Microwave assisted synthesis of some fused thiazolopyrimidines

Article abstract of DOI:10.1080/10426500490459795

A simple and fast synthesis of some fused thiazolopyrimidine compounds 2(a-g) in high yield has been developed using microwave assisted cyclocondensation reaction of 1 with chloroacetic acid, anhydrous sodium acetate, and corresponding aldehyde. Yields of products following recrystallization from ethanol were of the order of 88-94%. IR and ¹H NMR spectrscopies and elemental analysis were used for identification of these compounds.

Full text of DOI:10.1080/10426500490459795

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Phosphorus, Sulfur, and Silicon and the Related
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MICROWAVE ASSISTED SYNTHESIS OF SOME FUSED
THIAZOLOPYRIMIDINES
A. Mobinikhaledi a & N. Foroughifar a
a University of Arak, Arak, Iran
Published online: 16 Aug 2010.
To cite this article: A. Mobinikhaledi & N. Foroughifar (2004): MICROWAVE ASSISTED SYNTHESIS OF SOME FUSED
THIAZOLOPYRIMIDINES, Phosphorus, Sulfur, and Silicon and the Related Elements, 179:6, 1175-1180
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Phosphorus, Sulfur, and Silicon, 179:1175–1180, 2004
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Copyright Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500490459795
MICROWAVE ASSISTED SYNTHESIS OF SOME
FUSED THIAZOLOPYRIMIDINES
A. Mobinikhaledi and N. Foroughifar
University of Arak, Arak, Iran
(Received October 14, 2003; accepted October 16, 2003)
A simple and fast synthesis of some fused thiazolopyrimidine com-
pounds 2(a–g) in high yield has been developed using microwave as-
sisted cyclocondensation reaction of 1 with chloroacetic acid, anhydrous
sodium acetate, and corresponding aldehyde. Yields of products follow-
ing recrystallization from ethanol were of the order of 88–94%. IR and
1H NMR spectrscopies and elemental analysis were used for identifica-
tion of these compounds.
Keywords: Carboxylate; microwave irradiation; pyrimidine; thiazolo
Pyrimidine derivatives have been reported to possess a broad spec-
trum of pharmacological properties1−9 including antiviral, antiumor,
antibacterial,2 and antihypertensive3 effects. Thus pyrimidine has been
subjected to a large variety of structural modifications in order to
synthesize derivatives with different biological properties. In order
to prepare some new fused thiazolopyrimidine derivatives using a
fast and simple method we have investigated cyclocondensation reac-
tion of ethyl-4-aryl-6-methyl-2-thioxo-1,-2,3-4-tetrahydro-pyrimidine-
5-carboxylate with chloroacetic acid, anhydrous sodium acetate, and
substituted aromatic aldehydes by applying microwave irradiation in
solvent free conditions.
Microwave irradiation is a nonconventional energy source that has
blossomed recently into a useful technique for different applications in
organic synthesis.10−15 Some of the interesting features of this method
are the rapid reaction rates, simplicity, solvent-free and cleaner reac-
tion condition.1,11 Also microwave irradiation generates rapid intense
heating of polar substances, which results in reduction of reaction time
compared to conventional heating.
Address correspondence to A. Mobinikhaledi, Department of Chemistry, University
of Arak, Dr. Beheshti Avenue, Arak, Iran. E-mail: akbar mobini@yahoo.com
1175

1176
A. Mobinikhaledi and N. Forughifar
TABLE I Thiazolopyrimidine Derivatives
2(a–g)
Entry
Time of Irradiation (s)
Yield (%)
2a
2b
2c
2d
2e
2f
90
60
60
30
60
40
40
90
94
94
88
86
92
92
2g
RESULTS AND DISCUSSION
Pyrimidine thiazole derivative 1, chloroacetic acid, anhydrous sodium
acetate, and the corresponding aldehyde were reacted under microwave
irradiation to give the corresponding pyrimidine derivatives 2(a–g) in
high yields (Table I) according to Scheme 1.
a) Ar = C6H5, Arꢁ = p-BrC6H4
b) Ar = C6H5, Arꢁ = p-ClC6H4
c) Ar = C6H5, Arꢁ = p-NO2C6H4
d) Ar = C6H5, Arꢁ = p-(NCH3)2C6H4
e) Ar = C6H5, Arꢁ = C4H3S (Thienyl)
f) Ar = p-CH3C6H4, Arꢁ = p-ClC6H4
g) Ar = p-CH3C6H4, Arꢁ = p-OCH3C6H4
SCHEME 1
Two isomeric cyclization products may be expected from an at-
tack of the nucleophile on N-1 and N-3 of 1. However it is well
documented17,18 that N-3 in pyrimidine compound 1 is more reactive
toward electrophiles than the N-1, which is part of push-pull system
with the ester group in the 5-position of the pyrimidine ring. Also the
low field shift of pyrimididine proton in 2, which is due to a deshielding
effect of the neighboring carbonyl group, compared to that of 1 is in
support of a nucleophilic attack on N-3.

