Fluorous-phase conditions

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. 

In a variation of the above protocol, the Biginelli synthesis was easily adapted to fluorous-phase conditions.23,24 Here a fluorous urea derivative... 

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%...

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). 

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

Various other biphasic solutions to the separation problem are considered in other chapters of this book, but an especially attractive alternative was introduced by Horvath and co-workers in 1994.[1] He coined the term catalysis in the fluorous biphase and the process uses the temperature dependent miscibility of fluorinated solvents (organic solvents in which most or all of the hydrogen atoms have been replaced by fluorine atoms) with normal organic solvents, to provide a possible answer to the biphasic hydroformylation of long-chain alkenes. At temperatures close to the operating temperature of many catalytic reactions (60-120°C), the fluorous and organic solvents mix, but at temperatures near ambient they phase separate cleanly. Since that time, many other reactions have been demonstrated under fluorous biphasic conditions and these form the basis of this chapter. The subject has been comprehensively reviewed, [2-6] so this chapter gives an overview and finishes with some process considerations. 

The range of ligands developed for ionic liquid catalysis is much smaller than that for other immobilization solvents such as water and fluorous phases as off the shelf ligands and catalysts can often be used in ionic liquids. For example, a number of catalysts that were developed to operate in organic solvents under homogeneous conditions are salts themselves and do not need to be modified for use in ionic liquids [25],... 

A similar reaction has been conducted under fluorous biphasic conditions, using a perfluoroalkylated bipyridine as ligand to ensure that the copper species resides in the fluorous phase [22], The oxidation of a range of primary alcohols to the corresponding aldehydes was found to be possible, an example of which is shown in Scheme 9.11. The catalyst could be successfully recycled by phase separation, with analytically pure products being isolated even after... 

As would be expected, fluorous compounds are preferentially retained on fluorous silica gel [62]. Similarly, fluorous catalysts can be adsorbed on fluorous silica gel. These materials have been applied to reactions in organic solvents and water, both at room temperature and above [63-69]. The investigators have usually interpreted the transformations as bonded fluorous phase catalysis , which corresponds to sequence B-II in Fig. 1. However, there remains the possibility that at least some catalysis proceeds under homogeneous conditions via desorbed species. To our knowledge, fish-out experiments analogous to that conducted with the Teflon tape in Fig. 8 have not been conducted. 

Homogeneous hydrogenation in the fluorous phase has been so far reported only for a limited set of simple olefins (Richter et al., 1999, Rutherford et al., 1998), as exemplified with the neutral rhodium phosphine complex 18 as catalyst precursor (eq. 5.7). Isomerization of the substrate 1-dodecene (17a) was observed as a competing side reaction under the reaction conditions. The catalyst formed from 18 could be recycled using a typical FBS protocol, but deactivation under formation of metal deposits limited the catalyst lifetime. 

Complex 33 was found to also catalyze the epoxidation of various disubstituted olefins with 02 as the primary oxidant and isobutyraldehyde as the sacrificial co-oxidant (Mukayama conditions Klement et al., 1997). Yields of 70-85% were obtained after heating the olefins and 33 under oxygen atmosphere in a mixture of toluene and 1-bromoperfluorooctane to 50 °C for 5-12 h, as exemplified in eq. 5.10 for the synthesis of cyclo-octeneoxide 34. The ruthenium was held back almost quantitatively in the fluorous phase and could be separated after cooling to 0°C and reused several times. 

The vinylogous Pummerer reaction of an amido-substituted sulfoxide produces the tetrahydroisoquinoline (Equation 62) <1995JOC7082>. Benzoyltetrahydroisoquinolinones have also been synthesized under Pummerer-type conditions on polymer support <2005H(65)1881>. Additional later examples highlighted the same reaction incorporating a fluorous-phase cyclative-capture method <2005AGE452>. 

Fluorous biphase reactions have been reviewed extensively in the past few years, and most important types of reaction may now be conducted under fluorous conditions [46,51], However, partitioning of catalysts and reagents into the fluorous phase is seldom perfect - even a loss of 1-2% of an expensive catalyst may be unacceptable. Solubility and partitioning between phases relies on a complex balance of properties and interactions, and rather than simply adding more fluorocarbon chains to a catalyst (which is a common approach to the problem of leaching of catalyst from the fluorous phase), studies have indicated that the partition coefficients of fluorous compounds may better be optimised by... 

With < 1 mol% MTO cyclobutanones are fully converted within one hour. Another approach consists of the use of a fluorous Sn-catalyst under biphasic conditions [245]. A perfluorinated tin(IV) compound, Sn[NS02C8F17]4, was recently shown to be a highly effective catalyst for BV oxidations of cyclic ketones with 35% hydrogen peroxide in a fluorous biphasic system (Fig. 4.83). The catalyst, which resides in the fluorous phase, could be easily recycled without loss of activity. 

Fluorous biphasic catalysis exploits not only this principle, but also the ability of certain perfluo-rocarbon/hydrocarbon biphasic mixtures to form a homogenous solution at high temperatures. An extremely fluorinated catalyst can thus be applied under homogeneous conditions and recovered from the fluorous phase subsequent to a phase separation step at lower temperatures. 

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