Synthesis of some bicyclic thiazolopyrimidine derivatives

Article abstract of DOI:10.1080/714040967

Thiazolopyrimidine compounds 3(a-d) were synthesized by a simple one-pot condensation reaction of starting pyrimidine derivative 1 and 1,2-dibromoethane 2 in dimethylformamide. In a similar way thiazolopyrimidine compounds 5(d-e) were synthesized by react

Full text of DOI:10.1080/714040967

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Phosphorus, Sulfur, and Silicon and the Related
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Synthesis of Some Bicyclic Thiazolopyrimidine
Derivatives
A. Mobinikhaledi a , N. Forughifar a & F. Goodarzi a
a University of Arak, Arak, Iran
Published online: 18 Jun 2010.
To cite this article: A. Mobinikhaledi , N. Forughifar & F. Goodarzi (2003): Synthesis of Some Bicyclic Thiazolopyrimidine
Derivatives, Phosphorus, Sulfur, and Silicon and the Related Elements, 178:12, 2539-2543
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Phosphorus, Sulfur, and Silicon, 178:2539–2543, 2003
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ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500390248024
SYNTHESIS OF SOME BICYCLIC
THIAZOLOPYRIMIDINE DERIVATIVES
A. Mobinikhaledi, N. Forughifar, and F. Goodarzi
University of Arak, Arak, Iran
(Received April 23, 2003; accepted June 26, 2003)
Thiazolopyrimidine compounds 3(a–d) were synthesized by a simple
one-pot condensation reaction of starting pyrimidine derivative 1 and
1,2-dibromoethane 2 in dimethylformamide. In a similar way thia-
zolopyrimidine compounds 5(a–e) were synthesized by reaction of 1
and 2-bromopropionic acid 4 in dioxane under reflux condition. The
yields of products following recrystallization from ethanol were of the
order of 70–80%.
Keywords: 1,2-Dibromoethane; 2-bromopropionic acid; carboxylate;
pyrimidine; thiazolo
Pyrimidine derivatives are known as important heterocyclic compounds
for their considerable antibacterial and antifungal activities. Some
pyrimidines possess remarkable pharmacological efficiency.1−16 As a
result pyrimidine has been subjected to a large variety of structural
modifications in order to synthesize derivatives with different biologi-
cal effects. Various synthetic approaches for the synthesis of pyrimidine
derivatives have been reported in the literature.1,17−20 Most of them are
based on the simple Biginelli cyclocondensation reaction of β-ketoester,
aryl aldehyde, and thio (urea) derivatives,1,17,18 and in some case they
are based on multi-step processes.19
Here, due to versatile biological properties of pyrimidine derivatives,
we have extended the general method of Kappe18 in order to synthesize
some novel bicyclic pyrimidine derivatives in high yield.
Address correspondence to A. Mobinikhaledi, Chemistry Department, University of
Arak, Dr. Beheshti Ave, Arak, Iran. E-mail: akbar mobini@yahoo.com
2539

2540
A. Mobinikhaledi et al.
RESULTS AND DISCUSSION
Compounds 3(a–d) and 5(a–b) were synthesized according to proce-
dures A and B respectively.18 Reaction of the starting pyrimidine deriva-
tive 1 and 1,2-dibromoethane 2 in dimethylformamide under reflux
afforded 3(a–d) as HBr salts (Scheme 1). Also reaction of 1 and 2-
bromopropionic acid 3 as an cyclocondensation reagent in dioxane un-
der reflux gave compounds 5(a–e). These methods are very easy and can
be used to prepare various substituted thiazolopyrimidine compounds
(Scheme 1).
Reactions were usually carried out for 2 to 4 h. Yields of these one-
pot protocol reactions following recrystallization from ethanol were of
SCHEME 1

