Practical copper-catalyzed N-arylation of nitrogen heterocycles with aryl halides under ligand and additive free conditions

Article abstract of DOI:10.1016/j.tetlet.2006.11.050

N-arylation of a wide variety of nitrogen heterocycles with aryl iodides catalyzed by copper iodide under mild ligand and additive free conditions (ⁿBu₄NBr, PhMe, NaOH, reflux, 22 h) was accomplished in good to excellent yields (up to 95%) and substrate conversions (up to 99%).

Full text of DOI:10.1016/j.tetlet.2006.11.050

Tetrahedron Letters 48 (2007) 245–248
Practical copper-catalyzed N-arylation of nitrogen
heterocycles with aryl halides under ligand
and additive free conditions
Joyce Wei Wei Chang, Xiuhui Xu and Philip Wai Hong Chan*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, College of Science,
Nanyang Technological University, Singapore
Received 20 September 2006; revised 30 October 2006; accepted 9 November 2006
Abstract—N-arylation of a wide variety of nitrogen heterocycles with aryl iodides catalyzed by copper iodide under mild ligand and
additive free conditions (nBu4NBr, PhMe, NaOH, reflux, 22 h) was accomplished in good to excellent yields (up to 95%) and sub-
strate conversions (up to 99%).
ꢀ 2006 Elsevier Ltd. All rights reserved.
The ability to construct N-arylated nitrogen heterocy-
cles efficiently is currently an active area in organic syn-
thesis due to the prevalence of this structural motif in a
myriad of bioactive important natural products and
pharmaceutically interesting compounds.1 Among the
various strategies developed to date, the copper-cata-
lyzed Ullmann coupling reaction2 has proven to be
one of the most convenient synthetic routes for install-
ing the N-aryl functionality.2–9 However, such reactions
have traditionally suffered from high reaction tempera-
tures (typically above 140 ꢁC), the need for stoichio-
metric amounts of copper catalyst that make scale up
unfeasible and ecologically unfriendly, the use of toxic
and air-sensitive aryl coupling reagents that can be diffi-
cult to access, and excess aryl halide starting materials to
achieve reasonable product yields. In addition, low func-
tional group tolerance and poor substrate generality
that includes the lack of a general N-arylation method
for each of the major classes of nitrogen heterocycles
such as imidazoles, pyrazoles, and indoles, have lessened
the utility of these methods.2,3 In view of these short-
comings, the establishment of copper-mediated
approaches under milder conditions has been actively
pursued.4–9 A recent notable achievement has been the
use of ‘Cu + ligand’ (ligand = diamine or amino acid)
catalytic systems by Buchwald5 and Ma6 who showed
that the N-arylation of a variety of nitrogen heterocycles
could be achieved in good yields. Following these pio-
neering works, a number of groups have reported simi-
lar approaches using a variety of diamines, Schiff-bases,
[1,10]-phenanthroline, quinoline, aminoarenethiol, and
oxime-phosphine oxide derivatives as ligands for Cu-
catalyzed N-arylation of nitrogen heterocycles.7 Despite
these advances, examples on analogous reactions that
do not require a ligand or additive in tandem with aryl
halides as the starting materials have remained sparse.
As a result of a long standing interest in metal catalyzed
C–N bond formation in our group,10 we report herein
our preliminary findings on copper iodide catalyzed N-
arylation of a variety of nitrogen heterocycles with equi-
molar amounts of aryl iodides in yields up to 95% that
are comparable to those reported using ligand and addi-
tive promoted strategies.5–7
At the outset of this study, we found that treatment of
pyrrole (1 equiv) with iodobenzene (1 equiv), 5 mol %
CuI as catalyst, 5 mol % nBu4NBr as phase transfer
catalyst, and NaOH (2 equiv) in toluene at reflux for
22 h gave the best result, furnishing N-phenylpyrrole
in 95% yield (Table 1, entry 1).11 Similar product yields
were observed for reactions with catalyst loadings
increasing to 10 or 20 mol % (entries 3 and 4) and at this
latter catalyst loading with 3 equiv of NaOH (entry 6).
Slightly lower product yields (68–73%) were obtained
upon lowering either the catalyst loading of CuI
to 1 mol % (entry 2) or NaOH to 1 equiv in the
*
Corresponding author. Tel.: +65 6316 8760; fax: +65 6791 1961;
e-mail: waihong@ntu.edu.sg
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.11.050

