Redox-triggered cascade dearomative cyclizations enabled by hexafluoroisopropanol

Area of Science:

• Organic Chemistry
• Synthetic Methodology
• Catalysis

Background:

• Hydride transfer reactions are crucial in organic synthesis but often face limitations in redox-neutral processes.
• Developing efficient methods for constructing polycyclic amines, a common motif in pharmaceuticals, remains a challenge.

Purpose of the Study:

• To develop an unprecedented cascade dearomatization/rearomatization/dearomatization sequence for synthesizing polycyclic amines.
• To explore the role of hydrogen-bonding assistance in hydride transfer reactions.
• To overcome drawbacks associated with traditional hydride transfer-involved redox-neutral reactions.

Main Methods:

• Utilizing phenols and o-aminobenzaldehydes as starting materials.
• Employing a cascade sequence involving dearomatization, rearomatization, and a second dearomatization.
• Leveraging hydrogen-bonding assistance, particularly the aggregate effect of hexafluoroisopropanol (HFIP), to facilitate hydride transfer.

Main Results:

• Successfully realized a novel cascade dearomative cyclization reaction.
• Demonstrated the rapid buildup of polycyclic amines through an efficient synthetic pathway.
• The use of HFIP was key to enabling the cascade sequence and achieving high yields.

Conclusions:

• The developed method provides an unprecedented route to polycyclic amines via hydrogen-bonding-assisted hydride transfer.
• This transformation offers a unique and efficient alternative to existing methods for synthesizing complex amine structures.
• The study highlights the potential of aggregate effects in promoting challenging chemical transformations.