A metal-catalyst-free oxidative coupling of anilines to aromatic azo compounds in water using bleach

Article abstract of DOI:10.1016/j.tetlet.2018.08.053

A simple route toward the synthesis of symmetrical and unsymmetrical aromatic azo compounds through oxidative coupling of anilines using widely available NaOCl is presented. This metal catalyst-free protocol is performed in water and affords the desired products in high yields.

Full text of DOI:10.1016/j.tetlet.2018.08.053

Accepted Manuscript
A metal-catalyst-free oxidative coupling of anilines to aromatic azo compounds
in water using bleach
Gabriela F.P. de Souza, Theodora W. von Zuben, Airton G. Salles Jr.
PII:
S0040-4039(18)31054-2
https://doi.org/10.1016/j.tetlet.2018.08.053
TETL 50228
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
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27 July 2018
22 August 2018
27 August 2018
Please cite this article as: de Souza, G.F.P., von Zuben, T.W., Salles, A.G. Jr., A metal-catalyst-free oxidative
coupling of anilines to aromatic azo compounds in water using bleach, Tetrahedron Letters (2018), doi: https://
doi.org/10.1016/j.tetlet.2018.08.053
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A metal-catalyst-free oxidative coupling of
anilines to aromatic azo compounds in water
using bleach
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Gabriela F. P. de Souza, Theodora W. von Zuben and Airton G. Salles, Jr.

1
Tetrahedron Letters
A metal-catalyst-free oxidative coupling of anilines to aromatic azo compounds in
water using bleach
Gabriela F. P. de Souzaa , Theodora W. von Zubena and Airton G. Salles, Jr.a
a Department of Organic Chemistry, Institute of Chemistry, University of Campinas, P.O. Box 6154, Campinas, SP 13084-862, Brazil
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A simple route toward the synthesis of symmetrical and unsymmetrical aromatic azo compounds
through oxidative coupling of anilines using widely available NaOCl is presented. This metal
catalyst-free protocol is performed in water and affords the desired products in high yields.
2009 Elsevier Ltd. All rights reserved.
Available online
Keywords:
Anilines
Aromatic azo compounds
Oxidative coupling
Sodium hypochlorite
In water
1. Introduction
the presence of water could promote the formation of
dichloroamines from anilines using sodium hypochlorite as an
Aromatic azo compounds have proven to be a relevant class of
building blocks in chemical synthesis. Because of its synthetic
versatility, azo chemistry has been successfully applied to
various fields such as natural products synthesis, dyes, pigments,
indicators, food additives and therapeutic agents.1 The majority
of aromatic azo compounds are synthesized by conventional
methods involving reactive intermediates such as diazonium salts
and nitroso compounds from commercially available compounds
leading to labor-intensive multistep procedures.2 Significant
progress has been achieved employing catalytic protocols for the
oxidation of anilines. Nonetheless, these methods are hampered
by the use of environmentally unfriendly transition-metals and
intricate challenges still remain in the synthesis of unsymmetrical
aromatic azo compounds. More recently, transition-metal free
approaches have also been targeted by the group of Lei and Ma4,
Minakata5 and Hajra6. They succeeded in synthesizing a series of
azobenzenes by applying their methods; however, the use of
organic solvents and temperatures other than room temperature
render these protocols less attractive albeit very useful. To the
best of our knowledge, few metal-free alternatives at the expense
of organic solvents have been reported to date.7 Thus, it is highly
desirable to find new and mild procedures based on the use of
benign solvents to access this compound class.
oxidizing agent. From dichloroamines, oxidative coupling would
proceed efficiently towards azobenzenes.
Herein, we demonstrate the realization of our water-based
approach, which resulted in the development of an operationally
simple and scalable protocol to convert a broad range of anilines
into symmetrical and unsymmetrical aromatic azo compounds.
The method employs reagent-grade sodium hypochlorite solution
or commercial bleach at room temperature and uses the water
coming from the oxidant solution and from the acid aqueous
solution to achieve the required transformation in high yields.
2. Results and discussion
As an initial study, we selected the oxidative homocoupling
of aniline 1a as a representative transformation. By using 5.0
equiv. of NaOCl (6% active chlorine aqueous solution) as the
oxidant, at room temperature, only 10% of (E)-azobenzene 2a
was obtained after 3 h along with several by-products (Table 1,
entry 1). To our delight, adding 1.0 equiv. of concentrated HCl to
the reaction medium gave access to 2a in 95% yield (Table 1,
entry 2). Also, under these conditions, we did not observe aniline
polymerization. Other oxidants such as O2 (dioxygen
atmosphere), H2O2 and K2S2O8 failed to provide the targeted
product in acceptable yields (Table 1, entries 35). Although the
reaction under a dioxygen atmosphere led to the product in 14%
yield, we could not achieve further improvement upon re-
optimization using this oxidant. We then tried to decrease the
amount of HCl employed in this transformation. Using 0.25
equiv. or 0.50 equiv. of HCl delivered product 2a in inferior
The groups of Andres8 and Dlugogorski9 have studied
computationally the reaction between NH3 and HOCl leading to
dichloroamine and demonstrated a drastic reduction in the
reaction barrier with the assistance of discrete water molecules in
t—he—tra—nsition state. With this study in mind, we envisaged that
 Corresponding author. Tel.: +55-19-35218794; fax: +55-19-35213023; e-mail: asalles@iqm.unicamp.br

