A simple and practical phase-separation approach to the recycling of a homogeneous metathesis catalyst

Article abstract of DOI:10.1039/b517088e

The air stable asarone-derived Ru carbene 16, a robust olefin metathesis catalyst, can be easily separated after reaction by deposition on silica gel and reused up to nine times. This procedure provides products of excellent purity with low Ru content. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b517088e

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A simple and practical phase-separation approach to the recycling of a
homogeneous metathesis catalyst{
a
Anna Michrowska, Lukasz Gulajski and Karol Grela*
b
a
/
/
Received (in Cambridge, UK) 5th December 2005, Accepted 4th January 2006
First published as an Advance Article on the web 19th January 2006
DOI: 10.1039/b517088e
‘phase-tags’ for application in dendrimer-supported organic
The air stable asarone-derived Ru carbene 16, a robust olefin
metathesis catalyst, can be easily separated after reaction by
deposition on silica gel and reused up to nine times. This
procedure provides products of excellent purity with low Ru
content.
synthesis,10 soluble polymer-supported organic synthesis
(SPSOS),12 fluorous synthesis13 and ionic liquids14 have been
developed (Scheme 2).
We have recently reported on a new metathesis catalyst 16.15
Catalyst 16, very stable and easy to prepare from inexpensive
a-asarone, shows activity comparable to the parent Hoveyda
carbene 2b.15 Interestingly, complex 16 exhibits a high affinity for
silica gel when CH2Cl2 is used as eluent (TLC: Rf 5 0.00 in
CH2Cl2) which can potentially enable its efficient recovery. In the
present investigation we decided to scrutinize this observation.16
The model RCM reaction of N,N-diallyl-p-toluenesulfonamide
using 5 mol% of 16, followed by simple silica gel filtration (10 6
weight of the product), affords N-p-tosyl-2,5-dihydro-1H-pyrrole
as a colorless solid (Scheme 3 and Fig. 1). Inductively coupled
plasma mass spectrometry (ICP-MS) analysis of the crude product
sample indicated only 83 ppm Ru (0.0083 wt.%), which is
substantially lower than contamination levels obtained with
catalyst 2b (up to 22600 ppm Ru; 2.26 wt.%), where all of the
Despite the general superiority offered by modern homogeneous
Grubbs and Hoveyda–Grubbs catalysts 1–4 (Scheme 1),1 they
share some disadvantages. Since olefin metathesis reaction is
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 In many cases, ruthenium
levels of . 2000 ppm remain after chromatography of products
prepared by RCM with 5 mol% of Grubbs catalysts.3
Several protocols to remove toxic ruthenium impurities have
been proposed.3 Use of biphasic extraction,4 various scavengers,
such as lead tetraacetate,5 DMSO or phosphine additives6
(including supported phosphines)7 were reported to reduce the
ruthenium content to 200–1200 ppm. Alternatively, two cycles of
chromatography, followed by 12 h incubation with activated
charcoal, resulted in , 100 ppm.8 From an economic point of
view, in the whole chemical process the catalyst’s cost is another
important attribute. Therefore the development of improved
strategies for recovering homogeneous catalyst and for removal
of ruthenium decomposition by-products is of great importance.
One particularly innovative method involves the use of tagged
catalysts, which can be easily separated from untagged products by
a phase-transfer event (precipitation or liquid–liquid partition).9
Recently, numerous Hoveyda type11 catalysts bearing various
Scheme 1 Selected ruthenium precatalysts for alkene metathesis.
Cy 5 cyclohexyl; Mes 5 2,4,6-trimethylphenyl.
aInstitute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka
44/52, 01-224, Warsaw, Poland. E-mail: grela@icho.edu.pl
bFaculty of Chemistry, Warsaw University of Technology
(Politechnika), Noakowskiego 3, 00-664, Warsaw, Poland
{ Electronic supplementary information (ESI) available: experimental
section. See DOI: 10.1039/b517088e
Scheme 2 Selected ruthenium precatalysts for phase-separation applica-
tions (refs. [10–14]).
