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. 2021 Dec 28;87(1):606–612. doi: 10.1021/acs.joc.1c02616

Electrochemical Umpolung C–H Functionalization of Oxindoles

Miryam Pastor †, Marie Vayer †, Harald Weinstabl ‡, Nuno Maulide †,*
PMCID: PMC8749966  PMID: 34962127

Abstract

graphic file with name jo1c02616_0007.jpg

Herein, we present a general electrochemical method to access unsymmetrical 3,3-disubstituted oxindoles by direct C–H functionalization where the oxindole fragment behaves as an electrophile. This Umpolung approach does not rely on stoichiometric oxidants and proceeds under mild, environmentally benign conditions. Importantly, it enables the functionalization of these scaffolds through C–O, and by extension to C–C or even C–N bond formation.

Introduction

3-Oxa and 3-hydroxy-2-oxindoles constitute privileged classes of aromatic alkaloids that are encountered in numerous natural products and pharmaceuticals.1 This is particularly true for 3,3-disubstituted oxindole derivatives, which possess a documented broad range of biological and pharmacological activities that are intrinsically tied to that structural feature (Scheme 1A).2 For Convoluamydine A, a naturally occurring example, the biological activity mostly results from substitution at C-3.3

Scheme 1. Context and Strategy for the Direct C–H Functionalization of Oxindoles.

Scheme 1

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Given the valuable properties of these structures, significant effort has been devoted to the development of synthetic methods to access 3-oxygenated 2-oxindoles.2b,2c While manifold methods for the synthesis of hydroxy derivatives exist,4 there is a dearth of methods to directly access the 3 alkoxy congeners.5 Recently, Liu and Zhou described an efficient thermal substitution of 3-halooxindoles (Scheme 1B, eq 1),6 relying on the in situ formation of a dearomatized Michael acceptor as an intermediate, followed by an SN1 reaction using various alcohols.

The direct functionalization of unsubstituted, “naked” oxindoles represents an attractive approach to afford such motifs. Relevant transformations of the C-3 position, invariably employing the oxindole fragment as a nucleophile, include arylation,7 alkynylation,8 alkylation,9 fluorination,10 trifluoromethylation,11 nitration,12 azidation,13 amination,14 and thiolation.15 When it comes to its use as an electrophilic synthon, Kotagiri has described the stoichiometric use of an hypervalent iodine reagent [PhI(OCOCF3)2] for the oxidative alkoxylation of oxindoles (Scheme 1B, eq 2),16 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 1B, eq 3),17 featuring H2O2 as the terminal oxidant. 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 1B, eq 4).18b

As part of a research program focused on novel approaches to design drugs and given our interest in the development of umpoled synthons, we became interested in the sustainable preparation of 3,3-disubstituted oxindole derivatives, envisaging electrochemistry as a powerful tool to tackle this problem. The appeal of electrosynthesis lies mainly on its eco-friendly nature and generally mild reaction conditions, therefore, unsurprisingly, its use has gained significant traction in recent years.19

Results and Discussion

Initial studies of the redox behavior of 3-methylindolin-2-one 1a using cyclic voltammetry (CV) revealed an irreversible anodic oxidation peak at 1.8 V (see Supporting Information, Figure S1). This immediately hinted at the possibility of using electrochemistry for the direct C(sp3)–H functionalization of 2-oxindoles and related compounds.20 Herein, we report the synthesis of unsymmetrical 3,3-disubstituted oxindoles by direct electrochemical Umpolung C–H functionalization.

We commenced our search for optimal reaction conditions using 1a and relying on a simple undivided cell setup based on the ElectraSyn 2.0 package with a graphite (C) anode and a platinum (Pt) cathode (Table 1). These electrodes were initially used under a constant current of 10 mA, in the presence of tetraethylammonium p-toluenesulfonate (Et4NOTs) as the electrolyte in a mixture of MeCN/EtOH. Under these initial conditions, an ethoxylated product 2a was directly produced in 40% yield (entry 1). Replacing the platinum (Pt) cathode by an inexpensive graphite (C) cathode had a positive impact on the reaction outcome, yielding 2a in 57% or 72% based on recovered 1a (entry 2). On the other hand, the use of different electrolytes led to a decreased yield (entries 5–7 and see Supporting Information, Table S2). Neither the addition of stoichiometric acids (entry 6) nor the use of different silver salts as sacrificial oxidants (entry 7 and see Supporting Information, Table S3) delivered improved results. Various well-established electrochemical mediators were also tested, but to no avail (see Supporting Information, Table S3).21

