Thiazolo[4,5-d]pyrimidines: Synthesis and antibacterial evaluation

Article abstract of DOI:10.1515/HC.2011.016

The reaction of 4-amino-5-bromo-2-chloro-6-methylpyrimidine (1) with carbon disulfide in the presence of KOH in DMF quantitatively gave 5-chloro-7-methylthiazolo[4,5- d] pyrimidine-2 (3 H)-thione (2) which was then alkylated at the sulfur atom with variou

Full text of DOI:10.1515/HC.2011.016

Heterocycl. Commun., Vol. 17(1-2), pp. 43–47, 2011 • Copyright © by Walter de Gruyter • Berlin • Boston. DOI 10.1515/HC.2011.016
Thiazolo[4,5-d]pyrimidines: synthesis and antibacterial
evaluation
Mohammad Rahimizadeh1,*, Mehdi Bakavoli1,
2004; Bhattacharya et al., 2005) and vanilloid receptor I
TRPVI antagonism (Xi et al., 2005). Also, some thiazol-
opyrimidines have been found to possess anti-inflammatory
Ali Shiri1, Reyhaneh Faridnia1, Parvaneh Pordeli2
and Fatemeh Oroojalian3
and analgesic activities (Russo et al., 1993; Pawan and
Sawhney, 1997; Ashok et al., 2007).
Although thiazole ring construction has been reported
2 Department of Biology, School of Sciences, Ferdowsi
numerous times and adequately reviewed in the literature
University of Mashhad, 91775-1436 Mashhad, Iran
1 Department of Chemistry, School of Sciences, Ferdowsi
University of Mashhad, 91775-1436 Mashhad, Iran
3 Department of Microbiology, School of Sciences, Isfahan
University, Isfahan, Iran
(Metwally et al., 2004), there are few reports on the syn-
thesis of fused thiazolopyrimidines and especially thiazolo
[4,5-d] pyrimidines. Walek and coworkers (Walek, 1983;
Walek et al., 1984) prepared compound (I) by heating the
thiazole (II) at 180°C for 2 h, whereas Wobig (1989) pre-
pared thiazolopyrimidine derivatives (III) by cyclization
of aminothiazoles (IV) with formamide, formic acid, and
dimethyl malonate.
*Corresponding author
e-mail: rahimizh@yahoo.com
Abstract
The reaction of 4-amino-5-bromo-2-chloro-6-methylpyrim-
idine (1) with carbon disulfide in the presence of KOH in
DMF quantitatively gave 5-chloro-7-methylthiazolo[4,5-d]
pyrimidine-2 (3H)-thione (2) which was then alkylated at the
sulfur atom with various alkyl halides in the presence of Et3N
in acetonitrile to give alkylthio derivatives 3. The substitution
of the chlorine atom in 3 with morpholine was also investi-
gated. The synthesized compounds were subjected to antibac-
terial evaluations.
H
H2N
N
O
N
N
S
H
R
R
EtO
N
HN
S
O
O
O
(I)
(II)
R
N
H2N
N
N
SMe
SMe
N
R1HN
S
S
R1
O
O
(III)
(IV)
Keywords: antibacterial evaluation; heterocyclization;
thiazolo[4,5-d]pyrimidine.
Efficient synthesis of various derivatives of thiazolo-
pyrimidine have been reported by the reaction of 4,6-dichlo-
ro-5-aminopyrimidine with isothiocyanates (Liu et al., 2005;
Lebsack et al., 2009). The reaction of 4-chloro-2,3-dihydro-
thiazolidine-5-carboxaldehyde with urea in ethanol solution
at reflux in the presence of a catalytic amount of Et3N afforded
new polysubstituted thiazolopyrimidine derivatives (El Rady,
2008). Akbari et al. (2008) have synthesized 7-aryl-5-thioxo-
4,5,6,7-tetrahydro-3H-thiazolo[4,5-d]pyrimidin-2-ones by
the reaction of 2,4-thiazolidine with thiourea and different
aromatic aldehydes.
