Copper-free sonogashira coupling reaction using a trans-spanning 1,2-Bis(2-thienylethynyl)benzene ligand

Article abstract of DOI:10.1246/cl.2011.980

Novel copper-free Sonogashira coupling reaction of aryl halides with terminal acetylenes proceeded in the presence of 1,2-bis(2-thienylethynyl) benzene (1) as a trans-bidentatable ligand.

Full text of DOI:10.1246/cl.2011.980

doi:10.1246/cl.2011.980
980
Published on the web September 5, 2011
Palladium-catalyzed Carbon-Sulfur Cross-coupling Reactions
of Aryl Chlorides with Indium Tris(organothiolates)
Juntae Mo,1,2 Dahan Eom,1,2 Sung Hong Kim,3 and Phil Ho Lee*1,2
1Department of Chemistry, College of Natural Sciences, Kangwon National University, Chuncheon 200-701, Korea
2Institute for Molecular Science and Fusion Technology, Kangwon National University, Chuncheon 200-701, Korea
3Analysis Research Division Daegu Center, Korea Basic Science Institute, Daegu 702-701, Korea
(Received May 30, 2011; CL-110459; E-mail: phlee@kangwon.ac.kr)
Pd-Catalyzed carbon-sulfur cross-coupling reactions of aryl
Cl
S
cat. Pd
R
+
(RS)3In
FG
FG
chlorides with indium tris(organothiolates) were developed.
Aryl chlorides reacted with indium tris(organothiolates) (0.35
equiv) in the presence of 4 mol % of Pd(OAc)2, 4.2 mol % of
Xantphos, and Cs2CO3 as an additive, producing aryl-aryl and
aryl-alkyl sulfides in good to excellent yields.
Scheme 1. Pd-Catalyzed C-S cross-coupling reactions of aryl
chlorides with indium tris(organothiolates).
Table 1. Effect of additive and ligand on C-S cross-coupling
reactions
Cross-coupling reaction is one of the most straightforward
and versatile methods in organic synthesis.1 Advances in
transition-metal catalysis make it possible to couple an electro-
philic coupling partner with a nucleophilic coupling partner with
high efficiencies and broad substrate scopes. Especially, the
transition-metal-catalyzed carbon-sulfur cross-coupling reaction
is one of the fundamental processes in organic synthesis because
the sulfide group is widely used in pharmaceuticals, functional
materials, and synthesis of natural products.2 Over the last
decades, transition metals, such as Pd,3 Ni,4 Cu,5 and Fe,6 have
been applied in carbon-sulfur cross-coupling reactions, leading
to the effective synthesis of sulfides. In continuation of our
studies directed toward the development of efficient indium-
mediated organic reactions, we reported Pd-catalyzed cross-
coupling reactions using allylindiums,7 allenylindiums,8 1,3-
butadien-2-ylindiums,9 tetra(organo)indates,10 and vinylindi-
ums11 with a wide range of functional group tolerance.10a,12
Moreover, we developed recently indium tris(organothiolate) as
a nucleophilic cross-coupling partner in Pd-catalyzed C-S cross-
coupling reactions using aryl bromide and iodide as an electro-
phile.13 There is great interest in developing carbon-sulfur cross-
coupling reactions that use aryl chlorides because they are
