An easily accessible resin-supported palladium catalyst for Sonogashira coupling

Article abstract of DOI:10.1055/s-2003-39305

Readily available aminomethyl-polystyrene beads can be transformed in a one-pot reaction to an air-stable polymer-bound chelate phosphine, which can be used for the immobilization of homogeneous catalysts. Such prepared Pd catalysts have proven to be useful reagents for mediating Sonogashira-coupling reactions.

Full text of DOI:10.1055/s-2003-39305

LETTER
1049
An Easily Accessible Resin-Supported Palladium Catalyst for Sonogashira
Coupling
A
R
esin-Suppor
l
te
d
Pa
l
i
ladium
s
Catalyst
a
f
or Sonogas
b
hira Couplin
e
g
th Gonthier, Rolf Breinbauer*
Max-Planck-Institute for Molecular Physiology, Dortmund, and Fachbereich 3, University Dortmund, Germany, Otto-Hahn-Str. 11,
44227 Dortmund
Fax +49(231)1332499; E-mail: rolf-peter.breinbauer@mpi-dortmund.mpg.de
Received 6 March 2003
storage in normal bottles with unlimited shelf life (3).
Over the last few years the N,N-bis(diphenylphosphino-
methyl)amino-functionality has been used for the prepa-
ration of dendrimer-bound and supramolecular
homogeneous catalysts.3 Just recently insoluble versions
of this chelating ligand have been applied in Rh-catalyzed
hydroformylation and Ru-catalyzed hydrogenation.4 This
paper describes the simple and fast preparation of immo-
bilized Pd-catalysts fulfilling the criteria detailed above.5
Abstract: Readily available aminomethyl-polystyrene beads can
be transformed in a one-pot reaction to an air-stable polymer-bound
chelate phosphine, which can be used for the immobilization of ho-
mogeneous catalysts. Such prepared Pd catalysts have proven to be
useful reagents for mediating Sonogashira-coupling reactions.
Key words: combinatorial chemistry, catalyst, cross-coupling,
solid-phase, palladium
Parallel combinatorial synthesis in solution using immo-
bilized reagents, catalysts, and scavengers has emerged as
a powerful technique for the preparation of diverse librar-
ies of compounds. The groups of Ley and others have
demonstrated the practicability of this approach in synthe-
sizing complex natural products by multi-step sequences
requiring many different kinds of heterogenized reagents,
which can be removed by simple filtration.1 Especially the
immobilization of transition metal catalysts has attracted
a lot of attention, as the high cost of these metals defines
the recycling of these catalysts a desirable goal.2 Further-
more the intrinsic toxicity of most transition metals makes
the complete removal of even traces thereof an imperative
for providing substances qualified for biological testing.
Although many literature reports exist for the immobiliza-
tion of transition metal catalysts, most of these strategies
require multi-step sequences for the synthesis of the
ligands. Our approach was guided by three imperatives:
the polymeric reagent should be easily accessible (1),
starting from inexpensive reagents (2). The ligand should
be air stable at room temperature, which should allow its
Bis(diphenylphosphinomethyl)aminomethylpolystyrene
(3) can be easily synthesized by heating readily available
aminomethyl polystyrene (1) (Novabiochem 01-64-0010,
1% cross-linking, 200-400 mesh, 1.13 mmol/g loading)
with an excess of diphenylphosphinomethanol (2), which
resulted from adduct formation between diphenylphos-
phine and paraformaldehyde (Scheme 1).6 The identity of
the resin bound phosphine was confirmed by gel phase 31P
NMR, which revealed a single peak at d = –27 ppm, in
perfect agreement with the values reported for homoge-
neous analogues of this ligand.3 Elemental analysis re-
vealed that the modification of 1 has been carried out in
quantitative yield. In order to investigate its stability, resin
3 was stored at room temperature under air. After six
31
months this sample was subjected again to gel phase P
NMR. Additional formation of P(V)-species was not de-
tectable, which convincingly demonstrates the high stabil-
ity of these resin-bound bidentate ligands. After having
secured the identity of these ligands we explored its po-
tential for the preparation of transition metal catalysts.
