Copper-catalyzed N-arylation of diazoles with aryl bromides using KF/Al2O3: an improved protocol

Article abstract of DOI:10.1016/j.tetlet.2006.05.014

Copper-catalyzed N-arylation of diazoles can be accomplished using air-stable CuI as a copper source and 1,10-phenanthroline in the presence of KF/Al₂O₃ as a base. This is a simple and efficient method for the coupling of aryl bromide with diazoles. Different functionalized aryl bromides were coupled with diazoles using this system.

Full text of DOI:10.1016/j.tetlet.2006.05.014

Tetrahedron Letters 47 (2006) 5203–5205
Copper-catalyzed N-arylation of diazoles with aryl bromides using
KF/Al2O3: an improved protocol
Rahman Hosseinzadeh,a,* Mahmood Tajbakhsha and Mohammad Alikaramia,b
aFaculty of Basic Science, Mazandaran University, Babolsar, Iran
bIslamic Azad University, Ilam, Iran
Received 17 March 2006; revised 28 April 2006; accepted 4 May 2006
Available online 5 June 2006
Abstract—Copper-catalyzed N-arylation of diazoles can be accomplished using air-stable CuI as a copper source and 1,10-phenan-
throline in the presence of KF/Al2O3 as a base. This is a simple and efficient method for the coupling of aryl bromide with diazoles.
Different functionalized aryl bromides were coupled with diazoles using this system.
ꢀ 2006 Elsevier Ltd. All rights reserved.
N-Arylamines, N-arylpyrroles, N-arylindoles, N-arylim-
idazoles and N-arylpyrazoles are prevalent in compounds
that are of biological, pharmaceutical and material inter-
est.1–3 These compounds have been synthesized via SNAr
substitution of azoles with aryl halides bearing electron-
withdrawing substituents.4 Copper-catalyzed Ullmann-
type reactions are traditional methods for preparing these
compounds.5 These reactions have been carried out at
high temperatures and many functional groups are not
tolerated, and therefore their use is greatly limited.5 In
addition, these reactions often require the use of stoichio-
metric amounts of copper reagents, which, on scale-
up, leads to problems of waste disposal.6 To overcome
these drawbacks, several Pd-catalyzed C–N bond forma-
tion methods have been developed, which, together with
sterically hindered phosphine ligands, allow many
coupling reactions of aryl halides with N-containing
compounds to proceed under relatively mild conditions
and at low temperature.7 However, industrial use of these
methods is problematic in many cases due to their air and
moisture sensitivity, as well as the higher costs of Pd
catalysts and the ligands.8 Buchwald et al. and others
have reported a copper-based protocol for the formation
of N-aryl bonds.9–12 Most of these methods require long
reaction times and bases such as Cs2CO3, K3PO4, K2CO3,
etc. Cs2CO3 is very sensitive to moisture and this problem
reduces its ability as a base in moisture sensitive reactions.
On the other hand, the application of KF/Al2O3 to organ-
ic synthesis has provided new methods for a wide range of
organic reactions, many of which are staples of synthetic
organic chemistry.13 Its benefits include its strongly basic
character which has led to its replacing organic bases in a
number of reactions.14 In many cases, the use of this base
provides milder conditions and simpler procedures than
previously reported methods. We have modified the
copper-catalyzed N-arylation reaction of aryl bromides
using KF/Al2O3 as a base.
We have explored the CuI-catalyzed N-arylation of
imidazole, pyrazole and benzimidazole with aryl bro-
mides using 1,10-phenanthroline (20 mol %) as a simple
ligand and KF/Al2O3 as base in the presence of CuI
(20 mol %) (Scheme 1).
1,10-Phenanthroline as ligand and KF/Al2O3 as base in
the presence of CuI (20 mol %) were chosen as we have
recently used this system for C–N and C–O bond forma-
tions in N-amidation and O-arylation.15,16
The reaction conditions were optimized using the cross-
coupling reaction of bromobenzene and imidazole in the
presence of 1,10-phenanthroline, KF/Al2O3 and CuI in
xylene or toluene as solvent at 110–140 ꢁC. The yield
of N-phenylimidazole in xylene after 15 h was 92% while
in toluene after 15 h it was 87%.
Keywords: Copper-catalyzed; Coupling; N-arylation; Diazoles; Aryl
bromide.
Using the above protocol, we subjected a series of aryl
bromides to these reaction conditions (Table 1).
*
Corresponding author. Fax: +98 11252 42002;
r.hosseinzadeh@umz.ac.ir
e-mail:
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.014

