Heck reaction multicomponent reactions

The first part of this chapter deals with the effects of high pressure on cycloaddition reactions, particularly the Diels-Alder reaction, which is the most important cycloaddition reaction. The second part will illustrate applications of pressure to nucleophilic substitutions, condensations and other reactions (miscellaneous reactions), such as Mannich, Heck, ene, SeAr, Wittig, Horner-Wadsworth Emmons and multicomponent Strecker reactions. 

In Mizoroki-Heck reactions, the developer cannot just rely on ligands. All components of the catalytic system strongly influence the nature of the catalytic species. The nature of the ligands in the coordination sphere of the catalytically active species often remains unknown, being speculative at the most. More often than not, Mizoroki-Heck reactions proceed through intermediates with coordination shells filled by undefined ancillaries. The art of the Mizoroki-Heck reaction designer is thus the systematization and judicious choice of a multicomponent catalytic system involving substrates, reaction media, bases and additives. It should not be overlooked that the nature of the palladium complexes involved heavily depends on temperature. 

In general, intermolecular Mizoroki-Heck reactions using immobilized alkenes are not as common as the variant that deals with solid-supported aryl halides, but we will come across another example in Section 14.2,3 on multicomponent Mizoroki-Heck reactions. 

As an interesting multicomponent reaction, an efficient palladium-catalyzed protocol for the synthesis of 3-atylidene-2-oxindoles was developed in 2010 by Balalaie and co-workers (Scheme 2.127). In this approach, a sequential one-pot six-component reaction via Ugi-Heck carbocyclization-Sonogashira-nucleophilic addition was used for the synthesis of the desired skeleton. 

V. P. Mehta, S. G. Modha, E. Ruijter, K. Van Hecke, L. Van Meervelt, C. Pannecouque, B. Romano, R. V. A. Orru, E. Van derEycken,/ Org. Chem. 2011,76,2828-2839.Amicrowave-assisted diastereoselective multicomponent reaction to access dibenzo[c,e]azepinones synthesis and biological evaluation. 

Multicomponent sequential transition-metal-catalyzed reactions were accomplished by the group of Muller. Their approach involves cycloisomerizations or combinations of a Heck reaction and an insertion or allylic substitution reaction, yielding an intermediate from which by P-H-elimination an aldehyde is generated, which reacts with an amine to give an imine, which in turn is reduced or otherwise modified. This conceptually challenging approach allows the experimentally remarkably facile generation of a variety of compounds of interest in medicinal chemistry. 

Scheme 1.27 Multicomponent couplings involving the heck reaction...

In contrast, the carbonylative Heck reaction, representing a variant of the palladium based multicomponent olefination reactions, has only been described to a hmited extent. Nevertheless, the resulting a,/ -unsaturated ketones serve as very important building blocks, as demonstrated by the many applications of the Michael addition, and constimte an attractive entry point to the assembly of heterocyclic compounds including pyridines, pyrimidines and pyrazoles etc [97, 98]. 

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