Metal-free regioselective oxidative biaryl coupling leading to head-to-tail bithiophenes: Reactivity switching, a concept based on the iodonium(III) intermediate

Article abstract of DOI:10.1021/ol101498r

A new synthetic concept for obtaining unsymmetrical biaryl coupling products by an oxidative method is reported. Our synthetic strategy casts light on the reaction intermediate for switching the reactivity of 3-substituted thiophenes. On the basis of this

Full text of DOI:10.1021/ol101498r

ORGANIC
LETTERS
2010
Vol. 12, No. 17
3804-3807
Metal-Free Regioselective Oxidative
Biaryl Coupling Leading to Head-to-Tail
Bithiophenes: Reactivity Switching, a
Concept Based on the Iodonium(III)
Intermediate
Koji Morimoto,† Nobutaka Yamaoka,† Chieko Ogawa,‡ Tomofumi Nakae,†
Hiromichi Fujioka,‡ Toshifumi Dohi,†,‡ and Yasuyuki Kita*,†
College of Pharmaceutical Sciences, Ritsumeikan UniVersity, 1-1-1 Nojihigashi,
Kusatsu, Shiga 525-8577, Japan, and Graduate School of Pharmaceutical Sciences,
Osaka UniVersity, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan
kita@ph.ritsumei.ac.jp
Received June 30, 2010
ABSTRACT
A new synthetic concept for obtaining unsymmetrical biaryl coupling products by an oxidative method is reported. Our synthetic strategy
casts light on the reaction intermediate for switching the reactivity of 3-substituted thiophenes. On the basis of this strategy, a novel direct
method for the synthesis of head-to-tail bithiophenes using hypervalent iodine(III) reagents has been developed.
Heteroaromatic biaryls have received considerable attention
because of their importance as versatile building blocks in
the synthesis of natural products, pharmaceuticals, agricul-
tural chemicals, and electronic materials.1 Bithiophenes,
especially head-to-tail (H-T) dimers, in which two ꢀ-sub-
stituted thiophenes are coupled between the 2- and 5-posi-
tions of the thiophene ring, are useful precursors for the high
quality of well-defined regioregular oligo- and poly-
thiophenes and their derivatives.2 Therefore, the development
of a convenient regioselective synthesis of H-T dimers is
important in organic chemistry.
Theoretically, the direct oxidative coupling reaction of
thiophenes is conceptually attractive and convenient as a
(2) (a) Hale, K. J.; Manaviazar, S. In Second Supplements to the 2nd
Edition of Rodd’s Chemistry of Carbon Compounds; Sainsbury, M., Ed.;
Elsevier Science B. V.: Amsterdam, 1999; Vol. IV A, Chapter 3, p 337.
(b) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem.
ReV. 2002, 102, 1359. (c) Zhai, L.; Laird, W. D.; McCullough, D. R.
Langumuir 2003, 19, 6492. (d) Tonzola, J. C.; Alam, M. M.; Bean, A. B.;
Jenekhe, A. S. Macromolecules 2004, 37, 3554. (e) Osaka, I.; McCullough,
D. R. Acc. Chem. Res. 2008, 41, 1202.
† Ritsumeikan University.
‡ Osaka University.
(1) (a) Polycyclic Aromatic Hydrocarbons; Harvey, R. G., Eds.; Wiley-
VCH: New York, 1996. (b) Heterocyclic Chemistry; Joule, J. A., Mills,
K., Eds.; Blackwell Science: Malden, MA, 2000. (c) Capdeville, R.;
Buchdunger, E.; Zimmermann, J.; Matter, A. Nat. ReV. Drug DiscoVery
2002, 1, 493.
