Cu-catalyzed double S-alkenylation of potassium sulfide: A highly efficient method for the synthesis of various thiophenes

Article abstract of DOI:10.1021/ol101619s

An efficient synthetic approach to variously substituted thiophenes has been developed through copper-catalyzed tandem S-alkenylation of potassium sulfide with 1,4-diiodo-1,3-dienes.

Full text of DOI:10.1021/ol101619s

ORGANIC
LETTERS
2010
Vol. 12, No. 17
3930-3933
Cu-Catalyzed Double S-Alkenylation of
Potassium Sulfide: A Highly Efficient
Method for the Synthesis of Various
Thiophenes
Wei You, Xiaoyu Yan, Qian Liao, and Chanjuan Xi*
Key Lab of Organic Optoelectronics & Molecular Engineering of Ministry of
Education, Department of Chemistry, Tsinghua UniVersity, Beijing 100084, China, and
China State Key Laboratory of Elemento-Organic Chemistry, Nankai UniVersity,
Tianjin 300071, China
cjxi@tsinghua.edu.cn
Received July 14, 2010
ABSTRACT
An efficient synthetic approach to variously substituted thiophenes has been developed through copper-catalyzed tandem S-alkenylation of
potassium sulfide with 1,4-diiodo-1,3-dienes.
Substituted thiophenes have emerged as a class of important
heterocycles because of their presence in a broad spectrum
of natural and synthetic molecules with diverse biological
properties,1-4 material characteristics,5 and utility in organic
synthesis as versatile intermediates.6,7 The general synthetic
approaches to such thia-heterocycles involve either the
functionalization in the R- and ꢀ-position of the precon-
structed thiophene skeleton8,9 or the construction of the
thiophene ring from appropriately substituted open chain
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10.1021/ol101619s  2010 American Chemical Society
Published on Web 08/04/2010

precursors.10-12 Each of these approaches represents an
important advance toward the objective of a general method
for the synthesis of substituted thiophenes; each of them,
however, suffers from significant limitations in terms of harsh
conditions, low yields, expensive catalyst, or difficult
purification. Thus, new and efficient methodologies for the
construction of substituted thiophenes are still desirable.
Metal-catalyzed C-S bond formations have played an
important role in organosulfur chemistry.13 With the renais-
sance of Ullmann coupling in the past few years,14 the
copper-catalyzed cross-coupling reactions of thiols and aryl
halides have been demonstrated to be a powerful tool in the
formation of aryl C-S bonds.15 More recently, this meth-
odology was successfully extended to the synthesis of vinyl
sulfides by coupling of thiols with vinyl halides either in
intermolecular or intramolecular manner.16,17 It could be
envisioned that if a tandem vinylation could proceed between
an inorganic sulfide and a 1,4-dihalo-1,3-diene via an
intermolecular/intramolecular process, it might provide a
straightforward route for the synthesis of thiophene deriva-
tives. However, vinyl C-S cross-coupling reactions with
inorganic sulfides have rarely been reported,18 to the best of
our knowledge, despite one of the principal methods of
forming C-heteroatom bonds. These results have led us to
investigate the participation of K2S in C-S cross-coupling
reactions. Herein we would like to describe a copper-
catalyzed double alkenyl C-S bond formation by the reaction
of (1Z,3Z)-1,4-diiodo-1,3-dienes with potassium sulfide,
thereby allowing for the synthesis of a wide range of
structurally diverse thiophenes including alkyl-substituted
electron-rich thiophenes and silyl-substituted thiophenes
(Scheme 1).
Scheme 1. Retrosynthetic Analysis of Thiophene Core
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1,4-Diiodo-1,3-diene 1a, which was readily prepared in a
one-pot procedure from the coupling of two alkynes with a
low-valent metal complex followed by diiodonation,19a was
used as the model substrate for the optimization of reaction
conditions (Scheme 2). The results are summarized in Table
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Lett. 1998, 39, 9191. (j) Stephensen, H.; Zaragoza, F. J. Org. Chem. 1997,
Scheme 2. Cu-Catalyzed Tandem C-S Bond-Forming
Reactions of 1,4-Dihalo-1,3-dienes 1a
62, 6096. (k) Chen, J.; Song, Q.; Xi, Z. Tetrahedron Lett. 2002, 43, 3533
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1. Substrate 1a was first subjected to the following typical
conditions for Ullmann coupling: 10 mol % of CuI, 20 mol
% of 1,10-phenanthroline (A), toluene as solvent, at 110 °C
for 24 h. No reaction occurred (entry 1). When the reaction
was carried out in acetonitrile, at 110 °C for 24 h, the
expected coupling product 2a was achieved in 70% yield
along with 22% of 1a remained (entry 2). Prolonging the
reaction time to 48 h did not help (entry 3). However, when
the reaction was carried out in acetonitrile at 140 °C for 24 h,
the expected coupling product 2a was achieved in 99% yield
(entry 11). We screened several ligands. Surprisingly, all of
the ligands screened (A-H) (Figure 1) gave similar results
(entries 2, 4-10). These results let us suspect that the ligands
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catalyzed, see: (f) Lee, J.-Y.; Lee, P. H. J. Org. Chem. 2008, 73, 7413. (g)
Li, G. Y. J. Org. Chem. 2002, 67, 3643. (h) Murahashi, S.-I.; Yamamura,
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Ni-catalyzed, see: (j) Cristau, H. J.; Chabaud, B.; Labaudiniere, R.; Christol,
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Zhao, Q.; Li, L.; Fang, Y.; Sun, D.; Li, C. J. Org. Chem. 2009, 74, 459.
Pd-catalyzed, see: (b) Bryan, C. S.; Braunger, J. A.; Lautens, M. Angew.
Chem., Int. Ed. 2009, 48, 7064.
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Org. Lett., Vol. 12, No. 17, 2010
3931