Table 1. Optimization of Reaction Conditionsa.

graphic file with name jo1c02616_0006.jpg

entry deviation from above yieldb (%)
1 Pt cathode 40
2 none 57 (72% brsm)
3 nBu4NOTs instead of Et4NOTs 50
4 nBu4NPF6 instead of Et4NOTs 39
5 nBu4NClO4 instead of Et4NOTs 22
6 AcOH (1 equiv.) as an additive 46
7 AgPF6 (1 equiv.) as an additive 32
8 maintained at 0–10 °C 43
9 3 mA, 12 h instead of 10 mA, 3 h 29
10 15 mA instead of 10 mA 10
11 constant potential of 1.8 V for 28 h 53
12 3 Å MS 37
13 no electricity NRc
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a

Standard conditions: undivided cell, C-SK50 anode and cathode constant current = 10 mA, 1a (0.4 mmol), Et4NOTs (1.0 equiv), ACN/EtOH 1:1 (0.08 M), rt, 3 h.

b

Isolated yield.

c

NR = no reaction.

Lowering the temperature of the reaction, hoping to prevent potential deleterious decomposition of the precursor, proved detrimental to the outcome, as did changing the intensity of the current or the reaction time (entries 8–10). Working at a constant potential of 1.8 V afforded the product in 53% yield without recovering of the starting material (entry 11). A control experiment in the absence of electricity led to no product being detected (entry 13). It is noteworthy that the cyclic voltammogram of 2a showed an oxidation peak at 2.0 V, very close to that observed for 1a. In agreement with this, achieving full conversion of 1a without notable decomposition of product 2a proved unattainable.22

With the optimized reaction conditions in hand, the scope of this transformation was explored, as illustrated in Scheme 2. At the onset, the tolerance of various substituents at the C-3 position of the oxindole core was evaluated using EtOH as the nucleophile. Alkyl-substituted oxindoles were amenable to this reaction, delivering products 2a–h. Diverse functional groups, including an acetonide (2i), a nitrile (2j), and an ester (2k) were compatible with the reaction conditions and we observed that aryl substitution led to a slight increase of the yields (2i–s). Further functional-group modifications on the aromatic portion of the oxindole were tolerated under the standard conditions, notably including halides (4a–b, 4e), methoxy (4c, 4d), and nitro (4f) groups. In addition, the reaction is not limited to unprotected oxindoles but can be expanded to include alkyl- and aryl-substituted nitrogen atoms (6a–b), as well as an acid-labile carbamate protecting group (6c).

Scheme 2. Scope of the Reaction.

Scheme 2

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The ability to use either unprotected (NH) or diversely N-substituted oxindoles is a special feature of this method. In addition, a range of aliphatic alcohol nucleophiles was employed, affording products 7 in good to high yields. In particular, benzylic (7c) and propargylic (7e) alcohols were well tolerated, as well as alcohols bearing silyl (7g) and halide (7h) groups. It is worth mentioning that for alcohols of higher molecular weight, the amount of nucleophile could be reduced to 10–20 equivalents without any significant drop in the yield.

It should be noted that conditions were not reoptimized for each product 2–4–7; this is reflected in the broad yield range observed. We believe that the versatility of the process and the unique character of this oxidative transformation are bound to prove very useful to the synthetic practitioner.

Finally, extension of this electrochemical transformation to the formation of C–C bonds and C–N bonds was also investigated (Scheme 3). Gratifyingly, C–C bond formation was well within reach of the reaction, proceeding when a silyl enol ether was used as the nucleophile, affording the desired product 8 in a 62% yield.23 It was also possible to carry out an azidation reaction, leading to 9. Despite its low yield, this is an appealing direct C–N bond formation.

Scheme 3. Extension to a Silyl Enol Ether and TMSN3 as Nucleophiles.

