CuCl-catalyzed formation of C-N bond with a soluble base

Article abstract of DOI:10.1016/j.tetlet.2009.03.094

Tetramethylammonium hydroxide was used as a base instead of a traditional inorganic base in this copper-catalyzed system and some satisfactory results were obtained. Various functional groups were compatible under this reaction condition.

Full text of DOI:10.1016/j.tetlet.2009.03.094

Tetrahedron Letters 50 (2009) 2585–2588
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Tetrahedron Letters
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CuCl-catalyzed formation of C–N bond with a soluble base
*
Yi-Si Feng, Qiu-Shi Man, Pan Pan, Zong-Qin Pan, Hua-Jian Xu
School of Chemical Engineering, Hefei University of Technology, Hefei 230009, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Tetramethylammonium hydroxide was used as a base instead of a traditional inorganic base in this cop-
per-catalyzed system and some satisfactory results were obtained. Various functional groups were com-
patible under this reaction condition.
Received 6 January 2009
Revised 10 March 2009
Accepted 13 March 2009
Available online 18 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
In recent years, many significant improvements in the forma-
tion of carbon–nitrogen bond catalyzed by transition-metals have
been achieved.1 Much attention has been paid on Pd-catalyzed ary-
lation of amines in the past decades.2 However, the drawbacks of
Pd-catalyst systems such as high cost and toxicity are obvious.
These drawbacks limit their massive applications for industrial
scales. The use of a cheaper metal instead of Pd provides an attrac-
tive alternative. Due to the low price and environmental benignity,
copper-catalyzed C–N coupling reactions are particularly attrac-
tive.3 Several published reviews have detailed the recent progress
of copper-catalyzed C–N coupling reactions.3,4
In most reported methods, inorganic solid bases are used as
base in the C–N cross-coupling reaction while they are not usually
soluble or soluble partially in reaction system, which makes the
utilized efficiency of base reduce drastically. To the best of our
knowledge, thus far there has been only one reported example of
N-arylation with tetraethylammonium carbonate, a soluble base,
as base. But, only N-arylation of imidazoles has been achieved.5
Therefore, it is necessary and important to expand the scope of
amines used as nucleophiles in this reaction system with a soluble
base. Herein, we report a novel method to construct C–N bond
mediated by tetramethylammonium hydroxide.
Table 1
Optimization of reaction conditions for Cu-catalyzed N-arylation of benzylamine with
iodobenzene
H
I
N
NH2
[Cu], ligand
base,solvent
Ar, 80ºC, 24h
Entry
[Cu]
Ligand
Base
Solvent
Yielda,b (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
CuBr2
CuO
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
(CH3)4N+OHꢀ
ðEt4NþÞ2CO23ꢀ
KOH
K3PO4
Cs2CO3
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
86
31
19
18
17
52
61
17
25
29
19
72
K2CO3
(CH3)4N+OHꢀ
(CH3)4N+OHꢀ
(CH3)4N+OHꢀ
(CH3)4N+OHꢀ
(CH3)4N+OHꢀ
(CH3)4N+OHꢀ
(CH3)4N+OHꢀ
(CH3)4N+OHꢀ
(CH3)4N+OHꢀ
(CH3)4N+OHꢀ
(CH3)4N+OHꢀ
(CH3)4N+OHꢀ
(CH3)4N+OHꢀ
(CH3)4N+OHꢀ
(CH3)4N+OHꢀ
Dioxane
Isopropanol
Toluene
H2O
49
Trace
Trace
17
15
91
44
81
72
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
In our initial experiment, iodobenzene (1 equiv) was treated
with benzylamine (1.5 equiv) in DMSO at 80 °C for 24 h with
Cu2O (0.1 equiv)/L1 (0.1 equiv) and (CH3)4N+OHꢀ (2 equiv). To
our delight, N-benzylaniline was formed in more than 80% yields.
Encouraged by this finding, different reaction conditions were
tried. The results are listed in Table 1.
CuCl
CuSO4
Cu(Ac)2
CuI
a
Reaction conditions: Iodobenzene 1.0 mmol; benzylamine 1.5 mmol; copper
source 0.1 mmol; ligand 0.1 mmol; solvent 1 mL; base 2 mmol; temperature 80 °C;
24 h.
Bases influenced the progress of the reaction greatly. Moderate
b
yields were obtained when ðEt4NþÞ CO 2ꢀ, K2CO3, Cs2CO3, KOH,
Isolated yields.
2
3
and K3PO4 were used. A high yield was obtained only when
(CH3)4N+OHꢀ was used (Table 1, entries 1–5). Subsequently, sev-
eral ligands L1–L5 were investigated for this coupling reaction
O
O
O
O
OH
OH
OEt
MeHN
NHMe
N
N
L1
L2
L3
L4
L5
* Corresponding author. Tel.: +86 551 2904405; fax: +86 551 2901450.
E-mail address: hjxu@ustc.edu (H.-J. Xu).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.094

