Chemical Synthesis

Metathesis

Ruthenium-Based Metathesis Catalysts

Introduction

Olefin metathesis is now a well-entrenched synthetic technique, and is a powerful method for the clean construction of innumerable classes of chemical architectures. The broadly accepted belief that this key method transformed the landscape of synthetic chemistry ultimately led to the awarding of the 2005 Nobel Prize in Chemistry to the pioneers in olefin metathesis: Yves Chauvin, Robert H. Grubbs, and Richard R. Schrock. Late-transition metal alkylidene complexes, specifically ruthenium alkylidenes, have propelled this synthetic methodology in to the forefront of carbon–carbon bond forming techniques in large part because of the functional group tolerance of these catalysts, and their ability to be handled without the use of glove box or Schlenk techniques. As shown below, ruthenium alkylidenes participate in a host of reaction paradigms, all under the umbrella of olefin metathesis.1


A majority of the successful examples in the above reaction classes were achieved using the stalwarts of Ru-based olefin metathesis: the Grubbs 1st and 2nd generation catalysts, or the Hoveyda–Grubbs analogs thereof.


The original metathesis catalysts were of the “first-generation” type, bearing two phosphine ligands (e.g. the Grubbs 1st generation catalyst, above). Development of the second-generation catalysts and the Hoveyda–Grubbs modified catalysts were largely spurred by the need for more active catalysts that could effect transformations that the first-generation systems could not, such as the metathesis of sterically demanding and electron-poor olefins. While these improved catalysts broadened the realm of olefin metathesis reaction, there are instances where the first-generation catalysts continue to provide excellent or superior results in a given metathesis reaction. Thus, it is clear that in many cases, there is not a universal metathesis catalyst.2

Sigma-Aldrich is proud to be the exclusive research scale supplier of Materia’s ruthenium metathesis catalysts, including first- and second-generation Grubbs and Hoveyda–Grubbs catalysts. We have recently expanded our portfolio to include five state-of-the-art catalysts, with unique reactivities and tailored initiation rates. These “next-generation” catalysts expand the scope of this powerful reaction class, allowing for example, metathesis reactions to be performed at low temperatures, and for the formation of tetrasubstituted olefins via cross metathesis.

Advantages

  • One of the fastest and most general methods for olefin formation
  • Exceptional functional group tolerance
  • Excellent catalyst stability and handling characteristics
  • Large catalyst family allows for rapid reaction optimization
  • Clean reactions with minimal waste and by-products


 

Sigma-Aldrich Metathesis Portfolio

Product Number Application Notes Structure Add to Cart
578703 Kinetic application profile similar to that of Grubbs 1st generation catalyst.1

578681 Kinetic application profile similar to that of Grubbs 1st generation catalyst.1

682365 Slower to initiate than Grubbs 2nd generation catalyst, thus useful in highly exothermic ROMP applications. Displays unique reactivity towards previously metathesis-inactive olefins in CM and RCM. Also employed in tandem CM / Wittig olefination processes.1a,3,4

579726 Grubbs 1st generation catalyst-
First metathesis catalyst to be widely used in organic synthesis. Useful in ROMP of strained cyclic olefins, ethenolysis of internal olefins, and in ADMET, CM, and RCM of terminal olefins under a variety of reactions conditions, including protic media.1

569747 Grubbs 2nd generation catalyst-
Generally more active than 1st generation catalysts. Increased activity in RCM. Employed in CM of sterically demanding or deactivated olefins, including 1,1-disubstituted olefins and α,β-unsaturated carbonyls.1

577944 Hoveyda - Grubbs 1st generation catalyst-
Similar reactivity to Grubbs 1st generation catalyst. Proven to be useful in RCM to form macrocycles.1

569755 Hoveyda - Grubbs 2nd generation catalyst-
Comparable reactivity to Grubbs 2nd generation, but initiates more readily at lower temperatures. Efficient for metathesis of electron deficient substrates.1

682284 Highly reactive in metathesis of sterically hindered olefins, particularly in RCM. Useful for the preparation of tetrasubstituted olefins via CM and RCM.1a,5

682373 The Hoveyda–Grubbs analog of 682284, possessing similar reactivity. Initiates more slowly than 682284, but exhibits higher stability in solution. Depending on the substrate and reaction conditions, it may prove more effective than 682284.1a,5

