Eco-friendly strategy: design and synthesis of biologically potent benzimidazole-amine hybrids via visible-light generated oxidative C-H arylamylation of analenic amidines

Article abstract of DOI:10.1016/j.tetlet.2015.10.042

An operationally simple visible light mediated intramolecular cyclization of benzimidazole to 2-amino benzimidazole hybrid. The disclosed procedure is rapid and the convenient synthesis of benzimidazole-amine hybrids from easily available substituted cycl

Full text of DOI:10.1016/j.tetlet.2015.10.042

Accepted Manuscript
Eco-friendly Strategy: Design and Synthesis of biologically potent Benzimida-
zole-amine hybrids via visible-light generated oxidative C-H arylamylation of
analenic amidines
I.R. Siddiqui, Farah Ibad, Afshan Ibad, Malik Abdul Waseem, Geeta Watal
PII:
S0040-4039(15)30239-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.10.042
TETL 46871
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
14 August 2015
3 October 2015
10 October 2015
Please cite this article as: Siddiqui, I.R., Ibad, F., Ibad, A., Abdul Waseem, M., Watal, G., Eco-friendly Strategy:
Design and Synthesis of biologically potent Benzimidazole-amine hybrids via visible-light generated oxidative C-
H arylamylation of analenic amidines, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.
2
015.10.042
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Graphical Abstract
Eco-friendly Strategy: Design and Synthesis
of biologically potent Benzimidazole-amine
hybrids via visible-light generated oxidative
C-H arylamylation of analenic amidines
Leave this area blank for abstract info.
b
I.R.Siddiqui,* Farah Ibad, Afshan Ibad, Malik Abdul Waseem, Geeta Watal*
R1
H
N
N
R2
N
R1
R2
Neat Condition
N
Ru(byp)3Cl2
Blue LED
N
NH2

1
Tetrahedron Letters
Eco-friendly Strategy: Design and Synthesis of biologically potent
Benzimidazole-amine hybrids via visible-light generated oxidative C-H
arylamylation of analenic amidines
a
a
a
a
b
I.R.Siddiqui,  Farah Ibad, Afshan Ibad, Malik Abdul Waseem, Geeta Watal
a
Laboratory of Green Synthesis,Department of Chemistry, University of Allahabad-211002, India
Medicinal Research Lab, Department of Chemistry, University of Allahabad-211002, India
b
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An operationally simple visible light mediated intramolecular cyclization of benzimidazole to 2-
amino benzimidazole hybrid. The disclosed procedure is rapid and convenient synthesis of
benzimdazole-amine hybrids from easily available substituted cyclic, acyclic amines and
benzimidazole under neat conditions in presence of catalyst tris(2,2-bipyridine)ruthenium(II)
chloride. Indubitably this methodology gives facile and straightforward pathway to construct
benzimdazole-amine hybrid derivatives in an eco-friendly fashion. The reaction proved to be
economical interims of product yield, low loading of catalyst under solvent free condition. The
solvent free method has a supreme importance in industrial research. The scope and efficiency
of this new green method is significantly better than the existing methods.
Available online
Keywords:
Visible Light
tris(2,2-bipyridine)ruthenium (II) chloride
Benzimidazole-amine Hybrid
Neat Conditions
2
009 Elsevier Ltd. All rights reserved.
Green Protocol
1
. Introduction
pharmacological properties and frequently encountered in many
10-12
therapeutic
analgesic ,antihelmintic ,
antimicrobial , anti-HIV , antihypertensive , antiparasitic ,
antiproliferative ,
agents
,
some
antiamoebic ,
of
which
anticonvulsant ,
are,
The increasing need for more economical synthetic methods
13
14
15
16
and sustainable processes can be seen as a key driving force for
new innovations that inspires the creative rethinking of known
concepts which lead to the development of novel chemistry. In
recent times the energy considerations have become important
and one of the challenges in synthetic organic chemistry in the
development of renewable energy based organic transformations
to diminish the detrimental environmental impact associated with
chemical industries .The infinitely available, easily handled and
eco-friendly visible light make it attractive for chemists to
promote it for green chemical reactions . Visible light is
undoubtedly one of the emerging strategies to meet the
increasing demand for more sustainable processes
proposed strategy would help in the design and development of
environmentally benign, clean and efficient synthetic
methodologies for library of biologically potent heterocycles .
17
18
19
20
21
22
23
antiprotozoal ,
anti-inflammatory ,
24
25
26-31
antitubercular , anticancer , anti-HBV
.
The attachment of acyclic and cyclic amine derivatives add
further value of the targeted heterocyclic scaffold as it controls
unwanted growth of cancer cells and have some antiulcer and
antiallergic properties associated with it. Therefore the
combination of benzimidazole amine hybrid emerged as an
astounding combination which will prove its worth both in
synthetic chemistry and in medicinal chemistry research.
1-4
5-7
.The
Numerous elegant protocols for the synthesis of this scaffold,
involving various types of catalysts have been reported. Despite
these advances, there are still some potential limitations
including unsatisfactory yields, long reaction times, limited
8
The increasing need for more efficient synthetic methods which
show more specificity and high sustainability can be seen as a
major endeavor for new inventions. Most importantly light
activated reactions are often associated with photochemical
reactions.
substrate tolerances, use of expensive catalysts, toxic organic
32-34
solvents and cumbersome experimental procedures
These
necessities encouraged us to develop more efficient, convenient
and eco-friendly methodology for the synthesis of this
aesthetically appealing molecular scaffold.
Heterocyclic compounds are precious because of their
immense use in life saving pharmaceuticals . Benzimidazole is
The described strategy offers clean and efficient route for the
synthesis of benzimidazole amine hybrids using equimolecular
amounts of benzimidazole (1a), amine (2a) and Ru(byp) Cl
3 2
9
one of the leading pharmacaphore and is a vital motif in
medicinal chemistry bearing ample variety of biological and
—
——

