Palladium-catalyzed phosphine-free direct C-H arylation of benzothiophenes and benzofurans involving MIDA boronates

Article abstract of DOI:10.1055/s-0034-1379606

With high regioselectivity, a series of benzoheterocyclic compounds were synthesized via palladiium-catalyzed phosphine-free C-H arylation of benzothiophenes/benzofurans with aryl MIDA boronates at 30-50 °C in moderate to excellent yields. MIDA boronates were used in C-H arylation of heterocycles for the first time. Under the optimal conditions, the benzothiophenes could be transformed into the β-arylbenzothiophenes, and the benzofurans gave only α-aryl-substituted products.

Full text of DOI:10.1055/s-0034-1379606

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 531–536
letter
531
Z. Wang et al.
Letter
Synlett
Palladium-Catalyzed Phosphine-Free Direct C–H Arylation of
Benzothiophenes and Benzofurans Involving MIDA Boronates
Zhiwei Wang
no phosphine ligand
low reaction temperature
catalyst, Ag2O, BQ, Cs(tfa)
Me
N
B
Yabo Li
R
R
Ar
O
Beiqi Yan
+
Mengmeng Huang*
Yangjie Wu*
Ar
O
O
O
X
X
H2O–CF3SO3H–TFA, 30 °C
27 examples
up to 99%
X = S, O
College of Chemistry and Molecular Engineering, Henan Key
Laboratory of Chemical Biology and Organic Chemistry,
Key Laboratory of Applied Chemistry of Henan Universities,
Zhengzhou University, Zhengzhou 450052, P. R. of China
+
8
6
3
(
7
1
6
)
7
9
7
9
4
0
8
wyj@zzu.edu.cn
hmm@zzu.edu.cn
Received: 30.09.2014
Accepted after revision: 27.10.2014
Published online: 09.01.2015
aryl halides.4 Along this line, recent developments in direct
arylation of benzothiophenes at the C3-position are built
upon the pioneering works of the Itami group,5 Bach
group,6 and Oi group.7 Progress in the studies of Itami and
Bach is that low-toxicity arylboronic acids are successfully
used as one of the coupling partners to afford β-arylated
heterocyles with high regioselectivity.5,6 Nevertheless, there
are only two examples for the arylation of benzothiophene
in both studies. During the same period, Oi and co-workers7
developed a direct arylation of benzothiophenes with ex-
pensive aryltrimethylsilanes, and limitations in the C3/C2
selectivity of this approach are also apparent. In addition,
larger amounts of catalyst loading (5–10 mol%) or high re-
action temperature were observed in all of these studies.
As an useful coupling partner, MIDA boronates have
been successfully applied to synthesize biaryl compounds
in Suzuki reaction8 due to their versatility, low toxicity, and
enhanced stability relative to hard organometallic carbon
nucleophiles.9 Up to now only one report employed aryl
MIDA boronates to the oxidative arylation of n-butyl acry-
late.10 Accordingly, in the course of investigating catalytic
activity of N,O-ligand palladacycle catalysts (Figure 1),11
herein, we describe an operationally simple and highly re-
gioselective protocol for the direct arylation of benzothio-
phenes/benzofurans with various MIDA boronates under
mild reaction conditions.
DOI: 10.1055/s-0034-1379606; Art ID: st-2014-w0824-l
Abstract With high regioselectivity, a series of benzoheterocyclic
compounds were synthesized via palladiium-catalyzed phosphine-free
C–H arylation of benzothiophenes/benzofurans with aryl MIDA boro-
nates at 30–50 °C in moderate to excellent yields. MIDA boronates were
used in C–H arylation of heterocycles for the first time. Under the opti-
mal conditions, the benzothiophenes could be transformed into the β-
arylbenzothiophenes, and the benzofurans gave only α-aryl-substituted
products.
