Imidazolium chloride-catalyzed synthesis of benzimidazoles and 2-substituted benzimidazoles from o-phenylenediamines and DMF derivatives

Article abstract of DOI:10.1016/j.tet.2018.11.014

A facile, general, and economical synthesis of diversely functionalized benzimidazoles and 2-substituted benzimidazoles has been realized via the imidazolium chloride-catalyzed cyclization of o-phenylenediamines with DMF derivatives. This protocol shows a broad substrate scope for aliphatic, aromatic, and heteroaromatic amides. A series of benzimidazoles and 2-substituted benzimidazoles have been obtained in moderate to excellent yields.

Full text of DOI:10.1016/j.tet.2018.11.014

Accepted Manuscript
Imidazolium chloride-catalyzed synthesis of benzimidazoles and 2-substituted
benzimidazoles from o-phenylenediamines and DMF derivatives
Zongjie Gan, Qingqiang Tian, Suqing Shang, Wen Luo, Zeshu Dai, Huajun Wang,
Dan Li, Xuetong Wang, Jianyong Yuan
PII:
S0040-4020(18)31341-3
https://doi.org/10.1016/j.tet.2018.11.014
TET 29925
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 30 September 2018
Revised Date: 5 November 2018
Accepted Date: 8 November 2018
Please cite this article as: Gan Z, Tian Q, Shang S, Luo W, Dai Z, Wang H, Li D, Wang X, Yuan
J, Imidazolium chloride-catalyzed synthesis of benzimidazoles and 2-substituted benzimidazoles
from o-phenylenediamines and DMF derivatives, Tetrahedron (2018), doi: https://doi.org/10.1016/
j.tet.2018.11.014.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Graphical abstract

ACCEPTED MANUSCRIPT
Imidazolium chloride-catalyzed synthesis of benzimidazoles and
2-substituted benzimidazoles from o-phenylenediamines and DMF
derivatives
Zongjie Gan1, Qingqiang Tian1, Suqing Shang, Wen Luo, Zeshu Dai, Huajun Wang, Dan Li,
Xuetong Wang, Jianyong Yuan*.
a Department of Medicinal Chemistry, College of Pharmacy, Chongqing Medical University, Chongqing 400016,
PR China
b Chongqing Research Center for Pharmaceutical Engineering, Chongqing Medical University, Chongqing
400016, PR China
*Corresponding authors: Jianyong Yuan
1 These authors contributed equally to this work.
Email: enediyne@163.com
Tel.:86-23-68485161
1

ACCEPTED MANUSCRIPT
Abstract A facile, general, and economical synthesis of diversely functionalized benzimidazoles and 2-substituted
benzimidazoles has been realized via the imidazolium chloride-catalyzed cyclization of o-phenylenediamines with
DMF derivatives. This protocol shows a broad substrate scope for aliphatic, aromatic, and heteroaromatic amides. A
series of benzimidazoles and 2-substituted benzimidazoles have been obtained in moderate to excellent yields.
Keywords Imidazolium chloride; Benzimidazoles; 2-Substituted benzimidazoles; Synthesis;
1. Introduction
Benzimidazoles and 2-substituted benzimidazoles are fundamental structural motifs found in many kinds of
functional compounds, such as drugs, bioactive molecules1 or materials2 (Fig. 1). Furthermore, they can also be used
as fluorescent probes to detect ions, such as Cd2+ and F-, and fluorescence imaging in living cells3. Therefore,
benzimidazoles are consumed in large quantities in the biological, medical, and chemical industries. Inspired by the
broad applications of benzimidazoles, their facile, general, and economical synthesis holds extreme significance.
Traditionally, the most common strategy to prepare this ring system consists in the reaction of o-phenylenediamines
with aldehydes4, aryl chlorides5, acids6, or orthoesters7. As one of the most effective polar solvents, N,
N-dimethylformamide (DMF) has been employed as a widely utilized reactant in many organic reactions8. Typically,
it has been utilized as the carbon source for the preparation of benzimidazoles and represents one of the most
convenient and straightforward synthetic methods.
Fig. 1 Representative bioactive molecules and drugs containing benzimidazole group.
In 1995, Bourguignon9 reported the treatment of o-phenylenediamines with DMF for the synthesis of
benzimidazoles in the presence of SiCl4 in CH2Cl2. In later years, many improvements to the reaction have been made
by the use of alternative catalysts. For example, Kamble10 and Bhanage11 reported an improved method to form
2

