I2/TBHP promoted oxidative C–N bond formation at room temperature: Divergent access of 2-substituted benzimidazoles involving ring distortion

Article abstract of DOI:10.1016/j.tetlet.2018.05.028

A new ‘one pot’ tandem synthesis of 2-substituted benzimidazoles has been developed from 2-aminobenzyl alcohol/2-aminobenzamide and different coupling partners (nitriles, aldehydes and 1,3-diketones) via iodine and TBHP promoted oxidative ring contraction. The present strategy involves sequential C–N bond formation, cyclization, subsequent ring contraction and dehydrogenation to afford various medicinally important benzimidazole derivatives in moderate to good yields. This operationally simple synthetic approach proceeds at room temperature under base-free condition, broadly applicable to a wide array of nitriles and aldehydes bearing oxidation prone functional groups and noteworthy to mention that various acyclic 1,3-diketones undergo selective C–C bond cleavage leading to 2-alkyl benzimidazoles under mild condition.

Full text of DOI:10.1016/j.tetlet.2018.05.028

Accepted Manuscript
I2/TBHP promoted oxidative C-N bond formation at room temperature: Diver-
gent access of 2-substituted benzimidazoles involving ring distortion
Moumita Saha, Asish R. Das
PII:
S0040-4039(18)30627-0
https://doi.org/10.1016/j.tetlet.2018.05.028
TETL 49975
DOI:
Reference:
Tetrahedron Letters
To appear in:
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Revised Date:
Accepted Date:
11 April 2018
11 May 2018
13 May 2018
Please cite this article as: Saha, M., Das, A.R., I2/TBHP promoted oxidative C-N bond formation at room
temperature: Divergent access of 2-substituted benzimidazoles involving ring distortion, Tetrahedron Letters
(2018), doi: https://doi.org/10.1016/j.tetlet.2018.05.028
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2
Graphical Abstract
I2/TBHP promoted oxidative C-N bond
formation at room temperature: Divergent
access of 2-substituted benzimidazoles
involving ring distortion
Leave this area blank for abstract info.
1.1. Moumita Saha, Asish R. Das*

