Microwave-Assisted Heck Arylations of Non-Activated N-Acyl-3-pyrrolines with Arenediazonium Tetrafluoroborates

The carbon-carbon bond forming process is one of the most important transformations in organic synthesis aimed at the construction of complex molecules. In this regard, the Heck reaction poses as a pivotal synthetic methodology widely used for the formation of carbon-carbon bonds starting from olefins and an electrophile. An alternative of growing importance to the conventional Heck reaction was developed by Matsuda in 1977, using arenediazonium salts as arylating agents. The use of arenediazonium salts makes the arylation method significantly easier to carry out in laboratories, greener (phosphine-free), and faster. The higher reactivity of diazonium salts allows the efficient arylation of several olefin types under milder and simpler conditions. Notably, the arenediazonium tetrafluoroborates are crystalline and thermostable compounds, which can be easily prepared in several g scales from anilines, and stored for reasonably long periods. In the recent past, our group reported the use of Heck-Matsuda (HM) arylations of non-activated N-acyl3-pyrrolines as a critical step in the synthesis of several pharmacological active compounds as a series of arylated γ-aminobutyric acid (GABA) derivatives, including baclofen, and some neuroexcitatory aryl kainoids (Scheme 1). Very often, these transition metal catalyzed coupling reactions are performed under conventional heating. However, this heating technique has in many cases some disadvantages, such as longer reaction times, resulting in side products, which reduce the reaction efficiency. In contrast, microwaveassisted organic synthesis (MAOS) has appeared as a viable heating alternative in the last decades, leading in several occasions to shorter reaction times and cleaner reactions. The value of this technique has been recognized both in the academic and industrial settings, and has been successfully applied to several organic transformations including transition metal catalyzed couplings. Based on the potential benefits of microwave irradiation as an alternative heating mode and on the synthetic advantages of Heck-Matsuda reaction, we present herein our results regarding the optimization of the Heck-Matsuda arylations of non-activated N-acyl-3-pirrolines 1 and 2 under conventional heating and microwave conditions employing several arenediazonium tetrafluoroborates.