Xanthan sulfuric acid: An efficient bio-supported and recyclable solid acid catalyst for the synthesis of 2-aryl thiadiazolo benzimidazoles

Article abstract of DOI:10.1002/cjoc.201100137

Xanthan sulfuric acid is an efficient solid acid catalyst for the preparation of 2-aryl benzimidazoles in excellent yields. This method is applicable for the reaction of benzo[c][1,2,5]thiadiazole-4,5-diamine with aldehydes by simple physical grinding at

Full text of DOI:10.1002/cjoc.201100137

FULL PAPER
DOI: 10.1002/cjoc.201100137
Xanthan Sulfuric Acid: An Efficient Bio-supported and Recy-
clable Solid Acid Catalyst for the Synthesis of 2-Aryl
Thiadiazolo Benzimidazoles
Kuarm, B. Suresha
Janardan, B.a
Crooks, Peter A.b
Rajitha, B.*,a
a Department of Chemistry, National Institute of Technology, Warangal, AP, India
b Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little
Rock, AR 72205, U. S. A.
Xanthan sulfuric acid is an efficient solid acid catalyst for the preparation of 2-aryl benzimidazoles in excellent
yields. This method is applicable for the reaction of benzo[c][1,2,5]thiadiazole-4,5-diamine with aldehydes by sim-
ple physical grinding at room temperature. The salient features of the present methodology is cheaper process, easy
synthesis of stable catalyst and the catalyst can be easily recycled without significant loss of activity.
Keywords benzimidazoles, benzo[c][1,2,5]thiadiazole-4,5-diamine, biodegradable, recyclable, xanthan sulfuric
acid (XSA)
Introduction
zation of N-(N-arylbenzimidoyl)-1,4-benzoquinone-
imines.[11] Benzimidazoles have also been prepared on a
solid phase to provide a combinatorial approach.[12]
Various oxidative and catalytic reagents such as sul-
famic acid,[13] I2,[14] DDQ,[15] air,[16] oxone,[17] FeCl3•
6H2O,[18] In(OTf)3,[19] Yb(OTf)3,[20] Sc(OTf)3,[21]
KHSO4,[22] SASPSPE,[23] copper[24] and ionic liquid
were used for the synthesis of benzimidazoles.[25] Some
of these methods have suffered from the drawbacks
such as harsh reaction conditions (i.e., the condensation
of o-aryldiamines and carboxylic acids carried out by
conventional thermal heating, heating under pressure in
solvents, using a stoichiometric or excess amount of
acid, and very high reaction temperatures), use of haz-
ardous reagents, drastic reaction conditions, prolonged
One of the most challenging tasks in modern organic
chemistry is the synthesis of natural products containing
heterocyclic ring. Despite the considerable exploration
to date within this field, there is still a need for further
development of alternative methods for the synthesis of
heterocyclic compounds. The benzimidazole ring is a
crucial pharmacophore in drug discovery. Benzimida-
zole derivatives are unique, potent and broad-spectrum
class of antirhino/enteroviral agents. They exhibit sig-
nificant activities such as antihistaminics, antiparasitics,
antiulcers, antihypertensives, antivirals, antibacterial,
antifungals, anticancers and antitubercular.[1,2] Ben-
zimidazole and its derivatives have been used to act
EGFR, VEGFR-2 and PDGFR kinase inhibitors,[3] se-
lective neuropeptide Y Y 1 receptor antagonists,[4]
H+/K+-ATP enzyme inhibitors,[5] nitroreductase and
aminopeptidase activity in clinically important bacte-
ria.[6] In addition, benzimidazoles are very important
intermediates in organic reactions.[7] Therefore, the
preparation of benzimidazoles has gained considerable
attention in recent years. Despite their importance from
pharmacological, industrial, and synthetic point of
views, comparatively few methods for the preparation
of benzimidazoles have been reported. These include
the condensation of o-aryldiamines and aldehyde in re-
fluxing nitrobenzene,[8] the condensation of o-aryldi-
amines with carboxylic acids or their derivatives in the
presence of strong acids such as polyphosphoric acid[9]
or mineral acids,[10] and thermal or acid promoted cycli-
reaction
time,
tedious
work-up
procedures,
co-occurrence of side reactions, low yields, and expen-
sive reagents/catalysts. Some of the catalysts are de-
stroyed in the work-up procedure and cannot be recov-
ered or reused. Furthermore, the disposal of these acids
leads to environmental pollution. In view of the phar-
maceutical application values of 2-aryl benzimidazoles,
it is worthwhile to search continuously for a better cata-
lyst for the synthesis of 2-aryl benzimidazoles in terms
of operational simplicity, reusability of catalyst, low
cost and greater selectivity.
