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. 2022 Mar 23;144(13):5756–5761. doi: 10.1021/jacs.2c01852

Hypoiodite-Catalyzed Oxidative Umpolung of Indoles for Enantioselective Dearomatization

Hiroki Tanaka 1, Naoya Ukegawa 1, Muhammet Uyanik 1,*, Kazuaki Ishihara 1,*
PMCID: PMC8991020  PMID: 35319875

Abstract

graphic file with name ja2c01852_0007.jpg

Here we report the oxidative umpolung of 2,3-disubstituted indoles toward enantioselective dearomative aza-spirocyclization to give the corresponding spiroindolenines using chiral quaternary ammonium hypoiodite catalysis. Mechanistic studies revealed the umpolung reactivity of C3 of indoles by iodination of the indole nitrogen atom. Moreover, the introduction of pyrazole as an electron-withdrawing auxiliary group at C2 suppressed a competitive dissociative racemic pathway, and enantioselective spirocyclization proceeded to give not only spiropyrrolidines but also four-membered spiroazetidines that are otherwise difficult to access.

Indole-derived alkaloids are the largest group of nitrogen-containing secondary metabolites.1 Because of their wide range of biological and pharmacological activities, a tremendous amount of research has been devoted to the development of efficient methods for the synthesis of indole alkaloids in synthetic organic chemistry, especially for drug discovery.1c,2 From this perspective, dearomatization of structurally planar indoles into enantioenriched three-dimensional indoline or indolenine structures has emerged as a powerful tool for the asymmetric synthesis of indole-derived alkaloids.3 Because of the inherent nucleophilicity of indoles, especially at C3 due to enamine-like reactivity, dearomatization reactions often proceed by addition of electrophiles at C3 (Scheme 1a, left).3c,3d,4

Scheme 1. Oxidative Umpolung of Indoles for Dearomative Coupling Reactions.

Scheme 1

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Conventionally, the incorporation of strong electron-withdrawing substituents5b,6 or leaving groups7 on the indole nucleus is often required for inversion of the polarity (umpolung)8 of nucleophilic indoles to give electrophilic indoles. Recently, several asymmetric transformations of indole derivatives based on the C3 umpolung reactivity of 2-indolylmethanols have been achieved using chiral Brønsted acid catalysis.7b−7e On the other hand, methods for direct umpolung without preactivation would open a new avenue for the dearomative functionalization of indoles (Scheme 1a, right).5a However, only a few examples of oxidative umpolung of indoles have been reported.9−11 Recently, new methods, namely electro-10 and photochemical11 oxidation of indoles, have been developed. Enantioselective dearomative coupling of indoles has also been achieved in combination with chiral phosphate or phosphoric acid catalysts under photooxidation conditions. However, these methods have relied on the use of transition metal chromophores as photocatalyst as well as preoxidized nucleophiles such as nitroxyl radicals or hydroxylamine derivatives.11a,11b

We recently reported the quaternary ammonium hypoiodite-catalyzed12 oxidative C2-cyclization/peroxidation of homotryptamine derivatives (Scheme 1b).13 We envisioned that the introduction of a substituent at C2 of homotryptamines might sterically suppress cyclization or 1,2-migration14 at C2, allowing spirocyclization to proceed at C3 to form five-membered rings. Dearomative spirocyclization of homotryptamine derivatives to form aza-spiroindolenines has been reported.15 However, preinstallation of an O-based leaving group on an electrophilic nitrogen tether15a−15c or stoichiometric amounts of an organoiodine(III) as an oxidant15d were required. In addition, enantioselective dearomative aza-spirocyclization remains elusive. Here we report the oxidative umpolung of 2,3-disubstituted indoles toward enantioselective dearomatizative spirocyclization of not only homotryptamines but also tryptamines to afford the corresponding spiroindolenines using quaternary ammonium hypoiodite catalysis12a,16 (Scheme 1c). Mechanistic studies revealed the umpolung reactivity of indole by iodination at N1.

We began our investigation by examining the oxidative spirocyclization of C2-methyl substituted homotryptamine derivative 1a using tert-butyl hydroperoxide (TBHP) as an oxidant in the presence of 10 mol % n-tetrabutylammonium iodide (Bu4NI) (Scheme 2a). Although the desired spiroindolenine 2a was obtained in 31% yield, intermolecular coupling with TBHP also proceeded to give peroxyindolenine 3 as a byproduct. To suppress this side reaction, we used cumene hydroperoxide (CHP) as a more sterically hindered oxidant instead of TBHP, and to our delight, a cleaner reaction was observed to give 2a in 67% yield.17

Scheme 2. Investigation of Reaction Conditions and Chiral Catalysts.

