One-pot multicomponent reaction

The chemistry illustrated above demonstrates the outstanding potential of metal-catalyzed processes for the discovery of new multicomponent one-pot reactions. 

In convergent approaches, the reactive components A, B, and C -C3 (Figures 11-13) can be either combined in multicomponent one-pot reactions, where products P -P3 are formed directly and no intermediates of type D can be isolated,... 

Multicomponent one-pot reactions continue to be the focus of heterocyclic synthesis when multi-bonds are formed. Malononitrile condenses with 3-pyridinecarbaldehyde and a ketone to form a substituted bipyridine (Equation 179) <1995JCM146>. In another condensation, with aniline being the ultimate source of the tetrahydroquinoline nitrogen atom, iodine is used as a catalyst in a reaction that was optimized for yield and diastereoselectivity (Equation 180) <2005SL2357>. 

In another multicomponent one-pot reaction, Lu et al. reported the first use of iodine as a catalyst to synthesize a variety of pyrano[3,2-c]quinolines <05SL2357>. They reported a three-component reaction involving aldehydes 110, anilines 111, and 2,3-dihydropyran 112 resulting in diastereomeric mixtures of tetrahydroquinolines 113 114 as shown in Scheme 31. 

When looking at multicomponent reactions we have to differentiate between multicomponent one-pot reactions, where the reactive components react to a product without giving rise to isolable intermediates, and multigeneration reactions, where the reactions proceed via intermediates which can be trapped and isolated. The two reaction schemes differ significantly in their scope and application for combinatorial organic synthesis as schematically depicted in Figures 1.8.5.1 and... 

As typical for multicomponent one-pot reactions, the four components have potentially many possibilities to react in one way or another and many reversible equilibria will co-exist in the reaction mixture. After formation of the imine or immonium species which is still a reversible process, reaction of the isonitrile and the carboxylate with the imine generates a reactive acyloxy-imine, which in the case of a primary amine 3 can rearrange to form a A-alkylated dipeptide 5... 

In Scheme 1.8.5.4, three versions of the Hantzsch multicomponent one-pot reaction are shown leading to thiazoles, pyrroles and dihydropyridines.3 ... 

The following examples illustrate the important differences between multicomponent one-pot reactions and multigeneration reactions. Many of the previously mentioned multicomponent one-pot reactions proceeded via intermediately formed imines. Instead of forming these imines in situ they can be synthesised separately and engaged in a whole range of reactions as schematically shown in Scheme 1.8.5.16. 

In the initial phase the classification of reactophores was just an excercise to get an overview about the type of building blocks which were employed in solid-phase reactions. A careful analysis of those building blocks and reactions revealed that essentially all of them could be grouped into the above mentioned categories. In a second study we analysed the building blocks that were used in multicomponent one-pot reactions. Again, most of them fell into one of those categories. 

In Schemes 1.8.5.1 and 1.85.2 we have eluded to the fact that multicomjxrnent cascade reactions usually lead to a higher number of compounds based on a higher number of core structures as compared to multicomponent one-pot reactions. Reactive building blocks which allow the construction of several different core structures depending on the sequence of mixing bear definitely a novel potential in combinatorial organic synthesis as shown in Scheme 1.95.1. 

A multicomponent one-pot reaction involving fused cyclic ketones 154, aromatic aldehydes 156 and 2-aminothiophenol 155, promoted by tetrachlo-rosilane at ambient temperature, gave a series of indeno- and naphtho-fused 1,5-benzothiazepines 157 in good-to-excellent yields (14TL6039). 

An efficient method for the preparation of 5-iodo-l,4-disubstituted-1,2,3-triazole (23) with the dithiophosphate moiety has been realized by a multicomponent, one-pot reaction of azides with alkynes in the presence of the novel Cul/NBS catalytic system (Scheme 6) The high tolerance of various sensitive groups revealed potential applications of this method in organic synthesis and drug discovery. 

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