Intramolecular, Visible-Light-Mediated Aza Paternò-Büchi Reactions of Unactivated Alkenes

Abstract

Azetidines are of particular interest in medicinal chemistry for their favorable properties, including increased resistance to oxidative metabolism and lower lipophilicity. The recent development of [2 + 2] reactions has significantly expanded the limited repertoire of methods for azetidine synthesis, but access to more complex architectures still requires further development. Herein, we report a visible-light-enabled intramolecular [2 + 2] cycloaddition of unactivated alkenes that proved previously unreactive to access tricyclic azetidines with 3D complex structures and high levels of saturation.

Photochemical Strategies Enable the Synthesis of Tunable Azetidine-Based Energetic Materials

“…Additionally, efforts were undertaken to epimerize azetidine 10 with little success (Figure E). This inspired us to consider how aza Paternò–Büchi reactions might be leveraged in the synthesis of specific azetidine isomers with multiple functional groups amenable to nitration. − …”

“…Herein, we report viable solutions that overcome these challenges and enable access to desirable azetidines bearing distinct substitution patterns (Figure ). Our innovative approach complements existing nucleophilic substitution reactions and combines visible-light-mediated inter- and intramolecular aza Paternò–Büchi reactions to access functionalized azetidines in a stereodivergent manner to explore their potential as energetic materials and feasible alternatives to TNAZ. − Importantly, our synthetic strategies have generated the first nitroazetidine energetic materials that incorporate stereochemical considerations, which further enables tuning of the physical properties. Consequently, the new azetidine materials described represent more powerful energetics that exhibit higher densities, better oxygen balance, greater detonation pressures and velocities, and improved specific impulses than previously disclosed cyclobutane-based materials .…”

Visible Light-Mediated [2+2]-Cycloadditions for the Formation of Macrocyclic Dimers

“…For the analogous intramolecular [2+2]cycloaddition of 2-isoxazolines 1 and unactivated alkenes, this strategy addressed competing intermolecular reaction pathways and resulted in significantly improved yields for low-yielding substrates. 3 However, surprisingly, running this reaction at 0.05, 0.01, and 0.0025 M still resulted in exclusive formation of 11, albeit in diminished yields of less than 52% (Table 1, entries 6, 7, and 8).…”

“…The unique triplet state reactivity of 2-isoxazolines has recently gained attention for their use as protected imine equivalents in photochemical [2+2]-cycloadditions. [1][2][3] Recent work reported by our laboratory harnessed this triplet state reactivity for the development of an intermolecular [2+2]-cycloaddition between 2-isoxazolines and aryl-and alkyl-substituted alkynes to afford 1-and 2-azetine products, respectively. 2 Subsequently, an intramolecular aza Paternò-Büchi reaction was developed, in which 2-isoxazoline 1 containing an unactivated alkene moiety afforded exclusively monomeric, tricyclic azetidine products 2 in up to 84% yield (Fig.…”

“…1A). 3 While these works display the synthetic utility of 2-isoxazolines, there is a need for further exploration of this functional group in order to expand the scope of reactions enabled by them.…”