A highly efficient copper and ligand free protocol for the room temperature Sonogashira reaction

Article abstract of DOI:10.1039/c4ra09630d

A mild and efficient catalytic system based on PdCl₂ and Na₂SO₄ has been developed for the Sonogashira reaction of aryl iodides at room temperature. The system provides a simple route to obtain polyfunctional alkynes under ligand and copper free conditions. The procedure is equally efficient for aliphatic alkynes and aryl bromides. This journal is

Full text of DOI:10.1039/c4ra09630d

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A highly efficient copper and ligand free protocol
for the room temperature Sonogashira reaction
Cite this: RSC Adv., 2015, 5, 16
a
a
ab
*
Ankur Gogoi, Anindita Dewan and Utpal Bora
Received 2nd September 2014
Accepted 12th November 2014
DOI: 10.1039/c4ra09630d
www.rsc.org/advances
A mild and efficient catalytic system based on PdCl2 and Na2SO4 has ligands. In addition they also lead to waste disposal which have
been developed for the Sonogashira reaction of aryl iodides at room severe effect on the environment. So regarding the principles of
temperature. The system provides a simple route to obtain poly- Green chemistry it is the necessity to design catalytic system
functional alkynes under ligand and copper free conditions. The using cheap and non toxic reagents under mild reaction
procedure is equally efficient for aliphatic alkynes and aryl bromides. conditions. Thus the development of a protocol under ligand
and copper free condition for Sonogashira reaction is highly
desirable. For many years simple inorganic salts are oen use
are as an activator in different organic transformation.14 The
Introduction
The Pd-catalyzed Sonogashira reaction of a terminal alkyne with
an aryl halide is found to be a reliable tool for the construction
of polyfunctional alkynes, which nd extensive applications
ranging from pharmaceuticals to agrochemicals and in mate-
rials chemistry.1 This method was developed by Sonogashira,
Tohda, and Hagihara in 1975 and since its discovery, various
modications have been made to the reaction conditions.2,3
Initially these reactions were performed in an organic solvent
with the concomitant addition of ligand and a Cu-salt as co-
catalyst.2a Although the addition of copper is advantageous in
terms of reaction efficiency, the formation of undesired Glaser
type homocoupling from the alkyne is one of the major obsta-
cles associated with this reaction.4 So to address this issue
several other additives were used to maintain the reaction effi-
ciency such as Ag,5 Zn,6 Al,7 Sn,7 tetrabutyl ammonium salts8 etc.
On the other hand ligand plays a key role in the Sonogashira
reaction which is generally used to stabilize the active palla-
dium species in the reaction. Among the ligands designed for
this reaction signicant amount of success have been achieved
with phosphine based ligands such as electron rich bulky
phosphanes,9 water soluble phosphanes such as TPPTS and
TXPTS,10 nitrogen based ligands such as N-heterocyclic carbe-
nes,1c,11 oxime palladacycles,12 amines13 etc. Although complex
containing such ligands show excellent reactivity, however in
majority of cases principal drawbacks are the availability,
stability, and cost of the palladium complexes and related
innocuous nature and rate enhancing effect of these salts
makes them a suitable alternate for ligands in the Pd-catalyzed
Suzuki–Miyaura cross coupling reaction.15,16 Recently our group
has reported the efficiency of Na2SO4 as an activator in the
Suzuki–Miyaura cross coupling reaction.16 In order to extend
the scope of this protocol herein we reported the efficiency of
same catalytic species in Sonogashira cross coupling reaction of
aryl iodides with aryl acetylenes at room temperature.
Results and discussion
The enhancing effect of non-toxic salt particles in Suzuki–
Miyaura cross coupling reaction is well known.16 However to the
best of our knowledge; there is no report available on the effect
of non-toxic salt particles in Pd catalysed Sonogashira reaction.