10.1021/ol101498r  2010 American Chemical Society
Published on Web 08/06/2010

straightforward route to the synthesis of bithiophenes.3,4
However, electrochemical oxidation or heavy metal oxidants
not only for inducing oxidative coupling cannot be utilized
for dimerization, but for oligomerization, due to the lower
oxidation potential of the formed dimers compared to the
corresponding initial monomers.5 In addition, in the case of
the coupling reaction of ꢀ-substituted thiophenes, the result-
ing coupling products were thought to be a mixture of three
regioisomers, head-to-head (H-H), tail-to-tail (T-T), and
H-T dimers. However, only the oxidative syntheses of
symmetric H-H and T-T dimers have been accomplished
to date. The regioselective oxidative syntheses of these
dimers were typically realized through oxidative coupling
of ꢀ-substituted thiophenes having metal functionalities at
the 2-position or 5-position of the thiophene rings using a
metal oxidant such as Fe or Cu oxidants (Scheme 1, eqs 1
Herein, we describe a broadly applicable oxidative strategy
that proceeds via iodonium intermediates, which show a
unique reactivity at the 5-position, providing metal-free
unsymmetrical oxidative coupling product H-T dimers.
We have previously reported the metal-free oxidative
biaryl coupling reaction of aromatic compounds9 induced
by hypervalent iodine(III) reagents, such as PhI(OCOCF3)2
(PIFA), having useful oxidation abilities.10 Recently, we have
succeeded in applying our metal-free coupling reaction to
alkylthiophenes and pyrroles.11,12 Their mild oxidation
abilities as oxidants led us to consider the regioselective
synthesis of bithiophenes without using metal oxidants. First,
we employed 3-methoxythiophene 1a as a model substrate
and examined the reaction conditions. According to our
preliminary study, as expected, the use of BF3·Et2O and
TMSOTf,11 or TMSBr,12 as the activators of PIFA in CH2Cl2
provided the coupling products in low yield, and the resulting
products were a mixture of H-T dimer 2a (H-T) and H-H
dimer 2a (H-H). In contrast, when we performed the
reaction in (CF3)2CHOH (HFIP) in the presence of TMSBr,
the H-T-linked coupling product 2a (H-T) was obtained
as the major regioisomer albeit in moderate yield (Table 1,
Scheme 1. General Methods for Oxidative Coupling Reaction of
ꢀ-Substituted Thiophenes via Metalated Thiophenes
Table 1. Coupling Reaction of 3-Methoxythiophene 1a
and 2).6,7 These methods, although widely employed, were
not applicable to the synthesis of unsymmetric H-T dimers.
This is because carbon-carbon bond formations should occur
between the same metalated carbon atoms. Therefore, the
H-T regioselective oxidative coupling reaction has not been
reported, and their synthesis has been limited to transition-
metal-catalyzed coupling reactions, that is, the reaction of
halogenated and metalated thiophene derivatives.8
yieldb (%)
entry
I(III)
activator
2a (H-T)
2a (H-H)
1a
2a
3a
4a
5c
PIFA
PIFA
PIFA
HTIB
HTIB
TMSBr
BF3·Et2O
TMSOTf
TMSBr
TMSBr
57
>5
n.d.
n.d.
64
n.d.
n.d.
>5
(3) For recent reviews of the oxidative biaryl coupling reaction, see:
87
0
(a) McGlacken, G. P.; Bateman, L. M. Chem. Soc. ReV. 2009, 38, 2447.
a Performed using 1a (2 equiv), I(III) (1 equiv), and activator (2 equiv)
in solvent. b Isolated yield. c TMSBr was added after thiophene 1a reacted
with PhI(OH)OTs in (CF3)2CHOH.
(b) Ashenhurst, A. J. Chem. ReV. Soc. 2010, 39, 540
.
(4) Transition-metal-catalyzed oxidative coupling reaction: Mori, A.;
Sekiguchi, A.; Masui, K.; Shimada, T.; Horie, M.; Osakada, K.; Kawamoto,
M.; Ikeda, T. J. Am. Chem. Soc. 2003, 125, 1700
.
(5) (a) Julia´, L.; Davies, A. G.; Rueda, D. R.; Calleja, F. J. B. Chem.
Ind. 1989, 78. (b) Souto Maior, R. M.; Hinkelmann, K.; Eckert, H.; Wudl,
F. Macromolecules 1990, 23, 1268. (c) Tormo, J.; Moreno, F. J.; Ruiz, J.;
Fajar´ı, L.; Julia´, L. J. Org. Chem. 1997, 62, 878.
entry 1). Addition of BF3·Et2O and TMSOTf, which was
examined next, appeared to be less effective than TMSBr
(entries 2 and 3). We also evaluated other iodine reagents,
among which PhI(OH)OTs (HTIB) gave the best result in
(6) Iron-mediated coupling reaction: Marsella, M. J.; Carroll, P. J.;
Swager, T. M. J. Am. Chem. Soc. 1994, 116, 9347. Copper-mediated
coupling reaction :Allared, F.; Hellberg, J.; Remonen, T. Tetrahedron Lett.
