Palladium-Catalyzed C-H Homocoupling of Thiophenes: Facile Construction of Bithiophene Structure

Article abstract of DOI:10.1021/ja031855p

Palladium-catalyzed C-H homocoupling of thiophene derivatives takes place in the presence of silver(I) fluoride or acetate. A variety of bithiophenes are obtained in good to excellent yields. In particular, the reaction of 2-bromothiophene proceeds at room temperature to afford 5,5′-dibromo-2,2′-bithiophene, where the bromine atom is completely intact in the palladium-catalyzed reaction. XRD analysis reveals that silver fluoride is reduced to silver(0) during the reaction. Copyright

Full text of DOI:10.1021/ja031855p

Published on Web 03/31/2004
Palladium-Catalyzed C-H Homocoupling of Thiophenes: Facile Construction
of Bithiophene Structure
Kentaro Masui, Haruka Ikegami, and Atsunori Mori*
Chemical Resources Laboratory, Tokyo Institute of Technology, 4259 Nagatsuta, Yokohama 226-8503, Japan
Received December 19, 2003; E-mail: amori@res.titech.ac.jp
Table 1. Homocoupling of 2-Formylthiophenea
Organic molecules bearing heteroaromatic moieties have attracted
great attention recently as potential advanced materials.1 In par-
ticular, oligothiophenes have been a major concern of excellent
conductivity, electroluminescent behaviors, and characteristics as
organic TFT.2 A transition metal-catalyzed coupling reaction via
condensation of metalated thiophene and/or thienyl halide might
be a method of choice for the construction of oligothiophenes;3
however, it would be more straightforward if the carbon-carbon
bond formation is achieved directly by functionalization of a C-H
bond of heteroaromatics.4 Herein, we report that catalytic homo-
coupling at a C-H bond of thiophene derivatives with a palladium
complex takes place in the presence of AgF or AgOCOCH3 under
mild conditions. The well-defined bithiophene unit is constructed
via C-H functionalization, which is rather more atom economical
than the related coupling with a halogenated or metalated derivative.
We examined the palladium-catalyzed homocoupling of 2-for-
mylthiophene (1a) in the presence of several silver reagents and
palladium catalysts as summarized in Table 1. The reaction was
found to occur with silver(I) fluoride at 60 °C in DMSO to give
69% of 5,5′-diformyl-2,2′-bithiophene (2a). The product was
identical with the authentic sample, which was synthesized by
bromination of 1a followed by dehalogenative homocoupling in
refluxing DMF with a nickel catalyst in overall yield of ca. 30%.3b
The reaction with silver(I) acetate similarly effected homocoupling
although it took a longer reaction period. The reaction in DMF
and CH3CN proceeded in 22% and 13% yields, respectively, while
use of toluene or THF resulted in no reaction. Various palladium
catalysts such as PdCl2, PdCl2(PhCN)2, PdCl2(PPh3)2, Pd(OAc)2,
PdCl2(dppb), Pd2(dba)3, and Pd(PPh3)4 underwent the reaction,
while no reaction was observed without palladium. The reaction
in the absence of the silver reagent with catalytic or stoichiometric
palladium resulted in no homocoupling. Other silver(I) reagents
such as AgOTf, Ag2CO3, and Ag2O were also found to be
ineffective. Thus, it is considerably important to apply the combina-
tion of a palladium catalyst with a specific silver(I) reagent for the
reaction at the C-H bond. In addition, other additives such as
Cs2CO3, K2CO3, NaOCOCH3, CuCl2, and Cu(OAc)2 did not afford
2a at all. Such a catalytic C-H homocoupling reaction of a
heteroaromatic compound inVolVing thiophene has not been shown
previously to the best of our knowledge.5
catalyst
additive
AgF
AgF
AgF
AgF
none
AgOCOCH3
AgF
AgF
time, h
%yield
PdCl2(PhCN)2
PdCl2(PhCN)2
PdCl2(dppb)
none
5
5
5
5
5
24
5
5
12
5
5
69
45b
57
0
PdCl2(dppb)
PdCl2(dppb)
PdCl2(PPh3)2
Pd(OAc)2
0
44
54
56
0
62
69
c
Pd(OAc)2
none
AgF
AgF
Pd(PPh3)4
Pd2(dba)3‚CHCl3
d
a The reaction was carried out with 0.5 mmol of 1a, 1.0 mmol of the
additive in 3 mL of DMSO. b The reaction was carried out at 35 °C. c The
reaction was carried out with catalyst loading of 100 mol %. d The reaction
was carried out with catalyst loading of 1.5 mol %.
