Ninhydrin: an efficient ligand for the Cu-catalyzed N-arylation of nitrogen-containing heterocycles with aryl halides

Article abstract of DOI:10.1016/j.tetlet.2007.12.026

Cu₂O/ninhydrin was found to be an efficient catalyst system for the N-arylation of nitrogen-containing heterocycles with aryl and heteroaryl iodides, bromides and even unactivated chlorides to give the products in moderate to excellent yields.

Full text of DOI:10.1016/j.tetlet.2007.12.026

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 948–951
Ninhydrin: an efficient ligand for the Cu-catalyzed N-arylation
of nitrogen-containing heterocycles with aryl halides
Yi-Zheng Huang, Jin Gao, Hong Ma, Hong Miao, Jie Xu *
State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics, Graduate School of the Chinese Academy of Sciences, Chinese
Academy of Sciences, 457 Zhongshan Road, Dalian 116023, PR China
Received 12 October 2007; revised 4 December 2007; accepted 7 December 2007
Available online 14 December 2007
Abstract
Cu2O/ninhydrin was found to be an efficient catalyst system for the N-arylation of nitrogen-containing heterocycles with aryl and
heteroaryl iodides, bromides and even unactivated chlorides to give the products in moderate to excellent yields.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Ninhydrin; Cu-catalyzed; N-Arylation; Nitrogen-containing heterocycles
N-Arylheterocycles play important roles in medicinal,1
biological2 and N-heterocyclic carbene chemistry.3 Tradi-
tionally, these compounds were prepared mostly by Ull-
mann-type coupling reactions. However, these reactions
usually proceeded at high temperatures (around 200 °C)
and often required using stoichiometric amounts of copper
reagents, which make their further applications limited.4 To
overcome these drawbacks, great progresses have been
made on the modification of Ullmann-type coupling reac-
tions.5–9 A recent notable achievement has been made by
Buchwald and co-workers who discovered that in the pres-
ence of bidentate N,N-ligands, the Cu-catalyzed N-aryl-
ation of nitrogen-containing heterocycles with aryl halides
could be achieved in good yields under mild conditions.6
Following these pioneering works, a number of other
groups have reported similar approaches for these reactions
under mild conditions, with different kinds of copper
compounds and appropriate bidentate N,N-, N,O- or
O,O-ligands.7 However, the coupling partners of nitrogen-
containing heterocycles were generally confined to aryl
iodides and bromides. There are only a few reports where
aryl chlorides were used as coupling partners,7c–g,8b,9g–l
and the examples of unactivated aryl chlorides used as
coupling partners have remained sparse.
On the basis of the research efforts on Cu-catalyzed C–N
bond formations in our laboratory,8 we report our recent
results on Cu-catalyzed N-arylation of nitrogen-containing
heterocycles with aryl iodides, bromides and even unacti-
vated chlorides under mild conditions by using ninhydrin
as ligand.
In our initial experiment, iodobenzene (1 equiv) was
treated with imidazole (1.5 equiv) in DMSO at 90 °C for
24 h in the presence of Cu2O (0.1 equiv) and KOH
(2 equiv); only moderate yield of 1-phenylimidazole was
obtained. Prolonging the reaction time to 72 h led to only
a slight increase of yield (Table 1, entry 1). To our delight,
1-phenylimidazole was formed in quantitative yield when
20 mol % of ninhydrin was added (Table 1, entry 3). More
than 90% yields of 1-phenylimidazole were also obtained
when some other O,O-ligands (Fig. 1) were added (Table
1, entries 4–7). Solvents played an important role in this
reaction. When toluene, a less polar solvent, was used
instead of DMSO, only a trace amount of the desired prod-
uct was obtained (Table 1, entry 9). Bases influenced the
progress of the reaction greatly. Moderate yields were
obtained when K2CO3, Cs2CO3 and K3PO4 were used,
while only a low yield of 1-phenylimidazole was obtained
*
Corresponding author. Tel./fax: +86 411 84379245.
E-mail address: xujie@dicp.ac.cn (J. Xu).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.026

