A study of [2 + 2] cycloaddition–retroelectrocyclization in water: observation of substrate-driven transient-nanoreactor-induced new reactivity†
Organic solvents limit [2 + 2] cycloaddition–retroelectrocyclization (CA–RE) in biological fields. We examined the formation of 1,1,4,4-tetracyanobuta-1,3-dienes (TCBDs) through CA–RE reactions and their unusual reactivity to produce N-heterocyclic compounds when the nature of the surfactant and the concentrations were varied in the aqueous phase. An environment in which transient self-assemblies (vesicles) were induced by the substrate and surfactant molecules initiated new reactivity through H2O addition on the TCBD, generating the enol form of the intermediate, which results in the formation of the 6,6-dicyano-heteropentafulvene (amidofulvene) compound, while lamellar sheets at higher concentrations favored TCBD generation. Interestingly, the amidofulvene underwent a clean transformation to 6-membered heterocycles that resemble cardiotonic drugs (milrinone, amrinone) via keto–enol tautomerism mediated by a polar aprotic solvent, opening up a new avenue for drug discovery. Unlike organic-solvent-mediated CA–RE reactions, the present nanoreactor-mediated approach enabled the selective production of TCBDs as well as new heterocycles using H2O as a green solvent. In addition to the widely explored organic electronics/materials, we believe that this study will help to overcome the long-standing limitation of CA–RE reaction applicability in biological fields.