Suzuki-Miyaura coupling catalyzed by polymer-incarcerated palladium, a highly active, recoverable, and reusable Pd catalyst

Article abstract of DOI:10.1021/ol049429b

Equation presented. Suzuki-Miyaura coupling using a highly efficient and reusable polymer-incarcerated palladium (Pl Pd) is described. Various coupling reactions proceeded smoothly using Pl Pd with phosphine ligands, and the catalyst could be recovered by simple filtration and reused several times without loss of activity.

Full text of DOI:10.1021/ol049429b

ORGANIC
LETTERS
2004
Vol. 6, No. 12
1987-1990
Suzuki−Miyaura Coupling Catalyzed by
Polymer-Incarcerated Palladium, a
Highly Active, Recoverable, and
Reusable Pd Catalyst
Kuniaki Okamoto, Ryo Akiyama, and Shu¯ Kobayashi*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo,
Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
skobayas@mol.f.u-tokyo.ac.jp
Received March 26, 2004
ABSTRACT
Suzuki−Miyaura coupling using a highly efficient and reusable polymer-incarcerated palladium (PI Pd) is described. Various coupling reactions
proceeded smoothly using PI Pd with phosphine ligands, and the catalyst could be recovered by simple filtration and reused several times
without loss of activity.
Palladium-catalyzed Suzuki-Miyaura coupling has become
one of the most important, powerful, and common methods
for carbon-carbon bond formation1 and has been widely
used not only in academic laboratories but also in industry.
In general, soluble palladium complexes with ligands such
as phosphines, amines, or carbenes are used as the catalysts
for such couplings, where the choice of the ligands often
allows tuning of the catalytic activity and selectivity.2
However, many of the currently used catalysts are sensitive
to air oxidation and cannot be recovered in many cases.
Despite many attempts at using palladium metal immobilized
on supports, most have lower catalytic activity compared with
homogeneous catalysts, and moreover, the recovery and reuse
of such catalysts has often not been satisfactory.3,4 Although
(2) (a) Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc.
1998, 120, 9722. (b) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 1998,
37, 3387. (c) Herrmann, W. A.; Reisinger, C.-P.; Spiegler, M. J. Organomet.
Chem. 1998, 557, 93. (d) Zhang, C.; Huang, J.; Trudell, M. L.; Nolan, S.
P. J. Org. Chem. 1999, 64, 3804. (e) Bei, X.; Crevier, T.; Guran, A. S.;
Jandeleit, B.; Powers, T. S.; Turner, H. W.; Uno, T.; Weinberg, W. H.
Tetrahedron Lett. 1999, 40, 3855. (f) Wolfe, J. P.; Singer, R. A.; Yang,
B. Y.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 9550. (g)
Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020. (h)
Grasa, G. A.; Hillier, A. C.; Nolan, S. P. Org. Lett. 2001, 3, 1077. (i)
Kataoka, N.; Shelby Q.; Stambuli, J. P.; Hartwig J. F. J. Org. Chem. 2002,
67, 5553.
(3) For recent reviews, see: (a) de Miguel, Y. R. J. Chem. Soc., Perkin
Trans. 1 2000, 4213. (b) Shuttleworth, S. J.; Allin, S. M.; Wilson, R. D.;
Nasturica, D. Synthesis 2000, 1035. (c) Loch, J. A.; Crabtree, R. H. Pure
Appl. Chem. 2001, 73, 119. (d) Corain, B.; Kralik, M. J. Mol. Catal. A:
Chem. 2001, 173, 99. (e) Bergbreiter, D. E. Curr. Opin. Drug DiscoVery
DeV. 2001, 4, 736.
(4) Recently, a highly active hydroxyapatite-supported Pd(II) catalyst
has been reported. Mori, K.; Yamaguchi, K.; Hara, T.; Mizugaki, T.; Ebitani,
K.; Kaneda, K. J. Am. Chem. Soc. 2002, 124, 11572.
(1) For reviews, see: (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95,
2457. (b) Suzuki, A. J. Organomet. Chem. 1999, 576, 147. (c) Suzuki, A.
In Metal-Catalyzed Cross-coupling Reactions; Diederich, F., Stang, P. J.,
Eds.; Wiley-VCH: Weinheim, Germany, 1998; p 49. (d) Organometallics
in Synthesis: A Manual; Schlosser, M., Ed.; Miley: West Sussex, UK,
2002. (e) Stanforth, S. P. Tetrahedron 1998, 54, 263. (f) Thompson, L. A.;
Ellman, J. A. Chem ReV. 1996, 96, 555. (g) Tsuji, J. In Palladium Reagents
and Catalysts: InnoVations in Organic Synthesis; Wiley: Chichester, UK,
1995. (h) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M.
Chem. ReV. 2002, 102, 1359.
10.1021/ol049429b CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/13/2004

