Synthesis of functionalized benzimidazoles and quinoxalines catalyzed by sodium hexafluorophosphate bound Amberlite resin in aqueous medium

Article abstract of DOI:10.1016/j.tetlet.2012.09.045

A very simple, eco-friendly, and versatile method for the selective synthesis of 1,2-disubstituted benzimidazoles and quinoxalines in water-methanol (1:1) mixture with the aid of resin bound hexafluorophosphate ion as catalyst is reported. The method is also effective for the incorporation of quinoxaline nucleus at the A ring of pentacyclic triterpenoid, friedelin. A plausible mechanism for the formation of disubstituted benzimidazole has also been suggested.

Full text of DOI:10.1016/j.tetlet.2012.09.045

Tetrahedron Letters 53 (2012) 6483–6488
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Tetrahedron Letters
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Synthesis of functionalized benzimidazoles and quinoxalines catalyzed by
sodium hexafluorophosphate bound Amberlite resin in aqueous medium
⇑
Pranab Ghosh , Amitava Mandal
Natural Products and Polymer Chemistry Laboratory, Department of Chemistry, University of North Bengal, Darjeeling 734 013, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A very simple, eco-friendly, and versatile method for the selective synthesis of 1,2-disubstituted benzim-
idazoles and quinoxalines in water–methanol (1:1) mixture with the aid of resin bound hexafluorophos-
phate ion as catalyst is reported. The method is also effective for the incorporation of quinoxaline nucleus
at the A ring of pentacyclic triterpenoid, friedelin. A plausible mechanism for the formation of disubsti-
tuted benzimidazole has also been suggested.
Received 9 August 2012
Revised 8 September 2012
Accepted 12 September 2012
Available online 25 September 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Benzimidazole
Quinoxaline
Hexafluorophosphate ion
Friedelin
Functionalized benzimidazoles represent an important class of
N-containing heterocyclic compounds and have received consider-
able attention due to their applications as antiulcers, antihyperten-
sives, antivirals, antifungals, anticancers, and antihistamines
among others.1–7 They are important intermediates in many organ-
ic reactions8–10 and have found biomimetic applications as
well.11,12 In addition, the therapeutic effects of benzimidazoles in
diseases such as ischemia–reperfusion injury,13 hypertension,14
obesity,15 etc. have recently been reported. Furthermore, to facili-
tate evaluation of the exact mechanism of the observed biological
activity, it will be beneficial for a simple, eco-friendly, and versatile
synthesis of these heterocycles. Current literature is well vast in
documenting various synthetic methodologies for the synthesis
of benzimidazoles. Generally, the condensation of o-phenylenedi-
amines and carboxylic acids (or their derivatives such as nitriles,
imidates, and orthoesters) had been widely used for the benzimid-
azole synthesis, but harsh dehydrating conditions (170–180 °C) are
usually required.16–18 Alternative approaches such as palladium
catalyzed tandem carbonylation–cyclization reaction of o-phenyl-
enediamine,19 palladium catalyzed tandem dehydration coupling
reaction of 2-bromoaniline,20 rhodium catalyzed hydroformylation
reaction of N-alkenyl phenylenediamines,21 reductive cyclization
reaction of o-nitroaniline with aldehydes,22 solid-phase supported
synthesis,23 etc. have also been developed to prepare functionalized
benzimidazoles. However, one pot condensation–aromatization
reaction of o-phenylenediamines and aldehydes under oxidative
condition turned out to be the most facile and effective method
for the synthesis of 2-substituted benzimidazoles,24–32 4 and 1,2-
disubstituted benzimidazoles,33–37 3.
Among the reactions of o-phenylenediamine with aldehyde, the
selectivity in forming 1,2-disubstituted benzimidazole, 3 and 2-
substituted benzimidazole, 4 is an issue of high interest. Although,
a large body of protocols have been established for synthesizing
benzimidazoles of type 4, there are only a few methods available
for the direct synthesis of 1,2-disubstituted benzimidazole, 3 with
ideal selectivity.30–37 Recently, several elegant catalyst systems
have been developed to prepare 3 in excellent chemoselectivity
by employing water as the medium in the presence of costly orga-
nometallic catalysts or rare ionic liquids.34,36,37 Recently we have
also reported
a new method for the selective synthesis of
benzimidazole of type 3 in water catalyzed by SDS.30
The synthesis of quinoxaline is usually achieved by the reaction
of o-phenylenediamine with dicarbonyl compounds,38 the oxida-
tive cascade reactions of o-phenylenediamine with
a-hydroxy
ketones,39,40 epoxides,41 and diols42 in the presence of either noble
metal, additional oxidants or are microwave assisted. The synthe-
sis using multicomponent reactions has also been recently
reported.43 Interestingly, as an equivalent precursor of
a-hydroxy-
ketones,
a-bromoketones have been claimed in much less cases as
reaction partners of o-phenylenediamine to prepare quinoxa-
lines.44,45 People have so far reported the synthesis of quinoxaline
derivatives from a-bromoketones and o-phenylenediamine in the
44
presence of either HClO4–SiO2 or TMSCl45 as catalytic systems.
Although, useful, HClO4 has huge hazardous nature than its poten-
tial usefulness, whereas application of TMSCl requires a higher
temperature with a lower yield of the products.
Herein we report the excellent catalytic ability of (i) sodium
hexafluorophosphate (SHFP) and (ii) PF6 ion bound Amberlite
⇑
Corresponding author. Tel.: +91 353 2776381; fax: +91 353 2699001.
E-mail address: pizy12@yahoo.com (P. Ghosh).
À
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.09.045