ACCEPTED MANUSCRIPT
benzimidazoles from o-phenylenediamines and DMF, respectively. In their reports, a large amount of corrosive
concentrated hydrochloric acid (70%) or metal catalyst Zn(OAc)2 were employed as the catalyst (Scheme 1a and 1b).
Lately, Yadav12 reported a scalable CO2 mediated synthesis of benzimidazoles by cyclization of o-phenylenediamines
with DMF under the harsh reaction conditions (5 MPa and 150 °C) (Scheme 1c). Similarly, Liu13 and co-workers also
reported the CO2 promoted synthesis of N-containing heterocycles over B(C6F5)3 catalyst (Scheme 1d). However, the
practicality of these methods was offset by a special reactor and stoichiometric amount of catalyst. Recently, Sun14
presented a flexible and elegant protocol utilizing 4 equivalents of phenylsilicon (PhSiH3) as the catalyst for the
synthesis of benzimidazoles. However, this synthesis method showed non-compatibility when extended to substrates
containing electron-donating groups (Scheme 1e). In a similar way, Islami15 also reported a synthesis method of
benzimidazole from o-phenylenediamine and DMF or N, N-diethylformamide (DEF) in the presence of
hexamethyldisilazane (HMDS) (Scheme 1f).
Although diverse synthetic approaches have been developed, some of these methodologies still suffer from one or
more disadvantages. Besides, it is noteworthy that all above methods barely investigated the reaction of
o-phenylenediamines with DMF derivatives, such as N, N-dimethylacetamide (DMA), N, N-dimethylbenzamide
(DMBA), to form 2-substituted benzimidazoles.
Therefore, in view of this, an efficient and convenient methodology for the synthesis of benzimidazoles and
2-substituted benzimidazoles is still desirable. Our interest in the use of imidazolium chloride-based catalysis
prompted us to investigate the use of imidazolium chloride as a catalyst in the formation of benzimidazoles16. Herein,
we wish to report an efficient protocol for synthesis of benzimidazoles and 2-substituted benzimidazoles from
o-phenylenediamines and DMF derivatives in the presence of imidazolium chloride without any other catalysts or
additives under metal-free conditions (Scheme 1g).
Scheme 1. Synthesis methods for benzimidazoles and 2-substituted benzimidazoles
3

ACCEPTED MANUSCRIPT
2. Results and discussion
In our initial experiments, the cyclization of o-phenylenediamine with DMF catalyzed by imidazolium chloride was
carried out as a model reaction. The results are listed in Table 1. The cyclization reaction did not occur in DMF
without imidazolium chloride, and a control experiment, with 0.2 equiv of concentrated HCl or 0.2 equiv of imidazole,
was also found to give trace product (Table 1, entries 1-5). However, the coexistence of 20 mol % imidazolium
chloride and DMF significantly improved the reaction activity, affording benzimidazole in a good yield of 95% under
the same condition (Table 1, entries 7), suggesting the imidazolium chloride complex may be responsible for the
activation of DMF. Encouraged by this result, then the influence of the catalyst amount was tested. To our delight,
desired products could be obtained in good yield even with 10 mol % catalyst (Table 1, entries 8-9), demonstrating
that imidazolium chloride is highly efficient for this reaction. Next, upon varying temperatures of the reaction between
30 °C and 140 °C, the conversion declined, higher temperatures was proved to be benefit for the reaction. Specifically,
no target product was detected at 30 °C, and 68% yield of product was isolated at 90 °C (Table 1, entry 10), while a
satisfactory yield (95%) was observed when the reaction was conducted at 140 °C (Table 1, entry 8). In addition, the
screening of the reaction solvents indicated that DMF was the best solvent for the reaction in most cases, and other
solvents such as benzene, acetonitrile, and tetrahydrofuran gave lower yields, which were consist with our previous
results (Table 1, entries 11-14). Finally, the reaction was found to be efficient with 10 mol % of catalyst in 2 mL DMF
at 120 °C, affording a yield of the product with 94% within 6 h.
Table 1. Optimization of the reaction conditionsa
O
H
N
Cat (n equiv.)
T(°C), solvent
NH2
NH2
H3C
N
H
N
CH3
2a
DMF
1a
Entry
Catalyst (equiv.)
-
Solvent
Temp(°C)
140
Time(h)
6h
Yield(%)b
NRc
trace
29
1
2
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Imidazole (0.2eq)
140
6h
3
HCl (0.2eq)
140
6h
4
HCl (0.2eq)
120
6h
15
5
HCl (0.2eq)
90
6h
trace
96
6
Imidazolium chloride (0.3eq)
Imidazolium chloride (0.2eq)
Imidazolium chloride (0.1eq)
Imidazolium chloride (0.1eq)
Imidazolium chloride (0.1eq)
140
2h
7
140
2h
95
8
140
2h
95
9
120
6h
94
10
90
6h
68
4

