Highly selective reduction of nitrobenzenes to azoxybenzenes with a copper catalyst

Article abstract of DOI:10.1016/j.tetlet.2018.02.064

A convenient protocol for highly selective delivery of azoxybenzenes from reduction of nitrobenzenes was developed by utilizing a copper catalyst. A variety of functional groups and substitution were well tolerated.

Full text of DOI:10.1016/j.tetlet.2018.02.064

Accepted Manuscript
Highly selective reduction of nitrobenzenes to azoxybezenes with a copper cat-
alyst
Zhichao Chen, Yatao Qiu, Xiaoxing Wu, Yong Ni, Li Shen, Jun Wu, Sheng
Jiang
PII:
S0040-4039(18)30261-2
https://doi.org/10.1016/j.tetlet.2018.02.064
TETL 49749
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
17 December 2017
14 February 2018
23 February 2018
Please cite this article as: Chen, Z., Qiu, Y., Wu, X., Ni, Y., Shen, L., Wu, J., Jiang, S., Highly selective reduction
of nitrobenzenes to azoxybezenes with a copper catalyst, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/
j.tetlet.2018.02.064
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Highly selective reduction of nitrobenzenes
to azoxybezenes with a copper catalyst
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Zhichao Chena,b , Yatao Qiub, Xiaoxing Wub, Yong Nic, Li Shena, , Jun Wua,  and Sheng Jiangb, 

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Tetrahedron Letters
Highly selective reduction of nitrobenzenes to azoxybezenes with a copper catalyst
Zhichao Chena,b , Yatao Qiub, Xiaoxing Wub, Yong Nic, Li Shena, , Jun Wua,  and Sheng Jiangb, 
a Marine Drugs Research Center, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China
b State Key Laboratory of Natural Medicines, and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009,
China cLaboratory of Medicinal Chemistry, Guangzhou Institute of Biomedicine and Health, CAS, Guangzhou, 510530, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A convenient protocol for highly selective delivery of azoxybenzenes from reduction of
nitrobenzenes was developed by utilizing a copper catalyst. A variety of functional groups and
substitution were well tolerated.
2009 Elsevier Ltd. All rights reserved.
Available online
Keywords:
Copper catalyst
Azoxybenzene
Nitrobenzene
Reduction
Selectivity
Azoxybezenes are key materials for electronic devices due to
their liquid crystalline properties.1 In addition, these types of
azoxy compounds are one of key intermediates that are widely
used in dyes, reducing agents, analytical reagents, chemical
stabilizers, and polymerization inhibitors.2 Azoxybenzenes are
prepared mostly by the reduction of nitroarenes or the oxidation
of anilines. Among the reductive process, a variety of methods
have been documented to produce azoxybenzens.3 As well, azoxy
compounds can be prepared by electrolytic reduction of nitro
compounds.4
Figure 1. Possible intermediates and products during reduction
of nitrobenzene.
received great research interest. Further, the development of
transition-metal catalytic system5 for this reaction under mild
condition is still desirable. Feng’s group has demonstrated that
N,N’-dioxide amides are powerful ligands for various metals that
facilitate chemical transformation.6 In this regarding, the N,N’-
dioxide and copper complexes have found application in several
types of reactions.7 Herein, we reported the selective synthesis of
azoxybenzenes by utilizing copper-catalyzed reduction of
nitrobenzenes under the catalysis of CuI and L3 ligand.
Since several intermediates are involved in the reductive
process to potentially produce more than one products (Figure 1),
the manipulation of reaction conditions to improve selectivity has
We commenced our investigation on para-chloro-
nitrobenzene (1a) with copper iodide and ligand 3. The starting
material 1a was completely consumed in 1:1 DMSO/H2O8 at 80
ºC after 7 h in the presence of LiOH, affording desired
azoxybenzene 2a exclusively in Z-configuration in 30% yield
(Table 1, entry 1). Among the metal hydroxide screened, the use
of NaOH resulted in the highest yield (69%) (Table 1, entry 2-4).
It was not surprised to found that no reaction occurred in the
absence of base or ligand. The reaction temperature significantly
affected the outcome. Comparable yield of 2a was isolated at
higher temperature (100 ºC), whereas only 38% of or no desired
product 2a was obtained at 50 ºC and 30 ºC, respectively (Table
1, entry 5-7). Various amount of NaOH was then screened to
improve reaction efficiency. It was found that 4 equivalent of
———
 Corresponding author. Tel.: +18688888237; fax: +025- 83271516; e-mail:jiangsh9@gmail.com
 Corresponding author. Tel.: +13925044658; fax: +86-20-8522-2050; e-mail: shenli6025@jnu.edu.cn
 Corresponding author. Tel.: +13826420506; fax: +86-20-8522-2050; e-mail: wwujun2003@yahoo.com

