PhI(OAc)₂-mediated trifluoromethylthiolation/oxidative cyclization of ynamides

Area of Science:

• Organic Chemistry
• Synthetic Chemistry
• Medicinal Chemistry

Background:

• Oxazolidine-2,4-diones are important heterocyclic compounds with diverse biological activities.
• Trifluoromethylthiolation (CF3S-introduction) is a key strategy for modulating the physicochemical and pharmacokinetic properties of drug candidates.
• Developing efficient methods for synthesizing CF3S-substituted heterocycles remains a significant challenge in organic synthesis.

Purpose of the Study:

• To establish a novel synthetic route for accessing CF3S-substituted oxazolidine-2,4-diones.
• To investigate the trifluoromethylthiolation/oxidative cyclization of ynamides using the readily available Shen reagent.
• To create complex molecular architectures featuring a quaternary carbon center.

Main Methods:

• Employing phenyliodine(III) diacetate (PhI(OAc)2) as the oxidant.
• Utilizing the Shen reagent (N-(trifluoromethylthio)phthalimide) as the CF3S source.
• Reacting ynamides with the Shen reagent under PhI(OAc)2 mediation.

Main Results:

• A facile and efficient method for the synthesis of CF3S-substituted oxazolidine-2,4-diones was developed.
• The reaction provides access to compounds bearing a quaternary carbon center.
• Yields ranged from 38-85% with excellent chemoselectivities up to 99/1.

Conclusions:

• The developed trifluoromethylthiolation/oxidative cyclization offers a straightforward pathway to valuable CF3S-containing heterocycles.
• This methodology enables the construction of complex molecular scaffolds relevant to drug discovery.
• The reaction's efficiency and selectivity make it a promising tool for synthetic chemists.