ACCEPTED MANUSCRIPT
11d
12d
13d
14d
Imidazolium chloride (0.1eq)
DCM
THF
40
70
80
85
6h
6h
6h
6h
NRc
12
Imidazolium chloride (0.1eq)
Imidazolium chloride (0.1eq)
Imidazolium chloride (0.1eq)
CH3CN
Benzene
38
56
a Reactions were carried out with o-Phenylenediamine (0.54 g, 5 mmol, 1 equiv) and DMF (2 mL).
b Isolated yield.
c No reaction.
d DMF (0.46 mL, 6 mmol, 1.2 equiv) and solvent (5 mL)
With the optimized conditions in hand, we next set out to investigate the scope of this reaction, and the results are
summarized in Table 2. It appears that this method was very general for a wide range of substituted
o-phenylenediamines. The o-phenylenediamines bearing electron-donating and -withdrawing groups were both
well-tolerated in this reaction and provided the corresponding benzimidazoles in good to excellent yields (82 - 94%).
Mono- and bis-substituents on the benzene moiety showed no obvious influence on the reaction outcome and
produced desired products in good yields (Table 2, 2b - 2i). It is noteworthy to mention that functional groups like
bromo (1e) or chloro (1f) are tolerable under this condition. Notably, the reaction of naphthalene-2,3-diamine also
took place efficiently, and gave the target product in 87% yield (Table 2, 2j).
Table 2. Substrate scope with respect to substituted o-phenylenediaminesa
2a, 94%
2d, 93%
2g, 86%
2b, 92%
2e, 88%
2h, 84%
5
2c, 93%
2f, 85%
2i, 82%

ACCEPTED MANUSCRIPT
2j, 87%
a Experiments were performed with substituted o-phenylenediamines (1a- 1j, 5 mmol) and DMF (2 mL) at 120 °C for 6 h, isolated
yield.
Considering the synthetic usefulness of this reaction, we further illustrated its scalability. To our delight, when the
reaction was scaled up to 180 mmol (1a, 20 gram scale), the desired product 2a was isolated in 90% yield (Scheme 2).
Scheme 2. Gram Scale synthesis of benzimidazole
Furthermore, in order to explore the effects of different substituted amides on this reaction, some DMF derivatives
were investigated (Table 3). Although lower conversions were observed and longer reaction times were required in
some cases, the results showed that the reaction was quite general for a series of diversely substituted amides under
similar reaction condition. Replacement of H with methyl generated the corresponding products in moderate to good
yields (65 - 84%, Table 3, 3a-3f). However, for that with ethyl group, the substrate showed lower reactivity (Table 3,
3g, 63%), probably owing to the steric hindrance. On the other hand, aromatic-substituted substrates mirrored the
reactivity of the model reaction, inferior yields (62 - 83%) were obtained (Table 3, 3h-3j). The less nucleophilic
amides, N, N-dimethy-4-nitrobenzamide, gave the corresponding products in lower yields compared with N,
N-dimethyl-4-methoxylbenzamide and DMBA. This may be attributed to the fact that the electron-withdrawing
groups disfavor the formation of reaction activated intermediate. In addition, it was noted that the heteroaromatic
substrate was also compatible, the reaction preceded smoothly as well resulted in 3k with 73% yield.
Table 3. Substrate scope with respect to substituted amidesa
6

