Synthesis of 1,2-disubstituted benzimidazoles through DDQ-oxidized intramolecular dehydrogenative coupling of N,N′-dialkyl o-phenylenediamines

Article abstract of DOI:10.1016/j.tet.2020.131474

The synthetic methodology of 1,2-disubstituted benzimidazoles has been developed, which starts from N,N′-dialkyl o-phenylenediamines via intramolecular dehydrogenative coupling under the oxidation of DDQ with mild conditions. Through detailed optimization of reaction conditions, only DDQ was found essential without any additives to reach to the highest yield of 99%. In the cases of linear aliphatic substituents, the synthesis of 1-alkyl-2-phenylbenzimidazoles showed high selectivities and their structures were identified by 2D NMR COSY correlation analysis. A plausible mechanism was proposed to interpret the observed reactivities and selectivities.

Full text of DOI:10.1016/j.tet.2020.131474

Tetrahedron 76 (2020) 131474
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of 1,2-disubstituted benzimidazoles through DDQ-oxidized
intramolecular dehydrogenative coupling of N,N0-dialkyl o-
phenylenediamines
Youcai Ma, Ruimei Xiong, Yangyang Feng, Xiaohui Zhang, Yan Xiong*
School of Chemistry and Chemical Engineering, Chongqing Key Laboratory of Theoretical and Computational Chemistry, Chongqing University, Chongqing,
401331, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthetic methodology of 1,2-disubstituted benzimidazoles has been developed, which starts from
N,N0-dialkyl o-phenylenediamines via intramolecular dehydrogenative coupling under the oxidation of
DDQ with mild conditions. Through detailed optimization of reaction conditions, only DDQ was found
essential without any additives to reach to the highest yield of 99%. In the cases of linear aliphatic
substituents, the synthesis of 1-alkyl-2-phenylbenzimidazoles showed high selectivities and their
structures were identified by 2D NMR COSY correlation analysis. A plausible mechanism was proposed to
interpret the observed reactivities and selectivities.
Received 7 March 2020
Received in revised form
29 July 2020
Accepted 3 August 2020
Available online 23 August 2020
Keywords:
Benzimidazoles
Cyclizations
© 2020 Elsevier Ltd. All rights reserved.
DDQ
N,N0-dialkyl o-phenylenediamines
Oxidations
1. Introduction
activity was studied in the hydrosilylation of phenylacetylene [5],
and novel chelating benzimidazole-based Nickel(II) complexes
Benzimidazoles, as
a
kind of heterocyclic compound, are
have been utilized to catalyze Kumada coupling reaction [6]. In
addition, benzimidazole and its derivatives can also be used as
corrosion inhibitors [7], proton exchange membranes [8], photo-
chemical sensors [9], bioenzyme inhibitors [10] and polymer
electrolyte membranes [11].
There are two common methods to synthesis benzimidazole
and its derivatives. The first one is the reaction of o-phenylenedi-
amine and carboxylic acid with or without catalyst. In this method,
benzimidazoles were synthesized, involving successive N-acyla-
tion, addition and cyclization of amino group and carbonyl group
[12]. The second method is the reaction of o-phenylenediamine and
aldehyde. o-Phenylenediamine condensed with the carbonyl of
aldehyde to form a single or double schiff base, which then un-
derwent nucleophilic addition and dehydrogenation to obtain
benzimidazoles [13].
bioactive molecules widely existing in natural products. Their
unique structural characteristics and electron rich atmosphere
enable them to combine with many biological targets to produce
important activities. Therefore, they are widely used in drug dis-
covery and medicinal chemistry research in recent years [1].
Currently, benzimidazoles with different substituents have been
shown to possess antiviral, antibacterial, anti-tumor, anti-hyper-
tension, anti-diabetes, anti-HIV clinical and other biological activity
potential [2]. In agriculture, compounds with benzimdazole struc-
tures also have fungicidal and plant growth-regulating properties,
and are commonly used in agrochemicals [3]. And in the coordi-
nation chemistry, benzimidazoles can be used as raw materials for
catalyst prepration. For example, 1-(triphenylmethyl)benzimid-
azole-modified ruthenium-diphosphane precatalysts have been
employed to effectively promote enantioselective bifunctional hy-
drogenation of ketones [4], while 1,3-bis(N-alkylbenzimidazole)
benzene-based Rh complexes were synthesized and their catalytic
In other synthetic methodologies, the transformation has been
concentrated on N,N0-dialkyl o-phenylenediamines. Recently, in
Foss’s work, the reactions were executed by heating conditions,
catalyzed by FeCl3$6H2O, and the air was a green oxidation source
with good substrate compatibility [14]. In our previous work,
benzimidazoles had been synthesized with a metal-free method,
* Corresponding author.
