Passerini 3-component reaction development

A few years later Passerini, developed a new 3CR towards a-acyloxy amides 9 which are formed by reacting an aldehyde or ketone 6, a carboxylic acid 8 and an isocyanide 7 (Scheme 2) ([25] and see for review [26]). Since the first synthesis of isocyanides (formerly known as isonitriles [27]) in 1858, the Passerini 3-component reaction (P-3CR) was the first MCR involving these reactive species. It has become one of the renowned examples of an important subclass of MCRs, the isocyanide-based MCRs (IMCRs). Especially important for the Passerini reaction, but also for a lot of other IMCRs, is the ability of isocyanides to form a-adducts, by reacting with nucleophiles and electrophiles (at the carbon atom). The nucleophilic... 

This organic reaction is the first multi-component reaction based on isocyanides it currently plays a central role in combinatorial chemistry. Recently S. E. Denmark and Y. Fans have developed an enantioselective catalyst for asymmetric Passerini reactions, whose reaction mechanism is not well understood even to this day [12]. 

Multicomponent reactions (MCRs) have attracted much attention in the past decade because of advantages such as high atom economy, simple procedure, and high efficiency. [1] Because of their ability to generate complex structures economically and efficiently [2], numerous MCRs have been developed and widely studied, such as the Cu-catalyzed three-component reactions [3-6], Mannich reactions [7, 8], Passerini reactions [9, 10], and A3-coupling reactions [11]. Of these, multicomponent alkyne reactions have become quite popular recently and abundant literature has been published regarding the various MCRs of alkynes with all sorts of reactants [12, 13]. 

Isocyanides, formal divalent carbon functionalities, are ideal candidates for the development of MCRs. Their reaction with carbonyls and imines, through an a-addition process, generates a zwitterionic intermediate, which is then trapped by a nucleophile. The resulting double a-addition adduct is unstable and rapidly undergoes the Mumm rearrangement to afford the final product (Scheme 12.32). The venerable three-component Passerini reaction is the first MCR based on this type of reaction process [116]. It addresses the formation of a-acyloxycarboxamides, which constitute a class of very versatile synthons in organic chemistry. In the present context, this reaction was utilized by Schmidt and collaborators for the elaboration of intermediate 234 [117], a key fragment for the synthesis of the prolyl endopeptidase inhibitor Eurystatin A 231 (Scheme 12.33) [118]. 

Isocyanides have attracted much attention in synthetic organic chemistry, and have led to the development of a variety of useful synthetic transformations [1]. In particular, carbon-carbon bond forming reactions using isocyanides as key reagents have been extensively studied during the past 50 years, as they allow the realization of useful multi-component assembly reactions, such as the Ugi and Passerini reactions [2]. These have once again been highlighted in recent years with the development of combinatorial chemistry. The characteristic reactions of isocyanides are mostly ascribed to the unique reactivity of the isocyano carbon atom, which can be represented by a divalent, carbene-like electronic structure (Scheme 1). In this respect,... 

We have developed a (salen)AlCl (141 (-catalyzed enantioselective three-component Passerini reaction (Scheme 5.44) [87]. In order to overcome the catalyst turnover dilemma, using a chiral catalyst with only one coordination site available was the working hypothesis of our research, and this turned out to be rewarding. A variety of non-chelating aldehydes, including a-branched compounds, carboxylic acids, and isocyanides participated in this catalytic enantioselective process to afford Passerini adducts in good to excellent ee. Unfortunately, aromatic aldehydes were not acceptable as substrates under these catalytic conditions. The similar catalyst (salen)AlMe... 

Ganem and co-workers have developed the use of a Zn(OTf)2/TMSCl system to promote a variety of Passerini-type processes. The combination is active even for a,P-unsaturated aldehydes and usually problematic ketones. The promoter system was developed around a strategy of tethering nucleophilic functional groups to the isonitrile component to intercept the transient nitrilium species internally. Depending on the attached functionality either the a-hydroxy amide or a substituted oxazole could be obtained in high yield. For 1-isocyano-(2-morphilino)ethane (28), the reaction with... 

Based on the previously reported methodology by El Kaim and Grimaud [14], Taguchi s group developed the first metal-catalyzed Passerini reaction using alcohols instead of the carboxylic acid component allowing the construction of a chemical library of a-alkoxy amide derivatives 19 (Scheme 8.5) [17]. 

In one of the initial such examples, Domling and coworkers have reported both Ugi and Passerini-type MCR in concert with RCM. The general approach is outlined in Scheme 11.25, with the linear precursor (186) obtained from the MCR then subjected to standard RCM to give the macrocyclic products 187 or 188. In this manner, the representative 22-membered macrocycle (189) is produced from the Ugi four-component coupling reaction (4CR) of an acid, amine, isonitrile and paraformaldehyde. In a similar way, the exemplary 17-membered macrocycle (190) was prepared from the Passerini SCR of an acid, aldehyde and isonitrile. Methods for the synthesis of the starting materials also needed to be developed to ensure sufficient... 

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