Intermolecular cope-type hydroamination of alkenes and alkynes using hydroxylamines

Area of Science:

• Organic Chemistry
• Synthetic Methodology
• Catalysis

Background:

• Hydroamination reactions are crucial for synthesizing nitrogen-containing compounds.
• Existing methods often require harsh conditions, metal catalysts, or strong acids.
• Development of milder, more versatile hydroamination protocols is highly desirable.

Purpose of the Study:

• To develop a metal- and acid-free Cope-type hydroamination reaction.
• To explore the intermolecular reaction of hydroxylamines with alkenes and alkynes.
• To investigate the scope, limitations, and mechanistic aspects of this new synthetic method.

Main Methods:

• Utilized aqueous hydroxylamine and various alkenes/alkynes.
• Employed reaction optimization and additive screening (e.g., sodium cyanoborohydride).
• Conducted experimental studies alongside Density Functional Theory (DFT) calculations for mechanistic insights.

Main Results:

• Efficient synthesis of oximes from alkynes and N-alkylhydroxylamines from strained alkenes.
• Demonstrated reactivity with vinylarenes, yielding branched or linear products based on electronic properties.
• Identified compatibility with common protecting groups and functional handles.
• DFT analysis elucidated the critical role of proton transfer in the N-oxide intermediate.

Conclusions:

• The developed Cope-type hydroamination offers a mild and effective route for synthesizing valuable nitrogen-containing molecules.
• The reaction exhibits predictable regioselectivity with vinylarenes.
• Mechanistic understanding highlights the importance of specific intermediates and proton transfer steps.