Mild and highly efficient protocol for the synthesis of benzimidazoles using samarium triflate [Sm(OTf)3]

Article abstract of DOI:10.1080/00397910903534064

One-pot synthesis of benzimidazole compounds from ortho-phenylenediamine and a variety of aldehydes was developed under mild reaction conditions. All the reactions were carried out in the presence of samarium triflate (10mol%) in acetonitrile at room temperature. Copyright Taylor & Francis Group, LLC.

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Mild and Highly Efficient Protocol for
the Synthesis of Benzimidazoles Using
Samarium Triflate [Sm(OTf) ]
3
a
a
a
A. Venkat Narsaiah , A. Ramesh Reddy & J. S. Yadav
a
Organic Chemistry Division, Indian Institute of Chemical
Technology, Hyderabad, India
Version of record first published: 15 Dec 2010
To cite this article: A. Venkat Narsaiah, A. Ramesh Reddy & J. S. Yadav (2010): Mild and Highly
Efficient Protocol for the Synthesis of Benzimidazoles Using Samarium Triflate [Sm(OTf) ], Synthetic
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Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
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Synthetic Communications , 41: 262–267, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903534064
MILD AND HIGHLY EFFICIENT PROTOCOL FOR THE
SYNTHESIS OF BENZIMIDAZOLES USING SAMARIUM
TRIFLATE [Sm(OTf)3]
A. Venkat Narsaiah, A. Ramesh Reddy, and J. S. Yadav
Organic Chemistry Division, Indian Institute of Chemical Technology,
Hyderabad, India
One-pot synthesis of benzimidazole compounds from ortho-phenylenediamine and a variety
of aldehydes was developed under mild reaction conditions. All the reactions were carried
out in the presence of samarium triflate (10 mol%) in acetonitrile at room temperature.
Keywords: Aldehydes; benzimidazoles; ortho-phenylenediamine; samarium triflate
INTRODUCTION
The imidazole and substituted imidazole moiety is structurally related to purine
bases and is found in a variety of naturally occurring compounds, such as nonpeptide
luteinizing hormone-releasing hormone antagonist, lymphocyte specific kinase
inhibitor, N-methyl-D-aspartate antagonist, 5-lipoxygenase inhibitor, hepatitis C
virus NS5B polymerase inhibitor (1), neuropeptide NPY1 receptor antagonist (2),
nonpeptide thrombin inhibitor, and c-aminobutyric acid (GABA) receptor. The ben-
zimidazole derivatives also exhibit antitumor, antimicrobial, antihypertensive, antiul-
[1]
cer, antifungal, and antihistamine activity. The high profile of biological applications
of the benzimidazole compounds has prompted extensive studies of their syntheses.
In this context, numerous efforts have been made to synthesize benzimidazole
derivatives. One of the most common methods for the preparation of benzimidazole
derivatives involves the condensation of an arylenediamine and carbonyl compounds
such as aldehydes and acid derivatives. The condensation of ortho-phenylene diamine
with carboxylic acid (derivatives) often requires strong acidic conditions and high
[2]
temperatures. The other method involves the oxidative cyclodehydrogenation of
Schiff bases, which are generated from ortho-phenylenediamine and aldehyde in the
presence of various catalysts. This is the most popular approach in general for the
synthesis of benzimidazole derivatives. The catalysts are ceric ammonium nitrate
(
(
CAN), K PO , oxone, sulfamic acid, 2,3-dichloro-5,6-dicyanobenzoquinone
3 4
[3]
DDQ), PhI(OAc) , iodine, and KHSO . In addition, several catalysts such as metal
2
4
[4]
halides and metal oxychlorides, metal oxides, p-toluenesulfonic acid (PTSA), metal
Received September 17, 2009.
Address correspondence to A. Venkat Narsaiah, Organic Chemistry Division, Indian Institute of
Chemical Technology, Hyderabad 500 007, India. E-mail: vnakkirala2001@yahoo.com
2
62

