Bis-arylsulfonamide derivatives of 2-amino-5(6)-(4-aminophenylthio)benzimidazole

Article abstract of DOI:10.1023/A:1022571831161

Three different procedures have been developed for the preparation of bis-arylsulfonamide derivatives of 2-amino-5(6)-(4-aminophenylthio)benzimidazole, and biological activity of the products have been studied.

Full text of DOI:10.1023/A:1022571831161

Russian Journal of Organic Chemistry, Vol. 38, No. 12, 2002, pp. 1782 1789. Translated from Zhurnal Organicheskoi Khimii, Vol. 38, No. 12, 2002,
pp. 1843 1850.
Original Russian Text Copyright
2002 by Pilyugin, Mikhailyuk, Kosareva.
Bis-arylsulfonamide Derivatives
of 2-Amino-5(6)-(4-aminophenylthio)benzimidazole
V. S. Pilyugin, A. N. Mikhailyuk, and V. M. Kosareva
Research Technological Institute of Herbicides and Plant Growth Regulators,
Academy of Sciences of Bashkortostan Republic,
ul. Ul’yanovykh 65, Ufa, 450029 Bashkortostan, Russia
Received April 18, 2002
Abstract Three different procedures have been developed for the preparation of bis-arylsulfonamide
derivatives of 2-amino-5(6)-(4-aminophenylthio)benzimidazole, and biological activity of the products have
been studied.
A large number of methyl 5(6)-(4-aminophenoxy)-
and 5(6)-(4-aminophenylthio)-2-benzimidazolylcarba-
mate derivatives exhibit high antihelminthic activity
[1 16]. Unfortunately, most of them possess embryo-
toxic and teratogenic properties which restrict their
application in medical practice.
presence of triethylamine or sodium carbonate. In
turn, benzimidazoles III and IV can be prepared from
3,4,4 -triaminodiphenyl sulfide (V) or compounds VI
and VII which are products of the reaction of sulfonyl
chlorides I and II with calcium or sodium cyanamide
(VIII) (Scheme 1);
(2) Reaction of sulfonyl chlorides I and II with
methyl 5(6)-[4-(phenylsulfonylamino)phenylthio]-2-
benzimidazolylcarbamate (IX) or methyl 5(6)-[4-(p-
tolylsulfonylamino)phenylthio]-2-benzimidazolylcar-
bamate (X);
(3) Reaction of sulfonyl chlorides I and II with
2-amino-5(6)-(4-aminophenylthio)benzimidazole
which is prepared by alkaline hydrolysis of 5(6)-(4-
aminophenylthio)-2-benzoylaminobenzimidazole (XI).
The latter is available through the reaction of benzoyl
chloride (XII) with calcium or sodium cyanamide
(VIII), followed by condensation with triamine V.
We have developed a procedure for preparation of
new bis-arylsulfamide derivatives of 2-amino-5(6)-
(4-aminophenylthio)benzimidazole with the goal of
studying their antihelminthic activity, as well as
embryotoxicity and teratogenic action. Analysis of
published data has shown that the simplest possible
routes to bis-arylsulfamide derivatives (phenylsul-
fonyl or p-tolylsulfonyl) of 2-amino-5(6)-(4-amino-
phenylthio)benzimidazole are the following:
(1) Reaction of benzenesulfonyl chloride (I) or
p-toluenesulfonyl chloride (II) with 5(6)-(4-amino-
phenylthio)-2-phenylsulfonylaminobenzimidazole (III)
or 5(6)-(4-aminophenylthio)-2-(p-tolylsulfonylamino)-
benzimidazole (IV) in aprotic organic solvents in the
First of all, we have developed a procedure for the
synthesis of benzimidazole derivatives III and IV
Scheme 1.
I, III, VI, R = H; II, IV, VII, R = Me.
1070-4280/02/3812-1782$27.00 2002 MAIK Nauka/Interperiodica

BIS-ARYLSULFONAMIDE DERIVATIVES OF 2-AMINO-5(6)-.. .