Thiazolopyrimidines
2541
the order of 70–80%. In the IR spectra of compounds 3(a–d) and 5(a–e)
absence of the absorption at 3200–3400 cm−1, the characteristic absorp-
tion of NH group of starting material, is a good evidence of the expected
reactions.
EXPERIMENTAL
Pyrimidine thiazole derivatives were prepared using the method of
Kappe et al.18 Melting points were determined with an electrother-
mal digital melting point apparatus. IR spectra were recorded on a
Galaxy series FT-IR 5000 spectrophotometer by using KBr pellets.
1HNMR spectra were recorded on Bruker 400 and 500 MHz spectrom-
eters with using Me4Si (TMS) as an internal standard. mass spectra
were measured with an EI (70 eV)+Q1MSLMR up LP spectrometer.
Reaction courses and product mixtures were monitored by thin layer
chromatography.
Procedure A
Compound 3 was prepared as a HBr salt. 1,2-Dibromoethane (0.001
mmol) was added to a boiling solution of appropriate pyrimidine thi-
azole derivatives (0.001 mmol) in dimethylformamide (2 ml) and then
refluxed for 2 to 4 h. The reaction mixture was cooled and the precipitate
filtered off and washed with ethanol. The crude product was recrystal-
lized from ethanol. This procedure was used for synthesis of compounds
3(a–d) .
Ethyl-5-(4-methylphenyl)-2,3-dihydro-7-methyl-5H-thiazolo
[3,2-a]pyrimidine-6-carboxylate (3a) . Yield % 75, m.p. 202–204◦C.
IR (KBr): υ = 3100, 2985, 1693, 1535, 1300, 1110 cm−1
.
1HNMR
(DMSO-d6): δ = 1.05 (t, 3H, CH3), 2.3 (s, 3H, CH3), 2.6 (m, 4H,
CH2 CH2), 3.69 (q, 2H, CH2), 5.71 (s, 1H, H-5), 7.3 (m, 4H, H-arom).
Ms: m/z (%) = 315 (M+, 24), 287 (43), 224 (100), 196.5 (45).
Ethyl-5-(2-nitrophenyl)-7-methyl-5H-thiazolo pyrimidine-6-
carboxylate (3b). Yield % 70, m.p. 233–234◦C. IR (KBr): υ = 3067,
2964, 1692, 1532, 1324, 1264 cm−1. 1HNMR (DMSO-d6): δ = 1.0 (t, 3H,
CH3), 2.3 (s, 3H, CH3), 2.5 (m, 4H, CH2 CH2), 3.6 (q, 2H, CH2),
6.1 (s, 1H, H-5), 7.6 (m, 4H, H-arom). Ms: m/z (%) = 347 (M+, 20), 330
(75), 298 (100), 224 (60), 196 (65).
Ethyl-5-(3-chlorophenyl)-2,3-dihydro-7-methyl-5H-thiazolo
[3,2-a]pyrimidine-6-carboxylate (3c). Yield % 73, m.p. 204–206◦C.
IR (KBr): υ = 3050, 2950, 1676, 1197, 1117 cm−1. 1HNMR (DMSO-d6):
δ = 1.0 (t, 3H, CH3), 2.5 (s, 3H, CH3), 2.6 (m, 4H, CH2 CH2), 3.7

