Mesocellular foam-supported catalysts: Enhanced activity and recyclability for ring-closing metathesis

Article abstract of DOI:10.1002/adsc.200600442

Although ring-closing metathesis (RCM) has been one of the most powerful methodologies for creating cyclic compounds, the pharmaceutical industry has not yet widely adopted this process commercially due to the high costs and leaching problems of homogeneous ruthenium catalysts. To circumvent these problems, we have immobilized the second-generation Hoveyda-Grubbs catalyst effectively onto siliceous mesocellular foam (MCF). The open and interconnected pores of MCF facilitated ligand immobilization and substrate diffusion. We ave observed that the ligand and metal loadings significantly affected the catalytic activity and recyclability. Enhanced recyclability by suppression of ruthenium leaching was achieved by using excess immobilized ligands. The resulting novel heterogenized catalysts demonstrated excellent activity and reusability for the RCM of various types of substrates.

Full text of DOI:10.1002/adsc.200600442

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DOI: 10.1002/adsc.200600442
Mesocellular Foam-Supported Catalysts: Enhanced Activity and
Recyclability for Ring-Closing Metathesis
Jaehong Lim,a Su Seong Lee,a Siti Nurhanna Riduan,a and Jackie Y. Yinga,*
a
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, Singapore 138669
Fax : (+65)-6478-9020; e-mail: jyying@ibn.a-star.edu.sg
Received: August 28, 2006
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Although ring-closing metathesis (RCM) have observed that the ligand and metal loadings sig-
has been one of the most powerful methodologies nificantly affected the catalytic activity and recycla-
for creating cyclic compounds, the pharmaceutical in- bility. Enhanced recyclability by suppression of
dustry has not yet widely adopted this process com- ruthenium leaching was achieved by using excess im-
mercially due to the high costs and leaching prob- mobilized ligands. The resulting novel heterogenized
lems of homogeneous ruthenium catalysts. To cir- catalysts demonstrated excellent activity and reusa-
cumvent these problems, we have immobilized the bility for the RCM of various types of substrates.
second-generation Hoveyda–Grubbs catalyst effec-
tively onto siliceous mesocellular foam (MCF). The Keywords: heterogenized catalysts; immobilization;
open and interconnected pores of MCF facilitated recyclability; ring-closing metathesis; siliceous meso-
ligand immobilization and substrate diffusion. We cellular foam
Introduction
second-generation[8] Grubbsꢀ catalysts 1 (Figure 1)
were modified to improve their stability and reusabili-
Ring-closing metathesis (RCM)[1] has played a key ty,[9] Hoveyda and co-workers observed significant ac-
role in the generation of cyclic motifs since Grubbs tivity loss in repeated runs.[9b] In addition, the process
and co-workers reported the seminal discovery of was complicated by the need for purification by
well-defined and highly active ruthenium catalysts.[2] column chromatography.[9b]
Many academic research groups have utilized the ver-
In an attempt to overcome these drawbacks, several
satile process for the synthesis of various heterocyclic research groups reported immobilization methods
and macrocyclic compounds as well as biologically using soluble[10] and insoluble[11] polymers, monolithic
active natural products.[3] A great deal of industrial in- gels,[12] ionic liquids,[13] fluorous materials,[14] supercrit-
terest has been placed on the production of polymers ical fluids,[15] and silica.[16] Despite their improved re-
by
ring-opening
metathesis
polymerization usability, these supported catalysts suffered from
(ROMP).[4] Nevertheless, the pharmaceutical indus- shortcomings such as low reactivity due to diffusion-
try[5] has not yet widely adopted RCM in large-scale related issues, reduced activity upon reuse, and the re-
manufacturing,[6] due largely to the high costs of the quirement for further purification, etc.[12] Among the
ruthenium-containing catalysts, and the significant previous reports, the commercially available glass-
metal leaching problem.[7] Although the first- and type[12] and one-pot functionalized monolith[17] by
ROMP appeared to be complicated to fabricate, de-
spite the advantage of high-throughput synthesis for
use in combinatorial chemistry.[17c] A recent report on
a silica gel-supported metathesis catalyst was noted
for its facile synthesis, mild reaction conditions, high
turnover number and ease of purification.[18] Unfortu-
nately, the catalyst suffered from low recyclability
even for a reaction involving a simple substrate. Only
68% yield was achieved in three runs, which could
Figure 1. Structures of the ruthenium catalysts.
result from the inefficient loading and instability of
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the immobilized Grubbsꢀ catalyst. The bis-silylated Results and Discussion
Hoveyda-type ligands were recently reported to allow
for ease of preparation, and good activity towards Preparation of Catalysts
diene and enyne substrates.[19] Elias and co-workers
compared the performance of the supported catalysts The synthesis of the heterogenized catalysts 8 is illus-
generated by co-polymerization and by grafting meth- trated in Scheme 1. Hydroxy groups were introduced
ods, in conjunction with the issue of postcapping by to link the isopropoxystyrene ligand onto the surface
trimethylsilyl (TMS) groups. However, these hetero- of the MCF support. Starting with the commercially
genized catalysts fell short of achieving good recycla- available 3-bromo-4-hydroxybenzaldehyde and 2,5-di-
[19]
bility in upto five runs.
