Palladium - Catalyzed C - N Cross - Coupling Reactions Toward the Synthesis of Drug - Like Molecules

The development of methodologies for C-N bond formation reactions is an important scientific challenge because of many academic and industrial applications. This work will focus particularly on palladium-catalyzed cross-couplings of amine-containing compounds with aryl halides. The scope of the BrettPhos precatalyst for the cross-coupling of ortho-substituted aryl iodides with amides is studied using substrates with a variety of functional groups. Due to potential metal-chelating issues with some of the substrates used in this study, a proposed ligand synthesis is discussed in which one of the methoxy groups of BrettPhos is replaced with a morpholine capable of occupying palladium's open coordination site during its catalytic cycle. A final C-N bond formation study focuses on the cross-coupling of aryl halides with amidine salts. For this cross-coupling, a methodology has been developed that can be applied to various electron-rich, electron-poor, and electron-neutral substrates. Furthermore, the products of this cross-coupling can be used for a subsequent electrocyclization through a reaction with aldehyde, demonstrating that a relatively simple two-pot methodology can be used to make relatively complex substrates with pharmaceutical applications. Both amides and amidines are common moieties in drug-like molecules because of the various biological activities of these functional groups (1). Potential medicinal applications of the developed cross-coupling of amidine salts with aryl halides methodology are described (2). Thus, methodologies for various palladiumcatalyzed, C-N cross-couplings as well as a potential ligand synthesis to be used for palladium catalysis are herein discussed. Thesis Supervisor: Stephen L. Buchwald Title: Camille Dreyfus Professor of Chemistry