Benzazoles: I. Regioselective arylsulfonylation of benzimidazol-2-amine

Article abstract of DOI:10.1134/S1070428013010181

Benzimidazol-2-amine reacted with arenesulfonyl chlorides in the presence of triethylamine in regioselective fashion at the endocyclic nitrogen atom, the exocyclic amino group remaining intact. The yields of 1- arylsulfonylbenzimidazol-2-amines depend on the electronic properties of substituents in the benzene ring of arenesulfonyl chlorides.

Full text of DOI:10.1134/S1070428013010181

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2013, Vol. 49, No. 1, pp. 108–111. © Pleiades Publishing, Ltd., 2013.
Original Russian Text © T.N. Kaipnazarov, K.B. Abdireimov, N.S. Mukhamedov, R.Ya. Okmanov, B. Tashkhodjaev, G.E. Berdimbetova, Kh.M. Shakhido-
yatov, 2013, published in Zhurnal Organicheskoi Khimii, 2013, Vol. 49, No. 1, pp. 113–116.
Benzazoles: I. Regioselective Arylsulfonylation
of Benzimidazol-2-amine
T. N. Kaipnazarova, K. B. Abdireimovb, N. S. Mukhamedovc, R. Ya. Okmanovc,
B. Tashkhodjaevc, G. E. Berdimbetovaa, and Kh. M. Shakhidoyatovc
a Research Institute of Natural Sciences, Karakalpak Division, Academy of Sciences of Uzbekistan Republic,
Nukus, Uzbekistan
b Berdakh Karakalpak State University, Nukus, Uzbekistan
c Yunusov Institute of Chemistry of Plant Substances, Academy of Sciences of Uzbekistan Republic,
ul. M. Ulugbeka 77, Tashkent, 100170, Uzbekistan
e-mail: nasirxon@rambler.ru
Received May 21, 2012
Abstract—Benzimidazol-2-amine reacted with arenesulfonyl chlorides in the presence of triethylamine in
regioselective fashion at the endocyclic nitrogen atom, the exocyclic amino group remaining intact. The yields
of 1-arylsulfonylbenzimidazol-2-amines depend on the electronic properties of substituents in the benzene ring
of arenesulfonyl chlorides.
DOI: 10.1134/S1070428013010181
Increased interest in benzazoles, including benz-
imidazole derivatives, is determined by broad spec-
trum of their biological activity. Compounds exhibiting
hypotensive, neuroleptic, antitumor, and antibacterial
properties [1–5], as well as fungicidal and growth-
regulating effects [6, 7] were found among 2-substi-
tuted benzimidazoles. Relatively recently, Foks et al.
[8] reported on the synthesis of 2-aryl- and 2-cyclo-
alkyl-1-alkylsulfonylbenzimidazoles by reaction of
2-substituted benzimidazoles with methane- and ben-
zenesulfonyl chlorides, and the products were shown
to exhibit tuberculostatic activity [8]. This reaction was
later extended to 2-alkylbenzimidazoles and various
arenesulfonyl chlorides [9], and a number of 2-alkyl-1-
arylsulfonylbenzimidazoles were obtained. Analogous
reactions of benzimidazol-2-amine were not studied.
In the present work we synthesized benzimidazol-2-
amine and examined its reactions with arenesulfonyl
chlorides.
Benzimidazol-2-amine (II) was prepared by alka-
line hydrolysis of methyl 1H-benzimidazol-2-ylcarba-
mate (I) [10]. The reactions of II with arenesulfonyl
chlorides IIIa–IIIj (reactant molar ratio 1:1) in the
presence of triethylamine regioselectively occurred at
the endocyclic nitrogen atom without involving the
exocyclic amino group to produce the corresponding
1-arenesulfonyl-1H-benzimidazol-2-amines IVa–IVj
(Scheme 1). The yield of IVa–IVj depended on the
substituent nature in the initial arenesulfonyl chloride.
Electron-withdrawing substituents (such as NO2, Cl,
and NHCOMe) favored increased yield of sulfonyla-
tion products IV, whereas introduction of electron-
donating groups reduced the yield. Presumably, elec-
tron-withdrawing effect of substituent in the benzene
Scheme 1.
