Preparation of 1,2-substituted benzimidazolesviaa copper-catalyzed three component coupling reaction

Article abstract of DOI:10.1039/d1ra00650a

1,2-Substituted benzimidazoles were prepared by simply stirring a mixture of copper catalysts,N-substitutedo-phenylenediamines, sulfonyl azides and terminal alkynes. Particularly, the intermediateN-sulfonylketenimine occurred with two nucleophilic addition and the sulfonyl group was eliminatedviacyclization. In a way, sulfonyl azides and copper catalysts activated the terminal alkynes to synthesize benzimidazoles.

Full text of DOI:10.1039/d1ra00650a

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Preparation of 1,2-substituted benzimidazoles via
a copper-catalyzed three component coupling
reaction†
Cite this: RSC Adv., 2021, 11, 8701
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a
a
a
a
abc
*
*
Yu Zhao, Zitong Zhou, Li Li, Liao Cui and Hui Luo
Weiguang Yang,
1,2-Substituted benzimidazoles were prepared by simply stirring a mixture of copper catalysts, N-
substituted o-phenylenediamines, sulfonyl azides and terminal alkynes. Particularly, the intermediate N-
sulfonylketenimine occurred with two nucleophilic addition and the sulfonyl group was eliminated via
cyclization. In a way, sulfonyl azides and copper catalysts activated the terminal alkynes to synthesize
benzimidazoles.
Received 25th January 2021
Accepted 10th February 2021
DOI: 10.1039/d1ra00650a
rsc.li/rsc-advances
a catalytic approach without using oxidant and stable substrate
would overcome the above-mentioned disadvantages.
Introduction
Previous studies reported that the multicomponent reac-
tions (MCRs) of CuI-catalyzed terminal alkyne, sulfonyl azide,
and nucleophiles13 were applied to synthesize numerous
oxygen-containing and nitrogen-containing heterocyclic
compounds.14 The ketenimine intermediate generated by
copper-catalyzed terminal alkyne and sulfonyl azide could be
take reaction simultaneous employing of pronucleophiles (Nu–
H) and electrophiles (E) by designing the substrates. The o-
hydroxy or o-amino electrophiles-containing benzene was the
best strategy for the substrates, such as salicylaldehydes/o-
hydroxyl-acetophenones,15 2-acetyl aniline,16 phenolic schiffs'
bases,17 a-(ortho-hydroxyphenyl)-a,b-unsaturated ketones/o-
hydroxy-phenylpropiolates,18 o-hydroxybenzonitrile19 (Scheme
1a) etc. However, two pronucleophiles (Nu–H) simultaneous
nucleophilic addition with the ketenimine intermediate is rare.
The compounds of above MCRs contain the sulfonyl group,
which is stable and difficult to eliminate. Only a few examples
could eliminate the sulfonyl group, including the hydrolysis of
N-sulfonyl imidates with catalytic amounts of DBU,19 or N-
sulfonyl acetimid amide treated with 2% H2SO4 under reux
conditions.20 However, previous studies reported that N-
sulfonyl imidates can be hydrolyzed through in situ generated
H2O (Scheme 1b).21 Considering these facts, our study
Owing to their diverse biological activity and clinical applica-
tions,1 benzimidazole derivatives are the potential candidates
for a diverse set of biological activities including antiviral,2
antifungal,3 antibacterial,4 antiamoebic,5 anti-HIV,6 antiulcer,4,7
antihypertensive.8,9 One subset of such compounds are 1,2-
substituted benzimidazole derivatives, such as 5-nitro-
benzimidazoles (I) that exhibit antitumor activity against
melanoma and breast cancer,10 telmisartan (II) that acts as AT1
receptor antagonists and tentative angiotensin receptor blocker
therapeutic for COVID-19,11 and bendamustine (III) that acts as
an antileukemia agent12 (Fig. 1). The observed activity depends
upon the functional group attached to the moiety. In order to
obtain novel effective chemotherapeutic agents, more synthetic
methods and routes are required.
Classical types of reactions have focused on the preparation
of benzimidazole structural frameworks, such as metal cata-
lysed reaction, metal-free catalysed/reagent-based reaction,
green synthesis and photocatalyzed reaction.1a,1b The main
synthesis reaction of benzimidazole drug candidates is the
condensation of o-phenylenediamine with aldehydes, acyl
chloride, carboxylic acids and esters.1a,1b However, most of these
protocols suffer from strong acidic conditions (HCl, H2SO4, or
polyphosphoric acid), readily oxidized or unstable substrate, or
presence of numerous oxidative catalytic reagents. Therefore,
aGuangdong Key Laboratory for Research and Development of Natural Drugs, The
Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang,
524023, China. E-mail: 09ywg@163.com; luohui@gdmu.edu.cn
bThe Marine Biomedical Research Institute of Guangdong Zhanjiang, Zhanjiang,
Guangdong, 524023, China
cSouthern Marine Science and Engineering Guangdong Laboratory (Zhanjiang),
Zhanjiang, Guangdong, 524023, China
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d1ra00650a
Fig. 1 Some 1,2-substituted benzimidazole drug candidates.
