A new concept for the noncovalent binding of a ruthenium-based olefin metathesis catalyst to polymeric phases: Preparation of a catalyst on Raschig rings

Article abstract of DOI:10.1021/ja063561k

A new concept for noncovalent immobilization of a ruthenium olefin metathesis catalyst is presented. The 2-isopropoxybenzylidene ligand of a Hoveyda-Grubbs carbene is further modified by an additional amino group (7) and immobilization is achieved by trea

Full text of DOI:10.1021/ja063561k

Published on Web 09/15/2006
A New Concept for the Noncovalent Binding of a
Ruthenium-Based Olefin Metathesis Catalyst to Polymeric
Phases: Preparation of a Catalyst on Raschig Rings
Anna Michrowska,†,| Klaas Mennecke,‡ Ulrich Kunz,§ Andreas Kirschning,*,‡ and
Karol Grela*,†
Contribution from the Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka
44/52, 01-224, Warsaw, Poland, Institut fu¨r Organische Chemie, Leibniz UniVersita¨t HannoVer,
Schneiderberg 1B, D-30167 HannoVer, Germany, and Institut fu¨r Chemische Verfahrenstechnik,
Technische UniVersita¨t Clausthal, Leibnizstrasse 17, D-38678 Clausthal-Zellerfeld, Germany
Received June 2, 2006; E-mail: grela@icho.edu.pl; andreas.kirschning@oci.uni-hannover.de.
Abstract: A new concept for noncovalent immobilization of a ruthenium olefin metathesis catalyst is
presented. The 2-isopropoxybenzylidene ligand of a Hoveyda-Grubbs carbene is further modified by an
additional amino group (7) and immobilization is achieved by treatment with sulfonated polystyrene forming
the corresponding ammonium salt. In this novel strategy for the immobilization of ruthenium-based metathesis
catalysts, the amino group plays a two-fold role, being first an active anchor for immobilization and second,
after protonation, activating the catalysts (electron donating to electron withdrawing activity switch). The
polymeric support was prepared by precipitation polymerization which led to small bead sizes (0.2-2 µm)
and large surface areas. Compared to commercial resins this tailor-made phase showed superior properties
in immobilization of complex 7. This concept of immobilization was applied to glass-polymer composite
megaporous Raschig rings. Ru catalyst 7 on Raschig rings was used under batch conditions in various
metathesis reactions, including ring-closing (RCM), cross- (CM) and enyne metathesis, to give products of
high chemical purity with very low ruthenium contamination levels (21-102 ppm). The same ring can be
used for up to 6 cycles of metathesis.
Scheme 1. Synthesis of EDG-substituted Complex 7
1. Introduction
During recent years, olefin metathesis has gained a position
of increasing significance. The development of modern ruthe-
nium metathesis catalysts, such as Grubbs I-III (1, 2, 5) and
Hoveyda-Grubbs carbenes (3, 4, Figure 1) combining high
activity with an excellent tolerance to a variety of functional
groups has been the key to widespread applications of olefin
metathesis in organic synthesis and polymer chemistry.1
Despite general superiority offered by this family of catalysts,
they share some disadvantages. Since olefin metathesis reactions
are expected to be used in pharmaceutical processes, the most
undesirable feature of these complexes is that during the reaction
they form ruthenium byproducts, which are difficult to remove
from the reaction products.2 Several protocols to remove
ruthenium impurities by addition of various scavengers,2a-c
biphasic extraction,2d and silica gel chromatography2e have been
proposed. From an economic point of view on the whole
chemical process the catalyst’s cost is another important
attribute. In this respect, immobilization of homogeneous
catalysts offers inherent operational and economic advantages
over the parent soluble catalysts.3 Several attempts have been
† Institute of Organic Chemistry, Polish Academy of Sciences.
‡ Institut fu¨r Organische Chemie, Leibniz Universita¨t Hannover.
§ Institut fu¨r Chemische Verfahrenstechnik, Technische Universita¨t
Clausthal.
(2) For approaches where ruthenium impurities are removed by addition of
various scavengers, see (a) Maynard, H. D.; Grubbs, R. H. Tetrahedron
Lett. 2000, 40, 4137-4140. (b) Paquette, L. A.; Schloss, J. D.; Efremov,
I.; Fabris, F.; Gallou, Mendez-Andino, J.; Yang, J. Org. Lett. 2000, 2, 1259-
1261. (c) Ahn, Y. M.; Yang, K.; Georg, G. I. Org. Lett. 2001, 3, 1411-
1413. (d) For a recent example of use of biphasic extraction of ruthenium
remains in preparation of hepatitis C antiviral agent BILN 2061, see WO
2004/089974 A1 (2004, Boehringer Ingelheim International GmbH). (e)
For a phase separation approach, see Michrowska, A.; Gułajski, L-.; Grela,
K. Chem. Commun. 2006, 841-843
| Current address: Max-Planck-Institut fu¨r Kohlenforschung, Kaiser-
Wilhelm-Platz 1, D-45470, Mu¨lheim/Ruhr, Germany.
