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DOI: 10.1055/s-0036-1589191
Synthesis of Vismodegib through meta-Selective Nitration of Arenes
Publication History
Publication Date:
19 September 2016 (online)
Key words
vismodegib - C–H activation - ruthenium catalysis - meta nitration - ortho metalation - palladium catalysisSignificance
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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