Olefin isomerization/migration can be an annoying side reaction of olefin metathesis, in no small part because the side products are usually difficult to separate from the desired product. The isomerization is catalyzed by metal hydride species formed in the decomposition of the catalyst (see Schmidt, Eur. J. Org. Chem. 2004, 1865 for a review).
- Don’t beat on your reaction if you don’t need to. All of the following factors give increased rates of Ru-hydride formation, leading to isomerization issues – use just enough to get your reaction to go in a reasonable time frame and yield:
- High temperatures
- High catalyst loadings
- Long reaction times
- Try a 1st generation Grubbs catalyst instead of 2nd generation catalysts. They’re less likely to react with 1,2-disubstituted (product) olefins. This is a simple fix to try if you want to get your hands on a small amount of pure product, but when reaction cost is an issue, it’s worth trying to develop a process around a more efficient 2nd generation catalyst.
- Use an additive from the list below (no single solution works for everything).
- Benzoquinones (Grubbs, J. Am. Chem. Soc. 2005, 127, 17160). The Grubbs group showed that catalytic amounts (10 mol%) of 1,4-benzoquinones can prevent the isomerization of a number of allylic ethers and long chain aliphatic alkenes during RCM and cross metathesis.
- Acetic acid (Grubbs, J. Am. Chem. Soc. 2005, 127, 17160 also).
- Chlorocatecholborane (Arseniyadis & Cossy, Org. Lett. 2007, 9, 1695). For CM of α-methylene-γ-butyrolactone with the 2nd generation Grubbs catalyst.
- Cy2BCl (Elkaïm & Grimaud, Synlett 2005, 670). For cross metathesis of protected allylamines with the 2nd generation Hoveyda-Grubbs catalyst.
- Cy3PO (Nolan & Prunet, J. Organomet. Chem. 2002, 643, 247). For RCM to an 8-membered ring with second generation unsaturated IMes catalyst.
- PhOP(O)(OH)2 (Formentin, J. Org. Chem. 2005, 70, 8235). For cross metathesis reactions of urea and amide substituted olefins with the 2nd generation Grubbs catalyst.
- ClCH2CH2Cl as solvent (Johnson, J. Am. Chem. Soc. 2009, 131, 10370). In an RCM to make a 9-membered ring, chlorinated solvents inhibited olefin isomerization.
- Low temperature. I know it’s not an additive, but it bears repeating. In the cross metathesis example below using the 2nd generation Grubbs catalyst, 17.5% of impurities derived from olefin isomerization were identified when the reaction was run at 45 °C. Performing the equilibration at 5 °C led to <0.1% of the impurities (Pederson, Adv. Synth. Catal. 2002, 344(6), 728)