An efficient one-pot synthesis of new 2- Thioxo and 2-oxo-pyrimidine-5- carbonitriles in ball-milling under solvent-free and catalyst-free conditions

Article abstract of DOI:10.1080/10426507.2013.818995

Various 2-thioxo and 2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carbonitriles were synthesized in very high yields in 40 min through a direct condensation of an equimolar amount of an aldehyde, malononitrile, and thiourea/urea under ball mill solvent-free and catalyst-free conditions.

Full text of DOI:10.1080/10426507.2013.818995

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Phosphorus, Sulfur, and Silicon and the Related
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An efficient One-pot synthesis of new 2- thioxo and
2-oxo-pyrimidine-5-carbonitriles in Ball-Milling under
Solvent-Free and Catalyst-Free conditions
Mohamed Ould M'hamed a & Omar K. Alduaij a
a Department of chemistry, College of Sciences , Al Imam Mohammad Bin Saud Islamic
University , 11623 , Riyadh , Saudi Arabia
Accepted author version posted online: 12 Aug 2013.
To cite this article: Phosphorus, Sulfur, and Silicon and the Related Elements (2013): An efficient One-pot synthesis of new
2- thioxo and 2-oxo-pyrimidine-5-carbonitriles in Ball-Milling under Solvent-Free and Catalyst-Free conditions, Phosphorus,
Sulfur, and Silicon and the Related Elements, DOI: 10.1080/10426507.2013.818995
To link to this article: http://dx.doi.org/10.1080/10426507.2013.818995
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An efficient One-pot synthesis of new 2- thioxo and 2-oxo-pyrimidine-5-carbonitriles in
Ball-Milling under Solvent-Free and Catalyst-Free conditions
Mohamed Ould M’hamed*, Omar K. Alduaij
Department of chemistry, College of Sciences, Al Imam Mohammad Bin Saud Islamic
University, 11623 Riyadh, Saudi Arabia.
*Corresponding author. Tel: 0096612586774
E-mail address: medabdelwedoud@gmail.com
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Abstract:
Various 2-thioxo and 2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carbonitriles were synthesized in
very high yields in 40 min through a direct condensation of an equimolar amount of an aldehyde,
malononitrile and thiourea/urea under ball mill solvent-free and catalyst-free conditions.
CN
Ball-Mill
O
X
CN
CN
R
NH2
Solvent-Free
Catalyst-Free
+
+
HN
NH
H2N
R
H
NH2
X
R = p-CH3-O-C6H4, p-OH-C6H4, p-NO2-C6H4, p-Cl-C6H4, Ph
1a-j
X = S, O
Keywords:
Ball milling solvent-free reaction, catalyst-free, thioxo-pyrimidine, oxo-pyrimidine.
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1. Introduction
Ball milling is a mechanical technique that is widely used to grind minerals into extremely
fine particles, and the preparation or modification of inorganic solids [1-4]. The applications of
ball milling solvent-free in organic synthesis are relatively rare. However, in the last decade, it is
gaining noticeable attention due to its simplicity, low cost and friendly impact on the
environment, as well as its capability to achieve very high yields.
The applications of ball milling in organic synthesis [5-13], has inspired other researchers to
synthesis different types of organic materials including functionalized indan-1,3-diones [14],
coordination polymers [15], nitrones [16], the reductive benzylation of malononitrile [17],
preparation of phosphorus ylides [18], Knoevenagel condensations [19], the protection of diols
diamines [20], functionalization of fullerenes [21], Heck-type reactions [22-23], aldol reaction
[24,25], and Suzoku-type reaction [26-29].
Pyrimidine derivatives have a great importance due to their different biological properties
such as anticancer [30,31], antitumor [32], analgesic [33], antibacterial activity [34] and
fungicides [35] anti-inflammatory [36,37] and cardioprotective effects [38]. The commonly
method used for the synthesis of pyrimidines is the Biginelli reaction, which is a direct
condensation of an aldehyde, keto ester and thiourea / urea. This condensation is usually done by
using heat in different solvents and in the presence of a catalyst [39-43].
2. Results and Discussion
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Mashkouri et al. [44] used ball milling for the synthesis of pyrano [2,3-d] pyrimidines via
direct condensation of an aldehyde, malononitrile and barbituric acid. The authors failed to have
results with an ordinary ball milling system. An excellent yield is obtained only by using a
specific setup for the ball milling, by circulating warm water in order to heat the reaction.
