Water extract of onion catalyst: An economical green route for the synthesis of 2-substituted and 1,2-disubstituted benzimidazole derivatives with high selectivity

Article abstract of DOI:10.1002/jhet.4177

An efficient, environmental friendly and substrate controlled method of synthesis of 2-substituted benzimidazole derivatives 3 and 1,2-disubstituted benzimidazole derivatives 4 with high selectivity has been achieved from the reaction of o-phenylenediamine 1 and aldehydes 2 in the presence of water extract of onion and selecting suitable reaction medium. This method is widely applicable for variety of aldehydes such as aromatic/aliphatic/heterocyclic aldehydes and 1,2-diamines to afford 2-substituted benzimidazole derivatives 3 and 1,2-disubstituted benzimidazole derivatives 4 in good to excellent yields (up to 96%). The developed method of water extract of onion catalysis produced 2-substituted benzimidazoles 3 from aromatic aldehydes having electron-withdrawing groups, whereas aromatic aldehydes bearing electron donating groups selectively furnished 1,2-disubstituted benzimidazole 4 derivatives. The process described here has several advantages of cheap, low energy consumption, commercially available starting materials, operational simplicity and nontoxic catalyst. The use of water extract of onion makes this present methodology green and giving a useful contribution to the existing methods available for the preparation of benzimidazole derivatives. In addition, Hammett correlation of substituent constant (σ) vs percentage (%) yield has been established.

Full text of DOI:10.1002/jhet.4177

Water Extract of Onion Catalyst: An Economical Green Route
for the Synthesis of 2-substituted and 1,2-disubstituted
Benzimidazole Derivatives with high selectivity
Kaliyan Prabakaran, Selvaraj Loganathan and Muthu Seenivasa Perumal*
Department of Chemistry, The Gandhigram Rural Institute-Deemed to be University, Gandhigram, Dindigul district,
Tamilnadu-624 302, India. Corresponding author: Ph.: +91-97151 45939. Email: mspchem99@gmail.com
Abstract. An efficient, environmental friendly and substrate withdrawing groups, whereas aromatic aldehydes bearing
controlled method of synthesis of 2-substituted electron donating groups selectively furnished 1,2-
benzimidazole derivatives
3
and 1,2-disubstituted disubstituted benzimidazole 4 derivatives. The process
benzimidazole derivatives 4 with high selectivity has been described here has several advantages of cheap, low energy
achieved from the reaction of o-phenylenediamine 1 and consumption, commercially available starting materials,
aldehydes 2 in the presence of water extract of onion and operational simplicity and nontoxic catalyst. The use of
selecting suitable reaction medium. This method is widely water extract of onion makes this present methodology
applicable
for
variety of aldehydes
such
as green and giving a useful contribution to the existing
aromatic/aliphatic/heterocyclic aldehydes and 1,2-diamines methods available for the preparation of benzimidazole
to afford 2-substituted benzimidazole derivatives 3 and 1,2- derivatives. In addition, Hammett correlation of substituent
disubstituted benzimidazole derivatives 4 in good to constant (σ) versus percentage (%) yield has been
excellent yields (up to 96%). The developed method of water established.
