Direct C-H arylation of thiophenes at low catalyst loading of a phosphine-free bis(alkoxo)palladium complex

Article abstract of DOI:10.1021/jo402745b

An efficient phosphine-free direct C-H arylation of thiophenes at the α-position has been developed at low catalyst loading of bis(alkoxo)palladium complex (Cat.I, 0.1-0.2 mol %). The developed synthetic method can be applied to the synthesis of α-aryl/heteroaryl thiophenes from aryl or heteroaryl bromides in good to excellent yields and is compatible with the substrates bearing electron-donating or electron-withdrawing groups. The reactivities of the 2- and 5-positions of thiophenes are equivalent and not dependent on steric hindrance under optimal conditions. This condition can also be applied to other heterocyclic moieties such as benzothiophene, benzofuran, and pyrrole with high conversion yields.

Full text of DOI:10.1021/jo402745b

Article
pubs.acs.org/joc
Direct C−H Arylation of Thiophenes at Low Catalyst Loading of a
Phosphine-Free Bis(alkoxo)palladium Complex
Yabo Li, Jingran Wang, Mengmeng Huang,* Zhiwei Wang, Yusheng Wu, and Yangjie Wu*
College of Chemistry and Molecular Engineering, Henan Key Laboratory of Chemical Biology and Organic Chemistry, Key
Laboratory of Applied Chemistry of Henan Universities, Zhengzhou University, Zhengzhou 450052, P. R. China
S
* Supporting Information
ABSTRACT: An efficient phosphine-free direct C−H aryla-
tion of thiophenes at the α-position has been developed at low
catalyst loading of bis(alkoxo)palladium complex (Cat.I, 0.1−
0.2 mol %). The developed synthetic method can be applied to
the synthesis of α-aryl/heteroaryl thiophenes from aryl or
heteroaryl bromides in good to excellent yields and is
compatible with the substrates bearing electron-donating or electron-withdrawing groups. The reactivities of the 2- and 5-
positions of thiophenes are equivalent and not dependent on steric hindrance under optimal conditions. This condition can also
be applied to other heterocyclic moieties such as benzothiophene, benzofuran, and pyrrole with high conversion yields.
bromides, (2) could adapt well for thiophenes bearing multiple
reactive centers, and (3) could use low catalyst loadings of
bis(alkoxo)palladium(II) complex (Cat.I, 0.1−0.2 mol %) in
the absence of phosphine ligands at 100 °C (Figure 1).
INTRODUCTION
■
In recent years, much attention has been given to the synthesis
of thiophene derivatives due to their biological or physical
properties.1 Aryl/heteroaryl thiophenes as important building
blocks have been widely used in organic field-effect transistors
(OFETs),2 organic light emitting diodes (OLEDs),3 and
organic solar cells (OSC).4 Traditionally, arylthiophenes have
been prepared by palladium-catalyzed Suzuki, Stille, or Negishi
cross-coupling reactions which required the appropriate
functionalization of one or both coupling partners that may
not be readily available.5 In order to avoid these cumbersome
operations, in 1990, Ohta and co-workers developed a
palladium-catalyzed method of direct C−H arylation of
heteroaromatics.6 Recently, more successful improvements of
direct C−H activation of thiophenes have been achieved by
Doucet,7 Fagnou,8 Itami,9 and others.10 However, most of these
catalytic systems require high loadings of palladium salts (1−10
mol %) or the complexes associated with phosphine ligands and
other expensive additives.7b,e−h,8a,b,10 Doucet et al. reported a
ligand-free direct arylation of thiophenes using 0.01−0.5 mol %
Pd(OAc)2. However, the product yields were low in many
cases. Additionally their reaction could only proceed at 130−
150 °C.7c,d,i Furthermore, examples of five- or six-membered
heteroaryl bromides having the regioselective arylation with
thiophenes bearing multiple reactive centers are still rare.
Therefore, an effective phosphine-free method for direct C−H
arylation of thiophenes with aryl or heteroaryl bromides using
low catalyst loading at relatively low temperature is still need.
More recently, our research interest has been focused on the
catalytic application of N,O-ligand palladacycle catalysts:
bis(alkoxo)palladium(II) complexes which have been success-
fully applied to Sonogashira,11 Suzuki,12 and oxidative Heck-
type13 reactions as effective catalysts. Herein, we report an
effective and practical protocol that (1) could tolerate a wide
range of aryl bromides and five- or six-membered heteroaryl
RESULTS AND DISCUSSION
■
The reaction conditions were investigated using the coupling
between 2-methylthiophene (1a) and 4-bromoanisole (2a) in
PivOH/DMF with Na2CO3, and a low yield 42% of product 3a
was observed as a model study (Table 1, entry 1). Using K2CO3
as the base resulted in a high yield of 3a, and other bases such
as Cs2CO3, K3PO4, and KOAc gave slightly lower yields (Table
1, entries 1−5). When DMF was replaced with DMAc, the
yield of 3a was increased from 82% to 86% (Table 1, entries 6−
9). It was found that most of the acids evaluated in this catalytic
system were less effective except PivOH (Table 1, entries 6,
10−13). Subsequently, the catalytic activity of bis(alkoxo)
palladium complexes Cat.II and Cat.III was studied but did not
show better catalytic activity (Table 1, entries 14 and 15).
Although the product yield was reduced with lower reaction
temperature, it is worth reporting that the conversion yield
could be up to 69% at 80 °C (Table 1, entries 16−19).
Moreover, the catalytic activity was not obviously changed even
when the catalyst loading was decreased to 0.1 mol % (Table 1,
entries 20 and 21).
The substrates of direct C−H activation for the preparation
of α-arylthiophenes were investigated under the discovered
reaction conditions. The coupling reaction of 2-methylthio-
phene with aryl bromides could take place efficiently to afford
the desired products in good to excellent yields (Table 2).
Accordingly, aryl bromides having electron-withdrawing or
electron-donating groups were well tolerated in this reaction,
Received: December 10, 2013
Published: March 5, 2014
© 2014 American Chemical Society
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Figure 1. Structure of bis(alkoxo)palladium(II) complexes Cat.I, Cat.II, and Cat.III.
heteroaryl groups on the C-2, C-3, and C-4 positions generally
have high enough reactivity to give mono- or diarylated
products in good to excellent yields (Table 2, 3fb−qb).
The regioselectivity of some thiophenes with two or more
active sites (1m−p) has been examined (Table 3). It was found
that there are more than two different products formed
depending on the concentration of 4-bromotoluene. In all of
these examples, the conversion yield of 4-bromotoluene was
more than 85%. Even with equimolar amounts of thiophenes
and 4-bromobenzene, diarylated products 3mb−ob were found
more than monosubstituted compounds 3mb1−ob1 (Table 3,
entries 1−3). The unsymmetrical substrate 3-phenylthiophene
(1p) was transformed into diarylated thiophene 3pb and two
monosubstituted products 3pb1 and 3pb2 (Table 3, entry 4).
These results indicated that the reactivities of these thiophene
analogues are the same and independent of the steric hindrance
in this reaction.
Heteroaryl bromides such as pyridine, pyrimidine, quinoline,
thiophene, and furan derivatives were also investigated (Table
4). These heteroaryl bromides have higher reactivity in the
presence of 0.2 mol % catalyst to give the desired products in
good to excellent yields (Table 4, 3au−aac). However, 2-
bromo-5-methylthiophene showed lower activity, and the
isolated product 3aab was obtained in 51% yield (Table 4,
3aab). In one example, the ortho steric hindrance had
significant influence on this coupling reaction, where only a
trace amount of 2-bromo-3-methylpyridine was transformed as
determined by GC analysis. Under the optimized conditions, 2-
hexylthiophene and benzo[b]thiophene were reacted with 3-
bromopyridine to afford the desired products in 80% and 61%,
respectively (Table 4, 3bw and 3rw). To characterize the
structure of the obtained products, the crystal structures of 3ib,
3mb, and 3ax were analyzed by X-ray (see the Supporting
Information).
Table 1. Screening of the Influence of Reaction Conditions
for Palladium-Catalyzed Coupling of 2-Methylthiophene
a
with 4-Bromoanisole
temp
yield
(%)
entry
base
Na2CO3 DMF
K2CO3 DMF
Cs2CO3 DMF
solvent
acid
(°C) cat.
