An efficient route to regioselective functionalization of benzo[b]thiophenes via palladium-catalyzed decarboxylative Heck coupling reactions: Insights from experiment and computation

Article abstract of DOI:10.1039/c5ob01905b

Pd-catalyzed decarboxylative Heck-type coupling of 3-chlorobenzo[b]thiophene-2-carboxylic acids with styrenes have been developed as an efficient strategy for the construction of functionalized benzo[b]thiophenes. Theoretical analysis shows that AgCl generated during the reaction, instead of Pd, π-coordinates with the carboxyl O atom, making easy the rate-determining CO₂ dissociation. The divergent reactivities of the Cl-substituted and H-substituted 3-benzo[b]thiophene-2-carboxylic acids are mainly due to the presence of the Cl substituent, which reduces the adjacent π-π interplay, thereby significantly contributing to decarboxylation. Therefore, the presence of both AgCl and the Cl substituent are of key importance in ensuring the occurrence of the reaction under the given conditions.

Full text of DOI:10.1039/c5ob01905b

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An efficient route to regioselective
functionalization of benzo[b]thiophenes via
palladium-catalyzed decarboxylative Heck
coupling reactions: insights from experiment
and computation†
Cite this: DOI: 10.1039/c5ob01905b
Daoshan Yang,‡ Yuxia Liu,‡ Pengfei Sun, Ning Zhang, Wei Wei, Mingyang Sun,
Guang Chen, Siwei Bi and Hua Wang*
Pd-catalyzed decarboxylative Heck-type coupling of 3-chlorobenzo[b]thiophene-2-carboxylic acids with
styrenes have been developed as an efficient strategy for the construction of functionalized benzo[b]thio-
phenes. Theoretical analysis shows that AgCl generated during the reaction, instead of Pd, π-coordinates
with the carboxyl O atom, making easy the rate-determining CO2 dissociation. The divergent reactivities
of the Cl-substituted and H-substituted 3-benzo[b]thiophene-2-carboxylic acids are mainly due to the
presence of the Cl substituent, which reduces the adjacent π–π interplay, thereby significantly contribut-
ing to decarboxylation. Therefore, the presence of both AgCl and the Cl substituent are of key importance
in ensuring the occurrence of the reaction under the given conditions.
Received 14th September 2015,
Accepted 13th November 2015
DOI: 10.1039/c5ob01905b
www.rsc.org/obc
transformation has become challenging but a very attractive
target to pursue. Recently, exploring efficient and highly selec-
Introduction
Seeking efficient methods for the construction of C–C bonds tive methods for the direct functionalization of C–H bonds has
has always been a hot topic in the field of synthetic chemistry.1 become a hot topic in organic chemistry. Thus, the direct
Undoubtedly, seeking more mild, practical and selective alkenylation of C(sp2)−H bonds should be more economical
methods for the formation of C–C bonds has stimulated an and practical. In 2009, Gaunt’s group developed a mild and
impressive number of research studies. Typically, there are efficient aerobic palladium(II) catalyst system for C2 or C3
four methods for the construction of C–C bonds including alkenylation of pyrroles (Scheme 1a).6 In the same year,
nucleophilic substitution, nucleophilic additions, Friedel–
Crafts-type reactions and Diels–Alder reactions.2 It is worth
noting that, over 40 years ago, Mizoroki and Heck indepen-
dently discovered the Pd(0)-catalyzed arylation and vinylation
of aryl halides.3 This developed methodology, known world-
wide as the Heck reaction or Mizoroki–Heck reaction, has
been emerging as a versatile and powerful tool for the C–C
bond formation. Excitingly, because of its tremendous achieve-
ments in the C–C bond formation, it won the 2010 Nobel Prize
in chemistry.4 However, the substrates involved are mainly
aryl/vinyl halides or triflates in the Heck-type coupling.5 There-
fore, the development of alternative methods for this elegant
The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical
Intermediates and Analysis of Natural Medicine, School of Chemistry and Chemical
Engineering, Qufu Normal University, Qufu 273165, Shandong, China.
E-mail: huawang_qfnu@126.com
†Electronic supplementary information (ESI) available: Experimental details.
See DOI: 10.1039/c5ob01905b
Scheme 1 Strategies for the direct C2 or C3 alkenylation of
‡Authors with equal contribution.
heterocycles.
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Carretero and co-workers reported an efficient palladium-
catalyzed regioselective C-2 alkenylation of indoles and pyr-
roles via C–H bond activation (Scheme 1b).7 In 2012, Liu et al.
demonstrated a convenient and direct palladium-catalyzed ole-
fination of furans and thiophenes by using allylic esters and
ethers (Scheme 1c).8 In 2013, Iitsuka et al. developed a
rhodium/silver catalyst system for C3-alkenylation of thio-
phene and furan-2-carboxylic acids as well as 2-acetylthio-
phene with acrylates and styrenes (Scheme 1d).9 On the other
hand, carboxylic acids are common and important building
blocks, and they are easily prepared from readily available
chemicals. As a successful attempt, a decarboxylative cross-
coupling strategy has been introduced by Gooßen,10 Myers,11
and other groups12 as a reliable tool in the C–C bond for-
mation. Furthermore, DFT studies on decarboxylative cross-
coupling reactions have also been reported.13 In 2002, Myers
and co-workers initially developed a Pd-catalyzed decarboxyl-
ative Heck-type approach for the formation of vinyl arenes.14
Since then, this new kind of Heck-type coupling reactions have
been extensively studied. Nevertheless, investigations on the
synthetic strategy using heteroarene carboxylic acids as the
coupling partners are limited.15 Considering the important
application of heteroarene compounds in natural products,
pharmaceuticals, and materials science, it remains a challenge
and a high desire to explore new Heck-type coupling scope for
heteroarene carboxylic acids.
Table 1 Palladium-catalyzed coupling reaction of 3-chlorobenzo[b]-
thiophene-2-carboxylic acid (1a) with styrene (2a) leading to (E)-3-
chloro-2-styrylbenzo[b]thiophene: optimization of conditionsa
Temp.
