dihydro-pyrimidin-2-one (4) as shown in the
following equation:
INTRODUCTION
Coumarin derivatives received considerable attention by
researchers as one of the compounds that possess medical and
biological activities as well as industrial uses, where many of
the products that contain coumarin units showed a number of
pharmacological activities1-4. It is also found that compounds
containing pyrimidine ring play an important role in many
biological systems such as vitamins, enzymes assistance and
many antibiotics as well as its presence in the nucleic acids5,
which attracted multiple biological activities of compounds
pyrimidine much attention in the past fewyears, so the researchers
worked in the preparation of these compounds because of its
great diversity in the effectiveness of biological and pharma-
ceutical critria6,7. The pyrimidine derivatives are major inter-
mediate of a large number of pharmaceutical manufactured
which show a group of derivatives pyrimidine activity as anti-
microbial8, analgesic, antiviral, anti-inflammatory9, also anti-
HIV10, antitubercular11, antitumor12, antimalarial13 and diuretic14,
in addition to the pyrimidine compounds are also used as
hypnotic drugs for the nervous system15. It can also prepare
this type of compounds through many reactions as well as
Biginelli reaction16. They includes this reaction blending ethyl
acetoacetate (1) or its derivatives with benzaldehyde (2) or its
derivatives, urea (3) and that the process occurs, the reaction
is heating mixture of the three components dissolved in the
solvent particularly with the availability of acidic conditions
to produce through this method new derivatives pyrimidine
NH
H N
2
2
O
H+, EtOH
reflux
O
O
O
+
+
HN
OEt
O
OEt
O
N
H
Me
(
1)
(
2
)
(3)
(4)
Uracil is an important class of pyrimidine derivatives17a, where
exhibit various pharmacological and biological activity17b, for
example, fluorouracil (5) is used widely as an anticancer18.While
the compound 5-nitrouracil (6) used to inhibition of the enzyme
thymidine phosphorylase19 and also its derivative showed anti-
bacterial activity20. Also 5-cinnamoyl-6-aminouracil (7) deri-
vatives are used as agents inhibition against the growth of cancer
cells21. While 6-aminouracils (8) find wide application as
starting materials for the preparation of many of the active
compounds and biologically important as well as, its deriva-
tives can be used as a coupling component in dye chemistry22.
In addition to the above mentioned properties, it was prepared
a series of coumarin derivatives containing on pyrimidine ring
(Scheme-I) and so by taking advantage of Biginelli condensing23.
EXPERIMENTAL
The chemicals used in the synthesis of all compounds
were purchased from Aldrich, Merck and BDH Chemical

3688 Al-Radha et al.
Asian J. Chem.
F
O2N
O
of 4-methoxybenzadehyde and (0.18 g, 3 mmol) of urea. After
reflux the mix for 8.5 h. The compound 9 was obtained as
reddish brown precipitate, after recrystallization.Yield: 0.62 g
(59 %), m.p. = 117-119 °C, Rf = 0.64. Anal. calcd. (%) for
C20H16N2O4 (348.35): C, 68.96; H, 4.63; N, 8.04. Found (%):
C, 68.72; H, 4.48; N, 7.85.
N
NH
O
N
O
N
O
H
H
(5
)
(
6
)
O
H
N
Synthesis of 3,4-dihydro-4-(4-chlorophenyl)-6-(2-oxo-
2H-chromen-3-yl)pyrimidin-2(1H)-one (10): The compound
10 was prepared according to general method where taking
(0.56 g, 3 mmol) of compound 7 with (0.42 g, 3 mmol) of 4-
chlorobenzadehyde and (0.18 g, 3 mmol) of urea. After reflux
in the mixture for 11 h, compound 10 was obtained as brown
precipitate, after recrystallization. Yield: 0.74 g (69 %), m.p.
= 241-243 °C, Rf = 0.56. Anal. calcd. (%) for C19H13N2O3Cl
(352.77): C, 64.69; H, 3.71; N, 7.94. Found (%): C, 64.41; H,
3.56; N, 7.73.
O
O
HN
O
HN
HN
NH2
O
NH2
(7
)
(8)
Companies and used without further purification. The melting
points were measured on an Electrothermal Melting point/SMP
(Gallenkamp) and are uncorrected.
