A simple one-pot synthesis of 1,2,3,4-tetrahydro-2-thioxopyrimidine derivatives

Article abstract of DOI:10.1002/jhet.5570450532

(Chemical Equation Presented) 5-Benzoyl-4-(substituted phenyl)-6-phenyl-1, 2,3,4-tetrahydro-2-thioxopyrimidines (4a-d) were synthesized using the Biginelli three component cyclocondensation reaction of an appropriate β-diketone, arylaldehyde, and thiourea in acetic acid under reflux condition in approximately 52-65% yields. The acetylation of compounds 4a-d gave 3-acetyl thioxopyrimidine derivatives 5a-d. Also, pyrimidothiazine compounds 6a-d were prepared by a simple one-pot condensation reaction of starting pyrimidine derivatives 4a-d and 3-bromopropionic acid. The structures of compounds were characterized on the basis of elemental analyses, IR, ¹H and ¹³C-NMR spectra.

Full text of DOI:10.1002/jhet.5570450532

Sep-Oct 2008
1457
A Simple One-Pot Synthesis of 1,2,3,4-Tetrahydro-2-
thioxopyrimidine Derivatives
Esvet Akbaꢀa*, Furgan Aslanoꢁlua, Barıꢀ Anılb, and Ahmet ꢂenera
aYuzuncu Yil University, Faculty of Arts and Sciences, Department of Chemistry, Organic Chemistry Devision,
Zeve Campus, Van, Turkey.
bChemistry Department, Faculty of Arts and Sciences, University of Ataturk, Erzurum, Turkey.
E-mail: esvakbas@hotmail.com
Received April 18, 2007
X
O
O
H
N
X
Ac2O
Ph
CH3
O
Ph
N
H
S
H2N
+
S
O
H
H
Ph
NH
NH2
Ph
X
N
S
Ph
O
H
O
X
O
Ph
H
N
O
Br
OH
Ph
O
Ph
N
S
5-Benzoyl-4-(substituted
phenyl)-6-phenyl-1,2,3,4-tetrahydro-2-thioxopyrimidines
(4a-d)
were
synthesized using the Biginelli three component cyclocondensation reaction of an appropriate ꢀ-diketone,
arylaldehyde, and thiourea in acetic acid under reflux condition in approximately 52-65% yields. The
acetylation of compounds 4a-d gave 3-acetyl thioxopyrimidine derivatives 5a-d. Also, pyrimidothiazine
compounds 6a-d were prepared by a simple one-pot condensation reaction of starting pyrimidine
derivatives 4a-d and 3-bromopropionic acid. The structures of compounds were characterized on the basis
of elemental analyses, IR, 1H and 13C-NMR spectra.
J. Heterocyclic Chem., 45, 1457 (2008).
INTRODUCTION
pyrimidines (5a-d) and pyrimidothiazine compounds (6a-
d) were obtained.
The pyrimidines have been subjected to a large variety
of structural modifications in order to synthesize
derivatives with different biological properties. Many
substituted pyrimidine rings play an important role as
analgesic, antipyretic, antihypertensive and anti-
inflammatory drugs also as pesticides, herbicides, plant
growth regulators and organic calcium channel
modulators [1-7].
Scheme 1
O
H2N
O
O
H
H
II
EtO
Me
NH
NH2
Me
+
I
N
H
O
EtO
O
IV
O
III
Various synthesis methods have been reported in the
literature for pyrimidine derivatives [1-17]. Most of them
are based on the simple Biginelli three component
cyclocondensation reaction. This is very simple one-pot,
acid catalyzed cyclocondensation reaction of benzalde-
hyde (I), urea (II) and ethyl acetoacetate (III). The
reaction was carried out in ethanol with a few drops of
concentrated hydrochloric acid and finalized 3,4-di-
hydropyrimidine-2(1H)-one (IV) (Scheme 1)[18,19].
At present, our studies are continuing on the synthesis
of 1,2,3,4-tetrahydro-2-(oxo)thioxopyrimidines [20].