Palladium catalyst 4 was prepared by ligand metathesis
excess Ph2PCH2OH
1.1 equiv (COD)PdCl2
P
P
P
2
N
PdCl2
NH2
N
P
26 h, 60 °C
toluene, 100 °C, 1 d
1
3
4
Scheme 1 Synthesis of resin-bound Pd catalyst 4
Synlett 2003, No. 7, Print: 02 06 2003.
Art Id.1437-2096,E;2003,0,07,1049,1051,ftx,en;G29502ST.pdf.
© Georg Thieme Verlag Stuttgart · New York

1050
E. Gonthier, R. Breinbauer
LETTER
4 % 4
I
5 % CuI
1.4 eq
+
H
1,4-dioxane/piperidine
(2/1)
6a
7a
60 °C, overnight
5a
Run 1:
Run 2:
Run 3:
Run 4:
99 % yield
99 % yield
99 % yield
99 % yield
Scheme 2 Recycling experiments in the Sonogashira reaction with catalyst 4
reaction through stirring 3 with (COD)PdCl2. Quantitative highly attractive supported reagent for the parallel solu-
incorporation of Pd could be confirmed by elemental anal- tion phase synthesis of combinatorial libraries.
ysis and gel phase 31P NMR (d = 9.2 ppm).7 We screened
In conclusion, we have developed a simple strategy for the
our freshly prepared catalysts in the Sonogashira-cou-
preparation of Pd-catalysts bound on polymeric sup-
pling of a representative set of iodoaromatics with termi-
ports.11 These catalysts exhibited good reactivity in the
nal alkynes.8 Despite the general use of this reaction in
Sonogashira-coupling of iodoaromatics, which compares
organic synthesis, solid-supported catalysts have not been
well to all other published results with heterogenized Pd-
widely used for this reaction yet.9
catalysts.9 Additional studies on the reactivity of the resin
Using 4 mol% of catalyst 4 we investigated the catalytic bound Pd catalysts 4 and applications to the generation of
activity and recyclability of our catalyst. Even after 4 runs solution phase libraries are in progress and will be the sub-
we observed complete conversion of substrate 5a to prod- ject of future reports.
uct 7a overnight (Scheme 2).
Having identified the appropriate reaction conditions for Acknowledgment
the Sonogashira-reaction we investigated the scope of the
This work was supported by the Fonds der Chemischen Industrie,
reaction. We observed complete conversion for all sub-
strates after 2 hours at 60 °C, irrespective of the electronic
nature of the substituents of iodobenzenes 5a–e. Only the
reaction with the less reactive alkyne 1-hexyne (6b) re-
quired slightly longer reaction times, but also led to com-
plete conversion of starting materials (Scheme 2,
Table 1). After removal of the resin bound catalysts by fil-
tration coupling products 7a–m were isolated in very
good to excellent yields (Table 1).10 The good catalytic
performance and the easy accessibility of 4 make them a
Frankfurt, (Liebig-scholarship for R. B.) and the Max-Planck-So-
ciety (pre-doctoral stipend for E. G.). The authors thank C. Peters
and L. Wittenberg for helpful discussions. The ongoing support and
encouragement of Prof. H. Waldmann is gratefully acknowledged.
References
(1) For leading reviews see:.(a) Kirschnig, A.; Monenschein,
H.; Wittenberg, R. Angew. Chem. Int. Ed. 2001, 40, 650..
(b) Ley, S. V.; Baxendale, I. R.; Bream, R. N.; Jackson, P.
