An Electrochemical Approach to Directed Fluorination

Abstract

Electrosynthesis has made a revival in the field of organic chemistry and, in particular, radical-mediated reactions. Herein, we report a simple directed, electrochemical C−H fluorination method. Employing a dabconium mediator, commercially available Selectfluor, and RVC electrodes, we provide a range of steroid-based substrates with competent regioselective directing groups, including enones, ketones, and hydroxy groups, as well as never reported before lactams, imides, lactones, and esters.A resurgence of organic electrosynthesis has recently been observed after a long period of comparative stasis. 1 Recently, the drive for green, inexpensive methodology in conjunction with the emergence of novel radical/electron transfer-based reactions has permitted the field to blossom. 2 Nevertheless, relatively few methods have been developed to functionalize unactivated C(sp 3 )-H bonds. 3 Notable advances in the development of electrochemical conditions 4 that serve as guiding precedents for C−H oxidation processes 5 have been made by Baran 6 and others. 7 Herein, we report electrochemical, directed fluorination 8 of unactivated sp 3 C−H bonds with ketones, enones, and show proof of concept that imides, lactams, lactones, hydroxy groups, and esters are exploitable as directing groups as well (Scheme 1).Our mechanistic investigation of carbonyl-directed fluorination led us to the discovery that a Selectfluor radical dication (SRD) 9 can act as a coordinated hydrogen atom abstraction agent (Scheme 2). 10 Consequently, we envisioned that electrolysis could directly access this reactive intermediate (SRD) by employing the amine salt compound 1, 1-(chloromethyl)-4-aza-1-azoniabicyclo[2.2.2]octane tetrafluoroborate, as a promotor. 11 Ultimately, we found that using this amine, Selectfluor, and MeCN with RVC|RVC 1.8 V for 3 h successfully fluorinates at the predicted site. 12 This voltage was determined in previous work using cyclic voltammetry. Figure 1 demonstrates the observed peak oxidation values for

Competition between C–C and C–H Bond Fluorination: A Continuum of Electron Transfer and Hydrogen Atom Transfer Mechanisms

“…Recent literature also indicates that the SRD intermediate can be accessed electrochemically through anodic oxidation of compound 6 . , Thus, we briefly explored the possibility of acetal fluorination under electrochemical conditions to complement the BEt 3 /O 2 result (Scheme ). To our satisfaction, we obtained preliminary evidence that C–C bond fluorination of 2-aryl-substituted acetals can, in fact, proceed under mediated electrolysis conditions (i.e., compound 7 was converted to 8 in 74% yield).…”

Metal Ion‐Induced Large Fragment Deactivation: A Different Strategy for Site‐Selectivity in a Complex Molecule

“…under previously developed electrochemical conditions. [22] Methyl ether fluoride 2 was selectively generated in higher yield (57 %), possibly owing to the dual role served by excess NaBF 4 as supporting electrolyte. [23] The dramatic effect on selectivity in the presence of sodium ion can be understood from Monte Carlo conformational searches (MCCS) of Na + -1 and SRD.…”

Recent Advances in C—F Bond Formation from Carbon‐Centered Radicals

“…Recently, they realized more general directed C—H fluorination reactions using cationic TEDA and selectfluor via electrochemical method with RVC (reticulated vitreous carbon) electrodes (Scheme 9). [ 55 ] The reaction selectively introduces fluorine atoms on various substrates, bearing directing groups including ketones, enones, hydroxy groups, lactams, imides, lactones, and esters. The general mechanism involves the generation of cationic radical TEDA 2+● by electrolysis, which coordinates with the directing group on the substrate and abstracts the remote hydrogen atom, forming a carbon‐centered radical that undergoes fluorination with selectfluor.…”