Scheme 2

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Next, we investigated enantioselective spirocyclization using bis(binaphthyl)-based chiral quaternary ammonium iodide 4a, (Scheme 2b).12a,16,18 After optimization of the reaction conditions (Table S1),192a was obtained in 70% yield with 46% ee in a methyl tert-butyl ether (MTBE)/toluene mixed solvent. Toluene and MTBE were found to be effective as solvents to enhance the reactivity and enantioselectivity, respectively.

Since investigation of the substituents at the 3- and 3′-positions of bis(binaphthyl)ammonium cation 4 failed to improve the enantioselectivity, we explored the use of mono(binaphthyl)-based catalysts 4(18) (Table S3). The use of morpholine-derived mono(binaphthyl)ammonium iodides improved the enantioselectivity, and the best result (81% ee) was obtained with cis-2,6-dimethylmorpholine-derived 4b (Scheme 2b). To further improve the chemoselectivity, we used Na2SO4 as a desiccant to give 2a in 87% yield with 81% ee (Table S4). The absolute stereochemistry of 2a was assigned to be R by X-ray analysis of an enantiomerically pure sample that was obtained after a single recrystallization.

We examined the enantioselective dearomative aza-spirocyclization of several N-(4-nosyl)homotryptamines 1 under the optimized conditions (Scheme 3). 2-Methylindole derivatives 1a–f bearing electron-donating or -withdrawing substituents at C5 gave the corresponding spiroindolenines 2a–f in high yields with good to moderate enantioselectivities (59–81% ee). The optical purity of 2a–f could be improved to 88–99% ee after a single recrystallization. Good to excellent enantioselectivities (75–98% ee) were achieved for the reaction of 2-alkyl (larger than methyl)- or 2-phenyl-substituted indoles bearing electron-withdrawing substituents (1g–o, 1q–t) or no substituent (1p) on the indole nucleus. Interestingly, while the reaction of rac-1u using Bu4NI gave high diastereoselectivity (12:1), the use of chiral catalyst 4b afforded a 2:1 mixture of 2u and 2u′ with higher enantioselectivity for the minor diastereomer 2u′.

Scheme 3. Enantioselective Oxidative Aza-spirocyclization to Give Spiropyrrolidines 2 Under the Optimized Conditions.

Scheme 3

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Reaction conditions: 4b (10 mol %), CHP (2 equiv), Na2SO4, MTBE/toluene, 25 °C, 10–24 h.

After a single recrystallization.

Reaction conditions: Bu4NI (10 mol %), CHP (2 equiv), toluene, 25 °C, 10 h.

Control experiments revealed that the ammonium hypoiodite species might be the catalytically active species for the oxidative dearomative spirocyclization of 1 and that a free radical pathway might be unlikely (Table S7).

To gain further insight into the reaction mechanism, we performed kinetic studies using the oxidative dearomatization of 1v, a p-(trifluoromethyl)benzenesulfonyl-protected analogue of 1a, as a model reaction (Figures S1–S4).20 The reaction rate was found to have a zeroth-order dependence on the concentration of substrate 1v and a first-order dependence on the concentrations of both CHP and 4b. However, a difference in the initial reaction rates was observed depending on the substituent of 1, suggesting that oxidation of a catalyst–substrate complex might be the rate-determining step.21 To further evaluate the mechanism, we performed a Hammett analysis with a series of N-4-(trifluoromethyl)benzenesulfonyl homotryptamines 1v–y and N-sulfonyl 5-bromohomotryptamines 1z–ab to probe the electronic effects of the para substituents on the indole and sulfonamide nitrogens, respectively, on the reaction rate (Scheme 4a and Figures S5–S8). As a result, a linear correlation with a negative slope (ρ = −0.98) was observed from the corresponding plot of the σpara constants versus log(kR/kH) for indole substituents (R5). On the other hand, a poor correlation was observed from the corresponding plot of the σmeta constants, suggesting the accumulation of positive charge on the indole nitrogen rather than C3 in the rate-determining transition state.22,23 Although a linear correlation was also obtained for sulfonamide substituents (R), the reaction constant was much smaller (ρ = −0.15), suggesting that accumulation of positive charge on the sulfonamide nitrogen might be unlikely.

