Tailored-design Synthesis of Sulfapyrimidine Derivatives

Article abstract of DOI:10.1002/jhet.3439

In this paper, we report an efficient and convenient approach for the synthesis of tailored-design target sulfapyrimidine derivatives expected to show remarkable antimicrobial activities. The approach is based on reacting arylsulfonyl guanidine with α,β-unsaturated carbonyl compounds to afford N-(4,6-diarylpyrimidin-2-yl)arylsulfonamide or with ylidene derivatives to afford N-(6-aryl-5-cyanopyrimidin-2-yl)arylsulfonamide, N-(4-amino-5-cyano-6-(methylthio)-pyrimidin-2-yl)-arylsulfonamide, and N-(5-cyanopyrimidin-2-yl)arylsulfonamide compounds through Michael addition reaction. The structure of the newly synthesized compounds was confirmed from spectral data and elemental analysis.

Full text of DOI:10.1002/jhet.3439

Month 2018
Tailored-design Synthesis of Sulfapyrimidine Derivatives
*
Rasha A. Azzam
Chemistry Department, Faculty of Science, Helwan University, Cairo 11795, Egypt
*E-mail: rashaazzam8@gmail.com
Received September 14, 2018
DOI 10.1002/jhet.3439
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
In this paper, we report an efficient and convenient approach for the synthesis of tailored-design target
sulfapyrimidine derivatives expected to show remarkable antimicrobial activities. The approach is based
on reacting arylsulfonyl guanidine with α,β-unsaturated carbonyl compounds to afford N-(4,6-
diarylpyrimidin-2-yl)arylsulfonamide or with ylidene derivatives to afford N-(6-aryl-5-cyanopyrimidin-2-
yl)arylsulfonamide, N-(4-amino-5-cyano-6-(methylthio)-pyrimidin-2-yl)-arylsulfonamide, and N-(5-
cyanopyrimidin-2-yl)arylsulfonamide compounds through Michael addition reaction. The structure of the
newly synthesized compounds was confirmed from spectral data and elemental analysis.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
Sulfonamide-substituted heterocyclic
exhibit remarkable activities against both Gram-positive
and Gram-negative bacteria [1]. Undoubtedly, the
efficacy of the sulfonamide groups of this type of
compounds, the ease of their oral administration, and its
moderately low toxicity distinguish this class of
compounds as one of the important antibacterial
such as Escherichia coli enteritis in veterinary medicine
[11], cerebrospinal meningitis, and allergic reaction to
penicillins [12]. Sulfapyrimidine drugs with dimethyl
groups such as sulfisomidine (D) (Figure 1) are used for
treatment of urinary infections because of their
remarkable solubility in urine and absence of kidney
damage [13]. It is commonly used as a sulfa therapy in
human serum hemolytic complement system [14].
Sulfadoxine (E) (Figure 1) is used in combination with
pyrimethamine for treatment of malaria [15].
compounds
chemotherapeutic
agents.
Sulfapyrimidine
[2,3],
sulfapyridine [4], and sulfathiazole [5] were some of the
early representatives of this group of sulfonamides. The
unique antimicrobial properties of sulfapyrimidine
inspired the further synthesis of a large number of
pyrimidine derivatives of the sulfanilamide compounds,
many of which with surprising activity and low toxicity
characteristics [6]. Similar to other sulfonamides,
sulfapyrimidine derivatives were identified as an inhibitor
to dihydropteroate synthase enzyme, which some bacteria
use to synthesize folic acid [7,8]. Sulfadiazine, a
sulfapyrimidine drug (A) (Figure 1), is commonly used to
treat urinary tract infections and burns. Combination of
sulfadiazine and pyrimethamine can be used to treat
toxoplasmosis, which is caused by Toxoplasma gondii
[9,10]. Both sulfamerazine (B) and sulfadimidine (C)
(Figure 1) are used in some acute bacterial infections
Sulfadimethoxine (F) (Figure 1),
a
sulfonamide
antimicrobial agent, is regularly employed in veterinary
medicine because of its enduring half-life of
approximately 40 h. It is commonly used to treat several
bacterial infections such as respiratory, soft tissue, and
urinary tract infections [16]. It can also be administered
as a standalone or in combination with some other
ormetoprim to widen the spectrum of the target range
[17] as well as treating coccidian parasites infections [18].
Different approaches have been reported in the synthesis
of sulfapyrimidine derivatives. The condensation reaction
of B-diketones or B-ketocarboxylic esters with
arylsulfonyl guanidine is a well-known reaction for the
preparation of sulfapyrimidine derivatives [19–21].
Another approach for the synthesis of sulfapyrimidine
derivatives is by reacting different 2-aminopyrimidines to
© 2018 Wiley Periodicals, Inc.

R. A. Azzam
Vol 000
Figure 1. Structure of sulfapyrimidine drugs.
arylsulfonyl chloride [22]. Several derivatives of
RESULTS AND DISCUSSION
diphenysulfapyrimidine acetates have also been
synthesized by reacting chalcones with sulfaguanidine
acetate [23,24]. Our research group has also been
Arylsulfonyl guanidine 3a,b was first synthesized by
reacting arylsulfonyl chloride with excess guanidine
hydrochloride in the presence of potassium hydroxide in
1,4-dioxane at room temperature. To determine the
appropriate reaction conditions for the synthesis of
involved in synthesizing
a variety of substituted
heterocyclic derivatives with good biological activities
[25–30]. In this paper, we report on a new approach for
the synthesis of tailored-design target sulfapyrimidine
derivatives expected to show remarkable antimicrobial
activities. The approach is based on reacting arylsulfonyl
guanidine with α,β-unsaturated carbonyl compounds or
with ylidene derivatives of both malononitrile and ethyl
cyanoacetate.
N-(4,6-diarylpyrimidin-2-yl)arylsulfonamide
(Scheme 1), the reaction of 3-(4-chlorophenyl)-1-
phenylprop-2-en-1-one (1.2 mmol) 4a and
5a–h
benzenesulfonyl guanidine (1 mmol) 3a was chosen as a
model experiment. Different reaction conditions were
evaluated, and the results were all summarized in
Scheme 1. Synthesis of N-(4,6-diarylpyrimidin-2-yl)arylsulfonamide.
