Hydrogenation on palladium-containing granulated catalysts 3. Synthesis of aminobenzimidazoles by catalytic hydrogenation of dinitroanilines

Article abstract of DOI:10.1007/s11172-007-0184-z

Efficient hydrogenation of o-aminonitrobenzenes on palladium-containing granulated carbon catalysts in carboxylic acid solutions was accompanied by cyclization into aminobenzimidazoles. A simple hydrogenation reactor with a fixed gauze holding a reusable granulated catalyst was designed. Acylated and sulfonylated 4(7)-aminobenzimidazoles were obtained. In terms of electronic and geometrical parameters, they are close analogs of biologically active imidazo[1,5,4-e,f ][1,5]benzodiazepines.

Full text of DOI:10.1007/s11172-007-0184-z

Russian Chemical Bulletin, International Edition, Vol. 56, No. 6, pp. 1216—1226, June, 2007
1216
Hydrogenation on palladiumꢀcontaining granulated catalysts
3.* Synthesis of aminobenzimidazoles
by catalytic hydrogenation of dinitroanilines
V. V. Elkin, L. N. Tolkacheva,† N. B. Chernysheva, I. B. Karmanova, L. D. Konyushkin, and V. V. Semenovꢀ
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (495) 137 2966. Eꢀmail: vs@zelinsky.ru
Efficient hydrogenation of oꢀaminonitrobenzenes on palladiumꢀcontaining granulated
carbon catalysts in carboxylic acid solutions was accompanied by cyclization into aminoꢀ
benzimidazoles. A simple hydrogenation reactor with a fixed gauze holding a reusable granuꢀ
lated catalyst was designed. Acylated and sulfonylated 4(7)ꢀaminobenzimidazoles were obꢀ
tained. In terms of electronic and geometrical parameters, they are close analogs of biologically
active imidazo[1,5,4ꢀe, f ][1,5]benzodiazepines.
Key words: hydrogenation, aminobenzimidazoles, oꢀaminonitrobenzenes, dinitroanilines,
palladiumꢀcontaining granulated catalysts.
Polyaminobenzene derivatives and their cyclization
The same problems complicate the synthesis of aroꢀ
matic and heterocyclic polyamines via hydrogenation of
polyaminonitrobenzenes and fused furoxanes.14
Here we studied the possibility of "one pot" synthesis
of aminobenzimidazoles from accessible dinitroanilines
through catalytic hydrogenation of dinitroanilines to
triaminobenzenes followed by their condensation with
carboxylic acid derivatives.
Dinitroanilines 1a,b were hydrogenated in the presꢀ
ence of a catalyst (2—5% Pd on granulated graphite
Sibunit) in specially designed reactors15 ensuring contact
between a solution to be hydrogenated and a fixed layer of
the catalyst. Earlier,1 we have demonstrated that monoꢀ
nitroarenes and ꢀheteroarenes can be smoothly hydrogeꢀ
nated on a fixed catalyst layer.
In this study, we used a reactor (Fig. 1) in which
contact of the catalyst with a substrate to be hydrogenated
is ensured by motion of its solution through a stainless
steel box suspended in the reactor. A magnet was sealed in
a teflon holder under the box and stirring in the stainless
steel autoclave was carried out with a common magnetic
stirrer. Such a reactor design is convenient for hydrogeꢀ
nation of small amounts of substrates in small autoclaves
(40—700 mL).
To prevent deactivation of the catalyst, the reacting
solution should be periodically removed from the reactor
avoiding penetration of the ambient air and the reactor
should be filled with a solvent. In this case, the catalyst
can be recycled.
products (aminobenzimidazoles) are of considerable inꢀ
terest for various areas of clinical chemistry because of
their structural similarity with purine bases. For instance,
retigabine (a 1,2,4ꢀtriaminobenzene derivative) is an effiꢀ
cient anticonvulsant blocking ion channels.2
4ꢀSulfonylamino derivatives of 1,4ꢀdiaminoꢀ2,6ꢀdiꢀ
nitrobenzenes are highly effective against sleeping sickꢀ
ness (African trypanosomiasis).3
4ꢀAminobenzimidazoles are used in the synthesis
of many biologically active compounds, e.g., imidꢀ
azo[1,5,4ꢀe, f ][1,5]benzodiazepines, which are HIVꢀ1
replication inhibitors.4 5ꢀAminobenzimidazoles5 and their
sulfonylamino derivatives are inhibitors of thrombases6
and promising antagonists of NMDA receptors.7
A usual route to benzimidazoles containing an amino
group in different positions of the benzene ring involves
cyclization of nitrophenylenediamines followed by hydroꢀ
genation of the nitro group5,6,8,9 or direct synthesis from
appropriate triaminobenzenes.10 However, the starting
triaminobenzenes are readily oxidized in air and a major
part of the product becomes lost during isolation when
prepared by hydrogenation of dinitroanilines on both tin
dichloride11—13 and the Raney nickel.10 In addition,
triaminobenzenes form complexes with tin and nickel
salts, which also hinders to obtain them in the individual
state, especially when tin salts are removed with hydrogen
sulfide.13
Hydrogenation of aminonitrobenzenes on supported
palladium catalysts prevents complexation between the
* For Part 2, see Ref. 1.
† Deceased.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1171—1181, June, 2007.
1066ꢀ5285/07/5606ꢀ1216 © 2007 Springer Science+Business Media, Inc.

Synthesis of aminobenzimidazoles by hydrogenation Russ.Chem.Bull., Int.Ed., Vol. 56, No. 6, June, 2007
1217
H2
Scheme 1
5
4
N2
3
2
1: 4ꢀNO2 (a), 6ꢀNO2 (b); 2: 4ꢀNH2 (a), 3ꢀNH2 (b)
1
Comꢀ
pound
R
NHC(O)R
Comꢀ
pound
R
Position of the
NH2 group
Fig. 1. The hydrogenation reactor (V = 40—400 cm3): (1) magꢀ
netic stirring bar, (2) stainless steel box with Pd/Sibunit granules,
(3) valve, (4) discharge outlet, (5) thermometer.
3a
3b
4a
4b
5a
5b
H
H
Me
Me
CF3
CF3
5ꢀNHC(O)H
4ꢀNHC(O)H
5ꢀNHC(O)Me
4ꢀNHC(O)Me
5ꢀNHC(O)CF3
4ꢀNHC(O)CF3
6a
6b
7a
7b
8a
8b
H
H
Me
Me
CF3
CF3
5
4
5
4
5
4
resulting polyaminobenzenes and heavy metals, thus faꢀ
cilitating isolation of the reaction products. As the conseꢀ
quence, the yields of the target triaminobenzenes 2a,b
were increased to 90%.
tion because of diminished electronꢀdonating properties
of the aromatic ring.
In hydrogenation, a mineral acid (e.g., HCl in ethaꢀ
nol) can be added to a substrate. Protonated amino
groups impart electronꢀwithdrawing properties to the
aromatic ring and are resistant to oxidation, which
increases the yields of products isolated as dihydroꢀ
chlorides.
In neutral alcoholic media, the target triaminoꢀ
benzenes decompose rapidly: by more than 50% in an
hour after the hydrogenation. Subsequent cyclization of
dihydrochlorides of compounds 2 in carboxylic acids give
the corresponding NHꢀacylated benzimidazoles 3. The
acyl group can be easily removed in boiling 10% HCl
(Scheme 1).
