Synthesis of Unsymmetrical Azoxyarenes via Copper-Catalyzed Aerobic Oxidative Dehydrogenative Coupling of Anilines with Nitrosoarenes

Article abstract of DOI:10.1002/adsc.202001526

A copper-catalyzed oxidative dehydrogenative coupling of nitrosobenzenes with anilines for the synthesis of unsymmetrical azoxybenzenes was developed. This approach uses O₂ as the oxidant. The reaction products are diverse unsymmetrical azoxybe

Full text of DOI:10.1002/adsc.202001526

UPDATES
DOI: 10.1002/adsc.202001526
Synthesis of Unsymmetrical Azoxyarenes via Copper-Catalyzed
Aerobic Oxidative Dehydrogenative Coupling of Anilines with
Nitrosoarenes
Chongyang Shi,a Boxia Xu,a Xiaolan Fang,a Xiaochun Yu,a,* Huile Jin,a and
Shun Wanga,*
a
College of Chemistry and Materials Engineering, Wenzhou University, Chashan Town, Wenzhou 325035,
People’s Republic of China
E-mail: xiaochunyu@wzu.edu.cn; shunwang@wzu.edu.cn
Manuscript received: December 7, 2020; Revised manuscript received: January 25, 2021;
Version of record online: Februar 25, 2021
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202001526
Currently, the main approaches for synthesizing
unsymmetrical azoxyarenes are (1) nucleophilic addi-
Abstract: A copper-catalyzed oxidative dehydro-
genative coupling of nitrosobenzenes with anilines
tion of organomagnesium or aryliminomagnesium
for the synthesis of unsymmetrical azoxybenzenes
compounds with nitroarenes[5a] or nitrosohydroxyl-
was developed. This approach uses O2 as the
amine tosylates[5b] (Scheme 1a) and (2) transition-
oxidant. The reaction products are diverse unsym-
metrical azoxybenzenes rather than azobenzenes,
metal-catalyzed ortho CÀ H functionalization of sym-
metrical azoxyarenes for formation of unsymmetrical
which are obtained in the Mills reaction. The use of
azoxyarenes
via
halogenation,[6]
acylation,[7]
an inexpensive copper catalyst, a broad substrate
scope, and mild reaction conditions make this
protocol an atom-economic and step-economic
procedure for preparing unsymmetrical azoxy com-
pounds.
alkoxylation,[8] acetoxylation,[9] sulfonamidation,[10]
alkenylation,[11]
amidation,[12]
and
eth-
oxycarbonylation[13] (Scheme 1b). Recently, Chen’s
group developed a tungsten-catalyzed oxidative cou-
pling reaction of different secondary N-alkylanilines to
afford unsymmetrical azoxyarenes under mild condi-
tions (Scheme 1c).[14]
Keywords: Unsymmetrical azoxyarenes; Copper-
catalyzed; Oxidative dehydrogenative coupling; Ani-
lines; Nitrosoarenes
However, in many instances the practicality of these
methods is offset by the narrow scope, the toxicity of
the reagents, the use of expensive metals, poor
selectivity, harsh reaction conditions, and limited atom
economy. We recently developed a series of practical
Azoxybenzenes represent privileged frameworks. Be- and convenient methods for the synthesis of unsym-
cause of their chemical and physical properties, they metrical azoxybenzenes via oxidative coupling of
are found in a wide range of polymeric materials, dyes, aromatic amines with nitrosoarenes.[15] However, some
stabilizers, liquid crystals, natural products, and shortcomings still need to be addressed, such as the
pharmaceuticals.[1] Recently, azoxybenzenes have at- use of stoichiometric amounts of the oxidant and
tracted the attention of synthetic chemists for the additives. As part of our research program on the
construction of useful heterocycles.[2] The development efficient synthesis of unsymmetrical azoxyarenes, we
of efficient routes for the synthesis of azoxybenzenes have developed a novel approach to resolve restrictions
is therefore of great interest. Among possible ap- through the reaction between anilines and nitrosoben-
proaches, the oxidation of aromatic amines[3] and zenes with an inexpensive and commercially available
reduction of nitroarenes or nitrosobenzenes[4] are the copper catalyst under mild conditions (Scheme 1d). To
most common strategies for synthesizing azoxyben- the best of our knowledge, our efficient approach is the
zenes. However, these transformations have met with most atom-economic and step-economic procedure
limited success in the synthesis of symmetrical reported to date for preparing unsymmetrical azoxy
azoxyarenes, and unsymmetrical azoxyarenes have not compounds.
been obtained.
