Highly efficient Ru-pseudohalide catalysts for olefin metathesis

Article abstract of DOI:10.1021/ja042736s

Ruthenium alkylidene complexes containing one aryloxide "pseudohalide" ligand catalyze ring-closing metathesis of diene and ene-yne substrates with exceptionally high efficiency. Chromatographic removal of Ru residues is unexpectedly facile, offering a convenient means of isolating pure organic products in high yields. Copyright

Full text of DOI:10.1021/ja042736s

Published on Web 08/10/2005
Highly Efficient Ru-Pseudohalide Catalysts for Olefin Metathesis
Jay C. Conrad, Henrietta H. Parnas, Jennifer L. Snelgrove, and Deryn E. Fogg*
Department of Chemistry, UniVersity of Ottawa, Ottawa ON, Canada K1N 6N5
Received December 2, 2004; E-mail: dfogg@science.uottawa.ca
Scheme 1
The availability of robust, easily handled ruthenium catalysts for
olefin metathesis has had a tremendous impact on organic synthe-
sis.1 To date, the major goal in Ru catalyst design has focused on
increasing the activity of the Grubbs catalyst 1. Key advances
include the development of N-heterocyclic carbene (NHC) com-
plexes 2,2 derivatives of 2 containing a labile donor (e.g., PPh3,2c
pyridine (3),3 or styrenyl ethers activated by steric4 or electronic5
destabilization of the chelate ring (4)), and, most recently, phos-
phonium alkylidene 5.6 A limitation, however, lies in the conver-
gence of precatalysts 2-5 on 6 as the active species. Because 6 is
readily deactivated, advances in activity have not increased catalyst
productiVity; higher activity comes at the price of catalyst lifetime,
and turnover numbers remain generally low.7 The resulting require-
ment for high catalyst loadings is problematic for reasons of cost
(particularly in the industrial setting) and because isolated yields
of pure organic products are compromised by difficulties in
removing spent 6. Elimination of heavy metal residues is essential
in order to prevent Ru-catalyzed product degradation.8 We now
report new, highly efficient “pseudohalide” catalysts that do not
proceed via 6 and which are easily removed following reaction.
Several years ago, we reported that Cl-bridged dimers are
implicated in deactivation of Grubbs-class catalysts containing two
chloride ligands,9 and other examples have since emerged.10,11 This
discovery led us to explore routes to catalysts containing alternative
anionic ligands, of which bis(perfluorophenoxide) 7 (Scheme 1)
emerged as the first example of a high-performing pseudohalide
catalyst.12 Reaction of 3a with TlOC6X5 (where X ) Cl, Br, instead
of F) affords mono(aryloxide) products 8, owing to the increased
ligand bulk. The new complexes were characterized by detailed
spectroscopic studies and microanalysis. The geometry shown for
8, proposed on the basis of DFT calculations, corresponds to that
crystallographically established for 7.12 The pyridine ligand in 8 is
much more labile than that in 7, resulting in significantly higher
metathesis reactivity.
Table 1. RCM Efficiency of Pseudohalide versus Chloride
Catalystsa
Chart 1. IMes ) N,N′-Bis(mesityl)imidazol-2-ylidene
a Mol % Ru ) minimum required for high conversions in <1 h. b At 1
h, 0.05 mol % Ru: 7, 100; 8a, 17; 8b, 34; 2a, 24; 3a, 29%. c At 3 h, <6%
increase; 100% in 15 min at 5 mol % Ru. d 100% at 1 h. e Ru, diene added
dropwise; [S]max ) 0.005 M; 100% 18 at 12 h (7), 0.5 h (8a), 1 h (3a).
Conversion to 20 plateaus at 87% (3a; 1h), 83% (7; 3 h); no further change
up to 5 h; final E:Z ratio ) 9:1. f 1 mol % 8a added every 10 min.
probe reactions with 11 and 13 indicated faster RCM in this solvent,
versus C6D6 or CD2Cl2.13
Catalysts 7-8 show high activity at low catalyst loading for ring-
closing of substrates 9 and 11. The high efficiency in RCM of
linalool 11 (100% conversion in 15 min at 0.5 mol % Ru) is notable
given the presence of a sterically hindered trisubstituted olefin.16,17
Sulfide 13 presents a different challenge, in the susceptibility of
ruthenium to poisoning by soft sulfur donors.18 Metathesis via 8b
We evaluated the efficiency of the new catalysts in RCM of the
benchmark substrate 9 and other, more challenging substrates (Table
1). With the exception of the macrocycle syntheses (substrates 17
and 19), these reactions were carried out in refluxing CDCl3, as
9
11882
J. AM. CHEM. SOC. 2005, 127, 11882-11883
10.1021/ja042736s CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
of planar pseudohalide ligands, without detriment to catalyst
performance. Indeed, the high efficiency and productivity of the
aryloxide catalysts, in conjunction with their facile removal from
organic products, can be expected to offer new opportunities in
organic synthesis, particularly for metathesis of value-added
substrates such as natural products.