(1) General reviews: (a) Schrock, R. R.; Hoveyda, A. H. Angew. Chem., Int.
Ed. 2003, 42, 4592-4633. (b) Trnka, T. M.; Grubbs, R. H. Acc. Chem.
Res. 2001, 34, 18-29. (c) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39,
3012-3043. (d) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413-
4450. (e) Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1997,
36, 2037-2056. (f) Dragutan, V.; Dragutan, I.; Balaban, A. T. Platinum
Met. ReV. 2001, 45, 155-163.
9
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J. AM. CHEM. SOC. 2006, 128, 13261-13267
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A R T I C L E S
Michrowska et al.
Figure 2. Highly active EWG-substituted catalysts 6a and 6b.
mobilized homogeneous catalysts.9 The attachment ought to be
strong enough to suppress leaching of the catalyst. After
inactivation of the catalyst it is beneficial if it can be removed
from the solid phase and the reactor can be reactivated with
fresh catalyst by simple washing protocols. Thus, this concept
avoids physical removal of the fixed bed inside the reactor which
can be costly. Therefore, this strategy is of major relevance for
industrial applications, particularly when continuous-flow pro-
cesses with immobilized homogeneous catalysts or enzymes are
pursued for which the first examples are operating. Indeed, this
concept has been successfully demonstrated in research labo-
ratories and even in industrial processes for immobilized
enzymes.10
Some concepts for the noncovalent attachment of chemical
catalysts to solid supports have been developed.11 Recently,
Reiser and Werner disclosed electrostatic binding (Nafion
sulfonic acid) of azabis(oxazoline)-copper complexes and their
use in asymmetric cyclopropanations.12 Additionally, task-
specific ionic liquids can be loaded as liquid films on polar
supports such as silica gel.13 These polar layers have been used
to immobilize ionic transition metal catalyst14a,b and polar
organocatalysts.14c
Figure 1. Ruthenium-based catalysts 1-5 for olefin metathesis (Cy )
cyclohexyl, Mes ) 2,4,5-trimethylphenyl).
made to immobilize Grubbs-type carbenes 1-2 on solid or
soluble supports either via ligand L (Figure 1) or via the carbene
moiety.4 Hoveyda established catalysts 3-45 as remarkably
robust complexes promoting olefin metathesis by a release/return
mechanism.6 Recently, various Hoveyda-Grubbs carbenes were
attached to different resins or soluble supports preferentially
via the 2-alkoxybenzylidene fragment.7 Our group has recently
presented a Hoveyda-Grubbs complex covalently bound to a
PS-DES resin.7b
However, for practicability reasons noncoValent attachment
of catalysts to a solid phase is highly desirable. The possibility
of reloading the solid phase opens the door for utilizing solid
supports which have been specially designed for the individual
catalytic process without considering their costs as much as
would be relevant for covalently bound catalysts. Indeed, this
concept should be of particular relevance in continuous-flow
processes8 using reactors filled with heterogeneous or im-
(3) Reviews on polymer-bound reagents and catalysts: (a) Solodenko, W.;
Frenzel, T.; Kirschning, A. In Polymeric Materials in Organic Synthesis
and Catalysis; Buchmeiser, M. R., Ed.; Wiley-VCH: Weinheim, 2003; pp
201-240. (b) Clapham, B.; Reger, T. S.; Janda, K. D. Tetrahedron 2001,
57, 4637-4662. (c) Baxendale, I. R.; Storer, R. I.; Ley, S V. In Polymeric
Materials in Organic Synthesis and Catalysis; Buchmeiser, M. R., Ed.;
Wiley-VCH: Weinheim, 2003; pp 53-132. (d) Kirschning, A.; Monen-
schein, H.; Wittenberg, R. Angew. Chem., Int. Ed. 2001, 40, 650-679. (e)
Ley, S. V.; Baxendale, I. R.; Bream, R. N.; Jackson, P. S.; Leach, A. G.
Longbottom, D. A.; Nesi, M.; Scott, J. S.; Storer, R. I.; Taylor, S. J. J.
Chem. Soc., Perkin Trans. 1 2000, 3815-4195. (f) Drewry, D. H.; Coe,
D. M.; Poon, S. Med. Res. ReV. 1999, 19, 97-148.
(4) Reviews: (a) Kingsbury, J. S.; Hoveyda, A. H. In Polymeric Materials in
Organic Synthesis and Catalysis; Buchmeiser, M. R., Ed.; Wiley-VCH:
Weinheim, 2003; p 467. (b) Buchmeiser, M. R. New J. Chem. 2004, 28,
549-557.
(5) (a) Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J.; Hoveyda, A. H.
J. Am. Chem. Soc. 1999, 121, 791-799. (b) Garber, S. B.; Kingsbury, J.
S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122, 8168-
8179.
