Copper and zinc co-catalyzed synthesis of imidazoles via the activation of sp3 C-H and N-H bonds

Article abstract of DOI:10.1016/j.tet.2014.04.054

An efficient and facile approach to synthesize imidazoles from amidines and arylketone via oxidative coupling of sp³ C-H bond and N-H bond is reported. This strategy exhibits high performance in terms of regioselectivity with moderate to high y

Full text of DOI:10.1016/j.tet.2014.04.054

Accepted Manuscript
Copper and Zinc co-Catalyzed Synthesis of Imidazoles via the Activation of sp3 C−H
and N-H Bonds
Dong Tang, Xiao-Long Li, Xin Guo, Ping Wu, Ji-Hui Li, Kai Wang, Huan-Wang Jing,
Bao-Hua Chen
PII:
S0040-4020(14)00575-4
10.1016/j.tet.2014.04.054
TET 25504
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 16 January 2014
Revised Date: 9 April 2014
Accepted Date: 17 April 2014
Please cite this article as: Tang D, Li X-L, Guo X, Wu P, Li J-H, Wang K, Jing H-W, Chen B-H,
Copper and Zinc co-Catalyzed Synthesis of Imidazoles via the Activation of sp3 C−H and N-H Bonds,
Tetrahedron (2014), doi: 10.1016/j.tet.2014.04.054.
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
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Copper and Zinc co-Catalyzed Synthesis of
Imidazoles via the Activation of sp3 C−H
and N-H Bonds
Leave this area blank for abstract info.
Dong Tang, Xiao-Long Li, Xin Guo, Ping Wu, Ji-Hui Li, Kai Wang, Huan-Wang Jing, and Bao-Hua Chen*
a State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Gansu Lanzhou, 730000, P. R.
China
b Key Laboratoryof Nonferrous Metal Chemistry and Resources Utilization of Gansu Province, Lanzhou,
730000, P. R. China
R1
H
H
R3
N
NH
O
Cu(OAc)2, ZnI2
R1
N
H
H
+
R3
NH2
R2
N
H
o-Phen ,LiBr,DCB
R2
22 examples

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Copper and Zinc co-Catalyzed Synthesis of Imidazoles via the Activation of sp3
C−H and N-H Bonds
Dong Tang a,b, Xiao-Long Lia,b, Xin Guoa,b, Ping Wua,b, Ji-Hui Lia,b, Kai Wanga,b, Huan-Wang Jinga,b,
a,b,
and Bao-Hua Chen
*
a State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Gansu Lanzhou, 730000, P. R. China
b Key Laboratoryof Nonferrous Metal Chemistry and Resources Utilization of Gansu Province, Lanzhou, 730000, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient and facile approach to synthesize imidazoles from amidines and arylketone via
oxidative coupling of sp3 C−H bond and N-H bond is reported. This strategy exhibits high
performance in terms of regionselectivity with moderate to high yields by using easily available
materials, and provides an alternative method to synthesize multi-substituted imidazole
skeletons.
Available online
2014 Elsevier Ltd. All rights reserved
.
Keywords:
imidazoles
amidines
cycloaddition reaction
oxidative coupling
C-N bond formation
Ar1
1. Introduction
H
N
Copper-Catalyzed
Ar3
Ar3
N
NH
The imidazole ring, as a privileged scaffold, represents an
important class of heterocycle which has been frequently found
in various natural products.1 Moreover, imidazole derivatives
possess many significant biological properties such as anti-
plasmodium,2 anti-inflammatory,3 antifungal4 and antibacteria.5
Consequently, considerable efforts have been undertaken to
develop efficient synthetic routes.6 For example, Wolkenberg and
co-workers introduced the construction of imidazoles from
aldehydes and 1,2-diketones under microwave irradiation.7 Xie et
al. reported the synthesis of substituted imidazoles via
intramolecular C-N bond-forming reactions.8 In addition, α-
bromoketones and N-arylbenzamidines were also employed to
afford multisubstituted imidazoles.9 In spite of many
methodologies have been already described, most of them needed
complex reagents or suffer from some other drawbacks. Thus,
there is still an indispensable challenge to generate imidazoles
from easily available starting materials.
Ar1
O2N
+
Ar2
N
Ar2
b) this work
Ar1
Ar2
Copper and Zinc
co-Catalyzed
H
O
N
NH
Ar2
N
Ar1
Ar3
Ar3
+
N
Scheme 1. Strategies for the Synthesis of imidazoles in our
group.
In the past two years, we had reported copper-catalyzed [3 +2]
cycloaddition reaction to synthesize multisubstituted imidazoles,
and iron(III)-catalyzed synthesis of 1,2,4-trisubstituted
imidazoles through the reactions of amidines and aldehydes, as
shown in Scheme 1.10 Recently, the Hajra group reported the
synthesis of imidazo[1,2-a]pyridines from 2-aminopyridines and
ketones, respectively.11 Encouraged by previous works, we aim to
synthesize imidazoles by using easy-to-get reagents under mild
conditions. Hence, we develop a copper and zinc co-catalyzed
transformation for the synthesis of imidazoles, starting from
amidines and arylketones.
a) our previous work 10
Ar1
H
Iron-Catalyzed
N
NH
N
Ar1
OHC Ar3
+
Ar3
Ar2
Ar2
CH3NO2
N
2. Results and discussion
To evaluate the feasibility of our strategy, we initiated our
studies by examining N-phenylbenzamidine (1a) and
acetophenone (2a) as a model reaction, which was carried out in
the presence of 1.10-phenanthroline (o-phen) over co-catalysts of
____________
* Corresponding author. Fax: (+86) 931-8912582
E-mail: chbh@lzu.edu.cn (B. -H. Chen).

