CuCl-catalyzed aerobic oxidative reaction of primary aromatic amines

Article abstract of DOI:10.1016/j.tetlet.2008.04.089

The oxidations of primary aromatic amines were investigated. Cuprous chloride-air system can catalyze the oxidation of primary aromatic amines to azo derivatives, anils, and/or quinone anils. The experimental procedure is simple and the products could be easily isolated in high yields.

Full text of DOI:10.1016/j.tetlet.2008.04.089

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Tetrahedron Letters 49 (2008) 4011–4015
CuCl-catalyzed aerobic oxidative reaction of primary aromatic amines
Wenchao Lu, Chanjuan Xi *
Key Laboratory of Organic Optoelectronics and Molecular Engineering of Ministry of Education, Department of Chemistry,
Tsinghua University, Beijing 100084, China
Received 15 January 2008; revised 8 April 2008; accepted 15 April 2008
Available online 18 April 2008
Abstract
The oxidations of primary aromatic amines were investigated. Cuprous chloride-air system can catalyze the oxidation of primary aro-
matic amines to azo derivatives, anils, and/or quinone anils. The experimental procedure is simple and the products could be easily iso-
lated in high yields.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Aromatic amines; Cuprous chloride; Catalytic oxidation; Azo derivatives; Anils
Oxidation of arylamines is an important reaction in the
synthesis of many products such as azo, azoxy, anil, and
hydroxylamine compounds. Azo derivatives have been
utilized as organic dyes,1 indicators,2 radical reaction initi-
ators,3 and therapeutic agents.4 In addition, azo derivatives
have the potential for use in electronic5 and drug delivery
applications.6 A variety of oxidation methods have been
reported for the preparation of these compounds. For
example, aromatic amines can be oxidized with oxidants
such as peracetic acid,7 manganese dioxide,8 lead tetraace-
tate,9 Hg(OAc)2,10 barium manganate,11 phenyl iodoace-
tate,12 sodium hypochlorite,13 potassium ferricyanide,14
potassium ferrate,15 barium ferrate monohydrate,16 and
mercury(II) oxide.17
Most of these methods are based on stoichiometric pro-
cesses. In light of the current interest to develop more effi-
cient and environmentally friendly methods for chemical
synthesis,18 the use of oxygen as the oxidizing agents has
clearly the environmental advantages because it is inexpen-
sive, abundant, nontoxic, and convenient. Accordingly, it is
highly desirable to develop a transition-metal-catalyzed
oxidative reaction of aromatic amines under atmospheric
conditions. Only few examples of catalytic oxidation of
amines have been reported.19,20 Herein, we describe a
CuCl-catalyzed oxidation of primary aromatic amines to
afford azo derivatives, anils, and quinone anils under atmo-
spheric conditions (Scheme 1).
Copper derivatives have been known to mediate the oxi-
dative reaction. In this broad context, copper(II) reagent
was mainly used as an oxidant for the oxidative reaction.
Recently, we reported that N,N-dialkylanilines could be
oxidized with CuBr in the presence of H2O2 in water to give
benzidine derivatives in high yields.21 As part of a general
study, we chose CuCl-catalyzed aerobic oxidative reaction
of primary aromatic amines. At the beginning, various cop-
per salts such as CuCl2, Cu(OAc)2, CuCl/air, CuBr/air,
CuI/air, and CuCl2/air were examined as catalysts in the
model reaction of para-methoxyaniline 1a under atmo-
spheric conditions to ascertain the most optimum condi-
tions (Table 1). The Cu(II) salts were inefficient (entries 8
and 9) with the CuCl/air system proving to be superior
(entries 1 and 2). Control experiments carried out on
para-methoxyaniline 1a showed that, in the absence of
CuCl, no oxidation to azo compounds occurred (entry 3).
CuBr/air showed lower activity (entries 4 and 5) and
CuI/air appeared to be inert in this reaction (entries 6
and 7). In this reaction, several commonly used solvents
were tested (Table 1, entries 1 and 10–19). CH3OH was less
*
Corresponding author. Tel.: +86 10 62782695.
E-mail address: cjxi@tsinghua.edu.cn (C. Xi).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.089

4012
W. Lu, C. Xi / Tetrahedron Letters 49 (2008) 4011–4015
R2
R2
N
NH
R2
R1
R2
R1
R2
R1
R1
R2
R1
R2
aq. K2CO3
CuCl/air
rt
CuCl/air
rt
NH2
N
N
or
N
aq. HCl
O
R2 = H
R1
R1
R1 = R2
= ortho-substitutent
Scheme 1.
Table 1
effective (entry 18). H2O was not effective (entry 19) for this
reaction. Tetrahydrofuran (THF), ethoxyethane, propan-
2-one, dichloromethane, and N,N0-dimethylformamide
(DMF) were effective to give moderate yields for this reac-
tion (entries 13–17). Acetonitrile, toluene, pyridine, and tri-
ethylamine were much more effective to give high yields for
this reaction (entry 1 and entries 10–12). Finally we chose
the acetonitrile as a solvent and CuCl as a catalyst at room
temperature under atmospheric conditions for proceeding
the reactions.
Under the optimized conditions, various aromatic
amines were transformed to the corresponding azo deriva-
tives. Representative results are listed in Table 2. Using
para-activated aromatic amines led to excellent yields of
the oxidative reaction products (entries 1 and 5). Using
meta-activated aromatic amine resulted in good yields of
the desired product (entries 2 and 6). Using ortho-activated
aromatic aniline resulted in a moderate yield of the desired
product (entry 3). The oxidative reaction of aromatic
amines with electron-withdrawing substituted group such
as nitryl on the phenyl ring did not proceed (entry 9) and
chlorine on the phenyl ring gave low yields under the reac-
tion conditions (entries 7 and 8). This was suspected to be
the result of low electron density of phenyl ring. Represen-
tative procedure was shown in Ref. 22.
Various copper salts for the oxidation of 4-methoxyanilinea
copper salt/air
Solvent, rt
CH3O
NH2
CH3O
N
2a
N
OCH3
1a
Salts
Entry
Solvent
Amount
(equiv)
Time
(h)
Yieldb
(%)
1
2
3
4
5
6
7
8
9
CuCl
CuCl
CuCl
CuBr
CuBr
CuI
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Toluene
Pyridine
Et3N
0.2
0.5
0
0.2
1
0.2
1
1
10
5
71
74
0
11
13
Trace
Trace
0
10
24
24
48
48
48
48
30
10
48
10
10
10
24
48
30
48
CuI
CuCl2
Cu(OAc)2
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
1
0
10
11
12
13
14
15
16
17
18
19
a
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
70
70
67
57
51
50
53
45
15
0
THF
Et2O
CH3COCH3
CH2Cl2
DMF
CH3OH
H2O
Reaction conditions: 4-methoxyaniline (1 mmol), solvent (5 mL).
Isolated yield.
b
Table 2
Oxidation of aromatic anilines in the CuCl/air systema
Entry
1
Substract
Time (h)
10
Product
Yieldb (%)
71
NH2
MeO
N N
2a
OMe
MeO
MeO
1a
MeO
OMe
NH2
2
3
48
10
53
46
N N
2b
1b
NH2
OMe MeO
N N
2c
OMe
1c

W. Lu, C. Xi / Tetrahedron Letters 49 (2008) 4011–4015
4013
Table 2 (continued)
Entry
Substract
NH2
Time (h)
48
Product
Yieldb (%)
N N
4
5
33
85
2d
1d
NH2
1e
NH2
Me
Me
N N
Me
10
48
96
96
96
2e
Me
Me
6
7
8
63
26
8
N N
2f
1f
Me
NH2
Cl
N N
2g
Cl
Cl
NH2
1g
Cl
Cl
Cl
N N
2h
1h
NH2
NO2
N N
2i
NO2
9
0
O2N
1i
a
Reaction conditions: aromatic amine (1 mmol), solvent, CH3CN (5 mL), CuCl (0.2 mmol).
Yields are for isolated aza derivatives.
b
We next investigated the oxidation of disubstituted
Table 3
Oxidation of disubstituted benzeneamine in the CuCl/air systema
benzeneamines in a CuCl/air system.23 Representative
results are listed in Table 3. When disubstituted benzene-
amines were treated, quinone anils 3 were exclusively
formed in high yield after hydrolysis with acidic solution.
No azo derivatives 2 were observed. This may be attributed
to the steric hindrance of ortho-substituent in benzenea-
mine. When the reaction mixture was quenched by basic
solution, anils 4 were observed. The structure of 4j was fur-
ther confirmed by single-crystal X-ray diffraction analysis
(Fig. 1).
Entry
Substract
Product
Yieldb (%)
Me
Me
Me
NH2
1
70
N
N
O
O
3j
Me
Me
Et
Me
Et
1j
Et
NH2
Et
2
3
70
44
In connection with the mechanism of this reaction, two
key points should be considered: (1) Cu(I)/air was the
active species instead of Cu(II) salts. In other words, the
copper generated from Cu(I) and air should be a more
active species; (2) coordination process of amine to copper
species was suspected to be involved. In addition, X-ray
photoelectron spectroscopy (XPS) showed the existence
of both Cu(II) and Cu(I) in the residues of the reaction
mixtures. In combination of the experimental results,
accordingly, one possible mechanism is proposed in
Scheme 2. Firstly, Cu(I) salt was oxidized by air to give
more active Cu(II) precursor 5, which coordinated with
amine leading to complex 6. Compound 6 underwent one
electron transfer process resulting in radical cation 7, which
can be expressed as another resonance structure 8.24 Rad-
ical 7 dimerized via head-to-head to give hydrazo com-
3k
Et
Et
1k
iPr
iPr
iPr
NH2
N
N
O
iPr
3l
iPr
iPr
1l
Me
Me
Me
NH2
Me
4
65
NH
4j
Me
Me
1j
(continued on next page)

4014
W. Lu, C. Xi / Tetrahedron Letters 49 (2008) 4011–4015
Table 3 (continued)
ture 8 coupled with 7 via tail-to-head to form compound
10, which underwent oxidation process and hydrolysis to
afford quinone anil 3 and anil 4, respectively.
In summary, we have developed a CuCl-catalyzed oxi-
dative coupling reaction of primary aromatic amines under
atmospheric conditions to afford azo derivatives, anils, and
quinone anils, respectively. This approach was highly effi-
cient, low cost, and easy handling.
Entry
Substract
Product
Yieldb (%)
Et
Et
Et
Et
NH2
5
67
N
N
NH
NH
4k
4l
Et
Et
1k
iPr
iPr
iPr
Acknowledgments
NH2
6
49
This work was supported by the National Natural Sci-
ence Foundation of China (20572058). We thank Mr. Miao
Shen for the single crystal X-ray analysis.
iPr
iPr
iPr
1l
a
Reaction conditions: disubstituted benzeneamine (1 mmol), solvent
(5 mL), CuCl (1 mmol), and products (3j–l) were gotten after the reaction
mixture was quenched by 3 N HCl; the products (4j–l) were gotten after
the reaction mixture was quenched by a solution of K2CO3.
Supplementary data
b
Isolated yields.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2008.
04.089.
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Scheme 2.
pound 9, which underwent another oxidation process to
form the final product azobenzene 2. The resonance struc-

W. Lu, C. Xi / Tetrahedron Letters 49 (2008) 4011–4015
4015
´
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4000–400 cmꢁ1
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a
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23. A mixture of CuCl (100 mg, 1.0 mmol), CH3CN (5.0 mL), and
disubstituted benzeneamine (1.0 mmol) under air was stirred at room
temperature until aromatic amine totally disappeared. The reaction
mixture was quenched with 3 M HCl, followed by the extraction of
the organic phase with 3 ꢀ 5 mL portions of diethyl ether. The
combined organics were dried over MgSO4, filtered, and concen-
trated. The residue was isolated by column chromatography on silica
gel eluting (petroleum ether/ethyl acetate = 10/1) to provide the
quinone anil 3. The reaction mixture was quenched with aqueous
solution of K2CO3, followed by the extraction of the organic phase
with 3 ꢀ 5 mL portions of diethyl ether. The combined organics were
dried over Na2SO4, filtered, and concentrated. The residue was
isolated by column chromatography on neutral Al2O3 eluting
(petroleum ether/ethyl acetate = 10/1) to provide anil 4.
22. A mixture of CuCl (20 mg, 0.20 mmol), CH3CN (5.0 mL), and
aromatic amine (1.0 mmol) under air was stirred at room temperature
for 1–48 h. The reaction mixture was quenched with aqueous solution
of K2CO3, followed by extraction of the organic phase with 3 ꢀ 5 mL
portions of diethyl ether. The combined organics were dried over
Na2SO4, filtered, and concentrated. The residue was isolated by
column chromatography on silica gel eluting (petroleum ether/ethyl
acetate = 10/1) to provide the azo derivative 2. 1H NMR and 13C
NMR spectra were recorded on a JEOL 300 NMR spectrometer with
tetramethylsilane (TMS) as an internal standard. Mass spectra were
obtained using a Bruker Esquire ion trap mass spectrometer in
positive ion mode. Elemental analyses were performed on a Flash EA
1112 instrument. The IR spectra were obtained on a Perkin–Elmer
FT-IR 2000 spectrophotometer by using the KBr disc in the range of
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