One-pot strategy of copper-catalyzed synthesis of 1,2-disubstituted benzimidazoles

Article abstract of DOI:10.1039/c7ob00945c

A simple, one-pot and copper-catalyzed coupling reaction for the construction of 1,2-disubstituted benzimidazole derivatives is described. A low-cost copper salt and a weak base K₃PO₄ were utilized in this reaction. A variety of 1,2-disubstituted benzimidazoles were obtained in moderate to excellent yields.

Full text of DOI:10.1039/c7ob00945c

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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One–pot strategy of copper-catalyzed synthesis of 1,2-
disubstituted benzimidazoles
Received 00th January 20xx,
Accepted 00th January 20xx
Caixia Xie,a Xushuang Han,a Jian Gong,a Danyang Li,a and Chen Ma*a,b
A simple, one-pot and copper-catalyzed coupling reaction for the construction of 1,2-disubstituted benzimidazole
derivatives is described. Low-cost copper salt and weak base K3PO4 were utlized in this reaction. A variety of 1,2-
DOI: 10.1039/x0xx00000x
www.rsc.org/
disubstituted
benzimidazoles
were
obtained
in
moderate
to
excellent
yields.
Not surprisingly, the importance of this skeleton has stimulated
numerous efforts to build it efficiently. Despite variations of
Introduction
synthesis of benzimidazoles,7 it is urgent to find a highly efficient
route to build 1,2-disubstituted benzimidazoles. Traditionally,
strong base like NaH and t-BuOK is essential for N-alkylation of 2-
substituted benzimidazoles.8 The condensation of substituted 1,2-
diaminobenzenes with benzaldehydes or equivalents was also
commonly used. 9 Besides, some other methods are available for
this structure.10 For example, recently, Buchwald and co-workers
have disclosed a palladium-catalyzed method to synthesize N-
arylbenzimidazoles11 and a copper-catalyzed strategy to construct
N-alkylbenzimidazoles in two steps.12 However, low regioselectivity,
costly reagents, laborious procedures and hazardous reactants are
fatal weaknesses to simply synthesize 1,2-disubstituted
benzimidazoles. Hence, it should be of significant interest to
develop an efficient and simple synthesis of 1,2-disubstituted
benzimidazole derivatives. Copper-catalyzed Ullman-type C-N
coupling reactions of amides have emerged frequently to build
nitrogen containing heterocyclic compounds in one pot.13 We,
Benzimidazole derivatives form one of the most important classes
of nitrogen-containing compounds due to their diverse range of
biological and pharmacological properties.1 Among them, 1,2-
disubstituted benzimidazoles are privileged targets in drug
discovery. Amounts of drugs consisting of this skeleton are
registered in the pharmaceutical market (Scheme 1). For example,
Telmisartan and Candesartan are commonly used for treatment of
hypertension. And Astemizole and Tecastemizole are anti-parasites
of high efficacy. Maribavir is an effective inhibitor for human
cytomegalovirus and is used for resisting CMV retinitis of HIV
suffers.2 Moreover, many other derivatives perform well in non-
clinical and clinical trials and have potential of anti-cancers,3
antibacterials,4 anti-HIV5 and CB1 and CB2 receptors.6
HO
O
N
N
N
N
N
HO
N
N
N
O
NH
O
N
herein, report
a novel and simple copper-catalyzed one-pot
synthesis strategy to construct this structure.
Candesartan
Telmisartan
NH
F
O
Results and discussion
HO
N
N
OH
NH
N
HO
O
NH
We commenced our study of one-pot synthesis of 1,2-disubstituted
benzimidazole with N-benzyl-2-iodoaniline, benzamide, CuI, 1,10-
phenanthroline, and Cs2CO3 at 120 oC under nitrogen atmosphere
(Table 1, entry 1). Interestingly, 1-benzyl-2-phenyl-1H-
benzo[d]imidazole was obtained in 69% yield. CuI was the most
effective catalyst after several copper salts were screened and 20
mol% of it was proved to be efficient (Table 1, entries 1-11). Then,
several bases were employed and K3PO4 gave higher yield than
others (Table 1, entries 1 and 12-17). DMF was the most suitable
solvent for product formation with a 78% yield (Table 1, entries 13
and 18-21). Besides, 120 oC was proved to be the most suitable
temperature (Table 1, entries 13 and 23-24) and N,N'-
dimethylethane-1,2-diamine served as a better ligand after many
HN
Cl
N
N
N
N
Cl
F
Astemizole
Tecastemizole
Maribavir
Scheme 1 Selected examples of 1,2-substituted benzimidazole-
containing drugs
a.shool of Chemistry and Chemical Engineering, Shandong University, Jinan,
250100, P R China.
b.State Key Laboratory of Bioactive Substance and Function of Natural Medicines,
Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking
Union Medical College, Beijing, 100050, P. R. China. E-mail: chenma@sdu.edu.cn
Electronic Supplementary
DOI: 10.1039/x0xx00000x
Information
(ESI)
available:
See
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Table 1 Optimization of the reaction conditionsa
Entry
1
Catalyst
CuI
mol%
20
Base
Solvent
DMF
Temp.
120
Ligand
L1
Yield(%) b
69
Cs2CO3
2
CuBr
CuCl
Cu(OAc)2
Cu(SO3 CF3)2
CuBr2
CuCl2.2H2O
CuSO4.5H2O
CuI
20
20
20
20
20
20
20
10
50
100
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Na2CO3
K3PO4
DMF
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
110
130
120
120
120
120
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
--
59
60
58
65
34
21
61
43
67
69
trace
78
63
32
61
trace
34
66
13
41
24
72
69
41
49
89
21c
3
DMF
4
DMF
5
DMF
6
DMF
7
DMF
8
DMF
9
DMF
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
CuI
DMF
CuI
DMF
CuI
DMF
CuI
DMF
CuI
K2CO3
NaOH
t-BuOLi
NaHCO3
K3PO4
DMF
CuI
DMF
CuI
DMF
CuI
DMF
CuI
DMSO
NMP
Chlorobenze
1,4-dioxane
DMF
CuI
K3PO4
CuI
K3PO4
CuI
K3PO4
CuI
K3PO4
CuI
K3PO4
DMF
L1
L1
L2
L3
L4
L4
CuI
K3PO4
DMF
CuI
K3PO4
DMF
CuI
K3PO4
DMF
CuI
K3PO4
DMF
CuI
K3PO4
DMF
a1a (0.5 mmol, 0.155 g), 2a (0.5 mmol, 0.065g), solvent (3 mL), catalyst, base (0.75 mmol) and ligand, in a
sealed tube, N2 protected, 120 oC, 14 h (TLC monitored); bIsolated yields; cUnder air atmosphere.
