Remarkable influence of substituent in ionic liquid in control of reaction: Simple, efficient and hazardous organic solvent free procedure for the synthesis of 2-aryl benzimidazoles promoted by ionic liquid, [pmim]BF 4

Article abstract of DOI:10.1039/b823543k

A simple and efficient procedure for the synthesis of 2-substituted benzimidazoles has been developed by a one-pot reaction of o-phenylenediamine with aromatic aldehydes in the presence of an ionic liquid, 1-methyl-3- pentylimidazolium tetrafluoroborate,

Full text of DOI:10.1039/b823543k

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Remarkable influence of substituent in ionic liquid in control of reaction:
simple, efficient and hazardous organic solvent free procedure for the
synthesis of 2-aryl benzimidazoles promoted by ionic liquid, [pmim]BF4†
Debasree Saha, Amit Saha and Brindaban C. Ranu*
Received 5th January 2009, Accepted 11th February 2009
First published as an Advance Article on the web 4th March 2009
DOI: 10.1039/b823543k
A simple and efficient procedure for the synthesis of 2-substituted benzimidazoles has been
developed by a one-pot reaction of o-phenylenediamine with aromatic aldehydes in the presence of
an ionic liquid, 1-methyl-3-pentylimidazolium tetrafluoroborate, [pmim]BF4 at room temperature
in open air without any organic solvent. The ionic liquid is recycled. A remarkable influence of the
substituent on the imidazolium unit of the ionic liquid on the outcome of the reaction is observed.
The use of large volumes of volatile hazardous organic
1
Introduction
solvents in industrial processes posed a serious threat to the
environment. Thus, procedures involving alternative benign sol-
vents in reaction, isolation and purification are of high priority
in industry. The room temperature ionic liquids have been the
subject of considerable interest in the context of green chemistry
because of their relatively benign character, very low volatility,
thermal stability, efficiency as a catalyst and promoter and
reusability.7 As a part of our continued activities in this area,8 we
became interested to investigate this condensation reaction using
ionic liquid. From a literature search we found a recent report by
Wang et al.6l describing a reaction of o-phenylenediamine and
aromatic aldehydes using an ionic liquid, [Hbim]BF4 to produce
2-aryl-1-arylmethyl-benzimidazoles (Reaction 1). It was also
reported that their efforts to synthesize 2-aryl benzimidazoles
using this IL failed.6l
The benzimidazoles have received considerable attention in
recent times because of their applications as antiulcers, an-
tihypertensives, antivirals, antifungals, anticancers and anti-
histamines among others.1 In addition, they are important
intermediates in many organic reactions2 and act as ligands
to transition metals for modeling biological systems.3 This has
led to the development of several methods for the synthesis of
benzimidazoles during the last few years. Two protocols are
usually followed. One of them is the coupling of o-phenylenedi-
amines with carboxylic acids or their derivatives4 and the
second route involves condensation of o-phenylenediamine
and aldehydes followed by oxidative cyclo-dehydrogenation.5
However, the second approach has become more popular
probably because of the ease of accessibility of a variety of
substituted aldehydes. The reported procedures for this protocol
involved a wide spectrum of reagents including (bromodimethyl)
sulfonium bromide/MeCN,6a iodobenzene diacetate/1,4-
dioxane,6b H2O2/HCl in MeCN,6c chlorotrimethylsilane/
DMF,6d I2/KI/K2CO3/H2O,6e air/dioxane,6f ytterbium triflate
in neat,6g p-TsOH/DMF,6h Na2S2O5 in neat under microwave
irradiation,6i [(NH4)H2PW12O14] in dichloroethane,6j H2O2/
CAN,6k [Hbim]BF4,6l proline,6m p-TsOH/graphite,6n sodium
hydrogen sulfite,6o p-TsOH/silica gel6p and ytterbium(III)
perfluorooctanesulfonate.6q Although these methods are quite
satisfactory, many of them employed considerable amounts of
hazardous organic solvents either for carrying out the reactions
or for extraction and purifications (column chromatography)
or for both, which are not environmentally friendly. Moreover,
several of these reactions were carried out at higher temperatures
and using costly reagents.
