Cu(II)-catalyzed aerobic oxidative amidation of azoarenes with amides

Article abstract of DOI:10.1007/s11426-017-9175-2

A method for Cu(II)-catalyzed dehydrogenative amidation of azoarene using air as the terminal oxidant was developed. Various amides, such as arylamides, alkylamides, lactams, and imides, are all effective amidation reagents and provide the desired products in moderate to excellent yields. Notably, good yields can also be obtained on a gram-scale with this amidation reaction. In this protocol of azoarene amidation, the catalyst (Cu(OAc)₂) and oxidant (air) are inexpensive and readily available, and the process is highly efficient and atom economical.

Full text of DOI:10.1007/s11426-017-9175-2

SCIENCE CHINA
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Cu(II)-catalyzed aerobic oxidative amidation of azoarenes with
amides
Gang Li1,2*, Xiaoting Chen1†, Xulu Lv1†, Chunqi Jia1, Panpan Gao1, Ya Wang1 & Suling Yang1,2
1College of Chemistry and Chemical Engineering, Anyang Normal University, Anyang 455002, China;
2Henan Province Key Laboratory of New Optoelectronic Functional Materials, Anyang Normal University, Anyang 455002, China
Received September 21, 2017; accepted November 13, 2017; published online December 29, 2017
A method for Cu(II)-catalyzed dehydrogenative amidation of azoarene using air as the terminal oxidant was developed. Various
amides, such as arylamides, alkylamides, lactams, and imides, are all effective amidation reagents and provide the desired
products in moderate to excellent yields. Notably, good yields can also be obtained on a gram-scale with this amidation reaction.
In this protocol of azoarene amidation, the catalyst (Cu(OAc)2) and oxidant (air) are inexpensive and readily available, and the
process is highly efficient and atom economical.
copper, C−H activation, amination, aerobic oxidative, azo compounds
Citation:
Li G, Chen X, Lv X, Jia C, Gao P, Wang Y, Yang S. Cu(II)-catalyzed aerobic oxidative amidation of azoarenes with amides. Sci China Chem, 2018,
61, https://doi.org/10.1007/s11426-017-9175-2
Owing to their characteristic structural skeletons, azoarenes
and their derivatives are widely applied not only as tradi-
tional dyes and pigments but also as many newly developed
functional materials, such as indicators, light-responsive
materials, food additives and therapeutic agents [1]. There-
fore, the streamlined synthesis of azoarene derivatives in
recent years has attracted an enormous amount of attention.
Usually, symmetrical azoarene compounds can be readily
prepared via reduction of nitroarenes and oxidation of ar-
ylamines [2]. In addition, asymmetric compounds can be
obtained by cross coupling of arylamines with nitroarenes,
nitroso arenes, or diazonium salts with an electron-rich
aromatic ring [3]. However, these synthetic methodologies
usually suffer from harsh reaction conditions or narrow
substrate scopes. The modification and functionalization of
easily available symmetrical azoarenes are steps in an up-
and-coming method for the synthesis of unsymmetrical
azoarenes. In recent years, with the rapid development of
transition-metal catalyzed C–H bond activation, various
unsymmetrical azoarenes can now be obtained via selective
aryl C–H bond functionalization (e.g., acylation, alkoxyla-
tion, nitration, halogenation, olefination, alkylation, aryla-
tion, phosphorylation, cyanation, aminocarbonylation, and
tandem cyclization) of azoarenes using azo-metal chelation
[4].
Selective-C–H bond amidations of azoarenes have also
been used to synthesize 2-amino azoarenes in the presence of
transition metals. Lee, Xu and Jia et al. [5] reported rhodium-
catalyzed amidation of azobenzenes using azides as the
amidation reagents respectively (Scheme 1(a)). Most re-
cently, Lee, Patel and Kim et al. [6] independently synthe-
sized 2-amino azobenzene via rhodium-catalyzed C–H bond
functionalization employing dioxazolones as the amidation
reagent (Scheme 1(b)). In these amidation processes, not
only the price of the catalyst and the amidation reagent (azide
and dioxazolone) are high, but also the atom and step
economy is poor.
Undoubtedly, C–H amidation via cross-dehydrogenative
coupling (CDC) reaction is an intriguing method for the
*Corresponding author (email: ligang@aynu.edu.cn)
†The authors contributed equally to this work.
© Science China Press and Springer-Verlag GmbH Germany 2017 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . chem.scichina.com link.springer.com