Recently we have successfully tested the concept of nonco-
valent attachment in the preparation of Grubbs III generation
catalyst 5 coordinatiVely bound to polyvinyl pyridine resin.15
In this paper we describe a straightforward noncovalent
procedure for immobilization of a new Hoveyda-type Ru
complex by means of electrostatic binding.
2. Results and Discussion
Catalyst Design. We demonstrated that the 5- and 4-nitro-
substituted complexes 6a and 6b (Figure 2) initiate olefin
metathesis dramatically faster than the parent Hoveyda-Grubbs
catalyst 4.16,17 We proposed that the electron-withdrawing
(EWG) nitro group in the benzylidene fragment of 6a and 6b
would weaken OfRu chelation and facilitate faster initiation
of the catalytic cycle.16,17
(6) (a) For a short review, see Hoveyda, A. H.; Gillingham, D. G.; Van
Veldhuizen, J. J.; Kataoka, O.; Garber, S. B.; Kingsbury, J. S.; Harrity, J.
P. A. Org. Biomol. Chem. 2004, 2, 1-16.
(7) For syntheses of supported variants of 3-4, see inter alia: (a) Kings-
bury, J. S.; Garber, S. B.; Giftos, J. M.; Gray, B. L.; Okamoto, M. M.;
Farrer, R. A.; Fourkas, J. T.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2001,
40, 4251-4256. (b) Grela, K.; Tryznowski, M.; Bieniek, M. Tetrahedron
Lett. 2002, 43, 9055-9059. (c) Connon, S. J.; Dunne, A. M.; Blechert, S.
Angew. Chem., Int. Ed. 2002, 41, 3835-3838. (d) Dowden, J.; Savovic, J.
Chem. Commun. 2001, 37-38. (e) Yao, Q. Angew. Chem., Int. Ed. 2000,
39, 3896-3898. (f) Yao, Q.; Zhang, Y. Angew. Chem., Int. Ed. 2003, 42,
3395-3398. (g) Connon, S. J.; Blechert, S. Bioorg. Med. Chem. Lett. 2002,
12, 1873-1876. (h) Yao, Q.; Zhang, Y. J. Am. Chem. Soc. 2004, 12, 74-
75. (i) Yao, Q.; Motta, A. R. Tetrahedron Lett. 2004, 45, 2447-2451. (j)
Yang, L.; Mayr, M.; Wurst, K.; Buchmeiser M. R. Chem. Eur. J. 2004,
10, 5761-5770. (k) Krause, J. O.; Nuyken, O.; Wurst, K.; Buchmeiser,
M. R. Chem. Eur. J. 2004, 10, 777-784. (l) Krause, J. O.; Zarka, M. T.;
Anders, U.; Weberskirch, R.; Nuyken, O.; Buchmeiser, M. R. Angew.
Chem., Int. Ed. 2003, 42, 5965-5969. (m) Audic, N.; Clavier, H.; Mauduit,
M.; Guillemin, J.-C. J. Am. Chem. Soc. 2003, 125, 9248-9249. (n) Clavier,
H.; Audic, N.; Mauduit, M.; Guillemin, J.-C. G. Chem. Commun. 2004,
282-284.
In accordance with this assumption we observed that complex
718 (Scheme 1), bearing the electron-donating (EDG) diethyl-
(9) Kunz, U.; Leue, S.; Stuhlmann, F.; Sourkouni-Argirusi, G.; Wen, H.; Jas,
G.; Kirschning, A. Eur. J. Org. Chem. 2004, 3601-3610.
(10) Scho¨ning, K. U.; End, N.; Top. Curr. Chem. 2004, 242, 241-273 and 273-
319.
(11) For an excellent review on strategies of noncovalent immobilization of
catalysts refer to Horn, J.; Michalek, F.; Tzschucke, C. C.; Bannwarth, W.
Top. Curr. Chem. 2004, 242, 43-77.
(12) Fraile, J. M.; Garc´ıa, J. I.; Herrer´ıas, C. I.; Mayoral, J. A.; Reiser, O.;
Socue´llamos, A.; Werner, H. Chem. Eur. J. 2004, 10, 2997-3005.
(13) Mehnert, C. P. Chem. Eur. J. 2004, 14, 50-56.
(14) (a) Mehnert, C. P.; Mozeleski, E. J.; Cook, R. A. Chem. Commun. 2002,
3010-3011. (b) Hagiwara, H. Sugawara, Y.; Isobe, K.; Hoshi, T.; Suzuki,
T. Org. Lett. 2004, 6, 2325-2328. (c) Gruttadauri, M.; Riela, S.; Meo, P.
L.; Da´nna, F.; Noto, R. Tetrahedron Lett. 2004, 45, 6113-6116.
(15) Mennecke, K.; Grela, K.; Kunz, U.; Kirschning, A. Synlett 2005, 2948-
2952.
(8) (a) Kirschning, A.; Jas, G. Top. Curr. Chem. 2004, 242, 209-241. (b) Jas,
G.; Kirschning, A. Chem. Eur. J. 2003, 9, 5708-5723. (c) Fletcher, P. D.