Scheme 2 Selected ligands.
2 | J. Name., 2012, 00, 1-3
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trials with other commercially available ligands (Table 1, entries 13 we chose CuI (20 mol%) and N,N'-dimethylethane-1,2-diamine as
and 25-27). Furthermore, when the reaction was exposed to air, a the catalyst system, with K3PO4 as base and DMF as solvent to
lower yield of the product was obtained (Table 1, entry 28). Thus,
continue our investigation.
The versatility and limitation of the optimized reaction conditions
were then examined by employing various substituted 2-
iodoanilines and benzamides proceeded under standard conditions.
Generally, electronic effect played a key role in the yield of the
reaction. 2-Iodoanilines bearing electron-withdrawing groups gave
better yields than electron-donating groups (3b-3e, 3f-3g).
However, 3h and 3i were obtained in slightly lower yields, possibly
because of the lower bond energy of C-Br bond than C-Cl or C-F
bond and the hydrolysis of cyano in presence of base, respectively.
Electron-withdrawing groups and electron-donating groups on the
benzyl ring were tolerated (3j-3p). It was worth noting that 2-iodo-
Scheme 3 Substrate scope of N-benzyl-2-iodoanilinesa, b
N-(naphthalen-2-ylmethyl)aniline
and
N-([1,1'-biphenyl]-4-
ylmethyl)-2-iodoaniline both proceeded smoothly in this reaction
system(3q-3r). In addition, alkyl and alkenyl groups were also
suitable, providing the possibility for further functionalization (3s-
3t).
Scheme 4 Substrate scope of amidesa, b
a1 (0.5 mmol), 2 (0.5 mmol), solvent (3 mL), CuI (0.1 mmol), K3PO4
(0.75 mmol) and ligand (0.2 mmol), in a sealed tube, N2 protected,
120 oC, 12-24 h (TLC monitored); bIsolated yields.
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performed, but the result was unsatisfied, with 3a obtained in less
than 10% yield. We attempted to capture the intermediate M when
the reaction continued two hours under standard conditions and it
could be detected by HRMS. Finally, iodobenzene 8 was used and
the compound 9 was obtained smoothly in a yield of 95%.
To examine the scalability of the present strategy, a reaction of
N-benzyl-2-iodoaniline and benzamide was performed at the 10
mmol scales (Scheme 6). The corresponding 3a was obtained in 73%
isolated yield, which indicated that our method may be a practical
and scalable way to build the 1,2-disubstituted benzimidazole
derivatives.
a1 (0.5 mmol), 2 (0.5 mmol), solvent (3 mL), CuI (0.1 mmol), K3PO4
(0.75 mmol) and ligand (0.2 mmol), in a sealed tube, N2 protected,
120 oC, 12-24 h (TLC monitored); bIsolated yields.
Scheme 4 Substrate scope of N-benzyl-2-halogen anilinesa,b
a4 (0.5 mmol), 2 (0.5 mmol), solvent (3 mL), CuI (0.1 mmol), K3PO4
(0.75 mmol) and ligand (0.2 mmol), in a sealed tube, N2 protected,
160 oC, 40 h (TLC monitored); bIsolated yields.
Scheme 5 Control experiments
To further evaluate the efficiency of this methodology,
benzamides with different substituents were examined.
Benzamides bearing electron-withdrawing groups participated well
in the reaction to afford corresponding products in moderate to
good yields (3x-3ab). However, benzamides with an electron-
donating groups such as-Me, –OMe provided lower yields of
desired products (3v-3w). Thiophene-2-carboxamide successfully
participated in this reaction and gave a yield of 77% (3ac). It is
frustrating that aliphatic amide gave the desired product with lower
yields possibly because of the electron-giving effect (3ad-3af).
Intriguingly, 2-iodo-N-(naphthalen-2-ylmethyl)aniline and N-([1,1'-
biphenyl]-4-ylmethyl)-2-iodoaniline smoothly underwent this
transformation generating the desired products (3qa-3rc) in
moderate to good yields.
O
H
standard conditions
N
NH2
N
N
I
1a
2a
3a
10 mmol
3.09g
10 mmol
1.21g
2.07g
73%
Scheme 6 A gram-scale reaction.
Encouraged by these promising results, we further investigated
the N-benzyl-2-halogen anilines as shown in Scheme 4. With the
extension of reaction time and the rise of temperature, N-benzyl-2-
bromoaniline could react smoothly, but N-benzyl-2-chloroaniline
could not react. Obviously, reactants bearing an iodine group had
higher reactivity than those bearing a bromide or chlorine group.
To gain further insight into the reaction, several control
experiments were performed. Compounds 5 and 2a were mixed
under standard conditions, and only trace 6 was obtained, detected
Scheme 7 Proposed reaction mechanism
Based on the previous study14 and the results above, an assumed
pathway for the formation of 1,2-disubstituted benzimidazole
by HRMS. Then,
a three-component tandem reaction was
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derivatives is illustrated in Scheme 7. First, the Cu-catalyzed Ullman- 7.84 (d, J = 1.8 Hz, 1H), 7.69 (dd, J = 7.5 Hz, 1.8 Hz, 2H), 7.50-7.42(m,
type coupling reaction occurred with compounds 1a and 2a and 3H), 7.37-7.30 (m, 3H), 7.26 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 7.16-7.06
(m, 3H), 5.44 (s, 2H); 13C NMR (75 MHz, CDCl3): δ =155.33, 143.93,
intermediate M was generated. Then, intramolecular addition of M
afforded intermediate 10. Along with the dehydrating, the desired
product 3a was obtained.
135.92, 134.63, 130.22, 129.63, 129.25, 129.15, 128.84, 128.34,
127.97, 125.92, 123.48, 119.76, 111.31, 48.55. HRMS calcd for
C20H15N2Cl [(M+H)+]: 319.0997; found, 319.0990.
