A novel and facile synthesis of 4-arylquinolin-2(1H)-ones under metal-free conditions

Article abstract of DOI:10.1016/j.cclet.2015.05.008

Abstract A novel and facile synthesis of 4-arylquinolin-2(1H)-ones without metal catalysis has been developed. This reaction involved cyclization/elimination steps and was performed under metal-free conditions using inexpensive reagents such as NaI, selec

Full text of DOI:10.1016/j.cclet.2015.05.008

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CCLET-3312; No. of Pages 3
Chinese Chemical Letters xxx (2015) xxx–xxx
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Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
A novel and facile synthesis of 4-arylquinolin-2(1H)-ones under
metal-free conditions
*
*
Bin Sun, Wen-Peng Mai , Liang-Ru Yang, Pu Mao , Jin-Wei Yuan, Yong-Mei Xiao
School of Chemistry and Chemical Engineering, Henan University of Technology, Henan 450001, China
A R T I C L E I N F O
A B S T R A C T
Article history:
A novel and facile synthesis of 4-arylquinolin-2(1H)-ones without metal catalysis has been developed.
This reaction involved cyclization/elimination steps and was performed under metal-free conditions
using inexpensive reagents such as NaI, selectfluor and KOH.
Received 4 March 2015
Received in revised form 13 April 2015
Accepted 20 April 2015
Available online xxx
ß 2015 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Keywords:
4-Arylquinolin-2(1H)-one
Metal-free
Selectfluor
Synthesis
1. Introduction
2-quinolin-2(1H)-one [9], we focused on silver-catalyzed radical
tandem cyclization reactions. Herein, we wish to report a semi-
The scaffold of quinolin-2(1H)-one is an outstanding structural
motif found in many natural products and pharmaceutically active
compounds [1]. In particular, the derivatives of 4-arylquinolinones
have attracted considerable attention in organic chemistry due to
their anticancer, antiviral, antibiotic and other activities [2]. Many
analogs of this type of heterocyclic compounds have been
developed as the lead compounds or clinical candidates [3]. Thus,
the synthesis of these valuable compounds has attracted a great
deal of interest (Fig. 1).
one-pot synthesis of 4-arylquinolinones (Scheme 1).
2. Experimental
All reagents were used directly as obtained commercially or
after purification. Column chromatography was performed using
silica gel (300–400 mesh) and analytical TLC used silica 60-F24.
1H NMR and 13C NMR spectra were collected in CDCl3 on a Bruker
Fourier 400 MHz spectrometer and chemical shifts (d) were
Many strategies have been used in the synthesis of quinolin-
2(1H)-one derivatives including classic base-catalyzed Friedla¨nder
condensation or acid-catalyzed Knorr and Baylis–Hillman reac-
tions [4], palladium-catalyzed carbonylative annulation of alkynes
with 2-iodoanilines and CO [5], metal-catalyzed carbonylative
annulation of internal alkynes [6], palladium-catalyzed tandem
cyclization of 2-bromocinnamami-des and aryl iodides [7],
Ir-catalyzed annulation of N-arylcarba-moyl chlorides with inter-
nal alkynes [8]. However, some of these procedures needed strong
acids and the others were carried out in the presence of noble
metals. Nonmetal-catalyzed syntheses of 4-aryl-2-quinolinones
remain rare. During our previous work for the synthesis of
reported relative to the internal TMS. The substrate 1 was prepared
through a short sequence (Scheme 1). A 50 mL anhydrous flask was
charged with magnetic stir bar, cinnamic acid (5 mmol) and SOCl2
(5 mL). After stirring at 60 8C for 3 h, the redundant SOCl2 was
evaporated under reduced pressure and then the liquid was
dropwise added into another flask containing N-methylaniline
(10 mmol) in anhydrous CH2Cl2 (20 mL). The mixture was stirred
for 1 h at room temperature. The organic phase was then washed
by aqueous HCl and aqueous K2CO3, then dried over anhydrous
Na2SO4. After evaporating the CH2Cl2, the N-methyl-N-phenylcin-
namamide was obtained as a pale yellow solid in 97% yield. The
yield is almost quantitative and we used it without further
purifications.
Substrate 1: Pale yellow solid, 1H NMR (400 MHz, CDCl3):
d 7.70
(d, 1H, J = 16.0 Hz), 7.45 (dt, 2H, J = 6.4, 1.2 Hz), 7.36–7.38 (m, 1H),
7.22–7.32 (m, 7H, overlapping CDCl3), 6.39 (d, 1H, J = 16.0 Hz), 3.42
(s, 3H). 13C NMR (100 MHz, CDCl3):
d 166.17, 143.66, 141.70,
*
Corresponding authors.
E-mail addresses: maiwp@yahoo.com (W.-P. Mai),
maopu@haut.edu.cn (P. Mao).
http://dx.doi.org/10.1016/j.cclet.2015.05.008
1001-8417/ß 2015 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: B. Sun, et al., A novel and facile synthesis of 4-arylquinolin-2(1H)-ones under metal-free conditions,
Chin. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.05.008

