Date of Award
Spring 2021
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Chemistry
First Advisor
Yi. Chae
Second Advisor
Donaldson, William
Third Advisor
Fiedler, Adam
Abstract
Primary aliphatic amines which are ubiquitous in natural products, traditionally considered as inert to substitution reactions. Recent studies clearly demonstrated that the aliphatic deaminative coupling chemistry can be used to make valuable scaffolds through C–N bond activation on transition metal complexes. The catalytic system generated in situ from the tetranuclear Ru–H complex with a catechol ligand (2-9/2-16) and independently synthesized ruthenium catecholate complex 2-11 was found to be effective for the direct deaminative coupling of primary amines. The catalytic system formed in-situ from the reaction of cationic Ru–H complex 2-10 with 3,4,5,6-tetrachloro-1,2-benzoquinone 2-12 was found to mediate a regioselective deaminative coupling reaction of ketones with amines to form the -alkylated ketone products. The monitoring of the coupling reaction of acetophenone and 4-methoxybenzylamine showed a rapid formation of PhC(Me)=NCH2C6H4-4-OMe, which was slowly converted to the alkylation product. The Hammett plot obtained from the reaction of para-substituted imines showed a strong promotional effect by the amine substrates with electron-releasing group (ρ = -0.96 ± 0.1), while the analogous plot obtained from the reaction of para-substituted imines with benzylamine showed a moderate promotional effect from the ketone substrates with electron-withdrawing group (ρ = +0.24 ± 0.1). The most significant carbon isotope effect was observed on the -carbon of the alkylation product (C = 1.020). The empirical rate law was determined as rate = kobs[imine][Ru] from measuring the kinetics of the alkylation reaction of the isolated imine substrate. A catalytically active Ru-catecholate complex was synthesized and the DFT study revealed a stepwise mechanism of the [1,3]-carbon migration step via the formation of a Ru(IV)-alkyl species. A plausible mechanism of the catalytic alkylation reaction via an intramolecular [1,3]-alkyl migration of Ru-enamine intermediate has been proposed. The in situ formed ruthenium catalytic systems (2-10/2-16), (2-10/2-12) and the complex 2-11 was also found to be highly selective for the dehydrogenative/deaminative coupling reactions to form number of pharmaceutically important nitrogen heterocyclic products with amines. The catalytic coupling method provides an operationally simple and chemoselective synthetic protocol without using any reactive reagents or forming wasteful byproducts.