Palladium-Catalyzed Synthesis of 2,3-Disubstituted Benzothiophenes via the Annulation of Aryl Sulfides with Alkynes

Article abstract of DOI:10.1021/acs.orglett.6b02055

A new method has been developed for the synthesis of 2,3-disubstituted benzothiophenes involving the palladium-catalyzed annulation of aryl sulfides with alkynes. This convergent approach exhibited good functional group tolerance, providing rapid access to a diverse array of derivatives from simple, readily available starting materials. This protocol can also be used to synthesize 2-silyl-substituted benzothiophenes, which can be used as versatile platforms for the synthesis of 2,3-unsymmetrically substituted benzothiophenes.

Full text of DOI:10.1021/acs.orglett.6b02055

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Synthesis of 2,3-Disubstituted Benzothiophenes
via the Annulation of Aryl Sulfides with Alkynes
Yoshihiro Masuya,† Mamoru Tobisu,*,‡ and Naoto Chatani*,†
†Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
‡Center for Atomic and Molecular Technologies, Graduate School of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
S
* Supporting Information
ABSTRACT: A new method has been developed for the synthesis of
2,3-disubstituted benzothiophenes involving the palladium-catalyzed
annulation of aryl sulfides with alkynes. This convergent approach
exhibited good functional group tolerance, providing rapid access to a
diverse array of derivatives from simple, readily available starting
materials. This protocol can also be used to synthesize 2-silyl-substituted
benzothiophenes, which can be used as versatile platforms for the synthesis of 2,3-unsymmetrically substituted benzothiophenes.
he catalytic heteroannulation of alkynes is a useful method
for the convergent synthesis of a wide range of
require the use of hazardous reagents, such as peroxides,6a−c or
a large excess (>5 equiv) of the alkyne.7b,c Herein, we report
the development of a new method that successfully addresses
all of these issues involving the palladium-catalyzed annulation
of thiophenol derivatives with alkynes.
T
heteroarenes from simple, readily available building blocks.1
For example, the palladium-catalyzed annulation of o-haloani-
lines with internal alkynes allows for the rapid construction of
2,3-disubstituted indole derivatives (Larock indole synthesis,
Scheme 1, E = NR).2 This approach was successfully extended
The lack of a sulfur variant of the Larock indole synthesis can
be attributed, in part, to the poisoning of the catalyst by the
presence of a strongly coordinating SH group. Indeed, our
initial attempts to synthesize benzothiophene via the palladium-
catalyzed reaction of thiophenol 1-H with alkyne 2a afforded 1a
in only 9% yield (Table 1, entry 1). Our previous work
involving the synthesis of heterocycles via the cleavage of a
carbon−heteroatom bond9−11 led us to examine the corre-
sponding annulation reaction using sulfide derivatives. Pleas-
ingly, the use of methyl sulfide 1-Me or phenyl sulfide 1-Ph led
to a dramatic increase in the yield of 1a (entries 2 and 3).
Although switching the PPh3 ligand to several other common
ligands did not lead to an improvement in the yield of 1a,12
increasing the amount of PPh3 to 1 equiv relative to the
substrate afforded 1a in excellent yield. The nature of the base
also had a significant impact on the efficiency of this annulation
reaction. For example, the use of an amine base instead of
Na2CO3 generally resulted in a better yield of the desired
product in the presence of a catalytic amount of PPh3 (entries
4−6). Notably, DBU gave the best results of all of the bases
examined in the current study. The use of DBU was particularly
effective for the annulation with aromatic alkynes such as 2b
(entry 8), which performed much less efficiently when Na2CO3
was used as the base (entry 7). The suitability of methyl sulfide
1-Me, rather than thiophenol 1-H or phenyl sulfide 1-Ph, was
further corroborated by the low yields of 1b obtained when
DBU was used as the base (entries 9 and 10).