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were screened. Several other solvents were screened rst, and
a lower or comparable yield was obtained when toluene, THF,
DMF, DCE were used as solvents, while the MeCN gave 3a the
highest yield of 95% and the side product TsNH2 (Table 1,
entries 2–6). Thus, the optimal solvent was determined to be
MeCN. Encouraged by this promising result, numerous cata-
lysts were screened. Among the copper catalysts used, most Cu-
catalysts exhibited high catalytic reactivity in this reaction
whether CuI-catalysts or CuII-catalysts (Table 1, entries 7–11).
Other catalysts such as AgTFA failed to produce the desired
product (Table 1, entry 12). The effects of different bases were
evaluated. Screening results revealed that the use of Et3N ach-
t
ieved superior results than DMAP, DIPEA, BuONa and other
Scheme 1 MCR of sulfonyl azides and terminal alkynes.
bases (Table 1, entries 13–16). When the reaction temperature
was changed to 90 ꢀC, the reaction yield decreased and
produced side-products (Table 1, entries 17). It is worth noting
that the other sulfonyl azides such as MsN3 or PhSO2N3 were
also suitable for this reaction (Table 1, entries 18).
developed a novel strategy to eliminate the sulfonyl group
through the power of cyclization reaction (Scheme 1c).
With the optimized reaction conditions obtained, the
substrate diversity with the N-substituted o-phenylenediamines
1 were tested rst. As shown in Table 2, the electron effects of
the substituents R1 had slight inuences. For example,
substrates bearing 4-Me–C6H4CO–, 4-OMe–C6H4CO–, 4-F–
C6H4CO–, and 2-thienyl–C6H4CO–groups were examined, and
90–86% yield of 3b–3e were obtained. The substrates R1 bearing
the (CH3)2CHCO– and p-tosyl (Ts-) groups also can obtain 3f in
moderate yield of 54% and 3g in good yield of 86%. Next, the
scope and limitation of substrates R2 were examined by
employing 3,4-dimethyl and 3,4-dichloro groups, which
provided the corresponding benzimidazole derivatives, 3h and
3i, in moderate yield of 65% and 60%. It is noteworthy to
mention that when R1 was changed for methyl instead of
electron-withdrawing group acyl, the reaction also could
Results and discussion
We began our investigation by examining the synthesis of (2-
benzyl-1H-benzo[d]imidazol-1-yl)(phenyl)methanone 3a via N-
(2-aminophenyl)benzamide 1a, tosylazide and ethynylbenzene
2a. The reaction was carried out in the presence of CuI and Et3N
ꢀ
in CHCl3 at 80 C for 3.5 h, and 3a was isolated in 73% yield
(Table 1, entry 1). Based on this nding, the reaction conditions
Table 1 Optimization of catalytic conditionsa
Table 2 Substrate scopesa
Entry
Cat.
Base
Solvent
Yieldb (%) 3a
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
CuI
CuI
CuBr
CuCl
CuBr2
Cu(OAc)2
Cu(OTf)2
AgTFA
CuI
CuI
CuI
CuI
CuI
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
DMAP
DIPEA
Pyridine
tBuONa
Et3N
CHCl3
DCE
Toluene
MeCN
THF
73
90
31
95
84
15
92
94
90
86
82
ndc
15
75
43
30
88d
95e
DMF
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
9
10
11
12
13
14
15
16
17
18
CuI
Et3N
a
Reaction conditions: 1a (0.5 mmol), Cat. (10 mol%), base (1.2 eq.) in
the solvent (3 mL) was added TsN3 (1.2 eq.), 2a (1.2 eq.) stirring at
b
c
a
80 ꢀC for 3.5 h. Isolated yields. nd ¼ not detected the target
Unless otherwise noted, the reaction conditions were as follow: 1 (0.5
d
e
product. The reaction temperature was 90 ꢀC. MsN3 or PhSO2N3
was used instead of TsN3.
mmol), CuI (10 mol%), Et3N (1.2 eq.) in the MeCN (3 mL) was added
TsN3 (1.2 eq.), 2 (1.2 eq.) stirring at 80 ꢀC for 3.5 h.
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Table 3 Substrate scope of the terminal alkynes 2a
Scheme 3 Plausible reaction mechanism.
product when test the unsubstituted o-phenylenediamines 1k
(Table 2). To conrm the effects of tosylazide and elucidate the
mechanism of eliminating the sulfonyl group, few control
experiments were performed under the standard conditions. As
shown in Scheme 2, the reaction of 1a and 2a, without tosyla-
zide under the standard conditions was performed, and the
corresponding products 3a failed to generate. Other test was
carried out using the reactant of N,N0-(1,2-phenylene)dibenza-
mide 1l, which could not detect the target product 3a.
a
Unless otherwise noted, the reaction conditions were as follow: 1a (0.5
mmol), CuI (10 mol%), Et3N (1.2 eq.) in the MeCN (3 mL) was added
TsN3 (1.2 eq.), 2 (1.2 eq.) stirring at 80 ꢀC for 3.5 h.
On the basis of these above experimental results, a possible
reaction pathway for the synthesis of (2-benzyl-1H-benzo[d]
imidazol-1-yl)(phenyl)methanone 3a was proposed (Scheme 3).