ACCEPTED MANUSCRIPT
3aa, 84%
3ba, 75%
3ca, 77%
3da, 65%
3gb, 63%
3jc, 83%
3ea, 75%
3hc, 62%
3kc, 73%
3fa, 69%
3ic, 77%
a
Experiments were performed with o-phenylenediamine (5 mmol, 1 equiv) and DMA (2 mL) at 120 °C for 6 h, isolated yield. b
reaction temperature 140 °C. c Experiments were performed with substituted o-phenylenediamine (5 mmol, 1 equiv) and DMF
derivatives (7.5 mmol, 1.5 equiv) in 5 mL xylene at 140 °C for 8 h, isolated yield.
To gain insight into the reaction mechanism, we performed some additional experiments (Scheme 3). Stirring
o-phenylenediamine with DMA at 120 °C for 6 h in the presence of 1 equiv. concentrated HCl only furnished trace
product. On the other hand, to check the effect of free NH-group of imidazolium chloride, the reaction was conducted
using N-methylimidazole hydrochloride as the catalyst. However, the latter catalyst showed some activity but was not
efficient. These above studies indicate that imidazole is essential for the construction of benzimidazoles.
Scheme 3. Control experiments to elucidate the mechanism
7

ACCEPTED MANUSCRIPT
Scheme 4. Plausible mechanism for imidazolium chloride-catalyzed cyclization
Therefore, based on the results of our experiments and those from literature13, a plausible mechanism for the
formation of benzimidazoles is depicted in Scheme 4. First, amide is activated by H+ to afford cationic intermediate A,
which is attacked by imidazole results in the formation of a tetrahedral intermediate B. Breakdown of intermediate B
leads to the formation of reactive N-acylimidazole (intermediate C), which further undergoes nucleophilic addition
with an amine, followed by extrusion of one molecular imidazole generates intermediate D. The amino group on D
condenses with the carbonyl group to form a heterocycle and a subsequent dehydration and finally provide the
benzimidazoles.
3. Conclusion
In summary, we have developed an efficient and economical approach to synthesize benzimidazoles and
2-substituted benzimidazoles from o-phenylenediamines and DMF derivatives in the presence of imidazolium chloride
without any other catalysts or additives. The presented synthetic methodology reveals excellent reactivity and good
functional group tolerance with moderate to excellent yields. Further synthesis of other bioactive molecules or
important medical intermediates based on this method is in progress in our laboratory.
4. Experimental
4.1 General information
All reagents were obtained from Adamas, tansoole, and Macklin, and were used without further purification unless
8

ACCEPTED MANUSCRIPT
1
otherwise noted. H NMR and 13C HNMR spectra were obtained using a Bruker-600 MHz spectrometer with
DMSO-d6 or CDCl3 as solutions and TMS as the internal standard. Chemical shifts are reported in ppm and coupling
constants (J) in Hz. All reactions were monitored by TLC with GF254 silica gel coated plates. Flash column
chromatography was carried out by using 200-300 mesh silica gel. All substrates are known compounds and prepared
according to the literature.
4.2. General procedure for the synthesis of benzimidazole derivatives (2a-3e)
To a 10 mL three-necked round bottle was charged with 1a (0.54 g, 5 mmol), imidazolium chloride (0.09 g, 0.5
mmol) and N,N-dimethylformamide 2 mL. The resulting solution was warmed to 120°C and stirred at this temperature
for 6 h. When the reaction was completed, 25 mL water was added and the resulting mixture was extracted with 25
mL ethyl acetate twice. The combined organic layer was successively washed with H2O (50 mL) and then brine (50
mL), then dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified
by column chromatography on silica gel with petroleum ether and ethyl acetate or recrystallized from petroleum
ether/EA to give the title products.
4.3. General procedure for the synthesis of benzimidazole derivatives (3f-3j)
A mixture of 1a (0.54 g, 5 mmol), imidazolium chloride (0.09 g, 0.5 mmol) and N, N-dimethylbenzamide (0.55 g,
7.5 mmol) in 5 mL xylene was heated to 140°C and stirred at this temperature for 8 h. When the reaction was
completed, 50 mL water was added and the resulting mixture was extracted with 50 mL ethyl acetate twice. The
combined organic layer was successively washed with H2O (50 mL) and then brine (50 mL), then dried over
anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column
chromatography on silica gel using petroleum ether and ethyl acetate as the eluent or recrystallized from petroleum
ether/EA to give the desired products.
4.4.1. 1H-benzo[d]imidazole (2a)13. Yellow solid (94%); 1H NMR (600 MHz, DMSO-d6) (δ, ppm): 12.48 (s, 1H), 8.25
(d, J = 1.3 Hz, 1H), 7.62 (dd, J = 6.0, 3.4 Hz, 2H), 7.20 (dd, J = 6.0, 3.1 Hz, 2H).; 13C NMR (150 MHz, DMSO-d6) (δ,
ppm): 142.4, 135.6, 122.1, 115.3.
9

