Synthesis of 2-arylbenzimidazole analogues

Article abstract of DOI:10.3987/COM-14-12966

Substituted 2-arylbenzimidazoles (4) were easily synthesized in good yields starting from the condensation reaction of 1,2-diaminobenzenes (1) with β-ketosulfones (5) in the presence of boiling HOAc.

Full text of DOI:10.3987/COM-14-12966

HETEROCYCLES, Vol. 89, No. 5, 2014, pp. . © 2014 The Japan Institute of Heterocyclic Chemistry
Received, 18th February, 2014, Accepted, 17th March, 2014, Published online, 18th March, 2014
DOI: 10.3987/COM-14-12966
SYNTHESIS OF 2-ARYLBENZIMIDAZOLE ANALOGUES
Meng-Yang Chang,* Chieh-Kai Chan, and Yi-Chia Chen
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University,
Kaohsiung 807, Taiwan. Email: mychang@kmu.edu.tw
Abstract – Substituted 2-arylbenzimidazoles (4) were easily synthesized in good
yields starting from the condensation reaction of 1,2-diaminobenzenes (1) with
β-ketosulfones (5) in the presence of boiling HOAc.
Benzimidazole ring system is a key pharmacophore for an increasing important series of nitrogen
heterocycles which display a wide range of biological and therapeutic activities.1,2 A considerable number
of attempts have been made to develop the bicyclic benzannulated framework. Transition metal-catalyzed
intermolecular or intramolecular cyclization of 2-haloanilides/analogues3 and condensation of substituted
1,2-diaminobenzenes with benzaldehydes,4 carboxylic acids,5 or one-carbon synthons6 are two main
synthetic routes. In most cases, the prepared routes toward 2-arylbenzimidazoles analogues require
various oxidative reagents, the participation of strong acids, the involvement of different transition metals,
or microwave irradiation.
R
O
7a
O
N
N
Zn(OAc)
or
2
S X
Y
Y
3
R
O
O
O
7b
NH
NH
2
N
neat, W
R
2
Ar
HOAc
(our work)
5
R
R
Y
Ar
Y
N
8a
N
H
TsOH, MeCN
2
4
4
1
N
H
Scheme 1. Synthetic Route toward Substituted 2-Arylbenzimidazoles and Diazepines
Recently, Kidwai reported that Zn(OAc)2 promoted the synthesis of diazepines (3) through the reaction of
1,2-diaminobenzenes (1) and 1,3-diketones (2).7a The phenomena of double condensation reaction had
been demonstrated by Varma and Leazer under the solvent-free and microwave irradiation conditions (see
Scheme 1).7b To change the catalytic reaction conditions, Yu and Bao had developed that the synthesis of
2-arylbenzimidazole (4) by p-TsOH mediated the condensation reaction of 1,2-diaminobenzenes (1) and

