Synthesis of ?,?-Unstaurated N-Aryl Ketonitrones and Use as Precursors for Synthesis of C3-Quaternary Indolenines



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Our group recently discovered and developed a diastereoselective reaction yielding C3-quaternary indolenines from the combination of ?,?-unsaturated N-aryl ketonitrones and mono- or di-activated alkynes in toluene at 80 ?C. This reaction builds a high level of complexity in a single step, and the C3-quaternary indolenines produced show promise as precursors to indole-containing molecules of biological and medicinal interest. However, we found our substrate scope was limited by the methods available for the synthesis of the ?,?-unsaturated N-aryl ketonitrones necessary for the reaction.

As a result of this need, we sought to develop a new way to access these ?,?-unsaturated N-aryl ketonitrones. Our priorities were to develop a method that was expedient with regard to time and number of steps, modular, general, and could rely on inexpensive commercially available starting materials. The method that we have reported proceeds in three steps: starting with a commercially available aniline derivative and ?,?-unsaturated aldehyde an imine is synthesized and alkylated using an organolithium reagent. The resultant secondary amine is then oxidized using Oxone? to obtain the ?,?-unsaturated N-aryl ketonitrone. Only the nitrone is subject to a discrete purification step, and it can generally be isolated in yields of 50-80%. Unfortunately, the nitrones generated using this technique would not react with activated alkynes to yield indolenines.

The two techniques discussed herein offer valuable insight into a poorly understood area of nitrone reactivity and are both synthetically useful in their own right. The studies performed make it clear that nitrones are a very viable synthetic intermediate; many nitrones can be easily accessed and then used to create very complex molecules in a diastereoselective manner. Both of these synthetic techniques in combination offer a valuable alternative approach to many complex and biologically interesting indole containing alkaloids. It is hoped that this work will serve as fertile ground for further studies towards increasing the utility of this chemistry.