Scheme 1. Palladium-Catalyzed Synthesis of Heteroarenes
via the Annulation of Aryl Halide Derivatives with Alkynes
to the synthesis of benzofurans by the annulation of the
corresponding o-halophenol substrates (Scheme 1, E = O).3
Naturally, it was envisioned that the corresponding sulfur
variant would provide a valuable method for the synthesis of
benzothiophene derivatives (Scheme 1, E = S), which can be
found in numerous π-conjugated organic materials4 and
pharmaceutical agents.5 However, to the best of our knowledge,
there have been no reports in the literature pertaining to the
development of a catalytic annulation reaction for the
formation of benzothiophenes. As an alternative approach,
radical annulation reactions involving the addition of carbon-6
or sulfur-centered7 radicals to alkynes have been reported.8
Although these radical reactions are useful for synthesizing
certain types of benzothiophenes, their application has been
limited by several issues. For example, none of these methods
are applicable to the annulation with an aliphatic alkyne, most
likely because propargylic hydrogen can be abstracted by an aryl
or thiyl radical intermediate. Moreover, some of these reactions
With two different sets of conditions in hand [conditions A:
PPh3 (1 equiv), Na2CO3 (3 equiv); conditions B: PPh3 (30 mol
Received: July 14, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02055
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of the Reaction Conditions
Scheme 2. Pd-Catalyzed Synthesis of Benzothiophene
a
Derivatives from 1-Me and Various Alkynes
entry
R1
alkyne
base
NMR yield of 1
b
1
2
3
4
5
6
7
8
9
10
H
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
Na2CO3
Na2CO3
Na2CO3
Et3N
9 (35)
bc
,
Me
Ph
Me
Me
Me
Me
Me
H
39 (91)
37 (95)
65
b
DMAP
DBU
63
79
b
Na2CO3
DBU
6 (20)
c
90
DBU
7
0
Ph
DBU
a
Reaction conditions: 1 (0.30 mmol), 2 (0.45 mmol), Pd(OAc)2
(0.030 mmol), PPh3 (0.090 mmol), and base (0.90 mmol) in DMF
(1.0 mL) at 130 °C for 18 h. The NMR yield was determined using
b
1,1,2,2,-tetrachloroethane as an internal standard. PPh3 (0.30 mmol)
c
was used. Isolated yield.
%), DBU (3 equiv)], we proceeded to explore the scope of this
palladium-catalyzed intermolecular cyclization reaction using
various alkynes (Scheme 2). Pleasingly, these methods allowed
us to incorporate alkynes bearing both aliphatic (e.g., 1c and
1d) and aromatic (e.g., 1e, 1f and 1g) substituents. 1,4-
Dimethoxybut-2-yne can be successfully annulated under our
conditions to form 1d, with an oxygen functionality at the
propargylic position remaining intact.13 As shown in Table 1,
the use of DBU as a base (conditions B) allowed for the
annulation of an electronically diverse range of aromatic
alkynes, as well as alkynes bearing thiophenes (e.g., 2e). Several
sets of unsymmetrical internal alkynes were also examined. In
the case of alkynes bearing phenyl and alkyl groups, the phenyl
group was preferentially incorporated at the 2-position of the
resulting benzothiophene ring (1i and 1j). In the case of
alkynes bearing a SiEt3 group, the silyl group was predom-
inantly incorporated at the 2-position of the benzothiophene
ring (1k and 1l). In all of these cases, we observed a general
trend toward the formation of benzothiophene rings with the
larger of the two substituents from the alkyne substrate being
incorporated at the 2-position of the product. The
regioselectivity observed in this case was therefore similar to
that reported for the Larock indole synthesis.1d
We subsequently investigated the palladium-catalyzed
cyclization reaction of various sulfides with 2a (Scheme 3).
Several common functional groups, including chlorides (3a),
cyano (4a), and ketones (5a), were found to be compatible,
providing access to a wide range of functionalized benzothio-
phenes. Moreover, heterocyclic (6a) and π-extended (7a and
7b) fused thiophenes can also be assembled successfully. A
rapid buildup of increasingly complex ring systems was also
possible via the double annulation on the substrates bearing
two SMe groups using 2 equiv of alkynes (8a and 9a).
a
Reaction conditions: 1-Me (0.30 mmol), 2 (0.45 mmol), and
Pd(OAc)2 (0.030 mmol) in DMF (1.0 mL) at 130 °C for 18 h.