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Chem. Commun., 2006, 841–843 | 841

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Table 1 Reuse of catalyst 16 in the metathesis of 18 to 19a
Product 19a
Catalyst 16b
Cycle no
Yield % (mg) [Ru ppm]
Yield % (mg)
17 (wt.%)
1
2
3
4
5
6
7
8
9
a
96 (742.0)
85 (321.1) [110]
84 (199.1)
83 (99.5) [130]
79 (68.5)
73 (51.1) [130]
77 (39.0)
71 (30.6)
56 (60.0)
68 (32.1)
65 (18.3)
71 (10.2)
74 (7.4)
77 (5.6)
71 (4.0)
89 (3.6)
90 (3.1)c
3.1
—
3.2
5.7
5.7
5.8
—
6.4
—
73 (27.0)
Conditions: 5 mol% catalyst 16, 0.02 M in CH2Cl2, 22 uC, 2 h.
Conversions determined by GC. Level of Ru impurity determined by
ICP-MS and shown as percent by mass. The amount of 17
b
determined by analysis of 200 MHz 1H NMR spectrum of recovered
unpurified 16 after removal of EtOAc in vacuo. No benzylidene
Scheme 3 Phase-separation and catalyst 16 recovery experiment
c
(5 mol% Ru) using ordinary silica gel.
proton signal present in the 1H NMR spectrum.
of catalyst from the cartridge. The conversion of the substrate,
measured after 2 h of reaction, decreased from 96% (first run) to
73% (ninth run). All operations, including passing the reaction
mixture through silica gel, washing with reagent-grade CH2Cl2 and
ethyl acetate and concentration of the filtrate, can be carried out in
air. It should be noted, however, that no recovery of 16 was
possible after reactions at higher temperatures (50 uC).
The scope of this separation protocol was tested by conducting
several ring closing metathesis reactions under standard conditions
(0.3 mmol scale, 5 mol% of 16, 25–45 uC, 0.5–24 h), and the results
of these experiments are summarized in Scheme 4. All model
substrates cyclized smoothly to form various hetero- and
carbocycles, including polar 2,3,4-trimethoxybenzene-oxasilepine
(23) and 7,10-dihydro-3H-oxepino[3,2-e]indole (25) derivatives.
Conversions were good (99–79%), and the catalyst was recovered
in 76–92% yields in all but one case. After metathesis reaction
leading to 25 no catalyst 16 was recovered, probably due to its
sequestering by a free N-allyl substituent still present in the
product.
Next, the reactivity of 16 in some representative cross-metathesis
reactions with methyl acrylate, 2-methyl-2-butene and (Z)-4-
(acetyloxy)-2-butenyl acetate was tested under the standard
conditions, to obtain valuable products, such as 29, a pheromone
of the Leopard moth (Zeuzera pyrina) (Scheme 4).19
In our standard procedure, the crude reaction mixtures were
loaded onto ordinary silica gel glass cartridges (10–30 6 weight of
the substrate), which were eluted with CH2Cl2 to provide a
fraction containing organic products and with EtOAc to recover
Fig. 1 Purification of RCM product 19 (0.3 mmol scale, 5 mol% Ru) on
silica gel cartridges, using: A 5 Hoveyda–Grubbs catalyst 2b; B 5 asarone-
derived catalyst 16. Legend: a)–b) Crude reaction mixture loaded on silica
gel cartridge and washed with 5.0 mL of DCM; c)–d) the same cartridge
washed further with EtOAc (5 mL).
1
catalyst 16. Representative H NMR and GC/MS and ICP-MS
analyses show that the products 19–29 are of high purity and the
level of Ru contamination is typically below 400 ppm (Scheme 4).20
We have thus designed an efficient new strategy for homo-
geneous Ru-catalyst phase-separation and recovery which provides
products of excellent purity before silica gel chromatography or
distillation. Complex 16, a convenient and practical olefin
metathesis catalyst, exhibits high reactivity and can be easily
recycled without the need to use expensive fluorous solvents or
special silica gel. This process can be automated and has been
successfully applied to very small scale reactions. It therefore may
be found useful for preparing small quantities of pure compound
for biological screening.