According to the previous proposal, ketenimine A was generated
rst by the reaction of TsN3 and 2a. Then, similar to the pub-
lished work by Wang,20 ketenimine A was attacked by the
nucleophile to generate intermediate B. Subsequently, inter-
mediate B underwent an intramolecular cascade addition to
form intermediate C. At last, the desired product 3a and side
product TsNH2 were obtained by the cyclization of intermediate
C. Irrespective of change in the conditions, intermediates B and
C could not be detected. Therefore, the procedure from B to 3a
was fast and almost simultaneous. The sulfonyl group was
eliminated via cyclization and activated the terminal alkynes to
decompose into TsNH2 and N2.
smoothly obtain corresponding methyl-substituted products
3j–3m. However, interestingly, unsubstituted o-phenylenedi-
amines 1k could not obtain the desired product and gave
complex compounds.
Finally, the scope and limitation of terminal alkynes 2 were
examined. As shown in Table 3, the steric effects were clearly
observed for two groups of products, namely 3n–3o and 3p–3r,
in which both the substituents led to high yields and got
inuenced slightly. The electronic effects of substituents had an
obvious impact on the efficiency of this transformation. The
analogues R3 bearing an electron-withdrawing group (e.g., 4-Cl–
C6H4– and 4-Br–C6H4–) and strong electron-donating group
(e.g., –OMe) substituents produced a good yield of 3s, 3t and 3u.
The aliphatic alkynes were also suitable for this reaction
obtaining 3v, 3w, 3x in moderate yields of 77%, 58% and 68%,
respectively. However, the other functional groups of terminal
ynones such as the ethyl propiolate, propiolamide, propiolic
acid made the reactions less effective, which obtained complex
compounds or no corresponding desired products because the
terminal ynones undergo self-condensation under the alkaline
conditions.22
Conclusions
We developed a novel and an effective three-component
coupling approach to synthesize 1,2-substituted benzimid-
azoles in the presence of N-substituted o-phenylenediamines,
terminal alkynes, copper catalyst and TsN3. TsN3 activated the
terminal alkynes to generate ketenimine, took two nucleophilic
addition in the process, and eliminated through cyclization.
Nonetheless, we expect that this methodology could be applied
to build more 1,2-substituted benzimidazole block facility.
According to the above-mentioned experiments, there was
no sulfonyl group in the target product and detected only the
side product TsNH2. In addition, it could not obtain the desired
Experimental
General
All the melting points were determined on a Yanaco melting
point apparatus and were uncorrected. IR spectra were recorded
as KBr pellets on a Nicolet FT-IR 5DX spectrometer. All the
1
spectra of H NMR (400 MHz) and 13C NMR (100 MHz) were
Scheme 2 Control experiments.
recorded on a JEOL JNM-ECA 400 spectrometer in DMSO-d6 or
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CDCl3 (otherwise as indicated) with TMS was used as an
internal reference and J values are given in Hz. HRMS were
obtained on a Bruker micrOTOF-Q II spectrometer. All the o-
phenylenediamines (1a–1j, see ESI section 1†) were prepared by
previously reported methods.23
(2-Benzyl-1H-benzo[d]imidazol-1-yl)(thiophen-2-yl)
methanone (3e). 137 mg (86%), white solid, mp 115–117 ꢀC. IR
1
(KBr) n 3062, 2924, 2520, 1940, 1633, 1378 cmꢁ1; H NMR (400
MHz, CDCl3) d 7.78–7.73 (m, 2H), 7.38–7.37 (m, 1H), 7.29–7.25
(m, 1H), 7.22–7.10 (m, 6H), 7.06–7.02 (m, 2H), 4.49 (s, 2H); 13C
NMR (100 MHz, CDCl3) d 161.7, 154.5, 142.2, 136.2, 136.1, 136.0,
135.8, 134.2, 128.8 (2C), 128.4 (2C), 128.0, 126.7, 123.64, 123.58,
119.8, 112.5, 35.4; HRMS (ESI-TOF) (m/z). Calcd for C19H14N2OS,
[M + H]+ 319.0900; found 319.0904.
Preparation and characterizations of compounds 3a–3x
(2-Benzyl-1H-benzo[d]imidazol-1-yl)(phenyl)methanone (3a).