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P. Ghosh, A. Mandal / Tetrahedron Letters 53 (2012) 6483–6488
R2
R2
NH2
NH2
N
N
N
N
R2 CHO
R1
R2
R1
R1
R2
R1
N
N
H
R2
3a (42%)
1a
2a
5a (11%)
4a (47%)
Scheme 1. Plausible transformations.
900 (ClÀ) for the synthesis of 1,2-disubstituted benzimidazole and
quinoxaline derivatives. This is the first report of the synthesis of
1,2-disubstituted benzimidazole and quinoxaline derivatives using
the above catalysts in water.
Amberlite 900 (ClÀ) as
transformation.
a potential catalyst for the above
Polymeric resin bound hexafluorophosphate ion (PHP) was pre-
pared48 (Scheme 2) by washing Amberlite 900 resin (ClÀ) packed in
a column with 10% aqueous sodium hexafluorophosphate solution
repeatedly until the washing gave a negative response for the chlo-
ride ion (Scheme 6). Finally the solid was washed several times
with water and then dried under vacuum. The binding of hexa-
fluorophosphate ion on the surface of Amberlite 900 resin was con-
firmed by IR spectroscopy49 in the following way. IR spectrum of
PHP was taken in KBr discs (Fig. 1). PF6À belongs to Oh point group,
where six kinds of vibration modes are included in the molecule,
whose basic frequency number is 15. From the characteristics of
Oh point group, it can be calculated that for PF6À two energy levels
belonging to F1u have infrared activity which results from the flex-
ing vibration and bending vibration of F–P bonds, respectively.
Initially o-phenylenediamine and benzaldehyde were used in a
1:1 molar ratio in water for the titled transformation, but it failed
to produce the desired 1,2-disubstituted benzimidazole 3a as a
major product, instead a mixture of products was isolated (Scheme
1). Increase in the reaction time, temperature, and variation in the
molar proportion of the reactants did not make any influence on
the ratio of the product distribution. At this juncture and based
on the literature report46,47 on SHFP (sodium hexafluorophos-
phate) we undertook the above study by using 1 mmol of anhy-
drous SHFP in the above reaction mixture of o-phenylenediamine
and benzaldehyde (1:2 mmol). This revised protocol after a very
simple work-up gave only a single isolated product in 76% yield.
However, considering the recent emphasis on the development
of greener protocols we further worked on the above transforma-
tion to replace with a suitable greener catalyst the use of SHFP,
which has been reported to produce even more hazardous waste
due to its decomposition to phosphorus oxides and toxic hydroflu-
oridric acid.47 Working in this direction and looking intÀo the recent
literature of resin bound greener catalyst we used PF6 ion bound
À
Therefore, two strong absorption peaks of PF6 should appear at
820–860 and 550–565 cmÀ1. In the IR spectra of PHP, strong
absorption peak appeared at 557 and 832 cmÀ1, respectively
(Fig. 1). Appearance of the above said peaks did confirm the bind-
À
ing of PF6 ion on polymeric resin (Amberlite 900).
À
This resin bound PF6 ion (PHP) was then applied in place of
SHFP as the catalyst and it also showed excellent chemoselectivity
by giving 3a as the major product in water at room temperature
(Scheme 3). In a bid to increase the yield of the desired product,
we performed the same reaction in other green solvents, such as
ethanol, methanol, and mixtures of both water–methanol and
water-ethanol in varying proportions at room temperature as well
as in 50 °C (Table 1). Of the entire solvent systems studied, meth-
anol gave similar results as water, but ethanol performed poorly
(entry 3). A further study with mixed solvent systems indicated
Aq. NaPF6
NR3
NR3
10%; w/v
Cl
PF6
Amberlite 900
chloride form takem in water
Scheme 2. Preparation of PHP.
À
Figure 1. IR spectrum of the PF6 bound Amberlite 900 (PHP).