I.; Haswell, S. J.; Pombo-Villar, E.; Warrington, B. H.; Watts, P.; Wong,
S. Y.; Zhang, X. Tetrahedron 2002, 58, 4735-4757. (d) Kirschning, A.;
Solodenko, W.; Mennecke, K. Chem. Eur. J. 2006, 12, 5972-5990.
(16) Grela, K.; Harutyunyan, S.; Michrowska, A. Angew. Chem., Int. Ed. 2002,
41, 4038-4040; Angew. Chem. 2002, 114, 4210-4212.
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Noncovalent Immobilization of an Olefin Metathesis Catalyst
A R T I C L E S
Scheme 2. Model Reactions for Evaluating Catalysts 4 and 7 in
Solution.
One key issue that one shall address in this context is the nature
of the solid phase and the setting in which it is employed, aspects
which are often overlooked by synthetic organic chemists in
solid phase assisted synthesis.20 We have therefore decided to
investigate the nature of the solid phase in more detail, by
comparing the commercially available ion-exchange resin
Dowex 50Wx2 (loading 5 mmol/g dry resin; average particle
size 560 µm) with a tailor-made sulfonated polystyrene. We
have found that the latter can be prepared from a heated solution
(70 °C) of the monomers: styrene, divinylbenzene, and AIBN
as radical initiator in a nonpolar solvent (n-alkane C14-C17
mixture). After 12 h the precipitation of small interconnected
polymer particles occurred. In the following, sulfonation was
achieved by treatment of the filtered and washed polymeric
particles with a solution of chlorosulfonic acid to yield an acidic
ion-exchange resin A [3.25 mmol/g capacity; 5.3 mass% degree
of cross-linking; BET surface area is low (<5 m2/g) yielding
gel like polymer particles].21 This polymeric material consists
of very small particles (0.2-2 µm) compared to commercial
ion-exchange resins (10-50 µm). Despite the small size of the
individual beadlike particles the material can easily be filtered.
Indeed, the optimized polymerization process creates polymeric
bridges between these particles which results in an extended,
monolithic polymeric phase (Figure 3a and b).
a Complex 7 (5 mol %), CH2Cl2, 21°C, 1 h; GC conversion. b 7 (1
mol %), CH2Cl2, microwave heating (60 °C, 200 W), 4 min. c CSA )
camphor-10-sulfonic acid. d 7‚(-)-CSA (1 mol %), CH2Cl2, microwave
heating (60 °C, 200 W), 2 min. e Complex 7 (5 mol %), CH2Cl2, 21 °C, 16
h; GC conversion. f Under refluxing conditions conversion with 7 was
quantitative (45 °C, 16 h).
amino group19 shows little or no activity in olefin metathesis
with model substrates 10 and 11 (Scheme 2, entries 1, 6).
As it can be further seen from Scheme 2, complex 7 is only
able to promote RCM with diene 10 under microwave irradiating
conditions [entry 1; µw conditions: 7 (1 mol %), CH2Cl2, 60
°C, 200 W] to yield cyclopentene 12 in 25% (after 2 min) and
59% yield (after 4 min), respectively. However, in a striking
contrast, the in situ formed salts of aniline 7 obtained by
treatment with organic acids are of high activity (Scheme 2,
entries 4, 5, 7), surpassing the parent Hoveyda-Grubbs complex
4 in terms of initiation speed.18b Again, ring-closure of 10 can
be accelerated under microwave conditions leading to complete
transformation within 2 min (entry 5).
We envisaged that after reaction with polymer-supported
acids, like Dowex resin, the new Ru-complex 7 can be
conveniently immobilized by ion exchange. In this novel
strategy for the immobilization of ruthenium-based metathesis
catalysts, the amino group plays a two-fold role, being first an
active anchor for immobilization (vide supra) and second, after
protonation, activating the catalysts (electron donating to
electron withdrawing actiVity switch).
Treatment of this sulfonated polystyrene polymer (A) and
Dowex 50Wx2 resin (B) with a solution of catalyst 7 in
CH2Cl2 at ambient temperature for 3 h yielded functionalized
polymers 7A and 7B (Figure 4).22 Performance of these new
catalysts was compared by converting diene 11 into 13 (5
mol % catalyst, in CH2Cl2 at 45 °C) with the following obser-
vation: catalyst 7A 1st run >99%, 2nd run 88%, 3rd run 56%,
4th run 68%, 5th run 38%, and 6th run 10%; catalyst 7B 1st
run 98%, 2nd run 33%). From these primary experiments it is
evident that the sulfonated polystyrene A obtained through
precipitation polymerization shows properties for ion exchange
of larger species such as complex 7 superior to those of the
commercially available ion-exchange resin Dowex 50Wx2 (B).
