Electrochemical Vicinal Difluorination of Alkenes: Sustainable, Scalable, and Amenable to Electron-rich Substrates

Abstract

Fluorinated alkyl groups are important motifs in bioactive compounds, positively influencing pharmacokinetics, potency and F conformation. The oxidative difluorination of alkenes represents an H important strategy for their preparation, yet current methods are limited in their alkene-types and tolerance of electron-rich, readily oxidized functionalities, as well as in their scalability. Herein, we report a method for the difluorination of a number of unactivated alkene-types that is tolerant of electron-rich functionality, giving products that are otherwise unattainable. Key to success is the electrochemical generation of a hypervalent iodine mediator (in the presence of nucleophilic fluoride and HFIP) using an ‘ex-cell’ approach, which avoids the oxidative decomposition of the substrate. The more sustainable conditions give good to excellent yields of product in up to decagram scales<br>

Renewable Electricity Enables Green Routes to Fine Chemicals and Pharmaceuticals

“…Similar work has been reported from Lennox et al. in which alkene 55 undergoes difluorination to form alkane 56 by electrochemical oxidation using a mixture of pyridinium ploy(HF) in CH 2 Cl 2 ̸hexafluoroisopropanol (HFIP) and Et 3 N.3HF with 4‐iodotoluene as a mediator [191] (Scheme 26). During this conversion, a divided cell is used for oxidatively sensitive substrates while undivided cell is required for more oxidatively stable substrates.…”