Copper-free sonogashira coupling reaction using a trans-spanning 1,2-Bis(2-thienylethynyl)benzene Ligand

Article abstract of DOI:10.1246/cl.2011.925

Novel copper-free Sonogashira coupling reaction of aryl halides with terminal acetylenes proceeded in the presence of 1,2-bis(2-thienylethynyl) benzene (1) as a trans-bidentatable ligand.

Full text of DOI:10.1246/cl.2011.925

doi:10.1246/cl.2011.925
Published on the web September 5, 2011
925
Copper-free Sonogashira Coupling Reaction
Using a trans-Spanning 1,2-Bis(2-thienylethynyl)benzene Ligand
Shingo Atobe, Motohiro Sonoda,* Yuki Suzuki, Hiroyuki Shinohara, Takuya Yamamoto, and Akiya Ogawa*
Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University,
1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531
(Received March 24, 2011; CL-110250; E-mail: ogawa@chem.osakafu-u.ac.jp)
I
Novel copper-free Sonogashira coupling reaction of aryl
halides with terminal acetylenes proceeded in the presence of
1,2-bis(2-thienylethynyl)benzene (1) as a trans-bidentatable
ligand.
SiMe3
S
S
I
(a)
(b)
S
Br
S
SiMe3
1
A carbon-carbon triple bond is often found as a useful
moiety in natural products, bioactive compounds, and functional
materials, and the development of the synthetic methods of
acetylenes is an important research project in organic chemistry.1
From the organometallic approach, the Sonogashira coupling
reaction using a Pd/Cu system2 is one of the most convenient
methods for the synthesis of acetylenes. In this method,
however, the reaction has often suffered from an oxidative
coupling reaction of acetylene induced by Cu/O2 to afford
diyne. For the purpose of avoiding this problem, copper-free
Sonogashira coupling reactions have been developed for highly
selective reaction systems in the past decade by the use of, for
example, ionic liquid as a solvent,3 N-heterocyclic carbene
ligands,4 and heterogeneous palladium complexes.5,6
We are interested in transition-metal-catalyzed reactions
using bidentate ligands, which coordinate at trans-positions of
the metal center, known as trans-spanning ligands.7 Despite
the unique coordination structure, trans-spanning ligands have
been rarely employed for transition-metal-catalyzed reactions,
because those ligands often inhibit oxidative addition or
reductive elimination.8 Nonetheless, Ueda et al. reported that
the Mizoroki-Heck reaction took place in the presence of a rigid
trans-spanning ligand.9a Furthermore, Gelman suggested that
trans-spanning ligands have the tendency to form cationic
palladium species which facilitates olefin insertion.7b From these
viewpoints, trans-spanning ligands are expected to have a
potential to strongly affect the reactivity and/or the selectivity
of transition-metal-catalyzed reactions. Herein, we report a
Cu-free Sonogashira coupling reaction using a trans-spanning
ligand.
Scheme 1. Preparation of 1. Reagents and conditions:
(a) [Pd(PPh3)4], CuI, Et3N, 82%; (b) i) KOH, MeOH,
ii) [Pd(PPh3)4], CuI, Et3N, 27%.
Table 1. Cu-free Sonogashira coupling reaction using 1a
cat. (2 mol%)
1 (2 mol%)
Br
SiMe3
SiMe3
+
Et3N, solvent
reflux, 17 h
2a
3a
4a
Entry
Catalyst
Solvent
Yieldb/%
1
2
[Pd(PPh3)4]
[Pd(PPh3)4]
Et3N
THF
40
5
3
4
5
6
7
8
9c
10d
[Pd(PPh3)4]
[Pd(PPh3)4]
toluene
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
11
74
90
<5
<5
<5
35
22
[PdCl2(PPh3)2]
[PdCl2(PhCN)2]
[PdCl2(cod)]
[Pd(OAc)2]
[PdCl2(PPh3)2]
[PdCl2(PPh3)2]
aReagents and conditions: A mixture of 2a (0.5 mmol), 3a
(0.75 mmol), Et3N (1.7 mmol), catalyst (0.01 mmol), 1 (0.01
mmol), and solvent (1.5 mL) was refluxed for 17 h under N2
b
c
d
atmosphere. GC yield. 1 (6 mol%). Without 1.
amine (1.5 mL) was used as a solvent in the presence of
[Pd(PPh3)4] catalyst, the corresponding coupling product 4a was
obtained in 40% yield as shown in Table 1 (Entry 1). The use of
acetonitrile as the solvent was specifically suitable to give 4a in
good yield, though THF and toluene were ineffective (Entries 2,
3, and 4). When [PdCl2(PPh3)2] was employed, an enhance-
ment of the reactivity was observed (Entry 5), whereas
[PdCl2(PhCN)2], [PdCl2(cod)], and [Pd(OAc)2] were not effec-
tive (Entries 6, 7, and 8). The yield of 4a was considerably
diminished by employment of 6 mol% of 1 (Entry 9) or in the
absence of 1 (Entry 10).
To begin with, 1,2-bis(2-thienylethynyl)benzene (1) was
designed as a trans-spanning ligand. Both sulfur atoms of the
thiophene rings are coordinatable10,11 at trans-positions of the
metal because of the relatively rigid structure of 1. Indeed,
pyridine analogs, bearing two pyridine rings instead of thio-
phene rings, were reported as examples of the trans-spanning
ligands.9 Diethynylbenzene 1 was synthesized easily by repet-
itive Sonogashira coupling reactions from 2-bromothiophene in
3 steps (Scheme 1).
Now, we have examined Cu-free Sonogashira coupling
reaction using 1 (Table 1). A mixture of bromobenzene (2a)
(0.5 mmol), trimethylsilylacetylene (3a) (0.75 mmol), palladium
catalyst (0.01 mmol), 1 (0.01 mmol), triethylamine (1.7 mmol),
and a solvent (1.5 mL) was refluxed for 17 h. When triethyl-
Cu-free Sonogashira coupling reactions of various acety-
lenes with aryl halides were examined under the optimized
reaction conditions (Entry 5 in Table 1), and the results are
shown in Table 2. The reaction of phenylacetylene (3b) with
iodobenzene (2b) gave the corresponding coupling product 4b in
Chem. Lett. 2011, 40, 925-927
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

