Improved convenient and environmentally benign synthesis of biological active benzimidazoles using activated carbon and molecular oxygen

Article abstract of DOI:10.3987/COM-07-11222

The reaction of 1,2-phenylenediamine with a variety of aromatic aldehydes in xylenes gave the corresponding benzimidazole derivatives in good to excellent yields (82-93%) in the presence of dry activated carbon and bubbling molecular oxygen. The present r

Full text of DOI:10.3987/COM-07-11222

HETEROCYCLES, Vol. 75, No. 2, 2008
415
HETEROCYCLES, Vol. 75, No. 2, 2008, pp. 415 - 418. © The Japan Institute of Heterocyclic Chemistry
Received, 16th September, 2007, Accepted, 12th November, 2007, Published online, 13th November. 2007. COM-07-11222
IMPROVED CONVENIENT AND ENVIRONMENTALLY BENIGN
SYNTHESIS OF BIOLOGICAL ACTIVE BENZIMIDAZOLES USING
ACTIVATED CARBON AND MOLECULAR OXYGEN
Yoshinobu Tagawa,* Kenji Yamagata, and Kunihiro Sumoto
Faculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma 8-19-1,
Jonan-ku, Fukuoka 814-0180, Japan
Abstract - The reaction of 1,2-phenylenediamine with a variety of aromatic
aldehydes in xylenes gave the corresponding benzimidazole derivatives in good to
excellent yields (82-93%) in the presence of dry activated carbon and bubbling
molecular oxygen. The present reaction involves the simple procedure, easy
workup and environmentally benign materials such as molecular oxygen and
reusable activated carbon.
Benzimidazole derivatives have been used in human therapeutic areas as antiulcers, antihypertensives,
antivirals, antifungals or anticancers and in veterinarian medicine as anthelmintic.1 They are regarded as
‘privileged sub-structures’ for drug design by medicinal chemists.2 Accordingly developing a simple and
efficient methodology to prepare benzimidazole derivatives in preparative-scale, taking environmental
issues into consideration, would be of great significance. As a part of the study of developing such a
methodology, this paper deals with reaction of 1,2-phenylenediamine with aromatic aldehyde in the
presence of activated carbon and molecular oxygen.
While many strategies are available for benzimidazole synthesis,2 the most popular approaches generally
involve condensation-dehydration of 1,2-phenylenediamine with carboxylic acids (or equivalents) (path
A), or condensation with aldehydes under oxidative conditions (path B) (Scheme 1).
H
R2
N
R1
O
R2CO2H
NH2
H
N
－H2O
NH2
NH2
path A
－H2O
R2CHO
R1
R2
R1
N
－H2
H
N
－H2O
R2
R1
O
N
H
Scheme 1
path B

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HETEROCYCLES, Vol. 75, No. 2, 2008
The reaction with R2CO2H (path A) requires generally the harsh reaction conditions and proceeds
stepwise via intermediate amide, on the other hand extensive structural diversity is available
commercially in the reaction with aldehydes (path B) and the reaction proceeds through a
benzimidazoline, which requires an oxidative step for conversion to benzimidazole. Recently, it was
reported that the reaction of 1,2-phenylenediamine with benzaldehyde in the presence of activated carbon
and molecular oxygen gave 2-phenylbenzimidazole in 64% yield.3 However, the only reaction resulted
in a long reaction time (26 h) and relatively low yield (64%). So, it is commenced to evolve and
improve this reaction to find much better reaction conditions and reaction characteristics. We also have
tried to shed light on the utility and environmental friendliness of molecular oxygen and activated carbon
in the oxidation4 and extend the reaction examples. The reaction yields and reaction time (1 h in most
cases) were dramatically improved by use of dried activated carbon (200 ℃ for 10 h) and molecular
oxygen continuously bubbling into the solvent. Thus, a mixture of 1,2-phenylenediamine (0.5 g, 4.62
mmol), aromatic aldehyde (4.62 mmol), and activated carbon (Darco KB, 0.25 g, 50 weight%) was heated
at 110-115 ℃ for 1 h in xylenes (40 mL) with stirring under bubbling of molecular oxygen into xylenes.
After filtration, the usual workup of xylenes evaporation and SiO2-purification gave the corresponding
benzimidazoles in the yields shown in Table 1. As can be seen from Table 1, we obtained the desired
benzimidazoles in good to excellent yields. After the filtered activated carbon was dried, it was reused
several times to afford almost the same results as those in Table 1. It is of interest to note that without
activated carbon almost no reaction proceeded and the fact indicated us the important role of activated
carbon in the present reaction.
Table 1
H
NH2
O2－A.C.a)
N
RCHO
R
+
NH2
N
in xylenes (110 - 115 ℃), 1 h
2 a-j
1
3 a-j
Entry
1
Yield (%)
Product
3a
Entry
6
Product
Yield (%)
RCHO
OMe
RCHO
3f8
82
83
85
92
OHC
OHC
OHC
OHC
OHC
Br
90
OHC
OMe
OMe
3g5
Me
7
8
9
Cl
2
3b
86
OHC
Cl
3h7
3i9
NMe2
3c5
3d6
3
4
OHC
OHC
OMe
91
87
N
3j7
93
10
3e7
84
OHC
NO2
5
a) A.C. = activated carbon ( Darco KB )