2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Li et al. Sci China Chem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Table 1 Optimization of the aerobic oxidative amidation of azoarenes
Scheme 1 C–H amidation of azoarene (color online).
construction of C–N bond because it does not require pre-
activation of either substrate, reducing the reaction waste and
number of steps [7]. Generally, oxidants are a key part in the
amidation process. Although oxidants such as peroxides [8],
PhI(OAc)2 [9], Cu(II) salts [10], and Ag(I) salts [11] have
been demonstrated to be excellent and practical oxidants,
pure oxygen, particularly air, is an ideal oxidant due to its
environmental benignity and ready availability [12]. Here,
we achieved inexpensive copper-catalyzed dehydrogenative
amidation of azobenzenes with amides using air as the
terminal oxidant (Scheme 1(c)).
First, the low-cost azobenzene 1a and benzamide 2a were
employed as typical substrates to screen the conditions of the
dehydrogenative amidation. The reaction was performed
under an air atmosphere at 120 °C for 24 h, as shown in
Table 1. To our delight, when Cu(OAc)2 was employed as the
catalyst with aromatic solvents such as benzene, toluene, and
xylene, the desired product (3aa) was obtained in moderate
yields (entries 1–3). In acetonitrile, 1,4-dioxane, or even a
solvent-free system, the dehydrogenative coupling could still
proceed, although the yields were lower (entries 4–6). Fur-
ther research showed that a mixture of 0.1 mL xylene and
0.1 mL benzene was the most efficient solvent system, af-
fording the desired product in 81% isolated yield (entry 7).
Pure oxygen and air were both effective oxidants in the re-
action (entry 8). The volume of solvent was also critical for
this transformation. Both increasing and decreasing the vo-
lume of solvent remarkably depressed the yields of the
product (entry 9). The desired product was not obtained
under a nitrogen atmosphere (entry 10). CuBr was also an
efficient catalyst and gave product in a low yield (entry 11);
however, other Cu salts, such as CuBr2 and CuCl2, are in-
efficient in this transformation (entries 12, 13). When using
Pd(OAc)2 as the catalyst or without a catalyst, no desired
product was found in the reaction mixture (entries 14, 15).
With the optimized conditions in hand, the scope and
generality of the copper-catalyzed aerobic oxidative amida-
tion were explored using various azoarenes and amides, as
shown in Scheme 2. Initially, various amide derivatives were
employed as coupling partners with azobenzene. The ex-
perimental results indicated that many types of amides, such
as arylamides (3aa, 3ab), alkylamides (3ac–3aj), lactams
(3ak) and imides (3al, 3am) were all good amidation re-
agents in this dehydrogenative amidation process, affording
the desired products in moderate to excellent yields. Al-
though yields are low for imides using air as the oxidant, the
yield can be improved using pure oxygen as the oxidant (3al,
3am). Unfortunately, the desired product could not be ob-
tained in the amidation process when sulfonamides and
amines were used as coupling partners.
However, many azoarene derivatives were good substrates
in the dehydrogenative amidation. Phenyl rings with various
substitution patterns (ortho, meta and para) were compatible
with the transformation, although ortho-substituted sub-
strates displayed certain steric hindrance effects (3ba–3da).
Regardless of whether the substrates were electron rich or
electron deficient, all the substrates exhibited good to ex-
cellent reactivities (3ea–3ga). Halogen substituents survived
the transformation (3ha, 3ia), providing a significant op-
portunity for further functionalization from the C–X bond.
Unsymmetrical azobenzenes were also suitable substrates for
this transformation and gave the products in good to ex-
cellent yields. However, the regioselectivity was poor. Two
isolable isomers were obtained (3ja–3ma).
In a gram-scale experiment, the copper-catalyzed aerobic
oxidative amidation of azobenzene with amides also pro-
ceeded smoothly and provided the desired product in a good
yield with a prolonged reaction time (Scheme 3). The present

3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Li et al. Sci China Chem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
conditions provided predominantly 3fa. This result strongly
suggested that the amidation of azoarene was an electrophilic
reaction (Scheme 4(c)).
According to the experimental observations and mechan-
istic studies of other Cu(II)-catalyzed dehydrogenative cou-
plings in related literatures [7g–7j], a possible catalytic cycle
for the Cu(II)-catalyzed aerobic oxidative amidation of
azoarenes was proposed, as shown in Scheme 5. Initially,
under the chelation assistance of the azo group, ortho-C–H
Scheme 3 A gram-scale experiment (color online).
Scheme 2 Scope of Cu(II)-catalyzed aerobic oxidative amidation of
azobenzenes with amides (color online).
amidation provides a practical and cost-effective approach to
synthesizing 2-amino azoarene derivatives.
To gain insight into the mechanism of copper-catalyzed
aerobic oxidative amidation of azobenzene with amides,
several experiments were designed and conducted, as shown
Scheme 4 Designed experiments (color online).
in Scheme 4. First, the desired product could be obtained
when either the radical scavenger 2,2,6,6-tetramethyl-1-pi-
peridinyloxy (TEMPO) or radical inhibitors, such as BHT
and BQ, were added to the standard reaction (Scheme 4(a)).
This result indicates that amidation is not a radical process.
Second, in an intermolecular competitive reaction of azo-
benzene with arylamide (benzamide) and alkylamides
(acetamide) under the optimized conditions, product 3aa was
evidently favored over 3ae, indicating that the arylamide was
more reactivity than the alkylamide in the amidation of
azoarene (Scheme 4(b)). Third, to study impact of the elec-
tronics of the azoarene on the amidation, a scrambling test of
(E)-1,2-bis(4-(trifluoromethoxy)phenyl)diazene,
which
bears an electron-donating group, and (E)-1,2-bis(4-(tri-
fluoromethyl)phenyl)diazene, which bears an electron-
withdrawing group, with benzamide under the optimized
Scheme 5 The proposed catalytic cycle (color online).

4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Li et al. Sci China Chem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
2810–2813
bond electrophilic metalation of the arene with Cu(OAc)2
6
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further coupled with the amide to give active species II,
which delivers the dehydrogenative amidation product by
reductive elimination, followed by aerobic reoxidation of the
catalyst.
In conclusion, we developed a copper-catalyzed inter-
molecular dehydrogenative coupling of azoarenes with sev-
eral amides using air as the terminal oxidant. Good yields can
be obtained at the gram scale. This discovery provides an
efficient and practical method for the synthesis of 2-amino
azoarene derivatives, which are widely used as various
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