extract of onion catalysis produced 2-substituted
benzimidazoles 3 from aromatic aldehydes having electron-
Keywords: Water Extract of Onion, 2-substituted
benzimidazoles, 1,2-disubstituted benzimidazoles
Selectivity, Green Catalyst, 1,2-Diamines
of aldehydes 2 with 1,2-diamines 1 in the presence of
15
Introduction
14
catalysts such as trifluoroacetic acid, TiCl .SiO ,
4
2
1
6
17
18
19
Bi(OTf) , Bi(NO3)3, TMSCl, ZnO-NPs, L-
3
Benzimidazole is a bicyclic aromatic heterocyclic
compound, consists of fusion of benzene and
20
21
22
24
27
28
proline, Fe(ClO ) , solvent free SiO /ZnCl ,
4
3
2
2
23
1
Fe
CAN,
ZrOCl .nH O/montmorillonite
3
O
4
@SiO
2
@(NH
4
)
6
Mo
7
O
24
,
SDS micelles,
Phospho sulfonic acid,
K10,
imidazole unit. The imidazole core is a common
25
26
Cu(OTf)2,
2
moiety present in a large number of natural products
and pharmacologically active compounds. It is an
important pharmacophore and a privileged structure
2
29
30
31
montmorillonite K-10, NaPTSA, DBSA,
2
in medicinal chemistry. Benzimidazole and their
derivatives have displayed excellent biological
activities such as antihistaminic, antifungal,
3
4
antiulcer, antipyretic, and anesthetic and antiviral
5
6
activities like HIV, influenza, RNA, human
5
7
cytomegalovirus and herpes (HSV-1). In addition,
act as antibacterial agents against gram-negative
8
a-c
9
bacteria, MRSA, topoisomerase inhibitors,
selective neuropeptide YY1 receptor antagonists,
10
factor Xa inhibitor, angiotensin II inhibitors, and 5-
1
1
HT3
(Figure. 1). Therefore the synthesis of
benzimidazole derivatives have received great
attention nowadays. The well-known and exploited
route to benzimidazole 3 involves the direct
condensation of 1,2-diamines 1 with aldehydes 2 or
carboxylic acids in the presence of strong dehydrating
1
2
agent like H SO . Other improved procedures have
2
4
also been subsequently reported which include
Figure 1. Representative biologically active molecules
reductive cyclization reaction of o-nitroaniline with
containing 2-substituted benzimidazole
3
and 1,2-
aldhehyde,
palladium
catalyzed
tandem
1
3
disubstituted benzimidazole 4 moiety.
carbonylation- cyclization reaction and the reaction
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3
2
33
35
38
Alumina-sulfuric acid,
γ-Fe O @SiO
NPs,
limitations is poor selectivity of N-1 substitution,
results in the formation of mixture of 1,2-
disubstituted benzimidazole 4 and 2-substituted
benzimidazole 3. To best of our knowledge, only one
report available for selective synthesis of both 2-
substituted benzimidazole derivatives 3 and 1,2-
disubstituted benzimidazole derivatives 4 with a
2
3
2
34
RuCl (PPh ) ,
Lewis acidic ionic liquids,
2
3 3
3
6
37
CoCl .6H O,
PSFSI/SBA-15,
FeCl -PANI,
3
41
2
2
3
9
40
Sm(OTf)3,
Na S O ,
In(OTf)3,
microwave
2
2
5
4
2
43
irradiation, 1-heptanesulfonic acid sodium salt,
and BF ·OEt . Unluckily, many of these are have
major or minor limitations such as employing
considerable amounts of toxic solvents, drastic
reaction conditions, highly expensive catalyst and
some of the metal based Lewis acid catalyzed
reactions toxic to the environment. One of the major
44
3
2
2
4
particular catalyst (Scheme 1), where (NH ) S O
4
2
2
8
has been employed as additional oxidizing agent for
the synthesis of 2-disubstituted benzimidazoles 3.
Scheme 1. General scheme for the synthesis of benzimidazole derivatives.
Development of environmentally benign and cost
reductive synthesis is one of the important aspects in
organic synthesis. Elimination of harmful solvents
and substances are shown the regards due to
inexpensive, readily available and environmentally
benign. We report herein, chemoselective synthesis
of 2-substituted benzimidazole derivatives 3 and 1,2-
disubstituted benzimidazole derivatives 4 by using
water extract of onion as a green catalyst under mild
conditions.
reaction of o-phenylenediamine (1 equiv) 1 with
aldehyde (2 equiv) 2 in the presence of water extract
o
of onion (3 mL) at 90 C for 12 h in DMF (5 mL)
gave the mixture of 2-substituted 3 benzimidazoles
(67%) and 1,2-disubstituted (28%) 4 benzimidazoles
(Table 1, entry 1). The method of preparation of
required water extract of onion reported earlier from
4
5
our research group .
Primarily, efforts were
undertaken towards chemoselective synthesis of 2-
substituted benzimidazole derivatives 3 (scheme 1;
method A). Accordingly, to achieve the target we
have play around three parameters such as equivalent
of the substrates, polarity of the solvent, and loading
of the catalyst. For optimization study we have
Results and Discussion
In continuation of our previous work for the
4
5-47
development of green synthetic procedure
using
choose
o-phenenylenediamine
1
and
4-
water extract of onion as catalyst, we are very much
interested to develop the cost reductive,
bromobenzaldehyde 2g as the substrates. The results
are summarized in table 1.
chemoselective
synthesis
of
2-substituted
benzimidazole derivatives 3 and 1,2-disubstituted
benzimidazole derivatives 4, we have examined the
2
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Table 1. Optimization of reaction conditions with various solvents and loading of the catalyst for the synthesis of
compound 3
a
Entry
Substrate
equiv.)
