Convenient synthesis of novel sulfonamide derivatives as promising anticancer agents

Article abstract of DOI:10.1002/jhet.3849

Novel sulfonamide derivatives have been synthesized from the readily accessible N-(4-acetylphenyl)benzenesulfonamide (1). Condensation of 1 with phenylhydrazine in refluxing ethyl alcohol gave the corresponding phenylhydrazone 2, which was then added to the Vilsmeier-Haack reagent (POCl₃/DMF) to give the 4-formylpyrazole derivative 3. Fusion of 1 with thiourea in the presence of iodine at 130°C afforded the 2-aminothiazole derivative 4. Refluxing 1 with an excess of N, N-dimethylformamide dimethyl acetal furnished the enaminone 5. The chemical reactivity of enaminone 5 toward some nitrogen and carbon nucleophiles has been studied to obtain polyfunctionalized heteroaromatic systems bearing a sulfonamide moiety. Besides, the enaminone 5 undergoes the Gewald reaction and reacts with ethyl cyanoacetate and elemental sulfur in the presence of morpholine to yield the 2-aminothiophene derivative 18. Moreover, the utility of 5 for the synthesis of 4-(phenylsulfonamido)benzoic acid (19) was investigated. The synthesized sulfonamides were evaluated for their in vitro cytotoxic activities against two human cell lines, MCF-7 (breast adenocarcinoma cells) and RPE-1 (normal retina pigmented epithelium cells). The results revealed that compounds 1-3, 6-8, 10, 12b, 18, 19, and 21 have a potent cytotoxic effect on MCF-7 and less on RPE-1 cells compared to the positive control doxorubicin.

Full text of DOI:10.1002/jhet.3849

Received: 28 June 2019
DOI: 10.1002/jhet.3849
Revised: 11 November 2019
Accepted: 19 November 2019
A R T I C L E
Convenient synthesis of novel sulfonamide derivatives
as promising anticancer agents
Ahmed El-Mekabaty1
| Hanem M. Awad2
1Department of Chemistry, Faculty of
Science, Mansoura University, Mansoura,
Egypt
2Department of Tanning Materials and
Leather Technology, National Research
Centre, Cairo, Egypt
Abstract
Novel sulfonamide derivatives have been synthesized from the readily accessi-
ble N-(4-acetylphenyl)benzenesulfonamide (1). Condensation of 1 with
phenylhydrazine in refluxing ethyl alcohol gave the corresponding
phenylhydrazone 2, which was then added to the Vilsmeier-Haack reagent
(POCl3/DMF) to give the 4-formylpyrazole derivative 3. Fusion of 1 with thio-
urea in the presence of iodine at 130ꢀC afforded the 2-aminothiazole derivative
4. Refluxing 1 with an excess of N, N-dimethylformamide dimethyl acetal
furnished the enaminone 5. The chemical reactivity of enaminone 5 toward
some nitrogen and carbon nucleophiles has been studied to obtain poly-
functionalized heteroaromatic systems bearing a sulfonamide moiety. Besides,
the enaminone 5 undergoes the Gewald reaction and reacts with ethyl
cyanoacetate and elemental sulfur in the presence of morpholine to yield the
2-aminothiophene derivative 18. Moreover, the utility of 5 for the synthesis of
4-(phenylsulfonamido)benzoic acid (19) was investigated. The synthesized sul-
fonamides were evaluated for their in vitro cytotoxic activities against two
human cell lines, MCF-7 (breast adenocarcinoma cells) and RPE-1 (normal
retina pigmented epithelium cells). The results revealed that compounds 1-3,
6-8, 10, 12b, 18, 19, and 21 have a potent cytotoxic effect on MCF-7 and less on
RPE-1 cells compared to the positive control doxorubicin®.
Correspondence
Ahmed El-Mekabaty, Department of
Chemistry, Faculty of Science, Mansoura
University, El-Gomhoria Street, ET-35516
Mansoura, Egypt.
Email: elmekabaty@mans.edu.eg;
a_el_m11@yahoo.com
K E Y W O R D S
anticancer activity, enaminones, Pyrazole, pyrimidine, pyridine, sulfonamides
1 | INTRODUCTION
transcriptional activator NF-Y, and inhibition of angio-
genesis among others.[8] The most important one is their
Aryl/heteroaryl sulfonamides are versatile compounds of
significant synthetic and biological properties that are
widely applied.[1–4] The synthesis of various sulfonamide
derivatives has attracted substantial interest as many of
them show wonderful anticancer activity in vitro and
in vivo against diverse cancer cell lines.[5–7] There are a
number of mechanisms that illustrate the anticancer
action of sulfonamides, including carbonic anhydrase
inhibition, disruption of microtubule assembly, cell cycle
release in the G1 phase, functional suppression of the
ability to act as carbonic anhydrase inhibitors.[9,10] Car-
bonic anhydrases (CA) are a group of metalloenzymes able
to catalyze the hydration of carbon dioxide to bicarbonate
with generation of protons. Several carbonic anhydrase
isoforms have been identified, among them the transmem-
brane isoforms (hCA IX and hCA XII), associated with
some types of cancers induced by tumor hypoxia with lim-
ited expression in normal tissues.[11] Many sulfonamide
derivatives have been reported as selective inhibitors of
hCA IX and hCA XII.[11–13] In addition, sulfonamides are
J Heterocyclic Chem. 2019;1–10.
wileyonlinelibrary.com/journal/jhet
© 2019 Wiley Periodicals, Inc.
