Fluorous reactions

In a more recent report, Larhed and coworkers have presented microwave-mediated fluorous reaction conditions for palladium-catalyzed aminocarbonylations [100]. 

New fluorous reactions also present entertaining naming opportunities. For example, we call the fluorous Ugi reaction the flugi reaction. The fluginelli reactions follows accordingly. 

The ideal systems for these media are those which do not require any additional solvent, and in which the substrate is more soluble than the product, leading to preferential rejection of the product from the catalyst phase. For fluorous reactions, this would include oxidation reactions where oxygenated products are typically more polar than the substrates. In ionic liquids it is products less polar than the substrates that will normally be less soluble, although the ability to tune the structure of ionic liquids to match a particular application must... 

The Grignard reaction is one general method for the access to fiuori-nated phosphines [118]. Fluor mated phosphines are also related to catalysis applications in fluorous reaction media [119-121]. As a first example, trans-Co2(CO)6[P(z-Pr)2 3,5-fozs(CF3)-C6H3 ] (5b) was synthesized in two steps by the reaction of 3,5-fozs(CF3)-C6H3MgBr with (z-Pr)2PCl to 5a with a yield of 90%, followed by the complexation of Co2(CO)8 in refluxing benzene (Fig. 10). 

Heterogeneous reactions lend themselves to continuous flow reactors, which are desirable as they minimise the reacting volume. This reduces operation risks, and allows smaller, more efficient plants to be built. Flow reactors designed for fluorous reactions with both liquid and gaseous substrates have been demonstrated to be effective, at least on a bench scale [49]. Fluorous solvents have also recently found applications as liquid membranes to control the rate of addition of reagents and so control exothermic reactions such as alkene bromination (Fig. 6), and demethylation of anisoles by reaction with boron tribromide [50], This has potential as a clean route as the kinetic control gives improved selectivity. 

Ryu, Curran and their co-workers have achieved the fluorous hydroxymethyla-tion of organic halides using a catalytic quantity of a fluorous tin hydride [8] in the presence of sodium cyanoborohydride [10]. Interestingly, this fluorous reagent, as is usually the case for the related fluorous reactions [18], permits simple purification by a three-phase (aqueous/organic/fluorous) extractive workup. An example is given in Scheme 4-5. It should be noted that, unlike the cyclization-for-mylation sequence shown in the fourth equation in Scheme 4-3, the cyclization-hydroxymethylation sequence of the same substrate using a catalytic system was... 

The reactions involving fluorous tin reagents discussed above also require fluorous reaction solvents and/or extraction solvents. These solvents are expensive and hazardous to human health and to the environment. Preliminary investigations towards an easily contained alternative have involved a fluorous monolayer on silica (Figure 5.8.2). 

The possibility to run reactions in a homogeneous fashion is one of the attractive features of solution phase synthesis techniques over the conceptually related solid phase synthesis techniques. However, the incorporation of fluorous chains to permit molecules to partition into a fluorous phase naturally begins to alter the solubility properties of the resulting fluorinated organic molecules. Indeed, molecules with very large fluorous domains can have little or no solubility in many common organic solvents. Thus, solubility and selection of a reaction solvent are crucial considerations in designing fluorous reactions or reactions sequences. 

Biginelli reaction (Scheme 3.12) [64,67]. Excess (3-ketoester and aldehyde was separated from the fluorous reaction product by partitioning between toluene and FC-84 (mixture of isomers of C7Flft). The same system was used after cleavage of the silyl group with TBAF. In this case the toluene extracted the desired product while the fluorous silyl fluoride remained in the fluorous phase. 

Microwave-mediated fluorous reaction conditions for palladium-catalyzed aminocarbonylations have been discussed in a more recent report [101]. A set of aryl halides was reacted with carbonyl hydrazides and molybdenum hexacarbonyl [Mo(CO)e] as source of carbon monoxide, with fluorous triphenylphosphine (F-TPP) as ligand and the perfluorocarbon liquid FC-84 as perfluorinated solvent (Scheme 16.67). 

As reflected by the fluorous reactions described in Section 3.3, and quantified by data below, most organic compounds have very low affinities for fluorous phases compared with organic phases. Thus, products can often be separated from heavy fluorous catalysts or spent reagents using a simple liquid/liquid phase separation, as shown in Figure 3.2. If necessary, the fluorous phase can be extracted using additional organic solvent. 

Although fluorous reactions can be conducted under heterogeneous liquid/Uquid biphasic conditions, from a rate standpoint it will normally be advantageous to operate under homogeneous monophasic conditions, as in the top sequence in Figure 3.2. For this reason it is important to know at what temperatures various fluorous and non-fluorous solvents become miscible (Table 3.5). 

Heavy fluorous techniques use fluorous reaction components that have a large number of fluorines. Heavy fluorous molecules can have as few as 39 fluorines, but it is not uncommon for them to have >50 or even >100. Such a high fluorine content gives heavy fluorous molecules unusual properties, and they can be separated from reaction mixtures by simple separation techniques such as extraction with a fluorinated solvent or even just filtration (see Section 3.3). However, the unusual properties that facihtate separations can complicate reactions since heavy fluorous molecules sometimes do not behave well under standard reaction conditions, and a search for suitable solvents and reaction conditions is a prerequisite. 

Fluorous reactions in supercritical carbon dioxide (SCCO2) and fluorous triphasic reactions... 

In contrast, Beckman and Curran were looking for solvents that would dissolve both organic and fluorous reaction components and suggested supercritical CO2 as a general solution to fluorous reaction and separation problems. The setting was... 

Fluorous biphasic and triphasic reactions are at once similar and different. Like fluorous biphasic reactions (see Section 3.3), fluorous triphasic reactions use a fluorous reaction solvent. However, whereas biphasic reactions use heavy fluorous molecules, triphasic reactions use light fluorous molecules or sometimes no fluorous molecules at all. The reaction and separation occur simultaneously in triphasic reactions. Indeed, the reaction drives the separation in most triphasic processes, whereas a separation follows a reaction in biphasic methods. 

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