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Synthesis of Sulfapyrimidine Derivatives
Scheme
arylsulfonamide.
2. Synthesis
of
N-(6-aryl-5-cyanopyrimidin-2-yl)
Table 1. A preliminary screening of catalysts and solvents
for the reaction showed that the use of potassium
hydroxide and a nonpolar solvent such as 1,4-dioxane
under reflux are crucial for this particular cyclic
condensation reaction (Table 1, entry 6). Having
established the optimal conditions for the condensation
reaction, various α,β-unsaturated carbonyl compounds
4a–d (Scheme 1) were allowed to react with
benzenesulfonyl 3a and tosyl guanidine 3b separately to
form N-(4,6-diarylpyrimidin-2-yl)arylsulfonamide 5a–d
and 5e–h, respectively. The chemical structures of 5a–h
were assigned on the basis of its analytical and spectral
1
data. H NMR spectrum of compound 5f, for example,
exhibited two singlet signals at δ 2.29 and 2.37 ppm
assignable to the protons of two methyl groups as well as
four doublet signals at δ 7.16, 7.25, 7.75, and 7.95 ppm
for eight protons residing on the two 4-substituted
benzene rings. A singlet signal at δ 7.47 ppm was
assigned to the proton at C-5 of the pyrimidine ring.
We also attempted to react arylsulfonyl guanidine 3a,b
with arylidene-substituted malononitrile derivatives, 6a–
d, and arylidene-substituted ethyl cyanoacetate
derivatives, 10a–d, through Michael addition reaction
(Scheme 2). Different evaluated reaction conditions are
summarized in Table 2. The optimal condition for the
reaction of benzenesulfonyl guanidine 3a with 4-
chlorobenzylidene malononitrile 6b incorporated the use
of sodium ethoxide in ethanol under reflux (Table 2,
entry 4). Applying the same condition to the reaction of
benzenesulfonyl guanidine 3a with 4-chlorobenzylidene
ethyl cyanoacetate 10b to afford 5-cyano-6-oxo-1,6-
dihydropyrimidin-2-yl-benzenesulfonamide 13b resulted
reaction, we have extended the experimentations to
include various substituted benzylidene of both
malononitrile 6a–d and ethyl cyanoacetate 10a–d with
both benzensulfonyl 3a and tosyl guanidine 3b to yield
compounds 9a–f and 13a–h, respectively (Scheme 2).
The structures of these products were deduced from their
in
a lower yield. However, employing potassium
hydroxide in 1,4-dioxane (Table 2, entry 3) resulted in a
higher yield. To explore the scope and limitations of this
Table 1
Optimization of reaction condition of arylsulfonyl guanidine with α,β-unsaturated carbonyl compounds.
Entry
Catalyst
Solvent
Temp. (°C)
Time
Yield
1
2
3
4
5
6
Piperidine
K2CO3
NaOEt
NaOEt
KOH
Ethanol
Ethanol
Ethanol
Ethanol
1,4-Dioxane
1,4-Dioxane
Reflux
Reflux
RT
Reflux
RT
8
8
24
6
24
3
>10
>10
—
56
25
KOH
Reflux
88
RT, room temperature.
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Table 2
Optimization of reaction condition of arylsulfonyl guanidine with arylidene derivatives of malononitrile and ethyl cyanoacetate.
9a
13b
Entry
Catalyst
Solvent
Temp. (°C)
Time
Yield
Time
Yield
1
2
3
4
Piperidine
K2CO3
KOH
Ethanol
Ethanol
1,4-Dioxane
Ethanol
Reflux
Reflux
Reflux
Reflux
8
8
5
3
<20
30
50
16
10
3
<15
27
88
NaOEt
60
3
71
Scheme 3. Synthesis of N-(5-cyano-6-(methylthio)pyrimidin-2-yl)
arylsulfonamide.
respective IR, 1H NMR, 13C NMR, and elemental analysis.
The reaction of arylsulfonyl guanidine 3a,b with arylidene
derivatives of both malononitrile and ethyl cyanoacetate is
assumed to take place via the intermediacy of a non-
isolable Michael adducts 7 and 11, respectively, followed
by an intramolecular cyclization to afford the
aforementioned compounds. In the case of arylidene
malononitrile, this has occurred through the addition of
the amino group to one of the cyano groups of the
malononitrile, whereas in the case of arylidene ethyl
cyanoacetate, the cyclization has occurred through the
elimination of an ethanol molecule. The sulfapyrimidine
compounds 9a–f and 13a–h were then resulted from the
oxidation of non-isolable intermediates
respectively.
8 and 12,
In order to extend the scope of the reaction of
arylsulfonyl guanidine with ylidene compounds, we
explored the reaction between arylsulfonyl guanidine 3a,
b and ketene dithioacetal derivatives 16a,b. The reaction
of 2-cyano-3,3-bis(methylthio)acrylonitrile 16a, prepared
elsewhere [31], with arylsulfonyl guanidine in the
presence of sodium ethoxide in ethanol under reflux
gave N-(4-amino-5-cyano-6-(methylthio)pyrimidin-2-yl)
arylsulfonamide 17a,b (Scheme 3). Moreover, the
reaction of ethyl 2-cyano-3,3-bis(methylthio)acrylate 16b
with arylsulfonyl guanidine 3a,b afforded the
case of compound 18b, the IR spectra displayed
absorption bands at υ 3434, 2206, and 1644 cmÀ1 for
NH, CN, and C═O groups, respectively. The H NMR
1
spectrum of compound 17a exhibited one singlet signals
at δ 2.12 ppm due to SCH3 protons in addition to one
broad band at δ 6.57 ppm for NH2 protons while for
compound 18b, it showed two singlet signals at δ 2.16
and 2.33 ppm for SCH3 and CH3 protons, respectively.
