Sonogashira coupling catalyzed by the Cu(Xantphos)I–Pd(OAc)2system

Article abstract of DOI:10.1016/j.tetlet.2016.06.014

An efficient Pd(OAc)₂/Cu(Xantphos)I system for Sonogashira coupling is disclosed. Aryl bromides/iodides and electron-poor aryl chlorides were suitable for this reaction. The experimental results suggest that Cu(Xantphos)I plays a unique role in which the phosphine ligand coordinates with copper.

Full text of DOI:10.1016/j.tetlet.2016.06.014

Accepted Manuscript
Sonogashira coupling catalyzed by the Cu(Xantphos)I-Pd(OAc)2 system
Meilin Liu, Mingyan Ye, Yeye Xue, Guodong Yin, Dunjia Wang, Jinkun Huang
PII:
S0040-4039(16)30674-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.06.014
TETL 47741
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
15 April 2016
1 June 2016
3 June 2016
Please cite this article as: Liu, M., Ye, M., Xue, Y., Yin, G., Wang, D., Huang, J., Sonogashira coupling catalyzed
by the Cu(Xantphos)I-Pd(OAc)2 system, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.
2016.06.014
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Tetrahedron Letters
jo u r n a l h o m e p a g e : w w w . e ls e v ie r . c o m
Sonogashira coupling catalyzed by the Cu(Xantphos)I-Pd(OAc)2 system
Meilin Liu, Mingyan Ye, Yeye Xue, Guodong Yin*, Dunjia Wang and Jinkun Huang*
Hubei Collaborative Innovation Center for Rare Metal Chemistry, Hubei Key Laboratory of Pollutant Analysis and Reuse Technology, Hubei Normal University,
Huangshi 435002, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient Pd(OAc)2/Cu(Xantphos)I system for Sonogashira coupling is disclosed. Aryl
bromides/iodides and electron-poor aryl chlorides were suitable for this reaction. The
experimental results suggest that Cu(Xantphos)I plays a unique role in which the phosphine
ligand coordinates with copper.
Available online
Keywords:
Sonogashira coupling
Alkynylation
Co-catalyst
2015 Elsevier Ltd. All rights reserved.
Copper-phosphine ligand complex
novel Pd(OAc)2/Cu(Xantphos)I system for efficient Sonogashira
coupling reaction (Scheme 1, condition b).
1. Introduction
The Sonogashira cross-coupling reaction1,2 between aryl
halides and terminal alkynes has become a valuable and facile
method to prepare substituted alkynes, which are widely
employed in synthesis of numerous natural products,3 bioactive
and pharmaceutical molecules,4 organic materials,5 and
polymers.6 The reaction is typically performed using a palladium
complex as catalyst and copper(I) salt as a co-catalyst under basic
conditions (Scheme 1, condition a). Generally, palladium is
coordinated with a neutral ligand such as phosphines to form the
complex, e.g. Pd(PPh3)2Cl2,7 Pd(dppe)Cl2,8 Pd(OAc)2(PPh3)29 and
Pd(dppp)Cl2.10 Alternatively, chemists have devoted to develop
an impressive variety of effective catalytic palladium system, and
this includes the palladium–nitrogen complexes,11 palladium–
N,O complexes,12 palladium–P,N complexes,13 palladium–P,O
complexes,14 N-heterocyclic carbene (NHC) palladium
complexes,15 palladacycles16 and palladium nanoparticles.17
Although Au(I),18 Ni(II),19 Fe(III),20 Cu(I)21 and Cu(II)22 systems
sometimes could catalyze this coupling reaction, most of these
methods are only effective for aryl iodides or at high temperature.
Recently, Hierso reported the [Pd(allyl)Cl]2/copper(I) ferrocenyl
tetraphosphine complexes system for Sonogashira coupling
reaction at high temperature (120 oC), which was the first
example for the phosphine ligand complexation to copper instead
of palladium.23 Recently, we prepared the copper-phosphine
ligand complex Cu(Xantphos)I and found a highly efficient
palladium/Cu(Xantphos)I co-catalytic system for direct arylation
of heteroarenes. The high efficiency is attributed to the unique
role of Cu(Xantphos)I.24 In this paper, we would like to report a
Scheme 1
2. Results and discussion
On the light of our previous studies in the arylation of
heteroarenes catalyzed by the Pd/Cu(Xantphos)I system,24 we
envisioned that the similar system might be effective for the
Sonogashira coupling. Initially, we investigated the cross-
coupling between 1-bromo-4-methylbenzene (1a) and
phenylacetylene (2a) in the presence of Pd(OAc)2 (1%) and
Cu(Xantphos)I (1%) using Cs2CO3 as base in anhydrous DMF at
room temperature for 24 h, only trace amount of expected
alkynylation product 1-methyl-4-(phenylethynyl)benzene (3a)
was observed (Table 1, entry 1). The yield of 3a significantly
o
increased when the temperature was raised to 40 C (84%, entry
o
2). While the temperature was further elevated to 60 C, 3a was
obtained in nearly quantitative yield (98%, entry 3). After
screening other typical bases, such as Na2CO3, K2CO3,
K3PO4·H2O, NHEt2, NEt3, all of them afforded the yields above
90% except for NEt3 which gave a lower yield of 54% (entries 4–
8). The combination of Cu(Xantphos)I with other palladium
compounds, e.g. PdCl2, [Pd(allyl)Cl]2 and Pd2(dba)3, the yield
was in the range of 38–87% (entries 9–11). When the amount of
Pd(OAc)2 or Cu(Xantphos)I was reduced to 0.5% and 0.25%, the
coupling resulted in a corresponding lower yield (entries 12–15).
———
*Corresponding author. Tel./fax: +86 0714 6515602; e-mail address: gdyin@hbnu.edu.cn (G. Yin); jxhcm99@qq.com (J. Huang)

