An atom-economic route to thiophenes and 2,2′-bithiophenes by intramolecular transannulation of gem-dialkylthio enynes

Article abstract of DOI:10.1021/ol4017854

An atom-economic route to thiophenes and bithiophenes has been developed starting from the readily available gem-dialkylthio enynes. A range of functionalized thiophenes and bithiophenes, bearing a pendent vinylthio group, were obtained in good to high yields under mild conditions.

Full text of DOI:10.1021/ol4017854

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
An Atom-Economic Route to Thiophenes
and 2,20-Bithiophenes by Intramolecular
Transannulation of gem-Dialkylthio
Enynes
Guichun Fang,† Jichun Li,† Yeming Wang,§ Mingyu Gou,† Qun Liu,†
Xingqi Li,*,† and Xihe Bi*,†,‡
Department of Chemistry, Northeast Normal University, Changchun 130024, China,
State Key Laboratory of Elemento-Organic Chemistry, Nankai University,
Tianjin 300071, China, and Department of Chemistry, Jilin Normal University,
Siping 136000, China
bixh507@nenu.edu.cn; lixq653@nenu.edu.cn
Received June 24, 2013
ABSTRACT
An atom-economic route to thiophenes and bithiophenes has been developed starting from the readily available gem-dialkylthio enynes. A range
of functionalized thiophenes and bithiophenes, bearing a pendent vinylthio group, were obtained in good to high yields under mild conditions.
Thiophenes represent a class of important five-membered
heterocycles that are key structural units prevalent in
natural products and pharmaceuticals.1 Due to their var-
ious potential applications in organic electronic devices,
thiophene derivatives have become major components and
key precursors for the design and synthesis of novel
materials.2 As a result, the development of efficient
methods for thiophene syntheses has drawn substantial
attention in the past decades. The general synthetic ap-
proaches to this class of compounds mostly involve
the functionalization of the R- or β-position of a precon-
structed thiophene nucleus.3 By comparison, synthetic
strategies starting from acyclic precursors are especially
attractive because the desired functional groups can
be directly introduced onto the thiophene skeleton by
(4) For examples, see: (a) Ransborg, L. K.; Albrecht, Ł.; Weise, C. F.;
Bak, J. R.; Jørgensen, K. A. Org. Lett. 2012, 14, 724. (b) Jiang, H.; Zeng,
W.; Li, Y.; Wu, W.; Huang, L.; Fu, W. J. Org. Chem. 2012, 77, 5179. (c)
† Northeast Normal University.
§ Jilin Normal University.
‡ Nankai University.
(1) (a) The Chemistry of Heterocyclic Compounds: Thiophene and Its
ꢀ
Guilarte, V.; Fernandez-Rodrıguez, M. A.; Garcıa-Garcıa, P.; Hernando,
E.; Sanz, R. Org. Lett. 2011, 13, 5100. (d) Nandi, G. C.; Samai, S.; Singh,
M. S. J. Org. Chem. 2011, 76, 8009. (e) You, W.; Yan, X.; Liao, Q.; Xi, C.
Org. Lett. 2010, 12, 3930. (f) Aponick, A.; Li, C.-Y.; Malinge, J.;
Marques, E. F. Org. Lett. 2009, 11, 4624. (g) Henssler, J. T.; Matzger,
A. J. Org. Lett. 2009, 11, 3144. (h) Nakamura, I.; Sato, T.; Terada, M.;
Yamamoto, Y. Org. Lett. 2008, 10, 2649. (i) Shindo, M.; Yoshimura, Y.;
Hayashi, M.; Soejima, H.; Yoshikawa, T.; Matsumoto, K.; Shishido, K.
Org. Lett. 2007, 9, 1963. (j) Liang, F.; Li, D.; Zhang, L.; Gao, J.; Liu,
Q. Org. Lett. 2007, 9, 4845. (k) Yoshida, S.; Yorimitsu, H.; Oshima, K.
Org. Lett. 2007, 9, 5573. (l) Kasano, Y.; Okada, A.; Hiratsuka, D.;
Oderaotoshi, Y.; Minakata, S.; Komatsu, M. Tetrahedron 2006, 62, 537.