[°C]
Yieldb
[%]
Entry
Cat.
Base
Solvent
1
2
3
4
5
6
7
8
PdCl2
PdCl2
PdCl2
PdCl2
Pd(OAc)2
Pd(dba)2
—
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2O
DMSO
DMF
Toluene
110
110
110
110
110
110
110
110
110
110
110
80
0
20
5
86
48
11
0
37
33
6
12
52
DMSO/DMF(1 : 20)
DMSO/DMF(1 : 20)
DMSO/DMF(1 : 20)
DMSO/DMF(1 : 20)
DMSO/DMF(1 : 20)
DMSO/DMF(1 : 20)
DMSO/DMF(1 : 20)
DMSO/DMF(1 : 20)
DMSO/DMF(1 : 20)
9
AgOAc
Na2CO3
K2CO3
10
11
12
Ag2CO3
a Reaction conditions: 3-chlorobenzo[b]thiophene-2-carboxylic acid
(1a) (0.25 mmol), styrene (2a) (0.325 mmol), catalyst (0.0125 mmol),
base (0.75 mmol), solvent (1.0 mL), reaction time (24 h) under
nitrogen atmosphere. b Isolated yield.
ture, the benzo[b]thiophene derivatives were synthesized
under the optimized conditions: 5 mol% PdCl2 as the catalyst,
3 equiv. of Ag2CO3 as the base, and 1 mL DMSO/DMF (v1/v2 =
1 : 20) as the solvent at 110 °C under a nitrogen atmosphere.
With the optimized reaction conditions in hand, the scope
and generality of the palladium-catalyzed decarboxylative alke-
nylation of 3-chlorobenzo[b]thiophene-2-carboxylic acids was
explored, with the results summarized in Table 2. Generally,
3-chlorobenzo[b]thiophene-2-carboxylic acids and styrenes that
bear electron-donating or withdrawing groups on the aryl rings
were compatible with this reaction, and the desired products
were obtained in moderate to good yields (Table 2, 3a–3t).
Additionally, 2-vinylnaphthalene was also used in this trans-
formation to give the corresponding products 3d and 3k in
92% and 89% yields. The decarboxylative cross-coupling reac-
tions could tolerate some functional groups including methyl
(Table 2, 3b, 3c, 3f, 3h, 3i, 3j, 3m, 3n and 3q), methoxy
(Table 2, 3t), C–Cl bond (Table 2, 3a–3q), and C–Br bond
(Table 2, 3i, 3p, 3q), which could be employed for further
modification. Notably, strong electron-withdrawing groups
such as nitro and trifluoromethyl were also tolerated in the
present transformation, and afforded good yields in 77% and
91% respectively. Although aromatic olefins displayed good
reactivity, unfortunately, the aliphatic and acrylate ones were
poor substrates (Table 2, 3v and 3w). Besides this, (E)-prop-1-
enylbenzene was not a suitable substrate in the present reac-
tion (Table 2, 3x). Interestingly, 3-bromobenzo[b]thiophene-2-
carboxylic acid also afforded the corresponding product (E)-3-
bromo-2-(2-(naphthalen-2-yl)vinyl)benzo[b]thiophene in 44%
yield (Table 2, 3u). It should be pointed out that the above pro-
tocol can be well applied to 3-Cl substituted benzo[b]-
The benzo[b]thiophene skeleton is a key core structure
widely found in natural products and drug candidates, and
especially promises extensive applications in materials chemi-
stry.16 Developing novel, efficient and practical methods for
the formation or derivatization of benzo[b]thiophene motifs is
thereby of high ongoing interest.17 In the present work, we
report a new and efficient approach to regioselective alkenyl-
ation of benzo[b]thiophenes via the palladium-catalyzed de-
carboxylative Heck-type reactions.
Results and discussion
In order to identify the optimum reaction conditions, the reac-
tion of 3-chlorobenzo[b]thiophene-2-carboxylic acid (1a) and
styrene (2a) was chosen as the model reaction. As shown in
Table 1, four solvents, DMSO, DMF, toluene and DMSO/DMF
were investigated at 110 °C by using 0.05 equiv. of PdCl2 as the
catalyst, 3 equiv. of Ag2CO3 as the base, and 1 mL DMSO/DMF
(v1/v2 = 1 : 20) giving the highest yield (20%) (entries 1–4). The
common palladium catalysts, PdCl2, Pd(OAc)2 and Pd(dba)2
were tested in DMSO/DMF (v1/v2 = 1 : 20) (entries 4–6) using
Ag2CO3 as the base at 110 °C, and PdCl2 was found to be the
most effective catalyst in this reaction. Furthermore, the reac-
tion could not proceed in the absence of the catalyst (entry 7).
We attempted to use different bases (compare entries 4, 7–10),
and Ag2CO3 was superior to the other bases (entry 4). More-
over, further optimization indicated that 110 °C was more suit-
able for this transformation (entries 4, 11 and 12). After the
optimization process of bases, solvents, catalysts and tempera-
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(IM2 → IM7), olefin insertion (IM7 → IM9), and β-hydride
elimination (IM9 → P). In detail, as shown in Fig. 1, upon the
Pd center coordination with hydroxyl O in A, the concerted
metalation–deprotonation was initiated via the four-membered
transition state TS1, affording IM2 with the exclusion of HCl.
The excluded HCl is believed to immediately react with Ag2CO3
to give AgCl, which assisted the following processes. It needs
to be pointed out here that, once formed, AgCl would
smoothly achieve the metalation–deprotonation process with a
relative free energy of only 17.3 kcal mol−1 (IM11 in Fig. 2),
which is substantially lower than that for the transformation
A → IM2 (29.1 kcal mol−1 corresponding to TS1 in Fig. 1).