ACCEPTED MANUSCRIPT
4.4.2. 5-Methyl-1H-benzo[d]imidazole (2b)17. White solid (92%); 1H NMR (600 MHz, CDCl3) (δ, ppm): 9.20 (s, 1H),
8.12 (s, 1H), 7.60 (d, J = 8.1 Hz, 1H), 7.48 (s, 1H), 7.15 (d, J = 8.1 Hz, 1H), 2.50 (s, 3H).; 13C NMR (150 MHz,
CDCl3) (δ, ppm): 140.5, 137.4, 136.3, 132.7, 124.4, 115.4, 114.8, 21.6.
1
4.4.3. 5-Meothoxy-1H-benzo[d]imidazole (2c)17. White solid (93%); H NMR (600 MHz, CDCl3) (δ, ppm): 8.87 (s,
1H), 8.05 (d, J = 10.8 Hz, 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.10 (d, J = 2.1 Hz, 1H), 6.93 (dd, J = 8.8, 2.2 Hz, 1H), 3.82
(s, 3H).; 13C NMR (150 MHz, CDCl3) (δ, ppm): 156.6, 140.5, 137.7, 133.0, 116.5, 112.6, 97.6, 55.8.
4.4.4. 5, 6-Dimethyl-1H-benzo[d]imidazole (2d)18. Yellow solid (93%); 1H NMR (600 MHz, CDCl3) (δ, ppm): 8.22 (s,
1H), 8.01 (s, 1H), 7.44 (s, 2H), 2.37 (s, 6H); 13C NMR (150 MHz, CDCl3) (δ, ppm): 139.9, 136.2, 131.9, 115.5, 20.3.
1
4.4.5. 5-Bromo-1H-benzo[d]imidazole (2e)13. White solid (88%); H NMR (600 MHz, DMSO-d6) (δ, ppm): 12.67 (s,
1H), 8.28 (d, J = 3.6 Hz, 1H), 7.81 (s, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.34 (dd, J = 8.5, 1.1 Hz, 1H). 13C NMR (150
MHz, DMSO-d6) (δ, ppm): 143.7, 125.0, 114.4.
1
4.4.6. 5-Chloro-1H-benzo[d]imidazole (2f)13. Yellow solid (85%); H NMR (600 MHz, DMSO-d6) (δ, ppm): 8.28 (s,
1H), 7.66 (s, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.21 (d, J = 8.3 Hz, 1H).; 13C NMR (150 MHz, DMSO-d6) (δ, ppm): 143.4,
126.1, 121.9, 116.3, 115.2.
1
4.4.7. 5, 6-Dichloro-1H-benzo[d]imidazole (2g)13. Yellow solid (86%); H NMR (600 MHz, DMSO-d6) (δ, ppm):
12.74 (s, 1H), 8.35 (s, 1H), 7.94 (s, 1H), 7.82 (s, 1H).; 13C NMR (150 MHz, DMSO-d6) (δ, ppm): 145.2, 143.1, 133.3,
124.9, 124.2, 120.7, 113.6.
1
4.4.8. 5-Fluoro-1H-benzo[d]imidazole (2h)13. Grey solid (84%); H NMR (600 MHz, DMSO-d6) (δ, ppm): 12.61 (s,
1H), 8.30 (s, 1H), 7.62 (t, J = 6.4 Hz, 1H), 7.43 (d, J = 9.6 Hz, 1H), 7.08 (td, J = 9.3, 2.6 Hz, 1H). 13C NMR (150 MHz,
DMSO-d6) (δ, ppm): 159.7, 158.1, 143.8, 110.3, 100.0.
4.4.9. 5-Trifluoromethyl-1H-benzo[d]imidazole (2i)13. Yellow solid (82%); 1H NMR (600 MHz, DMSO-d6) (δ, ppm):
12.90 (s, 1H), 8.47 (s, 1H), 7.99 (s, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.53 (dd, J = 8.5, 1.1 Hz, 1H). 13C NMR (150 MHz,
DMSO-d6) (δ, ppm): 144.7, 127.7, 125.9, 124.1, 122.5, 122.3, 118.4.
10

