Highly efficient and reusable supported Pd catalysts for Suzuki-Miyaura reactions of aryl chlorides

Article abstract of DOI:10.1021/ol701460z

Syntheses of air- and moisture-stable heterogeneous (tert- butylarylphosphino)polystyrene-supported Pd catalysts and their use for versatile Suzuki-Miyaura reactions of aryl chlorides and arylboronic acids under non-anhydrous conditions are reported. The catalysts are easily recovered by filtration. They can be used many times (more than seven) without showing any loss of activity, and the amount of Pd leached is extremely low (<0.1%).

Full text of DOI:10.1021/ol701460z

ORGANIC
LETTERS
2
007
Vol. 9, No. 19
777-3780
Highly Efficient and Reusable Supported
3
Pd Catalysts for Suzuki
−
Miyaura
†
Reactions of Aryl Chlorides
St e´ phane Schweizer, Jean-Michel Becht,* and Claude Le Drian*
UniVersit e´ de Haute-Alsace, Ecole Nationale Sup e´ rieure de Chimie de Mulhouse
Laboratoire de Chimie Organique et Bioorganique, UMR-CNRS 7015,
3
rue Alfred Werner, 68093 Mulhouse cedex, France
jean-michel.becht@uha.fr
Received June 20, 2007
ABSTRACT
Syntheses of air- and moisture-stable heterogeneous (tert-butylarylphosphino)polystyrene-supported Pd catalysts and their use for versatile
Suzuki Miyaura reactions of aryl chlorides and arylboronic acids under non-anhydrous conditions are reported. The catalysts are easily
−
recovered by filtration. They can be used many times (more than seven) without showing any loss of activity, and the amount of Pd leached
is extremely low (<0.1%).
The Suzuki-Miyaura Pd-catalyzed cross-coupling reaction
of aryl halides with arylboronic acids is a fundamental
transformation in modern organic synthesis and offers a
powerful way for the construction of aryl-aryl bonds under
The Suzuki-Miyaura reaction is usually performed by
reacting aryl bromides or iodides with arylboronic acids in
7
the presence of a homogeneous (soluble) Pd catalyst. From
an industrial point of view, aryl chlorides are much more
advantageous due to their low price and to their large
1
mild reaction conditions. The resulting biaryls are often key
8
building blocks for the preparation of more elaborated
molecules which find widespread applications in the fields
availability. However, their major drawback is their relative
inertness. The development of highly active homogeneous
Pd catalysts for Suzuki-Miyaura reactions involving aryl
chlorides arose, therefore, considerable interest. Significant
success has been achieved in this field by the groups of
2
3
of medicinal chemistry, molecular recognition, liquid
4
5
crystals, and metal ligands for catalysis. In addition, their
synthesis is frequently performed on an industrial scale.
6
9
10
11
12
13
14
Buchwald, Fu, Beller, Herrmann, Nolan, and others.
†
This paper is dedicated to the memory of Prof. Charles Mioskowski,
who passed away on June 2, 2007.
(6) Corbet, J.-P.; Mignani, G. Chem. ReV. 2006, 106, 2651.
(1) (a) Diederich, F., Stang, P. J., Eds. Metal-Catalyzed Cross-Coupling
(7) (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457. (b) Hassan,
J.; S e´ vignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. ReV. 2002,
102, 1359.
Reactions; Wiley-VCH: Weinheim, 1998. (b) Tsuji, J. Palladium Reagents
and Catalysts; John Wiley and Sons: New York, 1995.
(
2) Lloyd-Williams, P.; Giralt, E. Chem. Soc. ReV. 2001, 3, 145 and
references therein.
3) (a) Pu, L. Chem. ReV. 1998, 98, 2405. (b) Schulte, J. L.; Laschat, S.;
Vill, V.; Nishikawa, E.; Finkelmann, H.; Nimtz, M. Eur. J. Org. Chem.
998, 2499.
4) (a) Poetsch, E. Kontakte 1988, 15. (b) Tietze, L. F.; Kettschau, G.;
Heuschert, U.; Nordmann, G. Chem.-Eur. J. 2001, 7, 368.
