One pot Pd(OAc)2-catalysed 2,5-diarylation of imidazoles derivatives

Article abstract of DOI:10.1016/j.tet.2014.09.012

The regioselective 2- or 5-arylation of imidazole derivatives with aryl halides using palladium catalysts has been described in recent years; whereas the arylation at both C2 and C5 carbons of imidazoles in high yields has not been performed. We found con

Full text of DOI:10.1016/j.tet.2014.09.012

Tetrahedron 70 (2014) 8316e8323
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One pot Pd(OAc)2-catalysed 2,5-diarylation of imidazoles derivatives
,
,c,
ꢀ a
Abdelilah Takfaoui a b, Liqin Zhao a, Rachid Touzani b , Jean-Franc¸ ois Soule ,
*
Pierre H. Dixneuf a, Henri Doucet a
Institut des Sciences Chimiques de Rennes, UMR 6226 CNRS-Universite de Rennes, “Organometalliques: Materiaux et Catalyse”, Campus de Beaulieu,
,
*
a
ꢀ
ꢀ
ꢀ
35042 Rennes, France
b
ꢀ
ꢀ
ꢀ
Laboratoire de Chimie Appliquee et Environnement (LCAE-URAC18), Faculte des Sciences, Universite Mohamed Premier, Oujda, Morocco
c
ꢀ
ꢀ
Faculte Pluridisciplinaire de Nador, Universite Mohammed Premier, BP: 300, Selouane 62700, Nador, Morocco
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 31 July 2014
Received in revised form 1 September 2014
Accepted 3 September 2014
Available online 16 September 2014
The regioselective 2- or 5-arylation of imidazole derivatives with aryl halides using palladium catalysts
has been described in recent years; whereas the arylation at both C2 and C5 carbons of imidazoles in
high yields has not been performed. We found conditions allowing the access to these 2,5-
diarylimidazoles via a one pot reaction. The choice of the base was found to be crucial to obtain these
products in high yields. Using CsOAc as the base, DMA as the solvent and only 2 mol % of the phosphine-
free Pd(OAc)2 the catalyst, the target 2,5-diarylated imidazoles were obtained in moderate to good yields
with a wide variety of aryl bromides. Substituents such as fluoro, trifluoromethyl, formyl, acetyl, pro-
pionyl, ester, nitro or nitrile on the aryl bromide were tolerated. Sterically congested aryl bromides or
heteroaryl bromides can also be employed. Surprisingly the nature of the substituent at position 1 on the
imidazole derivative exhibits a huge influence on the reaction.
Keywords:
Palladiun
Catalysis
CeH bond activation
Imidazoles
Ó 2014 Elsevier Ltd. All rights reserved.
Direct arylation
Aryl halides
1. Introduction
reported that the direct arylation of heteroaromatics with aryl
halides via a CeH bond activation proceed in moderate to good
Aryl-substituted imidazoles including 2,5-diarylimidazoles are
important structures due to their biological properties. For exam-
ple, Fenflumizol and Trifenagrel are platelet aggregation inhibitors
(Fig. 1).
yields using Pd(PPh3)4 as the catalyst.2 Since these exciting results,
the Pd-catalysed direct arylation of heteroaryls using aryl halides as
coupling partners has proved to be a very powerful method for
a simpler and greener access to a wide variety of arylated hetero-
cycles, as the major by-products of the reaction are a base associ-
ated to HX, instead of metallic salts produced under more classical
cross-coupling procedures.3 Moreover, the method avoids the
preliminary preparation of an organometallic derivative. However,
so far, the direct arylation of imidazoles has attracted less attention
than the arylation of thiophenes or thiazoles, and in most cases
mono-arylations have been described.4e6 The first example of di-
rect 5-arylation of imidazoles using chloropyrazines as coupling
partners and 5 mol % Pd(PPh3)4 as the catalyst was reported by Ohta
and co-workers in 1992.4 Since these results, several groups de-
scribed conditions allowing the intermolecular Pd-catalysed direct
2- or 5-arylation of imidazoles.5,6
Fig. 1. Examples of bioactive 2,5-diarylimidazoles.
Suzuki, Stille or Negishi palladium-catalysed cross-coupling
reactions are among the most efficient methods to prepare 2,5-
diarylimidazoles.1 However, they require the previous preparation
of an organometallic derivative. As early as 1990, Ohta et al.
So far, to our knowledge, only a few examples of Pd-catalysed
arylations at both C2 and C5 carbons of imidazoles in one pot
have been described.7e9 In 1998, Miura et al. reported the regio-
selectivity of the arylation of 1-methylimidazole using various re-
action conditions.8a In the presence of bromobenzene, they
observed the formation of a mixture of 5-arylation and 2,5-
diarylation products in a 54:24 ratio (Scheme 1, top). They also
* Corresponding authors. Tel.: þ33 2 23 23 63 84; fax: þ33 2 23 23 69 39; e-mail
address: henri.doucet@univ-rennes1.fr (H. Doucet).
http://dx.doi.org/10.1016/j.tet.2014.09.012
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

A. Takfaoui et al. / Tetrahedron 70 (2014) 8316e8323
8317
the solvent and KOAc as the base. The reactions were performed at
150 ꢀC under argon in the presence of Pd(OAc)2 catalyst. Using
only 0.5 mol % Pd(OAc)2, the reaction of
3 equiv of 4-
bromochlorobenzene with 1 equiv of 1-methylimidazole affords
the mono- and di-arylation products 1a:1b in a 73:27 ratio and the
target product 1b was isolated in a low yield of 18% (Table 1, entry
1). Then, we examined the influence of the amount of catalyst and
base for this reaction (Scheme 2, Table 1, entries 2e5). A larger
excess (4 equiv) of KOAc base affords the products 1a:1b in a 68:32
ratio. In the presence of 1 or 2 mol-% Pd(OAc)2 instead of 0.5 mol %,
an almost equimolar mixture of 1a:1b was obtained. A longer re-
action time (48 h instead on 20 h) led to products 1a:1b in 23:77
ratio and 1b was isolated in 62% yield (Table 1, entry 5). An im-
portant effect of the acetate countercations was observed. The use
of CsOAc instead of KOAc in the presence of 2 mol % Pd(OAc)2 gave
1a:1b in 12:88 ratio and 1b in 70% yield; whereas, NaOAc (2 equiv)
led to products 1a:1b in 89:11 ratio and allowed to isolate 1a in 64%
yield (Table 1, entries 8 and 10). A lower reaction temperature
(120 ꢀC) affords products 1a:1b in 92:8 ratio (Table 1, entry 9).
Table 1
Influence of the reaction conditions for palladium catalysed arylation of
1-methylimidazole with 4-bromochlorobenzene (Scheme 2)
Entry
Catalyst
(mol %)
Base (equiv)
Time (h)
Ratio 1a:1b
Yield in
1b (%)
Scheme 1. Reported examples of Pd-catalysed one pot access to 2,5-diarylimidazoles.
1
2
3
4
5
6
7
8
9
0.5
0.5
1
2
1
1
1
2
2
KOAc (3)
KOAc (4)
KOAc (4)
KOAc (4)
20
20
20
20
48
20
48
48
48
20
73:27
68:32
52:48
52:48
23:77
44:56
15:85
12:88
92:8a
89:11b
18
62
reported that the addition of 2 equiv of CuI to the reaction mixture,
using iodobenzene as the coupling partner, drastically modify the
selectivity of the reaction, as a mixture of C2 and C2,C5 arylation
products in a 37:40 ratio was obtained. It should be noted that CuI
itself promotes the C2 arylation of imidazole. Bellina, Rossi and co-
workers also studied the influence of several parameters for the
arylation of imidazoles, and succeeded in a few cases to obtain
directly the 2,5-diarylated imidazoles although in moderate
yields.8b A few 2,5-diarylimidazoles have also been prepared by
Shibahara, Murai et al. using a 1,10-phenanthroline containing Pd
KOAc (4)
KOAc (3) Cs2CO3 (3)
CsOAc (4)
CsOAc (4)
CsOAc (4)
NaOAc (2)
70
64
10
0.5
Conditions: Pd(OAc)2 0.5e2 mol %, 4-bromochlorobenzene (3 equiv), 1-
methylimidazole (1 equiv), DMA, 150 ꢀC, 20 h, isolated yields.
a
120 ꢀC.
b
4-Bromochlorobenzene (1.2 equiv), 1-methylimidazole (1 equiv), yield in 1a.
