Fluorous tags

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-... 

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-... 

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. 

Despite the lack of solubility of 15 in fluorocarbon solvents, the huge retention differences between organic compounds (solvent front) and fluorous-tagged compounds (>30 min for the longer tags) translate into simple separations by solid... 

Although the imidazolidinone catalysts used within these transformations are simple, cheap, readily accessible and in some cases recyclable using acid/base extraction, considerable efforts have been made to examine alternative methods to separate and recycle the catalyst with good success. Examination of the structure of imidazolidinone 22 shows two convenient points for the introduction of a polymer or fluorous support, R and R, both of which have been examined (Fig. 4). Curran has shown that identical reactivity, diastereoselectivity and enantioselectivity can be obtained using a fluorous tag (23) [53]. The catalyst can easily be recovered and recycled using F-SPE with excellent yield, purity and levels of activity. Polymer- (24) and silica-supported (25) imidazolidinones reported by Pihko [54] (R substitution)... 

Several years ago, Professor Hoveyda designed the chelated Ru complex 12a as a versatile and stable metathesis catalyst. Dennis P. Curran of the University of Pittsburgh has now introduced (J. Org. Chem. 2005, 70, 1636) the fluorous-tagged Ru catalyst 12b. The fluorous tag allows the facile recovery of most of the active catalyst. The advantages of this are two-fold the valuable catalyst can be re-used, and there will potentially be less Ru contamination in the cyclized product. 

For a practical transesterification reaction, next to high yields, an equimolar ratio of the reactants is desirable. The catalyst should be neutral and easily separable, and no special technology for alcohol removal should be needed [11]. These requirements are fulfilled by the fluorous tagged distannoxane catalyst 6. Transesterification yields are quantitative and the FC-72 solution (FC-72 and FC-75 are commercially available mixtures of perfluoroalkanes) of the catalyst can be reused. 

Fig. 1. Fluorous biphasic catalysis part I hydroformylation, hydro-boration, and transesterification with fluorous tagged catalysts.

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