Unimolecular Fragment Coupling and Single Carbon Atom Doping as Tools for Structural Reprogramming.

ConspectusOver the past decade, the precise deletion or insertion of atom(s) within a molecular skeleton has emerged as a powerful strategy for constructing and diversifying complex molecules. This approach is particularly valuable in organic synthesis, where subtle structural changes can dramatically impact reactivity, stability, and function, making it highly relevant to medicinal chemistry and material science.Our research focuses on two key structural reprogramming concepts: unimolecular fragment coupling (UFC) and single carbon atom doping (SCAD). These innovative strategies enable efficient molecular modifications that go beyond conventional functional group interconversions and coupling reactions, offering new synthetic opportunities for chemists.UFC involves the selective elimination of atom(s) from a molecular skeleton, followed by the recombination of the remaining fragments to form new bonds. A key advantage of this intramolecular process is its superior chemoselectivity and stereoselectivity compared to traditional intermolecular reactions. A prime example is our nickel(0)/N-heterocyclic carbene (NHC)-mediated decarbonylation of simple diaryl ketones, yielding biaryls via C-C bond activation. This approach offers an efficient alternative to cross-coupling reactions by leveraging the intrinsic connectivity of the substrate, enabling more direct and atom-economical transformations. We extended this concept to the catalytic decarbonylation of amides and acylsilanes, further broadening the scope of UFC to include diverse carbonyl-containing precursors.Expanding on this, we developed catalytic decarboxylative UFC of aryl carbamates, where a nickel(0) catalyst supported by a polystyrene-anchored bisphosphine ligand facilitates oxidative addition of the C(aryl)-O bond and extrusion of CO₂. This method provides a practical and sustainable route to biaryls while generating a CO₂ byproduct. Inspired by this decarboxylation reaction, we further explored deisocyanative UFC, enabling the late-stage removal of amide functionalities. This approach allows amides to serve as transient directing or protecting groups, significantly enhancing the synthetic utility and versatility of UFC-based strategies.On the other hand, SCAD involves the insertion of an atomic carbon into a molecular skeleton without atom loss from the substrate, leading to dramatic structural changes. We successfully applied SCAD to α,β-unsaturated amides using NHC as a one-carbon unit. Remarkably, this transformation forms four new bonds at a single carbon center in one step, generating lactams from acyclic precursors. This powerful skeletal modification unlocks new pathways for constructing cyclic frameworks with minimal synthetic steps.Together, UFC and SCAD introduce a new paradigm in skeletal editing, providing powerful tools for rapid and controlled molecular framework modifications. By enabling precise skeletal reprogramming, these methodologies expand the toolbox of synthetic chemists, accelerating complex molecule synthesis and streamlining access to novel molecular architectures. This Account highlights our contributions to this field, demonstrating their potential to drive both fundamental discoveries and practical applications in chemical synthesis.