immobilized palladium catalysts based on polymer-supported
phosphines or amines, etc., have been developed,5 only
immobilized ligands can be used because additional external
ligands often induce leaching of the metals.
Table 1. Effect of Phosphine Ligands
Recently, we developed a method for immobilizing metal
catalysts onto polymers: polymer incarceration (PI).6,7 The
method is based on microencapsulation8 and cross-linking
of polymer chains. Using this approach, Pd(PPh3)4 was
successfully immobilized to form polymer-incarcerated pal-
ladium (PI Pd, 1, Figure 1).9 PI Pd consists of phosphine-
a Isolated yield.
Figure 1. Polymer-incarcerated method.
Solvents and bases were next examined, and leaching of the
palladium was measured by fluorescence X-ray (XRF)
analysis10 after removal of the catalyst (Table 2). Although
leaching of the palladium was observed when THF or toluene
free palladium(0) and effectively catalyzes hydrogenations.6,7
In addition, allylation reactions proceed smoothly using this
catalyst in the presence of triphenylphosphine as an external
ligand.6 In this manner, PI Pd has an advantage as a
recoverable and reusable catalyst applicable to other reactions
by choosing suitable ligands. In this paper, we report a
remarkably high activity of PI Pd in Suzuki-Miyaura
couplings.
Table 2. Effect of Bases and Solvents
PI Pd (1) was initially examined in the coupling reaction
of 2-bromotoluene (2) with phenylboronic acid (3); several
phosphine ligands were tested as additives (Table 1).
Triphenylphosphine, tricyclohexylphosphine, and triphenyl
phosphite were not effective ligands under these reaction
conditions. On the other hand, triarylphosphines having
electron-donating groups gave the desired 2-methylbiphenyl
(4) in high yields. The best result was obtained when tris-
(o-methoxyphenyl)phosphine (5) was used as a ligand.
leachingb
yielda (%) of Pd (%)
entry
base
solvent
1
2
3
4
5
6
7
K3PO4
K3PO4
K2CO3
K2CO3
K3PO4
THF
97
54
89
83
88
48
86
33
44
15
nd
nd
nd
nd
toluene
THF-H2O (4/1)
toluene-H2O (4/1)
toluene-H2O (4/1)
Na2CO3 toluene-H2O (4/1)
K2CO3 toluene-EtOH (4/1)
(5) (a) Trost, B. M.; Keinan, E. J. Am. Chem. Soc. 1978, 100, 7779. (b)
Jang, S.-B. Tetrahedron Lett. 1997, 38, 1793. (c) Fenger, I.; Drian, C. L.
Tetrahedron Lett. 1998, 39, 4287. (d) Uozumi, Y.; Danjo, H.; Hayashi, T.
J. Org. Chem. 1999, 64, 3384. (e) Zecca, M.; Fisera, R.; Palma, G.; Lora,
S.; Hronec, M.; Kra´lik, M. Chem.sEur. J. 2000, 6, 1980. (f) Li, Y.; Hong,
X. M.; Collard, D. M.; Ei-Sayed, M. A. Org. Lett. 2000, 2, 2385. (g) Parrish,
C. A.; Buchwald, S. L. J. Org. Chem. 2001, 66, 3820. (h) Niu, Y.; Yeung,
L. K.; Crooks, R. M. J. Am. Chem. Soc. 2001, 123, 6840. (i) Mubofu, E.
B.; Clark, J. H.; Macquarrie, D. J. Green Chem. 2001, 3, 23. (j) Cammidge,
A. N.; Baines, N. J.; Bellingham, R. K. Chem. Commun. 2001, 2588. (k)
Gordon, R. S.; Holmes, A. B. Chem. Commun. 2002, 640. (l) Jansson, A.
M.; Grøti, M.; Halkes, K. M.; Meldal, M. Org. Lett. 2002, 4, 27. (m)
Yamada, Y. M. A.; Takeda, K.; Takahashi, H.; Ikegami, S. J. Org. Chem.
2003, 68, 7733.
(6) Akiyama, R.; Kobayashi, S. J. Am. Chem. Soc. 2003, 125, 3412.
(7) Okamoto, K.; Akiyama, R.; Kobayashi, S. J. Org. Chem. 2004, 69
2871.
(8) (a) Kobayashi, S.; Nagayama, S. J. Am. Chem. Soc. 1998, 120, 2985.
(b) Nagayama, S.; Endo, M.; Kobayashi, S. J. Org Chem. 1998, 63, 6094.
(c) Kobayashi, S.; Endo, M.; Nagayama, S. J. Am. Chem. Soc. 1999, 121,
11229. (d) Kobayashi, S.; Ishida, T.; Akiyama, R. Org. Lett. 2001, 3, 2649.
(e) Akiyama, R.; Kobayashi, S. Angew. Chem., Int. Ed. 2001, 40, 3469. (f)
Akiyama, R.; Kobayashi, S. Angew. Chem., Int. Ed. 2002, 41, 2602.
(9) Experimental details are shown in the Supporting Information.
a Isolated yield. b Measured by XRF analysis. nd ) not detected
(<0.94%).
was used as a solvent, addition of water was found to
decrease the leaching. In a toluene-H2O (4/1) cosolvent
system, no leaching of the palladium was detected. The
leaching of the palladium seems to be influenced by a phase
separation behavior.
The catalytic activity of PI Pd was compared with that of
the homogeneous catalysts palladium acetate and tetrakis-
(triphenylphosphine)palladium in the coupling reaction of
2-bromotoluene (2) with phenylboronic acid (3). Judging
from the time-yield curves using 5 mol % of the catalysts
(10) The lower detection limit is 5 ppm (0.94%).
1988
Org. Lett., Vol. 6, No. 12, 2004