To a solution of N-(2-aminophenyl)benzamide (1a, 106 mg, 0.5
mmol) and CuI (9.5 mg, 0.05 mmol) in MeCN (3 mL) was added
ethynylbenzene (2a, 61 mg, 1.2 mmol), TsN3 (118 mg, 1.2
mmol), Et3N (61 mg, 1.2 mmol). Aer the mixture was stirred at
room temperature for 10 min, and then at 80 ꢀC for 3.5 h
(monitored by TLC), the solvent was removed. The residue was
puried via ash chromatography (silica gel, 9% EtOAc in
petroleum ether) to give 148 mg (95%) of product 3a as a white
solid, mp 88–89 ꢀC (lit.24 308–310 ꢀC). 1H NMR (400 MHz,
CDCl3) d 7.76 (d, J ¼ 7.8 Hz, 1H), 7.64–7.60 (m, 1H), 7.56–7.54
(m, 2H), 7.44–7.40 (m, 2H), 7.27–7.17 (m, 5H), 7.15–7.11 (m,
1-(2-Benzyl-1H-benzo[d]imidazol-1-yl)-2-methylpropan-1-one
(3f). 75 mg (54%), white solid, mp 136–137 ꢀC. IR (KBr) n 3049,
2836, 2683, 1623, 1426 cmꢁ1; 1H NMR (400 MHz, CDCl3) d 7.80–
7.77 (m, 1H), 7.54–7.51 (m, 1H), 7.36–7.31 (m, 2H), 7.27–7.22
(m, 4H), 7.20–7.17 (m, 1H), 4.58 (s, 2H), 3.41–3.36 (m, 1H), 1.10
(s, 3H), 1.08 (s, 3H); 13C NMR (100 MHz, CDCl3) d 177.1, 155.1,
142.6, 136.4, 132.3, 129.0 (2C), 128.3 (2C), 136.7, 124.4, 124.0,
120.4, 112.8, 36.9, 35.8, 18.6 (2C); HRMS (ESI-TOF) (m/z). Calcd
for C18H18N2O, [M + H]+ 279.1492; found 279.1493.
2-Benzyl-1-tosyl-1H-benzo[d]imidazole (3g). 156 mg (86%),
1
yellow solid, mp 142–143 C (lit.25 118ꢁ120 C). H NMR (400
MHz, CDCl3) d 7.96–7.94 (m, 1H), 7.72–7.69 (m, 1H), 7.37–7.32
(m, 4H), 7.30–7.25 (m, 5H), 7.05 (d, J ¼ 8.2 Hz, 2H), 4.64 (s, 2H),
2.29 (s, 3H); 13C NMR (100 MHz, CDCl3) d 152.9, 145.5, 141.8,
135.9, 134.9, 132.9, 129.8 (2C), 129.2 (2C), 128.6 (2C), 126.9 (2C),
126.8, 124.8, 124.6, 120.1, 113.6, 35.6, 21.5.
ꢀ
ꢀ
1H), 7.02–7.03 (m, 1H), 6.63 (d, J ¼ 8.6 Hz, 1H), 4.52 (s, 2H); 13
C
NMR (100 MHz, CDCl3) d 168.6, 155.1, 142.2, 136.3, 134.1, 133.9,
133.0, 129.8 (2C), 128.80 (2C), 128.77 (2C), 128.4 (2C), 126.8,
123.8, 123.7, 119.9, 113.1, 35.9.
The products 3b–3x were prepared by the similar procedure.
(2-Benzyl-1H-benzo[d]imidazol-1-yl)(p-tolyl)methanone (3b).
147 mg (90%), white solid, mp 104–105 ꢀC. IR (KBr) n 3048,
2930, 1691, 1451 cmꢁ1; 1H NMR (400 MHz, CDCl3) d 7.76 (d, J ¼
8.2 Hz, 1H), 7.48 (d, J ¼ 8.2 Hz, 2H), 7.27–7.17 (m, 7H), 7.15–7.12
(m, 1H), 7.08–7.04 (m, 1H), 6.68 (d, J ¼ 8.2 Hz, 1H), 4.52 (s, 2H),
2.43 (s, 3H); 13C NMR (100 MHz, CDCl3) d 168.5, 155.2, 145.2,
144.2, 136.4 (2C), 134.2, 130.1 (2C), 129.5 (2C), 128.8 (2C), 128.4
(2C), 126.7, 123.65, 123.62, 119.8, 113.1, 35.8, 21.8; HRMS (ESI-
TOF) (m/z). Calcd for C22H18N2O, [M + H]+ 327.1492; found
327.1494.
(2-Benzyl-5,6-dimethyl-1H-benzo[d]imidazol-1-yl)(phenyl)
methanone (3h). 119 mg (70%), white solid, mp 130–132 ꢀC. IR
(KBr) n 3058, 2854, 1639, 1450 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 7.64–7.60 (m, 1H), 7.56–7.52 (m, 3H), 7.44–7.40 (m, 2H), 7.20–
7.10 (m, 5H), 6.43 (s, 1H), 4.47 (s, 2H), 2.31 (s, 3H), 2.13 (s, 3H);
13C NMR (100 MHz, CDCl3) d 168.6, 154.2, 140.8, 136.5, 133.7,
133.2, 132.8, 132.7, 132.6, 129.8 (2C), 128.71 (2C), 128.70 (2C),
128.4 (2C), 126.6, 119.9, 113.6, 36.0, 20.4, 20.0; HRMS (ESI-TOF)
(m/z). Calcd for C23H20N2O, [M + H]+ 341.1649; found 341.1650.