1

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EL-MEKABATY AND AWAD
1
widely used clinically as antimicrobial,[14] antithyroid,[15]
antioxidant,[3] antituberculosis,[5] hypoglycemic,[16] and
non-nucleoside HIV reverse transcriptase and HIV
integrase inhibitors.[8,17,18] Some noteworthy examples of
biologically active drugs containing sulfonamide are shown
in Figure 1.[3,8,19]
In the light of the immense biological significance of
sulfonamides and in the continuity of our research pro-
jects on the synthesis of biologically effective
compounds,[20–23] we have undertaken in this study the
synthesis of novel sulfonamide derivatives from the read-
ily accessible N-(4-acetylphenyl)benzenesulfonamide
(1)[24,25] to evaluate their cytotoxic activities in vitro.
9.28 ppm, respectively in the H-NMR spectrum of the
pyrazole 3. N-(4-(2-Aminothiazol-4-yl)phenyl)
benzenesulfonamide (4) could be obtained using a
Hantzsch's modified method that involves the
cyclocondensation of acetylsulfonamide 1 and thiourea in
the presence of iodine. This process yields the
2-aminothiazole derivative 4 as a hydroiodide salt, which
is converted into a free base when treated with an aqueous
alkaline solution. Two important absorption bands were
appeared in the IR spectrum of thiazole 4 at 3243-3170
cm−1, characteristic of the amino group. Besides, the H-
1
NMR spectrum disclosed two singlet signals at δ 6.99 and
6.94 ppm, indicating the presence of the thiazole-H5 and
amino protons, respectively. Moreover, the mass spectrum
showed the molecular ion at m/z = 331.25 (M+, 18.83)
and fragment ion peaks with m/z 325, 305, 299, 291,
287, 255, 145, and so on. The fragment ion peak at m/z
82 (40.81 %) identifying the thiazole unit. The key precur-
sor enaminone 5 was achieved in 81% yield by refluxing a
mixture of acetylsulfonamide 1 with an excess of
DMF/DMA (1:3 mole) for 3 h in the absence of solvent.
The enaminone 5 was formed exclusively through the 1H-
NMR spectrum that had two doublets at δ 7.45 and
5.80 ppm with J = 12.5 Hz attributable to the olefinic pro-
tons and two sharp singlet signals at δ 3.19 and 3.12 ppm
specific for N, N-dimethylamino protons.
2 | RESULTS AND DISCUSSION
2.1 | Chemistry
Condensation of 1 with phenylhydrazine in refluxing ethyl
alcohol afforded the corresponding phenylhydrazone 2,
which was added to the Vilsmeier-Haack reagent (POCl3/
DMF) to yield N-(4-(4-formyl-1-phenyl-1H-pyrazol-3-yl)
phenyl)benzenesulfonamide (3) (Scheme 1). We observed
the presence of two singlet signals of expressed the alde-
hyde proton (CHO) and pyrazole-H5 protons at δ 9.98 and
FIGURE 1 Biologically active
drugs bearing sulfonamide moiety
SCHEME 1 Synthesis of
pyrazole, thiazole, and
enaminone derivatives

EL-MEKABATY AND AWAD
3
Next, the reaction of enaminone 5 with nitrogen
nucleophiles such as hydrazine hydrate, urea, guanidine
and methyl 2-aminobenzoate, represents a simple syn-
thetic route for obtaining polyfunctionalized hetero-
aromatic systems bearing a sulfonamide moiety. In this
context, treatment of enaminone 5 with hydrazine
hydrate in refluxing acetic acid produced pyrazole
pharmacological properties.[26,27] Thus, N-(4-(4-oxo-1,-
4-dihydroquinoline-3-carbonyl)phenyl)
benzenesulfonamide (10) was obtained in 41% yield by
refluxing a mixture of 5 with methyl 2-aminobenzoate in
a Ph2O/methanol mixture in the presence of strong base
such as sodium methanolate. The reaction involves an
initial Michael-type addition of NH2 group in methyl
2-aminobenzoate to the activated ethylenic double bond
in enaminone 5 to give the nonisolable enaminoester
9 monitored by intramolecular enaminic cyclisation by
elimination of methanol molecule. 4-Quinolinone 10 can
exist as the 4-quinolinol tautomer 100.[28] The NMR
studies[29–31] revealed that only the 4-quinolinone 10
was present in DMSO-d6. The IR spectrum of the
4-quinolinone 10 showed a strong absorption bands at
νmax = 1677, 1641, 3391, and 3279 cm−1 for two CO and
two NH groups, respectively. Two important singlet sig-
1
6 through the H-NMR spectrum, which disclosed two
protons of the pyrazole ring as two doublets at δ 7.16 and
6.60 ppm with J = 7.5 Hz and a broad signal of highly
deshielded pyrazole-NH proton at δ 12.53 ppm. Its mass
spectrum showed a prominent molecular ion peak at m/z
299.16 (M+, 17.36), and a fragment ion peak at m/z
66 (46.48 %) corresponding to the pyrazole unit
(Scheme 2). The formation of pyrazole 6 may involve an
initial Michael-type addition of NH2 group in hydrazine
hydrate to the activated ethylenic double bond in
enaminone 5 monitored by cyclization through the elimi-
nation of (CH3)2NH and H2O molecules. Similarly,
enaminone 5 reacted with urea in refluxing acetic acid to
give 2-pyrimidinone 7. When 5 was subjected to react
with guanidine hydrochloride in ethanolic sodium
ethoxide under reflux, gave 2-aminopyrimidine 8 in a
good yield. The two protons of the formed pyrimidine
1
nals appeared in the H-NMR spectrum of 4-quinolinone
10 at δ 8.64 and 12.99 ppm due to quinolinone-H2 and
NH protons, respectively.
