Studies on reactions of pyrimidine compounds. 21. Microwave-assisted synthesis of 1,2,3,4-tetrahydro-2- thioxopyrimidine derivatives

Article abstract of DOI:10.1080/10426500701557021

The 5-benzoyl-4,6-diphenyl-1,2,3,4-tetrahydro-2-thioxopyrimidine (1a) and 5-benzoyl-4-(2-chlorophenyl)-6-phenyl-1,2,3,4-tetrahydro-2-thioxopyrimidine (1b) were synthesized using the Biginelli three-component cyclocondensation reaction of a -diketone, aryl

Full text of DOI:10.1080/10426500701557021

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Studies on Reactions of
Pyrimidine Compounds. 21.
Microwave-Assisted Synthesis
of 1,2,3,4-Tetrahydro-2-
Thioxopyrimidine Derivatives
Esvet Akbaş a & Furgan Aslanoğlu a
a Department of Chemistry, Faculty of Arts and
Sciences, University of Yuzuncu Yil, Kampus, Van,
Turkey
Published online: 20 Feb 2008.
To cite this article: Esvet Akbaş & Furgan Aslanoğlu (2007) Studies on Reactions of
Pyrimidine Compounds. 21. Microwave-Assisted Synthesis of 1,2,3,4-Tetrahydro-2-
Thioxopyrimidine Derivatives, Phosphorus, Sulfur, and Silicon and the Related
Elements, 183:1, 82-89, DOI: 10.1080/10426500701557021
To link to this article: http://dx.doi.org/10.1080/10426500701557021
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Phosphorus, Sulfur, and Silicon, 183:82–89, 2008
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500701557021
Studies on Reactions of Pyrimidine Compounds. 21.
Microwave-Assisted Synthesis of 1,2,3,4-Tetrahydro-2-
Thioxopyrimidine Derivatives
˘
Esvet Akbas¸ and Furgan Aslanoglu
Department of Chemistry, Faculty of Arts and Sciences,
University of Yuzuncu Yil, Kampus, Van, Turkey
The 5-benzoyl-4,6-diphenyl-1,2,3,4-tetrahydro-2-thioxopyrimidine (1a) and 5-ben-
zoyl-4-(2-chlorophenyl)-6-phenyl-1,2,3,4-tetrahydro-2-thioxopyrimidine (1b) were
synthesized using the Biginelli three-component cyclocondensation reaction of a
β-diketone, arylaldehyde, and thiourea under microwave irradiation. Thiazolopy-
rimidine (2), (3) and pyrimido[2,3-b]thiazine (4) derivatives were obtained by a sim-
ple one-pot condensation reaction of starting compound 1b and 2-bromopropionic
acid, bromoacetic acid and 3-bromopropionic acid, respectively. These reactions
performed under microwave irradiation and conventional conditions.
That study is suggested a simple and efficient route for the preparation of 1,2,3,4-
tetrahydro-2-thioxopyrimidine and derivatives.
Keywords Microwave-Assisted; Biginelli reaction; thioxopyrimidine; synthesis; cyclo-
condensation; multicomponent reaction
INTRODUCTION
Recently, there has been focused interest in the three-component cyclo-
condensation reaction of β-diketone, arylaldehyde, and (thio)urea under
Bro¨nsted acid catalysis that was firstly reported by Pietro Biginelli in
1893.2 The reaction products are dihydropyrimidine derivatives, which
display various types of biological and agricultural activities3 such
as analgesic,3a antipyretic,3b antihypertensive,3c anti-inflammatory,3d
Received 16 March 2007; accepted 5 June 2007.
This work was supported by the Scientific and Technical Research Council of Turkey
(TBAG 2392 103T136). The authors would like to thank Dr. Musa Turker from Depart-
ment of Biology, Faculty of Arts and Sciences, Yuzuncu Yil University for his linguistic
support.
Address correspondence to Esvet Akbas¸, Department of Chemistry, Faculty of Arts
and Sciences, University of Yuzuncu Yil, Zeve Campus, 65080, Van, Turkey. E-mail:
esvakbas@hotmail.com
82

