AlCl 3 -Mediated Synthesis of 4-Aryl-2-quinolone-3-carboxylates

Article abstract of DOI:10.1055/s-0036-1588798

4-Aryl-2-quinolones are important skeletons from both chemical and medicinal viewpoints. We herein report the development of an efficient synthetic method for 3-substituted 4-aryl-2-quinolones. The key reaction in this process involves an AlCl ₃

Full text of DOI:10.1055/s-0036-1588798

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–F
letter
A
en
S.-H. Yang et al.
Letter
Synlett
AlCl3-Mediated Synthesis of 4-Aryl-2-quinolone-3-carboxylates
Seung-Hye Yang◊
Seohyun Jo◊
NH2
R1
H
H
N
N
O
O
R1
R1
Dongyun Shin*
1. AlCl3
2. DDQ
O
O
O
O
two steps
College of Pharmacy, Gachon University, 191 Hambakmoe-ro,
Yeonsu-gu, Incheon 21936, South Korea
dyshin@gachon.ac.kr
Cl
R2
OEt
O
OEt
R2
OEt
R2
This paper is dedicated to Professor Young-Ger Suh on the occasion
of his 65th birthday
21 examples
up to 80% for two steps
R1 and R2 = alkyl, alkoxy, halide
◊ These two authors contributed equally to this work
Received: 18.02.2017
Accepted after revision: 27.03.2017
Published online: 02.05.2017
clization conditions employed, these synthetic methods can
be divided into two categories, namely dehydrative cycliza-
tion and transition-metal-catalyzed cyclization. Indeed,
several methods have been published for the synthesis of 4-
aryl-2-quinolones in the absence of transition-metal cata-
lysts, with key reactions including intramolecular or inter-
molecular aldol reactions,6,9,10 intramolecular Horner–Wad-
sworth–Emmons reactions,11 intramolecular amide forma-
tion, intramolecular Friedel–Crafts-type cyclizations,7 and
intramolecular haloarylation reactions.12 Examples of sub-
strates employed for these cyclization reactions are pre-
sented in Figure 2. Furthermore, the transition-metal-cata-
lyzed cyclizations can be classified as either cross-coupling
reactions of activated aryl rings (e.g., arylbromides and
aryliodides) using transition metals or coupling reactions
based on arene C–H activation. Selected examples of such
reactions are also summarized in Figure 2. In 2004,
Kadnikov and Larock reported the synthesis of 3,4-disubsti-
tuted 2-quinolones by the palladium-catalyzed annulation
of N-substituted o-iodoanilines and alkynes under a CO2 at-
mosphere.13 In addition, Battistuzzi et al. utilized the domi-
no Heck–Buchwald–Hartwig reaction of o-bromocinnama-
mide and aryl iodides for the synthesis of 4-aryl-2-quinolo-
nes.14 More specifically, a phosphine-free palladium(II)
acetate catalyst was employed along with a mixture of mol-
ten tetra(n-butyl)ammonium acetate/tetra(n-butyl)ammo-
nium bromide. Furthermore, substituted 2-quinolones have
been synthesized from N-methyl-N,3-diphenylpropiol-
amides via a palladium-catalyzed arene C–H activation pro-
tocol, as reported by Tang et al. in 2009,15 while Glasnov et
al. synthesized 4-aryl-2-quinolones from 4-hydroxy-2-
quinolones by sequential chlorination and Suzuki cou-
pling.16 More recently, the preparation of 4-aryl-2-quinolo-
nes from 3,3-diarylacrylamides through intramolecular
copper-catalyzed C–H functionalization–C–N bond forma-
tion was completed by Berrino et al.17 Moreover, the syn-
DOI: 10.1055/s-0036-1588798; Art ID: st-2017-u0119-l
Abstract 4-Aryl-2-quinolones are important skeletons from both
chemical and medicinal viewpoints. We herein report the development
of an efficient synthetic method for 3-substituted 4-aryl-2-quinolones.
The key reaction in this process involves an AlCl3-mediated intramolecu-
lar cyclization of substituted 2-(carbamoyl)-3-phenylacrylates, with op-
timized reaction conditions of 2.0 equivalents of AlCl3, nitrobenzene,
80 °C, and 3 hours. The chemical yields of cyclization were found to be
sensitive to all reaction conditions.
