Phosphine-free palladium-catalysed direct C2-arylation of benzothiophenes with aryl bromides

Article abstract of DOI:10.1016/j.tet.2013.06.037

Ligand-free Pd(OAc)₂ was found to catalyse very efficiently the direct C2-arylation of benzothiophene derivatives under low catalyst concentration. The reaction can be performed employing as little as 0.5-0.1 mol % catalyst with electron-deficient and some electron-rich aryl bromides. The presence of a methyl or a formyl substituent at C3 of benzothiophene has a minor influence on the reactivity, and even a bromo substituents at C3 is tolerated. A wide variety of functional groups on the aryl bromide, such as nitrile, nitro, acetyl, formyl, ester, chloro, fluoro or trifluoromethyl has been employed.

Full text of DOI:10.1016/j.tet.2013.06.037

Accepted Manuscript
Phosphine-free palladium-catalyzed direct C2-arylation of benzothiophenes with aryl
bromides
Liqin Zhao, Christian Bruneau, Henri Doucet
PII:
S0040-4020(13)00967-8
10.1016/j.tet.2013.06.037
TET 24513
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 30 April 2013
Revised Date: 6 June 2013
Accepted Date: 11 June 2013
Please cite this article as: Zhao L, Bruneau C, Doucet H, Phosphine-free palladium-catalyzed direct C2-
arylation of benzothiophenes with aryl bromides, Tetrahedron (2013), doi: 10.1016/j.tet.2013.06.037.
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ACCEPTED MANUSCRIPT
Leave this area blank for abstract info.
Phosphine-free palladium-catalyzed direct
C2-arylation of benzothiophenes with aryl bromides
Liqin Zhao, Christian Bruneau, Henri Doucet,*
Institut des Sciences Chimiques de Rennes, UMR 6226 CNRS-Université de Rennes "Organométalliques :
Matériaux et Catalyse", Campus de Beaulieu, 35042 Rennes, France.
R1
R2
R1
Pd(OAc)2
0.1-0.5 mol%
R3
R2
R3
+
Br
S
H
DMF or DMAc,
KOAc, 150 °C
S
R1 = H, Me, CHO, Br

ACCEPTED MANUSCRIPT
Page 1 sur 10
Tetrahedron
1
TETRAHEDRON
Pergamon
Phosphine-free palladium-catalyzed direct C2-arylation of
benzothiophenes with aryl bromides
Liqin Zhao, Christian Bruneau, Henri Doucet*
Institut des Sciences Chimiques de Rennes, UMR 6226 CNRS-Université de Rennes "Organométalliques : Matériaux et
Catalyse", Campus de Beaulieu, 35042 Rennes, France. Fax: (+33)2-23-23-63-84 E-mail: henri.doucet@univ-rennes1.fr
Abstract— Ligand-free Pd(OAc)2 was found to catalyze very efficiently the direct C2-arylation of benzothiophene derivatives under low
catalyst concentration. The reaction can be performed employing as little as 0.5-0.1 mol-% catalyst with electron-deficient and some elec-
tron-rich aryl bromides. The presence of a methyl or a formyl substituent at C3 of benzothiophene has a minor influence on the reactivity,
and even a bromo substituents at C3 is tolerated. A wide variety of functional groups on the aryl bromide such as nitrile, nitro, acetyl, for-
myl, ester, chloro, fluoro or trifluoromethyl has been employed. © 2013 Elsevier Science. All rights reserved
Keywords: palladium, catalysis, C-H bond functionalization, benzothiophenes, aryl bromides
stabilizing agent have not been reported to date. The use of
such conditions would be very attractive for industrial
1. Introduction
application, as it would reduce both the cost and wastes
formation of such couplings.
Benzothiophene derivatives are of considerable interest
for pharmaceutical chemistry due to their biological
activities.
For example, the 2-arylbenzothiophene
In 2003, de Vries and co-workers have described extremely
exciting results for the Heck and Suzuki reactions using a
low loading (0.1-0.01 mol-%) of ligand-free catalyst
Pd(OAc)2.9 They have demonstrated that, at elevated tem-
perature, when Pd(OAc)2 is employed as the catalyst pre-
cursor, soluble palladium(0) colloids or nanoparticles are
formed, and that the Heck or Suzuki reaction takes place.
We have recently reported that the use of the “de Vries
conditions” allows the coupling or several heteroaromatics
such as pyrroles,10c imidazoles,10d furans,10e thiophenes10e or
imidazopyridines10f using a very low loading (0.1-0.01
mol-%) of ligand-free Pd(OAc)2 catalyst.10 However, so
far, such procedure has not been employed for the direct
arylation of benzothiophenes.11
derivative Raloxifene is used in the prevention of
osteoporosis (Figure 1). Therefore, the development of
simple and convenient processes using readily accessible
benzothiophene derivatives for the synthesis of arylated
benzothiophenes is highly desirable.
N
O
O
OH
S
HO
Raloxifene
Figure 1. Example of bioactive 2-arylbenzothiophene.
Here, we wish to report on the coupling of benzothio-
phene derivatives with a variety of electronically and steri-
cally diverse aryl and heteroaryl bromides using low load-
ings of ligand-free Pd(OAc)2 catalyst.
The palladium-catalyzed direct arylation of several
heteroaromatics such as furans, thiophenes or pyrroles via a
C–H bond activation using aryl halides has led to successes
in recent years.1-5 Such couplings are very attractive
compared to classical palladium-catalysed reactions such as
Stille, Suzuki or Negishi couplings6 as they do not require
the preliminary synthesis of organometallic derivatives.
Some examples of such direct arylations using
benzothiophenes have also been reported.7,8 However, the
reported procedures either require 1-10 mol-% palladium
catalyst associated to 1-20 mol-% of phosphine ligands[7] or
2. Results and discussion
First, we examined the influence of the reaction
conditions for the coupling of benzothiophene with 4-
bromobenzonitrile (Scheme 1, Table 1). Starting form a
slight excess of benzothiophene (1.5 eq.) with respect to the
aryl bromide, in the presence of 0.5 mol-% Pd(OAc)2 as the
catalyst, KOAc as the base, and DMAc as the solvent at
employed
ammonium salts or crown ethers as stabilizing agents
producing important amount of wastes.8
To our
a
stoichiometric amount of quaternary
o
150 C, the desired product 1 was obtained in 69% yield;
whereas, a lower catalyst loading of 0.1 mol-% gave 1 in
only 55% yield due to an uncomplete conversion of the aryl
knowledge, the palladium-catalysed direct arylation of
benzothiophenes using ligand-free catalyst without

ACCEPTED MANUSCRIPT
2
Tetrahedron
bromide (Table 1, entries 1 and 2). The influence of a few
other bases was also examined; however, NaOAc, CsOAc,
KF or carbonates led to lower yields of 1 (Table 1, entries
3-8). Then, we explored the influence of a few other
solvents. Moderated yields were obtained in diethyl
carbonate or cyclopentyl methyl ether (Table 1, entries 11
and 12). On the other hand, the use of only 0.1 mol-%
Pd(OAc)2 in DMF gave 1 in 59% yield (Table 1, entry 9).
mides (Table 2, entries 13 and 14).
1
R
Pd(OAc)2
0.1-0.5 mol%
No phosphine
2
1
R
R
3
2
R
R
Br
+
3
R
S
H
DMF or DMAc,
KOAc, 150 °C
S
Scheme 2. Palladium-catalysed direct arylation of benzothiophene
derivatives with (hetero)aryl bromides.
Table 2. Palladium-catalysed arylation of benzothiophene with
(hetero)aryl bromides (Scheme 2).
Pd(OAc)2
Catalyst Yield
(mol-%) (%)
Br
CN
+
Aryl halide
Product
S
Entry
1
base
H
CN
S
1
Scheme 1. Palladium-catalysed direct C2-arylation of benzothio-
phene with 4-bromobenzonitrile.
O2N
O2N
Br
Br
0.1
51
S
2
3
2
3
0.1
0.5
22
61
F3C
O
F3C
O
Table 1. Influence of the reaction conditions for palladium-
catalysed direct C2-arylation of benzothiophene with 4-
bromobenzonitrile (Scheme 1).
S
4
0.1
72
Br
Br
S
4
O
Pd(OAc)2
(mol-%)
Yield in
1 (%)
O
5
6
0.5
0.5
66
Solvent
Base Conv. (%)
Entry
63a
S
5
O
EtO
Cl
1
2
3
4
5
6
7
8
9
0.5
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.5
0.5
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMF
KOAc
KOAc
CsOAc
NaOAc
Na2CO3
K2CO3
Cs2CO3
KF
100
67
12
43
25
7
90
36
80
70
54
69
55
-
O
EtO
Cl
7
8
0.5
0.5
76
Br
77a
S
6
37
18
6
9
10
0.5
0.5
73
Br
71a
S
7
11
12
0.5
0.5
80
0a
F
Me
tBu
F
Br
73a
S
8
30
59b
55b
48b
KOAc
KOAc
KOAc
Me
tBu
Br
Br
13
14
0.5
0.5
55
32
10
11
NMP
S
9
diethyl carbonate
cyclopentyl methyl
ether
12
0.5
0.5
KOAc
KOAc
51
10
42b
S
10
b
13
pentan-1-ol
-
a
Br
Pd(OAc)2, 4-bromobenzonitrile (1 mmol), benzothiophene (1.5
15
16
17
18
0.1
0.5
0.1
0.1
60
60
62
73
S
mmol), base (2 mmol), 150 °C, 16 h, under argon, co nversion of 4-
bromobenzonitrile. Formation of 4-bromobenzamide. Catalyst is
a solution prepared with 1 mg of Pd(OAc)2 in 1 mL of DMAc.
NC
NC
a
b
11
Br
S
We then studied the scope of 2-arylation of benzothio-
phene using 0.1 or 0.5 mol-% Pd(OAc)2 catalyst, KOAc as
the base and either DMF or DMAc as the solvent (Scheme
2, Table 2). A good yield in 4 was obtained from 4-
bromobenzaldehyde using only 0.1 mol-% Pd(OAc)2 (Ta-
ble 2, entry 4). However, in most cases, 0.5 mol-%
Pd(OAc)2 had to be employed to observe high conversions
of the aryl bromides and good yields of coupling products.
For example, with this catalyst loading, 4-
trifluoromethylbromobenzene, 4-bromoacetophenone, ethyl
12
Br
S
13
Br
Br
S
S
CN
CN
14
19
0.5
82a
4-bromobenzoate,
4-chlorobromobenzene
or
4-
15
fluorobromobenzene gave the expected C2-arylated ben-
zothiophenes 3, 5-8 in 61-80% yields (Table 2, entries 3, 5-
12). With these reactants, very similar yields were ob-
tained using DMF or DMAc as the solvent. It should be
noted that no cleavage of the C-Cl bond of 4-
chlorobromobenzene was observed under these reaction
conditions allowing further transformations. In the pres-
ence of the electron-rich aryl bromides, 4-bromotoluene
and 4-tert-butylbromobenzene, moderate yields in 9 and 10
were obtained, due to partial conversion of these aryl bro-
20
21
0.5
0.5
trace
83a
Br
Br
S
S
16
17
N
N
22
0.1
66
N
N
Conditions: Catalyst is a solution prepared with 1 mg of Pd(OAc)2
in 1 mL of DMAc (0.001 or 0.005 eq.), benzothiophene (1.5 eq.),

