Facile Synthesis of Some Novel Tetrasubstituted 2,4-Diaminopyrimidine Derivatives in Aqueous Glucose Solution as a Fully Green Medium and Promoter

Article abstract of DOI:10.1002/jhet.2514

A novel environmentally benign method toward the synthesis of some novel tetrasubstituted 2,4-diaminopyrimidine derivatives using an aqueous glucose-mediated one-pot three-component reaction of malononitrile with various benzaldehyde and amidine derivatives is reported. Some pyrimidine derivatives possessing α-amino acid moiety were synthesized by the present protocol for the first time. This protocol offers advantages including facile reaction conditions, using naturally occurring glucose as promoter and water as solvent, simple work-up, relatively short reaction times, and high yields of the products.

Full text of DOI:10.1002/jhet.2514

Month 2015
Facile Synthesis of Some Novel Tetrasubstituted 2,4-Diaminopyrimidine
Derivatives in Aqueous Glucose Solution as a Fully Green
Medium and Promoter
Reza Aryan*, Hamid Beyzaei, and Fatemeh Sadeghi
Department of Chemistry, Faculty of Science, University of Zabol, P.O. Box 9861335856, Zabol, Iran
*
E-mail: rezaaryanchemist@yahoo.com; rezaaryan@uoz.ac.ir
Received May 8, 2015
DOI 10.1002/jhet.2514
Published online 00 Month 2015 in Wiley Online Library (wileyonlinelibrary.com).
A novel environmentally benign method toward the synthesis of some novel tetrasubstituted 2,4-
diaminopyrimidine derivatives using an aqueous glucose-mediated one-pot three-component reaction of
malononitrile with various benzaldehyde and amidine derivatives is reported. Some pyrimidine derivatives
possessing α-amino acid moiety were synthesized by the present protocol for the first time. This protocol of-
fers advantages including facile reaction conditions, using naturally occurring glucose as promoter and water
as solvent, simple work-up, relatively short reaction times, and high yields of the products.
J. Heterocyclic Chem., 00, 00 (2015).
having 4-amino substituent includes the one-pot three-
component reaction of malononitrile, aromatic aldehydes,
and amidine derivatives using a basic catalyst [12–19].
Despite the fact that these methods all have their advan-
tages, the use of basic catalyst mostly metal oxides seems
necessary to promote the reaction. It appears that Lewis
acidity of metal ion synergistically cooperates with oxida-
tive and basic character of oxide anion in these cases. In
addition, some of these methods are stepwise, and the other
ones require high reaction temperatures and laborious puri-
fication of the products such as column chromatography.
In recent years, the development of multicomponent reac-
tions is expanding remarkably as this protocol has been
employed widely as a beneficial approach for the synthesis
of many classes of heterocyclic building blocks. This is due
tothefactthattheyplaytheroleofalternativestothestepwise
construction of complex heterocyclic structures of impor-
tance for medicinal research. The most significant features
of multicomponent synthetic strategies encompass charac-
teristic terms such as atom economy, cost-effectiveness,
and the product structure diversity [20,21].
INTRODUCTION
Pyrimidine derivatives specially have contributed in the
structure of many naturally occurring compounds such as
heteromines (Fig. 1a), crambescins, and manzacidins [1].
Many pharmaceutically active ingredients such as antibi-
otics [2], antimalarials [3], selective A3 adenosine receptor
antagonists [4], and antiproliferative agents [5], and some
novel specific radiotracers for positron emission tomogra-
phy [6] have been designed and studied possessing this
structural motif. Several valuable reviews are found
illustrating the medicinal and therapeutic properties of
pyrimidine derivatives [5,7,8]. Especially, pyrimidines
having amino group at positions 2 and 4 of the ring have
been reported to exhibit application in Alzheimer’s disease
treatment (Fig. 1b) [9].
