One-pot synthesis of 1-aryl-1 H,3 H-thiazolo[3,4-a[benzimidazoles using magnetite-linked sulfonic acid as catalyst

Article abstract of DOI:10.1080/10426507.2014.906421

A series of 1-aryl-1H,3H-thiazolo[3,4-a]benzimidazole derivatives have been synthesized via the three-component reaction of o-phenylenediamine, aromatic aldehydes, and 2-mercaptoacetic acid, catalyzed by magnetite-linked sulfonic acid. This method has the

Full text of DOI:10.1080/10426507.2014.906421

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Phosphorus, Sulfur, and Silicon and the Related
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One-pot synthesis of 1-aryl-1H,3H-thiazolo[3,4-
a]benzimidazoles using magnetite-linked sulfonic acid
as catalyst
Liqiang Wua & Xiao Wanga
a School of Pharmacy, Xinxiang Medical University, Xinxiang, Henan 453003, P. R China
Accepted author version posted online: 27 Oct 2014.
To cite this article: Liqiang Wu & Xiao Wang (2014): One-pot synthesis of 1-aryl-1H,3H-thiazolo[3,4-a]benzimidazoles
using magnetite-linked sulfonic acid as catalyst, Phosphorus, Sulfur, and Silicon and the Related Elements, DOI:
10.1080/10426507.2014.906421
To link to this article: http://dx.doi.org/10.1080/10426507.2014.906421
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One-pot synthesis of 1-aryl-1H,3H-thiazolo[3,4-a]benzimidazoles using magnetite-linked
sulfonic acid as catalyst
Liqiang Wu and Xiao Wang
School of Pharmacy, Xinxiang Medical University, Xinxiang, Henan 453003, P. R China
Received ; accepted
Address correspondence to Liqiang Wu, School of Pharmacy, Xinxiang Medical University,
Xinxiang, Henan 453003, P. R China. E-mail: wliq1974@sohu.com
Abstract A series of 1-aryl-1H,3H-thiazolo[3,4-a]benzimidazole derivatives have been
synthesized via the three-component reaction of o-phenylenediamine, aromatic aldehydes, and 2-
mercaptoacetic acid, catalyzed by magnetite-linked sulfonic acid. This method has the
advantages of high yield, extensive adaptability, easy operation and environmental friendliness.
Supporting this acid catalyst on magnetite particles offers a simple and non-energy-intensive
method for recovery and reuse of the catalyst by applying an external magnet.
Keywords Thiazolo[3,4-a]benzimidazoles; magnetite-linked sulfonic acid; multi-component
reactions; synthesis
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INTRODUCTION
One of the main challenges in medicinal chemistry is the design and synthesis of
biologically active molecules. Over the past few decades, multi-component reactions (MCRs)
and improvement of the methods for multi-component reactions, because of their flexible and
atom-efficient nature, have become one of the best tools in the synthesis of diverse and complex
compounds as well as small and drug like heterocycles.1 Thiazolo[3,4-a]benzimidazoles are an
important class of bioactive molecules, their use as anti HIV2 and anti cancer agents3 has proved
their vast potentiality both as direct drugs and as drug precursors for several disease
manifestations. The most common procedures for the synthesis of these compounds are three-
component one-pot condensation reaction between o-phenylenediamine, 2-mercaptoacetic acid
and aromatic aldehydes in benzene,2a, 3, 4 toluene2c and ionic liquid5 or using silica-supported
sodium hydrogen sulfate6 as a catalyst. Many of these methods suffer from drawbacks such as
low yields of products,4 the use of toxic organic solvent,2-4 the requirement for an inert
atmosphere,5 and the use of relatively expensive reagents.5 As a result, the development of new
synthetic methods for this purpose remains an attractive goal.
With increasing environmental concerns, the development of efficient and recoverable
heterogeneous catalysts has become an important research field. In this context, nanoparticles as
heterogeneous catalysts have attracted a great deal attention due to their interesting structures
and high catalytic activities.7 Furthermore, nanometer-sized particles are easily dispersible in
solution by forming stable suspensions.8 In spite of these advantages, the tedious recycling of
catalysts by filtration and the inevitable loss of some solid catalyst in the separation process,
especially with air sensitive materials, are some of the drawbacks of the traditional procedures.