The reaction proceeded via Michael addition of one of
the amino groups in the arylsulfonyl guanidine to the
C═C of the ketene dithioacetal compounds followed by
the elimination of CH3SH molecule and the subsequent
intramolecular cyclization.
corresponding
N-(5-cyano-4-(methylthio)-6-oxo-1,6-
dihydropyrimidin-2-yl)benzenesulfonamide 18a,b in
good yield using potassium hydroxide in 1,4-dioxane
(Scheme 3). The spectral and elemental analyses of
compounds 17a,b and 18a,b were consistent with their
structures. For example, IR spectrum of compound 17a
displayed absorption bands at υ 33430 and 3348 cmÀ1
for NH and NH2 groups, respectively, as well as a band
at υ 2197 cmÀ1 corresponding to the CN group. In the
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Synthesis of Sulfapyrimidine Derivatives
The reaction of arylsulfonyl guanidine with
ethoxymethylene compounds to produce new derivatives
of sulfapyrimidine was also investigated. Cyclization of
elimination of ethanol, intramolecular cyclization, and an
isomerization of the resultant molecule to afford the N-(5-
cyanopyrimidin-2-yl)arylsulfonamide
(Scheme 5).
products
compounds
arylsulfonyl
guanidine
3a,b
with
ethoxymethylenemalononitrile 19 in the presence of
sodium ethoxide and ethanol under reflux afforded the
corresponding products 20a,b (Scheme 4). Additionally,
the reaction of ethyl (ethoxymethylene)cyanoacetate 21
with arylsulfonyl guanidine 3a,b using KOH in 1,4-
dioxane under reflux resulted in the pyrimidine
derivatives 22a,b in good yield. All products were
characterized by spectral data and elemental analysis. The
IR spectrum of compound 22a was characterized by the
presence of absorption bands at υ 3414, 2220, 1669 cmÀ1
corresponding to NH, CN, and C═O groups, respectively.
CONCLUSION
In conclusion, we have described an efficient approach
for the preparation of 30 new derivatives of
sulfapyrimidines by reacting arylsulfonyl guanidine with
α,β-unsaturated carbonyl compounds or with ylidene
derivatives such as arylidene-substituted malononitrile,
arylidene-substituted ethyl cyanoacetate, 2-cyano-3,3-
bis(methylthio)acrylonitrile,
ethyl
2-cyano-3,3-
1
Moreover, its H NMR spectrum revealed the presence of
bis(methylthio)acrylate,
ethoxymethylenemalononitrile,
a singlet signal at δ 7.95 ppm for the CH proton of
pyrimidine ring and another singlet signal at δ 11.20 ppm
for the NH proton of the sulfonamide group. To
rationalize the aforementioned results, a possible reaction
mechanism is proposed, in which the ethoxymethylene
compounds underwent a Michael addition reaction with
the arylsulfonyl guanidines that is followed by the
and ethyl (ethoxymethylene)cyanoacetate through
Michael addition reaction. The structure of newly
synthesized compounds was confirmed spectroscopically
and by elemental analysis.
EXPERIMENTAL
All melting points were uncorrected on a Gallenkamp
melting point apparatus. IR spectra (KBr discs) were
recorded on an FTIR plus 460 or Pye Unicam SP-1000
Scheme 4. Synthesis of N-(5-cyanopyrimidin-2-yl)arylsulfonamide.
1
spectrophotometer. The H and 13C NMR spectra were
recorded on a Bruker Avance (III)-400 spectrometer (400
and 100 MHz, respectively) in DMSO-d6 using Si (CH3)4
as an internal standard at the Ain Shams University,
Cairo, Egypt. Elemental analyses were obtained from the
Microanalytical Data Center at Cairo University, Egypt,
and were performed on Vario El III Elemental CHNS ana-
lyzer. Progress of the reactions and the purity of com-
pounds were monitored and checked by thin-layer
chromatography (TLC) aluminum sheets coated with silica
gel F254 (Merck), using a mixture of petroleum ether and
ethyl acetates as an eluent.
General procedure for the synthesis of 5a–h. A solution
of arylsulfonyl guanidine 3a,b (0.01 mol) and chalcone
4a–d (0.012 mmol) in dry dioxane (20 mL) containing
potassium hydroxide (0.015 mol) was heated under reflux
for 2–4 h as judged by TLC. The reaction mixture was
cooled and poured into ice acidified with HCl. The solid
product formed was filtered off, washed by ethyl acetate,
and recrystallized from ethanol to give the respective
Scheme 5. Reaction mechanism for the synthesis of N-(5-
cyanopyrimidin-2-yl)arylsulfonamide.
products 5a–h.
N-(4-(4-Chlorophenyl)-6-phenylpyrimidin-2-yl)
benzenesulfonamide 5a.
Beige crystals; yield 88%; mp
262–263°C; IR (KBr, cmÀ1): υ 3433 (NH), 3061
(ArCH), 1562 (C═C), 1353, 1132 (SO2). 1H NMR
(400 MHz, DMSO-d6): δ 7.32–8.06 (m, 15H, 2C6H5,
C6H4 & CH═ pyrimidine). 13C NMR (100 MHz,
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DMSO-d6): δ 101.2 (CH═ pyrimidine), 125.9, 127.1,
127.4, 128.0, 128.9, 129.1, 129.4, 135.0, 137.6, 138.6,
148.1, 148.4, 162.9, 164.5, 165.4 (Ar–C). Anal. Calcd.
for C22H16ClN3O2S (421.90): C% 62.63; H% 3.82; N%
CH3), 7.16 (d, J = 8 Hz, 2H, C6H4), 7.25 (d, J = 8 Hz,
2H, C6H4), 7.43–7.44 (m, 3H, C6H5), 7.47 (s, 1H, CH═
pyrimidine), 7.75 (d, J = 8 Hz, 2H, C6H4), 7.95 (d,
J = 8 Hz, 2H, C6H4), 8.01–8.04 (m, 2H, C6H5). Anal.
Calcd. for C24H21N3O2S (415.51): C% 69.37; H% 5.09;
9.96. Found: C% 62.93; H% 3.91; N% 9.72.
N-(4-Phenyl-6-p-tolylpyrimidin-2-yl)benzenesulfonamide
5b. White crystals; yield 86%; mp 306–307°C; IR (KBr,
N% 10.11. Found: C% 69.67; H% 5.30; N% 9.88.
