Oxidative electro-organic synthesis of dimeric hexahydropyrrolo-[2,3-b]indole alkaloids involving PCET: total synthesis of (±)-folicanthine

Abstract

An efficient electrochemical strategy has been developed for the total synthesis of dimeric hexahydropyrrolo[2,3-b]indole alkaloids. In particular, oxidative dimerization of 3-alkyl 2-oxindoles was developed for this study. A detailed CV...

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

“…The pK a of the C−H proton of the pseudobenzylic position for 2a has been estimated to be ∼21 to 24, which is significantly higher than that of 1a (∼17 to 18), suggesting a significantly high energy requirement for the second electron transfer to generate a carbocation. 33 For the dimerization of 2a, the addition of base (NaH) was also required (vide supra). CVs of 2a also revealed an increase in current with increasing concentration of NaH, suggesting an involvement of base in the reaction mechanism (Figure 5a).…”

“…32 In recent time, we reported green electrochemical routes for dimerization of a variety of 2-oxindoles having the application for the total synthesis of dimeric hexahydropyrrolo [2,3-b] indole alkaloid, (±)-folicanthine, and so forth (Scheme 1c). 33,34 Interesting proton-coupled electron transfer (PCET) mechanisms were proposed, such as stepwise electron transfer (ET)−proton transfer (PT)−electron transfer (ET) or PT−ET−ET or ET− PT and so forth. 33,34 These syntheses were accomplished in metal and chemical oxidant-free mild reaction conditions.…”

“…5 Besides, electrode passivation due to direct substrate oxidation at the electrode surface resulted in a long time for the completion of the reaction (1−4 h), and the applied current (or voltage) was high, suggesting high energy requirement to accomplish the reaction. 33,34 To overcome these challenges, in this work, instead of direct oxidation of 2-oxindoles on the electrode surface, oxidation of 2-oxindoles was performed using TEMPO [(2,2,6,6-tetramethylpiperidin-1-yl)oxyl)] as the redox mediator. TEMPOcatalyzed electrochemical oxidations of alcohols and amines are reported frequently in the literature; 9,35−40 however, only a few reports are available for the traditional organic molecules' transformations.…”

“…More importantly, 3-alkyl-2-oxindoles show much higher oxidation potential than that of 3carboxylate-2-oxindoles (vide infra). 33,34 The reaction was attempted with the same condition by taking 2a as the substrate (Scheme 3); however, the dimeric product was not obtained. Therefore, the reaction conditions were further optimized by addition of different concentrations of base, that is, NaH (Table S2, Supporting Information).…”

“…The major disadvantage was a large amount of waste generation because of massive electrolyte usage, which distances it from one of the principles of green chemistry . Besides, electrode passivation due to direct substrate oxidation at the electrode surface resulted in a long time for the completion of the reaction (1–4 h), and the applied current (or voltage) was high, suggesting high energy requirement to accomplish the reaction. , …”