(m) Minetto, G.; Raveglia, L. F.; Sega, A.; Taddei, M. Eur. J. Org.
Chem. 2005, 5277.
Derivatives, Vol. 44, Parts 1ꢀ4; Weissberger, A., Taylor, E. C., Eds.;
€
Wiley: New York, USA, 1991. (b) Gronowitz, S.; Hornfeldt, A. B.
Thiophenes; Elsevier: Oxford, U.K., 2004.
(2) 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.
(3) (a) Biehl, E. R. Top. Heterocycl. Chem. 2012, 29, 347. (b) Sato, O.;
Nakayama, J. In Comprehensive Heterocyclic Chemistry III; Katritzky,
A. R., Ramsden, C. A., Scriven, E. F. V., Taylor, R. J. K., Eds.; Oxford, 2008;
pp 843ꢀ930. (c) Nakayama, J. In Comprehensive Heterocyclic Chemistry
II, Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Oxford, 1996; pp
607ꢀ677.
r
10.1021/ol4017854
XXXX American Chemical Society

choosing an appropriate substrate.4 Although the reported
approaches represent significant advances toward the
objective of the general method for the synthesis of thio-
phene and their derivatives, most of them suffered from
limitations such as harsh reaction conditions, low yields,
use of expensive catalysts, difficulty with purification, or
the lack of atom economy. Therefore, to match increasing
scientific and practical demands, the development of effi-
cient and atom-economic methods for the preparation of
thiophenes from readily available acyclic precursors re-
mains highly desirable.
Table 1. Conditions Optimization
entry
base
solvent
t (°C)
yield (%)a
1
2
3
4
5
6
7
NaOH
NaOH
NaOH
NaOH
NaOtBu
NaH
EtOH
80
80
80
rt
45
trace
90
0
Ketene dithioacetals are readily available intermediates
in organic synthesis. In the past three decades, these
compounds have been very operative as building blocks
for the construction of carbo- and heterocyclic com-
pounds.5 Alkynes, on the other hand, are among the most
important building blocks in organic synthesis.6 It is there-
fore indicative that an integration of ketene dithioacetal
and alkyne functional groups into a single molecule could
afford the versatile enyne precursor that could be useful
for the assemblage of ring molecules. This concept has
benefited our group immensely, and a number of ketene
dithioacetal-alkyne-integratedsyntheticintermediateshave
been achieved in high yields via a dehydration coupling
reaction between ketene ditioacetals and propargyl
alcohols.7 Exploration into their synthetic applications
has led to novel synthetic methods for several hetero-
cyclic systems such as pyrroles, thiophenes, δ-lactams,
and δ-lactones.8gem-Dialkylthio enynes (namely, R-alkynyl
ketene dithioacetals) belong to a special class of ketene
dithioacetal-alkyne-integrated intermediates in that the
alkynyl group is directly linked to the R-carbon of ketene
dithioacetals. In pioneering work, Liu and co-workers
have studied the synthetic potency of R-alkynyl ketene
dithioacetals and observed that these precursors acted as
unique alkynes to take part in [4 þ 2] cycloaddition and
GlaserꢀHay coupling reactions.9 However, reactions of
these compounds involving the ring opening of the 1,3-
dithialane moiety remains unknown to date. We therefore
wish to report herein a novel transannulation of the gem-
dialkylthio enynes under mild conditions, leading to a
range of functionalized thiophenes and 2,2-bithiophenes
in good to high yields.
toluene
DMSO
DMSO
DMSO
DMSO
DMSO
80
80
80
75
0
DBU
0
a Isolated yields.
