A simple and efficient mechanochemical route for the synthesis of 2-aryl benzothiazoles and substituted benzimidazoles

Article abstract of DOI:10.1039/c4ra07058e

An efficient and versatile mechanochemical route to 2-aryl benzothiazoles and both 2-substituted and 1,2-disubstituted benzimidazole derivatives has been developed via a simple mortar-pestle grinding method. The mechanochemical agitation was found to be sufficient for smooth condensation between a variety of aromatic aldehydes and o-aminothiophenol/o-phenylenediamine followed by cyclization leading to the formation of the corresponding 1,3-benzazoles. The salient features of this new protocol are catalyst-free reaction, cleaner reaction profiles, absence of a work-up step, high yields, and short reaction times.

Full text of DOI:10.1039/c4ra07058e

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A simple and efficient mechanochemical route for
the synthesis of 2-aryl benzothiazoles and
substituted benzimidazoles†
Cite this: RSC Adv., 2014, 4, 39606
a
a
Mainak Banerjee, Amrita Chatterjee, Vikash Kumar,a Zigmee T. Bhutia,a
Received 13th July 2014
Accepted 20th August 2014
*
*
Dipratn G. Khandare,a Mahesh S. Majikb and Biswajit Gopal Royc
DOI: 10.1039/c4ra07058e
www.rsc.org/advances
An efficient and versatile mechanochemical route to 2-aryl benzo- with great success for typical organic reactions2,3 such as aldol
thiazoles and both 2-substituted and 1,2-disubstituted benzimidazole condensation,3a–d Michael additions,3e,f Knoevenagel con-
derivatives has been developed via a simple mortar–pestle grinding densation,3g,h Morita–Baylis–Hillman reactions,3i cross-coupling
method. The mechanochemical agitation was found to be sufficient reactions,3k–o and click reactions.3p,q On the other hand, manual
for smooth condensation between a variety of aromatic aldehydes and grinding with a mortar and pestle is a very useful method at
o-aminothiophenol/o-phenylenediamine followed by cyclization laboratory scale due to simple and hazardless experimental set-
leading to the formation of the corresponding 1,3-benzazoles. The up. This technique is mostly used for condensation reactions4
salient features of this new protocol are catalyst-free reaction, cleaner including Schiff's base formation,4b–e oxime formation4f with
reaction profiles, absence of a work-up step, high yields, and short occasional exceptions.5 Recently, it is found to be equally
reaction times.
effective for the construction of heteroaromatic compounds of
biological interest.6
Benzofused heteroaromatic compounds, in particular benz-
imidazoles and benzothiazoles, are common structural scaffold
of biologically active compounds and natural products.7 These
heterocycles are of regular pharmaceutical interest as they show
a range of pharmacological activities such as antibacterial,
antiulcers, antihypertensives, antivirals, antifungals, antican-
cers, and antihistaminics.8 They are an integral part of various
clinical medicines as well, for example, 2-substituted benz-
imidazole, esomeprazole9 is an anti-ulcerative drug,
1,2-substituted benzimidazole, astemizole is an antihistamine
drug,10 whereas, a benzothiazole derivative, Riluzole (Rilutek)11
is used to treat motor neurone disease (Fig. 1). In addition, they
are important intermediates in various organic reactions12 and
key components of many functional materials.13 Therefore,
their synthesis is a frequently encountered mission for both
organic and medicinal chemists. The traditional methods for
the synthesis of the benzimidazoles14b,c and benzothiazoles14d
1. Introduction
The development of efficient and environmentally friendly
chemical processes for the synthesis of biologically active and
industrially useful molecules constitutes a major challenge for
chemists in organic synthesis. A sustainable and “greener”
method would focus on minimal to no use of solvents, reduc-
tion of other wastes, use of ambient conditions as well as
shortening of reaction time, and developing more facile ways of
product separation and purication. A mechanochemical
process, which typically involves the reactions induced by the
input of mechanical energy such as grinding or ball-milling,
facilitates most of the above mentioned features of sustainable
methods and therefore, such strategies have emerged as
attractive alternative to the traditional solution based synthetic
methods.1 Mechanosynthesis by “ball milling” has been used
involve
condensation
of
o-phenylenediamine/o-amino-
thiophenol with a carboxylic acid or its derivatives under harsh
dehydrating conditions.14 Recently, various alternative routes
have been developed for these heterocycles which include
transition metal catalyzed cyclization of ortho-haloanilides,15
metal catalyzed direct arylation via C–H bond activation,16 solid-
phase supported synthesis17 and many others.18 However,
dehydrative Schiff's base formation followed by oxidative cycli-
zation in one-pot between ortho-functionalized anilines and
aldehydes emerged as the most popular method for these
aDepartment of Chemistry, BITS, Pilani-K. K. Birla Goa Campus, NH 17 B Bypass Road,
Zuarinagar, Goa 403726, India. E-mail: mainak@goa.bits-pilani.ac.in; amrita@goa.
