A straight forward synthesis of 4-aryl substituted 2-quinolones via Heck reaction

Article abstract of DOI:10.1039/c4ra06284a

A variety of aryl halides have been successfully coupled with different olefins via Heck reaction in the presence of an active stimulant (Pd-NHC). An efficient one pot protocol for the easy access of structurally diverse 4-aryl-2-quinolones via domino Heck/cyclization reaction has been developed. This journal is

Full text of DOI:10.1039/c4ra06284a

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A straight forward synthesis of 4-aryl substituted 2-
quinolones via Heck reaction†
Cite this: RSC Adv., 2014, 4, 41148
Sumanta Gupta,‡ Bhaskar Ganguly‡ and Sajal Das*
Received 26th June 2014
Accepted 26th August 2014
A variety of aryl halides have been successfully coupled with different olefins via Heck reaction in the
presence of an active stimulant (Pd–NHC). An efficient one pot protocol for the easy access of
structurally diverse 4-aryl-2-quinolones via domino Heck/cyclization reaction has been developed.
DOI: 10.1039/c4ra06284a
www.rsc.org/advances
In Pd-catalyzed synthesis of 4-aryl-2-quinolones, cinnamides
are most commonly used starting compounds (Fig. 1b–d).
Introduction
The scaffold 2-quinolone is present in several natural products However, Cacchi's group for the rst time described the synthesis
1
and a wide variety of biologically active compounds. These are of 4-aryl-2-quinolones from methyl b-(o-acetamidophenyl) acry-
2
8h
well known for therapeutic value. Besides, 2-quinolones also late instead of cinnamides (Fig. 1a). But in this case, the amino
serve as crucial intermediates in numerous synthetic trans- group has to be protected before the reaction, otherwise it solely
formations. For example, these can readily be transformed into results in the unsubstituted 2-quinolone.
3
2
-(pseudo)/haloquinolines which could act as a key material
In light of these successful precedents, we anticipated that
4
for accessing structurally diverse compounds. Substituted 4- the Pd-catalyzed Heck reaction of b-(o-aminophenyl) acrylate
aryl-2-quinolone, tipifarnib is known to act as an anticancer with arylhalide followed by the intramolecular cyclization
5
agent. In addition, several synthesized products in this series would be an efficient protocol for easy access of structurally
6
7
are under clinical trial. Various strategies, both metal free
diverse 4-aryl-2-quinolones.
8,9
and metal catalyzed, are available in literature to access 2-
Very recently, we have demonstrated the benzimidazole
quinolone structural motifs. However, the metal-catalyzed based palladium-N-heterocyclic carbene (Pd–NHC) (Fig. 2) that
protocol proved to be a powerful and practical route for the effectively catalyzes the C–C cross-coupling reaction with a broad
10
synthesis of substituted 2-quinolones. Much attention has variety of substrates. In light of these achievements, herein we
been paid for the palladium catalyzed synthesis of 2-quino- address the details of Pd–NHC catalyzed Heck reaction and one-
lones. The domino Heck/Buchwald–Hartwig reaction of o-bro- pot efficient protocol for the synthesis of 4-aryl-2-quinolones.
8
b
mocinnamide with iodoarenes,
diarylacrylamides followed by intramolecular C–H amination,
carbonylative annulations of alkynes with anilines in presence
cyclization of 3,3-
8c
Result and discussion
8
d,8e
of gaseous CO, are frequently used techniques.
Very
We began our study to nd the suitable condition for Heck
cross-coupling reaction using our newly developed Pd–NHC
8
f
recently, Inamoto et al. reported the synthesis of 4-aryl-2-
quinolones via the Pd-catalyzed sequential Heck reaction and
intramolecular C–H amidation. Another alternative procedure,
the oxidative carbonylation of 2-vinylanilines was developed by
Alper's group. The ring closing metathesis (RCM) reaction of
N-phenylacrylamide, iridium catalyzed annulations of N-
8
g
9a
9b
arylcarbamoyl chloride, copper catalyzed cyclization of 3,3-
diarylacrylamides through C–H functionalization/C–N bond
9c
formation and nickel catalyzed cycloaddition of o-cyanophe-
9d
nylbenzamides with alkenes have also been reported to use
for the synthesis of functionalized 2-quinolones.
Department of Chemistry, North Bengal University, Darjeeling, 734013, India. E-mail:
sajal.das@hotmail.com; Fax: +91 353 269 9001; Tel: +91 353 277 6381
†
Electronic supplementary information (ESI) available: Spectral analysis, copies
1
13
of H and C spectra of all compounds. See DOI: 10.1039/c4ra06284a
Fig.
1
Synthesis of 4-aryl-2-quinolones via palladium catalyzed
‡
These authors contributed equally.
process.