1,3-diketones (2) in MeCN.8a The major difference for constructing two frameworks of diazepines (3) and
2-arylbenzimidazoles (4) was the reaction conditions. To avoid the uncontrollable condensation
conditions, β-ketosulfones (5) was chosen as a new one-carbon synthon for generating substituted
2-arylbenzimidazoles (4). Herein, we would like to describe a facile methodology for synthesizing
substituted 2-arylbenzimidazoles (4) via the condensation reaction of 1,2-diaminobenzenes (1) with
β-ketosulfones (5) in the presence of boiling HOAc.
β-Ketosulfones (5) were easily prepared from the nucleophilic substitution of commercially available
2-bromoacetophenone analogues (6, Ar = a, Ph; b, 4-ClPh; c, 4-MeOPh; d, 2,5-(MeO)2Ph; e, 4-NO2Ph; f,
4-PhPh) with sodium sulfinates (7, NaSO2X, X = a, Tol; b, Ph; c, Me) in nearly quantitative yields for 6 h
under a boiling co-solvent of 1,4-dioxane and water (v/v = 1/1) condition. Without further purification,
condensation of 1,2-diaminobenzenes (1) with the resulting β-ketosulfones (5) provided substituted
2-arylbenzimidazoles (4) in the presence of HOAc at reflux temperature. Adjusting the reaction time,
better results were detected in 5 h for the reaction of 1a with 5a. To elongate reaction time (20 h), product
4a provided with only 68% yield. Entries 1~13 showed that ten substituted 2-arylbenzimidazoles (4a-j)
were isolated in 77~90% yields via once purification, as shown in Table 1. The structure of
2-(4-chlorophenyl)-1H-benzoimidazole (4b) was determined using single-crystal X-ray analysis.9
Table 1. Synthesis of Substituted Benzimidazoles (4)a
O
O
Br
X
S
NH
NH
2
2
N
Na
S X
O
7
HOAc
O
Ar
Y
Y
+
O
O
dioxane/H O
reflux, 6 h
reflux, 5 h
N
H
2
Ar
Ar
6
5
1
4
Entry 6, Ar =
7, X =
7a, Tol 1a, H
7b, Ph 1a, H
1, Y =
4, yield (%)b
4a, 86
4a, 80
1
2
6a, Ph
6a, Ph
3
4
5
6a, Ph
6b, 4-ClPh
6c, 4-MeOPh
7c, Me 1a, H
7a, Tol 1a, H
7a, Tol 1a, H
4a, 82
4b, 78
4c, 90
6
7
8
6d, 2,5-(MeO)2Ph 7a, Tol 1a, H
4d, 86
4e, 77
4f, 82
6e, 4-NO2Ph
7a, Tol 1a, H
7a, Tol 1a, H
6f, 4-PhPh
9
—
—
—
—
—
—
—
—
1b, 2,3-diaminonaphthalene 4g, 80
10
11
12
1c, 4,5-Cl2
4h, 82
4i, 86
4j, 76
1d, 4,5-Me2
1e, 4-CO2Me
aThe reactions were run on a 5.0 mmol scale with 6 and a 1.0 mmol scale with 1.
bSkeleton 4 was >95% pure as determined by NMR analysis.

For the possible mechanism of 1a with 5a, the formation of intermediate A was first proposed via the
intermolecular condensation process, as shown in Scheme 2. After the intramolecular ring-closure was
occurred, intermediate B should be generated. Furthermore, by removal of MeSO2Tol, 4a was formed via
carbon-carbon bond cleavage under thermal conditions.8a
O
S
H
N
NH
N
O
S
2
O
S
Tol
HOAc
Tol
5a
4a
+
1a
+
Me
Tol
O
N
H
O
Ph
O
Ph
A
B
Scheme 2: Possible Mechanism of 2-Phenylbenzimidazole (4a)
Following this protocol, bis-benzimidazoles (9a-b) were formed in 65% and 54% yields, respectively
via the double condensation of bis-diaminobenzene (8) with two equivalents of β-ketosulfones (5a) or
(5e), as shown in Scheme 3.10 Interestingly, the symmetric bis-benzimidazole skeleton with antitumor
activities had been reported as a new class of DNA minor groove binding agents.10b
O
H N
NH
NH
2
2
N
N
HOAc
S
Tol
+
Ar
Ar
O
O
reflux, 5 h
N
H
N
H
H N
2
2
Ar
8
5a, 5e
(2 equiv)
9a, Ar = Ph (65%)
9b, Ar = 4-MeOPh (54%)
Scheme 3: Synthesis of Substituted Bis-benzimidazoles (9a-b)
In summary, we have successfully presented a facile route for the synthesis of 2-arylbenzimidazoles (4)
via the condensation reaction of 1,2-diaminobenzenes (1) with β-ketosulfones (5) in the presence of
boiling HOAc. Bis-benzimidazoles (9a-b) were also prepared by the method. This synthesis begins with
simple starting materials and reagents, and provides a new synthetic route toward 2-arylbenzimidazoles.
EXPERIMENTAL
General. THF was distilled prior to use. All other reagents and solvents were obtained from commercial
sources and used without further purification. Reactions were routinely carried out under an atmosphere
of dry nitrogen with magnetic stirring. Products in organic solvents were dried with anhydrous
magnesium sulfate before concentration in vacuo. Melting points were determined with a SMP3 melting
1
13
apparatus. H and C NMR spectra were recorded on a Varian INOVA-400 spectrometer operating at
400/200 and at 100 MHz, respectively. Chemical shifts (δ) are reported in parts per million (ppm) and the
coupling constants (J) are given in Hertz. High resolution mass spectra (HRMS) were measured with a
mass spectrometer Finnigan/Thermo Quest MAT 95XL. X-ray crystal structures were obtained with an

Enraf-Nonius FR-590 diffractometer (CAD4, Kappa CCD). Elemental analyses were carried out with
Heraeus Vario III-NCSH, Heraeus CHN-OS-Rapid Analyzer or Elementar Vario EL III.
A representative synthetic procedure of 2-arylbenzimidazoles (4) is as follows: Sodium sulfinates (7,
NaSO2X, 6.0 mmol) was added to a solution of 2-bromoacetophenones (6, 5.0 mmol) in co-solvent of
1,4-dioxane and water (20 mL, v/v = 1:1) at rt. The reaction mixture was stirred at reflux for 6 h. The
reaction mixture was cooled to rt, concentrated, and partitioned with CH2Cl2 (3 x 30 mL) and water (30
mL). The combined organic layers were washed with brine, dried, filtered and evaporated to afford crude
β-ketosulfones (5) under reduced pressure in nearly quantitative yields. Without further purification,
β-ketosulfones (5) (1.05 mmol) was added to a solution of 1,2-diaminobenzenes (1, 1.0 mmol) in HOAc
(1 mL) at rt. The reaction mixture was stirred at reflux for 5 h. The reaction mixture was cooled to rt,
concentrated, and partitioned with EtOAc (3 x 30 mL) and saturated NaHCO3(aq) (30 mL). The combined
organic layers were washed with brine, dried, filtered and evaporated to afford crude product under
reduced pressure. Purification on silica gel (hexanes/EtOAc = 1/1) afforded 2-arylbenzimidazoles (4).
o
2-Phenyl-1H-benzimidazole (4a).3c Yield = 86% (167 mg); mp 289-292 C (recrystallized from EtOAc);
1
HRMS (ESI, M++1) calcd for C13H11N2 195.0922, found 195.0933; H NMR (400 MHz, DMSO-d6): δ
12.93 (br s, 1H), 8.20-8.17 (m, 2H), 7.67 (br s, 1H), 7.58-7.47 (m, 4H), 7.22-7.20 (m, 2H); 13C NMR (100
MHz, DMSO-d6): δ 151.22, 143.81, 135.00, 130.17, 129.83, 128.95 (2x), 126.43 (2x), 122.52, 121.68,
118.87, 111.32.
2-(4-Chlorophenyl)-1H-benzimidazole (4b).3c Yield = 78% (178 mg); mp 288-290 oC (recrystallized from
1
EtOAc); HRMS (ESI, M++1) calcd for C13H10ClN2 229.0533, found 229.0540; H NMR (400 MHz,
DMSO-d6): δ 12.99 (br s, 1H), 8.23-8.17 (m, 2H), 7.69-7.56 (m, 4H), 7.22-7.21 (m, 2H); 13C NMR (100
MHz, DMSO-d6): δ 150.13 (2x), 134.47 (2x), 129.05 (2x), 128.30, 128.11 (2x), 122.71, 121.88, 118.96,
111.43. Single-crystal X-Ray diagram: crystal of compound (4b) was grown by slow diffusion of EtOH
into a solution of compound (4b) in EtOAc to yield colorless prisms. The compound crystallizes in the
orthorhombic crystal system, space group P b c a, a = 9.1642(7) Å, b = 9.7348(7) Å, c = 23.5043(18) Å,
V = 2096.9(3) Å3, Z = 8, dcalcd = 1.449 g/cm3, F(000) = 944, 2θ range 1.733~26.710o, R indices (all data)
R1 = 0.0347, wR2 = 0.0743.
o
2-(4-Methoxyphenyl)-1H-benzimidazole (4c).3c Yield = 89% (199 mg); mp 229-233 C (recrystallized
from EtOAc); HRMS (ESI, M++1) calcd for C14H13N2O 225.1028, found 225.1032; 1H NMR (400 MHz,
DMSO-d6 + CDCl3): δ 12.73 (br s, 1H), 8.13 (d, J = 8.8 Hz, 2H), 7.61 (br d, J = 6.0 Hz, 1H), 7.48 (br d, J
= 6.4 Hz, 1H), 7.17-7.13 (m, 2H), 7.09 (d, J = 8.8 Hz, 2H), 3.83 (s, 3H); 13C NMR (100 MHz, DMSO-d6
+ CDCl3): δ 160.57, 151.36, 143.86, 134.94, 127.98 (2x), 122.67, 121.98, 121.37, 118.40, 114.24 (2x),
110.96, 55.24.

2-(2,5-Dimethoxyphenyl)-1H-benzimidazole (4d).10a Yield = 86% (218 mg); mp 230-234 oC
1
(recrystallized from EtOAc); HRMS (ESI, M++1) calcd for C15H15N2O2 255.1134, found 255.1139; H
NMR (400 MHz, CDCl3): δ 8.15 (t, J = 2.0 Hz, 1H), 7.69-7.67 (m, 2H), 7.66 (br s, 1H), 7.29-7.24 (m,
13
2H), 6.98 (d, J = 2.0 Hz, 1H), 6.98 (s, 1H), 4.03 (s, 3H), 3.89 (s, 3H); C NMR (100 MHz, CDCl3): δ
154.28, 151.36, 149.25, 123.15 (2x), 119.07 (2x), 114.85, 113.15 (2x), 113.04 (3x), 56.51, 56.19.
o
2-(4-Nitrophenyl)-1H-benzimidazole (4e).10b Yield = 77% (184 mg); mp > 300 C (recrystallized from
1
EtOAc); HRMS (ESI, M++1) calcd for C13H10N3O2 240.0773, found 240.0768; H NMR (400 MHz,
DMSO-d6): δ 13.28 (br s, 1H), 8.43-8.36 (m, 4H), 7.70 (br s, 1H), 7.61 (br s, 1H), 7.27-7.26 (m, 2H); 13C
NMR (100 MHz, DMSO-d6): δ 149.00 (2x), 147.79, 136.02 (2x), 127.38 (2x), 124.28 (2x), 123.57,
122.42, 119.50, 111.85.
o
2-Biphenyl-4-yl-1H-benzimidazole (4f).10c Yield = 82% (221 mg); mp 296-300 C (recrystallized from
1
EtOAc); HRMS (ESI, M++1) calcd for C19H15N2 271.1235, found 271.1242; H NMR (400 MHz,
DMSO-d6): δ 12.98 (br s, 1H), 8.30-8.28 (m, 2H), 7.89-7.86 (m, 2H), 7.78-7.75 (m, 2H), 7.68 (br s, 1H),
7.56 (br s, 1H), 7.51-7.47 (m, 2H), 7.42-7.38 (m, 1H), 7.23-7.21 (m, 2H); 13C NMR (100 MHz,
DMSO-d6): δ 150.93, 148.83, 141.27, 139.25, 135.06, 129.14, 129.01 (2x), 127.86, 127.12 (2x), 127.00
(2x), 126.67 (2x), 122.52, 121.73, 118.85, 111.29.
2-Phenyl-1H-naphtho[2,3-d]imidazole (4g).5e Yield = 80% (195 mg); mp 212-216 oC (recrystallized from
1
EtOAc); HRMS (ESI, M++1) calcd for C17H13N2 245.1079, found 245.1083; H NMR (400 MHz,
DMSO-d6): δ 12.98 (br s, 1H), 8.31-8.28 (m, 2H), 8.03-8.01 (m, 3H), 7.63-7.55 (m, 3H), 7.41-7.32 (m,
3H); 13C NMR (100 MHz, DMSO-d6): δ 156.24, 155.36, 144.33, 135.79, 130.67, 130.30, 129.77, 129.03
(2x), 128.07, 127.39, 127.08 (2x), 123.78, 123.04, 115.22, 106.53.
o
5,6-Dichloro-2-phenyl-1H-benzimidazole (4h).5e Yield = 82% (215 mg); mp 210-213 C (recrystallized
from EtOAc); HRMS (ESI, M++1) calcd for C13H9Cl2N2 263.0143, found 263.0148; 1H NMR (200 MHz,
DMSO-d6): δ 12.57 (br s, 1H), 8.05-8.00 (m, 2H), 7.52-7.45 (m, 3H), 7.36 (s, 2H).
o
5,6-Dimethyl-2-phenyl-1H-benzimidazole (4i).5e Yield = 86% (191 mg); mp 190-192 C (recrystallized
1
from EtOAc); HRMS (ESI, M++1) calcd for C15H15N2 223.1235, found 223.1241; H NMR (200 MHz,
DMSO-d6): δ 12.90 (br s, 1H), 8.04-8.01 (m, 2H), 7.53-7.43 (m, 3H), 7.34 (s, 2H), 2.34 (s, 6H).
2-Phenyl-1H-benzimidazole-5-carboxylic acid methyl ester (4j).3g Yield = 76% (192 mg); mp 196-198 oC
1
(recrystallized from EtOAc); HRMS (ESI, M++1) calcd for C15H13N2O2 253.0977, found 253.0983; H
NMR (400 MHz, CDCl3): δ 8.32-8.31 (m, 1H), 8.13-8.10 (m, 2H), 7.93 (dd, J = 1.6, 8.4 Hz, 1H), 7.60 (br
s, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.42-7.34 (m, 3H), 3.90 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 167.77,
154.34, 142.75, 138.16, 130.80, 129.10 (2x), 128.91, 127.00 (2x), 124.73, 124.48, 117.02, 115.08, 52.18.
A representative synthetic procedure of bis-2-arylbenzimidazoles (9a-b) is as follows: β-Ketosulfones (5a
or 5e, 1.0 mmol) was added to a solution of bis-diaminobenzene (8, 96 mg, 0.45 mmol) in HOAc (1 mL)