Taking into account these findings and in continuation of
our efforts to develop novel and efficient routes to hetero-
cyclic derivatives of pyrimidine with potential biological
activities (Bakavoli et al., 2008, 2009, 2010a, b, 2011a, b), we
turned our attention to the synthesis of various new deriva-
tives of thiazolo[4,5-d]pyrimidine. It was of interest to inves-
tigate antibacterial activity of the new compounds against
Staphylococcus aureus PTCC 1431, Bacillus subtilis PTCC
1365, Escherichia coli HB101 BA 7601C, and Pseudomonas
aeruginosa PTCC 1074 bacteria.
Introduction
In medicinal chemistry, pyrimidine derivatives have been
known for their therapeutic applications. The presence
of a pyrimidine system in thymine, cytosine, and uracil,
which are the essential building blocks of nucleic acids,
is one possible reason for the activity (Amir et al., 2007).
Similarly, thiazole derivatives possess diverse pharmaco-
logical activities. Fused derivatives of pyrimidine and thi-
azole are also bioactive. For example, thiazolopyrimidine
derivatives have been the focus of a great deal of interest
owing to their antimicrobial (Vicini et al., 2003; Zitouni
et al., 2004), antiviral (Sircar et al., 1986; Nagahara et al.,
1990; Kini et al., 1991), and antitumor (El-Subbagh and
Alobaid, 1996) activities. They have been used as potent
and selective inhibitors of acetyl-CoA carboxylase 2 (Clark
et al., 2007) and VEGF receptors I and II (Kiselyov et al.,
2006). They have also shown potent and selective human
adenosine A3 receptor (Van Tilburg et al., 2001; Jung et al.,
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44 M. Rahimizadeh et al.
Results and discussion
Chemistry
A nucleophilic substitution of the chlorine atom at the 5-po-
sition of the pyrimidine ring of the synthesized compounds
3a–f with morpholine yielded the corresponding morpholine-
substituted derivatives 4a–f in good yields. The 1H NMR spec-
tra of all new compounds 4a–f exhibit the characteristic signals
of the morpholine unit, which along with other data unambigu-
ously confirm the desired structures of compounds 4a–f.
5-Bromo-2,4-dichloro-6-methylpyrimidine, which was pre-
pared as reported by us previously (Bakavoli et al., 2006),
was treated with ammonia in ethanol at room temperature to
give 4-amino-5-bromo-2-chloro-6-methyl-pyrimidine (1). The
heterocyclization of compound 1 with carbon disulfide in the
presence of KOH at room temperature quantitatively afforded
5-chloro-7-methyl-2,3-dihydropyrimido[4,5-d][1,3]thiazol-2-
thione (2). The 1H NMR spectrum of this compound shows a
singlet at δ 2.52 ppm and a broad singlet at δ 3.85 for the methyl
and NH groups of the compound 2, respectively. In the mass
spectra of this compound, molecular ion peak is observed at
m/z 217, which corresponds to the desired molecular formula.
To prepare new derivatives of thiazolo [4,5-d] pyrimidine, com-
pound 2 was treated with various alkyl halides bearing different
functional groups in the presence of Et3N in boiling acetonitrile.
The desired new derivatives of thiazolo[4,5-d]pyrimidine 3a–f
were obtained in good to excellent yields (Scheme 1).
The structures of the synthesized compounds 3 were deter-
mined by the spectral and microanalytical data. For example,
the 1H NMR spectrum of compound 3a does not exhibit a signal
for an NH moiety that is present at δ 3.85 in the spectrum of
the precursor 2. Product 3a shows two sharp singlets at δ 2.55
and δ 2.88 for two methyl groups. The IR spectrum of 3a does
not show the stretching vibration band at 3280 cm-1 for the NH
group that is found in the IR spectrum to the NH group of the
precursor 2. Instead, a new C=N stretching vibration band at
1640 cm-1 is observed. The molecular ion peaks in the mass
spectrum of compound 3a are observed at m/z 231 and 233,
which is consistent with the presence of one chlorine atom in the
molecule. These results, together with the results of microanaly-
sis fully support the molecular formula of C7H6ClN3S2 for 3a.