Another advantage of the tailor-made support A is that the
polymerization process can be carried out in the presence of
megaporous Raschig glass rings to yield a highly porous
polymer-glass composite material (C) (Figure 3c and d). In
this case the polymeric phase is protected toward mechanical
stress inside the glass pores which is an advantage in industrial
applications. Furthermore, when batch-type reactions are con-
ducted, the solid phase can be easily removed as a single piece
when required. Recently, we reported that such monolithic
polymer-glass composite materials, obtained by precipitation
polymerization, can be used in solid phase assisted solution
phase synthesis or applied in continuous-flow reactors (PASS-
flow microreactors).15,23,24
Preparation of the Polymeric Phases. Catalytic Perfor-
mance of Polymer-Bound 7A-7C. For the present application
a sulfonated polymeric phase was required which should be
suited for the ion exchange based immobilization of catalyst 7.
(17) (a) Michrowska, A.; Bujok, R.; Harutyunyan, S.; Sashuk, V.; Dolgonos,
G.; Grela, K. J. Am. Chem. Soc. 2004, 126, 9318-9325. (b) Grela K.
Boehringer Ingelheim International, U.S. Patent 6,867,303, 2005. For
applications of catalyst 6a and 6b, see (c) Ostrowski, S.; Mikus, A. Mol.
DiVers 2003, 6, 315-321. (d) Honda, T.; Namiki, H.; Kaneda, K.; Mizutani,
H. Org. Lett. 2004, 6, 87-89. (e) Honda, T.; Namiki, H.; Watanabe, M.;
Mizutani, H. Tetrahedron Lett. 2004, 45, 5211-5213. (f) Stellfeld, T.; Bhatt,
U.; Kalesse, M. Org. Lett. 2004, 6, 3889-3892. (g) Albert, B. J.;
Sivaramakrishnan, A.; Naka, T.; Koide, K. J. Am. Chem. Soc. 2006, 128,
2792-2793. (h) For a recent application in the synthesis of hepatitis C
antiviral agent Ciluprevir (BILN 2061), see WO 2004/089974 A1,
Boehringer Ingelheim International GmbH, 2004. (i) Mikus, A.; Sashuk,
V.; Ke¸dziorek, M.; Samojłowicz, C.; Ostrowski, S.; Grela, K. Synlett 2005,
1142-1146. (j) Vinokurov, N.; Michrowska, A.; Szmigielska, A.; Drzazga,
Z.; Wo´jciuk, G.; Demchuk, O. M.; Grela, K.; Pietrusiewicz, K. M.;
Butenscho¨n, H. AdV. Synth. Catal. 2006, 348, 931-938.
(18) (a) Michrowska, A. Ph.D. Thesis, Institute of Organic Chemistry, Polish
Academy of Sciences, Warsaw, Poland, 2006. (b) For a preliminary study
on activation of 7 and other complexes, see Gułajski, Ł.; Michrowska, A.;
Bujok, R.; Grela, K. J. Mol. Catal. A: Chem. 2006, 348, 931-938.
(19) (a) For water-soluble Grubbs ruthenium alkylidenes bearing quarternary
ammonium salts, see Lynn, D. M.; Mohr, B.; Grubbs, R. H.; Henling, L.
M.; Day, M. W. J. Am. Chem. Soc. 2000, 122, 6601-6609. (b) For an
example of a catalytically active ruthenium allenylidene complex bearing
a Me2N group see Fu¨rstner, A.; Liebl, M.; Lehmann, C.; Piquet, M.; Kunz,
R.; Bruneau, C.; Touchard, D.; Dixneuf, P. H. Chem. Eur. J. 2000, 6, 10,
1847-1857.
(20) Hodge, P. Chem. Soc. ReV. 1997, 26, 417-424 and references therein.
(21) Kunz, U.; Kirschning, A.; Hoffmann, U. EP 1268566 B1, 2004.
(22) Alternate immobilization procedures relied on mixing catalyst 4 and ligand
9 (1:1) in the presence of cationic exchange resins to reduce leaching during
RCM by trapping the active Ru species by the ligand. This procedure did
not give improved results: 1st run 98%, 2nd run 82%, 3rd run 45%, 4th
run 38%, 5th run 8%.
(23) (a) Kirschning, A.; Altwicker, C.; Dra¨ger, G.; Harders, J.; Hoffmann, N.;
Hoffmann, U.; Scho¨nfeld, H.; Solodenko, W.; Kunz, U. Angew. Chem.,
Int. Ed. 2001, 40, 3995-3998. (b) Kunz, U.; Scho¨nfeld, H.; Solodenko,
W.; Jas, G.; Kirschning, A. Ind. Eng. Chem. Res. 2005, 44, 8458-8467.
(24) (a) Solodenko, W.; Kunz, U.; Kirschning, A. Bioorg. Med. Chem. Lett.
2002, 12, 1833-1835. (b) Kunz, U.; Kirschning, A.; Altwicker, C.;
Solodenko, W. J. Chromatogr. A 2003, 1006, 241-249.
9
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A R T I C L E S
Michrowska et al.
Figure 3. Polymeric phases A and C used for immobilization of 7. (a) Sulfonated polymer A particles (0.2-2 µm diameter). (b) Bridging to neighboring
polymer particles visualized by scattering electron microscopy (SEM). (c) Megaporous glass Raschig rings. (d) View (visualized by SEM) on the sulfonated
glass polymer composite material (C) of Raschig rings.
