Selective β-Arylation of Thiophenes with Aryl Iodides Catalyzed by Dinuclear Palladium Carboxylate Complexes

Article abstract of DOI:10.1002/cctc.201501132

Novel dinuclear palladium complexes bearing acetoxy ligands were synthesized and characterized by X-ray crystal analysis. The complexes were utilized for the arylation of 2-ethylthiophene with iodobenzene to give ethylphenylthiophenes with high β selectiv

Full text of DOI:10.1002/cctc.201501132

DOI: 10.1002/cctc.201501132
Communications
Selective b-Arylation of Thiophenes with Aryl Iodides
Catalyzed by Dinuclear Palladium Carboxylate Complexes
Yohei Maki,[a] Takahiro Goto,[a] and Naofumi Tsukada*[a, b]
Novel dinuclear palladium complexes bearing acetoxy ligands
were synthesized and characterized by X-ray crystal analysis.
The complexes were utilized for the arylation of 2-ethylthio-
phene with iodobenzene to give ethylphenylthiophenes with
high b selectivity. The b-arylation was also applied to a variety
of iodoarenes and thiophenes, except those bearing conjugat-
ed carbonyl substituents.
ported by the Studer and Itami,[8] Oi,[9] Bach,[10] Doucet,[11] and
Glorius[12] groups.[13] In their work, various coupling partners
such as arylboron compounds,[8,10] arylsilanes,[9] arenesulfonyl
chlorides,[11] and aryliodonium salts[12] were used for the b-ary-
lation of thiophenes (Scheme 2). Itami’s catalytic system is still
In recent years, the direct arylation of CÀH bonds catalyzed by
transition-metal complexes has emerged as a simpler and
more atom-economical alternative to the conventional palladi-
um-catalyzed cross-coupling reactions.[1] The direct arylation of
thiophenes is a valuable and important method for the con-
struction of arylthiophenes, which are prevalent in biologically
active molecules[2] and organic materials.[3] However, it is diffi-
cult to achieve direct CÀH arylation at a specific position of
the thiophene ring. Whereas various catalytic systems for the
a-arylation of thiophenes have been reported,[4] the regioselec-
tive b-arylation of thiophenes is still rather limited, except for
reactions with thiophenes bearing directing groups[5] or thio-
phenes in which the a position is already substituted.[6] In
2009, Itami and co-workers reported the first method for the
selective b-arylation of thiophenes by using P[OCH(CF3)2]3 as
a ligand for palladium and aryl iodides as coupling partners
(Scheme 1).[7] Following this work, several methods were re-
Scheme 2. Previously reported Pd-catalyzed b-arylation of thiophenes with
aryl compounds.
the only example of an effective catalyst for selective b-aryla-
tion with inexpensive and commercially available aryl halides.
In the course of our studies on dinuclear complexes,[14] we
found that dinuclear palladium complexes 1 (Figure 1) bearing
Figure 1. Dinuclear methyl-, aryl-, and acetoxypalladium complexes bearing
a chelate-bridging ligand.
a chelate-bridging ligand were effective for the functionaliza-
tion of the CÀH bonds of arenes and heteroarenes.[15] To make
these dinuclear complexes more active toward CÀH bond func-
tionalization, we synthesized dinuclear acetoxypalladium com-
plexes 2 because palladium acetate and related complexes
bearing carboxylate ligands show outstanding catalytic activity
in many CÀH bond functionalization reactions.[16] Herein, we
report the synthesis of acetoxypalladium complexes 2 and
their catalytic activity in the arylation of thiophenes with io-
doarenes.
Scheme 1. Pd-catalyzed regioselective arylation of thiophenes with aryl hal-
ides reported by Itami’s group. Cy=cyclohexyl.
[a] Y. Maki, T. Goto, Dr. N. Tsukada
Department of Chemistry
Initially, we planned to synthesize acetoxy-bridged dinuclear
complex 4 from dinuclear allyl complex 3 by substitution of
a m-allyl ligand by acetic acid.[17] However, the reaction of 3
with acetic acid under an atmosphere of nitrogen was very
slow and provided a small amount of hydroxo-bridged dipalla-
dium(II) complex 2a instead of 4. To obtain 2a in higher yield,
the addition of several possible sources of the hydroxo ligand
or oxidizing agent were investigated. Although the addition of
water did not affect the reaction, if the reaction was performed
Graduate School of Science
Shizuoka University, Suruga-ku Ohya 836
Shizuoka 422-8529 (Japan)
E-mail: tsukada.naofumi@shizuoka.ac.jp
[b] Dr. N. Tsukada
Research Institute of Green Science and Technology
Shizuoka University, Suruga-ku Ohya 836
Shizuoka 422-8529 (Japan)
Supporting Information for this article is available on the WWW under
http://dx.doi.org/10.1002/cctc.201501132.