Moreover, pyrimidine derivatives have played a signifi-
cant role in agriculture as crop protection agents [10] and
in electro-optics as building blocks for calamitic liquid
crystals [11]. Accordingly, the endeavors toward introduc-
ing novel safer and more effective methods for the synthesis
of this class of heterocycles starting from non-cyclic raw
materials appear crucial and noteworthy. Recently, numer-
ous synthetic methods have been reported in the literature
for the synthesis of these valuable heterocycles through ring
construction of linear starting materials. The most impor-
tant strategy toward the synthesis of pyrimidine derivatives
Provided by environmental and social interests, the
emphasis on providing novel and safer synthetic
methodologies regarding the green chemistry principles
has arisen as a very important area of research [22].
Recently, having shifted the emphasis of green chemistry
fields of research toward engaging bio-based materials
© 2015 HeteroCorporation

R. Aryan, H. Beyzaei, and F. Sadeghi
Vol 000
continuation of our previous efforts toward the synthesis
of pyrimidine derivatives and their fused analogs [31–34],
and with a view of multicomponent reactions as powerful
tool for the pursuit in molecular complexity and diversity
[20,21], we herein wish to report
methodology for the synthesis of four substituted 2,4-
diaminopyrimidine-5-carbonitrile derivatives through
a novel green
a
one-pot catalyst and oxidant-free three-component reaction
of malononitrile with various benzaldehyde and amidine de-
rivatives in aqueous glucose solution as medium and pro-
moter. In the present study, we managed to synthesize
some novel pyrimidine derivatives possessing an α-amino
acid moiety at position 2 of the ring. The derivatives had
not been obtained by previously reported methodologies.
Figure 1. (a) The structures of three natural products having 2,4-
diaminopyrimidine scaffold. (b) The structure of 2,4-diaminopyrimidine
derivatives recently studied as a favorable template for Alzheimer’s dis-
ease treatment.
with various structures, an important research challenge for
green chemistry will also be retrieving the bio-based
building blocks in order to fulfill this requirement [23]. Be-
sides their biochemical significance, carbohydrates have
played a much serious role in today’s organic chemistry
research as raw materials for the synthesis of various or-
ganic compounds as well [24,25]. Glucose, as one of the
simple and straightforward polyhydroxy sugars, has been
used as a ligand with modified structure for some synthetic
and asymmetric catalysis purposes [26–28]. In addition,
the aqueous glucose solution has been utilized as a novel
polar and fully green reaction medium and promoter in
the synthesis of 2,6-dioxohexahydropyrimidines through
an isocyanide-based multicomponent reaction [29] and
the synthesis of benzimidazoles through oxidant-free
cyclodehydrogenation of aniline Schiff bases [30]. In
RESULTS AND DISCUSSION
Our main goal was to develop a green protocol for the
synthesis of some novel pyrimidine-5-carbonitrile deriva-
tives bearing amino groups at positions 2 and 4 of the ring.
With the aim of fulfilling the green chemistry requirement
as our secondary objective, the application of aqueous glu-
cose solution as medium and promoter was examined in
the absence of extra catalyst and oxidant. The reaction of
malononitrile (1 mmol), benzaldehyde (1mmol), and
benzamidine hydrochloride (1 mmol) was used as the
model reaction. Various glucose concentrations, solvents,
and reaction temperatures were scanned (Scheme 1), and
the results are presented in Table 1.
Scheme 1. The model reaction for the synthesis of 4-aminopyrimidine-5-carbonitrile derivatives.
Table 1
Screening various reaction conditions for the aqueous glucose-mediated synthesis of 4-aminopyrimidine-5-carbonitrile derivativesa.
Entry
Solvent
H2O
H2O
H2O
H2O
H2O
H2O
H2O/EtOH (50:50)
H2O/EtOH (50:50)
H2O/EtOH (50:50)
H2O/EtOH (50:50)
Glucose concentration (M)
Temperatureb (°C)
Time (h)
Yieldc (%)
1
2
3
4
5
6
7
8
9
No glucose
50
25
50
50
50
50
25
50
Reflux
Reflux
12
12
2
2
2
5
12
7
5.5
8
No reaction
No reaction
1
1
2
3
4
1
1
1
4
94
89
90
95
47d
33
42
31
10
aThe reactions were carried out with 1 mmol of the reactants in 5 mL of the solvents specified.
bWhen performed at reflux in aqueous glucose solution, not only was observed no remarkable rate acceleration but also the yields reduced to some extent.
cIsolated products.
dOnly benzylidene malononitrile (4) was formed (47%).