Scheme 3. Alternative Approaches for the Preparation of Catalyst
7A (powder) and 7C (Raschig rings)
Figure 4. Structure of immobilized 7A and 7B.
Therefore, we employed the polymer A and the megaporous
Raschig rings C as supports in the following studies by first
searching for the best immobilization procedure.25 As described
above, catalyst 7A can be obtained by direct immobilization of
diethylamine containing complex 7 in the presence of polymeric
sulfonic acid obtained from precipitation polymerization. Al-
ternatively, the same catalyst can be prepared indirectly by ion
exchange of easily accessible aniline derivative 9 (E/Z ratio 2:1;
Scheme 1) to yield functionalized polymer 14 which then was
subjected to cross olefin metathesis conditions in the presence
of Grubbs II catalyst 2 (Scheme 3). At this point it has to be
noted that the direct immobilization of 7 leads to a cationic
exchange resin with partial loading (some sulfonic acid moieties
remain unaltered) while the “indirect” immobilization strategy
allows saturation of all SO3-groups with both aniline 9 and the
carbene complex 7. Unlike the latter approach the direct
immobilization affords a resin which is still partially acidic.
Therefore, the “indirect” procedure was chosen for all further
experiments. Copper(I) chloride is well suited to force the
exchange of 14 with 2 to completion by trapping the phosphane
ligand.5 Indeed, with the resulting catalyst 7A the model RCM
of diene 11 yielded 13 in 100% conversion (5 mol % 7A, DCM,
45 °C, 3 h) while preparation of 7A from 2 in the absence of
CuCl furnished a catalyst which afforded the cyclization product
13 with only 50% conversion under identical reaction conditions.
Using the same “indirect” immobilization procedure we also
prepared catalyst 7C immobilized on glass-polymer composite
Raschig rings (Figure 3c) which can be used for combinatorial
chemistry and high-throughput screening.7a,26 For the final
recyclability studies catalyst 7C (loading 3 µmol Ru/ring) and
the model substrate 11 were used. After each run (5 mol % of
(25) This aspect is of particular importance when continuous flow processes
are envisaged.
(26) Mayr, M.; Wang, D.; Kro¨ll, R.; Schuler, N.; Pru¨hs, S.; Fu¨rstner, A.;
Buchmeiser, M. R. AdV. Synth. Catal. 2005, 347, 484-492.
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Noncovalent Immobilization of an Olefin Metathesis Catalyst
A R T I C L E S
Table 1. RCM and CM with Catalyst 7C (bound to Raschig rings)a
a Conditions: one Raschig ring 7C (loading 3 µmol Ru/ring, 5 mol %) per reaction was used. For a description of the equipment used, see ref 28. b Crude
products from entries 1-8 were obtained after removal of the Raschig ring, washing with dichloromethane, and evaporation of solvent under reduced
c
pressure. Conversions were calculated by 1H NMR spectroscopy and/or GC analysis. 7C (1 mol %), CH2Cl2, microwave heating (60 °C, 200 W), 4 min.
d Two Raschig rings 7C were used.
of product 13 with ruthenium was determined to be around 100
ppm (by ICP-MS). This is significantly lower than the ruthenium
contamination reported for Hoveyda’s catalyst on sol-gel pellets
(up to 1 wt %).7a It should be noted, however, that despite the
diminution in Ru loading, the catalytic activities of the recycled
Hoveyda’s pellets are still high and a single sol-gel pellet can
be used for up to 20 reaction cycles.6 Recently, another
interesting report on a disk-shaped monolithic Ru catalyst for
combinatorial chemistry has been published.26 In the case of
this system the reported leaching was >3% while the average
Figure 5. PASSflow reactor (without HPLC connectors) employed in
preliminary RCM experiments with 7C.
contamination of products with ruthenium was around 70 ppm.
The catalyst was, however, designed as “one-way” disks,
therefore no recycling or multiple use was attempted.
