Palladium-catalyzed C(sp3)-H arylation of benzo[b]thiophen-3(2H)-one 1,1-Dioxide

Article abstract of DOI:10.1155/2019/5032325

A new concise synthesis route of 2-phenylbenzo[b]thiophen-3(2H)-one 1,1-dioxide from benzo[b]thiophen-3(2H)-one 1,1-dioxide was developed using palladium-catalyzed C(sp³)-H arylation. Compared with the traditional route, this protocol can effec

Full text of DOI:10.1155/2019/5032325

Hindawi
Journal of Chemistry
Volume 2019, Article ID 5032325, 7 pages
https://doi.org/10.1155/2019/5032325
Research Article
Palladium-Catalyzed C(sp3)-H Arylation of Benzo[b]thiophen-
3(2H)-one 1,1-Dioxide
,
Hailong Liu,1 2 Wenjing Li,1 Haiyan Fu ,1 Hua Chen ,1 Ruixiang Li,1 and Yu Li2
1Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University,
Chengdu, China
2School of Chemistry and Materials Engineering, Liupanshui Normal University, Liupanshui, China
Correspondence should be addressed to Haiyan Fu; scufhy@scu.edu.cn and Hua Chen; scuhchen@scu.edu.cn
Received 30 July 2019; Accepted 9 September 2019; Published 27 November 2019
´
Academic Editor: Jose L. Arias Mediano
Copyright © 2019 Hailong Liu et al. *is is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
A new concise synthesis route of 2-phenylbenzo[b]thiophen-3(2H)-one 1,1-dioxide from benzo[b]thiophen-3(2H)-one 1,1-
dioxide was developed using palladium-catalyzed C(sp3)-H arylation. Compared with the traditional route, this protocol can
effectively save many steps and combine with the current research hotspot, C(sp3)-H activation. Moreover, this catalytic system is
easy to operate and a good yield can be achieved.
one case was reported with lower yield [8], involving the
SNAr arylation. In 2015, Chang and coworkers reported the
palladium-mediated α-arylation of β-ketosulfones with aryl
iodides in the presence of strong base (LiTMP), Lewis acid
(ZnF2), and complicated phosphine ligand (RuPhos) [9].
Moreover, the generation of six-member ring intermediate
with the auxiliary of Lewis acid is possibly necessary for this
type reaction [10]. However, the substrate in our work is a
cyclic compound which is unable to form a six-member ring
intermediate with Lewis acid. Herein, we describe the pal-
ladium-catalyzed C(sp3)-H arylation of benzo[b]thiophen-
3(2H)-one 1,1-dioxide, which has not been reported to the
best of our knowledge.
1. Introduction
In the past few decades, transition metal-catalyzed C-H
activation has developed into one of the most powerful tools
in organic synthesis, in contrast to traditional coupling
reaction, which has the advantages of no preactivation of
substrates and excellent atom economy, demonstrating the
future direction of organic synthesis methodology. *e
activation of active C-H bond has been well developed till
now. Besides, direct arylation of α-functionalized carbonyl
compounds has been well developed in recent years [1].
Arylated benzo[b]thiophen-3(2H)-one 1,1-dioxide is a kind
of important biological active intermediates, which has anti-
inflammation and anticoagulation effects [2, 3]. For these
compounds, the traditional synthesis methods [4, 5] are very
complex which need many steps to get the target products,
so that we decided to find a new way of shortening the
reaction steps (Scheme 1).
*e skeleton of β-ketosulfone is a useful building block
in synthetic chemistry [6]. *e related derivatives are useful
precursors for functional group transformations, which can
exhibit some biological activities for medicinal application
[7]. However, there are only few reports about α-arylation of
β-ketosulfones. In 2002, Kashin and coworkers found the
palladium-catalyzed arylation of sulfonyl CH-acids, but only
2. Results and Discussion
*is section may be divided by subheadings. It should
provide a concise and precise description of the experi-
mental results, their interpretation, and the experimental
conclusions that can be drawn.
2.1. Optimization of Phosphine Ligands. Initially, we carried
out the reaction in toluene at 110°C, in the presence of
10 mol% of Pd(OAc)2, 20 mol% PCy3·HBF4(L1), and KOtBu,

