One step synthesis of azo compounds from nitroaromatics and anilines

Article abstract of DOI:10.1016/j.tetlet.2011.05.054

A general and efficient method for synthesis of both symmetric and asymmetric aromatic azo compounds in one single step has been developed. The nitro compounds were reduced and the substituted anilines were oxidized by each other without any metal in the

Full text of DOI:10.1016/j.tetlet.2011.05.054

Tetrahedron Letters 52 (2011) 3805–3809
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
One step synthesis of azo compounds from nitroaromatics and anilines
Rui Zhao a,c, Chunyan Tan c, Yonghua Xie a,c, Chunmei Gao c, Hongxia Liu c, Yuyang Jiang b,c,
⇑
a Department of Chemistry, Tsinghua University, Beijing 100084, PR China
b School of Medicine, Tsinghua University, Beijing 100084, PR China
c Guangdong Provincial Key Laboratory of Chemical Biology, Graduate School of Shenzhen, Tsinghua University, Shenzhen 518055, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A general and efficient method for synthesis of both symmetric and asymmetric aromatic azo compounds
in one single step has been developed. The nitro compounds were reduced and the substituted anilines
were oxidized by each other without any metal in the base condition. Various azo compounds with hal-
ogen, methyl and methoxy functional group were obtained by using available, cheap nitro compounds
and substituted anilines. In addition, the electronic effect and substituent effect of the compounds have
been discussed.
Received 5 March 2011
Revised 6 May 2011
Accepted 13 May 2011
Available online 19 May 2011
Keywords:
Nitro compounds
Aniline
Ó 2011 Elsevier Ltd. All rights reserved.
Aromatic azo compound
Asymmetric
Redox reaction
Aromatic azo compounds are widely used in various fields. For
example, the azo compounds are used as organic dyes,1 indicators,2
radical reaction initiators,3 and therapeutic4 and drug delivery
agents.5 They are also important units in the area of nonlinear
optics,6 optical storage media,7 chemo sensors,8 photochemical
switches9 and electronic devices.10 Therefore, synthesis of aromatic
azo compounds has attracted great attention. Preparation of
symmetric aromatic azo compounds are often performed by the
oxidation of aromatic amines using stoichiometric amounts of
oxidants including transition metals11 (permanganate, lead tetra-
acetate or other metal-containing compounds) and halo oxo acids12
(Eq. 1 in Fig. 1), or by the reduction of nitro aromatics using equiv-
alent amounts of metals (Eq. 2 in Fig. 1).13 Recently, several oxida-
tion and reduction methods using novel metal catalysts have been
nitrous acid. Herein, we report a transition metal-free mediated
approach to aromatic azo compounds via direct couplings of readily
available nitroaromatics and substituted anilines (Eq. 3 in Fig. 1).
In order to optimize reaction conditions, 1-chloro-2-nitroben-
zene (1c) and 2-methoxybenzenamine (2h) were chosen as the
model substrates, and the effects of bases, solvents and tempera-
tures were investigated under nitrogen atmosphere. As shown in
Table 1, five bases (10 equiv) (relative to the amount of 1-chloro-
2-nitrobenzene) were tested in toluene at 110 °C (entries 1–5),
KOH and NaOH provided (E)-1-(2-chlorophenyl)-2-(2-methoxy-
phenyl) diazene (3l) in 45% and 25% yields, respectively (entries
1 and 2), whereas only trace amount of target product was afforded
for other bases, K2CO3, Cs2CO3 and Et3N (entries 3–5). We also
screened different solvents in the presence of KOH (entries 6–
10), and DMF gave better yield (44%) (entry 6). Interestingly, the
yield was greatly improved to 85% when reaction temperature
was raised to 150 °C (entry 11), which implied that high tempera-
ture could promote the formation of the aromatic azo product.
Trace amount of target product was observed in the absence of
base (entry 12), which means strong base is important. Therefore,
the optimal reaction condition for synthesis of aromatic azo com-
pounds is as follows: couplings of nitro aromatics and substituted
anilines were carried out at 150 °C under nitrogen atmosphere
with 10 equiv of KOH as the base and DMF as the solvent.
developed.14 Examples include
a gold-catalyzed oxidation of
anilines and reduction of nitroaromatics,14c,14d reduction of nitro-
aromatics by nano-sized iron,14b and Cu-catalyzed oxidation of ani-
lines. For synthesis of asymmetric aromatic azo compounds, the
coupling of aryl diazonium salts with electron-rich aromatics is a
common strategy.15 This coupling requires the in situ preparation
of a diazonium salt from the oxidation of corresponding aromatic
amine with nitrous acid.16 Although these methods above are effec-
tive for synthesis of aromatic azo compounds, they do not meet the
sustainable and environmentally benign conditions because of use
of environmentally unfriendly transition metals or hazardous
We investigated the scope of couplings of nitro aromatics and
substituted anilines under the optimized condition above. As
shown in Table 2, most of the examined substrates provided good
to excellent yields. The nitroaromatics containing electron-
deficient groups showed higher reactivity than those containing
⇑
Corresponding author. Tel.: +7 552 603 6017; fax: +7 552 603 6018.
E-mail address: jiangyy@sz.tsinghua.edu.cn (Y. Jiang).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.054