Corresponding author. Tel.: +0-000-000-0000; fax: +0-000-000-0000; e-mail: author@university.edu

2
photocatalyst under neat conditions. The general synthetic
protocol of the disclosed moiety is shown in Scheme 1.
presence of catalysts like CuI, InCl
different solvents still no product was observed (Table 1, entry 2,
, 4, 5, 6). However when the reaction was carried out in
3
, AgCl, ZnO and CuO in
3
n-Pr
sp2, C-H functionalization
presence of visible light using eosin as a photo catalyst in
methanol the reaction took long time to reach completion, with a
low yield of product (Table 1, entry 7).
n-pr
C-N bond formation
N
NH
ref 10
PMP
PMP
a
Table 1 Screening of catalysts for the synthesis of 4a
R1
N
R2
R1
sp2, C-H functionalization
C-O bond formation
H
N
NH2
N
Catalyst Screening
R2
N
O
OH
N
ref 11
N
1
4a
R1
N
Our work
H
N
N
R2
R
b
Entry
catalyst
-
Time (h)
Yield%
1
N
R
1
12
12
12
24
12
12
12
15
16
12
12
15
-
Ru(byp) Cl
3
N
2
2
NH2
Neat, 7h
2
CuI
-
3
InCl3
-
Scheme 1: Photo catalyzed synthesis of benzimidazole
pyridine hybrid under neat conditions.
4
AgCl
-
5
ZnO
-
6
CuO
-
This revealed synthetic protocol is efficient and facile ring
opening and ring closing intramolecular heterocyclization
reaction. One approach towards the catalytic activation of organic
molecules that has received much attention recently is visible
light photoredox catalysis. In a general sense, this approach relies
on the ability of metal complexes and organic dyes to engage in
single-electron transfer (SET) processes with organic substrates
upon photoexcitation with visible light. Many of the most
commonly employed visible light photocatalysts are polypyridyl
complexes of ruthenium are typified by the complex tris(2,2′-
bipyridine) ruthenium(II), or Ru(bpy)3 2+. this complex absorb
light in the visible region of the electromagnetic spectrum to give
7
Eosin
25
19
21
-
8
Rosebengal
Fluorescein
ZnO & light
CuO &light
AgCl & light
9
10
1
1
1
1
2
3
-
-
Ru(bpy)
3
Cl
2
&light 8
75
35,36
a
stable, long-lived photoexcited states.
Ru(bpy)3 2+ and its
Reaction condition: Benzimidazole (1mmol),derivatives of ammonia
1mmol)was used to form an intermediate o-anilinic amidines which was then
(
analogues have been used (i) as components of dye-sensitized
3
7
38
irradiate under 7 watt blue LED using Ru(bpy)
benzimidazole amine hybrids
3 2
Cl as a catalyst to give
solar cells and organic light-emitting diodes, (ii) to initiate
39
40
polymerization reactions, and (iii) in photodynamic therapy .
Ruthenium complex emerged as an efficient catalyst for
photoredox reactions. This photoredox catalyst has been proven
to be an important tool for building up of various complex
molecules and synthesis of various potential biodynamic
b
Isolated yield
Replacing eosin with other dyes, like rosebengal and fluorescein
again resulted in low yields and need longer reaction times