Despite this excellent yield, the disadvantage of this method is the use of a specific milling
machine allowing the circulation of warm water and that makes the milling system very
complicated and difficult to setup.
In this paper, we present a simple ball milling procedure without any specific setup for the
synthesis of new 2-thioxo and 2-oxo-pyrimidine-5-carbonitriles by direct condensation of an
aldehyde, malononitrile and the thiourea / urea using ball milling solvent-free, catalyst-free
(Scheme 1). In this one pot synthesis process, we need to change only the weight of the balls
used in the ball milling process in order to obtain high yield. This easy method can be used for
the synthesis of several others organic materials.
An equimolar amount (0.02 mol) of paramethoxybenzaldehyde, malononitrile and thiourea
(with a total mass of 5.56 g) were introduced in a stainless steel bowl. In order to optimize the
reaction conditions, several milling times and balls weights were used (Table 1). The progress of
the reaction was followed by determining the conversion rate calculated relative to the reagents.
The analysis of these results shows that when the ratio (balls weight / reagents weight) is equal to
1, the reaction does not change even after 4 h of grinding. With increasing value of the balls
weight, the conversion increases until the optimal value for the ratio: balls weight to reagents is
equal to 5.
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3. Conclusion
In conclusion, we have developed a simple and efficient method for the synthesis of new
functionalized pyrimidines (Table 2). This method allowed us to obtain the products synthesized
in pure form without further purification and in quantitative yields.
Experimental
Materials and techniques
The ball-mill was a SPEX 8000 mixer with 10 cm3 stainless steel vials. Melting points were
determined in open capillaries and were uncorrected. IR spectra were taken on a FT-IR-Tensor
1
27 spectrometer in KBr pellets. H and 13C NMR spectra were measured on a Jeol-400 NMR
spectrometer in DMSO-d6 using TMS as an internal standard and chemical shifts are expressed
as δ ppm units. Elemental analysis was carried out on an Elementar Vario EL analyzer. The
progress of all the reactions was monitored by thin layer chromatography on silica gel 60 for
TLC (Merck) using chloroform-ethanol.
General procedure for the synthesis of pyrimidine compound 1a
An equimolar amount (0.02 mol) of paramethoxybenzaldehyde, malononitrile and thiourea, were
introduced into stainless steel vials with 27.80 gram of stainless steel balls (12 mm in diameter)
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in a SPEX 8000 mixer. We obtained the product 1a after 40 min of milling in pure form without
further purification.
4.3. 6-amino-4-(4-methoxy-phenyl)- 2-thioxo 1,2,3,4- tetrahydro-pyrimidine-5-carbonitrile (1a).
0
1
Yield: 98%; Mp 199-200 C; IR(KBr): 3440, 3350, 3230, 2220, 1250; H NMR (400 MHz,
DMSO-d6) δ 7.30-7.28 (m, Ar, 2H), 7.11-7.08 (m, Ar, 2H), 6.31 (br, s, 2NH, NH2, 4H), 5.49 (s,
CH, 1H), 3.81 (s, 3H, OCH3); 13C NMR (100 MHz. DMSO-d6) δ 167.65, 163.27, 160.39,
137.33, 128.08, 119.19, 117.80, 81.90, 56.89, 52.99; Anal. Calcd. for C12H12N4OS (260.316): C
(55.37%), H (4.65%), N (21.52%), O (6.15%), S(12.32%). Found: C (55.01%), H (4.60%), N
(21.11%), O (5.98%), S (12.35%).
4.4. 6-Amino-4-(4-hydroxy-phenyl)-2-thioxo-1,2,3,4-tetrahydro-pyrimidine-5-carbonitrile (1b).
0
1
Yield: 96%; Mp 220-221 C; IR(KBr): 4510, 3430, 3360, 3220, 2221, 1260; H NMR (400
MHz, DMSO-d6) δ 7.26-7.24 (m, Ar, 2H), 6.80-6.78 (m, Ar, 2H), 6.60 (br, s, 2NH, NH2,OH,
5H), 5.51 (s, CH, 1H); 13C NMR (100 MHz. DMSO-d6) δ 167.65, 163.27, 159.39, 136.83,
127.68, 118.59, 117.89, 81.76, 52.16; Anal. Calcd. For C11H10N4OS (246.29): C (53.64%), H
(4.09%), N (22.75%), O (6.50%), S (13.02%). Found: C (53.24%), H (4.11%), N (22.80%), O
(6.13%), S (12.96%).
