Efficient ligand-free copper-catalyzed arylation of aliphatic amines

Article abstract of DOI:10.1055/s-0030-1259049

An efficient and practical protocol has been developed for the cross-coupling of alkyl amines and aryl iodides under ligand-free copper(I) iodide catalyzed conditions. A variety of alkyl amines undergo the catalytic system to afford the N-arylated products in moderate to good yields (up to 93%).

Full text of DOI:10.1055/s-0030-1259049

3068
LETTER
Efficient Ligand-Free Copper-Catalyzed Arylation of Aliphatic Amines
Ligand-Free
C
u
opper-Cataly
i
zedA
r
-
ylationo
F
f
A
liphatic
A
o
mines ng Yong, Yong-Chua Teo*
Natural Sciences and Science Education, National Institute of Education, Nanyang Technological University, 1 Nanyang Walk,
Singapore 637616, Singapore
Fax +65(6896)9414; E-mail: yongchua.teo@nie.edu.sg
Received 14 September 2010
veloped successful protocols for the cross-coupling of ni-
Abstract: An efficient and practical protocol has been developed
trogen heterocycles and aryl halides under ligand-free
for the cross-coupling of alkyl amines and aryl iodides under
conditions using Cu(I) halide salts.16 Van Koten also re-
ligand-free copper(I) iodide catalyzed conditions. A variety of alkyl
ported an efficient protocol for the coupling of various ni-
trogen nucleophiles with aryl halides under copper-
catalyzed ligand-free conditions.17 However, the protocol
requires a high reaction temperature, and a limited sub-
strate range of aliphatic amines was tested under the cata-
lytic conditions. Punniyamurthy demonstrated cross-
coupling of a variety of amines with iodobenzene using
CuO nanoparticles18. Wolf has developed a Cu2O cou-
pling procedure for the amination of aryl halides with var-
ious alkyl amines under ligand-free conditions which
necessitated the use of the strong base sodium tert-butox-
ide.19 In this paper, we report a ligand-free copper-cata-
lyzed system for the cross-coupling of aryl iodides with a
wide variety of aliphatic and cyclic amines.
amines undergo the catalytic system to afford the N-arylated prod-
ucts in moderate to good yields (up to 93%).
Key words: ligand-free, copper, aliphatic amines, N-arylation
Transition-metal-catalyzed cross-coupling reactions of
amines with aryl halides has emerged as one of the most
powerful strategy for the formation of C–N bonds in or-
ganic synthesis. In particular, the intense demand for the
synthesis of N-arylated amines has been fueled by their
applications as key synthons in natural products, pharma-
ceuticals, and in materials research.1 Among the various
strategies developed to date, the copper-catalyzed Ull-
mann-type coupling reaction has proven to be a conve-
nient and versatile method for rapidly accessing arylated
amines. Important developments made on the Ullmann-
type C–N cross-coupling reactions mostly involve widen-
ing the scope of such reactions in terms of substrate toler-
ance, copper loading, and practicality of the reaction
conditions.2 Generally, this goal is achieved via the addi-
tion of suitable mono- or bidentate ligands such as phos-
phines,3 diols,4 diketones,5 amino acids,6 1,10-
phenanthroline derivatives,7 oxalyldihydrazone,8 salicyla-
mides,9 and phosphoramidites10 to increase the yield and
generality of the reaction. Critical to the success of these
strategies is the need for the presence of an assisting
ligand in the reaction protocols.
In our initial study, benzylamine and iodobenzene were
chosen as model substrates for the N-arylation reaction.
Under ligand-free conditions, the reaction of benzylamine
(1 equiv) with iodobenzene (2 equiv), Cu2O (10 mol%) as
catalyst, and Cs2CO3 in toluene gave a moderate yield of
54% (Table 1, entry 1). Encouraged by this result, optimi-
zation studies were initiated to evaluate the efficiency of
various copper sources for the arylation reaction. Among
the various copper salts screened (entries 1–5), CuI
proved to be the best copper catalyst (entry 5), affording
the N-arylated product in a good yield of 70%. To rule out
the possibility that catalysis was assisted by other contam-
inants that might be present in the system, control experi-
ments revealed that no product was obtained in the
absence of the copper source (entry 6). Next, we probed
the solvent effect using a series of commonly used organic
solvents and water as reaction medium. In this study,
DMF was found to be the solvent of choice which gave the
product in an excellent yield of 93% (entry 8). Lower
yields were obtained in the case of toluene (entry 5) and
acetonitrile (entry 7) as the system solvent. A moderate
yield was also achieved when water was used as the only
