Ruthenium-catalyzed olefin metathesis in ionic liquids

Article abstract of DOI:10.1021/ol016769d

Figure presented Ionic liquid 1-butyl-3-methylimidazoliumhexafluorophosphate ([bmim]PF₆) is described as an effective medium for ring-closing metathesis (RCM) using Grubbs catalysts. When [bmim]PF₆ was used as solvent, the RCM showed

Full text of DOI:10.1021/ol016769d

ORGANIC
LETTERS
2001
Vol. 3, No. 23
3785-3787
Ruthenium-Catalyzed Olefin Metathesis
in Ionic Liquids
Rogier C. Buijsman,* Elizabeth van Vuuren, and Jan Gerard Sterrenburg
Lead DiscoVery Unit, N.V. Organon, P.O. Box 20, 5340 BH Oss, The Netherlands
rogier.buijsman@organon.com
Received September 18, 2001
ABSTRACT
Ionic liquid 1-butyl-3-methylimidazoliumhexafluorophosphate ([bmim]PF6) is described as an effective medium for ring-closing metathesis
(RCM) using Grubbs catalysts. When [bmim]PF6 was used as solvent, the RCM showed high conversions and a broad substrate tolerance.
[bmim]PF6 and the ruthenium catalyst were recycled after extraction of the product in the organic phase for at least three cycles.
Ring-closing metathesis (RCM) is widely recognized as a
powerful method for creating heterocycles, constrained
peptides, and complex natural products.1 The Grubbs ruthe-
nium catalysts 12 and 23 have been used most extensively in
immobilization by a solid support5 or on removal of the
catalyst by treatment with Pb(OAc)4,6 Ph3PO, or DMSO.7
In this Letter we present another viable alternative by
employing room temperature ionic liquids.
Ionic liquids are a new class of solvents entirely composed
of ions. Their use as an environmentally friendly alternative
for conventional solvents has gained much attention recently.8
Ionic liquids are known to be nonvolatile, nontoxic, reusable,
and compatible with many organic reactions.9 Some ionic
liquids are immiscible with water and organic solvents,
giving triphasic ionic liquid systems, which enables easy
extraction of products from the ionic liquid.10 Our specific
interest in ionic liquids was drawn by recent disclosures that
RCM because of their high reactivity, air-stability, and
remarkable functional group tolerance. However, the fact that
these catalysts are nonrecyclable and can only be removed
from the product by repeated chromatography severely
hampers their use in industrial processes. Several groups have
recently identified elegant solutions for this problem. Grubbs4
reported the removal of ruthenium complexes by exchange
of their hydrophobic ligands with hydrophilic ligands fol-
lowed by aqueous extraction. Other methods rely on catalyst
(1) For recent reviews on olefin metathesis, see: (a) Grubbs, R. H.;
Chang, S. Tetrahedron 1998, 54, 4413. (b) Armstrong, S. K. J. Chem. Soc.,
Perkin Trans. 1 1998, 371. (c) Wright, D. L. Curr. Org. Chem. 1999, 3,
211. (d) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000. 39, 3012.
(2) Nguyen, S. T.; Grubbs, R. H. J. Am. Chem. Soc. 1993, 115, 9858.
(3) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953.
(4) Maynard, H. D.; Grubbs, R. H. Tetrahedron Lett. 1999, 40, 4137.
(5) (a) Ahmed, M.; Barrett, A. G. M.; Braddock, D. C.; Cramp, S. M.;
Procopiou, P. A. Tetrahedron Lett. 1999, 40, 8657. (b) Schu¨rer, S. C.;
Gessler, S.; Buschmann, N.; Blechert, S. Angew. Chem., Int. Ed. 2000, 39,
3898. (c) Yao, Q. Angew. Chem., Int. Ed. 2000, 39, 3896.
(6) Paquette, L. A.; Schloss, J. D.; Efremov, I.; Fabris, F.; Gallou, F.;
Me´ndez-Andino, J.; Yang, J. Org. Lett. 2000, 2, 1259.
(7) Ahn, Y. M.; Yang, K.-L, Georg, G. I. Org. Lett. 2001, 3, 1411.
