A simple and efficient copper-catalyzed synthesis of N-alkynylimidazoles

Article abstract of DOI:10.1055/s-0031-1290340

A simple and efficient method for the synthesis of N-alkynylheteroarenes from 1,1-dibromo-1-alkenes was developed via a copper-catalyzed cross-coupling reaction. Generally superior yields and functional-group tolerance were obtained with TMEDA as ligand using imidazole and benzimidazole substrates in dioxane. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290340

LETTER
589
A Simple and Efficient Copper-Catalyzed Synthesis of N-Alkynylimidazoles
Synthesis of
N-Alkynya
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. of China
Fax +86(571)87951895; E-mail: shangzc@zju.edu.cn
Received 6 November 2011
cross-coupling reactions,1 and initially inspired by the
work of Evano’s group in the copper-catalyzed N-
alkynylation1d of amides, we thought that an attractive al-
ternative for the preparation of N-alkynylheteroarenes
Abstract: A simple and efficient method for the synthesis of N-
alkynylheteroarenes from 1,1-dibromo-1-alkenes was developed
via a copper-catalyzed cross-coupling reaction. Generally superior
yields and functional-group tolerance were obtained with TMEDA
as ligand using imidazole and benzimidazole substrates in dioxane. could be performed using catalytic amounts of copper(I)
salts from readily available 1,1-dibromo-1-alkyenes and
their further reaction with the appropriate N-containing
heterocycles. Herein, we report a simple and facile meth-
od for the synthesis of N-alkynylheteroarenes incorporat-
ing the imidazole and benzimidazole heterocyclic cores.
Key words: N-alkynylimidazoles, 1,1-dibromo-1-alkenes, copper,
cross-coupling reaction, alkynylation
Metal-catalyzed cross-coupling reactions are among the
most powerful methods available for the formation of car-
bon–carbon and carbon–heteroatom bonds.1,2 On the oth-
er hand, gem-dibromoolefins serve as important synthetic
intermediates in a variety of transformations,2 the most fa-
mous one probably being the Corey–Fuchs alkyne synthe-
sis.3 More recently, their reactivity in transition-metal-
mediated reactions was investigated, 1,1-dibromo-1-al-
kenes have been shown to be especially useful substrates
for palladium and copper catalysis since they participate
in a number of coupling reactions, and these procedures
have been used for the formation of a number of com-
pounds.4
Initially, imidazole (1a) and (2,2-dibromovinyl)benzene
(2a) were selected as the model substrates in search of a
better protocol. Under the reported conditions,1d the reac-
tion of imidazole (1a) with (2,2-dibromovinyl)benzene
(2a) and CuI in dioxane gave 1-(phenylethynyl)-1H-im-
idazole 3a13 in 41% yield (Table 1, entry 1); performing
the same reaction at 80 °C provided a 66% yield of the de-
sired product, together with a small amount of homocou-
pling product 4 (Table 1, entry 2). To our delight, with
TMEDA as ligand instead of DMEDA, amination product
3a was isolated in 82% yield, and none of the undesired
byproducts was observed (Table 1, entry 3); however, a
further increase in the reaction temperature from 80 °C to
reflux is detrimental. Under reflux conditions, fast disap-
pearance of the (2,2-dibromovinyl)benzene is accompa-
nied by the formation of the homocoupling product
(Table 1, entry 4,). After screening the amounts of base
and CuI, it was observed that four equivalents of base and
0.05 equivalents of CuI are the best (Table 1, compare en-
tries 5 and 6); other solvents and bases such as DMF or
K3PO4 led to a low yield (Table 1, entries 7–9). CuI exhib-
ited superior catalytical efficiency over all other examined
Cu catalysts (Table 1, entries 10 and 11). Thus, the above-
mentioned reactions with CuI and TMEDA provided to be
the best for the alkynylation of imidazoles to furnish the
desired N-alkynylimidazoles with little or no formation of
the homocoupled bisalkyne byproducts.
N-Alkynylheteroarenes are an interesting variation on
ynamines and share with ynamides the increased stability
engendered by delocalization of the lone pair of electrons
on the nitrogen atom,5 which are functional groups that
possess significant potential in organic chemistry for the
formation of carbon–carbon bonds yet underutilized inter-
mediates in organic synthesis6 and medicinal chemistry.7
The underlying reason is the dearth of mild and general
preparative methods of their formation. Current prepara-
tive methods for the synthesis of N-alkynylheteroarenes
include elimination from haloenamines8 or enol triflates,9
isomerization of propargyl groups,10 and coupling with
alkynyl iodonium salts.11 More recently, a modern variant
for the synthesis of N-alkynylheteroarenes has been de-
veloped, which is based upon transition-metal-mediated
coupling of N-heterocycles with bromoalkynes using con-
ventional heating protocols or microwave-assisted ones.12
However, all these methods suffer from either limited
substrate scope or formation of direct nucleophilic addi-
tion side products.12b,c Therefore, the development of a
general and efficient method for the preparation of N-
alkynylheteroarenes is still highly desirable. Drawing
from recent experiences in the field of copper-catalyzed
The scope of the copper-catalyzed alkynylation was ex-
amined by reacting 1a with a variety of 1,1-dibromo-1-
alkenes. As shown in Table 2, under the optimized condi-
tions (5 mol% of CuI, 10 mol% N,N,N¢,N¢-tetramethyleth-
ylenediamine) the alkynylation of imidazole 1a with 2
appeared to be quite general with respect to the substitu-
ents. Thus, 1,1-dibromoalkenes bearing electron-donating
and electron-withdrawing groups were smoothly aminat-
ed to give N-alkynylimidazoles 3a–g in moderate to good
yields. Electron-deficient substrates gave better yields.
Aromatic halides are tolerated, and no amination was ob-
served, so that this offers additional opportunity for fur-
SYNLETT 2012, 23, 589–594
x
x
.
x
x
.
2
0
1
2
Advanced online publication: 08.02.2012
DOI: 10.1055/s-0031-1290340; Art ID: W63411ST
© Georg Thieme Verlag Stuttgart · New York