2002, 43, 1553. Oxidative coupling reaction of 3-methylthiophene using
thallium(III) tris(trifluoroacetate): Barbosa, F.; Eberson, L.; Gesheidt, G.;
Gronowitz, S.; Hornfeldt, A.-B.; Persson, O. Acta Chem. Scand. 1998, 52,
1284
.
(9) (a) Tohma, H.; Morioka, H.; Takizawa, S.; Arisawa, M.; Kita, Y.
Tetrahedron 2001, 57, 345. (b) Dohi, T.; Ito, M.; Yamaoka, N.; Morimoto,
K.; Fujioka, H.; Kita, Y. Tetrahedron 2009, 6, 5–10797.
(7) (a) Tormo, J.; Moreno, F. J.; Ruiz, J.; Fajari, L.; Julia, L. J. Org.
Chem. 1997, 62, 878. (b) Wan, J.-H.; Feng, J.-C.; Wei, G.-A.; Wei, W.;
Fan, Q.-L.; Wang, C.-M.; Wang, H.-Y.; Zhu, R.; Yuan, X.-D.; Yuan, C.-
(10) (a) Zhdankin, V. V.; Stang, P. J. Chem. ReV. 2002, 102, 2523. (b)
HyperValent Iodine Chemistry (Top. Curr. Chem. 2003, 224); Wirth, T.,
Ed.; Springer: Berlin, 2003. (c) Wirth, T. Angew. Chem., Int. Ed. 2005, 44,
3656. (d) Zhdankin, V. V.; Stang, P. J. Chem. ReV. 2008, 108, 5299.
(11) (a) Tohma, H.; Iwata, M.; Maegawa, T.; Kiyono, Y.; Maruyama,
A.; Kita, Y. Org. Biomol. Chem. 2003, 1, 1647. (b) Dohi, T.; Morimoto,
K.; Kiyono, Y.; Maruyama, A.; Tohma, H.; Kita, Y. Chem. Commun. 2005,
H.; Huang, C.-H.; Huang, W. J. Org. Chem. 2006, 71, 2565
.
(8) Stepwise routes to H-T dimers: (a) Li, W.; Maddux, T.; Yu, L.
Macromolecules 1996, 29, 7329. (b) Ng, M.-K.; Yu, L. Angew. Chem.,
Int. Ed. 2002, 41, 3598. (c) Hagemann, O.; Jørgensen, M.; Krebs, F. C. J.
Org. Chem. 2006, 71, 5546. (d) Turner, D. J.; Anemian, R.; MacKie, P. R.;
Cupertino, D. C.; Yeates, S. G.; Turner, M. L.; Spivey, A. C. Org. Biomol.
Chem. 2007, 11, 1752
.
2930.
Org. Lett., Vol. 12, No. 17, 2010
3805

this coupling reaction (entry 4).13 Interestingly, we noticed
the importance of premixing of thiophene 1a and HTIB in
the control of the regioselectivity. Thus, TMSBr was added
to the stirred solution of 3-methoxythiophene 1a and HTIB,
and the yield and selectivity of the unsymmetrical coupling
product 2a (H-T) were complete at this stage (entry 5). The
obtained H-T dimer 2a (H-T) and related dimers should
be potentially valuable when synthesizing H-T regioregular
poly(3-alkoxythiophene)s, showing excellent conductivity,
stability, and optical characteristics.2 The observation de-
scribed in Table 1 clearly indicated the importance of
experimental procedure and the possibility of the existence
of a reaction intermediate leading to the bithiophenes.
