Visible-light-promoted synthesis of benzimidazoles

Article abstract of DOI:10.1002/ejoc.201402141

A simple and environmentally-friendly synthetic method for benzimidazoles, which are important structural motifs in many applications owing to their various biological functions, has been developed. The reaction of o-phenylenediamine and a variety of aliphatic/aromatic aldehydes in methanol proceeds at room temperature with only natural sources, molecular oxygen and visible light. A simple and eco-friendly synthetic method for benzimidazoles, which are important structural motifs in many applications owing to their various biological functions, has been developed. The reaction of o-phenylenediamine and a variety of aliphatic/aromatic aldehydes in methanol proceeds at room temperature with only natural sources, molecular oxygen and visible light. Copyright

Full text of DOI:10.1002/ejoc.201402141

Job/Unit: O42141
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FULL PAPER
DOI: 10.1002/ejoc.201402141
Visible-Light-Promoted Synthesis of Benzimidazoles
Sehyun Park,[a][‡] Jaehun Jung,[a][‡] and and Eun Jin Cho*[a,b]
Keywords: Synthetic methods / Photochemistry / Nitrogen heterocycles
A simple and environmentally-friendly synthetic method for
benzimidazoles, which are important structural motifs in
many applications owing to their various biological functions,
has been developed. The reaction of o-phenylenediamine
and a variety of aliphatic/aromatic aldehydes in methanol
proceeds at room temperature with only natural sources, mo-
lecular oxygen and visible light.
Introduction
The benzimidazole structural motif has been of great
interest in many applications, especially in pharmaceuticals,
owing to its broad range of biological functions (Fig-
ure 1),[1,2] and thus considerable effort has been expended
to develop efficient methods for the preparation of benz-
imidazole derivatives.[3] Common methods involve conden-
sation of o-phenylenediamine with carbonyl-containing
compounds, such as aldehydes, carboxylic acid, and acid
halides, in the presence of various oxidants [Scheme 1 (1)].[4]
Despite their efficiency, many currently available methods
have limitations, such as the use of hazardous and costly
materials or the requirement for harsh reaction conditions
(high temperature/pressure or the use of a microwave).
Therefore, the development of more efficient, convenient,
and eco-friendly methods is still desired. Herein, we present
an efficient, green process,[5] which uses visible light irradia-
tion,[6] for benzimidazole synthesis from o-phenylenedi-
amine and a variety of aldehydes in the presence of mo-
lecular oxygen as oxidant [Scheme 1 (2)].
Figure 1. Examples of pharmaceuticals that contain the benzimid-
azole structural motif.
This synthetic strategy is eco-friendly with the following
clear advantages: (1) It does not require any metal catalysts
or hazardous materials; (2) It uses only natural sources, mo-
lecular oxygen (open to atmosphere) and visible light, aside
from the starting materials; (3) Alcohol solvents, such as
methanol and ethanol, are used instead of harmful organic
solvents; and (4) The reaction conditions are very mild –
room temperature and atmospheric pressure.
Results and Discussion
Benzimidazole synthesis was examined by using o-phen-
ylenediamine (1) and benzaldehyde (2a) as model com-
pounds (Table 1). Desired benzimidazole product 3a was
obtained in the presence of molecular oxygen (air-equili-
brated solution) under visible light irradiation with blue
LEDs. Alcohols, such as ethanol and methanol, showed
good reactivity as solvent (Table 1, Entries 5 and 6),
whereas the reaction did not proceed in water, probably as
a result of substrate insolubility (Table 1, Entry 4). The re-
action proceeded optimally in MeOH at 0.1 m concentra-
tion (Table 1, Entry 6). The reaction concentration was crit-
ical to the reaction efficiency (Table 1, Entries 6–9). The re-
action did not proceed in a reasonable time frame at con-
centrations lower than 0.05 m, whereas at higher concentra-
tions the reaction gave lower yields of product 3a with for-
mation of diimine side product B from condensation of two
[a] Department of Bionanotechnology, Hanyang University,
55 Hanyangdaehakro, Sangnok-gu Ansan, Kyeonggi-do 426-
791, Republic of Korea
E-mail: echo@hanyang.ac.kr
http://ejcho.hanyang.ac.kr
[b] Department of Chemistry and Applied Chemistry,
55 Hanyangdaehakro, Sangnok-gu Ansan, Kyeonggi-do 426-
791, Republic of Korea
[‡] These authors contributed equally to this work.
