electrophilicity - the dark-side of indole chemistry.pdf

Organic &Biomolecular Chemistry

PERSPECTIVE

Cite this: Org. Biomol. Chem., 2013, 11,5206

Received 12th April 2013,Accepted 17th June 2013

DOI: 10.1039/c3ob40735g

www.rsc.org/obc

Electrophilicity: the “dark-side” of indole chemistry

Marco Bandini*

Indole is by far one of the most popular heterocyclic scaffolds in nature. The intriguing and challenging

molecular architectures of polycyclic, naturally occurring indolyl compounds constitute a continuous

stimulus for development in organic synthesis. The field had a formidable boom across the new millen-

nium when catalysis started revolutionizing the chemistry of indole, providing always more convincing

and sustainable solutions to the selective “decoration” of this pharmacophore. A common guideline of

these approaches relies on the intrinsic overexpression of electron density of the indole core. Despite

less diffusion, the “dark-side” of indole reactivity, electrophilicity, has been also elegantly documented

with direct applications towards the realization of specific interatomic connections that would be difficult

to obtain by means of conventional indole reactivity. The present Perspective article summarizes

the major findings that brought the research area from the pioneering findings of the 60s to the state of

the art.

Introduction

The prominent role of indole and indolyl compounds in multi-disciplinary fields is recognized worldwide.1 Pharmaceuticals,agrochemicals and more recently organic electronics havebeen deeply influenced by this bicyclic arene that still con-tinues to inspire tremendous developments in organic syn-thesis.2 As an example, focusing on reactivity, indole hasrapidly become a benchmark compound to screen new cataly-tic systems for Friedel–Crafts-type alkylations3 as well as acyla-tion reactions.4 A basic feature that accounts for this largediffusion in the literature is the spectacular nucleophilicity ofthe indolyl core, which is commonly dispatched through theC(3) position (i.e. enamine site) of the pyrrolyl ring.5 Moreover,hydrogen atom replacement has also been largely documentedat the N(1) and C(2) positions with the benzoic ring being byfar less reactive with respect to the pyrrolyl one.

The chemistry of indole is extremely vast and, from acertain point of view, well established and consolidated.However, in nature, it is common to encounter indolyl-contain-ing species featuring specific interatomic connections thatwould be difficult to be obtained via “conventional” indolereactivity. For instance, the direct replacement of the C(N)–Hpyrrolyl bonds with heteroatomic substituents would requirethe direct involvement of “exotic” “X+” species.6 Again, thedirect indolination of enolizable methylene groups is stilla nontrivial process to be realized under non-oxidative

conditions.7 In this direction, the availability of efficient syn-thetic methodologies for the treatment of “electrophilic”indoles will allow to significantly improve the current syntheticportfolio for indole manipulation (Fig. 1).

It should be mentioned that in contrast to the well-estab-lished electrophilic substitution processes, the nucleophilicreplacement of hydrogen atoms in indoles has received muchless attention.8

The “dark-side” of indole chemistry was first investigatedby Szmuszkovicz in the early 60s, by disclosing the regioselec-tive condensation of phenylmagnesium bromide with 3-ben-zoylindole derivatives (1, Fig. 2).9 In particular, the common

Fig. 1 The “dark-side” of indole chemistry.

Fig. 2 Pioneering the field of electrophilic indoles.

Department of Chemistry “G. Ciamician”, Alma Mater Studiorum – University of

Bologna, via Selmi 2, 40126 Bologna, Italy. E-mail: [email protected];

Fax: +39-051-2099456; Tel: +39-051-2099751

5206 | Org. Biomol. Chem., 2013, 11, 5206–5212 This journal is © The Royal Society of Chemistry 2013

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“enamine” reactivity property of the pyrrolyl N(1)–C(2)–C(3)framework can be reversed to a Michael acceptor characterwhen an electron-withdrawing group (EWG) is located at theβ-carbon of the indole ring. Interestingly, this seminal workwas recently re-considered and substantially expanded by Liuand coworkers with a range of Grignard reagents and 3-acyl-indoles in a highly diastereoselective manner.10 It should bementioned that, despite the intrinsic constraints of chemicaloutcome and starting material availability related to therequirement of electron withdrawing groups, large substratearrays are readily accessible via late chemical manipulationsinvolving the EWGs.

