Palladium-catalyzed C-H homocoupling of bromothiophene derivatives and synthetic application to well-defined oligothiophenes

Article abstract of DOI:10.1021/ja060749v

Synthesis of oligothiophenes of well-defined structures that possess 2-8 thiophene units is performed with a new synthetic strategy involving C-H homocoupling of bromothiophenes and cross-coupling with organostannanes. Tolerance of the carbon-bromine bond to the palladium-catalyzed C-H homocoupling results in oligothiophenes bearing C-Br bonds at the terminal thiophene rings, which allow further transformation by the catalysis of a transition-metal complex.

Full text of DOI:10.1021/ja060749v

Published on Web 07/29/2006
Palladium-Catalyzed C-H Homocoupling of Bromothiophene
Derivatives and Synthetic Application to Well-Defined
Oligothiophenes
Masabumi Takahashi, Kentaro Masui, Hiroki Sekiguchi, Nobuhiko Kobayashi,
Atsunori Mori,*,† Masahiro Funahashi,‡ and Nobuyuki Tamaoki‡
Contribution from the Chemical Resources Laboratory, Tokyo Institute of Technology,
R1-4 4259 Nagatsuta, Yokohama 226-8503, Japan, and National Institute of AdVanced Industrial
Science and Technology (AIST), Central 5, 1-1-1, Higashi, Tsukuba, Ibaraki, 305-8565, Japan
Received January 31, 2006; E-mail: amori@kobe-u.ac.jp
Abstract: Synthesis of oligothiophenes of well-defined structures that possess 2-8 thiophene units is
performed with a new synthetic strategy involving C-H homocoupling of bromothiophenes and cross-
coupling with organostannanes. Tolerance of the carbon-bromine bond to the palladium-catalyzed C-H
homocoupling results in oligothiophenes bearing C-Br bonds at the terminal thiophene rings, which allow
further transformation by the catalysis of a transition-metal complex.
Introduction
in the presence of silver(I) fluoride to afford the corresponding
bithiophenes highly efficiently.4,5 Worthy of note is that the
Oligothiophenes have recently attracted remarkable attention
as materials showing conductive, semiconductive, nonlinear
optical, and liquid crystalline characteristics. Hence, it becomes
important to synthesize oligothiophene derivatives with well-
defined structures in high efficiency.1 Homocoupling of thiophene
is one of the most simple and practical pathways for bithiophenes;
thus, repeating homocoupling of thiophene derivatives leads to
further oligomers. Several homocoupling reactions of thiophene
derivatives have been shown to proceed with a transition-metal
catalyst. Dehalogenative coupling of halothiophenes2 and oxida-
tive coupling of metalated thiophenes3 afford the corresponding
bithiophenes. On the other hand, the coupling of thiophene at
the carbon-hydrogen bond, which is much more straightfor-
ward, would be intriguing. We have preliminarily shown that
palladium-catalyzed homocoupling of several thiophene deriva-
tives takes place at the C-H bond adjacent to the sulfur atom
homocoupling reaction of 2-bromothiophene also occurs at the
C-H bond and the C-Br bond is completely intact. Accord-
ingly, the obtained bithiophene possesses two C-Br bonds,
which are readily available for a variety of transition-metal-
catalyzed coupling and other reactions forming carbon-carbon
bonds or carbon-heteroatom bonds.6 Herein, we describe further
studies on the homocoupling of several bromothiophene deriva-
tives, and the synthesis of oligothiophenes bearing 2-8
thiophene units of well-defined structure is performed with the
palladium-catalyzed C-H homocoupling of bromothiophene
derivatives.
Results and Discussion
When 2-bromothiophene (1a) was treated with silver(I)
fluoride in the presence of 3 mol % of PdCl2(PhCN)2 in DMSO,
5,5′-dibromo-2,2′-bithiophene (2a) was obtained in 77% yield
as shown in eq 1. The reaction was shown to occur at room
temperature, albeit the related homocoupling reaction of other
thiophene derivatives must be carried out at elevated temper-
atures (60 °C or higher). Despite the use of the palladium
complex as a catalyst, the C-Br bond of 1a was found to be
completely intact to afford the dibrominated bithiophene 2a.
† Present address: Department of Chemical Science and Engineering,
Kobe University, 1-1 Rokkodai, Nada, Kobe 657-8501, Japan.
‡ National Institute of Advanced Industrial Science and Technology
(AIST).
(1) (a) Briehn, C. A.; Schiedel, M.-S.; Bonsen, E. M.; Schuhmann, W.; Ba¨uerle,
P. Angew. Chem., Int. Ed. 2001, 40, 4680-4683. (b) Tour, J. M. Chem.
ReV. 1996, 96, 537-553. (c) Facchetti, A.; Yoon, M.-H.; Stern, C. L.; Katz,
H. E.; Marks, T. J. Angew. Chem., Int. Ed. 2003, 42, 3900-3903. (d)
McCullough, R. D. AdV. Mater. 1998, 10, 93-116. (e) Yamamoto, T.
Macromol. Rapid Commun. 2002, 23, 583-606. (f) Izumi, T.; Kobashi,
S.; Takimiya, K.; Aso, Y.; Otsubo, T. J. Am. Chem. Soc. 2003, 125, 5286-
5287. (g) Otsubo, T.; Aso, Y.; Takimiya, K. Bull. Chem. Soc. Jpn. 2001,
74, 1789-1801. (h) Funahashi, M.; Hanna, J.-I. AdV. Mater. 2005, 17,
594-598. (i) Wu, X.; Chen, T.-A.; Rieke, R. D. Macromolecules 1996,
29, 7671-7677. (j) Hassan, J.; Gozzi, C.; Schulz, E.; Lemaire, M. J.
Organomet. Chem. 2003, 687, 280-283.
Further studies revealed that the reaction was found to take
place with silver(I) nitrate/potassium fluoride system, which is
(2) (a) Wei, Y.; Wang, B.; Tian, J. Tetrahedron Lett. 1995, 36, 665-668. (b)
Hassan, J.; Lavenot, L.; Gozzi, C.; Lemaire, M.; Tetrahedron Lett. 1999,
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Tetarahedron Lett. 1977, 18, 4089.
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2002, 43, 7899-7902. (b) Ba¨uerle, P.; Fischer, T. Bidlingmeier, B.; Stabel,
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6752.
(4) (a) Masui, K.; Ikegami, H.; Mori, A. J. Am. Chem. Soc. 2004, 126, 5074-
5075. (b) Fre´chet recently employed CH coupling of a bromothiophene
derivative for the synthesis of polythiophene: Murphy, A. R.; Liu, J.;
Luscombe, C.; Kavulak, D.; Fre´chet, J. M. J.; Kline, R. J.; McGehee, M.
D. Chem. Mater. 2005, 17, 4892-4899.
9
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J. AM. CHEM. SOC. 2006, 128, 10930-10933
10.1021/ja060749v CCC: $33.50 © 2006 American Chemical Society

