Purification of Olefin Metathesis Reaction Products via Straightforward and Low-Cost Protocols

Over the past fifteen years, olefin metathesis [1-3] has been sophisticatedly used by scientists working in a variety of research fields to develop new synthetic routes, as well as a plethora of novel materials and industrial processes [4-8]. The huge impact of metathesis to chemical synthesis led to the awarding of the 2005 Nobel Prize in Chemistry to Yves Chauvin, Robert H. Grubbs, and Richard R. Schrock.


Introduction
Over the past fifteen years, olefin metathesis [1][2][3] has been sophisticatedly used by scientists working in a variety of research fields to develop new synthetic routes, as well as a plethora of novel materials and industrial processes [4][5][6][7][8]. The huge impact of metathesis to chemical synthesis led to the awarding of the 2005 Nobel Prize in Chemistry to Yves Chauvin, Robert H. Grubbs, and Richard R. Schrock.
The most commonly utilized olefin metathesis transformations in an organic synthesis laboratory, i.e. ring-closing metathesis (RCM) and cross metathesis (CM), are shown in scheme 1. RCM is primarily driven by entropic factors as one substrate molecule affords two molecules of products. Lacking the entropic driving force of RCM, CM is more challenging and can lead to relatively low yields of the desired cross-product [9,10].
Th e widespread use of olefin metathesis has been mainly triggered by the development of well-defined ruthenium catalysts with high air and moisture stability and functional group tolerance [1][2][3]. Unfortunately, however, the complete removal of residual ruthenium after the end of the reaction is a major problem, very often even after several consecutive SiO 2 column chromatographic purifications [11]. This is especially true when increased catalyst loadings are necessary, given that high catalyst loadings usually increase the residual ruthenium impurities in the metathesized product.
Purity is an issue of outmost importance during the synthesis of biologically-active compounds due to the relatively low acceptable transition metal content in pharmaceutical applications (the allowed levels for oral administration of ruthenium are 5 ppm or below). Moreover, residual ruthenium species may cause isomerization, decomposition, or other undesired side-reactions in subsequent synthetic steps or even during the purification of the metathesized compounds.
the removal of the residual ruthenium in homogeneous reactions utilizing common, commercially-available catalysts (complexes 1-4, Figure 1). These two approaches include either the purification of the products on SiO 2 in conjunction with treatment with activated carbon, or the use of common ruthenium scavengers, such as dimethyl sulfoxide, in combination with column chromatography [11]. The purification protocols based on these strategies do not require structural modifications on the catalyst in order to remove ruthenium residues. Note that these purification techniques also have weaknesses, including: i) the usually high required loading of the scavenger; ii) long processing times; and/or iii) numerous washings and extractions.

Abstract
From the point of view of an organic chemist, the discovery of novel and efficient carbon-carbon bond forming reactions is a continuous scientific quest. Olefin metathesis, a metal-catalyzed reaction, can be considered as one of the most robust tools in this respect. As a result, metathesis has been widely used over various chemistry and materials science fields. The increased popularity of this powerful transformation is mostly due to the development of highly efficient, functional group tolerant, and air-and moisture-stable ruthenium catalysts. However, the complete removal of ruthenium from the reaction products, in order to avoid undesired side-reactions, isomerization, or even the decomposition of products, is very often a highly challenging task. The present article focuses on the most straightforward and efficient methodologies for the removal of ruthenium residues from olefin metathesis post reaction mixtures. These purification protocols can be easily carried out in any common organic synthesis laboratory, needless of specialized reagents and experimental setup. The first series of ruthenium sequestration methods by-passing the need to introduce specialized reagents in order to remove the residual ruthenium were published in 2003 [12]. The most efficient approach in that work had to do with the removal of catalyst 1 ( Figure 1) from a series of RCM reactions mixtures and uses three consecutive purification steps: i) stirring of the crude reaction mixture with 10 equivalents (wt) SiO 2 relative to catalyst 1, followed by filtration through a pad of SiO 2 ; ii) stirring of this filtrate with 50 equivalents (wt) activated charcoal relative to the crude metathesized product for 12 hours at r.t., followed by filtration; and iii) SiO 2 column chromatographic purification. Under these conditions, the residual ruthenium levels in the RCM products were found to be between 12 and 106 ppm, without detectable loss of the products.
Another successful strategy for the removal of the catalyst from the metathesized products, involving the simple immobilization of catalyst 4 ( Figure 1) on commercial SiO 2 both in pellet and powder form, was reported in 2008. The adsorption of 4 was proposed to occur via the direct attachment of ruthenium species to the surface silanols via ligand exchange [14]. According to this method, SiO 2 is suspended in a toluene solution of catalyst 4 and stirred at room temperature for 2 hours. Filtration, washing with hexane and subsequent drying affords the final heterogeneous solid catalyst. This supported catalyst, stable for up to at least 4000TON, was successfully utilized in a series of RCM and CM transformations. The powdered catalyst is separated from the products by filtration, while the workup with pellets is carried out by simple decantation of the reaction mixture. Metathesis transformations carried out in hexane gave reaction mixtures with ruthenium content below the detection limit of ICP-MS (0.04 ppm); nevertheless, the use of more polar solvents such as diethyl ether led to ruthenium leaching in the reaction mixture. For the same reason, the use of highly polar substrates such as alcohols and acids with this catalytic system has to be avoided.
According to a similar protocol, catalysts 1, 2, and 4 ( Figure 1) can be easily immobilized in the pores of amorphous Al 2 O 3 with the aid of ionic liquids [15]. To obtain the supported catalysts, amorphous Al 2 O 3 is suspended in a solution of the respective ruthenium complex and ionic liquid in tetrahydrofuran and stirred at room temperature for 4 hours. Tetrahydrofuran is then evaporated under vacuum and the resulting material is rinsed with anhydrous diethyl ether twice before evacuated again to afford the final free-flowing powder. The asobtained immobilized catalysts were successfully utilized in a variety of RCM and macrocyclic RCM reactions, with benzene and toluene being the reaction solvents of choice. Ruthenium leaching from this kind of immobilized catalysts was reported to be 0 ppm, as measured by inductively coupled plasma atomic emission spectroscopy (ICP-AES).
Finally, an even simpler and highly efficient methodology was reported in 2005 for the removal of catalyst 1 from the reaction mixture, achieving very low ruthenium levels in the purified organic products [16]. This can be performed by treating the crude reaction mixture with SiO 2 (4 g per 0.01 mmol catalyst) and DMSO (50 molar equivalents relative to the catalyst) at room temperature for 12 hours. Ruthenium levels can thus be easily reduced to 8 ppm in the metathesized products.

Summary
The sequestration of ruthenium catalyst residues from olefin metathesis reaction products is quite often problematic. However, pharmaceutical chemistry applications demand final products of very high purity, while unsuccessful removal of ruthenium impurities during the production of fine chemicals may catalyze undesired sidereactions in subsequent steps. The goal of the present article is to briefly summarize the most efficient, straightforward, and inexpensive protocols for the quenching of ruthenium impurities from olefin metathesis post-reaction mixtures. All these strategies can be easily performed in any common organic synthesis laboratory.

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