Isolated yields are shown. The ratio in the parentheses refers to that of
regioisomers. Compounds denoted A were synthesized under the
conditions using PPh3 (0.30 mmol) and Na2CO3 (0.90 mmol).
Compounds denoted B were synthesized under the conditions using
b
PPh3 (0.090 mmol) and DBU (0.90 mmol). 2 (0.90 mmol) was used
at 160 °C. 2 (0.90 mmol) was used. Conditions A: PPh3 (0.30 mmol)
and Na2CO3 (0.90 mmol). Conditions B: PPh3 (0.090 mmol) and
DBU (0.90 mmol).
c
intermediates. For example, the TFA-mediated desilylation of
1l led to the formation of 10, which represents the formal
annulation product of a terminal alkyne. The silyl group in 1l
could also be substituted by various functional groups via
halogenation, providing access to a broad range of benzothio-
phenes bearing different substituents at their 1- and 2-positions.
A proposed mechanism for the palladium-catalyzed cycliza-
tion reaction is shown in Scheme 5. The oxidative addition of
the C−Br bond in 1-Me to Pd(0)14 would give the
arylpalladium species 12, which would subsequently add across
the alkyne to form the six-membered palladacycle intermediate
13. C−S bond-forming reductive elimination15 from 13 would
release the cyclic sulfonium salt 14 with the concomitant
regeneration of Pd(0). The methyl group of 14 would be
readily cleaved by Lewis basic species present in the reaction
mixture (e.g., PPh3, DMF or an external base), via an SN2-type
substitution process to afford the desired benzothiophene
derivative 1.6b,c,8c Indeed, the independently synthesized
sulfonium salt 15 gave the demethylation product 16 in high
yield when it was stirred in DMF at 130 °C.12 This result
therefore indicates that DMF can serve as a nucleophile
Our annulation protocol was found to be amenable to gram-
scale synthesis with a lower catalyst loading (5 mol %) (Scheme
4, top). Furthermore, the silyl-substituted benzothiophenes
prepared using this method can serve as useful synthetic
required for the C−S bond cleavage. In addition, MePPh3 Br−
+
was detected in the crude reaction mixture by 31P NMR
analysis when the reaction was conducted with 1 equiv of
B
DOI: 10.1021/acs.orglett.6b02055
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Pd-Catalyzed Synthesis of Benzothiophene
Derivatives from Various Aryl Sulfides and 2a
Scheme 5. Possible Mechanism
a
construction of molecular complexity using readily available
building blocks. Based on these attractive features, it is
envisioned that this newly developed method will be useful
for the diversity-oriented synthesis of benzothiophenes. Further
work toward the development of catalytic annulation reactions
via the cleavage of a carbon−heteroatom bond is ongoing in
our laboratories.
a
Reaction conditions: aryl sulfide (0.30 mmol), 2a (0.45 mmol),
Pd(OAc)2 (0.030 mmol), PPh3 (0.30 mmol), and Na2CO3 (0.90
mmol) in DMF (1.0 mL) at 130 °C for 18 h. Isolated yields are shown.
b
c
2 (0.90 mmol) was used at 160 °C. Aryl sulfide (0.30 mmol), 2b
(0.45 mmol), Pd(OAc)2 (0.030 mmol), PPh3 (0.090 mmol), and DBU
(0.90 mmol) in DMF (1.0 mL) at 130 °C for 18 h. Aryl sulfide (0.15
mmol), 2a (0.90 mmol), Pd(OAc)2 (0.030 mmol), PPh3 (0.30 mmol),
and Na2CO3 (0.90 mmol) in DMF (1.0 mL) at 130 °C for 18 h.
d
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02055.
■
S
Scheme 4. Scalability and Transformation of
Benzothiophene Derivatives
Detailed experimental procedures and characterization of
products (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: tobisu@chem.eng.osaka-u.ac.jp.