Scheme 2. Pd-catalysed direct diarylation of 1-methylimidazole with 4-bromobenzonitrile.
catalyst and aryl iodides as coupling partners.9 However, so far
sequential Pd-catalysed direct arylations remains the most reliable
method to prepare 2,5-diarylimidazoles in good yields.10
Therefore, the discovery of effective conditions, for the direct
coupling of aryl halides at both C2 and C5 positions of imidazole
derivatives in one pot, would constitute a considerable advantage
allowing a simpler access to 2,5-diarylimidazoles.
Then, using the most effective reaction conditions (DMA, CsOAc,
Pd(OAc)2, 150 ꢀC, 48 h) we explored the scope of this reaction using
para-, meta- and ortho-substituted aryl bromides and also some
heteroaryl bromides employing 1-methylimidazole as the coupling
partner (Scheme 3, Table 2).
Here, we wish to (i) report that Pd(OAc)2 catalyst without
any additional ligand promotes the direct access to 2,5-
diarylimidazoles in one pot, (ii) report on the reaction scope us-
ing a large set of electronically and sterically diverse aryl bromides,
(iii) reveal the influence of the imidazole N-substituent.
Scheme 3. Scope of the Pd-catalysed direct diarylation of 1-methylimidazole.
2. Results and discussion
First, we investigated the reaction of 1-methylimidazole
with several para-substituted aryl bromides (Scheme 3, Table 2). In
most cases, the reaction proceeds very smoothly in the presence of
2 mol % Pd(OAc)2 catalyst. With electron deficient aryl bromides
such as 4-bromoacetophenone, 4-bromopropiophenone, ethyl
We have recently reported the direct 5-arylation of a range of
imidazole derivatives using a phosphine-free palladium catalyst.11
Based on these results, for this study DMA was initially chosen as

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A. Takfaoui et al. / Tetrahedron 70 (2014) 8316e8323
Table 2
4-bromopropionate, 4-bromobenzaldehyde or 4-bromobenzonitrile,
yields of 55e65% in 2e6 were obtained (Table 2, entries 1e5). We
also obtained satisfactory results using 4-fluorobromobenzene,
bromobenzene or even the electron-rich 4-bromotoluene and
4-bromoanisole to afford 8e11 in 78e81% yields (Table 1, entries 7
and 10). On the other hand, the use of 4-bromonitrobenzene affords
the diarylated imidazole 7 in only 32% yield due to the formation of
a large amount of mono-arylated 1-methylimidazole (Table 2, entry
6). The general pattern revealed by these results shows that the
electron-withdrawing substituents are slightly less favourable to
obtaining the desired 2,5-diarylimidazoles. The presence of an
electron-deficient aryl group at C5 of imidazole appears to disfavour
the second arylation at carbon C2.
Palladium catalysed diarylation of 1-methylimidazole with aryl bromides (Scheme 3)
Entry
Aryl bromide
Product
Yield (%)
1
2
59
2
3
3
4
65
55
4
5
62
The influence of the presence of meta-substituents on the aryl
bromide is also reported in the Table 2. As expected, relatively
similar yields than in the presence of the para-substituted
substrates were obtained for the reactions performed with
5
6
60
32
78
80
81
78
3-bromobenzonitrile,
3-(trifluoromethyl)bromobenzene
or
3-bromotoluene using again 2 mol % Pd(OAc)2 catalyst (Table 2,
entries 12e14). 3-Bromonitrobenzene, affords 12 in higher yield
than the reaction performed with 4-bromonitrobenzene (Table 2,
entry 11). Surprisingly, with 3,5-bis(trifluoromethyl)bromo-
benzene, a mixture of di- and tri-arylation products 16a and 16b
was obtained in a 57:43 ratio (Table 2, entry 15).
Then, we examined the reactivity of 1-methylimidazole with
a set of ortho-substituted aryl bromides. Ortho-substituents on the
aryl bromides generally have an important effect on the reaction
rates of palladium-catalysed reactions due to their steric and/or
6
7
7
8
8
9
9
10
11
10
coordination
properties.
The
expected
2,5-diaryl-1-
methylimidazoles 17e19 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, the
coupling of 2-bromobenzonitrile or 2-fluorobromobenzene pro-
ceeds nicely to afford 17 and 18 in 78% and 59% yields, respectively
(Table 2, entries 16 and 17). Heteroaryl bromide, 3-bromopyridine
was also found to be a suitable reactant, as 20 was obtained in
72% yield (Table 2, entry 19).
11
12
12
13
62
60
With 1-n-butylimidazole, using similar reaction conditions, low
yields of the desired 2,5-diarylation products 21be23b were ob-
tained (Scheme 4). Surprisingly, with this imidazole derivative the
formation of very large amounts of mono-arylation products was
observed. With 4-bromochlorobenzene or 4-bromotoluene, mono-
arylation products 21a and 23a and di-arylation products 21b and
23b were formed in 71:29 and 69:31 ratios, respectively. These
results reveal that, unexpectedly the presence of a n-butyl sub-
stituent instead of a methyl substituent at position 1 of an imid-
azole dramatically decreases its reactivity for the second arylation
at C2.
13
14
14
15
59
79
15
16
16a
17
48a
78
17
18
19
18
19
20
59
54
72
Conditions: Pd(OAc)2 (0.02 equiv), ArBr (3 equiv), 1-methylimidazole (1 equiv),
CsOAc (4 equiv), DMA, 150 ꢀC, 48 h, isolated yields.
a
The formation of a large amount of tri-arylation product 16b was observed (ratio
16a:16b 57:43).
Scheme 4. Scope of the Pd-catalysed direct arylation of 1-n-butylimidazole.

A. Takfaoui et al. / Tetrahedron 70 (2014) 8316e8323
8319
In order to gain more insight into the lower reactivity of 1-n-
butylimidazole versus 1-methylimidazole, a competition reaction
to probe the substituent preference of this catalyst system for such
couplings was performed (Scheme 5). From an equimolar mixture
of 1-methylimidazole and 1-n-butylimidazole using 6 equiv of 4-
bromochlorobenzene as the coupling partner, in the presence of
catalyst in the presence of 4 equiv of CsOAc as base in DMA at
150 ꢀC. In the presence of 4-bromobenzonitrile, only the formation
of the mono-5-arylated imidazole 28a, without cleavage of the
benzyl group, was observed. On the other hand, the reaction with
3,5-bis(trifluoromethyl)bromobenzene affords a mixture of the
mono- di- and tri-arylation products 29a, 29b and 29c in a 15:40:45
ratio. From 4-chlorobromobenzene and 4-bromotoluene, mixtures
of mono- and di-arylation products were obtained. These selec-
tivities are very similar to those observed in the course of the
coupling with 1-n-butylimidazole (Scheme 2). Therefore, for the
access to N-benzyl substituted 2,5-diarylimizazoles, the sequential
arylation procedure reported by Bellina, Rossi et al. using 5 mol %
Pd(OAc)2 associated to 2 equiv of CuI for the second arylation at C2
should be preferred.10a
2
mol-% Pd(OAc)2 catalyst, the formation of a mixture of
1a:1b:21a:21b in a 27:27:43:3 ratio was observed. This result
confirms that a n-butyl substituent at position 1 of imidazole is
strongly deactivating for the second arylation.
In conclusion, we report here for the first time a simple one-pot
catalytic method leading to the direct synthesis of 2,5-
diarylimidazoles in good yields. We have established that, a phos-
phine-free and copper-free procedure using Pd(OAc)2 catalyst,
CsOAc as base in the presence of aryl bromides as coupling partners
promotes the 2,5-diarylation of 1-methylimidazole. A wide range of
functions such as fluoro, acetyl, formyl, propionyl, carboxylate, nitrile
or nitro on the aryl bromide are tolerated. Some sterically hindered
aryl bromides and heteroaromatic substrate 3-bromopyridines have
also been employed successfully. The substituents at position 1 on
imidazole were found to exhibit a very important influence on the
products distribution. 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 commercially
available, phosphine-free and air stable palladium source. Therefore,
there is no need to eliminate phosphine derivatives at the end of the
reaction. Moreover, a very wide variety of aryl bromides are com-
mercially available. These are practical advantages of this reaction.
