Palladium-catalyzed C-H homocoupling of furans and thiophenes using oxygen as the oxidant

Article abstract of DOI:10.1021/ol501019y

A general and efficient palladium-catalyzed intermolecular direct C-H homocoupling of furans and thiophenes has been developed. The reaction is characterized by using molecular oxygen as the sole oxidant and complete C5-position regioselectivity. Both C2- and C3-substituted furans or thiophenes are appropriate substrates. The approach provides a straightforward, facile, and economical route to bifurans and bithiophenes under mild reaction conditions.

Full text of DOI:10.1021/ol501019y

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed C−H Homocoupling of Furans and Thiophenes
Using Oxygen as the Oxidant
Na-Na Li, Yan-Lei Zhang, Shuai Mao, Ya-Ru Gao, Dong-Dong Guo, and Yong-Qiang Wang*
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, Department of Chemistry &
Materials Science, Northwest University, Xi’an 710069, P. R. China
S
* Supporting Information
ABSTRACT: A general and efficient palladium-catalyzed intermolecular direct
C−H homocoupling of furans and thiophenes has been developed. The reaction
is characterized by using molecular oxygen as the sole oxidant and complete C5-
position regioselectivity. Both C2- and C3-substituted furans or thiophenes are
appropriate substrates. The approach provides a straightforward, facile, and economical route to bifurans and bithiophenes under
mild reaction conditions.
a
i(hetero)aryls are important structural components in
natural products, pharmaceuticals, and functional materi-
Table 1. Optimization of Reaction Conditions
B
als.1,2 Typically, the components are synthesized by the cross-
coupling of an (hetero)aryl halide or a pseudohalide with an
organometallic reagent, an organoboron reagent, or an
electron-rich (hetero)arene (e.g., Stille, Negishi, and Suzuki
reaction),3 or by the homocoupling of two organometallic
reagents or two (hetero)aryl halides (e.g., Wurtz and Ullmann
reaction).4 Alternatively, direct oxidative homocoupling of two
unactivated (hetero)arenes using a C−H activation strategy
through the cleavage of two C−H bonds represents an
environmentally and economically more attractive method.5
In the past decade, direct catalytic homocoupling has been
successfully applied in many (hetero)arenes, such as arenes,6
thiophenes,7 indoles,8 indolizines,9 azoles,10 and pyridines.11
Nevertheless, to the best of our knowledge, the efficient
catalytic homocoupling of furans with a direct C−H
functionalization strategy has not been documented,12 despite
furans being very important heteroarenes and bifurans being
important building blocks for synthesizing poly- and oligofur-
ans. Furthermore, recently Bendikov et al. reported that
oligofurans have higher fluorescence, tighter herringbone
solid-state packing, and greater rigidity and solubility than the
workhorse compoundoligothiophenes in the field of organic
electronic materials.13 In addition, furan-based materials should
be biodegradable.13
Herein, we report the first efficient synthesis of bifurans by
the direct catalytic C−H homocoupling of furans with a C−H
activation strategy. The reaction is catalyzed by palladium(II)
using oxygen as the sole oxidant and has complete C5-position
regioselectivity. Also thiophenes are suitable substrates for the
reaction.
Initially, we investigated the homocoupling reaction of 2-
ethyl furan (1a) with 10 mol % Pd(OAc)2 as the catalyst and
oxygen as the oxidant in DMSO at room temperature (Table
1). The reaction was found to proceed in low conversion
(<10%) (entry 1). Considering trifluoroacetic acid (TFA) and
Pd(OAc)2 can facilitate the generation of more electropositive
[Pd(II)O2CCF3]+ species, which compared with [PdOAc]+ is
b
entry
cat.
acid (equiv) temp (°C) time (h) yield (%)
c
1
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
Pd(OH)2
PdCl2
−
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
72
24
24
24
24
24
24
36
24
<10
82
10
30
60
35
≤45
75
0
2
3
4
5
6
TFA (1.0)
TFA (0.1)
TFA (0.5)
TFA (2.0)
TFA (4.0)
TFA (1.0)
TFA (1.0)
TFA (1.0)
TFA (1.0)
TFA (1.0)
TFA (1.0)
d
7
8
9
10
4.5
0
e
11
Pd(OAc)2
Pd(OAc)2
24
48
65
66
f
g
12
a
Reaction conditions: 1a (1 mmol), catalyst (0.1 mmol), O2 (1 atm),
and TFA (1 mmol) in DMSO (1.5 mL) at room temperature.
