New strategies for the synthesis of 1- and 2-azetines and their applications as value-added building blocks.

Four-membered nitrogen-containing heterocycles are highly desirable functional groups with synthetic and biological applications. Unsaturated four-membered N-heterocycles, 1- and 2-azetines, are historically underexplored, but have recently been gaining interest due to the development of new synthetic methods to access these compounds, and to their potential as reactive intermediates. This review covers both the synthesis and applications of azetines, with a focus on synthetic methods to access azetines developed since 2018, and a comprehensive review of the reactivity and applications of azetines as starting materials or intermediates to access both other heterocycles and complex products.

1- and 2-Azetines via Visible Light-Mediated [2 + 2]-Cycloadditions of Alkynes and Oximes.

Azetines, four-membered unsaturated nitrogen-containing heterocycles, hold great potential for drug design and development but remain underexplored due to challenges associated with their synthesis. We report an efficient, visible light-mediated approach toward 1- and 2-azetines relying on alkynes and the unique triplet state reactivity of oximes, specifically 2-isoxazolines. While 2-azetine products are accessible upon intermolecular [2 + 2]-cycloaddition via triplet energy transfer from a commercially available iridium photocatalyst, the selective formation of 1-azetines proceeds upon a second, consecutive, energy transfer process. Mechanistic studies are consistent with a stepwise reaction mechanism via N-O bond homolysis following the second energy transfer event to result in the formation of 1-azetine products. Characteristic for this method is its operational simplicity, mild conditions, and modular approach that allow for the synthesis of functionalized azetines and tetrahydrofurans (via in situ hydrolysis) from readily available precursors.

Visible light-mediated aza Paternò-Büchi reaction of acyclic oximes and alkenes to azetidines.

The aza Paternò-Büchi reaction is a [2+2]-cycloaddition reaction between imines and alkenes that produces azetidines, four-membered nitrogen-containing heterocycles. Currently, successful examples rely primarily on either intramolecular variants or cyclic imine equivalents. To unlock the full synthetic potential of aza Paternò-Büchi reactions, it is essential to extend the reaction to acyclic imine equivalents. Here, we report that matching of the frontier molecular orbital energies of alkenes with those of acyclic oximes enables visible light-mediated aza Paternò-Büchi reactions through triplet energy transfer catalysis. The utility of this reaction is further showcased in the synthesis of epi-penaresidin B. Density functional theory computations reveal that a competition between the desired [2+2]-cycloaddition and alkene dimerization determines the success of the reaction. Frontier orbital energy matching between the reactive components lowers transition-state energy (ΔGǂ) values and ultimately promotes reactivity.

Synthesis of azetidines via visible-light-mediated intermolecular [2+2] photocycloadditions.

Intermolecular [2+2] photocycloadditions represent a powerful method for the synthesis of highly strained, four-membered rings. Although this approach is commonly employed for the synthesis of oxetanes and cyclobutanes, the synthesis of azetidines via intermolecular aza Paternò-Büchi reactions remains highly underdeveloped. Here we report a visible-light-mediated intermolecular aza Paternò-Büchi reaction that utilizes the unique triplet state reactivity of oximes, specifically 2-isoxazoline-3-carboxylates. The reactivity of this class of oximes can be harnessed via the triplet energy transfer from a commercially available iridium photocatalyst and allows for [2+2] cycloaddition with a wide range of alkenes. This approach is characterized by its operational simplicity, mild conditions and broad scope, and allows for the synthesis of highly functionalized azetidines from readily available precursors. Importantly, the accessible azetidine products can be readily converted into free, unprotected azetidines, which represents a new approach to access these highly desirable synthetic targets.