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402141.
Eur. J. Org. Chem. 0000, 0–0
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S. Park, J. Jung, E. J. Cho
FULL PAPER
Scheme 1. Synthesis of benzimidazoles.
Table 1. Optimization study for the synthesis of benzimidazole.[a]
tivity with 0.5 mol-% [Ru(bpy)3Cl2] was as good as that of
the reaction without a catalyst (Table 1, Entries 6 and 13).
To clearly assess the effect of a photocatalyst, a kinetic
study was conducted in which reactions were set up in the
presence and absence of [Ru(bpy)3Cl2], and the results are
shown in Figure 2. Product yields were detected by gas
chromatography over 4 hours. Although the reaction ini-
tially proceeded slightly faster in the presence of 0.5 mol-%
Entry
Conditions
Solvent
Product
(concentration)
yield [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
–
–
–
–
–
–
–
–
DMF (0.1 m)
CH2Cl2 (0.1 m)
MeCN (0.1 m)
H2O (0.1 m)
EtOH (0.1 m)
MeOH (0.1 m)
MeOH (0.05 m)
MeOH (0.2 m)
MeOH (0.25 m)
solvent-free
MeOH (0.1 m)
[D4]MeOH (0.1 m)
MeOH (0.1 m)
MeOH (0.1 m)
MeOH (0.1 m)
MeOH (0.1 m)
MeOH (0.1 m)
trace
25
28
trace
81
95
46
88
56
trace
Ͻ 5
22[c]
95
89
62
–
–
without O2 (bubbling with Ar)
without visible light
Ru(bpy)3Cl2 (0.5 mol-%)
Ru(phen)3Cl2 (0.5 mol-%)
fac-Ir(ppy)3 (0.5 mol-%)
Ir(ppy)2(dfbbpy)PF6 (0.5 mol-%)
Ir(dfppy)2(phen)PF6 (0.5 mol-%)
72
66
[a] Reaction conditions: 1 (0.2 mmol), 2a (0.21 mmol). [b] The
yields were determined by gas chromatography with dodecane as
an internal standard. [c] The reaction was conducted in [D4]MeOH,
Figure 2. Kinetic study of 3a in the presence and absence of
[Ru(bpy)3Cl2].
1
and the yield was determined by H NMR spectroscopy; DMF =
dimethylformamide.
molecules of 2a with diamine 1 (see the structure of B in
Figure 4). The use of oxygen as the oxidant was essential
for the reaction to proceed: the reaction did not proceed
after exclusion of oxygen from the solution through argon
bubbling (Table 1, Entry 11). The reactivity was promoted
significantly under visible light irradiation (Table 1, En-
tries 6 and 12). In the absence of visible light, a significant
amount of diimine B as the side product was generated
along with 3a (see Supporting Information, Scheme S1 and
Figure S1). As for a visible light source, the use of a fluores-
cent house lamp instead of a blue LED strip resulted in
longer reaction time. The reaction was also attempted with
several Ru and Ir complexes, which are known to be acti-
vated by visible light and lead to a variety of radical-medi-
Figure 3. UV/Vis absorption spectra and visual appearance of the
ated photoredox catalysis (Table 1, Entries 13–17).[7,8] Reac- solution of 1, 2a, and the mixture (100 μm in MeOH).
2
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Visible-Light-Promoted Synthesis of Benzimidazoles
of [Ru(bpy)3Cl2], the difference in final yields was negligi- overcome and reaction conditions were made more eco-
ble. Therefore, metal-free conditions were chosen for further friendly (e.g. the use of alcohol as solvent) by using visible
study owing to enhanced environmental benignity and com- light.[9]
patibility. The most significant difference between this and
An additional experiment with a UV/Visible spectropho-
previous works is the use of visible light as the energy tometer supported the fact that the reaction could be pro-
source. In very recent work by Jiao and co-workers, a moted by visible light (Figure 3).[10] Although o-phenylene-
metal-free reaction was reported with molecular oxygen, diamine (1) and benzaldehyde (2a) did not show absorption
which provided benzimidazoles from o-phenylenediamine in the visible light region, a mixture of 1 and 2a resulted in
and aliphatic aldehydes in toluene.[4e] However, the reaction a bathochromic shift, which indicates that an active inter-
has limited substrate scope, and works only for activated mediate was formed under visible light irradiation.[11] The
aliphatic aldehydes. In our current work, the limitation was formation of the active intermediate was confirmed visually
Figure 4. Proposed mechanism for the benzimidazole synthesis under visible light irradiation.
