Exploring the Reactivity of Hydroxylamine-Containing Species : O-Isocyanates and Cope-Type Hydroamination

Abstract

While the chemistry of hydroxylamines has been well investigated since the 19th century, new methodologies and uses of this distinctive functional group continue to be reported, largely for amination. The work reported within this thesis centers around two general uses of hydroxylamines: (1) as an electrophile within highly reactive O-isocyanates, and (2) as a nucleophile in Cope-type hydroamination reactions. O-Isocyanates are not stable species, homocoupling or degrading readily at ambient conditions, so various blocked carbamate precursors were assessed and developed to form O-isocyanates in equilibrium. This maintains a low concentration of free O-isocyanate, allowing for efficient substitution reactivity with amines. This blocking group strategy has also been applied to new [3+2] cycloaddition chemistry. Upon deblocking, free O-isocyanates can act as uncharged 1,3-dipole equivalents, forming highly reactive aza-oxonium ylide cycloadducts from intra- or intermolecular cycloaddition in stark contrast to conventional dipolar cycloaddition. The divergent reactivity of the novel charged species, aza-oxonium ylides, has been explored for the formation of bicyclic lactams, β-lactams, oxazinones, and isoxazolidinones depending on the reaction conditions and substrates chosen. Computational results support a concerted asynchronous [3+2] cycloaddition, though provided no potential means to broaden the intermolecular dipolarophile substrate scope. Conversely to the electrophilic reactivity of O-isocyanates, acyl and alkyl substituted hydroxylamines have been used to develop new Cope-type hydroamination reactivity, where the hydroxylamine nitrogen acts as a nucleophile. The cascade substitution and Cope-type hydroamination of N-oxyureas is reported, combining O-isocyanate and hydroamination reactivity in one sequence. A redox-enabled strategy for intramolecular Cope-type hydroamination was developed to bypass the synthetic difficulties associated with hydroxylamines and N-oxides. Using simple secondary amines as reagents, a robust process was developed that did not require the use of chromatography for purification. The successful overall reaction supports the further development of an oxygen-borrowing approach to hydroamination. These studies demonstrated significant solvent effects using trifluoroethanol, which in part, leads to more stable N-oxide products. Lewis interactions involving boron-substituted alkenes were also explored as a strategy to increase N-oxide stability. Significantly faster reactivity is observed with boron-substitution and the products are stable when X = H. Otherwise, bora-Cope elimination occurs readily, leading to observable alkene products as well as the assumed formation of O-borylhydroxylamines. While efforts to exploit O-borylhydroxylamines for bora-amination reactivity have not proven fruitful, this reactivity has been exploited for the selective semi-hydrogenation of alkynes via sequential hydroboration then hydroamination and bora-Cope elimination. A computational collaboration allowed for the elucidation of the effects boron substitution, including the lowering the HOMO-LUMO gap and stabilizing the increased electron density at carbon with the B-O π* orbital. This work overall demonstrates the breadth and efficiency of metal-free hydroxylamine reactivity. Further studies stemming from the discovery and initial work related to borrowing oxygen approach to hydroamination and the increased Cope-type hydroamination reactivity of vinylboronates are already proving productive.