Silica–ferric chloride (SiO2–FeCl3) catalyzed selective synthesis of 2-substituted benzimidazole through Csp2Csp3bond cleavage of β-ketoester/amide

Article abstract of DOI:10.1016/j.tetlet.2016.08.099

Silica–ferric chloride (SiO₂–FeCl₃) supported reagent was successfully utilized as recyclable catalyst for the general and highly efficient synthesis of 2-substituted benzimidazole by the condensation of 1,2-diamino benzene and β-ketoester/amide followed by original C_sp²C_sp³bond cleavage. Evidences in favor of C[sbnd]C (α–β) bond cleavage of β-ketoesters/amides are established.

Full text of DOI:10.1016/j.tetlet.2016.08.099

Accepted Manuscript
Silica-ferric chloride (SiO2-FeCl3) catalyzed selective synthesis of 2-substituted
benzimidazole through Csp2-Csp3 bond cleavage of β-ketoester/amide
Swapan Majumdar, Ankita Chakraborty, Subrata Bhattacharjee, Sudipto
Debnath, Dilip K. Maiti
PII:
S0040-4039(16)31148-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.08.099
TETL 48070
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
31 July 2016
30 August 2016
31 August 2016
Please cite this article as: Majumdar, S., Chakraborty, A., Bhattacharjee, S., Debnath, S., Maiti, D.K., Silica-ferric
chloride (SiO2-FeCl3) catalyzed selective synthesis of 2-substituted benzimidazole through Csp2-Csp3 bond cleavage
of β-ketoester/amide, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.08.099
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Graphical Abstract
Silica-ferric chloride (SiO2-FeCl3) catalyzed selective
synthesis of 2-substituted benzimidazole through
Csp2-Csp3 bond cleavage of -ketoester/amide
Swapan Majumdar, Ankita Chakraborty, Subrata
Bhattacharjee, Sudipto Debnath and Dilip K Maiti
Leave this area blank for abstract info.
O
O
N
R2
XR3
R2
NH2
NH2
N
H
R1
SiO2-FeCl3
ethanol, reflux
X = O, NH
upto 98% yield
18 example
R1
Silica-ferric chloride (SiO2-FeCl3) supported reagent was successfully
utilized as recyclable catalyst for the general and highly efficient synthesis
of 2-substituted benzimidazole by the condensation of aromatic 1,2-diamine
and -ketoester/amide followed by C-C bond cleavage.

Tetrahedron Letters
1
Tetrahedron Letters
Silica-ferric chloride (SiO2-FeCl3) catalyzed selective synthesis of 2-substituted
benzimidazole through Csp2-Csp3 bond cleavage of -ketoester/amide
Swapan Majumdara, Ankita Chakrabortya, Subrata Bhattacharjeea, Sudipto Debnathb and Dilip K. Maitib
a Department of Chemistry, Tripura University, Suryamaninagar, 799 022, INDIA
bDepartment of Chemistry, University of Calcutta, 92, A. P. C. Road, Kolkata 700 009, INDIA
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
Silica-ferric chloride (SiO2-FeCl3) supported reagent was successfully utilized as recyclable
catalyst for the general and highly efficient synthesis of 2-substituted benzimidazole by the
condensation of 1,2-diamino benzene and -ketoester/amide followed by original Csp2-Csp3 bond
cleavage. Evidences in favour of C-C (-) bond cleavage of -ketoesters/amides are established.
2009 Elsevier Ltd. All rights reserved.
Keywords:
SiO2 supported FeCl3 catalyst
Activation
C-C bond cleavage
Benzimidazole
Recyclable catalyst
Solid supported reagents have much attention in organic
synthesis owing to their characteristics properties such as enhanced
reactivity and selectivity, simple work-up procedure, minimization of
cost and waste generation and reuse of the catalysts with significant
catalyst turnover.1 Recently, iron compounds have drawn much
attention for their outstanding catalytic activity, selectivity, cost-
effectiveness, ready availability, sustainability, and environmentally
friendly properties towards wide range of organic transformations2
and synthesis of functionalized heterocycles. Over the past few
years, silica supported ferric chloride was extensively used in several
catalytic organic transformations3a-f with high efficiency.