catalyst, 21 °C, 24 h) the reaction mixture was removed with a
Pasteur pipet, and the ring was rinsed with minimal amounts
of dichloromethane and reused. As we found, the same ring
can be used for up to 6 runs of metathesis, however with gradual
Catalytic Performance of 7C Bound to Raschig Rings. Use
in High-Throughput Experiments. The practicability of Ra-
schig rings loaded with the Ru-complex 7 (3 µmol Ru/ring) in
high-throughput synthesis7a,17 was demonstrated by the examples
loss of activity: 1st run 85%, 2nd run 68%, 3rd run 54%, 4th
shown in Table 1.28 Ring-closing and enyne metathesis of
run 53%, 5th run 52%, 6th run 56%, 7th run 13%, and 8th run
representative substrates proceeds cleanly, with typically high
11%. At this point the solid phase can easily be reactivated by
a washing protocol (1 N HCl, H2O, 1 N NaOH, H2O, 1 N HCl,
H2O, methanol, and dichloromethane).27 The contamination level
1
conversion, as determined by GC/MS and H NMR analysis,
leading to various carbo- and heterocycles (entries 1-5)
including the rather labile octahydro-1H-cyclopenta[a]cycloocten-
1-one derivative 28 (entry 8), a potential building block in the
synthesis of terpenoid natural products.29 We have also dem-
onstrated the ability of 7C to perform homo cross-metathesis
(27) The reactivation of Raschig rings was tested using RCM of diethyl
diallylmalonate 16 (5 mol % of 7C, CH2Cl2, 45 °C, 2 h). After each reaction
cycle the old catalyst was removed from the ring by washing with 1 N
HCl, H2O, 1 N NaOH, 1 N HCl, H2O, and methanol. Then fresh catalyst
7 was loaded as described above and the “recharged” ring was used in the
next cycle of metathesis. This experiment gave the following results: Initial
catalyst, loading 3.0 µmol/ring, conversion 99%; 1st recharging, loading
3.0 µmol/ring, conversion 87%; 2nd recharging, loading 3.0 µmol/ring,
conversion >99%; 3rd recharging, loading 2.8 µmol/ring, conversion 99%.
See the Supporting Information for details.
(28) For high-throughput experiments described in Table 1 the Radleys 12 Place
Heated Carousel Reaction Station (www.radleys.com) was used.
(29) (a) Michalak, K.; Michalak, M.; Wicha, J. Tetrahedron Lett. 2005, 46,
1149-1153. (b) Michalak, M., Wicha, J. Synlett 2005, 2277-2280.
9
J. AM. CHEM. SOC. VOL. 128, NO. 40, 2006 13265

A R T I C L E S
Michrowska et al.
Scheme 4. Immobilization of Ru-complex 7 Inside a PASSflow Reactor and RCM under Continuous Flow Conditions
(CM) of functionalized alkenes (entries 6-7). Interestingly, the
homometathesis of 20 proceeds without double bond isomer-
ization,30,31 although complete conversion cannot be reached
after 24 h of reflux (entry 7). Surprisingly, homodimer 27 is
formed with remarkably high E/Z-selectivity (11:1) compared
to the Grubbs-I catalyst 1 which commonly yields dimeric
spacer-linked hexoses in the E/Z ratio of 3:1 to 5:1.32 This
excellent selectivity may be ascribed to the “bulkiness” of the
solid phase. At the end of the reaction the catalyst 7C can be
simply removed with a pair of tweezers and rinsed with minimal
amounts of dichloromethane, producing minimal solvent waste.
The resulting crude products were pure according to GC/MS
and 1H NMR analyses. Additionally, we checked the ruthenium
content in selected crude products and found low levels7a,26 of
ruthenium contamination as follows: 22, 102 ppm; 26, 21 ppm;
27, 77 ppm; 28, 30 ppm (ICP-MS analysis of Ru). These results
show the potential applicability of glass-polymer composite
Raschig rings in a high-throughput screening.33 The reaction
rates can be strongly accelerated by operating under microwave
irradiation conditions (vide supra), but the pure products were
isolated with slightly reduced yields (exemplified in entry 2).
a metal jacketed reactor equipped with HPLC-fittings at both
ends of the reactor for allowing connection to an HPLC-pump
(Figure 5).9
Different immobilization-modes for catalyst 7 were tested.
We found that the best strategy for immobilization is to pump
a solution of the Ru-complex 7 and an excess of aniline 9 (1:
19 mol ratio) in CH2Cl2 through the reactor in a circular mode
(Scheme 4). This protocol allows simultaneous immobilization
of both the catalyst and its ligand inside the reactor. At the same
time complete saturation of all SO3H groups is guaranteed.
As for any other boomerang system,4 leaching could be a
great problem under nonstatic conditions. However, we expected
that the Ru species released into solution during olefin metath-
esis can be re-trapped by excess of ionically bound ligand 9
when circulating through the PASSflow column.34 To test this,
diene 11 was dissolved in CH2Cl2 and circulated (2 mL/min,
no measurable pressure drop) at 40 °C for 5 h through this
catalytically active reactor (5 mol % of Ru) which quantitatively
afforded cyclopentene 13 (Scheme 4). The same reactor was
washed with CH2Cl2 and reused for a second run under identical
conditions. This time product 13 was obtained in 79% yield,
while the third run did not yield the desired product. Toluene
can be used as a solvent giving similar results. The reactor can
be reactivated by first washing with 1 N HCl, H2O (to pH 7),
1 N NaOH, H2O (to pH 7), 1 N HCl, H2O (to pH 7), dry
methanol, and CH2Cl2 followed by reloading with Ru-complex
7 and ligand 9 as described above.
