Photochemical Synthesis of Benzimidazoles from Diamines and Aldehydes

Article abstract of DOI:10.1002/ejoc.202001357

An efficient, green, cheap, and metal-free photochemical protocol for the synthesis of benzimidazoles has been developed. 2,2-Dimethoxy-2-phenylacetophenone was employed as the photoinitiator and CFL lamps were used as the light source, leading to the cyc

Full text of DOI:10.1002/ejoc.202001357

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Photochemical Synthesis of Benzimidazoles from Diamines and
Aldehydes
Authors: Elpida Skolia, Mary K. Apostolopoulou, Nikolaos F. Nikitas,
and Christoforos G. Kokotos
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202001357
Link to VoR: https://doi.org/10.1002/ejoc.202001357
01/2020

10.1002/ejoc.202001357
European Journal of Organic Chemistry
COMMUNICATION
Photochemical Synthesis of Benzimidazoles from Diamines and
Aldehydes
Elpida Skolia,†[a] Mary K. Apostolopoulou,†[a] Nikolaos F. Nikitas[a] and Christoforos G. Kokotos*[a]
Dedicated to Prof. Panagiota Moutevelis-Minakakis on the occasion of her retirement
[a]
E. Skolia, M. K. Apostolopoulou, N. F. Nikitas, Prof. Dr. C. G. Kokotos
Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis 15771, Athens, Greece.
† denotes equal contribution
Corresponding author. E-mail: ckokotos@chem.uoa.gr homepage: http://www.chem.uoa.gr/?page_id=2898&lang=el
Abstract: An efficient, green, cheap and metal-free photochemical
protocol for the synthesis of benzimidazoles has been developed.
2,2-Dimethoxy-2-phenylacetophenone was employed as the
photoinitiator and CFL lamps were used as the light source, leading
to the cyclization of substituted diamines with aldehydes and the
corresponding benzimidazoles were obtained in good to high yields.
Mechanistic studies were conducted, in order to determine a
plausible mechanism for the reaction.
Introduction
Photochemistry, the use of visible light to promote organic
reactions, exerts
a powerful impact on the activation of
molecules over the past few decades. Since 2008,
photochemistry has experienced a research explosion, utilizing
the term “photoredox catalysis”.[1] Most photoredox methods
utilize transition-metal complexes, which present good catalytic
properties; however, they are usually potentially toxic and
expensive. An alternative solution to metal complexes, as the
field of photochemistry expands, is the use of small organic
molecules as the photo-promoters.[2]
Scheme 1. Examples of biologically relevant benzimidazoles.
The introduction of novel, efficient and environmentally friendly
reaction protocols for the synthesis of important organic
intermediates or final products from readily available reagents
constitutes a key challenge in organic synthesis. Heterocyclic
compounds are frequently used in medicinal chemistry, due to
their active role in biological systems. Benzimidazole is one of
the oldest known nitrogen heterocycle, firstly synthesized by
Hoebrecker and later by Ladenburg and Wundt in the 1870s.[3]
The benzimidazole scaffold was firstly employed for its
therapeutic potential at 1944 by Woolley, who was the first to
introduce benzimidazoles as purine-substitutes to exhibit some
Two are the most general methods for the synthesis of 2-
substituted benzimidazoles. Primarily, benzimidazoles are
obtained via the coupling of 1,2-diaminobenzenes with
carboxylic acids[9] or their derivatives,[10] under harsh dehydrating
reaction conditions and high temperatures, utilizing strong acids,
such as hydrochloric acid, polyphosphoric acid, boric acid, or p-
toluenesulfonic acid. However, the use of milder reagents,
particularly Lewis acids, inorganic clays or mineral acids, has
improved the yield of this reaction (Scheme 2, A).[3d-3e,10] On the
other hand, the synthesis of benzimidazoles can be achieved
through the condensation of 1,2-diaminobenzenes with
aldehydes via a two-step procedure that includes an in situ-
generated Schiff’s base and requires an oxidative reagent to
generate the benzimidazole ring.[11] Various oxidative reagents
have been employed for this purpose (Scheme 2, B).[12] Due to
the ease of accessibility of a variety of aldehydes, the latter
method has been extensively used.[13,14] These processes
usually require stoichiometric or excess amount of oxidants to
be used, produce toxic or environmentally problematic by-
products, suffer from low yields, harsh reaction conditions, long
reaction times, and use of metals and expensive reagents.[15]
Therefore, the development of a cost-effective, safe and
environment friendly protocol is desirable.
