Dimeric natural products are a unique class of secondary metabolites that possess an array of biological functions, necessitating the development of new, reagent-based approaches for their synthesis. Dihalomucononitriles were synthesized and their reactivity evaluated to assess their ability to function as linchpin reagents for this purpose. Bis(2-chloroacrylonitrile) and bis(2-bromoacrylonitrile) were synthesized from 2,1,3-benzothiadiazole and undergo conjugate addition/elimination reactions with both nitrogen and carbon nucleophiles. Secondary amines undergo monosubstitutions (40−95% yield), while carbon nucleophiles are added twice (72−93% yield). The sequence of addition of the nucleophiles could be controlled to give mixed addition products. The multicomponent coupling products could then be converted to natural product like motifs using intramolecular Friedel-Crafts type cyclization reactions. Moreover, these dihalomucononitriles have been evaluated as dienophiles and dipolarophiles in Diels-Alder and [3+2] cycloaddition reactions, respectively (up to 88% yield). Iterative and programable cycloadditions with a wide variety of coupling-partners allowed for the formation of complex, nonsymmetric annulated products. Notably, the cycloadducts bear a-halonitrile moieties that were smoothly converted to the corresponding 1,4-dicarbonyl compounds, highlighting the utility of these reagents as bisketene equivalents. Furthermore, this reaction platform represents a complimentary approach to traditionally used oxidative coupling methodologies.

Investigation of dihalomucononitriles as linchpin reagents for complex molecule synthesis

ACS Fall 2021

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