THE DEVELOPMENT AND APPLICATION OF NEW PALLADIUM CATALYSTS IN CHALLENGING C-N AND C-O BOND FORMING REACTIONS
Lavery, Christopher B.
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In the pursuit of increasingly efficient and/or new chemical transformations, homogeneous transition metal catalysts are proving to be invaluable components of the synthetic chemist’s toolbox. Notwithstanding the many important contributions made to the area of synthetic chemistry utilizing other transition metal catalysts, palladium-catalyzed cross-coupling techniques have been demonstrated to allow for a plethora of otherwise very difficult or even impossible bond forming reactions to be realized. In this context, appropriately designed ancillary ligands, which upon binding to a metal center can influence metal-centred reactivity, have played an essential role in the advancement of palladium-catalyzed cross-coupling reactions. This thesis describes a multi-faceted approach to the identification of effective ligands for the palladium-catalyzed construction of (sp2)carbon-nitrogen and -oxygen bonds. A new series of P,O-DalPhos ligands were developed and applied in the synthesis of of N-substituted indoles via tandem palladium-catalyzed cross-coupling/cyclizations of ortho-alkynylhalo(hetero)arenes with primary amines. Notably, one P,O-DalPhos variant, OTips-DalPhos, was demonstrated to offer the broadest known substrate scope in this important class of transformations, affording a variety of structurally diverse indoles and related heterocyclic derivatives in high yields. Also described herein is the identification of the previously reported ligand BippyPhos as an extremely robust and versatile ligand in both palladium-catalyzed carbon-nitrogen and -oxygen cross-coupling applications. Indeed, the use of a Pd/BippyPhos catalyst enabled the cross-coupling of a range of (hetero)aryl (pseudo)halides with primary and secondary amines, NH heterocycles, amides, ammonia and hydrazine, with representative examples being accommodated in air. The unprecedented scope of the Pd/BippyPhos catalyst in carbon-nitrogen cross-coupling allowed for the development of two novel one-pot, two-step syntheses of N¬-aryl heterocycles from ammonia, ortho-alkynylhalo(hetero)arenes and (hetero)aryl halides through tandem N-arylation/hydroamination reactions. A marked selectivity profile was also observed for the Pd/BippyPhos catalyst and successfully exploited in the chemoselective monoarylation of substrates featuring two distinct and potentially reactive NH-containing moieties. Finally, Pd/BippyPhos mixtures served as robust and efficient catalysts for the hydroxylation of a range of (hetero)aryl halides and ortho-alkynyl(halo)heteroarenes to form phenols and phenol-derived heterocycles.