We have performed intensive studies in both batch and flow conditions. Specifically, we have focused on the enantioselective intermolecular α-arylation of carbonyl compounds through aminocatalysis. Despite our efforts, we were not able to observe the formation of the desired compound by any means.
In light of these results, we fall back on our contingency plan, that included the use of a specialized molecule, already adorned with a radical-trapping moiety, to assess the feasibility of electrochemically activating enamines. By simply placing a pendant olefin on the aldehyde core, we started observing formation of the cyclized product when using pyrrolidine as achiral catalyst for the non-asymmetric reaction. Unfortunately, already at this stage of the project we noticed how the use of flow was not beneficial to the overall yield of the reaction as well as on the rate of the process. We rationalized that, while the electrochemical steps are greatly enhanced by flow chemistry, the organocatalytic steps do not particularly benefit from this type of setup, thus the two modes of activation are outbalanced and results in lower yield of the desired product. In light of this, all the remaining experiments have been carried out in batch.
Next, we focused on the use of a chiral catalyst. We soon realized how the MacMillan Imidazolidinone catalyst was not effective for promoting this reaction since the product was not formed in its presence. On the contrary, the use of the Jorgensen catalyst, a silyl prolinol derivative, delivered the desired cyclized product in 25% yield and 87% enantiometic excess (ee). Intensive optimization of the reaction conditions lead to an increase in the yield to 45% and no change in the enantioinduction (87% ee). However, one thing that puzzled us was the fact that, in the vast majority of the optimization endeavors, the catalyst was always degraded at the end of the reaction. In order to better understand this somewhat suboptimal chemical efficiency, we monitored the conversion of the starting material, the yield of the product and the degradation of the catalyst over time. We noticed that the depletion of the starting material is somehow affecting the degradation of the starting material. We rationalized how, because the formation of the active enamine complex is an equilibrium, the lower the amount of aldehyde starting material, the higher the amount of organocatalyst free in solution, the higher the possibility of its degradation at the anode.