ACCEPTED MANUSCRIPT
1
4.4.10. 1H-Naphtho[2,3-d]imidazole (2j)13. Black solid (87%); H NMR (600 MHz, DMSO-d6) (δ, ppm): 12.54 (s,
1H), 8.49 (s, 1H), 8.12 (s, 2H), 8.01 (dd, J = 6.3, 3.3 Hz, 2H), 7.53 – 6.97 (m, 2H). 13C NMR (150 MHz, DMSO-d6) (δ,
ppm): 146.9, 130.1, 128.2, 123.8.
4.4.11. 2-Methyl-1H-benzo[d]imidazole (3a)19. White solid (84%); 1H NMR (600 MHz, DMSO-d6) (δ, ppm): 12.21 (s,
1H), 7.45 (dt, J = 6.8, 3.2 Hz, 2H), 7.11 (ddd, J = 6.0, 3.2, 1.2 Hz, 2H), 2.49 (s, 3H). 13C NMR (150 MHz, DMSO-d6)
(δ, ppm): 151.70, 121.48, 15.10.
4.4.12. 2-Methyl-5-Chloro-1H-benzo[d]imidazole (3b)20. Grey solid (75%); 1H NMR (600 MHz, DMSO-d6) (δ, ppm):
12.38 (s, 1H), 7.50 (s, 1H), 7.45 (s, 1H), 7.12 (d, J = 8.3 Hz, 1H), 2.48 (s, 3H).; 13C NMR (150 MHz, DMSO-d6) (δ,
ppm): 153.2, 125.7, 121.6, 15.1.
1
4.4.13. 2, 5-Dimethyl-1H-benzo[d]imidazole (3c)21. White solid (77%); H NMR (600 MHz, DMSO-d6) (δ, ppm):
12.05 (s, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.23 (s, 1H), 6.91 (dd, J = 8.1, 1.0 Hz, 1H), 2.45 (s, 3H), 2.38 (s, 3H).; 13C
NMR (150 MHz, DMSO-d6) (δ, ppm): 150.8, 129.9,122.3, 21.1, 14.5.
4.4.14. 2-Methyl-5-Nitro-1H-benzo[d]imidazole (3d)22. Yellow solid (65%); 1H NMR (600 MHz, DMSO-d6) (δ, ppm):
12.94 (s, 1H), 8.37 (s, 1H), 8.06 (dd, J = 8.7, 1.5 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 2.57 (s, 3H).; 13C NMR (150 MHz,
DMSO-d6) (δ, ppm):142.5, 117.6, 15.3.
4.4.15. 2, 5, 6-Trimethyl-1H-benzo[d]imidazole (3e)20. Brown solid (75%); 1H NMR (600 MHz, DMSO-d6) (δ, ppm):
14.97 (s, 1H), 7.51 (s, 2H), 2.78 (s, 3H), 2.36 (s, 6H).; 13C NMR (150 MHz, DMSO-d6) (δ, ppm): 150.2, 135.0, 129.6,
113.6, 20.2, 12.5.
1
4.4.16. 2-Methyl-5, 6-dichloro-1H-benzo[d]imidazole (3f)20. Grey solid (69%); H NMR (600 MHz, DMSO-d6) (δ,
ppm): 12.55 (s, 1H), 7.72 (s, 2H), 2.49 (s, 3H).; 13C NMR (150 MHz, DMSO-d6) (δ, ppm): 154.9, 143.8, 134.4, 122.,
121.6, 112.6, 15.1.
11

