Extractions fluorous solid-phase

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). 

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. 

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). 

A tin hydride attached to fluorous ponytails is quite versatile in respect of easy separation of the desired products from organotin compounds. When an iodoalkene was treated with NaCNBHs in the presence of a catalytic amount of fluor-oalkyltin hydride, the desired tricyclic ketones were produced (Scheme 12.133) [240]. Application of the crude mixture to a small plug of fluorous reversed-phase silica gel enabled facile separation of the cyclic ketone obtained (fluorous solid-phase extraction, FSPE). In contrast, when tris(trimethylsilyl)silane (TTMSH) was employed as a hydride source chromatographic purification of the nonpolar and somewhat volatile products was impossible because of contamination by nonpolar silicon-containing byproducts. 

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