Generation of Aromatic N‐Heterocyclic Radicals for Functionalization of Unactivated Alkenes

Abstract

Nitrogen‐centered radicals (NCRs) have been widely recognized as versatile synthetic intermediates for the construction of nitrogen containing molecules of high value. As such, there has been a long‐standing interest in the field of organic synthesis to develop novel nitrogen‐based radicals and explore their inherent reactivity. In this study, we present the generation of aromatic N‐heterocyclic radicals and their application in a novel and diverse functionalization of unactivated alkenes. Bench‐stable aromatic N‐heterocyclic pyridinium salts were employed as crucial NCR precursors, which enabled the efficient conversion of various unactivated alkenes into medicinally relevant alkylated N‐heterocyclic amines. This approach offers an unexplored retrosynthetic disconnection for the synthesis of related molecules that commonly possess therapeutic value. Furthermore, this platform can be extended to the synthesis of densely functionalized heterocyclic amines by utilizing disulfides and diethyl bromomalonate as radical quenchers. Mechanistic investigations indicate an energy transfer (EnT) pathway involving the formation of a transient aromatic N‐heterocyclic radical, radical addition to unactivated alkenes, and subsequent generation of the amination product through either hydrogen atom transfer (HAT) or radical addition processes.

Recent advances in C(sp3)–N bond formation via metallaphoto-redox catalysis

“…In 2023, the Zhang group documented a novel visible-light induced photoredox-catalyzed hydroamination reaction of unactivated alkenes 165 with pyridinium salt derived aromatic N-heterocyclic radicals (Scheme 24b). 82 In this process, the addition of Lewis acid Fe(OTf) 3 can increase the efficiency of the reaction. Mechanistic investigations showed that the key N-heterocyclic radical intermediate is generated through EnT-based activation of the corresponding pyridinium salt 164 .…”

Cooperative Phosphine-Photoredox Catalysis Enables N–H Activation of Azoles for Intermolecular Olefin Hydroamination

“…23 However, N-H azoles have not been reported. Recent work by the groups of Zhang 24 and Chen 25 have demonstrated the feasibility of alkene hydroamination via heterocylic NCRs using N-functionalized azoles, such as N-pyridinium salts and hydroxybenzotriazoles, respectively. Thus, identification of a mild and general strategy for N-H bond activation of azoles could prove highly enabling in the development of this and numerous other reactions that deliver medicinally relevant heterocyclic products.…”

Cooperative Phosphine-Photoredox Catalysis Enables N–H Activation of Azoles for Intermolecular Olefin Hydroamination

“…23 However, N−H azoles have not been reported as competent substrates. Recent work by the groups of Zhang 24 and Chen 25 have demonstrated the feasibility of alkene hydroamination via heterocyclic NCRs using N-functionalized azoles, such as Npyridinium salts and hydroxybenzotriazoles, respectively. Thus, identification of a mild and general strategy for N−H bond activation of azoles could prove highly enabling in the development of this and numerous other reactions that deliver medicinally relevant heterocyclic products.…”