Functionalized azetidines via visible light-enabled aza Paternò-Büchi reactions

Abstract

Azetidines are four-membered nitrogen-containing heterocycles that hold great promise in current medicinal chemistry due to their desirable pharmacokinetic effects. However, a lack of efficient synthetic methods to access functionalized azetidines has hampered their incorporation into pharmaceutical lead structures. As a [2+2] cycloaddition reaction between imines and alkenes, the aza Paternò-Büchi reaction arguably represents the most direct approach to functionalized azetidines. Hampered by competing reaction paths accessible upon photochemical excitation of the substrates, the current synthetic utility of these transformations is greatly restricted. We herein report the development of a visible light-enabled aza Paternò-Büchi reaction that surmounts existing limitations and represents a mild solution for the direct formation of functionalized azetidines from imine and alkene containing precursors.

Synthesis of azetidines by aza Paternò–Büchi reactions

“…19). 46 Similar to the pioneering work by Sivaguru and coworkers, 37 the developed aza Paternò-Büchi reaction protocol relies on activation of the alkene component via triplet energy transfer. Activated alkenes such as styrenes or dienes possess triplet energies that are accessible with visible light photocatalysts, which was previously utilized for the synthesis of cyclobutanes by Yoon and coworkers.…”

New Redox Strategies in Organic Synthesis by Means of Electrochemistry and Photochemistry

“…Furthermore, additional photocatalytic strategies such as energy transfer catalysis have seen broader and creative applications in synthetic contexts. 66 Finally, the incorporation of continuous flow technology in photocatalysis further renders light-driven reactions more amenable to practical synthetic applications at scale. 67 In this section, we discuss some of the most recent conceptual advances in the area of visible-light photocatalysis.…”

Recent Advances in Photocatalytic C–N Bond Coupling Reactions

“…Schindler and co-workers disclosed an interesting visible-light-mediated Paternò-Büchi reaction (Scheme 66). 70 The Ir-catalyzed coupling of imines and alkenes under blue LED irradiation furnishes functionalized azetidines. This approach relies on the selective activation of the alkene functionality upon energy transfer from a suitable photocatalyst to its corresponding triplet state.…”