Scheme 5. Competition reaction using
butylimidazole.
a mixture of 1-methylimidazole and 1-n-
The influence of an aryl group at position 1 on imidazole was
also investigated (Scheme 6). This copper and phosphine-free
procedure was found to afford selectively in all cases the mono
C5-arylated products 24a-27a. The presence of a para-methoxy or
a para-formyl substituent on the 1-arylimidazole has a minor in-
fluence on the selectivity and yield of the reaction. Again, the
presence of trifluoromethyl substituents on bromobenzene favours
the formation of 2,5-diarylated products 25b and 27b although in
very low yields.
3. Experimental
General Remarks: All reactions were run under argon in Schlenk
tubes using vacuum lines. DMA analytical grade was not distilled
before use. CsOAc (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 400 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
(230e400 mesh).
Scheme 6. Scope of the Pd-catalysed direct arylation of 1-arylimidazoles.
4. Experimental section
4.1. General procedure
We then turned our attention to the reactivity of
1-benzylimidazole for the Pd-catalysed 2,5-diarylations, as the
deprotection of imidazoles bearing benzyl substituents is easier
than the corresponding 1-methylimidazoles (Scheme 7). We se-
lected our previous best reaction conditions, i.e, 2 mol % Pd(OAc)2
In a typical experiment, the aryl bromide (3 mmol), imidazole
derivative (1 mmol), CsOAc (1.303 g, 4 mmol) and Pd(OAc)2 (4.4 mg,
0.02 mmol), were dissolved in DMA (5 mL) under an argon atmo-
sphere. The reaction mixture was stirred at 150 ꢀC for 48 h. After
evaporation of the solvent, the product was purified by silica gel
column chromatography.
4.1.1. 5-(4-Chlorophenyl)-1-methylimidazole
(1a).8c From
4-
bromochlorobenzene (0.230 g, 1.2 mmol), 1-methylimidazole
(0.082 g, 1 mmol) and NaOAc (0.164 g, 2 mmol) with Pd(OAc)2
(1.1 mg, 0.005 mmol), product 1a was obtained in 64% (0.123 g)
yield. 1H NMR (400 MHz, CDCl3)
7.22 (d, J¼8.4 Hz, 2H), 7.01 (s, 1H), 3.57 (s, 3H).
d
7.44 (s, 1H), 7.32 (d, J¼8.4 Hz, 2H),
4.1.2. 2,5-Bis(4-chlorophenyl)-1-methylimidazole (1b). From 4-
Scheme 7. Scope of the Pd-catalysed direct arylation of 1-benzylimidazole.
bromochlorobenzene (0.574 g,
3
mmol), 1-methylimidazole

8320
A. Takfaoui et al. / Tetrahedron 70 (2014) 8316e8323
(0.082 g, 1 mmol) and CsOAc (1.303 g, 4 mmol) with Pd(OAc)2
8.07 (d, J¼8.4 Hz, 2H), 7.89 (d, J¼8.4 Hz, 2H), 7.55 (s, 1H), 3.83 (s, 3H).
13C NMR (100 MHz, DMSOd6)
148.7, 147.6, 147.0, 136.8, 136.4, 135.1,
130.9, 130.0, 129.3, 124.6, 124.3, 35.0. C16H12N4O4 (324.29): Calcd C
59.26, H 3.73, N 17.28; Found C 59.04, H 3.49, N 17.38.
(4.4 mg, 0.02 mmol), product 1b was obtained in 70% (0.212 g) yield.
d
1H NMR (400 MHz, CDCl3)
d
7.56 (d, J¼8.4 Hz, 2H), 7.39 (d, J¼8.4 Hz,
2H), 7.37 (d, J¼8.4 Hz, 2H), 7.30 (d, J¼8.4 Hz, 2H), 7.12 (s, 1H), 3.58 (s,
3H). 13C NMR (100 MHz, CDCl3)
148.2, 135.3, 134.6, 134.4, 130.1,
d
129.9, 129.2, 129.0, 128.5, 128.2, 127.1, 33.9. C16H12Cl2N2 (303.19):
Calcd C 63.38, H 3.99, N 9.24; Found C 63.55, H 4.09, N 9.14.
4.1.9. 2,5-Bis(4-fluorophenyl)-1-methylimidazole
(8). From
4-
bromofluorobenzene (0.525 g, mmol), 1-methylimidazole
3
(0.082 g, 1 mmol) and CsOAc (1.303 g, 4 mmol) with Pd(OAc)2
4.1.3. 1,10-(4,40-(1-methylimidazole-2,5-diyl)bis(4,1-phenylene))di-
ethanone (2).7b From 4-bromoacetophenone (0.597 g, 3 mmol), 1-
methylimidazole (0.082 g, 1 mmol) and CsOAc (1.303 g, 4 mmol)
with Pd(OAc)2 (4.4 mg, 0.02 mmol), product 2 was obtained in 59%
(4.4 mg, 0.02 mmol), product 8 was obtained in 78% (0.210 g) yield.
1H NMR (400 MHz, CDCl3)
d
7.65e7.55 (m, 2H), 7.40e7.30 (m, 2H),
7.15e7.00 (m, 5H), 3.57 (s, 3H). 13C NMR (100 MHz, CDCl3)
d
163.1 (d,
J¼249.0 Hz), 162.7 (d, J¼249.0 Hz), 148.4, 134.4, 130.7 (d, J¼8.3 Hz),
130.5 (d, J¼8.3 Hz), 127.4, 126.9 (d, J¼3.3 Hz), 126.2 (d, J¼3.3 Hz),
115.9 (d, J¼17.3 Hz), 115.7 (d, J¼17.3 Hz), 33.6. C16H12F2N2 (270.28):
Calcd C 71.10, H 4.48, N 10.36; Found C 71.02, H 4.34, N 10.17.
(0.187 g) yield. 1H NMR (400 MHz, CDCl3)
d
8.02 (d, J¼8.4 Hz, 2H),
7.99 (d, J¼8.4 Hz, 2H), 7.77 (d, J¼8.4 Hz, 2H), 7.51 (d, J¼8.4 Hz, 2H),
7.28 (s, 1H), 3.70 (s, 3H), 2.60 (s, 3H), 2.59 (s, 3H).
4.1.4. 1,10-(4,40-(1-Methylimidazole-2,5-diyl)bis(4,1-phenylene))di-
propan-1-one (3). From 4-bromopropiophenone (0.639 g, 3 mmol),
1-methylimidazole (0.082 g, 1 mmol) and CsOAc (1.303 g, 4 mmol)
with Pd(OAc)2 (4.4 mg, 0.02 mmol), product 3 was obtained in 65%
4.1.10. 1-Methyl-2,5-diphenylimidazole
(9).9b From
4-
bromobenzene (0.471 g, 3 mmol), 1-methylimidazole (0.082 g,
1 mmol) and CsOAc (1.303 g, 4 mmol) with Pd(OAc)2 (4.4 mg,
0.02 mmol), product 9 was obtained in 80% (0.187 g) yield. 1H NMR
(0.225 g) yield. 1H NMR (400 MHz, CDCl3)
d
8.02 (d, J¼8.4 Hz, 2H),
(400 MHz, CDCl3)
1H), 3.62 (s, 3H).
d
7.63 (d, J¼8.4 Hz, 2H), 7.45e7.25 (m, 8H), 7.14 (s,
7.98 (d, J¼8.4 Hz, 2H), 7.75 (d, J¼8.4 Hz, 2H), 7.50 (d, J¼8.4 Hz, 2H),
7.27 (s, 1H), 3.71 (s, 3H), 2.95 (q, J¼7.5 Hz, 4H), 1.15 (t, J¼7.5 Hz, 6H).
13C NMR (100 MHz, CDCl3)
d
200.1, 200.0, 149.0, 136.9, 136.2, 135.3,
4.1.11. 1-Methyl-2,5-dip-tolylimidazole (10). From 4-bromotoluene
(0.513 g, 3 mmol), 1-methylimidazole (0.082 g, 1 mmol) and
CsOAc (1.303 g, 4 mmol) with Pd(OAc)2 (4.4 mg, 0.02 mmol),
product 10 was obtained in 81% (0.212 g) yield.
134.1, 133.9, 128.9, 128.6, 128.4, 128.3, 34.4, 32.0, 31.9, 8.3, 8.2.
22H22N2O2 (346.42): Calcd C 76.28, H 6.40, N 8.09; Found C 76.08,
C
H 6.21, N 7.88.