2
Tetrahedron
yields (Table 1, entries 6 and 7), thus confirming the necessity
suggests the oxidative homocoupling reaction is faster than
chlorination and once the azobenzene is formed, it is not prone to
electrophilic substitution anymore. Regrettably, we could not
obtain the corresponding products for any tested alkyl-substituted
amines. A complex reaction mixture was isolated.
of 1.0 equiv. of HCl in this protocol. Decreasing the amount of
NaOCl also led to inferior results (Table 1, entries 8 and 9). As
an excess of oxidant was employed, we tried to reuse the aqueous
solution for another reaction. Unfortunately, we could not obtain
any product, thus evidencing decomposition of the oxidant.
Gratifyingly, we observed that commercial bleach furnished
The outstanding reactivity of the hypochlorite-mediated
oxidative homocoupling of anilines inspired us to evaluate our
approach for the synthesis of unsymmetrical azobenzenes.
Considering the reaction times for the transformations leading to
2e and 2f in Scheme 1, we might sustain that anilines with
electron-donating groups undergo homocoupling much faster
than other anilines. Hence, for the heterocoupling reaction, an
excess of the more electron-deficient aniline (molar ratio 3:1)
was employed to improve the yield of the targeted products.
Indeed, using our approach, we were able to achieve the
unsymmetrical azobenzenes as a major product (Scheme 2,
3a˗3e). The formation of only a small amount of homocoupling
product was observed.
After flash chromatography purification, we could recover
around 70% of the remaining aniline used in excess.
Unfortunately, when we tried to decrease the molar ratio between
the two anilines, selectivity has eroded.
To demonstrate the scalability of our protocol, we carried out
a gram-scale oxidative heterocoupling between aniline and 4-
methoxyaniline (Scheme 3, see the Supporting Information for
details). Pleasingly, the transformation gave access to the product
3b in 80% yield after 6 h reaction time.
product 2a with no deleterious effect on yield (Table 1, entry 10).
With the optimized conditions in hand, we explored the
substrate scope of the oxidative homocoupling reaction (Scheme
1). Aniline derivatives having electron-withdrawing and -
donating substituents were all tolerated giving access to products
in high yields (Scheme 1, 2a−2f). Electron-poor aromatic amines
reacted smoothly to furnish the corresponding azobenzenes in
good yields, albeit with longer reaction times when compared to
electron-rich anilines. Interestingly, we did not detect lateral ring
chlorination products under these conditions. This observation
Based on the literature precedence5b, we assume that the
reaction begins with the formation of HOCl from hypochlorite
anion in acid medium. According to computational studies
reported by the groups of Andres and Dlugogorski8,9, a hydrogen-