biological
responses.[4]
Brink
later
identified
5,6-
dimethylbenzimidazole as a degradation product of vitamin B12
and subsequently presented that its derivatives have activities
similar to vitamin B12.[5] All seven positions of the benzimidazole
scaffold can be substituted, however, benzimidazole-based
compounds that bear functional groups at the 2 position usually
present interesting biological activities. Over the years,
benzimidazole and its derivatives have evolved as important
heterocyclic systems in the field of drugs and pharmaceuticals,
due to their presence in bioactive compounds, which exhibit
antiparasitic, anticonvulsant, analgesic, antihistaminic, antiulcer,
antihypertensive, antiviral, anticancer, antifungal and anti-
inflammatory action (Scheme 1).[6] Benzimidazoles derivatives
can also act as ligands to transition metals[7] and are important
intermediates in many organic reactions.[8] Organic chemistry is
continuously seeking new methods for the synthesis of
benzimidazole and its derivatives.
In recent years, greener catalytic processes for the
synthesis of benzimidazoles have been developed, in order to
1
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10.1002/ejoc.202001357
European Journal of Organic Chemistry
FULL PAPER
successfully synthesized different categories of compounds,
utilizing a variety of photocatalysts and cheap household lamps
as the irradiation source. Herein, we introduce an alternative,
direct and metal-free protocol that requires light, for the
synthesis of benzimidazoles from diamines and aldehydes. The
initiator employed is a low-cost and commercially available
compound that demonstrates high activity when irradiated. The
reaction requires exceptionally mild conditions to proceed, as it
occurs at room temperature under household bulb irradiation
(Scheme 2, G). Cyclization of a variety of substituted aldehydes
and diamines has been achieved and the corresponding
products were afforded in good to high yields. This method is
cheap and environmentally friendly, since it avoids the use of
any expensive and toxic oxidants or catalysts, it is operationally
simple and the starting reagents, as well as the visible light
sources, are inexpensive and readily available.
Results and Discussion
We initiated our study utilizing o-phenylenediamine (1a)
and benzaldehyde (2a) as the substrates. In the optimization of
the reaction conditions, a variety of different irradiation sources,
photocatalysts, solvents and stoichiometries were tested (Table
Table 1. Optimization of the reaction conditions for the photochemical
reaction of 1a with 2a.
Scheme 2. Approaches for the synthesis of benzimidazoles.
avoid the above mentioned problems. In 2015, Huang and
coworkers presented an electrochemical method for the
synthesis of benzimidazoles from alcohols and o-phenylene
diamine, utilizing a CoII salt as the catalyst (Scheme 2, C).[16] In
2017, Luo and coworkers synthesized benzimidazoles from
primary amines with molecular oxygen as the oxidant (Scheme 2,
D).[17] In a similar manner, an efficient copper-catalyzed strategy
for the amination of methyl arenes using aniline, TMSN3 and
heating has been reported for the preparation of functionalized
benzimidazoles,[18] while an oxidant-free copper-based
photocatalytic system that utilizes Cu2O-Fe2O3 nanoparticles
(NPs) for the construction of C–N bonds was developed by
Bhalla (Scheme 2, E).[19] Recently, Li and coworkers utilized an
organic dye, fluorescein, as the photocatalyst to synthesize
benzimidazoles via Blue LED irradiation (Scheme 2, F).[20]
Photochemistry has provided interesting approaches for the
synthesis of benzimidazoles from diamines and aldehydes,
either employing tetrazines,[21] or heterogeneous photocatalytic
systems.[22-26] Finally, a DMF-water (9:1) solvent system at 80 oC
has been shown to promote the synthesis of benzimidazoles.[27]
Limitations of these methods are the harsh reaction conditions,
the catalyst preparation, the cost and effect on the environment
and the limited substrate scope, especially when aldehydes
bearing aliphatic chains are employed.
