Dapson in heterocyclic chemistry, part IV: Synthesis of some novel diphenylsulfones containing acetamide, pyrrolidine, piperazine, and thiomorpholine moieties as antimicrobial and antitumor agents

Article abstract of DOI:10.1080/10426500802505457

Interaction of dapson [bis(4-aminophenyl)sulfone] 1 with [bis-(methylsulfonyl) methylidine]malononitrile 2 yielded the corresponding dicyano derivative 3, which was reacted with acetic anhydride, succinic anhydride, 4-chlorobenzaldehyde, phenyl isothiocya

Full text of DOI:10.1080/10426500802505457

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Dapson in Heterocyclic
Chemistry, Part IV: Synthesis of
Some Novel Diphenylsulfones
Containing Acetamide,
Pyrrolidine, Piperazine, and
Thiomorpholine Moieties as
Antimicrobial and Antitumor
Agents
M. M. Ghorab a , M. S. A. El Gaby b , N. E. Amin a ,
N. M. H. Taha c , M. A. Shehab d & I. M. I. Faker d
a Department of Drug Radiation Research , National
Center for Radiation Research and Technology
(NCRRT) , Nasr City, Cairo, Egypt
b Organic Chemistry Department, Faculty of Science
for Boys , Al-Azhar Universty , Asute, Cairo, Egypt
c Organic Chemistry Department, Faculty of Science
for Girls , Al-Azhar Universty , Cairo, Egypt
d Applied Organic Chemistry Department , National
Research Center , Cairo, Egypt
Published online: 03 Nov 2008.
To cite this article: M. M. Ghorab , M. S. A. El Gaby , N. E. Amin , N. M. H. Taha ,
M. A. Shehab & I. M. I. Faker (2008) Dapson in Heterocyclic Chemistry, Part IV:
Synthesis of Some Novel Diphenylsulfones Containing Acetamide, Pyrrolidine,
Piperazine, and Thiomorpholine Moieties as Antimicrobial and Antitumor Agents,
Phosphorus, Sulfur, and Silicon and the Related Elements, 183:12, 2929-2942, DOI:
10.1080/10426500802505457

To link to this article: http://dx.doi.org/10.1080/10426500802505457
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Phosphorus, Sulfur, and Silicon, 183:2929–2942, 2008
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802505457
Dapson in Heterocyclic Chemistry, Part IV: Synthesis of
Some Novel Diphenylsulfones Containing Acetamide,
Pyrrolidine, Piperazine, and Thiomorpholine Moieties as
Antimicrobial and Antitumor Agents
M. M. Ghorab,1 M. S. A. El Gaby,2 N. E. Amin,1 N. M. H.
Taha,3 M. A. Shehab,4 and I. M. I. Faker4
1Department of Drug Radiation Research, National Center for
Radiation Research and Technology (NCRRT), Nasr City, Cairo, Egypt
2Organic Chemistry Department, Faculty of Science for Boys, Al-Azhar
Universty, Asute, Cairo, Egypt
3Organic Chemistry Department, Faculty of Science for Girls, Al-Azhar
Universty, Cairo, Egypt
4Applied Organic Chemistry Department National Research Center,
Cairo, Egypt
Interaction of dapson [bis(4-aminophenyl)sulfone] 1 with [bis-(methylsulfonyl)
methylidine]malononitrile 2 yielded the corresponding dicyano derivative 3, which
was reacted with acetic anhydride, succinic anhydride, 4-chlorobenzaldehyde,
phenyl isothiocyanate to give the corresponding acetamide 4, succinamic acid
5, pyrrolidine 6, Shiff base 7 and thiourea 8, respectively. Treatment of 3 with
chloroacetyl chloride afforded the aminoacetyl chloride derivative 9. Further, the
interaction of compound 9 with thioglycolic acid, malononitrile, ethyl glycinate
hydrochloride, and/or potassium thiocyanate furnished compounds 10–15, re-
spectively. The structural characterization of the prepared compounds was based
on microanalytical and spectroscopic analyses. Some of the prepared compounds
were tested for their antimicrobial and antitumor activities. Compounds 9 and
12 showed promising antitumor activity compared with Doxorubicin as positive
control.
Keywords Diphenylsulfone having acetamide; pyrrolidine; piperazine; thiomorpholine
as antitumor and antimicrobial activities
INTRODUCTION
The fusion of diphenylsulfone with other biologically active nuclei
arouses considerable interest for synthetic organic chemists due to an
Received 30 September 2007; accepted 11 December 2007.
Address correspondence to M. M. Ghorab, Department of Drug Radiation Research,
National Center for Radiation and Technology (NCRRT), P.O. Box 29, Nasr City, Cairo,
Egypt. E-mail: mmsghorab@yahoo.com
2929

