Fluorous techniques

In their original incarnations,1201 fluorous techniques were designed with the notion that fluorous solvents should be used in both the reaction stage... 

By analogy to the usual usage of solid phase synthesis , we intend "fluorous synthesis to mean techniques in which the substrate or product is fluorous. However, the term fluorous synthesis is also sometimes used more broadly to encompass essentially any fluorous technique... 

Fluorous Techniques Progress in Reaction Processing and Purification... 

Curran, D.P. and Lu, Z. 2001. Fluorous techniques for the synthesis and separation of organic molecules. Green Chemistry, 3 G3-G7. 

Zhang, W. 2009a. Green chemistry aspects of fluorous techniques—Opportunities and challenges for small-scale organic synthesis. Green Chemistry, 11 911-20. 

Curran, D., Lee, Z. Fluorous Techniques for the Synthesis and Separation of Organic Molecules, Green Chem. 2001, 3(1), G3-G7. 

Even though many of these techniques in themselves are modem, there has been an interest to develop these methods, and invent new techniques, to further increase the speed of hit identification and lead optimization. In large, and in direct application to this chapter, these efforts can be divided into techniques that increase either the speed of synthesis, such as microwave and sonochemical approaches, or the speed of separation, such as fluorous techniques. 

Even if several groups have been active in the development of fluorous techniques, many of the early, seminal papers were presented by just a few groups, most notably Horvath, Gladysz, and Curran. In the last few years several excellent reviews have... 

In the last few years fluorous combinatorial chemistry has been extended and augmented by other fluorous techniques developed by analogy with established methods in solid-phase-supported synthesis. Use of fluorous condensation reagents for the Mitsunobu reaction [23] enables easy removal of all condensation reagents except the coupled starting materials after the reaction [24] (Scheme 3.23). A fluorous variant of the Swern [25] and Corey-Kim oxidations [26] enables handling of stoichiometric quantities of malodorous dimethyl sulfide to be avoided [27] (Scheme 3.24). 

The examples on fluorous chiral phosphine ligands described above indicate that finding a chiral phosphine ligand effective for recycling it by fluorous techniques... 

Fluorous biphasic catalysis has emerged since the late 1990s as an attractive alternative to traditional catalysis methods [1], Fluorous techniques take advantage of the temperature-dependent miscibility of organic and perfluorocarbon solvents to provide easier isolation of products and recovery of a fluorinated catalyst. The large-scale use of fluorous solvents, however, has drawbacks cost, and concern over environmental persistence. 

Heavy fluorous techniques use fluorous reaction components that have a large number of fluorines. Heavy fluorous molecules can have as few as 39 fluorines, but it is not uncommon for them to have >50 or even >100. Such a high fluorine content gives heavy fluorous molecules unusual properties, and they can be separated from reaction mixtures by simple separation techniques such as extraction with a fluorinated solvent or even just filtration (see Section 3.3). However, the unusual properties that facihtate separations can complicate reactions since heavy fluorous molecules sometimes do not behave well under standard reaction conditions, and a search for suitable solvents and reaction conditions is a prerequisite. 

Tesevic and Gladysz have demonstrated the utility of [bis(trifluoroacetoxy)iodo]perfluoroalkanes C F2 +iI(OCOCF3)2 with along fluorous alkyl chain (n = 7-12) as convenient recyclable oxidants [103,104]. Similarly to [bis(trifluoroacetoxy)iodo]benzene, [bis(trifluoroacetoxy)iodo]perfluoroalkanes 116 can serve as excellent reagents for the oxidation of phenolic substrates (Scheme 5.37). The reduced form of the reagents, the respective iodoperfluoroalkanes 118, can be efficiently separated from the reaction mixture using fluorous techniques and reused. In a specific example, reagents 116 (n = 8, 10, 12) can rapidly oxidize 1,4-hydroquinones 115 to afford quinones 117 in methanol at room temperature (Scheme 5.37). Subsequent addition of a fluorous solvent, such as perfluoro(methylcyclohexane), results in a liquid/liquid biphasic system. 

Solution phase combinatorial chemistry continues to provide an important technique particularly to the medicinal chemist engaged in lead optimisation work. We anticipate that next year will see further development and application of purification technologies which will allow more complex chemistries to be employed. Although work on fluorous techniques has, currently, only been exploited by the original workers, the development of a solid phase extraction with fluorous reverse phase silica [31] and a soluble fluorous phase polymer support [32] indicates the opportunity for further innovative application of the strategy to solution phase approaches. 

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