Intermediate Control: Unlocking Hitherto Unknown Reactivity and Selectivity in N-Conjugated Allenes and Alkynes.

ConspectusControlling selectivity through manipulation of reaction intermediates remains one of the most enduring challenges in organic chemistry, providing novel solutions for selective C-C π-bond functionalization. This approach, guided by activation principles, provides an effective method for selective functional group installation, enabling direct synthesis of organic molecules that are inaccessible through conventional pathways. In particular, the selective functionalization of N-conjugated allenes and alkynes has emerged as a promising research focus, driven by advances in controlling reactive intermediates and activation strategies. In this regard, our group, alongside others, has established some new approaches that have emerged as a suitable platform for the synthesis of functionalized enamides. This Account reviews recent developments in the field, highlighting new modes of reactivity and selectivity, atom-economical functionalizations, and strategies for regio- and stereocontrol, while providing mechanistic insights into related transformations.Our study is systematically organized into two sections based on substrate type and chronological research progression. In the first section, we establish a platform by controlling allenamide-derived intermediates, enabling both allenamide-alkyne (AA) cross-coupling and a few novel electrophile-promoted hydrofunctionalization reactions. The unprecedented selectivity in Pd-catalyzed allenamide-alkyne cross-coupling is achieved through neighboring group chelation, with phosphine ligand selection controlling the reaction outcome. In parallel, the electrophile-promoted functionalizations─including haloalkynylation, hydrooxycarbonylation, hydrodifluoroalkylation, and intermolecular hydroamination─are achieved through strategic selection of electrophiles or their precursors.Additionally, our findings demonstrate how ynamides' reactivity toward both electrophiles and nucleophiles, controlled through activator modulation, expands the scope of accessible transformations. Key findings include: (1) chemoselective [2 + 2 + 2] annulation through efficient trapping of N-arylated nitrilium electrophiles by ynamides, (2) divergent C-H annulation of indole-derived vinylogous ynamides controlled by metal and ligand selection via intramolecular hydroarylation, (3) bromoalkynylation-enabled functional group migration through a novel 1,3-alkynyl shift.The final section explores how N-electron polarization in 1,3-enynes enables new chemoselectivity in metal-free inter- and intramolecular couplings with indole substrates. Our findings demonstrate that modulating N-electron conjugation within the enyne skeleton─through both linear and cross conjugation─can direct activation pathways and control product selectivity.This Account aims to stimulate broader research into the intermediate-controlled functionalization of activated π-systems. Future research directions include advanced activator design, novel functional group migration strategies, and deeper mechanistic studies to enable rational reaction development.