5) Spivey, A. C.; Fekner, T.; Spey, S. E. J. Org. Chem. 2000, 65, 3154.
(8) (a) Grushin, V. V.; Alper, H. Chem. ReV. 1994, 94, 1047. (b) Littke,
A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176.
(
(9) (a) Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2004, 43, 1871. (b) Anderson, K. W.; Buchwald,
S. L. Angew. Chem., Int. Ed. 2005, 44, 6173. (c) Barder, T. E.; Walker, S.
D.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4685.
(10) (a) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 1998, 37, 3387.
(b) Liu, S.-Y.; Choi, M. J.; Fu, G. C. Chem. Commun. 2001, 2408.
1
(
(
1
0.1021/ol701460z CCC: $37.00
© 2007 American Chemical Society
Published on Web 08/23/2007

The major disadvantages of these Pd catalysts lie in the
difficulty to avoid the presence of small amounts of metal
in the reaction product and the impossibility to recover the
expensive catalysts for reuse. Because homogeneous Pd
catalysts have found widespread use in synthesis, the
development of heterogeneous alternatives where the metal
is grafted on inorganic or organic supports has attracted great
attention in the past years.15 Despite the fact that numerous
heterogeneous Pd catalysts have been described for Suzuki-
for the Pd-catalyzed coupling of electron-deficient aryl
chlorides and phenylboronic or 4-methylphenylboronic acid,
but only one coupling of a deactivated (i.e., electron-rich)
aryl chloride has been described, moreover affording a very
1
8c
low yield. The development of reusable Pd catalysts of
general application for Suzuki-Miyaura reactions using aryl
chlorides is therefore highly desirable. Herein, we describe
short syntheses of (aryl-tert-butylphosphino)polystyrene-
supported Pd catalysts and their use for Suzuki-Miyaura
16
19
Miyaura reactions involving aryl bromides or iodides, only
couplings of aryl chlorides.
few such Pd catalysts have been reported to date for cross-
Inspired by a precedent report from our group, the
couplings with aryl chlorides.1
7,18
Moreover, compared to
syntheses of catalysts 2a-f and 2′a were performed (Scheme
1
6f
their homogeneous analogues, heterogeneous Pd catalysts
often suffer from a lower efficiency, which sometimes
1). Elemental analysis proved that more than 99% of the
happens to decrease1 or even disappear after use. In 2000,
Miyaura and Inada have reported Suzuki-Miyaura reactions
of electron-deficient aryl chlorides or chloropyridines with
8c
18d
Scheme 1. Preparation of Catalysts 2a-f and 2′a
4-methylphenylboronic acid in the presence of relatively high
amounts of (diphenylphosphino)polystyrene-supported Pd (3
mol %).1 Later, Buchwald and Parrish have described a
five-step preparation of polymer-supported dialkylphosphi-
8a
1
8b
nobiphenyls which have been used as Pd ligands for
Suzuki-Miyaura couplings of aryl bromides or chlorides
under anhydrous conditions, but the reactions involving aryl
chlorides require a large excess of arylboronic acids (3 equiv)
and up to 1 mol % of Pd to afford the biaryls in high yields.
The group of Bedford has reported that polystyrene-supported
palladacycles performed Suzuki-Miyaura couplings involv-
ing aryl chlorides, but these heterogeneous catalysts cannot
1
8d
be reused. Finally, Sinou and his group have developed a
polymer-supported (dicyclohexylphosphino)biphenyl ligand
* 1f is commercially available.
amount of Pd used was grafted on the resin and that
comparable P/Pd ratios were obtained for 2a-f (for further
details see Supporting Information). Finally, catalysts 2a and
2′a were successfully prepared on a 20 g scale. They are
air- and moisture-stable and can therefore be easily stored
and handled.
The reactivity of catalysts 2a-f and 2′a for Suzuki-
Miyaura reactions was then evaluated using 4-chloroaceto-
phenone and phenylboronic acid as model substrates (Table
(
11) (a) Zapf, A.; Ehrentraut, A.; Beller, M. Angew. Chem., Int. Ed. 2000,
9, 4153. (b) Zapf, A.; Jackstell, R.; Rataboul, F.; Riermeier, T.; Monsees,
A.; Fuhrmann, C.; Shaikh, N.; Dingerdissen, U.; Beller, M. Chem. Commun.
