A diphenylphosphinoethane-functionalized polystyrene resin-supported Pd(0) complex as an effective catalyst for copper-free Sonogashira coupling reactions under aerobic conditions

Article abstract of DOI:10.1016/j.tetlet.2009.05.118

A polymer-supported palladium(0) diphenylphosphinoethane complex was found to be a highly active catalyst for the copper-free Sonogashira coupling reaction of aryl iodides with terminal alkynes, giving excellent yields of products (85-98%) under aerobic c

Full text of DOI:10.1016/j.tetlet.2009.05.118

Tetrahedron Letters 50 (2009) 6418–6420
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A diphenylphosphinoethane-functionalized polystyrene resin-supported
Pd(0) complex as an effective catalyst for copper-free Sonogashira coupling
reactions under aerobic conditions
*
Mohammad Bakherad , Ali Keivanloo, Bahram Bahramian, Samira Mihanparast
School 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
Article history:
A polymer-supported palladium(0) diphenylphosphinoethane complex was found to be a highly active
catalyst for the copper-free Sonogashira coupling reaction of aryl iodides with terminal alkynes, giving
excellent yields of products (85–98%) under aerobic conditions.
Received 14 March 2009
Revised 16 May 2009
Accepted 29 May 2009
Available online 6 June 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Copper-free
Sonogashira reaction
Supported catalyst
Aryl iodides
The Sonogashira coupling reaction of terminal alkynes with aryl
or vinyl halides is a powerful tool for carbon–carbon bond forma-
tion and has been widely applied in areas such as natural product
synthesis, pharmaceuticals, and materials science.1 This reaction
usually proceeds in the presence of a homogeneous palladium cat-
alyst and a copper salt. The presence of the copper co-catalyst facil-
itates the coupling reaction by the in situ generation of copper
acetylide. However, it can also induce a Glaser-type oxidative
homocoupling2 of the terminal acetylene to yield a diyne. Focusing
on suppression of the formation of this undesired side product,
several copper-free versions of the palladium-catalyzed Sonogash-
ira coupling have been developed.3
Numerous modifications have been reported for the Sonogash-
ira coupling procedure, such as reaction in ionic liquids,4 various
copper-free conditions,3l,5 a zeolite-supported reaction system,6
fluorous biphasic systems (FBS) using fluorous palladium cata-
lysts,7 phase-transfer catalytic reaction conditions,8 use of promot-
ers9 such as Zn, Mg, and Sn, and by employing microwave
irradiation.10
not been widely applied for this reaction yet.12 Thus, the study of
new types of polymer-supported palladium catalysts which might
be suitable for the Sonogashira reaction has practical significance.
Polymer-supported palladium complex catalysts derived from
chloromethyl polystyrene resin have been employed in both the
Heck13 and Suzuki14 reactions, and have shown lower leaching of
palladium during cross-coupling. This encouraged us to investigate
the diphenylphosphinoethane-functionalized polystyrene resin-
supported Pd(0) complex, PS–dpp–Pd(0) for the Sonogashira reac-
tion. We have already reported the use of an ethylenediamine-
functionalized polystyrene resin-supported Pd(II) complex15 as
an air-stable, active, and reusable catalyst in Sonogashira reactions.
We used known chloromethylated polystyrene cross-linked
with 2% divinylbenzene as the support as it allows grafting of
metallic atoms via ligands which are attached to the polymer
beads. Reaction of polystyrene resin with diphenylphosphinoeth-
ane in DMF at 100 °C, and then treatment of the phosphinated
polystyrene with a solution of [PdCl2(PhCN)2] in ethanol, and final-
ly reduction with hydrazine monohydrate resulted in covalent
attachment of the palladium complex to give the polymer-sup-
ported palladium(0) complex catalyst 1 (Scheme 1). Successful
functionalization of the polymer was confirmed by elemental anal-
ysis. The P content of the resin was found to be 4.25% by ICP, which
indicates that the resin had reacted with diphenylphosphinoeth-
ane. The metal loading of the polymer-supported palladium com-
plex, determined by neutron activation analysis (NAA), was 5.42%
(0.51 mmol/g). In the IR spectrum of the polymer-bound diphenyl-
phosphinoethane, the sharp C–Cl peak at 670 cmÀ1 (due to –CH2Cl
The use of heterogeneous catalysts for Sonogashira coupling
reactions leads to a reduction in waste. Polymer-supported transi-
tion metal complexes having high activity have attracted signifi-
cant interest because they can be easily recovered and reused.11
Despite numerous reports on the use of the Sonogashira reaction
in organic synthesis, polymer-supported palladium catalysts have
* Corresponding author. Fax: +98 2733335441.
