A practical, one-pot synthesis of highly substituted thiophenes and benzo[b]thiophenes from bromoenynes and o-alkynylbromobenzenes

Article abstract of DOI:10.1021/ol201970m

An efficient synthesis of thiophenes and benzo[b]thiophenes has been developed from easily available bromoenynes and o-alkynylbromobenzene derivatives. This novel one-pot procedure involves a Pd-catalyzed C-S bond formation using a hydrogen sulfide surrogate followed by a heterocyclization reaction. Moreover, in situ functionalization with selected electrophiles further expands the potential of this methodology to the preparation of the corresponding highly substituted sulfur heterocycles.

Full text of DOI:10.1021/ol201970m

ORGANIC
LETTERS
2011
Vol. 13, No. 19
5100–5103
A Practical, One-Pot Synthesis of Highly
Substituted Thiophenes and
Benzo[b]thiophenes from Bromoenynes
and o-Alkynylbromobenzenes
ꢀ
Veronica Guilarte, Manuel A. Fernandez-Rodrıguez, Patricia Garcıa-Garcıa,
Elsa Hernando, and Roberto Sanz*
ꢀ
´
´
´
ꢀ
Departamento de Quımica,Area de Quımica Organica, Facultad de Ciencias,
´
Universidad de Burgos, Pza. Misael Banuelos s/n, 09001-Burgos, Spain
´
ꢀ
~
rsd@ubu.es
Received July 22, 2011
ABSTRACT
An efficient synthesis of thiophenes and benzo[b]thiophenes has been developed from easily available bromoenynes and o-alkynylbromobenzene
derivatives. This novel one-pot procedure involves a Pd-catalyzed CÀS bond formation using a hydrogen sulfide surrogate followed by a
heterocyclization reaction. Moreover, in situ functionalization with selected electrophiles further expands the potential of this methodology to the
preparation of the corresponding highly substituted sulfur heterocycles.
Thiophenes, as well as its benzofused derivative
benzo[b]thiophenes, are basic skeletons found in new
electronic materials1 as well as in biologically active
molecules.2 Indeed, these sulfur heterocycles are essen-
tial components of clinically important drugs such as
clopidogrel,3 raloxifene,4 and zileuton.5 Consequently,
the development of facile and convenient synthetic
routes to these sulfur-based heterocycles is of high
interest.6 In particular, one of the most useful ap-
proaches to the synthesis of benzo[b]thiophenes involves
a 5-endo-dig cyclization reaction from o-alkynylaryl
thioether derivatives.7 These precursors are typically
(1) (a) Ebata, H.; Miyazaki, E.; Yamamoto, T.; Takimiya, K. Org.
Lett. 2007, 9, 4499–4502. (b) Zhou, Y.; Liu, W.-J.; Ma, Y.; Wang, H.; Qi,
L.; Cao, Y.; Wang, J.; Pei, J. J. Am. Chem. Soc. 2007, 129, 12386–12387.
(c) Funahashi, M.; Zhang, F.; Tamaoki, N. Adv. Mater. 2007, 19, 353–
358. (d) Handbook of Thiophene-Based Materials: Applications in
Organic Electronics and Photonics; Perepichka, I. F., Perepichka, D. F.,
Eds.; John Wiley & Sons: West Sussex, U.K., 2009.
(2) (a) Wu, C.; Decker, E. R.; Blok, N.; Bui, H.; You, T. J.; Wang, J.;
Bourgoyne, A. R.; Knowles, V.; Berens, K. L.; Holland, G. W.; Brock,
T. A.; Dixon, R. A. F. J. Med. Chem. 2004, 47, 1969–1986. (b) Guo,
H. F.; Shao, H. Y.; Yang, Z. Y.; Xue, S. T.; Li, X.; Liu, Z. Y.; He, X. B.;
Jiang, J. D.; Zhang, Y. Q.; Si, S. Y.; Li, Z. R. J. Med. Chem. 2010, 53,
1819–1829.
(6) For recent examples, see: Benzothiophenes: (a) Bryan, C. S.;
Braunger, J. A.; Lautens, N. Angew. Chem., Int. Ed. 2009, 48, 7064–
7068. (b) Li, C.-L.; Zhang, X.-G.; Tang, R.-Y.; Zhong, P.; Li, J.-H.
J. Org. Chem. 2010, 75, 7037–7040. (c) Duan, Z.; Ranjit, S.; Liu, X. Org.
Lett. 2010, 12, 2430–2433. (d) Zeng, F.; Alper, H. Org. Lett. 2011, 13,
2868–2871. Thiophenes: (e) You, W.; Yan, X.; Liao, Q.; Xi, C. Org.
