2,2'-biimidazole as an efficient ligand for copper(I)-catalyzed C-N coupling reactions

Article abstract of DOI:10.1080/00397910902964791

An efficient copper(I)-catalyzed system using 2,2'-biimidazole as the ligand was applied to N-arylation of a broad spectrum of nitrogen nucleophiles with aryl halides. The reactions were carried out in relatively mild conditions with good to excellent yields.

Full text of DOI:10.1080/00397910902964791

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2,2′-Biimidazole as an Efficient Ligand
for Copper(I)-Catalyzed C‒N Coupling
Reactions
a b
a
a
a
Zhang Hu
, Wei Ye , Hongbin Zou & Yongping Yu
a
College of Pharmaceutical Science, Zhejiang University, Hangzhou,
China
b
College of Science, Guangdong Ocean University, Zhanjiang, China
Published online: 29 Dec 2009.
To cite this article: Zhang Hu , Wei Ye , Hongbin Zou & Yongping Yu (2009): 2,2′-Biimidazole as an
Efficient Ligand for Copper(I)-Catalyzed C‒N Coupling Reactions, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 40:2, 222-228
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1
Synthetic Communications , 40: 222–228, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902964791
0
2
,2 -BIIMIDAZOLE AS AN EFFICIENT LIGAND FOR
COPPER(I)-CATALYZED CꢀN COUPLING REACTIONS
1
,2
1
1
Zhang Hu, Wei Ye, Hongbin Zou, and Yongping Yu
1
1
College of Pharmaceutical Science, Zhejiang University, Hangzhou, China
2
College of Science, Guangdong Ocean University, Zhanjiang, China
0
An efficient copper(I)-catalyzed system using 2,2 -biimidazole as the ligand was applied to
N-arylation of a broad spectrum of nitrogen nucleophiles with aryl halides. The reactions
were carried out in relatively mild conditions with good to excellent yields.
0
Keywords: N-Arylation; 2,2 -biimidazole; copper-catalyzed; ligand
The classical copper-mediated Ullmann-type couplings are well-known reactions
for C-N bond formation and have a history of being used for more than a century.
However, their applications are greatly limited because the reactions proceed under
[1]
harsh conditions with moderate yields. In the past years, much attention has
been paid to the improvement of Ullmann-type couplings, and significant progress
has been made. Recently, many efficient ligands have been introduced to
[
2]
promote copper-catalyzed C-N coupling, including diamines, 1,10-phenanthroline
[6]
[
3]
[4]
[5]
and its derivatives,
8
amino acids,
aminoarenethiol,
diethylsalicylamide,
[8]
ethylene glycol,
1,1,1-tris(hydroxymethyl)ethane,
[
7]
[9]
-hydroxyquinoline,
-aminopyrimidine-4,6-diol, 1,1 -binaphthyl-2,2 -diol, ethyl 2-oxocyclohexane-
[10]
0 0
[13]
[11]
2
carboxylate,
[
12]
and phosphine ligands.
Because of the high cost and=or poor
availability of the ligands, it is still necessary to develop more practical, efficient,
and versatile ligands for copper-catalyzed N-arylation.
Imidazoles and diamines have proved to be a remarkable class of ligands, cap-
[
2,14]
able of forming metal complexes that are able to catalyze a lot of reactions.
0
Recently, 2,2 -biimidazole and (s)-pyrrolidinylmethylimidazole have been disclosed
[
We report here that
readily available 2,2 -biimidazole can be used as an efficient ligand that accelerates
copper(I)-catalyzed N-arylation.
15]
to promote copper-catalyzed Ullmann coupling reactions.
0
The coupling of iodobenzene with benzylamine was studied to identify a suit-
able catalytic system. Ligands A–C were employed to search for the suitable ligand
(as shown in Table 1). It was found that the imidazoles A and B were effective. More-
over, unsubstituted 2,2 -biimidazole (A, entry 1) showed greater accelerating activity
0
Received May 28, 2008.
Address correspondence to Yongping Yu, College of Pharmaceutical Science, Zhejiang University,
Hangzhou, China. E-mail: yyu@zju.edu.cn
2
22

0
2
,2 -BIIMIDAZOLE AS LIGAND
223
Table 1. Copper-ligand–catalyzed coupling reaction of iodobenzene with
a
benzylamine
b
Entry
1
Ligand
Yield (%)
86
2
3
61
36
c
4
trace
a
Reaction conditions: iodobenzene (1.0 equiv), benzylamine (1.2 equiv),
CuI (10 mol%), ligand (20 mol%), Cs CO (2 equiv), under N atmosphere
2
3
2
ꢁ
at 100 C for 24 h.
b
Isolated yield.
DMF:H O (1:1) as solvent.
c
2
0
0
than substituted 1,1 -dimethyl-2,2 -biimidazole (B, entry 2). It is noteworthy that
[14]
0
unsubstituted 2,2 -biimidazole is readily available. However, there was only a
trace amount of the corresponding product obtained in the presence of diamine C
(entry 3). Some reports showed that the addition of water in some cases could
improve the reaction efficiency.
[7,13a]
However, in our catalytic system only a trace
amount of the corresponding desired product was obtained when dimethylforma-
mide (DMF)=H O was used as the solvent (entry 4).
2
The efficacy of the CuI=A system for general CꢀN bond formation between
aryl halides and N-containing compounds was further evaluated. As summarized
in Table 2, when the cross-coupling reactions were performed under the conditions
of 10 mol% CuI and 20 mol% A in the presence of Cs CO as a base in DMF, the
2
3
corresponding products were obtained in moderate to good yields. It was found that
primary amines (entries 4, 7, and 8) and cyclic secondary amines (entries 1 and 3)
afforded the desired coupling products in good yields, whereas acyclic secondary

224
Z. HU ET AL.
a
Table 2. Copper-catalyzed CꢀN coupling reaction
0
ꢁ
b
Entry
1
ArX
RR NH
Condition ( C=h)
Product
Yield (%)
85
100=24
100=24
120=24
120=24
2
3
4
43
72
75
5
6
120=24
120=24
61
63
7
120=24
66
c
8
9
120=36
120=24
81
68
64
1
1
0
1
120=24
120=36
74
a
Reaction conditions: aryl halide (1.0 equiv), N-containing compound (1.5 equiv), CuI (10 mol%), A
20 mol%), and Cs CO (2.0 equiv).
(
2
3
b
Isolated yield.
c
2
0 equiv of amine was used to avoid the low yield due to its low boiling point.

0
2
,2 -BIIMIDAZOLE AS LIGAND
225
amine (entry 2) gave less of the corresponding product. Notably, the poorly nucleo-
philic arylamines (entries 5 and 6), amides (entries 9 and 10), and benzimidazole
(entry 11) can also be used as nucleophilic reagents to yield the products in moderate
to good yields under the combination of CuI with A catalytic system. All these
results showed that A could be used as a good promoter for the copper-catalyzed
C-N coupling.
0
In summary, we have demonstrated that 2,2 -biimidazole can be used as an
efficient and general ligand for copper(I)-catalyzed arylation of a broad spectrum
of nitrogen nucleophiles at relatively low temperatures in the presence of the mild
base cesium carbonate. Because of the readily available ligand and air-stable
copper(I) iodide, the mild, general, and efficient reaction described here provides
an extremely good path for the synthesis of a variety of N-arylamines.
EXPERIMENTAL
Unless otherwise indicated, all reactions were carried out under dry nitrogen
atmosphere. DMF was freshly distilled from calcium hydride and degassed
prior to use. The other reagents were used directly without further purification.
Melting points were obtained on a B-540 B u¨ chi melting-point apparatus and
1
are uncorrected. H NMR data were recorded on DPX-400 with CDCl3 as
solvent and tetramethylsilane (TMS) as the internal standard. Chemical shifts are
given in parts per million (ppm), and spin–spin coupling constants, J, are given
in hertz.
General Procedure for the Copper(I)-Ligand-Catalyzed Coupling
Reaction of Iodobenzene with Benzylamine
A mixture of iodobenzene (2.0 mmol), benzylamine (2.4 mmol), CuI (0.2 mmol),
ꢁ
ligand (0.4 mmol), and Cs CO (4.0 mmol) in 5 mL of DMF was heated at 100 C for
2
3
2
4 h. The reaction mixture was then cooled to ambient temperature, diluted with
EtOAc, filtered through a pad of silica gel, and washed with EtOAc. The combined
filtrate was concentrated in vacuo, and the resulting residue was purified by column
chromatography (EtOAc–cyclohexane 1:20) to afford N-benzyl aniline as colorless
1
liquid. H NMR (CDCl , 400 MHz) d: 4.05 (br s, 1H), 4.36 (s, 2H), 6.66 (d,
3
J ¼ 7.6 Hz, 2H), 6.74 (t, J ¼ 7.6 Hz, 1H), 7.20 (dd, J ¼ 7.6 Hz, J ¼ 8.4 Hz, 2H),
1
2
7
.41–7.28 (m, 5H).
General Procedure for Copper-Catalyzed Coupling Reaction of Aryl
Halides with Nitrogen-Containing Compounds
A mixture of aryl halide (2 mmol), nitrogen-containing compound (3.0 mmol),
CuI (0.2 mmol), A (0.4 mmol), and Cs CO (4.0 mmol) in 5 mL of dimethylforma-
2
3
mide (DMF) was heated at the indicated temperature under a nitrogen atmosphere.
The resulting suspension was cooled to room temperature, diluted with EtOAc,
filtered through a pad of silica gel, and washed with EtOAc. The combined filtrate
was concentrated in vacuo, and the resulting residue was purified by column chroma-
tography on silica gel to provide the desired product.

226
Z. HU ET AL.
Data
-Phenylmorpholine (a). White solid; mp 49–51 C (lit. mp 53–55 C); H
NMR (CDCl , 400 MHz) d: 3.17 (t, 4H), 3.87 (t, 4H), 6.89–6.94 (m, 3H), 7.27–7.31
ꢁ
[16]
ꢁ
1
4
3
(m, 2H).
1
N-Methyl-N-benzylaniline (b). Colorless liquid;
H
NMR (CDCl3,
4
00 MHz) d: 3.08 (s, 3H), 4.60 (s, 2H), 6.79–6.84 (m, 3H), 7.28–7.38 (m, 7H).
1
N-Benzyl-4-methylaniline (c). Brown oil; H NMR (CDCl , 400 MHz) d:
3
2
7
.33 (s, 3H), 4.37 (s, 2H), 6.64 (d, J ¼ 8.4 Hz, 2H), 7.07 (d, J ¼ 8.8 Hz, 2H),
.33–7.46 (m, 5H).
ꢁ
[4b]
Diphenylamine (d). Yellow white solid; mp 49–51 C (lit. mp 51–52 C); H
ꢁ
1
NMR (CDCl , 400 MHz) d: 5.69 (br, 1H), 7.01 (m, 2H), 7.14 (d, J ¼ 8.0 Hz, 4H),
3
7
7
4
.34 (t, J ¼ 7.6 Hz, 4H).
,10-Dihydrophenazine (e). Brown oil; H NMR (CDCl , 400 MHz) d:
.84–7.87 (m, 4H), 8.25–8.28 (m, 4H).
1
5
3
1
-Benzyl-2-methylbenzoimidazole (f). Brown oil; H NMR (CDCl3,
1
00 MHz) d: 2.41 (s, 3H), 5.06 (s, 2H), 6.91–6.93 (m, 2H), 7.09–7.17 (m, 6H), 7.70
d J ¼ 8.0 Hz, 1H).
(
1
N-Allyl-4-methylaniline (g). Brown oil; H NMR (CDCl , 400 MHz) d: 2.24
3
(
(
s, 3H), 3.75 (s, 2H), 5.14–5.17 (m, 1H), 5.26–5.30 (m, 1H), 5.93–5.99 (m, 1H), 6.56
d, J ¼ 8.4 Hz, 2H), 6.99 (d, J ¼ 8.4 Hz, 2H).
N-Phenylacetamide (h). Colorless solid; mp 112–113 C (lit.
ꢁ
[17]
ꢁ
mp 113 C);
1
H NMR (CDCl , 400 MHz) d: 2.16 (s, 3H), 7.09 (t, J ¼ 7.6 Hz, 1H), 7.31 (t,
3
J ¼ 8.4 Hz, J ¼ 7.6 Hz, 2H), 7.49 (d, J ¼ 8.4 Hz, 2H).
1
2
ꢁ
[18]
N-Phenylbenzamide (i). Colorless solid; mp 165–167 C (lit.
1
mp
62–163 C); H NMR (CDCl , 400 MHz) d: 7.09–7.13 (m, 1H), 7.34–7.38 (m,
ꢁ
1
2
3
H), 7.51–7.59 (m, 3H), 7.80–7.82 (m, 2H), 7.97–7.99 (m, 2H), 10.26 (s, 1H).
1
-Phenylbenzoimidazole (j). Colorless liquid; H NMR (CDCl , 400 MHz)
1
3
d: 7.17–7.25 (m, 2H), 7.30–7.40 (m, 6H), 7.82 (d, J ¼ 7.6 Hz, 1H), 7.97 (s, 1H).
ACKNOWLEDGMENTS
We thank the National Natural Science Foundation of China (Nos. 30772652
and 90813026) and Major Projects the National Science and Technology ‘‘Creation
of major new drugs’’ (No. 2009ZX09501-010).
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