Antibacterial evaluation
The tested microorganisms were Gram-positive and Gram-
negativebacteria.Thesensitivityoftheselectedmicroorganisms,
S. aureus PTCC 1431, B. subtilis PTCC 1365, E. coli HB101 BA
7601C, and P. aeruginosa PTCC 1074, to all synthesized com-
pounds 3a–f and 4a–f was determined in vitro. The compounds
were dissolved in DMSO and the tests were carried out using a
disk diffusion method (Reeves and White, 1983). Streptomycin
was used as a reference bactericidal antibiotic (Table 1). The
evaluations were obtained in triplicate and the results with dif-
ferences greater than 5% were discarded, and the measurements
repeated. It can be concluded from the data in Table 1 that all
compounds 3a–f and 4a–f are highly active against B. subtilis
and P. aeruginosa. A slightly lower activity is observed against
S. aureus. Compounds 3c, 3d, and 4b are highly active against
E. coli, which is a Gram-negative bacteria.
Conclusion
In summary, a new series of thiazolo[4,5-d]pyrimidine deriva-
tives were synthesized and their antibacterial activities evalu-
ated. Many compounds proved to be more active against B.
subtilis and P. aeruginosa than streptomycin, the reference
H
N
Cl
N
NH2
Br
Cl
N
Cl
N
N
S
CS2
R-X
Et3N/CH3CN
SR
S
N
N
N
S
DMF/KOH
CH3
CH3
CH3
(1)
(2)
(3a-f)
3a: R=CH3
3d: R=CH2CN
3b: R=C2H5
3e: R=CH2COCH3
3f: R=CH2CO2Et
3c: R=CH2Ph
Morpholine
Et3N, EtOH
O
N
N
N
S
SR
N
CH3
(4a-f)
4a: R=CH3
4d: R=CH2CN
4b: R=C2H5
4c: R=CH2Ph
4e: R=CH2COCH3
4f: R=CH2CO2Et
Scheme 1 Synthesis of thiazolo[4,5-d]pyrimidines.
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Thiazolo[4,5-d]pyrimidines 45
Table 1 Antibacterial data for compounds 3a–f and 4a–f.
Compound
Gram-negative bacteria
Gram-positive bacteria
Escherichia coli
Pseudomonas aeruginosa
Staphylococcus aureus
Bacillus subtilis
HB101 BA 7601C
PTCC 1074
PTCC 1431
PTCC 1365
3a
3b
3c
3d
3e
3f
4a
4b
4c
4d
4e
4f
15a(-)b,c
17(+)
18(++)
18(++)
17(+)
17(+)
15(-)
20(++)
13(-)
14(-)
14(++)
15(++)
15.5(++)
13(++)
14(++)
15(++)
15.3(++)
15(++)
15.5(++)
16(++)
13(++)
9(-)
12(-)
12(-)
14(-)
14(-)
14(-)
13(-)
12(-)
13(-)
12(-)
15(+)
13(-)
14.5(-)
15
15(++)
15(++)
14(++)
14(++)
13(++)
14(++)
14(++)
14.5(++)
15(++)
14(++)
13.5(++)
14.3(++)
10
15(-)
17(+)
17
Streptomycin (standard)
10
a Zones of inhibition in millimeters.
b (++) highly sensitive; (+) moderately sensitive; (-) slightly sensitive.
c The maximum inhibition zone for each compound has been shown. Discs of each concentration were placed in triplicate in Muller-Hinton agar
medium seeded with fresh bacteria separately and the average was reported.
and the solution was heated under reflux for 2–3 h. The progress
of the reaction was monitored by TLC using n-hexane/EtOAc (6:4).
Then, the solvent was removed on a rotary evaporator and the result-
ing solid was crystallized from methanol.
antibiotic. Hence, it is concluded that there is a promising
scope for further development in this field.
Experimental
5-Chloro-7-methyl-2-(methylthio)thiazolo[4,5-d]pyrimidine
1
Melting points were recorded on an electrothermal type 9100 melting
point apparatus and are not corrected. The IR spectra were obtained
in KBr pellets on a Thermo Nicolet Avatar 370-FTIR spectrometer.
The 1H NMR (100 MHz) spectra were recorded on a Bruker AC 100
spectrometer in CDCl3 solution with TMS as an internal reference.
The electron impact mass spectra were obtained on a Varian Mat
CH-7 instrument at 70 eV. Elemental analysis was performed on a
Thermo Finnigan Flash EA 1112 instrument.