Key words C–H arylation, benzothiophene, benzofuran, MIDA boro-
nate, bis(alkoxo)palladium(II) complex
Benzoheterocycles as an important class of fused het-
erocycles are ubiquitous in biologically active compounds,
nature products, organic materials, and pharmaceuticals
(anti-inflammatory, antipsoriasis, antiulcers, migraine
drugs, and antiallergic).1 Numerous effective routes to aryl
benzoheterocycles exist, however, these generally require
the appropriate functionalization of one or both coupling
partners.2 Due to the easy operations and high atom effi-
ciency, direct C–H arylation of heterocycles represents a
more efficient approach, and considerable progress has
been made in this area using palladium catalysts.3 For valu-
able benzothiophene and benzofuran motifs, palladium-
catalyzed direct arylation has been well established with
N
N
N
Pr
O
O
O
Pd
N
Pd
N
Pd
N
2HOAc
2HOAc
2HOAc
O
O
O
Pr
II
III
I
Figure 1 The structure of bis(alkoxo)palladium(II) complexes I–III
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 531–536

532
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At the onset of our studies, the direct arylation of ben-
zothiophene (1a) and phenyl MIDA boronate (2a) was cho-
sen as a model reaction. Some of our results are shown in
Table 1. The model reaction was carried out at 30 °C in TFA
with 2 mol% of III as catalyst, K2CO3 as base, and Ag2O and
BQ as oxidants to afford 3-phenylbenzothiophene in 23%
(Table 1, entry 1). Several bases (e.g., K2CO3, Cs(tfa), and
Na2CO3) were investigated, and the best choice was Cs(tfa)
(Table 1, entries 1–4). It was found that large amounts of
water could be permitted hydrolysis of MIDA boronates to
increase the yield of 3aa12 [Figure 2, H2O (%)a]. Pleasingly,
when a small amount of CF3SO3H (2% of TFA) was intro-
duced into the reaction mixture, the yield of product 3aa
could be increased to 89% [Figure 2, CF3SO3H (%)b, and Table
1, entry 5].
Table 1 Optimization of Reaction Conditionsa
Me
catalyst,
N
oxidant,
O
additive,
+
Figure 2 Optimization of reaction conditions. a The content of
H2O[V(H2O)/V(H2O+TFA)] was optimized with 2 mol% III in 20 h. b The
content of CF3SO3H[V(CF3SO3H)/V(H2O+TFA +CF3SO3H)] was optimized
with 2 mol% III in 20 h. c The catalyst loading of III was optimized with
H2O–CF3SO3H–TFA (15:2:83; 1 mL) in 20 h. d Reaction time was opti-
mized with H2O–CF3SO3H–TFA (15:2:83; 1 mL) and 2 mol% III.
B
O
O
O
base,
solvent,
temp
S
S
3aa
1a
2a
Entry
Base
K2CO3
Oxidant
Yield (%)b
1c
Ag2O, BQ
Ag2O, BQ
Ag2O, BQ
Ag2O, BQ
Ag2O, BQ
Ag2CO3, BQ
AgOAc, BQ
AgF, BQ
23
In an attempt to further increase the yield of this reac-
tion, we proposed a number of oxidants. However, other
tested oxidants did not provide a higher yield than Ag2O
and BQ (Table 1, entries 6–13). Subsequently, the catalytic
activity was checked, and the bis(alkoxo)palldium complex-
es I, II, and Pd(OAc)2 did not show better catalytic activity
(Table 1, entries 14–16). A catalyst loading of 2 mol% was
detemineted to be optimal [Figure 2, III (mol%)c]. In addi-
tion, the reaction time was not less than 20 hours [Figure 2,
time (h)d].
Encouraged by the above results, diverse benzohetero-
cycles and aryl MIDA boronates were evaluated under the
optimized conditions (Scheme 1).13,14 The direct arylation
of benzothiophene (1a) could proceed well with various
aryl MIDA boronates to afford the β-arylbenzothiophenes
in moderate to excellent yields at 30 °C (Scheme 1, 3aa–i).