bits-pilani.ac.in; Fax: +91-832-2557-033; Tel: +91-832-2580-347; +91-832-2580-320
bBio-organic Chemistry Laboratory, CSIR-National Institute of Oceanography, Dona-
Paula, Goa 403 004, India
cDepartment of Chemistry, Sikkim University, 6th Mile, Tadong, Gangtok, Sikkim
737102, India
† Electronic supplementary information (ESI) available: Details of synthetic
procedure, spectral data, selected spectra of compounds, IR studies. See DOI:
10.1039/c4ra07058e
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and ground gently with a pestle under neat condition at
ambient temperature. The reaction produced a sticky solid
mass aer 5 min of grinding, which is partly intermediate imine
and partly unreacted starting materials in addition to trace
amount of desired product, as observed by TLC. As some of the
unreacted starting materials were trapped inside the solid mass
further reaction became sluggish under neat condition. Addi-
tion of little amount of solvent into the same reaction mixture
accelerated the rate of formation of the product to a great
extent. We observed that the added solvent could dissolve major
part of the solid intermediates and thereby, releases trapped
starting materials to facilitate their complete conversion to the
desired 2-phenylbenzothiazole (3a). It is well-documented that
liquid assisted grinding oen brings out better results than
“dry” grinding.5b,24 Therefore, we used various common organic
solvents for LAG and the percentage of isolated yields of the
product (3a) was analyzed to nd out the solvent of choice
(Table 1). The grinding was performed up to 30 min and the
progress of the reaction was monitored by TLC aer each 5 min
interval. In this regard, ethanol being relatively less volatile was
found to be most suitable in terms of yield and rate of the
reaction. The reaction goes to completion with slender amount
of ethanol (0.5 mL per 1 mmol of substrate) in just 15 min
(Table 1, entry 6). Whereas, only 46% of product was obtained
by grinding the reaction mixture under neat condition for
30 min; rest was intermediate imine and starting materials
(Table 1, entry 1). Although similar results were obtained with
MeOH as solvent like EtOH (Table 1, entry 5), it was not
considered for other reactions due to its higher toxicity prole.
The progress of the reaction was monitored by IR spectroscopy
(see ESI for details†). The IR spectra of reaction mixture were
recorded at regular interval and compared with the spectra of
Fig.
candidates.
1 Chemical structures of few 1,3-benzazole derived drug
1,3-benzazole derivatives.19–21 It is necessary to mention,
majority of these methods use metal catalysts and/or additional
reagents, and generate acidic and metallic wastes apart from
use of considerable amounts of hazardous organic solvents for
reaction and extraction processes. Therefore, their utility is
limited, especially in industrial applications. In the last few
years, several eco-friendly solution phase synthetic methods
have been developed for both benzothiazoles22 and benzimid-
azoles22,23 by us23a,b and others. In many of these methods, the
organic solvent is replaced by an environmentally benign
solvent and reaction is oen carried out in the presence of a
catalyst such as surfactant. However, an eco-friendly synthesis
can be turned more economical by avoiding use of catalysts,
additional reagents and solvents. In this direction, we report,
herein, development of an efficient mechanochemical route to
2-aryl benzothiazoles and both 2- and 1,2-disubstituted benz-
imidazoles (Scheme 1). The syntheses of benzimidazoles and
benzothiazoles are achieved in high yields by simply grinding of
a mixture of o-aminothiophenol/o-phenylenediamine and the
corresponding aldehydes in an Agate mortar–pestle.
