Microwave-assisted synthesis of tetrahydropyrimidines via multicomponent reactions and evaluation of biological activities

Article abstract of DOI:10.2174/157017811799304287

Various pyrimidine derivatives (1a-c) were synthesized using the Biginelli three component cyclocondensation reactions of a β-diketone, arylaldehyde, and thiourea, under microwave irradiation and conventional conditions. The acetylation of compound 1a gav

Full text of DOI:10.2174/157017811799304287

Letters in Organic Chemistry, 2011, 8, 663-667
663
Microwave-Assisted Synthesis of Tetrahydropyrimidines via Multicom-
ponent Reactions and Evaluation of Biological Activities
Esvet Akbas*,a, Ismet Berberb, Inci Akyazia, Baris Anilc and Ela Yildiza
aDepartment of Chemistry, Faculty of Sciences, University of Yuzuncu Yil, Van, Turkey
bDepartment of Biological, Faculty of Arts and Sciences, University of Sinop, Sinop, Turkey
cDepartment of Chemistry, Faculty of Sciences, University of Atatürk, Erzurum, Turkey
Received April 11, 2011: Revised July 01, 2011: Accepted July 26, 2011
Abstract: Various pyrimidine derivatives (1a-c) were synthesized using the Biginelli three component cyclocondensation
reactions of a ꢀ-diketone, arylaldehyde, and thiourea, under microwave irradiation and conventional conditions. The
acetylation of compound 1a gave 3-acetyl thioxopyrimidin 2. Also, thiazolopyrimidine (3) and (4) derivatives were
obtained by a simple one-pot condensation reaction of starting compounds 1a, and 1b with 2-bromopropionic acid. The
prepared compounds were screened for their antimicrobial activities against Gram-positive, Gram-negative bacteria and
fungi using micro dilution procedure. The results of the study showed that the compound 4 was effective and selective for
antimicrobial activity against the tested bacteria and fungi. Thus, we suggested that the compound 4 might be a new
potential antimicrobial substance for bacteria and fungi.
Keywords: Antimicrobial substances, microwave-assisted, multicomponent reactions.
INTRODUCTION
and it forms now the basis of a number of commercial
systems. Some interesting features of this method are the
rapid reaction rates, simplicity, solvent-free conditions, and
the case of work-up after the reaction. Also, microwave
irradiation generates rapid intense heating of polar
substances, which result in the reduction of reaction time
compared to conventional heating [14-17].
Recently, there has been focused interest in the
multicomponent reactions of ꢀ-diketone, arylaldehyde, and
(thio)urea under Brönsted acid catalysis that was firstly
reported by Pietro Biginelli in 1893. This is very simple one-
pot, acid catalyzed cyclocondensation reaction of
benzaldehyde (I), urea (II) and ethyl acetoacetate (III). The
reaction was carried out in ethanol with a few drops of
concentrated hydrochloric acid and finalized 3,4-
dihydropyrimidine-2(1H)-one (IV) (Scheme 1) [1, 2].
So far, our studies have been continuing on the synthesis
of pyrimidine derivatives by using conventional heating and
microwave irradiation. The purpose of the study is to extend
the Biginelli reactions to synthesize some pyrimidine
derivatives. Preparation of pyrimidine derivatives with
microwave irradiation are simple and efficient route.
H2N
O
O
O
H
H
II
NH2
Me
EtO
NH
CH3CH2OH/HCl
RESULTS AND DISCUSSION
+
I
N
H
O
Me
In the present study, we achieved the synthesis of the
pyrimidine derivatives via conventional heating as well as
microwave irradiation experiments. The reactions 1a-c were
performed with 1,3-diphenyl-1,3-propanedione, thiourea and
terephthalaldehyde (1a), 2-hydroxy-5-methylisophthalal-
dehyde (1b), 4-carboxybenzaldehyde (1c), respectively in
glacial acetic acid containing a few drops of concentrated
hydrochloric acid. The mixture was heated under reflux
condition for 8 h. The reaction was finalized in good yields
(60-81%) (Scheme 2).
EtO
IV
O
O
III
Scheme 1.