reaction medium for the reaction (entry 9). Further exper-
iments revealed that the nature of the bases has a pro-
nounced impact on the process. The choice of Cs2CO3 as
the base plays an important role for this coupling reaction,
as K2CO3, KOH, and K3PO4 were evaluated and shown to
be ineffective (entries 10–12). In summary, the optimized
conditions for our ligand-free copper-catalyzed cross-
coupling reactions use CuI (10 mol%) and Cs2CO3 (2
equiv) in DMF at 135 °C for 24 hours. It is noteworthy
Although significant progress has been achieved on the
aforementioned transformation, there still remains a need
to develop economical and sustainable protocols that op-
erate under environmentally friendly conditions.11 In this
respect, ligand-free Ullmann-type coupling protocols re-
main underdeveloped. Correa and Bolm have reported a
ligand-free Cu2O catalytic system for the cross-coupling
of aryl iodides with sulfoximines and nitrogen hetero-
cyles.12 Hu demonstrated the N-arylation of azoles using
copper powder without additional ligand.13 Xu reported
the reusable ligand-free Cu2O for N-arylation of nitrogen-
containing heterocycles with aryl halides.14 Rossi demon-
strated N-arylation of indole with aryl iodides under base-
free and ligand-free conditions using CuOAc.15 Chan de-
SYNLETT 2010, No. 20, pp 3068–3072
x
x
.x
x
.2
0
1
0
Advanced online publication: 17.11.2010
DOI: 10.1055/s-0030-1259049; Art ID: D25310ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Ligand-Free Copper-Catalyzed Arylation of Aliphatic Amines
3069
that the cross-coupling reaction is water-tolerant as shown
by the fact that product 3a was obtained in a good yield of
71% (entry 14) when the reaction was carried out in a mix-
ture of DMF and water (7.5:1).
Table 1 Optimization Studies of Ligand-Free Copper-Catalyzed
Cross-Coupling of Benzylamine and Iodobenzenea
NH2
To establish the generality of this protocol, a variety of
functionalized aryl halides was coupled with benzylamine
under the optimized conditions. The results are shown in
Table 2. In general, good to excellent yields were ob-
tained regardless of the electronic nature of the substituent
for aryl iodides. Aryl halides with ortho substitution are
not significantly hampered in the cross-coupling reaction,
affording the products in good yields (Table 2, entries 2
and 3), and no significant electronic effects were observed
for meta-substituted (entries 4–6) and para-substituted
(entries 7–11) aryl iodides. However, the use of bro-
mobenzene and 4-bromoanisole as coupling partners gave
only trace amounts of the products (entries 12 and 13).
This difference in reactivity of the halide substituent in the
electrophilic counterpart confers high chemoselectivity to
the catalytic process whereby coupling only takes place
on the carbon with the iodo substituent in the presence of
other halide groups (entries 8–10).
[Cu] (10 mol%)
base
1
+
I
N
solvent, 135 °C
24 h
H
3
2
Entry [Cu] source
Base
Solvent
toluene
toluene
toluene
toluene
toluene
toluene
MeCN
DMF
Yield (%)b
1
2
Cu2O
CuO
CuCl
CuBr
CuI
–
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
KOH
54
0
3
trace
66
4
5
70
6
0
7
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
62
In order to expand the scope of the ligand-free CuI-cata-
lyzed amination, we carried out cross-coupling reactions
between a series of aliphatic nitrogen nucleophiles and io-
dobenzene. As revealed by the data in Table 3, several
amine substrates can be arylated under the ligand-free cat-
alytic conditions. A variety of linear and branched aliphat-
ic primary amines afforded the products in good yields
ranging from 60–78% (entries 1–5). The arylation of a
representative cyclic primary amine, cyclohexylamine
also gave the arylated product with a good yield of 63%
(entry 6). Moreover, cyclic secondary amines such as pyr-
rolidine, morpholine, and piperazine also gave the corre-
sponding N-phenyl derivatives in good yields (entries 7–
9).
8
93
9
H2O
50
10
11
12
13
14
DMF
14
DMF
trace
33
K3PO4
Cs2CO3
Cs2CO3
DMF
DMF
80c
71d
DMF
a The reaction was carried out with benzylamine (1.47 mmol), iodo-
benzene (2.94 mmol), base (2.94 mmol), Cu source (10 mol%), sol-
vent (0.75 mL) at 135 °C for 24 h.
b Isolated yield after column chromatography.
c The reaction was performed with benzylamine (2.94 mmol) and
iodobenzene (1.47 mmol).
d The reaction was performed with a mixture of DMF and H2O (7.5:1)
as solvent.
Table 2 N-Arylation of Benzylamine with Aryl Halides Catalyzed by Ligand-Free CuI in DMFa
R
CuI (10 mol%)
Cs2CO3
NH2
N
+
X
H
DMF, 135 °C
24 h
R
Entry
1
ArX
Product
Yield (%)b
93
3a
3b
I
N
H
CI
2
80
N
H
I
CI
Synlett 2010, No. 20, 3068–3072 © Thieme Stuttgart · New York