SYNTHESIS OF BENZIMIDAZOLES
263
Figure 1.
[
5]
triflates,
(
ionic liquid, heteropoly acid, (bromodimethyl)-sulfonium bromide
[7]
BDSB), proline, solid-supported catalysts, and polymer-supported catalysts
[
6]
[8]
and microwave-promoted reactions have been reported in the literature. Unfortu-
nately, many of these methods suffer from drawbacks such as drastic reaction
conditions, poor yields, tedious workup procedures, and co-occurrence of several side
reactions. As a consequence, the introduction of an efficient and mild method is still
needed to overcome these limitations.
RESULTS AND DISCUSSION
As part of our on going program in developing new synthetic methodologies,
herein we report a simple and efficient protocol for the synthesis of benzimidazoles.
In a preliminary study, we have examined the reaction of 1,2-phenylenediamine or
ortho-phenylenediamine 1 and benzaldehyde 2 in the presence of samarium triflate
to optimize the reaction conditions. The ideal reaction condition can be claimed
as the use of ortho-phenylenediamine and aldehydes in 1:1.1 molar ratios, 10 mol%
catalyst, and the solvent acetonitrile at room temperature.
As per these ideal reaction conditions, the ortho-phenylenediamine and benzal-
dehyde reaction was completed within 4.0 h to give the corresponding product of
2
-phenylbenzimidazole 3a in excellent yield, as shown in Scheme 1. Encouraged by
the result obtained with benzaldehyde and ortho-phenylenediamine, the method
was applied for various aldehydes to establish the generality of the protocol. As
shown in the Table 1, aromatic, heteroaromatic, a,b-unsaturated aldehyde, and ali-
phatic aldehydes were reacted to afford the corresponding products of benzimida-
zole derivatives in very good to excellent yields. In general, the aromatic aldehydes
with electron-donating groups and heteroaromatic compounds reacted a little faster
when compared with other aldehydes. In a similar manner, the aliphatic aldehydes
and aromatic aldehydes containing electron-withdrawing groups are reacted com-
paratively slower in terms of conversion as well as had lesser yields.
Scheme 1.

264
A. V. NARSAIAH, A. R. REDDY, AND J. S. YADAV
Table 1. Samarium triflate–catalyzed synthesis of benzimidazoles
No.
a
Aldehyde
Product (3a–3o)
Reaction time (h)
Yield (%)
4.0
5.0
90
88
b
c
4.0
6.0
92
86
d
e
f
5.0
5.0
5.0
90
88
85
g
h
4.0
95
i
4.0
5.0
6.0
6.0
90
86
85
87
j
k
l
m
n
6.0
4.0
86
85
o
p
5.0
5.0
89
85

SYNTHESIS OF BENZIMIDAZOLES
265
Table 2. Comparative study of the solvent systems
No.
Solvent
Reaction time (h)
Yield (%)
1
2
3
4
5
6
DCM
DMF
10.0
6.0
5.0
6.0
8.0
4.0
80
84
86
83
79
90
MeOH
Dioxane
THF
3
CH CN
As shown in Table 2, a comparative study for the reaction of ortho-phenylen-
ediamine and benzaldehyde was carried out with different solvents using the same
reaction conditions. The results clearly show that among the organic solvents tested
for this condensation reaction, such as dichloromethane, dimethylformamide
(DMF), methanol, dioxane, tetrohydrofuran (THF), and acetonitrile, better conver-
sion and easy isolation of products were found with acetonitrile. In a similar manner,
the reaction with ortho-phenylenediamine and benzaldehyde was carried out without
any solvents. The observation shows that the reaction was not going to completion
(80%) even after stirring for a period of 12 h, and the reaction mixture showed a
number of spots in thin-layer chromatography (TLC).
In a similar manner, a comparative study on the role and requirement of
the catalyst for this condensation reaction has been carried out, and the obtained
results are clearly shown in Table 3. The reactants for this reaction are also
ortho-phenylenediamine and benzaldehyde in acetonitrile. From our observation,
a catalytic amount (10 mol%) of samarium triflate is enough to complete conver-
sion of the aldehyde and ortho-phenylene diamine into the required condensation
product.
A blank experiment was carried out with ortho-phenylenediamine and
benzaldehyde in the absence of the catalyst samarium triflate, and the required
benzimidazole product was not found even after stirring for 15 h. Finally, it
was decided that the suitable conditions for this condensation is in a solvent
and in the presence of an activator or promoter. In general, all the reactions were
completed within 4.0 to 6.0 h, and the obtained yields were 85% to 95%. All the
1
products were characterized by their H NMR, infrared (IR), and mass spec-
troscopy data.
Table 3. Comparative study of the catalyst
No.
Amount of catalyst [Sm(OTf)
3
] (eq)
Reaction time (h)
1
2
3
4
5
6
1.0
0.8
0.6
0.4
0.2
0.1
3.0
3.0
3.5
3.5
4.0
4.0

