Phosphine-free palladium-catalysed direct 5-arylation of imidazole derivatives at low catalyst loading

Article abstract of DOI:10.1016/j.tet.2009.09.084

The regioselective 5-arylation of imidazole derivatives with aryl bromides using a low loading of a phosphine-free palladium catalyst gives a simple and economic access to the corresponding 5-arylimidazoles. The choice of the base and of the solvent was f

Full text of DOI:10.1016/j.tet.2009.09.084

Tetrahedron 65 (2009) 9772–9781
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Phosphine-free palladium-catalysed direct 5-arylation of imidazole
derivatives at low catalyst loading
*
Julien Roger, Henri Doucet
Institut Sciences Chimiques de Rennes, UMR 6226 CNRS-Universite´ de Rennes 1, ‘Catalyse et Organometalliques’, Campus de Beaulieu, 35042 Rennes, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The regioselective 5-arylation of imidazole derivatives with aryl bromides using a low loading of
a phosphine-free palladium catalyst gives a simple and economic access to the corresponding 5-ar-
ylimidazoles. The choice of the base and of the solvent was found to be crucial to form these products in
high yields. Using KOAc as the base, DMAc as the solvent and only 0.5–0.01 mol % Pd(OAc)2 as the cat-
alyst, the target products were obtained in moderate to good yields with a wide variety of aryl bromides.
Substituents such as fluoro, trifluoromethyl, formyl, acetyl, propionyl, ester or nitrile on the aryl bromide
are tolerated. Sterically congested aryl bromides or heteroaryl bromides can also be employed. The
nature of the substituents on the imidazole derivative has an important influence on the yields.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 28 July 2009
Received in revised form
16 September 2009
Accepted 18 September 2009
Available online 22 September 2009
1. Introduction
first example of direct 5-arylation of imidazoles was reported by
Ohta and co-workers in 1992.12 The arylation of 1-methylimidazole
5-Arylimidazoles are important building blocks in organic syn-
thesis due to their biological properties. Suzuki, Stille or Negishi
palladium-catalysed cross-coupling reactions are among the most
efficient methods to prepare such compounds.1 However, they re-
quire the preliminary preparation of a requisite organometallic.
Ohta and co-workers reported in 1990 that the direct 2- or 5-ary-
lation of several heteroaromatics with aryl halides via a C–H bond
activation proceed in moderate to good yields using Pd(PPh3)4 as
the catalyst.2 Since these exciting results, the palladium-catalysed
direct arylation of heteroaryl derivatives with aryl halides or tri-
flates has proved to be a very powerful method for the synthesis of
a wide variety of arylated heterocycles.3–10 This reaction provides
a cost-effective and environmentally attractive access for the
preparation of such compounds. Indeed, the major by-products of
the reaction are a base associated to HX, instead of metallic salts
produced under more classical cross-coupling procedures such as
Suzuki, Negishi or Stille reactions. Moreover, the method avoids the
preliminary preparation of an organometallic derivative, reducing
then the number of steps to prepare these compounds. However, so
far, most of the results have been described using thiophenes,5
furans,7 thiazoles8 or oxazole9 derivatives. Several methods for the
2-arylation of imidazoles have also been reported.11 On the other
hand, the 5-arylation of imidazoles has attracted less attention and
led in several cases to poor yields and to mixtures of products. The
or 1,2-dimethylimidazole with three chloropyrazines using 5 mol %
Pd(PPh3)4 as the catalyst gave the 5-arylation products in 40–83%
yields. Since these results, four other groups have reported the
direct 5-arylation of imidazoles using 5–10 mol % Pd(OAc)2 associ-
ated to 10–20 mol % of phosphine or arsine ligands as the catalytic
systems.13 A SEM-protected 2-phenylimidazole has also been ary-
lated on C5 using iodobenzene as reactant and 2.5 mol % of palla-
dium complexes containing imidazolyl carbene ligands as the
catalysts. The coupling product was obtained in 54% yield.14 Very
recently, Fagnou and co-workers described the 5-arylation of
1-methylimidazole or 1,2-dimethylimidazole using 2 mol % of
Pd(OAc)2 associated with 4 mol % PCy3 as the catalytic system.
Using this relatively low catalyst loading, the 5-arylation products
were obtained in only 32–40% yields.15 Finally, a few examples of
direct 5-arylations of imidazoles via intramolecular cyclisation
have also been described.16
So far, to our knowledge, all the procedures reported for the
5-arylation via C–H bond activation of imidazoles required
2–10 mol % of palladium and 4–20 mol % of ligand.13–15 Therefore,
the discovery of more effective conditions, for the direct coupling of
imidazole derivatives with aryl halides under lower catalyst loading
conditions, would be a considerable advantage for industrial ap-
plications and for sustainable development. Moreover, the scope of
the reaction needs to be largely extended to a wider variety of aryl
halides and imidazoles. Here, we wish to report on the reaction of
a set of electronically and sterically diverse aryl bromides using
mono- or disubstituted imidazoles at low catalyst loadings using
a ligand-free palladium catalyst.
* Corresponding author. Tel.: þ33 2 23 23 63 84; fax: þ33 2 23 23 69 39.
E-mail address: henri.doucet@univ-rennes1.fr (H. Doucet).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.09.084

J. Roger, H. Doucet / Tetrahedron 65 (2009) 9772–9781
9773
Recently, Heck and Suzuki reactions under low catalyst loading
(0.1–0.01 mol %) using ligand-free catalyst Pd(OAc)2 have been
described by de Vries and co-workers.17 They have demonstrated
that, at elevated temperature, when Pd(OAc)2 is employed as cat-
alyst precursor, soluble palladium(0) colloids or nanoparticles are
formed, and that these reactions take place via the interaction of
the arylating agent with the palladium atoms in the outer rim of the
nanoparticles. This leads to the formation of monomeric or dimeric
anionic palladium complexes that undergo the usual steps of the
Heck or Suzuki mechanisms.
We have already reported the direct 5-arylation of a range of
thiazole, furans, pyrroles or thiophene derivatives using a phos-
phine-free palladium catalyst.18 Here, we wish to report on the
reaction of a set of imidazoles using a very wide variety of elec-
tronically and sterically diverse aryl or heteroaryl bromides at low
catalyst loadings using such phosphine-free palladium catalyst.
product 1; whereas, NaOAc and KOAc led to 1 in 12% and 44% yields,
respectively (Table 1, entries 1, 7–11).
Then, we examined the influence of the palladium source using
0.01 mol % catalyst. PdCl2 and [PdCl(C3H5)]2 led to lower conver-
sions of 3-bromopyridine and lower yield of 1 than Pd(OAc)2 (Table
1, entries 1, 12 and 17). For this reaction, the presence of bidentate
phosphine ligands such as dppe or dppb did not allowed to increase
the yields of 1 (Table 1, entries 13–16, 18 and 19). In order to obtain
a high isolated yield of 1, we also optimised the substrate/catalyst
ratio of the reaction. In the presence of 0.1 mol % catalyst, 1 was
obtained in 90% isolated yield (Table 1, entry 22).
Then, using the most efficient reaction condition (DMAc, KOAc,
Pd(OAc)2, 150 ꢀC), we explored the scope and limitations of this
reaction using para-, meta- and ortho-substituted aryl bromides
and also some heteroaryl bromides employing 1,2-dimethylimid-
azole as coupling partner (Scheme 2, Tables 2–5).
N
N
R
2. Results and discussion
Pd(OAc)2
Br
+
N
N
DMAc, base,
150 °C, 17 h
For this study, based on previous results,18 DMAc was initially
chosen as the solvent and KOAc as the base. The reactions were
performed at 150 ꢀC under argon in the presence 0.01 mol %
Pd(OAc)2 as the catalyst. Using these conditions, the coupling of 3-
bromopyridine with 1,2-dimethylimidazole gave 1 in a moderate
44% yield (Table 1, entry 1). First, we examined the influence of the
solvent for this reaction (Scheme 1, Table 1, entries 1–5). No con-
R
1-30
Scheme 2.
First, we have investigated the reaction of 1,2-dimethylimida-
zole with several para-substituted aryl bromides (Scheme 2, Table
2). In most cases, the reaction proceeds very smoothly in the
presence of 0.1–0.5 mol % Pd(OAc)2 as the catalyst. We observed
that yields of 73–81% can be obtained for activated substrates such
as 4-bromopropiophenone, 4-bromobenzaldehyde, 4-bromo-
benzonitrile or 4-trifluoromethylbromobenzene (Table 2, entries
1–11). We also obtained satisfactory results using 4-fluoro-
bromobenzene (Table 1, entries 13 and 14).