ACCEPTED MANUSCRIPT
Tetrahedron
3
aryl bromide (1 eq.), KOAc (2 eq.), DMF, 150 °C, 16 h, isolated
yields. a Solvent: DMAc.
The use of a higher catalyst loading allowed to improve the
yield in 18 to 33%, but some formation of unidentified
side-products was observed, and again, some formation of
biphenyl-4,4'-dicarbonitrile was detected (Table 3, entry 2).
On the other hand, in DMAc, using 0.5 mol-% Pd(OAc)2, a
clean reaction was observed, and 18 was isolated in 65%
yield (Table 3, entry 3). The stability of benzothiophene-3-
carbaldehyde in DMF appears to be limited. From the
more congested substrate 2-bromobenzonitrile, a good
yield in 20 was also obtained in DMAc (Table 3, entry 5).
With such substrates, the use of palladium associated to
phosphine ligands should be preferred. A few meta- and
ortho-substituted aryl bromides were also employed. 2-
and 3-bromobenzonitriles gave 11 and 14 in 60% and 73%
yields, respectively in the presence of 0.1 mol-% Pd(OAc)2
(Table 2, entries 15 and 18).
bromonaphthalene gave the expected products 15 and 13
(Table 2, entries 17 and 19). However, from 1-
Both 1- and 2-
bromonaphthalene, a higher yield in 15 was obtained when
using DMAc as the solvent. A similar tendency was ob-
served with 9-bromoanthracene. In DMF, a very low yield
in 16 was observed by GC/MS analysis due to the forma-
tion of several unidentified side-products; whereas a very
clean reaction was observed in DMAc to give 16 in 83%
yield (Table 2, entries 20 and 21). Therefore, for challeng-
ing aryl bromides, the use of DMAc as the solvent should
be preferred. We also examined the coupling of 5-
bromopyrimidine with benzothiophene. The desired prod-
uct 22 was isolated in 66% yield (Table 2, entry 22). For
all these reactions, no arylation at C3 of benzothiophene
was detected.
A
similar reactivity of 3-bromonitrobenzene, 4-
bromoisoquinoline or 5-bromopyrimidine was observed in
DMAc to give 19, 21 and 22 in 61-78% yields (Table 2,
entries 4, 6 and 7).
With 3-methylbenzothiophene in DMAc, very clean reac-
tions were observed in all cases using various aryl bro-
mides and 0.1-0.5 mol-% Pd(OAc)2 catalyst (Table 4). The
electron-deficient aryl bromides, 4-bromobenzonitrile and
ethyl 4-bromobenzoate gave 23 and 24 in 88% and 81%
yields, respectively using 0.5 mol-% Pd(OAc)2 catalyst
(Table 4, entries 1 and 2). A high yield in 25 resulting
from selective cleavage of the C-Br bond was also obtained
from 4-chlorobromobenzene (Table 4, entries 3 and 4).
The use of only 0.1 mol-% Pd(OAc)2 led to a high conver-
sion of this aryl bromide.
We then studied the reactivity of benzothiophene-3-
carbaldehyde with some aryl bromides (Table 3). We ob-
served that using 0.1 mol-% Pd(OAc)2 as the catalyst and
4-bromobenzonitrile as coupling partner in DMF, the 2-
arylated benzothiophene 18 was obtained in low yield (Ta-
ble 3, entry 1). Moreover, the formation of the homocou-
pling product biphenyl-4,4'-dicarbonitrile was also ob-
served.
Table
4.
Palladium-catalysed
C2-arylation
of
3-
methylbenzothiophene with (hetero)aryl bromides (Scheme 2).
Catalyst Yield
(mol-%) (%)
Aryl halide
Product
Entry
1
Table 3. Palladium-catalysed C2-arylation of benzothiophene-3-
carbaldehyde with (hetero)aryl bromides (Scheme 2).
0.5
0.5
88
81
NC
Br
NC
Catalyst Yield
(mol-%) (%)
Aryl halide
Product
O
Entry
S
23
O
1
2
3
0.1
0.5
0.5
13a
O
2
Br
33a
65
NC
Br
EtO
S
EtO
NC
O2N
24
S
18
O
3
4
0.1
0.5
72
88
O2N
Cl
Br
Cl
4
5
0.5
0.5
78
77
S
25
Br
S
19
O
5
6
7
0.5
0.5
0.1
66
79
70
Br
Br
Br
S
26
S
CN
CN
CN
20
O
S
S
CN
27
28
6
7
0.5
0.5
65
61
Br
Br
Br
S
N
N
N
N
21
22
N
N
O
N
N
N
N
8
0.1
61
3-
S
Br
S
Conditions: benzothiophene-3-carbaldehyde (1.5 eq.), aryl bro-
mide (1 eq.), KOAc (2 eq.), DMAc, 150 °C, 16 h, isolated yields.
29
0.005
Conditions:
Pd(OAc)2
(0.001
or
eq.),
a
In DMF with a solution of catalyst prepared with 1 mg of
methylbenzothiophene (1.5 eq.), aryl bromide (1 eq.), KOAc (2
eq.), DMAc, 150 °C, 16 h, isolated yields.
Pd(OAc)2 in 1 mL of DMAc.

ACCEPTED MANUSCRIPT
4
Tetrahedron
In order to have a better insight of the influence of the ben-
zothiophenes C3-substituents on their reactivity, we per-
formed a competitive experiment using an equimolar mix-
ture of 3-methylbenzothiophene and benzothiophene-3-
carbaldehyde in the presence of 4-bromobenzonitrile and
0.5 mol-% Pd(OAc)2 (Scheme 3). We observed the forma-
tion of a mixture of the products 23 and 18 in a 41:59 ratio.
This result indicates that the presence of electron-donating
or electron-withdrawing substituents at C3 of benzothio-
phenes only has a minor influence on their reactivity.
Again, no cleavage of the C-Cl bond was observed allow-
ing further transformations. A slightly lower yield was
obtained for the coupling of the electron-rich aryl bromide:
3-bromotoluene (Table 4, entry 5). It should be noted that
both 3-bromopyridine and 4-bromoisoquinoline could be
coupled with 3-methylbenzothiophene to give 28 and 29 in
high yields using only 0.1 mol-% Pd(OAc)2 (Table 4, en-
tries 7 and 8).
The reactivity of 5-chloro-3-methylbenzothiophene with a
set of (hetero)aryl bromides was also examined using 0.1-
0.5 mol-% Pd(OAc)2 catalyst (Table 5). In all cases, high
yields of the desired coupling products 30-38 were ob-
O
O
+
S
Pd(OAc)2
0.5 mol%
S
S
18
23
CN
CN
tained,
butylbromobenzene.
chlorobromobenzene,
except
with
the
For
electron-rich,
example, from
or
4-tert-
1.5 eq.
1.5 eq.
4-
2-
DMAc, KOAc,
150 °C, 16 h
3-nitrobromobenzene
Br
CN
+
S
bromobenzonitrile and 0.1 mol-% Pd(OAc)2, the products
32, 34 and 37 were obtained in 82-85% yields (Table 5,
entries 3, 5 and 8).
1 eq.
Ratio 18:23 = 59:41
Scheme 3. Competitive experiments using a mixture of 3-
methylbenzothiophene and benzothiophene-3-carbaldehyde.
Table 5. Palladium-catalysed C2-arylation of 5-chloro-3-
methylbenzothiophene with (hetero)aryl bromides (Scheme 2).
To our knowledge, the direct arylation at C2 of 3-
bromobenzothiophene has not been reported. So far, the
Yiel
d
(%)
Catalyst
(mol-%)
Aryl halide
Product
Entry
1
coupling
of
such
reactants
to
prepare
3-
arylbenzothiophenes employs organozinc intermediates.12
We observed that using 3-bromobenzothiophene and 2-
bromobenzonitrile in a 1.5:1 ratio and again 0.5 mol-%
Pd(OAc)2 catalyst, the desired product 39 was obtained in
62% yield without cleavage of the C-Br bond of the ben-
zothiophene derivative.
Cl
Cl
0.5
78
83
NC
Br
Br
NC
O
S
S
30
O
2
0.5
Br
NC
CN
31
32
Pd(OAc)2
0.5 mol%
Br
Br
+
Cl
S
3
4
5
6
7
8
9
0.1
0.1
0.1
0.5
0.1
0.1
0.1
85
58
83
80
88
82
76
Cl
Br
Br
H
Cl
KOAc, DMAc,
150 °C, 16 h
S
39 62%
S
S
Cl
Scheme 4. Palladium-catalysed direct arylation of 3-
bromobenzothiophene with 2-bromobenzonitrile.
tBu
tBu
33
O2N
Finally, the palladium-catalysed C3 direct arylation of 7
was examined (Scheme 5). The use of 0.5 mol-%
Pd(OAc)2 catalyst gave 40 as traces. On the other hand, in
the presence of 0.5 mol-% PdCl(C3H5)(dppb) catalyst, 40
was isolated in 47% yield, without cleavage of the C-Cl
bond of the aryl substituent, showing the beneficial effect
of the phosphine ligand in this case.
O2N
Cl
Br
S
34
Cl
Br
S
35
Cl
Br
CN
H
S
36
CN
PdCl(C3H5)(dppb)
0.5 mol%
Cl
Cl
Br
Br
S
7
Cl
KOAc, 150 °C, 20 h
S
S
+
CN
37
S
Br
CN
Cl
40 47%
N
N
38
Scheme 5. Palladium-catalysed direct C3 arylation of 2-
arylbenzothiophene 7 with 4-bromobenzonitrile.
Conditions: Pd(OAc)2 (0.001 or 0.005 eq.), 5-chloro-3-
methylbenzothiophene (1.5 eq.), aryl bromide (1 eq.), KOAc (2
eq.), DMAc, 150 °C, 16 h, isolated yields.

