Branched domino reaction

The second, albeit scarcely applied, class of radical domino reactions indudes intramolecular homolytic substitutions, which can also result in the formation of rings. As a consequence, the radical is ejected with the displaced center and does not remain with the main ring hence, this type of reaction is normally featured as terminating step. The most typical complication occurring within substitutions is an undesired branching of a sequence caused by the released radical. 

Diversity and molecular complexity are two important criteria that emich a compound collection in biological activity [48, 49). Therefore, strategies that efficiently build up diverse and relatively complex molecular architectures, in particular based on natural product frameworks, are highly desired. Branching pathways in DOS pose formidable challenge of incorporating scaffold diversity in a compound collection. Cascade or domino reaction sequences [50, 51] wherein more than one reaction happens consecutively in a one-pot strategy and molecular complexity is rapidly built up can immensely improve the efficiency of diversity syntheses endeavors (Box 27.3). Kumar and coworkers introduced a... 

Scaffold diversity is an important parameter to characterize any compound collection. Organic synthesis is expected to provide efficient approaches to create three-dimensionally complex and structurally diverse small molecules. Branching pathways in DOS is an elegant approach to access scaffold diversity that could lead to small, yet diverse, focused compound libraries. Branching cascades strategy has successfully demonstrated the power and application of cascade or domino reactions in compound collection synthesis to build rapidly complex scaffolds for library synthesis. Further synthesis endeavors toward branching pathways... 

The first iodine-catalyzed synthesis of 2-alkyl substituted oxazoles 130 by a decarboxylative domino reaction was reported. Aryl methyl ketones 128 were transformed in situ into a-iodo ketones and then, by the Kornblum oxidation, into 1,2-diketones. After the addition of the a-amino acid 129, an l2-mediated cyclization/decarboxylation gave oxazoles 130. The reaction proceeds better if the Ar has electron-donating substituents and if the R group is a branched alkyl chain or phenyl residue. The reaction used oxone to regenerate iodine (13JOC6065). 

In the last few years, several groups have developed enantioselective domino reactions catalysed by combinations of organocatalysts with palladium complexes. As an example, Murkheqee and List have reported a domino synthesis of p-all earbon quaternary amines on the basis of a highly enantioseleetive a-allqrlation of a-branched aldehydes, involving an achiral palladium catalyst and a chiral phosphoric acid. Under the catalysis of phosphoric acid, a secondary allylamine reacted with an a-branehed aldehyde to form an enammonium phosphate salt, which upon reaction with palladium catalyst afforded a cationic 7t-allyl palladium complex (Scheme 7.2). This intermediate resulted in the formation of an a-allylated iminium ion, whieh eould be reduced to the corresponding final chiral amine in high yield and exeellent enantioselectivity of 97% ee. The synthetic utility of this transformation was also demonstrated hy a formal synthesis of (+)-cuparene. 

Unusual -branched Baylis-Hillman adducts have been prepared by Li and coworkers by a novel Et2AlCl promoted domino Michael-aldol reaction of propynoates 50 with organo-cuprates and chiral p-toluenesulfinimines 52 (Scheme 10) [42], These condensations proceeded with very good diastereoselectivity to give allylic amines 53. The selectivity can be explained through the chairlike transition state 54. The anion intermediate approaches the sulfinimine from the sterically less hindered side of the lone pair of electrons. The nucleo-... 

Scheme 42.30 Domino three-component asymmetric Kabachnik-Fields reaction involving a dynamic kinetic resolution for a-branched aldehydes.

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