4.5. 6-Amino-4-(4-nitro-phenyl)--2-thioxo-1,2,3,4-tetrahydro-pyrimidine-5-carbonitrile (1c).
6
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0
1
Yield: 97%; Mp 215-216 C; IR(KBr): 3430, 3340, 3230, 2222, 1215; H NMR (400 MHz,
DMSO-d6) δ 8.30-8.24 (m, Ar, 2H), 7.81-7.78 (m, Ar, 2H), 6.30 (br, s, 2NH, NH2, 4H), 5.47 (s,
CH, 1H); 13C NMR (100 MHz. DMSO-d6) δ 167.97, 162.87, 151.39, 148.30, 132.14, 129.16,
118.91, 82.10, 53.29; Anal. Calcd. For C11H9N5O2S (275.29): C (47.99%), H (3.30%), N
(25.44%), O (11.62%), S (11.65%). found: C (47.19%); H (3.29%); N (25.36%); O (11.54%);
S (11.37%).
4.6. 6-Amino-4-(4-chloro-phenyl)-2-thioxo-1,2,3,4-tetrahydro-pyrimidine-5-carbonitrile (1d).
0
1
Yield: 95%; Mp 202-203 C; IR(KBr): 3420, 3350, 3220, 2221, 1260; H NMR (400 MHz,
DMSO-d6) δ 7.46-7.42 (m, Ar, 2H), 7.33-7.29 (m, Ar, 2H), 6.37 (br, s, 2NH, NH2, 4H), 5.45 (s,
CH, 1H); 13C NMR (100 MHz. DMSO-d6) δ 167.86, 163.11, 142.17, 133.16, 132.60, 128.77,
119.25, 81.10, 52.12; Anal. Calcd. For C11H9ClN4S (264.74): C (49.91%), H (3.43%), Cl
(13.39%), N (21.16%), S (12.11%). found: C (49.88%), H (3.38%), Cl (13.47%), N (21.11%), S
(12.03%).
4.7. 6-Amino-4-phenyl-2-thioxo-1,2,3,4-tetrahydro-pyrimidine-5-carbonitrile (1e).
0
1
Yield: 96%; Mp 196-197 C; IR(KBr): 3440, 3350, 3210, 2214, 1250; H NMR (400 MHz,
DMSO-d6) δ 7.63-7.28 (m, Ar, 5H), 6.41 (br, s, 2NH, NH2, 4H), 5.47 (s, CH, 1H); 13C NMR
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(100 MHz. DMSO-d6) δ 167.30, 162.05, 141.12, 133.47, 129.23, 127.81, 119.20, 81.66, 52.73;
Anal. Calcd. For C11H10N4S (230.29): C (57.37%), H (4.38%), N (24.33%), S (13.92%). found:
C (57.50%), H (4.21%), N (24.19%), S (14.01%).
4.8. 6-Amino-4-(4-methoxy-phenyl)-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carbonitrile (1f).
0
1
Yield: 96%; Mp 142-143 C; IR(KBr): 3415, 3340, 3230, 2222, 1678; H NMR (400 MHz,
DMSO-d6) δ 7.89-(s, NH. 1H), 7.24-7.04 (m, Ar, 4H), 6.35 (br, s, NH2, 2H), 6.12 (s, NH. 1H),
5.18 (s, CH, 1H), 3.84 (s, 3H, OCH3); 13C NMR (100 MHz. DMSO-d6) δ 162.65, 160.17,
152.63, 132.17, 127.05, 116.44, 115.43, 72.91, 56.19, 48.29; Anal. Calcd. For C12H12N4O2
(244.26): C (59.01%), H (4.95%), N (22.94%), O (13.10%). Found: C (58.92%), H (4.91%), N
(22.88%), O (13.26%).
4.9. 6-Amino-4-(4-hydroxy-phenyl)-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carbonitrile (1g).
0
1
Yield: 94%; Mp 189-190 C; IR(KBr): 3460, 3410, 3350, 3230, 2220, 1672; H NMR (400
MHz, DMSO-d6) δ 7.49 (s, NH, 1H),7.16-7.14 (m, Ar, 2H), 6.78-6.12 (m, Ar, NH2, OH, 5H),
6.21 (br, s, NH, 1H), 5.29 (s, CH, 1H); 13C NMR (100 MHz. DMSO-d6) δ 162.35, 160.57,
153.12, 133.23, 128.18, 118.67, 116.13, 72.97, 48.49; Anal. Calcd. For C11H10N4O2 (230.23): C
(57.39%), H (4.38%), N (24.34%), O (13.90%). Found: C (57.31%), H (4.32%), N (24.28%),
O (13.95%).