(
other catalysts under visible light was also investigated, but no
appreciable improvement was found in the reaction times or
yields of the product (Table 1, entries 10, 11 and 12). In order to
develop an easy and high yielding protocol for the synthesis of
this prominent motif, we planned our strategy to exploit
41,42,43
heterocyclic compounds.
With such wonderful applications
Table 1, entries 8 and 9). The conversion in the presence of
of Ru(bpy)3 2+ complex we have directed it in our synthesis. The
reaction strategy is new and will open new vistas in the field of
organic chemistry design.
2. Result and Discussion
In view of the above contemplations, and on the basis of our
Ru(bpy)
3
Cl
2
as a catalyst. The reaction went smoothly and
progressive endeavors in exploring green protocols for the
synthesis of heterocyclic scaffolds, herein we wish to uncover a
more practical and expedient visible light activated synthesis of
benzimidazole amine hybrids using benzimidazole, and cyclic
and acyclic amines, under solvent free conditions, in the presence
resulted in the formation of the desired product (4a) in an
excellent yield within a short time period (7 h), as monitored by
TLC. With Ru(bpy)
investigate the reaction by using different amounts of
Ru(bpy)
3 2
Cl as a good activator, we next intended to
3
Cl2.
3 2
of Ru(bpy) Cl without any post alteration (Scheme 1). This
synthetic protocol is simple, efficient, and allows easy placement
of various types of substituents around the periphery of the
heterocyclic ring system. Our careful literature survey revealed
that there is no report on the use of Ru(bpy)Cl as a catalyst in
2
the synthesis of benzimidazole amine hybrids using visible light
under solvent free conditions.
For this, we first examined the synthesis of 4a in the presence
of 0.1mol% Ru(bpy) Cl . After 10 h, the desired product 4a was
3
2
formed in a low amount (Table 2, entry 1). Using 0.3 and 0, 5
mol% of catalyst afforded the desired product with moderate to
good yields (Table 2 entries 2 and 3), while using 0.7 mol% of
catalyst appreciable increase in the yield of the product (Table 2,
entry 4). On increasing time and mol% of catalyst 0.8 to 0.9, no
change in product yield was observed table 2 entry 5, 6. Finally
we noticed that 0.7 mol% of Ru(bpy) Cl was the most
3 2
appropriate amount of catalyst for achieving the desired
conversion with an excellent yield, (Table 2, entry 5)
In our preliminary experiments, we investigated the optimal
conditions regarding the catalyst, solvent and energy source. For
this benzimidazole (1a) and Piperidine (2a) were selected as test
substrates. In order to find the optimum reaction condition,
equimolar amounts of the test substrates were stirred in the
absence of a catalyst, and no desired product was observed
(Table 1, entry 1). When the reaction was carried out in the