Another study by Bann- hydroxybenzaldehyde, the alcohol 3a and phenol 3b
warth and co-workers also illustrated the effect of were readily prepared, respectively, by known proce-
support materials.[15b] From these previous studies, it dures.[10,12] These unstable intermediates were immedi-
is obvious that the activity and recyclability of the ately reacted with the isocyanate 4 to generate the
heterogenized Hoveyda–Grubbs catalysts depend carbamates 5, which were used without further purifi-
considerably upon the physical and chemical proper- cation.[21]
ties of the support material. Other important factors
Monodisperse, spherical MCF microparticles were
may include the type of linker group and the reaction freshly prepared by a novel synthesis scheme.[22] They
conditions, such as temperature and substrate concen- were used either directly or subjected to partial pre-
tration.
capping by treatment with hexamethyldisilazane
In this article, we present the synthesis and applica- (HMDS) in toluene. The benefit of precapping with
tion of immobilized second-generation Hoveyda– TMS groups has been well demonstrated in other cat-
Grubbs catalysts using siliceous mesocellular foam alytic systems,[22] presumably by facilitating the uni-
(MCF) as the solid support. The physical and chemi- form immobilization and high dispersion of ligands.
cal robustness of MCF allowed this catalyst to be The hygroscopic nature of bare (uncapped) and parti-
easily handled at the laboratory scale, and to be ally TMS-precapped MCF 6 necessitated a thorough
scaled upoptentially for manufacturing. Moreover,
drying under vacuum at elevated temperatures prior
the three-dimensional pore structure of MCF with ul- to the immobilization process. Carbamate 5 was
tralarge cell-like pores (24–42 nm) interconnected by smoothly incorporated onto the surface of 6 in reflux-
windows (9–22 nm) should be suitable for reactions ing toluene for 24 h. The ligand loading was deter-
involving large substrates.[20] The resulting heterogen- mined by controlling the ratio of 5 to 6.[23] The re-
ized catalysts were easily recycled for reuse, which maining silanol groups were also capped with TMS
would be of great benefit both economically and envi- groups by treatment with HMDS under vapor-phase
ronmentally.
conditions.[22] This postcapping might play an impor-
tant role in minimizing undesired catalyst interactions
with the hydrophilic surface of MCF. The overall
yields from 3 were excellent (>88% in three steps),
and the Fourier-transform infrared (FT-IR) and cross-
Scheme 1. Synthesis of the heterogenized ruthenium catalysts 8.
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Table 1. Loadings of TMS, ligands and ruthenium in 8.
Table 2. The activity of 8 in the RCM of diene 11 in DCM.
Entry Cata- TMS in 6[a] Ligand in
Ru in 8[c] Ru/
[mmolgÀ1] ligand
ratio
lyst
[mmolgÀ1] 7[b]
[mmolgÀ1]
1
2
3
4
5
8a1
8a2
8a3
8b1
8b2
0.8
0.6
-
0.4
0.6
0.22
0.36
0.74
0.44
0.24
0.18[d]
0.21
0.14
0.17
0.13
0.91
0.64
0.20
0.42
0.57
Entry Catalyst Substrate concen-
tration [M]
Conversion [%][a]
0.5 h 1 h 1.5 h 2 h
1
2
3
4
5
6
7
8
8a1
8a2
8a3
8b1
8b2
0.05
0.10
0.05
0.10
0.05
0.10
0.05
0.10
0.05
0.10
0.05
0.05
78
89
60
89
26
58
81
89
79
89
95
98
96
>99 -
91 >99 -
>99 -
>99 -
[a]
-
Determined by the initial amount of HMDS, and con-
firmed by elemental analysis.
Determined by elemental analysis.
Determined by the weight gain in the product, and con-
firmed by elemental analysis, except for entry 1.
Determined by the weight gain in the product.
[b]
[c]
-
44
85
97
56
96
>99 -
63
>99
[d]
>99 -
-
9
97
99
>99
polarization magic angle spinning nuclear magnetic
resonance (CP-MAS NMR) 13C and 29Si spectra of 7
indicated the formation of well-dispersed Hoveyda-
type ligands on the surface of MCF. The heterogen-
ized catalysts 8 were isolated in good yields by reflux-
ing 1b and 7 in dichloromethane (DCM) in the pres-
ence of copper(I) chloride,[24] followed by filtration,
10
11
12
>99 -
>99 -
>99 -
-
-
-
10
2b
[a]
Determined by gas chromatography (GC).
washing, and drying. The ligand was smoothly ex- manipulations, such as column chromatography on
changed to achieve partial to full loading of rutheni- silica gel and recrystallization in organic solvents.[9a]
um, which caused the material to turn green in color.
Table 1 shows the loadings of TMS, ligands and
metal in 6, 7, and 8, respectively. It appeared that the Activity and Stability of Catalysts
ruthenium loading was saturated at ca. 0.2 mmolgÀ1
with the increased steric encumbrance between neigh- Heterogenized catalysts 8 were tested for RCM by
boring ligands. To our knowledge, 0.21 mmolgÀ1 in using diethyl diallylmalonate 11 as the benchmark
8a2 represents the highest density of ruthenium on substrate (Table 2). The diene 11 was smoothly trans-
silica reported thus far. The ultralarge pore size, high formed into the cyclized product 12 by using 5 mol%
surface area and high porosity of the MCF might ac- of 8 in DCM at ambient temperature. It was found
count for this efficient incorporation of ruthenium. that the reaction rates were influenced by the rutheni-
The uniform and effective grafting of the ligand might um/ligand ratio in 8a, while the effect of ruthenium
also contribute to this high level of loading. Catalysts density was rather negligible. The conversion rates de-
8 were found to be highly stable, and could be stored creased when the ruthenium/ligand ratio was reduced.
for more than several months without any decrease in Most notably, 8a3, which has excess ligand loading vs.
activity.[25]
ruthenium loading, showed significantly lower reac-
To examine the effect of the use of carbamate tion rates (entries 5 and 6). The abundance of free li-
groupin the linker, homogeneous catalyst 10 was pre- gands might have increased the probability of the re-
pared in good yield from alcohol 3a and n-butyl isocy- active ruthenium carbene species to return to the
anate in the same manner as 8a via the ligand 9 solid phase for stabilization,[9a] which slowed down
(Scheme 2). The derivative of the Hoveyda–Grubbs the progress of the reaction as a consequence. This
catalyst (10) maintained good stability in a series of tendency could be exploited to enhance the catalyst
Scheme 2. Synthesis of homogeneous carbamate catalyst 10.