Herein, we have reported the synthesis of 1,2,3,4-tetra-
hydro-2-thioxopyrimidines (4a-d), via the general method
of Biginelli cyclocondensation reaction in acetic acid.
Also their various derivatives such as 3-acetyl thioxo-
RESULTS AND DISCUSSION
5-Benzoyl-4-(substituted
phenyl)-6-phenyl-1,2,3,4-
tetrahydro-2-thioxopyrimidines (4a-d) were prepared
according to the Biginelli reaction which involves one-pot
condensation of 1,3-diphenyl-1,3-propandione, thiourea
and arylaldehydes (Scheme 2) under strongly acidic
condition in approximately 52-65% yields. All
compounds were characterized on the basis of their
spectral data and elementary analyses. The IR spectra of
the thioxopyrimidine compounds displayed absorption
bands characteristic for the NH (3426-3139 cm-1), C=O
(1635-1595 cm-1) and C=S (1280-1274 cm-1) functions.

1458
E. Akbaꢀ, F. Aslanoꢁlu, B. Anıl, and A. ꢂener
Vol 45
Scheme 2
X
X
O
S
H
N
H
OH
H
H
H
NH2 NH2
+
NH NH2
S
NH2
:
2
1
-H2O
X
S
X
X
1, 4
X
O
H
O
O
OH
O
a
b
c
4-Cl
4-Br
4-Me
3-NO2
H
Ph
NH
Ph
Ph
Ph
+
NH NH2
S
-H2O
d
N
S
Ph
H
4
Ph
3
In 1H NMR spectra, the formation of the
thioxopyrimidine ring in this reaction was clearly
demonstrated by the fact that the C4 methine proton of
compounds 4a-d appeared at 5.48-5.32 ppm as doublet.
The signals of the N3H and N1H protons of compounds
4a-d appeared one proton singlets at 10.12-9.86 and
10.85-10.55 ppm, respectively. The signals of the other
proton resonances are observed at the expected chemical
shifts and integral values.
(6a-d) were synthesized via the reactions of the starting
pyrimidine derivatives 4a-d and 3-bromopropionic acid
(Scheme 3).
In the IR spectra of compounds 6a-d, the absence of the
absorption at 3426-3139 cm-1 and the characteristic
absorption of NH group of starting materials are a good
evidence of the expected reactions.
The signals of two NH function groups of starting
1
materials 4a-d disappeared in the H NMR spectra of
The 3-acetyl thioxopyrimidine derivatives 5a-d were
prepared via reaction of compounds 4a-d with acetic
anhydride (Scheme 3).
compounds 6a-d which are the characteristic absorption
of NH groups of starting materials 4a-d. The H NMR
1
spectrum of compounds 6a-d revealed multiplet signals at
ꢀ 3.74-2.79 due to thiazine methylene protons.
The purpose of the present work is to extend the
Biginelli reactions in order to synthesize some 1,2,3,4-
tetrahydro-2-thioxopyrimidine derivatives. The method
reported here suggests a simple and efficient route for the
preparation of 1,2,3,4-tetrahydro-2-thioxopyrimidine
derivatives.
Scheme 3
X
O
O
S
H
N
Ac2O
Ph
CH3
Ph
N
H
X
5, 6
5
a
b
c
4-Cl
4-Br
4-Me
3-NO2
EXPERIMENTAL
4
X
Solvents were dried by refluxing with the appropriate drying
agents and distilled before use. Melting points were determined
on an Electrothermal Barnstead 9200 apparatus and are
uncorrected. Microanalyses were performed on LECO CHNS
932 Elemental Analyzer. The IR spectra were obtained in as
O
O
d
O
H
N
Br
OH
Ph
Ph
N
S
6
potassium bromide pellets using
a Mattson 1000 FTIR
spectrometer. The H and 13C NMR spectra were recorded on
Varian 400 or Bruker 300 spectrometers, using TMS as an
internal standard. All experiments were followed by TLC using
DC Alufolien Kieselgel 60 F 254 Merck and Camag TLC lamp
(254/366 nm).