readily available, inexpensive, and environmentally strategic
reagents.3d,14 Herein, Pd-catalyzed carbon-sulfur cross-coupling
reactions of aryl chlorides with indium tris(organothiolates) are
described (Scheme 1).
4 mol % Pd(OAc)2
ligand, additive
S
Cl
Ph
+ (PhS)3In
DMF, 110 °C, 4 h
(0.35 equiv)
O2N
O2N
1a
2a
3a
Entry Additive (equiv) Liganda (mol %)
Yieldb/%
1
2
3
4
5
6
7
8
9
10
11
12
13
14
DIPEAc (1)
NaI (1)
LiI (1)
LiI (2)
LiBr (1)
LiBr (2)
LiBr (2)
LiBr (2)
LiBr (2)
LiBr (2)
LiBr (2)
Na2CO3 (2)
Cs2CO3 (1)
Cs2CO3 (2)
Xantphos (4.2)
Xantphos (4.2)
Xantphos (4.2)
Xantphos (4.2)
Xantphos (4.2)
Xantphos (4.2)
(Biph)PCy2 (8.2)
Cy3P (8.2)
DPEDIPphos (4.2)
(p-MeO-C6H4)3P (8.2)
(p-CF3-C6H4)3P (8.2)
Xantphos (4.2)
Xantphos (4.2)
Xantphos (4.2)
30
30
52
50
69
75
78
0
81
0
0
0
84
92
aXantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene,
(Biph)PCy2: 2-(dicyclohexylphosphino)biphenyl, DPEDIPphos:
bis(2-diisopropylphosphinophenyl)ether.
cDIPEA: Diisopropylethylamine.
bIsolated
yield.
Although optimum conditions obtained from Pd-catalyzed
C-S cross-coupling reaction of aryl bromide with indium
tris(phenylthiolate) applied to p-chloronitrobenzene (1a),
4-nitrophenyl phenyl sulfide (3a) was produced in 30% yield.13
These results led us to investigate intensively Pd-catalyzed C-S
cross-coupling reaction of aryl chloride with indium tris(organo-
thiolate). First, several additives and ligands were examined and
the results are summarized in Table 1. Use of sodium iodide
gave similar results to DIPEA (Entry 2). Lithium iodide
afforded 3a in moderate yield (Entries 3 and 4), whereas lithium
bromide (2 equiv) increased to 75% yield (Entry 6). Next,
a wide range of ligand in the presence of lithium bromide
(2 equiv) as an additive was examined (Entries 7-11). Although
Cy3P, (p-MeO-C6H4)3P, and (p-CF3-C6H4)3P did not give 3a,
(Biph)PCy2 and DPEDIPphos produced 3a in 78% and 81%
yields, respectively (Entries 7 and 9). Coupling reaction did not
proceed with Na2CO3 as an additive (Entry 12). However, use
of Cs2CO3 (2 equiv) with 4 mol % Pd(OAc)2 and 4.2 mol %
Xantphos in DMF (110 °C, 4 h) provided 3a in 92% yield
(Entry 14). It is noteworthy that (PhS)3In (0.35 equiv) gave the
best result, indicating that all phenylthiolate groups attached to
indium were transferred to 1a with high atom efficiency.
To demonstrate the efficiency and scope of the present
method, we applied this catalytic system to various functional-
ized aryl chlorides 1 with indium tris(organothiolate) 2
containing aryl and alkyl groups and the results are summarized
in Table 2. Reaction of 1a with indium tris(isopropylthiolate)
(2b) gave isopropyl 4-nitrophenyl sulfide (3b) in 71% yield
(Entry 1). Although treatment of 4-chloroacetophenone having
labile ketone group with indium tris(phenylthiolate) (2a)
Chem. Lett. 2011, 40, 980-982
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

