Practical application of PhI(OAc)2/I2 combination to synthesize benzimidazoles from 2-aminobenzylamine through ring distortion strategy

Article abstract of DOI:10.1016/j.tetlet.2017.01.099

In this present work the combination of iodobenzenediacetate (PIDA)/iodine has been established as a promising reagent to promote the construction of 2-substituted benzimidazoles from 2-aminobenzylamine and a variety of easily available aldehydes/arylamines through a ring distortion strategy. The present protocol offers mild, metal free, robust conditions to synthesize 2-substituted benzimidazoles in good to excellent yields. In addition, the oxidation prone functional groups show tolerance during the reaction and after completion of the reaction pure products can be easily obtained applying hassle free filtration of the reaction mixture through silica gel bed.

Full text of DOI:10.1016/j.tetlet.2017.01.099

Accepted Manuscript
Practical application of PhI(OAc)2/I2 combination to synthesize benzimidazoles
from 2-aminobenzylamine through ring distortion strategy
Moumita Saha, Prasun Mukherjee, Asish R. Das
PII:
S0040-4039(17)30143-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.01.099
TETL 48602
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
26 December 2016
25 January 2017
27 January 2017
Please cite this article as: Saha, M., Mukherjee, P., Das, A.R., Practical application of PhI(OAc)2/I2 combination to
synthesize benzimidazoles from 2-aminobenzylamine through ring distortion strategy, Tetrahedron Letters (2017),
doi: http://dx.doi.org/10.1016/j.tetlet.2017.01.099
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Graphical Abstract
Practical application of PhI(OAc)2/I2
combination to synthesize benzimidazoles
from 2-aminobenzylamine through ring
distortion strategy
Leave this area blank for abstract info.
Moumita Saha, Prasun Mukherjee, Asish R. Das*

1
Tetrahedron Letters
Practical application of PhI(OAc)2/I2 combination to synthesize benzimidazoles from
2-aminobenzylamine through ring distortion strategy
Moumita Saha, Prasun Mukherjee, Asish R. Das*
Department of Chemistry, University of Calcutta, Kolkata-700009, India
*Corresponding author: Tel.: +913323501014, +919433120265; fax:913323519754;
E-mail address: ardchem@caluniv.ac.in , ardas66@rediffmail.com
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
In this present work the combination of iodobenzenediacetate (PIDA)/iodine has been
established as a promising reagent to promote the construction of 2-substituted benzimidazoles
from 2-aminobenzylamine and a variety of easily available aldehydes/arylamines through a ring
distortion strategy. The present protocol offers mild, metal free, robust conditions to synthesize
2-substituted benzimidazoles in good to excellent yields. In addition, the oxidation prone
functional groups show tolerance during the reaction and after completion of the reaction pure
products can be easily obtained applying hassle free filtration of the reaction mixture through
silica gel bed.
Available online
Keywords:
2-substituted benzimidazole
metal free
iodobenzene diacetate
ring distortion
iodine
2009 Elsevier Ltd. All rights reserved.
1. Introduction
Nitrogen-containing heterocycles are well abundant in
numerous natural products and synthesized compounds are
extremely valuable due to their widespread biological activities
and countless other significant utilities.1 Among them,
benzimidazoles have well recognized for their broad spectrum of
bioactivity along with their several additional applications.2
Furthermore, they have been found to be the key structural motif
in several potent naturally occurring compounds.3 Extensive
studies for bioactivity have revealed benzimidazole cores are
promising as antimicrobial compounds, anthelmintic and
antipsychotic drugs, and also antiulcer, anticancer agents.4 In
addition several benzimidazole derivatives are used as
phosphorescent emitters and ligands.5 The emergent significance
of benzimidazoles is also emphasized from the huge sale of the
drugs containing this heterocyclic core.6
Scheme 1. Synthesis of benzimidazoles
Recently, Sen et al, have demonstrated the synthesis of
benzimidazole
derivatives
from
aldehyde
and
2-
aminobenzylamine in presence of Oxone (scheme 1, entry 1).9
Despite of the large substrate scope, this method suffers from the
requirement of large amount of solvent (DMF), metal ion
containing toxic oxidant, relatively long reaction time and low
yield of the products which essentially demand an alternative
superior protocol to synthesize benzimidazoles from
Consequently, many synthetic advances have been well
established in order to access this particular heterocycle. Majority
of the reported procedures to synthesize benzimidazoles largely
rely on the reaction of o-phenylenediamine with carboxylic acids,
acid chlorides and carbaldehydes in presence of acid and
oxidizing agents at elevated temperature.7 Although, during the
past few decades several alternative methods have been
developed involving transition metal catalyzed intra molecular C-
N bond formation essentially.8 However majority of these
reported procedures suffers from harsh reaction conditions,
prolonged reaction time and expensive metal catalysts. Thus
developments of mild yet efficient protocols are still challenging
to synthesize these valuable heterocyclic entities.
carbaldehyde
and
2-aminobenzylamine
derivatives
circumventing the shortcomings. Hypervalent iodine reagents,
especially iodobenzenediacetate (PIDA) has successfully
employed in several transformations.10 Moreover, use of PIDA is
beneficial since it is comparatively less toxic, cheap and easily
available. Combination of PIDA and molecular iodine has been
established earlier as an efficient radical generator.11 However,
despite its efficacy, only a handful of reactions are available in
literature which apply this reagent combination.12 Following our
recent effort in hypervalent iodine promoted construction of