Well-Defined Oligothiophenes
A R T I C L E S
Table 1. Palladium-Catalyzed C-H Homocoupling of
Bromothiophene Derivativesa
examined. Synthesis of 2-bromo-3-(4-hydroxybutyl)thiophene
1f was carried out as outlined in Scheme 1. Sonogashira
coupling of 3-bromothiophene with 2-ethanolamine as an
activator at 60 °C followed by hydrogenation of the triple bond
and bromination with NBS afforded 1f.9 Treatment of 1f with
AgNO3/KF (2 equiv) in two portions in the presence of 3 mol
% of PdCl2(PhCN)2 afforded 2f in 70% yield. It should be
pointed out that the homocoupling reaction of a bromothiophene
derivative bearing a hydroxy group took place without protection
of the hydroxy group.
Scheme 1
a The reaction was carried out with PdCl2(PhCN)2 (3 mol %), AgF or
AgNO3/KF in DMSO at room temperature. b Method A: The reaction with
AgF (2 equiv). Method B: The reaction with AgNO3/KF (2 equiv/2 equiv,
addition in one portion). Method C: The reaction with AgNO3/KF (2 equiv/2
equiv, addition in two portions). c Unless noted, isolated yield was shown.
d The yield was estimated by 1H NMR, using trichloroethene as an internal
standard.
much less expensive than AgF, to afford 2a in 52% yield under
similar conditions. Table 1 summarizes the reaction of several
bromothiophene derivatives. It was also found that the addition
of AgF or AgNO3/KF in several portions improved the yield
of homocoupling. When the addition of AgNO3/KF in two
portions with stirring each 12 h was conducted at room
temperature, 2a was obtained in 81% yield. The homocoupling
reaction of 2,3-dibromothiophene (1b) and 2,4-dibromo-
bithiophene (1c) was shown to take place under conditions
similar to those of the reaction of 1a. The reaction proceeded
to afford the corresponding tetrabromobithiophenes 2b and 2c
in 70% and 59% yields, respectively. Bromine atoms at the 3-
and 4-positions were also intact under the palladium-catalyzed
reaction conditions. It was also found that the addition of
AgNO3/KF improved the yield of 2b and 2c to 90% and 75%,
respectively. A similar effect with the use of the AgNO3/KF
system instead of AgF was also observed in the related
palladium-catalyzed C-H substitution reaction of thiophene and
thiazole derivatives5b,7 although the role of the silver reagent is
completely different in that AgF was transformed into AgI in
the C-H substitution, while homocoupling afforded Ag(0).
We then performed the reactions of thiophene bearing an alkyl
substituent at the 3-position. Bromination of 3-hexylthiophene
and 3-methylthiophene with NBS afforded 2-bromo-3-hexyl-
thiophene (1d) and 2-bromo-3-methylthiophene (1e) regio-
selectively.8 Treatment of 1d with 1 mol % of PdCl2(PhCN)2
in the presence of silver(I) nitrate and potassium fluoride at 60
°C for 6 h underwent homocoupling to give 5,5′-dibromo-4,4′-
dihexyl-2,2′-bithiophene (2d) in 99% yield. The bithiophene
derived from 1e was also obtained in a similar manner. The
reaction with AgF at room temperature for 5 h resulted in giving
2e in 72% yield. The addition of AgNO3/KF (2 equiv) in two
portions and stirring at 60 °C for 3 h × 2 improved the yield
(80%).
Since the synthetic protocol for several dibromobithiophene
derivatives was in hand, we envisaged the synthesis of further
oligomers with the palladium-catalyzed homocoupling method.
Selective monodebromination of 2d was performed with 1 equiv
of n-butyllithium at -78 °C to afford 3, which was again
subjected to the palladium-catalyzed C-H homocoupling with
AgNO3/KF at 100 °C. Quaterthiophene 4 was obtained in 28%
yield after stirring at 100 °C for 24 h in DMSO. The low yield
of 4 in the homocoupling would be due to the steric congestion
of the head-to-head unit of the hexyl groups.
On the other hand, quaterthiophene with opposite head-tail
regularity was synthesized by the combination of sequential
nickel-catalyzed dehalogenative homocoupling2a,c and the pal-
ladium-catalyzed C-H homocoupling. Treatment of 1d with
zinc powder in the presence of a nickel catalyst underwent
debrominative homocoupling to afford 5 in a good yield. The
obtained 5 was then subjected to the selective monobromination
under mild conditions with NBS. The palladium-catalyzed C-H
homocoupling reaction of the monobrominated bithiophene 6
in the presence of AgNO3/KF furnished 7 in 50% yield (Scheme
2).
(5) See also: (a) Mori, A.; Sekiguchi, A.; Masui, K.; Shimada, T.; Horie, M.;
Osakada, K.; Kawamoto, M.; Ikeda, T. J. Am. Chem. Soc. 2003, 125, 1700-
1701. (b) Masui, K.; Mori, A.; Okano, K.; Takamura, K.; Kinoshita, M.;
Ikeda, T. Org. Lett. 2004, 6, 2011-2014.
(6) (a) Diederich, F., Stang, P. J., Eds. Metal-Catalyzed Cross-Coupling
Reactions; Wiley-VCH: Weinheim, 1998. (b) Metal-Catalyzed Cross-
Coupling Reactions, 2nd ed.; de Meiere, A., Diederich, F., Eds.; Wiley:
New York, 2004.
(7) Kobayashi, K.; Sugie, A.; Takahashi, M.; Masui, K.; Mori, A. Org. Lett.
2005, 7, 5083-5085.
(8) Barbarella, G.; Bongini, A.; Zambianchi, M. Macromolecules 1994, 27, 7,
3039-3045.
(9) (a) Mohamed Ahmed, M. S.; Sekiguchi, A.; Masui, K.: Mori, A. Bull.
Chem. Soc. Jpn. 2005, 78, 160-168. (b) Sonogashira, K.; Tohda, Y.;
Hagihara, N. Tetrahedron Lett. 1975, 16, 4467.
Homocoupling of a bromothiophene derivative that possessed
a hydroxy group in the alkyl chain at the 3-position was then
9
J. AM. CHEM. SOC. VOL. 128, NO. 33, 2006 10931