P. Ghosh, A. Mandal / Tetrahedron Letters 53 (2012) 6483–6488
6485
NH2
NH2
The generality of this methodology50 had been investigated
using a wide variety of 1,2-diamines and aldehydes. Except for val-
eraldehyde (Table 2, entry 25) the developed process was found to
be excellent both in terms of yield, selectivity, and time (Table 2).
The synthesis of such kind of benzimidazole derivatives from
aliphatic aldehydes was not addressed by many of the existing
methods. The aldehydes with electron donating (Table 2, entries
6, 7, and 12) as well as with electron withdrawing groups
(Table 2, entries 2–5, 8, 11, 20, and 21) participated in the reaction
uniformly. Apparently, the nature and position of substitution on
the aryl ring did not make much difference in reactivity except
for 3-nitrobenzaldehyde which required 24 h for completion
(Table 2, entry 8). Sensitive molecules like furan-2-aldehyde,
5-bromothiophene-2-aldehyde, and pyridine-4-carboxaldehyde
(Table 2, entries 13, 14, and 23) produced the corresponding benz-
imidazoles easily. Naphthalene-1-carboxaldehyde also underwent
the reaction and gave an excellent yield of the corresponding benz-
imidazole (Table 2, entry 16). The study in addition indicated that
unsubstituted aromatic aldehydes gave better yields of the prod-
ucts compared to the substituted systems and that the response
of aliphatic aldehydes toward the conversion is not so encouraging.
Based on these encouraging results, the utility of this selective
greener method was further extended to design some large benz-
imidazole derivatives that can serve as lead compounds in pharma-
ceutical research. To our delight we were able to synthesize a large
benzimidazole derivative A (Scheme 4) from the reaction.
PHP
N
N
R2 CHO
R1
R2
R1
Water-methanol, Rt
2
1
3
R2
Scheme 3. Preparation of 1,2-disubstituted benzimidazole.
Table 1
Selection of solvent
Entry
Solvent
Temperature (°C)
Time (h)
%Yield of 3
1
2
3
4
Water
Water
Ethanol
Water + ethanol
7:3
Water + ethanol
3:2
Water + ethanol
1:1
Water + ethanol
1:1
Methanol
Methanol
Water + methanol
(7:3)
Water + methanol
(3:2)
Water + methanol
(3:2)
Water + methanol
(1:1)
Water + methanol
(1:1)
rt
50
rt
1
2
10
10
76
76
55
72
rt
5
6
7
rt
10
10
10
70
74
76
rt
50
8
9
10
rt
50
rt
2
10
2
74
76
82
11
12
13
14
rt
2
8
1
1
86
88
96
96
50
rt
Encouraged by the above findings and based on the literature
reports we extended our aim to synthesize quinoxalines, another
novel class of heterocyclic compounds from
o-phenylenediamine (1:1) under similar condition51 (Scheme 5)
in excellent yields. The choice of -bromoketones was made be-
a-bromoketones and
50
a
cause they are less reactive, comparatively safe, light insensitive,
%Yield refers to the isolated yield of all the compounds.
and easy to prepare/handle under ordinary reaction condition.
A
a
number of both structurally and electronically diversified
-bromoketones were then tried to affect the quinoxaline synthe-
that a 1:1 mixture of water and methanol gave an excellent yield of
3a within 1 h at ambient temperature (Table 1, entry 13); increase
in reaction temperature had no effect on the isolated yield of the
reaction (entry 14).
sis effectively under the optimized reaction condition. To our
delight, all the employed -bromoketones furnished the respective
a
Table 2
Synthesis of diversified benzimidazole derivatives in aqueous SHFP
Entry
R1
R2
Time (h)
Temperature
Product
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
1
2
1.5
1.5
8
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
90 °C
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
90 °C
rt
rt
rt
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
96
88
87
85
79
85
83
82
85
82
79
82
85
75
78
69
82
76
74
72
75
84
82
68
Trace
84
4-CH3OC6H4
4-FC6H4
4-ClC6H4
4-NO2C6H4
4-NMe2C6H4
4-Isopropyl C6H4
3-NO2C6H4
3-OH2C6H4
3-OPhC6H4
2-ClC6H4
2
1.5
24
5
3
1.5
15
4
6
5
6
2
7
8
2-OHC6H4
Furan-2-yl
5-Bromo-thiophene-2-yl
PhCH@CH2
1-Naphthyl
4-Isopropyl C6H4
3-OPhC6H4
5-Bromo-thiophene-2-yl
2-ClC6H4
4-ClC6H4
Ph
Pyridine 4-carboxaldehyde
H
Valeraldehyde
Cyclohexyl
3-CH3
3-CH3
3-CH3
3-CH3
3-Benzoyl
3-Benzoyl
H
H
H
H
3s
3t
5
12
14
14
8
12
4
3u
3v
3w
3x
3y
3z
%Yield refers to the isolated yield of all the compounds after chromatographic separation. R1 and R2 belong to Scheme 3.