3
Table 2 Effect of the amount of catalyst on the synthesis of
a
4
a
Next, to explore the diversity of this methodology, various
derivatives of benzimidazole, cyclic and acyclic amine
derivatives were used for the construction of a library of
benzimidazole amine hybrids, were well discussed in table 4. The
corresponding functionalized benzimidazole-amines were
obtained in good yields. All of the results are shown in Table 4.
H
N
NH2
Mol% of Ru(byp) Cl
3
2
N
N
Blue LED
Solvent f ree
N
4a
1
b
Entry
Mol%
0.1
Time(h)
Yield%
Reactions with the substrates having electron rich and electron
poor groups at the benzimidazole and on amine resulted in the
corresponding products in high yields. No obvious electronic or
steric effects of the reactants were observed. Using the best
reaction conditions, we carried out the reaction of benzimidazole
with acyclic and cyclic amines. In this case, a slightly lower yield
was obtained in comparison to the cyclic amines. The structures
of all the compounds were confirmed with the help of elemental
1
2
3
4
5
6
10
10
8
65
75
83
91
91
91
0.3
0.5
0.7
7
0.8
8
1
13
0.9
9
and spectral ( H NMR, C NMR and MS) studies.
Table 4: Synthesis of benzimidazole amine hybrids under
neat conditions with good to moderate yield.
a
Reaction Condition: Benzimidazole (1mmol),derivatives of ammonia
(
1mmol)was used to form an intermediate o-anilinic amidines which was then
H
NH2
irradiate under 7 watt blue LED using Ru(bpy)
3
Cl
2
as a catalyst to give
Ru(byp) Cl
3
N
2
benzimidazole amine hybrids
N
N
N
1
Blue LED
Solvant free
b
4a
Isolated yield
b
Entry
Substituted
benzimidazole
Ammonia
derivative
Product 1-15
Yield of
During solvent optimization, the reaction was carried out in
different solvents such as EtOH, MeOH, 1.4 dioxane and DCM
product %
3 2
with Ru(bpy) Cl , but no superior results were obtained (Table 3,
entries 1, 2, 3 and 4). Whereas when the reaction was carried out
in an aqueous medium, the reaction again took longer time
H
N
N
4
a.
87
NH
N
N
H
(Table 3, entry 5).
N
When the reaction was performed in solvent free conditions
H
N
H
N
we observed that the yield of the product increased dramatically
in a short time period (Table 3, entry 6). In addition, we studied
the influence of intensity of visible light on the reaction time and
percentage yield. All of the results are shown in Table 3. Table 3
shows that blue light of 7 watt with 7hour was the optimum light
for maximum conversion. Increasing the intensity above 7 watt
neither improved the yield nor decreased the reaction time (Table
4b.
85
91
HN
O
N
O
N
N
ipr
ipr
N
N
N
H
4
4
c
NH2
N
N
CH2CH3
N
2
CH CH3
3
, entry 8). Whereas, reducing the intensity proved detrimental to
N
H
9
1
the reaction, resulting in a lower yield (Table 3, entry 9). When
the reaction was carried out under less than 7 watt, a very low
yield of product was obtained (Table 3, entry 10).
d
N
N
NH2
N
Table 3 Effect of various solvents and light intensity on the
a
synthesis of 4a
4e.
90
NH2
N
N
H
N
H
N
N
NH2
Ru(byp)3Cl2
N
N
N
N
7 Watt Blue Led
Solvant
4a
1
a
Entry
Solvent
Light Time(h)
Intensity
Yield%
N
H
4
f.
NH2
85
90
N
N
N
N
1
2
3
4
5
6
7
8
9
Ethanol
MeOH
7 watt
7 watt
7 watt
7 watt
7 watt
7 watt
7 watt
9 watt
5watt
6watt
5
6
55
63
75
64
71
91
91
91
73
65
ipr
ipr
N
NC
NC
N
N
H
4
g
NH2
NH2
N
1,4dioxane
DCM
7
N
5
ipr
ipr
water
10
6
EtOOC
EtOOC
H
4
h.
N
N
N
9
1
Solvent free
Solvent free
Solvent free
Solvent free
solvent free
N
N
7
8
10
9
1
0
a
Isolated yield

4
ipr
observed by TLC, without separating the intermediate the light
Cl
H
N
N
ipr
was used for further initiation .The key steps involve: (i)
formation of a nitrogen-centered distonic amidinium radical
cation 4′ from 1 through its oxidation (SET) involving reductive
quenching of photoexcited state of Ru+2*; (ii) abstraction of
anilinic proton by [O2]·– derived from catalyst turnover and
Cl
N
NH2
N
4
4
i.
j.
N
9
9
1
1
ipr
Br
H
N
ipr
Br
N
N
N
NH2
NH2
2
subsequent intramolecular heterocyclization of anilinic NH 5 to
N
the electrophilic carbon atom of amidinium radical cation
yielding aminyl radical 6; (iii) 1,2-H shift of aminyl radical 6 to
generate a carbon-centered radical 7; (iv) oxidation of 7 to
produce the corresponding heteroatom-stabilized carbocation 8,
and finally (v) aromatization through deprotonation to form the
product 4a.
ipr
EtOO
C
N
ipr
N
EtOOC
H
N
4
k.
N
89
87
N
ipr
EtOOC
H
N
EtOOC
N
NH2
N
4
l.
N
N
N
N
N
SET
N
ipr
ipr
NH2
1
NH2
+1
Ru
+2
Ru
4
'
ipr
ipr
H
O2
(air)
EtOOC
EtOOC
N
NH2
N
N
+2
Ru
N
N
8
5
6
H
OMe
OMe
N
N
4
m.
N
N
N
H
NH2
2a
H
N
CH2CH3
CH2CH3
H
N
1a
O2
HN
N
HO2
8
Photocatalytic
strategies
N
N
4
n.
o.
ipr
tbu
N
N
ipr
N
ibu
NH2
H
N
N
N
NH2
4
N
5
N
87
N
N
H
4a
a
Reaction condition : : Benzimidazole (1mmol),derivatives of ammonia
1mmol)was used to form an intermediate o-anilinic amidines which was then
N
N
(
HO2
H O
2
2
irradiate under 7 watt blue LED using Ru(bpy)
benzimidazole amine hybrids
3 2
Cl as a catalyst to give
N
H
6
b
Isolated yield
1
,2H shift
O2
HO2
Prompted by the straightforward preparation of benzimidazole
amine hybrids, which involves ring-opening reaction of
benzimidazole through direct nucleophilic addition of secondary
amines at their C-2 position under mild reaction conditions, we
also attempted to access benzimidazole amine hybrids starting
directly from benzimidazoles and amines in a one-pot sequential
procedure.(Scheme 2)
H
N
HO2
HO2
H
N
N
N
N
H
N
H
O2
7
O2
8
Scheme 3: Photo catalytic strategy for the synthesis of
benzimidazole a mine hybrids
3. Conclusion
HN
N
N
N
Ru(bpy)3Cl2
Piperidine 2a
1mmol)
In summary, we have disclosed a convenient and efficient two
component synthesis for the benzimidazole amine hybrid
framework by the reaction of benzimidazole and cyclic and
(0.5 mmol)
(
N
NH2
N
NH
Neat, rt,30 min
open to air
rt.6.5 hr
(
1 mmol)
acyclic amines in the presence of Ru(bpy)
3
Cl
2
in solvent free
1
a
1
4a
conditions. In this experimentally simple process, three new
bonds are formed in a single operation with all of the reactants
efficiently utilized. Moreover the acyclic amines react slightly
faster than cyclic amines and produce the titled product in better
yield. The product formation is accomplished through the ability
without isolation
Scheme 2: One pot reaction for formation of benzimidazole
amine hybrids
3 2
of Ru(bpy) Cl and light to function as an electron source and
energy source in this transformation. The short reaction times,
excellent yields and more importantly, natural source of energy
On the basis of the above results, a plausible mechanism for
the formation of benzimidazole amine hybrid derivatives can be
tentatively rationalized, and is depicted in Scheme 3. Presumably
this transformation is triggered by visible light generated free
(visible light), makes this protocol a good alternative to
previously reported methodologies. This solvent-free strategy
agrees with the current organic synthesis trend of developing
cleaner and greener organic processes because of pressing
environmental and energy problems.
15,16,17,18
radical. Based on literature standards
along with our
observations (Table 1), a feasible photoredox catalytic cycle for
the present oxidative ring-closing reaction of o-anilinic amidines
1
affording benzimidazole amine hybrids 4a is outlined in
Scheme 3. In the step one the intermediate formation was

