Synthesis and antimicrobial evaluation of some isoxazole based heterocycles

Article abstract of DOI:10.3987/COM-14-12954

The versatile hitherto unreported 2-cyano-N-(4-{[(5-methylisoxazol- 3-yl)amino]sulfonyl}phenyl)acetamide (3) was utilized for the synthesis of a variety of heterocycles incorporating sulfamoyl moiety. The 2-pyridone derivatives were obtained via reaction of cyanoacetamide with pentane-2,4-dione, arylidenes malononitrile, or terephthalaldehyde and malononitrile upon heating under reflux in the presence of a catalyst. Condensation of the cyanoacetamide 3 with salicylaldehyde furnished the corresponding chromene derivatives. Coupling of 3 with arene diazonium chlorides gave the hydrazone derivatives 13a-c, which upon treatment with hydrazine hydrate and ethyl chloroformate furnished the corresponding pyrazole and triazine derivatives, respectively. Reaction of 3 with carbon disulfide and 1,2-dibromoethane, 1,3-dibromopropane or dimethyl sulfate afforded 2-cyano-2-(1,3-dithiolan-2-ylidene)-N-(4-{[(5-methylisoxazol-3- yl)amino]sulfonyl}phenyl)acetamide (18), 2-cyano-2-(1,3-dithian-2-ylidene)-N- 4-{[(5-methylisoxazol-3-yl)amino]sulfonyl}phenyl)acetamide (19), and 2-cyano- N-(4-{[(5-methylisoxazol-3-yl)amino]sulfonyl}phenyl)-3,3-bis(methylthio) acrylamide (20). The newly synthesized compounds were evaluated for their in vitro antibacterial and antifungal activities, and showed promising results.

Full text of DOI:10.3987/COM-14-12954

HETEROCYCLES, Vol. 89, No. 6, 2014
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HETEROCYCLES, Vol. 89, No. 6, 2014, pp. 1393 - 1411. © 2014 The Japan Institute of Heterocyclic Chemistry
Received, 1st February, 2014, Accepted, 7th April, 2014, Published online, 16th April, 2014
DOI: 10.3987/COM-14-12954
SYNTHESIS AND ANTIMICROBIAL EVALUATION OF SOME
ISOXAZOLE BASED HETEROCYCLES
Elham. S. Darwish, Khalid A. Atia, and Ahmad M. Farag*
Department of Chemistry, Faculty of Science, Cairo University, Giza 12613,
Egypt
*Corresponding author: E-mail: afarag49@yahoo.com
Abstract – The versatile hitherto unreported 2-cyano-N-(4-{[(5-methylisoxazol-
3-yl)amino]sulfonyl}phenyl)acetamide (3) was utilized for the synthesis of a
variety of heterocycles incorporating sulfamoyl moiety. The 2-pyridone
derivatives were obtained via reaction of cyanoacetamide with pentane-2,4-dione,
arylidenes malononitrile, or terephthalaldehyde and malononitrile upon heating
under reflux in the presence of a catalyst. Condensation of the cyanoacetamide 3
with salicylaldehyde furnished the corresponding chromene derivatives. Coupling
of 3 with arene diazonium chlorides gave the hydrazone derivatives 13a-c, which
upon treatment with hydrazine hydrate and ethyl chloroformate furnished the
corresponding pyrazole and triazine derivatives, respectively. Reaction of 3 with
carbon disulfide and 1,2-dibromoethane, 1,3-dibromopropane or dimethyl sulfate
afforded
2-cyano-2-(1,3-dithiolan-2-ylidene)-N-(4-{[(5-methylisoxazol-3-
yl)amino]sulfonyl}phenyl)acetamide (18), 2-cyano-2-(1,3-dithian-2-ylidene)-N-
4-{[(5-methylisoxazol-3-yl)amino]sulfonyl}phenyl)acetamide (19), and 2-cyano-
N-(4-{[(5-methylisoxazol-3-yl)amino]sulfonyl}phenyl)-3,3-bis(methylthio)acryl-
amide (20). The newly synthesized compounds were evaluated for their in vitro
antibacterial and antifungal activities, and showed promising results.
INTRODUCTION
Cyanoacetamides are highly reactive bifunctional compounds. The carbonyl and the cyano functions of
these compounds are suitably situated to enable reactions with common reagents to form a variety of
heterocycles. Also, the active methylene of cyanoacetamide can take part in a variety of condensation and
substitution reactions. Moreover, cyanoacetamides and their related heterocyclic derivatives have
attracted great attention due to their interesting biological, therapeutic value and pharmaceutical activities

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HETEROCYCLES, Vol. 89, No. 6, 2014
such as antimicrobial,1,2 antifungal,3 insulin releasing,4 carbonic anhydrase inhibitory,5
anti-inflammatory,6 and antitumor properties.7 Some active sulfonamides as antibacterial are also known
for their immune-modifying effects.8,9 In addition, pyrazole derivatives have attracted much more
attention due to their utilities in the field of drug discovery and agricultural research.10-16 They are also
known for their anticancer,17-22 antipyretic,23 anti-inflammatory,24 antimicrobial activities,25-27 antiviral,28
tranquillizing,29 antihypertensive,30 antidepressant,31 anti-arrhythmic,32 anticonvulsant,33 and antidiabetic
activities.34 Moreover, some 2-pyridones are also reported to possess antitumor,35 antibacterial,36 elastase
inhibitors37 and other biological activities.38,39 In view of these observations and in continuation of our
previous work directed to the synthesis of novel heterocyclic compounds of potential biological and
pharmacological activities,40-57 we report here the synthesis of some new pyridone, pyrazole and
chromene derivatives incorporating sulfonamide moiety starting from 2-cyano-N-(4-{[(5-methylisoxazol-
3-yl)amino]sulfonyl}phenyl)acetamide (3) as an excellent building block for the synthesis of the target
compounds.
RESULTS AND DISCUSSION
Cyanoacetamide 3 was synthesized by cyanoacetylation of 4-amino-N-(5-methylisoxazole-3-yl)benzene-
sulfonamide (sulfamethoxazole) (1) with 3,5-dimethyl-1-cyanoacetylpyrazole (2)58 as previously
described (Scheme 1).
Scheme 1
One pot reaction of the cyanoacetamide derivative 3 with terephthalaldehyde and malononitrile (1: 1: 2
molar ratio), at reflux temperature in the presence of catalytic amount of piperidine afforded the
corresponding derivative 4 (Scheme 2). The mass spectrum of 4 showed a molecular ion peak at m/z 548
corresponding to a molecular formula C27H16N8O4S with a base peak at m/z 235 (100%). Knoevenagel
condensation of the cyanoacetamide 3 with aromatic aldehydes viz. benzaldehyde, p-anisaldehyde, and
p-chlorobenzaldehyde, furnished the corresponding arylidene derivatives 5a-c (Scheme 2). The IR
spectrum of compound 5a, taken as a typical example of the series prepared, revealed absorption bands at
1678, 2219, 3304 and 3194 cm-1 corresponding to carbonyl, nitrile and NH functions, respectively. Its 1H
NMR spectrum showed signals at δ 8.30, 10.77 and 11.35 (D2O-exchangeable) due to CH and 2NH
protons in addition to aromatic protons at δ 7.62-8.00. Its mass spectrum showed a molecular ion peak at