2
Tetrahedron
ACCEPTED MANUSCRIPT
Table 1. Optimization of the Reaction conditions a
H
O
N
NH
catalyst, additive
solvent
N
N
+
1a
3a
2a
entry
catalyst
ligand
additive
solvent
DCB
yield (%) b
48
1
Cu(OAc)2, ZnI2
CuCl2, ZnI2
o-Phen
o-Phen
o-Phen
o-Phen
o-Phen
o-Phen
o-Phen
o-Phen
o-Phen
o-Phen
o-Phen
o-Phen
2
DCB
47
3
CuI, ZnI2
DCB
47
4
CuBr, ZnI2
DCB
44
5
CuSO4, ZnI2
DCB
43
6 c
Cu(OAc)2, ZnI2
Cu(OAc)2, ZnI2
Cu(OAc)2, ZnI2
Cu(OAc)2, ZnI2
Cu(OAc)2, ZnI2
Cu(OAc)2, ZnI2
Cu(OAc)2, ZnI2
Cu(OAc)2, ZnI2
Cu(OAc)2
LiBr
DCB
59
d
7 c,
LiBr, aniline
LiBr, aniline
LiBr, aniline
LiBr, aniline
LiBr, aniline
LiBr, aniline
LiBr, aniline
LiBr, aniline
LiBr
DCB
66
8 c, d
DMSO
DMF
Dioxane
Toluene
DCB
NR
NR
trace
20
9 c, d
10 c, d
11 c, d
12 c, d, e
13 c, d, e
14 c, d, e
15 c, e
79
DCB
52
o-Phen
DCB
trace
44
Cu(OAc)2, ZnI2
ZnI2
DCB
16 c, d, e
17 c, d, e, f
18 c, d, e
19 c, d, e
o-Phen
o-Phen
o-Phen
o-Phen
LiBr, aniline
LiBr, aniline
LiBr, aniline
LiBr, aniline
DCB
trace
trace
33
Cu(OAc)2, ZnI2
Cu(OAc)2, ZnBr2
Cu(OAc)2, TfOH
DCB
DCB
DCB
NR
a Reaction conditions: 1a (0.2 mmol), 2a (0.2 mmol), catalyst (10 mol %), o-Phen (20 mol %), solvent (2 mL), 120 °C, 6 h under air.
b Isolated yield based on 2a.
c LiBr (3 equiv).
d aniline (5 mol %).
e The ratio of 1a and 2a: 1a (0.24 mmol)/2a = 1.2:1.
f under the nitrogen atomosphere.
Cu(OAc)2 and ZnI2 in 1,2-dichlorobenzene (DCB) under air at
120 oC for 6 h, and the desired product was isolated in 48% yield
(Table 1, entry 1). Various Cu sources, including CuCl2, CuI,
CuBr and CuSO4, showed the similar catalytic activities (Table
1, entries 2-5). To our surprise, with 3 equiv of LiBr added, a
59% yield of product was obtained (Table 1, entry 6), which is
probably serves as a desiccant due to its highly hygroscopic
property. 12 In addition, when amidine 1a with a trace amount of
aniline impurity was employed, higher result was received, and
further study indicated that a catalytic amount of aniline also
played an important role in promoting this reaction (Table 1,
also tested, and no better results were observed (Table 1, entries
18-19).
Table 2. Reactions of Acetophenone (2a) with Various
Substituted Amidines a
R1
H
O
N
NH
Cu(OAc)2, ZnI2
R1
N
+
NH2
R2
N
o-Phen ,LiBr,DCB
R2
1
2a
3b-j
entry
R1, R2
product
3b
yield (%) b
entry 7), which is probably, as
a ligand, assists some
13
rearrangement processes in the reaction transformation. The
investigation of solvents effect suggested that DCB was superior
to dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF),
dioxane or toluene (Table 1, entries 8-11). Moreover, raising the
ratio of 1a/2a to 1.2:1, the product was obtained in 79% yield
(Table 1, entry 12). Furthermore, controlled experiments for this
reaction confirmed that each of ZnI2, Cu(OAc)2, o-phen, oxygen
and aniline was essentially needed for this transformation. (Table
1, entries 13-17). Otherwise, other Lewis and Bronsted acids,
such as ZnBr2 and trifluoromethanesulfonic acid (TfOH), were
1
2
3
4
5
6
7
4-Me, H, 1b
4-Cl, H, 1c
81
77
88
72
84
86
67
3c
2-ethyl, H, 1d
3-Cl,H, 1e
3d
3e
4-OMe, H, 1f
H , 2-Cl, 1g
H, 4-CF3, 1h
3f
3g
3h