Therefore, in the following catalytic cycles, the metalation–
deprotonation route with the involvement of AgCl as shown in
Fig. 2 (A → IM11) was considered to be the favored one. The
decarboxylation step started with the coordination of AgCl to
the carbonyl O atom of IM2 and forms IM3. To facilitate the
subsequent π-coordination of Pd with the C1vC2 double
bond, IM3 isomerized into slightly more stable IM4 by rotating
the Pd–O single bond along the C3–O(Pd) σ-bond. The tandem
dissociation and association of one DMSO ligand is then fol-
lowed to obtain an energy-rich intermediate IM6. From IM6,
the reaction underwent the dissociation of CO2 through TS2
with an energy demand of 3.7 kcal mol−1 and generated a 16-
electron species IM7, which lay 5.6 kcal mol−1 below the reac-
tion entrance. After the dissociation of one DMSO ligand from
IM7, the styrene occupied the site left by the dissociated
DMSO ligand to give slightly more stable species IM8, with the
π-coordination of the phenylethylene CvC bond moiety with
the Pd center. And next, the olefin insertion into the Pd–C2
bond occurs via the transition state TS3, giving rise to inter-
mediate IM9. The barrier involved in this olefin insertion step
was calculated to be 11.2 kcal mol−1. Through TS4 with a
small barrier of 2.4 kcal mol−1, the β-hydride elimination takes
place by the migration of one H(CC2) atom to the Pd atom,
resulting in product P, from which L2PdHCl (L = DMSO) and
AgCl were simultaneously liberated. In order to initiate the Pd
catalyst regeneration (IM14 → L2PdCl2) for the next reaction
procedures, as indicated in Scheme 2, the reductive elimi-
nation of HL in IM14 occurred with a barrier of 20.1 kcal mol−1
to form Pd(0) intermediate IM15, that was then oxidized by the
oxidant Ag2CO3 in the presence of HCl to form L2PdCl2.
Table 2 Palladium-catalyzed decarboxylative Heck-type couplings
of benzo[b]thiophene-2-carboxylic acids (1) and styrenes (2)a,b
a Reaction conditions: the substituted alkenes (1 mmol), molecular
iodine (1.5 mmol), H2O (2 ml), 110 °C, 2 h, under air atmosphere.
b Isolated yield.
According to the above results, it was seen that the decar-
boxylation had an overall barrier of 30.4 kcal mol−1, in contrast
to 29.1 kcal mol−1 of metalation–deprotonation, 11.2
kcal mol−1 of olefin insertion, 2.4 kcal mol−1 of β-hydride elimi-
nation, and 20.1 kcal mol−1 of catalyst regeneration. There-
fore, the decarboxylation with the involvement of AgCl is the
rate-determining step along the reaction coordinate, consistent
with that of the direct decarboxylation pathway with no
assistor.18–20 However, the energy barrier value calculated for
the former (30.4 kcal mol−1) was apparently much lower than
that for the latter as shown in Fig. 1 (45.8 kcal mol−1 corres-
ponding to TS2′). The preference for decarboxylation in the
presence of AgCl over the case in the absence of AgCl is likely
ascribed to the fact that the π-coordination of Ag instead of Pd
thiophene-2-carboxylic acids but not the 3-H substituted ones
(Table 2, 3y and 3z).
To gain deeper insight into the reaction mechanisms for
Pd-catalyzed decarboxylative couplings of styrenes with Cl- and
H-substituted substrates, A and H-A, respectively, DFT calcu-
lations were carried out using the M06 methods.18 In this
section, we presented a mechanism, which featured the
involvement of a AgCl molecule generated during the reaction
process. And all other possible pathways are collected in the
ESI.†
For the Cl-substituted system, the formation of product P
(i.e. product 3 in Table 2) involves four key steps in sequence
(Fig. 1): metalation–deprotonation (A → IM2), decarboxylation
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Fig. 1 Calculated free energy profiles in DMF solution for the formation of P from the reaction of the Cl-substituted substrate A with styrene as well
as schematic structures of intermediates and transition states involved (L = DMSO). The relative free energies are given in kcal mol−1. TS2’ is a
decarboxylation transition state with no involvement of AgCl, corresponding to TS2.
Fig. 2 Calculated free energy profiles in DMF solution for the Cl- and H-substituted metalation–deprotonation process with the involvement of
AgCl as well as schematic structures of intermediates and transition states involved (L = DMSO). The relative free energies are given in kcal mol−1
.
ence of AgCl plays a critical role in ensuring the proceeding of
the reaction under the given conditions.
In the case of the H-substituted system, as illustrated in
Fig. 3, the intermediates and transition states were marked
with the capital letter “H” in the left superscript in order to
differentiate them from those with the Cl substituted version.
It was found that the H-substituted system involved the same
mechanisms and rate-determining step to the Cl-substituted
system discussed above. Thus, the relevant mechanism details
are not discussed again for simplification.
Scheme 2 The Pd catalyst regeneration pathway. The relative free
energies are given in kcal mol−1
.
In order to elucidate the different reactivities of two sub-
strates A and H-A, we compared the overall barriers for the
rate-determining steps (i.e., decarboxylation) of the two reac-
with the carboxyl O atom reduces the Pd–O π-interaction, thus
resulting in easier dissociation of CO2 as compared to the dec-
arboxylation with no AgCl involvement. Therefore, the pres-
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Fig. 3 Calculated free energy profiles in DMF solution for the formation of H-P from the reaction of the H-substituted substrate H-A with phenyl-
ethylene as well as schematic structures of intermediates and transition states involved (L = DMSO). The relative free energies are given in
kcal mol−1
.
tions. As shown in Fig. 3 the overall barrier of the decarboxyla- bonding fashion with the C π* orbital of the CO2 moiety. In
tion step for the H-substituted system was 32.8 kcal mol−1 (the contrast, in the HUMO of TS2, the p–π orbital of the C2 atom
energy difference between H-TS2 and H-A), which was 2.4 kcal interacted with the Pd center. Clearly, the presence of the Cl
mol−1 greater than that (30.4 kcal mol−1) for the Cl-substituted substituent in TS2 reduces the π–π interplay between C1 and
system in Fig. 1 (the energy difference between TS2 and A). C2 atoms and thereby strengthens the orbital overlaps of the
This result was consistent with the experimental finding that C2 atom and the Pd center, thus contributing to Pd⋯C2
Cl-substituted substrate A brings out the product P in 86% bonding and C2–C(O2) bond cleavage. These results point to
yield, whereas, upon replacement of the Cl substituent by a the fact that the introduction of a Cl substituent is of key
hydrogen atom, the H-substituted product H-P is achieved in importance for the stability of the decarboxylation transition
only 3% yield.
