α- and β-Amino C−H Functionalization through Cooperative Catalysis

Abstract

When a catalytic reaction is carried out between two reactants, usually only onereactant is activated by a single catalyst while the other component is pre-activated so that the sluggish reactivity was compensated. In order to broaden the substrate scope, the development of cooperative catalysts that can generate both electrophilic and nucleophilic species in situ represents a compelling research objective. This thesis is focused on the development of cooperative catalyst systems and their applications to α- and β-amino C−H bond functionalization. In the first chapter of this thesis, a brief summary of the present cooperative catalysts will be discussed. In the second chapter, the development of cooperative acid/acid catalysts for the α-alkynylation of N-alkylamines will be discussed. Typically, catalytic α-amino C−H alkynylation process is carried out under oxidative conditions, and enantioselective reactions are confined to tetrahydroisoquinoline derivatives. We disclose a strategy for the union of N-alkylamines and trimethylsilyl alkynes through cooperative actions of two Lewis acids, B(C 6 F 5 ) 3 and a Cu-based complex without the use of oxidants. We proposed that various propargylamines can be synthesized through the reaction between a L n Cu−alkynyl complex and an iminium ion that are generated in situ. Furthermore, the utility of this protocol was demonstrated by applications in late stage α-alkynylation of bioactive amines and stereoselective synthesis of propargylamines. In the third chapter of this thesis, catalytic and regioselective deuteration of β-amino C−H bonds in an array of N-alkylamine-based pharmaceutical compounds will be described. Isotopic labeling of β-amino C−H bond is promoted by the cooperative action of Lewis acidic B(C 6 F 5 ) 3 and Brønsted basic N-alkylamine, converting a bioactive amine first into an iminium ion and then the corresponding enamine. Meanwhile, the acid/base catalysts can also promote the dedeuteration of acetone-d 6 to afford a deuterated ammonium ion and a boron enolate. Ensuing deuteration of the enamine by deuterated ammonium ion followed by borohydride reduction leads to the formation of β-deuterated bioactive amines with up to 99% deuterium incorporation.