1
2
3
4
5
6
7
8
9
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
120
120
120
120
120
120
120
120
120
I
I
I
I
I
I
I
I
I
42
82
50
70
43
86
26
17
31
K3PO4
KOAc
K2CO3
K2CO3
K2CO3
K2CO3
DMF
DMF
DMAc
dioxane
toluene
DMAc/
EtOH
(7/1)
10
K2CO3
DMAc
p-toluenesulfonic
acid
120
I
21
11
12
13
14
15
16
17
19
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
PhCOOH
CF3SO3H
120
120
120
120
120
110
100
80
I
44
18
45
56
65
86
85
69
85
85
84
I
I
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
II
III
I
I
I
b
20
100
100
100
I
c
20
I
d
21
I
a
Reaction conditions: 2-methylthiophene (0.75 mmol), 4-bromoani-
sole (0.5 mmol), base (0.75 mmol), solvent (1.5 mL), catalyst (2.0
mol %), and acid (30 mol %) under a nitrogen atmosphere for 24 h.
Finally, these reaction conditions could also be applied to
benzofuran and pyrrole derivatives (Scheme 1). To our delight,
high conversion yields for all of these investigated heterocyclic
compounds were obtained. With an excess of 4-bromotoluene,
benzofuran could be transformed into mono- and disubstituted
products in an approximately 3:2 ratio.
b
c
d
Catalyst (1.0 mol %). Catalyst (0.5 mol %). Catalyst (0.1 mol %).
affording more than 80% yields of the arylated thiophenes 3aa−
at (Table 2, 3aa−at). An ortho steric effect was found to have
no significant influence on this coupling reaction, and high
yields (80−91%) were obtained with sterically hindered
substrates 3ar−at. An explanation for this phenomenon is
that ortho-substituents on the molecule of aryl halides may have
coordination properties with palladium, which may affect their
reaction rates and yields.7b Subsequently, the reactivity of
several thiophene derivatives has been examined (Table 2,
3bb−eb). It was found that thiophenes containing electron-
deficient groups tended to show higher reactivity compared
from those having electron-donor groups except thiophene-2-
carbonitrile 1e (73%). Moreover, in an excess amount of 4-
bromotoluene, the thiophenes substituted with aryl or
CONCLUSION
■
In summary, we have developed an efficient and regioselective
phosphine-free direct C−H arylation of thiophenes with aryl or
heteroaryl bromides using a low catalyst loading of bis(alkoxo)
palladium complex (Cat.I, 0.1−0.2 mol %) at 100 °C. This
optimal reaction protocol exhibits a wide range of applications
for various aryl, heteroaryl bromides and thiophene derivatives
to give the corresponding products in good to excellent yields.
In this catalytic reaction system, the reactivity of two or more
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a
Table 2. Palladium-Catalyzed Reaction of Aryl Bromides
with Thiophene Derivatives
Table 3. Reaction of Multiple C−H Bond Arylation
a
a
Reaction conditions: thiophene derivative (0.5 mmol), 4-bromoto-
luene (0.5 mmol), K2CO3 (0.6 mmol), DMAc (1.5 mL), catalyst (0.1
mol %), PivOH (30 mol %), 100 °C, 24 h.
Table 4. Palladium-Catalyzed Reaction of Heteroaryl
a
Bromides with Thiophene Derivatives
a
Reaction conditions: thiophene derivative (0.75 mmol), aryl bromide
(0.5 mmol), K2CO3 (0.75 mmol), DMAc (1.5 mL), Cat.I (0.1 mol %),
and PivOH (30 mol %), 100 °C, under a nitrogen atmoshphere for 24
b
h. Thiophene derivative (0.5 mmol), 4-bromotoluene (0.75 mmol),
K2CO3 (0.75 mmol), DMAc (1.5 mL), Cat.I (0.1 mol %), PivOH (30
c
mol %), 100 °C, under a nitrogen atmoshphere for 24 h. Thiophene
derivative (0.5 mmol), 4-bromotoluene (1.5 mmol), K2CO3 (1.5
d
mmol), DMAc (2.0 mL), Cat.I (0.5 mol %), PivOH (60 mol %). 4-
Bromotoluene (3.0 mmol), 28 h.
a
Reaction conditions: thiophene derivative (0.75 mmol), heteroaryl
bromide (0.50 mmol), K2CO3 (0.75 mmol), DMAc (1.5 mL), Cat.I
(0.2 mol %), PivOH (30 mol %), 100 °C, under a nitrogen
atmoshphere for 24 h. Cat.I (0.5 mol %).
active sites of thiophenes are the same and independent of the
steric hindrance. In addition, high conversion yields were
obtained for benzothiophene, benzofuran, and pyrrole deriva-
tives.
b
procedure.13,14 1H NMR and 13C NMR spectra were recorded on
400 and 100 MHz NMR instruments using CDCl3 as the solvent and
TMS as the internal standard. High-resolution mass spectrometry data
of the products were collected on an Q-TOF LC/MS instrument.
Melting points are uncorrected. Flash chromatographies were
performed on silica gel (200−300 mesh).
Preparation of PyCH3[CH2C(CH3)PhOH] (L2). To a stirred
solution of 2,6-lutidine (5.00 g, 5.4 mL, 46.7 mmol) in 100 mL of
THF was added 19.5 mL of a 2.4 M n-BuLi solution (46.7 mmol) in
EXPERIMENTAL SECTION
■
General Methods. All reactions were run under nitrogen in
Schlenk tubes using vacuum lines. DMAc analytical grade was not
distilled before use. Chemical reagents were purchased from
commercial suppliers and used without further purification. Complexes
Cat.I, PyCH3[CH2CPh2OH] (L1), and some thiophene derivatives
(1f−l and 1n−p) were prepared according to the literature
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was dissolved in H2O and extracted with ethyl acetate (3 × 15 mL).
The organic layer was collected and dried by Na2SO4 and then
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography to give the desired product.
5-(Thiophene-2-yl)benzo[c][1,2,5]oxadiazole (1k): Rf = 0.2
(hexane/ethyl acetate = 20:1); yellow solid; mp 118−119 °C; yield
Scheme 1. Direct Arylation of Other Heteroaromatics with
4-Bromotoluene
1
174 mg, (86%); H NMR (400 MHz, CDCl3) δ (ppm) 7.97 (s, 1H),
7.87 (d, J = 9.4 Hz, 1H), 7.79−7.71 (m, 1H), 7.51 (d, J = 3.4 Hz, 1H),
7.45 (d, J = 4.9 Hz, 1H), 7.21−7.13 (m, 1H); 13C{1H} (100 MHz,
CDCl3) δ (ppm) 149.6, 148.5, 141.7, 137.1, 131.7, 128.6, 127.5, 126.0,
116.9, 110.1; HRMS (ESI) calcd for C10H7N2OS [M + H]+ 203.0274,
found 203.0279.
Typical Procedure for Palladium-Catalyzed Reaction of Aryl
Bromides with Thiophenes and Other Heteroaromatics (3aa−
aac,bb−lb,3sb−vb,bw,rw). In a typical experiment, aryl or
heteroaryl bromide (0.5−0.75 mmol), thiophene derivative (0.5−
0.75 mmol), Cat.I (0.4−2.0 mg, 0.1−0.5 mol %), PivOH (15 mg, 30
mol %), and K2CO3 (104 mg, 1.5 mmol) were dissolved in DMAc (1.5
mL) under a nitrogen atmosphere. Unless otherwise noted, the
mixture was heated at 100 °C for 24 h. The suspension was cooled to
room temperature and extracted with ethyl acetate (3 × 15 mL). The
combined organic layers were dried with Na2SO4. After evaporation of
the solvents, the residue was purified by silica gel column
chromatography to afford the desired product.
hexane dropwise at −60 °C and stirred for 1 h, and then acetophenone
(5.61 g, 5.5 mL, 46.7 mmol) in 20 mL of THF was added. After
additional stirring within 12 h at room temperature a yellow solution
was formed, and then the reaction mixture was acidified to pH = 1
with 2 N HCl. After being stirred for 1 h, the mixture was neutralized
with 2 N NaOH. The aqueous layer was extracted twice with ethyl
acetate, and the organic layers were dried with Na2SO4. After
evaporation of the solvents in vacuo, the product was purified by
column chromatography (hexane/ethyl acetate = 10:1, Rf = 0.2) as a
2-Methyl-5-(p-methylphenyl)thiophene (3ab):9a Rf = 0.5
1
(100% hexane); white solid; mp 42−44 °C; yield 86 mg (92%); H
NMR (400 MHz, CDCl3) δ (ppm) 7.45 (d, J = 8.0 Hz, 2H), 7.17 (d, J
= 7.9 Hz, 2H), 7.07 (d, J = 3.4 Hz, 1H), 6.76−6.68 (m, 1H), 2.51 (s,
3H), 2.36 (s, 3H); 13C{1H} (100 MHz, CDCl3) δ (ppm) 142.1, 138.9,
136.8, 131.9, 129.4, 126.1, 125.4, 122.3, 21.1, 15.4; HRMS (ESI) calcd
for C12H13S [M + H]+ 189.0732, found 189.0730.