1-Benzyl-5-fluoro-2-phenyl-1H-benzo[d]imidazole (3c). Light yellow
solid (14 h, 87%). Mp: 146-148 oC. 1H NMR (400 MHz, CDCl3): δ =
7.69-7.67 (m, 2H), 7.54 (dd, J = 7.2 Hz, 2.0 Hz, 1H), 7.49-7.43 (m,
3H), 7.39-7.29 (m, 3H), 7.12-7.08 (m, 3H), 7.00 (td, J = 8.8 Hz, 1.8 Hz,
1H), 5.44 (s, 2H); 13C NMR(100MHz, CDCl3): δ = 160.86 (d, 1JC, F = 237
Hz, 1C), 155.57, 143,60 (d, 3JC, F = 12 Hz, 1C), 136.05, 132.53, 130.16,
129.76, 129.22, 129.15, 128.84, 127.95, 125.94, 111.50 (d, 2JC, F = 26
Conclusions
In summary, we have demonstrated a simple, one-pot and copper-
catalyzed coupling reaction of 1,2-disubstituted benzimidazole
derivatives. This method allows the synthesis of N-substituted
benzimidazoles in regioisomerically pure form. The strategy uses
cheap and readily available CuI as catalyst, substituted 2-
haloanilines and benzamides as the starting materials. Copper-
catalyzed Ullmann-type coupling and intramolecular nucleophilic
addition process were included. The corresponding products with
various substituents were obtained in moderate to excellent yields.
And it has potential applications in the synthesis of biological and
medical compounds.
3
2
Hz, 1C), 110.96 (d, JC, F = 10 Hz, 1C), 105.83 (d, JC, F = 12 Hz, 1C),
48.59. HRMS calcd for C20H15N2F [(M+H)+]: 303.1292; found,
303.1297.
1-Benzyl-2-phenyl-5-(trifluoromethyl)-1H-benzo[d]imidazole (3d).
o
1
White solid (14 h, 93%). Mp: 96-98 C. H NMR (300 MHz, CDCl3): δ
= 8.14 (s, 1H), 7.70-7.61 (m, 2H), 7.51-7.44 (m, 4H), 7.36-7.26 (m,
3H), 7.08 (dd, J = 7.8 Hz, 2.4 Hz, 2H), 5.48 (s, 2H); 13C NMR (75 MHz,
CDCl3): δ = 156.07, 142.59, 137.95, 135.71, 130.42, 129.41, 129.29,
129.21 (d, 1JC, F = 246 Hz, 1C), 128.92, 128.09, 126.01, 125.47 (d, 2JC, F
= 32 Hz, 1C), 123.01, 119.99 (t, 3JC, F = 4 Hz, 1C), 117.74 (t, 3JC, F = 4
Hz, 1C), 110.96, 48.61. HRMS calcd for C21H15N2F [(M+H)+]:
Experimental
General procedure
1H NMR and 13C NMR spectra were recorded with a 300 MHz Bruker
instrument or
tetramethylsilane (TMS) was used as the internal standard. HRMS
spectra were determined on Q-TOF spectrograph (ESI).
Compounds 1 and 4 were prepared (see supporting information)
according to the literature.15 Other reagents were commercially
available and were used without further purification. All reactions
were monitored by thin-layer chromatography (TLC).
a 400 MHz Bruker instrument in CDCl3, and 353.1260; found, 353.1268.
1-Benzyl-6-chloro-2-phenyl-1H-benzo[d]imidazole (3e).10c Light
yellow solid (14 h, 75%). Mp: 151-153 oC. 1H NMR (400 MHz, CDCl3):
δ = 7.77 (d, J = 8.8 Hz, 2H), 7.68 (dd, J = 7.6 Hz, 1.6 Hz, 2H), 7.50-
7.42 (m, 3H), 7.36-7.30 (m, 3H), 7.28 (dd, J = 8.8 Hz, 1.6 Hz, 1H),
7.19 (d, J = 2.0 Hz, 1H), 7.08 (d, J = 6.8 Hz, 2H), 5.40 (s, 2H); 13CNMR
(100 MHz, CDCl3): δ = 155.01, 141.87, 136.74, 135.85, 130.16,
129.68, 129.21, 128.85, 128.72, 128.01, 125.89, 123.42, 120.87,
110.56, 48.49. HRMS calcd for C20H15N2Cl [(M+H)+]: 319.0997;
found, 319.0996.
a
General experimental procedure for 1,2-disubstituted
benzimidazoles
1-Benzyl-5-methyl-2-phenyl-1H-benzo[d]imidazole (3f).16 Light
A mixture of N-benzyl-2-iodoaniline (0.5 mmol), Amide (0.5 mmol), yellow solid (20 h, 57%). Mp: 153-155 oC. 1H NMR (400 MHz, CDCl3):
CuI (0.1 mmol), N, N'-dimethylethane-1, 2-diamine (0.2mmol) and
δ = 7.69-7.65 (m, 3H), 7.48-7.41 (m, 3H), 7.34-7.25 (m, 3H), 7.10-
7.04 (m, 4H), 5.42 (s, 2H), 2.49 (s, 3H); 13C NMR (100 MHz, CDCl3): δ
= 154.11, 143.54, 136.55, 134.20, 132.37, 130.25, 129.81, 129.26,
K3PO4 (0.75 mmol) in DMF (3 mL) was stirred in a sealed tube under
N2 atmosphere. TLC monitored the end of the reaction. Then the
mixture was cooled to room temperature and Brine (100 ml) was
129.04, 128.72, 127.73, 125.99, 124.51, 119.79, 110.04, 48.39,
21.61; HRMS calcd for C21H18N2 [(M+H)+]: 299.1543; found,
poured into the solution. The mixture was extracted with EtOAc (5 ×
30 mL). The organic layers were combined and dried by anhydrous
299.1543.
Na2SO4. The product was purified by flash chromatography on silica
1-Benzyl-6-methyl-2-phenyl-1H-benzo[d]imidazole (3g).16 Light
gel (petroleum ether / EtOAc = 3: 1). Lastly, the desired product was
yellow solid (20 h, 65%). Mp: 184-186 oC. 1H NMR (400 MHz, CDCl3):
obtained after vacuum-rotary evaporation.
