Copper and amine free Sonogashira cross-coupling reaction catalyzed by efficient diphosphane-palladium catalyst

Article abstract of DOI:10.1016/j.cclet.2011.05.014

The commercially available diphosphane ligand MeO-BIPHEP was first investigated in the palladium-catalyzed Sonogashira reaction in the absence of copper and amine. The coupling of various aryl bromides and aryl chlorides with phenylacetylene gave moderate

Full text of DOI:10.1016/j.cclet.2011.05.014

Available online at www.sciencedirect.com
Chinese Chemical Letters 22 (2011) 1175–1178
www.elsevier.com/locate/cclet
Copper and amine free Sonogashira cross-coupling reaction
catalyzed by efficient diphosphane–palladium catalyst
a
Ting He , Lei Lei Wu , Xing Li Fu , Hai Yan Fu , Hua Chen , Rui Xiang Li
a
b
a
a,
a
*
a
Key lab of Green Chemistry and Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, China
b
Guangxi Vocational & Technical Institute of Industry, Nanning 530001, China
Received 17 February 2011
Available online 18 July 2011
Abstract
The commercially available diphosphane ligand MeO-BIPHEP was first investigated in the palladium-catalyzed Sonogashira
reaction in the absence of copper and amine. The coupling of various aryl bromides and aryl chlorides with phenylacetylene gave
moderate to excellent yields.
#
2011 Hua Chen. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: MeO-BIPHEP; Sonogashira reaction; Diphosphane ligand; Palladium complex
The Sonogashira reaction of aryl halides with terminal alkynes is an important tool in the synthesis of organic
intermediates, which are mostly encountered within natural products, pharmaceutical products, and molecular materials
[1]. This reaction was first reported in 1975, and catalyzed by (Ph P) PdCl together with CuI as co-catalyst [2]. In recent
3 2 2
years, various modifications have been improved, including the elimination of CuI, which usually caused the formation of
oxidative homocoupling products of terminal alkynes [3], and palladium free catalyst system is also possible [4]. By now,
several catalytic systems [5–8] have been reported, and it is undeniable that the most effective catalysts are still palladium–
phosphane complexes. For example, phosphanes P(tBu ) [9], PCy [10], (1-Ad) PBn (1-Ad = 1-adamantyl) [11], X-Phos
3
3
2
[12] have been successfully applied in this reaction. On the other hand, multidentate phosphane ligands were also reported
to improve the stability ofcatalysts appliedin the Sonogashira reaction. For instance,tedicyp [13] was a successful example
even in low palladium loading. However, only a few multidentate ligands (di-, tri-, tetradentate or more) have been tested.
In continuation of our work on transition metal diphosphane complexes as catalysts [14], herein is reported a
commercially available diphosphane ligand MeO-BIPHEP (Scheme 1) employed in the palladium catalyzed
Sonogashira reaction in the absence of copper and amine.
1
. Experimental
Unless especially indicated, all experiments were performed under argon atmosphere. All reactants were reagent
1
13
grade and used as purchased without further purification. Solvents were distilled before use. H NMR and C NMR
spectra were recorded on Bruker AV II-400 MHz in CDCl or DMSO-d .
3
6
*
Corresponding author.
E-mail address: scuhchen@163.com (H. Chen).
1001-8417/$ – see front matter # 2011 Hua Chen. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2011.05.014