981
Table 2. Pd-Catalyzed C-S cross-coupling reactions of aryl
chlorides with indium tris(organothiolates)
in the reaction of 1i with 2c and 2a (Entries 16 and 17). We
believe that DIPEA as a base might trap indium chloride and
then, yield of sulfide increase (Entry 15 vs. 16 and Entry 18 vs.
19). We were pleased to obtain tert-butyl and 4-methoxyphenyl
2-pyrimidinyl sulfide (3q and 3r) from the treatment of
2-chloropyrimidine (1j) with indium tris(organothiolate) 2c
and 2d under the optimum reaction conditions (Entries 18 and
20). Moreover, subjecting 1j to 2c with DIPEA afforded 3q in
91% yield (Entry 19). The present reaction did not proceed
without Pd catalyst, indicating that the reaction occurred through
cross-coupling reaction. However, chlorobenzene and aryl
halide having electron-donating groups such as methyl and
methoxy did not give sulfide under the present conditions
(Entry 14).
Although thiols in transition-metal-catalyzed cross-coupling
reactions were directly used as a nucleophilic coupling partner,
functional group tolerance is not so good sometimes. However,
the present reaction proceeded smoothly to provide the desired
sulfide in good yield regardless of the presence of labile
ethoxycarbonyl and formyl groups. Electrophilic coupling
partners have only stable functional groups such as methyl,
methoxy, fluoride, amino, nitro, and hydroxy.15 For control
experiment, reaction of chlorobenzaldehyde and ethyl 4-chloro-
benzoate with benzenethiol using KOH/DMSO at 130 °C was
carried out, providing the corresponding sulfide in low yield.
In summary, we have developed Pd-catalyzed carbon-sulfur
cross-coupling reactions of aryl chlorides with indium tris-
(organothiolates). Aryl chlorides having an electron-withdraw-
ing group such as formyl, acetyl, ethoxycarbonyl, and nitro, and
nitrogen heteroaryl chlorides reacted with indium tris(organo-
thiolates) (0.35 equiv) in the presence of 4 mol % of Pd(OAc)2,
4.2 mol % of Xantphos, and Cs2CO3 as an additive, producing
aryl-aryl and aryl-alkyl sulfides.16
4 mol % Pd(OAc)2
4.2 mol % Xantphos
Cl
S
R
+
(RS)3In
FG
FG
Cs2CO3 (2 equiv)
DMF, 110 °C
(0.35 equiv)
1
2
3
Entry
1
Aryl chloride
Cl
R
Sulfide Time/h Yielda/%
1a
1b
iso-Pr (2b)
3b
3
71
O2N
Ac
Cl
Cl
2
3
tert-Bu (2c)
Ph (2a)
3c
3d
2
3
70
88
4
5
6
2a
3e
3f
4
4
4
53
52
55
1c
p-Anisyl (2d)
p-Tolyl (2e)
EtO2C
OHC
3g
Cl
7
8
2c
2a
3h
3i
2
4
82
89
1d
1e
CHO
Cl
9
2a
3j
4
19
Cl
10
11
2c
2a
3k
3l
4
4
81
86
1f
OHC
NC
Cl
12
13
2c
2a
3m
3n
2
4
42
1g
25 (50)b
Cl
1h
1i
14
⎯
2d
15
0
15
16
17
N
2c
2c
2a
3o
3o
3p
2
2
2
39
78c
97c
N
Cl
Cl
This work was supported by the CRI Program (No. 2011-
0009011) funded by the National Research Foundation of Korea
(NRF), by NRF grant funded by the Korea government (MEST)
(No. 2009-0087013), and by the second phase of the Brain
Korea 21 Program in 2009. The NMR data were obtained from
the central instrumental facility in KNU.
18
19
20
2c
2c
3q
3q
2
2
86
N
91c
1j
N
2d
3r
2
65
b
c
aIsolated yield. Recovery yield of starting material. DIPEA
(1 equiv) was used.
This paper is in celebration of the 2010 Nobel Prize
awarded to Professors Richard F. Heck, Akira Suzuki, and
Ei-ichi Negishi.
provided the corresponding sulfide 3d in 88% yield, indium
tris(tert-butylthiolate) (2c) gave somewhat lower yield (70%)
due to steric hindrance (Entries 2 and 3). However, ethyl
4-chlorobenzoate reacted with a variety of indium tris(aryl-
thiolate) (2a, 2d, and 2e) afforded sulfides in 52-55% yields
using Cs2CO3 (2 equiv) (Entries 4, 5, and 6). Both 2- and
4-chlorobenzaldehyde (1d and 1f) reacted with 0.35 equivalent
of 2c and 2a, producing the desired sulfides in excellent yields
(81-89%), indicating that all of the thiolate groups were
transferred from indium to 1d and 1f with high atom efficiency
(Entries 7, 8, 10, and 11). Unfortunately, 3-chlorobenzaldehyde
(1e) provided the sulfide in 19% yield (Entry 9). Reaction of
3-chlorobenzonitrile (1g) with 2c gave tert-butyl 3-cyanophenyl
sulfide (3m) in 42% yield (Entry 12). Exposure of 2-chloropyr-
azine (1i) to 2c with Cs2CO3 produced tert-butyl 2-pyrazolyl
sulfide (3o) in 39% yield (Entry 15). However, use of DIPEA as
an additive gave 3o and 3p in 78% and 97% yield, respectively,
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