Entry
Catalyst
Solvent
MeCN
CFL Yield (%)[a]
Blue LED
/
Yield (%)[b]
1
3a
3b
3c
68 / 70
78 / 59
2
3
MeCN
MeCN
89 (85)[c] / 70
4
5
6
7
8
3d[d]
3c
68 / 85
53 / -
42 / -
30 / -
60 / -
MeCN
CH2Cl2
EtOAc
3c
3c
3c
MeOH
CHCl3
The use of o-phenylenediamine and aldehydes as
substrates is one of the most effective methods for the synthesis
of benzimidazoles, however, most current methods for their
preparation exhibit difficulties and limitations. Thus, there is still
need for an efficient, easy and green synthesis protocol. Our
group works in the field of photochemistry[28] and has
[a] All reactions were carried out with (1a) (0.30 mmol), (2a) (0.30 mmol),
solvent (1.0 mL) and catalyst (20 mol%), under 2 x 85W household lamps
(CFL) irradiation at room temperature for 16 h. Yields were determined by
GC-MS. [b] The reaction was performed under Blue LED irradiation for 16 h.
Yields were determined by GC-MS. [c] Yield of isolated product. [d] Catalyst
loading: 5 mol%.
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10.1002/ejoc.202001357
European Journal of Organic Chemistry
FULL PAPER
1).
A number of photoorganocatalysts-photoinitiators and
organic
dyes
were employed with 2,2-dimethoxy-2-
phenylacetophenone (3c) providing the highest yields in CFL
lamps, that comprise a cheaper and easier photochemical set-
up (Table 1, entries 1-4). For comparison purposes, the
previously described fluorescein catalyst was also employed
(Table 1, entry 4).[20] The optimum solvent for the reaction
proved to be MeCN (Table 1, entries 3 and 5-8).
Decreasing the amount of the catalyst loading or the
solvent resulted in lower reaction yields and a further increase of
them did not increase the yield (Table 2, entries 1-5). When
either substrate was used in excess, the product was afforded in
lower yields, due to formation of by-products, so a stoichiometric
amount of both regents was preferred (Table 2, entries 6 and 7).
We then studied the performance of the reaction with and
without the catalyst, or without air or without light (Table 2,
entries 8-10) and the results illustrated that in the absence of the
photoinitiator, light or air, no reaction took place. Various
reaction times were tested, with 16 h proving to be the optimum
for this substrate.[29]
After establishing the optimum reaction conditions for the
photochemical synthesis of benzimidazoles (Table 1, entry 3),
we began exploring the substrate scope (Schemes 3 and 4).
First,
a
variety of aldehydes were tested with o-
phenylenediamine (Scheme 3). Aromatic aldehydes proved to
be excellent substrates for the reaction, leading to the expected
benzimidazoles in good to high yields. When benzaldehyde is
Scheme 3. Substrate scope for the synthesis of benzimidazoles from aromatic
aldehydes.
employed, the yield of the product could reach 85% (Scheme 3,
4). The reaction proceeded with both electron-rich and deficient
aryl aldehydes, affording the corresponding products in good
yields. It is important to highlight that the reaction tolerates the
presence of a cyano- and a nitro-group, both in meta- and para-
position (Scheme 3, 8, 9 and 15, 16), halides including fluoro-
(Scheme 3, 5), chloro- (Scheme 3, 6) and bromo- (Scheme 3, 7),
isopropyl- (Scheme 3, 10), CF3- (Scheme 3, 14) and phenoxy-
group (Scheme 3, 12). Polyaromatic systems (Scheme 3, 11
and 13), as well as heterocyclic substrates, though they required
an increase in the reaction time (Scheme 3, 17 and 18), proved
to be good substrates for this methodology.
Moreover, in order to expand the substrate scope and search for
the limits of our methodology, aliphatic aldehydes were also
tested (Scheme 4). They proved to be suitable substrates when
increasing the reaction time, leading to the expected products in
moderate to good yields. This is not very usual in literature,
since most literature precedents employ only aromatic
aldehydes and not aliphatic aldehydes. Linear aldehydes both of
smaller and larger chains reacted effectively (Scheme 4, 19-22).
Branched aliphatic aldehydes led to the desired product in good
yields (Scheme 4, 23-27). This protocol could be extended into
different diamines which, when reacting with benzaldehyde,
afforded benzimidazoles in moderate yields (Scheme 4, 28 and
29).
Table 2. Final optimization of the reaction conditions for the photochemical
reaction of 1a with 2a. [a]
Entr
y
Catalyst
loading
(mol %)
Solvent
(mL)
1a
(equiv.)