(2-Benzyl-5,6-dichloro-1H-benzo[d]imidazol-1-yl)(phenyl)
methanone (3i). 133 mg (60%), white solid, mp 114–115 ꢀC. IR
1
(KBr) n 3053, 2925, 2851, 2626, 1630, 1458 cmꢁ1; H NMR (400
(2-Benzyl-1H-benzo[d]imidazol-1-yl)(4-methoxyphenyl)
methanone (3c). 137 mg (80%), white solid, mp 113–114 ꢀC. IR
(KBr) n 3067, 2935, 2840, 1692, 1450 cmꢁ1; 1H NMR (400 MHz,
CDCl3) d 7.77 (d, J ¼ 8.2 Hz, 1H), 7.56 (d, J ¼ 8.7 Hz, 2H), 7.27–
7.16 (m, 5H), 7.14–7.06 (m, 2H), 6.89 (d, J ¼ 8.7 Hz, 2H), 6.75 (d, J
¼ 8.2 Hz, 1H), 4.51 (s, 2H), 3.87 (s, 3H); 13C NMR (100 MHz,
CDCl3) d 167.8, 164.4, 155.1, 144.2, 136.4, 134.4, 132.6 (2C),
128.8 (2C), 128.4 (2C), 126.7, 124.9, 123.6, 123.5, 119.8, 114.1
(2C), 112.9, 55.6, 35.7; HRMS (ESI-TOF) (m/z). Calcd for
MHz, CDCl3) d 7.84 (s, 1H), 7.70–7.66 (m, 1H), 7.55–7.52 (m,
2H), 7.49–7.45 (m, 2H), 7.22–7.12 (m, 5H), 6.89 (s, 1H), 4.44 (s,
2H); 13C NMR (100 MHz, CDCl3) d 167.8, 167.0, 141.7, 135.6,
134.5, 133.3, 132.2, 129.9 (2C), 129.1 (2C), 128.8 (2C), 128.6 (2C),
128.0, 127.9, 127.0, 121.0, 114.5, 35.9; HRMS (ESI-TOF) (m/z).
Calcd for C21H14Cl2N2O, [M + H]+ 381.0556; found 381.0557.
2-Benzyl-1-methyl-1H-benzo[d]imidazole (3j). 91 mg (82%),
white solid, mp 71–73 ꢀC (lit.26 72 ꢀC). 1H NMR (400 MHz,
CDCl3) d 7.78–7.75 (m, 1H), 7.29–7.19 (m, 8H), 4.29 (s, 2H), 3.54
(s, 3H); 13C NMR (100 MHz, CDCl3) d 153.2, 142.4, 136.0, 135.9,
128.7 (2C), 128.3 (2C), 126.8, 122.2, 121.8, 119.3, 108.9, 34.3,
29.9.
C
22H18N2O2, [M + H]+ 343.1441; found 343.1444.
(2-Benzyl-1H-benzo[d]imidazol-1-yl)(4-uorophenyl)
methanone (3d). 144 mg (87%), white solid, mp 112–113 ꢀC. IR
(KBr) n 3050, 2836, 2882, 1703, 1426 cmꢁ1; 1H NMR (400 MHz,
CDCl3) d 7.78 (d, J ¼ 8.2 Hz, 1H), 7.61–7.58 (m, 2H), 7.30–7.26
(m, 1H), 7.20–7.18 (m, 4H), 7.16–7.07 (m, 4H), 6.65 (d, J ¼
8.3 Hz, 1H), 4.52 (s, 2H); 13C NMR (100 MHz, CDCl3) d 167.3,
166.0 (d, J ¼ 255.5 Hz, 1C), 155.1, 142.2, 136.2, 134.0, 132.6 (d, J
¼ 9.5 Hz, 2C), 129.0 (d, J ¼ 2.8 Hz, 1C), 128.7 (2C), 128.4 (2C),
126.8, 123.82, 123.76, 120.0, 116.1 (d, J ¼ 21.9 Hz, 2C), 112.8,
35.7; HRMS (ESI-TOF) (m/z). Calcd for C21H15FN2O, [M + H]+
331.1241; found 331.1242.
2-(4-Fluorobenzyl)-1-methyl-1H-benzo[d]imidazole (3k). 103 mg
(86%), yellow oil. IR (KBr) n 3054, 2944, 1894, 1602, 1506 cmꢁ1; 1H
NMR (400 MHz, CDCl3) d 7.76–7.73 (m, 1H), 7.26–7.15 (m, 3H),
7.19–7.15 (m, 2H), 6.97–6.92 (m, 2H), 4.24 (s, 2H), 3.53 (s, 3H); 13
C
NMR (100 MHz, CDCl3) d 161.6 (d, J ¼ 244.1 Hz, 1C), 152.9, 142.2,
135.8, 131.6 (d, J ¼ 2.9 Hz, 1C), 129.8 (d, J ¼ 8.6 Hz, 2C), 122.3,
121.9, 119.2, 115.5 (d, J ¼ 21.9 Hz, 2C), 109.0, 33.3, 29.8; HRMS
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(ESI-TOF) (m/z). Calcd for C15H13FN2, [M + H]+ 241.1136; found 120.0, 115.8 (d, J ¼ 21.9 Hz, 1C), 113.8 (d, J ¼ 21.0 Hz, 1C), 113.2,
241.1137.
35.6; HRMS (ESI-TOF) (m/z). Calcd for C21H15FN2O, [M + H]+
2-(4-Chlorobenzyl)-1-methyl-1H-benzo[d]imidazole
(3l). 331.1241; found 331.1242.