3
O
8
4-Me, 4-OMe, 1i
3i
83
12
3v
3x
84
39
ACCEPTED MANUSCRIPT
a Unless otherwise indicated, reactions were carried out with 1 (0.24 mmol),
2a (0.2 mmol), Cu(OAc)2 (10 mol %), ZnI2 (10 mol %), o-phen (20 mol %),
aniline (5 mol %), LiBr (3 equiv), DCB (2 mL), the ratio of 1:2a= 1.2:1, 120
oC, 6 h, under air.
, 2m
,2p
O
13
b Isolated yield based on 2a.
With the optimized conditions in hand, various amidines 1
and acetophenone (2a) were examined to establish the scope and
limitation of this reaction, and the results were presented in
Table 2. The catalytic system was applicable for 1b-1j providing
the corresponding products 3b-3j in 72-88% yields (Table 2,
entries 1-9). However, the electron-deficient group
trifluoromethyl reduced the yields apparently for 6 h (Table 2,
entry 7).
a Unless otherwise indicated, reactions were carried out with 1 (0.24 mmol),
2a (0.2 mmol), Cu(OAc)2 (10 mol %), ZnI2 (10 mol %), o-phen (20 mol %),
aniline (5 mol %), LiBr (3 equiv), DCB (2 mL), the ratio of 1:2a= 1.2:1, 120
oC, 6 h, under air.
b Isolated yield based on 2
O
Optimized conditions
1a
2a
No proudct
No proudct
To further investigate the reaction scope, a number of
arylketone derivatives (2b-2m) were employed to react with N-
phenylbenzamidine (1a), as shown in Table 3. To our delight,
regardless of the electron-withdrawing or -donating groups in the
aryl ring, the reactions of arylketones proceeded smoothly and
provided moderate to good yields. Notably, the substrates with
electron-withdrawing groups were utilized, and the
corresponding products were obtained in good yields (Table 3,
enties 9 and 10), and the ones with electron-donating groups in
the meta-position could offer better results (Table 3, enties 5 and
7). Additionally, the substrates with bulky aromatic groups, such
as 1-(5-methoxynaphthalen-2-yl)ethanone (2l) and1-(naphthalen-
2-yl)ethanone (2m), were also tolerated and produced imidazoles
3u, 3v in 83% and 84% yield, respectively (Table 3, enties 11
and 12). Moreover, this strategy was performed well for the
synthesis of tetrasubstituted imidazoles (Table 3, entry 13).
+
N
H
NH
N
N
Optimized conditions
+
Scheme 2 The experiment of substrates with heteroaryl group.
Disappointingly, the desired products were not found when
the substrates with substituents of amino and hydroxy such as 1-
(4-amino-phenyl)ethanone and 1-(4-hydroxyphenyl)ethanone. In
addition, alkylketones, such as cyclohexanone and butan-2-one,
were not the suitable partners for the reaction. Moreover, the
substrates with pyridine ring, such as 1-(pyridin-4-yl)ethanone
and N-phenylnicotinamidine, could not be apply to this strategy
(Scheme 2), which was probably due to the nitrogen on pyridine
ring coordinating to the catalyst to effect formation of the
intermediates.
Table 3 Reactions of Acetophenone (2a) with Various
Substituted Amidines a
H
R3
O
N
NH
O
Cu(OAc)2, ZnI2
N
O
X
+
R3
NH2
Optimized conditions
N
o-Phen ,LiBr,DCB
3k-x
1a
2
X: Cl, Br
R3
product
3k
yield (%) b
2a
4
entry
1
not observed
4-F, 2b
2-F, 2c
72
68
73
76
82
77
81
70
81
80
Scheme 3 The control experiment of reaction intermediate.
2
3l
3
3-CF3, 2d
3m
3n
To get further insight into our reaction, 1 equiv of a radical
scavenger (TEMPO) was added to the catalyst system, and the
yield did not reduce in our reaction system, which might rule out
a radical process. In addition, when acetophenone conducted in
absence of amidine under the optimized conditions, the α-
4
3,4,5-OMe, 2e
3-OMe, 2f
2-Me, 2g
3-Me, 2h
4-Me, 2i
4-Br, 2j
5
3o
6
3p
9
halogenated product which maybe an important intermediate
was not observed, as shown in scheme 3. Recently, similar
7
3q
8
3r
works had been reported to synthesize imidazoles through
tandem imine formation-oxidative cyclization,11,
hence, we
14
9
3s
supposed that the amidines in equilibrium with enamines reacted
with arylketones following an analogous catalyst process based
on those results. Further studies including the investigation of
mechanism and related transformations are undertaken in our
laboratory.
10
11
4-Cl, 2k
O
3t
3u
83
OMe
, 2l
a series of important imidazole skeletons in good yields
with high regionselectivity. Moreover, the reaction, using
air as oxidant, is economical, easy-to-operate and
environmentally friendly.
3. Conclusion
In summary, an efficient copper and zinc co-catalyzed
method to synthesize multisubstituted imidazoles from
amidines and arylketones was developed. In the synthetic
protocol, easily available materials were employed to access