Sterically hindered MIDA boronate 2c was not found to
have any influence on the product yield (95%; Scheme 1,
3ac). In addition, this protocol was also compatible with bi-
phenyl and naphthyl MIDA boronates (Scheme 1, 3aj–ak).
Surprisingly, the conversion yield of 3ah could be promoted
to 99% at 50 °C. Subsequently, the benzothiophene deriva-
tives were tested using the standard conditions. All of the
investigated benzothiophenes could smoothly react with
phenyl MIDA boronates at 30 °C to give the corresponding
products in moderate to good yields (Scheme 1, 3ba–ga).
The yields of 3da, 3ea, and 3ga were obviously increased at
50 °C, higher than at 30 °C. Compared with the benzothio-
phenes the direct arylation of benzofurans with aryl MIDA
2c
Na2CO3
Cs(tfa)
–
22
3c
32
4c
18
5
Cs(tfa)
Cs(tfa)
Cs(tfa)
Cs(tfa)
Cs(tfa)
Cs(tfa)
Cs(tfa)
Cs(tfa)
Cs(tfa)
Cs(tfa)
Cs(tfa)
Cs(tfa)
89
6
84
7
65
8
72
9
Cu(OAC)2, BQ
K2S2O4, BQ
TBHP, BQ
Ag2O
24
10
11
12d
13e
14f
15g
16h
trace
trace
22
BQ
12
Ag2O, BQ
Ag2O, BQ
Ag2O, BQ
80
75
30
a Reaction conditions: benzothiophene (0.25 mmol), phenyl MIDA boro-
nate (0.375 mmol), base (0.25 mmol), oxidant (0.5 mmol), BQ (0.125
mmol), catalyst (2 mol%), in the mixture solvent H2O–CF3SO3H–TFA
(15:2:83; 1 mL), under air, 20 h.
b Isolated yield.
c In TFA (1 mL).
d Ag2O (0.625 mmol) without BQ.
e BQ (0.625 mmol) without Ag2O.
f Pd(OAc)2.
g Cat. I.
h Cat. II.
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Me
III (2 mol%), Ag2O (2 equiv),
BQ (0.5 equiv), Cs(tfa) (1 equiv),
N
R
R
Ar
O
+
H2O–CF3SO3H–TFA (15:2:83; 1 mL),
30 °C, 20 h
Ar
B
O
O
O
X
X
1
2
3
S
S
S
S
3ac: 95%
3aa: 89%
3ab: 68%
3ad: 80%
O
COOMe
COOMe
OMe
S
S
S
S
3ae: 78%
3af: 79%
3ah: 58/99%a
3ag: 72%
Ph
CF3
S
S
S
S
3aj: 58/65%a
3ak: 71%
3ai: 69%
3ba: 86%
Ph
Cl
Br
S
S
S
S
Ph
3da: 29/62%a
3ea: 53/86%a
3ca: 64/66%a
3fa: 72%
O
O
O
S
Br
3ga: 45/87%a
3ha: 71%
3hd: 41%
3hc: 52%
O
O
O
O
O
COOMe
CF3
COOMe
3hg: 98%
3hh: 99%
3hf: 91%
3hi: 93%
Ph
Br
O
O
O
3ja: 77%
3ia: 57%
3hk: 64%
Scheme 1 Pd-catalyzed direct arylation of benzothiohenes and benzofurans with aryl MIDA boronates; isolated yields are given. Reagents and condi-
tions: III (2 mol%), Ag2O (0.5 mmol), benzoquinone (0.125 mmol), Cs(tfa) (0.25 mmol), benzothiophene or benzofuran (0.25 mmol), aryl MIDA boro-
nates (0.375 mmol), H2O–CF3SO3H–TFA (15:2:83; 1 mL), 30 °C, 20 h. a Reaction was carried out at 50 °C.