The previous results have prompted us to study the
reactivity of enaminone 5 with respect to some carbon
nucleophiles as potential synthetic route to achieve
pyridine and benzonitrile derivatives bearing a sulfon-
amide moiety. Thus, the behavior of 5 with ethyl
acetoacetate or acetylacetone and ammonium acetate
in refluxing acetic acid produced the corresponding
pyridine derivatives 12a,b, respectively (Scheme 3).
This process takes place by initial substitution of the
dimethylamino group followed by cyclization in the
presence of ammonium acetate. A similar formation of
pyridine derivatives 12a,b has already been reported in
1
ring are demonstrated on the H-NMR spectrum in the
form of two doublets at δ 8.46 and 6.95 ppm with the
same coupling constant (J = 6.0 Hz). Another important
broad singlet signal appeared at δ 6.03 ppm (D2O-
exchangable) due to NH2 protons. We have also studied
the reactivity of enaminone
5
toward methyl
2-aminobenzoate as an easy synthetic route to obtain
4-quinolinone analogs with a high scale of biological and
SCHEME 2 Reaction of
enaminone 5 with nitrogen
nucleophilic agents

4
EL-MEKABATY AND AWAD
the literature.[32–34] Heating enaminone 5 with diethyl
3-amino-2-cyanopent-2-enedioate in ethanolic sodium
ethoxide afforded the benzonitrile derivative 15
through the intermediates 13 and 14. Elemental and
spectral data were found to be in good agreement with
the benzonitrile derivative 15.
Despite extensive literature on the use of enaminones as
valuable precursors in heterocyclic synthesis, we have found
only a few examples of 2-aminothiophenes synthesis using
enaminones.[35–38] In this effort, the enaminone 5 undergoes
the Gewald reaction and smoothly reacts with ethyl
cyanoacetate and elemental sulfur in the presence of mor-
pholine to yield the 2-aminothiophene derivative 18 in 72%
yield (Scheme 4). As previously proposed,[37] the reaction
sequence involves Michael addition of active methylene of
ethyl cyanoacetate to the activated double bond of 5 to yield
the adduct 16, followed by the addition of sulfur to afford 17
that would be cyclized and aromatized by elimination of both
dimethylamine and H2S. The IR spectrum of 18 showed the
presence of an amino group at νmax = 3342–3270 cm−1 and
carbonyl of ester group at νmax
=
1679 cm−1.
2-Aminothiophene derivative 18 was also examined via 1H-
NMR spectrum that displayed a singlet signal in the region of
aromatic signals at δ 7.80 ppm corresponding to thiophene-
H4. In addition to the presence of amino protons at δ
7.18 ppm and ester protons (up-field region) as triplet signals
at δ 1.23 and quartet signals at δ 4.20 ppm.
To further explore the synthetic potentiality of
enaminone 5, we have studied its utility for the synthesis
of 4-(phenylsulfonamido)benzoic acid (19) (Scheme 5).
When 5 was subjected to react with sulfuryl dichloride, it
afforded a white crystalline product similar in all respects
SCHEME 3 Reaction of
enaminone 5 with carbon
nucleophilic agents
SCHEME 4 Synthesis of 2-aminothiophene derivative 18

EL-MEKABATY AND AWAD
5
(TLC, mp, and mixed mp) to that obtained previously in
the literature.[39] It should be noted that, a previous
report[40] described the reaction mechanism for the pro-
duction of acid 19 in a similar process. The reaction
mechanism involves the halogenation of enaminone 5 at
the electron-rich C-2 atom by sulfuryl dichloride that can
release positively induced chlorine and subsequent
hydrolysis of the resulting iminium ion to give the non-
isolable intermediate α-chloro-β-ketoaldehyde, which
was then hydrolyzed by atmospheric moisture to the aro-
matic carboxylic acid 19. The carboxylic group demon-
strated on the IR spectrum as two absorption bands at
3272 and 1677 cm−1. Besides, the 1H-NMR spectrum
exhibited downfield shifted singlet signal of COOH pro-
ton at δ 10.89 ppm. Treatment of 19 with an excess of
thionyl chloride gave the corresponding acid chloride
20,[41] which then readily reacted with 2-aminobenzoic
acid in dry pyridine to afford N-(4-(4-oxo-4H-3,-
The two remaining active compounds, namely 12a and
15 showed moderate activity with IC50 33.7 and 42.8 μM,
respectively. A single compound 5 showed a decrease in
its cytotoxic activity (Figure 2). In the case of the RPE-1
cell line, compound 5 showed diminishing in its cytotoxic
activity with IC50 at 107.8 μM. The lower activity has also
been demonstrated by compounds 1, 2, 12a, and 15 that
have IC50 at 88.6, 73.4, 74.2, and 89.8 μM, respectively,
while the remaining compounds exhibited moderate
activity. Only one compound 4 exhibited high cytotoxic
activity with IC50 at 19.5 μM (Figure 3). In general, com-
pound 4 showed high cytotoxicity against both human
cell lines. Also, compound 5 showed diminishing in its
cytotoxicity against the human normal cells; however, its
TABLE 1 The anticancer IC50 values of the synthesized
sulfonamides using the MTT assay against one human cancer cell
line (MCF-7) and one human normal cell line (RPE-1)
1-benzoxazin-2-yl)phenyl)benzenesulfonamide (21).
A
IC50 (μM) SD
strong lactone absorption band appeared in the IR spec-
trum of benzoxazinone 21 at 1764 cm−1. The mass spec-
trum revealed a prominent molecular ion peak at m/z
= 379.84 (M++1, 24.30).