2930
M. M. Ghorab et al.
important biological activity, property that many members of this fam-
ily exhibit.1–5 Some pyrrolidine, thiomorpholine and piperazine deriva-
tives are well known as cytotoxic6-9 with radioprotective activity.10–12
As a part of our studies on new heterocyclic compounds as new poten-
tial antitumor and radioprotective agents, we synthesized and tested
some new diphenylsulfone derivatives.
RESULTS AND DISCUSSION
The sequence of reactions that followed from the synthesis of the de-
signed compounds is summarized in Scheme 1.
O
S
O
S
H3CS
+
H3CS
CN
CN
DMF
H2N
NH2
H2N
NH
H3CS
CN
CN
1 : 1 mole
O
O
(2)
(3)
(1)
SCHEME 1
The reactivity of dapson 1 towards some electrophilic reagents was
studied. Thus, dapson 1 was reacted with [bis(methylsulfanyl)-methyl-
idene]malononitrile 2 in dimethylformamide under reflux. That
reaction furnished the corresponding 2-{[4-(4-amino-benzensulfonyl)-
phenyl-amino]-methylsu-lfanyl-methylene}-malononitrile
3.
The
structure of compound 3 was pro-ved by analytical and spectral data.
–1
The IR spectrum of 3 revealed bands at 3457, 3372, 3338, 3256 cm
–1 –1
(NH, NH2), 3039 cm (CH arom.), 2984, 2932 cm (CH aliph.), 2218
–1
–1
1
cm (C N), 1332, and 1144 cm (SO2). H–NMR spectrum of (3 in
DMSO-d6) showed signals at 2.8 [s, 3H, SCH3], 3.6 [hump, 3H, NH
+ NH2], 6.5, and 7.5 [2d, 8H, Ar-H, AB system]. Mass spectrum of 3
exhibited a molecular ion peak m/z at 369 (M-1, 2.23%) with a base
peak at 248 (100%), and other significant peaks appeared at 368 (M-
2, 0.43%), 313 (1.53%), 261 (2.44%), 184 (7.88%), 140 (56.12%), 108
(78.37%), and 65 (37.61%).
The acetamide derivative 4 was obtained via reaction of 3 with acetic
anhydride (Scheme 2).
O
Ac2O
(3)
HN
O
S
NH
H3CS
CN
CN
H3C
O
(4)
SCHEME 2

Novel Diphenylsulfones
2931
–1
The IR spectrum of 4 showed bands at 3334, 3256 cm
(NH),
–1
–1
–1
3100 cm (CH arom.), 2940 cm (CH aliph.), 1684 cm (C O), 1368,
–1
1
and 1150 cm (SO2). H-NMR spectrum of (5 in DMSO-d6) revealed
signals at 2.2 [s, 3H, SCH3], 2.6 [s, 3H, COCH3], 7.7, 7.9 [2d, 8H, Ar-H
AB system], and 10.3 [s, 2H, 2NH].
In addition, the behaviour of 3 towards succinic anhydride un-
der different conditions was also studied. Thus, refluxing of com-
pound 3 with succinic anhydride in boiling ethanol afforded a product
(C21H18N4O5S2) for which two structure, 5 and, 6 seemed possible.
Structure 5 was established for the reaction product on the basis of its
IR spectrum, while under condition of fusion the corresponding pyrro-
lidine 6 was obtained. Compound 6 was also obtained via heating of
compound 5 in dimethylformamide (Scheme 3).
O
OH
O
O
EtOH
HN
NH
H3CS
CN
CN
S
O
O
O
(5)
O
(3)
DMF
O
O
fusion
N
S
NH
H3CS
CN
CN
O
O
(6)
SCHEME 3
–1
The IR spectrum of compound 5 revealed bands at 3450 cm (OH),
–1 –1 –1
3374 cm (NH), 2926 cm (CH aliph.), 2210, 2200 cm (2C≡N),
–1
–1
1660, 1650 cm (2C=O), 1316, and 1148 cm (SO2). Mass spectrum
of compound 5 showed a molecular ion peak m/z at 471 (M+1, 3.04%),
with a base peak at 82 (100%), and other significant peaks appeared
at 452 (4.11%), 395 (5.38%), 338 (7.32%), 271 (20.88%), 234 (11.07%),
170 (3.75%), 110 (65.22%), and 75 (28.08%). The IR spectrum of 6 re-
–1
–1
–1
vealed bands at 3416 cm (NH), 3100 cm (CH arom.), 2950 cm
–1 –1
(CH aliph.), 2198, 2190 cm (2C N), 1705, 1696 cm (2C O), 1334,
–1
and 1158 cm (SO2). 1H-NMR spectrum of (6 in DMSO-d6) exhib-
ited signals at 1.2 [t, 4H, 2CH2], 2.9 [s, 3H, SCH3], 7.0, 7.5 [2d, 8H,
Ar-H, AB system], and 8.4 [s, 1H, NH]. Mass spectrum of 6 revealed