A R T I C L E S
Scheme 2
Takahashi et al.
Alternatively, the intermediate bithiophene 5 was obtained
from tetrabromobithiophene 2c as shown in eq 3. Selective
debromination took place at the 5,5′-positions in the presence
of Zn in AcOH to give 8,10a followed by a nickel-catalyzed
cross-coupling to introduce the hexyl group with Grignard
reagent that also led to 5.10a,11
unsubstituted thienyl group by cross-coupling with 2-thienyl-
stannanes was envisaged.12,13 Quaterthiophene 9 was obtained
in 76% yield when the Pd/Cu-catalyzed cross-coupling of 2d
was carried out with 2 equiv of thienyl(tributyl)stannane (10)
at 60 °C for 21 h. Monobromination of 9 with NBS followed
by C-H homocoupling led to the octamer 12.
On the other hand, treatment of the thienyl tin reagent with
excess 2d afforded terthiophene 13 in 71% yield (based on 10).
The palladium-catalyzed C-H homocoupling reaction of 13
gave the corresponding hexamer 14.
Properties of oligothiophenes 4, 7, 9′, 12, and 14 were
compared. The tetramer 9′ was prepared by bromination of 9
with 2 equiv of NBS. Table 2 shows the results of UV-vis
absorption and photoluminescent spectra of the oligothiophenes.
Among tetramers, 9′ exhibited the highest λmax values of UV-
Synthesis of further oligomers was carried out as outlined in
Scheme 3 with bithiophene 2d. To avoid the head-to-head
structure that may cause steric congestion, introduction of the
Scheme 3
9
10932 J. AM. CHEM. SOC. VOL. 128, NO. 33, 2006