2
Journal of Chemistry
O
O
O
O
S
S
NaOCH3
mCPBA
O
S
O
O
O
O
Cl
KOH
MeOH
reflux
6h
I
SH
SH
O
CH3OH
CuI
S
OH
O
COOH
O
HCl
NaNO2
KI
Zn
HOAc
COOH
NH2
(1) NaNO2 HCl
(2) Na2S2
S
S
COOH
COOH
NO2
COOH
(a)
O
O
O
O
O
O
H2SO4
SO3
0°C
EtOH
reflux
S
O
O
Commercial source
O
O
S
Catalyst, base, solvent
S
O
O
Br
O
O
(b)
Scheme 1: Traditional route vs. our route.
affording 1c in 60% yield (Table 1, entry 1). Since phos-
phine ligands are very important for the stability of catalyst
precursors, we first screened different kinds of phosphine
ligands (Scheme 2). *e results are shown in Table 1.
In this reaction, by testing a series of sterically and
electronically diverse mono- and bidentate ligands, we
found that the performance of the monodentate phosphine
ligands is relatively better than that of the bidentate
phosphine ligands. *e electron-rich monodentate phos-
phine ligand had better influence on this reaction (Table 1,
entry 1 vs. Table 1, entry 2). In contrast, when we tried to
increase the electron density on phosphine, the yield de-
creased to 38% (Table 1, entry 2 vs. Table 1, entry 8).
Moreover, the sterically hindered monodentate phosphine
ligand afforded 1c in a lower yield (Table 1, entry 1 vs.
Table 1, entry 7). In the literature, we found that chiral C-H
activation is a challenging study, so we investigated the
effect of racemic chiral phosphine ligands on this reaction.
Unfortunately, only low yields were achieved (Table 1,
entry 4, 47%, and Table 1, entry 9, 17%). 1c was not detected

Journal of Chemistry
Entry1
3
Table 1: Optimization of phosphine ligands.
Ligand
Yield (%)2
O
Br
O
Pd(OAc)2 base
+
Solvent temp
Ligand
S
S
O
O
O
O
1a
1b
1c
1
L1
L2
60
53
37
47
35
11
39
38
17
NR
NR
2
3
L3
4
L4
5
L5
6
L6
7
L7
8
L8
9
L9
10
11
L10
No ligand
1Reaction conditions: 10 mol% of Pd(OAc)2, 20 mol% of ligand, 0.25 mmol of 1a, 0.5 mmol of 1b, 0.75 mmol of KOtBu, and 1 mL of toluene, 110°C, 24 h. 2GC yield.
PPh2
PPh2
PPh2
PPh2
P
P
BISBI
L3
PCy3·HBF4
L1
TPP
L2
BINAP
L4
OCH3
P
Ph2P
PPh2
P
PPh2
Ph2P
H3CO
OCH3
PtBu3·HBF4
L7
4-MOTPP
L8
dppe
L6
dppb
L5
OCH3
N
H3CO
H3CO
PPh2
PPh2
N
P
N
N
N
OCH3
P-Phos
L9
L10
Scheme 2: Phosphine ligands.
using L10 as a ligand, but carbazole was found in reaction
system which indicated that P-N cleavage of L10 happened.
Without the addition of phosphine ligands, the target
product 1c was not obtained (Table 1, entry 11), demon-
strating that phosphine ligands were indispensable in this
reaction.

