Hydrogen-Mediated C-C Coupling to form Allylic Alcohols

“Direct Vinylation of Alcohols or Aldehydes Employing Alkynes as Vinyl Donors: A Ruthenium Catalyzed C-C Bond Forming Transfer Hydrogenation”  Patman, R. L.; Chaulagain, M. R.; Williams, V. M.; Krische, M. J. J. Am. Chem. Soc. 2009131, 2066-2067. DOI: 10.1021/ja809456u

In their 2007 JOC perspective on hydrogen-mediated C-C bond formation, Krische and co-workers point out that “upon consideration of the E-factor for various segments of the chemical industry, a strong inverse correlation between process volume and waste generation is observed.”(1) Given that the lower volume fine chemical and pharmaceutical sectors typically focus on the production of chemicals with higher degrees of molecular complexity then their bulk chemical counterparts, the authors propose that there is a persistent need for the development of selective, atom-economical reactions capable of producing these relatively specialized chemicals. As luck would have it, the Krische group has come to the rescue with a number of reactions that might fit the bill.

One such reaction is their recent report of the ruthenium-catalyzed vinylation of alcohols or aldehydes using alkynes as the vinyl donors (shown above).

I think this reaction is neat because it represents a departure from how people have typically gone about bringing alkynes and alcohols together to form allylic alcohols. In this early example from the Wipf group, Schwartz’s reagent is added across a terminal alkyne to form a vinyl zirconocene reagent which upon addition of dimethyl zinc, transmetallates to give the vinyl zinc reagent. Finally, this reagent can nucleophilically attack an aldehyde:

Not only does this synthetic sequence stoichiometrically generate zirconium and zinc waste products and require the oxidation of your alcohol of interest to the corresponding aldehyde, but it also requires the use of the pyrophoric chemical dimethyl zinc (skip to minute 3 of this video to see the related compound diethyl zinc producing a pretty nice flame when squirted into open air).

The Jamison group has developed an interesting catalytic alternative to this methodology with the nickel-catalyzed reductive coupling of alkynes and aldehydes. This procedure substitutes the generation of zirconium and zinc byproducts shown above for the generation of boron byproducts due to the use of the stoichiometric reductant BEt3, but affords excellent regio-, stereo-, and enantioselectivity.

The Krische group’s work enables a similar transformation to take place, but the redox capability of the ruthenium catalyst used allows the the use of either alcohol or aldehyde starting materials, which I think is the coolest aspect of this chemistry.

When starting from the alcohol, the products observed are the redox neutral allylic alcohol and a small amount of oxidized enone. In order to minimize this oxidation pathway a superstoichiometric amount of iso-propanol reductant is employed. When starting from the aldehyde using iso-propanol as the reductant, “low conversion was observed.” However, when formic acid was employed as the stoichiometric reductant, the allylic alcohol was obtained in good yield. In this case, catalytic amounts of sodium iodide were “found to supress over-oxidation leading to enone side products.” In this case, an olefin isomerization side product is obtained. There is no mention in the paper of having tried either formic acid or sodium iodide when starting from the alkyne and alcohol.

The coupling of unsymmetrical alkynes with either alcohols or aldehydes was also investigated. When starting from the alcohol, overoxidation to the enone was observed, through their reporting of the yield as “>1%” leaves the readers hanging on how much that actually is.

The products were isolated as single regioisomers, where C-C bond formation occurs at the less sterically hindered alkyne carbon. The authors make no further mention of this regioselectivity, but my guess, for whatever it’s worth, is that the mechanism proceeds by insertion of a ruthenium-hydride across the alkyne, with the ruthenium center residing preferentially on the less sterically-hindered carbon.

While this publication leaves a number of questions open as to the mechanism and true scope of this reaction, it does offer a unique way to synthesize allylic alcohol and enone products.

Finally, putting on my “green chemistry lenses”, this chemistry is nice in that it can shorten synthetic sequences and uses the relatively benign reductants iso-propanol and formic acid. It does however rely on highly reduced non-renewable alkyne feedstocks. The reactivity observed with the alcohol reacting partner however opens up the possibility of performing similar reactions on poly-hydroxylated renewable feedstocks.


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