The reaction products are dihydropyrimidine derivatives,
which display various types of biological activities [3] such
as anticancer [4], antifilarial [5], antihypertensive [6], anti-
inflammatory [7] and as modulators for the transport of
calcium channel blocking activity [8].
When 1,3-diketone, aryl aldehyde, thiourea and a few
drops of concentrated HCl were reacted in glacial acetic acid
under microwave irradiation for 15 min. the same final
products (1a-c) were obtained.
In the last few years, there has been an increasing interest
in the use of microwave heating in organic synthesis [9-13]
The IR, 1H and 13C NMR spectra of the isolated
compounds 1a-c confirm the expected structures. The IR
spectra of the thioxopyrimidine compounds (1a-c) displayed
*Address correspondence to this author at the Department of Chemistry,
Faculty of Sciences, University of Yuzuncu Yil, Van, Turkey; Tel: +90 432
225 10 24/2282; Fax: +90 432 225 11 88; E-mail: esvakbas@hotmail.com
1875-6255/11 $58.00+.00
© 2011 Bentham Science Publishers

664 Letters in Organic Chemistry, 2011, Vol. 8, No. 9
Akbas et al.
X
X
Y
H
H
Y
O
OH
H
H
HN
NH2
H
H2N
NH2
X
+
:N
NH2
-H2O
Y=S(1a-c), N(1d)
Y
X=Ph(4-CHO)(1a),
CHO
Ph(2-OH, 3-CHO, 5-CH3)(1b),
Ph(4-COOH)(1c), Ph (1d)
O
H
Ph
NH
H3C
O
CHO
OH
N
S
Ph
H
H
H
1a
O
O
O
Ph
NH
X
COOH
Ph
Ph
Ph
Ph
H
N
H
S
Ph
Ph
+
N
NH2
1b
-H2O
O
O
H
Y
Ph
NH
O
H
N
H
Ph
S
NH
1c
N
H
NH
Ph
[Ref. 18 ]
1d
Scheme 2.
absorption bands characteristic for the NH (3200-3096 cm-1),
CHO (1707-1652 cm-1), C=O (1692-1600 cm-1) and C=S
(1292-1273 cm-1) functions.
CHO
CHO
In 1H NMR spectra, the formation of the
thioxopyrimidine ring in this reaction was clearly
demonstrated by the fact that the C4 methine proton of
compounds 1a-c appeared at 5.3-5.7 ppm as doublet. The
signals of the N3H and N1H protons of compounds 1a-c
appeared on one proton singlets at 10.4, 9.8; 10.4, 9.4 and
10.7, 9.9 ppm, respectively. The signals of the other protons
were appeared at the expected chemical shifts and integral
values.
O
O
O
H
N
H
Ac
2O
Ph
CH3
Ph
NH
Ph
N
H
S
N
H
S
Ph
2
1a
Scheme 3.
The absorptions at 3446-3200 cm-1 disappeared in the IR
spectra of compounds 3 and 4. The characteristic absorption
of N3H group of starting compounds is good evidence of the
expected reactions. The H NMR data of the compounds 3
and 4 are in accord with the expected reaction products (See
The 3-acetyl thioxopyrimidine derivative 2 was prepared
via reaction of compound 1a with acetic anhydride (Scheme
3). H NMR spectra of the compounds 2 revealed the
absence of N3H signals instead they exhibited three proton
singlet at 2.9 ppm assigned for the N3COCH3 protons of the
acetyl group.
1
1
experimental for details).
On the other hand, the reactions of thioxopyrimidine
derivatives having the NH and C=S group in the suitable
position with various bromo compounds were convenient
methods to build the thiazolopyrimidine and pyrimido[2,3-
b]thiazine derivatives. Thus, the compound 1a,b were
The compounds 1a-c, 2-4 were also prepared under
microwave irradiation. In that way, we isolated the
corresponding thioxopyrimidine derivatives in good yields
within a few minutes. The reaction times are shortened from
480 min to 15 min (Table 1).
cyclized
with
2-bromopropionic
acid
to
the
All the prepared chemical compounds were screened in
vitro for their antibacterial activity against 4 Gram-positive
(S. aureus ATCC 6538, S. aureus ATCC 25923, B. cereus
thiazolopyrimidine (3) and (4) derivatives (Scheme 1), in
approximately 10% and 31% yields (Scheme 4).