E-mail address: xiong@cqu.edu.cn (Y. Xiong).
https://doi.org/10.1016/j.tet.2020.131474
0040-4020/© 2020 Elsevier Ltd. All rights reserved.

2
Y. Ma et al. / Tetrahedron 76 (2020) 131474
Table 2
which could effectively avoid metal ion pollution in product,
especially facing so strong coordination of benzimidazoles, and the
yield was initially in 74% at 80 ꢀC without further detailed opti-
mization of reaction conditions [15]. Hereby, along with our inter-
est in transformations of amines [16], we would like to report our
extension studies on by DDQ-oxidized intramolecular cycloaddi-
tion of N,N0-dialkyl o-phenylenediamines towards synthesis of
benzimidazoles under optimal and mild conditions with safe
profile.
Optimizations of additives, amount of DDQ and DMSO and timea.
Entry
DDQ (equiv)
DMSO (mL)
Additives
t h
Yield (%)
1
2
3
4
5
6
7
8
1.8
2.2
2.4
2.6
2.4
2.4
2.4
2.4
2.4
2.4
2.4
2.4
2.4
2.4
2.4
2
2
2
2
2
2
2
2
2
2
1.5
1
0.5
1
e
4
4
4
4
4
4
4
4
4
4
4
4
4
2
1
74
90
93
88
62
63
71
84
91
88
93
93
85
99
91
e
2. Results and discussion
e
e
We first investigated the treatment of N,N0-dibenzyl o-phenyl-
enediamine 1a and DDQ as model reaction to verify the possibility
of conversion of 1a. The reaction was initially carried out in an oil
bath of 30 ꢀC, where 2.0 equivalents of DDQ were reacted with
substrate in 2.0 mL of THF to produce 2a that was afforded in 74%
yield (Table 1, entry 1). Then we gradually increased the reaction
temperature，finding that product 2a had an better yield of 80% at
40 ꢀC (Table 1, entries 2 and 3). Under these conditions, the solvent
effect was investigated, discovering that solvents with medium to
weak polarity such as methylene chloride (CH2Cl2), chloroform
(CHCl3), diethyl ether (Et2O), toluene and 1,4-dioxane afforded
lower yields, however, the use of ethyl acetate (EtOAc) was slightly
lower than THF (Table 1, entries 4e9). While we used strong polar
solvents such as N,N-dimethyl formamide (DMF), methanol
(MeOH) and dimethyl sulfoxide (DMSO), it was found that the
yields were all improved, which DMSO provided the best yield in
89% (Table 1, entries 10e12). This is probably due to the high sol-
ubility of dimethyl sulfoxide, so that the reactants could be fully
dissolved.
The influences of amount of oxidants and additives on the re-
action were examined with the results shown in Table 2. When the
amount of oxidant was less than the stoichiometric ratio
(1a:DDQ ¼ 1:2), 1a was not completely converted to 2a due to the
insufficient amount of DDQ, and the yield was 74% (Table 2, entry
1). When the amount of DDQ increased gradually, the yield of
product 2a increased first and then decreased (Table 2, entries
2e4). When the amount of DDQ was 2.4 times of substrate 1a, the
yield of 2a reached to 93% (Table 2, entry 3). In order to further
increase the yield of the reaction, the trials of additives were
Na2SO4
HOAc
K2CO3
TEA
PhCOOH
4 Å MS
e
9
10
11
12
13
14
15
e
e
-
e
1
a
Reaction conditions: 1a (0.3 mmol) and DDQ (specified) in DMSO (specified) at
40 ꢀC for specified time.
performed. When acidic, basic and neutral substances such as so-
dium sulfate, acetic acid and potassium carbonate were used as
additives, the reaction yields significantly lowered to the range of
62e71% (Table 2, entries 5e7), while triethylamine, benzoic acid
and 4 Å molecular sieve resulted in slightly lower yields (Table 2,
entries 8e10). In general, these selected additives showed detri-
ments to maintain a high yield.
