New Procedure for the Synthesis of 2-Alkylbenzimidazoles

Article abstract of DOI:10.1080/00397910902730838

Simple, economical, and environmentally friendly method to synthesize 2-alkylbenzimidazoles was developed by modifying the conventional method between °-phenylenediamine and aldehyde.

Full text of DOI:10.1080/00397910902730838

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New Procedure for
the Synthesis of 2-
Alkylbenzimidazoles
a
b
Tomohiro Yamashita , Shozo Yamada , Yasundo
c
a
Yamazaki & Hideo Tanaka
a
Department of Applied Chemistry, Faculty of
Engineering, Okayama University, Okayama, Japan
b
Chemical Technology Laboratory, Taiho
Pharmaceutical Co., Saitama, Japan
c
Discovery and Development Laboratory II, Hanno
Research Center, Taiho Pharmaceutical Co., Hanno,
Saitama, Japan
Version of record first published: 14 Jul 2009
To cite this article: Tomohiro Yamashita, Shozo Yamada, Yasundo Yamazaki & Hideo
Tanaka (2009): New Procedure for the Synthesis of 2-Alkylbenzimidazoles, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 39:16, 2982-2988
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1
Synthetic Communications , 39: 2982–2988, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902730838
New Procedure for the Synthesis
of 2-Alkylbenzimidazoles
1
Tomohiro Yamashita, Shozo Yamada, Yasundo Yamazaki,
2
3
1
and Hideo Tanaka
Department of Applied Chemistry, Faculty of Engineering, Okayama
University, Okayama, Japan
1
2
Chemical Technology Laboratory, Taiho Pharmaceutical Co.,
Saitama, Japan
3
Discovery and Development Laboratory II, Hanno Research Center,
Taiho Pharmaceutical Co., Hanno, Saitama, Japan
Abstract: Simple, economical, and environmentally friendly method to synthesize
-alkylbenzimidazoles was developed by modifying the conventional method
between o-phenylenediamine and aldehyde.
2
Keywords: Benzimidazoles, o-phenylenediamine, sodium hydrogen sulfite
Benzimidazole is a key skeleton in the pharmaceutical area, so many
compounds with benzimidazole scaffolds were launched as antihistamatic
drugs, antiulcer drugs, anti-infectious, and anti-arrhythmic drugs (Fig. 1).
Several reports on the synthesis of benzimidazole derivative have
[1–11]
been published and applied to industrial methods.
Typical examples for the synthesis of benzimidazoles are (1) reaction
of o-phenylenediamine and carboxylic acid under strong acidic condi-
[
12]
tions, (2) ring-closure reaction under mild acidic conditions, of amide
[
13]
derivatives prepared from o-phenylenediamine and carboxylic acid,
Received September 22, 2008.
Address correspondence to Tomohiro Yamashita, Department of Applied
Chemistry, Faculty of Engineering, Okayama University, Tsushima-naka 3-1-1,
Okayama 700-8530, Japan. E-mail: tomyamas@taiho.co.jp
2982

Synthesis of 2-Alkylbenzimidazoles
2983
Figure 1. Structures of benzimidazole drugs.
and (3) direct condensation reaction between o-phenylenediamine and
[
aldehyde in the presence of an appropriate reagent.
14]
In the area of industrial applications, reasonable cost of chemicals,
applicability of reaction conditions, and environmental consciousness
are necessary.
During the process of development of our drug candidate, we needed
to establish an ideal reaction procedure to construct a benzimidazole ske-
leton: 2-substituted benzimidazole derivatives were of particular interest.
Even though a number of reports have been published regarding this
kind of reaction, most of them refer to the synthesis of 2-aryl benzimida-
zoles, and no procedures with satisfactory results were available for
2
-alkylbenzimidazole derivatives. To achieve our final purpose, we
planned a two-step strategy: (1) select the preferable reaction conditions
to synthesize benzimidazole skeleton, and (2) modify and optimize the
reaction condition(s) to fit our needs.
Because of its simple operation and mild reaction conditions, we
chose the reaction between o-phenylenediamine and aldehyde in the pre-
[
15]
sence of a sulfur reagent such as sodium disulfite,
[
sodium hydrogen
as a basic strategy, and
16]
[17]
sulfite,
assessment and optimization were conducted.
or potassium hydrogen sulfate
At first, the reaction between o-phenylenediamine and benzaldehyde
was carried out using three types of reagents under identical conditions
to compare them. In the case of sodium hydrogen sulfite and sodium
disulfite, the yields were almost quantitative: however, potassium hydro-
gen sulfate gave poor results (Table 1, entries 1, 11, and 20).