Scheme 3

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To gain further insights into the reaction mechanism, several control experiments were conducted (Scheme 4A). In the presence of a radical scavenger such as 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), no product was formed, although all the starting material was consumed. In the presence of butylated hydroxytoluene (BHT), however, 2m was obtained in a low yield alongside the coupling product 10 (9%; obtained in 54% in the absence of ethanol) [Scheme 4A(1)]. These results suggest the possibility of a radical mechanism being involved in our transformation.24

Scheme 4. Mechanistic Experiments and Plausible Mechanism.

Scheme 4

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Based on the above and previous reports,25 we proposed two mechanistic scenarios depending on the nucleophilic source used (Scheme 4B). One possibility is that the substrates undergo a two-electron oxidation at the anode, forming the corresponding carbocation which can be subsequently trapped [Scheme 4B(1)]. This could explain the need for excess amounts of the nucleophile (in some cases used as a co-solvent), justified due to its role of acting as a proton source for hydrogen evolution at the cathode. We hypothesize that depending on the nucleophile and its oxidation potential, a second possible pathway might become available: single-electron oxidation at the anode leading to formation of a radical cation followed by a loss of a proton would generate a captodative radical intermediate [Scheme 4B(2)]. This radical’s competence for C–C bond formation is showcased by the products formed (vide supra) when even comparably small amounts of BHT are employed—whereby we surmise the transient formation of a BHT-derived p-quinonemethide.

Conclusions

In conclusion, we have developed a general electrochemical method to access unsymmetrical 3,3-disubstituted oxindoles by direct C–H functionalization. This approach does not rely on stoichiometric oxidants and proceeds under mild, environmentally benign conditions. Importantly, it enables the functionalization of these scaffolds through C–O, and by extension to C–C or even C–N bond formation.

Experimental Section

General Procedure to Access 3,3-Disubstituted Oxindoles

With no precautions to exclude air or moisture, the ElectraSyn vial (10 mL) was charged with 3-susbtituted indolin-2-one 1a–s, 3a–f or 5a–c (0.40 mmol, 1.0 equiv), Et4NOTs (121.0 mg, 0.40 mmol, 1.0 equiv), ROH (2.5 mL), and MeCN (2.5 mL). The ElectraSyn vial cap equipped with the anode (graphite) and cathode (graphite) was inserted into the mixture. The reaction mixture was electrolyzed at a constant current of 10 mA for 3 h. The ElectraSyn vial cap was removed, and electrodes were rinsed with DCM (2.0 mL), which was combined with the crude mixture. Then, the crude mixture was concentrated under reduced pressure and purified by FC over silica gel (heptane/ethyl acetate, 100/0 to 50/50, gradient) to furnish the desired products 2a–s, 4a–f, 6a–c or 7a–i.

We do not possess any electrochemical devices which would allow for running these reactions in a scale larger than that reported herein.

Acknowledgments

The authors thank Dr. Wojciech Zawodny and Dr. Daniel Kaiser for useful discussions and careful proofreading. Financial support by the Austrian Federal Ministry for Digital and Economic Affairs, the National Foundation for Research, Technology and Development and the Christian Doppler Research Association is gratefully acknowledged. The authors are grateful to the University of Vienna for its continued support of our research programs.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.1c02616.

  • Additional optimization tables, experimental procedures, 1H and 13C NMR spectra, and characterization data of compounds (PDF)

Author Contributions

M.P. and M.V. contributed equally. All authors have given approval to the final version of the manuscript.

The authors declare no competing financial interest.

Supplementary Material

jo1c02616_si_001.pdf (10.8MB, pdf)

