Intermolecular amination of allenes via 2-fold photocatalytic nitrene transfer reactions

Abstract

The amination with monovalent, nitrogen-based intermediates constitutes an important reaction for the construction of valuable amines. The high basicity of reagents, reaction intermediates, or products, however, poses significant challenges to metal-catalyzed amination through coordination and blocking of catalytically active sites and hampering of their efficiency. In this context, high-yielding intermolecular amination reactions of allenes remain an unsolved challenge in organic synthesis, and general methods are not available. Herein, we describe a photochemical approach toward the intermolecular amination of allenes via free nitrene radical anions as the key reactive intermediate. This reaction proceeds without the participation of catalyst-bound nitrogen species and can thus overcome current limitations. We report on the application in the amination of allenes to give azetidine and cyclopropyl amines with a broad and general substrate scope. Experimental and theoretical studies were performed to provide an understanding of the reaction mechanism and rationalize the high efficiency of this photocatalytic approach. • Photocatalysis enables the intermolecular amination of allenes • Azetidines via 2-fold amination • Cyclopropyl amines via trapping of intermediate cyclopropyl imines • Experimental and theoretical studies explain the reaction mechanism Amines are the most important functional group in drug discovery and can be ubiquitously found in the vast majority of drugs. The synthesis of amines thus represents a key research topic in chemistry. Latest developments thus focus, e.g., on the reduction of economic and ecologic footprints of amination reactions or on the development of novel synthesis methods to expand chemical space and new opportunities in drug design. While basic properties of amines are highly desired in the design of new drugs, the same properties pose significant challenges to classic metal-catalyzed amination reactions. Herein, we demonstrate that photocatalysis leverages amination reactions via free nitrene intermediates to allow for intermolecular amination reaction of allenes, which, even today, represents one of the big challenges in the field. The photocatalytic reaction of iodinanes enables mild and efficient intermolecular amination reactions of allenes. This strategy overcomes current limitations of metal-catalyzed amination reactions and provides a high-yielding access to azetidines or cyclopropyl amines depending on the reaction conditions. Experimental and theoretical studies were performed to provide an understanding of the underlying reaction mechanism.