2a
(equiv.)
Yield[b] (%)
1
10
20
30
46
1
1
1
1
1
1
1
1
2
1
1
1
1
1
1
1
1
1
1
2
1
1
1
2
89 (85)[c]
3
83
63
80
27
38
0
4
20
20
20
20
0
0.5
1.5
1
5
6
7
1
8
1
9[d]
10[e]
0
20
20
1
0
In order to study the reaction mechanism, a variety of tools
were employed. Quantum yield measurements provide a useful
tool for identifying if photochemical reactions involve radical
chains. Based on literature, a closed photocatalytic system
lacking chain propagation exhibits a maximum theoretical
quantum yield of Φ = 1, which indicates that every photon
absorbed by the photocatalyst produces one molecule of
product. The chain processes, on the other hand, could
1
[a] All reactions were carried out with (1a) (0.30-0.60 mmol), (2a) (0.30-0.60
mmol), MeCN (0.5-1.5 mL) and 2,2-dimethoxy-2-phenyacetophenone (3c)
(5-30 mol%), under household lamps irradiation at room temperature for 16
h. [b] Yields were determined by GC-MS. [c] Yield of isolated product. [d]
Under Ar atmosphere. [e] The reaction was performed in the dark.
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10.1002/ejoc.202001357
European Journal of Organic Chemistry
FULL PAPER
Figure 1. On-off mechanistic experiments.
rapidly to afford 2-phenylbenzimidazole (4).[29]
Further mechanistic studies proved the radical nature of
the reaction, since addition of TEMPO or BHT, two known
radical scavengers, prevented the formation of the product.[29]
Instead, when the reaction mixture with TEMPO and BHT was
irradiated for 16 h, an adduct deriving from the benzoyl radical
with TEMPO and with BHT respectively, as well as an adduct
deriving from α,α-dimethoxybenzyl radical with TEMPO and BHT
respectively, were observed by GC-MS, confirming the
generation of the benzoyl and the α,α-dimethoxybenzyl radical
Scheme 4. Substrate scope for the synthesis of benzimidazoles from aliphatic
aldehydes and diamines.
from
2,2-dimethoxy-2-phenylacetophenone.
1H-NMR
mechanistic experiments of the reaction with BHT, also
confirmed that in the presence of the radical scavenger the
photochemical oxidation is inhibited. Finally, on-off experiments
were carried out and proved that constant irradiation is
necessary for the completion of the reaction. When the reaction
mixture was irradiated for 2 h and then left stirring under dark for
2 h, the yield remained low (Figure 1).[29]
potentially provide multiple equivalents of product from each
photon absorbed, therefore the quantum yield of a chain
reaction is Φ >> 1.[30] The quantum yield of the photochemical
reaction for the synthesis of 2-phenylbenzimidazole (4) was
calculated (Φ = 7), indicating a chain propagation mechanism.
UV-Vis experiments were also performed to determine
whether the reaction mechanism involves the formation of an
EDA complex.[31,32] An electron donor-acceptor (EDA) complex is
formed in situ by two structurally small molecules, one acting as
electron donor (D) and the other acting as electron acceptor (A).
Upon mixing of the two reagents, an EDA complex is formed,
resulting usually in an increase in the UV absorbance. Upon
Utilizing the results of the experiments above, we can propose a
plausible mechanism for the photochemical reaction of o-
phenylenediamine (1a) and benzaldehyde (2a) to provide 2-
phenylbenzimidazole (4) (Scheme 5). Firstly, 1a and 2a are
fastly condensed to afford the imine intermediate S1.
Subsequently, intramolecular cyclization affords S2.[20] Upon
irradiation by light, 2,2-dimethoxy-2-phenylacetophenone (3c),
that absorbs in the UV range (310-390 nm)[33] is excited to the
singlet state I, followed by intersystem crossing that leads to
triplet 2,2-dimethoxy-2-phenylacetophenone II. Through the
triplet state, II undergoes photochemical α-cleavage via Norrish
type I photo scission, to produce benzoyl radical III and α,α-
dimethoxybenzyl radical IV, with III exhibiting usually higher
reactivity.[33e] Either benzoyl radical III (more likely) or radical IV
performs a hydrogen abstraction (HAT) with S2 leading to
radical intermediate V. Reaction with oxygen leads to
intermediate VI, which via intramolecular shift leads to product 4
and VII, which propagates the reaction.
mixing
2,2-dimethoxy-2-phenylacetophenone
(3c),
o-
phenylenediamine (1a) and benzaldehyde (2a) in MeCN in
couples or as the reaction mixture, no increase in the UV
absorbance was observed. These results excluded the
possibility of an EDA complex formation.