118 mg (92%), white solid, mp 115–116 C (lit.27 117ꢁ119 C).
(2-(2-Fluorobenzyl)-1H-benzo[d]imidazol-1-yl)(phenyl)
ꢀ
ꢀ
1H NMR (400 MHz, CDCl3) d 7.76–7.74 (m, 1H), 7.26–7.22 (m, methanone (3r). 139 mg (84%), mp 82ꢁ83 C. IR (KBr) n 3054,
5H), 7.12 (d, J ¼ 8.7 Hz, 2H), 4.22 (s, 2H), 3.51 (s, 3H); 13C NMR 2738, 2620, 1702, 1451 cmꢁ1; 1H NMR (400 MHz, CDCl3) d 7.74
(100 MHz, CDCl3) d 152.5, 142.2, 135.8, 134.4, 132.6, 129.6 (2C), (d, J ¼ 8.2 Hz, 1H), 7.66–7.62 (m, 3H), 7.48–7.44 (m, 2H), 7.26–
ꢀ
128.8 (2C), 122.3, 121.8, 119.2, 109.0, 33.4, 29.8.
7.13 (m, 3H), 7.09–6.94 (m, 3H), 6.70 (d, J ¼ 8.2 Hz, 1H), 4.52 (s,
2-(4-Bromobenzyl)-1-methyl-1H-benzo[d]imidazole
(3m). 2H); 13C NMR (100 MHz, CDCl3) d 168.5, 160.7 (d, J ¼ 246.0 Hz,
136 mg (91%), white solid, mp 119ꢁ121 ꢀC (lit.28 no report). 1H 1C), 154.0, 142.3, 134.0, 133.9, 133.0, 130.7 (d, J ¼ 3.8 Hz, 1C),
NMR (400 MHz, DMSO-d6) d 7.58–7.56 (m, 1H), 7.51–7.46 (m, 129.9 (2C), 128.9 (2C), 128.7 (d, J ¼ 8.6 Hz, 1C), 124.11, 124.07,
3H), 7.25–7.14 (m, 4H), 4.28 (s, 2H), 3.69 (s, 3H); 13C NMR (100 123.84, 123.80 (d, J ¼ 15.2 Hz, 1C), 119.9, 115.3 (d, J ¼ 21.9 Hz,
MHz, DMSO-d6) d 153.1, 142.1, 136.3, 135.8, 131.4 (2C), 131.0 1C), 113.2, 29.4 (d, J ¼ 3.8 Hz, 1C); HRMS (ESI-TOF) (m/z). Calcd
(2C), 121.7, 121.4, 119.7, 118.5, 109.9, 32.3, 29.8.
for C21H15FN2O, [M + H]+ 331.1241; found 331.1244.
(2-(4-Methylbenzyl)-1H-benzo[d]imidazol-1-yl)(phenyl)
(2-(4-Chlorobenzyl)-1H-benzo[d]imidazol-1-yl)(phenyl)
methanone (3n). 142 mg (87%), white solid, mp 164–166 ꢀC. IR methanone (3s). 166 mg (96%), white solid, mp 111–113 ꢀC. IR
(KBr) n 3049, 2738, 2621, 1624, 1432 cmꢁ1; 1H NMR (400 MHz, (KBr) n 3059, 2744, 2624, 1628, 1491 cmꢁ1; 1H NMR (400 MHz,
CDCl3) d 7.76 (d, J ¼ 7.8 Hz, 1H), 7.64–7.56 (m, 3H), 7.45–7.41 CDCl3) d 7.76 (d, J ¼ 7.8 Hz, 1H), 7.66–7.63 (m, 1H), 7.58 (d, J ¼
(m, 2H), 7.27–7.22 (m, 1H), 7.10–6.99 (m, 5H), 6.64 (d, J ¼ 7.3 Hz, 2H), 7.47–7.43 (m, 2H), 7.27–7.23 (m, 1H), 7.20–7.16 (m,
8.2 Hz, 1H), 4.48 (s, 2H), 2.22 (s, 3H); 13C NMR (100 MHz, CDCl3) 4H), 7.08–7.04 (m, 1H), 6.61 (d, J ¼ 8.2 Hz, 1H), 4.49 (s, 2H); 13
C
d 168.6, 155.4, 142.2, 136.3, 134.1, 133.9, 133.2, 133.1, 129.8 NMR (100 MHz, CDCl3) d 168.4, 154.6, 142.2, 134.8, 134.0, 133.9,
(2C), 129.1 (2C), 128.8 (2C), 128.6 (2C), 123.748, 123.67, 119.8, 132.9, 132.6, 130.2 (2C), 129.8 (2C), 128.9 (2C), 128.5 (2C), 123.9,
113.1, 35.9, 20.9. HRMS (ESI-TOF) (m/z). Calcd for C22H18N2O, 123.8, 119.9, 113.2, 35.3. HRMS (ESI-TOF) (m/z). Calcd for
[M + H]+ 327.1492; found 327.1495.
C
21H15ClN2O, [M + H]+ 347.0946; found 347.0944.
