Copper-Catalyzed Electrophilic Amination Reactions of Alkenes by O-Acyl-N-Hydroxyamines for the Synthesis of C(sp3)-N(sp3) Bonds in Allylic Amines and Vicinal Diamines

Abstract

AbstractNitrogen atoms are ubiquitous in bioactive organic molecules where they are key contributors to molecular recognition, making the synthesis of nitrogen-containing molecules an important task in organic chemistry. Alkylamines are a privileged class of nitrogenous molecule where the alkyl substituents impart a district lipophilicity profile well-suited in pharmaceuticals. However, traditional preparation of alkylamines relies on methods with established shortcomings such as the separation of quaternary ammonium salts and the generation of alkali metal waste. As a result, the development of catalytic methodology for C(sp3)-N bond construction is ongoing. One such approach is the electrophilic amination which employs reactive N-electrophiles to initiate reactivity with alkenes and other SOMOphiles to achieve multi-component difunctionalization cascades, oxidative amination and hydroamination reactions. However, this approach as well as other amination reactions frequently rely on specialized nitrogen sources lacking structural diversity. The Wang laboratory has developed a copper-catalyzed platform for electrophilic amination using O-acyl-N-hydroxyamines as convenient precursors to alkylamino motifs. This dissertation describes the discovery and development of two reactions; one used for the synthesis of allylic amines and the other for the synthesis of vicinal diamines. The reactions were operated using standard techniques and materials in synthetic chemistry such as a Schlenk manifold. The reaction outcomes were characterized by chromatographic isolation of the products and analysis by NMR spectroscopy, mass spectrometry, and X-ray crystallography. The allylic amination reaction provides a method for the synthesis of tertiary N-alkyl allylamines from variously substituted alkenes. There are only a few other oxidative allylic amination reactions compatible with alkylamines. In comparison, this method incorporates secondary alkylamines more efficiently than some and reacts across a wider range of alkene substitution patterns. Investigation of mechanism for this catalytic process revealed the presence of radical intermediates, an electronic influence on the desaturation step, and an absence of kinetic isotope effect in C-H cleavage. These findings support a turnover-limiting step that precedes desaturation of the radical intermediate and favors an oxidative elimination mechanism of C-H cleavage. Vicinal diamine synthesis is accomplished by a copper-catalyzed three-component reaction of vinylarene, O-acyl-N-hydroxyamine, and protected alkylamines. There is a single other report of alkene diamination that installs two distinct alkylamino groups with regioselectivity. This reaction identifies an effective means to overcome the challenges associated with nucleophilic amines in transition metal catalysis. In the presence of a chiral catalyst, unprecedented enantioselective benzylic amination by alkylamino groups is achieved. An additive promotes the reactions and addition of co-sovlent improves efficiency further. Preliminary reaction conditions have yielded up to 60% diamine product with 85% enantiomeric excess (e.e.). The outcome of this reaction implicates the possibility of unique mechanistic features.