δ = 7.76 (d, J = 8.4 Hz, 1H), 7.66 (dd, J = 7.2 Hz, 1.2 Hz, 2H), 7.45-
1-Benzyl-2-phenyl-1H-benzo[d]imidazole (3a).10c White solid (14 h, 7.40 (m, 3H), 7.36-7.30 (m, 3H), 7.14-7.09 (m, 3H), 7.00 (s, 1H), 5.42
89%). Mp: 124-126 oC. 1H NMR (400 MHz, CDCl3): δ = 7.88 (d, J = 8.0
Hz, 1H), 7.69 (d, J = 6.4 Hz, 2H), 7.45 (d, J = 6.1 Hz, 3H), 7.32 (d, J =
7.2 Hz, 4H), 7.25-7.18 (m, 2H), 7.10 (d, J = 6.4 Hz, 2H), 5.44 (s, 2H);
13C NMR (100MHz, CDCl3): δ = 154.19, 143.24, 136.43, 136.11,
130.14, 129.92, 129.29, 129.08, 128.77, 127.79, 126.00, 123.05,
122.69, 120.03, 110.55, 48.40. HRMS calcd for C20H16N2 [(M+H)+]:
285.1386; found, 285.1385.
(s, 2H), 2.43 (s, 3H); 13CNMR (100MHz, CDCl3): δ = 153.69, 141.22,
136.57, 136.36, 133.14, 130.18, 129.78, 129.21, 129.07, 128.71,
127.72, 125.93, 124.34, 119.50, 110.30, 48.27, 21.86. HRMS calcd
for C21H18N2 [(M+H)+]: 299.1543; found, 299.1546.
1-Benzyl-5-bromo-2-phenyl-1H-benzo[d]imidazole (3h). Yellow
solid (16 h, 47%). MP: 158-160 oC. 1H NMR (400 MHz, CDCl3): δ =
7.99 (d, J = 2.0 Hz, 1H), 7.68-7.65 (m, 2H), 7.49-7.42 (m, 3H), 7.35-
1-Benzyl-5-chloro-2-phenyl-1H-benzo[d]imidazole (3b).16 White
solid (14 h, 81%). Mp: 172-174 oC. 1H NMR (300 MHz, CDCl3): δ = 7.30 (m, 4H), 7.06-7.04 (m, 3H), 5.42 (s, 2H); 13C NMR (100 MHz,
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CDCl3): δ = 155.21, 144.52, 135.91, 135.01, 130.24, 129.62, 129.26, 6.82 (t, J = 7.2 Hz, 1H), 5.50 (s, 2H)；13C NMR (100 MHz, CDCl3): δ =
1
129.16, 128.87, 127.99, 126.04, 125.93, 122.83, 115.68, 111.81,
161.09 (d, JC, = 245 Hz, 1C), 154.20, 143.11, 130.07, 129.91,
F
48.53. HRMS calcd for C20H15N2Br [(M+H)+]: 363.0491; 129.59 (d, JC, F = 8 Hz, 1C), 129.19, 128.86, 127.61, 127.57, 124.75
3
(d, 4JC, F = 4 Hz, 1C), 123.61, (d, 3JC, F = 13 Hz, 1C), 123.21 (d, 2JC, F = 36
Hz, 1C), 120.09, (d, 2JC, F = 21 Hz, 1C), 115.70, 110.31, 42.59 (d, 4JC, F
found,363.0492.
1-Benzyl-2-phenyl-1H-benzo[d]imidazole-5-carbonitrile (3i). Light
=
yellow solid (14 h, 23%). Mp: 173-174 oC. 1H NMR (400 MHz, CDCl3): 6 Hz, 1C). HRMS calcd for C20H15N2F [(M+H)+]: 303.1292; found,
δ = 8.18 (s, 1H), 7.70 (d, J = 6.8 Hz, 2H), 7.55-7.47 (m, 4H), 7.36 (d, J 303.1288.
= 6.8 Hz, 3H), 7.26 (s, 1H), 7.07 (d, J = 6.0 Hz, 2H), 5.49 (s, 2H); 13
C
1-(3-Chlorobenzyl)-2-phenyl-1H-benzo[d]imidazole (3o).17 Light
yellow solid (18 h, 76%). Mp: 88-90 C. 1H NMR (300 MHz, CDCl3): δ
o
NMR (100MHz, CDCl3): δ = 156.60, 142.69, 138.66, 135.27, 130.61,
= 7.89-7.86 (m, 1H), 7.67-7.61 (m, 2H), 7.49-7.40 (m, 3H), 7.33-7.15
129.21, 128.94, 128.17, 126.35, 125.81, 124.90, 119.72, 111.56,
105.98, 48.62. HRMS calcd for C21H15N3 [(M+H)+]: 310.1339; found, (m, 5H), 7.09 (s, 1H), 6.92 (d, J = 6.9 Hz, 1H), 5.37 (s, 2H); 13CNMR
310.1342.
(75 MHz, CDCl3): δ = 154.08, 143.21, 138.49, 135.88, 135.08,
1-(4-Methylbenzyl)-2-phenyl-1H-benzo[d]imidazole (3j). White
130.41, 130.06, 129.90, 129.20, 128.86, 128.12, 126.22, 124.13,
solid (18 h, 60%). Mp: 98-100 oC. 1H NMR (400 MHz, CDCl3): δ = 7.87 123.27, 122.89, 120.13, 110.33, 47.84. HRMS calcd for C20H15N2Cl
(d, J = 8.0 Hz, 1H), 7.69 (dd, J = 6.8 Hz, 1.6 Hz, 2H), 7.43 (d, J = 6.8 [(M+H)+]: 319.0997; found,319.0979.
1-(4-Bromobenzyl)-2-phenyl-1H-benzo[d]imidazole (3p). White
solid (18 h, 41%). Mp: 156-158 oC. 1H NMR (300 MHz, CDCl3): δ =
Hz, 2H), 7.30-7.26 (m, 1H), 7.22-7.16 (m, 2H), 7.11 (d, J = 7.2 Hz,
2H), 6.97 (d, J = 8.0 Hz, 2H), 5.37 (s, 2H), 2.30 (s, 3H); 13CNMR (100
MHz, CDCl3): δ = 154.17, 143.25, 137.50, 136.14, 133.41, 130.20, 7.89 (d, J = 7.8 Hz, 1H), 7.86 (dd, J = 7.2 Hz, 2.1 Hz, 3H), 7.49-7.41
129.90, 129.74, 129.31, 128.76, 125.94, 123.02, 122.65, 119.98, (m, 4H), 7.35-7.29 (m, 1H), 7.27-7.22 (m, 1H), 7.18 (d, J = 8.4 Hz,
1H), 6.97 (d, J = 8.4 Hz, 1H), 6.85 (d, J = 8.1 Hz, 1H), 5.38 (s, 2H); 13
C
110.63, 48.20, 21.11. HRMS calcd for C21H18N2 [(M+H)+]: 299.1543;
found, 299.1545.