Solvent
Cat. (mL)
Temp
Time
(h)
Product (equiv.)
o
(
( C)
b
Yield (%)
1
1
1
1
1
1
1
2g
2
3g
67
53
77
89
93
62
4g
c
1
DMF (5 mL)
EtOH (5 mL)
EtOH (5 mL)
EtOH (5 mL)
EtOH (15 mL)
3
3
90
70
12
12
12
16
18
24
28
24
10
5
d
2
2
3
4
5
6
1
3
70
1
1.5
0.5
0.5
70
1
RT
RT
-
1
EtOH/H O (2:1)
10
2
(
15 mL)
a)
Unless otherwise mentioned, all the reactions were carried out using o-phenylenediamine 1 (1 equiv.), 4-bromo
b)
benzaldehyde 2g (1 equiv.) in various solvent and water extract of onion; The products were characterized by using HR-
MS, IR, H NMR and C NMR spectroscopic techniques and the yields are all isolated products. The reaction was
1
13
c)
carried out using o-phenylenediamine 1 (1 equiv.), 4-bromo benzaldehyde 2g (2 equiv.) in DMF (5 mL) and water extract
o
d)
of onion (3 mL) at 90 C.; The reaction was performed using o-phenylenediamine 1(1 equiv.), 4-bromo benzaldehyde 2g
o
(
2 equiv.) in EtOH (5 mL) and water extract of onion (3 mL) at 70 C.
When the reaction was carried out using o-
phenylenediamine 1 (1 equiv.), an aldehyde 2g (2 equiv.)
in EtOH (5 mL) at 70 C for 12 h in the presence of onion
phenylenediamine 1 (1 equiv.) with 4-bromobenzaldehyde
2g (1 equiv.) in EtOH:H O (2:1; 15 mL) at room
2
o
temperature for 24 h in the presence of onion extract (0.5
mL), gave compounds 3g and 4g in 62% and 10% yields
respectively (Table 1, entry 6).
extract (3 mL) gave compounds 3g and 4g with 53% and
2
4% yields respectively (Table 1, entry 2). The reaction
was repeated under the same condition except substrate
ratio (1:1) to obtain products 3g and 4g with 77% and 10%
yields respectively (Table 1, entry 3). In order improve the
yield of compound 3g, the reaction was carried out using
o-phenylenediamine 1 (1 equiv.) with aldehyde 2g (1
Under the above optimized conditions, we have examined
the scope of the reaction for the construction of various 2-
substituted benzimidazoles 3 by altering the substituted
aldehydes 2 and o-phenylenediamine 1. As shown in Table
2, a wide range of substituted groups of aldehyde gave
excellent yields, which include methoxy, methyl, fluoro,
chloro, bromo, ester, cyano and nitro groups. It is
noteworthy that strong electron withdrawing substituent
containing aldehyde such as ester, cyano and nitro had
high yields (Table 2, entries 8-10). In addition, it should be
noted that good yields were also obtained by using other
aromatic systems containing electron donating substituents
(Table 2, entries 2-3), furfuraldehyde (Table 2, entry 12),
thiazole-2-carboxaldehyde (Table 2, entry 13) and aliphatic
aldehydes (Table 2, entries 14-15). However, aromatic
aldehyde contains strong electron donating hydroxyl group
(Table 2, entry 1) gave only 1,2-disubstituted
o
equiv.) in EtOH (5 mL) at 70 C for 16 h in the presence of
onion extract (1.5 mL) gave the desired products 3g and 4g
with 89% and 5% yields respectively (Table 1, entry 4).
We thought that the dilution as well as loading of the
catalyst may affect the selectivity.