1783
Table 1. Synthesis of 5(6)-(4-aminophenylthio)-2-phenylsulfonylbenzimidazole (III)
Phenylsulfonylcyanamide calcium
5(6)-(4-Aminophenylthio)-2-phenylsulfonyl-
Concentration,
wt %
salt (VI)a
benzimidazole (III)b
Yield
Run
no.
of crude
product,
wt %
amounts of reactants, mol
amounts of reactants, mol
hydro-
III
chloride
VIII
I
water
HCl
V
HCl
i-PrOHc AcOH
waterc
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
0.22
0.22
0.22
0.22
0.22
0.22
0.22
0.22
0.22
0.22
0.22
0.22
0.22
0.22
0.44
0.22
0.516
0.516
0.516
0.516
0.516
0.516
0.516
0.516
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.40
0.20
0.468
0.468
0.468
0.468
0.468
0.468
0.468
0.468
256
256
256
256
256
250
256
256
250
250
250
250
250
250
256
256
500
500
500
500
500
500
500
500
0.20
0.20
0.25
0.25
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.11
0.1
0.124
0.124
0.1
0.1
0.1
0.1
0.234
0.234
0.234
0.165
0.234
0.234
0.234
0.234
256
256
256
256
256
250
256
256
250
250
250
250
0.45
0.45
0.45
0.45
0.1
85.1
85.9
80.7
80.3
86.8
90.6
86.6
86.1
88.0
92.1
69.1
71.2
87.6
89.8
90.3
86.7
82.0
81.8
78.7
71.5
93.2
93.7
95.9
94.3
10.6
9.8
17.3
18.1
13.2
6.24
8.3
7.5
10.3
7.2
19.5
19.1
2.5
1.8
1.9
2.9
3.3
3.7
6.5
19.1
4.2
6.2
88.9
88.7
89.4
90.2
71.1
69.3
80.6
79.4
71.0
98.0
67.0
68.0
76.3
61.1
98.5
71.2
93.2
92.8
89.3
77.2
76.9
84.1
75.0
74.4
0.3
0.1
0.3
0.3
0.33
0.3
0.372
0.372
0.3
0.20
0.20
0.20
0.20
0.10
0.2
50
50
50
50
0.2
0.4
0.2
0.6
0.6
0.6
0.6
0.25
0.25
0.30
0.30
0.3
0.3
0.3
0.702
0.702
0.702
0.495
0.702
0.702
0.702
0.702
600
600
600
300
600
600
600
600
3.3
5.4
a
b
c
Reaction temperature 40 45 C.
Reaction temperature 80 85 C.
In ml.
from phenylsulfonyl- and p-tolylsulfonylcyanamide
calcium (or sodium) salts VI and VII and triamine V.
The reaction is carried out in water in the presence of
hydrochloric acid which converts cyanamide salt VI
or VII into more reactive neutral form. Condensation
of the latter with 3,4,4 -triaminodiphenyl sulfide (V)
yields benzimidazoles III and IV (Scheme 1). Table 1
lists the results of optimization of the reaction con-
ditions. According to the data of IR and NMR spec-
troscopy and elemental analysis, the major impurity
in the crude product is hydrochloride XII formed by
protonation of the amino group in the aniline fragment
of benzimidazole III.
hydrochloride XII in crude product III increases with
rise in the amount of hydrochloric acid used for
acidification of the filtrate in the first stage or added
in the second stage. The best results (93.0% concen-
tration of benzimidazole III in the crude product)
were obtained at a calcium cyanamide benzenesul-
fonyl chloride HCl triamine V molar ratio of 2.20:
2.0:4.28:1.0. The optimal volume ratio of water and
isopropyl alcohol in the second stage was 1.00:1.20.
Under these conditions, the yield of crude product III
is no less than 74%.
Condensation of benzimidazole III with sulfonyl
chlorides I and II in aprotic organic solvents (chloro-
form or dichloroethane) in the presence of triethyl-
amine at 60 80 C (reaction time 1.5 2.0 h) gave,
As follows from Table 1 (cf. run nos. 3 5 and
nos. 1, 2, 6, 10, 15, 16, 21 24), the concentration of
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 12 2002

1784
PILYUGIN et al.
