Grindstone chemistry: Protic ionic liquid-substrate tuned green synthesis of 1,2-disubstituted and 2-substituted benzimidazoles with outstanding selectivity

Article abstract of DOI:10.1039/c5ra08183a

An environmentally benign and highly catalyst-substrate controlled synthesis of 1,2-disubstituted and 2-substituted benzimidazoles with outstanding selectivity has been developed through grinding a mixture of o-phenylenediamines, suitable aldehydes and an

Full text of DOI:10.1039/c5ra08183a

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Grindstone chemistry: protic ionic liquid-substrate
tuned green synthesis of 1,2-disubstituted and 2-
substituted benzimidazoles with outstanding
selectivity†
Cite this: RSC Adv., 2015, 5, 51012
Received 4th May 2015
Accepted 28th May 2015
a
a
b
b
*
*
Swapan Majumdar, Mithun Chakraborty, Nabyendu Pramanik and Dilip K. Maiti
DOI: 10.1039/c5ra08183a
www.rsc.org/advances
An environmentally benign and highly catalyst-substrate controlled strategies is the prime task of organic chemists of academic and
synthesis of 1,2-disubstituted and 2-substituted benzimidazoles with industrial settings. Thus, over the last few decades tremendous
outstanding selectivity has been developed through grinding a mixture efforts have been devoted towards the exploration of eco-
of o-phenylenediamines, suitable aldehydes and an imidazolium tri- friendly methodology both in academia and industry. Volatile,
fluoroacetate protic ionic liquid catalyst. The newly developed metal- toxic and hazardous organic and inorganic reagents are
free catalysis approach produced 1,2-disubstituted benzimidazoles continuously being replaced by either the use of solvent-free
from aromatic aldehydes bearing electron donating group, whereas techniques,1 ionic liquids,2 water media,3 phase transfer cata-
aromatic aldehydes possessing electron withdrawing groups and lysts,4 microwave irradiation5 or ball-milling processes.6
aldehydes with 2-alkoxy substitution selectively furnished 2- Consequently solvent-free as well as metal-free catalytic reac-
substituted benzimidazoles and their chiral analogues. Low energy tions have tremendous potential and received considerable
consumption, short reaction time and solvent-free synthesis make this attention in the area of green synthesis. Thus use of grindstone
methodology green, providing a useful contribution to the existing chemistry7 is desirable for the synthesis of desired functional
procedures available for the synthesis of benzimidazole derivatives.
molecules through simple mixing of the precursors and
nonmetallic catalyst with much faster reaction rates and selec-
tivity under benign reaction conditions. In recent times much
attention has been focussed on organic transformations
promoted by ionic liquids at ambient temperature because of
their potential advantages to operate under environmentally
benign conditions. We and others have reported several strat-
egies for organic synthesis catalyzed by protic ionic liquids
(PILs) with high performance.8
Due to growing public sentiment in support of the environ-
ment, the focus of academia and industry has shied to reduce
or eliminate the use of volatile organic solvents during
manufacturing and processing. The scope of green chemistry
considers the environmental, health and safety problems
associated with modern chemical manufacturing processes and
legal instruments. It also considers some of the underlying
principles and concepts that should underpin chemistry and
chemical manufacturing in the future. To meet such demands,
present day organic synthesis has been driven to reduce or
eliminate the toxic and volatile organic solvents that are widely
used in huge quantity in organic synthesis because they pose
serious threats to the environment. Therefore, to keep the
environment clean and sustainable for future generations, the
development of efficient and environmentally benign synthetic
Heterocycles are predominant among all types of pharma-
ceuticals, agrochemicals, veterinary products, sensors and
materials.9 For instance benzimidazole is one of the funda-
mental structural units of the pharmaceutical, agricultural,
electronic, polymer science and technology industries.10 Owing
to the immense importance and wide range of bioactivities of
compounds bearing a benzimidazole motif, efforts have been
made to synthesize libraries of compounds and to screen the
compounds for potential pharmaceutical properties. Thus
benzimidazole has been considered as one of the most impor-
tant and privileged structures in medicinal chemistry, encom-
aDepartment of Chemistry, Tripura University, Suryamaninagar-799 022, India.