N-(4-(4-Methoxyphenyl)-6-phenylpyrimidin-2-yl)-4-
methylbenzenesulfonamide 5g. White crystals; yield 86%;
cmÀ1): υ 3435 (NH), 3056 (ArCH), 1563 (C═C), 1356,
1
1136 (SO2). H NMR (400 MHz, DMSO-d6): δ 2.36 (s,
mp 275–276°C; IR (KBr, cmÀ1): υ 3436 (NH), 1561
(C═C), 1356, 1143 (SO2). 1H NMR (400 MHz,
DMSO-d6): δ 2.29 (s, 3H, CH3), 3.83 (s, 3H, OCH3),
7.00 (d, J = 8 Hz, 2H, C6H4), 7.17 (d, J = 8 Hz, 2H,
C6H4), 7.43–7.44 (m, 4H, C6H5 & CH═ pyrimidine),
7.75 (d, J = 8 Hz, 2H, C6H4), 8.02-8.53 (m, 4H, C6H4
& C6H5). Anal. Calcd. for C24H21N3O3S (431.51): C%
66.80; H% 4.91; N% 9.74. Found: C% 67.00; H% 4.80;
3H, CH3), 7.23–8.00 (m, 15H, 2C6H5, C6H4 & CH═
pyrimidine). Anal. Calcd. for C23H19N3O2S (401.48): C%
68.81; H% 4.77; N% 10.47. Found: C% 68.98; H% 5.06;
N% 10.12.
N-(4-(4-Methoxyphenyl)-6-phenylpyrimidin-2-yl)
benzenesulfonamide 5c.
Beige crystals; yield 90%; mp
295–296°C; IR (KBr, cmÀ1): υ 3436 (NH), 3059
(ArCH), 1564 (C═C), 1356, 1135 (SO2). 1H NMR
(400 MHz, DMSO-d6): δ 3.82 (s, 3H, OCH3), 6.98 (d,
J = 8 Hz, 2H, C6H4), 7.31–7.45 (m, 7H, 2C6H5 & CH═
pyrimidine), 7.84–7.87 (m, 2H, C6H5), 7.99–8.01 (m, 4H,
C6H5 & C6H4). 13C NMR (100 MHz, DMSO-d6): δ 55.9
(OCH3), 100.5 (CH═ pyrimidine), 114.2, 127.1, 127.3,
127.9, 128.7, 128.8, 129.3, 130.1, 139.2, 148.6, 161.1,
164.1 (Ar–C). Anal. Calcd. for C23H19N3O3S (417.48):
C% 66.17; H% 4.59; N% 10.07. Found: C% 66.50; H%
4.42; N% 10.22.
N% 9.92.
N-(4,6-Bis(4-methoxyphenyl)pyrimidin-2-yl)-4-
methylbenzenesulfonamide 5h. White crystals; yield 89%;
mp 302–303°C; IR (KBr, cmÀ1): υ 3438 (NH), 1593
(C═C), 1362, 1168 (SO2). 1H NMR (400 MHz,
DMSO-d6): δ 2.28 (s, 3H, CH3), 3.83 (s, 6H, OCH3),
6.98 (d, J = 8 Hz, 4H, 2C6H4), 7.15 (d, J = 8 Hz, 2H,
C6H4), 7.38 (s, 1H, CH═ pyrimidine), 7.73 (d, J = 8 Hz,
2H, C6H4), 8.00 (d, J = 8 Hz, 4H, 2C6H4). Anal. Calcd.
for C25H23N3O4S (461.53): C% 65.06; H% 5.02; N%
9.10. Found: C% 65.33; H% 5.25; N% 9.20.
N-(4,6-Bis(4-methoxyphenyl)pyrimidin-2-yl)
benzenesulfonamide 5d.
White crystals; yield 86%; mp
General procedure for the synthesis of 9a–f.
To a
236–237°C; IR (KBr, cmÀ1): υ 3436 (NH), 3058
(ArCH), 1586 (C═C), 1363, 1164 (SO2). 1H NMR
(400 MHz, DMSO-d6): δ 3.85 (s, 6H, 2OCH3), 7.08–7.10
(m, 2H, C6H4), 7.54–7.62 (m, 6H, 2C6H4, C6H5 & CH═
pyrimidine), 8.07–8.19 (m, 7H, 2C6H4 & C6H5), 11.81
(s, 1H, NHSO2). Anal. Calcd. for C24H21N3O4S (447.51):
C% 64.41; H% 4.73; N% 9.39. Found: C% 66.53; H%
solution of sodium ethoxide in ethanol, prepared from
0.013 mol of sodium added to 10 mL of absolute ethanol,
and arylsulfonyl guanidine 3a,b (0.01 mol), arylidene
malononitrile 6a–d (0.012 mol) was added. After heating
the mixture under reflux for 2–4 h as judged by TLC, the
reaction mixture was cooled and poured into ice acidified
with HCl. The solid product was separated by filtration,
4.64; N% 10.21.
N-(4-(4-Chlorophenyl)-6-phenylpyrimidin-2-yl)-4-
methylbenzenesulfonamide 5e. White crystals; yield 83%;
washed ethanol, and dried under vacuum.
N-(4-Amino-6-(4-chlorophenyl)-5-cyanopyrimidin-2-yl)
benzenesulfonamide 9a.
Beige crystals; yield 60%; mp
>350°C; IR (KBr, cmÀ1): υ 3442, 3364 (NH, NH2),
3100 (ArCH), 2209 (CN), 1611 (C═C), 1328, 1145
mp 292–293°C; IR (KBr, cmÀ1): υ 3435 (NH), 2931
(ArCH), 1563 (C═C), 1357, 1135 (SO2). 1H NMR
(400 MHz, DMSO-d6): δ 2.29 (s, 3H, CH3), 7.16 (d,
J = 8 Hz, 2H, C6H4), 7.43–7.53 (m, 6H, 2C6H4, C6H5 &
CH═ pyrimidine), 7.62–7.65 (m, 2H, 2C6H4 & C6H5),
1
(SO2). H NMR (400 MHz, DMSO-d6): δ 7.34–8.06 (m,
11H, C6H5, C6H4 & NH2), 12.05 (s, 1H, NHSO2). 13C
NMR (100 MHz, DMSO-d6): δ 115.3 (CN), 90.9, 94.5,
128.0, 128.3, 130.2, 130.4, 131.3, 133.9, 135.8, 144.3,
155.1, 160.8 (Ar–C). Anal. Calcd. for C17H12ClN5O2S
(385.83): C% 52.92; H% 3.13; N% 18.15. Found: C%
8.02–8.05 (m, 4H, 2C6H4
&
C6H5). 13C NMR
(100 MHz, DMSO-d6): δ 21.3 (CH3), 101.2 (CH═
pyrimidine), 127.2, 127.4, 128.4, 128.7, 129.2, 130.3,
135.0, 137.6, 138.6, 139.0, 141.4, 145.1, 158.8, 164.5,
165.3 (Ar–C). Anal. Calcd. for C23H18ClN3O2S (435.93):
C% 63.37; H% 4.16; N% 9.64. Found: C% 63.57; H%
53.30; H% 3.23; N% 17.85.