6486
P. Ghosh, A. Mandal / Tetrahedron Letters 53 (2012) 6483–6488
CHO
H2N
H2N
NH2
N
PHP
N
+
Water-methanol
6h, r.t
N
N
NH2
A
Scheme 4. Preparation of a bis benzimidazole.
quinoxalines in excellent yields (Table 3). Substituents on both the
ketone part as well as the amine had minimal effect on the course
of the reaction. The overall results are tabulated in Table 3.
In another interesting attempt, we were successfully able to
incorporate the quinoxaline moiety in ring A of pentacyclic triter-
penoid, friedelin according to Scheme 6.
H2N
H2N
N
N
O
PHP,
RT, 6-8 h
+
Water-methanol
(1:1)
Br
Scheme 5. Preparation of quinoxaline derivatives from
a
-bromoketone.
Table 3
Synthesis of quinoxaline derivatives
Entry
a
-Bromo carbonyl compound
Diamine
Time (h)
6
Product
%Yield
94
O
H2N
Br
N
N
1
H2N
O
H2N
H2N
Me
Me
MeO
Br
Br
N
N
2
3
4
5
6
7
8
6
6
6
6
6
6
7
92
92
86
92
89
87
84
Me
Me
MeO
Br
O
H2N
H2N
Br
N
N
O
H2N
H2N
Br
N
N
O
H2N
H2N
Br
Br
N
N
O
H2N
H2N
Cl
N
N
Cl
O
H2N
H2N
I
Br
N
N
I
O
H2N
H2N
O2N
Br
N
O2N
Br
N
O
H2N
H2N
Br
N
9
6
8
87
85
Br
N
O
H2N
H2N
O2N
Br
N
10
O2N
N

P. Ghosh, A. Mandal / Tetrahedron Letters 53 (2012) 6483–6488
6487
Table 3 (continued)
Entry
a
-Bromo carbonyl compound
Diamine
Time (h)
7
Product
%Yield
O
H2N
Br
N
N
11
12
83
98
H2N
OH
Cl
OH
O
H2N
H2N
Cl
Br
N
N
6.5
7
Cl
Cl
O
H2N
H2N
MeO
MeO
MeO
MeO
Br
N
N
13
82
O
O
H2N
H2N
Me
Br
N
N
14
15
6
5
92
84
H2N
H2N
CN
CN
Br
N
N
CN
CN
%Yield refers to the isolated yield of all the compounds.
Br
O
N
N
a
62%
b
58%
O
Water+Methanol (1:1), o-phenylene diamine, RT, 6h
a, HBr, Br2, CH3COOH; b,
Scheme 6. Preparation of quinoxaline derivative of friedelin.
On the basis of the above experimental results as well as the
PF6
formation of a Schiff’s base as intermediate, which has been iso-
lated and characterized by NMR spectroscopy, a plausible mecha-
nism of functionalized benzimidazole formation has been
proposed (Scheme 7). Involvement of the Schiff’s base as interme-
diate is further supported by the fact that, separately prepared
Schiff’s base when subjected to undergo the same reaction under
identical condition, that is, at room temperature gave the target
product in an excellent yield. It is then followed by the nucleophilic
attack of the catalyst on one of the electrophilic imino carbon. Sub-
sequent cyclization and 1,3-hydride shift lead to the formation of
benzimidazoles (Scheme 7).
+
+
OHC
OHC
NH2
NH2
N
N
Water-Methanol
SHFP, RT
Step-I
Nucleaphilic attack on the electrophilic
centreby the catalyst
Step-II
Based on the above discussions, it can be concluded that com-
mercially available sodium hexafluorophosphate binds on Amber-
lite 900 (ClÀ) and PHP can be used as a cheap and greener source
compared to sodium hexafluorophosphate itself and may also effi-
ciently replace the use of costly, rare ionic liquids for the synthesis
of 1,2-disubstituted benzimidazole or quinoxaline derivatives in an
expeditious and selective way in water–methanol at ambient tem-
perature. The study also established that it is the hexafluorophos-
phate ion and not the counter cation which plays the key role for
the above transformation. We have also confirmed the catalyzing
ability of hexafluorophosphate ion in which it successfully binds
to Amberlite 900 resin and promotes the reaction. Several func-
tional groups such as chloro, bromo, nitro, methoxy, and sensitive
molecules like 5-bromo thiophene-2-carboxaldehyde and furan-2-
carboxaldehyde are compatible with the reaction conditions. The
F6P
N
N
N
N
Hydride ion transfer
H
+
PF6
Step-III
Scheme 7. Plausible mechanism of benzimidazole formation in water–methanol
catalyzed by hexafluorophosphate ion.
reaction procedure is operationally straightforward, mild, and is
environmentally friendly. Since benzimidazole derivatives are
often used in synthetic, medicinal, and biological chemistry, the
reaction procedure, being endowed with so many attractive
features, could find applications as alternative green reaction