When 3-methoxythiophene 1a reacted with HTIB in HFIP,
the iodonium salt 3a-OTs was rapidly yielded in nearly
quantitative yields.14 Surprisingly, the formed iodonium salt
3a-OTs could selectively react at the 5-position of the
thiophene ring with the 3-methoxythiophene 1a at the
2-position.15 Therefore, we considered that the realization of
this unique unsymmetrical coupling reaction proceeded via the
iodonium salts,13 and a variety of H-T dimers might be
synthesized using the thienyliodonium salts as the intermediates
without formation of other regioisomers (Scheme 2). The
Table 2. Scope of 3-Alkoxylthiophenes 1a
entry
R
yieldb (%)
1
2
3
4
5
6
7
8
Me (1a)
Hex (1b)
butyl (1c)
85
84
75
73
70
75
72
61
isobutyl (1d)
cyclohexyl (1e)
CH2(CF2)5CF3 (1f)
(CH2)2O(CH2)2OCH3 (1g)
Bn (1h)
a Performed using 1 (2 equiv), HTIB (1 equiv), TMSBr (2 equiv) in
HFIP at room temperature. b Isolated yield.
of soluble, conjugated polymer with excellent stability in air.2
The steric interaction affected neither the reactivity nor the
selectivity, and the reaction of 1d and 1e gave the coupling
products 2d (H-T) and 2e (H-T) in high yield. The
fluoroalkyl-substituted thiophene 1f also provided 2f (H-T)
as a single isomer in 75% yield.
Scheme 2
.
Iodonium(III) Strategy for Switching the Reactivity
of 3-Substituted Thiophenes
The presence of some protecting groups such as 2-(2-
methoxyethoxy)ethyl (MEET) and benzyl ethers was well
tolerated, affording the corresponding coupling products 2g
(H-T) and 2h (H-T) in good yield. In each case, phenyl
group transfer from the salts 3-OTs was not observed.
As illustrated in Scheme 3, the 3-alkylthiophenes 4 were
also efficient substrates for the unsymmetrical oxidative
strategy relies upon the use of iodonium intermediates 3-OTs
that activate the 5-position exclusively. Otherwise, H-H or
T-T dimers would be obtained.
Scheme 3. Scope of 3-Alkylthiophenes 4
Relying on this strategy, we examined various 3-substi-
tuted alkoxythiophenes 1 to explore the scope of the
substrates that could be used (Table 2). We noted that the
reactions proceeded smoothly and gave the corresponding
H-T bithiophenes 2 (H-T) in high yield as the single
isomer. The resulting bithiophenes, 2b (H-T) and 2c
(H-T), are useful precursors of conductive polymers (entries
2 and 3), such as the poly(3-butoxythiophene)s and poly(3-
hexaloxythiophene)s. These are frequently used as a class
coupling reaction, and the H-T bithiophenes 5 (H-T) were
obtained in high yield without reoptimization of the reaction
conditions. Similarly, alkylthiophenes 4a-c gave the unsym-
metrical coupling biaryls 5a-c (H-T) in excellent yield with
a high degree of regioselectivity. Sterically hindered sub-
strates 4d and 4e also coupled smoothly to give the expected
coupling products, respectively, which indicated that the
steric restriction was less influential in this strategy. The
bromo group of 4f was tolerable under the reaction condi-
tions. In each case, the resulting coupling products were
contaminated at less than 1% by other regioisomers.
(12) Regiopreference biaryl coupling reaction using hypervalent iodi-
ne(III) reagent with TMSBr in CH2Cl2 afforded a mixture of regioisomers:
(a) Dohi, T.; Morimoto, K.; Maruyama, A.; Kita, Y. Org. Lett. 2006, 8,
2007. (b) Dohi, T.; Morimoto, K.; Ito, M.; Kita, Y. Synthesis 2007, 2913.
(c) Dohi, T.; Morimoto, K.; Ogawa, C.; Fujioka, H.; Kita, Y. Chem. Pharm.
Bull. 2009, 57, 710.
(13) Kita, Y.; Morimoto, K.; Ito, M.; Ogawa, C.; Goto, A.; Dohi, T.
J. Am. Chem. Soc. 2009, 131, 1668.
(14) (a) Dohi, T.; Ito, M.; Morimoto, K.; Minamitsuji, Y.; Takenaga,
N.; Kita, Y. Chem. Commun. 2007, 4152.
