Synthesis of Novel Hexahydroindoles from the Dearomatization of Indoline Using a Tungsten Pi-Base

MacLeod, Brianna, Chemistry - Graduate School of Arts and Sciences, University of Virginia
Harman, Walter, Department of Chemistry, University of Virginia

Chapter 1 explores the reactivity of aromatic molecules in traditional organic chemistry. Due to their innate stability, arenes require harsh forcing conditions for substitution products and rarely are dearomatized. Through the use of transition metal complexes, this dearomatization is now possible. The use of electron deficient and electron rich metal systems are explored, though the main focus of this chapter is on the {TpW(NO)(PMe3)} metal fragment. This system has the ability to η2-coordination many arenes, but coordination of N,N-dimethylaniline and derivatives are of great importance. Through this coordination, these systems have synthesized multiple novel small molecules
Chapter 2 describes previous work completed towards the synthesis of naturally found alkaloids which contain indoles, indolines and perhydroindoles. The ability to expand the synthesis of biologically interesting molecules away from aromatic molecules and into fully saturated cores broadens the potential of compounds available for biological testing. This chapter elaborates on methods of how organic chemists are synthesizing the perhydroindoles synthetic core in various alkaloids and the biological interest of these alkaloids.
Chapter 3 explores the coordination of larger alkaloid like aromatics to the {TpW(NO)(PMe3)} metal system. These include N-alkylindoline and 1-methyl-1,2,3,4-tetrahydroquinoline. Through an acid trapping type synthesis, these alkaloids are bound through an η2-bond. The protonation of these systems in either an ortho vs para position is explored, as is protonation anti vs syn to the metal complex. The initial reactivity of the N-ethylindoline complex is investigated with H+ as an electrophile. Preliminary testing of 1,6-dimethyl-1,2,3,4-tetrahydroquinoline as a ligand, and subsequent reactivity, is explored.
Chapter 4 elaborates on the reactivity of the N-ethylindoline complex with various electrophiles, including isocyanates, mCPBA and halides. The reduction of the iminium bond is explored successfully, allowing the formation of multiple new complexes which have much lower reduction potentials. The oxidation of these systems generates novel hexahydroindoles with broad functionality.
Chapter 5 focuses on the exploration of new reactivity pathways for both the N-ethylindoline and N,N-dimethyaniline systems. The addition of NCS as an electrophile leads to the concept of possible double nucleophilic addition reactions. A ring turn product allows for the activation of a new position of the aniline and indoline systems through the addition of new electrophiles. The isolation of a new organic hexahydroindoles from this ring turn system is explored.

PHD (Doctor of Philosophy)
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