Scheme 2.
XIII, R = H; XIV, R = Me.
respectively, 5(6)-[4-(phenylsulfonylamino)phenyl-
thio]-2-phenylsulfonylaminobenzimidazole (XIII) and
5(6)-[4-(p-tolylsulfonylamino)phenylthio]-2-phenyl-
sulfonylaminobenzimidazole (XIV) (Scheme 2).
The obtained compounds turned out to be nontoxic
even at a dose of 500 mg/kg; they showed a high anti-
helminthic activity at a dose of 30 mg/kg against
gastrointestinal helminthiasis in sheeps, while no
embryotoxic effect was observed at both therapic
doses and at a dose of 100 mg/kg.
benzimidazole (XVI) and 2-amino-5(6)-[4-(p-tolyl-
sulfonylamino)phenylthio]-1-(p-tolylsulfonyl)benz-
imidazole (XVII) having sulfonyl groups in position
1 and in the aniline moiety (Scheme 3). The reactions
were carried out in the presence of triethylamine in
an aprotic organic solvent (chloroform or dichloro-
ethane) on heating under reflux. The same products
were synthesized in high yields by independent
method, namely by reaction of preliminarily prepared
methyl 2-benzimidazolylcarbamates IX and X with
arenesulfonyl chlorides I and II under analogous
conditions (Scheme 4).
By reactions of methyl 5(6)-(4-aminophenylthio)-
2-benzimidazolylcarbamate (XV) with arenesulfonyl
chlorides I and II we obtained 2-amino-5(6)-[4-
(phenylsulfonylamino)phenylthio]-1-phenylsulfonyl-
The biological activity of 2-aminobenzimidazoles
XVI and XVII turned out to be similar to that of their
Scheme 3.
XVI, R = H; XVII, R = Me.
Scheme 4.
IX, R = H; X, R = Me.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 12 2002

BIS-ARYLSULFONAMIDE DERIVATIVES OF 2-AMINO-5(6)-.. .
1785
Scheme 5.
isomers XIII and XIV. A number of drug formula-
tions have been developed on the basis of the above
compounds. They showed a 100% efficiency in the
treatment of sheep helminthiasis at a dose of 10
15 mg/kg (with respect to the acting component) with
no embryotoxic or teratogenic effect. The procedures
for their preparation and application were covered
by inventor’s certificate [17].
The reaction of benzoyl chloride XIX with calcium
or sodium cyanamide gave the corresponding benzoyl-
cyanamide salt XVIII which was brought into reac-
tion with triamine V. As a result, we obtained 2-ben-
zoylaminobenzimidazole derivative XI in 84% yield
(Scheme 5). The first stage of the process was carried
out in water. The yield of the product depends on the
size of calcium cyanamide particles in an aqueous
suspension and on the temperature. Better results
were obtained with preliminarily powdered calcium
cyanamide at 40 45 C. At a lower temperature, the
solubility of calcium cyanamide in water decreases,
which considerably reduced the rate of the process.
Due to the presence of acetic acid the acidity of the
medium is sufficient to convert benzoylcyanamide
calcium salt into more active neutral form XX. Also,
acetic acid binds the ammonia released during the
condensation. Partial protonation with acetic acid of
the amino group in position 4 of triamine V hampers
formation of guanidine derivative XXI as by-product
(Scheme 6). On the other hand, the acidity of acetic
acid is insufficient for complete protonation of com-
pound V, which could inhibit the main process.
The results of our experiments on optimization of
the conditions of synthesis of 2-benzoylaminobenz-
imidazole XI (Table 2) showed that the time neces-
sary for complete disappearance of triamine V from
the reaction mixture increases as the temperature
decreases. Increase of the reaction duration, the tem-
perature being the same, reduces the concetration of
target compound XI in the crude product and simul-
taneously increases the fraction of guanidine deriva-
tive XXI (cf. run nos. 2, 5, 7 and 1, 4, 6; Table 2).
