Synthesis of Vortioxetine via Catalyst-Free N-Arylation

Key words

vortioxetine - S_NAr reaction - fluorobenzenes - N-arylation - lithium dialkylamides

Significance

Diness and co-workers describe a method for the N-arylation of secondary amines A with unactivated fluorobenzene derivatives B. The base of choice is lithium hexamethyldisilazide because it cleanly metalates amine A without competing metalation of fluorobenzene B and consequent side reactions such as benzyne formation. Cyclic and acyclic secondary amines can be efficiently arylated. Moreover, these S_NAr reactions are compatible with a broad range of additional substituents on fluorobenzene B including alkyl, aryl, alkoxy, amine, azolyl, thioethers, fluorine, and chlorine groups.

Comment

Diness and co-workers describe 30 examples of this transition-metal-free N-arylation reaction, including four disubstitutions of difluorobenzene derivatives exemplified by the synthesis of vortioxetine, a serotonin modulator and stimulator that was approved by the FDA in 2013 for the treatment of major depression.