Highly efficient copper-catalyzed formation of N-aryl diazoles using KF/A12O3

Article abstract of DOI:10.1055/s-2006-947344

A simple and efficient method for the coupling of aryl iodides with heterocyclic compounds such as diazoles that does not require the use of alkoxide bases is described. The C-N bond forming procedure shows that the combination of air stable CuI and 1,10-phenanthroline in the presence of KF/Al₂O₃ comprises an extremely efficient and general catalyst system for the N-arylation of aryl iodides. Different functionalized aryl iodides were coupled with diazoles using this method. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-947344

2124
LETTER
Highly Efficient Copper-Catalyzed Formation of N-Aryl Diazoles Using
KF/Al2O3
C
opper-Catalyze
a
h
of
N
-
Aryl
D
m
iazoles an Hosseinzadeh,*a Mahmood Tajbakhsh,a Mohammad Alikaramia,b
a
Faculty of Basic Science, Mazandaran University, Babolsar, Iran
b
Islamic Azad University, Ilam, Iran
Fax +98(11252)42002; E-mail: r.hosseinzadeh@umz.ac.ir
Received 26 March 2006
as well as the higher costs have lessened the utility of this
method.12 Buchwald et al. reported the copper-based
protocol for the formation of N-aryl.13,14 Most of these
methods require Cs2CO3, K3PO4, K2CO3, etc. as a base in
Abstract: A simple and efficient method for the coupling of aryl
iodides with heterocyclic compounds such as diazoles that does not
require the use of alkoxide bases is described. The C–N bond form-
ing procedure shows that the combination of air stable CuI and 1,10-
phenanthroline in the presence of KF/Al2O3 comprises an extremely a sealed tube. The fact that Cs2CO3 has a high sensitivity
efficient and general catalyst system for the N-arylation of aryl
to moisture reduces its capability as a base in moisture
iodides. Different functionalized aryl iodides were coupled with
diazoles using this method.
sensitive reactions. On the other hand the application of
KF/Al2O3 to organic synthesis has provided new methods
for a wide array of organic reactions, many of which are
Key words: diazole, aryl iodides, copper iodide, coupling reaction,
staples of synthetic organic chemistry.15 Its benefits have
potassium fluoride on alumina
been achieved by taking advantage of the strongly basic
nature of KF/Al2O3 which has allowed it to replace organ-
ic bases in a number of reactions.16 In many cases, the use
of this base provides milder conditions and simpler proce-
dures than previously reported methods.
Nitrogen-containing heterocycles such as N-arylamines,
N-arylpyrroles, N-arylindoles, N-arylimidazoles and N-
arylpyrazoles are subunits found in numerous natural
products and in many biologically active pharmaceuticals
and recently, in the area of N-heterocyclic carbene chem-
istry.1–4 It is therefore important that general methods to
synthesize or to modify such compounds are developed.
Certain classes of compounds available through these pro-
cesses include N-arylated azoles,5 N-arylated oxazolidin-
2-ones,6,7 which are industrially important synthetic tar-
gets. One such reaction is the cross-coupling of NH-con-
taining heterocycles with aryl halides to form the
respective N-arylated heterocycle (Ullmann coupling). To
date, there have been numerous copper-mediated or cop-
per-catalyzed methods published to allow for such a trans-
formation.8 However, these reports, while significant
contributions, generally suffer from important limitations
such as high reaction temperatures (often 140 °C or high-
er), sometimes requiring stoichiometric amounts of cop-
per reagents, long reaction times and showing poor
substrate generality.9,10 Another limitation is that, to date,
no single method has found success with each of the major
classes of nitrogen heterocycles (imidazoles, pyrroles,
pyrazoles, etc.). Recently, the use of C–H bond function-
alization via palladium and ruthenium catalysis has been
applied to the arylation of several azoles.11 Those methods
provide access to a wide range of azole derivatives, but
high temperatures are necessary. Palladium-catalyzed
cross-coupling of N–H heterocycles with aryl halides has
been moderately successful, but limitations in terms of
generality, sensitivity of palladium to the air and moisture,
We have explored the CuI-catalyzed N-arylation of aryl
iodides with imidazole, 4-methylimidazole, pyrrazole and
benzimidazole using 1,10-phenanthroline (20 mol%) as a
simple ligand and KF/Al2O3 as a suitable base in the
presence of CuI (20 mol%, Scheme 1).
H
N
R
N
N
N
H
CuI (20 mol%), KF/Al2O3,
R
130–140 °C
N
R
N
I
+
N
1,10-phenanthroline (20 mol%)
N
N
R
N
H
N
N
Scheme 1
The choice of 1,10-phenanthroline as ligand and KF/
Al2O3 as base in the presence of CuI (20 mol%) was made
because we have recently used this system for C–N and
C–O bond formation.17,18
To find the optimum conditions, we chose the cross-cou-
pling reaction of iodobenzene and imidazole in the pres-
ence of 1,10-phenanthroline, KF/Al2O3 and CuI in xylene
and toluene as solvents at reflux. The yield of N-phen-
ylimidazole in xylene after 13 hours was 97% while in tol-
uene after 13 hours the yield was 92%.
SYNLETT 2006, No. 13, pp 2124–2126
Advanced online publication: 12.07.2006
DOI: 10.1055/s-2006-947344; Art ID: D06206ST
© Georg Thieme Verlag Stuttgart · New York
1
7
.0
8
.2
0
0
6
Using the above protocol, we subjected a series of aryl
iodides to these reaction conditions (Table 1).19

