Pd-Catalyzed one-pot sequential cross-coupling reactions of tetrabromothiophene

Article abstract of DOI:10.1039/c7ob02601c

Unsymmetrical one-pot sequential cross-coupling reactions of sterically hindered tetrabromothiophene with arylboronic acid and an alkyne/alkene to afford selective bi-, tri-, and tetrasubstituted aryl/alkynyl-thiophenes with the aid of a palladium catalys

Full text of DOI:10.1039/c7ob02601c

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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DOI: 10.1039/C7OB02601C
Journal Name
ARTICLE
Pd-Catalyzed One-Pot Sequential Cross-Coupling
Reactions of Tetrabromothiophene
Kapil Mohan Saini,‡ Rakesh K. Saunthwal‡ and Akhilesh K. Verma*
Received 00th January 20xx,
Accepted 00th January 20xx
Unsymmetrical one-pot sequential cross-coupling reactions of sterically hindered tetrabromo thiophene with aryl boronic
acid and alkyne/alkene to afford selective bi-, tri-, and tetrasubstituted aryl/alkynyl-thiophenes with the aid of a
palladium catalyst were described. Reaction proceeds via a site-selective Suzuki/Sonogashira coupling, followed by
selective Sonogashira, Suzuki and Heck coupling reactions. This methodology has demonstrated an important framework
for the synthesis of organic scaffolds.
DOI: 10.1039/x0xx00000x
www.rsc.org/
reported the synthesis of tetra-arylthiophene using Pd-catalyzed
site-selective Suzuki reaction (Scheme 1, ii).
.
a
l
(
r
A
un e
Ph
i
S
t
2006
Carbon-carbon bond formation reactions have fundamental
importance in organic synthesis as they provide a key step in building
complex, bio-active molecules.1 Cross-coupling reactions are
demonstrated as one of the most powerful synthetic tools for the
construction of various pharmaceutically essential drug molecules.2
Heck, Stille, Negishi, and Suzuki-Miyaura coupling reactions have an
enormous impact in the academic research as well as in the
industries.3,4 In the past few decades, transition-metal catalyzed
reactions have emerged as an attractive tool and allows a wide range
of chemically distinct partners to sustain synthetic transformations
like alkylation, alkynylation, alkenylation, benzylation, arylation, and
C–H functionalizations.5
)
)
i
TMSA
)
,
,
u
C
I
Pd PPh
(
iP 2NH
)
3
t
°
4
,
,
r
o uene
r
B
l
r
r
B
B
,
Ph
,
25
,
C
S
S
,
,
,
r
B
u
r
Pd PPh
C
I
e
r
B
r
B
ii KF
M
OH
t
(
)
3
4
)
S
,
,
r
o uene
t
°
iP 2NH
l
THF
,
25
C
r
A
Ph
.
a
l
(
an er e
ii
)
L
g
t
2007
)
r
B
r
B
-
r
B
-
r2
r
B
r2
A
r2
r1
A
A
B OH
A
B OH
( )
2
(
)
2
,
,
Pd PPh
(
K P
O4
oxane
r1
A
r
B
Pd PPh
)
3
4
K3PO4
oxane
r1
)
3
4
3
r
B
(
r1
r1
A
A
A
-
S
S
,
-
,
S
o uene
uene
T
l
/1 4 Di
o
T
l
/1 4 Di
90 o
C
90 o
C
.
c
m
e
r
a
l
iii S h idt
t
2011
(
)
)
-
r3
-
iii
)
r1
A
i
B OH
( )
2
i
)
A
B OH
(
r4
r3
A
A
)
2
r
B
B
r
B
r
B
-
r4
v
-
A
B OH
(
)
2
r2
)
ii
A
B OH
(
)
)
2
r1
r2
A
A
r
B
,
r
B
S
r1
Pd PPh
re an
lig
p d
r2
A
A
S
,
(
)
3
4
re an
lig
p d
S
Pd PPh
(
)
4
3
K3PO4
K3PO4
90 o
90 o
C
Polysubstituted thiophene is a potent molecule found in
materials and medicinal science6 as they exhibit photoluminescent,7
liquid crystals,8 semiconductors,9 partial structures of light-emitting
oligomers.10 Similarly, they have potassium channel blocking,11
antileishmanial,12 antitumor13 as well as antiparasitic14 activity. A
variety of multi-step synthetic methods for the synthesis of tetra-
substituted thiophene are existing,15 therefore, a novel and versatile
methodology for efficient one-pot sequential cross-coupling
reactions of tetrabromothiophene are still challenging.
Initially, Swager group elaborated two-step tetracatenars
synthesis via Sonogashira coupling reaction followed by CuCN-
promoted cyanation.16 In 2006, Sun et al. demonstrated the tetra-
alkynylated thiophene synthesis using two-step alkyne coupling
reaction followed by deprotection (Scheme 1 i).17 Langer groups18
C
2 BF4
Cl
Cl
e
Cl
M
M
N
N
re an
:
d
p
lig
N
N
e
Cl
v
i
s
wor
Thi
k
)
r
B
r
B
r1
A
r1
r
B
r
B
A
S
r2
r2
A
A
-
r1
A
i
)
A
2 B OH
r
i
)
(
)
2
S
S
r2
-
2 B OH
r
A
( )
2
A
r1
A
ii
)
ii
)
r2
Pd
A
r1
A
r1
A
Scheme 1: One-pot sequential cross-coupling reactions of
tetrabromo thiophene
In 2011, Schmidt and co-worker reported an attractive strategy
for the synthesis of mono to poly-arylations of tetrabromo thiophene
in four step using a cyclobutene-1,2-diylbisimi diazonium as a pre-
ligand (Scheme 1, iii).19 In continuation of our ongoing research on
the palladium-catalyzed cross-coupling reactions,20 herein we have
designed a general step-economical protocol, for the synthesis of
a.Department of Chemistry, University of Delhi, delhi-110007
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
‡These authors contributed equally to this work
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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ARTICLE
Journal Name
Pd(PPh3)2Cl2 (7)+ K2CO3 (3.5)
Pd(PPh3)2Cl2 (7) Cs2CO3 ( 2.5)
Pd(PPh3)2Cl2 (7)+ K2CO3 (3.5)
Pd(PPh3)2Cl2 (7) Cs2CO3 (2.5)
Pd(PPh3)2Cl2 (7)+ K2CO3 (3.5) DMF: EtOH 6/65+
Pd(PPh3)2Cl2 (7) Cs2CO3(2.5) (4:1) 8/100
Pd(PPh3)2Cl2 (7)+ K2CO3 (3.5) DMF: EtOH 6/65+
Pd(PPh3)2Cl2 (7) Cs2CO3 ( 2.5) (4:1) 12/100
DMF: EtOH 6/65+
unsymmetrically tetra-substituted thiophene by the one-pot
sequential cross-coupling reactions of tetrabromo thiophene with
aryl boronic acid and alkyne/alkene (Scheme 1 iv).
10
11
View Art4ic0le On3l0ine
DOI: 10.1039/C7OB02601C
(4:1)
6/65
DMF: EtOH 6/65+
40 45
25 55
00 70
(4:1)
8/65
12d
13d
Results and Discussion
A successful sequential cross-coupling reaction of sterically
hindered aryl halide requires a catalytic system with high efficiency
and chemoselectivity toward the first coupling and to sustain its
catalytic activity in the successive coupling reaction. We began our
investigation using tetrabromothiophene (1) with phenylboronic
acid (2a) as our model substrate (Table 1). The reaction of tetrahalide
1a with 2a using 4 mol % of Pd(PPh3)2Cl2 and 2.5 equiv of Et3N in
MeCN: H2O (4:1) for 2 h at 25 °C, did not give the corresponding
Suzuki coupling product X (Table 1, entry 1). When triethylamine was
screened with a polar solvent like DMF; the first chemoselective
coupling product X was observed in low yield (Table 1, entries 2-3).
It was observed that intermediate X was obtained in 25% and 35%
yields after running the reaction with 6 mol % of Pd-catalyst and 3.5
equiv of Et3N (Table 1, entries 3-4). While using EtOH instead of H2O
provided the intermediate X in 45% yield (Table 1, entry 5).