1176
T. He et al. / Chinese Chemical Letters 22 (2011) 1175–1178
MeO
MeO
PPh2
PPh2
Scheme 1. MeO-BIPHEP.
An oven-dried Schlenk tube equipped with a stir bar was charged with PdCl (0.9 mg, 0.005 mmol), MeO-BIPHEP
2
(
4.3 mg, 0.01 mmol), aryl halide (0.5 mmol), alkyne (0.7 mmol), K CO (138 mg, 1 mmol) and degassed DMF
2 3
(
2 mL). After stirring for 30 min at room temperature under argon atmosphere, the mixture was heated up until the
reaction was completed. The mixture was then quenched with water and extracted with 4 Â 5 mL EtOAc. The
combined organic phase was dried over anhydrous MgSO . After filtration, the filtrate was concentrated to dryness.
4
The desired product was isolated from the residue by column chromatography using hexane as eluent. The physical
and spectral data of all compounds were identical to those previously reported.
2
. Results and discussion
During the optimization studies, the effect of solvents on the Sonogashira reaction of bromobenzene with
phenylacetylene catalyzed by PdCl /MeO-BIPHEP was first investigated in the presence of Et N. As shown in Table 1,
2
3
polar solvents were more appropriate than nonpolar ones. There was no product to be detected using THF or toluene as
solvent (Table 1, entries1 and 2). Moderate yields were obtained in polar solvents (Table 1, entries 3 and 4) in 4 h. Ayield
of86%wasgainedwhenthereactiontimewasextendedto24 hinDMF(Table1, entry5). Whenthereactiontemperature
was increased to 130 8C, theyield was also increased (Table 1, entry 6). Then, K CO was tested instead of Et N (Table 1,
2
3
3
entries 7–10). Inspiringly, a good yield of 92% was given in DMF in 4 h (Table 1, entry 8). Ayield of 80% was detected
when the reaction temperature dropped from 130 8C to 120 8C (Table 1, entry 10). Other inorganic bases like NaOH and
Na CO (Table 1, entries 11 and 12) were less efficient than K CO . Thus, in the following experiments, copper free
2
3
2
3
Sonogashira reaction catalyzed by PdCl /MeO-BIPHEP was investigated using K CO as the base in DMF.
3
2
2
Table 1
Effect of reaction conditions on the cross-coupling of bromobenzene with phenylacetylene.
Entry
Solvent
Base
Temp. (8C)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
THF
Et
Et
Et
Et
Et
Et
3
3
3
3
3
3
N
N
N
N
N
N
80
90
4
4
Trace
Trace
44
Toluene
n-BuOH
DMF
90
4
90
4
30
DMF
90
24
4
86
DMF
130
100
130
130
120
130
130
130
76
n-BuOH
DMF
K
K
K
K
2
CO
CO
CO
CO
3
3
3
4
71
2
2
2
4
92
DMF
8
98
1
1
1
1
0
1
2
3
DMF
3
4
80
DMF
Na
2
CO
3
4
44
DMF
NaOH
CO
4
27
a
DMF
K
2
3
4
5
2 3
Reaction conditions: bromobenzene (0.5 mmol); phenylacetylene (0.7 mmol); PdCl (1% equiv.); MeO-BIPHEP (2% equiv.); solvent (2 mL); Et N
(
1.5 equiv.); inorganic base (2.0 equiv.); argon protected; GC yield.
a
Ligand free.

