Palladium-catalysed direct synthesis of benzo[b]thiophenes from thioenols

Article abstract of DOI:10.1039/b811362a

The one-pot conversion of thioenols into benzo[b]thiophenes was achieved by using a simple palladium catalyst such as PdCl₂ or PdCl ₂(cod). The Royal Society of Chemistry.

Full text of DOI:10.1039/b811362a

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Palladium-catalysed direct synthesis of benzo[b]thiophenes from
thioenolsw
Kiyofumi Inamoto,* Yukari Arai, Kou Hiroya and Takayuki Doi*
Received (in Cambridge, UK) 3rd July 2008, Accepted 7th August 2008
First published as an Advance Article on the web 24th September 2008
DOI: 10.1039/b811362a
Table 1 Optimisation of the reaction conditions
The one-pot conversion of thioenols into benzo[b]thiophenes was
achieved by using a simple palladium catalyst such as PdCl2 or
PdCl2(cod).
Multi-substituted benzo[b]thiophenes are of considerable im-
portance, as they exhibit various biological activities1 and also
provide useful properties in materials science.2 A number of
methods to synthesise this class of compounds have been
reported in recent years,3 most of which involve the cyclisation
of benzenethiol derivatives. However, facile and versatile
methods to access multi-substituted benzo[b]thiophenes are
still limited. Furthermore, catalytic cyclisation approaches
using transition metals for the construction of the benzo-
[b]thiophene skeleton, which would provide a more efficient
and practical route, are extremely rare in the literature,
presumably due to catalyst poisoning by sulfur. Only a few
reports of this nature have appeared,4 in which Au4a or Pd4b
catalysts have been employed to effect C–S bond formation.
In connection with our studies on the synthesis of hetero-
cyclic compounds via transition metal-catalysed reactions,5 we
recently developed an efficient method for the construction of
indazoles via a palladium-catalysed C–H activation/intra-
molecular amination sequence (Scheme 1, X = N, Y = NTs).5a
In this context, we became interested in whether this intra-
molecular C–H amination process could be extended to C–S
bond formation to prepare sulfur-based heterocycles, such as
benzo[b]thiophenes (Scheme 1, X = CR0, Y = S).
Yield (%)a
2a
3a
1a
Entry Catalyst system
Temp./1C
1
2
50 mol% Pd(OAc)2/
100 mol% Cu(OAc)2
25 mol% Pd(OAc)2/
100 mol% Cu(OAc)2
25 mol% Pd(OAc)2
25 mol% Pd(OAc)2
25 mol% Pd(TFA)2
25 mol% Pd(PPh3)4
25 mol% PdCl2
80
19
2
0
80
8
21
0
3
4
5
6
7
80
22
27
10
37
10
0
Trace
59
0
0
0
0
63
14
0
0
0
120
120
120
120
120
120
120
120
120
120
120
120
21
36
0
Trace
Trace
75
80
82
85
8
9
25 mol% PdCl2(cod)
10 mol% PdCl2
o3
2
2
10
11
12
13
14
15
a
10 mol% PdCl2(cod)
None
10 mol% NiCl2
10 mol% PtCl2
10 mol% RuCl3
10 mol% AuCl
Trace 11
Trace 14
8
13
4
23
32
46
b
b
Isolated yield. n-Hydrate (n = 1–3).
catalytic systems (palladium/reoxidant combinations) and sol-
vents, the desired 2,3-diphenylbenzo[b]thiophene (2a) was not
obtained in a satisfactory yield (up to 12% yield with 25 mol%
of palladium source). However, to our surprise, further opti-
misation revealed that this palladium-catalysed cyclisation
proceeded more efficiently in the absence of reoxidants.
Namely, the reaction of 1a using 25 mol% of Pd(OAc)2 and
100 mol% of Cu(OAc)2 as a catalyst system in DMSO at 80 1C
resulted in the formation of 2a in only an 8% yield (Table 1,
entry 2), while the use of Pd(OAc)2 as the sole catalyst
delivered 2a in a 22% yield (Table 1, entry 3). Increasing the
reaction temperature to 120 1C gave a slightly better result
(Table 1, entry 4). From subsequent examinations of various
palladium sources, PdCl2 and PdCl2(cod) proved to be the best
catalysts (Table 1, entries 9 and 10); 10 mol% of palladium
efficiently catalysed this cyclisation, producing 2a in high
yields (82 and 85%, respectively).6 DMSO is crucial for high
conversion in this process.6 Interestingly, disulfide 3a was
observed in almost all cases, yields of which were dependent
on the reaction conditions employed. Essentially none of the
desired product, 2a, was obtained in the absence of a
Initial studies to determine the optimal reaction conditions
were performed using 1,2,2-triphenylethenethiol (1a) as a
substrate (Table 1). Despite extensive screening of a range of
Scheme 1 A strategy for the synthesis of heterocycles via palladium-
catalysed C–H activation followed by intramolecular carbon–hetero-
atom bond formation.
Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3,
Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan.