2932
M. M. Ghorab et al.
a molecular ion peak m/z at 450 (M+, 2.02%), with a base peak at
65 (100%), and other significant peaks appeared at 358 (3.04%), 338
(2.04%), 261 (0.78%), 248 (43.83%), 184 (8.83%), 108 (10.53%), and 75
(1.20%).
The schiff’s base 7 was achieved by condensing compound 3 with
4-chlorobenzaldehyde (Scheme 4).
Cl
CHO
O
Cl
(3)
N
S
NH
H3CS
CN
CN
O
(7)
SCHEME 4
–1
The IR spectrum of 7 showed bands at 3366 cm (NH), 3060 cm
–1
–1
–1
1
(CH arom.), 2212, 2198 cm (2C N),1350, and 1144 cm (SO2). H-
NMR spectrum of (7 in DMSO-d6) revealed signals at 2.8 [s, 3H, SCH3],
6.5, 7.5 [2d, 8H, Ar-H, AB system], 7.7, 7.9 [2d, 4H, benzilidin Ar-H,
AB system], and 10.0 [s, 2H, NH, N CH].
When compound 3 was allowed to react with phenyl isothiocyanate
in absolute ethanol containing triethylamine under refux the thiosemi-
carbazide derivative 8 was obtained (Scheme 5).
S
O
Ph
PhN=C=S
N
H
N
H
S
NH
H3CS
CN
CN
(3)
O
(8)
SCHEME 5
–1
The IR spectrum of 8 showed bands at 3390, 3282 cm (NH), 2200,
–1
–1
2192 cm (2C N), 1314, and 1146 cm (SO2). 1H-NMR spectrum of
(8 in DMSO-d6) reveled signals at 2.4 [s, 3H, SCH3], 6.6–7.9 [m, 13H,
Ar-H], 11.2, 11.4, and 11.6 [3s, 3H, 3NH].
Treatment of compound 3 with chloroacetyl chloride in dimethyl-
formamide at room temperature afforded the corresponding N-[4-(4-
(2,2 - dicyano- 1 - (methylthio)vinylamino)phenyl - sulfonyl)phenyl) - 2-
chloroethanethioamide 9 in high yield (Scheme 6).

Novel Diphenylsulfones
2933
O
O
O
Cl
Cl
Cl
N
S
NH
H3CS
CN
CN
(3)
H
O
(9)
SCHEME 6
–1
The IR spectrum of 9 exhibited bands at 3270, 3198 cm (NH),
–1 –1 –1
3100 cm (CH arom.), 2940 cm (CH aliph.), 2212, 2205 cm (2
–1
–1
C≡N), 1686 cm (C O), 1340, and 1152 cm (SO2). Mass spectrum
of compound 9 revealed a molecular ion peaks at m/z 402 (M-SCH3,
66.4%), with a base peak at 77 (100%), and other significant peaks
appeared at 351 (37.2%), 324 (61.1%), 216, (36.3%), 184 (32.7%), 156
(18.6%), 140 (85.8%), 108 (97.3%), and 78 (38.1%).
The synthesis of thiomorpholine derivative 10 was isolated on hot
via reaction of compound 9 with thioglycolic acid in pyridine, while
thiomorpholine derivative 11 was obtained from the filtered of the re-
action mixture (Scheme 7).
O
O
N
O
O
S
HN
HS
OH
S
NH
H3CS
(9)
S
O
COOH
H2N
(10)
+
O
N
O
O
S
S
NH
H3CS
CN
CN
O
(11)
SCHEME 7
–1
IR spectrum compound 10 revealed bands at 3394 cm (br, NH,
NH2, OH), 2926 cm–1 (CH aliph.), 1702, 1680, 1654 cm–1 (3C O), 1356,
–1
and 1150 cm (SO2). 1H-NMR spectrum of (10 in DMSO-d6) exhibited
signal, at 2.4 [s, 3H, SCH3], 5.8 [s, 4H, 2CH2], 7.6–8.6 [m, 10H, Ar-H
+ NH2], 9.0, 9.1 [2s, 2H, 2NH], and 11.8 [s, 1H, OH]. Mass spectrum
of compound 10 showed a molecular ion peak m/z at 576 (M+, 1.19%),