4
Tetrahedron
ACCEPTED MANUSCRIPT
4. Experimental section
1-(4-methoxyphenyl)-2,4-diphenyl-1H-imidazole 3f:
0.2 mmol, 55 mg, 84%; yellow oil; H NMR (300 MHz,
1
Typical Procedure for the Preparation of multi-
substituted imidazoles 3. Synthesis of 1,2,4-triphenyl-1H-
imidazole (3a): The reaction was carried out in a round-
bottom sidearm flask (10 mL), 1a (0.24 mmol), 2a (0.2
mmol), Cu(OAc)2 (10 mol %), ZnI2 (10 mol %), aniline (5
mol %), 1,10-phenanthroline (20 mol %), LiBr (3.0 equiv),
and DCB (2 mL) were added to the flask with a magnetic
CDCl3) δ 7.89–7.85 (m, 2H), 7.47–7.44 (m, 2H), 7.40–7.34
(dt, J = 7.8, 0.9 Hz, 3H), 7.26–7.19 (m, 4H), 7.13–7.08 (m,
2H), 6.87–6.83 (m, 2H), 3.76 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 159.1, 146.9, 141.2, 133.8, 131.2, 130.2, 128.5,
128.4, 128.2, 128.0, 126.9, 126.8, 124.9, 118.8, 114.4, 55.3;
HRMS (ESI) calcd for C22H19N2O (M + H)+ 327.1492,
found 327.1490.
o
stirring bar at 120 C under air. After 6 h stirring at this
2-(2-chlorophenyl)-1,4-diphenyl-1H-imidazole 3g: 0.2
mmol, 57 mg, 86%; yellow oil; 1H NMR (300 MHz, CDCl3)
δ 7.92–7.87 (m, 1H), 7.55–7.49 (m, 1H), 7.40–7.34 (t, J =
7.6 Hz, 1H), 7.30–7.20 (m, 3H), 7.16–7.10 (m, 1H); 13C
NMR (75 MHz, CDCl3) δ 141.6, 137.6, 134.2, 133.6, 132.5,
130.5, 130.3, 129.5, 129.0, 128.4, 127.6, 126.9, 126.6,
124.9, 124.5, 124.4, 116.8.
temperature, the flask was took out and cooled to room
temperature. The mixture was filtered with ethyl acetate (3
× 50mL), and the filtrate was concentrated under reduced
pressure to distill ethyl acetate. Subsequently, the crude
product with DCB was dried under heat gun, which was
further purified by silica gel chromatography
(petroleum/ethyl acetate = 10/1 as eluent) to obtain product
3a. 1H NMR and 13C NMR spectra were determined on 300
MHz and 75 MHz in CDCl3. unknown products were
further characterized by HRMS (TOF-ESI), the melting
points of solid products (3u and 3v) were determined on a
microscopic apparatus. The structures of the products (3a,
1,4-diphenyl-2-(4-(trifluoromethyl)phenyl)-1H-
1
imidazole 3h: 0.2 mmol, 49 mg, 67%; yellow oil; H NMR
(300 MHz, CDCl3) δ 7.90– 7.86 (d, J = 7.4 Hz, 2H), 7.58–
7.54 (d, J = 8.4 Hz, 2H), 7.51–7.47 (d, J = 8.4 Hz, 2H), 7.45
– 7.36 (m, 6H), 7.30 – 7.21 (m, 3H); 13C NMR (75 MHz,
CDCl3) δ 145.2, 142.1, 138.0, 133.6, 133.5, 131.3, 129.7,
128.7, 128.6, 128.5, 127.2, 125.8, 125.1, 125.1, 125.0,
125.0, 119.9, 119.3; HRMS (ESI) calcd for C22H16F3N2 (M
+ H)+ 365.1260, found 365.1263.
3b, 3c, 3f and 3i) were identified according to the literature.
15
1,2,4-triphenyl-1H-imidazole 3a: 0.2 mmol, 47 mg,
79%; yellow oil; 1H NMR (300 MHz, CDCl3) δ 790–7.80
(dd, J = 8.2, 1.1 Hz, 2H), 7.45–7.42 (dd, J = 6.5, 3.2 Hz,
2H), 7.39–7.37 (dd, J = 4.3, 3.2 Hz, 3H), 7.34 –7.30 (m,
3H), 7.25–7.15 (m, 6H); 13C NMR (75 MHz, CDCl3) δ
146.8, 141.5, 138.3, 133.7, 130.1, 129.3, 128.6, 128.4,
128.3, 128.3, 128.0, 128.0, 126.8, 125.6, 124.9, 118.4.
2-(4-methoxyphenyl)-4-phenyl-1-p-tolyl-1H-imidazole
3i: 0.2 mmol, 56 mg, 83%; yellow oil; 1H NMR (300 MHz,
CDCl3) δ 7.89–7.85 (m, 2H), 7.40–7.34 (ddd, J = 8.3, 5.2,
1.6 Hz, 5H), 7.25–7.15 (ddd, J = 7.1, 6.1, 1.2 Hz, 1H),
7.14–7.07 (dt, J = 8.3, 4.7 Hz, 4H), 6.80–6.724 (m, 2H),
3.71 (s, 3H), 2.35 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
159.5, 146.8, 141.1, 137.9, 135.9, 133.9, 123.0, 129.9,
128.4, 126.7, 125.5, 124.8, 122.9, 118.1, 113.5, 55.0, 21.0.
2,4-diphenyl-1-p-tolyl-1H-imidazole 3b: 0.2 mmol, 50
1
mg, 81%; yellow oil; H NMR (300 MHz, CDCl3) δ 7.93–
7.84 (m, 2H), 7.50–7.41 (m, 2H), 7.40–7.30 (m, 3H), 7.26–
7.15 (m, 4H), 7.14–7.06 (ddd, J = 9.6, 7.3, 0.8 Hz, 4H),
2.34 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 146.8, 141.4,
138.0, 135.8, 133.8, 130.3, 129.9, 128.6, 128.4, 128.2,
128.0, 126.8, 125.4, 124.9, 118.5, 21.0.
1,4-diphenyl-2-p-tolyl-1H-imidazole 3j: 0.2 mmol, 48
1
mg, 77%; yellow oil; H NMR (300 MHz, CDCl3) δ 7.49–
7.44 (m, 2H), 7.00–6.85 (m, 8H), 6.83–6.73(m, 3H), 6.63–
6.60 (d, J = 8.4 Hz, 2H), 1.85 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 146.9, 141.4, 138.4, 138.1, 133.8, 129.2, 128.7,
128.5, 128.4, 127.9, 127.3, 126.7, 125.6, 124.9, 118.2, 21.1.
1-(4-chlorophenyl)-2,4-diphenyl-1H-imidazole 3c: 0.2
mmol, 51 mg, 77%; yellow oil; 1H NMR (300 MHz, CDCl3)
δ 7.89–7.85 (m, 2H), 7.44–7.39(m, 2H), 7.37–7.30 (m, 4H),
7.29–7.19 (m, 5H), 7.13–7.09 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ 146.8, 141.8, 136.8, 133.8, 133.5, 129.9, 129.5,
128.7, 128.5, 128.2, 127.0, 126.9, 124.9, 118.1.
4-(4-fluorophenyl)-1,2-diphenyl-1H-imidazole 3k: 0.2
mmol, 45 mg, 72%; yellow oil; 1H NMR (300 MHz, CDCl3)
δ 7.89–7.79 (m, 2H), 7.47–7.39 (m, 2H), 7.37–7.34 (dd, J =
5.1, 1.9 Hz, 4H), 7.27–7.17 (m, 5H), 7.10–7.03 (m, 2H); 13C
NMR (75 MHz, CDCl3) δ 163.6, 160.3, 146.9, 140.7, 138.2,
130.1, 130.0, 130.0, 129.4, 128.6, 128.4, 128.1, 126.6,
126.5, 125.7, 118.1, 115.5, 115.2; HRMS (ESI) calcd for
C21H16FN2 (M + H)+ 315.1292, found 315.1295.
1-(2-ethylphenyl)-2,4-diphenyl-1H-imidazole 3d: 0.2
mmol, 57 mg, 88%; yellow oil; 1H NMR (300 MHz, CDCl3)
δ 7.93–7.90 (dd, J = 5.2, 3.4 Hz, 2H), 7.49–7.45 (dd, J =
6.6, 3.3 Hz, 2H), 7.41–7.35 (dd, J = 10.3, 4.8 Hz, 3H), 7.34
– 7.29 (m, 2H), 7.28 – 7.22 (m, 3H), 7.22–7.16 (tt, J = 5.7,
2.6 Hz, 3H), 2.37–2.26 (ddd, J = 15.0, 12.1, 7.5 Hz, 2H),
0.99–0.94 (t, J = 7.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
147.2, 141.3, 140.6, 137.1, 133.8, 130.3, 129.4, 129.3,
128.5, 128.2, 128.1, 127.7, 126.8, 124.7, 118.9, 23.6, 13.9.
4-(2-fluorophenyl)-1,2-diphenyl-1H-imidazole 3l: 0.2
mmol, 43 mg, 68%; yellow oil; 1H NMR (300 MHz, CDCl3)
δ 8.39–8.33 (ddd, J = 7.7, 3.9, 2.5 Hz, 1H), 7.66–7.63 (d, J
= 4.0 Hz, 1H), 7.50–7.43 (m, 2H), 7.40–7.33 (m, 3H), 7.29–
7.20 (m, 7H), 7.13–7.04 (m, 1H); 13C NMR (75 MHz,
CDCl3) δ 159.1, 146.9, 141.2, 133.8, 131.2, 130.2, 128.5,
128.4, 128.2, 128.0, 126.9, 126.8, 124.9, 118.8, 114.4, 55.3;
HRMS (ESI) calcd for C21H16FN2 (M + H)+ 315.1292,
found 315.1294.
1-(3-chlorophenyl)-2,4-diphenyl-1H-imidazole 3e: 0.2
mmol, 48 mg, 72%; yellow oil; 1H NMR (300 MHz, CDCl3)
δ 7.90–7.835 (m, 2H), 7.46–7.40 (m, 2H), 7.38–7.33 (dd, J
= 9.2, 6.1 Hz, 3H), 7.31–7.21 (m, 7H), 7.05–7.01 (ddd, J =
7.8, 2.0, 1.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 146.8,
141.7, 136.8, 133.8, 133.5, 129.7, 129.5, 128.7, 128.5,
128.2, 127.0, 126.9, 124.9, 118.1.
1,2-diphenyl-4-(3-(trifluoromethyl)phenyl)-1H-
imidazole 3m: 0.2 mmol, 53 mg, 73%; yellow oil; 1H NMR
(300 MHz, CDCl3) δ 8.17 (s, 1H), 8.09 – 8.02(m, 1H),
7.52–7.42 (m, 5H), 7.42–7.34 (m, 3H), 7.29–7.21 (ddd, J =
9.7, 3.9, 2.5 Hz, 5H); 13C NMR (75 MHz, CDCl3) δ 147.3,

