Synthesis and Diversification of Bridged N-Heterocycles via Sequential Transition Metal-Catalyzed Reactions

Abstract

Of major interest to modern synthetic organic chemistry is the use of transition metal catalysis to achieve carbon-carbon bond formation. Over the past 40 years many of these versatile and simple methodologies have been developed including the Heck reaction, Stille coupling, Suzuki coupling, Sonogashira coupling, Buckwald-Hartwig reaction, Tsuji-Trost reaction, Negishi coupling and olefin metathesis. One application of these methods is in the formation of nitrogen-containing heterocycles, an omnipresent feature of many biologically active alkaloids and synthetic drugs. The goal of this dissertation is to expand the known applications of sequential transition metal catalysis to the synthesis of highly substituted bridged N-heterocycles and their subsequent diversification. Our future goal is to have the methodologies described herein applied to combinatorial library synthesis. The first project outlines a successful development of a new sequential transistion metal-catalyzed methodology utilizing a copper-catalyzed three-component coupling followed by a palladium-catalyzed Heck cascade to form an aryl-fused isoquinuclidine (2-azabicyclo[2.2.2]octane) core. Diversification of the bridged core is then explored including palladium-catalyzed allylic functionalization and ruthenium-catalyzed cross-metathesis. The second project described herein involves a sequential copper-catalyzed three-component coupling followed by a radical initiated intramolecular cyclization. By this process, diversification of the isoquinuclidine (2-azabicyclo[2.2.2]octane) core is achieved in the initial Cu-catalyzed reaction. The third project describes our preliminary efforts at developing a sequential transition metal-catalyzed method for the preparation of a bicyclobenzazepine (1-azabicyclo[3.2.2]nonane) scaffold and the challenges faced there in.