1
Tetrahedron Letters
1.1. I2/TBHP promoted oxidative C-N bond formation at room temperature:
Divergent access of 2-substituted benzimidazoles involving ring distortion
1.2. Moumita Saha, 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
A new ‘one pot’ tandem synthesis of 2-substituted benzimidazoles has been developed from 2-
aminobenzyl alcohol/2-aminobenzamide and different coupling partners (nitriles, aldehydes and
1,3-diketones) via iodine and TBHP promoted oxidative ring contraction. The present strategy
involves sequential C-N bond formation, cyclization, subsequent ring contraction and
dehydrogenation to afford various medicinally important benzimidazole derivatives in moderate
to good yields. This operationally simple synthetic approach proceeds at room temperature
under base-free condition, broadly applicable to a wide array of nitriles and aldehydes bearing
oxidation prone functional groups and noteworthy to mention that various acyclic 1,3-
diketones undergo selective C–C bond cleavage leading to 2-alkyl benzimidazoles under mild
condition.
Available online
1.
Keywords:
2-substituted benzimidazole
iodine
TBHP
ring distortion
C-C bond cleavage
2009 Elsevier Ltd. All rights reserved.
low toxicity and versatility.8 Particularly, the combination of I2
and TBHP has been proven as a promising reagent for the
2. Introduction
In recent years, reactions referring to the carbon-heteroatom
bond formations have constituted the central theme of modern
organic synthesis. Among those, direct oxidative C-N bond
forming reactions have witnessed a sudden expansion to
construct numerous pharmacology oriented heterocycles.1,2
Again, amid several pharmaceutical constituents, N-heterocycles
are the most abundant and integral scaffolds.3 In particular,
benzimidazoles are an important class of N-heterocycles due to
their diverse pharmacological properties and therapeutic
potentials like anti-cancer, anti-fungal, anti-bacterial, anti-
leishimanial and antiviral.4 Therefore, synthesis of benzimidazole
nucleus with enhanced scope and biological activity is interesting
to several synthetic and medicinal chemists. The conventional
route for the synthesis of benzimidazole core mainly involves
coupling of 1,2-phenylenediamines with aldehydes, carboxylic
acids, nitriles, methylarenes and ortho-esters followed by
oxidative cyclization.5,6 Other new methods such as transition
metal-catalyzed C−N coupling of N-(ortho-haloaryl)amidines or
construction of biologically significant scaffolds through C-C, C-
N, C-X (X = O, S) bond formation at room temperature.9
Currently, ring distortion strategy is an interesting approach
which enables generation of complex heterocyclic framework
from easily available precursors under mild condition. However,
only two examples on ring distortion strategy have been
documented in literature.10a-b Sen and co-workers first described
oxone catalyzed ring contraction to synthesize benzimidazoles
from 2-aminobenzylamine and aldehydes.10a Later, our group
reported the synthesis of 2-substituted benzimidazoles from 2-
aminobenzyl amine and aldehydes/aryl amines through molecular
iodine and iodobenzene diacetate promoted ring contraction.10b
Considering the synthetic advantages of ring distortion strategy,
additional mechanistic investigation and expansion of its scope is
desirable. Moreover, selective cleavage of unstrained C–C bond
using 1,3-diketones as starting materials hold significant
potentials for developing useful transformations in organic
synthesis. However, most of the reported methods require
transition-metal catalyst, strong acidic condition and high thermal
energy to avail selective C-C bond cleavage.11
N-(ortho-haloaryl)
amides,
aromatic
C−H
activation,
iodobenzene catalyzed C−H amination of N-substituted
amidines, oxidative C(sp3)–H amination of N-substituted 1,2-
phenylenediamines and N-Aryl imines have also been reported.7
Besides, the literature survey reveals that nitrile compounds
are viable nitrogen sources for the synthesis of several nitrogen
In spite of enough diversity, these methods are plagued with
certain limitations such as harsh reaction condition, toxic metal
oxidants, thermal energy and noxious halogenated reagents.
Hence, synthesis of biologically important heterocycles using
mild and inexpensive reaction condition is still highly
challenging. During the last few decades molecular iodine has
emerged as the key reagent in numerous oxidative
transformations due to its easy handling, commercial availability,
containing
compounds.12 However,
coupling
of
2-
aminobenzaldehyde and benzonitrile is less favourable due to the
rapid homo condensation tendency of 2-aminobenzaldehyde.13
Therefore, coupling of 2-animobenzyl alcohol with benzonitriles
is not well-explored and requires enough investigation to employ
these substrates in benzimidazole synthesis. The present
transformation proceeds via initial coupling of 2-aminobenzyl