Key words 2-quinolone, Lewis acid, intramolecular, cyclization, oxida-
tion
The 4-aryl-2-quinolone [1, 4-arylquinolin-2(1H)-one]
structure is an important scaffold that is commonly found
in many natural alkaloids (Figure 1).1 More specifically, var-
ious biologically and pharmacologically significant com-
pounds contain the 2-quinolone moiety as a structural and
pharmacophoric feature, and these compounds exhibit a
variety of functions, including anticancer activity, anti-
platelet activity, glycine NMDA receptor antagonism, 5-HT4
agonism, potassium channel opening activity, and antimi-
crobial activity.2–8
X
N
O
H
Figure 1 Structure of 4-aryl-2-quinolone (1)
Due to the chemical and medicinal importance of 4-
aryl-2-quinolones, a number of synthetic methods for their
preparation have been investigated to date. Based on the cy-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

B
S.-H. Yang et al.
Letter
Synlett
Selected examples of metal-mediated
Selected examples of nonmetal-mediated
cyclization (
)
cyclization (
)
Ar
Ar
O
[Pd]
R
Ar
N
H
O
Ar
O
Br H2N
I
O
+
+ CO
[Pd]
NH2
N
H
O
Ar
Ar
Ar
[Cu]
R
O
H2N
O
CO2R
NO2
Ar
N
H
Ar
[Pd]
O
P(O)(OEt)2
N
O
H
HN
Ar
O
O
O
+
Ar
Ar
Ar
Me
HO2C
R
CO2Et
N
Cl
+
N
O
O
+
[Ag]
O
NH2
[Ir]
Figure 2 Previous synthetic approaches to 4-aryl-2-quinolones
thesis of 3,4-disubstituted 2-quinolones was achieved by
the intramolecular annulation of N-arylcarbamoyl chlorides
and homosubstituted alkynes, catalyzed by [IrCl(cod)]2 (cod
= 1,5-cyclooctadiene),18 while a novel synthetic route to 3-
acyl-4-aryl-2-quinolones from 3-arylacrylamides via a sil-
ver-catalyzed radical tandem cyclization was developed by
Mai et al.19
One of the main interests of our group is the discovery
of novel bioactive molecules, and indeed we recently re-
ported an arylquinoline lactone as a promising anticancer
agent, in addition to expanding its chemical diversity to the
arylquinolones.20–23 Although several efficient synthetic
methods for 3-substituted 4-aryl-2-quinolones have been
developed, each method contains drawbacks in terms of the
synthetic readiness of the reaction precursors, substituent
diversity, chemical yields, or selectivity. Thus, we herein re-
port a novel approach to 3-substituted 4-phenyl-2-quinolo-
nes by the Lewis acid catalyzed cyclization of 2-(phenylcar-
bamoyl)-3-phenylacrylates and sequential aromatization–
oxidation (Scheme 1). We expect the main advantages of
this method to include the relative synthetic readiness of
the cyclization precursors via a variety of commercially
available anilines, high yields, and the potential for further
product derivatization.3,24
In the first step of our synthetic effort to 3-substituted
4-aryl-2-quinolones, acrylamide 5 (Table 1, entry 1) was
treated with polyphosphoric acid at 130 °C according to a
previously reported literature.25 However, in this case, the
expected cyclization product 3 was not obtained, with the
reaction instead yielding the decarboxylated cyclization
product 5. It is mechanistically plausible that ester hydroly-
sis followed by decarboxylation of the β-keto acid under the
acidic reaction conditions led to formation of decarboxylat-
ed 2-pyridone 5.
This result prompted us to search for reliable, reproduc-
ible, and effective reaction conditions for the desired cy-
clization reaction, that is, avoiding product decarboxyl-
ation. Initially, various protic acids, including trifluoroacetic
acid (TFA), p-toluenesulfonic acid (p-TsOH), and camphor-
H
H
N
H
N
O
O
N
O
R1
R1
R1
Lewis acid
[O]
CO2Et
R2
CO2Et
R2
CO2Et
R2
2
3
4
Scheme 1 Strategy for the preparation of 3-substituted 4-aryl-2-quinolones via a Lewis acid-catalyzed cyclization-oxidation pathway
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

C
S.-H. Yang et al.
Letter
Synlett
Table 1 Optimization of the Cyclization Conditions
With the optimized reaction conditions in hand, we ex-
amined the utility of this method. The synthesis of the cy-
clization precursor, namely ethyl 2-(phenylcarbamoyl)-3-
phenylacrylates, is presented in Scheme 2. Initially, selected
anilines 6 were acylated using commercially available ethyl
malonyl chloride to provide amides 7, which were subse-
quently subjected to Knoevenagel condensation with sub-
stituted benzaldehydes in the presence of piperidine to give
precursors 4 in high yields. The E and Z isomers generated
were separable by silica gel column chromatography; how-
ever, following separation, racemization between E and Z
isomers immediately took place. As such, E/Z mixtures of
ethyl 2-(phenylcarbamoyl)-3-phenylacrylate were em-
ployed for the subsequent cyclization reaction.
H
N
H
N
H
N
O
O
O
O
O
reagents
conditions
OEt
OEt
4aA
3aA
5
Entry
Reagents (equiv) Conditions
Yield of 3aA (%)a
1
2
PPA
130 °C, 6 h
(5, 42)
5
TFA
CH2Cl2, r.t., 12 h
CH2Cl2, r.t., 12 h
CH2Cl2, r.t., 12 h
3
CSA
–
4
p-TsOH
–
We then investigated the effect of electron-withdrawing
(e.g., Cl) and electron-donating (e.g., OMe, dioxolane) sub-
stituents on the aniline moiety in addition to electronically
different substituents on the benzaldehyde phenyl ring (Ta-
ble 2). Under the optimized conditions, the majority of sub-
5
BF3·OEt2 (1.0)
In(OTf)3 (1.0)
AlCl3 (1.0)
AlCl3 (1.0)
AlCl3 (0.7)
AlCl3 (1.0)
AlCl3 (2.0)
AlCl3 (6.0)
AlCl3 (2.0)
AlCl3 (2.0)
CH2Cl2, 40 °C, 12 h
CH2Cl2, 40 °C, 12 h
benzene, r.t., 12 h
benzene, 40 °C, 12 h
benzene, 80 °C, 3 h
benzene, 80 °C, 3 h
benzene, 80 °C, 3 h
benzene, 80 °C, 3 h
toluene, 80 °C, 3 h
nitrobenzene, 80 °C, 3 h
15
40
10
15
45
55
81
58
<40
98
6
7
8
9
H
10
11
12
13
14
N
O
NH2
O
O
Et3N
R1
R1
+
O
CH2Cl2
Cl
OEt
OEt
6
7
H
N
O
O
R2
R1
a Isolated yield.
O
piperidine
CH2Cl2
OEt
R2
sulfonic acid (CSA) were screened as acid catalysts; howev-
er, these acids proved to be not suitable for the desired cy-
clization reaction (Table 1). We then turned our attention to
Lewis acids, initially employing boron trifluoride ethyl
etherate (BF3·OEt2) with CH2Cl2 solvent. However, the de-
sired product was obtained in low yields. Use of indium(III)
trifluoromethanesulfonate (In(OTf)3) elevated the yield
slightly, but the result remained unsatisfactory. Subse-
quently, use of the commonly employed Lewis acid alumi-
num chloride (AlCl3) was investigated at a range of reaction
temperatures, times, and catalyst quantities. The results re-
vealed that both reaction temperature and Lewis acid quan-
tity were crucial in obtaining an acceptable yield. Solvent
choice also influenced the outcome of the reaction. For ex-
ample, when benzene was employed as the reaction sol-
vent, use of 2.0 equivalents AlCl3 at 80 °C over three hours
delivered optimal results with a yield of 81%. Other aromat-
ic solvents such as toluene and nitrobenzene were
screened, and nitrobenzene was found to be a more effec-
tive solvent in this reaction (98% yield) while toluene gave a
low yield. It was also observed that the cyclization yields
were particularly sensitive to the quality of AlCl3. Based on
the above results, we established the optimal reaction con-
ditions for this reaction (i.e., 2.0 equiv AlCl3, nitrobenzene,
80 °C, 3 h).
75–90%
4
H
N
H
H
O
N
O
N
O
O
O
O
O
O
MeO
OEt
OEt
OEt
7a, 93%
7b, 90%
7c, 95%
H
N
H
O
MeO
N
O
O
O
Cl
MeO
OEt
OEt
7d, 99%
7e, 96%
O
R2
O
O
O
O
Cl
MeO
O
O
A
B
C
D
Br
O
O
Me
OMe
F
E
Scheme 2 Synthesis of the cyclization precursors
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

D
S.-H. Yang et al.
Letter
Synlett
strates 4 were successfully cyclized to ethyl 1,2,3,4-tetrahy-
dro-2-oxo-4-phenylquinoline-3-carboxylate (3) in good to
excellent yields.25 However, in the case of benzo[d][1,3]di-
oxole compounds (Table 2, entries 7–11), a prolonged reac-
tion time produced traces of the dealkylated products. Fi-
nally, conversion of 3,4-dihydro-2-quinolones 3 to 2-quino-
lones 2 in the presence of DDQ was achieved in high yields.
In the case of the dimethoxycarbamoyl substrates, the
product yields were particularly sensitive to the reaction
times employed. Due to the nature of the aluminum chlo-
ride catalyst, cleavage of the methylether bond to give the
demethylated product was possible, and as such, a long re-
action time delivered a mixture of cyclized, demethylated,
and fully aromatized compounds. It was therefore neces-
sary to optimize the reaction time based on each substrate
employed. For example, as shown in Scheme 3, phenylacry-
late was rapidly converted into the cyclized compound
within 10 minutes (84% yield), while 4-chlorophenylacry-
late was cyclized over 30 minutes in 80% yield. Moreover,
after 1 hour, 4-methylphenylacrylate produced both the cy-
clized compound (75%) and the fully aromatized product
(22%).
In the course of this optimization study, it is observed
that prolonged reaction time delivered some amount of ful-
ly aromatized products. With expectation of one-step pro-
cess to aromatized products from acyclic precursors, we
tried cyclization reaction with three different substrates
under the same conditions of AlCl3 (2.0 equiv), nitroben-
zene, 80 °C, and long reaction time of 12 hours, and the re-
sults are presented in Scheme 4. The results were depen-
dent on the substrates. In case of phenycarbamoyl and 4-
chlorophenlcarbamoyl, the desired product was achieved in
moderate to high yield (80% and 50%, respectively), while 4-
methoxylphenylcarbamoyl was degraded in long reaction
time. Thus, considering the overall results, we concluded
that two-step reaction is more reliable and high-yielding.
We herein reported an efficient approach for the prepa-
ration of 4-aryl-2-quinolones. Such a synthetic route is of
particular interest due to the chemical and medicinal im-
portance of these compounds. Starting from commercially
available anilines, 2-(carbamoyl)-3-phenylacrylates were
prepared and subjected to AlCl3-mediated cyclization reac-
tions. Subsequent oxidation in the presence of DDQ provid-
ed the desired substituted 2-quinolones in high yields. This
method has a number of advantages over previous routes
Table 2 Effect of Different Aromatic Substituents on the Cyclization and Aromatization Reactions26
H
N
H
N
H
N
O
O
O
R1
R1
R1
AlCl3 (2.0 equiv)
O
O
O
DDQ
nitrobenzene
80 °C, 3 h
OEt
R2
OEt
R2
OEt
R2
3
2
4
Entry
R1
R2
Yield of 3 (%)a
Yield of 2 (%)a
1
2
H
H
3aA 98
3aB 95
3aC 75
3aF 91
3bA 77
3bE 83
3cA 89
3cB 90
3cC 70
3cD 85
3cE 82
3dA 91
3dB 90
3dC 81
3dE 88
2aA 83
2aB 95
2aC 78
2aF 80
2bA 86
2bE 82
2cA 88
2cB 80
2cC 83
2cD 89
2cE 87
2dA 85
2dB 92
2dC 87
2dE 83
H
H
H
4-Cl
3
3-OCH2O-4
5-Br-2-MeO
H
4
5
3-OCH2O-4
3-OCH2O-4
4-MeO
4-MeO
4-MeO
4-MeO
4-MeO
4-Cl
6
4-Me
7
H
8
4-Cl
9
3-OCH2O-4
4-MeO
4-Me
10
11
12
13
14
15
H
4-Cl
4-Cl
4-Cl
3-OCH2O-4
4-Me
4-Cl
a Isolated yield.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

E
S.-H. Yang et al.
Letter
Synlett
H
H
N
MeO
MeO
N
O
MeO
MeO
O
AlCl3
CO2Et
CO2Et
nitrobenzene
80 °C, 10 min
3eA (84%)
4eA
H
N
H
N
MeO
MeO
O
MeO
MeO
O
AlCl3
CO2Et
CO2Et
nitrobenzene
80 °C, 30 min
Cl
Cl
4eB
3eB (80%)
H
N
H
N
H
N
MeO
MeO
O
MeO
MeO
O
MeO
MeO
O
AlCl3
CO2Et
CO2Et
CO2Et
+
nitrobenzene
80 °C, 1 h
Me
4eE
Me
Me
3eE (75%)
2eE (22%)
Scheme 3 Cyclization of dimethoxyphenyl substrates
H
H
Funding Information
N
O
N
O
AlCl3
O
O
Basic Science Research Program through the National Research Foun-
dation of Korea (NRF) funded by the Ministry of Education (NRF-
2015R1D1A1A01056620)
nitrobenzene
80 °C, 12 h
OEt
OEt
Bio & Medical Technology Development Program through the Nation-
al Research Foundation of Korea (NRF) (NRF-2014M3A9B6069338)
4aA
2aA (80%)
H
H
N
N
O
O
References and Notes
O
O
AlCl3
Cl
Cl
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80 °C, 12 h
OEt
OEt
4dA
2dA (50%)
H
H
N
N
O
O
O
O
AlCl3
MeO
MeO
nitrobenzene
80 °C, 12 h
OEt
OEt
4cA
2cA (<10%)
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Scheme 4 Attempted cyclization in long reaction time
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tion to improved atom economy. We therefore expect that
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(26) Synthesis of 2aB
AlCl3 (1.81 mL, 1 M solution in nitrobenzene) was slowly added
to a solution of 4aB (300 mg, 0.906 mmol) in dry nitrobenzene
(5 mL) at 0 °C. The reaction mixture was warmed to 80 °C and
stirred for 3 h. After cooling, the reaction mixture poured into
ice-water and diluted with EtOAc. The organic layer was sepa-
rated and washed with sat. NaHCO3, H2O and brine, dried over
anhydrous MgSO4, and filtered. After evaporation of volatile sol-
vents under reduced pressure, the residue was purified by silica
gel column chromatography to afford the desired product 3aB;
1
283 mg (95%), white solid. H NMR (600 MHz, CDCl3): δ = 8.93
(s, 1 H), 7.31 (t, J = 7.3 Hz, 2 H), 7.20 (q, J = 7.32 Hz, 12.3 Hz, 1 H),
7.15 (m, 2 H), 6.97 (dd, J = 2.5, 7.3 Hz, 1 H), 6.88 (q, J = 4.8, 7.3
Hz, 1 H), 6.82 (m, 1 H), 4.65 (d, J = 4.6 Hz, 1 H), 4.11 (m, 2 H),
3.82 (d, J = 4.9Hz, 1 H), 1.10 (q, J = 5.0, 7.1 Hz, 3 H) ppm. 13C NMR
(150 MHz, CDCl3): δ = 168.2, 166.8, 137.7, 136.2, 133.5, 129.2,
128.5, 124.8, 123.9, 115.9, 61.7, 54.9, 44.9, 14.0 ppm. HRMS
(ESI-TOF): m/z [M + H]+ calcd for C18H19ClNO3: 330.0891; found:
330.0895
The mixture of DDQ (257 mg, 1.14 mmol) and 3aB (250 mg,
0.760 mmol) in benzene (5 mL) was stirred for 3 h. The reaction
mixture was diluted with water and extracted with EtOAc. The
organic layer was washed with sat. NaHCO3, H2O and brine,
dried over anhydrous MgSO4, and filtered. After evaporation of
volatile solvents under reduced pressure, the residue was puri-
fied by silica gel column chromatography to afford the desired
product 2aB; 236 mg (95%), white solid. 1H NMR (600 MHz,
CDCl3): δ = 9.23 (s, 1 H), 7.56 (d, J = 8.5 Hz, 2 H), 7.33 (t, J = 8.0
Hz, 2 H), 7.12 (t, J = 7.4 Hz, 1 H), 4.26 (q, J = 7.1 Hz, 2 H), 3.47 (s,
2 H), 1.33 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (151 MHz, CDCl3):
δ = 170.0, 162.9, 137.5, 129.0, 124.6, 120.1, 62.0, 41.5, 14.1 ppm.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C18H15ClNO3: 328.0735;
found: 328.0732.
(25) Liu, X.; Zhang, Q.; Zhang, D.; Xin, X.; Zhang, R.; Zhou, F.; Dong,
D. Org. Lett. 2013, 15, 776.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F