Thursday, June 9, 2011

Phenols from cyclohexanones!

A Science Express paper (doi: 10.1126/science.1204183) just came out by Shannon Stahl's group (Wisconsin-Madison) featuring chemistry that can aromatize substituted cyclohexanones or cyclohexenones to phenols using a palladium catalyst.  This type of double dehydrogenation reaction has previously been difficult to achieve under reasonable reaction conditions, typically requiring complex catalysts, continuous-flow reactors, and/or extremely high temperatures.  No side products are produced in this reaction other than water.  The only downside to me is the DMSO solvent... I hate that stuff.  The conditions seem relatively straightforward - I can't believe someone hasn't found - or at rather, explored (see below) - this sooner!

1 atm O2 and the relatively low temperature (compared to ~200-550 typically reported in the literature) make this an easily achievable benchtop reaction. The conditions were developed with the reasoning that the catalyst should be relatively electrophilic, since the key steps in the presumed reaction pathway were C-H activation (to nab the electron density you'd need an electrophilic catalyst) and β-hydride elimination.   The tosylic acid protonates the dimethyl amino group, rendering the ligand even more electron-deficient, thus the need for it in the reaction to improve the yield.
Figure 1A is the rationale for the transformation:

Electron donating and withdrawing groups are tolerated on aryl substituents, as are aryl ethers and esters, and halogens with the exception of para-bromide (28%) and iodide (16%), conveniently left out of the substrate table.  I'm sure the literature will reveal applications of this method to even more complex and highly functionalized systems, and hopefully the group continues mechanistic investigations so more reactions like this can be rationally developed.

It should be added that this is not the first time this type of reaction has been achieved at a reasonable reaction temperature with a palladium catalyst, but a previous (uncited!) Org. Lett. paper in 1998 saw phenol produced as a side product in selective dehydrogenation of ketones to produce allyl phenyl ethers, as in the following example from the screening table that produced undesired formation of phenol.

  • Yusuke Izawa, Doris Pun, & Shannon S. Stahl (2011). Palladium-Catalyzed Aerobic Dehydrogenation of Substituted Cyclohexanones to Phenols Science : 10.1126/science.1204183


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