N
N
[Pd]
Br
+
N
N
solvent, base
N
N
1
Scheme 1.
version of 3-bromopyridine was observed in toluene or dioxane,
when using 0.01 mol % catalyst (Table 1, entries 3 and 4). On the
other hand, the use of NMP or DMF led to partial conversion of this
aryl bromide, but did not allow to improve the yield of the reaction
(Table 1, entries 2 and 5). A very important effect of the nature of
the base was also observed. Carbonates, KF or tBuOK gave no target
On the other hand, with 4-t-butylbromobenzene or 4-bromo-
N,N-dimethylaniline, moderate yields of 11 and 13 were obtained
using KOAc as the base (Table 2, entries 19 and 23). Surprisingly,
with these deactivated aryl bromides, good yields were obtained
using K2CO3 as the base and 0.5 mol % catalyst (Table 2, entries 20
and 24). These results reveal that, as expected, the stability of this
Table 1
Influence of the reaction conditions for palladium catalysed arylation of 1,2-dimethylimidazole with 3-bromopyridine (Scheme 1)
Entry
Catalyst
Base
Solvent
Temperature (ꢀC)
Substrate/catalyst ratio
Conversion of 3-bromopyridine (%)
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
Pd(OAc)2/2 PPh3
Pd(OAc)2/dppb
Pd(OAc)2/dppe
KOAc
KOAc
KOAc
KOAc
KOAc
NaOAc
Na2CO3
K2CO3
Cs2CO3
KF
tBuOK
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
DMAc
NMP
toluene
dioxane
DMF
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
130
150
150
150
10,000
10,000
10,000
10,000
10,000
10,000
10,000
10,000
10,000
10,000
10,000
10,000
10,000
10,000
10,000
10,000
10,000
10,000
10,000
10,000
2000
53 (44)
28
0
0
32
17 (12)
0
0
0
0
0
33
10
37
49
7
16
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Pd(OAc)2/dppm
1
⁄
[PdCl(C3H5)]2
[PdCl(C3H5)]2/dppb
[PdCl(C3H5)]2/dppe
2
1
⁄
45
28
2
86 (78)
97 (90)
100
2
1
⁄
2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
1000
200
Conditions: [Pd], 3-bromopyridine (1 equiv), 1,2-dimethylimidazole (2 equiv), base (2 equiv), 17 h, GC and NMR conversion of 3-bromopyridine, yields in parenthesis are
isolated.

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J. Roger, H. Doucet / Tetrahedron 65 (2009) 9772–9781
Table 2
Palladium catalysed reaction of 1,2-dimethylimidazole with para-substituted aryl bromides (Scheme 2)
Entry
Aryl bromide
Product
Base
Substrate/cat. ratio
Yield (%)
N
1
2
KOAc
KOAc
200
1000
79
65
Br
N
O
O
2
N
3
4
KOAc
KOAc
200
1000
78
62
Br
N
O
O
3
O
O
N
O
O
5
6
KOAc
KOAc
200
1000
73
44
Br
N
4
N
Br
7
KOAc
1000
77
N
O
O
5
6
N
F3C
8
9
KOAc
KOAc
1000
10,000
80
17
F3C
Br
N
N
N
NC
O2N
F
10
11
KOAc
KOAc
1000
10,000
81a
12
NC
O2N
F
Br
Br
N
N
7
12
KOAc
1000
25
8
N
13
14
KOAc
KOAc
200
1000
75
54
Br
N
9
N
Me
15
16
17
18
KOAc
KOAc
K2CO3
K2CO3
200
1000
200
70
31
78
10
Me
Br
Br
N
10
1000
N
tBu
19
20
KOAc
K2CO3
200
200
50
77
tBu
N
11
12
N
MeO
21
22
KOAc
K2CO3
200
200
50
31
MeO
Br
N
23
24
KOAc
K2CO3
200
200
22
70
N
Me2N
Me2N
Br
N
13
Conditions: Pd(OAc)2, ArBr (1 equiv), 1,2-dimethylimidazole (2 equiv), base (2 equiv), DMAc, 150 ꢀC, 17 h, isolated yields.
a
Traces of homo-coupling of 4-trifluoromethylbromobenzene were also observed.
phosphine-free palladium active species largely depend on the
palladium concentration. However, it also depends on the nature of
the base. In general, when 0.01–0.1 mol % catalyst was employed,
the use of KOAc as the base gave higher conversions of the aryl
bromides than with K2CO3 (Table 1, entries 1 and 8). Under such
low palladium concentration, the aggregation of palladium into
‘palladium black’ seems relatively slow. On the other hand, when
0.5 mol % of catalyst was employed, the use of K2CO3 led in some
cases to similar or higher yields than KOAc for the reactions per-
formed with deactivated aryl bromides. We believe that K2CO3 is
a more suitable base for stabilising palladium species; whereas,
KOAc associated to palladium gives less stable but more active
palladium species.
The influence of the presence of meta-substituents on the aryl
bromide is reported in the Table 3. As expected, relatively similar
yields than in the presence of the para-substituted substrates were
obtained for the reactions performed with 3-bromoacetophenone,
3-bromobenzaldehyde, 3-bromobenzonitrile or 3-trifluoromethyl-
bromobenzene using 0.5 mol % catalyst (Table 3, entries 1–8). With
2-bromonaphthalene, a yield of 77% in 18 was obtained (Table 3,
entries 9 and 10).
Then, we examined the reactivity of 1,2-dimethylimidazole with
a set of ortho-substituted aryl bromides using the same reaction
conditions (Scheme 2, Table 4). ortho-Substituents on the aryl
bromides generally have a more important effect on the reaction
rates of palladium-catalysed reactions due to their steric or

J. Roger, H. Doucet / Tetrahedron 65 (2009) 9772–9781
9775
Table 3
Table 4
Palladium catalysed reaction of 1,2-dimethylimidazole with meta-substituted aryl
Palladium catalysed reaction of 1,2-dimethylimidazole with ortho-substituted aryl
bromides (Scheme 2)
bromides (Scheme 2)
Entry
Aryl bromide
Product
Substrate/
cat. ratio
Yield
(%)
Entry
Aryl bromide
Product
Substrate/
cat. ratio
Yield
(%)
O
O
O
O
N
N
N
N
1
200
38
1
2
200
1000
79
25
N
Br
N
Br
19
20
21
22
N
14
CN
CN
Br
O
2
3
200
1000
74
28
O
N
3
4
200
1000
58
76
N
Br
N
F
15
F
4
200
72
NC
Br
N
NC
N
5
6
1000
200
78
32
Br
N
Me
Me
Br
16
5
6
200
200
65
79a
F3C
N
OMe
N
F3C
N
7
8
1000
200
75
41
Br
N
OMe
Br
17
N
7
8
200
200
0
0a
9
10
1000
200
77
33
23
9
10
200
1000
76
33
N
N
Br
N
18
Br
N
Conditions: Pd(OAc)2, ArBr (1 equiv), 1,2-dimethylimidazole (2 equiv), KOAc
(2 equiv), DMAc, 150 ꢀC, 17 h, isolated yields.
24
Conditions: Pd(OAc)2, ArBr (1 equiv), 1,2-dimethylimidazole (2 equiv), KOAc
(2 equiv), DMAc, 150 ꢀC, 17 h, isolated yields.
a
K2CO3 (2 equiv) was used as the base.
coordination properties. The expected 5-aryl-1,2-dimethylimid-
azoles 19–24 were obtained in moderate to good yields. In some
cases, similar yields than in the presence of the para-substituted
aryl bromides were obtained. For example, we observed that the
coupling of 2-bromobenzonitrile or 2-fluorobromobenzene pro-
ceeds nicely to give 20 and 21 in 74 and 72% yields, respectively
(Table 4, entries 2 and 4).
On the other hand, 2-bromobenzaldehyde gave 19 in a lower
yield of 38%, due to the formation of unidentified side-products
(Table 4, entry 1). 1-Bromonaphthalene gave 24 in 76% yield (Table
4, entries 9 and 10). Even slightly deactivated and congested aryl
bromide, 2-bromotoluene led to the 5-arylated imidazole 22 in
good yield. However, with this substrate, a higher yield was
obtained using K2CO3 as the base (Table 4, entries 5 and 6). In the
presence of this phosphine-free catalyst, congested and deactivated
aryl bromide, 2-bromoanisole was recovered unreacted (Table 4,
entries 7 and 8).
coordination could poison the catalyst. We had previously ob-
served a similar phenomenon with such reactants for Heck
reaction.19
Next, we examined the influence of the nature of the imidazole
substituent on nitrogen (Table 6). Surprisingly, in the presence of
1-decyl-2-methylimidazole or 1-benzyl-2-methylimidazole, low
yields of 31 and 33 were obtained (Table 6, entries 1 and 3). The
reaction of 4-bromoacetophenone with an imidazole substituted
by a propionitrile on nitrogen gave no coupling product (Table 6,
entry 4). On the other hand, a yield of 71% of 32 was obtained when
using 1-isobutyl-2-methylimidazole as coupling partner (Table 6,
entry 2). This difference of reactivity might partially come from the
presence of some impurities in the reactants. In the presence of
1-isobutyl-2-methylimidazole, the formation of
amount of the 4-arylated imidazole was also detected by GC/MS
(Scheme 2).
a moderate
Heteroaryl bromides are also suitable reactants (Table 5). Pyri-
Then, using Bellina and Rossi procedure,11e we prepared
1-methyl-2-(4-trifluoromethylphenyl)-imidazole.Usingthisreactant
and4-bromobenzonitrilewith0.5 mol %Pd(OAc)2, 35 was obtained in
54% yield (Scheme 4). This method should allow the synthesis of
a very wide variety of 2,5-diarylimidazoles in only two steps.