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Therefore, there is more interest to introduce more efficient manners for catalyst recovery,
especially from the standpoint of green chemistry. To further address the issues of recyclability
and reusability, magnetic nanoparticles (MNPs) have emerged as excellent supports amenable to
simple magnetic separation.9 Moreover, magnetic nanoparticles can be functionalized easily
through appropriate surface modifications, which are able to load various functionalities.10
As a result of further address to the issues of the synthesis of potentially bioactive heterocyclic
compounds,11 herein we now report a highly efficient procedure for the preparation of 1-aryl-
1H,3H-thiazolo[3,4-a]benzimidazole derivatives via a one-pot, three-component reaction of o-
phenylenediamine, aromatic aldehydes, and 2-mercaptoacetic acid using nano magnetite-linked
sulfonic acid (nanomagnetite-SO3H) as an efficient and reusable catalyst in CH3CN (Scheme 1).
Nanomagnetite-SO3H was easily prepared as described references 12 by the reaction of nano
Fe3O4 with chlorosulfonic acid (Scheme 2).12
< Scheme 1>
< Scheme 2>
RESULTS AND DISCUSSION
Initially a series of experiments were carried out for the one-pot, three-component reaction
to optimize the reaction conditions. A mixture of o-phenylenediamine (1, 1 mmol),
benzaldehyde (2a, 1 mmol) and 2-mercaptoacetic acid (3, 1 mmol) was chosen as a model
reaction. The results are summarized in Table 1. The reaction was first carried out at 80 °C in
CH3CN in the absence and presence of nanomagnetite-SO3H. It was found that only 5% of the
target compound 4a was obtained in the absence of nanomagnetite-SO3H (Table 1, entry 1). We
evaluated the amount of nanomagnetite-SO3H required for this reaction. The results from Table 1
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(entries 3-6) showed that 150 mg nanomagnetite-SO3H/1mmol o-phenylenediamine (150
mg/mmol nanomagnetite-SO3H ) at 80 °C in CH3CN was sufficient to initiate the reaction.
Higher loading of the catalyst had no significant influence on the reaction yield. To find the
optimum reaction temperature, the reaction was carried out with 150 mg/mmol nanomagnetite-
SO3H in CH3CN at room temperature, 40 °C, 60 °C, and 80 °C, resulting in the isolation of 4a in
a trace amount, 51%, 79%, and 97% yields (Table 1, entries 5, 7-9), respectively. Thus, 150
mg/mmol nanomagnetite-SO3H, CH3CN and a reaction temperature at 80 °C were optimal
conditions. In addition, benzene, toluene, DMF, ethanol, methanol, and solvent-free (Table 1,
entries 10-15) were also tested as solvents. In these cases, product 4a was formed in slightly
lower yields, which could be explained that product 4 had a good solubility in CH3CN.
< Table 1>
Under these appropriate reaction conditions, a series of 1-aryl-1H,3H-thiazolo[3,4-a]
benzimidazoles 4 were synthesized. The results are summarized in Table 2. As shown in Table 2,
this protocol can be applied to the aromatic aldehydes with either electron-withdrawing groups
(such as nitro and halide groups) or electron-donating groups (such as methyl and methoxyl
groups). The position of the substituent on the benzene ring has minor effect on the reaction. The
products were characterized by comparison with literature data, all of the products 4 exhibited a
peak at about 1610 cm-1 was observed for C=N stretching in the IR spectrum, two doublet of
doublet at δ = 4.6 ppm for HB-3, and a doublet peak at δ = 4.2 ppm for HA-3.
Apart from the mild conditions of the process and its excellent results, the simplicity of
product isolation and the possibility to recover and recycle the nanomagnetite-SO3H as catalyst
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offer a significant advantage. The ferromagnetic property of nanomagnetite-SO3H made the
isolation and reuse of this catalyst very easy. After completion of the reaction, the catalyst was
recovered from the reaction mixture simply by applying an external magnet (Figure 1). Then, the
recovered catalyst was washed with diethyl ether, and dried at room temperature. The recovered
catalyst could be added to fresh substrates under identical conditions for seven runs without a
noticeable drop in the product yield and its catalytic activity (Figure 1).