*E-mail: chatani@chem.eng.osaka-u.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by ACT-C (J1210B2576) from JST,
Japan. We also thank the Instrumental Analysis Center, Faculty
of Engineering, Osaka University, for their assistance with
HRMS.
REFERENCES
■
(1) Selected reviews: (a) Larock, R. C. J. Organomet. Chem. 1999,
576, 111. (b) Zeni, G.; Larock, R. C. Chem. Rev. 2004, 104, 2285.
(c) Larock, R. C. Top. Organomet. Chem. 2005, 14, 147. (d) Zeni, G.;
Larock, R. C. Chem. Rev. 2006, 106, 4644. (e) Satoh, T.; Miura, M.
Chem. - Eur. J. 2010, 16, 11212. (f) Song, G.; Wang, F.; Li, X. Chem.
Soc. Rev. 2012, 41, 3651. (g) Majumdar, K. C.; Samanta, S.; Sinha, B.
PPh3,12 indicating that PPh3 could also behave as a nucleophile
during the cleavage of the sulfonium intermediate 14.
In summary, we have developed a new convergent method
for the synthesis of benzothiophene derivatives from aryl
sulfides and alkynes under palladium catalysis. This reaction
represents the first reported sulfur variant of the Larock indole
synthesis. Notably, this annulation protocol exhibited wide
functional group compatibility, allowing for the rapid
́
Synthesis 2012, 44, 817. (h) Chinchilla, R.; Najera, C. Chem. Rev. 2014,
114, 1783. (i) Yang, Y.; Li, K.; Cheng, Y.; Wan, D.; Li, M.; You, J.
Chem. Commun. 2016, 52, 2872.
(2) The first report: (a) Larock, R. C.; Kgun Yum, E. J. Am. Chem.
Soc. 1991, 113, 6689. Reviews: (b) Cacchi, S.; Fabrizi, G. Chem. Rev.
C
DOI: 10.1021/acs.orglett.6b02055
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
2011, 111, PR215. (c) Platon, M.; Amardeil, R.; Djakovitch, L.;
Hierso, J.-C. Chem. Soc. Rev. 2012, 41, 3929. (d) Guo, T.; Huang, F.;
Yu, L.; Yu, Z. Tetrahedron Lett. 2015, 56, 296.
(3) The first report: (a) Larock, R. C.; Yum, E. K.; Doty, M. J.; Sham,
K. K. C. J. Org. Chem. 1995, 60, 3270. Review: (b) Abu-Hashem, A.
A.; Hussein, H. A. R.; Aly, A. S.; Gouda, M. A. Synth. Commun. 2014,
44, 2285.
(4) Selected examples: (a) Gao, J.; Li, R.; Li, Q.; Meng, Q.; Jiang, H.;
Li, H.; Hu, W. Adv. Mater. 2007, 19, 3008. (b) Yin, J.; Zhou, Y.; Lei,
T.; Pei, J. Angew. Chem., Int. Ed. 2011, 50, 6320. (c) Zhang, W.; Sun,
X.; Xia, P.; Huang, J.; Yu, G.; Wong, M. S.; Liu, Y.; Zhu, D. Org. Lett.
2012, 14, 4382. (d) Jeon, J. H.; Lee, N. J.; Lee, J. H.; Suh, M. C. Dyes
Pigm. 2014, 111, 116. (e) Wu, Y.; Xie, Y.; Zhang, Q.; Tian, H.; Zhu,
W.; Li, A. D. Q. Angew. Chem., Int. Ed. 2014, 53, 2090.
(5) Selected examples: (a) Jones, C. D.; Jevnikar, M. G.; Pike, A. J.;
Peters, M. K.; Black, L. J.; Thompson, A. R.; Falcone, J. F.; Clemens, J.
A. J. Med. Chem. 1984, 27, 1057. (b) Qin, Z.; Kastrati, I.; Chandrasena,
R. E. P.; Liu, H.; Yao, P.; Petukhov, P. A.; Bolton, J. L.; Thatcher, G. R.
J. J. Med. Chem. 2007, 50, 2682. (c) Martín-Santamaría, S.; Rodríguez,
J.-J.; de Pascual-Teresa, S.; Gordon, S.; Bengtsson, M.; Garrido-
́
Laguna, I.; Rubio-Viqueira, B.; Lopez-Casas, P. P.; Hidalgo, M.; de
Pascual-Teresa, B.; Ramos, A. Org. Biomol. Chem. 2008, 6, 3486.
