Visible-light-induced condensation cyclization to synthesize benzimidazoles using fluorescein as a photocatalyst

Article abstract of DOI:10.1039/c9gc01359h

A mild strategy for visible-light-induced synthesis of benzimidazoles was developed using aromatic aldehydes and o-phenylenediamines as substrates. The use of an organic dye, fluorescein, as an innoxious photocatalyst provided a mild and inexpensive catalytic system to synthesize a series of benzimidazoles in moderate to excellent yields. It was originally applied to this system to obtain benzimidazoles. Besides, the catalytic system does not require an additional oxidant or metal which was good for the environment.

Full text of DOI:10.1039/c9gc01359h

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DOI: 10.1039/C9GC01359H
Journal Name
ARTICLE
Visible-light-induced condensation cyclization to synthesize
benzimidazoles using fluorescein as photocatalyst
Received 00th January 20xx,
Accepted 00th January 20xx
Zhuofei Li a,b, He Song a,b, Rui Guo a,b, Minghui Zuo a,b, Chuanfu Hou a,b, Shouneng Sun a,b, Xin He a,b
,
Zhizhong Sun a,b and Wenyi Chu a,b
*
DOI: 10.1039/x0xx00000x
A mild strategy for the visible-light-induced for synthesis of benzimidazoles was developed using aromatic aldehydes and
o-phenylenediamines as the substrates. Using of an organic dye, fluorescein, as an innoxious photocatalyst provided a mild
and inexpensive catalytic system to synthesize a series of benzimidazoles in moderate to excellent yields. It was originally
applied to this system to obtain benzimidazoles. On top of that, the catalytic system has no need for additional oxidant or
metal which was good for the environment.
www.rsc.org/
important structural unit of many medicine of
antihypertensive, anticancer, antiviral, psychotropic, antifungal
and anti-arrhythmic.13 Apart from that, they are not only used
Introduction
More recently, visible light, as a rich, readily available and
renewable clean energy source,1 has attracted extensive
interest in assisting catalytic organic synthesis reaction.2
Compared with traditional synthetic methods, visible light
assisted reactions meet the requirements of mild reaction
conditions, simple operation and environmental friendliness.3
However, most organic molecules cannot absorb visible light,
and only the selection of a suitable photocatalyst can promote
the reaction. Ruthenium and iridium complexes4 are the most
commonly used photocatalysts in organic reactions such as
activation of unactivated C-H bond,5 direct C-H arylation,6
aerobic oxidative radical addition7 or cyclization reaction.8
Although these complexes have excellent catalytic properties,
they are expensive and potentially toxic. Organic dyes, which
have shown similar photocatalytic activity in some reactions,
have been used as an attractive alternative to transition metal
complexes,9 because they are usually relatively cheap and less
toxic. In particular, fluorescein has been very recently
employed for radical alkoxycarbonylation of aryldiazonium
salts via visible-light catalysis by Wei Guo and co-workers.10 In
addition, Frank Glorius used gold and fluorescein to catalyze
intermolecular multicomponent oxyarylation of alkenes.11
Beyond that, it is rarely used in organic synthesis.
as important intermediates of organic reactions and ligands of
14, 15
transition metals but also applied in materials science.
Hence, it has been particularly attractive to synthesis
benzimidazoles and their derivatives, which is precisely based
on their great application prospects. Although many strategies
have been used to synthesize benzimidazoles till now, the
classical method is a condensation reaction between o-
phenylenediamine and carboxylic acid or its derivatives,16
nevertheless, the method is obliged to be carried out under
spirit of acids conditions or high temperature to ensure the
smooth progress of the reaction.17 In consequence, in order to
overcome the above problems, many novel methods of
synthesizing them have been reported in recent years. For
example, in 2009, Debasree Saha and co-workers used an ionic
liquid, [pmim]BF4, to promote the benzimidazoles synthesis
(Scheme 1a).14a In 2012, Gary A. Molander and his colleagues
utilized KHF2 as an oxidant to form benzimidazoles (Scheme
1b).18 In 2017, J. Chang research group developed the use of
molecular iodine to synthesize benzimidazoles under alkaline
conditions (Scheme 1c).19 In 2017, David Milstein used cobalt
complexes as a catalyst to synthesize benzimidazoles by
dehydrogenative coupling of aromatic diamines and alcohols
(Scheme 1d).20 In 2018, Palaniswamy Suresh reported
Brønsted acidic reduced graphene oxide as a carbocatalyst to
synthesize C-2-substituted benzimidazole (Scheme 1e).21 In
spite of these methods which are very efficient and satisfying,
they also suffer from some restriction in those aspects of
temperature, reaction time, catalyst preparation or application
and environment. In recent years, some synthetic method of
benzimidazole has dominated the development of green
catalytic processes to avoid the above problems.22 For
example, in 2015, the Huang group used electrochemical
method to synthesize benzimidazole from the alcohol and
Benzimidazole derivatives exist widely in the molecular
skeleton structure of biologically active molecules12 or as an
a. School of Chemistry and Materials Science, Heilongjiang University, Harbin
150080, P. R. China.
b. Key Laboratory of Chemical Engineering Process and Technology for High-
efficiency Conversion, College of Heilongjiang Province, Harbin 150080, P. R.
