Microwave-assisted synthesis and anti-bacterial activity of some 2-Amino-6-aryl-4-(2-thienyl)pyrimidines

Article abstract of DOI:10.1016/j.farmac.2005.01.012

Some novel 2-amino-6-aryl-4-(2-thienyl)pyrimidines were synthesized from 3-aryl-1-thien-2ylprop-2-en-1-ones and guanidine hydrochloride in presence of alkali by conventional heating in alcoholic medium and microwave heating in solvent-free conditions. The compounds were evaluated for in vitro anti-bacterial activity. The anti-bacterial data revealed that compounds 5a-e had better activity against tested Gram-positive organisms than the reference ciprofloxacin and norfloxacin. However, the compounds were nearly inactive against Gram-negative bacteria. Compounds 5c and e were the most active compounds against Gram-positive bacteria.

Full text of DOI:10.1016/j.farmac.2005.01.012

Il Farmaco 60 (2005) 279–282
http://france.elsevier.com/direct/FARMAC/
Microwave-assisted synthesis and anti-bacterial activity of some
2-Amino-6-aryl-4-(2-thienyl)pyrimidines
S. Chandrasekaran, S. Nagarajan *
Department of Chemistry, Annamalai University, Annamalai Nagar – 608 002, India
Received 2 December 2004; received in revised form 21 January 2005; accepted 31 January 2005
Abstract
Some novel 2-amino-6-aryl-4-(2-thienyl)pyrimidines were synthesized from 3-aryl-1-thien-2ylprop-2-en-1-ones and guanidine hydrochlo-
ride in presence of alkali by conventional heating in alcoholic medium and microwave heating in solvent-free conditions. The compounds
were evaluated for in vitro anti-bacterial activity. The anti-bacterial data revealed that compounds 5a–e had better activity against tested
Gram-positive organisms than the reference ciprofloxacin and norfloxacin. However, the compounds were nearly inactive against Gram-
negative bacteria. Compounds 5c and e were the most active compounds against Gram-positive bacteria.
© 2005 Elsevier SAS. All rights reserved.
Keywords: Microwave; 2-thienylpropen-2-ones; 2-aminopyrimidines; anti-bacterial activity
1. Introduction
recent years presents a therapeutic challenge to physicians
selecting anti-microbial agents.
Microwave heating has emerged as a powerful technique
to promote a variety of chemical reactions [1]. Microwave
reactions under solvent-free conditions are attractive in offer-
ing reduced pollution, low cost and offer high yields together
with simplicity in processing and handling [2]. The recent
introduction of single-mode technology [3] assures safe and
reproducible experimental procedures and microwave syn-
thesis has gained acceptance and popularity among the syn-
thetic chemist community.
Thus, the development of new agents with potent anti-
bacterial activities and fewer adverse effects is urgently
desired. In the present investigation, we report here the
microwave-mediated synthesis of some thienyl aminopyrim-
idines and their anti-bacterial activity.
2. Results and Discussion
Pyrimidine is the parent heterocycle of a very important
group of compounds that have been extensively studied due
to their occurrence in living systems. Pyrimidine moieties
were reported to have anti-bacterial, anti-fungal and anti-
HIV activities [4–7]. Substituted aminopyrimidine structures
are common in marketed drugs, such as anti-atherosclerotic
aronixil, anti-histaminic thonzylamine, anti-anxielytic bus-
pirone, anti-psoriatic enazadrem, and other medicinally rel-
evant compounds [8,9]. Thienyl compounds are also reported
for their anti-microbial and pharmaceutical activities [10–13].
The increase in drug-resistant bacterial strain isolates during
The equimolar quantities of 1-(2-thienyl)ethanone 1 with
a suitably substituted benzaldehyde 2 in the presence of alco-
holic alkali undergoes Claisen–Schmidt condensation and
yield 3-aryl-1-thien-2-ylprop–2-en-1-ones 3a–e. When 3-aryl-
1-thien-2ylprop-2-en-1-ones 3a–e are irradiated in the domes-
tic microwave oven or on refluxing [10] in alcohol conven-
tionally with guanidine hydrochloride 4 in presence of sodium
hydroxide gave the corresponding 2-amino-6-aryl-4-(2-
thienyl)pyrimidines 5a–e. The formed compounds are char-
acterized through analytical and 1H-NMR,13C/SEFT-NMR,
FT-IR, UV and Mass spectral techniques. The formation of
these compounds is given in Scheme 1.
In comparison to conventional (thermal) heating method,
microwave heating offers more advantages such as reduced
* Corresponding author. Tel.:+91 4144 238734. Fax: + 91 4144 238080.
E-mail address: drsn@sify.com (S. Nagarajan).
0014-827X/$ - see front matter © 2005 Elsevier SAS. All rights reserved.
doi:10.1016/j.farmac.2005.01.012

