Copper-catalyzed synthesis of primary arylamines from aryl halides and 2,2,2-trifluoroacetamide

Article abstract of DOI:10.1016/j.tetlet.2007.11.012

A catalytic method was developed to synthesize primary arylamines from the corresponding aryl bromides and iodides under mild conditions (yields = 80-99%). Crystalline 2,2,2-trifluoroacetamide was used as ammonia surrogate and CuI/N,N′-dimethyl ethylenediamine was used as catalyst to achieve the C-N cross-coupling.

Full text of DOI:10.1016/j.tetlet.2007.11.012

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 70–75
Copper-catalyzed synthesis of primary arylamines from aryl
halides and 2,2,2-trifluoroacetamide
a,
Chuan-Zhou Tao,a Juan Li,a Yao Fu,a Lei Liua,b, and Qing-Xiang Guo
*
*
aDepartment of Chemistry, University of Science and Technology of China, Hefei 230026, China
bDepartment of Chemistry, Tsinghua University, Beijing 100084, China
Received 20 September 2007; revised 31 October 2007; accepted 2 November 2007
Available online 6 November 2007
Abstract—A catalytic method was developed to synthesize primary arylamines from the corresponding aryl bromides and iodides
under mild conditions (yields = 80–99%). Crystalline 2,2,2-trifluoroacetamide was used as ammonia surrogate and CuI/N,N0-
dimethyl ethylenediamine was used as catalyst to achieve the C–N cross-coupling.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Primary arylamines are important intermediates in the
manufacture of agrochemicals, pharmaceuticals, dyes,
pigments, and rubber.1 These compounds were tradi-
tionally synthesized through the aryne route by amina-
tion of the corresponding aryl halides using ammonia
as the nucleophile.2 A problem associated with this syn-
thetic method is that the reaction has to be carried out
under fairly high temperature and pressure. Besides,
the amination reaction is often complicated by other
products arising from the highly unstable aryne interme-
diates.3 Due to these reasons, several groups have
recently studied the possibility of using transition metals
to catalyze the synthesis of primary arylamines from
aryl halides. For instance, in 2001 Lang et al. reported
Cu-catalyzed coupling reactions between aryl bromides
and NH3 under 100 psi.4 In 2006 Hartwig and Shen
reported Pd-catalyzed coupling of NH3 with aryl halides
under 80 psi.5 More recently Buchwald and Surry also
reported Pd-catalyzed coupling of NH3 (0.5 M in diox-
ane) with aryl halides at 80 ꢁC in a sealed test tube.6
not be operationally simple or safe from the applica-
tion’s perspective. Besides, several functional groups
(such as esters) cannot tolerate the above amination
reaction conditions (namely, concentrated NH3 +
elevated temperature), which further limits the applica-
bility of the above methods. To overcome the problem
of using NH3, a number of authors have recently
proposed the use of non-volatile ammonia surrogates
in the transition-metal catalyzed synthesis of primary
arylamines. Previously reported surrogates included
benzophenone imine,7 allylamines,8 lithium bis(tri-
methylsilyl)amide,9 N-trialkyl-silylimines,10 and zinc
trimethylsilylamide.11 These compounds were demons-
trated to be sufficiently active in the Pd-catalyzed C–N
cross-coupling with aryl halides under relatively mild
conditions.7–11 The corresponding C–N cross-coupling
products could subsequently be converted to the desired
primary arylamines after removing the protective groups
(Scheme 1).
Unfortunately all the above catalytic reactions using
NH3 as the nucleophile were still performed under a
relatively high pressure of NH3 at elevated tempera-
tures. A sealed reaction vessel had to be used under
these conditions and therefore, the procedures might
cross
R
R
coupling
N
+
P
X
N
P
ammonia
surrogate
R
deprotection
P
= protective
group
NH2
Keywords: Copper catalysis; Ammonia surrogate; Cross coupling;
Primary arylamines.
primary arylamine
*
Scheme 1. Synthesis of primary arylamines by using ammonia
surrogates as the nucleophile through transition-metal catalyzed
cross-coupling reactions.
Corresponding authors. Tel.: +86 10 62780027; fax: +86 10 62771149
(L.L.); e-mail addresses: lliu@mail.tsinghua.edu.cn; qxguo@ustc.
edu.cn
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.012