2
alcohol or 2-aminobenzamide with benzonitriles, aldehydes or
1,3-diketones followed by intramolecular cyclization, successive
ring contraction and oxidation. To our knowledge, this is the first
attempt of benzimidazole synthesis from the reaction of 2-
aminobenzyl alcohol or 2-aminobenzamide and various coupling
agents (nitriles, aldehydes or 1,3-diketones) (Scheme 1) through
a cascade ring distortion. The present method is environmentally
entries 17-19). Afterwards, different solvent systems were
screened including polar and non-polar such as toluene,
dichloroethane (DCE), acetonitrile (MeCN), DMF and DMSO
(Table 1, entries 7–11). Other solvents were inferior to DMF with
regard to the yield of 3a (66% yield in AcCN, 52% yield in
toluene) (Table-1, entries 8, 9-11). When the model reaction was
performed using degassed solvent (DMF) under nitrogen
atmosphere, the product yield was significantly reduced (Table-1,
entry-20). Additional experiments (control reactions, Scheme-2,
1-3) showed the necessity of both additive (I2) and oxidant
(TBHP) to achieve the targeted desired product. After identifying
the selective reaction condition, we next explored the substrate
scope of the cascade process (Table-3). The electronic properties
of the substituents on the aryl ring of nitriles influenced the
reaction yield to some extent. Generally, the nitriles bearing an
electron-withdrawing group (e.g. –Cl) (Table 3, entry 3i)
provided a slightly higher yield of desired products than those
bearing an electron-donating group (e.g., –CH3, –OH and –SMe)
(Table 3, entries 3b, 3c, 3d). Unfortunately, acetonitrile failed to
afford the expected product under the achieved conditions. The
heterocyclic nitriles appeared to be most effective, therefore
delivering the corresponding 3e, 3f and 3g in high yield.
transcendent, features
a
simple experimental procedure,
accommodates a broad substrates variety, generates clean by-
products and thus presents an efficient synthetic tool to achieve a
good number of benzimidazoles satisfactorily.
Scheme 1. Synthesis of benzimidazole involving ring distortion
Table 1. Optimization of the reaction conditions to synthesize
benzimidazolea from 2-aminobenzyl alcohol and nitrile
Entry
Additive
(mol %)
Oxidant
(equiv)
Solvent
Time (h)
Yieldb (%)
3a 3aa 4a
1
2
3
4
5
6
7
8
I2 (20)
I2 (20)
I2 (20)
I2 (30)
I2 (40)
I2 (50)
I2 (50)
I2 (50)
I2 (50)
I2 (50)
I2 (50)
I2 (50)
I2 (50)
I2 (100)
KI (50)
TBAI (50)
I2 (50)
I2 (50)
I2 (50)
I2 (50)
I2 (50)
TBHP (3)
TBHP (4)
TBHP (5)
TBHP (5)
TBHP (5)
TBHP (5)
TBHP (5)
TBHP (5)
TBHP (5)
TBHP (5)
TBHP (5)
TBHP (6)
TBHP (7)
TBHP (5)
TBHP (5)
TBHP (5)
Oxone (5)
H2O2 (5)
DCM
DCM
DCM
DCM
DCM
DCM
DCE
MeCN
DMF
DMSO
Toluene
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
10
10
10
9
8
8
8
8
8
8
8
8
8
8
8
8
8
8
30 trace nd
3. Results and Discussion
38 trace
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
trace
nd
nd
nd
nd
46
54
60
nd
nd
nd
To establish the optimal conditions of above hypothesis, 2-
aminobenzyl alcohol 1 and benzonitrile 2 were chosen as model
substrates. Initially, the reaction between 1 and 2 were carried out
in 5 ml DCM at r.t. using anhydrous ZnI2 (30 mol %), iodine (0.2
equiv) and TBHP (3.0 equiv) as Lewis acid, additive and oxidant
respectively (Table-1, entry 1) at room temperature. Gratifyingly,
after 10 h almost complete conversion of the starting materials
was noticed (TLC monitoring) and the desired product 3a was
isolated in 30% yield (Table 1, entry 1). The ESI mass spectral
data of the crude mixture (see SI, RM-1) indicates the presence
of unreacted 2-aminobenzyl alcohol and probably the coupling
product 3aa in traces. No quinazoline product 4a was detected in
ESI-MS data. The mass spectral analysis indicates that increase
in the ratio of both oxidant and additive might improve the yield
of 3a. However, the elevation of reaction temperature was not
effective. Moreover, the model reaction under microwave
condition (100 W, 0.8 h) furnished 3a in trace amount
accompanied by the formation of an inseparable reaction mixture
of several side products (Table-1, entry-21). The impact of
different Lewis acids was also examined and ZnI2 appeared to be
the most effective for this transformation (Table-2, entry 2). With
the increase in the amount of iodine (from 0.2 equiv to 0.5 equiv)
and TBHP (from 3 equiv to 5 equiv), the yield of 3a was
significantly increased to 72% (Table 1, entry 1-9). Further
increase in the amount of oxidant or additive led to slight
decrease in product yield (Table 1, entries 13, 14) showing iodine
(0.5 equiv) and TBHP (5.0 equiv) to be the most effective
reagent combination. After fixing the optimal conditions, the
combination of TBHP with other iodine salts such as KI, TBAI
etc. were tested but they showed lower catalytic activities (Table
1, entry 15, 16). Screening of similar oxidants such as DTBP,
H2O2, Oxone etc. revealed that TBHP is the best choice (Table 1,
64 nd
59 nd
66 nd
72 nd
71 nd
52 nd
73 nd
68 nd
65 nd
25 nd
44 nd
9c
10
11
12
13
14
15
16
17
18
19
20d
21e
nd
nd
trace nd
trace nd
DTBP (5)
TBHP (5)
TBHP (5)
8
8
0.8
52
nd
trace nd
a Reaction conditions: In each case 1 (1.0 mmol), benzonitrile 2
(1.0 mmol), anh. ZnI2 (30 mol %) in 5 mL of solvent were stirred
at rt for a stipulated period of time. n.d. means no product
detected. bIsolated yields of 3a. c Standardized reaction condition.
TBHP: tert-butyl hydroperoxide (70% in water); H2O2 (30 wt%
in H2O); DTBP: di-tert-butyl peroxide; KI: potassium iodide;
d
e
TBAI: tetrabutylammonium iodide. Under N2 atmosphere.
Under microwave condition.
To amplify the substrate scope, we then attempted the reaction
of anthranilamide with a variety of nitriles, aldehydes and acyclic
1,3-diketones under the optimized conditions and the results are
summarized in Table 4 and 5. Fortunately, notable success has
been achieved. Several additive and oxidant combinations were
screened and the combination of iodine (0.2 equiv) and TBHP
(2.0 equiv) was found to be the most efficient reagent
combination. In this case the similar electronic effects of the
substituent on nitriles as well as aldehydes have also been