1
colorless oil: yield 10.12 g (95%); H NMR (400 MHz, CDCl3) δ
(ppm) 7.54−7.44 (m, 2H), 7.39 (t, J = 7.7 Hz, 1H), 7.32−7.22 (m,
2H), 7.22−7.10 (m, 2H), 6.94 (t, J = 7.7 Hz, 1H), 6.77 (d, J = 7.6 Hz,
1H), 3.19 (m, 2H), 2.49 (s, 3H), 1.53 (s, 3H); 13C{1H} (100 MHz,
CDCl3) δ (ppm) 158.5, 156.9, 148.4, 137.0, 127.8, 126.0, 124.8, 121.2,
121.0, 74.5, 48.7, 30.5, 24.2; HRMS (ESI) calcd for C15H18NO [M +
H]+ 228.1383, found 228.1392.
2-(4-tert-Butylphenyl)-5-methylthiophene (3ac):15 Rf = 0.6
1
(100% hexane); white solid; mp 48−50 °C; yield 94 mg (82%); H
NMR (400 MHz, CDCl3) δ (ppm) 7.51−7.46 (m, 2H), 7.41−7.35
(m, 2H), 7.07 (d, J = 3.5 Hz, 1H), 6.74−6.68 (m, 1H), 2.53−2.48 (m,
3H), 1.34 (s, 9H); 13C{1H} (100 MHz, CDCl3) δ (ppm) 150.1, 142.1,
139.0, 132.0, 126.1, 125.7, 125.3, 122.5, 34.5, 31.3, 15.4; MS (EI) calcd
for C15H18S [M]+ 230.4, found 230.1.
Preparation of PyCH3[CH2C(CH3)C3H7OH] (L3). Analogously to
L2, L3 was prepared from 2,6-lutidine (5.00 g, 5.4 mL, 46.7 mmol) and
19.5 mL of n-BuLi solution (2.4 M, 46.7 mmol) in hexane and pentan-
2-one (4.02 g, 5.0 mL, 46.7 mmol). The product was purified by
column chromatography (hexane/ethyl acetate = 10:1, Rf = 0.2) as a
2-Methyl-5-phenylthiophene (3ad):9a Rf = 0.6 (100% hexane);
1
white solid; mp 44−46 °C; yield 71 mg (81%); H NMR (400 MHz,
1
CDCl3) δ (ppm) 7.62−7.53 (m, 2H), 7.41−7.34 (m, 2H), 7.31−7.22
(m, 1H), 7.16−7.10 (m, 1H), 6.78−6.72 (m, 1H), 2.53 (s, 3H);
13C{1H} (100 MHz, CDCl3) δ (ppm) 142.0, 139.5, 134.7, 128.8,
127.0, 126.2, 125.5, 122.9, 15.4; MS (EI) calcd for C11H10S [M]+
174.3, found 174.1.
pale yellow oil: yield 7.76 g (86%); H NMR (400 MHz, CDCl3) δ
(ppm) 7.51 (t, J = 7.7 Hz, 1H), 7.01 (d, J = 7.7 Hz, 1H), 6.91 (d, J =
7.6 Hz, 1H), 6.27 (s, 1H), 2.93−2.74 (m, 2H), 2.51 (s, 3H), 1.47−1.35
(m, 4H), 1.13 (s, 3H), 0.96−0.82 (m, 3H); 13C{1H} (100 MHz,
CDCl3) δ (ppm) 159.3, 157.2, 137.0, 121.2, 120.9, 72.5, 46.6, 45.0,
26.9, 24.3, 17.4, 14.7; HRMS (ESI) calcd for C12H20NO [M + H]+
194.1539, found 194.1556.
2-(4-Fluorophenyl)-5-methylthiophene (3ae):16 Rf = 0.5
1
(100% hexane); white solid; mp 87−89 °C; yield 82 mg (85%); H
NMR (400 MHz, CDCl3) δ (ppm) 7.54−7.45 (m, 2H), 7.09−6.98
(m, 4H), 6.75−6.68 (m, 1H), 2.50 (s, 3H); 13C{1H} (100 MHz,
CDCl3) δ (ppm) 162.0 (d), 140.9, 139.5, 131.0, 127.1 (d), 126.2,
122.9, 115.7 (d), 15.4; MS (EI) calcd for C11H9FS [M]+ 192.3, found
192.1.
Preparation of {PyCH3[CH2C(CH3)PhO]}2Pd·2AcOH (Cat.II). A
solution of L2 (466 mg, 2.05 mmol) in toluene (8 mL) was added to a
stirred solution of Pd(OAc)2 (224 mg, 1.0 mmol) in toluene (12 mL).
The mixture was stirred at room temperature. After 3 days, the
product was isolated by filtration to give Cat.II as a white solid: yield
618 mg (91%); NMR spectra were not recorded due to its poor
solubility; HRMS (ESI) calcd for C30H33N2O2Pd [M + H]+ 559.1499,
found 559.1582. Anal. Calcd for C30H32N2O2Pd·2AcOH (679.11): C,
60.13; H, 5.94; N, 4.13. Found: C, 60.25; H, 5.93; N, 4.02.
Preparation of {PyCH3[CH2C(CH3)C3H7O]}2Pd·2AcOH (Cat.III).
Analogously to Cat.II, Cat.III was prepared from L3 (396 mg, 2.05
mmol) and Pd(OAc)2 (224 mg, 1.0 mmol) in 20 mL of toluene. The
product was isolated by filtration to give Cat.III as a white solid: yield
550 mg (90%); NMR spectra were not recorded due to its poor
solubility; HRMS (ESI) calcd for C24H37N2O2Pd [M + H]+ 491.1884,
found 491.1901. Anal. Calcd for C24H36N2O2Pd·2AcOH (611.08): C,
55.03; H, 7.26; N, 4.58. Found: C, 55.03; H, 7.17; N, 4.56.
2-Methyl-5-(p-trifluoromethylphenyl)thiophene (3af):9a Rf =
0.7 (100% hexane); white solid; mp 117−119 °C; yield 109 mg
1
(90%); H NMR (400 MHz, CDCl3) δ (ppm) 7.67−7.56 (m, 4H),
7.19 (d, J = 3.5 Hz, 1H), 6.80−6.73 (m, 1H), 2.53 (s, 3H); 13C{1H}
(100 MHz, CDCl3) δ (ppm) 141.2, 140.2, 138.1, 128.7 (q), 126.5,
125.82, 125.78, 125.4, 124.4, 124.2 (q), 15.5; MS (EI) calcd for
C12H9F3S [M]+ 242.3, found 242.1.
2-(p-Acetylphenyl)-5-methylthiophene (3ag):9a Rf = 0.3
(hexane/ethyl acetate = 20:1); white solid; mp 140−142 °C; yield
99 mg (92%); 1H NMR (400 MHz, CDCl3) δ (ppm) 7.94 (d, J = 8.4
Hz, 2H), 7.62 (d, J = 8.4 Hz, 2H), 7.23 (d, J = 3.5 Hz, 1H), 6.80−6.72
(m, 1H), 2.60 (s, 3H), 2.53 (s, 3H); 13C{1H} (100 MHz, CDCl3) δ
(ppm) 197.3, 141.5, 140.5, 139.1, 135.3, 129.1, 126.7, 125.1, 124.6,
26.5, 15.5; HRMS (ESI) calcd for C13H13OS [M + H]+ 217.0682,
found 217.0682.
Typical Procedure for the Synthesis of Initial Thiophene
Derivatives (1f−l and 1n−p). To a flask were added Cat.I (0.8 mg,
0.1 mol %), phenylboronic acid (185 mg, 1.5 mmol), KOH (112 mg,
2.0 mmol), aryl bromide (1.0 mmol), and C2H5OH (3 mL). The
reaction mixture was stirred at 78 °C. After the reaction was
completed, it was cooled to room temperature. The reaction mixture
Methyl 4-(5-methylthiophene-2-yl)benzoate (3ah):10f Rf =
0.3 (hexane/ethyl acetate = 20:1); white solid; mp 149−150 °C; yield
108 mg (93%); 1H NMR (400 MHz, CDCl3) δ (ppm) 8.01 (d, J = 8.4
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Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 3.6 Hz, 1H), 6.76−6.74
(m, 1H), 3.92 (s, 3H), 2.52 (s, 3H); 13C{1H} (100 MHz, CDCl3) δ
(ppm) 166.8, 141.3, 140.6, 138.9, 130.2, 128.2, 126.6, 125.0, 124.4,
52.1, 15.5; HRMS (ESI) calcd for C13H13O2S [M + H]+ 233.0631,
found 233.0631.