Furthermore, it was found that when the amount of solvent
dimethyl sulfoxide decreased, the yield did not decrease signifi-
cantly where the best amount of solvent was kept in 1 mL because
of 0.5 mL of solvent not enough to dissolve the reactants (Table 2,
entries 11e13). Then the reaction time was investigated and as a
result for 2 h the yield reached to 99% (Table 2, entry 14). While the
reaction time continues to be shortened, the conversion of sub-
strate 1a was incomplete, resulting in a reduced yield in 91%
(Table 2, entry 15). Accordingly, the optimal reaction conditions
were acquired as 2.4 equivalents of DDQ stirred in 1.0 mL of
dimethyl sulfoxide at 40 ꢀC of oil bath for 2 h.
Table 1
Optimizations of solvent and temperaturea.
With the optimal reaction conditions in hand, the substrate
scope was then explored with the results summarized in Table 3,
The effects of R1, R2 and R3 groups of substrate 1 on the reactivities
were studied. The results show that when the 3- and 4-methyl
substituted 1a was employed as substrates, 4- and 6-methyl-1-
benzyl-2-phenyl benzimidazoles (2b and 2c) were obtained in
yields of 56% and 74%, respectively, where remoter 4-methyl sub-
stitution indicated less steric hindrance to this reaction and
therefore showed higher yield. 4-Chloro substituted 1a was used as
substrate, 5- and 6-chloro substituted products (2d and 2d′) were
obtained simultaneously in total yield of 88% with molar ratio of
1:3. Monobenzyl substituted substrate such as N-benzyl-o-phe-
nylenediamine was subjected to these conditions, reaction did not
take place and no 2-phenyl-1H-benzo[d]imidazole (2e) was ob-
tained, probably due to weaker basicity of aromatic primary amine.
When one benzyl group was substituted by a methyl ester group at
the para position, the yield of 2f dropped in 2 h, and prolonging
reaction time led to improved yield of 95%. m-Bromo substituent
gave rise to 1-(3-bromobenzyl)-2-phenyl-1H-benzo[d]imidazole
(2g) in good yield of 62% yet. In case of N1-n-octyl substituent, 1-
alkyl substituted benzimidazole (2h) was produced in high yield
Entry
Solvent (x mL)
T
oC
Yield (%)
1
2
3
4
5
6
7
8
THF (2)
THF (2)
THF (2)
EtOAc (2)
DCM (2)
CHCl3 (2)
Et2O (2)
Toluene (2)
1,4-dioxane (2)
DMF (2)
30
40
60
40
40
40
40
40
40
40
40
40
74
80
70
78
70
66
54
59
49
82
81
89
9
10
11
12
MeOH (2)
DMSO (2)
a
Reaction conditions: 1a (0.3 mmol) and DDQ (2.0 equiv) in solvent (2.0 mL) at
specified temperature for 4 h.

Y. Ma et al. / Tetrahedron 76 (2020) 131474
3
Table 3
Table 3 (continued )
Investigation on substrates.
Substrate
Product
Yield (%)a
30
Substrate
Product
Yield (%)a
99
1i
1j
2i
2j
26
66b
0
1a
2a
56
1b
2b
74
22
66
1k
2k
1c
2c
1l
2l
1d
2d
2d′
0
2e
1e
95b
1f
2f
62
1g
1h
2g
2h
86
Fig. 1. Key connections determined from 2D NMR 3-bond COSY correlation for 2h.

4
Y. Ma et al. / Tetrahedron 76 (2020) 131474
of 86% without the coexistence of isomer 2h′ (Fig. 1). However, the
equal mixture of 1i and 1j was used as starting materials, in which
the 6- and 5-methyl substituted products (2i and 2j) were obtained
in total yield of 56% with about 1:1 M ratio. The alkenyl substituted
substrate (1k) was employed as substrate with coexistence of 1a,
the transformation of 1a is quantitatively, and assembled benz-
imidazole (2k) was obtained in yield of 66% as well, in which low
yield was presumed probably due to the existence of active olefin.