Table 1 Optimization of the reaction condition for 2-substituted
benzothiazoles
We started our work with a focus on optimizing the reaction
conditions. In this direction, we rst examined whether
grinding under neat condition is useful or liquid assisted
grinding (LAG) is more effective by keeping a model reaction
between equimolar mixture of o-aminothiophenol (1a) and
benzaldehyde (2a). The reactants were taken in an Agate mortar
No. of equiv.
of 2a
Added
oxidant
Time
(min)
Yield
of 3a (%)
Entry
Solvent
1
2
3
4
5
6
7
8
Neat
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.1
1.2
1.0
1.0
1.0
—
—
—
—
—
—
—
—
30
30
30
30
30
20
15
15
15
10
15
15
46a
68a
72a
62a
42a
85
88
88
90
85
CH3Cl
EtOAc
CH3CN
H2O
MeOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
9
—
10
11
12
H2O2
(NH)4S2O8
Iodine
82
87
a
Scheme 1 Mechanochemical route to 2-substituted benzothiazoles
Some amount starting materials and imine were also isolated.
and both 2- and 1,2-disubstituted benzimidazoles.
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Table 2 Mechanochemical synthesis of 2-aryl benzothiazoles
pure starting materials and product. It was observed that the
characteristic stretching bands of starting materials like
carbonyl of aromatic aldehyde at 1691 cmÀ1 and amine N–H
bands at 3452 cmÀ1 and 3357 cmÀ1 almost disappeared aer 5
min and a sharp peak at 3388 cmÀ1 (presumably, N–H
stretching band of intermediate imine) appeared in the IR
spectrum due to condensation of benzaldehyde and amine
group of 2-aminothiophenol to form corresponding imine. The
same band signicantly diminished aer another 10 min
indicating conversion of intermediate imine to 2-phenyl-
benzothiazole. In continuation of our efforts towards stan-
dardizing the reaction condition, we also examined that 1 : 1
molar ratio of o-aminothiophenol (1a) and benzaldehyde (2a) is
ideal to achieve high yield of product (3a); excess aldehyde does
not impose any signicant improvement in the nal yield
(Table 1, entries 7 and 8). From the mechanistic point of view we
expected that the reaction will be initiated by spontaneous
formation of a Schiff's base when an aldehyde molecule comes
in contact with o-aminothiophenol with the removal of a water
molecule followed by the nucleophilic attack of sulphur atom to
imine carbon to convert it to corresponding 1,2-dihy-
drobenzothiazole derivative, which will be nally oxidized to the
desired 2-phenylbenzothiazole. Therefore, we used several
nonhazardous, easily available, cheap oxidizing agents to check
their effect in accelerating the aromatization step. However,
added oxidizing agent had hardly any effect in terms of speed of
the reaction and the yield of 2-phenylbenzothiazole (Table 1,
entry 9–11). This suggests that the nal oxidative aromatization
step is predominantly occurred by aerial oxygen23a during
mechanochemical agitation (Fig. 2). Therefore, we carried out
rest of the reactions in minimum volume of ethanol in the
absence of any added oxidizing agent.
Entry
Ar
Time (min)
Product
% Yield of 3a
1
2
3
4
5
6
7
8
Ph
15
10
15
15
15
20
15
15
10
15
60
45
60
40
20
20
20
25
60
60
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
88
80
83
78
81
79
81
85
87
83
82
78
78
83
88
94
88
92
10b
n.d.c
4-NO2C6H4
3-NO2C6H4
4-ClC6H4
3-ClC6H4
2-ClC6H4
4-BrC6H4
3-BrC6H4
4-FC6H4
4-CNC6H4
2-OHC6H4
4-OHC6H4
4-OH, 3-MeOC6H3
4-MeOC6H4
Furan-2-yl
Thiophene-2-yl
Indole-3-yl
Pyridine-4-yl
Cyclohexyl
Butaryl
9
10
11
12
13
14
15
16
17
18
19
20
3s
—
All yields refer to isolated product, characterized by 1H NMR 13C NMR
a
b
and mass. Corresponding imine was isolated as the major product.
c
No desired product was isolated and imine got decomposed during
column chromatography. n.d. is not determined.
found equally suitable for heteroaromatic aldehydes (Table 2,
To test the generality of this method, a series of aromatic and entries 15–18). Even sensitive substrates like furfuraldehyde
heteroaromatic aldehydes was treated with o-aminothiophenol (Table 2, entries 15) produced the desired product in high yield.
under optimal conditions. The mortar–pestle grinding However, the variation in the substituents in the aryl ring did
method25 was found to be excellent in terms of yield, reaction have inuence on the rate of the reaction. Although most of the
time and cleanliness resulting in a variety of 2-substituted reactions were completed within 30 min, presences of strong
benzothiazoles in high yields (Table 2). The products were electron donating groups in the aldehyde residue delayed
1
characterized by H NMR, 13C NMR and mass. The aldehydes complete conversion to some extent (Table 2, entry 12–14). On
with electron donating (Table 2, entries 11–14) as well as with the other hand, aldehydes with strong electron withdrawing
electron withdrawing groups (Table 2, entries 2–10) participated groups reacted faster (Table 2, entries 2, 9, 10, etc.), as per
in the reaction uniformly with no signicant distinction with expectation. However, to our dismay, reaction of aliphatic
regard to the yields of the target products. The method was aldehydes with o-aminothiophenol failed to produce expected
results (Table 2, entries 20 and 21). As a token of demonstration,
we carried out grinding of o-aminothiophenol with cyclo-
hexanecarboxaldehyde and butaraldehyde. Only 10% of desired
product (3s) was isolated aer grinding the mixture up to 1 h,
whereas, no product was isolated in pure form from the other
reaction. Apparently, the imine was formed in due course of
time but the cyclization step was retarded by the poor reactivity
of the aliphatic imine group. Therefore, we restricted our study
to aromatic aldehydes only.
In order to expand the scope of this method we treated
o-phenylenediamine with various aromatic aldehydes in vari-
able molar ratio under similar conditions, which resulted in the
formation of either 2-aryl benzimidazoles or 1,2-disubstituted
benzimidazoles as the major product. We observed that the
Fig. 2 Proposed mechanistic pathway for the formation of 2-phenyl-
benzothiazole via mortar–pestle grinding route.
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Table 3 Mechanochemical synthesis of 2-aryl and 1,2-disubstituted benzimidazoles
% Yield of 2-substituted
% Yield of 1,2-disubstituted
Entry
Ar
Equiv. of ArCHO
Time (min)
benzimidazole (5)a
benzimidazole (6)a
1
2
3
4
5
6
7
8
Ph
Ph
1
2.2
1
2.2
1
2.2
1
2.2
1
2.2
1
2.2
1
2.2
1
30
30
20
30
25
30
20
30
60
60
40
45
25
30
30
30
62 (5a)
06 (5a)
60 (5b)
04 (5b)
58 (5c)
08 (5c)
61 (5d)
06 (5d)
63 (5e)
05 (5e)
66 (5f)
07 (5f)
60 (5g)
04 (5g)
54 (5h)
05 (5h)
18 (6a)
84 (6a)
15 (6b)
85 (6b)
20 (6c)
79 (6c)
16 (6d)
78 (6d)
14 (6e)
82 (6e)
14 (6f)
76 (6f)
16 (6g)
86 (6g)
18 (6h)
84 (6h)
4-NO2C6H4
4-NO2C6H4
4-ClC6H4
4-ClC6H4
4-BrC6H4
4-BrC6H4
2-OHC6H4
2-OHC6H4
4-MeOC6H4
4-MeOC6H4
Thiophene-2-yl
Thiophene-2-yl
Furan-2-yl
Furan-2-yl
9
10
11
12
13
14
15
16
2.2
a
1
All yields refer to isolated product, characterized by melting point H NMR 13C NMR and mass.
selectivity of 2-substituted benzimidazole over 1,2-disubstituted o-aminophenol with either benzaldehyde or 4-nitro-
benzimidazole is mostly dependent on the availability of the benzaldehyde followed by cyclization did not lead to desired
aromatic aldehyde. It was found that portion-wise addition of benzoxazole derivatives. Although imine was formed, further
the aldehyde in the mortar containing o-phenylenediamine in reaction was proved to be difficult. Presumably, the oxygen atom
ethanol with continuous grinding would lead to 2-aryl benz- of o-aminophenol is reluctant to attack newly formed imine
imidazole as the major product with 15–20% of 1,2-disubsti- bond due to its poor nucleophilicity under the mild reaction
tuted benzimidazole. Whereas, addition of
1 equiv. of condition.
o-phenylenediamine and 2.2 equiv. of aromatic aldehydes
mostly led to 1,2-disubstituted benzimidazoles with negligible
amount of 2-substituted benzimidazoles making it a suitable
2. Conclusion
method for the preparation of 1,2-disubstituted benzimidazoles. In conclusion, we have developed an efficient and cost effective
It is worthy to note that 2-substituted benzimidazoles can be mechanochemical route to 2-aryl benzothiazoles and both
easily separated from 1,2-disubstituted benzimidazoles by 2- and 1,2-disubstituted benzimidazoles via a simple mortar–
column chromatography and therefore, the same method is pestle grinding method. A broad range of benzothiazoles and
useful for the syntheses of 2-substituted benzimidazoles as well. benzimidazoles have been synthesized starting from o-amino-
Each reaction was repeated for three times and the yields of thiophenol or o-phenylenediamine and a variety of aromatic
2-substituted and 1,2-disubstituted benzimidazoles were found aldehydes using this method. The operational simplicity, cata-
to be of negligible difference. The course of the reactions follows lyst free condition, cleaner reaction proles, absence of work-up
the same trend like formation of 2-aryl benzothiazoles. step, higher yields, and short reaction times make this protocol
Substituent effect was found to be insignicant in terms of superior to many other existing methods.
yields. However, aldehydes with strong electron withdrawing
groups reacted little faster (Table 3, entry 2) and reactions were
slow for aldehydes with strong electron donating groups
Acknowledgements
(Table 2, entries 9–12). In general, it was observed that benz- M.B. thanks CSIR (India) (project no. 02(0075)/12/EMR-II) for
imidazole formation takes relatively longer time for completion nancial support.
as compared to the time required for benzothiazoles. The slight
difference in reactivity may be attributed to the reduced nucle-
ophilicity of –NH moiety as compared to sulphur atom. We also
Notes and references
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both aromatic aldehyde (1 mmol) and o-aminothiophenol (1
mmol) were taken in an Agate mortar and 0.5 mL of ethanol
was added and the solution was gently ground by a pestle.
The reaction mixture turned to a pasty mass aer 5–10
min of grinding. The grinding was continued for the time
mentioned in Table 2. The progress of the reaction was
monitored by TLC aer each 5 min. In some cases, 0.2 mL
of EtOH was added aer 30 min to facilitate complete
conversion. The crude reaction mixture was directly
subjected to column chromatography (silica gel, 60–120
mesh) and eluted out in pure form by using variable
percentage of EtOAc in petroleum ether.
19 For few selected examples of synthesis of 1,3-benzazoles
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This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 39606–39611 | 39611