Exploring the Synthesis & Reactivity of Hydroxylamines: Hydroamination, Oxidation of Amines and Chemoselective N-O Bond Reduction

Abstract

Hydroamination reactions have been extensively developed over decades, providing a multitude of tools to approach this type of transformation. Both intramolecular and intermolecular hydroaminations can be catalyzed, notably by transition metal, photoredox and other types of catalysts, enabling the addition of NH bonds across C=C double bonds. Reactions of alkenes can proceed with high regioselectivity and enantioselectivity. Despite significant progress, formal hydroaminations involving hydroxylamines, which use retro-Cope elimination as a facilitating concerted mechanism, are relatively underexplored in the literature. These reactions, commonly referred to as Cope-type hydroaminations, have been documented for many years. This thesis concentrates on advancing classical hydroaminations through hydroxylamine intermediates, generated via the oxidation of amines. These intermediates can undergo Cope-type hydroamination to form N-oxides, which are subsequently deoxygenated to yield tertiary amines.

Chapter 2 reports a process for intramolecular hydroamination that uses a redox-enabled strategy relying on efficient in situ generation of hydroxylamines by oxidation, followed by Cope-type hydroamination, then reduction of the resulting pyrrolidine N-oxide. The steps are performed sequentially in a single pot, no catalyst is required, the conditions are mild, the process is highly functional group tolerant, and no chromatography is generally required for isolation. A robustness screen and a gram-scale example further support the practicality of this approach. Interestingly, the separation of amines by performing diborations on the alkene groups of starting materials is enabled by using B₂(OH)₄, recognized as excellent reductants for N-oxide reduction, in perfluorinated solvents (TFE or HFIP). This purification approach has proven effective across numerous substrates, facilitating column-free purification.

The oxidation of secondary amines has long posed challenges due to the uncontrolled over-oxidation of the resulting hydroxylamine products. Conventional indirect synthetic routes to secondary hydroxylamines often require multiple steps and are prone to undesirable side reactions. To address these limitations, Chapter 3 presents two direct oxidation methods for primary and secondary amines using UHP as an oxidant. The first method uses 2,2,2-trifluoroethanol (TFE) and a large excess of amine. Isolation of hydroxylamine products is enabled by selective salt formation, and recovery of excess amine is demonstrated. The second method uses hexafluoroacetone as an additive and is highlighted by the 1:1 stoichiometry between the oxidant and amine. During the oxidation of primary amines, not only are the desired secondary hydroxylamine products formed, but two additional N-O bond-containing species are also detected.

Despite major advances, intramolecular alkene hydroamination reactions often face limitations. In Chapter 4, a redox-enabled process featuring oxidation of an amine to a hydroxylamine, a concerted hydroamination step, followed by catalytic reduction of N-oxide is shown to be broadly applicable. Catalyst screening and optimization showed that a K₂OsO₂(OH)₄-pinacol complex rapidly and chemoselectively reduces the N-oxide cycloadduct in the presence of hydroxylamine and dimethyl sulfoxide. The selective reduction leverages Le Chatelier's principle to drive the equilibrium forward by selectively reducing N-oxide products without affecting hydroxylamines, contributing novel applications to the osmium (VI) chemistry. This approach also provides an efficient method to achieve complex structures previously unattainable in the hydroamination literature.

In Chapter 5, the redox-enabled Cope-type hydroamination strategy was extended to intermolecular reactions between hydroxylamines and activated alkenes or alkyl halides to generate in situ N-oxides, which underwent chemoselective N-oxide reduction to achieve various tertiary amines. Moreover, catalyst screening and optimization demonstrated that a K₂OsO₂(OH)₄-pinacol complex has proven effective in the N-oxide reduction. Additionally, preliminary studies on the reduction of chiral cyclic N-oxides with K₂OsO₂(OH)₄ and chiral ligands were performed. However, a maximum of 15% ee has been observed, necessitating further optimization and ligand/complex screening.

Overall, this thesis highlights the breadth and efficiency of hydroxylamine synthesis and chemoselective N-oxide reduction in Cope-type hydroaminations. Ongoing studies build upon these discoveries, advancing the catalytic redox strategy in hydroamination reactions.