Table 3. Reuse of PI Pda
run
1
2
3
4
5
yieldb (%)
leaching of Pdc
83
nd
88
nd
85
nd
85
nd
83
nd
a After the reaction, the mixture was diluted with hexane and the catalysts
was filtered off. The catalyst was reused after washing with THF, H2O,
and MeOH, successively, and dried. b Isolated yield. c Measured by XRF
analysis. nd ) not detected (<0.94%).
Figure 2. Plot of yield versus time for Suzuki-Miyaura coupling
using 5 mol % of catalyst: Yields were determined by GC analysis
with internal standard method. Reaction condition: 1.0 equiv of
2-bromotoluene, 1.5 equiv of phenylboronic acid, 2.0 equiv of K3-
PO4, 5 mol % of Pd catalyst, 5 mol % of 5, toluene-H2O (4/1),
reflux.
used as a ligand, yields were lower and some leaching of
palladium was observed. Recently, Buchwald et al. have
Table 4. PI Pd-Catalyzed Couplings of Various Substratesa
(Figure 2), the activity of PI Pd was almost the same as that
of palladium acetate and was higher than that of tetrakis-
(triphenylphosphine)palladium. To compare the activity of
PI Pd with that of the homogeneous catalysts more precisely,
we conducted the same reaction in the presence of 0.1 mol
% of the catalysts (Figure 3). It was exciting to find that PI
Pd exhibited higher activity than that of both homogeneous
catalysts.
Figure 3. Plot of yield versus time for Suzuki-Miyaura coupling
using 0.1 mol % of catalyst: Yields were determined by GC
analysis with internal standard method. Reaction conditions 1.0
equiv of 2-bromotoluene, 1.5 equiv of phenylboronic acid, 2.0 equiv
of K3PO4, 0.1 mol % of Pd catalyst, 0.1 mol % of 5, toluene-H2O
(4/1), reflux.
Furthermore, PI Pd was recovered by simple filtration and
could be reused several times without loss of activity. No
leaching of the palladium was detected by XRF analysis in
all runs shown in Table 3.
Several examples of PI Pd-catalyzed Suzuki-Miyaura
coupling of aryl halides with arylboronic acids are sum-
marized in Table 4. Both electron-rich and electron-deficient
arylhalides are reactive, and the desired coupling adducts
are obtained in good yields without any leaching of the
palladium.
a Reaction conditions: 1.0 equiv of aryl halide, 1.5 equiv of boronic
acid, 2.0 equiv of K3PO4, 5 mol % of 1 (0.15 mmol/g), 5 mol % of 5,
toluene-H2O (4/1), reflux, 2 h. Workup conditions: Reaction mixture was
diluted with hexane, and the catalyst was filtered off and then washed with
THF and MeOH. b Isolated yield. c Measured by XRF analysis. nd ) not
detected (<0.94%).
Sterically hindered substrates have also been examined
(Table 5). When tris(o-methoxyphenyl)phosphine (5) was
Org. Lett., Vol. 6, No. 12, 2004
1989