Xanthan and its derivatives,[26-28] have some unique
properties, which make them attractive alternatives for
conventional organic or inorganic supports for catalytic
applications. Xanthan is the most abundant bacterial
*
E-mail: rajithabhargavi@ymail.com; Tel.: 0091-0870-2459445; Fax: 0091-0870-2459547
Received July 17, 2011; accepted September 25, 2011; published online February 29, 2012.
Chin. J. Chem. 2012, 30, 947—950
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
947

Kuarm et al.
FULL PAPER
1
exopolysaccharide in the world, which is produced
through fermentation and it has been widely studied
during the past decades, as it is a biodegradable material
and a renewable resource. Unlike other gums, it is very
stable under a wide range of temperatures and pH val-
ues. Recently, xanthan sulfuric acid has emerged as a
promising biopolymeric solid support acid catalyst for
acid-catalyzed reactions, such as the synthesis of
α-aminonitriles and 2-amino selenazole-5-carboxy-
lates.[29] Xanthan sulfuric acid can be easily prepared by
the reaction of inexpensive xanthan with chlorosulfonic
acid.
(Table 3, Entry 3l): m.p. 270 ℃; H NMR (CDCl3)
δ: 5.39 (s, 1H), 7.61—8.08 (m, 6H), 9.17 (s, 1H); IR
－
1
(KBr) ν: 1622, 3433 cm ; EIMS (70 eV) m/z: 320
(M＋). Anal. calcd for C16H8N4O2S: C 59.99, H 2.52, N
17.49; found C 59.83, H 2.64, N 17.37.
(Table 3, Entry 3m): m.p. 156 ℃; 1H NMR (CDCl3)
δ: 5.42 (s, 1H), 7.57—8.14 (m, 5H), 9.20 (s, 1H); IR
－
1
(KBr) ν: 1625, 3434 cm ; EIMS (70 eV) m/z: 365
(M＋). Anal. calcd for C16H7N5O4S: C 52.60, H 1.93, N
19.17; found C 51.72, H 1.51, N 20.21.
(Table 3, Entry 3n): m.p. 160 ℃; 1H NMR (CDCl3)
δ: 5.40 (s, 1H), 7.58—8.12 (m, 7H); IR (KBr) ν: 1612,
－
＋
1
3406 cm ; EIMS (70 eV) m/z: 337 (M ). Anal. calcd
for C16H8ClN5S: C 56.89, H 2.39, N 20.73; found C
56.09, H 2.22, N 20.13.
(Table 3, Entry 3o): m.p. 140 ℃; H NMR (CDCl3)
δ: 2.12 (s, 3H), 5.62 (s, 1H), 7.38—7.92 (m, 6H); IR
(KBr) ν: 1653, 3492 cm ; EIMS (70 eV) m/z: 351
(M＋). Anal. calcd for C17H10ClN5S: C 58.04, H 2.86, N
19.91; found C 56.78, H 2.23, N 20.45.
Experimental
1
The progress of the reaction was monitored by TLC.
1H NMR spectra were measured on a Varian Gemini
200-MHz spectrometer using TMS as internal standard.
The C, H, and N analysis of the compound was done on
a Carlo Erba model EA1108. Mass spectra were re-
corded on a Jeol JMS D-300 spectrometer.
－
1
Results and Discussion
Preparation of xanthan sulfuric acid
To a magnetically stirred mixture of xanthan (5.00 g)
in CHCl3 (15 mL), chlorosulfonic acid (1.00 g) was
added dropwise at 0 ℃ during 2 h. After completion of
the addition, the mixture was stirred for 3 h. Then, the
mixture was filtered and washed with methanol (25 mL)
and dried at room temperature to obtain XSA as white
powder (5.30 g). Sulfur content of the samples by con-
ventional elemental analysis, was 0.62 mmol/g for XSA.
The number of H＋ site of xanthan-SO3H determined by
acid-base titration was 0.6 meq/g. This value corre-
sponds to about 92% of the sulfur content, indi-
cating that most of the sulfur species on the sample are
in the form of the sulfonic acid groups.