2984
T. Yamashita et al.
Table 1. Synthesis of benzazoles using some sulfur reagents
a
Entry
Reagent
NaHSO3
X
R
1
R
2
Yield (%)
1
2
3
4
5
6
7
8
9
NH
NH
NH
NH
NH
NH
NH
S
H
H
H
–Me
–Cl
H
H
H
H
H
H
H
H
–Me
–Cl
H
H
H
–Ph
89.6
NaHSO
NaHSO
3
3
–PhÀ4ÀOMe
–PhÀ4ÀCl
–Ph
91.9
Quant.
98.9
89.2
30.6
56.4
93.2
Trace
b
19.0
91.6
91.9
91.9
97.5
95.8
40.5
58.4
94.2
NaHSO3
NaHSO
NaHSO
3
3
–Ph
–(CH
2
)
5
CH
3
NaHSO3
–c Hex
–Ph
–Ph
NaHSO
NaHSO
3
3
O
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
NaHSO3
–Ph
–Ph
Na
Na
Na
Na S O
Na
Na
Na S O
Na
Na
2
2
2
S
S
S
2
2
2
O
O
O
5
5
5
5
5
5
5
5
5
NH
NH
NH
NH
NH
NH
NH
S
–PhÀ4ÀOMe
–PhÀ4ÀCl
–Ph
2
2
2
2
2
2
S
S
O
O
–Ph
–(CH
2
)
5
CH
3
–c Hex
–Ph
–Ph
2
2
2
2
2
2
S
S
O
O
O
H
H
H
H
H
H
Trace
25.2
13.3
Trace
Trace
Trace
KHSO4
NH
NH
NH
S
–Ph
–(CH
KHSO
KHSO
4
4
2
)
5
CH
3
–c Hex
–Ph
–Ph
KHSO4
KHSO4
O
a
b
1
All yields refer to isolated products.
ꢀ
20 C, 3 days.
Note. Spectroscopic data supported the structures of all compounds.
Simple substitutions on the substrates (ÀMe, ÀCl) did not affect to the
yields (Table 1, entries 4, 5, 14, and 15). Similarly, excellent yields of
-phenylbenzothiazoles were obtained from benzaldehyde and o-aminothio-
2
phenol; however, in the case of o-aminophenol, the yield was very poor
even after a longer reaction time (Table 1, entries 8, 9, 10, 18, 19, and 24).
Furthermore, the yield was less when aliphatic aldehydes were used,
[
17]
instead of benzaldehyde as described in the literature (Table 1, entries
, 7, 16, 17, 21, and 22).
6

Synthesis of 2-Alkylbenzimidazoles
2985
Table 2. Reaction of o-phenylenediamine and n-heptylaldehyde under various
conditions
ꢀ
a
Entry
6
NaHSO
3
(eq.)
Temp. ( C)
Time (h)
Yield (%)
1.0
1.0
1.5
1.0
1.0
100
120
100
100
100
2
2
2
4
2
30.6
34.6
26.7
42.0
2
2
2
2
5
6
7
8
b
64.8
a
b
All yields refer to isolated products.
A solution of aldehyde was added dropwise to a solution of diamine=NaHSO
3
mixture.
Up to this stage, sodium hydrogen sulfite and sodium disulfite
seemed to be candidates for the basic condition to prepare 2-alkylbenzi-
midazoles. Even though sodium disulfite gave slightly better yields
in some cases, we selected sodium hydrogen sulfite because of its
economical advantage.
Then, we tried to overcome problems such as poor yield for 2-alkyl-
benzimidazoles. Greater reaction temperature and an additional amount
of reagent had no effects, but longer reaction time improved the yield
slightly (Table 2). Considering the speculated reaction mechanism,
Scheme 1. Speculated reaction mechanism.

