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Synfacts 2016; 12(10): 1001
DOI: 10.1055/s-0036-1589191
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Vismodegib through meta-Selective Nitration of Arenes

Contributor(s):
Philip Kocienski
Fan Z, Ni J, Zhang A * Shanghai Institute of Materia Medica and University of Chinese Academy of Sciences, Beijing, P. R. of China
Meta-Selective CAr–H Nitration of Arenes through a Ru3(CO)12-Catalyzed Ortho-Metalation Strategy.

J. Am. Chem. Soc. 2016;
138: 8470-8475
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Further Information

Publication History

Publication Date:
19 September 2016 (online)

 
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Key words

vismodegib - C–H activation - ruthenium catalysis - meta nitration - ortho metalation - palladium catalysis

Significance

Zhang and co-workers report the first example of a meta-selective CAr–H nitration of arenes bearing diverse N-heterocycles as directing groups. The reaction employs Ru3(CO)12 as the catalyst and Cu(NO3)2 as the nitrating agent. The postulated 18-electron octahedral intermediate B was synthesized and characterized by X-ray crystallography. Complex B reacted with Cu(NO2)2 to give nitroarene C in 70% yield.


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Comment

A synthesis of hedgehog inhibitor vismodegib depicted together with a further 32 examples of various N-heterocyclic directing groups establish the broad scope of the reaction. Note the use of a palladium-catalyzed, heteroatom-directed ortho metalation of nitroarene C. For a strategically related synthesis of vismodegib featuring a ruthenium-catalyzed meta bromination, see: Q. Yu, L. Hu, Y. Wang, S. Zheng, J. Huang ­Angew. Chem. Int. Ed. 2015, 54,15284.


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