246
J. W. W. Chang et al. / Tetrahedron Letters 48 (2007) 245–248
Table 1. Optimization of the reaction conditionsa
CuI, nBu4NBr
N
+
X
N
base, PhMe
reflux, 22 h
H
X = I, Br
Entry
CuI (mol %)
nBu4NBr (mol %)
Baseb
Yieldc (%)
1
2
3
4
5
5
1
5
1
NaOH (2)
NaOH (2)
NaOH (2)
NaOH (2)
NaOH (1)
NaOH (3)
NaOH (2)
NaOH (2)
K3PO4 (3)
K3PO4 (3)f
K2CO3 (3)
K2CO3 (3)g
Al2O3 (3)
95d
68
88
87
73
86d
25d
4
10
20
20
20
5
10
20
20
20
5
—
20
20
20
20
20
20
20
20
20
6
7e
8
5
9
20
20
20
20
20
20
20
20
20
49
14
16
10
11
12
13
14
15
16
17
h
—
11
6
MgO (3)
LiOHÆH2O (3)
MeCO2Na (3)
Pyridine (3)
4
h
—
h
—
a All reactions were performed for 22 h with CuI:nBu4NBr:base, molar ratio as stated in the table in PhMe at reflux.
b Values in parentheses denote the equiv of base used.
c 1H NMR yield with CH2Br2 as the internal standard.
d Isolated yield.
e Reaction carried out with C6H5Br in place of C6H5I.
f Reaction carried out with K3PO4 in 5 mL of water.
g Reaction carried out with K2CO3 dried to a constant volume prior to use.
h No reaction.
presence of 20 mol % of CuI (entry 5). In contrast, when
bromobenzene was employed as the aryl halide reagent,
N-phenylpyrrole was afforded in a markedly lower yield
of 25% (entry 7).
hand, gave no reaction (entry 12) while the use of 5 mL
of a saturated solution of K3PO4 in water was also
found to be detrimental and a low product yield of
14% was obtained (entry 10).
Inspection of entries 9–11 and 13–15 in Table 1 revealed
that CuI-catalyzed coupling of pyrrole with iodobenzene
and other inorganic bases was significantly less effective.
Under the conditions of 1 equiv of pyrrole, 1 equiv of
To define the scope of the CuI-catalyzed N-arylation
reactions, we applied this process to a series of nitrogen
heterocycles and aryl iodide derivatives (Table 2). These
reactions afforded the corresponding N-arylated adducts
in good to excellent yields (up to 90%) and substrate
conversion (up to 99%) (entries 2–15). Notably, we were
able to exploit the difference in reactivity of aryl halides
(I > Br ꢀ Cl > F) in the present method by coupling
pyrrole and the aryl iodide selectively in the presence
of substrates containing aryl bromides, chlorides, and
fluorides (entries 2–4). The electronic nature of the aryl
iodide was also found to have no effect on the reaction
yield (cf. entries 2–4 and 5–8). Furthermore, in instances
where it was initially envisaged that the presence of a
sterically demanding methyl group ortho to the iodine
atom on the benzene ring of the aryl iodide would pre-
vent coupling, the corresponding adduct was furnished,
albeit in slightly lower yields (entries 9–10). Similarly,
the N-arylation of sterically hindered 2-acetylpyrrole
was shown to proceed smoothly to furnish the corre-
sponding N-phenyl-2-acetylpyrrole in 50% yield and
70% substrate conversion (entry 11).
n
iodobenzene, CuI (20 mol %), and Bu4NBr (20 mol %)
in toluene at reflux for 22 h, N-arylation with 3 equiv
of K3PO4, K2CO3, Al2O3, MgO or LiOHÆH2O as a base
gave N-phenylpyrrole in markedly lower yields of 4–
49%. The reactions of pyrrole using either MeCO2Na
or pyridine as the base are the only instances where no
reaction was observed and both starting materials were
recovered in quantitative yields (entries 16 and 17).
At this juncture, we would like to highlight that employ-
n
ment of Bu4NBr as a phase transfer catalyst and the
presence of a small amount of water intrinsically present
in commercially available inorganic bases was essential
for the N-arylation reaction. Under our experimental
n
conditions, when Bu4NBr was removed from the reac-
tion and 1 equiv of pyrrole was treated with 1 equiv of
iodobenzene in the presence of 5 mol % CuI and NaOH
(2 equiv) in toluene at reflux for 22 h, N-phenylpyrrole
was afforded in 4% yield (entry 8). Conducting the reac-
tion under the same conditions as those for entry 11 in
Table 1 but with K2CO3 dried to a constant weight un-
der reduced pressure at 200 ꢁC prior to use, on the other
The application of our catalytic system for the N-aryl-
ation of other classes of nitrogen heterocycles was also
examined (Table 2, entries 12–15). The reaction of