Very interestingly, we discovered that a change of substituent,
specifically a replacement of N-H by N-alkyl on the imida-
zolium unit of the ionic liquid, dramatically influences the course
of the reaction. The same condensation of o-phenylenediamine
and aromatic aldehydes when mediated by the ionic liquid, 1-
methyl-3-pentylimidazolium tetrafluoroborate [pmim]BF4 un-
der organic solvent-free conditions produced exclusively 2-aryl
benzimidazoles (Scheme 1) in contrast to 2-aryl-1-arylmethyl-
benzimidazole as reported by Wang et al.6l using [Hbim]BF4 and
the results are reported here.
Department of Organic Chemistry, Indian Association for the Cultivation
of Science, Jadavpur, Kolkata, 700 032, India. E-mail: ocbcr@iacs.res.in
2
Results and discussion
1
† Electronic supplementary information (ESI) available: Copies of H
NMR, 13C NMR and HRMS spectra of all the products listed in Table 2,
copies of 1H NMR spectra of ionic liquid, [pmim]BF4 of the fresh and
recovered (after reaction) samples and copies of 1H NMR and HRMS
spectra of compounds obtained as products listed in entries 8 and 10,
Table 3. See DOI: 10.1039/b823543k
The experimental procedure is very simple. A mixture of o-
phenylenediamine and an aromatic aldehyde was stirred at
room temperature in air in the presence of an ionic liquid,
[pmim]BF4 for the required period of time (TLC). The solid
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Scheme 1 Synthesis of 2-aryl benzimidazole.
Table 1 Standardisation of reaction conditions
Table 2 Synthesis of benzimidazoles
Entry Ar
Yielda (%)
Time/h Yielda (%) Mp/◦C (Lit M.P.) Ref.
Entry
IL
Temp./◦C
1
5
6
85
88
288 (289–291)
242 (243–244)
6b
1
2
3
4
[pmim]BF4
[pmim]BF4
[bmim]BF4
[pmim]Br
80
25
25
25
85
92
82
88
2
9
a Yields refer to those of purified isolated products characterized by
spectroscopic data (IR, 1H NMR and 13C NMR).
3
6
4
4
7
90
92
92
80
264 (264–266)
298 (299–300)
290 (292–294)
250 (250–251)
6b
6b
6b
6b
4
product was isolated by filtration and purified by crystallization
from ethanol. The ionic liquid, [pmim]BF4 was found to give
best results at room temperature (25 ◦C) in comparison to
other imidazolium based ionic liquids such as [pmim]Br and
[bmim]BF4 as illustrated in Table 1.
5b
6
The remaining ionic liquid, [pmim]BF4 after isolation of
product, was recycled for the first two subsequent reactions
without any significant loss of efficiency, while the next two
reactions showed some loss of efficiency in terms of yields of
products (Fig. 1). To find out any change of the recovered ionic
liquid from the fresh one the 1H NMR of the two samples
were checked. Both were found to be basically same except two
additional spikes in the region of 2–4 ppm in the spectrum of the
recovered one, probably due to contamination of trace impurities
from the reaction.
7
8
5
4
90
94
207 (209)
328 (327)
10
10
9
6
5
6
7
7
88
92
80
82
90
224 (224–226)
276–277 (277)
270 (272–274)
261–263
6b
6e
11
10c
11
12
13
332 (330)
6e
a Yields refer to those of purified isolated products characterized by
spectroscopic data (IR, 1H NMR and 13C NMR). b The reaction when
performed in 10 mmol scale under identical reaction conditions, the
corresponding product was formed in 88% yield. c The reaction when
performed in 10 mmol scale under identical reaction conditions, the
corresponding product was formed in 90% yield.
Fig. 1 Recyclability diagram for the reaction of o-phenylenediamine
and p-tolualdehyde.