Scheme 4. Mechanistic Studies.

Scheme 4

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Next, to evaluate the roles of the N–H groups of the indole and sulfonamide units for the oxidation reactions, N-methylindole 5 and N-methylsulfonamide 6 were prepared and examined under the standard conditions (Scheme 4b). While most of the starting material was recovered from the reaction of 5, the dearomatization of 6 proceeded smoothly to give peroxide adduct 7 in good yield. Consistent with the results of the Hammett analysis, these results indicated that umpolung of the indole moiety through the generation of an N–I indole intermediate might be crucial for the oxidative dearomatization reaction. On the other hand, the smooth reaction of 1d using N-iodosuccinimide as a stoichiometric I+ reagent under neutral conditions gave C3-iodine adduct 8 (Scheme 4c). C3 iodination was not observed under our catalytic conditions (Figure S9), and exposure of 8 to our conditions gave a complex mixture of several unidentified products; 2d was not observed, suggesting that spirocyclization via iodination of indole C3 might be unlikely.

On the basis of these experimental results and previous works,13a,16 a proposed catalytic reaction mechanism is depicted in Scheme 4d. Ammonium hypoiodite could be generated in situ as an active species from the oxidation of ammonium iodide with an oxidant. N-Iodo intermediate 9 might be produced by a reversible reaction of hypoiodite with the indole N–H directly or by iodination of the sulfonamide N–H followed by intramolecular iodo transfer.24 To enhance the electrophilicity21 of indole, N-iodine(III) intermediate 10 might be generated by rate-determining oxidation of 9. The accumulation of positive charge on the indole nitrogen in the rate-determining transition state with the generation of a highly electron-deficient iodine(III) species is also in agreement with the results of the Hammett analysis. Finally, reductive elimination of ammonium hypoiodite might proceed via intramolecular capture of highly electrophilic intermediate 10 by the chiral ammonium sulfonamide as the enantiodetermining step to give aza-spiroindolenine 2.

Given the high nucleofugality of hypervalent iodines,25 we considered that zwitterionic intermediate 11 might be generated by the competitive dissociation of ammonium hypoiodite prior to spirocyclization,26 which would render asymmetric induction difficult (Scheme 4d). A dissociative racemic pathway might preferentially proceed for the oxidation of electron-rich indoles (e. g., 1e and 1f) as a result of stabilization of cationic intermediate 11 by electron-donating substituents to give moderate enantioselectivity (Scheme 3). In addition, plotting log(e.r.)27 of products 2a–f against the corresponding σpara constants gave a linear correlation with a positive slope (Scheme 4d, inset), which might also support the existence of a dissociative pathway during umpolung of indole.

We envisioned that the introduction of an electron-deficient substituent at C2 might suppress the dissociative pathway by destabilization of cationic intermediate 11. In addition, an electron-deficient group at C2 would further reduce the LUMO energy at C3, which might enhance the rate of the spirocyclization step and further improve the chemoselectivity. Moreover, if an electron-deficient auxiliary could be used as a leaving group, the synthetic utility of the products would be enhanced. With these assumptions in mind, we focused on pyrazole as an electron-deficient auxiliary because it can be easily introduced28 and removed via nucleophilic acyl substitution.29 To our delight, spiroindolenines 2ac–ae were obtained after smooth reaction of the corresponding 2-pyrazol-1-ylhomotryptamine derivatives 1ac–ae (Scheme 5a). Most importantly, in sharp contrast to those for 2-methylindole analogues 2a, 2d, and 2f, good enantioselectivities (81–86% ee) were achieved regardless of the electron-donating or -withdrawing substituents at C5. A gram-scale oxidation of 1ac was also achieved with the use of 5 mol % 4b to give 2ac in enantiomerically pure form after recrystallization. In addition, an additive robustness screen analysis30 revealed that a wide range of functional groups were tolerated under our mild conditions, including carbonyls, amines, alkyne, and heteroarenes (Table S5).

Scheme 5. Harnessing an Electrophilic Indole by Introducing a Pyrazolyl Auxiliary.

Scheme 5

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4b (5 mol %).

After a single recrystallization.

