Fluorous Phase Techniques

Even if several groups have been active in the development of fluorous techniques, many of the early, seminal papers were presented by just a few groups, most notably Horvath, Gladysz, and Curran. In the last few years several excellent reviews have 

An elegant way out of the problem of low solubility was the advent of light fluorous chemistry (usually employing a fluoricity of below 40% w and fluo- 

A tempting comparison is that between standard solid-phase chemistry and fluorous chemistry. Both of these techniques have several attributes in common, including the use of linkers, frequent use of scavengers, and utility in many similar applications. Even though the use of standard solid-phase chemistry has many advantages, some aspects of polymer-supported synthesis strategies have drawbacks. Eluorous chemistry has in many ways marketed itself as an alternative to solid-sup-port chemistry due to its superior performance in a number of respects.  

Fluorous chemistry is in essence homogeneous and thus results in better reaction kinetics than solid-phase chemistry. 

Large excesses of reagents are seldom needed in fluorous chemistry, but often in standard solid-phase chemistry. 

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Figure 6.2 Separation of products by (a) cyclic anhydrides as acyl donors and (b) fluorous phase technique.

Accelerated Chemistry Microwave, Sonochemical, and Fluorous Phase Techniques... 

Abstract Current microwave-assisted protocols for reaction on solid-phase and soluble supports are critically reviewed. The compatibility of commercially available polymer supports with the relatively harsh conditions of microwave heating and the possibilities for reaction monitoring are discussed. Instrmnentation available for microwave-assisted solid-phase chemistry is presented. This review also summarizes the recent applications of controlled microwave heating to sohd-phase and SPOT-chemistry, as well as to synthesis on soluble polymers, fluorous phases and functional ionic liquid supports. The presented examples indicate that the combination of microwave dielectric heating with solid- or soluble-polymer supported chemistry techniques provides significant enhancements both at the level of reaction rate and ease of purification compared to conventional procedures. 

The strategy of using two phases, one of which is an aqueous phase, has now been extended to fluorous . systems where perfluorinated solvents are used which are immiscible with many organic reactants nonaqueous ionic liquids have also been considered. Thus, toluene and fluorosolvents form two phases at room temperature but are soluble at 64 °C, and therefore,. solvent separation becomes easy (Klement et ai, 1997). For hydrogenation and oxo reactions, however, these systems are unlikely to compete with two-phase systems involving an aqueous pha.se. Recent work of Richier et al. (2000) refers to high rates of hydrogenation of alkenes with fluoro versions of Wilkinson s catalyst. De Wolf et al. (1999) have discussed the application and potential of fluorous phase separation techniques for soluble catalysts. 

Finally - and perhaps most importantly - the fluorous tagging of the catalyst that introduces affinity for the fluorous phase can be a very mild immobilization technique, as there is no direct covalent link with a support and the sepa-... 

Finally, in our 1997 Science paper,1451 we introduced a number of fluorous phase switching techniques, and one of these is illustrated in Figure 12. Cycloaddition of nitriles with fluorous tin azide 20 provides... 

In addition, a novel fluorous support has been developed recently as an alternative to traditional polymer supports and applied successfully to oligosaccharide synthesis in combination with the trichloroacetimidate method [541]. Each intermediate in the fluorous oligosaccharide synthesis [542,543] could be obtained by simple fluorous-organic solvent extraction, and the reactions could be monitored by TLC, NMR and MS, in contrast to solid-phase reactions. Moreover, the new liquid-phase technique is anticipated to be easily applicable to the large-scale synthesis. 

Tris[(2-perfluorohexyl)ethyl]tin hydride has three perfluorinated segments with ethylene spacers and it partitions primarily (> 98%) into the fluorous phase in a liquid-liquid extraction. This feature not only facilitates the purification of the product from the tin residue but also recovers toxic tin residue for further reuse. Stoichiometric reductive radical reactions with the fluorous tin hydride 3 have been previously reported and a catalytic procedure is also well established. The reduction of adamantyl bromide in BTF (benzotrifluoride) " using 1.2 equiv of the fluorous tin hydride and a catalytic amount of azobisisobutyronitrile (AIBN) was complete in 3 hr (Scheme 1). After the simple liquid-liquid extraction, adamantane was obtained in 90% yield in the organic layer and the fluorous tin bromide was separated from the fluorous phase. The recovered fluorous tin bromide was reduced and reused to give the same results. Phenylselenides, tertiary nitro compounds, and xanthates were also successfully reduced by the fluorous fin hydride. Standard radical additions and cyclizations can also be conducted as shown by the examples in Scheme 1. Hydrostannation reactions are also possible, and these are useful in the techniques of fluorous phase switching. Carbonylations are also possible. Rate constants for the reaction of the fluorous tin hydride with primary radicals and acyl radicals have been measured it is marginally more reactive than tributlytin hydrides. ... 

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