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One-two punch converts benzenes to cyclohexenes

Tweaks to tungsten-benzene complex enable a tandem addition reaction for making drug intermediates

by Stephen K. Ritter
August 28, 2017 | A version of this story appeared in Volume 95, Issue 34

A reaction scheme shows a tungsten complex in which a trifluoromethyltoluene ligand undergoes dearomatization to form a cyclohexene.

Aromatic compounds are largely untapped as precursors for synthesizing cyclohexadienes and cyclohexenes, typically because of the harsh conditions needed to overcome the stability of the delocalized ring. But Katy B. Wilson has developed a tungsten-mediated reaction system that makes this dearomatization seem easy. Working in W. Dean Harman’s research group at the University of Virginia, Wilson has found that including a trifluoromethyl group on the benzene ligand of a tungsten complex, [trispyrazolylborate]W(NO)[P(CH3)3](η2-benzene), enhances the metal-arene interaction and exerts control over the sequential protonation and attack of two nucleophilic reagents on the aromatic ligand. The result, as Wilson described at the ACS national meeting, is a new tandem addition reaction for preparing highly functionalized trifluoromethylated cyclohexenes with regio- and stereocontrol, such as the example shown (J. Am. Chem. Soc. 2017, DOI: 10.1021/jacs.7b05118). Harman’s group has a history of using this type of metal complex to induce unexpected reactivity in aryl molecules, including dearomatization of aromatic and heteroaromatic rings and enabling pyridines to undergo Diels-Alder reactions. Dearomatizations are often a key step in building the core structures of natural products and other bioactive compounds. Wilson said the team isn’t out to synthesize natural products but is looking for reactions useful in midstage functionalizations during the optimization of drug leads.


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