In sharp contrast to previous methods,31 with the introduction of a pyrazole auxiliary at C2, site-selective spirocyclization of 2-pyrazol-1-yltryptamine 12 at C3 proceeded to give the difficult-to-access four-membered spiroazetidine 13 with good enantioselectivity (Scheme 5b).32

Finally, we demonstrated the synthetic utility of enantioenriched spiroindolenines 2 (Scheme 6). First, the 4-nosyl group of 2a could be easily removed under standard deprotection conditions to give free amine 14 (Scheme 6a).19 Deprotonation of 2a triggered by N-tosylation gave 2-methyleneindoline 15 in good yield (Scheme 6b, left). Similarly, N-methylation of 2a followed by condensation with salicylaldehyde afforded spiropyran 16, a structure that is commonly found in photochromic compounds33 (Scheme 6b, right). On the other hand, the pyrazole auxiliary of 2ac could be easily removed by Lewis acid-catalyzed hydrolysis to give oxindole 17 quantitatively (Scheme 6c).34 Formal nucleophilic substitution of pyrazole 2ac with a carbon nucleophile was accomplished by triflation of 17 followed by a Sonogashira coupling reaction to give 2-alkynylspiroindoline 18. In addition, ethanolysis13a of pyrazole 2ac proceeded smoothly to give imino ester 19 in good yield (Scheme 6d, left). Moreover, we found that scandium-catalyzed nucleophilic substitution of pyrazole 2ac by trimethylsilyl azide followed by intramolecular click cyclization gave tetrazoloindole 20 as a unique structure, which was confirmed by X-ray analysis (Scheme 6d, right). No loss of enantioselectivity was observed in any of these transformations.

Scheme 6. Transformations.

Scheme 6

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In summary, we have developed an oxidative umpolung strategy for the chiral ammonium hypoiodite-catalyzed enantioselective dearomative aza-spirocyclization of homotryptamine derivatives to give the corresponding aza-spiroindolenines with good to excellent enantioselectivity. Mechanistic studies revealed the unusual umpolung reactivity at C3 of indoles by N1 iodination. Moreover, by the introduction of pyrazole as an electron-deficient auxiliary at C2, site-selective spirocyclization of a tryptamine derivative was also achieved to give the difficult-to-access spiroazetidine in an enantioselective manner. Furthermore, to demonstrate the synthetic utility of our dearomative spirocyclization, 2-alkyl- and 2-pyrazole-substituted spiroindolenines were readily converted to various useful and unique structures. These results demonstrate the high potential of hypoiodite catalysis for oxidative umpolung of indoles toward the synthesis of polycyclic indole-derived alkaloids.

Acknowledgments

Financial support for this project was partially provided by JSPS KAKENHI (20K20559 to K.I., 21H01932 to M.U., and 18H01973 to M.U.), the Society of Iodine Science (to M.U.), and the Nagoya University Graduate Program of Transformative Chem-Bio Research (GTR). This work is partially supported by Nagoya University Research Fund.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.2c01852.

  • Additional information, synthesis procedures, and spectral data (PDF)

Accession Codes

CCDC 2143581, 2143588–2143591, and 2159841 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.

The authors declare no competing financial interest.

Supplementary Material

ja2c01852_si_001.pdf (38.2MB, pdf)