References

  1. a Ahmad R.; Salim F. Chapter 12 - Oxindole Alkaloids of Uncaria (Rubiaceae, Subfamily Cinchonoideae): A Review on Its Structure, Properties, and Bioactivities. Stud. Nat. Prod. Chem. 2015, 45, 485–525. 10.1016/b978-0-444-63473-3.00012-5. [DOI] [Google Scholar]; b Kaur M.Chapter 6 - Oxindole: A Nucleus Enriched With Multitargeting Potential Against Complex Disorders. In Key Heterocycle Cores for Designing Multitargeting Molecules; Silakari O., Ed.; Elsevier, 2018; pp 211–246. 10.1016/b978-0-08-102083-8.00006-6 [DOI] [Google Scholar]
  2. a Tokunaga T.; Hume W. E.; Umezome T.; Okazaki K.; Ueki Y.; Kumagai K.; Hourai S.; Nagamine J.; Seki H.; Taiji M.; Noguchi H.; Nagata R. Oxindole Derivatives as Orally Active Potent Growth Hormone Secretagogues. J. Med. Chem. 2001, 44, 4641–4649. 10.1021/jm0103763. [DOI] [PubMed] [Google Scholar]; b Peddibhotla S. 3-Substituted-3-hydroxy-2-oxindole, an Emerging New Scaffold for Drug Discovery with Potential Anti-Cancer and other Biological Activities. Curr. Bioact. Compd. 2009, 5, 20–38. 10.2174/157340709787580900. [DOI] [Google Scholar]; c Omprakash H. N. Synthesis of Oxindoles, Spirooxindoles, and Isatins with Prominent Bioactive Probes: Review. Org. Med. Chem. IJ. 2018, 5, 555671. 10.19080/OMCIJ.2018.05.555671. [DOI] [Google Scholar]; d Yu Z.; Chen Z.; Su Q.; Ye S.; Yuan H.; Kuai M.; Lv M.; Tu Z.; Yang X.; Liu R.; Hu G.; Li Q. Dual inhibitors of RAF-MEK-ERK and PI3K-PDK1-AKT pathways: Design, synthesis and preliminary anticancer activity studies of 3-substituted-5-(phenylamino) indolone derivatives. Bioorg. Med. Chem. 2019, 27, 944–954. 10.1016/j.bmc.2019.01.028. [DOI] [PubMed] [Google Scholar]; e Sakla A. P.; Kansal P.; Shankaraiah N. Syntheses and Applications of Spirocyclopropyl Oxindoles: A Decade Review. Eur. J. Org. Chem. 2021, 2021, 757–772. 10.1002/ejoc.202001261. [DOI] [Google Scholar]; f Brittain W. D. G.; Buckley B. R.; Fossey J. S. Kinetic resolution of alkyne-substituted quaternary oxindoles via copper catalysed azide–alkyne cycloaddition. Chem. Commun. 2015, 51, 17217–17220. 10.1039/c5cc04886a. [DOI] [PubMed] [Google Scholar]
  3. a Kamano Y.; Zhang H.-P.; Ichihara Y.; Kizu H.; Komiyama K.; Pettit G. R. Convolutamydine A, a Novel Bioactive Hydroxyoxindole Alkaloid from Marine Bryozoan Amathia convolute. Tetrahedron Lett. 1995, 36, 2783–2784. 10.1016/0040-4039(95)00395-s. [DOI] [Google Scholar]; b Rasmussen H. B.; MacLeod J. K. Total Synthesis of Donaxaridine. J. Nat. Prod. 1997, 60, 1152. 10.1021/np970246q. [DOI] [Google Scholar]; c Kawasaki T.; Nagaoka M.; Satoh T.; Okamoto A.; Ukon R.; Ogawa A. Synthesis of 3-hydroxyindolin-2-one alkaloids, (±)-donaxaridine and (±)-convolutamydines A and E, through enolization–Claisen rearrangement of 2-allyloxyindolin-3-ones. Tetrahedron 2004, 60, 3493–3503. 10.1016/j.tet.2004.02.031. [DOI] [Google Scholar]; d Thakur P. B.; Meshram H. M. “On water” catalyst-free, column chromatography-free and atom economical protocol for highly diastereoselective synthesis of novel class of 3-substituted, 3-hydroxy-2-oxindole scaffolds at room temperature. RSC Adv. 2014, 4, 5343–5350. 