Synthesis of Nafoxidine via Copper-Catalyzed Carboarylation

Key words

nafoxidine - copper-catalyzed carboarylation - diaryliodonium triflates - alkynes - vinyl cations

Significance

Nafoxidine is a nonsteroidal anti­estrogenic agent. The synthesis depicted features a copper-catalyzed alkyne carboarylation initiated through activation of diphenyliodonium triflate (B). The resultant catalytically generated aromatic electrophile equivalent reacts with the electron-rich alkyne A to form a stabilized trisubstituted ­vinyl cation type intermediate C that then undergoes a regioselective intramolecular Friedel–Crafts reaction to afford the dihydronaphthalene E preferentially.

 

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Comment

The scope of the carboarylation was explored via 31 examples, 28 of which were successful. The electronic requirements for the substituent on the alkyne were more rigid: It is essential to have a group capable of stabilizing the vinyl cation. Unsymmetrical analogues of the iodonium triflate B bearing a substituted arene and a mesityl group transferred the arene selectively. One example of an intermolecular carboarylation is described.

 

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