< Table 2>
< Figure 1>
The plausible mechanism of the reaction is shown in Scheme 3. It is conceivable that
nanomagnetite-SO3H catalyzes the formation of a carbocation in a reversible reaction with the
aromatic aldehyde. The higher reactivity of the carbocation compared with the carbonyl species
is utilized to facilitate condensation between arylaldehyde 2 and o-phenylenediamine 1 via
intermediate 5, The attack of the 2-mercaptoacetic acid at the C=N of imino derivative affords a
thiazolidinone 6 which cyclizes readily to give 4 with elimination of water.4
< Scheme 3>
To illustrate the efficiency of the proposed method, Table 3 compares some of our results
with some of those reported for relevant reagents in the literature, which demonstrates its
significant superiority. Compared with some of the reported methods in Table 3, the present
method has a short reaction time (1 hour ) and good yield (93%). Although the large amount of
the catalyst needed in the reaction, supporting this acid catalyst on magnetite particles offers a
simple and non-energy- intensive method for recovery and reuse of the catalyst by applying an
external magnet. In the reaction, nanomagnetite-SO3H was easily isolated from the reaction
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mixture by magnetic decantation using an external magnet and reused at least six times without
significant degradation in the activity.
< Table 3>
EXPERIMENTAL
IR spectra were determined on FTS-40 infrared spectrometer. 1H NMR spectra were
determined on Bruker AV-400 spectrometer at room temperature using tetramethylsilane (TMS)
as an internal standard (CDCl3 solution), coupling constants (J) were measured in Hz. Elemental
analysis were performed by a Vario-III elemental analyzer. Melting points were determined on a
XT-4 binocular microscope and were uncorrected.
Synthesis of nanomagnetite-SO3H12
In a two neck round bottom flask, equipped with a constant-pressure dropping funnel and a
gas inlet tube for conducting HCl gas was used. Fe3O4 (2 g) was stirred in a round bottom flask
and neat chlorosulfonic acid added (0.5 mL) dropwise over a period of 5 min at room
temperature. HCl gas immediately evolved from the reaction vessel. After addition, the mixture
was shaken for 30 min and solid material was collected as a brown solid of magnetic sulfonic
acid (nanomagnetite-SO3H) (2.09 g).
General procedure for the preparation of 1-aryl-1H,3H-thiazolo[3,4-a]benzimidazoles
To a mixture of o-phenylenediamine (1 mmol), aromatic aldehydes (1 mmol), 2-
mercaptoacetic acid (1 mmol) and CH3CN (5 mL), nanomagnetite-SO3H (150 mg) was added.
The mixture was stirred at 80 °C for an appropriate time (Table 2). The progress of the reaction
was monitored by TLC. After completion, the catalyst was separated by an external magnet,
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washed with diethyl ether, dried and re-used for a consecutive run under the same reaction
conditions. Evaporation of the solvent of the filtrate under reduced pressure gave a crude
product. The pure products were isolated by crystallization with ethanol. All products were
characterized by comparison of their spectral and physical data with those previously reported.2b,
4 All of the products 4 exhibited a peak at about 1610 cm-1 was observed for C=N stretching in
the IR spectrum, two doublet of doublet at δ = 4.6 ppm for HB-3, and a doublet peak at δ = 4.2
ppm for HA-3.
CONCLUSION
In conclusion, we have developed an efficient and convenient method for the preparation of
1-aryl-1H,3H-thiazolo[3,4-a]benzimidazole derivatives by the three-component reaction of o-
phenylenediamine, aromatic aldehydes, and 2-mercaptoacetic acid catalyzed by nanomagnetite-
SO3H. A variety of substrates can participate in the process with good yields. The used
procedure is a commercially available starting material and suitable for library synthesis and
drug discovery efforts. This method has the advantages of high yield, extensive adaptability, easy
operation, and environmental friendliness. Supporting this acid catalyst on magnetite particles
offers a simple and non-energy-intensive method for recovery and reuse of the catalyst by
applying an external magnet.
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Yoshioka, N.; Kondo, Y.; Takeuchi, T.; Yamashita, H. Green Chem. 2009, 11, 1337-1342;
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OSO3H
OSO3H
Ar
Fe3O4
NH2
NH2
O
S
N
N
+
ArCHO +
OSO3H
SH
HO
CH3CN, 80 oC
1
2
3
4
Scheme 1
OSO3H
+ HCl
OSO3H
O
OH
neat, r.t.