(15) For the calculation of electron density of ꢀ-substituted thiophenes,
see: Ando, S.; Ueda, M. Synth. Met. 2002, 129, 207.
3806
Org. Lett., Vol. 12, No. 17, 2010

Synthesis of extended oligomers was carried out utilizing
the H-T dimer product 2c (H-T) (Scheme 4). Recently,
of regioregular quarterthiophene 6c having an oxygen
substituent has never been reported. The measurement of the
UV-vis absorption spectra of quarterthiophene 6c shows 480
nm, the λmax value of which shifted to red by 60 or 90 nm
(see the Supporting Information), by comparison with the
other reported quaterthiophenes.16 This result reveals that
the λ max values of longer wavelength seem to be responsible
for its high coplanarity to avoid steric repulsion between the
OBu substituents.
Scheme 4. Quaterthiophene 6c from the H-T Dimer 2c (H-T)
In summary, a unique and selective oxidative coupling has
been realized by the use of an iodonium(III)-mediated
strategy. In combination with the unique reactivity of the
thienyliodonium salts 3-OTs and the high nucleophilicity of
the 2-position of the ꢀ-substituted thiophenes, the reactions
not only controlled the regioselectivity of the dimers but also
provided a new direct synthetic route to H-T-linked
bithiophenes without using transition-metal catalysts. The
H-T dimers thus obtained are useful units for the synthesis
of oligothiophenes having well-defined structures. Further
studies on the application of this strategy are now in progress.
oligothiophenes in their neutral form have been used to
prepare electronic and electro-optical devices.2 In these
studies, practical synthesis of oligothiophenes with well-
defined structures is highly important.16 We envisaged a
facile synthesis of extended regioregular oligomers by
repeated oxidative coupling.
As a result, quaterthiophene 6c was obtained in 51% yield
when the Cu-mediated homocoupling of lithiated monom-
ethylation product of 2c (H-T) was carried out. This type
Acknowledgment. This work was partially supported
by Grants-in-Aid for Scientific Research (A) from the
Japan Society for the Promotion of Science (JSPS), Young
Scientists (B) and Research Activity Start-up from the
Ministry of Education, Culture, Sports, Science and
Technology (MEXT), and the Ritsumeikan Global In-
novation Research Organization (R-GIRO) project. T.D.
also acknowledges support from the Industrial Technology
Research Grant Program from the New Energy and
Industrial Technology Development Organization (NEDO)
of Japan.
(16) Multistep synthesis was used in all reports: (a) Coupling of
R-lithiated thiophene in the presence of iron oxidants: Miller, L. L.; Yu, Y.
J. Org. Chem. 1995, 60, 6813. The cross-coupling of R-metalated thiophenes
with R-halothiophenes catalyzed by nickel or palladium: (b) Melucci, M.;
Barbarella, G.; Sotgiu, G. J. Org. Chem. 2002, 67, 8877. (c) Li, J.-C.; Lee,
S.-H.; Hahn, Y.-B.; Kim, K.-J.; Zong, K.; Lee, Y.-S. Synth. Met. 2008,
158, 150. Kumada cross-coupling of R-magnesium halide with R-bro-
mothiophene: (d) Mastragostino, M.; Arbizzani, C.; Bongini, A.; Barbarella,
G.; Zambianchi, M. Electrochim. Acta 1993, 38, 135. (e) Li, Z. H.; Wong,
M. S.; Tao, Y.; Fukutani, H. Org. Lett. 2007, 9, 3569. Pd/Cu-catalyzed
cross-coupling of R-bromothiophene: (f) Takahashi, M.; Masui, K.;
Sekiguchi, H.; Kobayashi, N.; Mori, A.; Funahashi, M.; Tamaoki, N. J. Am.
Chem. Soc. 2006, 128, 10930. Oxidative coupling reaction of perfluoroalkyl-
substituted H-T bithiophene: (g) Li, L.; Collard, M. D. Macromolecules
2005, 38, 372.
Supporting Information Available: Experimental pro-
cedures, details for optimization of the reaction conditions,
and compound characterization data. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
OL101498R
Org. Lett., Vol. 12, No. 17, 2010
3807