Electrochemical Deconstructive Functionalization of Cycloalkanols via Alkoxy Radicals Enabled by Proton-Coupled Electron Transfer

Abstract

Herein, we report a new electrochemical method for alkoxy radical generation from alcohols using a proton-coupled electron transfer (PCET) approach, showcased via the deconstructive functionalization of cycloalkanols. The electrochemical method is applicable across a diverse array of substituted cycloalkanols, accessing a broad range of synthetically useful distally functionalized ketones. The orthogonal derivatization of the products has been demonstrated through chemoselective transformations, and the electrochemical process has been performed on a gram scale in continuous single-pass flow.

Electrophotochemical Ce-Catalyzed Ring-Opening Functionalization of Cycloalkanols under Redox-Neutral Conditions: Scope and Mechanism

“…Carbon–carbon (C–C) bonds are the most widespread and fundamental building blocks that make up organic compounds. Selective cleavage and functionalization of these inert bonds is of great importance. , In particular, β-scission of C–C bonds in alcohols, which are abundant in biomass, has attracted extensive attention. − It is well-known that, as a key step of β-scission, the generation of an alkoxy radical from alcohol is often challenging due to the extremely high O–H bond dissociation energy (∼105 kcal/mol). Traditionally, to overcome the energy barrier, strong oxidants such as bromine, hypervalent iodide, − selectfluor, and so forth or high-valent metal salts are inevitable (Scheme a).…”

β-Scission by Direct Electrochemical Oxidation: Proton-coupled Electron Transfer Mechanism Dictated by Synthetic Study and Computations

“…1B). 12 Contrastingly, β-scission via direct electron transfer on the electrode, i.e. without the use of redox mediators, has not been proposed and analyzed to date.…”

Deconstructive Functionalization of Unstrained Cycloalkanols via Electrochemically Generated Aromatic Radical Cations

“…In comparison to batch, the flow process was performed using a lower electrolyte concentration ([ n -Bu 4 NPF 6 ] = 0.05 M vs [ n -Bu 4 NPF 6 ] = 0.1 M) and increased current density ( j anode = 22 mA/cm 2 vs j anode = 7.8 mA/cm 2 ), which resulted in higher productivity (4.1 mmol/h vs 0.08 mmol/h). The 4-methoxyphenyl ketone functionality within 2 can be readily converted to the corresponding ester or amide via Baeyer–Villiger or Beckmann rearrangements, respectively.…”

“…For example, our previously developed Mn-catalyzed deconstructive chlorination method was limited to 3-and 4-membered cycloalkanols, 9 whereas we recently described an alternative approach enabled by proton-coupled electron transfer, which tolerated cycloalkanols of various ring sizes, but was predominately limited to deconstructive bromination. 10 As part of our ongoing interest in the development of new electrosynthetic methodologies 11 and with a view to addressing the aforementioned limitations, herein we report an alternative electrochemical method for the deconstructive functionalization of cycloalkanols via the formation of aromatic radical cations and the associated weakening/breaking of β−C-C σ-bonds. This approach tolerates a broad range of ring sizes and employs nucleophiles, including alcohols, carboxylic acids, and N-heterocycles, to generate a more diverse array of valuable remotely functionalized ketones (Scheme 1C).…”

“…Despite these advances, most existing electrochemical approaches are characterized by limitations relating to the cycloalkanol ring size and/or the types of functionalizations possible, which impacts negatively the breadth of accessible products. For example, our previously developed Mn-catalyzed deconstructive chlorination method was limited to 3- and 4-membered cycloalkanols, whereas we recently described an alternative approach enabled by proton-coupled electron transfer, which tolerated cycloalkanols of various ring sizes, but was predominately limited to deconstructive bromination . As part of our ongoing interest in the development of new electrosynthetic methodologies and with a view to addressing the aforementioned limitations, herein we report an alternative electrochemical method for the deconstructive functionalization of cycloalkanols via the formation of aromatic radical cations and the associated weakening/breaking of β–C-C σ-bonds.…”