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Month 2015
Facile Synthesis of Some Novel Tetrasubstituted 2,4-Diaminopyrimidine
Table 2
The results in Table 1 imply some important points. The
model reaction did not proceed in pure water even at ele-
vated temperatures. When compared with the other data,
this observation represents the effect of glucose on the
model reaction. The increasing glucose concentration in re-
action medium did not have any enhancing effect on the
yield and the reaction times. The reaction yield increased
insignificantly, while the reaction rate decreased interest-
ingly going from 1M to 4M glucose solution. The mixed
solvent case (H2O/EtOH) proceeded in a similar manner.
The reaction rates and yields both decreased in this solvent
system unexpectedly, while higher reaction yields and
shorter reaction times were expected. Whereas only the
benzylidene malononitrile intermediate 4 was formed at
ambient temperatures, medium yields of the desired prod-
uct were obtained at elevated temperatures (Table 1, entries
7–10). This could be due to the fact that in mixed solvent,
the two reactants benzaldehyde and malononitrile dissolve
in EtOH better than in water, whereas benzamidine hydro-
chloride does not dissolve in EtOH at all. This keeps the re-
actants apart from each other causing reaction failure.
Besides in water as solvent containing glucose, the reac-
tants are excluded from solvent bulk and aggregated to
each other leading to faster reactions and higher yields of
the product (see entries 7–10 in comparison with entries
2–6, Table 1). The reactions were performed very well at
50°C, and elevated temperatures did not seem necessary
(Table 1, entries 3 to 6).
The scope and generality of the aqueous glucose solution for the synthesis
of 6-aryl-4-aminopyrimidine-5-carbonitrile derivativesa.
Compound Time
Yieldb
(%)
Entry
R1
R2
no.
(h)
1
2
3
4
5
6
7
8
H
H
H
H
Ph
NH2
5a
5b
5c
5d
5e
5f
2
1.5
5
4
1.5
2
94
88
83
87
90
95
84
81
77
92
86
75
NH-CH2COOH
SMe
Ph
4-Cl
4-AcNH Ph
4-Cl
4-Cl
4-NO2
4-AcNH NH2
4-Cl
4-NO2
SMe
5g
5h
5i
3.5
4
5
NH-CH2COOH
NH-CH2COOH
9
10
11
12
5j
5k
5l
1.5
2
4
NH2
NH2
a1 mmol of each reactant was used in 5 mL 1M aqueous glucose solution.
bIsolated yield.
derivatives with diverse electron demand and four unlike
amidine derivatives. Good reactivities in terms of yields
and reaction times were observed under the reaction condi-
tions in 1M glucose solution. The reactions were accom-
plished within relatively short reaction times (1.5 to 5h)
with good to excellent product yields. Guanidinium carbon-
ate was the most reactive amidine derivative according to ob-
served reaction times and yields (entries 2, 10, and 11). Only
when 4-nitrobenzaldehyde was used, a diminished reactivity
with guanidinium carbonate was noticed. The electron dona-
tion did not show a notable impact on reaction rates and
yields. A relatively small increment in reaction rates for 4-
acetamidobenzaldehyde was observed (entries 6 and 10
versus entries 1 and 2). With isothiouronium iodide as the
amidine source, the reactivities showed not much difference
for benzaldehyde and 4-chlorobenzaldehyde (entries 4 and
7). The N-amidinoglycine represented slowest reactions pro-
viding pyrimidine derivatives as novel amino acid derivative
with great yields. Again, no noticeable preference for elec-
tron donation and withdrawal was observed in this case.
Moreover, the reaction products were easily purified by fil-
tration and stirring in water for several minutes. In most
cases, no extra purification such as recrystallization was
needed. Finally, the insolubility of all products causes easy
separation by precipitation from the reaction mixture.
Then, the model reaction was performed under N2 inert at-
mosphere, and no desired product formed. Only benzylidene
malononitrile intermediate was obtained under this condi-
tion. This implies that the aerobic oxidation by molecular ox-
ygen is required for the complete formation of aromatic
pyrimidine ring. The reusability of aqueous glucose solution
was then examined. The glucose solution was recycled by
filtration and used four times successfully in the model reac-
tion without any obvious decrease in yield and increasing of
the reaction times (Fig. 2).
Regarding 1M aqueous glucose solution at 50°C as op-
timized conditions, the scope and generality of this proto-
col for the synthesis of novel 2,4-diaminopyrimidine
derivatives were examined. Various benzaldehyde and
amidine derivatives were utilized along with malononitrile
under optimized reaction conditions. As stated before, an
important aim of the present work was to introduce novel
2,4-diaminopyrimidine derivatives. In order to fulfill this
purpose, four different amidine derivatives were applied
in this protocol along with various benzaldehydes
(Scheme 2).
The results are presented in Table 2. Pyrimidine-5-
carbonitrile derivatives with diverse structural motifs on
positions 2 and 6 were formed by using benzaldehyde
Scheme 2. The scope and generality of the present method for the aque-
ous glucose-mediated ecofriendly synthesis of pyrimidine-5-carbonitrile
derivatives.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

R. Aryan, H. Beyzaei, and F. Sadeghi
Vol 000
The reason for reaction progress in aqueous glucose so-
lution as medium and promoter has not yet been investi-
gated. A plausible mechanistic explanation is provided in
Scheme 3. Probably, the polyhydroxy structure of glucose
forms multiple hydrogen bonds to water molecules consec-
utively leading to a very polar reaction medium. This po-
larity may stimulate the reactants’ dipole moments
resulting in facilitating the reaction promotion. The car-
bonyl oxygen in aldehyde becomes more susceptible to nu-
cleophilic attack by malononitrile (Scheme 3, State A).
The resulting benzylidene malononitrile then undergoes
a double nucleophilic attack by amidine through a
cyclodehydrogenative process (Scheme 3, State B) to fur-
nish the desired product.
Table 3 represents a comparative analysis for the present
protocol relative to the previously reported important
methods.
The data in Table 3 clearly indicate the preference of
the present work over the previously reported methods.
The common drawback of the previous methods is using
metallic oxides as catalyst, which requires thorough
work-up procedures to separate the products from the cat-
alyst. Also, using metallic catalysts may result in the for-
mation of toxic waste and is avoided according to green
chemistry principles. The use of high temperatures and
harmful organic solvents are the other most important
drawbacks of the previous methods. While in the present
study, the products are formed without using metallic cat-
alysts and easily separated from the reaction mixture by a
simple filtration with no need to laborious work-up.
Lower reaction temperatures, comparable yields, using
fully green reaction medium and promoter, and the syn-
thesis of novel pyrimidine derivatives possessing amino
acid moiety are the other advantages of the present
protocol.
Figure 2. Examination of recyclability and reusability of aqueous glu-
cose solution in the specified model reaction for the preparation of
2,4-diaminopyrimidine derivatives (reaction time 2 h).
Scheme 3. A plausible mechanistic explanation for aqueous 1M glucose solution-mediated synthesis of pyrimidine-5-carbonitrile derivatives.
Table 3
Comparison of the present protocol results with some previously reported methods.
Entry
Solvent
Catalyst
Nano MgO
Nano ZnO
Nano CuO
Nano Fe3O4
Bi(NO3)3.5H2O and NEt3
Glucose
Temperature
Time (h)
Yields (%)
Ref. [12]
Ref. [13]
Ref. [15]
Ref. [17]
Ref. [19]
Present work
CH3CN
H2O
H2O
None
CH3CN
H2O
Reflux
RT
RT
100°C
Reflux
40–50°C
<1
<1
<1
1–1.5
<1
70–96
91–98
86–98
94–98
71–96
77–94
1.5–4
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
Facile Synthesis of Some Novel Tetrasubstituted 2,4-Diaminopyrimidine
Physical and spectroscopic data for 4-aminopyrimidine-5-
CONCLUSIONS
carbonitrile derivatives. 4-Amino-2,6-diphenylpyrimidine-
5-carbonitrile (5a). mp 215°C (Lit. mp 212–213°C) [17].
