An environmentally benign multicomponent synthesis of some novel 2-methylthio pyrimidine derivatives using MCM-41-NH2 as nanoreactor and nanocatalyst

Article abstract of DOI:10.1002/jhet.1755

Some novel 4-amino-6-aryl-2-methylthio pyrimidine-5-carbonitrile derivatives were synthesized through a one-pot three-component reaction of an aldehyde, malononitrile, and S-methylisothiouronium iodide, using MCM-41-NH ₂ as nanoreactor and nanocatalyst. This protocol has some advantages including application of readily available and nonhazardous materials, benign reaction conditions (ambient temperature, solvent-free, and one-pot approach), easy work-up, and high overall yields of the products.

Full text of DOI:10.1002/jhet.1755

418
An Environmentally Benign Multicomponent Synthesis of Some Novel
2-Methylthio Pyrimidine Derivatives Using MCM-41-NH2 as
Nanoreactor and Nanocatalyst
Vol 51
*
Shahnaz Rostamizadeh and Masoomeh Nojavan
Department of Chemistry, Faculty of Science, K. N. Toosi University of Technology, P.O. Box: 15875–4416, Tehran, Iran
*
E-mail: shrostamizadeh@yahoo.com
Received March 16, 2012
DOI 10.1002/jhet.1755
Published online 18 November 2013 in Wiley Online Library (wileyonlinelibrary.com).
Some novel 4-amino-6-aryl-2-methylthio pyrimidine-5-carbonitrile derivatives were synthesized through
a one-pot three-component reaction of an aldehyde, malononitrile, and S-methylisothiouronium iodide, using
MCM-41-NH2 as nanoreactor and nanocatalyst. This protocol has some advantages including application of
readily available and nonhazardous materials, benign reaction conditions (ambient temperature, solvent-free,
and one-pot approach), easy work-up, and high overall yields of the products.
J. Hetercycl Chem, 51, 418 (2014).
INTRODUCTION
derivatives. Enhancement of the reaction efficiency
from both economic and ecological viewpoints through
solvent-free reaction conditions has given these kinds of
procedures an outstanding synthetic value [22], regarding
the concept of green chemistry. In recent years, more at-
tractive possibilities have been arisen by the development
of various new silica materials with ordered structure [23].
MCM-41—one of the best-known examples—is a structur-
ally well-ordered mesoporous material with a narrow pore
size distribution between 1.5 and 10 nm, depending on the
surfactant cation and a very high surface area up to
1500 m2 gÀ1[24].
There are some reports about catalytic applications of
functionalized MCM-41-NH2 [25,26]. Furthermore, to the
best of our knowledge, there is no report on the use of these
materials as nanocatalysts in the synthesis of 2-methylthio
pyrimidine derivatives.
Herein, we wish to report an efficient and environmentally
benign solvent-free multicomponent route for the synthesis
of some novel 2-methylthio pyrimidine derivatives from
the reaction of readily available and nonexpensive starting
materials including aldehyde, malononitrile, and S-methyli-
sothiouronium iodide, inside the channels of MCM-41-
NH2 as nanocatalyst.
The search toward introducing novel efficient methodolo-
gies for the synthesis of useful heterocyclic compounds is
one of the most widespread areas of research in organic
chemistry. 2-Methylthio pyrimidine derivatives constitute a
group of heterocyclic building blocks that are found in the
structure of many biologically active molecules. They also
are appropriate precursors for a vast number of compounds
with significant biological and pharmacological properties.
These compounds have shown biological and therapeutic
activities such as typical antipsychotic [1], thyroid stimulat-
ing hormone receptor agonists [2], fungicides [3], as well
as antitumor agents [4,5].
