Visible-Light-Mediated <i>aza</i> Paternò–Büchi Reactions and Related Cycloadditions for the Formation of Azetidines and Azetines

ConspectusFour-membered nitrogen-containing heterocycles, azetidines and azetines, have recently garnered interest as attractive targets in the discovery of new compounds for pharmaceutical applications. Despite this, the full potential of these heterocycles has not yet been realized due to a dearth of general, mild synthetic methods to access them. The <i>aza</i> Paternò-Büchi reaction, which is the photochemical [2 + 2]-cycloaddition of imines and alkenes, provides a simple, yet powerful method for accessing azetidines. However, this transformation has historically remained limited due to inherent challenges in capturing the excited state reactivity of imines - photoexcited imines can undergo radiationless decay to the ground state through <i>E</i>/<i>Z</i>-isomerization, which precludes productive cycloaddition reactivity. For this reason, the first few decades of progress for the <i>aza</i> Paternò-Büchi reaction relied on cyclic imine substrates to restrict isomerization and extend the excited state lifetime of the substrate. Recently, triplet energy transfer photocatalysis has emerged as a synthetic tool for generating reactive triplet state intermediates using mild visible light irradiation and commercially available catalysts. We saw an opportunity to use triplet energy transfer to access the excited states of imines and alkenes, thus allowing for access to unprecedented classes of transformations.In this Account, we present our body of work on visible-light-mediated imine-based [2 + 2]-cycloadditions, which rely on a key design principle of energy transfer photocatalysis - careful matching of the triplet energies of the photosensitizer and substrate for selective substrate sensitization. By virtue of using visible light irradiation, this limits sensitization to activated (i.e., conjugated) alkenes and certain types of imines, and renders unactivated (i.e., unconjugated) alkenes and alkynes inaccessible. Relying on this principle, we have developed six distinct strategies (Types I-VI reactions) for accessing azetidines and azetines. These strategies differentiate intra- and intermolecular transformations and the reactivity of three distinct substrate classes: activated alkenes, unactivated alkenes, and alkynes.First, we present an intramolecular <i>aza</i> Paternò-Büchi reaction of acyclic oximes and hydrazones with activated alkenes (Type I). Mechanistically, this relies on selective alkene sensitization to mitigate undesired reactivity that can arise from direct excitation of the imine, meaning that this strategy is not amenable to productively engaging unactivated alkenes. To enable access to this class of substrates, we harnessed the triplet state reactivity of 2-isoxazoline-3-carboxylates in intra- (Type II) and intermolecular (Type III) <i>aza</i> Paternò-Büchi reactions with unactivated alkenes. We also developed a set of intermolecular reactions relying on acyclic imines and activated alkenes (Type IV), providing direct access to monocyclic azetidines for the first time under visible light conditions. Next, we present an extension of the reactivity of 2-isoxazoline-3-carboxylates with untethered (Type V) and tethered (Type VI) alkynes in intermolecular [2 + 2]-cycloadditions to generate 1- and 2-azetines. Lastly, we demonstrate the synthetic and industrial applications of our azetidine compounds: Type I products can be subjected to Ru-catalyzed oxidative β-elimination to access 1-azetines (Type VII), while Type II and III products can be synthetically modified to access nitroazetidines that have potential applications as novel energetic materials.