Fluorous chromatography

Fig. 32 Fluorous mixture synthesis of fused-tricyclic hydantoins. Reagents and conditions a Mo(CO)6, DMSO, toluene, MW 150 °C, 35 min, closed system b TFA CH2CI2 (1 1), rt c PhC2H4NH2, PyBOP, i-Pr2EtN, MeOH, CH2CI2 followed by flash chromatography and F-HPLC d i-Pr2EtN, MeOH, MW 140 °C, 40 min, followed by F-SPE...

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. 

Parallel synthesis of a bicyclic proline library 29 has been developed by a two-step synthesis involving 1,3-dipolar cycloaddition of fluorous benzalde-hydes followed by Pd-catalyzed Suzuki coupling reactions with boronic acids (Scheme 20) [43]. Both reactions were conducted under microwave irradiation and the reaction mixtures were purified by F-SPE without the need of performing a following chromatography. 

An important part of fluorous synthesis is related to the development of fluorous linkers for chromatography-free purifications. In discovery and medicinal chemistry labs, a major task is to synthesize small-scale but large numbers of compounds ... 

In addition to fluorous solvents and ionie liquids, supercritical fluids sc-fluids, scf s), sueh as supercritical carbon dioxide (se-C02), constitute a third class of neoteric solvents that can be used as reaction media. Although sc-fluids have been known for a long time and have been advantageously used as eluants in extraction and chromatography processes (see Sections A.6 and A.7 in the Appendix), their application as reaction media for chemical processes has become more popular only during the last decade. Some of their physical properties and the supercritical conditions necessary for their existence have already been described in Section 3.2 (see Figure 3-2 and Table 3-4) see also references [209, 211-220, 224-230] to Chapter 3 for reviews on sc-fluids and their applications (particularly for SC-CO2 and SC-H2O). 

Intermediates as well as end products can be purified by reverse- or straight-phase fluorous chromatography as well as by ordinary chromatographic methods. 

Several fluorous counterparts of common reagents have been reported and many of these are also commercially available. Of some interest is the development of fluorous Mitsunobu reagents. A first generation fluorous DEAD reagent was found to have poor reactivity when difficult Mitsunobu reactions were encountered it has since been replaced with two enhanced, second-generation reagents, (1) and (2), for use in parallel or sequential fluorous chromatography and rapid F-SPE isolation, respectively. 

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