Copper-Catalyzed Aerobic Oxidative Cyclization of Anilines, Aryl Methyl Ketones and DMSO: Efficient Assembly of 2-Arylquinolines

Article abstract of DOI:10.1002/adsc.201800373

A Cu-catalyzed C?H cyclization of simple anilines with ketones and DMSO as a one-carbon source has been developed. Using an aerobic oxidative protocol, a number of ketones and anilines could be easily converted to 2-arylquinolines, rather than 4-arylquinolines, thus providing a highly atom-economical and simple approach to biologically significant 2-arylquinolines. Based on the preliminary experiments, a plausible mechanism is proposed. (Figure presented.).

Full text of DOI:10.1002/adsc.201800373

Title: Copper-catalyzed aerobic oxidative cyclization of anilines, aryl
methyl ketones and DMSO: efficient assembly of 2-arylquinolines
Authors: Yufeng Liu, Yuqun Hu, Zhongzhong Cao, Zhan Xi, Wei-Ping
Luo, Liu Qiang, and Can-Cheng Guo
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800373
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10.1002/adsc.201800373
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201
Copper-Catalyzed Aerobic Oxidative Cyclization of Anilines,
Aryl Methyl Ketones and DMSO: Efficient Assembly of 2-
Arylquinolines
Yufeng Liu a, Yuqun Hu a, Zhongzhong Cao a, Xi Zhan a, Weiping Luo a, Qiang Liu a*,
Cancheng Guo a*
a
College of Chemistry and Chemical Engineering, Advanced Catalytic Engineering Research Center of the Ministry of
Education, Hunan University, Changsha 410082, China
E-mail: fqiangliu@qq.com and ccguo@hnu.edu.cn
Received:
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. A Cu-catalyzed C–H cyclization of simple anilines biologically significant 2-arylquinolines. Based on the
with ketones and DMSO as a one-carbon source has been preliminary experiments,
developed. Using an aerobic oxidative protocol, a number of proposed.
ketones and anilines could be easily converted to 2-
a plausible mechanism is
arylquinolines, rather than 4-arylquinolines, thus providing
a highly atom-economical and simple approach to
Keywords: ketones; anilines; DMSO; 2-arylquinolines;
Recently, Jiang group reported a palladium-
catalyzed allylic C−H functionalization strategy
synthesized 2-arylquinolines using anilines and
Introduction
Quinolines are vital important compounds of allylbenzene.[8] Although the significant progress
many natural products and man-made compounds has been achieved, most of these elegant works
that display remarkable pharmaceutical and
suffer from certain limitations. Such as
biological activities.[1] Especially the 2- troublesome operation, harsh reaction conditions,
arylquinoline scaffolds, which show a wide range especially raw materials requiring special
of biological properties, such as P-selectin structure, all restrict their wider applications in
antagonism,
antimalarial,
Because of
and
the
antitumor
organic synthesis. Therefore, the development of
diverse efficient and simply approaches for the
activties.[2]
pharmacological value of 2-arylquinolines, preparation of 2-arylquinolines remains an active
considerable efforts have been made to develop
various synthetic methods for the synthesis of the
substituted quinolines. The Doebner−Miller
reactions, which is catalyzed by Lewis acids or
Brønsted acids and involves the formal [3+3]
cycloaddition between anilines and cinnamal-
dehyde derivatives, is an efficient method for
synthesizing 2-arylquinolines (Scheme 1a).[3] For
research area.
example, the Torok group described
microwave-assisted solid acid-catalyzed synthesis
of 2-arylquinolines from anilines and
a
cinnamaldehydes.[4] The Friedlꢀnder reaction of
methyl ketones with 2-aminobenzaldehyde is
also the classical method for synthesizing 2-
arylquinolines (Scheme 1b).[5] Notably, this
reaction can be performed using other material. In
2008, the Verpoort group developed a Ru-
catalysted oxidative cyclization of 2-aminobenzyl
alcohol with a variety of ketones, leading to 2-
arylquinolines.[6] Afterward, Yu group developed
an efficient method to synthesize 2-arylquinolines
from ketones with 2-amino benzylamines.[7]
Scheme 1. Synthesis of substituted quinolines.