1
1H NMR spectra of the compounds 5a-d revealed the
absence of N3H signals instead they exhibited three proton
singlets at 2.95-2.31 ppm assigned for the N3COCH3
protons of the acetyl groups. The 13C NMR spectrum of
5a revealed signals at ꢀ 194.6 (C=O, benzoyl), 177.9
(C=S), 173.5 (C=O, acetyl) and 27.3 ppm CH3.
General procedure for the synthesis of 5-benzoyl-4-
(substituted
pyrimidines (4a-d).
phenyl)-6-phenyl-1,2,3,4-tetrahydro-2-thioxo-
mixture of 1,3-diphenyl-1,3-
A
The compounds 7-benzoyl-6-(substituted phenyl)-8-
phenyl-4-oxo-2,3-dihydro-6H-pyrimido[2,3-b]thiazines
propanedione (3.58 g, 16 mmol), aryl aldehyde (11 mmol),
thiourea (0.84 g, 11 mmol) and 20 mL of glacial acetic acid

Sep-Oct 2008
A Simple One-Pot Synthesis of 1,2,3,4-Tetrahydro-2-thioxopyrimidine Derivatives
1459
containing a few drops concentrated hydrochloric acid was
heated under reflux for 8 h. The solution was allowed to stand
approximately 3-4 hours to yield 52-65% of product 4a-d.
5-Benzoyl-4-(4-chlorophenyl)-6-phenyl-1,2,3,4-tetrahydro-
2-thioxopyrimidine (4a). The compound 4a was prepared
according to the general procedure. The precipitate was
collected by filtration to give crude product that was
recrystallized from 2-propanol. Compound 4a was obtained in
yield 2.489 g (56%). Mp 200-201°C, IR (KBr): 3401 and 3147
cm-1 (2NH), 2967 cm-1 (C4H), 1622 (C=O) and 1276 cm-1 (C=S)
[15]. 1H-NMR (400 MHz, DMSO-d6): ꢀ 10.66 (s, 1H, NH), 9.92
(d, 1H, NH, J=2), 7.40-7.29 (dx2, 4H, 4-chlorophenyl, J= 10.8
Hz), 7.26-6.96 (m, 10H, two phenyl groups), 5.32 (d, 1H, C4H
J= 3.6 Hz). 13C NMR (DMSO-d6): ꢀ 195.39, 175.88, 145.99,
142.41, 139.54, 132.99, 131.69, 131. 78, 130. 97, 130.65,
129.27, 129.17, 129.13, 128.39, 128.21, 110.35, 55.40. Anal.
Calcd. for C23H17ClN2OS (404). C, 68.22; H, 4.23; N, 6.92.
Found: C, 68.32; H, 4.20; N, 6.90.
3-Acetyl-5-benzoyl-4-(4-chlorophenyl)-6-phenyl-1,2,3,4-
tetrahydro-2-thioxopyrimidine (5a). Compound 5a was
obtained in yield 0.232 g (52%). Mp 197-198ºC, IR(KBr): 3213
cm-1 (NH), 2964 cm-1 (C4H), 1715 and 1610 cm-1 (two C=O),
1
1268 cm-1 (C=S), H-NMR (300 MHz, CDCl3): ꢀ 11.96 (s, 1H,
NH), 7.52-7.06 (m, 14H, ArH), 6.46 (s, 1H, C4H), 2.83 (s, 3H,
CH3). 13C NMR (DMSO-d6): ꢀ 194.6, 177.9 [22], 173.5, 146.2,
137.9, 137.8, 132.5, 131.5, 131.2, 130.6, 130.4, 129.0, 128.5,
128.3, 127.8, 127.5, 114.3, 54.1, 27.3 ppm. Anal. Calcd. for
C25H19ClN2O2S (446). C, 67.18; H, 4.28; N, 6.27. Found: C,
67.22; H, 4.29; N, 6.25.