N
N
N
N
ArSO2Cl (IIIa–IIIj), Et3N
NaOH
NH
O
NH2
NH2
N
H
N
H
OMe
SO2Ar
IVa–IVj
I
II
Ar = Ph (a), 4-MeC6H4 (b), 4-MeOC6H4 (c), 4-ClC6H4 (d), 3-O2NC6H4 (e), 4-t-BuC6H4 (f), 4-MeCONHC6H4 (g),
2,4-Me2C6H3 (h), 3,4-Me2C6H3 (i), 2,4,6-Me3C6H2 (j).
108

BENZAZOLES: I.
ring of III weakens the S–Cl bond, thus making the
109
Cl1
C10
chlorine atom more labile.
C11
C12
C9
C8
The structure of compounds IVa–IVj was con-
firmed by their elemental compositions, IR, H NMR,
1
HB
N2
O2
HA
and mass spectra, and X-ray diffraction data for com-
pound IVd. The IR spectra of IVa–IVj contained
absorption bands typical of antisymmetric (1360–
1390 cm–1) and symmetric (1160–1190 cm–1) stretch-
ing vibrations of the sulfonyl group (see Experimen-
tal). Compounds IVa–IVj showed in the mass spectra
the molecular ion peaks and peaks from fragment ions
corresponding to the assumed structure. Regardless of
the substituent nature in the arylsulfonyl group, frag-
mentation of IVa–IVj under electron impact involved
cleavage of the S–N bond to produce [M – ArSO2]+
and [M – Ht]+ ions. Like 1-arylsulfonyl-2-alkylbenz-
imidazoles [9], the [M – ArSO2]+ ion was the most
abundant.
C13
S1
C2
N3
C3a
C4
O1
N1
C7a
C7
C6
C5
Structure of centrosymmetric dimer formed by molecules of
1-(4-chlorobenzenesulfonyl)-1H-benzimidazol-2-amine
(IVd) in crystal according to the X-ray diffraction data.
Inter- and intramolecular hydrogen bonds are shown with
dashed lines.
1
In the H NMR spectra of IVa–IVj we observed
Molecules IVd in crystal are linked to centrosym-
metric dimers via face-to-face intermolecular hydro-
gen bonds N2–HA ···N3 with the following parameters
N2···N3 2.967(4), H···N3 2.13 Å, ∠N2HN3 163° (1 –
x, 1 – y, 1 – z). In addition, the N2 atom is involved in
intramolecular hydrogen bond N2–HB···O2 [N2···O2
2.804(4), HB···O2 2.15 Å, ∠N2HBO2 133°].
signals at δ 6.92–7.97 ppm from the 4-H, 5-H, 6-H,
and 7-H protons in the benzimidazole fragment (multi-
plets, doublet of doublets, and a doublet), a broadened
signal from the primary amino group (δ 6.06–
6.92 ppm), and signals from aromatic protons (δ 6.86–
7.61 ppm) and alkyl substituents in the arenesulfonyl
fragment (δ 1.12–3.75 ppm). The only exception was
1-(3-nitrobenzenesulfonyl)-1H-benzimidazol-2-amine
(IVe) whose 1H NMR spectrum contained more down-
field signals at δ 8.78, 8.22, and 8.43 ppm (o-H, o′-H,
and p-H, respectively) due to electron-withdrawing
effect of the nitro group.
EXPERIMENTAL
The IR spectra were recorded on a Perkin Elmer
2000 spectrometer with Fourier transform from
samples dispersed in mineral oil. The 1H NMR spectra
were measured on a Varian Unity 400 Plus spectrom-
eter at 400 MHz using tetramethylsilane as internal
reference. The mass spectra (electron impact, 70 eV)
were obtained on a Kratos MS-30 instrument with
direct sample admission into the ion source. The prog-
ress of reactions and the purity of products were moni-
tored by TLC on Silufol UV-254 plates using benzene–
acetone (10 :1) as eluent; spots were detected by
treatment with iodine vapor or with a solution of 1 g of
potassium permanganate in a mixture of 96 ml of
water and 4 ml of sulfuric acid.