3806
R. Zhao et al. / Tetrahedron Letters 52 (2011) 3805–3809
N
N
N
oxidation
H2N
+
+
+
NH2
NO2
NO2
(1)
(2)
N
symmetric
R1
R1
R2
the previous method
R1
R1
R1
R1
R1
R2
R1
R1
R1
reduction
O2N
H2N
N
symmetric
the previous method
one step
(3)
N
symmetric and asymmetric
our method
Figure 1. The previous methods (Eq. 1 and 2) and our method (Eq. 3) for synthesis of aromatic azo compounds.
Table 1
Optimization of conditions for the synthesis of azo compounda
electron-rich groups. For example, 1-chloro-2-nitrobenzene (1c),
1-chloro-3-nitrobenzene (1d) and 1-iodo-4-nitrobenzene (1e) pro-
vided higher yields (more than 74%) (entries 12–20), while 1-
methoxy-2-nitrobenzene (1a) and nitrobenzene (1b) gave lower
yields (50–79%) (entries 1–11). For the substituted anilines, elec-
tronic variation in the substrates, including electron-withdrawing,
neutral and electron-donating effects, did not obviously affect the
efficiency of the reactions. Aniline gave better yields than the
substituted anilines when reacting with the same nitroaromatic
compound. Specifically, anilines with methoxy (entries 7, 8 and
10), methyl (entry 9) and fluoro groups (entry 11) provided the
similar yields in the range of 55–70%, whereas the nonsubstituted
aniline which reacted with the same nitrobenzene provided the
yield at 90% (Table 2, entry 6). Similar effects can be seen in the
reactions with methoxyl-nitrobenzene (entry 1 vs entries 2–5).
The coupling reactions could tolerate functional groups including
halo- (entries 5, 11–20), methyl- (entries 2–4 and 9) and meth-
oxy-substitutions (entries 1–5, 7, 8, 10, 12 and 16) in the sub-
strates. In addition, the synthesized aromatic azo compounds
showed most trans-forms, which were identified by NMR spectros-
copy, and the trans–cis transformation of some selective com-
pounds under UV/Vis was discussed (see Supplementary data).
In order to explore the reaction mechanism for synthesis of aro-
matic azo compounds, we performed the following control exper-
iments under our standard condition as shown in Scheme 1. As a
H3CO
N
H3CO
base, solvent
temp., N2, 16h
NO2
H2N
+
N
Cl
3l
1c
2h
Cl
Entry
Base
Solventb
Temp. (°C)
Yieldc (%)
1
2
3
4
5
6
7
8
9
KOH
NaOH
K2CO3
Toluene
Toluene
Toluene
Toluene
Toluene
DMF
Dioxane
DMSO
H2O
110
110
110
110
110
110
101
110
100
66d
150
150
45
25
Trace
Trace
Trace
44
42
21
0
40
Cs2CO3
Et3N
KOH
KOH
KOH
KOH
KOH
KOH
—
10
11
12
THF
DMF
DMF
85
Trace
a
Reaction condition: 1-chloro-2-nitrobenzene (1 mmol), 2-methoxybenzen-
amine (3 mmol), base (10 mmol), solvent (5 mL) under nitrogen atmosphere.
b
DMSO = dimethylsulfoxide. THF = tetrahydrofuran. DMF = N,N-dimethylform-
amide.
c
Isolated yield.
Under the reflux of THF (bp 66 °C).
d
Table 2
Synthesis of aromatic azo compoundsa
KOH, DMF
150°C, N2
12 - 48 h
R2
R2
R1
R1
N
N
NO2
H2N
+
1
3
2
Entry
1
1
2
3
Reaction time (h)
36
Yieldb (%)
H2N
N
NO2
OCH3
2a
2b
N
68
1a
OCH3
3a
3b
H3C
H2N
H3C
N
2
1a
32
60
N
OCH3