The large concentration of XXI in the crude product
obtained in this series of experiments is explained
by the low molar ratio triamine V benzoylcyanamide
XX (1.0:1.9). When the ratio V:XX is 1.0:1.3,
increase in the reaction time from 5 to 9 h leads to
decrease of the fraction of XI in the crude product
The reaction of benzoylcyanamide calcium salt
(XVIII) with 3,4,4 -triaminodiphenyl sulfide (V) was
performed in a mixture of isopropyl alcohol with
acetic acid (the latter dissolves triamine V) to which
an aqueous solution of salt VIII was slowly added.
Scheme 6.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 12 2002

1786
PILYUGIN et al.
Table 2. Effect of the temperature and reaction time on
the results of synthesis of 5(6)-(4-aminophenylthio)-2-ben-
zoylaminobenzimidazole (XI); molar ratio triamine V
benzoylcyanamide XX acetic acid 1.0: 1.9: 5.0, volume
ratio isopropyl alcohol water 0.4:1.0
from 91.5 to 81.5%, while the concentration of guani-
dine derivative rises from 0 to 8.5%. At a V-to-XX
molar ratio of 1.0:3.0, increase in the reaction time
from 5 to 15 h results in decrease of the concentration
of XI from 39.3 to 4.7% and increase of the concen-
tration of XXI from 55.1 to 82.8%.
Concentration, wt %
The data in Table 3 illustrate the effect of the
acetic acid triamine V molar ratio on the yield and
purity of 2-benzoylaminobenzimidazole XI. It is seen
that change in the molar ratio AcOH:V from 4:1 to
8.4:1 increases the concentration of target compound
XI in the crude product from 44 to 57% and reduces
the concentration of guanidine derivative XXI from
51 to 35%. The effect of the triamine V-to-benzoyl-
cyanamide XX ratio is illustrated by the data in
Table 4. Reduction of this ratio from 1.0:1.3 to
1.0:2.5 leads to a considerable increase of the fraction
of guanidine derivative XXI (from 0 to 56 wt %),
while the concentration of XI falls down from 91.5
to 39%. Further decrease of the V-to-XX ratio (the
reaction time remaining the same) has almost no
effect on the composition of the crude product.
Thus the opimal conditions are the following: the
presence of acetic acid as a component of the reaction
medium at a ratio of no less than 5:1 with respect
to 3,4,4 -triaminodiphenyl sulfide (V), temperature
80 85 C, and a ratio of triamine V to benzoylcyan-
amide XX of no less than 1.0:1.3; otherwise, the
yield of guanidine derivative XXI increases.
Run Tempera-
Time, h
no.
ture,
C
XI
XXI
1
2
3
4
5
6
7
60
9
11
7
4
7
44.1
38.2
46.3
50.7
47.8
57.5
49.4
49.5
53.3
46.7
43.5
45.5
34.7
43.5
60
71
78
78
86
86
4
7
Table 3. Effect of the molar ratio acetic acid triamine V
on the results of synthesis of 5(6)-(4-aminophenylthio)-
2-benzoylaminobenzimidazole (XI); molar ratio triamine
V benzoylcyanamide XX 1.0: 1.9, volume ratio isopropyl
alcohol water 0.4:1.0
Molar
ratio
AcOH: V
Concentration, wt %
Tempera-
ture,
Time, h
C
XI
XXI
It should be noted that the formation of even ap-
preciable amounts of guanidine derivative XXI in the
synthesis of 2-benzoylaminobenzimidazole XI does
not impair the quality of bis-arylsulfonamide deriva-
tives formed in the subsequent reaction of XI with
arenesulfonyl chlorides I and II. Both 2-benzoyl-
aminobenzimidazole XI and its guanidine derivative
react with alkali to give the same intermediate prod-
uct, 2-amino-5(6)-(4-aminophenylthio)benzimidazole
(XXII), which then react with sulfonyl chlorides I
and II to give compounds XVI and XVII, respec-
tively (Scheme 7).
