New ligands for copper-catalyzed C－N coupling reactions at gentle temperature

Article abstract of DOI:10.1002/cjoc.201400147

Pyridin-2-ol-N-oxide was designed as an efficient ligand for the coupling reaction of aryl iodides, aryl bromides and aryl chlorides, respectively, with primary amines, cyclic secondary amines or N-containing heterocycles at room or moderate temperature. The catalytic system showed great functional groups tolerance and excellent selective reactivity.

Full text of DOI:10.1002/cjoc.201400147

COMMUNICATION
DOI: 10.1002/cjoc.201400147
New Ligands for Copper-Catalyzed C－N Coupling
Reactions at Gentle Temperature†
Jinyue Su,a,b Yatao Qiu,b Sheng Jiang,*,b and Dayong Zhang*,a
a Center of Drug Discovery, China Pharmaceutical University, Nanjing, Jiangsu 210009, China
b Laboratory of Medicinal Chemistry, Guangzhou Institute of Biomedicine and Health, Guangzhou,
Guangdong 510530, China
Pyridin-2-ol-N-oxide was designed as an efficient ligand for the coupling reaction of aryl iodides, aryl bromides
and aryl chlorides, respectively, with primary amines, cyclic secondary amines or N-containing heterocycles at
room or moderate temperature. The catalytic system showed great functional groups tolerance and excellent
selective reactivity.
Keywords C－N coupling reactions, copper, corss-coupling, pyridin-2-ol-N-oxide, Ullmann reaction
Introduction
Copper-catalyzed Ullmann-type amination of aryl
halides is one of important methods to construct aryla-
mines, and has been widely used in a wide variety of
natural product synthesis and materials science.[1] Much
interest has been paid to discovering new ligands in im-
proving both reaction efficiency and generality. Re-
cently, several classes of coordination ligands have been
studied extensively to accelerate the coupling of aryl
halides with nitrogen nucleophiles.[2-11] Many of them
are suite for the coupling of aryl iodides, and to a lesser
extent aryl bromides, with nitrogen nucleophiles. And
only a few ligands could promote copper-catalyzed
coupling of aliphatic amines with aryl iodides at room
temperature.[9,10a,12] However the copper-catalyzed cou-
pling of nitrogen nucleophiles with aryl chlorides is
quite difficult due to the harsh reaction conditions.[13] So
far, we reported two ligands, which can be used to pro-
mote copper-catalyzed N-arylations with aryl chlorides
in cross-coupling reactions in elevated temperature.[8,9]
It is highly desirable to identify new ligands to improve
the efficiency and generality of copper-catalyzed
cross-coupling reactions.
N
O
OH
N
O
OH
L1
L2
Figure 1 Structures of the ligands.
In our study, the catalytic system was heterogeneous.
We define this coupling reaction as ”single-type”, with
a well-defined metal complex with strongly bound
ligands, depending on the type of catalyst precursor and
on the nature of catalytic system.[14]
Experimental
General experiment procedure
A flask was charged with CuI (19.0 mg, 0.1 mmol,
10%), L (16.5 mg, 0.15 mmol, 15%), Cs2CO3 (651 mg,
2.0 mmol), and any remaining solids (amine and/or aryl
halide). The flask was evacuated and backfilled with
argon. Aryl halide (1.0 mmol), amine (1.5 mmol) or
N-containing heterocycle (1.5 mmol), and DMF (2 mL)
were added to the flask under argon atmosphere. Then
the mixture was stirred at the indicated temperature until
complete consumption of the starting material, which
was monitored by TLC. After completion of the reac-
tion, the mixture was diluted with ethyl acetate and
passed through a fritted glass filter to remove the inor-
ganic salts, the solvent was removed with the aid of a
rotary evaporator. The residue was purified by column
chromatography on silica gel, using petroleum
ether/ethyl acetate as eluent to provide the desired
We assumed that pyridin-2-ol-N-oxide (L1) might
form transitional 5-membered cyclic structure with the
Cu ion, which may be favorable for copper-catalyzed
amination of aryl halides (Figure 1). Here, we report our
preliminary studies on the use of pyridin-2-ol-N-oxide
(L1) as an efficient ligand for the coupling of aryl io-
dides, aryl bromides or aryl chlorides with nitrogen nu-
cleophiles.
*
E-mail: jiang_sheng@gibh.ac.cn; Fax: 0086-020-32015318
Received March 12, 2014; accepted April 25, 2014; published online June 5, 2014.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201400147 or from the author.
Dedicated to Professor Chengye Yuan and Professor Li-Xin Dai on the occasion of their 90th birthdays.
†
Chin. J. Chem. 2014, 32, 685—688
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
685