Lett. 2010, 12, 3930–3933.
(7) Gold(I)-catalyzed: (a) Nakamura, I.; Sato, T.; Yamamoto, Y.
Angew. Chem., Int. Ed. 2006, 45, 4473–4475. (b) Nakamura, I.; Sato, T.;
Terada, M.; Yamamoto, Y. Org. Lett. 2007, 9, 4081–4083. Halonium
ion promoted: (c) Flynn, B. L.; Verdier-Pinard, P.; Hamel, E. Org. Lett.
2001, 3, 651–654. (d) Yue, D.; Larock, R. C. J. Org. Chem. 2002, 67,
1905–1909. Cupric halide promoted: (e) Lu, W.-D.; Wu, M.-J. Tetra-
hedron 2007, 63, 356–362. PTSA-mediated: (f) Jacubert, M.; Hamze, A.;
Provot, O.; Peyrat, J.-F.; Brion, J.-D.; Alami, M. Tetrahedron Lett.
2009, 50, 3588–3592.
(3) Rogers, E.; Araki, H.; Batory, L. A.; McInnis, C. E.; Njardarson,
J. T. J. Am. Chem. Soc. 2007, 129, 2768–2769.
(4) Qin, Z.; Kasrati, I.; Chandrasena, R. E. P.; Liu, H.; Yao, P.;
Petukhov, P. A.; Bolton, J. L.; Thatcher, G. R. J. J. Med. Chem. 2007, 50,
2682–2692.
(5) Guinchard, X.; Denis, J. N. J. Org. Chem. 2008, 73, 2028–2031.
r
10.1021/ol201970m
Published on Web 09/01/2011
2011 American Chemical Society

prepared by the treatment of o-metalated arylalkynes
with electrophilic sulfur reagents8 or SNAr reactions.9
On the other hand, in recent years we have been involved
in different projects on the synthesis of regioselectively
functionalized heterocyclic compounds.10 In this context,
we have reported an efficient access to 3-halo-7-oxygen-
functionalized benzo[b]thiophenes by combined ortho-
lithiationÀhalocyclization strategies,11 and we have also
devised useful preparations of regioselectively alkoxy-
functionalized indoles12 and benzo[b]furans.13 In this con-
text we decided to tackle the synthesis of the corresponding
oxygen-substituted benzo[b]thiophene derivatives, which
are interesting compounds not previously described
(Scheme 1). Herein we report a new, easy, and efficient
access to (benzo[b])thiophenes through a tandem CÀS
coupling/heteroannulation reaction employing different
hydrogen sulfide surrogates14 and the use of a related
one-pot protocol in the presence of electrophiles for the
synthesis of the corresponding functionalized highly sub-
stituted (benzo[b])thiophenes.
was 3-bromo-2-(phenylethynyl)phenol 2, formed by the
cleavage of the corresponding O-protecting group,15
whereas the expected benzo[b]thiophenes 3 were obtained
in less than 10% yield (Scheme 2). Alternatively, we
envisioned that another entry to the benzothiophene moiety
from the same starting materials 1 could entail a Pd-
catalyzed CÀS coupling16 with a thiol surrogate to afford a
protected arenethiol intermediate,17 which after removal
of the protecting group could undergo a subsequent
heterocyclization (Scheme 2).
After screening several thiol surrogates, catalyst sys-
tems, and reaction conditions for the coupling, as well as
various reagents for the deprotection step, we found two
different one-pot procedures that allowed the efficient
synthesis of the desired 4-oxygen-functionalized benzo-
thiophenes. In the first protocol (method A), reactions
of substrates 1a,b with triisopropylsilanethiol (HSTIPS)18
using the combination Pd2(dba)3/Xantphos (5 mol %)19
in toluene at 120 °C with LiHMDS as base occurred to
full conversion in less than 3 h to form silyl-protected
arenethiols 4. The following addition of an excess of
tetrabutylammonium fluoride (TBAF) afforded 3a,b in
high yields (Scheme 2). The second methodology involves
a cross-coupling reaction with potassium thioacetate20
using the same catalyst system and reaction conditions,
but in this case no additional base was needed. In this way,
and after treatment with cesium carbonate the expected
heterocycles were obtained, although prolonged reaction
times (14 h) were needed for the coupling reaction. Inter-
estingly, the later one-pot protocol could be conducted
under microwave irradiation (method B) dramatically
reducing the reaction times. However, lower yields were
obtained compared with the first procedure (Scheme 2).
