Synthesis of 2-amino-5(6)-(4-aminophenyl)benzimidazole derivatives: II. Reaction of 2-nitro-4-thiocyanatoaniline with 4-nitrochlorobenzene

Article abstract of DOI:10.1023/B:RUJO.0000003189.87809.53

The reaction of 2-nitro-4-thiocyanatoaniline with 4-nitrochlorobenzene in aqueous alkaline medium in the presence of phase-transfer catalyst at 95-100°C was studied with a view to obtain 4-amino-3,4′- dinitrodiphenyl sulfide. Optimal conditions for the synthesis and isolation of the product were found.

Full text of DOI:10.1023/B:RUJO.0000003189.87809.53

Russian Journal of Organic Chemistry, Vol. 39, No. 7, 2003, pp. 979 984. Translated from Zhurnal Organicheskoi Khimii, Vol. 39, No. 7, 2003,
pp. 1040 1046.
Original Russian Text Copyright
2003 by Pilyugin, Sapozhnikov, Shitov.
Synthesis of 2-Amino-5(6)-(4-aminophenyl)benzimidazole
Derivatives: II. Reaction of 2-Nitro-4-thiocyanatoaniline
with 4-Nitrochlorobenzene
V. S. Pilyugin, Yu. E. Sapozhnikov, and G. P. Shitov
Research Technological Institute of Herbicides and Plant Growth Regulators,
Academy of Sciences of Bashkortostan Republic, ul. Ul’yanovykh 65, Ufa, 450029 Bashkortostan, Russia
Received May 8, 2002
Abstract The reaction of 2-nitro-4-thiocyanatoaniline with 4-nitrochlorobenzene in aqueous alkaline
medium in the presence of phase-transfer catalyst at 95 100 C was studied with a view to obtain 4-amino-
3,4 -dinitrodiphenyl sulfide. Optimal conditions for the synthesis and isolation of the product were found.
4-Amino-3,4 -dinitrodiphenyl sulfide (I) is a start-
ing material for the synthesis of numerous antihel-
minthic compounds of the 5(6)-(4-aminophenyl)-2-
aminobenzimidazole series [1]. There are published
data on the preparation of alkyl aryl sulfides by reac-
tion of aryl thiocyanates with alkyl halides or alcohols
in the presence of stoichiometric amounts of metal
hydroxides or other bases in the temperature range
from 0 to 250 C [2 6]. We previously developed
a procedure for the synthesis of sulfide I by treatment
of 4-chloronitrobenzene with sodium sulfide, acyla-
tion of the resulting 4-amino-4 -nitrodiphenyl sulfide
with acetic anhydride, nitration of 4-acetylamino-4 -
nitrodiphenyl sulfide to 4-acetylamino-3,4 -dinitrodi-
phenyl sulfide, and removal of the acetyl protection
by reaction with aqueous alkali [7]. An alternative
route to 4-amino-3,4 -dinitrodiphenyl sulfide (I) via
reaction of 2-nitro-4-thiocyanatoaniline (II) with
4-chloronitrobenzene (III) attracts a certain interest.
In this case, the number of chemical steps is reduced
from four [7] to two. Moreover, 2-nitroaniline and
4-nitrochlorobenzene are large-scale chemicals, and
thiocyanation of 2-nitroaniline to 2-nitro-4-thio-
cyanatoaniline was studied by us in detail and was
reported in the preceding communication of this series.
In the present work we examined the reaction of
thiocyanate II with chloronitrobenzene III, which
leads to formation of the target sulfide I. The reaction
was carried out in aqueous alkali at 95 100 C in
the presence of phase-transfer catalyst (PEG-400 or
catamine AB). The process includes two stages. In the
first stage, 2-nitro-4-thiocyanatoaniline is converted
into sodium 4-amino-3-nitrobenzenethiolate (IV). In
the second stage, salt IV reacts with chloronitroben-
zene III to give disulfide I. Taking into account that
sodium cyanate formed in the first stage undergoes
hydrolysis to ammonia, the overall process may be
represented by Scheme 1.
The reaction of thiocyanate II with chloronitroben-
zene III can also be accompanied by side processes.
For example, sodium thiolate IV formed in the first
stage readily reacts with the second molecule of thio-
cyanate II, leading to formation of bis(4-amino-3-
nitrophenyl) disulfide (V) (Scheme 2). This side reac-
tion increases consumption of initial compound II
and sodium hydroxide and favors accumulation of
Scheme 1.
1070-4280/03/3907-0979$25.00 2003 MAIK Nauka/Interperiodica

980
PILYUGIN et al.
Scheme 2.
by-products. On the other hand, the formation of
disulfide V is reversible. By the action of sodium
cyanide, compound V can be converted back into
initial thiocyanate II and salt IV. Therefore, the
formation of V from II and IV can be suppressed by
the use of excess sodium cyanide. Also, diphenyl
disulfide V is readily formed as a result of oxidation
processes in the presence of atmospheric oxygen. To
avoid these, it is advisable to perform the second stage
under nitrogen.
In addition, it is possible that salt IV, which is
necessary for the synthesis of target product I, is
partially formed by hydrolysis of thiocyanate II
through the corresponding thiocarbamate VI [8 10]
(Scheme 3).
These data suggest a complex character of the process
which gives rise to a number of various products.
Most of the products are unstable and hence are dif-
ficult to identify.
Even more complex mixtures of products were
obtained in the presence of the second component,
4-chloronitrobenzene (III), necessary for the forma-
tion of the target compound (Table 2). Table 2 gives
the compositions of solid products which separated
from the mother liquor on acidification with hydro-
chloric acid. Product mixture C was isolated from
the filtrate obtained after separation of sulfide I in
a laboratory setup, and product D was isolated in
a similar way in a pilot setup. The compositions of
products C and D are fairly similar. They consist of
3 4 major components most of which are products of
side reactions.
Scheme 3.
Insofar as most of the above by-products are poorly
soluble in water at pH
7 but readily soluble in
alkaline solution, it is reasonable to wash the pre-
cipitate of sulfide I (after squeezing) first with
an aqueous alkaline solution and then with distilled
water (or steam condensate). As a result, the amount
of impurities in the final product considerably de-
creases. For example, acid VII, which is present in
initial compound II, in aqueous sodium hydroxide
decomposes into sulfur and disodium salt VIII which
is readily soluble in water. Salt VIII reacts with
We made an attempt to determine the ways of
hydrolysis of thiocyanate II to salt IV. Analysis of
the reaction mixtures showed that the hydrolysis of
1 mol of compound II in alkaline medium gave
0.013 mol of sodium carbonate, 0.039 mol of sodium
cyanate, and 0.051 mol of sodium cyanide. These data
indicate that the amount of sodium cyanide almost
coincides with the overall amount of sodium cyanate
and sodium carbonate. We also isolated and analyzed
insoluble organic by-products formed by transforma-
tion of thiocyanate II. Taking into account that
accumulation of sodium cyanide in the reaction mix-
ture promotes its further consumption for the reverse
reaction (decomposition of disulfide V according to
Scheme 2), we can state with certainty that the major
part of salt IV is formed through disulfide V. Table 1
gives the compositions of products A and B which
were isolated, respectively, from the reaction mixture
and the filtrate after hydrolysis of thiocyanate II.
Scheme 4.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 7 2003

SYNTHESIS OF 2-AMINO-5(6)-(4-AMINOPHENYL)BENZIMIDAZOLE DERIVATIVES: II.
981
liberated sulfur to give disodium salt IX. The latter is
stable in alkaline medium, but its treatment with
an acid leads to unstable water-soluble acid X which
is rapidly converted into insoluble acid VII [8, 11]
(Scheme 4). Direct reaction of disodium salt VIII
with hydrochloric acid gives yellow polymer XI of
unknown structure. By treatment with an aqueous
solution of sodium hydroxide, polymer XI is con-
verted back into disodium salt VIII [12] (Scheme 5).
Table 1. Compositions (wt %) of products isolated in the
hydrolysis of thiocyanate II in aqueous alkaline medium
Initial
compound
Component
Aa
Bb
Thiocyanate II
2-Nitroaniline
4-Bromo-2-nitroaniline
Disulfide V
97.5
0.91
1.12
1.57
0.26
0.68
0.67
1.61
1.40
96.01
77.63
Scheme 5.
Unidentified products
X1 X7
0.47
1.48
18.69
a
Solid product isolated by filtration of the reaction mixture
after hydrolysis.
Solid product isolated from the filtrate after acidification.
b
Table 2. Composition (wt %) of products isolated from
the filtrate obtained in the stage of synthesis of sulfide I
Products
Analogous behavior is typical of some other im-
purities present in starting compound II. Therefore,
during the synthesis of disulfide I, concomitant by-
products can be removed as water-soluble compounds
by treatment of the crude solid product with aqueous
alkali. They can be isolated from the filtrate and
washings by acidification and subsequent filtration.
Component
C
D
Sulfide I
4-Nitrochlorobenzene (III)
Disulfide V
Unidentified products
X1 X13
0.51
21.57
0.73
39.31
73.53
25.96
The ability of sodium hydroxide to convert acid
VII and polymer XI into water-soluble compounds
was studied by a special series of experiments. The
results are summarized in Table 3. It is seen that com-
pounds VII and XI are completely converted into
water-soluble compounds on heating in an aqueous
alkaline medium (Table 3, run nos. 1, 2). Heating of
acid VII and polymer XI in the presence of chloro-
nitrobenzene III leads to accumulation of products
insoluble in aqueous alkali (Table 3, run nos. 3, 4).
Presumably, the rate of the reaction of chloronitroben-
zene III with the above compounds is considerably
lower than the rate of its reaction with thiocyanate II.
Thus, after heating of chloronitrobenzene III with
acid VII for 5-h at 95 C (run no. 3), the reaction
mixture contained 60% of unchanged compound III,
about 22% of III was consumed for the formation of
insoluble (in aqueous alkali) compounds, and the
remaining part was converted into soluble products
(including losses). On the other hand, the reaction of
thiocyanatoaniline II with chloronitrobenzene III
under analogous conditions is complete in 40 60 min
(see below).
38.39
(Table 3, run no. 4), 63% of III is consumed for
formation of insoluble products, and about 30% is
converted into soluble compounds (including losses).
Using IR and 13C NMR spectroscopy and high-
performance liquid chromatography, among the isolat-
ed solid products we detected 4,4 -dinitrodiphenyl
sulfide (XII) and 4-amino-4 -nitrodiphenyl sulfide
(XIII). Their fractions were 59 83 and 8 24%, re-
spectively (the residual amount of III was not taken
into account). The other components were not iden-
tified. Dinitrodiphenyl sulfide XII is likely to be
formed by reaction of chloronitrobenzene III with
sulfides present in the reaction mixture. Presumably,
compound XII is then partially reduced to aminonitro-
diphenyl sulfide XIII with those sulfides.
Under analogous conditions we performed syn-
theses of sulfide I from thiocyanate II contaminated
with various amounts (0 to 27.5%) of water-insoluble
impurities (Table 4). In run no. 1 (Table 4) we used
thiocyanate II which was prepared in a laboratory
setup and purified by recrystallization from acetone.
Runs nos. 2 and 3 were performed with compound II
Chloronitrobenzene III reacts with decomposition
products of polymer XI at a higher rate. After the
same period, the precipitate contains only 7% of III
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 7 2003

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PILYUGIN et al.
Table 3. Reactivity of impurities present in technical-grade thiocyanatoaniline II (amounts of reactans: water, 120 ml;
NaOH, 16.8 g; PEG-400, 2 ml; temperature 93 95 C; reaction time 5 h)
Amounts of reactants, g
Product composition, wt %
Run
no.
Amount of solid
product, g
VII
22
XI
III
X1
X2
III
XIII
X3
X4
XII
1
2
3
4
22
22
28
15.5
15.5
12.0
11.0
75.7
1.9
2.2
20.2
53.2
0.36
1.66
9.98
21.5
0.80
12.5
Table 4. Amounts of impurities in initial thiocyanatoaniline II and composition of sulfide I obtained therefrom (molar
ratio II: III: NaOH: PEG-400: H2O = 1.0: 0.9: 4.0: 0.04: 45; temperature 95 C, reaction time 5 h)
Composition of II, wt %
Composition of I, wt %
Run
no.
main substance insoluble impurities main substance
XIII
XII
other impurities
1
2
3
4
100
95.0
93.0
72.5
99.5
97.1
97.0
91.86
0.50
1.45
1.50
4.00
5.0
7.0
27.5
0.25
0.30
0.75
1.20
1.20
3.39
which was synthesized in a laboratory setup and was
not subjected to additional purification, and the sub-
strate in run no. 4 was a nonstandard sample of II
obtained in a pilot setup. The results show that during
the synthesis of sulfide I a considerable part of
impurities present in initial compound II is converted
into soluble compounds which are removed by
washing of the target product. However, it is clearly
seen that the concentration of impurities in the final
product increases as the amount of impurities in the
initial compound increases. Despite the presence of
20 to 34 wt % of impurities in thiocyanate II, in
a large-scale synthesis we succeeded in obtaining
sulfide I containing no less than 91% of the main
substance. Nevertheless, the product contained im-
purities insoluble in aqueous alkaline medium. Some
of these, e.g., 2-nitro- and 4-bromo-2-nitroanilines,
come to the reaction mixture together with initial
compound II and are then transferred to the target
product.
The concentration of impurities in crude sulfide
I may increase during the synthesis as a result of its
thermal decomposition (Table 5). Reduction of the
concentration of the main substance becomes appreci-
able even after prolonged heating in water. In this
case, 3 4 new compounds are formed. In alkaline
medium, the concentration of the main substance
decreases more rapidly, due mainly to considerable
increase in the concentration of one by-product (X1).
The stability of sulfide I under the conditions of its
synthesis was studied by special experiments. For this
purpose, when the synthesis of I was complete, the
reaction mixture was further stirred at 100 C, and
samples were withdrawn, washed to remove water-
soluble impurities, and analyzed. The time of with-
drawal of the first sample was assumed to be the
initial moment. The results are given in Table 6. The
concentration of the main substance decreases mainly
Table 5. Composition of 4-amino-3,4 -dinitrodiphenyl
sulfide (I) after heating for 15 h at 100 C in water and
5% aqueous sodium hydroxide (40 ml)
Composition, wt %
Component
initial
water
5% NaOH
Sulfide I
Chloronitrobenzene
III
Unidentified
impurities
X1 X7
97.23
94.97
86.85
1.08
1.69
0.48
4.55
0.30
12.85
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SYNTHESIS OF 2-AMINO-5(6)-(4-AMINOPHENYL)BENZIMIDAZOLE DERIVATIVES: II.
983
at the expense of increase in the amount of two
unidentified products X1 and X2. However, in this
case, by-products can be formed not only by decom-
position of the main substance but also as a result
of other chemical processes.
Table 6. Stability of 4-amino-3,4 -dinitrodiphenyl sulfide
(I) during its synthesis (temperature 100 C)
Product composition, wt %
Component
initial
95.01
after 4 h after 10 h
The time necessary to complete the synthesis of
sulfide I was determined using a laboratory setup
(Table 7). As a rule, 40 60 min is sufficient. Increase
of the reaction time does not result in increased con-
centration of the main substance in the crude product,
but the amount of impurities rises. The data obtained
in a laboratory setup were then confirmed in enlarged
syntheses in a pilot setup. The latter was also used
to examine the effect of the reaction temperature on
the purity of the target product. Reduction of the
temperature from 100 to 80 C leads to increased con-
centration of chloronitrobenzene III in the product
(up to 4 7 wt %).
Sulfide I
94.37
90.37
Thiocyanatoaniline
II
2-Nitroaniline
4-Bromo-2-nitro-
aniline
Nitrochlorobenzene
III
Unidentified im-
purities X1 X3
0.37
0.25
0.34
0.27
0.31
0.24
1.02
2.09
1.26
1.10
1.94
1.98
1.10
1.15
8.93
Taking into account the above data, we performed
enlarged synthesis of sulfide I in a pilot setup using
a 400-l reactor. The results were consistent with those
obtained in a laboratory setup. The concentration of
the main substance in the crude product (without
additional purification) was within 92 97 wt %, and
it strongly depended on the purity of initial compound
II, reaction time, and temperature. The average yield
of 4-amino-3,4 -dinitrodiphenyl sulfide I, calculated
on 4-nitrochlorobenzene (III), was 90.5%.
Table 7. Composition of 4-amino-3,4 -dinitrodiphenyl
sulfide (I) depending on the reaction time
Composition, wt %
Time,
min
nitrochloro-
benzene III
other
impurities
sulfide I
30
40
60
225
240
295
92.24
93.89
94.75
93.62
93.15
92.17
1.55
1.03
0.38
0.32
0.35
0.35
6.21
5.08
4.97
6.06
6.50
7.48
EXPERIMENTAL
The progress of reactions was monitored by thin-
layer and high-performance liquid chromatography, as
well as by chemical analysis. Some products were
identified by IR and 13C NMR spectroscopy. The IR
spectra were recorded on a Jasco 810-IR spectrometer
from samples dissolved in CCl4 or dispersed in
mineral oil. The 13C NMR spectra were obtained on
Bruker CXP-100 instrument (22.63 MHz), both with
and without decoupling from protons; DMSO-d6 was
used as solvent, and HMDS, as internal reference. The
signals were assigned by analysis of the chemical
shifts, coupling constants, multiplicities, and intensity
ratios.
Initial compound II and crude disulfide I were
analyzed by HPLC using an Altex chromatograph;
25-cm 4.6-mm stainless steel column was packed
with Ultraspher-C8 reversed phase; eluent acetonitrile
water (45:55) with addition of 5% of DMSO (relative
to the overall amount of acetonitrile and water);
2-Nitro-4-thiocyanatoaniline (II) was synthesized
by the procedure reported [7]; reagent-grade 4-nitro-
chlorobenzene (III) contained 99.75 wt % of the main
substance.
A laboratory setup consisted of a glass reactor
equipped with a jacket, anchor stirrer, reflux con-
denser, thermometer, and dropping funnel. The reactor
was charged with a specified amount of water which
was heated to 65 70 C, and PEG-400, nitrochloro-
benzene III, and thiocyanatoaniline II were added in
succession under stirring. The mixture was heated
under stirring to 75 80 C, and a required amount of
40 44% aqueous sodium hydroxide was added over
a period of 25 30 min. The mixture was then heated
to 95 100 C and was stirred at that temperature for
a required time. During the synthesis, samples were
withdrawn for analysis. If the reaction mixture con-
tained an appreciable amount of chloronitrobenzene
UV detector,
= 254 nm. The components were
quantitated by the internal normalization technique
with respect to peak area using correction coefficients.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 7 2003

984
PILYUGIN et al.
III after 1.0 1.5 h, additional amounts of thiocyanato-
aniline II and sodium hydroxide were added, and the
process was continued; otherwise, the mixture was
cooled to room temperature and filtered, and the pre-
cipitate was washed on a filter first with aqueous
alkali and then with distilled water or steam con-
densate, dried, and analyzed.
The hydrolysis of compound II was studied as
follows. Compound II, 0.1 mol, was added to 200 ml
of a 2 M solution of carbonate-free alkali, and the
mixture was heated for 1 h at 100 C under vigorous
stirring (using a hydroacoustic setup). The mixture
was cooled to room temperature, and the precipitate
was filtered off, washed with water, dried, and
analyzed by HPLC (product A, Table 1). The filtrate
was combined with the washings and acidified with
hydrochloric acid. The precipitate was filtered off,
washed with water, dried, and analyzed (product B,
Table 1).
The time necessary for the synthesis of sulfide I
to be complete (in a laboratory setup) was determined
as follows. A 250-ml glass reactor was charged with
100 ml of distilled water, and 1 3 g of PEG-400,
0.4 mol of NaOH, 0.1 mol of chloronitrobenzene III,
and 0.1 mol of thiocyanatoaniline were added under
stirring. The mixture was quickly heated to 100 C,
and samples were withdrawn for analysis.
The synthesis of sulfide I in a pilot setup was
performed using a 400-l enameled reactor with a bot-
tom discharge equipped with a jacket, anchor stirrer
(65 135 rpm), and reflux condenser.
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