80 °C for 2.0 h, the desired thiophene 2a was obtained
in 45% yield, while toluene only resulted in a trace amount
of 2a (entries 1 and 2). To our delight, an excellent yield of
2a was obtained when DMSO was used as the solvent
(entry 3). An elevated temperature seems to be essential
also for this transformation because no reaction took place
at room temperature (entry 4). Lastly, our model reaction
also showed itself to be base-dependent. For example,
sodium tert-butoxide (NaOtBu) afforded a 75% yield
of 2a at 80 °C, whereas sodium hydride (NaH) and 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) did not give the
desired product 2a (entries 5ꢀ7). Therefore, the reaction
conditions listed in entry 3 were found to be optimal and
hence selected for further investigations.
With the optimal conditions in hand, the scope of gem-
alkylthio enynes 1 was investigated, and the results are
summarizedinScheme 1. To our delight, the compounds 1,
containing either a terminal or internal alkyne moiety,
were all smoothly converted into corresponding functio-
nalized thiophenes 2 in good to high yields. For example,
when the R1 is an electron-withdrawing group (EWG)
such as aroyl and carbamoyl groups, the donorꢀacceptor
substituted thiophenes 2bꢀ2f were obtained in excellent
yields (∼80ꢀ90%). The base-promoted fragmentation
reaction of the 1,3-dithialane ring in R-EWG ketene
dithioacetals was previously known.10 However, when we
applied R-(hetero)aryl gem-dialkylthio enynes (1gꢀ1k) to
this base-promoted transannulation reaction, transfor-
mations efficiently took place and afforded the corre-
sponding thiophene products (2gꢀ2k) in good to high
yields in comparable reaction times. Also, replacement
of the aryl group with an alkyl group did not affect
the outcome and 3-alkylthiophenes (2lꢀ2n) were also
obtained, albeit with slightly reduced yields. This result
is extremelly important because the fragmentation of the
1,3-dithialane ring of ketene dithioacetals that lacks
Initially, a study on the reaction parameters including
solvent, reaction temperature, and base was preformed
using a model reaction of compound 1a (Table 1). When
substrate 1a was treated with NaOH in ethanol (EtOH) at
(5) Lin, P.; Bi, X.; Liu, Q. Chem. Soc. Rev. 2013, 42, 1251.
(6) Acetylene Chemistry; Diederich, F., Stang, P. J., Tykwinski, R. R.,
Eds.; Wiley-VCH: Weinheim, 2005.
(7) (a) Li, Q.; Wang, Y.; Fang, Z.; Liao, P.; Barry, B. D.; Che, G.; Bi,
X. Synthesis 2013, 45, 609. (b) Song, J.; Fang, Z.; Liu, Y.; Li, R.; Xu, L.;
Barry, B. D.; Liu, Q.; Bi, X.; Liao, P. Synlett 2011, 2551.
(8) (a) Liu, Y.; Barry, B.-D.; Yu, H.; Liu, J.; Liao, P.; Bi, X. Org. Lett.
2013, 15, 2608. (b) Fang, Z.; Yuan, H.; Liu, Y.; Tong, Z.; Li, H.; Yang,
J.; Barry, B. D.; Liu, J.; Liao, P.; Zhang, J.; Liu, Q.; Bi, X. Chem.
Commun. 2012, 48, 8802.
(9) (a) Zhao, Y.; Liu, Q.; Zhang, J.-P.; Liu, Q. J. Org. Chem. 2005, 70,
6913. (b) Zhao, Y.; Li, D.; Han, X.; Chen, L.; Liu, Q. Adv. Synth. Catal.
2008, 350, 1537. (c) Zhao, Y.; Zhang, W.; Zhang, J.; Liu, Q. Tetrahedron
Lett. 2006, 47, 3157. (d) Zhao, Y.; Zhang, W.; Wang, S.; Liu, Q. J. Org.
Chem. 2007, 72, 4985.
(10) (a) Samuel, R.; Nair, S. K.; Asokan, C. V. Synlett 2000, 1804. (b)
Nair, S. K.; Samuel, R.; Asokan, C. V. Synthesis 2001, 573. (c) Li, Y.;
Liang, F.; Bi, X.; Liu, Q. J. Org. Chem. 2006, 71, 8006.