Microwave-Assisted Synthesis of Tetrahydropyrimidines
CHO
Letters in Organic Chemistry, 2011, Vol. 8, No. 9 665
14053, C. krusei ATCC 6258 and C. parapsilosis ATCC
22019) were given in Table 3. The MIC values calculated
toward fungal strains revealed that the compounds 1a, 1c and
4 had effective and selective antifungal activity with MICs in
the range of 40-80 ꢀg mL-1, while 1b, 1d, 2 and 3
compounds displayed poor activity. The compound 4 was
the most effective compound against tested yeast strains
(MIC values 40-80 ꢀg mL-1) (Table 3).
CHO
O
O
O
H
N
H
Br
COOH
Ph
Ph
NH
CH3
Ph
N
S
N
H
S
Ph
3
A number of studies reported that the various chemical
compounds containing pyrimidine ring and their derivatives
had higher activity against microorganisms [19-22]. The data
obtained from the study revealed that compound 4 displayed
effective and selective antibacterial activity against the tested
Gram-positive, Gram-negative bacteria and Candida strains.
However, compound 4 showed high biological activity
against the tested Gram-positive bacteria comparing to the
Gram-negative bacterium (E. coli ATCC 4230) and the
fungal strains. Here, we proposed that the reason for this low
efficiency toward the Gram-negative bacteria and yeast
strains might be related to rigid structure of cell wall of
fungi. The composition of the presence of an extra outer
membrane is acting as a barrier for foreign substances in the
gram-negative cell wall, such as antibiotics and other
antimicrobial drugs [23].
1a
H3C
O
CHO
OH
H3C
O
CHO
OH
H
H
Br
COOH
O
Ph
NH
Ph
N
N
H
S
Ph
CH3
N
S
Ph
4
1b
Scheme 4.
ATCC 7064 and M. luteus ATCC 9345), one Gram-negative
(E. coli ATCC 4230) bacteria, and 3 yeast (C. albicans
ATCC 14053, C. krusei ATCC 6258 and C. parapsilosis
ATCC 22019). Gram-positive and Gram-negative bacterial
strains tested MIC values 20-40 ꢀg mL-1. However, the
compound 4 was much less active against the tested
organisms, compared with the standard drug (Table 2).
CONCLUSION
In conclusion, we have described easy and efficient
yielding preparation for thioxopyrimidines by conventional
The antifungal activities of the newly synthesized
compounds against 3 yeast strains (Candida albicans ATCC
Table 1. Comparative Study of the Synthesis of 1a-c, 1d [Ref.18], 2- 4
Yield (%)
Reaction time/min
Compound
MW
CONV.
Medium
MW
CONV.
1a
1b
1c
1d
2
65
58
76
62
60
81
Glacial acetic acid
Glacial acetic acid
Glacial acetic acid
Ref. [18]
15
15
15
480
480
480
46
15
34
44
10
31
Acetic anhydride/THF
1,4-Dioxane
15
5
60
3
180
180
4
1,4-Dioxane
15
Table 2. MICs of the Compounds 1a-d, 2- 4 Derivatives Against Gram-Negative and Gram-Positive Bacterial Strains
Compounds
Bacillus cereus
Staphylococcus aureus
Staphylococcus aureus
Escherichia coli
Micrococcus luteus
ATCC 7064
ATCC 6538
ATCC 25923
ATCC 4230
ATCC 9345
1a
80
640
80
80
640
40
80
640
40
80
640
80
40
320
40
1b
1c
1d
320
640
320
40
320
640
160
20
320
320
160
20
640
320
640
40
320
80
2
3
4
160
20
Ampicillin
5
5
10
20
10
*The MICs values were determined as ꢀg ml-1 active compounds in medium.

666 Letters in Organic Chemistry, 2011, Vol. 8, No. 9
Akbas et al.