E-mail: smajumdar@tripurauniv.in; Fax: +91-381-2374802; Tel: +91-381-2379070
passing
a
plethora of useful biological activities.11
Benzimidazoles play a unique role in drug discovery programs
because of their wide spectrum of bioactivities, such as anti-
cancer, antihypertensive, anthelmintic, antiprotozoal, antimi-
crobial, antioxidant, antiinammatory and analgesic activity.12
Benzimidazole ring containing molecules also exhibit
bDepartment of Chemistry, University of Calcutta, 92 A.P.C. Road, Kolkata-700 009,
India. E-mail: dkmchem@caluniv.ac.in; Fax: +91-33-2351-9755; Tel: +91-33-2350-
9937
† Electronic supplementary information (ESI) available. CCDC 1062843. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c5ra08183a
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Scheme 1 PIL catalysed selective synthesis of benzimidazoles with varied precursors.
harmful impact of various chemicals and metals on the envi-
ronment is minimized and sustainability is improved.
Usually two protocols for the synthesis of benzimidazoles are
commonly used: one of them is the coupling of o-phenyl-
enediamines (OPDs) with carboxylic acids or their activated
derivatives16 and the second route involves the oxidative cyclo-
condensation of o-phenylenediamine with aldehydes.17 In
addition, 1,2-disubstituted benzimidazoles can also be accessed
by direct one-step condensation of OPDs with aldehydes under
the inuence of different acid catalysts.18 Although some of
these methods are quite satisfactory, many of these processes
suffer from serious limitations, such as drastic reaction condi-
tions, low yields, tedious work up and co-occurrence of several
side-reactions and disposal issues. Moreover, several of these
reactions were carried out with high energy consumption and
employed costly reagents. A recent synthesis of 2-aryl-1-aryl-
methyl-1H-benzimidazoles was developed by the condensation
of aromatic aldehydes and OPDs using 1-butyl-imidazolium
tetrauoroborate as promoter19 and 2-aryl-1H-benzimidazole
using 1-methyl-3-pentylimidazolium tetrauoroborate, [pmim]
BF4,17b but these reactions work at high temperature with a large
amount of ionic liquid (2 mL mmolÀ1 of substrate!), which was
difficult to recycle. Moreover preparation of tetrauoroborate
based protic ionic liquid is difficult since HBF4 is available only
Fig. 1 Synthesized protic ionic liquids for catalysis.
signicant activity against several viruses13 such as HIV, inu-
enza and human cytomegalo virus. In addition they are
important intermediates in many organic reactions9 and act as
ligands to transition metals for modeling biological systems.14,15
These impressive biological and physical properties of the
privileged benzimidazole nucleus has prompted us to develop a
new selective approach for preparing these important
compounds. Presently the design, development, and utilization
of efficient and environmentally benign synthetic processes
have become the conscientious choice of synthetic chemists
due to tight legislation and environmental issues. It is desirable
to design and develop an attractive metal-free strategy that can
also simplify the reaction procedure, product purication,
improve synthetic efficiency, and reduce consumption of toxic
solvents as well as their disposal. Consequently the potential
Table 1 Comparison of reaction results using different PIL
OPD : PhCHO
(mmol)
PIL catalyst
(mol%)
Conversion
(%)
Entry
Time (h)
Yielda (%) (3a)
1
2
3
4
5
6
7
8
9
10
1 : 1
1 : 1
Nil
48
2
2
2
2
2
2
2
4
75
100
100
100
100
100
100
100
100
90
Mixturec
41b,c
83c
I (10)
I (10)
I (10)
II (10)
III (10)
II (5)
II (3)
II (2)
II (1)
1 : 2.2
1 :'2.2
1 : 2.2
1': 2.2
1 : 2.2
1 : 2.2
1 : 2.2
1 : 2.2
83d
87c
80c
87c
86c
85c
24
75c
a
Yield was calculated on the basis of isolated pure product. b Reaction was performed in open air using mortar and pestle. c 33% starting material
recovered. d Stirring carried out under inert argon atmosphere.
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Scheme 2 Highly selective synthesis of 2-aryl-1-arylmethyl-1H-1,3-benzimidazoles.
as 40–50% aqueous solution that creates problems in isolation grinding. The 1,2-disubstituted product 3a (1-benzyl-2-
and the purication process. Ranu et al. showed17b that small phenylbenzimidazole) was obtained in 41% yield along with
differences in the structures of ionic liquids have a great the unreacted starting material OPD (ꢀ33%) aer 2 h (entry 2).
