A Study of [2+2] Cycloaddition–Retroelectrocyclization in Water: Observation of Substrate-driven Transient Nanoreactor Induced New Reactivity

Abstract

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 surfactant nature and concentrations were varied in the aqueous phase. An environment in which transient self-assembly (vesicles) was induced by substrate and surfactant molecules initiated new reactivity through H2O addition on the TCBD generating 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 via keto-enol tautomerism mediated by a polar aprotic solvent which resembles cardiotonic drugs (milrinone, amrinone), 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. Besides the widely explored organic electronics/materials, we believe that this study would help overcome the long-standing limitation of CA–RE reaction applicability in biological fields.