catalyzed coupling of o-haloacetanilide with amine/amidine to 2-
substituted benzimidazoles is known in the litrature.9 Bronsted acids
such phosphoric acid (H3PO4) or p-toluene sulfonic acid (p-TsOH)
catalyzed synthesis of benzimidazoles are successfully studied.10
However, despite of some notable advances, they generally suffer
from one or more drawbacks, such as requirement of stoichiometric
or excess amounts of strong oxidants, high temperatures, high
transition metal catalyst loading, harsh reaction conditions and also
non-recyclability of the catalysts or protic acids. In the field of
organic synthesis, C-C bond cleavage reaction is a topic of interest
that allows C-C/C-N bond annulation to construct new molecules of
interest. In spite of having lot of significant advances in this field,
most of the methods rely on transition metal catalyzed processes. But
recyclable metal catalyzed C-C bond cleavage reactions of eco-
friendly in nature to achieve unstrained molecules are still in its
infancy.
In the course of our ongoing research on the development of
efficient methods for heterocycle synthesis11 herein, we report that
benzimidazoles can readily be obtained from the substituted o-
phenylenediamines and ketoester or amide by the catalysis of
silica supported ferric chloride in a very short reaction time through
intermediate aminal formation followed by H-bond assisted selective
C−C bond cleavage. This method has several advantages such as (i)
oxidant free, (ii) very mind condition, (iii) low catalyst loading, (iv)
no co-occurance of side product specially 1,2-disubstituted
benzimidazole and (iv) catalyst recyclability etc. than direct
synthesis of benzimidazoles from o-phenylenediamine and aldehyde.
Recently, we have reported11c that ionic liquid could be utilized as an
activator at high temperature (>120oC) for the synthesis of
N-heterocycles are the most abundant and integral scaffolds
that occur ubiquitously in a large number of bioactive natural
products, drug intermediates, pharmaceuticals, and agrochemicals.
Benzimidazoles are a privileged class of compounds among the N-
heterocycles with a diverse spectrum of biological activities and
therapeutic potentialities.4 Benzimidazole derivatives have found
diverse applications in therapeutic areas5 including anti-ulcers, anti-
hypertensives, anti-virals, anti-fungals, anti-cancers, and anti-
histaminics. In addition, benzimidazoles are very important
intermediates in dyes and polymer synthesis6a and also widespread
applications in fluorescence,6b chemosensing,6c crystal engineering,6d
and corrosion science.6e Due to their wide spread use in different
segment of science and technology, a number of methods have been
reported for their synthesis. They are commonly prepared by the
condensation of aromatic 1,2-diamine with aldehydes7 using
oxidants or carboxylic acid derivatives under harsh conditions.
Recently, oxidative condensations of the alcohol or amines with
aromatic 1,2-diamine have also been developed.8 Copper (I)
———
 Corresponding author. Tel: +91-381-237-9070; Fax: +91-381-2374802; e-mail: smajumdar@tripurauniv.in

2
Tetrahedron Letters
benzimidazoles (Table 1, entry 13). Reaction under solvent free
benzimidazoles from aromatic 1,2-diamines (1) and -keto
condition results incomplete conversion due to the deposition of
solid product on the surface of solid catalyst which in turns shield
catalyst from the reactants. To explore the generality of the present
approach we have studied with various aromatic diamines and -
ketoesters under optimized condition (Table 1, entry 4). o-
Phenylenediamine reacts with methyl acetoacetate (2c) in the
presence of SiO2-FeCl3 (3 mol%) catalyst also produced 2-methyl
benzimidazole but it reacts with benzoyl acetone (2d) under same
conditions producing a mixture of 2-methyl benzimidazole (3a) and
2-phenyl benzimidazole (3b) in a ratio of 3:1 along with
acetophenone as by product (Table 2, entry 2). Formation of
acetophenone by-product indicated the cleavage of C-C bond in this
reaction. Similarly, ethyl 3-oxo hexanoate (2e) afforded 2-propyl
benzimidazoles (3c) in 90% yield (Table 2, entry 3). Isolation and
characterisation of cyclohexyl acetate, 4-methyl acetanilide and 4-
nitroacetanilide along with excellent yield of 2-methyl
benzimidazole from the reactions (Table 2, entries 4-6) provide
further evidences that the reaction proceed through C-C bond
cleavage reaction of -ketoesters or amides. -Ketoesters containing
aromatic ring with electron withdrawing (2i) substituent undergo
same type of reaction that yielded benzimidazoles (3d) without
difficulties (Table 2, entries 7). Diversity of the synthesis also
observed in the cases of other aromatic o-phenylenediamines 1b-f
and highly substituted benzimidazoles 3e-i were obtained in good to
excellent yield (Table 2, entries 8-12). Benzimidazoles containing
long alkyl chain at C-2 is very significant as so many studies have
been carried out to explore their aggregation and other physical
properties but they were prepared by heating aromatic diamines,
fatty acid and PPA at very high temperature.15 They were produced
generally in very low yield, required inert condition and critical work
up protocol made the process less interesting. In this context our
method produced 3j and 3k in 90% and 92% yields respectively
(Table 2, entry 13, 14). The N-mono substituted phenylenediamine
(1g) also participated benzimidazole formation reaction that
produced 1,2-disubtuted benzimidazoles 3l-m (table 2, entris 15, 16).
