Microwave-assisted synthesis of some pyrimidine derivatives

Article abstract of DOI:10.1080/10426500600862977

Oxo- and thioxopyrimidines 4a-i were synthesized using the Biginelli three-component cyclocondensation reaction of an appropriate β-diketone, arylaldehyde, and (thio)urea under microwave irradiation. Yields of products following recrystallization from eth

Full text of DOI:10.1080/10426500600862977

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Phosphorus, Sulfur, and Silicon
and the Related Elements
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Microwave-Assisted Synthesis
of Some Pyrimidine Derivatives
A. Mobinikhaledi a & N. Forughifar a
a Department of Chemistry , University of Arak ,
Arak, Iran
Published online: 01 Feb 2007.
To cite this article: A. Mobinikhaledi & N. Forughifar (2006) Microwave-Assisted
Synthesis of Some Pyrimidine Derivatives, Phosphorus, Sulfur, and Silicon and the
Related Elements, 181:11, 2653-2658, DOI: 10.1080/10426500600862977
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Phosphorus, Sulfur, and Silicon, 181:2653–2658, 2006
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500600862977
Microwave-Assisted Synthesis of Some
Pyrimidine Derivatives
A. Mobinikhaledi
N. Forughifar
Department of Chemistry, University of Arak, Arak, Iran
Oxo- and thioxopyrimidines 4a–i were synthesized using the Biginelli three-
component cyclocondensation reaction of an appropriate β-diketone, arylaldehyde,
and (thio)urea under microwave irradiation. Yields of products following recrystal-
lization from ethanol were of the order of 65–90%. 1H and 13C NMR spectroscopy
and elemental analysis were used for structural assignment.
Keywords Carboxylate; microwave; pyrimidine; thiazolo
INTRODUCTION
Pyrimidine derivatives have attracted considerable attention because
of their pharmacological properties,1−10 including antiviral, antitumor,
antibacterial,2 and antihypertensive3 effects. Thus pyrimidine has been
subjected to a large variety of structural modifications in order to syn-
thesize derivatives with different biological properties.
In the last few years there has been an increased interest in the use
of microwave heating in organic synthesis, and it forms now the ba-
sis of a number of commercial systems. Some interesting features of
this method are the rapid reaction rates, simplicity, solvent-free condi-
tions, the ease of work-up after the reaction, and better selectivity.1,11−13
Also, microwave irradiation generates rapid intense heating of polar
substances, which result in the reduction of reaction time compared to
conventional heating.
Continuing with our studies on the synthesis of pyrimidines using
microwave irradiation,9,14−16 we have extended the Biginelli reactions
in order to synthesize some new oxo- and thioxopyrimidine derivatives.
The reported method offers a simple and efficient route for the prepa-
ration of pyrimidines.
Received August 14, 2005; accepted May 27, 2006.
Address correspondence to A. Mobinikhaledi, University of Arak, Department of
Chemistry, Dr. Beheshti Avenue, Arak, Iran. E-mail: akbar mobini@yahoo.com
2653

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A. Mobinikhaledi and N. Forughifar
RESULTS AND DISCUSSION
1,3-diketone 1, aryl aldehyde 2, (thio)urea 3, a few drops of ethanol, and
HCl (37%) were reacted under microwave irradiation to give the corre-
1
sponding oxo- and thioxopyrimidines 4 (Scheme 1). H and 13C NMR
spectra of the isolated compounds 4a–i confirm the expected structures.
In 1H NMR spectra, the singlet at 2.00–2.38 ppm is due to the resonance
of the CH3 group of the pyrimidine ring. The CH3 group of the ester moi-
ety in 4a–g resonates at 0.85–1.20 ppm as a triplet, whereas CH3 of the
acyl group in 4h–i appears as a singlet at 2.35 ppm. The singlet and
multiplets at 5.00–5.90 and 7.10–7.60 ppm are assigned to H-4 and to
the aryl protons, respectively. The two NH protons give two broad sig-
nals at 9.05–9.78 and 10.00–10.50 ppm, in accord with the expected
reaction products.
SCHEME 1
Potsherd allows the rapid synthesis of these compounds without us-
ing polyphosphate ester as a reaction mediator, which has been sug-
gested by Kappe and coworkers.17 Rapid heating induced by microwave
irradiation using potsherd as a heat sink avoids the forcing classical
conditions and the decomposition of materials. This leads to the forma-
tion of products under mild conditions with increased yields (Table I).
In conclusion, we have described a highly efficient microwave-
induced procedure for the preparation of pyrimidine derivatives under
mild conditions using a microwave oven as the irradiation source.
EXPERIMENTAL
1H and 13C NMR spectra were recorded on a Brucker 500 MHz spec-
trometer. Chemical shifts are reported in ppm relative to TMS (tetram-
ethylsilane) as an internal standard. Spectra were acquired in DMSO.
Reaction progress was routinely monitored by TLC on silica gel plates.