(2-(3-Methylbenzyl)-1H-benzo[d]imidazol-1-yl)(phenyl)
(2-(4-Bromobenzyl)-1H-benzo[d]imidazol-1-yl)(phenyl)ꢀ
methanone (3o). 119 mg (89%), white solid, mp 111–113 ꢀC. IR methanone (3t). 156 mg (80%), white solid, mp 91ꢁ92 C. IR
(KBr) n 3055, 2836, 2684, 1655, 1429 cmꢁ1; 1H NMR (400 MHz, (KBr) n 3089, 2872, 2683, 1657, 1428 cmꢁ1; 1H NMR (400 MHz,
CDCl3) d 7.78 (d, J ¼ 7.8 Hz, 1H), 7.65–7.61 (m, 1H), 7.58–7.56 CDCl3) d 7.76 (d, J ¼ 8.2 Hz, 1H), 7.66–7.62 (m, 1H), 7.60–7.57
(m, 2H), 7.45–7.41 (m, 2H), 7.28–7.24 (m, 1H), 7.10–7.04 (m, (m, 2H), 7.47–7.43 (m, 2H), 7.34–7.31 (m, 2H), 7.27–7.23 (m,
2H), 6.99–6.93 (m, 3H), 6.66 (d, J ¼ 8.2 Hz, 1H), 4.48 (s, 2H), 2.21 1H), 7.12 (d, J ¼ 8.7 Hz, 2H), 7.08–7.03 (m, 1H), 6.61 (d, J ¼
(s, 3H); 13C NMR (100 MHz, CDCl3) d 168.6, 155.2, 142.2, 138.0, 8.2 Hz, 1H), 4.47 (s, 2H); 13C NMR (100 MHz, CDCl3) d 168.4,
136.1, 134.1, 133.9, 133.0, 129.9 (2C), 129.4, 128.8 (2C), 128.3, 154.4, 142.1, 135.2, 134.0, 133.9, 132.8, 131.5 (2C), 130.5 (2C),
127.5, 125.8, 123.8, 123.7, 119.8, 113.1, 35.9, 20.9. HRMS (ESI- 129.8 (2C), 128.9 (2C), 123.9, 123.8, 120.7, 119.9, 113.2, 35.3.
TOF) (m/z). Calcd for C22H18N2O, [M + H]+ 327.1492; found HRMS (ESI-TOF) (m/z). Calcd for C21H15ClN2O, [M + H]+
327.1493.
(2-(4-Fluorobenzyl)-1H-benzo[d]imidazol-1-yl)(phenyl)
391.0441; found 391.0442.
(2-(4-Methoxybenzyl)-1H-benzo[d]imidazol-1-yl)(phenyl)
ꢀ
methanone (3p). 150 mg (91%), white solid, mp 78ꢁ79 C. IR methanone (3u). 157 mg (92%), yellow oil. IR (KBr) n 3301, 3068,
(KBr) n 3047, 2870, 2616, 1635, 1508 cmꢁ1; 1H NMR (400 MHz, 2836, 2626, 1628, 1512 cmꢁ1; 1H NMR (400 MHz, CDCl3) d 7.76
CDCl3) d 7.77 (d, J ¼ 8.2 Hz, 1H), 7.67–7.63 (m, 1H), 7.59–7.57 (d, J ¼ 8.3 Hz, 1H), 7.66–7.61 (m, 1H), 7.58–7.56 (m, 2H), 7.46–
(m, 2H), 7.47–7.43 (m, 2H), 7.28–7.24 (m, 1H), 7.22–7.18 (m, 7.42 (m, 2H), 7.27–7.23 (m, 1H), 7.12 (d, J ¼ 9.1 Hz, 2H), 7.08–
2H), 7.08–7.04 (m, 1H), 6.92–6.87 (m, 2H), 6.62 (d, J ¼ 8.3 Hz, 7.04 (m, 1H), 6.76–6.73 (m, 2H), 6.64 (d, J ¼ 8.2 Hz, 1H), 4.45 (s,
1H), 4.50 (s, 2H); 13C NMR (100 MHz, CDCl3) d 168.5, 161.7 (d, J 2H), 3.70 (s, 3H); 13C NMR (100 MHz, CDCl3) d 168.6, 158.3,
¼ 244.1 Hz, 1C), 155.0, 142.2, 134.05, 134.00, 132.9, 131.9 (d, J ¼ 155.6, 142.2, 134.1, 133.9, 133.1, 129.8 (4C), 128.8 (2C), 128.3,
2.9 Hz, 1C), 130.4 (d, J ¼ 7.6 Hz, 2C), 129.8 (2C), 128.9 (2C), 123.8, 123.7, 119.8, 113.8 (2C), 113.1, 55.1, 35.0. HRMS (ESI-
123.9, 123.8, 119.9, 115.3 (d, J ¼ 37.7 Hz, 2C), 113.2, 35.1; HRMS TOF) (m/z). Calcd for C22H18N2O2, [M + H]+ 343.1441; found
(ESI-TOF) (m/z). Calcd for C21H15FN2O, [M + H]+ 331.1241; 343.1443.
found 331.1243.
(2-Heptyl-1H-benzo[d]imidazol-1-yl)(phenyl)methanone (3v).