Hydrogenation of 2,4ꢀ and 2,6ꢀdinitroanilines in conꢀ
centrated formic and acetic acids followed by heating the
reaction mixture in the autoclave afforded the correspondꢀ
ing aminobenzimidazoles.
Both reaction steps can be easily combined in a hydroꢀ
genation reactor to prevent air contact; the total yields of
aminobenzimidazoles are usually higher than in stepꢀbyꢀ
step isolation of intermediate products. In addition, the
final products can be isolated in air. Apparently, acylation
of the amino groups formed in the hydrogenation stabiꢀ
lizes an intermediate product and stimulates hydrogenaꢀ
As shown earlier,16 hydrogenation of oꢀnitroanilines
in acids in the presence of 10% Pd on powdered carbon
also results in cyclization leading, however, to aminoꢀ
benzimidazole Nꢀoxide.
In the case of hardly available or highꢀmelting carꢀ
boxylic acids, their solutions with hydrogen chloride can
be employed for simultaneous hydrogenation, cyclizaꢀ
tion, and deacylation. It should be emphasized that
4(7)ꢀaminobenzimidazoles are much more stable in storꢀ
age than 5(6)ꢀaminobenzimidazoles, which are best isoꢀ
lated and stored as Nꢀacylated derivatives.
Dinitroanilines can be hydrogenated in other cyclizaꢀ
tion solvents (e.g., ethyl acetate). In this way, we obtained
4(7)ꢀaminoꢀ2ꢀmethylbenzimidazole from 2,6ꢀdinitroꢀ
aniline (reactor charges up to 200 g).
This method is convenient for the synthesis of more
complex 4ꢀaminobenzimidazoleꢀ6ꢀcarboxylic acids
(Scheme 2). Esterification of acid 10 was carried out in
methanol in the presence of SOCl2.
The starting 4ꢀaminoꢀ3,5ꢀdinitrobenzoic acid (9) was
prepared by nitration of 4ꢀchlorobenzoic acid followed by
treatment with ammonia (for substitution of an amino
group for the Cl atom) according to a slightly modified
procedure.17 The total yield was 80%.

1218
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 6, June, 2007
Elkin et al.
Scheme 2
Starting from 2,4ꢀdinitroaniline (1a), one can obtain
hardly available 1,2,3,4ꢀdiimidazobenzene (14) in only
three steps (Scheme 3).
We found that nitration of acylated aminobenzꢀ
imidazoles 3a and 4a mainly occurs at position 4, yielding
compounds 12 and 13 and small amounts of the 7ꢀnitro
isomer. This is in conflict with previous data19 on excluꢀ
sive nitration of 5ꢀacetamidoꢀ2ꢀmethylbenzimidazole at
position 6. The nitration of 4ꢀacetamidobenzimidazole
(17a) proceeded nonselectively (at positions 5 and 7) to
give a 9 : 5 mixture of isomers 15a and 15b, respectively,
in a high total yield (78%). The structure of isomer 15b
1
was proved by homonuclear H—1H NOESY data. The
spectrum shows a crossꢀpeak due to a coupling of the
NH proton of the acetamido group with the H(5) proton
of the aromatic ring. This crossꢀpeak was not observed for
isomer 15a because a nitro group is ortho to the acetamido
fragment.
Acylation of 4(7)ꢀaminobenzimidazoles simultaꢀ
neously involved two centers (the amino group and the
ring N atom), regardless of the stoichiometric ratio
(Scheme 4). The acyl group at the ring N atom was easily
eliminated by heating in Et3N—MeOH.
In the case of 2ꢀtrifluoromethyl derivatives 19, the
acyl substituent at the ring N atom was eliminated more
easily (even on reꢀheating of the reaction mixture).
The resulting 4ꢀacylaminobenzimidazoles 17 can be
stabilized by intramolecular hydrogen bonding that closes
a sevenꢀmembered ring. In terms of electronic and geoꢀ
metrical parameters, they are close analogs of imidꢀ
azo[1,5,4ꢀe, f ][1,5]benzodiazepines and hence can exꢀ
hibit similar biological activity.4
This method is preparatively more convenient and subꢀ
stantially more efficient (97% yield) than a threeꢀstep
synthesis involving hydrogenation of one nitro group with
SnCl2, cyclization, and hydrogenation of the other nitro
group.17
Recently,18 cyclization of 4ꢀaminoꢀ3,5ꢀdinitrobenꢀ
zoate derivatives has been effected in one step in the
presence of SnCl2. However, the yields of 4ꢀaminoꢀ
benzimidazolecarboxylates did not exceed 30%, the benꢀ
zene ring always containing a chlorine atom.
Sulfonylated 4ꢀaminobenzimidazoles 18, which are
analogs of highly biologically active compounds,7,20 can
Scheme 3
R = H (3a, 12), Me (4a, 13)

Synthesis of aminobenzimidazoles by hydrogenation Russ.Chem.Bull., Int.Ed., Vol. 56, No. 6, June, 2007
1219
Scheme 4
6b: Z = H; 8b: Z = CF3
17: Z = H; R = Me (a), 3ꢀNCC6H4 (b), 4ꢀNCC6H4 (c), 2ꢀFꢀ4ꢀBrC6H3 (d), 4ꢀPhOC6H4 (e);
Z = CF3; R = Ph (f), 3,4ꢀOCH2OC6H3 (g), 2ꢀfuryl (h), 2ꢀthienyl (i), 4ꢀCF3C6H4 (j), 3ꢀCF3C6H4 (k)
18: Ar = 3ꢀClꢀ4ꢀFC6H3 (a), 3ꢀCF3OC6H4 (b), 4ꢀCF3OC6H4 (c), 4ꢀNCC6H4 (d), 4ꢀPhOC6H4 (e), 2ꢀFꢀ4ꢀBrC6H3 (f)
2,6ꢀDinitroaniline was prepared according to a known proꢀ
cedure.22 Commercial reagents were used. 2—5% Pd/Sibunit
catalysts were prepared and regenerated as described earlier.15
The yields and physicochemical and spectroscopic characꢀ
teristics of the compounds obtained are given in Tables 1 and 2.
4ꢀChloroꢀ3,5ꢀdinitrobenzoic acid (cf. Ref. 17). 4ꢀChloroꢀ
benzoic acid (20 g) was dissolved in H2SO4 (d = 1.835, 300 mL)
at 70—100 °C and KNO3 (66 g) was added. The reaction mixꢀ
ture was heated to 130—140 °C, kept for 1.5 h, cooled to ~20 °C,
and poured onto ice. The yield of 4ꢀchloroꢀ3,5ꢀdinitrobenzoic
acid was 26 g (82.5%), m.p. 153—156 °C (cf. Ref. 17).
4ꢀAminoꢀ3,5ꢀdinitrobenzoic acid (9) (cf. Ref. 17). 4ꢀChloroꢀ
3,5ꢀdinitrobenzoic acid (97.6 g) was dissolved in methanol
(200 mL) and aqueous 24% NH3 (600 mL) was gradually added.
The reaction mixture was stirred at ~20 °C for 2.5 h, refluxed
for 3 h, and left for ~14 h. The precipitate that formed was
filtered off and the filtrate was evaporated to dryness. The solid
residue was combined with the precipitate and water (50 mL)
and HCl (50 mL) were added. On stirring, the precipitate was
filtered off and washed with water to neutral reaction. The yield
of 4ꢀaminoꢀ3,5ꢀdinitrobenzoic acid (9) was 87 g (97%).17
Hydrogenation of dinitroanilines 1a,b in a solution of HCl in
methanol (general procedure A). A stainless steel autoclave was
charged with a solution of dinitroaniline 1a or 1b (20 mmol) in
be easily obtained by monosulfonylation of the amino
group.