References

  1. a Seigler D. S.Indole Alkaloids. In Plant Secondary Metabolism; Springer: Boston, MA, 1998; pp 628–654. [Google Scholar]; b Ban Y.; Murakami Y.; Iwasawa Y.; Tsuchiya M.; Takano N. Indole alkaloids in medicine. Med. Res. Rev. 1988, 8, 231–308. 10.1002/med.2610080205. [DOI] [PubMed] [Google Scholar]; c de Sá Alves F. R.; Barreiro E. J.; Manssour Fraga C. A. From nature to drug discovery: The indole scaffold as a ‘privileged structure’. Mini-Rev. Med. Chem. 2009, 9, 782–793. 10.2174/138955709788452649. [DOI] [PubMed] [Google Scholar]
  2. Ishikura M.; Abe T.; Choshi T.; Hibino S. Simple indole alkaloids and those with a nonrearranged monoterpenoid unit. Nat. Prod. Rep. 2015, 32, 1389–1471. 10.1039/C5NP00032G. [DOI] [PubMed] [Google Scholar]
  3. a Roche S. P.; Tendoung J.-J. Y.; Tréguier B. Advances in dearomatization strategies of indoles. Tetrahedron 2015, 71, 3549–3591. 10.1016/j.tet.2014.06.054. [DOI] [Google Scholar]; b Saya J. M.; Ruijter E.; Orru R. V. A. Total synthesis of aspidosperma and strychnos alkaloids through indole dearomatization. Chem. - Eur. J. 2019, 25, 8916–8935. 10.1002/chem.201901130. [DOI] [PubMed] [Google Scholar]; c Zheng C.; You S.-L. Catalytic asymmetric dearomatization (CADA) reaction-enabled total synthesis of indole-based natural products. Nat. Prod. Rep. 2019, 36, 1589–1605. 10.1039/C8NP00098K. [DOI] [PubMed] [Google Scholar]; d Sheng F.-T.; Wang J.-Y.; Tan W.; Zhang Y.-C.; Shi F. Progresses in organocatalytic asymmetric dearomatization reactions of indole derivatives. Org. Chem. Front. 2020, 7, 3967–3998. 10.1039/D0QO01124J. [DOI] [Google Scholar]; e Xia Z.-L.; Xu-Xu Q.-F.; Zheng C.; You S.-L. Chiral phosphoric acid-catalyzed asymmetric dearomatization reactions. Chem. Soc. Rev. 2020, 49, 286–300. 10.1039/C8CS00436F. [DOI] [PubMed] [Google Scholar]; f Zheng C.; You S.-L. Advances in Catalytic Asymmetric Dearomatization. ACS Cent. Sci. 2021, 7, 432–444. 10.1021/acscentsci.0c01651. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. a Bartoli G.; Bencivenni G.; Dalpozzo R. Organocatalytic strategies for the asymmetric functionalization of indoles. Chem. Soc. Rev. 2010, 39, 4449–4465. 10.1039/b923063g. [DOI] [PubMed] [Google Scholar]; b Lakhdar S.; Westermaier M.; Terrier F.; Goumont R.; Boubaker T.; Ofial A. R.; Mayr H. Nucleophilic reactivities of indoles. J. Org. Chem. 2006, 71, 9088–9095. 10.1021/jo0614339. [DOI] [PubMed] [Google Scholar]
  5. a Bandini M. Electrophilicity: the “dark-side” of indole chemistry. Org. Biomol. Chem. 2013, 11, 5206–5212. 10.1039/c3ob40735g. [DOI] [PubMed] [Google Scholar]; b Abou-Hamdan H.; Kouklovsky C.; Vincent G. Dearomatization reactions of indoles to access 3D indoline structures. Synlett 2020, 31, 1775–1788. 10.1055/s-0040-1707152. [DOI] [Google Scholar]
  6. Rkein B.; Bigot A.; Birbaum L.; Manneveau M.; De Paolis M.; Legros J.; Chataigner I. Reactivity of 3-nitroindoles with electron-rich species. Chem. Commun. 2021, 57, 27–44. 10.1039/D0CC06658C. [DOI] [PubMed] [Google Scholar]
  7. a Nagayoshi T.; Saeki S.; Hamana M. Studies on tertiary amine oxides. LXXII. Some nucleophilic reactions of 1-hydroxy-2-phenylindole. Chem. Pharm. Bull. 1981, 29, 1920–1926. 10.1248/cpb.29.1920. [DOI] [Google Scholar]; b Li C.; Zhang H.-H.; Fan T.; Shen Y.; Wu Q.; Shi F. Brønsted Acid-Catalyzed Regioselective Reactions of 2-Indolylmethanols with Cyclic Enaminone and Anhydride Leading to C3-Functionalized Indole Derivatives. Org. Biomol. Chem. 2016, 14, 6932–6936. 10.1039/C6OB01282E. [DOI] [PubMed] [Google Scholar]; c Zhang H.-H.; Wang C.-S.; Li C.; Mei G.