at rt. The reaction mixture was stirred at reflux for 5 h. The reaction mixture was cooled to rt,
concentrated, and partitioned with EtOAc (3 x 30 mL) and saturated NaHCO3(aq) (30 mL). The combined
organic layers were washed with brine, dried, filtered and evaporated to afford crude product under
reduced pressure. Purification on silica gel (hexanes/EtOAc = 1/1) afforded products (9a-b).
2,2'-Bis-phenyl-1H,1'H-[5,5']bibenzimidazolyl (9a).11a Yield = 65% (113 mg); mp > 300 oC
1
(recrystallized from EtOAc); HRMS (ESI, M++1) calcd for C26H19N4 387.1610, found 387.1620; H
NMR (400 MHz, DMSO-d6 + CDCl3): δ12.83 (br s, 2H), 8.17-8.15 (m, 4H), 7.81 (br s, 2H), 7.63 (d, J =
13
8.4 Hz, 2H), 7.51-7.39 (m, 8H); C NMR (100 MHz, DMSO-d6 + CDCl3): δ 151.68 (2x), 136.10 (2x),
129.58 (2x), 129.39 (2x), 128.41 (6x), 126.32 (6x), 122.00 (2x), 114.98 (2x), 112.73 (2x).
2,2'-Bis-(4-methoxyphenyl)-1H,1'H-[5,5']bibenzimidazolyl (9b).11b Yield = 54% (108 mg); mp 269-272
oC (recrystallized from EtOAc); HRMS (ESI, M++1) calcd for C28H23N4O2 447.1821, found 447.1826; 1H
NMR (400 MHz, DMSO-d6 + CDCl3): δ 8.10 (d, J = 8.4 Hz, 4H), 7.76 (br d, J = 1.2 Hz, 2H), 7.59 (d, J =
8.4 Hz, 2H), 7.46 (dd, J = 1.2, 8.4 Hz, 2H), 6.99 (d, J = 8.4 Hz, 4H), 3.82 (s, 6H); 13C NMR (100 MHz,
DMSO-d6 + CDCl3): δ 160.57 (2x), 151.80 (2x), 139.29 (2x), 138.30 (2x), 135.77 (2x), 127.90 (4x),
122.07 (2x), 121.58 (2x), 114.75 (2x), 113.87 (4x) , 112.35 (2x), 54.95 (2x).
ACKNOWLEDGEMENTS
The authors would like to thank the National Science Council of the Republic of China for its financial
support (NSC 102-2113-M-037-005-MY2).
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SUPPLEMENTARY MATERIAL
Scanned photocopies of 1H and 13C NMR spectral data were supported.