Isolated yield. No acid. Solvents: EtOAc, DMF, THF, n-hexane,
toluene, acetone, CH3CN, dioxane, Et2O, CH2Cl2, CHCl3, CH3NO2,
b
c
d
e
f
g
EtOH. Using air as the oxidant. Pd(OAc)2 (5 mol %) was used. The
conversion was 72%.
easier to form σ-furan-Pd complexes through electrophilic
substitution of C−H bonds,14 1 equiv of TFA was added to the
reaction system. To our delight, the reaction gave the bifuran
product (2a) in 82% yield with complete C5 regioselectivity
(entry 2). Changing the amount of TFA could not improve the
yield (entries 2−6). After careful solvent screening, DMSO
proved to be the best (entry 7). By using other palladium
sources, Pd(TFA)2 was observed to be an acceptable catalyst
for the reaction while Pd(OH)2 and PdCl2 could not promote
the reaction (entries 8−10). It is noteworthy that the reaction
rate and the yield were obviously reduced when air was used as
Received: April 8, 2014
Published: May 7, 2014
© 2014 American Chemical Society
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Letter
the oxidant instead of oxygen (entry 11). When the loading of
Pd(OAc)2 was lowered, e.g., to 5 mol %, the reaction was slow
and would proceed incompletely (entry 12). Accordingly, the
reaction conditions were optimized as follows: Pd(OAc)2 (10
mol %), TFA (1 equiv) under an oxygen atmosphere in
DMSO.
With the optimal reaction conditions in hand, we moved on
to explore the scope of the homocoupling reaction. The results
were summarized in Table 2. Furans substituted by various
position could not be detected by analyzing the reaction
mixtures. Additionally, the reaction could readily be enlarged to
gram scale with a slightly higher yield (entry 1).
Next, we turned our focus toward thiophene substrates.
Currently, oligothiophenes have been extensively studied and
applied in the field of organic semiconductors due to their
superior electronic properties.13,15 In 2004, Mori et al. first
reported the palladium-catalyzed C−H homocoupling of
thiophenes.7a In the approach, 1 equiv of AgF was employed
as an activator so that stoichiometric hydrogen fluoride was
generated as a byproduct; therefore the reaction should be
carried out in a well-ventilated hood with gloves throughout the
procedure. Later, they developed another cheap activator
system, AgNO3/KF, to take the place of AgF.16 In 2008, Tse
et al. reported an efficient gold-catalyzed oxidative homocou-
pling of arenes using PhI(OAc)2 as the oxidant.6a,17 With this
reaction they also examined the homocoupling of 2-
methylthiophene, but the yield was only 31%. It is significant
that this protocol did not need any silver salt to improve the
reactivity.
Table 2. Palladium-Catalyzed Homocoupling of 2-
a
Substituted Furans
Under our above optimal reaction conditions, a variety of 2-
substituted thiophenes were checked. Pleasingly, they all
successfully gave the desired homocoupling products in good
to excellent yields (Table 3). Moreover, the products were of
complete C5-position regioselectivity, and no product of
another position can be detected. Valuable advantages of the
method included operational simplicity using oxygen as the
oxidant without the requirement of special equipment.
Oligo-(3-alkyl)furans and oligo-(3-alkyl)thiophenes have
received considerable attention recently due to their application
in thin-film transistors (TFTs),18 light-emitting devices
(LEDs),19 and photovoltaics.20 Nevertheless, the homocou-
pling of 3-alkylfurans or 3-alkylthiophenes were very limited in
the literature.12a,21 Moreover, the substrates of the homocou-
pling reaction were confined to 3-substituted thiophenes.
Because of the high nucleophilicity of the C2 position of the 3-
substituted thiophenes, the reaction exclusively provided head-
to-tail (H−T) products and head-to-head (H−H) products,
with no tail-to-tail (T−T) products reported (Scheme 1).
Furthermore, the homocoupling of 3-alkylfurans has not been
shown previously to our knowledge. Thus, we investigated the
homocoupling reaction of 3-alkylfurans and 3-alkylthiophenes
with our above-mentioned homocoupling conditions. Delight-
edly, both 3-alkylfurans and 3-alkylthiophenes reacted smoothly
under similar conditions to afford homocoupling products in
moderate yield, albeit without complete conversion (Table 4).