However, in another case, when using N1,N1,N2-tri-
benzylbenzene-1,2-diamine (1l) as substrate, in which one of sec-
ondary amines was further substituted by benzyl, the reaction was
inhibited and the expected imidazolium salt (2l) was not formed.
Although there are two possible isomeric products (2h and 2h′)
from unsymmetrical 1h, only 2h was obtained with n-octyl sub-
stitution on N1, which is readily identified by the 2D NMR HeH
COSY correlation (Fig. 1). The triplet signal peak at 4.23 ppm was
assigned as Ha in 2h. The hydrogen Ha at the chemical displacement
of 4.23 ppm was observed correlation with the hydrogen Hb at
1.81e1.82 ppm, which implied that there are two neighbouring
hydrogens of methylene to Ha. If benzylic methylene was connected
to N1, the benzylic hydrogen would be resonated singlet signal peak
and shifted more downfield. Likewise, the structures of 2i-k were
identified as single products like 2h, respectively.
In the preparation of substrates, it was also found that in the
presence of acetic acid, mixing N1-benzylbenzene-1,2-diamine and
p-methylbenzaldehyde generated 2m in yield of 62% under reflux
conditions (Scheme 1.). The yield of 2n was 49% when N1-octyl-
benzene-1,2-diamine reacted with p-methylbenzaldehyde for 2 h.
While the aldehydes were cyano substituents, the yields of benz-
imidazoles (2o and 2p) were increased to 87% and 60%, respec-
tively. Higher activities was speculated from the properties of more
electron-deficiency of aldehydes. Similarly, the yield of 74% was
obtained for 2q, in which the aldehyde was substituted by strongly
electron-withdrawing fluorine.
Fig. 2. Plausible reaction mechanism.
free benzimidazoline is released. Repeatedly, by DDQ oxidation, a
single electron transfer and H-absorption eventually results in the
formation of final product.
In above mechanism, for unsymmetrical starting material 1h-k,
the possible two iminium intermediates, i.e. aromatic and aliphatic
iminiums, might be involved and proceed to generate two isomers.
The experimental results showed that the aliphatic groups are al-
ways connected with N1. Two simplified corresponding iminium
structures from N1-benzyl-N2-ethylbenzene-1,2-diamine were
therefore calculated to interpret the formation of 2h-k at the level
of B3LYP/6-31G (Fig. 3). The former showed high stability giving
8.7 kcal/mol lower energy than the latter, because of the larger
conjugation plane, even if the shortest distance of H$$$H is 2.39 Å in
this structure and is close to the sum of their Van der Waals radius.
This delivers the pathways through aromatic iminiums are more
preferable in these transformations than aliphatic ones.
3. Conclusion
In summary, we have developed a synthesis of 1,2- substitutive
benzimidazoles by DDQ oxidized intramolecular dehydrogenative
coupling of N,N0-dialkyl o-phenylenediamines under optimal con-
ditions. As a particular case, N-benzyl o-phenylenediamine was
able to be cyclized with para-cyano benzaldehyde by air oxidation
to form benzimidazole. The experimental results showed that N, N0-
dibenzyl and N-benzyl N0-linear aliphatic chain substitutions were
compatible in this transformation, which provided an alternative
protocol for the synthesis of versatile 1,2-disubstituted
benzimidazoles.
According to our experimental results, a reasonable mechanism
was proposed to explain the formation of benzimidazole through
the oxidative coupling of N,N0-dibenzyl o-phenylenediamine, as
shown in Fig. 2. First of all, N,N0-dibenzyl o-phenylenediamine
proceeeds via single electron transfer and dehydrogenation by DDQ
oxidation to form an iminium cation [17], which is hard to permit
the loss of second electron of another amine, due to the positive
charge of iminium intermediate, and intramolecular nuelceophilic
addition of amine to iminium generates protonated annulated
product benzimidazoline. Through hydrogen absorption of DDHQꢁ,
4. Experimental section
4.1. General
The product was characterized by 1H and 13C NMR using 500/
125 MHz NMR spectrometer at 20e25 ꢀC，CDCl3 (containing 0.03%
Scheme 1. Alternative method to synthesis of benzimidazoles. Reaction conditions:
diamine (0.3 mmol) and aldehyde (0.3 mmol) in EtOH (10.0 mL) at 80 ꢀC for 2 h under
air.
