Synthesis and fungicidal activity of bis(2-arylcarbonylamino-1H- benzimidazol-5-yl) sulfones

Article abstract of DOI:10.1134/S1070363208030195

A procedure has been developed for the synthesis of bis(2- arylcarbonylamino-1H-benzimidazol-5-yl) sulfones by reaction of the corresponding substituted benzoyl chloride with sodium cyanamide and subsequent treatment of the N-cyanobenzamide thus formed with 3,3′,4,4′- tetraaminodiphenyl sulfone in acid medium. The products were tested for fungicidal activity.

Full text of DOI:10.1134/S1070363208030195

ISSN 1070-3632, Russian Journal of General Chemistry, 2008, Vol. 78, No. 3, pp. 446–450. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © V.S. Pilyugin, S.L. Kuznetsova, Yu.E. Sapozhnikov, G.E. Chikisheva, G.V. Kiseleva, T.P. Vorob’eva, E.V. Klimakova,
N.A. Sapozhnikova, R.D. Davletov, Z.B. Galeeva, 2008, published in Zhurnal Obshchei Khimii, 2008, Vol. 78, No. 3, pp. 461–465.
Synthesis and Fungicidal Activity of Bis(2-arylcarbonylamino-
1H-benzimidazol-5-yl) Sulfones
V. S. Pilyugin, S. L. Kuznetsova, Yu. E. Sapozhnikov, G. E. Chikisheva, G. V. Kiseleva,
T. P. Vorob’eva, E. V. Klimakova, N. A. Sapozhnikova, R. D. Davletov, and Z. B. Galeeva
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 26, 2007
Abstract—A procedure has been developed for the synthesis of bis(2-arylcarbonylamino-1H-benzimidazol-5-yl)
sulfones by reaction of the corresponding substituted benzoyl chloride with sodium cyanamide and subsequent
treatment of the N-cyanobenzamide thus formed with 3,3′,4,4′-tetraaminodiphenyl sulfone in acid medium. The
products were tested for fungicidal activity.
DOI: 10.1134/S1070363208030195
While continuing search for new biologically active
substances (fungicides, antihelminthic agents, etc.) in
the series of 2-aminobenzimidazole derivatives [1–4],
we have synthesized compounds where, unlike those
reported previously [3, 4], two benzimidazole
fragments are linked through a sulfinyl bridge.
Bis(2-arylcarbonylamino-1H-benzimidazol-5-yl)
sulfones were synthesized according to Schemes 1 and
2. In the first step, 4-nitrochlorobenzene was treated
with sodium sulfide to obtain 4,4'-dinitrodiphenyl
sulfide (I) which was reduced to 4,4'-diaminodiphenyl
Scheme 1.
446

SYNTHESIS AND FUNGICIDAL ACTIVITY
447
sulfide (II) with hydrazine hydrate. Acylation of
diamine II at both amino groups with acetic anhydride
afforded 4,4′-bis(acetylamino)diphenyl sulfide (III),
and the latter was oxidized with hydrogen peroxide to
4,4′-bis(acetylamino)diphenyl sulfone (IV). Diphenyl
sulfone IV was converted into 4,4′-bis(acetylamino)-
3,3′-dinitrodiphenyl sulfone (V) by nitration with nitric
acid, and the acetyl protection was removed by
treatment with alkali. 4,4′-Diamino-3,3′-
dinitrodiphenyl sulfone (VI) thus obtained was
reduced to 3,3′,4,4′-tetraaminodiphenyl sulfone (VII)
by the action of hydrazine hydrate.
The structure of intermediate nitro- and amino-
substituted diphenyl sulfides and sulfones I–VII was
established using high-performance liquid chromato-
graphy (HPLC) and 13C NMR spectroscopy (Table 1).
The carbon signals were assigned by analysis of the
chemical
shifts,
coupling
constants,
signal
multiplicities, and intensity ratios. While interpreting
the 13C NMR spectra of I–VII, we used the
corresponding data for model compounds such as
diphenyl sulfide, diphenyl sulfoxide, and diphenyl
sulfone [6] and the calculated shielding constants of
carbon nuclei in the aromatic rings having various
substituents [5, 7–9].
Substituted N-cyanobenzamide or N-cyano-
benzenesulfonamide sodium salt (prepared by reaction
of the corresponding substituted benzoyl chloride or
benzenesulfonyl chloride with an aqueous suspension
of sodium cyanamide) was acidified with hydrochloric
acid, and neutral N-cyano amides VIII reacted with
3,3′,4,4′-tetraaminodiphenyl sulfone (VII) to give the
target bis(2-arylcarbonylamino-1H-benzimidazol-5-yl)
sulfones IX–XX (Scheme 2).
