Pd/phenanthroline-catalyzed arylative cyclization of o-(1-alkynyl)thioanisoles: Synthesis of 3-arylated benzo[b]thiophenes

Article abstract of DOI:10.1016/j.tetlet.2016.05.033

The arylative cyclization of o-(1-alkynyl)thioanisoles with aryl iodides in the presence of catalytic amounts of [Pd(phen)₂][PF₆]₂resulted in the efficient formation of 3-arylated benzo[b]thiophenes, and a range of aryl iodides with electron-donating or -withdrawing groups could be used. While this reaction proceeded in the presence of aromatic and aliphatic groups on the terminal alkynyl carbon atom, silyl and alkoxycarbonyl groups hampered the reaction. Furthermore, this method could be extended to the synthesis of 3-arylated indoles from N,N-dimethyl-o-(1-alkynyl)aniline. All these reactions proceeded smoothly via cleavage of the carbon-heteroatom bond. In addition to the desired cyclization products, the use of a o-(hydroxypropyl)phenylmethyl substituent on the sulfur atom afforded isochroman, which should be formed by the intramolecular attack of a hydroxy group onto the benzylic carbon atom.

Full text of DOI:10.1016/j.tetlet.2016.05.033

Accepted Manuscript
Pd/phenanthroline-catalyzed arylative cyclization of o-(1-alkynyl)thioanisoles:
Synthesis of 3-arylated benzo[b]thiophenes
Takayuki Yamauchi, Fumitoshi Shibahara, Toshiaki Murai
PII:
S0040-4039(16)30547-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.05.033
TETL 47652
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
22 March 2016
2 May 2016
10 May 2016
Please cite this article as: Yamauchi, T., Shibahara, F., Murai, T., Pd/phenanthroline-catalyzed arylative cyclization
of o-(1-alkynyl)thioanisoles: Synthesis of 3-arylated benzo[b]thiophenes, Tetrahedron Letters (2016), doi: http://
dx.doi.org/10.1016/j.tetlet.2016.05.033
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Pd/phenanthroline-catalyzed arylative
cyclization of o-(1-alkynyl)thioanisoles: the
synthesis of 3-arylated benzo[b]thiophenes
Takayuki Yamauchi, Fumitoshi Shibahara and Toshiaki Murai
Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, Yanagido, Gifu 501-1193, Japan

1
Tetrahedron Letters
journal h omepage: www.els evier. com
Pd/phenanthroline-catalyzed arylative cyclization of o-(1-alkynyl)thioanisoles:
synthesis of 3-arylated benzo[b]thiophenes
Takayuki Yamauchi, Fumitoshi Shibahara and Toshiaki Murai
a Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, Yanagido, Gifu 501-1193, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The arylative cyclization of o-(1-alkynyl)thioanisoles with aryl iodides in the presence of catalytic
amounts of [Pd(phen)2][PF6]2 resulted in the efficient formation of 3-arylated benzo[b]thiophenes,
and a range of aryl iodides with electron-donating or –withdrawing groups could be used. While this
reaction proceeded in the presence of aromatic and aliphatic groups on the terminal alkynyl carbon
atom, silyl and alkoxycarbonyl groups hampered the reaction. Furthermore, this method could be
extended to the synthesis of 3-arylated indoles from N,N-dimethyl-o-(1-alkynyl)aniline. All these
reactions proceeded smoothly via cleavage of the carbon-heteroatom bond. In addition to the desired
cyclization products, the use of a o-(hydroxypropyl)phenylmethyl substituent on the sulfur atom
afforded isochroman, which should be formed by the intramolecular attack of a hydroxy group onto
the benzylic carbon atom.