Currently, two distinct synthetic approaches are known forthe nucleophilic manipulation of indoles:

Indirect approach

Domino, dearomatization processes represent a well consoli-dated route to densely functionalized alkaloid derivatives.11

These protocols generally involve a classic electrophilic attackat the C(3)-position, leading to a transient, highly electrophiliciminium intermediate that can be conveniently trapped by anexternal nucleophile preventing a final rearomatization. Thismethodology has been extensively investigated also in enantio-selective variants and many entries addressing both metal-based and metal-free catalysis have been reported.

Direct approach

The methodology involves the direct nucleophilic attack atproperly functionalized neutral indole cores, in inter- or intra-molecular fashion (Fig. 3).

The latter approach will be addressed in the presentPerspective article with no aim at providing a comprehensivecollection of all the examples reported in the literature. In con-trast, a selection of studies will be presented in order toguide the reader across more than 60 years of the literature:from early achievements to the present application of late-transition-metal catalysis in the simultaneous synthesis andnucleophilic manipulation of indolyl cores.12

Finally, the well-established synthetic alternatives to thepresent nucleophilic manipulations, involving metal-assistedoxidative condensation of NuH species to indoles and metal-catalyzed hydrogenation of the pyrrolyl ring,13 will not bediscussed here. The readers are kindly directed to recent com-prehensive contributions.7

Indole carrying EWG or aryl substituentsand LG at the N(1)-position

The introduction of electron-deficient groups or aryl sub-stituents at the pyrrolyl unit, both C(2)- and C(3)-positions, hasbeen documented and represents a “smart” tool to reverse thenatural bias of the heterocyclic core towards electrophilic sub-stitutions.14 Certainly, introducing the EWG at the C(3)-sitewill confer on the C(2)-carbon a Michael acceptor-like beha-viour, but vice versa in the case of 2-EWG-indolyl systems. Nitro,carbonyl (both aldehydes and ketones) and carboxyl groupsare by far the most widely employed units to perform theumpolung15 of common indole reactivity. In combination withEWGs, the introduction of suitable leaving groups (i.e. halo-gens, OMe, OH, SO2Ar etc.) at the nitrogen atom completes themolecular architecture to facilitate a formal SN2′ attack onthe five-membered ring. Interestingly, an analogous behaviouris also obtainable by introducing an aryl substituent at theC(2)-position. Early achievements in this segment are attribu-ted to the study by Sundberg in 1965 in which the chemistryof 1-hydroxy-2-phenylindole (3) was investigated, leadingto dimers and trimers when activated by TsCl and pyridine(Scheme 1a).16 Later on, this work was substantially expandedby Hamana and coworkers showing the possibility to interceptthe N-OTs intermediate with the preformed enamine of thecyclohexanone 6, providing the corresponding ketone 7 undermild reaction conditions but in poor 23% yield (Scheme 1b).17

Despite the undoubted synthetic relevance, the presence ofaromatic substituents did not provide the necessary electronicactivation to completely reverse the innate propensity towardselectrophilic substitutions. In contrast, the presence of EWGsopened up access to a plethora of nucleophilic manipulationsof the indolyl core that will be discussed by means of anumber of representative examples, categorized by the natureof the chemical modifier.

Fig. 3 Examples of direct approaches to umpolung indole reactivity discussedin the present Perspective.

Scheme 1 Early achievements in the nucleophilic replacement of C–H bondson the indole ring.

Organic & Biomolecular Chemistry Perspective

This journal is © The Royal Society of Chemistry 2013 Org. Biomol. Chem., 2013, 11, 5206–5212 | 5207

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N(OMe) indoles

The electrophilic behaviour of indoles featuring simul-taneously one EWG substituent and OMe leaving group at thenitrogen atom has been described by Somei and coworkersover the past few years.18

Particularly relevant, 1-methoxy-3-(2-nitrovinyl)indoles 8reacted smoothly with NaOMe and NaOPr in DMF, providingthe corresponding 2-alkoxy derivative 9 in moderate to goodyield (55–85%). Interestingly, classic Michael-type additions atthe β-position of the nitroolefin occurred by switchingthe solvent to THF (Scheme 2a).19 The same team also appliedthis approach to the site-selective preparation of 2,3,6-trisubsti-tuted indoles. In this case, 1-MeO-6-NO2-3-CHO-indole 11was subjected to a range of C-, S- and N-based nucleophiles,providing the corresponding C(2)-functionalized species invery high yields (Scheme 2b).20

