A Simple and Efficient Palladium Catalyst of Nitrogen-Based Ligand for Cu(I)- and Amine-Free Sonogashira Reaction

Article abstract of DOI:10.1080/00397911.2014.989446

Glycine, as a kind of commercially available and inexpensive ligand, is used to prepare an air-stable and water-soluble catalyst used in Sonogashira reaction in our study. In the presence of 1% [PdCl₂(NH₂CH₂COOH)₂

Full text of DOI:10.1080/00397911.2014.989446

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A Simple and Efficient Palladium Catalyst of Nitrogen-
Based Ligand for Cu(I)- and Amine- Free Sonogashira
Reaction
ab
ab
a
a
a
a
Meng-Ping Guo , Shi-Wen Liu , San-Bao Chen , Yong-Ju Wen , Hui Liang & Mei-Yun Lv
a
Institue of Coordination Catalysis, College of Chemistry and Bio-Engineering, Yichun
University, Yichun, China
b
Engineering Center of Jiangxi University for Lithium Energy, Yichun University, Yichun,
China
Accepted author version posted online: 06 Dec 2014.
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To cite this article: Meng-Ping Guo, Shi-Wen Liu, San-Bao Chen, Yong-Ju Wen, Hui Liang & Mei-Yun Lv (2014): A
Simple and Efficient Palladium Catalyst of Nitrogen-Based Ligand for Cu(I)- and Amine- Free Sonogashira Reaction,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, DOI:
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A Simple and Efficient Palladium Catalyst of Nitrogen-based Ligand for Cu(I)- and
Amine- Free Sonogashira Reaction
1
,2
1,2
1
1
1
Meng-Ping Guo , Shi-Wen Liu , San-Bao Chen , Yong-Ju Wen , Hui Liang , Mei-Yun
1
Lv
1
Institue of Coordination Catalysis, College of Chemistry and Bio-Engineering, Yichun
2
University, Yichun, China, Engineering Center of Jiangxi University for Lithium Energy,
Yichun University, Yichun, China
Institue of Coordination Catalysis, College of Chemistry and Bio-Engineering, Yichun
University, Yichun 336000, China. E-mail: guomengping65@163.com
Abstract
Glycine, as a kind of commercially available and inexpensive ligand, is used to prepare
an air-stable and water-soluble catalyst used in Sonogashira reaction in our study. In the
presence of 1% [PdCl (NH CH COOH) ] as catalyst, excellent catalytic activity towards
2
2
2
2
the Sonogashira coupling of aryl iodides with terminal alkynes without using any additive
such as Cu(I)-cocatalyst is observed in a mixture of water and acetone (3mL:3mL) under
air at 60°C with NaOH as a base, giving products in good to excellent yields.
KEYWORDS: Catalysis; palladium complex; Sonogashira reaction; strategy
INTRODUCTION
1

The synthesis of alkynyl compounds has attracted considerable interest because of their
appearance in many biologically active natural products (such as panaxynol, panaxydol,
[
1]
panaxytriol showing certain anti-cancer effects ) and being as key intermediates of
[
2–3]
pharmaceuticals or drug-like molecules
and even being as monomers of polymer
[
4–5]
[6–7]
materials , liquid crystal material , showing great application perspective and
considerable economic value in the field of medicine, organic synthesis and materials
chemistry. Thus, much attention has been focused on the development of efficient and
selective methods for the synthesis of alkynes.
Easily, transition-metal-catalyzed cross-coupling reactions can be considered as
cornerstones in organic synthesis for the formation of carbon-carbon bonds. In these
reactions, the coupling of aryl or alkenyl halides with terminal alkynes catalyzed by
palladium in the presence of Cu(I) co-catalyst or not, commonly known as Sonogashira
2
cross-coupling reaction, is one of the most powerful methods for straightforward sp -sp
carbon-carbon bond formation reaction to prepare arylalkynes and conjugated enynes
[
8–9]
[10–11]
encountered frequently in natural products , bioactive molecules
, molecular
. Therefore, considerable
effort has been directed to the development of new and efficient palladium catalytic
[
12–13]
[14–15]
electronics
, dendrimeric and polymeric materials
[
16–21]
systems for Sonogashira cross-coupling reaction
. Generally, the Sonogashira
reaction is performed with palladium-phosphane ligand complex, such as Pd(PPh ) Cl ,
3
2
2
Pd(dppe)Cl and Pd(dppf)Cl , in the presence of Cu(I) salt as co-catalyst and an amine as
2
2
a solvent, such as triethylamine under homogeneous conditions. But when these
palladium species are employed, it often requires high loading of palladium (usually up to
2

