Microwave assisted synthesis of some pyrimidine derivatives using polyphosphate ester (PPE) in ceramic bath

Article abstract of DOI:10.1080/10426500307892

Pyrimidine derivatives, 4a-4m, were synthesized in high yield using a newly developed microwave-assisted cyclocondensation reaction of β-ketoester, aryl aldehyde, and (thio)urea. In all of these Biginelli reactions, a mixture of the appropriate β-ketoester, aryl aldehyde, and (thio)urea were subjected to microwave irradiation by using polyphosphate ester (PPE) as a reaction moderator. ¹H NMR and IR spectroscopies were used for characterization of compounds 4a-4m.

Full text of DOI:10.1080/10426500307892

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Phosphorus, Sulfur, and Silicon and the Related
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Microwave Assisted Synthesis of Some Pyrimidine
Derivatives Using Polyphosphate Ester (PPE) in Ceramic
Bath
N. Foroughifar a , A. Mobinikhaledi a & H. FathinejadJirandehi a
a Arak University , Arak, Iran
Published online: 27 Oct 2010.
To cite this article: N. Foroughifar , A. Mobinikhaledi & H. FathinejadJirandehi (2003) Microwave Assisted Synthesis of Some
Pyrimidine Derivatives Using Polyphosphate Ester (PPE) in Ceramic Bath, Phosphorus, Sulfur, and Silicon and the Related
Elements, 178:6, 1241-1246, DOI: 10.1080/10426500307892
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Phosphorus, Sulfur, and Silicon, 178:1241–1246, 2003
C
Copyright Taylor & Francis Inc.
ISSN: 1042-6507 print
DOI: 10.1080/10426500390200512
MICROWAVE ASSISTED SYNTHESIS OF SOME
PYRIMIDINE DERIVATIVES USING
POLYPHOSPHATE ESTER (PPE) IN CERAMIC BATH
N. Foroughifar, A. Mobinikhaledi, and H. FathinejadJirandehi
Arak University, Arak, Iran
(Received September 10, 2002; accepted October 15, 2002)
Pyrimidine derivatives, 4a–4m, were synthesized in high yield using
a newly developed microwave-assisted cyclocondensation reaction of
-ketoester, aryl aldehyde, and (thio)urea. In all of these Biginelli re-
actions, a mixture of the appropriate -ketoester, aryl aldehyde, and
(thio)urea were subjected to microwave irradiation by using polyphos-
phate ester (PPE) as a reaction moderator. 1H NMR and IR spectro-
scopies were used for characterization of compounds 4a–4m.
Keywords: Microwave irradiation; polyphosphate ester; 1,2,3,4-
tetrahydro-pyrimidine-5-carboxylate
Pyrimidines have been subjected to large number of different modifi-
cations in order to obtain derivatives having different biological prop-
erties. Several groups have studied the chemistry and pharmacolog-
14
ical properties of pyrimidine derivatives.1
Pyrimidines have been
found to have a broad range of biological effects including antivi-
ral, antitumor, antibacterial, anti-inflammatory,1 antihypertensive,2
cardiovascular agents,3 calcium channel blocking4 (e.g., nifedipine),
and neuropeptide Y (NPY) antagonists.15 Microwave irradiation is
a nonconventional energy source which has been of special inter-
19
est in organic chemistry in recent years.16
Some interesting fea-
tures of this method are the rapid reaction rates, simplicity, and
cleaner reaction conditions.5,13,16 The versatile biological properties
of pyrimidine derivatives prompted us to take up this project for
synthesizing some novel derivatives by using a newly developed
microwave-assisted cyclocondensation reaction of -ketoester, aryl
aldehyde, and (thio)urea.
Address correspondence to N. Foroughifar, Chemistry Department, Arak University,
Dr. Beheshti Ave, Arak, Iran. E-mail: N Foroughifar@yahoo.com
1241

1242
N. Foroughifar et al.
RESULTS AND DISCUSSION
-Ketoester 1, aryl aldehyde 2, (thio)urea 3, and polyphosphate ester
(PPE) were reacted under microwave irradiation to give the correspond-
ing pyrimidine derivative 4 (Scheme 1).
SCHEME 1
In all experiments a molar ratio 1.1:1.1:1.5 of the three components,
1, 2, and 3, were used as reactants.21 This method is very easy and it
can be utilized for different aldehydes 2 and (thio)ureas 3 depending on
X and Z groups to prepare entries 4a–4m (see Table I).
The advantage of PPE as a moderate in this reaction may be due to
specific interaction of PPE with N-acyliminium ion intermediate which
may formed from the aldehyde 2 and urea 3 in the initial reaction
step.22 Yields of these one-pot protocol reactions following recrystal-
lization in ethanol were of the order of 68–90% (see Table I), which
is very favorable as compared with the multistep method.23 1H NMR
TABLE I Pyrimidine Derivatives 4a–4m
Entry
Z
X
Yield%
4a
4b
4c
4d
4e
4f
4g
4h
4i
O
O
O
O
O
O
O
O
S
S
S
S
S
H
85
90
83
75
69
70
78
68
85
90
80
83
70
2,5-(MeO)2
4-N(Me)2
4-Cl
4-MeO
2-Me
3-NO2
4-Me
H
4j
4k
4l
2,5-(MeO)2
4-N(Me)2
4-Cl
4m
4-MeO

Microwave Assisted Synthesis of Some Pyrimidine Derivatives
1243
(500 MHz) measurements of these compounds confirmed their purity
1
to be more than 95%. In the H NMR spectra the sharp singlet signal
at 1.20–1.30 ppm with integrating 9 protons is assigned to the t-Bu
group. The singlet signal at 2.20–2.25 ppm with integrating 3 protons
is assigned to the resonance of the CH3 group on the pyrimidine ring.
Resonances at 6.87–8.00 ppm are attributed to aromatic protons of the
phenyl and pyrimidine rings. The protons of the pyrimidine ring res-
onate at higher field compared to those of the phenyl ring. The two
different broad signals at low field are due to resonance of the two NHs
of the pyrimidine ring. This was supported by IR spectra, which in-
cluded signals in the region 3126–3425 cm 1. Also, the IR spectra of all
compounds show absorption at 1698–1709 cm 1, which is characteristic
of the carbonyl group. In conclusion we have found that using PPE is
an efficient medium for the preparation of pyrimidine derivatives by
using microwave irradiation in solvent free conditions.
EXPERIMENTAL
All chemicals ( -ketoester, arylaldehyde, (thio)urea) were of reagent
grade quality and used without further purification. PPE was prepared
using the method of Cava and coworkers20 (yield 85%, d = 1.503 g/ml).
Melting points were determined on an electrothermal digital melting
point apparatus. H1 NMR spectra were recorded on a Brucker 500 MHz
spectrometer. TMS was used as internal standard. IR spectra were per-
formed on a Galaxy FT-IR 500 spectrophotometer. Reaction progress
was monitored routinely by thin layer chromatography on silica gel
(Merck) plates. Reactions were performed in a Samsung microwave
oven of household with a 230V-50Hz power source, 900W output, and
2450 MHz operating frequency.
General Procedure
-Ketoester (2.2 mmol), aryl aldehyde (3.0 mmol), (thio)urea (3.0 mmol),
along with PPE (300 mg) were placed in a 25 ml glass beaker and
stirred for 3 min with a magnetic stirrer. This beaker was placed inside a
ceramic bath and was then inserted into a microwave oven. The mixture
was subjected to microwave irradiation at 50% power level 3 times for
30 s (total irradiation time 90 s). The mixture was cooled for 1 and 2 min
after first and second irradiation respectively. After cooling the reaction
mixture, water (5 ml) was added and stirred at room temperature for
2 h. The crude products were filtered and recrystallized from ethanol
to give compounds 4a–4m.

1244
N. Foroughifar et al.
tert-Butyl-6-methyl-4-phenyl-2-oxo-1,2,3,4-tetrahydro
Pyrimidine-5-carboxylate (4a)
Yield 85%, m.p. 215–216 C
1
IR (KBr): = 3240, 3090, 1705, 1680, 1650 cm
1H NMR (DMSO-d6); (ppm) = 1.31 (s, 9H, t-Bu), 2.21 (s, 3H, CH3),
5.10 (d, 1H, j = 3.0 Hz), H-4), 6.87–7.21 (m, 5H, arom), 7.69 (brs, 1H,
NH), 9.01 (brs, 1H, NH)
tert-Butyl-6-methyl-4-(2,5-dimetothxy Phenyl)-2-oxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (4b)
Yield 90%, m.p. 200–202 C
1
IR (KBr): = 3294, 3182, 3045, 1708, 1654.8, 1600 cm
1H NMR (DMSO-d6); (ppm) = 1.22 (s, 9H, t-Bu), 2.24 (s, 3H, CH3),
5.39 (d, j = 3.0 Hz, 1H, H-4), 6.87 (m, 2H, arom), 7.10 (m, 1H, arom),
7.35 (brs, 1H, NH), 8.94 (brs, 1H, NH)
tert-Butyl-6-methyl-4-(4-dimethyl Amino Phenyl)-2-oxo-
1,2,3,4-tetrahydro Pyrimidine-5-carboxylate (4c)
Yield 83%, m.p. 213–214 C
1
IR (KBr): = 3126.8, 3010, 1701, 1650, 1618 cm
H1 NMR (DMSO-d6); (ppm) = 1.29 (s, 9H, t-Bu), 2.24 (s, 3H, CH3),
4.97 (d, j = 3.0 Hz, 1H, H-4), 6.71 (m, 2H, arom), 6.97 (m, 2H, arom),
8.46 (brs, 1H, NH), 9.10 (brs, 1H, NH)
tert-Butyl-6-methyl-4-(4-chloro Phenyl)-2-oxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (4d)
Yield 75%, m.p. 195–197 C
1
IR (KBr): = 3247, 3103.9, 1701.1, 1651 cm
H1 NMR (DMSO-d6); (ppm) = 1.28 (s, 9H, t-Bu), 2.22 (s, 3H, CH3),
5.07 (d, j = 3.0 Hz, 1H, H-4), 7.25–7.35 (m, 4H, arom), 7.69 (brs, 1H,
NH), 9.11 (brs, 1H, NH)
tert-Butyl-6-methyl-4-(4-methoxy Phenyl)-2-oxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (4e)
Yield 69%, m.p. 212–213 C
1
IR (KBr): = 3236, 3111, 1705, 1648, 1603 cm
H1 NMR (DMSO-d6); (ppm) = 1.25 (s, 9H, t-Bu), 2.22 (s, 3H, CH3),
5.08 (d, j = 3.0 Hz, 1H, H-4), 6.83–7.01 (m, 4H, arom), 8.01 (brs, 1H,
NH), 9.30 (brs, 1H, NH)
tert-Butyl-6-methyl-4-(2-methyl Phenyl)-2-oxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (4f)
Yield 70%, m.p. 200–201 C
1
IR (KBr): = 3236.3, 3109, 1701.1, 1678 cm