Table 3. MICs of the Compounds 1a-d, 2- 4 Derivatives Against Yeast Strains
Compounds
Candida albicans
Candida parapsilosis
Candida krusei
ATCC 14053
ATCC 22019
ATCC 6258
1a
80
160
80
80
160
40
40
320
40
1b
1c
1d
320
160
160
40
160
160
160
40
160
160
160
40
2
3
4
Fluconazole
5
5
10
*The MICs values were determined as ꢁg ml-1 active compounds in medium.
heating and microwave irradiation via Biginelli three-
component cyclocondensation reaction. Our investigations
are continuing on this subject and the results will be
published when our studies are completed. The new
synthesized chemical compounds containing pyrimidine ring
and their derivatives were screened invitro for the
antibacterial and the antifungal activities against some
bacteria and fungi. The results of the study showed that the
compound 4 was effective and selective for antimicrobial
activity against the tested bacteria and fungi. In recently,
multi-drug resistant microorganisms pose a serious challenge
to the medical community therefore there is an urgent need
to develop new compounds. Thus, we think that the
compound 4 could be a new potential antimicrobial
substance toward bacteria and fungi.
9.9 (s, 1H, CHO), 9.4 (s, 1H, NH), 7.5-7.0(m, 12H, Harom.),
5.7(d, J= 3.2Hz, 1H, C4-CH), 2.3 ppm (s, 3H, CH3). 13C-
NMR (DMSO-d6) ꢀ 197.3(C=O, benzoyl), 195.2 (C=O,
CHO), 175.7(C=S), 156.6, 144.3, 139.2, 136.6, 133.2, 131.9,
130.9, 130.3, 130.0, 129.5, 129.2, 129.1, 128.4, 128.2, 122.0,
109.7, 51.7, 20.7 ppm. Anal. Calc. for Anal. Calc. for
C25H20N2O3S(428): C, 70.07; H, 4.70; N, 6.54. Found: C,
71.00; H, 4.72; N, 6.56.
Compound 1c
mp 270-271ºC (acetic acide), IR (KBr) 3283 (OH), 3182-
3096 (NH), 1692(C=O, acid), 1649 (C=O, benzoyl), 1292
1
cm-1 (C=S). H-NMR (400MHz, DMSO-d6) ꢀ 12.3 (s, 1H,
OH), 10.7 (s, 1H, N3H), 9.9 (s, 1H, N2H), 7.9-6.9 (m, 14H,
Harom.), 5.4 (d, J= 3.6Hz, 1H, C4-CH). 13C-NMR (DMSO-
d6) ꢀ 195.4(C=O, benzoyl), 175.9 (C=S), 167.7 (C=O, acid),
148.1, 146.1, 145.4, 139.5, 132.9, 131.7, 130.9, 130.8, 130.4,
129.2, 128.4, 128.2, 127.4, 110.2, 55.8 ppm. MS (100eV):
m/e: 267.1, 321.1, 350.1, 377.1, 415.1(M+1). Anal. Calc. for
C24H18N2O3S (414). C, 69.55; H, 4.38; N, 6.76. Found: C,
69.55; H, 4.38; N, 6.76.
GENERAL EXPERꢀMENTAL PROCEDURE
A mixture of 1,3-dione (1.6 mmol), arylaldehyde (1.1
mmol), urea derivative (1.1 mmol) and 20 ml of glacial
acetic acid containing 0.2 ml concentrated hydrochloric acid
was heated under reflux for 8 h.
Compound 2
m.p. 230-231°C, IR(KBr): 3366 (NH), 3016 (CH), 1694
(C=O, CHO), 1687 (C=O, acetyl), 1614 (C=O, benzoyl),
Data for the Compounds
1
1286 cmꢀ1 (C=S). H-NMR (400MHz, DMSOd6): ꢀ 11.8 (s,
Compound 1a
1H, CHO), 8.6 (bs, 1H, NH), 7.4-7.0 (m,14H, Harom.), 6.4
(s, 1H, C4-CH), 2.9 ppm (s, 3H, CH3). Anal. Calcd. for
C26H20N2O3S (440). C, 70.89; H, 4.58; N, 6.36. Found: C,
71.01; H, 4.62; N, 6.56.
mp 205-206ºC (benzyl alcohol). IR (KBr): 3200 cm-1
(NH), 1707 cm-1 (CHO), 1604 (C=O) and 1288 cm-1 (C=S).