118.6, 113.0, 15.5; MS (EI) calcd for C12H9NS [M]+ 199.3, found
199.0.
2-(3,5-Bis(trifluoromethyl)phenyl)-5-methylthiophene
(3aq):16 Rf = 0.6 (100% hexane); white solid; mp 35−36 °C; yield 144
1
mg (93%); H NMR (400 MHz, CDCl3) δ (ppm) 7.92 (s, 2H), 7.72
4-(5-Methylthiophene-2-yl)benzonitrile (3ai):10f Rf = 0.3
(hexane/ethyl acetate =30:1); white solid; mp 140−141 °C; yield 89
(s, 1H), 7.24 (d, J = 3.6 Hz, 1H), 6.82−6.76 (m, 1H), 2.54 (s, 3H);
13C{1H} (100 MHz, CDCl3) δ (ppm) 142.1, 138.4, 136.7, 132.2 (q),
131.7, 126.8, 125.2, 125.1−125.0 (m), 123.3 (q), 120.1 (p), 15.5; MS
(EI) calcd for C13H8F6S [M]+ 310.3, found 310.1.
1
mg (89%); H NMR (400 MHz, CDCl3) δ (ppm) 7.61 (s, 4H), 7.22
(d, J = 3.6 Hz, 1H), 6.80−6.75 (m, 1H), 2.53 (s, 3H); 13C{1H} (100
MHz, CDCl3) δ (ppm) 142.2, 139.6, 138.9, 132.7, 126.8, 125.5, 125.1,
119., 109.9, 15.5; MS (EI) calcd for C12H9NS [M]+ 199.3, found
199.1.
2-Methyl-5-(o-methylphenyl)thiophene (3ar):9a Rf = 0.6
(100% hexane); colorless oil; yield 75 mg (80%); 1H NMR (400
MHz, CDCl3) δ (ppm) 7.42−7.35 (m, 1H), 7.29−7.23 (m, 1H),
7.23−7.16 (m, 2H), 6.88−6.83 (m, 1H), 6.77−6.71 (m, 1H), 2.53 (s,
3H), 2.44 (s, 3H); 13C{1H} (100 MHz, CDCl3) δ (ppm) 140.8, 139.6,
135.9, 134.5, 130.7, 130.3, 127.4, 126.2, 125.8, 125.3, 21.2, 15.2; MS
(EI) calcd for C12H12S [M]+ 188.3, found 188.0.
2-Methyl-5-(p-nitrophenyl)thiophene (3aj):9a Rf = 0.3 (hex-
ane/ethyl acetate = 40:1); yellow solid; mp 129−130 °C; yield 99 mg
1
(90%); H NMR (CDCl3, 400 MHz) δ (ppm) 8.21 (d, J = 8.8 Hz,
2H), 7.66 (d, J = 8.7 Hz, 2H), 7.28 (d, J = 3.6 Hz, 1H), 6.80 (d, J = 3.5
Hz, 1H), 2.54 (s, 3H); 13C{1H} (100 MHz, CDCl3) δ (ppm) 146.2,
143.0, 140.9, 139.1, 127.0, 125.8, 125.4, 124.4, 15.6; HRMS (ESI)
calcd for C11H10NO2S [M + H]+ 220.0427, found 220.0427.
Methyl 2-(5-Methylthiophene-2-yl)benzoate (3as):17 Rf = 0.3
1
(hexane/ethyl acetate = 20:1); yellow oil; yield 106 mg (91%); H
NMR (400 MHz, CDCl3) δ (ppm) 7.71−7.64 (m, 1H), 7.50−7.42
(m, 2H), 7.40−7.31 (m, 1H), 6.85−6.79 (m, 1H), 6.74−6.67 (m, 1H),
3.77 (s, 3H), 2.51 (s, 3H); 13C{1H} (100 MHz, CDCl3) δ (ppm)
169.4, 140.6, 139.6, 134.4, 131.5, 130.9, 129.3, 127.3, 126.2, 125.6,
52.2, 15.3; HRMS (ESI) calcd for C13H12NaO2S [M]+ 255.0450,
found 255.0451.
1,4-Bis(5-methylthiophene-2-yl)benzene (3ak).9a Following
the general procedure, 2-methylthiophene (1a) (185 μL, 1.5 mmol),
1,4-dibromobenzene (1k) (119 mg, 0.5 mmol), Cat.I (2.0 mg, 0.5 mol
%), PivOH (31 mg, 60 mol %), and K2CO3 (208 mg, 1.5 mmol) were
dissolved in DMAc (2 mL) under a nitrogen atmosphere. The reaction
mixture was stirred at 100 °C for 24 h. The suspension was cooled to
room temperature and extracted with ethyl acetate (3 × 15 mL). The
combined organic layers were dried with Na2SO4. After evaporation of
the solvents, the residue was purified by silica gel column
chromatography (Rf = 0.4, hexane/CH2Cl2 = 5:1) to give the desired
2-Methyl-5-(2-methylnaphthalen-1-yl)thiophene (3at): Rf =
1
0.6 (100% hexane); light yellow oil; yield 106 mg (89%); H NMR
(400 MHz, CDCl3) δ (ppm) 7.86−7.76 (m, 2H), 7.74−7.67 (m, 1H),
7.45−7.37 (m, 3H), 6.88−6.81 (m, 1H), 6.79−6.72 (m, 1H), 2.59 (s,
3H), 2.38 (s, 3H); 13C{1H} (100 MHz, CDCl3) δ (ppm) 140.3, 137.6,
135.9, 134.2, 131.8, 130.8, 128.4, 128.2, 127.7, 127.6, 126.1, 126.0,
125.2, 124.9, 21.0, 15.4. Anal. Calcd for C16H14S (238.35): C, 80.63;
H, 5.92. Found: C, 80.58; H, 5.93.
1
product as a white solid: mp 179−181 °C; yield 124 mg (92%); H
NMR (400 MHz, CDCl3) δ (ppm) 7.53 (s, 4H), 7.11 (d, J = 3.5 Hz,
2H), 6.77−6.70 (m, 2H), 2.51 (s, 6H); 13C{1H} (100 MHz, CDCl3) δ
(ppm) 141.6, 139.5, 133.3, 126.3, 125.8, 122.8, 15.5; HRMS (ESI)
calcd for C16H14S2 [M]+ 270.0531, found 270.0532.
2-(5-Methylthiophene-2-yl)pyridine (3au):10f Rf = 0.3 (hex-
ane/ethyl acetate = 20:1); pale yellow solid; mp 75−76 °C; yield 77
mg (88%); 1H NMR (400 MHz, CDCl3) δ (ppm) 8.56−8.49 (m, 1H),
7.67−7.60 (m, 1H), 7.60−7.54 (m, 1H), 7.38 (d, J = 3.6 Hz, 1H),
7.12−7.05 (m, 1H), 6.78−6.73 (m, 1H), 2.54−2.50 (m, 3H); 13C{1H}
(100 MHz, CDCl3) δ (ppm) 152.8, 149.4, 142.4, 136.5, 126.3, 124.6,
121.3, 118.3, 15.6; MS (EI): calcd for C10H9NS [M]+ 175.3; found
175.0.
2-Methyl-5-(naphthalen-1-yl)thiophene (3al):7k Rf = 0.4
(100% hexane); light yellow oil; yield 102 mg (91%); 1H NMR
(400 MHz, CDCl3) δ (ppm) 8.33−8.26 (m, 1H), 7.93−7.80 (m, 2H),
7.59−7.44 (m, 4H), 7.08−7.01 (m, 1H), 6.88−6.81 (m, 1H), 2.59 (s,
3H); 13C{1H} (100 MHz, CDCl3) δ (ppm) 140.2, 139.4, 133.9, 132.8,
131.8, 128.3, 128.1, 127.9, 127.2, 126.3, 125.9, 125.9, 125.5, 125.2,
15.3; MS (EI) calcd for C15H12S [M]+ 224.3, found 224.0.
5-Methyl-2-(5-methylthiophen-2-yl)pyridine (3av):18 Rf = 0.3
(hexane/ethyl acetate = 20:1); pale yellow solid; mp 70−72 °C; yield
2-(3,5-Dimethylphenyl)-5-methylthiophene (3am): Rf = 0.5
(100% hexane); light yellow oil; yield 82 mg (81%); 1H NMR
(CDCl3, 400 MHz) δ (ppm) 7.18 (s, 2H), 7.08 (d, J = 3.2 Hz, 1H),
6.90 (s, 1H), 6.78−6.66 (m, 1H), 2.51 (s, 3H), 2.34 (s, 6H); 13C{1H}
(100 MHz, CDCl3) δ (ppm) 142.2, 139.1, 138.3, 134.5, 128.7, 126.0,
123.4, 122.6, 21.3, 15.4. Anal. Calcd for C13H14S (202.31): C, 77.18;
H, 6.97. Found: C, 77.12; H, 6.99%.