Unfortunately 2-amino phenol/thiophrnol failed to produce
benzoxazole/benzothiazole. In the later case, thioaminal was
produced in 60 % yield, no change was observed upon heating at 120
oC. Although the exact mechanism of the silica-supported ferric
chloride catalyzed reaction is not clear to us but Lewis acid has
major role during the heterocyclization with C-C cleavage.
Adsorption of iron (III) chloride on the surface of silica is probably
make polynuclear iron complex, which activates ketone carbonyl of
-keto esters/amides or diketone for nucleophilic attack (A). Thus
aromatic dimines first produced imino ester (B) (equilibrium with
enamine is also possible) which undergo ring closing by second
amino group to form aminal (C) followed by H-bond assisted C-C
bond cleavage produces benzimidazole (Scheme 2). Silica being
water absorbent could facilitate the formation of B. Isolation of
thioaminal intermediate 5 from the reaction 2-amino thiophenol
ester/amides (2) via thermolysis of intermediate 1,5-benzodi-
azepinone. In contrast to our previous method, the present method
took place under mild conditions to produce both 2-alkyl (long alkyl
chain) and 2-aryl-substituted benzimidazoles (3, Scheme 1) in
excellent yields with a high tolerance to a variety of functional
groups.
O
R2
NH2
N
SiO2-FeCl3
R2
XR3
O
O
+
NH2
+
H3C
ethanol, reflux
XR3
N
H
H2C
R1
X =O or NH
R1
1
2
upto 98%
3
4
Scheme 1: SiO2-FeCl3 catalyzed synthesis of benzimidazole
using -keotester/amide as acyl source
To optimize the reaction condition, initially the reaction of o-
phenylene diamine (1a) and ethyl acetoacetate (2a) was chosen as
model using different heterogeneous catalysts. No reaction was
observed in the absence or presence of silica-gel (230-400 Mesh) in
refluxing ethanol (Table 1, entry 1). However, under identical
condition SiO2-KHSO4 (40 mg, 10% KHSO4),12 SiO2-HClO4 (40
mg, 10% w/v)13 and SiO2-FeCl3 (40 mg containing ~12.5% FeCl3)4
catalysts afforded 2-methyl benzimidazole (3a) in 83%, 90% and
98% respectively within 2 h (Table 1, entries 2-4). Reactions at room
temperature in ethanol or DCM or in refluxing DCM with silica-
FeCl3 were not successful. Further decrease of the quantity of SiO2-
FeCl3 also drops the yield dramatically (Table 1, entries 5). Our
study revealed that 5 mol% FeCl3 alone was affective for the
synthesis of 2-methyl benzimidazole in refluxing ethanol with longer
reaction time and lesser yield (Table 1, entry 6).