The reactivity of an imidazole substituted on position 2 by
a formyl group was also examined (Scheme 5). Using 4-bromo-
benzonitrile or 4-bromobenzaldehyde, the coupling products 36
and 37 were obtained in 52 and 69% yields, respectively. The
presence of such electron-withdrawing function on the imidazole
ring seems to slow down the arylation rate.
dines or quinolines are
p-electron deficient heterocycles and
therefore, their oxidative addition to palladium is, in general,
relatively easy. Using 3- or 4-bromopyridines, 3-bromoquinoline,
4-bromoisoquinoline or 5-bromopyrimidine and 1,2-dimethylimid-
azole as reactants, 1 and 26–29 were obtained in high yields using
0.1–0.5 mol % catalyst (Table 5, entries 2–10). On the other hand, in
the presence of 2-bromopyridine or 2-bromopyrimidine, the
formation of the expected products 25 and 30 was not detected
(Table 5, entries 1 and 11).
This might be due to some coordination of the nitrogen atoms
of 2-bromopyridine or 2-bromopyrimidine to palladium. Such

9776
J. Roger, H. Doucet / Tetrahedron 65 (2009) 9772–9781
Table 5
N
R3
N
Palladium catalysed reaction of 1,2-dimethylimidazole with heteroaryl bromides
(Scheme 2)
Pd(OAc)2 0.5 mol%
R1
R1
+
Br
N
R2
R3
N
R2
DMAc, KOAc,
150 °C, 17 h
Entry
1
Aryl bromide
Product
Substrate/
cat. ratio
Yield
(%)
31-34
N
N
N
Scheme 3.
200
0
Br
N
N
N
25
1
N
N
N
N
2
1000
90
N
Br
F3C
Br
N
Pd(OAc)2 0.5 mol%
DMAc, KOAc, 150 °C, 17 h
CN
N
+
F3C
N
CN
3
4
200
1000
84a
54a
HCl
N
N
Br
35 54%
26
Scheme 4.
N
5
6
200
1000
85
40
N
N
N
N
Br
27
O
N
N
N
O
Pd(OAc)2 0.5 mol%
7
8
200
1000
87
50
N
DMAc, KOAc, 150 °C, 17 h
+
Br
R
N
N
N
N
28
29
R = CN: 36 52%
R = CHO: 37 69%
Br
R
N
N
N
N
N
N
9
10
200
1000
85
78
Scheme 5.
Br
Br
can be arylated. Bellina, Rossi and co-workers have extensively
studied the arylation of such compounds. They have reported that
using 1-methyl, 1-benzyl or 1-phenylimidazoles, 5 mol % Pd(OAc)2,
10 mol % AsPh3 or P(2-furyl)3, CsF or K2CO3 as the bases and DMF as
the solvent, the 5-arylated imidazoles were obtained in 22–80%
yields.13c–13e Using our procedure, in the presence of 1-methyl-
imidazole and 0.5 mol % Pd(OAc)2, the regioselectivity in favour of
N
N
N
N
11
200
0
N
30
Conditions: Pd(OAc)2, ArBr (1 equiv), 1,2-dimethylimidazole (2 equiv), KOAc
(2 equiv), DMAc, 150 ꢀC, 17 h, isolated yields.
a
KOAc (3 equiv) was used as the base.
Table 6
Palladium catalysed reaction of 1-alkyl-2-methylimidazole with aryl bromides (Scheme 3)
Entry
1
Imidazole derivative
Aryl bromide
Product
Yield (%)
21
N
N
N
Br
Br
N
N
O
O
nDec
nDec
31
32
N
N
NC
N
2
3
71
34
NC
NC
N
N
N
NC
N
N
Br
Br
33
N
N
N
O
4
0
O
NC
NC
34
Conditions: Pd(OAc)2 (0.005 equiv), ArBr (1 equiv), 1-alkyl-2-methylimidazole (2 equiv), KOAc (2 equiv), DMAc, 150 ꢀC, 17 h, isolated yields.
Finally, we explored the direct arylation of 1-methylimidazole
using our low catalyst loading procedure (Scheme 6, Table 7). In the
course of this reaction, both the positions 2 and 5 of this reactant
the 5-arylation was high (Table 7). Moreover, good yields of target
compounds 38, 41 and 42 were obtained using activated aryl
bromides such as 4-bromobenzonitrile, 3-bromopyridine or

J. Roger, H. Doucet / Tetrahedron 65 (2009) 9772–9781
9777
N
3. Experimental
N
Pd(OAc)2
ArBr
+
Ar
DMAc, KOAc, 150 °C, 17 h
N
N
3.1. General remarks
All reactions were run under argon in Schlenk tubes using
vacuum lines. DMAc analytical grade was not distilled before use.
KOAc or K2CO3 (99%) was used. Commercial aryl bromides and
imidazoles were used without purification. The reactions were
followed by GC and NMR. 1H and 13C spectra were recorded with
a Bruker 200 MHz spectrometer in CDCl3 solutions. Chemical shifts
are reported in ppm relative to CDCl3 (7.25 for 1H NMR and 77.0 for
13C NMR). Flash chromatography was performed on silica gel
(230–400 mesh).
38-42
Scheme 6.
Table 7
Palladium catalysed reaction of 1-methylimidazole with aryl bromides (Scheme 6)
Entry
Aryl bromide
Product
Substrate/
cat. ratio
Yield
(%)
N
N
NC
1
2
200
1000
76
47
NC
Br
Br
N
N
38
39
3.2. General procedure
In a typical experiment, the aryl halide (1 mmol), imidazole
derivative (2 mmol), KOAc (0.196 g, 2 mmol) or K2CO3 (0.276 g,
2 mmol) (see tables) and Pd(OAc)2 (see tables), were dissolved in
DMAc (5 mL) under an argon atmosphere. The reaction mixture
was stirred at 150 ꢀC for 17 h. After evaporation of the solvent, the
product was purified by silica gel column chromatography.
Me
3
4
200
200
40
42
Me
N
MeO
MeO
Br
N
40
3.2.1. 5-(3-Pyridyl)-1,2-dimethylimidazole (1)20. From 3-bromopyr-
idine (0.158 g, 1 mmol), 1,2-dimethylimidazole (0.192 g, 2 mmol)
and KOAc (0.196 g, 2 mmol) with Pd(OAc)2 (0.22 mg, 0.001 mmol),
product 1 was obtained in 90% (0.156 g) yield.
N
5
6
200
1000
81
31
Br
Br
N
N
N
N
41
42
1H NMR (200 MHz, CDCl3)
d
8.50 (s, 1H), 8.48 (d, J¼4.8 Hz, 1H),
N
N
7.62 (d, J¼7.8 Hz, 1H), 7.34 (dd, J¼4.8, 7.8 Hz, 1H), 6.97 (s, 1H), 3.48
N
N
N
(s, 3H), 2.42 (s, 3H).
7
200
67
3.2.2. 5-(4-Acetylphenyl)-1,2-dimethylimidazole (2). From 4-bro-
moacetophenone (0.199 g, 1 mmol), 1,2-dimethylimidazole
(0.192 g, 2 mmol) and KOAc (0.196 g, 2 mmol) with Pd(OAc)2
(1.1 mg, 0.005 mmol), product 2 was obtained in 79% (0.169 g)
yield.
Conditions: Pd(OAc)2, ArBr (1 equiv), 1-methylimidazole (2 equiv), KOAc (2 equiv),
DMAc, 150 ꢀC, 17 h, isolated yields.
5-bromopyrimidine. On the other hand, in the presence of the
deactivated aryl bromides, 4-bromotoluene or 4-bromoanisole, 39
and 40 were obtained in moderate yields (Table 7, entries 3 and 4).
Fagnou and co-workers had also obtain a low yield of 40 using
2 mol % of Pd(OAc)2 associated with 4 mol % PCy3 as the catalyst.16
Therefore, the procedures described by Bellina and Rossi should be
preferred for the reactions in the presence of such challenging
substrates.13c–13e
1H NMR (200 MHz, CDCl3)
(d, J¼8.4 Hz, 2H), 6.96 (s, 1H), 3.50 (s, 3H), 2.52 (s, 3H), 2.37 (s, 3H);
13C NMR (50 MHz, CDCl3)
197.1, 146.9, 135.5, 134.7, 132.3, 128.5,
d
7.91 (d, J¼8.4 Hz, 2H), 7.37
d
127.7, 126.6, 31.4, 26.3, 13.3; C13H14N2O: calcd C 72.87, H 6.59; found
C 73.00, H 6.55.
3.2.3. 5-(4-Propionylphenyl)-1,2-dimethylimidazole
(3). From
In summary, we report here a simple and atom-economical
method for the synthesis of 5-arylimidazoles. We have established
that, using appropriate reaction conditions, ligand-free Pd(OAc)2
provides an efficient catalyst for the direct coupling of aryl bro-
mides with some imidazole derivatives. The reaction is highly
regioselective, as in most cases, only the 5-arylated imidazoles
were formed. In the presence of 1,2-dimethylimidazole as coupling
partner, a wide range of functions such as fluoro, acetyl, formyl,
benzoyl, carboxylate or nitrile on the aryl bromide are tolerated.
