One-Pot Synthesis of 4-Quinolone via Iron-Catalyzed Oxidative Coupling of Alcohol and Methyl Arene

Article abstract of DOI:10.1021/acs.orglett.0c03011

Herein, we describe the iron(III)-catalyzed oxidative coupling of alcohol/methyl arene with 2-amino phenyl ketone to synthesize 4-quinolone. Alcohols and methyl arenes are oxidized to the aldehyde in the presence of an iron catalyst and di-tert-butyl peroxide, followed by a tandem process, condensation with amine/Mannich-type cyclization/oxidation, to complete the 4-quinolone ring. This method tolerates various kinds of functional groups and provides a direct approach to the synthesis of 4-quinolones from less functionalized substrates.

Full text of DOI:10.1021/acs.orglett.0c03011

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Letter
One-Pot Synthesis of 4‑Quinolone via Iron-Catalyzed Oxidative
Coupling of Alcohol and Methyl Arene
Seok Beom Lee, Yoonkyung Jang, Jiwon Ahn, Simin Chun, Dong-Chan Oh, and Suckchang Hong*
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ABSTRACT: Herein, we describe the iron(III)-catalyzed oxidative
coupling of alcohol/methyl arene with 2-amino phenyl ketone to
synthesize 4-quinolone. Alcohols and methyl arenes are oxidized to
the aldehyde in the presence of an iron catalyst and di-tert-butyl
peroxide, followed by a tandem process, condensation with amine/
Mannich-type cyclization/oxidation, to complete the 4-quinolone
ring. This method tolerates various kinds of functional groups and
provides a direct approach to the synthesis of 4-quinolones from
less functionalized substrates.
methods still require multiple steps or specific substrates,
itrogen-containing heterocycles are widely found in
Nmany biologically active compounds and natural which have to be prepared separately (Scheme 1).
In 2017, Huang’s group reported an oxidative intermolecular
synthetic route for 2-aryl-4-quinolone from 2-amino-acetophe-
nones and benzaldehydes.16 However, only acetophenone
derivatives are applied as a starting material, and aldehyde
oxidation level starting materials still limit the generality of the
reaction. As part of our continuing studies in the synthesis of
heterocycle scaffolds using simple and less functionalized
substrates, herein, we report an intermolecular synthesis of 2-
substituted 4-quinolones using 2-amino phenyl ketones via
iron-catalyzed oxidative annulation. Recently, various types of
base metal-catalyzed oxidative annulation using peroxide have
been applied to the construction of heterocycles.17 Among the
base metals, iron is the most abundant transition metal with a
low price and low toxicity. Moreover, alcohol and hydrocarbon
oxidation level materials are more easily available than
aldehydes and are usually supplied as feedstocks. Many kinds
of aldehydes are prepared by the oxidation of the
corresponding alcohol. Therefore, direct use of these substrates
instead of labile aldehyde is more attractive for the generality
of the reaction scope. This procedure features a simple one-pot
operation using readily available starting materials and
catalysts. To the best of our knowledge, this is the first
products. Among them, 4-quinolone is regarded as a privileged
scaffold that imparts a variety of biological activities.1 Many
antibiotics contain 4-quinolone moieties due to their
significant antibacterial activity.2 In particular, 2-aryl-4-
quinolone, an aza analogue of flavone, was known to show
an inhibitory effect on tubulin polymerization and play a
crucial role in antitumor activity.3 In addition, recent studies
revealed that certain 2-aryl-4-quinolone derivatives possess
potent antiviral,4 antimalarial,5 and antiplatelet6 activity as well
as effects on cathepsin inhibition7 and xanthine oxidase.8
Additionally, these derivatives have been used as important
building blocks for various biologically active quinolone and
quinoline compounds because of the facile functionalization of
their reactive centers at positions 1, 3, and 4.9 The attractive
biological profile and synthetic importance have encouraged
researchers to develop various synthetic methods for this
scaffold.10 The most typical method is cyclocondensation, such
as Conrad−Limpach and Niementowski cyclization, which
proceeds via condensation of amine and carbonyl groups
followed by cyclization.11 However, most of these classical
methods suffer from harsh conditions and a limited substrate
scope. Another method is base-promoted cyclization of N-(o-
ketoaryl)amides, known as the Camps cyclization.12 This
reaction has been widely used in the synthesis of quinolones
but usually proceeds through two steps to employ an N-amide
group. Some improved methods were developed using o-
haloaryl acetylenic ketones/amines,13 o-aminoaryl acetylenic
ketones,14 or N-benzyl-2-aminoacetophenone,15 providing a
milder route toward 2-aryl-4-quinolone. However, these
Received: September 9, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03011
© XXXX American Chemical Society
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20 mol % Fe(OTf)3 and 3 equiv of di-tert-butyl peroxide
(DTBP) in DMSO at 100 °C under air, the desired quinolone
product 3aa was obtained in 42% yield (entry 1). Higher
conversion was achieved when the reaction temperature was
increased to 110 °C (entry 2). Only trace amounts of 3aa were
observed in the DMF solvent (entry 3). Next, various kinds of
oxidants and catalysts were explored in the reaction system.