2
Tetrahedron
carbon-heteroatom bond to synthesize biologically relevant
heterocycles,13 herein we wish to report a metal free, robust
synthesis of benzimidazoles employing
screened for this reaction. However, in each case 2a was obtained
in comparatively low yield after a much longer period of time
(Table 1, entry 7-11).
carbaldehydes/arylamines and 2-aminobenzylamine upon
application of PIDA/iodine combination using DCM as solvent
at room temperature (Scheme 1).
Achieving the optimized reaction conditions for our protocol
to synthesize benzimidazoles, we have then investigated the
substrate scope for this particular reaction. A large variety of
aromatic, heteroaromatic and aliphatic aldehydes were employed
for this reaction. These aldehydes along with 2-
aminobenzylamine were treated with PIDA (0.5 mmol) and
iodine (1.5 mmol) in 3 mL of DCM at room temperature. To our
delight, this protocol was found to be extremely facile to access a
library of functionalized benzimidazoles (Table 2, entry 2a-2s). It
is noteworthy to mention that the reaction is absolutely clean
producing solely 2-substituted benzimidazoles and no other side
products were detected. After completion of the reaction the pure
product was isolated by filtration of the reaction mixture through
a silica gel bed (mesh 100-200). A wide range of aromatic
2. Results and Discussion
To study the possibility of our hypothesis for the synthesis of
benzimidazoles, 2-aminobenzylamine 1a and benzaldehyde were
chosen as the model substrate. Initially, 1a (1.0 mmol) and
benzaldehyde (1.0 mmol) were taken in a 25 mL rb fitted with a
calcium chloride guard tube and then treated with 1.0 mmol
PIDA and 1.0 mmol of iodine in 3 mL DCM at rt. After 1.2 h
complete conversion of the starting materials was observed and
2a was obtained in 80% yield (Table 1, entry 1). Having such an
Table 1. Optimization of reaction condition to synthesize
benzimidazolesa
Table 2. Substrate scope for the synthesis of benzimidazolesa
yieldb (%)
2a
PhI(OAc)2
(mmol)
I2
solvent
time
(h)
entry
(mmol)
3a
nd
50
nd
nd
nd
nd
nd
nd
nd
nd
nd
2a,94%b
2c, 95%
2g, 96%
2b, 96%
1
2
1.0
1.5
0.8
0.5
0.4
0.5
0.5
0.5
0.5
0.5
0.5
1.0
0.5
1.2
1.5
1.6
1.0
1.5
1.5
1.5
1.5
1.5
DCM
DCM
1.2
1.1
1.2
1.0
1.3
2.0
2.0
2.0
4.0
3.0
4.0
80
30
86
94
75
60
84
70
60
72
52
2d, 92%
3
DCM
2e, 95%
2i, 96%
2f, 96%
2j, 92%
2h, 95%
2l, 88%
4
DCM
5
DCM
6
DCM
2k, 90%
2o, 84%
7
DCE
8
MeCN
THF
9
2p, 90%
10
Toluene
EtOAc
11
a
In each case 1a (1.0 mmol), benzaldehyde (1.0 mmol) and 3
mL of solvent were taken in a 25 mL rb fitted with a calcium
chloride guard tube at rt. b Yield of the isolated product.
2q, 88%
a
reaction conditions: 1a (1.0 mmol), aldehyde (1.0 mmol),
DCM (3 mL), PIDA (0.5 mmol) and I2 (1.5 mmol) were stirred
for 1.0 h in a 25 mL rb fitted with a calcium chloride guard tube.
b isolated yield of the product.
admirable result, we have then immediately started to
optimize the reaction conditions in favour of the formation of 2a.
To observe the effect of the amount of oxidants on the yield of 2a
we have then carried out the reaction employing PIDA and iodine
in different ratios (Table 1, entry 2-6).When a combination of 1.5
mmol PIDA and 0.5 mmol of iodine was used, 2a was obtained
in very low yield along with the formation of 3a in a considerable
amount (Table 1, entry 2). Interestingly, an increase in the
amount of iodine with a decrease in amount of PIDA improved
the yield of 2a to 86% yield (Table 1, entry 3) and 2a was
obtained in 94% when a combination of 0.5 mmol PIDA and 1.5
mmol molecular iodine was employed (Table 1, entry 4).
However, additional increase in the amount of iodine results in
the formation of 2a in low yield and an increase in reaction time
(Table 1, entry 5). When 0.5 mmol PIDA and 1.0 mmol iodine
were used 60% of 2a was obtained after 2 h. After that, solvents
such as DCE, MeCN, THF, toluene and ethyl acetate were also
aldehydes, possessing electron withdrawing as well as
electron donating functional groups, was chosen in this purpose.
Agreeably the efficiency of the reaction remained unperturbed
and product yield was found to be excellent in all the cases
(Table 2, entry 2a-2l). On the other hand the protocol was found
to be equally competent in case of aliphatic and heteroaromatic
aldehydes (Table 2, entry 2m-2r). It is worth mentioning that
PIDA and iodine promote the product formation
chemoselectively intacting the oxidation prone electron rich
aromatic rings as well as functional groups during the reaction
(Table 2, entry 2k, 2o, 2r and 2s). All the synthesized
benzimidazole derivatives have been well characterized by
spectral analysis (1H NMR, 13C NMR, HRMS, IR) and finally the