2542
A. Mobinikhaledi et al.
(q, 2H, CH2), 6.3 (s, 1H, H-5), 7.2 (m, 4H, H-arom). Ms: m/z (%) = 336
(M+, 48), 307 (85), 224 (90), 195.5 (100), 150 (30).
Ethyl-5-(2,5-dimethoxyphenyl)-2,3-dihydro-7-methyl-5H-thia-
zolo[3,2-a]pyrimidine-6-carboxylate (3d). Yield % 80, m.p. 211–
212◦C. IR (KBr): υ = 3060, 2960, 1670, 1530, 1312 cm−1
.
1HNMR
(DMSO-d6): δ = 1.07 (t, 3H, CH3), 2.34 (s, 3H, CH3), 2.90 (m, 4H,
CH2 CH2), 3.96 (q, 2H, CH2), 3.72 (s, 6H, OCH3), 5.86 (s, 1H,
H-5), 6.91 (m, 3H, H-arom). Ms: m/z (%) = 362 (M+, 48), 333 (80), 289.2
(35), 224.7 (100), 196 (100), 152.90 (40), 150 (25).
Procedure B
A mixture of appropriate pyrimidine thiazole derivatives, (0.001 mmol)
and 2-bromo propionic acid (0.001 mmol) in dioxane (3 ml) were refluxed
for 1 to 2 h. The reaction mixture was cooled and the precipitate filtered
off and then washed with ethanol. The crude product was recrystal-
lized from ethanol. This procedure was used for synthesis of compounds
5(a–e).
Ethyl-2,7-dimethyl-3-oxo-5-phenyl-2,3-dihydro-5H-thiazolo
[3,2,a]pyrimidine-6-carboxylate (5a). Yield % 80, m.p. 216◦C.
IR (KBr): ν = 3090, 1760, 1717, 1657, 1359 cm−1
.
1HNMR (CDCl3):
δ = 1.17 (t, 3H, CH3), 2.29 (d, 3H, CH3), 2.40 (s, 3H, CH3), 4.03 (q,
2H, CH2), 4.73 (q, 1H, CH), 6.63 (s, 1H, H-5), 7.15 (m, 5H, H-arom).
Ms: m/z (%) = 330 (M+, 70), 302 (25), 285 (22), 273 (30), 253 (90), 225
(90), 197 (30), 67 (40).
Ethyl-2,7-dimethyl-3-oxo-5-(4-methylphenyl)-2,3-dihydro-5H-
thiazolo[3,2,a]pyrimidine-6-carboxylate (5b). Yield
%
73,
m.p. 198◦C. IR (KBr): υ = 3075, 1757, 1685, 1595, 1283 cm−1
.
1HNMR(CDCl3): δ = 1.07 (t, 3H, CH3), 1.45 (d, 3H, CH3), 2.51 (s, 3H,
CH3), 4.03 (q, 2H, CH2), 4.68 (q, 1H, CH), 5.88 (s, 1H, H-5), 7.1 (m,
4H, Harom). Ms: m/z (%) = 344 (M+, 60), 316 (25), 287 (20), 271 (60),
253 (90), 225 (90), 197 (25), 169 (20), 80 (80).
Ethyl-2,7-dimethyl-3-oxo-5-(3-chorophenyl)-2,3-dihydro-5H-
thiazolo[3,2,a]pyrimidine-6-carboxylate (5c). Yield % 75, m.p.
218–219◦C. IR (KBr): υ = 2997, 1769, 1692, 1552, 1321, 1169, 1102
cm−1. 1HNMR (CDCl3): δ = 1.03 (t, 3H, CH3), 1.46 (d, 3H, CH3), 2.53
(s, 3H, CH3), 4.01 (q, 2H, CH2), 4.09 (q, 1H, CH), 5.95 (s, 1H, H-5),
7.13 (m, 4H, H-arom). Ms: m/z (%) = 364 (M+, 30), 336 (20), 307 (15),
253 (90), 225 (90), 197 (30), 80 (60).
Ethyl-2,7-dimethyl-3-oxo-5-(2,5-dimethoxyphenyl)-2,3-dihy-
dro-5H-thiazolo[3,2,a]pyrimidine-6-carboxylate (5d). Yield % 80,
m.p. 198–200◦C. IR (KBr): υ = 2953, 2731, 1763, 1712, 1662, 1278
cm−1
.
1HNMR (CDCl3): δ = 1.07 (t, 3H, CH3), 1.51 (d, 3H, CH3),

Thiazolopyrimidines
2543
2.34 (s, 3H, CH3), 3.70 (s, 6H, 2-OMe), 4.03 (q, 2H, CH2), 4.70 (q,
1H, CH), 6.04 (s, 1H, H-5), 6.90 (m, 3H, H-arom). Ms: m/z (%) = 390
(M+, 75), 359 (50), 334 (25), 253 (90), 225 (90), 197 (25), 181 (35), 153
(20), 80 (45).
Ethyl-2,7-dimethyl-3-oxo-5-[4-(N,N-dimethylamino)phenyl]-
2,3-dihydro-5H-thiazolo[3,2,a]pyrimidine-6-carboxylate (5e).
Yield % 80, m.p. 213–215◦C. IR (KBr): υ = 2970, 1762, 1683, 1558,
1278, 1175 cm−1. 1HNMR (CDCl3): δ = 1.04 (t, 3H, CH3), 1.46 (d, 3H,
CH3), 2.70 (s, 3H, CH3), 3.51 (s, 6H, N(CH3)2), 4.02 (q, 2H, CH2),
4.07 (q, 1H, CH), 6.40 (s, 1H, H-5), 7.80 (m, 4H, H-arom). Ms: m/z (%)
= 373 (M+, 90), 317 (25), 300 (20), 272 (70), 253 (90), 225 (90), 80 (80).
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