Synthesis of bis(arylcarbonylamino-1H-benzimidazol-5-yl) ethers

Article abstract of DOI:10.1134/S1070363206080305

A procedure has been developed for the synthesis of bis(arylcarbonylamino- 1H-benzimidazol-5-yl) ethers by reaction of the corresponding substituted benzoyl chloride with sodium cyanamide, followed by treatment of the resulting N-cyanobenzamide with 4-(3,4-diaminophenoxy)benzene-1,2-diamine in acid medium. Nauka/Interperiodica 2006.

Full text of DOI:10.1134/S1070363206080305

ISSN 1070-3632, Russian Journal of General Chemistry, 2006, Vol. 76, No. 8, pp. 1327 1330.
Pleiades Publishing, Inc., 2006.
Original Russian Text V.S. Pilyugin, Yu.E. Sapozhnikov, G.E. Chikisheva, G.V. Kiseleva, T.P. Vorob’eva, E.V. Klimakova, N.A. Sapozhnikova,
S.L. Kuznetsova, 2006, published in Zhurnal Obshchei Khimii, 2006, Vol. 76, No. 8, pp. 1383 1386.
Synthesis of Bis(arylcarbonylamino-1H-benzimidazol-5-yl)
Ethers
V. S. Pilyugin, Yu. E. Sapozhnikov, G. E. Chikisheva, G. V. Kiseleva,
T. P. Vorob’eva, E. V. Klimakova, N. A. Sapozhnikova, and S. L. Kuznetsova
Research Technological Institute of Herbicides and Plant Growth Regulators,
Academy of Sciences of Bashkortostan Republic, ul. Ul’yanovykh 65, Ufa, Bashkortostan, 450029 Russia
Received February 9, 2006
Abstract A procedure has been developed for the synthesis of bis(arylcarbonylamino-1H-benzimidazol-
5-yl) ethers by reaction of the corresponding substituted benzoyl chloride with sodium cyanamide, followed by
treatment of the resulting N-cyanobenzamide with 4-(3,4-diaminophenoxy)benzene-1,2-diamine in acid
medium.
DOI: 10.1134/S1070363206080305
1
Benzimidazole derivatives constitute a large and
versatile (from the chemical viewpoint) class of com-
pounds. They exhibit antihelminthic activity and are
also active against pathogenic fungi, viruses, and
bacteria [1 11]. An interesting group of benzimida-
zole derivatives consists of 2-benzimidazolylcarbamic
acid esters, which have found fairly wide application
as antihelminthic and fungicide agents. The simplest
benzimidazole derivative of this kind, which is widely
used in agriculture, is methyl 2-benzimidazolylcar-
bamate (BMC, Carbendazim, etc.). Unfortunately,
methyl (1H-benzimidazol-2-yl)carbamate, apart from
strong antihelminthic and fungicide activity, exhibits
an appreciable embryotoxicity [12]. In keeping with
the existing views on the mechanism of side effects
of this compound [12, 13], we presumed that intro-
duction of a substituent into position 5 of the benz-
imidazole ring could reduce or even eliminate its toxic
properties. The synthesis of methyl [5-(4-amino-
phenoxy)-1H-benzimidazol-2-yl]carbamate and
methyl [5-(2-aminophenoxy)-1H-benzimidazol-2-yl]-
carbamate was described for the first time in patent
[6]; the first of these was shown to be a highly ef-
ficient antihelminthic agent whose activity is com-
parable with that of the most known antihelminthic
agent, methyl 5-(phenylsulfanyl)benzimidazol-2-yl-
carbamate (Fenbendazole, Panacur). We tested these
methyl esters for antihelminthic activity and embrio-
toxicity [14]. The results showed high antihelminthic
activity of methyl [5-(4-aminophenoxy)-1H-benz-
strongylosis was only 70% at a dose of 20 mg kg .
Unfortunately, methyl [5-(4-aminophenoxy)-1H-benz-
imidazol-2-yl]carbamate exhibited a strong embryo-
toxicity at a therapeutic dose of 10 mg kg ; moreover,
it also exerted a general toxic effect. Experiments
showed that the presence of a free amino group
endows this compound with undesirable biological
properties. Presumably, the latter could be eliminated
via deamination or appropriate modification of the
amino group to obtain derivatives possessing desired
biological properties.
1
We previously synthesized bis[methoxy(ethoxy)-
carbonylamino-1H-benzimidazol-5-yl] ethers I and II
[15]. While continuing studies in this line, we de-
veloped a procedure for the synthesis of a series of
bis(arylcarbonylamino-1H-benzimidazol-5-yl) ethers
III XI and prepared required amounts of these com-
pounds to perform their biological testing.
Preliminarily, we synthesized substituted benzoyl
chlorides by treatment of the corresponding benzoic
acids in chloroform with 1.5 2.0 equiv of thionyl
chloride in the presence of several drops of DMF
under reflux (reaction time 5 8 h) [16]. When the re-
action was complete, excess thionyl chloride and the
solvent were distilled off under reduced pressure. The
yield of substituted benzoyl chlorides and the con-
centration of the main substance in the crude products
ranged from 95 to 99%.
1
imidazol-2-yl]carbamate; at a dose of 10 mg kg , its
Benzoyl chlorides were then brought into reaction
with cyanamide disodium salt in aqueous acetone to
obtain the corresponding N-cyanobenzamide sodium
salt. The latter is fairly readily soluble in water;
efficiency was 100%, while the efficiency of methyl
[5-(2-aminophenoxy)-1H-benzimidazol-2-yl]car-
bamate in the treatment of sheep gastrointestinal
1327

1328
PILYUGIN et al.
therefore, it was separated by filtration from all in-
soluble inorganic impurities present in cyanamide
sodium salt. The aqueous solution of N-cyanobenz-
amide sodium salt thus obtained was acidified to pH
3.0 4.0 with hydrochloric acid, and the precipitate of
N-cyanobenzamide (acid molecular form) was filtered
off. The precipitate was dried, analyzed for concentra-
tion of the main substance, and treated with 4-(3,4-di-
aminophenoxy)benzene-1,2-diamine (XII) in a mix-
ture of isopropyl alcohol with water in the presence
of hydrochloric acid. As a result, we obtained sub-
stituted bis(arylcarbonylamino-1H-benzimidazol-5-yl)
ethers III XI.
COR
RCOCl + Na2N CN
COR
Na N CN + NaCl,
COR
Na N CN + HCl
H N CN,
H2N
H2N
NH2
NH
2 + 2NC NH COR
N
O
N
O
HCl
NH3
,
C NHC(O)R
R(O)CHN C
N
H
N
H
III XI
III, R = Ph; IV, R = 2-MeO-5-ClC6H3; V, R = 2-MeO-5-BrC6H3; VI, R = 3-IC6H4; VII, R = 2-Cl-5-O2NC6H3; VIII,
R = 2-MeO-3,5-Cl2C6H2; IX, R = 4-O2NC6H4; X, R = 3-BrC6H4; XI, R = 2-BrC6H4.
4-(3,4-Diaminophenoxy)benzene-1,2-diamine (XII)
was synthesized in turn by condensation of sodium
4-nitrophenoxide with 4-nitrochlorobenzene in DMF
in the presence of K2CO3 at 145 150 C, reduction of
4-(4-nitrophenoxy)nitrobenzene thus obtained with
hydrazine to 4-(4-aminophenoxy)benzenamine, acyla-
tion of the latter with acetic anhydride, nitration of
N-[4-(4-acetylaminophenoxy)phenyl]acetamide to
N-[4-(4-acetylamino-3-nitrophenoxy)-3-nitrophenyl]-
acetamide, base hydrolysis of the nitration product
to 4-(4-amino-3-nitrophenoxy)-3-nitrobenzenamine,
and its subsequent reduction with hydrazine. The
procedures for the synthesis of intermediate products
in the above reaction sequence were described in
[15 23].
shielding of carbon nuclei in an aromatic ring were
used to interpret the spectral data. The presence of
benzimidazole fragments in molecules III XI gives
rise to a signal in the region
146.6 151.0 ppm,
which is characteristic of the C2Catom. Regardless of
the substitution pattern in the benzene ring, the 13C
NMR spectra of ethers I XI contained signals from
C4 ( 103.3 104.6 ppm), C5 ( 153.0 154.0 ppm),
C
C6
(
113.1 114.6 ppm), aCnd C7
(
114.3
C
C
115.6 ppm) in fairly narrow ranges. On the other hand,
magnetic shielding of C7a, C3a, and C8 depended on
the substituent effects to a greater extent; the corre-
sponding chemical shifts vary in the ranges
C
124.9 132.7, 133.0 138.3, and 154.7 169.9 ppm,
respectively. The chemical shifts of carbon atoms in
the acyl fragments of compounds II XI and their
analogs, amides derived from 2-aminobenzimidazole
and benzoyl chlorides [24], were almost similar.
The reaction of tetraaminodiphenyl ether XII with
N-cyanobenzamides was monitored by high-per-
formance liquid chromatography (HPLC) and NMR
spectroscopy. The 13C NMR parameters of ethers III
XI and model bis[methoxy(ethoxy)carbonylamino-
1H-benzimidazol-5-yl] ethers I and II are collected in
table. The signals were assigned on the basis of their
positions, coupling constants, and intensities. In addi-
tion, the corresponding chemical shifts of model com-
pounds and the results of calculation of magnetic
EXPERIMENTAL
Crude reaction products were analyzed on an Altex
liquid chromatograph equipped with
a
Model
110 pump, Model 153 UV detector, 20- l Model 210
loop sampler, and a 25 4.6-mm stainless steel
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 76 No. 8 2006

SYNTHESIS OF BIS(ARYLCARBONYLAMINO-1H-BENZIMIDAZOL-5-YL) ETHERS
1329
13C NMR spectra of bis[methoxy(or ethoxy or aryl)carbonylamino-1H-benzimidazol-5-yl] ethers I XI
H
N
H
N
7
7a
3a
6
2
NH
R 8
NH
R
5
O
N
O
O
N
4
C, ppm
C1
Comp.
no.
C2
C4
C5
C6
C7
C7a
C3a
C2
C3
C4
C5
C6
C8 OMe, OEt
I
II
148.9 104.2 153.5 113.1 115.0 132.4 137.7
148.5 104.3 153.5 113.4 114.8 132.7 137.7
154.7
154.8 61.9, 14.9
53.4
III
IV
V
149.5 104.0 153.7 113.9 114.9 131.7 136.2 134.5 128.9 128.7 132.7 128.0 128.0 168.3
147.2 104.6 153.7 114.0 115.6 125.1 137.5 124.8 156.8 115.0 129.9 125.1 133.2 164.3
147.2 104.6 153.7 114.0 115.4 124.9 137.4 124.9 157.0 115.4 136.2 112.7 136.7 164.0
150.8 103.6 153.8 114.2 114.4 130.0 137.9 134.6 128.3 131.1 140.8 95.0 137.9 168.5
57.2
57.1
VI
VII 146.6 103.8 154.0 114.6 114.6 129.8 138.3 138.3 134.4 132.3 126.2 150.3 125.3 168.0
VIII 148.5 104.2 153.0 114.2 115.2 131.7 136.2 133.9 153.8 129.1 128.7 132.1 128.7 166.1
62.7
IX
X
XI
149.7 103.3 154.0 114.0 114.5 128.4 133.0 142.8 130.3 123.9 152.2 123.9 130.3 169.9
151.0 103.6 153.7 114.3 114.3 129.8 138.3 135.0 131.6 122.2 134.4 131.1 127.9 168.7
148.1 104.4 153.7 114.0 115.3 132.3 136.8 138.2 132.3 119.7 135.5 129.8 128.2 168.1
column; samples were introduced using 30-, 50-, or
100- l Hamilton SNR microsyringes. HPLC was
performed on Rsil or Ultraspher ODS reversed phase;
eluent methanol water (65:35, by volume) with addi-
tion of 25 ml of a 10% solution of 18-crown-6 in
methanol per liter of the eluent. The chromatograms
were processed by the internal normalization technique
(with respect to peak areas).
The 13C NMR spectra were recorded both with and
without decoupling from protons on a Bruker CXP-
100 Fourier spectrometer operating at 22.63 MHz.
Dimethyl sulfoxide was used as solvent, and hexa-
methyldisiloxane, as reference.
taining 48.77% of cyanamide sodium salt) was added
under stirring to 1.0 l of water. A solution of 1 equiv
of appropriate substituted benzoyl chloride in
acetone was slowly added to the 14% suspension of
cyanamide sodium salt in water under vigorous stir-
ring. The rate of addition was maintained in such a
way that the temperature of the mixture did not ex-
ceed 30 C. When the addition was complete, the
mixture was vigorously stirred for an additional 15
20 min at 30 35 C. Zinc sulfate, 125.23 g, was added
to remove sulfide ions. The mixture was stirred, and
zinc sulfide (75.57 g) was filtered off. The filtrate was
acidified with hydrochloric acid to pH 3.5 4.5, and
the precipitate of N-cyanobenzamide (acid molecular
form) was filtered off, dried, and analyzed for the
main substance.
Bis(arylcarbonylamino-1H-benzimidazol-5-yl)
ethers III XI (general procedure). Commercial
cyanamide calcium salt or thiourea was used. Cyan-
amide sodium salt was prepared from thiourea as
follows. A mixture of solid thiourea and sodium
hydroxide (molar ratio 1:4) was stirred in a Z-mixer
on heating at 90 95 C. The reaction was complete in
20 25 min; the mixture was cooled on stirring; it
crystallized below 80 C and was disintegrated by
moving endless screw. The mixture was then addi-
tionally disintegrated in a centrifugal mixer. The
finely powdered mixture of cyanamide sodium salt
and sodium sulfide was then used in the synthesis of
N-cyanobenzamide sodium salts.
A mixture of N-cyanobenzamide and tetraamino-
diphenyl ether XII at a molar ratio of 2.6:1 in
aqueous isopropyl alcohol in the presence of hydro-
chloric acid was heated for 6 7 h at 85 95 C. The
ammonia liberated during the process was bound by
adding hydrochloric acid to maintain pH within the
range from 3.5 to 4.5. When the reaction was
complete, the precipitate was filtered off, thoroughly
washed with water on a filter to remove inorganic
salts, and dried in a vacuum roller drier. The yields of
ethers III XI reached 82%, and the concentration of
the main substance was up to 96%.
For this purpose, 140 g of the above mixture (con-
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PILYUGIN et al.
Chikisheva, G.E., Kiseleva, G.V., Kuznetsova, S.L.,
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