Some sterically hindered aryl bromides and several heteroaromatic
substrates such as bromopyridines have also been employed suc-
cessfully. The substituents on imidazole have a very important in-
fluence on the reaction rates and yields. It should be noted that,
despite their interest, most of the products prepared by this
method are new, indicating a relatively limited access to such
compounds using more traditional cross-coupling procedures. This
procedure employs a relatively low loading (0.5–0.01 mol %) of
a commercially available, phosphine-free and air stable palladium
source. Therefore, there is no need to eliminate phosphine de-
rivatives at the end of the reaction. Moreover, a very wide variety of
aryl bromides are commercially available. These are practical ad-
vantages of this reaction.
4-bromopropiophenone (0.213 g, 1 mmol), 1,2-dimethylimidazole
(0.192 g, 2 mmol) and KOAc (0.196 g, 2 mmol) with Pd(OAc)2
(1.1 mg, 0.005 mmol), product 3 was obtained in 78% (0.178 g) yield.
1H NMR (200 MHz, CDCl3)
d
7.90 (d, J¼8.4 Hz, 2H), 7.35 (d,
J¼8.4 Hz, 2H), 6.92 (s, 1H), 3.47 (s, 3H), 2.89 (q, J¼7.7 Hz, 2H), 2.34
(s, 3H), 1.10 (t, J¼7.7 Hz, 3H); 13C NMR (50 MHz, CDCl3)
d 199.7,
146.6, 135.2, 134.3, 132.2, 128.1, 127.6, 126.1, 31.4, 31.3, 13.1, 7.8;
C14H16N2O: calcd C 73.66, H 7.06; found C 73.45, H 7.15.
3.2.4. Methyl 4-(2,3-dimethylimidazol-4-yl)-benzoate (4). From
methyl 4-bromobenzoate (0.215 g, 1 mmol), 1,2-dimethylimidazole
(0.192 g, 2 mmol) and KOAc (0.196 g, 2 mmol) with Pd(OAc)2
(1.1 mg, 0.005 mmol), product 4 was obtained in 73% (0.168 g)
yield.
1H NMR (200 MHz, CDCl3)
(d, J¼8.4 Hz, 2H), 7.13 (s, 1H), 3.94 (s, 3H), 3.59 (s, 3H), 2.56 (s, 3H);
13C NMR (50 MHz, CDCl3)
166.5, 146.7, 133.8, 131.3, 130.0, 129.6,
d
8.10 (d, J¼8.4 Hz, 2H), 7.44
d
128.2, 124.5, 52.2, 31.6, 12.9; C13H14N2O2: calcd C 67.81, H 6.13;
found C 67.68, H 6.40.
3.2.5. 5-(4-Formylphenyl)-1,2-dimethylimidazole (5). From 4-bro-
mobenzaldehyde (0.185 g,1 mmol),1,2-dimethylimidazole (0.192 g,

9778
J. Roger, H. Doucet / Tetrahedron 65 (2009) 9772–9781
2 mmol) and KOAc (0.196 g, 2 mmol) with Pd(OAc)2 (0.22 mg,
3.2.12. 5-(4-Methoxyphenyl)-1,2-dimethylimidazole (12)15. From 4-
bromoanisole (0.187 g, 1 mmol), 1,2-dimethylimidazole (0.192 g,
2 mmol) and KOAc (0.196 g, 2 mmol) with Pd(OAc)2 (1.1 mg,
0.005 mmol), product 12 was obtained in 50% (0.101 g) yield.
0.001 mmol), product 5 was obtained in 77% (0.154 g) yield.
1H NMR (200 MHz, CDCl3)
d
9.94 (s, 1H), 7.85 (d, J¼8.4 Hz, 2H),
7.46 (d, J¼8.4 Hz, 2H), 7.02 (s, 1H), 3.54 (s, 3H), 2.40 (s, 3H); 13C NMR
(50 MHz, CDCl3)
d
191.0, 146.9, 135.7, 134.4, 131.8, 129.6, 127.6, 126.7,
1H NMR (200 MHz, CDCl3)
d
7.25 (d, J¼8.4 Hz, 2H), 6.94 (d,
31.2, 13.1; C12H12N2O: calcd C 71.98, H 6.04; found C 72.07, H 6.13.
J¼8.4 Hz, 2H), 6.87 (s, 1H), 3.81 (s, 3H), 3.47 (s, 3H), 2.43 (s, 3H).
3.2.6. 5-(4-Trifluoromethylphenyl)-1,2-dimethylimidazole (6). From
4-trifluoromethylbromobenzene (0.225 g, 1 mmol), 1,2-dimethyl-
imidazole (0.192 g, 2 mmol) and KOAc (0.196 g, 2 mmol) with
Pd(OAc)2 (0.22 mg, 0.001 mmol), product 6 was obtained in 80%
(0.192 g) yield.
3.2.13. 5-(4-Dimethylaminophenyl)-1,2-dimethylimidazole
(13). From 4-bromo-N,N-dimethylaniline (0.200 g, 1 mmol), 1,2-
dimethylimidazole (0.192 g, 2 mmol) and K2CO3 (0.276 g, 2 mmol)
with Pd(OAc)2 (1.1 mg, 0.005 mmol), product 13 was obtained in
70% (0.151 g) yield.
1H NMR (200 MHz, CDCl3)
d
7.64 (d, J¼8.4 Hz, 2H), 7.44 (d,
1H NMR (200 MHz, CDCl3)
d
7.25 (d, J¼8.2 Hz, 2H), 6.84 (s, 1H),
J¼8.4 Hz, 2H), 7.00 (s, 1H), 3.53 (s, 3H), 2.43 (s, 3H); 13C NMR
6.78 (d, J¼8.2 Hz, 2H), 3.47 (s, 3H), 2.95 (s, 6H), 2.41 (s, 3H); 13C NMR
(50 MHz, CDCl3)
d
146.7, 133.8, 132.0, 129.3 (q, J¼32.5 Hz), 128.2,
(50 MHz, CDCl3) d 149.7, 144.6, 133.7, 129.4, 123.9, 117.7, 112.0, 40.1,
126.2, 125.5 (q, J¼3.8 Hz), 124.0 (q, J¼272.0 Hz), 31.2, 13.2;
30.8, 13.3; C13H17N3: calcd C 72.52, H 7.96; found C 72.52, H 7.87.
C12H11F3N2: calcd C 60.00, H 4.62; found C 59.97, H 4.54.
3.2.14. 5-(3-Acetylphenyl)-1,2-dimethylimidazole (14). From 3-bro-
moacetophenone (0.199 g,1 mmol),1,2-dimethylimidazole (0.192 g,
2 mmol) and KOAc (0.196 g, 2 mmol) with Pd(OAc)2 (1.1 mg,
0.005 mmol), product 14 was obtained in 79% (0.169 g) yield.
3.2.7. 4-(2,3-Dimethylimidazol-4-yl)-benzonitrile (7). From 4-bro-
mobenzonitrile (0.182 g, 1 mmol), 1,2-dimethylimidazole (0.192 g,
2 mmol) and KOAc (0.196 g, 2 mmol) with Pd(OAc)2 (0.22 mg,
0.001 mmol), product 7 was obtained in 81% (0.160 g) yield.
1H NMR (200 MHz, CDCl3)
d
7.85–7.80 (m, 2H), 7.45–7.40
(m, 2H), 6.89 (s, 1H), 3.45 (s, 3H), 2.51 (s, 3H), 2.36 (s, 3H); 13C NMR
(50 MHz, CDCl3) 197.1,145.8,136.9,132.3, 132.0, 130.2, 128.5, 127.4,
1H NMR (200 MHz, CDCl3)
d
7.61 (d, J¼8.4 Hz, 2H), 7.39
(d, J¼8.4 Hz, 2H), 6.98 (s, 1H), 3.51 (s, 3H), 2.37 (s, 3H); 13C NMR
d
(50 MHz, CDCl3)
d
147.0, 134.3, 131.9, 131.2, 127.7, 126.7, 118.0, 110.1,
127.0,125.0, 30.9, 26.1,12.8; C13H14N2O: calcd C 72.87, H 6.59; found
C 73.02, H 6.50.
31.1, 13.0; C12H11N3: calcd C 73.07, H 5.62; found C 73.14, H 5.44.
3.2.8. 5-(4-Nitrophenyl)-1,2-dimethylimidazole (8). From 4-bromo-
nitrobenzene (0.202 g, 1 mmol), 1,2-dimethylimidazole (0.192 g,
2 mmol) and KOAc (0.196 g, 2 mmol) with Pd(OAc)2 (0.22 mg,
0.001 mmol), product 8 was obtained in 25% (0.054 g) yield.