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recyclability, which is discussed below. The reduced served in some of the heterogenized catalysts 8, justi-
reaction rates could be overcome by employing a fying further investigations.
higher substrate concentration. The reaction was ap-
Initial reaction rates of catalysts 8a were found to
parently accelerated at a substrate concentration of be higher when toluene was employed as a solvent
0.10M in all cases, without forming significant side- (Table 3) instead of DCM. In contrast, homogeneous
products, as indicated by NMR spectroscopy. The re- catalyst 10 was less reactive in toluene (Table 3,
action was completed in 2 h even with the least effi- entry 5) than in DCM (Table 2, entry 11).
cient catalyst, 8a3 (entry 6). It is interesting that the
To assess the thermal stability of catalysts 8, cata-
initial reaction rates were higher with catalysts 8b (en- lyst 8b2 was heated in toluene at a concentration of
tries 7 and 9), despite their lower ruthenium/ligand 2.5 mM at 808C for 24 h before testing for catalytic
ratios compared to 8a1 and 8a2. It is well known that activity. Under the same reaction conditions as in
the substituents of the benzylidene ligand have a Table 3, the conversion rate for 11 was decreased by
strong impact on the reaction rates,[26] and the direct only 5%, compared to a freshly prepared solution of
placement of the carbamate moiety seemed to en- 8b2 in toluene. These results were also consistent with
hance the reaction rate in this case. We note that a the observation of Hoveyda and co-workers that the
catalyst loading of less than 5 mol% was sufficient for decomposition of 2b was almost negligible upon expo-
the RCM reaction. One example showed the com- sure to 808C in toluene for 12 h.[25] Overall, catalysts
plete transformation of 11 to 12 in 2 h over 2.5 mol% 8 demonstrated good activity and stability for further
of 8a2 at room temperature. When 1 mol% of 8b2 reusability studies.
was used, full conversion was achieved in 7 h at 508C
in DCM.
Homogeneous catalyst 10 appeared comparable to Recyclability
the commercially available 2b in reaction rates (en-
tries 11 and 12). This showed that the carbamate The recyclability of 8 in the RCM of diene 11 was
moiety in the linker did not significantly affect the evaluated in DCM and toluene at ambient tempera-
catalytic activity.[27] Although the reaction rates were ture (Table 4). The reaction time was kept constant
compromised when the catalysts were immobilized on for all runs to monitor the variation in catalytic activi-
a solid support, high catalytic activities were still ob- ty. Good conversions (ꢀ90%) were obtained for up
to 5 runs in DCM, while substantial loss in activity
was noted after the first 2 runs in toluene. However,
the subsequent loss of activity in toluene was minor
so that ca. 80% conversion was still achieved in the
Table 3. The activity of 8 in the RCM[a] of 11 in toluene.
Entry Catalyst Concentration
[M]
Conversion [%][b]
10th run. Compounds 8a1 and 8b1 exhibited similar
recyclabilities at ambient temperature, suggesting that
the substituent at the 4-position of the styrene ligand
did not strongly impact the deactivation of catalytic
species.
The gradual loss of activity might be attributed to
the deactivation of the ruthenium-carbene complex in
the solution phase. The stabilization of the reactive
species by the ligands in the solid phase should be
crucial towards retaining the catalytic activity.[28] The
deactivated ruthenium complex could be leached out
at the end of the reaction. Moreover, with the de-
0.5 h 1 h 1.5 h 2 h
1
2
3
4
5
6
8a1
8a2
8b1
8b2
10
0.10
0.10
0.10
0.10
0.05
0.05
96
94
89
88
85
99
>99 -
97 >99 -
>99 -
>99 -
-
-
-
94
97
>99
-
2b
>99 -
[a]
All reactions were performed over 5 mol% of catalyst at
258C.
Determined by GC.
[b]
Table 4. Recyclability of 8 in the RCM[a] of diene 11.
Entry
Catalyst
Solvent
Conversion in each run [%][b]
Run 1
Run 3
Run 5
Run 7
Run 10
1
2
3
4
8a1
8b1
DCM
Toluene
DCM
>99
99
>99
95
97
80
98
78
94
85
90
87
85
86
85
87
79
79
77
81
Toluene
[a]
All reactions were performed over 5 mol% of catalyst for 2 h at 0.05M at 258C.
Determined by GC.
[b]
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creased ruthenium/ligand ratio due to metal leaching, substrate containing free alcohol (29), and the activity
conversion rates in RCM would be lowered in the was completely lost in 5 runs (entry 9). This could be
subsequent runs. Despite the reduced activity, com- attributed to the leaching problems associated with
plete conversions were attained with prolonged reac- the strong affinity of hydroxy groups to the Grubbsꢀ
tion times (i.e., with an additional 1–2 h) in the 10th ruthenium catalysts,[30] despite the relatively high
run in all cases. Catalysts 8 demonstrated superior re- compatibility to polar protic moieties.[31] It is notewor-
cyclability under mild conditions, compared to previ- thy that Grubbs and co-workers recently reported
ously reported systems under similar conditions[18,19] PEG-modified, water-soluble catalysts for metathesis
(e.g., silica-supported catalysts at ambient reaction reactions, which exhibited good compatibility and ac-
temperature).