China (E-mail: wenyichu@hlju.edu.cn; Fax: +86-451-86609135; Tel: +86-451-
86609135)
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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ortho-substituted aniline with a catalytic amount of a CoII mixture was extracted three times with ethyl acetate, then the
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salt.23 In 2017, Sanzhong Luo et al. were able to synthesize organic layers were combined and dried over anhydrous
DOI: 10.1039/C9GC01359H
benzimidazole from primary amines in high yields under mild Na2SO4 and the solvent was removed in vacuo. The crude
conditions with oxygen as the terminal oxidant without any product was purified by silica gel column chromatography to
metal promoter.24
give the target product.
a. Debasree Saha's work
NH2
+
NH2
N
N
[pmim]BF4
O
Results and Discussion
room temperature
R
R
In the initial experiment, o-phenylenediamine and
benzaldehyde were served as the foundational substrates and
were irradiated with a blue LED to optimize the reaction
conditions (Table 1). Primordially, we chose the most common
Ru(bpy)3 as a photocatalyst and found that the target product
was generated. Taking into account the price issue, we had
screened other common organic dyes and found that
fluorescein as a photocatalyst exhibited good catalytic effect
(Table 1, entries 1-4). Subsequently, a bunch of solvents were
screened and found to obtain the desired product 3a in 90%
yield in acetonitrile while in other solvents such as methanol,
toluene, tetrahydrofuran or DMF with lower yields (Table 1,
entries 4-8). It is noteworthy that 2 mol% of catalyst loading
was found to be the optimum (Table 1, entries 4 and 9-10).
Then, having tested the different reaction time, 2 hours was
the optimum reaction time (Table 1, entries 4 and 11-12). Due
to most of the cyclization reaction was under alkaline
conditions, Na2CO3was added to the reaction, but had no
significant effect on the reaction (Table 1, entry 13). Finally, a
comparative experiment was conducted, which illustrated
both the photocatalyst and the light source were important for
the reaction (Table 1, entries 14-15).
b. Gary A. Molander's work
H
N
NH2
+
CHO
CH3CN/EtOH(1:1) 40oC
BF3K
KHF2(10mol%), O2(1 atm)
R1
NH2
R2
KF3B
R2
N
R1
c. Junbiao Chang's work
NH2
(1)R2CHO,EtOH,reflux
(2) I2, K2CO3,CH2Cl2, rt
N
N
R1
R2
R1
PG
N
H
PG
d. David Milstein's work
H
NH2
NH2
N
[Co]
R'
R
R'
+
R
OH
N
e. Palaniswamy Suresh's work
NH2
+
NH2
N
N
G-SO3H
O
O
Solvent, Temperature
R
R
R
f. Our present work
H
N
NH2
NH2
fluorescein, Blue LED
+
R
N
CH3CN, room temperature
1) Visible-light assist
2) Mild reaction conditions
3) Without addition oxidant or metal
COOH
O
O
OH
Fluorescein
Scheme 1 Reported works and our work for synthesis of
benzimidazoles
Table 1 Optimization of the reaction conditionsa
Among them, using 1, 2-diaminobenzene and aldehyde as
substrates to synthesize benzimidazole is one of the most
effective synthesis methods, which received widespread
attention. Due to medicinal value of benzimidazoles, it also
should be avoided the presence of metals in the catalytic
system. Thus it is still very desirable to search for a gentle and
applicable green synthesis method.
Therefore, based on the inspiration of literatures and our
exploration of visible light assisted catalysis,25 we envisaged
using an organic dye, fluorescein, as photocatalyst to
synthesize the benzimidazoles. We are pleased that a novel
catalytic system of visible-light assisted is developed, and this
method synthesizes benzimidazoles under mild reaction
conditions. Herein, we hope to report that this new fluorescein
catalyzed using o-phenylenediamine and aromatic aldehydes
as substrates to obtain benzimidazoles (Scheme 1f).
