Fluorous isolation tags

Scheme 21.15 Synthesis of radicicol A and analogues using fluorous isolation tags (Winssinger et ai.).

Figure 7.11 Use of fluorous reagents/tags in synthesis to aid in product isolation.

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]. 

The time consuming chromatographical purification of heterocycles 28 and 29 slowed down the rate of library production. A phase separation using fluorous chemistry was employed by Zhang and Lu to address the workup and purification of fused 3-aminoimidazo[ l,2-a]pyridines (such as 30) [54]. Thus, attachment of a perfluorooctanesulfonyl tag to aldehydes and subsequent Ugi three-component microwave-assisted condensations with 2-aminopyridines and isocyanides furnished the desired heterocycles 30, which were conveniently isolated by fluorous solid-phase extraction. The fluorous tag could be subsequently used as an activating group in the post-condensation modifications, such as Suzuki-Miyaura cross-coupling reactions. 

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. 

Procter developed the new, fluorous-tagged chiral auxiliary 17 for the asymmetric, Sml2-mediated coupling of aldehydes and ogp-unsaturated esters.46 y-Butyrolactones are obtained in moderate to good isolated yield and in high enantiomeric excess. The fluorous tag allows the auxiliary to be conveniently recovered by fluorous solid-phase extraction (FSPE) and reused (Scheme 7.12). 

A perfluoro-tagged tert-butyloxycarbonyl group ( Boc) has been used for the protection of primary amino functions in the synthesis of a small amide library [29]. The Boc-protected amino acids were coupled wifh primary or secondary amines. The products were purified by preparative fluorous HPLC. After deprotection by add treatment, the products were isolated by conventional extractive work-up. 

Some syntheses using intermediates with ionic-liquid tags have been reported, but they are not as versatile as solid or fluorous supports. The tagged intermediates and products are often isolated by precipitation and an advantage of ionic liquids is that the affinity and solubility of the tagged compounds can be altered by exchange of the associated anion. 

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 same technique was also applied to the synthesis of a 10-member Ugi 4CC-derived solution library, where the fluorous tag was embedded into the carboxylic acid structure. The synthesis of the tag and the library synthetic scheme are shown in Figure 18. The tag was derived from a bromosilyl perfluorinated compound (CI0F21CH2CH2 rather than C6F)3CH2CH2 as for the isoxazolines) reacted with an orthothiobenzoate [102] and further elaborated with trivial chemistry. The library was produced using classical Ugi 4CC conditions, and the tag detachment was obtained via treatment with TBAF. The partition process into the triphasic system allowed the isolation of pure compounds (>85% HPLC) in good yields (average 70%). 

One early example of microwave-assisted fluorous synthesis involved palladium-catalyzed Stifle couplings of fluorous tin reagents with aryl halides or triflates (Scheme 16.59) [90]. The desired biaryl products were isolated in good yields and purity after a three-phase extraction. Similar results were also achieved by use of so-called F-21 fluorous tags (CFl2CFl2CioF2i) on the tin reagent [91]. 

In a simple view, both heavy and light fluorous molecules can be divided into an organic domain that controls the reaction chemistry and a fluorous domain that controls the separation chemistry. This view coincides with the principles of strategy level separations, which dictate that reactions should be purified only by simple workup-level procedures whenever possible. In the ideal separation, the target products of a reaction partitions into a phase that is different from all of the other reaction components, thereby allowing rapid and in many cases environment friendly isolation. The fluorous ponytails (permanent domains) or tags (temporary domains) on both heavy and light fluorous molecules allow them to partition into a fluorous phase under suitable workup conditions. 

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