PPh₃-Catalyzed Remote Aminofluorination Reactions: Regioselective Access to γ- and ε-Fluoroamines Containing Oxindole

Area of Science:

• Organic Chemistry
• Synthetic Chemistry
• Medicinal Chemistry

Background:

• Remote aminofluorination is crucial for synthesizing valuable fluoroamine compounds.
• Developing efficient and selective methods for creating 1,n-fluoroamines (n>2) remains a significant challenge in organic synthesis.

Purpose of the Study:

• To develop a novel catalytic remote 1,5-aminofluorination of spirovinylcyclopropyl oxindoles.
• To investigate the effect of additives on the regioselectivity of the aminofluorination reaction.
• To synthesize novel γ- and ε-fluoroamines containing oxindole scaffolds.

Main Methods:

• Catalytic remote 1,5-aminofluorination using triphenylphosphine (PPh3) as a catalyst.
• Investigation of N-fluorobenzenesulfonimide (NFSI) as the fluorine source.
• Exploration of trimethylsilyl cyanide (TMSCN) as an additive to control regioselectivity.
• Characterization of products using high-resolution mass spectrometry.

Main Results:

• Achieved remote 1,5-aminofluorination of spirovinylcyclopropyl oxindoles yielding ε-fluoroamines with up to 60% yield and high E:Z selectivity (>20:1).
• Demonstrated that TMSCN additive dramatically shifts the reaction to 1,3-aminofluorination, producing γ-fluoroamines with high yield (up to 99%) and diastereoselectivity.
• Proposed a plausible reaction mechanism based on experimental observations and mass spectrometry data.

Conclusions:

• Developed a versatile catalytic system for remote aminofluorination, enabling access to both γ- and ε-fluoroamines.
• Highlighted the significant impact of additives like TMSCN in controlling the regioselectivity of these transformations.
• The proposed methodology offers a powerful strategy for constructing complex fluoroamine-containing molecules for potential applications.