2934
M. M. Ghorab et al.
with a base peak at 51 (100%) and other significant peaks appeared at
577 (M+1, 1.27%), 480 (1.52%), 398 (1.78%), 362 (1.44%), 314 (1.69%),
202 (2.12%), 152 (3.98%), 79 (20.24). The IR spectrum of compound
–1
–1
11 revealed bands at 3250 cm (NH), 2218 cm (C N), 1706, 1670
–1
–1
cm (2C O), 1366, and 1150 cm (SO2). 1H-NMR spectrum of (11 in
DMSO-d6) exhibited signals at 2.4 [s, 3H, SCH3], 5.8 [s, 4H, 2CH2], 7.4–
8.4 [m, 8H, Ar-H], and 11.1 [s, 1H, NH]. Mass spectrum of compound
11 revealed a molecular ion peak m/z at 484 (M+, 16.90%), with a base
peak at 51 (100%) and other significant peaks appeared at 312 (19.72%),
260 (21.13%), 115 (26.76%), and 78 (32.39%).
The reaction of malononitrile with compound 9 was conducted
through normal addition reaction to yield the pyrrolidine derivative
12 (Scheme 8).
O
O
NC
CN
CN
CN
N
S
NH
H3CS
(9)
O
NC
NH
(12)
SCHEME 8
–1
The IR spectrum of compound 12 showed bands at 3322 cm (NH),
2938, 2856 cm–1 (CH aliph.), 2188 cm–1 (C N), 1694 cm–1 (C O), 1356,
–1
1
and 1150 cm (SO2). H-NMR spectrum of compound (12 in DMSO-
d6) revealed signals at 2.1 [s, 3H, SCH3], 4.1 [s, 2H, CH2], 7.5–8.0 [m,
8H, Ar-H], 10.4, and 10.9 [2s, 2H, 2NH]. Mass spectrum of compound
12 exhibited a molecular ion peak m/z at 474 (M+, 14.71%), with a
base peak at 57 (100%), and other significant peaks appeared at 213
(17.65%), 143 (27.94%), 113 (26.47%), 83 (29.41%), 72 (25.00%), and 53
(32.35%).
The piperazine derivative 13 was obtained also via reaction of com-
pound 9 with ethylglycinate hydrochloride (Scheme 9).
O
CH2CO2Et
O
NH2. HCl
HN
N
O
S
NH
H3CS
CN
CN
(9)
O
(13)
SCHEME 9