ACCEPTED MANUSCRIPT
Tetrahedron
5
4-Benzo[b]thiophen-2-ylbenzaldehyde (4)1
From 4-bromobenzaldehyde (0.185 g,
benzothiophene (0.201 g, 1.5 mmol), 4 was obtained in 72%
(0.171 g) yield. 1H NMR (400 MHz, CDCl3): δ 9.97 (s, 1H), 7.87
(d, J = 8.3 Hz, 2H), 7.80 (d, J = 8.3 Hz, 2H), 7.80-7.72 (m, 2H),
7.63 (s, 1H), 7.32 (t, J = 7.3 Hz, 1H), 7.28 (t, J = 7.3 Hz, 1H).
In summary, we have demonstrated that using as little as
0.5-0.1 mol-% of Pd(OAc)2 as the catalyst precursor, the
direct 2-arylation via C-H bond activation of benzothio-
phenes proceeds in moderate to high yields. This proce-
dure gave the best results using electron-deficient aryl bro-
mides. Several functions such as formyl, acetyl, propionyl,
nitro, nitrile, chloro, fluoro or trifluoromethyl are tolerated.
Congested aryl bromides such as 9-bromoanthracene, also
gave satisfactory results. This ligand-free low catalyst
loading procedure is economically and environmentally
attractive, as there is no need to eliminate phosphine de-
rivatives at the end of the reaction; and as with this C-H
bond activation procedure, no preparation of an or-
ganometallic derivative is required, reducing the number of
steps and therefore the mass of waste products. The major
waste is the relatively non-toxic AcOH/KBr instead of me-
tallic salts with more classical metal-catalysed coupling
reactions. For these reasons, the methodology developed
here is very promising for the sustainable synthesis of 2-
arylbenzothiophenes.
1
mmol) and
1-(4-Benzo[b]thiophen-2-yl-phenyl)-ethanone (5)1
From 4-bromoacetophenone (0.199 g,
benzothiophene (0.201 g, 1.5 mmol), 5 was obtained in 66%
(0.166 g) yield. 1H NMR (400 MHz, CDCl3): δ 7.93 (d, J = 8.3
Hz, 2H), 7.80-7.68 (m, 4H), 7.59 (s, 1H), 7.30 (t, J = 7.3 Hz, 1H),
7.27 (t, J = 7.3 Hz, 1H), 2.55 (s, 3H).
1
mmol) and
Ethyl 4-benzo[b]thiophen-2-yl-benzoate (6)7h
From ethyl 4-bromobenzoate (0.229 g,
benzothiophene (0.201 g, 1.5 mmol), 6 was obtained in 76%
(0.214 g) yield. 1H NMR (400 MHz, CDCl3): δ 8.01 (d, J = 8.3
Hz, 2H), 7.74 (d, J = 7.0 Hz, 1H), 7.70-7.65 (m, 3H), 7.56 (s, 1H),
7.30 (t, J = 7.3 Hz, 1H), 7.27 (t, J = 7.3 Hz, 1H), 4.32 (q, J = 7.2
Hz, 2H), 1.34 (t, J = 7.2 Hz, 3H).
1
mmol) and
2-(4-Chlorophenyl)-benzo[b]thiophene (7)7h
From 1-bromo-4-chlorobenzene (0.191 g,
1
mmol) and
3. Experimental
benzothiophene (0.201 g, 1.5 mmol), 7 was obtained in 73%
(0.178 g) yield. 1H NMR (400 MHz, CDCl3): δ 7.76 (d, J = 7.0
Hz, 1H), 7.70 (d, J = 7.0 Hz, 1H), 7.56 (d, J = 8.3 Hz, 2H), 7.44
(s, 1H), 7.32 (d, J = 8.3 Hz, 2H), 7.30-7.20 (m, 2H).
General: All reactions were performed in Schlenck tubes under
argon. Potassium acetate 99+ was used. Benzothiophenes and
aryl bromides were used without purification. 1H (400 MHz, 25
°C), 13C (100 MHz, 25 °C) spectra were recorded in CDCl3 solu-
tions. Chemical shifts are reported in ppm relative to CDCl3 (1H:
7.29 and 13C: 77.0). Flash chromatography was performed on
silica gel (230-400 mesh).
2-(4-Fluorophenyl)-benzo[b]thiophene (8)7h
From 1-bromo-4-fluorobenzene (0.175 g,
1
mmol) and
benzothiophene (0.201 g, 1.5 mmol), 8 was obtained in 80%
(0.182 g) yield. 1H NMR (400 MHz, CDCl3): δ 7.73 (d, J = 7.7
Hz, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.58 (dd, J = 8.6, 4.8 Hz, 2H),
7.37 (s, 1H), 7.27 (t, J = 7.3 Hz, 1H), 7.23 (t, J = 7.3 Hz, 1H),
7.03 (t, J = 8.6 Hz, 2H).
General procedure for the preparation of 1-40:
As a typical experiment, the reaction of the aryl bromide (1
mmol), benzothiophene (1.5 mmol) and KOAc (0.196 g, 2 mmol)
at 150 °C during 16 h in DMF or DMAc (4 mL) in the presence of
Pd(OAc)2 (0.224 mg, 0.001 mmol) or (1.12 mg, 0.005 mmol)
prepared as a solution in DMAc (1 mg of Pd(OAc)2 in 1 mL of
DMAc) under argon affords the coupling product after evapora-
tion of the solvent and purification on silica gel.
2-(4-Methylphenyl)-benzo[b]thiophene (9)7l
From 4-bromotoluene (0.171 g, 1 mmol) and benzothiophene
(0.201 g, 1.5 mmol), 9 was obtained in 55% (0.123 g) yield. 1H
NMR (400 MHz, CDCl3): δ 7.74 (d, J = 7.8 Hz, 1H), 7.68 (d, J =
7.8 Hz, 1H), 7.53 (d, J = 8.3 Hz, 2H), 7.42 (s, 1H), 7.26 (t, J = 7.3
Hz, 1H), 7.23 (t, J = 7.3 Hz, 1H), 7.20 (d, J = 8.3 Hz, 2H), 2.32 (s,
3H).
2-(4-Cyanophenyl)-benzo[b]thiophene (1)7l
From 4-bromobenzonitrile (0.182 g, 1 mmol) and benzothiophene
(0.201 g, 1.5 mmol), 1 was obtained in 69% (0.162 g) yield. 1H
NMR (400 MHz, CDCl3): δ 7.76 (d, J = 8.1 Hz, 1H), 7.72 (d, J =
7.9 Hz, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.59 (d, J = 8.4 Hz, 2H),
7.55 (s, 1H), 7.30 (t, J = 7.3 Hz, 1H), 7.28 (t, J = 7.3 Hz, 1H).
2-(4-tert-Butylphenyl)-benzo[b]thiophene (10)7h
From 1-tert-butylbromobenzene (0.213 g,
1
mmol) and
benzothiophene (0.201 g, 1.5 mmol), 10 was obtained in 32%
(0.085 g) yield. 1H NMR (400 MHz, CDCl3): δ 7.73 (d, J = 7.8
Hz, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.53 (d, J = 8.3 Hz, 2H), 7.42
(s, 1H), 7.36 (d, J = 8.3 Hz, 2H), 7.24 (t, J = 7.3 Hz, 1H), 7.21 (t,
J = 7.3 Hz, 1H), 1.27 (s, 9H).
2-(4-Nitrophenyl)-benzo[b]thiophene (2)7l
From 4-bromonitrobenzene (0.202 g,
1
mmol) and
benzothiophene (0.201 g, 1.5 mmol), 2 was obtained in 51%
(0.130 g) yield. 1H NMR (400 MHz, CDCl3): δ 8.20 (d, J = 8.4
Hz, 2H), 7.82-7.70 (m, 4H), 7.64 (s, 1H), 7.33 (t, J = 7.3 Hz, 1H),
7.31 (t, J = 7.3 Hz, 1H).
2-(3-Cyanophenyl)-benzo[b]thiophene (11)13a
From 3-bromobenzonitrile (0.182 g, 1 mmol) and benzothiophene
(0.201 g, 1.5 mmol), 11 was obtained in 60% (0.141 g) yield. 1H
NMR (400 MHz, CDCl3): δ 7.88 (s, 1H), 7.81 (d, J = 7.9 Hz, 1H),
7.76 (d, J = 7.8 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.51 (d, J = 7.9
Hz, 1H), 7.50 (s, 1H), 7.43 (t, J = 7.8 Hz, 1H), 7.30 (t, J = 7.3 Hz,
1H), 7.27 (t, J = 7.3 Hz, 1H).
2-[4-(Trifluoromethyl)phenyl]-benzo[b]thiophene (3)7j
From 1-bromo-4-trifluoromethylbenzene (0.225 g, 1 mmol) and
benzothiophene (0.201 g, 1.5 mmol), 3 was obtained in 61%
(0.170 g) yield. 1H NMR (400 MHz, CDCl3): δ 7.80-7.70 (m,
4H), 7.61 (d, J = 8.2 Hz, 2H), 7.56 (s, 1H), 7.32 (t, J = 7.3 Hz,
1H), 7.28 (t, J = 7.3 Hz, 1H).
2-m-Tolylbenzo[b]thiophene (12)13b
From 3-bromotoluene (0.171 g, 1 mmol) and benzothiophene
(0.201 g, 1.5 mmol), 12 was obtained in 60% (0.134 g) yield. 1H
NMR (400 MHz, CDCl3): δ 7.75 (d, J = 7.7 Hz, 1H), 7.69 (d, J =