1H-NMR (400MHz, DMSO-d6): ꢀ 11.8 (s, 1H, CHO), 10.4
(s, 1H, NH), 9.8 (s, 1H, NH), 7.4-6.9 (m, 14H, Harom.), 5.3
(d, J= 3.6 Hz, 1H, C4-CH). 13C NMR (DMSO-d6): ꢀ 195.4
(C=O, benzoyl), 175.8 (C=S), 172.6 (C=O, CHO), 145.9,
143.0, 142.9, 139.6, 133.0, 131.6, 130.6, 130.5, 129.1, 128.3,
128.1, 127.5, 127.4, 110.5, 55.8 ppm. MS (100eV): m/e:
255.0, 265.0, 279.0, 284.1, 297.0, 305.2, 311.1, 314.0, 319.0,
325.1, 329.0, 339.1, 347.0, 349.2, 353.0, 357.1, 363.2, 369.1,
374.1, 383.1, 389.1, 399.1(M+1). Anal. Calcd. for
C24H18N2O2S (398): C, 72.34; H, 4.55; N, 7.03. Found: C,
72.54; H, 4.52; N, 7.01.
Compound 3
mp 137-138ºC, IR(KBr): 3058, 2927, 2853 cm-1 (CH),
1766 (C=O, thiazolo), 1698 (C=O, CHO), 1649 cm-1 (C=O,
benzoyl). 13C-NMR (DMSO-d6): ꢀ 196.4 (C=O, benzoyl),
193.2 (C=O, thiazolo), 174.9 (C=O, CHO), 159.7, 147.9,
146.4, 138.1, 137.7, 136.7, 132.9, 130.9, 129.9, 129.8, 129.2,
128.6, 128.4, 116.1, 67.0, 57.7, 43.2, 19.4 ( CH3) ppm. Anal.
Calc. for C27H20N2O3S (452). C, 71.66; H, 4.45; N, 6.19.
Found: C, 71.68; H, 4.40; N, 6.21.
Compound 1b
Compound 4
mp 245-246ºC (butanol). IR (KBr) 3443 (OH), 3208
mp 105-106ºC. IR (KBr) 3446 (OH), 1738 (C=O,
thiazolo), 1698(C=O, CHO), (C=O, CHO), 1658 (C=O,
1
(NH), 1652 (CHO), 1600 (C=O), 1273 cm-1(C=S). H-NMR
1
benzoyl), 1597 cm-1 (C=N). H-NMR (400MHz, DMSO-d6)
(400MHz, DMSO-d6) ꢀ 11.1 (s,1H, OH), 10.4 (s, 1H, NH),

Microwave-Assisted Synthesis of Tetrahydropyrimidines
Letters in Organic Chemistry, 2011, Vol. 8, No. 9 667
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ꢀ 11.2 (bs, 1H, OH), 9.9 (s, 1H, CHO), 7.6-6.3 (m, 12H,
Harom.), 6.3 (s, 1H, C5-CH), 4.1 (q, J= 6Hz, 1H, C2-CH),
1.2 (d, J= 6.4Hz, 3H, C2-CH3). 13C-NMR (DMSO-d6) ꢀ
197.5(C=O, benzoyl), 196.7 (C=O, thiazolo), 171.6 (C=O,
CHO), 160.1, 157.3, 146.9, 138.8, 134.2, 132.9, 129.7,
129.6, 129.5, 129.3, 129.0, 128.8, 128.6, 128.4, 128.1, 126.9,
122.0, 114.9, 62.7, 55.3, 32.7 ppm.
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Microwave Mediated Synthesis
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A mixture of 1,3-diphenyl-1,3-propanedione (1.6 mmol),
arylaldehydes (1.1 mmol), thiourea (1.1 mmol) and
concentrated hydrochloric acid (0.2 ml) with glacial acetic
acid (10 ml) were stirred at room temperature for 5 min with
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oven. The mixture was subjected to microwave irradiation
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crude products were filtered and became recrystallized
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[18]
General Experimental Procedure for the Biological assay
Test compounds were dissolved in DMSO (12.5%) at an
initial concentration of 1280 μg mL-1 and then they were
serially diluted in culture medium.
[19]
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