C.-Z. Tao et al. / Tetrahedron Letters 49 (2008) 70–75
71
It is worth noting that the ammonia surrogate approach
has only been tested with the Pd catalysts.7–11 However,
the use of Pd catalysts may not be optimal from the
economic point of view because Pd is expensive and
contamination of the product by Pd has to be tightly
controlled.12 Besides, it is well known that expensive
phosphine ligands such as 2-dicyclohexylphosphino-
biphenyl are usually needed to effect the Pd-catalyzed
C–N cross coupling.13 Due to these reasons, we are
interested in developing a Cu-catalyzed approach to
achieve the ammonia surrogate strategy in the synthesis
of primary arylamines. This approach is expected to be
economically efficient because Cu-catalyzed C–N cross-
coupling reactions have been shown to proceed under
much less expensive conditions than Pd.14 In addition,
to further reduce the cost of the arylamine synthesis
we seek to use 2,2,2-trifluoroacetamide as ammonia sur-
rogate. This particular compound has not been tested in
the previous Pd-catalyzed approaches, but we expect it
to be an ideal ammonia surrogate because the trifluoro-
acetyl group can be readily removed under very mild
conditions.15
Evidently the key point of the Cu-catalyzed primary
arylamine synthesis using 2,2,2-trifluoroacetamide as
ammonia surrogate is the cross coupling between this
particular amide and aryl halides. Although a number
of catalytic systems (such as CuI/1,2-diamines and
CuI/1,10-phenanthroline)16 have been shown to pro-
mote the Cu-catalyzed amidation of aryl halides, it
remains unclear how the trifluoroacetyl group would
affect the amidation efficiency. Thus we systematically
evaluate the ligands in the cross coupling of iodobenzene
and bromobenzene with 2,2,2-trifluoroacetamide (Table
1). It is found that the amidation yield is zero when no
ligand is added (entry 1). Surprisingly, it is also found
that the amidation yield remains to be zero in the pres-
ence of glycine and N,N-dimethylglycine (entries 2 and
3), despite the fact that these amino acids ligands were
previously shown to be able to promote the amidation
Table 1. Copper-catalyzed cross-coupling of iodobenzene and bromobenzene with 2,2,2-trifluoroacetamidea
CuI/ligand
+
F3CCONH2
X
NHCOCF3
Entry
1
X
I
Ligand
Free
Base
Solvent
DMF
Temp (ꢁC)
Time (h)
24
Yieldb (%)
0
K3PO4
K3PO4
45
2
3
I
I
DMF
DMF
45
45
24
24
0
0
H2N
COOH
N
COOH
K3PO4
K3PO4
4
5
6
I
I
I
DMF
DMF
DMF
45
45
45
24
24
24
35
0
COOH
N
H
K3PO4
K3PO4
N
N
95
HN
NH
7
8
I
I
K3PO4
K3PO4
DMF
DMF
45
45
24
24
40
0
H2N
O
NH2
O
OEt
9
10
11
Br
Br
Br
K3PO4
K2CO3
K2CO3
DMF
75
75
75
24
24
24
0
HN
HN
HN
NH
NH
NH
DMF
36
Dioxane
96
a
˚
General conditions: PhX = 1.0 mmol, F3CCONH2 = 1.5 mmol, CuI = 5 mol %, ligand = 10 mol %, base = 2.0 equiv, solvent = 1.0 mL, 4 AMS =
500 mg.
b Isolated yield.

