Related Multicomponent Reactions

In a transition-metal-free approach to indolo[2,3-d]quinolizines, our group has shown that the four-component reaction between tryptamines, a,p-unsaturated aldehydes, p-dicarbonyl compounds, and ethanol in the presence of cerium(IV) ammonium nitrate as a Lewis acid catalyst gives direct access to indolo[2,3-a]quinolizines 93 (Scheme 3.29) [72], On the basis of previous work on related multicomponent reactions [73], this domino transformation was proposed to comprise the initial formation of a p-enaminone by reaction between the primary amine and dicarbonyl components, its Michael addition to the unsaturated aldehyde, a hemiaminalization reaction, and a final Pictet-Spengler reaction initiated by the formation of a vinylo-gous acyliminium species. This method could also be extended to the preparation of benzo[fl]quinolizines. 

Abstract Piperazines and its congeners, (di)keto piperazines are valuable tools in drug discovery, providing a natural path for the process peptide > peptidomimetic > small molecule also called depeptisation. Moreover, they can provide molecular probes to understand molecular pathways for diseases of unmet medical need. However, in order to better understand the design of such value added compounds, the detailed understanding of scope and limitation of their synthesis as well as their 3D structures and associated physicochemical properties is indispensables. Isocyanide multicomponent reaction (MCR) chemistry provides a prime tool for entering the chemical space of (di)(keto)piperazines since not less then 20 different ways exist to access a diversity of related scaffolds. 

Heterocycles with a l,2,3,4-tetrahydropyrrolo[l,2-a]pyrazine core are also available through this multicomponent reaction. Compounds with a related structure are of high interest either for synthetic applications or for biological purposes. For the first time we were able to propose a one-pot access to pyrrolopiperazine and azasteroide-type scaffolds, illustrating the potential of this ecocompatible sequence to create molecular complexity and diversity from simple and readily available substrates (Scheme 60) [164]. In this case, the primary amine partner bears a pyrrole nucleophile, which neutralizes the transient iminium intermediate to form a new C-C bond via an intramolecular Pictet-Spengler-type cyclization. 

Cyclization of imidoyl azides 150 into 1,5-disubstituted tetrazoles 5 (Equation 10) is widely used both in the laboratory and on an industrial scale. Imidoyl azides form in situ in the course of various multistage processes, and sometimes in the multicomponent reactions (MCRs). The problems related to generation of imidoyl azides and also to electrocyclization of these intermediates into 1-mono- and 1,5-disubstituted tetrazoles are of crucial importance for the tetrazole chemistry. These problems are traditionally treated at length in basic reviews <1984CHEC(4)791, 1996CHEC-II(5)621>. The traditional methods for the synthesis and cyclization of imidoyl azides into tetrazoles were broadly employed and further refined in more recent works <1997MI1375>. Several new methods based on this approach have also been developed. 

Recently a fairly inexpensive way of high-temperature experimentation has been found to investigate refractory sulfides and related multicomponent systems up to temperatures of nearly 2000 °C using resistance furnaces. These techniques are discussed below and applied to some sulfide systems, in particular of those metals which belong to the VI-B group. The binary systems chromium-sulfur, molybdenum-sulfur, tungsten-sulfur, as well as some other ternary and quaternary systems and their reactions are reviewed and completed within the limits of the new experimental procedure. 

As early as 1961, Ugi [55] theorized the use of multicomponent reactions for the generation of large collections of compounds and, in the following years, other related works were reported [56-58]. It was only recently, though, that the full potential of multiple component condensations (MCCs) for the generation of combinatorial libraries became apparent, due to the efforts of major pharmaceutical industries and academic research groups. 

Abstract The chapter reviews the classic Reissert reaction, the keystone of a broad family of multicomponent reactions involving azines, electrophilic reagents and nucleophiles to yield A,a-disubstituted dihydroazine adducts. The first sections deal with the standard nucleophilic attack upon activated azines, including asymmetric transformations. Section 5 focuses on the generation of dipolar intermediates by azine activation, and on their subsequent transformation chiefly in cycloadditions. Lastly, Sect. 6 is primarily devoted to a special branch of this chemistry involving isocyanides. It also covers the reactivity of dihydroazines and reviews the mechanistic proposals for related reactions. 

The most industrially significant and well-studied allylic oxidation reaction is the ammoxidation of propylene ( eq. 8 ) which accounts for virtually all of the 8 billion pounds of acrylonitrile produced annually world-wide. The related oxidation reaction produces acrolein ( eq. 9 ), another important monomer. Although ammoxidation requires high temperatures, the catalysts are, in general the same fof both processes and include bismuth molybdates, uranium antimonates (USb30j Q), iron antimonates, and bismuth molybdate based multicomponent systems. The latter category includes many of todays highly selective and active commercial catalyst systems. 

In addition, we have also included chapters that are related to the type of process as organocatalysis, enantio- and diastereoselective reactions, and multicomponent reactions as well as domino processes under microwave irradiation, high pressure, and in water. Finally, two chapters that are more product oriented have been included on the synthesis of compound collections and the synthesis of natural products and analogs. 

Another diarylprolinol ether has been used to catalyse several asymmetric domino Michael reactions. Therefore, Jorgensen et al. have demonstrated its efficiency for the asymmetric synthesis of 1,4-dihydropyridines, which are closely related to the NADH system, a biological system of utmost importance, and moreover these molecules are important drugs used in the treatment of a number of diseases, such as cardiovascular diseases and Alzheimer s disease. Thus, a series of chiral 1,4-dihydropyridines were prepared on the basis of a one-pot multicomponent reaction between a a,p-unsaturated aldehyde, a P-diketone... 

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