Y.-Z. Huang et al. / Tetrahedron Letters 49 (2008) 948–951
949
Table 1
O
Screening reaction conditions for copper-catalyzed N-arylation of imid-
azole with iodobenzenea
H
OH
OH
L1:
L2: Ph C C Ph L3: CH3COCOOK
O OH
[Cu], Ligand
base, DMSO
O
+
N
I
HN
Ph
L6: Ph C COOH
OH
H
L5: Ph C COOH
OH
N
H
N
L4: H3C C COOH
Entry
[Cu]
Ligand
Base
Yieldb (%)
OH
1
2
3
4
5
6
7
8
9d
10
11
12
13
14
15
16
17
18
a
Cu2O
—
—
—
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
K2CO3
Cs2CO3
K3PO4
(n-Pr)3N
KOH
KOH
KOH
KOH
KOH
49, 63c
0
100 (92)
94
91
92
94
49
4
83
74
70
24
87
70
54
44
82
Fig. 1. Ligands for copper-catalyzed N-arylation of imidazole.
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
CuI
L1
L2
L3
L4
L5
L6
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
when tripropylamine, an organic base, was used (Table 1,
entries 10–13). Other copper compounds (CuI, CuBr,
CuCl, CuO and Cu powders) were also evaluated but
proved inferior to Cu2O (Table 1, entries 14–18).
The efficacy of the Cu2O/ninhydrin system for general
N-arylation of imidazole with various aryl halides was
further evaluated, and the results are summarized in Table
2. The results indicate that the reactivity order of the aryl
halides is iodides > bromides > chlorides (compare Table
1, entry 3 and Table 2, entries 1, 8–11 and 13–16). Elec-
tron-withdrawing and -donating groups on the aryl halides
were all tolerated. Electron-withdrawing groups on the aryl
halides usually promoted the reactions (compare Table 2,
entries 6, 8 and 13 with Table 1, entry 3, Table 2, entries
10 and 15, respectively). Compared with iodobenzene, aryl
iodides with electron-donating groups needed a slightly
higher temperature to couple with imidazole in about
90% of isolated yields in 24 h (compare Table 2, entries
CuBr
CuCl
CuO
Cu
Reaction conditions: iodobenzene (1 mmol), imidazole (1.5 mmol),
[Cu] (0.1 mmol), ligand (0.2 mmol), base (2 mmol) and DMSO (2 ml)
under Ar atmosphere at 90 °C for 24 h.
b
GC yield, and yield in parentheses refer to isolated yield.
c
At 90 °C for 72 h.
d
With toluene as solvent instead of DMSO.
Table 2
Cu2O/ninhydrin-catalyzed N-arylation of imidazole with various aryl halidesa
u O
10 mol % C
2
ArX +
Ar N
HN
N
20 mol % ninhydrin
KOH, DMSO
N
X=Cl, Br, I
Entry
1
Aryl halide
Product
Temp (°C)
Time (h)
24
Yieldb (%)
91
N
N
110
I
CH3
CH3
N
N
I
2
3
110
110
24
24
90
89
CH3
CH3
N
N
I
H3C
H3C
N
N
I
4
5
6
110
110
90
24
24
16
90
89
H3CO
H3CO
N
N
I
I
OCH3
OCH3
N
N
92
CF3
CF3
(continued on next page)

950
Y.-Z. Huang et al. / Tetrahedron Letters 49 (2008) 948–951
Table 2 (continued)
Entry
Aryl halide
Product
Temp (°C)
Time (h)
24
Yieldb (%)
90
N
N
I
7
100
N
N
8
9
110
110
110
110
110
130
130
150
150
24
24
48
48
48
24
24
48
48
91
Br
CF3
CF3
N
N
Br
N
92
N
10
11
12
13
14
15d
80, 91c
76, 87c
78, 90c
90
N
N
Br
N
N
Br
Br
CH3
CH3
N
N
OCH3
OCH3
CF3
N
N
Cl
Cl
CF3
N
N
91
N
N
N
N
49
Cl
Cl
16d
46
N
N
CH3
CH3
a
Reaction conditions: aryl halide (1 mmol), imidazole (1.5 mmol), Cu2O (0.1 mmol), ninhydrin (0.2 mmol), KOH (2 mmol) and DMSO (2 ml) under Ar
atmosphere.
b
Isolated yields.
130 °C for 24 h.
c
d
Cu2O (0.2 mmol), ninhydrin (0.3 mmol).
1–5 with Table 1, entry 3). Furthermore, excellent yields of
N-aryl imidazole were obtained when hindered aryl halides
such as 2-methyliodobenzene and 2-methoxyiodobenzene
were used (Table 2, entries 3 and 4). This system was also
successfully applied to N-arylation of imidazole with hetero-
aryl halides such as 2-bromopyridine and 2-chloropyridine
(Table 2, entries 9 and 14). Remarkably, aryl chlorides
could be used as the coupling partners of imidazole. An
excellent yield was obtained when 4-chlorobenzotrifluo-
ride, an activated aryl chloride, was used (Table 2, entry
13). Moderate yields were still achieved even in the N-ary-
lation of imidazole with chlorobenzene and electron-donat-
ing aryl chloride such as 4-methylchlorobenzene (Table 2,
entries 15 and 16).
The efficacy of the Cu2O/ninhydrin system for general
N-arylation of various nitrogen-containing heterocycles
such as benzimidazole, indole, pyrazole and pyrrole with
iodobenzene was further evaluated, and the results are
summarized in Table 3. All the tested nitrogen-containing
heterocycles resulted in excellent yields (Table 3, entries
1–4).
In conclusion, ninhydrin was found to be an efficient
ligand for the Cu2O-catalyzed N-arylation of nitrogen-con-
taining heterocycles with aryl and heteroaryl iodides, bro-
mides and even unactivated chlorides.10 The mechanism
of the reactions and further studies to expand the applica-
tions of the catalytic system are currently underway in our
laboratory.

Y.-Z. Huang et al. / Tetrahedron Letters 49 (2008) 948–951
951
Table 3
(g) Altman, R. A.; Koval, E. D.; Buchwald, S. L. J. Org. Chem. 2007,
72, 6190.
Cu2O/ninhydrin-catalyzed N-arylation of various nitrogen-containing
heterocycles with iodobenzenea
7. (a) Verma, A. K.; Singh, J.; Sankar, V. K.; Chaudhary, R.; Chandra,
R. Tetrahedron Lett. 2007, 48, 4207; (b) Zhu, L. B.; Cheng, L.; Zhang,
Y. X.; Xie, R. G.; You, J. S. J. Org. Chem. 2007, 72, 2737; (c)
Sreedhar, B.; Kumar, K. B. S.; Srinivas, P.; Balasubrahmanyam, V.;
Venkanna, G. T. J. Mol. Catal. A: Chem. 2007, 265, 183; (d) Xie,
Y. X.; Pi, S. F.; Wang, J.; Yin, D. L.; Li, J. H. J. Org. Chem. 2006, 71,
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H. C.; Jiang, X. Z. J. Org. Chem. 2007, 72, 8943; (h) Guo, X.; Rao, H.
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H.; Liu, F. J. Org. Chem. 2007, 72, 8969; (k) Hosseinzadeh, R.;
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Lange, B.; Lambers-Verstappen, M. H.; van de Vondervoort, L. S.;
Sereinig, N.; de Rijik, R.; de Vires, A. H. M.; de Vires, J. G. Synlett
2006, 3105; (n) Hosseinzadeh, R.; Tajbakhsh, M.; Alikarami, M.
Synlett 2006, 2124; (o) Kuil, M.; Bekedam, E. K.; Visser, G. M.; van
den Hoogenband, A.; Terpstra, J. W.; Kamer, P. C. J.; van Leeuwen,
P. W. N. M.; van Strijdonck, G. P. F. Tetrahedron Lett. 2005, 46,
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10 mol % Cu2O
+
N-Het
I
Het-NH
20 mol % ninhydrin
KOH, DMSO
Entry
1
Het-NH
Product
Yieldb (%)
N
N
N
88
N
H
N
2
3
90
92
91
N
H
N
N
N
N
H
N
4
NH
a
Reaction conditions: iodobenzene (1 mmol), Het-NH (1.5 mmol),
Cu2O (0.1 mmol), ninhydrin (0.2 mmol), KOH (2 mmol) and DMSO
(2 ml) under Ar atmosphere at 110 °C for 24 h.
8. (a) Zhang, Z. J.; Mao, J. C.; Zhu, D.; Wu, F.; Chen, H. L.; Wan, B. S.
Tetrahedron 2006, 62, 4435; (b) Zhu, D.; Wang, R. L.; Mao, J. C.; Xu,
L.; Wu, F.; Wan, B. S. J. Mol. Catal. A: Chem. 2006, 256, 256; (c) Xu,
L.; Zhu, D.; Wu, F.; Wang, R. L.; Wan, B. S. Tetrahedron 2005, 61,
6553; (d) Zhang, Z. J.; Mao, J. C.; Zhu, D.; Wu, F.; Chen, H. L.;
Wan, B. S. Catal. Commun. 2005, 6, 784.
b
Isolated yields.
Acknowledgements
9. (a) Sperotto, E.; de Vries, J. G.; van Klink, G. P. M.; van Koten, G.
Tetrahedron Lett. 2007, 48, 7366; (b) Nandurkar, N. S.; Bhanushali,
M. J.; Bhor, M. D.; Bhanage, B. M. Tetrahedron Lett. 2007, 48,
6573; (c) Chang, J. W. W.; Xu, X. H.; Chan, P. W. H. Tetrahedron
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10. Typical experimental procedure: a mixture of aryl halide (1 mmol),
nitrogen-containing heterocycle (1.5 mmol), Cu2O (0.1 mmol), nin-
hydrin (0.2 mmol), KOH (2 mmol) and DMSO (2 ml) was stirred at
the temperature specified under Ar atmosphere until nearly complete
conversion of aryl halide as monitored by GC or TLC; the cooled
mixture was partitioned between ethyl acetate (10 ml) and water
(3 ml). The organic layer was separated, and the aqueous layer was
extracted with ethyl acetate (5 ml). The combined organic layers were
washed with brine (5 ml), dried over Na2SO4, and concentrated to
give the crude product, which was purified by column chromato-
graphy on silica gel (200–300 mesh) using ethyl acetate/methanol as
eluent to afford the desired product. All the products are known and
have been characterized by 1H NMR, 13C NMR, GC/MS (EI), and
the melting points of the solid products have also been determined.
The authors are grateful to the Chinese Academy of
Sciences and the National Natural Science Foundation
of China for their financial supports.
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