Fig. 3. Energy comparison of aromatic and aliphatic iminiums.

Y. Ma et al. / Tetrahedron 76 (2020) 131474
5
v/v TMS) was used as solvent. 1H NMR spectra was reported in parts
per million using tetramethylsilane (TMS,
¼ 0.00 ppm) as an in-
7.36e7.32 (m, 3H), 7.27 (d, J ¼ 10.0 Hz, 1H), 7.20 (s,1H), 7.09 (d,
d
J ¼ 6.5 Hz, 2H), 5.42 (s, 2H). 13C NMR (125 MHz, CDCl3)
d 155.2,
ternal standard, and 13C NMR was calibrated at 77.2 ppm for the
chemical shift of the deuterated chloroform peak. The NMR data are
reported as follows: chemical shift (ppm), integration, multiplicity
(s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quad, m ¼ multiplicity,
br ¼ wide state) and coupling constant (Hz). High resolution mass
spectra (HRMS) were obtained with a FT-ICRMS. Thin layer chro-
matography (TLC) was performed on a glass plate coated with
GF254 silica gel and observed under 254 nm UV light, while column
chromatography was performed using silica gel HG/T2354-2010.
All reagents are analytically pure, purchased from commercial
suppliers and used directly unless further purification is indicated
otherwise. All reactions were performed at atmospheric pressure
and all reagent weighing was performed at room temperature in
air.
142.0, 136.9, 136.0, 130.3, 129.8, 129.4, 129.0, 128.9, 128.2, 126.1,
123.6, 121.0, 110.7, 48.7.
4.2.6. Methyl 4-(1-benzyl-1H-benzo[d]imidazole-2-yl)benzoate
(2f) [18a]
Light yellow viscous liquid; 13% yield, 13.4 mg; 1H NMR
(500 MHz, CDCl3)
d
8.12 (d, J ¼ 8.0 Hz, 2H), 7.89 (d, J ¼ 8.5 Hz, 1H),
7.79e7.77 (d, J ¼ 7.5 Hz, 2H), 7.34e7.33 (m, 4H), 7.28e7.26 (m, 2H),
7.10 (d, J ¼ 7.0 Hz, 2H), 5.47 (s, 2H), 3.94 (s, 3H). 13C NMR (125 MHz,
CDCl3)
d 166.7, 153.1, 143.4, 136.5, 136.3, 134.6, 131.4, 130.1, 129.44,
129.35, 128.1, 126.1, 123.7, 123.2, 120.4, 110.8, 52.5, 48.7.
4.2.7. 1-(3-bromobenzyl)-2-phenyl-1H-benzo[d]imidazole (2g)
Light yellow solid; 62% yield, 67.6 mg; 1H NMR (500 MHz, CDCl3)
d
7.89 (s, 1H), 7.87 (d, J ¼ 6.5 Hz, 1H), 7.60 (d, J ¼ 8.0 Hz, 1H), 7.56 (d,
4.2. General method for the synthesis of benzimidazoles (2a-l)
J ¼ 7.5 Hz, 1H), 7.34e7.30 (m, 4H), 7.27e7.26 (m, 3H), 7.10 (d,
J ¼ 7.0 Hz, 2H), 5.45 (s, 2H). 13C NMR (125 MHz, CDCl3)
d 152.6,
Compounds 2a-l were synthesized by adding DDQ (0.72 mmol)
to o-phenylenediamine derivatives (1, 0.3 mmol) in 1.0 mL of
dimethyl sulfoxide at 40 ꢀC for 2 h. TLC was employed to monitor
the reaction. When N,N0-dialkyl o-phenylenediamine was con-
verted completely, saturate Na2S2O3 was dropped into reaction
mixture, and stirring was continued. Then the mixture was
extracted and evaporated, and the resulting residue was purified by
column chromatography on silica gel column using EtOAc-
petroleum ether solution as eluent to afford desired benzimid-
azole 2.