3
a
experienced. The oxidation prone functional groups on nitriles as
well as aldehydes exhibited good tolerance during the reaction
condition generating 3c, 3d, 3s and 3q satisfactorily. It is
important to mention that, exploitation of 1,3-diketone (e.g.
acetylacetone or ethylacetoacetate) has also materialized the
benzimidazole product 3ab (Table-5) indicating selective C-C
bond cleavage under the imposed reaction condition.
Reaction conditions: 1 (1.0 mmol), 2 (1.0 mmol), anh. ZnI2
(30 mol %), aq. TBHP (5.0 mmol) and I2 (0.5 mmol) in 5 ml
DMF were stirred in a 25 mL rb flask for 8.0 h; b Isolated yield.
Table 4. Substrate scope for the synthesis of benzimidazoles
from 2-aminobenzamide and nitrilea
Table 2. Influence of Lewis Acida
Entry
Lewis acid
ZnCl2
ZnI2
Time (h)
8.0
Yieldb (%)
3a, 80%b
3d, 78%
3g, 86%
3c, 75%
3f, 78%
3i, 84%
3b, 78%
3e, 84%
1
2
3
4
5
59
72
25
trace
-
8.0
CuI
8.0
Cu(OAc)2
Cu
8.0
8.0
a
Reaction conditions: 1 (1.0 mmol), 2 (1.0 mmol), Lewis acid
(30 mol %), I2 (0.5 mmol) and aq. TBHP (5.0 mmol) in DMF (5
3h, 83%
mL) were stirred in a 25 mL rb flask for 8.0 h. b Isolated yield.
a Reaction conditions: 1a (1.0 mmol), 2 (1.0 mmol), anh. ZnI2 (30
mol %), I2 (0.2 mmol) and aq. TBHP (2.0 mmol) in MeCN (5
mL) were stirred in a 25 mL rb flask for 3.0 h. b Isolated yield.
To probe the reaction mechanism, some control experiments
were conducted (Scheme 2). The control reaction (Scheme-2, No.
2) indicates that I2 did not react with the substrates directly but
generates a series of reactive radical species in the presence of
TBHP14 prior to reacting with 1 or 1a and 2a'/2a''. TEMPO
(2,2,6,6-Tetramethylpiperidine-N-oxyl) was added as a radical
scavenger under the standard reaction conditions which resulted
in a considerable decrease in product yield 3a (Scheme-2, 41%
isolated yield), indicating the possibility of radical pathway.
Table 5. Substrate scope for the synthesis of benzimidazolea from
2-aminobenzamide and aldehyde/1,3-diketonea
All the synthesized compounds have been well characterized
by spectral analysis (1H NMR, 13C NMR, HRMS, IR) and finally
the structure of the benzimidazole scaffold was confirmed
through X-ray crystallographic analyses of single crystals of
representative compounds 3d and 3n (CCDC 1822507 and
1820917, see the Supporting Information)
3a, 86%b
3m, 82%
3k, 83%
3o,86%
3j, 89%
3l, 81%
3p,88%
Table 3. Substrate scope for the synthesis of benzimidazoles
from 2-aminobenzyl alcohol and nitrilea
3n,85%
3r, 81%
3s, 78%
3t,72%
3q, 82%
3u, 76%
3a, 72%b
3c, 72%
3v, 89%
3w, 92%
3x, 87%
3b, 73%
3ab c,d
3y, 84%
3z, 86%
3f, 77%
3e, 80%
3d, 76%
a
Reaction conditions: 1a (1.0 mmol), 2a' (1.0 mmol) or 2a''
(1.1), aq. TBHP (2.0 mmol) and I2 (0.2 mmol) in MeCN (3 mL)
b
were stirred in a 25 mL rb flask for 2.0 h. Isolated yield of the
product (3a-3z). Reaction time: 16 h. Isolated yield of 3ab:
c
d
3g, 82%
3h, 82%
3i, 80%