Scheme 2. Reactions of substituted o-phenylenediamines.
Scheme 3. Synthesis of 2,2Ј-[1,5-pentanediylbis(oxy-1,4-phenylene)]bis-1H-benzimidazole. Reaction conditions: (a) 8 (2.4 equiv.), 9
(1 equiv.), K2CO3 (3 equiv.), DMF, 100 °C, 12 h, 82%. (b) 10 (1 equiv.), 1 (2.5 equiv.), O2, MeOH/MeCN (1:1, 0.05 m), blue LEDs (7 W),
room temp., 10 h, 56%.
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S. Park, J. Jung, E. J. Cho
FULL PAPER
Table 2. Scope of 2-substituted benzimidazole synthesis.[a]
Based on this evidence, we propose a plausible mecha-
nism for the benzimidazole synthesis in Figure 4. Imine A,
formed from the condensation between 1 and 2, can be acti-
vated under visible light irradiation to A* (or C*).[12] The
–
species reduces O2 to superoxide (O2 ) and becomes a radi-
cal cation. Its intramolecular radical reaction with the imine
moiety to form D, deprotonation by superoxide to E, and
hydrogen abstraction by hydroperoxyl radical (HOO·) pro-
duces desired benzimidazole 3. The H2O2 generated in the
last step was detected with a H2O2 indicator.
With the optimized, environmentally benign conditions,
we evaluated the reactions of o-phenylenediamine with a
variety of aldehydes for the synthesis of 2-substituted benz-
imidazoles (Table 2). Reactions of both electron-rich and
-poor aromatic aldehydes provided the corresponding benz-
imidazoles in good to excellent yields (Table 2, Entries 1–
8). In addition, aliphatic aldehydes were also suitable sub-
strates for the process (Table 2, Entries 9–11), which proves
the reaction efficiency. The mild conditions allowed the re-
action of aldehydes that contain a range of functional
groups.
Reactions of substituted o-phenylenediamines, such as
3,4-diaminotoluene (4) and 4,5-dichloro-o-phenylenediam-
ine (6) also provided excellent yields of the corresponding
benzimidazole products under the same conditions
(Scheme 2).
The utility and practicality of this green process was
proven by using it as the key step in the synthesis of a drug
candidate that contains a benzimidazole motif, 2,2Ј-[1,5-
pentanediylbis(oxy-1,4-phenylene)]bis-1H-benzimidazole
(11; Scheme 3). The bis(oxyphenlene)benzimidazole struc-
ture is known to have pharmacological activities such as
selective activity against Leishmania donovani.[13] Molecule
11 was obtained in two steps from commercially available
compounds. Key substrate 10 was obtained by an SN2 reac-
tion between 8 and 9,[14] and subjected to our reaction con-
ditions. The reaction of o-phenylenediamine (1) with alde-
hyde 10 in air-equilibrated methanol under visible-light ir-
radiation successfully provided desired benzimidazole prod-
uct 11.
Conclusions
An efficient and eco-friendly process for the synthesis of
benzimidazoles was developed by using o-phenylenediamine
and an aldehyde in MeOH. This remarkable process re-
quired only natural sources, molecular oxygen and visible
light. The use of visible light significantly improved the re-
activity, and thus the reaction worked for both aromatic
and aliphatic aldehydes. In addition, the utility of this pro-
cess was proved by successfully synthesizing a drug candi-
date. We present our protocol as an efficient and more eco-
friendly alternative to the current methods of benzimid-
azole derivatisation.
[a] Reaction conditions: 1 (1 mmol), 2a (1.05 mmol), 4–7 h. [b] The
given yields are the isolated yield and based on an average of two
runs.
by the colour change in the mixed solution into a yellow-
orange colour.
