N-Atom Deletion Involving Rearrangement of Sulfamoyl Azides or Triazanium Salts

ConspectusAmines are frequent structural components in natural products, pharmaceuticals, ligands, and catalysts, making their synthesis and transformation essential to organic chemistry. While C-N bond formation has become a well-established and reliable synthetic strategy, the selective cleavage of C-N bonds remains relatively underexplored. This challenge arises from the low heterolytic nucleofugality of nitrogen, a property that limits the practical application of C-N bond cleavage. This gap underscores a significant area in synthetic methodology in need of further development. In this context, N atom deletion─defined as the selective removal of a nitrogen atom <i>via</i> C-N bond cleavage, while preserving the integrity of the remaining framework─has emerged as a promising approach for skeletal editing. Since Levin's landmark 2021 report, N atom deletion has gained attention for its potential to precisely modify molecular skeletons. Building on the skeletal editing concepts advanced by Levin and Sarpong, particularly their strategies for modifying cyclic frameworks, we recognized the critical need for developing mild and efficient methods that enable the structural manipulation of cyclic systems.This Account summarizes our research since 2017, focusing on two approaches to N atom deletion with distinct mechanisms: the rearrangement of sulfamoyl azides and the conversion of triazanium intermediates. Initially, we explored and optimized the thermal rearrangement of sulfamoyl azides derived from secondary amines, discovering its potential as a viable synthetic strategy for N atom deletion. In 2024, we introduced an O-diphenylphosphinyl hydroxylamine (DPPH)-promoted N atom deletion, involving the generation and novel rearrangement of triazanium intermediates. Both methods enable the conversion of polar aliphatic amines into nonpolar scaffolds and are applicable to both linear molecules and cyclic systems of varying sizes. The DPPH-based approach, in particular, demonstrated exceptional effectiveness for sterically hindered substrates with mild reaction conditions and no need for anhydrous or oxygen-free environments. The mechanisms of two methods─both via isodiazene and radical intermediates─were elucidated through rigorous experimental investigation. Additionally, we observed the rapid formation of hydro(deutero)deamination products when primary amines were exposed to DPPH.Beyond its role as a typical skeletal editing strategy, N atom deletion of secondary amines has emerged as a crucial synthetic approach. Though with limitations, it transforms the challenging task of constructing C-C bonds into a more manageable sequence: the formation of C-N bonds following selective N atom removal. We have applied this strategy in the synthesis of natural products, ligands, hydrocarbon cages, and pharmaceuticals. We hope that this work will stimulate further interest in N atom deletion as a skeletal editing strategy and encourage its incorporation into advanced synthetic methodologies, thereby expanding its utility across diverse areas of organic chemistry.