926
Table 2. Cu-free Sonogashira coupling reaction of various aryl halides with acetylenesa
[PdCl2(PPh3)2] (2 mol%)
1 (2 mol%)
+
Ar
R
Ar
X
R
Et3N, CH3CN
reflux, 17 h
2
3
4
Entry
1
Ar
X
R
Yieldb/%
4a
Entry
10f
Ar
X
R
Yieldb/%
4j
2a
2b
2b
3a
81
Br
I
SiMe3
F3C
Br
Br
Br
I
2c
2d
2e
2f
3a
3a
3a
3a
82
2c,d
3b
3c
4b 84
11
12
13
4k 74
F
4c
3
CF3
98
4l
4l
47
83
4
5
2b
2b
3d
3e
4d 82
t-Bu
Br
Br
4e
95
14c
3a
4m
2g
I
90
OH
6
2b
2b
3f
4f 82
15
16
17
2h
2i
3a
3a
3a
4n 21
4o 17
4p 99
7c
3g
4g
38
n-Hex
Br
Br
8e
9e
(CH2)4OH
(CH2)3CN
2b
2b
3h
3i
4h 29
4i 70
N
2j
S
aReagents and conditions: A mixture of 2 (0.5 mmol), 3 (0.75 mmol), Et3N (1.7 mmol), catalyst (0.01 mmol), 1 (0.01 mmol), and
b
c
d
acetonitrile (1.5 mL) was refluxed for 17 h under N2 atmosphere. Isolated yield. At 60 °C. Diyne from 3b was detected in 7% yield
(based on 3b). At ambient temperature. Reaction time: 3 h.
e
f
84% yield (Entry 2).12 4-Substituted aromatic acetylenes such as
3c and 3d and conjugate enyne 3e also gave the corresponding
products in good to excellent yields (Entries 3, 4, and 5). An
aliphatic acetylene, 2-methyl-3-butyn-2-ol (3f), was applicable
to this coupling reaction (Entry 6). The reactions of 3g, 3h, and
3i, having hydrogen atoms at the propargylic position, also
proceeded selectively at lower temperature to yield the corre-
sponding products (Entries 7, 8, and 9). Next, the reactions of
electron-deficient aryl bromides such as 2c and 2d, gave the
desired products 4j and 4k in 82% and 74% yields, respectively
(Entries 10 and 11). In the case of 4-methyl-substituted aryl
halide, the use of iodide 2f instead of bromide 2e increased the
reactivity greatly to afford the corresponding product 4l in good
yield (Entries 12 and 13). The reaction of 1-bromo-2-iodoben-
zene (2g), having two different halides, proceeded efficiently
at 60 °C on the more reactive iodo position selectively to give
1-bromo-2-(trimethylsilylethynyl)benzene (4m) in 90% yield
(Entry 14). The result of the reaction of 1-bromonaphthalene
(2h) gave a low yield of 4n due to steric factors (Entry 15).
In this catalytic reaction, heteroaromatic halides were also
employable. 2-Bromopyridine (2i) reacted with 3a to give
the corresponding product 4o, though the reaction suffered
from unfavorable coordination of a nitrogen atom of 2i
(Entry 16). In contrast, 2-bromothiophene (2j) was converted
to give the desired product 4p quantitatively (Entry 17). In
most cases, trace amounts of diynes were detected by GC/
MS analysis, but the diynes could be removed from the
Sonogashira coupling products by purification using column
chromatography.
Table 3. Cu-free Sonogashira coupling reaction using various
additivesa
[PdCl2(PPh3)2] (2 mol%)
Br
additive (2 mol%)
+
SiMe3
3a
SiMe3
Et3N, CH3CN
reflux, 17 h
2a
4a
S
S
N
N
6, 7%
1, 90%
5, <5%
S
S
7, 34%
8b, 24%
b
aGC yield. 4 mol%.
In order to confirm the effect of the trans-spanning ligand 1,
the catalytic reaction was conducted in the presence of several
diethynylbenzene derivatives and related compounds (Table 3).
The use of 5 seemed to be unfavorable because two pyridine
moieties would coordinate strongly to the palladium. A
diethynylbenzene 6, which has no heteroatom as a coordination
site, was also unfavorable in this reaction. The use of 2 mol% of
2-thienylethynylbenzene (7) or 4 mol% of thiophene (8), giving
4a in 34% or 24% yield, respectively, resulted in similar
reactivity as observed in the case that no additive is employed
Chem. Lett. 2011, 40, 925-927
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