Switching, the organic base to inorganic base such as K2CO3, afforded
the desired product in improved yield (Table 1, entries 6-7). The
increase of the catalyst loading provided the intermediate X in 75%
yield (Table 1, entry 8). 3,4-Dibromo-2,5-diphenylthiophene X could
be further used as a versatile framework for coupling at 3 and 4
positions with excellent chemoselectivity.
[a]Unless otherwise noted all Suzuki reactions were carried out using
1 (0.5 mmol), phenylboronic acid 2a (1.2 mmol), catalyst and base in
[b]
2 mL solvent, under an inert atmosphere.
Isolated yield.
[c]Sonogashira condition: alkynes 3a (1.2 mmol) were added using
Pd(PPh3)2Cl2 as catalyst and Cs2CO3 as base under inert
atmosphere.[d] CuI (5 mol %) and L-proline (30 mol %)
After optimizing the regioselective Suzuki reaction at the 2 and
5-position of tetrabromo thiophene, our next target was to optimize
the reaction conditions for the successive Sonogashira reaction at 3
and 4 positions. With this objective, phenyl acetylene (3a) along with
additional 7 mol % of Pd(PPh3)2Cl2 was added to the intermediate X
(monitored by TLC) and reaction was further continued at 65 °C for 6
h, the desired product 4a was observed in 10% yield with
intermediate X in 60% yield (Table 1, entry 9). The addition of Cs2CO3
(2.5 equiv) gave the desired Suzuki/Sonogashira unsymmetrical
coupling product 4a in 30% yield (Table 1, entry 10). By Increasing
the temperature and reaction time afforded the product 4a in 45%
yield (Table 1, entry 11). Further, the addition of 30 mol % of L-
proline and CuI (5 mol %) as additive provided the desired product in
55% yield (Table 1, entry 12). With the Increase of reaction time from
8.0 h to 12.0 h was found effective for the formation of product 4a
in 70% yield (Table 1 entry 13).
Table 1. Optimization of the Sequential Suzuki/Sonogashira reactiona
Ph
a
a
2
r
3
A
r
r
B
B
r
B
-
r
B
Ph
Ph B
H
)
2
O
(
S
Scope of the Sequential Suzuki/Sonogashira Coupling Reaction:
With the optimized condition (Table 1, entry 13) of sequential
Suzuki/Sonogashira coupling; we studied the substrate scope of the
Suzuki/ Sonogashira coupling of tetrabromo thiophene (1) with a
variety of aryl boronic acid and alkynes (Scheme 2). Since the first
Suzuki coupling reaction of tetrabromothiophene 1 with phenyl
boronic acid 2a proceeded with an inclusive conversion to provide
the intermediate X under optimized conditions (Table 1, entry 8),
sequentially the second coupling using ethynylbenzene 3a and 4-
ethynyl anisole 3b afforded the desired product 4a-b in 70% and 77%
yields, respectively. The subsequent reaction of p-tolyl boronic acid
2b followed by the addition of electron-neutral, electron-releasing
and hetero alkynes gave the sequential products 4c-f in good yields.
Combination of ethyl boronic acid 2c and -H, -Me, -Et, nBu, -OMe and
3-thenyl substituted aryl alkynes fruitfully provided the desired
products 4g-l in 70-76% yields. Strong electron-donating (+R effect)
(4-methoxyphenyl)boronic acid 2d was also capable of providing the
coupling products 4m-o with ethyl, n-butyl, and methoxy substituted
aryl alkynes in good yields. (4-fluorophenyl)boronic acid 2e was well
tolerated with an electron-donating alkyne to provide the
corresponding products 4p-r in 72-77% yields (Scheme 2).
ca a
s
t ly t
ca a
s
t
Ph
t
ly
r
B
Ph
r
B
S
,
,
S
so ven me
l
t ti
so ven me
t ti
l
r
A
.
.
em
t
p
e
m
t
p
Ph
X
1
a
4
Entry Catalyst (mol %)
Base
Solvent
T(h) / Yield ( %)b
Xa 4ac
(equiv)
t(°C)
MeCN:H2O
(4:1)
DMF: H2O
(4:1)
DMF: H2O
(4:1)
DMF: H2O
(4:1)
DMF: EtOH
(4:1)
DMF: EtOH
(4:1)
DMF: EtOH
(4:1)
DMF: EtOH
(4:1)
1
2
3
4
5
6
7
8
9
Pd(PPh3)2Cl2 (4)
Pd(PPh3)2Cl2 (4)
Pd(PPh3)2Cl2 (4)
Pd(PPh3)2Cl2 (6)
Pd(PPh3)2Cl2 (6)
Pd(PPh3)2Cl2 (6)
Pd(PPh3)2Cl2 (6)
Pd(PPh3)2Cl2 (7)
Et3N (2.5)
Et3N (2.5)
Et3N (2.5)
Et3N (3.5)
Et3N (3.5)
K2CO3 (3.5)
2/25
00
15
25
35
45
55
65
75
-
-
-
-
-
-
-
-
2/25
4/25
6/25
6/25
6/25
6/50
6/65
K2CO3 (3.5)
K2CO3 (3.5)
Pd(PPh3)2Cl2 (7)+
Pd(PPh3)2Cl2 (7)
K2CO3 (3.5) DMF: EtOH 6/65+
(4:1) 6/65
60 10
2 | J. Name., 2012, 00, 1-3
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Journal Name
ARTICLE
2
r
A
1
2
o
r
3
A
MeCN at 25 C for 8 h, the intermediate Y was found in 35% yield
r
r
B
B
View Article Online
r
-
r
B
2
B
1
r
r
A
A
B
H
O
)
2
(
.
DOI: 10.1039/C7OB02601C
(Table 2, entry 1). Examined the highly polar solvent such as DMF,
S
.
con
d A
on
d B
1
1
C
r
r
A
r
A
B
r
B
S
S
1
provided the intermediate Y in improved yield (Table 2, entry 2). It
was observed, that increase of the reaction temperature, afforded
the intermediate Y in 60% yield (Table 2, entry 3). Increased the
catalyst loading afforded the desired product Y in 68% yield (Table 2,
entry 4). Raising the amount of base from 2.5 equiv to 3.5 equiv,
afforded the chemoselective Sonogashira coupling product Y in 80%
yield (Table 2, entry 5). Decreasing the reaction time 8 h to 4 h,
provided the coupling product Y in significant yield (Table 2, entry 6).
After screening the reaction condition for chemoselective
Sonogashira coupling reaction, we next examined the reaction
condition for the sequential Suzuki reaction using p-tolyl boronic acid
2b, 8.0 mol % of Pd(PPh3)2Cl2 and 3.0 equiv of K2CO3. The desired
product 6a was obtained in 60% yield along with 15% of unreacted
intermediate Y (Table 2, entry 7). The reaction using (6+8) mol % of
Pd-catalyst with increased reaction time, gave the product 6a in 72%
yield (Table 2 entry 8).
1
r
A
X
2
r
4
A
.
-
,
,
,
,
:
( )
C 2
%
2CO3
O
4 1 65 o 6 8 h
C
on on
:
m
:
o
e
u v
C
diti A Pd
l
PPh
7
) (
2
l
K
3 5 q i DMF Et
H
(
)
(
)
3
-
.
,
,
,
s
C
on on
:
m
u
I
m
r
n
m
o
30
l
o
l
o
o
e
C
diti B Pd
l
PPh
7
) (
2
5
l
L p li
C 2
%
)
C
%
%
)
2CO3
2 5
(
(
(
)
(
3
-
,
,
q i 100 oC 12 14 h
e u v
)
1R
1R
1R
1R
,
=
1R
1R
1R OM
H
7
1
%
c
4
;
,
=
=
;
4d
t
7
4
E
%
,
=
=
1R
H
7
0
%
77
%
a
;
4
e
4
e
;
7
8
%
1R OM
e
;
4b
S
S
e
e
M
M
1R
1R
S
S
,
=
=
1R
1R
1R
1R
1R OM
H
7
0
%
;
4g
,
e
;
4h
7
3
%
M
,
=
;
;
4i
t
7
,
E
2
%
n
=
u
4
j
7
B
0
%
7
5
%
,
=
S
e
;
4k
e
e
M
M
S
Et
,
Et
4f
7
5
%
1R
1R
1R
1R
S
S
Table 2. Optimization of the Sequential Sonogashira/Suzuki reaction
S
S
S
e
OM
F
Ph
e
F
M
O
Et
Et
e
M
,
t
,
7
5
%
=
=
=
1R
1R
E
n
7
4
%
1R
E
t
m
;
4p
;
1R
4
4
4
2b
a
,
3
r
B
r
B
,
n
,
4l
7
6%
=
=
-
-
u
B
n
;
u
;
4q
7
2
%
r
B
B
7
4
%
e
r
p M C6H4 B OH
B
(
)
2
Ph
,
,
=
1R OM
77
%
1R OM
7
8
r
4
e
o
;
e
;
%
S
ca a
s
ca a
s
t
ly t
t
ly t
r
B
S
r
Ph
B
,
Ph
,
ti
.