The progress of reactions of 3,3′,4,4′-
tetraaminodiphenyl
sulfone
(VII)
with
N-
cyanobenzamides and of the cyclization processes
leading to structures IX–XX was monitored by HPLC
and 13C NMR.
Fungicidal activity of compounds IX–XX at a
concentration of 0.003% was estimated on the basis of
____________
Scheme 2.
IX, R = 2-HO-5-ClC6H3CO; X, R = 4-O2NC6H4CO; XI, R = 4-ClC6H4CO; XII, R = 2-Cl-5-O2NC6H3CO; XIII, R = 2-
BrC6H4CO; XIV, R = PhSO2; XV, R = PhCO; XVI, R = 2-MeO-5-ClC6H3CO; XVII, R = 2,5-Cl2C6H3CO; XVIII, R =
3-IC6H4CO; XIX, R = 2-MeO-3,5-Cl2C6H2CO; XX, R = 2-MeOC6H4CO.
____________
growth inhibition of pathogenic fungi Fusarium
culmorum and Helminthosporium sativum using pure
cultures (Table 2). Primary results of laboratory tests
showed that the synthesized compounds are less toxic
than 2-aminobezimidazole derivatives reported
previously [5] against Fusarium culmorum and
Helminthosporium sativum.
frequency of 22.63 MHz both with complete
decoupling from protons and without it. Dimethyl
sulfoxide was used as solvent, and the chemical shifts
were measured relative to hexamethyldisiloxane.
4,4′-Dinitrodiphenyl sulfide (I). A three-neck flask
equipped with a stirrer, dropping funnel and reflux
condenser was charged with 25
g
of 4-
nitrochlorobenzene in 20 ml of dimethylformamide
(DMF). The mixture was heated to the boiling point,
and a solution of 28.5 g of sodium sulfide in 20 ml of
water was added dropwise from a dropping funnel.
EXPERIMENTAL
The 13C NMR spectra were recorded on a Bruker
CXP-100 spectrometer with Fourier transform at a
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448
PILYUGIN et al.
Table 1. 13C NMR spectra of some substituted diaryl sulfides, diaryl sulfoxides, and diaryl sulfones of the general formula
δС, ppm
C1' C2'
148.4 126.5 123.9 145.2 123.9 126.6 130.3 134.6 130.0 129.6 130.0 134.6
C1
C2
C3
C4
C5
C6
C3'
C4'
C5'
C6'
CO CH3
Z
X3
X4
Y3
Y4
H
S
S
H
H
H
H
H
H
H
H
H
H
H
H
H
H
NO2
NO2
NO2
NH2
NO2
H
H
H
H
H
NO2 142.7 131.6 124.6 147.4 124.6 131.6 142.7 131.6 124.6 147.4 124.6 131.6
NH2 144.6 125.6 124.1 151.0 124.1 125.6 112.4 137.4 115.6 151.6 115.6 137.4
NH2 121.9 133.2 115.2 148.7 115.2 133.2 121.9 133.2 115.2 148.7 115.2 133.2
NHAc 141.6 124.6 126.7 149.2 126.7 124.6 122.8 136.4 122.1 145.4 122.1 136.4
S
S
S
S
NH2 NH2 NH2 121.9 133.2 115.2 148.7 115.2 133.2 134.6 128.3 131.1 140.8 95.0 137.9 168.5
NH3 NH3 NH3 146.6 103.8 154.0 114.6 114.6 129.8 138.3 134.4 132.3 126.2 150.3 125.3 168.0
NO2 NO2 NHAc 139.7 128.5 124.8 146.2 124.8 128.5 124.8 142.5 130.4 146.2 139.7 125.8 166.1 24.7
NO2 NO2 NH2 147.3 126.1 124.3 149.3 124.3 126.1 115.0 131.5 141.8 145.5 121.5 133.8
S
S
S
S
NHAc
H
H
H
H
H
H
NHAc 129.2 131.9 120.5 139.2 120.5 131.9 129.2 131.9 120.5 139.2 120.5 131.9 168.9 24.5
145.1 126.7 128.2 131.7 128.2 126.7 145.1 126.7 128.2 131.7 128.2 126.7
SO
SO
SO
SO2
H
NO2
NHAc
H
NHAc 149.3 126.4 120.2 152.1 120.2 126.4 138.4 125.8 120.0 143.0 120.0 125.8 169.5 24.6
NHAc 140.0 126.0 120.1 142.3 120.1 126.0 140.0 126.0 120.1 142.3 126.0 120.1 169.5 24.6
H
141.6 127.6 129.3 133.2 129.3 127.6 141.6 127.6 129.3 133.2 129.3 127.6
SO2 NH2 NH2 NH2 NH2 130.5 112.5 135.0 140.1 117.7 113.2 130.5 112.5 135.0 140.1 117.7 113.2
SO2
SO2
SO2
H
H
H
NO2
NO2 NO2 NHAc 135.4 126.5 137.0 141.6 125.8 133.5 146.0 125.7 130.0 151.2 130.0 125.7 170.1 24.2
NHAc NHAc 142.7 125.4 119.3 146.0 119.3 125.4 142.7 125.4 119.3 146.0 119.3 125.4 170.0 24.7
H
NHAc 147.6 125.5 129.8 150.7 129.8 125.5 133.4 129.3 119.9 145.1 119.9 129.3 170.2 24.6
H
SO2 NO2 NHAc NO2 NHAc 142.8 126.7 134.6 141.6 121.9 130.6 142.8 126.7 134.6 141.6 121.9 130.1 169.5 24.1
Table 2. Fungicidal activity of 2-aminobenzimidazole deriv-
atives at a concentration of 0.003% against pure fungal cultures
When the addition of sodium sulfide was complete, the
mixture was stirred for 1 h at heating and poured into
water. The yellow precipitate of 4,4′-dinitrodiphenyl
sulfide (I) was filtered off, dried, and recrystallized
from acetic acid, mp 154–155°C. Yield 95%. The
product contained no less than 90% of the main
substance.