ACCEPTED MANUSCRIPT
4.4.17. 2-Ethyl-1H-benzo[d]imidazole (3g)23. Brown solid (63%); 1H NMR (600 MHz, DMSO-d6) (δ, ppm): 12.16 (s,
1H), 7.45 (s, 2H), 7.10 (dd, J = 5.9, 3.1 Hz, 2H), 2.82 (q, J = 7.6 Hz, 2H), 1.32 (t, J = 7.6 Hz, 3H).; 13C NMR (150
MHz, DMSO-d6) (δ, ppm): 156.6, 144.2, 121.5, 22.4, 12.6.
4.4.18. 2-(4-Nitrophenyl)-1H-benzo[d]imidazole (3h)24. Yellow solid (62%); 1H NMR (600 MHz, DMSO-d6) (δ, ppm):
13.31 (s, 1H), 8.64 - 8.19 (m, 4H), 7.75 (d, J = 7.9 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.28 (dt, J = 14.8, 7.0 Hz, 2H).;
13C NMR (150 MHz, DMSO-d6) (δ, ppm):149.4, 148.2, 144.3, 136.5, 135.7, 127.8, 124.7, 124.0, 122.7, 119.9, 112.2.
4.4.19. 2-Phenyl-1H-benzo[d]imidazole (3i)19. White solid (77%); 1H NMR (600 MHz, DMSO-d6) (δ, ppm): 12.98 (s,
1H), 8.23 (d, J = 7.9 Hz, 2H), 7.64 (s, 2H), 7.57 (t, J = 7.6 Hz, 2H), 7.51 (t, J = 7.3 Hz, 1H), 7.23 (dd, J = 5.9, 3.1 Hz,
2H). 13C NMR (150 MHz, DMSO-d6) (δ, ppm):.151.2, 130.1, 129.7, 128.9, 126.4, 122.1.
1
4.4.20. 2-(4-Methoxyphenyl)-1H-benzo[d]imidazole (3j)24. White solid (83%); H NMR (600 MHz, DMSO-d6) (δ,
ppm): 12.75 (s, 1H), 8.12 (d, J = 8.7 Hz, 2H), 7.62 (d, J = 7.5 Hz, 1H), 7.50 (d, J = 7.5 Hz, 1H), 7.27 - 7.14 (m, 2H),
7.12 (d, J = 8.7 Hz, 2H), 3.84 (s, 3H).; 13C NMR (150 MHz, DMSO-d6) (δ, ppm): 161.0, 151.8, 144.3, 135.4, 128.4,
123.1, 121.9, 118.9, 114.8, 111.4, 55.8.
4.4.21. 2-(pyridin-2-yl)-1H-benzo[d]imidazole (3k) 19. White solid (73%); 1H NMR (600 MHz, DMSO-d6) (δ, ppm):δ
13.14 (s, 1H), 8.75 (d, J = 4.6 Hz, 1H), 8.35 (d, J = 7.8 Hz, 1H), 8.01 (t, J = 7.4 Hz, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.66
- 7.42 (m, 2H), 7.21 - 7.24 (m, 2H). 13C NMR (150 MHz, DMSO-d6) (δ, ppm):151.2, 149.8, 149.0, 144.3, 138.0,
135.4, 125.1, 123.5, 122.3, 121.8, 119.7, 112.5.
Acknowledgements
We appreciate the finical support from the Fundamental Research Funds for the Chongqing Science and
Technology Commission (cstc2018jscx-msybX0294) and the Natural Science Foundation of Chongqing City
(cstc2017jcyjAX0228).
References
1. (a) Kim MK, Shin H, Park KS, Kim H, Park J, Kim K, Nam J,Choo H, Chong Y. J. Med. Chem. 2015: 58: 7596;
(b) Chen G, Liu Z, Zhang Y, Shan X, Jiang L, Zhao Y, He W, Feng Z, Yang S, Liang G. ACS Med. Chem. Lett.
12

ACCEPTED MANUSCRIPT
2013: 4: 69; (c) Singh M,Tandon V. Eur. J. Med. Chem. 2011: 46: 659-669; (d) Desai KG, Desai KR. Bioorg.
Med. Chem. 2006: 14: 8271.
2. (a) Zhang Z, Zhang H, Jiao C,Ye K, Zhang H, Zhang J, Wang Y. Inorg. Chem. 2015: 54: 2652; (b) Mondal E,
Hung WY, Chen YH, Cheng MH, Wong KT. Chemistry. 2013: 19: 10563.
3. Krishnaveni K, Iniya M, Jeyanthi D, Siva A, Chellappa D. Spectrochim Acta A. 2018: 205: 557.
4. (a) Cano NH, Uranga JG, Nardi M, Procopio A, Wunderlin DA, Santiago AN. Beilstein J. Org. Chem. 2016: 12:
2410; (b) Nagata K, Itoh T, Ishikawa H, Ohsawa A. Heterocycles. 2003: 61: 93.
5. (a) Tandon VK, Kumar M. Tetrahedron Lett. 2004: 45: 4185; (b) Heravi MM, Baghernejad B, Oskooie HA,
Malakooti R. J. Chin. Chem. Soc. 2008: 55: 1129.
6. (a) Das VK, Devi RR, Raul PK, Thakur AJ. Green Chem. 2012: 14: 847; (b) Obermayer D, Znidar D, Glotz G,
Stadler A, Dallinger D, Kappe CO. J. Org. Chem. 2016: 81: 11788; (c) El-Sayed TH, Aboelnaga A, Hagar M.
Molecules 2016: 21.
7. (a) Karami B, Ghashghaee V, Khodabakhshi S. Catal. Commun. 2012: 20: 71; (b) Vahdat SM, Baghery S. Comb.
Chem. High Throughput Screen. 2013: 16: 618.
8. (a) Srinivas M, Hudwekar AD, Venkateswarlu V, Reddy GL, Kumar KAA,Vishwakarma RA, Sawant SD.
Tetrahedron Lett. 2015: 56: 4775; (b) Lanigan RM, Starkov P, Sheppard TD. J. Org. Chem. 2013: 78: 4512.
9. Desaubry L, Wermuth CG, Bourguignon JJ. Tetrahedron Lett. 1995: 36: 4249.
10. Kattimani PP, Kamble RR, Meti GY. RSC Advances. 2015: 5: 29447.
11. Nale DB, Bhanage BM. Synlett. 2015: 26: 2835.
12. Rasal KB, Yadav GD. Org. Process. Res. Dev. 2016: 20: 2067.
13. Gao X, Yu B, Mei Q, Yang Z, Zhao Y, Zhang H, Hao L, Liu Z. New J Chem. 2016: 40: 8282.
14. Zhu J, Zhang Z, Miao C, Liu W, Sun W. Tetrahedron. 2017: 73: 3458.
15. Mostafavi H, Islami MR, Ghonchepour E, Tikdari AM. Chem Pap. 2018: 72: 2973.
16. Tian Q, Gan Z, Wang X, Li D, Luo W, Wang H, Dai Z, Yuan J. Molecules. 2018: 23: 2234.
17. Sun Z, Bottari G, Barta K. Green Chem. 2015: 17: 5172.
18. Zhang Z, Sun Q, Xia C, Sun W. Org. Lett. 2016: 18: 6316.
19. Wade AR, Pawar HR, Biware MV, Chikate RC. Green Chem. 2015: 17: 3879.
20. Sharma S, Bhattacherjee D, Das P. Org. Biomol. Chem. 2018: 16: 1337.
21. Fortenberry C, Nammalwar B, Bunce RA. Org. Prep. Proced. Int. 2013: 45: 57.
22. Mayo MS, Yu X, Zhou X, Feng X, Yamamoto Y, Bao M. Org. Lett. 2014: 16: 764.
13

ACCEPTED MANUSCRIPT
23. Wen X, El Bakali J, Deprez-Poulain R, Deprez B. Tetrahedron Lett. 2012: 53: 2440.
24. Bai G, Lan X, Liu X, Liu C, Shi L, Chen Q, Chen G. Green Chem. 2014: 16: 3160.
14