To conclude, we synthesized over 50 various
4(7)ꢀacylꢀ and 4(7)ꢀsulfonylaminobenzimidazoles*. Some
of them can suppress cell proliferation by breaking in vivo
polymerization of the cell tubulin according to our reꢀ
cent21 test system on sea urchin embryos.
4(7)ꢀSulfonylaminobenzimidazoles 18 can be regarded
as analogs of 4ꢀsulfonylamino derivatives of 1,4ꢀdiaminoꢀ
2,6ꢀdinitrobenzenes, which inhibit tubulin polymerizaꢀ
tion in curing African trypanosomiasis.3
Experimental
NMR spectra were recorded on a Bruker DRX500 instruꢀ
ment (500.13 MHz) in DMSOꢀd6 (unless otherwise specified).
Mass spectra were recorded on Kratos MSꢀ30 and Finnigan
MAT instruments (direct inlet probe, EI, 70 eV). The course of
the reactions was monitored by TLC on Silufol UVꢀ254 plates.
* The comprehensive list of the structures and their spectra have
been published on the website: www.chemblock.com (a search
for compounds by structural fragment is possible).
Table 1. Reaction conditions (temperature (T ), reaction time (t), pressure (P), and solvent) and the yields, melting points, spectroꢀ
scopic characteristics, and elemental analysis data for compounds 2—8 and 10—16
Comꢀ
pound
Yield
(%)
Reaction conditions
M.p./°C Found
(solvent) Calculated
Molecular
formula
1H NMR (DMSOꢀd6),
MS,
m/z
(%)
δ (J/Hz)
T/°C t/h Р/atm Solvent
(method)
(Irel (%))
С
H
—
N
—
2а•
•2HCl
81 (А) 50
86 (А) 50
4
4
60
60
МеОН 164—16710
(EtOH)
—
—
—
6.77 (d, 1 H, H(3), J = 1.5); 123 [M]+
6.95 (dd, 1 H, H(5), J = 8, (100),
J = 1.5); 7.17 (d, 1 H, H(6), 95 (83)
J = 8); 5.50—8.10a
6.75 (t, 1 H, H(5), J = 8.5); 123 [М[+
2b•
МеОН
>30012
—
—
—
•2HCl
(H2O—HCl)
7.25 (d, 2 H, H(4), H(6),
J = 8.5); 6.00—8.50a
(100),
95 (33)
(to be continued)

1220
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 6, June, 2007
Elkin et al.
Table 1 (continued)
Comꢀ
pound
Yield
(%)
Reaction conditions
M.p./°C Found
(solvent) Calculated
Molecular
formula
1H NMR (DMSOꢀd6),
MS,
m/z
(%)
N
δ (J/Hz)
T/°C t/h Р/atm Solvent
(method)
(Irel (%))
С
H
b
3а•
94 (B) 80
4
3
70
—
HCOOH 280—282 52.38 4.42 20.87 C9H9N3O3
HCOOH (H2O) 52.17 4.38 20.28
—
161 [М]+
(100),
•HCO2H 91 Reflux
(C)
133 (81),
105 (44)
See Ref. 4
3b
4a
78 (C) Reflux 2.5
—
HCOOH 173—174
(H2O),
—
—
—
—
See Ref. 4
173—1754,23
72.5 60—65
4
40
АсOH
239—241 63.54 5.81 22.28 C10H11N3O 2.00 (s, 3 H, MeCO); 3.35 189 [M]+
(B)
(10% HСl) 63.47 5.86 22.21
(s, 3 H, 2ꢀMe); 7.18 (d,
(64), 148
1 H, H(4), J = 8.6); 7.31 (21.6), 147
(d, 1 H, H(5), J = 8.6);
7.92 (s, 1 H, H(7)); 9.78
(br.s, 1 H, AcNH); 12.00
(br.s, 1 H, H(1))
—
(100), 105
(21.4)
4b
5a
83 (B) 60—65
85 (C) Reflux
4
3
40
—
АсOH 92—9923,24 63.38 5.75 22.30 C10H11N3O
(H2O—HCl) 63.47 5.86 22.21
—
CF3COOH
200
40.48 1.65 14.16 C10H5F6N3O 7.60 (br.s, 1 H, H(4));
297 [М]+
(100), 278
(15), 227
(19), 200
(87), 100
(61)
(decomp.) 40.42 1.70 14.14
7.75 (br.s, 1 H, H(5));
8.15 (s, 1 H, H(7)); 11.42
(s, 1 H, CF3CONH);
14.00 (br.s,1 H, H(1))
5b
63 (C) Reflux
3
4
—
CF3COOH 180—185 40.38 1.72 14.17 C10H5F6N3O 7.43 (t, 1 H, H(5), J = 8.4); 297 [М]+
40.42 1.70 14.14 7.52 (d, 1 H, H(4), J = 8.4); (46), 228
7.67 (d, 1 H, H(6), J = 8.4);
11.38 (s, 1 H, CF3CONH);
14.08 (br.s, 1 H, H(1))
(100),
200
(30)
6a•
•2HCl
57.5 60—65
(B) Reflux 2.5
40
—
—
HCOOH 223—225 40.88 4.51 20.43 C7H9Cl2N3 7.33 (d, 1 H, H(2), J = 8.6); 133 [М]+
HCOOH (aqueous 40.80 4.40 20.39
10% HCl ЕtOH)
7.62 (s, 1 H, H(7)); 7.81
(d, 1 H, H(5), J = 8.6);
9.43 (s, 1 H, H(1))
(100),
105 (39)
1
6b•
•2HCl
75 60—65
(B) Reflux 2.5
4
40
—
—
HCOOH 229—231 40.69 4.31 20.44 C7H9Cl2N3 6.10 (br.s, 3 H, N+H3);
133 [М]+
(100),
105
HCOOH (H2O— 40.80 4.40 20.39
6.72 (d, 1 H, H(6), J = 8.6);
6.96 (d, 1 H, H(4), J = 8.6);
1
10% HCl
HCl)
7.24 (t, 1 H, H(5), J = 8.6);
(24)
9.40 (s, 1 H, H(2));
14.87 (br.s, 1 H, H(1))
43.57 5.07 19.19 C8H11Cl2N3 2.78 (s, 1 H, 2ꢀMe); 7.33
