Synthesis of 2-arylbenzimidazoles and 2-arylbenzothiazoles in both room temperature and microwave condition catalyzed by hexamethylenetetramine-bromine complex

Article abstract of DOI:10.1016/j.cclet.2011.09.028

One-pot condensation of 2-aminothiophenol or 1,2-phenylenediamine with different aldehydes has been catalyzed by hexamethylenetetramine-bromine (HMTA-Bromine) as new, available and effective catalyst. 2-Arylbenzo-thiazoles and 2-aryl-benzimidazoles have b

Full text of DOI:10.1016/j.cclet.2011.09.028

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 61–64
www.elsevier.com/locate/cclet
Synthesis of 2-arylbenzimidazoles and 2-arylbenzothiazoles
in both room temperature and microwave condition catalyzed by
hexamethylenetetramine–bromine complex
a,
Kaveh Khosravi , Samira Kazemi
b
*
a
Department of Chemistry, Faculty of Science, University of Arak, Arak 38156-8-8349, Iran
b
Tehran Shahid tondgoyan Oil Refinery Company, Tehran, Iran
Received 5 July 2011
Available online 9 November 2011
Abstract
One-pot condensation of 2-aminothiophenol or 1,2-phenylenediamine with different aldehydes has been catalyzed by
hexamethylenetetramine–bromine (HMTA-Bromine) as new, available and effective catalyst. 2-Arylbenzo-thiazoles and 2-
aryl-benzimidazoles have been achieved in excellent yield and good purity.
#
2011 Kaveh Khosravi. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Benzothiazoles; Benzimidazoles; One-pot condensation; 1,2-Phenylenediamine; 2-Aminothiophenol; Hexamethylene-tetramine-
bromine; Microwave condition
2
-Disubstituted benzimidazoles have shown an extensive range of biological activities. They have applied as potent
nonnucleoside inhibitors of HIV-1 reverse transcriptase [1] and specific inhibitors of the NS5B polymerase of the
hepatitis C virus (HCV) [2]. Also, functionalized 2-disubstituted benzimidazoles are known as agonists against g-
butyric acid A receptor (GABA ) [3], moreover, they have shown potent thrombin inhibitory activity [4] and
A
antibacterial activity against Gram-positive bacteria [5].
Benzothiazoles are an important heterocyclic compounds with profound interest to medicinal/industrial chemist as
compounds that exhibit diverse biological properties such as antitumor [6], antimicrobial [7], antiglutamate/
+
2
antiparkinson [8], broad spectrum Ca channel antagonist [9], inhibition of enzymes such as aldose reductase [10],
monoamine oxidase [11], lepoxygenase [12], cyclooxygenase [13], acetylcholine esterase [14], thrombine [15],
+
+
proteases [16], H -K ATPase [17], carbonic anhyrase [18], HCV helicase [19], plant growth regulation [20], and have
industrial applications as antioxidants [21], and vulcanization accelerators [22].
Several methods have been reported for synthesis of 1,2-disubstituted benzimidazoles which include n-alkylation
of 2-substituted benzimidazoles in the presence a strong base [23], N-alkylation of O-nitroanilidines followed by
reductive cyclization [1], cyclocondensation of N-substituted O-aminoanilides [4], reductive cyclization of O-anilides
followed by N-alkylation in the presence of a strong base [1] and condensation of N-substituted phenylenediamines
*
Corresponding author.
E-mail address: khosravi.kaveh@gmail.com (K. Khosravi).
1001-8417/$ – see front matter # 2011 Kaveh Khosravi. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2011.09.028

