Advancing Electro-Organic Synthesis: Electrochemical Strategies for Late-Stage Funcationalization of Protected Amines and Development of Chiral Electrolyte for Direct Asymmetric Electrosynthesis
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Since the renaissance of electro-organic synthesis in 21st century, it has been enabling new chemical transformations through the generation of reactive intermediates at electrode surfaces. This work advances the field through two complementary strategies: (1) the development of Shono oxidation for late-stage functionalization of protected amines and (2) the design of chiral electrolytes to achieve direct asymmetric electrosynthesis.First, we expand the utility of Shono oxidation for late-stage C(sp³)–H functionalization. By replacing methanol (MeOH) with trifluoroethanol (TFE) as a solvent, competing solvent oxidation was suppressed, allowing efficient generation of N,O-acetal products. Transient protection of basic nitrogen groups with trifluoroacetic acid (TFA) during electrochemical oxidation steps allows toleration of N-heterocycles and free amines in the substrates. The N,O-acetals were then subjected to organozinc reagents for late-stage methylation, furnishing broad scope of methylated protected amines. Next, a tandem electrochemical strategy was developed for β-fluorination of amines. Modified Shono oxidation and tandem elimination was applied to generate enamines, which reacted with electrophilic fluorine sources to furnish β-fluorinated protect. Pyridine was used as an additive during electrochemical step to mitigate decomposition of acid-sensitive intermediates, enabling the synthesis of fluorinated derivatives from pharmaceuticals and bioactive molecules. Finally, we address the challenge of enantioselective direct electrolysis by introducing chiral electrolytes that engage radical cation intermediates via non-covalent interactions within the electrical double layer (EDL). High-throughput screening identified chiral phosphates as optimal electrolytes, enabling asymmetric sulfide and phosphine oxidations with up to 96:4 enantiomeric ratio (e.r.). Substrates with or without a directing group (secondary amides) were all tolerated. Mechanistic studies and molecular dynamics simulations were performed to confirm the critical role of higher concentration of chiral anions within EDL in controlling stereochemistry. This research demonstrated the use of chiral electrolyte could potentially serve as a general solution toward challenging asymmetric direct electrolysis.