state TS2, which makes the CO2 dissociation more accessible
We could understand the above fact by analyzing the fron- than that for the H-substituted system.
tier molecular orbitals of TS2 and H-TS2. Scheme 3 shows the
highest occupied molecular orbitals (HUMOs) calculated for
Conclusions
these two structures. In the HUMO of H-TS2, it was clear that
the C2 atom uses its sp2-hybridized orbital to interact in a σ
In summary, we have successfully developed a Pd-catalyzed
decarboxylative Heck-type coupling reaction for the highly
regioselective alkenylation of 3-chlorobenzo[b]thiophene-2-
carboxylic acids, providing an alternative approach for the for-
mation of diverse benzo[b]thiophenes. Theoretical studies
indicate that the involvement of AgCl generated during the
reaction process is of key importance for the proceeding of the
transformation. The greater reactivity of Cl substituted 3-benzo-
[b]thiophene-2-carboxylic acids over the H-substituted ones is
closely related to the presence of the Cl substituent, which can
reduce the adjacent π–π interaction, thus resulting in facile
decarboxylation as compared to the H substituent.
Experimental section
General information and materials
Scheme 3 Diagrams of the HUMOs of two decarboxylation transition
states, H-TS2 and TS2. For clarity, AgCl is omitted in the schematic dia-
All commercially available reagent grade chemicals were pur-
chased from chemical suppliers and used as received without
grams. The relative free energies are given in kcal mol−1
.
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further purification. 1H NMR and 13C NMR spectra were 1H NMR (CDCl3, 400 MHz, ppm) δ 7.82 (d, 1H, J = 8.0 Hz), 7.77
recorded in CDCl3 on a 400 MHz or 500 MHz spectrometer (d, 1H, J = 8.0 Hz), 7.60 (d, 2H, J = 8.0 Hz), 7.55 (d, 1H, J =
1
with TMS as an internal standard (400 MHz H, 100 MHz 13C; 16.0 Hz), 7.46–7.41 (m, 4H), 7.36 (d, 1H, J = 8.0 Hz), 7.07 (d,
500 MHz 1H, 125 MHz 13C) at room temperature, the chemical 1H, J = 16.0 Hz). 13C NMR (CDCl3, 100 MHz, ppm) δ 137.4,
shifts (δ) were expressed in ppm and the J values were given in 136.4, 136.1, 135.6, 132.3, 128.8, 128.5, 126.9, 126.0, 125.1,
Hz. Microanalyses were carried out using a chemical ionization 122.4, 121.8, 119.6, 119.0. MS (APCI) m/z = 271 [M + H]+. Anal.
method under atmospheric pressure (APCI). Column Calcd for C16H11ClS: C, 70.97; H, 4.09; Cl, 13.09; S, 11.84.
chromatography was performed on silica gel (200–300 mesh).
Found C, 70.94; H, 4.07; Cl, 13.10; S, 11.82.
(E)-3-Chloro-2-(4-methylstyryl)benzo[b]thiophene
Eluent petroleum ether/ethyl acetate (35 : 1). White solid, mp
(3b).
Computational methods
All calculations presented in this work were carried out using 145–146 °C. 1H NMR (CDCl3, 400 MHz, ppm) δ 1H NMR
the M06 functional18 with the Gaussian 09 suite of pro- (CDCl3, 400 MHz, ppm) δ 7.80 (d, 1H, J = 8.0 Hz), 7.75 (d, 1H,
grams,21 which had been shown to describe the static Pd- J = 8.0 Hz), 7.50 (d, 1H, J = 8.0 Hz), 7.48 (d, 2H, J = 8.0 Hz),
mediated organometallic systems reasonably well.22–24 The 7.46–7.38 (m, 2H), 7.20 (d, 2H, J = 8.0 Hz), 7.05 (d, 1H, J = 16.0
SDD25,26 basis set with the effective core potential was used for Hz), 2.51 (s, 3H). 13C NMR (CDCl3, 100 MHz, ppm) δ 138.6,
Pd, Ag, S, and Cl atoms, while the 6-31G(d,p) basis set was 137.5, 135.9, 135.8, 133.7, 132.3, 129.5, 126.8, 125.8, 125.1,
used for the remaining atoms. Geometry optimizations was 122.4, 121.7, 119.2, 118.0. MS (APCI) m/z = 285 [M + H]+. Anal.
conducted at the chosen level of theory, and the intrinsic reac- Calcd for C17H13ClS: C, 71.69; H, 4.60; Cl, 12.45; S, 11.26.
tion coordinate (IRC) analysis27 from the transition states had Found C, 71.65; H, 4.62; Cl, 12.43; S, 11.23.
been followed to confirm that such structures actually con-
(E)-3-Chloro-2-(3-methylstyryl)benzo[b]thiophene
(3c).
nected the two relevant minima. Frequency calculations at the Eluent petroleum ether/ethyl acetate (40 : 1). White solid, mp
same level of theory were also carried out to verify all the 110–112 °C. 1H NMR (CDCl3, 400 MHz, ppm) δ 1H NMR
stationary points as minima (zero imaginary frequencies) or (CDCl3, 400 MHz, ppm) δ 7.81 (d, 1H, J = 8.0 Hz), 7.77 (d, 1H,
first-saddle points (one imaginary frequency) and to provide J = 8.0 Hz), 7.53 (d, 1H, J = 16.0 Hz), 7.47–7.39 (m, 4H), 7.31 (t,
free energies at 298.15 K, which include entropic contributions 1H, J = 8.0 Hz), 7.16 (d, 1H, J = 8.0 Hz), 7.05 (d, 1H, J = 16.0
by considering the vibrations, rotations, and translations of Hz), 2.43 (s, 3H). 13C NMR (CDCl3, 100 MHz, ppm) δ 138.4,
the species.