tivity in water.[32]
The enyne substrate 31 produced a monocyclic
compound, which was not further transformed to the
desired bicyclic product 32 even with a prolonged re-
action time (entry 10). This lack of selectivity was
RCM of Various Dienes
The heterogenized catalysts were investigated for the consistent with the finding of Grela and co-workers
RCM of various dienes (Table 5). For each reaction, that the formation of the six-membered monocyclic
the reaction time was determined in the first run for a compound was unavoidable over the second-genera-
near-complete conversion of the specific substrate, tion Grubbs catalyst.[33] Thus, recyclability studies
and was kept constant for the subsequent runs to were not pursued for this particular reaction. With
monitor any decrease in catalytic activity. RCM of the the growing importance of macrocyclic compounds in
nitrogen-containing diene 13 over 5 mol% of 8a1 pro- the pharmaceutical industry,[34] the formation of eight-
duced the five-membered ring 14 in excellent yield membered ring 34 and macrocycle 36 was examined
for consecutive runs (entry 1), demonstrating a com- over heterogenized catalyst 8a2 at 508C (entries 11
parable reaction rate as in the case of 11. Although and 12). The reactions proceeded successfully in both
the recyclability decreased over 7 runs, the full con- cases, although the conversions decreased over con-
version could still be achieved by increasing the reac- secutive runs.
tion time. Formation of the seven-membered ring 16
was also efficient, with excellent activity retained over
7 runs (entry 2).[29] As the results in entry 3 indicated, Enhanced Recyclability
RCM involving the 1,1-disubstituted alkene of an a,b-
unsaturated carbonyl substrate was especially effec- As mentioned earlier in this article, the recyclability
tive with 8b1 as the catalyst. The reaction efficiency of the catalysts might be improved with the presence
appeared similar in the case of an internal olefin 19 of excess free ligands. Assuming that the return of the
(entry 4), but the recyclability was lower than in the reactive catalytic species to the MCF-supported iso-
case of the corresponding terminal olefin, presumably propoxystyrene ligand would be crucial towards re-
because the product inhibition became greater due to taining the catalytic activity, additional free ligands
the increased solubility of propene evolved in DCM. were introduced into the system. This strategy was ac-
The reaction involving a 1,1-disubstituted olefin (21) complished (i) by using catalyst 8a3 with a very high
proceeded more slowly for the synthesis of a trisubsti- ligand loading and a partial ruthenium loading (see
tuted cyclic alkene, and the activity was found to de- Table 1), or (ii) by adding MCF-supported free ligands
crease over consecutive runs (entry 5). Formation of a 7a1 to catalyst 8a2. In both cases the catalyst recycla-
tetrasubstituted cyclic alkene has been the most chal- bility was dramatically enhanced over 10 runs, com-
lenging target both in homogeneous and heterogene- pared with the results over catalyst 8a2 (Table 6). The
ous catalysis.[19] Surprisingly, our catalyst 8b2 was solid mixture of 8a2 and 7a1 microparticles also im-
highly efficient, completing the RCM of 23 essentially proved the catalyst recyclability over 10 runs
in 20 h at 808C in toluene (entry 6). This catalyst also (entry 3), giving a similar effect as 8a3 (entry 2) over
retained some activity in the second run.
consecutive runs by providing excess ligands for the
For oxygen-containing dienes, such as 25 and 27, re- return and stabilization of the reactive catalytic spe-
markably high conversions were achieved in 1 h for cies. Although the reaction was retarded with the in-
all 5 runs for the ether substrate 25 over catalyst 8b1 troduction of additional free ligands, this approach
(entry 7), while a slightly lower recyclability was at- successfully increased the catalyst recyclability, and
tained over catalyst 8a1 for the RCM of 27 (entry 8). the reaction rate could be compensated by using a
Guillemin and co-workers observed the poor recycla- higher substrate concentration of 0.10M. To the best
bility associated with catalyst decomposition and of our knowledge, this is the first report of using
leaching due to the coordinating ability of oxygen to excess free ligands to improve the recyclability of a
ruthenium.[13a] Catalyst 8a1 showed a significant loss heterogenized catalyst.
in activity over consecutive runs for the RCM of a
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Table 5. Recyclability of 8 in the RCM[a] of various dienes.
Entry
Run no.
Substrate
Product
Time [h]
Conversion[b] (Yield[c]) [%]
1
3
5
7
1.5
1.5
1.5
1.5
6
1.5
1.5
1.5
1.5
>99 (97)
97 (95)
92 (91)
84
>99 (97)
94 (93)
93 (91)
91 (90)
91 (90)
1
13
14
1
3
5
7
2
15
17
16
18
1
3
5
7
1
3
5
7
2
2
2
2
96 (93)
96 (94)
98 (95)
92 (90)
>99 (97)
98 (96)
86 (81)
55
95 (91)
96 (92)
91 (88)
76 (71)
53
3[d]
1.5
1.5
1.5
1.5
3
4.5
4.5
4.5
4.5
24
20
20
4
5
19
21
20
22
1
3
5
7
98 (92)
96 (95)
31
1
2
6[e]
7[d]
8
23
25
27
24
26
28
1
3
5
7
1
3
5
7
1
3
5
1
1
1
1
1.5
1.5
1.5
1.5
1.5
1.5
1.5
>99 (97)
99 (97)
98 (96)
97 (94)
94
91
88
86
84
23
2
9
29
31
30
32
10
1
24
67[f]
1
2
3
2
2
2
84
69
61
11[g]
33
35
34
36
1
2
3
2.5
2.5
2.5
94[h]
88[h]
83[h]
12[g]
[a]
Unless otherwise noted, all reactions were performed over 5 mol% of 8a1 at 258C at a substrate concentration of 0.05M
in DCM.