4
44% when R3=‘OEt’; 48% when R3=‘Me’ and 42% when R3=
‘OPh’ and in all cases R2=Me.
This protocol uses easily accessible 2-aminobenzyl alcohol and
2-aminobenzamide as starting materials avoiding pre-
functionalized or halogenated substrates, or oxidants and harsh
reaction conditions. The reaction proceeded smoothly with a
variety of nitriles and aldehydes containing oxidation prone
functional groups. Moreover, this protocol embraces an oxidative
C-N bond formation with concomitant C-C bond cleavage
representing the combination of I2 and TBHP as unique reagent
in synthetic chemistry.
4. Acknowledgments
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 is thankful to U.G.C, New Delhi, India for the grant
of her Junior Research fellowship. Crystallography was
performed at the DST-FIST, India-funded Single Crystal
Diffractometer Facility at the Department of Chemistry,
University of Calcutta.
Fig. 1. ORTEP diagram of compound 3d
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In summary, we have developed a practical one-flask protocol
for the assembly of diversified 2-substituted benzimidazoles
through iodine and TBHP facilitated oxidative ring contraction.

5
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To an oven dried rb flask with a magnetic stir bar were added 2-
amiobenzyl alcohol 1 (123.0 mg, 1.0 mmol), nitrile derivatives
(108.0 mg, 1.0 mmol) 2, anhydrous zinc iodide (0.3 equiv, 96 mg)
and the mixture were stirred in 5 mL DMF at room temperature
for 1h. Then iodine (127 mg, 0.5 mmol) and aq. TBHP (70%
solution in water, 0.66 mL, 5.0 mmol) were added successively
and stirring continued at room temperature for another 7h. After
completion of the reaction (monitored by TLC), the reaction
mixture was quenched by aq. Na2S2O3 solution (10%, 20 ml),
extracted with EtOAc (10 mL × 3), and the combined organic
extract was dried over anhydrous sodium sulfate. Removal of the
solvent under reduced pressure left a crude mass which was
purified by column chromatography using silica gel (60-120 mesh
size) (25% EtOAc/hexane) to afford pure 3a (140 mg; 72% yield).
2-phenyl-1H-benzo[d]imidazole (3a)10a,b
Compound 3a was obtained as a white solid (140 mg, 72% yield);
m.p. 292-294 0C; IR (KBr): 3188, 2981, 1627 cm-1; 1H NMR (300
MHz; DMSO-d6): δ 12.97 (br s, 1H), 8.21-8.19 (m, 2H), 7.62-7.54
(m, 5H), 7.23 (m, 2H); 13C NMR (75 MHz; DMSO-d6): δ 151.5,
143.8, 134.9, 130.5, 130.2, 129.1, 126.7, 122.1, 121.1, 118.9,
116.5; HRMS (ESI-TOF) m/z: [M
+
H]+ calculated for
(C13H10N2+ H)+: 195.1049, found 195.1057.
Supplementary Material
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B.; Ahamed, A. J. Org. Biomol. Chem. 2016, 14, 11061-11064. (d)
Gong, X.; Wu, J. Org. Biomol. Chem. 2015, 13, 11657-11662. (e)
Meesin, J.; Katrun, P.; Pareseecharoen, C.; Pohmakotr,
M.; Reutrakul, V.; Soorukram, D.; Kuhakarn, C. J. Org.
Chem. 2016, 81, 2744–2752. (f) Wang, Y.; Jiang, C. M.; Li, H.
L., He, F. S.; Luo, X.; Deng, W. P. J. Org. Chem.
2016, 81, 8653–8658.
Supplementary material that may be helpful in the review
process should be prepared and provided as a separate electronic
file. That file can then be transformed into PDF format and
submitted along with the manuscript and graphic files to the
appropriate editorial office.
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6
 I2/ TBHP promoted ring distortion leading
to 2-substituted benzimidazoles.
 2-aminobenzyl alcohol/2-aminobenzamide
are the substrates.
 Mild and base free protocol.
 Broad functional group tolerance.
 Selective C-C bond cleavage of 1,3-
diketones.