Remote Hydroxylation through Radical Translocation and Polar Crossover.

Area of Science:

• Organic Chemistry
• Catalysis
• Synthetic Methodology

Background:

• Aliphatic C-H bonds are typically inert and challenging to functionalize selectively.
• Remote functionalization strategies are highly desirable for complex molecule synthesis.
• Existing methods often require harsh conditions or lack site-selectivity.

Purpose of the Study:

• To develop a mild and site-selective method for the hydroxylation of aliphatic C-H bonds.
• To demonstrate the utility of this remote functionalization in synthesizing valuable organic compounds.
• To showcase a novel synthetic route to the antidepressant fluoxetine.

Main Methods:

• Employing fac-tris(2-phenylpyridine)iridium(III) ([Ir(ppy)3]) catalyst.
• Utilizing tosyl (Tz(o)) sulfonate esters and sulfonamides as directing groups.
• Radical translocation, carbocation oxidation, and nucleophilic trapping with water for C-H hydroxylation.

Main Results:

• Successful hydroxylation of various aliphatic C-H bonds under mild conditions.
• Demonstrated site-selective replacement of C-H with C-OH groups.
• Achieved methoxylation of two substrates via 1,6- and 1,7-hydrogen-atom transfer.
• Presented a synthesis of fluoxetine incorporating remote hydroxylation.

Conclusions:

• The developed method offers a powerful tool for remote C-H functionalization.
• This approach provides access to synthetically useful C-OH groups from inert C-H bonds.
• The strategy is applicable to the synthesis of complex pharmaceutical agents like fluoxetine.