Thiazolopyrimidines
1177
The 1H NMR spectra of compounds are very simple. The singlet sig-
nal at 2.20–2.55 ppm is due to the resonance of the CH3 group of the
pyrimidine ring. The CH3 of ester group resonates at 1.01–1.15 ppm
as a triplet signal. The singlet and multiplet signals at 6.00–6.10 and
7.20–7.7.50 ppm are assigned to H-5 and aryl protons respectively. The
broad signal at 7.65–8.15 ppm is attributed to the resonance of the
ylidene proton.
In the IR spectra of compounds 2(a–g) absence of the absorption at
3300–3500 cm−1, the characteristic absorption of NH group of starting
material, 1, is a good evidence of the expected reactions.
EXPERIMENTAL
Pyrimidine thiazole derivatives 1 were prepared using known
method.14,16 Melting points were measured on an electrothermal digital
melting point apparatus. H1 NMR spectra were recorded on a Brucker
500 MHz spectrometer. Chemical shifts are reported in ppm relative to
TMS (tetramethylsylan) as an internal standard. Spectra acquired in
CDCl3. IR spectra were performed on a Galaxy FT-IR 500 spectropho-
tometer. Reaction progress was routinely monitored by thin layer chro-
matography (TLC) on silica gel plates. Reactions were performed in a
Samsung microwave oven with a 230 V–50 Hz power source, 900 W
output, and 2450 MHz operating frequency.
General Procedure
For preparation of compounds 2(a–g) a mixture of the appropri-
ate pyrimidine thiazole derivative 1 (0.0025 mmol), chloroacetic acid
(0.0025 mmol) corresponding aldehyde (0.0025 mmol), and anhydrous
sodium acetate (0.5 g) were ground with a pestle in a mortar for 3–4 min.
The mixture was then placed in a 25 ml beaker. The beaker was put in
a watch glass and then inserted into the microwave oven. The mixture
was subjected to microwave irradiation at 100% power level for 30–90 s.
The resulting liquid solidified at room temperature after 1–2 h. The
crude product was dissolved in hot ethanol and filtered. The resulting
solution was crystallized after 12 h and the crystals were collected by
filtration.
Ethyl-5-phenyl-7-methyl-2-(4-bromophenyl)methylene-3-
oxo-2,3-dihydro-5H-thiazolo [a-2,3] Pyrimidine-6-
carboxylate (2a)
Yield 90%, m.p. 177–178◦C.
IR (KBr): ν = 3050, 2900, 1711, 1622, 1561, 1240, 1165 cm−1
.