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Table 1. Optimization of the reaction conditions.[a]
Scheme 1. Reaction design for the construction of azoxyben-
zenes.
The reaction between 4-chloroaniline (1a) and
nitrosobenzene (2a) was chosen for determining the
optimal conditions. The reaction in the presence of
CuBr (20 mol%) and pyridine (1.0 equiv.) was per-
[a] All the experiments were carried out with p-ClC6H4NH2
(0.2 mmol), C6H5NO (0.2 mmol), [Cu] (20 mol%), pyridine
°
formed in toluene (2 mL) at 65 C for 24 h in air. The
°
(0.2 mmol), toluene (2 mL), 65 C, air, 24 h unless otherwise
desired unsymmetrical azoxybenzene 3a was afforded
in 66% yield, along with liberation of azobenzene 4a
(Table 1, entry 1). Various copper sources were tested
as catalysts, namely CuO, CuCl, CuI, CuCl2, Cu-
(OAc)2, Cu2O, and CuSO4. CuCl gave the best catalytic
efficiency, with 80% yield of the unsymmetrical
azoxybenzene 3a (Table 1, entries 2–8). The desired
3a could not be obtained smoothly when the reaction
was performed under N2. When the reaction was
noted.
[b] Isolated yield.
[c] Under N2.
[d] Under O2.
[e] CuCl (3 mol%), pyridine (25 mol%), 0.5 M solution under
O2.
[f] At room temperature.
conducted in an O2 atmosphere, the yield increased to temperature (Table 1, entry 22). The optimal reaction
89%. These results indicate that O2 in air played a key conditions can be summarized as follows: 0.2 mmol of
role in the coupling reaction (Table 1, entries 10 and 1a and 0.2 mmol of 2a in toluene (0.4 mL) with a
11). Screening of other additives, namely 2,2’-bipyr- CuCl catalyst (3 mol%) and pyridine (25 mol%) at
°
idine, 1,10-phenanthroline, and some other common 65 C for 24 h in an O2 atmosphere.
bases, showed that pyridine was indispensable in the
With the optimal conditions in hand, we explored
reaction (see Supporting Information, Table S1). An the substrate scope of our copper-catalyzed aerobic
investigation of the effect of the solvent showed that oxidative dehydrogenative coupling of anilines with
the yield of 3a obtained with toluene was better than nitrosoarenes for the construction of unsymmetrical
those achieved with CHCl3, CH2Cl2, CH3CN, EtOH, azoxyarenes (Table 2). First, the aromatic aniline
DMF, DMSO, dioxane and water (Table 1, entries 12– compounds 1 bearing different functional groups were
20). To further improve the reaction efficiency, we investigated. Substrates bearing an o-, m-, or p-methyl
examined the effects of concentration, catalyst loading, substituent on the aniline were evaluated; 3b–3d were
and additive loading on the synthesis of unsymmetrical obtained in 92%–98% yields. The yield of 3c was
azoxybenzenes (see Supporting Information, Ta- lowest, possibly because of steric hindrance. 3,5-
bles S2–S4). The results show that the desired azox- Dimethylaniline and 2,6-dimethylaniline also reacted
ybenzene 3a was smoothly obtained in 92% yield with nitrosobenzene to afford the desired unsym-
when the reaction was performed with 3 mol% CuCl metrical azoxyarenes 3e and 3f in 94% and 92%
and 25 mol% pyridine in a 0.5 M solution under O2. yields, respectively. The electronic properties of sub-
(Table 1, entry 21). The reaction could not proceed stituents significantly affect this catalytic transforma-
smoothly when the reaction was performed at room tion. Strongly electron-withdrawing substituents at the
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Table 2. Scope of the copper-catalyzed synthesis of unsymmetrical azoxybenzene.[a]
[a]
°
All the experiments were carried out with 1 (1 mmol), 2 (1 mmol), CuCl (3 mol%), pyridine (25 mol%), toluene (2 mL), 65 C, O2,
24 h, unless otherwise noted.