ACCEPTED MANUSCRIPT
6
Tetrahedron
7.5 Hz, 1H), 7.50-7.40 (m, 3H), 7.25-7.20 (m, 3H), 7.08 (d, J =
7.4 Hz, 1H), 2.34 (s, 3H).
2-(3-Formylbenzo[b]thiophen-2-yl)-benzonitrile (20)8a
From 2-bromobenzonitrile (0.182 g, mmol) and
benzothiophene-3-carbaldehyde (0.243 g, 1.5 mmol), 20 was
obtained in 77% (0.202 g) yield. 1H NMR (400 MHz, CDCl3): δ
9.83 (s, 1H), 8.71 (d, J = 8.1 Hz, 1H), 7.81 (d, J = 7.8 Hz, 1H),
7.79 (d, J = 7.8 Hz, 1H), 7.67 (t, J = 7.8 Hz, 1H), 7.60-7.55 (m,
2H), 7.49 (t, J = 7.3 Hz, 1H), 7.43 (t, J = 7.3 Hz, 1H).
1
2-Naphthalen-2-yl-benzo[b]thiophene (13)7h
From 2-bromonaphthalene (0.207 g, 1 mmol) and benzothiophene
(0.201 g, 1.5 mmol), 13 was obtained in 62% (0.161 g) yield. 1H
NMR (400 MHz, CDCl3): δ 8.07 (s, 1H), 7.85-7.70 (m, 6H), 7.60
(s, 1H), 7.47-7.37 (m, 2H), 7.29 (t, J = 7.8 Hz, 1H), 7.23 (t, J =
7.3 Hz, 1H).
2-Isoquinolin-4-yl-benzo[b]thiophene-3-carbaldehyde (21)
2-Benzo[b]thiophen-2-yl-benzonitrile (14)
From 4-bromoisoquinoline (0.208 g,
1
mmol) and
From 2-bromobenzonitrile (0.182 g, 1 mmol) and benzothiophene
(0.201 g, 1.5 mmol), 14 was obtained in 73% (0.171 g) yield as a
white solid (mp 119-121 °C). 1H NMR (400 MHz, CDCl3): δ
7.80-7.72 (m, 3H), 7.67 (d, J = 7.7 Hz, 1H), 7.59 (d, J = 7.8 Hz,
1H), 7.52 (t, J = 7.3 Hz, 1H), 7.36-7.23 (m, 3H). 13C NMR (100
MHz, CDCl3): δ 140.3, 140.2, 139.2, 137.5, 134.5, 133.0, 130.2,
128.2, 125.3, 124.8, 124.5, 124.4, 122.1, 118.7, 110.5. elemental
analysis: calcd (%) for C15H9NS (235.30): C 76.56, H 3.86; found:
C 76.65, H 4.02.
benzothiophene-3-carbaldehyde (0.243 g, 1.5 mmol), 21 was
obtained in 65% (0.188 g) yield as a yellow solid (mp 132-134
°C). 1H NMR (400 MHz, CDCl3): δ 9.67 (s, 1H), 9.32 (s, 1H),
8.76 (d, J = 8.1 Hz, 1H), 8.61 (s, 1H), 8.02 (d, J = 7.6 Hz, 1H),
7.83 (d, J = 7.6 Hz, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.64 (t, J = 7.6
Hz, 1H), 7.62 (t, J = 7.7 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 7.43 (t,
J = 7.6 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 185.8, 154.4,
154.1, 144.6, 139.0, 136.4, 135.3, 133.1, 132.0, 128.2, 128.1,
126.6, 126.3, 125.3, 124.3, 121.7. elemental analysis: calcd (%)
for C18H11NOS (289.35): C 74.72, H 3.83; found: C 74.60, H
3.98.
2-Naphthalen-1-ylbenzothiophene (15)7l
From 1-bromonaphthalene (0.207 g, 1 mmol) and benzothiophene
(0.201 g, 1.5 mmol), 15 was obtained in 82% (0.213 g) yield. 1H
NMR (400 MHz, CDCl3): δ 8.18 (d, J = 8.0 Hz, 1H), 7.83-7.75
(m, 3H), 7.73 (d, J = 7.6 Hz, 1H), 7.54 (d, J = 7.0 Hz, 1H), 7.45-
7.22 (m, 6H).
2-Pyrimidin-5-yl-benzo[b]thiophene-3-carbaldehyde (22)
From 5-bromopyrimidine (0.159 g, 1 mmol) and benzothiophene-
3-carbaldehyde (0.243 g, 1.5 mmol), 22 was obtained in 61%
(0.146 g) yield as a yellow solid (mp 151-153 °C). 1H NMR (400
MHz, CDCl3): δ 10.00 (s, 1H), 9.30 (s, 1H), 8.94 (s, 2H), 8.70 (d,
J = 8.1 Hz, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.50 (t, J = 8.1 Hz, 1H),
7.44 (t, J = 8.1 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 184.6,
159.3, 157.0, 150.7, 138.4, 136.8, 131.7, 126.9, 126.7, 125.3,
121.9. elemental analysis: calcd (%) for C13H8N2OS (240.28): C
64.98, H 3.36; found: C 65.14, H 3.47.
2-Anthracen-9-yl-benzo[b]thiophene (16)13c
From 9-bromoanthracene (0.257 g, 1 mmol) and benzothiophene
(0.201 g, 1.5 mmol), 16 was obtained in 83% (0.257 g) yield. 1H
NMR (400 MHz, CDCl3): δ 8.49 (s, 1H), 7.99 (d, J = 8.4 Hz, 2H),
7.90-7.82 (m, 4H), 7.45-7.30 (m, 7H).
5-Benzo[b]thiophen-2-yl-pyrimidine (17)
4-(3-Methylbenzo[b]thiophen-2-yl)-benzonitrile (23)
From 4-bromobenzonitrile (0.182 g, 1 mmol) and 3-methyl-
benzothiophene (0.222 g, 1.5 mmol), 23 was obtained in 88%
(0.219 g) yield as a white solid (mp 125-127 °C). 1H NMR (400
MHz, CDCl3): δ 7.76 (d, J = 7.5 Hz, 1H), 7.67 (d, J = 7.8 Hz,
1H), 7.64 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H), 7.36 (t, J =
7.3 Hz, 1H), 7.30 (t, J = 7.3 Hz, 1H), 2.40 (s, 3H). 13C NMR (100
MHz, CDCl3): δ 141.0, 139.6, 139.1, 135.7, 132.3, 130.2, 129.4,
125.2, 124.6, 122.6, 122.3, 118.7, 111.3, 12.8. elemental analysis:
calcd (%) for C16H11NS (249.33): C 77.07, H 4.45; found: C
77.01, H 4.35.
From 5-bromopyrimidine (0.159 g, 1 mmol) and benzothiophene
(0.201 g, 1.5 mmol), 17 was obtained in 66% (0.140 g) yield as a
white solid (mp 128-130 °C). 1H NMR (400 MHz, CDCl3): δ
9.09 (s, 1H), 8.95 (s, 2H), 7.79 (d, J = 7.7 Hz, 1H), 7.75 (d, J =
7.5 Hz, 1H), 7.56 (s, 1H), 7.32 (t, J = 7.4 Hz, 1H), 7.29 (t, J = 7.4
Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 157.8, 153.9, 140.1,
139.9, 136.1, 128.7, 125.5, 125.1, 124.2, 122.5, 121.9. elemental
analysis: calcd (%) for C12H8N2S (212.27): C 67.90, H 3.80;
found: C 67.99, H 3.64.
4-(3-Formylbenzo[b]thiophen-2-yl)-benzonitrile (18)8a
From 4-bromobenzonitrile (0.182 g,
1
mmol) and
Ethyl 4-(3-methylbenzo[b]thiophen-2-yl)-benzoate (24)
benzothiophene-3-carbaldehyde (0.243 g, 1.5 mmol), 18 was
obtained in 65% (0.171 g) yield. 1H NMR (400 MHz, CDCl3): δ
9.97 (s, 1H), 8.71 (d, J = 8.1 Hz, 1H), 7.81 (d, J = 7.9 Hz, 1H),
7.75 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.4 Hz, 2H), 7.48 (t, J = 7.3
Hz, 1H), 7.42 (t, J = 7.3 Hz, 1H).
From ethyl 4-bromobenzoate (0.229 g, 1 mmol) and 3-methyl-
benzothiophene (0.222 g, 1.5 mmol), 24 was obtained in 81%
(0.240 g) yield as a yellow oil. 1H NMR (400 MHz, CDCl3): δ
8.05 (d, J = 8.2 Hz, 2H), 7.76 (d, J = 7.5 Hz, 1H), 7.67 (d, J = 7.8
Hz, 1H), 7.54 (d, J = 8.2 Hz, 2H), 7.35 (t, J = 7.3 Hz, 1H), 7.29 (t,
J = 7.3 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 2.41 (s, 3H), 1.34 (t, J =
7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 166.3, 141.1, 139.3,
139.1, 136.8, 129.8, 129.6, 129.5, 128.6, 124.7, 124.3, 122.4,
122.2, 61.1, 14.4, 12.8. elemental analysis: calcd (%) for
C18H16O2S (296.38): C 72.94, H 5.44; found: C 72.80, H 5.32.
2-(3-Nitrophenyl)-benzo[b]thiophene-3-carbaldehyde (19)
From 3-bromonitrobenzene (0.202, 1 mmol) and benzothiophene-
3-carbaldehyde (0.243 g, 1.5 mmol), 19 was obtained in 78%
(0.221 g) yield as a yellow solid (mp 136-138 °C). 1H NMR (400
MHz, CDCl3): δ 9.99 (s, 1H), 8.72 (d, J = 8.1 Hz, 1H), 8.40 (d, J
= 1.7 Hz, 1H), 8.32 (d, J = 8.3 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H),
7.82 (d, J = 8.4 Hz, 1H), 7.4867 (t, J = 7.3 Hz, 1H), 7.50 (t, J =
7.3 Hz, 1H), 7.45 (t, J = 7.3 Hz, 1H). 13C NMR (100 MHz,
CDCl3): δ 185.4, 156.3, 148.4, 138.2, 136.8, 136.2, 133.4, 131.1,
130.0, 126.7, 126.5, 125.4, 125.1, 124.6, 121.8. elemental
analysis: calcd (%) for C15H9NO3S (283.30): C 63.59, H 3.20;
found: C 63.42, H 3.04.
2-(4-Chlorophenyl)-3-methylbenzo[b]thiophene (25)
From 1-bromo-4-chlorobenzene (0.191 g, 1 mmol) and 3-methyl-
benzothiophene (0.222 g, 1.5 mmol), 25 was obtained in 88%
(0.227 g) yield as a white solid (mp 87-89 °C). 1H NMR (400
MHz, CDCl3): δ 7.74 (d, J = 7.5 Hz, 1H), 7.64 (d, J = 7.8 Hz,
1H), 7.39 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 8.2 Hz, 2H), 7.31 (t, J =
7.3 Hz, 1H), 7.27 (t, J = 7.3 Hz, 1H), 2.36 (s, 3H). 13C NMR (100