80
7.0
6.0
6.0
6.5
4: 1
5: 1
7: 1
42.8
55.4
56.0
57.5
51.8
39.7
35.3
34.5
86
80
80
8.4: 1
Table 4. Effect of the molar ratio triamine V benzoyl-
cyanamide XX on the results of synthesis of 5(6)-
(4-aminophenylthio)-2-benzoylaminobenzimidazole (XI);
molar ratio triamine V acetic acid 1.0: 5.0, volume ratio
isopropyl alcohol water 0.4: 1.0, temperature 86 C
When the reaction was carried out in a dioxane
water mixture (volume ratio 1.0:3.3), at an alkali
benzoylaminobenzimidazole XI molar ratio of 5.0:1.0
(temperature 90 95 C), the concentration of guani-
dine derivative XXI in the crude product at the initial
moment and 10 and 20 min after addition of alkali
was, respectively, 45.3, 19.2, and 6.1 wt %; after
30 min, compound XXI disappeared almost com-
pletely. 2-Aminobenzimidazole XXII thus formed is
readily soluble in water.
Concentration, wt %
Run
no.
Molar ratio
V: XX
Time, h
XI
XXI
1
2
3
4
5
6
7
5
9
5
5
5
1.0: 1.3
1.0: 1.3
1.0: 1.6
1.0: 1.9
1.0: 2.5
1.0: 3.0
1.0: 3.0
91.5
81.5
76.9
49.4
38.5
38.3
4.7
8.5
15.1
43.5
56.6
56.8
82.8
5
15
Using 2-benzoylaminobenzimidazole XI as model
compound, we examined hydrolysis of the benzoyl-
amino group with the goal of involving the hydrolysis
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 12 2002

BIS-ARYLSULFONAMIDE DERIVATIVES OF 2-AMINO-5(6)-.. .
1787
Scheme 7.
products in the synthesis bis-arylsulfonamide deriva-
tives XVI and XVII. Samples of the reaction mixture
were withdrawn during the process, and the concentra-
tions of benzoylaminobenzimidazole XI and 2-amino-
benzimidazole XXII were determined by HPLC. The
reaction was carried out in aqueous dioxane at 85 C,
the molar ratio water dioxane XI NaOH being
150:10:1:5. The results showed that the hydrolysis
takes at least 8 h to be complete. The mixture was
then cooled to 2 5 C, and benzenesulfonyl chloride
(I) or p-toluenesulfonyl chloride II was added to
obtain bis-arylsulfonamide derivatives XVI and XVII,
respectively.
Thus we have demonstrated the possibility, in
principle, for obtaining antihelminthic agents on the
basis of benzimidazole derivatives having other
substituents than those present in the known benz-
imidazolylcarbamates. Bis-arylsulfonamide derivatives
of 2-amino-5(6)-(4-aminophenylthio)benzimidazole
are low toxic, and they exhibit neither embryotoxic
nor teratogenic effect at therapeutic doses.
were obtained on a Bruker CXP-100 instrument at
22.63 MHz. The spectra were recorded with and
without decoupling from protons using dimethyl
sulfoxide as solvent and hexamethyldisiloxane as
reference. The signals were assigned on the basis of
the chemical shifts, coupling constants, and signal
multiplicities and intensities. Known data for model
compounds and calculated shielding constants for
aromatic carbon nuclei were also used.
Methyl 5(6)-(4-aminophenylthio)-2-benzimida-
zolylcarbamate XV was determined by HPLC using
a 0.25-m 4.6-mm stainless steel column packed with
Ultraspher-ODS reversed phase (grain size 5 m;
tested by Altex); eluent acetonitrile water (70:30, by
volume) with addition of 5% (of the overall volume)
of dimethylformamide; detection at
254 nm. The
quantitation was performed by the internal normaliza-
tion method (from peak areas).
Methyl ester XV in the reaction mixture obtained
at the stage of synthesis of methyl 5(6)-(4-phenylsul-
fonylphenylthio)-2-benzimidazolylcarbamate (IX) was
determined by thin-layer chromatography on silica gel
(Silufol plates), followed by diazotization and diazo
coupling with -naphthol; Rf 0.17 (XV), 0.05 (IX).