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a
Table 2 Heck coupling of aryl halides with different olefins
Fig. 2 Pd–NHC.
c
Entry
Ar
R
X
Product
Yield (%)
1
2
3
4
5
6
7
8
9
4-OCH
4-OCH
4-OCH
3
3
3
–C
–C
–C
6
6
6
H
H
H
5
5
5
CO
CN
Ph
2
C
4
H
9
I
I
I
I
I
I
I
I
I
I
I
I
Br
Br
Br
Br
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1c
1m
1n
1o
91
93
94
90
97
94
95
95
98
93
96
98
86
89
76
87
catalyst. 4-iodoanisole and n-butyl acrylate were selected as the
model coupling partners to screen the best reaction condition.
The detailed optimization results in respect of solvents and
bases are given in Table 1. The results clearly showed that, the
reaction responded well both in organic solvents as well as in
water. But the combination of DMF as solvent and triethylamine
as base, was proved to be the best suited condition in the
present study as it led to the desired coupled product in 91%
yield upon isolation (Table 1, Entry-6). Notably, 1 mol% of
4-CH
3
–C
6
H
5
CO
CO
Ph
2
C
C
4
H
H
9
2-F–C
6
H
5
2
2
5
4-Cl–C
6
H
5
2-CH –C H
3
6
5
CN
CO
CO
CO
CO
CO
Ph
2-NH
1-Naphthyl
2-OH–C
3-CH –C
3-OCH –C
2
–C
6
H
5
2
2
2
2
2
CH
3
C
4
C
2
C
4
H
9
H
5
H
9
1
1
1
0
1
2
6
H
5
3
6
H
5
3
6
H
5
CH
3
b
b
b
b
Pd–NHC catalyst was sufficient to catalyze the coupling reaction 13
4-OCH –C H
3
6
5
1
1
1
4
5
6
4-F–C
6
H
5
Ph
Ph
Ph
effectively.
With this optimized condition in hand, we turned our
interest to carry out the Heck reaction of different aryl halides
with various olens and the corresponding results are pre-
sented in Table 2.
4-COCH
4-CN–C
3
–C
6
H
5
6
H
5
a
Reaction conditions: aryl halides (1 mmol), substituted alkenes (1.5
ꢀ
mmol), Et
3
N (2 mmol), Pd–NHC (1 mol%, 0.0096 g), DMF, 90 C, 4 h.
b
ꢀ
c
K
2
CO
3
used instead of Et
3
N, 130 C, 6 h. Isolated yield aer
The results showed that aryl halides bearing electron with- column chromatography.
drawing and donating groups worked well under this optimized
condition and leading to the corresponding products in excel-
lent yield. Butylacrylate, acrylonitrile as well as styrene were groups such as –NH , –OH (Table 2, Entry-8 and 10) were
2
efficiently participating in cross-coupling reaction with 4- resulting in the high yields of the coupled product. No side
iodoanisole and resulted in the desired coupled products in product was detected in those cases. 1-iodonaphthalene
91%, 93% and 94% yields (Table 2, Entry-1, 2 and 3) respectively coupled with butylacrylate furnished the desired product in
upon isolation. Comparatively sterically hindered aryl halides 98% yield (Table 2, Entry-9). 3-substituted aryliodides were
also underwent the reaction smoothly to furnish the desired subjected to Heck reaction and desired coupled products were
coupled products in high yields (Table 2, Entry-5,7,8 and 10). On obtained in high yields (Table 2, Entry-11 and 12).
the other hand, aryl moieties containing sensitive functional
Aer successful completion of the Heck coupling reaction
with aryliodides, we then explored the possibility to apply this
technique in case of arylbromides. Accordingly, we attempted
the Heck reaction between 4-bromoanisole and styrene at our
optimized condition but the isolated yield of the desired
coupled product was not satisfactory (Table S1†, Entry-1). Then
Table 1 Optimization studies of reaction condition in Heck coupling
a
between 4-iodoanisole and n-butyl acrylate
we improved the reaction condition and it was found that at 130
ꢀ
2 3
C for 6 h in presence of K CO , arylbromides were smoothly
participating in the coupling reaction. Under this optimized
condition various arylbromides were subjected to Heck
coupling reaction with styrene (Table 2, Entry-13 to 16). Both the
electron rich and electron decient arylbromides were smoothly
coupled with styrene and the corresponding desired coupled
products were isolated in high yields (Table 2, Entry-13 to 16).
Several sensitive groups such as –CN, –COCH remain intact
3
under this reaction condition and results in the high yields of
the cross coupled products.
Pd–NHC
Temperature (mol%)
b
Entry Solvent
Base
Yield (%)
ꢀ
1
2
3
4
6
7
8
DMSO/H
Acetone/H
EtOH/H
2
O
K
2
K
2
K
2
K
2
CO
CO
CO
CO
3
3
3
3
90 C
2
2
2
2
1
1
1
71
66
39
69
91
81
83
ꢀ
2
O
70 C
ꢀ
2
O
90 C
c
ꢀ
H
2
O
90 C
ꢀ
DMF
DMSO
DMF
Et
Et
3
N
N
90 C
Aer that we turned to our main objective i.e. the synthesis of
ꢀ
3
90 C
4-aryl-2-quinolones (Scheme 1). Synthesis of 4-aryl-2-quinolones
ꢀ
K
2
CO
3
90 C
from the Heck coupled product methyl b-(o-aminophenyl)
acrylate (1h) is a two step process viz. Heck cross coupling and
cyclization reaction. We attempted to carry out both the reaction
in one pot. Aer completion of Heck reaction between
a
Reaction conditions: 4-iodoanisole (1 mmol), n-butylacrylate (1.5
b
mmol), base (2 mmol). Isolated yield aer column chromatography.
c
2
mmol TBAB was added.
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pot protocol for the synthesis of the valuable 4-aryl-2-quinolone
moieties. The process stands good with a range of arylhalides
including electron decient, electron rich as well as sterically
hindered entities.
Experimental
General methods
Unless stated otherwise, all reagents such as aryl halides,
potassium carbonate, triethylamine, alkenes, and solvents were
used as received from commercial suppliers. NMR spectra were
recorded on 300 MHz spectrometer at 298 K and calibrations
were done on the basis of solvent residual peak. Products were
isolated using column chromatography on silica gel (60–120
mesh) and a mixture of petroleum ether (60–80 C)/ethyl acetate
was used as an eluent. Reaction progress was monitored by
silica gel TLC.
Scheme 1 Synthesis of 4-aryl-2-quinolone.
ꢀ
a
Table 3 4-aryl-2-quinolones 2a–g produced via Scheme 1
b
Entry
R
Product
Yield (%)
1
2
3
4
5
6
7
4-OCH
3
2a
2b
2c
2d
2e
2f
75
72
71
64
61
67
65
General procedure for Heck reaction
4-CH
3-CH
3
A mixture of aryl halide (1 mmol), alkene (1.5 mmol), base (2
mmol Et N for aryliodides and 2 mmol K CO for aryl-
3 2 3
3
3-OCH
2-OCH
3
bromides), Pd–NHC (1 mol%, 0.0096 g) and 3 mL DMF were
taken in a 25 mL round bottom ask and the mixture was placed
3
2-CH
4-Cl
3
2g
ꢀ
ꢀ
in a preheated oil bath at 90 C for 4 h (at 130 C for 6 h in case
a
Reaction conditions: 1h (1 mmol), aryliodide (1.2 mmol), Et
3
N (2 of arylbromides). Then the reaction mixture was diluted with
ꢀ
b
mmol), Pd–NHC (2 mol%, 0.0192 g), DMF, 110 C, 20 h. Isolated
yield aer column chromatography.
water and extracted with DCM (3 Â 10 mL). The combined
organic layer was dried over anhydrous Na SO and concen-
2
4
trated under reduced pressure. The crude residue was puried
by silica gel column chromatography.
2
4
-iodoaniline and methyl acrylate, 1.2 equivalent amount of
-iodoanisole was added into it. Then the resulting reaction
ꢀ
General procedure for the synthesis of 4-aryl-2-quinolones (2)
mixture was further heated at 90 C and aer 20 h only 15% yield
of the corresponding cyclized product (2a) was obtained. While A mixture of 1h (1 mmol, 0.177 g), aryliodide (1.2 mmol), Et N (2
3
attempting the cyclization step under the same reaction condi- mmol, 0.202 g) and Pd–NHC (2 mol%) were taken in a 25 mL
tion from the pure intermediate (1h), we obtained only 36% yield round bottom ask. Then 3 mL DMF was added into it and the
ꢀ
of the cyclized compound (2a) upon isolation. Further, we mixture was stirred for 20 h at 110 C. Aer cooling to room
enhanced the reaction temperature and carried out the cycliza- temperature, the reaction mixture was diluted with DCM and
ꢀ
ꢀ
2 4
tion step at 100 C and 110 C which resulted in the 4-aryl-2- washed with water. The organic layer was dried over Na SO and
quinolone (2a) in 52% and 75% yield respectively. Very delight- concentrated under reduced pressure. The residue was puried
fully, we then applied this protocol with different aryliodides for by column chromatography.
accessing of structurally diverse 4-aryl-2-quinolones (Table 3).
It was found from the results that aryliodides were efficiently
participating in the reaction and resulted in the good yield of
Acknowledgements
the corresponding 4-aryl-2-quinolones. A marginal difference in
yield of the nal product was observed for electron donating
and withdrawing groups present in the aryl moiety. A little drop
We thank the Council of Scientic and Industrial Research, New
Delhi for nancial support (02(0022)/11/EMR-II). S.G. is thank-
ful to UGC for the award of fellowship.
3 3
in yield in case of o-OCH /–CH might be attributed to the steric
effect. Electron decient 4-chloroiodobenzene productively
participating in the reaction to form the desired 4-(4-chloro-
phenyl) quinolin-2(1H)-one (2g) in 65% yield and notably chloro
atom is well tolerated under this reaction condition.
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