Fluorous substrates

Zhang and coworkers have reported on a palladium-catalyzed carbon-sulfur cross-coupling of aryl perfluoroalkoxysulfonates with thiols (Scheme 7.78) [91]. The fluorous substrates were obtained from commercially available phenols by treatment with perfluorooctanesulfonyl fluoride (C8F17S02F) under basic conditions. Various thiols were reacted with a slight excess of the perfluorinated sulfonates in a... 

Scheme 2 Stifle reactions with fluorous substrates...

Fluorous tags can also be introduced as acid-labile protecting groups in the synthesis of carboxamides and sulfonamides. In this context, parallel generation of an 18-member library of biaryl carboxamides has been reported perfluorooctane-tagged iodopropane (C8Fi7(CH2)3l) was used to prepare the corresponding fluorous substrates (Scheme 16.63) [96]. After removal of the fluorous tag purification... 

Begue and coworkers recently achieved an improvement in this method by performing the epoxidation reaction in hexafluoro-2-propanol [120]. They found that the activity of hydrogen peroxide was significantly increased in this fluorous alcohol, in relation to trifluoroethanol, which allowed for the use of 30% aqueous H202. Interestingly, the nature of the substrate and the choice of additive turned out to have important consequences for the lifetime of the catalyst. Cyclic dis-ubstituted olefins were efficiently epoxidized with 0.1 mol% of MTO and 10 mol%... 

Compounds lb and 2b were the Urst fluorinated ligands tested in Mn-catalyzed alkene epoxidation [5,6]. The biphasic Uquid system perfluorooc-tane/dichloromethane led to excellent activity and enantioselectivity (90% ee) in the epoxidation of indene with oxygen and pivalaldehyde (Scheme 1, Table 1). In addition, the fluorous solution of the catalyst was reused once and showed the same activity and selectivity. This represents a considerable improvement over the behavior in the homogeneous phase, where the used catalyst was bleached and reuse was impossible. Unfortunately, indene was the only suitable substrate for this system, which failed to epoxidize other alkenes (such as styrene or 1,2-dihydronaphthalene) with high enantioselectivity. The system was also strongly dependent on the oxidant and only 71% ee was obtained in the epoxidation of indene with mCPBA at - 50 °C. 

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

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. 

Figure 6.1 The fluorous biphase concept illustrated for the hydro formylation of an alkene (substrate) to an...

Pozzi and co-workers have also reported a fluorous soluble cobalt complex, which is active in the aerobic epoxidation of alkenes in a fluorous biphasic system (FBS).[50] The ligand used in this complex was a fluorinated tetraarylporphyrin, with eight perfluorooctyl chains shown in Figure 6.13. The cobalt complex was dissolved in perfluorohexane and added to a solution of the alkene with 2-methylpropanal (aldehyde substrate — 2 1) at room temperature. 

The yields for reactions of unsubstituted terminal alkenes were lower than for substituted alkenes but they were still reasonable and could be increased further by increasing the aldehyde alkene ratio. Total conversions of substrate were reported with epoxide selectivity as high as 95% in some cases. The FBC system allows for a much higher substratexatalyst ratio (1000 1) than the non-fluorous epoxidation reported (20 1) previously. Recycling the fluorous layer once showed no reduction in conversion or selectivity. 

To produce 100 000 tonnes of nonanal per year (25% down time, 100% conversion of substrate, 80% selectivity to nonanal) requires a production rate from the reactors of 19 tonne h 1, so that each batch must be 6.3 tonnes. Assuming a 1 1 ratio by volume of fluorous solventdiquid substrate and a 75 % loading, each reactor must have a volume of 20 m3. If the distillation column were fully integrated into the system it would be required to handle 19 tonnes aldehyde h 1. An increase in selectivity to the linear product, which could be achieved using careful ligand design would reduce the reactor size by up to 25%. 

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