N-(4-Amino-5-cyano-6-(4-methoxyphenyl)pyrimidin-2-yl)
benzenesulfonamide 9b.
White crystals; yield 55%; mp
278–279°C; IR (KBr, cmÀ1): υ 3445, 3357 (NH, NH2),
3149 (ArCH), 2210 (CN), 1560 (C═C), 1318, 1158
4.31; N% 9.52.
4-Methyl-N-(4-phenyl-6-p-tolylpyrimidin-2-yl)
benzenesulfonamide 5f.
1
(SO2). H NMR (400 MHz, DMSO-d6): δ 3.83 (s, 3H,
White crystals; yield 80%; mp
289–290°C; IR (KBr, cmÀ1): υ 3433 (NH), 2918
(ArCH), 1567 (C═C), 1356, 1130 (SO2). 1H NMR
(400 MHz, DMSO-d6): δ 2.29 (s, 3H, CH3), 2.37 (s, 3H,
OCH3), 7.06 (d, J = 8 Hz, 2H, C6H4), 7.49–7.70 (m, 7H,
C6H5 & NH2), 8.04 (d, J = 8 Hz, 2H, C6H4), 11.81 (s,
1H, NHSO2). Anal. Calcd. for C18H15N5O3S (381.41):
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C% 56.68; H% 3.96; N% 18.36. Found: C% 56.95; H%
filtered off, washed by ethyl acetate, and recrystallized
4.10; N% 18.19.
from ethanol to give the respective products 13a–h.
N-(5-Cyano-6-oxo-4-phenyl-1,6-dihydropyrimidin-2-yl)
benzenesulfonamide 13a. Off white crystals; yield 85%;
N-(4-Amino-5-cyano-6-phenylpyrimidin-2-yl)-4-
methylbenzenesulfonamide 9c. White crystals; yield 75%;
mp 248–249°C; IR (KBr, cmÀ1): υ 3400, 3340 (NH,
NH2), 3246 (ArCH), 2215 (CN), 1556 (C═C), 1327,
mp >350°C; IR (KBr, cmÀ1): υ 3431 (NH), 3053 (ArCH),
2210 (CN), 1650 (C═O), 1563 (C═C), 1350, 1142 (SO2).
1H NMR (400 MHz, DMSO-d6): δ 3.57 (s, 1H, NH),
7.41–7.79 (m, 10H, 2C6H5), 11.32 (s, 1H, NHSO2). Anal.
Calcd. for C17H12N4O3S (352.37): C% 57.95; H% 3.43;
1
1159 (SO2). H NMR (400 MHz, DMSO-d6): δ 2.38 (s,
3H, CH3), 7.36 (d, J = 8 Hz, 2H, C6H4), 7.51–7.59 (m,
3H, C6H5), 7.69 (d, J = 8 Hz, 2H, C6H5), 7.95 (d,
J = 8 Hz, 2H, C6H4), 11.74 (s, 1H, NHSO2). 13C NMR
(100 MHz, DMSO-d6): δ 21.5 (CH3), 116.6 (CN), 81.4,
128.8, 128.9, 129.5, 131.5, 137.8, 143.8, 157.5, 164.8
(Ar–C). Anal. Calcd. for C18H15N5O2S (365.41): C%
59.16; H% 4.14; N% 19.17. Found: C% 59.39; H% 4.02;
N% 15.90. Found: C% 58.30; H% 3.58; N% 16.11.
N-(4-(4-Chlorophenyl)-5-cyano-6-oxo-1,6-dihydropyrimidin-
2-yl)benzenesulfonamide 13b. Beige crystals; yield 88%;
mp >350°C; IR (KBr, cmÀ1): υ 3438 (NH), 3057
(ArCH), 2207 (CN), 1650 (C═O), 1564 (C═C), 1348,
1
1143 (SO2). H NMR (400 MHz, DMSO-d6): δ 3.57 (s,
N% 19.32.
1H, NH), 7.42–7.51 (m, 7H, C6H5 & C6H4), 7.76–7.78
(m, 2H, C6H5), 11.34 (s, 1H, NHSO2). 13C NMR
(100 MHz, DMSO-d6): δ 118.7 (CN), 83.9, 127.3, 128.3,
128.4, 130.9, 130.7, 135.5, 136.5, 145.7, (Ar–C), 168.2
(CO). Anal. Calcd. for C17H11ClN4O3S (386.81): C%
52.79; H% 2.87; N% 14.48. Found: C% 53.08; H% 2.70;
N-(4-Amino-6-(4-chlorophenyl)-5-cyanopyrimidin-2-yl)-4-
methylbenzenesulfonamide 9d. White crystals; yield 78%;
mp 293–294°C; IR (KBr, cmÀ1): υ 3408, 3346 (NH,
NH2), 3161 (ArCH), 2215 (CN), 1554 (C═C), 1333, 1160
1
(SO2). H NMR (400 MHz, DMSO-d6): δ 2.35 (s, 3H,
CH3), 7.36 (d, J = 11 Hz, 2H, C6H4), 7.62 (d, J = 11 Hz,
2H, C6H4), 7.72 (d, J = 11 Hz, 2H, C6H4), 7.93 (d,
J = 11 Hz, 2H, C6H4), 11.75 (s, 1H, NHSO2). Anal.
Calcd. for C18H14ClN5O2S (399.85): C% 54.07; H% 3.53;
N% 17.51. Found: C% 54.45; H% 3.25; N% 17.72.
N-(4-Amino-5-cyano-6-(4-methoxyphenyl)pyrimidin-2-yl)-4-
N% 14.73.
N-(5-Cyano-4-(4-methoxyphenyl)-6-oxo-1,6-
dihydropyrimidin-2-yl)benzenesulfonamide
13c.
