Gold(I)-Catalyzed Enantioselective Hydroamination of Unactivated Alkenes by Seong Du Lee Department of Chemistry Duke University Date:_______________________ Approved: ___________________________ Ross A. Widenhoefer, Supervisor ___________________________ Jiyong Hong ___________________________ Katherine J. Franz ___________________________ Qiu Wang Dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Chemistry in the Graduate School of Duke University 2012 i v ABSTRACT Gold(I)-Catalyzed Enantioselective Hydroamination of Unactivated Alkenes by Seong Du Lee Department of Chemistry Duke University Date:_______________________ Approved: ___________________________ Ross A. Widenhoefer, Supervisor ___________________________ Jiyong Hong ___________________________ Katherine J. Franz ___________________________ Qiu Wang An abstract of a dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Chemistry in the Graduate School of Duke University 2012 i v Copyright by Seong Du Lee 2012 Abstract Numerous methodologies for efficient formation of carbon-nitrogen bonds have been developed over the decades due to the widespread importance of nitrogen containing compounds in pharmaceuticals and bulk commercial chemicals. Among many methods, hydroamination, in particular, has attracted considerable attention owing to its high atom economy and use of simple C-C substrates. As a result, numerous methods for hydroamination have been reported which employ a range of metal catalysts. However, the hydroamination of unactivated alkenes remains an unsolved challenge owing to the low reactivity of the C=C double bond. The recent development of gold(I) as an effective π-activation catalyst prompted us to develop efficient gold (I)-catalyzed methods for enatioselective intra- and intermolecular hydroamination of unactivated alkenes. A gold(I)-catalyzed method for the enantioselective intramolecular hydroamination of unactivated alkenes has been developed. Various gold(I) catalysts have been synthesized to examine their reactivity and enantioselectivity in asymmetric intramolecular hydroamination. Among the catalysts, bis(gold) complexes containing an axially chiral bis(phosphine) ligand catalyze the enantioselective intramolecular hydroamination of unactivated alkenes with carboxamide derivatives most effectively. The method was effective for both carbamate and urea nucleophiles to form pyrrolidine derivatives with up to 85 % ee. iv The first enantioselective intermolecular hydroamination of unactivated alkenes was realized by a gold(I)-catalyzed method. The gold(I) catalyst system adds cyclic ureas to unactivated 1-alkenes to produce corresponding enantiomerically enriched hydroamination product in good yield with enantioselectivity up to 78 % ee. Polymer-embedded ligands have been synthesized to demonstrate proof of concept for fluxional mechanocatalysis; the outcome of a catalytic reaction is influenced by the stress state of the catalyst. Polystyrene (PS) or styrene acrylonitrile (SAN) was introduced into a chiral bis(phosphine) ligand to generate polymer-embedded ligands. The catalytic reactivity of the synthesized PS and SAN-embedded ligands was examined in palladium catalyzed asymmetric allylic alkylation (AAA) and showed good enantioselectivity of 89 % and 92 % ee, respectively. However, the enantioselectivity of AAA under a shear stress in a bob rheometer displayed no changes compared with the enantioselctivity of AAA observed in the absence of a shear stress. v Dedicated to my wife, Boyoung Yoon, and my parents, Jungho Lee and Backhapja Lee . vi Contents Abstract ......................................................................................................................................... iv List of Tables .................................................................................................................................. x List of Figures ............................................................................................................................... xi Acknowledgements ................................................................................................................. xvii Chapter 1 ........................................................................................................................................ 1 Room Temperature Gold(I)-Catalyzed Enantioselective Intramolecular Hydroamination of Unactivated Alkenes ................................................................................................................ 1 1.0 Background ...................................................................................................................... 2 1.1 Introduction ...................................................................................................................... 3 1.1.1 Metal catalyzed Enantioselective Intramolecular Hydroamination of Unactivated Alkenes ............................................................................................................ 3 1.1.1.1 Enantioselective Hydroamination Catalyzed by Rare-Earth Metal Complexes ......................................................................................................................... 3 1.1.1.2 Enantioselective Hydroamination Using Group 4 Metal Catalysts ........... 10 1.1.1.3 Enantioselective Alkene Hydroamination Catalyzed by Late Transition Metal Complexes. ........................................................................................................... 15 1.1.2 Special Characteristics of Gold(I) in Homogeneous Catalysis ........................... 17 1.1.3 Project Motivation .................................................................................................... 18 1.2 Results and Discussion .................................................................................................. 20 1.2.1 Optimization and Substrate Scope .......................................................................... 20 1.2.2 Mechanism ................................................................................................................ 28 1.2.3. Summary................................................................................................................... 31 vii 1.3 Experimental Section ..................................................................................................... 32 1.3.1 General Methods ....................................................................................................... 32 1.3.2 Synthesis of Alkenyl Carbamate Substrates ......................................................... 33 1.3.3 Synthesis of Alkenyl Urea Substrates .................................................................... 36 1.3.4 Synthesis of N-(2-allylphenyl)acetamide (28) ....................................................... 39 1.3.5 Gold(I)-Catalyzed Enantioselective Intramolecular Hydroamination of Alkenyl Carbamates ........................................................................................................... 40 1.3.5 Gold(I)-Catalyzed Enantioselective Intramolecular Hydroamination of Alkenyl Ureas ..................................................................................................................... 45 1.3.6 Gold(I)-Catalyzed Enantioselective Intramolecular Hydroamination of N-(2- allylphenyl)acetamide (28) ................................................................................................ 48 1.3.7 Catalyst Synthesis ..................................................................................................... 50 Chapter 2 .................................................................................................................................... 122 Gold(I)-Catalyzed Enantioselective ........................................................................................ 122 Intermolecular Hydroamination of Unactivated .................................................................. 122 Alkenes ....................................................................................................................................... 122 2.1 Introduction .................................................................................................................. 123 2.2 Results and Discussion ............................................................................................... 128 1.2.1 Optimization and Substrate Scope ....................................................................... 128 2.2.2 Mechanism .............................................................................................................. 137 2.3 Experimental Section ................................................................................................... 138 2.3.1 General Methods ..................................................................................................... 138 viii 2.3.2 Gold(I)-Catalyzed Enantioselective Intermolecular Hydroamination of 1- Alkenes. ............................................................................................................................. 139 2.3.3 Control Reactions .................................................................................................... 142 Chapter 3 .................................................................................................................................... 146 Synthesis and Application of Polymer Embedded .............................................................