7a•
•2HCl
90 Reflux
(C)
3
1
—
—
АсOH
>2808
147 [М]+
(100), 146
(73), 119
(16), 105
(51)
10% HCl (decomp.) 43.65 5.04 19.09
(MeOH)
(d, 1 H, H(6), J = 8.2);
7.62 (s, 1 H, H(4)); 7.72
(d, 1 H, H(7), J = 8.2);
9.00—13.00a
c
7b•
•2HCl
84 Reflux 1.5
—
—
CF3COOH
10% HCl
—
43.74 5.01 19.20 C8H11Cl2N3 2.75 (s, 3 H, Me); 6.72 (d, 147 [М]+
43.65 5.04 19.09 1 H, H(5), J = 8.2); 6.91 (100), 146
(C)
1
(d, 1 H, H(7), J = 8.2);
7.18 (t, 1 H, H(6), J = 8.2);
5.85—7.35a
(34), 105
(15)
8a•
•2HCl
87 Reflux
(C)
3
1
—
—
CF3COOH 275—295 35.17 2.83 15.44 C8H8Cl2F3N3 7.40 (s, 1 H, H (7)); 7.90
201 [M]+
(100), 181
(68), 154
(8), 105
(22)
10% HCl (decomp.), 35.06 2.94 15.33
2909
(d, 2 H, H(4), H(5),
J = 8); 10.20—10.5 (d)
(to be continued)

Synthesis of aminobenzimidazoles by hydrogenation Russ.Chem.Bull., Int.Ed., Vol. 56, No. 6, June, 2007
Table 1 (continued)
1221
Comꢀ
pound
Yield
(%)
Reaction conditions
M.p./°C Found
(solvent) Calculated
Molecular
formula
1H NMR (DMSOꢀd6),
MS,
m/z
(%)
N
δ (J/Hz)
T/°C t/h Р/atm Solvent
(method)
(Irel (%))
С
H
8b•
•2HCl
76 Reflux
(C)
3
1
—
—
CF3COOH >350
10% HCl (H2O— 35.06 2.94 15.33
HCl)
35.21 2.87 15.38 C8H8Cl2F3N3 7.21 (d, 1 H, H(5), J = 8); 201 [М]+
7.36 (t, 1 H, H(6), J = 8); (100), 181
7.52 (d, 1 H, H(7), J = 8); (31), 162
5.10—10.00a
(36), 105
(13)
177 [М]+
(100), 105
(44)
10•
•2 HCl
97 (B) 70
4
6
70
—
HCOOH 260—263 38.48 3.69 16.75 C8H9Cl2N3O2 7.27 (s, 1 H, H(4)); 7.46
(МеOH) 38.42 3.63 16.80
(s, 1 H, H(6)); 9.50 (s,
1 H, H(2)); 5.20—9.90a
11•
•2HCl
81 Reflux
MeOH, 141—142 40.42 4.17 15.75 C9H11Cl3N2O3 3.72 (s, 3 H, ОMe); 7.29
191 [M]+
(100), 160
(44), 133
(35), 132
(55), 105
(17)
SOCl2
(МеOH) 40.32 4.14 15.67
(s, 1 H, H(4)); 7.48 (s,
1 H, H(6)); 9.50 (s, 1 H,
H(2)); 7.20—11.50a
12
13
80
50
80
0
0
2
2
—
—
100% HNO3 >300
46.21 2.87 39.33 C8H6N4O3
46.06 2.93 39.32
7.90 (br.s, 1 H, H(6));
206 [M]+
8.00 (d, 1 H, H(7), J = 8.4); (43), 178
8.36 (s, 1 H, H(2)); 8.48, (100), 132
8.50 (2 br.s, 1 H, COH)d; (87), 105
10.42, 10.67 (2 br.s, 1 H,
NH)d; 13.00 (br.s, 1 H, H(1))
(74)
100% HNO3 289—291 51.32 4.35 29.80 C10H10N4O3 2.10 (s, 3 H, Me); 2.45 (s, 234 [M]+
(H2O) 51.28 4.30 29.90
3 H, MeCO); 7.40 (br.s,
1 H, H(4)); 7.80 (br.s,
1 H, H(5)); 10.23 (br.s,
1 H, NH); 12.70 (br.s,
1 H, H(1))
(28), 192
(100), 146
(70), 104
(15)
14
20
5
2
1
30
—
—
HCOOH 321—324 53.18 3.94 44.36 С8H6N4
HCOOH (decomp.) 53.16 3.82 44.28
10% HCl (water—
7.76 (s, 2 H, H(8), H(9)); 158 [M]+
9.10 (s, 2 H, H(2), H(6)); (100), 131
(B) Reflux
13.50 (br.s, 2 H,
H(1), H(5))
(12), 104
(12)
acetone)
15а
50
20 1.5
—
100%
300
49.21 3.75 31.74 C9H8N4O3
2.12 (br.s, 3 H, Me); 7.50, 220 [M]+
HNO3 (decomp.) 49.09 3.66 31.81
7.65 (br.s, 1 H, H(4))d;
7.83 (br.s, 1 H, H(5));
(13), 178
(100), 148
8.49 (s, 1 H, H(2)); 10.15, (45), 132
10.45 (2 br.s, 1 H,
(50), 105
(70)
MeCONH)d; 12.80, 13.00
(2 br.s, 1 H, H(1))d
15b
16
29
20 1.5
—
—
100%
230—240 49.21 3.75 31.74 C9H8N4O3
2.29 (s, 3 H, Me); 8.15 (d, 220 [M]+
HNO3 (decomp.) 49.09 3.66 31.81
1 H, H(5), J = 8.2); 8.28 (d, (32), 178
1 H, H(6), J = 8.2); 8.40 (s,
(100),
1 H, H(2)); 10.45 (s, 1 H, 148 (51),
MeCONH); 13.30
(s, 1 H, H(1))
132 (50),
105 (67)
88 Reflux 0.5
10% HCl
260
47.25 3.46 15.75 C7H6N4O2
6.81 (d, 1 H, H(6), J = 7.6);178 [М]+
7.71 (d, 1 H, H(7), J = 7.6); (100),
7.82 (br.s, 2 H, NH2); 7.89 132 (55),
(s, 1 H, H(2)); 12.56 (br.s, 105 (42)
1 H, H(1))
(subl.) 47.19 3.39 15.67
a The signals for the NH2 group and sometimes for the H(1) atom are distributed between these values as a smooth convex line.
b The NMR spectrum is poorly resolved because of an impurity of formic acid in different stoichiometric ratios.
c No definite melting point.23,24
d The H(1) ↔ H(3) tautomerism.

1222
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 6, June, 2007
Elkin et al.