Despite the fact that a great number of methodologies
for the synthesis of common pyrimidine derivatives have
been reported in the literature recently [6–16], some reports
were found concerning direct synthesis of 2-methylthio
pyrimidines but most of them include 2-methylthio pyrimi-
dines possessing substituents other than aryl or cyano
groups [17–21]. Harsh reaction conditions, using harmful
organic solvents and reagents, moderate yields of products,
and relatively long reaction times were found as the
main drawbacks of these reports for the synthesis of
2-methylthio pyrimidines. As a result, both the growing
significance of 2-methylthio pyrimidine derivatives as
intermediates for the synthesis of biologically valuable
compounds along with various medicinal properties of
other derivatives and the low number of reports found in
the literature about their synthesis prompted us to find a
new efficient and eco-friendly procedure for the direct syn-
thesis of novel 2-methylthio pyrimidine-5-carbonitrile
RESULTS AND DISCUSSION
Initially, to optimize the reaction conditions, we used the
reaction of 4-chlorobenzaldehyde 1b (1 mmol), malononi-
trile 2 (1mmol), and S-methylisothiouronium iodide 3
(1mmol) as the model reaction (Scheme 1) and examined
© 2013 HeteroCorporation

March 2014
Multicomponent Synthesis of Some Novel 2-Methylthio Pyrimidine Derivatives
419
Scheme 1
the effect of the amount of MCM- 41-NH2 in this process
(Table 1). To prepare MCM-41-NH2, MCM-41 is modified
with trimethoxysilane n-propylamine according to the previ-
ously described method [27], with regard to the results; the
optimum amount of catalyst was found to be 0.06 g as shown
in Table 1. Further increasing the amount of catalyst did not
improve the yield and the reaction time (Table 1, entry 8).
Then, we examined different solvents under different
temperatures in the model reaction (Scheme 1, Table 1). To
show the high catalytic activity of MCM-41-NH2, the effect
of other catalysts such as basic Al2O3, CH3COONa, unfunc-
tionalized MCM-41, and SiO2 was also investigated in the
model reaction (Table 1, entries 10–13). As can be seen in
Table 1, the synthesis of 2-methylthio pyrimidine derivatives
was best accomplished with nano MCM-41-NH2 under
solvent-free conditions at 80ꢀC (Scheme 3, Table 1, entry 7).
The direct effect of nanosized MCM-41-NH2 in the
process is simply observable in entry 10 of Table 1. In this
case, the yield of the desired product is lower than optimized
conditions (entry 7, Table 1). As can be seen, the yields of
products were lower than when using nano MCM-41-NH2.
Unfunctionalized MCM-41 (Table 1, entry 13) was also used
as catalyst in the model reaction. Among solvents tested,
DMF as a polar aprotic solvent showed the best results, but
this result is still much lower than the optimized conditions
(Table 1, entry 6).
A mechanism for the reaction is given in Scheme 2. The ini-
tial step is the insertion of reactants into nanochannels of
MCM-41-NH2. Then, they are accumulated by inherent
hydrogen bonding of -OH groups, which are capable of bond-
ing with carbonyl oxygen of the aldehyde to generate interme-
diate A through activation of reactants. (In other words,
intermediate A is generated inside the nanoreactor by suffi-
cient energy released during the collapse and strong polarity
of the -OH groups.) Subsequently, the intermediate undergoes
Michael addition/cyclization A with S-methylisothiourea to
produce the pyrimidine product. On the basis of the results
of this study, it seems that the nanostructure of catalyst and
attachment of amino groups to the inside surface of channels
of MCM-41 improves the reaction times and yields.
We next examined the scope and generality of this reac-
tion using a variety of aromatic aldehydes, possessing both
electron-donating and electron-withdrawing substituents
(Scheme 3, Table 2).
All of the reactions were carried out under solvent-free
conditions within 1 h. The reaction worked well with elec-
tron-withdrawing (NO2, Cl) as well as electron-donating
(Me, MeO) groups, and all of the products were obtained
Table 1
The effect of the amount of MCM-41-NH2, solvent, and different catalysts for synthesis of 4b within 1 h.
