Photoinduced polarity-mismatched transformations of isoquinolines into naphthalenes.

Abstract

Isosteric replacement is an important strategy for lead optimization in drug-development paradigms. However, it is usually restricted to cost- and labor-intensive de novo syntheses. We here report a photochemical photosensitizer-free skeletal-editing strategy to directly transform easily accessible isoquinolines into synthetically challenging naphthalene derivatives in a single operation. Directed by density functional theory calculations, the key factor enabling the (4 + 2) cycloaddition between two polarity-mismatched species was harnessing photonic energy to overcome fundamental electronic hurdles by the combination of isoquinolinium carbonate as the electron-donor-acceptor complex. The high compatibility of this methodology was expanded to late-stage functionalization of commercial drugs, thus enriching optimization libraries. Importantly, value-adding access to valuable polycyclic aromatic hydrocarbons, numerous ligands and drug analogies is also demonstrated.