3
structural motif of the benzimidazole scaffold was established
through X-ray crystallographic analysis of single crystal of one
representative compound 2l (CCDC 1507083, see the Supporting
Information). In view of the above impressive results, we have
then tried to extend the scope of these protocols in realizing
benzimidazoles and quinazolines from 2-aminobenzylamine and
arylamine derivatives. To synthesize benzimidazole, some
selected aryl amines (1.0 mmol) were stirred in 3mL DCM in
Scheme 2. Plausible mechanism for the formation of
benzimidazoles
aziridine ring by a water molecule leads to the formation of
intermediate Va. Va then gets protonated to generate Vb which
can undergo fragmentation in order to produce VI. Oxidation by
molecular iodine then transforms VI to the desired benzimidazole
2. In case of arylamines (1c) initial oxidation of the amine takes
place in presence of PIDA to generate the corresponding
aldehyde. Then it follows essentially the same path to afford
product 2.
Table 3. Synthesis of benzimidazolesa
3. Conclusions
In conclusion 2-substituted benzimidazoles have been
efficiently synthesized from 2-aminobenzylamine and a variety
of easily available aldehydes/arylamines ( possessing electron
donating as well as electron withdrawing groups) by employing
iodobenzenediacetate/iodine combination. through
a
ring
2a, 88%b
2t, 92%
2l, 85%
distortion strategy. The protocol offers mild, metal free, robust
conditions to synthesize these heterocycles in good to excellent
yields by assisting the C-N bond formation at room temperature.
4. Acknowledgments
2u, 90%
We acknowledge the financial support from the centre of
CAS-V (Synthesis and functional materials) (support offered by
UGC, New Delhi) of the department of Chemistry, University of
Calcutta. MS and PM are thankful to U.G.C, New Delhi, India
for the grant of their Junior and Senior Research fellowships
respectively. Crystallography was performed at the DST-FIST,
India-funded Single Crystal Diffractometer Facility at the
Department of Chemistry, University of Calcutta.
a
reaction conditions: 1a (1.0 mmol), aryl amines (1.0 mmol),
PIDA (1.5 mmol), iodine (1.5 mmol) and DCM ( 3 mL) at rt for
1.3 h. b yield of the isolated product.
presence of 1.0 mmol of PIDA for 15 min followed by the
addition of 1a (1.0 mmol), 0.5 mmol PIDA and 1.5 mmol of
iodine at rt. Satisfyingly the corresponding benzimidazoles were
obtained in excellent yield (Table 3, entry 2a, l, t and u).
However, when n-octylamine was employed in place of aryl
amine this protocol have failed to generate the desired
benzimidazole derivative and the reactants have found to be
remain unaffected after a prolong time ( 24h). This may be due to
the less reactivity of alkyl amines towards the applied reagent
combination than that of arylamines under the experimental
condition as developed. In this case also, all the products were
fully characterized through spectral analysis (1H NMR, 13C
NMR, HRMS, IR).
A plausible mechanism for the formation of benzimidazole is
depicted in scheme 2. Initially 1a reacts with aldehyde 1b to form
the intermediate I. Reaction between 1.0 equiv PIDA and
1.0equiv iodine generates 2.0 equiv of IOAc in situ.14 This
electrophilic IOAc then reacts with (I) to generate intermediate II
which then immediately undergoes homolytic bond cleavage in
order to produce the radical intermediate III. Intermediate III then
undergoes a rearrangement in order to afford the strained
aziridinium intermediate IV. Then subsequent opening of
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5
Highlights
 2-substituted benzimidazoles from 2-aminobenzylamine and aldehydes.
 PhI(OAc)2/I2 reagent combination materializes ring distortion strategy.
 Benzylamines can also be used in lieu of aldehydes.
 Protocol offers well tolerance towards oxidation prone functional groups.
 Pure products can be obtained applying chromatography free technique.