72
C.-Z. Tao et al. / Tetrahedron Letters 49 (2008) 70–75
Table 2. Cu-catalyzed cross-coupling of substituted iodobenzenes and bromobenzenes with 2,2,2-trifluoroacetamidea
Cu
I
R
R
+
F3CCONH2
NHCOCF3
X
HN
NH
Entry
1
Aryl halide
Product
Temp (ꢁC)
Yieldb (%)
95
45
I
NHCOCF3
2
3
45
45
94
90
I
NHCOCF3
I
NHCOCF3
O
O
4
5
6
7
45
45
45
45
83
80
95
93
I
EtO2C
NHCOCF3
EtO2C
O2N
Br
I
O2N
Br
NHCOCF3
NHCOCF3
NHCOCF3
I
O
I
O
I
NHCOCF3
8
9
45
45
21c
15c
NHCOCF3
I
O
O
10
11
45
75
26c
96
I
NHCOCF3
NHCOCF3
Br
12
13
14
75
75
75
93
90
99
Br
NHCOCF3
O
N
Br
Br
Br
O
N
NHCOCF3
NHCOCF3
NHCOCF3
15
16
75
75
81
84
O
O
NC
NC
Br
NC
NC
NHCOCF3
Br
NHCOCF3
17
75
83

C.-Z. Tao et al. / Tetrahedron Letters 49 (2008) 70–75
73
Table 2 (continued)
Entry
Aryl halide
Product
Temp (ꢁC)
Yieldb (%)
98
18
19
20
75
Ph
NHCOCF3
Ph
Br
Br
NHCOCF3
75
75
61c
NH2
Br
NH2
NHCOCF3
6
a Conditions: ArX = 1.0 mmol, F3CCONH2 = 1.5 mmol, CuI = 5 mol %, N,N0-dimethylethylenediamine = 10 mol %, base = 2.0 equiv, solvent =
˚
1.0 mL, 4 AMS = 500 mg.
b Isolated yield.
c CuI = 10 mol %.
of phenyl halide by acetamide and benzamide.17 The
addition of proline as ligand can increase the yield to
35% (entry 4). However, 1,10-phenanthroline, an excel-
lent ligand in many Cu-catalyzed cross coupling reac-
tions,18 is completely inactive in this particular
transformation (entry 5). At this point, we are pleased
to find that N,N0-dimethyl ethylenediamine (DMEDA)
can dramatically increase the coupling yield to 95%
(entry 6). On the other hand, trans-cyclohexane-1,2-di-
amine and ethyl 2-oxocyclohexanecarboxylate (an excel-
lent ligand recently highlighted by Bao and Lv19) are not
found to be active enough (entries 7 and 8). All the
above observations indicate that 2,2,2-trifluoroaceta-
mide has a very different ligand demand as compared
to the ordinary amides. Furthermore, it should be noted
that although 45 ꢁC is sufficient for the amidation of an
aryl iodide, the reaction temperature has to be raised to
75 ꢁC for an aryl bromide (entries 9–11). The solvent
also has to be changed to dioxane, where the amidation
yield is as high as 96%.
applied to the coupling of 2,2,2-trifluoroacetamide with
various aryl iodides and bromides having different elec-
tronic and steric properties (Table 2).20 It is found that
both electron-rich and electron-deficient aryl halides
can be smoothly converted to the desired products with
satisfactory isolated yields (i.e. 80–95% for aryl iodides
and 81–99% for aryl bromides, respectively). However,
aryl halides carrying an ortho-substituent are not found
to readily participate in the reaction. For instance,
2-iodotoluene can only give an isolated yield of 15%
even in the presence of 10% CuI (entry 9), whereas the
amidation yield for 2-bromoaniline is as low as 6%
(entry 20). Similarly, the amidation yield is only 21%
for 1-iodo-naphthalene (entry 8) and 61% for 1-bromo-
naphthalene (entry 19), which are values significantly
lower than the phenyl cases. Thus the steric effect has
a much stronger influence than the electronic effect in
the cross-coupling with 2,2,2-trifluoroacetamide.
Certainly the above amidation products can now be
readily converted to the target primary arylamines using
the standard deprotection methods for the trifluoroace-
tyl group.15 However, in our hands we find fortuitously
Having identified the CuI/DMEDA catalytic system, we
next examined whether the same catalytic system can be
Table 3. Copper-catalyzed one-pot synthesis of primary arylamines from aryl halidesa
R
R
1) NH2COCF3, CuI
2) CH3OH/H2O
X
NH2
Entry
1
Aryl halide
Product
Temp (ꢁC)
Yieldb (%)
91
45
I
NH2
2
3
4
45
45
45
95
98
O
NH2
O
I
I
NH2
O
O
99
EtO2C
I
EtO2C
NH2
(continued on next page)