137.5, 136.4, 136.0, 135.7, 132.4, 129.3, 128.7, 127.5, 125.9,
The solvent effects have been introduced via single-point 124.1, 122.4, 121.7, 119.5, 118.8, 21.4. MS (APCI) m/z = 285
calculations on gas-phase-optimized geometries by employing [M + H]+. Anal. Calcd for C17H13ClS: C, 71.69; H, 4.60; Cl,
the simple self-consistent reaction field (SCRF) method28–30 12.45; S, 11.26. Found C, 71.65; H, 4.62; Cl, 12.43; S, 11.23.
based on the CPCM solvation model31 with UAKS cavities.32
(E)-3-Chloro-2-(2-(naphthalen-2-yl)vinyl)benzo[b]thiophene
The single-point energy calculations were performed using the (3d). Eluent petroleum ether/ethyl acetate (40 : 1). White solid,
1
larger basis set, i.e., SDD for Pd, Ag, S, and Cl atoms and mp 151–153 °C. δ H NMR (CDCl3, 400 MHz, ppm) δ 7.93 (s,
6-311+G(d,p) for the other atoms. Here, acetonitrile was used 1H), 7.89–7.78 (m, 6H), 7.66 (d, 1H, J = 16.0 Hz), 7.54–7.50 (m,
as a solvent, corresponding to the experimental conditions. In 2H), 7.48–7.40 (m, 2H), 7.25 (d, 1H, J = 16.0 Hz), 2.43 (s, 3H).
this paper, the relative free energies in solution were exclu- 13C NMR (CDCl3, 100 MHz, ppm) δ 137.5, 136.1, 135.7, 133.9,
sively used to describe the reaction mechanism throughout 133.6, 133.4, 132.3, 128.5, 128.2, 127.8, 127.4, 126.5, 126.4,
the study.
126.0, 125.1, 123.4, 122.4, 121.8, 119.7, 119.3. MS (APCI) m/z =
321 [M + H]+. Anal. Calcd for C20H13ClS: C, 74.87; H, 4.08; Cl,
11.05; S, 9.99. Found C, 74.72; H, 4.11; Cl, 11.13; S, 9.84.
General experimental procedures
A 25 mL Schlenk tube equipped with a magnetic stirring bar
(E)-3-Chloro-2-(4-chlorostyryl)benzo[b]thiophene
(3e).
was charged with PdCl2 (2.2 mg), Ag2CO3 (205.3 mg), substi- Eluent petroleum ether/ethyl acetate (40 : 1). White solid, mp
tuted 3-chlorobenzo[b]thiophene-2-carboxylic acids
(1) 156–158 °C. 1H NMR (CDCl3, 400 MHz, ppm) δ 7.81 (d, 1H, J =
(0.25 mmol) and styrenes (2) (0.325 mmol). The tube was evac- 8.0 Hz), 7.77 (d, 1H, J = 8.0 Hz), 7.52–7.48 (m, 3H), 7.45–7.40
uated twice and backfilled with nitrogen, and DMSO/DMF (m, 2H), 7.37 (d, 2H, J = 8.0 Hz), 7.00 (d, 1H, J = 16.0 Hz). 13C
(v1/v2 = 1 : 20) (1.0 mL) was added to the tube under a nitrogen NMR (CDCl3, 100 MHz, ppm) δ 137.4, 136.1, 135.2, 134.9,
atmosphere. The tube was sealed with a balloon and then the 134.1, 130.8, 129.0, 128.0, 126.2, 125.2, 122.4, 121.9, 120.0,
mixture was allowed to be stirred under a nitrogen atmosphere 119.6. MS (APCI) m/z = 305 [M + H]+. Anal. Calcd for
at 110 °C for 24 h. After completion of the reaction, the result- C16H10Cl2S: C, 62.96; H, 3.30; Cl, 23.23; S, 10.51. Found C,
ing solution was cooled to room temperature, and the solvent 62.87; H, 3.31; Cl, 23.26; S, 10.64.
was removed with the aid of a rotary evaporator. The residue
(E)-3-Chloro-6-methyl-2-styrylbenzo[b]thiophene (3f). Eluent
was purified by column chromatography on silica gel using petroleum ether/ethyl acetate (40 : 1). White solid, mp
petroleum ether/ethyl acetate as the eluent to provide the 131–133 °C. 1H NMR (CDCl3, 400 MHz, ppm) δ 7.68 (d, 1H, J =
desired product (3).
8.0 Hz), 7.59–7.57 (m, 3H), 7.52 (d, 1H, J = 16.0 Hz), 7.41 (t,
(E)-3-Chloro-2-styrylbenzo[b]thiophene (3a). Eluent pet- 1H, J = 8.0 Hz), 7.34 (d, 1H, J = 8.0 Hz), 7.26 (d, 1H, J = 8.0 Hz),
roleum ether/ethyl acetate (40 : 1). White solid, mp 139–141 °C. 7.03 (d, 1H, J = 16.0 Hz), 2.51 (s, 3H). 13C NMR (CDCl3,
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100 MHz, ppm) δ 136.6, 136.3, 136.2, 135.3, 134.4, 131.6, C21H15ClS: C, 75.32; H, 4.52; Cl, 10.59; S, 9.58. Found C, 75.27;
128.8, 128.3, 126.8, 122.3, 121.4, 119.5, 119.2, 21.6. MS (APCI) H, 4.41; Cl, 10.63; S, 9.51.
m/z = 285 [M + H]+. Anal. Calcd for C17H13ClS: C, 71.69; H,
(E)-3,6-Dichloro-2-styrylbenzo[b]thiophene (3l). Eluent pet-
4.60; Cl, 12.45; S, 11.26. Found C, 71.62; H, 4.57; Cl, 12.36; S, roleum ether/ethyl acetate (30 : 1). White solid, mp 128–129 °C.
11.16.
