From Deacylative Functionalization to Carbonyl Atom Swap: Aromatization-Driven Skeletal Modification of Ketones

Selective modification of molecular frameworks provides a powerful strategy for accessing structures that are difficult to prepare through conventional synthesis. This dissertation describes the development of new synthetic methods based on radical-mediated carbon–carbon (C–C) bond activation, with an emphasis on the use of ketones as programmable handles for late-stage functionalization and skeletal modification.

A major focus of this dissertation is aromatization-driven C–C bond activation of ketones. Conversion of ketones into pre-aromatic intermediates enables selective C–C fragmentation driven by aromatization, generating site-defined alkyl radicals. Control over the subsequent radical trapping step enabled deacylative thiolation, halogenation, and fluorination, establishing methyl ketones as stable precursors to a range of synthetically useful functional groups.

This strategy was subsequently extended from single C–C bond cleavage to sequential cleavage of both C–C bonds adjacent to the carbonyl group of cyclic ketones. Development of N′-alkyl hydrazonamide (NAHA) reagents enabled a second radical-triggered C–C cleavage, providing a general platform for carbonyl skeletal modification. This approach enabled carbonyl-to-sulfur and carbonyl-to-nitrogen atom swap, directly converting cyclic ketones into sulfur- and nitrogen-containing ring systems. The carbonyl-to-nitrogen transformation further enabled nitrogen scanning of sp³-rich scaffolds, providing rapid access to regioisomeric saturated nitrogen heterocycles from common ketone precursors.

Finally, the sequential double C–C cleavage strategy was extended to carbonyl removal. Complementary reductive and ring-contractive pathways enabled cyclic ketones to be converted into ring-opened and ring-contracted products. Collectively, these studies establish ketones as versatile and programmable functional groups for deacylative functionalization, atom substitution, and skeletal remodeling through controlled C–C bond activation.