S.; Leach, A. G.; Longbottom, D. A.; Nesi, M.; Scott, J. S.;
R3
1.6 % 4
I
2 % CuI
R3
1.4 equiv
H
+
R1
R2
R1
R2
1,4-dioxane/piperidine
(2/1)
6
7
60 °C
5
R2 =
R1 =
H
R2 =
Ph
(6a)
H
(5a)
(5b)
C4H9 (6b)
Me
H
H
OMe
Me
(6c)
O
(5c)
OH
Me
(5d)
(5e)
H
CO2Me
CO2Me
H
Scheme 3 Sonogashira coupling with resin-bound Pd catalyst 4
Synlett 2003, No. 7, 1049–1051 ISSN 1234-567-89 © Thieme Stuttgart · New York

LETTER
A Resin-Supported Palladium Catalyst for Sonogashira Coupling
1051
techniques. Aminomethyl-resin beads (1) are carefully
Table 1 Sonogashira Coupling Reactions (Scheme 3)
degassed by swelling the beads in dry toluene and removing
the solvent in vacuo (repeated 1×) (This procedure is
necessary to avoid P(V) formation during the preparation of
3 due to trapped oxygen molecules in untreated 1.
Meanwhile, a second Schlenk flask is charged with para-
formaldehyde (4 equiv), dry MeOH and diphenylphosphine
(4 equiv). This reaction mixture is heated to 60 °C until the
white suspension forms a colorless solution. After removal
of MeOH in vacuo the remaining viscous oil is diluted in dry
toluene. This solution is added to the beads swollen in dry
toluene. The reaction mixture is heated to 105 °C overnight.
In the cooler regions of the flask the water–toluene azeotrope
separates indicating the reaction progress. After cooling to
r.t. the beads are collected by filtration under argon. The
beads are washed extensively with dry toluene (4×), CH2Cl2/
THF (1/1) (2×) and CH2Cl2 (2×). The beads are dried in
vacuo until the weight remains constant. We have
successfully applied this procedure for the preparation of 3
using several types of polystyrene resins (varying in grain
size, degree of cross-linking, and loading), Tentagel-resin,
and macroporous beads.
Entry
5
6
7
Reaction Conversion Isolated
time
(h)
(%)
yield
(%)
1
2
5a
5a
5a
5b
5b
5b
5c
5c
5c
5d
5d
5d
5e
6a
6b
6c
6a
6b
6c
6a
6b
6c
6a
6b
6c
6a
7a
7b
7c
7d
7e
7f
2
21
2
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
99
86a)
89
92
99
91
99
99
94
98
99
93
97
3
4
2
5
21
2
6
7
7g
7h
7i
2
8
3
9
2
10
11
12
13
7j
2
(7) Experimental Procedure for Ligand Metathesis:
All reactions are carried out under an argon atmosphere
using Schlenk-techniques. To polystyrene beads 3 (3 g, 2.31
mmol), swollen in 120 mL degassed CHCl3, is added 1.1
equiv (COD)PdCl2. The reaction mixture is heated at 60 °C
for 26 h. After cooling to r.t. the beads are collected by
filtration under argon. The beads are washed extensively
with degassed CHCl3 (4 × 40 mL), EtOH (1 × 40 mL) and
dry CH2Cl2 (3 × 40 mL). The beads are dried in vacuo until
the weight remains constant. Elemental analysis: 0.81% N,
3.22% P, 5.72% Pd (elemental analyses have been carried
out by Mikroanalytisches Laboratorium H. Kolbe, Mülheim/
Ruhr).
7k
7l
8
2
7m
2
a Due to the volatility of this compound we were unable to isolate this
compound without residual solvent. The reported yield has been cal-
culated by subtracting residual solvent from isolated material based
on the 1H NMR signals.
Storer, R. I.; Taylor, S. J. J. Chem. Soc., Perkin Trans. 1
2000, 3815..(c) Parlow, J. J.; Devraj, R. V.; South, M. S.
Curr. Opin. Chem. Biol. 1999, 3, 320..(d) Kaldor, S. W.;
Siegel, M. G. Curr. Opin. Chem. Biol. 1997, 1, 101.
(2) Recent reviews:.(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.
(3) For example:.(a) Mizugaki, T.; Murata, M.; Ooe, M.;
Ebitani, K.; Kaneda, K. Chem. Commun. 2002, 52..(b) La
Pointe, A. M. J. Comb. Chem. 1999, 1, 101..(c) Reetz, M.
