Fluorous tagging

In fluorous synthesis, the possibility for separation on a fluorous solid phase allows for reduction of the fluorine content in the tags. Fluorous resins offer a way to confront the high molecular weight problem resulting from fluorous tagging and therefore the problem of atom economy in fluorous-phase chemistry. 

As an alternative to the use of fluorous tag, fluorous aqueous biphasic systems have also been explored. Recently, fluorous biphasic system composed of fluorous Lewis acid ytterbium perfluorooctanesulfonate [Yb(OPf)3], fluorous solvent perfluorocarbon has been used in the synthesis of benzodiazepines from OPD and carbonyl compounds [127]. Conceptually, the fluorous catalyst with perfluoroalkylated tails can dissolve into the fluorous phase containing the product after the reaction. The study has been extended later to the use of fluorous aqueous emulsion expecting that the organic substrate will remain in the interfacial area between a fluorous phase and aqueous media. Thus another synthesis of benzodiazepines has been reported by the same group by carrying out the reaction in a fluorous aqueous emulsion system composed of perfluorooctane and potassium perfluorooctanesulfonate at room temperature (Scheme 38) [128]. Moreover, the emulsion could be recovered and recycled without significant loss of activity. 

Scheme 7.79 Generation of dihydropteridinones by cyclative cleavage from a fluorous tag.

The described fluorous-tag strategy has also been applied to the synthesis of biaryl-substituted hydantoins (Scheme 7.81) [94]. 4-Hydroxybenzaldehyde was converted into the corresponding perfluorinated species, which was then subjected to a reductive amination. The resulting amine was treated with an isocyanate to produce the fluorous-tagged urea, which spontaneously cyclized to form the corresponding hydantoin. Finally, the fluorous tag was detached by a Suzuki-type carbon-carbon bond formation to furnish the desired target structure in good yield. 

In a related approach from the same laboratory, the perfluorooctylsulfonyl tag was employed in a traceless strategy for the deoxygenation of phenols (Scheme 7.82) [94], These reactions were carried out in a toluene/acetone/water (4 4 1) solvent mixture, utilizing 5 equivalents of formic acid and potassium carbonate/[l,T-bis(diphe-nylphosphino)ferrocene]dichloropalladium(II) [Pd(dppf)Cl2] as the catalytic system. After 20 min of irradiation, the reaction mixture was subjected to fluorous solid-phase extraction (F-S PE) to afford the desired products in high yields. This new traceless fluorous tag has also been employed in the synthesis of pyrimidines and hydantoins. 

Scheme 7.83 Suzuki reactions utilizing fluorous-tagged acid-labile protecting groups.

For this purpose, perfluorooctanesulfonyl-tagged benzaldehydes were reacted with 1.1 equivalents of a 2-aminopyridine (or 2-aminopyrazine), 1.2 equivalents of an isonitrile, and a catalytic amount of scandium(III) triflate [Sc(OTf)3] under micro-wave irradiation in a mixture of dichloromethane and methanol (Scheme 7.85). A ramp time of 2 min was employed to achieve the pre-set temperature, and then the reaction mixture was maintained at the final temperature for a further 10 min. The fluorous tag constitutes a multifunctional tool in this reaction, protecting the phenol in the condensation step, being the phase tag for purification, and serving as an acti-... 

Fluorous ligands introduce an ease of purification in that the tagged phosphine ligand, the palladium catalyst complexed ligand, and the oxidized ligand can be completely removed by direct fluorous solid-phase separation (F-SPE) prior to product isolation. Similarly, an example of a fluorous palladium-catalyzed microwave-induced synthesis of aryl sulfides has been reported, whereby the product purification was aided by fluorous solid-phase extraction [91]. 

Among the many applications of fluorous chemistry is the Stille coupling of tin reagents with fluorinated tags in which the products and excess of the tin-containing reagents can be conveniently removed from the reaction mixture, and recycled. Un-... 

Curran DP, Luo ZY (1999) Fluorous Synthesis with Fewer Fluorines (Light Flu-orous Synthesis) Separation of Tagged from Untagged Products by Solid-Phase Extraction with Fluorous Reverse-Phase Silica Gel. J Am Chem Soc 121 9069-9072... 

De Visser PC, van Helden M, Filippov DV, van der Marel GA, Drijfhout JW, van Boom JH, Noort D, Overkleeft HS (2003) A novel, Base-Labile Fluorous Amine Protecting Group Synthesis and Use as a Tag in the Purification of Synthetic Peptides. Tetrahedron Lett 44 9013-9016... 

Finally - and perhaps most importantly - the fluorous tagging of the catalyst that introduces affinity for the fluorous phase can be a very mild immobilization technique, as there is no direct covalent link with a support and the sepa-... 

Concept Organic molecules can be rendered fluorous111 by attachment of a suitable highly fluorinated domain ("F" in the graphic below). The resulting fluorous-tagged molecules resemble their organic parents in terms of reactivity, yet they can readily be sepa-... 

Organic compounds can be rendered soluble in fluorous solvents by attaching them to highly fluorinated tags, and some representative fluorous molecules are shown in Figure 1. The tags are often long... 

Fluorous compounds with removable (temporary) fluorinated domains (tags) ... 

A = the organic domain F = the fluorinated domain Figure 2. The size of the fluorous tag "F"... 

Reducing the number of fluorines on the fluorous tag also provides a general solution to the reaction solvent problem as the number of fluorines is reduced, the solubility in organic solvents tends to go up. Of course, the solubility in fluorous solvents tends to go down at the same time, and the residual tag must strike a balance between too many fluorines (low solubility in organic solvents) and too few fluorines (cannot easily be separated from organic compounds). However, thanks to the technique of fluorous solid-liquid extraction, there is surprisingly broad latitude here. 

The first demonstration of fluorous synthesis was in the preparation of small (8-12 members) isoxazo-line and isoxazole libraries by the three-step procedure outlined in Figure 8.1461 All reactions were purified by three-phase liquid-liquid extraction. The starting substrates were simple allylic alcohols which were tagged with the fluorous silyl halide 5 to make substrates 6 for an ensuing dipolar cycloaddition. This was conducted by the Mukaiyama method with a large excess of nitro compound and... 

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