HETEROCYCLES, Vol. 89, No. 6, 2014
1395
m/z 408. Pyridin-2(1H)-ones 7a-c were obtained through the reaction of the arylidene derivatives 5a-c
with malononitrile in dioxane containing a catalytic amount of piperidine. 2-Pyridone derivatives 7a-c
were also obtained via one-pot reactions of the cyanoacetamide derivative 3 with malononitrile and the
same aldehydes (1:1:1 molar ratio) at reflux temperature in the presence of piperidine. On the other hand,
the 2-pyridone derivatives 7a-c were also obtained via reaction of the cyanoacetamide 3 with
arylidenemalononitrile viz. benzylidenemalononitrile, 2-(4-chlorobenzylidene)malononitrile, or
2-(4-methoxybenzylidene)malononitrile upon heating under reflux in the presence of piperidine as a
catalyst. The spectroscopic data and elemental analyses of the obtained products were in complete
agreement with the assigned structures 7a-c.
O
CN
O
NH S
O
CN
CN
Me
CH=C
N
OHC
NC CN
CHO
O
N
H2N
CN
EtOH / piperidine
4
3 h, 80%
O
NH S
O
Me
NH CN
O
ArCHO
O
N
dioxane / piperidine
6 h, 60-80%
Ar
5a-c
NC
CN
NC CN
O
3
CN
Ar
H
Ar
6a-c
O
Me
NH S
O
N
dioxane / piperidine
or
O
N
+ ArCHO
NC CN
H2N
CN
7a-c
dioxane / piperidine
3 h, 40-56%
NC
OH
Me
O
O
O
O
Me
Me
Me
NH S
NH
..
O
O
dioxane / Et3N
8 h, 64%
O
N
Me
8
CN
H
N
OH
Me
O
N
CN
O
O
O
NH S
O
- 2H2O
Me
Me
NH S
O
Me
H
O
O
N
N
OH
Me
Me
9
10
5,7: a, Ar = Ph; b, Ar = 4-MeOC6H4; c, Ar = 4-ClC6H4
Scheme 2

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HETEROCYCLES, Vol. 89, No. 6, 2014
When the cyanoacetamide 3 was treated with pentane-2,4-dione, in dioxane in the presence of a catalytic
amount of triethylamine, it afforded the corresponding 2-pyridinone derivative 10 (Scheme 2). It can be
postulated that the reaction initially proceeds via a nucleophilic attack to form the Michael adduct which
in turn underwent cyclization via elimination of two water molecules, affording the final product (Scheme
2).
Similarly, cyclocondensation of the cyanoacetamide 3 with salicylaldehyde, in dioxane and in the
presence of a catalytic amount of piperidine afforded 2-iminochromene 11 (Scheme 3). On the other hand,
reaction of 3 with salicylaldehyde in the presence of AcOH/AcONa afforded chromenone 12. The
structure of compound 12 was further confirmed through its synthesis upon hydrolysis of 11 with
ethanolic HCl. (Scheme 3). The IR spectrum of compound 11 revealed the disappearance of cyano
absorption band and showed absorption bands at 1683, 3135, 3241 and 3301 cm-1 corresponding to
1
carbonyl and three NH functions, respectively. Its H NMR spectrum showed three D2O-exchangeable
signals at δ 9.29, 11.40 and 13.16 due to three NH protons, in addition to an aromatic multiplet in the
1
region 7.31-7.91. Its mass spectrum showed a molecular ion peak at m/z 424 whereas the H NMR
spectrum of compound 12 showed two D2O-exchangeable signal at δ 10.93 and 11.36 due to two NH
protons.
Scheme 3
The cyanoacetamide 3 coupled smoothly with arenediazonium salts, in pyridine to afford the respective
hydrazones 13a-c (Scheme 4). The analytical and spectral data of the latter products are consistent with
1
the proposed structures. The H NMR spectrum of 13a, taken as an example of the prepared series,
displayed, besides an aromatic multiplet at 7.13-7.95 ppm, D2O exchangeable signals at 10.23, 11.32 and
12.02 ppm corresponding to 3 NH protons. Its IR spectrum showed bands at 3382, 3243, 3080, 2217 and

HETEROCYCLES, Vol. 89, No. 6, 2014
1397
1684 cm-1 due to 3 NH, CN and CO groups, respectively. The latter hydrazones 13a-c underwent
intramolecular cyclization upon treatment with hydrazine hydrate to give products identified as the
3-aminopyrazole derivatives 15a-c. The IR spectra of 15a-c showed, in each case, the absence of nitrile
and carbonyl bands and revealed the appearance of three bands in the region 3460-3185 cm-1 due to NH2
and NH groups as depicted in Scheme 4. Their 1H NMR spectra displayed singlet in the region 6.05-6.07
and 9.97 and 10.82 ppm attributable to the NH2 and 2NH protons, respectively. Compounds 15a-c were
alternatively obtained by reaction of the aminopyrazole derivative 14 with diazotized aromatic amines in
pyridine. Compound 14 was prepared by the reaction of 3 with hydrazine hydrate in refluxing dioxane
(Scheme 4).
O
+
ArN2 Cl-
Me
NH S
O
NH CN
3
pyridine
60-70%
O
N
O
H N
N
13a-c
NH2NH2•H2O
dioxane, 6 h,
50%
Ar
NH2NH2•H2O
dioxane, 6 h,
40-75%
O
NH S
O
O
Me
NH
N
+
ArN2 Cl- Me
NH S
NH
O
N
N
O
O
N
pyridine,
40-75%
NH
N
N
NH2
N
15a-c
14
H
Ar
H2N
13,15: a, Ar = Ph;
b, Ar = 4-MeOC6H4
c, Ar = 4-ClC6H4
Scheme 4
Treatment of the hydrazones 13a-c with ethyl chloroformate in acetic acid, afforded the corresponding
triazine derivatives 16a-c (Scheme 5). The structures of compounds 16a-c were established based on their
elemental analyses and spectral data (see Experimental part).
Scheme 5
When the cyanoacetamide 3 was treated with carbon disulfide, in the presence of potassium hydroxide in
DMF followed by cycloalkylation with 1,2-dibromoethane or 1,3-dibromopropane, yielded

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HETEROCYCLES, Vol. 89, No. 6, 2014
2-cyano-2-(1,3-dithiolan-2-ylidene)-N-(4-{[(5-methylisoxazol-3-yl)amino]sulfonyl}phenyl)acetamide
(18), and 2-cyano-2-(1,3-dithian-2-ylidene)-N-(4-{[(5-methylisoxazol-3-yl)amino]sulfonyl}phenyl)-
acetamide (19), respectively in good yield (Scheme 6). Furthermore, reaction of 3 with CS2 in the
presence of KOH and dimethyl sulfate afforded 2-cyano-N-(4-{[(5-methylisoxazol-3-yl)amino]sulfonyl}-
phenyl)-3,3-bis(methylthio)acrylamide (20) (Scheme 6). The IR spectra of compounds 18, 19 and 20
1
showed, in each case, bands corresponding to NH, CH-aliphatic, C≡N and C=O groups. The H NMR
spectrum of the compound 18 showed signal at 3.95 (s, 4H, 2CH2-dithiolane). Its mass spectrum showed
1
a molecular ion peak at m/z 422. The H NMR spectrum of compound 19 showed signals for dithiene
moiety at 2.10 (m, 2H, J = 6.80 Hz, CH2), 3.03 (t, 2H, J = 6.6 Hz, CH2), 3.21 (t, 2H, J = 6.6 Hz, CH2).
Its mass spectrum showed a molecular ion peak at m/z 436.
Scheme 6
ANTIMICROBIAL ACTIVITY
The newly synthesized compounds 4, 5a, 5b, 7b, 10, 11, 14, 15a, 15b, 15c, 19, and 20 were evaluated for
their in vitro antibacterial activity against Streptococcus pneumoniae (RCMB-010010) (SP) and Bacillis
subtilis (RCMB-010067) (BS) as examples of Gram-positive bacteria and Pseudomonas aeruginosa
(RCMB-010043) (PA) and Escherichia coli (RCMB-010052) (EC) as examples of Gram-negative
bacteria. They were also evaluated for their in vitro antifungal activity against Aspergillus fumigatus
(RCMB-02568) (AF), Syncephalastrum racemosum (RCMB-05922) (SR), Geotricum candidum
(RCMB-05097) (GC) and Candida albicans (RCMB-05036) (CA) fungal strains. Inhibition zone
diameter (IZD) in mm was used as criterion for the antimicrobial activity using the diffusion technique.
The fungicide amphotericin B and the antibiotic sulfamethoxazole were used as references to evaluate the