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Me
N
III (2 mol%), Ag2O (2 equiv),
BQ (0.5 equiv), Cs(tfa) (1 equiv),
( a )
O
+
H2O–CF3SO3H–TFA (15:2:83; 1 mL), 20 h
Ph
B
O
O
O
S
S
3aa
5
2a
T = 30 °C, 9%
T = 80 °C, 35%
III (2 mol%), Ag2O (2 equiv),
BQ (0.5 equiv), Cs(tfa) (1 equiv),
Me
N
O
+
( b )
H2O–CF3SO3H–TFA (15:2:83; 1 mL), 20 h
O
S
Ph
B
O
O
S
7
6
2a
T = 30 °C, 8%
T = 80 °C, 19%
Scheme 2 Control experiments
boronates occured at the α-position to form α-arylbenzofu-
rans at 30 °C (Scheme 1, 3ha–ja). In contrast to benzothio-
phenes, the yields with the aryl MIDA boronates bearing
electron-withdrawing groups were higher than that of elec-
tron-donating groups (Scheme 1, 3ha–hd and 3hf–hi). The
structures of 3ia and 3fa were confirmed by X-ray diffrac-
tion analysis (see Supporting Information).
To gain insight into the mechanism of this transforma-
tion, a series of control experiments were carried out
(Scheme 2). Under the optimized conditions, the 2,3-di-
phenylbenzothiophene (5)15 was obtained from the reac-
tion of the β-phenyl benzothiophene 3aa with 2a in 9% at
30 °C and in 35% at 80 °C (Scheme 2, a). These results
showed that the primary reaction of the palladium(II) in-
termediate might occurs at C2, then the aryl group is deliv-
ered intra- or intermolecularly to the C3 carbon atom.5
When the 2-tolylbenzothiophene (6)16 was used, the 2,3-
diarylbenzothiophene 7 was isolated in 8% at 30 °C, and
19% at 80 °C (Scheme 2, b). It proves that the ArPd(II) inter-
mediate could also attack on the C3-positon of benzothio-
phenes, however, this is not a mainly route to get the β-aryl
benzothiophenes.
Ar
aryl-group
X
PdL2
migration
H
deprotonation
– H+
B
Ar
H
Ar
nucleophilic
attack
PdL2
PdL2
X
X
X
Ar
E
C
PdL2
nucleophilic
attack
L2Pd
Ar
X
D
reductive
elimination
A
deprotonation
– H+
H+
Ar
L2Pd(II)
Ar
X
C2 product
[O]
X
L2Pd(0)
F
Scheme 3 Possible mechanism
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 531–536

535
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Based on the above results and previous works,5 a plau-
sible mechanism is depicted in Scheme 3. Firstly, trans-
metalation of III with aryl MIDA boronate in an acid envi-
ronment might generate a cationic ArPd species A. Nucleo-
philic attack of benzothiophene/benzofuran to A (at the
most nucleophilic C2-position) leads to cationic intermedi-
ate B. Aryl-group migration from palladium to the C3-posi-
tion provides intermediate C (only for benzothiophenes).
On the other hand, nucleophilic attack of benzothio-
phene/benzofuran to A could also occur at the C3-position
to give cationic intermediate D. Subsequently, deprotona-
tion of intermediates C and D eventually produces C3-ary-
lated product 3 and the palladium(0) species F. Deprotona-
tion of B produces intermediate E, which proceeds reduc-
tive elimination to give C2-arylated product and the
palladium(0) species F. Finally, oxidation of F by oxidants
regenerates palladium(II) to close the catalytic cycle.
In conclusion, we developed an efficient and regioselec-
tive palladium-catalyzed C–H arylation using aryl MIDA bo-
ronates as one of thecoupling partners to synthesize aryl-
substituted benzothiophenes/benzofurans in moderate to
excellent yields. MIDA boronates were applied in C–H aryla-
tion of heterocycles for the first time. The direct arylation of
benzothiophenes could afford the β-arylbenzothiophenes,
and the arylation of benzofurans gave only α-aryl-substi-
tuted products. The reaction mechanism was proposed by
control experiments.
