Electrochemical Synthesis of Dimeric 2-Oxindole Sharing Vicinal Quaternary Centers Employing Proton-Coupled Electron Transfer

Abstract

Dimerization of 3-substituted 2-oxindoles has been developed under a mild electrochemical condition, avoiding toxic chemical oxidants and metal by-products. This methodology forms a C­(sp3)–C­(sp3) bond at the pseudobenzylic position of two partners of 2-oxindoles with a broad substrate scope. These dimeric structural motifs are important building blocks for the total synthesis of pyrroloindoline alkaloids. Furthermore, this work demonstrates in-depth mechanistic insights employing electrochemistry, which suggests a stepwise one proton transfer (PT) and two electron transfer (ET) processes. Most significantly, reaction rate acceleration has been demonstrated by exploiting the base-assisted proton-coupled electron transfer (PCET) pathway. Hence, this work brings a new dimension in the field of electro-organic synthesis with the help of nature’s favorite kinetic route, i.e., PCET, to lower the kinetic barrier.

Applications of Proton-Coupled Electron Transfer in Organic Synthesis

“…Similar to the work of Ooi's group, in 2020, Paul and co-workers [60] also developed a homo-coupling reaction route that accesses the dimerization of 3-substituted 2oxindoles under a mild electrochemical condition (Scheme 10). They explored the reaction under conditions with and without addition of base.…”

Selective electro-oxidation of phenol to 1,4-hydroquinone employing carbonaceous electrodes: surface modification is the key

“…[1][2][3] If harnessed properly these electrochemical transformations could become a rich playground for the synthesis of organic compounds as they do not involve environmentally hazardous oxidants/reductants. [4][5][6][7][8] Amongst many organic reactions, oxidation of phenol to hydroquinone, catechol, or resorcinol has great industrial relevance 8 as these oxidized products serve as intermediates in the synthesis of food preservatives, 9 pharmaceuticals, 10,11 dyes 12,13 and polymers. 14,15 Generally, oxidation of phenol is carried out by chemical methods, 16 involving metals, metal oxides, and enzymes as catalysts.…”

Electrochemical Umpolung C–H Functionalization of Oxindoles

“…Few methods were also reported for the direct CH-functionalization of oxindoles using electrochemistry. 18 In particular, a wide range of dimeric 2-oxindoles were recently prepared by an oxidative C–C coupling reaction ( Scheme 1 B, eq 4). 18b…”

“…When it comes to its use as an electrophilic synthon, Kotagiri has described the stoichiometric use of an hypervalent iodine reagent [PhI­(OCOCF 3 ) 2 ] for the oxidative alkoxylation of oxindoles (Scheme B, eq 2), and more recently, the oxidative intramolecular α-oxygenation and α-amination of oxindoles was reported by Zhong, employing a micellar catalytic system based on amphiphilic bifunctional iodide salts in water (Scheme B, eq 3), featuring H 2 O 2 as the terminal oxidant. Few methods were also reported for the direct CH-functionalization of oxindoles using electrochemistry . In particular, a wide range of dimeric 2-oxindoles were recently prepared by an oxidative C–C coupling reaction (Scheme B, eq 4)…”