1H NMR (400 MHz, CDCl3)
d
7.52 (d, J¼8.4 Hz, 2H), 7.27 (d,
J¼8.4 Hz, 4H), 7.23e7.17 (m, 4H), 7.10 (s,1H), 3.58 (s, 3H), 2.34 (s, 6H).
13C NMR (100 MHz, CDCl3)
148.9, 139.0, 138.0, 135.3, 129.5, 129.3,
4.1.5. Diethyl 4,40-(1-methylimidazole-2,5-diyl)dibenzoate (4). From
ethyl 4-bromobenzoate (0.687 g, 3 mmol), 1-methylimidazole
(0.082 g, 1 mmol) and CsOAc (1.303 g, 4 mmol) with Pd(OAc)2
(4.4 mg, 0.02 mmol), product 4 was obtained in 55% (0.208 g) yield.
d
128.8, 128.7, 127.4, 127.1, 126.2, 33.8, 21.4, 21.3. C18H18N2 (262.35):
Calcd C 82.41, H 6.92, N 10.68; Found C 82.50, H 6.98, N 10.89.
1H NMR (400 MHz, DMSOd6)
d
8.10 (d, J¼8.4 Hz, 2H), 8.07 (d,
J¼8.4 Hz, 2H), 7.92 (d, J¼8.4 Hz, 2H), 7.73 (d, J¼8.4 Hz, 2H), 7.39 (s,
4.1.12. 2,5-Bis(4-methoxyphenyl)-1-methylimidazole (11).8c From 4-
bromoanisole (0.561 g, 3 mmol), 1-methylimidazole (0.082 g,
1 mmol) and CsOAc (1.303 g, 4 mmol) with Pd(OAc)2 (4.4 mg,
0.02 mmol), product 11 was obtained in 78% (0.229 g) yield. 1H
1H), 4.36 (q, J¼7.5 Hz, 4H), 3.77 (s, 3H), 1.35 (t, J¼7.5 Hz, 6H). 13
C
NMR (100 MHz, DMSOd6)
d 165.9, 165.8, 149.0, 135.3, 135.2, 134.6,
130.1, 130.0, 129.8, 129.5, 129.2, 129.1, 128.5, 61.4, 61.3, 34.8, 14.6.
22H22N2O4 (378.42): Calcd C 69.83, H 5.86, N 7.40; Found C 69.71,
C
NMR (400 MHz, CDCl3)
d
7.55 (d, J¼8.4 Hz, 2H), 7.30 (d, J¼8.4 Hz,
H 5.70, N 7.55.
2H), 7.04 (s, 1H), 6.93 (d, J¼8.4 Hz, 2H), 6.92 (d, J¼8.4 Hz, 2H), 3.80
(s, 3H), 3.79 (s, 3H), 3.55 (s, 3H).
4.1.6. 4,40-(1-Methylimidazole-2,5-diyl)dibenzaldehyde (5). From 4-
bromobenzaldehyde (0.555 g,
3
mmol), 1-methylimidazole
4.1.13. 1-Methyl-2,5-bis(3-nitrophenyl)-imidazole (12). From 3-
(0.082 g, 1 mmol) and CsOAc (1.303 g, 4 mmol) with Pd(OAc)2
bromonitrobenzene (0.606 g,
3
mmol), 1-methylimidazole
(4.4 mg, 0.02 mmol), product 5 was obtained in 62% (0.180 g) yield.
(0.082 g, 1 mmol) and CsOAc (1.303 g, 4 mmol) with Pd(OAc)2
1H NMR (400 MHz, CDCl3)
d
10.03 (s, 1H), 10.01 (s, 1H), 7.96 (d,
(4.4 mg, 0.02 mmol), product 12 was obtained in 62% (0.201 g)
J¼8.4 Hz, 2H), 7.93 (d, J¼8.4 Hz, 2H), 7.85 (d, J¼8.4 Hz, 2H), 7.59 (d,
yield. 1H NMR (400 MHz, CDCl3)
d 8.52 (s, 1H), 8.35e8.15 (m, 3H),
J¼8.4 Hz, 2H), 7.33 (s, 1H), 3.73 (s, 3H). 13C NMR (100 MHz, CDCl3)
8.05 (d, J¼8.4 Hz, 1H), 7.74 (d, J¼8.4 Hz, 1H), 7.65 (d, J¼8.4 Hz, 1H),
d
191.6, 191.4, 149.3, 136.2, 135.9, 135.6, 131.5, 130.3, 130.0, 129.8,
7.62 (d, J¼8.4 Hz, 1H), 7.25 (s, 1H), 3.72 (s, 3H). 13C NMR (100 MHz,
129.2, 128.7, 127.5, 34.4. C18H14N2O2 (290.32): Calcd C 74.47, H 4.86,
N 9.65; Found C 74.55, H 4.99, N 9.47.
CDCl3) d 148.6, 148.4, 147.9, 134.7, 134.3, 134.0, 131.9, 131.3, 130.1,
130.0, 129.4, 123.8, 123.4, 123.1, 123.0, 34.0. C16H12N4O4 (324.29):
Calcd C 59.26, H 3.73, N 17.28; Found C 59.40, H 3.61, N 17.10.
4.1.7. 4,40-(1-Methylimidazole-2,5-diyl)dibenzonitrile (6). From 4-
bromobenzonitrile (0.546 g,
3
mmol), 1-methylimidazole
4.1.14. 3,30-(1-Methylimidazole-2,5-diyl)dibenzonitrile (13). From 3-
bromobenzonitrile (0.546 g, 3 mmol), 1-methylimidazole (0.082 g,
1 mmol) and CsOAc (1.303 g, 4 mmol) with Pd(OAc)2 (4.4 mg,
0.02 mmol), product 13 was obtained in 60% (0.170 g) yield. 1H NMR
(0.082 g, 1 mmol) and CsOAc (1.303 g, 4 mmol) with Pd(OAc)2
(4.4 mg, 0.02 mmol), product 6 was obtained in 60% (0.170 g) yield.
1H NMR (400 MHz, CDCl3)
d
7.83 (d, J¼8.4 Hz, 2H), 7.73 (d, J¼8.4 Hz,
4H), 7.55 (d, J¼8.4 Hz, 2H), 7.28 (s, 1H), 3.70 (s, 3H). 13C NMR
(400 MHz, CDCl3)
4H), 7.61 (d, J¼8.4 Hz,1H), 7.57 (d, J¼8.4 Hz, 1H), 7.23 (s, 1H), 3.68 (s,
3H). 13C NMR (100 MHz, CDCl3)
146.8, 134.1, 133.4, 133.2, 133.1,
132.4, 132.3, 132.1, 130.2, 130.1, 130.0, 118.0, 117.9, 113.6, 113.3, 34.2.
18H12N4 (284.31): Calcd C 76.04, H 4.25, N 19.71; Found C 76.29, H
d
7.99 (s, 1H), 7.98 (d, J¼8.4 Hz, 1H), 7.75e7.65 (m,
(100 MHz, CDCl3)
d 148.6, 134.9, 134.1, 133.9, 132.8, 132.6, 129.5,
129.3, 128.8, 118.4, 118.3, 112.9, 112.0, 34.4. C18H12N4 (284.31): Calcd
C 76.04, H 4.25, N 19.71; Found C 76.18, H 4.08, N 19.99.
d
C
4.1.8. 1-Methyl-2,5-bis(4-nitrophenyl)-imidazole
(7). From
4-
4.22, N 19.50.
bromonitrobenzene (0.606 g, 3 mmol), 1-methylimidazole (0.082 g,
1 mmol) and CsOAc (1.303 g, 4 mmol) with Pd(OAc)2 (4.4 mg,
0.02 mmol), product 7 was obtained in 32% (0.104 g) yield. 1H NMR
4.1.15. 1-Methyl-2,5-bis(3-(trifluoromethyl)phenyl)-imidazole
(14). From 3-bromobenzotrifluoride (0.675 g,
3 mmol), 1-
(400 MHz, DMSOd6)
d
8.39 (d, J¼8.4 Hz, 2H), 8.36 (d, J¼8.4 Hz, 2H),
methylimidazole (0.082 g, 1 mmol) and CsOAc (1.303 g, 4 mmol)

A. Takfaoui et al. / Tetrahedron 70 (2014) 8316e8323
8321
with Pd(OAc)2 (4.4 mg, 0.02 mmol), product 14 was obtained in 59%
product 19 was obtained in 54% (0.141 g) yield. 1H NMR (400 MHz,
CDCl3) 7.38e7.15 (m, 8H), 7.03 (s, 1H), 3.11 (s, 3H), 2.21 (s, 3H), 2.18
(s, 3H). 13C NMR (100 MHz, CDCl3)
147.7, 138.2, 132.4, 131.3, 130.6,
130.5, 130.4, 130.3, 129.7, 129.4, 129.0, 126.7, 125.9, 125.8, 31.5, 20.0,
19.7. C18H18N2 (262.35): Calcd C 82.41, H 6.92, N 10.68; Found C
82.50, H 6.98, N 10.40.