Microwave Synthesis of Thioxopyrimidine Derivatives
83
pesticides,3e herbicides,3f plant growth regulators,3g and as modulators
for the transport of calcium ions across the cell membrane.4
In the last few years there has been an increased interest in the use
of microwave heating in organic synthesis,5 and it forms now the ba-
sis of a number of commercial systems. Some interesting features of
this method are the rapid reaction rates, simplicity, solvent-free condi-
tions, and the case of work-up after the reaction, and better selectivity.
Also, microwave irradiation generates rapid intense heating of polar
substances, which result in the reduction of reaction time compared to
conventional heating.6
At present continuing with our studies on the synthesis of 1,2,3,4-
tetrahydropyrimidine derivatives using conventional heating and mi-
crowave irradiation. The purpose of that works is to extend the
Biginelli reactions in order to synthesize some 1,2,3,4-tetrahydro-2-
thioxopyrimidine derivatives. The reported method is suggested that
a simple and efficient route for the preparation of 1,2,3,4-tetrahydro-2-
thioxopyrimidine derivatives.
RESULTS AND DISCUSSION
In the present study, we achieved the synthesis of the pyrimidine deriva-
tives via conventional heating as well as microwave irradiation experi-
ments. The synthesis of derivative 1a via conventional heating method
was published in our previous work.7 The derivative is also available
in the product list of Aurora Fine Chemicals.8 The reaction was per-
formed 1,3-diphenyl-1,3-propanedione, benzaldehyde, and thiourea in
glacial acetic acid containing a few drops of concentrated hydrochloric
acid. The mixture was heated under reflux condition for 8 h. The reac-
tion was finalized in good yield (93%). In a similar way, the compound
1b was synthesized use 2-chlorobenzaldehyde instead of benzaldehyde
(Scheme 1). Yield of product following recrystallization from 1-butanol
was of the order of 90%.
When 1,3-diketone, aryl aldehyde, thiourea, and a few drops of con-
centrated HCl were reacted in glacial acetic acid under microwave ir-
radiation for 5 min obtained the same final products (1a,b).
1H and 13C NMR spectra of the isolated compounds 1a7,8 and1b con-
firm the expected structures. In 1H NMR spectra of compound 1b, the
singlets at 10.6 and 9.7 ppm are due to the resonance of the two NH
groups of the pyrimidine ring. The doublet and multiplet at 5.8 (J =
2.6) and 7.0–7.6 ppm are assigned to C4H and to the aryl protons,
respectively.
On the other hand, the reactions of thioxopyrimidine derivatives hav-
ing the NH and C S group in the suitable position with various bromo

˘
E. Akbas¸ and F. Asanoglu
84
SCHEME 1
compounds were convenient methods to build the thiazolopyrimidine
and pyrimido[2,3-b]thiazine derivatives.9,10 Thus, the compounds 1a
and 1b were cyclized with various bromo compounds to the thiazolopy-
rimidine (2,3) and pyrimido[2,3-b]thiazine (4) derivatives (Scheme 2),
in approximately 35–48% yields. (The reactions of 1a were described
Aslanog˘lu et al.7).
The reactions of 1b and 2-bromopropionic acid as a cyclocondensation
reagent in dioxane10 under reflux gave compound 2. The IR spectrum
of 2 showed absorption band at 1730, 1646 m−1 because of two carbonyl
absorption bands. In 1H NMR spectra, the singlet at 6.6 ppm is due to
SCHEME 2

Microwave Synthesis of Thioxopyrimidine Derivatives
85
TABLE I Comparative Study of the Synthesis of 1a, 1b, 2, 3, 4
Yield (%)
Reaction time/min
Compound
Medium
MW
CONV.
MW
CONV.
1a
1b
2
Glacial acetic acid
Glacial acetic acid
Dioxane
Glacial acetic acid
75
80
48
44
93
90
35
41
5
5
5
5
480
480
120
60
3
Acetic anhydride CH3COONa
Glacial acetic acid
4
30
48
5
120
Acetic anhydride CH3COONa
the resonance of the C5H proton. The quintet and doublet at 4.1 and
1.5 ppm (J = 7.2 Hz) are assigned to C2H and to the methyl protons,
respectively.
The reaction of 1b with bromoacetic acid lead to 6-benzoyl-5-
(2-chlorophenyl)-7-phenyl-3-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyrimi-
dine (3), whereas reaction with 3-bromopropionic acid afforded 7-
benzoyl-6-(2-chlorophenyl)-8-phenyl-4-oxo-2,3-dihydro-6H-pyrimido[2,
3-b]thiazine (4). In the IR spectra of compounds 3 and 4 absence of the
absorption at IR 3389 and 3146 cm−1, the characteristic absorption
of NH group of starting material, is a good evidence of the expected
reactions. The IR spectrum data of 3 and 4 are in agreement with
1
similar published data.9,10 The H NMR data of the compounds 3 and
4 are in accord with the expected reaction product (See Experimental
Section for details).
The compounds 2–4 were also prepared under microwave irradiation.
In that way, we isolated the corresponding thioxopyrimidine deriva-
tives, in good yields within a few minutes. The reaction times are short-
ened from 480 min to 5 min (Table I).
EXPERIMENTAL
Solvents were dried by refluxing with the appropriate drying agents
and distilled before use. Melting points were determined on a Barn-
stead Electrothermal 9200 apparatus and are uncorrected. Microanal-
yses were performed on LECO CHNS 932 Elemental Analyzer. The IR
spectra were obtained in as potassium bromide pellets using a Mattson
1
1000 FTIR spectrometer. The H and 13C NMR spectra were recorded
on Bruker Avance DPX-200 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). The