Table 2. Yields, physicochemical and spectroscopic characteristics, and elemental analysis data for compounds 17—19
Comꢀ Yield
Rf
M.p./°C
(solvent)
Found
Calculated
Molecular
formula
1H NMR, δ (J/Hz)
MS,
m/z (Irel (%))
(%)
poꢀ
(%)
und
С
H
N
17a
17b
67
0.55
(AcOEt—
MeOH,
4 : 1)
260
61.70 5.11 23.87 С9H9N3O
61.75 5.18 23.99
2.18 (s, 3 H, MeCO); 7.11 (t, 1 H,
H(5), J = 7.9); 7.28 (d, 1 H, H(4),
J = 7.9); 7.67 (br.s, 1 H, H(6));
8.14 (s, 1 H, H(2)); 9.68 (s, 1 H,
МеСОNH); 12.21 (br.s, 1 H, H(1))
7.21 (t, 1 H, H(5), J = 7.5); 7.46
(br.s, 2 H, H(4), H(6)); 7.78 (t,
1 H, H(5´), J = 8.6); 8.08 (d, 1 H,
H(6´), J = 8.6); 8.20 (s, 1 H, H(2´)); 102 (100)
8.33 (d, 1 H, H(4´), J = 8.6); 8.48
(s, 1 H, H(2)); 10.20, 10.40 (2 br.s,
1 H, ArCONH)*; 12.10, 12.50
175 [М]+ (43),
160 (3),
133 (100)
47
44
0.4
125—127
68.66 3.77 21.44 C15H10N4O
68.70 3.84 21.37
262 [М]+ (50),
233 (22), 130
(98), 105 (40),
(AcOEt— (MeCN)
MeOH,
9 : 1)
(2 br.s, 1 H, H(1))*
17c
0.4
242—243
68.77 3.91 21.45 C15H10N4O
68.70 3.84 21.37
7.18 (t, 1 H, H(5), J = 7.5); 7.48
(d, 1 H, H(4), J = 7.5); 7.57 (d,
1 H, H(6), J = 7.5); 8.01 (d, 2 H,
H(2´), H(6´), J = 8.6): 8.18 (d,
2 H, H(3´), H(5´), J = 8.6); 8.20
(s, 1 H, H(2)); 10.23 (s, 1 H, ArNH);
12.29 (br.s, 1 H, H(1))
262 [М]+
(100), 233
(47), 160 (24),
130 (82)
(AcOEt—
MeOH,
9 : 1)
17d** 26
0.8
230
50.38 2.65 12.66 C14H9BrFN3O 7.21 (t, 1 H, H(5), J = 7.6); 7.38
335 [М]+ (44),
333 (56), 307
(10), 305 (14),
205 (100), 203
(100), 177
(20), 175 (22),
132 (8)
329 [М]+ (30),
197 (100),
160 (4), 141
(28), 132 (22)
305 [М]+
(34.7), 105
(100), 79 (22),
77 (82)
349 [М]+ (17),
149 (100),
(C6H6—
AcOEt,
1 : 1)
50.32 2.71 12.58
(d, 1 H, H(4), J = 7.6); 7.57 (d,
1 H, H(3´), J = 10); 7.82 (br.s,
2 H, H(5´), H(6´)); 8.21 (s, 1 H,
H(2)); 10.06 (s, 1 H, ArNH);
12.38 (br.s, 1 H, H(1))
17e
17f
17g
27
96
60
0.9
(C6H6—
AcOEt,
1 : 1)
95—98
72.80 4.61 12.84 C20H15N3O2
72.93 4.59 12.76
7.12—8.07 (m, 12 H, H(4)—H(6),
С6H5ОС6H4); 8.20 (s, 1 H, H(2));
9.92 (s, 1 H, ArCONH); 12.28
(br.s, 1 H, H (1))
—
221—224
55.08 3.28 13.87 C15H10F3N3O 7.38 (t, 1 H, H(5), J = 8);
55.02 3.30 13.77
7.55—8.15 (m, 7 H, H(5), H(6),
Ph); 10.19 (s, 1 H, ArCONH);
13.78 (br.s, 1 H, H(1))
—
195—197
(water—
EtOH)
55.10 2.81 12.13 C16H10F3N3O3 6.12 (s, 2 H, ОСH2О); 7.08 (d,
55.02 2.89 12.03
1 H, H(4), J = 8); 7.37 (t, 1 H,
H(5), J = 8); 7.54 (d, 1 H, H(6),
J = 8); 7.58 (s, 1 H, H(6´)); 7.65
(d, 1 H, H(3´), J = 8.1); 7.72
174 (17)
(br.s, 1 H, H(2´)); 10.00 (s, 1 H,
ArCONH); 13.75 (br.s, 1 H, H(1))
17h
17i
99
75
—
—
182—184
163—166
52.81 2.75 14.27 C13H8F3N3O2 6.72 (br.s, 1 H, H(4)); 7.38—7.84
52.89 2.73 14.23
295 [М]+
(m, 5 H, H(5), H(6), H(2´)—H(4´)); (100), 276 (3),
8.00 (s, 1 H, H(2)); 9.82 (br.s, 1 H,
ArCONH); 13.90 (br.s, 1 H, H(1))
50.27 2.51 13.50 C13H8F3N3OS 7.24 (br.s, 1 H, H(4´)); 7.36
95 (55)
311 [М]+ (49),
128 (10),
111 (100)
50.16 2.59 13.50
(br.s, 1 H, H(3´)); 7.53 (br.s,
1 H, H(2´)); 7.67 (br.s, 1 H,
H(4)); 7.85(s, 1 H, H(5)); 8.06
(s, 1 H, H(6)); 10.12 (s, 1 H,
ArCONH); 13.74 (br.s, 1 H, H(1))
(to be continued)

Synthesis of aminobenzimidazoles by hydrogenation Russ.Chem.Bull., Int.Ed., Vol. 56, No. 6, June, 2007
Table 2 (continued)
1223
Comꢀ Yield
Rf
M.p./°C
(solvent)
Found
Calculated
Molecular
formula
1H NMR, δ (J/Hz)
MS,
m/z (Irel (%))
(%)
poꢀ
(%)
und
С
H
N
17j
61
—
181—183
(water—
EtOH)
51.44 2.48 11.27 C16H9F6N3O
51.48 2.43 11.26
7.38 (t, 1 H, H(5), J = 8); 7.56
(d, 1 H, H(4), J = 8); 7.72 (d,
1 H, H(6), J = 8); 7.92 (d, 2 H,
H(2´), H(6´), J = 8.3); 8.25 (d, 2 H,
H(3´), H(5´), J = 8.3); 10.40 (s, 1 H,
ArCONH); 13.73 (br.s, 1 H, H(1))
7.31 (t, 1 H, H(5), J = 8); 7.54
(d, 1 H, H(4), J = 8); 7.66 (br.s,
1 H, H(6)); 7.78 (t, 1 H, H(5´),
J = 8.3); 7.93 (d, 1 H, H(6´),
J = 8.3); 8.29 (d, 1 H, H(4´),
J = 8.3); 8.33 (s, 1 H, H(2));
10.50 (s, 1 H, ArCONH); 13.72
(br.s, 1 H, H(1))
373 [М]+ (19),
354 (3), 173
(100), 145 (50)
17k
66
—
195—197
(water—
EtOH)
51.41 2.51 11.31 C16H9F6N3O
51.48 2.43 11.26
373 [М]+ (19),
173 (100),
145 (51)
18a
78
0.64
234—236
47.85 2.70 12.93 C13H9ClFN3O2S 6.98 (br.s, 1 H, H(5)); 7.10 (m,
47.93 2.78 12.90
327 [M]+ (19),
325 (50),
262 (12),
(AcOEt— (PriOH)
MeOH,
1 H, H(4)); 7.36 (br.s, 1 H, H(6));
7.55 (t, 1 H, H(5´), J = 8);
9 : 1)
7.73 (br.s, 1 H, H(4´)); 7.97
(br.s, 1 H, H(6´)); 8.12 (s, 1 H,
260 (34),
132 (100),
H(2)); 10.06 (br.s, 1 H, ArSO2NH); 129 (18),
12.20, 12.43 (2 s, 1 H, H(1))*
47.16 2.88 11.78 C14H10F3N3O3S 6.90 (d, 1 H, H(4), J = 7.9); 7.05
47.06 2.82 11.76 (t, 1 H, H(5), J = 7.9); 7.32 (d,
105 (42)
18b
18c
93
78
0.80
149—151
357 [М]+ (18),
293 (6), 209
(AcOEt— (PriOH—
MeOH,
19 : 1)
C6H6)
1 H, H(6), J = 7.9); 7.58—7.80 (m, (22), 132
4 H, H(2´), H(4´), H(5´), H(6´));
8.14 (s, 1 H, H(2)); 12.44
(br.s, 1 H, H (1))
(100), 105 (37)
0.75
226—228
47.09 2.93 11.94 C14H10F3N3O3S 6.88 (br.s, 1 H, H(4)); 7.08 (t,
357 [М]+ (3),
293 (28),
194 (20),
(AcOEt— (PriOH)
MeOH,
47.06 2.82 11.76
1 H, H(5), J = 7.9); 7.33 (d, 1 H,
H(6), J = 7.9); 7.48 (d, 2 H,
19 : 1)
H(2´), H(6´), J = 8.6); 7.87 (d,
2 H, H(3´), H(5´), J = 8.6); 8.12
(s, 1 H, H(2)); 10.12 (br.s, 1 H,
ArSO2NH); 12.35 (br.s, 1 H, H(1))
132 (100)
18d
18e
74
94
0.76
218—220
56.28 3.42 18.85 C14H10N4O2S
56.36 3.38 18.78
6.92 (d, 1 H, H(4), J = 7.9); 7.08 (t, 298 [М]+ (22),
1 H, H(5), J = 7.9); 7.36 (d, 1 H, 233 (25),
H(6), J = 7.9); 7.92—8.00 (m, 4 H, 132 (100),
(AcOEt— (C6H6)
MeOH,
19 : 1)
H(2´), H(3´), H(5´), H(6´)); 8.13
(s, 1 H, H(2)); 12.42
105 (73)
(br.s, 1 H, H (1))
6.80 (d, 1 H, H(4), J = 7.5);
0.75
240—242
62.54 4.19 11.62 C19H15N3O3S
62.45 4.14 11.50
365 [М]+ (12),
(AcOEt— (EtOH)
MeOH,
19 : 1)
6.87—7.10 (m, 5 H, H (2″), H(3″), 301 (24),
H(4″), H(5″), H(6″)); 7.24 (t, 1 H,
H(5), J = 7.5); 7.32 (d, 1 H, H(6),
141 (20),
132 (100),
J = 7.5); 7.45 (t, 2 H, H(3´), H(5´), 105 (47)
J = 8); 7.80 (d, 2 H, H(2´), H(6´),
J = 8); 8.15 (s, 1 H, H(2)); 10.00
(br.s, 1 H, ArSO2NH); 12.30 (br.s,
1 H, H (1))
(to be continued)

1224
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 6, June, 2007
Elkin et al.