2
Next, we were pleased to find that at room temperature, aryl
iodides bearing electron-rich or electron-poor groups on the
phenyl ring could afford a nearly quantitative yield of 3b, 3c and
3l (entries 32–34). Notably, the reactions for electron-poor
(COCH3, CN, CF3) arylchlorides proceed smoothly and gave the
corresponding products 3a, 3h and 3j in good yields (entries 36–
38). However, this novel Pd/Cu co-catalyzed system was so far
ineffective for less reactive aryl chlorides. Only 20% GC yield of
Meanwhile, the reaction didn’t give the product in the absence
of the Pd(OAc)2 (entry 16) and was less effective when no
copper(I) salt was employed (entries 17 and 19). Replacement of
Cu(Xantphos)I by Cu(PPh3)3Br or Cu(PPh3)3I also furnished 3a
in a lower yield (entries 21, 22). Cu(Xantphos)Br was also
effective for the reaction (entry 23). However, the combination of
Pd(OAc)2 and CuI resulted in almost no reaction (<5%, entry 19).
Obviously, the addition of Cu(Xantphos)I significantly promotes
this coupling reaction (entries 18 and 20).
o
3a was obtained using 1-chloro-4-methylbenzene at 120 C with
high loading of 5% mmol Pd(OAc)2 and Cu(Xantphos)I
respectively (entry 35).
Table 1
Optimization of the reaction conditions for Sonogashira coupling
between 1-bromo-4-methylbenzene and phenylacetylenea
Table 2
Sonogashira reactions of aryl halides and alkynes catalyzed by
Pd(OAc)2/Cu(Xantphos)Ia
Yieldb
(%)
Entry
1c
2
[Pd] (mol%)
[Cu] (mol%)
Cu(Xantphos)Id (1)
Cu(Xantphos)I (1)
Base
Pd(OAc)2 (1)
Pd(OAc)2 (1)
Cs2CO3
Cs2CO3
<5
84
Entry
X
Ar
R
Product
Yieldb
(%)
97
98
96
92
91
85
93
94
84
89
95
94
91
96
92
94
90
92
95
97
94
90
93
89
96
92
93
90
95
92
90
98 (97f,
70g)
90
3e
Pd(OAc)2 (1)
Cu(Xantphos)I (1)
Cs2CO3
1
2
3
4
5
6
7
8
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
I
4-MeC6H4
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
3a
3b
3c
3d
3e
3f
3g
3h
3i
4
5
Pd(OAc)2 (1)
Pd(OAc)2 (1)
Pd(OAc)2 (1)
Cu(Xantphos)I (1)
Cu(Xantphos)I (1)
Cu(Xantphos)I (1)
Na2CO3
K2CO3
K3PO4·
H2O
96
96
4-MeOC6H4
4-N(CH3)2C6H4
4-NH2C6H4
4-OHC6H4
4-CHOC6H4
4-COCH3C6H4
4-COOEtC6H4
4-CNC6H4
4-CF3C6H4
4-NO2C6H4
1-naphthyl
3-furyl
6
7
8
9
Pd(OAc)2 (1)
Pd(OAc)2 (1)
PdCl2 (1)
Cu(Xantphos)I (1)
Cu(Xantphos)I (1)
Cu(Xantphos)I (1)
NHEt2
NEt3
95
54
60
87
38
76
39
93
67
0
<5
66
<5
87
84
80
94
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
10
11
12
13
14i
15i
16
17
18j
19
20j
21
22
23
[Pd(allyl)Cl]2 (1) Cu(Xantphos)I (1)
Pd2(dba)3h (1)
Pd(OAc)2 (0.5)
Pd(OAc)2 (0.25)
Pd(OAc)2 (1)
Pd(OAc)2 (1)
—
Cu(Xantphos)I(1)
Cu(Xantphos)I(1)
Cu(Xantphos)I (1)
Cu(Xantphos)I (0.5)
Cu(Xantphos)I (0.25)
Cu(Xantphos)I (1)
—
—
CuI (1)
CuI (1)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
3j
3k
3l
3m
3n
3o
3p
3q
3c
3r
3k
3s
Pd(OAc)2 (1)
Pd(OAc)2 (1)
Pd(OAc)2 (1)
Pd(OAc)2 (1)
Pd(OAc)2 (1)
Pd(OAc)2 (1)
Pd(OAc)2 (1)
2-thienyl
2-pyridyl
3-pyridyl
Cu(PPh3)3Br (1)
Cu(PPh3)3I (1)
Cu(Xantphos)Br (1)
C6H5
C6H5
C6H5
C6H5
4-MeOC6H4
4-n-C3H7C6H4
4-CF3C6H4
n-C6H13
CH(OH)CH3
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-CF3C6H4
n-C6H13
a All of the reactions were carried out with 1a (1.0 mmol), 2a (1.2 mmol) and
base (2.0 mmol) in anhydrous DMF (5 mL) at 60 oC for 16 h unless otherwise
specified.
C6H5
3t
4-MeOC6H4
4-N(CH3)2C6H4
4-NO2C6H4
1-naphthyl
3-pyridyl
4-COCH3C6H4
4-MeOC6H4
4-CF3C6H4
3-pyridyl
3u
3v
3w
3x
3y
3z
3A
3B
3C
3b
3c
3l
b
Yield was determined by GC or NMR after 16 h based on a purified
standard.
cAt room temperature for 24 h.
d Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.
e At 40 oC for 24 h.
f Isolated yield.
g Toluene was used as the solvent.
h dba = trans, trans-dibenzylideneacetone.
i At 60 oC for 24 h.
n-C6H13
n-C6H13
j 0.01 mmol Xantphos was added.
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
98c
95c
97c
20d
91d
89d
93d
I
I
Cl
Cl
Cl
Cl
4-MeOC6H4
4-NO2C6H4
4-MeC6H4
4-COCH3C6H4
4-CNC6H4
4-CF3C6H4
With the above optimal condition in hand, a variety of
substituted aryl halides were coupled with alkynes, and the
results are shown in Table 2. Excellent yields of 3a–l were
obtained regardless of the reactions using electron-neutral (H),
-rich (-OMe, -N(CH3)2, -NH2, -OH) or -poor (-CHO, -COCH3, -
COOEt, -CN, -CF3, -NO2) aryl bromides with phenylacetylene
(entries 2–12). 1-Bromonaphthalene and heterocyclic bromides
(furyl, thienyl and pyridyl) were also suitable for this reaction,
affording the corresponding products 3m–q in 90–96% isolated
yields (entries 13–17). Electron-rich or electron-poor substituted
phenylacetylenes and aliphatic alkynes also gave 3c, 3k and 3r–t
in excellent yields, respectively (entries 18–22). Furthermore,
under the above disclosed typical conditions, a variety of aryl
bromides and alkynes were coupled to form a structurally diverse
products 3u-z and 3A-C (entries 23–31).
3a
3h
3j
3k
a All of the reactions were carried out with 1 (1.0 mmol), 2 (1.2 mmol),
Pd(OAc)2 (0.01 mmol), Cu(Xantphos)I (0.01 mmol), Cs2CO3 (2.0 mmol) in
anhydrous DMF (5 mL) at 60 oC for 16 h unless otherwise specified.
b Isolated yields.
c At room temperature.
d Pd(OAc)2 (0.05 mmol) and Cu(Xantphos)I (0.05 mmol) were employed at
120 oC for 12 h.
In summary, we have disclosed a mild and efficient
Sonogashira
coupling
reactions
catalyzed
by
the
Pd(OAc)2/Cu(Xantphos)I system. This is an interesting catalytic

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Acknowledgments
We gratefully acknowledge support from the National Natural
Science Foundation of China (21542009) and the Educational
Commission of Hubei Province (D20142501).
Supplementary data
Supplementary data related to this article can be found, in the
online version at:
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Sonogashira coupling catalyzed by the
Cu(Xantphos)I-Pd(OAc)2 system
Leave this area blank for abstract info.
Meilin Liu, Mingyan Ye, Yeye Xue, Guodong Yin*,
Dunjia Wang and Jinkun Huang*
Hubei Collaborative Innovation Center for Rare Metal Chemistry, Hubei Key Laboratory of Pollutant Analysis
and Reuse Technology, Hubei Normal University, Huangshi 435002, China

*Highlights
Research highlights
 A novel Pd(OAc)2/Cu(Xantphos)I system for efficient Sonogashira
coupling reaction is disclosed.
 This is an interesting catalytic system in which the phosphine ligand
coordinates with copper.
 Cu(Xantphos)I plays a unique role in this coupling reaction.