Scheme 1. Synthesis of Alkoxy-Substituted Indoles, Benzo-
[b]furans, and Benzo[b]thiophenes from Methoxy-Substituted
2-Alkynylhalobenzenes
Using oxygen-functionalized o-halo-substituted ethynyl-
benzenes 1a and 1b as model substrates, we initially
considered the employment of sodium sulphide in NMP as
solvent at high temperature, following the procedure
described by Takimiya and co-workers.9 However, under
the reported conditions the main product in both reactions
Scheme 2. Synthesis of 4-Oxygen-Functionalized Benzo-
[b]thiophenes 3a,b: Proof of the Concept
(8) See, for instance: (a) Takimiya, K.; Kunugi, Y.; Konda, Y.;
Niihara, N.; Otsubo, T. J. Am. Chem. Soc. 2004, 126, 5084–5085. (b)
Okamoto, T.; Kudoh, K.; Wakamiya, A.; Yamaguchi, S. Org. Lett.
2005, 7, 5301–5304.
(9) (a) Kashiki, T.; Shinamura, S.; Kohara, M.; Miyazaki, E.;
Takimiya, K.; Ideda, M.; Kuwabara, H. Org. Lett. 2009, 11, 2473–
2475. (b) Shinamura, S.; Miyazaki, E.; Takimiya, K. J. Org. Chem. 2010,
75, 1228–1234.
ꢀ
(10) See, for instance: (a) Sanz, R.; Fernandez, Y.; Castroviejo, M. P.;
ꢀ
~
ꢀ
Perez, A.; Fananas, F. J. J. Org. Chem. 2006, 71, 6291–6294. (b) Sanz, R.;
Guilarte, V.; Garcıa, N. Org. Biomol. Chem. 2010, 8, 3860–3864.
(c) Guilarte, V.; Castroviejo, M. P.; Garcı
Rodrıguez, M. A.; Sanz, R. J. Org. Chem. 2011, 76, 3416–3437.
´
ꢀ
a-Garcıa, P.; Fernandez-
´
´
´
ꢀ
(11) Sanz, R.; Guilarte, V.; Hernando, E.; Sanjuan, A. M. J. Org.
Chem. 2010, 75, 7443–7446.
(12) Sanz, R.; Castroviejo, M. P.; Guilarte, V.; Perez, A.; Fananas,
ꢀ
~
ꢀ
F. J. J. Org. Chem. 2007, 72, 5113–5118.
(13) Guilarte, V.; Castroviejo, M. P.; Alvarez, E.; Sanz, R. Beilstein J.
Org. Chem. 2011, 7, in press.
´
(14) During the preparation of this manuscript a related paper has
appeared that reports the use of thiourea as a dihydrosulfide surrogate in
the synthesis of thioethers and benzo[b]thiophenes. See: Kuhn, M.; Falk,
F. C.; Paradies, J. Org. Lett. 2011, 13, 4100–4103.
(15) For the cleavage of methoxy groups with thiolates, see: Vyvyan,
J. R.; Holst, C. L.; Johnson, A. J.; Schwenk, C. M. J. Org. Chem. 2002,
67, 2263–2265.
Org. Lett., Vol. 13, No. 19, 2011
5101

These two sets of reaction conditions were applied in
reactions of a variety of representative o-alkynylbromo-
benzenes 1 to evaluate the scope of the one-pot procedures,
and the results are summarized in Table 1. Thus, benzo-
[b]thiophenes 3cÀj bearing phenyl, electron-deficient and
electron-rich aromatic, heteroaromatic, alkenyl, alkyl,
functionalized alkyl, and ester groups at the C-2 position
were efficiently prepared (entries 1À15). In addition, sub-
stitution at the benzenoid moiety of substrates 1, including
halides, was also well tolerated (entries 16À21). In general,
and as we previously observed with bromides 1a,b, the proto-
col involving the formation of silyl-protected benzenethiols
afforded the adducts 3 in higher yields. Moreover, the
catalyst loading for the coupling step with HSTIPS could
be reduced to 1 mol % by increasing the reaction time from 1
to 14 h without an appreciable decrease in the yield (entry 1).
Once we had demonstrated the feasibility of our tandem
method for the preparation of benzo[b]thiophenes, we
turned to our original goal, the synthesis of unknown
oxygen-substituted benzo[b]thiophenes. Pleasingly, reac-
tions of selected substrates 1nÀv possessing one or two
methoxy groups on the benzene unit and different substitu-
ents at the triple bond occurred toform the desired functio-
nalized heterocycles 3nÀv in high yields (entries 22À32).