Several substituted aromatic aldehydes underwent condensa-
tions with o-phenylenediamine by this procedure to produce the
corresponding 2-substituted benzimidazoles. The results were
summarized in Table 2. The aldehydes with electron donating
(entries 9 and 10, Table 2) as well as with electron withdrawing
groups (entries 2–8, Table 2) participated in this reaction
uniformly. Apparently, the nature and position of substitution
on the aryl ring did not make much difference in reactivity
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(entries 2, 3, 4 Table 2). The sensitive molecule like thiophen-
2-aldehyde (entry 13, Table 2) produced the corresponding
benzimidazole without any difficulty. The sterically hindered
9-anthraldehyde (entry 12, Table 2) also underwent reaction by
this procedure. The reactions of sterically hindered aldehydes
were not addressed by many of the existing methods. Signi-
ficantly, when the reaction of 9-anthraldehyde and o-phenyl-
enediamine was carried out using conventional reagents such
as I2/KI/K2CO3/H2O,6e O2/dioxane6f and H2O2/HCl6c no
appreciable product was isolated by us.
The reactions, in general are high yielding. No hazardous
organic solvent was used in this process. In several reactions,
dialdimines were formed in small amounts (2–8%) which were
separated during crystallization. Several functional groups such
as Cl, Br, NO2, OMe and sensitive molecules like thiophene-2-
carboxaldehyde are compatible with the reaction conditions. A
comparison of results of reactions with a few substrates using
ionic liquid, [pmim]BF4 with those reported by Wang et al.6l
using [Hbim]BF4 reveals that minor variations of substituents
in core imidazolium ionic liquid and reaction conditions (room
temperature from 60 ◦C) change the outcome of the reaction
producing 2-aryl benzimidazole I by [pmim]BF4 against 2-
aryl-1-arylmethyl benzimidazole II by [Hbim]BF4 without any
exception. These results are summarized in Table 3. The outcome
of the reaction with one substrate using a mixture of our ionic
liquid, [pmim]BF4 with [Hbim]BF4 (Wang et al.6l) in varying
proportions has also been investigated and the results are
included in entries 11–13, Table 3. Significantly, 1 : 1 and 1 : 3
mixture of these two ionic liquids led exclusively to Wang
et al.’s product, II, while 3 : 1 mixture of the same ionic liquids
produced 22% of our product, I. These results clearly indicate
a general tendency towards formation of 2-aryl-1-arylmethyl
benzimidazole II and our ionic liquid, [pmim]BF4 is powerful
enough to change the usual course of the reaction leading to I.
This dramatic influence of ionic liquid, although very surprising,
is not unprecedented.12
The ionic liquid (75 mol%) works here as catalyst as well as
reaction medium. Presumably, [pmim]BF4 activates the aldehyde
towards nucleophilic attack by o-phenylenediamine forming a
monoaldimine 1 which on cyclization followed by oxidative
dehydrogenation by air6f leads to benzimidazole (Scheme 2).
To check the role of O2 (air) in this process two simultaneous
reactions were run with 4-clorobenzaldehyde in air and in
argon. In the presence of air the intermediate A undergoes
oxidation to provide the product I, while in the presence of
argon condensation of A with another molecule of aldehyde is
facilitated leading to product II (Wang et al.’s compound6l) as
outlined in Scheme 3.
3
Experimental section
General
The ionic liquid, [pmim]Br was prepared following a reported
procedure13a and [pmim]BF4 was then obtained by a metathesis
reaction of [pmim]Br with NaBF4 also following a reported
procedure.13b
General experimental procedure for the synthesis of
2-arylbenzimodazole. Representative procedure for the
condensation of o-phenylenediamine and p-tolualdehyde
(entry 10, Table 2)
A mixture of o-phenylenediamine (108 mg, 1 mmol) and p-tolu-
aldehyde (120 mg, 1 mmol) was stirred at room temperature in
the presence of [pmim]BF4 (178 mg, 0.75 mmol) in air for 5 h
(monitored by TLC). After the reaction was over, H2O (10 mL)
was added and a solid product appeared. This crude product was
collected by filtration and recrystallized from ethanol to afford
Table 3 Comparison of reaction results using [pmim]BF4 and [Hbim]BF4
Entry
Ar
IL
Product ratio (I : II)
Yielda (%)
1b
2c
C6H5
C6H5
[pmim]BF4
[Hbim]BF4
[pmim]BF4
[Hbim]BF4
[pmim]BF4
[Hbim]BF4
[pmim]BF4
[Hbim]BF4
[pmim]BF4
[Hbim]BF4
[pmim]BF4+[Hbim]BF4 (1 : 1)
[pmim]BF4+[Hbim]BF4(1 : 3)
[pmim]BF4+[Hbim]BF4(3 : 1)
100 : 0
0 : 100
100 : 0
0 : 100
100 : 0
0 : 100
100 : 0
0 : 100
100 : 0
0 : 100
0 : 100
0 : 100
22 : 78
85
88
92
80
92
84
92
86
80
82
78
80
75
3b
4-ClC6H4
4-ClC6H4
4-H3CC6H4
4-H3CC6H4
4-BrC6H4
4-BrC6H4
4-FC6H4
4-FC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4c
5b
6c
7b
8d
9b
10d
11e
12e
13e
a Yields refer to those of purified isolated products characterized by spectroscopic data (IR, 1H NMR and 13C NMR). b The reaction where performed
◦
in 25 C for the required time period as mentioned in Table 2 in the text. c The reaction when performed at 60 ◦C for the required time period as
mentioned in ref. 6l. d The reactions were performed at 60 ◦C for 1 h. e The reactions were performed at 60 ◦C for 4 h.
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Scheme 2 Plausible mechanism.
Scheme 3 Comparison of plausible reaction pathway in air to that in argon atmosphere.
pure 2-tolylbenzimidazole (192 mg, 92%), mp 276–277 ◦C (mp
277 ◦C6e). The spectroscopic data (1H and 13C NMR) are in good
agreement with those reported for the authentic sample.6e The
ionic liquid, left in the reaction vessel was dried under vacuum
and was reused for subsequent reactions.
4
Conclusion
In conclusion, the present procedure using an easily available
ionic liquid, [pmim]BF4 provides a very simple and efficient
13
methodology for the synthesis of 2-aryl benzimidazoles by
condensation of o-phenylenediamine and aromatic aldehydes.
Besides mild reaction conditions (room temperature), low energy
consumption, high yields, and reusability of ionic liquids, this
procedure uses no hazardous organic solvents in the entire
process including workup and purification. To the best of our
knowledge this is the first report of condensation of aldehydes
and o-phenylenediamine to 2-aryl-benzimidazoles, promoted by
an ionic liquid without any other solvent and catalyst. Most sig-
nificantly, the influence of substituent on the imidazolium unit of
the ionic liquid to dictate the outcome of this reaction to produce
2-arylbenzimidazole exclusively, preventing further condensa-
tion as reported by Wang et al.6l using [Hbim]BF4 is remarkable
and induces further investigation for useful applications.
This procedure was followed for the synthesis of all the
products listed in Table 2. Although the general experimental
procedure was based on 1 mmol scale reaction multimol
reactions also produced similar results (entries 5 and 10,
Table 2). All the products are known compounds except one
(entry 12, Table 2). The known compounds were identified by
comparison of their spectral data with those reported earlier
(see references in Table 2). The new compound, 2-anthracen-
9-yl-1H-benzimidazole (entry 12, Table 2), a pale yellow solid,
mp 261–263 ◦C, was characterized by its IR, 1H NMR and 13
C
NMR and HRMS spectroscopic data: IR (KBr): 3435, 3350,
1
2956, 2862, 1612, 1595, 1296, 1082 cm-1; H NMR (300 MHz,
CDCl3) d 7.32–7.35 (m, 2H), 7.48–7.59 (m, 5H), 7.65–7.74 (m,
4H), 8.19–8.22 (d, J = 8.2 Hz, 2H), 8.86 (s, 1H); 13C NMR
(75 MHz, CDCl3) d 114.9 (2C), 122.0 (2C), 124.8 (2C), 125.1
(2C), 125.3 (2C), 126.6 (2C), 128.2 (2C), 128.7, 130.1 (4C), 130.2,
149.0; HRMS m/z calculated for C21H14N2 [M + H]+ 295.1233;
found: 295.1235.
Acknowledgements
We are pleased to acknowledge the financial support from
DST, New Delhi (grant no. SR/S5/GC-02/2006) for this
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investigation. D.S. and A.S. are thankful to CSIR for their
fellowships.
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