In continuation of our research work on new re-
agents,[30] we report here the cheaper and recyclable
xanthan sulfuric acid as an efficient mild Lewis acid
catalyst for the preparation of 2-aryl benzimidazoles in
excellent yields (Scheme 1). The plausible mechanism
for the formation of benzimidazole by using xanthan
sulfuric acid is shown as Scheme 2. The reaction was
carried out at room temperature for 2—10 min by sim-
ple physical grinding of benzo[c][1,2,5]thiadiazole-4,5-
diamine with aldehydes in the presence of xanthan sul-
furic acid to give the desired benzimidazoles in excel-
lent yields.
Scheme 1 Synthesis of 2-aryl benzimidazoles with XSA
Procedure for the synthesis of thiadiazolo benzimi-
dazoles
CHO
S
N
N
NH2
NH2
Xanthan sulfuric acid
r.t., 2 min
Mixture of xanthan sulfuric acid (0.1 g), aldehyde
(3.6 mmol) and benzo[c][1,2,5]thiadiazole-4,5-diamine
(3.0 mmol) was taken in a mortar, grinding with a pestle
at room temperature in the presence of air for the ap-
propriate time, as shown in Table 3. After completion of
reaction (progress of the reaction was observed by TLC),
CHCl3 (15 mL) was added. The catalyst (XSA) was
filtered off, solid was washed with CHCl3 (5 mL), com-
bined CHCl3 solution was concentrated in vacuum to
afford the crude product and the crude solid product was
further purified by column chromatography [V(hexane)/
V(ethyl acetate)＝8∶2].
R
2
1
S
N
N
N
R = aryl, chromone, quinoline
R
N
H
3a
3o
To illustrate the need of the xanthan sulfuric acid, an
experiment was conducted in the absence of xanthan
sulfuric acid, and yields obtained were very low, side
products were formed and reactants were not involved
completely in this reaction. Obviously, the xanthan sul-
furic acid is an important component of the reaction.
The efficiency of the xanthan sulfuric acid compared
to various sulfur analog acidic catalysts was also exam-
ined (Table 1). In this study it was found that xanthan
sulfuric acid is a more efficient and superior catalyst
Product characterization data
1
(Table 3, Entry 3a): m.p. 185 ℃; H NMR (CDCl3)
δ: 6.11 (s, 1H), 7.07—7.84 (m, 7H); IR (KBr) ν: 1617,
－
＋
1
3419 cm ; EIMS (70 eV) m/z: 252 (M ). Anal. calcd
for C13H8N4S: C 61.89, H 3. 20, N 22.21; found C 61.83,
H 3.21, N 22.24.
948
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Chin. J. Chem. 2012, 30, 947—950

Xanthan Sulfuric Acid: An Efficient Bio-supported and Recyclable Solid Acid Catalyst
Scheme 2 Proposed mechanism
Table 3 Synthesis of benzimidazoles by XSA
Time/ Yielda/
S
N
Entry Aldehyde
S
N
N
N
min
2
%
OH
O
NH2
NH2
H+
NH2
NH2
3a
3b
3c
3d
3e
3f
Benzaldehyde
96
91
95
90
92
95
83
88
89
87
80
82
+
R
H
R
H
H
4-Hydroxybenzaldehyde
4-Chlorobenzaldehyde
2-Chlorobenzaldehyde
4-Methylbenzaldehyde
4-Methoxybenzaldehyde
2-Nitrobenzaldehyde
4-Nitrobenzaldehyde
Naphthaldehyde
3
2
3
S
N
S
N
N
3
-H2O
N
NH2
N
NH2
OH
3
3g
3h
3i
2
N
H
R
H
R
2
S
N
N
3
S
N
N
H
NH2
-H2
Air
3j
4-Ethoxybenzaldehyde
Furanaldehyde
3
H
N
R
H
3k
3l
2
N
N
H
R
4-oxo-4H-Chromene-3-carbaldehyde
6-Nitro-4-oxo-4H-chromene-3-
carbaldehyde
3
S
N
3m
3n
3o
5
3
3
78
78
75
N
N
R
2-Chloroquinoline-3-carbaldehyde
2-Chloro-6-methylquinoline-3-
carbaldehyde
N
H
a Yields refer to isolated pure products.
Table 1 Effect of catalysts on yield
Table 4 Results of recyclability of the catalysta
Entry
Catalyst
Yielda/%
1
2
3
4
5
Xanthan sulfuric acid
Silica sulfuric acid
p-Toluene sulfonic acid
Sulfuric acid in acetic acid
No catalyst
96
92
85
55
10
Run
1
Cycle
Yieldb/%
0
1
2
3
96
94
88
71
2
3
4
a
a Yields refer to the pure isolated product.