J. W. W. Chang et al. / Tetrahedron Letters 48 (2007) 245–248
Table 2. CuI-catalyzed N-arylation of 1H-azoles with aryl iodidesa
247
Entry
Azole
Aryl iodide
Product
Yieldb,c (%)
1
95 (>99)
77 (>99)
90 (>99)
80 (>99)
86 (>99)
84 (>99)
88 (>99)
83 (94)
I
N
N
H
2
3
4
5
6
7
8
I
I
I
I
I
F
F
N
Br
Br
N
Cl
Cl
N
tBu
OMe
Me
N
But
MeO
Me
N
I
I
N
N
Me
Me
Me
I
I
N
9
62 (87)
63 (88)
Me
Me
Me
Me
N
10
Me
NH
N
11
12
50 (74)
I
I
O
O
N
N
80 (>99)
N
H
13
14
64 (73)
84 (88)
I
I
Me
Me
NH
N
N
N
N
N
15d
50 (80)
N
I
N
H
a All reactions were performed for 22 h with CuI:nBu4NBr:azole:aryl iodide:base, molar ratio = 1:1:20:20:40 in PhMe at reflux.
b Isolated yield.
c Values in parentheses denote substrate conversion based on the amount of aryl iodide consumed as determined by 1H NMR analysis.
d Reaction carried out with DMSO in place of PhMe as the solvent.
1 equiv of indole with 1 equiv of either iodobenzene or
p-iodotoluene and 5 mol % CuI, 5 mol % Bu4NBr and
NaOH (2 equiv) in toluene at reflux for 22 h, was shown
to proceed to give the corresponding N-arylated prod-
ucts in 80% and 64% yield with near quantitative and
73% substrate conversions, respectively (entries 12
and 13). Under similar conditions, the coupling reac-
tions of imidazole and indazole were found to give
n

248
J. W. W. Chang et al. / Tetrahedron Letters 48 (2007) 245–248
7. (a) Liu, L.; Frohn, M.; Xi, N.; Dominguez, C.; Hungate,
R.; Reider, P. J. J. Org. Chem. 2005, 70, 10135–10138; (b)
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N-phenylimidazole and N-phenylindazole, respectively,
in good yields and substrate conversions; in the latter
example, DMSO was used as the reaction medium due
to the poor solubility of indazole in toluene (entries
14–15).
In summary, we have demonstrated a practical and
straightforward CuI-catalyzed method for the N-aryl-
ation of nitrogen heterocycles with aryl iodides that pro-
ceeded in good to excellent product yields. The present
protocol is applicable to a variety of nitrogen heterocy-
cles and aryl iodides containing electron donating and
electron withdrawing, and sterically demanding sub-
strate combinations under mild conditions. A detailed
examination of the scope of the present reaction is cur-
rently underway and will be reported in due course as
part of a full letter.
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Acknowledgements
This work is supported by a College of Science Start-up
Grant and a University Research Grant (RG55/06) from
Nanyang Technological University. The authors would
like to thank Ms. Sheena Chee and Ms. Shiya Mak
(Ngee Ann Polytechnic, Singapore), for their help in
purifying some of the compounds reported in this work.
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11. Typical experimental procedure: To a round bottomed
flask containing the nitrogen heterocycle (15 mmol), aryl
iodide (15 mmol), CuI (0.75 mmol), nBu4NBr (0.75 mmol)
and NaOH (30 mmol) under a N2 atmosphere was added
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refluxed for 22 h. On cooling to room temperature,
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