Inhibition of growth of pathogenic fungi, %
Comp. no.
Fusarium culmorum Helminthosporium sativum
8.6
41.6
IX
6.8
7.6
28.1
38.4
X
4,4′-Thiodianiline (II). A 1-l three-neck flask
equipped with a reflux condenser, Dean–Stark trap,
thermometer, and dropping funnel was charged with 83
g of 4,4′-dinitrodiphenyl sulfide (I), 320 ml of butanol,
2 g of iron(III) chloride, and 15–20 g of activated
charcoal. The mixture was slowly heated to 30–35°C,
and 120 ml of 60% hydrazine hydrate was added
dropwise, while continuing to heat the mixture to the
XI
9.3
24.1
XII
XV
16.9; 19.4
32.3; 31.3
6.0
25.0
XVIII
18.6
34.0
30.3
17.6
XIX
XX
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SYNTHESIS AND FUNGICIDAL ACTIVITY
449
boiling point (95–105°C). The addition of hydrazine
hydrate required about 4 h. Simultaneously, azeotropic
mixture consisting of water, hydrazine, and butanol
distilled off, and the boiling point of the mixture
increased from 95 do 105°C as water was removed
therefrom. The reduction process was assumed to be
complete when water no longer separated and a white
foam appeared on the surface of the reaction mixture.
The overall time of the reduction of 4,4′-
dinitrodiphenyl sulfide (I) was 15–16 h. The mixture
was filtered while hot to remove charcoal, the filtrate
was cooled, and the colorless crystals were filtered off
and dried. The mother liquor containing some amount
of 4,4′-diaminodiphenyl sulfide (II) was used as
solvent for the reduction of another portion of
dinitrodiphenyl sulfide I. The yield of 4,4′-
diaminodiphenyl sulfide (II) in the first run was about
40%, and it increased in the subsequent runs.
N,N′-[4,4′-Sufinylbis(2-nitro-4,1-phenylene)]
diacetamide (V). A 250-ml flask was placed into a
cooling bath, and 70 ml of concentrated nitric acid (5-
fold weight amount with respect to sulfone IV) was
placed therein and cooled under stirring to –6 to –8°C.
Sulfone IV was added in small portions under stirring,
maintaining the temperature below –5°C. The time of
addition of sulfone IV was about 1 h. The mixture was
then stirred for 3 h at –6 to –10°C and poured into a
beaker containing crushed ice. Light yellow solid
separated. The mixture was left to stand overnight, and
the bright yellow precipitate was filtered off, washed
with water, and dried. Yield 75–85%.
4,4′-Sufinylbis(2-nitrobenzenamine) (VI). A 500-
ml flask was placed into a water bath and charged with
100 g of isopropyl alcohol, 25 g of sulfone V was
added under stirring, and a solution of 7.1 g of sodium
hydroxide in 16.6 ml of water was then added over a
period of 15–20 min under stirring; simultaneously, the
mixture was gradually heated to 80°C. It was stirred
for 20–30 min at that temperature and poured into
water. A few drops of hydrochloric acid were added to
the solution for better crystallization. After several
hours, the precipitate was filtered off, thoroughly
washed with water on a filter, and dried. Yield ~95%.