5
4. Acknowledgment
32. Yogesh S. Wagh, Bhalchandra M. Bhanage Tetrahedron Letters
012 53 6500–6503
2
3
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4. Juan Xu,Jiarong Li,Zhen Wei,Qi Zhang and Daxin Shi,RSC
Adv,;2013,3,9622-9624
We gratefully acknowledge Department of Chemistry
University of Allahabad for providing all the laboratory
facilities.We sincerely thank the SAIF, Punjab University,
Chandigarh, for providing spectra. The authors claim no financial
assistance.
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In a typical reaction procedure, Benzimidazole (1mmol), Different
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3 2
derivatives of ammonia (1mmol), 0.5 mol% [Ru(bpy) ]Cl were
2
taken in a single necked round bottom flask. The reaction mixture
was stirred at room temperature under blue light. The completion
of the reaction (indicated by disappearance of the starting material
and formation of new product, observed by TLC (30:70%) ethyl
acetate and hexane. After the product formation 15ml ethyl acetate
and 10ml water were added. The organic reactants and product
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1
1
2. 12
Ogahar,Takashi
Pharm,Bull.1993.41(2)301-309
3. Tupe AP*, Pawar PY, Mane BY, and Magar SD 2013 RJPBCS 4
. 931
Kiyushi
Taniguschi,Shinji
Fujitsu and Masaaki
Shigenga
,Takatomo
3 2
were taken out with ethyl acetate and [Ru(bpy) ]Cl were
Matsuo
Chem
dissolved and taken out with water. The crude product was dried
and has been purified by column chromatography. The purified
1
1
1
1
1
1
1
13
product was characterized by HNMR, CNMR, Mass spectral
data and Elemental analysis.
2
4. Srikanth Lingala1, Raghunandan Nerella, K. R. S. Sambasiva Rao
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4
5. Charecterisation data of compounds-
(
Compound 4a)
1
Yellow solid, isolated yield 94% HNMR (400 MHz,d
6
(
1
2
7
6
13
- DMSOꢔ δ
.95-7.31 (m, 1H CH Ar), 3.60 (s, 4H ), 1.62 (s 6H); CNMR
100 MHz, d - DꢍꢏO ꢔ δ 162.03, 1ꢓ8.11, 1ꢓ5.ꢓ3, 123.52, 120.31,
15.57, 108.21, 46.40, 25.06, 24.33; m/e calcd. For C12
01.12, found: 201.11. Anal. calcd for C12 : C; 71.63, H;
.53, N; 20.90,found C; 71.64, H; 7.54, N; 20.92 This compound
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M Johar; N Bharti; A Azam; AK
6
Singh. Eur. J. Med. Chem., 2002, 37, 835.
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15 3
H N :
15 3
H N
8. A Chimrri; AD Sarro GD Sarro; G Giho; M Zappala. Farmaco,
has been separated at an ratio of 19%(ethyl acetate:hexane) via
column chromatography.
2
001, 56, 821.
1
2
2
9. JS Shukla; S Saxena; R Rastogi. Curr. Sci., 1982, 51, 17.
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(
Compound 4b)
1
HNMR (400 MHz, d
.84 (t, J = 5.4 Hz, 4H), 3.63 (t, J = 4.2 Hz, 4H); CNMR (100
MHz, d - DMSO ꢔ δ 161.33, 147.19, 141.16, 123.32, 119.11,
15.23, 107.61, 65.53, 44.05; m/e calcd. for C11 O: 203.15,
found: 203.14 Anal. calcd for C11 O: C; 65.03, H; 6.47, N;
0.70,O;7.89,found C; 65.02, H; 6.49, N; 20.72,O;7.88
6
- DMSO ꢔ δ 7.03-7.38 (m, 1H, CH, Ar),
13
3
6
2
2
2
2
2. PS Solominova; VS Pilyugin; AA Pyurin. J. Pharm. Chem., 2004,
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13 3
H N
3
8, 425.
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13 3
H N
2
2
This compound has been separated at an ratio of 19%(ethyl
acetate:hexane) via column chromatography.
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1
3th Edition, Merk & Co. Inc., NJ. P-1785, Monograph Number,
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Highlights for reviewers





A novel process for the synthesis of benzimidazole-amine hybrid has been developed.
Non hazards and easily available visible light has been used as an energy source.
tris(2,2-bipyridine)ruthenium (II) has been used as an active photocatalyst.
Easily available molecular O
2
has been used as self oxidant.
The applied procedure is clean and atom economical.