A Two-Step Protocol for Umpolung Functionalization of Ketones Via Enolonium Species

Umpolung of ketone enolates by virtue of reversing natural activity, enables the development of unprecedented reactions to functionalized carbon neo-compounds. The key is the formation of electrophilic enolonium species as a discreet species. A main advantage of methods based on electrophilic enolonium species is that it obviates the need for older multiple step methods, allows the use of commercial starting materials and is simple to use.

We recently had the idea for this method when we were able to characterize the electrophilic enolonium species for the first time. Over the last year, we have developed a series of new reactions based on the two-step protocol presented here. Today, we will describe how enolonium species made in the first step can be used in in situ coupling with allyl-silanes, aromatic compounds, chloride, azide and azoles.

Keep in mind that the implications of this technique extend toward other reactions, because the type of nucleophile that may be used is much less restricted than earlier hypervalent iodine-based methods. Demonstrating the procedure will be Shlomy Arava, a graduate student in our group. In a dry round-bottomed flask equipped with a septum and a magnetic stir bar, add 1.5 equivalents of Koser’s reagent and flush the flask with nitrogen or argon.

Add dry dichloromethane to give a formal concentration of 0.234 millimolars per liter. Cool the resulting suspension to minus 78 degrees Celsius using a dry ice acetone bath. Then, add 1.5 equivalents of neat boron trifluoride etherate slowly.

Warm the heterogeneous mixture to room temperature until it becomes a yellow solution, which typically occurs within five minutes. Following this, cool the solution to minus 78 degrees Celsius. To the cooled solution, add one equivalent of previously prepared trimethylsilyl ether solution drop-wise over two to 10 minutes to afford the enolonium species.

This is the most critical step of the protocol. If the TMS-enolate ether is added too fast, dimerization products form. Add two equivalents of a previously prepared allyl trimethylsilane solution slowly to the prepared solution of enolonium species at minus 78 degrees Celsius with stirring.

After five minutes, remove the cooling bath and allow the reaction mixture to reach room temperature. Once the reaction is complete, add water to the reaction mixture and transfer to a separatory funnel. Then, extract three times with dichloromethane, using two to three times the reaction volume for each extraction.

Next, wash the combined organic layers twice with brine using the same volume of brine as the combined reaction volume. After transferring the combined organic layers to a flask, dry with anhydrous sodium sulfate for 30 minutes. Following this, remove the sodium sulfate by filtration.

Then, remove the solvent on a rotary evaporator under reduced pressure at 40 degrees Celsius. Purify the crude product by column chromatography on silica gel using hexane and ethyl acetate as the eluant to afford the pure corresponding alpha allyl ketone. For the benzyldimethyldecylammonium chloride reaction, add two equivalents of a previously prepared chloride solution drop-wise to the prepared solution of enolonium species at minus 78 degrees Celsius with stirring.

After five minutes, remove the cooling bath and allow the reaction mixture to reach room temperature. For azedation, add 2.5 equivalents of neat azedo trimethylsilane drop-wise to the prepared solution of enolonium species at minus 78 degrees Celsius with stirring. After 15 minutes, heat the reaction mixture to minus 55 degrees Celsius and stir for two to three hours until the reaction is complete by TLC.

For the azole reaction, add four to five equivalents of a previously prepared azole solution drop-wise to the prepared solution of enolonium species at minus 78 degrees Celsius with stirring. After 15 minutes, heat the reaction mixture to minus 55 degrees Celsius and stir for four to eight hours until the reaction is complete by TLC. For arylation, add 1.6 equivalents of a previously prepared aromatic substrate solution drop-wise to the solution of prepared enolonium species at minus 78 degrees Celsius with stirring.

After the addition of the aromatic substrate is complete, increase the temperature of the mixture to minus 55 degrees Celsius and stir for 20 minutes until the reaction is complete by TLC. A very large range of different ketones may be used successfully in the alpha functionalization reaction to give the products in good yields, as observed for the azidation. The scope of the reaction for introducing azoles in the alpha position of ketones includes most of the common monocyclic and bicyclic nitrogen-containing heterocycles.

The scope of the allylation procedure includes allyl-crotyl-and prenyl-trimethylsilane. The C-aryllation procedure works for both indoles and electron-rich benzene derivatives using only 1.5 to 1.6 equivalents of the aromatic substrate. Thiophene, furane and pyrroles are also good substrates but the products are isolated in slightly lower yields and five equivalents of aromatic substrate are required.

Once mastered, both steps of the protocol can be done in less than five hours for most of the reactions and overnight for the azole coupling. While attempting this procedure, it’s important to remember to add the TMS-enolate slowly when making enolorium species to avoid dimerization of the enolate as a side reaction. Don’t forget that working with azides can be hazardous and appropriate precautions such as limiting the scale should always be taken.

Following the allylation procedure, you can add the prenyl group to make a quaternary center which is something that cannot be done using other methods. Using the arylation procedure means that you don’t need to worry about using a transition metal catalyst or a halogenated aromatic starting material. Just use a aromatic substrate.

After watching this video, we hope that the enolate umpolung will be a familiar concept to you and that you’ll be tempted to develop new reactions of your own.