Fe3O4
Fe3O4
+ Cl S OH
O
OH
OH
OSO3H
Scheme 2
NH2
O
NH2
OH
SH
3
O
NH2
NH2
Ar
S
HO
1
Nanomegnetite-SO3H
Ar
H
N
H
Ar
H
Ar
H
N
HO
5
2
O
S
Ar
NH2
N
NH2
Nanomegnetite-SO3H
-H2O
Ar
Ar
S
N
N
N
H
S
HO
O
4
OH
6
Scheme 3
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Figure 1. Recycling experiments for the synthesis of 4a.
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Table 1. Optimization of the reaction conditions for the synthesis 1-phenyl-1H,3H-thiazolo[3,4-
a]- benzimidazole (4a).
Entry
Catalyst (mg)
Solvent
T. /°C Time/ h Yield/ %
1
2
-
CH3CN
80
80
80
80
80
80
25
40
60
80
80
24
10
2
5
10
Fe3O4 (100)
CH3CN
Nanomagnetite-SO3H (50)
Nanomagnetite-SO3H (100)
Nanomagnetite-SO3H (150)
Nanomagnetite-SO3H (200)
Nanomagnetite-SO3H (150)
Nanomagnetite-SO3H (150)
Nanomagnetite-SO3H (150)
Nanomagnetite-SO3H (150)
Nanomagnetite-SO3H (150)
CH3CN
CH3CN
3
62
4
1
88
5
CH3CN
1
97
6
CH3CN
1
97
CH3CN
7
24
12
12
5
trace
51
CH3CN
8
9
CH3CN
benzene
toluene
79
10
11
56
4
69
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Nanomagnetite-SO3H (150)
12
DMF
80
5
5
8
8
48
50
42
36
Nanomagnetite-SO3H (150)
13
Ethanol
reflux
reflux
80
Nanomagnetite-SO3H (150)
14
15
Methanol
neat
Nanomagnetite-SO3H (150)
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Table 2. Preparation of 1-aryl-1H,3H-thiazolo[3,4-a]benzimidazoles.
Entry
Ar
Time/ h Product Yield/
%
Mp/ ºC (lit.)
1
2
C6H5
1
1
1
3
2
3
1
1
2
2
2
1
2
1
2
3
97
96
94
89
90
87
89
94
87
88
90
84
86
93
80
76
133-134 (134-135)4
137-138 (136-138)2b
141-143 (140-142)2b
144-146 (146-148)2b
52-53 (54-55)2b
4a
4b
4c
4d
4e
4f
4-Cl-C6H4
3
4-F-C6H4
4
4-CN-C6H4
4-MeO-C6H4
4-CF3-C6H4
2-F-C6H4
5
6
171-173 (170-172)2b
120-122 (118-121)2b
155-157 (155-157)2b
133-135 (131-134)2b
183-184 (181-183)2b
144-145 (146-148)2b
195-197 (194-196)2b
90-91 (89-90)2b
7
4g
4h
4i
8
3-Br-C6H4
3-MeO-C6H4
2-Me-C6H4
3-Me-C6H4
2,6-Cl2-C6H3
3,4-Cl2-C6H3
2,6-F2-C6H3
2,4-F2-C6H3
9
10
11
12
13
14
15
4j
4k
4l
4m
4n
4o
4p
139-141 (140-142)2b
133-135 (135-137)2b
179-181 (178-180)2b
16 2-Cl-5-NO2-C6H3
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Table 3. Nanomagnetite-SO3H catalyzed synthesis of 4n in comparison with other literatures.
Entr
y
Reagents and conditions
Time/ h Yield/ %
Ref.
1
48
92
2c
Catalyst-free, toluene, reflux
2
Catalyst-free, benzene, reflux
48
1.5
1
52
72
91
93
4
3 Catalyst-free, [BMIM]BF4, N2 atmosphere, 80 °C
5
6
4
5
NaHSO4-SiO2 (200 mg), CH3CN, 75 °C
Nanomagnetite-SO3H (150 mg), CH3CN, 80 °C
1
This work
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