Attempts to Olefin Metathesis under Continuous Flow
Conditions. Catalyst 7C was also preliminarily tested under
continuous-flow conditions8b by introducing the functionalized
composite material shaped as a monolithic glass rod (see
analogous material shaped as Raschig rings, Figure 3d) inside
In principle, we demonstrated for the first time that RCM
can be conducted under PASSflow continuous flow conditions
using a noncovalently immobilized Ru-catalyst. However,
catalyst leaching is more pronounced compared to the corre-
sponding batch experiments with Raschig rings 7C (instead of
two, up to six runs were possible as described above) which
can be ascribed to the additional forces exerted by the convective
flow. Importantly reloading of the reactor is easily possible.
(30) (a) Review: Uma, R.; Crevisy, C.; Gree, R. Chem. ReV. 2003, 103, 27-
52. (b) Alcaide, B.; Almendros, P. Chem. Eur. J. 2003, 9, 1258-1262. (c)
Schmidt, B. J. Org. Chem. 2004, 69, 7672-7687 (d) Arisawa, M.; Terada,
Y.; Nakagawa, M.; Nishida, A. Angew. Chem. 2002, 114, 4926-4928. (e)
Gurjar, M. K.; Yakambram, P. Tetrahedron Lett. 2001, 42, 3633-3636.
(f) Braddock, D. C.; Wildsmith, A. J. Tetrahedron Lett. 2001, 42, 3239-
3242. (f) Hoye, T. R.; Zhao, H. Org. Lett. 1999, 1, 1123-1125.
(31) Interestingly, in the case of 5 immobilized on polyvinyl pyridine, exclusive
C-C double bond isomerization instead of CM was observed for this
substrate: ref 15.
(32) (a) Chen, G.-w.; Kirschning, A. Chem. Eur. J. 2002, 8, 2717-2729. (b)
Kirschning, A.; Chen, G.-w.; Jaunzems, J.; Jesberger, M.; Kalesse, M.;
Lindner, M. Tetrahedron 2004, 60, 3505-3521.
(33) The high activity of catalyst 7C has also been confirmed at Solvay GmbH
by its application in CM of allylated steroids with R,â-unsaturated
partners: Messinger, J.; Scho¨n, U.; Mennecke, K.; Harmrohlf, K.; Kir-
schning, A. unpublished results.
(34) It has been recently demonstrated that free Ru carbene intermediates in
solution can be scavenged by monolithic sol-gel glass-bound styrene ether
ligands prior to the onset of competing transition metal decomposition.
See Kingsbury, J. S.; Hoveyda, A. H. J. Am. Chem. Soc. 2005, 127, 4510-
4517.
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Noncovalent Immobilization of an Olefin Metathesis Catalyst
A R T I C L E S
Still, the Ru-complex 7 attached to the monolithic polymer C
obtained from precipitation shows a better performance under
continuous-flow conditions compared to batch reactions with
commercial anionic exchange resin B.
under PASSflow continuous flow conditions. Future work will
be focused on a next generation of noncovalently attached
catalysts which show a longer lifetime when repeatedly used
and which can be employed in multistep applications under
PASSflow continuous flow conditions. We believe that this
concept has a great potential for immobilizing many different
catalytic species.
Conclusions
In summary, we have described a new strategy for the
noncovalent immobilization of Ru-based olefin metathesis
catalyst 7 that relies on electrostatic binding. This concept allows
more efforts to be spent on the optimization of the solid phase,
as its reuse is easily possible through reloading of the active
catalyst by simple washing steps. We showed that for the present
applications solid phases generated by precipitation polymeri-
zation are superior to commercial Dowex 50 × 2. The solid-
phase bound catalyst 7 shows very good chemical reactivity
and good recyclability. Catalyst 7C on glass-polymer composite
Raschig rings can be applied in combinatorial chemistry and
high-throughput screening to give products of high purity and
of low ruthenium contamination (21-102 ppm). It therefore
may be found useful for preparing small quantities of com-
pounds for biological screening.33 This process can be automated
and has been successfully applied to a parallel reactor. After
deactivation the solid phase can be easily reactivated with fresh
catalyst.
Acknowledgment. The work was funded by the Deutsche
Forschungsgemeinschaft - Polisch Academy of Sciences joint
project “Synthetische Nutzung von immobilizierten Ruthenium-
Carben-Katalysatoren in Durchflussmikroreaktoren” (436 POL
113/109/0-1) and the Fonds der Chemischen Industrie. We thank
Prof. Jerzy Wicha and Mr. Michał Michalak for providing the
sample of diene 20. A gift of cesium salts from Chemetall
GmbH (Frankfurt am Main, Germany) is gratefully acknowl-
edged. We thank Prof. C. Vogt and S. Gruhl (Institute of
Inorganic chemistry, Leibniz Universita¨t Hannover) for conduct-
ing the ICP-MS analyses and T. Jo¨ge and B. Oelze for expert
preparative assistance.
Supporting Information Available: Full experimental pro-
cedures and spectral, analytical data for reaction products (PDF).
This material is available free of charge via the Internet at
http://pubs.acs.org/.
Even despite more pronounced catalyst deactivation, we
demonstrated for the first time that olefin metathesis is possible
JA063561K
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