Synthesis of 3,4-dihydro-4-(2,4-dichlorophenyl)-6-(2-
oxo-2H-chromen-3-yl)pyrimidin-2(1H)-one (11): The
compound 11 was prepared according to general method where
taking (0.56 g, 3 mmol) of compound 7 with (0.52 g, 3 mmol)
of 2,4-dichlorobenzadehyde and (0.18 g, 3 mmol) of urea.After
reflux the reaction mixture for 9 h, the compound 11 was
obtained as white precipitate, after recrystallization. Yield:
0.68 g (58 %), m.p. = 263-265 °C, Rf = 0.62. Anal. calcd. (%)
for C19H12N2O3Cl2 (387.22): C, 58.93; H, 3.12; N, 7.23. Found
(%): C, 58.72; H, 2.94; N, 7.07.
Synthesis of 3,4-dihydro-4-(4-bromophenyl)-6-(2-oxo-
2H-chromen-3-yl)pyrimidin-2(1H)-one (12): The compound
12 was prepared according to general method where taking
(0.56 g, 3 mmol) of compound 7 with (0.55 g, 3 mmol) of 4-
bromobenzadehyde and (0.18 g, 3 mmol) of urea. After reflux
the mix for 12 h. Compound 12 was obtained as brown preci-
pitate, after recrystallization.Yield: 0.72 g (60 %), m.p. = 237-
239 °C, Rf = 0.45.Anal. calcd. (%) for C19H13N2O3Br (397.22):
C, 57.45; H, 3.30; N, 7.05. Found (%): C, 57.32; H, 3.14; N, 6.84.
Synthesis of3,4-dihydro-4-(4-bromophenyl)-6-(2-oxo-
2H-chromen-3-yl)pyrimidin-2(1H)-one (13): The compound
13 was prepared according to general method where taking
(0.56 g, 3 mmol) of compound 7 with (0.44 g, 3 mmol) of 4-
bromobenzadehyde and (0.18 g, 3 mmol) of urea. After reflux
the mix for 9 h. Compound 13 was obtained as greenish yellow
precipitate, after recrystallization. Yield: 0.67 g (62 %), m.p.
= 209-211 °C, Rf = 0.54. Anal. calcd. (%) for C21H19N3O4
(361.39): C, 69.79; H, 5.30; N, 11.63. Found (%): C, 69.58;
H, 5.16; N, 11.47.
The spectral measurements are infrared spectroscopy of
type FT-IR spectrophotometer (Shimadzu). Nuclear magnetic
resonance spectroscopy of the proton and carbon-type Biospin
Auance III and 400 MHz (Germany) 600 MHz using (DMSO-
d6) as solvent and TMS as a reference. Thin layer chromato-
graphy (TLC) was performed onAlumina plates covered with
silica gel layer and the spots were developed with iodine
vapour. Elemental analyses (CHN) were carried out by using
Vario Elemental Anlayzer 3000 (Shimadzu, Japan).
Synthesis of compound 3-acetyl coumarin24 (7): Added
(12.21 g/0.1 mol) of salicyldehyde to (13.0 g/0.1 mol) of ethyl
acetoacetate, then put the mixture in a beaker capacity (100
mL) containing (20 mL) absolute ethanol and then added (5)
drops from catalyst (piperidine). The mixture was stirred for
0.5 h at 5-10 °C. The yellow solid separated was filtered off
subsequently washed with ethanol, dried and recrystallized
from ethanol to give 3-acetyl coumarin as yellow crystals.
Yield: 15.7 g (83 %), m.p. =116-118 °C (sawn 119-121 °C),
Rf = 0.42.
Preparation of a series of compounds 3,4-dihydro(4-
aryl-6-coumarin)pyrimidin-2-one23 (8-13):A solution of 3-
acetylcoumarin (5 mmol) in absolute ethanol (20 mL) containing
AlCl3 (10 mol %) was refluxed with the appropriate substituted
benzaldehyde (5 mmol) and urea (5 mmol) for about 8-12 h.
The progress of reaction was monitored by TLC. After the
completion of reaction, the reaction mixture was allowed to
reach ambient temperature and then the precipitate formed
was filtered, washed with water, dried and recrystallized from
ethanol to get pure powder.