tert-Butyl hydroperoxide (TBHP) showed low efficiency, and
H2O2 gave 3aa in a yield similar to that of DTBP (entries 4
and 5, respectively). Among the explored catalysts, Fe(OTs)3·
6H2O was found to be the best catalyst (entries 6−11). To
find more optimized conditions, we applied O2 or N2 gas to the
reaction system (entry 12 or 13, respectively). Interestingly,
the N2-charged reaction system gave the best yield with clean
conversion, and the exposure of the reaction mixture to O2
resulted in a lower yield. We supposed that O2 accelerated the
side reaction that originated from Baeyer−Villiger oxidation
(see page S56 of the Supporting Information). In the absence
of a catalyst, the reaction was very slow and was not completed
(entry 14, see page S52 of the Supporting Information). This
result demonstrates the important role of iron catalysts in the
oxidation process.
Scheme 1. Synthetic Approaches toward 2-Aryl-4-
quinolones
To evaluate the substrate scope of the reaction, a wide range
of alcohols 2 were reacted with 1a under the optimized
reaction conditions (Scheme 2). Benzylic alcohols with various
substituents were smoothly coupled with 1a to afford the
corresponding quinolone products 3ab−3am in good yields,
except for the methoxy group (3ae). In the case of 4-methoxy
benzyl alcohol, a complex product mixture was observed. We
example of a one-pot synthesis of 4-quinolone starting directly
from a 2-amino phenyl ketone with alcohols and methyl arene.
As shown in Table 1, we began our studies by optimizing
various reaction parameters in the reaction of 1-(2-amino-
phenyl)-2-phenylethanone (1a) with benzyl alcohol (2a). With
a
Scheme 2. Scope of Alcohols 2
Table 1. Optimization for the Reaction between 1-(2-
Aminophenyl)-2-phenylethanone (1a) and Benzyl Alcohol
a
(2a)
b
entry
catalyst
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
oxidant
yield (%)
c
1
DTBP
DTBP
DTBP
TBHP
H2O2
42
74
trace
50
2
3
d
4
5
Fe(OTf)3
73
6
7
8
9
10
11
12
13
14
Cu(OTf)2
I2
Mn(OAc)2
Fe(OAc)2
FeCl3·6H2O
Fe(OTs)3·6H2O
Fe(OTs)3·6H2O
Fe(OTs)3·6H2O
no catalyst
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
trace
5
4
13
trace
81
49
92
28
e
f
f
a
Reaction conditions: 1a (0.2 mmol), 2a (1.0 mmol), catalyst (20
mol %), and oxidant (0.6 mmol) in DMSO (0.8 mL) at 110 °C for 20
b
c
d
h under air. Isolated yield. Reaction temperature of 100 °C. DMF
e
f
a
b
solvent. O2 balloon. N2 balloon.
For 40 h. With 20 equiv of alcohol, 28 h.
B
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supposed that a side reaction originating from Baeyer−Villiger
oxidation could occur competitively in some cases. Other
substituents, such as tert-butyl, halogen, nitrile, and ester, were
well tolerated under the reaction conditions. The pyridine
group was employed at position 2 of the 4-quinolone products
in moderate yield (3an and 3ao). For further expansion of the
alcohol scope, allylic, propargylic, and aliphatic alcohols were
also explored. Cinnamyl and 3-phenylpropargyl alcohol could
participate in the reaction; however, products 3ap and 3aq
were obtained in low yields. Aliphatic alcohols also afforded
the desired products 3ar−3at, even though an excess amount
of alcohol was required. For the secondary alcohol, the
expected 2,3-dihydro-4-quinolone product 3au was formed in
moderate yield.
synthesis of 4-quinolones. Furthermore, the practical utility of
the developed method was demonstrated on a 1 g scale (6.7
mmol scale) reaction for 3ca (77%).