(0.218 g) yield. 1H NMR (400 MHz, CDCl3)
d
7.92 (s, 1H), 7.83 (d,
d
J¼8.4 Hz, 1H), 7.65e7.50 (m, 6H), 7.21 (s, 1H), 3.63 (s, 3H). 13C NMR
d
(100 MHz, CDCl3)
d
148.5, 134.5, 131.9, 131.8, 131.5 (q, J¼20.4 Hz),
131.4, 131.1 (q, J¼20.4 Hz), 130.7, 129.4, 129.2, 128.6, 125.7, (q,
J¼3.7 Hz), 125.6 (q, J¼3.7 Hz), 125.3 (q, J¼3.7 Hz), 124.8 (q,
J¼3.7 Hz), 122.5, 33.8. C18H12F6N2 (370.29): Calcd C 58.38, H 3.27, N
7.57; Found C 58.47, H 3.45, N 7.42.
4.1.21. 3,30-(1-Methylimidazole-2,5-diyl)dipyridine (20). From 3-
bromopyridine (0.474 g, 3 mmol), 1-methylimidazole (0.082 g,
1 mmol) and CsOAc (1.303 g, 4 mmol) with Pd(OAc)2 (4.4 mg,
0.02 mmol), product 20 was obtained in 72% (0.170 g) yield. 1H NMR
4.1.16. 1-Methyl-2,5-dim-tolylimidazole (15). From 3-bromotoluene
(0.513 g, 3 mmol), 1-methylimidazole (0.082 g, 1 mmol) and CsOAc
(1.303 g, 4 mmol) with Pd(OAc)2 (4.4 mg, 0.02 mmol), product 15
was obtained in 79% (0.207 g) yield. 1H NMR (400 MHz, CDCl3)
(400 MHz, CDCl3)
d
8.89 (s, 1H), 8.68 (s, 1H), 8.62 (d, J¼4.6 Hz, 1H),
8.58 (d, J¼4.6 Hz, 1H), 8.00 (d, J¼8.0 Hz, 1H), 7.73 (d, J¼8.0 Hz, 1H),
d
7.50 (s, 1H), 7.39 (d, J¼8.4 Hz, 1H), 7.30 (d, J¼8.4 Hz, 1H), 7.26 (d,
J¼8.4 Hz, 1H), 7.22e7.10 (m, 5H), 3.59 (s, 3H), 2.35 (s, 3H), 2.34 (s,
3H). 13C NMR (100 MHz, CDCl3)
174.1, 149.1, 138.5, 138.4, 135.5,
7.40e7.34 (m, 2H), 7.34 (s, 1H), 3.66 (s, 3H). 13C NMR (100 MHz,
CDCl3)
d 149.9, 149.4, 149.3, 149.2, 147.1, 136.3, 135.9, 132.6, 128.9,
d
126.6, 125.9, 123.7, 123.6, 33.7. C14H12N4 (236.27): Calcd C 71.17, H
5.12, N 23.71; Found C 71.08, H 5.20, N 23.49.
130.3,130.0,129.7, 129.5,128.8,128.7,128.4,126.7,125.8,125.7, 33.8,
21.5, 21.4. C18H18N2 (262.35): Calcd C 82.41, H 6.92, N 10.68; Found C
82.27, H 6.90, N 10.51.
4.1.22. 1-n-Butyl-2,5-bis(4-chlorophenyl)-imidazole (21b). From 4-
bromochlorobenzene (0.574 g,
3
mmol), 1-butylimidazole
4.1.17. 2,5-bis(3,5-bis(trifluoromethyl)phenyl)-1-methylimidazole
(16a). From 3,5-bis(trifluoromethyl)bromobenzene (0.879 g,
3 mmol), 1-methylimidazole (0.082 g, 1 mmol) and CsOAc (1.303 g,
4 mmol) with Pd(OAc)2 (4.4 mg, 0.02 mmol), product 16a was
obtained in 48% (0.243 g) yield. The 2,4,5-triarylated imidazole
16b was also isolated in 30% (0.215 g) yield. 16a: 1H NMR
(0.124 g, 1 mmol) and CsOAc (1.303 g, 4 mmol) with Pd(OAc)2
(4.4 mg, 0.02 mmol), product 21b was obtained in 24% (0.083 g)
yield. 1H NMR (400 MHz, CDCl3)
d
7.48 (d, J¼8.4 Hz, 2H), 7.39 (d,
J¼8.4 Hz, 2H), 7.38 (d, J¼8.4 Hz, 2H), 7.31 (d, J¼8.4 Hz, 2H), 7.06 (s,
1H), 3.99 (t, J¼7.5 Hz, 2H), 1.26e1.15 (m, 2H), 0.90e0.83 (m, 2H),
0.57 (t, J¼7.5 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d 148.3, 135.0,
(400 MHz, CDCl3)
d
8.13 (s, 2H), 7.89 (s, 1H), 7.85 (s, 3H), 7.31 (s,
147.6, 133.8, 132.7 (q,
134.2, 133.6, 130.2, 130.1, 129.9, 129.1, 128.9, 128.5, 44.9, 32.4, 19.3,
13.3. C19H18Cl2N2 (345.27): Calcd C 66.09, H 5.25, N 8.11; Found C
66.14, H 5.08, N 7.89. The mono-arylation product 21a was also
1H), 3.70 (s, 3H). 13C NMR (100 MHz, CDCl3)
d
J¼26.2 Hz), 132.1 (q, J¼26.2 Hz), 131.5, 129.6, 128.5, 128.4, 124.3,
122.8 (quint., J¼3.6 Hz), 122.1 (quint., J¼3.6 Hz), 121.6, 118.9, 33.9.
isolated in 45% yield (0.105 g): 1H NMR (400 MHz, CDCl3)
d 7.50 (s,
C
20H10F12N2 (506.29): Calcd C 47.45, H 1.99, N 5.53; Found C 47.40,
1H), 7.34 (d, J¼8.4 Hz, 2H), 7.23 (d, J¼8.4 Hz, 2H), 6.98 (s, 1H), 3.87
H 2.09, N 5.36. 16b: 1H NMR (400 MHz, CDCl3)
(s, 1H), 7.96 (s, 1H), 7.84 (s, 4H), 7.66 (s, 1H), 3.59 (s, 3H). 13C NMR
(100 MHz, CDCl3)
d 8.18 (s, 2H), 8.00
(t, J¼7.5 Hz, 2H), 1.53 (quint., J¼7.5 Hz, 2H), 1.16 (sext., J¼7.5 Hz, 2H),
0.77 (t, J¼7.5 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d 138.3, 134.0,
d
145.7, 136.4, 134.0, 132.3 (q, J¼34.8 Hz), 131.5
131.7, 130.0, 129.0, 128.7, 128.3, 45.1, 32.9, 19.6, 13.4.
(q, J¼34.8 Hz), 130.9 (q, J¼34.8 Hz), 130.7, 130.6, 129.6 (m), 128.6,
128.0 (m), 122.4 (m), 122.2 (m), 120.0 (m), 121.7 (q, J¼270.0 Hz),
121.6 (q, J¼270.0 Hz), 121.5 (q, J¼270.0 Hz), 32.6. C28H12F18N2
(718.38): Calcd C 46.81, H 1.68, N 3.90; Found C 46.99, H 1.88, N
3.99.