Su et al.
Table 2 CuI-catalyzed amination of aryl iodidesa
COMMUNICATION
product.
10 mol% CuI
15 mol% L1
HNR1R2
Results and Discussion
I
NR1R2
+
R
R
2.0 equiv. Cs2CO3
DMF, r.t.
2
Initially, we investigated the reaction between
4-methyl iodobenzene and benzylamine to evaluate the
catalytic activity of the designed ligand at room tem-
perature. These results are listed in Table 1. The result
showed that the highest yield (Table 1, Entry1, 89%)
was obtained when L1 was employed as the ligand. Re-
actions catalyzed by the combination of pyridin-2-ol-
N-oxide (L1) and different copper salts, such as CuI,
CuBr, CuCl and CuOAc, and CuI gave the best result
(Table 1, Entries 4－7). Meanwhile, the different sol-
vent such as DMF, DMSO, CH3CN, 1,4-dioxane and
toluene were also investigated, and DMF gave the
highest yield (Table 1, Entries 2, 7－11). Base also in-
fluenced the progress of the reaction, and Cs2CO3 was
preferred (Entries 2－4). After screening the bases, sol-
vents, and copper salts, the optimal condition was com-
bination of 10 mol% CuI, 15 mol% L1, and Cs2CO3
(2.0 equiv.) in DMF at room temperature.
1
3
Entry Product
1
Time/h
48
Yieldb/%
92
H
N
3a
H
N
F3C
2
33
33
33
24
33
48
33
85
86
56
92
72
66
58
3b
H
Cl
N
3
3c
NO2
H
N
4
5
6
7
8
HO
3d
Table 1 Designed ligands for the copper-catalyzed C－N cou-
pling reactiona
O
N
10 mol% CuX
3e
F
5 - 20 mol% L1
Base (2.0 equiv.)
I
H2N
+
Ar, Solvent, r.t., 24 h
N
1a
2a
NC
3f
H
N
N
O2N
3a
3g
Entry Ligand Base
Copper source Solvent
Yielda/%
67
N
1
2
L2
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
Cs2CO3
Cs2CO3
K2CO3
K3PO4
CuI
DMF
N
CuI
DMF
89
H3CO
3h
3
CuI
DMF
19
4
CuI
DMF
24
N
5
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
CuBr
CuCl
CuOAc
CuI
DMF
81
9
33
58
6
DMF
26
NO2
3i
7
DMF
24
N
8
DMSO
CH3CN
1,4-dioxane
toluene
80
N
O2N
10
24
95
9
CuI
7
10
CuI
10
3j
a Reaction conditions: ArI (1.0 mmol), amine (1.5 mmol), CuI
(0.10 mmol, 10 mol%), and L1 (0.15 mmol, 15 mol%) in 2.0 mL
of DMF at room temperature under argon. b Isolated yield.
11
CuI
25
a
1a (1.0 mmol), 2a (1.5 mmol), 10 mol% CuI, 15 mol% ligand,
base (2.0 mmol), solvent (2 mL), protected by Ar, at room
temperature, 12 h. b Isolated yield.
coupling reaction of aryl iodides and primary amines
gave excellent yields (85%－92%) (Entries 1－3). The
coupling reaction is also very chemoselective when
other potentially reactive groups were present in the
substrate. For example, aryl iodides coupled with
prop-2-en-1-amine without affecting chloro group pre-
sent in the aryl ring (Table 2, Entries 3). Surprisingly,
With an active catalyst system in hand, we studied
the scope of the CuI/L1 catalyst system under the opti-
mum conditions, and the results are summarized in Ta-
ble 2. A range of electron-rich, electron-neutral, and
electron-deficient aryl iodides showed similar reactivity
at room temperature. We found that, in all cases, the
686
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© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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New Ligands for Copper-Catalyzed C－N Coupling Reactions at Gentle Temperature
strong eletron-deficient aryl iodides were observed to
Continued
Yieldb/%
display poor yields (Table 2, Entries 4, 7, 9). One possi-
ble reason about this case is that the reactivity was high
enough to cause some side reactions. It is important to
note that the cyclic secondary amines displayed high
reactivity under the catalyst system at room temperature
(Entries 5 and 6). The CuI/L1 catalyst system was
further applied to N-arylation of nitrogen containing
heterocycles, which was also accomplished in high yield
(Entries 7－9).
We extended this amination process to aryl bro-
mides and the results are shown in Table 3. All the
examined aryl bromides coupled with primary amines,
cyclic secondary amines or nitrogen containing hetero-
cycles with good to excellent yields at 65 ℃. Good
yields were obtained even for those aryl bromides with
cyclic secondary amines (Entries 5 and 6). Noteworthy
is the fact that the reaction of 4-methoxyphenyl bromide
with pyrazole, which was a highly challenging case for
copper-catalyzed amination, giving the coupling product
at 65 ℃ in 68% yield (Entry 7).
Entry Product
Time/h
48
O
N
6
66
68
84
96
O2N
5f
N
N
7
48
24
24
H3CO
5g (3h)
N
N
8
5i
O
N
9
O2N
5j
a Reaction conditions: ArBr (1.0 mmol), amine (1.5 mmol), CuI
(0.10 mmol, 10 mol%), and L1 (0.15 mmol, 15 mol%) in 2.0 mL
of DMF at 65 ℃ under argon. b Isolated yield.
The scope of such coupling with aryl chlorides is
limitted, we further extended the CuI/L1 catalytic sys-
tem to the coupling reaction of aryl chlorides and
amines or N-containing heterocycles. As shown in Ta-
ble 4, the coupling reactions for most of the substrates
examined gave good to excellent yields at 85 ℃. The
coupling of cyclic secondary amines with aryl chlorides
achieved excellent yields (Entries 2－4). Interestingly,
the catalyst system exhibited high selectivity in a case
where the amine substrate contains more than one po-
tentially reactive group (Entry 1). In addition, the cou-
pling of various aryl chlorides with N-containing het-
erocycles occurred in good yields (Entries 4－8).
Table 3 CuI-catalyzed amination of aryl bromidesa
10 mol% CuI
15 mol% L1
Conclusions
NR1R2
HNR1R2
Br
+
R
R
In summary, pyridin-2-ol-N-oxide (L1) was de-
signed as a new ligand for the coupling of aryl iodides,
with aliphatic primary amines, cyclic secondary amines
or N-containing heterocycles at room temperature. In-
terestingly, our inexpensive catalytic system showed
great functional group compatibility and high selectivity
in the presence of multiple potentially reactive groups at
2.0 equiv. Cs2CO3
DMF, 65 oC
2
4
5
Entry
1
Product
Time/h
Yieldb/%
51
H
N
48
5a (3a)
Table 4 CuI-catalyzed amination of aryl chloridesa
10 mol% CuI
15 mol% L1
H
N
NR1R2
HNR1R2
2
3
4
33
24
33
73
88
77
Cl
+
R
R
2.0 equiv. Cs2CO3
DMF, 85 oC
NC
5b
7
2
6
H
N
O2N
Entry
1
Product
Time/h
48
Yieldb/%
92
5c
NO2
H
N
H
N
HO
7a (3d)
HO
F
5d
O
O
N
N
2
33
92
5
36
86
NO2
5e
O2N
7b (5f)
Chin. J. Chem. 2014, 32, 685—688
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
687

Su et al.
COMMUNICATION
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Yieldb/%
Entry
Product
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36
O
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3
87
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NO2
7c (5e)
N
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O2N
O2N
7d
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O2N
O2N
7f (5j)
N
N
7g
N
N
8
33
83
NO2
7h
a
Reaction conditions: ArCl (1.0 mmol), amine (1.5 mmol), CuI
(0.10 mmol, 10 mol%), and L1 (0.15 mmol, 15 mol%) in 2.0 mL
of DMF at 85 ℃ under argon. b Isolated yield.
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moderate temperature. Applications of this ligand in
other types of copper-catalyzed coupling reactions are
currently underway in our laboratory and the results will
be reported in due course.
Acknowledgement
We gratefully acknowledge the National Natural
Science Foundation (Nos. 81172934, 30973607,
20972160 and 21172220), the National Basic Research
Program of China (No. 2009CB940900), the Special
Foundation of President, and the Strategic Leading Sci-
ence & Technology Programme of the Chinese Acad-
emy of Sciences for their financial support.
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688
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© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2014, 32, 685—688