2
Tetrahedron
tolerated with F group (2d), while other electron-withdrawing
NaOH gave the optimal yield (Table 1, entry 8-11). The
groups including ester and cyano resulted in no formation of
desired products. To our delighted, substrate containing electron-
donating group OMe was efficiently converted to 2h
azoxybenzen in 86% yield. was well tolerated. In addition,
desired product was obtained from substrate with ortho-
substitution (2l).
formation of product 2a was further optimized when conducting
reaction in 1:2 ratio of DMSO and H2O as co-solvent (Table 1,
entry 12-13). For comparison, we prepared ligand 3’ with two
isopropyl groups at ortho position and obtained the desired
product in diminished yield (Table 1, entry 14). This could be
owing to the less electron-donating effect of 3’ than that of 3,
making it a less effective ligand for this transformation.
Table 1. Condition optimization for Cu-catalyzed conversion
of nitrobenzene to azoxybenzene.a
Entry
Base
Solvent
Temp
(ºC)
Yield%b
(2a)
1
LiOH (3 equiv.)
NaOH (3 equiv.)
KOH (3 equiv.)
CsOH (3 equiv.)
NaOH (3 equiv.)
NaOH (3 equiv.)
NaOH (3 equiv.)
NaOH (1 equiv.)
NaOH (2 equiv.)
NaOH (4 equiv.)
NaOH (6 equiv.)
NaOH (4 equiv.)
NaOH (4 equiv.)
NaOH (4 equiv.)
1:1 DMSO/H2O
1:1 DMSO/H2O
1:1 DMSO/H2O
1:1 DMSO/H2O
1:1 DMSO/H2O
1:1 DMSO/H2O
1:1 DMSO/H2O
1:1 DMSO/H2O
1:1 DMSO/H2O
1:1 DMSO/H2O
1:1 DMSO/H2O
1:2 DMSO/H2O
1:4 DMSO/H2O
1:2 DMSO/H2O
80
80
80
80
100
50
30
80
80
80
80
80
80
80
30
69
64
57
69
38
0
2
3
4
5
6
Although the exact reaction mechanism was not understood,
the formation of metal hydride species5b was unlikely due to the
lack of hydride source under these reaction conditions. Instead,
DMSO could reduce nitroarenes to nitrosoarenes and
arylhydroxyamines with catalytic amount of CuI (Scheme 1). A
7
8
53
62
81
81
88
85
46
9
10
11
12
13
14c
radical pathway could proceed and lead to oxidation of DMSO
10
intro Me2SO2
.
The condensation of nitroarenes and
arylhydroxyamines produced the corresponding azoxybenzenes
with loss of water under basic conditions.
aReaction condition: CuI (10 mol%), ligand 3 (0.5 equiv.), and under nitrogen
atmosphere. bIsolated yield. cLigand 3’ was used.
With the optimal condition in hand, we then explored the
substrate scope for this copper-catalyzed reduction of
nitrobenzene to azoxybenzene9. As shown below, a variety of
nitrobenzenes underwent reductive conversion to generate the
corresponding azoxybenzenes in high yield and exclusive Z-
selectivity. The halogen functional groups such as Cl, Br, and I
remained intact (2b-2c, 2i-2j), while they are incompatible with
hydrogenation condition. This reaction condition was also