4.1.23. 2,5-Bis(3,5-bis(trifluoromethyl)phenyl)-1-butylimidazole
(22b). From 3,5-bis(trifluoromethyl)bromobenzene (0.879 g,
3 mmol), 1-butylimidazole (0.124 g, 1 mmol) and CsOAc (1.303 g,
4 mmol) with Pd(OAc)2 (4.4 mg, 0.02 mmol), product 22b was
obtained in 35% (0.192 g) yield. 1H NMR (400 MHz, CDCl3)
d 8.05
4.1.18. 2,20-(1-Methylimidazole-2,5-diyl)dibenzonitrile (17). From 2-
bromobenzonitrile (0.546 g, 3 mmol), 1-methylimidazole (0.082 g,
1 mmol) and CsOAc (1.303 g, 4 mmol) with Pd(OAc)2 (4.4 mg,
0.02 mmol), product 17 was obtained in 78% (0.221 g) yield. 1H NMR
(s, 2H), 7.91 (s, 1H), 7.88 (s, 1H), 7.84 (s, 2H), 7.26 (s, 1H), 4.04 (t,
J¼7.5 Hz, 2H), 1.40e1.25 (m, 2H), 1.05e0.90 (m, 2H), 0.60 (t,
J¼7.5 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d 147.3, 133.0e131.5
(m), 130.4, 128.8, 128.6, 127.1, 124.4, 122.8 (q, J¼J¼3.7 Hz), 122.1
(q, J¼3.7 Hz), 121.6, 118.9, 45.4, 32.6, 19.2, 13.0. C23H16F12N2
(548.37): Calcd C 50.38, H 2.94, N 5.11; Found C 50.19, H 2.78, N
4.83. The 2,4,5-tri-arylation product 22c was also isolated in 33%
(400 MHz, CDCl3)
7.58e7.45 (m, 3H), 7.38 (s, 1H), 3.53 (s, 3H). 13C NMR (100 MHz,
CDCl3) 146.7, 134.1, 133.7, 133.6, 133.2, 133.0, 132.9, 131.7, 131.6,
d
7.76 (d, J¼8.4 Hz, 2H), 7.70e7.65 (m, 3H),
d
131.3, 130.5, 129.7, 129.0, 117.9, 117.8, 113.1, 33.3. C18H12N4 (284.31):
Calcd C 76.04, H 4.25, N 19.71; Found C 76.09, H 4.31, N 19.57.
yield (0.251 g): 1H NMR (400 MHz, CDCl3)
d 8.11 (s, 2H), 8.02
(s, 1H), 7.97 (s, 1H), 7.85 (s, 2H), 7.78 (s, 2H), 7.64 (s, 1H), 3.89
(t, J¼7.5 Hz, 2H), 1.40e1.25 (m, 2H), 1.05e0.90 (m, 2H), 0.60
(t, J¼7.5 Hz, 3H).
4.1.19. 2,5-Bis(2-fluorophenyl)-1-methylimidazole (18). From 2-
bromofluorobenzene (0.525 g,
3 mmol), 1-methylimidazole
(0.082 g, 1 mmol) and CsOAc (1.303 g, 4 mmol) with Pd(OAc)2
4.1.24. 1-n-Butyl-2,5-dip-tolylimidazole
(23b). From
4-
(4.4 mg, 0.02 mmol), product 18 was obtained in 59% (0.159 g) yield.
bromotoluene (0.513 g, mmol), 1-butylimidazole (0.124 g,
3
1H NMR (400 MHz, CDCl3)
d
7.56 (t, J¼8.0 Hz, 1H), 7.42e7.30 (m,
1 mmol) and CsOAc (1.303 g, 4 mmol) with Pd(OAc)2 (4.4 mg,
3H), 7.25e7.08 (m, 5H), 3.42 (s, 3H). 13C NMR (100 MHz, CDCl3)
0.02 mmol), product 23b was obtained in 25% (0.076 g) yield. 1H
d
160.0 (dd, J¼249.2, 7.4 Hz), 144.7, 132.4 (d, J¼2.7 Hz), 131.9 (d,
NMR (400 MHz, CDCl3)
d
7.46 (d, J¼8.4 Hz, 2H), 7.25 (d, J¼8.4 Hz,
J¼2.7 Hz), 131.2 (d, J¼8.1 Hz), 130.4 (d, J¼8.1 Hz), 129.3, 124.6 (d,
J¼3.4 Hz), 124.4 (d, J¼3.4 Hz), 119.1 (d, J¼14.9 Hz), 118.1 (d,
J¼14.9 Hz), 116.1 (d, J¼13.2 Hz), 115.9 (d, J¼13.2 Hz), 32.4.
2H), 7.23e7.17 (m, 4H), 7.02 (s, 1H), 3.99 (t, J¼7.5 Hz, 2H), 2.34 (s,
6H), 1.26e1.15 (m, 2H), 0.90e0.83 (m, 2H), 0.54 (t, J¼7.5 Hz, 3H). 13
C
NMR (100 MHz, CDCl3)
d 149.1, 138.5, 137.8, 134.3, 129.4, 129.2,
C
16H12F2N2 (270.28): Calcd C 71.10, H 4.48, N 10.36; Found C 71.27, H
128.8, 128.7, 128.0, 127.7, 44.7, 32.3, 21.4, 21.3, 19.3, 13.3. C21H24N2
(304.43): Calcd C 82.85, H 7.95, N 9.20; Found C 82.67, H 8.14, N
9.02. The mono-arylation product 23a was also isolated in 31% yield
4.55, N 10.51.
4.1.20. 1-Methyl-2,5-dio-tolylimidazole (19). From 2-bromotoluene
(0.513 g, 3 mmol), 1-methylimidazole (0.082 g, 1 mmol) and
CsOAc (1.303 g, 4 mmol) with Pd(OAc)2 (4.4 mg, 0.02 mmol),
(0.066 g): 1H NMR (400 MHz, CDCl3)
d 7.46 (s, 1H), 7.20e7.16 (m,
4H), 6.95 (s, 1H), 3.87 (t, J¼7.5 Hz, 2H), 2.34 (s, 3H), 1.60e1.40 (m,
2H), 1.20e1.05 (m, 2H), 0.77 (t, J¼7.5 Hz, 3H). 13C NMR (100 MHz,

8322
A. Takfaoui et al. / Tetrahedron 70 (2014) 8316e8323
CDCl3)
13.5.
d
137.8, 132.9, 129.4, 128.7, 127.9, 127.3, 45.0, 32.9, 21.2, 19.7,
3 mmol), 1-benzylimidazole (0.158 g, 1 mmol) and CsOAc (1.303 g,
4 mmol) with Pd(OAc)2 (4.4 mg, 0.02 mmol), product 29b was
obtained in 32% (0.186 g) yield. 1H NMR (400 MHz, CDCl3)
8.01 (s,
d
4.1.25. 5-(4-Chlorophenyl)-1-(4-methoxyphenyl)-imidazole
(24a). From 4-bromochlorobenzene (0.574 g, mmol), 1-(4-
methoxyphenyl)-imidazole (0.174 g, 1 mmol) and CsOAc (1.303 g,
2H), 7.81 (s, 1H), 7.76 (s, 1H), 7.67 (s, 2H), 7.38 (s, 1H), 7.28e7.20 (m,
3
3H), 6.81 (d, J¼8.4 Hz, 2H), 5.19 (s, 2H). 13C NMR (100 MHz, CDCl3)
d
147.7, 135.8, 133.5, 132.4 (q, J¼34.0 Hz), 132.3 (q, J¼34.0 Hz), 132.2,
4 mmol) with Pd(OAc)2 (4.4 mg, 0.02 mmol), product 25a was
131.6, 130.4, 129.4, 128.7 (m), 128.5, 125.4, 122.9 (q, J¼272.7 Hz),
122.8 (m), 122.7 (q, J¼272.7 Hz), 122.0 (m), 49.3. C26H14F12N2
(582.38): Calcd C 53.62, H 2.42, N 4.81; Found C 53.60, H 2.54, N
4.88. The 2,4,5-tri-arylation product 30c was also isolated in 34%
obtained in 62% (0.176 g) yield. 1H NMR (400 MHz, CDCl3)
d 7.57 (s,
1H), 7.16 (d, J¼8.4 Hz, 2H), 7.13 (s, 1H), 7.02 (d, J¼8.4 Hz, 2H), 6.99 (d,
J¼8.4 Hz, 2H), 6.83 (d, J¼8.4 Hz, 2H), 3.76 (s, 3H). 13C NMR
(100 MHz, CDCl3)
d
159.4, 139.4, 133.4, 132.1, 129.3, 129.2, 128.8,
yield (0.269 g): 1H NMR (400 MHz, CDCl3)
d 8.00 (s, 2H), 7.89 (s, 1H),
128.7, 128.0, 127.0, 114.7, 55.5. C16H13ClN2O (284.74): Calcd C 67.49,
H 4.60, N 9.84; Found C 67.28, H 4.37, N 10.08.