ACCEPTED MANUSCRIPT
Tetrahedron
7
MHz, CDCl3): δ 141.1, 138.9, 136.7, 133.9, 133.2, 130.9, 128.8,
127.9, 124.5, 124.3, 122.2, 122.1, 12.6. elemental analysis: calcd
(%) for C15H11ClS (258.77): C 69.62, H 4.28; found: C 69.79, H
4.09.
From 4-bromopropiophenone (0.213 g, 1 mmol) and 5-chloro-3-
methylbenzothiophene (0.274 g, 1.5 mmol), 31 was obtained in
83% (0.261 g) yield as a white solid (mp 136-138 °C). 1H NMR
(400 MHz, CDCl3): δ 7.94 (d, J = 8.3 Hz, 2H), 7.62-7.58 (m, 2H),
7.51 (d, J = 8.3 Hz, 2H), 7.27 (d, J = 8.5 Hz, 1H), 2.91 (q, J = 7.5
Hz, 2H), 2.34 (s, 3H), 1.16 (t, J = 7.5 Hz, 3H). 13C NMR (100
MHz, CDCl3): δ 200.1, 142.4, 138.8, 137.1, 136.1, 130.7, 129.7,
128.3, 128.1, 125.1, 123.2, 122.1, 31.9, 12.8, 8.3. elemental
analysis: calcd (%) for C18H15ClOS (314.83): C 68.67, H 4.80;
found: C 68.49, H 4.89.
3-Methyl-2-m-tolyl-benzo[b]thiophene (26)
From 3-bromotoluene (0.171 g,
1 mmol) and 3-methyl-
benzothiophene (0.222 g, 1.5 mmol), 26 was obtained in 66%
(0.157 g) yield as a colourless oil. 1H NMR (400 MHz, CDCl3): δ
7.72 (d, J = 7.8 Hz, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.35-7.18 (m,
5H), 7.10-7.05 (m, 1H), 2.36 (s, 3H), 2.32 (s, 3H). 13C NMR (100
MHz, CDCl3): δ 141.3, 138.9, 138.3, 138.2, 134.7, 130.4, 128.6,
128.5, 127.3, 126.9, 124.3, 124.1, 122.2, 122.1, 21.5, 12.7.
elemental analysis: calcd (%) for C16H14S (238.35): C 80.63, H
5.92; found: C 80.74, H 5.99.
5-Chloro-2-(4-chlorophenyl)-3-methylbenzo[b]thiophene (32)
From 1-bromo-4-chlorobenzene (0.191 g, 1 mmol) and 5-chloro-
3-methylbenzothiophene (0.274 g, 1.5 mmol), 32 was obtained in
85% (0.249 g) yield as a white solid (mp 137-138 °C). 1H NMR
(400 MHz, CDCl3): δ 7.60 (d, J = 8.2 Hz, 1H), 7.58 (s, 1H), 7.40-
7.30 (m, 4H), 7.20 (d, J = 8.3 Hz, 1H), 2.30 (s, 3H). 13C NMR
(100 MHz, CDCl3): δ 142.4, 138.7, 136.9, 134.2, 132.7, 130.9,
130.7, 128.9, 127.4, 124.9, 123.2, 121.9, 12.6. elemental analysis:
calcd (%) for C15H10Cl2S (293.21): C 61.44, H 3.44; found: C
61.59, H 3.31.
2-(3-Methylbenzo[b]thiophen-2-yl)-benzonitrile (27)
From 2-bromobenzonitrile (0.182 g, 1 mmol) and 3-methyl-
benzothiophene (0.222 g, 1.5 mmol), 27 was obtained in 79%
(0.197 g) yield as a white solid (mp 122-124 °C). 1H NMR (400
MHz, CDCl3): δ 7.75 (d, J = 7.5 Hz, 1H), 7.70 (d, J = 7.8 Hz,
1H), 7.68 (d, J = 7.8 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.48 (d, J =
7.2 Hz, 1H), 7.41 (t, J = 7.3 Hz, 1H), 7.36 (t, J = 7.3 Hz, 1H), 7.31
(t, J = 7.3 Hz, 1H), 2.30 (s, 3H). 13C NMR (100 MHz, CDCl3): δ
140.3, 139.6, 138.4, 133.3, 133.1, 132.5, 132.0, 131.2, 128.6,
125.1, 124.5, 122.7, 122.2, 117.9, 113.9, 13.0. elemental analysis:
calcd (%) for C16H11NS (249.33): C 77.07, H 4.45; found: C
77.40, H 4.57.
2-(4-tert-Butylphenyl)-3-methyl-benzo[b]thiophene (33)
From 1-tert-butylbromobenzene (0.213 g, 1 mmol) and 5-chloro-
3-methylbenzothiophene (0.274 g, 1.5 mmol), 33 was obtained in
58% (0.182 g) yield as a white solid (mp 134-136 °C). 1H NMR
(400 MHz, CDCl3): δ 7.64 (d, J = 8.2 Hz, 1H), 7.60 (s, 1H), 7.45-
7.35 (m, 4H), 7.22 (d, J = 8.3 Hz, 1H), 2.36 (s, 3H), 1.30 (s, 9H).
13C NMR (100 MHz, CDCl3): δ 151.2, 142.6, 140.3, 136.9, 131.3,
130.4, 129.3, 126.6, 125.6, 124.4, 123.1, 121.7, 34.8, 31.3, 12.6.
elemental analysis: calcd (%) for C19H20ClS (314.87): C 72.47, H
6.08; found: C 72.27, H 6.29.
3-(3-Methylbenzo[b]thiophen-2-yl)-pyridine (28)
From 3-bromopyridine (0.158 g,
1 mmol) and 3-methyl-
benzothiophene (0.222 g, 1.5 mmol), 28 was obtained in 70%
(0.157 g) yield as a white solid (mp 210-212 °C). 1H NMR (400
MHz, CDCl3): δ 8.73 (d, J = 1.2 Hz, 1H), 8.53 (d, J = 3.6 Hz,
1H), 7.80-7.70 (m, 2H), 7.66 (d, J = 8.0 Hz, 1H), 7.40-7.23 (m,
3H), 2.39 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 150.2, 148.8,
140.9, 139.1, 136.8, 133.9, 130.9, 129.0, 124.8, 124.4, 123.4,
122.4, 122.2, 12.6. elemental analysis: calcd (%) for C14H11NS
(225.31): C 74.63, H 4.92; found: C 74.57, H 4.69.
5-Chloro-3-methyl-2-(3-nitrophenyl)-benzo[b]thiophene (34)
From 3-bromonitrobenzene (0.202, 1 mmol) and 5-chloro-3-
methylbenzothiophene (0.274 g, 1.5 mmol), 34 was obtained in
83% (0.251 g) yield as a yellow solid (mp 176-177 °C). 1H NMR
(400 MHz, CDCl3): δ 8.30 (s, 1H), 8.16 (d, J = 8.3 Hz, 1H), 7.75
(d, J = 7.7 Hz, 1H), 7.68-7.60 (m, 2H), 7.57 (t, J = 8.0 Hz, 1H),
7.26 (d, J = 8.5 Hz, 1H), 2.37 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 148.4, 142.1, 137.0, 136.0, 135.5, 131.0, 129.7, 128.7,
125.5, 124.3, 123.3, 122.8, 122.2, 12.6. elemental analysis: calcd
(%) for C15H10ClNO2S (303.76): C 59.31, H 3.32; found: C 59.50,
H 3.48.
4-(3-Methylbenzo[b]thiophen-2-yl)-isoquinoline (29)
From 4-bromoisoquinoline (0.208 g, 1 mmol) and 3-methyl-
benzothiophene (0.222 g, 1.5 mmol), 29 was obtained in 61%
(0.168 g) yield as a yellow oil. 1H NMR (400 MHz, CDCl3): δ
9.24 (s, 1H), 8.53 (s, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.81 (d, J =
7.7 Hz, 1H), 7.75-7.70 (m, 2H), 7.65-7.55 (m, 2H), 7.40 (t, J = 7.8
Hz, 1H), 7.33 (t, J = 7.8 Hz, 1H), 2.16 (s, 3H). 13C NMR (100
MHz, CDCl3): δ 153.0, 144.8, 140.4, 139.9, 135.2, 131.9, 131.3,
131.0, 128.3, 128.0, 127.5, 125.9, 125.0, 124.7, 124.4, 122.3,
122.2, 12.7. elemental analysis: calcd (%) for C18H13NS (275.37):
C 78.51, H 4.76; found: C 78.51, H 4.87.
5-Chloro-3-methyl-2-m-tolyl-benzo[b]thiophene (35)
From 3-bromotoluene (0.171 g,
1 mmol) and 5-chloro-3-
methylbenzothiophene (0.274 g, 1.5 mmol), 35 was obtained in
80% (0.218 g) yield as a colourless oil. 1H NMR (400 MHz,
CDCl3): δ 7.58 (d, J = 8.3 Hz, 1H), 7.56 (s, 1H), 7.30-7.05 (m,
5H), 2.31 (s, 3H), 2.30 (s, 3H). 13C NMR (100 MHz, CDCl3): δ
142.6, 140.4, 138.4, 137.0, 134.2, 130.5, 130.3, 128.9, 128.6,
126.8, 126.7, 124.6, 123.1, 121.8, 21.5, 12.7. elemental analysis:
calcd (%) for C16H13ClS (272.79): C 70.45, H 4.80; found: C
70.32, H 4.68.
4-(5-Chloro-3-methylbenzo[b]thiophen-2-yl)-benzonitrile (30)
From 4-bromobenzonitrile (0.182 g, 1 mmol) and 5-chloro-3-
methylbenzothiophene (0.274 g, 1.5 mmol), 30 was obtained in
78% (0.221 g) yield as a white solid (mp 164-166 °C). 1H NMR
(400 MHz, CDCl3): δ 7.70-7.63 (m, 4H), 7.56 (d, J = 8.3 Hz, 2H),
7.27 (d, J = 8.5 Hz, 1H), 2.37 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 142.1, 139.0, 137.7, 137.2, 132.4, 130.9, 130.2, 128.7,
125.5, 123.3, 122.2, 118.6, 111.7, 12.8. elemental analysis: calcd
(%) for C16H10ClNS (283.78): C 67.72, H 3.55; found: C 67.81, H
3.41.
5-Chloro-3-methyl-2-naphthalen-2-yl-benzo[b]thiophene (36)
From 2-bromonaphthalene (0.207 g, 1 mmol) and 5-chloro-3-
methylbenzothiophene (0.274 g, 1.5 mmol), 36 was obtained in
88% (0.271 g) yield as a white solid (mp 128-129 °C). 1H NMR
(400 MHz, CDCl3): δ 7.85 (s, 1H), 7.80-7.70 (m, 3H), 7.65-7.55
(m, 2H), 7.51 (d, J = 8.3 Hz, 1H), 7.43-7.38 (m, 2H), 7.19 (d, J =
8.4 Hz, 1H), 2.34 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 142.6,
140.2, 137.2, 133.3, 132.8, 131.7, 130.6, 128.9, 128.3, 128.2,
127.8, 127.3, 127.2, 126.7, 126.6, 124.7, 123.2, 121.9, 12.8.
1-[4-(5-Chloro-3-methylbenzo[b]thiophen-2-yl)-phenyl]-
propan-1-one (31)