-J.; Li Y.; Shi F. Design and Enantioselective Construction of Axially Chiral Naphthyl-Indole Skeletons. Angew. Chem., Int. Ed. 2017, 56, 116–121. 10.1002/anie.201608150. [DOI] [PubMed] [Google Scholar]; d Zhang Y.-C.; Jiang F.; Shi F. Organocatalytic Asymmetric Synthesis of Indole-Based Chiral Heterocycles: Strategies, Reactions, and Outreach. Acc. Chem. Res. 2020, 53, 425–446. 10.1021/acs.accounts.9b00549. [DOI] [PubMed] [Google Scholar]; e Petrini M. New Perspectives in the Indole Ring Functionalization using 2-Indolylmethanols. Adv. Synth. Catal. 2020, 362, 1214–1232. 10.1002/adsc.201901245. [DOI] [Google Scholar]
  8. Seebach D. Methods of Reactivity Umpolung. Angew. Chem., Int. Ed. 1979, 18, 239–258. 10.1002/anie.197902393. [DOI] [Google Scholar]
  9. a Awang D. V. C.; Vincent A. Alkoxylation of 2,3-dialkylindoles utilizing iodosobenzene diacetate. Can. J. Chem. 1980, 58, 1589–1591. 10.1139/v80-250. [DOI] [Google Scholar]; b Dohi T.; Ito M.; Yamaoka N.; Morimoto K.; Fujioka H.; Kita Y. Hypervalent iodine(III): selective and efficient single-electron-transfer (SET) oxidizing agent. Tetrahedron 2009, 65, 10797–10815. 10.1016/j.tet.2009.10.040. [DOI] [Google Scholar]; c Caramenti P.; Waser J. Bench-stable electrophilic indole and pyrrole reagents: serendipitous discovery and use in C–H functionalization. Helv. Chim. Acta 2017, 100, e1700221. 10.1002/hlca.201700221. [DOI] [Google Scholar]
  10. a Wu J.; Dou Y.; Guillot R.; Kouklovsky C.; Vincent G. Electrochemical dearomative 2,3-difunctionalization of indoles. J. Am. Chem. Soc. 2019, 141, 2832–2837. 10.1021/jacs.8b13371. [DOI] [PubMed] [Google Scholar]; b Liu K.; Song W.; Deng Y.; Yang H.; Song C.; Abdelilah T.; Wang S.; Cong H.; Tang S.; Lei A. Electrooxidation enables highly regioselective dearomative annulation of indole and benzofuran derivatives. Nat. Commun. 2020, 11, 3. 10.1038/s41467-019-13829-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. a Gentry E. C.; Rono L. J.; Hale M. E.; Matsuura R.; Knowles R. R. Enantioselective synthesis of pyrroloindolines via noncovalent stabilization of indole radical cations and applications to the synthesis of alkaloid natural products. J. Am. Chem. Soc. 2018, 140, 3394–3402. 10.1021/jacs.7b13616. [DOI] [PMC free article] [PubMed] [Google Scholar]; b Cheng Y.-Z.; Zhao Q.-R.; Zhang X.; You S.-L. Asymmetric dearomatization of indole derivatives with N-hydroxycarbamates enabled by photoredox catalysis. Angew. Chem., Int. Ed. 2019, 58, 18069–18074. 10.1002/anie.201911144. [DOI] [PubMed] [Google Scholar]; c Yuan W.; Huang J.; Xu X.; Wang L.; Tang X.-Y. B(C6F5)3-Catalyzed electron donor-acceptor complex-mediated aerobic sulfenylation of indoles under visible-light conditions. Org. Lett. 2021, 23, 7139–7143. 10.1021/acs.orglett.1c02553. [DOI] [PubMed] [Google Scholar]; d Cheng Y.-Z.; Feng Z.; Zhang X.; You S.-L. Visible-light Induced Dearomatization Reactions. Chem. Soc. Rev. 2022, 51, 2145. 10.1039/C9CS00311H. [DOI] [PubMed] [Google Scholar]
  12. a Uyanik M.; Okamoto H.; Yasui T.; Ishihara K. Quaternary ammonium (hypo)iodite catalysis for enantioselective oxidative cycloetherification. Science 2010, 328, 1376–1379. 10.1126/science.1188217. [DOI] [PubMed] [Google Scholar]; b Uyanik M.; Ishihara K. Catalysis with in situ generated (hypo)iodite ions for oxidative coupling reactions. ChemCatChem 2012, 4, 177–185. 10.1002/cctc.201100352. [DOI] [Google Scholar]; c Finkbeiner P.; Nachtsheim B. J. Iodine in modern oxidation catalysis. Synthesis 2013, 45, 979–999. 10.1055/s-0032-1318330. [DOI] [Google Scholar]; d Chen R.; Chen J.; Zhang J.; Wan X. Combination of tetrabutylammonium iodide (TBAI) with tert-butyl hydroperoxide (TBHP): an efficient transition-metal-free system to construct various chemical bonds. Chem. Rec. 2018, 18, 1292–1305. 10.1002/tcr.201700069. [DOI] [PubMed] [Google Scholar]