10.1039/c3ra46271d. [DOI] [Google Scholar]; e Christensen M. K.; Erichsen K. D.; Trojel-Hansen C.; Tjørnelund J.; Nielsen S. J.; Frydenvang K.; Johansen T. N.; Nielsen B.; Sehested M.; Jensen P. B.; Ikaunieks M.; Zaichenko A.; Loza E.; Kalvinsh I.; Björkling F. Synthesis and Antitumor Effect in Vitro and in Vivo of Substituted 1,3-Dihydroindole-2-ones. J. Med. Chem. 2010, 53, 7140–7145. 10.1021/jm100763j. [DOI] [PubMed] [Google Scholar]
  4. Selected examples:; a Xiao Z.-K.; Yin H.-Y.; Shao L.-X. N-Heterocyclic Carbene-Palladium(II)-1-Methylimidazole Complex Catalyzed α-Arylation of Oxindoles with Aryl Chlorides and Aerobic Oxidation of the Products in a One-Pot Procedure. Org. Lett. 2013, 15, 1254–1257. 10.1021/ol400186b. [DOI] [PubMed] [Google Scholar]; b Wang B.; Zhu J.; Wei Y.; Luo G.; Qu H.; Liu L.-X. Cu2O-Catalyzed C(sp3)-H/C(sp3)-H Cross-Coupling Using TEMPO: Synthesis of 3-(2-Oxoalkyl)-3-hydroxyoxindoles. Synth. Commun. 2015, 45, 2841–2848. 10.1080/00397911.2015.1111383. [DOI] [Google Scholar]; c Bhagwan Chaudhari M.; Bisht G. S.; Kumari P.; Gnanaprakasam B. Ruthenium-catalyzed direct α-alkylation of amides using alcohols. Org. Biomol. Chem. 2016, 14, 9215–9220. 10.1039/c6ob01786j. [DOI] [PubMed] [Google Scholar]; d Zhang Q.-B.; Jia W.-L.; Ban Y.-L.; Zheng Y.; Liu Q.; Wu L.-Z. Autoxidation/Aldol Tandem Reaction of 2-Oxindoles with Ketones: A Green Approach for the Synthesis of 3-Hydroxy-2-Oxindoles. Chem.—Eur. J. 2016, 22, 2595–2598. 10.1002/chem.201504282. [DOI] [PubMed] [Google Scholar]; e Bai M.; You Y.; Chen Y.-Z.; Xiang G.-Y.; Xu X.-Y.; Zhang X.-M.; Yuan W.-C. An unprecedented protocol for the synthesis of 3-hydroxy-3-phenacyloxindole derivatives with indolin-2-ones and α-substituted ketones. Org. Biomol. Chem. 2016, 14, 1395–1401. 10.1039/c5ob02391b. [DOI] [PubMed] [Google Scholar]; f Wei W.-T.; Zhu W.-M.; Shao Q.; Bao W.-H.; Chen W.-T.; Chen G.-P.; Luo Y.-J.; Liang H. Transition-Metal-Free C(sp3)–H Hydroxylation of 2-Oxindoles with Peroxides via Radical Cross-Coupling Reaction in Water. ACS Sustainable Chem. Eng. 2018, 6, 8029–8033. 10.1021/acssuschemeng.8b01472. [DOI] [Google Scholar]; g Hu R. M.; Han D. Y.; Li N.; Huang J.; Feng Y.; Xu D. Z. Iron-Catalyzed Direct Oxidative Alkylation and Hydroxylation of Indolin-2-ones with Alkyl-Substituted N-Heteroarenes. Angew. Chem., Int. Ed. 2020, 132, 3904–3908. 10.1002/ange.201913400. [DOI] [PubMed] [Google Scholar]
  5. a Hsieh J.-C.; Cheng A.-Y.; Fu J.-H.; Kang T.-W. Copper-catalyzed domino coupling reaction: An efficient method to synthesize oxindoles. Org. Biomol. Chem. 2012, 10, 6404–6409. 10.1039/c2ob26110c. [DOI] [PubMed] [Google Scholar]; b Jhan Y.-H.; Kang T.-W.; Hsieh J.-C. Efficient copper-catalyzed intramolecular N-arylation for the synthesis of oxindoles. Tetrahedron Lett. 2013, 54, 1155–1159. 10.1016/j.tetlet.2012.12.082. [DOI] [Google Scholar]; c Li T.-Z.; Wang X.-B.; Sha F.; Wu X.-Y. Catalytic enantioselective addition of alcohols to isatin-derived N-Boc ketimines. Tetrahedron 2013, 69, 7314–7319. 