Fluorous Suzuki coupling

Fig. 41 Representative example of microwave-assisted Suzuki couplings in fluorous phase. Reagents and conditions [Pd(dppf)Cl2], K2CO3, toluene/acetone/H20, MW 130°C, 10 min, closed system, 78%...

R3 R1 HN rS fluorous Suzuki C-C or fluorous thiol C-S cross-coupling R1 R3 HN R2... 

The palladium nanoparticle is prepared from the reaction of the stabilizer, 4,4 -bis(perfluorooctyl)dibenzylideneacetone with palladium(II) chloride. The average size of the nanoparticle varied according the ratio of PdCF to the stabilizer, but was typically around 4 or 5 nm. The initial yield observed in the Suzuki coupling reaction was 90%, but decreased to 78% after five consecutive runs. Fluorous boronates (alternative precursors in Suzuki reactions), have also been developed for use in fluorous biphasic processes [12], A generic structure of a fluorous boronate is shown in Figure 10.2. 

Applications of this technique include peptide hydrolysis101, peptide coupling102, Suzuki couplings, Stille coupling63 103 104, parallel synthesis of 1,3,5-triazines105 and fluorous Stille coupling106. 

Parallel synthesis of a bicyclic proline library 29 has been developed by a two-step synthesis involving 1,3-dipolar cycloaddition of fluorous benzalde-hydes followed by Pd-catalyzed Suzuki coupling reactions with boronic acids (Scheme 20) [43]. Both reactions were conducted under microwave irradiation and the reaction mixtures were purified by F-SPE without the need of performing a following chromatography. 

Ladlow and coworkers recently developed an acid-labile fluorous benz-aldehyde protecting group 43 to facilitate the parallel synthesis of sulfonamides 44 (Scheme 25) [56]. The Suzuki coupling reaction was conducted under microwave irradiation. All the intermediates and the final products were purified by F-SPE. 

The successful demonstration of the fluorous biphasic concept for performing organometallic catalysis sparked extensive interest in the methodology and it has subsequently been applied to a wide variety of catalytic reactions, including hydrogenation [59], Heck and Suzuki couplings [60, 61] and polymerizations [62]. The publication of a special Symposium in print devoted to the subject [63] attests to the broad interest in this area. 

Zhang, W. and Chen, C.H.-T. 2005. Fluorous synthesis of biaryl-substituted prolines by 1,3-dipolar cycloaddition and Suzuki coupling reactions. Tetrahedron Letters, 46 1807-10. 

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... 

Fluorous Suzuki C-C or Fluorous Thiol C-S Cross Coupling... 

Bannwarth and co-workers have recently developed new protocols for the separation and recycling of perfluoro-tagged catalysts without the need for fluorous solvents [25]. They have employed Pd complexes 11c, lid, and 17, immobilized by adsorption on fluorous reversed-phase silica gels (FRPSG) 18 and 19, and demonstrated the application to Suzuki couplings in organic solvents. Coarse-grained... 

Water-soluble calix[n]arenes are powerful receptors for non-polar substrates in aqueous solution. These compounds are promising candidates as carrier molecules for the transport of non-polar substrates through bulk water as well as inverse phase-transfer catalysts, as proven for the Suzuki coupling of iodobenzene with phenyl boronic acid [91]. 1.5-bis(4,4 -bis(perfluorooctyl)penta-l,4-dien-3-one (39) stabilizes palladium 0) nanoparticles (transmission electron microscopy) formed in the reduction of palladium dichloride with methanol. These palladium colloids are soluble in perfluorinated solvents, and they are efficient recoverable catalysts for Suzuki crosscoupling under fluorous biphasic conditions (Equation 69) [92]. 

Cyclohexyl Isocyanide Several methods are available for the synthesis of cyclohexyl isocyanide. However, it can be readily prepared from the corresponding formamide in the presence of POCI3 or cyanuric chloride [98]. It is a colorless liquid having an offensive odor. Although cyclohexyl isocyanide (Izc) has been known for several years and commercially available, traditionally it has been used as a NCIC in MCRs. Recently, Yan and coworkers have reported that Izc can be used as a CIC in the presence of TFA in methanol under MWI. They employed this methodology for their fluorous synthesis of 1,4-BDZs 270 (Scheme 7.85), which can be further modified via the Suzuki coupling to obtain 272 [99]. Deprotection of cyclohexylamine has also been observed in the presence of Lewis acids [96]. 

A fluorous nano-paUadium catalyst based on pyrrolidine imide 22 was developed for the Suzuki coupling reaction (Scheme 7.12) [21]. The catalyst 22 promoted the coupling of aryl boronic acid and aryl halide with high yield, and the catalyst was recovered by fluorous liquid-liquid extraction and reused for three times. This fluorous nano-paUadium catalyst 22 was also employed in the Heck reaction in water [22]. The catalyst was recovered by fluorous liquid-liquid phase separation and reused for four times with Utde loss of catalytic activity. 

A fluorous paUadium-NHC complex 23 was developed for the Suzuki coupling reaction [28]. The catalyst could be recovered and reused without observable loss of catalytic activity, but a mixture of the solvents hexafluorobenzene and ethanol was found to give the best results. 

Further examples of microwave-assisted Suzuki cross-couplings involving supported substrates/catalysts or fluorous-phase reaction conditions are described in Chapter 7. 

Scheme 7.80 Fluorous phase Suzuki-type couplings.

To date, reports have involved palladium catalysts for Suzuki and Sono-gashira coupling reactions [63-66], rhodium catalysts for silylations of alcohols by trialkylsilanes [67,68], and tin-, hafnium-, and scandium-based Lewis acid catalysts for Baeyer-Villiger and Diels-Alder reactions [69]. Regardless of exact mechanism, this recovery strategy represents an important direction for future research and applications development. Finally, a particularly elegant protocol where CO2 pressure is used instead of temperature to desorb a fluorous rhodium hydrogenation catalyst from fluorous silica gel deserves emphasis [28]. 

Fluorous phase modifications of the Stille reaction were shown by Curran et al. to be accelerated by microwave irradiation.10 Similarly, Hallberg et al. demonstrated that such irradiation gives remarkably fast solid-phase Suzuki reactions, in the generation of biaryl units.9 Their reaction involved the coupling of a tethered (Rink amide TentaGel) aryl iodide or bromide with several boronic acids under 45 W of irradiation at 2450 MHz in sealed... 

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 same group reported on a library synthesis of 3-aminoimidazo[l,2-a]-pyridines/pyrazines by fluorous multicomponent reactions. Here the overall yields, as well as the yields for the separate Suzuki-Miyaura reactions that were a part of the synthesis, were relatively low due to competing reactions and the poor reactivities of the substrates, but the speed of the microwave-mediated syntheses and ease of separation underlined the usefulness of fluorous reagents [140]. A recent paper further illustrated the use of Suzuki-Miyaura couplings of aryl perfluorooctylsulfonates in the decoration of products derived from 1,3-dipolar cycloadditions [141]. 

Tzschucke, C.C., Marker , C., Glatz, H., and Bannwarth, W. 2002. Fluorous biphasic catalysis without perfluorinated solvents Application to Pd-mediated Suzuki and Sonogashira couplings. Angewandte Chemie International Edition, 41 4500-03. 

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