Reaction conditions: Mixture of xanthan sulfuric acid (0.1 g),
aldehyde (3.6 mmol) and benzo[c][1,2,5]thiadiazole-4,5-diamine
(3.0 mmol) was ground at room temperature. b Yields refer to the
pure isolated product.
over other acidic catalysts with respect to reaction time
and yield. It was also observed that the yield was only
10% in the absence of the xanthan sulfuric acid catalyst.
We examined the amount of catalyst in this reaction.
The best results were obtained using 0.1 g of catalyst
(96%). Using lower amounts of catalyst resulted in
lower yields, and in the absence of catalyst the yield of
the product was found to be very low (Table 2).
Conclusions
In conclusion, xanthan sulfuric acid has proved to be
an effective catalyst for the synthesis of benzimidazoles
under solid state conditions. The protocol offers several
advantages such as catalyst reusability, high yields of
product, short reaction time, simple work up procedures
and easy isolation, thus making it a viable alternative to
the existing methods. Further work is in progress to ex-
trapolate the catalytic activity of xanthan sulfuric acid to
other organic transformations
Table 2 Influence of the catalytic amounts of xanthan sulfuric
acid a
Entry Catalyst/g
Time/min
Yieldb/%
Trace
25
1
2
3
4
5
6
None
0.02
0.04
0.08
0.1
20
20
10
10
20
10
52
Acknowledgment
79
One of the authors B.S.K is grateful to Council of
Scientific and Industrial Research (CSIR), New Delhi,
Republic of India for providing financial support in the
form of CSIR-SRF.
96
0.1
96
a Yields refer to the pure isolated product.
The recovered catalyst can be reused at least three
additional times in subsequent reactions without sig-
nificant loss in product yield (Table 4).
References
[1] (a) Zarriumayeh, H.; Zimmerman, D. M.; Cantrell, B. E.; Schober, D.
Chin. J. Chem. 2012, 30, 947—950
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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949

Kuarm et al.
FULL PAPER
A.; Bruns, R. B.; Gackenheimer, S. L.; Ornstein, P. L.; Hipskind, P.
A.; Brittan, T. C.; Gchlert, D. R. Bioorg. Med. Chem. Lett. 1999, 9,
647; (b) Terzioglu, N.; Rijin, R. M. V.; Bakker, R. A.; Desch, I. J.;
Lecurs, R. Bioorg. Med. Chem. Lett. 2004, 14, 5251.
Heterocycles 2006, 68, 967.
[14] Gogoi, P.; Konwar, D. Tetrahedron Lett. 2006, 47, 79.
[15] Lee, K. J.; Janda, K. D. Can. J. Chem. 2001, 79, 1556.
[16] Lin, S.; Yang, L. Tetrahedron Lett. 2005, 46, 4315.
[17] Beaulieu, P. L.; Hache, B.; Von Moos, E. Synthesis 2003, 1683.
[18] Singh, M. P.; Sasmal, S.; Lu, W.; Chatterjee, M. N. Synthesis 2000,
1380.
[19] Trivedi, R.; De, S. K.; Gibbs, R. A. J. Mol. Catal. A: Chem. 2005,
245, 8.
[20] Massimo, C.; Francesco, E.; Francesca, M. Synlett 2004, 1832.
[21] Itoh, T.; Nagata, K.; Ishikawa, H.; Ohsawa, A. Heterocycles 2004,
63, 2769.
[22] Ma, H. Q.; Wang, Y. L.; Wang, J. Y. Heterocycles 2006, 68, 1669.
[23] Nasir, I.; Mohammadzade, N. S.; Niknam, K. Chin. Chem. Lett.
2011, 22, 1151.
[24] Peng, J.; Ye, M.; Zong, C.; Hu, F.; Feng, L.; Wang, X.; Wang, Y.;
Chen, C. J. Org. Chem. 2011, 76, 716.
[25] Ma, H. Q.; Wang, Y. L.; L i, J. P.; Wang, J. Y. Heterocycles 2007, 71,
135.
[26] Sargent, E. V.; Adolph, J.; Clemmons, M. K.; Kirk, G. D.; Pena, B.
M.; Fedoruk, M. J. J. Occup. Med. 1990, 32, 625.