T. He et al. / Chinese Chemical Letters 22 (2011) 1175–1178
1177
Table 2
Coupling of aryl halides with phenylacetylene.
.
Entry
ArX
[L]/[Pd]
Time (h)
Yield (%)
Entry
13
ArX
[L]/[Pd]
2
Time (h)
20
Yield (%)
81
1
2
3
4
5
6
7
8
9
4-BrC
2-BrC
2-BrC
3-BrC
4-BrC
4-BrC
3-BrC
4-BrC
2-BrC
2-BrC
4-BrC
4-BrC
6
6
6
6
6
6
6
6
6
6
6
6
H
4
H
4
H
4
H
4
H
4
H
4
H
4
H
4
H
4
H
4
H
4
H
4
Me
2
1
2
2
2
2
2
2
2
1
2
2
20
4
97
96
96
98
97
96
92
96
20
88
95
97
3, 5-Ditrifluoromethyl
-Bromobenzene
Me
Me
20
20
20
12
12
8
14
15
16
17
18
19
20
21
22
23
4-BrC
6
H
4
COOH
2
2
2
2
2
2
1
2
2
2
20
20
20
24
24
24
24
24
24
24
98
96
72
82
71
9
OMe
OMe
COMe
COMe
CN
3-Bromoquinoline
5-Bromopyrimidine
4-ClC
3-ClC
2-ClC
2-ClC
4-ClC
4-ClC
4-ClC
6
6
6
6
6
6
6
H
H
H
H
H
H
H
4
4
4
4
4
4
4
NO
NO
NO
NO
2
2
2
2
NO
NO
NO
2
2
2
20
20
8
70
60
78
50
1
1
1
0
1
2
COMe
CN
CF
3
20
CF
3
2 2 3
Reaction conditions: aryl halides (0.5 mmol); phenylacetylene (0.7 mmol); PdCl (1% equiv.); K CO (2 equiv.); DMF (2 mL); 130 8C; argon
protected; isolated yield; average of two runs; [L]/[Pd] = [MeO-BIPHEP]/[PdCl ].
2
Based on the optimal conditions obtained, various substrates were then examined. As shown in Table 2, both
activated and unactivated aryl bromides gave the desired products in good to excellent yields, even with crowded
ortho-substituted substrates. For example, 88% yield was obtained for 1-bromo-2-nitrobenzene (Table 2, entry 10).
And for more hindered substrate 3, 5-ditrifluoromethylbromo-benzene, the reaction still gave a good yield of 81%
(
Table 2, entry 13). In addition, the reaction of heteroaromatic bromides such as 3-bromoquinoline and 5-
bromopyrimidine also gave desired products in good yields of 96% and 72% (Table 2, entries 15 and 16). As far as we
know, this was the first successful example in the Sonogashira reaction of heteroaromatic bromides catalyzed by
palladium–diphosphane complex [15,16]. Entries of 17–23 represented the coupling of aryl chlorides with
phenylacetylene could also work well in the presence of PdCl /MeO-BIPHEP. Ayield of 82% was obtained in the case
2
of p-chloronitrobenzene (Table 2, entry 17). Other activated aryl chlorides still gave moderate yields, which was
significantly improved than previously reported palladium–diphosphane catalyst [16]. However, the coupling of
unactivated aryl chlorides in this system is still a challenging topic.
Interesting phenomena were observed in the reaction of ortho-substituted aryl halides. At first, unsatisfied results
were obtained with o-bromonitrobenzene (Table 2, entry 9). According to the mechanism of palladium catalyzed
Sonogashira reaction [3], the oxidative addition of aryl halides to the palladium complex here might be blocked
because of the steric hindrance of ortho-substituted groups. Thus the ratio of MeO-BIPHEP was reduced to 1% equiv.
in order to accelerate the oxidative addition of aryl halides on Pd active species. To our expectation, the reaction of o-
bromonitrobenzene with phenylacetylene (Table 2, entry 10) was significantly accelerated. In addition, a better yield
of o-bromotoluene (Table 2, entry 2) and o-chloronitrobenzene (Table 2, entry 20) were also obtained in the presence
of 1% equiv. of MeO-BIPHEP. However, the activity of the catalyst under this condition obviously decreased in the
case of meta- and para-substituted aryl halides (not shown). We suppose that in the reaction of ortho-substituted aryl
halides, steric hindrance is a main influence factor; therefore the reaction rate is effectively improved by the decrease
of ligand. In the case of meta- and para-substituted aryl halides, the stability of catalyst complex is more important,
thus the ratio of PdCl /MeO-BIPHEP is adjusted to 1/2 to maintain the stability of catalyst.
2
3
. Conclusions
In summary, an efficient catalytic system of PdCl /MeO-BIPHEP was developed for the copper and amine free
2
Sonogashira reaction. A number of aryl bromides, heteroaryl bromides and aryl chlorides with phenylacetylene were
carried out efficiently to afford the desired products in moderate to excellent yields. Various functional groups were

1178
T. He et al. / Chinese Chemical Letters 22 (2011) 1175–1178
tolerated under these conditions. Further efforts on the application of this catalyst system in organic synthesis are
underway in our laboratory.
Acknowledgment
We thank Analytical and Testing Center of Sichuan University for the support of characterization.
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