Well-Defined Oligothiophenes
A R T I C L E S
Table 2. Properties of Oligothiophene 4, 7, 9′, 12, and 14a
Measurement of UV-vis and photoluminescent spectra of 15
revealed λmax of 405 nm and emission peak of 492 nm (Φ )
0.15), respectively. Further studies on liquid crystalline char-
acteristics and electron mobility of 15 and several related
compounds will be described in due course.
UV
−
vis
emission
max, nmb
1
1
cmpd
λmax, nm
ꢀ
, M-
‚
cm-
λ
Φc
4 (4 mer)
7 (4 mer)
9′ (4 mer)
12(8 mer)
14(6 mer)
355
351
384
437
422
47900
27900
31600
75500
43600
469
460
471 (498)
542 (578)
521 (547, 574)
0.05
0.01
0.04
0.08
0.13
a UV-vis spectra were measured as 10-5 M chloroform solution.
Emission spectra were measured as 10-6 M chloroform solution. b In the
parentheses, shoulder peaks of emission are shown. c Quantum yield, Φ
was estimated by comparison of standard aqueous 1.0 M quinine sulfate
solution (Φ ) 0.546).
vis and emission spectra, while 4 and 7, which bear head-to-
head structures of two hexyl groups, showed λmax values of
shorter wavelength due to the steric repulsion. The λmax values
of UV-vis and emission spectra in further oligomers 12 and
14 red-shifted to 40-70 nm.
Since oligothiophenes 9′, 12, and 14 possess bromo groups,
it would be possible to introduce several functional groups at
the end with transtion-metal-catalyzed reactions. Oligo-
thiophenes bearing alkynyl moieties have recently been revealed
to show conductivities with novel electron transport behaviors
as well as liquid crystalline characteristics.1h Indeed, the reaction
of dibromoquaterthiophene 9′ with 1-octyne was carried out with
a Pd/Cu catalyst system in the presence of 2-ethanolamine as
an activator to afford 15 in 82% yield as shown in eq 4.9a
Conclusion
In summary, C-H homocoupling of bromothiophene deriva-
tives was found to take place under mild conditions. The use
of the new activator system, AgNO3/KF, was shown to be
similarly effective as AgF. Several oligothiophenes were
synthesized efficiently with repeating palladium-catalyzed C-H
homocoupling in the presence of the silver reagent system as
an activator. In addition, cross-coupling of thienyl tin reagent
with bromothiophene would also be remarkable for the ho-
mologation of thiophene unit for the synthesis of oligo-
thiophenes. With these methodologies, further oligomers of well-
defined structure would be prepared in a similar manner.
Acknowledgment. This work was supported by Sumitomo
Foundation and Grant-in-Aid for Scientific Research (No.
16550092) by Japan Society for the Promotion of Science.
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J. Phys. Chem. A 2002, 106, 1266-1276. (c) Kabir, S. M. H.; Miura, M.;
Sasaki, S.; Harada, G. Kuwatani, Y.; Yoshida, M.; Iyoda, M. Heterocycles
2000, 52, 761-774.
(11) Negishi, E.; Liu, F. In Metal-Catalyzed Cross-Coupling Reactions; Dieder-
ich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998, pp 1-47.
(12) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508.
(13) (a) Mee, S.; P. H.; Lee,; V.; Baldwin, J. E. Angew. Chem., Int. Ed. 2004,
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Supporting Information Available: Experimental details.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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