6488
P. Ghosh, A. Mandal / Tetrahedron Letters 53 (2012) 6483–6488
27. Baharami, K.; Khodaei, M. M.; Naali, F. J. Org. Chem. 2008, 73, 6835–6837.
28. Sharghi, H.; Aberi, M.; Doroodmand, M. M. Adv. Synth. Catal. 2008, 350,
2380–2385.
29. Chen, Y. X.; Qian, L. F.; Zhang, W.; Han, B. Angew. Chem., Int. Ed. 2008, 47,
9330–9333.
30. Ghosh, P.; Mandal, A. Catal. Commun. 2011, 12, 743–747. and the references
cited therein.
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methodology. In a nutshell, we have developed a green and novel
protocol for the selective synthesis of some heterocyclic com-
pounds using PHP as catalyst at ambient temperature. Explorations
of further applications of the newly developed green protocol and
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32. Wenge, C.; Robert, K. B.; Zohreh, S. H.; Feryan, A.; Jolicia, G. F. Synlett 2012, 23,
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Acknowledgment
33. For typical example in selective synthesis of 1,2-disubstituted benzimidazoles
using o-phenylenediamine and aldehyde, see: Kokare, N. D.; Sangshetti, J. N.;
Shinde, D. B. Synthesis 2007, 39, 2829–2834.
Financial support from UGC, India was gratefully acknowledged.
34. Salehi, P.; Dabiri, M.; Zolfigol, M. A.; Otokesh, S.; Baghbanzadeh, M. Tetrahedron
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Supplementary data
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Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.09.
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:
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hexafluorophosphate ion (PHP) was prepared (Scheme 6) by washing
Amberlite 900 resin (ClÀ) packed in a column with 10% aqueous sodium
hexafluorophosphate solution repeatedly until the washing gave a negative
response for the chloride ion (Scheme 6). Finally the solid was washed several
times with water and then dried under vacuum. The binding of
hexafluorophosphate ion on the surface of Amberlite 900 resin was
confirmed by IR spectroscopy.
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50. General procedure for 1,2-disubstituted benzimidazole: In
experimental procedure, o-phenlylenediamine and benzaldehyde in 1:2
molar ratios was taken in 100 ml round bottom flask. To this water–
a
typical
a
methanol (1:1) and 100 mg PHP was admixed. The reaction mixture was then
allowed to stir with magnetic spinning bar, after some time a yellowish mass
appeared which settles down like a precipitate after the completion of the
reaction (checked by TLC). It was then filtered; the solid reaction mixture was
dissolved with dichloromethane (25 mL) and evaporated under vacuum. The
crude product was then crystallised from ethanol. The desired product was
pure on TLC and characterized by spectral (IR, 1H and 13C NMR) data and
compared to those reported in literature.
51. General procedure for quinoxalines. In a typical experimental procedure, o-
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phenlylenediamine and
a-bromo ketone in 1:1 molar ratios was taken in a
100 mL round bottom flask. To this water–methanol (1:1) and 100 mg PHP was
admixed. The reaction mixture was then allowed to stir with magnetic
spinning bar, after some time a yellowish mass appeared which settles down
like a precipitate after the completion of the reaction (checked by TLC). It was
then filtered; the solid reaction mixture was dissolved with dichloromethane
(25 mL) and evaporated under vacuum. The crude product was then
crystallised from ethanol. The desired product was pure on TLC and
characterized by spectral (IR, 1H and 13C NMR) data and compared to those
reported in literature.
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