143.2,136.3,133.1,132.6,132.3,130.4,129.3,128.1,127.7,126.1,123.6,
123.09, 123.06, 120.4, 110.7, 48.6; HRMS (FT-ICR) m/z: [M þ H]þ
calcd for C20H15BrN2, 363.0491; found, 363.0480.
4.2.8. 1-Octyl-2-phenyl-1H-benzo[d]imidazole (2h) [18c]
Light yellow viscous liquid; 86% yield, 82.7 mg; 1H NMR
(500 MHz, CDCl3)
d
7.85 (d, J ¼ 5.5 Hz, 1H), 7.71 (dd, J1 ¼ 4.5 Hz,
J2 ¼ 2.0 Hz, 2H), 7.51 (s, 3H), 7.41 (t, J ¼ 3.0 Hz, 1H), 7.32 (s, 2H), 4.22
(t, J ¼ 7.0 Hz, 2H), 1.81 (s, 2H), 1.25e1.19 (m, 10H), 0.86 (t, J ¼ 6.5 Hz,
3H). 13C NMR (125 MHz, CDCl3)
d 153.6, 142.7, 135.4, 130.5, 129.9,
129.5, 128.8, 122.9, 122.6, 119.9, 110.3, 44.9, 31.8, 29.8, 29.1, 29.0,
26.8, 22.7, 14.2. HRMS (FT-ICR) m/z: [M þ H]þ calcd for C21H26N2,
307.2169; found, 307.2159.
4.2.1. 1-Benzyl-2-phenyl-1H-benzo[d]imidazole (2a) [18a]
White solid; 99% yield, 84.5 mg; 1H NMR (500 MHz, CDCl3)
d
7.87 (d, J ¼ 8.0 Hz, 1H), 7.69 (d, J ¼ 6.5 Hz, 2H), 7.49e7.44 (m, 3H),
7.35e7.28 (m, 4H), 7.24e7.20 (m, 2H), 7.11 (d, J ¼ 7.0 Hz, 2H), 5.46 (s,
2H). 13C NMR (125 MHz, CDCl3)
154.4, 143.4, 136.6, 136.3, 130.3,
4.2.9. 5-Methyl- and 6-methyl-1-octyl-2-phenyl-1H-benzo[d]
imidazole (2i, 2j)
d
130.1, 129.5,129.2,128.9,128.0,126.2,123.2,122.9,120.2,110.7, 48.6.
Light yellow viscous liquid; 56% yield, 56.2 mg; 1H NMR
(500 MHz, CDCl3)
d 7.68 (s, 5H), 7.61 (s, 1H), 7.49 (s, 6H), 7.28 (d,
4.2.2. 1-Benzyl-4-methyl-2-phenyl-1H-benzo[d]imidazole (2b)
[18a]
J ¼ 8.0 Hz, 1H), 7.18 (s, 1H), 7.12 (d, J ¼ 7.0 Hz, 2H), 4.17 (s, 4H), 2.53
(s, 3H), 2.50 (s, 3H), 1.79 (s, 4H), 1.25e1.19 (m, 20H), 0.87e0.84 (m,
White solid; 56% yield, 50.1 mg; 1H NMR (500 MHz, CDCl3)
6H). 13C NMR (125 MHz, CDCl3)
d 153.8, 153.4, 143.6, 141.4, 136.0,
d
7.66 (d, J ¼ 6.5 Hz, 2H), 7.44 (d, J ¼ 6.5 Hz, 3H), 7.31e7.25 (m, 3H),
7.13e7.07 (m, 4H), 7.04 (d, J ¼ 7.5 Hz, 1H), 5.40 (s, 2H), 2.75 (s, 3H).
13C NMR (125 MHz, CDCl3)
153.7, 142.7, 136.7, 135.8, 130.5, 130.3,
133.9, 132.7, 132.0, 131.0, 129.7, 129.6, 129.43, 129.42, 128.8, 124.2,
124.0, 119.8, 119.6, 110.1, 109.8, 44.8, 44.7, 31.8, 29.84, 29.81, 29.2,
29.1, 26.8, 22.7, 22.1, 21.7, 14.2. HRMS (FT-ICR) m/z: [M þ H]þ calcd
for C22H28N2, 321.2325; found, 321.2315.
d
129.9, 129.6, 129.2, 128.9, 127.9, 126.2, 123.2, 123.1, 108.2, 48.5, 17.0.