It should be mentioned that 5- and 6-nitroindoles haveproven remarkable suitability also in vicarious nucleophilicsubstitution reactions (VNSs). In these transformations,the regioselective replacement of one hydrogen atom of thebenzene ring can be performed by a range of carbanions carry-ing LG at the nucleophilic center (i.e. chloromethyl phenylsulfone and phenoxyacetonitrile).8,21

NSO2Ph indoles

1-Phenylsulfonylindoles have been largely investigated as elec-trophilic partners for nucleophilic aromatic substitution ofindoles in combination with strong electron-withdrawinggroups that are responsible for polarizing the indole C(2)–C(3)double bond. Joule and coworkers pioneered the field (1977)documenting a series of intramolecular processes requiringone carbonyl group at the C(2) position (13).22 Tetracycliccompounds embedding C(2)/C(3)-fused six- as well as seven-membered rings were readily accessible under Michael-type condensation at the C(3)-position. The protocol wasparticularly suitable for C(3)–O bond forming reactions(i.e. alcohols and phenols); however, sulphur- and nitrogen-based ring-closing events were also reported under basicconditions. Generally, the formation of correspondingsodium alcoholates with NaOH or NaH was carried out inorder to ensure satisfactory reaction rates. Mechanistically, the

choice between synchronous and stepwise channels is still amatter of debate; however, the presence of a carbonyl unit atthe C(2)-indole position proved to be mandatory for the overallprocess (Scheme 3).14

The synthetic applicability of phenylsulfone moiety as aleaving group23 in SNAr reactions was also emphasized byGribble and coworkers in a range of intermolecular nucleo-philic functionalizations of 2-nitro- and 3-nitroindoles.24

Interestingly, while 1-phenylsulfonyl-2-nitroindoles (15)afforded exclusively aromatized indole derivatives after theformal 1,4-addition with enolates and hetaryllithiumreagents,24a the 3-nitro congeners (17) provided the corres-ponding C(2)-substituted compound 18 or indoline 19 in thepresence of diethyl malonate or hetaryllithium reagentsrespectively.25

The authors suggest the stabilization of the lithium nitro-nate intermediate 20 by the carboxylate groups (or N-protect-ing group in the case of indolyllithium nucleophiles) as aplausible explanation for the divergent reaction channels(Scheme 4). It is worth mentioning that the conjugate additionof hetaryllithium to 17 constitutes a valuable synthetic alterna-tive to the α-lithiation of indole compounds with immediateimplications for the preparation of δ-carboline alkaloidsfeaturing pharmacological interest.

Scheme 2 N-OMe indole derivatives in nucleophilic substitutions. Scheme 3 Intramolecular nucleophilic substitution of 2-acyl-1-phenylsulfonyl-indoles. A hypothetical stepwise reaction profile is shown below.

Scheme 4 1-Phenylsulfone-nitroindoles as valuable Michael acceptors.

Perspective Organic & Biomolecular Chemistry


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Indolynes

Aryne derivatives of indoles are generally referred to indolynesand represent highly reactive intermediates that reverse theparadigm of the indole reactivity.26

Remarkably, indolynes also allowed addressing a stilllargely undeveloped chemistry of indole functionalizationthat involves the benzene ring. In this scenario, Garg andcoworkers documented important advances very recently.27

Readily available on the multi-gram scale, silyltriflate 20awas found to deliver in situ 4,5-indolyne 21 upon treatmentwith TBAF or CsF in CH3CN. The simultaneous presence ofcarbon- or heteroatom-based nucleophiles trapped the electro-philic indole surrogate 21, leading to a large chemical diversityin indole functionalization. Some representative examples (22)are reported in Scheme 5.

Shortly afterwards, the same team documented the suit-ability of the indolyne intermediate in the total synthesisof indolactam V 27 via nucleophilic trapping of transient6-bromoindolyne.28 In particular, the condensation ofsilyltriflate derivative 20b with peptide 23 led to a site-selectiveamination of the benzene ring of indole at the C(4)-position inthe presence of CsF, leading to 24 in 62% yield. Debromina-tion, dehydration and final ZrCl4-assisted Friedel–Crafts-typeannulation led to the advanced intermediate 26 in 39% overallyield (Scheme 6).