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Tetrahedron
elemental analysis: calcd (%) for C19H13ClS (308.83): C 73.89, H
4.24; found: C 74.08, H 4.01.
References
1.
Ohta, A.; Akita, Y.; Ohkuwa, T.; Chiba, M.; Fukunaga,
2-(5-Chloro-3-methyl-benzo[b]thiophen-2-yl)-benzonitrile (37)
From 2-bromobenzonitrile (0.182 g, 1 mmol) and 5-chloro-3-
methylbenzothiophene (0.274 g, 1.5 mmol), 37 was obtained in
82% (0.232 g) yield as a white solid (mp 161-163 °C). 1H NMR
(400 MHz, CDCl3): δ 7.71 (d, J = 8.3 Hz, 1H), 7.68-7.60 (m, 2H),
7.58 (t, J = 7.7 Hz, 1H), 7.50-7.40 (m, 2H), 7.25 (d, J = 8.6 Hz,
1H), 2.25 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 141.5, 137.8,
137.6, 135.1, 133.4, 132.6, 131.9, 130.8, 130.6, 128.9, 125.5,
123.2, 122.4, 117.8, 113.8, 12.9. elemental analysis: calcd (%) for
C16H10ClNS (283.78): C 67.72, H 3.55; found: C 67.57, H 3.59.
R.; Miyafuji, A.; Nakata, T.; Tani, N.; Aoyagi, Y. Heterocycles
1990, 31, 1951-1958;
2.
For reviews on palladium-catalyzed C–H bond func-
tionalization: (a) Satoh, T.; Miura, M. Chem. Lett. 2007, 36, 200-
205; (b) Campeau, L.-C.; Stuart, D. R.; Fagnou, K. Aldrichim.
Acta 2007, 40, 35-41; (c) Seregin, I. V.; Gevorgyan, V. Chem.
Soc. Rev. 2007, 36, 1173-1193; (d) Li, B.-J.; Yang, S.-D.; Shi, Z.-
J. Synlett 2008, 949-957; (e) Bellina, F.; Rossi, R. Tetrahedron
2009, 65, 10269-10310; (f) Ackermann, L.; Vincente, R.; Kapdi,
A. R. Angew. Chem. Int. Ed. 2009, 48, 9792-9826; (g) Chen, X.;
Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem. Int. Ed.
2009, 48, 5094-5115; (h) Roger, J.; Gottumukkala, A. L.; Doucet,
H. ChemCatChem 2010, 2, 20-40; (i) Fischmeister, C.; Doucet H.
Green. Chem. 2011, 13, 741-753; (j) Wencel-Delord J.; Glorius,
F. Nature Chem. 2013, 5, 369-375.
3-(5-Chloro-3-methylbenzo[b]thiophen-2-yl)-pyridine (38)
From 3-bromopyridine (0.158 g,
1 mmol) and 5-chloro-3-
methylbenzothiophene (0.274 g, 1.5 mmol), 38 was obtained in
76% (0.197 g) yield as a white solid (mp 116-118 °C). 1H NMR
(400 MHz, CDCl3): δ 8.58 (d, J = 1.1 Hz, 1H), 8.52 (d, J = 3.8
Hz, 1H), 7.69 (d, J = 7.9 Hz, 1H), 7.60-7.55 (m, 2H), 7.27 (dd, J =
7.7, 4.9 Hz, 1H), 7.20 (dd, J = 8.5, 1.8 Hz, 1H), 2.30 (s, 3H). 13C
NMR (100 MHz, CDCl3): δ 150.1, 149.2, 142.1, 137.1, 136.7,
136.0, 130.8, 130.4, 128.4, 125.1, 123.4, 123.2, 122.1, 12.5.
elemental analysis: calcd (%) for C14H10ClNS (259.75): C 64.73,
H 3.88; found: C 64.50, H 3.99.
3.
(a) Masui, K.; Ikegami, H.; Mori, A. J. Am. Chem. Soc.
2004, 126, 5074-5075; (b) Parisien, M.; Valette, D.; Fagnou, K. J.
Org. Chem. 2005, 70, 7578-7584; (c) Bellina, F.; Cauteruccio, S.;
Rossi, R. Eur. J. Org. Chem., 2006, 1379-1382; (d) Turner, G. L.;
Morris, J. A.; Greaney, M. F. Angew. Chem., Int. Ed. 2007, 46,
7996-8000; (e) Campeau, L.-C.; Bertrand-Laperle, M.; Leclerc, J.-
P.; Villemure, E.; Gorelsky, S.; Fagnou, K. J. Am. Chem. Soc.
2008, 130, 3276-3277; (f) Besselievre, F.; Mahuteau-Betzer, F.;
Grierson, D. S.; Piguel, S. J. Org. Chem. 2008, 73, 3278-3280; (g)
Schipper, D. J.; Fagnou, K. Chem. Mater. 2011, 23, 1594-1600;
(h) Nadres, E. T.; Lazareva, A.; Daugulis, O. J. Org.Chem. 2011,
76, 471-483; (i) Dröge, T.; Notzon, A.; Fröhlich, R.; Glorius, F.
Chem. Eur. J. 2011, 17, 11974-11977; (j) Pierre, C.; Baudoin, O.
Org. Lett. 2011, 13, 1816-1819; (k) Théveau, L.; Verrier, C.;
Lassalas, P.; Martin, T.; Dupas, G.; Querolle, O.; Van Hijfte, L.;
Marsais, F.; Hoarau, C. Chem. Eur. J. 2011, 17, 14450-14463.
2-(3-Bromobenzothiophen-2-yl)-benzonitrile (39)
From 2-bromobenzonitrile (0.182 g,
1 mmol), 3-bromo-
benzothiophene (0.319 g, 1.5 mmol), KOAc (0.196 g, 2 mmol) at
150 °C during 16 h in DMAc (4 mL) in the presence of Pd(OAc)2
(1.12 mg, 0.005 mmol), 40 was obtained in 62% (0.195 g) yield as
a brown solid (mp 174-176 °C). 1H NMR (400 MHz, CDCl3): δ
7.83 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 8.0
Hz, 1H), 7.63 (td, J = 7.7, 1.1 Hz, 1H), 7.55 (d, J = 7.2 Hz, 1H),
7.49 (td, J = 7.7, 1.1 Hz, 1H), 7.45 (t, J = 7.7 Hz, 1H), 7.39 (t, J =
7.7 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 138.6, 138.1, 136.7,
133.8, 133.5, 132.6, 132.0, 129.4, 126.2, 125.6, 124.1, 122.3,
117.5, 114.0, 109.1. elemental analysis: calcd (%) for C15H8BrNS
(314.20): C 57.34, H 2.57; found: C 57.50, H 2.86.
4.
For selected recent contributions on direct arylations of
heteroaromatics from our laboratory: (a) Derridj, F.; Roger, J.;
Djebbar, S.; Doucet, H. Org. Lett. 2010, 12, 4320-4323; (b) Chen,
L.; Roger, J.; Bruneau, C.; Dixneuf, P. H.; Doucet, H. Chem.
Commun. 2011, 47, 1872-1874; (c) Fu, H. Y.; Doucet H. Eur. J.
Org. Chem. 2011, 7163-7173; (d) Beydoun, K.; Zaarour, M.; Wil-
liams, J. A. G.; Doucet, H.; Guerchais, V. Chem. Commun. 2012,
48, 1260-1262; (e) Derridj, F.; Roger, J.; Djebbar, S.; Doucet, H.
Adv. Synth. Catal. 2012, 354, 747-750; (f) Bensaid, S.; Doucet, H.
ChemSusChem 2012, 5, 1559-1567.
4-[2-(4-Chlorophenyl)-benzo[b]thiophen-3-yl]-benzonitrile
(40)
From 2-(4-chlorophenyl)-benzothiophene 7 (0.244 g, 1 mmol), 4-
bromobenzonitrile (0.364 g, 2 mmol), KOAc (0.392 g, 4 mmol) at
150 °C during 20 h in DMAc (4 mL) in the presence of
PdCl(C3H5)(dppb) (3.1 mg, 0.005 mmol) 40 was obtained in 47%
(0.162 g) yield as a white solid (mp 178-180 °C). 1H NMR (400
MHz, CDCl3): δ 7.82 (d, J = 7.0 Hz, 1H), 7.64 (d, J = 8.3 Hz,
2H), 7.46 (d, J = 7.0 Hz, 1H), 7.37 (d, J = 8.3 Hz, 2H), 7.35-7.25
(m, 2H), 7.19 (d, J = 8.5 Hz, 2H), 7.12 (d, J = 8.5 Hz, 2H). 13C
NMR (100 MHz, CDCl3): δ 140.3, 139.8, 139.7, 139.0, 134.5,
132.6, 132.0, 131.6, 131.2, 130.9, 128.9, 125.2, 125.0, 122.8,
5.
For selected examples of palladium-catalyzed direct
arylation of thiophenes: (a) Okazawa, T.; Satoh, T.; Miura, M.;
Nomura, M. J. Am. Chem. Soc. 2002, 124, 5286-5287; (b) Koba-
yashi, K.; Sugie, A.; Takahashi, M.; Masui, K.; Mori, A. Org.
Lett. 2005, 7, 5083-5085; (c) Nakano, M.; Tsurugi, H.; Satoh, T.;
Miura, M. Org. Lett. 2008, 10, 1851-1854; (d) Si Larbi, K.; Djeb-
bar, S.; Doucet, H. Eur. J. Inorg. Chem. 2011, 3493-3502; (e)
Beydoun, K.; Doucet, H. Eur J. Org. Chem. 2012, 6745-6751.
122.4, 118.7, 111.4.
elemental analysis: calcd (%) for
C21H12ClNS (345.85): C 72.93, H 3.50; found: C 72.80, H 3.66.
Supporting information
6.
(a) Li, J. J.; Gribble, G. W. Palladium in Heterocyclic
Chemistry, Pergamon: Amsterdam, 2000; (b) Negishi, E. Ed.
Handbook of Organopalladium Chemistry for Organic Synthesis;
Wiley-Interscience: New York, 2002; Part III, p 213.
Copies of 1H and 13C NMR spectra of new compounds.
7.
For examples of intermolecular direct arylation of ben-
Acknowledgments
zothiophenes using palladium associated to phosphine ligands as
catalyst: (a) Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.;
Nomura, M. Bull. Chem. Soc. Jpn. 1998, 71, 467-473; (b) Na-
kano, M.; Satoh, T.; Miura, M. J. Org. Chem. 2006, 71, 8309-
We are grateful to the “Chinese Scholarship Council” for a
grant to Z. L. We thank the CNRS, “Région Bretagne” and
“Rennes Métropole” for providing financial support.