The other products do not interfere with the deter-
mination of XV.
EXPERIMENTAL
Analyses were performed with the use of an Altex
Model 330 isocratic liquid chromatograph equipped
with a Model 110A pump, Model 160 UV detector,
and Model 210 sample loop (20 l); samples were
injected with a 50- l Hamilton SNR microsyringe.
Unreacted benzoyl chloride in the synthesis of ben-
zoylcyanamide was determined by alkaline hydrolysis
and subsequent mercurimetric titration of chloride ion
in acid medium using diphenylcarbazone as indicator.
Preliminarily, the concentration of free chloride ions
in the sample was determined.
1
The IR spectra in the range from 4000 to 400 cm
were recorded on a Jasco 810-IR spectrometer from
samples prepared as solutions in carbon tetrachloride
or suspensions in mineral oil. The 13C NMR spectra
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 12 2002

1788
PILYUGIN et al.
The weight fractions of 2-aminobenzimidazoles
C19H16N4O2S. Calculated, %: C 57.55; H 4.07;
N 14.13; S 16.17.
XVI and XVII in the crude products were determined
by HPLC using an Ultraspher-ODS column (reversed
phase); eluent methyl alcohol water dimethylform-
amide (67.5:29.0:3.5, by volume) with addition of
4 ml/l of tetrabutylammonium phosphate (0.5 g per
20 ml of water). The compounds were quantitated by
the peak area normalization method or by the internal
standard technique (diphenylamine).
3,4,4 -Triaminodiphenyl sulfide (V) (in the syn-
thesis of 2-phenylsulfonylaminobenzimidazole III)
was analyzed by TLC, followed by thermal oxidation;
Rf 0.11 (V), 0.05 (III); eluent benzene ethanol (10:1);
the chromatograms were developed by heating for
5 min at 220 C. The other products do not interfere
with the determination of V.
Methyl 5(6)-(4-phenylsulfonylaminophenylthio)-
2-benzimidazolylcarbamate (IX). Benzenesulfonyl
chloride (I), 7.0 ml (0.055 mol), was added dropwise
to a solution of 15.75 g (0.05 mol) of methyl 2-benz-
imidazolylcarbamate XV in 80 ml of pyridine under
stirring at room temperature, and the mixture was left
overnight. It was then poured into water, and the
precipitate was filtered off, washed with a 25% solu-
tion of acetic acid and with water (until neutral), and
dried in air. Yield 20 g (88%), mp 160 162 C (from
alcohol). Found, %: N 12.48; S 14.65. C21H18N4O4S2.
Calculated, %: N 12.33; S 14.10.
Methyl 5(6)-[4-(p-tolylsulfonylamino)phenyl-
thio]-2-benzimidazolylcarbamate (X). Triethyl-
amine, 19.07 g (26.3 ml, 0.188 mol), or potassium
carbonate, 26.2 g (0.188 mol), was added to a suspen-
sion of 39.69 g (0.126 mol) of methyl 2-benzimida-
zolylcarbamate XV in 500 ml of dry dioxane. p-Tolu-
enesulfonyl chloride (II), 30.00 g (0.126 mol, purity
80%), was then added, and the mixture was stirred for
8 10 h at 60 C and poured into water. The precipitate
was filtered off, washed with water, and dried. Yield
57.2 g (97%), mp 135 136 C (from alcohol). Found,
%: N 11.82; S 13.61. C22H20N4O4S2. Calculated, %:
N 11.96; S 13.68.
2-Phenylsulfonylamino-5(6)-(4-phenylsulfonyl-
aminophenylthio)benzimidazole (XIII). Triethyl-
amine, 10.5 g (14.7 ml, 0.13 mol), and benzenesul-
fonyl chloride (I), 23 g (16.6 ml, 0.13 mol), were
added to a suspension of 39.6 g (0.1 mol) of 2-phenyl-
sulfonylaminobenzimidazole III in 200 ml of aceto-
nitrile. The mixture was heated for 1.5 2 h at 60
65 C and poured into 1 l of water. The resulting
mixture was vigorously stirred for 3 4 h, and the
precipitate was filtered off, washed with water, and
dried. Yield 50.9 g (95%), mp 160 162 C. Found, %:
N 10.36; S 17.44. C25H20N4O4S3. Calculated, %:
N 10.44; S 17.92.
