Palladium-catalyzed arylation/cyclization/desulfonation cascades toward 4-aryl quinolin-2(1H)-ones with diaryliodonium salts

Article abstract of DOI:10.1016/j.tetlet.2017.07.065

Palladium-catalyzed cascades of arylation/cyclization/desulfonation of ortho-aminocinnamate esters by using diaryliodonium salts afforded a wide range of 4-aryl quinolin-2(1H)-ones. As such, the desired 4-aryl quinolin-2(1H)-ones with potential biological activity has been synthesized in the yields of 34–96%.

Full text of DOI:10.1016/j.tetlet.2017.07.065

Accepted Manuscript
Palladium-Catalyzed Arylation/Cyclization/Desulfonation Cascades toward 4-
Aryl Quinolin-2(1H)-ones with Diaryliodonium Salts
Jianwei Han, Xunshen Wu, Zhiang Zhang, Limin Wang
PII:
S0040-4039(17)30920-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.07.065
TETL 49147
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
9 June 2017
11 July 2017
18 July 2017
Please cite this article as: Han, J., Wu, X., Zhang, Z., Wang, L., Palladium-Catalyzed Arylation/Cyclization/
Desulfonation Cascades toward 4-Aryl Quinolin-2(1H)-ones with Diaryliodonium Salts, Tetrahedron Letters
(2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.07.065
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Palladium-Catalyzed Arylation/Cyclization/Desulfonation
Cascades toward 4-Aryl Quinolin-2(1H)-ones with
Diaryliodonium Salts
Leave this area blank for abstract info.
Jianwei Han,*a, b Xunshen Wu,a Zhiang Zhang, a and Limin Wang*a
a130 Meilong Road, Shanghai 200237, P. R. China
b345 Ling Ling Road, Shanghai 200237, P. R. China

1
Tetrahedron Letters
Palladium-Catalyzed Arylation/Cyclization/Desulfonation Cascades toward 4-Aryl Quinolin-2(1H)-ones
with Diaryliodonium Salts
Jianwei Han,*[a, b] Xunshen Wu,[a] Zhiang Zhang, [a] and Limin Wang*[a]
aKey Laboratory for Advanced Materials, Institute of Fine Chemicals, School of Chemistry & Molecular Engineering, East China University of Science and
Technology, 130 Meilong Road, Shanghai 200237, P. R. China
bShanghai-Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry, The Chinese Academy of Sciences, 345 Ling Ling
Road, Shanghai 200032, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Palladium-catalyzed cascades of arylation/cyclization/desulfonation of ortho-aminocinnamate
esters by using diaryliodonium salts afforded a wide range of 4-aryl quinolin-2(1H)-ones. As
such, the desired 4-aryl quinolin-2(1H)-ones with potential biological activity has been
synthesized in the yields of 34-96%.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Arylation
Cyclization
Diaryliodonium salt
4-Aryl quinolin-2(1H)-ones
 Limin Wang. Tel.: +86-021-64253881; e-mail: wanglimin@ecust.edu.cn
 Jianwei Han. Tel.: +86-021-64253040; e-mail: jianweihan@ecust.edu.cn