Table 1. Optimization of Reaction Conditions for the Formation
of 2a
Table 2. Scope of the Cu-Catalyzed Tandem C-S
Bond-Forming Reactions of 1,4-Diiodo-1,3-diene 1
entry
ligand
solvent
temp (°C)
time (h)
yield (%)b
1
2
3
4
5
6
7
8
A
A
A
B
C
D
E
F
G
H
A
none
toluene
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
110
110
110
110
110
110
110
110
110
110
140
140
140
24
24
48
24
24
24
24
24
24
24
24
24
48
trace
70
73
60
59
58
55
66
63
9
10
11
12
13c
63
99 (79)
99
none
0
a Reactions were performed with 1a (1.0 mmol), K2S (3.0 mmol), CuI
(0.10 mmol), solvent (5 mL), ligand (0.2 mmol). b GC yield, isolated was
given in parentheses. c No CuI was used.
Figure 1. Structure of ligands.
might not participate in the coupling reaction at all because
dramatically different effects of ligands are usually observed
in Ullmann coupling. Indeed, we were pleased to find that,
in the absence of a ligand, the C-S coupling proceeded
smoothly, and the thiophene 2a formed also in excellent yield
(entry 12). On the other hand, without CuI, no thiophene
could be obtained (entries 13).
a Reactions were performed with substrate 1 (1.0 mmol), K2S (3.0
mmol), CuI (0.10 mmol). b Isolated yield. c Combined yield of 2,4-dimethyl-
3,5-diphenylthiophene and 3,4-dimethyl-2,5-diphenylthio-phene, which
could not be separated from the corresponding isomer.
Having established an effective catalytic system for the
coupling reactions, we next synthesized a variety of diiodo-
dienes19 to explore the scope of double alkenylation under
the optimized conditions (10 mol % of CuI, CH3CN as
solvent, at 140 °C). The results are summarized in Table 2.
The transformation described herein allows the synthesis of
di-, tri-, and tetrasubstituted thiophenes. At the beginning,
alkyl-substituted dienyl diiodides were examined, and alkyl-
substituted electron-rich thiophenes formed in excellent yields
(entries 1-3). Besides alkyl-substituted dienyl diiodides, aryl-
substituted dienyl diiodides were also suitable substrates.
Moreover, silyl-substituted dienyl diiodides were also suitable
substrates. The corresponding products were formed in high
yields in all cases. When a diiododiene fused with a six-
membered ring (1g and 1o) was used, the reactions smoothly
occurred to afford bicyclic thiophene 2g and 2o in high
yields, respectively (entries 7 and 15). Furthermore, reactions
of (Z)-1-iodo-2-(2-iodovinyl)benzenes were also examined,
and benzothiophenes were obtained in excellent yields
(entries 16 and 17). 2,2′-Diiodobiphenyl 1r was also achieved
smoothly in the conditions to afford dibenzothiophene 2r in
satisfying yield (entry 18).
In addition to acting as a directing group in the metal-
mediated cross-coupling of alkynes, the silyl group also
provides a convenient functional handle for further manipu-
lation (Scheme 3). Protodesilylation of 2i was near quantita-
tive with trifluoroacetic acid (TFA), thus allowing access to
other substitution patterns on the thiophene core. More
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3932
Org. Lett., Vol. 12, No. 17, 2010

simplicity, low cost, and tolerance of a wide variety of
substituted groups in a range of substitution patterns. Further
application of the system to the synthesis of various
heterocycles is in progress.
Scheme 3
.
Silyl-Substituted Thiophenes As Versatile
Intermediates
Acknowledgment. We thank the National Natural Science
Foundation of China (20872076, 20972085) and the Doctoral
Program of Higher Education (200800030072) for financial
support.
importantly, the reaction of 2i with ICl at room temperature
cleanly delivered 2-iodothiophene 2s in 86% isolated yield.
In summary, we have described an efficient copper-
catalyzed double vinylation of potassium sulfide with dienyl
diiodides. This methodology provided a facile route for the
synthesis of di-, tri-, and tetrasubstituted thiophenes in
excellent yields. The transformation is distinguished by
Supporting Information Available: Experimental pro-
cedures and full characterization including 1H NMR and 13
C
NMR data for compounds 2a-2s; NMR spectra for 2a-2s.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL101619S
Org. Lett., Vol. 12, No. 17, 2010
3933