10.1016/j.tet.2013.06.076. [DOI] [Google Scholar]; d Piemontesi C.; Wang Q.; Zhu J. Synthesis of 3,3-disubstituted oxindoles by one-pot integrated Brønsted base-catalyzed trichloroacetimidation of 3-hydroxyoxindoles and Brønsted acid-catalyzed nucleophilic substitution reaction. Org. Biomol. Chem. 2013, 11, 1533–1536. 10.1039/c2ob27196f. [DOI] [PubMed] [Google Scholar]; e Hillgren J. M.; Marsden S. P. Convenient Synthesis of 3-Alkoxy-3-aryloxindoles by Intramolecular Arylation of Mandelic Amides. J. Org. Chem. 2008, 73, 6459–6461. 10.1021/jo8010842. [DOI] [PubMed] [Google Scholar]
  6. Liu X.-L.; Yue J.; Chen S.; Liu H.-H.; Yang K.-M.; Feng T.-T.; Zhou Y. Thermal-mediated catalyst-free heterolytic cleavage of 3-halooxindoles: rapid access to 3-functionalized-2-oxindoles. Org. Chem. Front. 2019, 6, 256–262. 10.1039/c8qo01222a. [DOI] [Google Scholar]
  7. Liang K.; Li N.; Zhang Y.; Li T.; Xia C. Transition-metal-free α-arylation of oxindoles via visible-light-promoted electron transfer. Chem. Sci. 2019, 10, 3049–3053. and references cited therein 10.1039/c8sc05170d. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. a Huang H.-Y.; Cheng L.; Liu J.-J.; Wang D.; Liu L.; Li C.-J. Transition-Metal-Free Alkynylation of 2-Oxindoles through Radical–Radical Coupling. J. Org. Chem. 2017, 82, 2656–2663. 10.1021/acs.joc.6b03057. [DOI] [PubMed] [Google Scholar]; b Roy A.; Das M. K.; Chaudhuri S.; Bisai A. Transition-Metal Free Oxidative Alkynylation of 2-Oxindoles with Ethynylbenziodoxolone (EBX) Reagents. J. Org. Chem. 2018, 83, 403–421. 10.1021/acs.joc.7b02797. [DOI] [PubMed] [Google Scholar]; c Roy A.; Maity A.; Giri R.; Bisai A. Efficient Alkynylation of 2-Oxindoles with Alkynyl Dibenzothiophenium Triflates: Total Synthesis of (±)-Deoxyeseroline. Asian J. Org. Chem. 2020, 9, 226–232. 10.1002/ajoc.202000027. [DOI] [Google Scholar]
  9. Selected examples:; a Saito M.; Kobayashi Y.; Tsuzuki S.; Takemoto Y. Electrophilic Activation of Iodonium Ylides by Halogen-Bond-Donor Catalysis for Cross-Enolate Coupling. Angew. Chem., Int. Ed. 2017, 56, 7653–7657. 10.1002/anie.201703641. [DOI] [PubMed] [Google Scholar]; b He C.; Cao W.; Zhang J.; Ge S.; Feng X. Chiral N,N′-Dioxide/Scandium(III)-Catalyzed Asymmetric Alkylation of N-Unprotected 3-Substituted Oxindoles. Adv. Synth. Catal. 2018, 360, 4301–4305. 10.1002/adsc.201800877. [DOI] [Google Scholar]; c Di Gregorio G.; Mari M.; Bartolucci S.; Bartoccini F.; Piersanti G. Divergent reactions of oxindoles with amino alcohols via the borrowing hydrogen process: oxindole ring opening vs. C3 alkylation. Org. Chem. Front. 2018, 5, 1622–1627. 10.1039/c8qo00184g. [DOI] [Google Scholar]; d Wu Q.; Pan L.; Du G.; Zhang C.; Wang D. Preparation of pyridyltriazole ruthenium complexes as effective catalysts for the selective alkylation and one-pot C–H hydroxylation of 2-oxindole with alcohols and mechanism exploration. Org. Chem. Front. 2018, 5, 2668–2675. 10.1039/c8qo00725j. [DOI] [Google Scholar]