LETTER
Copper-Catalyzed Formation of N-Aryl Diazoles
2125
Table 1 The Copper-Catalyzed N-Arylation of Aryl Iodides in the Presence of KF/Al2O3
Entry
1
Aryliodide
Diazole
Producta
Time (h)
13
Yield (%)b
97
N
N
H
I
N
N
N
N
2
3
13
13
95
94
N
I
I
I
H
N
N
N
N
N
H
Me
N
4
5
6
13
15
15
95
94
94
N
N
H
N
Me
N
N
I
I
N
MeO
MeO
MeO
MeO
H
N
N
N
N
H
N
N
OMe
N
N
7
8
15
11
86
98
I
MeO
F3C
N
H
F3C
N
N
H
I
N
N
MeO
N
N
OMe
I
N
9
17
76
N
H
Me
I
Me
N
N
H
10
11
17
17
80
82
N
N
N
Me
Me
I
N
N
H
N
N
I
N
N
N
12
15
74
H
a Performed using 20 mol% of 1,10-phenanthroline as ligand,1.0 equiv of aryl iodide, 3 equiv of diazole, and 5 equiv of KF/Al2O3 as base at
130–140 °C.
b Isolated yields; products were characterized by 1H NMR spectroscopy and melting point.
As can be seen in Table 1, imidazole, 4-methylimidazole, the ortho- and para-position of the aromatic ring also give
pyrrazole and benzimidazole were successfully trans- excellent yield of the corresponding N-aryl compounds.
formed to their corresponding N-aryl compounds. The re- The fused compounds such as 1-iodonaphtalene with im-
action between these diazoles with iodobenzene gives idazole also gives excellent yield of the corresponding N-
excellent yields after 13 hours (entries 1–4). Substrates aryl compound (entry 12).
possessing electron-withdrawing groups such as CF3 in
In summary, we have developed an experimentally simple
meta-position (entry 8) and electron-releasing groups
and inexpensive catalyst system for the N-arylation of
such as OMe (entries 5–7, 9), and Me (entries 10, 11) in
diazoles. We believe that potassium fluoride supported on
Synlett 2006, No. 13, 2124–2126 © Thieme Stuttgart · New York

2126
R. Hosseinzadeh et al.
LETTER
(7) Moureau, F.; Wouters, J.; Vercauteren, D. P.; Collin, S.;
alumina (KF/Al2O3) provides an excellent complement to
the other bases such as Cs2CO3 in copper-catalyzed
methodology that has already been utilized in a number of
applications.
Evrard, G.; Durant, F.; Ducrey, F.; Koenig, J. J.; Jarreau, F.
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General Procedure
To a solution of diazole (3 mmol) and aryl iodides (1 mmol) in
xylene (3 mL) under argon atmosphere were added CuI (38 mg, 20
mol%) and 1,10-phenanthroline (40 mg, 20 mol%) followed by KF/
Al2O320 (5 equiv, 780 mg) and stirred at 130–140 °C for specified
times (Table 1). The progress of the reaction was monitored by
TLC. The reaction mixture allowed to cool to r.t. and was then par-
titioned between CH2Cl2 (30 mL) and sat. aq NH4Cl (3 × 10 mL).
The organic phase was washed with H2O (3 × 10 mL), dried
(Na2SO4), filtered and concentrated. The crude product was purified
by column chromatography on silica gel using hexane–EtOAc as
eluent (9:1).
Acknowledgment
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(b) Sezen, B.; Sames, D. J. Am. Chem. Soc. 2003, 125,
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Financial support of this work from the Research Council of
Mazandaran University is gratefully acknowledged.
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Entry 3: colorless solid; mp 96–98 °C (Lit.21 98 °C). 1H
NMR (90 MHz, CDCl3): d = 8.1 (1 H, s), 7.8 (1 H, m), 7.6–
7.3 (8 H, m). Anal. Calcd for C13H10N2: C, 80.38; H, 5.20; N,
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Entry 5: brown solid; mp 60–62 °C (Lit.9b 60–61 °C). 1H
NMR (90 MHz, CDCl3): d = 7.7 (1 H, br s), 7.3–7.1 (4 H, m),
7.12 (1 H, s), 6.8 (1 H, s), 3.9 (3 H, s). Anal. Calcd for
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5.67; N, 16.01.
Entry 6: liquid. 1H NMR (90 MHz, CDCl3): d = 7.8–7.5 (4
H, m), 7.2–6.9 (2 H, m), 6.5 (1 H, s), 3.9 (3 H, s). Anal. Calcd
for C10H10N2O: C, 68.94; H, 5.78; N, 16.08. Found: C,
68.81; H, 5.56; N, 16.19.
Entry 10: yellow oil. 1H NMR (90 MHz, CDCl3:) d = 7.5 (1
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for C10H10N2: C, 75.73; H, 6.47; N, 17.70. Found: C, 75.91;
H, 6.35; N, 17.80.
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Synlett 2006, No. 13, 2124–2126 © Thieme Stuttgart · New York