2
986
T. Yamashita et al.
Table 3. Synthesis of 2-alkylbenzimidazoles under improved conditions
a
Entry
R
Yield (%)
29
30
31
32
33
–Et
75.2
75.2
97.6
51.7
73.4
3 2 3
–CH(CH )CH CH
–tBu
–(CH
–c Hex
2 7 3
) CH
a
All yields refer to isolated products.
Note. Spectroscopic data supported the structures of all compounds.
[16]
reported previously, we expected that the formation of the bis-adduct
would be predominant if the final step (ring closure) was slow, and it
would cause poor yield of the desired product (Scheme 1). In the case
of aromatic aldehydes, ring-closure reaction takes place on the benzylic
carbon, proceeds smoothly, and provides a good yield of final products.
Therefore, we tried a reaction under a modified procedure, in which a
solution of aliphatic aldehyde was slowly dropped into a heated solution
of diamine to diminish the formation of bis-adduct. As a result, the yield
of the desired compound was dramatically increased (Table 1, entry 28).
To confirm the generality of this condition, several aliphatic
aldehydes were applied, and good to excellent yields of the desired
compounds were obtained (Table 3).
Furthermore, a similar reaction using cyclohexyl aldehyde was
carried out on a preparative scale. In this trial, we attempted to eliminate
the chromatographical purification. By adding a 2% sodium carbonate
solution to the cooled reaction mixture, the desired product was obtained
in 88.8% yield as a solid material.
In conclusion, we found an improved reaction procedure to synthe-
size 2-alkylbezimidazoles, which could be operated on a preparative scale
without chromatographical purification.
GENERAL PROCEDURE
A mixture of phenylenediamine (1.0 mmol), aldehyde (1.0 mmol), and
sulfur reagent (1.0 mmol) in N,N-dimethylacetamide (DMA) (2.0 mL)

Synthesis of 2-Alkylbenzimidazoles
2987
ꢀ
was heated at 100 C for 2 h. The reaction mixture was concentrated in
vacuo, and the residue was purified by flash chromatography.
Modified Procedure for Aliphatic Aldehyde
A DMA (1.0 mL) solution of aldehyde (1.0 mmol) was added dropwise to
a mixture of phenylenediamine (1.0 mmol), and sulfur reagent (1.0 mmol)
ꢀ
in DMA (1.0 mL) over a 10-min period at 100 C. After 2 h, the reaction
mixture was concentrated, and the residue was purified as described
previously.
Preparative Scale Procedure for 2-Cyclohexylbenzimidazole
A DMA (10 mL) solution of cyclohexyl aldehyde (6.1 mL, 50.0 mmol)
was added dropwise to a heated mixture of o-phenylenediamine (5.41 g,
5
0.0 mmol) and sodium hydrogen sulfite (5.21 g, 50.0 mmol) in DMA
ꢀ
(
50 mL) over a 10-min period at 100 C and stirred under the same condi-
tions. After the reaction was completed, the mixture was cooled, and 2%
ꢀ
sodium carbonate (10 mL) was less than at a temperature added 40 C.
Stirring continued for approximately 2 h. The solid was collected by suc-
tion, washed with water, and dried in the air. We obtained 8.9 g (88.8%)
of 2-cyclohexylbenzimidazole.
REFERENCES
1
. Hisano, T.; Ichikawa, M.; Tsumoto, K.; Tasaki, M. Synthesis of benzoxa-
zoles, benzothiazoles, and benzimidazoles and evaluation of their antifungal,
insecticidal, and herbicidal activities. Chem. Pharm. Bull. 1982, 30, 2996.
. Cheng, J. B.; Cooper, K.; Duplantier, A. J.; Eggler, J. F.; Kraus, K. G.;
Marshall, S. C.; Marfat, A.; Masamune, H.; Shirley, J. T.; Ticker, J. E.;
Umland, J. P. Synthesis and in vitro profile of a novel series of catechol
benzimidazoles: The discovery of potent, selective phosphodiesterase type
2
3
IV inhibitors with greatly attenuated affinity for the [ H] rolipram binding
site. Bioorg. Med. Chem. Lett. 1995, 5, 1969.
3
4
. Roth, T.; Morningstar, M. L.; Boyer, P. L.; Hughes, S. H.; Buckheit, R. W.
Jr.; Michejda, C. J. Synthesis and biological activity of novel nonnucleoside
inhibitors of HIV-1 reverse transcriptase: 2-Aryl-substituted benzimidazoles.
J. Med. Chem. 1997, 40, 4199.
. Singh, M. P.; Sasmal, S.; Lu, W.; Chatterjee, M. N. Synthetic utility of
catalytic Fe(III)=Fe(II) redox cycling towards fused heterocycles. Synthesis
2000, 10, 1380.