Determined by gas chromatography (GC) or liquid chromatography (LC), unless otherwise specified.
Isolated yield by column chromatography on silica gel.
Performed over 5 mol% of 8b1.
Performed over 5 mol% of 8b2 at 808C in toluene.
[b]
[c]
[d]
[e]
[f]
Formation of the monocyclic compound was also observed (27% conversion in GC).
[g]
[h]
Performed over 5 mol% of 8a2 at 508C.
1
Determined by H NMR spectroscopy (400 MHz).
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Table 6. Enhanced recyclability of 8 in the RCM[a] of diene
11 in DCM.
Table 7. Ruthenium leaching in the RCM[a] of diene 25 over
8a2.[b]
Entry Catalyst
Time
[h]
Conversion in each run [%][b]
Entry 7a1
Temperature Time
Ru in each run
[ppm][c]
[mol%] [8C]
[h]
Run Run Run Run Run
1
3
5
7
10
Run Run Run
1
3
5
1
2
3
4
8a2
8a3
1
2
2
0.5
>99 98
90
98
97
97
84
94
91
95
77
91
90
93
99
98
99
98
1
2
3
4
-
5
-
25
25
50
50
1
2
0.5
1
35
23
13
10
30
18
9
20
15
7
8a2+7a1[c]
8a2[d]
>99 98
5
9
9
[a]
Unless otherwise noted, all reactions were performed in
DCM over 5 mol% of 8a at 258C at a substrate concen-
tration of 0.10M in DCM.
[a]
[b]
[c]
All reactions were performed over 5 mol% of 8a2 at
0.05M in DCM.
[b]
[c]
[d]
Determined by GC.
Conversions (determined by GC) were above 98% in all
Performed in the presence of 5 mol% of 7a1.
Performed at 508C at a substrate concentration of 0.05M
in DCM.
runs.
Determined by ICP-MS.
It is noteworthy that the recyclability was substan- catalyst recyclability could be enhanced by the use of
tially improved at an elevated temperature (entry 4). additional MCF-supported free ligands and elevated
The elevated temperature greatly shortened the reac- reaction temperature, through suppressing ruthenium
tion time and might have facilitated the removal of leaching during the course of reaction.
ethylene generated in situ to drive the reaction equi-
Ruthenium leaching from 8a2 was also measured in
librium forward, so that the reactive metal carbene the RCM of 11 over 10 runs. On average only 4 ppm
species were less vulnerable to deactivation and of ruthenium were leached in each run. This level of
leaching.
ruthenium leaching was considerably lower than that
reported in previous studies.[37]
Ruthenium Leaching
Conclusions
Since metal contaminants significantly limit the appli-
cation of RCM in industrial processes, several ap- We have successfully developed MCF-supported Hov-
proaches have been reported on the removal of ruthe- eyda–Grubbs catalysts for RCM. These novel hetero-
nium residues from the final product of homogeneous genized catalysts demonstrated excellent activity and
catalysis.[35] Nevertheless, the application of solid-sup- recyclability under mild reaction conditions. The ul-
ported RCM has distinct advantages over the conven- tralarge pores and high surface area of MCF allowed
tional homogeneous catalysis, as demonstrated in pre- the ligands and catalytic complexes to be immobilized
vious reports.[36] In this work, the effect of ruthenium without steric hindrance, and facilitated the diffusion
leaching on the recyclability of the heterogenized cat- of bulky substrates during reaction. Partial precapping
alyst was examined. In particular, the ether-containing of silanol groups with TMS groups promoted the uni-
diene 25 was investigated due to the coordinating form dispersion of ligands and catalytic complexes on
ability of oxygen to ruthenium. The RCM of 25 over the surface of the siliceous support. Postcapping of
8a2 was efficient enough to reach conversions above the residual silanol groups with TMS groups mini-
98% in all runs (Table 7). In the presence of 5 mol% mized any undesired interactions between the sili-
of MCF-supported free ligand 7a1, the ruthenium ceous support and the catalytic species. The high effi-
concentration in the supernatant, as measured by in- ciency of the heterogenized catalyst was attributed to
ductively coupled plasma-mass spectroscopy (ICP- the well-defined structure of 8 obtained via a facile
MS) at the end of each run, was substantially reduced synthetic pathway. Although the gradual loss of activi-
despite the longer reaction time (entry 2). While the ty was unavoidable in multiple recycling runs over
suppression of ruthenium leaching by additional free Hoveyda–Grubbs catalysts, the reusability of the het-
ligand was more apparent in reactions run at room erogenized catalyst was significantly enhanced by in-
temperature, leaching was also reduced at elevated troducing additional MCF-supported free ligands. The
temperature and for shorter reaction periods (en- stable, versatile catalysts presented herein successfully
tries 3 and 4). This observation agreed with our find- catalyzed a wide variety of diene substrates. In con-
