Reaction combinatorial synthesis

Combinatorial electrochemical synthesis is defined as a method in which very large numbers of compounds are synthesized as ensembles (libraries) by combining a small number of building blocks together in all combinations defined by an electrochemical reaction. Combinatorial synthesis enables diversity oriented synthesis. If two building blocks (A and B) are combined by an electrochemical reaction and three different types of A and three different types of B are used, nine (3 x 3) different products (A-B) are produced. 100 types of each building block will yield 100 x 100 = 10,000 products. Use of such products as substrate for the next reaction leads to formation of a large number of compounds as chemical libraries. Combinatorial... 

Combinatorial chemistry has significantly increased the nurnjjers of molecules that can be synthesised in a modern chemical laboratory. The classic approach to combinatorial synthesis involves the use of a solid support (e.g. polystyrene beads) together with a scheme called split-mix. Solid-phase chemistry is particularly appealing because it permits excess reagent to be used, so ensuring that the reaction proceeds to completion. The excess... 

Memfield s concept of a solid phase method for peptide synthesis and his devel opment of methods for carrying it out set the stage for an entirely new way to do chem ical reactions Solid phase synthesis has been extended to include numerous other classes of compounds and has helped spawn a whole new field called combinatorial chemistry Combinatorial synthesis allows a chemist using solid phase techniques to prepare hun dreds of related compounds (called libraries) at a time It is one of the most active areas of organic synthesis especially m the pharmaceutical industry... 

The Biginelli reaction has also been extended to solid phase and combinatorial synthesis. In a recent combinatorial approach Kappe and coworkers used 4-chloroacetoacetate as a building block to create a library of diverse DHPMs under... 

The synthesis of imidazoles is another reaction where the assistance of microwaves has been intensely investigated. Apart from the first synthesis described since 1995 [40-42], recently a combinatorial synthesis of 2,4,5-trisubstituted and 1,2,4,5-tetrasubstituted imidazoles has been described on inorganic solid support imder solvent-free conditions [43]. Different aldehydes and 1,2 dicarbonyl compounds 42 (mainly benzil and analogues) were reacted in the presence of ammonium acetate to give the trisubstituted ring 43. When a primary amine was added to the mixture, the tetrasubstituted imidazoles were obtained (Scheme 13). The reaction was done by adsorption of the reagent on a solid support, such as silica gel, alumina, montmorillonite KIO, bentonite or alumina followed by microwave irradiation for 20 min in an open vial (multimode reactor). The authors observed that when a non-acid support was used, addition of acetic acid was necessary to obtain good yields of the products. 

The condensation between enaminones and cyanoacetamide is a well-established method for the synthesis of 2-pyridones (see c, Scheme 2, Sect. 2.1), and the use of malonodinitrile instead of the amide component has also been shown to yield 2-pyridones [39-41]. Recently, Gorobets et al. developed a microwave-assisted modification of this reaction suitable for combinatorial synthesis, as they set out to synthesize a small library of compounds containing a 2-pyridone scaffold substituted at the 3, 5, and 6-positions [42]. The 2-pyridones were prepared by a three-component, two-step reaction where eight different carbonyl building blocks were reacted with N,N-dimethylformamide dimethyl acetal (DMFDMA) to yield enaminones 7 (Fig. 2). The reactions were performed under solvent-free conditions at el-... 

For another investigation, amide formation was used as a model reaction to demonstrate the performance of parallel processing in micro-channel devices [23]. The target of such processing is combinatorial synthesis, the provision of multiple substances within one run. 

OS 30] ]R 30] [P 22] The synthesis of nine C-C bonded products was made from four carbamates and five silyl enol ethers [66, 67]. Conversions ranged from 49 to 69% the corresponding selectivities ranged from 67 to 100%. Similar performance was achieved when serially processing the same reactions (see Serial combinatorial synthesis). 

Liquid- and Liquid/Liquid-phase Reactions Serial combinatorial synthesis... 

Much attention has recently been focused on organoboronic acids and their esters because of their practical usefulness for synthetic organic reactions including asymmetric synthesis, combinatorial synthesis, and polymer synthesis [1, 3, 7-9], molecular recognition such as host-guest compounds [10], and neutron capture therapy in treatment of malignant melanoma and brain tumor ]11]. New synthetic procedures reviewed in this article wiU serve to find further appHcations of organoboron compounds. 

Another kind of combinatorial synthesis can be applied to reactions that assemble the product from several components in a single step, a multicomponent reaction. A particularly interesting four-component reaction is the Ugi reaction, which generates dipeptides from an isocyanide, an aldehyde, an amine, and a carboxylic acid. 