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Acknowledgment
We thank the National Science Foundation of China (No. 21172200)
for financial support given to this research.
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Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1379606.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
(11) Li, Y.-B.; Wang, J.-R.; Huang, M.-M.; Wang, Z.-W.; Wu, Y.-S.; Wu,
Y.-J. J. Org. Chem. 2014, 79, 2890.
(12) Preparation of 3aa; Typical Procedure
References and Notes
To a 10 mL round-bottom flask were added III (3.2 mg, 0.005
mmol, 2 mol%), Ag2O (116 mg, 0.5 mmol, 2 equiv), benzoqui-
none (14 mg, 0.125 mmol, 0.5 equiv), Cs(tfa) (64 mg, 0.25 mmol,
1 equiv.), benzothiophene (1a; 34 mg, 0.25 mmol, 1 equiv),
phenyl MIDA boronate (2a; 86 mg, 0.375 mmol, 1.5 equiv), and
H2O–CF3SO3H–TFA (15:2:83; 1 mL). The reaction mixture was
stirred at 30–50 °C for 20 h. The suspension was cooled to r.t.
and extracted with CH2Cl2 (3 × 10 mL). The combined organic
layers were washed with 20% aq NaHCO3 solution (40 mL). After
evaporation of the solvent the crude product was purified by
chromatography on silica gel to give 3-phenylbenzo[b]thio-
phene (3aa; 46.7 mg, 89% isolated yield) as a yellow oil. This
product has been reported previously.4f
(1) For reviews, see: (a) Hassan, J.; Sévignon, M.; Gozzi, C.; Schulz,
E.; Lemaire, M. Chem. Rev. 2002, 102, 1359. (b) Perepichaka, I. F.;
Perepichaka, D. F.; Meng, H.; Wudl, F. Adv. Mater. 2005, 17,
2281. (c) Coropceanu, V.; Cornil, J.; Filho, D. A. d. S.; Olivier, Y.;
Silbey, R.; Brédas, J.-L. Chem. Rev. 2007, 107, 926. (d) Murphy, A.
R.; Fréchet, J. M. J. Chem. Rev. 2007, 107, 1066. (e) Mishra, A.;
Ma, C.-Q.; Bäuerle, P. Chem. Rev. 2009, 109, 1141. (f) Cheng, Y.-J.;
Yang, S.-H.; Hsu, C.-S. Chem. Rev. 2009, 109, 5868. (g) Nicolaou,
K. C.; Hale, C. R. H.; Nilewski, C.; Ioannidou, H. A. Chem. Soc.
Rev. 2012, 41, 5185. (h) Wang, C.-L.; Dong, H.-L.; Hu, W.-P.; Liu,
Y.-Q.; Zhu, D.-B. Chem. Rev. 2012, 112, 2208.
(2) (a) Corbet, J.-P.; Mignani, G. Chem. Rev. 2006, 106, 2651.
(b) Jana, R.-J.; Pathak, T. P.; Sigman, M. S. Chem. Rev. 2011, 111,
1417. (c) Yang, J.-F.; Liu, S.-J.; Zheng, J.-F.; Zhou, J.-R. Eur. J. Org.
Chem. 2012, 6248. (d) Ortega, N.; Urban, S.; Beiring, B.; Glorius,
3-Phenylbenzo[b]thiophene (3aa)
1H NMR (400 MHz, CDCl3): δ = 7.95–7.88 (m, 2 H), 7.61–7.56 (m,
2 H), 7.51–7.45 (m, 2 H), 7.43–7.35 (m, 4 H) ppm. 13C NMR (100
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 531–536

536
Z. Wang et al.
Letter
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MHz, CDCl3): δ = 140.65, 138.06, 137.86, 135.98, 128.70, 128.69,
127.52, 124.38, 124.30, 123.39, 122.90 ppm. MS (EI): m/z calcd
for C15H12S [M]+: 210.1; found: 210.0.
