Diversity-oriented cascade reactions

Abstract Sequentially palladium-catalyzed reactions consist of combinations of identical, related, or significantly different palladium-catalyzed processes that occur in a sequential or consecutive fashion in the same reaction vessel without addition of further amounts of catalyst to the reaction media. This novel type of cascade reaction can be elaborated into both domino and multicomponent processes and represents a significant contribution to the highly topical field of diversity-oriented synthesis. 

However, the latter type of metal-catalyzed cascade reactions turns out to be even more challenging since issues of selectivity and efficiency are crucially dependent on the particular catalyst structure. This type can either be performed in a parallel or sequential fashion [16,21], Whereas parallel catalysis is significantly more difficult to develop, sequential catalysis offers the possibility of altering reaction conditions and additives from step to step in the sense of bi- or multicatalytic one-pot processes, assisted tandem catalysis, or auto tandem catalysis [1]. Therefore, a demanding goal is the development of one-catalyst multireaction sequences that set the stage for new reactions in diversity-oriented syntheses of complex molecular structures (for reviews on diversity-oriented syntheses see [27-33]). 

The dramatic increase in molecular complexity and the opportunity for divergency offered by this methodology has attracted the attention of groups interested in diversity-oriented syntheses of bioactive compound libraries (08NPR719). Indeed, the Nelson group (09CEJ2185) has extended the cascade to incorporate a Joullie-Ugi reaction, allowing further diversification (Scheme 39). 

D. B. Ramachary, C. Venkaiah, Y. V. Reddy, M. Kishor, Org. Biomol. Chem. 2009, 7, 2053-2062. Multi-catalysis cascade reactions based on the methoxycarbonylketene platform diversity-oriented synthesis of functionalized non-symmet-rical malonates for agrochemicals and pharmaceuticals. 

Sun et al. reported a diversity-oriented parallel synthesis for benzimidazole 54 and pyrrolo-/pyrido-benzimidazo-lones 55 56 linked isoindolo-benzimidazolones on IL support xmder microwave irradiation by utilizing the cascade cyclization (Schemes 21 and 22). The research group used key tandem reactions (1) aminoalkylation of immobilized o-phenylenediamine with ketoacids, (2) intramolecular cyclization through secondary amine on electrophilic imine carbon toward pentacyclic aza-ring, and (3) second amidocyclization to deliver cycloamide ring [125]. 

An impressive example that illustrates the power of F-C type reactions in diversity-oriented one-pot reaction cascades was reported recently (Scheme 35.20) [78]. In this study, optically active trans-2,3-dihydrobenzofurans 78 and 79 having three stereogenic centers were prepared in a straightforward manner by simple modification of the structure of the key intermediates, which resulted in different chemoselectivity of the organocascade reactions. 

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