4
Journal of Chemistry
Yield (%)2
Table 2: Optimization of solvents and bases.
Entry1
Solvents
Temp (°C)
Bases
O
Br
O
Pd(OAc)2 base
+
Solvent temp
L1
S
S
O
O
O
O
1a
1b
1c
1
Dioxane
THF
100
60
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
K3PO4
LiOtBu
KOAc
K3PO4
59
58
NR
28
NR
NR
62
2
3
MTBE
Anisole
DME
50
4
150
80
80
140
90
140
140
140
140
110
5
6
tBuOH
DMAc
DMC
7
8
NR
65
9
NMP
10
11
12
13
NMP
83 (73)3
46
NMP
NMP
NR
Toluene
73 (69)3
1Reaction conditions: 10 mol% of Pd(OAc)2, 20 mol% of L1, 0.25 mmol of 1a, 0.5 mmol of 1b, 0.75 mmol of bases, and 1 mL of solvent, 24 h. GC yield.
2
3Isolated yield in parentheses.
2.2. Optimization of Solvents and Bases. Due to the great
influence of the solvents and bases on the reaction, we
carried out a series of screenings for the solvents and bases
to further improve the yield, which are shown in Table 2. A
moderate yield (59%) can be obtained using dioxane as the
solvent (Table 2, entry 1). *en a series of ethers were
screened. We found that the yield in THF was 58%
(Table 2, entry 2), but the yields in the other ether are low
(Table 2, entries 3, 4, and 5). After that, the polar aprotic
solvents were screened, and the common high boiling
point solvents were selected and tested. To our delight,
when NMP was used as the solvent, the yield was in-
creased to 65% (Table 2, entry 9). In this type of reaction,
the pKa of the substrate has a great influence on the re-
action, so the kind of base used is critical to the process of
deprotonation to form the carbon anion intermediate
[11]. *erefore, we screened the bases. A moderate yield
was obtained using LiOtBu as a base (Table 2, entry 11),
but a large amount of bromobenzene was converted into
biphenyl through dehalogenated coupling. When K3PO4,
an inorganic salt, was used as a base, a good yield of 83%
was achieved (Table 2, entry 10). However, the product
was not detected while using KOAc as a base, probably
because the basicity KOAc is too weak to complete the
deprotonation process (Table 2, entry 12). It is generally
believed that polar aprotic solvents and higher temper-
ature may increase the possibility of aldol condensation of
substrate. So we tried to replace the solvent with toluene,
and a good result was also obtained (Table 2, entry 13).
Consequently, the optimized reaction conditions were
10 mol% of Pd(OAc)2, 20 mol% of L1, 0.75 mmol of
K3PO4, and 1 mL of NMP or toluene.
2.3. -e Scope of Substrates. Under the optimized conditions,
we tested several kinds of aryl bromides, affording the target
products (Table 3). Substrates with electron-donating group
had a positive effect on this reaction. *e yields were im-
proved to 75% and 71%, respectively (Table 3, entries 1 and 2).
Conversely, the yields were obviously decreased by the
substrates with electron-withdrawing groups, such as –Cl and
–CN (Table 3, entries 4 and 5). Unfortunately, aryl bromide
with large steric hindrance cannot be converted into target
product (Table 3, entry 3). Moreover, heteroaromatic bromide
was incompatible in our system (Table 3, entry 6).
2.4. Proposed Mechanism. To account for these outcomes, a
possible catalytic cycle (Scheme 3) was proposed based on
our experiments and the previous reports [11, 12]. *is
reaction is likely to proceed via a deprotonative cross-
coupling procedure [13].
Oxidative addition of the Pd(0) with bromobenzene
affords the Pd(II) organometallic intermediate 3. Depro-
tonation of 1a and ligand substitution of the bromide
provide 2. Finally, reductive elimination of 2 affords target
product 1c and regenerates the Pd(0) catalyst. In general,
reductive elimination is not the rate-limiting step of
coupling reaction. However, in this reaction, we believe

Journal of Chemistry
Entry1
5
Table 3: *e scope of aryl bromides.
Product
Aryl bromide
Yield (%)2
O
O
Pd(OAc)2 K3PO4
+
Aryl-Br
Aryl
Tol. 110°C
L1
S
S
O
O
O
O
c
1a
b
O
Br
OCH3
OCH3
S
1
2
75
71
O
2c
O
2b
O
Br
CH3
CH3
S
O
3c
O
3b
O
Br
S
3
NR
O
O
4b
4c
O
Br
Cl
Cl
S
4
5
6
62
33
O
5c
O
5b
O
Br
CN
CN
S
O
6c
O
6b
O
S
Br
N
N
NR
O
7c
O
7b
1Reaction conditions: 10 mol% of Pd(OAc)2, 20 mol% of L1, 0.25 mmol of 1a, 0.5 mmol of b, 0.75 mmol of bases, and 1 mL of solvent, 24 h. 2Isolated yield.

6
Journal of Chemistry
Br
Ln
PhBr(1b)
Oxidative addition
Pd0
Pd
O
O
3
Reductive elimination
Pd
O
O
S
O
S
Ln
O
Base
H
O
O
–
1c
2
S
S
O
O
O
O
1a
4
Scheme 3: Proposed mechanism.
that the reductive elimination is much slower to form the
aryl-alkyl bond from an arylmetal alkyl intermediate when
the alkyl group contains strong electron-withdrawing
groups on the α position [14].
Pd(OAc)2 (0.025 mmol, 5.6 mg), PCy·HBF4 (0.05 mmol,
18.5 mg), 1a (0.25 mmol, 45.5 mg), and KOtBu (0.75 mmol,
84 mg) were added to a Schlenk flask. And the mixture was
dissolved in 1 mL of toluene under a nitrogen atmosphere.
*e reaction mixture was stirred at 110°C for 24 h. *en,
ethyl acetate was used to dissolve the mixture as much as
possible (except for inorganic salt). Celatom was used to
filter undissolved substance. After this, the solvent was
evaporated under vacuum and the mixture was analyzed by
GC or purified by column chromatography on silica gel
(petroleum ether: ethyl acetate � 3 :1) to afford product 1c
as a pale yellow solid. 2-phenylbenzo[b]thiophen-3(2H)-
3. Experimental
All reactions were carried out in a dried Schlenk tube under
a nitrogen atmosphere. Unless otherwise indicated, re-
agents obtained from commercial sources were used
without further purification. DMAc, anisole, and NMP
were dried and distilled under reduced pressure and stored
1
˚
one 1,1-dioxide: C14H10O3S, pale yellow solid, H NMR
on molecular sieves (4 A). Dimethyl carbonate (DMC) was
˚
(400 MHz, CDCl3) δ � 8.10 (dd, J � 15.5, 7.8 Hz, 2H), 8.00
(t, J � 7.4 Hz, 1H), 7.87 (t, J � 7.5 Hz, 1H), 7.50 − 7.41 (m,
3H), 7.28 (dd, J � 6.4, 3.1 Hz, 2H), 5.17 (s, 1H). ESI-HRMS:
calcd for C14H10NaO3S+([M + Na+]) 281.0248, found
281.0255.
dried, distilled, and stored on molecular sieves (4 A). THF,
toluene, and dioxane were dried and distilled with sodium
and diphenylketone acts as an indicator. Gas chromatog-
raphy is Aglient GC 6890 N and the column is SE-30
(30 m × 0.32 mm × 0.25 μm). NMR spectra were recorded
on Bruker Avance II (400 MHz). HR-ESIMS spectra were
recorded using a commercial apparatus.
3.3. Characterization of Products. 2-(4-Methoxyphenyl)benzo
[b]thiophen-3(2H)-one 1,1-dioxide (2c): C15H12O4S, pale
yellow solid, 1H NMR (400 MHz, CDCl3) δ � 8.15 (dd,
J � 15.3, 7.7 Hz, 2H), 8.03 (t, J � 7.1 Hz, 1H), 7.93 (t,
J � 7.4 Hz, 1H), 7.15 − 7.01 (m, 2H), 6.85 (dd, J � 6.3, 3.2 Hz,
2H), 5.33 (s, 1H), 3.73 (s, 3H). ESI-HRMS: calcd for
C15H12NaO4S+([M + Na+]) 311.0354, found 311.0355.
2-(p-Tolyl)benzo[b]thiophen-3(2H)-one 1,1-dioxide (3c):
3.1. Synthesis of Benzo[b]thiophen-3(2H)-one 1,1-Dioxide
(1a). Ethyl benzoylacetate (2.5 mL, 14.6 mmol) was slowly
added dropwise into excess of 50% oleum at 0°C. *e mixture
was stirred for 30 min and poured into 50 mL ice-water
mixture and stirred. *e yellow precipitate was filtered and
recrystallized with ethanol. White crystal was achieved and the
yield was 50%. *e above crystals were dissolved in 10 mL 20%
H2SO4 and stirred for 10 min at 0°C. *en 10 mL ethanol was
added and refluxed. *e reaction progress was monitored by
TLC. After the reaction was completed, we cooled the mixture
in the refrigerator until the crystals were separated out. *e
crystals were then filtered and washed with a small amount of
distilled water. Finally, the pale yellow crystals were ob-
tained by recrystallization with ethanol, and the yield of 1a
was 70%. Benzo[b]thiophen-3(2H)-one 1,1-dioxide:
C8H6O3S, pale yellow crystal, 1H NMR (400 MHz, CDCl3)
δ � 8.06 − 7.99 (m, 2H), 7.96 (td, J � 7.6, 1.0 Hz, 1H),
7.87 − 7.81 (m, 1H), 4.10 (s, 2H). ESI-HRMS: calcd for
C8H6NaO3S+([M + Na+]) 204.9935, found 204.9943.
1
C15H12O3S, pale yellow solid, H NMR (400 MHz, CDCl3)
δ � 8.09 (dd, J � 15.4, 7.7 Hz, 2H), 8.01 (t, J � 7.2 Hz, 1H), 7.92
(t, J � 7.5 Hz, 1H), 7.45 − 7.34 (m, 2H), 7.12 (dd, J � 6.4, 3.3 Hz,
2H), 5.21 (s, 1H), 2.26 (s, 3H). ESI-HRMS: calcd for
C15H12NaO3S+([M + Na+]) 295.0405, found 295.0409.
2-(4-Chlorophenyl)benzo[b]thiophen-3(2H)-one 1,1-
dioxide (4c): C14H9ClO3S, white solid, 1H NMR (400 MHz,
CDCl3) δ � 8.12 (dd, J � 15.8, 7.9 Hz, 2H), 8.03 (t, J � 7.7 Hz,
1H), 7.89 (t, J � 7.6 Hz, 1H), 7.55 − 7.47 (m, 2H), 7.35 (dd,
J � 6.6, 3.3 Hz, 2H), 5.18 (s, 1H). ESI-HRMS: calcd for
C14H9ClNaO3S+([M + Na+]) 314.9859, found 314.9862.
4-(1,1-Dioxido-3-oxo-2,3-dihydrobenzo[b]thiophen-2-
yl)benzonitrile (5c): C15H9NO3S, white solid, 1H NMR
(400 MHz, CDCl3) δ � 8.16 (dd, J � 15.5, 7.8 Hz, 2H), 8.08 (t,
J � 7.3 Hz, 1H), 7.94 (t, J � 7.5 Hz, 1H), 7.57 − 7.49 (m, 2H),
7.43 (dd, J � 6.8, 3.2 Hz, 2H), 5.23 (s, 1H). ESI-HRMS: calcd
for C15H9NNaO3S+([M + Na+]) 306.0201, found 306.0197.
3.2. Typical Procedure for the Palladium-Catalyzed C(sp3)-H
Arylation of Benzo[b]thiophen-3(2H)-one 1,1-Dioxide (1a).

Journal of Chemistry
7
determined by an X-ray analysis,” Journal of Molecular
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4. Conclusions
[8] A. N. Kashin, A. V. Mitin, I. P. Beletskaya, and R. Wife,
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hedron Letters, vol. 43, no. 14, pp. 2539–2542, 2002.
[9] M.-Y. Chang, Y.-C. Chen, and C.-K. Chan, “Palladium-me-
diated α-arylation of β-ketosulfones: application to the syn-
thesis of functionalized sulfonyl phenanthrenes,” Tetrahedron,
vol. 71, no. 5, pp. 782–791, 2015.
[10] E. J. Hennessy and S. L. Buchwald, “A general and mild
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[11] T. Jia, A. Bellomo, K. E. Baina, S. D. Dreher, and P. J. Walsh,
“Palladium-catalyzed direct arylation of methyl sulfoxides
with aryl halides,” Journal of the American Chemical Society,
vol. 135, no. 10, pp. 3740–3743, 2013.
In summary, we have reported a new concise route to the
synthesis of 2-arylbenzo[b]thiophen-3(2H)-one 1,1-dioxide
via palladium-catalyzed C(sp3)-H arylation of benzo[b]
thiophen-3(2H)-one 1,1-dioxide (1a). Combined with the
current research hotspot, C(sp3)-H activation, this protocol
can effectively save many steps and provide 1c and its de-
rivatives in good to moderate yields.
Data Availability
*e data used to support the findings of this study are
available from the corresponding author upon request.
[12] M. Palucki and S. L. Buchwald, “Palladium-catalyzed α-ary-
lation of ketones,” Journal of the American Chemical Society,
vol. 119, no. 45, pp. 11108-11109, 1997.
[13] B. C. Hamann and J. F. Hartwig, “Palladium-catalyzed direct
α-arylation of ketones. Rate acceleration by sterically hindered
chelating ligands and reductive elimination from a transition
metal enolate complex,” Journal of the American Chemical
Society, vol. 119, no. 50, pp. 12382-12383, 1997.
[14] S. Ge, W. Chaładaj, and J. F. Hartwig, “Pd-catalyzed α-arylation
of α,α-difluoroketones with aryl bromides and chlorides. A
route to difluoromethylarenes,” Journal of the American
Chemical Society, vol. 136, no. 11, pp. 4149–4152, 2014.
Conflicts of Interest
*e authors declare no conflicts of interest.
Acknowledgments
*e authors are grateful to the Key Program of Sichuan
Science and Technology Project (No. 2018GZ0312), the
Academician Workstation of Liupanshui Normal University
(QKH Platform & Talent [2019]5604), the Science and
Technology Platform and Talent Team Project of Science and
Technology Department of Guizhou Province (QKH Plat-
form & Talent [2018]5777), and Guizhou Science and
Technology Project (QKH LH [2015]7616).
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Biochemistry
Spectroscopy
Nanotechnology
Research International
Hindawi
Hindawi
www.hindawi.com
Hindawi
www.hindawi.com
Hindawi
www.hindawi.com
www.hindawi.com
Volume 2018
Volume 2018
Volume 2018
Volume 2018