1
80 mg (85%); H NMR (400 MHz, CDCl3) δ (ppm) 8.36 (s, 1H),
7.52−7.40 (m, 2H), 7.31 (d, J = 3.5 Hz, 1H), 6.79−6.69 (m, 1H), 2.51
(s, 3H), 2.32 (s, 3H); 13C{1H} (100 MHz, CDCl3) δ (ppm) 150.3,
149.7, 142.4, 141.7, 137.1, 130.9, 126.2, 123.9, 117.9, 18.2, 15.6; MS
(EI) calcd for C11H11NS [M]+ 189.3, found 189.0.
3-(5-Methylthiophene-2-yl)pyridine (3aw):15 Rf = 0.3 (hexane/
ethyl acetate = 30:1); pale yellow solid; mp 78−79 °C; yield 79 mg
2-(m-Methoxyphenyl)-5-methylthiophene (3an):9a Rf = 0.3
1
(100% hexane); light yellow oil; yield 84 mg (82%); H NMR (400
1
(90%); H NMR (400 MHz, CDCl3) δ (ppm) 8.82 (d, J = 2.3 Hz,
MHz, CDCl3) δ (ppm) 7.27 (t, J = 7.9 Hz, 1H), 7.15 (d, J = 7.7 Hz,
1H), 7.13−7.06 (m, 2H), 6.84−6.76 (m, 1H), 6.76−6.69 (m, 1H),
3.85 (s, 3H), 2.51 (s, 3H); 13C{1H} (100 MHz, CDCl3) δ (ppm)
159.9, 141.8, 139.6, 136.1, 129.8, 126.1, 123.1, 118.1, 112.5, 111.2,
55.3, 15.4; MS (EI) calcd for C12H12OS [M]+ 204.3, found 204.0.
2-(m-Fluorophenyl)-5-methylthiophene (3ao): Rf = 0.5 (100%
1H), 8.46 (dd, J = 4.8, 1.4 Hz, 1H), 7.82−7.75 (m, 1H), 7.30−7.23
(m, 1H), 7.15 (d, J = 3.6 Hz, 1H), 6.79−6.73 (m, 1H), 2.55−2.49 (m,
3H); 13C{1H} (100 MHz, CDCl3) δ (ppm) 148.0, 146.6, 140.9, 137.9,
132.4, 130.7, 126.5, 124.1, 123.5, 15.4; HRMS (ESI) calcd for
C10H10NS [M + H]+ 176.0528, found 176.0530.
1
3,5-Bis(5-methylthiophene-2-yl)pyridine (3ax): Rf = 0.2
(hexane/ethyl acetate = 30:1); pale yellow solid, mp 68−69 °C;
yield 108 mg (80%); 1H NMR (400 MHz, CDCl3) δ (ppm) 8.66 (d, J
= 2.1 Hz, 2H), 7.87 (t, J = 2.1 Hz, 1H), 7.19 (d, J = 3.6 Hz, 2H),
6.80−6.75 (m, 2H), 2.53 (s, 6H); 13C{1H} (100 MHz, CDCl3) δ
(ppm) 144.8, 141.1, 137.6, 130.6, 128.8, 126.5, 124.4, 15.4; HRMS
(ESI) calcd for C15H14NS2 [M + H]+ 272.0562, found 272.0567.
5-(5-Methylthiophene-2-yl)pyrimidine (3ay):19 Rf = 0.1
(hexane/ethyl acetate =10:1); white solid; mp 59−60 °C; yield 66
hexane); white solid; mp 44−45 °C; yield 82 mg (85%); H NMR
(400 MHz, CDCl3) δ (ppm) 7.35−7.28 (m, 2H), 7.28−7.20 (m, 1H),
7.15−7.09 (d, J = 3.5 Hz, 1H), 6.98−6.89 (m, 1H), 6.77−6.70 (m,
1H), 2.51 (s, 3H); 13C{1H} (100 MHz, CDCl3) δ (ppm) 163.1 (d),
140.5 (d), 140.3, 136.9 (d), 130.3 (d), 126.3, 123.7, 122.0 (d), 113.7
(d), 112.2 (d), 15.4; MS (EI) calcd for C11H9FS [M]+ 192.3, found
192.0. Anal. Calcd for C11H9FS (192.04): C, 68.72; H, 4.72. Found: C,
68.69; H, 4.73.
3-(5-Methylthiophene-2-yl)benzonitrile (3ap):7e Rf = 0.6
(hexane/ethyl acetate =30:1); white solid; mp 74−75 °C; yield 88
1
mg (75%); H NMR (400 MHz, CDCl3) δ (ppm) 9.08 (s, 1H), 8.89
1
(s, 2H), 7.22 (d, J = 3.5 Hz, 1H), 6.82 (d, J = 2.7 Hz, 1H), 2.55 (s,
3H); 13C{1H} (100 MHz, CDCl3) δ (ppm) 156.7, 152.9, 142.4, 133.7,
128.9, 126.8, 125.2, 15.5; HRMS (ESI) calcd for C9H9N2S [M + H]+
177.0481, found 177.0482.
mg (88%); H NMR (400 MHz, CDCl3) δ (ppm) 7.79 (s, 1H), 7.73
(d, J = 7.8 Hz, 1H), 7.53−7.40 (m, 2H), 7.15 (d, J = 3.6 Hz, 1H),
6.79−6.73 (m, 1H), 2.52 (s, 3H); 13C{1H} (100 MHz, CDCl3) δ
(ppm) 141.3, 139.1, 135.9, 130.0, 129.6, 129.4, 128.6, 126.6, 124.3,
2894
dx.doi.org/10.1021/jo402745b | J. Org. Chem. 2014, 79, 2890−2897

The Journal of Organic Chemistry
Article
3-(5-Methylthiophene-2-yl)quinoline (3az):10d Rf = 0.1 (hex-
ane/ethyl acetate = 20:1); pale yellow solid; mp 91−93 °C; yield 100
mg (89%); 1H NMR (400 MHz, CDCl3) δ (ppm) 9.18−9.13 (m, 1H),
8.21−8.15 (m, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 8.1 Hz, 1H),
7.70−7.63 (m, 1H), 7.58−7.50 (m, 1H), 7.32−7.27 (m, 1H), 6.83−
6.78 (m, 1H), 2.56 (s, 3H); 13C{1H} (100 MHz, CDCl3) δ (ppm)
148.5, 147.1, 141.1, 138.3, 130.6, 129.3, 129.0, 128.0, 127.9, 127.7,
127.1, 126.6, 124.3, 15.5; HRMS (ESI) calcd for C14H12NS [M + H]+
226.0685, found 226.0687.
127.4, 125.6, 125.6, 123.9, 123.5, 21.2; MS (EI) calcd for C17H14S
[M]+ 250.4, found 250.1.
2,5-Di-p-tolylthiophene (3gb):23 Rf = 0.5 (hexane/ethyl acetate
1
=20:1); white solid; mp 170−172 °C; yield 112 mg (85%); H NMR
(400 MHz, CDCl3) δ (ppm) 7.54−7.48 (m, 4H), 7.22 (s, 2H), 7.20−
7.14 (m, 4H), 2.36 (s, 6H); 13C{1H} (100 MHz, CDCl3) δ (ppm)
143.2, 137.3, 131.6, 129.5, 125.5, 123.4, 21.2; MS (EI) calcd for
C18H16S [M]+ 264.4, found 264.1.
2-(4-Methoxyphenyl)-5-(4-methylphenyl)thiophene (3hb):24
Rf = 0.4 (hexane/CH2Cl2 = 6:1); white solid; mp 172−174 °C; yield
128 mg (91%); 1H NMR (400 MHz, CDCl3) δ (ppm) 7.63−7.44 (m,
4H), 7.24−7.10 (m, 4H), 6.92 (d, J = 8.2 Hz, 2H), 3.84 (s, 3H), 2.37
(s, 3H); 13C{1H} (100 MHz, CDCl3) δ (ppm) 159.2, 143.0, 142.8,
137.2, 131.7, 129.5, 127.3, 126.9, 125.5, 123.4, 122.9, 114.3, 55.4, 21.2;
MS (EI) calcd for C18H16OS [M]+ 280.4, found 280.1.