B
Org. Lett., Vol. XX, No. XX, XXXX

an R-EWG has not yet been reported.5 Furthermore,
3-alkenylthiophenes 2o and 2p were generated in 66%
and 80% yields, respectively, when the alkenyl-substituted
substrates were used. In addition to the terminal alkyne
modified substrates 1bꢀ1p (R2 = H), the gem-dialkylthio
enynes containing an internal alkyne unit were also appli-
cable to this transannulation reaction and led to 2,3,5-
trisubstituted thiophenes (2qꢀ2s) in moderate to good
yields. It is worth mentioning that all of the thiophene
products bear a pendent vinylthio group at the 2-position,
which would provide an opportunity for further synthetic
derivatization.11
Scheme 2. Synthesis of 4,40-Diaryl-2,20-bithiophenes 4
Scheme 1. Synthesis of Thiophenes 2
synthesis of thiophenes 2, we envisaged that 2,20-bithio-
phenes could be synthesized starting from the dimer of
gem-dialkylthio enynes 1. To test this hypothesis, the
dimers 3 were prepared by the oxidative coupling of
compounds 1 under the Ni/Pd-cocatalyzed conditions.9c
When the dimers 3 were subsequently subjected to the
above optimal reaction conditions, symmetrical 4,40-
diaryl-2,20-bithiophenes 4 were obtained in good to high
yields (Scheme 2). Delightfully, the reaction times were
dramatically reduced to 10ꢀ20 min. The symmetrical
structureof4, a2,20-bithiophene bearinga vinylthio group,
is quite unusual and is reported by our group for the
first time.1,2 As a result, we illustrate herein a novel
and highly efficient metal-free method for the synthesis
of 2,20-bithiophenes.14
2,20-Bithiophenes have been shown to be useful com-
pounds as organic semiconductors, fluorescent materials,
and precursors for nonlinear optical materials.12 The
synthesis of π-conjugated oligothiophenes is generally
achieved by palladium- or nickel-catalyzed cross-coupling
of either heteroaryl halides with arylmetals or aryl halides
with heteroarylmetals.13 However, one of the major prob-
lems in these reactions is isolation of the compounds in
their pure form. This has resulted in repeatedly long and
tedious chromatographic separations with generally low
yields of the final products. Following our success on the
(11) For examples of vinyl sulfides, see: (a) Zyk, N. V.; Beloglazkina,
E. K.; Belova, M. A.; Dubinina, N. S. Russ. Chem. Rev. 2003, 72, 769. (b)
Cao, C.; Fraser, L. R.; Love, J. A. J. Am. Chem. Soc. 2005, 127, 17614.
(c) Ranjit, S.; Duan, Z.; Zhang, P.; Liu, X. Org. Lett. 2010, 12, 4134 and
reference cited therein.
(12) (a) Wakamiya, A.; Mori, K.; Yamaguchi, S. Angew. Chem., Int.
Ed. 2007, 46, 4273. (b) Herbivo, C.; Comel, A.; Kirsch, G.; Manuela, M.;
Raposo, M. Tetrahedron 2009, 65, 2079. (c) Raposo, M. M. M.; Ferreira,
A. M. F. P.; Belsley, M.; Moura, J. C. V. P. Tetrahedron 2008, 64, 5878.
(13) (a) Fichou, D. Handbook of Oligo- and Polythiophenes; Wiley-
VCH: New York, 1999. (b) Press, J. B.; Russel, R. K. Prog. Heterocycl.
Chem. 1993, 5, 82.
In our attempt to prepare 4,40-benzoyl-2,20-bithiophene
4g from substrate 3g using this protocol, the debenzoylated
product 5 was unexpectedly isolated in 66% yield instead
of our target product 4g. The pathway for this transforma-
tion is hitherto obscure, and hence further experimental
(14) For an example relevant to the metal-free synthesis of bithio-
phenes, see: Zeika, O.; Hartmann, H. Tetrahedron 2004, 60, 8213.