Novel Diphenylsulfones
2935
–1
–1
The IR spectrum of compound 13 exhibited bands at 3370 cm
–1
(NH), 2924, 2854 cm–1 (CH aliph.), 2206 cm (C N), 1700, 1650 cm
–1
(2C O), 1300, and 1148 cm (SO2). Mass spectrum of compound 13
showed a molecular ion peak m/z at 467 (M+, 12.79%), with a base peak
at 65 (100%), and other significant peaks appeared at 328 (12.79%), 300
(15.12%), 212 (20.93%), 167 (22.79%), 108 (37.21%), and 75 (17.44%).
Treatment of compound
9 with potassium thiocyanate in
dimethy-lformamide afforded isothiocyanatoacetamide derivative 14
(Scheme 10).
O
O
KSCN
NCS
HN
S
NH
H3CS
CN
CN
(9)
O
(14)
SCHEME 10
The IR spectrum of compound 14 revealed bands at 3370 cm–1 (NH),
–1
–1
–1
1
2208 cm (C N), 1654 cm (C O), 1390, and 1150 cm (SO2). H-
NMR spectrum of compound (14 in DMSO-d6) showed signals at 2.8
(s, 3H, SCH3), 4.0 [s, 2H, CH2], and 6.6–8.0 [m, 10H, Ar-H + 2NH].
Mass spectrum of compound 14 exhibited a molecular ion peak m/z at
469 (M+, 4.71%), with a base peak at 69 (100%), and other significant
peaks appeared at 399 (5.49%), 365 (5.10%), 279 (7.06%), 217 (7.84%),
161 (8.63%), 149 (40.78%), 132 (16.08%), 97 (22.35%), and 76 (12.55%).
Antimicrobial Activity
Some of the newly synthesized compounds were screened for their an-
timicrobial activity using the diffusion agar technique.13 The tested
compounds were dissolved in N, N-dimethylformamide (DMF), which
showed no inhibition zones. Table (I and II) lists the screening results of
the tested compounds against the Gram-negative bacteria Escherichia
Coli, and salmonella typhi, Gram-positive bacteria staphylococcus au-
reus and bacillus subtillus, and the pathogenic fungi Aspergillus niger
and Aspergillus flavus. The reference antibiotic chloramphenicol and
fungicide Grisofluvine were used as positive controls for comparison.
The fungi cultures were maintained on Czapek’s Dox agar media.
Diphenylsulfone having free amino group and aminomethylsulf-anyl
methylenemalononiitrile moiety 3 and diphenyl containing 4-chloro-
benzylidene and aminomethylsulfanylmethylenemalononitrile 4 were
found to be the most active compounds against Gram-negative bac-

2936

Novel Diphenylsulfones
2937
teria Escherichia coli and salmonella typhi. Also, compound 3 and 7
showed high activity against Gram-positive bacteria staphylococcus
aureus and bacillus subtillus, while compound 7 revealed remarkable
activity against Aspergillus niger and Aspergillus flavus. These results
indicated that the biologically active compounds 3 and 7 were almost
as potent as the standard antibiotic chloramphenicol as positive con-
trol. In addition, compound 7 was nearly as active as Grisofluvine as
positive control.
Antitumor Activity (in-vitro study)
Reagents
1. RPMI 1640 medium (sigma).
2. Ehrlich Ascites Carcinoma cells (EAC) suspension (2.5 × 105 mL).
3. Trypan blue dye: A stock solution was prepared by dissolving 1 g
of the dye in distilled water (100 mL). The working solution was
then prepared by diluting 1 mL of the stock solution with 9 mL
of distilled water. The stain was used then for staining the dead
EAC cells.
4. The compounds tested were (3–14).
Procedure
1. EAC cells were obtained by needle aspiration of the ascetic fluid
from preinoculated mice under aseptic conditions.14
TABLE II Antifungal Activity of Some Synthesized Compounds
Aspergillus niger
Aspergillus vlavus
Compound. No.
1
2.5
5
1
2.5
5
3
4
7
11
12
DMF
++
+
++
+
++
++
+ + +
+
+
+
++
+
++
+
++
+
++
+
++
+
++
+
+ + +
+
+
+
+
+
++
0
++
0
0
0
0
0
Grisofluvine
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
Well diameter 1 cm (100 mL of each conc. was tested
Inhibition values = 0.1–0.5 cm beyond control = +
Inhibition values = 0.6–0.1 cm beyond control = ++
Inhibition values = 1.1–1.5 cm beyond control = + + +
Inhibition values => 1 cm beyond control = + + ++, 0 = not detected

2938
M. M. Ghorab et al.
TABLE III In-vitro Antitumor Activity of Some Newly Synthesized
Compounds
Non-viable cells (%)
Concentration (µg/ml)
Compound. No.
100
50
25
IC50
3
9
10
11
12
14
10
100
40
10
100
20
0
90
20
0
90
10
55
0
85
0
0
80
0
>100
0.5
>100
>100
0.5
>100
52
Doxorubicin
100
20
aIC50 >100 µg/ml is considered to be inactive.
2. The cells were tested for viability and contamination by staining
certain cell volume of this fluid by an equal volume of the working
solution of trypan blue dye.15–16
3. The ascetic fluid was diluted with saline (1 : 10) to contain 2.5
× 106 mL cells on a hemocytometer.
4. In a set of sterile test tubes 0.1 ml of tumor cells suspension,
0.8 ml RPMI 1640 media and 0.1 ml of each tested compound (cor-
responding to 100, 50 and 25 µg/ml) were mixed. The test tubes
were incubated at 37◦C for 2 hr. Trypan blue exclusion test15–16
was carried out to calculate the presence of nonviable cells. Com-
pounds producing more than 70% nonviable cells are considered
active.16
No. of non viable
Total No. of cells
% of non - viable cells =
× 100
The relationship between surviving fraction and drug concentration
was plotted to obtain the survival curve of EAC cell. The response pa-
rameter calculated was IC50 value which, corresponds to the compound
concentration causing 50% mortality in net cells (table III).
The results obtained from the study exhibited that the diphenyl-
sulfone having dicyano- and 2-chloroethane-thioamide moieties 9 and
diphenylsulphone bearing pyrrolidinone and malononitrile moieties 12
were almost active than the reference drug Doxorubicin as positive
control. These compounds exhibited non-viable cells about 85% and
80% at a concentration of 25 µg/ml with IC50 of 0.5 µg/ml.

Novel Diphenylsulfones
2939
EXPERIMENTAL
Melting points were uncorrected. IR spectra were recorded (KBr) on a
Perkin Elmer 1650 spectrophotometer. 1H-NMR spectra were recorded
on varian Gemini spectrometer 200 (200 MHz), using DMSO-d6 as a
solvent and TMS as internal standard chemical shifts were expressed
as δ ppm units. Mass spectra were recorded on a gas chromatography
GC-MS 9p 100 Ex (schiumadzu instrument) at 70 ev. Microanalytical
data were obtained from the Microanalytical Data Unit at the Cairo
University.
2 {4-(4-Amino-benzenesulfonyl)-phenylamino]-methy-
lsulfanylmethylene}-malononitrile (3)
Dapson 1 (0.01 mol) was mixed with [bis(methylsulfanyl)-methylidene]
malononitrile 2 (0.01 mol) in dimethylformamide (15 ml). The reaction
mixture was refluxed for 3 hr and then allowed to cool. The solid precip-
itate was collected by filtration and recrystallized from dioxan to give
(3) (Table IV).
N-{4-[4-(2,2-Dicyano-1-methylsulfanyl-vinylamino)-benzen-
esulfonyl]-phenyl}-acetamide (4)
A solution of 3 (0.01 mol) and acetic anhydride (10 mL) was heated
under refluxed for 5 hr. then allowed to cool. The solid product was
collected and recrystallized from ethanol to give (4) (Table IV).
N-{4-[4-(2,2-Dicyano-1-methylsulfanyl-vinylamino)-benzen-
esulfonyl]-phenyl}-succinamic acid (5)
A mixture of 3 (0.01 mol) and suiccinic anhydride (0.01 mol) in ethanol
(50 mL) was refluxed for 8 hr. The solid obtained was recr-ystallized
from dioxan to give (5) (Table IV).
2-({4-[4-(2,5-Dioxo-pyrrolidin-1-yl)benzenesulfonyl]-phenyl-
amino}-methylsulfanyl-methylene)-malononitrile (6)
Method (A)
A mixture of 3 (0.01 mol) and succinic anhydride (0.01 mol) was fused
in an oil bath at 220◦C for 15 min. The obtained solid was recrystallized
from dioxan to give (6) (Table IV).

