Isocyanide-Involved Multicomponent Reaction

SCHEME 235 Phosphoric acid-catalyzed asymmetric domino processes between isocyanides and imines or aldehydes. 

---

The imidazo[l,2-a]quinoxaline scaffold 233 was developed by Krasavin et al. via two isocyanide-based multicomponent reactions sequentially introducing four diversity elements to the final products [70]. The first step involves the synthesis of quinoxaUnes 237 from o-phenylenediamines 234 and followed by the Groebke-Blackbum-Bienayme multicomponent reaction (Scheme 43). The described methodology provides a tool to constmct the medicinally relevant heterocycles. 

Finally, in the most complex multicomponent reaction involving isocyanides, the 7-CC proposed by Ugi in 1993 [93], a moderate diastereoselectivity, leading to a 2 1 mixture of epimeric thiazolidines 109 was observed. The reaction is a combination between an Asinger condensation, involving an a-mercaptoaldehyde (generated from the a-bromoaldehyde and SH ) and an Ugi-type 4-CC with a monoalkyl car-boxylate as acid component (Scheme 1.38). Although the relative configuration of the major stereoisomer was not demonstrated, it is probably trans, in line with the results of Ugi condensation with chiral thiazolines, reported above in Scheme 1.19. 

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. 

One of the most prominent class of multicomponent reactions involves the use of isocyanides [5] and many synthetic methods have been developed to access heterocycles from isocyanide-based chemistry [6, 7]. There are a number of reviews covering the applications of isocyanide-based MCRs in drug discovery [8, 9]. fii this review, we will focus on the most recent developments in the field. 

In combinatorial chemistry, the development of multicomponent reactions leading to product formation is an attractive strategy because relatively complex molecules can be assembled with fewer steps and in shorter periods. For example, the Ugi multicomponent reaction involving the combination of an isocyanide, an aldehyde, an amine, and a carboxylic acid results in the synthesis of a-acyl amino amide derivatives [32]. The scope of this reaction has been explored in solid-phase synthesis and it allows the generation of a large number of compounds with relative ease. This reaction has been employed in the synthesis of a library of C-glycoside conjugated amino amides [33]. Scheme 14.14 shows that, on reaction with carboxylic acids 38, isocyanides 39, and Rink amide resin derivatized with different amino acids 40, the C-fucose aldehyde 37 results in the library synthesis of C-linked fucosyl amino acids 41 as potential mimics of sialyl Lewis. ... 

The roots of the U-4CR lie in research reported long before its discovery in the early 1960s. The first multicomponent reaction (MCR) is credited to Laurent and Gerhardt who, in 1838, isolated an unexpected product from a reaction involving benzaldehyde, ammonia, and hydrogen cyanide. The resulting benzoyl azotide (1) presents the Schiff base of the Strecker adduct and benzaldehyde. Ironically, Strecker described such a reaction more than a decade later. In the years that followed, many variations of MCRs were reported, but it wasn t until 1921 that Passerini first utilized the isocyanide functionality and its unique reactivity in a MCR. It was this work that inspired Ugi and led to focused investigations of this reaction process. 

If in Chapter 7 different aspects about Ugi reaction have been discussed, in this chapter, we are going to disclose to the reader a vision about the new contributions regarding other crucial isonitrile-based multicomponent reaction (MCR) the Passerini reaction (P-3CR) discovered in 1921 [1], The traditional multicomponent Passerini reaction [2] is another isonitrile-based MCR that provides easy access to a-acyloxycarboxamides 4 in a one-pot synthesis involving an aldehyde 1, a carboxylic acid 2, and an isonitrile 3 (Scheme 8.1), which has been subject of intensive studies in the last decade [3], The importance of using isocyanides lays in its dual role as nucleophile and electrophile, and moreover, if R R, a new stereocenter could be created under asymmetric conditions. 

Ddmling and coworkers adapted a four-component Ugi-type reaction sequence to the synthesis of highly substituted 3-pyrrolin-2-ones (Scheme 104 20040L39). The combination of aUyl isocyanide (395), primary amine 396, a-phosphonoacetic acid 397, and a-ketoaldehyde 398 gives the 5-carboxamido-3-pyrrolin-2-one 399. The two-step process involves an Ugi multicomponent reaction followed by an intramolecular Homer/ Wadsworth/Emmons cycHzation. 

The Ugi reaction is a multicomponent reaction in organic chemistry involving a ketone or aldehyde, an amine, isocyanide and carboxylic acid to form a bis-amide. 

In 2003, we reported a multicomponent approach toward highly substituted 2H-2-imidazolines (65) [157]. This 3CR is based on the reactivity of isocyano esters (1) toward imines as was studied in detail by Schollkopf in the 1970s [76]. In our reaction, an amine and an aldehyde were stirred for 2 h in the presence of a drying agent (preformation of imine). Subsequent addition of the a-acidic isocyanide 64 resulted in the formation of the corresponding 2//-2-imidazolines (65) after 18 h in moderate to excellent yield. The mechanism for this MCR probably involves a Mannich-type addition of a-deprotonated isocyanide to (protonated) imine (66) followed by a ring closure and a 1,2-proton shift of intermediate 68 (Fig. 21). However, a concerted cycloaddition of 66 and deprotonated 64 to produce 65 cannot be excluded. 

Ecteinascidin 743 262 (Scheme 12.37) represents a powerful antitumor agent, which has been submitted to clinical trial. This complex polyazacydic, polyaromatic compound was isolated from the marine tunicate, Ecteinascidia turbinate [131]. A total synthesis of this natural product, which featured an Ugi four-component reaction as pivotal step, was recently reported by Fukuyama and co-workers [132]. The highly decorated phenylglycinol 263 was obtained via an asymmetric Mannich-type reaction [133], and was engaged in a multicomponent condensation process involving the protected amino acid 264, p-methoxyphenyl isocyanide 265 and acetaldehyde to afford dipeptide 266 in high yield. This com-... 

New synthetic methods for benzodiazepine synthesis involving Ugi-type multicomponent/post-Ugi cyclization reactions continue to be of interest. Ugi reactions of indole-2-carboxaldehydes, isocyanides, amines, and 2-iodobenzoic acid derivatives led to intermediates which, with copper(I) catalysis, underwent intramolecular indole N-arylation to produce indolo-fused benzodiazepinones, such as 134 (13CC2894). 2-Azido-benzaldehyde, isocyanides, propargylamines, and nitrophenols underwent Ugi-type reaction, Smiles-type rearrangement, and intramolecular azide-alkyne cyclization to afford triazolo-fused benzodiazepinones such as 135... 

Compounds 81 are synthesized by the Ugi reaction, which is a multicomponent process involving o-fluoroaniline, aldehyde, isocyanide, and IH-imidazole-5-carboxylic acid. The reaction is initiated by condensation of aniline with aldehyde leading to the corresponding imine, which successively reacts with the acid and isocyanide to give target compounds 81. Trifluoroethanol is used as a solvent in this reaction (Scheme 4.38) (Spatz et al. 2007). 

---