682381 Latent initiator, but extremely active once initiated, similar to other 2nd generation catalysts. Useful in ROMP applications where longer monomer/catalyst resin handling times are desired. Potentially useful in non-ROMP applications as well.1a,6,7
682330 Labile pyridine ligands result in a very fast initiator (~0 °C). Effective in CM of acrylonitrile. Also effective in RCM and the ROMP production of block copolymers and polymers with narrow PDIs.1a,8,9,10,11

687944 Ruthenium Metathesis Catalysts Kit I: 11 samples of the above Ru-based metathesis catalysts

Additional Product Information


References:
(1) For recent reviews, see: (a) Schrodi, Y.; Pederson, R. L. Aldrichimica Acta 2007, 40, 45. (b) Adv. Synth. Catal. 2007, 349, 1–268 (Olefin Metathesis Special Issue). (c) Grubbs, R. H. Tetrahedron 2004, 60, 7117. (d) Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH: Weinheim, 2003; Vols. 1–3. (e) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18. (f) Fürstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012. (g) Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. 1997, 36, 2036.
(2) With the increase of the number of reported metathesis-active Ru-catalysts, a standardized set of reactions conditions has been proposed for the purposes of comparing catalyst performance. See: Ritter, T. et al. Organometallics 2006, 25, 5740.
(3) (a) Chatterjee, A. K. et al. J. Am. Chem. Soc. 2000, 122, 3783. (b) Chatterjee, A. K.; Grubbs, R. H. Org. Lett. 1999, 1, 1751.
(4) Murelli, R. P.; Snapper, M. L. Org. Lett. 2007, 9, 1749.
(5) Stewart, I. C. et al. Org. Lett. 2007, 9, 1589.
(6) Ung, T. et al. Organometallics 2004, 23, 5399.
(7) Benitez, D.; Goddard, W. A., III. J. Am. Chem. Soc. 2005, 127, 12218.
(8) Love, J. A. et al. Angew. Chem., Int. Ed. 2002, 41, 4035.
(9) Sanford, M. S. et al. Organometallics 2001, 20, 5314.
(10) Choi, T.-L.; Grubbs, R. H. Angew. Chem. 2003, 115, 1785.
(11) Ritter, T. et al. Organometallics 2006, 25, 5740.

Representative Applications

Ring-Closing Metathesis (RCM)

Innumerable instances of RCM employing Grubbs and Hoveyda–Grubbs first- and second-generation catalysts in small molecule and natural product syntheses have been reported. For example, the Danishefsky group employed Grubbs second-generation catalyst in the total synthesis of migrastin, a macrolide isolate from Streptomyces found to inhibit human tumor cell migration.1

Reference: Gaul, C. et al. J. Am. Chem. Soc. 2003, 125, 6042.

More recently, modified versions of the Grubbs and Hoveyda–Grubbs second-generation catalysts were reported to be highly active in the preparation of tetrasubstituted olefins via RCM. It is believed that the replacement of the mesityl substituents on the NHC ligand with o-tolyl groups creates a less sterically encumbered complex, allowing for coordination of bulkier olefins.

Reference: Stewart, I. C. et al. Org. Lett. 2007, 9, 1589.

Cross-Metathesis (CM)

Cross-metathesis is a powerful method for the rapid synthesis of simple and complex olefinic building blocks, and an excellent model has been developed by Grubbs to predict the outcome of cross-metathesis reactions, based upon reactant olefin type (i.e., propensity of the olefin towards homodimerization, and reactivity of those homodimers towards further metathesis) and catalyst used.1 Both first- and second-generation catalysts can be used in CM, with the latter exhibiting excellent reactivity in effecting the metathesis of sterically demanding or highly deactivated olefin substrates.2 Some examples of these more difficult metatheses employing second-generation catalysts are illustrated below.3

References: (1) Chatterjee, A. K. et al J. Am. Chem. Soc. 2003, 125, 11360. (2) For selected examples of CM reactions, see: (a) Vernall, A. J.; Abell, A. D. Aldrichimica Acta 2003, 36, 93. (b) Funk, T. et al. Org. Lett. 2005, 7, 187. (c) Lautens, M.; Maddess, M. L. Org. Lett. 2004, 6, 1883. (d) Chatterjee, A. K. et al. Org. Lett. 2002, 4, 1939. (e) Raju, R.; Howell, A. R. Org. Lett. 2006, 8, 2139. (3) See: Schrodi, Y.; Pederson, R. L. Aldrichimica Acta 2007, 40, 45 and references therein.