5
ACCEPTED MANUSCRIPT
140.3, 138.2, 134.7, 130.0, 129.5, 129.0, 128.8, 128.6,
128.3, 128.2, 128.0, 125.7, 123.42, 123.37, 121.9, 121.7,
121.6, 119.1; HRMS (ESI) calcd for C22H16F3N2 (M + H)+
365.1260, found 365.1263.
188–191 °C; 1H NMR (300 MHz, CDCl3) δ 8.37 (s, 1H),
7.94–7.88 (dd, J = 8.5, 1.7 Hz, 1H), 7.81–7.72 (dd, J = 13.0,
8.6 Hz, 2H), 7.52–7.44 (m, 3H), 7.40–7.35 (m, 3H), 7.30–
7.21 (dtd, J = 6.2, 3.3, 1.2 Hz, 5H), 7.16–7.11 (m, 2H), 3.88
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 157.4, 147.0, 141.7,
138.4, 133.7, 130.2, 129.6, 129.4, 129.2, 129.1, 128.8,
128.4, 128.1, 128.1, 126.9, 125.7, 124.2, 123.1, 118.8,
118.4, 105.8, 55.2; HRMS (ESI) calcd for C26H21N2O (M +
H)+ 377.1648, found 377.1651.
1,2-diphenyl-4-(3,4,5-trimethoxyphenyl)-1H-
imidazole 3n: 0.2 mmol, 59 mg, 76%; yellow oil; H NMR
1
(300 MHz, CDCl3) δ 7.49–7.41 (m, 3H), 7.41–7.36 (dt, J =
4.1, 2.2 Hz, 3H), 7.29–7.22 (m, 5H), 7.14 (s, 2H), 3.93 (s,
6H), 3.88(s, 3H); 13C NMR (75 MHz, CDCl3) δ 153.3,
146.7, 141.4, 138.2, 137.2, 123.0, 129.5, 129.3, 128.7,
128.4, 128.1, 125.6, 118.2, 102.1, 60.8, 56.0; HRMS (ESI)
calcd for C24H23N2O3 (M + H)+ 387.1703, found 387.1705.
4-(naphthalen-2-yl)-1,2-diphenyl-1H-imidazole
3v:
0.2 mmol, 58 mg, 84%; yellow solid; mp 202–203 °C; 1H
NMR (300 MHz, CDCl3) δ 8.45 (s, 1H), 7.93–7.81 (m, 3H),
7.54 (s, 1H), 7.51–7.34 (m, 7H), 7.31–7.20 (m, 5H); 13C
NMR (75 MHz, CDCl3) δ 147.2, 141.6, 138.4, 133.8, 132.7,
131.1, 130.2, 129.4, 129.0, 128.8, 128.5, 128.2, 128.1,
127.6, 126.1, 126.0, 125.8, 125.4, 123.6, 123.2, 119.0;
HRMS (ESI) calcd for C25H19N2 (M + H)+ 347.1543, found
347.1545.
4-(3-methoxyphenyl)-1,2-diphenyl-1H-imidazole 3o:
1
0.2 mmol, 53 mg, 82%; yellow oil; H NMR (300 MHz,
CDCl3) δ 7.54–7.50 (m, 1H), 7.47–7.41 (ddd, J = 4.1, 2.0,
0.9 Hz, 3H), 7.41–7.39 (d, J = 1.0 Hz, 1H), 7.37–7.31 (m,
3H), 7.31 – 7.26 (m, 1H), 7.26–7.18 (m, 5H), 6.85–6.78
(ddd, J = 8.2, 2.3, 1.0 Hz, 1H), 3.83 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 159.9, 146.7, 141.4, 138.2, 135.2, 130.1,
129.4, 129.3, 128.6, 128.3, 128.0, 125.6, 118.6, 117.4,
113.0, 110.0, 55.1; HRMS (ESI) calcd for C22H19N2O (M +
H)+ 327.1492, found 327.1490.
5-methyl-1,2-diphenyl-4-p-tolyl-1H-imidazole
3x:
0.2mmol, 25mg, 39%; white solid, mp 188–194 °C; 1H
NMR (300 MHz, CDCl3) δ 7.7–7.65 (d, J = 8.1 Hz, 2H),
7.47–7.43 (dt, J = 5.8, 2.9 Hz, 3H), 7.41 – 7.36 (m, 2H),
7.27 – 7.17(m, 7H), 2.39 (s, 3H), 2.25 (s, 3H). 13C NMR
(75 MHz, CDCl3) δ 145.9, 137.4, 136.0, 132.1, 130.6,
129.5, 129.0, 128.6, 128.3, 128.0, 127.9, 127.8, 127.1,
125.8, 120.1, 21.2, 11.1; HRMS (ESI) calcd for C23H21N2
(M + H) + 325.1699, found 325.1696.
1,2-diphenyl-4-o-tolyl-1H-imidazole 3p: 0.2 mmol, 48
1
mg, 77%; yellow oil; H NMR (300 MHz, CDCl3) δ 8.02–
7.98 (d, J = 7.8 Hz, 1H), 7.50–7.44 (m, 2H), 7.40–7.35 (dd,
J = 6.9, 2.5 Hz, 3H), 7.30– 7.17 (m, 9H), 2.56 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 145.9, 141.0, 138.4, 134.9, 133.1,
130.7, 130.2, 129.4, 128.7, 128.6, 128.3, 128.1, 128.0,
126.9, 125.9, 125.8, 120.9, 21.8; HRMS (ESI) calcd for
C22H19N2 (M + H)+ 311.1543, found 311.1541.
5. Acknowledgements
We are grateful to the project sponsored by the National
Natural Science Foundation of P. R. China (No. 21372102
and 21173106), the Project of National Science Foundation