5204
R. Hosseinzadeh et al. / Tetrahedron Letters 47 (2006) 5203–5205
H
R
R
N
N
N
N
H
R
ο
N
20 mol% CuI, KF/Al2O3, 130-140 C
N
N
Br
N
+
N
20 mol%1,10-phenanthroline
N
R
N
N
H
Scheme 1.
Table 1. The copper-catalyzed N-arylation of aryl bromides in the presence of KF/Al2O3
Entry
Aryl bromide
Diazole
Producta
Time (h)
15
Yield (%)b
92
N
Br
1
N
NH
N
N
N
N
2
3
15
15
92
90
Br
Br
NH
N
N
N
N
H
N
4
5
NH
15
16
91
89
Br
N
N
N
MeO
MeO
N
N
Br
NH
MeO
MeO
N
N
6
7
16
17
88
80
Br
Br
NH
N
N
N
N
N
OMe
MeO
Br
N
H
OMe
N
N
8
9
16
18
91
71
N
H
OMe
OMe
MeO
N
Br
N
N
N
H
Br
Br
CH3
N
N
CH3
10
11
12
13
18
18
17
15
80
81
71
90
NH
N
CH3
N
N
CH3
Br
NH
N
N
N
N
N
N
NH
NH
N
Br
N
N
a Reaction performed using 20 mol % of 1,10-phenanthroline as ligand, 1.0 equiv of aryl bromide, 3 equiv of diazole and 5 equiv of KF/Al2O3 as base
in xylene as solvent at 130–140 ꢁC.
b Isolated yields; products were characterized by 1H NMR and from mps.

R. Hosseinzadeh et al. / Tetrahedron Letters 47 (2006) 5203–5205
5205
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As can be seen in Table 1, imidazole, 4-methylimidazole,
pyrazole and benzimidazole were successfully trans-
formed to the corresponding N-aryl compounds. The
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In summary, we have developed an experimentally sim-
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of diazoles.17 We believe that potassium fluoride sup-
ported on alumina (KF/Al2O3) provides an excellent
complement to other bases such as Cs2CO3, in copper-
catalyzed coupling reactions which have already been
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Acknowledgements
Financial support of this work from the Research
Council of Mazandaran University is gratefully
acknowledged.
References and notes
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17. General procedure for the copper-catalyzed N-arylation of
aryl bromides in the presence of KF/Al2O3 (Table 1). To a
solution of diazole (3 mmol) and aryl bromide (1 mmol) in
xylene (3 ml) under an argon atmosphere were added CuI
(38 mg, 20 mol %) and 1,10-phenanthroline (40 mg,
18
20 mol %) followed by KF/Al2O3 (5 equiv, 780 mg)
and the reaction was stirred at 130–140 ꢁC for the specified
time (Table 1). The progress of the reaction was monitored
by TLC. The reaction mixture was allowed to cool to
room temperature and was then partitioned between
CH2Cl2 (30 ml) and saturated aqueous NH4Cl solution
(3 · 10 ml). The organic fraction was washed with water
(3 · 10 ml), dried (Na2SO4), filtered and concentrated. The
crude product was purified by column chromatography on
silica gel using hexane:ethyl acetate (1:9) as eluent to
afford the pure product.
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