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4.10. 6-Amino-4-(4-nitro-phenyl)-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carbonitrile (1h).
0
1
Yield: 93%; Mp 198-199 C; IR(KBr): 3420, 3350, 3230, 2220, 1660; H NMR (400 MHz,
DMSO-d6) δ 8.28-8.22 (m, Ar, 2H), 7.70-7.68 (m, Ar, 2H), 7.52 (s, NH, 1H), 6.56 (br, s, NH2,
2H), 6.22 (s, NH, 1H), 5.39 (s, CH, 1H); 13C NMR (100 MHz. DMSO-d6) δ 162.85, 153.67,
148.82, 147.63, 128.22, 125.21, 116.20, 71.97, 47.79; Anal. Calcd. For C11H9N5O3 (259.23): C
(50.97%), H (3.50%), N (27.02%), O (18.52%). Found: C (51.12%), H (3.17%), N (27.00%), O
(18.48%).
4.11. 6-Amino-4-(4-chloro-phenyl)-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carbonitrile (1i).
0
1
Yield: 92%; Mp 178-179 C; IR(KBr): 3386, 3360, 3230, 2220, 1650; H NMR (400 MHz,
DMSO-d6) δ 7.53 (s, NH, 1H), 7.39-7.36 (m, Ar, 2H), 7.22-7.18 (m, Ar, 2H), 6.55 (br, s, NH2,
2H), 6.13 (s, NH, 1H), 5.27 (s, CH, 1H); 13C NMR (100 MHz. DMSO-d6) δ 162.63, 152.33,
137.83, 134.52, 131.27, 126.29, 115.19, 71.24, 47.39; Anal. Calcd. For C11H9ClN4O (248.67): C
(53.13%), H (3.65%), Cl (14.26%), N (22.53%), O (6.43%). Found: C (52.79%), H (3.51%), Cl
(14.86%), N (22.21%), O (6.22%).
4.12. 6-Amino-2-oxo-4-phenyl-1,2,3,4-tetrahydro-pyrimidine-5-carbonitrile (1j).
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0
1
Yield: 92%; Mp 198-199 C; IR(KBr): 3340, 3327, 3137, 2220, 1654; H NMR (400 MHz,
DMSO-d6) δ 7.66-7.42 (m, Ar, NH, 4H), 7.21-7.15 (m, Ar, 2H), 6.39 (br, s, NH2, 2H), 6.29 (s,
13
NH, 1H), 5.41 (s, CH, 1H); C NMR (100 MHz. DMSO-d6) δ 161.95, 153.62, 140.31, 130.25,
128.68, 125.17, 115.49, 71.24, 46.31; Anal. Calcd. For C11H10N4O (214.23): C (61.67%), H
(4.71%), N (26.15%), O (7.47%). found: C (61.36%), H (4.62%), N (26.11%), O (7.51%).
Acknowledgments
We are very much thankful to King Abdulaziz City for Science and Technology (KACST)
and King Saud University (KSU) for recording the analysis of synthesized compounds.
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CN
Ball-Mill
O
X
CN
CN
R
NH2
Solvent-Free
+
+
Catalyst-Free
HN
NH
H2N
R
H
NH2
X
1a-j
R = p-CH3-O-C6H4, p-OH-C6H4, p-NO2-C6H4, p-Cl-C6H4, Ph
X = S, O
Schem1: Synthesis of 2-thioxo and 2-oxo-pyrimidine-5-carbonitriles
Table 1: Milling parameters and the conversion rate for the synthesis of 2-thioxo and 2-oxo
pyrimidine-5-carbonitriles
Entry* Balls(g)
Time (min)
Conversion (%)
1
2
3
4
5
5.56
11.12
16.68
22.24
27.80
240
240
180
60
0
20
40
70
100
40
*0.02 mol of paramethoxybenzaldhyde, malonitrile and thiourea (5.56 g)
Table 2: Synthesis of 2-thioxo and 2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-
carbonitriles using ball-mill
Entry
R
X
S
S
S
S
Product
1a
1
2
3
4
5
p-CH3-O-C6H4
p-HO-C6H4
p-NO2-C6H4
p-Cl-C6H4
Ph
1b
1c
1d
1e
S
6
7
8
9
p-CH3-O-C6H4
p-HO-C6H4
p-NO2-C6H4
p-Cl-C6H4
Ph
O
O
O
O
O
1f
1g
1h
1i
10
1j
15
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