HETEROCYCLES, Vol. 75, No. 2, 2008
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While in the reaction of 1,2-phenylenediamine with 4-(dimethylamino)benzaldehyde in the presence of
certain oxidant like oxone the side reaction occurred to afford 2H-benzimidazole,2 the present reaction
gave the corresponding benzimidazole in good yield (Entry 8). In summary, we revealed some features
of the present reaction; 1) the reaction comprises very simple procedures and simple workup gave the
corresponding benzimidazoles in good yields, 2) the reaction would be compatible with aromatic
aldehydes having redox-sensitive substituents, 3) the reaction is the environmental friendliness due to the
use of reusable activated carbon and molecular oxygen. It would also be interesting to explore the
reaction of 1,2-phenylenediamine derivatives with a variety of aldehydes (aliphatic, aromatic and
heteroaromatic) bearing electron-donating and electron-withdrawing substituents. The present reaction
should be equally applicable to the preparation of benzoxazole and related classes of fused heterocycles.
From these standpoints, our investigation is currently under way.
EXPERIMENTAL
Melting points were measured on a Yanagimoto micro melting points apparatus and are uncorrected.
Spectral data were recorded on the following spectrometers: 1H nmr spectra, JEOL GX-400 (400 MHz)
13
and JEOL A-500 (500 MHz); C nmr spectra, JEOL GX-400 (100 MHz) and JEOL A-500 (125MHz);
mass spectra, JEOL JMS-DX300 for EI-ms and JMS-HX110 for FAB-ms. The HH-COSY, CH-COSY,
and DEPT experiments were also used for the assignments of the structures. The chemical shifts are
given on the δscale. Elemental analyses were performed on a Heraeus CHN-O-RAPID instrument.
Medium pressure liquid chromatography (mplc) was carried out with a Yamazen 540 FMI-C pump and
Wakogel FC-40 (20-40 μm, Wako). Column chromatography was carried out with Kieselgel 60
(70-230 mesh, Merck).
General Procedure for reaction of 1,2-phenylenediamine with aromatic aldehyde in the presence of
activated carbon and molecular oxygen
A mixture of 1,2-phenylenediamine (0.5 g, 4.62 mmol), aromatic aldehyde (4.62 mmol), and activated
carbon (Darco KB, 0.25 g, 50 weight%) was heated at 110-115 ℃ for 1 h in xylenes (40 mL) with
stirring under bubbling of molecular oxygen into xylenes. The resulting solution was filtered and the
filtrate was furthermore filtered with Celite, washing with MeOH. After removal of the solvent, the
residue was worked up in the manner as shown below.

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HETEROCYCLES, Vol. 75, No. 2, 2008
2-(3,4,5-Trimethoxyphenyl)-1H-benzimidazole
This compound was recrystallized from AcOEt to give colorless cottony crystals, mp 267 ℃. 1H
NMR(DMSO-d6) δ(ppm): 3.75 (3H, s, Me), 3.91(6H, s, Me×2), 7.20 (2H, s, Ar-H), 7.52 (3H, s, Ar-H),
7.53 (1H, Ar-H), 12.81(1H, s, NH). 13C NMR(DMSO-d6) δ(ppm): 20.3 (q, Me), 56.1 (q, Me×2),
60.1 (q, Me), 103.9 (d, Ar), 111.1 (d, Ar), 118.6 (d, Ar), 121.6 (d, Ar), 122.4 (d, Ar), 125.4 (s, Ar), 139.0 (s,
Ar), 151.2 (s, Ar), 153.2 (s, Ar). EI-ms m/z(%): 284 (M+, 100), 269(37), 241(8), 211(12), 142(10).
Anal. Calcd for C16H16N2O3: C, 67.59; H, 5.67; N, 9.85. Found: C, 67.51; H, 5.70; N, 9.88.
2-(2,4-Dichlorophenyl)-1H-benzimidazole
This compound was recrystallized from benzene to give colorless scales, mp 232 ℃ . 1H
NMR(DMSO-d6) δ(ppm): 7.25 (2H, br s, Ar-H), 7.58-7.60(1H, br s, Ar-H), 7.95 (1H, d, J = 8.5Hz,
Ar-H), 12.75(1H, s, NH). 13C NMR(DMSO-d6) δ(ppm): 111.8 (d, Ar), 119.1 (d, Ar), 121.8 (d, Ar),
122.9 (d, Ar), 127.7 (d, Ar), 128.8 (s, Ar), 129.8 (d, Ar), 132.6 (s, Ar), 133.2 (d, Ar), 134.6 (s, Ar), 135.0
(s, Ar), 143.1 (s, Ar), 148.0 (s, Ar). EI-ms m/z(%): 266(11), 264(65), 262(M+, 100), 192(9), 90(8).
Anal. Calcd for C13H8N2Cl2: C, 59.34; H, 3.06; N, 10.65. Found: C, 59.35; H, 3.15; N, 10.63.
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