(d) Ai, T.; Xu, Y.; Qiu, L.; Geraghty, R. J.; Chen, L. J. Med. Chem.
2015, 58, 785.
(6) (a) Albertazzi, A.; Leardini, R.; Pedulli, G. F.; Tundo, A.; Zanardi,
G. J. Org. Chem. 1984, 49, 4482. (b) Hari, D. P.; Hering, T.; Konig, B.
̈
Org. Lett. 2012, 14, 5334. (c) Gao, L.; Chang, B.; Qiu, W.; Wang, L.;
Fu, X.; Yuan, R. Adv. Synth. Catal. 2016, 358, 1202. (d) Zang, H.; Sun,
J.-G.; Dong, X.; Li, P.; Zhang, B. Adv. Synth. Catal. 2016, 358, 1746.
(7) (a) Liu, K.; Jia, F.; Xi, H.; Li, Y.; Zheng, X.; Guo, Q.; Shen, B.; Li,
Z. Org. Lett. 2013, 15, 2026. (b) Yang, D.; Yan, K.; Wei, W.; Tian, L.;
Li, Q.; You, J.; Wang, H. RSC Adv. 2014, 4, 48547. (c) Wan, D.; Yang,
Y.; Liu, X.; Li, M.; Zhao, S. Eur. J. Org. Chem. 2016, 2016, 55.
(8) Other catalytic intermolecular methods for the synthesis of
benzothiophenes: (a) Inami, T.; Baba, Y.; Kurahashi, T.; Matsubara, S.
Org. Lett. 2011, 13, 1912. (b) Yan, K.; Yang, D.; Zhang, M.; Wei, W.;
Liu, Y.; Tian, L.; Wang, H. Synlett 2015, 26, 1890. (c) Yamauchi, T.;
Shibahara, F.; Murai, T. Tetrahedron Lett. 2016, 57, 2945.
(9) C−S bond cleavage: Tobisu, M.; Masuya, Y.; Baba, K.; Chatani,
N. Chem. Sci. 2016, 7, 2587.
(10) C−P bond cleavage: (a) Baba, K.; Tobisu, M.; Chatani, N.
Angew. Chem., Int. Ed. 2013, 52, 11892. (b) Baba, K.; Tobisu, M.;
Chatani, N. Org. Lett. 2015, 17, 70.
(11) C−Si bond cleavage: (a) Tobisu, M.; Onoe, M.; Kita, Y.;
Chatani, N. J. Am. Chem. Soc. 2009, 131, 7506. (b) Onoe, M.; Baba, K.;
Kim, Y.; Kita, Y.; Tobisu, M.; Chatani, N. J. Am. Chem. Soc. 2012, 134,
19477. (c) Onoe, M.; Morioka, T.; Tobisu, M.; Chatani, N. Chem. Lett.
2013, 42, 238. C−Ge bond cleavage: (d) Tobisu, M.; Baba, K.;
Chatani, N. Org. Lett. 2011, 13, 3282.
(12) See the Supporting Information for details.
(13) Review: Guo, L. N.; Duan, X. H.; Liang, Y. M. Acc. Chem. Res.
2011, 44, 111.
(14) (a) Amatore, C.; Jutand, A.; M’Barki, M. A. Organometallics
1992, 11, 3009. (b) Ozawa, F.; Kubo, A.; Hayashi, T. Chem. Lett. 1992,
2177.
(15) A related reductive elimination of C−S bond from six-
́ ́
membered palladacycle: Vicente, J.; Abad, J. A.; Lopez-Nicolas, R.
M. Organometallics 2011, 30, 4983.
D
DOI: 10.1021/acs.orglett.6b02055
Org. Lett. XXXX, XXX, XXX−XXX