N,N′-[4,4′-Thiobis(4,1-phenylene)]diacetamide
(III). A 500-ml flask was placed into a water bath and
charged with 50 g of sulfide II, 150–200 ml of
chlorobenzene, and a few drops of sulfuric acid. The
mixture was heated to 28–30°C, and ~50 ml of acetic
anhydride was added over a period of 15–20 min under
stirring. During the addition, the mixture turned thick
and colorless. When the addition was complete, the
mixture was stirred for 2 h at 70–75°C, cooled to 35–
40°C, and filtered. The precipitate was washed with a
small amount of alcohol, taking into account that
compound III is soluble therein. Yield ~100%.
4,4′-Sufinylbis(benzene-1,2-diamine) (VII).
A
250-ml flask equipped with a reflux condenser, Dean–
Stark trap, dropping funnel, and thermometer was
charged with 100 ml of butanol, 20 g of sulfone VI,
0.3 g of FeCl3, and 3 g of activated charcoal. The
mixture was heated to 40°C on a water bath without
stirring, and 50 ml of hydrazine hydrate was slowly
added in three approximately equal portions. The
mixture warmed up to 95°C and began to boil, and
water started to separate as azeotrope with butanol. As
water was removed, the temperature of the reaction
mixture rose to 105°C (~20 h). When water no longer
separated, the mixture was heated for an additional
1.5–2.0 h and filtered while hot to remove charcoal.
Sulfone VII started to crystallize from the filtrate
almost immediately. The light beige lustrous
precipitate was filtered off and washed with water. An
additional amount of product VII was isolated by
concentration of the mother liquor. Yield 40–50%.
N,N′-[4,4′-Sufinylbis(4,1-phenylene)]diacetamide
(IV). A 500-ml flask was charged with 60 g of sulfide
III, and 300 ml of concentrated sulfuric acid was
added. The mixture warmed up. It was cooled under
stirring to 15–20°C, and 28 ml of 30% hydrogen
peroxide was added dropwise very slowly (over a
period of 2.0–2.5 h), maintaining the temperature not
below 28–30°C. The mixture was stirred for 3 h at 30–
35°C (it turned thick and more transparent) and poured
into a beaker charged with crushed ice. A solid
immediately separated; its color varied from light pink
to lilac–gray. The mixture was left overnight, and the
precipitate was filtered off, stirred with a large volume
of water (to remove impurities), and dried. Yield 60–
70%.
Bis(2-acylamino-1H-benzimidazol-5-yl) sulfones
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PILYUGIN et al.
IX–XX (general procedure). Finely powdered calcium
cyanamide containing 27.5% of the main substance, 24 g,
was dispersed in 900 ml of water, and the
corresponding substituted benzoyl chloride or
benzenesulfonyl chloride (solid benzoyl chlorides were
added as solutions in anhydrous acetone), 0.33 mol,
was added under vigorous stirring at such a rate that
the temperature did not exceed 40–45°C. The mixture
was stirred for 1 h at 40–45°C, cooled to room
temperature, and filtered from inorganic salts present
in the initial calcium cyanamide. The filtrate was
adjusted to pH 3 by adding concentrated hydrochloric
acid, and the precipitate of RC(O)NHCN·HCl was
filtered off and dried in air in a hood. Depending on
the initial acyl chloride, the yield of the complex RC
(O)NHCN·HCl varied from 7.6 (5-chloro-2-
hydroxybenzoyl chloride) to 95% (benzenesulfonyl
chloride).
Potato glucose agar was used as substrate. Compounds
IX–XX were applied to the nutrient medium before
solidification (at 45–50°C), and it was then poured
onto Petri dishes in 15-cm3 portions. Each Petri dish
was inoculated with Fusarium culmorum and
Helminthosporium sativum mycelia simultaneously at
three points. In blank experiment, the fungal cultures
were inoculated into the same nutrient medium
containing no fungicides. The dishes were incubated
for 72 h at 25–26°C, and the average diameter of the
colonies was measured.
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A flask equipped with a mechanical stirrer, reflux
condenser, and thermometer was charged with 0.15
mol of sulfone VII, 0.45 mol of glacial acetic acid, 300
ml of water, 300 ml of isopropyl alcohol, and 0.3 mol
of the isolated complex. The mixture was heated to
75–78°C and stirred for 6–7 h at that temperature; the
progress of the reaction being monitored by TLC
(following the disappearance of the initial complex).
As a rule, a light beige solid separated during the
process (except for the benzenesulfonyl derivative).
The mixture was cooled to room temperature, and the
precipitate was filtered off, washed with water, and
dried. The yields of sulfones IX–XX ranged from 21 to
83%; their melting points were as follows,: IX, 96°C;
X, 269°C; XI, 275°C; XII, 340°C; XIII, 114°C; XIV,
231°C; XV, 162°C; XVI, 89°C; XVII, 153°C; XVIII,
224°C; XIX, 148°C; XX, 131°C.
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containing a compound to be tested. All compounds
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