Development of Photoinduced Copper-Catalyzed Amination of Alkyl Electrophiles: Synthesis and Mechanism

Citation

Cho, Hyungdo (2025) Development of Photoinduced Copper-Catalyzed Amination of Alkyl Electrophiles: Synthesis and Mechanism. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/1008-m865. https://resolver.caltech.edu/CaltechTHESIS:07052024-225058837

Abstract

The formation of carbon-nitrogen (C–N) bonds is crucial in organic chemistry due to the importance of nitrogen-containing functional groups. While traditional nucleophilic substitution reactions, such as SN1, SN2, and SNAr, are limited in scope and efficiency, transition metal-catalyzed versions of these reactions, particularly involving copper, offer a more versatile approach by activating electrophiles and facilitating C–N bond formation via oxidative addition and reductive elimination.

Copper-catalyzed C–N couplings have been extensively developed but are primarily effective for aryl electrophiles rather than alkyl electrophiles due to the need for thermal activation, which often leads to undesired side reactions in alkyl electrophiles. The development of photoinduced copper-catalyzed reactions by Fu and Peters addresses these challenges, enabling the activation of alkyl electrophiles without thermal activation.

Over the past decade, the Fu group has focused on expanding the scope of this novel approach. The research detailed in this thesis focuses on developing photoinduced copper-catalyzed C–N coupling reactions for more challenging substrates, such as sterically hindered alkyl electrophiles and amines.

Chapter 2 discusses the photoinduced, enantio-convergent coupling of racemic tertiary alkyl electrophiles with aniline nucleophiles, catalyzed by bisphosphine-copper complexes. The mechanism of this reaction was elucidated using various tools, identifying key copper-based intermediates, including a chiral copper(II)–anilido complex that couples with a tertiary organic radical to form the C–N bond with good enantioselectivity.

Chapter 3 presents the photoinduced, copper-catalyzed coupling of secondary alkyl amines with secondary or tertiary alkyl bromides to synthesize N-tertiary alkyl amines under mild conditions. This novel reaction provides unique stereoselectivity and compatibility with strained electrophiles, contributing valuable methodologies to the synthesis of bioisosteres and other complex amine structures.

Overall, this work broadens the understanding and application of photoinduced copper-catalyzed reactions, offering new pathways for the synthesis of sterically hindered amines.

Thesis Files