of Gansu Province P.R. China (No. 1208RJZA266).
1,2-diphenyl-4-m-tolyl-1H-imidazole 3q: 0.2 mmol, 50
mg, 81%; yellow oil; 1H NMR (300 MHz, CDCl3) δ 7.77 (s,
1H), 7.67–7.63 (d, J = 7.7 Hz, 1H), 7.46–7.42 (dd, J = 6.8,
2.8 Hz, 2H), 7.39 (s, 1H), 7.38–7.30 (m, 3H), 7.30–7.16 (m,
6H), 7.09–7.04 (d, J = 7.5 Hz, 1H), 2.38 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 146.7, 141.7, 138.3, 138.0, 133.6,
130.2, 129.3, 128.7, 128.3, 128.26, 128.0, 127.97, 127.7,
122.0, 118.5, 118.4, 21.4; HRMS (ESI) calcd for C22H19N2
(M + H)+ 311.1543, found 311.1539.
6. References and notes
1. (a)Maier, U. H.; Gundlach, H.; Zenk, M.H. Phytochemistry.
1998, 49, 1791. (b) Weinreb, S. M. Nat. Prod. Rep. 2007,
24, 931. (c) Jin, Z. Nat. Prod. Rep. 2011, 28, 1143. (d)
Morinaka, B. I.; Pawlik, J. R.; Molinski, T. F. J. Org. Chem.
2010, 75, 2453. (e) Silva, V. G.; Silva, R. O.; Damasceno,
S. R. B.; Carvalho, N. S.; Prudencio, R. S.; Aragao, K. S.;
Guimaraes, M. A.; Campos, S. A.; Veras, L. M. C.;
Godejohann, M.; Leite, J. R. S. A.; Barbosa, A. L. R.;
Medeiros, J. V. R. J. Nat. Prod. 2013, 76, 1071.
1,2-diphenyl-4-p-tolyl-1H-imidazole 3r: 0.2 mmol, 43
1
mg, 70%; yellow oil; H NMR (300 MHz, CDCl3) δ 7.80–
7.76 (d, J = 8.1 Hz, 2H), 7.47–7.41 (m, 2H), 7.38–7.32 (m,
4H), 7.25–7.17 (m, 7H), 2.34 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 146.7, 141.7, 138.4, 136.5, 131.0, 130.3, 129.3,
129.2, 128.7, 128.3, 128.1, 128.0, 125.7, 124.9, 118.0, 21.2.
2. Vlahakis, J. Z.; Lazar, C.; Crandall, I. E.; Szarek, W. A.
Bioorg. Med. Chem. 2010, 18, 6184.
3. (a) Sathe, B. S.; Jagtap, V. A.; Deshmukh, S. D.; Jain, B. V.
Int. J. Pharm. Pharm. Sci. 2011, 3, 220. (b) Lee, J. C.;
Laydon, J. T.; Mcdonnell, P. C.; Gallagher, T. F.; Kumar,
S.; Green, D.; Mckulty, D.; Blumenthal, M.; Heys, J. R.;
Landvatter, S. W.; Strikler, J. E. Mclaughlin, M. M.;
Siemen, I. R.; Fisher, S. M.; Livi, G. P.; White, J. R.;
Adams, J. L.; Young, P. R Nature 1994, 372, 739. (c)
Adams, J. L.; Boehm, J. C.; Gallagher, T. F.; Kassis, S.;
Webb, E. F.; Hall, R.; Sorenson, M.; Garigipati, R.;
Griswoldc, D. E.; Lee, J. C. Bioorg. Med. Chem. Lett. 2001,
11, 2867.
4-(4-bromophenyl)-1,2-diphenyl-1H-imidazole 3s: 0.2
mmol, 61 mg, 81%; yellow oil; 1H NMR (300 MHz, CDCl3)
δ 7.77–7.70 (m, 2H), 7.50–7.44 (m, 2H), 7.44–7.39 (m,
2H), 7.39–7.31 (m, 4H), 7.25–7.16 (ddt, J = 6.0, 2.5, 2.1
Hz, 5H); 13C NMR (75 MHz, CDCl3) δ 147.0, 140.4, 138.1,
132.8, 131.5, 129.9, 129.4, 128.6, 128.4, 128.1, 128.1,
126.4, 125.6, 120.4, 118.6.
4-(4-chlorophenyl)-1,2-diphenyl-1H-imidazole 3t: 0.2
mmol, 53 mg, 80%; yellow oil; 1H NMR (300 MHz, CDCl3)
δ 7.85–7.76 (m, 2H), 7.45–7.40 (m, 2H), 7.38–7.28 (m,
6H), 7.26–7.17 (m, 5H); 13C NMR (75 MHz, CDCl3) δ
147.0, 140.5, 138.1, 132.3, 130.0, 129.4, 128.6, 128.4,
128.1, 128.1, 126.1, 125.6, 118.5.
4. Koga, H.; Nanjoh, Y.; Makimura, K.; Tsuboi, R. Med.
Mycol. 2009, 47, 640.
5. Antolini, M.; Bozzoli, A.; Ghiron, C.; Kennedy, G.; Rossi,
T.; Ursini, A. Bioorg. Med. Chem. Lett. 1999, 9, 1023.
6. (a) Lavallo, V.; Grubbs, R H. Science 2009, 326, 559. (b)
Frantz, D. E.; Morency, L.; Murry, A.; Soheili, J. A.;
Grabowski, E. J. J.; Tillyer, R. D. Org. Lett. 2004, 6, 843.
4-(5-methoxynaphthalen-2-yl)-1,2-diphenyl-1H-
imidazole 3u: 0.2 mmol, 62 mg, 83%; yellow solid; mp