  10. a Hamashima Y.; Suzuki T.; Takano H.; Shimura Y.; Sodeoka M. Catalytic Enantioselective Fluorination of Oxindoles. J. Am. Chem. Soc. 2005, 127, 10164–10165. 10.1021/ja0513077. [DOI] [PubMed] [Google Scholar]; b Jiang X.; Wang H.; He H.; Wang W.; Wang Y.; Ke Z.; Yeung Y.-Y. Enantioseletive Fluorination of 3-Functionalized Oxindoles Using Electron-rich Amino Urea Catalyst. Adv. Synth. Catal. 2018, 360, 4710–4714. 10.1002/adsc.201801133. [DOI] [Google Scholar]
  11. Calvo R.; Comas-Vives A.; Togni A.; Katayev D. Taming Radical Intermediates for the Construction of Enantioenriched Trifluoromethylated Quaternary Carbon Centers. Angew. Chem., Int. Ed. 2019, 58, 1447–1452. 10.1002/anie.201812793. [DOI] [PubMed] [Google Scholar]
  12. Wei W.-T.; Zhu W.-M.; Ying W.-W.; Wang Y.-N.; Bao W.-H.; Gao L.-H.; Luo Y.-J.; Liang H. Metal-Free Nitration of the C(sp3)–H Bonds of 2-Oxindoles through Radical Coupling Reaction at Room Temperature. Adv. Synth. Catal. 2017, 359, 3551–3554. 10.1002/adsc.201700870. [DOI] [Google Scholar]
  13. Chen W.-T.; Gao L.-H.; Bao W.-H.; Wei W.-T. Metal-Free C(sp3)–H Azidation in a Radical Strategy for the Synthesis of 3-Azido-2-oxindoles at Room Temperature. J. Org. Chem. 2018, 83, 11074–11079. 10.1021/acs.joc.8b01678. [DOI] [PubMed] [Google Scholar]
  14. a Wei W.-T.; Zhu W.-M.; Bao W.-H.; Chen W.-T.; Huang Y.-L.; Gao L.-H.; Xu X.-D.; Wang Y.-N.; Chen G.-P. Metal-Free C(sp3)–H Amination of 2-Oxindoles in Water: Facile Synthesis of 3-Substituted 3-Aminooxindoles. ACS Sustainable Chem. Eng. 2018, 6, 5615–5619. 10.1021/acssuschemeng.8b00641. [DOI] [Google Scholar]; b Qian Z.-Q.; Zhou F.; Du T.-P.; Wang B.-L.; Ding M.; Zhao X.-L.; Zhou J. Asymmetric construction of quaternary stereocenters by direct organocatalytic amination of 3-substituted oxindoles. Chem. Commun. 2009, 6753–6755. 10.1039/b915257a. [DOI] [PubMed] [Google Scholar]; c Zhou F.; Ding M.; Liu Y. -L.; Wang C. -H.; Ji C. -B.; Zhang Y. -Y.; Zhou J. Organocatalytic Asymmetric α-Amination of Unprotected 3-Aryl and 3-Aliphatic Substituted Oxindoles using Di-tert-butyl Azodicarboxylate. Adv. Synth. Catal. 2011, 353, 29451–29452. 10.1002/adsc.201100379. [DOI] [Google Scholar]
  15. Qin H.; Li Q.; Xu J.; Zhang J.; Qu W.; Liu W.; Feng F.; Sun H. A Mild and Direct C(sp3)–S Cross-Coupling of Oxindoles with Thiols: Synthesis of Unsymmetrical 3-Thiooxindoles. J. Org. Chem. 2019, 84, 14342–14348. 10.1021/acs.joc.9b02205. [DOI] [PubMed] [Google Scholar]; and references cited therein
  16. Kotagiri R.; Adepu R. Alkoxylation Followed by Iodination of Oxindole with Alcohols Mediated by Hypervalent Iodine Reagent in the Presence of Iodine. Eur. J. Org. Chem. 2018, 2018, 4556–4564. 10.1002/ejoc.201800723. [DOI] [Google Scholar]
  17. Wang D.; Lu X.; Sun S.; Yu H.; Su H.; Wu Y.; Zhong F. Unified and Benign Synthesis of Spirooxindoles via Bifunctional and Recyclable Iodide-Salt-Catalyzed Oxidative Coupling in Water. Eur. J. Org. Chem. 2019, 2019, 6028–6033. 10.1002/ejoc.201900751. [DOI] [Google Scholar]