2940
M. M. Ghorab et al.
TABLE IV Physical and Analytical Data of the Synthesized
Compounds
Elemental analyses %
Required/Found
Compound
No.
m.p
(◦C)
Mol. Formul
(Mol. Wt)
yield
89
C
H
N
S
3
115–117
270–272
65–67
C17H14N4O2S2
(370)
55.13
55.50
55.33
55.10
53.62
53.90
55.75
55.50
58.48
58.20
57.03
57.30
51.06
51.30
47.91
48.20
52.06
52.20
55.69
55.40
53.96
53.70
51.17
51.30
3.78
3.50
3.88
3.50
3.83
3.50
3.54
3.20
3.45
3.30
3.76
3.50
3.35
3.60
3.47
3.20
3.30
3.10
2.95
2.70
3.64
3.40
3.19
3.40
15.13
15.40
13.59
13.30
11.92
12.20
12.39
12.70
11.37
11.50
13.86
13.60
12.54
12.80
9.72
17.29
17.50
15.53
15.20
13.62
13.40
14.16
14.40
12.99
12.70
19.00
19.30
14.33
14.60
22.22
22.40
19.83
19.50
13.50
13.30
13.70
13.50
20.46
20.20
4
86
91
79
64
75
71
48
42
66
68
74
C
C
C
19H16N4O3S2
(412)
21H18N4O5S2
(470)
21H16N4O4S2
(452)
5
6
182–184
62–64
7
C
24H17N4O2S2Cl
(492.5)
8
167–169
145–147
>300
C
24H19N5O2S3
(505)
9
C
19H15N4O3S2Cl
(446.5)
10
11
12
13
14
C
23H20N4O6S4
(576)
9.40
260–262
84–86
C
21H16N4O4S3
(484)
11.57
11.30
17.72
17.50
14.98
14.70
14.92
15.20
C
C
C
22H14N6O3S2
(474)
21H17N5O4S2
(467)
20H15N5O3S3
(469)
>300
>300
Method (B)
A solution of 5 (0.01 mol) in dimethylformamide (20 mL) was refluxed
for 14 hr. The reaction mixture was cooled and the obtained solid was
recrystallized from dioxan to give (6) (Table IV).
2-[(4-{4-(4-chloro-benzylidene)-amino]-benzenesulfonyl}-
phenyl-amino)-methylsulfanyl-methylene]-malononitrile (7)
A mixture of 3 (0.01 mol) and p-chlorobenzaldehyde (0.012 mol) in
ethanol (30 ml) containing triethylamine (0.5 ml) was refluxed for
5 hr. The solid obtained was recrystallized from ethanol, to give (7)
(Table IV).

Novel Diphenylsulfones
2941
1-{4-[4-(2,2-Dicyano-1-methylsulfanyl-vinylamino)-benzene-
sulfonyl]-phenyl}-3-phenyl-thiourea (8)
A solution of 3 (0.01 mol) and phenyl isothiocyanate (0.01 mol) in
ethanol (30 mL) containing triethylamine (0.5 mL) was refluxed for
5 hr. The solid product was recrystallized from ethanol to give (8)
(Table IV).
N-(4-(4-(2,2-dicyano-1-(methylthio)vinylamino)
phenylsulfonyl)-phe-nyl)-2-chloroethane thioamide (9)
A solution of 3 (0.01 mol) in dimethylformamide (20 mL), chloroacetyl
chloride (0.01 mol) was added dropwise, then stirred for 1 hr at room
temperature and poured into ice water. The solid thus obtained was
recrystallized from acetic acid to give (9) (Table IV).
3-Amino-4-({4-[4-(3,5-dioxo-thiomorpholin-4-yl)-benze-
nesulfonyl]-phenylamino}-methylsulfanyl-methylene)-5-
imino- 4,5-dihydro-thio-phene-2-carboxylic acid
(10)
A mixture of compound 9 (0.01 mol) and thioglycolic acid (0.01 mol)
in pyridine (20 mL) was refluxed for 8 hr. The reaction mixture was
filtered while hot to give 10, while compound 11 was isolated from the
filtered of the reaction mixture and recrystallized from ethanol to give
(10) (Table IV).
2-({4-[4-(3-Cyano-2-imino-5-oxo-pyrrolidin-1-yl)-benzen-
esulfonyl]-phenylamino}-methylsulfanyl-methylene)-malono-
nitrile (12)
A mixture of compound 9 (0.01 mol) and malononitrile (0.01 mol) in
pipredine (10 mL) was refluxed for 24 hr. Coold and diluted with dil
HCl. The precipitated solid was filtered and recrystallized from ethanol
to give (12) (Table IV).
2-({4-[4-(2,6-Dioxo-piperazin-1-yl)-benzenesulfonyl]-phenyl-
amino}-methylsulfanyl-methylene)-malononitrile (13)
A mixture of compound 9 (0.01 mol) and ethylglycinate hydrochloride
(0.01 mol) in piperidine (10 ml) was refluxed for 8 hr, cooled, poured

2942
M. M. Ghorab et al.
into ice-HCl and filtered. The solid obtained was recrystallized from
ethanol to give (13) (Table IV).
N-{4-[4-(2,2-Dicyano-1-methylsulfanyl-vinylamino-benzene-
sulfonyl]-pheny}-2-isothiocyanatoacetamide (14)
A mixture of compound 9 (0.01 mol) and potassium thiocyanate (0.02
mol) in dimethylformamide (15 mL) was refluxed for 5 hr, cooled, and
poured in to ice water. The solid obtained was recrystallized from dioxan
to give (14) (Table IV).
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