590
M.-G. Wang et al.
LETTER
Table 1 Optimization of the Copper-Catalyzed N-Alkynylation of Imidazole with (2,2-Dibromovinyl)benzenea
Br
[Cu]
Ph
N
N
NH
N
Ph +
Ph
+
Ph
Br
1a
2a
3a
4
Entry
1
Catalyst (mol%) Ligandb
Base (equiv)
Cs2CO3 (4)
Cs2CO3 (4)
Cs2CO3 (4)
Cs2CO3 (4)
Cs2CO3 (4)
Cs2CO3 (2)
Cs2CO3 (4)
Cs2CO3 (4)
K3PO4 (4)
Solvent
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
DMF
Temp (°C)
Yield of 3a (%)c Yield of 4 (%)c
CuI (5)
CuI (5)
CuI (5)
CuI (5)
CuI (10)
CuI (5)
CuI (5)
CuI (5)
CuI (5)
CuO (5)
CuCl (5)
DMEDA
DMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
60
41
66
82
67
77
29
50
27
73
trace
19
0
3
2
80
3
80
0
4
102 (reflux)
14
2
5
80
80
80
80
80
80
80
6d
7
3
12
0
8
toluene
dioxane
dioxane
dioxane
9
4
10
11
Cs2CO3 (4)
Cs2CO3 (4)
9
23
a Reactions were carried out using imidazole (1 mmol), (2,2-dibromovinyl)benzene (1.5 mmol), and ligand (0.1 mmol) in solvent (2 mL) for
24 h under N2.
b TMEDA = N,N,N′,N′-tetramethylethylenediamine; DMEDA = N,N′-dimethylethanediamine.
c Yields of isolated products after chromatographic purification.
d Reaction run at 80 °C for 48 h.
ther functionalization. It is worth noting that the olefins ever, that vinyl 1,1-dibromoalkenes such as 1,1-dibromo-
bearing heteroaryl groups can also be smoothly trans- 4-methylpenta-1,3-diene, which are definitely not the best
formed to the desired products in good yields (Table 2, reaction partners in copper-catalyzed cross-coupling reac-
entries 8 and 9). In contrast to the aromatic alkenes, the tions, were not suitable substrates (Table 2, entry 11).
coupling reaction of linear aliphatic olefins provided the
corresponding N-alkynylimidazoles as well but need a
longer reaction time (Table 2, entry 10). We found, how-
Table 2 Copper-Catalyzed Alkynylation of Imidazole with 1,1-Dibromo-1-alkenesa
CuI (5% equiv)
Br
Br
R
TMEDA (10% equiv)
N
N
N
R
NH
+
Cs2CO3 (4 equiv)
1,4-dioxane
1a
2
3
Entry
1
R
Product
Yield (%)b
Ph
2a
N
N
3a 82
4-MeC6H4
2b
N
N
2
3
3b 78
3c 80
4-ClC6H4
2c
N
N
Cl
Br
3-BrC6H4
4
5
3d 76
3e 81
N
N
2d
4-NCC6H4
2e
N
N
CN
Synlett 2012, 23, 589–594
© Thieme Stuttgart · New York

