Date on Master's Thesis/Doctoral Dissertation

8-2025

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Chemistry

Degree Program

Chemistry, PhD

Committee Chair

Luzzio, Frederick A.

Committee Member

Basemann, Kevin

Committee Member

Balabanoff, Morgan

Committee Member

Fu, Xiao-An

Author's Keywords

Isoindolinones; phthalimides; protecting groups; copper(II) catalyst; heterocycles

Abstract

Nitrogen-containing heterocycles are a foundational class of compounds in organic chemistry, playing critical roles in pharmaceuticals, agrochemicals, and natural products due to their structural diversity and biological relevance. Among them, isoindolinones are notable for their wide range of pharmacological activities. Structurally, isoindolinones possess a benzylic methylene group adjacent to the nitrogen atom, which allows for selective oxidative transformations to yield phthalimide derivatives, well-known intermediates in synthetic, pharmaceutical, and materials chemistry. Although phthalimide is traditionally employed as a protecting group for amines via the Gabriel synthesis, isoindolinone offers a valuable alternative. Through a modified Gabriel-like approach, isoindolinones can serve as more robust and synthetically versatile nitrogen protecting groups, with advantages in both reactivity and stability. Moreover, their straightforward synthesis further expands their utility as nitrogen-introducing intermediates in organic synthesis. Our research group has maintained a longstanding interest in exploring isoindolinones as alternative amine-protecting groups, focusing on the development of selective oxidative strategies to functionalize the benzylic C–H bonds of these scaffolds. This thesis describes the development of a mild and efficient copper(II)/tert-butyl hydroperoxide (Cu(II)/TBHP) catalytic system for the selective oxidation of N-substituted isoindolinones under inert conditions. The system demonstrates excellent chemoselectivity, targeting the benzylic methylene position α to the nitrogen center. The work further explores the use of molecular oxygen and air as terminal oxidants, offering a more sustainable route while retaining selectivity and efficiency. Notably, copper coordination complexes, such as Cu(II)-8-hydroxyquinoline (Cu(II)-8HQ), have proven to be effective alternatives to simple copper salts, thereby expanding the scope and tunability of the oxidation system. Additionally, hydroxylactams that had remained inert under previous oxidative protocols were successfully transformed under the optimized Cu(II)/TBHP conditions, underscoring the enhanced capability and broader applicability of this method. Beyond isoindolinone scaffolds, the methodology was extended to the benzylic C–H oxidation of unactivated hydrocarbons, further demonstrating its versatility. Mechanistic investigations, informed by prior literature, support a pathway involving copper(II)-mediated formation of isoindolinoyl radicals as key intermediates.

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