NMR (75 MHz, CDCl3): δ = 154.08, 143.16, 138.17, 135.84, 135.41,
132.24, 130.08, 129.89, 129.20, 128.86, 127.91, 127.71, 123.24,
122.90, 121.76, 120.13, 110.34. HRMS calcd for C20H15N2Br
1-(3-Methylbenzyl)-2-phenyl-1H-benzo[d]imidazole (3k). White
o
1
solid (18 h, 67%). Mp: 96-97 C. H NMR (400 MHz, CDCl3): δ = 7.91
(d, J = 8.0 Hz, 1H), 7.72-7.69 (m, 2H), 7.42-7.39 (m, 3H), 7.31-7.27 [(M+H)+]: 363.0491; found, 363.0492.
(m, 1H), 7.19-7.14 (m, 3H), 7.09 (d, J = 7.6 Hz, 1H), 6.90 (s, 1H), 6.86 1-(Nnaphthalen-2-ylmethyl)-2-phenyl-1H-benzo[d]imidazole (3q).
White solid (18 h, 84%). Mp: 184-186 oC. 1H NMR (300 MHz, CDCl3):
(d, J = 7.6 Hz, 1H), 5.35 (s, 2H), 2.26 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ = 154.18, 143.254, 138.83, 136.42, 136.21, 130.18, 129.94, δ = 7.96-7.90 (m, 3H), 7.82 (d, J = 8.4 Hz, 1H), 7.70 (d, J = 6.6 Hz, 2H),
129.31, 128.99, 128.79, 128.60, 126.62, 123.07, 122.70, 119.98, 7.58 (dd, J = 5.7 Hz, 2.7 Hz, 2H), 7.42-7.29 (m, 5H), 7.23-7.07 (m,
110.67, 48.35, 21.49. HRMS calcd for C21H18N2 [(M+H)+]: 299.1543;
2H), 6.93 (d, J = 7.2 Hz, 1H), 5.86 (s, 2H); 13CNMR (75 MHz, CDCl3): δ
= 154.35, 143.34, 136.40, 133.79, 131.39, 130.08, 129.95, 129.16,
129.02, 128.83, 128.32, 126.76, 126.27, 125.75, 123.14, 122.81,
found, 299.1548.
1-(4-(Tert-butyl)benzyl)-2-phenyl-1H-benzo[d]imidazole
(3l).
Colorless liquid (18 h, 71%). 1H NMR (400 MHz, CDCl3): δ = 7.87 (d, J 122.06, 120.11, 110.54, 46.58. HRMS calcd for C24H18N2 [(M+H)+]:
335.1543; found, 335.1546.
7.31-7.25 (m, 3H), 7.18 (d, J = 4.0 Hz, 2H), 7.00 (d, J = 8.0 Hz, 2H), 1-([1,1'-Biphenyl]-4-ylmethyl)-2-phenyl-1H-benzo[d]imidazole
= 8.0 Hz, 1H), 7.71 (dd, J = 7.2 Hz, 2.0 Hz, 2H), 7.41-7.39 (m, 3H),
o
1
(3r).18 White solid (24 h, 58%). Mp: 150-152 C. H NMR (300 MHz,
CDCl3): δ = 7.91 (d, J = 8.4 Hz, 1H), 7.74-7.71 (m, 2H), 7.58-7.54 (m,
4H), 7.49-7.40 (m, 5H), 7.37-7.30 (m, 2H), 7.26 (d, J = 5.2 Hz, 2H),
7.19 (d, J = 11.2 Hz, 2H), 5.50 (s, 2H); 13C NMR (75 MHz, CDCl3): δ =
154.16, 143.11, 140.77, 140.34, 136.05, 135.34, 130.00, 129.31,
128.85, 128.81, 127.76, 127.52, 127.02, 126.43, 123.14, 122.79,
5.36 (s, 2H), 1.27 (s, 9H); 13C NMR (100 MHz, CDCl3): δ = 154.16,
150.75, 143.27, 136.15, 133.37, 130.23, 129.88, 129.35, 128.76,
125.97, 125.76, 122.99, 122.63, 119.97, 110.72, 48.12, 34.56, 31.36.
HRMS calcd for C24H24N2 [(M+H)+]: 341.2012; found, 341.2019.
1-(3-Fluorobenzyl)-2-phenyl-1H-benzo[d]imidazole (3m). White
o
1
solid (18 h, 80%). Mp: 84-86 C. H NMR (400 MHz, CDCl3): δ = 7.89
(d, J = 8.0 Hz, 1H), 7.68 (d, J = 6.4 Hz, 2H), 7.47 (d, J = 6.4 Hz, 3H), 120.01, 110.58, 48.19. HRMS calcd for C26H20N2 [(M+H)+]: 361.1699;
7.34-7.23 (m, 4H), 7.14 (t, J = 9.2 Hz, 1H), 7.04 (t, J = 7.6 Hz, 1H), found, 361.1700.
1-Hexyl-2-phenyl-1H-benzo[d]imidazole (3s).18 Light yellow liquid
6.82 (t, J = 7.2 Hz, 1H), 5.50 (s, 2H)；13C NMR (100 MHz, CDCl3): δ =
1
1
(18 h, 81%). H NMR (300 MHz, CDCl3): δ = 7.84-7.81 (m, 1H), 7.71-
161.09 (d, JC, = 245 Hz, 1C), 154.20, 143.11, 130.07, 129.91,
F
3
7.68 (m, 2H), 7.52-7.48 (m, 3H), 7.41-7.37 (m, 1H), 7.32-7.25 (m,
2H), 4.22 (t, J = 7.5 Hz, 2H), 1.81 (q, J = 6.9 Hz, 2H), 1.26-1.20 (m,
6H), 0.84 (t, J = 6.6 Hz, 3H); 13CNMR (75 MHz, CDCl3): δ = 153.70,
129.59 (d, JC, F = 8 Hz, 1C), 129.19, 128.86, 127.61, 127.57, 124.75
(d, 4JC, F = 4 Hz, 1C), 123.61, (d, 3JC, F = 13 Hz, 1C), 123.21 (d, 2JC, F = 36
Hz, 1C), 120.09, (d, 2JC, F = 21 Hz, 1C), 115.70, 110.31, 42.59 (d, 4JC, F
=
6 Hz, 1C). HRMS calcd for C20H15N2F [(M+H)+]: 303.1292; found, 143.14, 135.62, 130.76, 129.65, 129.33, 128.66, 122.63, 122.28,
303.1288.