Figure shows the structure of 1-(4-chlorobenzene-
sulfonyl)-1H-benzimidazol-2-amine (IVd) determined
by X-ray analysis. Molecule IVd consists of planar
benzimidazole (±0.0204 Å) and benzene fragments
(±0.0059 Å) which form a dihedral angle of
89.7(1)° with each other. The bond lengths in molecule
IVd differ from those found previously for benzimid-
azol-2-amine [11]. The C7a–N1 and N1–C2 bonds in
IVd [1.420(4) and 1.414(4) Å, respectively] are longer,
while the C2–N3 and C2–N2 bonds are shorter [1.291(4)
and 1.338(4) Å, respectively] than the corresponding
bonds in benzimidazol-2-amine [1.383(2), 1.352(2),
1.321(2), and 1.349(2) Å, respectively]. In addition,
the sum of bond angles at N2 in IVd suggests its sp2
hybridization in contrast to sp3 hybridization of N2 in
benzimidazol-2-amine. This indicates π-electron con-
jugation system in the N3=C2–N2 fragment of molecule
IVd (benzimidazol-2-amine molecule is characterized
by conjugation in the N3=C2–N1 fragment).
Benzimidazol-2-amine (II). A solution of 1 g
(25 mmol) of sodium hydroxide in 3 ml of water was
added to a suspension of 1.91 g (10 mmol) of methyl
1H-benzimidazol-2-ylcarbamate (I) in 10 ml of water.
The mixture was heated for 2 h under reflux, 0.2 g of
activated charcoal was added, and the mixture was
heated for 30 min at the boiling point. The mixture was
filtered while hot, the charcoal was washed on a filter
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KAIPNAZAROV et al.
110
with hot water (4×5 ml), the filtrate was cooled and
carefully acidified with 0.8 ml of concentrated hydro-
chloric acid, and the precipitate was filtered off and
recrystallized from 10 ml of water. Yield 0.86 g (65%),
mp 229–230°C [10].
IR spectrum, ν, cm–1: 3440 s (NH2), 1377 s (SO2,
asym.), 1173 s (SO2, sym.). H NMR spectrum
1
(CD3OD), δ, ppm: 7.84 m (2H, 4-H, 5-H), 7.64 d.d
(1H, 6-H, J6,4 = 2.1, J6,5 = 7.5 Hz), 7.38 m (2H, o-H),
7.24 d (1H, 7-H, J7,6 = 7.5 Hz), 7.11 m (2H, m-H),
6.09 br.s (2H, NH2). Mass spectrum, m/z (Irel, %): 307
(34 for 35Cl) [M]+, 175 (100), 132 (45). Found, %:
C 51.02; H 3.38; Cl 11.78; N 13.87. C13H10ClN3O2S.
Calculated, %: C 50.81; H 3.25; Cl 11.56; N 13.65.
1-Arenesulfonyl-1H-benzimidazol-2-amines IVa–
IVj (general procedure). A solution of 1.33 g
(10 mmol) of benzimidazol-2-amine (II) and 1.01 g
(10 mmol) of triethylamine in 30 ml of acetone was
added dropwise to a solution of 10 mmol of arenesul-
fonyl chloride IIIa–IIIj in 20 ml of acetone. The
mixture was stirred for 4 h at room temperature, the
solvent was distilled off, the residue was treated with
50 ml of water, and the precipitate was filtered off and
recrystallized from appropriate solvent.
1-(3-Nitrobenzenesulfonyl)-1H-benzimidazol-2-
amine (IVe). Yield 3.02 g (95%), mp 235–236°C. IR
spectrum, ν, cm–1: 3460 s (NH2), 1372 s (SO2, asym.),
1
1183 s (SO2, sym.). H NMR spectrum (CD3OD), δ,
ppm: 8.78 m (1H, o′-H), 8.43 m (1H, p-H), 8.22 m
(1H, o-H), 7.69 m (2H, 4-H, 5-H), 7.21 m (3H, 6-H,
7-H, m-H), 6.07 br.s (2H, NH2). Mass spectrum, m/z
(Irel, %): 318 (27) [M]+, 186 (100), 132 (40). Found, %:
C 49.23; H 3.25; N 17.32. C13H10N4O4S. Calculated,
%: C 49.05; H 3.14; N 17.61.
1-Benzenesulfonyl-1H-benzimidazol-2-amine
(IVa). Yield 2.18 g (80%), mp 204–206°C. IR spec-
trum, ν, cm–1: 3430 s (NH2), 1369 s (SO2, asym.),
1
1183 s (SO2, sym.). H NMR spectrum (CD3OD), δ,
1-(4-tert-Butylbenzenesulfonyl)-1H-benzimid-
azol-2-amine (IVf). Yield 2.46 g (75%), mp 197–
199°C. IR spectrum, ν, cm–1: 3445 s (NH2), 1374 s
ppm: 7.92 m (2H, 4-H, 5-H), 7.61 m (4H, 6-H, 7-H,
o-H), 7.04 m (2H, m-H), 6.91 m (3H, p-H, NH2).