S
so ven me
so ven me
l
t
ti
l
t
Scheme 2: Pd-catalyzed one-pot Suzuki/Sonogashira sequential
unsymmetrical cross-coupling reactions
.
em
em
t
t
p
p
Y
1
e
M
Ph
a
6
Entry
Catalyst
(mol %)
Base
(equiv)
Solvent
T(h)/ t Yield ( %)b
We additionally investigated the sequential Suzuki and selective
Sonogashira coupling. We initiate the reaction with tetrahalide arene
(1) and boronic acid (2) using optimized condition (Table 1, entry 8);
the intermediate X was formed (monitored by TLC). Subsequently,
1.2 equiv of an alkyne, 5 mol % Pd(PPh3)2Cl2, 15 mol % L-proline and
(°C)
Ya
6ac
1
2
3
4
5
6
Pd(PPh3)2Cl2 (4)
Pd(PPh3)2Cl2 (4)
Pd(PPh3)2Cl2 (4)
Pd(PPh3)2Cl2 (6)
Pd(PPh3)2Cl2 (6)
Pd(PPh3)2Cl2 (6)
Et3N ( 2.5)
Et3N (2.5)
Et3N (2.5)
Et3N (2.5)
Et3N (3.5)
Et3N (3.5)
MeCN
DMF
DMF
DMF
DMF
DMF
8/25
35
-
8/25
8/50
8/70
8/70
4/70
4/70
50
60
68
80
85
-
-
-
-
-
o
2.0 equiv of Cs2CO3 was added at 100 C the selective Sonogashira
product 5a-d was observed in good yields (Scheme 3).
2
2
r
A
3
1
r
A
-
2
r
A
1
r
B
r
r
A
B
H
O
)
B
r
B
r
B
(
e u v2
.
.
e u v
1 2 q i
1 2 q i
con
d A
(
)
(
)
S
.
.
on
1
r
A
d B
1
C
r
A
r
B
r
B
S
r
B
Pd(PPh3)2Cl2 )6)+
Pd(PPh3)2Cl2 (8)
Pd(PPh3)2Cl2 (6)+
Pd(PPh3)2Cl2 (8)
Et3N (3.5)+
K2CO3 (3.0)
Et3N (3.5)+
K2CO3 (3.0)
DMF+
EtOH
DMF+
EtOH
S
1
r
A
7
8
15
60
1
5
X
8/100
4/70
10/100
.
-
,
,
,
,
on on
diti A Pd
:
m
:
:
o
e
u v
C
l
PPh
7
(
2
l
K
2 5 q i DMF Et
H
4 1 65 o 8 10 h
C 2
%
2CO3
u
O
C
)
(
)
)
(
)
(
3
-
,
.
,
,
on on
:
m
m
r
n
m
o
l
o
o
o
e
s
00
72
C
diti B Pd
l
PPh
(
5
(
2
l
I
5
l
L p li
15
(
1 5
(
C 2
%
C
%
)
%
C CO3
)
)
(
)
3
,
,
q i 100 oC 8 h
e u v
)
aUnless otherwise noted all Sonogashira reactions were carried out
e
e
M
M
e
O
Et
e
O
M
using 1 (0.5 mmol), phenylacetylene 3a (1.2 mmol), catalyst 5 mol %
M
b
S
CuI and base in 2 mL solvent, under an inert atmosphere. Isolated
c
yield. Suzuki condition: boronic acid (2b) (1.2 mmol) were added
S
S
S
S
r
B
r
B
using Pd(PPh3)2Cl2 as catalyst and K2CO3 as base and solvent DMF:
EtOH (4:1) under inert atmosphere.
r
B
r
B
,
a
,
e
M
O
5d
,
c
e
M
,
5
7
2
%
7
5
%
5
7
3%
5b
7
3%
Scope of the Sequential Sonogashira/Suzuki Coupling Reaction
(Scheme 4). After achieving the successful results, we next examined
the extent of sequential Sonogashira/Suzuki coupling reactions using
various aryl alkynes and aryl boronic acids (Scheme 4).
Phenylacetylene (3a) with p-Et substituted aryl boronic acid 2c
provided the desired product 6a in 72% yield. Tetrabromothiophene
1 participated well, in order to provide Sonogashira/Suzuki coupling
products 6b−d in good yields. 1-Ethyl-4-ethynylbenzene 3c and
electron donating boronic acid were capable for providing the
Scheme 3: Pd-catalyzed One-pot Suzuki/ selective-Sonogashira
sequential cross-coupling reactions
Our next investigation was towards sequential Sonogashira/Suzuki
coupling reactions (Table 2). Encouraged by the Sonogashira
condition we began our study using tetrabromo thiophene 1 with
phenyl acetylene (3a), 4 mol % of Pd-catalyst, 2.5 equiv of Et3N in
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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Organic & Biomolecular Chemistry
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ARTICLE
Journal Name
2
2
-
sequential product 6e-g in 72-75% yields. The reaction of ether-
linked aryl alkyne 3b with p-methyl/ethyl phenyl boronic acid 2b/2c
provided the coupling product 6h and 6i in 76% and 74% yield,
respectively.
View Article Online
-
1
r
A
B
H
u v
i
)
d A
2
O
r
r
r
(
)
2
B
A
B
H
O
( )
210.103
B
r
B
r
r
r
DOI:
B
9/C7OB02601C
B
B
.
.
e
1 0
q
e
q
.
u v
i
)
(
1 0
(
.
con
1
r
con
d b
r
2
B
r
B
A
r
1
r
A
r
A
B
S
S
1
S
P
Q
- -
- -
=
=
=
1; 2
r
r
e
p M C6H4
r
e
r
A
P1; 1
A
A
p OM C6H4
Q
Q
- -
- -
=
2
1
r
e
;
2
;
A
p E C6H4
t
P2
A
p M C6H4
3
r
c
A
2
r
r
3
B
.
B
r
r
-
r
B
on
C
B
A
d
r
A
B
(
H
)
r
O
.
A
.
2
,
,
on on
:
m
u v
:
o
e
e
C
diti A P
d
l
PPh
l
l
K
2
q
i
DMF Et
H
3
C 2
3
%
%
2CO3
0
O
r
(
)
(
)
(
)
3
2
A
S
2
r
.
A
-
,
,
4 1 50 oC 4 6 h
con
on
d B
:
)
d A
C
r
B
(
r
S
r
B
r
A
A
r
S
.
-
A
,
,
-
,
on on
diti B Pd
:
m
0
u v
o
C
PPh
(
K
2
q i
,
C 2
l
3
(
2CO3
0
6
5 o
C
e
4
6
h
)
2
)
(
)
3
S
1
,
Y
on on
:
m
u
m
r
n
o
l
o
o
C
diti C Pd
l
PPh
e u v
1
I
5
(
l
L p li
C 2
%
C
%
)
30
(
6
(
)
3
(
)
2
.
-
,
,
,
2CO3 3 0 q i 100 oC 12 16 h
r
mo
l
s
C
1
A
r
%
)
A
(
)
3
r
A
.
,
,
,
,
- -
on on
:
m
u
I
m
u v
m
o
o
e
=
C
diti A Pd
70 o 4 5 h
l
PPh
l
5
(
l
Et N
5
q i DMF
2
(
L
)
3
C 2
(
6
%
C
%
)
3
(
a
r
)
(
)
)
,
3 2
3
7 ;
A
p EtC6H4 60
%
,
-
,
- -
e
=
3
C
r
;
7b
A
p OM C6H4 58
%
.
.