Enyne Metathesis
Although not as thoroughly explored as olefin metathesis, enyne metathesis is a powerful method for the construction of 1,3-dienes, either in an intra- or intermolecular fashion.1 The intramolecular variant has been applied to the synthesis of heterocycles, and in the case of intermolecular reaction, stereoselective enyne cross-metatheses have been reported.2

References: (1) For recent reviews, see: (a) Diver, S. T.; Giessert, A. J. Chem. Rev. 2004, 104, 1317. (b) Hansen, E. C.; Lee, D. Acc. Chem. Res. 2006, 39, 509. (2) For some recent examples these reactions, see: (a) Núñez, A. et al. Chem. Commun. 2006, 2690. (b) Mori, M. Adv. Synth. Catal. 2007, 349, 121. (c) Kim, B. G.; Snapper, M. L. J. Am. Chem. Soc. 2006, 128, 52.

Ring-Opening Metathesis Polymerization (ROMP)

Some of the earliest commercial applications of Ru-based olefin metathesis catalysts were in the field of ring-opening metathesis polymerization of strained cycloolefins. The living polymerization of dicyclopentadiene has been extensively studied.

References: (1) Black, G.; Maher, D.; Risse, W. Living Ring-Opening Olefin Metathesis Polymerization. In Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH: Weinheim, 2003; Vol. 3, pp 2-71. (2) Harned, A. M. et al. Aldrichimica Acta 2005, 38, 3.

As shown below, the 3-bromopyridine-ligated ruthenium complex was found to be extremely active in the controlled living polymerization of norbornene and oxo-norbornene derivatives. Polymers generally exhibited narrow polydispersities, in contrast to polymers obtained using Grubbs second-generation catalyst.

Reference: Choi, T.-L.; Grubbs, R. H. Angew. Chem. 2003, 115, 1785.

Control of Olefin Isomerization During Metathesis Reactions

Several reports have been published on methods to suppress the olefin migration in the course of metathesis reactions, including using additives such as quinones as illustrated below.1 Alternatively, allyl to trans-propenyl isomerization can be purposely effected using Grubbs second-generation catalyst in MeOH at elevated temperatures (~60°C).2

References: (1) (a) Raju, R. et al. Org. Lett. 2007, 9, 1699. (b) Moise, J. et al. Org. Lett. 2007, 9, 1695. (c) Hong, S. H. et al. J. Am. Chem. Soc. 2005, 127, 17160. (2) Hanessian, S. et al. Org. Lett. 2006, 8, 5481.

Removal of Ru Metal from Metathesis Reaction Mixtures

A problem inherent to most metathesis reactions employing ruthenium carbenes is the effective removal of ruthenium impurities upon completion of the reaction. In addition to catalyst re-design,1 a variety of methods2 have been used to scavenge ruthenium species, including the use of: water-soluble phosphines,3 oxidizing agents (such as triphenylphosphine oxide,4 DMSO,4 or lead tetraacetate5), mesoporous silicates,6 polar isocyanides,7 and activated carbon.8

References: (1) For example, see: Hong, S. H.; Grubbs, R. H. Org. Lett. 2007, 9, 1955. (2) For a summary of existing methods for removal of Ru-species from metathesis reactions, see: Conrad, J. C.; Fogg, D. E. Curr. Org. Chem. 2006, 10, 185. (3) (a) Maynard, H. D.; Grubbs, R. J. Tetrahedron Lett. 1999, 40, 4137. (b) Grubbs, R. H. Org. React. 2004, 22, 123. (4) Ahn, Y. M. et al. Org. Lett. 2001, 3, 1411. (5) Paquette, L. A. et al. Org. Lett. 2000, 2, 1259. (6) McEleney, K. et al. Org. Lett. 2006, 8, 2663. (7) Galan, B. R. et al. Org. Lett. 2007, 9, 1203. (8) Cho, J. H.; Kim, B. M. Org. Lett. 2003, 5 531.

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