280
S. Chandrasekaran, S. Nagarajan / Il Farmaco 60 (2005) 279–282
Scheme 1
.
reaction time (1–1.1 min), low cost, simplicity in processing,
reduced pollution and high yield (Table 1).
C-N stretching vibration. The absorptions at 820–810 cm–1
are due to the C-H out-of-plane bending in 2-substituted
thiophene. The molecular weight of the compounds are deter-
mined by the atmospheric pressure chemical ionization mass
spectrometry (APcI) at 10 eV. The UV absorption spectrum
shows kmax(Benzene): 343–371.5 nm; kmax(1,4-Dioxane):
348–371.0 nm and kmax(Methanol): 351–374 nm. These
absorptions are due to p–p* transition. The kmax is shifted to
a higher wavelength with the increase in polarity of solvent.
The anti-bacterial activity of 5a–e was assessed in side-
by-side comparison with ciprofloxacin and norfloxacin against
some Gram-positive (S. aureus, and B. subtilis) and Gram-
negative (E. coli, K. peneumoniae and P. aeruginosa) bacte-
ria using conventional agar dilution procedure and the results
are summarized in Table 2. The anti-bacterial data indicated
that compounds 5a–e had a better activity against tested Gram-
positive organisms. However, all the compounds were nearly
inactive against tested Gram-negative bacteria. The anti-
The 1H-NMR spectrum of the compounds show a singlet
for two protons in the range of 5.16–5.53 ppm is assigned to
the amino protons. The singlet for H-5 proton is observed at
7.13–7.36 ppm. The aromatic protons resonate in the region
of 7.0–8.1 ppm. The 13C spectrum shows the signal at 101.0–
102.6 ppm for C-5. The signal observed at 159.9–161.9 ppm
is assigned to C-2. The signals of C-6 and C-4 are observed
at 163.4–165.9 ppm. The aromatic carbons are observed in
the region of 126.9–136.8 ppm.
The FT-IR spectrum shows the absorptions at 3480–
3280 cm–1 due to N-H asymmetric and symmetric stretching
vibrations of the primary amino group. The absorption fre-
quency at 2930–2900 cm–1 is assigned to aromatic C-H
stretching vibration. The band at 1644–1607 cm–1 indicates
N-H in plane bending vibrations of the primary amino group.
The absorption band at 1240–1225 cm–1 is consistent with
Table 1
The molecular formula, microwave irradiation/thermal heating time and yield of 5a–e.
Compound Molecular formula Microwave irradiation
Thermal heating
Refluxing time (h) Yield %
Time (sec) 320 W
Yield %
85
5a
5b
5c
5d
5e
C
C
C
C
C
14H11SN3
60
70
65
60
60
18
18
17
12
14
30
25
35
40
30
16H16SN4
90
14H10SN3F
14H10SN3Cl
14H10SN3Br
90
85
85

