engleski

From aminyl radicals to cations. Mechanism switch in Hofmann-Löffler-Freytag-like reactions

C-H functionalization methods are often used in late-stage functionalization synthesis in the pharmaceutical industry. Inside the “reaction toolbox of C-H functionalization” are amination reactions that combine remote C(sp3)-H bond activation at otherwise unfunctionalized positions with C-N bond formation in a synthetically attractive fashion.1 A traditional reaction in this class is the Hofmann-Löffler-Freytag (HLF) reaction.2 This reaction utilizes N-centered radicals, generated via heat or light from N- halogen homolytical bond breaking. After intramolecular 1, 5-HAT step, a δ-C-centered radical is formed, which is then subsequently functionalized. In this process stereo-information is not conserved. Recently, an ionic mechanism is proposed involving nitrenium cations.3 Heterolytically cleaved N-halogen bond produces nitrenium cation, that rearranges to carbocation with concerted nucleophilic attack that prevents loss of stereo- information. Substrates carrying a chiral benzylic position and a halogen activated nitrogen atom were transformed with full retention of configuration, which makes a radical mechanism less likely. Also, unlike many radical reactions, this transformation is promoted neither by light nor heat. In this work comparison between relative stabilities of radical species involved in typical HLF type of reactions, with relative stabilities of cationic species involved in this alternative ionic pathway will be discussed. Differentiation between pathways may suggest conditions needed to steer reactions through mechanisms that may (or may not) retain stereochemical information.

N-centered cations, N-centered radicals, rearrangement

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