1H NMR (CDCl3, 400 MHz, ppm) δ 7.16 (s, 1H), 7.70 (d, 1H, J =
(E)-3-Chloro-6-methyl-2-(4-methylstyryl)benzo[b]thiophene 8.0 Hz), 7.58 (d, 1H, J = 8.0 Hz), 7.49 (d, 1H, J = 16.0 Hz),
(3g). Eluent petroleum ether/ethyl acetate (30 : 1). White solid, 7.44–7.40 (m, 3H), 7.35 (d, 1H, J = 8.0 Hz), 7.06 (d, 1H, J = 16.0
mp 144–145 °C. 1H NMR (CDCl3, 400 MHz, ppm) δ 7.67 (d, Hz). 13C NMR (CDCl3, 100 MHz, ppm) δ 137.0, 136.2, 136.1,
1H, J = 8.0 Hz), 7.56 (s, 1H), 7.48–7.45 (m, 3H), 7.28–7.20 (m, 136.0, 132.7, 132.1, 128.9, 128.6, 126.9, 126.0, 122.6, 122.0,
3H), 7.01 (d, 1H, J = 16.0 Hz), 2.51 (s, 3H), 2.40 (s, 3H). 13C 119.2, 118.7. MS (APCI) m/z = 305 [M + H]+. Anal. Calcd for
NMR (CDCl3, 100 MHz, ppm) δ 138.4, 136.2, 136.1, 135.3, C16H10Cl2S: C, 62.96; H, 3.30; Cl, 23.23; S, 10.51. Found C,
134.7, 133.8, 131.6, 129.5, 126.8, 126.7, 122.3, 121.3, 119.1, 62.87; H, 3.31; Cl, 23.26; S, 10.64.
118.2, 21.6, 21.3. MS (APCI) m/z = 299 [M + H]+. Anal. Calcd for
C18H15ClS: C, 72.35; H, 5.06; Cl, 11.86; S, 10.73. Found C, Eluent petroleum ether/ethyl acetate (30 : 1). White solid, mp
(E)-3,6-Dichloro-2-(4-methylstyryl)benzo[b]thiophene (3m).
1
72.28; H, 5.11; Cl, 11.92; S, 10.64.
135–136 °C. δ H NMR (CDCl3, 400 MHz, ppm) δ 7.47 (s, 1H),
(E)-3-Chloro-2-(4-chlorostyryl)-6-methylbenzo[b]thiophene 7.69 (d, 1H, J = 8.0 Hz), 7.48–7.38 (m, 4H), 7.22 (d, 1H, J = 8.0
(3h):. Eluent petroleum ether/ethyl acetate (40 : 1). White Hz), 7.03 (d, 1H, J = 16.0 Hz), 2.40 (s, 3H). 13C NMR (CDCl3,
solid, mp 161–162 °C. δ 1H NMR (CDCl3, 400 MHz, ppm) δ 100 MHz, ppm) δ 138.8, 136.9, 136.4, 136.0, 133.5, 132.7,
7.68 (d, 1H, J = 8.0 Hz), 7.56 (s, 1H), 7.50–7.46 (m, 3H), 7.36 (d, 131.9, 129.6, 126.8, 125.9, 122.5, 122.0, 118.8, 117.7, 21.4. MS
2H, J = 8.0 Hz), 7.26 (d, 1H, J = 8.0 Hz), 6.95 (d, 1H, J = 16.0 (APCI) m/z = 319 [M + H]+. Anal. Calcd for C17H12Cl2S: C,
Hz), 2.51 (s, 3H). 13C NMR (CDCl3, 100 MHz, ppm) δ 136.5, 63.96; H, 3.79; Cl, 22.21; S, 10.04. Found C, 63.99; H, 3.72; Cl,
136.3, 135.2, 135.1, 134.0, 133.9, 130.1, 129.0, 127.9, 127.0, 22.23; S, 10.13.
122.3, 121.5, 120.0, 119.7, 21.6. MS (APCI) m/z = 319 [M + H]+.
Anal. Calcd for C17H12Cl2S: C, 63.96; H, 3.79; Cl, 22.21; S, Eluent petroleum ether/ethyl acetate (30 : 1). White solid, mp
(E)-3,6-Dichloro-2-(3-methylstyryl)benzo[b]thiophene
(3n).
1
10.04. Found C, 63.99; H, 3.72; Cl, 22.23; S, 10.13.
139–141 °C. δ H NMR (CDCl3, 400 MHz, ppm) δ 7.75 (s, 1H),
(E)-2-(4-Bromostyryl)-3-chloro-6-methylbenzo[b]thiophene 7.70 (d, 1H, J = 8.0 Hz), 7.47 (d, 1H, J = 16.0 Hz), 7.41–7.37 (m,
(3i). Eluent petroleum ether/ethyl acetate (30 : 1). White solid, 3H), 7.31 (t, 1H, J = 8.0 Hz), 7.16 (d, 1H, J = 8.0 Hz), 7.03 (d,
1
mp 171–173 °C. δ H NMR (CDCl3, 400 MHz, ppm) δ 7.68 (d, 1H, J = 16.0 Hz), 2.42 (s, 3H). 13C NMR (CDCl3, 100 MHz, ppm)
1H, J = 8.0 Hz), 7.56 (s, 1H), 7.53–7.41 (m, 5H), 7.26 (d, 1H, J = δ 138.5, 136.9, 136.2, 136.1, 136.0, 132.9, 132.0, 129.5, 128.7,
8.0 Hz), 6.94 (d, 1H, J = 16.0 Hz), 2.51 (s, 3H). 13C NMR (CDCl3, 127.5, 126.0, 124.1, 122.5, 122.0, 119.0, 118.5, 21.4. MS (APCI)
100 MHz, ppm) δ 136.6, 136.3, 135.5, 135.2, 134.0, 131.9, m/z = 319 [M + H]+. Anal. Calcd for C17H12Cl2S: C, 63.96; H,
130.2, 128.2, 126.9, 122.3, 122.1, 121.5, 120.0, 119.8, 21.6. MS 3.79; Cl, 22.21; S, 10.04. Found C, 63.99; H, 3.72; Cl, 22.23; S,
(APCI) m/z = 340, 342 [M + K]+. Anal. Calcd for C17H12BrClS: C, 10.13.