Org. Lett., Vol. XX, No. XX, XXXX
C

investigations are inevitable to account for the debenzoyl-
ation process.
Scheme 3. A Plausible Reaction Mechanism
Vinyl sulfones are versatile synthetic intermediates in
organic chemistry, especially participating in 1,4-addition
reactions and cycloaddition reactions.15 These compounds
are also biologically important because they act as inhibi-
tors of several types of enzymes.16 The oxidation of
vinylthio compounds is a convenient route to vinyl sul-
fones.17 In view of the pendent vinylthio group existing in
all thiophene products 2 and 4, we tried to search for the
conditions for the conversion of these compounds into
corresponding vinyl sulfones. To our delight, vinyl sul-
fone 6 was obtained in high yield (90%) from 2a in the
presence of a 3.0 equiv amount of 3-chloroperoxybenzoic
acid (m-CPBA) in dichloromethane (CH2Cl2) at room
temperature.
On the basis of these experimental results and related
precedents,10 a plausible reaction mechanism for the
formation of substituted thiophenes is outlined in
Scheme 3. The initial step involves the abstraction of
an acidic proton at one of the methylene groups of the
1,3-dithialane moiety by NaOH to generate intermedi-
ate A. Following the fragmentation reaction of the 1,3-
dithialane structural unit, the thiolate anion intermedi-
ate B was produced. Finally, the thiophenes 2 are formed
through a possible sequential intramolecular hetero-
annulation18 and protonation, with the release of NaOH
for the next reaction.
bithiophenes under mild conditions starting from the read-
ily available gem-alkylthio enynes. This reaction is parti-
cularly attractive due to the following advantages: atom
economy, operational simplicity, high efficiency, and high
product yields. These highly functionalizedthiophenes and
bithiophenes would draw the attention of chemists in the
field of developing thiophene-based photovoltaic and
electroluminescence devices.
Acknowledgment. This work was supported by NSFC
(21172029, 21202016, 31101010), CPSF (111293000), and
FRFCU (10JCXK005).
Supporting Information Available. Experimental pro-
cedures, 1H/13C NMR spectroscopic data, and copies for
all compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
In summary, we have developed a novel synthetic ap-
proach to a range of highly functionalized thiophenes and
(18) For one example of the base-mediated heteroannulation of
functionalized enynes, see: (a) Sashida, H.; Sadamori, K.; Tsuchiya, T.
Synth. Commun. 1998, 28, 713. At the present time, the possibility cannot
be excluded that the ring closing of intermediate B proceeds via an
6π-electron 5-atom electrocyclization for related references, see: (b)
Davies, I. W.; Guner, V. A.; Houk, K. N. Org. Lett. 2004, 6, 743. (c)
Davies, I. W.; Smitrovich, J. H.; Sidler, R.; Qu, C.; Gresham, V.; Bazaral,
(15) For general reviews of the chemistry of vinyl sulfones, see: (a)
Meadows, D. C.; Gervay-Hague, J. Med. Res. Rev. 2006, 26, 793. (b)
Simpkins, N. S. Tetrahedron 1990, 46, 6951.
(16) Supuran, C.; Casini, A.; Scozzafava, A. Med. Res. Rev. 2003, 23,
535.
(17) (a) Xue, Q.; Mao, Z.; Shi, Y.; Mao, H.; Cheng, Y.; Zhu, C.
Tetrahedron Lett. 2012, 53, 1851. (b) Brace, N. O. J. Org. Chem. 1993, 58,
4506.
ꢀ
C. Tetrahedron 2005, 61, 6425. (d) Stokes, B. J.; Jovanovic, B.; Dong, H.;
Richert, K. J.; Riell, R. D.; Driver, T. G. J. Org. Chem. 2009, 74, 3225.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX