Fluorous-Tagged Aldehyde

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. 

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). 

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. 

A copper catalysed click (azide-alkyne cycloaddition) reaction has been used to prepare a fluorous-tagged TEMPO catalyst (Figure 7.20). TEMPO is a stable organic free radical that can be used in a range of processes. In this case, its use in metal-free catalytic oxidation of primary alcohols to aldehydes using bleach as the terminal oxidant was demonstrated. The modified TEMPO can be sequestered at the end of the reaction on silica gel 60 and then released using ethyl acetate for reuse in further reactions in this way the TEMPO was used four times with no loss in activity. 

Ladlow and coworkers have reported the use of fluorous-tagged aldehydes as a protecting group in the synthesis of a library of sulfonamides. The F-aldehyde was prepared via a simple alkylation of 4-hydroxy-2-meoxybanzaldehyde with a perfluo-roalkyl halide. The authors have protected various primary amines with the F-aldehyde followed by reduction, sulfonylation and Suzuki coupling and acid-mediated deprotection. Filtration via a fluorous SPE (solid phase extraction) was... 

A similar oxidative protocol has been used for the oxidation of (fluoroalkyl)alkanols, Rf(CH2) CH20H, to the respective aldehydes [146], in the one-pot selective oxidation/olefination of primary alcohols using the PhI(OAc)2-TEMPO system and stabilized phosphorus ylides [147] and in the chemo-enzymatic oxidation-hydrocyanation of 7,8-unsaturated alcohols [148]. Other [bis(acyloxy)iodo]arenes can be used instead of PhI(OAc)2 in the TEMPO-catalyzed oxidations, in particular the recyclable monomeric and the polymer-supported hypervalent iodine reagents (Chapter 5). Further modifications of this method include the use of polymer-supported TEMPO [151], fluorous-tagged TEMPO [152,153], ion-supported TEMPO [154] and TEMPO immobilized on silica [148],... 

The 1,2,3-triazole-linked fluorous proline organocatalyst 32 was introduced by Pericas and coworkers in 2013 for the asymmetric aldol reactions of acetone with aromatic aldehydes, giving higher enantioselectivities than other proline derivatives (Scheme 11.27). ° The fluorous tag and the use of a per-fluorinated solvent allowed the easy recycling and reuse of 32, for at least six times. 

Fluorous tags can be attached to DABCO via halogen bonding for example, two moles of perfluoroctyl iodide yields a supramolecular fluorous catalyst (76). It allows MBH reactions of aldehydes and simple Michael acceptors to be complete in a day or two at ambient temperature, without solvent (except two equivalents of methanol), and is easily recovered/recycled by flltration. ... 

Later on, a fluorous organocatalyst 27 with a perfluorooctyl propanoxyl group on the aromatic ring was prepared from i-tyrosine by the same group (Scheme 7.26) [41]. It efficiently catalyzed the direct aldol reaction of aromatic aldehydes with cyclohexanone. In accordance with previous results, catalyst 27 showed higher efficiency than its non-fluorinated analog which is probably because the fluorous tag created a hydrophobic reaction field in brine. The catalyst 27 was easily recovered with FSG extraction and reused without further purification. 

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