Fluorous phases

There are only very few examples for Mizoroki-Heck reactions in fluorous systems. The catalyst systems, the fluorous or uoufluorous solvent and the additional base are listed in Table 15.1. There are detailed reviews on the Mizoroki-Heck reaction with nonconventional methods that also include fluorous media [12,63]. 

Most of the reported work on Mizoroki-Heck reactions in fluorous media applies palladium salts and free ligands. There are only five reports on the usage of preformed fluorous palladium complexes (Table 15.1, entries 1 ) [64-68]. They all used a biphasic system with an organic solvent and a fluorous catalyst that dissolved only at elevated temperatures. Gladysz and coworkers [64, 65] recovered the catalyst 22 in the only patent on Mizoroki-Heck reactions in fluorous media by simple filtration (Table 15.1, entries 1, 2). The first two runs with iodobenzene and methyl acrylate at 100 °C in DMF were almost quantitative after 2 h reaction time (TON 5251), but after the third run at 100 °C the activity decreased (TON 2500-2900) and the authors changed the reaction time in the fourth run to 10 h to receive again quantitative conversion and yield (TON 5251). 

The same catalyst was compared with another palladacycle (23) at 140 °C and longer reaction times (14-48 h) (Table 15.1, entry 2) [66]. The catalyst was very active in coupling iodobenzene with styrene or methyl acrylate (TON (1.3-1.5) x 10 ), whereas lower conversions and yields were observed due to catalyst deactivation for the less reactive bromoacetophenone for the coupling with methyl acrylate (TON (2.7-3.0) x 10 ). The catalytic system could be recycled after the addition of CgFnBr to give a biphasic mixture. The data obtained by transmission electron microscopy indicates that colloidal palladium nanoparticles were formed as active species for the Mizoroki-Heck reaction. 

Another fluorous palladium complex that was applied in a Mizoroki-Heck reaction is the SCS pincer palladium complex 24 (Table 15.1, entry 3) [67]. It was applied under thermal and microwave heating. No fluorous solvent was used and the insoluble catalyst dissolved at the reaction temperature of 140 °C. The catalyst was recovered after 30 to 45 min by solid-phase extraction with a fluorous silica gel. Depending on whether activated or nonactivated substrates were coupled, the yields ranged between 76 and 94%. 

Perfluorinated polyether-derivatized poly(propylene imine) dendrimers with palladium(0)-nanoparticels 

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A. Studer, S. Hadida, R. Ferritto, S.Y. Kim, P. Jeyer, P. Wipf, D.P. Curran, Fluorous synthesis — A fluorous-phase strategy for improving separation efficiency in organic synthesis. Science 275 823-826 1997. 

In comparison with traditional biphasic catalysis using water, fluorous phases, or polar organic solvents, transition metal catalysis in ionic liquids represents a new and advanced way to combine the specific advantages of homogeneous and heterogeneous catalysis. In many applications, the use of a defined transition metal complex immobilized on a ionic liquid support has already shown its unique potential. Many more successful examples - mainly in fine chemical synthesis - can be expected in the future as our loiowledge of ionic liquids and their interactions with transition metal complexes increases. 

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. 

Fig. 31 Composition of dihydropteridinone ring system using q clative cleavage in fluorous-phase. Reagents and conditions a EtOAc, MeOH, THE, MW 150 °C, 15 min, sealed vials. Y = C, N, O R = Me, Et, i-Bu, Bn R = H, aromatic or heteroaromatic ring...

Fig. 41 Representative example of microwave-assisted Suzuki couplings in fluorous phase. Reagents and conditions [Pd(dppf)Cl2], K2CO3, toluene/acetone/H20, MW 130°C, 10 min, closed system, 78%...

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

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

Only a few years after the development of the homogeneous chiral Mn(salen) complexes by Jacobsen and Katsuki, several research groups began to study different immobiUzation methods in both liquid and soUd phases. Fluorinated organic solvents were the first type of Uquid supports studied for this purpose. The main problem in the appUcation of this methodology is the low solubility of the catalytic complex in the fluorous phase. Several papers were pubUshed by Pozzi and coworkers, who prepared a variety of salen ligands with perfluorinated chains in positions 3 and 5 of the saUcyUdene moiety (Fig. 2). 

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. 

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

Scheme 7.78 Fluorous-phase palladium-catalyzed synthesis of aryl sulfides.

Scheme 7.80 Fluorous phase Suzuki-type couplings.

Scheme 7.81 Fluorous phase synthesis of N,N -disubstituted hydantoins.

Scheme 7.82 Fluorous phase traceless deoxygenation of phenols.

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. 

Scheme 7.85 Fluorous phase synthesis of imidazo[l,2-a]pyridine/pyrazine derivatives.

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