Copper-free Sonogashira coupling reactions catalyzed by a water-soluble Pd-salen complex under aerobic conditions

Article abstract of DOI:10.1016/j.tetlet.2009.01.053

The water-soluble Pd-salen complex, palladium(II) N,N′-bis{[5-(triphenylphosphonium)methyl]salicylidene}-1,2-ethanediamine chloride, is a highly active catalyst for the copper-free Sonogashira coupling of aryl iodides with terminal alkynes in water under

Full text of DOI:10.1016/j.tetlet.2009.01.053

Tetrahedron Letters 50 (2009) 1557–1559
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Tetrahedron Letters
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Copper-free Sonogashira coupling reactions catalyzed by a water-soluble
Pd–salen complex under aerobic conditions
*
Mohammad Bakherad , Ali Keivanloo, Bahram Bahramian, Mahdieh Hashemi
Faculty of Chemistry, Shahrood University of Technology, Shahrood, Iran
a r t i c l e i n f o
a b s t r a c t
The water-soluble Pd–salen complex, palladium(II) N,N0-bis{[5-(triphenylphosphonium)methyl]salicylid-
ene}-1,2-ethanediamine chloride, is a highly active catalyst for the copper-free Sonogashira coupling of
aryl iodides with terminal alkynes in water under aerobic conditions.
Article history:
Received 23 October 2008
Revised 23 December 2008
Accepted 13 January 2009
Available online 19 January 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Water
Copper-free
Sonogashira reaction
Pd–salen
Aryl iodides
1. Introduction
phines10f has been investigated. Moreover, the original Sonogash-
ira reaction conditions require degassed organic solvents, and
The Sonogashira cross-coupling reaction1 is a powerful method
for C(sp)–C(sp2) bond formation. It can be used for the synthesis of
a variety of compounds,2 including heterocycles,3 natural products,
and pharmaceuticals.4 In addition, oligomers and polymers have
also been prepared via the Sonogashira reaction.5
The reaction is generally carried out in an organic solvent such
as an amine, benzene, THF, or DMF with a palladium catalyst in
conjunction with copper(I) iodide as a co-catalyst, and in the pres-
ence of a stoichiometric amount of base.6
In recent years, a variety of modifications have been reported
for this reaction and great progress has been made.7 The most
important modification is elimination of the copper salt,8 since it
can induce Glaser-type homocoupling of the terminal alkynes in
the presence of oxidative agents or air.9
The use of aqueous media in palladium-catalyzed reactions has
become popular10 because water-based synthetic processes are
inherently safer (water is non-toxic and non-flammable) as well
as being inexpensive. Moreover, the products can be isolated easily
by extraction. Its use is particularly beneficial in the cross-coupling
reaction of peptides with alkyne ligands for the construction of
biomolecule-based systems, where the poor solubility of the reac-
tants often prevents the reaction being performed in common or-
ganic solvents. Thus, the use of water-soluble catalysts10g and
water-soluble phosphine ligands, for example, sulfonated phos-
have to be carried out under an inert atmosphere. This is particu-
larly inconvenient when the reactions are carried out in multiple
vessels for library generation. Therefore, the development of con-
venient methods for Sonogashira reactions is an important objec-
tive. Thus, we decided to concentrate on developing a novel
palladium catalyst that is highly active and air stable.
As part of our ongoing project on palladium-catalyzed reac-
tions,11 herein, we report the synthesis of water-soluble palla-
dium(II) N,N0-bis{[5-(triphenylphosphonium)methyl]salicylidene}
-1,2-ethanediamine chloride 2 and its catalytic activity in the cop-
per-free Sonogashira coupling reaction of aryl iodides with termi-
nal alkynes in water under aerobic conditions.
The palladium(II) salen complex 2 was synthesizedby the reaction
of the salen ligand N,N0-bis{[5-(triphenylphosphonium)methyl]-
salicylidene}-1,2-ethanediamine chloride 112 with bis(benzonitrile)-
palladium(II) chloride for 12 h in refluxing ethanol (Scheme 1).
The catalytic activity of complex 2 (1 mol %) was studied in the
copper-free Sonogashira reaction using aryl iodides and terminal
alkynes, in the presence of Cs2CO3 as base in water at 60 °C under
aerobic conditions.
N
N
N
O
N
O
[Pd(PhCN)2Cl2
EtOH, Reflux
]
Pd
OH
HO
_
_
_
_
+
+
+
+
ClPh3
P
PPh3Cl
ClPh3
P
PPh3Cl
1
2
* Corresponding author. Tel.: +98 2733335441.
E-mail address: mbakherad@shahroodut.ac.ir (M. Bakherad).
Scheme 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.053