E-mail address: mbakherad@shahroodut.ac.ir (M. Bakherad).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.05.118

M. Bakherad et al. / Tetrahedron Letters 50 (2009) 6418–6420
6419
DMF
[PdCl2(PhCN)2]
EtOH, reflux, 6 h
+
+
Ph2P
PPh2
Ph2P
Cl-
PPh2
Cl
100 ºC, 20 h
NH2NH2.H2O
+
+
Ph2P
Cl-
PPh2)2PdCl2
Ph2P
Cl-
PPh2)2Pd(0)
EtOH, 50 ºC, 5 h
1
Scheme 1.
Table 1
Table 2
Copper-free Sonogashira reactions of terminal alkynes with aryl iodidesa
Copper-free Sonogashira reaction of iodobenzene with phenylacetylene in the
presence of several bases and solventsa
Entry
R1
R2
Time (h)
Product
Yieldb (%)
Entry
Solvent
Base
PS–dpp–Pd(0)
(mol %)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Ph
Ph
Ph
Ph
Ph
Ph
n-C4H9
n-C4H9
n-C4H9
n-C4H9
Me3Si
Me3Si
Me3Si
Me3Si
Me3Si
CH2OH
CH2OH
CH2OH
H
2
2
3
3
3
5
2
2
3
5
4
3
4
3
6
6
5
7
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
97
98
94
95
88
85
90
97
93
86
90
96
92
90
85
87
90
85
4-NO2
3-NO2
2-NO2
4-COCH3
4-OCH3
H
4-NO2
4-COCH3
4-OCH3
H
4-NO2
3-NO2
2-NO2
4-OCH3
H
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
DMF
DMF
DMF
DMF
CH3CN
CH3CN
CH3CN
CH3CN
Piperidine
Pyrrolidine
Et3N
Et3N
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2.0
0.5
7
6
2
3
9
10
4
5
2
3
6
6
4
5
3
4
1.5
5
70
62
93
90
73
70
78
75
97
92
60
58
82
70
84
75
95
87
DIEAc
Piperidine
Pyrrolidine
Et3N
DIEA
Piperidine
Pyrrolidine
Piperidine
Pyrrolidine
Et3N
DIEA
Et3N
DIEA
Piperidine
Pyrrolidine
Piperidine
Piperidine
DIEA
Dioxane
Dioxane
Dioxane
Dioxane
Piperidine
Piperidine
3-NO2
4-OCH3
a
Reaction conditions: 2 (1.5 mmol), 3 (1.0 mmol), PS–dpp–Pd(0) (0.01 mmol),
piperidine (5 mL), room temperature, aerobic conditions.
a
b
Reaction conditions: iodobenzene (1.0 mmol), phenylacetylene (1.5 mmol),
base (2.0 mmol), solvent (5 mL), room temperature, aerobic conditions.
GC yield.
b
GC yield.
Diisopropylethylamine.
c
diphenylacetylene (entry 17). A low palladium concentration led
to a long reaction time (entry 18). The optimum conditions for
the coupling reaction were 1 mol % of PS–dpp–Pd(0) in piperidine
at room temperature (entry 9).
To examine the scope of this coupling reaction, a variety of ter-
minal alkynes 2 were coupled with various aryl iodides 3 contain-
ing electron-withdrawing or electron-donating groups (Scheme 2).
As shown in Table 2, the Sonogashira coupling reactions proceeded
smoothly under very mild conditions giving the corresponding
products in excellent yields.
The stability of PS–dpp–Pd(0) was studied in repeated Sono-
gashira coupling reactions of phenylacetylene with iodobenzene.
The catalyst was separated from the reaction mixture after each
experiment by filtration, washed with water and acetonitrile, and
dried carefully before use in subsequent runs. A yield of 4a of
93% was obtained from the 5th catalyst cycle (Table 3, entry 5).
groups) and the strong peak at 1260 cmÀ1 corresponding to the
H–C–Cl wagging modes in the starting polymer were virtually ab-
sent after introduction of diphenylphosphinoethane and palladium
to the polymer. This confirms binding of the metal complex on the
surface of the polymer.
The catalytic activity of complex 1 (1 mol %) was studied at
room temperature under aerobic conditions in a copper-free Sono-
gashira reaction using phenylacetylene and iodobenzene. Our
optimization data are shown in Table 1.
The reaction is influenced significantly by the nature of the base
employed. Among the bases tested, piperidine proved to be the
most efficient. Among the solvents used, piperidine was also the
best choice (entry 9). Increasing the amount of palladium catalyst
shortened the reaction time but did not increase the yield of
R2
R2
1 mol% PS-dpp-Pd(0)
piperidine, r.t.
