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

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-2oxindoles 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).

Automated summary

Dimerized 3-substituted 2-oxindoles were synthesized using TEMPO as a redox mediator and TEMPO+ as an in situ generated electrocatalyst. Two-electron and one-electron transfer pathways were observed depending on the oxidation potentials of the 2-oxindoles. This study also demonstrated the use of electron-transfer rate measurement, prevention of electrode passivation, electrolyte recovery, and mild reaction conditions in greener electro-organic synthesis. Finally, an efficient electrochemical oxidation strategy was employed for the total synthesis of two dimeric alkaloids.