Copper-free Sonogashira cross-coupling reaction catalyzed by polymer-supported N-heterocyclic carbene palladium complex

Article abstract of DOI:10.1016/j.tetlet.2007.08.015

A core-shell type of polymer-supported N-heterocyclic carbene (NHC) palladium catalyst was applied to Sonogashira cross-coupling reactions without copper cocatalyst under ambient atmosphere. This supported NHC-palladium complex efficiently catalyzed the c

Full text of DOI:10.1016/j.tetlet.2007.08.015

Tetrahedron Letters 48 (2007) 7079–7084
Copper-free Sonogashira cross-coupling reaction catalyzed
by polymer-supported N-heterocyclic carbene palladium complex
Jong-Ho Kim, Dong-Ho Lee, Bong-Hyun Jun and Yoon-Sik Lee*
School of Chemical and Biological Engineering, Seoul National University, Seoul 151-744, Republic of Korea
Received 25 June 2007; revised 3 August 2007; accepted 6 August 2007
Available online 8 August 2007
Abstract—A core-shell type of polymer-supported N-heterocyclic carbene (NHC) palladium catalyst was applied to Sonogashira
cross-coupling reactions without copper cocatalyst under ambient atmosphere. This supported NHC–palladium complex efficiently
catalyzed the copper-free Sonogashira reaction of various aryl iodides and bromides with terminal alkynes; the reaction exhibited
high dependency on the temperature and the amount of base as well as its nature. In addition, this heterogeneous catalyst exhibited
good reusability for the copper-free Sonogashira reaction.
ꢀ
2007 Elsevier Ltd. All rights reserved.
The Sonogashira reaction cocatalyzed by palladium and
copper is a powerful and straightforward method for the
as difficulties in recovery, separation and recycling of
the expensive, toxic catalysts and contamination of the
ligand residue into the final product, except ionic
1
construction of arylated internal alkyne compounds,
2
6c
C(sp )–C(sp) bond, which are important intermediates
liquid-mediated system. In order to avoid these draw-
2
in organic synthesis including natural products, biolog-
backs, several heterogeneous catalyst systems have also
3
4
11
ically active molecules, molecular electronics and poly-
been reported. Nevertheless, there is still a need for
5
mers. The original Sonogashira reaction was generally
an efficient heterogeneous catalyst that is air and
moisture stable and applicable to a wide range of
Sonogashira reactions without copper cocatalyst.
performed in the presence of large amounts of palladium
and copper(I) iodide as a cocatalyst under inert condi-
tions, which were economically and environmentally
malignant. This protocol has recently been improved
by several modifications such as reaction in aqueous
Herein, we report the copper-free, heterogeneous Sono-
gashira reactions catalyzed under ambient atmosphere
by a novel type of polymer-supported N-heterocyclic
carbene (NHC) palladium complex that we recently
6
media, ionic liquid or under microwave irradiation
and the use of promoters (Zn, Mg, Sn) or effective
7
12
ligands. Especially, the most significant improvement
developed, in which NHC is an emerging alternative
8
13
has focused on the omission of copper(I) iodide, be-
as an air and moisture stable ligand against phosphines.
cause it can induce oxidative homocoupled by-products
of acetylenes that are difficult to separate from the de-
sired product and copper acetylides can be explosive.
As shown in Scheme 1, this polymer-supported NHC
precursor bead has imidazolium on its surface and a bid-
entic NHC–palladium complex (1) forms on the beads.
9
Besides, the use of copper(I) iodide has also been shown
1
0
to inhibit the Sonogashira reaction.
We first investigated the effect of various solvents on the
model reaction of iodobenzene with phenylacetylene
catalyzed by 1 mol % of supported NHC–palladium
without copper iodide at ambient atmosphere. Cesium
carbonate (Cs CO ) was used as a base in this reaction.
However, most of the above reactions were carried out
homogeneously and, thus, had intrinsic problems such
2
3
As shown in Table 1, a solution of DMF/H O (3:1) gave
2
Keywords: Polymer-supported catalyst; N-Heterocyclic carbene (NH-
C); Heterogeneous catalysis; Palladium (Pd); Sonogashira reaction;
Copper-free.
the highest yield (entry 1, 85%) after 3 h at 60 ꢁC in the
copper-free reaction of iodobenzene with phenylacetyl-
ene. The yield of cross-coupled product was reduced
as the polarity of organic solvents decreased. In
*
Corresponding author. Tel.: +82 2 880 7080; fax: +82 2 876 9625;
e-mail: yslee@snu.ac.kr
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.08.015

