Two-Electron- and One-Electron-Transfer Pathways for TEMPO-Catalyzed Greener Electrochemical Dimerization of 3-Substituted-2-Oxindoles

Abstract

Dimerized 3-substituted 2-oxindoles are essential building blocks for the total synthesis of alkaloids. Herein, three different types of 3-substituted-2-oxindoles were dimerized with a total of 41 examples employing TEMPO as a redox mediator and TEMPO+ as an in situ generated electrocatalyst using control potential electrolysis at an applied potential of only 0.8 V versus a Ag/Ag+ nonaqueous reference electrode. These reactions did not yield any product formation in the absence of TEMPO, keeping other experimental conditions the same. Two-electron- and one-electron-transfer pathways were operational depending on the oxidation potentials of 2-oxindoles. 3-Carboxylate-2-oxindoles having a lower oxidative energy barrier for a two-electron-transfer pathway followed a hydride-transfer mechanism to generate a carbocation, which thereafter reacted with the enol form of oxindole to produce dimerized 2-oxindoles. On the other hand, 3-alkyl-2-oxindoles and 3-alkylcarboxylate-2-oxindoles had significantly higher oxidative energy barrier compared to 3-carboxylate-2-oxindoles and followed the one-electron-transfer pathway to generate a radical species for dimerization. The two-electron transfer pathway was significantly faster compared to the one-electron transfer pathway, evident from reaction time (15 min vs 1 h 20 min or longer), which was due to a faster second-order rate constant for the two-electron transfer pathway (1.2 M–1 s–1) compared to the one-electron transfer pathway (0.29 M–1 s–1). Furthermore, four aspects of transforming greener electro-organic synthesis have been demonstrated. They are as follows: (a) electron-transfer rate measurement as an alternative method for synthesis optimization instead of lengthy product isolation, (b) prevention of electrode passivation employing electrocatalysis routes, (c) recovery of the electrolyte, and (d) mild reaction conditions employing control potential electrolysis. Finally, an efficient electrochemical oxidation strategy has been demonstrated for the total synthesis of a dimeric hexahydropyrrolo[2,3-b]indole alkaloids, (±)-chimonanthine (I) and (±)-folicanthine (II).

Challenges and opportunities on sustainable electrochemical transformations: application towards the synthesis of pharmaceuticals and precursors of drug-like molecules

“…This protocol allows the dimerisation of 3-substituted 2-oxindoles under constant potential electrolysis in a three-electrode setup (Scheme 22b). 90 The oxidation potentials of 2-oxindoles were responsible for driving either two-electron or one-electron-transfer pathways. Furthermore, this simple and environment-friendly strategy has been employed in the total synthesis of dimeric hexahydropyrrolo [2,3-b]indole alkaloids, and (±)-chimonanthine 166, which can be easily converted to another alkaloid (±)-folicanthine 167 using aqueous paraformaldehyde and sodium tri-acetoxyborohydride.…”

“…This protocol allows the dimerisation of 3-substituted 2-oxindoles under constant potential electrolysis in a three-electrode setup (Scheme 22b). 90…”

Recent advances in the electrochemical generation of 1,3-dicarbonyl radicals from C–H bonds

“…Recently, TEMPO-catalyzed electrochemical dimerization of three different types of 3-substituted-2-oxindoles at a control potential of only 0.8 V vs. Ag/Ag + was developed by Bisai and Paul (Scheme 26). 54 The oxidation potentials of 3-substituted-2-oxindoles determine that the reaction process involves either a two-electron- or one-electron-transfer pathway. A radical–radical self-coupling process is proposed for the construction of dimerized 3-alkyl-2-oxindoles.…”

Recent advances in electrochemical synthesis of diversely functionalized oxindole derivatives

“…The reactions were performed in an undivided cell and charged by constant voltage (0.8 V vs. the Ag/Ag + reference electrode) under greener electrochemical conditions, leading to a range of dimeric 2-oxindoles in moderate to good yields through dimerization of three different types of 3-substituted-2-oxindoles (Scheme 33). 37 In contrast, the reaction failed to yield the dimeric oxindole in the absence of TEMPO, although the other experimental conditions were kept the same. This clearly indicates the crucial role of TEMPO in this process.…”

“…Notably, the two-electron transfer pathway was found to be much more efficient than the one-electron transfer pathway (Scheme 34). 37…”