Cu2O-catalyzed Ullmann-type reaction of vinyl bromides with imidazole and benzimidazole

Article abstract of DOI:10.1016/j.tetlet.2008.04.163

Cu₂O was found to be an efficient and economical metal catalyst in the Ullmann cross-coupling reaction of vinyl bromides with imidazole or benzimidazole. The system Cu₂O/ethyl 2-oxocyclohexanecarboxylate showed high catalytic activity in MeCN at 80-90 °C. The reaction gave the corresponding coupling products in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2008.04.163

Tetrahedron Letters 49 (2008) 4556–4559
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Cu2O-catalyzed Ullmann-type reaction of vinyl bromides with imidazole
and benzimidazole
*
Guodong Shen, Xin Lv, Weixing Qian, Weiliang Bao
Department of Chemistry, Xi Xi Campus, Zhejiang University, Hangzhou, Zhejiang 310028, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Cu2O was found to be an efficient and economical metal catalyst in the Ullmann cross-coupling reaction
of vinyl bromides with imidazole or benzimidazole. The system Cu2O/ethyl 2-oxocyclohexanecarboxylate
showed high catalytic activity in MeCN at 80–90 °C. The reaction gave the corresponding coupling prod-
ucts in good to excellent yields.
Received 19 December 2007
Revised 26 April 2008
Accepted 29 April 2008
Available online 20 May 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
Apparently, Cu2O was also an efficient catalyst in the Ullmann-type
coupling. In the suitable solvents the reaction conditions catalyzed
N-Vinylimidazoles are important building blocks and interme-
diates in the synthesis of polymers,1 natural product analogues,2
pharmaceutics and agriculture chemicals.3 For instance, poly(1-
vinylimidazole)s are involved in the preparation of polymeric dyes,
catalysts and ion-exchange resins.4 There are several methods to
synthesize N-vinylimidazoles, including direct addition of imidaz-
ole to alkynes,5 N-vinylation of imidazole with vinyl halides or ace-
tates,6 copper-catalyzed C–N bond cross coupling of benzimidazole
with vinylboronic acid7 and olefination of b-hydroxyimidazoles.8
The copper-catalyzed Ullmann-type coupling of vinyl halides with
imidazole would be an economic and versatile method. Catalyzed
by Cu2O will not be harsher than that catalyzed by CuI. In the re-
ported coupling reactions, the molar ratio of Cu2O was usually no
more than 5%. Obviously, the use of Cu2O is more economic than
the use of CuI. So, it is particularly interesting to use Cu2O as a cop-
per source owing to its inexpensiveness and low insensitivity to
light and air. Herein, we wish to report a new example of Cu2O
application: the synthesis of N-vinylimidazoles by N-vinylation of
imidazole with vinyl halides catalyzed by Cu2O/ethyl 2-oxocyclo-
hexanecarboxylate system.
We firstly conducted the coupling of b-bromostyrene and imid-
azole catalyzed by 5 mol % Cu2O and 10 mol % ethyl 2-oxocyclo-
hexanecarboxylate. The reaction conditions were systematically
evaluated (Table 1). Different solvents were tested initially. In a re-
cent report, it was suggested that less polar solvents will retard the
reaction because of the relative insolubility of Cs2CO3 or a polar Cu
complex. The reactivity of Cu2O–ligand system in nitrile solvents
was in the order of MeCN > EtCN > n-PrCN, opposite to the trend
of their boiling points in the same series.10b So we chose MeCN
from nitrile solvents. It was observed that in MeCN, the coupling
of b-bromostyrenes with imidazole gave the best result (Table 1,
entry 6). DMSO, DMF and NMP provided much lower yields (Table
1, entries 1, 2 and 4). When the reaction temperature was raised,
much higher yields could be obtained (entries 3 and 6). When
the dose of metal catalyst and the ligand was reduced to 60%, the
yield had only decreased a little (Table 1, entries 6 and 8). Then dif-
ferent bases were tested. Compared with Cs2CO3, K2CO3 was a bad
base (Table 1, entries 5 and 6). From the results in Table 1, it was
obvious that ethyl 2-oxocyclohexanecarboxylate was a more effi-
cient ligand (entries 9 and 10) and gave the coupling product in
98% yield. Consistent with our previous experiment, (Z)-vinyl bro-
mides were tried to react with imidazole under this condition and
the reaction seemed to be much slower and lower yield was
obtained, most likely because of their increased level of steric
by CuI/ -proline in ILs at 90–110 °C, vinyl bromides have been cou-
L
pled with imidazole and good to excellent yields were obtained.9
However, the required amounts of CuI and the corresponding li-
gands in many Ullmann-type coupling reactions were usually large
(often 10–30 mol % for CuI and 20–60 mol % for ligand). Moreover,
CuI, which was usually used in the Ullmann condensations in re-
cently published papers, is still expensive to the goal of practical
applications in industry.