˘
E. Akbas¸ and F. Asanoglu
86
microwave induced reactions for the synthesis of 1a,b were carried out
in a Sinbo SMO 3606 domestic oven with a 230 V–50 Hz power source,
700W output, and 2450 MHz operating frequency.
Conventional Synthesis— Preparation of the Starting
Compounds 1,2,3,4-Tetrahydro-2-thioxopyrimidines (1a,b)
A mixture of 1,3-diphenyl-1,3-propanedione (0.3584 g, 1.6 mmol), aryl
aldehyde (1.1 mmol), thiourea (0.084 g, 1.1 mmol) and 20 ml of glacial
acetic acid containing a few drops concentrated hydrochloric acid was
heated under reflux for 8 h. The solution was allowed several hours to
yield 0.36 g (90%) of product 1b, mp 198–199◦C (1-butanol). IR (KBr):
3389 and 3146 cm−1 (2NH), 2961 cm−1 (C4H), 1625 (C O) and 1270
cm−1 (C S)11. 1H-NMR (DMSO-d6): δ 10.6 (s, 1H, NH), 9.7 (s, 1H, NH),
7.0–7.6 (m, 14H, Harom.), 5.8 (d, J = 2.6, 1H, C4H). 13C NMR (DMSO-
d6): δ = 196.1 (C O), 176.5 (C S),12 145.3, 141.4, 140.2, 134.1, 133.6,
133.1, 131.6, 131.5, 131.4, 131.3, 131.1, 130.2, 129.5, 129.3, 129.2, 111.1,
55.6 ppm. Anal. Calcd. for C23H17ClN2OS (404): C, 68.22; H, 4.23; N,
6.92. Found: C, 68.13; H, 4.16; N, 6.79.
The Compound 1a was yield 93% which have been described in
Aslanog˘lu et al.7
6-Benzoyl-5-(2-chlorophenyl)-2-methyl-7-phenyl-3-oxo-2,3-
dihydro-5H-thiazolo[3,2-a] pyrimidine (2)
A mixture of 1b (0.404 g, 1 mmol) and 2-bromopropionic acid (0.1 ml,
1 mmol) in dioxane (5 ml) were refluxed for 2 h. The reaction mixture
was cooled and the precipitate filtered off and then washed with water.
The crude product was recrystallizsed from ethanol. Yield 0.16 g (35%).
M.p. 199–200◦C, IR(KBr): 3059 cm−1 (C5H), 1730, 1646 cm−1 (C O),
1H-NMR (DMSO-d6): δ 6.9–7.5 (m, 14H, Harom.), 6.6 (s,1H, C5H), 4.1
(q, 1H, C2H, J = 7.2 Hz), 1.5 (d, 3H, CH3, J = 7.2 Hz). Anal. Calcd.
for C26H19ClN2O2S (458). C, 68.04; H, 4.17; N, 6.10. Found: C, 68.10; H,
4.19; N, 6.06.
6-Benzoyl-5-(2-chlorophenyl)-7-phenyl-3-oxo-2,3-dihydro-5H-
thiazolo[3,2-a]pyrimidine(3)
A mixture of 1b (0.404 g, 1mmol), bromoacetic acid (0.153 g, 1.1 mmol),
anhydrous sodium acetate (2 mmol), acetic anhydride (1.2 ml) in acetic
acid (20 ml) was heated under reflux for 1 h. The residue was treated
with water (100 ml) and the precipitate filtered off and the formed crude
product was recrystallized from ethanol. Compound 3 was obtained in
yield 0.18 g (41%). M.p. 200–201◦C, IR(KBr): 3058 cm−1 (C5H), 1734,
1
1638 cm−1 (C O). H-NMR (CDCl3): δ 6.9–7.6 (m, 14H, Harom.), 6.4

Microwave Synthesis of Thioxopyrimidine Derivatives
87
(s, 1H, C5H), 3.8–4.0 (q, 2H, CH2, J = 8.7 Hz, AB system). Anal. Calcd.
for C25H17ClN2O2S (444). C, 67.49; H, 3.85; N, 6.30. Found: C, 67.52; H,
3.81; N, 6.36.
7-Benzoyl-6-(2-chlorophenyl)-8-phenyl-4-oxo-2,3-dihydro-6H-
pyrimido[2,3-b]thiazine (4)
A mixture of 1b (0.404 g, 1 mmol), 3-bromopropionic acid (0.168 g, 1.1
mmol), anhydrous sodium acetate (2 mmol), acetic anhydride (2 ml) in
acetic acid (20 ml) was heated under reflux for 2 h. The residue was
treated with water (100 ml) and the precipitate filtered off; the formed
crude product was recrystallized from 2-propanol. The compound 4 was
obtained in yield 0.22 g (48%). M.p. 257–258◦C, IR(KBr): 3059 cm−1
(C6H), 1707, 1638 cm−1 (C O), 13C-NMR (CDCl3-DMSO-d6): δ = 195.4
(C O, benzoyl), 167.5 (C O), 154.4, 145.4, 137.1, 136.9, 136.0, 132.0,
131.6, 130.5, 129.8, 129.3, 128.7, 128.5, 128.3, 127.3, 127.2, 126.9, 117.7,
52.7, 35.4, 21.4 ppm. Anal. Calcd. for C26H19ClN2O2S (458). C, 68.04;
H, 4.17; N, 6.10. Found: C, 68.49; H, 4.76; N, 6.45.
Microwave Mediated Synthesis—Preparation of the Starting
Compounds 1,2,3,4-Tetrahydro-2-thioxopyrimidines (1a,b)
A mixture of 1,3-diphenyl-1,3-propanedione (1.6 mmol), aryl aldehyde
(1.1 mmol), thiourea (1.1 mmol), and concentrated hydrochloric acid (0.2
ml) with glacial acetic acid (10 ml) were placed in a 25-ml glass beaker
and stirred at room temperature for 5 min with a magnetic stirrer. The
beaker was placed inside a larger container filled with boiling chips
and then was inserted into the microwave oven. The mixture was then
subjected to microwave irradiation, 5 min for the compound 1a and 1b.
5-Benzoyl-4,6-diphenyl-1,2,3,4-tetrahydro-2-
thioxopyrimidine (1a)
The reaction mixture was cooled and the crude products were filtered
and recrystallized from acetic acid to give the pure compound 1a, yield
75%.
5-Benzoyl-4-(2-chlorophenyl)-6-phenyl-1,2,3,4-tetrahydro-
2-thioxopyrimidine (1b)
The crude products were filtered and recrystallized from 1-butanol to
give 1b, yield 80%.
6-Benzoyl-5-(2-chlorophenyl)-2-methyl-7-phenyl-3-oxo-2,3-
dihydro-5H-thiazolo[3,2-a] pyrimidine (2)
A mixture of 1b (0.404 g, 1mmol) and 2-bromopropionic acid (0.1 ml,
1 mmol) in dioxane (2 ml) were stirred at room temperature for 5 min

˘
E. Akbas¸ and F. Asanoglu
88
with a magnetic stirrer. The mixture was irradiated for 5 min in mi-
crowave oven. The reaction mixture was cooled and then washed with
ethanol and the crude products were filtered. The crude product was
recrystallized from ethanol. Yield 0.22 g (48%).
6-Benzoyl-5-(2-chlorophenyl)-7-phenyl-3-oxo-2,3-dihydro-5H-
thiazolo[3,2-a]pyrimidine(3)
A mixture of 1b (0.404 g, 1 mmol), bromoacetic acid (0.153 g, 1.1 mmol),
anhydrous sodium acetate (2 mmol), acetic anhydride (1.2 ml) in acetic
acid (15 ml) were stirred at room temperature for 5 min with a magnetic
stirrer. The mixture was irradiated for 5 min in a microwave oven. The
reaction mixture was cooled and the residue was treated with water
(100 ml); the precipitate filtered off and the formed crude product was
recrystallized from ethanol. Yield 0.196 g (44%).
7-Benzoyl-6-(2-chlorophenyl)-8-phenyl-4-oxo-2,3-dihydro-6H-
pyrimido[2,3-b]thiazine (4)
A mixture of 1b (0.404 g, 1mmol), 3-bromopropionic acid (0.168 g, 1.1
mmol), anhydrous sodium acetate (2 mmol), acetic anhydride (2 ml) in
acetic acid (15 ml) were stirred at room temperature for 5 min with a
magnetic stirrer. The mixture was irradiated for 5 min in microwave
oven. The reaction mixture was cooled and the crude products were
filtered and washed with water and the formed crude product was re-
crystallized from 2-propanol. Yield 0.134 g (30%).
CONCLUSION
In conclusion, we have described a simple and good yielding prepa-
ration for thioxopyrimidines by conventional heating and microwave
irradiation via Biginelli three-component cyclocondensation reaction.
Our investigations will continue on this subject, and the results will be
published when our studies are complete.
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Microwave Synthesis of Thioxopyrimidine Derivatives
89
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