2586
Y.-S. Feng et al. / Tetrahedron Letters 50 (2009) 2585–2588
Table 2
CuCl/ L1-catalyzed N-arylation of alkyl amines and N-heterocycles with aryl iodides in the presence of (CH3)4N+OHꢀa
O
O
10mol% CuCl
R2
L1:
R2 R3
N
OEt
10mol% L1
I
N
R3
R1
+
R1
2 equiv (CH3)4N+OH-
1 ml DMSO
H
ethyl 2-oxocyclohexanecarboxylate
Ar, 80oC, 24h
Entry
1
Aryl iodides
Amines
Product
Yieldb (%)
80
H3C
I
H3C
NH
NH2
2
3
4
5
6
70
74
86
78
68
H3CO
I
O
NH
NH2
NH2
NH2
NH2
NH2
H3C
O
NH
H3COOC
Br
I
H3C
I
I
Br
Cl
NH
Cl
NH
I
NH
H
I
N
7
8
65
72
NH2
N
N
N
N
H
NH2
N
I
9
10
11
87
74
81
H2N
I
NH
H2N
H3C
Cl
I
H3C
Cl
NH
H2N
I
NH
12
13
68
56
H2N
H2N
O2N
I
O2N
NH
I
CH3
NH
CH3

Y.-S. Feng et al. / Tetrahedron Letters 50 (2009) 2585–2588
2587
Table 2 (continued)
Entry
Aryl iodides
Amines
Product
Yieldb (%)
14
59
H2N
NH
H3COOC
I
H3COOC
N
15
16
17
18
19
20
21
90
86
83
74
78
77
72
NH
NH
I
N
N
CH3
Cl
H3C
I
I
Cl
I
NH
O2N
NH
N
N
NO2
O
O
I
NH
H3C
CH3
I
O
HN
O
O
N
Cl
I
HN
Cl
N
O
N
N
O
22
23
67
O
HN
H3COOC
I
H3COOC
N
82
70
I
HN
HN
24
H3COOC
I
H3COOC
a
Reaction conditions: aryl iodides 1.0 mmol; amines 1.5 mmol; CuCl 0.1 mmol; L1 0.1 mmol; DMSO 1 mL; (CH3)4N+OHꢀ 2 mmol; 80 °C; 24 h.
Isolated yields.
b
and L1 gave the best result (entries 1, 6–9). Solvents also played an
strates. The reactions also appeared to work well (Table 2, entries
15–24). We discovered that the N-arylation reactions of amides
with p-substituted aryl halides were easier than with o-substituted
ones (Table 2, entries 10 and 13).
important role in this reaction. The experimental results suggested
that DMSO was the best solvent among the screened ones, such as
DMF, dioxane, toluene, and H2O (Table 1, entries 1, 10–14). Other
copper compounds (CuI, CuSO4, Cu(OAc)2, CuO, CuBr2, and CuCl)
were also evaluated. To our delight, CuCl gave a better yield even
than Cu2O (entries 1, 15–20).
With the optimum condition in hand, N-arylations of alkyl
amines and N-heterocycles with substituted aryl iodides were
examined to evaluate the scope and the generality of this catalytic
system. The results are summarized in Table 2.6
In conclusion, (CH3)4N+OHꢀ was found to be an efficient soluble
base for the CuCl-catalyzed N-arylation of amines with aryl io-
dides. The development of an effective catalytic system for the cou-
pling of amines and aryl iodides is still far from being satisfied. The
further work of the mechanism of the reactions and the applica-
tions of this catalytic system are ongoing in our laboratory.
We were delighted to find that the N-arylation of benzylamine
with a variety of aryl iodides proceeded smoothly to give the cor-
responding products in good yields (65–86%) (Table 2, entries 1–8).
Aliphatic amines also performed very well with 56–87% yields (Ta-
ble 2, entries 9–14). Subsequently, other N-heterocycles, such as
pyrrole, morpholine, and piperidine were also tested as the sub-
Acknowledgments
This research was financially supported by the National Natural
Science Foundation of China (No. 20802015, 20772115) and the
Doctoral Special Fund of Hefei University of Technology (No.
2007GDBJ021).

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6. General experimental procedure. All reagents and solvents, except the soluble
base-(CH3)4N+OHꢀ, were pure analytical grade materials purchased from
commercial sources and were used without further purification. The soluble
base, (CH3)4N+OHꢀ, was dissolved in pure water and frozen at ꢀ10 °C for 24 h till
they were turned into solid. Then, the base was put into lyophilizer and was
dried for 8 h. The 1H and 13C NMR spectra were recorded in CDCl3 on a 300 MHz
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(200–300). All reactions were carried out in a Schlenk tube equipped with a
magnetic stir bar under Ar atmosphere. A Schlenk tube was charged with Cu salt
(0.1 mmol), base (2 mmol), ligand (0.1 mmol), and solvent (1 ml) under Ar. The
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purified by silica gel chromatography.N-benzyl-4-methoxyaniline (entry 2,
Table 2). 1H NMR (300 MHz, CDCl3, d ppm): 7.36–7.25 (5H, m), 6.79 (2H, d,
J = 8.4 Hz), 6.65 (2H, d, J = 8.4 Hz), 4.28 (2H, s), 3.74 (3H, s); 13C NMR (300 MHz,
CDCl3): 152.4, 142.5, 139.8, 128.7, 127.6, 127.3, 115.1, 114.3, 55.9, 49.4 ppm.
HRMS m/z: 213.1154 (213.1160 calcd for C14H15NO).1-p-Tolyl-1H-pyrrole (entry
16, Table 2). 1H NMR (300 MHz, CDCl3, d ppm): 7.29–7.19 (4H, m), 7.05 (2H, d,
J = 1.5 Hz), 6.33 (2H, d, J = 1.5 Hz), 2.36 (3H, s); 13C NMR (300 MHz, CDCl3):
138.6, 135.3, 130.1, 120.5, 119.4, 110.1, 20.8 ppm. HRMS m/z: 157.0891
(157.0903 calcd for C11H11N).
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