1178
A. Mobinikhaledi and N. Forughifar
1H NMR (CDCl3): δ (ppm) = 1.01 (t, J = 7.2 Hz, 3H, CH3), 2.31
(s, 3H, CH3), 3.99, (q, J = 7.2 Hz, 2H, OCH2), 6.00 (s, 1H, H-5), 7.39
(m, 10H, Harom), 7.95 (brs, 1H, ylidene).
Anal. Calcd for C23H19N2O3SBr: C, 57.14; H, 3.93; N, 5.80%. Found:
C, 57.10; H, 4.10; N, 5.60.
Ethyl-5-phenyl-7-methyl-2-(4-chlorophenyl)methylene-3-
oxo-2,3-dihydro-5H-thiazolo [a-2,3] Pyrimidine-6-
carboxylate (2b)
Yield 94%, m.p. 154–155◦C.
IR (KBr): ν = 3050, 2900, 1711, 1609, 1549, 1227, 1165 cm−1
.
1H NMR (CDCl3): δ (ppm) = 1.05 (t, J = 7.2 Hz, 3H, CH3), 2.50 (s,
3H, CH3), 4.10, (q, J = 7.2 Hz, 2H, OCH2), 6.10 (s, IH, H-5), 7.35 (m,
10H, Harom), 7.75 (brs, 1H, ylidene).
Anal. Calcd for C23H19N2O3SCI: C, 62.93; H, 4.36; N, 6.39%. Found:
C, 62.88; H, 4.42; N, 6.37%.
Ethyl-5-phenyl-7-methyl-2-(4-nitrophenyl)methylene-3-
oxo-2,3-dihydro-5H-thiazolo [a-2,3]
Pyrimidine-6-carboxylate (2c)
Yield 94%, m.p. 188–189◦C.
IR (KBr): ν = 3000, 2980, 1711, 1609, 1560, 1339, 1165 cm−1
.
1H NMR (CDCl3): δ (ppm) = 1.10 (t, J = 7.2 Hz, 3H, CH3), 2.55 (s,
3H, CH3), 4.10, (q, J = 7.2 Hz, 2H, OCH2), 6.10 (s, 1H, H-5), 7.50 (m,
9H, Harom), 8.15 (brs, 1H, ylidene).
Anal. Calcd for C23H19N3O5S: C, 61.46; H, 4.26; N, 9.34%. Found: C,
61.39; H, 4.30; N, 9.31%.
Ethyl-5-phenyl-7-methyl-2-(4-N,N-dimethylaminophenyl)-
methylene-3-oxo-2,3-dihydro-5H-thiazolo [a-2,3]
Pyrimidine-6-carboxylate (2d)
Yield 88%, m.p. 225–226◦C.
IR (KBr): ν = 3050, 2920, 1707, 1580, 1155 cm−1
.
1H NMR (CDCl3): δ (ppm) = 1.10 (t, J = 7.2 Hz, 3H, CH3), 2.50 (s,
3H, CH3), 3.00 (s, 6H, NMe2), 4.05, (q, J = 7.2 Hz, 2H, OCH2), 6.10 (s,
1H, H-5), 7.20 (m, 9H, Harom), 7.70 (brs, 1H, ylidene).
Anal. Calcd for C25H25N3O3S: C, 67.09; H, 5.63; N, 9.38%. Found: C,
67.02; H, 5.63; N, 9.37%.
Ethyl-5-Phenyl-7-methyl-2-(thienyl)methylene-3-oxo-2,3-
dihydro-5H-thiazolo [a-2,3] Pyrimidine-6-carboxylate
(2e)
Yield 86%, m.p. 210–212◦C.

Thiazolopyrimidines
1179
IR (KBr): ν = 3080, 2990, 1703, 1595, 1547, 1236 cm−1
.
1H NMR (CDCl3): δ (ppm) = 1.10 (t, J = 7.2 Hz, 3H, CH3), 2.50 (s,
3H, CH3), 4.05, (q, J = 7.2 Hz, 2H, OCH2), 6.10 (s, 1H, H-5), 7.30 (m,
8H, Harom), 7.83 (brs, 1H, ylidene).
Anal. Calcd for C21H18N2O3S2: C, 61.41; H, 4.41; N, 6.87%. Found:
C, 61.45; H, 4.51; N, 6.89%.
Ethyl-5-methylphenyl-7-methyl-2-(4-chlorophenyl)-
methylene-3-oxo-2,3-dihydro-5H-thiazolo [a-2,3]
Pyrimidine-6-carboxylate (2f)
Yield 92%, m.p. 180–181◦C.
IR (KBr): ν = 3050, 2900, 1709, 1618, 1549, 1225 cm−1
.
1H NMR (CDCl3): δ (ppm) = 1.11 (t, J = 7.2 Hz, 3H, CH3), 2.20 (s,
3H, CH3), 2.30 (s, 3H, CH3), 4.00, (q, J = 7.2 Hz, 2H, OCH2), 6.00 (s,
1H, H-5), 7.35 (m, 8H, Harom), 7.65 (brs, 1H, ylidene).
Anal. Calcd for C24H20N2O3S2: C, 64.28; H, 4.45; N, 6.25%. Found:
C, 64.10; H, 4.55; N, 6.40%.
Ethyl-5-methylphenyl-7-methyl-2-(4-
methoxyphenyl)methylene-3-oxo-2,3-dihydro-5H-thiazolo
[a-2,3] Pyrimidine-6-carboxylate (2g)
Yield 92%, m.p. 180–182◦C.
IR (KBr): ν = 3050, 2900, 1711, 1595, 1547, 1300 cm−1
.
1H NMR (CDCl3): δ (ppm) = 1.15 (t, J = 7.2 Hz, 3H, CH3), 2.20 (s,
3H, CH3), 2.31 (s, 3H, CH3), 3.80 (s, 3H, OCH3), 4.00, (q, J = 7.2 Hz, 2H,
OCH2), 6.00 (s, 1H, H-5), 7.25 (m, 8H, Harom), 7.65 (brs, 1H, ylidene).
Anal. Calcd for C25H23N2O4S: C, 67.09; H, 5.18; N, 6.25%. Found: C,
66.95; H, 5.46; N, 6.20%.
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