Compound
MCF-7
RPE-1
1
26.2 3.2
21.1 2.9
21.2 2.6
8.9 1.1
88.6 5.1
73.4 4.3
67.9 3.5
19.5 1.6
107.8 4.6
68.5 3.2
63.3 4.8
66.6 3.7
52.5 2.9
74.2 4.1
68.2 3.4
89.8 4.3
53.7 3.7
65.2 4.2
62.4 3.9
40.2 2.1
2
3
4
2.2 | In vitro cytotoxic activity
5
81.5 4.5
24.8 2.6
27.6 3.1
27.1 2.8
26.8 2.1
33.7 3.5
28.3 2.7
42.8 3.9
22.8 2.6
26.3 2.5
27.3 1.9
18.6 1.4
Fifteen compounds were examined in vitro for their cyto-
toxic activities against human breast adenocarcinoma
cells (MCF-7) and human normal retina pigmented epi-
thelium cells (RPE-1) using the MTT colorimetric
assay.[42,43] These human cell lines were purchased from
ATCC (Rockville, MD). Doxorubicin® has been utilized
as a standard anticancer drug for comparison. The 50%
inhibitory concentration (IC50) was determined and
reported in Table 1. For activity against the MCF-7 cell
line, the highest cytotoxic activity was presented by com-
pound 4 with IC50 8.9 μM. A remarkable inhibitory activ-
ity has also been demonstrated by compounds 1-3, 6-8,
10, 12b, 18, 19, and 21 with IC50 range of 21.1–28.3 μM.
6
7
8
10
12a
12b
15
18
19
21
Doxorubicin®
SCHEME 5 Synthesis of
benzoxazinone 21

6
EL-MEKABATY AND AWAD
FIGURE 2 The dose dependent anticancer activity curves of the synthesized sulfonamides against human breast adenocarcinoma cells
(MCF-7)
FIGURE 3 The dose dependent cytotoxic activity curves of the synthesized sulfonamides against human normal retina pigmented
epithelium cells (RPE-1)
activity has been reversed to be cytoprotective and pro-
liferation stimulation on the human cancer cells.
Therefore, the tested compounds 1-3, 6-8, 10, 12b, 18,
19, and 21 may be used as promising anticancer drugs
as they have a relieve effect on normal cells (RPE-1)
and potent on cancer cells (MCF-7), compared to the
positive control doxorubicin®. We can conclude that
the observed anticancer activity of 4-formylpyrazole
derivative 3 could be attributed to the synergistic effect
of the pyrazole moiety. Also, the conversion of
acetylsulfonamide 1 to enaminone 5 unfortunately
decreases the cytotoxicity against MCF-7 cell line.
However, the cyclization of enaminone 5 through its
reactions with nitrogen and carbon nucleophiles is
very important for the production of highly effective
compounds as anticancer agents.
a relieving effect against normal cells (RPE-1) and potent
against cancer cells (MCF-7).
4 | EXPERIMENTAL
4.1 | General
Melting points were measured on an electrothermal Gal-
lenkamp apparatus (Germany) and are uncorrected. The
infrared spectra were determined on a Thermo Scientific
1
Nicolet iS10 FTIR spectrometer (Waltham, MA). The H
NMR and 13C NMR spectra were measured on a Bruker
Avance III spectrometer (Germany) at 400 and 100 MHz,
respectively. The mass spectra were run on Kratos MS
(Kratos Analytical Instrument, Ramsey, NJ) apparatus and
the ionizing voltage was 70 ev. Elemental analyses (C, H,
and N) were determined on Perkin Elmer 2400 analyzer.
3 | CONCLUSION
In brief, we have synthesized new sulfonamide deriva-
tives using an inexpensive and readily accessible starting
material to evaluate their cytotoxic activities in vitro. In
this study, compounds 1-3, 6-8, 10, 12b, 18, 19, and 21
may be used as promising anticancer drugs as they have
4.2 | N-(4-(1-(2-Phenylhydrazineylidene)
ethyl)phenyl)benzenesulfonamide (2)
A mixture of N-(4-acetylphenyl)benzenesulfonamide (1)
(1.37 g, 0.005 mol) and phenylhydrazine (0.54 g,

EL-MEKABATY AND AWAD
7
0.005 mol) was refluxed in 30 mL ethyl alcohol for 10 h.
The phenylhydrazone that formed after cooling was
picked up by filtration and can be used in the next reac-
tion without purification.
(1.37 g, 0.005 mol) and thiourea (0.76 g, 0.01 mol). After
the addition was complete, the thick mass was heated for
8 h at 130οC, then cooled and washed with methanol.
The crude product was dissolved in hot water and the
aminothiazole was precipitated by the addition of
NH4OH. The resulting crushed solid was picked up by fil-
tration and finally recrystallized by heating in
DMF/EtOH mixture (1:3).
Yellow crystals; yield 79%; mp 148–150ꢀC. IR (KBr,
cm−1) νmax: 3255, 3189 (2 NH), 3084 (C H, aromatic),
2932, 2850 (C H, aliphatic), 1600 (C N), 1501 (C C),
1
1332, 1158 (SO2). H-NMR (DMSO) δ (ppm): 10.68 (s,
1H, NH), 8.80 (s, 1H, NH), 7.97-7.14 (m, 14H, Ar H),
2.42 (s, 3H, CH3). MS (m/z, %): 365.49 (M+, 27.63), 359.31
(50.23), 325.10 (50.91), 284.33 (100.00), 245.37 (41.53),
158.88 (41.94), 141.68 (17.71), 113.70 (75.48), 90.39
(39.51). Anal. calcd. for C20H19N3O2S (365.45): C,
65.73; H, 5.24; N, 11.50%. Found: C, 65.76; H, 5.23; N,
11.53 %.