Entry
Solvent
Catalyst
Amount of catalyst (g)
T (ꢀC)
Yield of 4b (%)a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
H2O
H2O
EtOH
EtOH
DMF
DMF
—
—
—
—
—
MCM-41-NH2
MCM-41-NH2
MCM-41-NH2
MCM-41-NH2
MCM-41-NH2
MCM-41-NH2
MCM-41-NH2
MCM-41-NH2
MCM-41-NH2
—
0.06
0.06
0.06
0.06
0.06
0.06
0.06
0.08
0.04
—
RT
reflux
RT
reflux
RT
80
80
80
80
80
0
47
0
58
18
84
96
96
88
0
SiO2
CH3COONa
Al2O3
0.2
0.1
0.1
0.06
80
80
80
80
78
48
76
86
—
—
—
MCM-41
aIsolated yield.
Journal of Heterocyclic Chemistry
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420
S. Rostamizadeh and M. Nojavan
Vol 51
Table 2
Scheme 2. Proposed mechanism for the 2-methylthio pyrimidine deriva-
tives using MCM-41-NH2. [Color figure can be viewed in the online
issue, which is available at wileyonlinelibrary.com.]
Catalyst reusability in the model reaction for the synthesis of 2-methylthio
pyrimidine derivative 4b.
N
Yield (%)a
N
Entry
Run no.
Reaction time (h)
O
1
2
3
4
5
6
1
2
3
4
5
6
0.5
0.5
0.5
1
1
2
96
96
93
90
90
81
H
+
R
N
R
N
A
1
2
aIsolated yield.
Bomem Model FTLA200-100 instrument (Canada). 1H and 13C
NMR spectra were measured with a Bruker DRX-300 Avance
spectrometer (Germany) at 300 and 75 MHz using TMS as an
internal standard. Chemical shifts are reported (d) relative to TMS,
and coupling constants (J) are reported in Hertz (Hz). Mass spectra
were recorded on a Shimadzu QP 1100 EX mass spectrometer
with 70 eV ionization potential (Belgium). Elemental analyses of
new compounds were performed with a Vario EL III 0 Serial No.
11024054 instrument, and their results favorably agreed with
calculated values.
S
H2N
NH2I
N
S
R
3
NH2
N
N
4
Synthesis and functionalization of MCM-41. In the present
work, MCM-41 was modified to covalently anchor trimethoxysilan
n-propylamin on the inside surface of channels and provide the
silica supported material with Brönsted base properties [27]. The
MCM-41 was synthesized according to the previously described
method using cetyltrimethylammonium bromide, as the templating
agent [28]. The surfactant template was then removed from the
synthesized material by calcination at 540ꢀC for 6 h.
MCM-41 was modified by the cocondensation method by ad-
dition of the trimethoxysilan n-propylamin (3 g) to a suspension
of freshly activated MCM-41 silica (3 g) in refluxing toluene
(50 mL) and then stirred for 1.5 h. After distillation of a toluene
fraction containing ethanol, the heating and distillation sequences
were repeated two times. The modified solid was filtered, washed
in a Soxhlet apparatus with diethyl ether and dichloromethane,
and then dried at 393 K.
with excellent yields. Structures 4a–o were established on
the basis of IR measurement (KBr disk) that showed the pres-
ence of CN at region 2216 cmÀ1 and two sharp bands at 3318
and 3386 cmÀ1 and sharp bands at 1605 cmÀ1 because of
1
vibrations of the NH2 groups. The H and 13C NMR and
mass spectra were also in accordance with the proposed
structures (Table 3).
In summary, we reported the synthesis of some novel
2-methylthio pyrimidine derivatives through a one-pot,
three-component reaction between malononitrile, aromatic
aldehydes, and S-methylisothiouronium iodide in the presence
of nanocatalyst MCM-41-NH2. Short reaction times, excellent
yields of products, simple work-up, and performing the reac-
tion under solvent-free conditions are the advantages of the
present study.
General procedure.
Malononitrile (1 mmol), aldehyde
(1 mmol), S-methylisothiouronium iodide (1 mmol), and nanocatalyst
MCM-41-NH2 (0.06 g) were ground and placed in a test tube. The
reaction was then stirred under heat for 1 h at 80ꢀC and monitored
by TLC (EtOAc : Petroleum ether, 1:2).
