The Development of Catalysts for the Monoarylation of Ammonia and Related Challenging Cross-Coupling Reactions

Abstract

The use of homogeneous organometallic catalysis for otherwise challenging chemical transformations is a concept that has gained significant interest in recent decades, providing access to a variety of useful chemical products. The catalytic reactivity of transition metals and non-reactive ancillary ligands that bind to the metal center has played an important role in such methods, with notable breakthroughs being Nobel Prize-winning reactions (palladium-catalyzed C-C cross-coupling, 2010). The research compiled in the thesis further develops the themes of ligand design and catalytic applications currently studied in the Stradiotto group. Key ideas throughout the thesis are to establish an understanding of the palladium/Mor-DalPhos catalyst system in ammonia arylation with respect to mechanism and substrate scope, and to expand the reactivity profile of the DalPhos ligand set to more challenging C-N and related cross-coupling processes. The first section describes an examination of the [Pd(cinnamyl)Cl] dimer/Mor-DalPhos catalyst system in C-N cross-coupling employing ammonia to better understand the catalyst formation process and to provide a guide for the development of precatalysts for otherwise challenging room-temperature ammonia monoarylations. Oxidative addition complex [(Mor-DalPhos)Pd(Ph)Cl] proved to be the optimal catalyst for arylation of ammonia at room temperature using aryl halides and tosylates. In the second section, ammonia cross-coupling was extended by applying it in the construction of indole frameworks, for the first time, which gave access to NH-indoles directly from ortho-alkynylbromoarenes. The Pd/JosiPhos was the superior catalyst system in comparison to Pd/Mor-DalPhos for this reaction and further stoichiometric studies revealed the reasons for this may be that the bulky arylalkyne ligand induces loss of ammonia from (Mor-DalPhos)Pd catalytic intermediates, and that catalyst inhibition by the alkyne substrate through irreversible metal binding is also a possible factor prior to the oxidative addition step. The reactivity profile of the DalPhos ligand set was successfully expanded in the third section of the thesis to palladium-catalyzed aminocarbonylation of aryl bromides using a pyridine-derived DalPhos variant (Pyr-DalPhos). Several different aryl and some heteroaryl bromides were accommodated in the coupling reaction with ammonia and carbon monoxide as reagents, providing aryl amide products in synthetically useful yields. The methodology described in the final thesis section demonstrated the use of Mor-DalPhos and [Pd(cinnamyl)Cl] dimer mixtures for gaining access to the first examples of ketone alpha-arylation employing aryl methanesulfonates (mesylates) and expanding the scope of amination reactions involving these non-halide aryl electrophiles to primary alkyl amines for the first time. These transformations featured acetone and methylamine as coupling partners, both of which can be difficult substrates to monoarylate but were found to be coupled with ease in this chemistry.