Therefore we wish to study the effect of different metal salts in
the Sonogashira reaction of aryl iodides. For that purpose
iodobenzene (0.5 mmol) and phenyl acetylene (0.6 mmol) was
considered as model substrate. The preliminary investigation
for reaction optimization was performed with 2 mol% of PdCl2
and three equivalent of K2CO3 (1.5 mmol) in MeOH (2 mL) at
room temperature under aerobic condition. The results
obtained are highlighted in Table 1. It was found that MnCl2
has no effect in the cross coupling reaction (Table 1, entry 1).
The yield of cross coupling product was slightly increased when
ZnCl2 was used as an additive (Table 1, entry 2). Similar
observations were also noticed in case of ferrous and ferric salts
(Table 1, entries 3 and 4). Then we thought to incorporate alkali
metal salts in the reaction. It is interesting to observe that
Na2SO4 can enhance the efficiency of Sonogashira reaction and
aDepartment of Chemistry, Dibrugarh University, Dibrugarh-786004, Assam, India.
E-mail: utbora@yahoo.co.in; Fax: +91-373-2370323; Tel: +91-373-2370210
bDepartment of Chemical Sciences, Tezpur University, Napaam, Tezpur-784028,
Assam, India
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Table 1 Effect of salts on Sonogashira reaction of aryl iodidesa
Table 2 Effect of solvent and base on Sonogashira reactiona
Yieldb (%)
Entry
Solvent (3 mL)
Base
Yieldb (%)
Entry
Catalyst (2 mol%)
Additive
1
2
3
MeOH
EtOH
i-PrOH
MeOH : H2O
EtOH : H2O
H2O
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
Na3PO4$12H2O
NaHCO3
KOH
91
90
87
70
79
57
80
76
59
68
90
83
69
46
39
68
63
90
1
2
3
4
5
6
7
8
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
MnCl2
ZnCl2
FeSO4$7H2O
FeCl3
Na2SO4
LiCl
NaCl
NaOAc
—
—
—
Na2SO4
Na2SO4
Na2SO4
54
70
72
76
91
78
81
69
54
56
82
87
59
65
4c
5d
6
7
8
9
DMF
DMSO
PEG-300
CH3CN
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
9
PdCl2
10
11
12
13
14
15
16
17e
18f
10
11
12
13c
14d
Pd(OAc)2
Na2PdCl4
Pd(OAc)2
PdCl2 (1 mol%)
PdCl2 (1 mol%)
NaOH
Et3N
K2CO3
K2CO3
a
Reaction conditions: iodobenzene (0.5 mmol), phenyl acetylene (0.6
mmol); additive (10 mol%), K2CO3 (1.5 mmol), MeOH (3 mL) at room
b
c
temperature unless otherwise noted. Isolated yield. 1 mol% PdCl2
was used. 1 mol% of PdCl2 and 20 mol% of Na2SO4 was used.
EtOH
d
a
Reaction conditions: iodobenzene (0.5 mmol), phenyl acetylene (0.6
mmol); Na2SO4 (10 mol%), base (1.5 mmol), solvent (3 mL) at room
b
c
temperature unless otherwise noted.
Isolated yield.
1 : 1
d
e
provide excellent yield of isolated cross coupling product (Table
1, entry 5).
(MeOH : H2O) was used. 1 : 1 (EtOH : H2O) was used. 2 equivalent
of K2CO3 was used. f 4 equivalent of base was used.