Mass spectrum, m/z (Irel, %): 273 (52) [M]+, 141 (100),
132 (39). Found, %: C 57.40; H 4.34; N 15.51.
C13H11N3O2S. Calculated, %: C 57.14; H 4.02;
N 15.38.
1
(SO2, asym.), 1174 s (SO2, sym.). H NMR spectrum
(CD3OD), δ, ppm: 7.84 m (2H, 4-H, 5-H), 7.69 d.d
(1H, 6-H, J6,4 = 2.0, J6,5 = 7.8 Hz), 7.42 m (2H, o-H),
7.23 d (1H, 7-H, J7,6 = 7.8 Hz), 7.11 m (2H, m-H),
6.27 br.s (2H, NH2), 1.12 s (9H, t-Bu). Mass spectrum,
m/z (Irel, %): 329 (38) [M]+, 197 (100), 132 (36).
Found, %: C 61.77; H 6.01; N 13.01. C17H19N3O2S.
Calculated, %: C 62.00; H 5.77; N 12.76.
1-(4-Methylbenzenesulfonyl)-1H-benzimidazol-
2-amine (IVb). Yield 2.03 g (71%), mp 200–201°C.
IR spectrum, ν, cm–1: 3453 s (NH2), 1375 s (SO2,
1
asym.), 1187 s (SO2, sym.). H NMR spectrum
(CD3OD), δ, ppm: 7.81 m (2H, 4-H, 7-H), 7.57 d.d
(1H, 6-H, J6,4 = 2.1, J6,5 = 7.5 Hz), 7.26 m (2H, o-H),
7.02 m (2H, m-H), 6.92 m (3H, 7-H, NH2), 2.31 s
(3H, Me). Mass spectrum, m/z (Irel, %): 287 (48) [M]+,
155 (100), 132 (42). Found, %: C 58.25; H 4.65;
N 14.38. C14H13N3O3S. Calculated, %: C 58.53;
H 4.52; N 14.63.
N-[4-(2-Amino-1H-benzimidazole-1-sulfonyl)-
phenyl]acetamide (IVg). Yield 2.87 g (87%),
mp 235–237°C. IR spectrum, ν, cm–1: 3439 s (NH2),
1
1369 s (SO2, asym.), 1189 s (SO2, sym.). H NMR
spectrum (CD3OD), δ, ppm: 7.93 m (2H, 4-H, 5-H),
7.64 m (4H, 6-H, 7-H, o-H), 7.07 m (2H, m-H),
6.88 br.s (2H, NH2), 3.65 (COMe). Mass spectrum, m/z
(Irel, %): 330 (41) [M]+, 198 (100), 132 (47). Found, %:
C 54.68; H 4.43; N 17.16. C15H14N4O3S. Calculated,
%: C 54.54; H 4.24; N 16.96.
1-(4-Methoxybenzenesulfonyl)-1H-benzimid-
azol-2-amine (IVc). Yield 2.24 g (74%), mp 210–
212°C. IR spectrum, ν, cm–1: 3454 s (NH2), 1368 s
1
(SO2, asym.), 1172 s (SO2, sym.). H NMR spectrum
1-(2,4-Dimethylbenzenesulfonyl)-1H-benzimid-
azol-2-amine (IVh). Yield 2.22 g (74%), mp 230–
232°C. IR spectrum, ν, cm–1: 3435 s (NH2), 1353 s
(CD3OD), δ, ppm: 7.85 m (2H, 4-H, 5-H), 7.65 d.d
(1H, 6-H, J6,4 = 2.1, J6,5 = 7.9 Hz), 7.22 d (1H, 7-H,
J7,6 = 7.6 Hz), 7.07 m (2H, o-H), 6.86 m (2H, m-H),
6.06 br.s (2H, NH2), 3.75 s (3H, OMe). Mass spec-
trum, m/z (Irel, %): 303 (43) [M]+, 171 (100), 132 (45).
Found, %: C 55.64; H 4.38; N 14.14. C14H13N3O2S.