Synthesis of 3,4-dihydro-4-(4-hydroxyphenyl)-6-(2-oxo-
2H-chromen-3-yl)pyrimidin-2(1H)-one (8): The compound
8 was prepared according to general method where taking (0.56
g, 3 mmol) of compound 7 with (0.36 g, 3 mmol) of 4-hydroxy-
benzadehyde and (0.18 g, 3 mmol) of urea.After reflux the mix
for 10 h, the compound 8 was obtained as brown precipitate,
after recrystallization.Yield: 0.65 g (64 %), m.p. =193-195 °C,
Rf = 0.66. Anal. calcd. (%) for C19H14N2O4 (334.33): C, 68.26;
H, 4.22; N, 8.38. Found (%): C, 67.96; H, 4.12; N, 8.11.
Synthesis of 3,4-dihydro-4-(4-methoxyphenyl)-6-
(2-oxo-2H-chromen-3-yl)pyrimidin-2(1H)-one (9): The
compound 9 was prepared according to general method where
taking (0.56 g, 3 mmol) of compound 7 with (0.4 g, 3 mmol)
RESULTS AND DISCUSSION
The synthetic strategies adopted in the synthesis of the
intermediate and target compounds are depicted in the Scheme-
I. The base compound 3-acetyl coumarin 7 was prepared from
reaction of salicyldehyde with ethyl acetoacetate and a few
drops of piperdine as catalyst and ethanol as solvent according
to the following equation:
O
EtO
CHO
O
CH3
Piperidine
+
Room temp., 0.5 h
O
OH
O
O

Vol. 27, No. 10 (2015)
Synthesis of Some Substituted Pyrimidines Derived from 3-Acetyl Coumarin 3689
O
O
O
Piperidine/Ethanol
Room temp., 0.5 h
O
CH3
+
OEt
O
O
OH
(7)
EtOH
AlCl3
ArCHO
+
NH2CONH2
O
HN
NH
comp.
R
4-OH
4-OMe
4-Cl
2,4-di Cl
4-Br
4-N(CH3)2
8
R
9
10
11
12
13
O
O
(8-13)
Scheme-I: Synthetic pathway for the compounds 7-13 and their structures
The structure compound 7 was determined on the basis
of spectral data, as well as elemental analysis, according to
the literature25.
Coumarin derivatives (8-13) were synthesized through of
condensation 3-acetyl coumarin (7) with number of substituted
aromatic aldehydes and urea with a small amount of AlCl3 as
catalyst and ethanol absolute as solvent. According to the
following equation:
The mechanism proposed for this reaction includes two
steps26: The first aldol condensation between benzaldeyde and
methyl group to form a stabilized carbenium ion. A second
step is the nucleophilic addition of urea gives the intermediate,
which quickly dehydrates to give the desired product (Scheme-II).
The melting point was uncorrected which determined by
open capillary tube and was listed in the Table-1 as well as
other physical properties. The synthesized compounds were
characterized by their elemental analysis, IR, H NMR, C
NMR. The IR spectra of the compounds 8-13 showed charac-
teristic absorption bands at 3440-3172 cm–1(OH; NH) stretching,
1751-1712 cm–1 due to (lactone C=O) and1697-1643 cm–1
1
13
O
10mol% AlCl3
EtOH / reflux
CH3
ArCHO + NH2CONH2
+
O
O
TABLE-1
O
(7)
PHYSICO-CHEMICAL DATA OF THE COMPOUNDS 8-13
HN
NH
Comp.
No.
m.p.
(°C)
Yield
(%)
R
Colour
Rf
8
9
10
11
12
13
OH-4
OMe-4
4-Cl
2,4-Di(Cl)
4-Br
193-195
217-219
241-243
263-265
237-239
209-211
64
59
69
58
60
62
Brown powder
Reddish brown
Brown powder
White powder
Brown powder
Powder yellow
0.66
0.70
0.56
0.62
0.45
0.52
R
O
O
(
8-13)
R =
8
: 4-OH ,
12; 4-Br , 13; 4-N(CH3)2
9: 4-OMe , 10; 4-Cl , 11; 2,4-(Cl)2 ,
4-N(CH3)2
TABLE-2
FT-IR SPECTRA DATA (cm–1) OF THE COMPOUNDS 8-13
Comp. No.
N-H
3386
3326
3354
3332
3178
3201
C-H aromatic
3070
C=O lactone
1725
C=O amide
1697
C=C Olfe.
1565
1573
1567
1589
Other
OH 3440
O-CH3 1056
C-Cl 726
C-Cl 640, 684
C-Br 663
–
8
9
10
11
12
13
3039
3018
3008
3024
1720
1743
1751
1720
1676
1687
1650
1650
1596
1593
3070
1712
1643

3690 Al-Radha et al.
Asian J. Chem.