62
K. Khosravi, S. Kazemi / Chinese Chemical Letters 23 (2012) 61–64
with sodium salt of a-hydroxybenzoylsulphonic acid [5]. In addition, 1,2-disubstituted benzimidazoles can also be
prepared by direct one-pot condensation of O-phenylendimines with aldehydes under the influence of different acid
catalyst. But one of the limitations of these methodologies is that they show poor selectivity because of these methods
produce tow compounds include 2-substituted and 1,2-disubstituted benzinidazoles as a mixture [24]. We wish to
report the synthesis of 2-arylbenzimidazoles as only product by the reaction of O-phenylenediamines and aldehydes in
the presence of hexamethylenetetramine–bromine as a catalyst in room temperature or in microwave condition
(Scheme 1).
On the other hand, while many reports are available for preparation of 2-substituted benzothiazoles [25], the most
popular approaches generally involve one-pot condensation–dehydration of 2-aminothiophenol with carboxylic acids
[
19,26] or condensation with aldehydes under oxidative conditions [27].
Unfortunately, many of these processes suffer limitations, such as drastic reaction conditions, low yields, tedious
workup procedures and co-occurrences of several side reactions. As a consequence the introduction of new methods
and/or further work on technical important to overcome the limitations is still an important experimental challenge.
We wish to report using of hexamethylenetetramine–bromine as a new and effective catalyst for synthesis of different
2
-arylbenzothiazoles (Scheme 2).
Optimization of conditions of reaction for choice the best of amount of catalyst and best solvent for benzaldehyde
was carried out and regard to best yield and time of reactions, 10 mol% of catalyst was choose and MeCN has been
selected as the best solvent. To test generality of this reaction, a series of aromatic aldehydes was subjected in
optimized reaction condition (Table 1).
Benzaldehyde was selected as the references reaction and best conditions (amount of catalyst and solvent) were
studied and the best time reaction and yield were obtained with 10 mol% of catalyst in MeCN as the best solvent.
Several aldehydes were reacted with 2-aminothiophenol and corresponding benzothiazoles have been achieved in
excellent yields (Table 2).
It seems that hexamethylenetetramine–bromine as source of bromine activates the carbonyl group of aldehydes, so,
this activated carbonyl reacts with amino group of the 2-aminothiophenol or of the 1,2-phenylenediamine very faster.
Also, hexamethylenetetramine–bromine as the affective oxidizing agent in finally will result the aromaticity of
products by oxidizing them.
In conclusion, in present work, hexamethylenetetramine–bromine has been used as new, available and inexpensive
reagent for simple synthesis of the 2-arylbenzimidazoles and 2-arylbenzothiazoles in both room temperature and
microwave condition. This simple procedure is an efficient methodology that has advantages such as shorter reaction
times, high yields of products, mild condition, easy work-up and no need for complex purifications. It is clear that
reaction times for microwave condition are very shorter than room temperature condition.
All the chemicals were purchased from Merck Company. Melting points were measured by using the capillary tube
1
13
method with an electro thermal 9200 apparatus. H and C NMR spectra were recorded on a JEOL FX 90Q instrument
at 90 and 22.5 MHz, respectively using Me Si as internal standard in DMSO-d solvent. Melting points were measured
4
6
on a SMPI apparatus. IR spectra were run from KBr disk on a PerkinElmer GX FT-IR spectrometer.
Hexamethylenetetramine–bromine complex has been prepared as reported method [28].
N
N
N
NH2
NH2
HMTA-Bromine 10 mol%
MeCN, rt or MW
Ar
Ar
ArCHO
a-l
N
H
1
Ar
2
a-l
not found
Scheme 1.
NH2
SH
N
S
HMTA-Bromine 10 mol%
MeCN, rt or MW
ArCHO
a-o
Ar
1
3
a-o
Scheme 2.