Beige
crystals; yield 87%; mp >350°C; IR (KBr, cmÀ1): υ
3432 (NH), 3053 (ArCH), 2212 (CN), 1645 (C═O), 1554
(C═C), 1346, 1142 (SO2). 1H NMR (400 MHz,
DMSO-d6): δ 3.57 (s, 1H, NH), 3.82 (s, 3H, OCH3), 6.96
(d, J = 8 Hz, 2H, C6H4), 7.42–7.47 (m, 3H, C6H5), 7.52
(d, J = 8 Hz, 2H, C6H4), 7.78–7.80 (m, 2H, C6H5), 11.19
(s, 1H, NHSO2). Anal. Calcd. for C18H14N4O4S (382.39):
C% 56.54; H% 3.69; N% 14.65. Found: C% 56.90; H%
methylbenzenesulfonamide 9e.
Off white crystals; yield
80%; mp 290–291°C; IR (KBr, cmÀ1): υ 3418, 3350
(NH, NH2), 3149 (ArCH), 2214 (CN), 1567 (C═C),
1
1321, 1159 (SO2). H NMR (400 MHz, DMSO-d6): δ
2.33 (s, 3H, CH3), 7.08 (d, J = 8 Hz, 2H, C6H4), 7.35 (d,
J = 8 Hz, 2H, C6H4), 7.73 (d, J = 8 Hz, 2H, C6H4), 7.94
(d, J = 8 Hz, 2H, C6H4), 11.67 (s, 1H, NHSO2). 13C
NMR (100 MHz, DMSO-d6): δ 21.4 (CH3), 55.9
(OCH3), 117.0 (CN), 66.8, 80.2, 128.4, 129.5, 130.7,
138.1, 143.6, 162.0, 165.0 (Ar–C). Anal. Calcd. for
C19H17N5O3S (395.43): C% 57.71; H% 4.33; N% 17.71.
3.54; N% 14.94.
N-(5-Cyano-6-oxo-4-p-tolyl-1,6-dihydropyrimidin-2-yl)
benzenesulfonamide 13d. Beige crystals; yield 85%; mp
>350°C; IR (KBr, cmÀ1): υ 3431 (NH), 3052 (ArCH),
2206 (CN), 1651 (C═O), 1562 (C═C), 1347, 1140 (SO2).
1H NMR (400 MHz, DMSO-d6): δ 2.35 (s, 3H, CH3),
3.57 (s, 1H, NH), 7.21 (d, J = 8 Hz, 2H, C6H4), 7.39–
7.46 (m, 5H, C6H5 & C6H4), 7.79 (d, J = 8 Hz, 2H,
C6H5). 13C NMR (100 MHz, DMSO-d6): δ 21.3 (CH3),
118.7 (CN), 83.9, 127.5, 128.3, 128.7, 128.8, 130.9,
137.6, 140.7, 142.7, 156.7, 163.7 (Ar–C), 169.7 (CO).
Anal. Calcd. for C18H14N4O3S (366.39): C% 59.01; H%
Found: C% 57.95; H% 4.48; N% 17.92.
N-(4-Amino-5-cyano-6-p-tolylpyrimidin-2-yl)-4-
methylbenzenesulfonamide 9f. White crystals; yield 80%;
mp 289–290°C; IR (KBr, cmÀ1): υ 3417, 3347 (NH,
NH2), 3163 (ArCH), 2214 (CN), 1567 (C═C), 1321,
1
1158 (SO2). H NMR (400 MHz, DMSO-d6): δ 2.37 (s,
3H, CH3), 2.39 (s, 3H, CH3), 7.32–7.37 (m, 4H, 2 C6H4),
7.61 (d, J = 8 Hz, 2H, C6H4), 7.94 (d, J = 8 Hz, 2H,
C6H4), 11.66 (s, 1H, NHSO2). Anal. Calcd. for
C19H17N5O2S (379.44): C% 60.14; H% 4.52; N% 18.46.
Found: C% 60.47; H% 4.37; N% 18.25.
3.85; N% 15.29. Found: C% 59.35; H% 4.05; N% 15.04.
N-(5-Cyano-6-oxo-4-phenyl-1,6-dihydropyrimidin-2-yl)-4-
methylbenzenesulfonamide 13e. White crystals; yield 81%;
mp >350°C; IR (KBr, cmÀ1): υ 3434 (NH), 3051 (ArCH),
2209 (CN), 1651 (C═O), 1564 (C═C), 1349, 1142 (SO2).
1H NMR (400 MHz, DMSO-d6): δ 2.35 (s, 3H, CH3),
3.58 (s, 1H, NH), 7.24 (d, J = 13.6 Hz, 2H, C6H4), 7.42–
7.52 (m, 5H, C6H5), 7.68 (d, J = 11.2 Hz, 2H, C6H4),
11.24 (s, 1H, NHSO2). Anal. Calcd. for C18H14N4O3S
(366.39): C% 59.01; H% 3.85; N% 15.29. Found: C%
59.38; H% 3.98; N% 15.42.
General procedure for the synthesis of 13a–h.
A
solution of arylsulfonyl guanidine 3a,b (0.01 mol) and
arylidene ethyl cyanoacetate 10a–d (0.012 mmol) in dry
dioxane (20 mL) containing potassium hydroxide
(0.015 mol) was heated under reflux for 2–4 h as judged
by TLC. The reaction mixture was cooled and poured
into ice acidified with HCl. The solid product formed was
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

R. A. Azzam
Vol 000
N-(4-(4-Chlorophenyl)-5-cyano-6-oxo-1,6-dihydropyrimidin-
N-(4-Amino-5-cyano-6-(methylthio)pyrimidin-2-yl)-4-
2-yl)-4-methylbenzenesulfonamide 13f.
Beige crystals;
methylbenzenesulfonamide 17b.