Available online
Keywords:
arylative cyclization
o-(1-alkynyl)thioanisoles
[Pd(phen)2][PF6]2 catalyst
3-arylated benzo[b]thiophenes
Introduction
Multi-substituted benzo-fused heterocycles, such as
benzo[b]thiophenes, exhibit a diverse range of biological
activity1 and have been applied in functional materials.2
Accordingly, various efficient and selective methods for the
generation of such functionalized benzo-fused heterocycles
have been developed over the last decades. For the construction
of benzo-fused heterocycles, π-acidic transition metal-mediated
intramolecular cyclizations of 1-alkynylarenes with tethered
heteroatom nucleophiles at the o-position proved to be very
efficient.3 In the context of these cyclization reactions, Cacchi et
al., Larock et al., and others reported that Pd-catalyzed arylative
cyclizations of alkynylarenes, containing nucleophilic groups in
close proximity with e.g. nitrogen and oxygen atoms, represent
powerful tools for the formation of 3-arylated -benzofurans and
-indoles (eq. 1).4 These reactions can be carried out using
readily available o-alkynylarenes as starting materials in the
presence of a wide variety of Pd catalysts. As these reactions
are widely applicable and compatible with a broad range of
functional groups, a wide variety of substituted benzo-fused
heterocycles, can thus be obtained. However, this method is not
suitable for the synthesis of 3-arylated benzo[b]thiophenes, as
sulfur atoms often deactivate transition metal catalysts.5
able to mediate the direct arylation of heteroarenes with
thiocarbonyl groups, even though the latter may act as a strong
catalyst poison.7 During the course of this study, 3-arylated
benzo[b]thiophenes were obtained in 23% yield unexpectedly
from
the
reaction
of
heteroaryl-substituted
o-(1-
alkynyl)thioanisole and aryl halides under direct arylation
conditions using [Pd(phen)2][PF6]2 (eq. 3). This reaction
proceeded via an arylative cyclization involving the cleavage of
the C-S bond. We envisioned that such arylative cyclizations
should represent a more efficient synthetic route to 3-arylated
benzo[b]thiophenes compared to the corresponding halo-
cyclization/cross-coupling methods, and consequently carried
out further investigations. Herein, we report the first examples
for a Pd/phenanthroline-catalyzed arylative cyclization of o-(1-
alkynyl)thioanisoles and aryl iodides to afford 3-arylated
benzo[b]thiophenes (eq. 4).
Results and Discussions
Initially, we treated o-(1-alkynyl)thioanisole 1a with aryl
iodide 2a using the arylative cyclization conditions reported for
N,N-dialkyl-o-(1-alkynyl)anilines4c-d,
and
o-(1-
alkynyl)anisoles.8 However, these conditions did not furnish the
desired product 3 (Table 1, entries 1 and 2). In contrast, the use
of [Pd(phen)2][PF6]2 (5 mol%) as a catalyst yielded the desired
product 3aa, which was confirmed by GC-MS, albeit in fairly
low yield (entry 2). The addition of Na2CO3 furnished 3aa in
higher yield (entry 4), and further tests of other inorganic salts
Therefore,
a
two
step
synthesis
of
3-arylated
benzo[b]thiophenes, including halo-cyclization of o-(1-
alkynyl)thioanisoles and a cross-coupling reaction of 3-
halogenated benzothio[b]phenes with metalated arenes is
utilized (eq. 2).6 Recently, we reported that [Pd(phen)2][PF6]2 is
———
 e-mail: fshiba@gifu-u.ac.jp (FS)
 e-mail: mtosh@gifu-u.ac.jp (TM)

2
Tetrahedron Letters
revealed that Cs2CO3 provided the best results (entry 6). Also,
yield of 3aa was only moderate (Table 2, entry 1). Decreasing the
reaction temperature to 120 ºC increased the yield of 3aa to 66%
(entry 2), whereas lower yields were obtained at 110 ºC (entry 3)
and 90 ºC (entry 4). Prolonging the reaction time did not increase
the yield of 3aa (entry 5). Instead, several products including a
benzothiophene were observed by GC-MS.
other Pd-catalyzed systems (e.g. Pd(0)/1,10-phenanthroline)
gave poor yield (see Supporting Information.)