S. Chandrasekaran, S. Nagarajan / Il Farmaco 60 (2005) 279–282
281
Table 2
In vitro anti-bacterial activity of 5a–e and standards (MIC µg ml–1
)
Compounds 5
a
S. aureus
0.59
0.40
0.15
0.22
0.18
0.55
1
B. subtilis
0.55
E. coli
32
K. peneumoniae
P. aeruginosa
>60
24
>60
42
b
0.47
18
c
0.024
0.044
0.028
0.03
40
>60
>60
>60
0.07
0.32
>60
>60
>60
1
d
39
e
8
Ciprofloxacin
Norfloxacin
0.13
0.48
0.05
4.5
bacterial data revealed that the compounds 5a–e possesses
similar anti-bacterial profiles. The selective anti-bacterial
activity against Gram-positive bacteria is in contrast to the
good anti-bacterial activity of ciprofloxacin against both
Gram-positive and Gram-negative bacteria. The compounds
5c and e are more active than the rest of the compounds tested.
Among the halogenated compounds 4-fluoro 5c is more effec-
tive than 4-bromo and 4-chloro substituted compounds. Thus
the nature of the group has strong influence on the spectrum
and extent of anti-bacterial activity.
hydroxide pellets (0.5 mol) was mixed and finely powdered
in a pestle and mortar. The mixture was transferred into a
beaker and irradiated in the domestic microwave oven (LG
Grill, MG395 WA). The mixture was irradiated at 320 W for
60–70 sec. Then, distilled water was added to remove the
excess of alkali and then filtered and dried.
3.2.2. B. Thermal heating
A mixture of 3-aryl-1-thien-2ylprop-2-en-1-one 3a–e
(0.01 mol), guanidine hydrochloride 4 (0.01 mol) in ethanol
(50 ml) while a solution of NaOH (0.5 mol in 5 ml of water)
was added portion-wise for two hours. Refluxing was contin-
ued for further 12–18 h, and the mixture was concentrated.
Then, the product was filtered and dried.
3. Experimental
The products obtained by the above methodsA and B were
separated and purified by column chromatography using ben-
zene and ethyl acetate mixture as eluting solvent.
All melting points were taken in open capillary tubes and
are uncorrected. Purity of the compounds was checked by
TLC. IR spectra were recorded in an AVATAR 330 FT-IR
instrument. NMR spectra were recorded on BRUCKERAMX
3.3. 2-Amino-6-phenyl-4-thien-2ylpyrimidine 5a
1
400 MHz spectrometer using CDCl3 solvent for H NMR
and DMSO-d6 solvent for 13C-SEFT NMR. Mass spectra were
recorded on a Q-Tof microhybrid quadrupole time of flight
mass spectrometer by atmospheric pressure chemical ioniza-
tion [APcI]. The UV-Visible absorption spectra were recorded
on HITACHI U-2001 double beam spectrometer using analar
grade Benzene, 1,4-Dioxane and Methanol.
1H NMR (CDCl3), d, ppm: 5.53 (S, 2H: NH2); 7.26 (S,
1H: H-5); 7.1–8.0 (aromatic protons); 13C NMR (DMSO-
d6), d, ppm: 101.9 (C-5); 160-6 (C-2); 164.8 and 163.4
(C-6 and C-4); 126.9–129.1 (aromatic carbons); Mass, APcI,
10 eV: 266 (M + H); IR (KBr), cm–1: 3480 and 3340 c(N-H);
2923 c(C-H); 1225 c(C-N); 1615 c(N-H in plane bending);
820 c(C-H out-of-plane bending in 2-substituted thiophene);
UV, nm: kmax (Benzene): 343.0; kmax (1,4-Dioxane):
348.0 and 293.5; kmax (Methanol): 345.5 and 257.0; m.p. 130–
132 °C.
3.1. General procedure for preparation of 3-aryl-1-thien-
2ylprop-2-en-1-ones 3a–e
The compounds were prepared as per standard procedure
[14,15]. It involves a solution of suitably substituted benzal-
dehyde 2 (0.01 mol) and 1-(2-thienyl)ethanone 1 (0.01 mol)
in distilled ethanol (50 ml) containing aqueous sodium
hydroxide (0.5 mol in 5 ml of water) was heated over a water
bath for half-an-hour. The solution gradually turned red and
yellow crystals were formed, then heating was stopped and
cooled to room temperature. The product thus obtained was
filtered, washed with distilled water, dried and crystallized
from ethanol.Yields were in the range of 90–95%. The formed
products were confirmed through FT-IR spectra.
3.4. 2-Amino-6-[4-(dimethylamino)phenyl]-4-thien-2ylpyri-
midine 5b
1H NMR (CDCl3), d, ppm: 5.13 (S, 2H: NH2); 7.30 (S,
1H: H-5); 7.1–8.0 (aromatic protons); 3.04 (S, 6H; N (CH3)2);
SEFT (DMSO-d6), d, ppm: 101.08 (C-5); 159-9 (C-2);
163.4 and 165.9 (C-6 and C-4); 124.8–128.5 (aromatic car-
bons); 40.1 (CH3; N(CH3)2); Mass, APcI, 10 eV: 297.1
(M + H); IR (KBr), cm–1: 3398 and 3319 c(N-H); 2907 c(C-
H); 1241 c(C-N); 1607 c(N-H inplane bending); 810 c(C-H
out-of-plane bending in 2-substituted thiophene); UV, nm:
kmax (Benzene): 371.5; kmax (1, 4-Dioxane): 371.0 and 293.5;
kmax (Methanol): 374.0, 290.0 and 240.5; m.p. 174–176 °C.
3.2. General methods for preparation of 2-amino-6-aryl-4-
(2-thienyl)pyrimidines 5a–e
3.5. 2-Amino-6-(4-fluorophenyl)-4-thien-2ylpyrimidine 5c
3.2.1. A. Microwave irradiation
A mixture of 3-aryl-1-thien-2ylprop-2-en-1-one 3a–e
(0.01 mol), guanidine hydrochloride 4 (0.01 mol) and sodium
1H NMR (CDCl3), d, ppm: 5.24 (S, 2H: NH2); 7.36 (S,
1H: H-5); 7.0–8.1(aromatic protons); SEFT (DMSO-d6), d,