5
mol %) and a larger amount of the Cu(I) salt. Additionally, many phosphine ligands are
air-sensitive and not environmentally friendly, significantly limiting their synthetic
[
22–23]
applications
. Besides, the presence of Cu(I) salt can result in the formation of
[
24]
oxidative homocoupling reaction of alkynes . In the past decades, although significant
[25]
developments from the original palladium-phosphorus complexes to palladium-P,N or
[26]
[27 ]
palladium-P,O complexes , palladium-nitrogen complexes and N-Heterocyclic
[28]
[29]
Carbene palladium complexes , palladacycle patalysts , even the use of ligand-free
[
30]
palladium catalysts , have been achieved towards the Sonogashira reaction with
[
31 34]
–
moderate to high yields
, most systems still require high reaction temperatures in
organic solvents under an inert atmosphere and even need the presence of Cu(I) salt and
an amine as solvent. Therefore, to explore a more active catalyst for simpler, milder and
more effective reaction conditions with the Cu(I)-, amine- and phosphine-free catalytic
system becomes more significant and challenging for chemistry researchers.
Taking stability and safety into consideration and from an economic and environmental
viewpoint, recently we selected glycine as water-soluble nitrogen-based ligand to
synthesize a catalyst with palladium chloride and found that glycine was a highly
efficient ligand for the palladium catalyzed Suzuki–Miyaura cross-coupling reaction
[
35–36]
giving excellent yields for aryl bromides and moderate for aryl chlorides
so that we
expected to extend the use of this catalyst to other palladium-catalyzed transformations.
In this paper, we report a highly efficient [PdCl (NH CH COOH) ]-catalyzed
2
2
2
2
Sonogashira cross-coupling reaction of aryl halides with terminal alkynes to form internal
alkynes. In our studies, [PdCl (NH CH COOH) ], as a catalyst for the Sonogashira
2
2
2
2
3

[
37 39]
–
coupling reaction, has several advantages compared with those reported
. Firstly, the
ligand of the catalyst is glycine which possesses lots of properties, such as solubility,
stability and safety. Because of the properties of the ligand, the catalyst is also water-
soluble, stable and safe, which provides the possibility of catalyzing Sonogashira reaction
in water under air. Secondly, synthesis of the catalyst is extremely easy and it is obtained
only by stirring glycine with palladium chloride (PdCl ) in ethanol and acetic acid for 24
2
hours at room temperature under air. Thirdly, from an economic point of view, glycine is
commercially available and inexpensive, which creates feasible condition for industrial
production. Finally, the catalyst shows high efficiency to Sonogashira reaction in a
mixture of water and acetone (3mL:3mL) under air at 60°C with 1% catalyst and NaOH
as a base in 2 hours with the Cu-, amine- and phosphine-free catalytic system, giving
products in moderate to good yields.
RESULTS AND DISCUSSION
Optimization Of The Coupling Reaction Conditions
Initially, moderate yield (Table 1, entry 1-2) was observed when iodobenzene and phenyl
acetylene were selected to test the activity of the catalyst in a mixture of water and
ethanol or PEG-400 under air at 60°C with NaOH (2.0mmol) as a base for 2h. Thus, the
two compounds were chosen to establish guidelines for the optimization of our protocol
as the model reaction. Because of good solubility of the catalyst in water, we continued to
explore solvent system consisted of water and another organic solvent. As shown in Table
1
3
, when 1,4-dioxane or THF was selected to be as mix solvent with water (Table 1, entry
-4), low yield was observed. However, relatively high yield (Table 1, entry 5) was
4

observed when acetone was chosen as solvent with water in the proportion of 3mL:3mL.
Next, different proportions of acetone and water were studied but the reaction was not
performed well under other proportions (Table 1, entry 6-9) so that the mix solvent of
water and acetone(3mL:3mL) was found to be the best reaction solvent.
After the best reaction solvent was found, other reaction conditions, such as reaction
temperature or time, were studied in detail. Results of this preliminary survey are shown
in Table 2. As shown in Table 2, when the effect of the amount of the catalyst on the
coupling reaction was studied, from the results, we could see that lowering the amount of
Pd from 2% mol to 1% mol did not affect the reaction performance (Table 2, entry 4-5).
When the amount of the catalyst was reduced to 0.5%, it gave products in moderate
yield(Table 2, entry 3) and When being reduced to 0.1%, the coupling reaction could
hardly be performed (Table 2, entry 1-2). So, 1% mol catalyst was optimal for the system.
Next, we found that reaction temperature had also an important role on the coupling
reaction. Increasing the reaction temperature from 30℃to 60℃(Table 2, entry 6-8), the
yield also increased remarkably. It was worth noting that low yield (34%) was obtained
when reaction temperature was up to 80℃(Table 2, entry 9), indicating that high
temperature was not suitable for the proceeding of the reaction under this system. In
addition, prolonging the reaction time from 0.5h to 2h (Table 2, entry 10-12), the yield
increased from 86% to 93%. To further optimize the reaction condition, with the amount
of catalyst fixed as 1% mol, the reaction proceeded well when inorganic base NaOH was
used, affording the desired coupling product in excellent yield (Table 2, entry 12) under
air at 60°C for 2h. However, NEt and K PO used in this reaction gave moderate yield
3
3
4
5