O
H
NH2
N
H
conditions
+
N
NH2
2a
3a
1a
Entry Photocatalyst(mol%) Solvent Time(h) Yield(%)b
1
2
3
4
5
6
7
8
9
10
11
12
13c
14d
15
Ru(bpy)3 (2mol%)
Eosin Y (2mol%)
Rhodmine B (2mol%) CH3CN
CH3CN
CH3CN
2
2
2
2
2
2
2
2
2
2
1
2.5
2
2
82
78
49
90
42
fluorescein (2mol%)
fluorescein (2mol%)
fluorescein (2mol%)
fluorescein (2mol%)
fluorescein (2mol%)
fluorescein (1mol%)
fluorescein (3mol%)
fluorescein (2mol%)
fluorescein (2mol%)
fluorescein (2mol%)
fluorescein (2mol%)
-
CH3CN
MeOH
PhMe
THF
56
45
DMF
trace
73
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
90
64
90
91
Experimental
In a flat quartz glass jar with magnetic stirrer which contained
aromatic aldehyde (0.1 mmol), o-phenylenediamine (0.1
mmol), acetonitrile (1.5 mL) and fluorescein (3 mol%). The
open-air reaction container was placed under a 10W blue LED
lamp and stirred until the end of the reaction which was
observed in the Thin-layer chromatography (TLC) analysis. The
trace
trace
2
a.
o-Phenylenediamine(0.1mmol), benzaldehyde(0.1mmol),
photocatalyst(2mol%), 10 W blue LED, room temperature, air
atmosphere. Isolated yields. Under presence of Na2CO3 (3
equiv). d. Without blue LED.
b.
c.
2 | J. Name., 2012, 00, 1-3
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In summary, it was determined that the optimal reaction the 2-position (Table 2, 3q-3r). For the o-phenylenediamine
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DOI: 10.1039/C9GC01359H
system was o-phenylenediamine and benzaldehyde as the moiety, the substituents (-Cl, -Me) at the 4-position also gave
reaction substrates, fluorescein (2 mol%) as photocatalyst, a the desired product in high yield (Table 2,3s-3t). We also tried
10 W blue LED as light source in the air at room temperature to use 2-aminobenzamide and 2-amino-N-(quinolin-8-
for 2 hours.
yl)benzamide instead of o-phenylenediamine to react with
Table 2. Substrate scope of visible-light-induced condensation benzaldehyde, the yields of 3u and 3v were moderate at 55%
cyclization of aromatic aldehydes and o-phenylenediamine a
and 49%, respectively; but the reaction time needed to be
extended to 16h. In addition, the protocol is not suitable for
the preparation of 1,2-disubstituted benzimidazoles.
O
O
H
NH2
CH3CN, rt
H
N
+
fluorescein, Blue LED
NH2
H
NH2
R2
R2
NH2
N
N
R1
CH3CN, rt
H
R1
+
+
eq-1
2
N
3
1
N
NH2
N
N
N
N
N
1a
A
2a
B
N
N
H
N
H
H
H
Cl
Time (15 min) A: 21% B: 9%
Time (30 min) A: 29% B: 33%
Time (60 min) A: 34% B: 42%
Br
F
3a (90%)
3c (86%)
3b (94%)
3d (84%)
N
N
N
N
N
H
N
N
H
H
N
N
H
N
H
H
CH3CN, rt, 2 h
Cl
NO2
F
H3C
eq-2
3f (91%)
3g (95%)
3h (88%)
3e (80%)
fluorescein, Blue LED
N
N
H
B
3a (90%)
N
N
N
N
Cl
F
O
N
H
N
H
N
H
N
H
H
N
H
N
Blue LED
CH3
eq-3
eq-4
3j (93%)
3k (92%)
3l (85%)
3i (83%)
CH3CN, rt, 2 h
N
H
B
N
OCH3
OCH3
3a (trace)
N
N
N
O
N
Ph
H
N
H
N
N
H
N
H
N
H
N
N
fluorescein
H
CH3CN, rt, 2 h
N
H
3m (84%)
N
3n (75%)
N
3p (86%)
3o (87%)
N
B
3a (trace)
H
N
H
N
Scheme 2 Control Experiments
N
H
N
N
H
N
H3C
Cl
In order to explain the reaction mechanism in more depth, the
following control experiments were carried out (Scheme 2). As
can be seen from eq-1, when the reaction time was adjusted
to 15, 30 and 60 minutes, the yields of intermediate A were
21%, 29% and 34%, respectively, and the yields of were 9%, 33%
and 42%. It was indicated that intermediate A was first
obtained from 1a and 2a, and converted to intermediate B by
intramolecular cyclization. The intermediate B was used as the
substrate to give the target compound 3a in good yield under
the optimal reaction condition (eq-2). According to eq-1and
eq-2, it could be found that A and B were important
intermediates in this reaction. According to eq-3 and eq-4
illustrated that both blue light and photocatalyst were
essential for this reaction. In addition, fluorescence quenching
experiments were also studied to further demonstrate the
reaction mechanism, as shown in Figure S1. The fluorescence
intensity of fluorescein can be significantly quenched by
intermediate B.