,
,
,
L
)
,
00 oC
on on
:
m
m
o
l
e
u v
q i Et
)
C
diti B Pd
l
K
2CO3 3 0
H
5
1
C 2
PPh
(
8
%
O
0
)
(
)
(
(
3 2
-
8 10 h
Scheme 5: One-pot Palladium-Catalyzed Triple Successive
e
M
e
M
Unsymmetrical Cross-Coupling Reaction
Et
We performed the reaction of tetrabromo thiophene 1 with 1.2
equiv of boronic acid using 3 mol % Pd(PPh3)2Cl2, 2.0 equiv of K2CO3
in DMF: EtOH (4:1) at 50 oC for 4-6 h, the intermediate P
(monoarylated product) was observed (Monitored by TLC).
e
M
F
S
S
S
Et
e
M
F
Subsequently, 1.2 equiv of another boronic acid,
3 mol %
Pd(PPh3)2Cl2, and 2.0 equiv of K2CO3 was added at 65 oC the
intermediate Q was examined by TLC, followed by sequential
addition of 2.2 equiv alkynes leads to the formation of desired
product 7a and 7b in good yields (Scheme 5).
,
a
,
6b
7
0%
,
c
e
e
M
6
72
%
M
6
74
%
e
M
Et
Et
e
M
Et
e
M
O
1
2
r
8
A
S
r
S
r
S
B
B
r
-
r
B
r
B
1
r
B
A
B
H
e
CO2M
O
.
(
)
2
S
.
con
=
on
1
d A
C
d B
1
r
r
e
M
A
Et
r
:
A
B
r
B
S
S
1
e
M
e
M
O
CO2
1
-
-
r
A
r1
,
,
9 5
8%
A
p Et C6H4
X
76
%
.
,
,
,
:
,
2 5 q i DMF Et H 4 1 5 o
O
6
)
C 6
h
on on
d
on on
m
o
,
:
e
u v
e
iti
A
C
C
Pd
C 2
l
PPh
(
7
l
K
%
)
2CO3
M
)
(
l
(
)
(
3 2
Et
Et
,
,
e
7
3%
,
.
6d
7
6%
6
,
v
)
,
,
%
%
80 o
C
e u
q i DMF
12 h
6f 72
%
:
B
Pd
C 2
mo
mo
,
d
iti
l
l
PPh Et N 4
1
0
30
0
(
)
(
3
3
e
OM
Et
e
OM
e
M
e
M
O
Scheme 6. Pd-Catalyzed Suzuki/Heck coupling reaction
Et
Now, our next focus was to study towards the Suzuki/Heck coupling
reactions (Table 2). Inspired by the Suzuki condition we began our
investigation using 1 with p-ethyl boronic acid (3c), 7 mol % of
PdCl2(PPh3)2, 2.5 equiv of K2CO3 in DMF: EtOH (4:1) at 65oC for 6 h,
the intermediate X was obtained in 76% yield with excellent
S
S
S
e
M
e
M
O
Et
e
OM
Et
e
OM
,
,
6g 75
%
,
6i 74
%
6h 7
6%
chemoselectivity. The reaction of methyl acrylate
8 with
intermediate X using PdCl2 (10 mol %), 30 mol % PPh3 and 4.0 equiv
Et3N as a base in DMF at 80 oC afforded the desired product 9 in 58%
yields (Scheme 6).
6a
Conclusion
Scheme 4: Pd-catalyzed sequential Sonogashira/Suzuki cross-
coupling reactions. CCDC deposit number for 6a is 1576779.
After attaining the successful results for sequential
In conclusion, we have developed a versatile one-pot sequential
cross-coupling reactions of sterically hindered tetrabromothiophene
with aryl boronic acid and alkyne/alkene using palladium catalyst.
Suzuki/Sonogashira, Sonogashira/Suzuki coupling reaction, we
further investigated the scope of sequential Suzuki/Suzuki couplings The formation of the C-C bond has been well accomplished in one
pot under mild reaction conditions. Spectacularly, the broad
functional group tolerance of different substituent in the substrate
may play a prospective role in diverse synthetic applications.
at 2 and 5-position of tetrabromo thiophene 1 using different aryl
boronic acids 2 followed by consecutive Sonogashira coupling at 3
and 4 positions (Scheme 5).
4 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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Journal Name
ARTICLE
Developed sequential coupling methodology could be utilized for the (m, 4H), 6.96 (d, J = 8.0 Hz, 4H), 3.94 (s, 6H); 13C NMR (100 MHz,
View Article Online
DOI: 10.1039/C7OB02601C
syntheses of a broad range of organic intermediates which have a CDCl3) δ 159.7, 142.7, 139.3, 133.4, 133.0, 128.6, 127.6, 121.7, 115.6,
vital importance in organic synthesis.
114.0, 94.2, 83.7, 55.3; HRMS (ESI) Calcd for [C34H24O2S] requires
[M+H]+ 497.1575, found 497.1573.
Experimental Section
3,4-Bis(phenylethynyl)-2,5-di-p-tolylthiophene (4c). The compound
1
is obtained as yellow needles (164.8 mg, 71%); mp 163−165 °C; H
Information and Method. All the reactions were performed in an
oven-dried Schlenk flask under an inert atmosphere. Column
chromatography was performed using silica. TLC analysis was
performed on commercially prepared 60 F254 silica gel plates.
Visualization of spots on TLC plate was accomplished with UV light
NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.4 Hz, 4H), 7.55−7.52 (m, 4H),
7.35−7.32 (m, 6H), 7.29−7.26 (m, 4H), 2.41 (s, 6H); 13C NMR (100
MHz, CDCl3) δ 143.3, 138.5, 131.5, 130.5, 129.4, 128.4, 128.2, 127.5,
123.5, 120.8, 94.0, 85.0, 21.4; HRMS (ESI) Calcd for [C34H24S] requires
[M+H]+ 465.1677, found 465.1679.
1
(254 nm) and staining over I2 chamber. H NMR (400 MHz) and 13C
NMR (100 MHz) spectra were recorded in CDCl3 and DMSO-d6.
Chemical shifts for carbons are reported in ppm from
tetramethylsilane and are referenced to the carbon resonance of the
solvent. Data are reported as follows: chemical shift, multiplicity (s =
singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd =
doublet of doublet, brs = broad), coupling constants in Hertz, and
integration. High-resolution mass spectra were recorded with q-TOF
electrospray mass spectrometer, and Infrared spectra were recorded
on a FT-IR spectrophotometer. All purchased chemicals were used as
received. All melting points are uncorrected.
3,4-Bis((4-ethylphenyl)ethynyl)-2,5-di-p-tolylthiophene (4d). The
compound is obtained as yellow needles (192.4 mg, 74%); mp
188−190 °C; 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 7.6 Hz, 4H), 7.46
(d, J = 8.4 Hz, 4H), 7.25 (d, J = 8.4 Hz, 4H), 7.17 (d, J = 8.4 Hz, 4H), 2.66
(q, J = 7.6 Hz, 4H), 2.40 (s, 6H), 1.24 (t, J = 7.6 Hz, 6H); 13C NMR (100
MHz, CDCl3) δ 144.6, 142.9, 138.3, 131.5, 130.6, 129.3, 127.9, 127.5,
121.0, 120.7, 94.2, 84.4, 28.9, 21.3, 15.4; HRMS (ESI) Calcd for
[C38H32S] requires [M+H]+ 521.2303, found 521.2305.
3,4-Bis((4-methoxyphenyl)ethynyl)-2,5-di-p-tolylthiophene
(4e)
The compound is obtained as yellow needles (204.3 mg, 78%); mp
165−167 °C; 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 8.0 Hz, 4H), 7.45
(d, J = 8.8 Hz, 4H), 7.25−7.24 (m, 4H), 6.86 (d, J = 8.8 Hz, 4H), 3.81(s,
6H), 2.39 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 159.6, 142.5, 138.3,
132.9, 130.7, 129.3, 127.4, 121.1, 115.7, 114.0, 94.0, 83.9, 55.3, 21.3;
HRMS (ESI) Calcd for [C36H28O2S] requires [M+H]+ 525.1888, found
525.1889.