LETTER
Synthesis of N-Alkynylimidazoles
591
Table 2 Copper-Catalyzed Alkynylation of Imidazole with 1,1-Dibromo-1-alkenesa (continued)
CuI (5% equiv)
Br
Br
R
TMEDA (10% equiv)
N
N
N
R
NH
+
Cs2CO3 (4 equiv)
1,4-dioxane
1a
2
3
Entry
6
R
Product
Yield (%)b
4-OMeC6H4
2f
N
N
3f 65
3g 84
OMe
F
4-FC6H4
2g
N
N
7
2-furyl
2i
O
S
8c
3h 79
N
N
2-thienyl
2j
N
N
9
3i 83
3j 45
n-C11H23
2k
10d
N
N
n-C11H23
11d
n.r.e
2l
a Conditions: 1a (1.0 mmol) and 2 (1.5 mmol) at 80 °C for 24 h, under N2.
b Yields of isolated products after chromatographic purification.
c Reaction run at 60 °C.
d Reaction run at 80 °C for 48 h.
e No reaction.
The coupling of imidazoles bearing different substituents er general and allowed for the synthesis of a wide range of
with various 1,1-dibromo-1-alkenes 2 was investigated N-alkynylimidazoles possessing ethyl, propyl, isopropyl,
next under the optimized reaction conditions (Table 3). In and benzo[d] substituting groups. In the case of 4-meth-
general, the substituted imidazoles could be successfully ylimidazole (Table 3, entry 20), coupling with 2a gave a
used in this copper-mediated cross-coupling reaction to 7:1 mixture of regioisomeric N-alkynylimidazoles 5ta
give the desired products in moderate to good yields. For and 5tb. The regiochemistry of the major isomer 5ta was
example, when 2-methylimidazole was used, good yields established as 1,4 by NMR spectroscopy.
of the N-alkynylheteroarenes derived from the coupling of
the 1,1-dibromoalkenes 2a,b,d were observed (Table 3,
entries 6–8). The reaction was, however, found to be rath-
Table 3 Copper-Catalyzed Alkynylation of Imidazole and Benzimidazole with 1,1-Dibromo-1-alkenesa
CuI (5% equiv)
R2
N
N
N
Br
Br
TMEDA (10% equiv)
R1
R1
+
Cs2CO3 (4 equiv)
dioxane, 80 °C
N
H
1
2
5
R2
Entry
1
1
R2
Product
Yield (%)b
N
N
NH
N
Ph
2a
5a 79
1b
1b
N
N
4-MeC6H4
2b
2
5b 70
© Thieme Stuttgart · New York
Synlett 2012, 23, 589–594

592
M.-G. Wang et al.
LETTER
Table 3 Copper-Catalyzed Alkynylation of Imidazole and Benzimidazole with 1,1-Dibromo-1-alkenesa (continued)
CuI (5% equiv)
R2
N
N
N
Br
Br
TMEDA (10% equiv)
R1
R1
+
Cs2CO3 (4 equiv)
dioxane, 80 °C
N
H
1
2
5
R2
Entry
3
1
R2
Product
Yield (%)b
N
N
Cl
4-ClC6H4
2c
1b
1b
5c 81
N
N
N
N
3-BrC6H4
2d
4
5
6
5d 72
5e 82
5f 67
Br
CN
4-NCC6H4
2e
1b
Ph
2a
N
N
N
NH
1c
1c
4-MeC6H4
2b
7
8
5g 66
5h 71
N
N
Br
3-BrC6H4
2d
1c
N
N
N
N
NH
Ph
N
9
5i 68
2a
1d
1d
N
4-ClC6H4
2c
N
Cl
10
11
5j 80
4-MeC6H4
2b
5k 76
N
1e
1e
N
N
NH
4-ClC6H4
2c
12
13
5l 70
5m 81
N
N
Cl
Br
3-BrC6H4
2d
1e
N
N
Synlett 2012, 23, 589–594
© Thieme Stuttgart · New York