3.2.15. 5-(3-Formylphenyl)-1,2-dimethylimidazole
(15). From
3-bromobenzaldehyde (0.185 g, 1 mmol), 1,2-dimethylimidazole
(0.192 g, 2 mmol) and KOAc(0.196 g, 2 mmol) with Pd(OAc)2 (1.1 mg,
0.005 mmol), product 15 was obtained in 76% (0.152 g) yield.
1H NMR (200 MHz, CDCl3)
d
8.27 (d, J¼8.4 Hz, 2H), 7.53
1H NMR (200 MHz, CDCl3)
d
9.89 (s, 1H), 7.80–7.65 (m, 2H), 7.55–
7.45 (m, 2H), 6.87 (s,1H), 3.43 (s, 3H), 2.32 (s, 3H); 13C NMR (50 MHz,
CDCl3) 191.5, 146.2, 136.3, 133.7, 131.7, 131.0, 129.1, 128.6, 128.5, 125.7,
(d, J¼8.4 Hz, 2H), 7.12 (s, 1H), 3.62 (s, 3H), 2.48 (s, 3H); 13C NMR
(50 MHz, CDCl3)
d
148.0, 146.6, 136.9, 131.5, 128.3, 128.1, 124.1, 31.7,
d
13.7; C11H11N3O2: calcd C 60.82, H 5.10; found C 61.02, H 5.01.
31.1, 13.1; C12H12N2O: calcd C 71.98, H 6.04; found C 72.17, H 6.12.
3.2.9. 5-(4-Fluorophenyl)-1,2-dimethylimidazole (9). From 4-bro-
mofluorobenzene (0.175 g, 1 mmol), 1,2-dimethylimidazole
(0.192 g, 2 mmol) and KOAc (0.196 g, 2 mmol) with Pd(OAc)2
(1.1 mg, 0.005 mmol), product 9 was obtained in 75% (0.143 g)
yield.
3.2.16. 3-(2,3-Dimethylimidazol-4-yl)-benzonitrile (16). From
3-bromobenzonitrile (0.182 g, 1 mmol), 1,2-dimethylimidazole
(0.192 g, 2 mmol) and KOAc(0.196 g, 2 mmol) with Pd(OAc)2 (1.1 mg,
0.005 mmol), product 16 was obtained in 78% (0.154 g) yield.
1H NMR (200 MHz, CDCl3)
(s, 3H), 2.40 (s, 3H); 13C NMR (50 MHz, CDCl3)
d
d
7.40–7.20 (m, 4H), 6.94 (s, 1H), 3.49
146.8, 132.3, 131.5,
1H NMR (200 MHz, CDCl3)
d
7.31 (dd, J¼8.4, 5.5 Hz, 2H), 7.12
(t, J¼8.4 Hz, 2H), 6.93 (s, 1H), 3.50 (s, 3H), 2.47 (s, 3H); 13C NMR
131.2, 131.0, 130.7, 129.4, 126.5, 118.1, 112.7, 31.2, 13.3; C12H11N3:
calcd C 73.07, H 5.62; found C 73.18, H 5.42.
(50 MHz, CDCl3)
d
162.4 (d, J¼248 Hz), 145.7, 132.5, 130.5 (d,
J¼8.2 Hz), 126.3, 125.0, 115.7 (d, J¼21.6 Hz), 31.1, 13.4; C11H11FN2:
calcd C 69.46, H 5.83; found C 69.44, H 5.74.
3.2.17. 5-(3-Trifluoromethylphenyl)-1,2-dimethylimidazole
(17). From 3-trifluoromethylbromobenzene (0.225 g, 1 mmol), 1,2-
dimethylimidazole (0.192 g, 2 mmol) and KOAc (0.196 g, 2 mmol)
with Pd(OAc)2 (1.1 mg, 0.005 mmol), product 17 was obtained in
75% (0.180 g) yield.
3.2.10. 5-(4-Tolyl)-1,2-dimethylimidazole (10). From 4-bromoto-
luene (0.171 g, 1 mmol), 1,2-dimethylimidazole (0.192 g, 2 mmol)
and K2CO3 (0.276 g, 2 mmol) with Pd(OAc)2 (1.1 mg, 0.005 mmol),
product 10 was obtained in 78% (0.145 g) yield.
1H NMR (200 MHz, CDCl3)
(s, 3H), 2.45 (s, 3H); 13C NMR (50 MHz, CDCl3)
d
d
7.62–7.45 (m, 4H), 7.00 (s, 1H), 3.53
146.6, 132.0, 131.5,
1H NMR (200 MHz, CDCl3)
d
7.22 (m, 4H), 6.91 (s, 1H), 3.49
(s, 3H), 2.42 (s, 3H), 2.37 (s, 3H); 13C NMR (50 MHz, CDCl3)
d
145.4,
131.3, 131.1 (q, J¼32.2 Hz), 129.1, 126.6, 124.9 (q, J¼3.8 Hz), 124.1
(q, J¼3.7 Hz), 123.8 (q, J¼272.4 Hz), 31.2, 13.5; C12H11F3N2: calcd C
60.00, H 4.62; found C 60.10, H 4.71.
137.4, 133.3, 129.2, 128.4, 127.3, 125.0, 31.1, 21.0, 13.4; C12H14N2:
calcd C 77.38, H 7.58; found C 77.49, H 7.64.
3.2.11. 5-(4-tert-Butylphenyl)-1,2-dimethylimidazole
(11). From
3.2.18. 1,2-Dimethyl-5-naphthalen-2-ylimidazole (18)13a. From
2-bromonaphthalene (0.207 g, 1 mmol), 1,2-dimethylimidazole
(0.192 g, 2 mmol) and KOAc(0.196 g, 2 mmol) with Pd(OAc)2 (1.1 mg,
0.005 mmol), product 18 was obtained in 77% (0.171 g) yield.
d 7.95–7.70 (m, 4H), 7.50–7.30 (m,
3H), 7.03 (s, 1H), 3.45 (s, 3H), 2.40 (s, 3H).
4-tert-butylbromobenzene (0.213 g, 1 mmol), 1,2-dimethylimida-
zole (0.192 g, 2 mmol) and K2CO3 (0.276 g, 2 mmol) with Pd(OAc)2
(1.1 mg, 0.005 mmol), product 11 was obtained in 77% (0.176 g)
yield.
1H NMR (200 MHz, CDCl3)
1H NMR (200 MHz, CDCl3)
d
7.46 (d, J¼8.4 Hz, 2H), 7.29
(d, J¼8.4 Hz, 2H), 6.94 (s, 1H), 3.54 (s, 3H), 2.46 (s, 3H), 1.36 (s, 9H);
13C NMR (50 MHz, CDCl3)
150.7, 145.7, 133.5, 128.3, 127.6, 125.6,
d
3.2.19. 5-(2-Formylphenyl)-1,2-dimethylimidazole (19). From
2-bromobenzaldehyde (0.185 g, 1 mmol), 1,2-dimethylimid-
azole (0.192 g, 2 mmol) and KOAc (0.196 g, 2 mmol) with
125.5, 34.6, 31.4, 31.3, 13.7; C15H20N2: calcd C 78.90, H 8.83; found C
78.81, H 8.91.

J. Roger, H. Doucet / Tetrahedron 65 (2009) 9772–9781
9779
Pd(OAc)2 (1.1 mg, 0.005 mmol), product 19 was obtained in
(0.192 g, 2 mmol) and KOAc (0.196 g, 2 mmol) with Pd(OAc)2
(1.1 mg, 0.005 mmol), product 28 was obtained in 87% (0.194 g)
yield.
38% (0.076 g) yield.
1H NMR (200 MHz, CDCl3)
d
9.91 (s, 1H), 7.98 (d, J¼7.8 Hz, 1H),
7.64 (t, J¼7.5 Hz, 1H), 7.51 (t, J¼7.5 Hz, 1H), 7.34 (d, J¼7.6 Hz, 1H),
1H NMR (200 MHz, CDCl3)
d
9.17 (s, 1H), 8.35 (s, 1H), 7.93
(d, J¼8.0 Hz, 1H), 7.62–7.40 (m, 3H), 6.97 (s, 1H), 3.22 (s, 3H), 2.41
(s, 3H); 13C NMR (50 MHz, CDCl3)
152.7, 146.0, 144.1, 134.9, 130.9,
6.90 (s, 1H), 3.36 (s, 3H), 2.44 (s, 3H); 13C NMR (50 MHz, CDCl3)
d
191.4, 146.5, 134.9, 134.8, 133.6, 132.8, 131.6, 128.8, 128.5, 128.1,
d
30.9, 13.3; C12H12N2O: calcd C 71.98, H 6.04; found C 71.87, H 6.10.
127.9, 127.7, 127.5, 127.3, 127.2, 124.1, 121.4, 30.8, 13.2; C14H13N3:
calcd C 75.31, H 5.87; found C 75.40, H 5.99.
3.2.20. 2-(2,3-Dimethylimidazol-4-yl)-benzonitrile (20). From
2-bromobenzonitrile (0.182 g, 1 mmol), 1,2-dimethylimidazole
(0.192 g, 2 mmol) and KOAc (0.196 g, 2 mmol) with Pd(OAc)2 (1.1 mg,
0.005 mmol), product 20 was obtained in 74% (0.146 g) yield.
3.2.27. 5-(5-Pyrimidyl)-1,2-dimethylimidazole (29). From 5-bro-
mopyrimidine (0.159 g, 1 mmol), 1,2-dimethylimidazole (0.192 g,
2 mmol) and KOAc (0.196 g, 2 mmol) with Pd(OAc)2 (1.1 mg,
0.005 mmol), product 29 was obtained in 85% (0.148 g) yield.
1H NMR (200 MHz, CDCl3)
d
7.65 (d, J¼8.0 Hz, 1H), 7.56
(t, J¼7.8 Hz, 1H), 7.38 (t, J¼7.8 Hz, 1H), 7.31 (d, J¼8.0 Hz, 1H), 6.98 (s,
1H), 3.38 (s, 3H), 2.34 (s, 3H); 13C NMR (50 MHz, CDCl3)
146.7,
1H NMR (200 MHz, CDCl3)
d
9.12 (s, 1H), 8.72 (s, 2H), 7.05 (s, 1H),
d
3.54 (s, 3H), 2.42 (s, 3H); 13C NMR (50 MHz, CDCl3)
d
157.2, 155.3,
134.9, 133.2, 132.5, 130.6, 128.9, 128.1, 127.7, 117.6, 112.4, 31.0, 13.2;
C12H11N3: calcd C 73.07, H 5.62; found C 73.10, H 5.54.
147.7, 127.7, 126.3, 124.9, 31.3, 13.4; C9H10N4: calcd C 62.05, H 5.79;
found C 62.20, H 5.78.
3.2.21. 5-(2-Fluorophenyl)-1,2-dimethylimidazole (21). From 2-bro-
mofluorobenzene (0.175 g,1 mmol),1,2-dimethylimidazole (0.192 g,
2 mmol) and KOAc (0.196 g, 2 mmol) with Pd(OAc)2 (1.1 mg,
0.005 mmol), product 21 was obtained in 72% (0.137 g) yield.
3.2.28. 4-(3-Decyl-2-methylimidazol-4-yl)-benzaldehyde (31). From
4-bromobenzaldehyde (0.185 g, 1 mmol), 1-decyl-2-methyl-
imidazole (0.444 g, 2 mmol) and KOAc (0.196 g, 2 mmol) with
Pd(OAc)2 (1.1 mg, 0.005 mmol), product 31 was obtained in 21%
(0.069 g) yield.
1H NMR (200 MHz, CDCl3)
d
7.42–7.25 (m, 2H), 7.18 (t, J¼7.8 Hz,
1H), 7.13 (t, J¼7.8 Hz, 1H), 6.95 (s, 1H), 3.42 (s, 3H), 2.49 (s, 3H); 13C
1H NMR (200 MHz, CDCl3)
d
10.04 (s, 1H), 7.94 (d, J¼8.4 Hz, 2H),
NMR (50 MHz, CDCl3)
d
159.3 (d, J¼247.6 Hz), 146.0, 131.8, 130.1
7.51 (d, J¼8.4 Hz, 2H), 7.45 (s, 1H), 3.93 (t, J¼7.5 Hz, 2H), 2.46 (s, 3H),
(d, J¼8.2 Hz), 127.5, 126.4, 124.3 (d, J¼3.8 Hz), 118.1 (d, J¼15.4 Hz),
115.7 (d, J¼22.0 Hz), 31.0, 13.3; C11H11FN2: calcd C 69.46, H 5.83;
found C 69.34, H 5.90.
1.50–1.00 (m, 16H), 0.85 (t, J¼7.5 Hz, 3H); 13C NMR (50 MHz, CDCl3)
d
191.4, 137.0, 135.1, 131.4, 131.3, 130.1, 128.5, 127.4, 44.3, 31.7, 30.4,
29.4, 29.3, 29.2, 29.1, 28.9, 26.4, 22.5, 14.0; C21H30N2O: calcd C 77.26,
H 9.26; found C 77.17, H 9.34.
3.2.22. 5-(2-Tolyl)-1,2-dimethylimidazole (22). From 2-bromoto-
luene (0.171 g, 1 mmol), 1,2-dimethylimidazole (0.192 g, 2 mmol)
and K2CO3 (0.276 g, 2 mmol) with Pd(OAc)2 (1.1 mg, 0.005 mmol),
product 22 was obtained in 79% (0.147 g) yield.
3.2.29. 4-(3-Isobutyl-2-methylimidazol-4-yl)-benzonitrile
(32). From 4-bromobenzonitrile (0.182 g, 1 mmol), 1-isobutyl-2-
methylimidazole (0.276 g, 2 mmol) and KOAc (0.196 g, 2 mmol)
with Pd(OAc)2 (1.1 mg, 0.005 mmol), product 32 was obtained in
71% (0.170 g) yield.
1H NMR (200 MHz, CDCl3)
d
7.20–7.05 (m, 4H), 6.81 (s, 1H), 3.27
(s, 3H), 2.43 (s, 3H), 2.17 (s, 3H); 13C NMR (50 MHz, CDCl3)
d
144.8,
138.1, 131.9, 131.1, 130.1, 129.8, 128.5, 125.6, 125.5, 30.5, 19.9, 13.4;
C12H14N2: calcd C 77.38, H 7.58; found C 77.20, H 7.57.
1H NMR (200 MHz, CDCl3)
d
7.70 (d, J¼8.4 Hz, 2H), 7.45
(d, J¼8.4 Hz, 2H), 7.01 (s,1H), 3.78 (d, J¼7.6 Hz, 2H), 2.46 (s, 3H),1.67
(m, 1H), 0.69 (d, J¼6.6 Hz, 6H); 13C NMR (50 MHz, CDCl3)
d 147.5,
3.2.23. 1,2-Dimethyl-5-naphthalen-1-ylimidazole
(24)13a. From
135.8, 132.4, 131.2, 128.5, 128.2, 118.5, 110.9, 51.4, 29.4, 19.6, 14.0;
C15H17N3: calcd C 75.28, H 7.16; found C 75.30, H 7.14.
1-bromonaphthalene (0.207 g, 1 mmol), 1,2-dimethylimidazole
(0.192 g, 2 mmol) and KOAc (0.196 g, 2 mmol) with Pd(OAc)2 (1.1 mg,
0.005 mmol), product 24 was obtained in 76% (0.169 g) yield.
3.2.30. 4-(3-Benzyl-2-methylimidazol-4-yl)-benzonitrile (33). From
4-bromobenzonitrile (0.182 g, 1 mmol), 1-benzyl-2-methyl-
imidazole (0.344 g, 2 mmol) and KOAc (0.196 g, 2 mmol) with
Pd(OAc)2 (1.1 mg, 0.005 mmol), product 33 was obtained in 34%
(0.093 g) yield.
1H NMR (200 MHz, CDCl3)
1H), 7.60–7.30 (m, 4H), 7.03 (s, 1H), 3.26 (s, 3H), 2.52 (s, 3H).
d
7.96–7.90 (m, 2H), 7.65 (d, J¼8.0 Hz,
3.2.24. 5-(4-Pyridyl)-1,2-dimethylimidazole (26)20. From 4-bromo-
pyridine hydrochloride (0.194 g, 1 mmol), 1,2-dimethylimidazole
(0.192 g, 2 mmol) and KOAc (0.294 g, 3 mmol) with Pd(OAc)2
(1.1 mg, 0.005 mmol), product 26 was obtained in 84% (0.146 g)
yield.
1H NMR (200 MHz, CDCl3)
d
7.58 (d, J¼8.2 Hz, 2H), 7.40–7.20 (m,
5H), 7.16 (s, 1H), 6.94 (d, J¼8.2 Hz, 2H), 5.15 (s, 2H), 2.35 (s, 3H); 13C
NMR (50 MHz, CDCl3) d 147.8, 136.0, 134.7, 132.4, 132.0, 129.1, 128.3,
128.0, 127.8, 125.3, 118.4, 110.9, 47.4, 13.5; C18H15N3: calcd C 79.10, H
5.53; found C 79.31, H 5.54.
1H NMR (200 MHz, CDCl3)
(d, J¼6.0 Hz, 2H), 7.11 (s, 1H), 3.61 (s, 3H), 2.45 (s, 3H).
d
8.61 (d, J¼6.0 Hz, 2H), 7.26
3.2.31. 4-[3-Methyl-2-(4-trifluoromethylphenyl)-imidazol-4-yl]-ben-
zonitrile (35). From 4-bromobenzonitrile (0.182 g, 1 mmol),
1-methyl-2-(4-trifluoromethylphenyl)-imidazole (0.452 g, 2 mmol)
and KOAc (0.196 g, 2 mmol) with Pd(OAc)2 (1.1 mg, 0.005 mmol),
product 35 was obtained in 54% (0.177 g) yield.
3.2.25. 5-(3-Quinolyl)-1,2-dimethylimidazole (27). From 3-bromo-
quinoline (0.208 g, 1 mmol), 1,2-dimethylimidazole (0.192 g,
2 mmol) and KOAc (0.196 g, 2 mmol) with Pd(OAc)2 (1.1 mg,
0.005 mmol), product 27 was obtained in 85% (0.190 g) yield.
1H NMR (200 MHz, CDCl3)
d
8.81 (s, 1H), 8.01 (d, J¼8.0 Hz, 1H),
1H NMR (200 MHz, CDCl3)
d
7.83 (d, J¼8.2 Hz, 2H), 7.80–7.72
7.97 (s, 1H), 7.71 (d, J¼8.0 Hz, 1H), 7.61 (t, J¼7.8 Hz, 1H), 7.45
(m, 4H), 7.58 (d, J¼8.2 Hz, 2H), 7.33 (s, 1H), 3.74 (s, 3H); 13C NMR
(t, J¼7.8 Hz, 1H), 7.03 (s, 1H), 3.48 (s, 3H), 2.38 (s, 3H); 13C NMR
(50 MHz, CDCl3)
d 149.3, 134.2, 134.3, 133.6, 132.7, 131.3
(50 MHz, CDCl3)
d
149.8, 146.7, 146.6, 134.0, 129.8, 129.4, 128.8,
(q, J¼32.5 Hz), 129.6, 129.1, 128.6, 125.6 (q, J¼3.8 Hz), 124.0
(q, J¼272.0 Hz), 118.4, 111.5, 34.1; C18H12F3N3: calcd C 66.05, H 3.70;
found C 66.21, H 3.87.
127.5, 127.2, 126.9, 126.5, 123.3, 31.1, 13.2; C14H13N3: calcd C 75.31, H
5.87; found C 75.22, H 5.80.
3.2.26. 5-(4-Isoquinolyl)-1,2-dimethylimidazole (28). From 4-bro-
3.2.32. 4-(2-Formyl-3-methylimidazol-4-yl)-benzonitrile (36). From
moisoquinoline
(0.208 g, 1 mmol),
1,2-dimethylimidazole
4-bromobenzonitrile (0.182 g,1 mmol),1-methyl-2-formylimidazole

9780
J. Roger, H. Doucet / Tetrahedron 65 (2009) 9772–9781
3. (a) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174–238; (b)
Satoh, T.; Miura, M. Chem. Lett. 2007, 36, 200–205; (c) Doucet, H.; Hierso, J. C.
Curr. Opin. Drug Discov. Devel. 2007, 10, 672–690; (d) Campeau, L.-C.; Stuart, D.
R.; Fagnou, K. Aldrichimica Acta 2007, 40, 35–41; (e) Seregin, I. V.; Gevorgyan, V.
Chem. Soc. Rev. 2007, 36, 1173–1193; (f) Li, B.-J.; Yang, S.-D.; Shi, Z.-J. Synlett
2008, 949–957.
(0.220 g, 2 mmol) and KOAc (0.196 g, 2 mmol) with Pd(OAc)2 (1.1 mg,
0.005 mmol), product 36 was obtained in 52% (0.110 g) yield.
1H NMR (200 MHz, CDCl3)
d
9.85 (s, 1H), 7.78 (d, J¼8.4 Hz,
2H), 7.55 (d, J¼8.4 Hz, 2H), 7.39 (s, 1H), 3.98 (s, 3H); 13C NMR
(50 MHz, CDCl3)
d 182.4, 145.1, 137.6, 132.8, 132.4, 131.7, 129.5,
4. Roger, J.; Doucet, H. Org. Biomol. Chem. 2008, 6, 169–174.
118.1, 113.0, 33.4;; C12H9N3O: calcd C 68.24, H 4.29; found C
68.31, H 4.19.
5. For recent examples of direct arylations of thiophenes: (a) David, E.; Pellet-
Rostaing, S.; Lemaire, M. Tetrahedron 2007, 63, 8999–9006; (b) Battace, A.;
Lemhadri, M.; Zair, T.; Doucet, H.; Santelli, M. Adv. Synth. Catal. 2007, 349, 2507–
2516; (c) Amaladass, P.; Clement, J. A.; Mohanakrishnan, A. K. Tetrahedron 2007,
63, 10363–10371; (d) Derridj, F.; Gottumukkala, A. L.; Djebbar, S.; Doucet, H. Eur.
J. Inorg. Chem. 2008, 2550–2559; (e) Nakano, M.; Tsurugi, H.; Satoh, T.; Miura,
M. Org. Lett. 2008, 10, 1851–1854; (f) Dong, J. J.; Roger, J.; Doucet, H. Tetrahedron
Lett. 2009, 50, 2778–2781.
6. For recent examples of direct arylations of pyrroles or indoles: (a) Wang, X.;
Gribkov, D. V.; Sames, D. J. Org. Chem. 2007, 72, 1476–1479; (b) Lebrasseur, N.;
Larrosa, I. J. Am. Chem. Soc. 2008, 130, 2926–2927; (c) Fall, Y.; Doucet, H.;
Santelli, M. ChemSusChem 2009, 2, 153–157.
7. For recent examples of direct arylations of furans: (a) McClure, M. S.;
Glover, B.; McSorley, E.; Millar, A.; Osterhout, M. H.; Roschangar, F. Org.
Lett. 2001, 3, 1677–1680; (b) Glover, B.; Harvey, K. A.; Liu, B.; Sharp, M. J.;
Tymoschenko, M. F. Org. Lett. 2003, 5, 301–304; (c) Parisien, M.; Valette,
D.; Fagnou, K. J. Org. Chem. 2005, 70, 7578–7584; (d) Battace, A.; Lemhadri,
M.; Zair, T.; Doucet, H.; Santelli, M. Organometallics 2007, 26, 472–474; (e)
Lindahl, K.-F.; Carroll, A.; Quinn, R. J.; Ripper, J. A. Tetrahedron Lett. 2006,
47, 7493–7495; (f) Beccalli, E. M.; Broggini, G.; Martinelli, M.; Sottocornola,
S. Synthesis 2008, 136–140; (g) Gottumukkala, A. L.; Doucet, H. Adv. Synth.
Catal. 2008, 350, 2183–2188; (h) Smaliy, R. V.; Beaupe´rin, M.; Cattey, H.;
Meunier, P.; Hierso, J.-C.; Roger, J.; Doucet, H.; Coppel, Y. Organometallics
2009, 28, 3152–3160.
8. For recent examples of direct arylations of thiazoles: (a) Gottumukkala, A. L.;
Doucet, H. Eur. J. Inorg. Chem. 2007, 3629–3632; (b) Campeau, L.-C.; Bertrand-
Laperle, M.; Leclerc, J.-P.; Villemure, E.; Gorelsky, S.; Fagnou, K. J. Am. Chem. Soc.
2008, 130, 3276–3277; (c) Martin, T.; Verrier, C.; Hoarau, C.; Marsais, F. Org. Lett.
2008, 10, 2909–2912.
3.2.33. 5-(4-Formylphenyl)-1-methylimidazole-2-carbaldehyde
(37). From 4-bromobenzaldehyde (0.185 g, 1 mmol), 1-methyl-2-
formylimidazole (0.220 g, 2 mmol) and KOAc (0.196 g, 2 mmol)
with Pd(OAc)2 (1.1 mg, 0.005 mmol), product 37 was obtained in
69% (0.148 g) yield.
1H NMR (200 MHz, CDCl3)
d 10.06 (s, 1H), 9.84 (s, 1H), 7.99
(d, J¼8.4 Hz, 2H), 7.60 (d, J¼8.4 Hz, 2H), 7.40 (s, 1H), 4.00 (s, 3H); 13C
NMR (50 MHz, CDCl3) d 190.8, 181.8, 144.5, 137.8, 135.9, 133.1, 131.2,
129.6, 128.9, 32.9; C12H10N2O2: calcd C 67.28, H 4.71; found C 67.39,
H 4.61.
3.2.34. 4-(3-Methylimidazol-4-yl)-benzonitrile (38). From 4-bro-
mobenzonitrile (0.182 g, 1 mmol), 1-methylimidazole (0.164 g,
2 mmol) and KOAc (0.196 g, 2 mmol) with Pd(OAc)2 (1.1 mg,
0.005 mmol), product 38 was obtained in 76% (0.139 g) yield.
1H NMR (200 MHz, CDCl3)
d
7.64 (d, J¼8.0 Hz, 2H), 7.49
(d, J¼8.0 Hz, 2H), 7.28 (s, 1H), 7.13 (s, 1H), 3.67 (s, 3H); 13C NMR
(50 MHz, CDCl3)
d 140.0, 133.8, 132.0, 131.1, 129.2, 127.7, 118.1,
110.5, 32.4; C11H9N3: calcd C 72.11, H 4.95; found C 72.20, H
4.98.
9. For recent examples of direct arylations of oxazoles or isoxazoles: (a)
Hoarau, C.; Du Fou de Kerdaniel, A.; Bracq, N.; Grandclaudon, P.; Couture,
A.; Marsais, F. Tetrahedron Lett. 2005, 46, 8573–8577; (b) Turner, G. L.;
Morris, J. A.; Greaney, M. F. Angew. Chem., Int. Ed. 2007, 46, 7996–8002; (c)
Derridj, F.; Djebbar, S.; Benali-Baitich, O.; Doucet, H. J. Organomet. Chem.