Functionalization of unsubstituted indolesAlkoxylation reaction

Previous examples of C(3)-alkoxylation of indoles required thepre-installation of EWGs to perturb the electron-density distri-bution of the pyrrolyl unit. Interestingly, an analogous overallprocedure can be performed also in the presence of stoichio-metric metal-free oxidants (i.e. iodobenzene diacetate29a and

perchloro-cyclohexadienone derivatives) in the absence of pre-functionalized indoles.29b

In particular, by dissolving the 2,3-dimethylindole 28in alcoholic solvents (i.e. MeOH, EtOH, iPrOH, nPrOH) withPhI(OAc)2 (IBD) led to the corresponding indoline 29 in a mode-rate isolated yield (>60%). Interestingly, N-iodo intermediate30 is thought to play a major role in the nucleophilic attackby the alcohol at the C(3)-position delivering PhI and AcOH asby-products (Scheme 7).

Mechanistically, the iodine-assisted activation of indolerings towards nucleophilic condensation is still a matter ofdebate, and sometimes divergent reaction channels are alsoproposed in relation to the nature of the reaction partners. Inparticular, alongside the direct activation of the indolyl coredepicted in Scheme 7, oxidation of the nucleophile and sub-sequent condensation via classic electrophilic substitution/addition have been also hypothesized.

In this direction, Harran and coworkers highlighted thepotential of iodobenzene diacetate for the preparation of thefuroindoline core of (−)-diazonamide A (formal oxidative cyclo-addition).30 In particular, the treatment of peptidyl intermedi-ate 31 with 1.1 eq. of PhI(OAc)2 provided the desired aminal 33as a 3 : 1 diastereomeric mixture and moderate yield.

Scheme 6 Exploiting regioselective nucleophilic functionalization of indolynesin the total synthesis of indolactam V 27.

Scheme 7 In situ metal-free oxidative activation of 2,3-disubstituted indolestowards nucleophilic alkoxylation.

Scheme 5 Synthesis and reactivity of indolyne 21 as a valuable electrophilicindole surrogate.



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Mechanistically, the authors proposed a reaction channelinvolving the initial heterolytic oxidation of the phenol tophenoxenium ion 32 and subsequent trapping by the tetheredindolyl structure. Therefore, despite the similarity, divergentreaction mechanisms are involved (Scheme 8).31

Analogously, intermolecular variants were also developedby Nicolaou and Chen by means of PhI(CF3CO2)2 (PIFA) asa stoichiometric oxidant during the preparation ofhaplophytine.32

Allylation reaction

C(2) site-selective nucleophilic allylation and prenylation reac-tions of indoles with organoborane reagents have gained con-siderable attention over the past few years due to the largespectra of chemical entities conveniently accessible.33 Manyexamples involve the utilization of pre- or in situ formed 3H-indole imine tautomers as electrophilic counterparts, withremarkable applications also in total synthesis of naturallyoccurring alkaloids.34 However, most of these examples sufferfrom the need of large excesses of rather aggressive and scar-cely stable borane reagents, featuring a limited substrategenerality.

In this context, Batey and coworkers documented the directuse of allylic trifluoroborate salts 34 in the efficient allylationand crotylation reactions of indoles at the C(2)-position.35 Theuse of a stoichiometric amount of BF3·Et2O (100 mol%) is pro-posed to provide the necessary activation of the allylic nucleo-phile by abstracting one of the fluorine atoms from 34.Under optimal conditions, a range of synthetically relevant

2-substituted indolines 3536 was accessible in good yields and ahighly stereodefined manner, via allylation, crotylation, prenyl-ation and propargylation of indole precursors. Based on thehighly diastereospecific crotylation reactions, a cyclic Zimmer-man–Traxler-like transition state was hypothesized by theauthors. The inertness of N-Me indole supports such a state-ment (Scheme 9).

The possibility to chemically elaborate unfunctionalizedindolyl cores via nucleophilic reactions is certainly of high syn-thetic interest. However, focusing on the latter methodology, itshould be emphasized that the nucleophilic allylation at C(2)still suffers from important limitations mainly related to thechoice of the nucleophilic counterpart. In particular, whileless-reactive organometallic species such as allylboronateesters would not undergo the alkylation reaction, highly reac-tive species could be easily deactivated by the acidity of theN(H) proton atom.