6
Tetrahedron
ACCEPTED MANUSCRIPT
(c) Nie, Y. B.; Wang, L.; Ding, M. W. J. Org. Chem. 2012,
77, 696.
13. (a) Peng, C.; Cheng, J.; Wang, J. Adv. Synth. Catal. 2008,
350, 2359. (b) Raman, N.; Ravichandran, S.; Thangaraja, C.
J. Chem. Sci. 2004, 116, 215. (c) Newman, J. D. S.;
MacCrehan, W. A. Langmuir, 2009, 25, 8993.
7. Wolkenberg, S. E.; Wisnoski, D. D.; Leister, W. H.; Wang,
Y.; Zhao, Z.; Lindsley, C. W. Org. Lett. 2004, 6, 1453.
14. (a) Mohan, D. C.; Donthiri, R. R.; Rao, S. N.; Adimurthy, S.
8. Shen, H.; Xie, Z. J. Am. Chem. Soc. 2010, 132,
11473.
9. (a) Wiglenda, T.; Gust, R. J. Med. Chem. 2007, 50, 1475.
(b) Ung, G.; Bertrand, G. Chem. Eur. J. 2011, 17, 8269.
Adv. Synth. Catal. 2013, 355, 2217. (b) Meng, X.; Yu, C.;
Zhao, P. RSC Adv. 2014, 4, 8612.
15. (a) Necdet, C.; Meliha, C. Tetrahedron 2010, 66, 2053. (b)
Auricchio, S.; Truscello, A. M.; Lauria, M.; Meille, S. V.
Tetrahedron 2012, 68, 7441. (c) Li, J.; Neuville, L. Org.
Lett. 2013, 15, 1752.
10. (a) Tang, D.; Wu, P.; Liu, X.; Chen, Y. X.; Guo, S. B.;
Chen, W. L.; Li, J. G.; Chen, B. H. J. Org. Chem. 2013, 78,
2746. (b) Liu, X.; Wang, D.; Chen, Y.; Tang, D.; Chen, B.
Adv. Synth. Catal. 2013, 355, 2798. (c) Liu, X.; Wang, D.;
Chen, B. Tetrahedron, 2013, 69, 9417.
7. Supplementary Material
1H NMR and 13C NMR spectra of products associated
with this article can be found in the online version at
http://dx.doi.org/10.1016/j.tet.xxxxxx..
11. (a) Bagdi, A. K.; Rahman, M.; Santra, S.; Majee, A.; Hajra,
A. Adv. Synth. Catal. 2013, 355, 1741. (b) Cai, Z. J.; Wang,
S. Y.; Ji, S. J. Adv. Synth. Catal. 2013, 355, 2686.
12. Rudrawar, S. Synlett, 2005, 7, 1197.

