Fluorous separation methods

The surge in interest, in the early 2000s, in fluorous derivatives of trivalent phosphorus(III) compounds has stemmed primarily from the ease with which catalysts can be recovered using fluorous biphasic separation methods. Preparative routes to highly fluorous-soluble analogs, of those more commonly used in classic organic-based solvents, are based on those general methods illustrated in Sections 1.12.2.4.1 and 1.12.2.4.2. 

On reaching the stage of fluorous separation, three methods are usually used for the rapid separation of fluorous compounds from the reaction mixture fluorous hquid-phase extraction, fluorous solid-phase extraction [6], and fluorous HPLC [7]. 

Fluorous separation is based on the fact that fluorophilic molecules have an affinity for fluorous media under certain condition, while non-fluorous ones do not have such affinity. Fluorous media can differentiate such affinity, therefore, can rapidly separate fluorous compounds from the rest The choice of the method depends on the nature of the components in the mixture to be separated and the purpose of the synthesis. 

Separation method Fluorous liquid phase extraction (F-LPE) ... 

Dinh is illustrative of the methods and their potential (Figure 4).1261 Hydrosilylation of enones like cydo-hexenone was conducted in two different ways. Under biphasic reaction conditions, an organic solvent like toluene containing the enone and phenyl-dimethyl silane was heated with a fluorocarbon solvent (perfluoromethylcyclohexane) containing a fluorous rhodium catalyst. The hydrosilylation reaction occurred over 10 h, and the reaction mixture was cooled and the phases were separated. Distillation of the residue from the organic phase gave the hydrosilylated products in excellent isolated yields... 

These examples reveal the attractive features of fluorous biphasic catalysis methods for chemical processes. Reactions occur in the liquid phase and can be either homogeneous or biphasic. In either case, biphasic conditions are established at the end of the reaction so the separation is easy. Fluorous sol-... 

Some potential limitations associated with this protocol merit note. For example, with sequence A in Fig. 1, insoluble by-products will interfere with catalyst recovery. With sequence B, interference will depend upon the type of support. For instance, the Teflon tape in Fig. 8 should be easily separable from another solid material, as would a mesh or reactor liner. Also, since heating is required to achieve homogeneity, the method is best suited for reactions conducted at elevated temperatures. However, there are many reactions which proceed rapidly under fluorous/organic liquid/liquid biphase conditions (i.e., before the miscibility temperature is reached) [55-57,70]. Therefore, it is not unreasonable to expect that sohd fluorous catalysts with little or no solubility can also efficiently promote certain reactions, as represented by sequence A-1 in Fig. 1 [29]. 

Although the imidazolidinone catalysts used within these transformations are simple, cheap, readily accessible and in some cases recyclable using acid/base extraction, considerable efforts have been made to examine alternative methods to separate and recycle the catalyst with good success. Examination of the structure of imidazolidinone 22 shows two convenient points for the introduction of a polymer or fluorous support, R and R, both of which have been examined (Fig. 4). Curran has shown that identical reactivity, diastereoselectivity and enantioselectivity can be obtained using a fluorous tag (23) [53]. The catalyst can easily be recovered and recycled using F-SPE with excellent yield, purity and levels of activity. Polymer- (24) and silica-supported (25) imidazolidinones reported by Pihko [54] (R substitution)... 

The variety of separation processes offered by fluorous chemistry will undoubtedly continue to have an impact on new synthetic methods requiring efficient separation procedures. Besides being compatible with a wide variety of chemical reactions, fluorous chemistry works well with several new synthetic technologies, including automated synthesis, the use of supercritical C02, and microwave synthesis. 

This new experimental technique, using fluorous solvents or fluorous biphasic systems (FBS) with fluorous biphase catalysis (FBC), was developed by Vogt and Kaim [884] and by Horvath and Rabai [885] in 1991 and 1994, respectively. Since then, this method has found many applications in synthetic organic chemistry and has already been reviewed repeatedly [886-893]. Incidentally, temperature-dependent two-phase one-phase transitions are not limited to combinations of fluorous solvents with organic solvents. For example, certain mixtures of water and l-cyclohexylpyrrolidin-2-one form one phase at ambient temperature and a two-phase system at higher temperatures >ca. 50 °C), also allowing interesting separation possibilities. 

Even though many of these techniques in themselves are modem, there has been an interest to develop these methods, and invent new techniques, to further increase the speed of hit identification and lead optimization. In large, and in direct application to this chapter, these efforts can be divided into techniques that increase either the speed of synthesis, such as microwave and sonochemical approaches, or the speed of separation, such as fluorous techniques. 

The applications of fluorous chemistry in high-throughput or parallel synthesis are many since fluorous reagents and separation techniques can be used in all stages of synthesis and work-up. As a result, fluorous chemistry can today offer a whole parallel synthetic strategy to traditional chemical methods. 

An important reagent in fluorous chemistry is the fluorous version of the Marshall resin, dubbed FluoMar (4). This separation tag is reported to dissolve readily in dichloromethane, tetrahydrofuran, and ethyl acetate and can, as many other fluorous reagents, be monitored by traditional chromatographic and spectroscopic methods. The usefulness of (4) was demonstrated in a multistep parallel synthesis of a 3 X 3 array of diamides, where the final products were efficiently purified by F-SPE and cleaved from the FluoMar tag. Tentative results indicated that the homogeneous kinetics of the soluble (4) resulted in reactions that proceeded approximately three times faster than polymer-support bound reactions using standard Marshall resin. 

Microwave-assisted fluorous Ugi reactions were presented where the reaction times and convenient separation techniques appeared more attractive than the corresponding room temperature methods with traditional scavenging techniques. ... 

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