Synthesis of some 2-oxo and 2-thioxo substituted pyrimidines using solvent-free conditions

Article abstract of DOI:10.1002/jhet.5570440329

(Chemical Equation Presented) A series of oxo- and thioxopyrimidines 4(a-m) were synthesized by one-pot three components cyclocondensation reaction of β-ketoester, aldehyde and urea/thiourea using benzyltriethylammonium chloride as a catalyst under solvent-free conditions. The yields of products following recrystallization from ethanol were of the order of 65-87%. IR and ¹HNMR spectroscopy and elemental analysis were used for identification of these compounds.

Full text of DOI:10.1002/jhet.5570440329

May-Jun 2007
697
Synthesis of Some 2-Oxo and 2-Thioxo Substituted Pyrimidines
Using Solvent-free Conditions
Akbar Mobinikhaledi1ꢀ, Naser Forughifar1, Jila. Alipour Safari1 and Ehsan. Amini2
1) Department of Chemistry, University of Arak, Dr. Beheshti, Ave, Arak-Iran
2) Department of Chemistry, University of Imam Hossein, Tehran-Iran
Email: akbar_mobini@yahoo.com
Received February 23, 2006
O
R
O
O
NH2
X
CH3CH2O
H3C
NH
TEBA
+
+
RCHO
CH3CH2O
CH3
H2N
N
H
X
A series of oxo- and thioxopyrimidines 4(a-m) were synthesized by one-pot three components
cyclocondensation reaction of ꢁ-ketoester, aldehyde and urea/thiourea using benzyltriethylammonium
chloride as a catalyst under solvent-free conditions. The yields of products following recrystallization from
ethanol were of the order of 65-87%. IR and 1HNMR spectroscopy and elemental analysis were used for
identification of these compounds.
J. Heterocyclic Chem., 44, 697 (2007).
INTRODUCTION
required. In organic chemistry, the subject of green
chemistry is becoming increasingly important and calls
for clean procedures that can avoids the use of organic
solvents, which also lead to safety and environmental
respects. In view of this, we wish to report synthesis of
some oxo- and thioxopyrimidines under solvent-free
conditions using benzyltriethylammonium chloride
(TEBA) as a transfer catalyst.
Multicomponent reactions (MCRs) have received
significant attention in organic and medicinal chemistry
[1-4]. Multicomponent reactions are convergent reactions,
in which three or more starting materials are generally
combined together in a single event to form a final
product displaying features of all components, thus
offering greater possibilities for molecular diversity per
step with a minimum of synthetic time. Biginelli reaction
[5] is a multicomponent reaction of an aldehyde, ketoester
and urea or thiurea in the presence of catalytic amount of
acid to produce pyrimidine derivatives, which show
various interesting pharmacological properties including
antiviral [6], antibacterial [7], antitumor [8] and
antihypertensive [9] effects. Biginelli reaction often
suffers from low yileds, especially in the case of
substituted aldehydes [10]. Several papers have been
published for the synthesis of pyrimidines including
classical conditions or solvent-free conditions with
microwave irradiation [11-28]. However most of them use
the procedure which concerned with enhancing of
chemical safety and yields of products. Rarely attentions
are paid to the fact that many of these methods involve
use of highly toxic reagents, expensive catalyst or non-
available materials [18] and strongly acidic conditions.
Therefore, the development of a new catalyst which
promotes the Biginelli reaction under simple conditions is
RESULTS AND DISCUSSIONS.
The cyclocondensation reaction for the preparation of
substituted 3,4-dihydro-2H-pyrimidone, DHPMs, was
first described by Biginelli in 1893 [5]. This multi-
component synthesis involving the one-pot cycloconden-
sation of ꢁ-ketoester, 1, with an aldehyde, 2, and urea/
thiourea, 3, suffers from low yields. For example reaction
of urea and ethyl acetoacetate with aliphatic aldehydes
gives related pyrimidines in yields less than 30-40%.
This led to the development of multi step methods to
improve yields and reaction rates. However many of these
methods involve expensive catalyst or materials that are
not readily available. In view of this, we have developed a
solvent-free strategy for the preparation of substituted 3,4-
dihydropyrimidines by using benzyltriethylammonium
chloride (TEBA), which is commonly used as a phase
transfer catalyst in organic synthesis [29]. Here we wish
to disclose our results employing this catalyst. This
proposed method is general and involves Biginelli's one
Scheme 1
O
R
O
O
NH2
CH3CH2O
H3C
NH
TEBA
+
+
RCHO
CH3CH2O
CH3
H2N
X
N
H
X
1
2
3
4

698
A. Mobinikhaledi, N. Forughifar, J. A. Safari and E. Amini
Vol 44
6-Methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbox-
ylic acid ethyl ester (4a). Yield 65%, lit 87% [30], mp= 235-
236 °C; IR (KBr): ꢀ = 3205, 3160, 3026, 2987, 1714, 1658,
pot-condensation of three components, 1, 2 and 3 in the
present of TEBA to give 4 (Scheme 1 and Table 1).
This simple procedure gives the products in high yields
(65-87%, Table 1) and avoids the use of highly toxic
reagents or expensive catalyst. Furthermore, we have
studied the reaction with different amounts of catalyst and
found that use of just 10-mol % of TEBA is sufficient to
carry out the reaction. At higher than 10-mol % of TEBA,
there are no improvements in the reaction rate and yields.
1
1612 cm-1; HNMR (DMSO-d6): ꢁ (ppm) = 1.19 (t, J=8.4 Hz,
3H, CH3-ester), 2.17 (s, 3H, CH3-pyrimidine), 3.88 (s, 2H, H-
pyrimidine), 4.08 (q, J=8.4 Hz, 2H, CH2-ester), 8.94 (bs, 1H,
NH), 9.93 (bs, 1H, NH). Anal. Calcd. for C8H12N2O2S: C, 47.98;
H, 6.04; N, 13.99%. Found: C, 48.36; H, 5.96; N, 14.24%.
4,6-Dimethyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-car-
boxylic acid ethyl ester (4b). Yield 65%, lit %95 [30], mp=
189-191 °C; IR (KBr): ꢀ = 3310, 3176, 3126, 2989, 1662, 1583
1
cm-1; H NMR (DMSO-d6):ꢀ (ppm)= :ꢀ (ppm) =1.22-1.29 ( m,
Table 1
6H, CH3-ester and CH3-C4), 2.23 (s, 3H, CH3-pyrimidine), 4.12-4.40 (m,
3H, CH2-ester and H-pyrimidine), 9.20 (bs, NH ),10.09 (bs, NH ).
Anal. Calcd. for C9H14N2O2S: C, 50.44; H, 6.59; N, 13.07%.
Found: C, 50.16; H, 6.68; N, 13.40%.
TEBA- Catalyzed Efficient Synthesis of DHMPs
Products
R
X
Time (h) Yield (%)
4-Ethyl-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-
carboxylic acid ethyl ester (4c). Yield 85%, lit %74 [18], mp=
142-143 °C; IR (KBr): ꢀ = 3321, 3182, 3119, 2982, 1660, 1577
4a
4b
4c
4d
4e
4f
4g
4h
4i
H
methyl
ethyl
propyl
isopropyl
butyl
isobutyl
H
methyl
ethyl
propyl
butyl
S
S
S
S
S
S
S
O
O
O
O
O
O
0.5
1
2
3
1.5
3
3
0.5
1
2
1
65
65
85
77
86
87
82
77
86
74
76
81
85
1
cm-1; HNMR (DMSO-d6): ꢀ (ppm) = 0.77 (t, J=7.5 Hz, 3H,
CH3-ethyl), 1.18 (t, J=7 Hz, 3H, CH3-ester), 1.42 (m, 2H, CH2-ethyl),
2.20 (s, 3H, CH3-pyrimidine), 4.02-4.13 (m, 3H, CH2-ester and H-
-
), 9.23 (bs, 1H, NH ), 10.08 (bs, 1H, NH). Anal. Calcd.
for C10H16N2O2S: C, 52.61; H, 7.06; N, 12.27%. Found: C,
52.83; H, 7.41; N, 12.11%.
pyrimidine
4j
4k
4l
6-Methyl-4-Propyl-2-thioxo -1,2,3,4-tetrahydropyrimidine-
5-carboxylic acid ethyl ester (4d). Yield 77%, mp= 168-169
°C; IR (KBr): ꢀ = 3323, 3180, 3134, 2955, 1666, 1576 cm-1;
1HNMR (DMSO-d6): ꢀ (ppm) = 0.85 (t, J=7.8 Hz, 3H, CH3-propyl),
1.17-1.38 (m, 7H, CH3-ester and 2 x CH2-propyl), 2.20 (s, 3H, CH3-
pyrimidine), 4.07-4.13 (m, 3H, CH2-ester and H-pyrimidine), 9.21 (bs, 1H,
NH), 10.05 (bs, 1H, NH). Anal. Calcd. for C11H18N2O2S: C,
54.52; H, 7.49; N, 11.56%. Found: C, 54.12; H, 7.21; N, 11.51%.
4-Isopropyl-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-
5-carboxylic acid ethyl ester (4e). Yield 86%, mp= 172-173
3
3
4m
isobutyl
1H NMR spectra of all synthesized compounds showed the
two different broad signals at low field assigned to the
resonance of two NHs of the pyrimidine ring. This was
supported by IR spectra, which included signals in the region
3200-3400 cm-1. Elemental analysis data of all compounds
showed good agreement with those of calculated.
1
°C; IR (KBr): ꢀ = 3323, 3186, 2960, 1662, 1581 cm-1; HNMR
(DMSO-d6): ꢀ (ppm) = 0.75 (dd, J=6.8Hz, 6H, 2 CH3-isopropyl),
1.18 (t, J=7Hz, 3H, CH3-ester), 1.65 (m, 1H, CH-isopropyl), 2.21 (s,
3H, CH3-pyrimidine), 3.96 (t, J=4.1 Hz, 1H, H-pyrimidine), 4.06 (m, 2H,
CH2-ester), 9.22 (bs, 1H, NH), 10.08 (bs, 1H, NH). Anal. Calcd.
for C11H18N2O2S: C, 54.53; H, 7.49; N, 11.56%. Found: C,
54.78; H, 7.31; N, 11.66%.
4-Butyl-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-
carboxylic acid ethyl ester (4f). Yield 87%, mp= 180-181 °C;
IR (KBr): ꢀ = 3230, 3151, 2945, 1710, 1651, 1597 cm-1;
1HNMR (DMSO-d6): ꢀ =0.84 (t, J=6.8 Hz, 3H, CH3-butyl), 1.38-
1.63 (m, 9H, CH3-ester and 3 CH2-butyl), 2.19(s, 3H, CH3-pyrimidine),
4.02-4.12 (m, 3H, CH2-ester and H-pyrimidine), 9.25 (bs, 1H, NH),
10.09 (bs, 1H, NH). Anal. Calcd. for C12H20N2O2S: C, 56.21; H,
7.86; N, 10.92%. Found: C, 56.48; H, 7.58; N, 11.12%.
Conclusion.We have developed a solvent-free method
for the Biginelli condensation of aldehydes with
ethylacetoacetae and urea/thiourea. This mild and
efficient catalytic method avoids the use of the more
traditional heating method. Several pyrimidine derivatives
can be easily prepared in good overall yields and purity
under short reaction times and mild conditions using
TEBA as a catalyst.
EXPERIMENTAL
Melting points were determined on an electrothermal digital
melting point apparatus.1H NMR spectra were recorded on a
Bruker (300 MHz) Spectrometer using DMSO as a solvent. The
IR spectra were recorded on Galaxy FT-IR 5000 Spectrometer.
Reactions were monitored by thin layer chromatography. All
chemicals were purchased from Merck Co.
General Procedure for Synthesis of 4(a-m). A mixture of
the appropriate aldehyde (0.01 mol), thiourea/urea (0.015 mol),
ethylacetoacetate (0.01 mol) and benzyltriethylammonium
chloride (0.001 mol) was heated at 100 °C for the desired time.
The reaction mixture was kept at room temperature overnight
and then poured into 10 ml of ice-cooled water. The precipitate
was collected by filtration and then recrystallizd from ethanol.
4-Isobutyl-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-
5-carboxylic acid ethyl ester (4g). Yield 82%, mp= 150-152
°C; IR (KBr): ꢁ=3217, 3155, 2985, 1710, 1653, 1589 cm-1;
1HNMR (DMSO-d6): ꢀ (ppm) = 0.86 (t, J=6.3Hz, 6H, 2 CH3-
isobutyl), 1.03-1.21 (m, 4H, CH3-ester and CHa-isobutyl), 1.19 (t, J=7 Hz,
3H), 1.33-1.48 (m, 1H, CHb-isobutyl), 1.67 (m, 1H, CH-isobutyl), 2.19
(s, 3H, CH3-pyrimidine), 3.98-4.13 (m, 3H, CH2-ester and H-pyrimidine),
9.35 (bs, 1H, NH), 10.15 (bs, 1H, NH). Anal. Calcd. for
C12H20N2O2S: C, 56.22; H, 7.86; N, 10.93%. Found: C, 56.29; H,
8.15; N, 10.78%.
6-Methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic
acid ethyl ester (4h). Yield 77%, mp= 23-255°C. IR (KBr):
1
ꢀ =3261, 3140, 2958, 1739, 1710, 1666 cm-1. HNMR (DMSO-

May-Jun 2007
2-Oxo and 2-Thioxo Substituted Pyrimidines Using Solvent-free Conditions
699
d6): ꢀ (ppm) = 1.17 (t, J=7Hz, 3H, CH3-ester), 2.14 (s, 3H, CH3-
pyrimidine), 3.87 (d, 2H, H-pyrimidine), 4.05 (q, J=7 Hz, 2H, CH2-ester),
7.02 (bs, 1H, NH), 8.85 (bs, 1H, NH). Anal. Calcd. for
C8H12N2O3: C, 52.17; H, 6.57; N, 15.21%. Found: C, 52.28; H,
6.58; N, 15.46%.
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1
1562 cm-1; HNMR (DMSO-d6): ꢀ (ppm) =1.11 (d, J=7.5 Hz,
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pyrimidine), 4.02-4.14 (m, 3H, CH2-ester and H-pyrimidine), 7.18 (bs, 1H,
NH), 8.95 (bs, 1H, NH). Anal. Calcd. for C9H14N2O3: C, 54.53;
H, 7.12; N, 14.13%. Found: C, 54.69; H, 6.86; N, 14.40%.
4-Ethyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-car-
boxylic acid ethyl ester (4j). Yield 74%, lit 73% [18], mp=
179-181 °C. IR (KBr): ꢀ = 3230, 3126, 2962, 1722, 1710, 1645,
1660 cm-1. 1HNMR (DMSO-d6): ꢀ (ppm) =0.78 (t, J=7.3 Hz, 3H,
CH3-ethyl), 1.17 (t, J= 7 Hz, 3H, CH3-ester), 1.42 (m, 2H, CH2-ethyl),
2.15 (s, 3H, CH3-pyrimidine), 4.01-4.10 (m, 3H, CH2-ester and H-
pyrimidine), 7.29 (bs, NH), 8.92 (bs, 1H, NH). Anal. Calcd. for
C10H16N2O3: C, 56.59; H, 7.60; N, 13.20%. Found: C, 56.89; H,
7.44; N, 13.58%.
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6-Methyl-2-oxo-4-propyl-1,2,3,4-tetrahydropyrimidine-5-
carboxylic acid ethyl ester (4k). Yield 76%, lit 83% [10], mp=
183-185 °C; IR (KBr): ꢀ = 3317, 3192, 3128, 2966, 1658, 1579
1
cm-1; HNMR (DMSO-d6): ꢀ (ppm) =0.84 (t, J=8.1Hz, 3H, CH3-
propyl), 1.16-1.43 (m, 7H, CH3-ester and 2 x CH2-propyl), 2.16 (s, 3H,
CH3-pyrimidine), 4.01-4.11 (m, 3H, CH2-ester and H-pyrimidine ), 7.33 (bs,
1H, NH), 8.93 (bs, 1H, NH). Anal. Calcd. for C11H18N2O3: C,
58.39; H, 8.02; N, 12.38%. Found: C, 58.68; H, 7.68; N, 12.47%.
4-Butyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-
carboxylic acid ethyl ester (4l). Yield 81%, mp= 161-163 °C;
IR (KBr): ꢀ = 3256, 3119, 2950, 1724, 1710, 1651 cm-1;
1HNMR (DMSO-d6): ꢀ (ppm) =0.84 (t, J=6.5 Hz, 3H, CH3-butyl),
1.15-1.39 (m, 9H, CH3-ester and 3 x CH2-butyl), 2.15 (s, 3H, CH3-
pyrimidine), 3.99-4.11 (m, 3H, CH2-ester and H-pyrimidine), 7.32 (bs, NH),
8.93 (bs, 1H, NH). Anal. Calcd for C12H20N2O3: C, 59.98; H,
8.39; N, 11.66%. Found: C, 59.81; H, 8.40; N, 11.89%.
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4-Isobutyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-
carboxylic acid ethyl ester (4m). Yield 85%, mp= 187-189 °C;
IR (KBr): ꢀ = 3250, 3113, 2933, 1707, 1651, 1465 cm-1;
1HNMR (DMSO-d6): ꢁ (ppm) =0.83 (d, J=6.4 Hz, 6H, 2 x CH3-
isobutyl), 1.03-1.19 (m, 4H, CH3-ester and CHa-isobutyl), 1.31-1.40 (m,
1H, CHb-isobutyl), 1.66 (m, 1H, CHa-isobutyl), 2.14 (s, 3H, CH3-
pyrimidine), 4.04 (m, 2H, CH2-ester), 7.42 (bs, NH), 8.95 (bs, 1H,
NH). Anal. Calcd. for C12H20N2O3: C, 59.98; H, 8.39; N,
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