Brown powder; yield 59%; mp 204–206ꢀC. IR (KBr,
cm−1) νmax: 3415 (NH), 3243-3170 (NH2), 3059 (C H,
aromatic), 1639 (C N), 1585 (C C), 1366, 1124 (SO2).
1H-NMR (DMSO) δ (ppm): 8.68 (s, 1H, NH), 7.94-7.26
(m, 9H, Ar H), 6.99 (s, 1H, thiazole-H5), 6.94 (s, 2H,
NH2). 13C-NMR (DMSO) δ (ppm): 167.87 (thiazole-C2),
153.41 (thiazole-C4), 141.96, 140.80, 135.19, 129.99,
128.19, 126.36, 123.33, 116.36 (Ar-C), 101.44 (thiazole-
C5). MS (m/z, %): 331.25 (M+, 18.83), 325.07 (47.39),
305.67 (46.31), 299.70 (59.41), 291.41 (60.28), 287.93
(51.55), 255.26 (85.11), 145.24 (100.00), 118.14 (35.73),
97.88 (37.80), 92.04 (67.13), 82.99 (40.81), 64.42 (57.74).
Anal. calcd. for C15H13N3O2S2 (331.41): C, 54.36; H,
3.95; N, 12.68 %. Found: C, 54.32; H, 3.96; N, 12.64 %.
4.3 | N-(4-(4-Formyl-1-phenyl-1H-
pyrazol-3-yl)phenyl)
benzenesulfonamide (3)
To a cold solution of phenylhydrazone 2 (1.46 g,
4 mmol) in DMF (10 mL), phosphorus oxychloride
(0.55 mL, 6 mmol) was added dropwise with stirring
for 15 min. Stirring was continued for 1 h at room tem-
perature. The mixture was heated at 70–80ꢀC for 2 h,
then cooled at 25ꢀC and poured onto ice-cold water. A
saturated solution of K2CO3 was added to neutralize
the mixture. The 4-formylpyrazole 3 was filtered off,
washed extensively with water and recrystallized by
boiling in ethyl alcohol.
4.5 | N-(4-(3-(Dimethylamino)acryloyl)
phenyl)benzenesulfonamide (5)
A mixture of sulfonamide 1 (2.75 g, 0.01 mol) and N, N-
dimethylformamide dimethyl acetal (3.57 g, 0.03 mol)
was refluxed for 3 h, then allowed to cool in the refrigera-
tor. The enaminone that formed was separated and rec-
rystallized by heating in ethyl alcohol.
Orange needles; yield 81%; mp 211-213ꢀC. IR (KBr,
cm−1) νmax: 3434 (NH), 3061 (C H, aromatic), 2929, 2858
(C H, aliphatic), 1678 (C O), 1599 (C C), 1350, 1172
(SO2). 1H-NMR (DMSO) δ (ppm): 8.88 (s, 1H, NH),
7.93-7.29 (m, 9H, Ar H), 7.45, 5.80 (2d, 2H, CH CH,
J = 12.5 Hz), 3.19 (s, 3H, NCH3), 3.12 (s, 3H, NCH3). MS
(m/z, %): 330.67 (M+, 15.67), 286.48 (12.40), 259.17
(40.08), 246.23 (41.74), 231.34 (28.07), 160.57 (46.01),
156.79 (38.12), 124.04 (34.62), 117.04 (100.00), 109.20
(41.02), 64.83 (40.49). Anal. calcd. for C17H18N2O3S
(330.40): C, 61.80; H, 5.49; N, 8.48 %. Found: C, 61.78; H,
5.47; N, 8.45%.
Grey powder; yield 51%; mp 176–178ꢀC; IR (KBr,
cm−1) νmax: 3443 (NH), 3110 (C H, aromatic), 1674
1
(C O), 1631 (C N), 1590 (C C), 1362, 1166 (SO2). H-
NMR (DMSO) δ (ppm): 9.98 (s, 1H, CHO), 9.28 (s, 1H,
pyrazole-H5), 8.47 (s, 1H, NH), 7.99-7.02 (m, 14H, Ar-H).
13C-NMR (DMSO) δ (ppm): 185.14 (CHO), 154.34
(pyrazole-C3), 133.55 (pyrazole-C5), 139.59, 139.05,
135.06, 130.28, 129.85, 129.61, 128.14, 127.10, 124.90,
122.54, 121.28, 119.45 (Ar-C), 117.55 (pyrazole-C4). MS
(m/z, %): 404.67 (M++1, 37.26), 403.32 (M+, 28.14),
344.75 (57.59), 315.74 (76.87), 241.87 (39.61), 235.97
(50.39), 193.29 (100.00), 159.02 (50.24), 103.50 (52.67),
93.16 (16.66), 65.36 (31.00). Anal. calcd. for C22H17N3O3S
(403.46): C, 65.49; H, 4.25; N, 10.42 %. Found: C,
65.46; H, 4.27; N, 10.38 %.
4.6 | Reaction of enaminone 5 with
hydrazine hydrate and urea
4.4 | N-(4-(2-Aminothiazol-4-yl)phenyl)
benzenesulfonamide (4)
Hydrazine hydrate or urea (0.01 mol) was added to a
solution of enaminone 5 (3.30 g, 0.01 mol) in 30 mL gla-
cial acetic acid and refluxed for 6 h. The reaction mixture
(after cooling) was poured onto crushed ice and the solid
Iodine (1.27 g, 0.005 mol) was added portionwise to a
mixture of N-(4-acetylphenyl)benzenesulfonamide (1)

8
EL-MEKABATY AND AWAD
formed was filtered off and recrystallized by heating in
ethyl alcohol.
aromatic), 1652 (C N), 1585 (C C), 1323, 1155 (SO2).