HETEROCYCLES, Vol. 89, No. 6, 2014
1399
potency of the tested compounds under the same conditions. The results are depicted in Table 1. As it
can be seen from the data present in Table 1, all the synthesized derivatives showed moderate to good
activity against the tested microorganisms. The most active compounds were 15a,b,c and 7b which
revealed strong inhibitory activity to the tested bacteria and fungi. The elevated activity of 15a,b,c and 7b
is attributed to the presence of pharmacological pyrazole moiety in compound 15a,b,c and pyridone ring
in 7b.
Table 1. Antibacterial and antifungal activities of the synthesized compounds
Compound
Inhibition Zone Diameter (cm)
Gram (-ve)
(PA) (EC)
13.8± 15.3±
Gram (+ve)
Fungi
(GC)
28.7±
Standard
values*
(SP)
(BS)
(AF)
23.7±
(SR)
19.7±
(CA)
25.4±
26.6±
0.2
18.2±
0.3
0.1
11.8±
0.36
0.3
10.80±
0.44
0.1
18.70±
0.36
0.2
16.90±
0.27
0.2
13.40±
0.65
0.1
10.90±
0.23
4
12.90± 13.20±
0.63 0.58
16.90± 18.20±
0.58 0.44
16.30± 18.30±
0.55 0.25
16.90± 18.20±
5a
10.70±
0.34
11.90±
0.63
15.70±
0.33
13.80±
0.25
18.30±
0.34
15.20±
0.53
5b
7b
10
11.60±
0.19
15.40±
0.39
17.30±
0.44
12.60±
0.25
19.00±
0.58
16.9±
0.25
9.80±
0.27
11.90±
0.63
16.20±
0.36
15.00±
0.44
17.60±
0.58
14.10±
0.43
0.58
0.44
16.30±
0.33
19.0±
0.25
10.20±
0.31
13.50±
0.34
16.60±
0.38
13.20±
0.56
19.50±
0.16
15.80±
0.40
11
14.60± 14.30±
0.58 0.58
12.30± 12.70±
0.58 0.37
16.70± 19.20±
0.36 0.27
18.30± 22.60±
10.20±
0.32
9.40±
0.44
13.60±
0.25
11.70±
0.34
16.50±
0.58
13.40±
0.45
14
10.10±
0.39
8.50±
0.37
17.60±
0.58
15.40±
0.25
12.6±
0.38
11.30±
0.34
15a
15b
15c
19
13.30±
0.36
13.60±
0.36
16.80±
0.39
13.40±
0.58
19.60±
0.19
15.90±
0.44
19.30±
0.52
17.80±
0.44
20.60±
0.58
16.70±
0.33
22.40±
0.36
17.60±
0.58
0.25
23.0±
0.2
0.44
32.40±
0.3
17.30±
0.1
19.90±
0.3
23.70±
0.1
19.70±
0.20
28.70±
0.20
25.40±
0.10
12.10± 12.50±
0.56 0.34
16.90± 17.60±
0.42 0.31
11.30±
0.31
10.60±
0.41
17.40±
0.55
15.00±
0.23
12.40±
0.35
10.50±
0.11
20
12.90±
0.28
14.70±
0.40
13.90±
0.42
11.80±
0.31
13.70±
0.34
14.00±
0.29
Data are expressed in the form of mean ± SD. Mean zone of inhibition in mm ± standard deviation beyond well diameter; (6
mm) produced on a range of environmental and clinically pathogenic microorganism using (5 mg/mL) concentration of tested
sample (100 L was tested).
* The antifungal used: amphotericin B and the antibacterial used: sulfamethoxazole.

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EXPERIMENTAL
Melting points were determined in open glass capillaries with a Gallenkamp apparatus. The IR spectra
were recorded using KBr disks on a Pye Unicam SP 3-300 or a Shimadzu FTIR 8101 PC IR
spectrophotometer. The NMR spectra were recorded with a Varian Mercury VXR-300 NMR
13
spectrometer at 300 and 75 MHz (1H and C NMR spectra, respectively) using CDCl3 and DMSO-d6 as
solvents. Chemical shifts were related to that of the solvent. Mass spectra (EI) were obtained at 70 eV
with a Shimadzu GCMQP 1000 EX spectrometer. Elemental analyses were carried out at the
Micro-analytical Center of Cairo University, Giza, Egypt. The biological evaluation of the products was
carried out in the Medical Mycology Laboratory of the Regional Center for Mycology and Biotechnology
of Al-Azhar University, Cairo, Egypt.
2-Cyano-N-(4-{[(5-methylisoxazol-3-yl)amino]sulfonyl}phenyl)acetamide (3). A mixture of 4-amino-
N-(5-methylisoxazole-3-yl)benzenesulfonamide (1) (5.06 g, 20 mmol) and 3,5-dimetyl-1-
cyanoacetylpyrazole (2) (3.26 g, 20 mmol) in dioxane (20 mL) was refluxed for 3 h. The reaction mixture
was poured into crushed ice and the resulting precipitate was filtrated off, washed with EtOH, dried, and
finally crystallized from DMF/MeOH (1:3) to give 3. Yield (80%), mp 220-222 ºC (from DMF/MeOH);
1
IR (KBr) νmax/ cm-1: 3329, 3277 (2NH), 2964, 2861 (aliphatic CH), 2262 (C≡N), 1691 (C=O); H NMR
(DMSO-d6) δ 2.29 (s, 3H, CH3), 3.94 (s, 2H, CH2), 6.11 (s, 1H, isoxazole-H-4), 7.71 (d, 2H, J = 9 Hz,
ArH), 7.83 (d, 2H, J = 9 Hz, ArH), 10.67 (s, 1H, D2O-exchangeable, NH), 11.32 (s, 1H,
D2O-exchangeable, NH); 13C NMR (DMSO-d6) δ 11.9, 26.9, 66.3, 95.3, 119.1, 128.1, 133.9, 142.5, 157.4,
161.8, 170.2; MS (m/z, %): 322 (M++2, 2.7), 321 (M++1, 2.9), 320 (M+, 4.1), 256 (8.2), 238 (2.9), 223
(11.7), 186 (80.1), 159 (62.9), 132 (41.3), 97 (6.2), 82 (3.1), 68 (100). Anal. Calcd for C13H12N4O4S
(320.32): C, 48.74; H, 3.78; N, 17.49; S, 10.01. Found: C, 48.70; H, 3.72; N, 17.43; S, 9.88%.
6-Amino-4-(4-(2,2-dicyanovinyl)phenyl)-1-(N-(4-{[(5-methylisoxazol-3-yl)amino]sulfonyl}phenyl)-
2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile (4). To a mixture of the acetamide 3 (0.01 mol),
terephthalaledehyde (0.01 mol) and malononitrile (0.02 mol) in EtOH (30 mL), few drop of piperidine
was added. The reaction mixture was heated under reflux for 3 h. The formed solid product while hot,
was filtrated off, washed with EtOH, dried, and finally crystallized from dioxane to give 4 as white
crystals. Yield (80%), mp > 300 ºC (from dioxane); IR (KBr) νmax/cm-1: 3435, 3148 (NH, NH2), 2959
1
(aliphatic-H), 2214 (C≡N), 1639 (C=O); H NMR (DMSO-d6) δ 2.20 (s, 3H, CH3), 6.00 (s, 1H,
isoxazole-H-4), 7.39 (m, 4H, Ar-H), 7.44 (s, 1H, D2O-exchangeable, NH), 7.74 (s, 1H, olefinic-H), 7.91
(m, 4H, ArH), 8.40 (s, 2H, D2O-exchangeable NH2); 13C-NMR (DMSO-d6) δ 12.2, 43.6, 66.3, 75.3, 87.8,
96.6, 112.0, 114.0, 115.4, 116.0, 127.9, 128.3, 128.7, 129.5, 135.3, 136.2, 146.9, 157.0, 159.4, 160.2,
163.9, 167.1; MS (m/z, %): 549 (M++1, 78.1), 548 (M+, 89.5), 474 (66.7), 466 (54.3), 451 (67.6), 331
(59.1), 235 (100), 215 (49.5), 153 (70.5), 77 (59.1). Anal. Calcd for C27H16N8O4S (548.53): C, 59.12; H,