  13. a Uyanik M.; Tanaka H.; Ishihara K. Hypoiodite-catalyzed chemoselective tandem oxidation of homotryptamines to peroxy- and epoxytetrahydropyridoindolenines. Org. Lett. 2020, 22, 8049–8054. 10.1021/acs.orglett.0c03001. [DOI] [PubMed] [Google Scholar]; b Uyanik M.; Tanaka H.; Ishihara K. I+/TBHP catalysis for tandem oxidative cyclization to indolo[2,3-b]quinolines. Asian J. Org. Chem. 2021, 10, 164–169. 10.1002/ajoc.202000570. [DOI] [Google Scholar]
  14. Zheng C.; You S.-L. Exploring the chemistry of spiroindolenines by mechanistically-driven reaction development: Asymmetric Pictet–Spengler-type reactions and beyond. Acc. Chem, Res. 2020, 53, 974–987. 10.1021/acs.accounts.0c00074. [DOI] [PubMed] [Google Scholar]
  15. a Tanaka K.; Mori Y.; Narasaka K. Synthesis of spiro[indoline-3,2′-pyrrolidine] derivatives from β-3-indolyl ketone oximes. Chem. Lett. 2004, 33, 26–27. 10.1246/cl.2004.26. [DOI] [Google Scholar]; b Ma X.; Farndon J. J.; Young T. A.; Fey N.; Bower J. F. A simple and broadly applicable C–N bond forming dearomatization protocol enabled by bifunctional amino-reagents. Angew. Chem., Int. Ed. 2017, 56, 14531–14535. 10.1002/anie.201708176. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Wang P.-F.; Chen C.; Chen H.; Han L.-S.; Liu L.; Sun H.; Wen X.; Xu Q.-L. Concise synthesis of spiro[indoline-3,2′-pyrrolidine] and 1-azacarbazole derivatives via copper-catalyzed cyclization of indoles. Adv. Synth. Catal. 2017, 359, 2339–2344. 10.1002/adsc.201700073. [DOI] [Google Scholar]; d Zhou Y.; Li D.; Tang S.; Sun H.; Huang J.; Zhu Q. PhI(OAc)2-mediated dearomative C–N coupling: facile construction of the spiro[indoline-3,2′-pyrrolidine] skeleton. Org. Biomol. Chem. 2018, 16, 2039–2042. 10.1039/C8OB00343B. [DOI] [PubMed] [Google Scholar]
  16. Uyanik M.; Hayashi H.; Ishihara K. High-turnover hypoiodite catalysis for asymmetric synthesis of tocopherols. Science 2014, 345, 291–294. 10.1126/science.1254976. [DOI] [PubMed] [Google Scholar]
  17. Almost no reaction was observed with the use of hydrogen peroxide as an oxidant, suggesting nonproductive decomposition of the oxidant. See:; Uyanik M.; Sahara N.; Tsukahara M.; Hattori Y.; Ishihara K. Chemo- and enantioselective oxidative a-azidation of carbonyl compounds. Angew. Chem., Int. Ed. 2020, 59, 17110–17117. 10.1002/anie.202007552. [DOI] [PubMed] [Google Scholar]
  18. Ooi T.; Maruoka K. Recent advances in asymmetric phase-transfer catalysis. Angew. Chem., Int. Ed. 2007, 46, 4222–4266. 10.1002/anie.200601737. [DOI] [PubMed] [Google Scholar]
  19. Considering further synthetic study, we used a p-nitrobenzenesulfonyl (4Ns) group as a useful protecting group for easy deprotection (Table S2). See:; Kan T.; Fukuyama T. Ns strategies: a highly versatile synthetic method for amines. Chem. Commun. 2004, 353–359. 10.1039/b311203a. [DOI] [PubMed] [Google Scholar]
  20. Considering the better solubility of substrates 1 under the reaction conditions, we selected a (trifluoromethyl)benzenesulfonyl group as a protecting group for kinetic and Hammett studies.
  21. Bosnidou A. E.; Muñiz K. Alkyliodines in high oxidation state: enhanced synthetic possibilities and accelerated catalyst turn-over. Chem. - Eur. J. 2019, 25, 13654–13664. 10.1002/chem.201902687. [DOI] [PubMed] [Google Scholar]