ing that the recyclability was higher under refluxing junction with the remarkably low leaching of rutheni-
DCM (Table 6, entry 3). Table 7 confirmed that the um to the reaction mixture, this cost-effective and en-
1072
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ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2007, 349, 1066 – 1076

Mesocellular Foam-Supported Catalysts
FULL PAPERS
The general procedure using 3b (752 mg, 4.22 mmol) gave
carbamate 5b as a colorless oil, which was used without fur-
ther purification; yield: 1.77 g (99%). H NMR (400 MHz,
vironmentally benign catalytic process may be poten-
tially employed in continuous reactor applications.[38]
1
CDCl3): d=0.68 (t, 2H, J=8.0 Hz), 1.24 (t, 9H, J=7.2 Hz),
1.33 (d, 6H, J=6.0 Hz), 1.70 (quintet, 2H, J=8.0 Hz), 3.26
(q, 2H, J=8.0 Hz), 3.83 (q, 6H, J=7.2 Hz), 4.46 (septet,
1H, J=6.0 Hz), 5.24 (dd, 1H, J=11.2, 1.4 Hz), 5.42 (bs,
1H), 5.69 (dd, 1H, J=17.6, 1.4 Hz), 6.84 (d, 1H, J=8.8 Hz),
6.96 (dd, 1H, J=8.8, 2.2 Hz), 7.02 (dd, 1H, J=17.6,
11.2 Hz), 7.22 (d, 1H, J=2.2 Hz); 13C NMR (100 MHz,
CDCl3): d=7.4, 18.7, 22.0, 22.9, 43.3, 58.3, 71.3, 114.3, 114.9,
119.0, 121.4, 128.5, 131.1, 144.4, 152.2, 154.8; MS (FAB): m/z
(%)=426 (37) [M+ +H], 380 (100) [(MÀEtOH)+H]+, 178
Experimental Section
General Remarks
FT-IR spectra were recorded on a Digilab FTS 7000 FTIR
spectrometer equipped with an MTEC-300 photoacoustic
detector. Solution NMR spectra were recorded on a Bruker
1
spectrometer (400 MHz for H and 100 MHz for 13C) at am-
bient temperature in the solvents indicated, and referenced
to the solvent peaks. 13C and 29Si CP-MAS NMR spectra of
the immobilized catalysts were recorded on a 400 MHz
Bruker spectrometer. Samples were packed into 4 mm ZrO2
rotors and spun at 5 kHz. The spinning sideband suppression
method was used for 13C CP-MAS NMR. Elemental analy-
ses were performed with a CE440 CHN Analyzer (Exeter
Analytical). ICP-MS data were obtained by use of an Elan
DRC II, Perkin Elmer SCIEX, USA. Mass spectra were ob-
tained at the Elemental Analysis Laboratory, Department
of Chemistry, National University of Singapore, Singapore.
Conversions for RCM of dienes were determined by GC
(Agilent 6890N) and LC (Agilent 1100 series), unless other-
(69);
HR-MS
(FAB):
m/z=426.2299,
calcd.
for
C21H36NO6Si: 426.2306.
Immobilized Ligands 7
A Schlenk flask was charged with MCF (2.05 g), and placed
under vacuum for 24 h at 1208C. The flask was purged with
argon at room temperature, and charged with anhydrous tol-
uene (20 mL) and the corresponding triethoxysilane
5
(0.85 mmol). The resulting mixture was heated at 1108C for
24 h. Upon cooling to room temperature, the solid was thor-
oughly rinsed successively by toluene, DCM, methanol, and
DCM (50 mL each). The white solid was transferred to a
Schlenk flask, and dried under vacuum for 12 h at 808C.
After cooling to room temperature, HMDS (1 mL) was
added to the sealed flask. The flask was placed in a liquid
nitrogen bath for 10 min under vacuum. It was sealed and
then kept at 808C for 5 h. The resulting solid was cooled to
room temperature, washed thoroughly with DCM (100 mL),
and then dried under vacuum for 24 h to give the corre-
sponding immobilized ligand as a white powder.
1
wise noted. H NMR spectroscopy was used to monitor the
conversion of 35. Isolated yields were determined after pu-
rification by column chromatography on silica gel (Merck).
Unless otherwise noted, reactions were carried out using
standard Schlenk techniques. All chemicals were purchased
from Aldrich, except for 3-isocyanatopropyltriethoxysilane
(Gelest). Solvents were either purified by passage through a
column of activated alumina or purchased in sealed bottles
from Aldrich.
The general procedure using the derivative of 3a (200 mg,
0.45 mmol) and MCF (1.95 g, precapped with 0.8 mmol of
TMS/g) gave 7a1 (Table 1, entry 1); yield: 2.15 g. 29Si CP-
MAS NMR: d=À109.0, À65.0, À57.5, À46.6, 13.2; 13C CP-
MAS NMR: d=1.7, 11.1, 18.5, 23.3, 25.7, 46.0, 52.0, 61.4,
68.2, 72.5, 113.6, 115.7, 130.6, 134.5, 157.9; FT-IR: n=759,
810, 842, 1085, 1494, 1715, 2904, 2962, 3090 cmÀ1; anal.
Carbamates 5
A Schlenk flask was charged with alcohol 3a (1.60 g,
8.35 mmol), 3-isocyanatopropyltriethoxysilane (4) (1.98 mL,
8.09 mmol), 4-dimethylaminopyridine (12 mg, 0.10 mmol),
triethylamine (2.79 mL, 20.0 mmol), and anhydrous DCM
(10 mL) under argon. The reaction mixture was heated for
48 h under reflux. DCM and triethylamine were removed
under reduced pressure. Hexane (10 mL) was added, and
the precipitate was removed by filtration. The filtrate was
concentrated under reduced pressure, and dried under
vacuum to give the carbamate 5a as a colorless oil, which
was used without further purification; yield: 3.63 g (99%).
