Nucleophilic addition/cycloaddition cascade reactions

Keywords Absolute configuration, Amines, Amino acids, Carbenes, Cascade reactions, 2-chloro-2-cyclopropylideneacetates. Combinatorial libraries. Cycloadditions, Cyclobutenes, Cyclopropanes, Diels-Alder reactions. Heterocycles, Michael additions. Nitrones, Nucleophilic substitutions, Peptidomimetics, Palladium catalysis. Polycycles, Solid phase synthesis, Spiro compounds. Thiols... 

A copper-catalyzed cascade reaction involving a [3 + 2]-cycloaddition between l-aryl-2-(aryl(prop-2-ynyl)amino)ethanol 108 and p-toluenesulfonyl azide 109 formed a putative Af-sulfonylketimine intermediate 110, which subsequendy underwent intramolecular nucleophilic addition and hydrolysis to form 2,4-diaryl-l,4-oxazepan-7-ones 111 in good yields (14RA37526). 

Alkylideneindolones are particularly good electrophiles, especially toward Michael additions, and therefore constitute excellent starting materials for the synthesis of spirooxindoles by multiple bond-forming approaches. The general strategy of the cascade reactions consists of an initial Michael reaction followed by a nucleophilic addition of the in situ formed enolate intermediate to various electrophiles. In the last years, several electrophilic partners with different scaffolds that lead to formal cyclizations, such as [3+2] cycloadditions [8a], Diels-Alder reactions [8b], and cyclopropanation [8c], have been used to afford a plethora of new spirooxindole scaffolds with excellent stereocontrol. 

Lu, Wang et al. developed an efficient preparation of dihydropyrimidin-4-ones from readily available AT-(prop-2-yn-l-yl)amides and sulfonyl azides using Cul as catalyst (Scheme 8.108). This cascade reaction includes copper-catalyzed alkyne-azide cycloaddition, formation and intramolecular nucleophilic addition of ketenimine, and subsequent rearrangement. The C(sp)-H bond was activated through copper-catalyzed alkyne-azide cycloaddition process in this reaction [182]. 

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