IR (potassium bromide): 3393 (NH), 3278 (NH), 3079
In summary, a novel safe and green methodology for the
synthesis of some novel fully substituted pyrimidine-5-
carbonitrile derivatives was reported through a one-pot
three-component reaction of malononitrile, aromatic alde-
hydes and some amidine derivatives mediated by aqueous
glucose solution. The reactions were carried out success-
fully at 50°C, and the products were simply isolated from
the reaction mixture by vacuum filtration. The most impor-
tant aspects of the present protocol include using a fully
green and biocompatible glucose solution as medium and
promoter, mild reaction conditions, good to excellent
yields of the products, easy work-up, and the synthesis of
derivatives having α-amino acid moiety for the first time.
The pyrimidine derivatives having amino acid moiety are
being studied for their possible bioactivities.
(CH), 3052 (CH), 2219 (CN), 1603 (C=N) cmÀ1 1H
.
NMR (400MHz, DMSO-d6) δ 7.37–7.40 (m, 1H),
7.43 (d, J= 4.4 Hz, 4H), 7.46–7.48 (m, 2H), 7.56–7.59
(m, 3H), 7.77 (d, J = 5.4 Hz, 2H) ppm. 13C NMR
(100 MHz, DMSO-d6):
δ 80.21 (pyrimidine carbon
bearing CN), 115.72 (CN), 126.39, 127.24, 128.11, 129.53,
130.28, 130.87, 132.30, 139.62, 162.89 (pyrimidine
ring C), 165.68 (pyrimidine ring C), 168.78 (pyrimidine
ring C) ppm.
2,4-Diamino-6-phenylpyrimidine-5-carbonitrile(5b). mp
232°C (Lit. mp 237–239°C) [14]. IR (potassium bromide):
3427 (NH), 3388 (NH), 3311 (NH), 3291 (NH), 3143,
3088, 2263 (CN), 1611 (C=N) cmÀ1. 1H NMR (400MHz,
DMSO-d6) δ 7.128 (bs, 4H), 7.37–7.40 (m, 1H), 7.47–7.50
(m, 3H), 7.74–7.77 (m, 1H) ppm. 13C NMR (100MHz,
DMSO-d6): δ 74.09 (pyrimidine carbon bearing CN),
114.67, 127.91, 130.18, 135.79, 140.47, 164.67
(pyrimidine ring C), 165.78 (pyrimidine ring C), 168.26
(pyrimidine ring C) ppm.
EXPERIMENTAL
Chemicals were purchased from Merck and Acros
Organics companies (Merck Company, Hessen, Germany;
Acros Organics Company, Geel, Belgium) and were used
without further purification. Melting points were recorded
on a KRUSS KSP-1N Serial No. 1306560 apparatus and
are uncorrected. Infrared (IR) spectra were recorded on a
Bruker Tensor 27, type No. 121000 instrument (Bruker
Optiks, Prague, Czech Republic). 1H and 13C NMR spectra
were measured with a Bruker DRX-400 Avance spectrom-
eter (Rheinstetten, Ettlingen, Germany) at 400 and
100MHz using tetramethylsilane (TMS) as an internal stan-
dard. Chemical shifts (δ) are reported relative to TMS, and
coupling constants (J) are reported in hertz (Hz). Mass
spectra were recorded on a Shimadzu QP 1100 EX mass
spectrometer (Shimadzu Company, Tokyo, Japan) with
70eV ionization potential. Elemental analyses of new com-
pounds were performed with a Vario EL III 0 serial no.
11024054 instrument (Elementar Analysensysteme GmbH,
Hanau, Germany).