After completion of the reaction, the reaction mixture was cooled
to room temperature, EtOAc added, and the mixture stirred for at
least 10min. The reaction mixture was filtered off to remove the cat-
alyst and evaporated in vacuo to obtain a solid product. The residues
were further purified by crystallization from EtOH.
EXPERIMENTAL
General.
Melting points were recorded on a Buchi B-540
apparatus (Germany). IR spectra were recorded on an ABB
Scheme 3
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March 2014
Multicomponent Synthesis of Some Novel 2-Methylthio Pyrimidine Derivatives
421
Table 3
Synthesis of 4-amino-6-aryl-2-methylthio pyrimidine-5-carbonitrile in solvent-free conditions catalyzed with MCM-41-NH2.
Entry
Product
R
Time (h)
Yielda (%)
mp (ꢀC)
Lit. mp (ꢀC)
212 [17,18]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
Ph
4-Cl-Ph
4-Br-Ph
0.5
0.5
0.5
0.5
0.75
0.5
0.5
0.5
0.5
0.75
0.75
0.5
0.5
0.5
0.5
98
96
95
98
95
96
96
96
96
90
92
95
95
96
96
210
225.5
233
265
211.5
197
4-CN-Ph
4-MeO-Ph
2,4-diCl-Ph
2,3-diCl-Ph
4-NO2-Ph
3-NO2-Ph
2-thienyl
207 [18]
215 [18]
264
216.6
225.5
244
228.4
198
299.5
186
215
245 [17]
228 [17]
2-furyl
2-Br-Ph
4-CH3CONH-Ph
2-Cl-Ph
4-Me-Ph
188 [17]
218 [17]
aIsolated yield.
Analytical data for the pyrimidine-5-carbonitrile derivatives
7.82 (d, 1H, J = 0.4 Hz), 8.23 (br s, 2H, NH2); 13C NMR
(75 MHz, DMSO-d6): d 13.5, 85.3, 114.9, 127.7, 129.3,
131.7, 132.1, 134.5, 135.3, 162.1, 166.3, 174.2; ms: m/z
311 (33, M+), 310 (100, M+), 264 (43), 229 (59), 124 (25),
74 (27), 45 (12). Anal. Calcd for C12H8Cl2N4S: C, 46.32;
H, 2.59; N, 18.00. Found: C, 46.41; H, 2.33; N, 17.98.
4-Amino-6-(2,3-dichlorophenyl)-2-methylthiopyrimidine-
4-Amino-6-phenyl-2-methylthiopyrimidine-5-carbonitrile
(4a).
White powder, mp 210ꢀC; [Lit. 212ꢀC]; 1H NMR
(300 MHz, CDCl3): d 2.58 (s, 3H), 5.66 (br s, 2H, NH2), 7.48–7.58
(m, 3H), 8.00 (d, 2H, J=7.7Hz); 13C NMR (75MHz, CDCl3): d
14.2, 83.0, 116.4, 128.7, 131.5, 135.7, 163.4, 167.2, 175.5.
4-Amino-6-(4-chlorophenyl)-2-methylthiopyrimidine-5-carbonitrile
Pale yellow powder, mp 225.5ꢀC; 1H NMR (300 MHz,
5-carbonitrile (4g).
White powder, mp 264ꢀC; 1H NMR
(4b).
(300MHz, DMSO-d6): d 2.44 (s, 3H), 7.51 (d, 2H, J = 4.8Hz),
7.81 (t, 1H, J = 4.8Hz), 8.25 (br s, 2H, NH2); 13C NMR (75MHz,
DMSO-d6): d 13.5, 85.0, 114.8, 128.7, 128.9, 129.1, 131.8, 132.2,
137.7, 162.1, 166.8, 174.3; ms: m/z 311 (7, M+), 310 (19, M+),
167 (25), 149 (75), 97 (31), 71 (61), 57 (100), 43 (87). Anal.