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CCLET-3312; No. of Pages 3
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B. Sun et al. / Chinese Chemical Letters xxx (2015) xxx–xxx
performed at 100 8C, but the results did not improve (Table 1,
entry 12). For the step 2, the reaction did not occur using DCE as a
solvent (Table 1, entry 13).
After screening the reaction conditions, the substrates testing
were carried out subsequently. As shown in Fig. 2, the N-alkyl-
N-arylcinnamamides bearing electron-donating or electron-
withdrawing groups on the phenyl ring A at the ortho, meta,
and para positions are all reactive in the reaction, the
corresponding products were obtained in moderate yields
(Fig. 2, 2–4, 12–13). Different substituents such as OMe, Br, Cl,
F and Me could be tolerated in the catalytic processes. It is worth
noting that halogen atoms (F, Cl, and Br) were well tolerated
under the conditions, enabling further functionalization of the
corresponding quinolin-2(1H)-ones at the halogenated positions
using palladium-catalyzed cross-coupling reactions.
Fig. 1. Some representative compounds containing the 4-arylquinolinone.
In addition, switching the N-protecting group of the substrate to
Et or n-Bu, the reaction still proceeded well (Fig. 2, 5 and 11).
Unfortunately, substituents such as F and Cl at the ortho or para
position of aniline (phenyl ring B) affect the efficiency of the
reaction dramatically and only a trace amount of products was
observed. The NO2 group at the para position of aniline completely
shut down the reaction. However, the reaction could proceed when
a methyl group is at the para position of the aniline and 38%
product was obtained (Fig. 2, 8).
Scheme 1. Semi-one-pot synthesis of 4-arylquinolinones.
135.22, 129.63, 129.49, 128.68, 127.85, 127.59, 127.35, 118.76,
37.58.
Based on the previous work which described the oxidation of
iodide to iodine cation [10], a mechanism for the cyclization/
elimination processes has been proposed (Scheme 2). At first,
the iodine anion was oxidized to iodine cation by selectfluor.
Then I+ is attacked by the electron-rich double bond of
N-methyl-N-phenyl-cinnamamide (1) to form intermediate 2.
After that, the iodinium ion undergoes nucleophilic attack by
phenyl ring to form the six-membered ring. Finally, compound 3
eliminate hydroiodic acid under basic condition to produce
compound 4.
3. Results and discussion
N-Methyl-N-phenylcinnamamide 1 was selected for screening
the optimal reaction conditions (Scheme 1, Eq. 2).
The substrate 1 and 1.0 equiv. of NaI were added to a flask,
then 2.0 equiv. of selectfluor and 5 mL of CH3CN were added, the
reaction proceeded at 70 8C for 6 h, after that, the solvent was
evaporated and 1.0 equiv. of KOH, 3 mL of EtOH were added to
the residue, the mixture was subsequently stirred at 70 8C for 2 h,
the desired product was obtained in 35% yield (Table 1, entry 1).
Changing the solvent to dichloroethane (DCE), the desired
product could be obtained in 55% yield after two steps
(Table 1, entry 5). However, other solvents such as dioxane,
acetone and CH2Cl2 were not favorable for this transformation
(Table 1, entries 2–4). Different oxidants such as DTBP, K2S2O8
and PhI(OAc)2 were also examined under the same conditions
(Table 1, entries 9–11), only PhI(OAc)2 showed measurable
catalytic effect (Table 1, entry 11). The reaction was also
Table 1
Optimization of the reaction.
Entry
Step 1
Step 2
Total
yield (%)a
Solvent
Temp (8C)
Oxidant
Solvent
1
2
CH3CN
Dioxane
Acetone
CH2Cl2
DCE
70
70
70
70
70
70
70
70
70
70
70
100
70
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
DTBP
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
DCE
35
0
3
Traceb
Traceb
55
4
5
6
Toluene
DMF
0
7
Traceb
0
8
DMSO
DCE
9
Traceb
0
10
11
12
13
DCE
K2S2O8
DCE
PhI(OAc)2/I2
Selectfluor
Selectfluor
<10b
50
DCE
DCE
Traceb
a
Isolated yield after two steps.
The yield of step 2.
Fig. 2. Structures of synthesized 4-arylquinoline-2(1H)-ones with isolated yield
b
after two steps.
Please cite this article in press as: B. Sun, et al., A novel and facile synthesis of 4-arylquinolin-2(1H)-ones under metal-free conditions,
Chin. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.05.008

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3
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4. Conclusion
In conclusion, we have developed a novel approach for the
convenient synthesis of 4-arylquinolin-2(1H)-ones under metal-
free conditions. This transformation represents a novel and facile
method for the construction of quinolin-2(1H)-one motif without
metal catalysis. A mechanism has also been proposed for this
transformation.
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Acknowledgments
This work was financially supported by the National Natural
Science Foundation of China (Nos. 21302042 and 21172055),
the Program for Innovative Research Team from Zhengzhou
(No. 131P-CXTD605), and the Plan for Scientific Innovation Talent
of Henan University of Technology (No. 171147)
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Appendix A. Supplementary data
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Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.cclet.2015.05.008.
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Please cite this article in press as: B. Sun, et al., A novel and facile synthesis of 4-arylquinolin-2(1H)-ones under metal-free conditions,
Chin. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.05.008