Fluorous triphasic reactions

Fluorous reactions in supercritical carbon dioxide (SCCO2) and fluorous triphasic reactions... 

Fluorous biphasic and triphasic reactions are at once similar and different. Like fluorous biphasic reactions (see Section 3.3), fluorous triphasic reactions use a fluorous reaction solvent. However, whereas biphasic reactions use heavy fluorous molecules, triphasic reactions use light fluorous molecules or sometimes no fluorous molecules at all. The reaction and separation occur simultaneously in triphasic reactions. Indeed, the reaction drives the separation in most triphasic processes, whereas a separation follows a reaction in biphasic methods. 

Triphasic reactions. For example, fluorous-organic-aqueous phases or two organic phases separated by a fluorous phase in a U-tube reaction flask. ... 

The use of a triphasic extraction system, where an organic solvent, an aqueous phase and FC-72 [163] were used, allowed after any reaction step the isolation of the pure intermediates and eventually of the clean reaction products. The switch caused by the fluorous tag allowed the total partition of the library intermediates in the fluorous phase, where any other component of the reaction mixture was not dissolved, while after final deprotection the products were cleanly recovered from the organic phase and the tag moiety remained trapped by the fluorous phase. The eight isoxazoline alcohols were recovered with extremely high GC purities (> 91 %, average > 95%) and with moderate to good yields (from 29% to 99%). The low yields were probably due to the volatility of some of the final products. 

The synthesis of array L7 is reported in Fig. 8.22. Compound 8.38 was reacted simultaneously with amines (Mi, two representatives), aldehydes (Mi, five representatives), and isonitriles (Ms, two representatives) to give 10 compounds (not all the combinations were reacted). The reaction was performed in trifluoroethanol (TFE), another hybrid fluorous-organic solvent (step a. Fig. 8.22), and after evaporation of the TFE, the crude product 8.39 was purified by two-phase extraction between fluorous solvents and benzene (step b). After evaporation of the solvent, the fluorous tag was cleaved with TBAF (step c) and a triphasic extraction (step d, Eig. 8.22) was performed to remove the fluorosilane tag and acid 8.38-related impurities extracted into the fluorous layer. Excess TBAE and TBAE-related impurities partitioned into the acidic aqueous layer. Yields and purities of the synthetic protocol are reported together with the structures of the library members L7a-j in Table 8.2. 

After removal of the solvent, the silyl tag was cleaved (step e) and the final triphasic extraction (step b, Fig. 8.23) gave the array L8 in the organic phase, removing TBAF-related impurities and the fluorous tag by extraction into the aqueous and fluorous phases, respectively. Yields and purities are reported together with the structures of the library individuals L8a-j in Table 8.3. A few compounds were obtained as mixtures, probably due to lower reactivity of corresponding monomers and occurrence of side reactions. 

Another recent addition to the fluorous biphase toolbox is the discovery of fluorous phase transfer catalysts for halide substitution reactions in aqueous-fluorous systems.This class of reactions is academically intriguing, as an ionic displacement reaction has taken place in one of the least polar solvents known. They make use of fluorous phosphonium salts under biphasic conditions but can also make use of non-fluorous phosphonium salts in a triphasic system. Further information and reactions using such systems will no doubt be reported in the next few years. 

The use of a triphasic extraction system, where an organic solvent, an aqueous phase, and FC-72 [101] were used, allowed after any reaction step the isolation of the pure intermediates and eventually of the clean reaction products. The switch caused by the fluorous tag allowed the total partition of the library intermediates in the fluorous phase, where any other component of the reaction... 

The Ru-catalyzed epoxidation of tran -stilbene in the presence of NaI04 was carried out using a bipyridyl ligand with a fluorous ponytail at the 4 and 4 positions. As illustrated by the first equation in Scheme 8, a triphasic system comprising water, dichloromethane and perfluorooctane was employed in the reaction. The reaction was complete in 15 min at 0°C and tran -stilbene oxide 5 was obtained from the dichloromethane layer in a 92% yield. The fluorous layer, containing the catalyst, could be recycled for four further runs without any addition of RuCls. The same perfluoroalkyl-substituted bipyridyl ligand was used successfully in the copper(i)-catalyzed TEMPO (2,2, 6,6 -tetramethylpiperidine (V-oxyl)-oxidation of primary and secondary alcohols under aerobic conditions (Scheme 8, second equation). ... 

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