N-Amino Pyridinium Salts in Organic Synthesis.

C-N bond forming reactions hold immense significance to synthetic organic chemistry. In pursuit of efficient methods for the introduction of nitrogen in organic small molecules, myriad synthetic methods have been developed, and methods based on both nucleophilic and electrophilic aminating reagents have received sustained research effort. In response to continued challenges - the need for substrate prefunctionalization, the requirement for vestigial N-activating groups, and the need to incorporate nitrogen in ever more complex molecular settings - the development of novel aminating reagents remains a central challenge in method development. N-aminopyridinums and their derivatives have recently emerged as a class of bifunctional aminating reagents, which combine N-centered nucleophilicity with latent electrophilic or radical reactivity by virtue of the reducible N-N bond, with broad synthetic potential. Here, we summarize the synthesis and reactivity of N-aminopyridinium salts relevant to organic synthesis. The preparation and application of these reagents in photocatalyzed and metal-catalyzed transformations is discussed, showcasing the reactivity in the context of bifunctional platform and its potential for innovation in the field.

N-Aminopyridinium reagents as traceless activating groups in the synthesis of N-Aryl aziridines.

N-functionalized aziridines, which are both useful intermediates and important synthetic targets, can be envisioned as arising from the addition of nitrenes (i.e., NR fragments) to olefinic substrates. The exceptional reactivity of most nitrenes, in particular with respect to unimolecular decomposition, prevents general application of nitrene-transfer to the synthesis of N-functionalized aziridines. Here we demonstrate N-aryl aziridine synthesis via 1) olefin aziridination with N-aminopyridinium reagents to afford N-pyridinium aziridines followed by 2) Ni-catalyzed C-N cross-coupling of the N-pyridinium aziridines with aryl boronic acids. The N-pyridinium aziridine intermediates also participate in ring-opening chemistry with a variety of nucleophiles to afford 1,2-aminofunctionalization products. Mechanistic investigations indicate aziridine cross-coupling proceeds via a noncanonical mechanism involving initial aziridine opening promoted by the bromide counterion of the Ni catalyst, C-N cross-coupling, and finally aziridine reclosure. Together, these results provide new opportunities to achieve selective incorporation of generic aryl nitrene equivalents in organic molecules.

Traceless Benzylic C-H Amination via Bifunctional N-Aminopyridinium Intermediates.

C-H amination reactions provide the opportunity to streamline the synthesis of nitrogen-containing organic small molecules. The impact of intermolecular C-H amination methods, however, is currently limited the frequent requirement for the amine precursors to bear activating groups, such as N-sulfonyl substituents, that are both challenging to remove and not useful synthetic handles for subsequent derivatization. Here, we introduce traceless nitrogen activation for C-H amination-which enables application of selective C-H amination chemistry to the preparation of diverse N-functionalized products-via sequential benzylic C-H N-aminopyridylation followed by Ni-catalyzed C-N cross-coupling with aryl boronic acids. Unlike many C-H amination reactions that provide access to protected amines, the current method installs an easily diversifiable synthetic handle that serves as a lynchpin for C-H amination, deaminative N-N functionalization sequences.

Diversification of Amidyl Radical Intermediates Derived from C-H Aminopyridylation.

The N-activating substituents typically encountered in C-H amination chemistry are challenging to remove and have limited scope for synthetic elaboration. Here, we demonstrate that N-benzylaminopyridinium species provide a platform for synthetic elaboration via reductive N-N bond activation to unveil electrophilic N-centered radicals. These reactive intermediates can be trapped either via anti-Markovnikov olefin carboamination to provide access to tetrahydroisoquinolines or via aza-Rubottom chemistry with silyl enol ethers to provide α-amino ketones.