927
Chem. Rev. 2001, 101, 1031. b) L. Kaganovsky, K.-B. Cho, D.
Gelman, Organometallics 2008, 27, 5139. c) P. Štěpnička, M.
Krupa, M. Lamač, I. Císařová, J. Organomet. Chem. 2009, 694,
2987.
(Entry 10 in Table 1). These results imply that rigid and trans-
coordinatable diethynylbenzene, bearing relatively weak coor-
dination sites such as thiophene,13 would be effective for this
catalytic reaction. Additionally, unfavorable effect of trans-
coordination on the catalytic process could be mitigated due to
the weak coordination of thiophene groups, though pyridine
analog 5 clearly decreased the reactivity. The fundamental effect
of 1 in Cu-free Sonogashira reaction14 is unclear. However,
according to the fact that the reaction was promoted by ligand 1,
trans-Pd complex with 1 may have an important role in this
system.15-17
In summary, we have developed Cu-free Sonogashira
coupling reaction using the trans-spanning ligand 1. The sulfur
atom of thiophene, which coordinates weakly to the metal,
would be suitable for this reaction. Further studies on the
mechanistic insight are now in progress.
8
9
To the best of our knowledge, no report clearly mentions that
trans-coordination inhibits oxidative addition, but it is consid-
ered that the inhibition exists in the same theory as reductive
elimination. For the inhibition of reductive elimination, see: A.
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This work was supported in part by the Grant-in-Aid for
Young Scientists (B) from The Ministry of Education, Culture,
Sports, Science and Technology (MEXT) of Japan
(No. 19750082), and by a Shionogi Pharmaceuticals Inc. Award
in Synthetic Organic Chemistry, Japan, through The Society of
Synthetic Organic Chemistry, Japan, granted to M.S.
12 When bromobenzene (2a) was used instead of iodobenzene
(2b), some by-products having enyne structures from phenyl-
acetylene (3b) were formed together with the corresponding
product 4b.
13 Although attempts to obtain X-ray quality crystals of transition-
metal complex of 1 have been unsuccessful because of its
relatively weak binding ability of 1,11 the formation of the
trans-bidentate complex of 1, as well as 5,9 was conceivable
according to the DFT calculation.
14 There are a few reports mentioned about the reaction pathways
of Cu-free Sonogashira reactions, see: a) V. Grosshenny, F. M.
Romero, R. Ziessel, J. Org. Chem. 1997, 62, 1491. b) J. Cheng,
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16 In our system, trans-[Pd(Ar)(X)(1)] complex was likely to
generate after an oxidative addition of aryl halide, though
our experimental efforts for detection of the complex were
unsuccessful.
17 In some Pd-catalyzed reactions, trans-[Pd(Ar)(X)L2] complexes
are considered as key intermediates in a transmetallation step,
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This paper is in celebration of the 2010 Nobel Prize
awarded to Professors Richard F. Heck, Akira Suzuki, and
Ei-ichi Negishi.
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18 Supporting Information is available electronically on the CSJ-
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7
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Chem. Lett. 2011, 40, 925-927
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/