The isolation of the intermediate for further mechanistic
studies was not possible probably owing to its high reactiv-
ity. However, we could detect an imine intermediate, which
was generated from condensation between o-phenylenedi-
1
amine (1) and benzaldehyde (2a), by H NMR experiment
Experimental Section
1
done in [D4]MeOH and by gas chromatography. In the H
NMR spectra no detectable amount of benzimidazoline,
another possible intermediate, was observed.
General Reagent Information: Anhydrous methanol (MeOH) in
Sure-Seal bottles was purchased from Sigma Aldrich and degassed
4
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Visible-Light-Promoted Synthesis of Benzimidazoles
by repeated sonication under reduced pressure and replenishing the
atmosphere with argon.
m/z calcd. for C14H12N2O [M + H]+ 225.0950; found 225.1015. Rf
= 0.38 (hex/EtOAc, 1:1).
2-{4-[(tert-Butyldimethylsilyl)oxy]phenyl}-1H-benzimidazole
(3c):
o-Phenylenediamine and commercially available aldehydes were
purchased from Sigma Aldrich, Alfa Aesar, or TCI, and used as
received. Flash column chromatography was performed with
Merck silica gel 60 (70–230 mesh).
1
Yellow solid. H NMR (400 MHz, DMSO): δ = 12.77 (br. s, 1 H),
8.07 (d, J = 8.8 Hz, 2 H), 7.60–7.50 (m, 2 H), 7.20–7.14 (m, 2 H),
7.02 (d, J = 8.8 Hz, 2 H), 0.97 (s, 9 H), 0.24 (s, 6 H) ppm. 13C
NMR (101 MHz, DMSO): δ = 159.18, 151.80, 143.83, 135.05,
128.16, 121.67, 121.13, 118.33, 115.70, 111.10, 25.84, 17.84,
General Analytical Information: The benzimidazole products were
characterized by 1H NMR, 13C NMR, and FTIR spectroscopy.
NMR spectra were recorded with a Bruker 400 MHz instrument
(400 MHz for 1H NMR and 101 MHz for 13C NMR). Copies of 1H
and 13C NMR spectra can be found at the end of the Supporting
Information. 1H NMR spectroscopic data are referenced relative
to residual DMSO (δ = 2.50 ppm) or chloroform (δ = 7.26 ppm) in
the deuterated solvent. 13C NMR spectra are reported in ppm rela-
tive to [D6]dimethyl sulfoxide (δ = 39.51 ppm) or deuteriochloro-
form (δ =77.23 ppm). 13C NMR signals for carbons 3a, 4, 5, 6, 7a
of benzimidazole moiety shown in Figure 5 are broad, and they are
difficult or impossible to detect in some cases. FTIR spectra were
recorded with a Bruker Alpha FTIR spectrometer with KBr plates.
HRMS data were obtained on an Agilent 6530 Accurate-Mass Q-
TOF LC/MS. UV/Vis spectra were obtained with a PDA UV/Vis
Spectrophotometer (cell length: 1 cm).
–3.16 ppm. IR (neat): νmax = 3368, 2255, 2128, 1654, 1005 cm–1. Rf
˜
= 0.60 (EtOAc).
2-[4-(1-Methylethoxy)phenyl]-1H-benzimidazole (3d): Yellow solid.
1H NMR (400 MHz, DMSO): δ = 12.88 (br. s, 1 H), 8.13 (d, J =
8.2 Hz, 2 H), 7.70–7.50 (m, 2 H), 7.40 (d, J = 8.2 Hz, 2 H), 7.20–
7.18 (m, 2 H), 2.93 (heptet, J = 6.8 Hz, 1 H), 1.22 (d, J = 6.8 Hz, 6
H) ppm. 13C NMR (101 MHz, DMSO): δ = 151.43, 150.38, 143.87,
135.06, 127.87, 126.91, 126.55, 122.23, 121.68, 118.67, 111.26.
33.39, 23.69 ppm. IR (neat): ν
= 3442, 2250, 2124, 1661,
˜
max
1063 cm–1. Rf = 0.51 (hex/EtOAc, 2:1).