3-Acetyl-5-benzoyl-4-(4-bromophenyl)-6-phenyl-1,2,3,4-
tetrahydro-2-thioxopyrimidine (5b). Compound 5b was
obtained in yield 0.299 g (61%). Mp 200-201ºC, IR(KBr): 3218
cm-1 (NH), 2965 cm-1 (C4H), 1716 and 1609 cm-1 (two C=O),
1
1268 cm-1 (C=S), H-NMR (400 MHz, CDCl3): ꢀ 8.49 (s, 1H,
NH), 7.48-7.02 (m, 14H, ArH), 6.69 (s, 1H, C4H), 2.88 (s, 3H,
CH3). Anal. Calcd. for C25H19BrN2O2S (490). C, 61.10; H, 3.90;
N, 5.70. Found: C, 61.08; H, 3.91; N, 5.72.
5-Benzoyl-4-(4-bromophenyl)-6-phenyl-1,2,3,4-tetrahydro-
2-thioxopyrimidine (4b) [21]. Compound 4b was obtained in
yield 2.562 g (52%). Mp 239-240°C (2-propanol), IR (KBr):
3426 and 3171 cm-1 (2NH), 1635 (C=O) and 1274 cm-1 (C=S).
1H-NMR (400 MHz, DMSO-d6): ꢀ 10.68 (s, 1H, NH), 9.95 (d,
1H, NH, J=2.4), 7.60-7.58 (dx2, 4H, 4-bromophenyl, J= 6.6 Hz),
7.41-6.98 (m, 10H, two phenyl groups), 5.34 (d, 1H, C4H, J= 3.6
Hz). 13C NMR (DMSO-d6): ꢀ 195.39, 175.88, 146.07, 142.84,
139.53, 132.99, 132.21, 131.71, 130.68, 130.97, 129.52, 129.21,
128.40, 128.22, 121.59, 110.29, 55.52. Anal. Calcd. for
C23H17BrN2OS (448). C, 61.48; H, 3.81; N, 6.23. Found: C,
61.38; H, 3.82; N, 6.25.
3-Acetyl-5-benzoyl-4-tolyl-6-phenyl-1,2,3,4-tetrahydro-2-
thioxopyrimidine (5c). Compound 5c was obtained in yield
0.235 g (54%). Mp 213-214ºC, IR(KBr): 3223 cm-1 (NH), 2963
cm-1 (C4H), 1707 and 1598 cm-1 (two C=O), 1270 cm-1 (C=S),
1H-NMR (400 MHz, CDCl3): ꢀ 8.09 (s, 1H, NH), 7.38-7.00 (m,
14H, ArH), 5.96 (s, 1H, C4H), 2.85 (s, 3H, CH3), 2.31 (s, 3H,
CH3, tolyl). Anal. Calcd. for C26H22N2O2S (426). C, 73.21; H,
5.20; N, 6.57. Found: C, 73.18; H, 5.19; N, 6.59.
3-Acetyl-5-benzoyl-4-(3-nitrophenyl)-6-phenyl-1,2,3,4-tetra-
hydro-2-thioxopyrimidine (5d). Compound 5d was obtained in
yield 0.255 g (54%). Mp 205-206ºC, IR(KBr): 3258 cm-1 (NH),
3085 cm-1 (C4H), 1712 and 1601 cm-1 (two C=O), 1267 cm-1
5-Benzoyl-4-tolyl-6-phenyl-1,2,3,4-tetrahydro-2-thioxopy-
rimidine (4c). The compound 4c was obtained in yield 2.378 g
(55%). Mp 200-201°C (xylene), IR (KBr): 3425-3139 cm-1
1
(C=S), H-NMR (400 MHz, CDCl3): ꢀ 8.87 (s, 1H, NH), 7.41-
7.14 (m, 14H, ArH), 5.82 (s, 1H, C4H), 2.95 (s, 3H, CH3). Anal.
Calcd. for C25H19N3O4S (457). C, 65.63; H, 4.19; N, 9.18.
Found: C, 65.65; H, 4.17; N, 9.21.