2
Tetrahedron Letters
reaction (Table 1). According to the conditions of our previous
arylation/cyclization of cinnamate ester,[6] the procedure also used DMF
(dimethylformamide) as solvent in the presence of 10 mol% Pd(OAc)2 as
1. Introduction
4-Aryl quinolin-2(1H)-ones are valuable class of biologically active
substances in pharmaceutical research, such as HBV inhibitor (A, Figure
1), Viridicatin (B, Figure 1), Tipifamib (C, Figure 1) and an efficient
maxi-K opener (D, Figure 1) to elicit penile erection with a novel
mechanism for the treatment of male erectile function.[1] In light of their
synthesis, various synthetic methods towards 4-aryl quinolin-2(1H)-ones
were documented.[2] The condensation of 2-acetamidobenzaldehydes, the
cyclization of cinnamanilides or N-aryl amides of 3-arylpropynoic acids
under the action of strong acids or transition-metal catalysts have been
developed to access 4-aryl 2-quinolinone structural motifs.[3] Noteworthy
reports are transition-metal catalysed cyclization of cascades, which
provided a more efficient and practical route. [4]
o
catalyst at 110 C，it was pleased to find that the desired product of 3a
was obtained in 81% yield (Table 1, entry 1). Interestingly, the tosyl
group was cleaved off by a desulfonation reaction in one pot under the
reaction conditions. The reaction does not work without palladium
catalyst, and no product was observed by thin-layer chromatography
when copper catalysts of CuI and Cu(OTf)2 or nickel complex of
Ni(dppp)Cl2 as catalyst were employed in this reaction (Table 1, entries
2-5).
Table 1. Screening of Reaction Conditions for Synthesis of 4-Aryl
Quinolin-2(1H)-ones.[a]
X-
Solvent
Loading
(mol %)
Yield
(%) [b]
Entry
Cat.
1
2
Pd(OAc)2
--
10
10
10
10
10
10
10
5
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
BF4
OTs
PF6
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
DCE
81
0
Figure 1. Selective samples of 4-arylcoumarin derivatives.
Recently, diaryliodonium salts (Ar2I+X-) were well studied in the
electrophilic arylations due to their excellent reactivity.[5] By using
Ar2I+X-, we reported in 2015 that arylation/cyclization of ortho-
hydroxylcinnamates by palladium catalysis afforded 4-arylcoumarin
derivatives in good yields.[6] In a similar pattern, (E)-ethyl 3-(2-
aminophenyl)-acrylate was also employed in this protocol; however,
only nitrogen-arylated product was furnished without cyclization to give
4-arylquinolinone (1, Scheme 1). Of note, concurrently Kumar and co-
workers reported a microwave-assisted oxygen-arylation of quinolones
with diaryliodonium salts in the presence of a base, aryloxyquinolines
were furnished in good yields (2, Scheme 1). [7]
3
CuI
0
4
Cu(OTf)2
Cu(OAc)2
PdCl2
0
5
0
6
88
91
93
75
59
0
7
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
8
9
1
10
11
12
13
14
15[c]
16
17
18
19
20[d]
5
5
5
NMP
Dioxane
MeCN
DMF
DMF
DMF
DMF
DMF
DMF
48
trace
trace
96
90
75
86
trace
0
5
5
5
5
5
5
Scheme 1. Reactions towards 4-arylquinolines by using diaryliodonium
salts.
5
Br
5
PhI
In principle, diaryliodonium salts were tended to oxyphilic arylations
or N-arylations of arylamines under a basic reaction medium.[5] We
reasoned that modification of amine group of ethyl 3-(2-aminophenyl)-
acrylate to reduce the basicity of arylamine by using a tosyl group, in
which the reactivity of ArNHTs was allowed to undergo the cyclization
process without N-arylative attack, therefore producing 4-aryl quinolin-
2(1H)-ones (3, Scheme 1). Herein, we reported in detail the cascades of
arylation/cyclization/desulfonation in the presence of palladium catalysts
by using diaryliodonium salts.
[a] Reaction conditions: 1a (0.5 mmol), 2a (1 mmol), catalyst, and solvents (2 mL) at
110 oC for 12 h. [b] Isolated yield. [c] The reaction temperature was 120 oC. [d]
Iodobenzene was used in place of 2a.
The evaluation of the activity of palladium catalysts showed that 5
mol% Pd(PPh3)4 gives the best yield of 93% (Table 1, entries 6-9). The
examination of the solvent effect with experiments performed in
dimethylsulfoxide, dichloroethane, N-methyl pyrrolidinone, acetonitrile,
dioxane and N, N-dimethyl formamide suggested that DMF as solvent is
the best choice (Table 1, entries 8 and 10-14). Reaction temperature and
reaction time were also examined, the temperature of 120 oC and the
reaction time of 12 hours were found to be the optimal to give the highest
yield of 96% (Table 1, entry 15). The influence of counter-anions of
2. Results and Discussion
At the outset of the study, palladium-catalyzed arylative cyclization
cascade of ethyl (E)-3-(2-((4-methylphenyl) sulfonamido)phenyl)acrylate
1a with diphenyliodonium triflate 2a was investigated as a model