56.14; H, 3.33; Br, 21.97; Cl, 9.75; S, 8.82. Found C, 56.21; H,
3.24; Br, 21.91; Cl, 9.85; S, 8.84.
(E)-3,6-Dichloro-2-(4-chlorostyryl)benzo[b]thiophene
(3o).
Eluent petroleum ether/ethyl acetate (30 : 1). White solid, mp
1
(E)-3-Chloro-6-methyl-2-(3-methylstyryl)benzo[b]thiophene 157–159 °C. δ H NMR (CDCl3, 400 MHz, ppm) δ 7.75 (s, 1H),
(3j). Eluent petroleum ether/ethyl acetate (30 : 1). White solid, 7.70 (d, 1H, J = 8.0 Hz), 7.50 (d, 2H, J = 8.0 Hz), 7.45 (d, 1H, J =
1
mp 146–147 °C. δ H NMR (CDCl3, 400 MHz, ppm) δ 7.68 (d, 16.0 Hz), 7.42–7.37 (m, 3H), 6.99 (d, 1H, J = 16.0 Hz). 13C NMR
1H, J = 8.0 Hz), 7.56 (s, 1H), 7.51 (d, 1H, J = 16.0 Hz), 7.39 (d, (CDCl3, 100 MHz, ppm) δ 137.0, 135.9, 135.7, 134.7, 134.3,
2H, J = 8.0 Hz), 7.32–7.25 (m, 2H), 7.15 (d, 1H, J = 8.0 Hz), 7.01 132.3, 131.2, 129.1, 128.0, 126.1, 122.7, 122.1, 119.6, 119.3. MS
(d, 1H, J = 16.0 Hz), 2.51 (s, 3H), 2.43 (s, 3H). 13C NMR (CDCl3, (APCI) m/z = 338 [M + H]+. Anal. Calcd for C16H9Cl3S: C, 56.58;
100 MHz, ppm) δ 138.4, 136.5, 136.3, 135.3, 134.6, 131.8, H, 2.67; Cl, 31.11; S, 9.44. Found C, 56.51; H, 2.76; Cl, 31.06; S,
129.2, 128.7, 127.4, 126.8, 124.0, 122.3, 121.4, 119.4, 118.9, 9.45.
21.6, 21.4. MS (APCI) m/z = 299 [M + H]+. Anal. Calcd for
C18H15ClS: C, 72.35; H, 5.06; Cl, 11.86; S, 10.73. Found C, petroleum ether/ethyl acetate (30 : 1). White solid, mp
72.28; H, 5.11; Cl, 11.92; S, 10.64.
161–162 °C. 1H NMR (CDCl3, 400 MHz, ppm) δ 7.91 (s, 1H),
(E)-6-Bromo-3-chloro-2-styrylbenzo[b]thiophene (3p). Eluent
(E)-3-Chloro-6-methyl-2-(2-(naphthalen-2-yl)vinyl)benzo[b]- 7.64 (d, 1H, J = 8.0 Hz), 7.58 (d, 2H, J = 8.0 Hz), 7.54 (d, 1H, J =
thiophene (3k). Eluent petroleum ether/ethyl acetate (30 : 1). 8.0 Hz), 7.49 (d, 1H, J = 16.0 Hz), 7.42 (t, 2H, J = 8.0 Hz), 7.35
1
White solid, mp 162–164 °C. H NMR (CDCl3, 400 MHz, ppm) (d, 1H, J = 8.0 Hz), 7.06 (d, 1H, J = 16.0 Hz). 13C NMR (CDCl3,
δ 7.92 (s, 1H), 7.87 (d, 1H, J = 8.0 Hz), 7.84–7.78 (m, 2H), 7.69 100 MHz, ppm) δ 137.3, 136.3, 136.2, 136.1, 132.8, 128.9,
(d, 1H, J = 8.0 Hz), 7.64 (d, 1H, J = 16.0 Hz), 7.59 (s, 1H), 128.7, 128.6, 126.9, 124.9, 122.8, 119.9, 119.3, 118.7. MS (APCI)
7.52–7.49 (m, 2H), 7.27 (d, 1H, J = 8.0 Hz), 7.19 (d, 1H, J = 16.0 m/z = 348, 350 [M + H]+. Anal. Calcd for C16H10BrClS: C, 54.96;
Hz), 2.52 (s, 3H). 13C NMR (CDCl3, 100 MHz, ppm) δ 136.4, H, 2.88; Br, 22.85; Cl, 10.14; S, 9.17. Found C, 54.91; H, 2.96;
136.3, 135.3, 134.5, 134.1, 133.6, 133.3, 131.7, 128.5, 128.2, Br, 22.89; Cl, 10.03; S, 9.11.
127.8, 127.3, 126.8, 126.5, 126.3, 123.4, 122.4, 121.4, 119.6,
(E)-6-Bromo-3-chloro-2-(3-methylstyryl)benzo[b]thiophene
119.4, 21.7. MS (APCI) m/z = 335 [M + H]+. Anal. Calcd for (3q). Eluent petroleum ether/ethyl acetate (30 : 1). White solid,
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mp 178–181 °C. δ H NMR (CDCl3, 400 MHz, ppm) δ 7.91 (s, (CDCl3, 400 MHz, ppm) δ 7.80 (d, 1H, J = 8.0 Hz), 7.73 (d, 1H,
1H), 7.64 (d, 1H, J = 8.0 Hz), 7.54 (d, 2H, J = 8.0 Hz), 7.47 (d, J = 8.0 Hz), 7.54 (d, 1H, J = 8.0 Hz), 7.42–7.31 (m, 6H). 13C
1H, J = 16.0 Hz), 7.38 (d, 1H, J = 8.0 Hz), 7.30 (t, 1H, J = 8.0 NMR (CDCl3, 100 MHz, ppm) δ 142.9, 140.2, 138.9, 136.6,
Hz), 7.16 (d, 1H, J = 8.0 Hz), 7.04 (d, 1H, J = 16.0 Hz), 2.42 (s, 130.9, 128.8, 128.0, 126.6, 124.7, 124.5, 123.4, 123.3, 122.3,
3H). 13C NMR (CDCl3, 100 MHz, ppm) δ 138.5, 137.3, 136.3, 122.2. MS (APCI) m/z = 237 [M + K]+. Anal. Calcd for
136.2, 136.1, 132.9, 129.5, 128.8, 128.6, 127.6, 124.9, 124.1, C17H12BrClS: C, 81.31; H, 5.12; S, 13.57; found C, 81.27; H,
122.8, 119.8, 119.1, 118.4. MS (APCI) m/z = 340, 342 [M + K]+. 5.15; S, 13.59.