Triamine V, 2-benzoylaminobenzimidazole XI, and
2-aminobenzimidazole XVI in the reaction mixture
were detected by TLC on silica gel using benzene
ethanol (10 : 1) as eluent. Dioxane was added to
samples of the reaction mixture for dissolution.
Methyl 5(6)-(4-aminophenylthio)-2-benzimida-
zolylcarbamate (XV). Methyl chloroformate, 49.4 g
(40 ml, 0.52 mol), was added dropwise to a suspen-
sion of 54.0 g (0.51 mol) of 77% calcium cyanamide
(VIII) in 450 ml of distilled water under stirring at
38 41 C. The mixture was stirred for 1 h at that
temperature and filtered from undissolved inorganic
material, and the precipitate was washed with 60 ml
of water on a filter. The filtrate was added to a solu-
tion of 62.45 g (0.27 mol) of 3,4,4 -triaminodiphenyl
sulfide (V) in a mixture of 200 ml of 2-propanol and
110 ml of acetic acid, and the mixture was heated for
6 h under reflux. Yield 69.50 g (82%), mp 247
249 C; published data [5]: mp 249 C; Rf 0.42 (ben-
zene ethanol, 3:1).
5(6)-(4-Aminophenylthio)-2-phenylsulfonyl-
aminobenzimidazole (III). Benzenesulfonyl chloride
I, 27.56 g (20 ml, 0.156 mol), was added dropwise to
a suspension of 17.86 g (0.172 mol) of 77% calcium
cyanamide (VIII) in 420 ml of distilled water under
stirring at 40 45 C. The mixture was stirred for 1 h
at that temperature and filtered, and the precipitate
was washed on a filter with 40 ml of water. The fil-
trate was added to a solution of 18.04 g (0.078 mol)
of triamine V in a mixture of 200 ml of 2-propanol
and 20 ml of acetic acid, 20 ml of 36% hydrochloric
acid was added, and the mixture was heated for 12 h
under reflux. It was then cooled, and the precipitate
was filtered off, washed with acetic acid and water,
and dried. Yield 14.0 g (45%), mp 260 262 C.
Found, %: C 57.46; H 3.92; N 14.32; S 15.85.
Benzimidazole XIV was synthesized in a similar
way. Yield 92.7%, mp 118 120 C. Found, %:
N 10.22; S 17.32. C26H22N4O4S3. Calculated, %:
N 10.17; S 17.46.
2-Amino-1-phenylsulfonyl-5(6)-(4-phenylsul-
fonylaminophenylthio)benzimidazole (XVI). A mix-
ture of 62.8 g (0.2 mol) of methyl 2-benzimidazolyl-
carbamate XV, 77.0 g (55.6 ml, 0.44 mol) of benzene-
sulfonyl chloride (I), and 64.7 g (89.8 ml, 0.64 mol)
of triethylamine in 200 ml of chloroform was heated
for 14 h under reflux. Water, 1.0 l, was added, the
mixture was thoroughly stirred, the aqueous organic
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 12 2002

BIS-ARYLSULFONAMIDE DERIVATIVES OF 2-AMINO-5(6)-.. .
1789
layer was separated, an additional amount of water
was added, and the mixture was thoroughly stirred for
3 4 h. The precipitate was filtered off, washed with
water, and dried. Yield 91 g (85%), mp 169 171 C.
Found, %: C 55.80; H 3.62; S 17.61. C25H20N4O4S3.
Calculated, %: C 55.95; H 3.76; S 17.92.