Yellow crystals; yield
yield 88%; mp >350°C; IR (KBr, cmÀ1): υ 3436 (NH),
3047 (ArCH), 2206 (CN), 1649 (C═O), 1565 (C═C),
55%; mp 262–263°C; IR (KBr, cmÀ1): υ 3435, 3340
(NH, NH2), 3246 (ArCH), 2207 (CN), 1558 (C═C),
1
1
1348, 1141 (SO2). H NMR (400 MHz, DMSO-d6): δ
1409, 1136 (SO2). H NMR (400 MHz, DMSO-d6): δ
2.34 (s, 3H, CH3), 3.57 (s, 1H, NH), 7.24 (d, J = 8 Hz,
2H, C6H4), 7.50–7.55 (m, 4H, 2C6H4), 7.67 (d, J = 8 Hz,
2H, C6H4). Anal. Calcd. for C18H13ClN4O3S (400.84):
C% 53.94; H% 3.27; N% 13.98. Found: C% 54.24; H%
2.17 (s, 3H, SCH3), 2.30 (s, 3H, CH3), 6.48 (s, 2H,
NH2), 7.22 (d, J = 8 Hz, 2H, C6H4), 7.65 (d, J = 8 Hz,
2H, C6H4). Anal. Calcd. for C13H13N5O2S2 (335.40): C%
46.55; H% 3.91; N% 20.88. Found: C% 46.87; H% 4.18;
N% 20.55.
3.03; N% 14.22.
N-(5-Cyano-4-(4-methoxyphenyl)-6-oxo-1,6-
dihydropyrimidin-2-yl)-4-methylbenzenesulfonamide 13g.
General procedure for the synthesis of 18a,b. A solution
of arylsulfonyl guanidine 3a,b (0.01 mol) and 16b
(0.012 mmol) in dry dioxane (20 mL) containing
potassium hydroxide (0.015 mol) was heated under reflux
for 2–4 h as judged by TLC. The reaction mixture was
cooled and poured into ice acidified with HCl. The solid
product formed was filtered off, washed by ethyl acetate,
and recrystallized from ethanol to give the respective
White crystals; yield 87%; mp >350°C; IR (KBr, cmÀ1):
υ 3432 (NH), 3195 (ArCH), 2212 (CN), 1646 (C═O),
1557 (C═C), 1345, 1140 (SO2). 1H NMR (400 MHz,
DMSO-d6): δ 2.34 (s, 3H, CH3), 3.83 (s, 3H, OCH3),
6.98 (d, J = 8 Hz, 2H, C6H4), 7.24 (d, J = 8 Hz, 2H,
C6H4), 7.57 (d, J = 8 Hz, 2H, C6H4), 7.68 (d, J = 8 Hz,
2H, C6H4), 11.19 (s, 1H, NHSO2). 13C NMR (100 MHz,
DMSO-d6):δ 21.3 (CH3), 55.8 (OCH3), 119.0 (CN), 83.0,
113.7, 127.5, 128.7, 129.8, 130.7, 140.7, 142.7, 156.5,
161.6, 163.9 (Ar–C), 168.9 (CO). Anal. Calcd. for
C19H16N4O4S (396.42): C% 57.57; H% 4.07; N% 14.13.
products 18a,h.
N-(5-Cyano-4-(methylthio)-6-oxo-1,6-dihydropyrimidin-2-yl)
benzenesulfonamide 18a. Pale yellow crystals; yield 80%;
mp >350°C; IR (KBr, cmÀ1): υ 3448 (NH), 3043 (ArCH),
2213 (CN), 1653 (C═O), 1556 (C═C), 1472, 1144 (SO2).
1H NMR (400 MHz, DMSO-d6): δ 2.10 (s, 3H, SCH3),
7.44–7.48 (m, 3H, C6H5), 7.74–7.76 (m, 2H, C6H5),
11.12 (s, 1H, NHSO2). 13C NMR (100 MHz, DMSO-d6):
δ 12.6 (SCH3), 117.1 (CN), 81.5, 126.6, 128.6, 130.9,
145.5, 155.1, 174.3 (Ar–C), 162.8 (C═O). Anal. Calcd.
for C12H10N4O3S2 (322.36): C% 44.71; H% 3.13; N%
Found: C% 57.92; H% 4.28; N% 13.97.
N-(5-Cyano-6-oxo-4-p-tolyl-1,6-dihydropyrimidin-2-yl)-4-
methylbenzenesulfonamide 13h.
White crystals; yield
82%; mp >350°C; IR (KBr, cmÀ1): υ 3438 (NH), 3027
(ArCH), 2206 (CN), 1651 (C═O), 1573 (C═C), 1346,
1
1146 (SO2). H NMR (400 MHz, DMSO-d6): δ 2.34 (s,
3H, CH3), 2.36 (s, 3H, CH3), 7.21–7.30 (m, 4H, 2C6H4),
7.41 (d, J = 8 Hz, 2H, C6H4), 7.66 (d, J = 8 Hz, 2H,
C6H4), 11.19 (s, 1H, NHSO2). 13C NMR (100 MHz,
DMSO-d6): δ 21.3, 21.4 (2CH3), 118.8 (CN), 83.6,
126.0, 127.5, 128.7, 129.4, 134.8, 140.6, 140.8, 142.7,
157.6, 163.7 (Ar–C), 169.6 (CO). Anal. Calcd. for
C19H16N4O3S (380.42): C% 59.99; H% 4.24; N% 14.73.
Found: C% 60.30; H% 4.03; N% 14.97.
17.38. Found: C% 44.97; H% 3.00; N% 17.64.
N-(5-Cyano-4-(methylthio)-6-oxo-1,6-dihydropyrimidin-2-
yl)-4-methylbenzenesulfonamide 18b.
Yellow crystals;
yield 87%; mp >350°C; IR (KBr, cmÀ1): υ 3434 (NH),
3045 (ArCH), 2206 (CN), 1644 (C═O), 1558 (C═C),
1
1464, 1144 (SO2). H NMR (400 MHz, DMSO-d6): δ
2.16 (s, 3H, SCH3), 2.33 (s, 3H, CH3), 7.24 (d, J = 8 Hz,
2H, C6H4), 7.62 (d, J = 8 Hz, 2H, C6H4), 11.03 (s, 1H,
NHSO2). 13C NMR (100 MHz, DMSO-d6): δ 12.6
(SCH3), 21.3 (CH3), 117.4 (CN), 81.3, 126.7, 129.0,
140.7, 142.8, 155.2, 174.1 (Ar–C), 161.7 (C=O). Anal.
Calcd. for C13H12N4O3S2 (336.39): C% 46.42; H% 3.60;
N% 16.66. Found: C% 46.88; H% 3.45; N% 16.87.
General procedure for the synthesis of 17a,b.