Calcd for C12H8Cl2N4S: C, 46.32; H, 2.59; N, 18.00. Found: C,
CDCl3): d 2.57 (s, 3H), 5.71 (br s, 2H, NH2), 7.49 (d, 2H,
J= 13.6 Hz), 7.97 (d, 2H, J= 13.6 Hz); 13C NMR (75 MHz, DMSO-
d6): d 13.5, 82.4, 116.1, 128.6, 130.4, 134.8, 135.9, 163.2,
166.0,173.9; ms: m/z 278 (32, M+), 276 (100, M+), 231 (62), 205 (12),
112 (51), 114 (13), 95 (17), 48 (28), 28 (10). Anal. Calcd for
C12H9ClN4S: C, 52.08; H, 3.28; N, 20.24. Found: C, 52.41; H, 3.33;
46.35; H, 2.41; N, 18.01.
N, 19.98.
4-Amino-6-(4-nitrophenyl)-2-methylthiopyrimidine-
4-Amino-6-(4-bromophenyl)-2-methylthiopyrimidine-5-carbonitrile
5-carbonitrile (4h). Yellow powder, mp 216.6ꢀC; [Lit. 215ꢀC ];
1H NMR (300 MHz, DMSO-d6): d 2.58 (s, 3H), 6.01 (br s, 2H,
NH2), 8.55 (d, 2H, J = 11.3Hz), 8.60 (d, 2H, J = 11.3Hz); 13C
NMR (75MHz, DMSO-d6): d 13.6, 83.2, 115.8, 123.7, 130.1,
141.9, 148.7, 163.0, 165.5, 174.2.
(4c). Pale yellow powder, mp 233ꢀC; 1H NMR (300 MHz, CDCl3): d
2.58 (s, 3H), 5.71 (br s, 2H, NH2), 7.89 (d, 2H J= 13.6 Hz), 8.34 (d, 2H,
J=13.6Hz); 13C NMR (75MHz, DMSO-d6): d 13.5, 82.3, 116.2,
128.6, 124.8, 130.6, 131.6, 135.1, 163.2, 166.1, 173.9; ms: m/z 322
(100, M+), 320 (95, M+), 275 (48), 273 (45), 195 (40), 149 (47), 126
(24), 69 (28), 43 (20). Anal. Calcd for C12H9BrN4S: C, 44.87; H, 2.82;
4-Amino-6-(3-nitrophenyl)-2-methylthiopyrimidine-5-carbonitrile
(4i).
Pale yellow powder, mp 225.5ꢀC; 1H NMR (300 MHz,
N, 17.44. Found: C, 44.63; H, 3.01; N, 17.58.
DMSO-d6): d 2.58 (s, 3H), 6.01 (br s, 2H, NH2), 7.76 (dd, 1H,
J=7Hz, J= 9 Hz), 8.12 (d, 1H, J= 7 Hz), 8.33 (s, 1H), 8.48 (d, 1H,
J=9Hz); 13C NMR (75 MHz, DMSO-d6): d 13.5, 82.8, 115.9,
123.2, 125.5, 130.3, 134.8, 137.4, 147.6, 163.0, 165.0, 174.2; ms:
m/z 287 (100, M+), 241 (36), 194 (18), 167 (24), 149 (51), 114 (13),
83 (17), 57 (28), 41 (10). Anal. Calcd for C12H9N5O2S: C, 50.17; H,
4-Amino-6-(4-cyanophenyl)-2-methylthiopyrimidine-5-
carbonitrile (4d).
Yellow powder, mp 263.3ꢀC; 1H NMR
(300 MHz, CDCl3): d 2.58 (s, 3H), 5.92 (br s, 2H, NH2), 8.92
(d, 2H, J = 11.3 Hz), 8.64 (d, 2H, J = 11.3 Hz); 13C NMR
(75 MHz, CDCl3): d 13.5, 83.0, 113.3, 115.8, 129.4, 132.4,
140.2, 162.9, 165.8, 174.1; ms: m/z 267 (100, M+), 220 (63),
194 (14), 129 (11), 102 (14), 75 (7), 43 (4). Anal. Calcd for
C13H9N5S: C, 58.41; H, 3.39; N, 26.20. Found: C, 58.26; H,
3.16; N, 24.38. Found: C, 50.02; H, 3.21; N, 24.24.