Table 2 (continued)
Comꢀ Yield
Rf
M.p./°C
(solvent)
Found
Calculated
Molecular
formula
1H NMR, δ (J/Hz)
MS,
m/z (Irel (%))
(%)
poꢀ
(%)
und
С
H
N
18f
73
0.8
245—247
42.28 2.57 11.47 C13H9BrFN3O2S 6.92 (d, 1 H, H(4), J = 7.5); 7.10 (t, 371 [М]+ (8),
(AcOEt— (EtOH)
MeOH,
42.17 2.45 11.35
1 H, H(5), J = 7.5); 7.38 (d, 1 H,
H(6), J = 7.5); 7.52 (d, 1 H, H(3´), (34), 349 (34),
369 (8), 351
19 : 1)
J = 8); 7.67 (t, 1 H, H(2), J = 8);
7.72 (d, 1 H, H (5´), J = 10); 8.18
(s, 1 H, H(2)); 12.38
(br.s, 1 H, H (1))
2.18 (s, 3 H, 1ꢀMeCO); 2.73 (s, 3 H, 217 [M]+ (61),
4ꢀMeCO); 7.34 (t, 1 H, H(6),
J = 8.4); 7.83 (d, 1 H, H(7),
J = 8.4); 8.07 (d, 1 H, H(5), J = 8.4);
8.85 (s, 1 H, H(2)); 9.88 (s, 1 H,
MeCONH)
287 (55), 285
(55), 179 (96),
132 (80), 105
(89), 76 (100)
19а
86
0.57
(AcOEt—
MeOH,
9 : 1)
138—140
60.89 5.11 19.21 C11H11N3O2
60.77 5.06 19.33
175 (75), 160
(33), 133 (100)
* The NH(1) ↔ NH(3) tautomerism.
** Isolated by column chromatography (dry column, C6H6—AcOEt). A diacyl derivative (0.107 g) with Rf 0.9 (C6H6—AcOEt, 1 : 1)
and the starting acid (0.062 g) with Rf 0.7 (C6H6—AcOEt, 1 : 1) were also detected.
methanol (70 mL) and aqueous HCl (10 mL). Hydrogenation
was carried out over a catalyst (2% Pd/C, 1 mL) placed in a
gauze container. The container was immersed for 4—6 h (deꢀ
pending on the temperature and the pressure) in the solution
stirred with a magnetic stirring bar. The hydrogen pressure was
varied from 40 to 70 atm at 50—60 °C. On cooling, the catalyst
was withdrawn from the reactor, the reaction mixture was filꢀ
tered to remove catalyst particles, and the solvent was removed
in a rotary evaporator. The residue was recrystallized from ethaꢀ
nol or dilute HCl. The yields of triaminobenzenes 2a,b as
dihydrochlorides were 80—85% (for more soluble nitrobenzenes,
we employed more concentrated (3—4 times) solutions). For
catalyst recycling, the gauze with the catalyst was placed in the
same solvent as in the hydrogenation.
Hydrogenation and cyclization with carboxylic acids (general
procedure B). A stainless steel autoclave (650 mL) was charged
with dinitroaniline 1a or 1b (0.1 mol) and a carboxylic acid
(200 mL). A gauze container containing a 2% Pd/C catalyst
(7—10 mL) was placed in the autoclave in such a way that the
catalyst was immersed in solution. The dinitroaniline was hydroꢀ
genated at 20—80 °C and a hydrogen pressure up to 30—80 atm
for 4—6 h. The reaction mixture was stirred with a magnetic
stirring bar. The autoclave was discharged, the reaction mixture
was refluxed for 6 h to complete the cyclization, and the excess
of the carboxylic acid was removed in a rotary evaporator. Reꢀ
crystallization of the residue gave Nꢀacylated benzimidazoles
3a,b—5a,b (see Table 1). To eliminate the acetyl group, the
product was dissolved in 10% HCl (200 mL), refluxed for 1 h,
and cooled. The solvent was removed in a rotary evaporator.
Dihydrochlorides of aminobenzimidazoles 6a,b—8a,b were reꢀ
crystallized from 10% HCl or ethanol.
The autoclave was discharged and the reaction mixture was
refluxed for 6 h to complete the cyclization. The solvent was
removed in a rotary evaporator in water aspirator vacuum and
the residual acid was removed with methanol (2×5 mL). The
resulting gray crystals were dissolved in methanol (20 mL) and
refluxed with activated carbon for 1 h. The solution was filtered
and evaporated to dryness to give grayish crystals (4.00 g, 94%).
The compound obtained was used without additional purificaꢀ
tion for subsequent nitration.
For large amounts of the reagents, we employed an autoꢀ
clave with a turbostirrer and a catalyst (50 mL) fixed in a net
holder (see Ref. 15). For instance, hydrogenation of 2,4ꢀdiꢀ
nitroaniline (90 g) in formic acid (450 mL) for 17 h (hydrogen
pressure 55—70 atm, 50—70 °C) gave 5(6)ꢀformamidobenzimidꢀ
azole formate 3a•HCOOH (97 g, 93%).
5(6)ꢀAminobenzimidazole (6a), dihydrochloride. 2,4ꢀDinitroꢀ
aniline (1a) (2.34 g, 12.8 mmol) in 85% formic acid (20 mL) was
hydrogenated in a stainless steel autoclave over a 5% Pd/C cataꢀ
lyst for 6 h (hydrogen pressure 40 atm, 60—65 °C). The autoꢀ
clave was discharged and the reaction mixture was refluxed for
6 h to complete the cyclization. The solvent was removed in a
rotary evaporator in water aspirator vacuum and the residual
acid was removed with methanol (2×5 mL). The resulting gray
crystals were dissolved in 10% HCl (20 mL) and the solution was
refluxed for 30 min and evaporated to dryness. The black crysꢀ
tals that formed were twice refluxed in ethanol (10 mL) and
filtered off to give grayish crystals (1.52 g, 57.5%).