Accordingly, we have examined the reaction of o-
phenylenediamine 1 (1 equiv.) with 4-bromobenzaldehyde
2
g (1 equiv.) in EtOH (15 mL) at room temperature for 18
h in the presence of onion extract (0.5 mL), gave
compound 3g in 93% yield and did not observed any traces
of compound 4g (Table 1, entry 5). An increasing the
polarity of the solvent may interfere in the selectivity,
therefore, we have carried out the reaction of o-
benzimidazole
4a,
not
3
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Table 2. Synthesis of 2-substituted benzimidazole derivatives 3
a
b
c
Entry
R
Time (h)
Products 3/4
Method A Yield (%)
3
4
1
2
3
4
5
6
7
8
9
4-OH-C H4
2a
2b
2c
2d
2e
2f
21
24
24
18
18
18
18
18
18
18
18
18
18
20
18
4a
3b
3c
3d
3e
3f
-
88
6
4-OMe-C H4
80
83
84
86
88
93
94
93
96
84
88
83
72
79
Trace
6
4-Me-C H4
Trace
6
C H
-
-
-
-
-
-
-
-
-
-
-
-
6
5-
4-F-C H4
6
4-Cl-C H4
6
4-Br-C H4
2g
2h
2i
3g
3h
3i
6
4-CO Me-C H
2
6
4
4-CN-C H4
6
1
1
1
1
1
1
0
1
2
3
4
5
4-NO -C H
4
2j
3j
2
6
2-NO -C H
4
2k
2l
3k
3l
2
6
2-Furfuryl
2-Thiophenyl
n-Butyl
2m
2n
2o
3m
3n
3o
Cyclohexyl
a)
All the reaction were carried out using o-phenylenediamine 1 (1 equiv.) and aldehyde 2 (1 equiv.), EtOH (15 mL) and
b)
water extract of onion (0.5 mL) at room temperature, appropriate time mentioned in the table. All the products were
characterized by using H NMR, C NMR, HR-MS and IR spectroscopic techniques. The yields are all isolated.
1
13
c)
observed even traces of 2-substituted benzimidazole 3
under similar conditions. Probably, the strong electron
donating hydroxyl group prevent the intramolecular
cyclization results to form diimine intermediate 9 and then
cyclized.
4
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In addition, the scope of the reaction using onion extract
catalyst with 1,2-diamine: aldehyde (1:2) in EtOH: Water
here the catalyst water extract of onion was added after 3 h.
The results are summarized in table 3. Under the same
conditions, to increase the equivalent of aldehyde 2g from
(
2:1) to give 1,2-disubstituted benzimidazoles 4 was
o
evaluated. The above observation (Table 1. Entry 6), we
thought that to increase the equivalent of aldehyde and
polarity of the solvent may prevent the intramolecular
cyclization of imine 6. Accordingly, we have examined the
reaction of 1,2-diamine 1 (1 equiv.) with an aldehyde 2g (2
equiv.) in EtOH (5 mL) in the presence of onion extract (2
mL) at room temperature for 24 h to give 2-substituted 3g
and 1,2-disubstituted 4g benzimidazoles 31% and 66%
yields respectively (Table 3, entry 2) . In order to obtain
2.0 to 2.5 at 70 C gave 3g and 4g 24% and 73% yields
respectively (Table 3, entry 4). We felt that to increase the
solvent polarity, we could able to achieve selectively
compound 4g. Accordingly, the reaction was carried out by
using 1,2-diamine 1 (1 equiv.) with an aldehyde 2g (2.5
equiv.) in EtOH: Water (2:1; 6 mL) in the presence of
onion extract (2 mL) at room temperature for 12 h gave 2-
substituted benzimidazole 3g and 1,2-disubstituted
benzimidazole 4g in 9% and 81% yields (Table 3, entry 5).
good yields, the reaction was carried out similar conditions, Further increase the polarity of the medium would not give
gave 2-substituted benzimidazole 3g and 1,2-disubstituted better yield (Table 3, entries 6-7).
g benzimidazole 22% and 68% yields (Table 3, entry 3),
4
Table 3. Optimization of reaction condition with various solvents and loading of onion extract for the synthesis of
compound 4
.
a
Entry
Substrate
equiv.)
Solvent
Cat.
(mL)
Temp
( C)
Time (h)
Product (equiv.)