4-(5-Methylthiophene-2-yl)isoquinoline (3aaa): Rf = 0.1
(hexane/ethyl acetate = 20:1); light yellow oil; yield 96 mg (85%);
1H NMR (400 MHz, CDCl3) δ (ppm) 9.19 (s, 1H), 8.58 (s, 1H), 8.27
(d, J = 8.5 Hz, 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.70 (t, J = 7.5 Hz, 1H),
7.61 (t, J = 7.5 Hz, 1H), 7.08 (d, J = 3.4 Hz, 1H), 6.86 (d, J = 2.7 Hz,
1H), 2.57 (s, 3H); 13C{1H} (100 MHz, CDCl3) δ (ppm) 152.0, 143.3,
141.2, 135.3, 134.1, 130.7, 128.3, 127.9, 127.8, 127.2, 126.5, 125.8,
124.6, 15.3; HRMS (ESI) calcd for C14H12NS [M + H]+ 226.0685,
found 226.0689.
2-(5-(p-Tolyl)thiophene-2-yl)pyridine (3ib): Rf = 0.1 (hexane/
ethyl acetate = 10:1); yellow solid; mp 124−126 °C; yield 104 mg
1
(83%); H NMR (400 MHz, CDCl3) δ (ppm) 8.57 (d, J = 4.7 Hz,
5,5′-Dimethyl-2,2′-bithiophene (3aab):7b Rf = 0.5 (100%
1H), 7.71−7.63 (m, 2H), 7.60−7.50 (m, 3H), 7.28 (d, J = 3.9 Hz,
1H), 7.21 (d, J = 7.9 Hz, 2H), 7.16−7.11 (m, 1H), 2.38 (s, 3H);
13C{1H} (100 MHz, CDCl3) δ (ppm) 152.6, 149.6, 146.4, 143.3,
137.8, 136.6, 131.5, 129.6, 125.7, 125.4, 123.5, 121.7, 118.5, 21.2;
HRMS (ESI) calcd for C16H14NS [M + H]+ 252.0841, found
252.0845.
1
hexane); white solid; mp 59−61 °C; yield 50 mg (51%); H NMR
(400 MHz, CDCl3) δ (ppm) 6.86 (d, J = 3.4 Hz, 2H), 6.62 (d, J = 3.0
Hz, 2H), 2.45 (s, 3H); 13C{1H} (100 MHz, CDCl3) δ (ppm) 138.4,
135.5, 125.7, 122.8, 15.3; MS (EI) calcd for C10H10S2 [M]+ 194.3;
found 194.0.
5-(5-Methylthiophene-2-yl)furan-2-carbaldehyde (3aac):7b
Rf = 0.3 (hexane/ethyl acetate = 30:1); orange oil; yield 78 mg
(81%); 1H NMR (400 MHz, CDCl3) δ (ppm) 9.58 (s, 1H), 7.33 (d, J
= 3.6 Hz, 1H), 7.28−7.24 (m, 2H), 6.79−6.73 (m, 1H), 6.57 (d, J =
3.7 Hz, 1H), 2.53 (s, 3H); 13C{1H} (100 MHz, CDCl3) δ (ppm)
176.7, 155.2, 151.3, 142.9, 129.3, 126.6, 126.5, 106.8, 15.4; MS (EI)
calcd for C10H8O2S [M]+ 192.2, found 192.0.
3-(5-(p-Tolyl)thiophen-2-yl)pyridine (3jb): Rf = 0.1 (hexane/
ethyl acetate = 10:1); white solid; mp 158−160 °C; yield 112 mg
1
(89%); H NMR (400 MHz, CDCl3) δ (ppm) 8.90 (d, J = 2.0 Hz,
1H), 8.51 (dd, J = 4.8, 1.4 Hz, 1H), 7.91−7.81 (m, 1H), 7.53 (d, J =
8.1 Hz, 2H), 7.34−7.26 (m, 3H), 7.21 (d, J = 8.1 Hz, 2H), 2.38 (s,
3H); 13C{1H} (100 MHz, CDCl3) δ (ppm) 148.3, 146.7, 145.2, 138.9,
137.9, 132.5, 131.1, 130.4, 129.7, 125.7, 125.1, 123.6, 123.6, 21.2;
HRMS C16H14NS [M + H]+ 252.0841, found 252.0849.
5-(5-(p-Tolyl)thiophene-2-yl)benzo[c][1,2,5]oxadiazole
(3kb): Rf = 0.3 (hexane/CH2Cl2 = 10:1); yellow solid; mp 188−190
°C; yield 132 mg (90%); 1H NMR (400 MHz, CDCl3) δ (ppm) 7.95
(s, 1H), 7.87−7.82 (m, 1H), 7.79−7.72 (m, 1H), 7.55 (d, J = 8.1 Hz,
2H), 7.47 (d, J = 3.9 Hz, 1H), 7.31 (d, J = 3.9 Hz, 1H), 7.23 (d, J = 7.9
Hz, 2H), 2.39 (s, 3H); 13C{1H} (100 MHz, CDCl3) δ (ppm) 149.7,
148.5, 146.9, 140.0, 138.5, 137.0, 131.3, 130.8, 129.8, 127.0, 125.8,
123.9, 116.8, 109.3, 21.3; HRMS C17H13N2OS [M + H]+ 293.0743,
found 293.0749.
1-(3-ZPhenyl-5-(p-tolyl)thiophene-2-yl)ethanone (3lb): Rf =
0.1 (hexane/ethyl acetate = 10:1); white solid; mp 74−76 °C; yield
117 mg (80%); 1H NMR (400 MHz, CDCl3) δ (ppm) 7.56 (d, J = 8.1
Hz, 2H), 7.45−7.43(m, 5H), 7.25−7.19 (m, 3H), 2.39 (s, 3H), 2.13 (s,
3H); 13C{1H} (100 MHz, CDCl3) δ (ppm) 191.9, 149.7, 147.8, 139.2,
138.2, 136.7, 130.3, 129.8, 129.0, 128.4, 128.3, 127.4, 126.0, 29.1, 21.3;
HRMS (ESI) calcd for C19H17OS [M + H]+ 293.0995, found
293.0998.
5-(1-Hexyl)-2-(p-methylphenyl)thiophene (3bb):20 Rf = 0.5
1
(100% hexane); white solid; mp 49−50 °C; yield 105 mg (81%); H
NMR (400 MHz, CDCl3) δ (ppm) 7.45 (d, J = 8.0 Hz, 2H), 7.16 (d, J
= 7.9 Hz, 2H), 7.07 (d, J = 3.5 Hz, 1H), 6.73 (d, J = 3.3 Hz, 1H),
2.89−2.74 (m, 2H), 2.35 (s, 3H), 1.77−1.62 (m, 2H), 1.45−1.28 (m,
6H), 0.94−0.85 (m, 3H); 13C{1H} (100 MHz, CDCl3) δ (ppm) 145.2,
141.8, 136.7, 132.0, 129.4, 125.4, 124.8, 122.1, 31.6, 31.6, 30.3, 28.8,
22.6, 21.1, 14.1; HRMS (ESI) calcd for C17H23S [M + H]+ 259.1515,
found 259.1512.
Methyl 5-(p-tolyl)thiophene-2-carboxylate (3cb):17 Rf = 0.2
(hexane/ethyl acetate = 40:1); white solid; mp 95−97 °C; yield 99 mg
1
(85%); H NMR (400 MHz, CDCl3) δ (ppm) 7.75 (d, J = 3.9 Hz,
1H), 7.56−7.50 (m, 2H), 7.25 (d, J = 3.9 Hz, 1H), 7.24−7.19 (m,
2H), 3.90 (s, 3H), 2.38 (s, 3H); 13C{1H} (100 MHz, CDCl3) δ (ppm)
162.7, 151.5, 138.9, 134.4, 131.4, 130.7, 129.8, 126.1, 123.1, 52.1, 21.2;
MS (EI) calcd for C13H12O2S [M]+ 232.3, found 232.0.
1-(5-(p-Tolyl)thiophene-2-yl)ethanone (3db):21 Rf = 0.2
(hexane/ethyl acetate = 40:1); pale yellow solid; mp 111−113 °C;
yield 95 mg (88%); 1H NMR (400 MHz, CDCl3) δ (ppm) 7.65 (d, J =
3.9 Hz, 1H), 7.55 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 3.9 Hz, 1H), 7.22
(d, J = 7.9 Hz, 2H), 2.56 (s, 3H), 2.38 (s, 3H); 13C{1H} (100 MHz,
CDCl3) δ (ppm) 190.5, 153.1, 142.6, 139.2, 133.5, 130.6, 129.8, 126.2,
123.4, 26.5, 21.3; HRMS (ESI) calcd for C13H13OS [M + H]+
217.0682, found 217.0682.