7ꢀAminobenzimidazoleꢀ5ꢀcarboxylic acid (10), dihydrochloꢀ
ride. An autoclave was charged with 4ꢀaminoꢀ3,5ꢀdinitrobenzoic
acid (9) (20 g, 88 mmol), 80% formic acid (250 mL), and a
2% Pd/C catalyst (10 mL). The autoclave was purged with hydroꢀ
gen up to a pressure of 80 atm. The reaction mixture was stirred
at ~20 °C for 2 h, heated to 70 °C, and kept at a hydrogen
pressure of 70 atm for 4 h until the hydrogen absorption ceased.
The reaction mixture was discharged hot and the formic acid
was removed in a rotary evaporator. The residue was dissolved in
10% HCl (200 mL) and the resulting solution was refluxed for 1 h,
Selected syntheses according to general procedure B are
given below.
5(6)ꢀFormamidobenzimidazole formate (3a•HCOOH).
2,4ꢀDinitroaniline (1a) (3.66 g, 20 mmol) in 85% formic acid
(20 mL) was hydrogenated in a stainless steel autoclave over a
2% Pd/C catalyst for 4 h (hydrogen pressure 70—80 atm, 80 °C).

Synthesis of aminobenzimidazoles by hydrogenation Russ.Chem.Bull., Int.Ed., Vol. 56, No. 6, June, 2007
1225
cooled, and concentrated in a rotary evaporator. The yield of
4(7)ꢀaminobenzimidazoleꢀ5(6)ꢀcarboxylic acid (10) as dihydroꢀ
chloride was 21.3 g (97%), m.p. 260—263 °C (MeOH).
Methyl 4(7)ꢀaminobenzimidazoleꢀ5ꢀcarboxylate (11), diꢀ
hydrochloride. A fourꢀneck flask fitted with a stirrer, a conꢀ
denser, a thermometer, and a dropping funnel was charged with
methanol (250 mL) and the dihydrochloride of (4)7ꢀaminoꢀ
benzimidazoleꢀ5(6)ꢀcarboxylic acid (10) (21 g). Thionyl chloꢀ
ride (48 g) was added dropwise to the resulting iceꢀcooled
(5—7 °C) suspension and the solution was refluxed for 6 h and
left for ~14 h. The solvent was partially removed and the preꢀ
cipitate that formed was filtered off. The yield of methyl
(4)7ꢀaminobenzimidazoleꢀ5(6)ꢀcarboxylate (11) as dihydroꢀ
chloride was 18 g (81%).
Cyclization of triaminobenzenes with carboxylic acids (genꢀ
eral procedure C). Triaminobenzene dihydrochloride (0.1 mol)
was dissolved in a carboxylic acid (100 mL) (HCOOH, AcOH,
or CF3COOH). The resulting solution was refluxed for 3—15 h
and concentrated. The residue (a diacyl derivative of aminoꢀ
benzimidazole) was dissolved in 10% HCl (300 mL) and the
solution was refluxed for 1 h and concentrated to precipitation.
The suspension was cooled and the crystals that formed were
filtered off and dried.
portions at –10 °C for 1.5 h to continuously stirred conc. HNO3
(d = 1.516, 50 mL) so that the reaction temperature did not
exceed –10 °C. After the cooling bath was removed, the reacꢀ
tion mixture was carefully poured at 0 °C into vigorously stirred
water with ice (100 mL). The resulting crystalline solid was
filtered off on a porous glass filter, thoroughly squeezed, and
suspended in water (100 mL). The suspension was neutralized
with concentrated aqueous ammonia to pH 7. The crystals were
filtered off again, thoroughly washed with water, and dried in air
and then in vacuo over P2O5 to give yellow crystals (6.4 g, 80%).
5(6)ꢀAcetamidoꢀ2ꢀmethylꢀ4(7)ꢀnitrobenzimidazole (13) was
obtained analogously from 5(6)ꢀacetamidoꢀ2ꢀmethylbenzimidꢀ
azole (4a) (10 g). The yield was 6.2 g (50%), yellow crystals.
5(6)ꢀAminoꢀ4(7)ꢀnitrobenzimidazole (16). 5(6)ꢀFormylꢀ
aminoꢀ4(7)ꢀnitrobenzimidazole (12) (3.09 g, 15 mmol) was reꢀ
fluxed in 10% HCl (50 mL) for 30 min. The solvent was removed
and the residue was dissolved in water (50 mL). Concentrated
NH4OH was added to a weakly basic reaction and the solution
was neutralized with acetic acid. The crystals that formed were
filtered off, thoroughly washed with water (5×10 mL), and dried
to give red crystals (2.35 g, 88%).
1,2,3,4ꢀDiimidazobenzene (14). 5(6)ꢀAminoꢀ4(7)ꢀnitroꢀ
benzimidazole (16) (1.93 g) in formic acid (30 mL) was hydroꢀ
genated with stirring in a reactor over a 2% Pd/C catalyst
(0.6 mL) for 5 h (hydrogen pressure 30 atm, ~20 °C). The
catalyst was withdrawn and the solution was filtered and reꢀ
fluxed for 2 h to complete the cyclization. The solvent was
removed and the residual formic acid was removed with methaꢀ
nol. The resulting solid was dissolved in methanol (10 mL) and
refluxed with conc. HCl (1 mL) for 1 h. The solution was conꢀ
centrated and the residue was dissolved in water (10 mL). The
product was precipitated from the solution with acetone (70 mL).
The crystals that formed were washed with acetone (3×10 mL)
and dried to give grayish crystals (1.37 g, 80%).
Compound 14 was obtained analogously from compound 12.
Nitration of 4(7)ꢀacetamidobenzimidazole (17a). 4(7)ꢀAcetꢀ
amidobenzimidazole (17a) (0.88 g, 5 mmol) was added in porꢀ
tions at 0 °C for 10 min to stirred fuming HNO3 (d = 1.52,
3.5 mL). The reaction mixture was kept at this temperature for
30 min, warmed to ~20 °C in 20 min, and left for 1 h. Ice with
water (20 g) was added. After several minutes, the voluminous
yellow precipitate that formed was filtered off, washed with ice
water (2×10 mL), and dried to give yellow crystals. The yield of
a mixture of 4(7)ꢀacetamidonitrobenzimidazoles 15a,b as niꢀ
trates was 1.19 g (84%). To a suspension of this mixture (1.13 g,
4 mmol) in water (5 mL), 15% aqueous NH3 was added dropwise.
The precipitate that formed was filtered off, washed with water,
and dried to give yellow crystals. The yield of a mixture of
acetamidonitrobenzimidazoles 15a,b was 0.86 g (78.4%) (Rf 0.18
and 0.55, AcOEt—MeOH (9 : 1) as an eluent). The mixture of
the nitro derivatives (0.6 g) was separated by column chromaꢀ
tography on silica gel 5/40 in benzene—AcOEt with increasing
polarity and then in AcOEt—MeOH with increasing polarity.
Fractions with equal Rf values were combined and evaporated to
dryness. The residue was dried in vacuo to give 7ꢀacetamidoꢀ
4ꢀnitrobenzimidazole (15b) (0.18 g) with Rf 0.55 and 7ꢀacetꢀ
amidoꢀ6ꢀnitrobenzimidazole (15a) (0.32 g) with Rf 0.18
(AcOEt—MeOH, 9 : 1).