Interestingly, the reaction exhibited complete tail-to-tail (T−T)
regioselectivity. The great C5-position regioselectivity is
probably attributed to the steric hindrance of the 3-position
substituent group that limits the palladation of the C2-position.
To gain insight into the reaction mechanism, a kinetic
isotope effect (KIE) competition experiment was carried out by
using the reaction of 1d and its derivative deuterated at the C5
position ([D]-1d) (Supportig Information). The KIE value was
2.17, indicating that the C−H bond breaking was involved in
the rate-determining step in the overall catalytic cycle. Our
current understanding of the mechanism of the reaction is
shown in Scheme 2. Pd(OAc)2 is treated with TFA to obtain
active Pd(O2CCF3)+,14,22 which affords the C2-palladated
species I through electrophilic addition of furan and following
rearomatization. Then the electrophilic palladation with the
second furan leads to bis-furanylpalladium species II.7a,8c The
following reductive elimination generates the bifuran product,
a
Reaction conditions: 1 (1 mmol), catalyst (0.1 mmol), O2 (1 atm),
b
and TFA (1 mmol) in DMSO (1.5 mL) at 50 °C for 20−48 h. The
reaction proceeded at room temperature. Isolated yield. 10 mmol of
2-ethyl furan were used.
c
d
alkyl groups at the C2-position smoothly underwent the
homocoupling reaction to give corresponding bifuran products
in 78−86% yields (entries 1−6). Furans bearing an ester, ether,
or amide functional group were also reacted successfully and
provided the coupling products in good yields with the
functional group intact (entries 7−10). These groups could be
further transformed into other functionalities. It is worth
mentioning that all reactions proceeded with complete C5-
position regioselectivity of the furans. The product of another
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Letter
Table 3. Palladium-Catalyzed Homocoupling of 2-
Substituted Thiophenes
Table 4. Palladium-Catalyzed Homocoupling of 3-
Substituted Furans and Thiophenes
a
a
a
Reaction conditions: 5 (1 mmol), catalyst (0.1 mmol), O2 (1 atm),
and TFA (1 mmol) in DMSO (1.5 mL) at 50 °C for 36−48 h.
b
c
Isolated yield. Yield in parentheses based on recovered starting
material.
Scheme 2. Plausible Mechanism for the Homecoupling
a
Reaction conditions: 3 (1 mmol), catalyst (0.1 mmol), O2 (1 atm),
b
and TFA (1 mmol) in DMSO (1.5 mL) at 50 °C for 24−48 h. The
reaction proceeded at room temperature. Isolated yield.
c
substituted furans or thiophenes are appropriate substrates. The
reaction proceeds with complete C5-position regioselectivity.
The approach provides a straightforward, facile, and economical
route to bifurans and bithiophenes under mild reaction
conditions. The method should have many applications in
organic and material chemistry. Detailed mechanistic inves-
tigations and the applications of the reaction are currently
underway.
Scheme 1. Homocoupling of 3-Substituted Thiophene
and the Pd0 can be reoxidized to Pd(O2CCF3)+ by O2 in the
presence of TFA to complete the catalytic cycle.23
In summary, we have developed an efficient C−H
homocoupling of furans and thiophenes with the C−H
activation strategy. The reaction is catalyzed by palladium(II),
in which oxygen is used as the sole oxidant. Both C2- and C3-
ASSOCIATED CONTENT
■
S
* Supporting Information
Detailed experimental procedures including spectroscopic and
analytical data. This material is available free of charge via the
Internet at http://pubs.acs.org.
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Letter
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2010, 12, 1200. (b) Monguchi, D.; Yamamura, A.; Fujiwara, T.;
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: wangyq@nwu.edu.cn.
Notes
The authors declare no competing financial interest.
(12) Bifurans were obtained as a byproduct only in low yield
(<15%); see: (a) Dohi, T.; Morimoto, K.; Kiyono, Y.; Maruyama, A.;
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ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Natural
Science Foundation of China (NSFC-20972126, 21272185),
the Program for New Century Excellent Talents in University
of the Ministry of Education China (NCET-10-0937), and
Education Department of Shaanxi Provincial Government
(09JK776).
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