7.87 (s, 1H), 7.84 (s, 2H), 7.64 (s, 1H), 7.59 (s, 2H), 7.25e7.20 (m, 3H),
6.73 6.81 (d, J¼8.4 Hz, 2H), 5.08 (s, 2H). 13C NMR (100 MHz, CDCl3)
d
146.9, 137.7, 135.2, 134.9, 133.1 (q, J¼34.0 Hz), 132.5 (q, J¼34.0 Hz),
4.1.26. 5-(3,5-Bis(trifluoromethyl)phenyl)-1-(4-methoxyphenyl)-im-
131.1, 131.7, 131.6, 130.8 (m), 129.4, 129.0 (m), 128.7, 126.5 (m), 125.6,
123.3 (m), 122.9 (q, J¼272.7 Hz), 122.7 (q, J¼272.7 Hz), 122.5 (q,
J¼272.7 Hz), 120.9 (m), 49.4.
idazole
(25a). From
3,5-bis(trifluoromethyl)bromobenzene
(0.879 g,
3
mmol), 1-(4-methoxyphenyl)-imidazole (0.174 g,
1 mmol) and CsOAc (1.303 g, 4 mmol) with Pd(OAc)2 (4.4 mg,
0.02 mmol), product 25a was obtained in 75% (0.289 g) yield. 1H
4.1.31. 1-Benzyl-5-(4-chlorophenyl)-imidazole (30a).10a From 4-
NMR (400 MHz, CDCl3)
d
7.62 (s, 1H), 7.62 (s, 1H), 7.46 (s, 2H), 7.35
bromochlorobenzene (0.574 g, 3 mmol), 1-benzylimidazole
(0.158 g, 1 mmol) and CsOAc (1.303 g, 4 mmol) with Pd(OAc)2
(4.4 mg, 0.02 mmol), product 30a was obtained in 44% (0.118 g)
(s, 1H), 7.05 (d, J¼8.4 Hz, 2H), 6.88 (d, J¼8.4 Hz, 2H), 3.76 (s, 3H). 13
C
NMR (100 MHz, CDCl3)
d
160.0, 140.4, 131.7 (q, J¼34.0 Hz), 130.4,
130.1, 128.4, 127.3 (m), 127.1, 123.0 (q, J¼272.7 Hz), 120.6 (m), 115.0,
55.6. C18H12F6N2O (386.29): Calcd C 55.97, H 3.13, N 7.25; Found C
55.79, H 3.20, N 7.41. The di-arylation product 25b was also isolated
yield. 1H NMR (400 MHz, CDCl3)
d
7.51 (s, 1H), 7.28e7.15 (m, 5H),
7.12 (d, J¼8.4 Hz, 2H), 7.06 (s,1H), 6.92 (d, J¼8.4 Hz, 2H), 5.06 (s, 2H).
13C NMR (100 MHz, CDCl3)
139.0, 136.5, 134.2, 132.3, 130.1, 129.0,
128.9, 128.6, 128.2, 128.1, 126.5, 48.8. The di-arylation product 30b
was also isolated: 1H NMR (400 MHz, CDCl3)
d
in low yield: 1H NMR (400 MHz, CDCl3)
d 7.79 (s, 2H), 7.70 (s, 1H),
7.66 (s, 1H), 7.50 (s, 1H), 7.47 (s, 2H), 7.03 (d, J¼8.4 Hz, 2H), 6.92 (d,
d
7.43 (d, J¼8.4 Hz,
J¼8.4 Hz, 2H), 3.78 (s, 3H).
2H), 7.27 (d, J¼8.4 Hz, 2H), 7.21e7.16 (m, 6H), 7.13 (d, J¼8.4 Hz, 2H),
6.77 (d, J¼8.4 Hz, 2H), 5.15 (s, 2H).
4.1.27. 4-(5-(4-Chlorophenyl)-imidazol-1-yl)benzaldehyde
(26a). From 4-bromochlorobenzene (0.574 g, 3 mmol), 4-(1-
imidazol-1-yl)benzaldehyde (0.172 g,
4.1.32. 1-Benzyl-5-p-tolylimidazole (31a).10a From 4-bromotoluene
(0.513 g, 3 mmol), 1-benzylimidazole (0.158 g, 1 mmol) and
CsOAc (1.303 g, 4 mmol) with Pd(OAc)2 (4.4 mg, 0.02 mmol),
product 31a was obtained in 31% (0.077 g) yield. 1H NMR (400 MHz,
1 mmol) and CsOAc
(1.303 g, 4 mmol) with Pd(OAc)2 (4.4 mg, 0.02 mmol), product 26a
was obtained in 53% (0.149 g) yield. 1H NMR (400 MHz, CDCl3)
d
9.97 (s, 1H), 7.87 (d, J¼8.4 Hz, 2H), 7.70 (s, 1H), 7.27 (d, J¼8.4 Hz,
CDCl3) d 7.48 (s, 1H), 7.30e7.15 (m, 3H), 7.10 (s, 4H), 7.04 (s, 1H), 6.95
2H), 7.22 (s, 1H), 7.20 (d, J¼8.4 Hz, 2H), 6.99 (d, J¼8.4 Hz, 2H). 13
C
(d, J¼8.0 Hz, 2H), 5.06 (s, 2H), 2.29 (s, 3H). 13C NMR (100 MHz,
NMR (100 MHz, CDCl3)
d
190.7,141.1,135.6,134.0,131.0,130.0,129.4,
CDCl3) d 138.4, 138.0, 136.9, 133.5, 129.4, 128.9, 128.8, 128.0, 127.9,
129.0, 127.4, 125.7. C16H11ClN2O (282.72): Calcd C 67.97, H 3.92, N
9.91; Found C 67.75, H 3.97, N 9.72.
126.8, 126.7, 48.7, 21.2. The di-arylation product 31b was also iso-
lated: 1H NMR (400 MHz, CDCl3)
7.37 (d, J¼8.4 Hz, 2H), 7.20e7.00
(m,10H), 6.77 (d, J¼8.4 Hz, 2H), 5.17 (s, 2H), 2.26 (s, 3H), 2.25 (s, 3H).
13C NMR (100 MHz, CDCl3)
138.7, 138.0, 137.9, 134.9, 129.3, 129.2,
d
4.1.28. 4-(5-(3,5-Bis(trifluoromethyl)phenyl)-imidazol-1-yl)benzal-
d
dehyde
(27a). From
3,5-bis(trifluoromethyl)bromobenzene
128.9, 128.7, 128.6, 128.2, 127.9, 127.3, 125.8, 48.4, 21.3, 21.2.
(0.879 g, 3 mmol), 4-(1-imidazol-1-yl)benzaldehyde (0.172 g,
1 mmol) and CsOAc (1.303 g, 4 mmol) with Pd(OAc)2 (4.4 mg,
0.02 mmol), product 27a was obtained in 52% (0.200 g) yield. Trace
of diarylation product were observed by GC/MS analysis of the
Acknowledgements
We thank the Centre National de la Recherche Scientifique,
“Rennes Metropole”, the Universite Mohamed Premier and “Faculte
des Sciences d’Oujda” for providing financial support.
crude mixture. 1H NMR (400 MHz, CDCl3)
d 10.00 (s, 1H), 7.92 (d,
ꢀ
ꢀ
J¼8.4 Hz, 2H), 7.77 (s, 1H), 7.70 (s, 1H), 7.47 (s, 2H), 7.40 (s, 1H), 7.30
(d, J¼8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3)
d 190.4, 140.4, 139.9,
136.1, 132.2 (q, J¼34.0 Hz), 131.4, 131.2, 131.1, 127.7 (m), 126.0, 122.4
(q, J¼272.7 Hz), 121.3 (m). C18H10F6N2O (384.28): Calcd C 56.26, H
2.62, N 7.29; Found C 56.41, H 2.47, N 7.48.
References and notes
1. (a) Li, J. J.; Gribble, G. W. Palladium in Heterocyclic Chemistry; Pergamon: Am-
sterdam, 2000; (b) Schnurch, M.; Flasik, R.; Khan, A. F.; Spina, M.; Mihovilovic,
€
M. D.; Stanetty, P. Eur. J. Org. Chem. 2006, 3283e3307.
2. Ohta, A.; Akita, Y.; Ohkuwa, T.; Chiba, M.; Fukunaga, R.; Miyafuji, A.; Nakata, T.;
Tani, N.; Aoyagi, Y. Heterocycles 1990, 31, 1951e1958.
4.1.29. 4-(1-Benzylimidazol-5-yl)benzonitrile
(28a). From
4-
bromobenzonitrile (0.546 g, 3 mmol), 1-benzylimidazole (0.158 g,
1 mmol) and CsOAc (1.303 g, 4 mmol) with Pd(OAc)2 (4.4 mg,
0.02 mmol), product 28a was obtained in 41% (0.106 g) yield. 1H
3. For reviews on Pd-catalysed C-H functionalisations: (a) Alberico, D.; Scott, M.
E.; Lautens, M. Chem. Rev. 2007, 107, 174e238; (b) Satoh, T.; Miura, M. Chem. Lett.
2007, 36, 200e205; (c) Li, B.-J.; Yang, S.-D.; Shi, Z.-J. Synlett 2008, 949e957; (d)
Bellina, F.; Rossi, R. Tetrahedron 2009, 65, 10269e10310; (e) Li, B.-J.; Yang, S.-D.;
Shi, Z.-J. Synlett 2008, 949e957; (f) Ackermann, L.; Vincente, R.; Kapdi, A. R.
Angew. Chem., Int. Ed. 2009, 48, 9792e9826; (g) Roger, J.; Gottumukkala, A. L.;
Doucet, H. ChemCatChem 2010, 2, 20e40; (h) Wu, X.-F.; Anbarasan, P.; Neu-
mann, H.; Beller, M. Angew. Chem., Int. Ed. 2010, 49, 7316e7319; (i) Kuhl, N.;
Hopkinson, M. N.; Wencel-Delord, J.; Glorius, F. Angew. Chem., Int. Ed. 2012, 51,
10236e10254; (j) Yamaguchi, J.; Yamaguchi, A. D.; Itami, K. Angew. Chem., Int.
Ed. 2012, 51, 8960e9009; (k) Wencel-Delord, J.; Glorius, F. Nat. Chem. 2013, 5,
369e375; (l) Kuzhushkov, S. I.; Potukuchi, H. K.; Ackermann, L. Catal. Sci.
Technol. 2013, 3, 562e571; (m) Yuan, K.; Doucet, H. ChemCatChem 2013, 5,
3495e3496; (n) Rossi, R.; Bellina, F.; Lessi, M.; Manzini, C. Adv. Synth. Catal.
NMR (400 MHz, CDCl3)
J¼8.4 Hz, 2H), 7.26e7.20 (m, 3H), 7.17 (s, 1H), 6.93 (d, J¼8.4 Hz, 2H),
5.13 (s, 2H). 13C NMR (100 MHz, CDCl3)
140.2, 136.1, 134.3, 132.5,
d
7.57 (s, 1H), 7.55 (d, J¼8.4 Hz, 2H), 7.31 (d,
d
131.7, 130.0, 129.1, 128.8, 128.3, 126.4, 118.5, 111.5, 49.1. C17H13N3
(259.31): Calcd C 78.74, H 5.05, N 16.20; Found C 78.40, H 4.99, N
15.91.
4.1.30. 1-Benzyl-2,5-bis(3,5-bis(trifluoromethyl)phenyl)-imidazole
(29b). From 3,5-bis(trifluoromethyl)bromobenzene (0.879 g,

A. Takfaoui et al. / Tetrahedron 70 (2014) 8316e8323
8323
ꢀ
2014, 356, 17e117; (o) He, M.; Soule, J. F.; Doucet, H. ChemCatChem 2014, 6,
1824e1859.
Gowrisankar, S.; Kim, J. N. Tetrahedron 2008, 64, 7183e7190; (i) Storr, T. E.;
Firth, A. G.; Wilson, K.; Darley, K.; Baumann, C. G.; Fairlamb, I. J. S. Tetrahedron
2008, 64, 6125e6137; (k) Zhao, D.; Wang, W.; Lian, S.; Yang, F.; Lan, J.; You, J.
Chem.dEur. J. 2009, 15, 1337e1340.
4. Aoyagi, Y.; Inoue, A.; Koizumi, I.; Hashimoto, R.; Miyafuji, A.; Kunoh, J.; Honma,
R.; Akita, Y.; Ohta, A. Heterocycles 1992, 33, 257e272.
5. For examples of intermolecular direct 5-arylation of imidazole derivatives: (a)
Kondo, Y.; Komine, T.; Sakamoto, T. Org. Lett. 2000, 2, 3111e3113; (b) Bellina, F.;
Cauteruccio, S.; Mannina, L.; Rossi, R.; Viel, S. J. Org. Chem. 2005, 70,
3997e4005; (c) Toure, B. B.; Lane, B. S.; Sames, D. Org. Lett. 2006, 8, 1979e1982;
7. For examples of Pd-catalysed intermolecular direct 5-arylations of imidazole
derivatives with formation of 2,5-diarylated imidazole in low yield: (a) Arai, N.;
Takahashi, M.; Mitani, M.; Mori, A. Synlett 2006, 3170e3172; (b) Kumar, P. V.;
Lin, W.-S.; Shen, J.-S.; Nandi, D.; Lee, H. M. Organometallics 2011, 30, 5160e5169.
8. For Pd-catalysed direct 2,5-diarylations of imidazoles in the presence of CuI: (a)
Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Bull. Chem. Soc.
Jpn. 1998, 71, 467e473; (b) Bellina, F.; Cauteruccio, S.; Mannina, L.; Rossi, R.;
Viel, S. Eur. J. Org. Chem. 2006, 693e703; (c) Bellina, F.; Cauteruccio, S.; Di Flore,
A.; Rossi, R. Eur. J. Org. Chem. 2008, 5436e5445.
ꢀ
(d) Chiong, H. A.; Daugulis, O. Org. Lett. 2007, 9, 1449e1451; (e) Liegaut, B.;
Lapointe, D.; Caron, L.; Vlassova, A.; Fagnou, K. J. Org. Chem. 2009, 74,
1826e1834; (f) Skogh, A.; Fransson, R.; Skoeld, C.; Larhed, M.; Sandstroem, A. J.
Org. Chem. 2013, 78, 12251e12256; (g) Bellina, F.; Lessi, M.; Manzini, C. Eur. J.
Org. Chem. 2013, 5621e5630.
6. For selected examples of direct 2-arylation of imidazole derivatives: (a) Gracias,
V.; Gasiecki, A. F.; Pagano, T. G.; Djuric, S. W. Tetrahedron Lett. 2006, 47,
8873e8876; (b) Bellina, F.; Cauteruccio, S.; Rossi, R. Eur. J. Org. Chem. 2006,
1379e1382; (c) Cerna, I.; Pohl, R.; Klepetarova, B.; Hocek, M. Org. Lett. 2006, 8,
5389e5392; (d) Bellina, F.; Calandri, C.; Cauteruccio, S.; Rossi, R. Tetrahedron
2007, 63, 1970e1980; (e) Bellina, F.; Cauteruccio, S.; Rossi, R. J. Org. Chem. 2007,
72, 8543e8546; (f) Majumdar, K. C.; Debnath, P.; Taher, A.; Pal, A. K. Can. J.
Chem. 2008, 86, 325e332; (g) Sahnoun, S.; Messaoudi, S.; Peyrat, J.-F.; Brion, J.-
D.; Alami, M. Tetrahedron Lett. 2008, 49, 7279e7283; (h) Lee, H. S.; Kim, S. H.;
9. For Pd-catalysed direct 2,5-diarylations of imidazoles: (a) Shibahara, F.; Ya-
maguchi, E.; Murai, T. Chem. Commun. 2010, 2471e2473; (b) Shibahara, F.; Ya-
maguchi, E.; Murai, T. J. Org. Chem. 2011, 76, 2680e2693.
10. For sequential direct 2,5-diarylation of imidazoles: (a) Bellina, F.; Cauteruccio,
S.; Di Fiore, A.; Marchetti, C.; Rossi, R. Tetrahedron 2008, 64, 6060e6072; (b) Joo,
J. M.; Toure, B. B.; Sames, D. J. Org. Chem. 2010, 75, 4911e4920; (c) Shibahara, F.;
Yamauchi, T.; Yamaguchi, E.; Murai, T. J. Org. Chem. 2012, 77, 8815e8820.
11. Roger, J.; Doucet, H. Tetrahedron 2009, 65, 9772e9781.