[(4-Amino-5-cyano-6-phenyl-2-pyrimidinyl)amino]acetic
acid (5c). mp 201°C. IR (potassium bromide): 3461 (NH),
3385 (NH), 3311 (NH), 3089, 3063, 2912, 2279 (CN), 1597
1
(C=N)cmÀ1. H NMR (400 MHz, DMSO-d6): δ 3.84 (s,
2H, Aliphatic CH2), 7.61–7.64 (m, 4H), 7.68–7.73
(m, 2H), 7.96 (d, J=8.0Hz, 2H), 8.57 (s, 1H), 11.56
(s, 1H, COOH) ppm. 13C NMR (100MHz, DMSO-d6): δ
39.2 (Aliphatic CH2), 86.37 (pyrimidine carbon bearing
CN), 114.88, 129.51, 129.90, 130.42, 134.28, 161.49
(pyrimidine ring C), 162.18 (pyrimidine ring C), 164.48
(pyrimidine ring C), 169.62 (COOH) ppm. MS (m/z): 269
(5), 211 (100), 141 (40), 179 (35). Anal. Calcd for
C13H11N5O2: C, 57.99; H, 4.12; N, 26.01. Found: C,
58.21; H, 3.89; N, 25.77.
4-Amino-2-methylthio-6-phenylpyrimidine-5-carbonitrile
(5d). mp 215°C (Lit. mp 210°C) [34]. IR (potassium
bromide): 3453 (NH), 3387 (NH), 3203, 3162, 2911 (CH3),
General procedure for the aqueous glucose solution-mediated
three-component synthesis of pyrimidine-5-carbonitrile
derivatives. A mixture of malononitrile (1.0mmol),
.
2303 (CN), 1591 (C=N) cmÀ1 1H NMR (400 MHz,
DMSO-d6): δ 2.51 (s, 3H, CH3), 7.62 (t, J= 7.5 Hz, 2H),
7.69 (d, J=7.5 Hz, 1H), 7.96 (d, J= 7.5 Hz, 2H), 8.28 (s,
1H) ppm. 13C NMR (100MHz, DMSO-d6): δ 15.89
(Aliphatic CH3), 77.22 (pyrimidine carbon bearing CN),
128.67, 129.58, 130.72, 131.53, 134.61, 159.92 (pyrimidine
ring C), 167.93 (pyrimidine ring C), 176.89 (pyrimidine
ring C) ppm.
benzaldehyde derivative (1.0mmol), and amidine derivative
(1.2mmol) was transferred into a reaction tube containing
5mL 1M glucose solution and heated at 50°C for the
specified reaction times. After completion of the reaction
(monitored by TLC analysis, ethyl acetate/n-hexane
mixtures), the reaction mixture was allowed to be cooled
down to room temperature. Then, the precipitates were
vacuum filtered off by a Büchi funnel and stirred in 10mL
water for 30min in order to remove the glucose residues.
The products were then filtered off and dried at ambient
temperature and crystallized from ethanol/water mixtures
whenever necessary to furnish the desired four substituted
pyrimidine-5-carbonitrile derivatives.
4-Amino-6-(4-chlorophenyl)-2-phenylpyrimidine-5-
carbonitrile (5e). mp 219°C (Lit. mp 222°C) [17]. IR
(potassium bromide): 3347, 3291, 3154, 3106, 2291,
1
1609cmÀ1. H NMR (400MHz, DMSO-d6): δ 7.56 (d,
J=8.8Hz, 2H), 7.73 (d, J=8.8Hz, 2H), 7.95 (t, J=8.4Hz,
5H), 8.56 (s, 2H) ppm. 13C NMR (100MHz, DMSO-d6): δ
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R. Aryan, H. Beyzaei, and F. Sadeghi
Vol 000
79.87 (pyrimidine carbon bearing CN), 116.89 (CN),
127.33, 128.28, 129.38, 131.08, 132.23, 138.69, 139.77,
140.58, 163.23 (pyrimidine ring C), 165.11 (pyrimidine
ring C), 169.43 (pyrimidine ring C) ppm.
(60), 129 (45). Anal. Calcd for C13H10N6O4: C, 49.69; H,
3.21; N, 26.74. Found: C, 49.83; H, 3.03; N, 26.51.
2,4-Diamino-6-(4-acetamidophenyl)pyrimidine-5-carbonitrile
(5j). mp 240°C. IR (KBr): 3452 (NH), 3412 (NH), 3388
(NH), 3312 (NH), 3127, 2265 (CN), 1601 (C=N) cmÀ1
.