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under an oxygen atmosphere complete conversion of 3 was
observed. However, the yield of 2a was not high, because sev-
eral unidentified products were also generated along with 2a.
Finally, oxidation of 3 in air gently proceeded to give 2a in
92% yield. Acetoxypalladium complex 2a can be converted
into trifluroroacetoxypalladium complex 2b by treatment with
an excess amount of trifluoroacetic acid at room temperature
(Scheme 3).
which is slightly shorter than this distance in the chloride-
bridged dipalladium complex (3.24 Š).[14a]
Dinuclear acetoxypalladium complex 2a was found to be an
efficient catalyst for the arylation of thiophenes with aryl io-
dides. The reaction of 2-ethylthiophene with iodobenzene in
the presence of 2a and Ag2CO3 gave ethylphenylthiophenes in
90% yield (Table 1, entry 1). Unlike reactions performed with
Table 1. Palladium-catalyzed reactions of 2-ethylthiophene with iodoben-
zene.[a]
Entry
Catalyst [mol%]
Additive [mol%]
Yield[b] [%]
5a/5b[c]
1
2
3
4
5
6
7
8
9
10
2a (5)
2b (5)
1a (5)
1a (5)
1a (5)
1a (5)
1a (5)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
–
–
–
90
80
42
93
58
6
82
74
25
33
95:5
96:4
95:5
96:4
83:17
83:17
89:11
94:6
85:15
79:21
CH3CO2H (10)
CH3CO2H (30)
CH3CO2K (100)[d]
tBuCO2H (10)
dpfamH[e] (5)
dpfamH[e] (10)
–
Scheme 3. Synthesis of acetoxy- and trifluoroacetoxypalladium complexes 2.
Crystallization of 2a by vapor diffusion of diethyl ether into
a solution of THF afforded a yellow crystal suitable for X-ray
analysis.[18] The molecular structure of 2a is shown in Figure 2.
Complex 2a adopts a symmetrical A-frame structure similar to
chloride-bridged dipalladium complexes bearing the same che-
late-bridging ligand.[14a] The m-OH ligand is positioned symmet-
rically relative to the metal centers. Each palladium center has
[a] A mixture of 2-ethylthiophene (0.30 mmol), iodobenzene (0.30 mmol),
and AgCO3 (0.30 mmol) in 1,4-dioxane (0.75 mL) was stirred at 1208C for
15 h in the presence of the catalyst and the additive. [b] GC yield. [c] De-
termined by 1H NMR spectroscopy. [d] Without Ag2CO3. [e] N,N’-Bis(2-di-
phenylphosphinophenyl)formamidine.
a
square-planar geometry, in which the PÀPdÀN angle
[83.84(13)8] is slightly acute owing to the bidentate PC6H4N
unit, and both the PÀPdÀO1 [171.28(14)8] and NÀPdÀO2
angles [172.1(4)8] are distorted. The symmetrical position of C1
relative to the nitrogen atoms indicates that the double bond
of the amidinate is delocalized. The PdÀPd distance is 3.082 Š,
the use of ordinary palladium catalysts, the reaction with 2a
showed high b selectivity and gave 2-ethyl-4-phenylthiophene
(5a) and 2-ethyl-5-phenylthiophene (5b) in a 95:5 ratio. A simi-
lar result was obtained in the reaction with trifluoroacetoxypal-
ladium complex 2b (Table 1, entry 2). Complex 1a, which has
no carboxylate ligand, showed lower reactivity, though the re-
gioselectivity was high (Table 1, entry 3). The addition of acetic
acid (2 equiv.) improved the catalytic ability of 1a (Table 1,
entry 4). However, the addition of a larger amount of acetic
acid decreased both the yield and the regioselectivity (Table 1,
entry 5). The use of potassium acetate instead of acetic acid
and silver carbonate resulted in a lower yield and lower selec-
tivity (Table 1, entry 6). Other bases including various carbo-
nates and silver salts were also less effective than silver carbon-
ate.[19] Pivalic acid, which is an effective additive for many CÀH
functionalization reactions,[16] was also effective in the reaction
with 1a, though the regioselectivity slightly decreased (Table 1,
entry 7). The dinuclear structure of the catalysts may be essen-
tial for reactivity and selectivity in the b-arylation reaction.