119.96, 110.10, 44.69, 31.12, 29.68, 26.32, 22.41, 13.87. HRMS
1-(2-Fluorobenzyl)-2-phenyl-1H-benzo[d]imidazole (3n). White calcd for C19H22N2 [(M+H)+]: 279.1856; found, 279.1854.
o
1
1-(3-Methylbut-2-en-1-yl)-2-phenyl-1H-benzo[d]imidazole
(3t).
solid (18 h, 79%). Mp: 84-86 C. H NMR (400 MHz, CDCl3): δ = 7.89
(d, J = 8.0 Hz, 1H), 7.68 (d, J = 6.4 Hz, 2H), 7.47 (d, J = 6.4 Hz, 3H),
Light yellow solid (18 h, 76%). Mp: 73-74 oC. 1H NMR (400 MHz,
7.34-7.23 (m, 4H), 7.14 (t, J = 9.2 Hz, 1H), 7.04 (t, J = 7.6 Hz, 1H), CDCl3): δ = 7.84-7.82 (m, 1H), 7.73-7.71 (m, 2H), 7.51-7.46 (m, 3H),
7.36-7.33 (m, 1H), 7.29-7.25 (m, 2H), 5.35 (t, J = 6.4 Hz, 1H), 4.78 (d,
6 | J. Name., 2012, 00, 1-3
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3
J = 6.0 Hz, 2H), 1.73 (s, 3H), 1.70 (s, 3H); 13C NMR (100 MHz, CDCl3): Hz, 1C), 129.63, 129.23, 128.02, 125.84, 125.79 (d, JC, F = 4 Hz, 1C),
1
125.71 (d, 3JC, F = 4 Hz, 1C), 125.20, 123.66, 123.07 (d, JC, F = 278 Hz,
δ = 153.65, 143.14, 135.99, 135.82, 130.46, 129.68, 129.51, 128.66,
1C), 122.49, 110.61, 48.42. HRMS calcd for C21H15N2F3 [(M+H)+]:
122.68, 122.38, 119.87, 119.66, 110.25, 43.39, 25.58, 18.15. HRMS
calcd for C18H18N2 [(M+H)+]: 263.1543; found, 263.1557.
353.1260; found, 353.1264.
5-Chloro-1-(3-chlorobenzyl)-2-phenyl-1H-benzo[d]imidazole (3u).
1
Light yellow solid (16 h, 90%). Mp: 171-173 oC. H NMR (400 MHz,
1-Benzyl-2-(3-chlorophenyl)-1H-benzo[d]imidazole (3aa). White
o
1
solid (15 h, 81%). Mp: 90-92 C. H NMR (400 MHz, CDCl3): δ = 7.88
(d, J= 8.0 Hz, 1H), 7.73 (s, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.43 (d, J= 8.8
Hz, 2H), 7.35-7.21 (m, 7H), 7.07 (d, J = 6.8 Hz, 2H), 5.42 (s, 2H); 13C
NMR (100 MHz, CDCl3): δ = 152.57, 143.06, 136.15, 134.87, 131.85,
130.04, 130.01, 129.55, 129.17, 127.97, 127.16, 125.97, 123.47,
122.95, 120.17, 110.61, 48.42. HRMS calcd for C20H15N2Cl [(M+H)+]:
319.0997; found,319.0995.
CDCl3): δ = 7.85 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 6.4 Hz, 2H), 7.47 (d, J
= 6.4 Hz, 3H), 7.34-7.23 (m, 4H), 7.14 (t, J = 9.2 Hz, 1H), 7.04 (t, J =
7.6 Hz, 1H), 6.82 (t, J = 7.2 Hz, 1H), 5.50 (s, 2H); 13C NMR (100 MHz,
CDCl3): δ = 155.28, 143.99, 138.00, 135.25, 134.45, 130.50, 130.36,
129.45, 129.19, 128.95, 128.53, 128.32, 126.18, 124.03, 123.69,
119.94, 111.08, 48.01. HRMS calcd for C20H14N2Cl2 [(M+H)+]:
353.0607; found, 353.0610.
1-Benzyl-2-(p-tolyl)-1H-benzo[d]imidazole (3v).16 White solid (20 h,
54%). Mp: 129-131 oC. 1H NMR (400 MHz, CDCl3): δ = 7.87 (d, J = 8.0
Hz, 1H), 7.59 (d, J = 8.0 Hz, 2H), 7.31-7.27 (m, 4H), 7.24 (d, J = 8.0
Hz, 2H), 7.21-7.19 (m, 2H), 7.01 (d, J = 6.8 Hz, 2H), 5.43 (s, 2H), 2.39
(s, 3H); 13C NMR (100 MHz, CDCl3): δ = 154.34, 143.15, 140.10,
136.51, 136.09, 129.48, 129.17, 129.06, 127.75, 127.13, 125.98,
122.91, 122.63, 119.88, 110.49, 48.39, 21.45. HRMS calcd for
C21H18N2 [(M+H)+]: 299.1543; found, 299.1550.
1-Benzyl-2-(3-fluorophenyl)-1H-benzo[d]imidazole (3ab). White
solid (14 h, 87%). Mp: 113-115 oC. 1H NMR (400 MHz, CDCl3): δ =
7.88 (d, J= 8.0 Hz, 1H), 7.45-7.36 (m, 3H), 7.36-7.26 (m, 4H), 7.24-
7.20 (m, 2H), 7.18-7.13 (m, 1H), 7.08 (d, J = 6.8 Hz, 2H), 5.44 (s, 2H);
1
13C NMR (100 MHz, CDCl3): δ = 163.95 (d, JC, = 246 Hz, 1C),
F
4
3
152.70(d, JC, F = 3 Hz, 1C), 143.06, 136.13, 132.20 (d, JC, F = 8 Hz,
3
1C), 130.50 (d, JC, F = 8 Hz, 1C), 129.17, 127.95, 125.92, 124.90 (d,
4JC, F = 3 Hz, 1C), 123.44, 122.93, 120.16, 117.09 (d, 2JC, F = 21 Hz, 1C),
1-Benzyl-2-(4-methoxyphenyl)-1H-benzo[d]imidazole
(3w).10d
2
116.60 (d, JC, = 23 Hz, 1C), 110.61, 48.39. HRMS calcd for
C20H15N2F [(M+H)+]: 303.1292; found, 303.1297.
o
White solid (20 h, 62%). Mp: 133-135 C. 1H NMR (400 MHz, CDCl3):
δ = 7.86 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.33-7.24 (m, 2H),
7.21 (dd, J = 14.8 Hz, 8.0 Hz, 2H), 7.09 (d, J = 6.8 Hz, 2H), 6.96-6.93
(m, 2H), 5.41 (s, 2H), 3.81 (s, 3H); 13C NMR (100 MHz, CDCl3): δ =
160.95, 154.18, 143.22, 136.55, 136.16, 130.70, 129.08, 127.75,
125.96, 122.79, 122.59, 122.41, 119.76, 114.23,110.40, 55.37,
48.38. HRMS calcd for C21H18N2O [(M+H)+]: 315.1492; found,
315.1496.