General experimental procedure for Pd-catalyzed one-pot
Suzuki/Sonogashira sequential 4a-r: To
a
solution of
tetrabromothiophene 1 (0.5 mmol) in 2 mL of DMF:EtOH (4:1), 7
mol % of Pd(PPh3)2Cl2 was added. Then, 3.5 equiv of K2CO3 and 1.2
mmol of boronic acid 2 were added to the reaction mixture. The
reaction vial was then sealed and flushed with nitrogen. The reaction
was then stirred at 65 °C until TLC revealed complete conversion of
the starting material. After the completion of the first coupling
reaction (Monitored by TLC) 7 mol % of Pd(PPh3)2Cl2, 1.2 mmol of
alkyne 3, 2.5 equiv of Cs2CO3, CuI (5 mol %) and L-proline (30 mol %)
was added under nitrogen atmosphere. The reaction was then
stirred at 100 °C until TLC revealed complete conversion of the
starting material. The reaction mixture was then allowed to cool and
diluted with H2O and extracted with EtOAc (3X10 mL). The combined
organic layers were dried over Na2SO4, concentrated under vacuum,
and purified by column chromatography using 100−200 mesh size
silica gels (hexane) to afford the corresponding product.
3,
3'-((2,5-Di-p-tolylthiophene-3,4-diyl)bis(ethyne-2,1-
diyl))dithiophene (4f). The compound is obtained as yellow needles
1
(178.5 mg, 75%); mp 169−171 °C; H NMR (400 MHz, CDCl3) δ 7.84
(d, J = 7.6 Hz, 4H), 7.48−7.47 (m, 2H), 7.29−7.27 (m, 2H), 7.25 (d, J =
8.4 Hz, 4H), 7.17 (d, J = 5.3 Hz, 2H), 2.39 (s, 6H); 13C NMR (100 MHz,
CDCl3) δ 143.1, 138.5, 130.5, 129.8, 129.4, 128.5, 127.4, 125.4, 122.5,
120.7, 89.1, 84.4, 21.3; HRMS (ESI) Calcd for [C30H20S3] requires
[M+H]+ 477.0805, found 477.0806.
2,5-Bis(4-ethylphenyl)-3,4-bis(phenylethynyl)thiophene (4g). The
compound is obtained as yellow needles (172.2 mg, 70%); mp
166−168 °C; 1H NMR (400 MHz, CDCl3) δ 7.92−7.90 (m, 4H),
7.55−7.53 (m, 4H), 7.36−7.32 (m, 6H), 7.29 (d, J = 7.3 Hz, 4H), 2.70 (q,
J = 7.8 Hz, 4H), 1.30−1.26 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 144.8,
143.3, 131.5, 130.8, 128.4, 128.2, 127.6, 123.5, 120.8, 94.0, 85.1,
28.7, 15.4; HRMS (ESI) Calcd for [C36H28S] requires [M+H]+ 493.1990,
found 493.1991.
2,5-Diphenyl-3,4-bis(phenylethynyl)thiophene (4a). The compound
is obtained as pale yellow needles (152.6 mg, 70%); mp 175−177 °C;
1H NMR (400 MHz, CDCl3) δ 7.99−7.96 (m, 4H), 7.54−7.51 (m, 4H),
7.47−7.44 (m, 4H), 7.39−7.36 (m, 2H), 7.35−7.31 (m, 6H); 13C NMR
(100 MHz, CDCl3) δ 143.5, 133.3, 131.5, 128.7, 128.5, 128.4, 128.3,
127.7, 123.4, 121.4, 94.2, 84.8; HRMS (ESI) Calcd for [C32H20S]
requires [M+H]+ 437.1364, found 437.1362.
2,5-Bis(4-ethylphenyl)-3,4-bis(p-tolylethynyl)thiophene (4h). The
compound is obtained as yellow needles (189.8 mg, 73%); mp
136−138 °C; 1H NMR (400 MHz, CDCl3) δ 8.02−7.99 (m, 4H),
7.54−7.51 (m, 4H), 7.36 (d, J = 8.3 Hz, 4H), 7.23 (d, J = 7.8 Hz, 4H),
2.78 (q, J = 7.8 Hz, 4H), 2.44 (s, 6H), 1.36 (t, J = 7.8 Hz, 6H); 13C NMR
3,4-Bis((4-methoxyphenyl)ethynyl)-2,5-diphenylthiophene
(4b)
The compound is obtained as yellow needles (167.9 mg, 77%); mp
157−159 °C; 1H NMR (400 MHz, CDCl3) δ 7.59−7.57 (m, 4H),
7.46−7.42 (m, 4H), 7.35−7.31 (m, 2H), 7.26−7.21 (m, 2H), 7.18−7.13
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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Organic & Biomolecular Chemistry
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ARTICLE
Journal Name
(100 MHz, CDCl3) δ 144.6, 142.9, 138.3, 131.4, 130.9, 129.1, 128.1,
127.5, 121.0, 120.5, 94.2, 84.5, 28.7, 21.5, 15.4; HRMS (ESI) Calcd for
[C38H32S] requires [M+H]+ 521.2303, found 521.2301.
CDCl3) δ 7.92−7.89 (m, 4H), 7.44−7.42 (m, 4H), 7.13 (d,VJie=w8A.4rticHlez,O4nHlin)e,
6.98−6.94 (m, 4H), 3.85 (s, 6H), 2.60 (t, J = 7.D6OHI:z1,04.H10)3, 91/.C671O−B10.52560(m1C,
4H), 1.39−1.30 (m, 4H), 0.92 (t, J = 6.9 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ 159.6, 143.3, 142.3, 131.4, 128.9, 128.5, 126.2, 120.7, 120.4,
114.0, 94.0, 84.5, 55.3, 35.6, 33.4, 22.3, 13.9; HRMS (ESI) Calcd for
[C42H40O2S] requires [M+H]+ 609.2827, found 609.2828.
2,5-Bis(4-ethylphenyl)-3,4-bis((4-ethylphenyl) ethynyl)thiophene
(4i). The compound is obtained as yellow needles (197.2 mg, 72%);
mp 152−154 °C; 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 7.6 Hz, 4H),
7.46 (d, J = 8.4 Hz, 4H), 7.28 (d, J = 8.4 Hz, 4H), 7.17 (d, J = 7.6 Hz, 4H),
2.73−2.64 (m, 8H), 1.30−1.23 (m, 12H); 13C NMR (100 MHz, CDCl3) δ
144.6, 142.9, 131.5, 130.9, 128.2, 127.9, 127.6, 121.0, 120.7, 94.3,
84.5, 28.9, 28.7, 15.4, 15.37; HRMS (ESI) Calcd for [C40H36S] requires
[M+H]+ 549.2616, found 549.2617.
2,5-Bis(4-methoxyphenyl)-3,4-bis((4-
methoxyphenyl)ethynyl)thiophene (4o) The compound is obtained
1
as yellow needles (216.2 mg, 78%); mp 173-175 °C; H NMR (400
MHz, CDCl3) δ 7.91−7.89 (m, 4H), 7.46−7.44 (m, 4H), 6.97−6.95 (m,
4H), 6.86−6.84 (m, 4H), 3.85 (s, 6H), 3.81(s, 6H); 13C NMR (100 MHz,
CDCl3) δ 159.6, 159.5, 141.9, 132.9, 128.8, 126.2, 120.4, 115.7, 114.0,
93.7, 83.9, 55.31, 55.28; HRMS (ESI) Calcd for [C36H28O4S] [M+H]+
557.1787, found 557.1788.
3,4-Bis((4-butylphenyl)ethynyl)-2,5-bis(4-ethylphenyl)thiophene
(4j). The compound is obtained as brown needles (211.4 mg, 70%);
mp 133−135 °C; 1H NMR (400 MHz, CDCl3) δ 7.92−7.90 (m, 4H),
7.46−7.44 (m, 4H), 7.27 (d, J = 8.2 Hz, 4H), 7.14 (d, J = 8.2 Hz, 4H),
3,4-Bis((4-ethylphenyl)ethynyl)-2,5-bis(4-fluorophenyl)thiophene
2.69 (q, J = 7.3 Hz, 4H), 2.61 (t, J = 7.8 Hz, 4H), 1.64−1.56 (m, 4H), (4p). The compound is obtained as yellow needles (195.1 mg, 74%);
1.40−1.33 (m, 4H), 1.30−1.26 (m, 6H); 13C NMR (100 MHz, CDCl3) δ mp 137−139 °C; 1H NMR (400 MHz, CDCl3) δ 7.95−7.91 (m, 4H), 7.43
144.6, 143.3, 142.9, 131.4, 130.9, 128.5, 128.1, 127.5, 121.1, 120.7,
94.3, 84.5, 35.6, 33.4, 28.7, 22.3, 15.4, 13.9; HRMS (ESI) Calcd for
[C44H44S] requires [M+H]+ 605.3242, found 605.3241.
(d, J = 8.4 Hz, 4H), 7.19−7.12 (m, 8H), 2.67 (q, J = 7.6 Hz, 4H), 1.25 (t,
J = 7.6 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 162.7 (d, J = 249.2 Hz,
1C), 145.0, 141.7, 131.5, 129.4 (d, J = 7.6 Hz, 1C), 128.0, 121.6, 120.3,
115.7 (d, J = 22.0 Hz, 1C), 94.5, 83.8, 28.9, 15.4; HRMS (ESI) Calcd for
[C36H26F2S] requires [M+H]+ 529.1802, found 529.1800.
2,5-Bis(4-ethylphenyl)-3,4-bis((4-methoxyphenyl)ethynyl)
thiophene (4k) The compound is obtained as yellow needles (207.1
1
mg, 75%); mp 170−172 °C; H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 3,4-Bis((4-butylphenyl)ethynyl)-2,5-bis(4-fluorophenyl)thiophene
(4q). The compound is obtained as yellow needles (210.2 mg, 72%);
4H), 3.81 (s, 6H), 2.69 (q, J = 8.0, 4H), 1.27 (t, J = 8.0 Hz, 6H); 13C NMR mp 151−153 °C; 1H NMR (400 MHz, CDCl3) δ 7.94−7.91 (m, 4H), 7.42
8.0 Hz, 4H), 7.47−7.45 (m, 4H), 7.27 (d, J = 8.0 Hz, 4H), 6.89−6.85 (m,
(100 MHz, CDCl3) δ 159.6, 144.6, 142.5, 133.0, 130.9, 128.1, 127.5,
121.1, 115.7, 114.0, 94.0, 83.9, 55.3, 28.7, 15.4; HRMS (ESI) Calcd for
[C38H32O2S] requires [M+H]+ 553.2201, found 553.2202.
(d, J = 7.6 Hz, 4H), 7.16−7.11 (m, 8H), 2.62 (t, J = 7.6 Hz, 4H),
1.64−1.56 (m, 4H), 1.38−1.31 (m, 4H), 0.97−0.91 (m, 6H); 13C NMR
(100 MHz, CDCl3) δ 162.7 (d, J = 249.2 Hz, 1C), 143.7, 141.7, 131.4,
129.5 (d, J = 7.7 Hz, 1C), 128.5, 121.6, 120.3, 115.7 (d, J = 22.0 Hz, 1C),
94.5, 83.9, 35.6, 33.4, 22.3, 13.9; HRMS (ESI) Calcd for [C40H34F2S]
requires [M+H]+ 585.2428, found 585.2429.
3,3'-((2,5-Bis(4-ethylphenyl)thiophene-3,4-diyl)bis(ethyne-2,1-
diyl))dithiophene (4l). The compound is obtained as brown needles
(191.5 mg, 76%); mp 136−138 °C; 1H NMR (400 MHz, CDCl3) δ
7.89−7.87 (m, 4H), 7.49−7.48 (m, 2H), 7.30−7.27 (m, 6H), 7.19−7.17 2,5-Bis(4-fluorophenyl)-3,4-bis((4-
(m, 2H), 2.70 (q, J = 7.8 Hz, 4H), 1.28 (t, J = 7.3 Hz, 6H); 13C NMR (100 methoxyphenyl)ethynyl)thiophene (4r). The compound is obtained
1
MHz, CDCl3) δ 144.8, 143.1, 130.7, 130.0, 128.5, 128.2, 127.5, 125.4,
122.5, 120.7, 89.2, 84.5, 28.7, 15.4; HRMS (ESI) Calcd for [C32H24S3]
requires [M+H]+ 505.1118, found 505.1116.
as yellow needles (204.8 mg, 77%); mp 160−162 °C; H NMR (400
MHz, CDCl3) δ 7.95−7.91 (m, 4H), 7.46−7.43 (m, 4H), 7.16−7.12 (m,
4H), 6.89−6.86 (m, 4H), 3.83 (s, 6H); 13C NMR (100 MHz, CDCl3) δ
162.7 (d, J = 248.2 Hz, 1C), 159.8, 141.3, 133.0, 129.4 (d, J = 7.7 Hz,
1C), 121.6, 115.7 (d, J = 22.0 Hz, 1C), 115.3, 114.1, 94.3, 83.3, 55.3;
HRMS (ESI) Calcd for [C34H22F2O2S] requires [M+H]+ 533.1387, found
533.1389.
3,4-Bis((4-ethylphenyl)ethynyl)-2,5-bis(4-
methoxyphenyl)thiophene (4m). The compound is obtained as
1
yellow needles (207.2 mg, 75%); mp 99−101 °C; H NMR (400 MHz,
CDCl3) δ 7.93−7.91 (m, 4H), 7.45 (d, J = 8.4 Hz, 4H), 7.17 (d, J = 7.6 Hz,
4H), 6.98 (d, J = 8.4 Hz, 4H), 3.86 (s, 6H), 2.66 (q, J = 7.6 Hz, 4H), 1.24
(t, J = 7.6 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 159.7, 144.6, 142.3,
131.5, 128.9, 127.9, 126.2, 120.7, 120.4, 114.0, 94.0, 84.5, 55.4, 28.9,
15.4; HRMS (ESI) Calcd for [C38H32O2S] requires [M+H]+ 553.2201,
found 553.2204.
General experimental procedure for Pd-catalyzed one-pot
Suzuki/slective Sonogashira sequential 5a-d: To a solution of
tetrabromothiophene 1 (0.5 mmol) in 2 mL of DMF:EtOH (4:1), 7
mol% of Pd(PPh3)2Cl2 was added. Then, 3.5 equiv of K2CO3 and 1.2
mmol of boronic acid 2 were added to the reaction mixture. The
reaction vial was then sealed and flushed with nitrogen. The reaction
was then stirred at 65 °C until TLC revealed complete conversion of
the starting material. After the completion of the first coupling
reaction (Monitored by TLC) 5 mol% of Pd(PPh3)2Cl2, 0.52 mmol of
3,4-Bis((4-butylphenyl)ethynyl)-2,5-bis(4-
methoxyphenyl)thiophene (4n). The compound is obtained as
yellow needles (224.5 mg, 74%); mp 120−122 °C; 1H NMR (400 MHz,
6 | J. Name., 2012, 00, 1-3
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alkyne 3, 1.5 equiv of Cs2CO3, CuI (5 mol %) and L-proline (15 mol %) was then stirred at 70 °C until TLC revealed completeVcieownAvreticrlseioOnnlionef
DOI: 10.1039/C7OB02601C
was added under nitrogen atmosphere. The reaction was then the starting material. After the completion of the first coupling
stirred at 100 °C until TLC revealed complete conversion of the reaction (Monitored by TLC) 8 mol% of Pd(PPh3)2Cl2, 1.2 mmol of
starting material. The reaction mixture was then allowed to cool and boronic acid 2, 3.0 equiv of K2CO3, and 0.5mL EtOH were added under
diluted with H2O and extracted with EtOAc (3X10 mL). The combined nitrogen atmosphere. The reaction was then stirred at 100 °C until
organic layers were dried over Na2SO4, concentrated under vacuum, TLC revealed complete conversion of the starting material. The
and purified by column chromatography using 100− 200 mesh size reaction mixture was then allowed to cool and diluted with H2O and
silica gels (hexane) to afford the corresponding product.
extracted with EtOAc (3X10 mL). The combined organic layers were
dried over Na2SO4, concentrated under vacuum, and purified by
column chromatography using 100−200 mesh size silica gels (hexane)
to afford the corresponding product.
3-Bromo-2,5-diphenyl-4-(thiophen-3-ylethynyl)thiophene (5a). The
compound is obtained as yellow needles (154.0 mg, 72%); mp
137−139 °C; 1H NMR (400 MHz, CDCl3) δ 7.96−7.94 (m, 2H),
7.72−7.70 (m, 2H), 7.48−7.44 (m, 6H), 7.42−7.36 (m, 2H), 7.16 (d, J =
8.4 Hz, 2H), 2.37 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 144.2, 138.7,
136.5, 133.2, 132.6, 131.5, 129.1, 129.0, 128.7, 128.6, 127.5, 121.0,
119.9, 112.0, 94.8, 84.0, 21.6; HRMS (ESI) Calcd for [C25H17BrS]
requires [M+H]+ 429.0313, found 429.0313.
3,4-Bis(4-ethylphenyl)-2,5-bis(phenylethynyl)thiophene (6a). The
product was obtained as a yellow needles (177.1 mg, 72%); mp 119–
121 oC; 1H NMR (400 MHz, CDCl3) δ 7.38–7.35 (m, 4H), 7.29–7.27 (m,
6H), 7.23–7.20 (m, 4H), 7.11–7.09 (m, 4H), 2.64 (q, J = 7.8Hz, 4H),
1.25–1.21 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 145.0, 143.3, 132.2,
131.3, 130.0, 128.3, 128.26, 127.2, 122.9, 120.2, 95.2, 83.4, 28.6,
15.3. HRMS (ESI) [M+H]+ Calcd for [C36H28S] 493.1990, found
493.1991.
3-Bromo-2,5-diphenyl-4-(thiophen-3-ylethynyl)thiophene (5b). The
compound is obtained as yellow needles (152.9 mg, 73%); mp
119−121 °C; 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 6.9 Hz, 2H), 7.68
(d, J = 6.9 Hz, 2H), 7.52−7.50 (m, 1H), 7.45−7.41 (m, 4H), 7.38−7.35
(m, 2H), 7.30−7.26 (m, 1H), 7.20−7.17 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 144.5, 136.6, 133.1, 132.5, 129.7, 129.0, 128.7, 128.6,
128.58, 127.5, 125.6, 125.4, 122.0, 120.8, 111.8, 89.7, 84.0; HRMS
(ESI) Calcd for [C22H13BrS2] requires [M+H]+ 420.9720, found
420.9721.
3,4-Di-p-tolyl-2,5-bis(p-tolylethynyl)thiophene (6b). The compound
1
is obtained as yellow needles (172.2 mg, 70%); mp 178−180 °C; H
NMR (400 MHz, CDCl3) δ 7.28−7.26 (m, 4H), 7.18−7.16 (m, 4H),
7.11−7.06 (m, 8H), 2.33 (s, 12H); 13C NMR (100 MHz, CDCl3) δ 144.6,
138.6, 137.0, 132.1, 131.2, 130.0, 129.1, 128.5, 120.2, 119.9, 95.4,
82.7, 21.5, 21.3; HRMS (ESI) Calcd for [C36H28S] requires [M+H]+
493.1990, found 493.1991.
3-Bromo-4-((4-methoxyphenyl)ethynyl)-2,5-di-p-tolylthiophene
(5c). The compound is obtained as yellow needles (172.2 mg, 73%);
mp 111−113 °C; 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 8.4 Hz, 2H),
7.58 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 9.2 Hz, 2H), 7.24 (d, J = 7.6 Hz, 4H),
6.87 (d, J = 8.4 Hz, 2H), 3.81 (s, 3H), 2.39 (s, 6H); 13C NMR (100 MHz,
CDCl3) δ 159.8, 143.8, 138.2, 136.6, 133.0, 130.5, 129.8, 129.38,
129.33, 129.3, 128.9, 127.3, 126.7, 120.6, 114.0, 111.5, 94.5, 83.6,
55.3, 21.3; HRMS (ESI) Calcd for [C27H21BrOS] requires [M+H]+
473.0575, found 473.0575.
3,4-Bis(4-fluorophenyl)-2,5-bis(p-tolylethynyl)thiophene (6c). The
compound is obtained as yellow needles (185.0 mg, 74%); mp
154−156 °C; 1H NMR (400 MHz, CDCl3) δ 7.27−7.21 (m, 8H), 7.11 (d,
J = 8.2 Hz, 4H), 7.00−6.96 (m, 4H), 2.34 (s, 6H); 13C NMR (100 MHz,
CDCl3) δ 162.2 (d, J = 247.3 Hz, 1C), 143.3, 138.9, 131.9 (d, J = 7.7 Hz,
1C), 131.2, 130.8, 129.2, 120.7, 119.5, 114.9 (d, J = 21.1 Hz, 1C), 95.9,
82.1, 21.5; HRMS (ESI) Calcd for [C34H22F2S] requires [M+H]+
501.1489, found 501.1487.
3,4-Bis(4-methoxyphenyl)-2,5-bis(p-tolylethynyl)thiophene (6d).
3-Bromo-4-((4-ethylphenyl)ethynyl)-2,5-bis(4-
The compound is obtained as yellow needles (199.1 mg, 76%); mp
123−125 °C; H NMR (400 MHz, CDCl3) δ 7.29 (d, J = 8.2 Hz, 4H),
methoxyphenyl)thiophene (5d). The compound is obtained as
yellow needles (188.2 mg, 75%); mp 116−119 °C; 1H NMR (400 MHz,
CDCl3) δ 7.93−7.90 (m, 2H), 7.68−7.65 (m, 2H), 7.51 (d, J = 8.4 Hz, 2H),
7.24−7.21 (m, 2H), 7.01 (d, J = 8.4 Hz, 4H), 3.88 (s, 6H), 2.70 (q, J = 7.6
Hz, 2H), 1.28 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 159.8,
159.7, 144.9, 143.7, 135.5, 131.5, 130.3, 128.8, 127.9, 125.9, 125.1,
120.3, 119.8, 114.0, 113.95, 94.5, 84.2, 55.3, 28.8, 15.4; HRMS (ESI)
Calcd for [C28H23BrO2S] requires [M+H]+ 503.0680, found 503.0684.
1
7.25−7.21 (m, 4H), 7.11 (d, J = 8.2 Hz, 4H), 6.83−6.81 (m, 4H), 3.80 (s,
6H), 2.34 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 158.7, 144.2, 138.5,
131.3, 131.2, 129.0, 127.4, 119.8, 113.2, 95.3, 82.8, 55.1, 21.5; HRMS
(ESI) Calcd for [C36H28O2S] requires [M+H]+ 525.1888, found
525.1889.
2,5-Bis((4-ethylphenyl)ethynyl)-3,4-di-p-tolylthiophene (6e). The
product was obtained as a yellow needles (189.8 mg, 73%); mp 181–
183 oC 1H NMR (400 MHz, CDCl3) δ 7.32–7.30 (m, 4H), 7.20–7.18 (m,
4H), 7.14–7.12 (m, 4H), 7.09–7.07 (m, 4H), 2.63 (q, J = 7.3Hz, 4H),
2.33 (s, 6H), 1.22 (t, J = 7.7Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 144.9,
144.6, 136.9, 132.1, 132.0, 131.8, 130.9, 130.5, 129.5, 129.0, 128.4,
128.2, 128.17, 127.9, 127.8, 127.3, 120.2, 120.1, 95.4, 82.7, 28.8,
General experimental procedure for Pd-catalyzed one-pot
sequential Sonogashira/Suzuki 6a-i: To
a
solution of
tetrabromothiophene 1 (0.5 mmol) in 2 mL of DMF, 6 mol % of
Pd(PPh3)2Cl2 and CuI (5 mol %) was added. Then, 3.5 equiv of Et3N
and 1.2 mmol of alkyne 3 were added to the reaction mixture. The
reaction vial was then sealed and flushed with nitrogen. The reaction
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21.4, 21.2, 15.3. HRMS (ESI) [M+H]+ Calcd for [C38H32S] 521.2303,
found 521.2304.
7.91−7.86 (m, 4H), 7.48−7.45 (m, 4H), 7.28−7.24 (m, 4H), 6.87−6.85
View Article Online
(m, 4H), 3.81 (s, 6H), 2.69 (q, J = 6.9 Hz, 2H)D, 2O.I3: 910(.s1,0339H/)C,71O.2B702(6t,0J1C=
7.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 159.6, 144.6, 142.5, 138.3,
132.9, 130.9, 130.7, 129.3, 128.1, 127.5, 127.4, 121.1, 121.0, 115.7,
114.0, 94.0, 83.9, 55.3, 28.7, 21.3, 15.4; HRMS (ESI) Calcd for
[C37H30O2S] requires [M+H]+ 539.2045, found 539.2044.
3,4-Bis(4-ethylphenyl)-2,5-bis((4-ethylphenyl)ethynyl)thiophene
(6f). The product was obtained as a yellow needles (197.2 mg, 72%);
1
mp 160–162 oC; H NMR (400 MHz, CDCl3) δ 7.30–7.28 (m, 4H), 7.22–
7.20 (m, 4H), 7.13–7.08 (m, 8H), 2.66–2.59 (m, 8H), 1.25–1.19 (m,
12H); 13C NMR (100 MHz, CDCl3) δ 145.0, 144.8, 143.4, 132.4, 131.4,
130.2, 128.0, 127.3, 120.31, 120.28, 95.5, 83.0, 29.0, 28.7, 15.5, 15.4.
HRMS (ESI) [M+H]+ Calcd for [C40H36S] 549.2616, found 549.2617.
General experimental procedure for Pd-catalyzed Suzuki and
slective Heck coupling 9: To a solution of 3,4-dibromo-2,5-bis(4-
ethylphenyl)thiophene X (0.5 mmol) in 2 mL of DMF, 7 mol% of
Pd(PPh3)2Cl2 was added. Then, 3.5 equiv of Et3N and 1.2 mmol of
methyacrylate 8 were added to the reaction mixture. The reaction
vial was then sealed and flushed with nitrogen. The reaction was
then stirred at 80 °C until TLC revealed complete conversion of the
starting material. The reaction mixture was then allowed to cool and
diluted with H2O and extracted with EtOAc (3X10 mL). The combined
organic layers were dried over Na2SO4, concentrated under vacuum,
and purified by column chromatography using 100−200 mesh size
silica gels (hexane:ethylacetate/95:5) to afford the corresponding
product.
2,5-Bis((4-ethylphenyl)ethynyl)-3,4-bis(4-
methoxyphenyl)thiophene (6g). The product was obtained as a
yellow needles (207.0 mg, 75%); mp 195–197 oC; 1H NMR (400 MHz,
CDCl3) δ 7.31 (d, J = 7.8Hz, 4H), 7.24–7.21 (m, 4H), 7.13 (d, J = 8.2Hz,
4H), 6.82 (q, J = 8.2Hz, 4H), 3.80 (s, 6H), 2.63 (q, J = 7.3Hz, 4H), 1.22
(t, J = 7.3Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 158.7, 144.9, 144.2,
131.4, 131.3, 127.9, 127.5, 120.1, 119.8, 113.2, 95.3, 82.8, 55.1, 28.8,
15.3. HRMS (ESI) [M+H]+ Calcd for [C38H32O2S] 553.2201, found
553.2202.
2,5-Bis((4-methoxyphenyl)ethynyl)-3,4-di-p-tolylthiophene (6h).
The product was obtained as a yellow needles (199.1 mg, 76%); mp:
173–175 oC; 1H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 8.4Hz, 4H), 7.24–
7.22 (m, 4H), 7.12–7.11 (m, 4H), 6.86 (d, J= 8.4Hz, 4H), 3.82 (s, 6H),
2.37 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 159.6, 144.2, 136.9, 132.8,
132.1, 130.0, 128.4, 120.1, 115.0, 113.9, 95.1, 82.1, 55.2, 21.3. HRMS
(ESI) [M+H]+ Calcd for [C36H28O2S] 525.1888, found 525.1889.
3,4-Dibromo-2,5-bis(4-ethylphenyl)thiophene (X). The compound is
obtained as yellow needles (171 mg, 76%); mp 103−105 °C; 1H NMR
(400 MHz, CDCl3) δ 7.55−7.53 (m, 4H), 7.25 (d, J = 8.2 Hz, 4H), 2.66
(q, J = 7.3 Hz, 4H), 1.24 (t, J = 7.8 Hz, 6H); 13C NMR (100 MHz, CDCl3)
δ 145.0, 137.9, 130.2, 128.9, 128.2, 128.1, 126.9, 111.8, 28.7, 15.3;
HRMS (ESI) Calcd for [C20H18Br2S] requires [M+H]+ 448.9574, found
448.9571.
3,4-Bis(4-ethylphenyl)-2,5-bis((4-
Methyl
(E)-3-(4-bromo-2,5-bis(4-ethylphenyl)
thiophen-3-
methoxyphenyl)ethynyl)thiophene (6i). The compound is obtained
as yellow needles (204.2 mg, 74%); mp 86−88 °C; 1H NMR (400 MHz,
CDCl3) δ 7.32 (d, J = 8.7 Hz, 4H), 7.22 (d, J = 8.2 Hz, 4H), 7.11 (d, J =
8.2 Hz, 4H), 6.83 (d, J = 8.7 Hz, 4H), 3.79 (s, 6H), 2.65 (q, J = 7.8 Hz,
4H), 1.24 (t, J = 7.8 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 159.7, 144.3,
143.2, 132.8, 132.6, 132.3, 131.8, 130.9, 130.0, 127.7, 127.4, 127.2,
127.0, 120.1, 115.1, 114.7, 113.9, 95.1, 82.2, 55.3, 28.6, 15.3; HRMS
(ESI) Calcd for [C38H32O2S] requires [M+H]+ 553.2201, found
553.2202.
yl)acrylate (9). The compound is obtained as white needles (131.6
mg, 58%); mp 101−103 °C; H NMR (400 MHz, CDCl3) δ 7.69 (d, J =
1
16.5 Hz, 1H), 7.56−7.54 (m, 2H), 7.36−7.34 (m, 2H), 7.29−7.26 (m,
4H), 6.53 (d, J = 16.0 Hz, 1H), 3.76 (s, 3H), 2.70 (q, J = 7.3 Hz, 4H),
1.30−1.28 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 167.5, 145.3, 144.9,
144.5, 138.2, 137.5, 130.8, 130.3, 130.0, 129.4, 129.37, 128.5, 128.1,
124.0, 123.5, 121.0, 109.1, 51.7, 28.6, 15.3; HRMS (ESI) Calcd for
[C24H23BrO2S] requires [M+H]+ 455.0680, found 455.0684.
3,4-Bis((4-ethylphenyl)ethynyl)-2-(4-methoxyphenyl)-5-(p-
tolyl)thiophene (7a). The compound is obtained as yellow needles
(160.8 mg, 60%); mp 161−163 °C; 1H NMR (400 MHz, CDCl3) δ
7.93−7.87 (m, 4H), 7.46 (d, J = 8.4 Hz, 4H), 7.24 (d, J = 7.6 Hz, 2H),
7.17 (d, J = 7.6 Hz, 4H), 6.97 (d, J = 9.2 Hz, 2H), 3.84 (s, 3H), 2.66 (q, J
= 7.6 Hz, 4H), 2.39 (s, 3H), 1.26−1.22 (m, 6H); 13C NMR (100 MHz,
CDCl3) δ 159.7, 144.6, 142.7, 142.4, 138.2, 131.5, 130.7, 129.3, 128.9,
127.9, 127.4, 126.1, 120.9, 120.7, 120.5, 114.0, 94.2, 94.0, 84.5, 55.3,
28.9, 21.3, 15.4; HRMS (ESI) Calcd for [C38H32OS] requires [M+H]+
537.2252, found 537.2256.
Acknowledgements
We gratefully acknowledge the DST-SERB and CSIR for financial
support and USIC, the University of Delhi for providing
instrumentation facilities. K.M.S. and R.K.S. are thankful to CSIR for
fellowship
Notes and references
Synthetic Organic Chemistry Research Laboratory, Department of
ethynyl)-5-(p- Chemistry, University of Delhi, Delhi, 110007, India, E-mail:
2-(4-Ethylphenyl)-3,4-bis((4-methoxyphenyl)
averma@acbr.du.ac.in
Tel: Phone: 91-11-27666272(Ext.175).Electronic Supplementary
Information (ESI) available: [details of any supplementary
tolyl)thiophene (7b). The compound is obtained as yellow needles
(156.0 mg, 58%); mp 147−149 °C; 1H NMR (400 MHz, CDCl3) δ
8 | J. Name., 2012, 00, 1-3
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information available should be included here]. See
DOI: 10.1039/c000000x/
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Dadhwal, R. Kumar and A. Sinha, Angew. Chem., Int. Ed.
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Zapf, W. Mägerlein, Chem. Eng. Technol. 2001, 24, 575.
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1975, 16, 4467. (b) R. Chinchilla, C. N. jera, Chem. Rev.
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