To a
solution of sodium ethoxide in ethanol, prepared from
0.013 mol of sodium added to 10 mL of absolute ethanol,
and arylsulfonyl guanidine 3a,b (0.01 mol), 16a
(0.012 mol) was added. After heating the mixture under
reflux for 2–4 h as judged by TLC, the reaction mixture
was cooled and poured into ice acidified with HCl. The
solid product was separated by filtration, washed ethanol,
General procedure for the synthesis of 20a,b.
To a
solution of sodium ethoxide in ethanol, prepared from
0.013 mol of sodium added to 10 mL of absolute ethanol,
and arylsulfonyl guanidine 3a,b (0.01 mol), 19
(0.012 mol) was added. After heating the mixture under
reflux for 2–4 h as judged by TLC, the reaction mixture
was cooled and poured into ice acidified with HCl. The
solid product was separated by filtration, washed ethanol,
and dried under vacuum.
N-(4-Amino-5-cyano-6-(methylthio)pyrimidin-2-yl)
benzenesulfonamide 17a. Yellow crystals; yield 65%; mp
228–229°C; IR (KBr, cmÀ1): υ 3430, 3348 (NH, NH2),
3242 (ArCH), 2197 (CN), 1555 (C═C), 1403, 1132
1
(SO2). H NMR (400 MHz, DMSO-d6): δ 2.12 (s, 3H,
and dried under vacuum.
SCH3), 6.57 (s, 2H, NH2), 7.36–7.37 (m, 3H, C6H5),
7.77–7.79 (m, 2H, C6H5). Anal. Calcd. for
C12H11N5O2S2 (321.38): C% 44.85; H% 3.45; N% 21.79.
Found: C% 45.10; H% 3.62; N% 22.00.
N-(4-Amino-5-cyanopyrimidin-2-yl)benzenesulfonamide
20a. Off white crystals; yield 50%; mp 210–211°C; IR
(KBr, cmÀ1): υ 3406, 3323 (NH, NH2), 3219 (ArCH),
2218 (CN), 1555 (C═C), 1414, 1134 (SO2). 1H NMR
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Synthesis of Sulfapyrimidine Derivatives
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(400 MHz, DMSO-d6): 7.43 (s, 2H, NH2), 7.51–7.53 (m,
3H, C6H5), 7.82–7.83 (m, 2H, C6H5), 8.32 (s, 1H, CH═
pyrimidine), 14.51 (s, 1H, NHSO2). Anal. Calcd. for
C11H9N5O2S (275.29): C% 47.99; H% 3.30; N% 25.44.
2032.
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Found: C% 48.33; H% 3.52; N% 25.17.
N-(4-Amino-5-cyanopyrimidin-2-yl)-4-
methylbenzenesulfonamide 20b. Off white crystals; yield
60%; mp 208–209°C; IR (KBr, cmÀ1): υ 3438, 3351
(NH, NH2), 3230 (ArCH), 2109 (CN), 1527 (C═C),
1
1409, 1132 (SO2). H NMR (400 MHz, DMSO-d6): δ
2.35 (s, 3H, CH3), 7.31 (d, J = 8 Hz, 2H, C6H4), 7.92 (d,
J = 8 Hz, 2H, C6H4), 8.37 (s, 1H, CH═ pyrimidine).
Anal. Calcd. for C12H11N5O2S (289.31): C% 49.82; H%
3.83; N% 24.21. Found: C% 50.17; H% 3.60; N% 24.57.
General procedure for the synthesis of 22a,b. A solution
of arylsulfonyl guanidine 3a,b (0.01 mol) and 21
(0.012 mmol) in dry dioxane (20 mL) containing
potassium hydroxide (0.015 mol) was heated under reflux
for 2–4 h as judged by TLC. The reaction mixture was
cooled and poured into ice acidified with HCl. The solid
product formed was filtered off, washed by ethyl acetate,
and recrystallized from ethanol to give the respective
products 22a,b.
N-(5-Cyano-6-oxo-1,6-dihydropyrimidin-2-yl)
benzenesulfonamide 22a. Off white crystals; yield 73%;
mp >350°C; IR (KBr, cmÀ1): υ 3414 (NH), 3065
(ArCH), 2220 (CN), 1669 (C═O), 1534 (C═C), 1361,
1
1144 (SO2). H NMR (400 MHz, DMSO-d6): δ 7.39–
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7.46 (m, 3H, C6H5), 7.77–7.79 (m, 2H, C6H5), 7.95 (s,
1H, CH═ pyrimidine), 11.20 (s, 1H, NHSO2). Anal.
Calcd. for C11H8N4O3S (276.27): C% 47.82; H% 2.92;
N% 20.28. Found: C% 48.14; H% 2.71; N% 20.66.
N-(5-Cyano-6-oxo-1,6-dihydropyrimidin-2-yl)-4-
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Acta Cryst E73 2017 1820.
[26] Azzam, R. A.; Elgemeie, G. H.; Elsayed, R. E.; Jones, P. G.
Acta Cryst E73 2017 1041.
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Nucleot Nucl 2016, 35, 211.
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1055.
methylbenzenesulfonamide 22b. Beige crystals; yield 75%;
mp >350°C; IR (KBr, cmÀ1): υ 3420 (NH), 3061 (ArCH),
2208 (CN), 1665 (C═O), 1544 (C═C), 1365, 1145 (SO2).
1H NMR (400 MHz, DMSO-d6): δ 2.32 (s, 3H, CH3),
7.21 (d, J = 8 Hz, 2H, C6H4), 7.67 (d, J = 8 Hz, 2H,
C6H4), 7.94 (s, 1H, CH═ pyrimidine), 11.09 (s, 1H,
NHSO2). Anal. Calcd. for C12H10N4O3S (290.30): C%
49.65; H% 3.47; N% 19.30. Found: C% 49.89; H% 3.54;
N% 19.10.
[31] Gompper, R.; Töpfl, W. Chem Ber 1962, 95, 2871.
REFERENCES AND NOTES
SUPPORTING INFORMATION
[1] Schnitzer, R. J.; Hawking, F. Chemotherapy of Bacterial Infec-
tions, 1st ed.; Elsevier, 1964.
[2] Roblin, R. O. Jr.; Williams, J. H.; Winnek, P. S.; English, J. P.
Chemotherapy J Am Chem Soc 1940, 62, 2002.
Additional supporting information may be found online
in the Supporting Information section at the end of the
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet