doi:10.1002/adsc.201500374 transition metal-catalyzed c ...szolcsanyi/education/files... · alyzed...

DOI: 10.1002/adsc.201500374

Transition Metal-Catalyzed C¢H Activation of Indoles

Alexander H. Sandtorva,*a Department of Chemistry, University of Bergen, All¦gaten 41, N-5007 Bergen, Norway

E-mail : [email protected]

Received: April 12, 2015; Revised: May 2, 2015; Published online: August 3, 2015

Abstract: The last decades have seen a tremendousexpanse in the application of C¢H activation ofmany different substrate classes, including the invalu-able indole scaffold. Following the exciting emer-gence of C¢H activation as a multi-faceted platformfor functionalization, a versatile tool box has beendeveloped for the preparation of structurally diverseindoles. This review article discusses recent advancesand strategies for transition metal-catalyzed C¢H ac-tivation of indoles.

1 Introduction2 C¢H Activation at the C-2 Position of the

Indole Framework2.1 Arylation2.2 Alkynylation and Alkenylation2.3 Alkylation2.4 Acylation2.5 Annulation2.6 Introduction of Groups Containing Nitrogen

2.7 C¢B and C¢P Bond Formation through C¢HActivation

3 C¢H Activation at the C-3 Position of theIndole Framework

3.2 Alkynylation and Benzylation3.3 Alkenylation and Acylation3.4 Alkylation3.5 Synthesis of Bis(indolyl)methanes through C¢

H Activation3.6 Annulation3.7 Introduction of Groups Containing Nitrogen4 Regioselective Processes that Involve C¢H Ac-

tivation at either C-2 or C-3 Positions, or In-volve Dual C¢H Activation at both C-2 and C-3 Positions

5 C¢H Activation at C-4, C-5, C-6 and C-7 of theIndole Nucleus

6 Conclusion

Keywords: C¢H activation; C¢H functionalization;indoles; nitrogen heterocycles; transition metals

1 Introduction

Indole is a nitrogen-containing heterocycle with a cen-tral position in organic chemistry and is considered tobe a “privileged” structure in medicinal chemistry(Figure 1).[1] Moreover, the indole scaffold is encoun-tered in a large number of drug candidates associatedwith the treatment of cancer,[2] type 2 diabetes[3] andHIV.[4] The indole framework is also ubiquitouslypresent in natural products,[5] structures that possessimpressive biological activities and therefore consti-tute targets in organic synthetic chemistry.[6] Further-more, indole-based ligands can readily complex tometal centres, and have been reported to function ascatalytic systems with high efficiencies.[7]

There are three main strategies appropriate for thesynthesis of functionalized indoles (Scheme 1). Thefirst approach involves de novo cyclization reactionswherein the indole ring and embedded functionalitiesare constructed from benzoid precursors[8] or otherstructures (step a) through condensation reactions or

by metal-catalyzed means.[10g] The second and thirdstrategies comprise the functionalization of the indoleframework itself, either through halogenation andsubsequent cross-coupling methodology (step b)[9] orthrough direct C¢H activation (step c).

The first condensation strategy has received consid-erable interest and development from the syntheticcommunity,[10] but the direct modification of theindole nucleus has emerged as a viable and diverseapproach[11] especially following the advent of Pd-cat-alyzed cross-coupling methodology[12] and transitionmetal-catalyzed C¢H activation.[13]

During the last few decades, C¢H activation hasadvanced as an attractive method[14] for the function-alization of organic molecules, characterized by sever-al appealing features, such as high atom economy,high step economy and synthetic practicality.[13a] How-ever, one of the main challenges associated with thisapproach is the inherent low reactivity of C¢Hbonds,[15] which entails that harsh reaction conditionsare often required to provide the target products in

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REVIEWS

synthetically useful yields.[16] Furthermore, regioselec-tivity is an integral challenge when several similar C¢H bonds exist in the same molecule.

Some pioneering examples of C¢H activation of in-doles have been reported as early as the 1980s,[17–19]

but it was not until the 2000s that this methodologyfully advanced. The approach has developed beyondsimple reaction discovery studies to be incorporatedin the mainstream synthetic community, exemplifiedby the increasing exploitation of C¢H activation inthe preparation of architecturally complicated indole-

containing natural products and pharmaceutically im-portant moieties.[20]

Although a review[21] dedicated to C¢H activationof the indole nucleus was published in 2012, onlysome facets of the literature were discussed and a sig-nificant number of additional contributions has beenrevealed. In fact, over fifteen new articles were pub-lished concerning this very topic during the prepara-tion of this manuscript,[22] clearly demonstrating theimportance of this field and its emergence as a frontierin transition metal catalysis.

This review will discuss the contemporary literaturededicated to transition metal-catalyzed C¢H activa-tion of the indole nucleus. The focus will be to high-light the synthetic versatility of the methodology thatis currently available. The review is organized accord-ing to the structural class of the products obtained, sothat protocols that yield the same class of products(by potentially very different mechanisms) are organ-ized together.

Although the primary focus of this review is thedirect transition metal-catalyzed C¢H activation of in-doles, some examples will be provided that involvethe formal loss of an indole C¢H bond, but notthrough the formation of organometallated species,such as the Friedel–Crafts reaction[23] and some annu-lation reactions. For clarity, methods for metal-freefunctionalization of indole are not covered and onlytransition metal-catalyzed C¢H activation of theindole framework is discussed, not C¢H activation ofprecursors to create the indole framework.

2 C¢H Activation at the C-2 Position ofthe Indole Framework

A versatile tool box has been developed for the directmodification of the C¢H bond at the C-2 position ofthe indole scaffold which is the site most prone to

Alexander H. Sandtorv wasborn in Trondheim (Norway)in 1986. He studied chemistryat the University of Bergenin the group of ProfessorHans-RenÀ Bjørsvik and de-fended his PhD thesis enti-tled Functionalization on theimidazole backbone in Febru-ary 2015. From the fall of2015, he will pursue a post-doc in Assistant ProfessorDavid R. StuartÏs group at Portland State Universityas a Fulbright scholar. His research interests includesynthetic methodology for metal-catalyzed function-alization of nitrogen heterocycles such as Pd-cata-lyzed cross-coupling reactions.

Figure 1. Indole and some indole-containing derivatives.

Scheme 1. Three distinct strategies to functionalized indolesinvolving condensation reactions from benzoid precursors(step a) or direct functionalization of the indole frameworkthrough halogenation and cross-coupling (step b) or C¢Hactivation (step c).

2404 asc.wiley-vch.de Õ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Adv. Synth. Catal. 2015, 357, 2403 – 2435

REVIEWSAlexander H. Sandtorv

http://asc.wiley-vch.de

metallation. Methods that form new C¢C bonds havebeen studied extensively, and to date aryl, alkynyl, al-kenyl and even alkyl groups can be successfully intro-duced at this position. Certain cobalt-based catalyticsystems have also been found to be extremely versa-

tile and can perform a wide array of coupling reac-tions.[24] An important strategy in achieving high siteselectivity, has been the exploitation of directing aux-iliaries that are bound to the N-1 atom of the indolenucleus, where the 2-pyrimidine group has emerged

Table 1. Overview of important reaction sequences that involve C¢H activation followed by a new bond formation at the C-2 position of indoles.

Entry Reaction Coupling partner/reagent Catalyst References

1 arylation aryl halides Rh [25]

2 Pd [26,27,31–33]

3 arenes Pd [28–30]

4 diaryliodonium salts Pd [33,35]

5 arylboron reagents Pd [36–38]

6 Rh, Ru [39,40]

7 arylsilanes Rh [41]

8 Pd [42]

9 benzoic acid Rh [43]

10 alkynylation alkynes Pd [44]

11 alkenylation Pd [46,50–52,54,55]

12 alkenes Rh [48,53,59]

13 Ru [53b,60]

14 vinylcarboxylic acids Rh [61]

15 Ru [49]

16 alkynes Fe [56]

17 Co [58]

18 alkylation alkyl halides Pd [63,65]

19 Co [66]

20 Pd [70]

21 Fe [56]

22 alkenes Ir [67,71]

23 Co [69]

24 Ir [72]

25 acylation aldehydes Pd [75]

26 Rh [76]

27 annulations Co [57]

28 Pd [77,80,81]

29 alkenes Rh [87a]

30 Ir [87f]

31 alkyltriazoles Rh [82]

32 Pd [84a,85,87d,g]

33 alkynes Rh [87e]

34 Co [86]

35 aryl halides Pd [84b,87b,c]

36 cyanation N-cyano-N-phenyl-p-sulfonamides Co [88]

37 Rh [89]

38 acetonitriles Cu [90]

39 amination N-aminopyridinium salts Ru [91]

40 N-sulfonylimines Rh [92]

41 amidation N-phenylacetamides Cu [93]

42 benzoyloxyacetamides Rh [94]

43 sulfonyl azides Co [95]

44 Rh [96]

45 borylation boranes Ir [98,99]

46 phosphoramidation azido phosphate esters Co [100]

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REVIEWS Transition Metal-Catalyzed C¢H Activation of Indoles


as one of the most robust and versatile auxiliaries forthis purpose. Processes to couple functionalities thatcontain nitrogen have also been divulged, such asmethods for amidation, amination and cyanation.Table 1 shows an overview of important reactions thathave been developed for C¢H activation and newbond formation.

2.1 Arylation

An early example of the oxidative arylation of indolewas revealed by Sames and co-workers who employedRh catalysis for the coupling of aryl iodides andindole[25] (Scheme 2). The protocol was composed ofthe catalyst precursor [Rh(coe)2Cl2]2 (coe =cis-cyclo-octene), CsOPv as base and an electron-deficientphosphine ligand. This system efficiently performedC-2-arylation on electronically diverse, unprotectedindoles.

Another protocol was developed by the Samesgroup for C-2 arylation, exploiting SEM [2-(trimethyl-silyl)ethoxymethyl] protected indoles (Scheme 3).[26]

A Pd-NHC complex successfully coupled bothbromo- and iodoarenes to the indole nucleus in mod-erate to excellent yields, depending on the substitu-tion pattern on the coupling partners.

In keeping with general trends for Pd-catalyzedcoupling chemistry, iodoarenes were better substratesthan bromoarenes in this study, affording higheryields and requiring lower catalyst loadings.

A third method was disclosed by the Sames labora-tory for C-2 arylation, utilizing aryl halides as cou-pling partner, Pd(OAc)2 as catalyst and CsOAc asbase under ligandless conditions (Scheme 4).[27] The

scope of the method was thoroughly investigated andprovided the 2-arylated indoles in moderate to goodyields. During the investigations, it was discoveredthat the presence of halides in the reaction mixturehad a profound effect on the efficiency and selectivityof the arylation process. When iodoarenes were usedas coupling partners, the formation of 2-arylindolewas substantially favored over 3-arylindole. However,when bromobenzenes were exploited, the selectivityfor 3-arylindole was markedly increased. Further-more, the presence of CsI in the reaction mixturewhen bromobenzenes were present was completelydetrimental for the coupling reaction.

In order to approach a process with very high atomeconomy, Fagnou and co-workers[28] developeda method that permitted the utilization of two C¢Hbonds in the synthesis of 2-arylindoles (Scheme 5).They exploited Pd(TFA)2 as catalyst in combinationwith AgOAc as oxidant. They observed that AgOAc

Scheme 2. Rh-catalyzed C-2 arylation of indoles with aryl io-dides.

Scheme 3. Pd-catalyzed arylation of indoles with bromo-and iodoarenes.

Scheme 4. Pd-catalyzed arylation of indoles.

Scheme 5. Direct arylation of indoles with arenes.




favored C¢H activation at the 2 position of indoles,whereas Cu(OAc)2 favored the C-3 position.[29] Goodyields were achieved when benzene was used as thecoupling partner, but moderate to good yields wereachieved with disubstituted arenes. Although the re-action conditions were not overly mild, this exampleconstitutes a significant contribution towards trulyatom economic processes. Other groups have also ex-plored dual C¢H activation in the formation of 2-ary-lindoles.[30]

An intramolecular, direct arylation reaction was ex-ploited in the synthesis of peptidic macrocycles(Scheme 6) described by James and co-workers.[31]

The method employed Pd(OAc)2 as catalyst andAgBF4 as oxidant and required the presence of o-ni-trobenzoic acid as an additive. The benzoic acid wasimperative for the success of the reaction sequence,presumably due to the coordinating ability of the car-boxylate that contributed beneficially to the electro-philicity of the active palladium species.

Lavilla and co-workers[32] divulged a process appro-priate for C-2 arylation of tryptophan derivatives(Scheme 7). The method involved iodoarenes as cou-pling partners, Pd(OAc)2 as catalyst and AgBF4 asa halide scavenger and provided 2-arylindoles in mod-erate to good yields.

The amino acid side chain played an integral partin the reaction mechanism (Scheme 8). The mecha-nism was initiated by coordination of the carboxylicside chain to form a cyclopalladated intermediate thatthus afforded the high selectivity for the C-2 position

that was observed (step a). The aryl iodide was oxida-tively added to Pd(II) to form a Pd(IV) species (stepb) that could be reductively eliminated to afford the2-arylindole target mediated by Ag(I) (step c). A freeamino group (R1 = H) was allowed on the indole sidechain because of the poor coordinating ability of thisgroup under the acidic conditions employed.

The successful exploitation of alternative couplingpartners other than aryl halides[33] has been reportedfor the C-2 arylation of indoles. One important classof reagents is diaryliodonium salts, employed by San-ford and co-worker (Scheme 9).[34] A Pd-NHC com-plex efficiently catalyzed the reaction even at roomtemperature. The authors rationalized that the feasi-bility of this process was due to the reaction proceed-ing through a Pd(II)/(IV) mechanism. The rate-deter-mining electrophilic palladation was thus favored withthe electron-deficient system employed in their stud-ies. Diaryliodonium salts have also been employed forarylation with other catalytic systems, such as hetero-geneous Pd catalysts.[35]

Scheme 6. Intramolecular direct arylation to form peptidicmacrocycles.

Scheme 7. Arylation of tryptophans.

Scheme 8. Proposed mechanism for the arylation of trypto-phans.




Arylboronic acids have been exploited in oxidativearylation to form 2-arylindoles. Shi and co-workers[36]

coupled indoles to phenylboronic acids catalyzed byPd(OAc)2 under an oxygen atmosphere in acetic acid(Scheme 10). The desired 2-arylindoles were achieved

in moderate to excellent yields in high regioselectivity,as negligible amounts of 3-arylindoles were obtained.The reaction could also be scaled up to a one gramscale. Pd-based nanoparticles have also been shownto successfully catalyze oxidative arylation reac-tions.[37]

Cheng and co-workers[38] exploited aryltrifluorobo-rate salts as coupling partners in the presence ofPd(OAc)2 and Cu(OAc)2 in air (Scheme 11). Aryltri-fluoroborate salts elaborated with severely electron-withdrawing groups (such as F or CF3) operated

poorly, but reagents that did not possess these struc-tural features afforded the 2-arylindoles in mostlygood yields. The authors also studied the use of aryl-boronic acids as coupling partners, but found thatthey were inferior to aryltrifluoroborate salts withtheir method.

N-Methoxy-1H-indole-1-carboxamides were arylat-ed by means of phenylboronic acids, as reported byCui and co-workers (Scheme 12).[39] Two products

were obtained, depending on the oxidant present inthe reaction mixture. When Cu(OAc)2 was employed,a Suzuki-type coupling reaction took place, furnishing2-arylated indoles in mostly good yields (mediumyields were obtained when the arylboronic acid con-tained an electron-withdrawing group). However,when Ag2O was present, the 2-arylated indole under-went an oxidative C¢N bond formation to afford a tet-racyclic indole derivative. The mechanisms for thesetwo transformations were discussed and the oxidant-dependent regioselectivity was explained by the insitu generation of two distinct catalytic species whenthe pre-catalyst reacted with the oxidant in question.Other methods involving Ru as catalyst have alsobeen utilized in oxidative arylation of indoles.[40]

C¢H activation/Hiyama coupling have been realiz-ed for indoles to prepare 2-arylindoles in mostly goodyields, as reported by Loh and co-workers(Scheme 13).[41] The protocol involved [Cp*RhCl2]2 ascatalyst with AgF as fluoride source and Cu(OAc)2 asoxidant in aqueous THF. The method relied on thepyrimidine auxiliary, but the group of Zhang was ableto successfully implement the Hiyama coupling with-out the use of coordinating auxiliaries with a catalyticsystem consisting of Pd(OAc)2, Ag2O and TBAF.[42]

Arylation of indole has also been accomplishedusing benzoic acids as coupling partners.[43]

Scheme 9. Pd-catalyzed arylation of indoles with diaryliodo-nium salts.

Scheme 10. Oxidative arylation of indoles.

Scheme 11. Pd-catalyzed arylation of indoles with aryltri-fluoroborate salts.

Scheme 12. Oxidant dependent protocol for either oxidativearylation or tetracycle formation from indoles.




2.2 Alkynylation and Alkenylation

The Waser group reported the first C-2 selective alky-nylation of indoles (Scheme 14).[44] The hypervalentiodine reagent triisopropylsilylethynyl-1,2-benziodox-ol-3(1H)-one (TIPS-EBX) was used to introduce theethynyl substituent in the presence ofPd(MeCN)4(BF4)2 at room temperature. The methodexhibited excellent functional group tolerance andeven permitted the presence of halogens on theindole scaffold.

Reaction sequences combining C¢H activation andHeck-type alkenylation[45] have been realized for in-troduction of alkene groups. An early example was

described by Corey and co-worker[46] who employeda Pd-catalyzed C¢H activation followed by an intra-molecular olefination in the synthesis of a key tricy-clic intermediate for the formal synthesis of (++)-aus-tamide (Scheme 15).

One of the principal strategies for mediating site se-lective C¢H activation/alkenylation sequences is theexploitation of nitrogen-containing auxiliaries thatdirect the catalyst to the desired position.[47] To datea wide array of such groups has been successfully em-ployed, including the pyrimidine group,[48] the pyri-dine group,[49] 2-pyrimidylmethyl auxiliary,[50] the 2-pyridylsulfonyl group,[51] the o-aminophenyl group[52]

and the N,N-dimethylcarbamoyl group,[53] (Figure 2).

The directing auxiliaries are not required to bebound to the N-1 atom of the indole nucleus andeven carboxylic acids attached to a carbon atom inthe indole nucleus have been exploited in vinylation/decarboxylation sequences.[54] This strategy has alsobeeny implemented for many other reaction types,see elsewhere in this review.

Carretero and co-workers[55] engaged a 2-pyridylsul-fonyl auxiliary to mediate the C¢H activation eventthat was subsequently alkenylated with an olefin cou-pling partner (Scheme 16). The scope of the divulged

Scheme 13. Rh-catalyzed Hiyama-type arylation of indoles.

Scheme 14. Pd-catalyzed alkynylation of indoles using TIPS-EBX as alkynylation reagent.

Scheme 15. Intramolecular olefination in the formal synthesis of (++)-austamide.

Figure 2. Coordinating auxiliaries that mediate direct alke-nylation at the C-2 position.

Scheme 16. 2-Pyridylsulfonyl auxiliary-mediated alkenyla-tion of indoles.




process was extensively documented and the methoddemonstrated a high functional group tolerance, pro-viding the corresponding 2-alkenylindoles in moder-ate to excellent yields. The reductive removal of theauxiliary group could be achieved using either Zn orMg, thus demonstrating the synthetic versatility of therevealed process.

Yoshikai and co-workers utilized an imine group(PMP =p-methoxyphenyl) on the C-3 position to me-diate C¢H activation that was subsequently combinedwith alkylation or alkenylation in the presence of aniron-NHC catalyst.[56] The active catalyst was formedin situ by the reaction of Fe(acac)3, a Grignard re-agent and an NHC ligand. Two distinct productclasses could be obtained, depending on the identityof the coupling partner involved (Scheme 17). If al-kenes were used, 2-alkyl-3-formylindoles could be ob-tained after aqueous work-up, whereas alkynes fur-nished 2-alkenyl-3-formylindoles in mostly goodyields. The Yoshikai group also utilized this strategyin the Co-catalyzed intramolecular olefin hydroaryla-tion of indoles bearing alkenyl groups, leading to di-hydropyrroloindoles and tetrahydropyridoindoles.[57]

The Yoshikai group also utilized Co-catalysis to al-kenylate indoles with alkynes (Scheme 18).[58] The re-vealed method was highly efficient and the desired in-doles were obtained in mostly good to excellentyields.

Sha and co-workers investigated an alternative,non-N-heterocyclic directing auxiliary, namely o-hy-droxy- and o-aminoaryls, in the Rh-catalyzed oxida-tive alkenylation (Scheme 19).[59] The desired 2-alke-nylindoles were obtained in mostly good yields. Rucatalysis can also be exploited for the coupling of in-doles and olefins to prepare 2-alkenylindoles[60] andvinylcarboxylic acids have been used as coupling part-ners to prepare 2-alkenylindoles.[61]

Allylation was also recently achieved at the C-2 po-sition of indoles, exploiting pyrimidine auxiliaries todirect the C¢H activation.[62]

2.3 Alkylation

The literature reports several methods for the intro-duction of alkyl groups, utilizing either olefins oralkyl halides as coupling partners. Bach and co-worker were the first to describe a protocol that al-lowed the coupling of alkyl bromides and indoles.[63]

The method relied on a Pd-catalyzed norbornenemediated cascade C¢H activation sequence(Scheme 20). The 2-alkylindoles were obtained in

Scheme 17. Fe-NHC-catalyzed alkylation or alkenylation.

Scheme 18. Co-catalyzed alkenylation of indoles.

Scheme 19. o-Hydroxy- or o-aminoaryl-directed alkenyla-tion.




moderate to good yields and the reaction proceededwith excellent functional group tolerance.

Although a preliminary mechanism for the abovereaction was discussed, the Bach group later discloseda revised mechanism based on NMR studies, charac-terization of intermediates and deuterium labellingexperiments.[64]

The proposed mechanism (Scheme 21) was com-posed of a reversible NH activation (step a), amino-palladation of norbornene (step b) followed by base-mediated C¢H activation to form the correspondingpalladacycle (step c). Oxidative addition of the alkylbromide furnished a Pd(IV) intermediate (step d)that through reductive elimination (step e), norbor-nene expulsion (step f) and lastly hydrolysis (step g)furnishing the desired 2-alkylindole.

The Bach group also exploited the norbornene-pro-moted C¢H activation reaction in the C-2-alkylationof tryptophans.[65]

The cheaper alkyl chlorides have also been used ascoupling partners to alkylate the C-2 position of in-doles, as revealed by the Ackermann group.[66]

Another report was divulged in 2012, when thegroup of Shibata[67] utilized Ir catalysis to successfullycouple indoles and terminal olefins to furnish eitherlinear or branched alkylindoles, depending on the di-recting auxiliary present on the N-1 position of theindole ring (Scheme 22). It was observed that whenthe acetyl group was exploited as auxiliary, un-branched 2-alkylindoles were obtained, whereas thebenzoyl auxiliary favored the formation of branched2-alkylindoles.

Hiyama and co-workers demonstrated thatbranched 2-alkylindoles could be selectively obtainedfrom the coupling of indoles and vinyl arenes, cata-lyzed by a Ni-NHC catalyst (Scheme 23).[68]

The Yoshikai group investigated a Co-catalyzedprocess that successfully coupled indoles and vinylsi-lanes to afford 2-ethylsilylindoles.[69] C-2 alkylated in-doles were prepared in moderate yields in most casesexploiting this protocol (Scheme 24).

Scheme 20. Pd-catalyzed norbornene-mediated alkylation ofindoles.

Scheme 21. Proposed mechanism for the alkylation of in-doles.

Scheme 22. Coupling of indoles and olefins to afford eitherlinear or branched alkylindoles.

Scheme 23. Selective preparation of branched alkylindoles.




The pharmacologically relevant Iboga alkaloidswere constructed through intramolecular C¢H activa-tion/alkenylation catalyzed by Ni and Pd(Scheme 25).[70] Although the method had some obvi-ous shortcomings such as the utilization of stoichio-metric Pd salt and low yield, further optimization anddevelopment could cement the method as a viableroute to the Iboga alkaloids.

Enantioselective alkylation at the C-2 positon ofindole has been described by Hartwig and co-worker,who coupled norbornene and indoles (Scheme 26).[71]

The Ir-catalyzed process utilized optically active phos-phorus ligands to obtain high enantioselectivity (over90% ee in most cases).

Shibata and co-workers reported an additional ap-plication of Ir-catalyzed, enantioselective alkylation inthe synthesis of tricyclic indoles.[72] The protocol ex-ploited a cationic Ir complex and a chiral phosphineligand to afford the 5-exo-products in mostly goodyields and in excellent ees in most cases (Scheme 27).

A method for C-2 trifluoromethylation utilizingmethyltrioxorhenium as catalyst was revealed byTogni and co-worker.[73] Although the study was notdedicated to indole functionalization, three exampleswere demonstrated (Scheme 28a). TogniÏs reagent waslater successfully employed in Cu catalysis, reportedby the group of Sodeoka,[74] (Scheme 28b).

2.4 Acylation

The introduction of acyl groups at the C-2 position ofindoles was described by Liu and co-workers(Scheme 29).[75] The method involved the coupling ofindoles and aldehydes to form 2-acylindoles and ex-hibited excellent functional group tolerance. Rh catal-ysis can also successfully be utilized to achieve similarcoupling reactions of indoles and benzaldehydes.[76]

Scheme 24. Co-catalyzed alkylation of indoles exploiting vi-nylsilanes as coupling partners.

Scheme 25. An intramolecular C¢H activation/alkenylationsequence to Iboga alkaloids.

Scheme 26. Ir-catalyzed, enantioselective alkylation of in-doles.

Scheme 27. Intramolecular, enantioselective alkylation of in-doles.

Scheme 28. Two methods for the trifluoromethylation of in-doles.




2.5 Annulation

C¢H activation has been exploited in annulation reac-tions that permit the formation of fused indole-basedring systems. An early example of intramolecularindole annulation was described by Stoltz and co-worker, (Scheme 30).[77] Indoles bearing alkenyl

groups at the C-3 position were used as starting mate-rials to form annulated tri- and tetracyclic indoleswith Pd(OAc)2 as catalyst under an oxygen atmos-phere in the presence of ethyl nicotinate. Both 5- and6-membered fused rings were accessible in goodyields using this method.

The Oestreich group has studied several importantreactions that encompass C¢H activation, such asa Fujiwara–Moritani annulation of indoles[78] or Pd-catalyzed dehydrogenation of cyclohexene-1-carbony-lindole amides.[79] In a recent study, they utilized anintramolecular Pd-catalyzed annulation of C-3 substi-tuted indoles, but followed this reaction by a subse-quent amide cleavage and ester formation to furnishindoles bearing a,b-unsaturated esters at the C-2 posi-tion in moderate to good yields in most cases(Scheme 31).[80]

The Oestreich group also reported a Pd-catalyzeddiastereoselective intramolecular oxidative alkenyla-tion of prochiral indoles to form annulated indoles.[81]

The tertiary hydroxy group present on the indole sidechain functioned as a directing group to form the de-sired, annulated indoles in excellent diastereomericratios (Scheme 32).

Tang and Shi developed a Rh-catalyzed intramolec-ular annulation reaction that provided N-bridgeheadazepine frameworks of biological significance.[82] Indo-lyltriazoles were exploited as starting material thatupon treatment with the Rh catalyst formed a rhodi-um carbene which provided the target tricyclic scaf-

Scheme 29. Pd-catalyzed acylation of indoles.

Scheme 30. Intramolecular annulation of alkenylindoles.

Scheme 31. Two-step procedure to form indoles bearing a,b-unsaturated esters.

Scheme 32. Stereospesific synthesis of annulated indoles.

Scheme 33. Annulation of indoles for the synthesis of N-bridgehead azepines.




folds in mostly good yields after subsequent reactionsteps (Scheme 33).

The literature reports the preparation of severalclasses of fused multicyclic ring systems encompassingindole. Dihydrobenzo[a]carbazoles were synthesizedfrom indoles by means of a Pd-catalyzed domino an-nulation in moderate to good yields.[83] Indoloquinoli-nones were also prepared by similar sequences.[84] Flu-orescent pyrido[1,2-a]indoles were prepared by Pd-catalyzed intermolecular annulation between 3-substi-tuted indoles and internal alkynes that proceededthrough C¢H/N¢H bond activation sequence.[85] The

desired pyridoindoles were obtained in mostly goodyields (Scheme 34).

Pyrroloindolones could be prepared by a Co-cata-lyzed, directed C¢H alkenylation/annulation se-quence, described by Kanai and co-workers(Scheme 35).[86] [Cp*Co(C6H6)](PF6)2 was an efficientcatalyst for two distinct transformations, dependingon the auxiliary present on the N-1 ring atom of theindole substrate and the reaction conditions em-ployed. Pyrroloindolones were formed through an in-tramolecular nucleophilic addition when a mixture ofindole morpholine urea and alkyne was treated withthe above catalyst in the presence of KOAc ina dilute reaction mixture (0.1 M) at 130 88C for 20 h.

However, 2-alkenylindoles were readily formedthrough an irreversible protodemetallation when in-doles elaborated with non-cyclic amides were treatedwith the Co catalyst in the presence of KOAc(10 mol%) at concentrated solutions (0.5 M) at 80 88Cfor 20 h.

Several other annulation pathways are alsoknown.[87]

2.6 Introduction of Groups Containing Nitrogen

The inclusion of groups containing nitrogen has beenrealized through transition metal catalyzed C¢H bondactivation at the C-2 position. To date cyano, amidoand amino functionalities can be readily introduced.

A remarkable Co-catalyzed procedure for cyanationof N-heterocycles was disclosed by the Ackermanngroup (Scheme 36).[88] They utilized the 2-pyrimidineauxiliary to mediate the C¢H activation step that wascatalyzed by [Cp*CoI2(CO)]. N-Cyano-N-phenyl-p-sulfonamide was employed as cyanation reagent inthe presence of AgSbF6 and KOAc in DCE. Themethod exhibited excellent functional group toleranceand provided the desired 2-cyanoindoles in mostly ex-cellent yields.

Scheme 34. Pd-catalyzed synthesis of pyrido[1,2-a]indoles.

Scheme 36. Co-catalyzed cyanation of indoles.

Scheme 35. Co-catalyzed synthesis of either pyrroloindolones (path a) or alkenylindoles (path b).




The active catalyst was formed upon reaction of thepre-catalyst, AgSbF6 and KOAc (step a, Scheme 37).A reversible C¢H metallation between the catalystand the substrate formed a cyclometallated complex(step b). A reversible coordination of the reagent tothe catalyst (step c) was followed by an insertion(step d) that after reductive elimination (step e) fur-nished the desired product.

N-Cyano-N-phenyl-p-sulfonamide was also em-ployed by Anbarasan and co-worker for the Rh-cata-lyzed cyanation of indole.[89] Acetonitrile has beenemployed for direct C-2 cyanation of indoles, as de-scribed by Zhu and co-workers.[90] 2-Cyanoindoleswere obtained using the Cu-mediated process inmostly good yields (Scheme 38).

N-Aminopyridinium salts were used to form 2-ami-noindoles under photoredox conditions(Scheme 39).[91] The method operated well with struc-turally diverse indoles and furnished the desired 2-

aminoindoles in mostly good yields. The methodfailed, however, when the N-1 atom of the indole nu-cleus was substituted with either an acetyl or a Bocgroup.

A reaction mechanism was initiated by an LED-in-duced excitation of the catalyst Ru(bpy)3

2++ to form

Ru(bpy)32++* by absorption of blue light (step a,

Scheme 40). The pyridinium salt was then reducedthrough SET and fragmentation of this radical formedthe sulfonamidyl radical (step b) that was added tothe C-2 position of the indole nucleus (step c). Oxida-tion of this species by Ru(bpy)3

3++ led to the formationof an indolyl cation that could be deprotonated toform the desired product (step d).

Rh catalysis has also been employed for the intro-duction of methanamine derivatives, namely in thecoupling between N-functionalized indoles and N-sul-fonylimines, as reported by Li and co-workers.[92] Themethod exhibited little sensitivity to steric and elec-tronic variations in the N-sulfonylimine coupling part-ner and provided the desired products in moderateyields. Introduction of amide moieties at the C-2 posi-tion of indole through a C¢H activation step has beenstudied.

Scheme 37. A proposed mechanism for the Co-catalyzed cy-anation of indoles.

Scheme 38. Cu-mediated cyanation of indoles using acetoni-trile.

Scheme 39. Ru-catalyzed amination of indoles.

Scheme 40. Proposed mechanism for the Ru-catalyzed ami-nation.




The group of Li[93] studied Cu(I) as a catalyst tocouple indoles and amides in the presence of tert-butyl hydroperoxide (TBHP) as oxidant (Scheme 41).The desired 2-amidoindoles were obtained in mediumyields in most cases.

In their endeavors to obtain new PPARg modula-tors, the groups of Xu and Yi developed a highly re-gioselective Rh-catalyzed method for introducingamide groups at the C-2 position of indoles.[94] Theyexploited the 2-pyrimidine moiety as a directinggroup and performed a reaction sequence that encom-passed C¢H activation, N¢O cleavage and C¢N for-

mation to furnish the 2-amidoindoles in mostly goodyields (Scheme 42).

The application of Co[95] and Rh[96] catalysis hasalso been studied for the coupling of sulfonyl azidesand indoles for the introduction of amide groups atthe C-2 position, and for the coupling of sulfonyli-mines and indoles.[97]

2.7 C¢B and C¢P Bond Formation through C¢HActivation

C-2 borylation through C¢H activation has been stud-ied, with emphasis on Ir catalysis. Beller and co-work-ers achieved C-2 borylation of indoles through homo-

geneous Ir catalysis (Scheme 43, a),[98] whereas thegroup of Jones[99] developed a novel heterogeneous Ircatalyst for the same purpose (Scheme 43, b).

Phosphoramidation at the C-2 position of indoleshas been achieved, as reported by Matsunaga andKanai and co-workers, exploiting Co catalysis.[100]

3 C¢H Activation at the C-3 Position ofthe Indole Framework

Several key transformations have been described forthe direct functionalization of the C-3 position ofindole, but the chemistry is not as rich as that of C-2derivatization. Arylation has been achieved witha wider array of coupling partners than what has beendescribed for the analogous C-2 functionalization, butthe corresponding alkylation, however, has only beenachieved by more classic approaches, such as Friedel–Crafts alkylation and asymmetric allylic alkylation.Although these reactions do not involve carbometal-lated intermediates, they will be briefly discussed heredue to the high synthetic value of the products. Ashort summary of the reaction processes that involveC¢H activation and new bond formation at the C-3position of indoles is provided in Table 2.

3.1 Arylation

Considerable effort has been dedicated to developingmethods for oxidative arylation at the C-3 position ofindoles. Several classes of coupling partners havebeen investigated for this purpose. He and co-workersdeveloped an arylation procedure that relied on a pal-ladium complex bearing phosphinous acid ligands inthe presence of base with bromoarenes as couplingpartners (Scheme 44).[101] Moderate to good yieldswere obtained in most cases, but the method did not

Scheme 41. Cu-catalyzed synthesis of 2-amidoindoles.

Scheme 42. Rh-catalyzed synthesis of 2-amidoindoles.

Scheme 43. Two protocols for borylation of indoles employ-ing homogeneous (a) or heterogeneous (b) Ir catalysis.




permit electron-withdrawing groups on the substrateor coupling partner.

Rossi and co-workers[102] employed Pd(OAc)2 ascatalyst in the presence of a phase-transfer catalyst toachieve arylation at the C-3 position (Scheme 45).The effect of several ligands was studied, but surpris-ingly the process operated optimally in the absence ofligands. The method afforded 3-arylindoles in goodyields in most cases. The presence of the lipophilicphase-transfer catalyst (PTC) was imperative for theefficiency of the process, a fact that was explained bythe known ability of lipophilic quaternary ammonium

salts to stabilize palladium clusters and decrease theconversion to inactive palladium black.[103]

Heterogeneous catalysis has also been investigatedfor oxidative arylation. Djakovitch and co-worker[104]

demonstrated that [Pd(NH3)4]2++ on NaY zeolite in the

presence of K2CO3 in refluxing dioxane achieved the3-arylation of indoles in good yields in some cases(Scheme 46). Unfortunately only a limited substitu-tion pattern was permitted on both substrate and re-agent, as about half of the 18 examples reported gaveyields under 20%.

Table 2. Overview of important reaction sequences that involve C¢H activation followed by a new bond formation at the C-3 position of indoles.

Entry Reaction Coupling partner/reagent Catalyst References

1 arylation aryl halides Pd [101,102,104,105]

2 benzoic acids Pd [107]

3 arylhydrazines Pd [108]

4 cyclohexanones Pd [109]

5 diaryliodonium salts Cu [110]

6 N-heterocyclic compounds Pd [111–114]

7 alkynylation alkynes Au [115]

8 benzylation benzylic alcohols Au [116]

9 olefination alkenes Pd [117,118]

10 acylation benzaldehydes Pd [119]

11 TMEDA Cu [120]

12 nitriles Pd [121]

13 CO and alcohols Rh [122]

14 a-amino carbonyl compounds Cu [123]

15 Pd [124]

16 synthesis of bisindoles alcohols Pd [141,142]

17 aldehydes Ag [143]

18 amines Pd [144]

19 annulation alkenes Pd [145a]

20 alkynes Pd [145b,c]

21 cyanation CuCN Pd [150]

22 K4[Fe(CN)6] Pd [151]

23 t-BuNC Pd [152]

24 NH4HCO3 and DMSO Pd [153]

25 amidation isocyanides Pd [154]

Scheme 44. Pd-catalyzed arylation.Scheme 45. PTC-mediated, oxidative arylation of indoles.




An intramolecular C¢H activation event at the C-3position was employed in the synthesis of indole-based allocolchicine derivatives, described by thegroups of Schmalz and Fedorov and co-workers.[105]

Two slightly divergent methods were employed de-pending on the substituent on the N-1 ring atom toafford the corresponding annulated indoles in goodyields (Scheme 47).

Although aryl halides[106] are well suited for oxida-tive arylation, several other functional groups besideshalides can be utilized as leaving groups for this pur-pose. The group of Larrosa[107] investigated benzoicacids as coupling partners (Scheme 48). The methodafforded C-3-arylated indoles in medium to goodyields, but the method failed completely when theortho position of the benzoic acid did not contain anelectron-withdrawing group.

Arylhydrazines also operate as coupling partners,as demonstrated by Chen and co-workers.[108] Moder-ate to good yields were obtained in most cases, butextremely electron-deficient indoles (elaborated withCN or NO2 groups at C-5 position) were sluggish sub-strates (Scheme 49).

The group of Deng[109] showed that cyclohexanonescould function as coupling partners, furnishing 3-ary-lindoles in moderate to good yields in most cases(Scheme 50) after spontaneous aromatization of thecyclohexyl moiety. However, the protocol did not tol-

erate hindered cyclohexanones (such as 2-methylcy-clohexanone).

Diaryliodonium salts were used as coupling part-ners in a tandem C¢H and N¢H arylation, describedby the group of Greaney.[110] The Cu-catalyzed proce-dure comprised dtbpy (2,6-di-tert-butylpyridine) andDMEDA (N,N-dimethylethylenediamine) as ligands,and K3PO4 as base (Scheme 51). A key feature of thisprocedure was the high atom economy, as both arylmoieties of the iodonium salt were incorporated intothe product. When symmetrical diaryliodonium saltswere used, the corresponding N-aryl-3-arylindoles

Scheme 46. 3-Arylation of indoles employing heterogeneousPd catalysis.

Scheme 47. Intramolecular arylation in the synthesis of allocolchicine derivatives.

Scheme 48. Coupling of indoles and benzoic acids in the syn-thesis of 3-arylindoles.

Scheme 49. Coupling of indoles and arylhydrazines for thesynthesis of 3-arylindoles.




were obtained in moderate yields. Unsymmetrical dia-ryliodonium salts were also explored, but in this case,one of the aryl groups consisted of a dimethyluracilmoiety. The uracil unit was exclusively coupled to theN-1-atom, whereas the aryl group was coupled to theC-3 position of the indole ring.

Dual C¢H activation/arylation reactions have alsobeen described, such as the elegant coupling reactionsbetween indoles and imidazole N-oxides,[111] pyridineN-oxides,[112] azine N-oxides,[113] or caffeine,[114]

(Scheme 52).

3.2 Alkynylation and Benzylation

The group of Waser studied the Au-catalyzed C-3 al-kynylation of indoles using the hypervalent iodine re-agent TIPS-EBX (Scheme 53).[115] The authors notedthat the alkynylation reaction was completely ineffi-cient when Pd or Cu catalysis was employed, thusdemonstrating that Au was essential for the disclosedtransformation and complementing their previous C-2alkynylation protocol[44] (see Section 2.2). The alkyny-lation proceeded in mostly excellent yields, but when

Scheme 50. Pd-catalyzed arylation of indoles using cyclohexanones as coupling partners.

Scheme 51. Cu-catalyzed diarylation of indoles.

Scheme 52. Dual C¢H activation for the coupling of imida-zoles and various N-heterocycles.




the C-3 position of the indole framework was blockedby a substituent, C-2 alkynylation took place instead.

Hikawa, Azumaya and co-worker reported the Au-catalyzed coupling of indoles and benzylic alcohols toform 3-benzylindoles (Scheme 54).[116] CommonBrønsted and Lewis acids were ineffective catalystsfor the benzylation, however, NaAuCl4·2 H2O andsodium diphenylphosphinobenzene-3-sulfonate suc-cessfully catalyzed the benzylation in water as reac-tion medium in mostly good yields.

3.3 Alkenylation and Acylation

The introduction of alkenyl groups at the C-3 positionof indoles is an important transformation,[117] but hasunfortunately not received the same attention as theanalogous transformation on the C-2 position. Maand co-worker[118] developed a Pd-catalyzed couplingof 2-acetoxymethyl-substituted alkenes with electron-withdrawing groups to the indole nucleus. Moderateyields were achieved in most cases (Scheme 55).

Acyl groups have been attached to the C-3 positionof indoles, by the coupling of benzaldehydes and in-doles,[119] (Scheme 56) or in the Cu-catalyzed formyla-tion reaction,[120] (Scheme 57).

3-Acylindoles were also accessible from indoles andnitriles[121] in mostly good yields (Scheme 58).

The groups of Xia and Li prepared indole-3-carbox-ylates by Rh-catalyzed reaction of indoles, CO and anappropriate alcohol (Scheme 59).[122] The reaction se-

Scheme 53. Au-catalyzed alkynylation of indoles.

Scheme 54. Au-catalyzed benzylation of indoles.

Scheme 56. Pd-catalyzed coupling of indoles and benzalde-hydes.

Scheme 55. Pd-catalyzed synthesis of alkenylindoles.




quence involved C¢H activation and CO insertion toprovide the desired products in moderate to goodyields. However, when the N-1 ring atom was substi-tuted with either Boc or Tos groups, only traces ofproduct were obtained.

The formation of 3-acylated indoles from indolesand a-aminocarbonyl substances was reported, eitherby Cu catalysis[123] as described by LiÏs group, or byPd catalysis[124] as reported by Xiang and Li,(Scheme 60a and b, respectively).

3.4 Alkylation

Investigations have been dedicated to the introduc-tion of alkyl substituents on the C-3 position of in-

doles, but this transformation has not been achievedthrough C¢H activation. The stereoselective Friedel–Crafts reaction has been studied extensively.[125] Jør-gensen and co-workers[126] reported an early exampleof the Friedel–Crafts alkylation of indoles utilizingchiral bisoxazoline ligands, achieving good to excel-lent yields, but moderate stereoselectivity. A furtherdevelopment was revealed by Wan and co-workers,[127]

who developed an extremely efficient method for theasymmetric Friedel–Crafts reaction achieving veryhigh stereoselectivity (Scheme 61). Several other sys-tems for the asymmetric Friedel–Crafts reaction atthe C-3 position of indoles have also been report-ed.[128–131]

An additional approach for the introduction ofalkyl groups on the C-3 position of indole is the allylicalkylation reaction. An early method exploited Mocatalysis to achieve allylation of electron-rich hetero-cycles, as reported by Kocovsky and co-workers.[132] Afew examples involving indole was disclosed and twostructural isomers were obtained in either moderateor good yield, depending on the R1 substituent,(Scheme 62).

A further development of regiochemical control inallylation reactions of indoles was described byUmani-Ronchi and co-workers, (Scheme 63).[133]

Through elegant reaction studies, they could performthe allylation at either the N-1 (kinetic product) posi-tion or the C-3 position (thermodynamic product) ofthe indole substrate. The regioselectivity was con-trolled by fine-tuning the experimental conditions,namely the base and the reaction media. When a mix-ture of indole and an allylic ester was treated with thebase system Li2CO3 and BSA [bis-(trimethylsilyl)ace-tamide] in a reaction medium composed of a low co-ordinating solvent (such as DCM), the C-3 allylatedindole was furnished in an excellent yield. Moreover,if the same substrate and reactant were treated withthe ligand dppe [1,2-bis(diphenylphosphino)ethane] inCs2CO3 and a highly coordinating solvent (such asDMF), the corresponding N-allylated indole wasformed in excellent yield.

Scheme 57. Cu-catalyzed formylation of indoles.

Scheme 58. Formation of 3-acylindoles by Pd-catalyzed cou-pling of indoles and nitriles.

Scheme 59. Synthesis of indole-3-carboxylates through Rh-catalyzed reaction of indole, CO and alcohols.

Scheme 60. Two protocols for the synthesis of 3-acylated in-doles by Cu or Pd catalysis.




Low coordinating solvents favored the formation ofthe contact indolyl–metal ion pair that leads to thethermodynamic product (the C-3 coupled indole),whereas highly coordinating solvents with bases withlarger cationic radius drives the regiochemistry to-wards the solvent-separated indolyl–metal ion parthat affords the kinetic product (the N-1 coupledindole), (Scheme 64). Other methods for asymmetricallylic alkylation have also been developed.[134–139]

3.5 Synthesis of Bis(indolyl)methanes through C¢HActivation

Bis(indolyl)methanes and related compounds are bio-logically important moieties,[140] that are usually avail-

able through condensation reactions. However, recentinvestigations have shown that these scaffolds are ac-cessible through more direct means. Hikawa and Yo-koyama studied the synthesis of bis(indolyl)methanesthrough C¢H activation.[141] Indoles containing car-boxylic acid moieties were coupled to benzylic alco-hols in mostly good yields (Scheme 65), utilizing a cat-alytic system composed of Pd(OAc)2 and a phosphino-sulfonate, in water as reaction medium.[142] Indoles

Scheme 61. Cu-catalyzed, stereospesific Friedel–Crafts alkylation of indoles.

Scheme 62. Allylic alkylation of indoles.

Scheme 63. Regiochemical approach to either 3-allylated or1-allylated indoles.

Scheme 64. Solvent effect on the formation of either C-allyl-or N-allylindoles.

Scheme 65. Pd-catalyzed synthesis of bis(indolyl)methanesfrom indoles and benzylic alcohols.




bearing sterically demanding substituents at C-2failed to provide the desired products.

Bisindoles were also accessible from indole and al-dehydes by utilizing AgOTf as catalyst, a method thatwas divulged by Herrera and co-workers(Scheme 66).[143] The corresponding bisindoles couldbe prepared in mostly good to excellent yields usinga operationally simple protocol. Perumal and co-workers reported the preparation of 1,1-alkylbisin-doles through the Pd-catalyzed reaction of tertiaryamines and indoles.[144]

3.6 Annulation

The employment of Pd-catalyzed oxidative annulationreactions to form polycyclic indole derivatives hasbeen thoroughly documented. Broggini and co-work-ers reported the intramolecular annulation of indole-2-carboxamides to afford either b-carbolines or pyra-zino[1,2-a]indoles according to the different reactionconditions employed (Scheme 67).[145a]

Also b- or g- carbolines were accessible from theannulation of indolecarboxamides and alkynes,[145b] orthe reaction of N-substituted indolecarboxaldehydesand alkynes.[145c] The intramolecular coupling of in-doles bearing allenol moieties has been describedusing gold[146,147] and palladium catalysis.[148] However,such reactions are believed to proceed through carbo-metallation and do not involve direct C¢H activa-tion.[149]

3.7 Introduction of Groups Containing Nitrogen

The literature reports some methods for cyanation atthe C-3 position. Reddy and co-workers[150] utilizedCuCN as the cyanating agent in the presence of cata-lytic Pd(OAc)2, co-catalytic CuBr2 and air as oxidant.The method afforded the corresponding 3-cyanoin-doles in good yields in most cases (Scheme 68).

Wang and co-workers[151] introduced the use of thenon-toxic K4[Fe(CN)6] as cyanation agent(Scheme 69). The reaction performance and outcomewere reliant on the substitution pattern of the indolesexploited as substrates. Non-substituted N-1 indolesproceeded in medium yields, but indoles substitutedon the N-1 position afforded the corresponding 3-cya-noindoles in good to excellent yields in most cases.

A mechanism for this transformation was discussed

(Scheme 70). The first step involved the slow cyano-transmetallation Fe!Pd to form a cyanopalladiumcomplex (step a) that underwent a C-3 electrophilicpalladation of the indole nucleus (step b). This com-plex then furnished the desired 3-cyanoindole aftera reductive elimination (step c). Pd(0) was reoxidizedto Pd(II) (step d) by a distinct catalytic cycle involv-ing Cu(I)/Cu(II) (step e).

Relatively non-toxic reaction protocols that achievecyanation in the absence of cyanometal salts havealso been reported utilizing isonitriles,[152] and a mix-ture of ammonium bicarbonate and DMSO.[153]

Amidation at the C-3 position of indoles have beenachieved by employing isonitriles as coupling part-ners, (Scheme 71).[154] The process involved Pd-cata-

Scheme 66. Synthesis of bis-indoles from the Ag-catalyzedcoupling of indoles and aldehydes.

Scheme 68. Cyanation of indoles with CuCN.

Scheme 69. Cyanation of indoles with the non-toxicK4[Fe(CN)6] as cyanation reagent.

Scheme 67. Preparation of b-carbolines or pyrazino[1,2-a]in-doles.




lyzed C¢H activation and isocyanide insertion to fur-nish carboxamidated indoles in good to excellentyields.

4 Regioselective Processes that InvolveC¢H Activation at either C-2 or C-3Positions, or Involve Dual C¢HActivation at both C-2 and C-3 Positions

Although the pursuit of regioselective methods fordirect functionalization of the C-2 or C-3 positions is

highly desirable, exciting developments have beenmade in the selective functionalization of either ofthese positions. The elegant expoitation of auxiliarygroups can to direct the reaction to the desired site.Coordinating auxiliaries favor reaction at the C-2 po-sition, whereas non-coordinating auxiliaries favor re-action at the more electrophilic C-3 position. Evenfine-tuning of the reaction parameters can be exploit-ed to directly control the regioselectivity.[155]

An early example of the study of regioselectivitybetween C-2 or C-3 arylation of indoles was revealedby the Sames laboratory.[156] The key feature of theirprocedure was the exploitation of indolylmagnesiumsalts and in-depth investigations led them to formu-late a regioselective procedure that could form either2-arylindole or 3-arylindole. Mainly steric factors in-fluenced the regioselectivity (Scheme 72). When steri-cally undemanding auxiliaries were present at the N-1 atom of the indole nucleus such as MgOH, the cou-pling proceeded smoothly on the C-2 position. How-ever, when sterically demanding groups were present,such as Mg[Si(CH3)3]2, the C-2 position was blockedand the coupling event took place at the C-3 position.This strategy was exploited in the regioselective syn-thesis of 2-aryl- or 3-arylindoles in good to excellentyields.

The cheaper aryl chlorides have also been utilizedin the Pd-catalyzed arylation of indoles, reported byDaugulis and co-workers.[157] The arylation reactiontook place on either C-2 or C-3 depending on whichposition was blocked by a substituent.

A Cu-catalyzed process for regioselective arylationwith diaryliodonium salts was reportged by Gauntand co-workers (Scheme 73).[158] The Gaunt groupalso utilized N-auxiliaries to control the regioselectivi-ty, but in their case it was the stabilizing effect ofthese groups that was exploited, not the steric de-mands that such groups impart. When the N-1 ringatom was elaborated with either H or CH3, exclusiveC-3 arylation was achieved. When the N-1 ring atom

Scheme 71. Amidation of indoles.

Scheme 72. N-Auxiliary group-mediated regioselective arylation of indoles.

Scheme 70. Proposed mechanism for the Pd-catalyzed cyan-ation of indoles.




bore an acetyl group, C-2 arylation proceededsmoothly.

The mechanism (Scheme 74) was initiated by theoxidative addition of the iodonium salt to the coppercatalyst to form an electrophilic Cu(III) species (stepa) followed by addition of the indole substrate to thecatalyst (step b). Depending on the substituent on thenitrogen atom, two paths were possible. If a non-coor-dinating group was present, the C-3 arylated productwas obtained after deprotonation (step c) and reduc-tive elimination (step d). However, if an acetyl groupwas present on the N-1 atom position, a C-3 to C-2migration of the copper catalyst took place, stabilizedby the acetyl group (steps e and f). The C-3 arylatedproduct was then obtained after reductive elimination(step g).

A similar observation was made by Studer and co-workers.[159] They developed a Pd-catalyzed, oxidativearylation procedure that involved arylboronic acids,KF and TEMPO (Scheme 75). The method couldeither perform an oxidative arylation at the C-2 posi-tion, or perform an arylation/carboaminoxylation se-quence at the C-2 and C-3 positions, respectively.

Both processes were extremely mild, proceeding atroom temperature and requiring only one hour forcompletion in most cases. The oxidative arylationcould be carried through when non-coordinating aux-iliaries were present on the N-1-position (R1 =H orCH3) and provided the corresponding 2-arylindoles inmostly good yields. When auxiliaries with carbonylgroups attached to the N-1 ring position were utilized,an unexpected carboaminoxylation with trans stereo-chemistry took place.

Directing auxiliaries as regioselectivity handleswere also investigated by the group of Xu, who stud-ied the regioselective cyanation of indole using isoni-triles.[160]

Utilizing auxiliaries is not the only strategy to con-trol regioselectivity. The Djakovitch group discloseda remarkable method that allowed arylation on eitherthe C-2 or C-3 position simply by tuning the halide ofthe aryl halide coupling partner and the nature of thebase employed (Scheme 76).[161] The process em-

Scheme 73. Auxiliary mediated and regioselective arylationof indoles.

Scheme 74. Proposed mechanism for the arylation of in-doles.

Scheme 75. Mild Pd-catalyzed procedure for the synthesis of either 2-arylindoles, or trans-2-aryl-3-TEMPO-indoles.




ployed Pd(OAc)2 and bisdiphenylphosphinomethane(dppm) as ligand. When AcOK was used as base andaryl iodides as coupling partners, C-2 arylation tookplace in mostly good yields. However, whenLiOH·H2O was used as base in the presence of arylbromides, C-3 arylation was the prevalent coupling re-action.

The electronics of the coupling partner can also bea decisive parameter, as described by Su and co-work-ers,[162] (Scheme 77). They studied the intermoleculararylation of indoles with benzoic acid, Pd(TFA)2,Ag2CO3 in propionic acid and TMSO. C-2 regioselec-tivity was obtained when the benzoic acids containedelectron-donating groups, whereas high C-3 regiose-lectivity was observed when the benzoic acids con-tained electron-withdrawing groups. Two distinct reac-tion mechanisms were believed to operate dependingon the electronics of the benzoic acid.

The ligand/catalyst system can be used to controlregioselectivity, as described by the Stahl group. A re-markable dual C¢H activation sequence was devel-oped that coupled benzenes and indoles which, more-over, could be tuned to provide either 2-arylindolesor 3-arylindoles.[163]

Procedures that involve dual C¢H activations atboth C-2 and C-3 positions of the indole substrate to

form polycyclic derivatives have been studied. Wuand Wen[164] coupled indoles to cyclic diaryliodoniumsalts in medium yields in most cases (Scheme 78).

Rh has been employed as catalyst in the intermo-lecular annulation of indoles and terminal alkynes,disclosed by Xu and co-workers.[165] The method ex-hibited excellent regioselectivity and functional grouptolerance and provided the corresponding carbazolesin mostly good yields (Scheme 79).

Scheme 76. Aryl halide-dependent procedure for either 2-aryl- or 3-arylindoles.

Scheme 77. Regioselective procedure for indole arylation governed by the electronic character of the benzoic acid couplingpartner.

Scheme 78. Dual C¢H activation of both C-2 and C-3 posi-tions of the indole nucleus.




The Snîrch group needed access to the biologicallysignificant 1-(1,2-diarylindol-3-yl)tetrahydroisoquino-line scaffold that they believed could be obtainedthrough various direct transition metal-catalyzedstrategies.[166] They performed a comprehensive over-view of the different reaction sequences that could beemployed in the pursuit of the desired class of targets,depending on the substitution pattern of the indolestarting material (Scheme 80).

Au catalysis has been employed for the annulationof structurally diverse indole derivatives. The inter-molecular annulation of indoles by enynones to pre-pare biologically relevant indoles containing a [6,5,9]-fused tricyclic unit was disclosed by Carbery and co-workers.[167] They were able to prepare a wide rangeof targets in mostly good to excellent yields(Scheme 81). Based on deuterium labelling experi-ments, the authors proposed a catalytic cycle for theannulation.

The mechanism (Scheme 82) was initiated by theformation of the active catalyst (step a), followed byindole auration (step b). Reaction with the enynonereagent (step c) and reformation of the carbonylthrough kinetic protonation led to the trans-inter-mediate (step d) that was followed by a new indoleauration step (step e). The resulting indole spirocyclecould form the desired product after ring expansion(step f).

The group of Roy prepared the biologically impor-tant indeno[1,2-a]indole and indeno[1,2-b]indole scaf-folds by utilizing C¢H activation at either the C-2 orC-3 positions of the indole starting material.[168] Thedirect introduction of thio- and selenoethers has alsobeen realized, as reported by Kambe and co-work-ers,[169] (Scheme 83). The thioether formation tookplace at both C-2 and C-3 positions when unsubstitut-ed indoles were employed.

Scheme 79. Rh-catalyzed synthesis of carbazoles.

Scheme 80. Diverse approaches to tetrahydroisoquinolines.

Scheme 81. Au-catalyzed synthesis of biologically relevantindoles.




5 C¢H Activation at C-4, C-5, C-6 andC-7 of the Indole Nucleus

The selective functionalization of the C-2 and C-3 po-sitions of the indole nucleus has received widespreadattention from the synthetic community, but the re-maining positions of the indole framework have beeninaccessible, until the last decade, by such means. Pio-neering works have recently described the successfulC¢H activation of the C-4 to C-7 positions of theindole nucleus. Application of directing groups andauxiliaries has been the prevailing strategy to achievesuch functionalization that through coordination led

to thermodynamically favored cyclopalladated inter-mediates at the desired site.

The first example of direct alkenylation on the C-4position of the indole ring was disclosed by Jia andco-workers, (Scheme 84).[170] The method involveda Pd-catalyzed olefination of N-TIPS protected tryp-tophan derivatives with AgOAc as oxidant in toluene.The site selectivity for the C-4 position over the C-2position for the coupling was markedly improved bythe utilization of the bulky TIPS protecting groupthat successfully blocked the C-2 position for metalla-tion. The 4-olefinated indoles were obtained in goodyields in most cases and with high Z-selectivity, al-though 1,1-disubstiuted alkenes were a challengingclass of substrates and only afforded low yields of thecorresponding products.

The Jia group further elaborated the direct func-tionalization of the C-4 position in the formal synthe-sis of the telomerase inhibitors dictyodendrins B andE (Scheme 85).[171] The group designed a late step C¢H activation step of the C-4 position of a substitutedindole to approach an intermediate that through sub-sequent elaboration furnished the desired targets.

The group of Prabhu demonstrated that formylgroups on the C-3 position could mediate the Ru-cat-

Scheme 82. Proposed mechanism for the Au-catalyzed for-mation of [6,5,9]-fused tricyclic structures containing indole.

Scheme 84. C-4 alkenylation of indoles.

Scheme 83. Formation of thioethers.




alyzed C¢H activation/Heck olefination at the C-4position of the indole framework.[172]

A method for the synthesis of C-3 to C-4 annulatedindoles was described by You and co-workers.[173]

They made the important discovery that indoles sub-stituted with allylic carbonates on the C-3 positioncan form indole-based nine-membered rings employ-

ing Pd catalysis (in moderate yields), or stereoselec-tive seven-membered rings exploiting Ir catalysis. Inmost cases moderate yields were obtained and veryhigh ees, (Scheme 86).

Scheme 85. Synthesis of telomerase inhibitors.

Scheme 86. Synthesis of annulated indoles.Scheme 87. Synthesis of dearomatized indoles or enantiose-lective annulated indoles.




Furthermore, they found that indoles bearing sub-stituents on the C-3 position and substituted with al-lylic carbonates on the C-4 position furnished eitherdearomatized fused nine-membered rings under Pdcatalysis in moderate yields and moderate to good ee,or yielded six-membered rings under Ir catalysis inmoderate yields, but good to excellent ee(Scheme 87).

A method appropriate for C-6 olefination was re-vealed by the groups of Movassaghi and Yu.[174] Theyutilized an unique “U-shaped” directing group situat-ed at the N-1 ring atom to direct the C¢H activationat the appropriate site. Although the study wasmostly related to indolines, a few indoles were also in-vestigated in the reaction scope to afford the corre-sponding, 6-olefinated indoles in yields ranging from49 to 87% (Scheme 88).

Functionalization of the C-7 position has been de-scribed as early as the 1980s, but these methods didnot encompass C¢H activation.[175] Recently, however,Ir-catalyzed C¢H activation of this position has beenrealized. The groups of Maleczka Jr, and Smith III de-

veloped a borylation procedure that took place at theC-7 position of 2-subsituted indoles (Scheme 89).[176]

The C-7-borylated indoles could subsequently be cou-pled to aryl bromides under Suzuki cross-couplingconditions to furnish 7-arylated indoles in one-pot.When C-2 unsubstituted indoles were utilized as sub-strates, bis-borylation took place to afford the corre-sponding 2,7-diborylated indole.

The group of Hartwig made a substantial contribu-tion to this field as they were able to borylate C-2 un-substituted indoles.[177] This elegant method was ach-ieved by utilizing silyl groups as directing auxiliariesto favor the C¢H activation event at the C-7 position,over the more active C-2 position. The method in-volved an Ru-catalyzed silylation of the N-1 ringatom, followed by an Ir-catalyzed borylation, per-formed in one-pot to furnish the 7-borylated indolesin modest to good yields (Scheme 90).

Scheme 88. “U-shaped” directing group for the C-6 alkeny-lation of indoles.

Scheme 89. Ir-catalyzed borylation of the C-7 position of indoles.

Scheme 90. Regioselective C-7 borylation of 2-unsubstitutedindoles.

Scheme 91. One-pot synthesis of the natural product hippa-diene




The group versatility of this methodology was dem-onstrated by the one-pot synthesis of hippadiene, anindole-based natural product (Scheme 91).

Alkenylation has also been achieved at the C-7 po-sition through a one-pot sequence involving the for-mation of N-carbamoylindolines that through oxida-tive coupling formed the corresponding 7-alkenylin-doles in moderate to good yields ( Scheme 92).[178]

6 Conclusion

The last two decades have seen a remarkable devel-opment of the direct transition metal-catalyzed func-tionalization of the indole framework. In this relative-ly short time span, a wide array of reactions has beencombined with the C¢H activation event to forma versatile tool box for functionalization of the entireindole nucleus. Although the methodology is not fullycomprehensive, a vast selection of functionalities canbe introduced. This chemistry is rich and well devel-oped for the C-2 and C-3 positions, the remaining C-4to C-7 positions have just recently been functionalizedby such means.

The methodology is currently flawed with certaindrawbacks. Many protocols rely on harsh reactionconditions and the use of stoichiometric metal oxi-dants, features that undoubtedly decrease the atomeconomy of the processes and negate one of the mostattractive features of the C¢H activation methodolo-gy: namely the high atom economy in direct utiliza-tion of a C¢H bond. Moreover, the application of co-ordinating auxiliaries to achieve high regioselectivityentails insertion and removal of such groups, decreas-ing the overall efficiency of the process.

Further development from the synthetic communityin this exciting frontier of transition metal catalysiswill surely see the discovery and investigation of in-creasingly sophisticated reaction systems that willremedy these faults.

Acknowledgements

The author wishes to acknowledge the University of Bergenfor funding his fellowship.

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