2-(4-Bromophenyl)-1H-benzimidazole (3e): Yellow solid. 1H NMR
(400 MHz, DMSO): δ = 13.05 (br. s, 1 H), 8.11 (d, J = 8.6 Hz, 2
H), 7.76 (d, J = 8.6 Hz, 2 H), 7.76–7.55 (m, 2 H), 7.26–7.17 (m, 2
H) ppm. 13C NMR (101 MHz, DMSO): δ = 150.24, 131.99, 129.40,
128.38, 123.27, 122.35 ppm. IR (neat): ν
= 3298, 2257, 2129,
˜
max
1650, 1026, 827 cm–1. Rf = 0.49 (hex/EtOAc, 2:1).
2-(4-Fluorophenyl)-1H-benzimidazole (3f): Yellow solid. 1H NMR
(400 MHz, DMSO): δ = 12.98 (br. s, 1 H), 8.24 (dd, J = 8.8, 5.6 Hz,
2 H), 7.65–7.56 (m, 2 H), 7.40 (dd, J = 8.8, 8.7 Hz, 2 H), 7.24–7.17
(m, 2 H) ppm. 13C NMR (101 MHz, DMSO): δ = 163.12 (d, J =
248.3 Hz), 150.46, 143.96, 135.18, 128.78 (d, J = 8.7 Hz), 126.84
Figure 5. Structure of 2-substituted benzimidazole.
(d,
J
=
3.0 Hz), 122.21, 119.34, 116.05 (d,
J
=
21.9 Hz),
General Procedure for the Synthesis of Benzimidazoles: An open
test tube equipped with a magnetic stir bar was charged with o-
phenylenediamine (1.0 mmol). Then MeOH (10 mL, 0.1 m) and an
aldehyde (1.05 mmol) were added. The open test tube was placed
under blue LEDs (7 W) and stirred at room temperature for 4–7 h.
Reaction progress was checked by thin layer chromatography
(TLC) or gas chromatography (GC). The reaction mixture was con-
centrated in vacuo, and the benzimidazole products were purified
by recrystallization (with hot ethanol and water) or flash column
chromatography.
111.38 ppm. IR (neat): ν
= 3441, 2251, 2125, 1659, 1020,
˜
max
824 cm–1. Rf = 0.42 (hex/EtOAc, 2:1).
2-[3-(Trifluoromethyl)phenyl]-1H-benzimidazole (3g): Yellow solid.
1H NMR (400 MHz, DMSO): δ = 13.21 (br. s, 1 H), 8.53 (s, 1 H),
8.48 (d, J = 7.6 Hz, 1 H), 7.85 (d, J = 7.6 Hz, 1 H), 7.79 (dd, J =
7.6, 7.5 Hz, 1 H), 7.70–7.60 (m, 2 H), 7.30–7.20 (m, 2 H) ppm. 13
C
NMR (101 MHz, DMSO): δ = 172.25, 149.77, 131.21, 130.31,
129.93 (q, J = 32.0 Hz), 126.86 (q, J = 273.7 Hz), 126.33 (q, J =
3.7 Hz), 122.89 (q, J = 3.7 Hz) ppm. IR (neat): ν
= 3425, 2253,
˜
max
2127, 1656, 1026, 825 cm–1. Rf = 0.47 (hex/EtOAc, 2:1).
2,2Ј-[1,5-Pentanediylbis(oxy-1,4-phenylene)]bis-1H-benzimidazole
(11): An open test tube equipped with a magnetic stir bar was
charged with o-phenylenediamine (0.5 mmol). Then MeOH/MeCN
(1:1, 0.05 m), and 1,5-pentanediylbis(oxy)dibenzaldehyde (10,
0.2 mmol) were added to it. The open test tube was placed under
blue LEDs (7 W) and stirred at room temperature for 10 h. Reac-
tion progress was checked by TLC. The reaction mixture was con-
centrated in vacuo, and desired product 11 (yellow solid) was puri-
fied by flash column chromatography.
2-(4-Pyridinyl)-1H-benzimidazole (3h): Yellow solid. 1H NMR
(400 MHz, DMSO): δ = 13.32 (br. s, 1 H), 8.76 (d, J = 6.0 Hz, 2
H), 8.12 (dd, J = 6.0, 1.4 Hz, 2 H), 7.72–7.63 (m, 2 H), 7.28–7.24
(m, 2 H) ppm. 13C NMR (101 MHz, DMSO): δ = 172.19, 150.54,
148.88, 139.42, 137.22, 122.99, 120.43 ppm. IR (neat): νmax = 3432,
˜
2251, 2125, 1606, 1028 cm–1. Rf = 0.60 (EtOAc).