ACCEPTED MANUSCRIPT
Supporting Information
Copper and Zinc co-Catalyzed Synthesis of Imidazoles via the
Activation of sp3 C−H and N-H Bonds
Dong Tang a,b, Xiao-Long Lia,b, Xin Guoa,b, Ping Wua,b, Ji-Hui Lia,b, Kai Wanga,b,
a,b,
Huan-Wang Jinga,b, and Bao-Hua Chen
*
a State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Gansu Lanzhou, 730000, P. R. China
b Key Laboratoryof Nonferrous Metal Chemistry and Resources Utilization of Gansu Province, Lanzhou, 730000, P. R. China
Fax: (+86) 931-8912582
E-mail: chbh@lzu.edu.cn (B. -H. Chen).
Table of Contents
1) 1H and 13C NMR spectra of the products…………………………………… S2-S23
1

ACCEPTED MANUSCRIPT
N
N
3a
N
N
3a
2

ACCEPTED MANUSCRIPT
N
N
3b
N
N
3b
3

ACCEPTED MANUSCRIPT
Cl
N
N
3c
Cl
N
N
3c
4

ACCEPTED MANUSCRIPT
N
N
3d
N
N
3d
5

ACCEPTED MANUSCRIPT
Cl
N
N
3e
Cl
N
N
3e
6

ACCEPTED MANUSCRIPT
MeO
N
N
3f
MeO
N
N
3f
7

ACCEPTED MANUSCRIPT
N
N
Cl
3g
N
N
Cl
3g
8

ACCEPTED MANUSCRIPT
N
N
F3C
3h
N
N
F3C
3h
9

ACCEPTED MANUSCRIPT
N
N
MeO
3i
N
N
MeO
3i
10

ACCEPTED MANUSCRIPT
N
N
3j
N
N
3j
11

ACCEPTED MANUSCRIPT
N
N
F
3k
N
F
N
3k
12

ACCEPTED MANUSCRIPT
N
N
F
3l
N
N
F
3l
13

ACCEPTED MANUSCRIPT
N
N
CF3
3m
N
N
CF3
3m
14

ACCEPTED MANUSCRIPT
OMe
OMe
OMe
N
N
3n
OMe
OMe
OMe
N
N
3n
15

ACCEPTED MANUSCRIPT
N
N
OMe
3o
N
N
OMe
3o
16

ACCEPTED MANUSCRIPT
N
N
3p
N
N
3p
17

ACCEPTED MANUSCRIPT
N
N
3q
N
N
3q
18

ACCEPTED MANUSCRIPT
N
N
3r
N
N
3r
19

ACCEPTED MANUSCRIPT
N
N
Br
3s
N
Br
N
3s
20

ACCEPTED MANUSCRIPT
N
Cl
N
3t
N
Cl
N
3t
21

ACCEPTED MANUSCRIPT
N
OMe
N
3u
N
OMe
N
3u
22