Lithium-mediated Ferration of Fluoroarenes

Area of Science:

• Polar organometallic chemistry
• Synthetic organic chemistry
• Fluorinated aromatic compounds

Background:

• Fluoroaryl groups are vital in pharmaceuticals.
• Deprotonating fluoroarenes with organolithium bases is challenging due to unstable intermediates.
• Existing methods often lead to unwanted side reactions at low temperatures.

Purpose of the Study:

• To develop a novel method for selective fluoroarene deprotonation at room temperature.
• To investigate the mechanism of deprotonation using a mixed-metal base.
• To characterize the resulting organometallic intermediates and assess their stability.

Main Methods:

• Utilizing a mixed-metal base composed of lithium amide (LiHMDS) and FeII(HMDS)2.
• Performing deprotonation reactions on pentafluorobenzene and 1,3,5-trifluorobenzene at room temperature.
• Structural elucidation of organometallic intermediates using techniques like X-ray crystallography (implied).

Main Results:

• Selective deprotonation of fluoroarenes was achieved at room temperature using the mixed-metal base [(dioxane)LiFe(HMDS)₃].
• The deprotonation was identified as a ferration process, with iron occupying the deprotonated site.
• The resulting intermediates, [(dioxane)Li(HMDS)₂Fe(Ar^F)], were thermally stable and did not undergo LiF elimination or benzyne formation.
• Lithium was found to be essential for the reaction, as FeII(HMDS)2 alone was inactive.

Conclusions:

• The developed mixed-metal base provides an efficient and selective route for fluoroarene functionalization.
• This ferration strategy offers a stable alternative to traditional organolithium-mediated deprotonations.
• The findings advance the understanding of polar organometallic chemistry involving iron and lithium.