2988
T. Yamashita et al.
5
6
. Lee, K. J.; Janda, K. D. Traceless solid-phase synthesis of 5-benzoylbenzimi-
dazoles. Can. J. Chem. 2001, 79, 1556.
. Nagata, K.; Itoh, T.; Ishikawa, H.; Ohsawa, A. Synthesis of 2-substituted
benzimidazoles by reaction of o-phenylenediamine with aldehydes in the
3
presence of Sc(OTf) . Heterocycles 2003, 61, 93.
7
. Beaulieu, P. L.; Hache, B.; von Moos, E. A practical oxone-mediated,
high-throughput, solution-phase synthesis of benzimidazoles from 1,2-pheny-
lenediamines and aldehydes and its application of preparative scale synthesis.
Synthesis 2003, 11, 1683.
8
. Kawashita, Y.; Nakamichi, N.; Kawabata, H.; Hayashi, M. Direct and
practical synthesis of 2-arylbenzoxazoles promoted by activated carbon.
Org. Lett. 2003, 5, 3713.
9. Curini, M.; Epifano, F.; Montanari, F.; Rosati, O.; Taccone, S. Ytterbium
trifrate promoted synthesis of benzimidazole derivatives. Synlett 2004, 10,
1832.
1
0. Gogoi, P.; Konwar, D. An efficient and one-pot synthesis of imidazolines and
benzimidazoles via anaerobic oxidation of carbon-nitrogen bonds in water.
Tetrahedron Lett. 2006, 47, 79.
1
1. Bahrami, K.; Khodeai, M. M.; Kavianinia, I. A simple and efficient one-pot
synthesis of 2-substituted benzimidazoles. Synthesis 2007, 547.
2. Lu, J.; Yang, B.; Bay, Y. Microwave irradiation synthesis of 2-substituted
banzimidazoles using PPA as a catalyst under solvent-free conditions. Synth.
Commun. 2002, 32, 3703.
1
1
1
1
3. Renneberg, D.; Dervan, P. B. Imidazopyridine=pyrrole and hydroxybenzimi-
dazole=pyrrole pairs for DNA minor groove recognition. J. Am. Chem. Soc.
2003, 125, 5707.
4. Yadagiri, B.; Lawn, W. Convenient routes to substituted benzimidazoles and
imidazolo[4,5-b]pyridines using nitrobenzene as oxidant. Synth. Commun.
1990, 20, 955.
5. Frey, M. J.; Kooper, K.; Parry, M. J.; Richardson, K.; Steele, J. Novel
antagonists of platelet-activated factor, 1: Synthesis and structure–activity
relationships of benzodiazepine and benzazepine derivatives of 2-methyl-1-
phenyldiamino[4,5-c]pyridine. J. Med. Chem. 1995, 38, 3514.
1
1
6. Jones, R.; Klockow, M.; Lues, I.; Prucher, H.; Schliep, H. J.; Wurziger, H.
Synthesis and biological activities of meribendan and related heterocyclic
benzimidazo-pyridazinones. Eur. J. Med. Chem. 1993, 28, 129.
7. Ma, H.; Wang, Y.; Wang, J. A simple KHSO -promoted synthesis of
4
2-arylsubstituted benzimidazoles by oxidative condensation of aldehydes
with o-phenylenediamine. Heterocycles 2006, 68, 1669.