004, 38.
12) Gst o¨ ttmayr, C. W. K.; B o¨ hm, V. P. W.; Herdtweck, E.; Grosche,
M.; Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1363.
13) (a) Zhang, C.; Huang, J.; Trudell, M. L.; Nolan, S. P. J. Org. Chem.
999, 64, 3804. (b) Navarro, O.; Kelly, R. A.; Nolan, S. P. J. Am. Chem.
Soc. 2003, 125, 16194.
14) (a) Ackermann, L.; Born, R. Angew. Chem., Int. Ed. 2005, 44, 2444.
b) Colacot, T. J.; Shea, H. A. Org. Lett. 2004, 6, 3731. (c) Botella, L.;
3
2
(
(
1
(
(
N a´ jera, C. Angew. Chem., Int. Ed. 2002, 41, 179. (d) Dai, Q.; Gao, W.;
Liu, D.; Kapes, L. M.; Zhang, X. J. Org. Chem. 2006, 71, 3928.
1
). This coupling was initially performed using catalyst 2′a
(% Pd ) 0.1) and Na CO as a base in a 5:1:1 mixture of
toluene/EtOH/H O at reflux. The biaryl 3a was obtained
(
15) (a) Yin, L.; Liebscher, J. Chem. ReV. 2007, 107, 133. (b) Guin o´ ,
M.; Hii, K. K. Chem. Soc. ReV. 2007, 36, 608. (c) McNamara, C. A.; Dixon,
M. J.; Bradley, M. Chem. ReV. 2002, 102, 3275. (d) Leadbeater, N. E.;
Marco, M. Chem. ReV. 2002, 102, 3217.
2
3
16f
2
quantitatively in the presence of only 0.05 mol % of
supported Pd. However, the second use of catalyst 2′a
afforded only a <40% yield of 3a. It should be noted that
because the loss of Pd during the first use of the catalyst
was only 1% of the initial amount the deactivation of the
catalyst is not linked with a loss of precious metal. Similar
observations were made with catalyst 2a (% Pd ) 0.3).
Therefore, the reaction conditions had to be optimized to
allow reuse of the catalyst, and it turned out that hydroxylic
solvents should be avoided because the catalyst lost its
(16) (a) Uozomi, Y.; Danjo, H.; Hayashi, T. J. Org. Chem. 1999, 64,
3
384. (b) Yamada, Y. M. A.; Takeda, K.; Takahashi, H.; Ikegami, S. J.
Org. Chem. 2003, 68, 7733. (c) Kang, T.; Feng, Q.; Luo, M. Synlett 2005,
5, 2305. (d) Yamada, Y. M. A.; Takeda, K.; Takahashi, H.; Ikegami, S.
Org. Lett. 2002, 4, 3371. (e) Fenger, I.; Le Drian, C. Tetrahedron Lett.
998, 39, 4287. (f) Schweizer, S.; Becht, J.-M.; Le Drian, C. AdV. Synth.
Catal. 2007, 349, 1150.
17) For examples of Pd catalysts supported on inorganic supports, see:
a) Choudary, B. M.; Madhi, S.; Chowdari, N. S.; Kantam, M. L.; Sreedhar,
1
1
(
(
B. J. Am. Chem. Soc. 2002, 124, 14127. (b) Baleizao, C.; Corma, A.; Garc ´ı a,
H.; Leyva, A. Chem. Commun. 2003, 606. (c) Sayah, R.; Glegola, K.;
Framery, E.; Dufaud, V. AdV. Synth. Catal. 2007, 349, 373.
(18) For examples of Pd catalysts supported on organic supports, see:
(
a) Inada, K.; Miyaura, N. Tetrahedron 2000, 56, 8661. (b) Parrish, C. A.;
Buchwald, S. L. J. Org. Chem. 2001, 66, 3820. (c) Glegola, K.; Framery,
E.; Pietrusiewicz, K. M.; Sinou, D. AdV. Synth. Catal. 2006, 348, 1728. (d)
Bedford, R. B.; Coles, S. J.; Hursthouse, M. B.; Scordia, V. J. M. Dalton
Trans. 2005, 991. (e) Sommer, W. J.; Weck, M. AdV. Synth. Catal. 2006,
48, 2101. (f) Leyva, A.; Garc ´ı a, H.; Corma, A. Tetrahedron 2007, 63,
097.