1H NMR (400 MHz, CDCl3): d=0.64 (t, 2H, J=8.0 Hz),
1.24 (t, 9H, J=7.2 Hz), 1.35 (d, 6H, J=6.0 Hz), 1.62 (m,
2H), 3.19 (m, 2H), 3.82 (q, 6H, J=7.2 Hz), 4.54 (septet,
1H, J=6.0 Hz), 5.01 (bs, 1H), 5.03 (s, 2H), 5.25 (dd, 1H,
J=11.2, 1.4 Hz), 5.75 (dd, 1H, J=17.6, 1.4 Hz), 6.86 (d, 1H,
J=8.4 Hz), 7.04 (dd, 1H, J=17.6, 11.2 Hz), 7.22 (dd, 1H,
J=8.4, 2.2 Hz), 7.48 (d, 1H, J=2.2 Hz); 13C NMR
(100 MHz, CDCl3): d=7.6, 18.3, 22.1, 23.3, 43.4, 58.4, 66.4,
70.9, 106.6, 114.0, 114.3, 126.9, 128.6, 129.0, 131.7, 155.1,
156.5; MS (FAB): m/z (%)=438 (38) [MÀH]À, 392 (20)
[(MÀEtOH)ÀH]À, 364 (16), 297 (5), 264 (18), 220 (89), 174
(100); HR-MS (FAB): m/z=438.2328, calcd. for
C22H36NO6Si: 438.2331.
found:
C 8.16, H 1.66, N 0.31; loading of ligand:
0.22 mmolgÀ1.
The general procedure using the derivative of 3a (184 mg,
0.42 mmol) and MCF (1.00 g, precapped with 0.6 mmol of
TMS/g) gave 7a2 (Table 1, entry 2); yield: 1.13 g. FT-IR:
identical to that of 7a1; anal. found: C 10.77, H 1.91, N,
0.51; loading of ligand: 0.36 mmolgÀ1.
The general procedure using the derivative of 3a (967 mg,
2.20 mmol) and MCF (2.00 g, not precapped with TMS)
gave 7a3 (Table 1, entry 3); yield: 2.52 g. 29Si CP-MAS
NMR: d=À108.6, À64.0, À60.0, À46.4, 14.0; 13C CP-MAS
NMR: d=1.8, 10.8, 19.2, 22.6, 37.5, 44.7, 51.6, 61.2, 68.4,
71.9, 114.9, 130.0, 133.6, 158.0, 165.8; FT-IR: identical to
that of 7a1; anal. found: C 14.15, H 2.02, N 0.95; loading of
ligand: 0.74 mmol.
The general procedure using the derivative of 3b (255 mg,
0.60 mmol) and MCF (1.17 g, precapped with 0.4 mmol of
TMS/g) gave 7b1 (Table 1, entry 4); yield: 1.34 g. 29Si CP-
MAS NMR: d=À107.7, À99.7, À64.3, À55.8, 14.5; 13C CP-
MAS NMR: d=1.6, 10.7, 21.5, 24.9, 44.8, 49.9, 51.9, 53.6,
60.4, 72.0, 112.8, 115.6, 119.9, 122.6, 126.2, 130.2, 132.9,
Adv. Synth. Catal. 2007, 349, 1066 – 1076
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asc.wiley-vch.de
1073

Jaehong Lim et al.
FULL PAPERS
146.8, 150.9, 153.7, 156.9; FT-IR: n=759, 806, 846, 1083,
1484, 1753, 2851, 2904, 2962, 3090 cmÀ1; anal. found: C 9.77,
H 1.72, N 0.62; loading of ligand: 0.44 mmolgÀ1.
The general procedure using the derivative of 3b (681 mg,
1.60 mmol) and MCF (3.19 g, precapped with 0.6 mmol of
TMS/g) gave 7b2 (Table 1, entry 5); yield: 3.48 g. FT-IR:
identical to that of 7b1; anal. found: C 8.78, H 1.80, N 0.46;
loading of ligand: 0.24 mmolgÀ1.
6.0 Hz), 1.47 (m, 2H), 3.19 (m, 2H), 4.54 (septet, 1H, J=
6.0 Hz), 4.70 (bs, 1H), 5.02 (s, 2H), 5.25 (dd, 1H, J=11.2,
1.4 Hz), 5.75 (dd, 1H, J=17.6, 1.4 Hz), 6.86 (d, 1H, J=
8.4 Hz), 7.04 (dd, 1H, J=17.6, 11.2 Hz), 7.22 (dd, 1H, J=
8.4, 2.2 Hz), 7.48 (d, 1H, J=2.2 Hz).
A two-necked flask equipped with a reflux condenser was
charged with ligand 9 (260 mg, 0.89 mmol), second-genera-
tion Grubbsꢀ catalyst (680 mg, 0.80 mmol), copper chloride
(97 mg, 0.98 mmol), and anhydrous DCM (10 mL) under
argon. The reaction mixture was stirred overnight at room
temperature in a stream of argon. The reaction mixture
gradually changed from dark brown to deepgreen. The re-
sulting mixture was concentrated under reduced pressure,
and purified by flash column chromatography (hexane:E-
tOAc:DCM=4:1:1), followed by recrystallization over
hexane and diethyl ether to give catalyst 10 as a green
Immobilized Catalysts 8
A two-necked flask equipped with a reflux condenser was
charged with the ligand 7a1 (1.00 g, 0.22 mmolgÀ1 of load-
ing), the second-generation Grubbsꢀ catalyst 1b (186 mg,
0.22 mmol), copper chloride (22 mg, 0.22 mmol), and anhy-
drous DCM (10 mL) under argon. The reaction mixture was
heated overnight under reflux in a stream of argon. The re-
action mixture gradually changed from dark brown to deep
green. After cooling to room temperature, the fine powder
was washed thoroughly with DCM (100 mL) under the open
atmosphere, and dried under vacuum for 24 h to give the
immobilized catalyst 8a1 as a green powder (Table 1,
entry 1); yield: 1.09 g (91%, based on 7a1). FT-IR: n=759,
808, 847, 1085, 1487, 1720, 2739, 2903, 2961 cmÀ1; loading of
ruthenium: 0.18 mmolgÀ1 (based upon the weight gain of
8a1).
