Synthesis of benzo[b]thiophenes by electrophilic cyclization

Article abstract of DOI:10.1016/S0040-4039(01)01149-2

2,3-Disubstituted benzo[b]thiophenes are readily prepared in excellent yields under very mild reaction conditions by the Pd/Cu-catalyzed cross-coupling of commercially available o-iodothioanisole and terminal alkynes, followed by electrophilic cyclization

Full text of DOI:10.1016/S0040-4039(01)01149-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6011–6013
Synthesis of benzo[b]thiophenes by electrophilic cyclization
Richard C. Larock* and Dawei Yue
Department of Chemistry, Iowa State University, Ames, IA 50011, USA
Received 15 June 2001; revised 18 June 2001; accepted 27 June 2001
Abstract—2,3-Disubstituted benzo[b]thiophenes are readily prepared in excellent yields under very mild reaction conditions by the
Pd/Cu-catalyzed cross-coupling of commercially available o-iodothioanisole and terminal alkynes, followed by electrophilic
cyclization by I2, Br2, NBS, p-O2NC6H4SCl or PhSeCl. © 2001 Published by Elsevier Science Ltd.
Benzo[b]thiophenes are of great current interest because
of their common occurrence in nature and their consid-
erable biological activity.1 A number of synthetic
(2)
approaches to this class of compounds have been intro-
duced in recent years.2 One common approach to hete-
rocycles that has been utilized for the synthesis of
benzofurans3 and indoles4 has been electrophilic
cyclization of the corresponding 2-(1-alkynyl)phenols
or -anilines (Eq. (1)). Our recent interest in the prepara-
tion of these same heterocycles by the Pd-catalyzed
annulation of alkynes5 has encouraged us to look at an
analogous approach to the benzo[b]thiophene ring sys-
tem. Although many transition metals, including Pd,
are often incompatible with sulfur-containing sub-
strates, we were nevertheless encouraged to examine the
possibility of preparing benzo[b]thiophenes by a strat-
egy involving a palladium-catalyzed coupling, followed
by electrophilic cyclization. Flynn and co-workers have
recently reported the synthesis of benzo[b]thiophenes
by a related process involving the iodocyclization of
o-(1-alkynyl)phenyl benzyl sulfides (Eq. (2)).6 Unfortu-
nately, the preparation of these sulfides required several
synthetic steps from commercially available starting
materials and the yields are not particularly good.
Furthermore, the scope of the cyclization step has not
been examined. We wish to report a much more
efficient approach to benzo[b]thiophenes involving the
Pd/Cu-catalyzed coupling of o-iodothioanisole and ter-
minal alkynes, followed by electrophilic cyclization by a
range of electrophiles.
The sulfur-containing arylalkynes required for our
approach are readily prepared by the Sonogashira
coupling7 of commercially available o-iodothioanisole
(5 mmol) and terminal alkynes (6 mmol) using a cata-
lyst consisting of 2 mol% PdCl2(PPh3)2 and 1 mol% CuI
in the presence of Et3N (12.5 ml) as solvent at room
temperature for 3 h (Eq. (3)). The yields of this process
range from 93 to 100% and this procedure should
accommodate considerable functionality.
(3)
Since Flynn and co-workers had previously established
that analogous benzyl sulfides undergo facile iodocy-
clization, we first examined the reaction of our
thiomethyl-containing alkynes 1a–c (0.25 mmol in 3 ml
of CH2Cl2) with I2 (2.0 equiv. in 2 ml of CH2Cl2). We
were pleased to see that our methyl sulfides reacted in
less than 10 min at room temperature to afford the
3-iodobenzo[b]thiophenes in 97–100% yields (Eq. (4)).
Clearly, the benzyl leaving group is not critical to this
cyclization. Virtually no difference in the rates of reac-
tion or the overall yields were observed using alkynes
(1)
* Corresponding author. Tel.: +1-515-294-4660; fax: +1-515-294-0105;
e-mail: larock@iastate.edu
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(01)01149-2

6012
R. C. Larock, D. Yue / Tetrahedron Letters 42 (2001) 6011–6013
bearing a long-chain alkyl group (1a), an aryl group
(1b) or a vinylic group (1c).
methyl group is as easily removed as the benzyl group
of Flynn and co-workers. Virtually all electrophiles
react with each of these substituted alkynes at about the
same rate and almost all yields are above 90%.
(4)
We believe that this approach to 2,3-disubstituted benzo-
[b]thiophenes should prove quite useful in synthesis,
particularly when one considers that there are many
ways to transform the resulting halogen, sulfur and
selenium functional groups into other substituents. For
example, the resulting heterocyclic iodides should be
particularly useful as intermediates in many palladium-
catalyzed processes, like Sonagashira, Suzuki and Stille
cross-coupling processes.
Alkyne
E+
% Yield
1a
1b
1c
1a
1b
1c
1c
1a
1b
1c
1a
1b
1c
I2
–
–
Br2
–
–
100
100
97
91
92
–
74
70
97
95
91
100
97
Acknowledgements
NBS
p-O2NC6H4SCl
–
–
PhSeCl
–
–
We thank the donors of the Petroleum Research Fund,
administered by the American Chemical Society, for
partial support of this research and Johnson Matthey,
Inc., and Kawaken Fine Chemicals Co., Ltd., for dona-
tions of palladium salts.
References
This approach to benzo[b]thiophenes has been extended
to a range of other readily available electrophiles (Eq.
(4)). We were pleased to find that Br2 reacts in 10 min
or less with the alkynes 1a and 1b to afford the corre-
sponding 3-bromobenzo[b]thiophenes in 91 and 92%
yields, respectively. We were not too surprised to find
that the bromocyclization of the olefinic substrate 1c
failed to provide any of the desired 3-bromobenzo-
[b]thiophene. Presumably, Br2 addition to the carbonꢀ
carbon double bond is occurring faster than cyclization.
Fortunately, alkyne 1c reacts cleanly at room tempera-
ture with 1.2 equiv. of N-bromosuccinimide (NBS)
to afford the desired 3-bromo derivative in 74% yield,
although the reaction takes 2 days.
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