  18. a Hou Y.; Higashiya S.; Fuchigami T. Highly Regioselective Anodic Monofluorination of Oxindole and 3-Oxo-1,2,3,4-tetrahydroisoquinoline Derivatives. Synlett 1997, 1997, 655–656. 10.1055/s-1997-3272. [DOI] [Google Scholar]; b Sharma S.; Roy A.; Shaw K.; Bisai A.; Paul A. Electrochemical Synthesis of Dimeric 2-Oxindole Sharing Vicinal Quaternary Centers Employing Proton-Coupled Electron Transfer. J. Org. Chem. 2020, 85, 14926–14936. 10.1021/acs.joc.0c01621. [DOI] [PubMed] [Google Scholar]
  19. Selected reviews:; a Yan M.; Kawamata Y.; Baran P. S. Synthetic Organic Ele.ctrochemical Methods Since 2000: On the Verge of a Renaissance. Chem. Rev. 2017, 117, 13230–13319. 10.1021/acs.chemrev.7b00397. [DOI] [PMC free article] [PubMed] [Google Scholar]; b Barham J. P.; König B. Synthetic Photoelectrochemistry. Angew. Chem., Int. Ed. 2020, 59, 11732–11747. 10.1002/anie.201913767. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Phillips A. M. F.; Pombeiro A. J. L. Electrochemical asymmetric synthesis of biologically active substances. Org. Biomol. Chem. 2020, 18, 7026–7055. 10.1039/d0ob01425g. [DOI] [PubMed] [Google Scholar]
  20. In a seminal report, Moeller et al. have shown a single example for the anodic oxidation of ((4-methoxyphenyl)acetyl)pyrrolidine at the benzylic position to form the corresponding product.; a Moeller K. D.; Sharif T.; Mohammad R M. Electrochemical amide oxidations in the presence of monomethoxylated phenyl rings. An unexpected relationship between the chemoselectivity of the oxidation and the location of the methoxy substituent. Tetrahedron Lett. 1989, 30, 1213–1216. 10.1016/s0040-4039(00)72718-3. [DOI] [Google Scholar]; b Moeller K. D.; Wang P. W.; Tarazi S.; Marzabadi M. R.; Wong P. L. Anodic amide oxidations in the electron-rich phenyl rings: evidence for an intramolecular electron-transfer mechanism. J. Org. Chem. 1991, 56, 1058–1067. 10.1021/jo00003a029. [DOI] [Google Scholar]
  21. Tamirat A. G.; Guan X.; Liu J.; Luo J.; Xia Y. Redox mediators as charge agents for changing electrochemical reactions. Chem. Soc. Rev. 2020, 49, 7454–7478. 10.1039/d0cs00489h. [DOI] [PubMed] [Google Scholar]
  22. See Supporting Information, Figure S1 for further details.
  23. In preliminary experiments, reaction with silylketeneacetals or allylsilanes also delivered C–C coupling products in low (unoptimised) yields (see Supporting Information, section 8 for further details). Reaction with anisole as nucleophile afforded no product.
  24. Reaction with p-cresol leads to low conversion and only trace amounts of the desired product.
  25. a Maia F. J. N.; Clemente C. d. S.; Oliveira T. M. B. F.; Lomonaco D.; Oliveira T. I. S.; Almeida M. O.; de Lima-Neto P.; Correia A. N.; Mazzeto S. E. Electrochemical and Computational Studies of Phenolic Antioxidants from Cashew Nut Shell Liquid. Electrochim. Acta 2012, 79, 67–73. 10.1016/j.electacta.2012.06.086. [DOI] [Google Scholar]; b Qiu Y.; Struwe J.; Meyer T. H.; Oliveira J. C. A.; Ackermann L. Catalyst- and Reagent-Free Electrochemical Azole C-H Amination. Chem.—Eur. J. 2018, 24, 12784–12789. 10.1002/chem.201802832. [DOI] [PubMed] [Google Scholar]

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