R. Zhao et al. / Tetrahedron Letters 52 (2011) 3805–3809
3807
Table 2 (continued)
Entry
1
2
3
Reaction time (h)
Yieldb (%)
CH3
CH3
H2N
N
3
1a
1a
1a
32
50
50
56
2c
N
OCH3
3c
N
CH3
H2N
CH3
N
2d
4
5
30
28
OCH3
3d
F
F
N
H2N
N
2e
OCH3
3e
N
N
NO2
6
7
8
9
2a
12
24
24
24
90
55
70
56
1b
3f
OCH3
OCH3
H2N
H2N
N
N
1b
1b
1b
2f
3g
OCH3
N
OCH3
N
2g
3h
H3C
N
2b
N
3i
H3CO
H3CO
N
H2N
10
11
1b
1b
24
18
70
65
2h
2i
N
3j
F
F
H2N
N
N
3k
H3CO
N
NO2
Cl
12
13
2h
2i
16
14
85
88
1c
N
Cl
Cl
3l
F
N
N
1c
3m
Cl
Cl
H2N
H2N
N
N
14
15
1c
1c
14
12
93
95
2j
Cl
Cl
3n
N
N
OCF3
OCF3
2k
3o
(continued on next page)

3808
R. Zhao et al. / Tetrahedron Letters 52 (2011) 3805–3809
Table 2 (continued)
Entry
16
1
2
3
Reaction time (h)
Yieldb (%)
OCH3
N
N
1c
1c
Cl
2f
18
88
Cl
3p
Br
Br
H2N
N
N
17
18
14
12
90
92
2l
Cl
3q
F
NO2
N
N
2i
1d
Cl
3r
O
NH2
HN
N
19
20
1c
14
16
74
80
N
H2N
H2N
2m
Cl
3s
N
I
I
I
NO2
1e
2n
I
N
3t
a
Reaction condition: reaction temperature (150 °C), nitroaromatic (1 mmol), aniline (3 mmol), KOH (10 mmol), DMF (5 mL) under nitrogen atmosphere.
Isolated yields.
b
O-
KOH, DMF
+
150 °C, N2
N
N
+
H2N
(1)
(2)
N
16h
N
4
2a
3f
yield < 10%
KOH, DMF
150 °C, N2
16 h
N
+
NO
H2N
N
3f
yield 96%
2a
5
Scheme 1. Reactions of (4) or (5) with aniline (2a) under the standard condition.
O-
+
N
OH
KOH
N
O
H
H2N
O
H
N
R1
1
HO
N
R1
R2
I
R2
II
R2
2
O
OH
N
N
N
N
H2N
N
III
R2
H
H2O
R1
3
R1
R1
R2
IV
R2
2
Scheme 2. Possible mechanism for the synthesis of aromatic azo compounds.
result, reaction of azoxybenzene (4) with aniline only produced
small amount of 1,2-diphenyldiazene (3f) (less than 10% yield)
(Eq. 1 in Scheme 1), while coupling of nitrosobenzene (5) with ani-
line provided the corresponding azo product (3h) in 96% yield (Eq.
2 in Scheme 1). This indicated that nitrosobenzene intermediate
could appear during reactions of nitroaromatics and substituted
anilines under the standard condition.
Furthermore, we used GC–MS to analyze the mixture of reac-
tion solution from coupling of nitrobenzene with aniline, and a
mass spectral peak at m/z 107 corresponding to the molecular

R. Zhao et al. / Tetrahedron Letters 52 (2011) 3805–3809
3809
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Therefore, a possible mechanism for synthesis of both aromatic
azo compounds is suggested in Scheme 2. Nucleophilic attack of
amino group on the aniline (2) to nitro group on the nitroaromatic
(1) firstly formed intermediate I in the presence of base (KOH), and
cleavage of I under heating produced nitroso compound III in the
similar fashion reported before.17 The coupling of nitrosobenzene
and aniline then provided the target product (3) by nucleophilic at-
tack to form intermediate IV and dehydration.
In summary, we have developed a simple, general and efficient
KOH-promoted method for synthesis of both symmetric and asym-
metric aromatic azo compounds via direct couplings of readily
available nitroaromatics and substituted anilines, and the corre-
sponding target products were obtained in good to excellent yields.
The method is of tolerance toward functional groups in the sub-
strates. It avoids the use of environmentally unfriendly transition
metals and hazardous nitrous acid. Therefore, this convenient
and practical approach is anticipated to attract much attention.
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Acknowledgments
We would like to thank the financial support which was pro-
vided by the Ministry of Science and Technology of China
(2009ZX09501-004), the National Natural Science Foundation of
China (Grant No. 20872077 and 90813013) and Shenzhen Sci. &
Tech. Bureau.
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Supplementary data
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Supplementary data (experimental procedures and full spectro-
scopic data for all compounds) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2011.05.054.
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