HETEROCYCLES, Vol. 89, No. 6, 2014
1401
2.94; N, 20.43; S, 5.85. Found: C, 59.01; H, 2.90; N, 20.39; S, 5.80%.
N-[4-(Aminosulfonyl)phenyl]-3-aryl-2-cyanoacrylamide (5a-c).
General Procedure: To a solution of the cyanoacetamide 3 (0.320 g, 1 mmol) and the appropriate
aromatic aldehydes (1 mmol) in dioxane (20 mL), was added few drops of piperidine and the reaction
mixture was refluxed for 6 h. The formed solid product was filtered off, washed with EtOH, dried, and
finally recrystallized from proper solvent to give 5a-c.
2-Cyano-N-(4-{[(5-methylisoxazol-3-yl)amino]sulfonyl}phenyl)-3-phenylacrylamide (5a). Yield
(80%), mp 282-284 ºC (from dioxane); IR (KBr) νmax/cm-1: 3304, 3194 (2NH), 2892, 2838 (aliphatic CH),
2219 (C≡N), 1678 (C=O); 1H NMR (DMSO-d6)  2.30 (s, 3H, CH3), 6.13 (s, 1H, isoxazole-H-4), 7.62 (d,
2H, J = 9 Hz, ArH), 7.84-7.86 (m, 5H, ArH), 8.00 (d, 2H, J = 9 Hz, ArH), 8.30 (s, 1H, olefinic-H), 10.77
(s, 1H, D2O-exchangeable, NH), 11.35 (s, 1H, D2O-exchangeable, NH). MS (m/z, %): 410(M++2, 5.5),
409 (M++1, 5.5), 408 (M+, 7.3), 326 (4.6), 311 (3.2), 236 (4.0), 171 (5.5), 156 (96.3), 128 (100), 101
(39.1), 77 (77.0). Anal. Calcd for C20H16N4O4S (408.43): C, 58.81; H, 3.95; N, 13.72; S, 7.85. Found: C,
58.78; H, 3.88; N, 13.70; S, 7.80%.
2-Cyano-3-(4-methoxyphenyl)-N-(4-{[(5-methylisoxazol-3-yl)amino]sulfonyl}phenyl)acrylamide
(5b).59 Yield (80%), mp 260-262 ºC (from dioxane); IR (KBr) νmax/cm-1: 3322, 3091 (2NH), 2993, 2843
(aliphatic CH), 2215 (C≡N), 1685 (C=O); 1H NMR (DMSO-d6)  2.29 (s, 3H, CH3), 3.87 (s, 3H, OCH3),
6.14 (s, 1H, isoxazole-H-4), 7.19 (d, 2H, J = 9 Hz, ArH), 7.85-7.89 (m, 4H, ArH), 8.04 (d, 2H, J = 9 Hz,
ArH), 8.23 (s, 1H, olefinic-H), 10.64 (s, 1H, D2O-exchangeable, NH), 11.35 (s, 1H, D2O-exchangeable,
NH); MS (m/z, %): 439 (M++1, 4.7), 438 (M+, 6.2), 412 (6.2), 341 (4.2), 304 (10.6), 279 (6.7), 206 (4.1),
186 (100), 158 (26.5), 97 (14.3); Anal. Calcd for C21H18N4O5S (438.45): C, 57.53; H, 4.14; N, 12.78; S,
7.31. Found: C, 57.50; H, 4.09; N, 12.72; S, 7.28%.
3-(4-Chlorophenyl)-2-cyano-N-(4-{[(5-methylisoxazol-3-yl)amino]sulfonyl}phenyl)acrylamide (5c).
Yield (60%), mp 275-277 ºC (from dioxane); IR (KBr) νmax/cm-1: 3300, 3087 (2NH), 2988, 2898
1
(aliphatic CH), 2220 (C≡N), 1682 (C=O); H NMR (DMSO-d6)  2.29 (s, 3H, CH3), 6.14 (s, 1H,
isoxazole-H-4), 7.80 (d, 2H, ArH), 7.84 (d, 2H, Ar-H), 7.88 (d, 2H, J = 9 Hz, ArH), 7.95 (d, 2H, J = 9 Hz,
ArH), 9.93 (s, 1H, olefinic-H), 10.76 (s, 1H, D2O-exchangeable, NH), 11.34 (s, 1H, D2O-exchangeable,
NH); MS (m/z, %): 444 (M++2, 4.8), 443 (M++1, 5.8), 442 (M+, 6.3), 363 (15.4), 345 (9.5), 308 (36.9),
281 (21.9), 254 (5.7), 237 (4.1), 206 (8.8), 190 (100), 161 (45.0), 97 (13.4); Anal. Calcd for
C20H15ClN4O4S (442.87): C, 54.24; H, 3.41; Cl, 8.01; N, 12.65; S, 7.24. Found: C, 54.20; H, 3.36; Cl,
8.00; N, 12.62; S, 7.20%.
Synthesis of the pyridones 7a–c.
Method A: A mixture of 5 (10 mmol) and malononitrile (0.66 g, 10 mmol) in dioxane (30 mL)