Table 1: Optimization of reaction condition and substrate scopea
N
R
NH2
Catalyst
R
O
ethanol, reflux
+
N
CO2Et
H
3a: R = Me
3b: R = Ph
NH2
1a
2a-b
Entry Catalyst
Solvent
R
Time Yield
(h)
(%)
1
SiO2
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
2.0
NR
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
2
SiO2-KHSO4
SiO2-HClO4
2.0
1.5
1.5
4.0
5.0
2.0
2.0
2.0
3.0
48.0
8.0
2.0
83
3
90
4
SiO2-FeCl3 (3 mol%)
SiO2-FeCl3(2 mol%)
FeCl3 (5 mol%)
Amberlyst 15
98
5
76
6
75
7
92b
94b
98c
92
8
Amberlite IR120 H+
9
nanoTS1
10
11
12
13
SiO2-FeCl3 (3 mol%)
Amberlite IR120 H+
nanoTS1
73b
Ph
20
98d
Ph
SiO2-FeCl3(3 mol%)
EtOH
Me
a
b
reaction performed in 1 mmol scale; 40 mg resin was used in each
entries; c 5 mg nano TS1 was employed; d reaction was in 20 mmol scale
NH2
O
H
N
OR'
We have also investigated the reaction using commercially available
two sulphonic acid resins (Amberlyst-15 and Amberlite IR 120H+)
and nano titania-silica (TS1).14 All of these immobilized catalysts
shows promising activity in all most same level of efficiency (Table
1, entry 7-9) as like as silica-FeCl3 catalyst. However, the resin
catalyzed or TS1 catalyzed reactions are very slow and produced
lesser yield in cases of other -ketoesters 2b (R = Ph, Table 1, entries
11, 12 vs entries 8, 9) although these catalysts showed excellent
recyclability (results not shown). It is observed from the results
assembled in Table 1 that SiO2-FeCl3 showed better catalytic activity
for the synthesis of 2-methyl and 2-phenyl benzimidazoles (3a-b) in
98% and 92% yield respectively. The present protocol is also
compatible for large scale synthesis (20 mmol) of 2-methyl
R
OR'
2
NH2
R1
R
1
O
O
5
(A)
S
Cl
Fe Cl
H
N
HO
OH
H2O
Cl
Si
N
R1
3
O
R
H
N
NH2
R
OR'
N
CH2CO2R'
OH
N
(B)
Fe
(C)
HO
Fe
Si
HO
OH
Si
Scheme 2: Probable mechanism SiO2-FeCl3 catalysed reaction

Tetrahedron Letters
3
Table 2: Diversity in the synthesis of substituted benzimidazoles using SiO2-FeCl3 (3-5 mol%) as recyclable catalyst.
Entry
Diamine (1)
Product (3)
Time (h)
Yield (%)
-ketoester/amide (2)
NH2
N
O
9411c
Me
CO2Me
1
1.0
N
H
3a
NH2
1a
2c
NH2
N
O
O
60 (3a)
2
3
4
5
6
3.0
2.0
1.5
1.0
2.0
15 (3b)11c
R
3a: R = Me
3b: R = Ph
N
H
Ph
Me
NH2
2d
1a
NH2
N
O
9016
85
CO2Et
N
2e
NH2
3c
H
1a
OAc
NH2
O
O
O
N
+
N
OC6H11
NHAr
NH2
1a
H
N
N
2f
3a
NHAc
NH2
O
90
+
NH2
1a
3a H
Ar = p-tolyl (2g)
NHAc
NH2
O
O
N
88
+
NHAr
N
NH2
1a
3a H
Ar = 4-nitrophenyl(2h)
NO2
N
NH2
O
NO2
7
CO2Et
4.0
1.5
7811b
7711c
N
H
NH2
3d
O2N
1a
2i
O
N
NH2
Ph
CO2Et
8
9
N
H
2b
NH2
3e
3f
1b
NH2
N
O
CO2Et
2a
1.0
1.5
8711c
8211c
N
NH2
H
1c
NH2
N
O
10
CO2Et
2a
N
Cl
Cl
NH2
H
3g
1d
NH2
N
O
11
12
CO2Et
2a
2.0
8411c
N
HO2C
O2N
HO2C
O2N
NH2
H
1e
NH2
3h
N
O
CO2Et
2a
2.5
3.0
3.0
7811c
90
N
NH2
H
3i
1f
NH2
N
O
( )10
13
CO2Et
2j
C11H23
N
H
N
NH2
NH2
3j
1a
1a
O
O
( )14
3k
CO2Et
2k
14
15
92
N
H
C15H31
O
NH2
NH2
N
2.0
3.0
8717
CO2Et
N
N
Ph
N
Ph
1g
2a
H
3l
NH2
N
16
Ph
Ph
8511b
CO2Et
2b
N
Ph
1g
H
3m
and ethyl acetoacetate supports our suggestion although this
intermediate thioaminal (5, see SI) became inert to carbon-carbon
bond cleavage because in this aminal N-H remains in the form of
hydrogen bonded (Scheme 2, inset). Elimination of enolate has
prevented due to poor donor activity of sulphur atom. Finally, we