7080
J.-H. Kim et al. / Tetrahedron Letters 48 (2007) 7079–7084
1) Pd(OAc)2
DMSO
o
n
5
h, 50 C
m
n
m
Ph
Ph
Ph
Ph
N2
2
) 30 min
o
1
00 C
H C
CH2
N
2
N2
PF6
N
N
-
Pd
PF6
N
N
N
PF6
Polymer-supported NHC-Pd (1)
Scheme 1. Core-shell type of polymer-supported NHC–Pd catalyst (1).
a
Table 1. Effect of the solvent on the reaction of iodobenzene with phenylacetylene without copper iodide
NHC-Pd Complex 1
I
(
1 mol%)
+
Cs CO
2
3
(
1.6 eq.)
without CuI
Temperature
ꢁC)
1
.2 eq.
b
Entry
Solvent
Time
(h)
Yield
(%)
(
1
2
3
4
DMF/water (3:1)
CH CN/water (3:1)
THF/water (3:1)
60
60
60
60
3
3
3
3
85
45
5
3
Dioxane/water (3:1)
25
a
Iodobenzene (0.5 mmol), phenylacetylene (0.6 mmol), supported NHC–Pd (1 mol %), Cs
Isolated by column chromatography.
2
CO
3
(0.8 mmol), without CuI.
b
addition, no homocoupled by-product was formed
under any solvent conditions.
observed in the copper-free reaction of electron-neutral
and deficient aryl iodides, even at high temperature.
We identified the phenylacetylene-added side product
as ((Z)-1-(4-methoxyphenyl)-4-phenylbut-1-en-3-yn-2-l)-
After selecting a DMF/H O (3:1) solution as the opti-
2
1
4
mal solvent, we investigated the influence of various
bases on the copper-free Sonogashira reaction of elec-
tron-neutral iodobenzene and electron-rich 4-iodoani-
sole with phenylacetylene using 1 mol % of supported
NHC–palladium catalyst at ambient atmosphere. We
found that the copper-free Sonogashira reaction was
highly dependent on the amount of base as well as its
nature. According to the results shown in Table 2,
Cs CO gave excellent yield (entry 1, 85%) in the reac-
benzene. This kind of side reaction was previously re-
1
1c
ported by Djakovitch et al.,
who hypothesized that
the side product originated from the thermal coupling
of the desired product with excess phenylacetylene at
temperatures above 80 ꢁC. In our study, however, this
side product also formed at lower temperature (60 ꢁC).
This finding led us to more intensively investigate the
base for the copper-free reaction of electron-rich aryl
iodide. First, we investigated the influence of the amount
of piperidine used in the copper-free Sonogashira reac-
tion. As illustrated in Table 2, when larger amounts of
base were used, less side product was obtained. When
5 equiv of piperidine was used, the yield of the side prod-
uct declined to 14% (Table 2, entry 12), while the con-
version into desired product was maintained. In
addition, the formation of side product was completely
suppressed when 10 equiv of piperidine was used, and
the desired coupling product formed cleanly (Table 2,
entry 13). However, neither the desired product nor
the side product was synthesized when 15 equiv of piper-
idine was used in the copper-free reaction of 4-iodoani-
sole with phenylacetylene (Table 2, entry 14). These
results indicate that excess amount of the base, piperi-
dine, suppresses not only the side reaction, but also
the desired reaction. We speculate that the large excess
2
3
tion of electron-neutral iodobenzene with phenylacetyl-
ene under mild conditions (3 h at 60 ꢁC). Piperidine
also produced a similar yield (entry 4, 79%) to Cs CO .
2
3
However, the results with the deactivated substrate, elec-
tron-rich 4-iodoanisole, were different from the electron-
neutral one. An inorganic base, Cs CO , gave poor con-
2
3
version of 4-iodoanisole to the corresponding product
entry 5, 20% yield) for 2 h at 80 ꢁC. Other inorganic
(
bases such as NaOAc and NaOH also provided low
transformation of deactivated aryl iodide to the desired
product (Table 2, entries 7 and 8). The best result for
electron-rich 4-iodoanisole was obtained using 1.6 equiv
of piperidine for 2 h at 80 ꢁC (Table 2, entry 11, 51%).
However, a 29% yield of the side product was formed
from the desired product under the above conditions
with 1.6 equiv of piperidine; this side product was not