2-Heptyl-1H-benzimidazole (3i): Brown solid. 1H NMR (400 MHz,
CDCl3): δ = 10.04 (br. s, 1 H), 7.55 (dd, J = 6.0, 2.8 Hz, 2 H),
7.24–7.18 (m, 2 H), 2.94 (td, J = 7.6, 2.4 Hz, 2 H), 1.86 (tt, J =
7.6, 7.5 Hz, 2 H), 1.40–1.31 (m, 2 H), 1.30–1.16 (m, 6 H), 0.83 (t,
J = 7.2 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 155.76,
138.74, 122.25, 114.78, 31.84, 29.58, 29.53, 29.17, 28.59, 22.76,
2-Phenyl-1H-benzimidazole (3a): Brown solid. 1H NMR (400 MHz,
DMSO): δ = 12.95 (br. s, 1 H), 8.17 (d, J = 6.0 Hz, 2 H), 7.70–7.45
(m, 5 H), 7.20 (d, J = 6.0 Hz, 2 H) ppm. 13C NMR (101 MHz,
DMSO): δ = 151.31, 143.83, 135.05, 130.17, 129.98, 129.07, 126.51,
14.21 ppm. IR (neat): νmax = 3425, 2252, 2126, 1659, 1027 cm–1. Rf
= 0.37 (hex/EtOAc, 2:1).
122.65, 121.81, 118.92, 111.45 ppm. IR (neat): ν
= 3367, 2255,
˜
max
˜
2128, 1654, 1002 cm–1. Rf = 0.41 (hex/EtOAc, 2:1).
2-(4-Methoxyphenyl)-1H-benzimidazole (3b): Brown solid. 1H
2-(2-Phenylethyl)-1H-benzimidazole (3j): Brown solid. 1H NMR
NMR (400 MHz, DMSO): δ = 12.75 (br. s, 1 H), 8.12 (dd, J = 8.0, (400 MHz, DMSO): δ = 12.23 (br. s, 1 H), 7.54–7.49 (m, 1 H),
4.0 Hz, 2 H), 7.62 (d, J = 8.0 Hz, 1 H), 7.49 (d, J = 8.0 Hz, 1 H), 7.44–7.49 (m, 1 H), 7.30–7.24 (m, 4 H), 7.20–7.15 (m, 1 H), 7.14–
7.20–7.13 (m, 2 H), 7.11 (d, J = 8.0 Hz, 2 H), 3.84 (s, 3 H) ppm.
13C NMR (101 MHz, DMSO): δ = 151.37, 143.89, 134.98, 128.02,
122.69, 122.09, 121.48, 118.50, 114.38, 111.06, 55.34, 14.10 ppm.
7.07 (m, 2 H), 3.13–3.10 (m, 4 H) ppm. 13C NMR (400 MHz,
DMSO): δ = 154.39, 143.31, 141.05, 134.27, 128.41, 128.28, 126.09,
121.50, 120.89, 118.15, 110.79, 33.35, 30.42 ppm. IR (neat): ν
=
˜
max
IR (neat): νmax = 3448, 2251, 2125, 1656, 1047 cm–1. HRMS (ESI):
3442, 2251, 2125, 1659, 1059 cm–1. Rf = 0.32 (hex/EtOAc, 1:1).
˜
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S. Park, J. Jung, E. J. Cho
FULL PAPER
2-Cyclohexyl-1H-benzimidazole (3k): Brown solid. 1H NMR
(400 MHz, DMSO): δ = 12.12 (br. s, 1 H), 7.51 (d, J = 6.6 Hz, 1
H), 7.39 (d, J = 6.6 Hz, 1 H), 7.09 (m, 2 H), 2.83 (tt, J = 11.3,
3.6 Hz, 1 H), 2.05–1.97 (m, 2 H), 1.85–1.75 (m, 2 H), 1.74–1.54 (m,
3 H), 1.44–1.20 (m, 3 H) ppm. 13C NMR (101 MHz, DMSO): δ =
158.91, 143.06, 134.18, 121.35, 120.73, 118.19, 110.75, 37.72, 31.27,
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25.59, 25.54 ppm. IR (neat): ν
= 3442, 2251, 2125, 1660,
˜
max
1025 cm–1. HRMS (ESI): m/z calcd. for C13H16N2 [M + H]+
201.1313; found 201.1377. Rf = 0.49 (hex/EtOAc, 1:1).