Scheme 1. Substrate scope of the arylative cyclization of o-(1-
alkynyl)thioanisoles 1 and I-Ar 2
Table 1. Arylative cyclization of o-(1-alkynyl)thioanisole 1a
entry
1
conditions
Pd(PPh)2Cl2 (10 mol%), n-Bu4NI (10
mol%) CH3CN, 90 ºC (MW), 1 h
yielda
n.d.
2b
3
Cu(OTf)2 (10 mol%), DCE, 60 ºC, 10 h
n.d.
[Pd(phen)2][PF6]2 (5 mol%)
DMA, 150 ºC, 20 h
trace
[Pd(phen)2][PF6]2 (5 mol%)
Na2CO3 (1.1 equiv)
DMA, 150 ºC, 20 h
[Pd(phen)2][PF6]2 (5 mol%)
K2CO3 (1.1 equiv)
DMA, 150 ºC, 20 h
[Pd(phen)2][PF6]2 (5 mol%)
Cs2CO3 (1.1 equiv)
24%
24%
46%c
４
5
6
DMA, 150 ºC, 20 h
a Yields determined by GC analysis using n-heptadecane as an
b
internal standard;
Ph2IPF6 was used instead of I-Ar;
c isolated yield; d n.d. = not detected.
Table 2. Optimization of reaction conditions
a Isolated yield; b K2CO3 was used instead of Cs2CO3; c relative to
the amount of I-Ar.
With optimized conditions in hand, we examined the scope of
this arylative cyclization with respect to o-(1-alkynyl)thioanisoles
1 and aryl iodides 2 (Scheme 1). We observed that the electronic
properties of the aromatic rings in 2 had a strong impact on the
yield of 3 (entries 1-6). For instance, reactions with 2a-d, which
contain electron-withdrawing -CF3, -CN, -COOEt, and -NO2
groups, afforded the arylative cyclization products 3aa-3ad in
good yield (entries 1-4). In contrast, low yields were obtained
when 4-iodoanisole (2e) and iodobenzene (2f) were used (entries
5 and 6). The reaction of various o-(1-alkynyl)thioanisoles 1a-f
with 2a furnished the corresponding benzo[b]thiophenes 3ba-3fa
in good yield, regardless of the electronic character and steric
hindrance of the aromatic groups (R) attached to the alkynyl
entry
1
2
T (ºC)
150
120
110
90
yielda
46%b
conv.
100%
72%
33%
7%
78%(66%b)
33%
3
4
5%
60%
5c
120
89%
a Yields determined by GC analysis using n-heptadecane as an
internal standard; b isolated yield; c t = 31 h.
Subsequently, we tried to optimize the reaction temperature, as
starting material 1a was completely consumed at 150 ºC, but the

3
carbon atoms (entries 7-11). Substrate 1g, which carried an alkyl
group on the alkynyl carbon atom, also afforded the arylative
cyclization product 3ga in 47% yield (entry 12). Silyl 1h and
alkoxycarbonyl groups 1i were not compatible with these
arylative cyclization conditions, and yielded 2,3-diarylated
benzo[b]thiophene 3ba in 44% and 39%, respectively (entries 13
and 14).
sulfur atom, and treated it with aryl iodide 2a under identical
cyclization conditions. Using (o-alkynylphenyl)sulfide 1j as a
substrate furnished, in addition to the arylative cyclization
product 3aa, benzaldehyde (8) in 7% yield, even though the mass
balance of the reaction was low (eq. 8). The low yield of the
products derived from the benzyl group on the sulfur atom may
be due to several follow-up reactions of the initially formed
products. To efficiently trap the substituents of the sulfur atom,
we envisioned an approach, in which the substituents within the
starting material trap themselves. Accordingly, we carried out the
[Pd(phen)2][PF6]2-catalyzed reaction between 1k and 2a (eq. 9).
