Isocyanides classical reactions

An especially effective and fruitful way to synthesize novel scaffolds is by isocyanide-based MCRs (IMCRs). They mostly rely on the classical reactions of the pioneers of this chemistry, Passerini and Ugi (Figure 3.1). Passerini was born in 1891 in Scandicci and was a Professor of Chemistry in Italy, from 1930 to 1932 at the University of Siena and from 1932 at the University of Florence. He died in 1962. Ivar Ugi was bom in 1930 in Estonia. After being Forschungsdirektor of the Zentrallabor in Leverkusen at BAYER , he accepted a chair as full professor at the USC in Los Angeles from 1967 to 1970. From there he moved to the Technische Universitat Miinchen in 1970, where he held the prestigious Emil Fischer chair until 2001. 

Besides numerous applications of a-acidic isocyanides in classical IMCRs, such as the Ugi and Passerini reaction, the presence of an a-acidic proton enables other reaction paths and, subsequently, the development of novel MCRs. Here we focus on novel MCRs involving a-acidic isonitriles that have been described in literature since 1998. 

In the classical Passerini reaction [11], an isocyanide is condensed with a carbonyl compound and a carboxylic acid to afford a-acyloxyamides 7 (Scheme 1.2). When the carbonyl compound is prochiral, a new stereogenic center is generated. It is generally accepted that the reaction proceeds through intermediate 6, which rearranges to the product. The way this intermediate is formed is more debated. A possibility is a concerted non-ionic mechanism involving transition state 5. Since the simultaneous union of three molecules is not a very likely process, another possibility is a stepwise mechanism, with the intermediacy of a loosely bonded adduct 4 between the carbonyl compound and the carboxylic acid [2], Since all three... 

In 1996 we performed a classical U-4CR of primary amines, aldehydes and isocyanides, but instead of using carboxylic acids we employed thiocarboxylic acids [17]. The reaction leads highly chemoselectively to a-aminoacyl thioamides and no trace of a-aminothioacyl amides is found. This finding is not noteworthy per se and... 

In the classic Passerini reaction (P-3CR), an a-acyloxy carboxamide is formed from the reaction of an isocyanide, an aldehyde (or ketone), and a carboxylic acid. The... 

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. 

Shaabani et al. reported a facile method for the synthesis of imidazo[ 1,2-a]azines by a one-pot three-component condensation of an aldehyde, a 2-aminoazine, and trimethylsilylcyanide, as an isocyanide equivalent, in the presence of l-n-butyl-3-methyUmidazolium bromide ([bmim][Br]) as a promoter under classical heating conditions in high yields with rather short reaction times (Fig. 12.16) [12]. 

Classical and Modern Chemistry of Isocyanides and Multicomponent Reactions... 

In a classic Ugi reaction, a primary amine is used, which is converted to a tertiary amide at the end of the reaction [43]. Giovenzana and Tron et al. developed a so-called split-Ugi reaction [44], The basic idea (Scheme 5.22) is to split the primary amine into a two-tethered secondary amine (76). One reacts with the carbonyl group to afford an iminium ion, which then interacts with the isocyanide and the carboxylate... 

The realization that this was a new type of compound, isomeric to the nitriles, and the elaboration of the classical methods for the preparation of isocyanides, the alkylation method and the carbylamine method by Gautier and Hofmann, initiated an active period of isocyanide chemistry that ended by the turn of the century with Nef s investigations on the reactions of the formally divalent carbon atom in the isocyanides. - TTie discovery of the Passerini reaction in 1921 led to a brief renaissance of isocyanide chemistry. 

A-Benzyl PRT groups. An obvious solution to the conformation problem discussed above is the use of or/Z/u-halobenzyl PRT groups instead of the benzoyl derivatives [117]. Ito [121] and Undheim [122] have demonstrated the synthetic potential of this approach. Under classical tin hydride conditions, excellent yields for the alkylation of amines have been obtained as shown in Scheme 33 (Eq. 33.1) [122]. Starting from a chiral 1,3-oxazolidine, a novel approach for the functionalization of aminoalcohols has been reported [123]. When samarium iodide was used for such reactions, the formation of an organosamarium intermediate at the a-N position was achieved. This corresponds to the metallation of an amine under non-basic conditions. Subsequent reaction of the organosamarium species with electrophiles such as ketones [121, 124, 125[ (Eq. 33.2) and isocyanides [121, 124[ has been reported. 

In the following months, we read a lot on carbene chemistry, and in 1989 we published a paper entitled [Bis(diisopropylamino)phosphino]trimethylsilyl-carbene A stable nucleophilic carbene . [23] We found that 17 readily underwent at room temperature the classical cyclopropanation reaction with electron-poor olefins such as methyl acrylate leading to 23 in high yield. Moreover, it appeared that 17 also cleanly reacted with tert-hvfifi isocyanide to give the ketene imine 24 in 90% yield this was an example of carbene-carbene-like coupling reaction. 

A recent procedure describes a one-pot, two-step mutlicomponent reaction of bromoani-lines 13, aldehydes 14, acids 15 and isocyanides 16 yielding polysubstituted indoles 18 [34]. It is based on a Ugi four-component reaction yielding the precursor 17 for the in situ performed classical intramolecular Mizoroki-Heck reaction, thereby providing a facile access to highly substituted dihydro-indoles, l//-indoles and l//-indole-2-carboxyhc... 

A plausible reaction sequence that accounted for the formation of a-ketoamides is shown in Scheme 15.33. The condensation of an N-hydroxylmethylamine and an aldehyde gave the nitrone 112, which reacted with an isocyanide to afford the nitrilium intermediate 113. The classic Ugi reaction manifold would lead to the formation of a-acyloxyaminoamide 115 via the imidate intermediate 114. -Elimination of acetic acid under the optimized conditions would afford the a-iminoamide 116, which would then be hydrolyzed to 117. 

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