Fluorous phase reactions

Further examples of microwave-assisted Suzuki cross-couplings involving supported substrates/catalysts or fluorous-phase reaction conditions are described in Chapter 7. 

Fig. 3. Fluorous-phase reactions single-phase reaction versus reaction with phase changes.

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. 

Farnesyl protein inhibitor 2 Flavones 254 Fluorous phases 112 Fluorous Ugi reactions 115 Functional group transformations 25... 

The term fluorous biphase has been proposed to cover fully fluorinated hydrocarbon solvents (or other fluorinated inert materials, for example ethers) that are immiscible with organic solvents at ambient conditions. Like ionic liquids the ideal concept is that reactants and catalysts would be soluble in the (relatively high-boiling) fluorous phase under reaction conditions but that products would readily separate into a distinct phase at ambient conditions (Figure 5.5). 

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. 

Furthermore, multicomponent reactions can also be performed under fluorous-phase conditions, as shown for the Ugi four-component reaction [96], To improve the efficiency of a recently reported Ugi/de-Boc/cyclization strategy, Zhang and Tempest introduced a fluorous Boc group for amine protection and carried out the Ugi multicomponent condensation under microwave irradiation (Scheme 7.84). The desired fluorous condensation products were easily separated by fluorous solid-phase extraction (F-SPE) and deprotected by treatment with trifluoroacetic acid/tet-rahydrofuran under microwave irradiation. The resulting quinoxalinones were purified by a second F-SPE to furnish the products in excellent purity. This methodology was also applied in a benzimidazole synthesis, employing benzoic acid as a substrate. 

Some of the disadvantages of the Stille reaction, e. g. the low reactivity of some substrates, separation difficulties in chromatography, and the toxicity of tin compounds, have been ameliorated by recent efforts to improve the procedure. Curran has, in a series of papers, reported the development of the concept of fluorous chemistry, in which the special solubility properties of perfluorinated or partly fluorinated reagents and solvents are put to good use [45]. In short, fluorinated solvents are well known for their insolubility in standard organic solvents or water. If a compound contains a sufficient number of fluorine atoms it will partition to the fluorous phase, if such a phase is present. An extraction procedure would thus give rise to a three-phase solution enabling ready separation of fluorinated from nonfluorinated compounds. 

Better retention into the fluorous phase was observed when using a polar fluorous solvent and hexane (>99.82%, insoluble catalyst emulsified in homogeneous reaction mixture) than when using a PFMC and acetone (97.5%), as expected for the ionic... 

The fluorous phase contained the active catalyst, and it was reused two times to repeat the reaction. Yields in runs two and three were comparable to run one and turnover numbers were 100-115 for each run, although each successive run was slower than its predecessor. 

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