Liquid-phase combinatorial chemistry,

While PEG-based supports are widely used for liquid-phase combinatorial chemistry, other non-PEG-based soluble polymers have also been reported for combinatorial applications. A recent review (276) contains an exhaustive list of homo- and copolym-eric soluble supports used in peptide, oligonucleotide, and oligosaccharide synthesis, including combinatorial chemistry. Two of these supports have also been used for small organic molecule synthesis. Homopolymeric polyvinyl alcohol was used in conjunction with PEG for a protection/derivatization strategy in solution (284), and the copolymer between isopropylacrylamide and acrylic acid was used in the catalytic hydrogenation of a Cbz group (285). 

Yeh and Sun have combined the advantages of microwave technology with liquid phase combinatorial chemistry to facilitate the synthesis of thioxotetrahydropyrimi-dinones [90]. The reactions were significantly accelerated. 

The advantages of MW technology combined with liquid-phase combinatorial chemistry were also successfully applied to a rapid synthesis of quinoxalin-2-ones. PEG bound o-fluoronitrobenzene 716 was synthesized by coupling of 4-fluoro-3-nitrobenzoic acid (715) with PEG 714, in the presence of DCC and a catalytic... 

Sun, C.-M., Recent advances in liquid-phase combinatorial chemistry. Comb. Chem. High Throughput... 

Although interesting with respect to diversity, liquid phase combinatorial chemistry has scarcely been tapped. An interesting example was provided by Boger and co-workers. 

The possible functionalizations during cleavage are gaining increasing importance as they add yet another dimension of diversity. When soluble supports are used, the removal of the catalyst and excess may not be as trivial. This problem may be solved by the use of immobilized palladium catalysts in association with volatile reagents. Another option, which has not yet been pursued, is to use efficient scavenger resins to sequester the catalyst. This possibility will also give some new impulses to liquid phase combinatorial chemistry. 

Bazureau et al. reported the synthesis of poly(ethyleneglycol) functionalized -ionic liquid phases as functionalized ionic liquids which are promising tools for synthetic applications in ionic-phase combinatorial chemistry [97], Moreover, several research groups have described ionic liquids with imidazolium cations carrying amino functionality. Davis et al. [98] reported for the first time a functionalized ionic liquid with NH2 group, n-propylamine-3-butylimidazohum tetrafluoroborate 18, for capturing C02 (Scheme 17). 

An extension of the combinatorial synthesis in solution is achieved by the use of soluble polymeric supports [80, 81], which combines some of the advantages of chemistry in solution and on solid phase. The so-called liquid-phase combinatorial synthesis is based on the physical properties of poly (ethylene glycol) monomethyl ether. The polymer is soluble in a variety of aqueous and organic solvents, which allows reactions to be conducted in homogeneous phase whereas the propensity to crystallize in appropriate solvents facilitates the isolation and purification of the compound at each step of the combinatorial synthesis. 

Potentially useful heterocyclic libraries can also be prepared by the application of solution-phase combinatorial chemistry. Although multiple reactions in solution have often been complicated by the difficulties with liquid-liquid extractions the introduction of solid scavengers and equipment to automate these extraction processes allows hundreds of reactions to be managed simultaneously. A typical example is a series of aminothiazole derivatives which has been prepared starting from acyclic precursors (Scheme 3.9). Naturally one-pot multicomponent condensations such as the Ugi (library 84) [332], Passerini or Biginelli reactions present one of the simplest... 

The concept of combinatorial chemistry is often intended as closely related, or even coincident, with solid-phase chemistry [1-5], This technique (thoroughly addressed by some chapters of this book [6-8]) has many advantages for easy and reliable combinatorial synthesis, and in fact solid-phase combinatorial libraries with different formats and sizes have been dealt with in many excellent reviews [9-11]. Nevertheless, a significant amount of combinatorial efforts have been devoted to solution techniques. The term solution has to be intended in a broader sense, meaning that the chemical steps leading to library synthesis are performed in a homogeneous liquid medium rather than at the interface between two phases as in solid-phase combinatorial chemistry. This, as the reader may easily imagine, is a fundamental difference which leads to completely different, and sometimes complementary, properties with respect to solid phase. 

When performing a synthetic combinatorial chemistry experiment, several basically different strategies may be followed to create a library of compounds. The most commonly used are mixelsplU (or split and pool) synthesis [1] masking strategies [15, 16] and parallel synthesis. In this chapter, the attention is focussed on the application of parallel synthesis to catalysis in the liquid phase. 

Janda KD, Han H, Combinatorial chemistry a liquid-phase approach, in Methods in Enzymology Combinatorial Chemistry (Ed. J.N. Abelson), pp. 234-246, 1996, Academic Press, San Diego. 

Undoubtedly, NMR is the most informative method for characterization of organic compounds. However, it has limited application in combinatorial chemistry due to several factors. NMR is a relatively insensitive and slow method, requires homogeneous samples, and consumes quite expensive deuterated solvents. Here we will discuss the most recent developments of this method that overcome the major limitations and make NMR one of the promising techniques in combinatorial chemistry. It relates to the application of NMR, not only for analyzing compounds attached to polymer support and for monitoring reactions on a solid phase, but also as a detector for liquid chromatography (LC/NMR). For the most recent review, see [10]. 

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