Ugi and Biginelli multicomponent

A. Studer, P. Jeger, P. Wipf, D. P. Curran, Fluorous Synthesis Fluorous Protocols for the Ugi and Biginelli Multicomponent Condensations ,/. Org. Chem. 1997,62,2917. 

In a fluorous variant of the Ugi and Biginelli multicomponent reactions, it has been... 

Studer A, Jeger P, Wipf P, Curran DP, Fluorous synthesis Fluorous protocols for the Ugi and Biginelli multicomponent condensations, J. Org. Chem., 62 2917-2924, 1997. 

Some of the syntheses of pyrimidines and quinazolines were automated so that combinatorial libraries of compounds could be generated. For instance, 2-thioxo-4-dihydropyrimidinones were prepared in this fashion by reductive alkylation of p-amino acids with aldehydes, addition of isothiocyanates, and then cyclization <97JOC9358>. The use of highly fluorinated substrates in the Ugi and Biginelli multicomponent reactions led to a combinatorially-suitable preparation of dihydropyrimidines 15 <97JOC2917>, and efficient solid phase syntheses of chiral quinazoline-... 

Heterocyclic chemistry has been a major beneficiary of MW-expedited solvent-lfee chemistry utilizing mineral supported reagents. It has been exploited for parallel synthesis, a strategy that is adaptable for multicomponent reactions, such as Ugi " and Biginelli reactions " , for rapid assembly of a library of compoimds. A representative multi-component condensation reaction to create a small-molecule library of imidazo[l,2-a]pyridines, imidazo[l,2-a] pyrazines, and imidazo[l,2-a]pyrimidines is depicted in Scheme 3. 

Even though the history of multicomponent reactions dates baek to the second half of the 19th century with the reactions of Strecker, Hantzsch, and Biginelli, it was only in recent decades with the work of Ugi that the concept of the multicomponent reaction has emerged as a powerful tool in synthetic... 

Furthermore, multicomponent reactions, as represented by Ugi reaction and Biginelli reaction, are attractive strategies for the selective construction of complex organic molecules from several simple starting materials in a single operation. Recently, Wang and Zhu et al. reported asymmetric synthesis of 5-(l-hydroxyalkyl)tetrazoles 60 from aldehydes, isocyanide, and hydrazoic acid via chiral salen-organoaluminum complex 59 catalyzed asymmetric Passerlni-type reaction (Scheme 43) [76]. 

The manufacturer of the commercially available Syrris Africa system [14] reports on the optimization of several multicomponent reactions Passerini, Biginelli and Ugi reaction. However, only the details of the three-component Passerini reaction were available [15]. 

The synthesis of small arrays of organic compounds derived from multicomponent condensations was recently reported by Studer et al. (119). A 10-member amino acid amide library L7 (Fig. 8.21) was prepared using the fluorous Ugi ( Flugi ) condensation, and another 10-member dihydropyrimidine library L8 (Fig. 8.21) was prepared using the Biginelli ( Fluginelli ) condensation adapted to the fluorous phase. The key intermediates for library preparation were the silyl bromide 8.36, prepared from a fluorous iodide (120), and the acyl bromide 8.37 and the acid 8.38, prepared from an orthothiobenzoate (121), as shown in Fig 8.21. The structure of the fluorous tag was... 

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... 

Contrary to the general perception, MCR occupies an important position in the development of modern organic chemistry. Indeed, many important named reactions such as the Strecker amino nitrile synthesis (1850) [6], the Hantzsch dihydropyridine synthesis (1882) [7], the Biginelli dihydropyrimidine synthesis (1891) [8], the Mannich reaction (1912) [9], the isocyanide-based Passerini reaction (1921) [10], and the Ugi (1959) reaction [11], among others, are all multicomponent processes. In spite of the significant contribution of MCRs to the state of the art of modern organic chemistry and its demonstrated potential in the synthesis of... 

The Passerini synthesis is one of the oldest and most important multicomponent reactions (chronologically preceded by the reaction of Biginelli [1] and followed by the equally well-known Ugi four-component condensation reaction [2], currently widely studied for its originality in terms of application and mechanism). Surprisingly, little information is available regarding its discoverer, the Florentine chemist Mario Passerini. The reasons for the lack of a biography of this scientist can be traced, in part, to Passerini s reserved nature, reserved to the point of erroneously being perceived as shadowy. ... 

Despite the chemical complexity of multicomponent reactions (MCRs), the dawn of MCRs was fairly early in the history of organic chemistry. The first MCR was the so-called Strecker reaction discovered in 1850 [1, 2], which generates amino acids via a three-component reactiOTi between amines, aldehydes (or ketones), and hydrogen cyanide (Scheme 1). Since then, organic chemists have devoted much effort to the discovery of additional MCRs. Thus, we now can find a number of MCRs, including the Biginelli reaction [3], the Gewald reaction [4], the van Leusen three-component reaction [5], the Hantzsch reaction [6], the Mannich reaction [7], the Kabachnik-Fields reaction [8, 9], the Passerini reaction [10], the Ugi reaction [11, 12] and numerous variations thereof [13]. 

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