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containing piperidine (0.5 mL) was heated under reflux for 3 h, then left to cool. The solid product was
filtered off, washed with EtOH, dried, and finally recrystallized from the proper solvent to give 7a-c.
Method B: Equimolar amounts of 3 (10 mmol) and the appropriate 2-(arylidene)malononitrile (10 mmol)
in dioxane (30 mL) was added piperidine (0.5 mL) and the reaction mixture was heated under reflux for 3
h, then left to cool. The solid product was filtered off, washed with EtOH, dried, and finally recrystallized
from the proper solvent to give 7a-c.
Method C: A mixture of 3 (10 mmol), the appropriate aromatic aldehyde (10 mmol), piperidine (0.85
mmol), and malononitrile (0.66 g, 10 mmol) in dioxane (30 mL) was heated under reflux for 3 h, then left
to cool. The solid product was filtered off, washed with EtOH, dried, and finally recrystallized from the
proper solvent to give 7a-c.
4-(6-Amino-3,5-dicyano-2-oxo-4-phenylpyridin-1(2H)-yl)-N-(5-methylisoxazol-3-yl)benzenesulfon-
amide (7a). Yield (54%), mp > 300 ºC (from dioxane); IR (KBr) νmax/cm-1: 3362, 3316, 3217 (NH, NH2),
2970, 2889 (aliphatic CH), 2217 (C≡ N), 1629 (C=O); 1HNMR (DMSO-d6)  2.33 (s, 3H, CH3), 4.31 (br.,
2H, D2O-exchangeable, NH2), 6.22 (s, 1H, isoxazole-H-4), 7.51-7.57 (m, 5H, ArH), 7.67 (d, 2H, J = 9 Hz,
ArH), 8.06 (d, 2H, J = 9 Hz, ArH), 11.60 (s, 1H, D2O-exchangeable, NH); 13C NMR (DMSO-d6) δ 12.0,
66.3, 75.5, 87.9, 95.4, 116.0, 127.8, 128.6, 128.8, 130.0, 130.3, 134.5, 138.0, 141.1, 156.8, 157.4, 159.3,
161.5, 170.3; MS (m/z, %): 473 (M++1, 42.3), 472 (M+, 69.2), 397 (54.6), 390 (66.9), 373 (46.2), 283
(68.5), 235 (50.0), 175 (60.0), 157 (43.9), 80 (100). Anal. Calcd for C23H16N6O4S (472.47): C, 58.47; H,
3.41; N, 17.79; S, 6.79. Found: C, 58.42; H, 3.38; N, 17.75; S, 6.74%.
4-[6-Amino-4-(4-methoxyphenyl)-3,5-dicyano-2-oxopyridin-1(2H)-yl]-N-(5-methylisoxazol-3-yl)ben-
zenesulfonamide (7b). Yield (56%), mp > 300 ºC (from dioxane); IR (KBr) νmax/cm-1: 3324, 3280, 3191
1
(NH, NH2), 2985, 2846 (aliphatic CH), 2215 (C≡N), 1688 (C=O); H NMR (DMSO-d6) δ 2.32 (s, 3H,
CH3), 3.85 (s, 3H, OCH3), 4.9 (br., 2H, NH2), 6.23 (s, 1H, isoxazole-H-4), 7.14 (d, 2H, Ar-H), 7.51 (d,
2H, Ar-H), 7.67 (d, 2H, ArH), 8.05 (d, 2H, ArH), 11.75 (s, 1H, D2O-exchangeable, NH); MS (m/z, %):
503 (M++1, 10.1), 502 (M+, 16.3), 419 (11.0), 404 (7.7), 267 (14.9), 186 (100), 158 (27.2), 106 (11.0), 97
(15.8). Anal. Calcd for C24H18N6O5S (502.50): C, 57.36; H, 3.61; N, 16.72; S, 6.38. Found: C, 57.33; H,
3.58; N, 16.70; S, 6.36%.
4-4-[6-Amino-4-(4-chlorophenyl)-3,5-dicyano-2-oxopyridin-1(2H)-yl]-N-(5-methylisoxazol-3-yl)ben-
zenesulfonamide (7c). Yield (40%), mp > 300 ºC (from dioxane); IR (KBr) νmax/cm-1: 3324, 3204, 3093
1
(NH, NH2), 2993, 2892 (aliphatic CH), 2220 (C≡N), 1654 (C=O); H NMR (DMSO-d6) δ 2.33 (s, 3H,
CH3), 4.31 (br., 2H, D2O-exchangeable, NH2), 6.22 (s, 1H, isoxazole-H-4), 7.57 (d, 2H, J = 9 Hz, ArH),
7.58-7.74 (m, 4H, ArH), 8.06 (d, 2H, J = 9 Hz, ArH), 11.60 (s, 1H, D2O-exchangeable, NH); MS
(m/z, %): 507 (M++1, 69.3), 506 (M+, 94.7), 409 (76.3), 295 (73.7), 264 (59.7), 221 (47.4), 157 (57.9),
137 (100), 111 (45.6). Anal. Calcd for C23H15ClN6O4S (506.92): C, 54.49; H, 2.98; Cl, 6.99; N, 16.58; S,

HETEROCYCLES, Vol. 89, No. 6, 2014
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6.33. Found: C, 54.45; H, 2.93; Cl, 6.94; N, 16.56; S, 6.30%.
4-(3-Cyano-4,6-dimethyl-2-oxopyridin-1(2H)-yl)-N-(5-methylisoxazol-3-yl)benzenesulfonamide
(10).
To a mixture of the cyanoacetamide 3 (1.60 g, 5 mmol) and pentane-2,4-dione (0.50 g, 5 mmol) in
dioxane (20 mL), triethylamine (0.5 mL) was added and the reaction mixture was refluxed for 8 h. On
cooling, the separated solid was filtered, washed with EtOH, dried, and finally crystallized from DMF to
afford the corresponding sulfonamide (10). Yield (64%), mp 295-297 ºC (from dioxane); IR (KBr)
νmax/cm-1: 3082 (NH), 2983, 2870 (aliphatic CH), 2217 (C≡N), 1651 (C=O); 1H NMR (DMSO-d6) δ 2.01
(s, 3H, CH3), 2.26 (s, 3H, CH3), 2.39 (s, 3H, CH3), 6.20 (s, 1H, isoxazole-H-4), 6.48 (s, 1H, pyridine-H),
7.63 (d, 2H, J = 9 Hz, ArH), 8.03 (d, 2H, J = 9 Hz, ArH), 11.60 (s, 1H, D2O-exchangeable, NH);
13C-NMR (DMSO-d6) δ 12.0, 20.6, 21.3, 95.4, 100.0, 109.1, 115.5, 128.0, 129.4, 140.2, 141.3, 151.4,
157.3, 160.0, 160.2, 170.5; MS (m/z, %): 384 (M+, 13.2), 321 (15.5), 288 (17.2), 239 (15.5), 222 (18.9),
148 (20.8), 97 (19.6), 79 (100). Anal. Calcd for C18H16N4O4S (384.41): C, 56.24; H, 4.20; N, 14.57; S,
8.34. Found: C, 56.20; H, 4.16; N, 14.52; S, 8.30%.
2-Imino-N-(4-{[(5-methylisoxazol-3-yl)amino]sulfonyl}phenyl)-2H-chromene-3-carboxamide (11).
A mixture of equimolar amounts of the cyanoacetamide 3 (1.60 g, 5 mmol) and salicylaldehyde (0.61 g, 5
mmol) in dioxane (25 mL) containing a catalytic amount of piperidine was heated under reflux for 2 h,
then left to cool. The solid product formed was filtrated off, washed with EtOH, dried, and finally
crystallized from dioxane to give 11. Yield (60%), mp 255-257 ºC (from dioxane); IR (KBr) νmax: 3301,
1
3241, 3135 (3NH), 2926, 2888 (aliphatic CH), 1683 (C=O) cm-1; H NMR (DMSO-d6) δ 2.29 (s, 3H,
CH3), 6.13 (s, 1H, isoxazole-H-4), 7.31 (d, 2H, Ar-H), 7.60 (s, 2H, Ar-H), 7.62 (s, 1H, CH), 7.80-7.91 (m,
3H, Ar-H), 8.56 (s, 1H, CH), 9.29 (br., 1H, D2O-exchangeable, NH), 11.40 (br., 1H, D2O-exchangeable,
NH), 13.16 (br., 1H, D2O-exchangeable, NH); MS (m/z, %): 425 (M++1, 8.4), 424 (M+, 17.9), 343 (4.8),
328 (4.4), 279 (19.8), 253 (4.8), 236 (4.4), 187 (5.4), 172 (100), 145 (54.2), 97 (6.3), 83 (11.2). Anal.
Calcd for C20H16N4O5S (424.43): C, 56.60; H, 3.80; N, 13.20; S, 7.56. Found: C, 56.57; H, 3.78; N,
13.18; S, 7.53%.
N-(4-{[(5-Methylisoxazol-3-yl)amino]sulfonyl}phenyl)-2-oxo-2H-chromene-3-carboxamide (12).60
Method A: To a solution of 3 (1.60 g, 5 mmol) in acetic acid (30 mL) containing 0.5 g of fused sodium
acetate, salicylaldehyde (0.61 g, 5 mmol) was added. The mixture was heated under reflux for 2 h. After
cooling, the formed product was filtrated off, washed with EtOH, dried, and finally crystallized from
DMF to give 12.
Method B: The iminochromene derivatives 11 (1.06 g, 2.5 mmol) was dissolved in dioxane (40 mL) and
treated with HCl (5 mL). The reaction mixture was heated under reflux for 2 h, left to cool. The obtained
solid product was filtered off, washed with cold water, dried, and finally crystallized from dioxane. Yield