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8311; (c) Fournier Dit Chabert, J.; Chatelain, G.; Pellet-Rostaing,
S.; Bouchu, D.; Lemaire, M. Tetrahedron Lett. 2006, 47, 1015-
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Satoh, T.; Miura, M. Chem. Lett. 2007, 36, 1336-1337; (g) David,
E.; Lejeune, J.; Pellet-Rostaing, S.; Schulz, J.; Lemaire, M.;
Chauvin, J.; Deronzier, A. Tetrahedron Lett. 2008, 49, 1860-
1864; (h) Liegault, B.; Lapointe, D.; Caron, L.; Vlassova, A.;
Fagnou, K. J. Org. Chem. 2009, 74, 1826-1834; (i) Rene, O.;
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Baghbanzadeh, M.; Pilger, C.; Kappe, C. O. J. Org. Chem. 2011,
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Satoh, T.; Miura, M. Chem. Lett. 2011, 40, 1015-1017.
8.
For examples of intermolecular direct arylation of ben-
mol-% Pd(OAc)2 associated to
zothiophenes using
5
a
stoechiometric amount of quaternary ammonium salts or crown
ethers as stabilizing agents: (a) Fournier Dit Chabert, J.; Joucla,
L.; David, E.; Lemaire, M. Tetrahedron 2004, 60, 3221-3230; (b)
David, E.; Perrin, J.; Pellet-Rostaing, S.; Fournier dit Chabert, J.;
Lemaire, M. J. Org. Chem. 2005, 70, 3569-3573; (c) David, E.;
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Joucla, L.; Broussous, S.; Bouhours, P.; David, E.; Pellet-
Rostaing, S.; Marquet, B.; Moreau, N.; Lemaire, M. Bioorg. Med.
Chem. 2007, 15, 4482-4497.
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(a) de Vries, A. H. M.; Mulders, J. M. C. A.; Mommers,
J. H. M.; Henderickx, H. J. W.; de Vries, J. G. Org. Lett. 2003, 5,
3285-3288; (b) Reetz, M. T.; de Vries, J. G. Chem. Commun.
2004, 15591563; (c) Alimardanov, A.; Schmieder-van de Vonder-
voort, L.; de Vries, A. H. M.; de Vries, J. G. Adv. Synth. Catal.
2004, 346, 1812-1817; (d) de Vries, J. G. Dalton Trans. 2006,
421-429.
10.
For direct arylations of heteroaromatics with aryl hal-
ides using ligand-less palladium catalysts: (a) Parisien, M.;
Valette, D.; Fagnou, K. J. Org. Chem. 2005, 70, 7578-7584; (b)
Wang, X.; Gribkov, D. V.; Sames, D. J. Org. Chem. 2007, 72,
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2010, 352, 696-710; (f) Fu, H. Y.; Chen, L.; Doucet, H. J. Org.
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11.
For recent examples of 2-arylbenzothiophenes synthe-
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2007, 1364-1368.

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SUPPORTING INFORMATION
Phosphine-free palladium-catalyzed direct C2-arylation of
benzothiophenes with aryl bromides
Liqin Zhao,[a] Christian Bruneau,[a] and Henri Doucet*[a]
Institut Sciences Chimiques de Rennes, UMR 6226 CNRS-Université de Rennes1 "Organométalliques Matériaux et
Catalyse e", 35042 Rennes, France. Tel: 33 (0)2 23 23 63 84; E-mail: henri.doucet@univ-rennes1.fr
1H and 13C NMR spectra of all new compounds
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5
4
N
15
8
14
7
3
10
H
11
O
12
22
0
-500
195
190
185
180
175
170
165
160
155
f1 (ppm)
150
145
140
135
130
125
120
115
110
6

ACCEPTED MANUSCRIPT
HD-LQ-269-P
11000
10000
9000
8000
7000
6000
5000
4000
3000
2000
1000
0
1H NMR (400 MHz, CDCl3)
CH
3
16
6
3
15
11
14
12
9
1
2
5
4
8
10
13
17
N
18
S
7
23
-1000
8.2 8.0 7.8 7.6 7.4 7.2 7.0 6.8 6.6 6.4 6.2 6.0 5.8 5.6 5.4 5.2 5.0 4.8 4.6 4.4 4.2 4.0 3.8 3.6 3.4 3.2 3.0 2.8 2.6 2.4 2.2
f1 (ppm)
HD-LQ-269-P
23000
22000
21000
20000
19000
18000
17000
16000
15000
14000
13000
12000
11000
10000
9000
13C NMR (100 MHz, CDCl3)
CH
3
16
6
3
15
11
14
12
9
1
2
5
4
8
10
13
17
N
18
S
7
23
8000
7000
6000
5000
4000
3000
2000
1000
0
-1000
-2000
150
140
130
120
110
100
90
80
f1 (ppm)
70
60
50
40
30
20
10
7

ACCEPTED MANUSCRIPT
9000
8500
8000
7500
7000
6500
6000
5500
5000
4500
4000
3500
3000
2500
2000
1500
1000
500
HD-LQ-360-P
1H NMR (400 MHz, CDCl3)
5
2
15
11
14
12
S
9
6
1
4
3
8
10
13
16
O
18
7
20
CH
19
3
O
17
24
0
-500
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
f1 (ppm)
4.5
4.0
3.5
3.0
2.5
2.0
1.5
HD-LQ-360-P
50000
45000
40000
35000
30000
25000
20000
15000
10000
5000
13C NMR (100 MHz, CDCl3)
5
2
15
14
12
S
9
6
4
3
8
10
13
16
O
18
1
7
11
20
CH
3
O
17
19
24
0
180
170
160
150
140
130
120
110
100
90
f1 (ppm)
80
70
60
50
40
30
20
10
8

ACCEPTED MANUSCRIPT
HD-LQ-286-P
18000
17000
16000
15000
14000
13000
12000
11000
10000
9000
8000
7000
6000
5000
4000
3000
2000
1000
0
1H NMR (400 MHz, CDCl3)
CH
3
10
6
3
16
12
15
13
9
1
2
5
4
8
11
14
Cl
17
S
7
25
-1000
8.0
7.5
7.0
6.5
6.0
5.5
5.0
f1 (ppm)
4.5
4.0
3.5
3.0
2.5
22000
21000
20000
19000
18000
17000
16000
15000
14000
13000
12000
11000
10000
9000
HD-LQ-286-P
13C NMR (100 MHz, CDCl3)
CH
3
10
6
3
16
12
15
13
9
1
2
5
4
8
11
14
Cl
17
S
7
25
8000
7000
6000
5000
4000
3000
2000
1000
0
-1000
-2000
140
130
120
110
100
90
80
70
60
50
40
30
20
10
f1 (ppm)
9

