Palladium catalyzed oxidative arylation of heterocyclic substrates

Kyle C Pereira, University of Rhode Island


Recently there has been extensive development in the study and understanding of reactions involving the activation of relatively inert C-H bonds to form new C-C bonds between two unsymmetric arenes. Contemporary methods require the prefunctionalization of each substrate in order to facilitate a palladium catalyzed cross-coupling reaction. The additions of these functional groups are costly, and the groups themselves become waste material following the reaction. Herein, we report the discovery and optimization of methods involving catalytic metalation of unfunctionalized C-H bonds, which reductively eliminate to yield a new C-C bond linking two unsymmetric arene substrates. The main focus of this thesis is the discussion of evolving methods in which the regioselective arylation of electron rich substrates such as benzofuran and indole can be achieved by employing the use of transition metal catalysts such as palladium(II) acetate and metallic oxidants such as copper(II) acetate and silver(I) acetate. The first manuscript entitled "Regioselective Oxidative Arylation of Indoles Bearing N-Alkyl Protecting Groups: Dual C-H Functionalization via a Concerted Metalation-Deprotonation Mechanism" is focused on regioselective palladium catalyzed oxidative cross-coupling of N-acetylindole in the presence of stoichiometric oxidants like silver(I) acetate and copper(II) acetate. We have developed and optimized conditions for the selective C2/C3 arylation of N-acetylindoles, in non-acidic media, in the presence of an oxidant. We have demonstrated the kinetic isotope effects for both the major and minor products of reactions oxidized by both AgOAc and Cu(OAc)2, which were determined using GC/MS analysis of benzene/benzene-d6. Computational and experimental data was used to thoroughly elucidate the mechanism of the reaction. The second manuscript entitled "Conversion of Cellulose to Glucose and Levulinic Acid via Solid-Supported Acid Catalysis" is focused on the controlled decomposition of cellulose to afford valuable bio-fuel precursors. We have observed that accessing the beta(1-4) linkage between glucose units, for consequent hydrolysis, is considerably difficult due to the secondary lattice structure between cellobiose monomers. This lattice is comprised of relatively strong hydrogen bonds and is the primary reason for the poor solubility observed for cellulose. We have discovered recyclable conditions which can hydrolyze the beta(1-4) linkage, albeit, in low yields, however, comparable to currently available technology and under relatively mild conditions. The third manuscript entitled "Mechanistic Insight into the Palladium Catalyzed Oxidative Arylation of Benzofuran" is focused on the effects of oxidant choice and pH of medium on the regioselectivity and reactivity of the reaction. It was observed that regioselectivity can be controlled simply by varying the terminal oxidant. Furthermore, we found that the rate of the reaction is directly correlated to the concentration of acidic additive. During the course of these investigations it was also observed that benzofuran substrates can be coupled to benzene under aerobic conditions using metallic oxidants in catalytic amounts coupled with stoichiometric oxygen.

Subject Area

Organic chemistry

Recommended Citation

Kyle C Pereira, "Palladium catalyzed oxidative arylation of heterocyclic substrates" (2011). Dissertations and Master's Theses (Campus Access). Paper AAI1491629.