catalyst remains in the product (Fig. 1).17 Complex 16 can be
eluted in a next chromatographic pass by washing with ethyl
acetate, allowing 81% catalyst recovery (Scheme 3).18
Regenerated 16 contains 3–6 wt.% of 2,4,5-trimethoxybenzalde-
hyde 17 and other compounds,10 but can be used similarly to the
pristine catalyst, and this process can be continued through nine
cycles (Table 1). In those recycling experiments the reaction
mixtures were loaded onto a silica gel containing glass cartridge
(shown in Fig. 1) and eluted with CH2Cl2 and EtOAc,
allowing isolation of 56–90% of 16. The lower recovery at larger
scale (120–160 mg of 16) can be explained by incomplete removal
842 | Chem. Commun., 2006, 841–843
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5 L. A. Paquette, J. D. Schloss, I. Efremov, F. Fabris, F. Gallou,
J. Mendez-Andino and J. Yang, Org. Lett., 2000, 2, 1259.
6 Y. M. Ahn, K. Yang and G. I. Georg, Org. Lett., 2001, 3, 1411.
7 (a) H. Maynard and R. H. Grubbs, Tetrahedron Lett., 1999, 40, 4137;
(b) M. Westhus, E. Gonthier, D. Brohm and R. Breinbauer,
Tetrahedron Lett., 2004, 45, 3141.
8 J. H. Cho and B. M. Kim, Org. Lett., 2003, 5, 531.
9 C. C. Tzschucke, C. Markert, W. Bannwarth, S. Roller, A. Hebel and
R. Haag, Angew. Chem., Int. Ed., 2002, 41, 3964.
10 5a, 5b: S. B. Garber, J. S. Kingsbury, B. L. Gray and A. H. Hoveyda,
J. Am. Chem. Soc., 2000, 122, 8168.
11 For reviews, see: (a) A. H. Hoveyda, D. G. Gillingham, J. J.
Van Veldhuizen, O. Kataoka, S. B. Garber, J. S. Kingsbury and
J. P. A. Harrity, Org. Biomol. Chem., 2004, 2, 1; (b) R. M. Buchmeiser,
New J. Chem., 2004, 28, 549.
12 (a) For 6a see: Q. Yao, Angew. Chem., Int. Ed., 2000, 39, 3896; (b) 7b:
Q. Yao and A. R. Motta, Tetrahedron Lett., 2004, 45, 2447; (c) 8b:
S. J. Connon, A. M. Dunne and S. Blechert, Angew. Chem., Int. Ed.,
2002, 41, 3835.
13 (a) For 9a, 10a and 10b see: M. Matsugi and D. P. Curran, J. Org.
Chem., 2005, 70, 1636; (b) 11b and 12b: K. Grela, R. Bujok and
B. Bieniek, unpublished results; (c) 13b: Q. Yao and Y. Zhang, J. Am.
Chem. Soc., 2004, 126, 74.
14 (a) 14a: Q. Yao and Y. Zhang, Angew. Chem., Int. Ed., 2003, 42, 3395;
(b) 14b, see: Q. Yao, J. Organomet. Chem., 2005, 690, 3577; (c) 15a:
H. Clavier, N. Audic, M. Mauduit and J. C. Guillemin, J. Am. Chem.
Soc., 2003, 125, 9248; (d) 15b: H. Clavier, N. Audic, M. Mauduit and
J. C. Guillemin, Chem. Commun., 2004, 2282. See also: H. Clavier,
N. Audic, M. Mauduit and J. C. Guillemin, J. Organomet. Chem., 2005,
690, 3585.
15 (a) K. Grela and M. Kim, Eur. J. Org. Chem., 2003, 963; (b)
Interestingly, the isomeric complex 16b shows significantly lower
stability when compared with 2b and 16. A. Michrowska, MSc
Thesis, Department of Organic Chemistry, Warsaw University of
Technology, Warsaw, Poland, 2003
Scheme 4 Library of ring-closing and cross-metathesis reactions cata-
lyzed by 16 (products shown only; 0.3 mmol scale, 5 mol% Ru). For a
description of the equipment used, see ref. [19]. Conversions were
1
determined by analysis of H NMR or GC/MS of the reaction mixture.