One-pot catalytic synthesis and nucleophilic manipulation ofindoles

Umpolung reactivity on indole chemistry has recently beendeveloped also under the metal-catalyzed regime. Gold(I) cata-lysis offered a valuable opportunity to develop a one-pot syn-thesis and concomitant nucleophilic functionalization of theindolyl core starting from ortho-azidophenylalkyne 36. Almostsimultaneously, two research teams independently reported onthe efficiency of cationic gold(I) species in promoting acascade process involving the initial intramolecular nitrenetransfer from the azido group leading to highly reactive goldcarbenes 37. The intrinsic electrophilic character of the C(3)-position inspired the authors to further study site-selectivetrapping played by a range of neutral nucleophiles(Scheme 10).

Gagosz and coworkers documented the role of the cationiccomplex [(PPh3)AuCl]/AgOTf (8 mol%) in the synthesis of C(2)-functionalized oxindoles 38 via a final thermal Claisenrearrangement. Generally, excellent yields and high diastereo-selectivity were obtained (Scheme 11a).37

Scheme 8 Synthesis of furoindolinyl scaffolds under oxidative conditions.

Scheme 9 Stereospecific C(2)-functionalization of indoles in the presence oftrifluoroborate salts and BF3·OEt2.



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In the same direction, Zhang and coworkers exploited theefficiency of tBuXPhosAuNTf2 and IPrAuNTf2 species (5 mol%)in promoting the nitrene transfer and subsequent trapping ofthe gold-carbene with a range of nucleophiles (i.e. electron-rich arenes and alcohols). Remarkably, both inter- as well asintramolecular protocols were developed (Scheme 11b).38

Conclusions

A common thought in heterocyclic chemistry is to considerindole synthesis/manipulation as a well consolidated andestablished research field. This state of the art is referred to itsintrinsic and unique nucleophilicity. However, the possibilityto expand the chemical portfolio of indole decoration, vianucleophilic substitutions and additions, is still largelyundeveloped.

The Perspective collects some of the most salient examplesof umpolung indole reactivity in the organic syntheticscenario. While molecular constraints are still mandatory toensure appreciable transformations, leading examples ofnucleophilic manipulation of unfunctionalized indoles areknown. The chemical diversity that can be created throughthese approaches is extremely vast and encompasses site-

selective functionalization of both pyrrole and benzene ringsand dearomatization processes.

Prospectively, the development of this unnatural indolereactivity can be reasonably expected, with particular regard tochemical and stereochemical catalysis that up to now has onlymarginally influenced the field.

The author acknowledges the FIRB Project “Futuro inRicerca”, Innovative sustainable synthetic methodologies for C–Hactivation processes, PRIN Project PRIN 20099PKHH_004, “Pro-gettazione e Sviluppo di Nuovi Sistemi Catalitic Innovativi”(MIUR, Rome), and Università di Bologna.

Notes and references

1 (a) R. J. Sundberg, The Chemistry of Indoles, AcademicPress, New York, 1970; (b) R. J. Sundberg, Pyrroles andtheir benzoderivatives: synthesis and applications, inComprehensive Heterocyclic Chemistry, ed. A. R. Katritzkyand C. W. Rees, Pergamon, Oxford, UK, 1984, vol. 4, p. 313;(c) R. J. Sundberg, in Indoles: Best Synthetic Methods,Academic Press, New York, 1996; (d) Indoles, ed.R. J. Sundberg, Academic Press, London, 1996;(e) T. C. Barden, Top. Heterocycl. Chem., 2010, 26, 31;(f ) E. D. Głowacki, G. Voss, L. Leonat, M. Irimia-Vladu,S. Bauer and N. S. Sariciftci, Isr. J. Chem., 2012, 52, 540.

2 (a) R. Vicente, Org. Biomol. Chem., 2011, 9, 6469;(b) T. Lindel, N. Marsch and S. K. Adla, Top. Curr. Chem.,2012, 309, 67.

3 M. Bandini and A. Umani-Ronchi, Catalytic AsymmetricFriedel–Crafts Alkylations, Wiley-VCH, Weinheim, 2009.

4 G. Sartori and R. Maggi, Advances in Friedel–Crafts AcylationReactions, CRS Press Inc., 2009.

5 (a) T. B. Poulsen and K. A. Jørgensen, Chem. Rev., 2008,108, 2903; (b) M. Bandini and A. Eichholzer, Angew. Chem.,Int. Ed., 2009, 48, 9608; (c) S. L. You, Q. Cai and M. Zeng,Chem. Soc. Rev., 2009, 38, 2190; (d) G. Bartoli,G. Bencivenni and R. Dalpozzo, Chem. Soc. Rev., 2010, 39,4449.