Anal. Calcd for C17H12BrClS: C, 56.14; H, 3.33; Br, 21.97; Cl,
9.75; S, 8.82. Found C, 56.21; H, 3.24; Br, 21.91; Cl, 9.85; S,
8.84.
Acknowledgements
(E)-3-Chloro-2-(2-(naphthalen-2-yl)vinyl)-6-(trifluoromethyl)-
benzo[b]thiophene (3r). Eluent petroleum ether/ethyl acetate The authors gratefully acknowledge the financial support from
(25 : 1). White solid, mp 168–170 °C. 1H NMR (CDCl3, the National Natural Science Foundation of China (No.
500 MHz, ppm) δ 8.02 (s, 1H), 7.91 (s, 1H), 7.85–7.81 (m, 4H), 21302110, 21375075, 21473100 and 21403123), the Taishan
7.76 (d, 1H, J = 10.0 Hz), 7.64–7.58 (m, 2H), 7.49 (t, 2H, J = 5.0 Scholar Foundation of Shandong Province, the Natural Science
Hz), 7.24 (d, 1H, J = 10.0 Hz). 13C NMR (CDCl3, 125 MHz, ppm) Foundation of Shandong Province (ZR2013BQ017 and
δ 139.8, 139.0, 135.8, 133.9, 133.6(q, J = 36.3), 128.7, 128.3, ZR2013BQ019), the Project of Shandong Province Higher
128.1, 127.9, 127.8, 127.7, 126.7, 126.4 (q, J = 270.1), 125.3, Educational Science and Technology Program (J13LD14 and
123.2, 122.1, 121.9 (d, J = 3.7), 119.8, 119.3, 118.7. MS (APCI) J14LC17) and the Doctoral Start-Up Scientific Research
m/z = 389.0 [M + H]+. Anal. Calcd for C21H12ClF3S: C, 64.87; H, Foundation of Qufu Normal University (BSQD2012021 and
3.11; Cl, 9.12; F, 14.66; S, 8.25. Found C, 64.81; H, 3.06; Cl, BSQD2012018).
9.04; F, 14.57; S, 8.16.
(E)-3-Chloro-6-nitro-2-styrylbenzo[b]thiophene (3s). Eluent
petroleum ether/ethyl acetate (20 : 1). Yellow solid, mp
Notes and references
147–149 °C. δ 1H NMR (CDCl3, 500 MHz, ppm) δ 7.74–7.71 (m,
3H), 7.67 (s, 1H), 7.56 (d, 1H, J = 10.0 Hz), 7.40–7.35 (m, 2H),
6.81 (dd, 1H, J = 10.0 Hz), 5.80 (d, 1H, J = 20.0 Hz), 5.26 (d, 1H,
J = 20.0 Hz). 13C NMR (CDCl3, 125 MHz, ppm) δ 135.9, 134.0,
132.5, 132.1, 127.1, 127.0, 126.6, 125.3, 125.2, 124.9, 122.1,
113.1. MS (APCI) m/z = 316 [M + H]+. Anal. Calcd for
C16H10ClNO2S: C, 60.86; H, 3.19; Cl, 11.23; N, 4.44; O, 10.13; S,
10.15. Found C, 60.63; H, 3.27; Cl, 11.08; N, 4.37; O, 10.16; S,
10.42.
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(E)-3-Chloro-5-methoxy-2-(4-methylstyryl)benzo[b]thiophene
(3t). Eluent petroleum ether/ethyl acetate (30 : 1). White solid,
mp 116–118 °C. δ H NMR (CDCl3, 500 MHz, ppm) δ 7.57 (d,
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1H, J = 5.0 Hz), 7.45–7.41 (m, 3H), 7.19–7.15 (m, 3H), 7.01–6.98
(m, 2H), 3.89 (s, 3H), 2.36 (s, 3H). 13C NMR (CDCl3, 125 MHz,
ppm) δ 171.2, 158.2, 138.5, 138.4, 137.0, 133.7, 132.0, 129.5,
128.9, 126.8, 123.2, 118.1, 116.2, 103.7, 55.6, 21.1. MS (APCI)
m/z = 315 [M + H]+. Anal. Calcd for C18H15ClOS: C, 68.67; H,
4.80; Cl, 11.26; O, 5.08; S, 10.18. Found C, 68.46; H, 4.59; Cl,
11.19; O, 5.14; S, 10.09.
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(3u). Eluent petroleum ether/ethyl acetate (30 : 1). White solid,
1
mp 172–174 °C. δ H NMR (CDCl3, 500 MHz, ppm) δ 7.90 (s,
1H), 7.86–7.82 (m, 3H), 7.80–7.75 (m, 3H), 7.62 (d, 1H, J = 15.0
Hz), 7.51–7.48 (m, 2H), 7.43 (t, 1H, J = 5.0 Hz), 7.38 (t, 1H, J =
5.0 Hz), 7.25 (d, 2H, J = 10.0 Hz). 13C NMR (CDCl3, 125 MHz,
ppm) δ 138.9, 137.4, 136.5, 133.9, 133.6, 133.4, 132.8, 128.6,
128.2, 127.8, 127.5, 126.6, 126.4, 126.1, 125.3, 123.4, 123.1,
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for C20H13BrS: C, 65.76; H, 3.59; Br, 21.87; S, 8.78. Found C,
65.66; H, 3.47; Br, 21.83; S, 8.69.
(E)-2-Styrylbenzo[b]thiophene
ether/ethyl acetate (30 : 1). White solid, mp 83–84 °C. H NMR
(3y).33 Eluent
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