Developing C–H bond Functionalization, Organocatalytic Hydrophosphination Reactions and Anti-Invasion Agents

Abstract

In chapters 1-3, we will discuss the development of iron alkoxide complexes for C–H bond functionalization. Currently, methods for C–H bond functionalization rely on precious metal catalysts that present environmental and health concerns. Earth abundant metals have been explored as sustainable catalysts; however, these systems are difficult to develop because of their distinct chemical properties and reactivity patterns compared to 4d and 5d metals. Several reported monometallic iron imido MLMB species capable of nitrene group transfer do so by accessing high-spin states, although their instability limits their applications. Bimetallic species were proposed to improve stability, but these complexes are difficult to synthesize and appeared to be unreactive. Herein, we disclose the Lewis base enhanced C–H bond functionalization mediated by a diiron alkoxide species. Alkoxide ligands were employed to synthesize high-spin bimetallic species due to their weak field and π-donor character, and substituted pyridines were utilized as a handle for nuclearity and reactivity control. Sterically encumbered pyridines allowed access to asymmetric bimetallic complexes (2.5a and 2.6a) and electron rich pyridines resulted in the monometallic analogs (2.2a-2.4a). Electron withdrawing p-trifluoromethylpyridine selectively accessed both the asymmetric dinuclear and mononuclear species indicative of electronic and steric controls. Diiron imido species were isolated with and without pyridine via nitrene capture with aryl azides (3.2a, 3.2b, 3.6a, and 3.6b) and demonstrated Lewis based enhanced toluene amination through a bimetallic pathway. In chapter 5, we will discuss the phosphine-catalyzed regio- and stereoselective hydrophosphination of 1,3-diynes. Diynes are important scaffolds for synthesizing π-conjugated organic frameworks for applications in organic synthesis and materials. The selective functionalization of diynes allows researchers to control the chemical properties of highly conjugated compounds for applications in optic and data storage devices. Phosphines have been shown to enhance the photochemical properties of unsaturated frameworks because of their unique metal-like properties; however, the hydrophosphination of 1,3-diynes is scarcely reported and requires the use of precious metals, alkali metals, or prefunctionalized materials. In this dissertation, we describe a facile method to access previously unreported (E)-(1,4-diphenylbut-1-en-3-yn-2-yl)diphenylphosphanes via the organocatalytic hydrophosphination of 1,4-diphenylbuta-1,3-diynes. The reaction employs catalytic n-tributylphosphine, has a mild substrate scope, and proceeds in a regio- and stereoselective fashion. In chapter 4, we will discuss the development of small molecule anti-invasion agents for the treatment of metastatic cancer. Metastasis remains the leading cause of anti-cancer treatment therapy and cancer-related death. The rapid spread and mutation of the cancerous cells complicates treatment and increases the chance of recurrence. Treatment options are limited because most anti-cancer agents inhibit tumor growth or cause apoptosis, but do not inhibit cancer spread, which is imperative for treating metastatic cancer. Recently, small molecule PDZ1i displayed anti-invasion activity and showed improved survival in multiple in vivo metastatic cancer mouse models. Inspired by PDZ1i, we conducted a structure activity relationship study of related small molecules with the aim of improving anti-invasion activity. Herein, we report a focused library of substituted 1-(benzo[d]thiazol-2-yl)-3-phenylurea derivatives inspired by the anti-invasion and anti-metastatic agent, PDZ1i. Our studies revealed that 1-(benzo[d]thiazol-2-yl)-3-phenylurea derivatives bearing 6-trifluoromethyl (4.3y) and 6-bromo (4.3aa) substituents display anti-invasion activity comparable to PDZ1i. The reported 1-(benzo[d]thiazol-2-yl)-3-phenylurea derivatives serve as promising starting points for future investigations of small molecule anti-invasion agents with potential to prevent and treat metastatic cancers.