Fig. 4 Combinatorial synthesis of coumarin library using Pd-mediated cross-coupling reaction and 3D scatter plot of representative coumarin derivatives according to their excitation, emission wavelength, and quantum yield. All the photophysical properties were measured in ethanol...

Fig. 5 Combinatorial synthesis of triazolylcoumarin library using Cu(I)-catalyzed 1,3-dipolar cycloaddition reaction. Each letter represents the relative fluorescence intensities H High, M Middle, L Low. The excitation and emission spectra were recorded in DMF. Reproduced with permission from reference [45]... 

Biologically important arylamines, various kinds of heterocycles, and macrocyclic compounds have been prepared by using resin-bound nitro halo compounds via SNAr reactions. Such a process is very important for combinatorial synthesis of biologically important compounds. Typical examples are presented in Eqs. 9.13—9.21,22-31... 

The bottleneck of conventional parallel/combinatorial synthesis is typically optimization of reaction conditions to afford the desired products in suitable yields and purities. Since many reaction sequences require at least one or more heating steps for extended time periods, these optimizations are often difficult and time-consum-... 

A similar strategy has been used for the Biginelli condensation reaction to synthesize a set of pyrimidinones (65-95%) in a household MW oven [152]. This MW approach has been successfully applied to combinatorial synthesis [153]. Yet another example is the convenient synthesis of pyrroles (60-72 %) on silica gel using readily available enones, amines and nitro compounds [154]. 

One of the cornerstones of combinatorial synthesis has been the development of solid-phase organic synthesis (SPOS) based on the original Merrifield method for peptide preparation [19]. Because transformations on insoluble polymer supports should enable chemical reactions to be driven to completion and enable simple product purification by filtration, combinatorial chemistry has been primarily performed by SPOS [19-23], Nonetheless, solid-phase synthesis has several shortcomings, because of the nature of heterogeneous reaction conditions. Nonlinear kinetic behavior, slow reaction, solvation problems, and degradation of the polymer support, because of the long reactions, are some of the problems typically experienced in SPOS. It is, therefore, not surprising that the first applications of microwave-assisted solid-phase synthesis were reported as early 1992 [24],... 

The first use of room temperature ionic liquids as potential novel soluble phases for combinatorial synthesis has recently been described. As model reaction the Knoevenagel condensation of salicyl aldehyde grafted on to an imidazolium-derived ionic liquid was studied under the action of microwave irradiation (Scheme 12.19) [66]. Reactions were performed without additional solvent in the presence of a basic catalyst, utilizing microwave irradiation in a designated monomode microwave reac-... 

Applications of the cross-metathesis reaction in more diverse areas of organic chemistry are beginning to appear in the literature. For example, the use of alkene metathesis in solution-phase combinatorial synthesis was recently reported by Boger and co-workers [45]. They assembled a chemical library of 600 compounds 27 (including cisttrans isomers) in which the final reaction was the metathesis of a mixture of 24 oo-alkene carboxamides 26 (prepared from six ami-nodiacetamides, with differing amide groups, each functionalised with four to-alkene carboxylic acids) (Eq.27). 

An intramolecular Heck cyclization strategy was developed for the construction of indole and benzofuran rings on solid support [82], enabling rapid generation of small-molecular libraries by simultaneous parallel or combinatorial synthesis. Sn2 displacement of resin-bound y-bromocrotonyl amide 97 with o-iodophenol 96 afforded the cyclization precursor 98. A subsequent intramolecular Heck reaction using Jeffery s ligand-free conditions furnished, after double bond tautomerization, the resin-bound benzofurans, which were then cleaved with 30% TFA in CH2CI2 to deliver the desired benzofuran derivatives 99 in excellent yields and purity. 

The cation pool method serves as a powerful tool for parallel combinatorial synthesis.25 Required for successful combinatorial synthesis are reactions of high generality to couple any desired combination of molecules we want. The cation pool method seems to be suitable for this purpose, because organic cations generated by this method are usually so highly reactive as to couple with a wide range of nucleophiles. 

Palladium-catalyzed coupling reactions are very efficient for the introduction of new carbon- carbon bonds onto molecules attached to solid support. The mild reaction conditions and compatibility with a broad range of functionalities and high reaction yields, have made this kind of transformation a very common tool for the combinatorial synthesis of small organic molecules. The literature for synthetic methods of palladium-catalyzed reactions on solid supports has recently been reviewed [237-239]. 

---