In this case, the intramolecular SN2 cyclization of the substituent
on the sulfur atom occurred readily and generated isochroman (9)
in 38% yield in addition to 3ka (66%). On the basis of these
results, the cleavage of the carbon-sulfur bonds in a catalytic
cycle may be suggested to involve ionic processes. Additionally,
catalytic cycles involving Pd(II) and Pd(IV) species appears to be
involved.7
We then turned our attention to the reaction of other
nucleophilic heteroatom-containing o-(1-alkynyl)arenes. Initially,
the arylative cyclization of N,N-dimethyl-o-(1-alkynyl)aniline 4
proceeded smoothly to afford the corresponding 3-arylated
indoles 5 in excellent yield, regardless of the electronic character
of the aryl iodides (2), albeit that higher reaction temperatures
were required (eq. 5). However, when [Pd(phen)][BArF]2 (BArF =
tetrakis[3,5-bis(trifluoromethyl)phenylborate]) was used as a
catalyst, a reaction using o-(1-alkynyl)anisole 6 produced merely
trace amounts of 3-arylated benzofuran 7 (eq. 6).
We previously reported that [Pd(phen)2][PF6]2 exhibits
catalytic activity towards the C-H bond arylation of heteroarenes.9
Based on these reports, it became clear that the following
question requires answering: does the intramolecular cyclization
of o-(1-alkynyl)thioanisoles 1 initially generates a 3-unsubstituted
benzo[b]thiophene, which is subsequently transformed into 3-
arylated benzo[b]thiophene 3 via C-H bond arylation. When the
preformed 3-unsubstituted benzo[b]thiophene 8 was treated with
aryl iodide 2a under arylative cyclization conditions, 3-arylated
benzo[b]thiophene 3da was obtained (eq. 7). However, the yield
was substantially lower than in the reaction with the
corresponding alkyne 1d (cf. Scheme 1, entry 9). Furthermore, the
reaction of o-(1-alkynyl)thioanisoles 1 in the absence of aryl
iodides 2 under arylative cyclization conditions did not proceed at
all. These results indicate that the present reaction should be a
tandem, rather than a one-pot reaction.
In conclusion, we developed an arylative cyclization between
o-(1-alkynyl)thioanisoles 1 and aryl iodides 2, involving a
demethylation and subsequent coupling reaction with aryl halides.
To the best of our knowledge, this study presents the first
examples of arylative cyclizations via the cleavage of the C-S
bonds in o-(1-alkynyl)thioanisoles 1. The addition of inorganic
salts such as Cs2CO3 was essential for this arylative cyclization,
although its role in the reaction still remains to be ascertained.
Nevertheless, a range of aromatic substituents could be
incorporated into the products 3. Further studies on the use of
[Pd(phen)2][PF6]2 as an arylative cyclization catalyst for other
substrates such as alkynyl sulfides and alkenes are in currently in
progress in our laboratories.
Acknowledgments
This work was supported by ACT-C from JST, Japan. T.Y.
would like to thank to the JSPS for a Research Fellowship for
Young Scientists.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at XX.
In order to gain insight into the reaction mechanism of the
cleavage of the C-S bond during the arylative cyclization of 1,
further examinations were carried out. For similar transition
References and notes
1.
a) Clouser, C. L.; Chauhan, J.; Bess, M. A.; Oploo, J.; Zhou, D.;
Dimick-Gray, S.; Mansky, L. M.; Patterson, S. E. Bioorg. Med. Chem.
Lett. 2012, 22, 6642-6646. b) Li, L.; Chang, L.; Pellet-Rostaing, S.;
Liger, F.; Lemaire, M.; Buchet, R.; Wu, Y. Bioorg. Med. Chem. Lett.