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(50%), mp > 300 ºC (from dioxane); IR (KBr) νmax/cm-1: 3212, 3127 (2NH), 2960, 2867 (aliphatic CH),
1708 (C=O), 1669 (C=O); 1H NMR (DMSO-d6) δ 2.30 (s, 3H, CH3), 6.13 (s, 1H, isoxazole-H-4), 7.56 (d,
2H, J = 9 Hz, ArH), 7.75-7.91 (m, 4H, ArH), 8.02 (d, 2H, J = 9 Hz, ArH), 8.90 (s, 1H, CH), 10.93 (s, 1H,
D2O-exchangeable, NH), 11.36 (s, 1H, D2O-exchangeable, NH); 13C NMR (DMSO-d6) δ 11.9, 66.3, 95.3,
116.2, 118.3, 119.6, 125.2, 128.1, 130.3, 134.2, 134.4, 142.0, 147.7, 153.9, 157.4, 160.1, 160.5, 170.2;
MS (m/z, %): 426 (M++1, 6.7), 425 (M+, 14.5), 353 (11.0), 328 (11.8), 278 (9.5), 253 (9.7), 188 (14.8),
173 (100), 145 (11.8), 101 (37.1), 82 (10.5). Anal. Calcd for C20H15N3O6S (425.41): C, 56.47; H, 3.55; N,
9.88; S, 7.54. Found: C, 56.43; H, 3.51; N, 9.85; S, 7.50%.
Coupling of 2-cyano-N-(4-{[(5-methylisoxazol-3-yl)amino]sulfonyl}phenyl)acetamide
(3) with
arenediazonium salts. Formation of the hydrazones 13a-c.
General procedure: To a cold solution of the cyanoacetamide 3 (1.60 g, 5 mmol) in pyridine (20 mL),
was added the appropriate diazonium salt of the appropriate aromatic amine (aniline, 4-methoxyaniline
and 4-chloroaniline) (5 mmol), prepared according to literature procedures.61 The addition was carried out
portionwise with stirring at 0-5 oC over a period of 30 min. After complete addition, the reaction mixture
was stirred for further 4 h then kept in an ice chest for 12 h and finally diluted with water. The
precipitated solid was collected by filtration, washed with water, dried and finally recrystallized from the
proper solvent to afford the corresponding hydrazones 13a-c.
2-Cyano-N-(4-{[(5-methylisoxazol-3-yl)amino]sulfonyl}phenyl)-2-(phenylhydrazono)acetamide
o
(13a). Yield (60%), mp 272-274 C (from dioxane); IR (KBr) νmax/cm-1: 3382, 3243, 3080 (3NH), 2992,
1
2890 (aliphatic CH), 2217 (C≡N), 1684 (C=O); H NMR (DMSO-d6)  2.30 (s, 3H, CH3), 6.14 (s, 1H,
isoxazole-H-4), 7.13-7.43 (m, 5H, ArH), 7.82 (d, 2H, J = 9 Hz, ArH), 7.95 (d, 2H, J = 9 Hz, ArH), 10.23
(s, 1H, D2O-exchangeable, NH), 11.32 (s, 1H, D2O-exchangeable, NH), 12.02 (s, 1H, D2O-exchangeable,
NH); MS (m/z, %): 425 (M++1, 6.0), 424 (M+, 9.5), 326 (10.12), 290 (30.9), 279 (14.9), 252 (2.2), 187
(3.1), 172 (19.1), 97 (14.6), 92 (96.2), 77 (100). Anal. Calcd for C19H16N6O4S (424.43): C, 53.77; H,
3.80; N, 19.80; S, 7.55. Found: C, 53.75; H, 3.79; N, 19.78; S, 7.50%.
2-Cyano-2-[(4-methoxyphenyl)hydrazono]-N-(4-{[(5-methylisoxazol-3-yl)amino]sulfonyl}phenyl)-
o
acetamide (13b). Yield (70%), mp 283-295 C (from dioxane); IR (KBr) νmax/cm-1: 3375, 3240, 3084
1
(3NH), 2993, 2896 (aliphatic CH), 2212 (C≡N), 1680 (C=O); H NMR (DMSO-d6)  2.29 (s, 3H, CH3),
3.76 (s, 3H, OCH3), 6.14 (s, 1H, isoxazole-H-4), 6.99 (d, 2H, J = 7.8 Hz, ArH), 7.68 (d, 2H, J = 7.8 Hz,
ArH), 7.84 (d, 2H, J = 9 Hz, ArH), 7.95 (d, 2H, J = 9 Hz, ArH), 10.16 (s, 1H, D2O-exchangeable, NH),
11.32 (s, 1H, D2O-exchangeable, NH), 11.98 (s, 1H, D2O-exchangeable, NH); MS (m/z, %): 455 (M++1,
7.1), 454 (M+, 11.8), 372 (2.6), 357 (1.2), 319 (5.1), 292 (16.1), 217 (1.2), 201 (4.2), 155 (24.4), 135
(21.9), 122 (100), 107 (72.6), 97 (20.9). Anal. Calcd for C20H18N6O5S (454.46): C, 52.86; H, 3.99; N,
18.49; S, 7.06. Found: C, 52.83; H, 3.96; N, 18.45; S, 7.05%.

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2-[(4-Chlorophenyl)hydrazono]-2-cyano-N-(4-{[(5-methylisoxazol-3-yl)amino]sulfonyl}phenyl)-
o
acetamide (13c). Yield (70%), mp 290-292 C (from dioxane); IR (KBr) νmax/cm-1: 3384, 3258, 3079
1
(3NH), 2981, 2887 (aliphatic CH), 2216 (C≡N), 1686 (C=O); H NMR (DMSO-d6)  2.29 (s, 3H, CH3),
6.13 (s, 1H isoxazole-H-4), 7.46 (d, 2H, J = 8.7 Hz, ArH), 7.74 (d, 2H, J = 8.7 Hz, ArH), 7.85 (d, 2H, J =
9 Hz, ArH), 7.94 (d, 2H, J = 9 Hz, ArH), 10.27 (s, 1H, D2O-exchangeable, NH), 11.32 (s, 1H,
D2O-exchangeable, NH), 12.15 (s, 1H, D2O-exchangeable, NH); MS (m/z, %): 459 (M++1, 23.0), 458
(M+, 11.6), 360 (10.4), 325 (7.2), 303 (0.3), 296 (33.8), 279 (20.1), 205 (10.6), 155 (20.8), 140 (19.9), 126
(66.4), 111 (100), 97 (30.3). Anal. Calcd for C19H15ClN6O4S (458.87): C, 49.73; H, 3.29; Cl, 7.73; N,
18.31; S, 6.99. Found: C, 49.71; H, 3.27; Cl, 7.70; N, 18.30; S, 6.96%.
4-[(5-Amino-1H-pyrazol-3-yl)amino]-N-(5-methylisoxazol-3-yl)benzenesulfonamide (14). To
a
solution of the compound 3 (1.60 g, 5 mmol) in dioxane (20 mL), hydrazine hydrate (80%, 1.0 mL) was
added and the reaction mixture was refluxed for 6 h and then allowed to cool. The solid product was
filtered, washed with EtOH and dried. Recrystallized from dioxane afforded 14. Yield (50%), mp
o
1
245-246 C (from dioxane); IR (KBr) νmax/cm-1: 3476, 3372, 3266 (NH, NH2), 1629 (C=O); H NMR
(DMSO-d6)  2.03 (s, 3H, CH3), 4.15 (br., 2H, D2O-exchangeable, NH2), 5.77 (s, 1H, isoxazole-H-4),
6.30 (s, 1H, CH), 6.60 (d, 2H, J = 9 Hz, ArH), 6.85 (s, 1H, D2O-exchangeable, NH), 7.48 (d, 2H, J = 9
Hz, ArH), 7.84 (s, 1H, D2O-exchangeable, NH), 10.45 (s, 1H, D2O-exchangeable, NH); MS (m/z, %): 335
(M++1, 3.9), 334 (M+, 5.3), 272 (5.5), 253 (4.6), 236 (4.1), 172 (67.4), 156 (58.4), 108 (69.8), 92 (85.4),
80 (40.6), 65 (100). Anal. Calcd for C13H14N6O3S (334.35): C, 46.70; H, 4.22; N, 25.14; S, 9.59. Found:
C, 46.67; H, 4.20; N, 25.10; S, 9.55%.
Synthesis of aminopyrazole derivatives 15a-c.
Method A: To a solution of the appropriate hydrazone 13 (5 mmol) in dioxane (20 mL) was added
hydrazine hydrate (5 mmol). The reaction mixture was refluxed for 6 h, and then left to cool. The solid
product was collected, washed with EtOH, dried and finally recrystallized from dioxane to afford the
corresponding 4-arylazopyrazole derivatives 15a-c, respectively.
Method B: To a stirred cold solution of the pyrazole derivative 14 (1.67 g, 5 mmol) in pyridine (30 mL)
was added the appropriate arenediazonium chloride61 (5 mmol) portionwise over a period of 30 min at
0-5 °C. After complete addition, the reaction mixture was stirred for further 3 h at 0-5 °C. The solid
product was collected, washed with water, dried, and finally recrystallization from dioxane afforded the
corresponding aminopyrazoles 15a-c.
4-({5-Amino-4-[phenyldiazenyl]-1H-pyrazol-3-yl}amino)-N-(5-methylisoxazol-3-yl)benzenesulfon-
o
amide (15a). Yield (40%), mp 248-250 C (from dioxane); IR (KBr) νmax/cm-1: 3431, 3367 (NH, NH2),
2921 (aliphatic CH); 1H NMR (DMSO-d6)  2.28 (s, 3H, CH3), 6.05 (s, 2H, D2O-exchangeabl, NH2), 6.14