K. Khosravi, S. Kazemi / Chinese Chemical Letters 23 (2012) 61–64
63
Table 1
Synthesis of different 2arylbenzimidazoles under optimized condition.
a,b
Product
c
Ar
Time (h)
Yield (%)
Mp (8C)
Found
Reported
2
9
9
9
1
9
1
9
0
9
9
0
9
2
2
2
2
2
2
2
2
2
2
2
2
a
b
c
d
e
f
C
6
H
5
4 (0.05)
85 (83)
81 (81)
79 (80)
78(78)
290–292
262–264
222–224
156–158
231–233
248–250
284–286
293–285
286–288
263–265
304–306
202–204
289–290
264–265
223–225
157–158
234–236
250–251
284–286
294–296
285–287
264–266
307–309
203–204
2
2
3
2
3
2
3
2
2
3
2
4-MeC
6
H
4
4.5 (0.06)
4 (0.06)
4-MeOC
2-MeOC
6
H
4
4
6
H
4.5 (0.06)
5.5 (0.06)
6.5 (0.06)
4.5 (0.05)
4.5 (0.06)
4.5 (0.06)
4.5 (0.04)
4.5 (0.05)
4.5 (0.05)
2-HOC
4-FC
4-ClC
4-BrC
2-Furyl
4-Me NC
6
H
4
79 (80)
78 (78)
85 (88)
82 (83)
76 (76)
81 (88)
82 (85)
80 (81)
6 4
H
g
h
i
6 4
H
6 4
H
j
2
6 4
H
k
l
4-NO
3-NO
2
C
C
6
H
H
4
2
6
4
a
The reaction data obtained under microwave irradiation are given in parentheses.
1 13
All the isolated products were characterized on the basis of their physical properties and IR, H NMR and C NMR spectral analysis and by
b
direct comparison with authentic materials.
c
Isolated yield.
Table 2
Synthesis of different 2-arylbenzothiazoles under optimized condition.
a,b
Product
c
Ar
Time (h)
Yield (%)
Mp (8C)
2
8
Found
Reported
3
3
3
3
3
3
3
3
3
3
3
3
a
b
c
d
e
f
C
6
H
5
6 (0.06)
7 (0.08)
7 (0.05)
7 (0.08)
8 (0.08)
8 (0.06)
7 (0.06)
7 (0.06)
6 (0.06)
4.5 (0.05)
5 (0.05)
5 (0.05)
85 (90)
80 (87)
81 (86)
78 (84)
80 (82)
76 (88)
84 (90)
76 (80)
71 (76)
74 (83)
85(90)
112–115
83–85
110–112
85–87
4-MeC
6
H
4
4-MeOC
2-MeOC
6
H
4
122–124
100–102
226–228
206–209
117–119
82–84
120–121
99–102
227–228
205–208
116–117
81–83
6
H
4
4-HOC
2-HOC
6
H
H
4
6
4
g
h
i
4-ClC
2-ClC
6
H
H
4
4
6
2-Furyl
4-CNC
102–103
166–168
229–230
132–135
100–103
165–166
229–230
133–135
j
6
H
4
k
l
4-NO
2-NO
2
C
C
6
H
H
4
2
6
4
79 (88)
a
The reaction data obtained under microwave irradiation are given in parentheses.
1 13
All the isolated products were characterized on the basis of their physical properties and IR, H NMR and C NMR spectral analysis and by
b
direct comparison with authentic materials.
c
Isolated yield.
General procedure for the synthesis 2-arylbenzimidazoles in room temperature. To a solution of 1 mmol of
aldehyde and 1 mmol of 1,2-phenylendiamine in MeCN (5 ml), 0.1 mmol of hexamethylenetetramine–bromine was
added. The mixture was stirred at room temperature for proper time. The Progress of reaction was monitored by TLC.
After completion of the reaction, the reaction mixture was filtrated and then poured onto 50 g of crushed ice and
stirring was continued for few minutes. The solid products were filtered, washed with cold water (2 Â 50 mL) and
recrystallized from ethanol.
General procedure for the synthesis 2-arylbenzimidazoles in microwave irradiation. A mixture of O-
phenylenediamine (0.11 g, 1 mmol) and aldehyde (1 mmol) dissolved in MeCN (10 mL) was added 0.1 mmol
hexamethylenetetramine–bromine was capped and irradiated in a microwave oven (model: Black & Decker, MX30PG
1000 W) for the appropriate time (Table 2). The progress of the reaction was monitored by intermittent rapid cooling
of the mixture to room temperature every 1 min and analyzing by TLC (n-hexane/ethyl acetate, 2:8). After complete

64
K. Khosravi, S. Kazemi / Chinese Chemical Letters 23 (2012) 61–64
conversion of the substrate as indicated by TLC analysis, the reaction mixture was filtrated and then poured onto 50 g
of crushed ice and stirring was continued for few minutes. The solid products were filtered, washed with cold water
(
2 Â 50 mL) and recrystallized from ethanol.
General procedure for the synthesis 2-arylbenzothiazoles in room temperature. To a mixture of 1 mmol of aldehyde
and 1 mmol of 2-aminothiophenol dissolved in 5 ml of MeCN, 0.1 mmol of hexamethylenetetramine–bromine was
added. The mixture was riled at room temperature for proper time. The progress of reaction was monitored by TLC.
After completion of the reaction, the reaction mixture was filtrated and then poured onto 50 g of crushed ice and
stirring was continued for few minutes. The solid products were filtered, washed with cold water (2 Â 50 mL) and
recrystallized from ethanol.
General procedure for the synthesis 2-arylbenzothiazoles in microwave irradiation. A mixture of 2-amino-
thiophenol (0.125 g, 1 mmol) and aldehyde (1 mmol) dissolved in MeCN (10 mL) was added 0.1 mmol of
hexamethylenetetramine–bromine was capped and irradiated in a microwave oven (model: Black & Decker, MX30PG
1
000 W) for the appropriate time (Table 2). The progress of the reaction was monitored by intermittent rapid cooling
of the mixture to r.t. every 1 min and analyzing by TLC (n-hexane/ethyl acetate, 2:8). After complete conversion of the
substrate as indicated by TLC analysis, the reaction mixture was filtrated and then poured onto 50 g of crushed ice and
stirring was continued for few minutes. The solid products were filtered, washed with cold water (2 Â 50 mL) and
recrystallized from ethanol.
1
13
All the products are known compounds which were characterized by their IR, H and C NMR spectral data and
their mps compared with literature reported mps (Tables 1 and 2).
References
[
[
[
[
[
[
[
[
[
1] T. Roth, M.L. Morningstar, P.L. Boyer, et al. J. Med. Chem. 40 (1997) 4199.
2] P.L. Beaulieu, M. Bos, Y. Bousquet, et al. Bioorg. Med. Chem. Lett. 14 (2004) 119.
3] J.L. Falco, M. Pique, M. Gonzalez, et al. Eur. J. Med. Chem. 41 (2006) 985.
4] K. Takkeuchi, J.A. Bastian, D.S. Gifford-Moore, et al. Bioorg. Med. Chem. Lett. 10 (2000) 2347.
5] H. Goker, S. Ozden, S. Yildiz, D.W. Boykin, Eur. J. Med. Chem. 40 (2005) 1062.
6] I.H. Hall, N.J. Peaty, J.R. Henry, et al. Arch. Pharm. 332 (1999) 115.
7] P.J. Palmer, R.B. Trigg, J.V. Warrington, J. Med. Chem. 14 (1971) 248.
8] A. Benazzouz, T. Boraud, P. Dub e´ dat, et al. Eur. J. Pharmacol. 284 (1995) 299.
9] B. Lara, L. Gandia, A. Tores, et al. Eur. J. Pharmacol. 325 (1997) 109.
[10] B.L. Mylari, E.R. Larson, T.A. Beyer, et al. J. Med. Chem. 34 (1991) 108.
[11] G. Sato, T. Chimoto, T. Aoki, et al. J. Toxicol. Sci. 24 (1999) 165.
[12] D.J. Hadjipavlou-Litina, A.A. Geronikaki, Drug Des. Discov. 15 (1997) 199.
[13] R. Paramashivappa, P. Phani Kumar, P.V. Subba Rao, et al. Bioorg. Med. Chem. Lett. 13 (2003) 657.
[14] A.A. Nagel, D.R. Liston, S. Jung, et al. J. Med. Chem. 38 (1995) 1084.
[15] J.H. Matthews, R. Krishnan, M.J. Costanzo, et al. J. Biophys. (1996) 2830.
[16] R.G. Caccese, J.F. DiJoseph, J.S. Scotnicki, et al. Agents Actions 34 (1991) 223.
[17] S.K. Sohn, M.S. Chang, W.S. Choi, et al. Can. J. Physiol. Pharmacol. 77 (1999) 330.
[18] M.F. Surgue, P. Gautheron, C. Schmitt, et al. J. Pharmacol. Exp. Ther. 232 (1985) 534.
[19] C.W. Phoon, P.Y. Ng, A.E. Ting, et al. Bioorg. Med. Chem. Lett. 11 (2001) 1647.
[20] D. Loos, E. Sidoova, V. Sutoris, Molecules 4 (1999) 81 (the references cited therein).
[21] S.K. Ivanov, V.S. Yuritsyn, Neftekhimiya 11 (1971) 99;
S.K. Ivanov, V.S. Yuritsyn, Chem. Abstr. 74 (1971) 124487m.
[22] Monsanto Co. Brit Pat. 1,106,577, 1968.
Chem. Abstr. 68 (1968) 96660t.
[
[
[
[
[
[
23] A.R. Porcari, R.V. Devivar, L.S. Kucera, et al. J. Med. Chem. 41 (1998) 1252.
24] J.G. Smith, I. Ho, Tetrahedron Lett. 12 (1971) 3541.
25] A. Couture, P. Grandclaudon, Heterocycles 22 (1984) 1383.
26] E. Kashiyama, I. Hutchinson, M.S. Chau, et al. J. Med. Chem. 42 (1999) 4172.
27] A. Ben-Alloum, S. Bakkas, M. Soufiaoui, Tetrahedron Lett. 38 (1997) 6395.
28] M.M. Heravi, N. Abdolhosseini, H.A. Oskooie, Tetrahedron Lett. 46 (2005) 8959.