6-(4-Acetamidophenyl)-4-amino-2-phenylpyrimidine-5-
carbonitrile (5f). mp 250°C (245°C) [17]. IR (potassium
bromide): 3383 (NH), 3342 (NH), 3167, 3087, 2936
1H NMR (400 MHz, DMSO-d6):
δ 2.1 (s, 3H,
NHCOCH3), 7.11 (s, 2H, NH), 7.72 (d, J = 8.0 Hz, 2H,
Aromatic CH), 7.83 (s, 2H, NH), 8.11 (d, J = 8.0 Hz, 2H,
Aromatic CH), 8.8 (s, 1H, NHCO). 13C NMR (100 MHz,
DMSO-d6): δ 24.07 (NHCOCH3), 71.12 (pyrimidine
carbon bearing CN), 112.89 (CN), 117.28, 135.73,
139.15, 141.37, 164.09 (pyrimidine ring C), 164.78
(pyrimidine ring C), 166.32 (pyrimidine ring C), 167.23
(COOH) ppm. MS (m/z): 268 (22), 224 (100), 155 (55),
70 (40). Anal. Calcd for C13H12N6O: C, 58.20; H, 4.51;
N, 31.33. Found: C, 57.91; H, 4.83; N, 31.72.
1
(Aliphatic CH), 2291 (CN), 1616 (C=N)cmÀ1. H NMR
(400MHz, DMSO-d6): δ 2.11 (s, 3H, COCH3), 7.52–7.57
(m, 3H), 7.78 (d, J=8.4Hz, 2H, Aromatic CH), 8.00 (d,
J=8.4Hz, 2H, Aromatic CH), 8.39–8.43 (m, 2H), 10.3 (s,
1H, NHCO). 13C NMR (100MHz, DMSO-d6): δ 24.08
(CH3), 83.47 (pyrimidine carbon bearing CN), 116.59 (CN),
118.32, 128.41, 128.53, 129.49, 130.72, 131.47, 136.68,
141.83, 163.91 (pyrimidine ring C), 164.82 (pyrimidine
ring C), 167.33 (pyrimidine ring C), 168.8 (C=O) ppm. MS
(m/z): 329 (25), 271 (100), 198 (40), 194 (55).
2,4-Diamino-6-(4-chlorophenyl)pyrimidine-5-carbonitrile
(5k). mp 259°C (Lit. mp 265–266°C) [14]. IR (potassium
bromide): 3443 (NH), 3387 (NH), 3265 (NH), 3212
4-Amino-6-(4-chlorophenyl)-2-methylthiopyrimidine-5-
carbonitrile (5g). mp 221°C (Lit. mp 225) [32]. IR
(potassium bromide): 3378 (NH), 3312 (NH), 3132
(Aromatic CH), 3099, 2911 (Aliphatic CH), 2311 (CN),
1
(NH), 3177, 3088, 2273 (CN), 1597 (C=N). H NMR
(400 MHz, DMSO-d6): δ 6.86 (s, 2H, NH), 7.61 (d,
J = 8.8 Hz, 2H, Aromatic CH), 7.83 (s, 2H, NH), 8.06 (d,
J = 8.8 Hz, 2H, Aromatic CH) ppm. 13C NMR (100 MHz,
DMSO-d6): δ 77.36 (pyrimidine carbon bearing CN),
117.08 (CN), 127.93, 136.42, 139.46, 140.55, 163.69
(pyrimidine ring C), 165.73 (pyrimidine ring C), 170.34
(pyrimidine ring C) ppm.
1622 (C=N) cmÀ1 1H NMR (400 MHz, DMSO-d6): δ
.
2.52 (s, 3H, Aliphatic CH3), 7.09 (s, 2H, NH2), 7.69 (d,
J = 7.9 Hz, 2H, Aromatic CH), 8.04 (d, J = 7.9Hz, 2H,
Aromatic CH) ppm. 13C NMR (100 MHz, DMSO-d6): δ
13.47 (Aliphatic CH3), 81.39 (pyrimidine carbon bearing
CN), 116.58 (CN), 118.32, 129.33, 130.22, 141.88,
163.38 (pyrimidine ring C), 166.29 (pyrimidine ring C),
173.61 (pyrimidine ring C) ppm.