3
diaryliodonium salts was studied, the results showed that OTf performs
better than other counter-anions (BF4, OTs, and PF6), the
diphenyliodonium bromide only gave a trace amount of desired product
of 3a (Table 1, entries 8, 16-19). It is a remarkable fact that when
iodobenzene was used in replacement of diphenyliodoniums, no reaction
occurred under the standard conditions (Table 1, entry 20).
Additionally, unsymmetrical aryl-mesity iodonium salts 2m-2o were
also employed, we were delighted to find that aryl-mesityl iodonium
salts transferred the aryl group to furnish the corresponding products
3ma-3oa in good yields of 48-79% (Table 3, entry 13-15).
Table 3. One-pot synthesis of 4-aryl quinolin-2(1H)-ones
3
from various
diaryliodonium salts 2. [a, b]
With the optimized conditions in hand, the substrate scope of this
palladium-catalyzed process was then explored with a range of substrates
1. To explain our proposal of rendering reactivity by modification of
amine group with a tosyl group, other electron-withdrawing groups on
the amine group of 3-(2-aminophenyl)acrylic ester were attempted. As
shown in table 2, we found that 1b-c with benzoyl and acetyl (R3) can
also undergo the cyclization process to produce 3aa in moderate yields
of 68% and 34%, respectively (Table 2, entries 1-2). However, substrate
1 with trifluoroacetyl as a leaving group didnot afford the product of 3aa
(Table 2, entry 3). Regarding the cyclization step of intramolecular
amidation of esters with arylamines, the cascade reactions of substrates 1
with different ester groups of methyl, n-butyl, tert-butyl and
cyclopententyl took place smoothly, giving the desired product 3aa in
good yields of 57-85% (Table 2, entries 4-7). Additionally, to further
probe the scope of this reaction, three examples of aryl-substituted
derivatives of 1 were employed under the established conditions with
diphenyliodonium triflate (2a), the reaction gave the corresponding 4-
aryl quinolin-2(1H)-ones 3ab-3ad bearing chloride, fluorine or methyl
group in 86%, 77%, and 84%, respectively (Table 2, entries 8-10).
Entry
2
X
Ar1
Ar2
Produc
t
Yield(%)
1
2
2a
2b
2c
2d
2e
2f
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
PF6
C6H5
4-BrC6H4
4-ClC6H4
4-FC6H4
4-tBuC6H4
4-MeOC6H4
4-MeC6H4
3-MeC6H4
3-NO2C6H4
4-CF3C6H4
3-FC6H4
C6H5
3aa
3ba
3ca
3da
3ea
3fa
96
90
4-BrC6H4
4-ClC6H4
4-FC6H4
3
73
4
83
5
4-tBuC6H4
4-MeOC6H4
4-MeC6H4
3-MeC6H4
3-NO2C6H4
4-CF3C6H4
3-FC6H4
94
6
81
7
2g
2h
2i
3ga
3ha
3ia
74
8
78
9
62
10
11
12
13
14
15
2j
BF4
OTf
OTf
OTf
OTf
OTf
3ja
60
2k
2l
3ka
3la
72
Table 2. One-pot synthesis of 4-aryl quinolin-2(1H)-ones
3
from various
Mesityl
Mesityl
Trace
51
cinnamate esters 1 [a, b]
2m
2n
2o
Mesityl
4-CF3OC6H4
4-BrC6H4
4-CO2EtC6H4
3ma
3ba
3oa
Mesityl
79
Mesityl
48
a] 1a (0.5 mmol), 2 (1 mmol), Pd(PPh3)4 (0.025 mmol), and DMF (2 mL) at 120 oC for
12 h. [b] Isolated yield.
3. Conclusion
Entry
R1
H
R2
-Et
R3
-COC6H5
-COCH3
-COCF3
Ts
Product
