Lewis acids activated and catalyzed cyclization and addition reactions of aminyl radicals from N-hydroxypyridine-2-thione carbamates

Abstract

This dissertation discusses the use of Lewis acids to activate and catalyze cyclization and addition reactions of aminyl radicals generated from N-hydroxypyridine-2-thione carbamates to unsaturated systems under very mild reaction conditions. Most neutral aminyl radicals are nucleophilic in nature and relatively stable; thus, they offer little synthetic utility. Complexation of the metal ion to the aminyl radical changes the radical from a nucleophilic species to an electrophilic radical, which then readily undergoes cyclization or intermolecular addition to a double bond. The effect of Lewis acids on the reactivities of aminyl radicals generated from their carbamate precursors was examined by varying the reactions conditions (temperature, identity, and amount of Lewis acids employed). The generality of the methodology was analyzed by employing different types of Lewis acids as promoters. The utility of the Lewis acid activation method was determined by studying both 5-exo cyclizations and intermolecular addition reactions of complexed nitrogen-centered radicals to activated and unactivated olefins. The potential of employing chiral Lewis acids to influence the enantioselectivity of the addition reactions of aminyl radicals to olefins also was investigated. Our results demonstrated Lewis acid catalysis of aminyl cyclizations and addition reactions. The chemistry is similar to other methods of activating aminyl radicals (Bronsted acids, redox agents, or UV irradiation), but the reaction conditions are much milder. Low temperatures and aprotic solvents could be employed, and, in some cases, only a catalytic amount of a Lewis acid was needed to obtain a high yield of desired product. Therefore, Lewis acid activation should be useful in aminyl radical reactions where the substrates bear acid labile groups. The results indicate that Lewis acid activated radical chain cyclization and addition reactions of aminyl radicals from PTOC carbamates may be a useful synthetic tool for constructing and functionalizing nitrogen heterocycles.