Yield (%)
o
b
(
3
g
4g
1
2
1
2
1
2
EtOH (5 mL)
EtOH (5 mL)
0.1
2
RT
RT
12
24
32
31
55
1
1
1
1
2
2
66
68
73
81
c
3
4
5
EtOH (5 mL)
2
2
2
RT
70
24
12
12
22
24
09
2.5 EtOH (5 mL)
2.5 EtOH/H O (2:1; 6 mL)
RT
2
6
1
1
2.5 EtOH/H O (1:2; 6 mL)
2
2
RT
RT
36
12
18
26
43
51
2
7
2.5 H O (6 mL)
2
a)
Unless otherwise mentioned, all the reactions were carried out using o-phenylenediamine 1 (1 equiv.), 4-bromo
b)
benzaldehyde 2g (2.5 or 2 equiv.) in different solvent and water extract of onion at room temperature. The products were
characterized by using Mass, IR, H NMR, C NMR and HPLC spectroscopic techniques and the yields are all isolated
products. The reaction was carried out using o-phenylenediamine 1 (1 equiv.), 4-bromo benzaldehyde 2g (2 equiv.) in
1
13
c)
EtOH (5 mL) stirred at RT for 3 h, then water extract of onion (2 mL) was added and further stirred at same temperature
for
24
h.
Once optimized conditions in hand, we have examined the
scope of the reaction for the construction of various 1,2-
substituted benzimidazoles 4 by altering the substituted
aldehydes 2 and o-phenylenediamines 1. It is noteworthy
that strong electron donating substituted groups of
aldehyde such as hydroxyl, methoxy, methyl, electron
withdrawing fluoro, chloro, bromo and heteroaromatic
systems like 2-furfuryl and 2-thiophenyl groups had high
yields (Table 4, entries 1-3, 5-7 and 11-12). It was
observed that under the same conditions, the strong
5
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electron withdrawing groups such as ester, cyano and nitro
Table 4, entries 8-10) gave exclusively compound 3. This
may be due to the electron withdrawing nitro group
increase the electrophilicity of the imine 6 carbon so that
an intramolecular cyclization happened to form compound
3.
(
Table 4. Synthesis of 1,2-disubstituted benzimidazole 4 derivatives
a
b
c
Entry
R
Time
h)
Products 4/3
Yield (%)
(
Method B
3
4
1
2
3
4
5
6
7
8
9
4-OH-C H4
2a
2b
2c
2d
2e
2f
10
12
12
12
10
10
8
4a
4b
4c
4d
4e
4f
-
92
89
86
83
80
6
4-OMe-C H4
09
6
4-Me-C H4
-
6
C H5
6
-
4-F-C H4
trace
6
4-Cl-C H4
11
18
84
87
96
78
81
-
6
4-Br-C H4
2g
2h
2i
4g
3h
3i
6
4-CO Me-C H
8
2
6
4
4-CN-C H4
8
-
6
1
0
4-NO -C H
4
2j
8
3j
-
2
6
1
1
1
2
2-Furfuryl
2-Thiophenyl
2l
8
8
4h
4i
-
91
80
2m
12
a)
All the reaction were carried out using o-phenylenediamine 1 (1 equiv.) and aldehyde 2 (2.5 equiv.), EtOH/ water (2: 1)
b)
and water extract of onion (2 mL) at room temperature, appropriate time mentioned in the table. All the products were
characterised by using H NMR, C NMR, HR-MS and IR spectroscopic techniques. The yields are all isolated products.
1
13
c)
To further expand the scope of the diamine substrates, we
proceeded smoothly to provide good yields of 2-substituted
benzimidazoles with different ratios of isomers 5 and 5’. In
the case of 4-OMe-C H and benzaldehyde derivatives, the
employed 4-OMe, H and 4-NO benzaldehydes as model
2
substrates and examined different diamines. When the
reaction was carried out using 1,2-diamine 1a and
aldehydes (1 equiv.) (method A) such as 4-OMe-C H 2b,
6
4
1
isomers 5a, 5a’ and 5b, 5b’ were clearly seen in the H
NMR spectrum but could not able to isolate. For example,
6
4
1
-
C H 2d, 4-F-C H 2e, 4-NO -C H 2j, the reaction
compound 5b and 5b’ the H NMR at δ 2.42, 2.44
6
5
6
4
2
6
4
6
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corresponds to methyl and δ 12.74, 12.77 corresponds to
imidazole –NH (Table 5, entries 1-2 see supplementary,
page No. S36-S37).. Whereas, the compound containing
electron withdrawing 4-F-C H4 2e, 4-NO -C H 2j,
equiv) 4-NO -C H 2j, gave only 2-substituted
6 4
2
benzimidazoles 5d. In the case of 4- chlorobenzene-1,2-
diamine 1b with aldehydes (1 equiv. or 2.5 equiv) failed to
give isomeric mixture of 1,2-disubstituted benzimidazoles,
Instead gave only 2-substituted benzimidazole in moderate
to good yields (Table 5, entries 5-7 and 11-13; see
supplementary, page No. S40-S42). In general, electron
withdrawing group present in X or R position gave only 2-
substituted benzimidazoles. This may probably, due to fast
exchange of hydrogen between imidazole nitrogen the
6
2
6
4
derivatives, the isomeric separation were not observed
Table 5, entries 3-4 see supplementary, page No. S38-
(
S39). When we examined the reaction with 4-
methylphenylene-1,2-diamine 1a and aldehydes (2.5
equiv)
such as 4-OMe-C H4 2b, -C H5 2d, in
6
6
Ethanol:water (2:1) system (method B), gave isomeric
1
mixture of 1,2-disubstituted benzimidazoles 5h/5h’ and
isomeric separation of the product could not see in H
5
i/5i’ respectively (Table 5, entries 8-9 see supplementary,
NMR spectrum.
page No. S43-S44). Whereas in the case of aldehyde (2.5
Table 5. Synthesis of 1,2-disubstituted benzimidazole 5/5’ derivatives able Caption.
a
Entry
X
R
R1
Time (h)
Product
/5’
Yield
b
5
(%) 5/5’
1
2
3
4
5
6
7
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Cl (1b)
Cl (1b)
Cl (1b)
Me (1a)
4-OMe
H
(2b)
(2d)
(2e)
(2j)
(2b)
(2d)
(2j)
(2b)
H
18
16
16
16
16
18
24
12
5a/5a’
5b/5b’
5c
81
89
87
93
79
65
73
83
H
4-F
H
4-NO2
4-OMe
H
H
5d
H
5e
H
5f
4-NO2
4-OMe
H
5g
c
8
4-OMe- C H CH -
5h/5h’
6
4
2
c
9
Me (1a)
H
(2d)
C H CH
8
5i/5i’
87
6
5
2
c
1
1
1
1
0
1
2
3
Me (1a)
Cl (1b)
Cl (1b)
Cl (1b)
4-NO2
4-OMe
H
(2j)
(2b)
(2d)
(2j)
H
H
H
H
12
15
12
24
5d
5e
5f
82
73
91
56
c
c
c
4-NO2
5g
a)
Unless otherwise mentioned, all the reaction were carried out using 1,2-diamine 1a/1b (1 equiv.) and aldehyde 2 (1
equiv.), EtOH (15 mL) and water extract of onion (0.5 mL) at room temperature, appropriate time mentioned in the table.
b)
c)
Yields are all isolated yields. All the reaction were carried out using 1,2-diamine 1a /1b (1 equiv.) and aldehyde 2 (2.5
equiv.), EtOH/ water (2: 1; 6 mL) and water extract of onion (2 mL) at room temperature, appropriate time mentioned in
the table.
In order to understand clearly the formation of the products
(Table 2) and 4 (Table 4), the plot were drawn
and 4 as shown in Figure 2. The strong electron donating
substituent 4-OH-C H having σ value -0.37 gave only 1,2-
3
6
4
substituent constant (σ) vs yields of the products (%) of 3
disubstituted benzimidazole 4 with 92% yield. In the same
7
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way the strong electron withdrawing substituent 4-NO2-
decreases. Substituent constant σ directly proportional to
yield of compound 3 and indirectly proportional to
compound 4. At the neutral point substituent constant is 0,
both the product 3 and 4 are formed almost same yield.