MHz, CDCl3): δ = 140.88, 139.54, 138.85, 135.52, 134.24, 133.24,
130.43, 129.61, 128.63, 128.33, 127.68, 127.36, 124.51, 124.42,
123.34, 122.05 ppm. MS (EI): m/z calcd for C20H14S [M]+: 286.1;
found: 286.0.
(13) CCDC-1008524 (3fa) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
(14) CCDC-1008525 (3ia) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
(16) Preparation of 6; Typical Procedure
To a 10 mL round-bottom flask were added III (3.2 mg, 0.005
mmol, 2 mol%), Ag2O (116 mg, 0.5 mmol, 2 equiv), benzoqui-
none (14 mg, 0.125 mmol, 0.5 equiv), Cs(tfa) (64 mg, 0.25 mmol,
1 equiv), 6 (56mg, 0.25 mmol, 1 equiv), phenyl MIDA boronates
(115 mg, 0.5 mmol, 2.0 equiv), and H2O–CF3SO3H–TFA (15:2:83;
1 mL). The reaction mixture was stirred at 30 °C and 80 °C for 20
h. The suspension was cooled to r.t. and extracted with CH2Cl2
(3 × 10 mL). The combined organic layers were washed with
20% aq NaHCO3 solution (40 mL). After evaporation of the
solvent the crude product was purified by chromatography on
silica gel to give 3-phenyl-2-(p-tolyl)benzo[b]thiophene (6.0
mg, 8% at 30 °C/14.3 mg, 19% at 80 °C isolated yield) as a white
solid; mp 149–151 °C. This product has been reported previ-
ously.18
(15) Preparation of 5; Typical Procedure
To a 10 mL round-bottom flask were added III (3.2 mg, 0.005
mmol, 2 mol%), Ag2O (116 mg, 0.5 mmol, 2 equiv), benzoqui-
none (14 mg, 0.125 mmol, 0.5 equiv), Cs(tfa) (64 mg, 0.25 mmol,
1 equiv), 3aa (52.5 mg, 0.25 mmol, 1 equiv), phenyl MIDA boro-
nate (115 mg, 0.5 mmol, 2.0 equiv), and H2O–CF3SO3H–TFA
(15:2:83; 1 mL). The reaction mixture was stirred at 30 °C and
80 °C for 20 h. The suspension was cooled to r.t. and extracted
with CH2Cl2 (3 × 10 mL). The combined organic layers were
washed with 20% aq NaHCO3 solution (40 mL). After evapora-
tion of the solvent the crude product was purified by chroma-
tography on silica gel to give 2,3-diphenylbenzo[b]thiophene
(5; 6.4 mg, 9% at 30 °C/25.0 mg, 35% at 80 °C isolated yield) as a
white solid; mp 111–113 °C. This product has been reported
previously.17
3-Phenyl-2-(p-tolyl)benzo[b]thiophene (7)
1H NMR (400 MHz, CDCl3): δ = 7.90–7.85 (m, 1 H), 7.59 (d, J =
8.2 Hz, 1 H), 7.45–7.31 (m, 7 H), 7.27–7.21 (m, 2 H), 7.10–7.04
(m, 2 H), 2.33 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
141.00, 139.73, 138.73, 137.61, 135.72, 132.80, 131.33, 130.46,
129.44, 129.08, 128.62, 127.30, 124.37, 123.22, 122.01, 21.17
ppm. MS (EI): m/z calcd for C21H16S [M]+: 300.1; found: 300.0.
(17) Yue, D.-W.; Larock, R. C. J. Org. Chem. 2002, 67, 1905.
(18) Lu, W.-D.; Wu, M.-J. Tetrahedron 2007, 63, 356.
2,3-Diphenylbenzo[b]thiophene (5)
1H NMR (400 MHz, CDCl3): δ = 7.88–7.84 (m, 1 H), 7.61–7.56 (m,
1 H), 7.42–7.28 (m, 9 H), 7.25–7.20 (m, 3 H) ppm. 13C NMR (100
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 531–536