266
A. V. NARSAIAH, A. R. REDDY, AND J. S. YADAV
CONCLUSION
In conclusion, samarium triflate has been employed as a novel and efficient
catalyst for the synthesis of benzimidazoles in good yields from ortho-phenylenedi-
amine and a wide variety of aldehydes. All the reactions were carried out at room
temperature, while using the catalyst samarium triflate in 10 mol%. The reaction
conditions were very mild, and the isolation of products was very easy.
EXPERIMENTAL
General Methods
Melting points were recorded on a Buchi R-535 apparatus and are uncorrected.
IR spectra were recorded on a Perkin-Elmer Fourier transform (FT)–IR 240-c spec-
1
trophotometer using KBr discs. H NMR spectra were recorded on a Gemini-200
spectrometer in CDCl using tetramethylsilane (TMS) as internal standard. Mass
3
spectra were recorded on a Finnigan MAT 1020 mass spectrometer operating at
7
0 eV.
General Procedure
A mixture of ortho-phenylenediamine (2 mmol) and aldehyde (2.2 mmol) in the
presence of samarium triflate (10 mol%) was stirred in acetonitrile (5 ml) at room
temperature. The progress of the reaction was monitored by TLC. After completion
of the reaction as indicated by TLC, the solvent was removed under reduced press-
ure. The residue was dissolved in ethylacetate and washed with water and brine. The
organic layer was dried over Na SO and concentrated under reduced pressure. The
2
4
crude products were purified by column chromatography. All the products were
1
identified by their H NMR, IR, and mass spectroscopy data and compared with
[3a,3e,4a]
literature reports.
ACKNOWLEDGMENT
A. R. R. thanks the Council of Scientific and Industrial Research, New Delhi,
for the fellowships.
REFERENCES
1
. (a) Nakano, H.; Inoue, T.; Kawasaki, N.; Miyataka, H.; Matsumoto, H.; Taguchi, T.;
Inagaki, N.; Nagai, H.; Satoh, T. Synthesis of biologically activities of novel anti-allergic
agents with 5-lipoxygenase inhibiting action. Bioorg. Med. Chem. 2000, 8, 373–380; (b)
Hauel, N. H.; Nar, H.; Priepke, H.; Ries, U.; Stassen, J.; Wienen, W. Structure-based
design of novel potent nonpeptide thrombin inhibitors. J. Med. Chem. 2002, 45, 1757–
1766; (c) He, Y.; Wu, B.; Yang, J.; Robinson, D.; Risen, L.; Ranken, R.; Blyn, L.; Sheng,
S.; Swayze, E. E. 2-Piperidin-4-yl-benzimidazoles with broad spectrum antibacterial activi-
ties. Bioorg. Med. Chem. Lett. 2003, 3253–3256.
. (a) Hisano, T.; Ichikawa, M.; Tsumoto, K.; Tasaki, M. Synthesis of benzoxazoles,
2
benzothiazoles, and benzimidazoles and evalution of their antifungal, insecticidal, and