The three-component annulation reaction of
readily available materials has become one of the
most effective methods for the synthesis of
quinolines. The three-component Povarov
reaction using suitable arylamine, aldehyde and
alkenes or alkynes, is an efficient method to
construction of quinolines (Scheme 1d).[9] The
1
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10.1002/adsc.201800373
Advanced Synthesis & Catalysis
transition metal-catalyzed C−H activation
strategy, using anilines, methyl ketones and
aldehyde (or DMSO), has been developed to
build quinoline products (Scheme 1e).[10]
Recently, Wu group took advantage of methyl
ketones as one carbon source for building 2-acyl-
4-arylquinolines or 2-acyl-3-arylquinolines with
p-toluidine and aldehyde (Scheme 1f).[11]
Although some achievements have been made in
this area, most of the products remain restricted
to 2, 3-substituted, 2, 4-substituted or 4-
substituted quinolines because of the one carbon-
source usually assembled at C2 position of
quinolines. The one carbon-source assembled at
C4 position to constructe 2-arylquinolines by
three-component annulation strategy has not been
reported. Herein, we conducted a study on
efficient Cu-catalyzed C–H cyclization of simple
anilines, ketones, and DMSO to assembly of 2-
arylquinolines via formal [3+2+1] cycloaddition
(Scheme 1g). In contrast to the well-known three-
component aerobic oxidative strategy, this
chemistry use DMSO as one carbon-source
assembled at C4 position of 2-arylquinolines.[12]
screen the optimal reaction conditions and the results
summarized in Table 1. The desired product (4aa)
was isolated in 71% yield with Cu(OAc)2 as catalyst
and O2 as oxidant for 24 h (entry 1). After screening
.
metal catalysts, we found that CuCl2 2H2O was the
most effective catalyst for this reaction (entry 8 vs
entries 1-7). An oxidant screen revealed that O2
preformed best for this transformation, giving the
desired product (4aa) in 78% yield (entries 9-12).
The reaction was also sensitive to temperature, both
elevating and decreasing the reaction temperature led
to dramatically decreased yield (Table 1, entries 13,
14). When we tried this transformation with 1.0
mmol of aniline (2a), the reaction did occur, but the
yield of product decreased to 61%, elevating the
amount of aniline (2a) also led to a decreased yield
(Table 1, entries 15, 16).
With the established aerobic oxidative conditions in
hand, we explored the substrate scope and functional-
group tolerance of this protocol with a range of
ketones. In general, both electron-rich and electron-
deficient acetophenones reacted with aniline and
DMSO, producing the corresponding products in high
yields. Delightfully, a series of para-substituted aryl
methyl ketones, including some with electron-
donating groups (Me, OMe, SMe, tBu) and some with
electron-withdrawing groups (COOMe, and CN),
were converted into the corresponding 2-substituted
Results and Discussion
We commenced our studies with acetophenone
(1a) aniline (2a) and DMSO as the model substrate to
Table 1. Optimization of Reaction Conditions.a)
Temp
(℃)
120
120
120
120
120
120
120
120
120
120
120
120
100
130
120
120
Yield
(%)b)
Entry
Catalyst
Oxidant
1
2
Cu(OAc)2
O2
O2
71
62
65
30
26
67
65
78
34
13
21
trace
49
76
61
77
.
FeCl2 4H2O
3
FeCl3.6H2O
O2
.
4
CoCl2 6H2O
O2
.
5
NiCl2 6H2O
O2
6
CuBr2
O2
.
7
CuSO4 5H2O
O2
.
8
CuCl2 2H2O
O2
.
9
CuCl2 2H2O
K2S2O8
TBHP
DTBP
H2O2
O2
.
10
11
12
13
14
15c)
16d)
CuCl2 2H2O
.
CuCl2 2H2O
.
Scheme 2. Cu-catalyzed C–H cyclization of simple
ketones, anilines, and DMSO.
CuCl2 2H2O
.
CuCl2 2H2O
.
CuCl2 2H2O
O2
.
CuCl2 2H2O
O2
quinolines in moderate to excellent yields
.
(
4aa−4ga). The halo-substituted products like
CuCl2 2H2O
O2
4ha and 4ia could also be readily prepared by
using the current strategy, facilitating further
functionalization via cross coupling. Furthermore,
acetophenone bearing the same substituents at
different positions had influence on the efficiency
a)
Reaction conditions: acetophenone (1a, 0.5 mmol),
aniline (2a, 1.5 mmol), DMSO (2.5 mL), catalyst (10
b)
c)
mol %), oxidant (1 mmol) for 24 h.
Isolated yield.
aniline (2a, 1 mmol), d) aniline (2a, 2 mmol).
2
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10.1002/adsc.201800373
Advanced Synthesis & Catalysis
of this transformation. For example, 2-methyl-
quinoline product. This result further proved that C
would be the key intermediate in this reaction (eq 2).
When the reaction was performed only with
acetophenone under otherwise identical conditions,
the intermediate C was not observed, indicating that
aniline was essential to the process of acetophenone
convert into enone C. When propylamine was added
instead of aniline, the standard conditions did provide
acetophenone (1k) gave a lower yield than 4-/3-
methyl-acetophenone (1b/1j). The disubstituted
acetophenone also gave the corresponding
product in high yield (4la). A heterocyclic, 2-
acetylthiophene also provided the 2-substituted
quinoline in 78% yield (4ma). Furthermore, 2-
acetonaphthone readily underwent the reaction to
generate the expected products in high yield
.
the enone C (eq 3). Without CuCl2 2H2O, compound
(
4na).
C could be converted to 4aa in 71% yield. In contrast,
the transformation did not proceed in the absence of
O2 (eq 4). It can thus be concluded that the
conversion from intermediate C into product 4aa
Subsequently, the scope of the cyclization
reaction was further explored using a variety of
substituted anilines. For example, arylamine
bearing electron-rich (e.g., 4-Me, 4-iPr, 2-Me, 2-
Ph and 3,5-CH3), and electron-deficient (e.g., 4-
Cl, 4-F, 4-CF3, 4-COOMe, 3-Cl and 3-Br) groups
were tolerated, affording the corresponding
.
does not require CuCl2 2H2O and O2 plays an
important role in this process. Deuterium-
experiments were also carried out. By using DMSO-
d6 instead, the partially deuterated product 4a-d1 was
isolated, which confirmed that DMSO was a source
of methylene units. (eq 5).
products in moderate to good yields (4ab-4al).
Scheme 4. Control Experiments.
On the basis of the experimental results
described above and previous literatures,[13]
possible reaction path is shown in Scheme 4.
Initially, DMSO is activated by the aniline to give
a
Scheme 3. Cu-catalyzed C–H cyclization of simple
ketones, anilines, and DMSO
B
. The intermediate
enolate and undergoes demethylthioation to
generate species . The condensation of aniline
with to provide imine , followed by
annulation and aromatization of to afford the
corresponding product 4aa
B can be intercepted by the
A
In order to probe the possible mechanism of
quinoline formation, several control experiments
were conducted (scheme 4). By addition of 2 equiv of
the radical inhibitor, BHT, product 4aa was still
produced in high yield under similar reaction
conditions, indicating that this reaction may not
involve a radical process (eq 1). When the model
reaction was stopped at 5 h, ca. 11% 1-phenylprop-2-
en-1-one (C) and 24% 4aa were detected. By further
heating the reaction mixture for aditional 19 h, C
disappeared, whereas the yield of 4aa was increased
to 75%, implying that C is a key intermediate in this
reaction (eq 2). Subjecting enone C to the standard
conditions instead of acetophenone did provide the
C
C
D
D
.
3
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10.1002/adsc.201800373
Advanced Synthesis & Catalysis
Figure 1. Possible Mechanism.
[3] c) O. Doebnerand, W. von Miller, Ber. Dtsch. Chem.
Ges, 1881, 14, 2812-2817; b) J. J. Eisch, T.
Dluzniewski, J. Org. Chem. 1989, 54, 1269−1274; c) J.
X. Xu, J. Sun, J. W. Zhao, B. Huang, X. H. Li, Y. L. Sun,
RSC Adv. 2017, 7, 36242–36245.
Conclusion
In summary, we have disclosed a Cu-catalyzed
C–H cyclization of simple ketones, anilines, and
DMSO for the synthesis of 2-arylquinolines using
O2 as oxidant and DMSO as carbon source. A
wide range of ketones and anilines are
significantly employed in this cyclization
protocol and this enables a direct route to 2-
arylquinolines. On the basis of control
experiments, a plausible reaction path including
C-H/C-H cross coupling, demethylthioation,
condensation and annulation is proposed.
[4] O. De Paolis, L. Teixeira, B. Torok, Tetrahedron Lett.
2009, 50, 2939-2942.
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[8] C. S. Li, J. X. Li, Y. N. An, J. W. Peng, W. Q. Wu, H.
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Experimental Section
[9] a) L. S. Povarov, Russ. Chem. Rev. 1967, 36, 656-
663, b) A. Kulkarni, B. Torok, Green Chem. 2010,
Typical experimental procedure for the formation of
pyridines from arylketones. In a Schlenk tube of 25 mL,
acetophenone (1a, 0.5 mmol), aniline (2a, 1.5 mmol) and
12, 875-878; c) S. P. Midya, M. K. Sahoo, V.
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.
CuCl2 2H2O were dissolved in DMSO (2.5 mL). The
mixture was stirred at 120 ºC for 24 h under O2 atmosphere.
After completion of the reaction, the resulting solution was
cooled to room temperature; the solution was diluted with
ethyl acetate (10 mL), washed with water (5 mL), extracted
with ethyl acetate (3×5 mL), and dried over anhydrous
Na2SO4 and concentrated in vacuo. The crude product was
purified by flash column chromatography on silica gel to
give the desired product.
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Acknowledgements
G. F. Zhang, Y. J. Jian, Z. W. Gao, RSC Adv, 2017
,
7, 28616-28625.
Financial support from the National Science Foundations of
China (No. 21572049) are gratefully acknowledged.
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4
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10.1002/adsc.201800373
Advanced Synthesis & Catalysis
FULL PAPER
Copper-Catalyzed Aerobic Oxidative Cyclization
of Anilines, Ketones and DMSO: Efficient
Assembly of 2-Arylquinolines
Adv. Synth. Catal. Year, Volume, Page – Page
Yufeng Liu a, Zhongzhong Cao a, Xi Zhan a, Yuqun
Hu a, Weiping Luo a, Qiang Liu a*, Cancheng Guoa*
5
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