4-Amino-2-methylthio-6-(2-thienyl)pyrimidine-5-carbonitrile
(4j).
(300 MHz, DMSO-d6):
White powder, mp 244ꢀC; [Lit. 245ꢀC]; 1H NMR
3.33; N, 26.03.
d
2.49 (s, 3H), 7.28 (dd, 1H,
4-Amino-6-(4-methoxyphenyl)-2-methylthiopyrimidine-
5-carbonitrile (4e).
Pale yellow powder, mp 211.5ꢀC; [Lit.
J = 4.98 Hz, J = 3.9 Hz), 7.93 (dd, 1H, J = 5.04 Hz, J = 0.9 Hz),
8.18 (dd, 1H, J = 3.87 Hz, J = 0.9 Hz), 8.04 (br s, 2H, NH2); 13C
NMR (75 MHz, DMSO-d6): d 13.9, 83.4, 113.2, 124.4, 124.6,
207ꢀC]; 1H NMR (300 MHz, CDCl3): d 2.59 (s, 3H), 3.74 (s,
3H), 5.89 (br s, 2H, NH2), 7.33 (d, 2H, J = 12.4Hz), 7.82 (d, 2H,
J = 12.4 Hz); 13C NMR (75 MHz, CDCl3): d 13.5, 81.4, 113.9,
133.3, 153.0, 165.6, 170.7, 176.3.
4-Amino-6-(2-furyl)-2-methylthiopyrimidine-5-carbonitrile
116.7, 128.1, 130.4, 161.6, 163.4, 166.3, 173.6.
4-Amino-6-(2,4-dichlorophenyl)-2-methylthiopyrimidine-5-
(4k).
(300 MHz, DMSO-d6):
J = 3.5 Hz, J = 1.7 Hz), 7.44 (d, 1H, J = 3.5 Hz), 8.05 (d, 1H,
White powder, mp 228.4ꢀC; [Lit. 228ꢀC ]; 1H NMR
carbonitrile (4f).
NMR (300 MHz, DMSO-d6): d 2.45 (s, 3H), 7.58 (s, 2H),
Yellow powder, mp 197–198ꢀC; 1H
d 2.49 (s, 3H), 6.77 (dd, 1H,
Journal of Heterocyclic Chemistry
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S. Rostamizadeh and M. Nojavan
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J = 1.7 Hz), 8.28 (br s, 2H, NH2); 13C NMR (75 MHz,
DMSO-d6): d 13.5, 78.1, 115.7, 127.4, 128.6, 133.3, 149.6,
155.0, 163.3, 173.7.
4-Amino-6-(2-bromophenyl)-2-methylthiopyrimidine-5-carbonitrile
[5] Abdel-Mohsen, T. H.; Ragab, F. A. F.; Ramla, M. M.; Diwan,
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(4l). Pale yellow powder, mp 198ꢀC; 1H NMR (300 MHz, DMSO-
d6): d 2.58 (s, 3H), 7.18 (dd, 1H, J=9Hz, J= 7 Hz), 7.67 (t, 1H,
J= 7 Hz), 7.82 (d, 1H, J= 7 Hz), 7.95 (d, 1H, J= 9 Hz), 7.04 (br s, 2H,
NH2); 13C NMR (75 MHz, DMSO-d6): d 13.9, 89.4, 116.0, 127.5,
128.6, 130.0, 132.1, 136.9, 146.1, 159.2, 163.7, 178.3; ms: m/z 322
(100, M+), 320 (96, M+), 275 (52), 273 (45), 196 (38), 156 (42), 126
(24), 78 (14), 48 (12). Anal. Calcd for C12H9BrN4S: C, 44.87; H, 2.82;
N, 17.44. Found: C, 44.48; H, 2.91; N, 17.10.
6-(4-N-Acetamidophenyl)-4-amino-2-methylthiopyrimidine-
5-carbonitrile (4m). Pale yellow powder, mp 299.5ꢀC; 1H NMR
(300MHz, DMSO-d6): d 2.08 (s, 3H), 2.49 (s, 3H), 7.72 (d, 2H,
J = 8.76Hz), 7.85 (d, 2H, J = 8.64 Hz), 8.36 (br s, 1H, NH2),
10.24 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6): d 13.5, 24.1,
81.5, 116.6, 118.3, 129.4, 130.1, 141.9, 163.3, 166.3, 168.8,
173.6; ms: m/z 299 (27, M+), 257 (19), 211 (29), 169 (93), 142
(15), 106 (19), 69 (23),43 (100). Anal. Calcd for C14H13N5OS: C,
[14] Hekmatshoar, R.; Nanva Kenary, G.; Sadjadi, S.; Beheshtiha,
Y. S. Synth Commun 2010, 40, 2007.
[15] Ahmadi, S. J.; Sadjadi, S.; Hosseinpour, M. Monatsh Chem
2011, 142, 1163.
56.17; H, 4.38; N, 23.40. Found: C, 56.29; H, 4.52; N, 23.33.
4-Amino-6-(2-chlorophenyl)-2-methylthiopyrimidine-5-carbonitrile
1
(4n). Pale yellow powder, mp 186ꢀC; [Lit. 188ꢀC]; H NMR
(300 MHz, DMSO-d6): d 2.58 (s, 3H); 7.29 (dd, 1H, J = 7.4Hz,
J = 9 Hz), 7.56 (t, 1H, J = 9 Hz), 7.80 (d, 1H, J =7.4 Hz), 7.89
(d, 1H, J = 9 Hz), 7.01 (br s, 2H, NH2); 13C NMR (75 MHz,
DMSO-d6): 13.9, 93.8, 116.0, 125.5, 128.6, 129.3, 136.1, 137.9,
[16] Anderson, L.; Zhou, M.; Sharma, V.; McLaughlin, J. M.; San-
tiago, D. N.; Fronczek, F. R.; Guida, W. C.; McLaughlin, M. L. J Org
Chem 2010, 75, 4288.
[17] El-Sharabsy, S. A.; Gawad, S. M. A.; Hussain, S. M. J Prakt
Chem 1989, 331, 207.
[18] Daboun, H. A.; El-Reedy, A. M. Z Naturforsch B 1983, 38,
1686.
[19] Madruga, C. C.; Clerici, E.; Marcos, A. P. J Heterocycl Chem
1995, 32, 735.
[20] Zanatta, N.; Madruga, C. C.; Marisco, P. C.; Da Rosa, L. S.;
Fernandes, L. S.; Flores, D. C.; Flores, A. F. C.; Burrow, R. A.; Bona-
corso, H. G.; Martins, M. A. P. J Heterocycl Chem 2008, 45, 221.
[21] Zanatta, N.; Madruga, C. C.; Marisco, P. C.; da Rosa, L. S.; da
Silva, F. M.; Bonacorso, H. G.; Martins, M. A. P. J Heterocycl Chem
2010, 47, 1234.
144.1, 161.7, 163.9, 176.3.
4-Amino-6-(4-methylphenyl)-2-methylthiopyrimidine-5-carbonitrile
(4o).
Pale yellow powder, mp 215ꢀC; [Lit. 218ꢀC]; 1H NMR
(300 MHz, DMSO-d6): d 2.37 (s, 3H), 2.49 (s, 3H), 5.78 (br s, 2H,
NH2), 7.34 (d, 2H, J= 8.09 Hz), 7.76 (d, 2H, J=8.09Hz); 13C NMR
(75 MHz, DMSO-d6): d 13.5, 21.1, 81.9, 116.7, 128.5, 129.1, 133.2,
141.1, 163.3, 167.1, 173.7.
REFERENCES AND NOTES
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F. Catal Today 2001, 68, 191.
[25] Demicheli, G.; Maggi, R.; Mazzacani, A.; Righi, P.; Sartoria,
G.; Bigi, F. Tetrahedron Lett 2001, 42, 2401.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet