Transition Metal-Catalyzed Nitrogen Atom Insertion into Carbocycles

Conspectus N -Heterocycles are essential in pharmaceutical engineering, materials science, and synthetic chemistry. Recently, skeletal editing, which involves making specific point changes to the core of a molecule through single-atom insertion, deletion, or transmutation, has gained attention for its potential to modify complex substrates. In this context, the insertion of nitrogen atoms into carbocycles to form N -heterocycles has emerged as a significant research focus in modern synthetic chemistry owing to its novel synthetic logic. This distinctive retrosynthetic approach enables late-stage modification of molecular skeletons and provides a different pathway for synthesizing multiply substituted N -heterocycles. Nevertheless, nitrogen atom insertion into carbocycles has proven challenging because of the inherent inertness of carbon-based skeletons and difficulty in cleaving C–C bonds. Therefore, selective insertion of nitrogen atoms for skeletal editing remains a challenging and growing field in synthetic chemistry. This Account primarily highlights the contributions of our laboratory to this active field and acknowledges the key contributions from other researchers. It is organized into two sections based on the type of the carbocycle. The first section explores the insertion of nitrogen atoms into cycloalkenes. Recent Co-catalyzed oxidative azidation strategies have enabled nitrogen atom insertion into cyclobutenes, cyclopentenes, and cyclohexenes, facilitating the synthesis of polysubstituted pyridines, which has been conventionally challenging through pyridine cross-coupling. The subsequent section highlights our discovery in the realm of nitrogen atom insertion into arenes. The site-selective skeletal editing of stable arenes is challenging in synthetic chemistry. We developed a method for the intramolecular insertion of nitrogen atoms into the benzene rings of 2-amino biaryls by suppressing the competing C–H insertion process by using a paddlewheel dirhodium catalyst. In addition, to address the challenging site-selective issues in nitrogen atom insertion, we employed arenols as substrates, which could act as selective controlling elements in site-selective skeletal editing. We reported a Cu-catalyzed nitrogen atom insertion into arenols, which proceeds through a dearomative azidation/aryl migration process, enabling the site-selective incorporation of nitrogen atoms into arenes. Inspired by this result, we recently extended the reaction model by using a Fe-catalyst to facilitate the ring contraction of the nitrogen-inserted product, achieving the carbon-to-nitrogen transmutation of arenols. Various complex polyaromatic arenols could effectively undergo the desired atom’s transmutation, presenting considerable potential for various applications in materials chemistry. In this Account, we present an overview of our achievements in nitrogen atom insertion reactions, with a focus on the reaction scopes, mechanistic features, and synthetic applications. We anticipate that this Account will provide valuable insights and propel the development of innovative methodologies in both skeletal editing and N -heterocycle synthesis.