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(s, 1H, isoxazole-H-4), 6.59 (d, 2H, ArH), 7.18 (d, 2H, J = 9 Hz, ArH), 7.47 (d, 3H, ArH), 7.84 (d, 2H, J
= 9 Hz, ArH), 7.92 (s, 1H, D2O-exchangeable, NH), 10.20 (s, 1H, D2O-exchangeable, NH), 10.82 (s, 1H,
D2O-exchangeable, NH); MS (m/z, %): 439 (M++1, 27.9), 438 (M+, 37.6), 424 (39.3), 356 (58.1), 333
(38.2), 314 (50.6), 251 (40.9), 238 (29.0), 203 (53.8), 186 (29.6), 105 (33.9), 92 (100), 77 (59.7). Anal.
Calcd for C19H18N8O3S (438.46): C, 52.05; H, 4.14; N, 25.56; S, 7.31. Found: C, 52.00; H, 4.10; N,
25.53; S, 7.30%.
4-({5-Amino-4-[(4-methoxyphenyl)diazenyl]-1H-pyrazol-3-yl}amino)-N-(5-methylisoxazol-3-yl)ben-
o
zenesulfonamide (15b). Yield (72%), mp 234-236 C (from dioxane); IR (KBr) νmax/cm-1: 3345, 3219
1
(NH, NH2), 2970, 2857 (aliphatic CH); H NMR (DMSO-d6)  2.29 (s, 3H, CH3), 3.39 (s, 3H, OCH3),
6.05 (s, 2H, D2O-exchangeable, NH2), 6.13 (s, 1H, isoxazole-H-4), 7.09 (d, 2H, J = 7.8 Hz, ArH), 7.37 (d,
2H, J = 9 Hz, ArH), 7.51 (d, 2H, J = 7.8 Hz, ArH), 7.87 (d, 2H, J = 9 Hz, ArH), 7.93 (s, 1H,
D2O-exchangeable, NH), 9.97 (s, 1H, D2O-exchangeable, NH), 10.40 (s, 1H, D2O-exchangeable, NH);
MS (m/z, %): 469 (M++1, 12.2), 468 (M+, 10.6), 458 (10.8), 437 (10.2), 368 (16.9), 255 (13.3), 206 (10.8),
156 (34.1), 135 (10.2), 119 (43.7), 108 (58.8), 92 (100). Anal. Calcd for C20H20N8O4S (468.49): C, 51.27;
H, 4.30; N, 23.92; S, 6.84. Found: C, 51.24; H, 4.28; N, 23.90; S, 6.82%.
4-({5-Amino-4-[(4-chlorophenyl)diazenyl]-1H-pyrazol-3-yl}amino)-N-(5-methylisoxazol-3-yl)benze-
nsulfonamide (15c). Yield (75%), mp 250-252 oC (from dioxane); IR (KBr) νmax/cm-1: 3460, 3369, 3185
1
(NH, NH2), 2922, 2856 (aliphatic CH); H NMR (DMSO-d6)  2.28 (s, 3H, CH3), 5.83 (s, 1H,
isoxazole-H-4), 6.07 (s, 2H, D2O-exchangeable, NH2), 6.59 (d, 2H, J = 8.7 Hz, ArH), 7.47 (d, 2H, J = 9
Hz, ArH), 7.59 (d, 2H, J = 8.7 Hz, ArH), 7.84 (d, 2H, J = 9 Hz, ArH), 7.95 (s, 1H, D2O-exchangeable,
NH), 10.52 (s, 2H, D2O-exchangeable, 2NH); MS (m/z, %): 473 (M++1, 47.5), 472 (M+, 71.3), 440 (72.9),
292 (60.7), 237 (100), 219 (59.8), 152 (50.8), 111 (46.7), 98 (47.5), 82 (60.7). Anal. Calcd for
C19H17ClN8O3S (472.90): C, 48.26; H, 3.62; Cl, 7.50; N, 23.69; S, 6.78. Found: C, 48.24; H, 3.60; Cl,
7.48; N, 23.66; S, 6.76%.
Reaction of hydrazones 13a-c with ethyl chloroformate. Formation of the triazine derivatives 16a-c.
To a solution of the hydrazone 13a-c (1 mmol) in acetic acid (20 mL), ethyl chloroformate (1 mmol) was
added and the reaction mixture was refluxed for 8 h, then left to cool. The solid product was filtered off,
washed with EtOH, dried, and finally recrystallized from dioxane afforded the corresponding triazine
derivatives 16a-c.
4-(6-Cyano-3,5-dioxo-2-phenyl-2,5-dihydro-1,2,4-triazin-4(3H)-yl)-N-(5-methylisoxazol-3-yl)benz-
enesulfonamide (16a). Yield (70%), mp > 300 ºC (from dioxane); IR (KBr) νmax/cm-1: 3383 (NH), 2992,
1
2894 (aliphatic CH), 2219 (C≡N), 1682 (C=O); H NMR (DMSO-d6)  2.30 (s, 3H, CH3), 6.14 (s, 1H,
isoxazole-H-4), 7.18 (s, 1H, ArH), 7.43 (d, 2H, J = 9 Hz, ArH), 7.73 (s, 2H, ArH), 7.85 (s, 2H, ArH),