1
(2NH), 1595 (C=O) and 1275 cm-1 (C=S). H-NMR (400 MHz,
DMSO-d6): ꢀ 10.55 (s, 1H, NH), 9.86 (d, 1H, NH, J=2), 7.33-
6.96 (m, 14H, ArH), 5.32 (d, 1H, C4H, J= 3.6 Hz), 2.30 (s, 3H,
CH3). 13C NMR (DMSO-d6): ꢀ 195.48, 175.64, 145.52, 140.59,
139.61, 137.59, 133.15, 131.68, 130.59, 130.33, 129.47, 128.96,
128.39, 128.21, 127.18, 110.88, 55.89, 21.39. Anal. Calcd. for
C24H20N2OS (384). C, 74.97; H, 5.24; N, 7.29. Found: C, 75.00;
H, 5.22; N, 7.30.
Synthesis of 7-benzoyl-6-(substituted phenyl)-8-phenyl-4-
oxo-2,3-dihydro-6H-pyrimido[2,3-b]thiazine (6a-d).
General Procedure. A mixture of 4(a-d) (1 mmol), 3-bromo-
propionic acid (0.17 g, 1.1 mmol), anhydrous sodium acetate
(0.16 g, 2 mmol), acetic anhydride (2.0 g, 21 mmol) in acetic
acid (20 mL) was heated under reflux for 2 h. The residue was
treated with water (100 mL) and the precipitate collected by
filtration to give crude product was recrystallized from suitable
solvents to give 6 a-d.
7-Benzoyl-6-(4-chlorophenyl)-8-phenyl-4-oxo-2,3-dihydro-
6H-pyrimido[2,3-b]thiazine (6a). Compound 6a was obtained
in yield 0.225 g (46%). Mp 221-222ºC, IR(KBr): 1696, 1622
cm-1 (C=O). 1H-NMR (400 MHz, CDCl3): ꢀ 7.65-7.07 (m, 14H,
ArH.), 5.87 (s,1H, -CH), 2.86-3.74 (m, 4H, thiazine -CH2). Anal.
Calcd. for C26H19ClN2O2S (458). C, 68.04; H, 4.17; N, 6.10.
Found: C, 68.01; H, 4.18; N, 6.08.
5-Benzoyl-4-(3-nitrophenyl)-6-phenyl-1,2,3,4-tetrahydro-
2-thioxopyrimidine (4d). The compound 4d was obtained in
yield 2.960 g (65%). Mp 213-214°C (2-propanol), IR (KBr):
3291 and 3152 cm-1 (2NH), 2989 cm-1 (C4H), 1601 (C=O) and
1
1280 cm-1 (C=S). H-NMR (400 MHz, DMSO-d6): ꢀ 10.85 (s,
1H, NH), 10.12 (d, 1H, NH, J=2.8 Hz), 8.33-7.00 (m, 14H,
ArH), 5.48 (d, 1H, C4H, J= 4 Hz). 13C NMR (DMSO-d6): ꢀ
195.35, 176.07, 148.62, 147.26, 145.51, 139.42, 133.97, 132.78,
131.76, 131.08, 130.95, 130.82, 129.31, 128.47, 128.23, 123.42,
122.02, 109.38, 55.07. Anal. Calcd. for C23H17N3O3S (415). C,
66.49; H, 4.12; N, 10.11. Found: C, 66.51; H, 4.14; N, 10.14.
7-Benzoyl-6-(4-bromophenyl)-8-phenyl-4-oxo-2,3-dihydro-
6H-pyrimido[2,3-b]thiazine (6b). Compound 6b was obtained
in yield 0.294 g (55%). Mp 179-180ºC, IR(KBr): 1704, 1626
Preparation of 3-acetyl-5-benzoyl-4-(substituted phenyl)-6-
phenyl-1,2,3,4-tetrahydro-2-thioxopyrimidines (5a-d).
1
cm-1 (C=O), H-NMR (400 MHz, CDCl3): ꢀ 7.45-6.97 (m, 14H,
ArH.), 5.63 (s,1H, -CH), 2.84-3.72 (m, 4H, thiazine -CH2). 13C
NMR (DMSO-d6): ꢀ 196.19, 169.42, 156.67, 148.71, 139.72,
138.16, 136.98, 132.76, 132.69, 129.96, 129.75, 129.57, 129.41,
128.58, 128.30, 122.29, 118.47, 52.27, 35.85, 21.85. Anal.
