Skeletal Editing through Cycloaddition and Subsequent Cycloreversion Reactions

Conspectus Skeletal editing, which involves adding, deleting, or substituting single or multiple atoms within ring systems, has emerged as a transformative approach in modern synthetic chemistry. This innovative strategy addresses the ever-present demand for developing new drugs and advanced materials by enabling precise modifications of molecular frameworks without disrupting essential functional complexities. Ideally performed at late stages of synthesis, skeletal editing minimizes the need for the cost- and labor-intensive processes often associated with de novo synthesis, thus accelerating the discovery and optimization of complex molecular architectures. While current efforts in skeletal editing predominantly focus on monatomic-scale modifications, editing molecules through cycloaddition followed by cycloreversion offers a unique strategy to manipulate molecular frameworks on a double-atomic scale. This introduces new possibilities for chemical transformations and enables transformations such as double-atom transmutation, formal single-atom transmutation, and atom insertion. Early examples of such skeletal editing processes often relied on the inherent high reactivity of the substrates, which needed to be sufficiently active to undergo cycloaddition and possess good leaving groups for the subsequent fragmentation (cycloreversion) step. Recently, however, the structural editing of relatively inert substrates has become achievable through substrate activation strategies designed to enhance either the cycloaddition or subsequent cycloreversion step. Along these lines, we recently developed a dearomative process for activating pyridines. In a simple high-yielding chemical operation, oxazinopyridines are readily obtained as activated dearomatized isolable intermediates. This method enabled us to achieve the transformation of pyridines into benzenes and naphthalenes through a cycloaddition/cycloreversion sequence. In this Account, related recent contributions from other research groups are highlighted as well, alongside early examples involving tetrazines, triazines, diazines, and other similar heterocycles as cycloaddition reaction partners. By offering a streamlined route to modify molecular structures, these approaches have demonstrated their ability to interconvert arenes and heteroarenes and have shown significant potential for late-stage editing applications as well as advancing drug discovery and the synthesis of bioactive molecules. In the future, these approaches will undoubtedly see broader development in the field of skeletal editing. New strategies for substrate activation should be devised to enable not only the incorporation of nitrogen and other heteroatoms into rings─rather than their deletion─but also to achieve ring contraction and expand the application of this strategy to non-aromatic rings. We hope that the advancements summarized in this Account will inspire chemists to explore and expand skeletal editing methodologies. By pushing the boundaries of these approaches, researchers can unlock new opportunities for constructing and modifying complex molecular frameworks, eventually paving the way for innovative applications in chemistry, biology, and materials science.