LETTER
Synthesis of N-Alkynylimidazoles
593
Table 3 Copper-Catalyzed Alkynylation of Imidazole and Benzimidazole with 1,1-Dibromo-1-alkenesa (continued)
CuI (5% equiv)
R2
N
N
N
Br
Br
TMEDA (10% equiv)
R1
R1
+
Cs2CO3 (4 equiv)
dioxane, 80 °C
N
H
1
2
5
R2
Entry
14
1
R2
Product
Yield (%)b
4-F3CC6H4
2h
1e
5n 69
5o 55
N
N
CF3
4-ClC6H4
2c
15
N
1f
1f
N
N
NH
Cl
Br
3-BrC6H4
2d
16
17
5p 78
5q 60
N
N
4-F3CC6H4
2h
1f
N
N
CF3
3-BrC6H4
2d
Br
18
19
5r 77
5s 58
N
N
N
NH
1g
4-F3CC6H4
2h
1g
N
N
CF3
5t 71c
N
Ph
2a
N
NH
20
(5ta/
N
5tb = 7:1)d
1h
1b
N
N
n-C11H23
n-C11H23
2k
21e
5u 39
a Conditions: 1 (1.0 mmol) and 2 (1.5 mmol) at 80 °C for 24 h, under N2.
b Yields of isolated products after chromatographic purification.
c GC yield.
d The ratio of the isomeric products was determined by GC.
e Reaction run at 80 °C for 48 h.
In summary, a copper-mediated synthesis of N-alky- bromo-1-alkenes. Further studies in this area are being
nylimidazoles has been described. This reaction has been conducted in our laboratory.
shown to be general and provides a straightforward entry
to N-alkynylheteroarenes from readily available 1,1-di-
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
© Thieme Stuttgart · New York
Synlett 2012, 23, 589–594

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M.-G. Wang et al.
LETTER
Heterocycles 2004, 63, 1455. (e) Mulder, J. A.; Kurtz,
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Acknowledgment
The project was supported by the National Natural Science Found-
ation of China (grant No. 31071720).
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References and Notes
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(13) Typical Procedure for the Synthesis of N-Alkynyl-
imidazole
A vessel with a magnetic stir bar was charged with imidazole
(1a, 68 mg, 1 mmol), CuI (10 mg, 0.05 mmol), Cs2CO3 (1.3
g, 4 mmol), and TMEDA (12 mg, 0.1 mmol) under a
nitrogen atmosphere. The reaction vessel was evacuated and
backfilled with nitrogen three times. In a separate flask, a
solution of dry dioxane (2 mL) containing the (2,2-dibromo-
vinyl)benzene (2a, 1.5 mmol) was evacuated and back-filled
with nitrogen gas three times. The dioxane solution was then
added to the reaction flask with a syringe, and the reaction
mixture was heated to 80 °C for 24 h. The reaction mixture
was cooled to r.t., quenched with a sat. NH4Cl solution (5
mL), and extracted with EtOAc (3 × 20 mL). The combined
organic phases were dried over anhyd Na2SO4, filtered, and
concentrated. The residue was purified by flash column
chromatography with EtOAc and PE (1:4) as eluent to afford
the 1-(phenylethynyl)-1H-imidazole (3a) as a yellow oil;
yield 82%. 1H NMR (500 MHz, CDCl3): d = 7.82 (s, 1 H),
7.61–7.45 (m, 2 H), 7.42–7.32 (m, 3 H), 7.20 (d, J = 1.1 Hz,
1 H), 7.09 (s, 1 H). 13C NMR (125 MHz, CDCl3): d = 140.2,
131.9, 129.4, 129.2, 128.7, 121.9, 78.2, 70.6. ESI-MS: m/z =
169.1 [M + H]+.
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Synlett 2012, 23, 589–594
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Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
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However, users may print, download, or email articles for individual use.