Solid fluorous

Microwave and fluorous technologies have been combined in the solution phase parallel synthesis of 3-aminoimidazo[l,2-a]pyridines and -pyrazines [63]. The three-component condensation of a perfluorooctane-sulfonyl (Rfs = CgFiy) substituted benzaldehyde by microwave irradiation in a single-mode instrument at 150 °C for 10 min in CH2CI2 - MeOH in the presence of Sc(OTf)3 gave the imidazo-annulated heterocycles that could be purified by fluorous solid phase extraction (Scheme 9). Subsequent Pd-catalyzed cross-coupling reactions of the fluorous sulfonates with arylboronic acids or thiols gave biaryls or aryl sulfides, respectively, albeit it in relatively low yields. 

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. 

Furthermore, multicomponent reactions can also be performed under fluorous-phase conditions, as shown for the Ugi four-component reaction [96], To improve the efficiency of a recently reported Ugi/de-Boc/cyclization strategy, Zhang and Tempest introduced a fluorous Boc group for amine protection and carried out the Ugi multicomponent condensation under microwave irradiation (Scheme 7.84). The desired fluorous condensation products were easily separated by fluorous solid-phase extraction (F-SPE) and deprotected by treatment with trifluoroacetic acid/tet-rahydrofuran under microwave irradiation. The resulting quinoxalinones were purified by a second F-SPE to furnish the products in excellent purity. This methodology was also applied in a benzimidazole synthesis, employing benzoic acid as a substrate. 

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 utility of a new fluorine supported chiral auxiliary was established in a series of catalyzed and uncatalyzed 1,3-dipolar cycloaddition reactions with diphenylnitrone (637b) (Scheme 2.281) (797). The yields and selectivities of the cycloadducts (645a—d) compare favorably with those obtained with conventional Evans-type auxiliaries (798). Purification of the products was greatly improved by using fluorous solid phase extraction (FSPE). 

The assembly of tetrapeptide 19 that contains all possible 0-dipeptide bonds, (03-03)-, (03-02)-, and (02-03), and also a turn inducing 03-(R)-Ala-02-(R)-Val element was achieved employing a Boc-strategy (Scheme 5). A fluorous benzyl group was incorporated in the first amino acid to streamline the purification procedure by fluorous solid phase extraction (LSPE) (Lilippov et al. 2002 de Visser et al. 2003). Thus, the assembly of the fully protected tetrapeptide commenced with the construction of the first 03-03-peptide bond by applying the previously established conditions. A residence time of 3 min at 90°C provided the Boc-protected dipeptide 15 in 91% isolated yield after LSPE. Notably, the product precipitated in the collection flask, which was kept at ambient temperature, indicating the poor solubility of this class of compounds (Hessel et al. 2005). 

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. 

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. 

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. 

Systems have been developed that allow the recycling of catalysts. The first case study involved simple adsorption of proline onto silica gel [6], but the system suffered from a loss in enantioselectivity. More recently, promising results have been obtained with fluorous proline derivatives [64] used for aldol reactions the recycling of fluorous catalysts has been demonstrated using fluorous solid-liquid extraction. Solid phase-supported catalysts through covalent bonds [65] and through noncovalent interactions [66] were also used for aldol reactions. Proline and other catalysts can be recycled when ionic liquids or polyethylene glycol (PEG) were used as reaction solvents [67]. 

Seeberger and coworkers prepared synthetically useful amounts of P-peptides (0.2-0.6mmol) by using a microreactor (reactor volume = 78.3 pi). The reaction of add fluoride and the TFA salt of amino acid benzyl ester in the presence of N-methylmorpholine (NMM) at 90 °C (3 min residence time) gave the dipeptide in 92% yield (Scheme 4.19). A fluorous tag method was used for an effident synthesis of tetrapeptides. Amino acid esters having fluorous tags were used to facilitate purification by fluorous solid-phase extraction (FSPE) (Scheme 4.20). 

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). 

Zhang, W. and Curran, D.P. 2006. Synthetic applications of fluorous solid-phase extraction (F-SPE). Tetrahedron, 62 11837-65. 

Zhang and co-workers [186] reported a microwave-assisted one-pot, three-component [3-f2] cycloaddition reaction of a fluorous amino ester, an aldehyde and a maleimide to afford bicyclic prolines 135 in yields up to 94%. Fluorous solid phase extraction (F-SPE) has been used effectively to separate the product from the reaction mixture (Scheme 105). 

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