2,4-Diamino-6-(4-nitrophenyl)pyrimidine-5-carbonitrile
(5l). mp 261°C. IR (potassium bromide): 3497 (NH),
3423 (NH), 3387 (NH), 3319 (NH), 3277 (Aromatic
CH), 3176 (Aromatic CH), 3062 (Aromatic CH), 2293
[(4-Amino-5-cyano-6-(4-chlorophenyl)-2-pyrimidinyl)amino]acetic
acid (5h). mp 142°C. IR (potassium bromide): 3486 (NH),
3393 (NH), 3297, 3110, 2963 (CH), 2292 (CN), 1608
(CN), 1603 (C=N) cmÀ1
.
1H NMR (400 MHz,
1
(C=N) cmÀ1. H NMR (400MHz, DMSO-d6): δ 3.31 (s,
DMSO-d6): δ 7.17 (s, 2H, NH), 8.07 (d, J=9.6Hz, 2H,
Aromatic CH), 8.31 (s, 2H, NH), 8.67 (d, J=9.6Hz, 2H,
Aromatic CH) ppm. 13C NMR (100 MHz, DMSO-d6): δ
74.67 (pyrimidine carbon bearing CN), 117.22 (CN),
121.18, 135.57, 138.21, 141.33, 163.48 (pyrimidine ring
C), 165.13 (pyrimidine ring C), 171.88 (pyrimidine ring C)
ppm. MS (m/z): 256 (20), 200 (60), 186 (100), 69 (70).
Anal. Calcd for C11H8N6O2: C, 51.56; H, 3.15; N, 32.80.
Found: C, 51.23; H, 3.44; N, 32.51.
2H, CH2), 6.95 (s, 2H), 7.73 (d, J= 8.8 Hz, 2H, Aromatic
CH), 7.96 (d, J = 8.8 Hz, 2H, Aromatic CH), 8.56 (s, 1H),
11.76 (s, 1H, COOH). 13C NMR (100 MHz, DMSO-d6): δ
39.17 (Aliphatic CH2), 82.48 (pyrimidine carbon bearing
CN), 115.69 (CN), 129.08, 135.77, 138.62, 141.21,
163.93 (pyrimidine ring C), 164.22 (pyrimidine ring C),
166.08 (pyrimidine ring C), 169.39 (COOH) ppm. MS
(m/z): 303 (9), 244 (100), 175 (33), 128 (45). Anal. Calcd
for C13H10ClN5O2: C, 51.41; H, 3.32; N, 23.06. Found:
C, 51.09; H, 3.58; N, 23.33.
Acknowledgments. The corresponding author kindly
acknowledges Dr. Khosrow Jadidi from Shahid Beheshti
University, G. C. for sincere guidance, and the University of
Zabol Research Board for partial financial support of this study.
[(4-Amino-5-cyano-6-(4-nitrophenyl)-2-pyrimidinyl)amino]
acetic acid (5i). mp 212°C. IR (KBr): 3491, 3401, 3309,
3205, 2979, 2303, 1616 cmÀ1 1H NMR (400MHz,
.
DMSO-d6): δ 3.42 (s, 2H, SCH3), 7.03 (s, 2H, NH), 8.22
(d, J= 9.6 Hz, 2H, Aromatic CH), 8.47 (d, J = 9.6 Hz, 2H,
Aromatic CH), 8.79 (s, 1H, NH), 12.07 (s, 1H, COOH).
13C NMR (100 MHz, DMSO-d6): δ 43.11 (SCH3), 79.37
(pyrimidine carbon bearing CN), 116.92 (CN), 122.31,
138.28, 141.79, 143.57, 165.17 (pyrimidine ring C),
165.79 (pyrimidine ring C), 168.13 (pyrimidine ring C),
169.72 (COOH) ppm. MS (m/z): 314 (10), 255 (100), 187
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