After successful synthesis of 4-quinolones using alcohol, our
interest moved to methyl arene as a coupling partner. On the
basis of our previous synthesis of quinazolinone,17a we
envisioned that methyl arene can also be oxidized to the
corresponding aldehyde under these conditions and participate
in oxidative annulation. As shown in Table 2, a preliminary
Table 2. Optimization for the Reaction between 2-
a
Aminopropiophenone (1c) and Toluene (4a)
Next, we employed a series of 2-amino aryl ketones 1 for
further extension of the substrate scope (Scheme 3). From
a
b
Scheme 3. Scope of 2-Amino Aryl Ketones 1
entry
4a
DMSO (mL)
yield (%)
c
1
1.2 mL (60 equiv)
1.2 mL (60 equiv)
1.9 mL (90 equiv)
1.9 mL (90 equiv)
1.9 mL (90 equiv)
0.8
0.8
0.8
1.0
1.2
52
57
67
72
64
2
3
4
5
a
Reaction conditions: 1c (0.2 mmol), 4a, Fe(OTs)3·6H2O (20 mol
%), and DTBP (0.6 mmol) in DMSO at 110 °C for 40 h under air.
b
c
Isolated yield. N2 balloon.
study was performed with the cyclization between 2-amino-
propiophenone (1c) and toluene (4a). In contrast to the
reaction with alcohol, methyl arene was less reactive; thus,
competitive Baeyer−Villiger oxidation is often observed in
substrate 1a. The phenyl group of 1a was replaced with a
methyl group to suppress migration during Baeyer−Villiger
oxidation. Considering the lower reactivity of methyl arene,
excess 4a was used as a cosolvent. Fortunately, 4a was also
readily applied in the annulation and gave desired product 3ca
in 52% yield (entry 1). On the basis of our experience and
previous reports,17a we expected that O2 gas would help the
oxidation of methyl arene to the aldehyde. As expected, when
the reaction mixture was exposed to air, an improved yield was
obtained with clean conversion (entry 2). After the 4a/solvent
ratio had been controlled, the optimized condition was
selected as entry 4 (72%).
Then, we investigated the substrate scope for the synthesis
of 4-quinolone using methyl arene (Scheme 4). Under the
optimized conditions, various ketone-substituted starting
materials 1 reacted with toluene 4a and afforded the desired
quinolone products in moderate to good yield (3aa−3da and
3fa). Similar to the reaction using an alcohol substrate, the 3-
pyridyl quinolone product 3la was obtained in low yield along
with unoxidized intermediate 3la′. Initially, we had expected
the pyridine group to be oxidized in the reaction, but any N-
oxidation products were not detected. Thus, we proposed
another possibility that Lewis basic pyridine captures Lewis
acidic iron salt and disrupts the iron-mediated oxidation from
the dihydroquinolone intermediate to the quinolone product.
The phenylethanone substrate (1a) smoothly reacted with
toluene and gave 3aa in good yield. However, some
inseparable mixture was obtained in the reaction with other
methyl arenes, which is presumed to originate from Baeyer−
Villiger-type side reactions. On the contrary, propiophenone
substrate 1c could react with various methyl arenes, and
a
b
With 10 equiv of alcohol. For 40 h.
most simple methyl ketone 1b, the desired product 3ba was
obtained in moderate yield. In addition to methyl ketones,
variously substituted ketone substrates could be successfully
applied for 4-quinolone formation (3ca−3ia). Generally, a
substituent that can activate the α-position of the ketone
showed a high yield, such as nitrile and aryl groups (3fa−3ia).
For the isopropyl group, the reaction was slow due to steric
effects; thus, a longer reaction time was required for a
satisfactory yield (3ea). The 5-methyl substituent on the
phenyl group of substrate 1 showed a negative result compared
with the chloride substituent (3ja and 3ka). The introduction
of pyridine instead of a phenyl group resulted in a lower yield
of the desired products (3la and 3ma), and a small amount of
unoxidized dihydroquinolone remained. In the case of 2-amino
benzofuran-3-ketone 1n, the tricyclic product 3na was
obtained in a trace amount. N-Substituted 1o could also
participate in oxidative cyclization and afford the N-methyl-4-
quinolone product 3oa. The broad range of substrates
demonstrates the synthetic potential of this method for the
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group at position 4, and 4-phenyl quinoline 6 was synthesized.
Furthermore, direct nucleophilic substitution with thiophenol
afforded 4-sulfide quinoline 7.18 O-Alkylation could also be
achieved directly from 3ca using alkyl halide and K2CO3, and
quinoline product 8 was obtained, which has an ether linkage
at position 4.19 In addition to the ketone group at position 4,
the position 1 − N could be substituted directly with
iodomethane in the presence of NaH as a base.20 Under
these conditions, N-methylated quinolone 9 was synthesized
selectively in high yields.
Scheme 4. Substrate Scope in the Reaction between 2-
Amino Phenyl Ketones 1 and Methyl Arene 4
On the basis of the experimental results and previous
studies,17 we proposed a plausible reaction mechanism (see
page S58 of the Supporting Information). Initially, the reaction
begins with oxidation of alcohol 2a to benzaldehyde.
Condensation of benzaldehyde with 1 produces imine
intermediate A, followed by Mannich-type cyclization to
form dihydroquinolone 3′. Final oxidation of intermediate 3′
affords quinolone product 3. Iron salt can mediate each
oxidation process and also act as the Lewis acid in the
cyclization process. In the presence of O2, Baeyer−Villiger
oxidation of 1 is accelerated, and the corresponding alcohol
side-2 is generated after hydrolysis of ester. This alcohol side-2
can participate in the annulation with another 1 to produce
side-3. Methyl arene 4a is also converted to benzaldehyde by
iron-mediated oxidation; however, aldehyde formation is less
favored than that of alcohol 2a. Thus, for methyl arene, O2
promotes aldehyde formation through benzyl hydroperoxide
intermediate and has a positive effect in the reaction.
In conclusion, we have described the iron-catalyzed
oxidative annulation of 2-amino phenyl ketone with a low-
oxidation level substrate for the synthesis of 4-quinolone. Iron
is an earth-abundant and low-toxicity metal, and all of the
substrates and reagents used in the reaction were readily
available. Moreover, the broad substrate scope, large scale
reaction, and diverse chemical conversion of 4-quinolone
products demonstrate the synthetic potential of the developed
method. Importantly, this is the first report of the synthesis of
4-quinolone via intermolecular coupling of 2-amino phenyl
ketone with alcohol and methyl arene. Further expansion of
the oxidative annulation using low-oxidation level substrates to
access other N-heterocycles is currently being investigated in
our research group.
desired products 3cb−3cd, 3cg, and 3cl were readily
synthesized without side products. Thiophene was also applied
to position 2 of the 4-quinolone product under the developed
conditions.
To demonstrate the synthetic potential of the developed
method, we tried to convert 4-quinolone products 3ca to
various quinoline compounds via functionalization of the
ketone moiety at position 4 (Scheme 5). Halogenation with
PBr3 and POCl3 provided the corresponding 4-haloquinolines
5a and 5b, respectively. Suzuki coupling introduced a phenyl
Scheme 5. Diverse Chemical Conversions of 4-Quinolone
3ca
ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03011.
1
Experimental procedures, characterization data, H and
13C NMR spectra, mechanistic studies, and the proposed
mechanism (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Suckchang Hong − Research Institute of Pharmaceutical
Sciences, College of Pharmacy, Seoul National University, Seoul
08826, Republic of Korea; orcid.org/0000-0003-4975-
9192; Email: schong17@snu.ac.kr
Authors
Seok Beom Lee − Research Institute of Pharmaceutical Sciences,
College of Pharmacy, Seoul National University, Seoul 08826,
Republic of Korea
D
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Letter
(9) Mphahlele, M. J. J. Heterocycl. Chem. 2010, 47, 1−14.
Yoonkyung Jang − Research Institute of Pharmaceutical
Sciences, College of Pharmacy, Seoul National University, Seoul
08826, Republic of Korea
Jiwon Ahn − Research Institute of Pharmaceutical Sciences,
College of Pharmacy, Seoul National University, Seoul 08826,
Republic of Korea
Simin Chun − Research Institute of Pharmaceutical Sciences,
College of Pharmacy, Seoul National University, Seoul 08826,
Republic of Korea
Dong-Chan Oh − Natural Products Research Institute, College
of Pharmacy, Seoul National University, Seoul 08826, Republic
of Korea; orcid.org/0000-0001-6405-5535
́
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Complete contact information is available at:
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(13) (a) Zhao, T.; Xu, B. Org. Lett. 2010, 12, 212−215. (b) Shao, J.;
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This work was supported by a National Research Foundation
of Korea (NRF) grant funded by the Korea government
(2018R1C1B6005607 and 2018R1A4A1021703) and the
Creative-Pioneering Researchers Program through Seoul
National University (SNU).
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Org. Biomol. Chem. 2020, 18, 5435−5441. (b) Wang, X.; Liu, H.; Xie,
C.; Zhou, F.; Ma, C. New J. Chem. 2020, 44, 2465−2470. (c) Yogesh
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