R1
R1
C
C
I
C
CH
+
2
3
4
Scheme 2.

6420
M. Bakherad et al. / Tetrahedron Letters 50 (2009) 6418–6420
Table 3
Acknowledgment
Copper-free Sonogashira reaction of iodobenzene with phenylacetylene catalyzed by
the recycled catalysta
The authors are grateful to the Research Council of Shahrood
University of Technology for financial support of this work.
PS-dpp-Pd(0)
CH
I
+
piperidine, r.t., 2 h
References and notes
4a
1. (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 4467; (b)
Erdelyi, M.; Gogoll, A. J. Org. Chem. 2001, 66, 4165.
Entry
Cycle
Yieldb (%)
2. Glaser, C. Ber. Dtsch. Chem. Ges. 1869, 2, 422.
1
2
3
4
5
1
2
3
4
5
97
96
96
94
93
3. (a) Alami, M.; Ferri, F.; Linstrumelle, G. Tetrahedron Lett. 1993, 34, 6403; (b)
Heidenreich, R. G.; Khler, K.; Krauter, J. G. E.; Pietsch, J. Synlett 2002, 1118; (c)
Soheili, A.; Albaneze-Walker, J.; Murry, J. A.; Dormer, P. G.; Hughes, D. L. Org.
Lett. 2003, 5, 4191; (d) Leadbeater, N. E.; Tominack, B. J. Tetrahedron Lett. 2003,
44, 8653; (e) Fukuyama, T.; Shinmen, M.; Nishitani, S.; Sato, M.; Ryu, I. Org. Lett.
2002, 4, 1691; (f) Urgaonkar, S.; Verkade, J. G. J. Org. Chem. 2004, 69, 5752; (g)
Li, J.-H.; Liang, Y.; Xie, Y.-X. J. Org. Chem. 2005, 70, 4393; (h) Liang, Y.; Xie, Y.-X.;
Li, J.-H. J. Org. Chem. 2006, 71, 379; (i) Consorti, C. S.; Flores, F. R.; Rominger, F.;
Dupont, J. Adv. Synth. Catal. 2006, 348, 133; (j) Arques, A.; Aunon, D.; Molina, P.
Tetrahedron Lett. 2004, 45, 4337; (k) Gholap, A. R.; Venkatesan, K.; Pasricha, R.;
Daniel, T.; Lahoti, R. J.; Srinivasan, K. V. J. Org. Chem. 2005, 70, 4869; (l) Yi, C.;
Hua, R. Catal. Commun. 2006, 7, 377; (m) Li, J.-H.; Zhang, X.-D.; Xie, Y.-X. Eur. J.
Org. Chem. 2005, 4256; (n) Galdino de Lima, P.; Antunes, O. A. C. Tetrahedron
Lett. 2008, 49, 2506.
a
Reaction conditions: phenylacetylene (1.5 mmol), iodobenzene (1.0 mmol), PS–
dpp–Pd(0) (0.01 mmol), piperidine (5 mL), room temperature, aerobic conditions.
b
GC yield.
In conclusion, we have developed PS–dpp–Pd(0) as a reusable
catalyst for the heterogeneous copper-free Sonogashira coupling
reaction of terminal alkynes with aryl iodides under aerobic
conditions.
4. Fukuyama, T.; Shinmen, M.; Nishitani, S.; Sato, M.; Ryu, I. Org. Lett. 2004, 4,
1691.
5. (a) Cwik, A.; Hell, Z.; Figueras, F. Tetrahedron Lett. 2006, 47, 3023; (b) Cheng, J.;
Sun, Y.; Wang, F.; Guo, M.; Xu, J.-H.; Pan, Y.; Zhang, Z. J. Org. Chem. 2004, 69, 5428.
6. (a) Corma, A.; Garciá, H.; Primo, A. J. Catal. 2006, 241, 123; (b) Markert, C.;
Bannwarth, W. Helv. Chim. Acta 2002, 85, 1877; (c) Tzschucke, C. C.; Markert, C.;
Glatz, H.; Bannwarth, W. Angew. Chem., Int. Ed. 2002, 41, 4500; (d) Tzschucke, C.
C.; Andrushko, V.; Bannwarth, W. Eur. J. Org. Chem. 2005, 5248.
7. (a) Garcia-Bernabé, A.; Tzschucke, C. C.; Bannwarth, W.; Haag, R. Adv. Synth.
Catal. 2005, 347, 1389; (b) Lu, N.; Chen, Y.-C.; Chen, W.-S.; Chen, T.-L.; Wu, S.-J.