6 For a collection of examples addressing the synthesis ofC(3)-hetero-indole derivatives see: (a) K. Cariou, B. Ronan,S. Mignani, L. Fensterbank and M. Malacria, Angew. Chem.,Int. Ed., 2007, 46, 1881; (b) J. S. Yadav, B. V. Subba Reddyand B. B. Murali Krishna, Synthesis, 2008, 3779; (c) A. Pews-Davtyan, A. Tillack, A.-C. Schmöle, S. Ortinau, M. J. Frech,A. Rolfs and M. Beller, Org. Biomol. Chem., 2010, 8, 1149.

7 (a) M. Zhang, Adv. Synth. Catal., 2009, 351, 2243;(b) L. Joucla and L. Djakovitch, Adv. Synth. Catal., 2009,351, 673; (c) E. M. Beck and M. J. Gaunt, Top. Curr. Chem.,2010, 292, 85; (d) J. Roger, A. L. Gottumukkala andH. Doucet, ChemCatChem, 2010, 2, 20; (e) N. Lebrasseurand I. Larrosa, Adv. Heterocycl. Chem., 2012, 105, 309.

8 M. Mąkosza and K. Wojciechowski, Chem. Rev., 2004, 104,2631.

9 J. Szmuszkovicz, J. Org. Chem., 1962, 27, 511.10 L. Wang, Y. Shao and Y. Liu, Org. Lett., 2012, 14, 3978.

Scheme 10 Gold(I)-catalyzed synthesis and formal umpolung reactivity of theC(3)-position from ortho-azidophenylalkynes 36.

Scheme 11 Representative examples of the inter- and intramolecular gold-catalyzed synthesis of indoles/oxindoles and subsequent nucleophilicfunctionalization of the C(3)-position.



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11 (a) C. C. J. Loh and D. Enders, Angew. Chem., Int. Ed., 2012,51, 46; (b) C.-X. Zhuo, W. Zhang and S.-L. You, Angew.Chem., Int. Ed., 2012, 51, 12662.

12 (a) J. A. Joule, in Progress in Heterocyclic Chemistry,Pergamon, 1999, ch. 3, vol. 11, pp. 45–65; (b) J. A. Joule, Sci.Synth., 2000, 10, 541.

13 (a) A. Baeza and A. Pfaltz, Chem.–Eur. J., 2010, 16, 2036;(b) D.-S. Wang, Q.-A. Chen, W. Li, C.-B. Yu, Y.-G. Zhou andX. Zhang, J. Am. Chem. Soc., 2010, 132, 8909.

14 M. Mąkosza, Synthesis, 2011, 2341.15 D. Seebach, Angew. Chem., Int. Ed. Engl., 1979, 18, 239.16 R. J. Sundberg, J. Org. Chem., 1965, 30, 3604.17 (a) T. Nagayoshi, S. Saeki and M. Hamana, Heterocycles,

1977, 6, 1666; (b) T. Nagayoshi, S. Saeki and M. Hamana,Chem. Pharm. Bull., 1981, 29, 1920.

18 For reviews see: (a) M. Somei, Heterocycles, 1999, 50, 1157;(b) M. Somei, Advances in Heterocyclic Chemistry,ed. A. R. Katritzky, Elsevier Science, USA, 2002, vol. 82,pp. 101–155; (c) F. Yamada, D. Shinmyo, M. Nakajou andM. Somei, ARKIVOK, 2012, 86, 435, and references therein.

19 K. Yamada, F. Yamada and M. Somei, Heterocycles, 2002,57, 1231.

20 K. Yamada, F. Yamada, T. Shiraishi, S. Tomioka andM. Somei, Heterocycles, 2009, 77, 971.

21 (a) M. Mąkosza and J. Winiarski, Acc. Chem. Res., 1987, 20,282; (b) M. Mąkosza, Chem. Soc. Rev., 2010, 39, 2855, andreferences therein.