C H having σ value 0.78 gave only 2-substituted
6
4
benzimidazole 3 with 96% yield. The figure 2, clearly
shows that the substituent constant σ increases, the yield of
compound 3 also increases and yield of compound 4
Figure 2. Plot of substituent constants Vs yields (%) of the products 3 and 4
Although the effect of reaction conditions to direct the
of onion extract (2 mL) in EtOH: water (2:1; 6 mL) at
subsequent processes to 2-substituted benzimidazole 3 and
room temperature, with TLC monitoring the formation of
1
,2-disubstituted benzimidazole 4 systems respectively
intermediates 6 and 9 respectively, which was separated
and identified by H NMR spectral technique. Based on the
1
remains to be fully clarified, the polarity of the solvent and
equivalent of substrate must play a role in determining the
product distribution.
observations and the similar mechanisms conferred in the
22,33,48
literature
a plausible mechanism for this reaction was
proposed as shown in Figure 3. Initially, the imine
intermediate 6 was formed from the condensation of
aldehyde 2 and o-phenylenediamine 1, facilitated by onion
extract. Then the formed imine 6 contains electron
withdrawing group the electrophilicity of imine attached
carbon (-N=C-) increased. Hence, another amine
nucleophile present in the 1 immediately attacked
electrophilic carbon center in an intramolecular fashion to
form 2-substituted benzimidazole 3. The formed imine
contains electron donating group the electrophilicity of
imine attached carbon (-N=C-) decreased. Therefore,
In order to evaluate the possibility of applying this
methodology in a large scale, we carried out the reaction of
equimolar amounts (10 mmol) of diamine 1 with 4-NO2
benzaldehyde 2j. The 2-substituted benzimidazole 3j was
obtained in similar yield as that of the small scale reaction
(
2 mmol).
To probe the mechanism of the reaction, several control
experiments were performed. The reaction was carried out
with 1 (1 equiv) and 2 (1 equiv) in the presence of water
extract of onion (0.5 mL) in EtOH (15 mL) and the
reaction of 1 (1 equiv) and 2 (2.5 equiv) in the presence
another -NH of the o-phenylenediamine 1 condensed with
2
available aldehyde 2 to form intermediate 9. Further, the
intermediate 9 undergo intramolecular cyclization followed
49
by 1,3-hydride transfer
to form 1,2-disubstituted
benzimidazole 4.
8
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Figure 3. Plausible mechanism
Conclusions
phenylenediamine 1a, 4-chloro-1,2-phenylenediamine 1b
and aldehydes like aromatic/aliphatic/heteroaromatic were
also studied. The intermediates 6 and 9 were also isolated,
characterized and plausible mechanism was discussed. The
high yields of the products, operational simplicity, non-
toxic and high chemoselectivity are the main advantages of
this method. The use of onion extract makes this procedure
is cheap, safe and environmentally benign.
In conclusions, we have demonstrated an efficient and
practical approach for the chemoselective synthesis of 2-
substituted benzimidazole derivatives
disustituted 4 benzimidazole derivatives from 1,2-diamines
and aldehydes 2 in the presence of water extract of onion
3
and 1,2-
1
as green catalyst. The broad substrate scopes of 1,2-
diamines such as 1,2-phenylenediamine 1, 4-methyl-1,2-
9
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Supplementary information
[
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10] Z. Zhao, D. O. Arnaiz, B. Griedel, S. Sakata, J. L.
Dallas, M. Whitlow, L. Trinh, J. Post, A. Liang, M. M.
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The Supplementary information file containing general
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1,2-disubstituted
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compounds 3, 4, 5 and intermediates 6 & 9 (3c-3o ; 4b-4i,
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0, 963.
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a-5i) ; and Copies of NMR spectra.
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We are thankful to the SERB, New Delhi, UGC-BSR New Delhi for
a research grant. K. Prabakaran thank SERB, New Delhi for
financial support. We are also grateful to DST, New Delhi and
UGC, Newdelhi for support under “DST-FIST” and SAP (DRS-II)
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Yu, J. Chang, J. Org. Chem. 2017, 82, 3152. (c) T. H.
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1
1

ARTICLE
Water Extract of Onion Catalyst: An
Economical Green Route for the Synthesis of 2-
substituted and 1,2-disubstituted Benzimidazole
Derivatives with high selectivity
J. Heterocyclic Chem. Year, Volume, Page – Page
Kaliyan Prabakaran, Selvaraj Loganathan and
Muthu Seenivasa Perumal*
1
2
This article is protected by copyright. All rights reserved.