1558
M. Bakherad et al. / Tetrahedron Letters 50 (2009) 1557–1559
Table 2
For optimization of the reaction conditions, we chose the cross-
Effect of catalyst and surfactant on the Sonogashira reaction of iodobenzene with
coupling of iodobenzene or 4-iodoanisole with phenylacetylene as
model reactions, and the effects of the base, surfactant, and cata-
lyst were examined. We first investigated the influence of various
bases on the copper-free Sonogashira reaction of electron-neutral
iodobenzene and electron-rich 4-iodoanisole with phenylacetylene
using 1 mol % of 2 in water under aerobic conditions. We found
that the reaction was highly dependent on the amount of base as
well as its nature. According to the results obtained (Table 1),
Cs2CO3 gave an excellent yield (entry 2, 95%) in the reaction of
electron-neutral iodobenzene with phenylacetylene; K2CO3 also
gave a similar yield (entry 3, 90%).
phenylacetylene in watera
Pd-salen complex
I
Ph
HC
Ph
+
surfactant, Cs2CO3, H2O
Entry Pd–salen complex
(mol %)
Sodium lauryl sulfate
(mol %)
Time
(h)
Yieldb
(%)
1
2
3
4
5
6
2
0.5
1
1
1
7
7
7
3
10
—
7
12
9
12
12
12
92
80
95
62
30
30
The results with the deactivated electron-rich substrate 4-iodo-
anisole were similar. The best result was obtained in the case of ce-
sium carbonate as the base (Table 1, entry 10). The influence of the
amount of surfactant and catalyst was investigated using the reac-
tion of iodobenzene with phenylacetylene, Table 2. Increasing the
amount of the palladium catalyst reduced the reaction time but
did not increase the yield (entry 1). A low palladium concentration
prolonged the reaction time and decreased the yield (entry 2). The
use of a surfactant was also critical for the success of the reaction:
without a surfactant/phase-transfer reagent, the yield dropped
from 95% to 30% (compare entries 3 and 6); however, increasing
the amount of the surfactant did not improve the yield (entry 5).
A low surfactant concentration decreased the yield (entry 4).
Using the optimized reaction conditions (0.01 mmol of 2,
0.07 mmol of sodium lauryl sulfate, 2.0 mmol of Cs2CO3), we ex-
plored the general applicability of the Pd–salen complex 2 as a cat-
alyst for coupling different alkynes 3 and aryl iodides 4 containing
electron-withdrawing or donating substituents, and the results are
shown in Table 3. Alkynes reacted with aryl iodides such as iodo-
benzene, nitroiodobenzene, p-iodoacetophenone, and p-iodoani-
sole, delivering the corresponding products in good to excellent
yields. Unsurprisingly, p-nitroiodobenzene was found to be the
most reactive amongst the aryl iodides studied (entries 2, 6, and
12). As expected, aryl iodides with electron-withdrawing groups
reacted faster than aryl iodides possessing electron-donating
groups to give the desired products in high yields.
1