[b]
[c]
°
80 C, 48 h.
°
65 C, 48 h.
para position, e.g., À NO2, À COOCH3, À CF3 and À CN time to 48 h (3p–3s). 4-Naphthyl-substituted aniline
negatively affected the reaction. In particular, a high was also tolerated well and 3u was obtained in 87%
°
temperature (80 C) and long reaction time (48 h) were yield.
needed to obtain satisfactory yields of 3g–3j. Hetero-
We next examined the substituent effects for nitro-
aromatic amines such as pyridin-3-amine and quinolin- soarenes. Electron-donating groups on the nitrosoar-
3-amine were also tolerated well in current trans- enes lowered the reaction efficiency. For example, the
formation (3k–3l). The reaction tolerates the entire reactions of N,N-dimethyl-4-nitrosoaniline with a
range of halogen substituents, although the yields of chloro-, bromo-, or methyl- substituted aniline afforded
the desired products 3m–3s were lower than those the corresponding products 3v–3x in moderate yields.
achieved with electron-sufficient substrates (e.g., with Electron-withdrawing substituents such as methyl 4-
an À OMe substituent). This method therefore enables nitrosobenzoate, 1-chloro-4-nitrosobenzene, and 1-
access to more complex compounds when used in bromo-4-nitrosobenzene showed positive effects on
combination with cross-coupling transformations. The this transformation; the corresponding azoxybenzenes
yields of the desired halo-substituted unsymmetrical 3y–3zc were obtained in good yields.
azoxyarenes were improved by prolonging the reaction
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The efficiency of this catalytic system was further
investigated by performing the transformation on a
laboratory preparative scale. For example, the gram
scale (10 mmol) reaction of 4-chloroaniline with nitro-
sobenzene gave 3a in 87% isolated yield after 48 h
(Scheme 2).
The mechanism of this transformation was inves-
tigated by performing the oxidation of azobenzene in
the presence of a copper catalyst under O2 (Sche-
me 3a). However, no azoxybenzene was detected. The
reaction between an N-arylhydroxylamine and nitro-
sobenzene was then performed under the optimal
conditions to determine whether N-arylhydroxylamines
were likely to be formed in situ during the reaction.
Scheme 4. Proposed mechanism.
The desired azoxybenzene was not formed (Sche- was not formed, indicating that the reaction involved a
me 3b). The reaction of aniline with nitrobenzene was radical pathway.
investigated, but still no azoxybenzene was detected
Based on the above observations and previous
(Scheme 3c). All these results indicate that azoben- reported works, a plausible reaction mechanism is
zene, N-arylhydroxylamine, or nitrobenzene intermedi- proposed (Scheme 4). First, aniline can oxidize to
ates were not involved in this oxidative coupling cataion radical A via a single electron transfer
process. We initially thought that the oxygen atom of (SET),[16] which can react with nitroso moiety to form
3a could be derived from O2. We therefore performed radical intermediate B, followed by subsequent radical
the reaction of nitrosoarene with aniline in an 18O2 exchange of B with aniline forms hydroxylamine
atmosphere under the optimal conditions. However, the intermediate C. Hydroxylamine C is further oxidized
desired 3a-18O product was not detected by HRMS by the Cu(II) or dioxygen to generate the correspond-
(Scheme 3d). At last, the present reaction was carried ing azoxyarene product.[17] Further experimental and
out in the presence of the radical scavenger butylated theoretical work will be undertaken to clarify the
hydroxytoluene (BHT), and the desired product 3a mechanism.
In summary, we have developed a novel catalytic
approach to the synthesis of unsymmetrical aromatic
azoxy compounds. A series of unsymmetrical azoxy
compounds were prepared by dehydrogenative cou-
pling between nitrosoarenes and substituted anilines,
with CuCl as the catalyst and O2 as the oxidant. The
reaction is operationally simple and can be performed
on the gram scale. Studies are ongoing in our
Scheme 2. Gram-scale transformation.
laboratory to clarify the reaction mechanism and to
develop other catalytic systems for the synthesis of
diverse azoxybenzenes.
Experimental Section
General Procedure for the Synthesis of 3
In a 25 mL Schlenk reaction tube, A solution of anilines 1
(1 mmol), nitrosoarenes 2 (1 mmol), CuCl (3 mol%) were
dissolved in toluene (2.0 mL) under O2. The reaction mixture
°
was then heated at 65 C (oil bath) with vigorous stirring for
24 hours. After the reaction equilibrium, the reaction was
concentrated in vacuo and purified by a silica gel packed flash
chromatography column with hexane/ethyl acetate as the eluent
to afford the desired products 3.
Acknowledgements
Financial support from the National Natural Science Founda-
tion of China (No. 21302143 and 51572198), and Natural
Scheme 3. Mechanistic studies.
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Science Foundation of Zhejiang Province (No. LY13B020006
and No. LZ17E020002) are greatly appreciated.
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