6-Methyl-2-phenyl-1H-benzimidazole (5): Brown solid. 1H NMR
(400 MHz, DMSO): δ = 12.80 (br. s, 1 H), 8.15 (d, J = 8.0 Hz, 2
H), 7.54 (t, J = 8.0 Hz, 2 H), 7.47 (t, J = 8.0 Hz, 1 H), 7.44–7.40
(m, 2 H), 7.02 (d, J = 8.0 Hz, 1 H), 2.42 (s, 3 H) ppm. 13C NMR
(101 MHz, DMSO): δ = 151.35, 130.67, 130.18, 129.41, 126.76,
123.89, 118.82, 21.79 ppm. IR (neat): ν
= 3424, 2252, 2126,
˜
max
1657, 1027 cm–1. Rf = 0.42 (hex/EtOAc, 2:1).
5,6-Dichloro-2-phenyl-1H-benzimidazole (7): Brown solid. 1H NMR
(400 MHz, DMSO): δ = 8.16 (d, J = 8.0 Hz, 2 H), 7.83–7.80 (m, 2
H), 7.55 (dd, J = 8.0, 4.0 Hz, 3 H), 3.49 (br. s, 1 H) ppm. 13C NMR
(101 MHz, DMSO): δ = 153.82, 130.52, 129.27, 129.04, 126.73,
= 3425, 2252, 2126, 1659, 1026 cm–1.
[4]
124.49 ppm. IR (neat): ν
˜
max
Rf = 0.51 (hex/EtOAc, 2:1).
4,4Ј-[1,5-Pentanediylbis(oxy)]bis-benzaldehyde (10): White solid. 1H
NMR (400 MHz, CDCl3): δ = 9.86 (s, 2 H), 7.82 (d, J = 8.0 Hz, 4
H), 6.89 (d, J = 8.0 Hz, 4 H), 4.07 (t, J = 4.0 Hz, 4 H), 1.90 (tt, J
= 8.0, 7.9 Hz, 4 H), 1.73–1.63 (m, 2 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 191.09, 164.30, 132.24, 130.03, 114.93, 68.27, 28.99,
22.88 ppm. IR (neat): ν
= 2945, 1690, 1427, 1318, 1122,
˜
max
1067 cm–1. Rf = 0.55 (EtOAc).
2,2Ј-[1,5-Pentanediylbis(oxy-1,4-phenylene)]bis-1H-benzimidazole
[5]
[6]
[7]
1
(11): Yellow solid. H NMR (400 MHz, DMSO): δ = 12.79 (br. s,
1 H), 8.10 (d, J = 8.8 Hz, 4 H), 7.74–7.64 (m, 4 H), 7.19–7.14 (m,
4 H), 7.10 (d, J = 8.8 Hz, 4 H), 4.10 (t, J = 6.2 Hz, 4 H), 1.83 (tt,
J = 6.2, 6.1 Hz, 4 H), 1.70–1.58 (m, 2 H) ppm. IR (neat): ν
=
˜
max
3426, 2251, 2125, 1638, 1027 cm–1. Rf = 0.61 (hex/EtOAc, 1:1).
Supporting Information (see footnote on the first page of this arti-
cle): Details of the synthesis of benzimidazole without visible-light
irradiation, the UV/Vis absorption spectra of the solution of 1,
2a, and the mixture, and NMR spectra of all new compounds are
provided.
Acknowledgments
This work was supported by the research fund of Hanyang Univer-
sity (HY-2014-G).
[8]
For examples on Ru- and Ir-catalysed photoredox catalysis that
include our previous work, see: a) D. A. Nicewicz, D. W. C.
MacMillan, Science 2008, 322, 77; b) M. A. Ischay, M. E. An-
zovino, J. Du, T. P. Yoon, J. Am. Chem. Soc. 2008, 130, 12886;
c) J. M. R. Narayanam, J. W. Tucker, C. R. J. Stephenson, J.
Am. Chem. Soc. 2009, 131, 8756; d) S. Lin, M. A. Ischay, C. G.
Fry, T. P. Yoon, J. Am. Chem. Soc. 2011, 133, 19350; e) H.
Kim, C. Lee, Angew. Chem. Int. Ed. 2012, 51, 12303; Angew.
Chem. 2012, 124, 12469; f) N. Iqbal, S. Choi, E. Ko, E. J. Cho,
Tetrahedron Lett. 2012, 53, 2005; g) N. Iqbal, S. Choi, E. Kim,
E. J. Cho, J. Org. Chem. 2012, 77, 11383; h) E. Kim, S. Choi,
H. Kim, E. J. Cho, Chem. Eur. J. 2013, 19, 6209; i) C. Yu, K.
Lee, Y. You, E. J. Cho, Adv. Synth. Catal. 2013, 355, 1471; j)
N. Iqbal, S. Choi, Y. You, E. J. Cho, Tetrahedron Lett. 2013, 54,
6222; k) M. T. Pirnot, D. A. Rankic, D. B. C. Martin, D. W. C.
MacMillan, Science 2013, 339, 1593; l) X. Wang, G. D. Cuny,
T. Noel, Angew. Chem. Int. Ed. 2013, 52, 7860; Angew. Chem.
[1] For selective reviews on benzimidazoles, see: a) P. N. Preston,
Chem. Rev. 1974, 74, 279; b) D. A. Horton, G. T. Bourne,
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arya, P. Chaudhuri, Curr. Med. Chem. 2008, 15, 1762.
[2] For biological functions of benzimidazoles, see: a) D. D. Ra-
jadhyaksha, D. W. Rangnekar, J. Chem. Technol. Biotechnol.
1986, 36, 300; b) W. A. Denny, G. W. Rewcastle, B. C. Baguley,
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2002, 12, 2221; e) C. G. Mortimer, G. Wells, J. P. Crochard,
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6
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42141
/KAP1
Date: 20-05-14 18:27:26
Pages: 8
Visible-Light-Promoted Synthesis of Benzimidazoles
2013, 125, 8014; m) N. Iqbal, J. Jung, S. Park, E. J. Cho, Angew.
Chem. Int. Ed. 2014, 53, 539.
[12] Although benzimidazoline intermediate C was not detected, a
process that involves C still cannot be excluded.
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[9] Before submission of this manuscript we found that the Chen
group reported a benzimidazole synthesis under similar condi-
tions but without a concentrated visible light source. Under
their conditions, only aromatic aldehydes lead to a reaction
with lower yields, see: G.-F. Chen, H.-D. Shen, H.-M. Jia, L.-
Y. Zhang, H.-Y. Kang, Q.-Q. Qi, B.-H. Chen, J.-L. Cao, J.-T.
Li, Aust. J. Chem. 2013, 66, 262.
[10] UV/Vis absorption spectra with molar absorptivity (ε) as the
vertical axis is provided in the Supporting Information Figure
S2.
[11] Recently the Melchiorre group described the photochemical ac-
tivity of in-situ-formed electron donor-acceptor complexes un-
der visible light irradiation, see: E. Arceo, I. D. Jurberg, A.
Álvarez-Fernández, P. Melchiorre, Nat. Chem. 2013, 5, 750.
[14] There have been reports on the reaction between 8 and 9. Our
conditions were slightly modified, see ref.[13c]: K.-S. Marie, B.
Raymond, C. Stefan, Synlett 2012, 23, 2053.
Received: February 25, 2014
Published Online: ᭿
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7

Job/Unit: O42141
/KAP1
Date: 20-05-14 18:27:26
Pages: 8
S. Park, J. Jung, E. J. Cho
FULL PAPER
Benzimidazole Synthesis
S. Park, J. Jung, E. J. Cho* ............. 1–8
Visible-Light-Promoted Synthesis of Benz-
imidazoles
A simple and eco-friendly synthetic meth-
od for benzimidazoles, which are import-
ant structural motifs in many applications
owing to their various biological functions,
has been developed. The reaction of o-
phenylenediamine and a variety of ali-
phatic/aromatic aldehydes in methanol pro-
ceeds at room temperature with only natu-
ral sources, molecular oxygen and visible
light.
Keywords: Synthetic methods
/ Photo-
chemistry / Nitrogen heterocycles
8
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