a
Reaction conditions: iodobenzene (1.0 mmol), phenylacetylene (1.5 mmol),
cesium carbonate (2.0 mmol), water (5 mL) at 60 °C under aerobic conditions.
b
GC yields.
using sodium lauryl sulfate as the surfactant and Cs2CO3 as base
under aerobic conditions.
2. Preparation of palladium(II) N,N0-bis{[5-(triphenylphospho-
nium)methyl]salicylidene}-1,2-ethanediamine chloride 2
A mixture of N,N0-bis{[5-(triphenylphosphonium)methyl]sali-
cylidene}-1,2-ethanediamine dichloride 112 (1.8 g, 2 mmol) and
[PdCl2(C6H5CN)2] (0.76 g, 2 mmol) in absolute ethanol (10 mL)
was heated under reflux for 12 h. The resulting precipitate was fil-
tered off and recrystallized from ethanol to afford the title com-
pound. Yield, 80%; mp 195–196 °C; IR,
m (KBr disc): 3415 (s),
3055 (m), 3038 (m), 2915 (m), 2854 (m), 1624 (vs), 1583 (s),
1555 (s), 1530 (s), 1463 (s),1433 (s), 1382 (s), 1326 (m), 1212
(w), 1148 (m), 1105 (s), 1040 (m), 810 (s), 745 (s), 730 (m), 710
(s), 688 (sh), 620 (w), 595 (w), 540 (m), 520 (w), 510 (s), 490
(m), 475(m), 445 (w), 439 (w) cmꢀ1; UV–vis, (MeOH) kmax (nm):
406 (sh), 315 (sh), 285 (sh).
In summary, we have shown that the water-soluble palladium–
salen complex 2 efficiently catalyzes the copper-free Sonogashira
coupling reaction of aryl iodides with terminal alkynes in water
Table 3
Copper-free Sonogashira reaction of terminal alkynes with aryl iodidesa
R2
R2
Pd-salen complex
R1
R1
C
CH
I
+
surfactant, Cs2CO3, H2O
Table 1
3
4
5
Effect of base on the Sonogashira reactions of aryl iodides with phenylacetylene in
watera
Entry
R1
R2
Time (h)
Product
Yieldb (%)
Pd-salen complex, base
R
I
HC
Ph
R
Ph
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
n-C4H9
n-C4H9
n-C4H9
n-C4H9
Ph
Ph
Ph
Ph
Ph
H
4-NO2
8
6
7
12
9
6
6
7
8
11
10
7
7
8
12
10
8
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
5r
92
98
90
82
95
98
94
95
92
85
94
97
95
96
80
86
90
78
+
surfactant, H2
O
4-COCH3
4-OCH3
H
4-NO2
3-NO2
2-NO2
4-COCH3
4-OCH3
H
4-NO2
3-NO2
2-NO2
4-OCH3
H
Entry
R
Base
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
H
H
H
H
H
H
H
MeO
MeO
MeO
MeO
MeO
MeO
MeO
KOH
Cs2CO3
K2CO3
Et3N
DIEA
Pyrrolidine
Piperidine
KOH
K2CO3
Cs2CO3
Et3N
40
95
90
45
35
48
55
22
65
85
20
25
34
30
Ph
Me3Si
Me3Si
Me3Si
Me3Si
Me3Si
CH2OH
CH2OH
CH2OH
DIEA
Pyrrolidine
Piperidine
3-NO2
4-OCH3
12
a
a
Reaction conditions:
3
(1.5 mmol),
4
(1.0 mmol), Pd–salen complex
Reaction conditions: aryl iodide (1.0 mmol), phenylacetylene (1.5 mmol), Pd–
salen complex (0.01 mmol), sodium lauryl sulfate (0.07 mmol), base (2.0 mmol),
water (5 mL), 60 °C, 12 h under aerobic conditions.
(0.01 mmol), sodium lauryl sulfate (0.07 mmol), Cs2CO3 (2.0 mmol), water (5 mL) at
60 °C under aerobic conditions.
b
b
GC yields.
GC yields.

M. Bakherad et al. / Tetrahedron Letters 50 (2009) 1557–1559
1559
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