282
S. Chandrasekaran, S. Nagarajan / Il Farmaco 60 (2005) 279–282
ppm: 102.6 (C-5); 161-9 (C-2); 165.4 and 164.2(C-6 and C-4);
127.9–136.8 (aromatic carbons); Mass, APcI, 10 eV: 272
(M + H); IR (KBr), cm–1: 3394 and 3368 c(N-H); 2930 c(C-
H); 1240 c(C-N); 1635 c(N-H inplane bending); 818 c(C-H
out-of-plane bending in 2-substituted thiophene); 1038 c(C-
F); UV, nm: kmax (Benzene): 349.0;kmax(1, 4-Dioxane):
356.0 and 293.0; kmax (Methanol): 356.5 and 263.0; m.p. 172–
174 °C.
effect on bacterial growth, a control test was performed with
test medium supplemented with DMSO at the same dilutions
as used in the experiment.
Acknowledgements
The authors are extremely grateful to the reviewers for their
valuable suggestions and comments.
3.6. 2-Amino-6-(4-chlorophenyl)-4-thien-2ylpyrimidine 5d
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1H NMR (CDCl3), d, ppm: 5.16 (S, 2H: NH2); 7.13 (S,
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ppm: 102.2 (C-5); 160-9 (C-2); 164.8 and 163.4 (C-6 and
C-4); 127.0–136.0 (aromatic carbons); Mass, APcI, 10 eV:
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kmax (1, 4-Dioxane): 351.0 and 293.0; kmax (Methanol):
351.0 and 261.0; m.p. 164–166 °C.
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