(3a) Yield 60%; mp 137–144°C; H NMR: δ 2.55 (s, 3H, CH3-
pyrimidine), 2.88 (s, 3H, -SCH3); IR: ν 3010, 1650 cm-1; MS: m/z 231
(M+), 233 (M++2). Analysis calculated for C7H6ClN3S2: C, 36.28; H,
2.61; N, 18.13; S, 27.67. Found: C, 36.01; H, 2.57; N, 18.02; S, 27.44.
5-Chloro-2-(ethylthio)-7-methylthiazolo[4,5-d]pyrimidine
(3b) Yield 65%; mp 107°C; 1H NMR: δ 1.53 (t, 3H, CH3), 2.70 (s,
3H, CH3-pyrimidine), 3.43 (q, 2H, -SCH2); IR: ν 3015, 1630 cm-1;
MS: m/z 245 (M+), 247 (M++2). Analysis calculated for C8H8ClN3S2:
C, 39.10; H, 3.28; N, 17.10; S, 26.10. Found: C, 38.88; H, 3.20; N,
16.90; S, 25.78.
5-Chloro-7-methylthiazolo[4,5-d]pyrimidine-
2(3H)-thione (2)
To a magnetically stirred solution of 4-amino-5-bromo-2-chloro-6-
methyl-pyrimidine (1) (1 mmol, 0.22 g) and carbon disulfide (0.1 ml)
in dry DMF (5 ml), powdered KOH (1 mmol, 0.056 g) was added,
and the mixture stirred for 2 h at room temperature. Then, the mixture
was heated at 70–80°C for 0.5 h. After cooling, water (10 ml) was
added and the solution was neutralized with acetic acid. The resulting
precipitate was filtered off and crystallized from ethanol: yield 80%;
mp 197°C (decomp.); 1H NMR: δ 2.52 (s, 3H, CH3-pyrimidine), 3.85
(s, 1H, NH, D2O exchangeable); IR: ν 3010, 1233 (C=S) cm-1; MS:
m/z 217 (M+ for 35Cl), 219 (M+ for 37Cl). Analysis calculated for
C6H5ClN3S2: C, 33.00; H, 1.85; N, 19.30; S, 29.45. Found: C, 29.91;
H, 2.71; N, 16.95; S, 21.54.
2-(Benzylthio)-5-chloro-7-methylthiazolo[4,5-d]pyrimidine
(3c) Yield 70%; mp 98–100°C; 1H NMR: δ 2.70 (s, 3H, CH3), 4.71
(s, 2H, CH2), 7.31–7.62 (m, 5H, phenyl); IR: ν 3000, 1660 cm-1; MS:
m/z 307 (M+), 309 (M++2). Analysis calculated for C13H10ClN3S2:
C, 50.72; H, 3.27; N, 13.65; S, 20.83. Found: C, 50.66; H, 3.16; N,
13.57; S, 20.69.
2-(5-Chloro-7-methylthiazolo[4,5-d]pyrimidin-2-ylthio) ace-
1
tonitrile (3d) Yield 63%; mp 104–110°C; H NMR: δ 2.78 (s, 3H,
CH3), 4.32 (s, 2H, CH2); IR: ν 2990, 2215, 1640 cm-1; MS: m/z 256
(M+), 258 (M++2). Analysis calculated for C8H5ClN4S2: C, 37.43; H,
1.96; N, 21.82; S, 24.98. Found: C, 37.22; H, 1.88; N, 21.90; S, 24.89.
1-(5-Chloro-7-methylthiazolo[4,5-d]pyrimidin-2-ylthio)propan-
2-one (3e) Yield 73%; mp 114°C; 1H NMR: δ 2.41 (s, 3H, CH3),
2.82 (s, 3H, CH3-pyrimidine), 4.41 (s, 2H, -SCH2); IR: ν 3010, 1710,
1660 cm-1; MS: m/z 273 (M+), 275 (M++2). Analysis calculated for
C9H8ClN3OS2: C, 39.49; H, 2.95; N, 15.35; S, 23.43. Found: C,
39.51; H, 2.92; N, 15.18; S, 23.35.
