Synthesis of benzimidazoles and benzoxazoles using TiCl3OTf in ethanol at room temperature

Article abstract of DOI:10.1016/j.tetlet.2015.11.092

An efficient and practical procedure for the synthesis of benzimidazoles and benzoxazoles in high yields by the coupling of o-phenylenediamines or o-aminophenol with aldehydes using TiCl₃OTf in ethanol at ambient temperature is described.

Full text of DOI:10.1016/j.tetlet.2015.11.092

Accepted Manuscript
Synthesis of benzimidazoles and benzoxazoles using TiCl OTf in ethanol at
3
room temperature
Javad Azizian, Parviz Torabi, Jalil Noei
PII:
S0040-4039(15)30402-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.11.092
TETL 47032
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
12 June 2015
2 November 2015
28 November 2015
Please cite this article as: Azizian, J., Torabi, P., Noei, J., Synthesis of benzimidazoles and benzoxazoles using
TiCl OTf in ethanol at room temperature, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.
3
2
015.11.092
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Synthesis of benzimidazoles and benzoxazoles using TiCl OTf in ethanol at
3
room temperature
a, *
Javad Azizian , Parviz Torabi , Jalil Noei
a
b, *
a
Department of Chemistry, Faculty of Science, Science and Research Branch, Islamic Azad University, Tehran
1365, Iran
Department of Chemistry, Mahshahr Branch, Islamic Azad University, Mahshahr 63519, Iran
1
b
*
E-mail: noei0655@yahoo.com
Abstract
An efficient and practical procedure for the synthesis of benzimidazoles and benzoxazoles in high yields by the
3
coupling of o-phenylenediamines or o-aminophenol with aldehydes using TiCl OTf in ethanol at ambient
temperature is described.
3
Keywords: Benzimidazoles, benzoxazoles, TiCl OTf, Ethanol, Room temperature
1
. Introduction
The benzimidazole and benzoxazole motif constitutes the core unite of many biologically active compounds,
that are employed in pharmaceutical and medicinal chemistry. Compounds based on these core templates have
been shown to act as antibacterial, antiulcer, antihypertensive, antihistamic, anticancer, antiemetic, antipsychotic
1-5
and anti-inflammatory. A variety of methods have been developed for the preparation of benzimidazoles and
benzoxazoles. Substituted benzimidazole derivatives are generally synthesized from the reaction of o-
6
phenylenediamines or 2-nitroanilines with carboxylic acids or their derivatives (e.g. nitriles, imidates, or
7, 8
orthoesters).
On the other hand, the syntheses of benzimidazoles and benzoxazoles from the direct
condensation-aromatization of o-phenylenediamines or o-aminophenol with aldehydes in the presence of
9
10
, sulfamic acid, FeCl
11
O, ZrCl
12
13
14
15
12
21
catalysts such as NaHSO
3
3
.6H
2
4
,
Sc(OTf)
3
,
Pb(OAC)
4
,
In(OTf)
3 4
, HfCl ,
1
6
17
18
19
20
2 2 3
Heuland natural zeolite, NaYzeolite, AlKT-5, Co(OH) /CoO(II), nano In O ,
iron(III)sulfate-silica,
2
2
2
23
MoO /CeO
3
2
-ZrO
and Fe(HSO
4 3
) ,
have previously been reported. Despite the merits of the proposed
methods for the synthesis of benzimidazoles and benzoxazoles, some of them suffer from drawbacks including
the use of expensive and/or toxic catalyst, long reaction times, and high temperature. Recently, we reported the
use of trichlorotitanium(IV) trifluoromethanesulfonate as a catalyst for synthesis of thioamides and aryl nitriles
2
4, 25
from aldoximes.
Herein, we report a simple, and efficient method for the synthesis of benzimidazoles and
2
OTf in 1ethanol at room temperature (Scheme 1).
6
27
benzoxazoles using TiCl
3

Scheme 1
2
. Results and discussion
Initially, to explore the scope of this method, the reaction of benzaldehyde (1.0 mmol) and o-phenylenediamine
1.0 mmol) was selected as a model, and the role of solvent and catalyst loading were investigated. As shown in
(
Table 1, water and various organic solvents such as dichloromethane, acetonitrile and ethanol were investigated
using 10 mol%. of catalyst and it was found that ethanol was the best solvent for this transformation. Next, the
3
effect of catalyst loading was investigated using different amounts of TiCl OTf in ethanol. The best loading
was found to be 10 mol% (Table 1, entry 4). The reaction was also tested without catalyst, however, the yield
was very low (Table 1, entry 8).
a
Tabel 1: Influence of catalyst loading and solvent on the synthesis of 4a
Amount of catalyst (mol %)
b
Entry
Solvent
CH Cl
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
10
2
2
70
70
70
70
70
70
70
70
20
40
50
84
82
45
55
20
10
CH
3
2
CN
O
10
H
10
C
2
H
5
OH
OH
OH
OH
OH
20
2 5
C H
1
2 5
C H
5
2 5
C H
No catalyst
2 5
C H
a
Reaction conditions: benzaldehyde (1 equiv), o-phenylenediamine (1 equiv).
b
Isolated yields.
In order to demonstrate the generality and usage of the method, we utilised the optimized reaction conditions
to synthesize a series of 2-arylbenzimidazole derivatives. We observed that the reaction of o-phenylenediamine
with arylaldehydes, bearing electron-donating groups such as methoxy, hydroxyl and methyl as well as electron-
withdrawing groups such as nitro, bromo and chloro afforded the corresponding 2-arylbenzimidazoles in 81-
9
0% yield after 50-70 min. (Table 2, entries 4a-4m ). To further develop this method, we used o-aminophenol

instead of o-phenylenediamine to synthesize the corresponding benzoxazoles in moderate to good yields (70-
0% yield after 80-130 min) (Table 2, entries 4n-4t ). Although the detailed mechanism of the reaction is not
clear, a plausible rationalization may be advanced to explain the product formation (Scheme 2). Presumably, the
aryl aldehyde is first activated by TiCl OTf , then o-phenylendiamine/o-aminophenol attack to the activated
9
3
carbonyl group of compound, and the intermediate A and then B are formed. Finally, aromatization of
intermediate B under air produces the corresponding 2-aryl benzimidazole/benzoxazole.
a
Table 2: Synthesis of benzimidazoles and benzoxazoles using TiCl
3
OTf in ethanol at room temperature
Time
Yield
Ref.
Mp(ᵒC)
Entry
Aldehyde
Product
b
(
%)
(
min)
2
2
4a
70
84
289-291
2
2
4
b
55
85
284-286
2
2
4
c
65
50
80
86
230-232
2
8
4
d
294-296
2
9
4
e
65
60
50
65
90
85
90
83
251
2
2
4
f
304-306
30
4g
250
2
2
4
h
222-224

2
2
4
i
65
65
82
87
234-236
2
9
4
j
213
2
2
4
k
65
60
86
82
262-264
2
2
4
l
286-288
1
5
4
m
60
84
80
200-202
2
8
1
4
n
130
100-103
3
4
o
p
q
90
100
80
85
85
90
80
85
148-149
2
8
1
1
4
4
155-156
3
266-268
3
4
r
120
130
133-136
3
1
4
s
83-85
2
8
4
t
120
70
117-118
a
Reaction conditions: aldehydes (1 equiv), o-phenylenediamine /o-aminophenol (1 equiv), Catalyst (10
b
mol%). Isolated yields.

Scheme 2
3
. Conclusion
In summary, we have developed a new and efficient procedure for the synthesis of 2-substituted
benzimidazole and benzoxazole derivatives at room temperature. The mild reaction conditions, operational
simplicity, clean reaction profiles, short reaction times and easy work up, make this method convenient for the
synthesis of 2-substituted benzimidazoles and benzoxazoles .
Acknowledgment
The authors are grateful to the Islamic Azad university, Tehran Science and Research Branch for the partial
support of this work.
References
1.
M.Gaba, M.; Singh, S.; Mohan, C. Eur. J. Med. Chem. 2014, 76, 494.
2
.
Spasov, A. A.; Yozhitsa, I. N.; Bugaeva, L. I.; Anisimova, V. A. Pharm. Chem. J. 1999, 33 (5), 232.
Vyas, V. K.; Ghate, M. Mini-Rev. Med. Chem. 2010, 10 (14), 1366.
3.
4
.
Khokra, S. L.; Choudhary, D. Asian J. Biochem. Pharm. Res. 2011, 3 (1), 476.
Desai, N. C.; Shihory, N. R..; Kotadiya, G. M.; Desai, P. Eur. J. Med. Chem. 2014, 82, 480.
5.

6.
(a) Wright, J. B. Chem. Rev. 1951, 48, 396.; (b) Middleton, R. W.; Wibberley, D. G. J. Heterocycl.
Chem. 1980, 17, 1757.; (c) Hisano, T.; Ichikawa, M.; Tsumoto, K.; Tasaki, M. Chem. Pharm. Bull.
1
982, 30, 2996.;(d) Geratz, J. D.; Stevens, F. M.; Polakoski, K. L.; Parrish. R. F. Arch. Biophys. 1979,
97, 551.
1
7
.
Kin, J.;Kim, J.; Lee, H.; Lee, B. M.; Kim, B. H. Tetrahedron, 2011, 67, 3027.
(a) Czarhy, A.; Wilson, W. D.; Boykin, W. D J. Heterocycl. Chem. 1996, 33, 1393.; (b) Tidwell, R. R.;
Geratz, J. D.; Dann, O.; Volz, J.; Zeh, D.; Loewe, H. J. Med. Chem. 1978, 21, 613.
Auste,S. C.; Kane, J. M.; J. Heterocycl. Chem. 2001, 38, 979.
8.
9
1
1
1
1
.
0. Chakrabarty, M.; Karmakar, S.; Mukherji, A.; Arima, S.; Harigaya, Y. Heterocycles, 2006, 16, 4169.
1. Singh, M. P.; Sasmal, S.; Lu, W.; Chatterjee, M. N. Synthesis 2000, 1380.
2. Zhang, Z. H.;Yin, L.; Wang, Y. M. Catal. Commun. 2007, 8, 1126.
3. (a) Itoh, T.; Nagata, K.; Ishikawa, H.; Ohsawa, A. Heterocycles 2004, 63, 2769.; (b) Nagata, K.; Itoh,
T.; Ohsawa, A. Heterocycles 2003, 61, 93.
1
1
1
1
4. Stephens, F.F.; Bower,J. D. J. Chem. Soc.1949, 2971.
5. Trivedi, R.; De, S. K.; Gibbs, R. A. J. Mol. Cat. A: Chem. 2006, 245, 8.
6. Heravi, M. M.; Tajbakhsh, M.; Ahmadi, A. N.; Mohajerani, B. Monatshefte für Chemie 2006, 137, 175.
7. Mobinikhaledi, A.; Forughifar, N.; Zendehdel, M.; Jabbarpour, M. Synth. React. Inorg. Met.-Org.
Nano-Metal Chem. 2008, 38, 390.
1
1
2
2
2
2
2
2
2
8. Chari, M. A.; Shobha, D.; Zaidi, S. M. J.; Reddy, B. V. S.; Vinu, A. Tetrahedron Lett. 2010, 51, 5195.
9. Chari, M. A.; Shobha, D.; Sasaki, T. Tetrahedron Lett. 2011, 52, 5575.
0. Santra, S.; Majee, A.; Hajra, A. Tetrahedron Lett. 2012, 53, 1974.
1. Paul, S.; Basu, B. Tetrahedron Lett. 2012, 53, 4130.
2. Rathod, S. B.; Lande, M. K.; Arbad, B. R. Bull. Korean Chem. Soc. 2010, 31, 2835.
3. Eshghi, H.; Rahimizadeh, M.; Shiri, A.; Sedaghat, P. Bull. Korean Chem. Soc. 2012, 33, 515.
4. Noei, J.; Khosropour, A. R. Tetrahedron Lett. 2008, 49, 6969.
5. Noei, J.; Khosropour, A. R.; Mirjafari, A. Bull. Korean Chem. Soc. 2012, 33, 2102.
6. TiCl
999, 29, 2747.
7. General procedure: To a stirred solution of o-phenylenediamine or o-aminophenol (1 mmol) and
aldehyde (1 mmol) in ethanol (5 mL) at room temperature was added TiCl OTf (10 mol%). The
3
OTf was prepared according to the literature, see: Iranpoor, N.; Zeynizadeh, B. Synth. Commum.
1
2
3

reaction mixture was stirred at ambient temperature for the specified time (see Table 2), when the
reaction was complete (TLC), the mixture was filtered to separate the catalyst and the filtrate was
concentrated under reduced pressure. Then cold water (10 mL) was added to precipitate the product.
1
This was collected by filtration and recrystllised from ethanol-water. IR and H NMR data of selected
-1
1
compounds are given below. Compound (4a): IR (KBr): ν (cm ) 3426, 3058, 1587, 1318; H NMR
400 MHz, CDCl ) δ 11.60 (br, 1H, NH), 8.21-8.19 (m, 2H), 7.69-7.43 (m, 5H), 7.29-7.20 (m, 2H).
Compound (4b): IR (KBr): ν (cm ) 3501, 3061, 1603, 1279; H NMR (400 MHz, CDCl
(
3
-
1
1
3
) δ 11.15 (br,
-
1
1
3
7
H, NH), 8.20-8.18 (m, 2H), 7.66-7.58 (m, 4H), 7.25-7.21 (m, 2H). Compound (4c): IR (KBr): ν (cm )
1
3
448, 3054, 1589, 1279; H NMR (400 MHz, CDCl ) δ 10.28 (br, 1H, NH), 8.49-8.46 (m, 1H), 7.87-
-
1
1
.33 (m, 7H). Compound (4d): IR (KBr): ν (cm ) 3432, 3054, 1589, 1273; H NMR (400 MHz,
CDCl
IR (KBr): ν (cm ) 3462, 3069, 1618, 1287; H NMR (400 MHz, CDCl
.04 (m, 2H), 7.67-7.63 (m, 2H), 7.32-7.28 (m, 2H), 7.21-7.17 (m, 2H). Compound (4f): IR (KBr): ν
3
) δ 10.6 (br, 1H, NH), 7.95-7.93 (m, 2H), 7.96-7.64 (m, 4H), 7.33-7.31 (m, 2H). Compound (4e):
-
1
1
3
) δ 10.04 (br, 1H, NH), 8.08-
8
-
1
1
(
3
cm ) 3423, 3034, 1611, 1348; H NMR (400 MHz, CDCl ) δ 12.60 (br, 1H, NH), 8.42-8.26 (m, 4H),
-
1
1
7
.67-7.66 (m, 2H), 7.28-7.26 (m, 2H). Compound (4n): IR (KBr): ν (cm ) 3065, 1563, 1480, 1246; H
NMR (400 MHz, CDCl ) δ 8.32-8.27 (m, 2H), 7.78-7.55 (m, 5H), 7.40-7.33 (m, 2H).
3
28. Bachhav, H. M.; Bagat, S. B.; Telvekar, V. N. Tetrahedron Lett. 2011, 52, 5697.
29. Lopez, S. E.; Restrepo, J.; Perez, B.; Ortiz, S.; Salazar, J. Bull. Korean Chem. Soc. 2009, 30, 1628.
30. Goswami, S. V.; Thorat, P. B.; Kadam, V. N.; Bhusare, S. R. J. Chem. Bio. Phy. Sci. 2011, 1, 164.
31. Shelkar, R.; Sarode, S.; Nagarkar, J. Tetrahedron Lett. 2013, 54, 6886.