Strähler, Sebastian
[UCL]
Riant, Olivier
[UCL]
Piperidine and its functionalized derivatives have become one of the most encountered heterocycles in drugs and are also found in numerous naturally-occurring alkaloids which display interesting biological properties. The ability of these saturated heterocycles to carry substituents around their core structure in the three-dimensional space has been greatly exploited in medicinal chemistry to generate structure and shape diversity. Consequently, although many synthetic strategies to prepare these molecules already exist, the exploration of novel methodologies is still needed and could result in great benefits to mankind. In addition, the selective introduction of fluorine in organic scaffolds has been increasingly utilized to induces changes in the lipophilicity, basicity, metabolic stability, and binding affinity of molecules. However, the incorporation of a gem-difluoromethylene group (CF2) has been much less investigated compared to other fluorinated functionalities. The goal of this master’s research project was thus to combine these two observations to develop a new synthetic method that enables the one-pot synthesis of CF2-substituted piperidine scaffolds, using earth abundant copper as catalyst. For this purpose, an optimization of the reaction conditions was first undertaken, by investigating different parameters such as the catalyst, solvent, temperature, time, additives, and the stoichiometry of the reagents. Furthermore, a radical scavenger was used to demonstrate that radical intermediates are involved in the transformation. In parallel, a broad range of substrates were synthesized and, once the conditions were optimized, they were used in the reaction to establish a scope of twelve accessible fluorinated piperidine scaffolds with yields ranging from 20% to 70%. Lastly, in an attempt to further expand the scope of this new methodology, it was envisioned to prepare other substrates that would give access to an indole derived product or a morpholine moiety. However, only the latter was successfully obtained, and other ideas of substrates were thus discussed for follow up projects.
Bibliographic reference |
Strähler, Sebastian. Synthesis of fluorinated piperidines via a copper-catalyzed intramolecular aminodifluoroalkylation of alkenes. Faculté des sciences, Université catholique de Louvain, 2022. Prom. : Riant, Olivier. |
Permanent URL |
http://hdl.handle.net/2078.1/thesis:35408 |