2-Amino-1-(p-tolylsulfonyl)-5(6)-[4-(p-tolylsul-
fonylamino)phenylthio]benzimidazole (XVII) was
synthesized in a similar way. Yield 82%, mp 172
174 C. Found, %: C 57.39; H 4.52; S 16.72.
C27H24N4O4S3. Calculated, %: C 57.42; H 4.28;
S 17.04.
In strongly alkaline media benzenesulfonyl chloride
and p-toluenesulfonyl chloride undergo appreciable
hydrolysis to give, respectively, benzenesulfonic acid
and p-toluenesulfonic acid. In order to minimize the
contribution of this process, the reactions were carried
out at a reduced temperature in relatively weakly
alkaline media. Excess alkali which remained in the
reaction mixture after hydrolysis of 2-benzoylamino-
benzimidazole XI and its guanidine derivative XXI
(Scheme 7) was bound with sodium hydrogen carbo-
nate. When the synthesis of bis-arylsulfonamide
derivatives XVI and XVII was complete, the mixture
was poured in a 3 4-fold amount of cold water and
was vigorously stirred for 3 4 h. The product was
filtered off, thoroughly washed from inorganic and
organic impurities on a filter, and dried.
5. FRG Patent no. 2348104, 1973; Ref. Zh., Khim.,
1975, no. 24O112.
6. FRG Patent no. 2348120, 1973; Ref. Zh., Khim.,
1975, 24O111.
7. Kosareva, V.M., Solonenko, I.G., Mikhailyuk, A.N.,
Sorokina, O.N., Novik, T.S., Vertinskaya, M.K.,
Belen’kii, L.I., and Demidov, N.V., USSR Inventor’s
Certificate no. 1207114, 1984; Byull. Izobret., 1986,
no. 3.
8. Khomutov, M.A., Mikhailyuk, A.N., Belen’kii, L.I.,
Novik, T.S., Berezkina, S.V., Pilyugin, V.S., Vali-
tov, R.B., and Demidov, N.V., USSR Inventor’s
Certificate no. 1340073, 1987; Byull. Izobret., 1987,
no. 35.
9. Sorokina, O.N., Kosareva, V.M., Mikhailyuk, A.N.,
Chukina, S.I., Novik, T.S., Berezkina, S.V., Volko-
va, G.N., Pilyugin, V.S., and Valitov, R.B., USSR
Inventor’s Certificate no. 1573817, 1990; Byull.
Izobret., 1990, no. 23.
10. US Patent no. 3935209, 1974; Izobret. SSSR
Rubezh., 1976, no. 18-24.
11. Vird, S.S., Edvards, D.A., and Frid, D.Kh., USSR
Inventor’s Certificate no. 727143, 1972; Byull.
Izobret., 1980, no. 13.
12. US Patent no. 3682952, 1972; Ref. Zh., Khim.,
1973, no. 12N320.
13. FRG Patent no. 2726838, 1977; Izobret. SSSR
Rubezh., 1978, no. 20-55.
14. FRG Patent no. 2816694, 1977; Izobret. SSSR
Rubezh., 1978, no. 5-55.
REFERENCES
15. US Patent no. 3929821, 1975; Ref. Zh., Khim.,
1. FRG Patent no. 2332343, 1975; Ref. Zh., Khim.,
1976, no. 20O370.
1975, no. 17O130.
16. US Patent no. 3401171, 1969; Ref. Zh., Khim.,
2. FRG Patent no. 2332398, 1975; Ref. Zh., Khim.,
1969, no. 22N382.
1975, no. 16O185.
17. Kosareva, V.M., Solonenko, I.G., Valitov, R.B.,
Pilyugin, V.S., Vorob’eva, T.P., Mikhailyuk, A.N.,
Novik, T.S., Sorokina, O.N., and Belen’kii, L.I.,
USSR Inventor’s Certificate no. 1246563, 1986;
Byull. Izobret., 1986, no. 27.
3. FRG Patent no. 2332486, 1973; Ref. Zh., Khim.,
1975, no. 23O165.
4. FRG Patent no. 2332487, 1973; Ref. Zh., Khim.,
1975, no. 17O131.
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