Electrochemical decarboxylation in flow: anodic and cathodic strategies for the synthesis of key pharmaceutical intermediates

Electrochemical synthesis has emerged as a powerful tool in modern organic chemistry, offering efficient and sustainable approaches to a variety of molecular transformations. This cumulative dissertation comprises three independent studies that each focus on the development of electrochemical methodologies for key functional group conversions relevant to pharmaceutical chemistry and molecular building blocks. The following chapters outline these contributions. Chapter 3 The synthesis of peptide-based linkers for antibody-drug conjugates (ADCs) involves an oxidative decarboxylation step. Traditional Hofer-Moest electrolysis conditions are not suitable for this transformation due to the presence of an oxidatively labile Fmoc-protecting group. A solvent-enabled electrochemical procedure was developed, in which the electrochemical window of the solvent prevents degradation of the protecting group. The method was successfully applied to various relevant peptides, yielding the desired products in good to very good yields (64–92 %).Chapter 4 The introduction of fluorine into organic molecules is of major importance in the synthesis of active pharmaceutical ingredients (APIs). While many fluorine sources exist, issues such as safety, cost, and environmental impact remain problematic. This work introduces hexafluorosilicate salts as an inexpensive and accessible nucleophilic fluorine source in organic synthesis. An electrochemical decarboxylative fluorination was developed using anodically generated carbocations and in situ released fluoride ions. The key to this method was the synthesis of a soluble bis(5-ethyl-2-methylpyridin-1-ium) hexafluorosilicate(IV) salt. The protocol enabled the synthesis of 22 aliphatic fluorides in up to 85 % yield and was further transferred to a flow electrolysis setup. Additionally, the applicability of the fluorinating reagent was demonstrated for benzylic C–H fluorination. Chapter 5 Boron-containing compounds are essential in synthetic chemistry. While B₂Cat₂ has enabled alkyl borane synthesis via radical pathways, the resulting catechol boranes are typically unstable and require in situ conversion. This study presents a continuous-flow electrochemical decarboxylative borylation strategy telescoped with pinacol exchange to yield stable and isolable boronic esters. The optimized protocol, performed in a single-pass electrochemical microreactor, required no supporting electrolyte. The method was validated with 11 examples, covering primary, secondary, and tertiary alkyl carboxylic acids.

Equipment used in this paper: SF-10 Laboratory Pump

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