  22. Richter J. M.; Whitefield B. W.; Maimone T. J.; Lin D. W.; Castroviejo M. P.; Baran P. S. Scope and mechanism of direct indole and pyrrole couplings adjacent to carbonyl compounds: total synthesis of acremoauxin A and oxazinin 3. J. Am. Chem, Soc. 2007, 129, 12857–12869. 10.1021/ja074392m. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Nandi R. K.; Perez-Luna A.; Gori D.; Beaud R.; Guillot R.; Kouklovsky C.; Gandon V.; Vincent G. Triflic Acid as an Efficient Brønsted Acid Promoter for the Umpolung of N-Ac Indoles in Hydroarylation Reactions. Adv. Synth. Catal. 2018, 360, 161–172. 10.1002/adsc.201701074. [DOI] [Google Scholar]
  24. Although we could not isolate and fully characterize N-iodo intermediate 9, possibly because of inherent instability of the compound and rapid equilibrium with 1, NMR and mass analysis of the reaction mixture suggested iodination of the indole to give a transient intermediate (Figures S9 and S10).
  25. Yoshimura A.; Zhdankin V. V. Advances in synthetic applications of hypervalent iodine compounds. Chem. Rev. 2016, 116, 3328–3435. 10.1021/acs.chemrev.5b00547. [DOI] [PubMed] [Google Scholar]
  26. Uyanik M.; Nishioka K.; Kondo R.; Ishihara K. Chemoselective oxidative generation of ortho-quinone methides and tandem transformations. Nat. Chem. 2020, 12, 353–362. 10.1038/s41557-020-0433-4. [DOI] [PubMed] [Google Scholar]
  27. Wendlandt A. E.; Vangal P.; Jacobsen E. N. Quaternary stereocentres via an enantioconvergent catalytic SN1 reaction. Nature 2018, 556, 447–451. 10.1038/s41586-018-0042-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Wu W.-B.; Huang J.-M. Highly regioselective C–N bond formation through C–H azolation of indoles promoted by iodine in aqueous media. Org. Lett. 2012, 14, 5832–5835. 10.1021/ol302609m. [DOI] [PubMed] [Google Scholar]
  29. Tokumasu K.; Yazaki R.; Ohshima T. Direct catalytic chemoselective a-amination of acylpyrazoles: A concise route to unnatural α-amino acid derivatives. J. Am. Chem, Soc. 2016, 138, 2664–2669. 10.1021/jacs.5b11773. [DOI] [PubMed] [Google Scholar]
  30. Collins K.; Glorius F. A Robustness Screen for the Rapid Assessment of Chemical Reactions. Nat. Chem. 2013, 5, 597–601. 10.1038/nchem.1669. [DOI] [PubMed] [Google Scholar]
  31. Hexahydropyrroloindole structures were often obtained via cyclization of tryptamine at C2. See:; Ruiz-Sanchis P.; Savina S. A.; Albericio F.; Álvarez M. Structure, bioactivity and synthesis of natural products with hexahydropyrrolo[2,3-b]indole. Chem. - Eur. J. 2011, 17, 1388–1408. 10.1002/chem.201001451. [DOI] [PubMed] [Google Scholar]
  32. Although there remains room for improvement in the enantioselectivity, preliminary experiments demonstrated the prospects of the use of the 2-pyrazole auxiliary to expand the reaction scope to spiroaziridination and spirolactonization. See Scheme S1.
  33. Kortekaas L.; Browne W. R. The evolution of spiropyran: fundamentals and progress of an extraordinarily versatile photochrome. Chem. Soc. Rev. 2019, 48, 3406–3424. 10.1039/C9CS00203K. [DOI] [PubMed] [Google Scholar]
  34. Quite recently, Zhong and colleagues reported the enantioselective synthesis of spiroindolyloxindoles as related compounds by chiral ammonium hypoiodite-catalyzed oxidative α-aminocyclization of carbonyl compounds. See:; Wang D.; Zhang W.; Lu X.; Zhou H.; Zhong F. Cinchona Alkaloid Derived Iodide Catalyzed Enantioselective Oxidative α-Amination of Carbonyl Compounds toward the Construction of Spiroindolyloxindole. Org. Lett. 2022, 24, 842–847. 10.1021/acs.orglett.1c04118. [DOI] [PubMed] [Google Scholar]

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