It was reported that Cu2O could efficiently catalyze the coupling
of nitrogen-nucleophiles with aryl iodides and bromides under
mild conditions.10 In Taillefer’s report, imidazole was shown to
be less reactive than pyrazole, which could couple with bromoben-
zene under the catalysis of Cu2O/salicylaldoxime in CH3CN at 82 °C.
Buchwald reported that coupling of imidazole with aryl iodides
and bromides could be realized in high yields under the catalysis
of Cu2O/4,7-dimethoxy-1,10-phenanthroline system in n-PrCN at
the temperature range of 80–110 °C. It was also proved that
Cu2O could be used in ligand-free cross-coupling protocol.10d
* Corresponding author. Fax: +86 571 88273814.
E-mail address: wlbao@css.zju.edu.cn (W. Bao).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.163

G. Shen et al. / Tetrahedron Letters 49 (2008) 4556–4559
4557
Table 1
Screening the reaction conditions for Cu2O-catalyzed coupling of b-bromostyrene 1 with imidazole 2a
O
O
N
N
X
Cu O/ -keto ester/MeCN
OEt
β
2
N
N
80-90 ºC, base
X=Br, Cl
H
ligand
3
2
1
Entry
X
Solvent
Tc (°C)
t (h)
Base
Yieldb (%)
1
2
3
4
5
6
7
8
9
Br
Br
Br
Br
Br
Br
Cl
Br
Br
Br
Br
Br
NMP
85
90
75
85
85
85
85
85
85
28
28
24
28
24
24
24
24
24
24
30
24
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
33.6
38.5
25.0
30.7
55.6
98.2
20.1
88.7d
44.7e
85.2f
48.0g
80.0h
DMSO
MeCN
DMF
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
10
11
12
110
120
85
a
Reaction conditions: vinyl halide (1.5 mmol), imidazole (1.0 mmol) and Cu2O (0.05 mmol), ligand (0.10 mmol) and Cs2CO3 (2.0 mmol) in 1.5 mL solvent under N2.
b
c
d
e
f
Isolated yields based on imidazole.
Oil-bath temperature.
Reaction conditions: vinyl halide (1.5 mmol), imidazole (1.0 mmol), Cu2O (0.03 mmol), ligand (0.06 mmol) and Cs2CO3(2 mmol) in 1.5 mL solvent under N2.
1,10-Phenanthroline as the ligand.
L
-proline as the ligand.
g
h
(Z)-1-(2-Bromovinyl)-4-chlorobenzene was used as the substrate, and was performed in a sealed tube at 120 °C.
Without ligand.
Table 2
Coupling of imidazole and benzimidazole with vinyl bromidesa,c
N
R'
N
H
N
X
N
Cu O/ -Keto ester
β
2
R'
R
Cs2CO3
MeCN
85-130 ºC
R
N
X=Br, Cl
Entry
1
Vinyl bromide
Imidazole
Product
Me
Yieldb (%)
90.8
E/Zd
Br
N
N
1a
>99:1
2a
3a
N
H
Me
N
Br
N
2
3
1b
1c
2a
3b
3c
92.6
72.3
98:2
MeO
MeO
N
Br
N
2a
>99:1
MeO
OMe
MeO
OMe
N
Br
N
4
5
1d
2a
2a
3d
99.0
98.5
>99:1
>99:1
Cl
F
Cl
F
N
Br
Br
N
1e
3e
N
N
6
7
1f
2a
2a
3f
97.7
70.1
98:2
1g
3g
97:3
O
N
O
N
Br
(continued on next page)

4558
G. Shen et al. / Tetrahedron Letters 49 (2008) 4556–4559
Table 2 (continued)
Entry
Vinyl bromide
Imidazole
Product
Yieldb (%)
60.3
E/Zd
N
Br
8
9
2a
97:3
N
1h
3h
N
N
Br
N
1
2b
3i
82.2
77.6
90.5
70.8
53.6
>99:1
96:4
N
H
N
Br
N
10
11
12
13
1d
2b
2b
2b
2b
3j
Cl
Cl
N
Br
N
1e
3k
>99:1
>99:1
>99:1
F
F
N
Br
N
1a
3l
Me
MeO
Me
MeO
N
N
Br
Br
N
1b
1c
3m
N
14
2b
3n
60.4
98:2
MeO
OMe
MeO
OMe
N
N
N
Br
Cl
Cl
15
16
1
2c
3o
3a
3a
61.5
97:3
>99:1
>99:1
N
N
N
H
2a
45.6e
53.2e,f
N
N
17
2a
a
Reaction conditions: b-bromostyrene (1.5 mmol), imidazole (1.0 mmol), Cu2O (0.05 mmol), ligand (0.10 mmol) and Cs2CO3 (2 mmol) in 1.5 mL suitable solvent at 85 °C
under N2.
b
c
d
e
f
Isolated yields based on imidazole or benzimidazole.
Reaction time 24 h.
The ratio was based on 1H NMR spectrum.
Conducted in a sealed tube and the oil-bath temperature is 130 °C.
Reaction time 45 h.
hindrance (entry 11). Interestingly, if the reaction was run without
ligand, 80% yield was obtained (entry 12)! Actually, we already
have found that the imidazole was a ligand in the Cu(I)-catalyzed
couplings, though it was inferior to ethyl 2-oxocyclo-
hexanecarboxylate.
After reaction condition was optimized, the scope was explored
with various vinyl halides and imidazoles. The results are listed in
Table 2.11 It was found that the b-bromostyrenes bearing both elec-
tron-donating and electron-withdrawing groups were suitable for
this reaction and the desired N-vinylimidazoles were obtained in
excellent yields under the above reaction condition (entries 1, 2,
4, 5 and 6). The hetero-aryl vinyl bromides can also give the prod-
uct preferably (entry 7). The reaction seemed sensitive to the ster-
ical hindrance on the substrate. Compared with the coupling of
vinyl bromides with imidazole, the yields were relatively lower
when benzimidazole was used (entries 9–14). We also employed
2-methylimidazole as a nucleophilic substrate, it only gave a mod-
erate yield (entry 15). Vinyl chloride was also successfully coupled
under our reaction conditions, whereas higher reaction tempera-
ture and longer reaction time were required (entries 16 and 17).
The reaction was also stereoselective for the (E)-vinyl halide in-
volved coupling. The double bond geometry of the N-vinylimidaz-
oles from the (E)-vinyl halide was retained, and the E- to -Z ratio
was up to 99:1.
2. Conclusions
In summary, we have developed a mild, economic and efficient
method for the Cu2O-catalyzed coupling of imidazole or benzimid-
azole with vinyl bromides. Versatile new vinyl imidazoles could be
successfully synthesized by using ethyl 2-oxocyclohexanecarbox-
ylate as ligand with low loading of catalyst Cu2O under relatively
mild conditions. The yields were from good to excellent, and the

G. Shen et al. / Tetrahedron Letters 49 (2008) 4556–4559
4559
7. Lam, P. Y. S.; Vincent, G.; Clark, C. G.; Deudon, S.; Jadhav, P. K. Tetrahedron Lett.
2001, 42, 3415–3418.
stereoselectivity for the coupling of (E)-vinyl halide with imidazole
was satisfactory.
8. (a) Cooper, G.; Irwin, W. J. J. Chem. Soc., Perkin Trans. 1 1976, 545–549; (b)
Cooper, G.; Irwin, W. J. J. Chem. Soc., Perkin Trans. 1 1975, 798–803.
9. Wang, Z. M.; Bao, W. L.; Jiang, R. Chem. Commun. 2005, 2849–2851.
10. (a) Altman, R. A.; Buchwald, S. L. Org. Lett. 2006, 8, 2779–2782; (b) Altman, R.