E-mail: inamoto@mail.pharm.tohoku.ac.jp;
doi_taka@mail.pharm.tohoku.ac.jp; Fax: +81 22-795-6864;
Tel: +81 22-795-6866
w Electronic supplementary information (ESI) available: Experi-
mental procedures and spectroscopic data for thioenols and
benzo[b]thiophenes. See DOI: 10.1039/b811362a
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Table 2 Benzo[b]thiophene synthesis from symmetrically-substituted
thiolsa
palladium catalyst (Table 1, entry 11). Furthermore, other
metal salts, such as NiCl2, PtCl2, RuCl3 and AuCl, were not
effective catalysts (Table 1, entries 12–15).
Intrigued by this benzo[b]thiophene ring formation, we next
investigated the scope of the reaction by employing several
kinds of thioenol, 1 (Table 2). In the case of substrates that
had identical Ar1 substituents (‘symmetric’ substrates),
substituted 2,3-diarylbenzo[b]thiophenes 2 were generally ob-
tained in good to high yields from the corresponding 4,40- and
3,30-substituted thioenols, 1 (Table 2, entries 1–5). No regioi-
Yield (%)b
PdCl2 PdCl2(cod)
Entry Starting material Product
1
somers,
such
as
3-(3-methoxyphenyl)-7-methoxy-2-
77
74
72
85
81
74
78
89
phenylbenzo[b]thiophene, were observed in the reaction of
the substrate with methoxy groups at the 3- and 30-positions
(1f) (Table 2, entry 5). In contrast, a satisfactory result was not
obtained from the reaction of 1g, which had an ortho-methoxy
group on each Ar1 (Table 2, entry 6). In addition, 2-anisoyl-3-
phenylbenzo[b]thiophene (2h) was obtained in high yield
(Table 2, entry 7). The formation of a small amount of the
corresponding disulfide was observed in some cases (Table 2,
entries 1, 2, 3 and 6).
2
3
4
The reaction of a substrate that had only one methoxy-
substituted benzene ring (‘dissymmetric’ substrate) was also
examined using our optimal reaction conditions. Despite the
starting thioenol, 1i, being a single isomer, the cyclised product
obtained was a mixture of two benzo[b]thiophenes, 2i-A and
2i-B, suggesting that the E/Z-isomerisation of the thioenol
could be occurring relatively easily during this process
(Scheme 2).
The reaction conditions developed above were also success-
fully applied to the cyclisation of another class of substrates,
1j and 1k, which were readily prepared from rhodanine
and benzaldehyde. As
a result, 2-alkoxycarbonylbenzo-
[b]thiophenes 2j and 2k were obtained in high yields, although
a relatively high catalyst loading was necessary for the best
conversion (Scheme 3).
Although extensive mechanistic studies have not yet been
conducted, we believe that this palladium-catalysed cyclisation
proceeds via the formation of disulfide 3 (Fig. 1). DMSO
itself,7 or in combination with a variety of acidic co-reagents,8
has been known to mediate the transformation of thiols to
5
72
63
6
7
o16 o13
Scheme 2 The reaction of ‘dissymmetric’ substrate 1i.
89
78
a
Reagents: 1 (1 equiv.), ‘‘Pd’’ (10 mol%) and DMSO (0.05 M).
Isolated yield.
b
Scheme 3 The synthesis of 2-alkoxycarbonylbenzo[b]thiophenes.
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Notes and references
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sous, P. Bouhours, E. David, S. Pellet-Rostaing, B. Marquet, N.
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2 For selected recent examples, see: (a) J. Gao, R. Li, L. Li, Q. Meng,
H. Jiang, H. Li and W. Hu, Adv. Mater., 2007, 19, 3008–3011;
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251111-1–251111-3; (c) V. A. Bren, A. D. Dubonosov, V. I. Minkin,
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3 For selected recent examples, see: (a) K. Kobayashi, D.
Nakamura, S. Fukamachi and H. Konishi, Heterocycles, 2008,
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Lett., 2007, 9, 5573–5576; (c) H. J. Jeong, U. Y. Yoon, S. H. Jang,
U.-A. Yoo, S. N. Kim, B. T. Truong, S. C. Shin, Y.-J. Yoon, O. M.
Singh and S.-G. Lee, Synlett, 2007, 1407–1410; (d) C. T. Bui and B.
L. Flynn, J. Comb. Chem., 2006, 8, 163–167; (e) C. F. Roberts and
R. C. Hartley, J. Org. Chem., 2004, 69, 6145–6148; (f) D. Allen, O.
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hedron Lett., 2004, 45, 9645–9647; (g) S.-M. Yang, J.-J. Shie, J.-M.
Fang, S. K. Nandy, H.-Y. Chang, S.-H. Lu and G. Wang, J. Org.
Chem., 2002, 67, 5208–5215; (h) B. L. Flynn, P. Verdier-Pinard and
E. Hamel, Org. Lett., 2001, 3, 651–654; (i) R. C. Larock and D.
Yue, Tetrahedron Lett., 2001, 42, 6011–6013.
4 (a) I. Nakamura, T. Sato and Y. Yamamoto, Angew. Chem., Int.
Ed., 2006, 45, 4473–4475; (b) M. C. Willis, D. Taylor and A. T.
Gillmore, Tetrahedron, 2006, 62, 11513–11520; (c) N. Arnau, M.
Moreno-Manas and R. Pleixats, Tetrahedron, 1993, 47,
11019–11028.
5 (a) K. Inamoto, T. Saito, M. Katsuno, T. Sakamoto and K. Hiroya,
Org. Lett., 2007, 9, 2931–2934; (b) K. Inamoto, M. Katsuno, T.
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63, 2695–2711; (c) K. Hiroya, S. Matsumoto, M. Ashikawa, K.
Ogiwara and T. Sakamoto, Org. Lett., 2006, 8, 5349–5352.
6 The use of a reduced amount of palladium catalyst, such as 5
mol% PdCl2, led to a decreased yield (44% of 2a along with 27%
of 3a). See the ESIw for the detailed results of screening.
7 (a) W. E. Fristad and J. R. Peterson, Synth. Commun., 1985, 15, 1–5;
(b) T. J. Wallace, J. Am. Chem. Soc., 1964, 86, 2018–2021; (c) C. N.
Yiannios and J. V. Karabinos, J. Org. Chem., 1963, 28, 3246–3248.
8 (a) J. B. Arterburn, M. C. Perry, S. L. Nelson, B. R. Dible and M.
S. Holguin, J. Am. Chem. Soc., 1997, 119, 9309–9310; (b) A.
Fig. 1 A plausible reaction mechanism.
Scheme 4 The conversion of disulfide 3a into benzo[b]thiophene 2a.
disulfides. The palladium catalyst may also be involved in this
oxidation step because the heating of 1a in DMSO in the
absence of palladium resulted in the formation of disulfide 3a
in only an 11% yield (Table 1, entry 11).8a,b,9 Disulfide 3,
formed from the corresponding thioenol, 1, undergoes oxida-
tive addition to palladium, leading to complex 4.10 Electro-
philic attack of the aryl ring, either at the palladium centre
(Fig. 1; path A, 4 to 5) or at the sulfur atom (path B, 4 to 2),
may occur next. From the former pathway, the formation of
six-membered palladacycle 5, followed by reductive elimina-
tion, provides benzo[b]thiophene 2. The direct formation of 2,
along with starting thioenol 1 and reduced palladium, occurs
in the latter pathway. Direct C–H activation of thioenol 1 is
unlikely, although we cannot completely rule out this mecha-
nism at present.
The above-proposed mechanism complements the following
observations: (1) the formation of a small amount of disulfide
compound was observed in most cases, (2) oxidants are not
necessary for this process and (3) isolated disulfide 3a can be
converted into benzo[b]thiophene 2a in the presence of a
palladium catalyst (Scheme 4).11,12
Cervilla, A. Corma, V. Fornes, E. Llopis, P. Palanca, F. Rey
´
and A. Ribera, J. Am. Chem. Soc., 1994, 116, 1595–1596; (c) T.
Aoda, T. Akasaka, N. Furukawa and S. Oae, Bull. Chem. Soc.
Jpn., 1976, 49, 1441–1442.
In summary, we have developed a novel method for the
direct synthesis of multi-substituted benzo[b]thiophenes
through the unprecedented palladium-catalysed cyclisation
of thioenols. The procedure presented here employs a simple
catalyst system, in which PdCl2 or PdCl2(cod) is the sole metal
source required, and where additional redox-active reagents
are not necessary. For this transformation, we postulate a
reaction mechanism in which palladium might be playing a
dual role, both in the formation of disulfides and in the
subsequent cyclisation. This direct high-yielding and atom-
economical procedure for the synthesis of benzo[b]thiophenes
will find applications in a range of areas, including medicinal
and materials chemistry. Further investigations to expand the
substrate scope, as well as to clarify the precise reaction
mechanism, are now in progress.
9 Some metal compounds are also known to be involved in the
oxidation of thiols. For selected examples, see: (a) M. Kirihara, K.
Okubo, T. Uchiyama, Y. Kato, Y. Ochiai, S. Matsushita, A.
Hatano and K. Kanamori, Chem. Pharm. Bull., 2004, 52,
625–627; (b) N. Iranpoor and B. Zeynizadeh, Synthesis, 1999,
49–50; (c) T. J. Wallace, J. Org. Chem., 1966, 31, 1217–1221.
10 For selected recent examples of the oxidative addition of S–S
bonds to Pd(0), see: (a) V. P. Ananikov, M. A. Kabeshov, I. P.
Beletskaya, V. N. Khrustalev and M. Y. Antipin, Organometallics,
2005, 24, 1275–1283; (b) J. M. Gonzales, D. G. Musaev and K.
Morokuma, Organometallics, 2005, 24, 4908–4914.
11 Interestingly, Pd(0) has no catalytic activity for this transfor-
mation; only 4% of 2a, along with 92% of recovered 3a, was
obtained in the presence of 20 mol% Pd2(dba)3.
12 Either Pd(0) and Pd(II), Pd(II) and Pd(IV), or both mechanisms can
be operating during this process. Detailed mechanistic studies are
currently under way.
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Chem. Commun., 2008, 5529–5531 | 5531