Microwave-Assisted Synthesis of Pyrimidines
2655
TABLE I Pyrimidine Derivatives 4a–i
Z
X
R
Time (s) Yield (%)
4a
4b
4c
4d
4e
4f
4g
4h
4i
S
S
S
S
S
S
O
S
O
2-NO2
OEt
OEt
OEt
OEt
OEt
OEt
40
40
40
50
50
50
25
30
30
86
85
90
70
66
68
73
65
75
3-NO2
4-NO2
3-Cl
4-Cl
3-Br
4-acetamido OEt
4-NMe2
4-acetamido
Me
Me
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
The corresponding 1,3-diketone (2.2 mmol), aryl aldehyde (3.0 mmol),
and (thio)urea (3.0 mmol), along with a few drops of ethanol (or without
solvent) and HCl (37%), were placed in a 25-mL glass beaker and stirred
at r.t. for 3 min with a magnetic stirrer. The beaker was placed inside
a larger container filled with potsherd and then was inserted into the
microwave oven. The mixture was then subjected to microwave irradi-
ation at 50% power level for the desired time. After cooling the reaction
mixture, water (5 mL) was added, and the mixture was stirred at r.t. for
2 h. The crude products were filtered and recrystallized from ethanol
to give the pure compounds.
Ethyl-4-(2-nitrophenyl)-6-methyl-2-thioxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (4a)
Yellow crystals, m.p. 115◦C. 1H NMR (DMSO-d6): δ = 0.91 (t, J =
7.2 Hz, 3H, CH3), 2.30 (s, 3H, CH3), 3.90 (q, J = 7.2 Hz, 2H, CH2),
5.90 (bs, 1H, H-4), 7.25 (m, 4H, Harom), 9.05 (bs, 1H, NH), 10.30 (bs,
1H, NH). 13C NMR (DMSO-d6): δ = 174.3, 164.6, 147.4, 145.9, 138.1,
134.3, 129.6, 129.2, 124.3, 99.9, 59.6, 49.3, 17.2, 13.8. Anal. calcd. for
C14H15N3O4S: C, 52.33; H, 4.70; N, 13.08%. Found: C, 52.27; H, 4.53; N,
13.47%.
Ethyl-4-(3-nitrophenyl)-6-methyl-2-thioxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (4b)
Pale yellow crystals, m.p. 111◦C. 1H NMR (DMSO-d6): δ = 1.11 (t, J =
7.3 Hz, 3H, CH3), 2.38 (s, 3H, CH3), 4.00 (q, J = 7.2 Hz, 2H, CH2),

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A. Mobinikhaledi and N. Forughifar
5.30 (bs, 1H, H-4), 7.85 (m, 4H, Harom), 9.75 (bs, 1H, NH), 10.50 (bs,
1H, NH). 13C NMR (DMSO-d6): δ = 174.5, 164.7, 147.7, 145.7, 145.4,
132.8, 130.2, 122.5, 121.0, 99.8, 59.6, 53.4, 17.1, 13.8. Anal. calcd. for
C14H15N3O4S: C, 52.33; H, 4.70; N, 13.08%. Found: C, 52.31; H, 4.41; N,
13.40%.
Ethyl-4-(4-nitrophenyl)-6-methyl-2-thioxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (4c)
Yellow crystals, m.p. 135◦C. 1H NMR (DMSO-d6): δ = 0.85 (t, J =
7.2 Hz, 3H, CH3), 2.25 (s, 3H, CH3), 3.75 (q, J = 7.2 Hz, 2H, CH2),
5.45 (bs, 1H, H = 4), 7.13 (m, 4H, Harom), 9.50 (bs, 1H, NH), 10.25 (bs,
1H, NH). 13C NMR (DMSO-d6): δ = 183.9, 173.8, 164.7, 145.5, 140.5,
131.7, 129.4, 129.3, 127.7, 99.7, 59.4, 51.6, 16.9, 13.8. Anal. calcd. for
C14H15N3O4S: C, 52.33; H, 4.70; N, 13.08%. Found: C, 52.12; H, 4.51; N,
13.42%.
Ethyl-4-(3-chlorophenyl)-6-methyl-2-thioxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (4d)
White crystals, m.p. 161◦C. 1H NMR (DMSO-d6): δ = 0.85 (t, J =
7.2 Hz, 3H, CH3), 2.20 (s, 3H, CH3), 3.85 (q, J = 7.2 Hz, 2H, CH2),
5.04 (bs, 1H, H-4), 7.20 (m, 4H, Harom), 9.50 (bs, 1H, NH), 10.00 (bs,
1H, NH). 13C NMR (DMSO-d6): δ = 174.4, 164.8, 145.7, 145.3, 139.5,
132.9, 130.0, 128.6, 127.4, 100.1, 61.1, 59.5, 17.0, 13.8. Anal. calcd. for
C14H15N2O2SCl: C, 54.10; H, 4.86; N, 9.01%. Found: C, 54.31; H, 4.55;
N, 9.33%.
Ethyl-4-(4-chlorophenyl)-6-methyl-2-thioxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (4e)
White crystals, m.p. 188◦C. 1H NMR (DMSO-d6): δ = 1.10 (t, J =
7.2 Hz, 3H, CH3), 2.31 (s, 3H, CH3), 4.00 (q, J = 7.2 Hz, 2H, CH2),
5.10 (bs, 1H, H-4), 7.35 (m, 4H, Harom), 9.70 (bs, 1H, NH), 10.40
(bs, 1H, NH). 13C NMR (DMSO-d6): δ = 174.2, 165.0, 145.3, 142.3,
132.2, 128.5, 128.2, 100.3, 59.6, 53.4, 17.1, 13.9. Anal. calcd. for
C14H15N2O2SCl: C, 54.10; H, 4.86; N, 9.01%. Found: C, 53.78; H, 4.44;
N, 9.20%.
Ethyl-4-(3-bromophenyl)-6-methyl-2-thioxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (4f)
White crystals, m.p. 171◦C. 1H NMR (DMSO-d6): δ = 0.91 (t, J =
7.2 Hz, 3H, CH3), 2.11 (s, 3H, CH3), 4.01 (q, J = 7.2 Hz, 2H, CH),