Microwave Assisted Synthesis of Some Pyrimidine Derivatives
1245
1H NMR (DMSO-d6); (ppm) = 1.30 (s, 9H, t-Bu), 2.24 (s, 3H, CH3),
5.12 (d, j = 3.0 Hz, 1 H, H-4), 6.90–7.10 (m, 4H, arom), 7.66 (brs, 1H,
NH), 8.66 (brs, 1H, NH)
tert-Butyl-6-methyl-4-(3-nitro Phenyl)-2-oxo-1,2,3,4-
tetrahhydropyrimidine-5-carboxylate (4g)
Yield 78%, m.p. 195–196.5 C
1
IR (KBr): = 3240, 3105, 1705, 1674, 1535, 1350 cm
1H NMR (DMSO-d6); (ppm) = 1.29 (s, 9H, t-Bu), 2.24 (s, 3H, CH3),
5.10 (d, J = 3.0 Hz, 1H, H-4), 7.25 (m, 2H, arom), 7.90 (brs, 1H, NH),
8.10 (m, 2H, arom), 9.34 (brs, 1H, NH)
tert-Butyl-6-methyl-4-(4-methyl Phenyl)-2-oxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (4h)
Yield 68%, m.p. 206–207 C
1
IR (KBr): = 3186, 3080, 1705, 1655, 1634 cm
1H NMR (DMSO-d6); (ppm) = 1.27 (s, 9H, t-Bu), 2.21 (s, 3H, CH3),
5.01 (d, j = 3.0 Hz, 1H, H-4), 6.85–6.98 (m, 4H, arom), 7.25 (brs, 1H,
NH), 8.35 (brs, 1H, NH)
tert-Butyl-6-methyl-4-phenyl-2-thioxo-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (4i)
Yield 85%, m.p. 206–207 C
1
IR (KBr): = 3165, 3050, 1703.2, 1562 cm
1H NMR (DMSO-d6); (ppm) = 1.27 (s, 9H, t-Bu), 2.25 (s, 3H, CH3),
5.10 (d, j = 3.0 Hz, 1H, H-4), 7.24 (m, 5H, arom), 9.55 (brs, 1H, NH),
10.19 (brs, 1H, NH)
tert-Butyl-6-methyl-(2,5-dimethoxy Phenyl)-2-thioxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (4j)
Yield 90%, m.p. 201–202 C
1
IR (KBr): = 3176, 3010, 1709, 1655 cm
1H NMR (DMSO-d6); (ppm) = 1.31 (s, 9H, t-Bu), 2.22 (s, 3H, CH3),
5.25 (d, j = 3.0 Hz, 1H, H-4), 6.98 (m, 2H, arom), 7.35 (m, 1H, arom),
7.85 (brs, 1H, NH), 8.90 (brs, 1H, NH)
tert-Butyl-6-methyl-4-(4-dimethylamino Phenyl)-2-thioxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (4k)
Yield 80%, m.p. 206–207 C
1
IR (KBr): = 3425, 3169.6, 1701.1, 1650 cm
1H NMR (DMSO-d6); (ppm) = 1.30 (s, 9H, t-Bu), 2.24 (s, 3H, CH3),
5.01 (d, j = 3.0 Hz, 1H, H-4), 6.99 (m, 2H, arom), 7.40 (m, 2H, arom),
9.46 (brs, 1H, NH), 10.10 (brs, 1H, NH)

1246
N. Foroughifar et al.
tert-Butyl-6-methyl-4-(4-chloro Phenyl)-2-thioxo-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (4l)
Yield 83%, m.p. 214–215 C
1
IR (KBr): = 3250, 3105, 1703, 1680 cm
1H NMR (DMSO-d6); (ppm) = 1.32 (s, 9H, t-Bu), 2.23 (s, 3H, CH3),
5.20 (d, j = 3.0 Hz, 1H, H-4), 7.40–7.80 (m, 4H, arom), 7.95 (brs, 1H,
NH), 8.90 (brs, 1H, NH)
tert-Butyl-6-methyl-4-(4-methoxyphenyl)-2-thioxo-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (4m)
Yield 70%, m.p. 183–185 C
1
IR (KBr): = 3313.5, 3170.8, 3105, 1698, 1666 cm
1H NMR (DMSO-d6); (ppm) = 1.28 (s, 9H, t-Bu), 2.25 (s, 3H, CH3),
5.01 (d, j = 3.0 Hz, 1H, H-4), 7.20 (m, 2H, arom), 7.40 (m, 2H, arom),
7.65 (brs, 1H, NH), 9.01 (brs, 1H, NH)
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