J.-H. Kim et al. / Tetrahedron Letters 48 (2007) 7079–7084
7081
a
Table 2. Effect of the base on the reaction of iodobenzene and 4-iodoanisole with phenylacetylene without copper iodide
NHC-Pd Complex 1
I
(
1 mol%)
+
X
DMF/H O
X
2
(
3:1)
1
.2 eq.
without CuI
X= H, OCH3
Base
Cs CO
b
Entry
X
Temperature (ꢁC)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
H
H
H
H
2
3
60
60
60
60
80
80
80
80
80
80
80
80
80
80
100
3
3
3
3
2
2
2
2
2
2
2
2
2
2
2
85
75
60
79
20 (14)
46 (23)
TEA
TBAOAc
Piperidine
c
OCH
OCH
OCH
OCH
OCH
OCH
OCH
OCH
OCH
OCH
OCH
3
3
3
3
3
3
3
3
3
3
3
Cs
2
CO
3
c
TEA
NaOAc
NaOH
DMAP
Pyridine
c
20 (50)
7
0
0
1
1
1
1
1
1
c
Piperidine (0.8 mmol)
Piperidine (2.5 mmol)
Piperidine (5 mmol)
Piperidine (7.5 mmol)
Piperidine (5 mmol)
51 (29)
47 (14)
43 (0)
0 (0)
c
c
c
c
85 (0)
a
b
c
Aryl iodides (0.5 mmol), phenylacetylene (0.6 mmol), supported NHC–Pd (1 mol %), base (0.8 mmol), DMF/H
Isolated by column chromatography.
The yield in the round bracket is for the side product induced from the desired product.
2
O (3:1), without CuI.
of piperidine prohibits the acetylenes from coordinating
to palladium in copper-free Sonogashira reaction,
resulting in no progress in the reactions. In order to
optimize the copper-free reaction further, reaction tem-
perature was then varied. As the temperature increased
up to 100 ꢁC in the copper-free reaction of 4-iodoanisole
with phenylacetylene using 10 equiv of piperidine as a
base, the yield of the desired product sharply increased
to 85% after 2 h. No side product was induced from
the desired product and no homocoupled by-product
from terminal alkynes was also observed, even at high
temperature (Table 2, entry 15). Based on the results
thus far, we found that the amount of base, as well as
its nature, such as basicity and steric bulkiness, and
the temperature were critical for the copper-free Sono-
gashira reaction of deactivated aryl iodides, 4-iodoani-
sole and 4-iodotoluene, which is directly correlated
with the reaction of electron-deficient and rich aryl
bromides.
(60 ꢁC, Cs CO ) were poor for aryl iodides with elec-
2
3
tron-donating groups such as p-OCH and p-CH , in
3
3
which the phenylacetylene-added side product of the
internal alkyne of the desired product was also ob-
served even at low temperature. Therefore, piperidine
was used as a base for copper-free reactions of elec-
tron-rich aryl iodides and aryl bromides at the elevated
temperature (100 ꢁC). Thus, 4-iodoanisole and 4-iodo-
toluene clearly gave the corresponding products in
90% and 91% yields, respectively, after 2.5 h at
100 ꢁC using 10 equiv of piperidine, and did not pro-
duce any side products. In addition, the steric hin-
drance of the substituent did not influence the
product yield in the copper-free Sonogashira reaction
of deactivated aryl iodides using the polymer-supported
NHC–palladium catalyst (Table 3, entry 8). The poly-
mer-supported NHC–palladium catalyzed the copper-
free reactions so rapidly that all of the electron-rich
aryl iodides were converted to the desired products
within 2.5 h, which is excellent catalytic efficiency com-
pared to the results of the previous heterogeneous sys-
tem. When less reactive aryl bromides with electron-
withdrawing groups were used in the copper-free reac-
tion, the coupling products were also obtained in excel-
lent yields after longer reaction times (Table 3, entries 9
and 10) and without any side products. We next exam-
ined the copper-free reactions of several kinds of termi-
nal alkynes catalyzed by 1 mol % of polymer-supported
NHC–palladium, as shown in Table 3. The reactions of
phenylacetylenes that had electron-donating groups
We next investigated the copper-free reactions of a
variety of aryl iodides and bromides with several alky-
nes catalyzed by 1 mol % of polymer-supported NHC–
1
5
palladium complex under ambient atmosphere. As
summarized in Table 3, 1.6 equiv of Cs CO was effec-
2
3
tive as a base for electron-neutral and deficient aryl
iodides because its reactivity was sufficient to obtain
the desired products in high yields. Also, Cs CO was
2
3
easily removed in the extraction step after the reaction.
Electron-neutral iodobenzene was converted to the cor-
responding product in 95% yield after 4 h at 60 ꢁC.
Aryl iodides with electron-withdrawing groups such
as p-COCH3 and p-NO2 were more smoothly con-
verted to the products in high yields (94% and 95%)
under mild conditions, after 1 h at 60 ꢁC (Table 3, en-
tries 2 and 3). However, the above reaction conditions
0
with 4 -iodoacetophenone gave the desired products
in good yields after longer reaction times at 60 ꢁC than
those required for phenylacetylene. There was no
homocoupled by-product induced from terminal alky-
nes (Table 3, entries 11–13). The less reactive aliphatic
alkyne, 1-octyne, was also converted to the desired