Microwave-Assisted Synthesis of Pyrimidines
2657
5.90 (bs, 1H, H-4), 7.35 (m, 4H, Harom), 9.45 (bs, 1H, NH), 10.10 (bs,
1H, NH). 13C NMR (DMSO-d6): δ = 174.3, 164.6, 145.6, 145.5, 132.0,
130.9, 129.0, 128.4, 127.5, 100.0, 60.8, 59.3, 17.0, 13.7. Anal. calcd. for
C14H15N2O2SBr: C, 47.33; H, 4.26; N, 7.89%. Found: C, 47.46; H, 4.31;
N, 7.53%.
Ethyl-4-(4-acetamidophenyl-6-methyl-2-oxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (4g)
Yellow crystals, m.p. 285◦C. 1H NMR (DMSO-d6): δ = 1.20 (t, J =
7.2 Hz, 3H, CH3), 2.00 (s, 3H, CH3), 2.20 (s, 3H, CH3), 3.80 (q, J =
7.2 Hz, 2H, CH2), 5.00 (bs, 1H, H-4), 7.25 (m, 4H, Harom), 7.60 (bs, 1H,
NH), 9.10 (bs, 1H, NH), 9.85 (bs, 1H, NH). 13C NMR (DMSO-d6): δ =
201.9, 167.3, 164.4, 151.3, 147.1, 138.9, 137.5, 125.7, 118.2, 98.6, 58.2,
52.7, 22.9, 16.9, 13.2. Anal. calcd. for C16H19N3O4: C, 60.56; H, 6.03; N,
13.24%. Found: C, 60.84; H, 6.19; N, 13.49%.
4-(4-Dimethylaminophenyl)-6-methyl-2-thioxo-
1,2,3,4-tetrahydropyrimidine-5-methylketo-ne (4h)
Green crystals, m.p. 239◦C. 1H NMR (DMSO-d6): δ = 2.20 (s, 3H, CH3),
2.35 (s, 3H, CH3), 2.40 (s, 6H, 2 × CH3), 5.40 (bs, 1H, H-4), 7.10 (m, 4H,
H
arom), 9.30 (bs, 1H, NH), 10.30 (bs, 1H, NH). 13C NMR (DMSO-d6):
δ = 193.3, 185.9, 181.6, 172.7, 155.8, 147.6, 93.2, 91.1, 67.5, 55.5, 31.6,
15.9. Anal. calcd. for C15H19N3OS: C, 62.25; H, 6.62; N, 14.52%. Found:
C, 61.87; H, 6.49; N, 14.70%.
4-(4-Acetamidophenyl)-6-methyl-2-oxo-
1,2,3,4-tetrahydropyrimidine-5-methylketone (4i)
Green crystals, m.p. 119◦C. 1H NMR (DMSO-d6): δ = 2.00 (s, 3H, CH3),
2.20 (s, 3H, CH3), 2.35 (s, 3H, CH3), 5.20 (bs, 1H, H-4), 7.35 (m, 4H,
Harom), 9.10 (bs, 1H, NH), 9.75 (bs, 1H, NH). 13C NMR (DMSO-d6):
δ = 201.9, 194.1, 167.9, 151.8, 147.6, 138.7, 138.3, 129.6, 126.6, 119.1,
109.4, 53.4, 29.9, 23.7, 18.6. Anal. calcd. for C15H17N3O3: C, 62.71; H,
5.96; N, 14.63%. Found: C, 62.36; H, 6.31; N, 14.29%.
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