Triftosylhydrazone in Single-Atom Skeletal Editing.

Area of Science:

• Organic Chemistry
• Synthetic Chemistry
• Catalysis

Background:

• Single-atom skeletal editing offers a powerful strategy for rapid molecular construction and diversification.
• Carbene-initiated skeletal editing, particularly carbon-atom insertion into heteroarenes, has historical roots but faced limitations in scope and efficiency.
• Previous methods relied on specific α-halocarbene precursors, restricting functional group compatibility and late-stage applications.

Purpose of the Study:

• To develop versatile and operationally safe carbene precursors for single-atom skeletal editing.
• To expand the scope and improve the efficiency of carbene-initiated skeletal editing, especially for medicinally relevant heterocycles.
• To investigate the mechanistic pathways and synthetic applications of this skeletal editing strategy.

Main Methods:

• Development and application of *o*-trifluoromethylbenzenesulfonylhydrazones (triftosylhydrazones) as diazo surrogates.
• Transition-metal-catalyzed carbene transfer reactions for skeletal editing of acyclic 1,3-dicarbonyls and heterocycles (pyrroles, indoles, 1,2-diazoles).
• Generation of key intermediates like cyclopropane, *N*-ylide, and *O*-ylide for skeletal modification.

Main Results:

• Demonstrated successful skeletal editing of acyclic 1,3-dicarbonyls to access 1,4-dicarbonyls via cyclopropanation/ring-opening.
• Achieved highly selective single-atom skeletal editing of medicinally important heteroarenes using triftosylhydrazones.
• Extended skeletal editing to strained nitrogen- and oxygen-containing heterocycles, showcasing broad applicability.

Conclusions:

• Triftosylhydrazones serve as effective and safe carbene precursors for diverse single-atom skeletal editing reactions.
• The developed methodologies offer improved functional group tolerance and potential for late-stage molecular diversification.
• This work provides valuable insights into carbene chemistry and skeletal editing, paving the way for new synthetic strategies.