22 For a representative collection of studies:(a) W. R. Ashcroft, M. G. Bead and J. A. Joule, J. Chem. Soc.,Chem. Commun., 1981, 994; (b) M. M. Cooper, G. J. Hignettand J. A. Joule, J. Chem. Soc., Perkin Trans. 1, 1981, 3008;(c) M. G. Beal, W. R. Ashcroft, M. M. Cooper and J. A. Joule,J. Chem. Soc., Perkin Trans. 1, 1982, 435; (d) M. M. Cooper,I. M. Lovell and J. A. Joule, Tetrahedron Lett., 1996, 37,4283.

23 For a recent review: A. El-Awa, M. N. Noshi, X. M. duJourdin and P. L. Fuchs, Chem. Rev., 2009, 109, 2315.

24 (a) E. T. Pelkey, T. C. Barden and G. W. Gribble, TetrahedronLett., 1999, 40, 7615; (b) E. T. Pelkey and G. W. Gribble,Synthesis, 1999, 1117.

25 (a) P. E. Alford, T. L. S. Kishbaugh and G. W. Gribble,Heterocycles, 2010, 80, 831; (b) D. C. Qian, P. E. Alford,

T. L. S. Kishbaugh, S. T. Jones and G. W. Gribble, ARKIVOC,2010, iv, 66; (c) T. L. S. Kishbaugh, in Heterocyclic ScaffoldII: Reactions and Applications of Indoles, ed. G. W. Gribble,Topics in Heterocyclic Chemistry, 2010, vol. 26, p. 117.

26 M. Julia, Y. Huang and J. Igolen, C. R. Acad. Sci., Ser. C,1967, 265, 110.

27 (a) S. M. Bronner, K. B. Bahnck and N. K. Garg, Org. Lett.,2009, 11, 1007; (b) G.-Y. J. Im, S. M. Bronner, A. E. Goetz,R. S. Paton, H.-Y. Cheong, K. N. Houk and N. K. Garg,J. Am. Chem. Soc., 2010, 132, 17933.

28 S. M. Bronner, A. E. Goetz and N. K. Garg, J. Am. Chem.Soc., 2010, 133, 3832.

29 (a) D. V. C. Awang and A. Vincent, Can. J. Chem., 1980, 58,1589; (b) P. H. H. Hermkens, R. Plate, C. G. Kruse,H. W. Scheeren and H. C. J. Ottenheijm, J. Org. Chem.,1992, 57, 3881.

30 A. W. G. Burgett, Q. Li, Q. Wei and P. G. Harran, Angew.Chem., Int. Ed., 2003, 42, 4961.

31 For a recent study on Fe(III)-assisted hydroarylation of elec-trophilic N-acetyl indoles with electron-rich heteroarenessee: R. Beaud, R. Guillot, C. Kouklovsky and G. Vincent,Angew. Chem., Int. Ed., 2012, 51, 12546.

32 (a) K. C. Nicolaou, U. Majumder, S. P. Roche andD. Y.-K. Chen, Angew. Chem., Int. Ed., 2007, 46, 4715;(b) K. C. Nicolaou, S. M. Dalby, S. Li, T. Suzuki andD. Y.-K. Chen, Angew. Chem., Int. Ed., 2009, 48, 7616.

33 T. R. Ramadhar and R. A. Batey, Synthesis, 2011, 1321, andreferences therein.

34 Selected examples: (a) J. M. Schkeryantz, J. C. G. Woo,P. Siliphaivanh, K. M. Depew and S. J. Danishefsky, J. Am.Chem. Soc., 1999, 121, 11964; (b) C. A. Kuttruff, H. Zipseand D. Trauner, Angew. Chem., Int. Ed., 2011, 50, 1402;(c) J. M. Finefield and R. M. Williams, J. Org. Chem., 2010,75, 2785.

35 F. Nowrouzi and R. A. Batey, Angew. Chem., Int. Ed., 2013,52, 892.

36 D. Liu, G. Zhao and L. Xiang, Eur. J. Org. Chem., 2010,3975.

37 A. Wetzel and F. Gagosz, Angew. Chem., Int. Ed., 2011, 50,7354.

38 B. Lu, Y. Luo, L. Liu, L. Ye, Y. Wang and L. Zhang, Angew.Chem., Int. Ed., 2011, 50, 8358.



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electrophilicity - the dark-side of indole chemistry.pdf

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