3
Eur. J. Org. Chem. 2006; 48844886. (c) Liu Z, Jiang M J.
Mater.Chem. 2007; 17:42494252.
bonded chain of water molecules is capable of reducing the
reaction barrier for the ionic chlorination of the amine (Step I,
Scheme 4, using aniline as a representative substrate in an
oxidative homocoupling). In the subsequent step (Step II,
3. (a) Acharyya SS, Ghosh S, Bal R. ACS Sustainable Chem. Eng.
2014; 2: 584589; (b) Ghosh S, Acharyya SS, Sasaki T, Bal R.
Green Chem. 2015; 17: 18671876; (c) Zhu YG, Shi Y. Org. Lett.
2013; 15:19421945; (d) Goyal R, Dumbre D, Konathala LNS,
Pandey M, Bordoloi A. Catal. Sci. Technol. 2015; 5: 36323638;
(e) Grirrane A, Corma A, Garcia H, Science. 2008; 322:
16611664; (f) Cai SF, Rong HP, Yu XF, Liu XW, Wang DS, He
W, Li YD. ACS Catal. 2013; 3: 478486; (g) Zhang C, Jiao N.
Angew. Chem. Int. Ed. 2010; 49: 61746177; (h) Dutta B, Biswas
S, Sharma V, Savage NO, Alpay SP, Suib SL. Angew. Chem. Int.
Ed. 2016; 55: 21712175; (i) Wang M, Ma J, Yu M, Zhang Z,
Wang F. Catal. Sci. Technol. 2016; 6: 19401945; (j) Singh S,
Chauhan P, Ravi M, Taneja I, Wahajuddin W, Yadav PP. RSC
Adv. 2015; 5: 6187661880; (k) Reddy CBR, Reddy SR, Naidu S.
Catal Commun. 2014; 56: 5054.
Scheme 4), the same effect allows the formation of
a
dichloroamine which can undergo a nucleophilic attack by
another molecule of aniline to produce the intermediate A (Step
III, Scheme 4). Finally, elimination of HCl from intermediate A
affords the corresponding azo compounds (Step IV, Scheme 4).
3. Conclusion
In summary, we have developed
a metal-catalyst-free
oxidative coupling of anilines in water to deliver symmetrical
and unsymmetrical azocompounds using a very straightforward
experimental protocol. Bleach is the suitable oxidant for this
transformation and the execution of the reaction at room
temperature allows its scale-up with no safety concerns. Despite
the use of an excess of one aniline, it is recovered after
purification and is prone to be reused. We believe our approach
can be a suitable alternative to obtain azocompounds in large
scale using low-cost reagents and energy input.
4. Ma H, Li W, Wang J, Xiao G, Gong Y, Qi C, Feng Y, Li X, Bao Z,
Cao W, Sun Q, Veaceslav C, Wang, F, Lei Z. Tetrahedron 2012;
68: 83588366.
5. (a) Takeda Y, Okumura S, Minakata S. Angew. Chem. Int. Ed.
2012; 51: 78047808; (b) Okumura S, Lin CH, Takeda Y,
Minakata S. J. Org. Chem. 2013; 78: 1209012105.
6. Monir K, Ghosh M, Mishra S, Majee A, Hajra A. Eur. J. Org.
Chem. 2014; 2014: 10961102.
7. (a) Kus NS. Monatsh. Chem. 2010; 141: 10891091; (b) Paris E,
Bigi F, Cauzzi D, Maggi R, Maestri G. Green Chem. 2018:
382386. (c) Sarkar P, Mukhopadhyay C. Green Chem. 2016; 18:
442451.
8. Andrés J, Canle LM, García MV, Rodríguez LF, Santaballa JA.
Chem. Phys. Lett. 2001; 342: 405410.
9. Rayson MS, Altarawneh M, Mackie JC, Kennedy EM, Dlugogorski
BZ. J. Phys. Chem. A. 2010; 114: 25972606.
10. Oakes J, Gratton P. J. Chem. Soc. Perkin Trans. 2. 1998;
18571864.
Acknowledgments
We thank Fundaꢀꢁo de Amparo ꢂ Pesquisa do Estado de Sꢁo
Paulo (FAPESP, Sꢁo Paulo, Brazil) and Faepex-UNICAMP for
financial support (Grant FAPESP 2017/18400-6)
References and notes
Supplementary Material
1.
2.
Merino E. Chem. Soc. Rev. 2011; 40: 38353853.
(a) Dabbagh HA, Teimouri A, Chermahini AN. Dyes Pigm. 2007;
73: 239243; (b) Barbero M, Cadamuro S, Dughera S, Giaveno C.
Supplementary data (experimental procedures, H, 13C NMR
and MS data for the described compounds) associated with this
article can be found, in the online version, at
1
Graphical Abstract

4
Tetrahedron
To create your abstract, type over the instructions in the
template box below.
Fonts or abstract dimensions should not be changed or altered.
A metal-catalyst-free oxidative coupling of
anilines to aromatic azo compounds in water
using bleach
Leave this area blank for abstract info.
Gabriela F. P. de Souza, Theodora W. von Zuben and Airton G. Salles, Jr.
Highlights
 Synthesis of symmetrical and
unsymmetrical aromatic azo compounds
from anilines using a straightforward
protocol in water
 Low-cost reagents (Bleach and HCl)
 Low-cost energy input (room temperature)
 Gram-scale reaction with no safety concerns

5
Table 1. Optimization of the oxidative self-coupling of
aniline 1a.a
Entry
1
Oxidant
Acid
-
Yield
10%
NaOCl (5.0 equiv.)
2
NaOCl (5.0 equiv.)
O2
HCl (1.0
equiv.)
95%
14%
traces
traces
38%
70%
45%
62%
90%
3b
4
HCl (1.0
equiv.)
H2O2 (5.0 equiv.)
K2S2O8 (5.0 equiv.)
NaOCl (5.0 equiv.)
NaOCl (5.0 equiv.)
NaOCl (1.0 equiv.)
NaOCl (2.5 equiv.)
HCl (1.0
equiv.)
5
6
HCl (1.0
equiv.)
HCl (0.25
equiv.)
7
HCl (0.50
equiv.)
8
HCl (1.0
equiv.)
9
HCl (1.0
equiv.)
10
commercial bleach
(5.0 equiv.)
HCl (1.0
equiv.)
o
a General conditions: 1a (1.0 mmol), NaOCl (5.0 eq), 25 C, 3
h. Yields of isolated products after column chromatography. b O2
atmosphere, 12 h reaction time.