Metathesis catalysts and reducing olefin isomerization

November 5th, 2017 Leave a reply »

Bottom line: to minimize side products arising from isomerization, minimize decomposition of the metathesis catalyst.  This includes removing impurities that inhibit a catalyst or promote its decomposition.  Catalyst screening and conducting the metathesis at a lower temperature may also be helpful.

Overview In 2005 Yves Chauvin, Robert Grubbs, and Richard Schrock received a Nobel Prize for their work in metathesis.  Professors Grubbs, Schrock and others have expanded this chemistry from polymers to synthetic organic chemistry to pharma.  Metatheses in pharma have been recently reviewed [1, 2], and wider-ranging resources are available [3, 4, 5].  For pharmaceutical and specialty chemical applications, ring-closing metatheses (RCMs) [6] are more common than cross metatheses.

Metatheses are equilibrium reactions and need to be actively quenched on scale [7].  Differences in reactivity and stability of metathesis catalysts to O2 and other species may be pronounced [1].  O2 can decompose catalysts, so it may be best to degas (deoxygenate) the solvent before charging catalyst.  Instead of sparging to remove O2, heating a solvent to reflux and cooling under N2 is more effective [8], probably because boiling breaks the surface tension of the liquid.  By heating to reflux some solvent may be distilled off, potentially azeotroping off H2O, which can decompose the catalyst.  Metatheses can be driven by boiling the solvent or by purging with N2 to remove low-molecular weight olefins formed; ethylene has been shown to decompose the Grubbs I catalyst bis(tricyclohexylphosphine)benzylideneruthenium dichloride [9].  Gradually adding the catalyst while gradually adding the starting material helped drive a metathesis [10].   Vigorous agitation and not filling a reactor completely so that there is significant headspace above the reaction mixture may also be helpful.  Basic impurities such as morpholine [11] and DBU can deprotonate and thus decompose an active catalyst [12].  Impurities that might chelate Ru can slow metatheses, as GSK found with a urea and a beta-hydroxy secondary amide arising from opening the corresponding beta-hydroxy phthalimide with iPrOH.  Those researchers found that impurities can act synergistically [13].  Some tips on removing Ru species are discussed in an earlier Process Tip on this website.

Materia Inc. was founded in partnership with Prof. Grubbs and Caltech to expand the use of metathesis.  Users can now purchase metathesis (pre)catalysts from Materia to make commercial APIs without negotiating a license.  Materia also offers process guidance and other technical services [14].  Materia’s business model should facilitate pharma’s use of metathesis for preparing APIs.

Olefin isomerization and subsequent metathesis can generate impurities that are difficult to remove, such as 1) olefins from isomerization of the metathesis product; 2) olefins arising from loss of a CH2, due to olefin isomerization away from the terminal position followed by metathesis; and 3) olefins including an additional CH2, from isomerization of an internal olefin towards the end of the chain [6, 15].  Ruthenium hydride species, formed by decomposition of metathesis catalysts, have been shown to be responsible for isomerized side products [16, 17].  Additives such as AcOH or benzoquinone [18], 2,6-dichlorobenzoquinone [10], tricyclohexylphosphine oxide [19] and the monophenyl ester of phosphoric acid [20, 21] have been shown to reduce olefin isomerization, presumably by quenching the hydride species.  These additives may also slow or stop metatheses from proceeding to completion.  Lower reaction temperatures can also prevent isomerization [22].  The use of these and other reagents for minimizing olefin isomerization has been reviewed [23, 24].

The research group of Professor Fogg has investigated the mechanisms for catalyst decomposition.  They have shown that Lewis donors can promote decomposition of Grubbs catalysts, with the generation of MePCy3Cl from the PCy3 ligand; such Lewis donors include pyridine, MeOH, THF, and H2O [25].  In an RCM with Grubbs II (IMes) reagent, only isomerized products were found in reactions run in dimethoxyethane, while reactions in 1,2-dichloroethane exhibited little isomerization [19]; the ability of DME to act as a Lewis donor may have promoted the decomposition of the catalyst.  The second-generation Hoveyda catalysts (PCy3-free) can be decomposed by reacting with (basic) amines, generating Ru hydride species [26].  Ruthenium nanoparticles have also been shown to isomerize olefins, and these nanoparticles can be produced by decomposition of the Grubbs II reagent.  Removal of these nanoparticles did not halt isomerization, as further catalyst decomposition produced more nanoparticles [27].

In a recent development, a 2-isopropyl-6-methyl-CAAC [cyclic alkyl amino carbene] Ru complex has been shown to produce low levels of isomerization in metatheses.  For instance, an RCM at 150 ºC produced 42% of isomerized side products with a second-generation Hoveyda-Grubbs catalyst, but only 13% of isomerization using the CAAC catalyst.  Experimentally and by calculations this complex was shown to be resistant to the formation of Ru hydride species [28].  While this catalyst was quite effective in the presence of ethylene [29], more exploration is warranted on the potential impact of other impurities on this relatively new catalyst, which may not yet be commercially available.

Hence it is important to avoid decomposing the catalyst by controlling the impurities in the starting materials and the reaction mixtures.  Recrystallizing the starting materials and purifying the solvents may be necessary for rugged reactions [10, 13].  Minimizing side products from olefin isomerization in a metathesis is reminiscent of minimizing protodeboronation from a Suzuki reaction: to minimize the opportunity for side reactions to occur, the best approach may be to find conditions that lead to rapid conversion to the desired product.

I thank Professor Deryn Fogg and Dr. Philip Wheeler for helpful discussions.