F
1-Benzyl-2-(thiophen-2-yl)-1H-benzo[d]imidazole (3ac).16 White
solid (16 h, 77%). Mp: 128-130 oC. 1H NMR (400 MHz, CDCl3): δ =
7.86 (d, J= 8.0 Hz, 1H), 7.48-7.44 (m, 1H), 7.34-7.27 (m, 5H), 7.24-
7.22 (m, 2H), 7.11 (d, J= 6.8 Hz, 2H), 7.06 (dd, J= 5.2 Hz, 4.0 Hz, 1H),
5.57 (s, 2H); 13C NMR (100 MHz, CDCl3): δ = 148.10, 143.07, 136.35,
136.09, 132.11, 129.17, 128.80, 128.62, 127.89, 127.83, 127.31,
127.12, 125.88, 123.29, 122.95, 119.89, 110.02, 48.20. HRMS calcd
for C18H14N2S [(M+H)+]: 291.0950; found, 291.0957.
1-Benzyl-2-(4-chlorophenyl)-1H-benzo[d]imidazole (3x).10d White
solid (14 h, 73%). Mp: 137-139 oC. 1H NMR (400 MHz, CDCl3): δ =
7.87 (d, J = 7.6 Hz, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 7.6 Hz,
2H), 7.35-7.27 (m, 4H), 7.09 (d, J = 6.4 Hz, 2H), 5.42 (s, 2H); 13CNMR
(100 MHz, CDCl3): δ = 152.96, 143.11, 136.22, 136.20, 136.18,
129.17, 129.08, 128.57, 127.93, 125.88, 123.34, 122.90, 120.09,
110.51, 48.39. HRMS calcd for C20H15N2Cl [(M+H)+]: 319.0997;
found, 319.0997.
1-Benzyl-1H-benzo[d]imidazole (3ad).20 Yellow solid (24 h, 62%).
Mp: 107-110 oC. 1H NMR (400 MHz, CDCl3): δ = 7.91 (s, 1H), 7.84 (d,
J = 7.2 Hz, 1H), 7.35-7.30 (m, 3H), 7.28-7.22 (m, 3H), 7.18 (d, J = 6.0
Hz, 2H), 5.34 (s, 2H); 13CNMR (100 MHz, CDCl3): δ = 143.93, 143.21,
135.48, 133.95, 129.06, 128.29, 127.11, 123.12, 122.31, 120.43,
110.06, 48.86. HRMS calcd for C14H12N2 [(M+H)+]: 209.1073;
found,209.1077.
1-Benzyl-2-(4-fluorophenyl)-1H-benzo[d]imidazole (3y).19 White
solid (12 h, 91%). Mp: 118-120 oC. 1H NMR (400 MHz, CDCl3): δ =
7.87 (d, J = 8.0 Hz, 1H), 7.68-7.65 (m, 2H), 7.35-7.29 (m, 4H), 7.27-
7.20 (m, 2H), 7.15-7.07 (m, 4H), 5.42 (s, 2H); 13C NMR (100 MHz,
1-Benzyl-2-methyl-1H-benzo[d]imidazole (3ae).21 Colorless liquid
1
1
(24 h, 51%). H NMR (400 MHz, CDCl3): δ = 7.74 (d, J= 7.6 Hz, 1H),
CDCl3): δ = 165.01 (d, JC, F = 249 Hz, 1C), 153.17, 143.05, 236.26,
3
4
7.31-7.26 (m, 3H), 7.23-7.17 (m, 3H), 7.05 (d, J= 7.6 Hz, 2H), 5.28 (s,
2H), 2.55 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 151.90, 142.70,
135.89, 130.88, 129.00, 127.91, 126.24, 122.29, 122.02, 119.16,
109.36, 47.10, 13.97. HRMS calcd for C15H14N2 [(M+H)+]: 223.1230;
found, 223.1226.
131.32 (d, JC, F = 9 Hz, 1C), 129.15, 127.90, 126.28 (d, JC, F = 3 Hz,
2
1C), 125.90, 123.21, 122.82, 120.00, 116.06 (d, JC, F = 22 Hz, 1C),
110.49, 48.36. HRMS calcd for C20H15N2F [(M+H)+]: 303.1292; found,
303.1293.
1-Benzyl-2-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole (3z).
1-Benzyl-2-ethyl-1H-benzo[d]imidazole (3af).22 Colorless liquid (24
h, 47%). 1H NMR (400 MHz, CDCl3): δ = 7.79 (d, J= 7.6 Hz, 1H), 7.30-
7.17 (m, 6H), 7.02 (d, J= 6.0 Hz, 2H), 5,28 (s, 2H), 2.86 (q, J = 7.6 Hz,
2H), 1.42 (t, 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ = 156.38,
142.65, 136.04, 135.52, 128.98, 127.86, 126.16, 122.31, 121.97,
o
White solid (12 h, 84%). Mp: 107-109 C. 1H NMR (400 MHz, CDCl3):
δ = 7.90 (d, J= 8.0 Hz, 1H), 7.82 (d, J= 8.0 Hz, 2H), 7.71 (d, J= 8.4 Hz,
2H), 7.35-7.28 (m, 4H), 7.27-7.23 (m, 2H), 7.09 (d, J= 6.4 Hz, 2H),
5.44 (s, 2H); 13C NMR (100 MHz, CDCl3): δ = 152.46, 143.13, 136.26,
2
2
136.05, 133.65, 132.26 (d, JC, F = 34 Hz, 1C), 131.61 (d, JC, F = 33
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119.30, 109.42, 46.78, 20.94, 11.71. HRMS calcd for C16H16N2 1-([1,1'-Biphenyl]-4-ylmethyl)-2-(4-methoxyphenyl)-1H-
[(M+H)+]: 337.1385; found, 237.1384.
benzo[d]imidazole (3rc) White solid (24 h, 56%). Mp: 171-173 oC.
