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Synfacts 2017; 13(04): 0339
DOI: 10.1055/s-0036-1590107
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Vortioxetine via Catalyst-Free N-Arylation

Contributor(s):
Philip Kocienski
Jacobsen CB. Meldal M. Diness F. * University of Copenhagen, Denmark
Mechanism and Scope of Base-Controlled Catalyst-Free N-Arylation of Amines with Unactivated Fluorobenzenes.

Chem. Eur. J. 2017;
23: 846-851
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Further Information

Publication History

Publication Date:
17 March 2017 (online)

 
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Key words

vortioxetine - SNAr 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 SNAr reactions are compatible with a broad range of additional substituents on fluorobenzene B including alkyl, aryl, alkoxy, amine, azolyl, thioethers, fluorine, and chlorine groups.


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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.


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No conflict of interest has been declared by the author(s).



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