Yield(%)
68
In summary, we have developed
a novel palladium-catalyzed
1
2
3aa
3aa
3aa
3aa
3aa
3aa
3aa
3ab
3ac
3ad
arylation/cyclization/desulfonation of ortho-aminocinnamate ester
derivatives by using diaryliodonium salts, which afforded 4-aryl
quinolin-2(1H)-ones in good to excellent yields (up to 96% yield). This
cascade of arylation/cyclization/desulfonation process exhibited good
substrate scope and functional group tolerance and low catalytic loading
of tetrakis- (triphenylphosphine)palladium. Furthermore, the products of
4-aryl quinolin-2(1H)-ones produced by this procedure may have
potential applications in pharmaceutical research.
H
-CH2CH3
-CH2CH3
-CH3
-nC4H9
-tC4H9
34
3
H
0
4
H
85
5
H
Ts
80
6
H
Ts
57
7
H
-cyclopentyl
-CH2CH3
-CH2CH3
-CH2CH3
Ts
72
8
4-Cl
4-F
4-CH3
Ts
86
9
Ts
77
Acknowledgments
10
Ts
84
[a] 1 (0.5 mmol), 2a (1 mmol), Pd(PPh3)4 (0.025 mmol), and DMF (2 mL) at 120 oC for
The work was supported by the National Nature Science Foundation of
China (NSFC 21472213, 21272069), National Key Program
(2016YFA0200302, Study on application and preparation of aroma
nanocomposites) and the Fundamental Research Funds for the Central
Universities, Key Laboratory of Organofluorine Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences.
12 h. [b] Isolated yield.
Subsequently, the reactions of Pd-catalyzed cyclized cascade of ethyl
(E)-3-(2-((4-methylphenyl)sulfonamido)phenyl)acrylate 1a with various
diaryliodonium salts 2 were examined. As shown in Table 3, a number of
substituted symmetrical diaryliodonium triflates regardless of the
electronic nature of the substituents, such as di-(4-bromophenyl)-
iodonium triflate, di-(4-chlorophenyl)-iodonium triflate, di-(4-
fluorophenyl)-iodonium triflate, di-(4-tertbutylphenyl)-iodonium triflate,
di-(4-methoxyphenyl)-iodonium triflate, di-(4-methylphenyl)-iodonium
triflate, and di-(4-trifluoromethylphenyl)-iodonium triflate, reacted
efficiently with 1a to afford the desired products 3aa-3ja in good yields
(Table 3, entries 2-10). However, it was found that the electronic
properties of aryl group of diaryliodonium salts affected reaction
efficiency. For example, diaryliodonium salts with electron-donating (4-
Me, 3-Me, 4-OMe, 4-tBu) groups gave good to excellent yields (Table 3,
74-94%, entries 5-8). However, the diaryliodonium salts with electron-
withdrawing groups (3-NO2, 4-CF3) only gave moderate yields (Table 3,
60-62%, entries 9, 10). Steric factor severely affected the reactivity, bis-
(2,4,6-trimethylphenyl)-iodonium triflate (2l) only gave a trace amount
of the product which can not be isolated with column chromatography.
References and notes
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5
Highlights



Palladium-catalyzed arylative
cascades of ortho-aminocinnamate
esters is developed.
4-Aryl quinolin-2(1H)-ones were
synthesized in good to excellent
yields.
Diaryliodonium salts was used as
efficient arylating reagents.