Next we considered that the developed one-pot pro-
cedure could be applied as well for the synthesis of
thiophenes using 1-bromo-1,3-enynes as starting mate-
rials. To test this hypothesis selected enynes 5 were
prepared and reacted under the optimized conditions
employing HSTIPS as a thiol surrogate. As expected, the
tandem CÀS coupling/heterocyclization methodology
turned out to be also suitable for the synthesis of 2,3,5-
trisubstituted thiophenes. As shown in Scheme 3, both
aliphatic and aromatic substituents are well tolerated at
the different positions of the final products 6, which are
obtained in high yields (Scheme 3).
Table 1. Synthesis of 2-Substituted Benzo[b]thiophenes 3a
entry
1
R1
R2
method 3b yield (%)c
1
1c Ph
H
H
H
H
H
H
H
H
A
B
A
B
A
B
A
B
A
B
A
B
A
B
B
A
B
A
B
A
B
A
A
B
A
A
A
A
A
A
B
A
3c
3d
3e
3f
88 (87)d
70
2
3
1d 3-FC6H4
89
4
62
5
1e 4-MeOC6H4
66
Scheme 3. Synthesis of Thiophenes 6 from Bromoenynes 5
6
64
7
1f
1g c-C6H9
1h n-C6H13
3-The
77
8
69
f
9
3g
3h
3i
66
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
59
84
53
1i
(CH2)3CN
86
67
1j
CO2Et
3j
60
1k 3-The
1l Ph
6-Me
3k
75
59
6-F
3l
92
72
1m n-C5H11
6-Cl
3m 72
54
1n n-C5H11
1o Ph
4-MeO
3n
3o
80
82
68
85
70
73
70
90
71
58
76
4,5-(MeO)2
(16) For a review, see: (a) Beletskaya, I. P.; Ananikov, V. P. Chem.
ꢀ
Rev. 2011, 111, 1596–1636. For leading references, see: (b) Fernandez-
Rodrıguez, M. A.; Shen, Q.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128,
1p 4-MeC6H4
1q n-Bu
1r 3-The
4,5-(MeO)2
4,5-(MeO)2
4,6-(MeO)2
4,6-(MeO)2
4,7-(MeO)2
4,7-(MeO)2
3p
3q
3r
3s
3t
´
2180–2181. (c) Fernandez-Rodrıguez, M. A.; Hartwig, J. F. J. Org.
ꢀ
´
Chem. 2009, 74, 1663–1672.
(17) For reports about the use of different mercapto surrogates in Pd-
catalyzed CÀS couplings, see: (a) Itoh, M.; Mase, T. J. Org. Chem. 2006,
71, 2203–2206. (b) Yi, J.; Fu, Y.; Xiao, B.; Cui, W.-C.; Guo, Q.-X.
Tetrahedron Lett. 2011, 52, 205–208.
1s n-C6H13
1t
Ph
1u 3-The
3u
(18) For the use of HSTIPS in Pd-catalyzed CÀS couplings, see: (a)
€
ꢀ
Kreis, M.; Brase, S. Adv. Synth. Catal. 2005, 47, 313–319. (b) Fernandez-
1v n-C5H11
4,7-(MeO)2
3v
Rodrıguez, M. A.; Hartwig, J. F. Chem.;Eur. J. 2010, 16, 2355–2359.
´
a Reactions were conducted using either method A or B. Method A:
HSTIPS (1.2 equiv), Pd2(dba)3 (2.5 mol %)/Xantphos (5 mol %),
LiHMDS (1.2 equiv) in toluene at 120 °C for 1À6 h, then TBAF (3
equiv) at rt for 2 h. Method B: KSAc (1.5 equiv), Pd2(dba)3 (2.5 mol %)/
Xantphos (5 mol %) in toluene under MW at 130 °C for 25À60 min, then
Cs2CO3 (1.5 equiv) under MW at 130 °C for 10À30 min. b Position of R2
referred to the benzo[b]thiopene moiety. c Isolated yield after column
chromatography referred to starting material 1. d Reaction conducted
with 1 mol % of catalyst. e 3-Thienyl. f 1-Cyclohexenyl.
(19) The efficiency of the catalysts generated from Pd2(dba)3 and
different phosphine ligands such as Josiphos CyPFtBu (see ref 18b),
XPhos, SPhos, DavePhos, and dppf for this coupling was comparable in
terms of reaction rates and turnover numbers to the catalyst generated
from Xantphos ligand. However, we selected Xantphos as a ligand due
to its better availability.