SYNTHESIS OF BENZIMIDAZOLES
267
herbicidal activities. Chem. Pharm. Bull. 1982, 30, 2996–3004; (b) Kumar, B. V. S.; Vaidya,
S. D.; Kumar, R. V.; Bhirud, S. B.; Mane, R. B. Synthesis and anti-bacterial activity of
some novel 2-(6-fluorochroman-2-yl)-1-alkyl=acyl=aroyl-1H-benzimidazoles. Eur. J. Med.
Chem. 2006, 41, 599–604.
3. (a) Bahrami, K.; Khodaei, M. M.; Naali, F. Mild and highly efficient method for the syn-
thesis of 2-arylbenzimidazoles and 2-arylbenzothiazoles. J. Org. Chem. 2008, 73, 6835–
6
837; (b) Zheng, N.; Anderson, K. W.; Huang, X.; Nguyen, H. N.; Buchwald, S. L. A
palladium-catalyzed regiospecific synthesis of N-arylbenzimidazoles. Angew. Chem. 2007,
6, 7509–7512; (c) Beaulieu, P. L.; Hache, B.; Moon, V. E. A practical oxone-mediated,
4
high-through, solution-phase synthesis of benzimidazoles from 1,2-phenylenediamines
and aldehydes and its application to preparative-scale synthesis. Synthesis. 2003, 1683–
1
692; (d) Eynde, J. J. V.; Delfosse, F.; Lor, P.; Van, Y. H. 2,3-Dichloro-5,6-dicyano-1,4-
benzoquinone, a mild catalyst for the formation of carbon–nitrogen bonds. Tetrahedron.
995, 51, 5813–5818; (e) Du, L. H.; Wang, Y. G. A rapid and efficient synthesis of benzi-
1
midazoles using hypervalent iodine as oxidant. Synthesis 2007, 675–678; (f) 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, 79–82.
. (a) Singh, M. P.; Sasmal, S.; Lu, W.; Chatterjee, M. N. Synthetic utility of catalytic Fe(III)=
Fe(II) redox cycling towards fused heterocycles: A facile access to substituted benzimida-
zoles, bisbenzimidazoles, and imidazopyridine derivatives. Synthesis 2000, 1380–1390; (b)
Wang, X. J.; Zhang, L.; Xu, Y.; Murthy, D. K.; Senanayake, C. S. A practical synthesis
of 2-(N-substituted)-amino-benzimidazoles utilizing CuCl-promoted intramolecular cycli-
zation of N-(2-aminoaryl) thioureas. Tetrahedron Lett. 2004, 45, 7167–7170; (c) Alloum,
A. B.; Bougrin, K.; Soufiaoui, M. Synthese chimioselective des benzimidazoles sur silice
traitee par le chlorure du thionyle. Tetrahedron Lett. 2003, 44, 5935–5937; (d) Yang, D.;
Fu, H.; Hu, L.; Jiang, Y.; Zhao, Y. Copper-catalyzed synthesis of benzimidazoles via cas-
cade reactions of o-haloacetanilide derivatives with amidine hydrochlorides. J. Org. Chem.
4
2
008, 73, 7841–7844.
. (a) Tandon, V. K.; Kumar, M. BF
synthesis of 2-substituted benzimidazoles and 3,1,5-benzoxadiaze pines. Tetrahedron Lett.
004, 45, 4185–4187; (b) Trivedi, R.; De, S. K.; Gibbs, R. A. A convenient one-pot
synthesis of 2-substituted benzimidazoles. J. Mol. Catal. A. 2006, 245, 8–11; (c) Lin, S.;
Yang, L. A simple and efficient procedure for the synthesis of benzimidazoles using air
as the oxidant. Tetrahedron Lett. 2005, 46, 4315–4319.
. (a) Nadaf, R. N.; Siddiqui, S. A.; Daniel, T.; Lahoti, R. J.; Srinivasan, K. V.
Room-temperature ionic liquid–promoted regioselective synthesis of 2-aryl benzimidazoles,
benzoxazoles, and benzthiazoles under ambient conditions. J. Mol. Catal. A. 2004, 214,
5
6
3
Á Et
2
O-promoted one-pot expeditious and convenient
2
155–160; (b) Heravi, M. M.; Sadjadi, S.; Oskooie, H. A.; Shoar, R. H.; Bamoharram, F.
F. Heteropolyacids as heterogeneous and recyclable catalysts for the synthesis of benzimi-
dazoles. Catal. Commun. 2008, 8, 504–507; (c) Das, B.; Holla, H.; Srinivas, Y. Efficient
(bromodimethyl) sulfonium bromide–mediated synthesis of benzimidazoles. Tetrahedron
Lett. 2007, 48, 61–64.
7
8
. (a) Zou, B.; Yuan, Q.; Ma, D. Synthesis of 1,2-disubstituted benzimidazoles by a
Cu-catalyzed cascade aryl amination=condensation process. Angew. Chem. 2007, 46,
2
598–2601; (b) Varala, R.; Nasreen, A.; Enugala, R.; Adapa, S. R. L-Proline catalyzed
selective synthesis of 2-aryl-1-arylmethyl-1H-benzimidazoles. Tetrahedron Lett. 2007, 48,
9–72.
6
. (a) Wu, C. H.; Sun, C. M. Parallel synthesis of amino bis-benzimidazoles by multistep
microwave irradiation. Tetrahedron Lett. 2006, 47, 2601–2604; (b) Wang, Y.; Sarris, K.;
Sauer, D. R.; Djuric, S. W. A simple and efficient one step synthesis of benzoxazoles
and benzimidazoles from carboxylic acids. Tetrahedron Lett. 2006, 47, 4823–4826.