2
efficiency when refluxed in toluene/EtOH/H O. Upon opti-
mization using catalyst 2a, we found that CsF as a base in
3
7
(19) Schweizer, S.; Becht, J.-M.; Le Drian, C. Fr. Patent Application 07
54500, 04/16/07.
3778
Org. Lett., Vol. 9, No. 19, 2007

21
filtration was less than 0.1% of the initial amount. Finally,
catalyst 2′a was studied by transmission electronic micros-
copy which showed only very scarce Pd crystallites. Interest-
ingly, many crystallites appeared in 2′a very quickly during
use: they were already present after 20 min of reaction.
However, neither their size (up to ca. 15 nm) nor their
abundance changed significantly thereafter, even after seven
uses (see TEM images in Supporting Information). Identical
results, within experimental error, were obtained for the Pd
contents of the fresh catalyst and of the catalyst recovered
after seven uses.
Table 1. Suzuki-Miyaura Reaction between
4-Chloroacetophenone and Phenylboronic Acid Using Catalysts
2a-f and 2′a
Various aryl chlorides and arylboronic acids were reacted
in the presence of catalyst 2′a (Table 3). The couplings of
entry
catalysta
Pd (mol %)
calculated yield (%)b
1
2
3
4
5
6
7
8
9
0
2a
2b
2c
2d
2e
2f
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.05
0.4
0.4
84
29
74
83
31
36
Table 3. Suzuki-Miyaura Reactions between Various Aryl
Chlorides and Arylboronic Acids Using 2′a
c
2′a
2′a
100
45
no reaction
no reaction
d
Pd Encat TPP30
Pd EnCat NP30
d
1
a
Reactions performed with 1.0 equiv of 4-chloroacetophenone, 1.4 equiv
b
of phenylboronic acid, and 1.5 equiv of CsF in toluene/H2O. Yields were
1
c
calculated by H NMR of the crude reaction mixtures. When the reaction
was performed with 1.0 equiv of 4-chloroacetophenone, 1.1 equiv of
phenylboronic acid and 1.5 equiv of CsF, a 84% yield was obtained. d The
starting materials were recovered unchanged.
entrya
R1
R2
R3
yield (%)b
product
1
2
3
4
5
6
7
8
9
H
4-Ac
4-Ac
4-Ac
4-Ac
4-Ac
4-Ac
3-Ac
2-Ac
4-NO2
H
4-Me
4-OMe
4-Cl
3-Me
2-Me
2-Me
2-Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
6-Me
6-Me
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
90
93
69
90
86
78
78
90
86
98
86
72
66
79
82
88
61
4-OMe
3-NH2
4-Me
2-Me
3-NO2
H
H
H
H
H
H
H
H
H
H
2-Me
c
toluene containing only traces of H
4% yield, in the presence of 0.4 mol % of supported Pd
entry 1). The catalyst was then reusable. No improvement
2
O (0.3%) gave 3a in a
8
(
c
was achieved by using catalysts 2b-f (entries 2-6) which,
moreover, are somewhat more difficult to prepare. Interest-
ingly, the use of 2′a (0.4 mol % of supported Pd) under these
optimized reaction conditions resulted in a considerable
increase of the yield (entry 7). Noteworthily, decreasing the
amount of supported Pd (entry 8), the excess of phenyl-
boronic acid, or the temperature afforded 3a only in lower
yields. The commercially available Pd EnCat TPP30 and Pd
EnCat NP30 turned out to be totally inefficient (entries 9
1
1
1
0
1
2
d
13
14
1
1
5
6
20
17
and 10). The possibilities of reuse of catalyst 2′a were then
ascertained (Table 2): the catalyst was used seven times
a
Reactions performed with 1.0 equiv of aryl chloride, 1.4 equiv of
arylboronic acid and 1.5 equiv of CsF in toluene/H2O. b Isolated yields
after flash chromatography of the crude reaction mixture
c
on silica gel.
