Overcoming Catalyst Decomposition in Acrylate Metathesis: Polyphenol Resins as Enabling Agents for PCy3-Stabilized Metathesis Catalysts

Abstract

Phosphine-stabilized metathesis catalysts are among the most popular and widely used catalysts in organic synthesis. The second-generation Grubbs catalyst GII, in particular, dominates synthetic applications of olefin metathesis. This is commonly true even for reactions that are fundamentally incompatible with free PCy3, which is released upon entry of GII into the catalytic cycle. A leading example is cross-metathesis with electron-deficient olefins such as acrylates, for which yields are seriously degraded by a deleterious side reaction involving attack of free PCy3 on the acrylate olefin, and production of an enolate anion that decomposes the active catalyst. Here we describe a simple, powerful means of upgrading the performance of GII and its indenylidene analogue M2 to levels matching or exceeding that of the important, but more costly, phosphine-free Hoveyda catalyst HII. Key to this improvement is carrying out the reaction in the presence of a phenol-functionalized polymer resin. We demonstrate that, at standard catalyst loadings (which correspond to low concentrations of PCy3), the beneficial effect of phenol arises not from protonation of PCy3 itself, but from protonation of the enolate, thereby converting this aggressive base into an innocuous phosphonium salt. The methodology is showcased in the demanding cross-metathesis of the renewable phenylpropanoid trans-anethole with 2-ethylhexyl acrylate (an efficient route to the high-value antioxidant octylmethoxycinnamate, an active ingredient in sunscreen formulations with the tradename Octinoxate), as well as methyl acrylate, a ubiquitous and more sterically accessible coupling partner. Experiments with water-saturated toluene indicate that water cannot be substituted for the resin as a sacrificial proton donor, such treatment resulting in drastically reduced productivity. Control experiments involving macrocyclization indicate that the resin has an additional protective function beyond enolate quenching, potentially due to hydrogen bonding of polar contaminants present as impurities in the reagents or reaction medium.