(8) For recent reviews on ionic liquids, see: Welton, T. Chem. ReV. 1999,
99, 2071. Wasserscheid, P.; Keim, W. Angew. Chem., Int. Ed. 2000, 39,
3772. Seddon, K. R. J. Chem. Technol. Biotechnol. 1997, 68, 351.
10.1021/ol016769d CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/13/2001

these novel solvents dissolve and stabilize many organo-
metallic catalysts,11 thus providing an excellent medium for
recycling.
Initial studies at our laboratory were aimed at investigating
the viability of performing a RCM12 in the most frequently
used ionic liquid, 1-butyl-4-methylimidazolium hexafluoro-
phosphate [bmim]PF6 (i.e., liquid 3b), using compound 413
as a substrate (see Scheme 1). When a temperature of 50 °C
To find the optimal ionic liquid in terms of conversion
and catalyst leakage, we first studied the RCM of 4 in five
different ionic liquids (3a-e) and combinations thereof
(1:1, 1:2, and 1:3). Only seven of the 54 reactions gave over
69% conversion, the products of which were subsequently
evaluated on their ruthenium content using ICP-AES analy-
sis14 (see Table 1). These studies clearly indicated that
Table 1. Conversions of RCMa in Different (Mixtures of)
Ionic Liquids and Ru Contaminant Level in RCM Product 5
Scheme 1
ratio
(v:v)
convn
(%)b
Ru residue,
entry
solvent
µg/mg
1c
2
3
4
5
6
7
8
DCM
3b
100
98
95
77
77
81
92
69
1.7
3.2
9.7
5.2
6.3
5.4
5.2
3.6
3b:3a
3b:3d
3b:3c
3b:3e
3b:3c
3b:3e
1:1
1:1
2:1
2:1
3:1
3:1
was applied, a substrate concentration of 55 mg/mL and 5
mol % of catalyst resulted in complete formation to the
bicyclic hydantoin 5 after 20 h. Isolation of the product could
easily be accomplished by extraction with diethyl ether. Next,
recycling of the catalyst was studied using the residual
solution for the next reaction cycle. Unfortunately, the RCM
only showed 15% conversion after 20 h. This poor result
could have been caused either by the decomposition of the
catalyst or by extraction of the catalyst to the organic phase.
a All reactions were performed at 50 °C, a substrate concentration of 55
mg/mL, and 5 mol % of 1 for 24 h. b Conversions were measured after
extraction with diethyl ether and subsequent HPLC analysis. c Reaction in
DCM was evaporated after 1 h, and product was purified using silica column
chromatography.
[bmim]PF6 (entry 2) is the best solvent, giving a 98%
conversion of 4 and a ruthenium contamination of 3.2 µg
per mg of product. On the basis of the low ruthenium content
observed in the products, it can be concluded that the catalyst
remains present in the ionic liquid and the poor recycling is
most probably caused by catalyst decomposition. With the
objective of reducing catalyst decomposition, further efforts
were aimed at optimizing the reaction time. Spectacular
results were obtained by increasing the temperature to at least
80 °C (see Table 2), which reduces the reaction time 20-
(9) For some examples of organic reactions in ionic liquids, see the
following. Alkylation: Earle, M.; McCormac, P. B.; Seddon, K. R. Chem.
Commun 1998, 2245. Beckmann rearrangement: Peng, J.; Deng, Y.
Tetrahedron Lett. 2001, 42, 403. Diels-Alder reaction: Fisher, T.; Sethi,
A.; Welton, T.; Woolf, J. Tetrahedron Lett. 1999, 40, 793. Earle, M. J.;
McCormac, P. B.; Seddon, K. R. Green Chem. 1999, 23. Friedel-Crafts
reactions: Adams, C. J.; Earle, M. J.; Roberts, G.; Seddon, K. R Chem.
Commun 1998, 2097. Oxidation of aldehydes: Howarth, J. Tetrahedron
Lett. 2000, 41, 6627. Reduction of aldehydes: Kabalka, G.; Malladi, R. R.
Chem. Commun. 2000, 2191. Wittig reaction: Le Boulaire, V.; Gree, R.
Chem. Commun. 2000, 2195.
(10) Carmichael, A. J.; Earle, M. J.; Holbrey, J. D.; McCormac, P. B.;
Seddon, K. R. Org. Lett. 1999, 1, 977.
(11) For some examples of transition-metal catalyzed reactions in ionic
liquids, see the following. (Asymmetric) epoxidation: Owens, G. S.; Abu-
Omar, M. M. Chem. Commun. 2000, 1165. Song, C. E.; Roh, E. J. Chem.
Commun. 2000, 837. Asymmetric hydrogenation: Brown, R. A.; Polett,
P.; McKoon, E.; Eckert, C. A.; Liotta, C. L.; Jessop, P. G. J. Am. Chem.
Soc. 2001, 123, 1254. Asymmetric ring opening of epoxides: Song, C. E.;
Rim Oh, C.; Roh, E. J.; Choo, D. J. Chem. Commun. 2000, 1743. Aza-
Diels-Alder reaction: Zulfiqar, F.; Kitazume, T. Green Chem. 2000, 137.
Coupling of aryl halides: Howarth, J.; James, P.; Dai, J. Tetrahedron Lett.
2000, 41, 10319. Suzuki cross-coupling: Mathews, C. J.; Smith, P. J.;
Welton, T. Chem. Commun. 2000, 1249. Heck arylation of vinyl ethers:
Xu, L.; Chen, W.; Ross, J.; Xiao, J. Org. Lett. 2001, 3, 295. Heck reaction:
Kaufmann, D. E.; Nouzoorian, M.; Henze, H. Synlett 1996, 7, 1091.
Carmichael, A. J.; Earle, M. J.; Holbrey, J. D.; McCormac, P. B.; Seddon,
K. R. Org. Lett. 1999, 1, 977. Hydrogenation/hydroformylation: Chauvin,
Y.; Mussmann, L.; Olivier, H. Angew. Chem., Int. Ed. Engl. 1995, 34, 2698.
Suarez, P. A. Z.; Dullius, J. E. L.; Einloft, S.; De Souza, R. F.; Dupont, J.
Polyhedron 1996, 15, 1217. Wasserscheid, P.; Waffenschmidt, H.; Mach-
nitzki, P.; Kottsieper, K. W.; Stelzer, O. Chem. Commun. 2001, 451. Negishi
cross-coupling: Sirieix, J.; Ossberger, M.; Betzemeier, B.; Knochel, P. Synlett
2000, 11, 1613. Pd-catalyzed allylation reaction: Chen, W.; Xu, L.;
Chatterton, C.; Xiao, J. Chem. Commun. 1999, 1247. Stille coupling: Handy,
S. T.; Zhang, X. Org. Lett. 2001, 3, 233. Trost-Tsuji reaction: Toma, S.;
Gotov, B.; Kmentova, I.; Solcaniova, E. Green Chem. 2000, 149.
(12) Ru-catalyzed RCM in ionic liquids has been described in a recent
patent application. Gurtler, C.; Jautelat, M. EP 1035093 A2, 2000. First
example of an olefin metathesis (Ni-catalyzed) in ionic liquids has been
described by Chauvin, Y.; Olivier-Bourbigou, H. CHEMTECH 1995, 9,
26.
a
Table 2. Influence of Temperature on RCM in [bmim]PF6
entry
temp (°C)
convn (%)b
1
2
3
4
5
6
50
60
70
80
90
30
68
88
100
100
100
100
a Reactions were performed using 4 with a concentration of 55 mg/mL
and 5 mol % of 1 for 1 h. b Conversions were measured after extraction
with diethyl ether and subsequent HPLC analysis.
fold. Optimal substrate concentration and amount of catalyst
were studied in a series of reactions depicted in Figure 1.
From these studies it can be concluded that the substrate
concentration should not exceed 30 mg/mL and that the
biggest change in conversion at this concentration occurs
going from 3 to 5 mol % of catalyst.15
(13) Dyatkin, A. B. Tetrahedron Lett. 1997, 38, 2065.
3786
Org. Lett., Vol. 3, No. 23, 2001

a
Table 4. RCM of Different Substrates in [bmim]PF6
Figure 1. Influence of mol % of 1 and concentration of 4 on RCM
in [bmim]PF6. Reactions were performed at 60 °C for 30 min;
conversions were measured after extraction with diethyl ether and
subsequent HPLC analysis.
Having established the optimal reaction conditions, atten-
tion was focused on recycling of the catalyst in [bmim]PF6.
Interestingly, the catalyst proved to be stable in at least three
consecutive runs, although the third run resulted in a
markedly decreased conversion (see Table 3, entry 3). The
a All reactions were performed at 80 °C, a substrate concentration of 30
mg/mL, and 5 mol % of 1 for 1 h. b Conversions were measured 1H NMR
analysis of the crude reaction mixture after extraction with ether. The
numbers in parentheses represent the conversion of the RCM in DCM.
c Reaction was allowed to run for 20 h.
Table 3. Recycling of 1 and 2 and Ru Contaminant Level in
RCM Product 5a
Ru residue,
entry
catalyst
recycling
convn (%)b
µg/mg
shown in Table 4, conversions of substrates were satisfactory
and comparable to those obtained in DCM (entries 1 and
2). In some cases (entries 3-5) the conversions of the RCM
were even slightly better in ionic liquid.
In summary, we have established that ionic liquid
[bmim]PF6 is an excellent solvent in which to carry out the
RCM. The reaction proceeds readily with a variety of
substrates, and the resulting products could be separated from
the ionic liquid in a straightforward manner. Furthermore, it
is possible to efficiently reuse the catalyst and ionic solvent.
1
2
3
4
5
6
1
1
1
2
2
2
97
94
61
95
88
74
3.9
4.8
5.3
1.6
1.6
1.3
entry 1
entry 2
entry 4
entry 5
a All reactions were performed at 80 °C, a substrate concentration of 30
mg/mL, and 5 mol % of catalyst for 1 h. b Conversions were measured
after extraction with ether and subsequent HPLC analysis.
Acknowledgment. The autors thank Aard Florijn (N.V.
Organon) for the ICP-AES measurements. Huib Ovaa (Lei-
den University) is acknowledged for a sample of catalyst 2.
recycling potential of the more robust dihydroimidazole
catalyst 2 was also investigated. As expected, this catalyst
showed an increased conversion in the third cycle. Moreover,
the use of 2 resulted in products having less ruthenium
contamination than that obtained with catalyst 1. Contamina-
tion levels are now well in the range of those obtained by
other methods.4-7
Supporting Information Available: Spectroscopy data
and analytical data of compounds prepared in Table 4. This
material is available free of charge via the Internet at
http//pubs.acs.org.
To establish the general applicability of this method, we
tested the RCM in [bmim]PF6 on several substrates. As
OL016769D
(15) General procedure for RCM in ionic liquid: To a reaction tube
was added 1,5-diallyl-3-benzyl-5-isobutylimidazolidine-2,4-dione (4) (9 mg,
28 µmol) which was dissolved in [bmim]PF6 (300 µL) by heating to 80 °C
for 10 min under a flow of nitrogen gas. Grubbs catalyst 1 (1.1 mg, 1.4
µmol, 5 mol %) was subsequently added to the reaction mixture. The
reaction was stirred for 1 h at 80 °C, afterwhich the reaction mixture was
extracted with diethyl ether (3 × 1 mL). The combined organic layers were
concentrated in vacuo, which yielded a slightly colored oil (8.2 mg, 27.4
µmol, 98%). TLC analysis (Rf ) 0.40 (heptane/EtOAc, 6/4, v/v)) indicated
(14) All ICP-AES (inductively coupled plasma-atomic emission spec-
trometer) samples were prepared first by accurately weighing the samples
(∼4 mg) and then adding 10 mL of 0.12 M hydrochloric acid in glacial
acetic acid. To correct for matrix effects, a Pt standard was added to the
sample (100 µL, 1 mg Pt/mL, Baker Instra analyzed, AAS standard).
Samples were analyzed on a Perkin-Elmer Optima 3000 ICP-AE spectrom-
eter. Intensities of spectral lines at 240.272 and 349.894 nm were measured
in all samples and standards. The Ru level in the samples was determined
by comparing the intensity of the spectral line with a ruthenium standard
curve. Each sample was measured three times, and the average Ru
contaminant level of these measurements has been reported.
1
complete formation of 5. H NMR (CDCl3): δ 7.44-7.22 (m, 5H), 5.73
(s, 2H), 4.68 (s, 2H), 4.44 (d, 1H), 3.56 (d, 1H), 2.25 (d, 2H), 1.88 (m,
2H), 1.55 (q, 1H), 0.83 (d, 3H), 0.61 (d, 3H). ESI-MS: [M + H]+ 299.
Org. Lett., Vol. 3, No. 23, 2001
3787