Investigation into the Electrochemical Ndealkylation of Tertiary Amides

Kaur, Mandeep (2021) Investigation into the Electrochemical Ndealkylation of Tertiary Amides. Masters by Research thesis (MPhil), Manchester Metropolitan University.

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Abstract

This thesis reports a novel reagent-less dealkylation of benzylic amides with varying steric effects and electronic properties of an attached group. Complex drug structures are explored to probe the feasibility of the reaction. Electrosynthetic experiments were performed at room temperature in an undivided cell using tetrabutylammonium perchlorate (TBAP) as an electrolyte. Reticulated vitreous carbon (RVC) was used as both the working and counter electrode. The constant current method was employed for the reactions. An optimisation survey found that changing the electrochemical process from controlled voltage to controlled current conditions led to deethylation. Methanol was found to be essential for N-deethylation to occur. Using the controlled current method N-deethylation of N,NDiethylbenzamide (106) was achieved with an isolated yield of 86%. The proposed reaction mechanism indicates the reaction proceeds via one of the two pathways, pathway A dominates and proceeds via the typical Shono α-methoxylation initiation. Chapter 1 introduces and includes examples of general electrochemical concepts that apply to organic electrosynthesis. The chapter consists of electrochemical methods and techniques for the analysis of small molecules. The literature review compares the emerging trends using electrochemistry coupled to LC-MS to detect the presence of N-dealkylated drug metabolites and current trends for the Ndealkylation of amides, including conventional methods. Chapter 2 reports the optimisation survey of 106 for electrochemistry and purification method, LSV of the compounds is discussed, and the reaction mechanism is proposed. Chapter 3 reports the electrosynthetic dealkylation survey of amides. LSV survey of the selected compounds were analysed and indicated that stronger electrondonating substituents did not give dealkylation. The use of electrochemistry to study the N-dealkylation of drug and herbicides molecules are also described. The LSV of molecules were examined, and HPLC was explored to purify the products. Ndealkylation of complex compounds requires further probing using electrochemical methods and optimisation to obtain the final product. Finally, the chapter summaries key research findings for the work. The Chapter also explores future work and the iv diverse approaches for further research, such as; use of flow cells for the oxidation of the amides. Chapter 4 presents the procedures for the synthesis of amides and electrochemical methods used during the thesis. It contains compound characterisation using the following methods: LC-MS, 1H-NMR and C13 -NMR.