(Table 2, entry 13-14). In contrast, K CO and Pyridine slightly promoted the reaction
2 3
(Table 2, entry 15-16) and organic base 1,2-propanediamine scarcely promoted the
reaction (Table 2, entry 17).
Scope And Limitations Of The Substrates
To further investigate the scope and limitations of this methodology, we carried out cross-
couplings of different aryl halides including electron-neutral, electron-rich and electron-
poor aryl iodides with various terminal alkynes under optimized conditions. As shown in
Table 3, although all the aryl iodides could couple smoothly with various terminal
alkynes under the optimized reaction condition, aryl iodides with electron-donating
groups such as 4-iodoanisole (Table 3, entry 12-15), gave moderate yields (70-79%) in 2
hours, showing slightly low reactivity. In contrast, aryl iodides with electron-withdrawing
groups such as 4-fluoroiodobenzene (Table 3, entry 9-11), gave good yields (78%-88%)
under the same reaction condition, showing slightly high reactivity. Additionally,
electron-neutral aryl iodides such as iodobenzene or 4-iodotoluene coupling with terminal
alkynes also gave desired products in moderate to good yields (Table 3, entry 1-8). On
the other hand, the terminal alkynes also have a significant effect on the coupling reaction.
As shown in Table 3, the reaction of phenylacetylene, 1-hexyne, 3-butyn-1-ol with aryl
halides gave the superior yields of the products to 3,3-dimethyl-1-butyne, indicating that
terminal alkynes with steric hindrance, such as 3,3-dimethyl-1-butyne, gave products in
moderate yields, significantly being lower than the 1-hexyne or 3-butyn-1-ol without
steric hindrance. Moreover, the relatively low activity was obtained when aryl bromides
coupling with various terminal alkynes.
6

Possible Mechanism Of The Catalyst For Sonogashira Reaction
The mechanism of the copper-free Sonogashira reaction is still not well-known.
The possible mechanism is as follow. The first step would be the oxidative addition of
aryl halides to the palladium(0) complex. However, the second step is under debate. The
base employed is usually hard to deprotonate the alkyne for the reaction with the
oxidative addition palladium(0) complex(trans-R PdXL ) so that complexation of the
1
2
alkyne to the complex is supposed to proceed first with displacement of one ligand to
give intermediate complex(RCCH)-PdXL . The ligated alkyne would be more easily
2
deprotonated by base such as NaOH used in the reaction, forming the new complex
R Pd-(CCR )L , which gives the coupling product R -CC-R by reductive elimination.
1
2
2
1
2
Reagents And Machines
All reagents employed in the reaction were analytical grade, obtained commercially from
1
13
J&K China Chemical ltd and used without further purification. H and C NMR spectra
was recorded on a Bruker Avance III (400MHz) spectrometer using tetramethylsilane as
the internal standard and CDCl as the solvent. Elemental analyses (C, H, N) were carried
3
out on a Perkin Elmer model 240 C automatic instrument. Electrospray mass spectra (ES-
MS) were recorded on a Finnigan LCQ mass spectrometer.
Synthesis Of The Catalyst
A mixture of glycine (10.2mmol, 0.765g), palladium chloride (5.0mmol,0.886g), ethanol
(30mL) and acetic acid(5mL) was stirred at room temperature under air for 24h in a
round-bottomed flask. After 24h, large amounts of light brown precipitate emerged in
7

the solution. Then, the precipitate was filtered and washed with ethanol. Lastly, a light
brown compound was obtained after dried by vacuum. On the basis of elemental analysis,
the complex was found to have the composition of C (14.90%), H (3.10%), N (8.56%);
ESI-MS(m/z): 326.8[M+1]. Yield: 0.93g, 57%.
Recovery And Recycling Of The Catalyst
The palladium catalyst can be easily recovered by simple extraction. Because the
catalyst is water-soluble and reaction solvent is consisted of water and acetone so that the
catalyst can be separated from products and recovered by simple extraction. In addition,
The catalyst used in the reaction is recyclable really. But the catalytic efficiency is
decreasing gradually with recyclable time increasing from 93% initially to 53% lastly.
From Table 4, the recycling of catalyst was investigated using iodobenzene and phenyl
acetylene as model substrates. We can see that the efficiency of catalyst’ recycling
decreasing apparently, even prolonging the reaction time.
General Procedure For The Synthesis
The aryl halides (1.0 mmol), terminal alkynes (1.2 mmol), catalyst (1% mol, 0.003268g),
NaOH (2.0 mmol, 0.08g), water/acetone (3mL:3mL) were added to a flask and stirred
under air at 60°C for 2 hours. Then, the 5mL brine was added to quench the reaction and
the mixture was extracted with ethyl acetate (3×15 ml). The combined organic phase was
dried with Na SO for 3 hours. Next, the organic phase was filtrated and removed on a
2
4
rotary evaporator. Finally, the products was isolated by thin layer chromatography and the
1
13
purified products were identified by H and C NMR.
8

CONCLUSION
In summary, in the present letter it has been shown that the use of
[
PdCl (NH CH COOH) ] as catalysts in a mixture of water and acetone (3mL:3mL)
2 2 2 2
under air at 60°C with NaOH as a base is a very convenient way to carry out Sonogashira
coupling reaction with the Co-, amine- and phosphine-free catalytic system, which gives
an extremely fast, highly efficient and much more green approach to obtain alkynyl
compounds found easily in natural products, bioactive molecules, dendrimeric and
polymeric materials, demonstrating great industrial application perspective and
considerable economic value in the field of medicine, organic synthesis and material
chemistry.
ACKNOWLEDGMENTS
We are grateful to the Scientific Research Fund of Jiangxi Provincial Education
Department (No. 10703) for financial support.
SUPPORTING INFORMATION
Supplemental data for this article can be accessed on the publisher’s website.
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1

Table 1. Optimization of the reaction solvent
a
Entry
water/organic solvent
Yield (%)
1
2
3
4
Water/ethanol(3mL:3mL)
Water/PEG-400(3mL:3mL)
Water/THF(3mL:3mL)
55
74
44
30
Water/1,4-dioxane(3mL:3mL)
5
6
7
8
9
Water/acetone(3mL:3mL)
Water/acetone(0mL:6mL)
Water/acetone(2mL:4mL)
Water/acetone(4mL:2mL)
93
37
34
48
50
Water/acetone(6mL:0mL)
a
Reaction condition: Isolate yield was based on aryl halides.
1
2

Table 2. Optimization of the other reaction conditions
Entry
Catalyst (mol%) Bases (2.0mmol) Time (h)
Temperatur Yield (%)
e(℃)
1
2
3
4
5
6
7
8
9
0.05
0.1
0.5
1
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
1
60
60
60
60
60
30
45
60
80
60
60
60
60
60
60
60
60
0
13
75
86
88
44
61
86
34
86
89
93
55
56
15
11
trace
2
1
1
1
1
1
0
1
11
1
1
1
1
1
1
1
2
3
4
5
6
7
1
2
1
K PO4
3
2
1
NEt3
2
1
K CO3
2
2
1
pyridine
2
1
1,2-
2
propanediamine
1
3

Table 3. Sonogashira reaction under optimized conditions
Entry
Aryl halides
Terminal alkynes
Products
Yield (%)
0
1
9
3
7
Ph
I
I
0
2
8
0
0
3
4
7
8
2
I
I
OH
OH
9
0
0
5
6
8
5
4
Ph
I
I
8
0
0
0
7
8
9
7
0
5
I
I
I
OH
OH
9
F
88
F
Ph
1
4

1
1
0
1
F
F
85
78
I
I
F
F
1
1
2
3
OMe
OMe
78
79
MeO
Ph
I
I
MeO
MeO
1
1
4
5
OMe
OMe
70
81
I
I
OH
O
MeO
1
1
1
6
7
8
5
0
3
Ph
Br
5
Ph
Br
Br
OM
42
MeO
Ph
a
Reaction condition: Isolated yield was based on aryl halides.
1
5

Table 4. Recycling of catalyst for Sonogashira reaction of iodobenzene with phenyl
acetylene
Entry
recycle
Time (h)
Isolated yield (%)
1
2
3
4
5
1
2
3
4
5
2
93
77
80
53
14
2
4
16
24
1
6

Scheme 1. Optimization of the reaction solvent
1
7

Scheme 2. Optimization of other reaction conditions
1
8

Scheme 3. Sonogashira reaction under optimized conditions
1
9