Figure 1. Purification of RCM product 10 (5 mol % Ru) by silica gel
chromatography. 5% EtOAc:hexanes: 7, 8: <100 ppm Ru (1: 30 900; 2a:
57 900 ppm). 15% EtOAc:hexanes: 1: 2450 ppm Ru (7: 600 ppm).
Acknowledgment. This work was supported by NSERC of
Canada, the Canada Foundation for Innovation, and the Ontario
Innovation Trust.
appears unimpeded by coordination of 14; even at 0.5 mol % Ru,
RCM is complete within 20 min. Conversions are lower with the
other catalysts (including 3a), with minimal improvement after 3
h, though 2a can effect complete RCM14 at higher loadings and
increased temperatures. RCM of diphenyldiallylsilane 15 proves
more difficult, and 5 mol % Ru is required for quantitative ring-
closing, as previously noted.15 Catalysts 8b and 3a are most
effective, though all of the aryloxide catalysts outperform 2a.
Macrocyclic targets present enthalpic and entropic barriers to
ring-closing. The new catalysts show unprecedented efficiency in
macrocyclization of substrates 17 and 19. The products are 14- and
16-membered lactones that constitute the macrocycle cores of
gloeosporone and epothilone A.19-21 RCM of 17 using 1 and related
catalysts is reportedly incomplete even after 30 h, while 2b effects
72-87% ring-closing within 2-4 h.19 In comparison, 8b effects
quantitative formation of 18 within 15 min. Ring-closing via 7 or
3a is slower, but proceeds to completion in 12 or 1 h, respectively.
RCM of 19 is rapid using either 8a or 8b, but plateaus at ca. 85%
conversion for both 7 and 3a.
Acrylate 21 proved unexpectedly19d problematic, possibly be-
cause chelation of the carbonyl functionality22 is favorable. RCM
proceeds to 73% conversion only on addition of 8b in five boluses
of 1 mol % each, over a period of 1 h. Finally, RCM of ene-yne
23 is facile, even at catalyst loadings an order of magnitude lower
than those reported for 2b. In RCM of sterically encumbered 25,
8b significantly outperforms both 2b and catalysts of type 4.5b
Paquette has pointed out that the efficiency of Ru-catalyzed
metathesis in multistep organic syntheses is compromised by
difficulties in removing residual Ru.23a Ruthenium levels of >2000
ppm remain after chromatography of samples of 10 prepared by
RCM with 5 mol % of 1 or 2a (Figure 1). Use of lead or phosphine
(including supported phosphine) additives is reported to reduce the
ruthenium content to 200-1200 ppm.23a-d Alternatively, two cycles
of chromatography, followed by 12 h incubation with activated
charcoal, results in <100 ppm Ru.23e The aryloxide catalysts, in
comparison, have a high affinity for silica, enabling their efficient
removal, without incubation, in a single chromatographic pass.
Thus, RCM of 9 using 5 mol % of 7 or 8, followed by flash
chromatography, affords colorless oils in which the residual Ru
content is below the 100 ppm detection limit of ICP-AES
(inductively coupled plasma atomic emission spectroscopy). The
purity of the organic product obtained by this simple and routine
procedure is comparable to the best of the literature methods.
The foregoing demonstrates that the structural diversity of
ruthenium metathesis catalysts can be expanded by incorporation
Supporting Information Available: Synthetic and catalytic details.
This material is available free of charge via the Internet at http://
pubs.acs.org.
References
(1) Grubbs, R. H. Handbook of Metathesis; Wiley-VCH: Weinheim, Ger-
many, 2003.
(2) (a) Weskamp, T.; Schattenmann, W. C.; Spiegler, M.; Herrmann, W. A.
Angew. Chem., Int. Ed. 1998, 37, 2490. (b) Herrmann, W. A. Angew.
Chem., Int. Ed. 1999, 38, 262. (c) Huang, J.; Stevens, E. D.; Nolan, S. P.;
Peterson, J. L. J. Am. Chem. Soc. 1999, 121, 2674. (d) Scholl, M.; Ding,
S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953.
(3) (a) Sanford, M. S.; Love, J. A.; Grubbs, R. H. Organometallics 2001, 20,
5314. (b) Love, J. A.; Morgan, J. P.; Trnka, T. M.; Grubbs, R. H. Angew.
Chem., Int. Ed. 2002, 41, 4035.
(4) (a) Wakamatsu, H.; Blechert, S. Angew. Chem., Int. Ed. 2002, 41, 2403.
(b) Wakamatsu, H.; Blechert, S. Angew. Chem., Int. Ed. 2002, 41, 794.
(5) (a) Grela, K.; Harutyunyan, S.; Michrowska, A. Angew. Chem., Int. Ed.
2002, 41, 4038. (b) Michrowska, A.; Bujok, R.; Harutyunyan, S.; Sashuk,
V.; Dolgonos, G.; Grela, K. J. Am. Chem. Soc. 2004, 126, 9318. (c) Zaja,
M.; Connon, S. J.; Dunne, A. M.; Rivard, M.; Buschmann, N.; Jiricek, J.;
Blechert, S. Tetrahedron 2003, 59, 6545.
(6) Romero, P. E.; Piers, W. E.; McDonald, R. Angew. Chem., Int. Ed. 2004,
43, 6161.
(7) Ulman, M.; Grubbs, R. H. J. Org. Chem. 1999, 64, 7202.
(8) Alcaide, B.; Almendros, P. Chem.sEur. J. 2003, 9, 1259.
(9) (a) Amoroso, D.; Yap, G. P. A.; Fogg, D. E. Organometallics 2002, 21,
3335. (b) Amoroso, D.; Snelgrove, J. L.; Conrad, J. C.; Drouin, S. D.;
Yap, G. P. A.; Fogg, D. E. AdV. Synth. Catal. 2002, 344, 757.
(10) Conrad, J. C.; Fogg, D. E. Curr. Org. Chem. 2005, in press.
(11) Hong, S. H.; Day, M. W.; Grubbs, R. H. J. Am. Chem. Soc. 2004, 126,
7414.
(12) Conrad, J. C.; Amoroso, D.; Czechura, P.; Yap, G. P. A.; Fogg, D. E.
Organometallics 2003, 22, 3634.
(13) In preliminary experiments with 19, RCM rates showed the trend C6H6
> CH2Cl2 > CHCl3. For RCM of 17, reaction was faster in CH2Cl2.
(14) Spagnol, G.; Heck, M. P.; Nolan, S. P.; Mioskowski, C. Org. Lett. 2002,
4, 1767.
(15) Schmidt, B.; Pohler, M.; Costisella, B. J. Org. Chem. 2004, 69, 1421.
(16) Hoye, T. R.; Zhao, H. Org. Lett. 1999, 1, 1123.
(17) Braddock, D. C.; Matsuno, A. Tetrahedron Lett. 2002, 43, 3305.
(18) (a) Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371. (b) Schrock,
R. R.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2003, 42, 4592.
(19) (a) Jafarpour, L.; Heck, M.-P.; Baylon, C.; Lee, H. M.; Mioskowski, C.;
Nolan, S. P. Organometallics 2002, 21, 671. (b) Fu¨rstner, A.; Ackermann,
L. Chem. Commun. 1999, 95. (c) Fu¨rstner, A.; Langemann, K. J. Org.
Chem. 1996, 61, 3942. (d) Fu¨rstner, A.; Thiel, O. R.; Ackermann, L.;
Schanz, H.-J.; Nolan, S. P. J. Org. Chem. 2000, 65, 2204. (e) Fu¨rstner,
A.; Langemann, K. J. Am. Chem. Soc. 1997, 119, 9130.
(20) Fu¨rstner, A.; Mathes, C.; Lehmann, C. W. Chem.sEur. J. 2001, 7, 5299.
(21) Rivkin, A.; Cho, Y. S.; Gabarda, A. E.; Yoshimura, F.; Danishefsky, S.
J. J. Nat. Prod. 2004, 67, 139.
(22) Fu¨rstner, A.; Thiel, O. R.; Lehmann, C. W. Organometallics 2002, 21,
331.
(23) (a) Paquette, L. A.; Schloss, J. D.; Efremov, I.; Fabris, F.; Gallou, F.;
Mendez-Andino, J.; Yang, J. Org. Lett. 2000, 2, 1259. (b) Ahn, Y. M.;
Yang, K.; Georg, G. I. Org. Lett. 2001, 3, 1411. (c) Maynard, H.; Grubbs,
R. H. Tetrahedron Lett. 1999, 40, 4137. (d) Westhus, M.; Gonthier, E.;
Brohm, D.; Breinbauer, R. Tetrahedron Lett. 2004, 45, 3141. (e) Cho, J.
H.; Kim, B. M. Org. Lett. 2003, 5, 531.
JA042736S
9
J. AM. CHEM. SOC. VOL. 127, NO. 34, 2005 11883