Continuous Flow Electrochemical Oxidative Cyclization and Successive Functionalization of 2-Pyrrolidinones

Abstract

2-Pyrrolidinones are important scaffolds found in numerous pharmacologically active compounds, such as brivaracetam and levetiracetam (antiepileptic drugs) or piracetam and pramiracetam (age-related memory impairment drugs). Among the numerous targets, nootropic agents represent an attractive class of compounds since they selectively improve cognitive functions. In this study, we report the successful translation of an electrochemical batch oxidative cyclization/functionalization of 2-pyrrolidinones, using the Kolbe reaction, from a batch type cell to a continuous flow electrochemical reactor. Combining organic electrosynthesis with continuous flow chemistry offers numerous advantages over batch electrolysis such as a faster reaction time and better mixing of the heterogeneous reaction. Moreover, due to the use of continuous flow electrochemical cells, which have a precise geometry, a small interelectrode gap, and large electrode surface area to reactor volume ratio, the productivity of organic electrosynthesis can be easily improved. Additionally, the translation of a batch electrochemical transformation to a continuous flow reactor is a critical step in the development of an electrochemical process given that flow chemistry is the most straightforward approach for the scale-up of this type of reactions. In this study, the application of continuous flow electrochemistry in our process allowed for an excellent productivity of 0.40 g/(h·mL) and an up to 81% yield of 2-pyrrolidinone within a loop-reactor setup (equipped with a 5 mL container).