3-(5-Hexylthiophene-2-yl)pyridine (3bw): Rf = 0.1 (hexane/
ethyl acetate = 20:1); pale yellow solid; mp 26−27 °C; yield 98 mg
1
(80%); H NMR (400 MHz, CDCl3) δ (ppm) 8.83 (d, J = 2.1 Hz,
1H), 8.46 (dd, J = 4.8, 1.3 Hz, 1H), 7.84−7.76 (m, 1H), 7.30−7.24
(m, 1H), 7.18 (d, J = 3.6 Hz, 1H), 6.78 (d, J = 3.5 Hz, 1H), 2.83 (t, J =
7.6 Hz, 2H), 1.76−1.63 (m, 2H), 1.46−1.26 (m, 6H), 0.90 (t, J = 6.9
Hz, 3H); 13C{1H} (100 MHz, CDCl3) δ (ppm) 146.9, 146.2, 145.6,
136.5, 131.4, 129.7, 124.3, 122.9, 122.6, 30.6, 30.6, 29.2, 27.8, 21.6,
13.1; HRMS (ESI) calcd for C15H20NS [M + H]+ 246.1311, found
246.1314.
5-(p-Tolyl)thiophene-2-carbonitrile (3eb): Rf = 0.4 (hexane/
ethyl acetate = 30:1); yellow solid; mp 107−108 °C; yield 73 mg
1
(73%); H NMR (400 MHz, CDCl3) δ (ppm) 7.56 (d, J = 4.0 Hz,
1H), 7.51−7.46 (m, 2H), 7.25−7.19 (m, 3H), 2.39 (s, 3H); 13C{1H}
(100 MHz, CDCl3) δ (ppm) 152.0, 139.7, 138.3, 129.9, 129.5, 126.2,
122.7, 114.5, 107.6, 21.3; MS (EI) calcd for C12H9NS [M]+ 199.3,
found 199.0. Anal. Calcd for C12H9NS (199.05): C, 72.33; H, 4.55; N,
7.03. Found: C, 72.30; H, 4.57; N, 7.02.
3-(Benzo[b]thiophene-2-yl)pyridine (3rw):10f Rf = 0.2 (hex-
ane/ethyl acetate = 5:1); pale yellow solid; mp 127−129 °C; yield 64
mg (61%); 1H NMR (400 MHz, CDCl3) δ (ppm) 8.99 (d, J = 1.5 Hz,
1H), 8.57 (d, J = 4.0 Hz, 1H), 7.96 (d, J = 7.9 Hz, 1H), 7.83 (dd, J =
18.3, 7.4 Hz, 2H), 7.61 (s, 1H), 7.42−7.31 (m, 3H); 13C{1H} (100
MHz, CDCl3) δ (ppm) 149.1, 147.4, 140.3, 140.2, 139.7, 133.5, 130.3,
124.9, 124.8, 123.8, 123.7, 122.3, 120.7; HRMS (ESI) calcd for
C13H10NS [M + H]+ 212.0528, found 212.0530.
2-Phenyl-5-(p-tolyl)thiophene (3fb):22 Rf = 0.4 (hexane/
CH2Cl2 = 6:1); white solid; mp 141−143 °C; yield 100 mg (80%);
1H NMR (400 MHz, CDCl3) δ (ppm) 7.63 (d, J = 7.4 Hz, 2H), 7.53
(d, J = 8.0 Hz, 2H), 7.44−7.35 (m, 2H), 7.32−7.27 (m, 2H), 7.26−
7.23 (m, 1H), 7.20 (d, J = 7.9 Hz, 2H), 2.38 (s, 3H); 13C{1H} (100
MHz, CDCl3) δ (ppm) 143.8, 143.1, 137.4, 134.4, 131.6, 129.6, 128.9,
2-(p-Tolyl)benzofuran (3sb):10c Rf = 0.4 (100% hexane); white
1
solid; mp 131−133 °C; yield 61 mg (59%); H NMR (400 MHz,
CDCl3) δ (ppm) 7.75 (d, J = 8.2 Hz, 2H), 7.59−7.54 (m, 1H), 7.53−
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7.48 (m, 1H), 7.30−7.18 (m, 4H), 6.96 (d, J = 0.7 Hz, 1H), 2.39 (s,
3H); 13C{1H} (100 MHz, CDCl3) δ (ppm) 156.2, 154.7, 138.6, 129.5,
129.3, 127.7, 124.9, 124.0, 122.8, 120.7, 111.1, 100.5, 21.4; HRMS
(ESI) calcd for C15H13O [M + H]+ 209.0961, found 209.0960.
2,3-Di-p-tolylbenzofuran (3tb):25 Rf = 0.3 (100% hexane); white
solid; mp 89−90 °C; yield 60 mg (40%); 1H NMR (400 MHz,
CDCl3) δ (ppm) 7.56 (d, J = 8.2 Hz, 2H), 7.52 (d, J = 8.1 Hz, 1H),
7.50−7.46 (m, 1H), 7.41−7.35 (m, 2H), 7.33−7.27 (m, 1H), 7.27−
7.18 (m, 3H), 7.11 (d, J = 8.0 Hz, 2H), 2.42 (s, 3H), 2.33 (s, 3H);
13C{1H} (100 MHz, CDCl3) δ (ppm) 153.9, 150.6, 138.2, 137.2,
130.4, 129.9, 129.6, 129.6, 129.1, 127.9, 126.9, 124.4, 122.7, 119.9,
116.7, 111.1, 21.3; HRMS (ESI) calcd for C22H18O [M]+ 298.1352,
found 298.1354.
7.17 (m, 6H), 7.14 (d, J = 3.8 Hz, 2H), 2.37 (s, 6H). Anal. Calcd for
C22H18S2 (346.51): C, 76.26; H, 5.24. Found: C, 76.30; H, 5.27%. 13
NMR spectra were not recorded due to its poor solubility.
C
5-(p-Tolyl)-2,2′-bithiophene (3ob1): Rf = 0.5 (hexane/CH2Cl2 =
1
10:1); yellow solid; mp 126−128 °C; yield 49 mg (38%); H NMR
(400 MHz, CDCl3) δ (ppm) 7.50 (d, J = 8.1 Hz, 2H), 7.23−7.16 (m,
5H), 7.16−7.11 (m, 1H), 7.05−7.00 (m, 1H), 2.38(s, 3H); 13C{1H}
(100 MHz, CDCl3) δ (ppm) 143.3, 137.5, 131.3, 129.6, 127.8, 125.5,
124.5, 124.2, 123.5, 123.2, 21.2; HRMS (ESI) calcd for C15H12S2 [M]+
256.0375, found 256.0377.
3-Phenyl-2,5-di-p-tolylthiophene (3pb): Rf = 0.2 (100%
hexane); white solid; mp 103−104 °C; yield 140 mg (82%); 1H
NMR (400 MHz, CDCl3) δ (ppm) 7.53 (d, J = 8.0 Hz, 2H), 7.36−
7.25 (m, 6H), 7.23−7.17 (m, 4H), 7.07 (d, J = 8.0 Hz, 2H), 2.37 (s,
3H), 2.33 (s, 3H); 13C{1H} (100 MHz, CDCl3) δ (ppm) 142.3, 138.5,
137.6, 137.4, 137.2, 136.8, 131.4, 131.4, 129.6, 129.2, 129.1, 129.0,
128.4, 126.9, 126.0, 125.5, 21.2; HRMS (ESI) calcd for C24H20S [M]+
340.1280; Fonud 340.1284.
4-Phenyl-2-(p-tolyl)thiophene (3pb1): Rf = 0.3 (100% hexane);
colorless oil; yield 11 mg (9%); 1H NMR (400 MHz, CDCl3) δ (ppm)
7.37−7.26 (m, 5H), 7.25−7.22 (m, 1H), 7.19 (d, J = 8.1 Hz, 2H), 7.14
(d, J = 5.2 Hz, 1H), 7.06 (d, J = 7.9 Hz, 2H), 2.23 (s, 3H); 13C{1H}
(100 MHz, CDCl3) δ (ppm) 138.8, 137.7, 137.2, 136.7, 131.4, 130.4,
129.2, 129.1, 128.3, 126.7, 123.8, 21.2; HRMS (ESI) calcd for C17H14S
[M + H]+ 250.0811, found 250.0813.