ACCEPTED MANUSCRIPT
HD-LQ-329-P
20000
19000
18000
17000
16000
15000
14000
13000
12000
11000
10000
9000
8000
7000
6000
5000
4000
3000
2000
1000
0
1H NMR (400 MHz, CDCl3)
CH
3
16
8
6
3
15
11
14
12
9
1
2
5
4
10
13
B (d)
7.72
D (m)
7.09
S
7
F (s)
2.32
CH
3
17
A (d)
7.61
C (m)
7.27
E (s)
2.36
26
-1000
8.2 8.0 7.8 7.6 7.4 7.2 7.0 6.8 6.6 6.4 6.2 6.0 5.8 5.6 5.4 5.2 5.0 4.8 4.6 4.4 4.2 4.0 3.8 3.6 3.4 3.2 3.0 2.8 2.6 2.4 2.2 2.0
f1 (ppm)
HD-LQ-329-P
24000
23000
22000
21000
20000
19000
18000
17000
16000
15000
14000
13000
12000
11000
10000
9000
13C NMR (100 MHz, CDCl3)
CH
3
16
6
3
15
11
14
12
9
1
2
5
4
8
10
13
S
7
CH
17
3
26
8000
7000
6000
5000
4000
3000
2000
1000
0
-1000
-2000
145 140 135 130 125 120 115 110 105 100 95
90
85
80
f1 (ppm)
75
70
65
60
55
50
45
40
35
30
25
20
15
10
5
10

ACCEPTED MANUSCRIPT
HD-LQ-272-P
11000
10000
9000
8000
7000
6000
5000
4000
3000
2000
1000
0
1H NMR (400 MHz, CDCl3)
CH
3
16
6
3
15
11
14
12
9
1
2
5
4
8
10
13
S
7
17
N
18
27
-1000
8.2 8.0 7.8 7.6 7.4 7.2 7.0 6.8 6.6 6.4 6.2 6.0 5.8 5.6 5.4 5.2 5.0 4.8 4.6 4.4 4.2 4.0 3.8 3.6 3.4 3.2 3.0 2.8 2.6 2.4 2.2
f1 (ppm)
HD-LQ-272-P
15000
14000
13000
12000
11000
10000
9000
8000
7000
6000
5000
4000
3000
2000
1000
0
13C NMR (100 MHz, CDCl3)
CH
3
16
6
3
15
11
14
12
9
1
2
5
4
8
10
13
S
7
17
N
18
27
-1000
150
140
130
120
110
100
90
80
f1 (ppm)
70
60
50
40
30
20
10
11

ACCEPTED MANUSCRIPT
HD-LQ-273-P
10000
9000
8000
7000
6000
5000
4000
3000
2000
1000
0
1H NMR (400 MHz, CDCl3)
CH
3
16
6
15
11
14
9
1
2
5
4
8
10
13
S
7
N
12
3
28
9.0
8.5
8.0
7.5
7.0
6.5
6.0
f1 (ppm)
5.5
5.0
4.5
4.0
3.5
3.0
2.5
HD-LQ-273-P
23000
22000
21000
20000
19000
18000
17000
16000
15000
14000
13000
12000
11000
10000
9000
13C NMR (100 MHz, CDCl3)
CH
3
16
8
6
3
15
11
14
9
1
2
5
4
10
13
S
7
N
12
28
8000
7000
6000
5000
4000
3000
2000
1000
0
-1000
-2000
160
150
140
130
120
110
100
90
80
f1 (ppm)
70
60
50
40
30
20
10
12

ACCEPTED MANUSCRIPT
HD-LQ-288-P
12000
11000
10000
9000
8000
7000
6000
5000
4000
3000
2000
1000
0
1H NMR (400 MHz, CDCl3)
19
18
CH
20
3
10
17
6
9
16
1
2
5
4
15
8
11
14
S
7
12
3
N
13
29
-1000
9.5
9.0
8.5
8.0
7.5
7.0
6.5
6.0
f1 (ppm)
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
HD-LQ-288-P
18000
17000
16000
15000
14000
13000
12000
11000
10000
9000
8000
7000
6000
5000
4000
3000
2000
1000
0
13C NMR (100 MHz, CDCl3)
19
18
CH
20
3
10
17
6
9
16
1
2
5
4
15
8
11
14
S
12
3
7
N
13
29
-1000
160
150
140
130
120
110
100
90
f1 (ppm)
80
70
60
50
40
30
20
10
13

ACCEPTED MANUSCRIPT
16000
15000
14000
13000
12000
11000
10000
9000
8000
7000
6000
5000
4000
3000
2000
1000
0
HD-LQ-300-P
1H NMR (400 MHz, CDCl3)
CH
3
10
8
6
3
Cl
17
13
16
14
9
11
1
2
5
4
12
15
18
N
19
S
7
30
-1000
8.4
8.0
7.6
7.2
6.8
6.4
6.0
5.6
5.2
f1 (ppm)
4.8
4.4
4.0
3.6
3.2
2.8
2.4
HD-LQ-300-P
16000
15000
14000
13000
12000
11000
10000
9000
8000
7000
6000
5000
4000
3000
2000
1000
0
13C NMR (100 MHz, CDCl3)
CH
10
3
6
3
Cl
17
13
16
14
9
11
1
2
5
4
8
12
15
18
N
19
S
7
30
-1000
150
140
130
120
110
100
90
80
f1 (ppm)
70
60
50
40
30
20
10
14

ACCEPTED MANUSCRIPT
HD-LQ-328-P
8000
7500
7000
6500
6000
5500
5000
4500
4000
3500
3000
2500
2000
1500
1000
500
1H NMR (400 MHz, CDCl3)
CH
3
10
6
3
Cl
O
19
17
13
16
14
9
CH
3
11
1
2
5
4
20
8
12
15
18
21
S
7
31
0
-500
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
f1 (ppm)
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
34000
32000
30000
28000
26000
24000
22000
20000
18000
16000
14000
12000
10000
8000
HD-LQ-328-P
13C NMR (100 MHz, CDCl3)
CH
3
10
6
3
Cl
11
O
19
17
13
16
14
9
CH
20
3
1
2
5
4
8
12
15
18
21
S
7
31
6000
4000
2000
0
-2000
210
200
190
180
170
160
150
140
130
120
110
100
f1 (ppm)
90
80
70
60
50
40
30
20
10
0
-10
15

ACCEPTED MANUSCRIPT
HD-LQ-336-P
19000
18000
17000
16000
15000
14000
13000
12000
11000
10000
9000
8000
7000
6000
5000
4000
3000
2000
1000
0
1H NMR (400 MHz, CDCl3)
CH
10
3
6
3
Cl
17
13
16
14
9
11
1
2
5
4
8
12
15
Cl
18
S
7
32
-1000
8.2 8.0 7.8 7.6 7.4 7.2 7.0 6.8 6.6 6.4 6.2 6.0 5.8 5.6 5.4 5.2 5.0 4.8 4.6 4.4 4.2 4.0 3.8 3.6 3.4 3.2 3.0 2.8 2.6 2.4 2.2 2.0
f1 (ppm)
18000
17000
16000
15000
14000
13000
12000
11000
10000
9000
8000
7000
6000
5000
4000
3000
2000
1000
0
HD-LQ-336-P
13C NMR (100 MHz, CDCl3)
CH
3
10
6
3
Cl
17
13
16
14
9
11
1
2
5
4
8
12
15
Cl
18
S
7
32
-1000
170
160
150
140
130
120
110
100
90
f1 (ppm)
80
70
60
50
40
30
20
10
0
16

ACCEPTED MANUSCRIPT
HD-LQ-337-P-1
20000
19000
18000
17000
16000
15000
14000
13000
12000
11000
10000
9000
8000
7000
6000
5000
4000
3000
2000
1000
0
1H NMR (400 MHz, CDCl3)
CH
3
10
6
3
Cl
11
17
13
16
14
9
CH
3
1
2
5
4
19
8
12
15
18
CH
3
20
CH
S
7
3
21
33
-1000
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
f1 (ppm)
4.0
3.5
3.0
2.5
2.0
1.5
HD-LQ-337-P-1
45000
40000
35000
30000
25000
20000
15000
10000
5000
13C NMR (100 MHz, CDCl3)
CH
10
3
6
3
Cl
17
13
16
14
9
CH
11
3
1
2
5
4
19
8
12
15
18
CH
3
20
CH
S
7
3
21
33
0
160
150
140
130
120
110
100
90
80
f1 (ppm)
70
60
50
40
30
20
10
17

ACCEPTED MANUSCRIPT
HD-LQ-335-P
15000
14000
13000
12000
11000
10000
9000
8000
7000
6000
5000
4000
3000
2000
1000
0
1H NMR (400 MHz, CDCl3)
CH
3
10
8
6
3
Cl
17
13
16
14
9
11
1
2
5
4
12
15
S
7
+
O
N
19
18
-
O
34
20
-1000
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
f1 (ppm)
5.0
4.5
4.0
3.5
3.0
2.5
2.0
HD-LQ-335-P
18000
17000
16000
15000
14000
13000
12000
11000
10000
9000
8000
7000
6000
5000
4000
3000
2000
1000
0
13C NMR (100 MHz, CDCl3)
CH
3
10
8
6
3
Cl
17
13
16
14
9
11
1
2
5
4
12
15
S
7
+
O
N
19
18
-
O
20
34
-1000
160
150
140
130
120
110
100
90
80
f1 (ppm)
70
60
50
40
30
20
10
18

ACCEPTED MANUSCRIPT
18000
17000
16000
15000
14000
13000
12000
11000
10000
9000
8000
7000
6000
5000
4000
3000
2000
1000
0
HD-LQ-330-P
1H NMR (400 MHz, CDCl3)
CH
3
10
6
3
Cl
17
13
16
14
9
11
1
2
5
4
8
12
15
S
7
CH
3
18
35
-1000
8.0 7.8 7.6 7.4 7.2 7.0 6.8 6.6 6.4 6.2 6.0 5.8 5.6 5.4 5.2 5.0 4.8 4.6 4.4 4.2 4.0 3.8 3.6 3.4 3.2 3.0 2.8 2.6 2.4 2.2
f1 (ppm)
HD-LQ-330-P
60000
55000
50000
45000
40000
35000
30000
25000
20000
15000
10000
5000
13C NMR (100 MHz, CDCl3)
CH
3
10
6
3
Cl
17
13
16
14
9
11
1
2
5
4
8
12
15
S
7
CH
3
18
35
0
-5000
150
140
130
120
110
100
90
80
f1 (ppm)
70
60
50
40
30
20
10
19