The amount of aldehyde 17 in recovered catalyst 16 is given in parentheses.
aRu impurity 83 ppm. bCatalyst recovered from previous experiment. cRu
e
impurity 420 ppm. dAll 5 allyl. See discussion in text. CM reaction of
.
f
5-hexen-2-one with 10 equiv. of 2-methyl-2-butene. CM reaction of tert-
g
butyl(5-hexenyloxy)dimethylsilane with 2 equiv. of methyl acrylate. CM
reaction of 1-heptadecene with 2 equiv. of (Z)-4-(acetyloxy)-2-butenyl
acetate. Ru impurity 320 ppm.
16 This investigation was in part inspired by recent elegant work of Fogg
et al. on new aryloxide Ru complexes, which show also a high affinity
for silica gel. See ref. [3].
17 We thank Ms. Zuzanna Kaczmarska and Mr Michal Barbasiewicz for
the photographic documentation of this experiment.
We thank Prof. C. Vogt and S. Gruhl (Institute of Inorganic
Chemistry, University of Hannover) for conducting the ICP-MS
analyses and the Institute of Organic Chemistry, Polish Academy
of Sciences for support. This work would not have been possible
without the help of Prof. Andreas Kirschning and Mr Klaas
Mennecke (Institut fur Organische Chemie, University of
Hannover), who are gratefully acknowledged.
18 Representative procedure of metathesis and catalyst recovery: A
reaction flask equipped with a magnetic stirring bar was charged under
argon with CH2Cl2 (30 mL), catalyst 16 (20.2 mg, 0.031 mmol) and
diene 18 (155 mg, 0.61 mmol). The reaction mixture was stirred for 2 h
at RT. After complete conversion (TLC), the reaction mixture was
passed through a cartridge containing silica gel (1.4 g). The cartridge was
washed with an additional portion of CH2Cl2 (10 mL) and then with
EtOAc (20 mL). The CH2Cl2 fraction was concentrated under reduced
pressure to yield N-p-tosyl-2,5-dihydro-1H-pyrrole (19) as a colorless
solid (137 mg, 99% yield, . 95% purity (GC), 83 ppm Ru). After
evaporation of the EtOAc fraction catalyst 16 was obtained as an olive
green microcrystalline solid (16.5 mg, 81% yield, 96% purity (NMR)).
19 The product library presented in Scheme 4 was obtained using the
‘‘Radleys Heated Carousel Reaction Station’’ parallel reactor (www.ra-
dleys.com). We suppose that the catalyst recovery step can also be
automated, e.g. by using the ‘‘Radleys Carousel Work-Up Station’’ or
similar equipment.
Notes and references
1 Pertinent reviews: (a) R. H. Grubbs, Handbook of Metathesis, Wiley-
VCH: Weinheim, vols. 1–3, 2003; (b) T. M. Trnka and R. H. Grubbs,
Acc. Chem. Res., 2001, 34, 18; (c) A. Fu¨rstner, Angew. Chem., 2000, 112,
3140; A. Fu¨rstner, Angew. Chem., Int. Ed., 2000, 39, 3012; (d)
R. H. Grubbs and S. Chang, Tetrahedron, 1998, 54, 4413; (e)
M. Schuster and S. Blechert, Angew. Chem., 1997, 109, 2124.
2 T. Nicola, M. Brenner, K. Donsbach and P. Kreye, Org. Process Res.
Dev., 2005, 9, 513.
3 J. C. Conrad, H. H. Parnas, J. L. Snelgrove and D. E. Fogg, J. Am.
Chem. Soc., 2005, 127, 11882.
4 WO 2004/089974 A1 (2004, Boehringer Ingelheim International
GmbH).
20 In the case of fluorous solid-phase separation of 9a and 10a, 10b the
remaining ruthenium levels were in the range 1000–4000 ppm, see
ref. [13].
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Chem. Commun., 2006, 841–843 | 843