1H-NMR (DMSO) δ (ppm): 8.80 (s, 1H, NH), 8.46 (d, 1H,
pyrimidine-H6, J = 6.0 Hz), 7.97-6.92 (m, 9H, Ar H),
6.95 (d, 1H, pyrimidine-H5, J = 6.0 Hz), 6.03 (b, 2H,
NH2). 13C-NMR (DMSO) δ (ppm): 167.90 (pyrimidine-
C4), 158.66 (pyrimidine-C2), 153.54 (pyrimidine-C6),
135.98, 133.26, 131.23, 130.40, 129.76, 128.96, 125.44,
115.94 (Ar-C), 112.71 (pyrimidine-C5). MS (m/z, %):
328.39 (M++2, 19.73), 327.69 (M++1, 25.23), 326.29 (M+,
16.71), 297.64 (23.28), 269.92 (41.87), 131.22 (26.25), 94.35
(17.95), 89.18 (100.00), 78.38 (22.74), 64.98 (23.98). Anal.
calcd. for C16H14N4O2S (326.37): C, 58.88; H, 4.32; N,
17.17%. Found: C, 58.90; H, 4.30; N, 17.19%.
N-(4-(1H-Pyrazol-3-yl)phenyl)benzenesulfonamide
(6). Pale yellow crystals; yield 72%; mp 169–171ꢀC. IR
(KBr, cm−1) νmax: 3249, 3159 (2 NH), 3063 (C H, aro-
1
matic), 1604 (C N), 1575 (C C), 1334, 1161 (SO2). H-
NMR (DMSO) δ (ppm): 12.53 (s, 1H, pyrazole-NH), 8.80 (s,
1H, NH), 7.96-6.71 (m, 9H, Ar-H), 7.16 (d, 1H, pyrazole-H5,
J = 7.5 Hz), 6.60 (d, 1H, pyrazole-H4, J = 7.5 Hz). MS (m/z,
%): 299.16 (M+, 17.36), 284.23 (66.35), 256.26 (34.44), 214.97
(64.79), 199.69 (47.15), 165.85 (52.93), 121.20 (59.22), 102.26
(57.32), 89.12 (97.53), 66.84 (46.48), 57.19 (100.00). Anal.
calcd. for C15H13N3O2S (299.35): C, 60.19; H, 4.38; N, 14.04
%. Found: C, 60.21; H, 4.37; N, 14.07%.
4.10 | Ethyl 2-amino-3-cyano-4-hydroxy-
5-(4-(phenylsulfonamido)benzoyl)
benzoate (15)
4.7 | N-(4-(2-Oxo-1,2-dihydropyrimidin-
4-yl)phenyl)benzenesulfonamide (7)
Yellow crystals; yield 51%; mp 201–203ꢀC. IR (KBr, cm−1
)
Gray needles; yield 52%; mp 196–198ꢀC. IR (KBr, cm−1
)
νmax: 3372, 3262 (2 NH), 3058 (C H, aromatic), 1677
νmax: 3300 (OH), 3261-3160 (NH, NH2), 3109 (C H, aro-
matic), 2953, 2926 (C H, aliphatic), 2265 (CN), 1694
(CO, ester), 1614 (CO), 1551 (C C), 1385, 1158 (SO2). 1H-
NMR (DMSO) δ (ppm): 12.77 (s, 1H, OH), 8.80 (s, 1H,
NH), 7.86-7.24 (m, 10H, Ar H), 6.94 (b, 2H, NH2), 4.21
(q, 2H, CH2-ester, J = 7.2 Hz), 1.24 (t, 3H, CH3-ester,
J = 7.2 Hz). MS (m/z, %): 465.18 (M+, 22.68), 424.50
(58.95), 403.26 (50.36), 303.05 (55.73), 283.84 (50.91),
232.28 (35.54), 120.71 (76.95), 105.26 (100.00), 83.10
(95.16). Anal. calcd. for C23H19N3O6S (465.48): C,
59.35; H, 4.11; N, 9.03%. Found: C, 59.38; H,
4.12; N, 9.05%.
1
(CO), 1596 (C N), 1512 (C C), 1336, 1160 (SO2). H-
NMR (DMSO) δ (ppm): 10.49 (s, 1H, pyrimidine-NH),
8.80 (s, 1H, NH), 7.87-7.06 (m, 9H, Ar-H), 7.52 (d, 1H,
pyrimidine-H6, J = 7.5 Hz), 5.63 (d, 1H, pyrimidine-H5,
J = 7.5 Hz). MS (m/z, %): 326.98 (M+, 33.41), 290.09
(35.66), 172.92 (71.88), 163.05 (51.50), 128.62 (100.00),
100.62 (96.42), 94.41 (29.57), 79.95 (31.24). Anal. calcd.
for C16H13N3O3S (327.36): C, 58.71; H, 4.00; N, 12.84%.
Found: C, 58.68; H, 4.02; N, 12.87%.