General procedure for the synthesis of thiazolo[4,5-d]
pyrimidines 3a–f
To a solution of 5-chloro-7-methyl-2,3-dihydropyrimido[4,5-d][1,3]
thiazol-2-thione (1) (1 mmol, 0.21 g) and Et3N (1 mmol, 0.1 g) in
CH3CN (15 ml), the appropriate alkyl halide (1.1 mmol) was added,
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46 M. Rahimizadeh et al.
Ethyl-2-(5-chloro-7-methylthiazolo[4,5-d]pyrimidin-2-ylthio)
acetate (3f) Yield 58%; mp 109°C; 1H NMR: δ 1.38 (t, 3H, CH3),
2.73 (s, 3H, CH3-pyrimidine), 4.31 (q, 2H, -SCH2); IR: ν 3010, 1680,
1630 cm-1; MS: m/z 303 (M+), 305 (M++2). Analysis calculated for
C10H10ClN3O2S2: C, 39.54; H, 3.32; N, 13.83; S, 21.11. Found: C,
39.45; H, 3.29; N, 13.78; S, 20.79.
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General procedure for the substitution of chlorine
atom in 5-position with morpholine (4a–f)
To a solution of compounds (3a–f) (1 mmol) and morpholine
(1.1 mmol, 0.088 g) in ethanol (10 ml), Et3N (1.1 mmol, 0.1 g) was
added and the solution was heated for approximately 8 h. The solvent
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7-Methyl-2-(methylthio)-5-morpholinothiazolo[4,5-d]pyrimi-
1
dine (4a) Yield 64%; mp 204–205°C; H NMR: δ 2.52 (s, 3H,
CH3), 2.83 (s, 3H, CH3-pyrimidine), 3.71–3.92 (m, 8H, morpho-
line); IR: ν 3020, 1610 cm-1; MS: m/z 282 (M+). Analysis calculated
for C11H14N4OS2: C, 46.79; H, 5.00; N, 19.84; S, 22.71. Found: C,
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1
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(4b) Yield 50%; mp 129–131°C; H NMR: δ 1.47 (t, 3H, CH3),
2.51 (s, 3H, CH3), 3.43 (q, 2H, -SCH2), 3.71–4.05 (m, 8H, morpho-
line); IR: ν 3030, 1650 cm-1; MS: m/z 296 (M+). Analysis calculated
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48.52; H, 5.41; N, 18.86; S, 21.53.
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2-(Benzylthio)-7-methyl-5-morpholinothiazolo[4,5-d]pyrimi-
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CH3), 3.72–4.03 (m, 8H, morpholine), 4.71 (s, 2H, -SCH2), 7.31–
7.52 (m, 5H, phenyl); IR: ν 3050, 1630 cm-1; MS: m/z 358 (M+).
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1
2-(7-Methyl-5-morpholinothiazolo[4,5-d]pyrimidin-2-ylthio)
acetonitrile (4d) Yield 48%; mp 185–189°C; 1H NMR: δ 2.48 (s,
3H, CH3), 3.72–3.91 (m, 8H, morpholine), 4.33 (s, 2H, -SCH2); IR:
ν 3030, 2215, 1650 cm-1; MS: m/z 307 (M+). Analysis calculated
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46.75; H, 4.22; N, 22.77; S, 20.79.
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propan-2-one (4e) Yield 43%; mp 185–189°C; H NMR: δ 2.48
(s, 3H, CH3), 2.72 (s, 3H, CH3), 3.72–3.93 (m, 8H, morpholine), 4.46
(s, 2H, -SCH2); IR: ν 3010, 1720, 1640 cm-1; MS: m/z 324 (M+).
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1
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1
ylthio)acetate (4f) Yield 43%; mp 173–180°C; H NMR: δ 1.32
(s, 3H, CH3), 2.61 (s, 2H, -SCH2), 3.82 (m, 8H, morpholine), 4.27
(s, 2H, -OCH2). IR: ν 3030, 1690, 1630 cm-1. MS: m/z 354 (M+).
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S, 18.09. Found: C, 47.39; H, 5.04; N, 15.69; S, 17.89.
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Acknowledgments
Financial support for this work by the Research Affairs of Ferdowsi
University of Mashhad is gratefully acknowledged.
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Thiazolo[4,5-d]pyrimidines 47
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Received May 14, 2011; accepted May 27, 2011
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