have investigated catalytic recyclability of the catalyst SiO2-
FeCl3 (40 mg/mmol substrate) from the reaction of
ethylacetoacetate and o-phenylenediamine (20 mmol). After
completion of reaction catalyst was filtered, washed several times
with dicloromethane and dried under vacuum and used for next
cycle. The results (98% initial, 96%, 95%, 92% and 90%)
evidently showed that the loss of catalytic efficiency is retained
(Figure 1). In conclusion, we have developed a novel, non-
conventional, very fast, simple and efficient method to synthesize
highly substituted benzimidazoles from the reaction between -
ketoesters or amides and aromatic diamines through C-C bond
cleavage using silica supported ferric chloride (3 mol%) as
recyclable catalyst. On the basis of our results we were able to
demonstrated mechanistic evidences in favour of the suggested
mechanism. Our study also reveals that the catalyst can be recycled
up to five cycles without significant loss of its activity.

4
Tetrahedron Letters
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Figure 1: Test of recyclability of SiO2-FeCl3 reaction
Typical procedure for benzimidazole formation: To a solution of
aromatic diamine (1 mmol), -ketoester (1 mmol) in ethanol (5 mL)
SiO2-FeCl3 (40 mg) was added followed by reflux for appropriate
time indicated in Table 1 and Table 2. After completion of reaction
(TLC), the catalyst was filtered through whatmann 42 filter paper;
residue was washed several times with dichloromethane. The
combined filtrate was evaporated to dryness to obtain crude product
which was re-crystalized or passing through short pad silica-gel
column to get analytically pure product. 2-n-Pentadecyl-1H-
benzimidazole (3l): Yield 92%, amorphous solid, m. p. 90-92oC;
1H NMR (300 MHz, CDCl3)  9.29 (bs, 1H), 7.75-7.72 (m, 2H),
7.38-7.26 (m, 2H), 3.24 (t, J = 7.5 Hz, 2H), 2.0 (t, J = 7.2 Hz,
2H), 1.37-1.16 (m, 24H); 13C NMR (75 MHz, CDCl3) 154.2,
132.5, 124.9, 114.0, 31.9, 29.7, 29.6, 29.5, 29.4, 29.2, 28.0, 27.2,
22.7, 14.1 HRMS calcd for C22H36N2+H+ 329.2957; found
329.2957
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Acknowledgments
Financial supports by Council of Scientific and Industrial
Research (CSIR), Govt. of India is gratefully acknowledged
(Project no. 02(0235)/15/EMR-II). One of the authors (A. C.) is
thankful to Department of Science and Technology (DST), Govt.
of India for providing DST-INSPIRE research fellowship.
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Tetrahedron Letters
5
Title of the manuscript: Silica-ferric
chloride (SiO2-FeCl3) catalyzed selective
synthesis of 2-substituted benzimidazole
through Csp2-Csp3 bond cleavage of -
ketoester/amide
Authors: Swapan Majumdar, Ankita
Chakraborty, Subrata Bhattacharjee,
Sudipto Debnath and Dilip K. Maiti
Submitted to Tetrahedron Letters
HIGHLIGHTS
 SiO2-FeCl3 was found as effective
catalyst for facile synthesis of
benzimidazole
 Reaction proceed through C-N
annulation followed by C-C bond
cleavage
 The catalyst can be re-used upto five
cycle without loss in catalytic
activity.
———
 Corresponding author. Tel: +91-381-237-9070; Fax: +91-381-
2374802; e-mail: smajumdar@tripurauniv.in