Calculated, %: C 55.44; H 4.29; N 13.86.
1
(SO2, asym.), 1174 s (SO2, sym.). H NMR spectrum
(CD3OD), δ, ppm: 7.91 d.d (1H, 4-H, J4,6 = 2.0, J4,5
=
8.5 Hz), 7.68 m (2H, 5-H, 6-H), 7.46 d.d (1H, 7-H,
J7,5 = 2.0, J7,6 = 8.5 Hz), 7.37 m (1H, o-H), 7.29 m
(2H, m-H), 6.09 br.s (2H, NH2), 2.45 s (3H, 2-Me),
2.38 s (3H, 4-Me). Mass spectrum, m/z (Irel, %): 301
(42) [M]+, 169 (100), 132 (38). Found, %: C 60.04;
1-(4-Chlorobenzenesulfonyl)-1H-benzimidazol-
2-amine (IVd). Yield 2.76 g (90%), mp 197–198°C.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 1 2013

BENZAZOLES: I.
111
H 5.21; N 13.74. C15H15N3O2S. Calculated, %:
C 59.80; H 4.98; N 13.95.
against F2 by the least-squares procedure in full-matrix
anisotropic approximation to R = 0.0456, RW = 0.1110
for 1955 reflections; goodness of fit S = 1.092. Hydro-
gen atoms were placed into positions calculated on the
basis of geometry considerations and were refined with
fixed isotropic displacement factors Uiso = nUeq, where
n = 1.2 for methylene groups and aromatic carbon
atoms, and Ueq is the equivalent isotropic displacement
factor of the corresponding carbon atom. The set of
crystallographic parameters for compound IVd was
deposited to the Cambridge Crystallographic Data
Centre (entry no. CCDC 831010).
1-(3,4-Dimethylbenzenesulfonyl)-1H-benzimid-
azol-2-amine (IVi). Yield 2.16 g (72%), mp 216–
218°C. IR spectrum, ν, cm–1: 3453 s (NH2), 1372 s
1
(SO2, asym.), 1165 s (SO2, sym.). H NMR spectrum
(CD3OD), δ, ppm: 7.97 d.d (1H, 4-H, J4,6 = 2.1, J4,5
=
8.4 Hz), 7.63 m (3H, 5-H, 6-H, 7-H), 7.38 m (3H,
C6H3), 6.08 br.s (2H, NH2), 2.34 s (6H, Me). Mass
spectrum, m/z (Irel, %): 301 (39) [M]+, 169 (100),
132 (44). Found, %: C 59.51; H 4.74; N 14.23.
C15H15N3O2S. Calculated, %: C 59.80; H 4.98;
N 13.95.
REFERENCES
1-(2,4,6-Trimethylbenzenesulfonyl)-1H-benz-
imidazol-2-amine (IVj). Yield 2.20 g (70%), mp 196–
198°C. IR spectrum, ν, cm–1: 3461 s (NH2), 1384 s
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1
(SO2, asym.), 1188 s (SO2, sym.). H NMR spectrum
(CD3OD), δ, ppm: 7.67 m (2H, 4-H, 5-H), 7.39 m (2H,
6-H, 7-H), 7.23 s (2H, C6H2), 6.12 br.s (2H, NH2),
2.44 s (6H, 2′-Me, 6′-Me), 2.35 s (3H, 4′-Me). Mass
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(36). Found, %: C 61.27; H 5.67; N 13.07.
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of 1-(4-chlorobenzenesulfonyl)-1H-benzimidazol-2-
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solution in ethanol at room temperature. The unit cell
parameters were determined and refined using a Stoe
Stadi-4 diffractometer (CuKα irradiation, graphite
monochromator, 300 K). Monoclinic crystal system,
space group P21/c; unit cell parameters: a = 16.391(3),
b = 5.1797(10), c = 15.677(3) Å; β = 95.43(3)°; V =
1325.0(5) Å3; M 307.75; Z = 4; dcalc = 1.543 g/cm3; μ =
4.079. Scan range 2.71 ≤ θ ≤ 59.9°; crystal dimensions
0.60×0.25×0.20 mm. A three-dimensional set consist-
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reflections) was acquired. A correction for absorption
was introduced using the Psi-scan method. The struc-
ture was solved by the direct method using SHELXS-
97 software and was refined using SHELXL-97. The
positions of all non-hydrogen atoms were refined
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