Multi-component chemistry

A set of three aldehydes, three carboxylic acids and two isonitriles (Fig. 7.11) was used for the generation of the 18-member acylamino amide library. 

Interestingly the sulphonyl chloride resin couldbe quantitatively regenerated by treatment of the by-product sulphonic acid resin with phosphorous pentachloride (PCl5) in 

DMF at room temperature. Solid-phase-mediated iso nitrile synthesis under microwave irradiation led to much faster reactions and in many cases improved yields therefore, allowing rapid access to this important class of compounds, amenable for a broad range of subsequent synthesis. 

As shown in Fig. 7.12, various aldehydes, ketones and acylating agents have been employed to generate the desired thiophene products in high yields (81-99%) and in generally good purities (70-99% as determined by HPLC). The resulting products could be purified by preparative HPLC if necessary to allow structural confirmation analysis. 

---

Kappe CO (2003) The generation of dihydropyrimidine libraries utilizing Biginelli multi-component chemistry. QSAR Comb Sci 22 630-645... 

Domling A (2002) Recent advances in isocyanide-based multi-component chemistry. Curr Opin Chem Biol 6 306-313... 

The Pictet-Spengler reaction has been combined with Ugi multi-component chemistry to construct a number of polycyclic indoles. Isonitrile derivatives prepared from tryptamine (or methyl tryptophanate), a carboxylic acid and formaldehyde condense with aminoacetaldehyde diethyl acetal. A few examples employed substituted aldehydes [352]. 

The three reactivity motifs are of particular interest in terms of multi-component chemistry as one functional group is retained after cyclization in each case (Scheme 35, highhghted in red), which are available for further transformations. Despite their advantages, alkynediones 3 have rarely been studied with respect to their reactivity and apphcation in heterocyclic synthesis, most likely due to their notoriously difficult accessibihty. 

In another report, aspects for automating preparative chemistry are described [130]. A comprehensive description of the Ugi reaction is given in [132] and the vision of a micro multi-component reaction as automated parallel micro-channel synthesis is sketched. An interesting point is to convert aldehydes, chiral primary amines, carboxylic adds and isocyanates into corresponding a-amino acids and peptides (U-4CR). 

Weber, L. (2002) Multi-Component Reactions and Evolutionary Chemistry. Drug Discovery Today, 7, 143-147. 

Weber, L. (2002) The Application of Multi-Component Reactions in Drug Discovery. Current Medicinal Chemistry, 9, 1241-1253. 

Ugi, L, Werner, B., Domling, A. (2003) The Chemistry of Isocyanides, Their Multi-Component Reactions and Their Libraries. Molecules, 8, 53-66. 

The set of possible dependent properties and independent predictor variables, i.e. the number of possible applications of predictive modelling, is virtually boundless. A major application is in analytical chemistry, specifically the development and application of quantitative predictive calibration models, e.g. for the simultaneous determination of the concentrations of various analytes in a multi-component mixture where one may choose from a large arsenal of spectroscopic methods (e.g. UV, IR, NIR, XRF, NMR). The emerging field of process analysis,... 

The multi-component systems developed quite recently have allowed the efficient metal-catalyzed stereoselective reactions with synthetic potential [75-77]. Multi-components including a catalyst, a co-reductant, and additives cooperate with each other to construct the catalytic systems for efficient reduction. It is essential that the active catalyst is effectively regenerated by redox interaction with the co-reductant. The selection of the co-reductant is important. The oxidized form of the co-reductant should not interfere with, but assist the reduction reaction or at least, be tolerant under the conditions. Additives, which are considered to contribute to the redox cycle directly, possibly facilitate the electron transfer and liberate the catalyst from the reaction adduct. Co-reductants like Al, Zn, and Mg are used in the catalytic reactions, but from the viewpoint of green chemistry, an electron source should be environmentally harmonious, such as H2. 

Another aspect of modern analytical chemistry is the possibility of multi-component analysis. Especially spectroscopic and chromatographic methods are able to detect and determine a large number of species simultaneously. Therefore, such methods like ICP-OES, ICP-MS, TXRF, and chromatography are the work-horses in today s analytical chemistry. 

The past two decades have produced a revival of interest in the synthesis of polyanhydrides for biomedical applications. These materials offer a unique combination of properties that includes hydrolytically labile backbone, hydrophobic bulk, and very flexible chemistry that can be combined with other functional groups to develop polymers with novel physical and chemical properties. This combination of properties leads to erosion kinetics that is primarily surface eroding and offers the potential to stabilize macromolecular drugs and extend release profiles from days to years. The microstructural characteristics and inhomogeneities of multi-component systems offer an additional dimension of drug release kinetics that can be exploited to tailor drug release profiles. 

Domino reactions increasingly gain importance in the search for new drugs. Especially appropriate is the use of multi-component reactions in solution combinatorial chemistry. In such a process described by Wessel et al.1231 an alkoxy-nitroenone 48 was treated with different anilines 49 to give ketene-NO-acetals which in the presence of aromatic aldehydes and TfOH are transformed into 50 (scheme 10). The substrate 48 is readily available by oxidation of the nitrosugar 47. 

Domino reactions present a modern approach in organic synthesis since they allow the preparation of complex molecules starting from simple substrate in a few steps and in many cases with high stereoselectivity. Moreover, as multi-component transformation they are highly suitable for combinatorial chemistry and give access to libraries of great diversity. 

In the field of solid-state chemistry an important group of substances is represented by the intermetallic compounds and phases. In binary and multi-component metal systems, in fact, several crystalline phases (terminal and intermediate, stable and metastable) may occur. A few introductory remarks about these substances will be presented in relation to the mentioned figures. 

Multi-component condensation reactions offer tremendous scope for increasing diversity in combinatorial chemistry programs since, in a single reaction, structurally advanced compounds can be realized from very simple starting materials. In... 

Wessjohann LA, Ruijter E (2005) Molecular Diversity 9(1) (in print) 2nd International Conference on Multi Component Reactions, Combinatorial and Related Chemistry (2003) Genova, April 14-16, 2003... 

Hulme C, Gore V (2003) Multi-component reactions emerging chemistry in drug discover. From xylocain to crixivan. Curr Med Chem 10 51-80... 

Banfi L, Basso A, Cemlli V, Guanti G, Riva R (2009) IV international conference on multi-component reactions and related chemistry , 24—28/5. Ekaterinburg (Russia), p S16... 

Chebanov VA, Sakhno YI, Saraev VE, Muravyova EA, Andrushchenko AY, Desenko SM (2009) Multicomponent heterocyclizations control of chemo- and regioselectivity. Fourth international conference multi-component reactions and related chemistry , Ekaterinburg, Russia, 1-3... 

Keywords 1,3-Dicarbonyls, Biginelh reaction, Hantzsch reaction, Heterocyclic chemistry, Knoevenagel condensation, Mannich reaction, Michael addition, Multi-component reactions... 

Ugi, I., Domling, A. and Werner, B., Since 1995 the new chemistry of multi-component reactions and their libraries, including their heterocyclic chemistry, J. Heterocyd. Chem., 2000,37, 647. 

While the early examples of this cyclocondensation process typically involved a / -ketoester, aromatic aldehyde and urea, the scope of this heterocycle synthesis has now been extended considerably by variation of all three building blocks, allowing access to a large number of multifunctionalized pyrimidine derivatives. For this particular heterocyclic scaffold the acronym DHPM has been adopted in the literature and is also used throughout this chapter. Owing to the importance of multi-component reactions in combinatorial chemistry there has been renewed interest in the Biginelli reaction, and the number of publications and patents describing... 

---