2009, 17, 7290-7300. c) Shahapurkar, S.; Kawathekar, N.; Chaturvedi,
S. C. Pharmazie 2005, 60, 254-258. d) He, S.; Jain, P.; Lin, B.; Ferrer,
M.; Hu, Z.; Southall, N.; Hu, X.; Zheng, W.; Neuenswander, B.; Cho,
C.; Chen, Y.; Worlikar, S.; Aube, J.; Larock, R. C.; Schoenen, F. J.;
Marugan, J. J.; Liang, T. J.; Frankowski, K. J. ACS Comb. Sci. 2015, 17,
641-652. e) Rana, M.; Lachmann, J.; Ungermann, C. Mol. Biol. Cell
2015, 26, 2535-2549. f) Laube, M; Gassner, C.; Sharma, S. K.; Günther,
metal-catalyzed
intramolecular
cyclizations
of
o-(1-
alkynyl)arenes, usually an SN2-type cleavage of the carbon-
heteroatom bond is proposed.10 Alternatively, the involvement of
radical species is conceivable.11 However, the addition of radical
inhibitors such as Galvinoxyl, 2,2,6,6-tetramethylpiperidine-1-
oxyl (TEMPO), or dibutylhydroxytoluene (BHT) did not hamper
the arylative cyclization (see SI).
In order to capture the substituents eliminated from the sulfur
atom, we prepared a substrate with a bulky substituent on the

4
Tetrahedron Letters
R.; Pigorsch, A.; König, J.; Köckerling, M.; Wuest, F.; Pietzsch, J.;
Kniess, T. J. Org. Chem. 2015, 80, 5611-5624. g) Luz, J. G.; Carson, M.
W.; Condon, B.; Clawson, D.; Pustilnik, A.; Kohiman, D. T.; Barr, R. J.;
Bean, J. S.; Dill, M. J.; Sindelar, D. K.; Maletic, M.; Coghian, M. J. J.
Med. Chem. 2015, 58, 6607-6618.
2.
a) Chen, H.; Delaunay, W.; Li, J.; Wang, Z.; Bouit, P.; Tondelier, D.;
Geffroy, B.; Mathey, F.; Duan, Z.; Réau, R.; Hissier, M. Org. Lett. 2013,
15, 330-333. b) Tsuji, H.; Mitsui, L.; Ilies, L.; Sato, Y.; Nakamura, E. J.
Am. Chem. Soc. 2007, 129, 11902-11903. c) Tsuji, H.; Yokoi, Y.; Mitsui,
C.; Ilies, L.; Sato, Y.; Nakamura, E. Chem. Asian. J. 2009, 4, 655- 657.
d) Takimiya, K.; Kunugi, Y.; Konda, Y.; Niiharam N.; Otsubo, T. J. Am.
Chem. Soc. 2004, 126, 5084-5085.
For reviews, see: a) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104,
2127-2198. b) Battistuzzi, G.; Cacchi, S.; Fabrizi, G. Eur. J. Org. Chem.
2002, 2671-2681. c) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873-
2920. d) Cacchi, S.; Fabrizi, G.; Goggiomani, A. Heterocycles 2002, 56,
613-632. e) Balme, G.; Bouyssi, D.; Lomberget, T.; Monterio, N.
Synthesis 2003, 14, 2115-2134. f) Zeni, G.; Larock, R. C. Chem. Rev.
2004, 104, 2285-2310. g) Larock, R. C. Top. Organomet. Chem. 2005,
14, 147.
a) Cacchi, S.; Fabrizi, G.; Goggiamani, A. Adv. Synth. Catal. 2006, 348,
1301-1305. b) Cacchi, S.; Fabrizi, G.; Goggiamani, A.; Perboni, A.;
Sferrazza, A.; Stabile, P. Org. Lett. 2010, 12, 3279-3281. c) Ha, T. M.;
Yao, B.; Wang, Q.; Zhu, J. Org. Lett. 2015, 17, 1750-1753. d) Chen, Y.;
Markina, N. A.; Larock, R. C. Tetrahedron 2009, 65, 8908-8915. e) Hu,
Y.; Nawoschik, K. J.; Liao, Y.; Ma, J.; Fathi, R.; Yang, Z. J. Org. Chem.
2004, 69, 2235-2239.
Highlights
Arylative cyclization of o-(1-alkynyl)thioanisoles
with aryl iodides is featured.
[Pd(phen)2][PF6]2 works as a catalyst, and
organosulfur-containing functional groups do not
hamper the catalytic reactions.
3.
4.
A range of 3-arylated benzo[b]thiophenes are
provided.
The reaction involves the cleavage of the carbon-
sulfur bond.
5.
6.
a) Kulishkin, N. T.; Mashkina, A. V. React. Kinet. Catal. Lett. 1991,
45, 41-47. b) Fitzharris, W. D.; Manogue, W. H. Journal of Catalysis
1982, 76, 369-384. c) Kitayama, Y.; Hayakawa, M. Chem. Lett. 1973,
181-184. d) Nakamura, I.; Sato, T.; Yamamoto, Y. Angew. Chem. Int.
Ed. 2006, 45, 4473-4475.
a) Scott, S. A.; Specer, C. T.; O’Reilly, M. C.; Brown, K. A.; Lavieri,
R. R.; Cho, C.; Jung, D.; Larock, R. C.; Brown, H. A.; Lindsley, C. W.
ACS Chem. Biol. 2015, 10, 421-432. b) Cho, C.; Neuenswander, B.;
Lushington, G. H.; Larock, R. C. J. Comb. Chem. 2009, 11, 900-906. c)
Lu, W.; Wu, M. Tetrahedron 2007, 356-362. d) Cho, C.; Jung, D.;
Larock, R. C. Tetrahedron Lett. 2010, 51, 6485-6488. e) Cho, C.; Jung,
J.; Neuenswander, B.; Larock, R. C. ACS Comb. Sci. 2011, 13, 501-
510.
7.
8.
Yamauchi, T.; Shibahara, F.; Murai, T. Org. Lett. 2015, 17, 5392-5395.
Chen, J.; Chen, C.; Chen, J.; Wang, G.; Qu, H. Chem. Commun. 2015,
51, 1356-1359.
9.
a) Shibahara, F.; Yamaguchi, E.; Murai, T. Chem. Commun. 2010, 46,
2471-2473. b) Shibahara, F.; Yamaguchi, E.; Murai, T. J. Org. Chem.
2011, 76, 2680-2693. c) Shibahara, F.; Yamauchi, T.; Yamaguchi, E.;
Murai, T. J. Org. Chem. 2012, 77, 8815-8820. d) Shibahara, F.; Murai,
T. Asian J. Org. Chem. 2013, 2, 624-636. e) Yamauchi, T.; Shibahara,
F.; Murai, T. J. Org. Chem. 2014, 79, 7185-7192.
10. For reports on eliminated heteroatom-derived substituents via SN2
mechanisms, see: a) Xia, X.; Wang, N.: Zhang, L.; Song, X.; Liu, X.;
Liang, Y. J. Org. Chem. 2012, 77, 9163-9170. b) Yao, B.; Wang, Q.;
Zhu, J. Angew. Chem. Int. Ed. 2012, 51, 12311-12315. c) Chen, J.;
Chen, C.; Chen, J.; Wang, G.; Qu, H. Chem. Commun. 2015, 51, 1356-
1359.
11. For reports on the cleavage of C-S bonds via radical mechanisms, see:
a) Baciocchi, E.; Bettoni, M.; Giacco, T. D.; Lanzalunga, O.;
Mazzonna, M.; Mencarelli, P. J. Org. Chem. 2011, 76, 573-582. b)
Kitamura, T.; Kobayashi, S.; Taniguchim H. Chem. Lett. 1988, 1637-
1638. c) Baciocchi, E.; Lanzalunga, O.; Malandrucco, S. J. Am. Chem.
Soc. 1996, 118, 8973-8974.