7082
J.-H. Kim et al. / Tetrahedron Letters 48 (2007) 7079–7084
a
Table 3. Copper-free Sonogashira reaction of various aryl iodides and bromides with terminal alkynes
b
Entry
1
Aryl halide
Base
Product
Temperature (ꢁC)
Time (h)
4
Yield (%)
I
Cs
2
2
CO
3
3
60
95
94
I
2
3
4
5
Cs
CO
H COC
60
60
1
3
H COC
3
I
Cs
2
Cs
2
Cs
2
CO
CO
CO
3
3
3
O N
1
95
93
94
90
2
O N
2
I
Cl
60
3
Cl
I
F3C
60
3
F3C
I
c
6
Piperidine
H CO
100
2.5
3
H CO
3
I
c
7
Piperidine
Piperidine
Piperidine
Piperidine
H C
100
100
100
100
60
2.5
2.5
5
91
92
91
92
96
3
H C
3
CH3
CH3
c
I
8
Br
9
O N
2
O2N
Br
1
1
0
1
NC
7
NC
I
I
Cs
2
2
CO
3
3
H COC
4
3
H COC
3
12
Cs
CO
H COC
60
5
92
3
H COC
3
I
I
I
1
1
1
3
4
5
Cs
2
Cs
2
Cs
2
CO
CO
CO
3
3
3
H COC
OCH3
CN
60
60
60
5
94
90
80
3
H COC
3
H COC
1.5
8
3
H COC
3
H COC
C H
6 13
3
H COC
3
a
b
c
2
Aryl halide (0.5 mmol), terminal alkyne (0.6 mmol), supported NHC–Pd catalyst 1 (1 mol %), base (0.8 mmol), DMF/H O (3:1), without CuI.
Isolated by column chromatography.
10 equiv of piperidine (5 mmol) were used.
product with 80% yield under mild conditions, at 60 ꢁC
ylacetylene after 1 h at 60 ꢁC using 1.6 equiv of Cs CO
2
3
for 8 h (Table 3, entry 15).
as a base. After the first run, the catalyst (1 mol %) was
filtered and extensively washed with DMF and DCM
and then reused under the same conditions. The product
was obtained in 93%, 93% and 94% yields for the sec-
ond, third and forth runs, respectively, indicating that
Finally, we explored the reusability of the polymer-sup-
ported NHC–palladium catalyst for the copper-free
0
Sonogashira reaction of 4 -iodoacetophenone with phen-