AlCl3
H
O
AlCl3
CH3
O
OH
O
O
AlCl
3
OH
Ar
Ar'
CH3
Ar'
Ar'
Ar
C
Ar'
CH2
H2
-H2O
Ar
AlCl3
O
Cl3Al
O
O
O
CH
H
H2N
NH2
AlCl
3
Ar'
Ar'
Ar
Ar'
Ar
C
C
H
NH2
H
N
H
O
P.T
O
H
N
Ar
Ar
AlCl3
O
O
NH
HN
-H2O
P.T
H2C
CH2
NH
Ar
Ar'
Ar'
Ar'
NH2
HN
OH
O
R
Ar =
Ar' =
O
O
[79]=R=4-OH , [80]=R=4-OMe , [81]=R=4-Cl , [82]=R=2,4-(Cl)2 , [83]=R=4-Br , [84]=R=4-N(CH3)2
Scheme-II
13
attributed to the (amide C=O) stretching vibration. The absorp-
tion bands at 1596-1565 cm–1 region could be attributed to the
(C=C) stretching and other absorption bands were listed inTable-
2. The 1H NMR spectra of the compounds 8-13 showed singlet
in the range 11.18-9.81 ppm, which is characteristic for N-H
and singlet in the range 9.01-8.22 ppm due to H-4 for coumarin,
as well as aromatic protons which is showed at range 7.98-7.00
ppm and other singles were listed in Table-3. The C NMR
spectra of the compounds 8-13 showed singlet in the range
167.75-162.05 ppm which is characteristic of (lactone C=O) and
singlet in the range 160.02-156.71 ppm attributed to (amid C=O),
as well as aromatic atoms carbon which is showed at range 139.6-
116.06 ppm and other singles were listed in Table-4. Elemental
analysis (C-H-N) was listed in Table-5.
TABLE-3
1H NMR SPECTRA DATA (ppm) OF COMPOUNDS 8-13
Comp. No.
H-4 coumarin
8.79
H-5' pyrimidine
Ar-H
N-H (2H)d
6.86
H-4' pyrimidine
Other
OH 5.27
O-CH3 3.87
8
9
10
11
12
13
8.07
7.97
8.52
8.75
8.19
8.27
7.98-7.16
7.80-7.01
7.38-7.23
7.65.7.17
8.08-7.67
7.71-7.00
6.74
6.11
5.83
5.93
5.58
5.93
8.67
8.72
8.79
8.22
6.90
6.81
6.96
6.44
–
–
–
9.01
96.6
N-(CH3)2 3.22
TABLE-4
13C NMR SPECTRA DATA (ppm) OF COMPOUNDS 8-13
C4''-arom.
phenyl
158.93
157.52
137.63
150.12
142.70
150.62
Comp.
No.
C=O
lactone
C1''-arom.
phenyl
C=O amide
C8a coum.
C-arom.
C5'-pyri.
C4'-pyri.
Other
8
9
10
11
12
13
167.75
165.45
162.43
164.58
162.24
162.05
158.12
157.56
160.02
156.71
157.85
156.88
157.67
160.80
154.34
150.90
156.62
153.25
154.92
139.26
149.18
150.82
145.97
146.02
134.6-116.6
133.3-118.2
134.5-116.6
139.6-119.7
132.9-118.8
137.6-128.3
116.33
112.58
112.86
116.29
115.20
108.40
64.95
61.15
81.22
85.44
56.70
62.05
–
OMe 60.42
–
–
–
N(CH3)2 40.05

Vol. 27, No. 10 (2015)
Synthesis of Some Substituted Pyrimidines Derived from 3-Acetyl Coumarin 3691
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TABLE-5
ELEMENTAL ANALYSIS OF COMPOUNDS 8-13
Elemental analysis (%): Calcd. (Found)
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Comp. No.
C
H
N
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8
9
10
11
12
13
68.26 (67.96)
68.96 (68.72)
64.69 (64.41)
58.93 (58.72)
57.45 (57.32)
69.79 (69.58)
4.22 (4.12)
4.63 (4.48)
3.71 (3.56)
3.12 (2.94)
3.30 (3.14)
5.30 (5.16)
8.38 (8.11)
8.04 (7.85)
7.94 (7.73)
7.23 (7.07)
7.05 (6.84)
11.63 (11.47)
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