The general procedure using 1b (170 mg, 0.20 mmol),
copper chloride (20 mg, 0.20 mmol), and the ligand 7a2
(500 mg) gave 8a2 as a green powder (Table 1, entry 2);
yield: 554 mg (65%, based on 7a2). FT-IR: similar to that of
8a1; anal. found: C 15.28, H 2.23, N 1.06; loading of rutheni-
um: 0.21 mmolgÀ1.
The general procedure using 1b (93 mg, 0.11 mmol),
copper chloride (11 mg, 0.11 mmol), and the ligand 7a3
(500 mg) gave 8a3 as a green powder (Table 1, entry 3);
yield: 546 mg (27%, based on 7a3). FT-IR: similar to that
of 8a1; anal. found: C 17.26, H 2.31, N 1.30; loading of
ruthenium: 0.14 mmolgÀ1.
1
powder; yield: 560 mg (85%). H NMR (400 MHz, CDCl3):
d=0.93 (t, 3H, J=7.2 Hz), 1.26 (d, 6H, J=6.0 Hz), 1.35 (m,
2H), 1.48 (m, 2H), 2.41 (s, 9H), 2.47 (s, 9H), 3.19 (m, 2H),
4.18 (s, 4H), 4.64 (bs, 1H), 4.80 (septet, 1H, J=6.0 Hz), 5.04
(s, 2H), 6.76 (d, 1H, J=8.4 Hz), 6.91 (d, 1H, J=2.2 Hz),
7.07 (s, 4H), 7.53 (dd, 1H, J=8.4, 2.2 Hz), 16.53 (s, 1H);
13C NMR (100 MHz, CDCl3): d=13.7, 15.3, 19.9, 21.0, 21.1,
25.9, 32.0, 40.8, 51.5, 65.7, 65.9, 75.3, 112.9, 122.9, 129.4,
129.8, 130.6, 138.9, 145.2, 152.1, 211.1, 296.8; anal. calcd. for
C37H49ClNO3Ru: C 58.80, H 6.53, N 5.56; found: C 58.73, H
6.64, N 5.31.
Testing of Catalytic Activity
A sintered vial equipped with a septum and a stirring bar
was charged with catalyst 8a1 (280 mg, 0.050 mmol) and an-
hydrous DCM (20 mL). The green suspension was stirred at
258C under argon. Substrate 11 (0.24 mL, 1.00 mmol) was
injected via a syringe, and a small aliquot was taken from
the reaction mixture every 15 min. The conversion to prod-
uct 12 at each time point was monitored by GC, after filter-
ing the aliquot through a short pad of silica gel by elution
with DCM.
The general procedure using 1b (188 mg, 0.22 mmol),
copper chloride (22 mg, 0.22 mmol), and the ligand 7b1
(500 mg) gave 8b1 as a green powder (Table 1, entry 4);
yield: 541 mg (40%, based on 7b1). FT-IR: similar to that of
8a1; anal. found: C 12.81, H 2.02, N 1.06; loading of rutheni-
um: 0.17 mmolgÀ1.
LC and NMR were used for monitoring the conversion of
several substrates in Table 5, as specified in the footnotes.
Testing of Catalyst Recyclability
A sintered vial equipped with a septum and a stirring bar
was charged with catalyst 8a1 (280 mg, 0.050 mmol) and an-
hydrous DCM (20 mL). The green suspension was stirred at
258C under argon, and substrate 11 (0.24 mL, 1.00 mmol)
was injected via a syringe. After a given time period known
from the activity test (2 h, in this case), the supernatant was
taken after centrifugation to determine the conversion by
GC and the isolatied yield by flash column chromatography.
The catalyst 8a1 in the vial was thoroughly rinsed with
DCM (10 mL) three times prior to the next run.
The general procedure using 1b (280 mg, 0.24 mmol),
copper chloride (24 mg, 0.24 mmol), and the ligand 7b2
(1.00 g) gave 8b2 as a green powder (Table 1, entry 5);
yield: 1.07 g (52%, based on 7b2). FT-IR: similar to that of
8a1; anal. found: C 11.85, H 2.08, N 0.81; loading of rutheni-
um: 0.13 mmolgÀ1.
Homogeneous Catalyst 10
A Schlenk flask was charged with the alcohol 3a (192 mg,
1.00 mmol), n-butyl isocyanate (109 mg, 1.10 mmol), 4-dime-
Reactions were run in a similar manner for the substrates
in Table 5. LC and NMR were used for monitoring the con-
version of several substrates in Table 5, as specified in the
footnotes.
thylaminopyridine
(1 mg,
0.01 mmol),
triethylamine
(0.28 mL, 2.00 mmol), and anhydrous DCM (5 mL) under
argon. The reaction mixture was stirred overnight at room
temperature. The resulting mixture was concentrated under
reduced pressure, and purified by flash column chromatog-
raphy (hexane:EtOAc=4:1) to give carbamate 9 as a color-
1
less oil; yield: 270 mg (93%). H NMR (400 MHz, CDCl3):
d=0.92 (t, 3H, J=7.2 Hz), 1.33 (m, 2H), 1.34 (d, 6H, J=
1074
asc.wiley-vch.de
ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2007, 349, 1066 – 1076

Mesocellular Foam-Supported Catalysts
FULL PAPERS
[7] Ruthenium residue levels must be less than 5 ppm and
0.5 ppm for oral and parental drug products according
to the guidelines of European Agency for the Evalua-
tion of Medicinal Products. For details, see: A. Thayer,
Chem. Eng. News 2005, 83, 55.
Acknowledgements
This work is supported by the Institute of Bioengineering and
Nanotechnology (Biomedical Research Council, Agency for
Science, Technology and Research, Singapore).
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Adv. Synth. Catal. 2007, 349, 1066 – 1076