4.8 | Reaction of enaminone 5 with
guanidine hydrochloride and diethyl
3-amino-2-cyanopent-2-enedioate
4.11 | N-(4-(4-Oxo-1,4-dihydroquinoline-
3-carbonyl)phenyl)
To a solution of sodium ethoxide [prepared from (0.12 g,
0.005 mol) of sodium in 30 mL ethyl alcohol], guanidine
hydrochloride or diethyl 3-amino-2-cyanopent-2-enedioate
(0.005 mol) was added with stirring for 10 min. Enaminone
5 (1.65 g, 0.005 mol) was added to this solution and the
reaction mixture was refluxed for 11 h, then cooled and
poured onto ice-cold water containing dilute HCl. The
resulting product thus formed was separated and washed
with water. Recrystallization of the products was carried
out by boiling in ethyl alcohol.
benzenesulfonamide (10)
To a solution of sodium methoxide [prepared from
(1.15 g, 0.05 mol) of sodium in 10 mL methanol] and
40 mL diphenyl ether, methyl 2-aminobenzoate (1.51 g,
0.01 mol) was added. The appropriate enaminone
5 (3.30 g, 0.01 mol) was added to this solution and
refluxed for 12 h. Cool and then poured onto cold water
containing dilute HCl. The 4-quinolinone obtained was
separated by filtration and finally purified by recrystalli-
zation from DMF/EtOH (1:3).
Gray powder; yield 41%; mp 218–220ꢀC. IR (KBr,
4.9 | N-(4-(2-Aminopyrimidin-4-yl)
phenyl)benzenesulfonamide (8)
cm−1) νmax: 3391, 3279 (2 NH), 3079 (C H, aromatic),
1
1677, 1641 (2 C O), 1606 (C C), 1371, 1124 (SO2). H-
NMR (DMSO) δ (ppm): 12.99 (s, 1H, NH), 8.80 (s, 1H,
NH), 8.64 (s, 1H, quinolinone-H2), 7.97-7.15 (m, 13H, Ar-
H). MS (m/z, %): 404.89 (M+, 5.78), 333.16 (27.80), 260.19
White needles; yield 72%; mp 243–245ꢀC. IR (KBr, cm−1
νmax 3422 (NH), 3354-3280 (NH2), 3103 (C H,
)
:

EL-MEKABATY AND AWAD
9
(39.42), 173.83 (18.37), 144.20 (14.35), 111.56 (15.21),
96.76 (43.11), 68.73 (100.00). Anal. calcd. for
C22H16N2O4S (404.44): C, 65.34; H, 3.99; N, 6.93%.
Found: C, 65.35; H, 3.98; N, 6.96%.
C20H18N2O3S (366.44): C, 65.56; H, 4.95; N, 7.65%.
Found: C, 65.58; H, 4.94; N, 7.67%.
4.12.4 | Ethyl 2-amino-
5-(4-(phenylsulfonamido)benzoyl)
thiophene-3-carboxylate (18)
4.12 | Reaction of enaminone 5 with
ethyl acetoacetate and acetylacetone
A mixture of enaminone 5 (1.65 g, 0.005 mol), ethyl
cyanoacetate (0.57 g, 0.005 mol) and elemental sulfur
(0.11 g, 0.005 mol) in 30 mL ethyl alcohol was treated
with 2 mL morpholine and refluxed for 6 h. Cool and
pour onto ice water. The 2-aminothiophene derivative
that formed was separated by filteration and rec-
rystallized from ethyl alcohol.
4.12.1 | Preparation of pyridine
derivatives 12a,b
To a solution of enaminone 5 (1.65 g, 0.005 mol) and
ammonium acetate (1 g) in 25 mL acetic acid, ethyl
acetoacetate or acetylacetone (0.005 mol) was added and
refluxed for 3 h. The solvent was evaporated in vacuo
and the solid formed was purified by recrystallization
from ethyl alcohol.
Pale yellow powder; yield 72%; mp 187–189ꢀC. IR (KBr,
cm−1) νmax: 3423 (NH), 3342-3270 (NH2), 3112 (C H, aro-
matic), 2956, 2899 (C H, aliphatic), 1679, 1652 (2 C O),
1
1594 (C C), 1387, 1170 (SO2). H-NMR (DMSO) δ (ppm):
8.84 (s, 1H, NH), 7.90-7.28 (m, 10H, Ar-H, thiophene-H4),
7.18 (s, 2H, NH2), 4.20 (q, 2H, CH2-ester, J = 7.5 Hz), 1.23
(t, 3H, CH3-ester, J = 7.5 Hz). MS (m/z, %): 430.67 (M+,
24.37), 418.14 (48.08), 393.94 (46.82), 322.53 (59.21), 296.68
(91.63), 159.35 (52.76), 98.18 (100.00), 80.96 (27.27), 76.54
(52.14). Anal. calcd. for C20H18N2O5S2 (430.49): C, 55.80; H,
4.21; N, 6.51%. Found: C, 55.82; H, 4.20; N, 6.50%.
4.12.2 | Ethyl 2-methyl-
6-(4-(phenylsulfonamido)phenyl)
nicotinate (12a)
Pale yellow powder; yield 61%; mp 211-213ꢀC. IR (KBr,
cm−1) νmax: 3266 (NH), 3095 (C H, aromatic), 2923, 2854
(C H, aliphatic), 1695 (CO, ester), 1611 (C N), 1595
(C C), 1371, 1149 (SO2). 1H-NMR (DMSO) δ (ppm): 8.67
(s, 1H, NH), 7.87-7.26 (m, 9H, Ar H), 7.77 (d, 1H,
pyridine-H4, J = 8.0 Hz), 7.06 (d, 1H, pyridine-H5,
J = 8.0 Hz), 4.18 (q, 2H, CH2-ester, J = 7.2 Hz), 2.69 (s,
3H, CH3), 1.20 (t, 3H, CH3-ester, J = 7.2 Hz). MS (m/z,
%): 396.22 (M+, 20.61), 387.04 (46.88), 333.23 (49.86),
273.41 (59.62), 144.05 (66.23), 118.44 (40.33), 91.21
(100.00), 75.72 (21.54), 64.98 (49.16). Anal. calcd. for
C21H20N2O4S (396.46): C, 63.62; H, 5.08; N, 7.07%.