123 mg (77%), yellow oil. IR (KBr) n 3061, 2928, 2626, 1712,
(2-(3-Fluorobenzyl)-1H-benzo[d]imidazol-1-yl)(phenyl)
methanone (3q). 140 mg (85%), white solid, mp 71ꢁ73 ꢀC.IR 1538 cmꢁ1
;
1H NMR (400 MHz, CDCl3) d 7.77–7.67 (m, 4H),
(KBr) n 3060, 2873, 2635, 1653, 1454 cmꢁ1; 1H NMR (400 MHz, 7.54–7.50 (m, 2H), 7.28–7.22 (m, 1H), 7.08–7.04 (m, 1H), 6.73 (d,
CDCl3) d 7.77 (d, J ¼ 7.8 Hz, 1H), 7.67–7.63 (m, 1H), 7.60–7.58 J ¼ 8.2 Hz, 1H), 3.08–3.04 (m, 2H), 1.90–1.82 (m, 2H), 1.40–1.26
(m, 2H), 7.48–7.44 (m, 2H), 7.29–7.25 (m, 1H), 7.20–7.15 (m, (m, 8H), 0.87–0.84 (m, 3H); 13C NMR (100 MHz, CDCl3) d 168.6,
1H), 7.09–7.05 (m, 1H), 7.01 (d, J ¼ 7.8 Hz, 1H), 6.96–6.93 (m, 157.0, 142.3, 133.9, 133.7, 133.3, 129.9 (2C), 128.9 (2C), 123.6,
1H), 6.87–6.82 (m, 1H), 6.63 (d, J ¼ 8.3 Hz, 1H), 4.53 (s, 2H); 13
C
123.2, 119.5, 113.1, 31.5, 29.8, 29.2, 28.8, 27.8, 22.4, 13.9; HRMS
NMR (100 MHz, CDCl3) d 168.5, 162.7 (d, J ¼ 245.0 Hz, 1C), (ESI-TOF) (m/z). Calcd for C21H24N2O, [M + H]+ 321.1962; found
154.4, 142.2, 138.7 (d, J ¼ 7.6 Hz, 1C), 134.1, 134.0, 132.9, 129.9, 321.1964.
129.8 (2C), 128.9 (2C), 124.5 (d, J ¼ 2.9 Hz, 1C), 123.95, 123.92,
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(2-(Cyclohexylmethyl)-1H-benzo[d]imidazol-1-yl)(phenyl)
methanone (3w). 92 mg (58%), white solid, mp 77–78 ꢀC. IR
(KBr) n 3056, 2925, 2625, 1711, 1449 cmꢁ1; 1H NMR (400 MHz,
CDCl3) d 7.76–7.67 (m, 4H), 7.54–7.50 (m, 2H), 7.26–7.22 (m,
1H), 7.08–7.04 (m, 1H), 6.73 (d, J ¼ 8.2 Hz, 1H), 2.98 (d, J ¼
7.3 Hz, 2H), 1.92–1.86 (m, 1H), 1.73–1.60 (m, 5H), 1.26–0.99 (m,
5H); 13C NMR (100 MHz, CDCl3) d 168.7, 155.8, 142.3, 134.0,
133.8, 133.3, 129.9 (2C), 128.9 (2C), 123.6, 123.3, 119.5, 113.0,
37.4, 36.9, 33.0 (2C), 26.1, 25.9 (2C); HRMS (ESI-TOF) (m/z).
Calcd for C21H24N2O, [M + H]+ 321.1962; found 321.1964.
(2-(Cyclopropylmethyl)-1H-benzo[d]imidazol-1-yl)(phenyl)
methanone (3x). 94 mg (68%), yellow oil. IR (KBr) n 3065, 2925,
1
2623, 1709, 1538 cmꢁ1; H NMR (400 MHz, CDCl3) d7.78–7.74
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(m, 3H), 7.70–7.66 (m, 1H), 7.53–7.49 (m, 2H), 7.26–7.22 (m,
1H), 7.07–7.03 (m, 1H), 6.67 (d, J ¼ 8.2 Hz, 1H), 3.05 (d, J ¼
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[M + H]+ 277.1336; found 277.1337.
All the NMR spectra please see ESI section 3.†
Conflicts of interest
8 (a) M. T. Khan, M. T. Razi, S. U. Jan, M. Mukhtiar, R. Gul,
IzharUllah, A. Hussain, A. M. Hashmi, M. T. Ahmad,
N. A. Shahwani and I. Rabbani, Pak. J. Pharm. Sci., 2018,
31, 1067; (b) Y. Zhang, J. Xu, Y. Li, H. Yao and X. Wu,
Chem. Biol. Drug Des., 2015, 85, 541.
There are no conicts to declare.
Acknowledgements
Financial support by Foundation and Applied Basic Research
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Fund
project
of
Guangdong
Province
of
China
(2019A1515110918); Medical Scientic Research Foundation of
Guangdong Province (A2020202); Science and Technology
Planning Project of Zhanjiang (2019A01018); funds for PhD
researchers of Guangdong Medical University in 2019
(B2019015); and the Science and Technology Program of
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