Compared with the efficiency of Na2SO4, other alkali metal
salts viz. LiCl, NaCl and NaOAc showed slightly lower activity
(Table 1, entries 6–8). However the yield of the cross coupling solvent (Table 2, entry 6). On the other hand moderate to good
product decreased signicantly when the reaction was per- yield were obtained in case of other organic solvents such as
formed in absence of Na2SO4 (Table 1, entries 9 & 10) which DMF, DMSO, PEG-300, MeCN (Table 2, entries 7–10). So we have
clearly conrms the role of Na2SO4 in the reaction. The use of in considered EtOH for further optimization process. Next we
situ generated complex Na2PdCl4 results 82% of isolated cross thought to examine the effect of bases in the Sonogashira
coupling product (Table 1, entries 11). It is important to reaction of iodobenzene (0.5 mmol) with phenyl acetylene (0.6
mention here that the amount of Glaser type homo-coupling mmol) in presence of 2 mol% PdCl2 with 10 mol% Na2SO4 at
product in case of Na2SO4 is minimized to only 1%. A typical room temperature. Among the bases tested maximum yield was
reaction with Pd(OAc)2 and Na2SO4 results 87% of desired noted with K2CO3 (Table 2, entry 1). Similar yields can be also
product (Table 1, entries 12). In order to check the effect of obtained from Cs2CO3 and Na3PO4 (Table 2, entries 11 & 12).
amounts of PdCl2 and Na2SO4, reactions were performed with But considering the cost factor and hygroscopic nature of
various amounts of catalyst and additive. Finally we observed Cs2CO3 and Na3PO4, we choose K2CO3 for the further optimi-
that 2 mol% of PdCl2 was necessary for optimum yield (Table 1, zation process. Whereas, poor yields were recorded with bicar-
entries 5 vs. 13 & 14). Recently PdCl2/Na2SO4 system has been bonate, hydroxide and organic bases (Table 2, entries 13–16).
found to be very effective for the Suzuki–Miyaura coupling Further optimization conrms that 3 equivalent of K2CO3 was
reaction.16,17 Although the exact role of Na2SO4 is not clear, it is optimum for efficient coupling (Table 2, entries 1 vs. 17 & 18).
believed that the addition of sodium sulfate, could provide
soluble ate complex of palladium, Na2Pd(SO4)2, which is the have tested several electronically diverse aryl iodide and aryl
actual catalytic species.16,17
acetylene under the optimized condition and the results
To verify the scope and limitation of the present system we
Our next goal was to identify a suitable solvent which can obtained are highlighted in Table 3. It was noticed that presence
accelerate the reaction at good rate. A myriad number of of electron donating or withdrawing group at the para position
aqueous and non-aqueous solvents were examined. The results of aryl iodide furnishes excellent yield of isolated cross coupling
are listed in Table 2. It has been observed that alcoholic solvents product (Table 3, entries 2–5). The sterically demanding 2-
viz. MeOH, EtOH and i-PrOH are most suited for the reaction as nitroiodobenzne also affords good yield with phenyl acetylene
excellent yield of cross coupling product was obtained in all (Table 3, entries 6). The reaction also proceeds well in case of
cases (Table 2, entries 1–3). However, the yield dramatically falls meta substituted electron rich and electron decient aryl
when aqueous alcoholic solvents were used (Table 2, entries 4 & iodides (Table 3, entries 7 & 8). We also investigated the reaction
5). The reaction fails to complete when water was used as a of substituted aryl acetylenes and aliphatic alkynes. In all cases
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Table 3 Sonogashira coupling of aryl iodides using PdCl2/Na2SO4
dried over by Na2SO4. Aer evaporation under reduced pres-
sure, the residue was puried by ash chromatography (silica
gel, hexane) to give the pure product. Formation of the product
systema
was conrmed by comparing FTIR spectra, 1H NMR spectra, 13
C
NMR spectra, melting point measurement and high resolution
GC-MS with authentic compounds.
R1
R2
X
Yieldb (%)
Acknowledgements
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
I
I
I
I
I
I
I
I
91
92
86
99
97
91
95
90
4-Me
4-OMe
4-NO2
4-COCH3
2-NO2
3-NO2
3-Me
H
We wish to thank UGC, New Delhi for nancial support of this
Project (no. 41 254/2012 (SR)).
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4-Me
I
89
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18 | RSC Adv., 2015, 5, 16–19
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