2008, 693, 135–144; (d) Ohnmacht, S. A.; Mamone, P.; Culshaw, A. J.;
Greaney, M. F. Chem. Commun. 2008, 1241–1243; (e) Besselievre, F.; Ma-
huteau-Betzer, F.; Grierson, D. S.; Piguel, S. J. Org. Chem. 2008, 73, 3278–
3280; (f) Fall, Y.; Reynaud, C.; Doucet, H.; Santelli, M. Eur. J. Org. Chem.
2009, 4041–4050.
3.2.35. 5-(4-Tolyl)-1-methylimidazole (39)21. From 4-bromotoluene
(0.171 g, 1 mmol), 1-methylimidazole (0.164 g, 2 mmol) and KOAc
(0.196 g, 2 mmol) with Pd(OAc)2 (1.1 mg, 0.005 mmol), product 39
was obtained in 40% (0.069 g) yield.
1H NMR (200 MHz, CDCl3)
7.25 (d, J¼8.2 Hz, 2H), 7.08 (s, 1H), 3.65 (s, 3H), 2.40 (s, 3H).
d
7.51 (s, 1H), 7.29 (d, J¼8.2 Hz, 2H),
10. For recent examples of direct arylations of triazoles: (a) Chuprakov, S.; Cher-
nyak, N.; Dudnik, A. S.; Gevorgyan, V. Org. Lett. 2007, 9, 2333–2336; (b) Iwasaki,
M.; Yorimitsu, H.; Oshima, K. Chem. Asian. J. 2007, 2, 1430–1435; (c) Ackermann,
L.; Vincente, R.; Born, R. Adv. Synth. Catal. 2008, 350, 741–748.
3.2.36. 5-(4-Methoxyphenyl)-1-methylimidazole
(40)15. From
4-bromoanisole (0.187 g, 1 mmol), 1-methylimidazole (0.164 g,
2 mmol) and KOAc (0.196 g, 2 mmol) with Pd(OAc)2 (1.1 mg,
0.005 mmol), product 40 was obtained in 42% (0.079 g) yield.
11. For examples of direct 2-arylation of imidazole derivatives: (a) Gracias, V.;
Gasiecki, A. F.; Pagano, T. G.; Djuric, S. W. Tetrahedron Lett. 2006, 47, 8873–
8876; (b) Bellina, F.; Cauteruccio, S.; Mannina, L.; Rossi, R.; Viel, S. Eur. J.
Org. Chem. 2006, 693–703; (c) Bellina, F.; Cauteruccio, S.; Rossi, R. Eur. J.
Org. Chem. 2006, 1379–1382; (d) Cerna, I.; Pohl, R.; Klepetarova, B.; Hocek,
M. Org. Lett. 2006, 8, 5389–5392; (e) Bellina, F.; Calandri, C.; Cauteruccio,
S.; Rossi, R. Tetrahedron 2007, 63, 1970–1980; (f) Bellina, F.; Cauteruccio, S.;
Rossi, R. J. Org. Chem. 2007, 72, 8543–8546; (g) Majumdar, K. C.; Debnath,
P.; Taher, A.; Pal, A. K. Can. J. Chem. 2008, 86, 325–332; (h) Sahnoun, S.;
Messaoudi, S.; Peyrat, J.-F.; Brion, J.-D.; Alami, M. Tetrahedron Lett. 2008, 49,
7279–7283; (i) Lee, H. S.; Kim, S. H.; Gowrisankar, S.; Kim, J. N. Tetrahedron
2008, 64, 7183–7190; (j) Storr, T. E.; Firth, A. G.; Wilson, K.; Darley, K.;
Baumann, C. G.; Fairlamb, I. J. S. Tetrahedron 2008, 64, 6125–6137; (k) Zhao,
D.; Wang, W.; Lian, S.; Yang, F.; Lan, J.; You, J. Chem.d Eur. J. 2009, 15,
1337–1340.
1H NMR (200 MHz, CDCl3)
7.05 (s, 1H), 6.99 (d, J¼8.0 Hz, 2H), 3.87 (s, 3H), 3.65 (s, 3H).
d
7.53 (s, 1H), 7.32 (d, J¼8.0 Hz, 2H),
3.2.37. 3-(3-Methylimidazol-4-yl)-pyridine (41)13d. From 3-bromo-
pyridine (0.158 g, 1 mmol), 1-methylimidazole (0.164 g, 2 mmol)
and KOAc (0.196 g, 2 mmol) with Pd(OAc)2 (1.1 mg, 0.005 mmol),
product 41 was obtained in 81% (0.129 g) yield.
1H NMR (200 MHz, CDCl3)
d
8.61 (s, 1H), 8.54 (d, J¼4.8 Hz, 1H),
7.66 (d, J¼7.8 Hz, 1H), 7.53 (s, 1H), 7.33 (dd, J¼4.8, 7.8 Hz, 1H), 7.10
(s, 1H), 3.63 (s, 3H).
12. Aoyagi, Y.; Inoue, A.; Koizumi, I.; Hashimoto, R.; Miyafuji, A.; Kunoh, J.; Honma,
R.; Akita, Y.; Ohta, A. Heterocycles 1992, 33, 257–272.
13. (a) Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Bull. Chem. Soc.
Jpn. 1998, 71, 467–473; (b) Chiong, H. A.; Daugulis, O. Org. Lett. 2007, 9, 1449–
1451; (c) Bellina, F.; Cauteruccio, S.; Mannina, L.; Rossi, R.; Viel, S. J. Org. Chem.
2005, 70, 3997–4005; (d) Bellina, F.; Cauteruccio, S.; Di Flore, A.; Rossi, R. Eur. J.
Org. Chem. 2008, 5436–5445; (e) Bellina, F.; Cauteruccio, S.; Di Fiore, A.; Mar-
chetti, C.; Rossi, R. Tetrahedron 2008, 64, 6060–6072; (f) Kondo, Y.; Komine, T.;
Sakamoto, T. Org. Lett. 2000, 2, 3111–3113.
14. Toure, B. B.; Lane, B. S.; Sames, D. Org. Lett. 2006, 8, 1979–1982.
15. Lie´gaut, B.; Lapointe, D.; Caron, L.; Vlassova, A.; Fagnou, K. J. Org. Chem. 2009,
74, 1826–1834.
16. For examples of intramolecular direct 5-arylation of imidazoles: (a) Kuroda, T.;
Suzuki, F. Tetrahedron Lett. 1991, 32, 6915–6918; (b) Delest, B.; Tisserand, J.-Y.;
Robert, J.-M.; Nourrisson, M.-R.; Pinson, P.; Duflos, M.; Le Baut, G.; Renard, P.;
Pfeiffer, B. Tetrahedron 2004, 60, 6079–6083; (c) Arai, N.; Takahashi, M.; Mitani,
M.; Mori, A. Synlett 2006, 3170–3172.
17. (a) de Vries, A. H. M.; Mulders, J. M. C. A.; Mommers, J. H. M.; Henderickx,
H. J. W.; de Vries, J. G. Org. Lett. 2003, 5, 3285–3288; (b) Reetz, M. T.; de
Vries, J. G. Chem. Commun. 2004, 1559–1563; (c) de Vries, J. G. Dalton
Trans. 2006, 421–429; (d) Alimardanov, A.; Schmieder-van de
3.2.38. 5-(3-Methylimidazol-4-yl)-pyrimidine (42). From 5-bromo-
pyrimidine (0.159 g, 1 mmol), 1-methylimidazole (0.164 g, 2 mmol)
and KOAc (0.196 g, 2 mmol) with Pd(OAc)2 (1.1 mg, 0.005 mmol),
product 42 was obtained in 67% (0.107 g) yield.
1H NMR (200 MHz, CDCl3)
7.24 (s, 1H), 3.72 (s, 3H); 13C NMR (50 MHz, CDCl3)
d
9.20 (s, 1H), 8.80 (s, 2H), 7.61 (s, 1H),
157.6, 155.4,
d
140.7, 130.1, 126.4, 124.5, 32.6; C8H8N4: calcd C 59.99, H 5.03; found
C 60.10, H 5.08.
References and notes
1. (a) Li, J. J.; Gribble, G. W. Palladium in Heterocyclic Chemistry; Pergamon: Am-
sterdam, 2000; (b) Schnu¨rch, M.; Flasik, R.; Khan, A. F.; Spina, M.; Mihovilovic,
M. D.; Stanetty, P. Eur. J. Org. Chem. 2006, 3283–3307.
2. Ohta, A.; Akita, Y.; Ohkuwa, T.; Chiba, M.; Fukunaga, R.; Miyafuji, A.; Nakata, T.;
Tani, N.; Aoyagi, Y. Heterocycles 1990, 31, 1951–1958.

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19. Berthiol, F.; Feuerstein, M.; Doucet, H.; Santelli, M. Tetrahedron Lett. 2002, 43,
5625–5628.
ꢀ
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20. McLoughlin, P. T. F.; Clyne, M. A.; Aldabbagh, F. Tetrahedron 2004, 60,
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