1-Methyl-5-(p-tolyl)-1H-pyrrole-2-carbaldehyde (3ub):26 Rf =
0.2 (hexane/ethyl acetate = 20:1); colorless oil; yield 92 mg (93%);
11H NMR (400 MHz, CDCl3) δ (ppm) 9.56 (s, 1H), 7.33−7.26 (m,
4H), 6.97 (d, J = 4.1 Hz, 1H), 6.28 (d, J = 4.1 Hz, 1H), 3.92 (s, 3H),
2.41 (s, 3H); 13C{1H} (100 MHz, CDCl3) δ (ppm) 179.4, 144.4,
138.6, 132.8, 129.3, 129.1, 128.1, 124.5, 110.5, 34.3, 21.3; HRMS
(ESI) calcd for C13H14NS [M + H]+ 200.1070, found 200.1071.
Methyl 1-methyl-5-(p-tolyl)-1H-pyrrole-2-carboxylate
(3vb):26 Rf = 0.3 (hexane/ethyl acetate = 20:1); white solid; mp
1
38−40 °C; yield 105 mg (92%); H NMR (400 MHz, CDCl3) δ
(ppm) 7.32−7.21 (m, 4H), 7.01 (d, J = 4.0 Hz, 1H), 6.17 (d, J = 4.0
Hz, 1H), 3.87 (s, 3H), 3.83 (s, 3H), 2.40 (s, 3H); 13C{1H} (100 MHz,
CDCl3) δ (ppm) 161.9, 141.8, 138.0, 129.22, 129.19, 129.17, 123.1,
117.6, 108.9, 51.0, 34.3, 21.2; HRMS (ESI) calcd for C14H16NO2 [M +
H]+ 230.1176, found 230.1176.
3-Phenyl-2-(p-tolyl)thiophene (3pb2): Rf = 0.3 (100% hexane);
1
white solid; mp 97−98 °C; yield 11 mg (9%); H NMR (400 MHz,
CDCl3) δ (ppm) 7.65−7.59 (m, 2H), 7.57−7.51 (m, 3H), 7.44−7.37
(m, 2H), 7.35 (d, J = 1.4 Hz, 1H), 7.33−7.27 (m, 1H), 7.20 (d, J = 8.1
Hz, 2H), 2.37 (s, 3H); 13C{1H} (100 MHz, CDCl3) δ (ppm) 145.2,
143.0, 137.6, 135.9, 131.6, 129.6, 128.8, 127.2, 126.3, 125.7, 121.8,
119.2, 21.2; HRMS (ESI) calcd for C17H14S [M + H]+ 250.0811,
found 250.0813.
Typical Procedure for the Reaction of Multiple C−H Bond
Arylation (3mb−qb,mb1−pb2,qb). In a typical experiment, the 4-
bromotoluene (61−185 μL, 0.5−1.5 mmol), thiophene derivative (0.5
mmol), Cat.I (0.4−2.0 mg, 0.1−0.5 mol %), PivOH (15−30 mg, 30−
60 mol %), and K2CO3 (83−208 mg, 0.6−1.5 mmol) were dissolved in
DMAc (1.5−2 mL) under a nitrogen atmosphere. Unless the
otherwise noted, the mixture was heated at 100 °C for 24 h. The
suspension was cooled to room temperature and extracted with ethyl
acetate (3 × 15 mL). The combined organic layers were dried with
Na2SO4. After evaporation of the solvents the residue was purified by
silica gel column chromatography to give the desired product.
2,3-Dihydro-5,7-bis(4-methylphenyl)thieno[3,4-b][1,4]-
dioxine (3mb): Rf = 0.3 (hexane/CH2Cl2 = 5:1); pale yellow solid;
mp 152−153 °C; yield 150 mg (93%); 1H NMR (400 MHz, CDCl3) δ
(ppm) 7.63 (d, J = 8.2 Hz, 4H), 7.17 (d, J = 8.1 Hz, 4H), 4.33 (s, 4H),
2.35 (s, 6H); 13C{1H} (100 MHz, CDCl3) δ (ppm) 138.2, 136.3,
130.2, 129.3, 126.0, 114.9, 64.5, 21.2; HRMS (ESI) calcd for
C20H18O2S [M]+ 322.1022, found 322.1025.
2,2′,5,5′-Tetra-p-tolyl-3,3′-bithiophene (3qb). 4-Bromoto-
luene (370 μL, 3.0 mmol), 3,3′-bithiophene (0.5 mmol), Cat.I (2.0
mg, 0.5 mol %), PivOH (62 mg, 120 mol %), and K2CO3 (416 mg, 3
mmol) were dissolved in DMAc (3 mL) under a nitrogen atmosphere.
The mixture was heated at 100 °C for 28 h. The suspension was
cooled to room temperature and extracted with ethyl acetate (3 × 15
mL). The combined organic layers were dried with Na2SO4. After
evaporation of the solvents, the residue was purified by recrystalliza-
tion (toluene) to afford the desired product: pale yellow solid; mp
292−293 °C; Rf = 0.5 (hexane/CH2Cl2 = 5:1); yield 232 mg (88%);
1H NMR (400 MHz, C6D6) δ (ppm) 7.51−7.43 (m, 8H), 7.23 (s,
2H), 6.90 (d, J = 7.9 Hz, 4H), 6.79 (d, J = 8.0 Hz, 4H), 2.06 (s, 6H),
1.97 (s, 6H). Anal. Calcd for C36H30S2 (526.75): C, 82.08; H, 5.74.
Found: C, 82.04; H, 5.76%. 13C NMR spectra were not recorded due
to its poor solubility.
5-(p-Tolyl)-2,3-dihydrothieno[3,4-b][1,4]dioxine (3mb1):27 Rf
= 0.3 (hexane/CH2Cl2 = 5:1); pale yellow solid; mp 50−51 °C; yield
1
16 mg (7%); H NMR (400 MHz, CDCl3) δ (ppm) 7.59 (d, J = 8.2
Hz, 2H), 7.17 (d, J = 8.0 Hz, 1H), 6.26 (s, 1H), 4.34−4.19 (m, 4H),
2.35 (s, 3H); 13C{1H} (100 MHz, CDCl3) δ (ppm) 142.2, 137.7,
136.4, 130.3, 129.3, 126.0, 117.6, 97.0, 64.9, 64.6, 21.2; MS (EI) calcd
for C13H12O2S [M]+ 232.3, found 232.0.
ASSOCIATED CONTENT
■
S
* Supporting Information
All spectral data (1H and 13C) and data of X-ray analysis were
indicated by figures. This material is available free of charge via
the Internet at http://pubs.acs.org.
3,4-Diphenyl-2,5-di-p-tolylthiophene (3nb):28 Rf = 0.6 (hex-
ane/ethyl acetate = 20:1); white solid; mp 179−181 °C; yield 198 mg
1
(95%); H NMR (400 MHz, CDCl3) δ (ppm) 7.16−7.07 (m, 10H),
7.01 (d, J = 8.0 Hz, 4H), 6.99−6.94 (m, 4H), 2.29 (s, 6H); 13C{1H}
(100 MHz, CDCl3) δ (ppm) 139.1, 138.3, 136.9, 136.7, 131.4, 130.9,
129.0, 127.8, 126.5, 109.6, 21.2; MS (EI) calcd for C30H24S [M]+
416.6, found 416.3.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: hmm@zzu.edu.cn.
*E-mail: wyj@zzu.edu.cn.
3,4-Diphenyl-2-(p-tolyl)thiophene (3nb1): Rf = 0.3 (100%
hexane); white solid; mp 185−186 °C; yield 51 mg (31%); 1H
NMR (400 MHz, CDCl3) δ (ppm) 7.28 (s, 1H), 7.23−7.13 (m, 6H),
7.13−7.06 (m, 4H), 7.05−6.97 (m, 4H), 2.30 (s, 3H); 13C{1H} (100
MHz, CDCl3) δ (ppm) 143.7, 140.7, 137.0, 137.0, 136.2, 131.6, 130.9,
129.2, 129.0, 128.9, 128.1, 127.9, 126.7, 126.6, 121.7, 21.2; HRMS
(ESI) calcd for C23H18S [M]+ 326.1124, found 326.1125.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
5,5′-Di-p-tolyl-2,2′-bithiophene (3ob):29 Rf = 0.4 (hexane/
CH2Cl2 = 10:1); yellow solid; mp 179−181 °C; yield 156 mg (90%);
1H NMR (400 MHz, CDCl3) δ (ppm) 7.50 (d, J = 8.1 Hz, 4H), 7.22−
We are grateful to the National Natural Science Foundation of
China (No. 21172200 and 21302172) for financial support to
this research.
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(12) Li, Y.; Mi, X.; Huang, M.; Cai, R.; Wu, Y. Tetrahedron 2012, 68,
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