Scheme 1. Plausible Reaction Mechanism of Homocoupling
A, which is formed by electrophilic C-H substitution of PdIIX2
with 1 to give B and following disproportionation. AgF would serve
as an effective promotor (although it is not incorporated into the
stoichiometry) in forming the intermediate B through a specific
interaction with the palladium catalyst and the sulfur atom of 1.
Silver fluoride then serves as an oxidizing agent of the formed
Pd(0) species also to regenerate the Pd(II) catalyst. Hence, use of
more than a stoichiometric amount of AgF toward 1a would be
required for the effective homocoupling reaction.
Hydrogen fluoride, which would be formed during homocou-
pling, neither inhibited the catalytic reaction nor damaged the
glassware significantly, probably due to the formation of a stablizing
complex with DMSO, whose signal in the 19F NMR spectrum
appeared at -164.2 ppm as singlet.8,9 (CAUTION! The reaction
should be carried out in a well-ventilated hood with gloves
throughout the procedure.)
To study the mechanism, the reaction was carried out with
various amounts of AgF. The reaction took place smoothly with 2
mol amounts of AgF toward 1a, while the yield of 2a diminished
with decreasing the amount of employed AgF.6 We then performed
XRD analysis of the silver residue after the reaction, the result of
which showed that several peaks of the diffraction pattern were
found to be identical with those of authentic silver(0).7
Thus, we consider that homocoupling proceeds as illustrated in
Scheme 1 via reductive coupling of bis-heteroarylpalladium species
9
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J. AM. CHEM. SOC. 2004, 126, 5074-5075
10.1021/ja031855p CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Palladium-Catalyzed Homocoupling of Heteroaromatic
Compoundsa
The reaction took place at room temperature within 5 h to give
the coupling product at the 5-position in 77% isolated yield, while
the bromo group did not react at all. On the other hand, synthesis
of 8 has been conventionally carried out with nickel-catalyzed
dehalogenative homocoupling of 7 followed by re-bromination.11
Accordingly, a direct and practical synthesis of dihalogenated
bithiophene via C-H homocoupling is extremely noteworthy since
8 is a key intermediate of a variety of oligothiophene derivatives,
which are widely applied as advanced organic materials.2
Supporting Information Available: Experimental details and
characterization of coupling products. This material is available free
of charge via the Internet at http://pubs.acs.org.
References
a The reaction was carried out under similar conditions shown in Table
1. b AgOCOCH3 and PdCl2(dppb) were employed instead of AgF and
PdCl2(PhCN)2.
(1) (a) Mori, A.; Sekiguchi, A.; Masui, K.; Shimada, T.; Horie, M.; Osakada,
K.; Kawamoto, M.; Ikeda, T. J. Am. Chem. Soc. 2003, 125, 1700. (b)
Mochizuki, H.; Hasui, T.; Kawamoto, M.; Shiono, T.; Ikeda, T.; Adachi,
C.; Taniguchi, Y.; Shirota, T. Chem. Commun. 2000, 1923. (c) Do¨lling,
K.; Zaschke, H.; Schubert, H. J. Prakt. Chem. 1979, 321, 643.
(2) (a) Briehn, C. A.; Schiedel, M.-S.; Bonsen, E. M.; Schumann, W.; Ba¨uerle,
P. Angew. Chem., Int. Ed. 2001, 40, 4680. (b) Facchetti, A.; Yoon, M.-
H.; Stern, C. L.; Katz, H. E.; Marks, T. J. Angew. Chem., Int. Ed. 2003,
42, 3900. (c) Yamamoto, T.; Arai, M.; Kokubo, H.; Sasaki, S. Macro-
molecules 2003, 36, 7986.
(3) (a) Tour, J. M. Chem. ReV. 1996, 96, 537. (b) Wei, Y.; Wang, B.; Tian,
J. Tetrahedron Lett. 1995, 36, 665. (c) Parrish, J. P.; Jung, Y. C.; Floyd,
R. J.; Jung, W. Tetrahedron Lett. 2002, 43, 7899. (d) Hassan, J.; Gozzi,
C.; Lemaire, M. C. R. Acad. Sci., Ser. IIc: Chim. 2000, 3, 517.
(4) (a) Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Bull.
Chem. Soc. Jpn. 1998, 71, 467. (b) Yokooji, A.; Okazawa, T.; Satoh, T.;
Miura, M.; Nomura, M. Tetrahedron 2003, 59, 5685. (c) Kondo, Y.;
Komine, T. Sakamoto, T. Org. Lett. 2000, 2, 3111. (d) Sezen, B.; Sames,
D. J. Am. Chem. Soc. 2003, 125, 5274. (e) Sezen, B.; Sames, D. J. Am.
Chem. Soc. 2003, 125, 10580. (f) Sezen, B.; Sames, D. Org. Lett. 2003,
5, 3607. (g) Lewis, J. C.; Wiedemann, S. H.; Bergman, R. G.; Ellman, J.
A. Org. Lett. 2004, 6, 35. (h) Kamigata, N. Yoshikawa, M. Shimizu, T.
J. Fluorine Chem. 1998, 87, 91. For a review: (i) Miura, M.; Nomura,
M. Top. Curr. Chem. 2002, 219, 211.
On the other hand, C-H cross coupling was found to occur when
the palladium-catalyzed reaction of 1a in the presence of AgF was
carried out with iodobenzene (3), affording the coupling product 4
in 58% yield (eq 1). Worthy of note is that AgF played a markedly
different role from homocoupling. XRD analysis of the silver
residue in the cross-coupling reaction indicated the formation of
AgI.7 It is also a remarkably mild C-H functionalization reaction
that takes place at the 5-position of thiophene derivatives.10
(5) Dimerization of 1a with stoichiometric Pd(OAc)2 is shown to take place
much less efficiently: Itahara, T.; Hashimoto, M.; Yumisashi, H. Synthesis
1984, 255.
(6) Yields of 2a were 54, 24, and <4%, respectively, when 1.0, 0.5, and
0.05 equiv of AgF were employed for the homocoupling reaction.
(7) See Supporting Information.
Table 2 shows results of homocoupling with various thiophene
derivatives. The reaction of ethyl thiophene-2-carboxylate (1b) and
2-acetylthiophene (1c) similarly proceeded. In addition to electron-
deficient thiophene derivatives 1a-1c, thiophenes bearing alkyl and
aryl groups effected homocoupling. Benzothiophene (1f) also
furnished 2f in 41% yield. It was found that homocoupling of 2-(4-
methoxyphenyl)thiazole (5) took place at the 5-position to afford
the corresponding bithiazole 6 in a good yield. Both additives AgF
and AgOCOCH3 effected homocoupling smoothly.
(8) The 19F NMR spectrum of commercially available Et3N‚3HF in DMSO
appeared at δ -158.7 ppm. The reaction mixture in the presence of Et3N,
which also effected homocoupling of 1a in 51% yield, showed the
ccorresponding signal at -152.1 ppm.
(9) Although the fluoro-Pummerer rearrangement may partially occur, the
characteristic triplet signal of CH3SCH2F was not detected by the
measurement of 19F NMR. McCarthy, J. R.; Peet, N. P.; LeTourneau, M.
E.; Inbasekaran, M. J. Am. Chem. Soc. 1985, 107, 735.
(10) This cross-coupling reaction was found to occur with several thiophene
and thiazole derivatives also. Details will be described in due course.
(11) Albers, W. M.; Canters, G. W.; Reedijk, J. Tetrahedron 1995, 51, 3895.
It should be pointed out that the reaction of 2-bromothiophene
(7) afforded 5,5′-dibromo-2,2′-bithiophene (8) as shown in eq 2.
JA031855P
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J. AM. CHEM. SOC. VOL. 126, NO. 16, 2004 5075