74
C.-Z. Tao et al. / Tetrahedron Letters 49 (2008) 70–75
Table 3 (continued)
Entry
Aryl halide
Product
Temp (ꢁC)
Yieldb (%)
80
5
6
7
8
9
45
Br
I
Br
NH2
75
75
75
75
93
91
93
99
Br
NH2
Br
NH2
O2N
NC
Br
Br
O2N
NC
NH2
NH2
Br
NH2
10
75
95
NC
O
NC
O
11
12
13
75
75
75
87
90
93
Br
NH2
NH2
NH2
N
Br
N
Ph
Br
Ph
Br
NH2
14
75
50c
a Conditions: (1) ArX = 1.0 mmol, F3CCONH2 = 1.5 mmol, CuI = 5 mol %, N,N0-dimethylethylenediamine = 10 mol %, base = 2.0 equiv,
˚
solvent = 1.0 mL, 4 AMS = 500 mg. (2) MeOH/H2O = 3.0 mL:3.0 mL.
b Isolated yield.
c CuI = 10 mol %.
that the trifluoroacetyl group can be removed directly
after the amidation step by adding CH3OH and H2O
to the reaction vessel. The success of this method is
presumably due to the use of K3PO4 or K2CO3 in the
amidation step, which promotes the hydrolysis of the
trifluoroacetyl group once water is added. Taking
advantage of this finding, we developed a one-pot
method for the synthesis of primary arylamines from
aryl halides without the need to separate any intermedi-
ate.21 As shown in Table 3, this one-pot method can be
successfully applied to a variety of aryl iodides and
bromides (entries 1–13, yields = 80–99%). 1-bromo-
naphthalene can also be successfully converted to
1-naphthalenamine with a yield of 50% (entry 14).
described in the present report may be found useful in
a number of fields such as pharmaceutical research
and organic material design.
Acknowledgment
This study was supported by the NSFC (No. 20472079).
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2007.11.012.
To conclude, in the present study we report a novel
method for the synthesis of primary arylamines from
the corresponding aryl halides. 2,2,2-Trifluoro-acetam-
ide is used as ammonia surrogate and CuI is used as
the catalyst to achieve the C–N coupling under mild
conditions. Given the fact that primary arylamines are
becoming increasingly more important intermediates in
the synthesis of functional materials,1 the method
References and notes
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Schlenk tube was charged with CuI (10 mg), base
(2.0 mmol, K3PO4 for ArI and K2CO3 for ArBr), and
˚
4 AMS (500 mg). The tube was evacuated and back-
filled with Ar. Then aryl halide (1.0 mmol), trifluoro-
acetamide (170 mg), DMEDA (12 lL), and solvent
(1.0 mL, DMF for ArI and dioxane for ArBr) were
added under Ar. The reaction mixture was stirred for
24–36 h at 45 ꢁC (for ArI) or 75 ꢁC (for ArBr). The
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˚
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and backfilled with Ar. Then aryl halide (1.0 mmol),
trifluoro-acetamide (170 mg), DMEDA (12 lL) and
solvent (1.0 mL, DMF for ArI and dioxane for ArBr)
were added under Ar. The reaction mixture was stirred for
24–48 h at 45 ꢁC (for ArI) or 75 ꢁC (for ArBr). Sub-
sequently to the reaction mixture was added CH3OH/H2O
(3.0 mL/3.0 mL) under Ar. The reaction was further
stirred for 5–12 h. The resulting suspension was cooled
to room temperature, concentrated and extracted with
ethyl acetate (20 mL · 3). The combined organic layers
were concentrated and the residue was purified by column
chromatography to afford the product.