Reactions performed in the presence of EtOH (see
Supporting Information). d Reaction performed with 1.0 equiv of 1,4-
dichlorobenzene, 1.1 equiv of phenylboronic acid and 1.2 equiv of CsF in
toluene/H2O.
Table 2. Recycling Test of Catalyst 2′a
runa
1
2
3
4
5
6
7
calculated yieldsb
100
95
100
98
100
98
98
a
According to Table 1, entry 7. b Yields were calculated by H NMR
1
4-chloroacetophenone with electron-deficient or electron-rich
arylboronic acids afforded the expected biaryls in very good
isolated yields (entries 1-6). Similar results were also
obtained by cross-coupling phenylboronic acid with aryl
of the crude reaction mixtures.
without showing any loss of efficiency. Additionally, a hot
filtration test was performed. For this purpose, after 20 min
of reaction (Table 1, entry 7), 2′a was filtered (yield of 3a
at that point: 73%), and the filtrate was heated at reflux for
another 20 h after which the yield reached only 74%. The
amount of Pd present in the filtrate obtained after hot
(20) (a) Ramarao, C.; Ley, S. V.; Smith, S. C.; Shirley, I. M.; DeAlmeida,
N. Chem. Commun. 2002, 1132. (b) Ley, S. V.; Ramarao, C.; Gordon, R.
S.; Holmes, A. B.; Morrison, A. J.; McConvey, I. F.; Shirley, I. M.; Smith,
S. C.; Smith, M. D. Chem. Commun. 2002, 1134.
(
21) Phan, N. T. S.; Van Der Sluys, M.; Jones, C. W. AdV. Synth. Catal.
2006, 348, 609 and references therein.
Org. Lett., Vol. 9, No. 19, 2007
3779

chlorides bearing both electron-rich and electron-deficient
substituents (entries 7-16). Noteworthily, 2-substituted, 2,6-
disubstituted, and even 2,6,2′-trisubstituted biaryls could be
prepared in good yields (entries 5, 8, and 15-17). 1,4-
Dichlorobenzene reacted with 1.1 equiv of phenylboronic
acid to give the monosubstituted biaryl 3m in 66% yield
seven times with no loss of efficiency. Moreover, it is well-
known that the presence of Pd in the reaction products is
often a drawback of Pd-catalyzed reactions, especially in the
pharmaceutical industry. Here, only less than 4 microequiva-
lents of Pd are lost during the reaction; therefore, the crude
product obtained contains only a negligible amount of Pd,
which greatly simplifies its purification.
(entry 13). However, in the presence of 2.8 equiv of
phenylboronic acid and 3.1 equiv of CsF, p-terphenyl was
obtained in 86% yield. Finally, 2′a can be successfully used
for cross-couplings involving heterocyclic aryl chlorides or
heterocyclic arylboronic acids. The reaction between
Acknowledgment. We are grateful to the Centre National
de la Recherche Scientifique (UMR-CNRS 7015) for finan-
cial support and to Dr. D. Le Nou e¨ n (UMR-CNRS 7015)
for NMR spectra. Special thanks are due to Dr. L. Vidal
3-thiopheneboronic acid and 4-chloroacetophenone gave the
expected biaryl 3r in 64% yield, whereas the cross-coupling
of 2-chloropyridine and phenylboronic acid afforded 2-phen-
ylpyridine (3s) in 88% isolated yield.
In summary, we have reported here the short synthesis of
an air- and moisture-stable heterogeneous (tert-butylphen-
ylphosphino)polystyrene-supported Pd catalyst and its ap-
plication for the Suzuki-Miyaura coupling of aryl chlorides
with arylboronic acids. These heterogeneous catalysts can
easily be recovered by filtration and can be reused more than
(UPR 9069) for TEM images.
Supporting Information Available: Full experimental
1
31
details, copies of H and P NMR spectra of compounds
1
1
a-e, H NMR spectra of biaryls 3a-s, and TEM images
of catalysts 2′a are given. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL701460Z
3780
Org. Lett., Vol. 9, No. 19, 2007