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8.06 (d, 2H, J = 9 Hz, ArH), 10.23 (s, 1H, D2O-exchangeable, NH); MS (m/z, %): 450 (M+, 38.0), 416
(52.8), 368 (42.9), 355 (44.8), 337 (33.1), 284 (47.9), 268 (50.3), 213 (60.1), 136 (45.4), 77 (86.5), 65
(100). Anal. Calcd for C20H14N6O5S (450.42): C, 53.33; H, 3.13; N, 18.66; S, 7.12. Found: C, 53.31; H,
3.11; N, 18.63; S, 7.09%.
4-[6-Cyano-2-(4-methoxyphenyl)-3,5-dioxo-2,5-dihydro-1,2,4-triazin-4(3H)-yl]-N-(5-methylisoxazol-
o
3-yl)benzenesulfonamide (16b). Yield (75%), mp 292-294 C (from dioxane); IR (KBr) νmax/cm-1 3381
1
(NH), 2991, 2896 (aliphatic CH), 2214 (C≡ N), 1682 (C=O); H NMR (DMSO-d6)  2.32 (s, 3H, CH3),
3.85 (s, 3H, OCH3), 6.23 (s, 1H, isoxazole-H-4), 7.14 (d, 2H, J = 9 Hz, ArH), 7.51 (d, 2H, J = 8.7 Hz,
ArH), 7.67 (d, 2H, J = 8.7 Hz, ArH), 8.05 (d, 2H, J = 9 Hz, ArH), 11.60 (s, 1H, D2O-exchangeable, NH);
MS (m/z, %): 481 (M++1, 23.7), 480 (M+, 18.1), 457 (16.7), 397 (19.0), 375 (16.9), 307 (18.4), 240 (16.7),
237 (16.1), 215 (20.8), 133 (20.5), 111 (18.1), 107 (16.9), 97 (60.6), 92 (16.1), 80 (100). Anal. Calcd for
C21H16N6O6S (480.45): C, 52.50; H, 3.36; N, 17.49; S, 6.67. Found: C, 52.48; H, 3.33; N, 17.46; S,
6.65%.
4-[2-(4-Chlorophenyl)-6-cyano-3,5-dioxo-2,5-dihydro-1,2,4-triazin-4(3H)-yl]-N-(5-methylisoxazol-3-
yl)benzenesulfonamide (16c). Yield (65%), mp > 300 ºC (from dioxane); IR (KBr) νmax/cm-1: 3427 (NH),
1
2927 (aliphatic CH), 2197 (C≡N), 1628 (C=O); H NMR (DMSO-d6)  2.28 (s, 3H, CH3), 6.02 (s, 1H,
isoxazole-H-4), 7.74-7.77 (m, 4H, ArH), 7.82 (d, 2H, ArH), 8.25 (s, 2H, ArH), 10.65 (s, 1H,
D2O-exchangeable, NH); MS (m/z, %): 485 (M++1, 5.2), 484 (M+, 83.2), 450 (61.1), 402 (66.3), 373
(61.1), 347 (57.9), 278 (82.1), 249 (80.0), 237 (54.7), 138 (90.5), 110 (65.3), 98 (100). Anal. Calcd for
C20H13ClN6O5S (484.87): C, 49.54; H, 2.70; Cl, 7.31; N, 17.33; S, 6.61. Found: C, 49.51; H, 2.68; Cl,
7.29; N, 17.31; S, 6.59%.
Synthesis of compounds 18, 19 and 20.
General procedure:
To a stirred suspension of finely powdered potassium hydroxide (0.26 g, 5 mmol) in dry DMF (20 mL)
cyanoacetamide 3 (1.60 g, 5 mmole) was added. The resulting mixture was cooled at 10 oC in an ice bath,
then carbon disulfide (5 mmol) was added slowly over the course of 10 min. After complete addition,
stirring was continued for additional 2 h, then dibromoethane or dibromopropane or dimethyl sulfate (5
mmol) was added to the mixture while cooling (~15 oC) and stirring for 1 h. then poured into crushed ice,
the resulting precipitate was filtrated off, dried, and finally crystallized from the proper solvent to give
18-20.
2-Cyano-2-(1,3-dithiolan-2-ylidene)-N-(4-{[(5-methylisoxazol-3-yl)amino]sulfonyl}phenyl)acetamide
(18). Yield (70%), mp 200-202 oC (from dioxane); IR (KBr) νmax/cm-1: 3327, 3277 (2NH), 2962 (aliphatic
CH), 2190 (C≡N), 1692 (C=O); 1H NMR (DMSO-d6)  2.28 (s, 3H, CH3), 3.95 (s, 4H, 2CH2), 6.11 (s, 1H,

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HETEROCYCLES, Vol. 89, No. 6, 2014
isoxazole-H-4), 7.72 (d, 2H, J = 9 Hz), 7.84 (d, 2H, J = 9 Hz), 10.69 (s, 1H, D2O-exchangeable, NH),
11.32 (s, 1H, D2O-exchangeable, NH); 13C NMR (DMSO-d6) δ 11.9, 29.9, 95.3, 112.5, 115.5, 119.0,
128.1, 133.8, 142.5, 153.2, 157.4, 161.8, 170.2; MS (m/z, %): 422 (M+, 35.7), 353 (54.1), 338 (44.3), 326
(33.5), 284 (36.8), 252 (37.8), 238 (35.1), 186 (100), 169 (28.1), Anal. Calcd for C16H14N4O4S3 (422.50):
C, 45.48; H, 3.34; N, 13.26; S, 22.77. Found: C, 45.46; H, 3.31; N, 13.24; S, 22.75%.
2-Cyano-2-(1,3-dithian-2-ylidene)-N-(4-{[(5-methylisoxazol-3-yl)amino]sulfonyl}phenyl)acetamide
(19). Yield (50%), mp 205-207 oC (from dioxane); IR (KBr) νmax/cm-1: 3324, 3277 (2NH), 2960 (aliphatic
1
CH), 2208 (C≡N), 1691 (C=O); H NMR (DMSO-d6)  2.10 (m, 2H, J = 6.80 Hz, CH2), 2.29 (s, 3H,
CH3), 3.03 (t, 2H, J = 6.6 Hz, CH2), 3.21 (t, 2H, J = 6.6 Hz, CH2), 6.11 (s, 1H, isoxazole-H-4), 7.74 (d,
2H, J = 9 Hz, ArH), 7.83 (d, 2H, J = 9 Hz, ArH), 10.68 (s, 1H, D2O-exchangeable, NH), 11.32 (s, 1H,
D2O-exchangeable, NH); MS (m/z, %): 436 (M+, 9.4), 356 (8.4), 335 (12.3), 280 (11.8), 255 (17.2), 253
(8.4), 238 (13.1), 200 (16.2), 186 (98.7), 155 (16.5), 97 (15.4), 68 (100). Anal. Calcd for C17H16N4O4S3
(436.53): C, 46.77; H, 3.69; N, 12.83; S, 22.04. Found: C, 46.75; H, 3.66; N, 12.80; S, 22.00%.
2-Cyano-N-(4-{[(5-methylisoxazol-3-yl)amino]sulfonyl}phenyl)-3,3-bis(methylthio)acrylamide (20).
o
Yield (90%), mp 180-182 C (from EtOH); IR (KBr) νmax/cm-1: 3325, 3275 (2NH), 2969 (aliphatic CH),
2186 (C≡N), 1640 (C=O); 1H NMR (DMSO-d6)  2.29 (s, 3H, CH3), 2.44 (s, 3H, CH3), 2.49 (s, 3H, CH3),
6.14 (s, 1H, isoxazole-H-4), 7.80 (d, 2H, J = 9 Hz, ArH), 7.95 (d, 2H, J = 9 Hz, ArH), 10.68 (s, 1H,
D2O-exchangeable, NH), 11.34 (s, 1H, D2O-exchangeable, NH); MS (m/z, %): 425 (M++1, 28.5), 424
(M+, 42.5), 392 (41.9), 342 (38.3), 327 (30.1), 236 (40.4), 186 (33.7), 171 (41.9), 144 (27.9), 99 (34.2), 82
(49.2), 64 (100). Anal. Calcd for C16H16N4O4S3 (424.52): C, 45.27; H, 3.80; N, 13.20; S, 22.66. Found: C,
45.25; H, 3.78; N, 13.17; S, 22.64%.
Antimicrobial Evaluation
The antibacterial and antifungal activity assays were carried out in the Medical Mycology Laboratory of
the Regional Center for Mycology and Biotechnology of Al-Azhar University, Cairo, Egypt. Using the
diffusion plate method.62-64 A bottomless cylinder containing a measured quantity (1 mL, mg/mL) of the
sample is placed on a plate (9 cm diameter) containing a solid bacterial medium (nutrient agar broth) or
fungal medium, which has been heavily seeded with a spore suspension of the test organism. After
incubation (24 h for bacteria and 5 days for fungi), the diameter of the clear zone of inhibition
surrounding the sample is taken as measure of the inhibitory power of the sample against the particular
test organism. The solvent used was DMSO and the concentration of the sample used is 100 μg/mL. The
results of antimicrobial activity are summarized in Table 1.

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