1H NMR (400 MHz, CDCl3): δ = 7.88 (d, J = 7.6 Hz, 1H), 7.69 (d, J = 8.8
Hz, 2H), 7.57 (dd, J = 7.6 Hz, 1.6 Hz, 4H), 7.45 (t, J = 7.2 Hz, 2H),
7.36-7.29 (m, 2H), 7.25 (t, J = 4.0 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H),
6.99 (d, J = 8.8 Hz, 2H), 5.48 (s, 2H), 3.84 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ = 160.99, 154.18, 143.13, 140.73, 140.37, 136.12, 135.49,
130.73, 128.87, 127.79, 127.53, 127.04, 126.41, 122.88, 122.69,
122.29, 119.77, 114.27, 110.43, 55.40, 48.19. HRMS calcd for
C27H22N2O [(M+H)+]: 391.1805; found, 391.1804.
N-phenylbenzamide (9) White solid (95%). Mp: 163-165 oC. 1H NMR
(400 MHz, CDCl3): δ = 7.94 (s, 1H), 7.86-7.84 (m, 2H), 7.65 (d, J = 7.6
Hz, 2H), 7.53-7.51 (m, 1H), 7.47 (t, J = 7.0 Hz, 2H), 7.37 (t, J = 7.8 Hz,
2H), 7.16 (t, J = 7.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ = 165.83,
137.96, 135.02, 131.82, 129.09, 128.77, 127.05, 124.58, 120.28.
HRMS calcd for C13H11NO [(M+H)+]: 198.0913; found, 198.0914.
2-(4-Fluorophenyl)-1-(naphthalen-2-ylmethyl)-1H-
benzo[d]imidazole (3qa). Light yellow solid (16 h, 92%). Mp: 59-61
oC. 1H NMR (300 MHz, CDCl3): δ = 7.99-7.91 (m, 3H), 7.86 (d, J = 8.1
Hz, 1H), 7.71-7.66 (m, 2H), 7.62-7.59 (m, 2H), 7.37 (t, J = 8.1 Hz, 2H),
7.22 (d, J = 8.1 Hz, 1H), 7.16 (d, J = 8.1 Hz, 1H), 7.09-7.01 (m, 2H),
6.92 (dd, J = 7.2 Hz, 1.2 Hz, 1H), 5.88 (s, 2H); 13C NMR (75 MHz,
1
CDCl3): δ = 165.46 (d, JC, F = 249 Hz, 1C), 153.27, 142.93, 136.28,
3
133.80, 131.12, 131.09 (d, JC, F = 8 Hz, 1C), 129.98, 129.21, 128.46,
4
126.86, 126.35, 125.95 (d, JC, F = 3 Hz, 1C), 125.72, 123.34, 121.94,
2
120.00, 116.20 (d, JC, F = 22 Hz, 1C), 110.51, 46.56. HRMS calcd for
C27H14N2F [(M+H)+]: 353.1449; found, 353.1447.
2-(4-Chlorophenyl)-1-(naphthalen-2-ylmethyl)-1H-
o
benzo[d]imidazole (3qb). White solid (18 h, 87%). Mp: 206-207 C.
1H NMR (400 MHz, CDCl3): δ = 7.98-7.91 (m, 3H), 7.84 (d, J = 8.4 Hz,
1H), 7.64-7.57 (m, 4H), 7.36-7.30 (m, 4H), 7.23 (t, J = 7.6 Hz, 1H),
7.14 (d, J = 8.0 Hz, 1H), 6.90 (d, J = 6.8 Hz, 1H), 5.85 (s, 2H); 13CNMR
(100 MHz, CDCl3): δ = 153.11, 143.10, 136.30, 133.81, 131.11,
130.27, 129.97, 129.23, 129.17, 128.50, 128.31, 126.91, 126.40,
125.74, 123.46, 123.06, 123.00, 121.95, 120.14, 110.54, 46.60.
HRMS calcd for C24H17N2Cl [(M+H)+]: 369.1153; found, 369.1153.
2-(4-Methoxyphenyl)-1-(naphthalen-2-ylmethyl)-1H-
Acknowledgements
We are grateful to the National Science Foundation of China (No.
21572117) and State Key Laboratory of Bioactive Substance and
Function of Natural Medicines, Institute of Materia Medica, Chinese
Academy of Medical Sciences and Peking Union Medical College (No.
GTZK201405) for financial support of this research.
benzo[d]imidazole (3qc). Light yellow solid (20 h, 57%). Mp: 232-
233 oC. 1H NMR (400 MHz, CDCl3): δ = 7.97-7.90 (m, 3H), 7.83 (d, J =
8.4 Hz, 1H), 7.64 (d, J = 8.8 Hz, 2H), 7.60-7.57 (m, 2H), 7.34-7.29
7.36-7.30 (m, 2H), 7.18 (t, J = 7.6 Hz, 1H), 7.08 (d, J = 8.0 Hz, 1H),
6.94 (d, J = 6.8 Hz, 1H), 6.86 (d, J = 8.4 Hz, 2H), 5.86 (s, 2H), 3.75 (s,
3H); 13C NMR (100 MHz, CDCl3): δ = 161.00, 154.32, 143.20, 136.39,
133.80, 131.46, 130.47, 130.08, 129.17, 128.30, 126.76, 126.27,
125.78, 123.12, 122.89, 122.74, 122.18, 122.07, 119.81, 114.31,
110.38, 55.32, 46.62. HRMS calcd for C24H17N2Cl [(M+H)+]:
365.1648; found, 365.1644.
Notes and references
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8 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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Journal Name
Rodriguez-Lens, A. Shima, M. Takeuchi, I. Tran, T. Young,
View Article Online
DOI: 10.1039/C7OB00945C
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Organic & Biomolecular Chemistry
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DOI: 10.1039/C7OB00945C
One–pot strategy of copper-catalyzed synthesis of 1,2-disubstituted
benzimidazoles
Caixia Xie,a Xushuang Han,a Jian Gong,a Danyang Li,a and Chen Ma*a,b
A simple, one-pot and copper-catalyzed coupling reaction for the construction of
1,2-disubstituted benzimidazole derivatives is described. Low-cost copper salt and
weak base K2CO3 were utlized in this reaction. A variety of 1,2-disubstituted
benzimidazoles were obtained in moderate to excellent yields.
Key words: copper-catalyzed, one–pot synthesis, 1,2-disubstituted benzimidazoles