Calcd. for C26H19BrN2O2S (503). C, 62.03; H, 3.80; N, 5.56.
Found: C, 62.07; H, 3.78; N, 5.58.
General Procedure. A mixture of 4 (a-d) (1 mmol) in acetic
anhydride (3 mL) was heated under reflux for 1 h, then the
reaction mixture was allowed to cool to room temperature and
poured over crushed ice and stirred several min. The separated
solid was collected by filtration, washed with water and
recrystallized from suitable solvents to give 5a-d.

1460
E. Akbaꢀ, F. Aslanoꢁlu, B. Anıl, and A. ꢂener
Vol 45
[4] Nega, S.; Aionso, J.; Diazj, A.; Junquere, F. J. Heterocycl.
Chem. 1990, 27, 269.
7-Benzoyl-6-tolyl-8-phenyl-4-oxo-2,3-dihydro-6H-pyrim-
ido[2,3-b]thiazine (6c). Compound 6c was obtained in yield
0.216 g (45%). Mp 236-237ºC, IR(KBr): 1697, 1626 cm-1
[5] Shishoo, C. J.; Jain, K. S. J. Heterocycl. Chem. 1992, 29, 883.
[6] Kappe, C. O. Molecules. 1998, 3, 1.
[7] Pathak, P.; Kaur, R.; Kaur, B. Arkivoc, 2006 (xvi), 160-167.
[8] Yarım, M.; Saraç, S.; Kılıç, F.S.; Erol, K. II Farmako. 2003,
1
(C=O). H-NMR (400 MHz, CDCl3): ꢀ 7.84-6.98 (m, 14H,
ArH.), 5.56 (s,1H, -CH), 2.91-3.62 (m, 4H, thiazine -CH2), 2.36
(s, 3H, CH3, tolyl). Anal. Calcd. for C27H22N2O2S (438). C,
73.95; H, 5.06; N, 6.39. Found: C, 73.92; H, 5.08; N, 6.41.
7-Benzoyl-6-(3-nitrophenyl)-8-phenyl-4-oxo-2,3-dihydro-
6H-pyrimido[2,3-b]thiazine (6d). Compound 6d was obtained
in yield 0.275 g (55%). Mp 220-221ºC, IR(KBr): 1707, 1630
cm-1 (C=O). 1H-NMR (400 MHz, CDCl3): ꢀ 7.42-7.10 (m, 14H,
ArH.), 5.53 (s,1H, -CH), 2.79-3.64 (m, 4H, thiazine -CH2). Anal.
Calcd. for C26H19N3O4S (469). C, 66.51; H, 4.08; N, 8.95.
Found: C, 66.54; H, 4.09; N, 8.93.
17.
[9] Elgazzar, A. B. A.; Gafaar, A. M.; Hafez, H. N.; Aly, A. S.
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[10] Xu, J. M.; Yao, S. P.; Wu, W. B.; Lv, D. S.; Lin, X. F. J.
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Acknowledgement.
This work was supported by the
[14] Mobinikhaledi, A.; Forughifar, N.; Goodarzi, F. Phosphorus,
Sulfur, and Silicon and the Related Elements. 2003, 178, 2539.
[15] Aly, A.A. Phosphorus, Sulfur, and Silicon and the Related
Elements 2006, 181,1285.
Scientific and Technical Research Council of Turkey (TBAG
2392 103T136). The authors would like to thank Department of
Chemistry, Faculty of Arts and Sciences, Ataturk University for
providing spectroanalytical facilities and Dr. Musa Turker from
Department of Biology, Faculty of Arts and Sciences, Yuzuncu
Yil University for his linguistic support.
[16] Aslanoꢁlu, F; Akbaꢀ
, E; Sönmez, M; and Anıl, B.
Phosphorus, Sulfur, and Silicon and the Related Elements 2007, 182,
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