Fluorous Stille reactions

Compared to the previously described transition metal-catalyzed transformations in this chapter, microwave-assisted Stille reactions [74] involving organotin reagents as coupling partners are comparatively rare. A few examples describing both inter- and intramolecular Stille reactions in heterocyclic systems are summarized in Scheme 6.38 [47, 75-77]. Additional examples involving fluorous Stille reactions are described in Section 7.3. 

Stille coupling involves the use of tin reactants. Tin is both toxic and difficult to remove. In an elegant extension of the pioneering work of Horvath [59], Curran and his coworkers prepared fluorous tin reactants that facilitated Stille reactions and enabled the convenient isolation and separation of products afterwards [60], Probably owing to low solubility of fluorine-containing compounds in organic solvents, the reactions normally required about one day at 80 °C. With microwave heating, they were completed within minutes [61]. 

The efficiency of fluorous Stille coupling reactions [5 a] is enhanced by use of microwave irradiation (Scheme 8.2). The reaction proceeds in 79% yield after 2 min with DMF as the microwave-active solvent. 

Some of the disadvantages of the Stille reaction, e. g. the low reactivity of some substrates, separation difficulties in chromatography, and the toxicity of tin compounds, have been ameliorated by recent efforts to improve the procedure. Curran has, in a series of papers, reported the development of the concept of fluorous chemistry, in which the special solubility properties of perfluorinated or partly fluorinated reagents and solvents are put to good use [45]. In short, fluorinated solvents are well known for their insolubility in standard organic solvents or water. If a compound contains a sufficient number of fluorine atoms it will partition to the fluorous phase, if such a phase is present. An extraction procedure would thus give rise to a three-phase solution enabling ready separation of fluorinated from nonfluorinated compounds. 

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... 

Larhed, M. Hoshino, M. Hadida, S. Curran, D. P, Hallberg, A. Rapid Fluorous Stille Coupling Reactions Conducted under Microwave Irradiation, J. Org. Chem. 1997, 62, 5583-5587. 

Larhed M, Hoshino M, Hadida S, Curran DP, Hallberg A, Rapid fluorous Stille coupling reactions conducted under microwave irradiation, J. Org. Chem., 62 5583-5587, 1997. 

By replacing insoluble cross-linked resins with soluble polymer supports, the well-estabhshed reaction conditions of classical organic chemistry can be more readily apphed, while still fadhtating product purification. However, soluble supports suffer from the hmitation of low loading capacity. The recently introduced fluorous synthesis methodology overcomes many of the drawbacks of both the insoluble beads and the soluble polymers, but the high cost of perfluoroalkane solvents, hmitation in solvent selection, and the need for specialized reagents may hmit its apphcations. 

Among the many applications of fluorous chemistry is the Stille coupling of tin reagents with fluorinated tags in which the products and excess of the tin-containing reagents can be conveniently removed from the reaction mixture, and recycled. Un-... 

The yields for reactions of unsubstituted terminal alkenes were lower than for substituted alkenes but they were still reasonable and could be increased further by increasing the aldehyde alkene ratio. Total conversions of substrate were reported with epoxide selectivity as high as 95% in some cases. The FBC system allows for a much higher substratexatalyst ratio (1000 1) than the non-fluorous epoxidation reported (20 1) previously. Recycling the fluorous layer once showed no reduction in conversion or selectivity. 

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