J. Organomet. Chem. 2009, 694, 278.
8. Chow, H.-F.; Wan, C.-W.; Low, K.-H.; Yeung, Y.-Y. J. Org. Chem. 2001, 66, 1910.
9. (a) Powell, N. A.; Rychnosky, S. D. Tetrahedron Lett. 1996, 37, 7901; (b) Crisp, G.
T.; Turner, P. D.; Stephens, K. A. J. Organomet. Chem. 1998, 570, 219; (c)
Nakamura, K.; Ohubo, H.; Yamaguchi, M. Synlett 1999, 549.
Diphenylphosphinoethane-functionalized polymer-supported Pd(0)
complex 1: To a 250 mL round-bottomed flask equipped with a
magnetic stirrer bar, and containing DMF (100 mL), were added
chloromethylated polystyrene (2 g, 1.25 mmol/g of Cl) and diphen-
ylphosphinoethane (25 mmol), and the reaction mixture was stirred
for 20 h at 100 °C. The reaction mixture was filtered and washed
thoroughly with benzene or methanol and dried in vacuo for 20 h.
The diphenylphosphinoethane-functionalized polymer (1.5 g) was
treated with ethanol (50 mL) for 30 min. An ethanolic solution of
0.12 g of [PdCl2(PhCN)2] was added and the mixture heated to
80 °C for 6 h. The resulting bright-yellow colored polymer, impreg-
nated with the metal complex, was filtered, washed with ethanol,
and then stirred with hydrazine monohydrate (1 g) in ethanol
(20 mL) at 50 °C under Ar for 5 h. The resulting product was filtered,
washed with ethanol, and dried at 50 °C to give PS–dpp–Pd(0)
(Scheme 1).
Sonogashira coupling reaction; General procedure: A round-bot-
tomed flask was charged with aryl iodide (1.0 mmol), terminal
acetylene (1.5 mmol), PS–dpp–Pd(0) (0.01 mmol), and piperidine
(5 mL). The mixture was stirred at room temperature for 2–7 h un-
der aerobic conditions. Upon completion of the reaction, the solu-
tion was concentrated in vacuo, and the crude product was
subjected to silica gel column chromatography using CHCl3–
CH3OH (98:2) as eluent to afford the pure product (Table 2).
10. Kabalka, G. W.; Wang, L.; Namboodiri, V.; Pagni, R. M. Tetrahedron Lett. 2000,
41, 5151.
11. (a) McNamara, C. A.; Dixon, M. J.; Bradley, M. Chem. Rev. 2002, 102, 3275; (b)
Clapham, B.; Reger, T. S.; Janda, K. D. Tetrahedron 2001, 57, 4637; (c) de Miguel,
Y. R.; Brule, E.; Margue, R. G. J. Chem. Soc., Perkin Trans. 1 2001, 3085; (d) Nishio,
R.; Sugiura, M.; Kobayashi, S. Chem. Asian. J. 2007, 2, 983; (e) Ye, Z.-W.; Yi, W.-B.
J. Flou. Chem. 2008, 129, 1124; (f) Chen, L.; Hong, S.; Zhou, X.; Zhou, Z.; Hou, H.
Catal. Commun. 2008, 9, 2221.
12. (a) Leese, M. P.; Williams, J. M. J. Synlett 1999, 1645; (b) Lin, C.-A.; Luo, F.-T.
Tetrahedron Lett. 2003, 44, 7565; (c) Gonthier, E.; Breinbauer, R. Synlett 2003,
1049; (d) Tyrrell, E.; Al-Saardi, A.; Millet, J. Synlett 2005, 487.
13. Phan, N. T. S.; Brown, D. H.; Adams, H.; Spey, S. E.; Styring, P. Dalton Trans. 2004,
1348.
14. (a) Phan, N. T. S.; Brown, D. H.; Styring, P. Tetrahedron Lett. 2004, 45, 7915; (b)
Byun, J. W.; Lee, Y. S. Tetrahedron Lett. 2004, 45, 1837; (c) Vassylyev, O.; Chen,
J.; Panarello, A. P.; Khinast, J. G. Tetrahedron Lett. 2005, 46, 6865; (d) Shimizu,
K.; Koizumi, S.; Hatamachi, T.; Yoshida, H.; Komai, S.; Kodama, T.; Kitayama, Y.
J. Catal. 2004, 228, 141.
15. Bakherad, M.; Bahramian, B.; Isfahani, H. N.; Keivanloo, A.; Doostmohammadi,
N. J. Heterocycl. Chem. 2009, 46, 100.