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Overcoming Catalyst Decomposition in Acrylate Metathesis: Polyphenol Resins as Enabling Agents for PCy3-Stabilized Metathesis Catalysts Alexandra G. Santos, Gwendolyn A Bailey, Eduardo Nicolau dos Santos, and Deryn Elizabeth Fogg ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b03557 • Publication Date (Web): 20 Mar 2017 Downloaded from http://pubs.acs.org on March 21, 2017
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ACS Catalysis
Overcoming Catalyst Decomposition in Acrylate Metathesis: Polyphenol Resins as Enabling Agents for PCy3-Stabilized Metathesis Catalysts Alexandra G. Santos,a,‡ Gwendolyn A. Bailey,b,‡ Eduardo N. dos Santos*,a and Deryn E. Fogg*,b a
b
Departamento de Química-ICEx, Universidade Federal de Minas Gerais, 31270-901 Belo Horizonte, Brazil. Department of Chemistry and Biomolecular Sciences; Centre for Catalysis Research & Innovation, University of Ottawa, Ottawa, Ontario, Canada K1N 6N5 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 analog 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 trade-name 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 hydrogenbonding of polar contaminants present as impurities in the reagents or reaction medium.
KEYWORDS Poly(vinylphenol); olefin metathesis; cross metathesis; acrylate; phenylpropanoid, octinoxate; secondgeneration Grubbs catalyst; catalyst decomposition INTRODUCTION Olefin metathesis is the most powerful and general methodology now known for the construction of carbon-carbon bonds.1-3 Metathesis methodologies are ubiquitous in organic synthesis in academia, while emerging applications in process chemistry range from pharmaceutical manufacturing to the transformation of renewable plant oils into specialty chemicals.4-8 The second-generation Grubbs catalyst GII remains the dominant catalyst in academic use today, although the past decade has seen expanding use of the indenylidene and phosphine-free catalysts (see M2, HII; Chart 1a).
dene intermediate (Ru-1; Chart 1b) is profoundly deactivating. Strong binding of PCy3 traps the catalyst in its off-cycle resting state,11 greatly retarding re-entry into the catalytic cycle.20 Nucleophilic attack of PCy3 on the methylidene carbon is even more deleterious. This initiates a "ligand stripping" pathway that culminates in loss of [MePCy3]Cl10-16 and formation of isomerization-active species (including Ru nanoparticles).21
Notwithstanding the transformative impact of GII and its analogs on organic and materials synthesis, the past decade has seen a steady accumulation of evidence demonstrating that the PCy3 ligand – which must be dissociated to permit the catalyst to enter the active cycle – has an adverse impact on both activity and productivity.9-19 Recoordination of PCy3 to the methyli-
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Chart 1. (a) Dominant metathesis catalysts. (b) Key intermediates in olefin or acrylate metathesis. Less widely recognized, despite prominent developments in nucleophilic phosphine organocatalysis (including phosphine-enabled annulation and other conjugate additions with electron-deficient olefins, allenes, or alkynes),22-25 is the potential for additional reactions arising from the high nucleophilicity of free PCy3. We recently described a particularly aggressive decomposition pathway operative in acrylate metathesis.9 Nucleophilic attack of PCy3 on the acrylate olefin generates a stabilized α-carbanion (A, Scheme 1) or enolate,9 as recognized decades ago in Morita-Baylis-Hillman chemistry.26 This potent Bronsted base27 deprotonates the active catalyst, possibly metallacyclobutane intermediate Ru-2 (R = CO2Me). The resulting decomposition cascade occurs with great rapidity,9 accounting for the high catalyst loadings required to maximize product yields when using GII for acrylate cross-metathesis.28-30 The problem is not limited to GII. Because all metathesis catalysts converge on the identical set of active species (examples of which are shown in Chart 1b), use of any PCy3stabilized precatalyst – whether M2, GII, or another – results in the same limitations.
Scheme 1. Generation of a potent Bronsted base via nucleophilic attack by PCy3 on methyl acrylate. Such challenges to productivity are especially important given the dominance of GII in synthetic applications, as noted above. The enormous popularity of this catalyst is undoubtedly due in part to familiarity, but simple economics are also relevant, GII being among the cheapest available Ru-NHC metathesis catalysts (see SI, Table S1). Offsetting such gains, however, are the high catalyst loadings required to compensate for its short lifetime in acrylate metathesis. Further, catalyst decomposition has an adverse effect on product selectivity and purity, owing to competing C=C isomerization (the most common side-reaction in metathesis chemistry),21,31-33 and challenges in removing decomposed ruthenium products from the organic constituents.34 Of note, distillation has been reported to significantly promote product isomerization5 or decomposition,35,36 while column chromatography is hampered by streaking of the decomposed Ru species on the column.37,38
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nate in the ability of the phenol to sequester PCy3 and to stabilize Ru-1 via H-bonding.41,42 The utility of the original protocol was undermined, however, by the need for large amounts of the phenol (500 equiv vs. Ru, or 2.5 g of p-cresol for cross-metathesis of 9 mL of 1-decene), removal of which by basic extraction or column chromatography is non-trivial. We were therefore intrigued by the potential of poly(vinylphenol) resins as convenient, readily removed, potentially recyclable catalyst promoters. Here we report that such phenol-functionalized polymer resins dramatically increase metathesis yields in acrylate cross-metathesis, via a previously unconsidered enolate-quenching mechanism. The resin bearing sequestered phosphonium salt is simply filtered off at the end of reaction. This approach offers a simple, powerful means of upgrading the metathesis performance of GII and M2 to match – or, in the case of methyl acrylate, to exceed – that of the important, widely-used phosphinefree catalyst HII. RESULTS AND DISCUSSION Impact of catalyst loading on yields. Synthetic organic chemists regard the Grubbs catalyst as “de rigueur” for the metathesis of electron-deficient olefins. Issues of catalyst performance, while critical in (e.g.) pharmaceutical process chemistry, are often viewed with less concern in target-driven synthesis or discovery applications, where catalyst decomposition is normally compensated for by increasing the proportion of catalyst as required. From this perspective, however, the performance in Figure 1 is enlightening. The demanding cross-metathesis of anethole 1 with 2-ethylhexyl acrylate (EHA), which yields the high-value cinnamate 2, is shown to proceed to ca. 70% yield at a catalyst loading of 0.1 mol%. Complete cessation of metathesis is evident by 30 min, indicating catalyst decomposition. The more striking aspect of the figure, however, is the marginal improvement in yield following a 30-fold increase in catalyst loading, to 3 mol% GII. To put this in perspective, carrying out the latter reaction on 10 g of 1 would require nearly a gram of GII (see Table S1) to achieve