Found: C, 63.60; H, 5.09; N, 7.09%.
4.12.5 | 4-(Phenylsulfonamido)benzoic
acid (19)
A mixture of the respective enaminone 5 (1.65 g,
0.005 mol) and 2 mL sulfuryl dichloride was stirred at
room temperature for 2 h. Add 10 mL benzene and stir-
ring was continued for 30 min. The resulting crude prod-
uct after evaporation of solvent in vacuo was
recrystallized from ethyl alcohol.
White crystals; yield 48%; mp 232–234ꢀC. IR (KBr,
cm−1) νmax: 3272 (OH, NH), 3074 (C H, aromatic), 1677
1
4.12.3 | N-(4-(5-Acetyl-6-methylpyridin-
(C O), 1608 (C C), 1385, 1161 (SO2). H-NMR (DMSO) δ
2-yl)phenyl)benzenesulfonamide (12b)
(ppm): 10.89 (s, 1H, COOH), 8.80 (s, 1H, NH), 7.88-7.25 (m,
9H, Ar H). MS (m/z, %): 277.67 (M+, 5.87), 253.15 (41.52),
186.48 (19.83), 124.83 (38.99), 74.87 (100.00), 60.00 (60.80).
Anal. calcd. for C13H11NO4S (277.29): C, 56.31; H, 4.00; N,
5.05%. Found: C, 56.30; H, 4.02; N, 5.07%.
Pale yellow powder; yield 74%; mp 199-201ꢀC. IR (KBr,
cm−1) νmax: 3450 (NH), 3097 (C H, aromatic), 2955, 2924
(C H, aliphatic), 1678 (C O), 1598 (C N), 1543 (C C),
1
1351, 1173 (SO2). H-NMR (DMSO) δ (ppm): 8.80 (s, 1H,
NH), 7.91-7.28 (m, 9H, Ar H), 7.54 (d, 1H, pyridine-H4,
J = 8.0 Hz), 7.22 (d, 1H, pyridine-H5, J = 8.0 Hz), 2.94 (s,
3H, CH3), 2.59 (s, 3H, COCH3). MS (m/z, %): 368.05
(M++2, 11.80), 366.18 (M+, 7.85), 360.54 (32.85), 347.34
(30.47), 324.36 (75.40), 290.76 (73.15), 282.41 (100.00),
240.38 (40.44), 171.34 (40.50), 128.26 (49.08), 89.28
(38.24), 76.62 (16.63), 65.58 (59.82). Anal. calcd. for
4.12.6 | N-(4-(4-Oxo-4H-3,1-benzoxazin-
2-yl)phenyl)benzenesulfonamide (21)
To a solution of 2-aminobenzoic acid (0.69 g, 0.005 mol)
in 30 mL dry pyridine, the acid chloride 20 (2.96 g,
0.01 mol) was added portionwise with stirring for 5 min.

10
EL-MEKABATY AND AWAD
Stirring was continued for a further 3 h at 25ꢀC. The pre-
cipitated solid obtained after pouring the mixture onto
100 mL cold water was filtered off and recrystallized by
boiling in ethyl alcohol.
[19] S. M. Awad, M. M. Youns, N. M. Ahmed, Pharmacophore
2018, 9(3), 13.
[20] A. El-Mekabaty, H. M. El-Shora, Chem. Heterocycl. Compd.
2018, 54, 618.
[21] A. El-Mekabaty, H. A. Etman, A. Mosbah, J. Heterocycl. Chem.
2016, 53, 894.
[22] A. El-Mekabaty, O. M. O. Habib, M. Abd El-Moneim,
A. S. Hussein, Heterocycles 2018, 96, 677.
[23] A. El-Mekabaty, A. A. Fadda, J. Heterocycl. Chem. 2018, 55, 2303.
[24] O. S. Moustafa, R. A. Ahmed, Phosphorus Sulfur Silicon Relat.
Elem. 2003, 178, 475.
[25] A. M. Fahim, M. A. Shalaby, J. Mol. Struc. 2019, 1176, 408.
[26] S. K. Srivastava, P. M. S. Chauban, A. P. Bhaduri, N. Fatima,
R. K. Chatterjee, J. Med. Chem. 2000, 43, 2275.
[27] C. Sissi, M. Palumbo, Curr. Med. Chem. AntiCancer Agents
2003, 3(6), 439.
Yellow crystals; yield 44%; mp 154-156ꢀC. IR (KBr,
cm−1) νmax: 3255 (NH), 3069 (C H, aromatic), 1764
(C O, lactone), 1625 (C N), 1598 (C C), 1372, 1156
(SO2). 1H-NMR (DMSO) δ (ppm): 8.63 (s, 1H, NH),
8.31-7.17 (m, 13H, Ar H). MS (m/z, %): 379.84 (M++1,
24.30), 378.06 (M+, 3.86), 316.80 (10.71), 286.91 (19.89),
147.48 (11.44), 126.82 (15.81), 63.09 (100.00). Anal. calcd.
for C20H14N2O4S (378.40): C, 63.48; H, 3.73; N, 7.40%.
Found: C, 63.45; H, 3.70; N, 7.36%.
ORCID
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Ahmed El-Mekabaty https://orcid.org/0000-0002-6139-
9129
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SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of this
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How to cite this article: El-Mekabaty A,
Awad HM. Convenient synthesis of novel
sulfonamide derivatives as promising anticancer
agents. J Heterocyclic Chem. 2019;1–10. https://doi.
org/10.1002/jhet.3849
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