T.; Lohmer, G.; Schwickardi, R. Angew. Chem., Int. Ed.
Engl. 1997, 36, 1526..(d) Reetz, M. T.; Waldvogel, S. R.
Angew. Chem., Int. Ed. Engl. 1997, 36, 865.
(4) (a) Reetz, M. T.; Becker, M. unpublished results..
(b) Becker, M. Diplomarbeit; Universität: Marburg, 1997..
(c) Arya, P.; Panda, G.; Rao, N. V.; Alper, H.; Bourque, S.
C.; Manzer, L. E. J. Am. Chem. Soc. 2001, 123, 2889..
(d) Hudkins, C. M. G.; Knights, K. A.; Johnson, B. F. G.; de
Miguel, Y. R.; Raja, R.; Thomas, J. M. Chem. Commun.
2001, 2624..(e) Kayaki, Y.; Shimokawatoko, Y.; Ikariya, T.
Adv. Synth. Catal. 2003, 345, 175.
(8) Tsuji, J. Palladium Reagents: Innovations in Organic
Synthesis; Wiley: New York, 1998.
(9) (a) Uozumi, Y.; Kobayahsi, Y. Heterocycles 2003, 29,
1255..(b) Leese, M. P.; Williams, J. M. J. Synlett 1999,
1645..(c) Cai, M.-Z.; Song, C.-S.; Huang, X. Synth.
Commun. 1997, 27, 1935..(d) Bergbreiter, D. E.; Liu, Y.-S.
Tetrahedron Lett. 1997, 38, 7843..(e) Villemin, D.; Goussu,
D. Heterocycles 1989, 29, 1255..(f) Terasawa, M.; Kaneda,
K.; Imanaka, T.; Teranishi, S. J. Organomet. Chem. 1978,
162, 403.
(10) Representative Experimental Procedure: Synthesis of
Diphenylacetylene (7a):
In a light protected Schlenk-flask polystyrene-supported Pd-
catalyst 4 (44.2 mg, 0.024 mmol Pd) was allowed to swell 5
min under argon atmosphere in degassed 1,4-dioxane:
piperidine (2:1) (15 mL). Iodobenzene (5a) (1.5 mmol,
306.3 mg), phenylacetylene (6a) (2.1 mmol, 214.8 mg) and
copper(I)iodide (0.03 mmol, 5.8 mg) were added to the
catalyst. The mixture was slowly stirred under argon at
60 °C for 2 h. The Pd-beads were separated from the mixture
by filtration and washed with CH2Cl2 (4 × 20 mL). The
solution was washed with a sat. solution of ammonium
chloride (1 × 30 mL) (this extractive step removes Cu-
impurities by formation of the water soluble Cu-tetraamine
complex) and the aqueous layer was extracted with CH2Cl2
(2 × 15 mL). The combined organic layers were dried over
Na2SO4 and the solvent removed in vacuo. Purification by
flash chromatography (SiO2, pentane) provided 265.2 mg 7a
(99%, colorless crystals).
(5) Parallel to our work the group of Uozumi has prepared
amphiphilic Pd catalysts for Suzuki- and Heck-couplings
using Argogel–NH2 applying a similar strategy:.
(a) Uozumi, Y.; Nakai, Y. Org. Lett. 2002, 4, 2997..
(b) Uozumi, Y.; Kimura, T. Synlett 2002, 2045..(c)
Palladium complexes immobilized on dendrimer modified
silica and their application in the Heck reaction have also
been reported: Alper, H.; Prabhat, A.; Bourque, S. C.;
Jefferson, G. R.; Manzer, L. E. Can. J. Chem. 2000, 78, 920.
(6) General Experimental Procedure: All reactions are
carried out under an atmosphere of argon using Schlenk-
(11) Polymeric bound Pd catalyst 4 can be stored for several
months without any significant loss of activity (Schlenk
flask, argon, 4 °C).
Synlett 2003, No. 7, 1049–1051 ISSN 1234-567-89 © Thieme Stuttgart · New York