one advantage of PI Pd over other polymer-supported
palladium catalysts is that various ligands can be selected
in each reaction.
Table 5. PI Pd-Catalyzed Couplings of Hindered Substratesa
Finally, we evaluated the minimum amount of catalyst that
could be used to mediate several coupling reactions (Table
6). Reactions that use very small amounts of the catalyst
also afford the desired coupling products with high turnover
numbers (TONs). The maximum TON reached 53 600 (entry
5). In this system, we carefully looked for any catalytic effect
for the filtrate (Scheme 1). Thus, after coupling 7 (0.5 mmol)
Scheme 1. Filtrate Test in Suzuki-Miyaura Coupling Using
PI Pd
a Reaction conditions: 1.0 equiv of aryl bromide, 1.5 equiv of boronic
acid, 2.0 equiv of K3PO4, 5 mol % of 1 (0.15 mmol/g), 5 mol % of ligand,
toluene-H2O (4/1), reflux, 2 h. Workup conditions: Reaction mixture was
diluted with hexane, and the catalyst was filtered off and then washed with
THF and MeOH. b Isolated yield. c Measured by XRF analysis. nd ) not
detected (< 0.94%).
reported that 2-(dicyclohexylphosphino)biphenyl (6) is an
effective ligand for the Suzuki-Miyaura coupling of hin-
dered substrates.2f We tested this ligand and confirmed that
6 was also effective for the coupling reactions with the
hindered substrates of our system. It is noteworthy that not
only were the yields improved but also the leaching of the
palladium was suppressed using the new phosphine ligand.
We assumed at this stage that the palladium might leach out
as palladium(II) intermediates from PI Pd when regeneration
of palladium(0) was prevented in a catalytic cycle. In general,
the character of palladium are strongly dependent on the
ligands selected. It should be noted from these results that
with 8 (0.75 mmol) using 0.1 mol % each of PI Pd and ligand
(5) and potassium phosphate (1.0 mmol), the PI Pd was
removed by simple filtration, and to the filtrate were added
7 (0.5 mmol), 8 (0.75 mmol), and potassium phosphate (1.0
mmol). The mixture was refluxed for 72 h, but no additional
formation of 9 was observed. This result showed that
dissolved active palladium species did not exist in the
solution phase of the reaction mixture.
In summary, we have revealed that PI Pd is a highly
efficient reusable catalyst for Suzuki-Miyaura coupling.
Various coupling reactions proceeded smoothly by using PI
Pd. PI Pd was recovered by simple filtration and reused
several times without loss of activity, and no leaching of
the palladium was detected under all optimized conditions.
It is noted that the activity of PI Pd is even higher than that
of homogeneous palladium catalysts. One characteristic
feature of PI Pd as an immobilized catalyst is that the activity
of the catalyst is remarkably improved by changing the
external phosphine ligands. Further investigations on other
PI Pd-catalyzed coupling reactions are now in progress.
Table 6. The Minimum Amount of the Catalysta
Acknowledgment. This work was partially supported by
CREST, SORST, and ERATO, Japan Science Technology
Agency (JST), and a Grant-in-Aid for Scientific Research
from the Japan Society of the Promotion of Sciences (JSPS).
Supporting Information Available: Experimental pro-
cedures and spectral data for products. This material is
available free of charge via the Internet at http://pubs.acs.org.
a Reaction conditions: 1.0 equiv of aryl bromide, 1.5 equiv of boronic
acid, 2.0 equiv of K3PO4, 1/5 ) 1, toluene-H2O (4/1), reflux. b Isolated
yield. c GC yield.
OL049429B
1990
Org. Lett., Vol. 6, No. 12, 2004