4.2.3. 1-Benzyl-6-methyl-2-phenyl-1H-benzo[d]imidazole (2c)
4.2.10. 1-(Hex-5-en-1-yl)-2-phenyl-1H-benzo[d]imidazole (2k)
[18a]
Light yellow viscous liquid; 23% yield, 15.5 mg; 1H NMR
White solid; 74% yield, 66.2 mg; 1H NMR (500 MHz, CDCl3)
d
7.74
(500 MHz, CDCl3)
d
7.84e7.83 (d, J ¼ 7.5 Hz, 1H), 7.70e7.68 (m, 2H),
(d, J ¼ 6.5 Hz, 1H), 7.67 (s, 2H), 7.45 (s, 3H), 7.34e7.32 (m, 3H),
7.52 (s, 2H), 7.46e7.41 (m, 1H), 7.33e7.32 (m, 2H), 7.26e7.20 (m,
1H), 5.74e5.66 (m, 1H), 4.94 (d, J ¼ 13.0 Hz, 2H), 4.24 (t, J ¼ 7.0 Hz,
2H), 2.00e1.99 (m, 2H), 1.85e1.82 (m, 2H), 1.37e1.34 (m, 2H). 13C
7.15e7.12 (m, 3H), 7.01 (s, 1H), 5.43 (s, 2H), 2.44 (s, 3H). 13C NMR
(125 MHz, CDCl3)
d 153.9, 141.5, 136.8, 136.6, 133.3, 130.4, 129.9,
129.4, 129.2, 128.9, 127.9, 126.1, 124.5, 119.7, 110.5, 48.4, 22.0.
NMR (125 MHz, CDCl3) d 153.9, 143.3, 138.0, 135.7, 130.9, 129.9,
129.5, 128.9, 122.5, 115.3, 110.2, 44.7, 33.1, 29.2, 26.0. HRMS (FT-ICR)
4.2.4. 1-Benzyl-5-chloro-2-phenyl-1H-benzo[d]imidazole (2d)
[18a]
m/z: [M þ H]þ calcd for C19H20N2, 277.1699; found, 277.1691.
Light yellow solid; 22% yield, 21.0 mg; 1H NMR (500 MHz, CDCl3)
4.3. Procedure for synthesis of benzimidazole (2m-q)
d
7.84 (s, 1H), 7.68 (d, J ¼ 4.0 Hz, 2H), 7.47 (m, 3H), 7.34 (m, 3H), 7.20
(d, J ¼ 8.5 Hz, 1H), 7.10 (m, 3H), 5.45 (s, 2H). 13C NMR (125 MHz,
To a round bottom flask that was equipped with a stirring bar,
corresponding monosubstituted o-phenylenediamine (0.3 mmol)
and ethanol (10.0 mL) were added successively and the resulting
mixture was stirred thoroughly for 10 min, followed by addition of
acetic acid (0.2 mL) and corresponding aldehydes (0.3 mmol, 1.0
equiv) to the dispersion solution in turn, and refluxed at 80 ꢀC for
2 h. After completion of the reaction, the reaction mixture was
cooled to room temperature and monitored by TLC. Then the
CDCl3)
d 155.6, 144.2, 136.1, 134.8, 130.4, 129.9, 129.4, 129.3, 129.0,
128.5, 128.2, 126.1, 123.6, 120.0, 111.5, 48.7.
4.2.5. 1-Benzyl-6-chloro-2-phenyl-1H-benzo[d]imidazole (2d’)
[18b]
Light yellow solid; 66% yield, 63.1 mg; 1H NMR (500 MHz, CDCl3)
d
7.77 (d, J ¼ 8.5 Hz, 1H), 7.67 (d, J ¼ 2.0 Hz, 2H), 7.49e7.46 (m, 3H),

6
Y. Ma et al. / Tetrahedron 76 (2020) 131474
solvent was evaporated and the resulting residue was purified by
column chromatography on silica gel column using EtOAc-
petroleum ether solution as eluent to afford desired benzimid-
azoles 2m-q.