Whereas in the presence of a 1:2 mixture of the chelate-bridg-
ing ligand and Pd(OAc)2 the reaction afforded a result similar
to that obtained in the reaction with 2, the yield and selectivity
for 5a were lower for the reaction performed in the presence
of a 1:1 mixture, which would form a mononuclear complex
in situ (Table 1, entries 8 and 9). Although the reaction without
Figure 2. Molecular structure of 2a with 50% thermal ellipsoids. Hydrogen
atoms and solvent molecules are omitted for clarity. Selected bond length-
s [Š] and angles [8]: Pd1ÀP1 2.02052(16), Pd1ÀO1 2.057(4), Pd1ÀO2
2.018(10), Pd1ÀN2 2.032(5), N2ÀC1 1.321(5); P1-Pd1-N2 83.84(13), P1-Pd1-O1
171.28(14), O2-Pd1-N2 172.1(4), Pd1-O1-Pd1i 97.0(2), N2-C1-N2i 127.4(6).
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the chelate-bridging ligand also gave 5a preferentially, the
yield and selectivity were low (Table 1, entry 10).
Table 2 summarizes the results of the arylation of various thi-
ophenes with various aryl iodides in the presence of 2a. After
Scheme 4. Reaction of 1a with acetic acid.
Table 2. Reactions of thiophenes with aryl iodides in the presence of
2a.[a]
with 1a (Table 1, entry 4). Unfortunately, stoichiometric reac-
tions of 2a with 2-ethylthiophene and iodobenzene gave mix-
tures of many unidentified complexes. Therefore, details of the
reaction mechanism are unclear at the present time.
In summary, we found that a new dinuclear palladium com-
plex bearing acetoxy ligands shows b selectivity in the aryla-
tion of thiophenes with iodoarenes. Mechanistic studies and
applications to other heteroarenes are in progress.
Entry
R1
R2
Ar
Product Yield[b] [%] a/b[c]
1
2
3
4
5
6
7
8
Et
Me
Cl
Ph
COCH3
CHO
H
H
Et
Et
Et
H
H
H
H
H
H
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
5
6
69 (99)
76
95:5
95:5
7
8
9
10
11
12
13
14
15
16
73
80
51
47
65
trace
78
76
80
79
64
64
89:11
80:20
0:100
0:100
97:3
–
97:3
94:6
100:0
100:0
88:12
64:36
Experimental Section
General procedure for the arylation of thiophenes
A pressure vial was charged with a mixture of 2a (0.015 mmol,
14 mg) and Ag2CO3 (0.30 mmol, 83 mg) in toluene (1.5 mL), and
then the thiophene (0.30 mmol) and the iodoarene (0.30 mmol)
were added. After stirring at 1208C for 15 h, the mixture was
cooled to room temperature and filtered through a short plug of
silica gel (ethyl acetate). The yield was determined by GC analysis
of the filtrate or by isolation of the product by column chromatog-
raphy (silica gel, hexane/ethyl acetate). The isomer ratio was deter-
mined by 1H NMR spectroscopy.
COCH3 Ph
9
H
H
H
H
H
H
p-Me
o-Me
p-MeO
m-MeO
p-CH3CO 17
p-NO2 18
10
11
12
13
14
Et
Et
Et
[a] A mixture of the substituted thiophene (0.30 mmol), iodoarene
(0.30 mmol), and AgCO3 (0.30 mmol) in toluene (1.5 mL) was stirred at
1208C for 15 h in the presence of 2a. [b] Yield of isolated product. GC
1
yield is given in parentheses. [c] Determined by H NMR spectroscopy.
Acknowledgements
We gratefully acknowledge Prof. Mitsuru Kondo (Research Insti-
tute of Green Science and Technology, Shizuoka University) for X-
ray crystal analysis.
extensive screening of various solvents,[19] toluene was found
to be more suitable for the arylation than 1,4-dioxane (Table 2,
entry 1). The reactions of several thiophenes bearing substitu-
ents such as Me, Ph, and Cl at the C2 position gave b-arylation
products as major products as well as the reaction of 2-ethyl-
thiophene (Table 2, entries 2–4). There are few reports concern-
ing the direct b-arylation of thiophenes bearing conjugated
carbonyl substituents.[12] Unfortunately, the b-arylation of these
thiophenes could not be accomplished by using 2a as a cata-
lyst (Table 2, entries 5, 6, and 8). The reactions of 2-acetylthio-
phene and 2-thenaldehyde afforded only a-phenylthiophenes.
The methyl substituent in 3-methylthiophene did not disturb
the arylation reaction at the b position (Table 2, entry 7). Aryla-
tion with iodobenzenes bearing electron-donating groups in
the ortho, meta, and para position gave the b-arylated prod-
ucts with high selectivities (Table 2, entries 9–12). The reactions
of iodoarenes bearing electron-withdrawing groups also af-
forded b-arylated products in good yields, although the selec-
tivity was low (Table 2, entries 13 and 14).
Keywords: CÀH activation
· carboxylate ligands · cross-
coupling · heterocycles · palladium
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Received: October 16, 2015
Published online on January 5, 2016
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