J.-H. Kim et al. / Tetrahedron Letters 48 (2007) 7079–7084
7083
the polymer-supported NHC–palladium catalyst had
consistent activity for copper-free Sonogashira reaction
after recycling. The recovered catalyst was analyzed by
an inductively coupled plasma-atomic emission spec-
trometer (ICP-AES) and no significant decrease in palla-
dium content on polymer beads was observed.
Shinmen, M.; Nishitani, S.; Sato, M.; Ryu, I. Org. Lett.
002, 4, 1691.
. (a) Powell, N. A.; Rychnovsky, S. D. Tetrahedron Lett.
996, 37, 7901; (b) Crisp, G. T.; Turner, P. D.; Stephens,
K. A. J. Organomet. Chem. 1998, 570, 219; (c) Nakamura,
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Choudary, B. M.; Madhi, S.; Chowdari, N. S.; Kantam,
M. L.; Sreedhar, B. J. Am. Chem. Soc. 2002, 124, 14127;
2
7
1
In summary, the polymer-supported NHC–palladium
complex efficiently catalyzed the copper-free Sonogash-
ira cross-coupling reactions of various aryl iodides and
bromides with terminal alkynes under ambient atmo-
sphere; these reactions were highly dependent on the
amount and nature of the base as well as on the tem-
perature. The catalyst also maintained its catalytic
activity for copper-free Sonogashira reaction after recy-
cling four times. This supported NHC–palladium cata-
lyst system offers many advantages such as complete
recovery and reuse of the catalyst, easy work-up proce-
dure, reactions under ambient conditions and no
copper cocatalyst.
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This work was supported by the Nano-Systems Insti-
tute-National Core Research Center (NSI-NCRC) pro-
gramme of the Korean Science and Engineering
Foundation (KOSEF), Korea. The authors also wish
to acknowledge the financial assistance provided by
the Nano Bioelectronics and Systems Research Center
of Seoul National University, which is supported by
KOSEF, and the Brain Korea 21 Programme supported
by the Ministry of Education.
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3
14. The side product induced from the desired product; [(Z)-1-
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1
6
H NMR (300 MHz, DMSO-d ): d (ppm) 3.81 (s, 3H,
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C@C–C
3
), 7.08 (d, 2H, m-C@C–C
6
H
4
–OMe), 7.46 (m, 9H, o-
, m and p-C@C–
), 7.84 (d, 1H, o-C@C–
6
H
4
–OMe, m and p-C„C–C
6
H
5
C
6
H
5
), 7.61 (m, 2H, o-C„C–C
), 8.08 (d, 1H, o-C@C–C
): d (ppm) 55.25 (CH
alkyne), 96.39 (C„C–C , alkyne), 113.95 (m-C@C,
C@C–C –OMe, benzene carbon), 120.02 (C–C„C,
, benzene carbon), 122.39 (HC@C–C„C), 125.87
(o-C@C, HC@C–C , benzene carbon), 127.72 (o-C@C,
6
H
5
1
3
C
6
H
5
6
H
5
). C NMR (500 MHz,
), 88.62 (C„C–C@C,
DMSO-d
6
3
6 5
H
2
04.
6 4
H
4
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C H
6 5
H
5
6
C@C–C
C@C–C
6
H
H
4
–OMe, benzene carbon), 127.82 (C–C@C,
–OMe, benzene carbon), 128.53 (p-C@C,
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4
5
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Nagano, A.; Naemura, K. Angew. Chem., Int. Ed. 1998,
HC@C–C
, benzene carbon), 128.91 (p-C@C, C„C–C
benzene carbon), 129.04 (m-C@C, HC@C–C , benzene
carbon), 130.61 (o-C@C, C„C–C , benzene carbon),
131.32 (o-C@C, C„C–C , benzene carbon), 138.62
, benzene carbon), 141.80 (HC@C–C
H , benzene carbon), 128.84 (m-C@C, C„C–
6 5
C
6
H
5
6 5
H ,
6
H
5
3
7, 1285; (c) Onitsuka, K.; Fujimoto, M.; Ohshiro, N.;
6 5
H
Takahashi, S. Angew. Chem., Int. Ed. 1999, 38, 689.
. (a) Genet, J. P.; Blart, E.; Savignac, M. Synlett 1992, 715;
H
6 5
6
(HC@C–C
6
H
5
6 5
H ,
(
b) Kabalka, G. W.; Wang, L.; Namboodiri, V.; Pagni, R.
alkene), 159.60 (CH O–C@C, benzene carbon). GC–MS:
3
M. Tetrahedron Lett. 2000, 41, 5151; (c) Fukuyama, T.;
m/z 310.

7084
J.-H. Kim et al. / Tetrahedron Letters 48 (2007) 7079–7084
such as Cs CO (0.8 mmol, 1.6 equiv) for activated aryl
2
3
halides or piperidine (5 mmol, 10 equiv) for deactivated
aryl halides, was added to the reaction vessel, the reaction
mixture was agitated in a shaking incubator at 60 ꢁC or at
H CO
3
1
00 ꢁC for certain period of time. All of the coupling
reactions were performed under ambient atmosphere. The
resulting reaction mixture was filtered and washed with
distilled water (4 mL · 5) and diethyl ether (4 mL · 5).
4
The organic phase was separated, dried over MgSO and
1
5. General procedure for copper-free Sonogashira cross-
evaporated under reduced pressure. The final product was
isolated by column chromatography and identified by gas
chromatography/mass spectroscopy (GC–MS) and
nuclear magnetic resonance spectroscopy (NMR). The
isolation yield was calculated from the mass value of the
product.
coupling reaction: The polymer-supported NHC–Pd com-
plex (50 mg, 1 mol % Pd, 0.11 mmol-Pd/g) was suspended
in DMF/water (3:1, 4 mL), and then aryl halides
(
0.5 mmol) and terminal acetylenes (0.6 mmol, 1.2 equiv)
were added to the bead dispersion. After a suitable base,