A.; Koval, E. D.; Buchwald, S. L. J. Org. Chem. 2007, 72, 6190–6199; (c) Cristau, H.
J.; Cellier, P. P.; Spindler, J. F.; Taillefer, M. Chem. Eur. J. 2004, 10, 5607–5622; (d)
Correa, A.; Bolm, C. Adv. Synth. Catal. 2007, 349, 2673–2676; (e) Xu, L.; Zhu, D.;
Wu, F.; Wang, R. L.; Wan, B. Tetrahedron 2005, 61, 6553–6560.
Acknowledgement
This work was financially supported by the National Natural
Science Foundation of China (No. 20572095).
11. General experimental procedure. All reagents and solvents were pure
analytical grade materials purchased from commercial sources and were
used without further purification, if not stated otherwise. All E-vinyl bromides
were prepared according to the known literature.1 All melting points are
References and notes
1. (a) Briscoe, M. W.; Chambers, R. D.; Mullins, S. J.; Nakamura, T.; Vaughan, J. F. S.
J. Chem. Soc., Perkin Trans. 1 1994, 21, 3119–3124; (b) Feiring, A. E.; Wonchoba,
E. R. J. Org. Chem. 1992, 57, 7014–7017; (c)Comprehensive Polymer Science;
Allen, G., Ed.; Pergamon Press: New York, 1989; Vol. 3,.
2. Hormi, O. E. O.; Hirvel, W. L. Tetrahedron Lett. 1993, 34, 6463–6466.
3. (a) Hamada, Y.; Shinomoto, S.; Yamada, I.; Koike, H. EP 162359, 1985.; (b) Ross,
W. J.; Jamieson, W. B.; McCowen, M. C. J. Med. Chem. 1973, 16, 347–352.
4. (a) Barker, S. J.; Storr, R. C. J. Chem. Soc., Perkin Trans. 1 1990, 485–488; (b)
Masquestiau, A.; Beugnies, D.; Flammang, R.; Katritzky, A. R.; Soleiman, M.;
Davis, T.; Lam, J. N. J. Chem. Soc., Perkin Trans. 2 1988, 1071–1075; (c) Wender, P.
A.; Cooper, C. B. Tetrahedron 1986, 42, 2985–2991; (d) MWrky, M.; Schmidt, H.
J.; Hansen, H. Helv. Chim. Acta 1979, 62, 2129–2153.
5. (a) Aiscar, B. J. J.; Henkelmann, J.; Preiss, T.; Knochel, P.; Tzalis, D.; Koradin, C. EP
1055653, 2000.; (b) Tzalis, D.; Koradin, C.; Knochel, P. Tetrahedron Lett. 1999,
40, 6193–6195.
6. (a) Hayat, S.; Rahman, A.; Choudhary, M. I.; Khan, K. M.; Schumann, W.; Bayer,
E. Tetrahedron 2001, 57, 9951–9957; (b) Henkelmann, J.; Heider, M.; Ruehl, T.
EP 752422, 1997.
uncorrected. The NMR spectra were recorded in CDCl3 on
a 400 MHz
instrument with TMS as internal standard. IR spectra were taken at KBr
plates. TLC was carried out with 0.2 mm thick silica gel plates (GF254). The
columns were hand packed with silica gel 60 (200–300). All reactions were
carried out in an over-dried Schlenk tube equipped with a magnetic stir bar
under N2 atmosphere. Unknown compound was additionally confirmed by 13
C
NMR and Elemental analysis. An over-dried Schlenk tube was charged with
Cu2O (0.05 mmol), base (2.0 mmol, Cs2CO3), imidazole or benzimidazole
(1 mmol). The tube was placed under vacuum for twenty minutes and
backfilled with N2. Then vinyl halide (1.5 mmol), the ligand ethyl 2-
oxocyclohexanecarboxylate (0.1 mmol) and MeCN (1.5 mL) were added
under N2. The reaction mixture was stirred for 24 h at 85 °C. The resulting
suspension was cooled to room temperature and filtered through a pad of filter
paper with the help of 10 mL of ethyl acetate. The filtrate was concentrated,
and the residue was purified by chromatography to afford the products
(petroleum ether/AcOEt v/v 1/2 for the products of imidazole and v/v 1:1 for
the products of benzimidazole).