3q (78%)
3r (82%)
3s (92%)
3t (89%)
O
N
N
O
N
NH
3u (55%)
3v (49%)
N
a.o-Phenylenediamine(0.1mmol), aromatic aldehydes (0.1
mmol), fluorescein(2mol%), 10 W blue LED, room temperature.
b. Isolated yields.
After determining the optimal reaction system, we further
explored the range of photocatalytic condensation reaction of
aromatic aldehydes with different substituents, and the results
were summarized in Table 2. First of all, when there is no
substituent on the benzaldehyde 2a, the yield of the product
3a could reach 90%. When benzaldehyde has -F, -Cl, -Br and -
CH3 in the o-position, it could be found that the yield with
electron withdrawing groups were superior to that of the
electron donating group (Table 2, 3b-3e). When the
substituent was in the m- and p- positions, the target product
can be obtained in good yields (Table 2, 3f-3m). When the
same substituent was at different position, the yield of the p-
position can be found to be better than the o- and m- positions
because of the steric hindrance effect (Table 2, 3d, 3h and 3k).
In addition, benzaldehyde with multiple substituents gave a 75%
yield (Table 2, 3n). This may be due to the presence of two
electron donating groups on the benzaldehyde. It is
noteworthy that furaldehyde or picolinaldehyde as the
substrates obtained the corresponding products in moderate
yields (Table 2, 3o-3p), indicating that the catalytic system was
also effective for heteroaromatic aldehydes. It is worth
mentioning that this system is also suitable for the synthesis of
benzimidazoles with an alkyl group and a cycloalkyl group at
Based on the above experimental results and previous
literature reviews,26 a possible mechanism for obtaining 2-
arylbenzimidazoles by visible light assisted catalysis was
described in Scheme 3. First, o-phenylenediamine 1a and
benzaldehyde 2a are dehydrated and condensed to form imine
intermediate A. Subsequent intramolecular cyclization gives
intermediate B (Eox = +0.242 V) as shown in Figure S2, the
fluorescein (Fl) under visible light generates excited
ox
fluorescein* (Fl*) species (E1/2 = +0.87 V)27 and oxidation of
intermediate
B to intermediate C. Fluorescein radical
anion(Fl*-) is oxidized to ground state fluorescein by O2 (from
the air). The desired product 3a is produced by deprotonation
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11 M. N. Hopkinson, B. Sahoo, F. Gloriusa, Adv. Synth. Catal.,
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O
H2O
NH2
N
H
N
H
Intramolecular
Cyclization
A
N
H
2a
B
FI*
NH2
NH2
FI
14 (a) D. Saha, A. Saha, B. C. Ranu, Green Chem., 2009, 11, 733.
(b) T. Selvaraj, R. Rajalingam, V. Balasubramanian, Appl. Surf.
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1a
FI*-
O2
O2
HO2
15 (a) J. Peng, M. Ye, C. Zong, F. Hu, L. Feng, X. Wang, Y. Wang,
C. Chen, J. Org. Chem., 2011, 76, 716. (b) J. A. Asensio, E. M.
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H
N
H
N
H
H
N
HO2
N
N
H
N
H2O2
C
D
3a
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Eur. J., 2011, 17, 12544; (b) S. Rojas-Buzo, P. García-García,
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Scheme 3 The possible reaction mechanism.
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Conclusions
To sum up, we developed a method for the synthesis of by a
visible-light-induced condensation cyclization of aromatic
aldehydes and o-phenylenediamines using fluorescein as
20 P. Daw, Y. Ben-David, D. Milstein, ACS Catal., 2017, 7, 7456.
21 M. Karthik, P. Suresh, New J. Chem., 2018, 42, 17931.
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26 J. Kovvuri, B. Nagaraju, A. Kamal, A. K. Srivastava, ACS Comb.
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photocatalyst.
This
method
could
synthesize
2-
arylbenzimidazoles in moderate to excellent yields with good
functional group tolerance in mild conditions. In addition, the
catalytic system avoids the use of oxidants or metals, in line
with the concept of green chemistry. The development of
other photocatalytic studies is still in progress.
27 N. A. Romero, D. A. Nicewicz, Chem. Rev., 2016, 116, 10075.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This work was supported by Fund of Natural Science
Foundation of Heilongjiang Province of China (No. B2018012).
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