  1. Higman, C. S.; Lummiss, J. A. M.; Fogg, D. E. Chem. Int. Ed. 2016, 55, 3552.
  2. Wheeler, P.; Phillips, J. H.; Pederson, R. L. Process Res. Dev. 2016, 20, 1182.
  3. Virtual issue on metathesis: see Fogg, D. E. Organometallics, 2017, 36, 1881.
  4. Olefin Metathesis: Theory and Practice; Grela, K., Ed.; Wiley 2014.
  5. Handbook of Metathesis; Grubbs, R. H.; Wenzel, A. G.; O’Leary, D. J.; Khosravi, E., Eds.; Wiley-VCH, Weinheim, Germany; 2015.
  6. van Lierop, B. J.; Lummiss, J. A. M.; Fogg, D. E., Chapter 3: “Ring-Closing Metathesis,” in Olefin Metathesis: Theory and Practice, First Edition; Grela, K., Ed.; John Wiley & Sons, Inc.; 2014; pp 85 – 152.
  7. Yee, N. K.; Farina, V.; Houpis, I. N.; Haddad, N.; Frutos, R. P.; Gallou, F.; Wang, X.; Wei, X.; Simpson, R. D.; Feng, X.; Fuchs, V.; Xu, Y.; Tan, J.; Zhang, L.; Xu, J.; Smith-Keenan, L. L.; Vitous, J.; Ridges, M. D.; Spinelli, E. M.; Johnson, M. Org. Chem. 2006, 71, 7133.
  8. Königsberger, K.; Chen, G.-P.; Wu, R. R.; Girgis, M. J.; Prasad, K.; Repic, O.; Blacklock, T. J. Process Res. Dev. 2003, 7, 733; Rassias, G.; Hermitage, S. A.; Sanganee, M. J.; Kincey, P. M.; Smith, N. M.; Andrews, I. P.; Borrett, G. T.; Slater, G. R. Org. Process Res. Dev. 2009, 13, 774.
  9. Burdett, K. A.; Harris, L. D.; Margl, P.; Maughon, B. R.; Mokhtar-Zadeh, T.; Saucier, P. C.; Wasserman, E. P. Organometallics 2004, 23,
  10. Kong, J.; Chen, C.; Balsells-Padros, J.; Cao, Y.; Dunn, R. F.; Dolman, S. J.; Janey, J.; Li, H.; Zacuto, M. J. Org. Chem. 2012, 77, 3820.
  11. Less than 20 ppm of morpholine was found in the batch of toluene used as solvent for a metathesis. Under the dilute conditions for the RCM about one equivalent of morpholine was present relative to the catalyst.  Nicola, T.; Brenner, M.; Donsbach, K.; Kreye, P. Process Res. Dev. 2005, 9, 513.
  12. Ireland, B. J.; Dobigny, B. T.; Fogg, D. E. ACS Catal. 2015, 5,
  13. Wang, H.; Goodman, S. N.; Dai, Q.; Stockdalem, G. W.; Clark, W. M., Jr. Process Res. Dev. 2008, 12, 226; Wang, H., in Transition Metal-Catalyzed Couplings in Process Chemistry; Magano, J.; Dunetz, J., Eds.; Wiley-VCH; 2013; pp 233 – 251.
  14. http://pharma.materia-inc.com/process-development
  15. Reaction of a metallacyclobutane intermediate with a base can also generate an olefin impurity with an additional CH2: see reference 11.
  16. Schmidt, B. J. Org. Chem., 2004, 9, 1865.
  17. Courchay, F. C.; Sworen, J. C.; Ghivirga, I.; Abboud, K. A.; Wagener, K. B. Organometallics 2006, 25,
  18. Hong, S. K.; Sanders, D. P.; Lee, C. W.; Grubbs, R. H. Am. Chem. Soc., 2005, 127, 17160.
  19. Bourgeois, D.; Pancrazi, A.; Nolan, S. P.; Prunet, J. Organomet. Chem. 2002, 643-644, 247.
  20. Formentín, P.; Gimeno, N.; Steinke, J. H. G.; Vilar, R. Org. Chem. 2005, 70, 8235.
  21. Firth, B. E.; Kirk, S. E. US 9481627 B2, 2016 (to Elevance Renewable Sciences, Inc.).
  22. Pederson, R. L.; Fellows, I. M.; Ung, T. A.; Ishihara, H.; Hajela, S. P. Synth. Catal. 2002, 344, 728.
  23. Stoianova, D., 2009:http://allthingsmetathesis.com/inhibiting-olefin-isomerization/
  24. Discussion Addendum for: Ring-closing Metathesis Synthesis of N-Boc-3-pyrroline: O’Leary, D. J.; Pederson, R.; Grubbs, R. H. Synth. 2012, 89, 170; DOI: 10.15227/orgsyn.089.0170.
  25. McClennan, W. L.; Rufh, S. A.; Lummiss, J. A. M.; Fogg, D. E. Amer. Chem. Soc. 2016, 138, 14668.
  26. Bailey, G.; Lummiss, J.; Foscato, M.; Occhipinti, G.; McDonald, R.; Jensen, V.; Fogg, D. Am. Chem. Soc. XXXX, XXX, XXXX; DOI: 10.1021/jacs.7b08578.
  27. Higman, C. S.; Lantera, A. E.; Marin, L. M.; Scaiano, J. C.; Fogg, D. E. ChemCatChem 2016, 8, 2446.
  28. Butilkov, D.; Frenklah, A.; Rozenberg, I.; Kozuch, S.; Lemcoff, N. G. ACS Catal., 2017, 7, 7634; DOI: 1021/acscatal.7b02409.
  29. Marx, V. M.; Sullivan, A. H.; Melaimi, M.; Virgil, S. C.; Keitz, B. K.; Weinberger, D. S.; Bertrand, G.; Grubbs, R. H. Chem. 2015, 127, 1939.

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