Electrochemical Vicinal Difluorination of Alkenes: Scalable and Amenable to Electron‐Rich Substrates

Abstract

Fluorinated alkyl groups are important motifs in bioactive compounds, positively influencing pharmacokinetics, potency and conformation. The oxidative difluorination of alkenes represents an 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 safety and 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 using an “ex‐cell” approach, which avoids oxidative substrate decomposition. The more sustainable conditions give good to excellent yields in up to decagram scales.

Electrochemical C−C bond cleavage of cyclopropanes towards the synthesis of 1,3-difunctionalized molecules

“…Both TMS and halogen groups could be tolerated (55)(56). The electronically deficient arylcyclopropane could also give 1,3dioxygenation products with high yields (57)(58).…”

“…The following nucleophilic attack to the benzyl carbonium can finally yield the 1,3-difunctionalization product. Fluorinated products could be prepared by employing Et 3 N•3HF as nucleophilic fluorine source [53][54][55][56][57][58] . In this work, we develop the electrochemical 1,3-difluorination, 1,3-oxyfluorination, and 1,3-dioxygenation of arylcyclopropanes with a high chemoselectivity and regioselectivity by the strategic choice of nucleophiles.…”

Electrochemistry Enabled Selective Vicinal Fluorosulfenylation and Fluorosulfoxidation of Alkenes

“…30,31 In addition, the precise control of a minimally sufficient potential also allows better functional compatibility. 32 In particular, electrochemical methods have been demonstrated to be capable of incorporating either sulfur 33,34 or fluorine [35][36][37][38] functionalities into diverse organic frameworks. Inspired by the elegant sulfonyl fluoride (RSO2-F) synthesis via the electrochemical oxidative coupling of thiols (RSH) and potassium fluoride (KF) reported by Noël and co-workers, 39,40 we speculated that electrochemistry should be an ideal solution to simultaneously 41 introduce both fluorine and sulfur in a controllable oxidation state into alkenes.…”

“…Alkenes substituted by a naphthalene (28 and 29), alkene (30), alkyne (31), heterocycle (32)(33)(34)(35) or estrone derivative (36) also underwent the desired transformations. This protocol was also readily transferred to the preparation of the analogous chlorosulfide (37) and bromosulfide (38). Furthermore, a variety of thiophenols bearing electron-donating or electronwithdrawing groups all reacted to afford the desired fluorosulfides in moderate to good yields (39-46, 38%-87%).…”

Electrochemical C-C Bond Cleavage of Cyclopropanes towards the Synthesis of 1,3-Difunctionalized Molecules

“…1,3-di uorination, 1,3-oxy uorination and 1,3-dioxygenation of arylcyclopropanes could be accessible with a highly chemo-and regioselectivity by the strategic choice of nucleophiles, and uorinated products could be prepared by employing Et 3 N•3HF as nucleophilic uorine source. [53][54][55][56][57][58] A wide variety of arylcyclopropanes with electron-donating and electron-withdrawing groups could be converted to the 1,3-difunctionalized molecules.…”