(20) For the use of KSAc in Pd-catalyzed CÀS couplings, see: (a) Lai,
C.; Backes, B. J. Tetrahedron Lett. 2007, 48, 3033–3037. (b) Hoogenband,
A. v. d.; Lange, J. H. M.; Bronger, R. P. J.; Stoit, A. R.; Terpstra, J. W.
Tetrahedron Lett. 2010, 51, 6877–6881. (c) Park, N.; Park, K.; Jang, M.;
Lee, S. J. Org. Chem. 2011, 76, 4371–4378.
5102
Org. Lett., Vol. 13, No. 19, 2011

On the other hand, we considered the possibility of
further functionalizing the final benzothiophenes and
thiophenes by adding an electrophile in the reaction
sequence. At this point, it is worth noting that although
the direct synthesis of 2,3-disubstituted indoles and
benzofurans is easily achieved from o-alkynyl anilines
and phenols, respectively, with organopalladium species
(Cacchi reaction),21 this methodology is inapplicable to
benzothiophenes7a as it is not possible to obtain o-akynyl
benzenethiols due to their high tendency to afford the
corresponding 2-substituted benzothiophenes.22 How-
ever, considering the anionic character of the reaction
conditions used for the cleavage of the silyl group from
intermediates 4 in the above-reported procedure, we en-
visaged that the preparation of 2,3-disubstituted benzo-
[b]thiophenes 7 could be possible (Scheme 4). The main
requisites for the success of this idea are the simultaneous
presence of a suitable electrophilic species during the
cyclization step and the absence of protons from the
reaction media. So, the removal of the reagents used for
the CÀS coupling (mainly HMDS), previous to the addi-
tion of the fluoride source and the electrophile, resulted in
being compulsory.23
Scheme 5. Synthesis of 3-Functionalized Benzo[b]thiophenes 7
and 3-Functionalized Thiophenes 8
Scheme 4. Proposal for the Direct Synthesis of 2,3-Disubstituted
Benzo[b]thiophenes 7
transformation (7f,g). Interestingly, carbon-based electro-
philes such as aldehydes could also be introduced, leading to
the corresponding alcohols in high yields (7h,i). Moreover,
this methodology was efficiently applied to the synthesis of
the analogous tetrasubstituted thiophenes 8a,b from the
corresponding starting bromoenynes 5.
In summary, we have developed an efficient route to
2-substituted benzo[b]thiophenes and 2,3,5-trisubstituted
thiophenes through a tandem CÀS coupling/heterocycli-
zation reaction from easily available substrates. In addi-
tion, further functionalization could be introduced in the
cyclization step by eletrophilic quenching leading to highly
substituted sulfur heterocycles.
After some experimentation we determined that the use
of anhydrous CsF in THF were the best conditions for the
introduction of electrophiles (Scheme 5).
Thus, a series of selected 3-methylthiobenzo[b]thiophenes
7aÀe could be synthesized in good yields, by performing the
deprotection step of the corresponding arylthiosilanes 4 in
the presence of dimethyldisulfide.24 Aromatic disulfides
as well as iodine25 are also suitable electrophiles for this
Acknowledgment. We gratefully thank Junta de Castilla
ꢀ
y Leon (BU021A09 and GR-172) and Ministerio de
Ciencia e Innovacion (MICINN) and FEDER (CTQ2010-
ꢀ
(21) Battistuzzi, G.; Cacchi, S.; Fabrizi, G. Eur. J. Org. Chem. 2002,
2671–2681.
15358 and CTQ2009-09949/BQU) for financial support.
P.G.-G. and M.A.F.-R. thank MICINN for “Juan de la
ꢀ
Cierva” and “Ramon y Cajal” contracts.
(22) Malte, A. M.; Castro, C. E. J. Am. Chem. Soc. 1967, 89, 6770.
(23) A simple filtration through a short pad of neutral alumina gel with
a hexane/Et2O (2/1) mixture as eluent and subsequent evaporation of the
solvents afforded arylthiosilanes 4, which were not further purified.
(24) The corresponding 3-unsubstitued derivatives 3 were also formed
in small variable amounts. Nevertheless, they could be separated from the
3-functionalized benzo[b]thiophenes 7 by column chromatography.
(25) TheuseofCsFforthecleavage ofthe SÀSi bond is not necessary in
this case. A direct iodine-promoted cyclization provided similar results.
Supporting Information Available. Experimental pro-
cedures and characterization data for compounds; copies
1
of H and 13C NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 19, 2011
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