Comprehensive Summary Single carbon atom insertion (SCAI) has rapidly evolved from a specialized synthetic curiosity into a sophisticated and indispensable paradigm for modern molecular scaffold editing. By leveraging simple, readily available precursors, this versatile strategy provides a streamlined and remarkably efficient avenue for constructing complex molecular architectures through a variety of transformative pathways, including cyclization, ring expansion, chain extension, and direct atomic embedding. Fundamentally, SCAI offers a logically distinct alternative to conventional multi‐step synthesis, which often relies on the tedious, bond‐by‐bond assembly of a framework. Instead, it empowers synthetic chemists to perform precise skeletal reorganization on existing scaffolds, significantly enriching the chemical toolbox and enabling direct access to structurally diverse core frameworks that are ubiquitous in pharmaceuticals and bioactive natural products. The field has been further propelled by the design of innovative, stable, and scalable atomic carbon precursors that circumvent the hazards associated with traditional, highly reactive reagents. The successful integration of these precursors with emerging synthetic technologies, such as photocatalysis and electrochemistry, has allowed various SCAI transformations to proceed under exceptionally mild and sustainable conditions. Crucially, many of these modern methods bypass the requirement for costly or toxic transition metal catalysts, which not only enhances reagent controllability and substrate generality but also drastically improves the overall reaction efficiency. These advancements have fundamentally expanded the boundaries of chemical application, moving the technique from theoretical exploration to practical utility in high‐stakes synthesis. Today, by enabling the direct incorporation of a single carbon atom into established molecular frameworks, SCAI has become a vital instrument for late‐stage functionalization and the strategic expansion of complex ring systems. This capability is particularly invaluable in the synthesis of natural products and drug discovery, where maintaining high structural fidelity while exploring new chemical space is paramount. As researchers continue to refine these methods, SCAI stands as a transformative approach that maximizes atom economy and provides an elegant solution to some of the most challenging structural modifications in organic chemistry. Key Scientists
Da et al. (Fri,) studied this question.