This procedure was used to obtain compounds 3a,b, 5a,b,
7a,b, and 8a,b. Selected syntheses are given below.
5(6)ꢀFormamidobenzimidazole formate (3a•HCOOH).
1,2,4ꢀTriaminobenzene dihydrochloride (80 g) was refluxed in
formic acid (400 mL) for 3 h. The acid was evaporated almost to
dryness and the residue was dissolved in distilled water (200 mL).
The solution was neutralized with concentrated aqueous ammoꢀ
nia and left for crystallization. The crystals that formed were
filtered off and dissolved in distilled water (200 mL). The soluꢀ
tion was refluxed with activated carbon, filtered hot, and cooled.
The resulting crystals were filtered off and dried to give a powꢀ
dery solid (55.2 g). The mother liquor was concentrated to crysꢀ
tallization in the hot solution and refluxed with a small amount
of activated carbon for 3 h. The solution was filtered and
cooled and the crystals that formed were filtered off and dried.
An additional crop was 18.1 g. The total yield of 5(6)ꢀformꢀ
amidobenzimidazole formate was 73.3 g (91%).
4(7)ꢀAminoꢀ2ꢀtrifluoromethylbenzimidazole (8b), dihydroꢀ
chloride. A fourꢀneck flask fitted with a stirrer, a condenser,
a dropping funnel, and a thermometer was charged with dilute
(1 : 1) HCl (210 mL) and 1,2,3ꢀtriaminobenzene dihydrochloride
(21 g, 0.107 mol). Trifluoroacetic acid (37 g, 27 mL, 0.324 mol)
was gradually added. The reaction mixture was refluxed for 3 h
until 1,2,3ꢀtriaminobenzene was completely consumed (TLC,
PriOH—AcOEt—aqueous NH3 (7 : 9 : 4) as an eluent). Then the
mixture was refluxed four times with a fresh portion of activated
carbon to the formation of a transparent solution. The solvent
was removed in a rotary evaporator. The residue was dissolved
under heating in dilute (1 : 3) HCl with activated carbon. The
solution was filtered and concentrated in a rotary evaporator.
The residue was cooled and the crystals that formed were filꢀ
tered off and dried. The yield of 4(7)ꢀaminoꢀ2ꢀtrifluoroꢀ
methylbenzimidazole (8b) as dihydrochloride was 22.4 g (76.3%).
5ꢀAminoꢀ2ꢀtrifluoromethylbenzimidazole (8a), dihydrochloꢀ
ride, was obtained analogously. The product was purified by
reflux in butyl acetate for 1.5 h.
7ꢀAcetamidoꢀ1ꢀacetylbenzimidazole (19a). Acetic anhydride
(1.25 g, 12 mmol, 1.13 mL) was added dropwise to a stirred
suspension of the dihydrochloride of 4(7)ꢀaminobenzimidazole
5(6)ꢀFormamidoꢀ4(7)ꢀnitrobenzimidazole (12). 5(6)ꢀFormꢀ
amidobenzimidazole (3a) (8.00 g, 38.6 mmol) was added in

1226
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 6, June, 2007
Elkin et al.
(6b) (1.03 g, 5 mmol) in anhydrous pyridine (3 mL). The reacꢀ
tion mixture was stirred at ~20 °C for 0.5 h and at 60—70 °C for
2 h. The solvent was removed in vacuo and ice water (5 mL) was
added to the residue. The resulting precipitate was filtered off,
washed with ice water (2×0.5 mL) to neutral reaction, and
dried in oil pump vacuum while heating over P2O5. The yield of
compound 19a was 0.94 g (87%), white crystals, Rf 0.52
(AcOEt—MeOH, 9 : 1, twice).
tallized from an appropriate solvent. Whenever an oily product
did not crystallize, it was extracted with tertꢀbutyl methyl ether
(3×25 mL). The extracts were combined, washed with water,
and dried over calcined MgSO4. On removal of the ether, the
residue was crystallized by trituration.
References
4(7)ꢀAcetamidobenzimidazole (17a). Anhydrous methanol
(40 mL) and anhydrous triethylamine (2 mL) were added to
4(7)ꢀacetamidoꢀ1ꢀacetylbenzimidazole (19a) (4.5 g). The reꢀ
sulting solution remained homogeneous for 2—3 min and then a
voluminous white precipitate formed. The precipitate was filꢀ
tered off, washed with a required minimum amount of ice water,
and dried to give white crystals. The yield of compound 17a was
3.045 g (67%), Rf 0.55 (AcOEt—MeOH, 4 : 1).
Synthesis of compounds 17b—k via acylation of 4(7)ꢀaminoꢀ
benzimidazoles 6b and 8b (general procedure). 1) A mixture of an
appropriate benzoic acid (2—2.5 mmol) and thionyl chloride
(1.3—1.5 mmol) was refluxed for 3 h. Residual thionyl chloride
was removed in vacuo. Benzene (1 mL) was added and residual
SO2 and HCl were removed in vacuo.
2) The resulting solution of substituted benzoyl chloride was
diluted with anhydrous benzene (4 mL) and added dropwise to a
stirred solution of 4(7)ꢀaminobenzimidazole (2—2.5 mmol) in
anhydrous pyridine (3—4 mL). The reaction mixture was left at
~20 °C for ~14 h, the solvents were removed in vacuo, and water
(6—7 mL) was added to the residue. The precipitate of a
dibenzoyl derivative that formed was washed with water (3×6 mL)
and thoroughly dried in vacuo over P2O5.
3) Anhydrous methanol (5—10 mL) and anhydrous triethylꢀ
amine (1 mL) were added to the dibenzoyl derivative obtained.
The reaction mixture was refluxed for 1 h to complete homogꢀ
enization. The solution was cooled, filtered, and concentrated.
The residue was recrystallized from an appropriate solvent. In
the case of compound 17e, water treatment gave a viscous
noncrystallizable oil. The product was extracted from the oil
with CH2Cl2, the solvent was removed, and the residue was
purified by column chromatography (see Table 2).
Synthesis of compound 17f via acylation of 4(7)ꢀaminoꢀ2ꢀ
trifluoromethylbenzimidazole (8b). Benzoyl chloride (0.7 g,
51 mmol) was added dropwise at ~20 °C to a solution of the
dihydrochloride of 4(7)ꢀaminoꢀ2ꢀtrifluoromethylbenzimidazole
(8b) (0.7 g, 25.5 mmol) in anhydrous pyridine (5 mL). The
reaction mixture was left for 20 h, heated at ~70 °C for 40 min,
and cooled. The solvent was removed in water aspirator vacuum.
A small amount of water was added to the residue. The crystals
that formed were filtered off, repeatedly washed with hot water
and acetonitrile, and dried to give compound 17f (0.75 g).
Synthesis of compounds 18a—f by sulfonylation of benzimidꢀ
azoles (general procedure). A solution of an appropriate arylꢀ
sulfonyl chloride (2—3 mmol) in anhydrous pyridine (3—4 mL)
was added to a suspension of the dihydrochloride of 4(7)ꢀaminoꢀ
benzimidazole (6b) (2—3 mmol) in anhydrous pyridine
(5—7 mL). The reaction mixture underwent selfꢀheating, turned
red, and produced a voluminous precipitate. The mixture was
heated at 100 °C for 3 h and the excess pyridine was removed
in vacuo. Water (10—15 mL) was added to the residue and the
resulting oil was crystallized by trituration. The crystals were
filtered off, washed with water to neutral reaction, and recrysꢀ
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Received December 19, 2006;
in revised form April 12, 2007