[2] (a) Erhardt, P. W. J. Med. Chem. 1987, 30, 231; (b) Ries, U. J.;
Mihm, G.; Narr, B.; Hasselbach, K. M.; Wittenben, H.; Entzeroth,
M.; Meel, J. C. A. V.; Wienen, W.; Hauel, N. H. J. Med. Chem. 1993,
36, 4040; (c) Mann, J.; Baron, A.; Opoku-Boahen, Y.; Johansson, E.;
Parkinson, G.; Kelland, L. R.; Neidle, S. J. Med. Chem. 2001, 44,
138; (d) Song, X.; Vig, B. S.; Lorenzi, P. L.; Darach, J. C.; Town-
send, L. B.; Amiadon, G. L. J. Med. Chem. 2005, 48, 1274; (e) Ren,
X.; Chen, J.; Le, X. Chin. J. Chem. 2011, 29, 1380; (f) Camacho, J.;
Barazarte, A.; Gamboa, N.; Rodrigues, J.; Rojas, R.; Vaisberg, A.;
Gilman, R.; Charris, O. Bioorg. Med. Chem. 2011, 19, 2023.
[3] Li, Y.; Tan, C.; Gao, C.; Zhang, C.; Luan, X.; Chen, X.; Liu, H.; Ji-
ang, Y. E. Bioorg. Med. Chem. 2011, 19, 4529.
[4] Zarrinmayeh, H.; Zimmerman, D. M.; Cantrell, B. E.; Schober, D.
A.; Bruns, R. F. Bioorg. Med. Chem. Lett. 1999, 9, 647.
[5] Yan, Y.; Liu, Z.; Zhang, J.; Xu, R.; Hu, X.; Liu, G. Bioorg. Med.
Chem. Lett. 2011, 21, 4189.
[6] Cellier, M.; Fabrega, O. J.; Fazackerley, E.; James, A. L.; Orenga, S.;
Perry, J. D.; Salwatura, V. L.; Stanforth, S. P. Bioorg. Med. Chem.
2011, 19, 2903
[27] Handbook of Water-Soluble Gums and Resins, Ed.: Davidson, R. L.,
McGraw-Hill, New York, 1980.
[7] Hasegawa, E.; Yoneoka, A.; Suzuki, K.; Kato, T.; Kitazume, T.;
Yangi, K. Tetrahedron 1999, 55, 12957.
[8] Sun, Q.; Yan, B. Bioorg. Med. Chem. Lett. 1998, 8, 361.
[9] Preston, P. N. In Chemistry of Heterocyclic Compounds, Part 1, Vol.
40, Eds.: Weissberger, A.; Taylor, E. C., Wiley, New York, 1981, p.
6.
[10] Grimmet, M. R. In Comprehensive Hetero cyclic Chemistry, Vol. 5,
Eds.: Kartitzky, A. R.; Ress, C. W., Pergamon, Oxford, 1984, p. 457.
[11] Benincori, T.; Sannicolo, F. J. Heterocycl. Chem. 1998, 25, 1029.
[12] (a) Wu, Z.; Rea, P.; Wickam, G. Tetrahedron Lett. 2000, 41, 9871; (b)
Mazurov, A. Bioorg. Med. Chem. Lett. 2000, 10, 67.
[28] Industrial Gums: Polysaccharides and Their Derivatives, Eds.:
Whistler, R. L.; BeMiller, J. N., Academic Press, New York, 1973.
[29] (a) Shaabani, A.; Maleki, A.; Soudi, M. R.; Mofakham, H. Catal.
Commun. 2009, 10, 945; (b) Suresh Kuarm, B.; Venu Madhav, J.;
Rajitha, B. Lett. Org. Chem.2011, 8, 549
[30] (a) Madhav, J. V.; Reddy, Y. T.; Reddy, P. N.; Nikhil, R. M.; Kuarm,
S.; Crooks, P. A.; Rajitha, B. J. Mol. Catal. A 2009, 304, 85; (b)
Kuarm, B. S; Reddy, Y. T.; Madhav, J. V.; Crooks, P. A.; Rajitha, B.
Bioorg. Med. Chem. Lett. 2011, 21, 524; (c) Madhav, J. V.; Kuarm, B.
S; Rajitha, B. Arkivoc 2008, (xiii), 145; (d) Kuarm, B. S.; Madhav, J.
V.; Rajitha, B.; Reddy, Y. T.; Reddy, P. N.; Crooks, P. A. Synth.
Commun. 2011, 41, 662.
[13] Chakrabarty, M.; Karmakar, S.; Mukherji, A.; Arima, S.; Harigaya, Y.
(Cheng, F.)
950
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