inuence on the outcome of the selectivity of the reaction.17b As However the other precursor benzaldehyde was consumed
a part of our ongoing programme to design and develop solvent- completely (TLC) in this experiment. On treatment of 2.2 mmol
free and metal-free strategies for organic synthesis,8a–d we were of benzaldehyde with 1.0 mmol of o-phenylenediamine (OPD)
interested to observe the effect of PILs as catalysts for the the cyclocondensation reaction was complete in 2 h and the
synthesis of both 1,2-disubstituted (3, path a, Scheme 1) and 2- yield was improved to 85% (entry 3). The di-substituted product
substituted benzimidazoles (4, path b, Scheme 1) with high 3a was found as a sole product, which is in very good agreement
selectivity. Herein the direct syntheses of the two classes of with the results obtained by Wang and colleagues19 using imi-
benzimidazoles were investigated by the reaction of o-phenyl- dazolium tetrauoroborate ionic liquid in large excess under
enediamines and suitable aldehydes in the presence of imida- heating conditions (70 ꢁC). Surprisingly it was found that there
zolium triuoroacetate PIL catalysts (2–10 mol%) under a is no inuence of molecular oxygen on the cyclocondensation
solvent-free grindstone approach.
process because it smoothly produced the desired product in
We have synthesized three PILs namely 1-butylimidazolium the presence or absence of oxygen (entries 3 and 4). On use of
triuoroacetate (I), 1-butyl-2-methyl imidazolium tri- PIL-II and PIL-III (Fig. 1) under similar reaction conditions the
uoroacetate (II) and 1-butyl benzimidazolium triuoroacetate heterocycle 3a (entries 5 and 6) was produced in comparable
(III) by adding triuoroacetic acid to the corresponding N- yields (87% and 80% respectively). We continued optimization
butylated imidazole/benzimidazole derivative8d,20 in dichloro- of the reaction with the most efficient catalyst PIL-II. Gratify-
methane (Fig. 1) to investigate the selective cyclocondensation ingly the reaction was successfully optimized (entries 7–10) with
catalysis. The potential catalysts were dried under vacuum in only 2 mol% of PIL-II producing the 1,2-disubstituted product
order to remove any traces of triuoroacetic acid present and 3a with 85% yield (entry 9).
were fully characterized by spectroscopic techniques. The PILs
The scope of the cyclization process was successfully inves-
have shown tremendous ability activating various functional tigated by using large varieties of aromatic aldehydes bearing
groups8 including aldehydes for highly selective organic trans- electron releasing and highly sensitive functionalities such as
formations under metal-free conditions.
–OH, –OMe, and –NMe2 under solvent-free grindstone condi-
Initially one experiment was conducted in the absence of PIL tions (Scheme 2). In all cases the nonmetallic catalyst efficiently
using OPD and benzaldehyde of one mmol each at ambient furnished 1-arylmethyl-2-aryl substituted benzimidazoles (3b–i)
temperature under an inert atmosphere. Aer 48 h of stirring a as exclusive products at ambient temperature with high yields
thick mass (Table 1, entry 1) was obtained showing a complex (70–90%) and fast reaction rates (0.5–2.0 h). The OPD possess-
mixture of products, which was detected using thin layer ing a –COOH (R1, Scheme 1, path a) functional group also
chromatography (TLC). The column chromatographic separa- reacted in the same fashion with benzaldehyde to afford cor-
tion of the mass has not shown formation of the desired responding 1,2-disubstituted benzimidazole (3f) in 2 h with
products (3a and 4a, Table 1). Next the reaction was carried out high yield (75%), whereas the reaction was unsuccessful with o-
with 10 mol% of PIL-I using a mortar and pestle with occasional phenylenediamine bearing a strongly electron withdrawing 4-
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Table 2 Selective synthesis of 2-substituted benzimidazoles
Entry
Aldehyde
Product
Time (h)
1
Yield (%)
72
1
2
3
0.5
2
82
79
4
5
1
1
81
85
6
6
77
7
8
9
6
4
5
65
75
81
10
5
71
nitro substituent. The reaction of strongly electron releasing powerful catalyst guided the reaction towards the formation of
indole-3-carboxaldehyde with OPD is not addressed by most of other possible 2-arylbenzimidazoles products (4, Table 2,
the existing methods. In our protocol it smoothly produced the entries 1–5) in excellent yield (72–85%). Next we turned our
desired 1,2-disubstituted benzimidazole 3i in 90% yield aer attention to use sugar-based aldehydes for synthesis of valuable
purication by crystallization from methanol–water.
Surprisingly on use of aldehydes bearing electron with- isopropylidenexylose-5-carboxaldehyde
drawing substituents such as halogen and nitro groups the isopropylidenexylose-5-carboxaldehyde only the corresponding
chiral benzimidazoles.21 On treatment of 3-O-benzyl-1,2-O-
or O-allyl-1,2-O-
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Scheme 3 Mechanistic rationale of PIL-substrate controlled selectivity to benzimidazoles.
2-substituted benzimidazoles were furnished in 77% and 65% substituted benzimidazole derivatives were accomplished
yield respectively (4f and g, entries 6 and 7). Surprisingly no 1,2- exclusively in very good yield even if excess aldehyde is
disubstituted benzimidazoles were detected in both cases. employed (4h–j, entries 8–10). There was almost no discrimi-
Herein alkoxy substituents present at the b-position might play nation in reaction rate and yield using aldehydes possessing 2-
a vital role along with the catalyst PIL-II for controlling the allyloxy, 2-benzyloxy and 2-butyloxy substituents using the
outcome of the reaction. Thus we have synthesized different powerful catalyst PIL-II.
alkoxy aldehydes using salicylaldehyde through alkylation
A literature search reveals that in a similar reaction the
under basic conditions and successfully used them for the presence or absence of oxygen sometimes makes a differ-
synthesis of functionalized benzimidazoles. In each case, 2- ence.17b,19 Usually the presence of oxygen favours formation of 2-
Fig. 2 Single crystal structure and crystal packing of 4j.
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substituted benzimidazole and the absence of oxygen leads to aldehydes favour 2-substituted benzimidazoles. The easy
1,2-disubstituted benzimidazole using excess aldehydes. It was accessibility of the protic ionic liquid catalyst (II), shorter
speculated22 that both the –NH2 groups of OPD react with reaction time, solvent-free medium and high yield of the
aldehydes to form dibenzamidine A, which on cyclisation products makes this method very green. To the best of our
generates intermediate C, and a subsequent 1,3-hydride shi knowledge this is the rst report for the substrate-PIL
produces 1,2-disubstituted benzimidazoles. In our experiments controlled highly selective annulation of aldehydes and o-phe-
PIL-II is expected to activate aldehyde rst and rapidly perform nylenediamines to valuable 1,2-disubstituted and 2-substituted
condensation with one of the –NH2 groups of OPD to form A, benzimidazoles and their chiral analogues at ambient temper-
which on ring closing followed by a hydride shi furnished 3 as ature using grindstone chemistry.
the sole product (eqn (1), Scheme 3). Indeed we have recorded
the FTIR spectrum of an equimolar mixture of p-methoxy
General experimental procedure
benzaldehyde and PIL-II; immediate lowering of the carbonyl
stretching frequencies (ꢀ21 cmÀ1) was observed. It supports our
A mixture of o-phenylenediamine (10 mmol), aromatic aldehyde
(22 mmol), and protic ionic liquid (5 mol%) was ground by
means of mortar and pastel at room temperature. The reaction
was monitored by TLC. Aer completion of the reaction the
residue was poured on crushed ice and the solid was ltered
and washed thoroughly with water. The product was re-
hypothesis regarding the rst role of PIL-II as an activator of the
carbonyl functionality of aldehydes.
Under the reaction conditions bis-imine (A, eqn (1)) forma-
tion with aromatic aldehydes possessing an electron with-
drawing group might be disrupted by the powerful PIL-II
catalyst and the second amino group of monoimine (B, eqn (2))
crystallized from ethanol–water to obtain the pure product.
is allowed for ring closing to construct the dihy-
For the products displayed in Table 2, 1.2 mmol of aldehyde
drobenzimidazole-PIL-II intermediate (D).23 Subsequent release
were used with respect to o-phenylenediamine. The structures
of PIL-II$H leads to synthesis of 2-substituted benzimidazoles
of the products were conrmed through analysis of FTIR, NMR
(4). We performed another experiment using 2-chlor-
spectral data and were compared with the melting point
reported in literature. All new compounds were fully charac-
obenzaldehyde and OPD in the presence of 5 mol% of PIL-II
under a N2 atmosphere, we were pleased to observe that only 2-
terised by FTIR, 1H and 13C NMR and HRMS spectral data
(2-chlorophenyl) benzimidazole (4a) was formed aer 1 h at
(ESI†).
room temperature in 72% yield (Table 2, entry 1). A possible
mechanism to explain the exclusive formation of the 2-disub-
stituted benzimidazoles from the reaction between OPD and 2- Acknowledgements
alkoxy aldehyde is depicted in eqn (3) (Scheme 3). Presumably,
One of the authors M. C. is thankful to the Council of Scientic
the –NH2 group of OPD attacks the PIL-II activated aldehyde
& Industrial Research (CSIR), Govt. of India for providing
fellowship.
forming an imine (E), which is arrested immediately aer its
formation via hydrogen bonding and immediately undergoes
ring closing to dihydrobenzimidazole F followed by aromatiza-
tion to afford 2-substituted benzimidazoles (4).
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2) clearly indicated the presence of strong hydrogen bonds
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favour 1,2-disubstituted benzimidazoles whereas aromatic
aldehydes with ‘electron withdrawing’ substituents or 2-alkoxy
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51018 | RSC Adv., 2015, 5, 51012–51018
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