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White solid; 62% yield, 55.5 mg; 1H NMR (500 MHz, CDCl3)
d
7.87 (d, J ¼ 7.5 Hz, 1H), 7.58 (d, J ¼ 7.5 Hz, 2H), 7.34e7.29 (m, 4H),
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140.3, 136.7, 136.2, 129.6, 129.3, 129.2, 127.9, 127.2, 126.1, 123.1,
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Light yellow solid; 49% yield, 47.1 mg; 1H NMR (500 MHz, CDCl3)
d
7.83e7.81 (m, 1H), 7.59 (d, J ¼ 7.0 Hz, 2H), 7.39e7.38 (m, 1H),
7.32e7.28 (m, 4H), 4.19 (t, J ¼ 7.0 Hz, 2H), 2.43 (s, 3H), 1.79 (s, 2H),
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d 154.0, 143.2, 139.8, 135.7, 129.5, 129.3, 127.9, 122.6, 122.3,
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[18d]
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d
7.89 (s, 1H), 7.81 (s, 2H), 7.72 (s, 2H), 7.34e7.27 (m, 6H), 7.08 (s,
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d
151.9, 143.2, 136.4,
135.9, 134.6, 132.6, 129.9, 129.4, 128.2, 125.9, 124.1, 123.4, 120.5,
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CDCl3)
d
7.88e7.82 (m, 5H), 7.45 (d, J ¼ 6.5 Hz, 1H), 7.38e7.33 (m,
2H), 4.24 (t, J ¼ 7.0 Hz, 2H), 1.82 (s, 2H), 1.25e1.21 (m, 10H), 0.87 (t,
J ¼ 7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3)
d 151.5,143.1,135.9,135.3,
132.7, 130.1, 123.7, 123.1, 120.5, 118.4, 113.6, 110.5, 45.1, 31.8, 30.0,
29.2, 29.1, 26.8, 22.7, 14.2. HRMS (FT-ICR) m/z: [M þ H]þ calcd for
C
22H25N3, 332.2121; found, 332.2111.
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4.3.5. 1-Benzyl-2-(4-fluorophenyl)-1H-benzo[d]imidazole (2q)
[18a]
White solid; 74% yield, 56.2 mg; 1H NMR (500 MHz, CDCl3)
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d
7.87 (d, J ¼ 8.0 Hz, 1H), 7.67 (t, J ¼ 5.5 Hz, 2H), 7.35e7.31 (m, 4H),
7.26e7.22 (m, 2H), 7.14 (t, J ¼ 8.5 Hz, 2H), 7.09 (d, J ¼ 7.0 Hz, 2H),
5.44 (s, 2H). 13C NMR (125 MHz, CDCl3)
164.9, 162.9, 153.3, 143.2,
d
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(b) H. Shen, X.H. Zhang, Q. Liu, J. Pan, W. Hu, Y. Xiong, X.M. Zhu, Tetrahedron
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Declaration of competing interest
(c) X.G. Ling, Y. Xiong, R.F. Huang, X.H. Zhang, S.T. Zhang, C.G. Chen, J. Org.
Chem. 78 (2013) 5218e5226;
(d) Q. Liu, X.H. Zhang, Y. He, M.I. Hussain, W. Hu, Y. Xiong, X.M. Zhu, Tetra-
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(2015) 700e708.
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
Acknowledgments
[17] R.M. Xiong, M.I. Hussain, Q. Liu, W. Xia, Y. Xiong, Tetrahedron 76 (2020)
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We gratefully acknowledge the National Natural Science Foun-
dation of China (No. 21372265) and the Natural Science Foundation
Project of CQ CSTC (cstc2018jcyjAX0155) for financial support.
(b) J.E.R. Sadig, R. Foster, F. Wakenhut, M.C. Willis, J. Org. Chem. 77 (2012)
9473e9486;
(c) W. Senapak, R. Saeeng, J. Jaratjaroonphong, V. Promarak, U. Sirion, Tetra-
hedron 75 (2019) 3453e3552;
Appendix A. Supplementary data
(d) P. Roy, A. Pramanik, Tetrahedron Lett. 54 (2013) 5243e5245.
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2020.131474.