Next, 1H-NMR mechanistic experiments were performed.
o-Phenylenediamine (1a), benzaldehyde (2a), 2,2-dimethoxy-2-
phenylacetophenone (3c) were employed in MeCN-d3 and the
1
reaction was monitored frequently through H-NMR mechanistic
experiments, after 1 h, 2 h, 3 h, 4 h, 6 h, 9 h, 12 h and 14 h of
irradiation.[29] After 2 h of irradiation, peaks that can be attributed
to benzaldehyde (2a), 2-benzylideneaminoaniline (S1), 2-
phenyldihydrobenzimidazole (S2) and 2-phenylbenzimidazole
(4) were observed. After 14 h of irradiation, peaks that can be
attributed to 2-phenyldihydrobenzimidazole (S2) and 2-
phenylbenzimidazole (4) were observed. These results suggest
that benzaldehyde (2a) is fastly consumed to afford S1, which is
the intermediate in the reaction mixture. Intramolecular
cyclization affords S2 and the photochemical oxidation occurs
Conclusions
In conclusion, an efficient, green, metal-free and
sustainable new protocol for the photochemical synthesis of
benzimidazoles, by cyclization of diamines and aldehydes, was
developed. The reaction takes place under mild conditions
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10.1002/ejoc.202001357
European Journal of Organic Chemistry
FULL PAPER
fellowship, which is co-financed by Greece and the European
Union (European Social Fund-ESF) through the Operational
Programme “Human Resources Development, Education and
Lifelong Learning” in the context of the project “Strengthening
Human Resources Research Potential via Doctorate Research”
(MIS-5000432), implemented by the State Scholarships
Foundation (IKY)”. Also, COST Action C-H Activation in organic
synthesis (CHAOS) CA15106 is acknowledged for helpful
discussions.
Keywords: Aldehydes • Diamines • Benzimidazoles • HAT •
Photochemistry • Green Chemistry
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Scheme 5. Proposed reaction mechanism.
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successfully, leading to products in moderate to excellent yields.
Mechanistic studies were performed in order to determine the
reaction’s mechanism. This novel approach employs cheap,
green and sustainable materials, in order to synthesize more
complex compounds.
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Experimental Section
General Photochemical Procedure for the Synthesis of
Benzimidazoles: In a glass vial containing diamine 1 (1 equiv., 0.30
mmol), aldehyde
2
(1 equiv., 0.30 mmol), 2,2-dimethoxy-2-
phenylacetophenone (3c) (15 mg, 0.06 mmol, 20 mol%) and MeCN (1.0
mL) were added. The vial was sealed with a screw cap and left stirring
under household bulb irradiation (2 x 85W household lamps) for 16-72 h.
The desired product was purified by column chromatography (Pet. Ether /
AcOEt : 7/3, CH2Cl2 / AcOEt : 9/1).
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Acknowledgements
The authors gratefully acknowledge the Hellenic Foundation for
Research and Innovation (HFRI) for financial support through a
grant, which is financed by 1st Call for H.F.R.I. Research
Projects to Support Faculty Members & Researchers and the
procurement of high-cost research equipment grant (grant
number 655). N. F. N. would like to thank the State Scholarships
Foundation (IKY) for financial support through a doctoral
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10.1002/ejoc.202001357
European Journal of Organic Chemistry
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This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001357
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents
Photochemistry
Elpida Skolia, Mary K. Apostolopoulou,
Nikolaos F. Nikitas and Christoforos G.
Kokotos*
Page No. – Page No.
Photochemical Synthesis of
Benzimidazoles from Diamines
and Aldehydes
Photochemistry. A green, facile, mild and metal-free protocol for the synthesis of
benzimidazoles by cyclization of diamines and aldehydes was developed, using
cheap household lamps as the light source and an organic molecule as the
photoinitiator.
Institute and/or researcher Twitter usernames: @KokotosCG
This article is protected by copyright. All rights reserved.