3
1323; (m) Lu, Y.; Liu, J.; Diffee, G.; Liu, D.; Liu, B.
Scheme 1. A plausible reaction mechanism for reductive
coupling of nitrobenzenes into azoxybenzenes.
Tetrahedron Lett. 2006, 47, 4597; (n) Hwu, J. R.; Das, A. R.;
Yang, C. W.; Huang, J.-J.; Hsu, M.-H. Org. Lett. 2005, 7, 3211.
4. (a) De Groot, H.; Van den Heuvel, E.; Barendrecht, E.; Janssen, L.
J. J. Ger. Pat. 3020846, 1980; Chem. Abstr. 1981, 94, 54,934s; (b)
Ohba, T.; Ishida, H.; Yamaguchi, T.; Horiuchi, T.; Ohkubo. K. J.
Chem. Soc., Chem Commun 1994, 263.
In conclusion, an efficient copper catalyst was developed to
convert nitrobenzenes to corresponding azoxybenzenes in high
selectivity. This reaction condition was well tolerated not only
with a number of functional groups, but also with various
substitution positions. The reaction mechanism will be further
explored to expand its application.
5. (a) Busch, M.; Schulz, K. Chem. Ber. 1929, 62B, 1458; (b) Kim, J.
H.; Park, J. H.; Chung, Y. K.; Park, K. H. Adv. Synth. Catal. 2012,
354, 2412.
6. (a) Wang, J.; Liu, X.; Feng, X. Chem. Rev. 2011, 111, 6947; (b)
Liu, X.; Zheng, H.; Xia, Y.; Lin, L.; Feng, X. Acc. Chem. Res.
2017, 50, 2621.
7. (a) Xiao, X.; Lin, L.; Lian, X.; Liu, X.; Feng, X. Org. Chem.
Front. 2016, 3, 809; (b) Mei, H.; Xiao, X.; Zhao, X.; Fang, B.;
Liu, X.; Lin, L.; Feng, X. J. Org. Chem. 2015, 80, 2272; (c) Dong,
Z.; Feng, J.; Fu, X.; Liu, X.; Lin, L.; Feng, X. Chem. Eur. J. 2011,
17, 1118; (d) Chang, L.; Kuang, Y.; Qin, B.; Zhou,X.; Liu, X.;
Lin, L.; Feng, X. Org. Lett. 2010, 12, 2214.
Acknowledgments
This work was supported by the National Natural Science
Foundation (21472191, 81773559, 21672050), the International
Cooperation Special Grant (2016A050502036) from the Science
and Technology Development Project of Guangdong Province,
the International Cooperation Grant (201704030099) of
Guangzhou, and the Science and Technology Planning Project of
Guangdong Province (2013A022100019) and Chinese
8. No superior results were achieved with other solvents screened.
9. General procedure: to a Schlenk tube were added nitroarene (1
mmol), ligand 3 (0.5 mmol, 0.5 equiv.), CuI (0.1 mmol, 10 mol%),
and NaOH (4 mmol, 4.0 equiv.). The tube was evacuated and
backfilled with argon for three times. A mixture of DMSO and
H2O (1:2 ratio, 2 mL) was added via syringe. The mixture was
then stirred in a sealed tube under argon atmosphere. The reaction
mixture was stirred at 80 °C till complete consumption of starting
material (monitored by TLC). The mixture was diluted with ethyl
acetate (10 mL) and H2O (10 mL). The two layers were separated
and the aqueous layer was extracted with ethyl acetate (2 × 10
mL). The combined organic layers were washed with brine, dried
over anhydrous MgSO4, and concentrated in vacuo. The residue
was purified by column chromatography on silica gel using
petroleum ether/ethyl acetate as eluent to provide the desired
product.
Pharmaceutical
Innovation Foundation.
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Biopharmaceutical
References and notes
10. Lin, M.; Wang, Z.; Fang, H.; Liu, L.; Yin, H.; Yan, C.-H.; Fu, X.
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Supplementary Material
Supplementary material that may be helpful in the review
process should be prepared and provided as a separate electronic
file. That file can then be transformed into PDF format and
submitted along with the manuscript and graphic files to the
appropriate editorial office.
3. For selected examples of reductive process, see: (a) Newbold, B.
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Tetrahedron
Highlights
. Observation of a reduction of nitrobenzenes to
azoxybezenes.
. Well tolerance of many functional groups.
Environment friendly.