3070
F.-F. Yong, Y.-C. Teo
LETTER
Table 2 N-Arylation of Benzylamine with Aryl Halides Catalyzed by Ligand-Free CuI in DMFa (continued)
R
CuI (10 mol%)
Cs2CO3
NH2
N
+
X
H
DMF, 135 °C
24 h
R
Entry
3
ArX
Product
Yield (%)b
53
3c
3d
3e
3f
N
H
I
I
I
4
5
6
74c
84
82
N
H
CI
N
H
CI
CF3
N
H
CF3
I
I
OMe
7
3g
66c
OMe
N
H
F
8
9
3h
3i
84
I
I
I
F
N
H
CI
90
CI
N
H
Br
10
11
12
3j
88
Br
N
H
CF3
3k
3a
60
I
CF3
N
H
trace
Br
N
H
OMe
3g
trace
13
Br
OMe
N
H
a The reaction was carried out with benzylamine (1.47 mmol), aryl halides (2.94 mmol), Cs2CO3 (2.94 mmol), CuI (10 mol%), DMF (0.75 mL)
at 135 °C for 24 h.
b Isolated yield after column chromatography.
c The reaction was performed with CuI (20 mol%).
Synlett 2010, No. 20, 3068–3072 © Thieme Stuttgart · New York

LETTER
Ligand-Free Copper-Catalyzed Arylation of Aliphatic Amines
3071
Table 3 N-Arylation of Amines with Iodobenzene Catalyzed by Ligand-Free CuI in DMFa
CuI (20 mol%)
R1
R2
R1
R2
Cs2CO3 (2 equiv)
+
NH
N
I
DMF, 135 °C
24 h
Entry
1
Amine
Product
Yield (%)b
75
4a
4b
4c
4d
NH2
N
H
2
3
4
62
72
78
NH2
N
H
MeO
NH2
MeO
N
H
NH2
N
H
H
N
5
6
4e
4f
60
63
NH2
NH
NH2
7
8
9
4g
4h
4i
82
64
75
NH
N
O
NH
O
N
Ph
N
NH
Ph
N
N
a The reaction was carried out with amines (1.47 mmol), iodobenzene (2.94 mmol), Cs2CO3 (2.94 mmol), CuI (20 mol%), DMF (0.75 mL) at
135 °C for 24 h.
b Isolated yield after column chromatography.
In summary, we have developed a versatile, operationally
simple, and practical ligand-free CuI-catalyzed cross-cou-
pling protocol for the arylation of various aliphatic nitro-
gen nucleophiles with differently substituted aryl iodides.
In most instances, the N-arylated derivatives are obtained
in good to excellent yields. This renders the current ap-
proach an attractive alternative to access various N-arylat-
ed aliphatic amines20 and will also provide a valuable
platform for chemists who are interested in large-scale ap-
plications. Exploration of this ligand-free Cu catalytic
system to other cross-coupling is ongoing.
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Acknowledgment
We thank the National Institute of Education and Nanyang Techno-
logical University for their generous financial support.
Synlett 2010, No. 20, 3068–3072 © Thieme Stuttgart · New York

3072
F.-F. Yong, Y.-C. Teo
LETTER
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(20) Representative Procedure for N-Arylation of Aliphatic
Amines
A mixture of CuI (Sigma-Aldrich, 99.99% purity, 0.147
mmol), Cs2CO3 (2.94 mmol) was dissolved in (0.75 mL)
DMF, the aryl halide (2.94 mmol), and the aliphatic amine
(1.47 mmol) were added, and the mixture was stirred under
air in a closed system at 135 °C for 24 h. The heterogeneous
mixture was then cooled to r.t. and diluted with CH2Cl2. The
resulting solution was directly filtered through a pad of
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crude product was purified by silica gel column
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Synlett 2010, No. 20, 3068–3072 © Thieme Stuttgart · New York

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